Asymmetric synthesis of the highly potent anti-metastatic prostacyclin analogue cicaprost and its isomer isocicaprost

Article abstract of DOI:10.1021/ja030200l

An asymmetric synthesis of the anti-metastatic prostacyclin analogue cicaprost and a formal one of its isomer isocicaprost by a new route are described. A key step of these syntheses is the coupling of a chiral bicyclic C6-C14 ethynyl building block with

Full text of DOI:10.1021/ja030200l

Published on Web 07/19/2003
Asymmetric Synthesis of the Highly Potent Anti-Metastatic
Prostacyclin Analogue Cicaprost and Its Isomer Isocicaprost
Marco Lerm, Hans-Joachim Gais,* Kejun Cheng, and Cornelia Vermeeren
Contribution from the Institut fu¨r Organische Chemie der Rheinisch-Westfa¨lischen Technischen
Hochschule (RWTH) Aachen, Prof.-Pirlet-Str. 1, D-52056 Aachen, Germany
Received March 31, 2003; E-mail: Gais@RWTH-Aachen.de
Abstract: An asymmetric synthesis of the anti-metastatic prostacyclin analogue cicaprost and a formal
one of its isomer isocicaprost by a new route are described. A key step of these syntheses is the coupling
of a chiral bicyclic C6-C14 ethynyl building block with a chiral C15-C21 ω-side chain amide building
block with formation of the C14-C15 bond of the target molecules. A highly stereoselective reduction of
the thereby obtained C6-C21 intermediate carrying a carbonyl group at C15 of the side chain was
accomplished by the chiral oxazaborolidine method. The chiral phosphono acetate method was used for
the highly stereoselective attachment of the R-side chain to the bicyclic C6-C21 intermediate carrying a
carbonyl group at C6. Asymmetric syntheses of the bicyclic C6-C14 ethynyl building blocks were carried
out starting from achiral bicyclic C6-C12 ketones by using the chiral lithium amide method. In the course
of these syntheses, a new method for the introduction of an ethynyl group at the R-position of the carbonyl
group of a ketone with formation of the corresponding homopropargylic alcohol was devised. Its key steps
are an aldol reaction of the corresponding silyl enol ether with chloral and the elimination of a trichlorocarbinol
derivative with formation of the ethynyl group. In addition, a new aldehyde to terminal alkyne transformation
has been realized. Its key steps are the conversion of an aldehyde to the corresponding 1-alkenyl
dimethylaminosulfoxonium salt and the elimination of the latter with a strong base. Two basically different
routes have been followed for the synthesis of the enantiomerically pure C15-C21 ω-side chain amide
building block. The first is based on the chiral oxazolidinone method and features a highly stereoselective
alkylation of (4R)-N-acetyl-4-benzyloxazolidin-2-one, and the second encompasses a malonate synthesis
of the racemic amide and its efficient preparative scale resolution by HPLC on a chiral stationary phase
containing column.
ity.10 However, its medicinal application is severely hampered
by short chemical and metabolic half-lifes, which are mainly
Introduction
Prostacyclin (1) (Figure 1), which was discovered in the
vascular endothelium by Vane et al.,1 is the most potent
endogenous vasodilator that affects both the systemic and
pulmonary circulation.1-7 It prevents vascular smooth muscle
proliferation and inhibits blood platelet adhesion and aggrega-
tion. Prostacyclin has been shown to interfere with steps of the
metastatic cascade as for example tumor cell-blood interaction
and tumor cell adhesion.8,9 These features make prostacyclin
an attractive drug for a therapy of solid tumor metastasis9 and
of cardiovascular diseases, in particular of peripheral vascular
obstruction, major contributors to human morbidity and mortal-
due to the facile hydration of its enol ether moiety and the rapid
enzymatic modification of both side chains. Thus, intensive
efforts have been made to find stable and potent analogues in
a quest for drug candidates.3,5,6 These investigations led to the
finding of the carbacyclin derivative iloprost (2)11,4 and of the
prostacyclin derivative beraprost (3),12 which are chemically
stable and pharmacologically highly potent prostacyclin receptor
agonists. Iloprost and beraprost have already been marketed as
ilomedin and procycline, respectively, for the treatment of
peripheral vascular diseases,13,14 and both are being currently
studied in clinical trails for the treatment of patients with primary
pulmonary hypertension, an increasingly common and fatal
disease.15,16 Although beraprost and iloprost are orally active,
their relatively short biological half-life and insufficient oral
availability require frequent oral or invasive administration.17
(1) Moncada, S.; Gryglewski, R. J.; Bunting, S.; Vane, J. R. Nature 1976,
263, 633.
(2) Prostacyclin; Vane, J. R.; Bergstro¨m, S., Eds.; Raven Press: New York,
1979.
(3) Nickolson, R. C.; Town, M. H.; Vorbru¨ggen, H. Med. Res. ReV. 1985, 5,
1.
(4) Prostacyclin and its Stable Analogue Iloprost; Gryglewski, R. J., Stock,
G., Eds.; Springer-Verlag: Berlin, 1987.
(5) Collins, P. W.; Djuric, S. W. Chem. Rew. 1993, 93, 1533.
(6) Schinzer, D. in Organic Syntheses Highlights II; Waldmann, H., Ed.;
VCH: New York, 1995; p 301.
(10) Anon, N. Z. Am. J. CardioVasc. Drugs 2002, 2, 345.
(11) Skuballa, W.; Vorbru¨ggen, H. Angew. Chem. 1981, 93, 1080; Skuballa,
W.; Vorbru¨ggen, H. Angew. Chem., Int. Ed. Engl. 1981, 20, 1046.
(12) Wakita, H.; Yosjiwara, H.; Nishiyama, H.; Nagase, H. Heterocycles 2000,
53, 1085.
(7) Platelets and Their Factors; Bruchhausen, F.; Walter, U., Eds.; Springer-
Verlag: Berlin, 1997.
(8) Honn, K. V.; Cicone, B.; Skoff, A. Science 1981, 212, 1270.
(9) Schneider, M. R.; Tang, D. G.; Schirner, M.; Honn, K. V. Cancer Met.
ReV. 1994, 13, 349.
(13) Duthois, S.; Cailleux, N.; Levesque, H. J. Malad. Vasc. 2000, 25, 17.
(14) Melian, E. B.; Goa, K. L. Drugs 2002, 62, 107.
(15) Spiekerkoetter, E.; Fabel, H.; Hoeper, M. M. Deut. A¨rztebl. 2001, 98, A2104.
9
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A R T I C L E S
Lerm et al.
to interfere with several steps of metastasis including tumor cell-
platelet interaction and the extravasation, adaptation and intra-
vasation of tumor cells. Because cicaprost is also active on
already established metastases as for example of tumors in an
advanced stage of growth or those residing after surgery, it may
be a candidate for an adjuvant therapy after tumor surgery.29-31
Intrigued by the exceptional potential medicinal prospects of
cicaprost, we have been engaged in a program aimed at its
asymmetric synthesis. Included was its isomer, the isocarba-
cyclin derivative isocicaprost (5),32 which is expected to have
a similar chemical and metabolic stability as cicaprost.33
Preliminary biological studies showed isocicaprost to be a strong
inhibitor of blood platelet aggregation.32 Future tests will have
to show whether isocicaprost exhibits similar anti-metastatic
effects as cicaprost. Surprisingly, only a few studies have been
conducted directed toward the asymmetric synthesis of cicaprost
and isocicaprost. Skuballa et al. disclosed in 1986 in a
communication the first asymmetric synthesis of cicaprost18 and
a second one was described by Shibasaki et al. in a full paper
in 1988.20 Finally, a synthesis of isocicaprost had been reported
by Skuballa et al. in 1990 in the patent literature.32 A key feature
of the syntheses of cicaprost and isocicaprost is the coupling
of a chiral bicyclic C4-C13(C6-C13) building block with a
chiral C14-C21 ω-side chain building block with formation
of a C4-C21(C6-C21) intermediate carrying a C13-C15
R-bromo-enone moiety.34 After reduction of the carbonyl group
of these intermediates, the C13-C14 triple bond was generated
by elimination of HBr. Although these syntheses are imaginative
and efficient, the methods applied for joining of the two building
blocks with the stepwise generation of the C13-C14 triple bond
seem to be not trivial. In addition, lengthy sequences are required
for the attainment of the key bicyclic C4-C13(C6-C13)
building blocks in enantiomerically pure form. Thus, we were
seeking asymmetric syntheses of both cicaprost and isocicaprost
by a new and more concise route, which would also allow an
easy access to other ω-side chain modified derivatives. The later
aspect is of particular importance because the biological activity
of carbacyclin and isocarbacyclin derivatives is strongly de-
pendent on the structure of the ω-side chain.3,5 Herein, is
presented a detailed account of the investigations which led to
a fully stereocontrolled asymmetric synthesis of cicaprost and
isocicaprost by a new and flexible strategy which also features
a new method for the introduction of an ethynyl group at
R-position of a carbonyl group and a new aldehyde to terminal
alkyne transformation.
Figure 1. Prostacyclin and its analogues (prostacyclin numbering).
These deficiencies of both prostacyclin analogues led to the
development of the carbacyclin derivative cicaprost (4).18-22 Of
all of the prostacyclin analogues known, cicaprost seems to hold
the most promising prospects. It is not only the most potent
and prostacyclin receptor selective analogue but also has a long
lasting oral activity and a high oral availability.23,24 The high
oral activity and metabolic stability of cicaprost are due to the
special structures of its side chains. The oxygen atom of the
R-side chain prevents its degradation via â-oxidation and the
two triple bonds in combination with the methyl group at C16
not only add to the metabolic stability of the molecule but also
contribute to its high biological activity. These features make
cicaprost an attractive candidate for example for the treatment
of pulmonary hypertension at an acceptable dosing regimen.
The most interesting feature of cicaprost, however, is its strong
inhibitory effect in a series of spontaneously metastasizing
rodent tumors upon oral administration.25-28 It has been shown
Results and Discussion
(16) Olschewski, H.; Simonneau, G.; Nazzareno, G.; Higenbottam, T.; Naeije,
R.; Rubin, J. R.; Nikkho, S.; Speich, R.; Hoeper, M. M.; Behr, J.; Winkler,
J.; Sitbon, O.; Popov, W.; Ghofrani, H. A.; Manes, A.; Kiely, D. G.; Ewert,
R.; Meyer, A.; Corris, P. A.; Delcroix, M.; Gomez-Sanchez, M.; Siedentop,
H.; Seegers, W. New Engl. J. Med. 2002, 347, 322.
Retrosynthetic Analysis. A key feature of our retrosynthetic
analysis of cicaprost is the coupling of a chiral bicyclic C6-
(26) Schirner, M.; Kraus, C.; Lichtner, R. B.; Schneider. M. R.; Hildebrand,
M. Prostagl. Leukotr. Ess. Fatty Acids 1998, 58, 311.
(27) Schirner, M.; Lichtner, R.; Graf, H.; Schneider. M. R. AdV. Exp. Med. Biol.
1997, 400B, 751.
(28) Schneider, M. R.; Schirner, M.; Lichtner, R. B.; Graf, H. Breast Cancer
Res. Treat. 1996, 38, 133.
(29) Sava, G.; Bergamo, A. Anticancer Res. 1999, 19, 1117.
(30) Mundy, G. R. Nature ReV. Cancer 2002, 2, 584.
(31) Ghadimi, B. M.; Schlag, P. M. Chirurg 1998, 69, 1315.
(32) Skuballa, W.; Stuerzebecher, C. S.; Thierauch, K. H. German patent DE
3909329 A1 1990; Chem. Abstr. 1991, 115, 28 973.
(33) Kojima, K.; Amemiya, S.; Koyama, K.; Saito, S.; Oshima, T.; Ito, T. Chem.
Pharm. Bull. 1987, 35, 4015.
(17) Saji, T.; Nakayama, T.; Ishikita, T.; Matsuura, H. Jpn. J. Clin. Med. 2001,
59, 1132.
(18) Skuballa, W.; Schillinger, E.; Stu¨rzebecher, C. S.; Vorbru¨ggen, H. J. Med.
Chem. 1986, 29, 313.
(19) Rehwinkel, H.; Skupsch, J.; Vorbru¨ggen, H. Tetrahedron Lett. 1988, 29,
1775.
(20) Takahashi, A.; Shibasaki, M. J. Org. Chem. 1988, 53, 1227.
(21) Harre, M.; Trabandt, J.; Westermann, J. Liebigs Ann. Chem. 1989, 1081.
(22) Harre, M.; Nickisch, K.; Westermann, J. Tetrahedron Lett. 1993, 34, 3123.
(23) Stuerzebecher, C. S.; Haberey, M.; Mueller, B.; Schillinger, E.; Schroeder,
G.; Skuballa, W.; Stock, G.; Vorgru¨ggen, H.; Witt, W. Prostaglandins 1986,
31, 95.
(24) Stuerzebecher, C. S.; Loge, O.; Schroeder, G.; Mueller, B.; Witt, W. Prog.
Clin. Biol. Res. 1987, 242, 425.
(25) Schneider, M. R.; Schirner, M.; Lichtner, R. B.; Graf, H. Top. Mol. Med.
1995, 1, 231.
(34) Because of clarity the prostacyclin numbering is used for cicaprost,
isocicaprost and all building blocks througout this paper except in the
experimental part where the numbering of the compounds follows the
nomenclature rules.
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Synthesis of Cicaprost and Isocicaprost
A R T I C L E S
tionalities at C6 being equivalent to a carbonyl group, were
chosen in order to provide synthetic flexibility in the crucial
introduction of the ethynyl group (vide infra). The synthetic
plan required an enantioselective ethynylation of ketone 11 at
C12. We planned to use as key step for this transformation an
enantioselective deprotonation of 11 with a chiral lithium amide
with formation of the corresponding lithium enolate.37-41
Because methods for the ethynylation of lithium enolates or
enol ethers at the â-position are scarce,42,43 and most likely only
ill-suited in the present case, a new method would perhaps have
to be developed. The lithium acetylide of alkyne 10 should be
acylated44,45 with amide 9a with formation of ketone 8 which
has to be stereoselectively reduced to give, after some functional
group manipulations and the establishment of the carbonyl group
at C6, the protected hydroxy ketone 7. Alternatively, a stereo-
selective hydroxy alkylation of the lithium acetylide of 10 with
aldehyde 9b can be envisaged, which could give, after similar
group manipulations, more directly 7. Because the asymmetric
induction provided by the substrates 8, 9, and 10 in these steps
is expected to be low, a chiral reducing reagent46-48 and a chiral
auxiliary,49 respectively, would have to be applied. A similar
situation will be faced in the attachment of the R-side chain,
which requires an E-stereoselective olefination of the carbonyl
group of ketone 7. Two different methods can be envisioned
for the E-stereoselective generation of the C5-C6 double bond
of the target molecule. The first would involve a diastereose-
lective olefination of ketone 7 with a chiral phosphono acetate
with formation of ester E-6, a method previously developed in
our and other laboratories for the stereoselective olefination of
chiral and prochiral ketones of this type.19,40,50,51 The second
would include a diastereoselective conversion of ketone 7 by
using a chiral lithiomethyl sulfoximine to give an E-configured
alkenyl sulfoximine and the subsequent replacement of the
sulfoximine group by a protected hydroxymethyl group through
a nickel catalyzed cross-coupling reaction, a method which we
have previously developed for the stereoselective olefination
of ketones of this type.52-55 Particularly appropriate, however,
(35) Bertz, S. H.; Cook, J. M.; Gawish, A.; Weiss, U. In Organic Syntheses;
Wiley: New York, 1990; Col. Vol. VII; p 50.
