Chapter 3 Three-membered ring systems

Chapter 3 Three-Membered Ring Systems ALBERT PADWA Emory University, Atlanta, GA, USA and

S. SHAUN MURPHREE Miles Inc., Charleston, SC, USA 3.1

INTRODUCTION

Thrce-membered ring systems encompass the smallest of heterocycles, but by no means the least active. Indeed, these compounds are extremely valuable substrates for the organic chemist, as versatile synthetic intermediates or as reagents with unique selectivity. A yearly review chapter in PHC clearly can not be comprehensive in covering the progress in this highly active field. The following pages are meant to provide a sampling of highlights extracted from the year's literature representing significant and novel transformations, particularly those of interest to heterocyclic chemists. The organization of the review follows that of previous years.

3.2 3.2.1

EPOXIDES Preparation of Epoxides

Since epoxides are valuable intermediates for the synthesis of natural products and other bioactive compounds, recent literature shows a strong emphasis on general methods for the preparation of optically active epoxides. The asymmetric approaches used can be generally divided into "Sharpless" and "non-Sharpless" methodology. The former, firmly entrenched and thoroughly characterized, is a basis upon which continuing innovation takes place. For example, Ko and co-workers [94JOC2570] have added a twist to the Sharpless asymmetric dihydroxylation reaction to access erythro-diols. TBDMS-protected allyl alcohols (e.g., 1) are dihydroxylated to give threo-diols (e.g., 2). Once activated (cyclic sulfate) and deprotected, these substrates undergo quasi-Payne rearrangement (providing the requisite inversion) to give terminal epoxides (e.g., 5). Treatment with a nucleophile results in attack at the least substituted epoxide carbon, providing erythro-diols (e.g., 7). ,,OTBDMS OH TBAF AD ~S~O BnO"'~'~'OTBDMS ~ B n O " ~ ~SOTBDMS 1. S0Cl2 2. RuGI3 BnO = NalO4 2 1 OH B n O " ~ . ~" ~

T~-s'o~ 4

_ BnO'~,t,~

OH ~,t,~,,SPh H SPh H+ ----P" BnO OH ~so~"

PhSNa ~ BnO~

~so~" S

6

43

7

44

Three-Membered Ring Systems

This methodology [94TL3601] was used to construct the optically active erythro-diol 8, which was then stereospecifically converted to (+)- disparlure (9), the sex attractant pheromone of the female gypsy moth. This transformation represents a formal asymmetric epoxidation across a nonfunctionalized olefin, not a direct option with traditional Sharpless asymmetric epoxidation technology. This clever variation using initial Sharpless dihydroxylation (applicable to nonfunctionalized olefins) and subsequent epoxide formation is starting to be recognized as a useful indirect method for asymmetric epoxidation. I. MeC(OMe),3 2. AcBr 3. K2CO3/MeOH 8

9; (+)-Disparlure

Chiral (salen)Mn(III) catalysts have also emerged as useful reagents to help fill the lacuna among unfunctionalized alkene epoxidations. In their recent review on the chemical and biological synthesis of chiral epoxides, Besse and Veschambre [94TET8885] declared that the "use of metalloporphyrins and related salen complexes..." is undoubtedly the method of the future. Which is not to say that this methodology is without limitations. However, Jacobsen and coworkers, whose pioneering work brought chiral (salen)Mn(III) mediated epoxidations to the fore, have in the past year examined some of the thorny problems commonly associated with these catalysts in an effort to broaden the scope of such asymmetric epoxidations. With an eye toward industrial applications, Jacobsen recently published a practical method for the large-scale preparation of the di-tert-butyl (salen)Mn(III) catalyst 10a [94JOC1939]. This addresses the question concerning the ready availability of the catalyst, but the mechanistic details of this reaction have thus far evaded a completely unified picture. H~'IIH

~t-Bu CI t-B/ lOe: R = t-Bu 10b:

R = (i-Pr)3SiO

Generally speaking, (salen)Mn(III) catalyzed epoxidations are believed to proceed via a stepwise mechanism in which initial attack of the substrate forms a radical intermediate, the configuration of which is determined by the facial selectivity of the catalyst. This intermediate can either collapse directly to the epoxide or undergo rotation and subsequent collapse, an event whose fate is determined by the diastereoselectivity of the catalyst toward ring closure and/or the relative lifetime of the radical intermediate. Thus, the product distribution is determined by the influence of at least two independent factors [94JA425]. These parameters were probed in an in-depth study dealing with the epoxidation of cis-cinnamate esters 11, a protocol Jacobsen has used for the enantioselective synthesis of diltiazem (13), a commercial anti-hypertensive agent [94TET4323]. Surprisingly, electronic and steric factors on the phenyl moiety exercise practically no influence on the enantioselectivity (lst step) of the reaction, whereas increasing steric

Three-Membered Ring Systems

45

R1 c~

R2 A.,,~R1

R2

trans

O'S, R2

+ O II LM LM-O_ I

minor

I

IIR2

' R2

R1

trans

O~e/R2

bulk about the ester group results in a profound improvement ( l l b vs. lld). Where electronic effects did come into play was in the cis/trans selectivity (2nd step). A strong correlation was observed between the Hammett sigma values and the cis/trans ratio, with electron withdrawing groups favoring trans formation ( l l a vs. lie). This latter effect is probably due to an increased lifetime of the intermediate radical, which is then able to partition to the trans-isomer before collapsing to the product. tOMe

O ' ~ ~ X"

CO=R

v

(R,R)-I 0a

_

COp

r

NaOCi 4-MeCeH4NO

X

12

v

11a: X = OMe; R = I-Pr 11b: X = H; R = Me

- .N...~O

13; Dlltlazem L,~ NMe2 9HCI

119 X = NO2;R =Me 11d: X= H; R =i-Pr

Considering these and other results, Jacobsen formulated that the following substrate properties are important for high enantioselectivity: (1) an aryl, alkenyl, or alkynyl group be conjugated to the alkene, (2) a cis double bond linkage is necessary as well as a bulky R group, and (3) the presence of an allylic oxygen substituent. An ideal substrate is one that possesses at least three of the aforementioned characteristics. In light of the observed insensitivity of the enantioselectivity towards steric bulk on the phenyl ring, a new model for initial substrate-catalyst binding was proposed in which the substrate approaches in a skewed manner where the aromatic portion is turned away from the catalyst and the R group is poised to exert significant steric influence. Mechanistically, this scenario is rationalized as being a "least-motion" path, since the initially formed radical is not far from a stable conformation. The proposed transition state is consistent with the observation that trans-alkenes are notoriously difficult to epoxidize using these reagents (slow reaction rates, low ee's), since the position of the Ar

