Asymmetric Synthesis of 3-Oxacarbacyclin and 3-Oxaisocarbacyclin by a Common Enantioselective Deprotonation Based Route

FULL PAPER

Asymmetric Synthesis of 3-Oxacarbacyclin and 3-Oxaisocarbacyclin by a

Common Enantioselective Deprotonation Based Route

Irene Vaulont, Hans-Joachim Gais*, Norbert Reuter, Elmar Schmitz, and Rainer K. L. Ossenkamp

Institut für Organische Chemie der Rheinisch-Westfälischen Technischen Hochschule Aachen,

Professor-Pirlet-Straße 1, D-52056 Aachen, Germany

Fax: (internat.) ϩ49(0)241/8888127

E-mail: Gais@RWTH-Aachen.de

Received December 22, 1997

Keywords: (ϩ)-3-Oxacarbacyclin / (ϩ)-3-Oxaisocarbacyclin / Chiral base / Chiral phosphonoacetate /

Asymmetric synthesis

Asymmetric total syntheses of 3-oxacarbacyclin (4) and 3-

oxaisocarbacyclin (5) have been achieved by a new and com-

meric acetate 48 and a Mitsunobu reaction of the allylic alco-

hol 49. The key step in the construction of the α-side chain

mon route. The key step of these syntheses is an enantiose- in 4 is a Horner-Wadsworth-Emmons reaction of ketone 7c

lective deprotonation of the prochiral ketone 25 with lithium

(R,R)-bis(phenylethyl)amide (12) in the presence of LiCl.

Treatment of the thus formed enolate 26 with ClSiEt₃gave

with the 8-phenylnormenthol-containing phosphonoacetate

56 which gave ester 60 of 90% de. Ester 60 was obtained

diastereomerically pure by chromatography in 72% yield

the enol ether 27 of 92% ee in 94% yield. Deprotonation of from 7c. Reduction of 60 furnished the allylic alcohol 62

the analogous prochiral ketone 9 with 12 in the presence of

LiCl followed by reaction of the enolate 13 with ClSiEt₃led

to isolation of the silyl enol ether 8b of 92% ee in 95% yield.

A study of the deprotonation of 9 with the chiral lithium ami-

des 14؊19 showed that 12 in combination with LiCl is the

optimal base in terms of enantioselectivity and accessibility.

The ω-side chain in 4 and 5 was established by a Mukaiyama

reaction of 27 with the unsaturated aldehyde 28, leading to

ketone 39 of 90% de, in combination with a stereoselective

Pd-catalyzed allylic rearrangement of acetate 47 to the iso-

which was converted to 4 in a standard fashion. It is at the

stage of the α,ß-unsaturated ester 60 where divergence into

synthesis of 5 was made. Selective isomerization of 60 to the

ß,γ-unsaturated ester 66 of 97% ie in 91% yield was accom-

plished by deprotonation of 60 with 12 to enolate 65 and its

subsequent regioselective protonation. By a similar reaction

sequence the isomeric α,ß-unsaturated ester 61 was con-

verted to the ß,γ-unsaturated ester 69 of 97% ie in 88% yield.

Reduction of 66 afforded the homoallylic alcohol 71 which

was converted to 5 in a standard fashion.

Introduction

prevented. Prostacyclin analogs 2 and 3 are orally active and

their anti-aggregatory potency exceeds that of 1 consider-

Prostacyclin (PGI₂) (1)^[1](Figure 1) is the most potent ably. Intensive studies of cicaprost 2 revealed, in addition to

endogenous inhibitor of blood platelet aggregation known a nephroprotective activity^[9], a high in vivo potency for the

and a strong vasodilator^[2]. The characteristic modes of ac- inhibition of metastasis development^[10][11]. Thus, 2 is also

tion of this important regulator of the cardiovascular system an interesting candidate for a medicinal anti-metastatic ther-

are mediated by specific cell-surface receptors^[3]which are apy. Furthermore, cicaprost was shown recently to have a

apparently widespread expressed not only in peripheral or- suppressing effect on the tumor necrosis factor-α production

gans but also in the central nervous system^[4]. The latter in human peripheral blood mononuclear cells^[12][13]. Asym-

finding suggests that 1 plays also an important role in neu- metric syntheses of 2^{[7][14][15][16]}and 3^[8]as well as of the

ronal activity. The medicinal application of 1 is, however, parent compounds 4^[17][18]and 5^[8][19]have been described

severely hampered by a short in vivo half-life which is by Skuballa et al., Shibasaki et al., Kojima et al. and by us.

mainly due to the hydrolytic sensitivity of the enol ether Because of the considerable medicinal potential of 3-oxacar-

moiety and the enzymatic degradation of the α-side chain. bacyclins and 3-oxaisocarbacyclins, it was our intention to

The intensive search for stable analogs of 1^[2a][5][6]has cul- provide for a new asymmetric entry to these prostacyclin

minated in the synthesis of the 3-oxacarbacyclin derivative analogs by using the prochiral ketone 9 as starting material

2^[7]and the 3-oxaisocarbacyclin derivative 3^[8]. The formal (cf. Scheme 2). This entry should permit for the attachment

exchange between the ring oxygen atom and the methylene of a segment containing carbon atoms 13 to 20(21) to 9 in

group in 1 as well as the modification of the ω-side chains one step and allow for the synthesis of 3-oxacarbacyclins as

not only convey high biological activity but also high chemi- well as of 3-oxaisocarbacyclins through divergence at a late

cal and metabolic stability to 2 and 3. Because of the oxygen stage of the synthesis of the former. We report in this paper

atom in 3-position, enzymatic β-hydroxylation, which is the such an entry to 4 and 5 which is based on enantioselec-

first step of a rapid degradation of the α-side chain in 1, is tive deprotonation.

Eur. J. Org. Chem. 1998, 805Ϫ826

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805

I. Vaulont, H.-J. Gais, N. Reuter, E. Schmitz, R. K. L. Ossenkamp

FULL PAPER

Figure 1. Prostacyclin and its 3-oxaanalogs

Figure 2. Retrosyntheses of 3-oxacarbacyclin (4) and 3-oxaisocar-

bacyclin (5)

Results and Discussion

allow for the stereoselective introduction of the ω-side chain

Retrosynthetic Analysis: The choice of ketone 9, which via a Mukaiyama aldol reaction^[28a]with (E)-2-octenal in

is readily accessible from diketone 10^[20][21][22], as starting combination with a Pd-catalyzed transposition of the allylic

material for the synthesis of 4 and 5 poses two chal- hydroxy group^{[29][30][31][32]}. Such a sequence was success-

lenges^{[5][6][17][18]}. The first is the enantioselective introduc- fully applied by Danishefski et al.^[31]for the construction

tion of the ω-side chain and the second challenge is the of the ω-side chain of the prostaglandin F_2α. Alternatively,

stereoselective introduction of the α-side side chain as well an aldol reaction^[28b]of the lithium enolate derived from 9

as of the endocyclic double bond. Because of their bicyclic with (E)-2-octenal can be envisaged. We were confident that

structure, chiral derivatives of 9, containing either the α- a stereoselective HWE reaction of 7 under formation of es-

or the ω-side chain, e. g. 7, provide in general only a low ter 6 could be accomplished by using a chiral phos-

asymmetric induction in the functionalization of the re- phonoacetate like the one we^[15][17]and others^[33]have suc-

spective cyclopentanone ring^[23]

.

cessfully introduced for the stereoselective olefination of 9

Figure 2 shows the retrosynthetic analysis of 4 and 5 on and ketones of type 7. It is at the point of ester 6 where

which the synthetic strategy was based. Thus, disassembly divergence into 3-oxaisocarbacyclin (5) will be made. Pre-

of the ether moiety in 4 and oxidation of the allylic alcohol cedent exists, suggesting that the pivotal selective rearrange-

derived thereof led, retrosynthetically, to ester 6. Retrosyn- ment of the α,ß-unsaturated ester 6 to the ß,γ-unsaturated

thetic oxidative cleavage of the double bond gave ketone 7, ester 11 should be feasible^{[8][34][35][36]}

.

a

known intermediate in the synthesis of carbacy-

Enantioselective Deprotonation: At the beginning of our

clin^{[5][6][24][25]}. Protection of the carbonyl group and disas- investigation of the synthesis of 8 from 9 the enantioselec-

sembly of the ω-side chain allowed for the generation of the tive deprotonation of a variety of prochiral mono- and bi-

enol ether 8. Work on the enantioselective deprotonation of cyclic ketones had been studied by using chiral lithium ami-

prochiral cyclohexanone derivatives with chiral bases^[26][27]des^[26][27]. From the large number of lithium amides investi-

suggested the possibility of a similar reaction of 9 and, thus, gated the C₂-symmetrical amide 12 (Scheme 1) seemed to

its enantioselective conversion to 8. The enol ether 8 should be the most promising one. We therefore began our investi-

806

Eur. J. Org. Chem. 1998, 805Ϫ826

Asymmetric Synthesis of 3-Oxacarbacyclin and 3-Oxaisocarbacyclin

FULL PAPER

gation of the enantioselective deprotonation of ketone 9 tonations of the ketone with 14؊17 were run without

with this base^[37]

Scheme 1

.

ClSiMe₃. Koga et al.^[52]have studied the deprotonation of

9 with various phenyl glycine derived asymmetric lithium

amides and reported on the synthesis of ent-8a, having an

ee value of 94%, by using ent-19 in THF the presence of

HMPA. Leonhard et al.^[53]have investigated the depro-

tonation of the monoethylene ketal derivative of 10 by using

12 as well as lithium (α-phenylethyl)isopropylamide and re-

corded ee values of 48% and 72%, respectively, for the cor-

responding silyl enol ether. However, in our hands depro-

tonation of 9 with 19 in THF the presence of HMPA led to

8a of only 84% ee. In the present work determination of the

ee values of 8a, ent-8a and 8b was made directly and not

1

indirectly^[52][53]by H-NMR spectroscopy of the silyl enol

Reagents and conditions: see Table 1.

ethers in the presence of Pr(tfc)₃/Ag(fod) (tfc ϭ tris-[3-

Amide 12 is readily accessible on a large scale in three (trifluoromethylhydroxymethylene)]-d-camphorato, fod ϭ

steps from (R)-α-phenylethylamine^[38]and shows a high en- 6,6,7,7,8,8,8-heptafluor-2,2-dimethyl-3,5-octandionato)^[54]

antioselectivity in deprotonation reactions^[26][27][39]. Treat- [∆∆δ (ϭCHϪR) ϭ 0.04 and 0.06, respectively].

ment of 12 in THF at low temperatures with ketone 9 and

Table 1. Deprotonation of ketone 9 with the lithium amide 12

trapping of the lithium enolate 13 formed by reaction with

ClSiMe₃gave the enol ether 8a which had, however, only a

low ee value (Table 1, entry 1). Deprotonation proceeded

with a significantly higher enantioselectivity if ClSiMe₃was

added to 12 prior to the addition of ketone 9 (Table 1, entry

2). Previous studies of the deprotonation of ketones with

12 have shown that a high enantioselectivity can only be

attained with this base if ClSiMe₃is present in the depro-

tonation step^[26][27][40]. This has been attributed to the for-

mation of a mixed aggregate^[41]between LiCl, formed by

reaction of the respective lithium enolate with ClSiMe₃, and

12^[42]which is more reactive and selective than the mono-

mer or dimer of 12^[43]. Thus in another experiment 12 was

treated first with LiCl, to generate 12·LiCl, followed by the

sequential addition of 9 and ClSiMe₃. In this case 8a was

isolated with a high ee value (Table 1, entry 3). In case LiCl

was added before the deprotonation step the sequence of

the addition of 9 and ClSiMe₃had almost no bearing upon

the enantioselectivity (Table 1, entries 3 and 4). Because of

the ready hydrolysis of 8a on silica gel, which made its chro-

matographic purification on a preparative scale exceedingly

difficult, the triethylsilyl ether 8b was prepared. Depro-

tonation of 9 was carried out with 12·LiCl, which was pre-

pared directly by treatment of (R,R)-bis(phenylethyl)am-

monium chloride^[38]with 2 equivalents of nBuLi^[40][41]. Re-

action of thus formed 13 with ClSiEt₃gave 8b with an ee

value of 92% in 95% yield (Table 1, entry 5). Silyl ether

8b proved to be hydrolytically much more stable than 8a.

Reaction of 13 with ClSiEt₃required higher temperatures

than that with ClSiMe₃. Our results support the previously

put forward notion that the actual chiral base in depro-

Entry Method^[a]

Product ee

Yield

[%] [%]

1

2

3

4

5

A: 1. 12, 2. 9, 3. ClSiMe₃

8a

30

86

92

93

92

62

80

88

83

95

B: 1. 12, 2. ClSiMe₃, 3. 9

C: 1. 12, 2. LiCl, 3. ClSiMe₃, 4. 9 8a

D: 1. 12, 2. LiCl, 3. 9, 4. ClSiMe₃8a

E: 1. (R,R)-bis(phenylethyl)-

8b

ammonium chloride, 2. 2 nBuLi,

[b]

3. 9, 4. ClSiEt₃

[a]

[b]

Reactions were run at Ϫ100°C. Ϫ At Ϫ78°C.

Figure 3. Synthesis of 8a, ent-8a and 8b from 9 with chiral lithium

amides

The absolute configurations of 8a and 8b were deter-

tonations with 12 in the presence of ClSiR₃is the mixed mined in an indirect manner by comparison with the silyl

aggregate 12·LiCl, which has a higher reactivity and selec- enol ethers 21 and 22 formed via deprotonation of the chi-

tivity than monomeric or dimeric 12. Besides 12 we have ral ketone 20^[15]with 12 and ent-12 (Scheme 2).

studied the chiral lithium amides 14^[44], 15^[45], 16^[46], 17^[47]

Because of their roof-shaped structures, ketones 20 and 9

and 18^[48]in the deprotonation of 9 and recorded invariably resemble each other closely in regard to the cyclopentanone

lower enantioselectivities in the formation of ent-8a, 8a and rings. The stereogenic centers in 20 are expected to exert

8b, respectively^[49][50][51]. Whereas deprotonation of 9 with only a minor asymmetric induction in the deprotonation

18 was carried out in the presence of ClSiMe₃depro- with 12 and ent-12. Thus, it is safe to assume that at least

Eur. J. Org. Chem. 1998, 805Ϫ826

807

I. Vaulont, H.-J. Gais, N. Reuter, E. Schmitz, R. K. L. Ossenkamp

Scheme 3

FULL PAPER

Scheme 2

Reagents and conditions: (a) NaBH₄, EtOH, Ϫ45°C; (b) tBuPh_2-

SiCl, ImH, DMF, 0°C; (c) pTsOH, acetone, H₂O, room temp.

Scheme 4

Reagents and conditions: (a) 1. 12, THF; 2. 20, Ϫ95°C; 3.

ClSiMe₃, Ϫ90°C.

the sense of asymmetric induction in the deprotonation of

9 and 20 with 12 should be the same. Treatment of 12 with

ClSiMe₃followed by addition of 20 led to isolation of a

mixture of 21 and 22 in a ratio of 95:5 in 87% yield. The

use of ent-12 in the deprotonation of 20 gave a mixture of

21 and 22 in an opposite ratio of 14:86 in 85% yield. The

lower selectivity in the deprotonation of 20 by using ent-12

can be attributed to a steric effect of the silyloxymethyl

group. The structure of 21 and, thus, of 22 was unequivo-

cally established by NOE experiment after a complete as-

Reagents and conditions: (a) THF, Ϫ100°C; (b) ClSiEt₃, Ϫ78°C.

Construction of the ω-Side Chain: According to the retro-

synthetic scheme a segment containing carbon atoms 12 to

20 of the ω-side chain was going to be attached to 8a or 8b

in one step followed by a transposition of the allylic

hydroxy group. In pursuing this goal we began with a study

of the aldol reaction of 13 with (E)-aldehyde 28 (Scheme

5). Treatment of 13, which was prepared by deprotonation

of 9 with 12·LiCl (cf. Table 1, entry 5), with 28 in THF at

Ϫ78°C gave a mixture of the aldol products 29 and 30 in a

ratio of 2:1 in 95% yield. Thus, the aldol reaction had oc-

curred with high stereoselectivity in regard to C-12 (prosta-

glandin numbering) but with a low selectivity in regard to

1

signment of its signals in the H-NMR spectrum. On the

basis of the above considerations and results the absolute

configurations of 8a and 8b were assigned as depicted in

Scheme 1. This is in accordance with the results of an inde-

pendent assignment by chemical correlation^[52]

.

Because of the possible interference of the ketal group in

8a and 8b with the Lewis acid necessary for the planned

Mukaiyama reaction of the silyl enol ether we included in

the deprotonation studies ketone 25 which carries a less

sensitive silyloxy group instead of the ketal group (Scheme

3). Reduction of 9 with NaBH₄in EtOH at Ϫ45°C pro-

ceeded highly stereoselective and afforded alcohols 23 and

epi-23^[55]in a ratio of 98:2 in 98% yield. Although both

alcohols 23 and epi-23 could be used in principle for the

syntheses of 4 and 5, epi-23 was removed by chromatogra-

phy in order to simplify analysis of the products in the sub-

sequent steps. Ketone 25 was prepared in two steps in 96%

overall yield from 23 via silylation with tBuPh₂SiCl, yield-

ing the silyl ether 24, followed by the pTsOH-catalyzed

cleavage of the ketal group in the latter in acetone.

Scheme 5

Following the optimal protocol developed for the depro-

tonation of 9 (cf. Table 1), (R,R)-bis(phenylethyl)ammon-

ium chloride was treated with two equivalents of nBuLi,

providing 12·LiCl, followed by addition of 25 at Ϫ100°C

(Scheme 4). The thus formed lithium enolate 26 was treated

at Ϫ78°C with Et₃SiCl. This led to isolation of the stable

silyl ether 27 in 94% yield, which had an ee value of 92%,

according to ¹H-NMR spectroscopy in the presence of

Pr(tfc)₃/Ag(fod), [∆∆δ (ϭCHR) ϭ 0.08].

Reagents and conditions: (a) THF, hexanes, Ϫ78°C.

Eur. J. Org. Chem. 1998, 805Ϫ826

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Asymmetric Synthesis of 3-Oxacarbacyclin and 3-Oxaisocarbacyclin

FULL PAPER

C-13. Unfortunately the major diastereomer 29 has, in syn- Scheme 7

thetic terms, the wrong configuration at C-13. Thus, its use

for the synthesis of 4 and 5 would require an additional

stereochemical correction step at a latter stage. The dia-

stereomers 29 and 30 were readily separated by chromatog-

raphy. Since we did not determine the enantiomeric compo-

sition of 29 and 30 independently we assume that the aldol

products have the same ee value as the silyl ethers 8a and

8b.

Reduction of ketone 29 with NaBH₄in EtOH at Ϫ45°C

gave diols 31 and 32 in a ratio of 96:4 in 84% yield (Scheme

6). A similar reduction of ketone 30 afforded diols 33 and

34 in a ratio of 96:4 in 84% yield.

Scheme 6

Reagents and conditions: (a) acetone, Me₂C(OMe)₂, ω-camphor-

sulfonic acid, room temp.

of 35 and 36 were established by NOE experiments on the

basis of a complete assignment of the signals in the ¹H- and

¹³C-NMR spectra by APT-, (H,H)-COSY-, (H,C)-COSY

and H-delayed-(H,H)-COSY-experiments. The more im-

portant details of the NOE experiments are summarized in

formulas 35A and 36A. Thus, aldehyde 28 had attacked the

double bond in 13 exclusively from the sterically less hin-

dered convex side but giving the syn aldol product with low

diastereoselectivity. Because of the low selectivity of the al-

dol reaction leading to 29 and 30 in regard to the configura-

tion of C-13, we studied, as planned, the reaction of the

silyl enol ether 8b (92% ee) with aldehyde 28 in the presence

of TiCl₄. However, with this Lewis acid a mixture of several

products was formed. Analysis of the reaction products re-

vealed a competing reaction of TiCl₄with the ketal

group^[57]in 8b as well as in the aldol products formed.

These side reactions could be avoided completely, however,

by using BF₃as the Lewis acid. Reaction of 8b of 92% ee

with 28 in the presence of BF₃·OEt₂in CH₂Cl₂at Ϫ95°C

gave under a partial transfer of the silyl group^[31]a mixture

of the silyl ethers 37 and 38 in a ratio of 4:1 in 62% yield

and a mixture of alcohols 29 and 30 in a ratio of 4:1 in 15%

yield (Scheme 8).

The configurations of 37 and 38 were determined by their

desilylation to diols 29 and 30, respectively. Although the

Reagents and conditions: (a) NaBH₄, EtOH, Ϫ45°C.

Diols 31Ϫ34 were readily obtained diastereomerically diastereoselectivity of the aldol reaction could be improved

pure by chromatography. In order to assign the configura- by an increase of the reaction temperature and a decrease

tions of diols 31Ϫ34 at C-11 to C-13 diols 32 and 33 were of the reaction time, the yields of 37 and 38 became unac-

converted to acetonides^[56]35 and 36, respectively, which ceptably low. Thus we turned our attention to the Mukai-

were isolated in 66% and 96% yield (Scheme 7).

yama reaction of the silyl enol ether 27, being devoid of the

Conversion of diol 31 to the corresponding acetonide ketal group, with 28 (Scheme 9).

could not be achieved under these conditions. This is pre-

A mixture of aldehyde 28 and BF₃·Et₂O was prepared at

sumably due to a 1,3-diaxial interaction between the methyl room temperature, cooled immediately to Ϫ78°C and

group and the alkenyl group in the transition state of ace- treated with 27 of 92% ee. After a reaction time of 1 h, a

tonide formation of 31. The configurations at C-11 to C-13 mixture of the silyl ethers 39 and 40 in a ratio of 95:5 was

Eur. J. Org. Chem. 1998, 805Ϫ826

809

I. Vaulont, H.-J. Gais, N. Reuter, E. Schmitz, R. K. L. Ossenkamp

determined by NOE experiments on the basis of a complete

FULL PAPER

Scheme 8

1

assignment of the signals in the H- and ¹³C-NMR spectra

by ATP-, (H,H)-COSY-, (H,C)-COSY and H-delayed-

(H,H)-COSY-experiments. The more important details of

the NOE experiments are summarized in formula 44A.

Scheme 10

Reagents and conditions: (a) BF₃·OEt₂, CH₂Cl₂, Ϫ78°C.

Scheme 9

Reagents and conditions: (a) NaBH₄, EtOH, Ϫ45°C; (b) acetone,

Me₂C(OMe)₂, ω-camphorsulfonic acid, room temp.

Having attached a unit containing C-13 to C-20 enanti-

oselectively to 9, we turned our attention to the structural

adjustment of the side chain in 41 according to the ω-side

chain in the target compounds 4 and 5. We therefore envis-

aged a reduction of the carbonyl group of 41, or of a deriva-

tive thereof, followed by a transposition of the allylic

hydroxy group in the resulting diol from the 13- into the

15-position by a Pd-catalyzed rearrangement^{[29][30][31][32]}

.

Protection of the hydroxy group in 41 by treatment with

acetyl chloride and pyridine gave acetate 45 (Scheme 11).

Reduction of ketone 45 with NaBH₄in EtOH at Ϫ45°C

led to isolation of a mixture of alcohols 46 and epi-46 in a

ratio of 91:9 in 84% yield. A higher selectivity in the re-

duction of 45 was achieved by using Zn(BH₄)₂in ether at

Ϫ30°C, which delivered a mixture of alcohols 46 and epi-

46 in a ratio of 97.5:2.5 in 87% yield. Chromatography af-

forded the diastereomerically pure alcohol 46 (85%) which

was benzoylated to give benzoate 47 in 96% yield. The in-

Reagents and conditions: (a) BF₃·OEt₂, CH₂Cl₂, Ϫ78°C; (b)

AcOH, H₂O, THF, room temp.

isolated in 69% yield. Obviously, aldehyde 28 had entered troduction of two different protecting groups for the

preferentially with the Si-side the enol ether 27 from the hydroxy groups at C-11 and C-13 in 47 was deemed neces-

convex side under formation of the syn aldol product under sary because of the inversion of configuration at C-15 which

silyl group transfer. As side products alcohols 41 and 42 has to be carried out after the allylic rearrangement. Treat-

were obtained in an opposite ratio of 1:2 in 15% yield. ment of 47 with a catalytic amount of Pd(MeCN)₂Cl₂in

Selective cleavage of the silyl ethers 39 and 40 with aqueous THF at room temperature gave the isomeric acetate 48 as

AcOH gave a mixture of alcohols 41 and 42 in a ratio of a single diastereomer. Unfortunately the allylic rearrange-

95:5 in 80% yield. Alcohols 41 and 42 were obtained dia- ment of 47 could not be brought to completion. An equilib-

stereomerically pure by chromatography. The configura- rium consisting of 75% of 48 and 25% of 47 was established

tional assignment of 41 and 42 was made by NMR spec- instead. The same observation was made in the case of the

troscopy of acetonide 44 derived from the reduction prod- Pd-catalyzed rearrangement of the allylic diacetate derived

uct of the minor alcohol 42, 43 (Scheme 10). Thus, re- from diol 31^[51]and of a similar bicyclic allylic diace-

duction of 42 with NaBH₄in EtOH at Ϫ45°C afforded diol tate^[32a]. These results are in contrast to reports of unidirec-

43 of 98% de in 86% yield. Ketalization of 43 with 2,2- tional Pd-catalyzed rearrangements of analogous mono-

dimethoxypropane in acetone led to isolation of ketal 44 in cyclic allylic acetates^[31]. Fortunately, a separation of both

99% yield. The configurations at C-11 to C-13 in 44 were isomers could be achieved by chromatography, affording 48

810

Eur. J. Org. Chem. 1998, 805Ϫ826

Asymmetric Synthesis of 3-Oxacarbacyclin and 3-Oxaisocarbacyclin

Scheme 11

FULL PAPER

phosphonoaceates 56 or 57^{[15][17][33][59]}(Scheme 12). We

have recently introduced 56 for the diastereoselective olefin-

ation of ketone 9^[17]. Phosphonoacetate 56 contains as chi-

ral auxiliary (1S-trans)-8-phenylnormenthol, which is much

more readily accessible than (1S,2R,5S)-8-phenylmen-

thol^[60]. The highest selectivity in the olefination of 9 with

56 was obtained in THF at low temperatures in the pres-

ence of LiCl. With LiCl as additive the yield and diastereo-

selectivity increased noticeably^[17]

.