(36) Piers, E.; Karunaratne, V. Can. J. Chem. 1989, 67, 160.
(37) Vaulont, I.; Gais, H.-J.; Reuter N.; Schmitz, E.; Ossenkamp, R. K. L. Eur.
J. Org. Chem. 1998, 805.
(38) Hemmerle, H.; Gais, H.-J. Angew. Chem. 1989, 101, 362; Hemmerle, H.;
Gais, H.-J. Angew. Chem., Int. Ed. Engl. 1989, 28, 349.
(39) Izawa, H.; Shirai, R.; Kawasaki, H.; Kim, H.; Koga, K. Tetrahedron Lett.
1989, 30, 7221.
(40) Gais, H.-J.; Ossenkamp, R. K. L. Liebigs Ann./Recl. 1997, 2433.
(41) Gais, H.-J.; van Bergen, M. J. Am. Chem. Soc. 2002, 124, 4321.
(42) (a) Kende, A. S.; Fludzinski, P. Tetrahedron Lett. 1982, 23, 2373. (b) Kende,
A. S.; Fludzinski, P. Synthesis 1982, 455. (c) Kende, A. S.; Fludzinski, P.;
Hill, J. H.; Swenson, W.; Clardy, J. J. Am. Chem. Soc. 1984, 106, 3551.
(43) Arisawa, M.; Amemiya, R.; Yamaguchi, M. Org. Lett. 2002, 4, 2209.
(44) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(45) For a review on the synthesis of ketones from N-methoxy-N-methylamides,
see: Mentzel, M.; Hoffmann, H. M. R. J. prakt. Chem. 1997, 339, 517.
(46) Itsuno, M. Org. React. 1998, 52, 395.
(47) Corey, E. J.; Helal, C. J. Angew. Chem. 1998, 110, 2092; Corey, E. J.;
Helal, C. J. Angew. Chem., Int. Ed. Engl. 1998, 37, 1986.
(48) Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1997, 38, 7511.
(49) Fa¨ssler, R.; Frantz, D. E.; Tomooka, C. S.; Carreira, D. E. Acc. Chem.
Res. 2000, 33, 373.
(50) Gais, H.-J.; Schmiedl, G.; Ball, W. A.; Bund, J.; Hellmann, G.; Erdelmeier,
I. Tetrahedron Lett. 1988, 29, 1773.
(51) Gais, H.-J.; Ossenkamp, R. K. L. Liebigs Ann./Recl. 1997, 2419.
(52) Erdelmeier, I.; Gais, H.-J.; Lindner, H. J. Angew. Chem. 1986, 98, 912;
Erdelmeier, I.; Gais, H.-J.; Lindner, H. J. Angew. Chem., Int. Ed. Engl.
1986, 25, 935.
(53) Gais, H.-J.; Bu¨low, G. Tetrahedron Lett. 1992, 33, 461.
(54) Gais, H.-J.; Bu¨low, G. Tetrahedron Lett. 1992, 33, 465.
(55) Bund, J.; Gais, H.-J.; Schmitz, E.; Erdelmeier I.; Raabe, G. Eur. J. Org.
Chem. 1998, 1319, 9.
Figure 2. Retrosynthetic analysis of cicaprost and isocicaprost.
C14 building block carrying a C13-C14 ethynyl group with a
chiral C15-C21 ω-side chain building block with formation
of the C14-C15 bond of the target molecules (Figure 2). It
was hoped that this strategy would not only allow an efficient
joining of the two building blocks but also provide a high degree
of flexibility in regard to the synthesis of derivatives with
different ω-side chains. Thus, the retrosynthetic analysis identi-
fied the alkyne 10 as the bicyclic building block and the amide
9a, or alternatively the aldehyde 9b, as the ω-side chain building
block. We selected achiral bicyclic ketones 11a and 11b as
starting material for the synthesis of alkyne 10 because of their
ready availability from cis-bicyclo[3.3.0]-octan-2,5-dione on
large scale.35-37 The two ketones, which carry different func-
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A R T I C L E S
Lerm et al.
Scheme 1. Asymmetric Synthesis of the Bicyclic Alkyne 10a (R )
Sit-BuPh2)a
Figure 3. Selected NOEs of 10a, 10b, and 22.
a Reagents and conditions: (I) THF, -105 °C. (II) Me3SiCl, -105 °C
f -78 °C. (III) TiCl4, CCl3CHO, CH2Cl2, -78 °C. (IV) NaBH4, EtOH,
-45 °C. (V) Et3SiCl, imidazole, DMF, rt. (VI) MeSO2Cl, DABCO, THF,
rt. (VII) n-BuLi, THF, -20 °C; H2O.
59,60
with chloral in the presence of TiCl4
gave ketone 15 with
g 98% de with respect to C12 and with 60% de with respect to
C13. The configuration of 15 at C12 was determined by H
1
NMR spectroscopy at a later stage intermediate and that of C13
of the major diastereomer of 15 was tentatively assigned as
depicted. Reduction of the major diastereomer of ketone 15 with
NaBH4 furnished the trichlorocarbinol 16 with g 98% de with
respect to C11 in 75% overall yield, based on 14, after column
chromatography. As hoped for, the formation of the C12-C13
bond and the reduction of the carbonyl group both had occurred
with high diastereoselectivities. Silylation of diol 16 with Et3-
SiCl selectively gave the silyl ether 17 in 79% yield together
with 12% of the corresponding disilyl ether. A quantitative
conversion of alcohol 17 to the mesylate 18 was achieved upon
treatment with MeSO2Cl and DABCO in THF.61 Interestingly,
the use of NEt3 as base and CH2Cl2 as solvent saw only an
incomplete conversion of alcohol 17 to the mesylate. Elimination
of mesylate 18 with 3.5 equiv of n-BuLi cleanly afforded alkyne
10a in 90% yield after aqueous work-up. Alkyne 10a had an
ee-value 94%, which was determined indirectly at a later stage
for the development of a joint route to both cicaprost and
isocicaprost would be the first method because a regioselective
isomerization33,37 of the bicyclic R,â-unsaturated ester E-6 could
also give, at a late stage of the synthesis, an ultimate precursor
for the synthesis of isocicaprost.
Asymmetric Synthesis of the Bicyclic C6-C14 Ethynyl
Building Block 10a. The enantioselective deprotonation of
ketone 11a with the LiCl containing chiral lithium amide 1256
and the treatment of the lithium enolate 13a with ClSiMe3
afforded the silyl enol ether 14 in 92% yield after column
chromatography (Scheme 1).37 Because 14 is slowly hydrolyzed
on silica gel with formation of ketone 11a, the chromatographic
separation of 14 and the amine, derived from 12, is carried out
as rapidly as possible. The ee-value of 14, determined indirectly
at a later stage of the synthesis (vide infra), was 94%. According
to the synthetic plan, an ethynylation of 14 at the â-position
was now required. Surprisingly, only a few methods have been
described for the ethynylation of lithium enolates or enol ethers
in the literature, and these methods are apparently restricted to
derivatives having no protons at the R- and the R’-position.42,43
Thus, we have devised a new stepwise method which is based
on the facile elimination of trichlorocarbinol derivatives with
formation of alkynes.57,58 Aldol reaction of the enol ether 14
1
of the synthesis (vide infra). H NMR spectroscopy of alkyne
10a in combination with NOE experiments confirmed the
configurations of C11 and C12. In particular, the observation
of strong NOE’s between 10-Hâ and 12-Hâ and between 11-
HR, 8-HR and 9-HR was instrumental in the assignment of the
configuration (Figure 3).
Asymmetric Synthesis of the Bicyclic C6-C14 Ethynyl
Building Block 10b. Having developed an asymmetric synthesis
of alkyne 10a from ketone 11a, we were interested in an
asymmetric synthesis of alkyne 10b from ketone 11b (cf. Figure
2). In contrast to 10a, the alkyne 10b already contains a
(56) For reviews on the use of this chiral base, see: (a) Cox, P. J.; Simpkins,
N. S. Tetrahedron: Asymmetry 1991, 2, 1. (b) Gais, H.-J. In StereoselectiVe
Synthesis (Houben-Weyl); Helmchen, G., Hoffmann, R. W., Mulzer, J.,
Schaumann, Eds.; Thieme: Stuttgart, 1995; E21a, p 589. (c) Majewski,
M. AdV. Asymm. Synth. 1998, 3, 39. (d) O’Brien, P. J. Chem. Soc., Perkin
Trans. 1 1998, 1439.
(57) Takano, S.; Kubodera, N.; Iwata, H.; Ogasawara, K. Heterocycles 1977,
8, 325.
(58) Wang, Z.; Campangna, S.; Yang, K.; Xu, G.; Pierce, M. E.; Fortunak, J.
M.; Confalone, P. N. J. Org. Chem. 2000, 65, 1889.
(59) Banno, K. Bull. Chem. Soc. Jpn. 1976, 49, 2284.
(60) Mukaiyama, T. Org. React. 1982, 28, 203.
(61) Hartung, J.; Hu¨nig, S.; Kneuer, R.; Schwarz, M.; Wenner, H. Synthesis
1997, 1433.
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Synthesis of Cicaprost and Isocicaprost
A R T I C L E S
Scheme 2. Asymmetric Synthesis of the Bicyclic Aldehyde 24 (R
) Sit-BuMe2)a
Figure 4. Structure of nitrile 21 in the crystal.
combination with a selective reduction of the cyano group to
the aldehyde group at a later stage. Therefore, ketone 11b was
enantioselectively deprotonated with the LiCl containing lithium
amide 12 and the lithium enolate 13b37 was cyanated through
treatment with 2 equiv of TsCN67 in THF. Crucial to the success
of the transformation was the addition of 13b to the solution of
the cyanating reagent. The thereby formed R-cyano ketones 19
and 20 were not isolated68 but reduced directly with NaBH4 to
furnish after chromatography a mixture of the hydroxy nitriles
22 and 21 in a ratio of 3.6:1 in 95% yield. Separation of the
nitriles by column chromatography or, more efficiently, by
preparative HPLC afforded nitrile 22 in 69% yield and nitrile
21 in 19% yield. According to GC analysis, the nitrile 22 had
an ee-value of 92%. Hence, nitrile 21 must have also had an
ee-value of 92%. Although the structure of nitrile 21 was
determined by X-ray crystal structure analysis (Figure 4), the
configuration of the isomeric nitrile 22 was revealed by NOE
experiments. The assignment of the configuration of 22 rests
on the observation of strong NOE’s between 10-Hâ and 12-Hâ
and between 11-HR, 8-HR, and 9-HR (cf Figure 3).
a Reagents and conditions: (I) THF, -105 °C. (II) TsCN, THF, first
-105 °C and then -78 °C. (III) NaBH4, EtOH, -40 °C. (IV) t-BuMe2SiCl,
imidazole, DMF, rt. (V) DIBALH, toluene, -78 °C f rt; EtOH, H2O. (VI)
LDA, THF, first -105 °C and then -78 °C. (VII) Aqueous NaCl, -78 °C.
In concluding the synthesis of aldehyde 24, the alcohol 22
(92% ee) was silylated, which gave the silyl ether 23 in 98%
yield. Reduction of nitrile 23 (92% ee) with DIBALH69,70 in
toluene or hexane afforded aldehyde 24 with 92% ee in 85%
yield after column chromatography.
To make the synthesis of aldehyde 24 from nitrile 22 more
efficient, a recycling of the unwanted epimeric nitrile 21 was
attempted. We envisioned a double deprotonation of 21 with
formation of the dianion 25b, followed by a protonation. It was
speculated that the dianion 25a formed first from 21 would
isomerize to the diastereomeric dianion 25b and that its
protonation would preferentially lead to 22. The structure of
doubly lithiated â-hydroxy nitriles is not known. However, given
the large contribution of the polar inductive-field effect to the
stabilization of a negative charge by the cyano group,71,72 it
seems not unreasonable to assume that the anionic C-atoms of
25a and 25b73 are pyramidalized and endowed with a low barrier
protected carbonyl group at C6, which is required for the
attachment of the R-side chain at a later stage of the synthesis.
The method used for the synthesis of alkyne 10a from ketone
11a is, however, not well-suited for the synthesis of 10b from
11b. It turned out that the acetal group of the silyl enol ether
derived from 11b is not compatible with TiCl4,37 required for
its aldol reaction with chloral. Thus, we envisioned a synthesis
of alkyne 10b from ketone 11b via the aldehyde 24 (Scheme
2). Aldehyde 24 is an important intermediate in the synthesis
of cicaprost (4)18 and iloprost (2)4,11 by Skuballa et al. Although
high-yielding syntheses of aldehyde 24 from ketone 11b have
been developed,62-66 they all use a microbial kinetic resolution
of an advanced racemic intermediate for its attainment in
enantiomerically pure form. We felt that a perhaps more direct
asymmetric synthesis of 24 could be developed on the basis of
the enantioselective deprotonation methodology through a
cyanation of the lithium enolate derived from ketone 11b in
(67) Kahne, D.; Collum, D. B. Tetrahedron Lett. 1981, 22, 5011.
(68) NMR spectroscopy of a crude mixture of 19 and 20 indicated the presence
of the corresponding enol as a third equilibrium component.
(69) For a review, see: Winterfeldt, E. Synthesis 1975, 617.
(70) Hayashi, M.; Yoshiga, T.; Oguni, N. Synlett 1991, 479.
(71) For a review, see: Bradamante, S.; Pagani, G. A. AdV. Carbanion Chem.
1996, 2, 189.
(62) Skuballa, W.; Dahl, H. German patent DE 3638757 A1 1988; Chem. Abstr.
1989, 110, 7940.
(63) Dahl, H. German Patent DE 3816801 A1 1989; Chem. Abstr. 1990, 113,
23 512.
(64) Harre, M.; Westermann, J. German Patent DE 3835162 A1 1990; Chem.
Abstr. 1990, 113, 31889.
