Applications of Palladium Chemistry to the Total Syntheses of Naturally Occurring Indole Alkaloids

Chapter Three

Applications of Palladium Chemistry to the Total Syntheses of Naturally Occurring Indole Alkaloids JieJackLi Parke-Davis Pharmaceutical Research Division Warner-Lambert Company 2800 Plymouth Road Ann Arbor, Ml 48105 USA.

CONTENTS 1. 2. 3

4. 5. 6. 7. 8. 9.

INTRODUCTION OXIDATIVE CYCLIZATION USING Pd(II) SUZUKI, STILUS, AND NEGISHI REACTIONS 3.1. Suzuki Reaction 3.2. Stille Reaction 3.3. Negishi Reaction HECK AND INTRAMOLECULAR HECK REACTIONS 4.1. Heck Reaction 4.2. Intramolecular Heck Reaction TSUJI-TROST REACTION CARBON-NITROGEN BOND FORMATION REPRESENTATIVE EXPERIMENTAL PROCEDURES CONCLUDING REMARKS REFERENCES

438 438 446 446 455 464 469 469 474 485 491 494 499 499

438

JJ. LI

1. INTRODUCTION Since the monumental accomplishments of Woodward's total syntheses of strychnine in 1954 [1] and reserpine in 1958 [2], the arsenal of synthetic methods in indole alkaloid synthesis has greatly expanded. In the same time period, the use of palladium chemistry in organic syntheses h&> also witnessed tremendous growth with an ever-expanding repc Joire of synthetic methods and their applications to total synthesis. The use of palladium chemistry for the synthesis of indole alkaloids has been explored, and several examples have been included in recent reviews [3-6]. This account attempts to present a comprehensive collection of total syntheses of naturally occurring indole alkaloids where palladium chemistry plays a central role in the syntheses. This chapter is divided according to the five most popular types of palladium-mediated reactions: (1) oxidative cyclization reactions promoted by palladium(II) species; (2) reactions involving transmetallation with organoboranes (Suzuki), organostannanes (Stille), and organozinc reagents (Negishi); (3) inter- and intramolecular Heck reactions; (4) reactions involving nallylpalladium as the intermediate (Tsuji-Trost); and finally, (5) reactions that use the C-N bond formation as the key step for the total synthesis of naturally occurring indole alkaloids. 2. OXIDATIVE CYCLIZATION The oxidative coupling of aromatic compounds using Pd(OAc)2 was known in the 1960s. However, it was not until in 1975 when Akermark et al. revealed pioneering work on palladium(II)-promoted oxidative intramolecular cyclization of diphenylamines 1 to furnish carbazoles 2 [7, 8] (Scheme 1). Later, Itahara reported that intramolecular ring closure of 3benzoylindole 3 led to 5-methyl-5,10-dihydroindeno[l,2-&]indol-10-one (4) by refluxing 3 with 0.5 equivalent of palladium acetate in acetic acid [9]. When 2-methyl benzoylindole 5 was subjected to similar reaction conditions, poly cyclic indole 6, bridged at the peri position of the indole ring, was obtained as the major product in low yield. Furthermore, 6-oxo-6//isoindolo[2,l-a]indoles 8 were prepared by refluxing 7 with Pd(OAc)2 in acetic acid [10]. The role of acetic acid in such oxidative cyclization processes is to protonate the acetate ligand, making Pd(II) more electrophilic. The initial step in these oxidative cyclization reactions is electrophilic palladation of the aromatic ring. The total synthesis of ellipticine by Miller et al. [11] is one of the first syntheses of naturally occurring indole alkaloids using Pd(OAc)2 via the oxidative cyclization mechanism (Scheme 2). Exposure of 6-anilino-5,8-dimethylisoquinoline (9) to two equivalents of Pd(OAc)2 in TFA/AcOH facilitated the oxidative cyclization to the desired ellipticine (10). Recently, the same indole formation strategy that uses the Pd(OAc)2-mediated oxidative cyclization has been the cornerstone of several synthetic approaches directed toward ellipticine analogs. For instance, oxidative cyclization of diphenylamine 11 was carried out with Pd(OAc)2 in acetic acid to provide

Applications of Palladium Chemistry

R

439

2cqpj(oAch

O . J O '" N i X

. ""CXO

HOAc, reflux, ^0-80%

X 2

1

X = H, CH3; R = CH3, CH 3 0, Cl, Br, N0 2 , C0 2 H O

O HOAc, reflux, 60%

Ca^O N CH3

0.5 eq. Pd(OAc)2 i

HOAc, reflux, 30%

CH3 CH3

Pd(OAc)2 HOAc, reflux, 7-47%

R! = H, Cl, Me; R2 = H, Cl, Me Scheme 1. Early examples of oxidative cyclization of indoles an entry to carbazole 12 [12], which was then converted to 8,10-dimethoxyellipticine by the sulfonamide modification of the Pomeranz-Fritsch cyclization [13]. A similar oxidative cyclization was also used to synthesize carbazoles from novel «o-2-oxazolidinone dienes [14]. Another example is found in the synthesis of 14, an N-methylpyrazole analog of ellipticine, from diphenylamine 13 [15]. A remarkably concise synthesis of quindoline (16), an antimalarial agent isolated from a West African plant Cryptolepis sanguinolenta, was achieved in two steps in an

440

JJ . LI

overall 22% yield [16]. The precursor, 3-anilinoquinoline (15), was prepared by phenylation of 3aminoquinoline with Ph,Bi(OAc), in the presence of metallic copper. The crucial cyclization of 15 was then effected by Pd(OAc), in refluxing trifluoroacetic acid to afford quindoline (16).

Pd(OAc)2 10% CF3C02H, in HO Ac, 15-25%

CN Pd(OAc) 2 H

HOAc,32%

3co CH3 12

1.5 eq. Pd(OAc)2

H3CO

H3CO

•

HOAc, 20% 13

14

OXX) "

15

2 eq. Pd(OAc) 2 ^ CF,C0 2 H, 90*C,23%

H quindoline (16)

Scheme 2. Indole formation by palladium (Il)-promoted oxidative cyclization Hippadine (R\ R2 = -CH 2 -, 18a), pratorimine (R1 = H, R2 = CH,, 18b), pratorinine (R1 = CH,, R = H, 18c), and pratosinine (R1 = CH,, R2 = CH,, 18d, Scheme 3) belong to a family of pyrrolophenanthridone alkaloids isolated from the bulbs of Crinum pratense collected at 2

Applications of Palladium Chemistry

441

flowering time. Their biological importance emerged when they were found to exhibit reversible inhibition of fertility among male rats. Black et al. devised a short and effective synthesis of these

V ^

N

1.1 eq Pd(OAc>2, HOAc, 15-50% » 2. DDQ, quant.

^

OR* 17a-17d

18a-18d

Scheme 3. Direct, short and effective synthesis of pyrrolophenanthridone alkaloids

Pd(OAc)2 ||

HOAc

6-^ 19

O

21

Scheme 4. An 0-palladation gives five membered rings

442

JJ. U

pyrrolophenanthridone alkaloids and many of their analogs [17, 18]. The N-acylindoline (17) was derived from piperonyloyl chloride and indoline. Treatment of 17a with Pd(OAc)3 in glacial acetic acid at 115-120 °C afforded dihydrohippadine in 15% yield, along with 10% of the other regioisomer. Quantitative dehydrogenation of the cyclized in-.line, dihydrohippadine, gave hippadine (18a). Utilizing Itahara's mciiiodology [10], /V-piperonyl indole 19 was subjected to the same conditions. Palladium(II)-catalyzed intramolecular arylation of 19 occurred exclusively at the indole C(2) position to give a mixture of the two regioisomers 22 and 23 [17, 18]. As rationalized in Scheme 4, palladation intermediates 20 and 21 would be chelated and stabilized by the oxygen atom of the carbonyl group as in a typical o-palladation process. The intramolecular arylation at the C(2) position is favored because it gives a 5-membered palladium chelate 21 while palladation at the C(7) position gives a 6-membered intermediate 20.

H O^N (^

0

'taSs 1

Yv^TlT ji

/

\

^ N

CI

\\

N

O'ioH

CI 1

HO. NHMe Staurosporine (24)

\ OH OMe

Rebeccamycin (25)

1

Figure 1. Staurosporine and rebeccamycin are protein kinase C inhibitors Staurosporine (24) and rebeccamycin (25) (Figure 1), members of the indolo[2,3tfjcarbazole family, were isolated from Streptomyces staurosporeus [19, 20] in 1977 and from Saccharothrix aerococlonigens in 1985 [21], respectively. Like many indolo[2,3-a]carbazole alkaloids, they are protein kinase C (PKC) inhibitors. Their synthesis and those of their analogs have elicited great interest. Synthesis of the aglycone has also been the focus of many synthetic efforts because the aglycone fragment of staurosporine (24) is known to retain much of the activity of the parent. One example employing Pd(OAc)2-mediated oxidative cyclization for the C(2)-C(T) bond formation between the two indole rings was reported by Hill's group [22]. The precursor, arcyriarubin A (26), was easily prepared by condensation of dibromomaleimide with

Applications of Palladium Chemistry

443

four equivalents of indolylmagnesium bromide in refluxing benzene [23]. Treatment of 26 with one equivalent of Pd(OAc), in acetic acid at reflux for 18 hours led to the construction of the desired six-membered product as arcyriaflavin A (27, scheme 5).

Pd(OAc)2, AcOH 110°C,75% 27

26 Scheme 5. Synthesis of the aglycone of staurosporine

Reduction of imide 27 with LiAlH4 gave the corresponding hydroxylactam, which was then hydrogenolyzed to afford the desired aglycone as a lactam. In addition, the authors also examined the oxidative cyclization of other analogs of arcyriarubin A (26). In one scenario, when one of the two indole rings of 26 was replaced by a phenyl or 1-methylindole rings, Pd(OAc)2 was still the reagent of choice to effect the oxidative cyclization. Interestingly, when both indole rings were replaced by phenyl or 1-methylindole rings, no cyclization products were observed under the same conditions. Hill's oxidative cyclization strategy was also the key step for a new and efficient method to prepare pharmaceutically important bisindolylmaleimides [24].

PdCl2 BnO

*N N' H H 28aR=10-OH 28b R = 9-OH 28c R = H

DMF

BnO 29a 100% 29b 95% 29c 85%

Scheme 6. Remarkably high yields obtained in the oxidative cyclization of bisindole 28 In the synthesis of several arcyriaflavins (29a-c) [25], which are analogs of the staurosporine aglycone, the oxidative cyclization was realized by Ohkubo el al. in a remarkable 85-100% yield using PdCl, in DMF (Scheme 6). The original attempt to cyclize 28 using

JJ. LI Pd(OAc)2 in acetic acid by applying Hill's method [22] was unsuccessful because of the labile nature of the substrate under acidic conditions. This is the only reported example in which the cyclization was accomplished by using PdCl2 under neutral conditions instead of Pd(OAc)2 in acetic acid.

CH3

Pd(OAc)2,AcOH

H3C

reflux, 78%

H3»C C

H

II O

30

O II

kP°Sr

'CH 3 I

O pyrayaquinone- A (31)

CH3 H O

I OCH3

(l)Pd(OAc)2,AcOH reflux, 30 min. 84%

(2)BrCN,Et3N,DMAP,97% (3)Pyridine»HCl,200°C,42%

CN

32 O HO

f CH3 HO 7-deoxyprekinamycin (34) Scheme 7. Total synthesis of carbazolequinone alkaloids

VJT\

^=asx

~^~ ~CH3 1

N I CN prekinamycin (35) O

OH

Applications of Palladium Chemistry

445

Indole formation by palladium-assisted intramolecular ring closure was the key step of the Furukawa group*s total synthesis of the carbazolequinone alkaloids, pyrayaquinones-A through C, and murrayaquinones -A through -D [26]. Murrayaquinone A has been found to show cardiotonic activity on guinea pig papillary muscxs. The synthetic route to pyrayaquinone-A (31) is highlighted here to showcase their strategy (Scheme 7). Treatment of 2-anilino-5-methyl-l,4benzoquinone 30, obtained via Michael addition of the corresponding arylamine to methyl-1,4benzoquinone, with one equivalent of Pd(OAc)2 in acetic acid at reflux afforded pyrayaquinone-A (31). Prekinamycin (35), like kinamycins A-F, was isolated from Streptomyces murayamaensis. Carbazole 33, a regioisomer of 7-deoxyprekinamycin (34), was synthesized in only four steps utilizing Pd(OAc)2 promoted oxidative cyclization as the pivotal step [27]. Similar to Furukawa's approach, the anilino-l,4-naphthoquinone 32 was obtained via Michael addition of the corresponding 2-methoxy-4-methyl-aniline to 1,4-naphthoquinone. Oxidative cyclization proceeded in 84% yield. The first oxidative cyclization using catalytic Pd(OAc)2 in the synthesis of naturally occurring indole alkaloids was published by Kn6lker's group [28]. As illustrated in Scheme 8, the reoxidization of palladium(O) to palladium(II) with cupric acetate makes the reaction catalytic with respect to palladium [29, 30]. Anilinobenzoquinone 36 was obtained via Michael addition of the corresponding arylamines to 2-methyl-3-methoxy-l,4-benzoquinonc. Catalytic oxidative cyclization of 36 provided 37, which was then treated with methyllithium to give carbazomycins G (38a) and H (38b), respectively. Recently, carbazoquinocin C and (±)-carquinostatin A have been synthesized using the same strategy [31, 32]. This finding is of great significance because Knolker et al. have demonstrated for the first time that the catalytic cycle for oxidative cyclization is viable, like most palladium-mediated reactions. An analogy can be made to the Wacker process which in principle would eliminate the consumption of a stoichiometric amount of expensive Pd(OAc)2, making the method a more practical one, especially on an industrial scale. In summary, oxidative cyclization using Pd(II) provides a direct, short, and effective method for preparing many naturally occurring indole alkaloids. Palladium acetate is the reagent of choice. In one example, PdCl2 was superior to Pd(OAc)2 because the substrate decomposed in acetic acid. Generally, PdCl2 oxidation only proceeds in the presence of a base. Alternatively, the oxidative cyclization process has been conducted by using a mixture of PdCl2 and NaOAc, or a mixture of PdCl2 and AgNO,. A catalytic process in which Pd(0) is reoxidized back to Pd(II) has been developed analogous to the Wacker process. This catalytic approach should be the direction of future application of the oxidative cyclization method. The methodology can provide facile access to complicated, functionalized indole alkaloids which are otherwise not easily synthesized in a concise manner.