Scheme 12

Reagents and conditions: (a) MeCOCl, pyridine, THF, room temp.;

(b) Zn(BH₄)₂, ether, Ϫ30°C; (c) PhCOCl, pyridine, 0°C; (d)

Pd(MeCN)₂Cl₂, THF, room temp.; (e) MeOH, K₂CO₃, room

temp.; (f) PPh₃, EtOOCϪNϭNϪCOOEt, PhCOOH, THF, Ϫ30°C.

in 71% yield besides 47 in 24% yield. The acetoxy group

in 48 was cleaved selectively with 1% K₂CO₃in MeOH.

Deacetylation was stopped before it had gone to com-

pletion in order to prevent the concomitant cleavage of the

benzoyloxy group. Thus, alcohol 49 was obtained in 79%

yield besides a 12% recovery of 48. The final step of the

completion of the ω-side chain consisted in the inversion of

Reagents and conditions: (a) Bu₄NF·H₂O, THF, room temp.; (b)

(COCl)₂, DMSO, NEt₃, CH₂Cl₂, Ϫ60°C; (c) MeOH; NaOH, room

configuration at C-15 in 49. Mitsunobu reaction^[58]of 49 temp.; (d) 3,4-dihydro-2H-pyran, pyridinium p-toluenesulfonate,

CH₂Cl₂, room temp.; (e) THF, LiCl, Ϫ62°C; (f) MeOH, pyridinium

with diethyl azodicarboxylate, triphenylphosphane and ben-

zoic acid at Ϫ30°C delivered the epimeric benzoate 50 in

p-toluenesulfonate, room temp.

83% yield. As a side product the isomeric benzoate 51 was

The required ketone 7b was prepared in a straight for-

isolated in 4% yield. Finally, a configurational correlation ward manner from the silyl ether 50 in three steps. Desilyl-

between diol 43 (cf. Scheme 10) and dibenzoate 50 was ation of 50 with Bu₄NF gave alcohol 55, which, upon Swern

made through acetylation of the former to give diacetate 52 oxidation with DMSO, (COCl)₂and NEt₃at Ϫ60°C, af-

which was submitted to the Pd-catalyzed rearrangement to forded ketone 7a. Finally, cleavage of the benzoyloxy

afford a 75:25 mixture of 53 and 52 in 95% yield. Cleavage groups in 7a with NaOH in MeOH delivered 7b^[24][25]in

of the acetoxy groups in 53 followed by a benzoylation of 76% overall yield from 50. In order to study the influence

54 gave dibenzoate 50 in 95% yield.

of the hydroxy groups in 7b upon the stereoselectivity of

3-Oxacarbacyclin: According to the synthetic plan, we the olefination reaction with 56^[33]we prepared as a further

envisaged the stereoselective attachment of the α-side chain substrate the bis-THP ether 7c from 7b^[24][25]by treatment

in 4 and 5 via reaction of ketone 7 with the chiral lithium of the latter with 3,4-dihydro-2H-pyran in the presence of

Eur. J. Org. Chem. 1998, 805Ϫ826

811

I. Vaulont, H.-J. Gais, N. Reuter, E. Schmitz, R. K. L. Ossenkamp

FULL PAPER

pyridinium p-toluenesulfonate in 99% yield. Reaction of ke- Scheme 13

tone 7b with 3 equivalents of 56 in THF gave, after a reac-

tion time of 7 d at Ϫ62°C, a mixture of esters 58 and 59 in

a ratio of 93:7 in 72% yield, according to HPLC analysis

and NMR spectroscopy. LiCl had almost no effect upon

the rate and selectivity of the reaction of 7b with 56. In

accordance with previous observations in the case of 9^[17]

the reaction of 7b with 56 showed a linear temperatureϪ

diastereoselectivity relationship^[61]. The reaction of the bis-

THP ether 7c with 56 in THF at Ϫ62°C took a similar

course. In this case, however, addition of LiCl slightly raised

the diastereoselectivity of the olefination. Cleavage of the

THP groups in the thus obtained mixture of esters 60 and

61 gave a mixture of diols 58 and 59 in a ratio of 95:5 in

82% overall yield from 7c. MPLC allowed for the removal

of the unwanted diastereomer 59 and afforded 58 in 72%

yield as a single stereoisomer, according to HPLC analysis

and NMR spectroscopy. It was presumably at this stage

where the second unwanted diastereomer of 58, stemming

from ent-27, was separated as well.

The preferential formation of 58 and 60 can be rational-

ized by assuming a highly selective and irreversible addition

of (E)-phosphonoenolate 56 from its least hindered Re-side

(C-1) to ketones 7b and 7c from the convex side^[17]. A com-

parison with the olefination of the prochiral ketone 9 shows

that the side chains in the chiral ketones 7b and 7c have

almost no influence upon the stereoselectivity of the olefin-

ation with 56.

Reagents and conditions: (a) 3,4-dihydro-2H-pyran, pyridinium p-

toluenesulfonate, CH₂Cl₂, room temp.; (b) DIBALϪH, THF, 0°C

Ǟ room temp.; (c) BrCH₂COOtBu, Bu₄NHSO₄, CH₂Cl₂, NaOH-

H₂O, room temp; (d) EtOH, pyridinium p-toluenesulfonate, room

temp.; (e) MeOH, NaOH-H₂O, room temp.

The α-side chain in 4 starting from 58 was completed

following an established protocol^{[7][8][14][18]}. Treatment of was treated with two equivalents of nBuLi, providing

diol 58 with 3,4-dihydro-2H-pyran and pyridinium p-tolu- 12·LiCl, which was treated with 60 at Ϫ100°C. Subsequent

enesulfonate gave the bis-THP ether 60 in 99% yield, which, protonation of the thus formed lithium enolate 65, whose

upon reduction with DIBAL-H, afforded the allylic alcohol configuration was not determined, with saturated aqueous

62 in 86% yield (Scheme 13). In addition to 62 (1S-trans)- NaHCO₃at Ϫ78°C led to isolation of the β,γ-unsaturated

8-phenylnormenthol was formed. (1S-trans)-8-phenylnor- ester 66 in 91% yield. ¹H-NMR spectroscopy of the alcohol

menthol was not isolated but its recovery in high yield 67, obtained by cleavage of crude 66, showed the admixture

should pose no problems. Etherfication of 62 by reaction of only 1.5% of the isomeric alcohol 70. Deprotonation of

with tert-butyl bromoacetate in the presence of NaOH pro- the isomeric α,ß-unsaturated ester 61 with 12·LiCl gave en-

vided ester 63 in 85% yield. Cleavage of the bis-THP ether olate 68, whose configuration was not determined. Sub-

63 with pyridinium p-toluenesulfonate in EtOH delivered sequent protonation of 68 afforded ester 69 in 88% yield.

diol 64 in 94% yield. Finally, saponification of ester 64 un- ¹H-NMR spectroscopy of alcohol 70, obtained by cleavage

der basic conditions gave (ϩ)-3-oxacarbacyclin (4) in 85% of crude 69, showed the admixture of only 1.5% of the iso-

yield. The NMR spectroscopic data and the optical rotation meric alcohol 67. The structures of alcohols 67 and 70 were

22

20

of 4 ([α]_Dϭ ϩ64.2 (c ϭ 0.30, MeOH), ref^[18][α]_D

ϩ62.3 (c ϭ 0.40, MeOH) matched those reported in the lit- of 12 nor of the ester group apparently have any influence

erature^[18]

upon the selectivity of the deprotonation of 60 and 61. Thus

ϭ

determined by NOE experiments. Thus, neither the chirality

.

3-Oxaisocarbacyclin: According to the retrosynthetic it seems reasonable to assume that an achiral base like LDA

scheme the synthesis of 3-oxaisocarbacyclin (5) will be car- could be used as well^[35][36]. The highly selective depro-

ried out by divergence of the synthesis of 4 at a late stage. tonations of 60 and 61 can be best explained by a coordi-

This called for the isomerization of the α,β-unsaturated es- nation of 12 to the carbonyl groups in the esters followed

ter 60 to the β,γ-unsaturated ester 66 (Scheme 14).

This transformation requires two

by an intramolecular deprotonation^[34d]

Completion of the α-side chain in 5 starting from 66 was

.

selective

steps^{[8][34][35][36]}, deprotonation at the methylene group cis accomplished in a similar manner as described above in the

to the ester group under formation of the vinylogous enol- synthesis of 4. Reduction of 66 with DIBAL-H afforded the

ate 65, and, secondly, protonation of 65 at the α-position. allylic alcohol 71 in 71% yield (Scheme 15). In addition to

Because of the highly selective deprotonation of 9 with 12, 71 (1S-trans)-8-phenylnormenthol was formed. (1S-trans)-

we choose this chiral base for the regioselective depro- 8-phenylnormenthol was not isolated but its recovery in

tonation of 60. (R,R)-Bis(phenylethyl)ammonium chloride high yield should be possible. Etherification of 71 by reac-

812

Eur. J. Org. Chem. 1998, 805Ϫ826

Asymmetric Synthesis of 3-Oxacarbacyclin and 3-Oxaisocarbacyclin

Scheme 14

FULL PAPER

Scheme 15

Reagents and conditions: (a) DIBALϪH, THF, 0°C Ǟ room

temp.; (b) BrCH₂COOtBu, Bu₄NHSO₄, CH₂Cl₂, NaOH-H₂O,

room temp.; (c) EtOH, pyridinium p-toluenesulfonate; (d) MeOH,

NaOH-H₂O, room temp.

Financial support of this research by the Deutsche Forschungsge-

meinschaft, the Schering AG, Berlin, and the Fonds der Chemischen

Industrie is gratefully acknowledged. The authors are indebted to

Professor Dr. H. Vorbrüggen and Dr. W. Skuballa for stimulating

discussions. The authors further acknowledge Dr. H. Dahl for a

generous supply of ketone 9 and Dr. J. Runsink for NOE experi-

ments.

Reagents and conditions: (a) 1. THF, Ϫ100°C; 2. 60, Ϫ100°C; (b)

NaHCO₃, H₂O, Ϫ78°C; (c) MeOH, pyridinium p-toluenesulfonate,

room temp.

Experimental Section

All reactions were carried out in oven-dried glassware under an

argon atmosphere unless otherwise noted. Diethyl ether and THF

were distilled from sodium/benzophenone, CH₂Cl₂and DMF were

tion with tert-butyl bromoacetate in the presence of NaOH

provided ester 72 in 85% yield. Cleavage of the bis-THP distilled from CaH₂, EtOH was distilled from sodium, and pyridine

was distilled from KOH. nBuLi was standardized by titration with

diphenylacetic acid. Ϫ TLC analysis was performed with Merck

silica gel coated aluminum foil. Ϫ Chromatography was performed

with Merck silica gel 60 (0.063Ϫ0.100 mm). Ϫ MPLC was per-

formed with Impaq silica gel (particle size 1.61 µm) on a Kronwald

apparatus. Ϫ HPLC analysis was performed with a Chiracel OD

(Baker) column. Ϫ IR spectra were recorded on a Perkin-Elmer PE

1760 spectrometer. Only peaks of ν˜ > 900 cm^Ϫ1in the IR spectra

are listed. Ϫ ¹H-NMR spectra and ¹³C-NMR spectra were re-

corded on a Varian VXR 300 or a Varian Unity 500 spectrometer.

Chemical shifts are reported relative to TMS (δ 0.00) as the internal

standard. Splitting patterns in the ¹H NMR spectra are designated

as s, singlet; d, doublet; dd, double doublet; t, triplet; q, quartet;

quin, quintet; m, multiplet. Peaks in the ¹³C NMR spectra are de-

noted as Љu“ for carbons with zero or two attached protons or as

Љd“ for carbons with one or three attached protons, as determined

from the APT puls sequence. Ϫ Optical rotations were measured

with a Perkin-Elmer Model 241 polarimeter at 22°C. Ϫ Mass spec-

tra were obtained with a Finnigan MAT 212 spectrometer (EI, 70

eV). Only peaks of m/z >100 and an intensity of >10% in the MS

ether 72 with pyridinium p-toluenesulfonate in EtOH deliv-

ered diol 73 in 85% yield. Finally, saponification of ester 73

under basic conditions gave (ϩ)-3-oxaisocarbacyclin (5) in

87% yield. The NMR spectroscopic data and the optical

22

rotation of 5 ([α]_Dϭ ϩ6.9 (c ϭ 4.60, MeOH), ref.^[8]

20

[α]_Dϭ ϩ6.2 (c ϭ 0.40, MeOH) matched those reported

in the literature^[8]

.

Conclusion

In this article, we have described new asymmetric synth-

eses of 3-oxacarbacyclin (4) and 3-oxaisocarbacyclin (5)

from 9 by a common route which is characterized by diver-

gence at a late stage and which should allow for the syn-

thesis of other 3-oxacarbacyclins and 3-oxaisocarbacyclins

as well. We are currently exploring the synthesis of 2 and

of 3 from 27 by using, for the construction of the ω-side

chains^[7][14][62]

,

(E,S)-2-bromo-4-methylnon-6-yn-2-enal

and (E,S)-4-methyloct-5-yn-2-enal, respectively.

Eur. J. Org. Chem. 1998, 805Ϫ826

813

I. Vaulont, H.-J. Gais, N. Reuter, E. Schmitz, R. K. L. Ossenkamp

FULL PAPER

spectra are listed. Ϫ Elemental analyses were performed by the

acetone). Ϫ IR (neat): ν˜ ϭ 3060 (s), 1645 (s), 1325 (s), 1250 (s),

Institut für Organische Chemie Microanalytical Laboratory. Ϫ H 1195 (s), 1115 (s). Ϫ H NMR (300 MHz, CDCl₃): δ ϭ 0.20 (s, 9

1

NMR shift experiments with Eu(tfc)₃and Ag(fod) were carried out

with freshly prepared solutions of the reagents.

H), 0.95 (s, 3 H), 0.97 (s, 3 H), 1.50Ϫ1.60 (m, 2 H), 1.96Ϫ2.05 (m,

1 H), 2.24Ϫ2.40 (m, 2 H), 2.49Ϫ2.69 (m, 2 H), 3.01Ϫ3.14 (m, 1

H), 3.46 (s, 2 H), 3.49 (s, 2 H), 4.59Ϫ4.62 (m, 1 H). Ϫ H NMR

1

Deprotonation of 9 with 12. Ϫ Method A: A solution of (R,R)-

bis(phenylethyl)amine (1.34 mmol) in THF (5 ml) was cooled to

Ϫ78°C and nBuLi (1.55  in hexanes, 1.33 mmol) was added drop-

wise. The mixture was warmed to 0°C and recooled to Ϫ100°C. A

solution of the ketone (0.67 mmol) in THF (5 ml) was added drop-

wise and the mixture was stirred for 15 min. After addition of

ClSiR₃(3.34 mmol), the mixture was stirred for 60 min. at Ϫ100°C.

The mixture was treated with saturated aqueous NaHCO₃(5 ml),

warmed to ambient temp. and extracted with ether (3 ϫ 30 ml).

The organic phase was dried (MgSO₄) and concentrated in vacuo.

(300 MHz, CDCl₃, 100 mol% Ag(fod)/(ϩ)-Pr(tfc)₃): δ (ϭCH-R)

(ent-8a) ϭ 4.43, δ (ϭCH-R) (8a) ϭ 4.47. Ϫ ¹³C NMR (75 MHz,

CDCl₃): δ ϭ 0.04 (d), 22.53 (d), 22.55 (d), 30.09 (u), 35.51 (d),

39.88 (u), 40.16 (u), 41.19 (u), 43.18 (d), 71.40 (u), 72.73 (u), 107.18

(d), 108.86 (u), 152.71 (u). Ϫ MS; m/z (%): 296 [M^ϩ] (30), 209

(72), 206 (63), 167 (94), 128 (96), 73 (100). Ϫ C₁₆H₂₈O₃Si: calcd.

296.18077, found 296.1805 (MS).

(3ЈaR-cis)-Triethyl-[[3Ј,3Јa,4Ј,6Јa-tetrahydro-5,5-dimethylspiro-

[1,3-dioxane-2,2Ј(1ЈH)-pentalen]-5Ј-yl]oxy]silane (8b): Following

Chromatography (hexanes/EtOAc, 1:1) of the residue gave the silyl method E, 9 (2.00 g, 8.90 mmol) in THF (40 ml) gave 8b (2.87 g,

enol ether.

95%, 92% ee) as a colorless oil, [α]_Dϭ ϩ0.6 (c ϭ 9.8, THF). Ϫ IR

(neat): ν ϭ 3060 (w), 2960 (s), 2910 (s), 2880 (s) 1740 (w), 1645 (s),

˜

Method B: A solution of (R,R)-bis(phenylethyl)amine (2 mmol)

in THF (10 ml) was cooled to Ϫ90°C and nBuLi (1.58  in hex-

anes, 1.98 mmol) was added dropwise. The mixture was warmed to

ambient temp. and recooled to Ϫ95°C. A solution of ClSiR₃(5

mmol) in THF (4 ml) was added dropwise and the mixture was

stirred for 5 min. After addition of a solution of the ketone (1

mmol) in THF (4 ml), the mixture was stirred for 30 min. at

Ϫ90°C. The mixture was treated with saturated aqueous NaHCO₃

(10 ml) and warmed to ambient temp. After work up as described

above (method A), the silyl enol ether was obtained.

1465 (m), 1415 (w), 1395 (w), 1325 (s), 1280 (w), 1250 (s), 1195 (s),

1

1115 (s), 1005 (s), 930 (m). Ϫ H NMR (300 MHz, CDCl₃): δ ϭ

0.67 (q, J ϭ 8.0 Hz, 6 H), 0.95 (s, 6 H), 0.97 (t, J ϭ 8.0 Hz, 9 H),

1.51Ϫ1.63 (m, 2 H), 1.99Ϫ2.05 (m, 1 H), 2.31 (ddd, J ϭ 13.1, J ϭ

8.7, J ϭ 2.0 Hz, 1 H), 2.36 (ddd, J ϭ 12.7, J ϭ 7.7, J ϭ 2.0 Hz, 1

H), 2.51Ϫ2.66 (m, 2 H), 3.05Ϫ3.09 (m, 1 H), 3.45 (s, 2 H), 3.49 (s,

1

2 H), 4.61 (q, J ϭ 1.8 Hz, 1 H). Ϫ H NMR (300 MHz, CDCl₃,

100 mol% Ag(fod)/(ϩ)-Pr(tfc)₃): δ (ϭCH-R) (ent-8b) ϭ 4.44, δ (ϭ

CH-R) (8b) 4.51. Ϫ ¹³C NMR (75 MHz, CDCl₃): δ ϭ 4.81 (u),

6.62 (d), 22.55 (d), 22.57 (d), 30.13 (u), 35.60 (d), 39.97 (u), 40.09

(u), 41.20 (u), 43.19 (d), 71.42 (u), 72.83 (u), 106.97 (d), 108.90 (u),

153.00 (u). Ϫ MS; m/z (%): 338 [M^ϩ] (30), 252 (18), 251 (54), 223

(13), 210 (17), 209 (40), 207 (14), 206 (70), 129 (26), 128 (100), 115

(48), 103 (18). Ϫ C₁₉H₃₄O₃Si (338.5): calcd. C 67.40, H 10.12;

found C 67.77, H 10.37.

Method C: A solution of (R,R)-bis(phenylethyl)amine (1.34

mmol) in THF (5 ml) was cooled to Ϫ78°C, and nBuLi (1.55  in

hexanes, 1.33 mmol) was added dropwise. The mixture was warmed

to 0°C, treated with a solution of LiCl (43 mg, 1.01 mmol) in THF

(2 ml) and recooled to Ϫ100°C. Subsequently ClSiR₃(3.34 mmol)

was added dropwise. After addition of a solution of the ketone

(0.67 mmol) in THF (5 ml), the mixture was stirred for 60 min. at

Ϫ100°C. The mixture was treated with saturated aqueous NaHCO₃

(5 ml) and warmed to ambient temp. After work up as described

above (method A), the silyl enol ether was isolated.

[1S-(1Ͱ,2β,3aͰ,6aͰ)]-(1,1-Dimethylethyl)-[2-[1,2,3,3a,6,6a-

hexahydro-1-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]methyl]-5-

[(trimethylsilyl)oxy]pentalenyl]oxy]dimethylsilane (21) and [1S-

(1Ͱ,2β,3aͰ,6aͰ)]-(1,1-Dimethylethyl)-[2-[1,2,3,3a,4,6a-hexa-

hydro-1-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]methyl]-5-

[(trimethylsilyl)oxy]pentalenyl]oxy]dimethylsilane (22): Following

method B, 20 (586 mg, 2.22 mmol) in THF (4 ml) and 12 gave

after chromatography (hexanes/EtOAc, 9:1) 900 mg (87%) of an

unseparable mixture of 21 and 22 in a ratio of 95:5 as a colorless

oil.

Method D: A solution of (R,R)-bis(phenylethyl)amine (1.34

mmol) in THF (5 ml) was cooled to Ϫ78°C and nBuLi (1.55  in

hexanes, 1.33 mmol) was added dropwise. The mixture was warmed

to 0°C, treated with a solution of LiCl (43 mg, 1.01 mmol) in THF

(2 ml) and recooled to Ϫ100°C. A solution of the ketone (0.67

mmol) in THF (5 ml) was added dropwise and the mixture was

stirred for 15 min. After addition of ClSiR₃(3.34 mmol), the mix-

ture was stirred for 60 min. at Ϫ100°C. The mixture was treated

with saturated aqueous NaHCO₃(5 ml) and warmed to ambient

temp. After work up as described above (method A), the silyl enol

ether was isolated.

21: ¹H NMR (500 MHz, CDCl₃): δ ϭ 0.04 (t, J ϭ 2.1 Hz, 9 H),

0.19 (s, 12 H), 0.87 (s, 9 H), 0.89 (s, 9 H), 1.22Ϫ1.29 (m, 1 H), 1.58

(ddt, J ϭ 9.5, J ϭ 5.3, J ϭ 3.4 Hz, 1 H), 2.06Ϫ2.12 (m, 1 H),

2.12Ϫ2.17 (m, 1 H), 2.34 (m, 1 H), 2.51 (ddt, J ϭ 16.0, J ϭ 9.5,

J ϭ 2.0 Hz, 1 H), 2.86 (m, 1 H), 3.61 (dd, J ϭ 10.0, J ϭ 5.0 Hz,

1 H), 3.69 (dd, J ϭ 10.0, J ϭ 3.5 Hz, 1 H), 3.82 (dt, J ϭ 9.5, J ϭ

7.0 Hz, 1 H), 4.63 (q, J ϭ 1.8 Hz, 1 H). Ϫ ¹³C NMR (125 MHz,

CDCl₃): δ ϭ Ϫ5.55 (d), Ϫ5.40 (d), Ϫ4.83 (d), Ϫ4.43 (d), 0.10 (d),

18.08 (u), 18.35 (u), 25.88 (d), 25.98 (d), 37.33 (d), 39.57 (u), 41.64

(d), 41.88 (u), 56.53 (d), 61.78 (u), 73.11 (d), 107.58 (d), 152.52 (u).

Method E: A suspension of (R,R)-bis(phenylethyl)ammonium

chloride (1.67 mmol) in THF (10 ml) was cooled to Ϫ78°C and

nBuLi (1.44  in hexanes, 3.26 mmol) was added dropwise. The

mixture was warmed to 0°C, recooled to Ϫ105°C and treated drop-

wise with a solution of the ketone (1.11 mmol) in THF (5 ml).

After stirring the mixture for 30 min. at Ϫ105°C, it was warmed

to Ϫ78°C and treated with ClSiEt₃(1.45 mmol). After stirring the

mixture for 15 min., saturated aqueous NaHCO₃(5 ml) was added

and the mixture was warmed to ambient temp. After work up as

described above (method A), the silyl enol ether was obtained.

1

22: H NMR (300 MHz, CDCl₃, in part) δ ϭ 4.69 (q, J ϭ 1.8

Hz, 1 H). Ϫ ¹³C NMR (75 MHz, CDCl₃, in part): δ ϭ Ϫ5.55 (d),

Ϫ5.41 (d), Ϫ4.83 (d), Ϫ4.43 (d), 0.05 (d), 18.05 (u), 18.33 (u), 25.88

(d), 25.98 (d), 33.90 (d), 40.67 (u), 43.03 (u), 46.96 (d), 56.86 (d),

63.33 (u), 73.59 (d), 106.82 (d), 152.05 (u).

By the same procedure but using ent-12, 20 gave a mixture of 21

and 22 in a ratio of 14:86 in 85% yield.

(3ЈaR-cis)-Trimethyl-[[3Ј,3Јa,4Ј,6Јa-tetrahydro-5,5-dimethyl-

spiro[1,3-dioxane-2,2Ј(1ЈH)-pentalen]-5Ј-yl]oxy]silane (8a): Fol-

lowing method D, 9 (150 mg, 0.67 mmol) in THF (5 ml) gave 8a

(165 mg, 83%, 92% ee) as a colorless oil, [α]_Dϭ ϩ16.9 (c ϭ 10.1,

(3ЈaͰ,5Јβ,6ЈaͰ)-Hexahydro-5,5-dimethylspiro[1,3-dioxane-2,2Ј-

(1ЈH)-pentalen]-5Ј-ol (23) and (3ЈaͰ,5Јα,6ЈaͰ)-Hexahydro-5,5-di-

814

Eur. J. Org. Chem. 1998, 805Ϫ826

Asymmetric Synthesis of 3-Oxacarbacyclin and 3-Oxaisocarbacyclin

FULL PAPER

methylspiro[1,3-dioxane-2,2Ј(1ЈH)-pentalen]-5Ј-ol (epi-23): A solu-

tion of 9 (20.00 g, 89.17 mmol) in EtOH (250 ml) was cooled to

13.7, J ϭ 4.7, J ϭ 4.7 Hz, 2 H), 2.01 (ddd, J ϭ 13.7, J ϭ 7.7, J ϭ

6.0 Hz, 2 H), 2.35 (dd, J ϭ 18.7, J ϭ 4.3 Hz, 2 H), 2.50 (dd, J ϭ

Ϫ45°C and NaBH₄(6.75 g, 178.32 mmol) was added. After stirring 18.9, J ϭ 9.6 Hz, 2 H), 2.57Ϫ2.68 (m, 2 H), 4.33 (m, 1 H),

the mixture for 4 h, saturated aqueous NH₄Cl (20 ml) was added.

The mixture was warmed to ambient temp. and extracted with di-

ethyl ether. The organic phase was dried (MgSO₄) and concentrated

7.34Ϫ7.45 (m, 6 H), 7.63Ϫ7.67 (m, 4 H); ¹³C NMR (75 MHz,

CDCl₃): δ ϭ 19.0 (u), 26.9 (d), 37.8 (d), 42.8 (u), 45.3 (u), 76.2 (d),

127.6 (d), 129.6 (d), 134.0 (u), 135.8 (d), 221.0 (u). Ϫ MS; m/z (%):

in vacuo. Chromatography (hexanes/EtOAc, 1:1) of the residue 322 (28), 321 (100), 200 (17), 243 (9), 199 (89), 139 (28). Ϫ

gave 23 (19.37 g, 96%) and epi-23 (395 mg, 2%) as white waxy C₂₄H₃₀O₂Si (378.6): calcd. C 76.14, H 7.99; found C 75.81, H 7.92.

solids.

