Fully stereocontrolled syntheses of 3-oxacarbacyclin and carbacyclin by the conjugate addition-azoalkene-asymmetric olefination strategy

Article abstract of DOI:10.1021/jo060551t

A fully stereocontrolled synthesis of 3-oxacarbacyclin (3) and a formal synthesis of carbacyclin (2) are described. The syntheses are based on the conjugate addition-azoalkene-asymmetric olefination strategy. Its key features are (1) the stereoselective e

Full text of DOI:10.1021/jo060551t

Fully Stereocontrolled Syntheses of 3-Oxacarbacyclin and
Carbacyclin by the Conjugate Addition-Azoalkene-Asymmetric
Olefination Strategy
Mikhail Kim and Hans-Joachim Gais*
Institut fu¨r Organische Chemie der Rheinisch-Westfa¨lischen Technischen Hochschule (RWTH) Aachen,
Landoltweg 1, D-52056 Aachen, Germany
gais@rwth-aachen.de
ReceiVed March 13, 2006
A fully stereocontrolled synthesis of 3-oxacarbacyclin (3) and a formal synthesis of carbacyclin (2) are
described. The syntheses are based on the conjugate addition-azoalkene-asymmetric olefination strategy.
Its key features are (1) the stereoselective establishment of the complete ω-side chain of 2 and 3 through
conjugate addition of the enantiopure C13-C20 alkenylcopper derivative 10 to the enantiopure
C6-C12 bicyclic azoalkene 9 and (2) the 5E-stereoselective construction of the R-side chain through a
Horner-Wadsworth-Emmons olefination of the bicyclic ketone 7 with the chiral lithium phosphonoacetate
26 with formation of ester E-27. The allylic alcohol 6 serves at late stage as the joint intermediate in the
synthesis of 2 and 3.
Introduction
(4)1d,2b-e are chemically stable and strong agonists. They have
turned out to be excellent probes for the elucidation of the
biological functions of prostacyclin and structure of its recep-
tors.3 Moreover, iloprost is a valuable drug for the treat-
ment of vascular obliterative deceases and pulmonary hyperten-
sion.1d,4 Although carbacyclin and iloprost are chemically much
more stable than 1, they still suffer a rapid metabolization via
â-oxidation of the R-side chain. 3-Oxacarbacyclin (3)5c,6 and
3-oxailoprost (5)7,8 are expected to have a higher metabolic
stability because of the inhibition of the â-oxidation by the
oxygen atom in 3-position.9,10 Generally, the most challenging
problems in the synthesis of 2 and 3 are the stereoselective
establishment of both the hydroxy group at C15 and the
exocyclic double bond at C5.2,11 The synthesis of 2 and 3, which
Prostacyclin (1) (Figure 1) has attracted the attention of
chemistry, biology, and medicine ever since its discovery in
1976 by Vane et al.1 It is the strongest endogenous inhibitor of
blood platelet aggregation and a strong vasodilator. Prostacyclin
plays an important role not only in the vascular and central
nervous system but also in inflammation. Studies of prostacyclin
and its medicinal application are hindered, however, by short
chemical and metabolic half-lives. While the chemical instability
of prostacyclin is caused by a fast hydration of the enol ether
moiety even under physiological conditions, the metabolic
instability is due to a rapid oxidation in the â-position to the
carboxy group, leading finally to a degradation of the R-side
chain. The carbocyclic analogous carbacyclin (2)2 and iloprost
10.1021/jo060551t CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/17/2006
4642
J. Org. Chem. 2006, 71, 4642-4650

Syntheses of 3-Oxacarbacyclin and Carbacyclin
of the complete 15S,16S-configured ω-side chain through the
stereoselective conjugate addition of an enantio- and diastereo-
pure alkenylcopper compound to an enantiopure bicyclic azo-
alkene, (2) the stereoselective construction of the 5E-configured
R-side chains via an asymmetric Horner-Wadsworth-Emmons
olefination,5c,6,7,10,14,15 and (3) the establishment of the R-side
chain of 4 through a highly selective allylic alkylation. We now
describe a fully stereocontrolled synthesis of 3-oxacarbacyclin
(3) and a formal synthesis of carbacyclin (2) by the conjugate
addition-azoalkene-asymmetric olefination strategy. The suc-
cessful syntheses of 2 and 3 together with the previous ones of
4 and 5 demonstrate that this strategy allows a general access
to carbocyclic prostacyclin analogues.16,17
Results and Discussion
Retrosynthesis. The retrosynthetic analysis of 2 and 3 called
for the conjugate addition of the C13-C20 alkenylcopper
derivative 10 to the C6-C12 bicyclic azoalkene 9 with forma-
tion of hydrazone 8 and the chemo- and stereoselective con-
version of the latter to ketone 7 (Scheme 1). Ketone 7 has
already served as an intermediate in a number of unselective
syntheses of carbacyclin (2).2,18 The crucial 5E-stereoselective
construction of the R-side chains of 2 and 3 ought to be
accomplished via an asymmetric HWE-olefination of 7, leading
finally to the allyl alcohol 6. Alcohol 6, which is obtained at a
late stage, is thus planned to be the joint intermediate in the
synthesis of 2 and 3. The final steps on route from 6 to 2 and
3 include a regio- and stereoselective allylic alkylation and an
etherification, respectively. Transformations of this type have
already been successfully implemented in the syntheses of 4
and 5 starting from a structurally closely related allylic alcohol.7
Asymmetric Synthesis of Building Blocks. Azoalkene 9 of
96% ee was obtained in 50% overall yield starting from the
readily available achiral bicyclic ketone 1119 via the intermedi-
ates 12-14 (Scheme 2).7,20 The key step of the synthesis of 9
FIGURE 1. Prostacyclin and carbacyclins.
we had described previously, failed to accomplish stereocontrol
at C15.5c,6,12 Recently, we have developed a new and common
strategy for the fully stereocontrolled synthesis of iloprost (4)
and 3-oxailoprost (5).7 Its key steps are (1) the establishment
(1) (a) Moncada, S.; Gryglewski, R. J.; Bunting, S.; Vane, J. R. Nature
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(12) Erdelmeier, I.; Gais, H.-J. J. Am. Chem. Soc. 1989, 111, 1125-
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M.; Sodeoka, M.; Ogawa, Y. J. Org. Chem. 1984, 49, 4098-4099.
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Erdelmeier, I. Tetrahedron Lett. 1988, 29, 1773-1774.
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29, 1775-1776.
(16) For a synthesis of racemic carbacyclin featuring the conjugate
addition of a racemic C13-C20 alkenylcopper derivative to a racemic C6-
C12 bicyclic enone, see: Iseki, K.; Mase, T.; Okazaki, T.; Shibasaki, M.;
Ikegami, S. Chem. Pharm. Bull. 1983, 31, 4448-4455.
(17) Because of clarity the prostacyclin numbering is used for carbacyclin,
3-oxacarbacyclin and all building blocks through out this paper except in
the experimental part where the numbering of the compounds follows the
nomenclature rules.
(18) (a) Morton, D. R.; Brokaw, F. C. J. Org. Chem. 1979, 44, 2880-
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Ossenkamp, R. K. L.; Gais, H.-J. Liebigs Ann./Recueil 1997, 2433-2441.
(c) Gais, H.-J.; Schmiedl, G.; Ossenkamp, R. K. L. Liebigs Ann./Recueil
1997, 2419-2431.
(6) Vaulont, I.; Gais, H.-J.; Reuter, N.; Schmitz, E.; Ossenkamp, R. K.