~

R 0 ii

,m~Mnm

I

Three-Membered Ring Systems

46

Ar group in these substrates would be expected to encounter considerable steric hindrance. It is somewhat unusual that certain trisubstituted olefins (e.g., 14), have been found to undergo smooth reaction at low temperatures to give epoxides (e.g., 15) with high enantioselectivity [94JOC4378]. Interestingly, the asymmetric induction in these cases occurs in an opposite sense than that observed for the disubstituted olefins. [ ~

NaOCI Ph

catalyst

14

Ph 15

Pyridine N-oxide derivatives were found to produce a remarkable rate enhancement. It is not believed that they function as an axial ligand on the active catalyst species, since product ee's and cis/trans epoxide ratios are insensitive to the presence of these additives. Current theory suggests that the active Mn(V) oxo complex exists in equilibrium with an inactive dimer with the Mn(III) complex (see below). By binding to the latter, pyridine N-oxide derivatives shift the equilibrium toward the free active catalyst and thus enhance the reaction rates. It has also been observed that in dichloromethane, N-methylmorpholine N-oxide (NMO) and mchloroperbenzoic acid (MCPBA) produce a 1:1 salt which is unreactive toward olefins yet which is very efficient in oxidizing the (salen)Mn catalyst. This is significant in preserving the enantioselectivity of the process, as it prevents uncatalyzed racemic side-oxidation of the substrate [94JA9333]. CI-Mn Iv , O---MnlV--ci

0 II Mnv + I CI

.~._.._~y

L Mn"l I CI

_

_

0 II Mnv I CI

+

PyO MnllI I CI

As previously noted, optically active trans-epoxides are not easily available through the (salen)Mn-catalyzed epoxidation of trans-olefins. However, a modification in the conditions for cis-alkene epoxidation can provide access to trans-epoxides [94JA6937]. Addition of an cinchona alkaloid derivative such as 18 promotes a remarkable crossover in diastereoselectivity, such that the trans-epoxide 17 can be prepared in 90% de from cis-B-methylstyrene (16). It is not yet clear whether these chiral quaternary ammonium salts fundamentally change the nature of the manganesebased oxidant, or rather somehow prolong the lifetime of the radical intermediate, allowing rotation before collapse.

h/=~cHa P 16

lOb

N.oc,_ PhCI 18

OMe Cl- ~

z~ J P~

CH3 17 18

In the case of terminal olefins, asymmetric epoxidation typically results in relatively low enantiomeric excess. For (salen)Mn(III) catalysis, it is not clear whether the low degree of asymmetric induction is due to poor enantiofacial selectivity during

Three-Membered Ring Systems

47

the first discrete step, or more facile rotation of the intermediate radical, which is unencumbered by alpha-substitution. Since both of these are thermodynamic events, it would be expected that selectivity would be improved by lowering the reaction temperature. Indeed, when styrene (19) is epoxidized at-78oc, a slightly improved enantiomeric excess is observed compared to the room temperature reaction [94JA9333]. The asymmetric induction may be further improved by modifying the catalyst. Replacing the tert-butyl group with the triisopropylsiloxy group affords a catalyst (i.e., 10b) which is not only sterically more defined but also electronically attenuated, thus presumably milder and more selective [94TL669]. Using this catalyst at low temperatures, a dramatic increase in the enantiomeric excess was observed. 10b

MCPBA

Ph

NMO

O

19

20

This catalyst also resulted in a somewhat higher selectivity in the epoxidation of cyclic 1,3-dienes (e.g., 21-o22) when compared to the tert-butyl derivative lOa [94TL669].

[~ 21

OAo

lOb

~

OAc

NaOCI 22

Catalysts of type 10 have also been examined in the epoxidation of unfunctionalized cis- and trans-alkenes using hydrogen peroxide as a terminal oxidant [94TL941]. The Katsuki group have focused their attention on (salen)Mn(III) catalysts of a slightly different configuration (e.g., 23 and 2,4), which are characterized as having chiral residues at the aromatic 3,3'-positions. Recent studies into the epoxidation of conjugated cis-olefins [94SL356], including chromene derivatives such as 25 [94SL255], have led to the hypothesis of a flanking substrate attack which is steered by both steric interactions (e.g., the cyclohexyl residue) as well as n-n repulsive forces. The latter directing parameter was invoked to explain the apparent reversal of facial selectivity in the epoxidation of enyne 27 [94SL479], although it is not entirely clear which outcome would be predicted on the basis of sterics alone. Furthermore, the enantiofacial selection ofcis-olefins in these catalyst systems appears to be influenced mainly by the chirality at the C 1" and C2" positions (e.g., cyclohexyl), whereas transolefin epoxidation seems to be directed more by the C3 and C3' substituents [94TET4311].

HII',~H

%o" 'o-4 ~h

E~" n

23

24

48

Three-Membered Ring Systems

o2.

. AcNH"

v

v

H202

AcNH 26

25

23

---/

,..

PhlO v CH3CN

k

27

28

Mukaiyama's work with the related 6-ketoiminato Mn(III) complex 29 has revealed that this catalytic system induces the aerobic epoxidation ofunfunctionalized cis-olefins with good enantiofacial selectivity, albeit in moderate yield and with significant trans-epoxide formation [94CL1259].

