Synthesis of Cembranoid Natural Products by Intramolecular SE′ Additions of Allylic Stannanes to Ynals

Chapter 9

SYNTHESIS OF CEMBRANOID NATURAL PRODUCTS BY INTRAMOLECULAR SE' ADDITIONS OF ALLYLIC STANNANES TO YNALS James A. Marshall Department of Chemistry The University of South Carolina Columbia, South Carolina

I. II. III. IV. V. VI. VII.

VIII.

I.

Introduction Preliminary S t u d i e s — S E ' Additions and H o r n e r - E m m o n s Condensations . . . a-(Alkoxy)allyl Stannanes—Efficient S E ' Partners in Cyclizations Leading to Cembranoids Elaboration of the C e m b r a n o i d System—Synthesis of a Racemic Cembranolide Optically Active a-(Alkoxy)allyl S t a n n a n e s — P r e p a r a t i o n and S E ' Chemistry A Stereorational and Highly Enantioselective Cembranolide Synthesis Extensions, D i s a p p o i n t m e n t s , and Pleasant Surprises A. Remote Diastereocontrol B. Applications to O t h e r Ring S i z e s — A n Unexpected Isomerization Summary References

347 349 355 359 362 366 369 369 373 377 378

Introduction

The family of diterpenes now known as "cembranes" was formalized in 1962 following structure elucidation of the hydrocarbon cembrene (I) from pine oleoresins, 1 ' 2 and the diols I I and I I I (stereochemistry unassigned) from tobacco. 3 In the intervening years STRATEGIES AND TACTICS IN ORGANIC SYNTHESIS, VOL. 3

347

Copyright © 1991 by Academic Press, Inc. All rights of reproduction in any form reserved.

348

JAMES A. MARSHALL

hundreds of cembranes have been isolated, mainly from three sourcestobacco, Caribbean gorgonians, and Pacific soft corals. Cembranes are the most widely occurring diterpenes in Nature. 4 ' 5 Some representative examples are depicted in Figure l . 6 - 1 1 In general, the lactonic cembranes come from marine sources. A range of biological activities has been reported for cembranes. Most of the marine derived compounds are highly toxic to fish suggesting that they serve as chemical deterrents against predators for their otherwise defenseless host organisms. T h e tobacco cembranoids a and jß-CBT are effective inhibitors of tumor promotion and most α-methylene lactonic cembranes are potent cytotoxic agents. 12 In the late 1970s we became interested in cembranes as synthetic targets. W e were intrigued by their novel structures and diverse OH ,

II a-CBT 3 ' 6

I Cembrene *'

OH

III ß-CBT3'

r ei>r Λχ -γ .φ:Γ

IV Anisomelic Acid7

VII No Name 10 Lobophytum michaelae

V Lobohedleolide0

VI Isolobophytolide

VIII No Name 1 J

IX No Name 11

Efflantounaria variabilis FIG. 1.

Representative Cembrane diterpenes.

9

SYNTHESIS OF CEMBRANOID NATURAL PRODUCTS

349

biological profiles. 12 ' 13 Furthermore, the general area of macrocyclic synthesis seemed ripe for exploration. 1 3 O u r then current work on the chemistry of betweenanenes had enhanced our awareness of the unique conformational properties of (i?)-cycloalkenes. Thus, we viewed the cembrane ring system, with multiple (E)-double bonds, as a potentially rigid array having well-defined conformations. We planned to develop strategies based on acyclic stereocontrol to assemble likely precursors and then utilize macrocyclic conformational analysis, with the help of molecular modeling, to guide further manipulations of cyclic intermediates. 1 4 O n e of our foremost considerations was devising suitable methodology for closure of the 14-membered ring. 13 A number of different approaches were examined and considerable effort was invested in fashioning stereochemically unambiguous routes to suitable acyclic precursors. T h e methodology to be discussed in this chapter evolved from a planned synthesis of lobohedleolide (V) initiated in 1983 with graduate student Brad DeHoff. II.

Preliminary Studies—S E ' Additions and Horner-Emmons Condensations

The plan, as outlined in Figure 2, was appealing because it offered two ring closure options, both involving strategic bond formation. Furthermore, literature precedent could be found for both cyclizations. Thus, Stork 15 and Nicolaou 1 6 had just established the viability of the intramolecular Horner-Emmons reaction, at least for the formation of macrocyclic lactones, in support of X I —> X. Precedent for the alternative cyclization, X I I —> X, could be found in Still's ingenious synthesis of asperdiol, published that same year, in which an in situ generated allychromium species underwent smooth intramolecular S E ' addition to an enal moiety. 17 An additional attractive feature of our plan was its modularity, requiring only two closely related subunits X I I I / X I V and X V / X V I . After considering various options for M in X I I or XV, we chose the Bu 3 Sn derivative for the following reasons: (1) allyl stannanes were known to be stable isolable intermediates, 1 8 (2) Lewis-acid promoted additions of allyl stannanes to aldehydes were known to proceed under mild conditions and in high yield, 19 (3) BF 3 -catalyzed additions were known to be highly syn selective, independent of double bond geometry, 19 and (4) additions leading to anti products could be effected through in situ transmetallation of the allyl stannane with

350

JAMES A. MARSHALL

V Lobohedleolide

Zy-C02R

eb

/""

XI Z = PO(OR)2

U

XV

XII

n

XVI Z = PO(OR)2 FIG. 2.

Synthetic plan for lobohedleolide.

9

351

SYNTHESIS OF CEMBRANOID NATURAL PRODUCTS

TiCl 4 . 2 0 This last point was of interest for the synthesis of trans fused cembranolides such as anisomelic acid (IV). 7 We initiated our investigations with a series of model studies designed to probe the applicability of allyl stannane additions to aldehydes similar in structure to our intended application. We felt this was necessary because prior examples of these additions had employed relatively simple reaction partners. 1 9 We selected allyl stannane 2, easily prepared from the ally lie alcohol 1 by the method of Ueno et al.> as our model system (Eq. I). 2 1 BF 3 promoted addition of this stannane to /ra^-crotonaldehyde (3) proceeded readily affording a 9 0 : 10 -SnBu-, (1) 2

TBSO —/

·

Bu

3SnH'

MBN

>

C

6H6

T B S 0

.

mixture of syn and anti products 4 and 5 (Eq. 2). The TiCl 4 -promoted addition yielded the same two adducts with the anti isomer 5 predominating 95 : 5. 2 2 T h e lower yield of the latter addition may result from partial cleavage of the O T B S group by the Lewis acid.

