Asymmetric synthesis of 1,2,3-trisubstituted cyclopentanes and cyclohexanes as key components of substance P antagonists

Article abstract of DOI:10.1021/jo025883m

An efficient asymmetric synthesis of 1,2,3-trisubstituted cyclopentanes and cyclohexanes is described. Three methods were developed for the preparation of the 2,3-disubstituted cyclopentenones and cyclohexenones, which are key achiral building blocks. These intermediates are reduced catalytically with (R)-2-methyloxazaborolidine in high yield (82-98%) and excellent ee (89-96%). Directed reduction of the chiral allylic alcohols using Red-Al gives exclusively the 1,2-anti stereochemistry (>99:1). Epimerization of the ester center followed by saponification/crystallization affords the desired hydroxyacids in good yield (65-70%) and in high enantiomeric excess (>99%).

Full text of DOI:10.1021/jo025883m

Asym m etr ic Syn th esis of 1,2,3-Tr isu bstitu ted Cyclop en ta n es a n d
Cycloh exa n es a s Key Com p on en ts of Su bsta n ce P An ta gon ists
J effrey T. Kuethe,* Audrey Wong, J immy Wu, Ian W. Davies, Peter G. Dormer,
Christopher J . Welch, Michael C. Hillier, David L. Hughes, and Paul J . Reider
Department of Process Research, Merck & Co., Inc., P.O. Box 2000, Rahway, New J ersey 07065
J effrey_Kuethe@merck.com
Received April 30, 2002
An efficient asymmetric synthesis of 1,2,3-trisubstituted cyclopentanes and cyclohexanes is
described. Three methods were developed for the preparation of the 2,3-disubstituted cyclopen-
tenones and cyclohexenones, which are key achiral building blocks. These intermediates are reduced
catalytically with (R)-2-methyloxazaborolidine in high yield (82-98%) and excellent ee (89-96%).
Directed reduction of the chiral allylic alcohols using Red-Al gives exclusively the 1,2-anti
stereochemistry (>99:1). Epimerization of the ester center followed by saponification/crystallization
affords the desired hydroxyacids in good yield (65-70%) and in high enantiomeric excess (>99%).
In tr od u ction
nanomolar) for the hNK-1 receptor.7,8 Key to the success
of the preparation of 1 is the asymmetric synthesis of
the core hydroxy acid intermediate 2. The challenging
aspect of the synthesis of the trans,trans-cyclopentyl core
of 2 is control of the relative and absolute stereochem-
istry. The enantioselective synthesis of 2 and model
studies for the further extension to a cyclohexyl core are
discussed.
Primarily associated with sensory neurons and located
in specific areas of the central nervous system (CNS),
neurokinin-1 (NK1) is a member of the seven-transmem-
brane G-protein-coupled receptor family. The natural
ligand for NK1 is the tachykinin peptide Substance P and
has been implicated in the pathophysiology of a wide
range of conditions including anxiety, asthma, cystitis,
depression, emesis, inflammatory bowel disease, mi-
graine, movement disorders, pain, and psoriasis.1 The
search for potent, nonpeptide antagonists of the human
neurokinin-1 (hNK-1) receptor is an intensive area of
investigation.2,3 Efforts to target potent, orally active
hNK-1 antagonists have motivated further interest in the
antidepressant activity exhibited by a neuropeptide
antagonist being developed by Merck.4-6 Recently, a
series of cyclopentane-based compounds such as 1 have
been identified to have significant binding affinity (sub-
Resu lts a n d Discu ssion
(1) (a) Quatara, L.; Maggi, C. A. Neuropeptides 1998, 32, 1. (b)
Rupniak, N. M. J .; Kramer, M. S. Trends Pharmacol. Sci. 1999, 20,
485.
(2) Hale, J . J .; Mills, S. G.; MacCoss, M.; Finke, P. E.; Cascieri, M.