PW" 0

29

29, 02

_

(CH3)3CCHO 30

31

Although chiral catalysts continue to dominate the literature in this arena, there are a number of novel achiral alternatives. Examples of the latter are a manganese porphyrin/tetrabutylammonium periodate system, useful for neutral homogeneous conditions [94TL945], as well as a polybenzimidazole-supported molybdenum(VI) catalyst suitable for industrial application in the Halcon process for propene epoxidation [94CC55]. Chiral catalysts are not de rigueur for the preparation of optically active cpoxides. Given that the substratc olefin can itself be chiral, there are often structural features which allow for stereoselective functionalization. In their study on the epoxidation of partial ergot alkaloids and conformationally-fixed styrenes (e.g., 32), Martinclli and co-workers found that these reactions exhibit remarkable facial selectivity which could not be satisfactorily rationalized by steric arguments. Force-field modeling indicates that torsional steering is most likely responsible for the observed effects. Thus, treatment of 32 with MCPBA results in the formation of the anti epoxide 33 in excellent yield and with high stereoselectivity (98:2). The analogous syn epoxide (34) was prepared indirectly via the bromohydrin, since bromine attack also occurs in an en fashion [94JOC2204].

Three-Membered Ring @stems

R

R

~

R

MCPBA~,

1. NBS/H20. 2. NaOH

kl___.#.,,,H

B~

49

33

32

. ~ H 34

Often, the diastereoselectivity may be attributed to the presence of one or more discrete functional groups, as in the epoxidation ofchiral (E)-crotylsilanes which represents a key step for the asymmetric synthesis of substituted tetrahydrofurans (i.e., 35--->37). Both catalyzed and uncatalyzed peracid oxidation conditions result in high anti selectivity, a phenomenon which is associated with the phenyldimethylsilyl and free hydroxyl groups. Epoxidation of the O-protected species gives a 1"1 mixture of syn and anti isomers [94TL6453]. B

I

ArCO3H I

s SiMo2Ph 35

0

~

OH 1 SiMo2Ph

PhM~o'~R HO

36

37

Similarly, enone 38 has been shown to undergo ketone-directed epoxidation when treated with MCPBA to give exclusively the syn epoxyketone 40. As for the mechanism, hydrogen bonding effects were discounted on the basis of solvent insensitivity. Intramolecular attack by some oxidized form of the ketone moiety could be operative, although 180 labelling studies have ruled out a dioxirane intermediate as the active epoxidizing species. Thus, the observed stereoselectivity was rationalized on the basis of intramolecular epoxidation by an alpha-hydroxy peroxide (i.e., 39) or possibly by a carbonyl oxide intermediate [94TL6155 180

le O

MCPBA

O 39

38

40

During the past year, Adam and his group have added some fine tuning in their direct synthesis of epoxy alcohols from olefins [94ACR57]. The photooxygenation of alkenes in the presence of transition-metal catalysts typically suffers from low regioselectivity during the initial singlet oxygen enr reaction (Schenck reaction). However, the use of vinylsilanes as substrates significantly improves the overall selectivity of the method. The silyl group directs the photooxygenation by favoring geminal hydrogen abstraction (cf. 41--->42). Steric requirements also help direct the metal-catalyzed epoxidation, providing silyl epoxy alcohols 43 in fair yields and with

SiMe3 R

R 41

1. 102 ~

HOy ~

2. NaBH4

R

SiMe3 R 42

tBuOOH =

MeaSi~O HO

VO(acac)2

R R 43

Three-Membered Ring Systems

50

excellent diastereomeric ratios [94JOC3341]. Vinylstannanes give similar results [94CB 1441]. A novel synthesis of epoxides from aldehydes and sulfur ylides has been reported this past year [94JA5973]. This reaction, which gives predominantly trans epoxides, proceeds through an interesting catalytic cycle in which the sulfur ylide is generated in situ from a diazo precursor, which is slowly added into a reaction medium containing catalytic rhodium(II) acetate and substoichiometric amounts of dimethyl sulfide. The use of a chiral sulfide produced observable (11%) enantioselectivity. RCHO

R 4 ~ ,R'

3.2.2

R2S=CHR'[Rh2(OAc)4]

N2CHR'

N2 [R2S]

Rh=CHR'

Reactions of Epoxides

A quintessential epoxide reaction is the addition of nucleophiles to give ringopened products. The broad range of usable nucleophiles lends an enviable flexibility to the protocol, while continuing advances in regio- and stereoselection expand its applicability. For example, synthetically useful halohydrins are available directly from olefins through hydrohalo addition, although the application of this approach to asymmetric synthesis sometimes proves problematic. On the other hand, the cleavage of epoxides with metal halides, a subject recently reviewed by Bonini and Righi [94SYN225], provides a regio- and chemoselective preparation of halohydrins, a method which is easily carried over to chiral substrates as demonstrated in the synthesis of the marine natural product 2-bromo-B-chamigrene (46).

THF HO~~ Br 44

46

2-bromo-l]-chamlgrene

4S

The regiochemist~ of the ring opening reaction can sometimes be controlled by means of chelation. For example, the complete C-4 selectivity observed in the ring opening of pyran epoxide 47 by organometallic reagents such as Me2CuLi and AIMe3 has been rationalized on the basis of a bidentate chelate intermediate (i.e., 48). This hypothesis is supported by the observation of lower selectivity when crown ethers are added to the reaction medium [94TET1261 ].

0

[

]

o

Me"

Me

0

47

48

49

Three-Membered Ring Systems

51

In a related observation, Guanti and coworkers [94 TET2219] observed that both the rate and regiosclectivity in the rcductivc ring opening ofchiral epoxide 49 can be enhanced by Lewis acids. The efficiency ofregioselection is highly dependent upon a variety of reaction parameters, such as the choice of Lewis acid and hydride donor, as well as of the O-protecting groups. Thus, a tfibutyltin hydride/magnesium iodide system mediated the regioselectivc ring-opening of chiral epoxy dio150.

/OTIPS ~OPMP

/OTIPS [H]

~ O P M-~P OH 51

50

Regioselectivity may also be controlled by g-interaction, as seen in the aluminum hydride reduction of unsaturated cyclic epoxides (e.g., 52). The observed rcgiochemical outcome was explained by an intermediate g-complex (53) in which the substrate is essentially planar. This model, which is supported by semiempirical calculations, minimizes axial-attack effects and emphasizes subtle electronic factors as well as hydride donor-carbon distances [94TL6647].