L. Eur. J. Org. Chem. 1998, 805-826.
J. Org. Chem, Vol. 71, No. 12, 2006 4643

Kim and Gais
SCHEME 1. Retrosynthesis of Carbacyclin and 3-Oxacarbacyclin Based on the Conjugate Addition-Azoalkene-Asymmetric
Olefination Strategy
SCHEME 2. Asymmetric Syntheses of the C6-C12 and C13-C20 Building Blocks
is the efficient desymmetrization of the ketone through depro-
tonation with the chiral base in the presence of ClSiMe3, leading
to the formation of the enol ether 12.6,7,20,21
Silylation of alcohol 17 afforded the silyl ether 18 in practically
quantitative yield.24
Connection of Building Blocks. A crucial step of the
synthesis of 2 and 3 is the stereoselective conjugate addition of
the alkenylcopper derivative 10 to the azoalkene 9 (Scheme 3).
To achieve a high efficiency in the coupling step, it was of
importance to apply the two building blocks in a ratio of or
close to 1:1. We had previously shown in the case of the
synthesis of 4, 5,7 and a 13,14-dinor-interphenylene carbacy-
clin20 that this can be accomplished by using alkenyl- and
arylcopper reagents derived from the corresponding lithiumor-
ganyls and either CuI/PBu325a or CuCN/2LiCl.25b Lithiation of
iodide 18 with BuLi gave the alkenyllithium derivative 2026
that was converted to the alkenylcopper derivative 10 upon
treatment with 1.05 equiv of CuCN and 2.12 equiv of LiCl in
THF. Surprisingly, treatment of the alkenylcopper reagent 10
with 0.81 equiv of azoalkene 9 afforded hydrazone 8 only in
low yields. It was eventually found that an efficient and
Several different enantioselective syntheses of the alkenyl
iodide 17, which is a key intermediate in the synthesis of
prostaglandins,2a,d have already been described.22 We selected
for the synthesis of alcohol 17 the catalytic asymmetric reduction
of the readily available ketone 1522a,23 with catecholborane in
the presence of 15 mol % of oxazaborolidine 16.22d Thereby
the alcohol of 96-98% ee was obtained in 95% yield. A high
enantioselectivity in the reduction of 15 was only ensured by
the slow addition of the ketone to the reducing reagent.22e
(19) (a) Dahl, H. DE 3816801, 1989; Chem. Abstr. 1989, 113, 23512.
(b) Bertz, S. H.; Cook, J. M.; Gawish, A.; Weiss, U. Org. Synth. 1986, 64,
27-38.
(20) van Bergen, M.; Gais, H.-J. J. Am. Chem. Soc. 2002, 124, 4321-
4328.
(21) Izawa, H.; Shirai, R.; Kawasaki, H.; Kim, H. D.; Koga, K.
Tetrahedron Lett. 1989, 30, 7221-7224.
(22) (a) Kluge, A. F.; Untch, K. G.; Fried, J. H. J. Am. Chem. Soc. 1972,
94, 7827-7832. (b) Sih, C. J.; Heather, J. B.; Sood, R.; Price, P.; Peruzzotti,
G.; Lee, L. F. H.; Lee, S. S. J. Am. Chem. Soc. 1975, 97, 865-874. (c)
Kitano, Y.; Matsumoto, T.; Wakasa, T.; Okamoto, S.; Shimazaki, T.;
Kobayashi, Y.; Sato, F.; Miyaji, K.; Arai, K. Tetrahedron Lett. 1987, 28,
6351-6354. (d) Corey, E. J.; Bakshi, R. K. Tetrahedron Lett. 1990, 31,
611-614. (e) Rodr´ıguez, A.; Nomen, M.; Spur, B. W.; Godfroid, J.-J. Eur.
J. Org. Chem. 1999, 2655-2662.
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7211.
(25) (a) Suzuki, M.; Kwagishi, T.; Suzuki, T.; Noyori, R. Tetrahedron
Lett. 1982, 23, 4057-4060. (b) Knochel, P.; Parea, J. J. A.; Jones, Jones,
P. Tetrahedron. 1998, 54, 8275-8319.
(26) (a) Iguchi, S.; Nakai, H.; Hayashi, M.; Yamamoto, H.; Maruoka,
K. Bull. Chem. Soc. Jpn. 1981, 54, 3033-3041. (b) Noyori, R.; Tomino,
I.; Yamada, M.; Nishizawa, M. J. Am. Chem. Soc. 1984, 106, 6717-6725.
(23) Luo, F. T.; Negishi, E. J. Org. Chem. 1985, 50, 4762-4766.
4644 J. Org. Chem., Vol. 71, No. 12, 2006

Syntheses of 3-Oxacarbacyclin and Carbacyclin
SCHEME 3. Conjugate Addition of Alkenylcopper
Derivative 10 to Azoalkene 9a
SCHEME 4. Conjugate Addition of the Racemic
Alkenylcopper Derivative rac-10 to Azoalkene 9a
a Reagents and conditions: (I) 0.98 equiv of BuLi, THF, -78 °C, 1 h.
(II) 20, 1.1 equiv of CuCN×2LiCl, THF, -78 °C, 30 min (method A) or
20, 2.2 equiv of CuCN×2LiCl, THF, -78 °C, 30 min (method B). (III) (a)
1.2 equiv of 10, 9, 1.3 equiv of CuCN×2LiCl, THF, -78 °C, 30 min
(method A) or 1.2 equiv of 10, 9, THF, -78 °C, 30 min (method B); (b)
1.2 equiv of Bu3SnCl, -78 °C, 15 min; (c) NH4Cl/NH3 (9:1), -78 °C to
rt. (IV) 20 equiv of cyclohexene, 1.05 of equiv (PhSeO)2O, THF, rt, 1 h.
(V) 4 equiv of NaBH4, EtOH, -40 °C, 7 h. (VI) (a) 1.2 equiv of 10, 9, 1.1
equiv of CuCN×2LiCl, THF, -78 °C; (b) 1.2 equiv of Bu3SnCl, THF,
-78 °C; (c) H2O, NH4Cl, THF, -78 °C to rt; (d) 1.05 equiv of (PhSeO)2O,
20 equiv of cyclohexene, THF, rt; (e) 6 equiv of NaBH4, EtOH, 0 °C; (f)
H2O, NH4Cl, 0 °C to rt. (VII) TsOH, acetone/water, rt, 16 h. (VIII)
t-BuMe2SiCl, imidazole, DMF, rt.
a Reagents and conditions: see Scheme 3.
based on 8. The synthesis of alcohol 22 has also been carried
out without the isolation of hydrazone 8 and ketone 21 in 52%
overall yield based on azoalkene 9. The treatment of acetal 22
with acetone/water and TsOH afforded ketodiol 236,18 in 87%
yield after purification by column chromatography. Silylation
of diol 23 finally gave the protected ketodiol 7 in 94% yield.
Because of analytical and synthetic reasons, the diastereo-
meric diols 23 and 25 (Scheme 4) were synthesized starting
from azoalkene 9 of 96% ee and the racemic iodide rac-18.
Treatment of 9 with 4 equiv of rac-10, according to the one-
pot reaction sequence described above, finally gave a mixture
of alcohols 22 and 24 in a ratio of 1:1 in 62% yield. The mixture
of alcohols 22 and 24 was treated with TsOH in acetone/water,
which furnished diol 236,18 in 42% yield and diol 2518 in 44%
yield after separation by column chromatography. A comparison
of the 1H NMR spectra of 23 and 25 with the 1H NMR spectrum
of 23 obtained starting from 9 (96% ee) and 10 (98% ee) showed
diol 23 to be pure. This was confirmed by a HPLC analysis of
23. Thus the purification of 23 by column chromatography had
efficiently removed the minor diasteromers ent-25 and 25,
derived from the 2% of ent-9 and 1% of ent-18, which were
contained in azoalkene 9 and iodide 18, respectively.