(65) Petzold, K.; Dahl, H.; Skuballa, W.; Gottwald, M. Liebigs Ann. 1990, 1087.
(66) Mori, K.; Tsuji, M. Tetrahedron 1986, 42, 435.
(72) For a review, see: Boche, G. Angew. Chem. 1989, 101, 286; Boche, G.
Angew. Chem., Int. Ed. Engl. 1989, 28, 277.
9
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A R T I C L E S
Lerm et al.
Scheme 3. Synthesis of the Bicyclic Alkyne 10b from Aldehyde
24 and Sulfoximine 27 (R ) Sit-BuMe2)a
Scheme 4. Asymmetric Synthesis of the ω-Side Chain Building
Block 9aa
a Reagents and conditions: (I) (a) 31, NaN(SiMe3)2, THF, -78 °C; (b)
32, -78 °C. (II) EtOH; Ti(OEt)4, reflux. (III) (a) [Me(OMe)NH2]Cl,
i-PrMgCl, THF; (b) 34, -19 °C; (c) HPLC.
alkylidenecarbenes.78 It was tempting to see whether this
elimination could be used as a key step of an alternative
synthesis of alkyne 10b from aldehyde 24. Synthesis of the
alkenyl sulfoximine 29 from aldehyde 24 require an addition
of a lithiomethylsulfoximine to the aldehyde followed by an
elimination.79 To this end, aldehyde 24 was treated with the
lithiomethylsulfoximine 27, which gave alcohol 28 as a mixture
of diastereomers in essentially quantitative yield. As anticipated,
no â-elimination of 24 was observed. Mesylation of alcohol 28
with MeSO2Cl and NEt3 and the subsequent in situ elimination
of the corresponding mesylate with DBU furnished the E-
configured alkenyl sulfoximine 29 in 95% yield. Methylation
of sulfoximine 29 with Me3OBF4 afforded the dimethylamino-
sulfoxonium salt 30 in essentially quantitative yield. Finally,
elimination of salt 30 with LiN(H)t-Bu gave alkyne 10b in 89%
overall yield, based on 29. PhS(O)NMe2, H2Nt-Bu and LiBF4
were also formed, which could easily be separated. For the
synthesis of 29, the enantiomerically pure sulfoximine 2780 was
used to avoid the formation of a mixture of diastereomers of
29, which might have complicated its NMR spectroscopic
analysis. Although it has not been investigated, the conversion
of 24 into alkyne 10b should also be possible by using rac-27.
According to GC analysis, alkyne 10b had an ee-value of 92%.
The configurations of C11 and C12 of alkyne 10b were
determined by 1H NMR spectroscopy in combination with NOE
experiments. Instrumental for the assignment of the configura-
tions were the observation of strong NOEs between 10-Hâ and
12-Hâ, and between 11-HR, 8-HR and 9-HR (cf Figure 3).
Synthesis of the C15-C21 Amide Building Block. Asym-
metric Synthesis. With the synthesis of the two key bicyclic
building blocks accomplished, we opted for the acylation-
reduction route for the synthesis of the alcohol 7 (cf. Figure 2).
This route requires the enantiomerically pure amide 9a as the
ω-side chain building block. A precursor for amide 9a is the
ester 3448 (Scheme 4) which had been synthesized previously
by the following routes: (1) from methyl (S)-3-hydroxy-2-
methyl propionate and 1-bromobutyne,48 (2) through pent-2-
a Reagents and conditions: (I) THF, -78 °C f rt. (II) n-BuLi, MeSO2Cl,
Et3N; DBU, -78 °C f rt. (III) Me3OBF4, CH2Cl2, rt. (IV) LiN(H)t-Bu,
THF, -78 °C.
toward inversion.72,74 To this end, nitrile 21 was treated with
2.8 equiv of LDA followed by a protonation of dianion 25 with
H2O. This delivered a mixture of nitriles 22 and 21 in a ratio
of 1:1 in 90% yield. HPLC of the mixture of both nitriles
afforded nitrile 22 in 37% yield and nitrile 21 in 36% yield.
GC analysis showed the nitrile 22 to have an ee-value of g99%
ee. The sample of the nitrile 21 used in the recycling experiment
had been recrystallized (90% recovery) prior to its use. This
measure obviously raised its ee-value to g 99%. Therefore, the
nitrile 21 obtained in the epimerization experiment also was of
g 99% ee. Under the conditions used, the dianion 25 was
sufficiently stable and its elimination with formation of the
unsaturated nitrile 26 (5%) could largely be suppressed. The
use of other reagents for the protonation of 25 as for example
methyl salicylate and MeOH saw no change of the ratio of the
hydroxy nitriles.
A mild method was now required for the conversion of the
aldehyde 24 to the alkyne 10b (Scheme 3), because of its
propensity for â-elimination. Although the successive treatment
of aldehyde 24 with CBr4/PPh3 and n-BuLi75 gave alkyne 10b
in only 30% yield, that with [Ph3PCHBr2]Br/KO-tBu76 furnished
the alkyne in 90% yield. However, the presence of large amounts
of phosphorus compounds rendered the isolation and purification
of 10b difficult. Because of our failure to achieve the desired
aldehyde-alkyne conversion by other reagents including lithio-
trimethylsilyldiazomethane,77 a new sulfoximine based conver-
sion was investigated. We have recently described a facile
elimination of 1-alkenyl aminosulfoxonium salts with formation
of alkynes, which presumably proceeds via formation of
(73) For a recent computational study of the position of metalation of lithiated
nitriles, see: Carlier, P. R.; Madura, J. D. J. Org. Chem. 2002, 67, 3832.
(74) Boehme, W. R.; Schipper, E.; Scharpf, W. G.; Nichols, J. J. Am. Chem.
Soc. 1958, 80, 5488.
(75) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.
(76) Michel, P.; Rassat, A. Tetrahedron Lett. 1999, 40, 8575.
(77) (a) Ohira, S.; Okai, K.; Moritani, T. J. Chem. Soc., Chem. Commun. 1992,
721. (b) Conversion of 24 to 10b with dimethyl (diazomethy)phosphonate
(Mu¨ller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521)
was not studied.
(78) Gais, H.-J.; Reddy, L. R.; Woo, C. W. J. Am. Chem. Soc. 2002, 124, 10 427.
(79) Gais, H.-J.; Hainz, R.; Mu¨ller, H.; Bruns, P. R.; Giesen, N.; Raabe, G.;
Runsink, J.; Nienstedt, S.; Decker, J.; Schleusner, M.; Hachtel, J.; Loo,
R.; Woo, C.-W.; Das, P. Eur. J. Org. Chem. 2000, 3973.
(80) Gais, H.-J.; Brandt, J. Tetrahedron: Asymmetry 1997, 8, 909.
9
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Synthesis of Cicaprost and Isocicaprost
A R T I C L E S
ynylation of a chiral iron acetyl complex81 and of (4R,5S)-N-
acetyl-4-methyl-5-phenyl-oxazolidin-2-one,21 and (3) by resolu-
tion.18 These routes, however, are not very practical either
because of nontrivial steps, moderate yields and selectivities or
lengthy sequences. Nevertheless, the oxazolidinone route seemed
to hold the most prospects for the development of a more
efficient synthesis of 34. The benzyl substituted oxazolidinone
3182a was selected in anticipation82b of a higher selectivity and
yield. Deprotonation of oxazolidinone 31 with NaN(SiMe3)2 and
treatment of the resulting sodium enolate with iodide 32,
prepared from commercially available 2-pentyne-1-ol,21 gave
the substituted oxazolidinone 33 with 97% de in 93% yield.
Thus, pent-2-ynylation of 31 proceeded much more efficiently
than that of N-acetyl-4-methyl-5-phenyl-oxazolidin-2-one, which
proceeded with only 80% de and 62% yield.21 At this stage of
the synthesis of the 9a, the 1.5% of the unwanted diastereo-
isomer of 33 could neither be separated by HPLC nor by
crystallization. Treatment of oxazolidinone 33 with Ti(OEt)4
in refluxing EtOH gave ester 34 with 97% ee (GC) in 81%
yield. Finally, amidation of ester 34 with MeO(Me)NMgCl,
prepared in situ from [MeO(Me)NH2]Cl and 2 equiv of
i-PrMgCl in THF,83,84 afforded amide 9a in 92% yield. HPLC
analysis showed the amide to have an ee-value of 97%.
Preparative HPLC of amide 9a (10 g) with 97% ee on a Daicel
Chiralcel AD column (250 × 50 mm) allowed the ready
separation of ent-9a (900 mg of 9a per injection) and furnished
amide 9a with g 99% ee in 90% yield.
Scheme 5. Synthesis of Amide 9a through Malonate Synthesis of
the Racemate and Resolutiona
a Reagents and conditions: (I) (a) LDA, THF, -78 °C; (b) 32. (II) LiCl,
DMSO, H2O, reflux. (III) [Me(OMe)NH2]Cl, i-PrMgCl, THF -19 °C. (IV)
HPLC.
Scheme 6. Coupling of the Bicyclic Building Block 10a with the
ω-Side Chain Building Block 9a (R1 ) Sit-BuPh2)a
Symmetric Synthesis and Chromatographic Resolution.
Although amide 9a could be efficiently synthesized from
oxazolidinone 31 and iodide 32, all three steps required carefully
defined reaction conditions to achieve a high diastereoselectivity
and to avoid a partial racemization. The facile preparative scale
separation of 9a and ent-9a by HPLC on a chiral stationary
phase containing column led us to consider, as an alternative,
the attainment of 9a through synthesis of the racemic amide
rac-9a and its chromatographic resolution. The racemic ester
rac-34 was efficiently prepared by malonate synthesis (Scheme
5).85 Thus, deprotonation of malonate 35 with 1.05 equiv of
LDA and treatment of the resulting lithium enolate with iodide
32 (1.3 equiv) afforded the substituted malonate 36 in 91% yield.
Deethoxycarbonylation86 of malonate 36 with LiCl in DMSO
and water furnished the racemic ester rac-34 in 75% yield.
Finally, amidation of rac-34 with MeO(Me)NMgCl gave amide
rac-9a in 92% yield. The separation of rac-9a on a 4.2 g scale
by HPLC on a Daicel Chiralcel AD column (250 × 50 mm)
readily (750 mg of rac-9a per injection) afforded 9a with g
99% ee in 47% yield and ent-9a with g 99% ee in 47% yield.
Interestingly, a HPLC separation of ester rac-34 by using this
chiral stationary phase failed.
Synthesis of the C6-C21 Ketone Intermediate. Coupling
of the C6-C14 Alkyne 10a With the C15-C21 Amide. With
the building blocks 9a, 10a, and 10b in hand, their coupling
was required next. Special attention had to be paid to the
a Reagents and conditions: (I) (a) 10a, n-BuLi, THF, -78 °C f 0 °C;
(b) 9a, -19 °C. (II) Catecholborane, 37, CH2Cl2, -78 °C. (III) Aqueous
HCl, THF, rt. (IV) (a) PhCOCl, pyridine, 0 °C f rt; (b) NBu4F, THF, rt.
(V) DMSO, (COCl)2, Et3N, CH2Cl2, -60 °C. (VI) NaOH, MeOH, rt.
(81) Bodwell, G. J.; Davies, S. G. Tetrahedron: Asymmetry 1991, 2, 1075.
(82) (a) Evans, D. A.; DiMare, M. J. Am. Chem. Soc. 1986, 108, 2476. (b)
Evans, D. A.; Ennis, M. D.; Mahtre, D. J. J. Am. Chem. Soc. 1982, 104,
1737.
potential configurational lability of C16 of ketone 8a (cf. Figure
2) in the presence of a base. Coupling44 of the alkyne 10a with
the amide 9a was thus carried out as follows (Scheme 6). Alkyne
10a in THF was treated at -78°C with 1 equiv of n-BuLi in
hexane and the solution was warmed to room temperature to
ensure a complete deprotonation of the alkyne. The solution
(83) Levin, J. I.; Turos, E.; Weinreb, S. M. Synth. Commun. 1982, 12, 989.
(84) Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.; Dolling, U.
H.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461.
(85) The malonate synthesis of the racemic acid was cursory described in a
footnote of ref 18.
(86) Krapcho, A. P.; Gadamasetti, G. J. Org. Chem. 1987, 52, 1880.
9
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A R T I C L E S
Lerm et al.
Scheme 7. Coupling of the Bicyclic Building Block 10b with the
was then cooled to -78°C and transferred via cannula to a -19
°C cold solution of 1.15 equiv of amide 9a with g 99% ee in
THF. Quenching of the reaction mixture after 2 h with aqueous
NH4Cl and purification by chromatography furnished ketone
8a in 92% yield. Alkyne 10a was recovered in 8% yield. Under
these conditions formation of the C16 epimer of 8a could be
completely avoided.
ω-Side Chain Building Block 9a (R1 ) Sit-BuMe2)a
It was to be expected that a highly diastereoselective reduction
of ketone 8a with an achiral reducing reagent with formation
of the (S)-configured alcohol 38 would be difficult to achieve
(vide infra). Thus, a chiral reducing reagent had to be applied
and we selected the oxazaborolidine-catalyzed reduction with
a borane.46,47 This method had already been successfully
employed for a highly diastereoselective reduction of a structur-
ally related ketone carrying a bulky silyl group instead of the
bicyclooctanyl group.47 Because it has been reported that the
enantioselectivity of oxazaborolidine-catalyzed reduction of
ketones with boranes can critically be dependent on the purity
of the catalyst, the pure oxazaborolidine 37 was prepared from
n-butylboroxine and 1 equiv of (R)-R,R-diphenyl-2-pyrro-
lidinemethanol in refluxing C6D6.87 The reduction of ketone 8a
was carried out through addition of catecholborane to a mixture
of the ketone and 20 to 30 mol % of 37 in CH2Cl2 at -78 °C.
Thereby, the alcohol 38 could be reproducibly isolated with
g 99% de in regard to C15 in 88% yield after column
chromatography. The selectivity of the reduction was determined
by 1H NMR spectroscopy. For comparison purposes a 1:1
mixture of 38 and its 15R-diastereomer was prepared through
reduction of ketone 8a with NaBH4 in EtOH at -40 °C. The
use of wet EtOH as a quenching reagent in the reduction of
ketone 8a produced a partial desilylation of the silyl ether 38
with formation of diol 39 in 77% yield and 38 in 18% yield.