[2S-(2Ͱ,3aβ,6aβ)]-(1,1-Dimethylethyl)-[2-[1,2,3,3a,4,6a-

23: IR (KBr): ν ϭ 3290 (br), 2950 (s), 2860 (s), 1470 (s), 1395

˜

hexahydro-5-[(triethylsilyl)oxy]pentalenyl]oxy]diphenylsilane

(27): Following method E (vide supra), 25 (15.00 g, 39.62 mmol)

in THF (225 ml) gave 27 (18.36 g, 94%, 92% ee) as a colorless oil,

[α]_Dϭ ϩ6.4 (c ϭ 13.2, THF). Ϫ IR (neat): ν˜ ϭ 3070 (m), 2960 (s),

2880 (s), 1645 (s), 1590 (m), 1460 (m), 1430 (m), 1375 (m), 1340

(m), 1330 (m), 1285 (m), 1240 (m), 1220 (m), 1190 (m), 1110 (s),

975 (m), 925 (m), 900 (m). Ϫ ¹H NMR (300 MHz, CDCl₃): δ ϭ

0.68 (q, J ϭ 7.9 Hz, 6 H), 0.98 (t, J ϭ 7.9 Hz, 9 H), 1.04 (s, 9 H),

1.30Ϫ1.54 (m, 2 H), 1.94Ϫ2.10 (m, 3 H), 2.30 (m, 1 H), 2.49 (dd,

J ϭ 15.8, J ϭ 9.4 Hz, 1 H), 2.78 (m, 1 H), 4.04 (m, 1 H), 4.62 (d,

(m), 1360 (s), 1310 (s), 1270 (s), 1255 (s), 1220 (s), 1330 (s), 1125

(s), 1110 (s), 1045 (s), 1015 (s), 995 (s), 980 (s), 950 (m). Ϫ ¹H

NMR (300 MHz, CDCl₃): δ ϭ 0.96 (s, 6 H), 1.52 (ddd, J ϭ 13.1,

J ϭ 5.7, J ϭ 5.7 Hz, 2 H), 1.89 (dd, J ϭ 13.4, J ϭ 5.7 Hz, 2 H),

2.09 (ddd, J ϭ 13.1, J ϭ 5.9, J ϭ 5.9 Hz, 2 H), 2.22 (dd, J ϭ 13.4,

J ϭ 9.4 Hz, 2 H), 2.48 (s, 1H), 2.45Ϫ2.59 (m, 2 H), 3.47 (s, 2 H),

3.50 (s, 2 H), 4.20 (m, 1 H). Ϫ ¹³C NMR (75 MHz, CDCl₃): δ ϭ

22.5 (d), 30.1 (u), 38.5 (d), 40.8 (u), 42.5 (u), 71.9 (u), 72.2 (u), 75.5

(d), 110.5 (u). Ϫ MS; m/z (%): 226 [M^ϩ] (31), 183 (79), 181 (12),

155 (37), 141 (57), 131 (13), 128 (43), 124 (15), 123 (45), 122 (17).

Ϫ C₁₃H₂₂O₃(226.3): calcd. C 68.99, H 9.80; found C 69.37, H 9.77.

1

J ϭ 1.7 Hz, 1 H), 7.33Ϫ7.44 (m, 6 H), 7.65Ϫ7.70 (m, 4 H). Ϫ H

NMR (300 MHz, CDCl₃, 100 mol% Ag(fod)/(ϩ)-Pr(tfc)₃): δ (ϭ

CH-R) (ent-27) ϭ 4.47, δ (ϭCH-R) (27) ϭ 4.55. Ϫ ¹³C NMR (75

MHz, CDCl₃): δ ϭ 4.85 (u), 6.67 (d), 19.12 (u), 26.90 (d), 35.38

(d), 40.51 (u), 41.91 (u), 43.19 (u), 43.32 (d), 74.77 (d), 107.32 (d),

127.47 (d), 129.43 (d), 134.62 (u), 135.75 (d), 152.48 (u). Ϫ MS;

m/z (%): 492 [M^ϩ] (0.4), 437 (13), 436 (36), 435 (100), 199 (19), 135

(7), 115(5), 87 (21). Ϫ C₃₀H₄₄O₂Si₂(492.9): calcd. C 73.11, H 9.00;

found C, 73.18, H 9.08.

epi-23: IR (KBr): ν ϭ 3290 (br), 2960 (s), 2860 (s), 1470 (s), 1435

(m), 1395 (m), 1335 (s), 1295 (s), 1225 (s), 1120 (s) 1020 (s), 975

(m), 945 (m), 910 (m). Ϫ H NMR (300 MHz, CDCl₃): δ ϭ 0.96

(s, 6 H), 1.46 (s, 1 H), 1.57Ϫ1.68 (m, 4 H), 1.81 (ddd, J ϭ 13.1,

J ϭ 8.4, J ϭ 4.4 Hz, 2 H), 2.23 (dd, J ϭ 13.4, J ϭ 9.3 Hz, 2 H),

2.66Ϫ2.74 (m, 2 H), 3.46 (s, 2 H), 3.47 (s, 2 H), 4.41 (m, 1 H). Ϫ

¹³C NMR (75 MHz, CDCl₃): δ ϭ 22.5 (d), 30.1 (u), 38.0 (d), 40.2

(u), 42.2 (u), 71.8 (u), 72.3 (u), 74.8 (d), 110.0 (u). Ϫ MS; m/z (%):

226 [M^ϩ] (74), 183 (74), 155 (41), 141 (74), 128 (45), 96 (44). Ϫ

C₁₃H₂₂O₃(226.3): calcd. C 68.99, H 9.80;. found C 69.16, H 10.01.

˜

1

[3ЈaS-[3ЈaͰ,4ЈͰ(1S*,2E),6Јaα]]-Tetrahydro-4Ј-(1-hydroxy-2-

octenyl)-5,5-dimethylspiro[1,3-dioxane-2,2Ј(1ЈH)-pentalen]-5Ј-

(3ЈH)-one (29) and [3ЈaS-[3ЈaͰ,4ЈͰ(1R*,2E),6ЈaͰ]]-Tetrahydro-

4Ј-(1-hydroxy-2-octenyl)-5,5-dimethylspiro[1,3-dioxane-2,2Ј(1ЈH)-

pentalen]-5Ј(3ЈH)-one (30): A suspension of (R,R)-bis(phenyleth-

yl)ammonium chloride (3.04 g, 11.60 mmol) in THF (65 ml) was

cooled to Ϫ78°C, and nBuLi (1.44  in hexanes, 15.7 ml, 22.6

mmol) was added dropwise. The mixture was warmed to ambient

temp. until it became a clear yellow solution. The solution was

cooled to Ϫ105°C, treated dropwise with a solution of 9 (2.00 g,

8.90 mmol) in THF (35 ml) and stirred for a further 30 min. at

Ϫ105°C. Subsequently, the mixture was warmed to Ϫ78°C and

treated with 28 (1.69 g, 13.40 mmol). After stirring the mixture for

3 h, saturated aqueous NaHCO₃(25 ml) was added. The mixture

was warmed to ambient temp. and extracted with ether. The or-

ganic phase was dried (MgSO₄) and concentrated in vacuo. MPLC

(hexanes/EtOAc, 2:1) of the residue provided 29 (1.98 g, 63%) and

30 (0.99 g, 32%) as colorless oils.

(3ЈaͰ,5Јβ,6ЈaͰ)-(1,1-Dimethylethyl)-[hexahydro-5,5-dimethyl-

spiro[1,3-dioxane-2,2Ј(1ЈH)-pentalen]-5Ј-yloxy]diphenyl-

silane (24): A solution of 23 (18.44 g, 81.46 mmol) in DMF (350

ml) was cooled to 0°C and imidazole (13.87 g, 203.64 mmol) was

added, followed by the dropwise addition of ClSitBuPh₂(24.63 g,

89.60 mmol). After stirring the mixture for 30 min. at 0°C, it was

warmed to ambient temp. and concentrated in vacuo. Chromatog-

raphy (hexanes/EtOAc, 10:1) of the residue provided 24 (37.50 g,

99%) as a colorless oil. Ϫ IR (CHCl₃): ν˜ ϭ 3070 (w), 2950 (s), 2860

(s), 1590 (w), 1470 (m), 1430 (m), 1395 (m), 1365 (m), 1335 (m),

1310 (w), 1255 (m), 1240 (m), 1220 (m), 1110 (s), 1045 (m), 995

1

(m), 905 (m). Ϫ H NMR (300 MHz, CDCl₃): δ ϭ 0.96 (s, 6 H),

1.05 (s, 9 H), 1.57 (ddd, J ϭ 12.9, J ϭ 5.5, J ϭ 5.5 Hz, 2 H),

1.78Ϫ1.91 (m, 4 H), 2.25Ϫ2.37 (m, 4 H), 3.47 (s, 2 H), 3.50 (s, 2

H), 4.21 (m, 1 H), 7.32Ϫ7.42 (m, 6 H), 7.65Ϫ7.69 (m, 4 H). Ϫ ¹³C

NMR (75 MHz, CDCl₃): δ ϭ 19.1 (u), 22.6 (d), 26.9 (d), 30.1 (u),

37.9 (d), 40.5 (u), 41.8 (u), 71.5 (u), 72.7 (u), 77.0 (d), 110.2 (u),

127.5 (d), 129.5 (d), 134.4 (u), 135.8 (d). Ϫ MS; m/z (%): 464 [M^ϩ]

(2), 407 (29), 322 (29), 321 (100), 200 (12), 199 (64), 139 (15). Ϫ

C₂₉H₄₀O₃Si (464.7): calcd. C 74.95, H 8.68; found C 75.14, H 8.78.

29: [α]_Dϭ Ϫ30.0 (c ϭ 9.9, THF). Ϫ IR (CHCl₃): ν˜ ϭ 3460 (s,

br), 2960 (s), 2930 (s), 2860 (s), 1735 (s), 1670 (w), 1470 (m), 1400

(m), 1350 (m), 1330 (m), 1295 (m), 1240 (m), 1210 (m), 1115 (s),

1050 (m), 1010 (m), 975 (m), 910 (w). Ϫ ¹H NMR (300 MHz,

CDCl₃): δ ϭ 0.89 (t, J ϭ 6.9 Hz, 3 H), 0.95 (s, 3 H), 0.97 (s, 3 H),

1.24Ϫ1.43 (m, 6 H), 1.71 (dd, J ϭ 13.4, J ϭ 5.7 Hz, 1 H), 1.92

(dd, J ϭ 14.1, J ϭ 3.4 Hz, 1 H), 2.04 (dt, J ϭ 7.0, J ϭ 7.0 Hz, 2

H), 2.20Ϫ2.35 (m, 5 H), 2.45 (dd, J ϭ 18.8, J ϭ 9.1 Hz, 1 H), 2.77

(m, 2 H), 3.43 (s, 2 H), 3.48 (s, 2 H), 4.51 (m, 1 H), 5.44 (ddt, J ϭ

15.3, J ϭ 6.5, J ϭ 1.3 Hz, 1 H), 5.71 (dtd, J ϭ 15.3, J ϭ 6.7, J ϭ

1.0 Hz, 1 H). Ϫ ¹³C NMR (75 MHz, CDCl₃): δ ϭ 14.05 (d), 22.44

(d), 22.50 (u), 28.84 (u), 30.07 (u), 31.35 (u), 32.16 (u), 35.20 (d),

37.86 (d), 41.06 (u), 41.51 (u), 45.35 (u), 60.01 (d), 71.92 (d), 72.07

(3aͰ,5β,6aͰ)-Hexahydro-5-[(1,1-dimethylethyl)diphenyl-

silyloxy]-2(1H)-pentalenone (25): A solution of 24 (37.50 g, 80.69

mmol) in acetone (600 ml) was treated with water (8 ml) and

pTsOH (0.9 g, 5.23 mmol). The clear solution was stirred for 3 h

at ambient temp., treated with saturated aqueous NaHCO₃(3 ml)

and concentrated in vacuo. Chromatography (hexanes/EtOAc, 5:1)

of the residue gave 24 (1.02 g, 3%) and 25 (29.71 g, 97%) as color-

less oils.

25: IR (neat): ν˜ ϭ 3070 (m), 2960 (s), 2930 (s), 2860 (s), 1740 (s), (u), 72.18 (u), 109.64 (u), 129.66 (d), 133.02 (d), 221.49 (u). Ϫ MS;

1590 (w), 1470 (m), 1430 (s), 1175 (m), 1110 (s), 1025 (s), 935 (m). m/z (%): 350 [M^ϩ] (4), 224 (29), 181 (19), 155 (23), 154 (17),141

1

Ϫ H NMR (300 MHz, CDCl₃): δ ϭ 1.03 (s, 9 H), 1.61 (ddd, J ϭ (15), 139 (12), 138 (15), 129 (17), 128 (36), 95 (30), 91 (24). Ϫ

Eur. J. Org. Chem. 1998, 805Ϫ826

815

I. Vaulont, H.-J. Gais, N. Reuter, E. Schmitz, R. K. L. Ossenkamp

FULL PAPER

C₂₁H₃₄O₄(350.5): calcd. C 71.96, H 9.78; found C 71.98, H 10.06. hydroxy-2-octenyl)-5,5-dimethylspiro[1,3-dioxane-2,2Ј(1ЈH)-pen-

talen]-5Ј-ol (34): Following the procedure described for the prep-

30: [α]_Dϭ ϩ2.6 (c ϭ 10.9, THF). Ϫ IR (CHCl ): ν ϭ 3460 (m,

˜

3

aration of 31, 30 (159 mg, 0.45 mmol) in EtOH (10 ml) and NaBH₄

(34 mg, 0.90 mmol) gave after chromatography (hexanes/EtOAc,

1:1) 33 (120 mg, 76%) and a mixture of 34 and 33 (7 mg, 4%, ratio

2:1) as colorless oils.

br), 2960 (s), 2860 (m), 1725 (m), 1115 (m). Ϫ ¹H NMR (300 MHz,

CDCl₃): δ ϭ 0.89 (t, J ϭ 6.7 Hz, 3 H), 0.97 (s, 6 H), 1.18Ϫ1.43

(m, 6 H), 1.73 (dd, J ϭ 13.4, J ϭ 7.4 Hz, 1 H), 1.98 (dd, J ϭ 14.1,

J ϭ 4.1 Hz, 1 H), 2.05 (dt, J ϭ 6.8, J ϭ 6.8 Hz, 2 H), 2.18Ϫ2.56

(m, 6 H), 2.74 (m, 1 H), 3.45 (s, 2 H), 3.47 (s, 2 H), 3.75 (s, br, 1

H), 4.13 (dd, J ϭ 8.1, J ϭ 8.1 Hz, 1 H), 5.41 (dd, J ϭ 15.1, J ϭ

6.8 Hz, 1 H), 5.71 (dt, J ϭ 15.1, J ϭ 6.8 Hz, 1 H). Ϫ ¹³C NMR

(75 MHz, CDCl₃): δ ϭ 14.04 (d), 22.44 (d), 22.52 (u), 28.79 (u),

30.07 (u), 31.42 (u), 32.18 (u), 34.67 (d), 40.23 (d), 41.19 (u), 44.76

(u), 59.22 (d), 72.08 (u), 72.21 (u), 74.37 (d), 109.35 (u), 129.28 (d),

134.42 (d), 222.86 (u). Ϫ MS; m/z (%): 350 [M^ϩ] (8), 224 (55), 223

(11), 181 (26), 155 (26), 141 (20), 139 (13), 138 (25), 129 (34), 128

(43), 109 (11), 95 (36), 91 (14). Ϫ C₂₁H₃₄O₄(350.5): calcd. C 71.96,

H 9.78; found C 71.87, H 9.95.

33: [α]_Dϭ ϩ17.0 (c ϭ 9.7, THF). Ϫ IR (CHCl₃): ν˜ ϭ 3400 (s,

br), 2960 (s), 2930 (s), 2860 (s), 1735 (w), 1670 (w), 1470 (m), 1435

(m), 1395 (m), 1365 (m), 1330 (m), 1310 (m), 1290 (m), 1255 (m),

1240 (m), 1220 (m), 1190 (m), 1110 (s), 990 (m), 925 (w), 910 (w).

Ϫ

¹H NMR (300 MHz, CDCl₃): δ ϭ 0.89 (t, J ϭ 6.9 Hz, 3 H),

0.93 (s, 3 H), 0.98 (s, 3 H), 1.27Ϫ1.41 (m, 6 H), 1.49 (ddd, J ϭ

11.4, J ϭ 11.4, J ϭ 11.4 Hz, 1 H), 1.64Ϫ1.74 (m, 3 H), 1.93Ϫ2.12

(m, 4 H), 2.16Ϫ2.28 (m, 2 H), 2.32Ϫ2.43 (m, 1 H), 2.62 (s, br, 1

H), 3.39 (s, br, 1 H), 3.41 (d, J ϭ 11.1 Hz, 1 H), 3.44 (d, J ϭ 11.1

Hz, 1 H), 3.47 (d, J ϭ 11.1 Hz, 1 H), 3.50 (d, J ϭ 11.1 Hz, 1 H),

3.93Ϫ4.01 (m, 2 H), 5.45 (ddt, J ϭ 15.4, J ϭ 7.9, J ϭ 1.2 Hz, 1

H), 5.67 (dt, J ϭ 15.4, J ϭ 6.7 Hz, 1 H). Ϫ ¹³C NMR (75 MHz,

CDCl₃): δ ϭ 14.04 (d), 22.52, 22.59, 28.90 (u), 30.07 (u), 31.45 (u),

32.14 (u), 35.68 (d), 39.40 (u), 40.50 (d), 40.84 (u), 41.07 (u), 58.37

(d), 71.86 (u), 72.29 (u), 79.26 (d), 79.61 (d), 110.16 (u), 131.77 (d),

133.37 (d). Ϫ MS; m/z (%): 352 [M^ϩ] (53), 281 (33), 267 (24), 249

(13), 248 (13), 223 (33), 208 (17), 183 (17), 181 (12), 177 (10), 169

(13), 168 (10), 155 (14), 141 (15), 139 (17), 129 (39), 128 (100), 127

(15), 125 (28), 123 (12), 122 (18), 121 (13), 115 (13), 109 (13). Ϫ

C₂₁H₃₆O₄(352.5): calcd. C 71.55, H 10.29; found C 71.39, H 10.63.

[3ЈaS-[3ЈaͰ,4ЈͰ(1S*,2E),5Јβ,6ЈaͰ]]-Hexahydro-4Ј-(1-hydroxy-

2-octenyl)-5,5-dimethylspiro[1,3-dioxane-2,2Ј(1ЈH)-pentalen]-5Ј-ol

(31) and [3ЈaS-[3ЈaͰ,4ЈͰ(1S*,2E),5ЈͰ,6ЈaͰ]]-Hexahydro-4Ј-(1-

hydroxy-2-octenyl)-5,5-dimethylspiro[1,3-dioxane-2,2Ј(1ЈH)-pen-

talen]-5Ј-ol (32): A solution of 29 (1.01 g, 2.89 mmol) in EtOH (60

ml) was cooled to Ϫ45°C and treated with NaBH₄( 0.22 g, 5.78

mmol). After stirring the mixture for 3 h, saturated aqueous NH₄Cl

(20 ml) was added. The mixture was warmed to ambient temp. and

extracted with ether. The organic phase was dried (MgSO₄) and

concentrated in vacuo. Chromatography (hexanes/EtOAc, 1:1) of

the residue afforded 31 (827 mg, 81%) and 32 (32 mg, 3%) as color-

less oils.

[4ЈR-[4ЈͰ(E),4Јaβ,4ЈbͰ,7ЈaͰ,8ЈaͰ]-Hexahydro-4Ј-(1-heptenyl)-

2Ј,2Ј,5,5-tetramethylspiro[1,3-dioxane-2,6Ј(5ЈH)-4ЈH-

pentaleno[2,1-d]-1,3-dioxine] (35): Following the procedure de-

scribed for the preparation of 44 (vide infra), 32 (32 mg, 0.09 mmol)

in acetone (4.0 ml) and 2,2-dimethoxypropane (1.0 ml) gave in the

presence of ω-camphorsulfonic acid (3 mg) after chromatography

31: [α]_Dϭ ϩ15.2 (c ϭ 4.8, THF). Ϫ IR (CHCl₃): ν˜ ϭ 3400 (s,

br), 2960 (s), 2930 (s), 2870 (s), 1735 (s), 1665 (w), 1625 (w), 1470

(m), 1435(m), 1400 (m), 1380 (m), 1365 (m), 1350 (m), 1330 (m),

1315 (m), 1290 (m), 1260 (m), 1240 (w), 1220 (m), 1175 (m), 1110

(s), 1045 (s), 975 (m), 930 (w), 910 (w). Ϫ ¹H NMR (300 MHz,

CDCl₃): δ ϭ 0.88 (t, J ϭ 7.0 Hz, 3 H), 0.94 (s, 3 H), 0.96 (s, 3 H),

1.23Ϫ1.40 (m, 6 H), 1.48 (ddd, J ϭ 12.1, J ϭ 9.6, J ϭ 9.6 Hz, 1

H), 1.74Ϫ1.91 (m, 3 H), 2.05 (dt, J ϭ 6.8, J ϭ 6.8 Hz, 2 H),

2.10Ϫ2.41 (m, 7 H), 3.46 (s, 2 H), 3.48 (s, 2 H), 4.00 (ddd, J ϭ 9.4,

J ϭ 9.4, J ϭ 6.4 Hz, 1 H), 4.20 (dd, J ϭ 7.0, J ϭ 5.0 Hz, 1 H),

5.55 (dd, J ϭ 15.5, J ϭ 7.4 Hz, 1 H), 5.70 (dt, J ϭ 15.1, J ϭ 6.7

Hz, 1 H). Ϫ ¹³C NMR (75 MHz, CDCl₃): δ ϭ 14.11 (d), 22.55 (u),

22.60 (d), 28.93 (u), 30.15 (u), 31.47 (u), 32.31 (u), 35.89 (d), 39.54

(d), 40.05 (u), 40.24 (u), 41.67 (u), 58.69 (d), 72.05 (u), 72.23 (u),

74.29 (d), 75.18 (d), 110.48 (u), 130.36 (d), 133.97 (d). Ϫ MS; m/z

(%): 352 [M^ϩ] (25), 281 (32), 267 (15), 249 (12), 248 (13), 225 (37),

223 (30), 208 (13), 183 (18), 181 (12), 177 (15), 169 (13), 168 (11),

155 (15), 141 (18), 139 (18), 129 (35), 128 (100) 127 (24), 125 (30),

123 (15), 122 (22), 121 (14), 115 (13), 109 (17).

(hexanes/EtOAc, 1:1) 35 (24 mg, 66%) as a colorless oil, [α]_D

ϭ

ϩ31.3 (c ϭ 6.1, THF). Ϫ IR (CHCl₃): ν˜ ϭ 2960 (s), 2930 (s), 2860

(s), 1470 (m), 1435 (m), 1380 (s), 1365 (m), 1350 (m), 1310 (m),

1250 (m), 1220 (m), 1200 (s), 1130 (s), 1105 (s), 1050 (m), 1030 (m),

1000 (m). Ϫ ¹H NMR (500 MHz, CDCl₃): δ ϭ 0.89 (t, J ϭ 7.0

Hz, 3 H), 0.93 (s, 3 H), 0.98 (s, 3 H), 1.23Ϫ1.32 (m, 4 H), 1.38 (s,

3 H), 1.37Ϫ1,41 (m, 2 H), 1.45 (s, 3 H), 1.51 (ddd, J ϭ 13.4, J ϭ

8.9, J ϭ 3.4 Hz, 1 H), 1.64 (ddd, J ϭ 8.5, J ϭ 3.0, J ϭ 3.0 Hz, 1

H), 1.70Ϫ1.74 (m, 1 H), 1.76Ϫ1.80 (m, 1 H), 1.98 (dd, J ϭ 13.4,

J ϭ 7.8 Hz, 1 H), 2.02Ϫ2.08 (m, 4 H), 2.75Ϫ2.83 (m, 2 H), 3.41

(d, J ϭ 11.2 Hz, 1 H), 3.45 (d, J ϭ 11.2 Hz, 1 H), 3.48 (d, J ϭ

11.2 Hz, 1 H), 3.49 (d, J ϭ 11.2 Hz, 1 H), 4.31 (dd, J ϭ 3.3, J ϭ

3.3 Hz, 1 H), 4.53 (dd, J ϭ 6.9, J ϭ 2.5 Hz, 1 H), 5.44 (ddt, J ϭ

15.4, J ϭ 7.0, J ϭ 1.5 Hz, 1 H), 5.73 (dtd, J ϭ 15.4, J ϭ 6.7, J ϭ

1.0 Hz, 1 H). Ϫ ¹³C NMR (125 MHz, CDCl₃): δ ϭ 14.06 (d), 19.48

(d), 22.56 (u), 22.57 (d), 22.68 (d), 28.87 (u), 30.09 (u), 30.10 (d),

31.55 (u), 32.34 (u), 37.43 (d), 38.89 (d), 40.63 (u), 50.40 (d), 70.11

(d), 71.85 (u), 72.28 (u), 75.62 (d), 97.95 (u), 110.78 (u), 129.23 (d),

132.65 (d). Ϫ MS; m/z (%): 392 [M^ϩ] (29), 377 (12), 335 (19), 334

(49), 321 (19), 263 (11), 250 (11), 249 (22), 248 (11), 231 (26), 213

(13), 209 (12), 208 (56), 207 (13), 206 (11), 155 (11), 141 (19), 129

(34), 128 (100), 122 (28), 121 (12), 105 (10). Ϫ C₂₄H₄₀O₄(392.6):

calcd. C 73.43, H 10.27; found C 73.44, H 10.22.