(2) TBSO

Conditions

Yield

4:5

1.1 eq BF 3 -OEt 2 , CH2C12, -78°C

73%

90:10

1.1 eq T1CI4/2 followed by 3, -78°C

47%

5:95

Surprisingly, the seemingly trivial extension of this addition to the /3,/3-disubstituted aldehydes 6 and 7 failed completely (Eq. 3). At — 78°C, even with a large excess of BF 3 · O E t 2 and long reaction times, only starting materials were recovered. At temperatures between — 30°C and 0°C, decomposition of the reactants was observed. These results were quite discouraging and could well have signaled the end of this approach and possibly our involvement with allylstannane chemistry. However, my co-worker Brad DeHoff decided to

352

JAMES A. MARSHALL

Me

H (3)

2 6 R = (CH2)3OTBS

TBSO

7 R = (CH2)2CH=CMe2 Conditions

Result

2 - 10 eq. BF3-OEt2, CH2C12, -78°C to -30°C

no reaction

2 - 10 eq. BF3*OEt2, CH2C12, -30° to 0°C

decomposition

e x a m i n e a c e t y l e n i c a l d e h y d e 9 as t h e e l e c t r o p h i l i c p a r t n e r ( E q . 4 ) . T h i s a d d i t i o n w a s e x t r e m e l y r a p i d giving rise to m a i n l y syn or anti a d d u c t 1 0 or 1 1 , d e p e n d i n g u p o n r e a c t i o n c o n d i t i o n s .

&

TBSO^

A

(4) TBSO

Conditions

TBSO

TBSO

Yield

1.1 eq. BF 3 .OEt 2 , CH2C12, -78°C 81% 1.1 eq. T1CI4/2 followed by 9, CH2C12, -78° 60%

10:11 90:10 5:95

I n t e r e s t i n g l y , t h e j8-iodo e n a l 12 afforded t h e a d d u c t s 1 3 a n d 14 w i t h allyl s t a n n a n e 2 ( E q . 5 ) . T h u s , jß-substituents per se d o n o t disfavor t h e a d d i t i o n .

I

OTBS

H

12 TBSO 14

13 Conditions 1.1 eq. BF3.OEt2, CH2C12, -78°C

Yield 57%

13:14 75:25

9

353

SYNTHESIS OF CEMBRANOID NATURAL PRODUCTS

The unreactivity of aldehydes 6 and 7 relative to 3, 9 and 12 may stem from inductive stabilization of the aldehyde-BF 3 complex A by R1

R1

H

H A

H

κΛΛο7^3

BF,

Stability 1

R = alkyl > R 1 = H or I

the second /3-alkyl substituent in the former leading to decreased electrophilic character. In any case, success with aldehydes 9 and 12 revived our approach, as the adducts obtained from these enals could be converted to the requisite jS-methyl compounds by known methodology, as illustrated in Eq. 6.

PH II 1. Red-A1,THF 2. I2orNIS

10 R = TBS 15 R = Bn

(6)

13 R = TBS 16 R = Bn

8 R = TBS 17 R: Bn

Although the foregoing results showed promise, we temporarily turned our attention from allylstannane chemistry to investigate an ongoing parallel strategy utilizing condensations of a-(alkoxy)allyl titanium reagents, as reported by Hoppe and co-workers, to construct a precursor such as XI(Figure 2). 2 3 Hoppe found that allylic carbamates X V I I can be Hthiated with n-BuLi and then treated with Ti(Oi-Pr) 3 to afford transient allyl Ti species X I X which react in situ with aldehydes to afford mainly anti products X X (Eq. 7).

Λ XVII R = alkyl, Rz = i-Pr 1

OH OCb NR2,

1. BuLi, TMEDA * - R1 OCb 2. XTi(0-i-Pr)3 Cb = CON(i-Pr)2 XVIII M = Li XIX M = Ti(0-i-Pr)3

(7) R1 XX

354

JAMES A. MARSHALL

In view of the conditions required to obtain the allyl titanium intermediate X I X , we felt that intramolecular applications of the Hoppe reaction would not succeed. We therefore decided to utilize Hoppe's allyl titanium methodology to couple fragment X X I with X I I I and carry out the ensuing ring closure by intramolecular Horner-Emmons condensation. T h e known anti diastereoselectivity of the Hoppe addition made anisomelic acid (IV) the ideal synthetic target. O u r approach is illustrated in Figure 3. The synthesis was achieved according to plan as shown in Scheme l. 2 4 Not surprisingly, the key cyclization step 22—»23, the first of its kind for cembrane synthesis, was found to be concentration dependent. At 0.004 M as much as 2 7 % of a cyclic dimer (28-membered ring!) was formed in addition to 4 2 % of the desired product 2 3 . Under optimized conditions 23 could be obtained in 7 1 % yield. Interestingly, the cyclization led to a 9 : 1 mixture of conjugated esters favoring the (Z)-isomer 2 3 . The analogous intermolecular Horner-Emmons condensation gave mainly the (E) -product by an 8 5 : 15 preference. 25 Evidently conformational factors exert a major

1

OH

OCb

XXII

gpr IV Anisomelic Acid

XXIII FIG. 3.

Synthetic plan for anisomelic acid (IV).

9

355

SYNTHESIS OF CEMBRANOID NATURAL PRODUCTS

PH OCb see eg. ^

OTBS OCb

v

\ OTBS

V V-

V

1. LiAlH4 2. HC(OMe)3 PPTS

19

V^OMe 1. Siam2BH;OOH"

Y^ OTBS

V-

y

2. Ph 3 P,I 2 ,Im 3. ZCH2C02Me, NaH (Z = (MeO)2PO)

1. MeOH.PPTS 2. Swern

20

V-^OMe / (MeO) 2 P-T—C0 2 Me

/"

1. DBU, LiCl, CH3CN 2. PPTS,H 2 0 3. PCC

23 R1 = Me, R2 = H2 IV R1 = H, R2 = CH2

22 S C H E M E 1.

T o t a l synthesis of (±)-anisomelic acid.

influence on the stereochemistry of the condensation. This turns out to be an important general phenomenon but, because of current limitations in transition state modeling, it is one that is difficult to predict. We shall encounter other examples as our story proceeds. III. a-(Alkoxy)allyl Stannanes—Efficient SE' Partners in Cyclizations Leading to Cembranoids The foregoing synthesis, though relatively efficient and straightforward, suffers from a number of drawbacks as a general strategy. Foremost, the Horner-Emmons cyclization does not readily accommodate the vast majority of cembranolide natural products with a C 8 - C H 3 substituent. Furthermore, the route is not readily amenable to the synthesis of optically active cembranes. As a possible solution to both problems we turned to a modified version of our

356

JAMES A. MARSHALL

initial plan in which cyclization would be effected with an a(alkoxy)allyl stannane (Figure 4). This plan offers several important advantages over our initial one. Foremost, it opens up the possibility for asymmetric synthesis by virtue of the stereogenic (starred) a-(alkoxy) center in the stannane precursor X X I V or X X V I . In addition, the oxidation state of the enol ether side chain is more closely matched to that of the eventual lactone target. α-Hydroxy stannanes are readily prepared by the method of Still. 26 Thomas was able to resolve the hydroxy stannane derived from crotonaldehyde by separation of the diastereomeric 0-(menthyl)oxymethyl ethers. He utilized these stannanes in highly stereoselective thermal additions to aldehydes leading to 5-(alkoxy)homoallylic alcohols (Eq. 8). 2 7 However, such additions had not been attempted under Lewis acid catalysis. Accordingly, we began our investigations with some model studies. 2 8

XXVI

X X V I I R2 = I X X V I I I R 2 = CH 3

FIG. 4. Cembranolide synthesis by intramolecular S E ' addition of a-(alkoxy)allyl stannanes to aldehydes.