Stereoselective Construction of R-Side Chain. For the
stereoselective establishment of the R-side chain of 3, an
asymmetric HWE olefination of ketone 7 was selected as the
key step. We had already successfully applied an olefination
of this type in the synthesis of 4 and 57 and the previous
syntheses of 3.5b,6 Thus treatment of ketone 7 with 4.3 equiv of
the chiral lithium phosphonoacetate 265c,6,7,10,14 in THF at -62
°C for 6 days finally gave a mixture of the diastereomeric esters
E-27 and Z-27 in a ratio of 95:5 in 88% yield (Scheme 5).
reproducible conjugate addition of 10 to azoalkene 9 could be
achieved by using both building blocks in a ratio of 1.22:1 in
the presence of an additional amount of CuCN (1.05 equiv)
and LiCl (2.12 equiv). The reaction was carried out either by
adding a solution of CuCN/LiCl and azoalkene 9 in THF to a
solution of 10 in THF or by adding a THF solution of 10 and
CuCN/LiCl to a THF solution of azoalkene 9. Thereby the
diastereomerically pure hydrazone 8 was obtained in 71-73%
yield. Quenching of the reaction mixture with Bu3SnCl led to
the isolation of stannane 1927 in 29% yield based on iodide 18.
A lithiation of stannane 19 with formation of the alkenyllithium
derivative 20 has already been described.27
The chemoselective cleavage of hydrazone 8 was achieved
by treatment with 1.05 equiv of (PhSeO)2O in the presence of
20 equiv of cyclohexene, which presumably serves as a radical
scavenger.7,20,28 Because of the lability of 21 on silica gel, the
ketone was not further purified but reduced with NaBH4, which
gave the diastereomerically pure alcohol 22 in 61% overall yield
(27) (a) Corey, E. J.; Niimura, K.; Konishi, Y.; Hashimoto, S.; Hamada,
Y. Tetrahedron Lett. 1986, 27, 2199-2202. (b) Johnson, C. R.; Penning,
T. D. J. Am. Chem. Soc. 1988, 110, 4726-4735.
(28) Barton, D. H. R.; Okano, T.; Parekh, S. I. Tetrahedron 1991, 47,
1823-1836
J. Org. Chem, Vol. 71, No. 12, 2006 4645

Kim and Gais
SCHEME 5. Asymmetric Olefination and Completion of the Synthesis of 3-Oxacarbacyclin (3)a
a Reagents and conditions: (I) (a) 4.4 equiv 26, THF, -62 °C, 6 d; (b) NH4Cl, -62 °C to rt; (c) HPLC. (II) (i-Bu)2AlH, THF, 0 °C. (III) (a) Bu4NHSO4,
50% NaOH, BrCH2COOt-Bu, CH2Cl2, rt; (b) Bu4NF, THF, rt. (IV) MeOH, 1 N NaOH, NaH2PO4, pH 4-5, rt.
SCHEME 6. 5E-Stereoselective Synthesis of Iloprost via Allylic Alkylation7
Preparative HPLC afforded ester E-27 of g99% de in 81% yield.
The reduction of ester E-27 with (i-Bu)2AlH in THF gave the
allylic alcohol 6 in 88% yield. The treatment of alcohol 6 with
an excess of BrCH2COOt-Bu and 50% aqueous NaOH in
CH2Cl2 in the presence of Bu4NHSO4 followed by the desily-
lation of the corresponding bissilyl ether with Bu4NF furnished
the dihydroxy ester 28 in 89% overall yield. Finally, the
hydrolysis of ester 13 with NaOH in MeOH and protonation of
the corresponding carboxylate salt with NaH2PO4 to pH 4-5
afforded 3-oxacarbacyclin (3)5b,6 in 90% yield.
The synthesis of the allyl alcohol 6 can be regarded as a
formal asymmetric synthesis of carbacyclin (2). We had
previously described a synthesis of iloprost (4), the key step of
which is the highly stereo- and regioselective allylic alkylation
of the allyl acetate 29 with the C1-C3-organocuprate with
formation of silyl ether 30 (Scheme 6).7 Therefore, it seems
safe to assume that the analogous allylic alkylation of the acetate
of alcohol 6 will also proceed efficiently to give the corre-
sponding C1-C20 alcohol.
The alteration of the structure of the ω-side chain of
prostacyclin and prostaglandins has turned out to be the most
important means for obtaining analogues with high and specific
biological activities2 as shown, for example, by iloprost (4).1d
The prostaglandin synthesis by the conjugate addition-enone
strategy2a,d,29 has made available a large number of structurally
different alkenyl iodides and stannanes of the type shown in
Figure 2.30 Further ω-side chain building blocks of this type
will be accessible either through an enantioselective reduction
of the corresponding iodo and stannyl enones or a hydrozir-
conation-iodination of the corresponding propargylic alcohols.30e,31
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(d) Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org. Chem. 2004,
4095-4105.
(32) Mature, D. J.; Jones, T. K.; Xavier, L. C.; Blacklock, T. J.; Reamer,
R. A.; Mohan, J. J.; Jones, E. T. T.; Hoogsteen, K.; Baum, M. W.;
Grabowski, E. J. J. J. Org. Chem. 1991, 56, 751-762.
Conclusion
We have described an asymmetric synthesis of 3-oxacarba-
cyclin (3) and a formal synthesis of carbacyclin (2), which
achieve full stereocontrol of all stereogenic elements. The
successful syntheses of carbacyclin, 3-oxacarbacyclin, iloprost,
and 3-oxailoprost demonstrate the generality of the conjugate
addition-azoalkene-asymmetric olefination strategy for the
synthesis of carbacyclins, which takes advantage of the avail-
ability of the bicyclic ketone 11 on a large scale.
4646 J. Org. Chem., Vol. 71, No. 12, 2006

Syntheses of 3-Oxacarbacyclin and Carbacyclin
FIGURE 2. Conjugate addition-azoalkene-asymmetric olefination route to carbacyclins and 3-oxacarbacyclins carrying a modified ω-side chain.
-78 °C, a cold solution of CuCN (298 mg, 3.33 mmol) and LiCl
(283 mg, 6.66 mmol) in THF (4 mL) was added at -78 °C via
cannula. The resulting yellow solution was stirred at -78 °C for
30 min. Then a cold solution (-78 °C) of azoalkene 9 (96% ee,
500 mg, 1.28 mmol) in THF (4 mL) was added via cannula,
followed by stirring at -78 °C for 30 min. Then Bu3SnCl (500
mg, 1.54 mmol) was added, followed by stirring at -78 °C for 15
min. Subsequently water (3 mL) was added and the mixture was
warmed to room temperature. Then the mixture was diluted with
Et2O (100 mL) and washed with a mixture of saturated aqueous
NH4Cl and concentrated aqueous NH3 (10:1, 3 × 20 mL). The
combined aqueous phases were extracted with Et2O (3 × 20 mL),
and the combined organic phases were dried (MgSO4) and
concentrated in vacuo. Purification by chromatography (hexanes/
Et2O, 2:1) gave hydrazone 8 (577 mg, 71%) and stannane 19 (243
mg, 29%).