Desilylation of the disilyl ether 38 with diluted aqueous HCl in
THF also selectively afforded diol 39. Diol 39 was isolated in
93% overall yield based on 8a. To establish a carbonyl group
at C6 of 39 the diol was dibenzoylated and the corresponding
dibenzoate was deprotected at the silyloxy group through
treatment with NBu4F, which gave the alcohol 40 in 86% overall
yield, based on 38. Oxidation of alcohol 40 with DMSO,
a Reagents and conditions: (I) (a) 10b, n-BuLi, THF, -78 °C f rt; (b)
9a, THF, -19 °C. (II) Catecholborane, 37, CH2Cl2, -78 °C, HPLC. (III)
Acetone, TsOH, H2O, rt. (IV) t-BuMe2SiCl, imidazole, DMF, rt.
could serve as the starting material for a more concise synthesis
of diol 7a (Scheme 7). To this end, the two building blocks 9a
and 10b were coupled by following the same procedure used
in the synthesis of ketone 8a. Thus, the lithium acetylide derived
from 10b with 92% ee was treated with 1.15 equiv of amide
9a (g 99% ee) in THF at -19 °C, and the reaction mixture
was quenched with aqueous NH4Cl at this temperature. Thereby,
ketone 8b was obtained in 92% yield after chromatography.
As in the case of the synthesis of ketone 8a, the reaction
temperature had to be kept at -19 °C to avoid a partial
epimerization at C16 and, at the same time, to provide for a
sufficiently high reaction rate. According to 1H NMR spectros-
copy at higher temperatures the coupling step was accompanied
by a partial epimerization at C16.
88
(COCl)2 and NEt3 afforded ketone 41 in 89% yield. Finally,
The reduction of ketone 8b with catecholborane in the
presence of 9 mol % of 37 in toluene or CH2Cl2 at -78 °C
gave alcohol 42 with 95% de in regard to C15 in 98% yield.
Alcohol 42 contained 2.5% of its 15R-diastereomer and 4% of
the diastereomer having the opposite configurations at C8, C9,
C11, and C12 (Supporting Information, Scheme S12), which
arose from the use of alkyne 10b with 92% ee as starting
hydrolysis of dibenzoate 41 with 1 N NaOH in MeOH furnished
the dihydroxy ketone 7a18 in 90% yield. 1H NMR spectroscopy
of 8a, 40, and 41 revealed the admixture of approximately 3%
of the respective diastereomers, having the opposite configura-
tions at C6, C8, C9, C11, and C12 (Supporting Information,
Scheme S10), which are derived from ent-10a. This result shows
that the starting alkyne 10a had an ee-value of 94%. An
1
material. All three diastereomers were readily detected by H
1
unequivocal H NMR spectroscopic assignment of the minor
NMR spectroscopy. Preparative HPLC of 42 at a 5 g scale on
a Daicel Chiralcel OD column (250 × 20 mm) allowed for the
ready separation of the two minor diastereomers and gave
alcohol 42 as a single diastereomer (g 99% de) in 90% yield.
Treatment of acetal 42 with TsOH in acetone resulted in a
cleavage of all three protecting groups and afforded the
dihydroxy ketone 7a which upon silylation with t-BuMe2SiCl
furnished the disilyl ether 7b18 in 95% overall yield, based on
42.
Assignment of the Configuration at C15. Crucial to the
synthesis of cicaprost and isocicaprost was the determination
of the configuration of the alcohols 38 and 42. NMR spectros-
copy had revealed the identity of ketone 7a obtained by the
diastereomer of ketone 8a and thus of the minor diastereomers
of 38, 39, 40, 41, and 7a was made possible by the synthesis of
the enantiomer of the minor diastereomer of 8a through coupling
of alkyne 10a of 94% ee with the enantiomeric amide ent-9a
of g 99% ee (Supporting Information, Scheme S11).
Coupling of the C6-C14 Alkyne 10b With the C15-C21
Amide. In keeping with the strategy outlined in Figure 2, we
wanted to evaluate whether the acetal protected alkyne 10b
(87) (a) Mathre, 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. (b) Jones; T. K.; Mohan, J. J.; Xavier,
L. C.; Blacklock, T. J.; Mathre, D. J.; Sohar, P.; Jones, E. T. T.; Reamer,
R. A.; Roberts, F. E.; Grabowski, E. J. J. J. Org. Chem. 1991, 56, 763.
(88) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651.
9
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Synthesis of Cicaprost and Isocicaprost
A R T I C L E S
menthol to solve stereoselectivity problems of this type.18,37,50,51
We selected for the present case the dimethylphosphono acetate
derived from (1S,2R)-8-phenylnormenthol because of the ready
availability of this alcohol in enantiomerically pure form.89
Treatment of ketone 7b (g 99% de) with 4.5 equiv of the lithium
salt 4337 in THF first at -62 °C for 6 d, then at -30 °C for 15
h, and finally at room temperature for 30 min gave a mixture
of the diastereomeric esters E-6 and Z-6 in a ratio of 95:5 in
99% yield after aqueous work up and column chromatography.
Although the E- and Z-configured esters could be readily
separated by preparative HPLC (vide infra), the mixture of the
esters E-6 and Z-6 was reduced with DIBALH in THF to give
a 95:5 mixture of the allylic alcohols E-44 and Z-44.18
Separation of the allylic alcohols by column chromatography
or, more efficiently, by preparative HPLC afforded the allylic
alcohol E-44 in 84% total yield, based on E-6. 8-Phenylnor-
menthol was recovered in 86% yield. It is important to note
that during the separation of the allylic alcohols the minor
diastereomeric allylic alcohols resulting from the use of the
alkynes 10a and 10b with only 92% ee and 94% ee, respectively,
were also separated (Supporting Information, Scheme S13). The
E-configuration of the double bond of E-44 was secured by NOE
experiments, which revealed strong NOEs between 6a-H and
4-H and between 5-H and 7-H. The synthesis of cicaprost was
completed following the route previously described.18,20,37 Thus,
etherification of alcohol E-44 (g 99% de) through treatment
with excess BrCH2COOt-Bu under phase transfer conditions
in the presence of 50% aqueous NaOH and the subsequent
desilylation of the corresponding disilyl ether with Bu4NF gave
the dihydroxy ester 45 in 91% total yield, based on E-44. Finally,
the hydrolysis of ester 45 with NaOH in MeOH furnished
cicaprost (4) with g 99% de and g 99% ee in 94% yield.
Scheme 8. Attachment of the R-Side Chain to Ketone 7b via
Reaction with the Chiral Phosphate 43 (R ) Sit-BuMe2)a
Formal Asymmetric Synthesis of Isocicaprost. The syn-
thetic plan also called for a synthesis of isocicaprost (5) from
ester E-6 (Scheme 9). This first required a regioselective shift
of the double bond of E-6 with formation of the isomeric ester
47. On the basis of previous results with the isomerization of
an ester carrying a different ω-side chain, we envisioned a
regioselective deprotonation of ester E-6 with amide 12 resulting
in the selective formation of the lithium enolate 46 followed
by a regioselective protonation at the R-position.37 Deprotonation
of the E-configured ester E-6 (g 99% de) with 2 equiv of 12 in
THF at -105 °C gave the lithium enolate 46 whose protonation
with aqueous NaHCO3 at -78 °C afforded the â,γ-unsaturated
ester 47 with g 99% de (1H NMR) in 98% yield after
chromatography. Although a chiral base was used for the
deprotonation of E-6, previous results with the deprotonation
of a similar esters suggest that an achiral lithium amide could
be used as well.37,90,91 Deprotonation of R,â-unsaturated esters
including E-6 with lithium amides is perhaps an intramolecular
process following the coordination of the lithium amide to the
carbonyl O-atom of the ester group.92-94 Reduction of ester 47
with LiAlH4 in THF afforded alcohol 48 in an nonoptimized
yield of 59%. Since the conversion of alcohol 48 to isocicaprost
a Reagents and conditions: (I) THF, first 6 d, at -62 °C then 15 h at
-30 °C and finally 30 min at room temperature. (II) DIBALH, THF, 0 °C,
HPLC. (III) NBu4HSO4, 50%, NaOH, BrCH2COOtBu, CH2Cl2, rt. (IV)
NBu4F, THF, rt. (V) NaOH, MeOH, rt.
two different routes depicted in Schemes 6 and 7. Alcohols 38
and 42 were assigned the 15S-configuration in agreement with
the reduction of similar ynones with catecholborane/37 and on
the basis of its NMR data in comparison with those of a
reference sample.46-48
Attachment of the R-Side Chain and Completion of the
Synthesis of Cicaprost. Continuation of the synthetic plan
called for a diastereoselective conversion of ketone 7b to the
E-configured R,â-unsaturated ester E-6 (Scheme 8). Although
ketone 7b is chiral, the asymmetric induction it provides in
diastereoselective olefination reactions with achiral phosphono
acetates is low. Thus, the situation encountered in the olefination
of 7b may be compared to that of the enantioselective olefination
of the achiral ketones 11a and 11b. We and others had
previously introduced the dimethylphosphono acetates derived
from 8-phenylmenthol, 8-phenylneomenthol, and 8-phenylnor-
(89) Commins, D. L.; Salvador, J. M. J. Org. Chem. 1993, 58, 4656.
(90) Duhamel, L.; Ravard, A.; Plaquevent, J.-C. Tetrahedron: Asymmetry 1990,
1, 347.
(91) Brandt, U. Ph.D. Theses, RWTH Aachen 1997.
(92) Rathke, M. W.; Sullivan, D. Tetrahedron Lett. 1972, 4249.
(93) Herrmann, J. L.; Kieczykowski, R.; Schlessinger, R. H. Tetrahedron Lett.
1973, 2433.
(94) Harris, F. L.; Weiler, L. Tetrahedron Lett. 1984, 25, 1333.
9
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A R T I C L E S
Lerm et al.
general method.95 Whether the same holds true for the new
sulfoximine based conversion of an aldehyde to a terminal
alkyne, used in the synthesis of alkyne 10b from aldehyde 24,
remains to be shown.
Scheme 9. Formal Asymmetric Synthesis of Isocicaprost (R )
Sit-BuMe2)a
The ω-side chain building block 9a was synthesized by two
different routes. The first utilizes the chiral oxazolidinone
method for the generation of the stereogenic center of the target
molecule and the second relies on a malonate synthesis of the
racemate and a chromatographic resolution. In our view, the
malonate-resolution route to 9a, if combined with a racemization
of ent-9a, should offer some advantages over the asymmetric
synthesis because of the problems associated with the one
stereogenic center in R-position to the carbonyl group.
Experimental Section
General. All reactions were carried out under an argon atmosphere
in absolute solvents with syringe and Schlenk techniques in oven-dried
glassware. THF and Et2O were distilled under argon from lead/sodium
in the presence of benzophenone, and CH2Cl2 was distilled from CaH2.
Bulk solvents for column chromatography and extraction were distilled
prior to use. Reagents and DMF including catecholborane were obtained
from commercial sources and used without further purification unless
otherwise stated. n-BuLi was standardized by titration with dipheny-
lacetic acid. (R,R)-Bis-(phenylethyl)amine hydrochloride96 with g 99%
ee and (1S,2R)-8-phenylnormenthol89 with g98% ee were prepared
according to the literature. Oxazaborolidine 37 was prepared from (R)-
R,R-diphenyl-2-pyrrolidinemethanol and 0.33 equiv of pure n-butyl-
boroxine (NMR) in refluxing C6D6 (7 d) by using a Dean-Stark trap
whose sidearm contained activated molecular sieve.87 According to
NMR spectroscopy the thus prepared sample of 37 was free of the
starting materials. TLC was performed on E. Merck precoated plates
(silica gel 60 F254, layer thickness 0.2 mm), and column chromatography
was performed with E. Merck silica gel 60 (0.040-0.063 mm) in the
flash mode with a nitrogen pressure of 0.2 to 1.0 bar. HPLC was carried
out with a Dynamax SD-1 pump by using Varian 320 UV/VIS and
Knauer RI detectors. GC analyses were run on Varian 3800, Chrompack
CP-9000 and Carlo Erba Mega instruments. Melting points were
a Reagents and conditions: (I) THF, -105 °C. (II) Aqueous NaHCO3,
-78 °C. (III) LiAlH4, THF, -20 °C, HPLC.
(5) by the same procedure used for the synthesis of cicaprost
from alcohol E-44 had already been described,32 the attainment
of 48 represents a formal asymmetric synthesis of isocicaprost.
Conclusion
1
determined with a Bu¨chi 535 apparatus and are uncorrected. H and
13C NMR spectra were recorded on a Varian VXR 300, a Varian
Mercury 300, a Varian Inova 400 or a Varian Unity 500 instrument.
Chemical shifts are reported relative to TMS (δ 0.00 ppm) as internal
standard. The following abbreviations are used to designate the
multiplicity of the peaks in 1H NMR spectra: s ) singlet, d ) doublet,
t ) triplet, q ) quartet, m ) multiplet, br ) broad and combinations
thereof. Peaks in the 13C NMR spectra are denoted as “u” for carbons
with zero or two attached protons or as “d” for carbons with one or
three attached protons, as determined from the APT pulse sequence.
Assignments in the 1H NMR spectra were made by GMQCOSY,
GNOE, and HETCOR experiments and those in the 13C NMR spectra
were made by DEPT experiments. IR spectra were recorded on a Perkin-
Elmer PE 1759 FT instrument. Only peaks of ν > 1000 cm-1 are listed,
s ) strong, m ) medium, w ) weak. Low resolution mass spectra
were recorded on a Varian MAT 212 mass spectrometer using either
electron impact ionization (EI, 70 eV) or chemical ionization (CI, CH4,
isobutane or NH3). Only peaks of m/z >80 and an intensity >10%,
except decisive ones, are listed. High resolution mass spectra were
recorded either on a Varian MAT 95 mass spectrometer or on a
Micromass LCT Spectrometer (ESI, TOF). Optical rotations were
measured with a Perkin-Elmer model 241 polarimeter at approximately
22 °C. Specific rotations are in grad‚mL/dm‚g, and c is in g/100 mL.
Elemental analyses were performed by the Institut fu¨r Organische
Chemie Microanalytical Laboratory.
In this article, we report an asymmetric synthesis of cicaprost
from the achiral bicyclic ketones 11a (15 steps, 19% yield) and
11b (11 steps, 22% yield) and the amide 9a. Ketones 11a (3
steps, 70%) and 11b (2 steps 90%) are accessible from
commercially available bicyclo[3.3.0]octan-2,5-dione on large
scale. The same route leading to cicaprost also allowed diversion
of a late stage intermediate to achieve a formal asymmetric
synthesis of isocicaprost. The key step of these syntheses is the
coupling of a bicyclic C6-C14 building block carrying a C13-
C14 ethynyl group with a C15-C21 amide building block. It
is this step, which should also permit the synthesis of further
ω-side chain modified analogues of cicaprost and isocicaprost.
Because of the particular structures of the key intermediates,
chiral reagents had to be employed for the diastereoselective
reduction of the C15 carbonyl group and the diastereoselective
olefination of the C6 carbonyl group. This was accomplished
with high stereoselectivities by using the chiral oxazaborolidine/
borane and chiral phosphono acetate methods. In the course of
the asymmetric synthesis of alkyne 10a from the silyl enol ether
14, we have devised a new route for the introduction of an
ethynyl group at the R-position of a ketone with formation of
the corresponding homopropargylic alcohol. Preliminary results
with other ketones by using an acetal protection of the carbonyl
group give hope that this sequence can be developed into a
(95) Gais, H.-J.; Lerm, M., unpublished results.