H~.I--H

52

53

54

Many epoxides undergo efficient ring-opening by oxygen nucleophiles in the presence of tris[trinitratocerium(IV)]paraperiodate, a heterogeneous catalyst [94SC1959]. In this case, the regiochemistry is presumed to depend upon the fate of a proposed epoxide radical cation (55). \ /

/N /x 55

Carbon nucleophiles may also serve as epoxide ring-opening agents, providing a particularly useful method for preparing long chain secondary alcohols. For example, terlmnal epoxides react with 2-(trialkylsilyl)allyl organometallics (e.g., 57) to give good yields of 1-substituted 4-(trimethylsilyl)-4-penten-1-ol products (e.g., 58). a-Haloepoxides proceed in a similar manner giving long-chain halohydrins (e.g., 59-->60). Depending upon the reagent and substrate, Lewis acid additives are sometimes needed for optimal conversion [94JOC4138].

.SIMe2Ph ( ~Cu(CN)Li2 92 S7

Or ~ ~

57 .78oc

56

81Me2Ph 58 OH $1Me2Ph

59

--40~

CI

60

OH

Three-Membered Ring Systems

52

A similar protocol provides for the formal alkylation of alkenes via the organolithium reductive alkylation of epoxides. For example, treatment of epoxide 61 with excess tert-butyllithium results in the direct formation of the disubstituted alkene 63 in excellent yield. Variously substituted epoxides may serve as substrates, although the study was limited to the readily available alkyllithium reagents. A preference for the formation of trans-olefins was observed, which became more pronounced with bulkier bases (e.g., tert-BuLi). The proposed mechanism proceeds via metallation at the primary carbon atom from the less hindered side, giving a chelated lithioepoxide (62) which undergoes anti-addition of the alkyl group and subsequent syn-elimination of Li20 to give trans-substituted olefins [94TL7943].

0

sec-BuLi,,. ,,O:

H ~ H9 RL......~i 2 H/ ~ C 4 H 9 61

H~C4H9 --C4H9 ~

ecBu~ H ~C4H9

,/ i.,i

S

C4H9

-

63

62

Epoxide ring opening can occur with concomitant elimination, as seen in the above example, or with subsequent oxidation. For example, a novel copper-catalyzed tandem ring opening and oxidation of optically active (trifluoromethyl)-epoxide (64) was the basis for a recent synthesis of optically pure trifluoropropionic acid (65). The method appears to be applicable to substrates with electron-withdrawing substituents, since electron-rich epoxides undergo degradation under the reaction conditions [94SL507]. OH

F3C~,~

1. HNO3,Cacat_ o. o0oc

,~

-

coo.

64

65

Such nucleophilic ring opening reactions can also take place in an intramolecular fashion, forming other ring systems. Thus, optically active oligo(tetrahydrofurans) have been prepared using an epoxide cascade reaction. Diepoxide 66 underwentp-toluenesulfonic acid-catalyzed rearrangement to form the THF-trimer 67 [94TL7629]. p-TsOH

m,,.-

P O ~ O H 66

67

Upon treatment with cobalt octacarbonyl, acetylenic epoxy alcohols (e.g., 68) form Nicolas-type complexes which undergo Lewis acid-catalyzed rearrangement to give tetrahydropyranol derivatives 69. It is interesting to note that the cyclization proceeds exclusively via a 6-endo process and with exclusive retention of configuration at the propynyl position. Both cis- and trans-2-ethynyl-3-hydroxytetrahydropyran derivatives can be prepared stereospecifically [94TL2179].

1. Co2(CO)8 ~ 2. BF3.OEt2

O Ph 68

HO~,~ M ~ O ') Ph 69

(96%)

Three-Membered Ring Systems

53

When the attacking nucleophile is carbon-centered, intramolecular epoxide ring-opening reactions provide an entry into carbocyclic systems. For example, epoxy allylsilane 70 cyclizes in an overwhelmingly 5-exo fashion under Lewis acid catalysis to form a putative silyl-stabilized carbocation intermediate (71) which then undergoes B-elimination and lactonization to give the alpha-methylene-f)-lactone 72. A side product (73) arises from the internal capture of the intermediate carbocation 71. This procedure has been applied to the synthesis of (-)-teucriumlactone (74) [94TL7809].

:•0

LA J

EtOOC"+.&'T~

5-exo

EtOOC ~

H

71

70

72

It EtOOC~

~

3 ~ _

.~

74;teucrlumlactone 73

Benedetti and coworkers have examined the intramolecular ring opening of epoxides by bis-activated carbanions, a process exemplified by the rearrangement of phenylsulfonyl epoxide 75 in a sodium ethoxide-ethanol medium to the phenylsulfonyl cyclopentano176. This quantitative study on the effect of ring size in such cyclizations revealed similarities to the intramolecular radical addition onto alkenes [94JOC 1518]. H

PhSO2~~~]

O

NaOEt

CN 75

PhS~

CNIN" ~OH 76

More complex heterocycles can be obtained by a type of double addition or cycloaddition onto epoxidcs. Insertion ofisocyanates was found to be catalyzed by late rare earth chlorides [94SL129] producing oxazolidinones, as seen in the high yield conversion of epoxidr 77 to oxazolidinone 78. This protocol appears to be general, although cyclic epoxides give poorer yields. A similar transformation involves the insertion of carbon dioxide, a reaction which has been carded out enantioselectively by using chirally modified Zr- and Ti-complexes as catalysts. In this way enantiomericaUy enriched 1,3-dioxolanones (e.g., 80) were prepared [94SL69].