Thus, the conjugate addition-azoalkene route should allow the
fully stereocontrolled synthesis of a wide range of ω-side chain
modified carbacyclins.7,20
Experimental Section
(-)-(E)-N′-((3a′S,4′R,6a′R)-4′-((S,E)-3-(tert-Butyldimethylsi-
lyloxy)oct-1-enyl)-5,5-dimethyldihydro-1′H-spiro[[1,3]dioxane-
2,2′-pentalene]-5′(3′H,6′H,6a′H)-ylidene)-4-methyl-benzenesulfono-
hydrazide (8). Method A. BuLi (0.96 mL, 1.6 M in hexanes, 1.54
mmol) was added to a solution of iodide 18 (98% ee, 578 mg,
1.57 mmol) in THF (3 mL) at -78 °C. After the mixture was stirred
for 1 h at -78 °C, a cold solution of CuCN (149 mg, 1.66 mmol)
and LiCl (141 mg, 3.33 mmol) in THF (2 mL) was added at -78
°C via cannula. The resulting yellow solution was stirred at -78
°C for 30 min. Then a cold solution of azoalkene 9 (ee 96%, 500
mg, 1.28 mmol), CuCN (149 mg, 1.66 mmol) and LiCl (141 mg,
3.33 mmol) in THF (4 mL) was added via cannula, followed by
stirring at -78 °C for 30 min. Then Bu3SnCl (500 mg, 1.54 mmol)
was added, followed by stirring at -78 °C for 15 min. Subsequently
water (3 mL) was added and the mixture was warmed to room
temperature. Then the mixture was diluted with Et2O (100 mL)
and washed with a mixture of saturated aqueous NH4Cl and
concentrated aqueous NH3 (10:1, 3 × 20 mL). The combined
aqueous phases were extracted with Et2O (3 × 20 mL), and the
combined organic phases were dried (MgSO4) and concentrated in
vacuo. Purification by chromatography (hexanes/Et2O, 2:1) gave
hydrazone 8 (589 mg, 73%) and stannane 19 (246 mg, 29%). 8:
colorless foam; Rf 0.40 (hexanes/EtOAc, 2:1), [R]D -39.0 (c 1.0,
THF). 1H NMR (400 MHz, d8-THF): δ 0.03 (s, 3 H, SiCH3), 0.07
(s, 3 H, SiCH3), 0.87-0.92 (m, 18 H, SiC(CH3)3, C(CH3)2,
CH2CH3), 1.19-1.55 (m, 8 H), 1.56-1.63 (m, 1 H), 1.75-1.82
(m, 1 H), 2.08-2.29 (m, 4 H), 2.37 (s, 3 H, PhCH3), 2.44-2.63
(m, 2 H), 2.97 (t, 1 H, J ) 7.1 Hz, CHCHCHdC), 3.34-3.42 (m,
4 H, 2 × OCH2), 4.05-4.12 (m, 1 H, CdCHCHOSi), 5.34 (ddd,
1 H, J ) 1.1, J ) 6.6, J ) 15.4 Hz, CHdCH), 5.50 (dd, 1 H, J )
6.6, J ) 15.4 Hz, CH)CH), 7.26 (d, 2 H, J ) 8.0 Hz, Ph), 7.77
(d, 2 H, J ) 8.2 Hz, Ph), 8.77 (br s, 1 H, NH). 13C NMR (100
MHz, d8-THF): δ -4.6 (d), -3.7 (d), 14.4 (d), 18.8 (u), 21.4 (d),
22.6 (d), 22.6 (d), 23.4 (u), 25.8 (u), 26.3 (d), 30.4 (u), 32.7 (u),
33.6 (u), 38.7 (d), 39.3 (u), 39.9 (u), 42.1 (u), 47.2 (d), 53.3 (d),
72.1 (u), 72.7 (u), 74.2 (d), 110.6 (u), 128.6 (d), 129.5 (d), 129.7
(d), 135.3 (d), 138.3 (u), 143.2 (u), 166.6 (u). IR (KBr): ν 3431
(m, br), 3222 (m), 2932 (s), 2858 (s), 1654 (m), 1601 (m), 1544
(w), 1497 (w), 1470 (m), 1400 (m), 1341 (m), 1289 (w), 1254 (m),
1217 (w), 1168 (s), 1115 (s), 1039 (w), 1007 (w), 968 (m), 926
(m), 874 (w) 836 (s), 813 (m). MS (EI, 70 eV) m/z (relative
intensity, %): 575 (M+ - t-Bu, 17), 477 (M+ - Ts, 7), 429 (36),
346 (16), 345 (58), 262 (18), 261 (100), 260 (13), 259 (56), 231
(12), 215 (24), 213 (25), 149 (40), 91 (18). HRMS calcd for
C34H56N2O5SiSNa+: 655.3577, found 655.3576. 19: colorless oil;
(-)-(3a′S,4′R,5′R,6a′R)-4′-((S,E)-3-(tert-Butyldimethylsilyl-
oxy)oct-1-enyl)-5,5-dimethyl-hexahydro-1′H-spiro[[1,3]dioxane-
2,2′-pentalen]-5′-ol (22). A solution of hydrazone 8 (300 mg, 0.47
mmol) and cyclohexene (0.96 mL, 9.48 mmol) in THF (15 mL)
was treated with (PhSeO)2O (179 mg, 0.50 mmol) at room
temperature, whereby a gas evolution occurred. The mixture was
stirred at room temperature for 1 h, and then saturated aqueous
NaHCO3 (2 mL) was added. The mixture was extracted with
hexanes (2 × 20 mL), and the combined organic phases were dried
(MgSO4) and concentrated in vacuo. The crude ketone 21 [HRMS
(ESI, TOF) calcd for C27H48O4SiNa+: 487.3220, found 487.3212]
was dissolved in EtOH (30 mL), and the solution was treated with
NaBH4 (72 mg, 1.90 mmol) at -40 °C. After the mixture was stirred
at -40 °C for 7 h, saturated aqueous NH4Cl (3 mL) was added,
and the mixture was warmed to room temperature and extracted
with Et2O (3 × 30 mL). The combined organic phases were dried
(MgSO4) and concentrated in vacuo. Purification by chromatog-
raphy (hexanes/EtOAc, 8:1) gave alcohol 22 (134 mg, 61%) as a
colorless oil. Rf 0.54 (hexanes/EtOAc, 2:1), [R]D -2.5 (c 1.1, THF).