9

357

SYNTHESIS OF CEMBRANOID NATURAL PRODUCTS

OH ,SnBu3

RCHO

O^^OMen

130°C

XXX Men = (-)-menthyl

(8)

,OMen

(X

XXXI a R = Ph (70-80%) b R = c-C6Hn(80%) c R = PhCH=CH (68%)

Addition of the racemic a-(alkoxy)crotyl stannane 25 to enal 24 was not successful under thermal or Lewis acid conditions. In the former case prolonged heating caused decomposition of the reactants. With B F 3 O E t 2 , starting aldehyde was recovered after extended treatment at —78 to — 30°C while higher temperatures caused decomposition (Eq. 9). Recalling our earlier experience with allyl stannane

ΟΜΟΜ

(9) OTBS 24

2, we carried out the same reactions on acetylenic aldehyde 27. Both additions were successfully achieved. The thermal reaction, complete within 5 minutes, gave a 1 : 1 mixture of syn and anti diastereomers 28 and 29 (Eq. 10). T h e BF 3 reaction was also facile. Addition took place

OTBS

OTBS 25 OTBS

29

28 H

//— OMOM UMU

OTBS

OTBS

~f..r 31

30 Conditions

(10) OH

OH

27

140°C,5min BF3»OEt2, CH2C12,-78°C, 1 h

--c>

OMOM

OH OMOM

28

29

45% 35%

55% 15%

30 35%

31 15%

svn:anti 45:55 70:30

OMOM

358

J A M E S A. M A R S H A L L

at —78° within 1 hour leading to the four isomeric products 28—31 in high yield. Although the ease of the foregoing additions to ynal 27 was highly encouraging, the poor stereoselectivity was of some concern. However, we felt that conformational factors would play the major role in controlling the stereochemistry of the intramolecular addition, as was the case with the Horner-Emmons cyclization (Scheme 1). We therefore set this concern aside and proceeded to the next stage of our investigation. An appropriate cyclization precursor was prepared by Brad DeHoff and postdoctoral collaborator Stephen Crooks, as shown in Scheme 2, starting from the readily available tetrahydropyranyl (THP) ether of geraniol (32). 28 Highly selective allylic oxidation followed by bromide formation, cyanomethylcopper 2 9 homologation and nitrile reduction led to aldehyde 34. Horner-Emmons condensation, then T H P

v. "OTHP >L_

{Τ^ΟΤΗΡ \ _ /

W'

l.SeO^TBHP 2. NBS, Me2S

1. CuCH2CN 2. DIBAH:

r. uinr \ _

n \

Q

h

Ph

Ρ-ΓΗΓΠ Μ , 3P=CHC0 2 Me

COjMe

2. EtMgBr, Cul; TEPSOCCH2MgBr

2. TBAF; LDA, CH 2 0 3. ί-BuOMgBr, ADD

OH OMOM SnBu

3

BF 3 OEt 2 CH2C12, -78^C

OH OMOM Red-Al; NIS*

SCHEME 2. Synthesis of the cembrane skeleton by intramolecular S E ' addition of an a(alkoxy)allyl stannane to an ynal.

9

SYNTHESIS OF CEMBRANOID NATURAL PRODUCTS

359

ether cleavage, and allylic chloride formation afforded 35 which was reduced and coupled as the magnesium alkoxide with the triisopropylsilyl (TIPS) protected propargylmagnesio cuprate to give the alcohol 36. T h e T I P S grouping sterically prevents S N ' coupling at the propargylic triple bond. 3 0 Significant amounts of allenic byproducts were formed when the unprotected propargylic cuprate was used in this step. Desilylation and oxidation led to aldehyde 37 which was readily converted to the alcohol precursor of allyl stannane aldehyde 38. However, oxidation of that alcohol proved quite problematical. Cr(VI) reagents caused complete decomposition of the stannane moiety and Swern oxidation proceeded in low yield. Denmark 3 1 found the Mukaiyama protocol employing l,l'-(azodicarbonyl)dipiperidine (ADD) 3 2 to be effective for oxidations of alcohols containing allylic stannane groupings. This methodology served admirably for the production of aldehyde 38 ( 8 1 % yield). Cyclization of this ynal was readily effected by BF 3 · O E t 2 at — 78°C to give an 88 : 12 mixture of racemic syn and anti alcohols 40 and 39 in 8 8 % yield. This cyclization is one of the most efficient yet reported for cembranoid systems. 13

IV.

Elaboration of the Cembranoid System—Synthesis of a Racemic Cembranolide

At this point our goal seemed assured as we had only to apply the hydroalanation-iodination-methylation sequence, 3 3 as in our model system (Eq. 6), to reach the cembrane carbon skeleton and then perform the straightforward conversion of the 5-(alkoxy)homoallylic alcohol array to a fused γ-lactone. Unfortunately, we underestimated the nucleophilic reactivity of the enol ether double bond. Hydroalanation of the alkyne proceeded readily, as evidenced by the conversion of propargylic alcohol 4 0 to the (E) -allylic alcohol 4 1 upon treatment with Red-Al® followed by aqueous quench. However, iodination of the intermediate alanate with I 2 or N-iodosuccinimide (NIS) gave the vinyl iodide 42 in only 15% yield. A mixture of products 4 3 arising from iodoetherification of the enol ether double bond accounted for the remainder of the material. Moreover, treatment of the purified vinyl iodide 42 with Me 2 CuLi gave none of the desired methylated product 4 4 even with a tenfold excess of cuprate.

360

JAMES A. MARSHALL

The apparent unreactivity of iodide 42 forced us to devise an alternative means for methylation of alkyne 4 0 . It also gave us an opportunity to examine conformationally directed reactions in macrocarbocyclics, one of the initial goals of our cembrane program. To that end, the mixture of syn and anti alcohols 4 0 and 3 9 was oxidized to ketone 4 5 . Addition of M ^ C u L i afforded a nearly 1 : 1 mixture of (Z) and (E) 1,4-adducts 4 6 and 4 7 (Scheme 3). 3 4 Molecular mechanics calculations indicated that the (E) isomer 4 7 should be of lower energy. 14 In fact, equilibration of the mixture with LiS(t-Pr),THF

SCHEME 3. Final methylation-reduction sequence leading to (±)-cembranolide 52.

9

SYNTHESIS OF CEMBRANOID NATURAL PRODUCTS

361

LiS-iPr in T H F afforded the (E) isomer 47 exclusively. Reduction of ketone 4 7 with L-Selectride gave a single diastereomeric alcohol 4 8 . Molecular mechanics calculations show that the local environment of the ketonic grouping in 47 is similar for the major low energy conformers and conducive to stereoselective additions of nucleophiles. At the threshold of our objective, we were once again diverted by a subtle unforeseen neighboring group effect. Thus, acidic hydrolysis of the enol ether 4 8 and subsequent oxidation of the intermediate lactols afforded varying mixtures of trans and eis lactones 4 9 and 50 even though the starting alcohol 4 8 was stereochemically homogeneous. Evidently, the allylic alcohol, or the derived lactol, is prone to solvolytic dissociation with possible participation by a side chain oxygen substituent (Eq. 11).