A.; Sadowski, S.; Ber, E.; Chicchi, G. C.; Kurtz, M.; Metzger, J .;
Eiermann, G.; Tsou, N. N.; Tattersall, F. D.; Rupniak, N. M. J .;
Williams, A. R.; Rycroft, W.; Hargreaves, R.; MacIntyre, D. E. J . Med.
Chem. 1998, 41, 4607.
(3) (a) Regoli, D.; Boudon, A.; Fauchere, J .-L. Pharmacol. Rev. 1994,
46, 551. (b) Swain, C. J . In Progress in Medicinal Chemistry; Ellis, G.
P., Luscombe, D. K., Oxford, A. W., Eds.; Elsevier Science BV:
Amsterdam, 1998; Vol. 35, pp 57-81. (c) Harrison, T.; Williams, B. J .;
Swain, C. J .; Ball, R. G. Bioorg. Med. Chem. Lett. 1994, 4, 2545. (d)
Snider, R. M.; Constantine, J . W.; Lowe, J . A., III; Longo, K. P.; Lebel,
W. S.; Woody, H. A.; Drozda, S. E.; Desari, M. C.; Vinick, F. J .; Spencer,
R. W.; Hess, H.-J . Science 1991, 251, 435.
(4) Hale, J . J .; Mills, S. G.; MacCoss, M.; Shah, S. K.; Qi, H.; Mathre,
D. J .; Cascieri, M. A.; Sadowski, S.; Strader, C. D.; MacIntyre, D. E.;
Metzger, J . M. J . Med. Chem. 1996, 39, 1760.
(5) Hale, J . J .; Mills, S. G.; MacCoss, M.; Dorn, C. P.; Finke, P. E.;
Budhu, R. J .; Reamer, R. A.; Huskey, S. W.; Luffer-Altlas, D.; Dean,
B. J .; McGowan, E. M.; Feeney, W. P.; Chiu, S.-H. L.; Cascieri, M. A.;
Chicchi, G. G.; Kurtz, M. M.; Sadowski, S.; Ber, E.; Tattersall, F. D.;
Rupniak, N. M. J .; Williams, A. R.; Rycroft, W.; Hargreaves, R.;
Metzger, J . M.; MacIntyre, D. E. J . Med. Chem. 2000, 43, 1234.
Substituted cyclopentanes and cyclohexanes comprise
a large and diverse class of naturally occurring and
pharmacologically important molecules.9 Stereoselective
(6) Kramer, M. S.; Cutler, N.; Feighner, J .; Shrivastava, R.; Carman,
J .; Sramek, J . J .; Reines, S. A.; Liu, G.; Snavely, D.; Wyatt-Knowles,
E.; Hale, J . J .; Mills, S. G.; MacCoss, M.; Swain, C. J .; Harrison, T.;
Hill, R. G.; Hefti, F.; Scolnick, E. M.; Cascieri, M. A.; Chicchi, G. C.;
Sadowski, S.; Williams, A. R.; Hewson, L.; Smith, D.; Carlson, E. J .;
Hargreaves, R. J .; Rupniak, N. M. J . Science 1998, 281, 1640.
(7) (a) Finke, P. E.; Meurer, L.; MacCoss, M.; Mills, S. G.; Sadowski,
S.; Cascieri, M. A.; Metzger, J .; Eiermann, G.; MacIntyre, D. E.
Presented at the 219th National Meeting of the American Chemical
Society, San Francisco, CA, March 2000, Abstract 98. (b) Meurer, L.;
Finke, P. E.; MacCoss, M.; Mills, S. G.; Tsou, N.; Ball, R. G.; Sadowski,
S.; Cascieri, M. A.; Metzger, J .; Eiermann, G.; MacIntyre, D. E.;
Rupniak, N. M. J .; Williams, A.; Presented at the 219th National
Meeting of the American Chemical Society, San Francisco, CA, March
2000; Abstract 99. (c) Desai, R. C.; Cicala, P.; Meurer, L. C.; Finke, P.