1H NMR (300 MHz, CDCl3): δ 0.03 (s, 3 H, SiCH3), 0.05 (s, 3 H,
SiCH3), 0.85-0.92 (m, 12 H, SiC(CH3)3, CH2CH3), 0.96 (s, 6 H,
C(CH3)2), 1.20-1.58 (m, 9 H), 1.74-1.87 (m, 2 H), 2.02-2.32
(m, 5 H), 2.37-2.52 (m, 1 H), 3.44-3.52 (m, 4 H, 2 × OCH2),
3.74 (dt, 1 H, J ) 6.4, J ) 9.2 Hz, CHOH), 4.02-4.11 (m, 1 H,
CHOSi), 5.43 (dd, 1 H, J ) 7.2, J ) 15.3 Hz, CH)CH), 5.54 (dd,
1 H, J ) 5.9, J ) 15.3 Hz, CHdCH). 13C NMR (75 MHz,
CDCl3): δ -4.7 (d), -4.1 (d), 14.1 (d), 18.3 (u), 22.6 (d), 22.7
(u), 25.2 (u), 26.0 (d), 30.1 (u), 31.8 (u), 35.6 (d), 38.3 (u), 38.5
(u), 40.6 (u), 43.8 (d), 57.8 (d), 72.1 (u), 72.1 (u), 73.4 (d), 78.2
(d), 110.3 (u), 130.7 (d), 135.8 (d). IR (neat): ν 3424 (m, br), 2932
(s), 2858 (s), 1467 (m), 1393 (w), 1360 (w), 1328 (m), 1253 (m),
1219 (m), 1180 (w), 1114 (s), 1009 (m), 970 (m), 870 (m), 836
(s). MS (EI, 70 eV) m/z (relative intensity, %): 448 (12), 410 (24),
409 (M+ - t-Bu, 100), 378 (25), 377 (84), 334 (20), 324 (23), 323
(90), 317 (30), 305 (13), 291 (11), 263 (14), 251 (15), 232 (12),
231 (58), 230 (12), 223 (21), 213 (16), 209 (19), 203 (15), 187
(22), 188 (11), 175 (30), 173 (11), 161 (37), 159 (15), 149 (24),
147 (15), 135 (16), 133 (23), 131 (19), 129 (10), 128 (27), 119
(13), 117 (22), 107 (11), 105 (22), 99 (17), 95 (17), 93 (15), 91
(17), 83 (14), 81 (16). Anal. Calcd for C27H50O4Si: C, 69.48; H,
10.80. Found: C, 69.32; H, 11.19.
Rf 0.90 (hexanes/EtOAc, 2:1), [R]D -16.2 (c 1.4, CHCl3) [lit. [R]23
D
-12.0 (c 1.0, CHCl3)].27a 1H and 13C NMR spectra of 19 matched
those reported previously.27b
Method B. BuLi (0.96 mL, 1.6 M in hexanes, 1.54 mmol) was
added to a solution of iodide 18 (98% ee, 578 mg, 1.57 mmol) in
THF (3 mL) at -78 °C. After the mixture was stirred for 1 h at
J. Org. Chem, Vol. 71, No. 12, 2006 4647

Kim and Gais
Preparation of Alcohol 22 from Azoalkene 9 without Isolation
of Hydrazone 8 and Ketone 21. BuLi (0.96 mL, 1.6 M in hexanes,
1.54 mmol) was added to a solution of iodide 18 (98% ee, 578
mg, 1.57 mmol) in THF (3 mL) at -78 °C. After the mixture was
stirred for 1 h at -78 °C, a cold solution (-78 °C) of CuCN (298
mg, 3.33 mmol) and LiCl (283 mg, 6.66 mmol) in THF (4 mL)
was added at -78 °C via cannula. The resulting yellow solution
was stirred at -78 °C for 30 min. Then a cold solution (-78 °C)
of azoalkene 9 (96% ee, 500 mg, 1.28 mmol) in THF (4 mL)
was added via cannula, followed by stirring at -78 °C for 30 min.
Bu3SnCl (500 mg, 1.54 mmol) was added, followed by stirring at
-78 °C for 15 min. Then water (3 mL) was added, and the mixture
was warmed to room temperature. The mixture was diluted with
Et2O (100 mL) and washed with a mixture of saturated aqueous
NH4Cl and concentrated aqueous NH3 (10:1, 3 × 20 mL). The
combined aqueous phases were extracted with Et2O (3 × 20 mL),
and the combined organic phases were dried (MgSO4) and
concentrated in vacuo. The residue was dissolved in THF (20 mL),
cyclohexene (2.60 mL, 25.61 mmol) was added, and the solution
was treated with (PhSeO)2O (461 mg, 1.28 mmol) at room
temperature, whereby a gas evolution occurred. Then the mixture
was stirred at room temperature for 40 min and cooled to 0 °C,
and EtOH (30 mL) was added. Subsequently NaBH4 (291 mg, 7.68
mmol) was added at 0 °C, followed by stirring at 0 °C for 1 h.
Then saturated aqueous NH4Cl (3 mL) was added, and the mixture
was warmed to room temperature. The mixture was concentrated
in vacuo, and the residue was dissolved in mixture of Et2O (100
mL) and water (10 mL). The aqueous phase was extracted with
Et2O (3 × 20 mL), and the combined organic phases were dried
(MgSO4) and concentrated in vacuo. Purification by chromatog-
raphy (hexanes/EtOAc, 8:1) gave alcohol 22 (313 mg, 52%) and
stannane 19 (236 mg, 70%).
(3a′S,4′R,5′R,6a′R)-4′-((S,E)-3-(tert-Butyldimethylsilyloxy)oct-
1-enyl)-5,5-dimethyl-hexahydro-1′H-spiro[[1,3]dioxane-2,2′-pen-
talen]-5′-ol (22) and (3a′S,4′R,5′R,6a′R)-4′-((R,E)-3-(tert-Bu-
tyldimethylsilyloxy)oct-1-enyl)-5,5-dimethylhexahydro-1′H-
spiro[[1,3]-dioxane-2,2′-pentalen]-5′-ol (24). BuLi (3.20 mL, 1.6
M in hexanes, 5.12 mmol) was added to a solution of iodide rac-
18 (1.924 g, 5.22 mmol) in THF (12 mL) at -78 °C. After the
mixture was stirred for 1 h at -78 °C, a cold solution (-78 °C) of
CuCN (596 mg, 6.66 mmol) and LiCl (563 mg, 13.32 mmol) in
THF (8 mL) was added at -78 °C via cannula. The resulting yellow
solution was stirred at -78 °C for 30 min. Then a cold solution
(-78 °C) of azoalkene 9 (96% ee, 500 mg, 1.28 mmol) in THF (4
mL) was added via cannula, followed by stirring at -78 °C for 30
min. Bu3SnCl (1.667 g, 5.12 mmol) was added, followed by stirring
at -78 °C for 15 min. Then water (4 mL) was added, and the
mixture was warmed to room temperature. Subsequently the mixture
was diluted with Et2O (150 mL) and washed with a mixture of
saturated aqueous NH4Cl and concentrated aqueous NH3 (10:1, 3
× 15 mL). The combined aqueous phases were extracted with Et2O
(3 × 20 mL), and the combined organic phases were dried (MgSO4)
and concentrated in vacuo. The residue was dissolved in THF (20
mL), cyclohexene (2.60 mL, 25.61 mmol) was added, and the
solution was treated with (PhSeO)2O (461 mg, 1.28 mmol) at room
temperature, whereby a gas evolution occurred. Then the mixture
was stirred at room temperature for 40 min and cooled to 0 °C,
and EtOH (30 mL) was added. Subsequently NaBH4 (388 mg, 10.24
mmol) was added at 0 °C, followed by stirring at 0 °C for 1 h.