446

R

J.J. Li

O Y^j \fYOCU3 ^^N^sArii H H CH3 36

0.1Pd(OAc)2, 25Cu(OAc \ AcOH, reflux,* 19 h, 71-73%

R

MeLi, THF », -78°Cto25°C

*y<^

O R V ^ _ J Y O C H

3

W N I ^ L A ™

^^

N Y 37

CH

3

O Jk^OCH,

^N^S C"CH3 H

HO CH3 38a, carbazomycin G, R =H, 71% 38b, carbazomycin H, R =OCH3, 41%

Scheme 8. Palladium-catalyzed oxidative cyclization 3. SUZUKI, STILLE, AND NEGISHI REACTIONS 3.1. Suzuki Reaction The Suzuki reaction is palladium-catalyzed cross-coupling between organoboranes and aryl or vinyl halides or triflates. There have been many elegant applications to the total syntheses of naturally occurring indole alkaloids. In the synthesis of aurantioclavine (44), Hegedus et al documented one of the first applications of the Suzuki reaction in the syntheses of indole natural products [33]. Aurantioclavine (44), isolated from Penicillium aurantiovirens, is an analog of clavicipitic acid which possesses the 3,4,5,6-tetrahydro-6-(2-methyl-l-propenyl)azepino[5,4,3a/]indole tricyclic system. The Hegedus total synthesis utilized a chemoselective Suzuki coupling between 3-iodo-4-bromo-l-tosylindole (39) and tri(2-ethoxyethenyl)borane to install the ethyl vinyl ether 40 (Scheme 9). Unfortunately, the process was very sensitive to the purity of the boron reagent and to the freshness of the catalyst, resulting in inconsistent yields. In contrast, the corresponding Ni(0)-catalyzed oxidative addition-transrnetallation from zirconium was a reliable method to produce 40 in 75-80% yields. After acetal formation from vinyl ether 40 to give 41, the tertiary allylic alcohol 42 was assembled by Heck olefination of the 4-bromoindole 41 with 2methy-3-buten-2-ol. The cyclization product 43 arises from the subsequent condensation of 42 with p-toluenesulfonamide in the presence of p-toluenesulfonic acid. Reductive detosylation of 43

447

Applications of Palladium Chemistry

using NaBH4 under photolytic conditions removed both tosylate groups and also reduced the enamine, yielding (±)-aurantioclavine (44).

OEt 1

J

PdL4 (cat.), NaOH,0-77%

BBr3, SMe2, then 1

B(^OE$;

EtOH, NaHC0 3 96%

Ts 39

40

OH EtCK ^.OEt

^foH

EUX ^OEt

Pd(OAc)2, (o-tolyl)3P Et3N, CH3CN, 100 °C 5 h, sealed tube, 92% 42

41

pTsNH2 CH3CN pTsOH 90 °C, 4 h 56%

NaBH4 DME/MeOH/H20 1

hv,94%

Scheme 9. Total synthesis of (i)-aurantioclavine Early examples of the total synthesis of naturally occurring indole alkaloids employing the Suzuki reaction include ellipticine (10) as reported by Miller et al. [34]. The aryl bromide, 6amino-7-bromo-5,8-dimethylisoquinoline (45) was derived from 2,5-dimethylaniline in nine steps. The Suzuki coupling of 45 with phenylboronic acid was carried out using catalytic tetrakis(triphenylphosphine)palladium in benzene and with Na3CO, serving as the base to furnish 6-amino-5,8-dimethyl-7-phenylisoquinoline (46, Scheme 10). The reaction conditions were compatible with a free amino group on the isoquinoline ring even though the Suzuki reaction of

448

JJ . Li

the corresponding acetyl derivative also proceeded in good yield. The amino group on 46 was converted to the corresponding azide by diazotization followed by treatment with NaN3. Solvent phase thermolysis of the resulting azidophenylisoquinoline in dodecane at 180 °C provided ellipticine (10) via a nitrene intermediate.

CH3 N

PhB(OH)2 Pd(Ph3P)4(cat.) aq. 2 M Na 2 C0 3 reflux, 99%

H2N

CHi

46

Pd(Ph3P)4, Na2C03/DME reflux, 40-49% B(OH)2 CHO 47a-b

R

^

V-o

49a-b

1. cat. Pd(Ph3P)4

N

>CL 51 OHC^^^B(OH)2 2. NaBH4,26%, 2 steps

Scheme 10. Application of Suzuki coupling in natural indole alkaloid synthesis Hippadine (18a), whose total synthesis employing the oxidative cyclization strategy is summarized in Section 2, was alternatively synthesized using a Suzuki reaction to form the C-C bond between the two benzene rings. Snieckus et al. described a short synthesis based on the onepot cross-coupling-cyclization sequence of halo indoline 47 and o-formyl arylboronic acids 48 [35]. For instance, 47a (R = H, X = I) and 48 underwent a cascade of reactions involving Suzuki

Applications of Palladium Chemistry

449

coupling, cyclization, and air oxidation of the intermediate carbinol amine to give lactam 49a, which was subsequently oxidized with DDQ to provide hippadine (18a). In an analogous fashion, 49b was obtained from 47b (R = OMs, X = Br). Reduction of 49b with excess Red-Al afforded ungermine, another member of the pyrrolophenanthridine alkaloid family. 1-Chloro-p-carboline (50) was prepared from tryptamine in three steps. It served as a common intermediate for palladium-catalyzed cross-coupling reactions that offered easy access to three natural indole alkaloids [36]. The Suzuki reaction of 50 with 5-formylfuranyl-2-boronic acid (51) formed the C-C bond between the pyridine and the furan rings. Reduction of the resulting adduct with NaBH4 yielded perlolyrine (52, Scheme 10). In the same manner, the Suzuki reaction

w

/7-NH 2

x ^

Q

"^i

-x1

\

N' ^ H

N H

nortopsentin A (53a, X] = X2 = Br) B (53b, X, = Br, X2 = H) C (53c, X, = H, X2 = Br) B(OH) B< 2

oi

I ^

55

N SEM 54

•N TBS

Pd(Ph3P)4, Na 2 C0 3 ,45%

TBS 56 B(OH)2

1.

£tf

Br

58

TBS 53c

2. H 2 0,74%

SEM

TBS 57

Scheme 11. Total synthesis of nortopsentin C

Pd(Ph3P)4,Na2C03 2.TBAF,50% 3.20% HC1,74%

450

Jjr. Li

with tri(m-propyl)phenylborate afforded komaroine. Alternatively, Stille coupling of 50 with tributylvinylstannane produced pavettine. A family of imidazole marine alkaloids, nortopsentins A-C (53a-c) were isolated from the marine sponge Spongosorites ruetzleri. They all possess a characteristic 2,4-bisindolylimidazole skeleton and exhibit cytotoxic and antifungal activities. Successive and regioselective diarylation via Suzuki coupling reactions using halogenated imidazole to make nortopsentins was disclosed by the Ohta group [37, 38]. The total synthesis of nortopsentin C is summarized here as a

Oo — ^ ^ N

2.B

OMe 59 NH2 1. NaN02, HCl N'

2.KI,84%

Ts 61 60, PdCl2(Ph3P)2,5 mol% THF, Ar, reflux, 38%

2 MeMgl, ether, rt ^N~

H

o:5

TBS i

Cr o

66

B r B r

65

toluene 110 °C, 20h946%

Scheme 12. Total synthesis of arcyriacyanin A

Applications of Palladium Chemistry

451

representative example. As depicted in Scheme 11, the JV-protected 2,4,5-triiodoimidazole (54) was coupled with one equivalent of the 3-indolylboronic acid 55 to give the adduct 56. The Suzuki reaction proceeded regioselectively at C(2) of the imidazole ring. A regioselective halogen-metal exchange reaction took place predominantly at C(5) to provide 57. A second Suzuki coupling reaction at C(4) of 57 with 6-bromo-3-indolylboronic acid 58 resulted in the assembly of the entire skeleton. Two consecutive deprotection reactions removed all three silyl groups to give the natural product (53c). This is a fine example of the chemoselectivity of the Suzuki reaction between an arylbromide and an aryliodide. The desired regioselectivity was achieved via an elegant manipulation of the substrate functionalities. A method developed by Ishikura et al [39-41] was the foundation of the synthetic endeavors towards the total synthesis of several indole natural products, including arcyriacyanin A (67) and structural analogs (e.g. 73) of yuechukene (74). The structural features of arcyriacyanin A (67) are different from that of the aglycone of staurosporine (24) and rebeccamycin (25). Besides the different indole orientations, the two indole rings on arcyriacyanin A (67) are connected by a seven- membered ring whereas staurosporine (24) and rebeccamycin (25) are tethered by a six-membered ring. In Ishikura*s methodology, the bis-aryl skeleton was assembled by Suzuki coupling between aryl halides and a novel indolylborate reagent, triethyl(lmethoxyindol-2-yl)borate (60), which is derived from regioselective deprotonation at C(2) of 59 with subsequent quenching by triethylborane. The crucial step in the total synthesis of arcyriacyanin A (67) by Tobinaga et al. [42] involved a Suzuki cross-coupling reaction between indoleborate 60 and 4-iodoindole (63). As outlined in Scheme 12, 4-iodo-l-tosyl-indole (62) was derived from 4-amino-l-tosyl-indole (61) by diazotization and iodination. Desulfonation of 62 with 40% NaOH in refluxing methanol led to 63. Employing the methodology developed by Ishikura, unsymmetrical bisindole 64 was prepared by Suzuki cross-coupling between 63 and 60. Protection of indole 63 at C(l) increased the yields for the Suzuki coupling (1-tosyl analog, 46%; 1-TBS analog, 51%, respectively). The bisindole 65 was treated with two equivalents of methylmagnesium iodide in ether and condensation of the resulting bisiodomagnesium salt with the TBS protected 3,4-dibromomaleimide (66) in refluxing toluene [23] furnished arcyriacyanin A (67). In the same PKC inhibitor arena, synthesis of staurosporine analogs using the Suzuki coupling reaction was also reported. For example, bromophthalimidine was coupled with pmethoxyphenylboronic acid to furnish bisphenyl phthalimidine as a staurosporine analog [43]. Utilizing the Suzuki coupling of l-tosylindolyl-2-boronic acid with an indolylmaleimide triflate to make a bisindolylmaleimide [44], Ishikura synthesized a structural analog (73, Scheme 13) of yuechukene (74) [45]. Yuechukene (74) was isolated from the root bark of Murraya paniculata and exhibits strong anti-implantation activity in rats, mice and pigs. Indolylborate 69, generated in situ from 1 -methylindole (68), underwent a palladium-catalyzed carbonylative cross-coupling reaction with vinyl triflate 70 to provide the desired 2-acylindole 71. Upon heating with acid

452

JJ. Li

(10% HC1), closure of the C ring was achieved with formation of inden[2,l-&]indole 72 with the requisite cis configuration at the C/Dringjuncture. Reduction of the carbonyl functionality in 72 with DIBAL provided the intrinsically unstable ally lie alcohol, which when treated with indole and BF,*OEt2 furnished the yuechukene analog 73.

Li©'

OQ^ Me

68

BuLi,THF

2. BEt3, THF

Me 69

PdCI2*(Ph3P)4 CO/THF,60% 1. DIBAL 1

2. Indole BF 3 OEt 2 65%

Scheme 13. Palladium-catalyzed cross-coupling reaction to synthesize yuechukene analogs Another use of the indolylborate reagent (69) was reported in the total synthesis of ellipticine analogs by the Ishikura group [46]. As illustrated in Scheme 14, vinylbromide 75 and indolylborate 69 underwent a tandem intramolecular Heck-Suzuki reaction to give hexatriene 76 which was then converted to the desired pyrido[4,3-fc]carbazoIe 77 using the well-known photocyclization protocol for styrylindole systems.