(96) Overberger, C. G.; Marullo, N. P.; Hiskey, R. C. J. Am. Chem. Soc. 1961,
83, 1374.
9
9662 J. AM. CHEM. SOC. VOL. 125, NO. 32, 2003

Synthesis of Cicaprost and Isocicaprost
A R T I C L E S
(-)-(1S,3aS,6aS,5S)-5-(tert-Butyl-diphenyl-silanyloxy)-1-
(2,2,2-trichloro-1-hydroxy-ethyl)-hexahydro-pentalen-2-
one (15). To a solution of chloral (790 mg, 5.3 mmol) in CH2Cl2 (20
mL) was added TiCl4 (0.55 mL, 5.0 mmol) at ambient temperature,
and the mixture was stirred at ambient temperature for 5 min. Then
the mixture was cooled to -78 °C, and a solution of the silyl enol
ether 14 (1.8 g, 4.0 mmol) in CH2Cl2 (10 mL) was added dropwise.
After the mixture was stirred for 1 h at -78 °C, saturated aqueous
NaHCO3 (20 mL) was added and the mixture was warmed to ambient
temperature. The aqueous phase was separated and extracted with CH2-
Cl2 (2 × 20 mL). The combined organic phases were dried (MgSO4)
and concentrated in vacuo. Purification by column chromatography
(hexanes/EtOAc, 5:1) afforded ketone 15 (1.58 g, 75%) with g 98%
de as a colorless solid and 380 mg of a 7:3 mixture of 13-epi-15 and
ketone 11a.
H, CHOSi), 4.40 (d, J ) 6.0 Hz, 1 H, CHCCl3), 7.31-7.44 (m, 6 H,
Ph), 7.62-7.68 (m, 4 H, Ph); 13C NMR (75 MHz, CDCl3): δ 19.00
(u), 26.96 (d), 36.25 (d), 37.95 (d), 41.03 (u), 41.24 (u), 43.08 (u),
55.22 (d), 76.64 (d), 77.06 (d), 81.11 (d), 103.54 (u), 127.28 (d), 129.30
(d) 129.33 (d), 133.77 (u), 133.88 (u), 135.53 (d); IR (CHCl3): ν 3623
(w), 3444 (w), 3017 (s), 2929 (s), 2857 (m), 1223 (s), 1209 (s), 1107
(m), 1022 (m) cm-1; MS (CI, isobutane) m/z (relative intensity, %):
531 (34), 530 (33), 529 (100), 528 (36), 527 (M+ + H, 97), 495 (15),
493 (30), 491 (14), 456 (11), 99 (20). Anal. Calcd for C26H33Cl3O3Si
(527.98): C, 59.15; H, 6.30. Found: C, 58.81; H, 6.04.
(-)-(1S,2R,3aR,5S,6aS)-5-(tert-Butyl-diphenyl-silanyloxy)-1-ethy-
nyl-2-(triethyl-silanyloxy)-octahydro-pentalene (10a): To a solution
of mesylate 18 (450 mg, 0.59 mmol) in THF (4 mL) was added n-BuLi
(1.5 mL, 1.6 M in hexanes, 2.4 mmol) dropwise at -20 °C. After the
mixture was stirred at -20 °C for 20 min, it was warmed to ambient
temperature. Then the mixture was stirred for 60 min, and saturated
aqueous NaCl (0.25 mL) was added. The mixture was diluted with
Et2O (25 mL), dried (MgSO4) and concentrated in vacuo. Purification
by column chromatography (hexanes/Et2O, 1:25) afforded alkyne 10a
(281 mg, 90%) as a colorless oil. Rf 0.60 (hexanes/EtOAc, 10:1); [R]D
-11.4 (c 0.77, Et2O); 1H NMR (400 MHz, C6D6): δ 0.65-0.75 (dq, J
) 8.0, J ) 4.5 Hz, 6 H, SiCH2Me), 1.09 (t, J ) 8.0 Hz, 9 H, SiCH2Me),
1.18 (s, 9 H, t-Bu), 1.50-1.73 (m, 3 H), 1.79-1.95 (m, 3 H), 1.99-
2.11 (m, 2 H), 2.31 (m, 1 H), 3.07 (dt, J ) 8.5, J ) 2.5 Hz, 1 H,
CHCtCH), 4.07-4.14 (m, 1 H, CHOSiEt3), 4.19-4.26 (m, 1 H,
CHOSit-BuPh2), 7.21-7.25 (m, 6 H, Ph), 7.73-7.79 (m, 4 H, Ph).
13C NMR (100 MHz, C6D6): δ 5.37 (u), 7.18 (d), 19.28 (u), 27.14 (d),
37.40 (d), 40.89 (u), 42.33 (u), 42.64 (u), 46.27 (d), 46.95 (d), 69.53
(u), 77.19 (d), 79.76 (d), 87.04 (u), 127.74 (d), 129.66 (d), 129.70 (d),
134.28 (u), 134.47 (u), 136.02 (d); IR (neat): ν 3308 (m), 3070 (w),
3049 (w), 2955 (s), 2876 (s), 1461 (m), 1427 (m), 1374 (m), 1263 (w),
1239 (m), 1141 (s), 1113 (s), 1035 (s), 1017 (s) cm-1; MS (CI,
15: Rf 0.20 (hexanes/EtOAc, 5:1); mp 87 °C; [R]D -15.8 (c 1.25,
Et2O); 1H NMR (300 MHz, CDCl3): δ 1.03 (s, 9 H, t-Bu), 1.62 (m, 1
H), 1.85-2.05 (m, 3 H), 2.53-2.74 (m, 3 H), 3.24-3.34 (m, 2 H),
3.71 (d, J ) 5.2 Hz, 1 H, OH), 4.40 (m, 1 H, CHOSi), 4.77 (d, J ) 5.2
Hz, 1 H, CHOH), 7.32-7.45 (m, 6 H, Ph), 7.60-7.65 (m, 4 H, Ph);
13C NMR (75 MHz, CDCl3): δ 18.82 (u), 26.80 (d), 36.10 (d), 37.31
(d), 42.88 (u), 43.22 (u), 45.45 (u), 56.87 (d), 76.66 (d), 81.27 (d),
102.71 (u), 127.35 (d), 129.41 (d), 133.42 (u), 133.50 (u), 135.50 (d),
219.90 (u); IR (KBr): ν 3348 (s), 3071 (m), 3047 (m), 3012 (w), 2957
(s), 2932 (s), 2901 (m), 2857 (s), 1724 (s), 1471 (m), 1428 (m), 1386
(m), 1360 (w), 1309 (w), 1252 (w), 1177 (m), 1107 (s), 1020 (m) cm-1
;
MS (EI) m/z (relative intensity, %): 471 (M+ - HOCl, 37), 470 (28),
469 (100), 468 (27), 467 (95), 417 (14), 416 (18), 415 (64), 414 (28),
413 (99), 377 (22), 237 (11), 235 (57), 234 (10), 233 (81), 219 (16),
217 (42), 200 (15), 199 (84), 197 (39), 193 (10), 191 (14), 183 (16),
181 (31), 179 (18), 175 (11), 173 (17), 157 (22), 155 (25), 153 (17),
151 (13), 139 (14), 136 (11), 135 (23), 121 (11), 105 (23), 91 (11), 81
(26). Anal. Calcd for C26H31Cl3O3Si (525.97): C, 59.37; H, 5.94.
Found: C, 59.40; H, 5.80.
isobutane) m/z (relative intensity, %): 521 (22), 520 (48), 519 (M+
+
H, 100); MS (EI) m/z (relative intensity, %): 489 (M+ - Et, 7), 463
(4), 462 (11), 461 (28), 331 (13), 329 (15), 315 (11), 314 (29), 313
(100), 302 (11), 301 (39), 285 (11), 253 (39), 234 (10), 233 (49), 199
(25), 135 (14), 131 (43), 91 (16), 87 (11). Anal. Calcd for C32H46O2Si2
(518.88): C, 74.07; H, 8.94. Found: C, 73.91; H, 8.98.
13-epi-15: Rf 0.50 (hexanes/EtOAc, 5:1) (together with 11a) 1H
NMR (400 MHz, CDCl3) (partial data): δ 2.22-2.30 (m, 1 H), 2.70-
2.78 (m, 1 H), 3.19 (m, 1 H), 4.12 (dd, J ) 8.5, J ) 3.5 Hz, 1 H,
CHOH), 4.40 (m, 1 H, CHOSi), 5.18 (d, J ) 8.5 Hz, 1 H, OH); 13C
NMR (75 MHz, CDCl3): δ 19.06 (u), 27.07 (d), 35.56 (d), 41.34 (u),
43.01 (u), 45.02 (d), 45.78 (u), 54.73 (d); 76.87 (d), 84.42 (d), 102.90
(u), 127.73 (d), 129.82 (d), 133.67 (u), 133.73 (u), 135.80 (d), 135.85
(d), 219.93 (u)
(+)-(3a’S,4’S,5’R,6a’R)-[4’-Cyano-octahydro-5,5-dimethyl-spiro-
[1,3-dioxan-2,2(1’H)-pentalene]]-5-ol (22) and (+)-(3a’S,4’R,5’R,-
6a’R)-[4’-Cyano-octahydro-5,5-dimethyl-spiro[1,3-dioxan-2,2’(1’H)-
pentalen]]-5-ol (21): To a suspension of (R,R)-bis-(phenylethyl)amine
hydrochloride (1.2 g, 4.6 mmol) in THF (33 mL) was added n-BuLi
(5.4 mL of 1.6 M in hexanes, 8.6 mmol) at -78 °C. The mixture was
warmed to ambient temperature, whereby a clear yellow solution of
the lithium amide 12 was formed. Then the mixture was cooled to -105
°C and a solution of ketone 11b (780 mg, 3.5 mmol) in THF (10 mL)
was added within 10 min. After the stirring of the mixture for 60 min
at -105 °C, it was transferred into a -105 °C cold solution of TsCN
(1.3 g, 7.2 mmol) in THF (20 mL) by means of a double tipped ended
needle. After the mixture was stirred first for 20 min at -105 °C and
then for 80 min at -78 °C, EtOH (45 mL) and NaBH4 (800 mg, 21
mmol) were added. Then, the mixture was gradually warmed to -40
°C within 4 h. After the mixture was warmed to ambient temperature,
the solvents were removed in vacuo (HCN!). The solid residue was
dissolved in Et2O, and the solution was washed with aqueous NaHCO3.
The organic phase was dried (MgSO4) and concentrated in vacuo.
Purification by column chromatography (first hexanes/EtOAc, 4:1, then
hexanes/EtOAc, 1:2) or HPLC (Merck Lichrospher, 250 × 20 mm,
EtOAc, RI detector). afforded nitrile 22 (610 mg, 69%) with 92% ee
(GC: Chrompack Chirasil-Dex-CB (Beta I-CP), 25 m, tR (ent-22) )
32.01 min, tR (22) ) 32.33 min) and nitrile 21 (169 mg, 19%) as
colorless solids. Nitrile 21 was recrystallized from EtOAc (90%).
(1R,2R,3aR,5S,6aS)-5-(tert-Butyl-diphenyl-silanyloxy)-1-(2,2,2-
trichloro-1-hydroxy-ethyl)-octahydropentalen-2-ol (16): To a solu-
tion of chloral (14.4 g, 97.7 mmol) in CH2Cl2 (200 mL) was added
TiCl4 (9 mL, 82.1 mmol) at ambient temperature. After stirring the
mixture at ambient temperature for 5 min, it was cooled to -78 °C,
and a solution of the silyl enol ether 14 (10 g, 22.2 mmol) in CH2Cl2
(20 mL) was added within 2 min. After the mixture was stirred for 2
h at -78 °C, saturated aqueous NaHCO3 (200 mL) was added and the
mixture was warmed to ambient temperature. The mixture was filtered
through a pad of Celite and the residue was washed with Et2O (200
mL). The aqueous phase was extracted with Et2O (3 × 100 mL), and
the combined organic phases were dried (MgSO4) and concentrated in
vacuo. The residue containing 15 was dissolved in a 1:1 mixture of
Et2O/EtOH (500 mL) and the solution was cooled to -45 °C. Then
NaBH4 (6.1 g, 161 mmol) was added and the suspension was stirred
for 16 h at -45 °C. After the mixture was warmed to ambient
temperature, it was concentrated in vacuo and the residue was dissolved
in Et2O (400 mL). The solution was washed with water (300 mL), dried
(MgSO4) and concentrated in vacuo. Purification by column chroma-
tography (hexanes/EtOAc, 1:1) provided diol 16 (8.84 g, 75%) as a
colorless, sticky wax. Rf 0.45 (hexanes/EtOAc, 1:1); [R]D -19.8 (c
1
0.65, CDCl3); H NMR (300 MHz, CDCl3): δ 1.06 (s, 9 H, t-Bu),
Epimerization of Nitrile 21: A solution of nitrile 21 (2.0 g, 7.9
mmol) in THF (40 mL) was added dropwise to a solution of freshly
prepared LDA (22 mmol) in THF (50 mL) at -78 °C. After the mixture
1.58-1.90 (m, 5 H), 2.12-2.38 (m, 3 H), 2.50-2.65 (m, 2 H), 3.97
(d, J ) 6.0 Hz, 1 H, CH(OH)CCl3), 4.02 (m, 1 H, CHOH), 4.27 (m, 1
9
J. AM. CHEM. SOC. VOL. 125, NO. 32, 2003 9663

A R T I C L E S
Lerm et al.
was stirred for 60 min at this temperature, aqueous NaCl (10 mL) was
added, and the mixture was warmed to ambient temperature. The
organic phase was dried (MgSO4) and concentrated in vacuo to give a
mixture of nitriles 21, 22, and 26 in a ratio of 4.5:4.5:1 (GC: CP-Sil
8). HPLC (Merck Lichrospher, 250 × 20 mm, EtOAc, RI detector)
afforded nitrile 22 (740 mg, 37%) with g 99% ee (GC), nitrile 21
(720 mg, 36%) and nitrile 26 (93 mg, 5%).
organic phases were dried (MgSO4) and concentrated in vacuo to give
alcohol 28 as a 3:2 mixture of diastereomers. Alcohol 28 was dissolved
in THF (20 mL), and n-BuLi (1.6 M in hexanes, 0.68 mL, 1.1 mmol)
was added at -78 °C. After the mixture was stirred for 30 min at
-78°C, NEt3 (0.3 mL, 2.1 mmol) and MeSO2Cl (0.12 mL, 1.5 mmol)
were added. Then the mixture was stirred at -78 °C for 3 h.