E. Tetrahedron Lett. 2002, 43, 4569.
(8) Finke, P. E.; MacCoss, M.; Meurer, L. C.; Mills, S. G.; Caldwell,
C. G.; Chen, P.; Durette, P. L.; Hale, J .; Holson, E.; Kopka, I.;
Robichaud, A. PCT Int. Appl. WO 9714671, 1997.
10.1021/jo025883m CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/18/2002
J . Org. Chem. 2002, 67, 5993-6000
5993

Kuethe et al.
SCHEME 1. Retr osyn th etic Ap p r oa ch to
Hyd r oxya cid 2
SCHEME 2
SCHEME 3
and enantioselective routes for the construction of these
compounds have led to numerous methods for their
synthesis.9-12 Cyclopentenones and cyclohexenones often
serve as precursors for the synthesis of their saturated
counterparts. In addition, the cyclopentenone and cyclo-
hexenone moieties are found in several biologically
important compounds.10 Therefore, the development of
new synthetic processes that offer improved efficiency for
the enantioselective preparation of these compounds
remains a challenge.
Our retrosynthetic approach to 2 involves the prepara-
tion of cyclopentenone 5, which possesses all the features
of 2 and requires an enantioselective reduction of the
ketone followed by a hydroxyl-directed reduction of the
R,â-unsaturated ester 4 (Scheme 1). Epimerization of the
ester center gives the thermodynamically more stable
trans,trans-cyclopentane 3. Finally, saponification of 3
gives the required hydroxyacid 2.
SCHEME 4
P r ep a r a tion of Cyclop en ten on e 5. Cyclopentenone
5 was prepared by two different routes. Bromination of
commercially available 3-methoxy-2-cyclopentenone 6
with N-bromosuccinimide provided 2-bromo-3-methoxy-
cyclopentenone 7 in quantitative yield (Scheme 2).13
Suzuki-Miyaura cross coupling14 with 4-fluorophenyl-
boronic acid afforded the coupled product 8 in 89% yield.
Examination of workup conditions for the coupling reac-
tion showed that quenching the cooled reaction mixture
with aqueous K3PO4 significantly improved the purity of
the isolated product by effectively removing excess bo-
ronic acid. Conversion of the methoxy group to the
corresponding bromide was effected with phosphorus
tribromide (PBr3) in refluxing 1,2-dichloroethane, provid-
ing bromide 9 in 65% isolated yield.15 Palladium-
SCHEME 5
(9) (a) The Total Synthesis of Natural Products; ApSimon, J ., Ed.;
Wiley: New York,1981; Vol. 1-4 and references therein. (b) Harre,
M.; Raddatz, P.; Walenta, R.; Winterfeldt, E. Angew. Chem., Int. Ed.
Engl. 1982, 21, 480. (c) Noyori, R.; Suzuki, M. Angew. Chem., Int. Ed.
Engl. 1984, 23, 847. (d) Taylor, R. J . K.; Pyke, S. G.; Pyke, S. M. In
Second Supplements to the 2nd Edition of Rodd’s Chemistry of Carbon
Compounds; Sainsbury, M., Ed.; Elsevier: Amsterdam, 1992; pp 221-
282. (e) Gribble, G. W. In Second Supplements to the 2nd Edition of
Rodd’s Chemistry of Carbon Compounds; Sainsbury, M., Ed.; Elsevi-
er: Amsterdam, 1992; Vols. IIA and IIB(partial), pp 375-4452 and
references therein.
(10) (a) Ogasawara, K. Pure Appl. Chem. 1994, 66, 2119. (b) Schultz,
A. G. Accts. Chem. Res. 1990, 207 and references therein.
(11) Hudlicky, T.; Price, J . D. Chem. Rev. 1989, 89, 1467.
(12) Yakura, T.; Yamada, S.; Kunimune, Y.; Ueki, A.; Ikeda, M. J .