Applications of Palladium Chemistry

76

453

77

Scheme 14. Total synthesis of ellipticine analogs using indolylboronate Qugguiner's group has made great strides in the syntheses of naturally occurring indole alkaloids by using a combination of metallation of azines and diazines and cross-coupling strategies. The synergy between the directed metallation reaction and palladium-catalyzed crosscoupling reaction creates a powerful tool for the construction of unsymmetrical biaryl natural products. Application of this strategy has resulted in the total syntheses of more than a dozen natural indole alkaloids, including harm an, 2-ethyl-p-carboline, pavettine, 6-hydroxyharman, fascaplysin, lavendamycin derivatives, nitramarine, and 1-flouroellipticine. The aforementioned accomplishments were reviewed in 1995 by Qu6guiner et al. [5J. Only two representative examples of the total syntheses of naturally occurring indole alkaloids reported after their review are described here. One example employing their strategy that combines a directed metallation reaction with the Suzuki reaction is the total synthesis of bauerine B (84), a P-carboline natural product [47]. Bauerine B (84) was isolated from the terrestrial blue green alga Dachothrix baueriana GO-25-2. This cytotoxic alkaloid is active against herpes simplex virus type 2. As detailed in Scheme 15, 2,3-dichloroaniline (78) is protected as the corresponding pivaloylaminobenzene 79. Lithiation occurs regioselectively at the ortho position, and the resulting anion is quenched by trimethylborate to provide boronic acid 80 after hydrolysis. The Suzuki reaction between 80 and 3-fluoro-4-iodopyridine (81) leads to the desired biaryl product 82 contaminated with primary amine (ca. 30%). Indole formation to P-carboline 83 was accomplished by boiling the mixture with pyridinium chloride at 215 °C. Subsequent Nmethylation by using phase-transfer catalysis with methyl iodide completed the total synthesis of bauerine B (84). Another P-carboline natural product, the antibiotic eudistomin T (85), and a few other hydroxy p-carbolines were synthesized in the same fashion [48,49].

454

JJ. LI

PivCl, 10% Na 2 C0 3 C r ^y 'NH 2 CI

NHCOtBu

C1

CH2C12,1.5 h, rt, 92%

78 l.BuLi,THF -15 °C, 6 h

N

>T

Pd(Ph3P)4, 2M K 2 C0 3 1

toluene, reflux, 30 h

2.B(OMe) 3 ,-15°C,2h 3. hydrolysis, 65%

1. Pyridinium chloride, reflux, 15 min 2.NH4OH,ice,83% 82a, R = COtBu,60% 82b, R = H, 25%

•eXCO 83

CH31,50% NaOH HS04NBu4 Toluene, 2 d, rt, 97%

CI Me bauerine B (84)

Scheme IS. Total synthesis of bauerine B The total synthesis of an indoloquinoline natural product, quindoline (16), is summarized in Scheme 16 [50]. 2-Iodo-3-fluoro-quinoline (86) was prepared by treatment of 3-fluoro-4iodoquinoline with LDA followed by quenching with water. The fluoro-directed lithiation is a kinetic process and occurs at C(2), but an isomerization occurred (the so-called "halogen-dance" process) to give the more stable 4-lithioquinoline, which was protonated upon quenching with water to give 86. The Suzuki reaction of 86 with boronic acid 87 proceeded in a solution of ethanol and toluene and the resulting biaryl product 88 was then converted to quindoline (16) in a manner analogous to the synthesis of 83. An additional application of the Suzuki reaction is found in the total synthesis of cryptosanguinoline (92) by Timdri et al. [51]. The Suzuki reaction

Applications of Palladium Chemistry

455

between 3-bromoquinoline (89) and boronic acid 87 gave 90. Simple functional group transformations of the pivaloylamino group into the corresponding azido group provided 91, which was thermolyzed in 0-dichlorobenzene (180 °C) to furnish cryptosanguinoline (92) via a nitrene intermediate.

— i*OC N 86

I

B
^"'^NHCOtBu 87

NHCOtBu

Pd(Ph3P)4, EtOH toluene,94% reflux, Ar

*• Pyridinium chloride, reflux, 15 min 2.NH4OH,ice,83%

Br

quindoline (16)

87 Pd(Ph3P)4, EtOH, •

N

toluene, reflux, Ar,94%

89 1. o-dichlorobenzene 180°C,5h,75% 2. Me 2 S0 4 , CH3CN reflux, 5 h, K 2 C0 3 93% Scheme 16. Total synthesis of quindoline and cryptosanguinoline 3.2. Stille Reaction Among palladium-catalyzed reactions, the Stille reaction is unique because it proceeds under neutral conditions and is tolerant of a wide variety of functional groups. In addition, organostannane reagents enjoy ease of preparation and purification by standard synthetic techniques. The most frequently employed techniques for organostannane preparation include: (a) palladium(0)-catalyzed reaction between an aryl halide with hexaalkylditin; (b) halogen/metal exchange of an aryl halide followed by quenching with a stannyl electrophile; and (c) direct

456

JJ.LI

metallation of a substrate followed by quenching with a stannyl electrophile. Despite the toxicity of organostannanes, the Stille reaction has enjoyed many applications to the total syntheses of a plethora of natural products, including indole alkaloids.

Pd(0),(Me3Sn)2 » Xylene, 140 °C 24 h, 60%

O

W Br

B113S11

NH2

hippadine (18a)

49a

OEt ^.

Br

^^ 90%

OEt

Pd(PPh3)2Cl2 Et4NCI,MeCN 68%

(C02H)»2H20 tt

I

96%

94

Br 96

95

NaH,THF,72%

Pd(Ph3P)2Cl2 (Bu3Sn)2

COC1

H

Et4NBr, Li 2 C0 3 toluene, 68%

hippadine (18a)

& 97

98

Scheme 17. An intramolecular aryl dihalide tandem cyclization via the Stille reaction An attractive protocol using a Pd(0)/ditin catalyst system was utilized for two syntheses of hippadine (18a) via an intramolecular aryl dihalide tandem cyclization mechanism. In Grigg's approach [52], as depicted in Scheme 17, diiodide 93 was subjected to the Pd(0)/ditin catalyst system to form the C-C bond in lactam 49a. Oxidation of indoline moiety in 49a using DDQ (2,3-dichloro-5,6-dicyano-l,4-benzoquinone) completed the total synthesis of hippadine (18a). In a similar manner, another concise synthesis of hippadine was delineated by the Sakamoto group [53J. Their synthesis began with a Stille coupling of 2,6-dibromoaniline (94) with the masked carbonyl reagent, Z-l-tributylstannanyl-2-ethoxyethene, to provide 95. The phase-transfer agent,

Applications of Palladium Chemistry

457

tetraethylammonium chloride, provided a high concentration of chloride anions which stabilized and activated the palladium(O) complex during the Stille reaction. Cyclization of 95 was effected by oxalic acid to give 7-bromoindole (96). The TV-acylation of 96 with 2-bromo-3,4methylenedioxybenzoyl chloride (97) led to the 1-benzoylated indole 98. The intramolecular Stille coupling of 98, using the same protocol as Grigg's, delivered hippadine (18a). The Stille reaction was also pivotal to the convergent nature of Watanabe's synthesis of hippadine (18a) [54]. As illustrated in Scheme 18, the 7-stannylated indoline 100 was prepared by ortho-Utiaiion of 1-terf-butoxycarbonylindoline (99) followed by quenching with tributyltin chloride. The Stille coupling between 100 and 101 [Pd(OAc)2-P(o-Tol)3-Et3N (1:2:2) (10 mol%)/DMF/70 °C, 50 h] led to the adduct 102 in 63% yield. The more common palladium catalysts Pd(Ph3P)4 and Pd(PPh3)2Cl2 gave substantially inferior yields (8 and 14%, respectively). This is a good example of the functional group tolerance of the Stille reaction in which protection of the aldehyde was not required. Deprotection and basification of 102 provided the cyclized hemiaminal which was oxidized to anhydrolycorin-7-one. Dehydrogenation of anhydrolycorin-7one with DDQ completed the total synthesis of hippadine (18a). Pratosine (18b), oxoassoanine and kalbretorine were also synthesized in the same fashion.

Br

Q-J

,.,„.BuU,TMEDA ( V p LBoc 2-Bu,S„CI,6S%

BujSl

99

Af™

t

kc

qQT

100

1. cone. HCI 2.A g 2 0 » 3. DDQ 80%, 3 steps

Pd(OAc)2,P(o-ToI)3 » Et3N,DMF, 63% V-O

101

hippadine (18a)

102

Scheme 18. Application of 7-stannylated indoline in the synthesis of hippadine Carbazole alkaloids have drawn considerable attention from synthetic chemists due to their significant biological activities, including antimicrobial, antiviral, and cytotoxic properties.Two simple carbazole alkaloids, glycozolinine and glycozolidine (107) were

458

J.J. LI

synthesized by Watanabe et al. {55] via a tandem Stille and aryne-mediated cyclization sequence. The regiospecific synthesis of glycozolidine (107) is shown in Scheme 19. Stannane 104 was prepared by orf/io-lithiation of 103 followed by quenching with tributyltin chloride. The bromide 105, in turn, was derived in 96% yield from 2-chloro-6-methylphenol by sequential bromination

OMe

OMe l./-BuLi,THF . . 0 „ -78°Cto-20°C <\ / ~ S n B u 3 NH 2.Bu3SnCl Boc 103

MeO OMe NH Boc 106

NH

Br

Pd(Ph3P)2CI2 DMF,90°C

+

*-

Me 25 h, 56%

I

Boc 104 KNH2, liq. NH3 99%

H glycozolidine (107)

Scheme 19. Glycozolidine synthesis via consecutive Stille and aryne-mediated cyclization (PhCH2N Me,Br,\ CH2Cl2-MeOH, rt, 5 h) and methylation (Mel, K2CO,, acetone, reflux, 4 h). Stille coupling employing Pd(PPh,)2Cl2 as the catalyst provided the biphenyl 106. Upon treatment with amide in ammonia, 106 was cyclized via the aryne intermediate to furnish glycozolidine (107) in a remarkable 99% yield. 1-Chloro-P-carboline (50) not only was the precursor for Suzuki coupling to synthesize perlolyrine (52, Scheme 10), but was also the precursor for Stille reactions in the synthesis of several other indole alkaloids including pavettine [36], nitramarine, and annomontine [56]. Nitramarine was synthesized by Qulquiner et al. by applying their 0/7/10-lithiation and Suzuki combination strategy {vide supra). As depicted in Scheme 20 [56], the Stille reaction of 50 with tributyl(l-ethoxyvinyl)tin followed by acidic hydrolysis delivered 1-acetyl-p-carboline (108), which serves as a common intermediate for both nitramarine (110) and annomontine (112). The Friedlaender quinoline synthesis was accomplished by treating 108 with aminobenzaldehyde (109) in the presence of Triton B as the base to give nitramarine (110). Similarly, enamineketone 111, generated when 108 was treated with the Brederecks reagent [ferf-butoxy-bis(diamino)methane], was treated with guanidine carbonate to give annomontine (112). In yet another example, Stille coupling of tributyl(l-ethoxyvinyl)tin as a two-carbon building block was also an

Applications of Palladium Chemistry

459

1. Pd(Ph3P)2Cl2

Cu

Co

N EtO

CI

N'

S11B113 J

2.HC1,H 2 0,83%

so

a:

*0 108

CHO

H

109

NH2

Triton B, 49%

CgCJ^

BuOCH(NMe2)2

CuO N H

Me2N 108

H 111

guanidine carbonate 56%, 2 steps annomontine (112) Scheme 20. (Continued on next page)

460

jjr. Li

Continued from page 23

CH3 F catPd(Ph3P)4,95%

7 EtO

Cc H

S11B113

113

N

^OEt 114

CH3 F HC1, HOAc, Ac 2 0 > 54%

f

(T^r -r^r \KJ* H \KJ CH3

1

N1 1

l-fluoroellipticine (115) 1 Scheme 20. The Stille reaction using tributyK l-ethoxyvinyl)tin in alkaloid synthesis important tactic in Qulquiner's synthesis of l-fluoroellipticine (115). The 4-pyridylbromide 113 was assembled by applying their metallation/halogen-dance strategy starting from 2fluoropyridine [57]. Stille coupling of 113 with tributyK l-ethoxyvinyl)tin constructed the 4-(lethoxyethenyl)pyridine 114, which yielded l-fluoroellipticine (115) upon treatment with acid. Additional examples of carbazole alkaloid synthesis using the Stille coupling are found in Hibino's synthesis of polysubstituted carbazoles, including marine alkaloids carbazostatin, hyellazole, and carbazoquinocins B-F [58, 59]. The total syntheses of carbazostatin (123) and carbazoquinocin C (124) are summarized in Scheme 21. Carbazostatin (123) is a radical scavenger isolated from Streptomyces chromfuscus. Carbazoquinocin C (124), along with carbazoquinocins A, B, D, E, and F, is found in Streptomyces violaceus 2448-SVT2. They all have the
Applications of Palladium Chemistry

461

l.I 2 ,KOH,DMF N H

•CnC'