/0• CICH2/ 77

n.C3H7NCO YCI3 (10%)

/~CH2CI n-C3H7--N~O O 78

Three-Membered Ring Systems

54

CO2 1,,. Ti(OI-Pri4/Binol

R'~ O

R-~O O.~o

79

80

The Lewis-acid catalyzed rearrangementofepoxides to carbonyl compounds has been studied and it has been found that either ketones or aldehydes can be selectively obtained by the proper selection of reaction conditions. For example, spiroepoxide 81 undergoes rearrangement to aldehyde 82 upon treatment with methylaluminum bis(4-bromo-2,6-di-tert-butylphenoxide), or MABR, whereas ketone 83 is formed predominantly when antimony pentafluoride is used [94TET3663]. Bu

Bu CHO

Lewisacid

Bu

82

81

83

O

This rearrangement has been used to prepare the interesting triol I]6. Thus, optically active ketoepoxide 84 undergoes acyl migration in the presence of boron trifluoride etherate with inversion of configuration to give the unstable ketoaldehyde 85, which is directly reduced to give 86 in 75% overall yield [94CL157]. Similarly, treatment of epoxy alkynols 87 with boron trifluoride etherate gave a mixture of cumulenals 88 and hydroxyallenes 89 [94TL6977]. O

Me O Me~CO2Me

~'-

84

O Me~ ~ J ~ ~'ICO2Me M~ "CHO

v

OH Me--OH Me I

8S

OH

86

OH

BF3- Et20

2

CH3

R2

87

CHO

H

88

CHO 89

Dittmer and coworkers have published a catalytic variation on their method of allylic hydroxyl group transposition mediated by tellurium. The process calls for the epoxidation of an allylic alcohol (e.g., 90), usually with Sharpless conditions, followed by protection of the alcohol to give epoxide 91. These compounds then undergo rearrangement and elimination in the presence oftellurium(II) to produce new allylic alcohols 92 which are formally the products of a 1,3-allylic isomerization. The recent modification allows for the use of catalytic amounts (0.1 equiv) of tellurium which is regenerated in situ by the presence of rongalite as a terminal reductant [94TL5583]. This protocol has been used in the synthesis of (-)-boivinose (93), the unnatural isomer of a stroboside constituent [94JOC4311 ]. t-BuL

1.TBHP,Ti(Oi-Pr)4,(+)-DET OH 90

t-BuL

Te2-

2. TsCI

t-Bu~ H

Ts 91

92

Three-Membered Ring Systems

55

OH 93

Replacing rongalite with a more active reducing agent, such as lithium triethylborohydride, and using a less electronegative protecting group, such as acetate, results in a crossover in reactivity. Thus, glycidyl acetates 94 undergo deoxygenation and deacetylation to provide allylic alcohols 95 in yields of 70% or greater with retention of configuration at the carbinol center [94JOC1004].

Rs,,~H Te = R3,~H R2,~ OAc UE6BHY R2~'~ OH R1

R1

94

95

Another extremely mild epoxide deoxygenation protocol involves the use of bis(cyclopentadienyl)titanium(III)chloride, which promotes homolytic cleavage of the epoxide C-O bond. The mildness of this reagent is showcased in the deoxygenation of epoxide 96 which gives the highly sensitive methoxydihydrofuran derivative 97 in 66% yield. While the deoxygenation is in itself quite useful, this general method of epoxide-based radical generation lends itself to a variety of applications. Significantly, the regioselectivity of the epoxide cleavage is often quite high, itself being determined by the stability of the resultant radical, and sometimes opposite to what is expected for a classical SN2 epoxide ring opening. For example, treatment of the spiroepoxide 98 with Cp2TiCI leads to an intermediate carbon radical which can be trapped by a H-atom donor, in this case cyclohexadiene, to give the secondary alcohol 99. By comparison, a "classical" reductive ring opening with lithium triethylborohydride gives only the tertiary alcohol 100. Finally, the intermediate radical can be trapped intramolecularly by, for example, an olefinic residue to give carbocyclic products. This is nicely illustrated by the preparation of the bicyclooctanemethanol derivative 102 in 88% yield from epoxide 101 [94JA986]. O

TrO~U,j-,~OMe ..'"~'~OTr

(66~176 TrO~~1 O' ~ ~ s OTr "~ / ~OMe

96

97

OH

(91%)

(>95%)

11111

98

99

Three-Membered Ring Systems

56

o6 " lol

3.3 3.3.1

H 102

DIOXIRANES Preparation of Dioxiranes

Sander and co-workers [94ACIE2212] have reported the first preparativescale synthesis of a dioxirane via carbene oxidation. Thus, the relatively stable dimesityldioxirane 106 was prepared by the low-temperature 02 oxidation of carbene 104 in matrix isolation in CFCI3; an intermediate carbonyl oxide (105) was observed spectroscopically.

hv A r ~ =N2 Ar

~--

103

3.3.2

At, r>: A

02

A-

104

Ar~ sO" Ar/3"~O+

hV =

Ar,= 0 ArX( ~

105

R = Mesityl

106

Reactions of Dioxiranes

This field is heavily dominated by the chemistry of dimethyldioxirane (DMD, 107) which, because of its ready availability and unique reactivity, has become a useful oxidant in the organic chemist's repertoire of reagents. The utility of DMD lies in its mildness and consequent ability to provide labile products which are not available by other methods. For example, substituted benzofurans 108 [94SYN111 ] as well as N-acylindoles 110 [94JOC2733] are converted to the labile epoxides 109 and 111, respectively, in excellent yields upon treatment with DMD. R"

R=

e

~

.R 108

~"-CH3 O 110

3 Me 109

CH2R2 Ra'~~t,~'/O

CH2R2 Ra~CH2R1

~ R

DMD r

U ..L 7 "-c"'R' ~CH3 O 111

Three-Membered Ring Systems

57

Even though DMD is by far the most common of the dioxirane oxidants, other members of this family occasionally offer advantage. This can be seen from the epoxidation of 1,3-dimethylcyclohexene (112). Under normal DMD conditions, the corresponding epoxide (114) is produced in 56% yield and with a cisltrans ratio of 14:86. On the other hand, using the dioxirane 113, itself easily prepared by treatment of2-chlorocyclohexanone with Oxone, results in the quantitative formation ofepoxide 114 with a cisltrans ratio of 4:96 [94TL1577].

=..