In order to avoid this unwanted epimerization, we effected enol ether hydrolysis at the ketone stage. Subsequent oxidation of the resulting keto aldehyde and esterification of the derived acid with C H 2 N 2 gave the keto ester 5 1 . Reduction with N a B H 4 was stereoselective producing a 9 : 1 mixture of the eis and trans-lactonts 50 and 4 9 directly. Stereochemistry was readily assigned from the characteristic chemical shift and Rvalues of the carbinyl protons (Table I). Interestingly, the reductions of ketones 47 and 51 show opposite stereoselectivity. This unexpected result must reflect subtle conformational differences between the two as reduction of ketone 47 with N a B H 4 afforded a 1 : 1 mixture of epimeric alcohols.

362

JAMES A. MARSHALL

TABLE I δΗ 2 (J2>i) FOR FUSED CEMBRANE LACTONES.

V/IV

VII/XXXII

50/49

eis

5.44 (7.5)

5.39 (7.5)

5.19 (7.0)

trans

4.86 (4.1)

4.86 (3.5)

4.70 (2.0)

Lactone 50 was hydroxymethylated by treatment with lithium diisopropylamide (LDA) and formaldehyde. Dehydration of the derived hydroxymethyl lactone was effected with the water soluble diimide 1 -cyclohexyl-3- (2-morpholinoethyl) carbodiimide metho-jfrtoluenesulfonate ( M C D I ) , 3 5 affording the racemic lactone 52. Spectroscopic comparison of racemic 52 with the optically active natural product V I I confirmed their identity. V. Optically Active a-(Alkoxy)allyl Stannanes—Preparation and SE' Chemistry Although the foregoing synthesis suffered from a number of shortcomings, it showed the cyclization methodology to be highly efficient and stereoselective. Accordingly with the help of postdoctoral associate Benjamin (Wei) Gung, we turned our attention to the preparation of nonracemic a-(alkoxy)allyl stannanes hoping to synthesize optically active cembranolides. As previously noted, Thomas had prepared the optically active a-(menthyloxy)crotyl stannane X X X by etherification of the a-(hydroxy)allyl stannane with (-)-(menthyloxy)methyl chloride and separation of the diastereomeric ethers by careful column chromatography (Eq. 12). 27 We examined this approach with several alkyl homologs of X X X but were unable to separate the diastereomeric (-)-(menthyloxy)methyl ethers. We then decided to explore a route to enantioenriched α-hydroxy stannanes by asymmetric synthesis, thus bypassing an intrinsically inefficient optical resolution.

9

363

SYNTHESIS OF CEMBRANOID NATURAL PRODUCTS

\^γ 3

0

H

i. LiSnBu3 2. (-)-MenOCH2Cl

(12)

XXX

The preparation of optically active alcohols by reduction of ketones with chiral hydride reagents is well known. 3 6 Furthermore, a selection of such reagents is available for the synthesis of both (S) and (/?) alcohols. It therefore seemed reasonable to apply this methodology to an acyl stannane such as 5 5 (Eq. 13).

OH

0 SnBu3

5 4 , R = Bu

►

R^Ai

R ^ ^ V ^ ^SnBu3

►

or

γ^

( 1 3 )

55

O u r first task was to develop a general route to acyl stannanes. These compounds were virtually unknown at the onset of our work and published routes to the few examples were not well suited to our purpose. 3 7 A seemingly straightforward b u t previously unexplored approach through oxidation of readily available α-hydroxy stannanes such as 54, was appealing in its simplicity. However, the instability of α-hydroxy stannanes to acid and base and the lability of the acyl stannane products to further oxidation caused complications. A number of the more common oxidizing agents for alcohols were examined but none was suitable. Recalling our problems with oxidation of the (alkoxy)allyl stannane alcohol precursor of aldehyde 38, we turned to the Mukaiyama reagent /-BuOMgBr—ADD. 32 T h e results were highly promising. W e eventually developed a one-step protocol in which the lithio (alkoxy)allyl stannane adduct was directly treated with ADD thereby circumventing isolation of the unstable hydroxy stannane intermediate (Eq. 14). Reduction of the acyl stannane 5 5 was readily effected with Noyori's (S) and (Ä)-BINAL-H reagents. 3 8 I n each case hydroxy

364

JAMES A. MARSHALL

on LiSnBiH

SnBu ADD

THF

Χ ^ ^V*

58

(14)

55

stannane 56 or 57 of > 9 0 % ee was obtained. The configuration of these α-hydroxy stannanes was surmised from the characteristic chemical shift differences of the vinylic protons in the *H N M R spectra of the (5)-a-(methoxy)phenylacetic ester derivatives. 39 In addition, the (S)-isomer 56 was converted to (£)-2-octanol (61) of high enantiomeric excess (ee) along the lines of Thomas by the sequence outlined in Scheme 4. 2 7 It is well established that a-(alkoxy)alkyl stannanes can be lithiated with retention of configuration and the derived lithio species are configurationally stable. 4 0 We found that reduction of acyl stannane 55 with (/?)-( + )BINAL-H affords the (S)-carbinol 56. This outcome was contrary to prediction based on Noyori's findings that enones are converted to (Ä)-carbinols by the (R) reagent. 3 8 The disparity can be attributed to chelation between the Bu 3 Sn and alkoxy ligand of the BINAL-H reagent in the transition state E as illustrated in Figure 5. Noyori postulates that, for vinylic ketones, transition state D with an axial R 2 and an equatorial vinyl group is favored over the epimeric axial vinyl/equatorial R 2 arrangement because of electronic repulsion between an axial vinyl grouping and the unshared electron pair on the BINAL oxygen in the latter. T h e alternative (flipped) chair with axial R 2 /equatorial vinyl suffers from steric interactions between R 2 and one of the napthalene rings of the BINAL ligand. In our case, transi-

O OH O OBn M (*H+)-BINAL-H U ?nOCH ? q I BiT " ^ V ^ ^SnBu 3 BiT ^ - ^ ^SnBu 3 ► ΒιΤ " ^ 5 ^ ^SnBu 3 55

TsNHNHg

56

O I

OBn

NaOAc* B u X V s - ^ X S n B u 3 S C H E M E 4.

BuLi, THF;

58

O JU)

(MeO)2Sc£ B u ^ ^ ^ ^ M e

OBn Na, NH3 ^

OH I

^Bu'^'^^'^Me

59 60 61 Correlation of α-hydroxy s t a n n a n e 5 6 with (£)-( + )-2-octanol (61).