CHO 2.NaH,MOMCl DMF,94%

N' CHO MOM 117

116 OEt

BujSns^fif^

Pd(Ph3P)2Cl2, Et4N+CI',67%

l.HCCMgBr.THF

**" • CnO°

2.MOMC1,/ CH2C12:i,i-Pr , 2NEt 50 C 93% ' ° '

118 r-BuOK, r-BuOH 90 °C, 92%

CnCTMOM

OMOM 120

OEt 9-BBN-C7H15 PdCl2(dppf)

OX<

CHa

OTf

NaOH, THF 85%

Et

^ ^ t f ^ MOM r MOM119OMOM MHCl,/-PrOH,61%

TMSC1, Nal, MeCN, -20 °C 3. Tf 2 0, Pyr. 85%

O7QC,

121

OEt

CH3 C7HI5 122

BBr3, CH2C12 -78 °C to rt W%

(PhSeO)20 THF,50°C 95%

Scheme 21. Total synthesis of carazostatin and carbazoquinocin C 119. The protection was necessary in order to avoid the formation of the enone-type compounds during the generation of the allene intermediate. Heating 119 in the presence of potassium tbutoxide generated the allene intermediate which underwent an in situ electrocyclic cyclization to furnish the desired trisubstituted carbazole 120 after tautomerization. Triflate 121 was obtained

462

JJT. Li

Et3N, CH2CI2

«

lie

Br^ "*^ "COC1 Br"*^< 126

125

cvQr Br' 127

reflux, 84%

AcCl, CH2C12 reflux, 5 h, 42%

.N 128

i^^SnBua

Pd(Ph3P)4, toluene, DMF, 100°C,95%

O

N

CO (80 psi) Me4Sn Pd(Ph3P)4 m HMPA, LiCl 75°C,23%

Scheme 22. A bromopryridine as a common intermediate for Stille reactions

Applications of Palladium Chemistry

463

after exhaustive deprotection of the two MOM groups, followed by sulfonation. The Suzuki coupling of 121 with 9-heptyl-9-borabicyclo[3,3,l]nonane (easily derived from 1-heptene and 9BBN) provided 122. Subsequent removal of the ethyl ether furnished carbazostatin (123). Oxidation of 123 with benzeneselenic anhydride led to carbazoquinocin C (124). Hyellazole and other carbazoquinocin family members were also synthesized in a similar fashion. Additionally, in the synthesis of the novel p-carboline alkaloid oxopropaline G by Hibino et al. [60], a Stille reaction between 2-formyl-3-iodoindole and isopropenyl tributyltin as a three carbon building block was successfully applied. Several indolopyridine alkaloids were synthesized using the Stille reaction via a pyridylbromide [61]. Examples include angustine (129) and naucletine (130), which belong to the Vallasiachotaman class of monoterpenoid indole alkaloids. The synthesis began with the condensation of harman (125) with 3-bromonicotinoyl chloride hydrochloride (126) to give enamide 127 (Scheme 22). Treatment of 127 with acetyl chloride led to the formation of the pentacyclic lactam 128 through a sequence involving intramolecular nucleophilic addition of the enamide moiety to the y-position of the 7V-acyl-3,5-disubstituted pyridinium cation (formed from reaction of the pyridine nitrogen with AcCl) followed by autoxidation of the resulting 1,4dihydropyridine. The Stille reaction of 128 with tributylvinyltin gave angustine (129). Naucletine (130) was produced by a palladium-catalyzed carbonylation of 128 with tetramethyltin. As a side note, a palladium-mediated reduction of 128, using sodium methoxide as the hydrogen donor (Helquist method [62]), furnished nauclefine. Stille reaction has also enjoyed applications to the total synthesis of bis-indole alkaloids, including staurosporinone [63], didemnimide C [64], and the topsentins [65]. The total synthesis of staurosporinone (138) by Beccalli et al. is presented here as an example. The synthesis commenced with acylation of both NH and OH groups of the readily available 3-cyano-2hydroxy-3-(l//-indo-3-yl)-acrylic acid ethyl ester (131) followed by chemoselective deprotection of the carbonate to give 132 (Scheme 23). Following synthesis of vinyl triflate 133, the Culaccelerated Stille reaction employing indolylstannane 134 led to the construction of bis-indole 135, which was treated with Pd(OAc)2 in acetic acid to promote an oxidative cyclization to give pentacyclic bisindole 136. The two protecting groups, ethyl carbamate and benzenesuifonamide, were simultaneously removed using sodium ethoxide in refluxing ethanol to give 137. Reduction of the nitrile with sodium borohydride-cobaltous chloride completed the total synthesis of staurosporinone (138).

JJ. LI

464

-_.

CN

1. ClC02Et, Et3N CH2C12,90%

C0 2 Et OH

/ =

C02Et

•

OH

2. Me2NH, CH2C12 %

131 (CF 3 S0 2 ) 2 0

OTV C 0 2 E < O r

iPr2NEt,85%** \N i-U Et0 2 C

OTf

+

Ph0 2 SN"^

SnBu3

Pd(Ph3P)4 CuI,LiCl THF, reflux 89%

Scheme 23. Total synthesis of staurosporinone c. Negishi Reaction The Negishi reaction is the palladium-catalyzed cross-coupling between organozinc reagents and aryl- or alkenyl halides or triflates. It is compatible with some functional groups that can tolerate the presence of the organozincs, including ketones, esters, amines and cyano groups.

Applications of Palladium Chemistry

465

However, because organozinc reagents are usually generated and used in situ by transmetallation of with Grignard or organolithium reagents with ZnCl2, which are not compatible with many functional groups. As a result, the Negishi reaction has met with limited applications in indole synthesis and has not been as widely used as the Stille or the Suzuki reactions.

a

j Q ^N^ S0 2 Ph

1.LDA,THF,0°C •

^

2.ZnCI 2 ,THF,25°C

N' ^ZnCl £Q ph 140

PdCl2(Ph3P)2, DIBAL THF, reflux

142

.Br 7 Sk-BuMe2 143

ZnCl 2. ZnCI2, THF, 25 °C

^^

N Sif-BuMe2 144

£>77X PdCl2(Ph3P)2, DIBAL THF, reflux

Me2f-BuSi

R2 145

Scheme 24. The Negishi reactions of 2- and 3-indolylzinc with 2-halopyridines (X = Br, or CI) The Negishi reactions of both 2- and 3-indolylzinc derivatives with diversely substituted 2-halopyridines resulted in the assembly of 2- and 3-(2-pyridyl)indoles, which became important intermediates in indole alkaloid synthesis [66-69]. As shown in Scheme 24, the 2-indolylzinc reagent 140 was easily prepared by metallation of l-(benzenesulfonyl)-indole (139) with LDA

JJ . Li

466

followed by treatment of the resulting 2-lithioindole with anhydrous zinc chloride. The Negishi reaction of 140 with 2-halopyridine 141 provided 2-(2-pyridyl)indole 142. Since 1(benzenesulfonyl)-3-lithioindole tends to isomerize into the corresponding 2-lithioindole analog, the silyl protected derivative, 3-bromo-l-(terf-butyldimethylsilyl)indole (143) is utilized to generate the 3-indolylzinc intermediate. Thus, 3-indolylzinc 144, prepared by halogen-metal exchange with terf-butyllithium followed by treatment with anhydrous zinc chloride, reacted with 2-halopyridine 141, resulting in formation of 3-(2-pyridyl)indole 145.

ZnCI N' Si/-BuMe2 144

C0 2 Me

141

1. PdCl2(Ph3P)2, DIBAL THF, reflux, 2.p-TsOH, EtOH, refux, 42% HH

HCI, MeOH, then H2, Pt0 2 , MeOH 60%

f j j

J"T

^

Et" H = H " C0 2 Me H

C02Me 145

Ba(OH)2, H 2 0 dioxane, reflux 1

then PPA 85-90 °C, 36%

146

LiAIH4, dioxane reflux, 33%

Cc& N H

148 Scheme 25. An application of 3-indolylzinc to the total synthesis of indole alkaloids Another application of this methodology is described above through the total synthesis of nordasycarpidone (147), which in turn serves as an intermediate for preparation of several other indole alkaloids [70, 71]. As depicted in Scheme 25, application of this well-developed methodology led to 3-(2-pyridyl)indole 145, which upon treatment with HCI and hydrogenation

Applications ot Falladium Chemistry

467

stereoselectively furnishes the all-cw-piperidine 146. Hydrolysis of ester 146 with Ba(OH)2 followed by cyclization of the resulting piperidine-4-carboxylic acid using PPA (polyphosphoric acid) led to the natural product (l)-nordasycarpidone (147). (±)-Nordasycarpidone (147) is an intermediate for uleine-type alkaloids, including dascarpidol, uleine, and 16,17-dihydrouleine. Reduction of (±)-nordasycarpidone (147) with LiAlH4 gave tetracycle 148, which constitutes a formal total synthesis of tubotaiwine, a Strychnos alkaloid with the aspidosermatan skeleton. Similarly, assembly of 3-(2-pyridyl)indole provided an alternative entry to tetracyclic ABCD substructures of akuammiline alkaloids [72]. The utility of 1-halo-p-carbolines as versatile building blocks was demonstrated by the applications to the total synthesis of perlolyrine (52) via a Suzuki coupling, nitramarine (110) and annomontine (112) via Stille coupling reactions {vide supra). The versatility of 1-halo-pcarbolines was further proven by the total synthesis of nitramarine (110) via a Negishi reaction [73]. Thus, 1-bromo-p-carboline (149) was sequentially treated with KH and terf-butyl lithium to give 1,9-dimetallated p-carboline 150, which was transmetallated to the corresponding organozinc reagent and then underwent a Negishi reaction with 2-chloroquinoline to provide an alternative access to nitramarine (110). In another example, Qu^guiner et al. synthesized eudistomin U (154) combining orf/to-lithiation and the Negishi reaction [74]. As depicted in Scheme 26, the organozinc reagent was prepared by regioselective ortho-\'\th\at\on of 151 with n-butyllithium followed by a transmetallation of the resulting lithio species with zinc chloride. Subsequent Negishi reaction of the organozinc reagent with 3-bromoindole 152 provided the corresponding trisubstituted pyridine 153. Ultimately, eudistomin U (154) was completed by boiling 153 with pyridinium chloride followed by a basic workup. In the synthesis of inverto-yuehchukene (160), an analog of yuehchukene (74), an intriguing extension of the Negishi reaction was employed [75]. The central transformation from acetate 158 and 2-indolylzinc 140 into bisindole 159 involves a cross-coupling of a nallylpalladium intermediate with an indolylzinc reagent. As delineated in Scheme 27, treatment of 3-indolylzinc with acid chloride 155 led to the formation of divinyl ketone 156 in 80% yield. The indolylzinc reagent was found to be superior here than the corresponding Grignard reagent for the coupling reaction with 155. Nazarov cyclization of the divinyl ketone 156 in refluxing HCl/1,4dioxane afforded the tetracycle 157 with the cis C/D ring juncture stereochemistry. The tetracycle 157 was converted to acetate 158. The pivotal reaction of 158 with 2-indolylzinc 140 in the presence of Pd(0) catalyst, derived in situ from PdCl2(PPh3)2 and DIBAL, gave 18% of the desired coupling product 159. Finally, reductive removal of the protecting groups afforded invertoyuehchukene (160).

468

JJ. LI

1. KH, THF B l n

2.2 eq. f-BuLi Br

149

1. ZnCl2 2.Pd(Ph3P)4 2-chloroquinoline 53%

1. BuLi, THF, -75 °C, 1 h 2. ZnCl2, -25 °C to rt F NHCOtBu 151

3. Pd(Ph3P)4

Br

NHCOtBu S02Ph

S0 2 Ph

153

1. pyridinium chloride reflux 2. NH4OH, ice, 80% Scheme 26. Synthesis of nitramarinc and cudistomin Uby using the Negishi reaction The Negishi reaction of oxazol-2-ylzinc chloride with 6-iodo partial ergoline alkaloid was also documented to synthesize potent 5-HTIA agonists [76].