O

cis/trans = 4:96

113 112

114

Aside from the epoxidation reactions, DMD is also a useful reagent for other interesting oxidative transformations. For example, Murray and Gu have studied the DMD-mediated hydroxylation of alkenes (e.g., 115--->116)and found that the reaction is facilitated by solvents with hydrogen bond donor properties. This pronounced effect led the authors to propose that site selectivity could be directed by pendant hydrogen bond donor groups on the substrate [94JCS(P2)451 ]. Another handy application of DMD is the very high yield preparation of vicinal triketones and related compounds (119) starting from 1,3-dicarbonyl compounds [94SC695]. 1tS~ H3H CH3

DMD = "-

/ ' ~ . . . ~ OC'H3 H ~~~CH3 CI 116 H

O

O

R'~~R,

TsN3

R~y" N2

117

3.4

,,,,O O

100

R'

o

o

R"~R' O

118

119

OXAZIRIDINES

Among this interesting class of heterocycles, perfluorodialkyloxaziridines (i.e., 120) have been shown to be versatile oxidizing agents for certain types of reaction. For example, 56-steroids 121 are hydroxylated in good yields with complete regio- and stereoselectivity to the corresponding 56-hydroxy derivatives lZZ [94JOC5511 ]. In addition, these reagents are useful for the enantioselective conversion of silanes (123) to silanols (124) [94TL6329] as well as for the controlled stepwise oxidation of sulfides 125 to sulfoxides 126 or sulfones 127 [94JOC2762]. 3

R1

I .R6

pO C3F7 ,, F,C4~'N : "'" ~'F =

~

120

H O ~ RI

.R3 S

I R.8 -4

Three-Membered Ring Systems

58

R1 R2'"~Si--H R3

120 ~

RI~ ~, R2'"~Si--uH R3

123

124

120 RISER '

~ 2.2 eq

125

0~_/I0 RI~R'

o

120 <

R~ ~R'

1.0 eq

127

126

Oxaziridines as substrates undergo an interesting photolytic rearrangement to ring expanded lactams, a transformation which appears to be accelerated by the presence of an aromatic ring within the substrate or by the addition of an external sensitizer [94JA6439]. This rearrangement has been used as a key step (i.e., 128--->129) in the total synthesis of yohimbine alkaloids [94JA9009]. CO2CH3

CO2CH3

H

H

O~ ~ ~ I P H

129

128

3.5

AZIRIDINES

3.5.1

Preparation of Aziridines

Tanner has recently published several important review articles dealing with the synthesis of chiral aziridines and their use as chiral auxilliaries and ligands [94ACIE599, 94TET9797, 94TL4631 ]. In addition, Evans has issued a retrospective on the very useful copper-catalyzed olefin aziridination reaction, in which electronrich and electron-deficient olefins undergo efficient aziridination using the nitrene precursor (N-(p-tolylsulfonyl)imino)phenyliodinane in the presence of soluble Cu(I) and Cu(II) salts [94JA2742]. R2 R1

Ts R3

PhI="NTs

M1

R3

Aziridine-2-carboxylic acid derivatives 133 may be prepared in a stereochemically predictable method by using the Oppolzer camphor sultam as a chiral auxilliary. The standard protocol of amine addition onto an alpha-bromoacrylate is imbued with stereodifferentiation by the face-selective alpha-protonation of enolate 131, a step which the chiral auxilliary dictates to occur in a si-fashion [94TL 1653].

Three-Membered Ring @stems

O

RNH2

H. ,H"O,:

59

si-protonation

=,..-

131

130

O

SN2

RHN'-'~

H

(~ "O 132

133

A method has been reported this past year for the direct synthesis of Ndiphenylphosphinyl (DPP) protected aziridines 135 from 2-aminoalcohols 134. The DPP group combines the advantanges of (1) activation of the aziridine ring towards nucleophilic attack and (2) subsequent ease of removal [94SL 145]. 1. DPPCI, Et3N, CH2CI2 R • O H .........

NH2

2. TsCI, Et3N, DMAP

Nail, THF "-

R~-- 7 N I

135

134

DPP

In a similar vein, Davis and co-workers have found the p-toluenesulfinyl group to be useful for such purposes. Aziridine-2-carboxylic acid derivatives 138 are prepared in high diastereomeric purity by a Darzens-type reaction of the lithium enolate of methyl bromoacetate (137) with enantiopure sulfinimines (e.g., 136) [94JOC3243]. These compounds have been employed as intermediates in the asymmetric synthesis of the antibiotic (+)-thiamphenicol (139) [94TL7525].

p: H p-Tolyl~S.,,N~.~Ar

OMo Br~OLi

,\

,co M.

H/~N4f~H

o 0H3SO2'~1~ I H'-~,,'~ CHCl2

137 136

3.5.2

138

OH

139;thlamphenicol

Reactions of Aziridines

Aziridines can be N-alkylated using a variety of base systems. A particularly mild environment is obtained by using potassium carbonate in the presence of 18crown-6, a mixture which avoids proton-catalyzed ring-opening sometimes observed under other conditions. For example, alkylation of aziridine 140 with benzyl bromide in triethylamine/tetrahydrofuran gives only 19% of the alkylated aziridine along with significant amounts of ring-opened product 142. Changing the base to K2CO3 (with 18-crown-6) increased the yield of intact 141 to 84% [94SC1121].

Three-Membered Ring Systems

60

BnBr N~'Bn OTBDPS ~ ~OTBDPS 140

Br + ~[,~~OTBDPSNBn2

141 142

As in the analogous epoxide reactions, ring-opening is often the desired transformation, especially when it occurs with concomitant C-C bond formation. These reactions often occur with high regioselectivity, although predicting the outcome is not always so easy. For example, the rigid aziridine 143 undergoes ring opening at C-2 by the soft nucleophile N-methylindole, even though this same nucleophile is known to react with other aziridine-2-carboxylic esters at C-3 under similar conditions. The observed regioselectivity in this orbital-controlled ring opening was rationalized on the basis of LUMO coefficients [94JOC434]. Alkylative ring opening can also be carried out using copper(I)-modified Grignard reagents. Thus, the DPP activated aziridine 146 underwent ring-opening without deprotection to give the phosphinyl amine 147 in 73% yield. This protocol could not be extended to aziridine-2-carboxylic esters, as attack at the carbonyl group competed [94TL2739].