9

365

SYNTHESIS OF CEMBRANOID NATURAL PRODUCTS

R2

0-^

I

T^T

Ri"

Al

D

XXXIV

Me

.Li. HO R1'

„

R l X ^ V < S(S) ) s S SnBu i 3

Bu3Sii-

E

Ae

XXXV

FIG. 5. Transition states for the reduction of unsaturated ketones and acylstannanes with (Ä)-( + )-BINAL-H.

tion state E enables the electropositive Sn to associate with the basic O M e oxygen. Addition of the (£)-a-(benzyloxy)methoxy allylic stannane 58 to the model aldehyde 2-heptynal (62) afforded four products 63—66 in 8 8 % yield (Eq. 15). In each case the relationship between the enol ether geometry and the allylic sp3 stereocenter was consistent with exclusive anti S E ' addition of the allylstannane to the aldehyde, as illustrated in Figure 6 for the adduct 64. 4 1 This finding together with our previous cyclization result virtually assured a successful outcome for our planned synthesis of enantioenriched cembranoids. Bu s

Biu OH

^

(S) (R)

l(S)

"OBn

SnBu3

BuOCCHO 62 BF 3 .OEt 2 , -78°C

(

OBOM

Bu

RN'

(S)J

Bu"

63 (51%)

.OH

J

OBOM

64 (25%) Bu

58

(S)T

.OH

OBOM

(S)

OBOM 65 (7%)

(15)

Bu" 66 (17%)

366

JAMES A. MARSHALL

Bu

BOMO H ^ ^ J - ^ ^ * ^

Bu3Sru

BOMO H^ J t ^ H (Z) I H

V

J0>

" K ^Bu OH 64

FIG. 6. Anti S E ' transition state for addition of (»^-«-(alkoxyjallyl stannane 58 to 2-heptynal (62).

VI.

A Stereorational and Highly Enantioselective Cembranolide Synthesis

Cychzation of the racemic a-(alkoxy)allyl stannane ynal 38 afforded the eis (Z) isomer 40 (Z enol ether) as the major product (Scheme 2). Thus, following an anti S E ' pathway, the (S) enantiomer of 58 would expectedly lead to the (15, 2R) isomer corresponding to 64 as the major cychzation product. The absolute configuration of our target, the unnamed cembranolide V I I , had not been established but considering its genesis from South Pacific soft coral we suspected it to be (IS*).4 We therefore reduced the acyl stannane obtained from aldehyde 37 with (R)-( + )-BINAL-H to secure the (S) a(hydroxy)allyl stannane 67 (Scheme 5). The methyloxymethyl ( M O M ) ether derivative 68 readily cyclized upon treatment with BF 3 *OEt 2 at - 7 8 ° C to a mixture of four products 6 9 - 7 2 . These could be separated by careful column chromatography and analyzed for ee and absolute configuration by means of the *H N M R spectra of the O-methyl mandelates. As expected, the double bond geometry and allylic sp3 configuration of these products show the same relationship as those of intermolecular addition (Eq. 15), consistent with an anti S E ' process. However, the ratios of products are significantly different. Thus, as previously noted, conformational constraints imposed by the connecting carbon chain profoundly influence the preferred transition state geometry. However, these constraints do not alter stereoelectronic preferences. In our previous synthesis of the racemic cembranolide 52 ({ — ) V I I ) , we converted the cychzation products to the ynone 4 5 prior to introduction of the C 4 methyl substituent by 1,4-addition (Scheme 3). In the present case we wished to preserve both of the stereocenters produced in the cychzation. We therefore elected to re-examine the Corey hydroalanation-iodination-methylation sequence for introduc-

9

367

SYNTHESIS OF CEMBRANOID NATURAL PRODUCTS

OMOM 1. M0MC1 (/-Pr)2NEtr 2. LDA,CH 2 0 3. ί-BuOMgBr, ADD

V) SnBu3

OMOM

S C H E M E 5. Stereoselective synthesis of cembranolide precursor 7 6 by S E ' cyclization of the ( l S')-a-(alkoxy)allyl s t a n n a n e ynal 6 8 .

tion of this substituent. 3 3 To avoid the disastrous iodoetherification side reaction, we converted enol ether 72 to diol 73 by hydrolysis and reduction. Diol 73 was smoothly transformed to a 7 : 1 mixture of vinyl iodide 75 and protonolysis product 74 in 8 0 % yield. Treatment of the former with Me 2 CuLi afforded the methylated product 76 in 8 5 % yield. This reaction was significantly slower than its acyclic counterpart (Eq. 6). However, in view of our failure to methylate iodide 4 2 , we were pleased with the outcome. Preliminary investigations on the conversion of diol 76 to the required γ-lactone were carried out on the protonolysis product 74 as a model system. Attempts to effect this conversion in one step by

368

JAMES A. MARSHALL

selective oxidation with various oxidizing agents were unsuccessful. We therefore explored a protecting group approach (Scheme 6). Selective silylation followed by acetylation afforded the tbutyldimethylsilyl (TBS) ether acetate 77. Removal of the TBS protecting group with tetra-n-butyl ammonium fluoride (TBAF) unexpectedly gave the primary acetate 78. Apparently the basic desilylation conditions are conducive to transacetylation. To avoid this unwelcome complication we employed the less reactive pivalate derivative 79 and effected desilylation with H F . The desired primary alcohol 80 was thereby secured in high yield. Two stage oxidation, first with pyridinium chlorochromate (PCC) then pyridinium dichromate (PDC), gave the carboxylic acid 8 1 . The foregoing sequence was next applied to diol 76 (Scheme 7). However, cleavage of the TBS ether 82, the methyl homologue of 79, with H F - C H 3 C N led not to the expected alcohol but afforded the fused tetrahydrofuran 83 instead. This product presumably arises by an assisted S N ' solvolysis of pivalate 82 (cf. B —» C, Eq. 11). The contrasting behavior of the close analogs 79 vs 82 can be attributed to enhanced inductive stabilization of the polarized transition state for the S N ' reaction by the methyl substituent of 82 (cf. A). The problem was easily circumvented. In fact, it was unnecessary to employ the pivalate grouping. T h e protected acetate 84 underwent TBS cleavage without transacetylation or furan formation upon treatment with TBAF in the presence of acetic acid. T h e alcohol 85 was subjected to OH

74

I

^

y\

77

OAc

78

1. TBSC1.DMAP 2. Me3CCOCl, C5H5N OPiv

>v

>K

.OPiv

>v

ys.

.OPiv C02H

C^Cr^- C / v t.r M t s C / H./ 79

80 S C H E M E 6.

Model studies for side chain oxidation.

81

9

SYNTHESIS OF CEMBRANOID NATURAL

^

369

PRODUCTS

y

76 1. TBSC1.DMAP - 2. Ac 2 0, C5H5N

87

88

SCHEME 7.

VII

Conversion of diol 76 to the unnamed cembranolide VII.

a two-stage oxidation to give acid 86 in 6 0 % yield. Acetate cleavage and lactonization were then carried out without isolation of the intermediate hydroxy acid. T h e final steps of the synthesis involved hydroxymethylation of the lactone 87 and dehydration via the mesylate derivative. T h e synthetic lactone VII showed a rotation of + 78° in close agreement with the value reported for the natural product. Thus, the absolute configuration is established as shown.