Subsequently, DBU (0.3 mL, 2 mmol) was added, and the mixture
was warmed to ambient temperature. After the mixture was stirred for
12 h at ambient temperature, it was diluted with Et2O (50 mL) and
washed successively with aqueous NH4Cl, 10% aqueous Na2CO3 and
water. The organic phase was dried (MgSO4) and concentrated in vacuo.
Purification by column chromatography (hexanes/EtOAc, 1:2) afforded
the alkenyl sulfoximine 29 (495 mg, 95%) as a colorless solid. Mp
1
22: mp 95 °C; Rf 0.73 (EtOAc); [R]D +33.2 (c 2.65, CDCl3), H
NMR (400 MHz, C5D5N): δ 0.89 (s, 3 H), 0.91 (s, 3 H), 1.78 (m, 1
H), 2.00 (m, 2 H), 2.05-2.20 (m, 1 H), 2.31 (m, 1 H), 2.55 (m, 1 H),
2.75 (m, 1 H), 3.05 (t, J ) 6.6 Hz, 1 H, CHCN) 3.39 (s, 2 H), 3.43 (s,
2 H), 4.46 (m, 1 H, CHOH), 7.58 (brs, 1 H, OH);13C NMR (100 MHz,
C5D5N): δ ) 22.36 (d), 22.38 (d), 29.95 (u), 36.18 (d), 38.19 (u),
39.60 (u), 41.52 (u), 43.10 (d), 43.84 (d), 71.37 (u), 72.09 (u), 76.46
(d), 109.65 (u), 122.82 (u); IR (KBr): ν 3450 (s), 2958 (s), 2931 (s),
2911 (s), 2872 (s), 2241 (s), 1481 (s), 1451 (m), 1423 (s), 1397 (m),
1365 (m), 1355 (m), 1336 (m), 1318 (m), 1289 (m), 1265(s), 1247 (s),
1213 (m), 1185 (m), 1176 (m), 1141 (s), 1124 (s), 1106 (s), 1058 (s),
1050 (s), 1018 (s) cm-1; MS (EI, 70 eV) m/z (relative intensity %):
252 (7), 251 (M+, 47), 183 (59), 167 (20), 166 (24), 141 (10), 128
(100), 97 (10), 94 (15). Anal. Calcd for C14H21NO3 (251.32): C, 66.91;
H, 8.42; N, 5.57. Found: C, 66.64; H, 8.36; N 5.46.
1
88°C, Rf 0.3 (hexanes/EtOAc, 1:1); [R]D -4.5 (c 1.0, CHCl3); H
NMR (400 MHz, CDCl3): δ -0.28 (s, 3 H, SiMe), -0.12 (s, 3 H,
SiMe), 0.65 (s, 9 H, t-Bu), 0.91 (s, 3 H), 0.99 (s, 3 H), 1.44 (m, 1 H)
1.83 (m, 2 H), 2.09 (m, 3 H), 2.33 (m, 1 H), 2.45 (m, 2 H), 2.72 (s, 3
H, SO2Me), 3.45 (m, 4 H), 3.76 (m, 1 H, CHOSi), 6.52 (d, J ) 14.8
Hz, 1 H, HCdCHS), 6.76 (dd, J ) 14.8, J ) 9 Hz, 1 H, HCdCHS),
7.55 (m, 3 H), 7.88 (m, 2 H); 13C NMR (100 MHz, CDCl3): δ -5.15
(d), -4.68 (d), 17.17 (u), 22.36 (d), 22.56 (d), 25.52 (d), 29.38 (d),
29.98 (u), 35.34 (d), 37.08 (u), 41.05 (u), 41.69 (u), 42.77 (d), 56.69
(d), 71.78 (u), 71.96 (u), 77.92 (d), 109.65 (u), 128.58 (d), 129.07 (d),
130.42 (d), 132.26 (d), 138.87 (u), 147.96 (d); IR (KBr): ν 3060 (w),
2954 (s), 2891 (s), 2856 (s), 2801 (m), 1634 (m), 1472 (s), 1446 (m),
1392 (m), 1360 (w), 1360 (w), 1329 (m), 1313 (w), 1250 (s), 1184
(w), 1116 (s), 1080 (s), 1063 (m), 1038 (m), 1014 (m) cm-1; MS (EI,
70 eV) m/z (%): 519 (M+, 5), 464 (13), 463 (33), 462 (100), 221 (11),
212 (14). Anal. Calcd for C28H45NO4SSi (519.81): C, 64.70; H, 8.73;
N 2.69. Found: C, 64.38; H, 8.80; N 2.62.
1
21: Mp 150 °C; Rf 0.63 (EtOAc); [R]D +11.1 (c 3.1, CDCl3); H
NMR (400 MHz, C5D5N): δ 0.87 (s, 3 H), 0.95 (s, 3 H), 1.93 (m, 2
H), 2.19 (m, 1 H), 2.50-2.75 (m, 4 H), 2.89 (m, 1 H), 3.16 (t, J ) 4.7
Hz, 1 H, CHCN), 3.40-3.55 (m, 4 H), 4.63 (m, 1 H, CHOH), 7.23
(brs, 1 H, OH); 13C NMR (100 MHz, C5D5N): δ ) 22.32 (d), 22.56
(d), 30.06 (u), 37.38 (u), 38.90 (d), 40.42 (u), 40.80 (d), 41.87 (d),
41.91 (u), 70.90 (u), 72.88 (u), 75.57 (d), 109.39 (u), 120.36 (u).
1
26: H NMR (400 MHz, CDCl3): δ 0.90 (s, 3 H), 1.03 (s, 3 H),
1.64 (m, 1 H), 2.02 (m, 1 H), 2.23-2.40 (m, 3 H), 2.73-2.93 (m, 2
H), 3.35-3.54 (m, 5 H), 6.50 (q, J ) 2.0 Hz, CHdCCN); 13C NMR
(100 MHz, CDCl3) 22.29 (d), 22.54 (d), 30.01 (u), 35.83 (u), 37.42
(d), 40.36 (u), 42.27 (u), 49.40 (d), 71.92 (u), 72.25 (u), 108.33 (u),
116.50 (u), 118.01 (u), 146.99 (d).
(-)-(3aS,4S,5R,6aR)-5-(tert-Butyl-dimethyl-silyloxy)-[4-ethynyl-
octahydro-5,5-dimethyl-spiro[1,3-dioxan-2,2’(1’H)-pentalene] (10b):
The alkenyl sulfoximine 29 (520 mg, 1 mmol) and Me3OBF4 (192 mg,
1.3 mmol) were placed in a Schlenk flask. The flask was evacuated
and refilled with dry argon (3 times). Then CH2Cl2 (30 mL) was added,
and the mixture was stirred at ambient temperature for 60 min.
Subsequently, water (10 mL) was added, and the mixture was stirred
for 15 min. Then, the mixture was extracted with CH2Cl2 (30 mL),
and the combined organic phases were dried (MgSO4) and concentrated
in vacuo. The thus obtained salt 30 was dried in vacuo (10-3 mbar) for
3 h and subsequently dissolved in THF (50 mL). The solution was
cooled to -78 °C and treated with LiN(H)t-Bu, which was freshly
prepared from t-BuNH2 (0.21 mL, 2 mmol) and n-BuLi (1.6 M in
hexanes, 1.25 mL, 2 mmol) in THF (2 mL). After the mixture was
stirred first for 30 min at -78 °C and then for 15 h at ambient
temperature, aqueous NaHCO3 (25 mL) was added and stirring was
continued for 10 min. The mixture was extracted with Et2O (100 mL),
and the combined organic phases were dried (MgSO4) and concentrated
in vacuo. Purification by column chromatography (hexanes/EtOAc, 9:1)
gave alkyne 10b (320 mg, 89%) with 92% ee (GC: Macherey-Nagel
Lipodex-C, 25 m, tR (ent-10b) ) 193.07 min, tR (10b) ) 195.30 min)
as a colorless oil. Rf 0.59 (hexanes/EtOAc, 3:1); [R]D -1.5 (c 5.4,
(3aS,4R,5R,6aR)-5-(tert-Butyl-dimethyl-silyloxy)-[octahydro-5,5-
dimethyl-spiro[1,3-dioxan-2,2’(1’H)-pentalen]]-4-carbaldehyde (25):
To a solution of nitrile 23 (1.0 g, 2.7 mmol) in toluene (20 mL) was
added DIBALH (1 M in hexanes, 4.0 mmol, 4 mL) at -78 °C. After
the mixture was stirred for 3 h at -78 °C, it was warmed to ambient
temperature and a 1:1 mixture of EtOH/H2O (4 mL) was added. Then
the mixture was diluted with Et2O (50 mL) and treated with aqueous
NH4Cl (50 mL). The organic phase was dried (MgSO4) and concentrated
in vacuo. Purification by column chromatography afforded aldehyde
25 (860 mg, 85%) as a colorless oil: Rf 0.62 (hexanes/EtOAc, 3:1);
1H NMR (400 MHz, [D8]-THF): δ 0.03 (s, 3 H), 0.05 (s, 3 H), 0.87
(s, 9 H, t-Bu), 0.90 (s, 3 H), 0.93 (s, 3 H), 1.56 (m, 1 H), 1.84 (m, 2
H), 2.07 (m, 3 H), 2.44 (m, 1 H), 2.60 (m, 2 H), 3.41 (d, J ) 2.8 Hz,
2 H), 3.44 (s, 2 H), 4.29 (m, 1 H, CHOSi), 9.62 (d, J ) 2.2 Hz, 1 H,
CHO); 13C NMR (100 MHz, [D8]-THF): δ -4.86 (d), -4.50 (d), 18.31
(u), 22.56 (d), 22.65 (d), 25.97 (d), 30.36 (u), 37.14 (d), 38.83 (d),
39.03 (u), 40.59 (u), 42.39 (u), 66.88 (d), 72.08 (u), 72.16 (u), 75.79
(d), 110.11 (u), 201.74 (d).
1
CDCl3); H NMR (500 MHz, C6D6): δ 0.12 (s, 3 H), 0.19 (s, 3 H),
0.64 (s, 3 H), 0.82 (s, 3 H), 1.01 (s, 9 H), 1.53 (m, 1 H), 1.80 (dd, J
) 5.0, J ) 13.0 Hz, 1 H), 1.95 (d, J ) 2.5 Hz, 1 H, CtCH), 1.96-
2.07 (m, 4 H), 2.28 (m, 1 H), 2.50 (m, 1 H), 2.68 (dt, J ) 2.5, J ) 8.8
Hz 1 H, CHCtCH), 3.09-3.17 (m, 2 H), 3.22 (s, 2 H), 4.02 (m, 1 H,
CHOSi); 13C NMR (100 MHz, C6D6): δ -4.53 (d), -4.27 (d), 18.30
(u), 22.26 (d), 22.56 (d), 26.04 (d), 29.80 (u), 35.70 (d), 37.58 (u),
41.30 (u), 41.67 (u), 45.35 (d), 45.51(d), 69.79 (u), 71.50 (u), 71.92
(u), 79.60 (d), 86.72 (u), 109.74 (u); IR (neat): ν 3311 (s), 2955 (s),
2886 (s), 2857 (s), 2738 (s), 2708 (s), 2280 (w), 2115 (w), 1472 (s),
1464 (s), 1435 (m), 1395 (s), 1362 (s), 1352 (s), 1330 (s), 1312 (m),
1284 (m), 1256 (s), 1221 (s), 1210 (m), 1190 (m), 1171 (s), 1118 (s),
1049 (s), 1019 (s), 1007 (s) cm-1; MS (EI, 70 eV) m/z (relative
intensity, %): 364 (M+, 6), 308 (19), 307 (80), 222 (18), 221 (100),
(-)-(3a’S,4’S,5’R,6a’R)-5’-(tert-Butyl-dimethyl-silanyloxy)-
[4’-(2-((RS,E)-N-methyl-S-phenyl-sulfonimidoyl)-ethenyl)-octahydro-
5,5-dimethyl-spiro[1,3-dioxan-2,2’(1’H)-pentalene]] (29): To a solu-
tion of (R)-N,S-dimethyl-S-phenylsulfoximine (169 mg, 1 mmol) in THF
(10 mL) was added n-BuLi (1.6 M in hexanes, 0.69 mL, 1.1 mmol) at
-78 °C. After the mixture was stirred for 30 min at -78 °C, it was
warmed to ambient temperature over a period of 30 min to ensure
complete formation of salt 27. Subsequently the mixture was cooled
to -78 °C and a solution of aldehyde 25 (368 mg, 1 mmol) in THF (2
mL) was added. After the mixture was stirred for 2 h at -78 °C, it
was warmed to ambient temperature over a period of 12 h. Then
aqueous NH4Cl (10 mL) was added, and the aqueous phase was
separated and extracted with EtOAc (50 mL). The combined
9
9664 J. AM. CHEM. SOC. VOL. 125, NO. 32, 2003

Synthesis of Cicaprost and Isocicaprost
A R T I C L E S
1
203 (46), 179 (18), 178 (89), 128 (15), 105 (12). Anal. Calcd for
C21H36O3Si (364.59): C, 69.18; H, 9.95. Found: C, 69.11; H, 9.97.
0.8, THF); H NMR (300 MHz, C6D6): δ 1.00 (t, J ) 7.4 Hz, 3 H,
CtCCH2Me); 1.19 (s, 9 H, t-Bu); 1.29 (d, J ) 6.6 Hz, 3 H, CHMe);
1.55-1.64 (m, 2 H); 1.66-1.88 (m, 3 H), 1.94-2.14 (m, 4 H), 2.16-
2.30 (m, 2 H), 2.34-2.55 (m, 2 H), 3.04 (dt, J ) 9.1, J ) 1.2 Hz, 1
H, CHMe); 3.75 (d, J ) 4.2 Hz, 1 H, CtCCHOH), 3.97 (d, J ) 1.5
Hz, 1 H, CHOH-CHCtCCHOH), 4.00-4.15 (m, 1 H, CHOH-CHCt
C), 4.17-4.26 (m, 1 H, CHOSit-BuPh2), 4.54 (m, 1H, CtCCHOH),
7.22-7.32 (m, 6 H), 7.74-7.80 (m, 4 H); 13C NMR (100 MHz,
C6D6): δ 12.80 (u), 14.53 (d), 15.49 (d), 19.29 (u), 22.70 (u), 27.22
(d), 37.08 (d), 40.11 (d), 40.65 (u), 41.24 (u), 42.58 (u), 46.52 (d),
66.26 (d), 77.46 (d), 78.01 (u), 79.45 (d), 81.62 (u), 83.27 (u), 88.57
(u), 128.00 (d), 129.90 (d), 129.94 (d), 134.49 (u), 134.54 (u), 136.20
(d); MS (CI, isobutane) m/z (relative intensity, %): 529 (M+ + H, 3),
511 (3); 493 (13); 405 (10), 125 (100). HRMS calcd for C30H35O3Si+
(M+ - t-Bu) 471.23554, found 471.23568.