1

32: H NMR (300 MHz, CDCl₃): δ ϭ 0.89 (t, J ϭ 6.7 Hz, 3 H),

0.95 (s, 3 H), 0.96 (s, 3 H), 1.22Ϫ1.43 (m, 6 H), 1.55 (ddd, J ϭ

13.1, J ϭ 9.4, J ϭ 3.4 Hz, 1 H), 1.68Ϫ1.72 (m, 1 H), 1.74Ϫ1.84

(m, 2 H), 1.92 (dd, J ϭ 13.4, J ϭ 7.4 Hz, 1 H), 2.04 (dt, J ϭ 7.0,

J ϭ 7.0 Hz, 2 H), 2.06Ϫ2.19 (m, 2 H), 2.65Ϫ2.88 (m, 4 H), 3.45

(s, 2 H), 3.48 (s, 2 H), 4.39 (dd, J ϭ 3.2, J ϭ 3.2 Hz, 1 H), 4.53

(dd, J ϭ 6.2, J ϭ 3.9 Hz, 1 H), 5.53 (ddt, J ϭ 15.4, J ϭ 6.7, J ϭ

1.2 Hz, 1 H), 5.69 (dtd, J ϭ 15.4, J ϭ 6.5, J ϭ 0.8 Hz, 1 H). Ϫ

¹³C NMR (75 MHz, CDCl₃): δ ϭ 14.12 (d), 22.59 (u), 22.66 (d),

28.99 (u), 30.14 (u), 31.50 (u), 32.23 (u), 37.91 (d), 38.94 (d), 39.40

(u), 40.46 (u), 42.58 (u), 56.72 (d), 72.00 (u), 72.19 (u), 73.39 (d),

79.36 (d), 110.79 (u), 131.45 (d), 131.92 (d).

[4ЈS-[4ЈͰ(E),4ЈaͰ,4Јbβ,7Јaβ,8Јaβ]]-Hexahydro-4Ј-(1-heptenyl)-

2Ј,2Ј,5,5-tetramethyl-5,5-dimethylspiro[1,3-dioxane-2,6Ј(5ЈH)-4ЈH-

pentaleno[2,1-d]-1,3-dioxine] (36): Following the procedure de-

scribed for the preparation of 44 (vide infra), 33 (106 mg, 0.30

[3ЈaS-[3ЈaͰ,4ЈͰ(1R*,2E),5Јβ,6ЈaͰ]]-Hexahydro-4Ј-(1-hydroxy- mmol) in acetone (12.8 ml) and 2,2-dimethoxypropane (3.2 ml)

2-octenyl)-5,5-dimethylspiro[1,3-dioxane-2,2Ј(1ЈH)-pentalen]-5Ј-ol gave in the presence of ω-camphorsulfonic acid (8 mg) after chro-

(33) and [3ЈaS-[3ЈaͰ,4ЈͰ(1R*,2E),5ЈͰ,6ЈaͰ]]-Hexahydro-4Ј-(1- matography (hexanes/EtOAc, 1:1) 36 (114 mg, 96%) as a colorless

816

Eur. J. Org. Chem. 1998, 805Ϫ826

Asymmetric Synthesis of 3-Oxacarbacyclin and 3-Oxaisocarbacyclin

FULL PAPER

oil, [α]_Dϭ ϩ23.2 (c ϭ 22.1, THF). Ϫ IR (neat): ν˜ ϭ 3000 (m), stirred for 1 h. The mixture was treated with saturated aqueous

2960 (s), 2930 (s), 2860 (m), 1465 (m), 1380 (m), 1365 (w), 1335 NaHCO₃(5 ml), warmed to ambient temp. and extracted with

(m), 1265 (m), 1220 (m), 1195 (m), 1165 (m), 1115 (s), 1040 (m), ether. The organic phase was concentrated in vacuo. Chromatogra-

1000 (m), 957 (m). Ϫ ¹H NMR (500 MHz, CDCl₃): δ ϭ 0.89 (t, phy (hexanes/EtOAc, 4:1) of the residue gave a mixture of 39 and

J ϭ 6.9 Hz, 3 H), 0.93 (s, 3 H), 0.98 (s, 3 H), 1.28Ϫ1.32 (m, 4 H), 40 (128 mg, 69%, ratio 95:5) as a colorless oil. Data for 39 and 40:

1.35Ϫ1.42 (m, 4 H), 1.45 (s, 3 H), 1.48 (s, 3 H), 1.63 (dd, J ϭ 13.1,

J ϭ 7.6 Hz, 1 H), 1.67Ϫ1.73 (m, 1 H), 1.99Ϫ2.08 (m, 4 H), 2.19 (m), 2960 (s), 2930 (s), 2880 (s), 2860 (s), 1740 (s), 1590 (w), 1460

(ddd, J ϭ 11.0, J ϭ 7.9, J ϭ 6.1 Hz, 1 H), 2.29 (dd, J ϭ 13.1, J ϭ (w), 1430 (s), 1375 (m), 1240 (m), 1110 (s), 1005 (s), 975 (m), 940

8.7 Hz, 1 H), 2.38Ϫ2.46 (m, 1 H), 3.45 (d, J ϭ 11.3 Hz, 1 H), 3.46 (m), 900 (m). Ϫ ¹H NMR (300 MHz, CDCl₃) (39): δ ϭ 0.51 (q,

(d, J ϭ 11.3 Hz, 1 H), 3.48 (d, J ϭ 11.3 Hz, 1 H), 3.49 (d, J ϭ J ϭ 8.1 Hz, 6 H), 0.88 (t, J ϭ 7.9 Hz, 9 H), 0.90 (t, J ϭ 7.0 Hz, 3

[α]_Dϭ Ϫ33.2 (c ϭ 10.3, THF). Ϫ IR (neat): ν˜ ϭ 3170 (w), 3150

11.3 Hz, 1 H), 3.60 (ddd, J ϭ 10.9, J ϭ 10.9, J ϭ 6.1 Hz, 1 H), H), 1.01 (s, 9 H), 1.20Ϫ1.40 (m, 6 H), 1.45Ϫ1.63 (m, 2 H),

4.07 (dd, J ϭ 10.1, J ϭ 7.9 Hz, 1 H), 5.43 (ddt, J ϭ 15.4, J ϭ 7.8, 1.93Ϫ2.90 (m, 9 H), 4.31 (m, 1 H), 4.66 (d, J ϭ 5.7 Hz, 1 H), 5.41

J ϭ 1.5 Hz, 1 H), 5.73 (dt, J ϭ 15.4, J ϭ 6.7 Hz, 1 H). Ϫ ¹³C

(ddt, J ϭ 15.4, J ϭ 6.4, J ϭ 1.3 Hz, 1 H), 5.62 (dtd, J ϭ 15.4, J ϭ

NMR (125 MHz, CDCl₃): δ ϭ 14.63 (d), 20.96 (d), 23.05 (d), 23.12 6.7, J ϭ 1.0 Hz, 1 H), 7.33Ϫ7.45 (m, 6 H), 7.60Ϫ7.65 (m, 4 H). Ϫ

(u), 23.14 (d), 29.33 (u), 30.58 (d), 30.64 (u), 32.06 (u), 32.84 (u),

35.74 (d), 37.96 (u), 38.39 (d), 39.70 (u), 39.86 (u), 54.16 (d), 72.41

¹H NMR (300 MHz, CDCl₃) (40, in part): δ ϭ 4.47 (dd, J ϭ 6.0,

J ϭ 6.0 Hz, 1 H). Ϫ ¹³C NMR (75 MHz, CDCl₃) (39): δ ϭ 4.98

(u), 72.86 (u), 75.14 (d), 78.93 (d), 100.33 (u), 110.97 (u), 129.61 (u), 6.89 (d), 14.15 (d), 19.05 (u), 22.58 (u), 26.94 (d), 28.94 (u),

(d), 134.71 (d). Ϫ MS; m/z (%): 392 [M^ϩ] (11), 334 (24), 317 (75), 31.46 (u), 32.13 (u), 36.69 (d), 38.42 (d), 43.18 (u), 43.35 (u), 46.48

263 (13), 231 (41), 208 (66), 128 (100). Ϫ C₂₄H₄₀O₄(392.6): calcd. (u), 62.79 (d), 72.98 (d), 76.51 (d), 127.64 (d), 129.64 (d), 131.03

C 73.43, H 10.27; found C 73.36, H 10.14.

(d), 131.61 (d), 134.21 (u), 135.87 (d), 221.95 (u). Ϫ MS; m/z (%):

619 [M^ϩ] (0.5), 590 (20), 589 (42), 563 (18), 562 (49), 561 (100),

435 (11), 333 (23), 241 (39), 200 (11), 199 (51), 189 (15), 187 (23),

135 (14), 115 (27), 103 (17).

[3ЈaS-[3ЈaͰ,4ЈͰ(1S*,2E),6Јaα]]-Tetrahydro-4Ј-(1-triethyl-

silyloxy-2-octenyl)-5,5-dimethylspiro[1,3-dioxane-2,2Ј(1ЈH)-

pentalen]-5Ј(3ЈH)-one (37) and [3ЈaS-[3ЈaͰ,4ЈͰ(1R*,2E),6ЈaͰ]]-

Tetrahydro-4Ј-(1-triethylsilyloxy-2-octenyl)-5,5-dimethylspiro[1,3-

dioxane-2,2Ј(1ЈH)-pentalen]-5Ј(3ЈH)-one (38): A solution of 28

(69 mg, 0.55 mmol) in CH₂Cl₂(4 ml) was treated at room temp.

with Et₂O·BF₃(78 mg, 0.55 mmol), and the resulting mixture was

cooled immediately to Ϫ95°C. After the addition of a solution of

8b (169 mg, 0.50 mmol) (92% ee) in CH₂Cl₂(100 ml), the resultant

orange mixture was stirred for 1 h. The mixture was treated with

saturated aqueous NaHCO₃(6 ml), warmed to ambient temp. and

extracted with ether. The organic phase was dried (MgSO₄) and

concentrated in vacuo. Chromatography (hexanes/EtOAc, 1:1) of

the residue provided a mixture of 37 and 38 (144 mg, 62%, ratio

4:1), 29 (21 mg, 12%) and 30 (5 mg, 3%) as colorless oils. Data for

37 and 38: [α]_Dϭ Ϫ30.8 (c ϭ 3.30, THF). Ϫ IR (neat): ν˜ ϭ 3010

(w), 2960 (s), 2930 (s), 2880 (s), 1740 (s), 1460 (m), 1360 (w), 1330

(w), 1240 (m), 1215 (m), 1110 (s), 1050 (m), 975 (m), 910 (w). Ϫ

¹H NMR (300 MHz, CDCl₃) (37): δ ϭ 0.51 (q, J ϭ 8.1 Hz, 6 H),

0.89 (t, J ϭ 7.9 Hz, 12 H), 0.95 (s, 3 H), 0.96 (s, 3 H), 1.22Ϫ1.43

(m, 6 H), 1.65 (dd, J ϭ 13.1, J ϭ 7.4 Hz, 1 H), 1.81 (dd, J ϭ 13.3,

J ϭ 4.6 Hz, 1 H), 2.01 (dt, J ϭ 7.0, J ϭ 7.0 Hz, 2 H), 2.18 (dd,

J ϭ 18.8, J ϭ 4.2 Hz, 1 H), 2.23Ϫ2.31 (m, 3 H), 2.39 (dd, J ϭ

18.8, J ϭ 9.4 Hz, 1 H), 2.75 (m, 1 H), 3.00 (m, 1 H), 3.41 (s, 2 H),

3.48 (s, 2 H), 4.63 (dd, J ϭ 6.6, J ϭ 1.2 Hz, 1 H), 5.42 (ddt, J ϭ

15.4, 6.6, J ϭ 1.4 Hz, 1 H), 5.63 (dtd, J ϭ 15.4, J ϭ 6.7, J ϭ 1.0

[1S-(1Ͱ(1S*,2E),3aͰ,5β,6aͰ)]-5-[(1,1-Dimethylethyl)-

diphenylsilyloxy]hexahydro-1-(1-hydroxy-2-octenyl)-2(1H)-pen-

talenone (41) and [1S-(1Ͱ(1R*,2E),3aͰ,5β,6aͰ)]-5-[(1,1-Dimeth-

ylethyl)diphenylsilyloxy]hexahydro-1-(1-hydroxy-2-octenyl)-

2(1H)-pentalenone (42): A solution of 28 (6.02 g, 47.73 mmol) in

CH₂Cl₂(200 ml) was treated with Et₂O·BF₃(6.77 g, 47.73 mmol)

and the resulting mixture was cooled immediately to Ϫ78°C. After

the addition of a solution of 27 (21.38 g, 43.39 mmol) (92% ee) in

CH₂Cl₂(100 ml), the resultant orange mixture was stirred for 1 h.

The mixture was treated with saturated aqueous NaHCO₃(100 ml),

warmed to ambient temp. and extracted with ether. The organic

phase was concentrated in vacuo and the residue was dissolved in

a mixture of AcOH (300 ml), water (100 ml) and THF (100 ml).

The mixture was stirred for 12 h at room temp. and concentrated

in vacuo. Chromatography (hexanes/EtOAc, 3:1) of the residue

gave 41 (14.48 g, 66%) and 42 (2.97 g, 14%) as colorless oils.

41: [α]_Dϭ Ϫ15.8 (c ϭ 14.4, THF). Ϫ IR (neat): ν˜ ϭ 3440 (br),

3070 (m), 2960 (s), 2930 (s), 2860 (s), 1735 (s), 1590 (w), 1470 (m),

1430 (s), 1380 (s), 1110 (s), 1025 (s), 900 (m). Ϫ ¹H NMR (300

MHz, CDCl₃): δ ϭ 0.88 (t, J ϭ 6.8 Hz, 3 H), 1.02 (s, 9 H),

1.23Ϫ1.41 (m, 6 H), 1.52Ϫ1.70 (m, 2 H), 1.95Ϫ2.06 (m, 4 H), 2.25

(d, J ϭ 5.4 Hz, 1 H), 2.42Ϫ2.67 (m, 5 H), 4.35 (m, 1 H), 4.53 (m,

1 H), 5.42 (ddt, J ϭ 15.3, J ϭ 6.7, J ϭ 1.3 Hz, 1 H), 5.70 (dtd,

J ϭ 15.3, J ϭ 6.7, J ϭ 1.3 Hz, 1 H), 7.34Ϫ7.46 (m, 6 H), 7.62Ϫ7.65

(m, 4 H). Ϫ ¹³C NMR (75 MHz, CDCl₃): δ ϭ 14.12 (d), 19.04 (u),

22.55 (u), 26.95 (d), 28.89 (u), 31.42 (u), 32.22 (u), 36.22 (d), 39.15

(d), 42.93 (u), 43.10 (u), 46.17 (u), 60.97 (d), 72.03 (d), 76.62 (d),

127.68 (d), 129.72 (d), 129.81 (d), 132.91 (d), 134.08 (u), 135.84 (d),

222.43 (u). Ϫ MS; m/z (%): 503 [M^ϩϪ 1] (0.1), 370 (11), 369 (37),

322 (13), 321 (44), 243 (11), 213 (18), 201 (11), 200 (20), 199 (100),

189 (11), 183 (11), 181 (36), 139 (63), 135 (17), 129 (11), 121 (12),

105 (17). Ϫ C₃₂H₄₄O₃Si (504.8): calcd. C 76.14, H 8.79; found C

76.40, H 8.94.

1

Hz, 1 H). Ϫ H NMR (300 MHz, CDCl₃) (38, in part): δ ϭ 4.43

(dd, J ϭ 6.0, J ϭ 6.0 Hz, 1 H). Ϫ ¹³C NMR (75 MHz, CDCl₃)

(37): δ ϭ 4.89 (u), 6.80 (d), 14.07 (d), 22.45 (d), 22.53 (u), 28.87

(u), 30.06 (u), 31.38 (u), 32.06 (u), 35.67 (d), 37.17 (d), 41.14 (u),

41.87 (u), 45.54 (u), 61.91 (d), 71.99 (u), 72.21 (u), 72.86 (d), 109.67

(u), 131.27 (d), 220.93 (u). Ϫ MS; m/z (%): 464 [M^ϩ] (4), 436 (34),

435 (100), 350 (17), 349 (55), 338 (27), 291 (15), 242 (14), 241 (70),

171 (11), 115 (18), 103 (80).

[1S-(1Ͱ(1S*,2E),3aͰ,5β,6aͰ)]-5-[(1,1-Dimethylethyl)-

diphenylsilyloxy]hexahydro-1-(1-triethylsilyloxy-2-octenyl)-2(1H)-

pentalenone (39) and [1S-(1Ͱ(1R*,2E),3aͰ,5β,6aͰ)]-5-[(1,1-

Dimethylethyl)diphenylsilyloxy]hexahydro-1-(1-triethylsilyloxy-2-

octenyl)-2(1H)-pentalenone (40): A solution of 28 (42 mg, 0.33

mmol) in CH₂Cl₂(3 ml) was treated with Et₂O·BF₃(47 mg, 0.33

42: [α]_Dϭ Ϫ7.2 (c ϭ 12.0, THF). Ϫ IR (neat): ν˜ ϭ 3460 (br),

3070 (m), 3050 (m), 2960 (s), 2930 (s), 2860 (s), 1725 (s), 1590 (w),

1460 (s), 1430 (s), 1310 (w), 1260 (w), 1110 (s), 1025 (s), 975 (m),

1

mmol), and the resulting mixture was cooled immediately to 940 (w). Ϫ H NMR (300 MHz, CDCl₃): δ ϭ 0.88 (t, J ϭ 6.5 Hz,

Ϫ78°C. After the addition of a solution of 27 (148 mg, 0.30 mmol)

(92% ee) in CH₂Cl₂(1.5 ml), the resultant orange mixture was

3 H), 1.04 (s, 9 H), 1.20Ϫ1.40 (m, 6 H), 1.56Ϫ1.76 (m, 2 H),

1.86Ϫ2.05 (m, 4 H), 2.28Ϫ2.61 (m, 5 H), 3.95 (s, 1 H), 4.11 (dd,

Eur. J. Org. Chem. 1998, 805Ϫ826

817

I. Vaulont, H.-J. Gais, N. Reuter, E. Schmitz, R. K. L. Ossenkamp

FULL PAPER

J ϭ 8.1 Hz, 1 H), 4.35 (m, 1 H), 5.38 (dd, J ϭ 15.5, J ϭ 7.7 Hz, 133.81 (d), 134.37 (u), 135.90 (d). Ϫ MS; m/z (%): 546 [M^ϩ] (0.1),

1 H), 5.68 (dt, J ϭ 15.5, J ϭ 6.7 Hz, 1 H), 7.34Ϫ7.46 (m, 6 H), 471 (5), 431 (35), 353 (12), 215 (100), 199 (49), 149 (14). Ϫ

7.63Ϫ7.67 (m, 4 H). Ϫ ¹³C NMR (75 MHz, CDCl₃): δ ϭ 14.14 C₃₅H₅₀O₃Si (546.9): calcd. C 76.87, H 9.22; found C 77.10, H 9.46.

(d), 19.04 (u), 22.58 (u), 26.99 (d), 28.81 (u), 31.48 (u), 32.20 (u),

[1S-(1Ͱ(1S*,2E),3aͰ,5β,6aͰ)]-5-[(1,1-Dimethylethyl)-

diphenylsilyloxy]hexahydro-1-(1-acetyloxy-2-octenyl)-2(1H)-pen-

talenone (45): To a solution of 41 (94 mg, 0.19 mmol) in THF (7.5

ml) were added pyridine (90 mg, 1.14 mmol) and acetyl chloride

35.71 (d), 41.61 (d), 42.64 (u), 43.19 (u), 45.72 (u), 60.03 (d), 74.66

(d), 76.52 (d), 127.71 (d), 127.73 (d), 129.63 (d), 129.76 (d), 129.89

(d), 134.00 (u), 134.18 (d), 135.84 (d), 135.87 (d), 223.97 (u). Ϫ

MS; m/z (%): 447 (19), 431 (12), 430 (30), 429 (77), 369 (25), 325

(89 mg, 1.14 mmol). The suspension was stirred for 16 h at ambient

(15), 323 (32), 322 ( 77), 321 (100), 243 (28), 231 (17), 225 (14), 201

temp. and then concentrated in vacuo. Chromatography (hexanes/

(24), 200 (68), 199 (90), 197 (39), 183 (41), 182 (11), 181 (59), 165

(16), 140 (10),139 (76), 137 (11), 135 (30), 123 (13), 121 (22), 117

(11), 105 (32). Ϫ C₃₂H₄₄O₃Si (504.8): calcd. C 76.14, H 8.79; found

EtOAc, 4:1) of the residue gave 45 (87 mg, 85%) as a colorless oil,

[α]_Dϭ Ϫ24.7 (c ϭ 12.7, THF). Ϫ IR (neat): ν˜ ϭ 3070 (w), 3050

(w), 2960 (s), 2930 (s), 2860 (s), 1750 (s), 1590 (w), 1465 (m), 1430

C 76.00, H 8.85.

(m), 1370 (m),1235 (s), 1110 (s), 1020 (s), 970 (m), 940 (w), 900

(w). Ϫ ¹H NMR (300 MHz, CDCl₃): δ ϭ 0.88 (t, J ϭ 6.9 Hz, 3

H), 1.02 (s, 9 H), 1.23Ϫ1.40 (m, 6 H), 1.51Ϫ1.74 (m, 2 H), 1.98 (s,

3 H), 1.96Ϫ2.07 (m, 4 H), 2.41Ϫ2.74 (m, 5 H), 4.36 (m, 1 H), 5.39

(ddt, J ϭ 15.4, J ϭ 6.7, J ϭ 1.3 Hz, 1 H), 5.60 (dd, J ϭ 6.7, J ϭ

2.3 Hz, 1 H), 5.69 (dtd, J ϭ 15.4, J ϭ 6.7, J ϭ 1.0 Hz, 1 H),

7.34Ϫ7.46 (m, 6 H), 7.62Ϫ7.65 (m, 4 H). Ϫ ¹³C NMR (75 MHz,

CDCl₃): δ ϭ 14.11 (d), 19.03 (u), 21.16 (d), 22.52 (u), 26.95 (d),

28.65 (u), 31.40 (u), 32.20 (u), 36.09 (d), 39.96 (d), 42.90 (u), 43.04

(u), 45.62 (u), 59.16 (d), 73.58 (d), 76.50 (d), 126.02 (d), 127.69 (d),

129.73 (d), 134.02 (u), 134.55 (d), 135.84 (d), 169.68 (u), 218.43 (u).

Ϫ MS; m/z (%): 547 [M^ϩ] (0.2), 447 (28), 431 (11), 430 (35), 429

(100), 411 (12), 370 (22), 369 (84), 241 (13), 231 (19), 213 (23), 199

(84), 197 (13), 189 (11), 183 (14), 181 (37), 139 (30), 135 (17), 105

(13). Ϫ C₃₄H₄₆O₄Si (546.8): calcd. C 74.68, H 8.48; found C 74.52,

H 8.47.

[1R-(1Ͱ(1S*,2E),2β,3aͰ,5β,6aͰ)]-5-[(1,1-Dimethylethyl)-

diphenylsilyloxy]octahydro-1-(1-hydroxy-2-octenyl)-2-pentalenol

(43): A solution of 42 (120 mg, 0.23 mmol) in EtOH (5 ml) was

cooled to Ϫ45°C and treated with NaBH₄(18 mg, 0.48 mmol).

After stirring the reaction mixture for 2 h, saturated aqueous

NH₄Cl (2 ml) was added. The mixture was warmed to ambient

temp. and extracted with ether. The organic phase was dried

(MgSO₄) and concentrated in vacuo. Chromatography (hexanes/

EtOAc, 4:1) of the residue afforded 43 (104 mg, 86%) as a colorless

oil, [α]_Dϭ ϩ2.3 (c ϭ 10.0, THF). Ϫ IR (CHCl₃): ν˜ ϭ 3360 (br),

3070 (s), 3050 (s), 2940 (s), 2860 (s), 1960 (w), 1890 (w), 1825 (w),

1670 (w), 1590 (w), 1460 (s), 1430 (s), 1375 (s), 1340 (s), 1220 (m),

1190 (m), 1110 (s), 1025 (s), 975 (s) Ϫ ¹H NMR (300 MHz, CDCl₃):

δ ϭ 0.88 (t, J ϭ 6.9 Hz, 3 H), 1.06 (s, 9 H), 1.23Ϫ1.39 (m, 6 H),

1.48Ϫ2.03 (m, 9 H), 2.12Ϫ2.28 (m, 2 H), 2.52 (s, 1 H), 3.22 (s, 1

H), 3.91Ϫ4.00 (m, 2 H), 4.19 (m, 1 H), 5.40 (ddt, J ϭ 15.4, J ϭ

7.7, J ϭ 1.3 Hz, 1 H), 5.60 (dt, J ϭ 15.4, J ϭ 6.7 Hz, 1 H),

7.33Ϫ7.44 (m, 6 H), 7.65Ϫ7.70 (m, 4 H). Ϫ ¹³C NMR (75 MHz,

CDCl₃): δ ϭ 14.05 (d), 19.09 (u), 22.49 (u), 26.96 (d), 28.79 (u),

31.44 (u), 32.07 (u), 36.60 (d), 41.74 (d), 42.00 (u), 42.13 (u), 58.51

(d), 77.14 (d), 79.56 (d), 79.93 (d), 127.50 (d), 129.49 (d), 132.00

(d), 132.96 (d), 134.27 (u), 134.39 (u), 135.82 (d). Ϫ MS; m/z (%):

504 [M^ϩ] (0.02), 431 (18), 233 (27), 217 (30), 216 (20), 215 (96),

200 (19), 199 (100), 197 (13), 183 (10), 181 (12), 149 (15), 145 (13),

139 (33), 135 (27), 131 (19), 127 (18), 125 (18), 121 (13), 117 (17),

109 (19), 107 (24), 106 (12), 105 (19). C₃₂H₄₆O₃Si (506.8): calcd. C

75.84, H 9.15; found C 76.18, H 9.14.

[1R-(1Ͱ(1R*,2E),2β,3aͰ,5β,6aͰ)]-1-(1-Acetyloxy-2-octenyl)-

5-[(1,1-dimethylethyl)diphenylsilyloxy]octahydro-2-pentalenol (46)

and [1R-(1Ͱ(1R*,2E),2Ͱ,3aͰ,5β,6aͰ)]-1-(1-Acetyloxy-2-octenyl)-

5-[(1,1-dimethylethyl)diphenylsilyloxy]octahydro-2-pentalenol

(epi-46): To a solution of 41 (11.20 g, 22.30 mmol) in THF (500

ml) were added pyridine (10.57 g, 133.70 mmol) and acetyl chloride

(10.49 g, 133.70 mmol). After 5 min. a white solid separated. The

suspension was stirred for 16 h at ambient temp., concentrated in

vacuo and the residue, containing 45, dissolved in ether (500 ml).

The solution was cooled to Ϫ30°C and a solution of Zn(BH₄)₂

(8.47 g, 89.2 mmol) in ether (50 ml) was added. After stirring the

mixture for 6 h, saturated aqueous NH₄Cl (150 ml) was added. The

mixture was warmed to ambient temp. and extracted with ether.

The organic phase was dried (MgSO₄) and concentrated in vacuo.

Chromatography (hexanes/EtOAc, 2:1) of the residue gave 46

(10.40 g, 85%) and epi-46 (0.27 g, 2%) as colorless oils.