VII. Extensions, Disappointments, and Pleasant Surprises A.

REMOTE DIASTEREOCONTROL

In 1983 Still and Mobilio reported that the racemic epoxy enal X X X V I cyclizes upon treatment with CrCl 2 to an 8 0 : 2 0 mixture of diastereomers X X X V I I and X X X V I I I (Eq. 16). 17 This observation suggests that remote substituents can exert significant influence on

370

JAMES A. MARSHALL ^ΟΒΟΜ

^OBOM

OBOM Br

^S > CrCl2

0--\

O-J

HO

X

(16)

^>

^>

XXXVIII (20%)

XXXVII (80%)

XXXVI

diastereomeric transition states in such cyclizations. With a view toward an eventual synthesis of the unnamed epoxy cembranolides V I I I and I X , graduate student J a y Markwalder set out to examine an a-(alkoxy)allyl stannane version of the Still-Mobilio cyclization (Eq. 17). Initially we were concerned that the B F 3 # O E t 2 catalyst might promote unwanted reactions of the epoxide so we formulated our

OH OMOM

OMOM BF3-OEt2 SnBu3

XXXIX

RO

VIII or (17) IX

RO

XL

first plan around the acetonide 9 7 . This intermediate was prepared from diol 9 3 along the lines shown in Scheme 8 and Scheme 9. 42 The optically active epoxy alcohol 92 of high ee was readily secured through Sharpless kinetic resolution of allylic alcohol 90. Coupling of this epoxy alcohol with the anion derived from allylic sulfone 96 was markedly assisted by prior formation of the bromomagnesio alkoxide. 43 For our preliminary cyclization trials we employed a 1 : 1 mixture of diastereomeric alkoxy stannanes 97. Treatment with Β Ε 3 · Ο Ε ί 2 for short periods afforded a product ( ~ 5 0 % yield) with the expected spectroscopic properties but the mass spectrum showed it to be dimeric (Eq. 18). None of the monomeric cyclic product could be

9

371

SYNTHESIS OF CEMBRANOID NATURAL PRODUCTS

OMOM BF 3 OEt 2

(18)

found. We speculate that conformational constraints imposed by the acetonide ring of 97 prevent favorable alignment of the aldehyde and allylstannane moieties in the cyclization transition state. Consequently, bimolecular coupling occurs preferentially. The resultant intermediate, with its greater conformational flexibility, can attain the requisite geometry for ring closure to the 28-membered cyclic product 98. It is worth noting that a ring of this size can be so easily formed by the allylstannane methodology. Recalling our success with the unsaturated analogue of 97 (Scheme 2, 38—»39) we decided to employ the geometrically similar epoxy derivatives 102 and 104 despite misgivings about epoxide MgBr HO

TMS H

II

89 H0JSVV V / X^__ = _ T M S 91

ΗΩ

H O

90

>^V - v ^ ^_==_TMS 92

0.6 eq Ti(Q/Pr)4 ί-BuOOH, D-O-DIPT

= —TMS

H 0

OTBS -=E-TMS

· .

*· ΕίΜ^Β;

HO4—

2. 96, n-BuLi

/

-v >rx'^x/ S02Ph 1

93 TBSO.

C02Me

= \

94 Z = S0 2 Ph S C H E M E 8.

l. 03,CH2C12; C5H5N 2. Ph3P = CHCC^Me |

f = '

11. /-Bu AlH 2

_

2. TBSCl.Et^ Z

A 96

Synthesis of the diol precursor 9 3 to acetonide 9 7 and epoxide 102.

372

JAMES A. MARSHALL

stability. Accordingly, diol 9 3 was desulfonylated and converted to epoxide 99 via the secondary mesylate derivative (Scheme 9). Desilylation followed by Swern oxidation, addition of Bu 3 SnLi and in situ oxidation of the hydroxy stannane adduct with A D D afforded the keto stannane 100. Conversion to the (S)-a-(alkoxy) allyl stannane 102 was effected as previously described for the des-epoxy analogue 68 (Scheme 5). The diastereomeric (R,S,S) epoxy a-(alkoxy) ally 1 stannane aldehyde 104 was similarly prepared (Scheme 10) from the unepoxidized ally lie alcohol 91 recovered from the Sharpless resolution of racemic 90 (Scheme 8). We were pleased to find that both allylic stannanes 102 and 104 cyclized with retention of the epoxy function upon treatment with B F 3 O E t 2 at — 78°C (Figure 7). As expected the two diastereomers gave rise to different ratios of eis products indicative of a matched and mismatched pairing of stereocenters. The S, R, S isomer 102 afforded a 2.3: 1 mixture of cis-(Z) and eis-(E) products 105 and 106 in 60%

93

OTBS !· Bu4NF 2. Swern

1. Na(Hg) % 2. MsCl,C5H5N 3. BnNMe3+, OH

OMOM 1. BINAL-H 2. MOMC1 (i-Pr)2NEt

SnBil·13

2. /-BuOMgBr, ADD 102

101

S C H E M E 9. Enantioselective synthesis of the (S, R, S) alkoxy stannane epoxy aldehyde cyclization substrate 102.

H 0

^ ^

S

^ = - T M S

HO

Ti(0-/-Pr)4

\ 91

/-BuOOH, L-(+)-DIPT

S C H E M E 10. Enantioselective synthesis of the (R, S, S) alkoxy stannane epoxy aldehyde cyclization substrate 104.

9

Om

373

SYNTHESIS OF CEMBRANOID NATURAL PRODUCTS

—f

OH OMOM

OMOM ^ = s

SnBu3

= -78°C (60%)

( V—'

SnBu3

BF3-QEt2 . 7 8 oc " (71%)

0

(\

^

Λ Ί

I

J

+ tfi 108 (<2%)

^

SnBu3

J {

OH OMOM

OMOM ^

+ trans products (14%)

OH OMOM

107 (86%)

104

I,— OMOM

106 (26%)

105 (60%)

102

BF3»OEt2^ -78°C (88%)

8P · 72 (80%)

FIG. 7.

y^^—=

>«-4

~{J ♦ o'

OMOM

71 (8%)

Diastereodifferentiation in cyclizations of a-(alkoxy)allyl stannane aldehydes.

yield whereas the Ä, 5, S isomer 104 cyclized to a > 40 : 1 mixture of products 107 and 108. In comparison the unsaturated analog 68 gave the products 72 and 71 as a 10 : 1 mixture in 8 8 % yield. In all three cases trans products accounted for ca. 12-14% of the cyclized material. The lower overall yield obtained with the matched epoxy stannane 104 vs the unsaturated counterpart 68 may result from Lewis-acid promoted side reactions of the epoxide grouping. Epoxy alcohol 107 is a likely precursor for the unnamed cembranolide I X (Figure 1) following a sequence analogous to that employed for VII (Scheme 7). We have found that Mitsunobu inversion of propargylic alcohols such as 107 can be effected in high yield. 44 B. APPLICATIONS TO OTHER RING SIZES- -AN UNEXPECTED ISOMERIZATION

The remarkable efficiency of the a-(alkoxy)allyl stannane cyclization, as applied to cembranes, encouraged our examination of other ring sizes. Historically, 10-membered rings have been the most difficult to prepare. This ring system is most commonly encountered in

374

JAMES A. MARSHALL

the widespread germacrane class of terpenic natural products. Postdoctoral Benjamin (Wei) Gung began our investigations into this area with a planned synthesis of costunolide X L I I I (Eq. 19).