HPLC Separation of rac-9a: Preparative HPLC (Ciralcel AD, 250
× 50 mm, i-PrOH/hexanes 5:95, UV: 254 nm, flow 30 mL/min, 750
mg of racemate per injection) of rac-9a (4.2 g) gave 9a (2.0 g, 47%)
and ent-9a (2.0 g, 47%) each with g 99% ee (GC). 9a: [R]D +15.5 (c
4.5, CDCl3); ent-9a: [R]D -15.5 (c 4.5, CDCl3).
(1S,2R,3aR,5S,6aS)-1-[5-(tert-Butyl-diphenyl-silanyloxy)-2-(triethyl-
silanyloxy)-octahydro-pentalen-1-yl]-(4S)-methyl-nona-1,6-diyn-3-
one (8a): To a solution of alkyne 10a (1.0 g, 1.9 mmol) in THF (10
mL) was added n-BuLi (1.6 M in hexanes, 1.2 mL, 1.9 mmol) at -78
°C. The mixture was warmed to ambient temperature for 10 min, cooled
to -78 °C and then transferred to a -19 °C cold stirred solution of
amide 9a (560 mg, 3.1 mmol) in THF (10 mL) by means of a double-
tipped ended needle. After the mixture was stirred for 3 h at -19 °C,
saturated aqueous NH4Cl (2 mL) and water (5 mL) were added.
Subsequently, the mixture was warmed to ambient temperature, and
the aqueous phase was separated and extracted with Et2O (3 × 30 mL).
The combined organic phases were dried (MgSO4) and concentrated
in vacuo. Purification by column chromatography (hexanes/ Et2O, 20:
1) afforded ketone 8a (1.13 g, 92%) with 94% de (1H NMR: δ (CH2Me)
0.960, δ (CHMe) 1.266 (8a); δ (CH2Me) 0.958, δ (CHMe) 1.275 (8a’))
and alkyne 10a (80 mg, 8%). Rf 0.53 (hexanes/EtOAc, 5:1); [R]D -25.0
(+)-(3aS,4S,5R,6aS)-5-Hydroxy-4-((3S)-hydroxy-4(S)-methyl-
nona-1,6-diynyl)-hexahydro-pentalen-2-on (7a): To a solution of
diester 41 (170 mg, 0.34 mmol) in MeOH (2.5 mL) was added aqueous
NaOH (1 M, 1 mL, 1.0 mmol). After the mixture was stirred at ambient
temperature for 3 h, TLC showed a complete conversion of the diester.
The mixture was diluted with Et2O (20 mL) and washed with NaOH
(1 M, 5 mL). The organic phase was dried (MgSO4) and concentrated
in vacuo. Purification by column chromatography (Et2O/hexanes/
MeOH, 20:10:1) afforded diol 7a (90 mg, 90%) as a colorless oil. Rf
1
(c 0.92, Et2O); H NMR (500 MHz, C6D6): δ 0.61-0.72 (m, 6 H,
1
0.5 (EtOAc); [R]D +38.0 (c 1.75, Et2O); H NMR (400 MHz, C6D6):
SiCH2Me), 0.96 (t, J ) 7.4 Hz, 3 H, CtCCH2Me), 1.08 (t, J ) 7.9
Hz, 9 H, SiCH2Me), 1.17 (s, 9 H, t-Bu), 1.27 (d, J ) 6.8 Hz, 3 H,
CHMe), 1.46-1.61 (m, 3 H), 1.79-1.89 (m, 2 H), 1.94-2.06 (m, 4
H), 2.19-2.27 (m, 1 H), 2.38-2.44 (m, 1 H), 2.61-2.69 (m, 2 H),
3.21 (t, J ) 8.8 Hz, 1 H, COSiEt3-CHCtC), 4.02-4.08 (m, 1 H,
CHOSiEt3), 4.20-4.25 (m, 1 H, CHOSit-BuPh2), 7.23-7.27 (m, 6 H),
7.73-7.77 (m, 4 H). 13C NMR (75 MHz, C6D6): δ 5.29 (u), 7.13 (d),
12.72 (u), 14.39 (d), 15.59 (d), 19.28 (u), 22.50 (u), 27.18 (d), 37.69
(d), 40.67 (u), 42.22 (u), 42.95 (u), 46.56 (d), 46.66 (d), 48.30 (d),
76.81 (u), 77.35 (d), 79.38 (d), 81.21 (u), 83.66 (u), 96.78 (u), 128.00
(d), 129.97 (d), 130.03 (d), 134.35 (u), 134.46 (u), 136.22 (d), 188.59
(u); IR (neat): ν 3070 (w), 3048 (w), 2956 (s), 2876 (s), 2203 (s),
1674 (s), 1459 (m), 1427 (m), 1374 (m), 1321 (w), 1264 (w), 1239
(m), 1175 (m), 1140 (s), 1113 (s), 1064 (m), 1019 (s) cm-1; MS (EI,
70 eV) m/z (relative intensity, %): 640 (M+, 0.7), 612 (24), 611 (48),
593 (11), 585 (19), 584 (52), 583 (100), 506 (10), 505 (22), 451 (13),
451 (14), 427 (14), 365 (16), 355 (54), 337 (24), 313 (21), 254 (11),
253 (48), 199 (41), 197 (20), 195 (12), 183 (17), 181 (12), 135 (22),
129 (10), 115 (11), 87 (25). Anal. Calcd for C40H56O3Si2 (641.04): C,
74.94; H, 8.81. Found: C, 75.04; H, 9.14.
δ 1.02 (t, J ) 7.4 Hz, 3 H, CtCCH2Me), 1.29 (d, J ) 6.6 Hz, 3 H,
CHMe), 1.36-1.44 (m, 1 H), 1.93-2.53 (m, 13 H), 3.42 (d, J ) 5.2
Hz, 1 H, CtCCHOH), 3.52 (d, J ) 6.1 Hz, 1 H, CHOH-CHCtC),
4.12-4.17 (m, 1 H, CHOH-CHCtC), 4.54 (m, 1 H, CtCCHOH).
13C NMR (100 MHz, C6D6): δ 12.79 (u), 14.52 (d), 15.46 (d), 22.72
(u), 35.64 (d), 40.09 (d), 41.20 (u), 43.34 (u), 44.88 (d), 45.44 (u),
46.29 (d), 65.99 (d), 77.70 (u), 79.06 (d), 82.50 (u), 83.41 (u), 86.87
(u), 218.52 (u). IR (neat) ν 3397 (s), 2969 (s), 2933 (s), 1732 (s), 1455
(m), 1403 (m), 1322 (w), 1284 (w), 1249 (w), 1171 (w), 1117 (w),
1091 (w), 1023 (m); MS (CI, isobutane) m/z (relative intensity, %):
289 (M+ + H, 10), 273 (9), 272 (21), 271 (100), 253 (19). Anal. Calcd
for C18H24O3 (288.38): C, 74.97; H, 8.39. Found: C, 74.84; H, 8.76.
(-)-(3a’S,4’S,5’R,6a’R)-5’-[(tert-Butyl-dimethyl-silanyloxy)]-[(4’-
(3-oxo-4S-methyl-nona-1,6-diynyl)-octahydro-5,5-dimethyl-spiro-
[1,3-dioxan-2,2’(1’H)-pentalene]] (8b): To a solution of alkyne 10b
(1.5 g, 4.1 mmol) (92% ee) in THF (20 mL) was added n-BuLi (1.6 M
in hexanes, 2.55 mL, 4.1 mmol) at -78 °C. The mixture was warmed
to ambient temperature for 10 min and then cooled to - 78 °C. Then,
the mixture was added to a -19 °C cold solution of amide 9a (890
mg, 4.8 mmol, g99% ee) in THF (10 mL) by means of a double tipped
ended needle. After the mixture was stirred for 40 min at -19 °C,
aqueous NH4Cl (10 mL) was added, and the mixture was warmed to
ambient temperature. Water was added until two clear phases were
formed. The aqueous phase was separated and extracted with Et2O (3
× 20 mL). The combined organic phases were dried (MgSO4) and
concentrated in vacuo. Column chromatography (hexanes/EtOAc, 5:1)
afforded ketone 8b (1.8 g, 90%) with 92% de (1H NMR: δ (CH2Me)
0.960, δ (CHMe) 1.266 (8b); δ (CH2Me) 0.958, δ (CHMe) 1.275 (8b’)
and alkyne 10b (120 mg, 0.24 mmol, 8%) both as colorless oils. Rf
(+)-(1S,2R,3aR,5S,6aS)-1-[5-(tert-Butyl-diphenyl-silanyloxy)-
2-hydroxy-octa-hydro-pentalen-1-yl]-4(S)-methyl-nona-1,6-diyn-
3(S)-ol (39): To a solution of ketone 8a (750 mg, 1.16 mmol) in CH2-
Cl2 (15 mL) was added oxazaborolidine 37 (0.86 M solution in C6D6,
0.3 mL, 0.25 mmol). The mixture was cooled to -78 °C, and
catecholborane (0.5 mL, 4.7 mmol, diluted with 0.5 mL CH2Cl2) was
added within 5 min. After the mixture was stirred for 16 h at -78 °C,
EtOH (1 mL) was added, and the mixture was warmed to ambient
temperature and concentrated in vacuo. Column chromatography first
with hexanes/Et2O, 1:1, afforded the silyl ether 38 (140 mg, 18%) and
then with CH2Cl2/EtOH, 1:1, gave diol 39 admixed with catechol. The
mixture of 39 and catechol was dissolved in Et2O (50 mL) and the
solution was washed with NaOH (2 N, 50 mL). The organic phase
was dried (MgSO4) and concentrated in vacuo. Purification by column
chromatography (CH2Cl2/Et2O, 1:1) afforded diol 39 (480 mg, 77%)
as a colorless oil. The silyl ether 38 was dissolved in THF (2 mL) and
diluted aqueous HCl (0.5 mL) was added. After the mixture was stirred
for 1 h at ambient temperature, it was neutralized with NaOH and
extracted with Et2O (15 mL). The organic phase was dried (MgSO4)
and concentrated in vacuo. Purification by column chromatography
(CH2Cl2/Et2O, 1:1) afforded diol 39 (99 mg, 16%) as a colorless oil.
The total yield of diol 39 was 93%. Rf 0.64 (EtOAc); [R]D +9.2 (c
1
0.59 (hexanes/EtOAc, 3:1); [R]D -2.2 (c 2.3, CDCl3); H NMR (400
MHz, C6D6): δ 0.09 (s, 3 H, SiMe), 0.16 (s, 3 H, SiMe), 0.68 (s, 3 H),
0.80 (s, 3 H), 0.96 (t, J ) 7.4 Hz, 3 H, CtCCH2Me), 0.98 (s, 9 H,
t-Bu), 1.26 (d, J ) 6.8 Hz, 3 H, CHMe), 1.44-1.54 (m, 1 H), 1.80
(dd, J ) 13.4, J ) 4.9 Hz, 1 H), 1.90-2.01 (m, 6 H), 2.18-2.30 (m,
1 H), 2.36-2.46 (m, 2 H), 2.59-2.71 (m, 2 H), 2.79 (t, J ) 9.0 Hz, 1
H, CH-CtCCO), 3.13 (m, 2 H), 3.22 (s, 2 H), 3.98 (m, 1 H,
CHOSi);13C NMR (100 MHz, C6D6): δ -4.53 (d), -4.48 (d), 12.67
(u), 14.35 (d), 15.57 (d), 18.17 (u), 22.28 (d), 22.44 (d), 22.48 (u),
25.95 (d), 29.83 (u), 35.85 (d), 37.78 (u), 40.73 (u), 41.87 (u), 44.97
(d), 45.59 (d), 48.18 (d), 71.47 (u), 72.03 (u), 76.61 (u), 79.08 (d),
81.23 (u), 83.57 (u), 96.07 (u), 109.62 (u), 188.22 (u). IR (neat): ν
9
J. AM. CHEM. SOC. VOL. 125, NO. 32, 2003 9665

A R T I C L E S
Lerm et al.
2954 (s), 2857 (s), 2204 (s), 1674 (s), 1472 (m), 1462 (m), 1434 (m),
1394 (m), 1376 (m), 1361 (m), 1351 (m), 1330 (m), 1253 (s), 1221
(m, 5 H); 13C NMR (100 MHz, C6D6): δ -4.86 (d), -4.45 (d), 4.38
(d), 3.99 (d), 12.78 (u), 14.56 (d), 15.56 (d), 18.21 (u), 18.45 (u), 22.51
(u), 24.93 (u), 25.49 (d), 26.02 (d), 26.06 (d), 26.24 (u), 27.31 (u),
27.82 (d), 34.07 (u), 38.92 (u), 39.33 (d), 40.03 (u), 40.48 (u), 40.79
(d), 42.39 (u), 45.68 (d), 46.90 (d), 51.38 (d), 66.85 (d), 73.39 (d),
77.72 (u), 79.42 (d), 82.08 (u), 83.15 (u), 87.29 (u), 114.27 (d), 124.98
(d), 125.66 (d), 128.13 (d), 151.64 (u), 164.89 (u), 165.09 (u); IR
(neat): ν 3021 (w), 2931 (s), 2857 (s), 1708 (s), 1659 (m), 1496 (w),
1468 (m), 1374 (m), 1323 (w), 1253 (s), 1213 (s), 1188 (m), 1128 (s),
1074 (s), 1030 (m), 1006 (m) cm-1; MS (CI, isobutane) m/z (relative
intensity, %): 761 (12), 760 (M+ + H, 22), 759 (37), 629 (25), 628
(34), 627 (74), 497 (12), 495 (11), 428 (11), 428 (27), 427 (88), 295
(26), 202 (11), 201 (72), 200 (15), 199 (51), 175 (12), 134 (12), 133
(100), 123 (56), 119 (56), 105 (10). Anal. Calcd for C47H74O4Si2
(759.26): C, 74.35; H, 9.82. Found: C, 74.36; H, 9.91.
(m), 1175 (m), 1139 (s), 1118 (s), 1048 (m), 1020 (m), 1001 (m) cm-1
;
+
MS (CI, isobutane) m/z (relative intensity, %): 488 (36), 487 (M+
H, 100), 429 (13), 355 (21). Anal. Calcd for C29H46O4Si (486.76): C,
71.56; H, 9.53. Found: C, 71.75; H, 9.75.