Then saturated aqueous NH4Cl (3 mL) was added, and the mixture
was warmed to room temperature. The mixture was concentrated
in vacuo, and the residue was dissolved in mixture of Et2O (100
mL) and water (10 mL). The aqueous phase was extracted with
Et2O (3 × 15 mL), and the combined organic phases were dried
(MgSO4) and concentrated in vacuo. Purification by chromatog-
raphy (hexanes/EtOAc, 8:1) gave a mixture of alcohols 22 and 24
in a ratio of 1:1 (373 mg, 62%) and stannane rac-19 (2.163 g, 92%)
as colorless oils. Rf 0.54 (hexanes/EtOAc, 2:1). 1H NMR (400 MHz,
CDCl3): δ 0.03 (s, 2 × 3 H, 2 × SiCH3), 0.05 (s, 2 × 3 H, 2 ×
SiCH3), 0.86-0.91 (m, 2 × 12 H, 2 × SiC(CH3)3, 2 × CH2CH3),
0.95 (s, 3 H, C(CH3)2, 24), 0.96 (s, 3 H, C(CH3)2, 22), 0.97 (s, 3
H, C(CH3)2, 22), 0.98 (s, 3 H, C(CH3)2, 24), 1.20-1.58 (m, 2 × 9
H), 1.67-1.89 (m, 2 × 3 H), 2.01-2.30 (m, 2 × 5 H), 2.38-2.51
(m, 2 × 1 H), 3.44-3.51 (m, 2 × 4 H, 4 × OCH2), 3.72 (dt, 1 H,
J ) 6.6, J ) 9.6 Hz, CHOH, 24), 3.75 (dt, 1 H, J ) 6.6, J ) 9.6
Hz, CHOH, 6), 4.02-4.10 (m, 2 × 1 H, CHOSi), 5.40 (dd, 1 H, J
) 8.2, J ) 15.4 Hz, CHdCH, 24), 5.43 (dd, 1 H, J ) 7.1, J )
15.4 Hz, CHdCH, 22), 5.53 (dd, 1 H, J ) 6.6, J ) 15.4 Hz, CHd
CH, 24), 5.55 (dd, 1 H, J ) 6.0, J ) 15.4 Hz, CHdCH, 22). 13C
NMR (100 MHz, CDCl3): δ -4.7 (d), -4.6 (d), -4.2 (d), -4.1
(d), 14.0 (d), 18.3 (d), 22.5 (d), 22.6 (d), 22.6 (u), 25.1 (u), 25.9
(d), 30.0 (u), 31.7 (u), 35.4 (d), 35.5 (d), 38.0 (u), 38.2 (u), 38.4
(u), 40.5 (u), 40.6 (u), 40.6 (u), 40.7 (u), 43.7 (d), 43.8 (d), 57.7
(d), 57.8 (d), 71.9 (u), 71.9 (u), 72.0 (u), 72.0 (u), 73.2 (d), 73.5
(d), 78.0 (d), 78.1 (d), 110.1 (u), 110.1 (u), 130.4 (d), 130.7 (d),
135.6 (d), 135.8 (d). IR (neat): ν 3409 (m, br), 2953 (s), 2858 (s),
1468 (m), 1393 (w), 1360 (w), 1329 (m), 1253 (m), 1219 (m), 1115
(s), 1009 (m), 970 (m), 870 (m), 836 (s). MS (CI, CH4) m/z (relative
intensity, %): 467 (18), 465 (12), 451 (M+ - Me, 25), 450 (15),
449 (37), 410 (21), 409 (M+ - t-Bu, 67), 378 (14), 377 (50), 363
(14), 335 (22), 334 (13), 333 (15), 323 (34), 318 (25), 317 (100),
249 (12), 231 (43), 221 (11), 215 (15).
(-)-(3aS,4R,5R,6aR)-5-Hydroxy-4-((S,E)-3-hydroxyoct-1-enyl)-
hexahydropentalen-2(1H)-one (23) and (-)-(3aS,4R,5R,6aR)-5-
Hydroxy-4-((R,E)-3-hydroxyoct-1-enyl)hexa-hydropentalen-2(1H)-
one (25). A mixture of acetals 22 and 24 (1.300 g, 2.79 mmol),
obtained from azoalkene 9 (96% ee) and iodide rac-18, was
dissolved in acetone (100 mL) and water (10 mL). TsOH (230 mg)
was added at room temperature, and the mixture was stirred at room
temperature for 16 h. Then saturated aqueous NaHCO3 (8 mL) was
added. The mixture was extracted with Et2O (3 × 80 mL), and the
combined organic phases were dried (MgSO4) and concentrated in
vacuo. Purification by chromatography (hexanes/EtOAc, 1:3) gave
ketodiol 23 (314 mg, 42%) and ketodiol 25 (330 mg, 44%). 23:
colorless oil, Rf 0.40 (hexanes/EtOAc, 1:4), [R]D -7.9 (c 1.4,
CHCl3) (lit. [R]23 -8.2 (c 1.53, CHCl3)18c). 25: colorless oil, Rf
D
0.32 (hexanes/EtOAc, 1:4), [R]D -23.5 (c 1.1, CHCl3) [lit. [R]24
D
-23.9 (c 1.58, CHCl3)18c]. IR, H and 13C NMR spectra of 236,18
1
and 2518 matched those reported previously.
(-)-(3aS,4R,5R,6aR)-5-Hydroxy-4-((S,E)-3-hydroxyoct-1-enyl)-
hexahydropentalen-2(1H)-one (23). Acetal 22 (400 mg, 0.857
mmol), obtained from azoalkene 9 (96% ee) and iodide 18 (98%
ee), was dissolved in a mixture of acetone (30 mL) and water (3
mL). TsOH (70 mg) was added at room temperature, and the
mixture was stirred at room temperature for 16 h. Then saturated
aqueous NaHCO3 (3 mL) was added. The mixture was extracted
with Et2O (3 × 20 mL), and the combined organic phases were
dried (MgSO4) and concentrated in vacuo. Purification by chro-
matography (hexanes/EtOAc, 1:3) gave ketodiol 23 (198 mg, 87%)
and ketodiol 25 (4 mg, 2%).
(-)-(3aS,4R,5R,6aR)-5-(tert-Butyldimethylsilyloxy)-4-((S,E)-
3-(tert-butyldimethyl-silyl-oxy)oct-1-enyl)hexahydropentalen-
2(1H)-one (7). A solution of ketodiol 23 (250 mg, 0.94 mmol) in
DMF (25 mL) was treated with imidazole (319 mg, 4.69 mmol) at
0 °C, followed by stirring at 0 °C for 30 min. Then ClSiMe2t-Bu
(311 mg, 2.06 mmol) was added at 0 °C. The mixture was stirred
at room temperature for 16 h, then diluted with Et2O (150 mL),
washed with water (2 × 10 mL), dried (MgSO4), and concen-
trated in vacuo. Purification by chromatography (hexanes/Et2O,
10:1) gave ketone 7 (435 mg, 94%) as a colorless oil. [R]22D -34.4
(c 0.5, THF). 1H NMR (300 MHz, CDCl3): δ 0.01 (s, 3 H, SiCH3),
0.04 (s, 6 H, 2 × SiCH3), 0.04 (s, 3 H, SiCH3), 0.84-0.92 (m,
21 H, 2 × SiC(CH3)3, CH2CH3), 1.20-1.54 (m, 9 H), 2.12-2.62
(m, 7 H), 2.64-2.80 (m, 1 H), 3.91-4.00 (m, 1 H, CH(OSi)-
CHCHdC), 4.01-4.09 (m, 1 H, CdCHCHOSi), 5.39-5.54 (m, 2
H, CHdCH). 13C NMR (75 MHz, CDCl3): δ -4.7 (d), -4.6 (d),
-4.6 (d), -4.2 (d), 14.1 (d), 18.1 (u), 18.3 (u), 22.7 (u), 25.1 (u),
25.9 (d), 25.9 (d), 31.9 (u), 35.7 (d), 38.6 (u), 42.4 (u), 43.1 (d),
4648 J. Org. Chem., Vol. 71, No. 12, 2006

Syntheses of 3-Oxacarbacyclin and Carbacyclin
43.2 (u), 46.1 (u), 57.6 (d), 73.1 (d), 79.3 (d), 129.7 (d), 135.2 (d),
220.2 (u). IR (CHCl3): ν 2931 (s), 2857 (s), 1742 (s), 1467 (m),
1406 (m), 1385 (m), 1363 (m), 1254 (s), 1121 (s), 1081(m), 1004
(m), 971 (m), 940 (w), 897 (m), 837 (s). MS (EI, 70 eV)
m/z (relative intensity, %): 479 (M+ - Me, 1.5), 439 (14), 438
(40), 437 (M+ - t-Bu, 100), 327 (12), 305 (16), 291 (12), 189
(12), 171 (10), 149 (13), 147 (61), 117 (12). HRMS calcd for
C28H54O3Si2-C4H9: 437.290728, found 437.290783.