Chem. Soc., Perkin Trans. 1 1997, 24, 3643.
catalyzed carbonylation (40 psi CO, 100 °C, MeOH, 3 mol
% Pd(PPh3)2Cl2) provided the key intermediate 5 in 90%
isolated yield.16 Use of the protocols outlined in Schemes
2-5 allowed a series of variously substituted cyclopen-
tenones and cyclohexenones to be prepared (Table
1).17
(15) Kress, M. H.; Kishi, Y. Tetrahedron Lett. 1995, 36, 4583.
(16) Schoenberg, A.; Bartoletti, I.; Heck, R. F. J . Org. Chem. 1974,
39, 3318.
(17) Complete experimental procedures and characterization data
for all intermediates used in the synthesis of the cyclopentenones and
cyclohexenones listed in Table 1 can be found in Supporting Informa-
tion.
(13) Belmont, D. T.; Paquette, L. A. J . Org. Chem. 1985, 50, 4102.
(14) Suzuki, A. Pure Appl. Chem. 1985, 57, 1749.
5994 J . Org. Chem., Vol. 67, No. 17, 2002

Asymmetric Synthesis of Cyclopentanes and Cyclohexanes
While the chemistry outlined in Scheme 2 provided
bromide intermediate 9, a more streamlined approach
to 5 was developed and is outlined in Schemes 3-5. In
an extension of the chemistry developed by Buchwald,19
heating dione 10 in the presence of 1-bromo-4-fluoroben-
zene (11), K3PO4, Pd(OAc)2 (1 mol %), and 2-(di-tert-
butylphosphino)biphenyl (2 mol %) in refluxing 1,4-
dioxane gave 13 in 85% yield (HPLC).20 This reaction can
also be carried out with the corresponding aryl chloride
(12) and has been optimized in terms of the catalyst/
ligand loading with the chloride. Potassium phosphate
(K3PO4, powdered, anhydrous) was found to be the best
base, giving the most consistent results. Other bases
screened gave either no product or significant amounts
of aldol adduct 14.21 The reaction was carried out by
sequentially charging the Pd(OAc)2, ligand, 1,3-cyclopen-
tanedione, and K3PO4. The solids were degassed (three
times) with vacuum/nitrogen backfill cycles, and the 1,4-
dioxane was added followed by 1-chloro-4-fluorobenzene.
The reaction mixture was again degassed (three times)
with vacuum/nitrogen backfill. It was particularly im-
portant that the degassing of both the solids and the
reaction mixture was carried out prior to heating the
reaction mixture. When these degassing procedures were
not carried out, low conversion to product was noted
(<30%). The addition of more catalyst and ligand at this
point failed to bring about any further conversion. The
heterogeneous mixture was then heated at reflux for 12-
14 h and cooled to room temperature. The workup was
simply a matter of dilution with water, which gave a
homogeneous solution, and acidification with concen-
trated HCl, which precipitated the product 13 as a solid
in 92% yield.
Due to the toxicity of 1,4-dioxane, a change in the
reaction solvent from 1,4-dioxane to THF was necessary.
When the reagents were added together as described
above and heated to reflux in THF, low conversion
(<35%) to 13 was noted. However, when the reaction was
conducted in a pressurized vessel (RC1 Reaction Calo-
rimeter)22 at 100 °C (25 psi), a 73% yield was obtained
with 12% remaining starting material. Increasing the
internal temperature to 105 °C (30 psi) resulted in an
increase in the yield for 13 to 83% with 3-5% remaining
starting material. Optimal results were obtained by
heating the reaction at 110 °C (36 psi) and afforded 13
in 87-90% yield. Upon dilution of the mixture with
water, the THF was removed by distillation in order to
obtain a high recovery of the product. Addition of 6 N
HCl at 50 °C resulted in a crystalline, free-flowing pro-
duct that was filtered to give 13 in 86% isolated yield.