Applications of Palladium Chemistry

469

EtMgBr, then ZnCl22

O

v /

cone. HCI, 1,4-dioxane *. reflux, 4 h 92%

H

156 1. BuLi, PhS02Cl, -78 °C 2. Superhydride, THF, 0 °C 15 min, 86% 3. Ac 2 0, DMAP, TEA CH2C12, rt, 0.5 h, 86%

' H S0 2 Ph 158

157

I

Na/Hg aq. NaH 2 P0 4

ZnCI

140 SQ2Ph

Et 2 OMeOH rt,78% |

•d(Ph3P)2CI2, DIBAL THF, reflux, 18% 159

A

160

Scheme 27. Synthesis of inverto-yuehchukene 4. INTER- AND INTRAMOLECULAR HECK REACTIONS 4.1. Heck Reaction In 1984, Hegedus and Harrington reported a synthesis of 3- and 4-substituted indoles [77] employing Heck's well-established process: Pd(0)-catalyzed functionalization of aryl halides by the oxidative addition-olefin insertion-P-hydride elimination. In this instance, 4-bromo-ltosylindole (161, Scheme 28) was converted to several diversely functionalized 4-substituted 1tosylindoles. Selective electrophilic substitutions at the C(3) position of 161 provided access to 3(chloromercurio)-l-tosylindole and 3-iodo-l-tosylindole (162), which then underwent a Heck

470

J.J. Li

reaction to give 3-substituted 1-tosylindoles. Another application of the Heck reaction involving 4-iodo-3-(2-nitrovinyl)indole and 3-buten-2-ol was documented by Somei etal [78, 79]. The most important applications of the intermolecular Heck reaction to indole alkaloid synthesis have been the total syntheses of ergot alkaloids, noticeably (±)-clavicipitic acid and (±)lysergic acid. The ergot alkaloids are metabolites of the parasitic fungus Claviceps with unique structures and pharmacological properties. Aside from the well-known hallucinogen lysergic acid diethylamide (LSD), many ergot alkaloids are biologically active and are in clinical use. The elegant total synthesis yV-acetyl-(±)-clavicipitic acid methyl ester by the Hegedus group is a classic example of the applications of organopalladium chemistry to indole alkaloid synthesis [80]. As shown in Scheme 28,4-bromo-l-tosylindole (161) was transformed into 4-bromo-3-

AcHN^,C0 2 Me

NHAc 1. Hg(OAc)2 cat. HCI04

l

!L J 2.12,97%

N ^ 5%Pd(OAc)2 Ts Et3N, MeCN 60% 162

N Ts

161

^k

OH

1

163

OH ,C02Me

AcHN^C0 2 Me || 15% 11 PdCI2(CH3CN)2

5% Pd(OAc)2/Et3N P(
CH3CN, 95% 165

NaBH4, Na 2 C0 3 4:2:1 MeOH/DME/H20 Av,-20°C

^(T H

Ac £0 2 Me

1

)

|" I T ^ H 166

AC2

\l

°

MeOH

H

N-

JL

f02H

1

\

y

\X 7 k^A ~N H

11 1

clavicipitic acid (167) 1

Scheme 28. An illustration of the efficacy of palladium chemistry in the total synthesis of Nacetyl-(±)-clavicipitic acid methyl ester

Applications of Palladium Chemistry

471

iodo-1-tosylindole (162) via a mercuration/iodination process. A chemoselective Heck reaction at the C(3) position of 162 with methyl a-acetamidoacrylate produced exclusively the Z-isomer 163, along with 15-20% of the deiodinated product 161. An additional Heck reaction at the C(4) position of 163 with 2-methyl-3-buten-2-ol proceeded under more forcing conditions [8 mol% palladium acetate and tri(o-toluene)phosphine) to install the tertiary allylic alcohol side-chain in 164. In general, use of tri(o-toluene)phosphine ligand is beneficial in Heck reactions involving arylbromides, whereas the Heck reactions involving aryliodides proceed smoothly without such ligands. Typically, phosphine ligands not only facilitate the oxidative additions of arylbromides, but also prevent Pd(0) from precipitating via chelation. The intramolecular aminopalladation of 164 was accomplished by a Pd(ll)-catalyzed process to give the tricyclic azepinoindole 165. The

OH AcHN, ,C0 2 Me 1. Rh(COD)2BF4/DIPAMP H2 (4 atm), MeOH, rt, 96 h

ACHNO^H

2. 0.1 eq. PdCl2(Ph3P)2/Ag2C03 100 °C in DMF-Et3N, 3 h, 83% 168

163

1. HCI, EtOAc 0 °C, 30 min » 2. Et3N, rt, 15 min 169 (29%)

Mg/MeOH 170

» rt, 1 h, 64-72%

Scheme 29. Synthesis of optically pure clavicipitic acid

170 (62%)

KOH MeOH-H2Q 79-80%

c,avicipitic add(167)

472

J.J. Li

mechanism of this interesting palladium-catalyzed cyclization may involve nucleophilic attack on a palladium(II)-alkene ic-complex, followed by preferential elimination of palladium(II) oxide [81]. Even though aminopalladation usually requires stoichiometric palladium, in this particular reaction, palladium(II) hydroxide (HO-Pd-Cl), instead of palladium hydride, was the ostensible elimination product, regenerating Pd(II). Therefore, no reoxidation of palladium(O) was required to maintain the catalytic activity. The p-toluenesulfonamide in 165 was cleaved by photochemical reduction, which also resulted in the stereoselective reduction the double bond to give the desired Af-acetyl-(±)-cIavicipitic acid methyl ester as two diastereomers (166), which were identical to those prepared from natural (±)-clavicipitic acid (167). An asymmetric version of the total synthesis of clavicipitic acid was reported by Yokoyama et al. [82-84]. As illustrated in Scheme 29 asymmetric hydrogenation of the known 4bromodehydrotryptophan 163 was best achieved (94% ee) using the optically active Monsanto bidentate phosphine, DIP AMP. The Heck vinylation in the presence of Ag2C03 gave the C(4)vinylated product 168 without racemization. Treatment of 168 with HCl-EtOAc effected the cyclization to give the tricyclic azepinoindole 170 (62%), air ig with diene 169 (29%). Cleavage of the sulfonamide (Mg/MeOH) afforded 171 which underwent saponification (KOH) to give optically active clavicipitic acid (167).

Scheme 30. Heck reaction in the synthesis of annonidine

473

Applications of Palladium Chemistry

Somei et al. also reported an early application of the Heck process in a total synthesis of the naturally occurring indole alkaloid annonidine (176), which was isolated from the stem bark of the west African medicinal plant, annonidium mannii [79J. As depicted in Scheme 30, the Heck reaction of 7-iodoindoline (172) with 2-methyl-3-buten-2-ol gave rise to 173. Additionally, 7-(3methyl-2-buten-l-yl)indole (174) was prepared from 173 by a three-step sequence that included hydrogenation (H2, 10% Pd/C), dehydration (p-TsOH, refluxing PhH), and oxidation (cat. salcomine, dioxygen, CH3OH, it). Condensation of 173 and 174 was facilitated by 2 N HCI in THF to afford 175 in a regiospecific fashion. Subsequent oxidation with catalytic salcomine and dioxygen afforded annonidine (176). In the total synthesis of (±)-lysergic acid (182) [85], the known Kornfeld's ketone (177) was converted to vinyl triflate 178 (Scheme 31). The Heck reaction between 178 and acrylate 179 furnished aminodienoate 180 with the desired E-geometry in 26% yield. Cleavage of the BOC group under acidic conditions followed by the treatment with NaHCO, produced the lysergic acid framework 181 as a mixture of two epimers. Since transformation of the major diastereomer of 181 to (±)-lysergic acid (182) is known, this work constitutes a formal total synthesis of (±)lysergic acid (182).

O

OTf

II

Me0 2 C

Boc

JU

Me

179

3 moI% Pd(OAc)2,6 mol% Ph3P 2.5 eq. Et3N, DMF, 60 °C, 24 h, 26%

C0 2 Me

C0 2 Me 2.5 N HCI AcOEt » 1.5 h, rt 60%

BzN

1 180

BzN 181

Scheme 31. Formal total synthesis of (±)-lysergic acid Two additional syntheses of indole alkaloids which utilize the Heck reaction are (±)-cistrikentrin A (185) and infractin (187). As outlined in Scheme 32,7-bromoindole 183 was coupled with an excess of methyl crotonate to give 184 under the Heck reaction conditions [86]. 184 was

474

J.J. Li

then converted to (±)-ci5-trikentrin A (185). The olefin geometry of the newly-formed trisubstituted double bond in the Heck reaction was inconsequential because k was subsequently reduced. In another case, P-carboline-1-triflate (186) was transformed into the naturally occurring P-carboline infractin (187) in two steps via a Heck reaction with methyl acrylate followed by a hydrogenation [87].

O

^A 183

4 mol% Pd(OAc)2 9 mol% P(o-toIyl)3 Et3N, CH3CN, 115 °C, 14h,61% O

1. Pd(OAc)2 P(o-Tol)3,18%

» 2.H 2 ,Pd-C,85% Scheme 32. Total synthesis of (±)-ci5-trikentrin A and infractin 4.2. Intramolecular Heck Reaction In the synthesis of the desethylibogamine alkaloid skeleton described by Trost and Genet [88], a mechanism similar to the Heck arylation (7-exo cyclization) was involved. As illustrated in Scheme 33, the dilithio indole 188 with a pendant olefin was treated sequentially with HgCl2, PdCl2, and then NaBH4 to give desethylibogamine (189). The difference from a common Heck reaction is that the last step is a simple reduction of the palladium intermediate instead of the usual reductive elimination. This method was also applied by Williams et al. in their total synthesis of (+)-paraberquamide B, where a heptacycle was synthesized from an indole ring with a pendant olefin using Trost's conditions [89]. An indole alkaloid synthesis employing a bona fide intramolecular Heck reaction was documented in Sundberg's preparation of 5,6-homoiboga derivatives [90]. Several attempts to construct 5,6-homoiboga derivative 191 using inter- or intramolecular Heck reaction conditions with phosphine ligands led to poor yields. Application of Jeffery's "ligand-free" phase-transfer

Applications of Palladium Chemistry

475

catalysis conditions [91] to the intramolecular Heck reaction (8-endo-cyclization) of 190 provided 191 in an exceptionally good yield.

^

Nl N LiLi 188

^

1. HgCI2 2.PdCl2,THF

N N H

1

3. NaBH4

C0 2 Et ^

I ^ \ A Pd(OAc)2, ' N 1 OCH3 «-BU 4 NC1, KOAC N^NA^/^CH, CH3 i o 2 C H 3

vx

f

^

DMF,80°C 89%

190

CH 3 C0 2 CH 3 191

Scheme 33. Examples of 1-exo and %-endo Heck cyclization reactions A 6-exo Heck cyclization plays a central role in Rawal's elegant total synthesis of strychnine (201). Strychnine is a member of Strychnos alkaloids, which were isolated from the seeds of Strychnos nux-vomica L., Loganiaceae and beans of S. ignitti, Berg. Its powerful biological activity (extremely poisonous) combined with the intriguing heptacyclic framework elicited tremendous efforts toward its synthesis. After Woodward's monumental accomplishment of a strychnine synthesis in 1954, it took nearly forty years to witness several additional total syntheses. Among those, Rawal's approach [92] is the most concise route, with an intramolecular Diels-Alder reaction and an intramolecular Heck cyclization as the key features. As illustrated in Scheme 34, commercially available o-nitrophenylacetonitrile (192) was converted to pyrroline 193 in 79% yield over five steps, including a Stevens' cyclopropyl iminium ion rearrangement [93J to prepare the pyrroline ring. In a manner analogous to Rawal's total synthesis of (±)dehydrotubifoline [94], 193 was transformed into dienamine 195 by condensation with aldehyde 194 (Z:E = 9:1) followed by quenching with methyl chloroformate. An intramolecular DielsAlder cyclization of 195 proceeded in quantitative yield with complete stereocontrol to give the desired tetracycle 196. Global demethylation using iodotrimethylsilane furnished the pentacyclic lactam 197. Alkylation of 197 with allylic bromide 198 (prepared in five steps from butynediol) resulted in substrate 199, a precursor for the pivotal intramolecular Heck cyclization. Employing Jeffery's phase-transfer catalysis modification of the Heck reaction, vinyl iodide 199 with a pendant olefin was converted into a hexacyclic strychnan 200 (74% yield).

476

JJ. LI

a

^ CCfi N

steps 55 steps

Mr*. "N02

^^^ ^s A>v V N -^C O j M e

-row* 79%

k^JL * 5 s ^ ! ^ NH MU 2

192

193

W l

m

** then ClC02Me, PhNEt2 85% ,C0 2 Me /—N

,N"C0 2 Me

Me0 2 C

J neat, 25 °C **^

PhH,185°C, 4 h, 99%

\^C02Me

Me0 2 C

k^COiMe 196

195 TMS-I (10 equiv.) CHC13, reflux,

K 2 C0 3 ,5:1 acetone:DMF 75%

CH3OH quench 90%

OTBS Pd(OAc)2 (0.3 eq.) ^. BU4NCI, DMF, K 2 C0 3 70°C,3h,74% OTBS 200

199

1.2N HC1, THF i

2. KOH,EtOH

Scheme 34. Rawal's total synthesis of strychnine

Applications of Palladium Chemistry

477

After the removal of the silyl protecting group, the resulting isostrychnine was subjected to a base-mediated isomerization and subsequent Michael addition to give strychnine (201). The longest linear sequence in Rawal's synthesis required 12 steps. If the synthesis of two fragments 197 and 201 are included, the total operations involved 21 steps [95]. The yield of 201 is about 9% (24% based on recovered isostrychnine that can be recycled). Considering there are 7 transfused rings with 6 contiguous asymmetric centers, the approach is remarkably efficient. The intramolecular Heck cyclization proceeded with complete stereocontrol, and the geometry of the olefin was kept intact. In contrast, in another case [96], an inversion of olefin geometry was observed when the carbamate protecting group of the indole ring was present. Rawal and coworkers speculated that the presence of a carbamate moiety intercepted the a-palladium Heck cyclization intermediate through coordination. Therefore, p-hydride elimination did not occur due to chelation after the normal ejro-cyclization. Instead, ejco-cyclization was followed by cyclopropane formation, rearrangement, and elimination to give the olefin with inversion of the double bond geometry.