(19) Π 0

RO^

^SnBu 3 XLII

XLI

XLIII

O u r synthesis of the cyclization substrate X L I followed a route similar to that used for our cembranolide precursors. Selective ozonolysis of geranyl acetate (109) followed by Wittig condensation and methanolysis afforded the hydroxy ester 110 (Scheme l l ) . 4 5 Coupling 1. C^M^S 2. Ph3P=CHC02Me 3. K2C03,MeOH

OAc

QH

109

1. Bu3SnLi 2. BOMC1

EtMgBr ^

1

H

^0

113

112

OBOM

117

SCHEME 11. Synthesis of a potential germacranolide precursor, alkoxy stannane aldehyde 115, and its unexpected cyclization to the 1,2-diol derivative 116.

9

375

SYNTHESIS OF CEMBRANOID NATURAL PRODUCTS

of the derived chloride 111 with the T I P S propargyl cuprate led to dienyne 112. T h e previous sequence of desilylation, Swern oxidation, stannylation and alkyne homologation smoothly led to the requisite stannyl alkynal 115 in racemic form. Cyclization of aldehyde 115 proceeded slowly to give not the expected cyclodecynol 117, but the cyclododecynol 116 in 2 5 % yield along with unidentified decomposition products. We suspected that conformational and geometric constraints must prevent the alkoxy stannane double bond from attaining the proper alignment with the ynal carbonyl. Hence decomposition and bimolecular addition can compete with cyclization. T h e formation of cyclododecynol 116 suggested that 1,3-isomerization of the a-(alkoxy) allyl stannane had taken place and that the resulting intermediate was more favorably disposed toward ring closure (Figure 8). In support of this postulate we could isolate small amounts of the γ-(alkoxy) allyl stannane 118 after brief exposure of the a-isomer 115 to B F 3 - O E t 2 at -78°C. At this point we decided to examine the Co-complexed alkynal 120 as a possible cyclization substrate hoping that the bending of the linear alkyne linkage by the bridging Co atoms would place the

-frRO 115

SnBu3 117

SnBu3 OBOM

118

116

118-

FIG. 8. Cyclization of a-(alkoxy)allyl stannane 115 to cyclododecynol 116 via y(alkoxy)allyl stannane 118.

376

JAMES A. MARSHALL

123 SCHEME 12. Cyclization of the Co 2 (CO) 6 complex 120 of alkynal 115.

carbonyl group into more favorable juxtaposition with the allylstannane double bond. 4 6 We were uncertain as to how readily such an intermediate could be prepared and if the aldehyde carbonyl would be sufficiently reactive to undergo addition by the weakly nucleophilic allylstannane. Both concerns proved unwarranted. The propargylic alcohol 119 afforded the complex 120 in 9 5 % yield upon mixing with C o 2 ( C O ) 8 following close literature precedent. 4 7 Oxidation to the aldehyde 121 proved somewhat problematical but, happily, the Mukaiyama protocol again saved the day. 3 2 Slow addition of aldehyde 121 to a cold solution of B F 3 - O E t 2 in CH 2 C1 2 afforded a cyclization product in 70% yield. However, upon oxidative removal of the bridging Co moieties only the previously obtained alkynol 116 was obtained. Thus, bending the alkyne triple bond appears to improve the transition state geometry, but not sufficiently to allow 10-membered ring formation.

9

SYNTHESIS OF CEMBRANOID NATURAL PRODUCTS

377

Interestingly, when the foregoing sequence was repeated with (R)a-(alkoxy)allyl stannane 119 of 6 0 % ee the (S,S) product 116 of 60% ee was obtained. T h u s , the presumed 1,3-isomerization of 121 to 122 must be highly stereoselective, if not stereospecific. Although it is beyond the scope of this chapter we might mention that in subsequent studies we have found the 1,3-isomerization of a-(alkoxy)allyl stannanes to be a general reaction which can be used to prepare y-(alkoxy)allyl stannanes (Eq. 20) . 48 Contrary to our expectation, the reaction proceeds by a stereospecific intermolecular anti

R■N.V ^> -XS n B u 333 „ _ _ _ .SnBu \;^>\,' AR2 OR

XLIV

BF3«OEt2 -78°C (80-90%)

R R1^' ^ ^/ -^^

^ ^ ^ 1 cn 0R2

Bu ßU3Sn

ÜR

R3CH0

BF3-OEt2 (70-90%)

(20)

XLV = alkyl; R^ = MOM syn:anti« 85:15-95:5

process. y-(Alkoxy)allyl stannanes undergo S E ' additions to aldehydes affording monoprotected syn 1,2-diols with high stereoselectivity. This methodology, currently under investigation by co-workers Greg Welmaker and George Luke, has excellent potential for the synthesis of acyclic and cyclic polyols.

VIII.

Summary

The impetus for the research described in this chapter was to devise an efficient route to cembranoid natural products. A major goal was to develop effective strategies for the conversion of acyclic precursors to the 14-membered cembranoid system with control of relative and absolute stereochemistry. T h e a-(alkoxy)allyl stannane/ynal cyclization admirably fulfills both objectives. With this methodology the cembrane ring system is assembled efficiently and two crucial stereocenters are introduced with predictable absolute stereochemistry. Once formed, the cembranolide intermediates can be modified and additional stereocenters can be introduced stereoselectively. Of equal or greater interest, the enantioenriched a-(alkoxy)allyl stannanes undergo facile stereospecific isomerization to y-(alkoxy)allyl stannanes. These novel reagents condense with aldehydes to afford

378

JAMES A. MARSHALL

monoprotected 1,2-diols with high stereoselectivity. Furthermore, the addition can be used to form cyclic 1,2-diol derivatives. These serendipitous findings considerably extend the scope of the methodology to include cyclic and acyclic polyol natural products. References 1. 2. 3. 4.

5. 6. 7. 8. 9. 10. 11. 12.

13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25.