Bromination conditions utilized for 8 (PBr3 in refluxing
1,2-dichloroethane) gave bromide 9 in 65% yield. While
the reaction proceeded to completion, the significant
byproduct of this reaction was dione 13. Bromination of
13 with PBr3 in refluxing 1,2-dichloroethane gave 9 in
78% yield (the remainder was starting material). Pro-
longed reaction times and the addition of excess PBr3 to
these reactions failed to drive the reactions to the
complete formation of 9. Switching from PBr3 to Ph3PBr2
as the brominating reagent in MeCN at 60 °C resulted
in clean transformation of 13 to 9 in 96% yield (HPLC);
however, a significant problem was the generation of
triphenylphosphine oxide, which was difficult to remove
without resorting to chromatography. Bromination with
phosphorus oxybromide (POBr3) gave better results with
bromide 9 obtained in 96% yield (HPLC). Optimal condi-
tions involved treatment of dione 13 with 0.75 equiv of
POBr3 in MeCN with 0.5 equiv of Na2HPO4 at 65 °C for
1.5 h. The workup involved cooling the reaction mixture
to room temperature, quenching with 1 N KOH, and
separating the bottom aqueous layer. Concentration of
the acetonitrile layer and addition of water precipitated
the product, which was isolated in 92% yield. Upon
completion of the reaction, it was discovered that ap-
proximately 4% of tribromide impurities 15 and 16 (6:1
by HPLC) were present in the crude reaction mixture.
During the course of the KOH quench, it was noted that
15 and 16 were converted to a new impurity with a
molecular weight determined by LCMS to be 210. We
have tentatively assigned the structure of this impurity
as 17. These impurities were effectively removed during
the crystallization step.
Having developed a practical process for the prepara-
tion of bromide 9, we revisited the carbonylation reaction.
To eliminate the need for chromatography, improvements
were needed over the initial carbonylation conditions. In
addition, significant amounts (∼5-8%, HPLC) of 8 were
formed under the reaction conditions. After experimenta-
tion with a variety of catalyst systems and solvents, the
best conditions involved running the reaction in di-
methylacetamide (1 M in 9) with 5 equiv of MeOH, 2
equiv of n-Bu3N, 1 mol % of 5 wt % Pd/C at 60 °C at 10
psi CO for 12 h.23 These conditions eliminated the
formation of 8 and resulted in the formation of 5 in 96%
yield (HPLC). Filtration of the catalyst and removal of
the MeOH by distillation were followed by precipitation
of the methyl ester by addition of 1-1.3 volumes of 1 N
HCl and afforded 5 in 90% yield.
While the bromide 9 was contaminated with small
amounts of 15-17, these impurities remained either
unreactive (17) or decomposed under the reaction condi-
tions (15 or 16). In addition, these impurities were
removed during the crystallization of 5.
Con ver sion of 5 to Hyd r oxya cid 2. The conversion
of 5 to hydroxyacid 2 involved a series of transformations
where acid 2 was the only isolated product. The enanti-
oselective reduction of ketone 5 was achieved by addition
of 5 to a preformed mixture of (R)-2-methyloxazaboroli-
dine 18 (10 mol %) and BH3‚SMe2 (0.6 equiv) in toluene
at -20 °C (Scheme 6).24,25 The chiral allylic alcohol 4 was
formed in >95% yield (HPLC) with 92-94% ee. The use
of BH3‚SMe2 was significant since the use of BH3‚THF
(18) Zhao, D.; Xu, F.; Chen, C.; Tillyer, R. D.; Grabowski, E. J . J .;
Reider, P. J . Tetrahedron 1999, 55, 6001.
(19) Fox, J . M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J . Am. Chem.
Soc. 2000, 122, 1360.
(20) The HPLC yields refer to quantitative HPLC analysis of crude
reaction mixtures using an analytically pure standard.
(21) Eskola, S. Suom. Kemistil. 1957, 30B, 34; Chem. Abstr. 1957,
53, 16014f.
(23) Davies, I. W.; Matty, L.; Hughes, D. L.; Reider, P. J . J . Am.
Chem. Soc. 2001, 123, 10139.
(24) Corey, E. J .; Bakshi, R. K.; Shibata, S.; Chem, C.-P.; Sinch, V.