CH30

~_.j

o

NI Ac

,•

c.,o

Me 144 BF3.Et20 ~

0 4

AcHN

7'

0

$

~

~ I Me

143

145

Ph~.~O ph~

/N\

EtMgBrCuBr.Et2S _

Ph.~p , ,HN ~ Ph II '" O Bn

ar~~" 146

147

The ring-opening reaction is not limited to carbon-based nucleophiles. For example, 1,2-diamines 150 may be prepared by the ytterbium triflate-catalyzed addition of amines to N-protected aziridines 148 [94TL7395]. In addition, certain Naryl and N-alkyl azifidines undergo reductive ring cleavage upon treatment with lithium powder in the presence of naphthalene to give dilithiates (e.g., 152) which can be subsequently alkylated with various electrophiles [94JOC3210]. R iI I

/N~R' + R/

NR1R2NH

cat. Yb(OTf)3 ---

NHR" R'~~

R'

NR1R2

149

148 150

Three-Membered Ring Systems

Ph I /N\

Li, CloH6cat.

NPhLi

61

E+ ,,.._

NHPh

R/ 152

151

153

With functionalized aziridines, eliminative ring-opening becomes a possibility. For example, 2-bromomethylaziridines 154 can be made to undergo radical induced opening either by treatment with tributyltin hydride in refluxing benzene [94SL287] or by reduction with a zinc-copper couple in methanol at room temperature under sonochemical conditions [94CC 1221 ]. The usual products are allylamines 156.

R1y R 2 /NN~.

R1yR2

n-Bu3SnH AIBN I--

R2

/N

154

156

155

N-Functionalized vinyl aziridines 157 undergo an interesting aza-[2,3]Wittig rearrangement upon treatment with LDA to form exclusively cis-2,6-disubstituted tetrahydropyridines 159. The observed results are rationalized by proposing a transition state conformation represented by structure 158, in which the tert-butyl acetate group and the alkene moiety are in a cis-like alignment while the vinylic group adopts an endo orientation [94JA9781 ].

R~.N'~/CO2t'Bu ~LDA

R J'J.LiL"O.....,,"~1~1.! 1

R1 157

~ R~N,~CO2t-Bu

._~

v

Ot-Bu

-- R1

159

158

Finally, Alper has reported the preparation of imidazolidinethiones 162 by the palladium(II)-catalyzed cyclization ofaziridines 160 and sulfur diimides. Through a mechanism not yet fully elucidated, the methylene carbon of the aziridine is incorporated into both the thiocarbonyl and methylene positions of the product in this fascinating palladium catalyzed reaction [94JA1220].

R / ~ R'

+

ArN=S=NAr 161

160

PdCI2(PhCN)2

flH s

t~ =R' 162

3.6

References

94ACIE599 94ACIE2212

D. Tanner, Angew. Chem., Int. Ed. Engl. 1994, 33, 599. A. Kirschfeld, S. Muthusamy, W. Sander, Angew. Chem., Int. Ed.

62

94ACR57 94CB 1441 94CC55 94CC1221 94CL157 94CL1259 94JA425 94JA986 94JA1220 94JA2742 94JA5973 94JA6439 94JA6937 94JA9009 94JA9333 94JA9781 94JCS(P2)451 94JOC434 94JOC1004 94JOC1518 94JOC1939 94JOC2204 94JOC2570 94JOC2733 94JOC2762 94JOC3210 94JOC3243 94JOC3341 94JOC4138 94JOC4311 94JOC4378 94JOC5511 94SC695 94SC 1121

Three-Membered Ring Systems

Engl. 1994, 33, 2212. W. Adam, M. J. Richter, Acc. Chem. Res. 1994, 27, 57. W. Adam, P. Klug, Chem. Ber. 1994, 127, 1441. M. M. Miller, D. C. Sherrington, J. Chem. Soc., Chem. Commun. 1994, 55. N. De Kimpe, R. Jolie, D. De Smaele, J. Chem. Soc., Chem. Commun. 1994, 1221. K. Okada, T. Katsura, H. Tanino, H. Kakoi, S. Inoue, Chem. Lett. 1994, 157. T. Nagata, K. Imagawa, T. Yamada, T. Mukaiyama, Chem. Lett. 1994, 1259. W. Zhang, N. H. Lee, E. N. Jacobsen, J. Am. Chem. Soc. 1994, 116, 425. T. V. RajanBabu, W. A. Nugent, J. Am. Chem. Soc. 1994, 116, 986. J. -O. Baeg, H. Alper, J. Am. Chem. Soc. 1994, 116, 1220. D. A. Evans, M. M. Faul, M. T. Bilodeau, J. Am. Chem. Soc. 1994, 116, 2742. V. K. Aggarwal, H. Abdel-Rahman, R. V. H. Jones, H. Y. Lee, B. D. Reid, J. Am. Chem. Soc. 1994, 116, 5973. A. J. Post, S. Nwaukwa, H. Morrison, J. Am. Chem. Soc. 1994, 116, 6439. S. Chang, J. M. Galvin, E. N. Jacobsen, J. Am. Chem. Soc. 1994, 116, 6937. J. Aub6, S. Ghosh, M. Tanol, J. Am. Chem. Soc. 1994, 116, 9009. M. Palucki, P. J. Pospisil, W. Zhang, E. N. Jacobsen, J. Am. Chem. Soc. 1994, 116, 9333. J. Ahman, P. Somfai, J. Am. Chem. Soc. 1994, 116, 9781. R. W. Murray, D. Gu, J. Chem. Soc., Perkin Trans. 2 1994, 451. L. Dubois, A. Mehta, E. Tourette, R. H. Dodd, J. Org. Chem. 1994,59, 434. D. C. Dittmer, Y. Zhang, R. P. Discordia, J. Org. Chem. 1994, 59, 1004. F. Benedetti, F. Berti, S. Fabrissin, T. Gianferrara, J. Org. Chem. 1994, 59, 1518. J. F. Larrow, E. N. Jacobsen, J. Org. Chem. 1994, 59, 1939. M. Martinelli, B. C. Peterson, V. V. Khau, D. Hutchison, M. R. Leanna, J. E. Audia, J. J. Droste, J. Org. Chem. 1994, 59, 2204. S. Y. Ko, M. Malik, A. F. Dickinson, J. Org. Chem. 1994, 59, 2570. W. Adam, M. Ahrweiler, K. Peters, B. Schmiedeskamp, J. Org. Chem. 1994, 59, 2733. D. D. DesMarteau, V. A. Petrov, V. Montanari, M. Pregnolato, G. Resnati, J. Org. Chem. 1994, 59, 2762. J. Almena, F. Foubelo, M. Yus, J. Org. Chem. 1994, 59, 3210. F. A. Davis, P. Zhou, G. V. Reddy, J. Org. Chem. 1994, 59, 3243. W. Adam, M. J. Richter, J. Org. Chem. 1994, 59, 3341. L. E. Overman, P. A. Renhowe, J. Org. Chem. 1994, 59, 4138. A. S. Pepito, D. C. Dittmer, J. Org. Chem. 1994, 59, 4311. B. D. Brandes, E. N. Jacobsen, J. Org. Chem. 1994, 59, 4378. A. Arnone, M. Cavicchioli, V. Montanari, G. Resnati, J. Org. Chem. 1994, 59, 5511. A..Saba, Synth. Commun. 1994, 24, 695. J. Ahman, P. Somfai, Synth. Commun. 1994, 24, 1121.