[4S-[4Ͱ(E),4aͰ,4bβ,6Ͱ,7aβ,8aβ]]-(1,1-Dimethylethyl)-

[[octahydro-4-(1-heptenyl)-2,2-dimethyl-4H-pentaleno[2,1-d]-1,3-

dioxine-6-yl]oxy]diphenylsilane (44): A solution of 43 (146 mg, 0.29

mmol) in acetone (12.8 ml) containing 2,2-dimethoxypropane (3.2

ml) was treated with ω-camphorsulfonic acid (8 mg) and stirred for

1 h. After the addition of NEt₃(0.02 ml), the mixture was concen-

trated in vacuo. Chromatography (hexanes/EtOAc, 10:1) of the resi-

46: [α]_Dϭ Ϫ11.7 (c ϭ 10.1, THF). Ϫ IR (neat): ν˜ ϭ 3470 (br),

3070 (w), 3050 (w), 2960 (s), 2930 (s), 2830 (s), 1735 (s), 1590 (w),

due gave 44 (158 mg, 99%) as a colorless oil, [α]_Dϭ ϩ10.1 (c ϭ 1460 (m), 1430 (s), 1370 (s), 1240 (s), 1110 (s), 1040 (s), 970 (m),

1

10.8, THF). Ϫ IR (CHCl₃): ν˜ ϭ 3070 (w), 3050 (w), 2990 (m), 2930

945 (m). Ϫ H NMR (300 MHz, CDCl₃): δ ϭ 0.88 (t, J ϭ 6.9 Hz,

(s), 2860 (s), 1590 (w), 1460 (s), 1430 (s), 1380 (s), 1360 (s), 1260 3 H), 1.06 (s, 9 H), 1.22Ϫ1.42 (m, 6 H), 1.54Ϫ1.67 (m, 2 H),

(w), 1195 (s), 1165 (s), 1110 (s), 1050 (s), 1025 (s), 970 (m), 940 1.71Ϫ1.87 (m, 3 H), 1.99Ϫ2.22 (m, 6 H), 2.03 (s, 3 H), 2.40 (s, 1

1

(m). Ϫ H NMR (500 MHz, CDCl₃): δ ϭ 0.89 (t, J ϭ 7.0 Hz, 3 H), 3.74 (m, 1 H), 4.22 (m, 1 H), 5.38 (dd, J ϭ 7.6, J ϭ 4.5 Hz, 1

H), 1.07 (s, 9 H), 1.25Ϫ1.39 (m, 6 H), 1.46 (s, 3 H), 1.47 (s, 3 H), H), 5.45 (ddt, J ϭ 14.8, J ϭ 7.7, J ϭ 1.3 Hz, 1 H), 5.75 (dt, J ϭ

1.52 (ddd, J ϭ 13.4, J ϭ 4.8, J ϭ 4.8 Hz, 1 H), 1.55Ϫ1.68 (m, 3

H), 1.73Ϫ1.89 (m, 3 H), 1.95Ϫ2.08 (m, 2 H), 2.17 (m, 1 H), 2.25

14.6, J ϭ 6.7 Hz, 1 H), 7.33Ϫ7.46 (m, 6 H), 7.66Ϫ7.70 (m, 4 H).

Ϫ

¹³C NMR (75 MHz, CDCl₃): δ ϭ 14.11 (d), 19.15 (u), 21.35 (d),

(m, 1 H), 3.57 (ddd, J ϭ 10.9, J ϭ 10.9, J ϭ 5.7 Hz, 1 H), 4.03 22.53 (u), 27.01 (d), 28.70 (u), 31.47 (u), 32.26 (u), 36.49 (d), 40.70

(dd, J ϭ 9.8, J ϭ 7.9 Hz, 1 H), 4.25 (m, 1 H), 5.40 (ddt, J ϭ 15.4, (d), 41.08 (u), 42.16 (u), 42.26 (u), 58.39 (d), 75.15 (d), 75.75 (d),

J ϭ 7.8, J ϭ 1.5 Hz, 1 H), 5.68 (dt, J ϭ 15.4, J ϭ 6.7 Hz, 1 H),

77.38 (d), 127.04 (d), 127.61 (d), 129.60 (d), 134.28 (u), 134.36 (u),

7.34Ϫ7.43 (m, 6 H), 7.65Ϫ7.69 (m, 4 H). Ϫ ¹³C NMR (125 MHz, 134.97 (d), 135.92 (d), 170.82 (u). Ϫ MS; m/z (%): 431 (30), 353

CDCl₃): δ ϭ 14.07 (d), 19.09 (u), 20.46 (d), 22.52 (u), 26.98 (d), (11), 216 (22), 215 (100), 200 (12), 199 (64), 183 (10), 181 (36), 159

28.78 (u), 30.15 (d), 31.52 (u), 32.27 (u), 36.29 (d), 38.01 (u), 39.45 (10), 149 (17), 145 (15), 139 (20), 135 (19), 131 (15), 117 (18), 105

(d), 40.20 (u), 41.86 (u), 53.51 (d), 74.76 (d), 77.50 (d), 78.74 (d), (15). Ϫ C₃₄H₄₈O₄Si (548.8): calcd. C 74.42, H 8.82; found C 74.39,

99.65 (u), 127.55 (d), 127.57 (d), 129.47 (d), 129.54 (d), 129.56 (d),

H 9.10.

818

Eur. J. Org. Chem. 1998, 805Ϫ826

Asymmetric Synthesis of 3-Oxacarbacyclin and 3-Oxaisocarbacyclin

FULL PAPER

epi-46: [α]_Dϭ ϩ10.1 (c ϭ 14.2, THF). Ϫ IR (neat): ν˜ ϭ 3470 H), 7.66Ϫ7.72 (m, 4 H), 8.02Ϫ8.06 (m, 2 H). Ϫ ¹³C NMR (75

(br), 3070 (m), 3050 (m), 2960 (s), 2930 (s), 2860 (s), 1740 (s), 1590 MHz, CDCl₃): δ ϭ 13.95 (d), 19.12 (u), 21.41 (d), 22.35 (u), 24.64

(w), 1460 (s), 1370 (s), 1240 (s), 1110 (s), 1035 (s), 975 (m), 905 (u), 26.99 (d), 31.46 (u), 34.40 (u), 37.43 (d), 38.35 (u), 40.02 (u),

1

(m). Ϫ H NMR (300 MHz, CDCl₃): δ ϭ 0.88 (t, J ϭ 6.7 Hz, 3 42.37 (u), 44.89 (d), 54.83 (d), 74.85 (d), 77.24 (d), 79.48 (d), 127.58

H), 1.04 (s, 9 H), 1.25Ϫ1.40 (m, 6 H), 1.46Ϫ1.88 (m, 6 H), 1.97 (s, (d), 128.26 (d), 129.55 (d), 129.59 (d), 129.97 (d), 130.54 (u), 132.76

3 H), 1.98Ϫ2.07 (m, 3 H), 2.25 (ddd, J ϭ 9.2, J ϭ 9.2, J ϭ 3.3 Hz,

(d), 134.05 (u), 134.17 (u), 134.59 (d), 135.84 (d), 135.85 (d), 166.19

1 H), 2.36 (m, 1 H), 2.67 (m, 1 H), 4.22Ϫ4.32 (m, 2 H), 5.40 (dd, (u), 170.26 (u). Ϫ MS; m/z (%): 535 (18), 473 (23), 303 (25), 244

J ϭ 9.3, J ϭ 7.7 Hz, 1 H), 5.50 (ddt, J ϭ 15.1, J ϭ 7.7, J ϭ 1.4 (12), 243 (60), 216 (18), 215 (100), 199 (22), 181 (41), 135 (10), 117

Hz, 1 H), 5.80 (dt, J ϭ 14.9, J ϭ 6.8 Hz, 1 H), 7.33Ϫ7.44 (m, 6

(11), 105 (99). Ϫ C₄₁H₅₂O₅Si (652.9): calcd. C 75.42, H 8.03: found

H), 7.65Ϫ7.70 (m, 4 H). Ϫ ¹³C NMR (75 MHz, CDCl₃): δ ϭ 14.64 C 75.06, H 8.10.

(d), 19.66 (u), 21.98 (d), 23.05 (u), 27.54 (d), 29.24 (u), 31.93 (u),

[1S-(1Ͱ(1E,3S*),2β,3aͰ,5β,6aͰ)]-5-[(1,1-Dimeth-

32.79 (u), 40.66 (d), 41.96 (u), 42.42 (u), 43.45 (d), 44.42 (u), 57.35

(d), 77.13 (d), 77.36 (d), 78.38 (d), 128.13 (d), 128.16 (d), 128.66

(d), 130.16 (d), 134.76 (u), 134.98 (u), 135.29 (d), 136.41 (d), 136.46

(d), 170.87 (u). Ϫ MS; m/z (%): 432 (12), 241 (11), 216 (19), 215

(100), 200 (13), 199 (66), 183 (12), 182 (11), 181 (75), 159 (11), 149

(17), 145 (16), 139 (24), 135 (27), 131 (15), 121 (14), 119 (10), 117

(18), 107 (10), 105 (17). Ϫ C₃₄H₄₈O₄Si (548.8): calcd. C 74.42, H

8.82; found C 74.35, H 8.98.

ylethyl)diphenylsilyloxy]-octahydro-1-(3-hydroxy-1-octenyl)-2-

pentalenyl 2-Benzoate (49): To a solution of 48 (12.25 g, 18.76

mmol) in MeOH (400 ml) was added K₂CO₃(3.16 g). After stirring

the mixture for 100 min., it was extracted with hexane and the

organic phase was concentrated in vacuo. Chromatography (hex-

anes/EtOAc, 4:1) of the residue provided 48 (1.45 g, 12%) and 49

(9.01 g, 79%) as colorless oils. Data for 49: [α]_Dϭ Ϫ37.5 (c ϭ 12.6,

THF). Ϫ IR (neat): ν˜ ϭ 3480 (br), 3070 (m), 2960 (s), 2930 (s),

2860 (s), 1720 (s), 1605 (m), 1585 (m), 1450 (s), 1430 (s), 1375 (s),

1315 (s), 1275 (s), 1110 (s), 1070 (s), 1025 (s), 970 (s), 940 (m). Ϫ

¹H NMR (300 MHz, CDCl₃): δ ϭ 0.78 (t, J ϭ 6.9 Hz, 3 H), 1.11

(s, 9 H), 1.04Ϫ1.28 (m, 6 H), 1.30Ϫ1.50 (m, 2 H), 1.67Ϫ2.01 (m,

6 H), 2.22 (m, 1 H), 2.39Ϫ2.52 (m, 2 H), 3.06 (m, 1 H), 4.02 (m, 1

H), 4.37 (m, 1 H), 5.07 (ddd, J ϭ 9.6, J ϭ 9.6, J ϭ 6.0 Hz, 1 H),

5.47Ϫ5.61 (m, 2 H), 7.33Ϫ7.46 (m, 8 H), 7.54 (tt, J ϭ 7.4, J ϭ 1.5

Hz, 1 H), 7.67Ϫ7.72 (m, 4 H), 8.03Ϫ8.06 (m, 2 H). Ϫ ¹³C NMR

(75 MHz, CDCl₃): δ ϭ 14.07 (d), 19.21 (u), 22.53 (u), 25.05 (u),

27.08 (d), 31.77 (u), 37.26 (u), 37.50 (d), 38.47 (u), 40.13 (u), 42.46

(u), 45.08 (d), 54.94 (d), 73.12 (d), 77.39 (d), 79.65 (d), 127.68 (d),

127.69 (d), 128.36 (d), 129.64 (d), 129.70 (d), 130.65 (u), 132.51 (d),

132.86 (d), 134.20 (u), 134.74 (d), 135.94 (d), 135.96 (d), 166.38 (u).

Ϫ MS; m/z (%): 535 (2), 431 (7), 303 (27), 243 (95), 215 (88), 199

(49), 105 (100). Ϫ C₃₉H₅₀O₄Si (610.9): calcd. C 76.68, H 8.25;

found C 76.37, H 8.34.

[1R-(1Ͱ(1R*,2E),2β,3aͰ,5β,6aͰ)]-1-(1-Acetyloxy-2-octenyl)-

5-[(1,1-dimethylethyl)diphenylsilyloxy]octahydro-2-pentalenyl Ben-

zoate (47): A solution of 46 (8.14 g, 14.83 mmol) in pyridine (200

ml) was cooled to 0°C and treated with benzoyl chloride (12.51g,

89.00 mmol). After stirring the mixture for 3 h, it was concentrated

in vacuo. Chromatography (hexanes/EtOAc, 4:1) of the residue

gave 47 (9.35 g, 96%) as a colorless oil, [α]_Dϭ Ϫ29.3 (c ϭ 8.3,

THF). Ϫ IR (CHCl₃): ν˜ ϭ 3070 (s), 2960 (s), 2930 (s), 2860 (s),

1730 (s), 1605 (m), 1590 (m), 1450 (s), 1430 (s), 1370 (s), 1315 (s),

1275 (s), 1240 (s), 1110 (s), 1070 (s), 1030 (s), 985 (s), 950 (s), 900

(s). Ϫ ¹H NMR (300 MHz, CDCl₃): δ ϭ 0.83 (t, J ϭ 6.9 Hz, 3 H),

1.10 (s, 9 H), 1.10Ϫ1.27 (m, 6 H), 1.66Ϫ1.99 (m, 7 H), 1.94 (s, 3

H), 2.25 (m, 1 H), 2.34Ϫ2.49 (m, 2 H), 2.71 (ddd, J ϭ 8.7, J ϭ

8.7, J ϭ 6.1 Hz, 1 H), 4.31 (m, 1 H), 5.17 (ddd, J ϭ 9.1, J ϭ 9.1,

J ϭ 6.4 Hz, 1 H), 5.28 (dd, J ϭ 7.7, J ϭ 6.1 Hz, 1 H), 5.42 (ddt,

J ϭ 15.1, J ϭ 7.7, J ϭ 1.3 Hz, 1 H), 5.68 (dt, J ϭ 15.1, J ϭ 6.7

Hz, 1 H), 7.33Ϫ7.46 (m, 8 H), 7.55 (tt, J ϭ 7.4, J ϭ 1.3 Hz, 1 H),

7.66Ϫ7.73 (m, 4 H), 8.04Ϫ8.07 (m, 2 H). Ϫ ¹³C NMR (75 MHz,

CDCl₃): δ ϭ 14.01 (d), 19.11 (u), 21.26 (d), 22.41 (u), 26.97 (d),

28.41 (u), 31.38 (u), 32.14 (u), 37.45 (d), 38.81 (u), 41.46 (d), 41.93

(u), 42.01 (u), 54.82 (d), 76.10 (d), 76.87 (d), 77.19 (d), 126.30 (d),

126.42 (d), 127.57 (d), 128.26 (d), 129.60 (d), 130.54 (u), 132.78 (d),

134.08 (u), 134.18 (u), 135.30 (d), 135.82 (d), 135.88 (d), 165.94 (u),

170.07 (u). Ϫ MS; m/z (%): 652 [M^ϩ] (0.013), 535 (7), 473 (23), 303

(25), 244 (14), 243 (75), 216 (16), 215 (83), 199 (42), 181 (51), 135

(11), 131 (11), 117 (14), 106 (10), 105 (100). Ϫ C₄₁H₅₂O₅Si (652.9):

calcd. C 75.42, H 8.03; found C 75.44, H 8.29.

[1S-(1Ͱ(1E,3R*),2β,3aͰ,5β,6aͰ)]-1-(3-Benzoyloxy-1-octenyl)-

5-[(1,1-dimethylethyl)diphenylsilyloxy]octahydro-2-pentalenyl

Benzoate (50) and [1R-(1Ͱ(1S*,2E),2β,3aͰ,5β,6aͰ)]-1-(1-benz-

oyloxy-2-octenyl)-5-[(1,1-dimethylethyl)diphenylsilyloxy]-

octahydro-2-pentalenyl Benzoate (51): A solution of 49 (6.72 g,

10.99 mmol), triphenylphosphane (5.70 g, 13.19 mmol) and benzoic

acid (2.66 g, 13.19 mmol) in THF (55 ml) was treated dropwise at

Ϫ30°C with a solution of diethylazodicarboxylate (2.30 g, 13.19

mmol) in THF (23 ml). After stirring the mixture for 1 h, saturated

aqueous NaHCO₃(5 ml) was added. The mixture was warmed to

ambient temp. and extracted with ether. The organic phase was

dried (MgSO₄) and concentrated in vacuo. MPLC (hexanes/EtOAc,

10:1) of the residue gave 50 (6.53 g, 83%) and 51 (0.31 g, 4%) as

colorless oils.

[1S-(1Ͱ(1E,3S*),2β,3aͰ,5β,6aͰ)]-1-(3-Acetyloxy-1-octenyl)-5-

[(1,1-dimethylethyl)diphenylsilyloxy]octahydro-2-pentalenyl Benzo-

ate (48): A solution of 47 (24.49 g, 37.51 mmol) in THF (500 ml)

was treated with Pd(MeCN)₂Cl₂(175 mg, 0.67 mmol) at room

temp. After stirring the mixture for 16 h, it was concentrated in

vacuo. MPLC (hexanes/EtOAc, 10:1) of the residue afforded 47

(5.82 g, 24%) and 48 (17.45 g, 71%) as colorless oils. Data for 48:

[α]_Dϭ Ϫ18.3 (c ϭ 11.6, THF). Ϫ IR (neat): ν˜ ϭ 3070 (m), 2960

(s), 2930 (s), 2860 (s), 1720 (s), 1605 (w), 1585 (w), 1450 (s), 1430

50: [α]_Dϭ Ϫ33.7 (c ϭ 9.0, THF). Ϫ IR (CHCl₃): ν˜ ϭ 3070 (m),

2960 (s), 2930 (s), 2860 (m), 1720 (s), 1605 (w), 1585 (w), 1450 (m),

1430 (m), 1365 (w), 1315 (m), 1275 (s), 1175 (m), 1110 (s), 1070

1

(m), 1025 (s), 970 (m), 940 (w). Ϫ H NMR (300 MHz, CDCl₃):

δ ϭ 0.82 (t, J ϭ 7.0 Hz, 3 H), 1.10 (s, 9 H), 1.17Ϫ1.33 (m, 6 H),

(s), 1370 (s), 1315 (s), 1275 (s), 1240 (s), 1175 (m), 1110 (s), 1070 1.55Ϫ1.98 (m, 7 H), 2.20 (m, 1 H), 2.41Ϫ2.53 (m, 2 H), 3.07 (ddd,

(s), 1025 (s), 965 (m). Ϫ ¹H NMR (300 MHz, CDCl₃): δ ϭ 0.77 (t, J ϭ 8.6, J ϭ 8.6, J ϭ 8.6 Hz, 1 H), 4.35 (m, 1 H), 5.07 (ddd, J ϭ

J ϭ 6.4 Hz, 3 H), 1.11 (m, 15 H), 1.35Ϫ1.56 (m, 2 H), 1.66Ϫ2.00 9.3, J ϭ 9.3, J ϭ 5.9 Hz, 1 H), 5.45 (dt, J ϭ 6.5, J ϭ 6.5 Hz, 1

(m, 5 H), 2.01 (s, 3 H), 2.22 (m, 1 H), 2.41Ϫ2.51 (m, 2 H), 3.04 H), 5.57 (dd, J ϭ 15.1, J ϭ 6.4 Hz, 1 H), 5.72 (dd, J ϭ 15.1, J ϭ

(ddd, J ϭ 8.9, J ϭ 8.9, J ϭ 8.9 Hz, 1 H), 4.35 (m, 1 H), 5.06 (ddd, 7.9 Hz, 1 H), 7.32Ϫ7.45 (m, 10 H), 7.47Ϫ7.55 (m, 2 H), 7.66Ϫ7.71

J ϭ 9.4, J ϭ 9.4, J ϭ 6.1 Hz, 1 H), 5.16 (dt, J ϭ 7.0, J ϭ 7.0 Hz, (m, 4 H), 7.94Ϫ8.02 (m, 4 H). Ϫ ¹³C NMR (75 MHz, CDCl₃): δ ϭ

1 H), 5.44 (dd, J ϭ 15.4, J ϭ 7.4 Hz, 1 H), 5.61 (dd, J ϭ 15.4, J ϭ

14.05 (d), 19.21 (u), 22.53 (u), 24.78 (u), 27.08 (d), 31.62 (u), 34.54

8.3 Hz, 1 H), 7.33Ϫ7.46 (m, 8 H), 7.55 (tt, J ϭ 7.4, J ϭ 1.3 Hz, 1 (u), 37.53 (d), 38.42 (u), 40.11 (u), 42.51 (u), 44.86 (d), 54.78 (d),

Eur. J. Org. Chem. 1998, 805Ϫ826

819

I. Vaulont, H.-J. Gais, N. Reuter, E. Schmitz, R. K. L. Ossenkamp

FULL PAPER

74.89 (d), 77.31 (d), 79.67 (d), 127.66 (d), 128.30 (d), 129.62 (d),

130.66 (u), 130.89 (u), 132.68 (d), 134.05 (d), 134.19 (u), 134.25 (u),

1370 (s), 1245 (s), 1110 (s), 1050 (m), 1025 (s), 970 (w), 900 (w). Ϫ

¹H NMR (300 MHz, CDCl₃): δ ϭ 0.88 (t, J ϭ 6.7 Hz, 3 H), 1.07

135.93 (d), 165.83 (u), 166.31 (u). Ϫ MS; m/z (%): 303 (17), 243 (s, 9 H), 1.24Ϫ1.31 (m, 6 H), 1.49Ϫ2.41 (m, 10 H), 2.03 (s, 3 H),

(50), 215 (31), 199 (13), 105 (100). Ϫ C₄₆H₅₄O₅Si (715.0): calcd. C

77.27, H 7.61; found C 77.66, H 7.78.

2.05 (s, 3 H), 2.82 (ddd, J ϭ 9.4, J ϭ 9.4, J ϭ 8.1 Hz, 1 H), 4.32

(m, 1 H), 4.79 (ddd, J ϭ 9.7, J ϭ 9.7, J ϭ 6.4 Hz, 1 H), 5.21 (dt,

J ϭ 6.7, J ϭ 6.7 Hz, 1 H), 5.40 (dd, J ϭ 15.4, J ϭ 6.7 Hz, 1 H), 5.55

(dd, J ϭ 15.4, J ϭ 7.7 Hz, 1 H), 7.34Ϫ7.46 (m, 6 H), 7.65Ϫ7.69 (m,

4 H). Ϫ ¹³C NMR (75 MHz, CDCl₃): δ ϭ 14.00 (d), 19.11 (u),

21.13 (d), 21.37 (d), 22.54 (u), 24.74 (u), 26.95 (d), 31.53 (u), 34.36

(u), 37.13 (d), 38.24 (u), 39.96 (u), 42.41 (u), 44.66 (d), 54.43 (d),

74.38 (d), 77.25 (d), 78.91 (d), 127.56 (d), 129.44 (d), 133.98 (d),

129.57 (d), 134.16 (u), 135.84 (d), 170.29 (u), 170.85 (u). Ϫ MS;

m/z (%): 473 (22), 241 (18), 216 (17), 215 (87), 199 (47), 183 (10),

182 (15), 181 (100), 149 (11), 145 (11), 139 (20), 135 (16), 131 (15),

117 (18), 105 (11). Ϫ C₃₆H₅₀O₅Si (590.9): calcd. C 73.18, H 8.53;

found C 73.19, H 8.71.

51: [α]_Dϭ Ϫ42.4 (c ϭ 9.1, THF). Ϫ IR (neat): ν˜ ϭ 3070 (w),

2960 (s), 2930 (s), 2860 (s), 1720 (s), 1605 (m), 1585 (m), 1455 (s),

1430 (s), 1370 (s), 1315 (s), 1275 (s), 1110 (s), 1070 (s), 1025 (s),

1

970 (s), 940 (m). Ϫ H NMR (300 MHz, CDCl₃) δ ϭ 0.82 (t, J ϭ

6.9 Hz, 3 H), 1.09 (s, 9 H), 1.15Ϫ1.32 (m, 6 H), 1.68Ϫ2.03 (m, 7

H), 2.28 (m, 1 H), 2.35Ϫ2.56 (m, 2 H), 2.88 (ddd, J ϭ 8.3, J ϭ

8.3, J ϭ 5.6 Hz, 1 H), 4.31 (m, 1 H), 5.37 (ddd, J ϭ 8.7, J ϭ 8.7,

J ϭ 6.4 Hz, 1 H), 5.47Ϫ5.60 (m, 2 H), 5.77 (dt, J ϭ 14.4, J ϭ 6.7

Hz, 1 H), 7.28Ϫ7.42 (m, 10 H), 7.42Ϫ7.56 (m, 2 H), 7.65Ϫ7.70 (m,

4 H), 7.95Ϫ8.04 (m, 4 H). Ϫ ¹³C NMR (75 MHz, CDCl₃): δ ϭ

14.11 (d), 19.22 (u), 22.52 (u), 27.08 (d), 28.62 (u), 31.49 (u), 32.32

(u), 37.75 (d), 39.00 (u), 41.47 (u), 41.92 (d), 42.29 (u), 54.90 (d),

76.21 (d), 77.12 (d), 77.88 (d), 126.35 (d), 127.68 (d), 128.30 (d),

129.70 (d), 130.56 (u), 132.80 (d), 134.25 (u), 135.30 (d), 135.92 (d),

165.83 (u), 166.08 (u). Ϫ MS; m/z (%): 470 (10), 415 (10), 414 (37),

413 (100), 379 (6), 335 (13), 303 (24), 244 (12), 243 (55), 215 (22),

214 (44), 199 (46), 135 (12), 131 (12), 129 (11), 117 (19), 105 (92). Ϫ

C₄₆H₅₄O₅Si (715.0): calcd. C 77.27, H 7.61; found C 77.03, H 7.98.