- t-Bu, 3), 481 (14), 480 (39), 479 (100), 404 (11), 347 (26), 329
(20), 273 (16), 119 (81), 105 (65), 91 (15). MS (CI, CH4) m/z
(relative intensity, %): 737 (6), 736 (10), 735 (17), 722 (16),
721 (33), 681 (10), 680 (28), 679 (59), 607 (12), 606 (39),
605 (83), 521 (35), 481 (14), 480 (37), 479 (100), 474 (16), 473
(57), 433 (19), 406 (25), 405 (99), 389 (16), 387 (27), 347 (23),
310 (17), 301 (11), 283 (15), 282 (95), 280 (29), 273 (63), 201
(61), 199 (11), 123 (20), 119 (40), 105 (18). HRMS calcd for
C45H76O4Si2-C19H29: 479.301293, found 479.301165.
(+)-(E)- and (-)-(Z)-((1S,2R)-2-(2-Phenylpropan-2-yl)cyclo-
hexyl) 2-((3aS,4R,5R,6aS)-5-(tert-Butyldime-thylsilyloxy)-4-((S,E)-
3-(tert-butyldimethylsilyloxy)oct-1-enyl)hexahydro-pentalen-
2(1H)-ylidene)acetate (E-27 and Z-27). BuLi (0.76 mL, 1.6 M in
hexanes, 1.33 mmol) was added to a solution of (1S,2R)-2-(2-
phenylpropan-2yl)cyclohexyl 2-(dimethoxyphosphoryl)acetate (491
mg, 1.33 mmol) in THF (2 mL) at -78 °C. The solution of the
lithium salt 26 was warmed to room temperature for 15 min and
then cooled to -62 °C. Then a solution of ketone 7 (150 mg, 0.30
mmol) in THF (0.8 mL) was added within 10 min. The mixture
was stirred at -62 °C for 5 days. Then saturated aqueous NH4Cl
(10 mL) was added, and the mixture was warmed to room
temperature. The aqueous phase was separated and diluted with
water until a clear solution was formed. The aqueous phase was
extracted with Et2O (3 × 20 mL), and the combined organic phases
were dried (MgSO4) and concentrated in vacuo. Purification by
chromatography (hexanes/Et2O, 20:1, then 10:1) afforded a mixture
of esters E-27 and Z-27 (197 mg, 88%) (Rf 0.62 (hexanes/EtOAc,
10:1)) in a ratio 95:5 (1H NMR: δ (CdCHCO) 5.11 (E-27); δ
(CdCHCO) 5.16 (Z-27)) as a colorless oil. HPLC (Kromasil-Si-
100, 250 × 30 mm, hexanes/EtOAc, 98:2, UV: 254 nm) gave ester
E-27 (181 mg, 81%) of g99% de as a colorless oil. E-27: [R]D
(E)-2-((3aS,4R,5R,6aS)-5-(tert-Butyldimethylsilyloxy)-4-((S,E)-
3-(tert-butyldimethyl-silyloxy)oct-1-enyl)hexahydropentalen-
2(1H)-ylidene)ethanol (6). (i-Bu)2AlH (0.57 mL, 1 M in THF)
was added to a solution of ester E-27 (140 mg, 0.19 mmol) in THF
(4 mL) at 0 °C. The mixture was warmed to ambient temperature
and stirred for 2 h. Then aqueous NH4Cl (5 mL) was added at 0
°C. Water (50 mL) was added, and the mixture was extracted with
CH2Cl2 (5 × 30 mL) and Et2O (5 × 30 mL). The combined organic
phases were dried (MgSO4) and concentrated in vacuo. Purification
by chromatography (hexanes/EtOAc, 10:1) afforded alcohol 6 (87
mg, 88%) as a colorless oil. Rf 0.13 (hexanes/EtOAc, 10:1), [R]D
+17.1 (c 0.43, THF). 1H NMR (300 MHz, C6D6): δ 0.09 (s, 3 H,
SiCH3), 0.12 (s, 3 H, SiCH3), 0.15 (s, 3 H, SiCH3), 0.15 (s, 3 H,
SiCH3), 0.80 (bs, 1 H, OH), 0.92 (t, 3 H, J ) 6.7 Hz, CH2CH3),
0.99 (s, 9 H, SiC(CH3)3), 1.06 (s, 9 H, SiC(CH3)3), 1.23-1.74 (m,
9 H), 1.94-2.42 (m, 8 H), 3.73 (dt, J ) 6.7, J ) 8.9 Hz, 1 H,
dCHCHCHOSi), 3.96 (d, 2 H, J ) 6.7 Hz, CH2OH), 4.10-4.17
(m, 1 H, dCHCHOSi), 5.45-5.53 (m, 1 H, dCHCH2OH), 5.53-
5.67 (m, 2 H, CHdCH).13C NMR (75 MHz, C6D6): δ -4.9 (d),
-4.7 (d), -4.6 (d), -4.2 (d), 13.9 (d), 18.0 (u), 18.1 (u), 22.7 (u),
25.3 (u), 25.8 (d), 25.8 (d), 31.9 (u), 35.8 (u), 37.9 (d), 38.2 (u),
38.8 (u), 42.5 (u), 44.7 (d), 56.3 (d), 60.2 (u), 73.1 (d), 78.4 (d),
121.8 (d), 130.9 (d), 134.6 (d), 144.5 (u). IR (CHCl3): ν 3362 (m,
br), 2932 (s), 2858 (s), 1677 (w), 1466 (m), 1363 (m), 1253 (s),
1114 (s), 1005 (m), 971 (m), 910 (w), 838 (s). MS (EI, 70 eV) m/z
(relative intensity, %): 507 (1), 466 (13), 465 (31), 451 (20), 449
(14), 448 (30), 447 (77), 390 (25), 374 (28), 373 (100), 334 (11),
333 (40), 319 (10), 242 (14), 241 (75), 215 (13), 171 (27), 157
(11), 149 (22), 147 (24), 145 (33), 143 (17), 129 (11), 117 (12),
105 (19), 93 (12), 91 (11). MS (CI, CH4) m/z (relative intensity,
%): 524 (0.5), 523 (1.7), 522 (2.6), 521 (6.6), 507 (14), 465 (17),
391 (30), 389 (12), 375 (12), 374 (28), 373 (100), 241 (16). HRMS
calcd for C30H58O3Si2-C4H9: 465.322028, found 465.321982.
tert-Butyl 2-((E)-2-((3aS,4R,5R,6aS)-5-Hydroxy-4-((S,E)-3-
hydroxyoct-1-enyl)hexa-hydro-pentalen-2(1H)-ylidene)ethoxy)-
acetate (28). A solution of alcohol 6 (73 mg, 0.14 mmol) and
Bu4NHSO4 (47 mg, 0.14 mmol) in CH2Cl2 (3 mL) was treated with
aqueous 50% NaOH (2.5 mL) and BrCH2COOt-Bu (82 mg, 0.42
mmol). The mixture was stirred for 3 h. Then a further portion of
BrCH2COOt-Bu (82 mg, 0.42 mmol) was added. After the reaction
mixture was stirred for 2 h, ice (5 g) was added. The mixture was
extracted with CH2Cl2 (4 × 20 mL), and the organic phases were
dried (MgSO4) and concentrated. The residue was dried in high
vacuo and dissolved in THF (3 mL), and NBu4F (1.0 solution in
THF, 0.84 mL, 0.84 mmol) was added. The mixture was stirred
for 16 h at ambient temperature. Then the mixture was diluted with
Et2O (10 mL) and washed with saturated aqueous NaCl (40 mL).