OH 202

(±)-geissoschizal (203)

(±)-isogeissoschizal (204)

Pd(Ph3P)4 LiCN 26%

N02 O 206

Pd(OAc)2,Ph3P HC02Na, Et3N/CH3CN C0 2 Me 207

reflux, 12 h, 43% C02Me 208

Scheme 35. Applications of 6-exo Heck cyclization in indole alkaloid synthesis

478

J J. Li

The intramolecular Heck cyclization employed in Rawal's total synthesis of strychnine was a 6-exo cyclization. A similar strategy using a 6-exo Heck cyclization was applied to Rawal's total synthesis of the (±)-geissoschizine skeleton [97a], the biogenetic precursor to virtually all other families of monoterpenoid indole alkaloids. In contrast to strychnine, geissoschizine does not contain a bicyclic bridged system that would dictate the stereochemical outcome of the cyclization. As shown in Scheme 35, the "classical" Heck conditions [Pd(OAc)2, KjCO,, Et3N, PPhj] for substrate 202 favored (±)-isogeissoschizal 204, whereas Jeffery's "ligand-free" modification [Pd(OAc)2, K^CO,, Bu4NBr] produced the desired (±)-geissoschizal (203) as the predominant product. In contrast to the intramolecular Heck reaction conditions employed in the (±)-geissoschizal (203) synthesis, a very "non-polar" set of conditions [Pd(OAc)2, PPh3, proton sponge, K2C03, PhMe, 100 °C, 18 h] was found to be most suitable for the intramolecular Heck reaction in Rawal's synthesis of the apogeissoschizine skeleton [97b]. Other applications of the 6-exo Heck cyclization strategy can be found in the synthesis of pentacyclic Strychnos alkaloids by Bosch et ai [98] and tabersonine by Kuehne et al. [99]. As illustrated in Scheme 35, 6-exo Heck cyclization of substrate 205 was successful only when Grigg's [100] modified Heck conditions [Pd(OAc)2, LiCN] were employed to give the tricyclic intermediate 206. Another 6-exo reductive Heck reaction successfully cyclized tetracyclic substrate 207 into pentacyclic tabersonine (208). As shown in Scheme 36, a Heck polyannulation reaction was realized between dibromo(indolyl)maleimide 209 and diacetylenyl trifluoroacetanilide 210 to assemble indolo[2,3a]carbazole 211, the N-protected aglycone of rebeccamycin (25). Four bonds were formed in one step from a single monocyclic 1,3-diacetylene precursor [101] and the trifluoroacetyl protecting groups were readily cleaved during the workup.

Bn i

\=\ Br

209

Pd(Ph3P)4,K2C03 CH3CN,

Br

50 °C, 52% ^ W H NH

1

HN^V HN COCF3 COCF3 210

Scheme 36. Polyannulation Heck reaction for indolo[2,3-a]carbazole synthesis For intramolecular Heck reactions, the migratory insertion of the initial organopalladium species occurs not only with simple olefins, but also with dienes (e.g. 207 to 208) and aromatic rings. Examples of an aromatic ring as the migratory insertion recipient can be found in the bisindolylmaleimide field. For instance, an intramolecular Heck cyclization of inflate 212

Applications of Palladium Chemistry

479

furnished TV-methyl arcyriacynin A (213) through formation of C(2)-C(4*) bond linkage between the two indole rings (Scheme 37). The migratory insertion of the oxidative addition intermediate from 212 took place to an indole ring. In this particular case, the triflate was chosen because the bromide analog was unstable towards Grignard reagents and a reductive loss of the aromatic bromine atom was observed. When the triflate was used, successful intramolecular Heck reaction was achieved in 81% yield to give the desired product 213. Transformation of N-methyl arcyriacynin A (213) into arcyriacynin A (67) was accomplished by basic hydrolysis followed by acidic workup and treatment of the resulting anhydride with hexamethyldisilazane. In another approach to JV-methyl arcyriacyanin A (213), a domino intramolecular Heck was achieved between bromo(indolyl)maleimide 214 and 4-bromoindole (215, Scheme 37). Examples of migratory insertion to aromatic rings also include the total syntheses of anhydrolycorine-7-one (217) [102] and the E-azaeburnane series [103]. As illustrated in Scheme 38, an intramolecular Heck reaction of N-acylindoline 216 installed the six-membered lactam in anhydrolycorine-7-one (217). In a similar process, the tetracyclic pyrido-[2*,3*-^]pyridazino[2,3a]indole (219) was prepared from bromopyridine 218 under phase-transfer catalysis conditions. Pyridyl indole 219 is a precursor of the pentacyclic skeleton of the £-azaeburnane series.

CH, \_l

OTf

0.12% Pd(OAc)2, 0.14% dppp, Excess Et3N, DMF, 110 °C, 18h,81%

212

213

CH Pd(OAc)2, Ph3P, Et3N,CH3CN, 213

N Boc 214

80°C,3h, 10-30% 215

Scheme 37. Domino Heck cyclization

480

J.J. Li

Pd(OAc)2,K2C03

Q

DMA, 160-70 °C, 55%

°9X)

Pd(OAc)2,Ph3P, K 2 C0 3 , #tBu4NBr, » DMF, 120 °C, 92%

O 218 Scheme 38. Migratory insertions take place to aromatic rings An additional application of 1-exo Heck cyclization was found in Kelly's synthesis of maxonine (223), which was isolated from the root of a plant Simira maxonii endemic to the Costa Rican tropical forest. As shown in Scheme 39, the migratory insertion step of the intramolecular Heck cyclization of substrate 220 took place to both the pendant olefin and the benzene ring of the indole moiety simultaneously, giving rise to dihydropyridine 221 and seven-membered 222, respectively [104]. Oxidative cleavage of the stilbene double bond in 222 produced maxonine (223), which was identical to authentic maxonine. Kelly's synthesis of maxonine (223) revised the original structural assignment of the natural indole alkaloid. Aside from 8, 7, 6-endo, and 8, 7, 6-exo Heck cyclizations, 5-exo Heck cyclization is also feasible, although 5-endo cyclization is not favored. Kurihara et al. revealed a 5-exo Heck cyclization in their synthesis of the indole analog of magallanesine [105]. As depicted in Scheme 39, 5-exo Heck cyclization converted substrate 224 into 225, the indole analog of magallanesine (226) in 28% yield. The intermediate of the vinylic substitution was a palladium enolate, which underwent a syn P-hydride elimination after isomerization. (±)-Gelsemine (236) was isolated from Gelsemium sempervirens (Carolina jasmine) in 1870. Due to its intriguing bridged poly cyclic structure, (±)-gelsemine (236) has been a target of intensive synthetic endeavors. In fact, one of the first applications of intramolecular Heck reactions to form a quaternary center was documented by Overman et al. [106] in the synthetic studies towards (±)-gelsemine (236). As outlined in Scheme 40, when the cyclization precursor 227 was submitted to the "ligandless" conditions [Pd2(dba)3, Et3N] in the weakly coordinating solvent toluene, the quaternary center was formed as a 9:1 ratio of diasteromers (229:228 =

Applications of Palladium Chemistry

481

89:11). Addition of a silver salt in polar solvent THF completely reversed the sense of asymmetric induction in this cyclization reaction (229:228 = 3:97).

Pd(OAc)2

221 220

Os0 4 ,10 4 '

222

O

OMe OMe

Pd(OAc)2, Ph3P >TlOAc, D M F , 130 °C 28%

O

OMe ,OMe

Ph02S O

225

magallanesine (226)

Scheme 39. Total syntheses of maxonine and the indole analog of magallanesine In the total synthesis of (±)-gelsemine (236), Hiemstra and Speckamp [107J utilized Overman's "ligandless" intramolecular Heck conditions and achieved the synthesis of a spirooxindole in a 2:1 ratio favoring the desired stereoisomer. As depicted in Scheme 41, The key cyclization substrate 233 was derived from the carbonylation reaction between vinyltriflate 230

JJ. Li

482

-SEM

Pd2(dba)3,Et3N,PhCH3

r

110 °C, 80-95%

O SEM

V3o

Me0 2 C / Br

Me0 2 C

227

Pd2(dba)3,Ag3P04 THF,60°C,77%

Meo2c

Scheme 40. The stereochemical outcome is dependant on the choice of palladium catalyst and 2-bromoaniline (231). Since it is known that the Heck cyclization is low yielding with unprotected anilides, 232 was protected as its corresponding trimethylsilylethoxymethyl ether 233. Cyclization of 233 under the standard Heck arylation conditions produced a single spirooxindole product possessing the opposite spiro stereochemistry of (±)-gelsemine (236). When Overman's "ligandless" conditions were applied to substrate 233, a 2:1 ratio of the spiro-oxindole was obtained with desired product as the major isomer. Therefore, the desired spiro-oxindole 234 was obtained in 60% yield after removal of the TDS (thexyldimethylsilyl) protective group, along with 30% of the epimeric spiro-oxindole. With substrate 234 in hand, a mercury(II) triflate and /V,N-dimethylaniIine-initiated cyclization provided the tetrahydropyran ring formation and the resultant organomercurial intermediate was reduced with alkaline sodium borohydride. Removal of the SEM protective group delivered 21-oxogelsemine (235), which is a natural product itself. Selective reduction of the lactam moiety of 235 with alane in THF led to the formation of (±)gelsemine (236).

Applications of Palladium Chemistry

^

OTf

483

Pd(OAc)2,Ph3P,Et3N, CO,DMF,rt,24h,70%

O R

H2N-HT) OTDS 230

rxi 231

Br

232 R m H 233R = SEM 1. HgO, Tf 2 0, MeN0 2 , rt, N,N-dimethylaniline, 3 d

1. Pd2(dba)3, Et3N, PhMe, reflux, 4 h

».

^2. TBAF, THF, rt, 2 h Q 60% for 2 steps

OH 234

2. NaBH4, NaOH, CH2C12, EtOH, 3. TBAF, THF, 4 MS, reflux, 4 h, 43.2%

A1H3, THF, -65toO°C, 4 h, 50%

Scheme 41. Total synthesis of (±)-gelsemine At the early stage of Heathcock's biomimetic total syntheses of discorhabdins [108], a 5exo Heck cyclization was employed for the synthesis of 3,6,7-functionalized indole. As highlighted in Scheme 42, when precursor 237 was exposed to catalytic palladium acetate, tri-otolylphosphine, and stoichiometric base, indole 238 was smoothly produced in 89% yield. Subsequently, the total syntheses of discorhabdin C (239) and discorhabdin E (240) were accomplished using indole 238 as the common intermediate.

484

J.J.LI

NC 5 mol% Pd(OAc)2 •

(o-tol)3P, Et3N, CH3CN reflux, 3 h, 89 %

MeO

« N MeO" 71 H OBn 238

O Riv

-

R

discorhabdin C (239) R, = R2 = Br

2.

I N *1| N H

O

\ \ \ "N 1 H 1

discorhabdin E (240) R, = H, R2 = Br

Scheme 42. 5-exo Heck cyclization in the total synthesis of discorhabdins

COL

Br^

N I

CO,Me

Pd(Ph3P)3,KOAc dioxane, reflux, 91 %

\-6

241

1. L1AIH4 2. Dess-Martin 3. Mn0 2 4.RhCl(Ph3P)3

Scheme 43. An intramolecular "aryl-Heck" cyclization in the total synthesis of hippadine

Applications of Palladium Chemistry

485

One of the latest additions to the impressive repertoire of indole alkaloid total syntheses using intramolecular Heck strategy is the total synthesis of hippadine (18a) [109]. As depicted in Scheme 43, an intramolecular "aryl-Heck" cyclization of substrate 241 under normal Heck conditions gave the cyclized product 242, which was transformed into hippadine (18a) upon further manipulations. 5. TSUJI-TROST REACTION The Tsuji-Trost reaction is the Pd(0)-catalyzed allylation of nucleophiles [110]. Even though extensive applications of Tsuji-Trost reaction can be found in many areas, including heterocycles, applications to the indole field have been relatively rare. Nevertheless, several elegant total syntheses of indole alkaloids have used the Tsuji-Trost reaction as the key feature of the synthetic approaches to achieve great convergency.