[1S-(1Ͱ(1E,3R*),2β,3aͰ,5β,6aͰ)]-5-[(1,1-Dimethylethyl)-

diphenylsilyloxy]octahydro-1-(3-hydroxy-1-octenyl)-2-

pentalenol (54): To a solution of 53 (2.84 g, 4.80 mmol) in MeOH

(125 ml) was added K₂CO₃(1.00 g). After stirring the mixture for

6 h, it was concentrated in vacuo. Chromatography (hexanes/

EtOAc, 1:1) of the residue provided 54 (2.34 g, 96%) as a colorless

oil, [α]_Dϭ Ϫ10.1 (c ϭ 1.17, THF). Ϫ IR (ether): ν˜ ϭ 3350 (s, br),

3070 (s), 3050 (s), 2940 (s), 2860 (s), 1960 (w), 1890 (w), 1825 (w),

1775 (w), 1670 (w), 1590 (m), 1460 (s), 1430 (s), 1375 (s), 1330 (s),

1260 (m), 1190 (m), 1110 (s), 1020 (s), 970 (s), 940 (m). Ϫ ¹H NMR

(300 MHz, CDCl₃): δ ϭ 0.89 (t, J ϭ 6.7 Hz, 3 H), 1.06 (s, 9 H),

1.26Ϫ1.36 (m, 6 H), 1.44Ϫ2.31 (m, 10 H), 2.45 (ddd, J ϭ 9.4, J ϭ

9.4, J ϭ 8.0 Hz, 1 H), 2.59 (s, 2 H), 3.71 (ddd, J ϭ 9.4, J ϭ 9.4,

J ϭ 6.0 Hz, 1 H), 4.03 (dt, J ϭ 6.7, J ϭ 6.7 Hz, 1 H), 4.27 (m, 1

H), 5.44 (dd, J ϭ 15.1, J ϭ 8.1 Hz, 1 H), 5.53 (dd, J ϭ 15.1, J ϭ

6.7 Hz, 1 H), 7.33Ϫ7.45 (m, 6 H), 7.65Ϫ7.69 (m, 4 H). Ϫ ¹³C NMR

(75 MHz, CDCl₃): δ ϭ 14.12 (d), 19.17 (u), 22.71 (u), 25.26 (u),

27.07 (d), 31.81 (u), 36.74 (d), 37.25 (u), 39.92 (u), 41.47 (u), 42.68

(u), 45.34 (d), 58.60 (d), 73.30 (d), 77.36 (d), 78.26 (d), 127.61 (d),

129.61 (d), 133.96 (d), 135.11 (d), 134.31 (u), 135.92 (d). Ϫ MS;

m/z (%): 233 (67), 216 (15), 215 (75), 200 (15), 199 (80), 149 (21),

145 (16), 139 (25), 135 (27), 131 (23), 121 (16), 119 (100), 105 (24).

Ϫ C₃₂H₄₆O₃Si (506.8): calcd. C 75.84, H 9.15; found C 75.96, H

9.49.

Synthesis of 50 from 54: A solution of 54 (2.30 g, 4.54 mmol) in

pyridine (50 ml) was cooled to 0°C and treated with benzoyl chlo-

ride (3.83 g, 27.24 mmol). After stirring the mixture for 3 h, it was

concentrated in vacuo. Chromatography (hexanes/EtOAc, 4:1) of

the residue gave 50 (3.24 g, 99%) as a colorless oil.

[1R-(1Ͱ(1S*,2E),2β,3aͰ,5β,6aͰ)]-1-(1-Acetyloxy-2-octenyl)-

5-[(1,1-dimethylethyl)diphenylsilyloxy]-octahydro-2-pentalenyl

Acetate (52): A solution of 43 (3.58 g, 7.08 mmol) in THF (250 ml)

was treated with acetyl chloride (3.33 g, 42.48 mmol) and pyridine

(3.36 g, 42.48 mmol). After stirring the mixture for 3 h, it was

concentrated in vacuo. Chromatography (hexanes/EtOAc, 2:1) of

the residue gave 52 (3.90 g, 93%) as a colorless oil, [α]_Dϭ Ϫ8.0

(c ϭ 0.87, THF). Ϫ IR (neat): ν˜ ϭ 3070 (w), 3050 (w), 2960 (s),

2930 (s), 2860 (s), 1740 (s), 1590 (w), 1465 (m), 1430 (s), 1370 (s),

1250 (s), 1110 (s), 1025 (s), 970 (m), 905 (w). Ϫ ¹H NMR (300

MHz, CDCl₃): δ ϭ 0.87 (t, J ϭ 6.9 Hz, 3 H), 1.07 (s, 9 H),

1.22Ϫ1.39 (m, 6 H), 1.57Ϫ2.40 (m, 10 H), 2.00 (s, 3 H), 2.05 (s, 3

H), 2.51 (ddd, J ϭ 8.6, J ϭ 8.6, J ϭ 6.0 Hz, 1 H), 4.27 (m, 1 H),

4.94 (ddd, J ϭ 9.1, J ϭ 9.1, J ϭ 6.4 Hz, 1 H), 5.25 (dd, J ϭ 6.9,

J ϭ 6.9 Hz, 1 H), 5.36 (ddt, J ϭ 15.1, J ϭ 7.7, J ϭ 1.3 Hz, 1 H),

5.67 (dt, J ϭ 15.1, J ϭ 6.7 Hz, 1 H), 7.33Ϫ7.46 (m, 6 H), 7.65Ϫ7.69

(m, 4 H). Ϫ ¹³C NMR (75 MHz, CDCl₃): δ ϭ 14.12 (d), 19.17 (u),

21.33 (d), 21.36 (d), 22.53 (u), 27.00 (d), 28.65 (u), 31.45 (u), 32.30

(u), 37.51 (d), 38.81 (u), 41.07 (d), 42.02 (u), 42.14 (u), 54.40 (d),

75.85 (d), 77.09 (d), 77.42 (d), 126.07 (d), 127.64 (d), 129.66 (d),

134.26 (u), 135.39 (d), 135.89 (d), 170.22 (u), 170.64 (u). Ϫ MS;

m/z (%): 473 (14), 241 (14), 216 (13), 215 (76), 199 (45), 182 (14),

181 (100), 149 (11), 145 (12), 139 (20), 135 (16), 131 (15), 117 (18),

105 (12), 91 (15). Ϫ C₃₆H₅₀O₅Si (590.9): calcd. C 73.18, H 8.53;

found C 73.18, H 8.68.

[1S-(1Ͱ(1E,3R*),2β,3aͰ,5β,6aͰ)]-1-(3-Benzoyloxy-1-octenyl)-

octahydro-2,5-pentalendiol 2-Benzoate (55): A solution of 50 (9.30

g, 13.01 mmol) in THF (200 ml) was treated with a solution of

Bu₄NF (6.16 g, 19.51 mmol) in THF (50 ml). After stirring the

mixture for 16 h, it was concentrated in vacuo. Chromatography

(hexanes/EtOAc, 3:1) of the residue provided 55 (6.13 g, 99%) as a

colorless oil, [α]_Dϭ Ϫ32.3 (c ϭ 12.1, THF). Ϫ IR (ether): ν˜ ϭ

3500 (br), 2930 (s), 2860 (m), 1720 (s), 1600 (w), 1585 (w), 1490

(w), 1450 (m), 1315 (s), 1275 (s), 1175 (m), 1115 (s), 1070 (m), 1030

1

(m), 975 (m), 935 (w). Ϫ H NMR (300 MHz, CDCl₃): δ ϭ 0.82

(t, J ϭ 6.9 Hz, 3 H), 1.16Ϫ1.35 (m, 6 H), 1.55Ϫ1.78 (m, 6 H),

1.96Ϫ2.12 (m, 2 H), 2.26 (m, 1 H), 2.38Ϫ2.56 (m, 2 H), 2.82 (ddd,

J ϭ 9.1, J ϭ 9.1, J ϭ 7.7 Hz, 1 H), 4.38 (m, 1 H), 5.04 (ddd, J ϭ

9.4, J ϭ 9.4, J ϭ 6.0 Hz, 1 H), 5.44 (dt, J ϭ 6.4, J ϭ 6.4 Hz, 1

[1S-(1Ͱ(1E,3R*),2β,3aͰ,5β,6aͰ)]-1-(3-Acetyloxy-1-octenyl)- H), 5.62 (dd, J ϭ 15.4, J ϭ 6.4 Hz, 1 H), 5.73 (dd, J ϭ 15.4, 7.4

5-[(1,1-dimethylethyl)diphenylsilyloxy]-octahydro-2-pentalenyl Hz, 1 H), 7.31Ϫ7.41 (m, 4 H), 7.46Ϫ7.55 (m, 2 H), 7.94Ϫ8.02 (m,

Acetate (53): A solution of 52 (3.85 g, 6.52 mmol) in THF (80 ml)

was treated with Pd(CH₃CN)₂Cl₂(34 mg, 0.13 mmol) at room 24.81 (u), 31.64 (u), 34.55 (u), 37.54 (d), 38.48 (u), 40.36 (u), 42.76

4 H). Ϫ ¹³C NMR (75 MHz, CDCl₃): δ ϭ 14.09 (d), 22.56 (u),

temp. After stirring the mixture for 16 h, it was concentrated in

vacuo. MPLC (hexanes/EtOAc, 4:1) of the residue afforded 52 (0.92

(u), 44.67 (d), 55.14 (d), 74.96 (d), 76.03 (d), 79.73 (d), 128.31 (d),

128.35 (d), 129.61 (d), 129.63 (d), 129.88 (d), 130.52 (u), 130.83 (u),

132.76 (d), 132.80 (d), 133.71 (d), 165.87 (u), 166.42 (u). Ϫ MS;

m/z (%): 354 (9), 232 (46), 199 (12), 106 (10), 105 (100).- C₃₀H₃₆O₅

g, 24%) and 53 (2.73 g, 71%) as colorless oils. Data for 53: [α]_D

ϭ

Ϫ27.0 (c ϭ 0.71, THF). Ϫ IR (CHCl₃): ν˜ ϭ 3070 (m), 3050 (w),

2960 (s), 2930 (s), 2860 (s), 1740 (s), 1590 (w), 1460 (m), 1430 (m), (476.6): calcd. C 75.60, H 7.61; found C 76.00, H 7.94.

820 Eur. J. Org. Chem. 1998, 805Ϫ826

Asymmetric Synthesis of 3-Oxacarbacyclin and 3-Oxaisocarbacyclin

FULL PAPER

[3aS-(3aͰ,4Ͱ(1E,3R*),5β,6aͰ)]-5-Benzoyloxy-4-(3-benzoyl- (d), 18.83 (u), 18.88 (u), 19.63 (u), 19.69 (u), 19.73 (u), 19.90 (u),

oxy-1-octenyl)hexahydro-2(1H)-pentalenone (7a): A solution of

22.69 (u), 24.91 (u), 25.42 (u), 25.54 (u), 25.62 (u), 25.62 (u), 30.78

(COCl)₂(1.82 g, 14.30 mmol) in CH₂Cl₂(32.5 ml) was cooled to (u), 30.87 (u), 30.93 (u), 31.84 (u), 31.90 (u), 34.76 (u), 34.85 (u),

Ϫ60°C and treated with DMSO (2.44 g, 31.20 mmol). After stir-

35.48 (d), 35.70 (u), 35.78 (d), 35.87 (d), 36.03 (d), 37.95 (u), 40.24

ring the mixture for 10 min. a solution of 55 (6.20 g, 13.00 mmol) (u), 40.31 (u), 42.73 (u), 42.89 (u), 43.00, 43.04, 43.19, 43.26 (d),

in CH₂Cl₂(13 ml) was added and stirring was continued for 15 45.88 (u), 45.93 (u), 54.99 (d), 55.14 (d), 55.44 (d), 55.58 (d), 61.53

min. The mixture was treated with NEt₃(6.58 g, 65.00 mmol) and (u), 62.06 (u), 62.18 (u), 62.35 (u), 62.62 (u), 62.71 (u), 75.77 (d),

warmed to ambient temp. After treatment of the mixture with

75.85 (d), 77.16 (d), 77.29 (d), 80.26 (d), 80.74 (d), 83.49 (d), 83.68

water (39 ml), it was extracted with CH₂Cl₂. The organic phase (d), 94.52 (d), 95.75 (d), 95.85 (d), 97.20 (d), 97.40 (d), 98.92 (d),

was dried (MgSO₄) and concentrated in vacuo. Chromatography 99.26 (d), 131.47 (d), 131.52 (d), 132.28 (d), 132.61 (d), 132.85 (d),

(hexanes/EtOAc, 3:1) of the residue gave 7a (5.91 g, 96%) as a white

133.28 (d), 134.43 (d), 219.90 (u), 220.15 (u). Ϫ MS; m/z (%): 248

waxy solid, [α]_Dϭ Ϫ63.8 (c ϭ 11.2, THF). Ϫ IR (ether): ν˜ ϭ 3060 (21), 204 (4), 177 (6), 152 (14), 96 (10), 85 (100). Ϫ C₂₆H₄₂O₅

(w), 2930 (m), 2860 (m), 1740 (s), 1720 (s), 1600 (w), 1585 (w), 1455 (434.6): calcd. C 71.85, H 9.74, found C 71.67, H 9.76.

(m), 1315 (m), 1275 (s), 1175 (m), 1115 (s), 1070 (m), 1030 (m), 970

2-(1-Methyl-1-phenylethyl)cyclohexyl [3aS-[2E(1R*,2S*),

(w). Ϫ ¹H NMR (500 MHz, CDCl₃): δ ϭ 0.84 (t, J ϭ 7.0 Hz, 1

3aͰ,4Ͱ,5β,6aͰ]]-[Hexahydro-5-hydroxy-4-(3-hydroxy-1-

H), 1.21Ϫ1.27 (m, 4 H), 1.28Ϫ1.36 (m, 2 H), 1.60Ϫ1.79 (m, 3 H),

octenyl)-2(1H)-pentalenylidene]acetate (58) and 2-(1-Methyl-1-

2.17 (ddd, J ϭ 19.2, J ϭ 7.0, J ϭ 1.5 Hz, 1 H), 2.28 (d, J ϭ 18.9

phenylethyl)cyclohexyl [3aS-[2Z(1R*,2S*),3aͰ,4Ͱ,5β,6aͰ]]-[He-

Hz, 1 H), 2.50 (ddd, J ϭ 18.9, J ϭ 9.2, J ϭ 1.2 Hz, 1 H), 2.52Ϫ2.76

(m, 4 H), 2.85 (m, 1 H), 5.21 (ddd, J ϭ 7.4, J ϭ 7.4, J ϭ 7.4 Hz,

1 H), 5.47 (dt, J ϭ 6.4, J ϭ 6.4 Hz, 1 H), 5.66 (dd, J ϭ 15.6, J ϭ

xahydro-5-hydroxy-4-(3-hydroxy-1-octenyl)-2(1H)-pentalenyl-

idene]acetate (59): From 7c: A solution of (1S-trans)-(dimeth-

oxyphosphanyl)-2-(1-methyl-1-phenylethyl)cyclohexyl acetate (166

mg, 0.45 mmol) in THF (1 ml), containing LiCl (19 mg, 0.45

6.4 Hz, 1 H), 5.75 (dd, J ϭ 15.4, J ϭ 7.6 Hz, 1 H), 7.34Ϫ7.44 (m,

4 H), 7.49Ϫ7.55 (m, 2 H), 7.92Ϫ8.00 (m, 4 H). Ϫ ¹³C NMR (125

mmol), was cooled to Ϫ78°C, treated with nBuLi (1.52  in hex-

MHz, CDCl₃): δ ϭ 14.05 (d), 22.53 (u), 24.80 (u), 31.58 (u), 34.46

anes, 0.29 ml, 0.44 mmol) and warmed to 0°C for 10 min. The

(u), 35.93 (d), 38.68 (u), 42.81 (u), 42.94 (d), 45.65 (u), 54.52 (d),

74.64 (d), 79.92 (d), 128.40 (d), 128.43 (d), 129.59 (d), 129.64 (d),

130.09 (u), 130.69 (u), 131.18 (d), 132.10 (d), 132.87 (d), 133.07 (d),

165.81 (u), 166.24 (u), 219.21 (u). Ϫ MS; m/z (%): 352 (1), 247 (4),

mixture, containing 56, was recooled to Ϫ62°C and treated with

7c (65 mg, 0.15 mmol). After keeping the mixture at Ϫ62°C for 7

days without stirring, it was treated with saturated aqueous NH₄Cl

(1 ml). The mixture was warmed to ambient temp., treated with

230 (6), 105 (100). Ϫ C₃₀H₃₄O₅(474.6): calcd. C 75.92, H 7.22;

water (0.5 ml) and extracted with EtOAc. The organic phase was

found C 75.65, H 7.54.

dried (MgSO₄) and concentrated in vacuo. The crude product, con-

[3aS-(3aͰ,4Ͱ(1E,3R*),5β,6aͰ)]-Hexahydro-5-hydroxy-4-(3-

hydroxy-1-octenyl)-2(1H)-pentalenone (7b): To a solution of 7a

(248 mg, 0.52 mmol) in MeOH (10 ml) was added NaOH (0.08 g).

After stirring the mixture for 16 h at ambient temp., it was concen-

trated in vacuo. Chromatography (hexanes/EtOAc, 1:10) of the resi-

due gave 7b (111 mg, 80%) as a colorless oil, [α]_Dϭ Ϫ18.7 (c ϭ

9.4, THF). Ϫ IR (neat): ν˜ ϭ 3380 (br), 2960 (s), 2930 (s), 2860 (s),

1740 (s), 1670 (w), 1460 (m), 1405 (m), 1380 (m), 1340 (m), 1250

(w), 1165 (m), 1095 (m), 1020 (m), 970 (m). Ϫ ¹H NMR (300 MHz,

CDCl₃): δ ϭ 0.88 (t, J ϭ 6.6 Hz, 3 H), 1.23Ϫ1.62 (m, 9 H),

1.95Ϫ2.20 (m, 3 H), 2.34Ϫ2.78 (m, 5 H), 3.27 (s, 1 H), 3.84Ϫ3.94

(m, 2 H), 4.02 (dt, J ϭ 6.7, J ϭ 6.7 Hz, 1 H), 5.43 (dd, J ϭ 15.1,

J ϭ 8.0 Hz, 1 H), 5.53 (dd, J ϭ 15.1, J ϭ 7.0 Hz, 1 H). Ϫ ¹³C

NMR (75 MHz, CDCl₃): δ ϭ 14.11 (d), 22.69 (u), 25.26 (u), 31.76

(u), 34.76 (d), 37.18 (u), 41.13 (u), 42.35 (u), 42.94 (d), 46.04 (u),

57.85 (d), 73.25 (d), 77.59 (d), 132.47 (d), 136.30 (d), 220.21 (u). Ϫ

MS; m/z (%): 248 (47), 204 (26), 191 (20), 177 (100), 152 (62), 135

(39), 117 (32), 107 (29), 96 (60). Ϫ C₁₆H₂₆O₃(226.4): calcd. C

72.14, H 9.84; found C 72.08, H 10.02.

taining 60 and 61, was dissolved in MeOH (2 ml) and the solution

was treated with pyridinium p-toluenesulfonate (110 mg, 0.45

mmol). After stirring the mixture for 16 h at ambient temp., it was

concentrated in vacuo to give a mixture of 58 and 59 in a ratio of

95:5 (HPLC, hexanes/isopropanol, 95:5, t_R(58) ϭ 19.7 min.,

t_R(59) ϭ 23.9 min.). MPLC (n-hexane/EtOAc, 1:3) of the residue

afforded 58 (55 mg, 72%) and 59 (3 mg, 4%) as colorless oils.

58: [α]_Dϭ ϩ30.5 (c ϭ 16.8, THF). Ϫ IR (CHCl₃): ν˜ ϭ 3380

(br), 2930 (s), 2860 (s), 1700 (s), 1655 (m), 1600 (w), 1495 (w), 1450

(m), 1420 (w), 1375 (m), 1220 (s), 1190 (m), 1130 (s), 1090 (m),

1

1030 (m), 970 (m). Ϫ H NMR (300 MHz, CDCl₃): δ ϭ 0.90 (t,

J ϭ 6.7 Hz, 3 H), 1.02Ϫ1.39 (m, 18 H), 1.45Ϫ1.70 (m, 5 H),

1.80Ϫ1.95 (m, 2 H), 2.00Ϫ2.21 (m, 3 H), 2.34Ϫ2.58 (m, 4 H),

2.66Ϫ2.90 (m, 2 H), 3.80 (ddd, J ϭ 9.4, J ϭ 9.4, J ϭ 7.4 Hz, 1 H),

4.07 (dt, J ϭ 6.7, J ϭ 6.7 Hz, 1 H), 4.79 (ddd, J ϭ 10.3, J ϭ 10.3,

J ϭ 4.0 Hz, 1 H), 5.14 (s, 1 H), 5.48 (dd, J ϭ 15.1, J ϭ 8.1 Hz, 1

H), 5.58 (dd, J ϭ 15.1, J ϭ 6.7 Hz, 1 H), 7.07Ϫ7.13 (m, 1 H),

7.22Ϫ7.29 (m, 4 H). Ϫ ¹³C NMR (75 MHz, CDCl₃): δ ϭ 14.04

(d), 22.63 (u), 24.77 (u), 25.22 (u), 25.59 (d), 26.03 (u), 27.17 (u),

27.30 (d), 31.72 (u), 33.63 (u), 37.25 (u), 38.55 (d), 39.42 (u), 39.97

(u), 41.23 (u), 45.06 (d), 51.21 (d), 56.83 (d), 73.14 (d), 73.90 (d),

77.67 (d), 113.68 (d), 124.70 (d), 125.53 (d), 127.88 (d), 132.81 (d),

135.76 (d), 151.73 (u), 165.77 (u), 166.01 (u). Ϫ MS; m/z (%): 389

(3), 290 (13), 273 (13), 272 (10), 200 (10), 120 (11), 119 (100), 118

(33), 105 (31), 91 (20). Ϫ C₃₃H₄₈O₄(509.8): calcd. C 77.91, H 9.51;

found C 77.62, H 9.54.

[3aS-(3aͰ,4Ͱ(1E,3R*),5β,6aͰ)]-Hexahydro-5-[(tetrahydro-

2H-pyran-2-yl)oxy]-4-[3-(tetrahydro-2H-pyran-2-yl)oxy-1-

octenyl)-2(1H)-pentalenone (7c): A solution of 7b (450 mg, 1.69

mmol) in CH₂Cl₂(6 ml) was treated with 3,4-dihydro-2H-pyran

(1.42 g, 16.90 mmol) and pyridinium p-toluenesulfonate (20 mg,

0.08 mmol). After stirring the mixture for 16 h, it was concentrated

in vacuo. Chromatography (hexanes/EtOAc, 1:1) of the residue

gave 7c (740 mg, 99%) as a colorless oil, [α]_DϪ32.7 (c ϭ 10.2,

THF). Ϫ IR (neat): ν˜ ϭ 2940 (s), 2870 (s), 1740 (s), 1670 (w), 1455

59: [α]_Dϭ Ϫ23.4 (c ϭ 7.3, THF). Ϫ IR (CHCl₃): ν˜ ϭ 3360 (br),

(s), 1440 (s), 1405 (m), 1380 (m), 1350 (m), 1320 (m), 1285 (m), 2930 (s), 2860 (s), 1700 (s), 1655 (s), 1600 (m), 1495 (m), 1450 (s),

1260 (m), 1200 (s), 1185 (m), 1160 (s), 1130 (s), 1080 (s), 1020 (s), 1370 (s), 1280 (s), 1260 (s), 1205 (s), 1130 (s), 1090 (s), 1030 (s),

1

975 (s), 915 (m). Ϫ H NMR (300 MHz, CDCl₃): δ ϭ 0.85Ϫ0.90 970 (s), 915 (w). Ϫ H NMR (300 MHz, CDCl₃): δ ϭ 0.89 (t, J ϭ

(m, 3 H), 1.23Ϫ1.35 (m, 6 H), 1.42Ϫ1.87 (m, 16 H), 2.07Ϫ2.80 (m,

7 H), 3.39Ϫ3.58 (m, 2 H), 3.75Ϫ4.12 (m, 4 H), 4.55Ϫ4.97 (m, 2

6.9 Hz, 3 H), 1.00Ϫ1.39 (m, 18 H), 1.46Ϫ1.52 (m, 4 H), 1.81Ϫ2.07

(m, 4 H), 2.16Ϫ2.48 (m, 5 H), 2.61Ϫ2.87 (m, 3 H), 3.80 (ddd, J ϭ

H), 5.26Ϫ5.68 (m, 2 H). Ϫ ¹³C NMR (75 MHz, CDCl₃): δ ϭ 14.15 9.4, J ϭ 9.4, J ϭ 7.1 Hz, 1 H), 4.05 (dt, J ϭ 6.2, J ϭ 6.2 Hz, 1

Eur. J. Org. Chem. 1998, 805Ϫ826

821

I. Vaulont, H.-J. Gais, N. Reuter, E. Schmitz, R. K. L. Ossenkamp

FULL PAPER

H), 4.77 (ddd, J ϭ 10.2, J ϭ 10.2, J ϭ 4.6 Hz, 1 H), 5.17 (s, 1 H),

(hexanes/EtOAc, 4:1) 61 (46 mg, 91%) as a colorless oil, [α]_Dϭ Ϫ38.2°

5.45Ϫ5.59 (m, 2 H), 7.09Ϫ7.14 (m, 1 H), 7.21Ϫ7.28 (m, 4 H). Ϫ (c ϭ 1.10, THF). Ϫ IR (ether): ν˜ ϭ 3090 (w), 3060 (w), 2940 (s), 2860

¹³C NMR (75 MHz, CDCl₃): δ ϭ 14.05 (d), 22.61 (u), 24.79 (u), (s), 1710 (s), 1655 (m), 1600 (w), 1495 (m), 1465 (m), 1450 (s), 1370

25.18 (u), 26.01 (u), 26.19 (d), 26.78 (d), 27.24 (u), 31.72 (u), 33.66

(u), 35.58 (u), 36.77 (d), 37.35 (u), 40.04 (u), 40.47 (u), 43.15 (u), (s), 1080 (s), 1020 (s), 975 (s), 915 (m). Ϫ ¹H NMR (300 MHz,

46.88 (d), 51.22 (d), 57.63 (d), 72.98 (d), 73.91 (d), 77.73 (d), 113.48 CDCl₃): δ ϭ 0.86Ϫ0.91 (m, 3 H), 0.95Ϫ2.95 (m, 44 H), 3.40Ϫ4.09

(s), 1355 (s), 1320 (m), 1275 (m), 1260 (m), 1200 (s), 1160 (s), 1125

(d), 124.85 (d), 125.51 (d), 127.85 (d), 132.32 (d), 135.54 (d), 151.55 (m, 6 H), 4.59Ϫ4.98 (m, 3 H), 5.16 (s, 1 H), 5.24Ϫ5.69 (m, 2 H),

(u), 165.80 (u), 166.16 (u). Ϫ MS; m/z (%): 389 (4), 290 (13), 273 7.08Ϫ7.16 (m, 4 H), 7.22Ϫ7.30 (m, 4 H). Ϫ ¹³C NMR (75 MHz,

(13), 200 (7), 119 (100), 105 (33), 91 (21). From 7b: A solution of

CDCl₃): δ ϭ 14.12 (d), 18.64 (u), 19.47 (u), 19.57 (u), 19.77 (u), 22.63

(1S-trans)-(dimethoxyphosphanyl)-2-(1-methyl-1-phenylethyl)- (u), 24.79 (u), 25.43 (u), 25.60 (u), 26.02 (u), 26.24 (d), 26.32 (d), 26.66

cyclohexyl acetate (166 mg, 0.45 mmol) in THF (1 ml) was cooled (d), 26.73 (d), 27.26 (u), 30.80 (u), 31.80 (u), 31.86 (u), 33.67 (u), 34.74

to Ϫ78°C, treated with nBuLi (1.52  in hexanes, 0.29 ml, 0.44

mmol) and warmed to 0°C for 10 min. The mixture, containing 56, (u), 40.05 (u), 43.01 (u), 46.71 (u), 46.90 (u), 51.22 (d), 54.41 (d), 54.70

was recooled to Ϫ62°C and treated with 7b (40 mg, 0.15 mmol). (d), 55.30 (d), 55.50 (d), 61.14 (u), 62.14 (u), 62.59 (u), 62.69 (u), 73.83

After keeping the mixture at Ϫ62°C for 7 days without stirring, it (d), 75.87 (d), 75.98 (d), 76.87 (d), 77.05 (d), 79.70 (d), 80.05 (d), 83.59

was treated with saturated aqueous NH₄Cl (1 ml). The mixture was (d), 83.88 (d), 94.51 (d), 95.39 (d), 96.75 (d), 97.06 (d), 99.17 (d), 99.48

(u), 34.87 (u), 35.90 (u), 36.16 (u), 37.14 (d), 37.30 (d), 37.44 (d), 39.54

warmed to ambient temp., treated with water (0.5 ml) and extracted (d), 113.24 (d), 113.36 (d), 124.85 (d), 125.52 (d), 127.86 (d), 131.60

with EtOAc. The organic phase was dried (MgSO₄) and concen- (d), 131.80 (d), 132.20 (d), 132.46 (d), 135.18 (d), 151.56 (u), 165.75

trated in vacuo to give a mixture of 58 and 59 in a ratio of 93:7 (u), 166.37 (u), 166.73 (u). Ϫ MS: m/z (%) ϭ 291 (13), 290 (40), 273

(HPLC, n-hexane/isopropanol, 95:5, t_R(58) ϭ 19.7 min., t_R(59) ϭ

23.9 min.). MPLC (hexanes/EtOAc, 1:3) of the residue afforded 58

(51 mg, 67%) and 59 (4 mg, 5%) as colorless oils.