The aqueous phase was extracted with Et2O (4 × 20 mL), and the
combined organic phases were dried (MgSO4) and concentrated in
vacuo. Purification by chromatography (hexanes/EtOAc, 5:2)
afforded ester 28 (51 mg, 89%) as a colorless oil. Rf 0.42 (hexanes/
1
+9.7 (c 1.5, THF). H NMR (400 MHz, CDCl3): δ 0.03 (s, 3 H,
SiCH3), 0.04 (s, 6 H, 2 × SiCH3), 0.06 (s, 3 H, SiCH3), 0.85-0.91
(m, 21 H, 2 × SiC(CH3)3, CH2CH3), 1.00-1.54 (m, 14 H), 1.23
(s, 3 H, CHCH3), 1.33 (s, 3 H, CHCH3), 1.63-1.73 (m, 3 H),
1.87-2.32 (m, 6 H), 2.41-2.52 (m, 2 H), 2.70-2.87 (m, 2 H),
3.77-3.85 (m, 1 H, CH(OSi)CHCHdC), 4.05-4.11 (m, 1 H,
CdCHCHOSi), 4.73-4.81 (m, 1 H, CHOCO), 5.10-5.12 (m, 1
H, CdCHCO), 5.43-5.54 (m, 2 H, CHdCH), 7.07-7.29 (m, 5
H, Ph). 13C NMR (100 MHz, CDCl3): δ -4.5 (d), -4.4 (d), -4.3
(d), -3.9 (d), 14.3 (d), 18.3 (u), 18.4 (u), 22.8 (u), 25.0 (u), 25.3
(u), 25.5 (d), 26.1 (d), 26.1 (d), 26.2 (u), 27.3 (u), 27.8 (d), 32.0
(u), 33.8 (u), 38.8 (u), 38.9 (d), 39.6 (u), 40.0 (u), 40.1 (u), 42.6
(u), 44.6 (d), 51.3 (d), 56.1 (d), 73.3 (d), 73.8 (d), 78.9 (d), 113.3
(d), 124.8 (d), 125.5 (d), 127.9 (d), 130.4 (d), 134.7 (d), 151.6 (u),
165.7 (u), 166.7 (u). IR (neat): ν 2931 (s), 2858 (s), 1708 (s), 1659
(m), 1600 (w), 1496 (w), 1467 (m), 1368 (m), 1253 (s), 1214 (s),
1125 (s), 1031 (m), 1006 (w), 968 (m), 910 (m), 838 (s). MS (CI,
isobutane) m/z (relative intensity, %): 737 (1.4), 736 (1.2), 735
(1.1), 679 (M+ - t-Bu, 9), 607 (14), 606 (46), 605 (95), 479 (18),
406 (28), 405 (100), 273 (12), 201 (37), 119 (19). Anal. Calcd for
C45H76O4Si2: C, 73.31; H, 10.39. Found: C, 73.30; H, 10.02.
Z-27: colorless oil, [R]D -39.8 (c 1.7, THF). 1H NMR (300 MHz,
CDCl3): δ 0.01 (s, 3 H, SiCH3), 0.02 (s, 3 H, SiCH3), 0.03 (s, 3
H, SiCH3), 0.05 (s, 3 H, SiCH3), 0.81-0.92 (m, 21 H, 2×C(CH3)3,
CH2CH3), 0.92-1.72 (m, 17 H), 1.23 (s, 3 H, CHCH3), 1.32 (s, 3
H, CHCH3), 1.90-2.46 (m, 7 H), 2.56-2.89 (m, 3 H), 3.82 (dt, 1
H, J ) 6.9, J ) 8.2 Hz, CH(OSi)CHCHdC), 4.02-4.10 (m, 1 H,
CdCHCHOSi), 4.73-4.83 (m, 1 H, CHOCO), 5.16-5.18 (m, 1
H, CdCHCO), 5.39-5.52 (m, 2 H, CH)CH), 7.07-7.29 (m, 5
H, Ph). 13C NMR (75 MHz, CDCl3): δ -4.7 (d), -4.5 (d), -4.5
(d), -4.1 (d), 14.1 (d), 18.2 (u), 18.3 (u), 22.7 (u), 24.8 (u), 25.2
(u), 25.9 (d), 26.0 (d), 26.1 (u), 26.4 (d), 26.7 (d), 27.3 (u), 31.9
(u), 33.7 (u), 36.1 (u), 37.2 (d), 38.7 (u), 40.1 (u), 41.7 (u), 43.3
(u), 46.8 (d), 51.3 (d), 57.1 (d), 73.0 (d), 73.8 (d), 79.0 (d), 113.2
(d), 124.9 (d), 125.6 (d), 127.9 (d), 130.4 (d), 134.6 (d), 151.6 (u),
165.8 (u), 167.0 (u). IR (KBr): ν 2933 (s), 2858 (s), 1703 (s), 1656
(m), 1600 (w), 1497 (w), 1466 (m), 1366 (m), 1325 (w), 1253 (m),
1208 (s), 1126 (s), 1037 (m), 1005 (w), 967 (m), 937 (w), 904
(m), 838 (s). MS (EI, 70 eV) m/z (relative intensity, %): 679 (M+
EtOAc, 1:4), [R]D +64.8 (c 0.73, THF) [lit. [R]22 +65.6 (c 10.5,
D
1
THF)5b,6]. H and 13C NMR spectra were identical with those of
28 reported previously.5b,6
(2-((E)-2-((3aS,4R,5R,6aS)-5-Hydroxy-4-((S,E)-3-hydroxyoct-
1-enyl) hexahydro-pentalen-2(1H)-ylidene)ethoxy)acetic acid)
(3). A solution of ester 28 (41 mg, 0.10 mmol) in MeOH (2 mL)
was treated with aqueous NaOH (1.0 M, 0.6 mL). The mixture
was stirred for 4 h at ambient temperature, and then saturated
aqueous NH4Cl (2.5 mL) and water (2.5 mL) were added. The pH
J. Org. Chem, Vol. 71, No. 12, 2006 4649

Kim and Gais
value of the solution was adjusted to 4-5 by the portion-wise
addition of solid NaH2PO4. The mixture was extracted with EtOAc
(5 × 15 mL), and the combined organic phases were dried (MgSO4).
Concentration in vacuo gave acid 3 (32 mg, 90%) as a colorless
Methods”) is gratefully acknowledged. We thank Dr. J. Runsink
for NMR spectroscopic investigations, Dr. H. Dahl, Schering
AG, Berlin, for a most generous gift of cis-tetrahydropentalene-
2,5(1H,3H)-dione, and C. Vermeeren for HPLC separations.
1
oil. Rf 0.24 (CH2Cl2/MeOH, 4:1). H and 13C NMR spectra of 3
matched those reported previously.5b,6
Supporting Information Available: Copies of the NMR spectra
of 3, 6-8, 19, 23-25, E-27, Z-27, and 28. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. Financial support of this work by the
Deutsche Forschungsgemeinschaft (Collaborative Research
Center “Asymmetric Synthesis with Chemical and Biological
JO060551T
4650 J. Org. Chem., Vol. 71, No. 12, 2006