?AC

J! % ffS

Pd(Ph3P)4, Et3N f^. / 3 C N ' 7 0 C,L5h (/ y—(

243

OCOtBu

\ , N

CH

244

i ^ c r t JI\

N H

OCOtBu

OCOtBu 245

246

Scheme 44. r|3-Allylpalladium intermediate in the synthesis of indole alkaloids In the total synthesis of desethylibogamine [88a], Trost and Gen6t transformed an allylacetate with a pendant secondary amine (243) into the desired isoquinuclidine 244 (Scheme 44). The cyclization took place via nucieophilic attack on a ft-allylpalladium intermediate by the secondary amine. An asymmetric version of the above transformation was accomplished by Trost, Godleski, and Genet [88b]. Such an operation involving the ft-allylpalladium intermediate appears to have proceeded with complete stereocontrol, since the ee (60%) remained constant throughout the transformation. Moreover, Trost, Godleski, and Belletire [88c] utilized the rc-allylpalladium method to achieve a formal synthesis of (±)-catharanthine. Under the same reaction conditions as

486

J J . Li

employed for the formation of 244, amino bis-pivalate 245 underwent a transformation sequence to isoquinuclidine 246 via formation of the r|3-allylpalladium intermediate and nucleophilic attack by the secondary amine (Scheme 44). Intermediate 246 was then manipulated to give (±)catharanthine. Many ergot alkaloids are important clinical agents for the treatment of hypertension, migraine attacks, Parkinson's disease, etc. Genet devised an efficient synthesis of ergoline precursors employing 7t-ally {palladium intermediate chemistry as the central step [111]. An ergoline synthon could be prepared from indole-4-carboxaldehyde (247) in six steps and 38-43% yield. The entire sequence proceeded without indole Af-protection. An asymmetric version was achieved by the addition of catalysts bearing different chiral ligands on the palladium [112]. The catalytic enantioselective carbocyclization via Tt-allylpalladium intermediates occurred with ee's ranging from 19% [(-)-CHIRAPHOS, THF, NaH at 65 °C] to 70% [R-CHIRAPHOS, DME, KF/alumina at 20 °C]. This methodology was used by Genet et al. in their asymmetric total synthesis of (-)chanoclavine (252) [113]. The Horner-Emmons olefination of indole-4-carboxaldehyde (247) with ethyl diethylphosphinoacetate, using potassium carbonate as the base, gave the a,f3unsaturated ester 248 with exclusive E geometry (Scheme 45). Reduction and acetylation of 248 produced allyl acetate 249. The installation of the nitroethyl side chain at C(3) could be accomplished by treatment of 249 with 1-dimethylamino-2-nitroethylene in the presence of TFA followed by sodium borohydride reduction to give nitroacetate 250. Alternatively, 250 could be synthesized via a classical three-carbon functionalization involving a Mannich condensation: treatment of 249 with di methyl ami ne/formaldehyde in acetic acid followed by treatment with methyl nitroacetate in refluxing toluene constructed 250 with concurrent decarbomethoxylation. The crucial intramolecular allylation was best achieved by employing Pd(OAc)2, and (£)-(-)BINAP in THF at room temperature, giving rise to 251 with up to 95% ee. The increase of diastereoselectivity and enantioselectivity using bidentate phosphine ligands, in comparison with other monodentate phosphine ligands, could be rationalized by the ligand pocket effect. With BINAP, the electrophilic rf-allylpalladium complex is a seven-membered ring. The steric effects cause an increase of the asymmetric induction during addition of the oc-anion to the nitro anion. With the tricyclic indole (251) in hand, straightforward transformations produced (-)chanoclavine (252) in 6 steps.

Applications of Palladium Chemistry

487

C0 2 Et 1. UAIH4, Et 2 0, 0°C,3h,9S%

CHO

60 N H

(EtO)2P(0)CH2C02Et K 2 C0 3 , THF, reflux, 24 h, 95%

N H 248

247

,OAc

»

2. Ac 2 0, Et3N, 0 °C, CH2C12 95%

1. Me2NCH=CHN02 TFA,CH2CI2,0°C 70%

,OAc

2. NaBH4, MeOH THF, 20 °C, 80%

Pd(OAc)2,3%, (S)-(-)-BINAP 6% 1

K 2 C0 3 , THF rt, 60%

6 steps 6% overall yield

Scheme 45. Asymmetric total synthesis of (-)-chanoclavine Godleski envisioned a unique way to assemble the D, E ring juncture of alloyohimbone (257) [114]. As summarized in Scheme 46, Diels-Alder adduct 253 was treated with tryptamine and the intermediate imine was reduced by NaBH, to give aminoallylic acetate 254. Acylation of the secondary amine on 254 provided the 7t-allylpalladium precursor 255. Anion formation with NaH and the subsequent reaction with Pd(diphos), gave 256 possessing exclusively the m-fused D, E-ring juncture. Notably, the Tsuji-Trost conditions afforded complete stereocontrol via the intermediacy of a n-allylpalladium complex. Desulfonylation of 256 using sodium amalgam in methanol in the presence of NaH,P04 (91%) followed by a Bischler-Napieralski reaction [POCI,, PhH, 80 °C, then CH,CI2. LiAl(OtBu),H, 72%] and an acid-facilitated hydrolysis (6 N HCI, CH,CN) of the vinyl sulfide provided alloyohimbone (257).

488

JJ . LI

9HO AcO^^*.

SPh 253

tryptamine, CH2C12, MgS0 4 , -23 °C, 11 h

^ \ — ^ ^ N

then, NaBH4, MeOH, -63°C,0.75h,85% 254

COCH2S02Tol, L A JJ°V ~~\^ :3N, -23X94% TJ^CO^

SPh

NaH, DME, 0 °C, then Pd(diphos)2, *• 85 °C, 10 min, 84%

SPh 255

O

j

J O ^ N.

N ^H w^ 1 v ToI02S' H

i. N a ( H g ) , 91 % K»H sph

2.BischIerNapieralski 84% 3.6 N HC1,64%

256 Scheme 46. Total synthesis of alloyohimbone The Tsuji-Trost reaction was also employed in the synthesis of a very intricate indole alkaloid, koumine (262). Koumine (262), possessing a particularly unique cage structure, is a principal Gelsemium alkaloid isolated from the Chinese toxic medicinal plant Hu-Mang-Teng. The Sakai group devised a biomimetic synthesis of koumine starting from naturally abundant 18hydroxygardnutine (258). Based on their successful partial synthesis of 11-methoxykoumine [115], 258 was transformed into 18-hydroxy-l 1-demethoxygardnerine (259) in 7 steps [116J. As shown in Scheme 47, treatment of 259 with methyl chloroformate resulted in carbamate 260 with concurrent C-N bond cleavage and C-O bond formation to install the tetrahydropyran ring. LiAIH4 reduction and acetylation furnished 18-O-acetyl-hydroxytaberpsychine analog (261). After generating the indole anion using NaH, the intramolecular Tsuji-Trost reaction of 261 was realized by the addition of Pd(OAc), and triphenylphosphine in DMF at 80-90 °C to tether C(7) and C(20), giving rise to koumine (262).

Applications of Palladium Chemistry

489

HO-

MeO

259

OH

2. LiAIH4, THF,

1. CIC02Me,

41%, 2 steps IF-H2 0, THF-H rt, 2.5 h

H

3. Ac 2 0, pyr. rt, 1 h, 96% 260

Cud N H

, Me

NL

OH

NaH, D M F , rt, 10 min

then Pd(OAc)2, Ph3P » 90 °C, lh,80%

261 Scheme 47. Total synthesis of OAc koumine An ingenious extension of the Tsuji-Trost reaction was the cornerstone of Oppolzer's enantioselective synthesis of a heteroyohimbine alkaloid, (+)-3-isorauniticine (267) [117J. Substrate 263 was prepared from a commercially available glycinate equivalent by N-alkylation, installation of the sultam chiral auxiliary followed by a sultarn-directed C-alkylation. As illustrated in Scheme 48, the crucial double cyclization was accomplished by the treatment of 263 with Pd(dba)3, Bu,P, in the presence of carbon monoxide (1 atm) in acetic acid to give enone 264 and two other stereoisomers in a 67:22:11 ratio. In this case, an allyl carbonate, rather than an allyl acetate, was used as the allyl precursor. Since carbonate is an irreversible leaving group, formation of the 7C-allylpalladium complex occurs readily. In the presence of Pd(0), the allylic carbonate is converted into a rt-allylpalladium complex with concurrent release of CO, and

490

J JT. Li

p2 o

so2

Ar O1 S02 Pd(dba)2,Bu3P,AcOH J -'^ X* CO,80°C,3h,45-53% ' ^H CH2 OC02Me 264

263 carbonylation, cyclization, & p-hydride elimination

oxidative addition

CSO

insertion

265

266

PdLn

Scheme 48. Enantioselective synthesis of (+)-3-isorauniticine alkoxide, which in turn serves as a base. Therefore, the allylation reaction can be conducted under neutral conditions without the addition of external bases. The transformation from 263 to 264 has been rationalized via the following mechanism: coordination of the K-allylpalladium complex with the pendant olefin to give 265 followed by an insertion reaction to provide 266. Subsequently, 266 underwent a carbonylation, a 5-exo Heck cyclization and finally P-hydride

Applications of Palladium Chemistry

491

elimination to furnish the desired exo-cnont 264. The natural product, (+)-3-isorauniticine (267), was obtained from 264 via several additional manipulations. 6. CARBON-NITROGEN BOND FORMATION In Section 5, the total syntheses of monoterpenoid alkaloids, alloyohimbone (257) and (+)3-isorauniticine (267) via palladium chemistry were reviewed. Two additional yohimbane alkaloids, 15,16,17,18,19,20-hexadehydroyohimbane and rutecarpine (273) were also synthesized using palladium chemistry. However, instead of the Tsuji-Trost reaction strategy as employed in the syntheses of 257 and 267, the syntheses of 15,16,17,18,19,20-hexadehydroyohimbane and rutecarpine (273) involved the formation of a carbon-nitrogen bond as the key feature. As illustrated in Scheme 49, the bromo-p-carboline substrate 268 was treated with Pd(OAc)2 and PPh, in the presence of /iBu3N under carbon monoxide atmosphere to assemble 21-oxoyohimbane 269. Subsequent reduction of 269 with LiAlH4 afforded 15,16,17,18,19,20hexadehydroyohimbane [118]. In the synthesis of rutecarpine (273) [119], N-carbomethoxy-oiodoaniline (271) and tryptamine (270) were allowed to react with carbon monoxide (1 atm) in the

Br

CSO Pd(OAc)2,Ph3P nBu3N, 100 °C, 76h,56%

268

Q O O N „ 2 • MK.!CNH.1 H

%J>

270

H »J T

HN

NW»^

K2CO3,120°C,77%

271

POCl3, CH2C12 • 60 °C, 3 h, 40%

272 Scheme 49. C-N bond formation with concurrent CO insertion

|

rutecarpine (273)

492

JJ.Li

presence of Pd(OAc)2, PPh3, and K^CO, as the base, to install quinazolinone derivative 272. Treatment of quinazolinone 272 with POC1, in dichloromethane at 60 °C for 3 hours furnished rutecarpine (273). As described in Section 4.1. (Scheme 29), in the frequently reviewed synthesis of Nacetyl-(±)-clavicipitic acid methyl ester (167) by Hegedus [80, 81], intramolecular aminopalladation of 164 was accomplished by a Pd(II)-catalyzed process to give the tricyclic azepinoindole 165. During the last few years, a novel Pd(0)-catalyzed method for C-N bond formation from amines and aryl halides has emerged largely due to contributions from the Buchwald and Hartwig groups [120, 121]. In one application, an intramolecular C-N bond linkage was realized using classic palladium catalysis condition in Buchwald's synthesis of tetrahydropyrroloquinoline

O

NMe2 NH2 Br

cAo^Me

3 steps

1. DCE, reflux

52%

2.EtOH,DCE, reflux, 83%

275

1

NHMe

"M

Me>.

10moI%Pd(Ph3P)4

t C02Me

Me

K 2 C0 3 , Et3N, tol, 200°C,81% 277

276

71 "Yt Me-N

1. BBr3 » 2. Mel 50%

CI

l

O L*NH7 111

MeO

dehydrobufotenine 1 (278) | Scheme SO. Synthesis of tetrahydropyrroloquinoline alkaloids

C02Me

Applications of Palladium Chemistry

493

alkaloids [122]. As shown in Scheme 50, tryptamine derivative 275 was prepared from 2-bromo4-methoxyaniline (274) using the intramolecular insertion reaction of zirconocene-stabilized benzyne complex [123]. Chemoselective demethylation of the tertiary amine was achieved by exposure of 275 to ACE-C1 (1-chloroethyl chloroformate) in DCE (dichloroethane) to provide secondary amine 276 while the methyl ether remained intact. Exposure of 276 to classic palladium catalysis conditions [Pd(OAc)2, I^CO,, Et,N, tol, 200 °C] led to the formation of tricyclic indole intermediate 277 in 81% yield. Buchwald's optimal intramolecular Pd-catalyzed aryl amination conditions [120, 124] were not compatible with this cyclization because the presence of NaO/Bu caused the cleavage of the carbamate, and none of the desired product was obtained. Finally, cleavage of the aryl methyl ether with concurrent removal of the carbamate using BBr3 followed by in situ quaternization by the addition of excess Mel and KHC03 produced the toad poison dehydrobufotenine (278) as its iodide salt. Using the same intramolecular C-N bond formation strategy as the crucial step, Buchwald also prepared tricyclic indole 279, a known intermediate in the total syntheses of makaluvamine C and damirones A and B.