(17), 272 (24), 246 (13), 201 (22), 200 (11), 119 (75), 118 (12), 105 (26),

91 (12), 85 (100), 67 (12), 57 (13). Ϫ C₄₃H₆₄O₆(676.9): calcd. C76.29,

H 9.53; found C 76.39, H 9.74.

2-(1-Methyl-1-phenylethyl)cyclohexyl [3aS-[2E(1R*,2S*),

[3aS-(2E,3aͰ,4Ͱ(1E,3R*),5β,6aͰ)]-2-[Hexahydro-5-[(tetrahydro-

3aͰ,4Ͱ,5β,6aͰ]]-[Hexahydro-5-[(tetrahydro-2H-pyran-2-yl)- 2H-pyran-2-yl)oxy]-4-[3-(tetrahydro-2H-pyran-2-yl)oxy-1-octenyl]-

oxy]-4-[3-(tetrahydro-2H-pyran-2-yl)oxy-1-octenyl]-2(1H)-pen- 2(1H)-pentalenylidene]ethanol (62): A solution of 60 (835 mg, 1.23

talenylidene]acetate (60): Following the procedure described for the

mmol) in THF (13 ml) was cooled to 0°C and a solution of DIBAL-

preparation of 7c, 58 (650 mg, 1.28 mmol) in CH₂Cl₂(5 ml) and H in CH₂Cl₂(1.0 , 3.72 ml, 3.72 mmol) added dropwise. The mixture

3,4-dihydro-2H-pyran (1.07 g, 12.75 mmol) in the presence of pyri-

dinium p-toluenesulfonate (15 mg, 0.06 mmol) gave after chroma-

tography (hexanes/EtOAc, 4:1) 60 (870 mg, 99%) as a colorless oil,

was warmed to ambient temp. within 2 h and saturated aqueous

NH₄Cl (15 ml) was added. The precipitated aluminum salts were dis-

solved by addition of water (15 ml) and saturated aqueous NH₄Cl (15

[α]_Dϭ ϩ12.6 (c ϭ 9.5, THF). Ϫ IR (ether): ν˜ ϭ 2940 (s), 2860 (s), ml). The mixture was extracted with CH₂Cl₂. The organic phase was

1720 (s), 1655 (m), 1600 (w), 1495 (w), 1440 (m), 1375 (m), 1350 dried (MgSO₄) and concentrated in vacuo. Chromatography (hexanes/

(m), 1320 (m), 1260 (m), 1200 (s), 1185 (s), 1125 (s), 1020 (s), 975 EtOAc, 1:1) of the residue provided 62 (492 mg, 86%) as a colorless

1

(s), 915 (w). Ϫ H NMR (300 MHz, CDCl₃): δ ϭ 0.86Ϫ0.92 (m, 3 oil, [α]_Dϭ ϩ20.1 (c ϭ 10.6, THF). Ϫ IR (ether): ν˜ ϭ 3430 (br), 2940

H), 1.00Ϫ1.35 (m, 16 H), 1.40Ϫ1.96 (m, 19 H), 1.99Ϫ2.27 (m, 4 (s), 2870 (s), 1670 (w), 1455 (m), 1440 (m), 1380 (m), 1350 (m), 1320

H), 2.31Ϫ2.56 (m, 3 H), 2.67Ϫ2.94 (m, 2 H), 3.40Ϫ3.52 (m, 2 H), (w), 1280 (w), 1260 (w), 1200 (m), 1180 (m), 1120 (s), 1075 (s), 1020

3.77Ϫ4.13 (m, 4 H), 4.64Ϫ4.82 (m, 3H), 5.13 (s, 1 H), 5.28Ϫ5.65 (s), 980 (s), 915 (w). Ϫ ¹H NMR (300 MHz, CDCl₃): δ ϭ 0.85Ϫ0.90

(m, 2 H), 7.07Ϫ7.16 (m, 1 H), 7.22Ϫ7.32 (m, 4 H). Ϫ ¹³C NMR

(m, 3 H), 1.07Ϫ1.92 (m, 22 H), 2.00Ϫ2.21 (m, 4 H), 2.30Ϫ2.50 (m, 4

(75 MHz, CDCl₃): δ ϭ 14.06 (d), 14.09 (d), 18.67 (u), 18.73 (u), H), 3.40Ϫ3.52 (m, 2 H), 3.68Ϫ3.93 (m, 3 H), 3.97Ϫ4.17 (m, 3 H),

19.51 (u), 19.61 (u), 19.68 (u), 19.82 (u), 22.63 (u), 24.78 (u), 24.86 4.61Ϫ4.75 (m, 2 H), 5.22Ϫ5.64 (m, 3 H). Ϫ ¹³C NMR (75 MHz,

(u), 25.41 (u), 25.50 (u), 25.60 (u), 26.05 (u), 27.17 (u), 27.28 (d),

CDCl₃): δ ϭ 14.07 (d), 18.59 (u), 18.64 (u), 19.44 (u), 19.54 (u), 19.57

27.38 (d), 27.51 (d), 30.77 (u), 30.84 (u), 31.80 (u), 31.77 (u), 31.86 (u), 19.74 (u), 19.79 (u), 22.62 (u), 24.83 (u), 25.35 (u), 25.37 (u), 25.42

(u), 31.89 (u), 33.63 (u), 34.73 (u), 34.86 (u), 35.79 (u), 35.88 (u),

37.78 (u), 37.83 (u), 38.73 (d), 38.81 (d), 39.15 (d), 39.21 (d), 39.39

(u), 25.47 (u), 25.60 (u), 25.63 (u), 30.67 (u), 30.74 (u), 30.81 (u), 31.75

(u), 31.76 (u), 31.83 (u), 31.87 (u), 34.70 (u), 34.82 (u), 35.74 (u), 35.84

(u), 39.49 (u), 39.64 (u), 39.82 (u), 39.94 (u), 40.26 (u), 40.30 (u), (u), 35.92 (u), 35.97 (u), 35.99 (u), 37.78 (d), 37.84 (d), 37.88 (u), 37.95

44.87 (d), 44.95 (d), 45.02 (d), 51.19 (d), 53.50 (d), 53.81 (d), 54.46 (u), 38.08 (u), 38.12 (u), 38.24 (u), 38.37 (u), 40.42 (u), 40.47 (u), 44.70

(d), 54.66 (d), 61.18 (u), 61.99 (u), 62.18 (u), 62.39 (u), 62.51 (u), (d), 44.82 (d), 53.63 (d), 53.99 (d), 54.70 (d), 54.93 (d), 60.52 (u), 61.07

63.36 (u), 73.76 (d), 75.80 (d), 75.90 (d), 77.09 (d), 77.18 (d), 79.58 (u), 61.97 (u), 62.10 (u), 62.53 (u), 62.63 (u), 75.90 (d), 76.00 (d), 77.02

(d), 80.03 (d), 83.46 (d), 83.68 (d), 94.47 (d), 95.42 (d), 95.58 (d), (d), 77.15 (d), 78.92 (d), 79.38 (d), 83.07 (d), 83.30 (d), 94.43 (d), 95.32

96.92 (d), 97.15 (d), 99.07 (d), 99.37 (d), 113.43 (d), 113.55 (d),

124.73 (d), 124.79 (d), 125.50 (d), 127.89 (d), 131.90 (d), 132.15 (d),

(d), 95.47 (d), 96.76 (d), 97.02 (d), 99.22 (d), 99.48 (d), 121.00 (d),

121.12 (d), 131.60 (d), 131.79 (d), 132.19 (d), 132.46 (d), 132.56 (d),

132.25 (d), 132.43 (d), 132.79 (d), 135.25 (d), 135.30 (d), 151.63 (u), 135.54 (d), 135.62 (d), 145.71 (u), 145.74 (u), 145.92 (u), 145.96 (u).

151.70 (u), 151.74 (u), 165.71 (u), 165.75 (u), 166.23 (u), 166.33 (u), Ϫ MS; m/z (%): 276 (9), 258 (12), 214 (15), 201 (26), 85 (100). Ϫ

166.55 (u), 166.69 (u). Ϫ MS; m/z (%): 490 (3), 371 (4), 290 (19), C₂₈H₄₆O₅(462.7): calcd. C 72.69, H 10.02; found C 72.77, H 10.20.

272 (15), 201 (15), 200 (17), 119 (83), 105 (28), 91 (19). Ϫ C₄₃H₆₄O₆

(677.0): calcd. C 76.29, H 9.53; found C 76.43, H 9.85.

1,1-Dimethylethyl [3aS-(2E,3aͰ,4Ͱ(1E,3R*),5β,6aͰ)]-[2-

[Hexahydro-5-[(tetrahydro-2H-pyran-2-yl)oxy]-4-[3-tetrahydro-

2-(1-Methyl-1-phenylethyl)cyclohexyl [3aS-[2Z(1R*,2S*), 2H-pyran-2-yl)oxy-1-octenyl]-2(1H)-pentalenylidene]-

3aͰ,4Ͱ(1E,3R*),5β,6aͰ]]-[Hexahydro-5-tetrahydro-2H-pyran-2-yl)- ethoxy]acetate (63): A solution of 62 (468 mg, 1.01 mmol) and

oxy]-4-(3-(tetrahydro-2H-pyran-2-yl)-oxy-1-octenyl)-2(1H)-pen- Bu₄NHSO₄(258 mg, 0.78 mmol) in CH₂Cl₂(6 ml) was treated with

talenylidene]acetate (61): Following the procedure described for the aqueous 50% NaOH (12 ml) and tert-butyl bromoacetate (303 mg,

preparation of 7c, 59 (38 mg, 0.08 mmol) in CH₂Cl₂(2 ml) and 3,4- 1.55 mmol). The mixture was stirred for 2 h, cooled to 0°C, diluted

dihydro-2H-pyran (620 mg, 0.79 mmol) in the presence of pyridinium with water (17 ml) and extracted with CH₂Cl₂. The organic phase was

p-toluenesulfonate (7.5 mg, 0.03 mmol) gave after chromatography dried (MgSO₄) and concentrated in vacuo. Chromatography (hexanes/

822

Eur. J. Org. Chem. 1998, 805Ϫ826

Asymmetric Synthesis of 3-Oxacarbacyclin and 3-Oxaisocarbacyclin

FULL PAPER

EtOAc, 4:1) of the residue gave 63 (496 mg, 85%) as a colorless oil, (u), 32.92 (u), 36.91 (u), 38.31 (u), 38.85 (d), 39.29 (u), 42.67 (u), 46.24

[α]_Dϭ ϩ31.0 (c ϭ 9.5, THF). Ϫ IR (ether): ν˜ ϭ 2940 (s), 2870 (s),

(d), 57.70 (d), 67.30 (u), 69.55 (u), 73.90 (d), 78.21 (d), 118.57 (d),

1750 (s), 1730 (m), 1455 (m), 1370 (s), 1300 (m), 1260 (m), 1225 (m), 133.87 (d), 135.93 (d), 149.56 (u), 174.27 (u). Ϫ MS; m/z (%): 258

1160 (s), 1130 (s), 1080 (s), 1035 (s), 1020 (s), 980 (s), 940 (w), 915 (14), 217 (14), 216 (48), 202 (10), 201 (41), 187 (29), 169 (11), 161 (13),

(m). Ϫ ¹H NMR (300 MHz, CDCl₃): δ ϭ 0.85Ϫ0.90 (m, 3 H), 160 (10), 159 (27), 158 (14), 157 (18), 145 (38), 144 (48), 143 (69), 141

1.12Ϫ1.85 (m, 30 H), 1.97Ϫ2.22 (m, 4 H), 2.29Ϫ2.51 (m, 4 H), (10), 135 (21), 134 (29), 133 (19), 132 (14), 131 (37), 128 (13), 121 (15),

3.40Ϫ3.51 (m, 2 H), 3.70Ϫ4.10 (m, 8 H), 4.61Ϫ4.75 (m, 2 H), 119 (23), 118 (33), 117 (50), 115 (12), 109 (13), 107 (20), 106 (42), 105

5.23Ϫ5.64 (m, 3 H). Ϫ ¹³C NMR (75 MHz, CDCl₃): δ ϭ 14.05 (d), (61), 104 (17). Ϫ C₂₀H₃₂O₅(352.5): calcd. C 68.15, H 9.15; found C

14.07 (d), 18.59 (u), 18.64 (u), 19.46 (u), 19.58 (u), 19.73 (u), 22.62 67.91, H 9.11.

(u), 24.84 (u), 25.35 (u), 25.38 (u), 25.44 (u), 25.50 (u), 25.60 (u), 28.12

(d), 30.74 (u), 30.83 (u), 31.76 (u), 31.77 (u), 31.83 (u), 31.88 (u), 34.71

(u), 34.82 (u), 35.75 (u), 35.84 (u), 36.16 (u), 36.19 (u), 37.80, 37.89,

37.96, 38.08, 38.15, 38.19, 38.25, 38.40, 40.35 (u), 40.40 (u), 44.70 (d),

44.82 (d), 44.93 (d), 53.68 (d), 54.05 (d), 54.71 (d), 54.94 (d), 61.05

(u), 62.01 (u), 62.12 (u), 62.50 (u), 62.59 (u), 67.32 (u), 67.36 (u), 67.41

2-(1-Methyl-1-phenylethyl)cyclohexyl [3aS-[2(1R*,2S*),

3aͰ,5β,6Ͱ(1E,3R*),6aͰ]]-[1,3a,4,5,6,6a-Hexahydro-5-

[(tetrahydro-2H-pyran-2-yl)oxy]-6-[3-(tetrahydro-2H-pyran-2-

yl)oxy-1-octenyl]-2-pentalenyl]acetate (66): A suspension of (R,R)-bi-

s(phenylethyl)ammonium chloride (68 mg, 0.26 mmol) in THF (5 ml)

was cooled to Ϫ78°C, and nBuLi (1.51  in hexanes, 0.34 ml, 0.5

(u), 67.45 (u), 68.48 (u), 68.66 (u), 68.71 (u), 75.90 (d), 76.00 (d), 77.01

mmol) was added dropwise. The mixture was warmed to ambient

(d), 77.11 (d), 78.93 (d), 79.37 (d), 81.40 (u), 81.81 (u), 83.08 (d), 83.33

temp. until it became a clear yellow solution. The solution was cooled

(d), 94.46 (d), 95.29 (d), 95.44 (d), 96.77 (d), 97.02 (d), 98.73 (d), 99.17

to Ϫ105°C and treated dropwise with a solution of 60 (85 mg, 0.13

mmol) in THF (2 ml). After stirring the mixture for 30 min. at

Ϫ105°C, it was warmed to Ϫ78°C, and saturated aqueous NaHCO₃

(2 ml) was added. After warming the mixture to ambient temp., it

was extracted with ether. The organic phase was dried (MgSO₄) and

concentrated in vacuo. Chromatography (hexanes/EtOAc, 4:1) of the

(d), 99.44 (d), 117.39 (d), 117.54 (d), 131.62 (d), 131.83 (d), 132.18

(d), 132.48 (d), 132.54 (d), 135.51 (d), 135.58 (d), 148.00 (u), 148.04

(u), 148.25 (u), 148.30 (u), 169.85 (u). Ϫ MS; m/z (%): 334 (4), 275

(4), 258 (11), 240 (6), 214 (7), 85 (100). Ϫ C₃₄H₅₆O₇(576.8): calcd. C

70.80, H 9.79; found C 70.70, H 9.88.

1,1-Dimethylethyl [3aS-(2E,3aͰ,4Ͱ(1E,3R*),5β,6aͰ)]-[2- residue provided a mixture of 66 and 69 (77 mg, 91%, ratio 98.5:1.5)

[Hexahydro-5-hydroxy-4-(3-hydroxy-1-octenyl)-2(1H)- as a colorless oil. Data for 66 and 69: [α]_Dϭ Ϫ19.9 (c ϭ 10.0, THF).

pentalenylidene]ethoxy]acetate (64): A solution of 63 (460 mg, 0.80 Ϫ IR (neat): ν˜ ϭ 2930 (s), 2860 (s), 1730 (s), 1600 (w), 1440 (s), 1260

mmol) in EtOH (6.5 ml) was treated with pyridinium p-toluenesulfon- (s), 1200 (s), 1130 (s), 1080 (s), 1020 (s), 980 (s), 915 (m). Ϫ ¹H NMR

ate (40 mg, 0.16 mmol). After stirring the mixture for 4 days at ambi- (300 MHz, CDCl₃): δ ϭ 0.84Ϫ0.94 (m, 3 H), 0.96Ϫ2.56 (m, 43 H),

ent temp., it was concentrated in vacuo. Chromatography (hexanes/ 2.88Ϫ3.04 (m, 1 H), 3.40Ϫ4.02 (m, 6 H), 4.62Ϫ4.82 (m, 3 H),

EtOAc, 1:10) of the residue provided 64 (307 mg, 94%) as a colorless 5.24Ϫ5.64 (m, 3 H), 7.09Ϫ7.17 (m, 1 H), 7.19Ϫ7.35 (m, 4 H). Ϫ ¹³C

oil, [α]_Dϭ ϩ65.6 (c ϭ 10.5, THF). Ϫ IR (neat): ν˜ ϭ 3390 (br), 2930

NMR (75 MHz, CDCl₃): δ ϭ 14.17 (d), 18.70 (u), 19.52 (u), 19.72

(s), 2860 (s), 1745 (s), 1460 (s), 1430 (s), 1395 (s), 1370 (s), 1300 (s), (u), 22.74 (u), 24.78 (u), 24.97 (d), 25.50 (u), 25.73 (u), 26.05 (u), 27.11

1

1250 (s), 1225 (s), 1160 (s), 1125 (s), 1035 (w), 970 (s). Ϫ H NMR (u), 28.06 (d), 30.89 (u), 31.89 (u), 33.47 (u), 34.86 (u), 34.97 (u), 35.74

(300 MHz, CDCl₃): δ ϭ 0.88 (t, J ϭ 6.7 Hz, 3 H), 1.13Ϫ1.66 (m, 9 (u), 35.91 (u), 35.99 (u), 36.94 (u), 38.33 (u), 39.38 (u), 39.60 (u), 39.94

H), 1.49 (s, 9 H), 1.82 (ddd, J ϭ 9.5, J ϭ 9.5, J ϭ 8.0 Hz, 1 H), (u), 43.89 (d), 44.07 (d), 45.45 (d), 45.63 (d), 50.87 (d), 54.51 (d), 54.81

2.03Ϫ2.18 (m, 3 H), 2.27Ϫ2.50 (m, 4 H), 3.13 (s, 1 H), 3.35 (s, 1 H), (d), 55.54 (d), 55.72 (d), 61.13 (u), 62.15 (u), 62.25 (u), 62.42 (u), 62.52

3.68 (ddd, J ϭ 9.7, J ϭ 9.7, J ϭ 6.7 Hz, 1 H), 3.94 (s, 2 H), 3.98Ϫ4.11 (u), 74.77 (d), 76.05 (d), 76.17 (d), 76.73 (d), 77.15 (d), 78.30 (d), 78.72

(m, 3 H), 5.39Ϫ5.54 (m, 3 H). Ϫ ¹³C NMR (75 MHz, CDCl₃): δ ϭ

(d), 82.82 (d), 83.07 (d), 94.56 (d), 95.26 (d), 95.39 (d), 96.75 (d), 97.00

14.13 (d), 22.70 (u), 25.26 (u), 28.22 (d), 31.82 (u), 36.18 (u), 37.18 (d), 99.34 (d), 99.58 (d), 125.11 (d), 125.49 (d), 126.86 (d), 128.04 (d),

(u), 37.60 (d), 38.22 (u), 41.36 (u), 44.94 (d), 57.26 (d), 67.51 (d), 68.72 131.79 (d), 132.07 (d), 132.33 (d), 132.51 (d), 132.68 (d), 133.90 (u),

(d), 73.30 (d), 77.22 (d), 81.70 (u), 117.60 (d), 133.62 (d), 135.65 (d), 134.00 (u), 134.09 (u), 135.68 (d), 151.72 (u), 170.55 (u). Ϫ MS; m/z

148.19 (u), 170.06 (u). Ϫ MS; m/z (%): 372 (5), 333 (12), 316 (18), 275 (%): 676 [M^ϩϪ 1] (0.1), 490 (12), 446 (11), 291 (28), 290 (90), 289

(15), 258 (24), 241 (12), 214 (49), 187 (15), 159 (14), 145 (25), 144 (20), (10), 272 (14), 246 (12), 201 (21), 119 (63), 105 (40), 91 (17). Ϫ

134 (25), 117 (18), 106 (15), 105 (23), 99 (32).- C₂₄H₄₀O₅(408.6): calcd. C₄₃H₆₄O₆(677.0): calcd. C 76.29, H 9.53; found C 76.03, H 9.57.

C 70.55, H 9.87; found C 70.26, H 9.96.

2-(1-Methyl-1-phenylethyl)cyclohexyl

[3aS-[2(1R*,2S*),3aͰ,

3-Oxacarbacyclin (4): A solution of 64 (256 mg, 0.63 mmol) in 5β,6Ͱ(1E,3R*),6aͰ]]-[1,3a,4,5,6,6a-Hexahydro-5-hydroxy-6-(3-

MeOH (40 ml) was treated with aqueous NaOH (1.0 , 1.2 ml). After hydroxy-1-octenyl)-2-pentalenyl]acetate (67): A solution of 66 (77 mg,

stirring the mixture for 4 h at ambient temp., saturated aqueous 0.11 mmol) in MeOH (2 ml) was treated with pyridinium p-toluene-

NH₄Cl (100 ml) and solid NaH₂PO₄were added until a pH of 4Ϫ5

sulfonate (80 mg, 0.33 mmol). After stirring the mixture for 12 h at

was reached, and the mixture was extracted with EtOAc. The organic ambient temp., it was concentrated in vacuo. Chromatography (hex-

phase was dried (MgSO₄) and concentrated in vacuo. Dissolution of anes/EtOAc, 1:10) of the residue gave 67 (44 mg, 76%), containing

the residue in ether, filtration and concentration of the filtrate gave 4

(158 mg, 71%) as a colorless oil, [α]_Dϭ ϩ64.2 (c ϭ 3.0, MeOH). Ϫ

1.5% of 70, as a colorless oil. Data for 67 and 70: [α]_Dϭ ϩ12.3 (c ϭ

7.7, THF). Ϫ IR (CHCl₃): ν˜ ϭ 3380 (br), 2930 (s), 2860 (s), 1730 (s),

IR (neat): ν˜ ϭ 3380 (br), 2930 (s), 2860 (s), 1740 (s), 1460 (m), 1430 1600 (w), 1495 (m), 1445 (s), 1390 (m), 1370 (m), 1320 (m), 1300 (m),

1

(s), 1375 (s), 1240 (s), 1120 (s), 1045 (s), 970 (s). Ϫ H NMR (500 1245 (s), 1170 (m), 1130 (s), 1090 (s), 1025 (s), 970 (s). Ϫ H NMR

MHz, CDCl₃): δ ϭ 0.91 (t, J ϭ 7.0 Hz, 3 H), 1.20 (ddd, J ϭ 12.5, (300 MHz, CDCl₃): δ ϭ 0.89 (t, J ϭ 6.9 Hz, 3 H), 1.06 (dddd, J ϭ

J ϭ 9.9, J ϭ 7.5 Hz, 1 H), 1.26Ϫ1.60 (m, 8 H), 1.83 (ddd, J ϭ 9.8, 12.5, J ϭ 12.5, J ϭ 12.5, J ϭ 2.7 Hz, 1 H), 1.20 (s, 3 H), 1.31 (2s, 3

J ϭ 9.8, J ϭ 7.8 Hz, 1 H), 2.10Ϫ2.21 (m, 3 H), 2.30 (ddd, J ϭ 12.5, H), 1.11Ϫ1.40 (m, 10 H), 1.42Ϫ1.50 (m, 1 H), 1.54Ϫ1.61 (m, 1 H),

J ϭ 8.1, J ϭ 7.0 Hz, 1 H), 2.41Ϫ2.54 (m, 3 H), 3.70 (ddd, J ϭ 9.7,

1.65Ϫ1.71 (m, 2 H), 1.71Ϫ1.77 (m, 1 H), 1.83Ϫ1.88 (m, 1 H),

J ϭ 9.7, J ϭ 7.0 Hz, 1 H), 3.99 (dt, J ϭ 6.6, J ϭ 6.6 Hz, 1 H), 4.04 1.88Ϫ1.95 (m, 2 H), 2.07 (ddd, J ϭ 12.0, J ϭ 10.5, J ϭ 3.6 Hz, 1 H),

(s, 2 H), 4.03Ϫ4.13 (m, 2 H), 4.89 (s, 3 H), 5.44Ϫ5.48 (m, 1 H), 5.47 2.23Ϫ2.31 (m, 2 H), 2.39 (dd, J ϭ 16.4, J ϭ 8.7 Hz, 1 H), 2.46 (s, 2

(dd, J ϭ 15.4, J ϭ 6.7 Hz, 1 H), 5.54 (dd, J ϭ 15.4, J ϭ 7.8 Hz, 1 H), 2.76 (s, 2 H), 2.95Ϫ3.02 (m, 1 H), 3.73 (ddd, J ϭ 9.4, J ϭ 9.4,

H). Ϫ ¹³C NMR (75 MHz, CDCl₃): δ ϭ 14.36 (d), 23.69 (u), 26.35 J ϭ 7.0 Hz, 1 H), 4.04 (dt, J ϭ 6.7, J ϭ 6.7 Hz, 1 H), 4.77 (ddd, J ϭ

Eur. J. Org. Chem. 1998, 805Ϫ826

823

I. Vaulont, H.-J. Gais, N. Reuter, E. Schmitz, R. K. L. Ossenkamp

FULL PAPER

10.4, J ϭ 10.4, J ϭ 4.6 Hz, 1 H), 5.32 (d, J ϭ 1.1 Hz, 1 H), 5.46 (dd, 1 H), 5.46Ϫ5.55 (m, 2 H), 7.11Ϫ7.15 (m, 1 H), 7.26Ϫ7.29 (m, 4 H),

J ϭ 15.3, J ϭ 8.3 Hz, 1 H), 5.52 (dd, J ϭ 15.3, J ϭ 7.1 Hz, 1 H), ¹³C NMR (75 MHz, CDCl₃): δ ϭ 14.06 (d), 22.63 (u), 24.66 (d), 24.69

7.11Ϫ7.16 (m, 1 H), 7.26Ϫ7.29 (m, 4 H). Ϫ ¹³C NMR (75 MHz, (u), 25.18 (u), 25.93 (u), 26.97 (u), 28.15 (d), 31.74 (u), 33.32 (u), 36.48

CDCl₃): δ ϭ 14.06 (d), 22.65 (u), 24.54 (d), 24.69 (u), 25.24 (u), 25.94 (d), 36.55 (u), 37.20 (u), 39.82 (u), 42.03 (u), 42.76 (u), 50.75 (d), 54.67

(u), 26.96 (u), 28.27 (d), 31.75 (u), 33.37 (u), 36.73 (u), 37.18 (u), 39.03 (d), 57.38 (d), 73.18 (d), 74.83 (d), 77.54 (d), 125.06 (d), 125.42 (d),

(u), 39.55 (u), 39.80 (u), 44.56 (d), 45.74 (d), 50.72 (d), 58.01 (d), 73.24 127.98 (d), 130.47 (d), 133.62 (d), 134.66 (d), 135.07 (u), 151.72 (u),

(d), 74.77 (d), 77.07 (d), 125.05 (d), 125.42 (d), 128.01 (d), 132.60 (d), 170.62 (u). Ϫ MS; m/z (%): 446 (11), 290 (14), 289 (22), 246 (23), 201

133.39 (d), 134.00 (u), 135.58 (d), 151.72 (u), 170.63 (u). Ϫ MS; m/z (9), 119 (100), 105 (65), 91 (34).