K. J . Am. Chem. Soc. 1987, 109, 7925.
(25) Mathre, D. J .; J ones, T. K.; Xavier, L. C.; Blacklock, T. J .;
Reamer, R. A.; Mohan, J . J .; J ones, T. T.; Hoogsteen, K.; Baum, M.
W.; Grabowski, E. J . J . J . Org. Chem. 1991, 56, 751.
(22) The internal temperature and pressure were monitored by a
Mettler-Toledo RC1 Reaction Calorimeter.
J . Org. Chem, Vol. 67, No. 17, 2002 5995

Kuethe et al.
SCHEME 6
selectivity (>99.9% 19); however, the catalyst only sur-
vived three turnovers.29
After experimenting with a number of reducing agents
for the reduction of 4 to either 19 or 3, we discovered
that reaction with Red-Al resulted in clean reduction and
gave the desired 1,2-anti stereochemistry exclusively.30,31
There was no evidence of any of the 1,2-syn product 20
being formed in the reaction resulting from anti addition
of hydride. Optimal conditions involved addition of 1.5
equiv of Red-Al to a solution of 4 in 3:2 toluene/THF at
-40 °C (Scheme 8). Warming the reaction mixture to -25
resulted in significant erosion in ee (56-84% ee). When
BH3‚NHMe2 was used as the reductant, the starting
material was recovered unchanged. Once the reaction
was complete (2 h), the reaction mixture was quenched
with 6 equiv of MeOH and allowed to warm to 20 °C.
After being washed with 1 N HCl, the toluene solution
was azeotropically dried for the stereoselective reduction
of the double bond.
SCHEME 8
With an efficient synthesis of allylic alcohol 4 in hand,
our attention turned to the selective reduction of the
double bond. Since a high degree of stereocontrol has
been achieved by transition-metal-catalyzed hydrogena-
tions directed by proximal hydroxyl groups, these catalyst
systems were screened.26 Crabtree reduction27 (20 mol
% Ir(COD)(py)(PCy3)PF6, 500 psi, 12 h) of 4 gave a 63%
yield (the remainder was starting material) of 19 as a
single isomer (>99:1) where the stereochemistry was
confirmed by NOE studies (Scheme 7). The rhodium
SCHEME 7
°C drives the reaction to completion. The use of THF as
a cosolvent was important since it helps solubilize the
Red-Al at low temperatures. When Red-Al was added to
4 in toluene alone at low temperatures, the Red-Al was
slow to solubilize and the reaction took considerably
longer to go to completion. Inverse addition of the
reaction mixture to a 2 M solution of NaHSO4 afforded
approximately a 4:1 mixture of 19:3 in 83% yield together
with 5-8% over-reduction byproduct 21.
To gain mechanistic insight into the formation of 19
and 3, the reaction was monitored by measuring hydro-
gen evolution and by ReactIR.32 The addition of 0.5 equiv
of Red-Al resulted in the evolution of 2 mol of H2 and
the formation of intermediate 22 (Scheme 9).33 Figure 1
shows the cumulative evolution of hydrogen (mmol) and
the cumulative amount (mmol) of Red-Al added vs time.
The hydrogen evolution abruptly stops after 0.5 equiv of
Red-Al is added, and the molar rate of hydrogen release
catalysts Rh(COD)(dppb)PF6 and Rh(C7H8)(dppb)PF6
were also examined.28 Although these reactions proceeded
to completion, they were generally nonselective and gave
varying amounts of 19 and the all-cis isomer 20. Due to
incomplete reductions and the expense of Crabtree’s
catalyst, alternative methods for the stereoselective
reduction of 4 were examined. Using the more stable
iridium-carbene complexes recently described by Nolan
(chlorobenzene, 80 °C, 50 psi H2) gave excellent stereo-
(29) Lee, H. M.; J iang, T.; Stevens, E. D.; Nolan, S. P. Organome-
tallics 2001, 20, 1255.