^^N"^Br H 280 O

CH3I, reflux 70%

6H ° y ^ J V " 9

282 r*\ BOCNH/^° LiHMDS,SnCI4 -78°C,4h,57%

^ ^ N Br CH3 281

TFA/Me2S (1:3)

\ ^ x , A _ J„mn„ lh,rt,90% ? BrNHBOC CH3 283

O

^ ^ _ ^

a s

ILJCTX

O

X > ^dCdba^BINAP^ ^ Y ^ T ^ V ^

A 'BuONa,DMF,

N Br NH2 CH3 284

80°C,48h,51

«!VA A *k/° CH3 285

Scheme 51. Pd-catalyzed intramolecular C-N bond formation in a-carboline synthesis

494

JJ . LI

The Pd-catalyzcd C-N formation method developed by the Hartwig and Buchwald groups has also found applications to the synthesis of a-carboline 285, which contains the pyrido[2,36]indole skeleton of several naturally occurring alkaloids [125]. As illustrated in Scheme 51,2bromoindole-3-carboxaldehyde (280) was methylated to give 281. y-Lactone 282 was easily derived from 2[5//]-furanone in a two step sequence comprising a Michael addition of Nbenzylamine followed by a catalytic hydrogenation in the presence of di-ter/-butyl dicarbonate. The aldol condensation between 281 and 282 was conducted using lithium hexamethyldisilazide in the presence of stannic chloride to afford the aldol product 283 as a mixture of diastereomers. Simultaneous deprotection of the amino group and dehydration by treating 283 with trifluoroacetic acid and dimethyl sulfide gave the precursor 284. The intramolecular C-N bond formation was achieved by using Pd-catalyzed intramolecular C-N bond formation conditions [Pd(dba)3, sodium ferf-butoxide and BINAP] to assemble the desired a-carboline 285. 7. REPRESENTATIVE EXPERIMENTAL PROCEDURES 7.1. 2-Methyl-3,6-dimethoxycarbazoIe-l,4-quinone (37) [31J A solution of the benzo-1,4-quinone 36 (195 mg, 0.714 mmol), cupric acetate (324 mg, 1.78 mmol) and palladium(H) acetate (15.9 mg, 0.071 mmol) in glacial acetic acid (10 mL) was heated at reflux under air for 19 h. Silica gel (2 g) was added to the reaction mixture, the glacial acetic acid was evaporated in vacuum, and the resid»?e was purified by filtration over silica gel (EtOAcMeOH, 10:1). After removal of the solveiu, the residue was taken up in chloroform (5 mL), heated at reflux, and subsequently cooled to -30 °C. The resulting precipitate was isolated by filtration, washed with chloroform, and dried in a vacuum to afford the desired product 2-methyl3,6-dimethoxycarbazole-l,4-quinone (37) (142 mg, 73%) as a black-green solid.

OCH3

0.1 Pd(OAc)2, 2.5Cu(OAc)2

„ „3 "

AcOH, reflux, 19 h, 71-73%

c

O 36

Scheme 52. Catalytic oxidative cyclization using Pd(II)

Me

°

37

495

Applications of Palladium Chemistry 7.2. 2-[3-[l-(-/erf-Butyldimethylsilyl)indolyl]]-4,5-diiodo-l-[2-(trimethylsilyl)ethoxy-l//imidazole (56) [38]

A mixture of l-(-te^butyldimethylsilyl)indolyl-3-boronic acid (55, 0.5 mmol) and 2,4,5-triiodol-[[2-(trimethylsilyl)cthoxy]mcthyl]-l//-imidazole (54, 173 mg, 0.3 mmol), benzene (10 mL), methanol (2 mL), 2 M sodium carbonate (0.5 mL), and tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol) was refluxed for 8 h under N2 atmosphere. The reaction mixture was cooled to room temperature and anhydrous sodium sulfate was added. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude mixture. After purification by PTLC (AcOEt/w-hexane = 1/10), the product was recrystallized from EtOH-HaO to give 56 as colorless crystals (91 mg, 45%).

B(OH)2 "^

V

55 N SEM 54

TBS

Pd(Ph3P)4, Na 2 C0 3 ,45%

TBS 56

Scheme S3. The Suzuki coupling reaction in indole alkaloid synthesis 7.3.3-[l-[4-(l-Ethoxyethenyl)-2-nuoro-3-pyrldyl]ethyl]indole (114) [57] A mixture of (l-ethoxyvinyl)tributyltin (0.95 g, 3 mmol), bromide 113 (1.2 g. 3.3 mmol), and tetrakis(triphenylphospnine)palladium(0) (0.07 g, 0.06 mmol) in toluene (20 mL) was refluxed until precipitation of black palladium. Filtration and evaporation to dryness afforded a crude solid, which was crystallized from diethyl ether/hexane (1:1) to yield 95% of 114.

II

CH3 F EtO N Br H 113

SnBu3

catPd(Ph3P)4,95%

Scheme 54. The Stille reaction using (l-ethoxyvinyl)tributyltin

496

JJ.U

7.4. l-(te^.Butyldiinethylsilyl)-3-(2-pyridyl)indole (145a) [71] A solution of f-BuLi (1.7 M in pentane, 2.0 cquiv.) was slowly added to a 0.8 M solution of 3bromo-l-(terr-butyldimethylsilyl)indole (143) (2.0 g, 6.6 mmol) in anhydrous THF at -78 °C, and the resulting mixture was stirred for 10 min at this temperature. Then, a 0.3S M solution of ZnCl2 (1.1 equiv.) in THF was added to this solution, and the stirring was continued for 30 min at 25 °C to give 3-indolozinc 144. In a separates flask, a 0.54 M solution of 2-chloropyridine (141a) in anhydrous THF was added to 2 mol% of a catalyst prepared by reaction of a 0.014 M solution of Pd(Ph3P)2Cl2 in anhydrous THF with 2 equiv. of diisobutylaluminum hydride (1.0 M in hexane), and the mixture was stirred at 25 °C for 5 min. The resulting mixture was transferred via cannula to the solution of indolylzinc chloride 144 (1.5 equiv.) prepared as described above, and the solution was heated at reflux for 4 h, cooled and poured into saturated aqueous NajCO,. The aqueous phase was extracted with ether, and the organic extracts were dried and concentrated. The residue was chromatographed (CH2CI2) to afford 145a (1.1 g, 80%), along with l,T-bis(rer/butyldimethylsilyl)-3,3'-bisindole (200 mg, 13%), the homo-coupling product.

ca

B r

Z n C I

^ ^

1. /-BuLi, THF, -78 °C -»2. ZnCl2, THF, 25 °C

\ \ \

? Sif-BuMe2 144

Si/-BuMe2 143

TOPdCI2(Ph3P)2, DIBAL THF, reflux, 80%

if

OrO Me2*-BuSi 145a

Scheme 55. The Negishi reaction of 3-indolozinc with 2-chloropyridine 7.5.

4-(3-Methyl-2-buten-3-ol)-3-(2-acetylamido-2-carbomethoxyethen-l-yl)-l-tosylindole

(164) [80] A mixture of 3-[2-acetylamido-2-carbomethoxyethen-l-yl]-4-bromo-l-tosylindole (163) (0.219 g, 0.446 mmol), 2-methyl-3-buten-2-ol (0.171g, 2.0 mmol, 4.5 equiv.), palladium(II) acetate (0.008 g, 8 mol%), tri-0-tolylphosphine (0.027 g, 20 mol%), and triethylamine (0.068 g, 0.67 mmol, 1.5

Applications of Palladium Chemistry

497

equiv.) in 0.5 mL of acetonitrilc was heated at 100 °C in a sealed tube for 5 h. The mixture was cooled to room temperature, dissolved in 50 mL of dichloromethane, and filtered through Celite. The filtrate was evaporated under reduced pressure, leaving 0.36 g of a yellow oil which was purified by radial chromatography on silica gel. Hexane-ethyl acetate (1:1) eluted tri-otolylphosphine and Hexane-ethyl acetate (1:2) eluted the product. Evaporation of the solvent gave 0.184 g (83%) of 164 as a white solid. Recrystallization from hexane-ethyl acetate furnished the analytical sample.

AcHN^CC^Me ^

O

T

H

5% Pd(OAc)2/Et3N P(o-ToI)3/MeCN 83% 163

154

Scheme 56. Phosphine ligands can facilitate the Heck reaction of aryl bromides 7.6. The ferr-butyldimethylsilyl ether of isostrychnine (200) (92] A catalytic amount of Pd(OAc)2 (8.1 mg, 0.037 mmol) was added at room temperature to a mixture of vinyl iodide 199 (101 mg, 0.18 mmol), K^CO, (124 mg, 0.90 mmol) and n-Bu4NCl (75 mg, 0.27 mmol) in DMF (10 mL). The mixture was stirred at 70 °C for 3 h. The dark brown solution was cooled to room temperature, diluted with water, and extracted four times with ether. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography over silica gel (elution with 30% ethyl acetate in hexane) to afford the TBS ether of isostrychnine 200 as a colorless oil (60 mg, 74% yield).

OTBS 0.3 eq. Pd(OAc)2 >, Bu 4 NCl,DMF,K 2 C0 3 70°C,3h,74% OTBS 199 Scheme 57. Intramolecular Heck cyclization in Rawal's strychnine synthesis

200

498

JJ. Li

7.7. (4J?^J7)-4-Nitro-5-vinyl-l>39495-tetrahydrobenz[c>if]indole (251) [113] A mixture of K^CO, (9.58 g, 69.4 mmol)f Pd(OAc)2 (0.187 g, 0.83 mmol) and (5)-(-)-BINAP (1.048 g, 1.66 mmol) in dry THF (30 mL) was stirred at room temperature under argon. The mixture turned from light orange to dark red. A solution of (£)-3-[(2-nitroethyl)-4-indolyl]propenyl acetate 250 (8 g, 27.7 mmol) in dry THF (60 mL) was added dropwise, then stirred for 6 h. The reaction was filtered through silica gel, and the crude residue was washed with THF. The solvent was removed under reduced pressure. Flash chromatography (AcOEt/cyclohexane:l/9) yielded the titled product 251 as a white solid (3.6 g, 57%).

.OAc

N0 2

N02

Pd(OAc)2,3%, (5)-(-)-BIBAP,6% 1

K 2 C0 3 , THF rt,57% 250 Scheme 58. The Tsuji-Trost reaction in the synthesis of (-)-chanoclavine 7.8.

l-Carbomethoxy-5-methoxy-5-methyl-l,3,4,5-tetrahydropyrrolo[4,3,2-Je]quinoline

(277)[122J

To a mixture of 5-methoxy-4-iodo-3-(2-methylamino-ethyl)-l-carboethoxy-indole (276) (0.32 g, 0.80 mmol), Et,N (4 mL), and K^CO, (0.33 g, 2.4 mmol) in toluene (10 mL) was added Pd(Ph,P)4. The yellow mixture was heated to 200 °C for 15 h, cooled to room temperature, and poured into a separatory funnel containing Et^O (15 mL) and water (15 mL). The organic layer was washed with water (10 mL) and brine (10 mL), dried over MgS04, and filtered, and the solvents were removed using a rotary evaporator. The product was purified by flash chromatography (4:1 hexane/ethyl acetate) to give the desired product 277 as a white powder (0.18 g, 82% yield).

NHMe

Me. 10mol%Pd(Ph3P)4

MeQ

K2C03,Et3N,tol, 200°C,81% 276 Scheme 59. Pd(0)-catalyzed intramolecular C-N bond formation

277

Applications of Palladium Chemistry

8.

499

CONCLUDING REMARKS

The maturation of palladium chemistry in organic synthesis has resulted in many applications to the total syntheses of naturally occurring indole alkaloids. Oxidative cyclization using Pd(II) is an efficient strategy for intramolecular aryl-aryl coupling. The development of processes to reoxidize Pd(0) to Pd(II) by using Cu(II) species, peroxides, and other oxidants, enables this transformation to be conducted with economy using catalytic palladium as manifested in Knttlker's synthesis of carbamycins. The Suzuki and the Stille reactions, in turn, are the two most popular methods for palladium-promoted coupling in indole alkaloid synthesis. Since the Suzuki reaction requires basic conditions to enable the transmetallation step, the Stille reaction is the method of choice for base sensitive substrates. Negishi's conditions can be applied to otherwise difficult substrates such as arylchlorides. On many occasions, the organozinc reagents react chemoselectively in the presence of organoboronic acids, providing a handle for further manipulations of the reaction products. However, due to the demanding reaction conditions to prepare organozinc reagents, limited success has been achieved in the application to indole alkaloid synthesis. Even though only limited applications of the intermolecular Heck reaction have been found in indole alkaloid synthesis, the intramolecular Heck reaction is a versatile strategy for C-C bond formation. The recipients for migratory insertion can be a double bond, a dicne, or an aromatic ring. The reaction generally proceeds with high regioselectivity. High stereoselectivities were also obtained when the substrates possess steric bias, as manifested in Rawal's strychnine synthesis. Quaternary carbon centers can be constructed via intramolecular Heck reactions, sometimes asymmetrically by using appropriate substrates or chiral ligands. In the total synthesis of naturally occurring indole alkaloids, applications of ft-allylpalladium intermediate and C-N bond formation are developing areas [126]. With the advent of new methodologies in these fields, especially with the successes of the Buchwald and Hart wig's chemistry, more syntheses using those strategies are to be expected. ACKNOWLEDGMENTS The author is indebted to Drs. Martin A. Berliner, Michael D. Kaufman, and Jessica E. Reed for proofreading the manuscript. Helpful comments and suggestions from Profs. Louis S. Hegedus, Viresh H. Rawal and Christian M. Rojas are greatly appreciated. 9. REFERENCES: 1.

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