(%): 446 (4), 290 (33), 246 (9), 201 (9), 120 (10), 119 (100), 105 (53),

[3aS-[3aͰ,5β,6Ͱ(1E,3R*),6aͰ]]-2-[1,3a,4,5,6,6a-Hexahydro-5-

91 (30). Ϫ C₃₃H₄₈O₄(509.8): calcd. C 77.91, H 9.51; found C 77.66,

[(tetrahydro-2H-pyran-2-yl)oxy]-6-[3-(tetrahydro-2H-pyran-2-yl)-

oxy-1-octenyl]-2-pentalenyl]ethanol (71): Following the procedure de-

H 9.56.

2-(1-Methyl-1-phenylethyl)cyclohexyl [3aS-[2(1S*,2R*),

3aͰ,4Ͱ(1E,3S*),5β,6aͰ]]-[1,3a,4,5,6,6a-Hexahydro-5-

[(tetrahydro-2H-pyran-2-yl)oxy]-4-[3-(tetrahydro-2H-pyran-2yl)-

oxy-1-octenyl]-2-pentalenyl]acetate (69): Following the procedure de-

scribed for the preparation of 66, (R,R)-bis(phenylethyl)ammonium

chloride (68 mg, 0.26 mmol) in THF (5 ml), nBuLi (1.51  in hexanes,

0.34 ml, 0.26 mmol) and 61 (85 mg, 0.13 mmol) in THF (2 ml) gave

after chromatography (hexanes/EtOAc, 1:1) a mixture of 69 and 66

(74 mg, 88%, ratio 98.5:1.5) as a colorless oil. Data for 69 and 66:

[α]_Dϭ ϩ12.3 (c ϭ 10.2, THF). Ϫ IR (CHCl₃): ν˜ ϭ 2940 (s), 2860

(m), 1730 (s), 1600 (w), 1495 (w), 1445 (m), 1390 (m), 1370 (m), 1350

(m), 1340 (m), 1320 (m), 1260 (m), 1215 (m), 1200 (m), 1180 (m),

scribed for the preparation of 62, 66 (240 mg, 0.36 mmol) in THF (4

ml) and DIBAL-H in CH₂Cl₂(1.0 , 1.07 ml, 1.07 mmol) gave after

chromatography (hexanes/EtOAc, 1:1) 71 (116 mg, 71%) as a colorless

oil, [α]_Dϭ Ϫ15.3 (c ϭ 9.5, THF). Ϫ IR (neat): ν˜ ϭ 3460 (br), 2940

(s), 2870 (s), 1740 (w), 1670 (w), 1455 (s), 1440 (s), 1385 (m), 1350

(m), 1320 (m), 1285 (m), 1260 (m), 1200 (s), 1120 (s), 1080 (s), 1020

(s), 980 (s), 915 (m). Ϫ ¹H NMR (300 MHz, CDCl₃): δ ϭ 0.86Ϫ0.90

(m, 3 H), 1.20Ϫ2.51 (m, 29 H), 2.98Ϫ4.08 (m, 9 H), 4.62Ϫ4.75 (m, 2

H), 5.25Ϫ5.71 (m, 3 H). Ϫ ¹³C NMR (75 MHz, CDCl₃) δ 14.06 (d),

18.69 (u), 18.80 (u), 19.48 (u), 19.58 (u), 19.72 (u), 22.63 (u), 24.85

(u), 25.39 (u), 25.48 (u), 25.60 (u), 30.71 (u), 30.76 (u), 30.83 (u), 31.78

(u), 31.84 (u), 34.27 (u), 34.77 (u), 34.86 (u), 35.78 (u), 35.87 (u), 36.09

(u), 36.15 (u), 38.55 (u), 39.64 (u), 39.76 (u), 39.87 (u), 40.06 (u), 43.83

(d), 43.93 (d), 45.79 (d), 45.88 (d), 46.00 (d), 46.12 (d), 54.92 (d), 55.10

(d), 55.21 (d), 55.78 (d), 55.99 (d), 60.51 (u), 60.55 (u), 61.20 (u), 61.30

(u), 62.01 (u), 62.16 (u), 62.51 (u), 75.94 (d), 76.05 (d), 77.18 (d), 77.22

(d), 78.71 (d), 79.28 (d), 83.06 (d), 83.21 (d), 94.46 (d), 95.40 (d), 95.64

(d), 96.87 (d), 97.08 (d), 99.30 (d), 99.52 (d), 130.81 (d), 130.90 (d),

130.96 (d), 131.56 (d), 131.85 (d), 132.12 (d), 132.46 (d), 132.58 (d),

132.62 (d), 135.58 (d), 137.89 (u), 138.02 (u), 138.10 (u). Ϫ MS; m/z

(%): 462 [M^ϩ] (0.02), 316 (7), 277 (22), 276 (8), 258 (13), 246 (13), 232

(29). Ϫ C₂₈H₄₆O₅(462.7): calcd. C 72.69, H 10.02; found C 72.71,

H 10.12.

1

1160 (m), 1130 (s), 1080 (s), 1025 (s), 975 (m), 910 (w). Ϫ H NMR

(300 MHz, CDCl₃): δ ϭ 0.85Ϫ0.90 (m, 3 H), 0.99Ϫ2.84 (m, 44 H),

3.40Ϫ4.09 (m, 6H), 4.61Ϫ4.81 (m, 3 H), 5.47Ϫ5.75 (m, 3 H),

7.10Ϫ7.18 (m, 1 H), 7.24Ϫ7.30 (m, 4 H), ¹³C NMR (75 MHz,

CDCl₃): δ ϭ 14.08 (d), 14.09 (d), 18.67 (u), 19.44 (u), 19.65 (u), 22.63

(u), 24.69 (u), 24.70 (d), 24.86 (u), 25.35 (u), 25.39 (u), 25.47 (u), 25.52

(u), 25.60 (u), 25.63 (u), 25.67 (u), 25.94 (u), 28.10 (d), 30.79 (u), 30.84

(u), 31.78 (u), 31.80 (u), 31.85 (u), 31.90 (u), 33.29 (u), 34.66 (u), 34.79

(u), 35.75 (u), 35.86 (u), 36.26 (d), 36.32 (d), 36.39 (d), 36.48 (d), 36.73

(u), 38.28 (u), 38.35 (u), 39.82 (u), 41.07 (u), 42.53 (u), 50.75 (d), 53.85

(d), 53.89 (d), 54.04 (d), 54.31 (d), 54.85 (d), 55.17 (d), 61.07 (u), 62.10

(u), 62.18 (u), 62.35 (u), 62.44 (u), 74.66 (d), 75.90 (d), 76.00 (d), 76.87

(d), 77.05 (d), 78.82 (d), 79.20 (d), 83.01 (d), 83.32 (d), 94.49 (d), 95.28

(d), 95.40 (d), 96.69 (d), 96.97 (d), 99.12 (d), 99.42 (d), 125.00 (d),

125.39 (d), 127.94 (d), 129.82 (d), 130.05 (d), 130.11 (d), 130.41 (d),

131.07 (d), 131.22 (d), 131.67 (d), 131.90 (d), 133.17 (d), 133.20 (d),

134.46 (u), 134.68 (u), 134.90 (u), 136.02 (d), 136.15 (d), 151.67 (u),

170.44 (u), 170.47 (u). Ϫ MS; m/z (%): 490 (6), 447 (16), 446 (43), 290

(27), 289 (22), 247 (12), 246 (56), 201 (21), 175 (8), 119 (61), 105 (58),

95 (11), 91 (14). Ϫ C₄₃H₆₄O₆(677.0): calcd. C 76.29, H 9.53; found

C 76.19, H 9.62.

1,1-Dimethylethyl

[3aS-[3aͰ,5β,6Ͱ(1E,3R*),6aͰ]]-[2-[1,3a,4,

5,6,6a-Hexahydro-5-[(tetrahydro-2H-pyran-2-yl)oxy]-6-[3-(te-

trahydro-2H-pyran-2-yl)oxy-1-octenyl]-2-pentalenyl]ethoxy]acetate

(72): Following the procedure described for the preparation of 63, 71

(110 mg, 0.24 mmol) in CH₂Cl₂(1.5 ml), Bu₄NHSO₄(61 mg, 0.18

mmol), aqueous 50% NaOH (2.8 ml) and tert-butyl bromoacetate (71

mg, 0.36 mmol) gave after chromatography (hexanes/EtOAc, 4:1) 72

(117 mg, 85%) as a colorless oil, [α]_Dϭ Ϫ16.4 (c ϭ 9.8, THF). Ϫ IR

(ether): ν˜ ϭ 2940 (s), 2870 (m), 1750 (s), 1730 (m), 1455 (m), 1440

(m), 1390 (m), 1370 (s), 1300 (m), 1260 (m), 1225 (m), 1200 (m), 1160

(s), 1135 (s), 1080 (s), 1035 (s), 1025 (s), 1020 (s), 980 (m), 920 (m).

Ϫ ¹H NMR (300 MHz, CDCl₃): δ ϭ 0.85Ϫ0.91 (m, 3 H), 1.10Ϫ2.54

(m, 37H), 2.92Ϫ3.06 (m, 1 H), 3.40Ϫ4.10 (m, 10 H), 4.62Ϫ4.76 (m,

2 H), 5.27Ϫ5.70 (m, 3 H). Ϫ ¹³C NMR (75 MHz, CDCl₃): δ ϭ 14.06

(d), 18.60 (u), 19.45 (u), 19.63 (u), 22.63 (u), 24.85 (u), 25.39 (u), 25.52

(u), 25.62 (u), 25.69 (u), 28.13 (d), 30.72 (u), 30.82 (u), 31.28 (u), 31.78

(u), 31.84 (u), 34.77 (u), 34.87 (u), 35.80 (u), 35.88 (u), 35.97 (u), 36.04

(u), 38.58 (u), 39.93 (u), 40.25 (u), 43.56 (d), 43.70 (d), 45.50 (d), 45.69

(d), 54.60 (d), 54.96 (d), 55.64 (d), 55.88 (d), 61.04 (u), 62.10 (u), 62.35

(u), 68.50 (u), 68.80 (u), 70.18 (u), 75.99 (d), 76.10 (d), 77.07 (d), 78.37

(d), 78.80 (d), 81.48 (u), 81.82 (u), 82.84 (d), 83.08 (d), 94.47 (d), 95.17

(d), 95.32 (d), 96.73 (d), 96.97 (d), 99.23 (d), 99.48 (d), 129.62 (d),

129.69 (d), 131.60 (d), 132.15 (d), 132.49 (d), 132.65 (d), 135.64 (d),

137.92 (u), 138.05 (u), 169.03 (u), 169.72 (u). Ϫ MS; m/z (%): 346

(13), 334 (14), 290 (11), 258 (12), 214 (31). Ϫ C₃₄H₅₆O₇(576.8): calcd.

C 70.80, H 9.79; found C 70.40, H 9.61.

2-(1-Methyl-1-phenylethyl)cyclohexyl [3aR-[2(1S*,2R*),3aͰ,4Ͱ

(1E,3S*),5β,6aͰ]]-[1,3a,4,5,6,6a-Hexahydro-5-hydroxy-4-(3-

hydroxy-1-octenyl)-2-pentalenyl]acetate (70): A solution of 69 (77 mg,

0.11 mmol) in MeOH (2 ml) was treated with pyridinium p-toluene-

sulfonate (80 mg, 0.33 mmol). After stirring the mixture for 12 h at

ambient temp., it was concentrated in vacuo. Chromatography (hex-

anes/EtOAc, 1:10) of the residue gave 70 (48 mg, 83%), containing

1.5% of 67, as a colorless oil. Data for 70 and 67: [α]_Dϭ ϩ34.3 (c ϭ

8.5, THF). Ϫ IR (CHCl₃): ν˜ ϭ 3370 (br), 2930 (s), 2860 (s), 1725 (s),

1600 (w), 1495 (m), 1450 (s), 1390 (m), 1370 (m), 1320 (m), 1255 (m),

1

1215 (m), 1165 (m), 1130 (m), 1090 (m), 1025 (m), 970 (m). Ϫ H

NMR (300 MHz, CDCl₃): δ ϭ 0.89 (t, J ϭ 7.0 Hz, 3 H), 1.05 (ddd,

J ϭ 12.5, J ϭ 12.5, J ϭ 2.7 Hz, 1 H), 1.20 (s, 3 H), 1.31 (s, 3 H),

1.11Ϫ1.38 (m, 10 H), 1.42Ϫ1.49 (m, 1 H), 1.52Ϫ1.59 (m, 1 H),

1.65Ϫ1.76 (m, 3 H), 1.84Ϫ1.89 (m, 1 H), 1.97Ϫ2.09 (m, 3 H), 2.28

(ddd, J ϭ 12.3, J ϭ 8.3, J ϭ 5.9 Hz, 1 H), 2.45 (s, 2 H), 2.51 (dd,

J ϭ 16.0, J ϭ 9.3 Hz, 1 H), 2.59 (m, 1 H), 2.79 (m, 1 H), 3.70 (ddd,

J ϭ 9.5, J ϭ 8.3, J ϭ 5.9 Hz, 1 H), 4.03 (dt, J ϭ 6.6, J ϭ 6.6, 1 H),

1,1-Dimethylethyl

[3aS-[3aͰ,5β,6Ͱ(1E,3R*),6aͰ]]-[2-[1,3a,

4.77 (ddd, J ϭ 10.3, J ϭ 10.3, J ϭ 4.6 Hz, 1 H), 5.36 (d, J ϭ 1.9 Hz, 4,5,6,6a-Hexahydro-5-hydroxy-6-(3-hydroxy-1-octenyl)-2-penta-

824 Eur. J. Org. Chem. 1998, 805Ϫ826

Asymmetric Synthesis of 3-Oxacarbacyclin and 3-Oxaisocarbacyclin

FULL PAPER

Nenci, M. C. Fioretti, Adv. Prostagl. Thromb. and Leukotr. Res.

1990, 21, 917Ϫ920.

lenyl]ethoxy]acetate (73): Following the procedure described for the

preparation of 64, 72 (98 mg, 0.17 mmol) in EtOH (1.5 ml) and pyridi-

nium p-toluenesulfonate (34 mg, 0.14 mmol) gave after chromatogra-

phy (hexanes/EtOAc, 1:10) 73 (59 mg, 85%) as a colorless oil, [α]_Dϭ

ϩ1.7 (c ϭ 9.8, THF). Ϫ IR (neat): ν˜ ϭ 3380 (br), 2930 (s), 2870 (s),

1750 (s), 1670 (w), 1460 (m), 1430 (m), 1395 (m), 1370 (s), 1300 (m),

1255 (s), 1225 (s), 1165 (s), 1135 (s), 1095 (s), 1025 (m), 970 (s). Ϫ ¹H

NMR (300 MHz, CDCl₃): δ ϭ 0.89 (t, J ϭ 6.7 Hz, 3 H), 1.18Ϫ1.69

(m, 9 H), 1.48 (s, 9 H), 1.91 (ddd, J ϭ 9.5, J ϭ 9.5, J ϭ 8.0 Hz, 1

H), 2.01 (d, J ϭ 17.3 Hz, 1 H), 2.23Ϫ2.53 (m, 5 H), 2.50Ϫ3.00 (s, br,

2 H), 2.94Ϫ3.08 (m, 1 H), 3.62 (t, J ϭ 6.9 Hz, 2 H), 3.73 (ddd, J ϭ

9.5, J ϭ 9.5, J ϭ 7.0 Hz, 1 H), 3.96 (s, 2 H), 4.04 (dt, J ϭ 6.5, J ϭ

6.5 Hz, 1 H), 5.38 (s, 1 H), 5.43Ϫ5.58 (m, 2 H). Ϫ ¹³C NMR (75

MHz, CDCl₃): δ ϭ 14.05 (d), 22.62 (u), 25.21 (u), 28.14 (d), 31.24

(u), 31.74 (u), 37.16 (u), 39.46 (u), 39.91 (u), 44.23 (d), 45.76 (d), 58.15

(d), 68.78 (u), 70.06 (u), 73.24 (d), 77.11 (d), 81.58 (u), 129.70 (d),

133.43 (d), 135.49 (d), 138.21 (u), 169.78 (u). Ϫ MS; m/z (%): 346

(11), 334 (17), 316 (10), 290 (39), 258 (21), 214 (41), 187 (20), 166 (17),

159 (16), 150 (15), 145 (22), 144 (25), 143 (41), 134 (26), 131 (19), 117

(20), 106 (25), 105 (35). Ϫ C₂₄H₄₀O₅(408.6): calcd. C 70.55, H 9.87;

found C 70.52, H 10.14.

[12]

[13]

D. J. Crutschley, L. B. Conanan, B. G. Que, J. Pharmacol. Exp.

Ther. 1994, 271, 446Ϫ451.

B. Siegmund, A. Eigler, J. Moeller, T. F. Greten, G. Hartmann, S.

Endres, Eur. J. Pharmacol. 1997, 321, 231Ϫ239.

A. Takahashi, M. Shibasaki, J. Org. Chem. 1988, 53, 1227Ϫ1231.

H.-J. Gais, G. Schmiedl, W. A. Ball, J. Bund, G. Hellmann, I.

Erdelmeier, Tetrahedron Lett. 1988, 29, 1773Ϫ1774.

H.-J. Gais, G. Bülow, Tetrahedron Lett. 1992, 33, 465Ϫ468.

H.-J. Gais, G. Schmiedl, R. K. L. Ossenkamp, Liebigs Ann.

1997, 2419Ϫ2431.

[14]

[15]

[16]

[17]

[18]

H.-J. Gais. R. K. L. Ossenkamp, Liebigs Ann. 1997, 2432Ϫ2441.

^{[19] [19a]}K. Kojima, K. Koyama, S. Amemija, S. Saito, Chem. Pharm.

[19b]

Bull. 1987, 35, 948Ϫ956. Ϫ

1995, 29Ϫ31.

K. Mikami, A. Yoshida, Synlett

[20]

[21]

S. H. Berz, J. M. Cook, A. Gawish, U. Weiss, Org. Synth. 1990,

Coll. Vol. 7, 50Ϫ56.

M. Shibasaki, J. Ueda, S. Ikegami, Tetrahedron Lett. 1979,

433Ϫ436.

[22]

[23]

E. Piers, V. Karunaratne, Can. J. Chem. 1989, 67, 160Ϫ164.

For a notable exception, see: J. Westermann, M. Harre, K. Nick-

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K. Kojima, K. Sakai, Tetrahedron Lett. 1978, 3743Ϫ3746.

M. Shibasaki, J. Ueda, S. Ikegami, Tetrahedron Lett. 1979,

433Ϫ436.

[24]

[25]

[26]

[27]

For a review, see: P. J. Cox, N. S. Simpkins, Tetrahedron: Asym-

metry 1991, 2, 1Ϫ26.

3-Oxaisocarbacyclin (5): Following the procedure described for the

preparation of 4, 73 (40 mg, 0.10 mmol) in MeOH (6 ml) and NaOH

(1.0 , 0.2 ml) gave 5 (30 mg, 87%) as a colorless oil, [α]_Dϭ ϩ6.9

For a review, see: H.-J. Gais in Methods of Organic Chemistry

(Houben-Weyl) 1996, vol. E21a, pp. 589Ϫ643.

^{[28] [28a]}For a review, see: T. Mukaiyama, Organic Reactions 1982, 28,

(c ϭ 4.6, MeOH). Ϫ IR (CHCl ): ν ϭ 3360 (br), 2930 (s), 2860 (s),

˜

3

[28b]

203Ϫ331. Ϫ

For a review, see: M. Braun in Methods of Or-

1735 (s), 1445 (s), 1380 (m), 1345 (m), 1220 (s), 1130 (s), 970 (s). Ϫ

¹H NMR (500 MHz, CDCl₃): δ ϭ 0.89 (t, J ϭ 6.7 Hz, 3 H),

1.24Ϫ1.37 (m, 7 H), 1.42Ϫ1.50 (m, 1 H), 1.54Ϫ1.63 (m, 1 H), 1.97

(ddd, J ϭ 9.3, J ϭ 9.3, J ϭ 9.3 Hz, 1 H), 2.08 (d, J ϭ 16.2 Hz, 1 H),

2.25Ϫ2.34 (m, 3 H), 2.37Ϫ2.47 (m, 2 H), 3.01 (d, J ϭ 7.9 Hz, 1 H),

3.66 (t, J ϭ 6.4 Hz, 2 H), 3.75 (ddd, J ϭ 9.5, J ϭ 9.5, J ϭ 7.2 Hz, 1

H), 4.04 (dt, J ϭ 6.9, J ϭ 6.9 Hz, 1 H), 4.05 (d, J ϭ 16.6 Hz, 1 H),

4.11 (d, J ϭ 16.6 Hz, 1 H), 5.24 (s, br, 3 H), 5.39 (s, 1 H), 5.45 (dd,

J ϭ 15.2, J ϭ 8.4 Hz, 1 H), 5.52 (dd, J ϭ 15.2, J ϭ 7.6 Hz, 1 H). Ϫ

¹³C NMR (125 MHz, CDCl₃): δ ϭ 14.04 (d), 22.61 (u), 25.21 (u),

30.99 (u), 31.67 (u), 36.72 (u), 39.05 (u), 39.44 (u), 44.20 (d), 45.69

(d), 57.73 (d), 67.98 (u), 70.12 (u), 73.59 (d), 77.27 (d), 130.30 (d),

133.61 (d), 135.36 (d), 138.31 (u), 172.96 (u). Ϫ MS; m/z (%): 334

(11), 316 (6), 290 (26), 187 (15), 159 (18), 145 (21), 144 (28), 143 (43),

134 (22), 131 (37), 129 (30), 119 (20), 118 (17), 117 (41), 115 (17), 107

(19), 106 (30), 105 (72). Ϫ C₂₀H₃₂O₅(352.5): calcd. C 68.15, H 9.15;

found C 68.33, H 9.31.

ganic Chemistry (Houben Weyl) 1996, vol. E21a, pp. 1603Ϫ1666.

P. A. Grieco, T. Takigawa, S. L. Bongers, H. Tanaka, J. Am. Chem.

Soc. 1980, 102, 7587Ϫ7588.

[29]

[30]

U. Hofmann, C. O. Meese, M. Hecker, V. Ullrich, Tetrahedron

Lett. 1987, 28, 5655Ϫ5658.

[31] [31a]

S. J. Danishefsky, M. P. Cabal, K. Chow, J. Am. Chem. Soc.

1989, 111, 3456Ϫ3457. Ϫ ^[31b]S. J. Danishefsky, K. Chow, J. Org.

Chem. 1989, 54, 6016Ϫ6018.

[32] [32a]

R. Mahrwald, H. Schick, K. K. Pivnitsky, J. Prakt. Chem.

[32b]

1990, 332, 403Ϫ413. Ϫ

H. Schick, J. Spanig, R. Mahrwald,

M. Bohle, T. Reiher, K. K. Pivnitsky, Tetrahedron 1992, 48,

5579Ϫ5586.

[33]

H. Rehwinkel, J. Skupsch, H. Vorbrüggen, Tetrahedron Lett. 1988,

29, 1775Ϫ1776.

[34] [34a]

M. W. Rathke, D. Sullivan, Tetrahedron Lett. 1972,

[34b]

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Article Doi

Asymmetric Synthesis of 3-Oxacarbacyclin and 3-Oxaisocarbacyclin by a Common Enantioselective Deprotonation Based Route

DOI: 10.1002/(SICI)1099-0690(199805)1998:5<805::AID-EJOC805>3.0.CO;2-R

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