Three-Membered Ring @stems 94SC1959 94SL69 94SL129 94SL145 94SL255 94SL287 94SL356 94SL479 94SL507 94SYN111 94SYN225 94TET1261 94TET2219 94TET3663 94TET4311 94TET4323 94TET7629 94TET7809 94TET7943 94TET8885 94TET9797 94TL669 94TL941 94TL945 94TL1577 94TL1653 94TL2179 94TL2739 94TL3601 94TL4631 94TL5583 94TL6155 94TL6329 94TL6453 94TL6647 94TL6977 94TL7525

63

N. Iranpoor, F. Sh. Zasrdaloo, Synth. Commun. 1994, 24, 1959. M. Brunner, L. Mu6mann, D. Vogt, Synlett 1994, 69. C. Qian, D. Zhu, Synlett 1994, 129. H. M. I. Osborn, J. B. Sweeney, Synlett 1994, 145. R. Irie, N. Hosoya, T. Katsuki, Synlett. 1994, 255. N. De Kimpe, D. De Smaele, P. Bogaert, Synlett 1994, 287. H. Sasaki, R. Irie, T. Katsuki, Synlett. 1994, 356. T. Hamada, R. Irie, T. Katsuki, Synlett. 1994, 479. T. Katagiri, F. Obara, S. Toda, K. Furuhashi, Synlett 1994, 507. W. Adam, K. Peters, M. Sauter, Synthesis, 1994, 111. C. Bonini, G. Righi, Synthesis 1994, 225. M. Chini, P. Crotti, C. Gardelli, F. Macchia, Tetrahedron 1994, 50, 1261. G. Guanti, L. Banff, V. Merlo, E. Nadsano, Tetrahedron 1994, 50, 2219. K. Maruoka, N. Murase, R. Bureau, T. Ooi, H. Yamamoto, Tetrahedron 1994, 50, 3663. N. Hosoya, A. Hatayama, R. Irie, H. Sasaki, T. Katsuki, Tetrahedron 1994,50, 4311. E. N. Jacobsen, L. Deng, Y. Furukawa, L. E. Martinez, Tetrahedron 1994, 50, 4323. U. Koert, H. Wagner, M. Stein, Tetrahedron 1994, 50, 7629. K. Nishitani, Y. Harada, Y. Nakamura, K. Yokoo, K. Yamakawa, Tetrahedron 1994, 50, 7809. E. Doris, L. Dechoux, C. Mioskowski, Tetrahedron 1994, 50, 7943. P. Besse, H. Veschambre, Tetrahedron 1994, 50, 8885. D. Tanner, C. Birgersson, A. Gogoll, Tetrahedron 1994, 50, 9797. S. Chang, R. M. Heid, E. N. Jacobsen, Tetrahedron Lett. 1994, 35, 669. P. Pietik~iinen, Tetrahedron Lett. 1994, 35, 941. D. Mohajer, S. Tangestaninejad, Tetrahedron Lett. 1994, 35, 945. M. Kurihara, S. Ito, N. Tsutsumi, N. Miyata, Tetrahedron Lett. 1994, 35, 1577. P. Garner, O. Dogan, S. Pillai, Tetrahedron Lett. 1994, 35, 1653. C. Mukai, Y. Ikeda, Y. Sugimoto, M. Hanaoka, Tetrahedron 1994, 50, 2179. H. M. I. Osborn, J. B. Sweeney, Tetrahedron Lett. 1994, 35, 2739. S. Y. Ko, Tetrahedron Lett. 1994, 35, 3601. D. Tanner, P. G. Andersson, A. Harden and P. Somfal, M. Kurihara, S. Ito, N. Tsutsumi, N. Miyata, Tetrahedron Lett. 1994, 35, 4631 A. Kumar, D. C. Dittmer, Tetrahedron Lett. 1994, 35, 5583. A. Armstrong, P. A. Barsanti, P. A. Clarke, Tetrahedron Lett. 1994, 35, 6155. M. Cavicchioli, V. Montanari, G. Resnati, Tetrahedron Lett. 1994, 35, 6329. J. S. Panek, R. M. Garbaccio, N. F. Jain, Tetrahedron Lett. 1994, 35, 6453. E. F. Healy, J. D. Lewis, A. B. Minniear, Tetrahedron Lett. 1994, 35, 6647. X. Wang, B. Ramos, A. Rodriguez, Tetrahedron Lett. 1994, 35, 6977. F. A. Davis, P. Zhou, Tetrahedron Lett. 1994, 35, 7525.