D a u b e n , W. G.; Thiesen, W. E.; Resnich, P. K.J. Am. Chem. Soc. 1962, 84, 2015. Kobayashi, H.; Akiyoshi, S. Bull. Chem. Soc. Japan 1 9 6 2 , 5 5 , 1044. Roberts, D. L.; Rowland, R. L. J. Org. Chem. 1962, 27, 3989. For a comprehensive review of cembrane natural products, see Weinheimer, J . A.; C h a n g , C. W . J ; Matson, J . A. Fortschritte der Chemie Organischer Naturstoffe 1979, 36, 286. Wahlberg, L; Forsblom, I.; Vogt, C ; Eklund, A-M.; Nishida, T.; Enzell, C. R.; Berg, J-E.J. Org. Chem. 1985, 50, 4527. Springer, J . P.; Clardy, J.; Cox, R. H.; Cutler, H . G.; Cole, P. J . Tetrahedron Lett. 1975, 2737. P u r u s h o t h a m a n , K.; Bhima Rao, R.; Kalyani, K. Indian J. Chem. 1 9 7 5 , 1 3 , 1357. Uchio, Y.; Toyota, J.; Nozaki, H.; Nakayama, M.; Nishizona, Y.; Hase, T. Tetrahedron Lett. 1 9 8 1 , 22, 4089. Marshall, J . A.; Andrews, R. C ; Lebioda, L. J. Org. Chem. 1987, 52, 2378. Coll, J . C ; Mitchell, S. J.; Stokie, G. J . Aust. J. Chem. 1977, 30, 1859. Bowden, B. F.; Coll, J . C ; Englehardt, L. M.; Meehan, G. V.; Pegg, G . G . ; Tapiolas, D. M.; White, A. H.; Willis, R. H . Aust. J. Chem. 1986, 39, 123. (a) Weinheimer, A . J . ; Matson, J . A. Lloydia 1979, 38, 378. (b) Weinheimer, A. J.; Matson, J . A.; van der Helm, D.; Poling, M . Tetrahedron Lett., 1977, 1295. (c) K a u l , P. N . Fourth Food and Drugs from the Sea Conference Abstracts, Marine Tech. Soc. Washington 1976, p. 299. (d) Perkins, D. L.; Ciereszko, L. S. J. Protozool. Suppl. 1970, 17, 20. (e) Ciereszko, L. S. Trans. New York Acad. Sei. 1962, 24, 502. (f) Saito, Y. et al. Carcinogenesis 1985, 6, 1189. For a recent review of cembrane synthesis, see Tius, M . Chem. Rev. 1988, 88, 719. Cf Still, W . C ; Galynker, I. Tetrahedron 1 9 8 1 , 37, 3981. Stork, G.; N a k a m u r a , E. J. Org. Chem. 1979, 44, 4010. Nicolaou, K. C ; Seitz, S.; Paiva, M . J. Am. Chem. Soc. 1982, 104, 2030. Still, W. C ; Mobilio, D. J. Org. Chem. 1983, 48, 4786. Cf. Pereyre, M.; Q u i n t a r d , J - P . ; R a h m , A. " T i n in Organic Synthesis," Butterworths, London (1987) pp. 2 1 1 - 2 3 1 . Y a m a m o t o , Y. Ace. Chem. Res. 1987,20, 243. Yamamoto, Y. Aldrichim. Acta. 1987, 20, 45. Keck, G. E.; Abbott, D. E. Tetrahedron Lett. 1984, 25, 1883. Keck, G. E.; Boden, E. P. Tetrahedron Lett. 1984, 25, 1879. Ueno, Y.; Sano, H.; O k a w a r a , M . Tetrahedron Lett. 1980, 21, 1767. Marshall, J . A.; DeHoff, B. S. J. Org. Chem. 1986, 51, 863. H o p p e , D. Angew. Chem. Int. Ed. Eng. 1984, 23, 932. Marshall, J . A.; DeHoff, B. S. Tetrahedron 1987, 43, 4849. Marshall, J . A.; DeHoff, B. S.; Clearly, D. G. J. Org. Chem. 1986, 51, 1735.

379

9

SYNTHESIS OF CEMBRANOID NATURAL PRODUCTS

26. 27. 28. 29. 30. 31. 32.

Still, W. C. J. Am. Chem. Soc. 1978, 100, 1481. J e p h c o t e , V . J . ; Pratt, A . J . ; T h o m a s , E.J.J. Chem. Soc. D. 1984, 800. Marshall, J . A.; Crooks, S. L.; DeHoff, B. S. J. Org. Chem. 1988, 53, 1616. Corey, E. J.; Kuwagima, I. Tetrahedron Lett. 1972, 487. Corey, E. J.; Rücker, C. Tetrahedron Lett. 1982, 23, 719. Denmark, S. E.; Weber, E . J . J . Am. Chem. Soc. 1984, 106, 7970. Narasaka, K.; Morikawa, A.; Sargo, K.; Mukaiyama, T. Bull. Chem. Soc. Japan 1977, 50, 2773. Cf. Corey, E. J.; Posner, G. H . J. Am. Chem. Soc. 1968, 90, 5610. Marshall, J . A.; Crooks, S. L. Tetrahedron Lett. 1987, 28, 5081. Andrews, R. C ; Marshall, J . A.; DeHoff, B. S. Synthetic Comm. 1986, 16, 1593. For a review of chiral hydrides, see Asymmetric Syntheses', Morrison, J . D., Ed.; Academic Press, 1983; Vol. 2; p p 4 5 - 1 2 2 . (a) Peddle, G. J . D. J. Organomet. Chem. 1968, 14, 139. (b) Verlhac, J . D.; Chanson, E.; J o u s s e a u m e , B.; Quintard, J . P. Tetrahedron Lett. 1985, 26, 6075. (c) Subsequently, two approaches have appeared. C h a n , P. C-M.; Chong, J . M . J. Org. Chem. 1988,55, 5586. S o d e r q u i s t J . A.; Hassner, A. Tetrahedron Lett. 1988, 29, 1899. Noyori, R.; Tomino, I.; Tanimoto, Y.; Nishizawa, M . J. Am. Chem. Soc. 1984,106, 6709. Noyori, R.; Tomino, I.; Y a m a d a , M.; Nishizawa, M . J. Am. Chem. Soc. 1984, 106, 6717. In the present work " B I N A L - H " refers to the methoxy derivative. Trost, B. M.; Belletire, J . L.; Godleski, S.; McDougal, P. G.; Balkovec, J . M.; Baldwin, J . J . ; Christy, M . E.; Ponticello, G. S.; Varga, S. L.; Springer, J . P. J . Org. Chem. 1986, 51, 2370. Cf. Still, W . C ; Sreekumar, C. J. Am. Chem. Soc. 1980, 102, 1201. Hutchinson, D. K.; Fuchs, P. L.J. Am. Chem. Soc. 1987,109, 4930 and references cited therein. Marshall, J . A.; Gung, W. Y. Tetrahedron 1989, 45, 1043. Marshall, J . A.; Markwalder, J . A. Tetrahedron Lett. 1988, 29, 4811. Marshall, J . A.; Andrews, R. C. J. Org. Chem. 1985, 50, 1602. Marshall, J . A.; Lebreton, J . J. Am. Chem. Soc. 1988, 110, 2925. Marshall, J . A.; Gung, W . Y. Tetrahedron Lett. 1989, 30, 309. For a prior application of this concept see Schreiber, S. L.; Sammakia, T.; Crow, W. E. J. Am. Chem. Soc. 1986, 108, 3128. M a g n u s , P.; Lewis, R. T.; Huffman, J . C. J. Am. Chem. Soc. 1988, 110, 6921 and ref. 47. Nicholas, K. M . Ace. Chem. Res. 1987, 20, 207. Marshall, J . A.; Gung, W . Y. Tetrahedron Lett. 1989, 30, 2183.

33. 34. 35. 36. 37.

38.

39.

40. 41. 42. 43. 44. 45. 46.

47. 48.