(-)-(3a’S,4’S,5’R,6a’R)-5’-(tert-Butyl-dimethyl-silanyloxy)-[(4’-
(3S-hydroxy-4S-methyl-nona-1,6-diynyl)-octahydro-5,5-dimethyl-
spiro[1,3-dioxan-2,2’(1’ H)-pentalene]] (42): To a solution of ketone
8b (1.57 g, 3.23 mmol) in CH2Cl2 (20 mL) was added oxazaborolidine
37 (0.86 M solution in C6D6, 0.35 mL, 0.3 mmol). The mixture was
cooled to -78 °C and a solution of catecholborane (0.95 mL, 8.9 mmol)
in CH2Cl2 (5 mL) was added within 60 min by means of a syringe
pump. After the mixture was stirred for 4.5 h at -78 °C, MeOH (15
mL) was added at this temperature and the mixture was warmed to
ambient temperature and kept at this temperature for 12 h. Concentration
in vacuo and purification by column chromatography (hexanes/EtOAc,
3:1) gave alcohol 42 (1.55 g, 98%) with 92% de (1H NMR: δ (CH2CH3)
1.24 (42); δ (CH2CH3) 1.17 (42’)) colorless oil. HPLC (Daicel Chiralcel
OD 250 × 20 mm, EtOH/hexanes 1:99, RI-detector, flow 6 mL/min,
40 mg per injection) afforded alcohol 42 (1.39 g, 90%) with g 99%
de. Rf 0.43 (hexanes/EtOAc, 3:1); [R]D +20.6 (c 1.26, CDCl3), 1H NMR
(400 MHz, C6D6): δ 0.13 (s, 3 H, SiMe), 0.19 (s, 3 H, SiMe), 0.69 (s,
3 H), 0.82 (s, 3 H), 0.98 (t, J ) 7.4 Hz, 3 H, CtCCH2Me), 1.02 (s, 9
H, t-Bu), 1.24 (d, J ) 6.8 Hz, 3 H, CHMe), 1.50-1.60 (m, 1 H), 1.83
(dd, J ) 13.1, J ) 5.3 Hz, 1 H), 1.90 (d, J ) 5.7 Hz, 1 H, CtCCHOH),
1.95-2.18 (m, 7 H), 2.30-2.55 (m, 4 H), 2.75 (dt, J ) 8.8, J ) 1.5
Hz, 1 H, CH-CtC), 3.14-3.22 (m, 2 H), 3.26 (s, 2 H), 4.02 (m, 1 H,
CHOSi), 4.46 (dt, J ) 6.0, J ) 1.6 Hz,1 H, CtCCHOH). 13C NMR
(100 MHz, C6D6): δ -4.43 (d), -4.31 (d), 12.74 (u), 14.49 (d), 15.49
(d), 18.29 (u), 22.32 (d), 22.53 (d), 22.58 (u), 26.05 (d), 29.85 (u),
35.94 (d), 38.18 (u), 39.98 (d), 41.04 (u), 41.72 (u), 45.69 (d), 45.79
(d), 66.14 (d), 71.65 (u), 71.94 (u), 77.78 (u), 79.76 (d), 81.65 (u),
83.12 (u), 88.33 (u), 109.88 (u); IR (neat): ν 3452 (m), 2954 (s), 2857
(s), 1470 (m), 1435 (w), 1393 (w), 1377 (w), 1362 (w), 1329 (m), 1254
(s), 1118 (s), 1019 (m) cm-1; MS (CI, isobutane) m/z (relative intensity,
%): 491 (13), 490 (14), 489 (M+ + H, 100), 487 (12), 473 (18), 472
(29), 471 (84), 369 (17), 341 (12), 340 (16), 339 (71). Anal. Calcd for
C29H48O4Si (488.77): C, 71.26; H, 9.90. Found: C, 71.14; H, 10.09.
(+)-[(2E)-2-[(3aS,4S,5R,6aS)-Hexahydro-5-hydroxy-4-[(3S,4S)-3-
hydroxy-4-methyl-1,6-nonadiynyl]-2(1H)-pentalenylidene]ethoxy-
acetic acid (4): To a solution of ester 45 (220 mg, 0.15 mmol) in MeOH
(8 mL) was added 1 N NaOH (3 mL, 3 mmol), and the mixture was
stirred for 5 h at ambient temperature. Then water (20 mL) was added
to the mixture and its pH value was adjusted first to 5 through addition
of solid NaH2PO4 and then to 2 through addition of aqueous 1 N HCl.
The solution was extracted with Et2O (6 × 30 mL), and the combined
organic phases were dried (MgSO4) and concentrated in vacuo. Drying
of the residue in vacuo (10-3 mbar) afforded cicaprost (4) (180 mg,
94%) with g 99% de as a colorless oil. [R]D +92.0 (c 4.15, CDCl3);
1H NMR (400 MHz, CD2Cl2): δ 1.07 (d, J ) 6.8 Hz, 3 H, CHMe),
1.11 (t, J ) 7.4 Hz, 3 H, CtCCH2Me), 1.14-1.23 (m, 1 H), 1.81-
1.90 (m, 1 H, CHMe), 2.10-2.56 (m, 12 H), 3.92-4.00 (m, 1 H,
CHOH-CHCtC), 4.02-4.16 (m, 4 H, CH2OCH2), 4.36 (dd, J ) 6.4,
J ) 1.7 Hz, 1 H, CtCCHOH), 5.50 (m, 1 H, CdCH), 6.00-6.15 (brs,
3 H, 3 × OH); 13C NMR (100 MHz, CD2Cl2): δ 12.75 (u), 14.58 (d),
15.19 (d), 22.46 (u), 35.88 (u), 37.84 (d), 39.07 (u), 39.79 (d), 41.08
(u), 44.99 (d), 46.38 (d), 66.17 (d), 66.55 (u), 68.89 (u), 77.42 (u),
78.16 (d), 81.11 (u), 83.44 (u), 87.62 (u), 117.92 (d), 148.03 (u), 173.47
(u); IR (neat): ν 3398 (s), 2966 (s), 2934 (s), 2245 (w), 1734 (s), 1455
(m), 1431 (m), 1375 (w), 1322 (w), 1245 (m), 1213 (m), 1119 (s),
1095 (s), 1018 (m) cm-1; MS (CI, NH3) m/z (relative intensity, %):
392 (M+ + NH4, 5), 318 (15), 317 (22), 316 (100), 314 (21), 299 (12),
281 (10).
(-)-(E,3aS,4S,5R,6aS)-{5-(tert-Butyl-dimethyl-silanyloxy)-4[(3S)-
tert-butyl-dimethyl-silanyloxy)-4S-methyl-nona-1,6-diynyl]-hexahy-
dropentalen-2-ylidene}acetic acid-(2R-(1-methyl-1-phenylethyl)-1S-
cyclohexyl ester (E-6): To a solution of (1S,2R)-dimethoxyphosphanyl-
2-(1-methyl-1-phenylethyl)-cyclohexyl acetate (2.9 g, 7.87 mmol) in
THF (12 mL) was added n-BuLi (1.6 M in hexanes, 4.5 mL, 7.2 mmol)
at -78 °C. The solution of 43 thus formed was warmed to ambient
temperature for 15 min and cooled to -62 °C. Then a solution of ketone
7b (910 mg, 1.76 mmol) in THF (5 mL) was added within 10 min.
Subsequently the mixture was stirred first for 144 h at -62 °C and
then for 15 h at -30 °C. After the mixture was stirred for 30 min at
ambient temperature, it was treated with aqueous NH4Cl (30 mL), and
the aqueous phase was separated and diluted with water until a clear
solution was formed. The aqueous phase was extracted with Et2O (4
× 40 mL) and the combined organic phases were dried (MgSO4) and
concentrated in vacuo. Column chromatography (hexanes/EtOAc, 10:
1) afforded a mixture of esters E-6 and Z-6 (1.32 g, 99%) in a ratio of
95:5 (1H NMR: δ (CtCCHOSi) 4.57, δ (CHOCO) 5.31 (E-6); δ (Ct
CCHOSi) 4.51, δ (CHOCO) 5.40 (Z-6)) as a colorless oil. HPLC
(Chiralcel OD, 250 × 20 mm, hexanes/0.15% i-PrOH, UV: 254 nm)
gave ester E-6 with g 99% de in 90% yield. Rf 0.52 (hexanes/EtOAc,
10:1); [R]D -16.7 (c 0.72, Et2O); 1H NMR (400 MHz, C6D6): δ 0.10
(s, 3 H), 0.18 (s, 3 H), 0.22 (s, 3 H), 0.30 (s, 3 H), 0.80-1.58 (m, 12
H) 1.00 (s, 9 H), 1.05 (s, 9 H), 1.16 (s, 3 H), 1.30 (d, J ) 6.8 Hz, 3 H,
CHMe), 1.37 (s, 3 H), 2.00-2.55 (m, 13 H), 2.80-3.10 (m, 2 H), 4.00
(m, 1 H, CHOSi-CHCtC), 4.57 (dd, J ) 6.3, J ) 1.6 Hz, 1 H, Ct
CCHOSi), 5.00 (m, 1 H,CdCH), 5.31 (m, 1 H, CHOCO), 7.16-7.31
(3aS,5R,6S,6aS)-{5-(tert-Butyl-dimethyl-silanyloxy)-6-[(3S,4S)-3-
tert-butyl-dimethyl-silanyloxy)-4-methyl-nona-1,6-diynyl]-1,3a,4,5,6,6a-
hexahydropentalen-2-yl}-acetic acid-[(2R,1S)-2-(1-methyl-1-phen-
ylethyl)-1-cyclohexyl ester] (47): To a suspension of (R,R)-bis-
(phenylethyl)amine hydrochloride (350 mg, 1.33 mmol) in THF (15
mL) was added n-BuLi (1.6 M in hexanes, 1.7 mL, 2.7 mmol) at -78
°C. The suspension was warmed to ambient temperature whereby a
clear yellow solution of 12 was formed. Then the solution was cooled
to -105 °C and a solution of ester E-6 (500 mg, 0.65 mmol) (g 99%
de) in THF (5 mL) was added slowly along the cold inner side of the
flask. After the mixture was stirred for 15 min at -105 °C, it was
warmed to -78 °C within 30 min, and stirring was continued for 60
min. Then aqueous NaHCO3 was added at this temperature. The mixture
was warmed to ambient temperature and aqueous NH4Cl (10 mL) was
added. Subsequently water was added until two clear phases were
formed. The aqueous phase was separated and extracted with Et2O (20
mL) and pentanes (20 mL). The combined organic phases were dried
(MgSO4) and concentrated in vacuo. Purification by column chroma-
tography (hexanes/EtOAc, 3:1) provided ester 47 (490 mg, 98%) with
g 99% de (1H NMR) as a colorless oil. Rf 0.52 (hexanes/EtOAc, 10:
1
1), H NMR (400 MHz, C6D6) δ 0.11 (s, 3 H, SiMe), 0.20 (s), 0.205
(s, 3 H, SiMe), 0.29 (s, 3 H, SiMe)), 0.75-1.56 (m, 12 H) 1.00 (s, 9
H, t-Bu), 1.03 (s, 9 H, t-Bu), 1.11 (s, 3 H), 1.28 (d, J ) 6.8 Hz, 3 H,
CHMe), 1.31 (s, 3 H), 1.92-2.10 (m, 5 H), 2.26 (d, 1 H) 2.38-2.64
(m, 6 H), 2.79 (m, 1 H), 3.93 (m, 1 H), 4.53 (dd, J ) 6.3, J ) 1.4 Hz,
1 H, CtCCHOSi), 4.90 (m, 1 H), 5.25 (m, 1 H), 7.05 (m, 1 H), 7.18-
9
9666 J. AM. CHEM. SOC. VOL. 125, NO. 32, 2003

Synthesis of Cicaprost and Isocicaprost
A R T I C L E S
7.23 (m, 4 H), 13C NMR (100 MHz, C6D6): δ -4.88 (d), -4.34 (d),
-4.29 (d), -3.96 (d), 12.77 (u), 14.57 (d), 15.60 (d), 18.23 (u), 18.44
(u), 22.44 (u), 24.86 (u), 25.23 (d), 26.05 (d), 26.07 (d), 26.14 (u),
27.20 (u), 27.99 (d), 33.79 (u), 36.93 (u), 39.91 (u), 40.08 (u), 40.48
(u), 40.74 (d), 45.85 (d), 46.16 (d), 51.01 (d), 66.87 (d), 74.40 (d),
77.80 (u), 78.13 (d), 81.71 (u), 83.00 (u), 87.49 (u), 125.11 (d), 125.56
(d), 127.69 (d), 131.91 (d), 134.29 (u), 151.62 (u), 169.28 (u); IR
(neat): ν 3056 (w), 3032 (w), 2930 (s), 2884 (s), 2856 (s), 2279 (w),
1730 (s), 1496 (w), 1471 (m), 1462 (m), 1449 (m), 1374 (w), 1361
(w), 1339 (w), 1323 (w), 1252 (s), 1120 (s), 1074 (s), 1025 (m), 1005
(m), 939 (w), 905 (m), 838 (s), 815 (m) cm-1; MS (CI, isobutane) m/z
(relative intensity, %): 760 (M+ + H, 11), 759 (17), 427 (11), 202
(17), 201 (100), 119 (33), 105 (17).
Dr. C. Bolm and H. G. Do¨teberg, Gru¨nenthal, Aachen, for
allowing us to use their preparative Chiralcel AD and OD HPLC
columns, J. Lausberg and S. Reumkens, Gru¨nenthal, Aachen,
for the recording of the high resolution ESI/TOF mass spectra,
Dr. H. Dahl, Schering AG, Berlin, for a most generous gift of
bicyclo[3.3.0]octan-2,5-dione, and Dr. B. Buchmann, Schering
AG, Berlin, for copies of NMR spectra and MS data of cicaprost
and alcohol 42, and Degussa AG, Du¨sseldorf, for D-phenyl-
alanine.
Supporting Information Available: Schemes S10, S11, S12
and S13 referred to in the text, copies of the 1H and 13C NMR
spectra of compounds 4, 7a, 16, 23, 24, 26, 29, 36, 39, 40, 41,
E-44, 47, and 48, data of the crystal structure analysis of 21,
and procedures for the synthesis and analytical data of com-
pounds 7b, 9a, rac-9a, 14, 17, 18, 23, 33, 34, rac-34, 36, 38,
40, 41, E-44, 45, and 48 (66 pages, print/PDF). 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 (SFB 380 “Asymmetric
Synthesis with Chemical and Biological Methods” and GK 440
“Methods in Asymmetric Synthesis”) and the Fonds der
Chemischen Industrie is gratefully acknowledged. We thank Dr.
L. R. Reddy for his help with the synthesis and elimination of
salt 30, Dr. G. Raabe for the crystal structure analysis, Prof.
JA030200L
9
J. AM. CHEM. SOC. VOL. 125, NO. 32, 2003 9667