(30) For the reduction of R,â-unsaturated ester using Red-Al, see:
(a) SarKar, A.; Rao, B. R.; Konar, M. M. Synth. Commun. 1989, 19,
2313. (b) Malek, J . Org. React. 1988, 36, 249.
(31) For the reduction of R,â-unsaturated ester using Red-Al and
copper (I) bromide, see: (a) Semmelhack, M. F.; Stauffer, R. D.;
Yamashita, A. J . Org. Chem. 1977, 42, 3180. (b) Semmelhack, M. F.;
Stauffer, R. D. J . Org. Chem. 1975, 40, 3619.
(32) ReactIR refers to the real-time, in situ monitoring of the IR
spectrum of the reaction with a ReactIR 4000 Reaction Analysis System
available from ASI Applied Systems.
(26) For a review of directed hydrogenations, see: Brown, J . M.
Angew. Chem., Int. Ed. Engl. 1987, 26, 190.
(27) (a) Stork, G.; Kahne, D. E. J . Am. Chem. Soc. 1983, 105, 1072.
(b) Crabtree, R. H.; Davies, M. W. Organometallics 1983, 2, 681.
(28) Evans, D. A.; Morrissey, M. M. J . Am. Chem. Soc. 1984, 106,
3866.
(33) (a) Malek, J . Org. React. 1988, 36, 249 and references therein.
(b) Malek, J . Org. React. 1985, 34, 1.
5996 J . Org. Chem., Vol. 67, No. 17, 2002

Asymmetric Synthesis of Cyclopentanes and Cyclohexanes
SCHEME 9
SCHEME 10
F IGURE 1. Amount (mmol) of H2 evolved and equiv of Red-
Al added vs time.
(3:19) (Scheme 10). There was a small amount (<1.0%,
HPLC) of hydroxyacid 2 that formed under the reaction
conditions. Saponification of the mixture by the direct
addition of 6 N NaOH (3.5 equiv), water, and MeOH (2.6
equiv) to the toluene solution and vigorous stirring for 3
h at 20 °C gave 2. In addition, small amounts of 25 were
present in the reaction mixture. Aqueous workup and
crystallization from 3:1 heptane/isopropyl acetate gave
2 in 65% overall yield from 4. The crystallization not only
completely removed 25 but also increased the ee of 2 from
92 to 94% ee to >99.9% ee.
We also expanded the reduction methodology to the
preparation of a number of substituted cyclopentanes and
cyclohexanes. Enantioselective reduction of ketones 26a-f
proceeded in good to excellent yield and in high ee
(Scheme 11, Table 1). There was no significant loss in
enantioselectivity going from a five- to a six-membered
ring. In addition, the substituent at the 2-position of the
enone was observed to have no detrimental effect on the
yield or ee. Reduction of 27a -c with Red-Al afforded the
anti-syn products 28a -c and anti-anti cyclopentanes
29a -c as a 4:1 mixture of diastereomers. Epimerization
of the crude reaction mixtures with NaOMe followed by
saponification of the methyl ester gave the corresponding
hydroxy acids 30a -c in good yield and in >99% ee.
Interestingly, reduction of the six-membered ring ana-
is approximately 2 times the molar rate of Red-Al added.
The IR shows the complete disappearance of the OH
stretch of 4 after 0.5 equiv of Red-Al was added. Quench-
ing the intermediate at this stage resulted only in the
recovery of starting material. However, the addition of
additional Red-Al to 22 led to the rapid formation of 19
and 3. We speculate that addition of 1.0 equiv of Red-Al
leads to the formation of intermediate 23,34,35 where
intramolecular hydride delivery occurs diastereoselec-
tively from the R-face to give the observed 1,2-anti
stereochemistry. The formation of intermediate 24 was
monitored by IR where the disappearance of the carbonyl
absorption of the ester of 22 (1722 cm-1) and the
formation of the enolate (1690 cm-1) of 24 was observed.
Epimerization of the crude toluene solution containing
19 and 3 was conducted by adding 0.4 equiv of NaOMe
to the dry toluene solution from the Red-Al reduction at
50 °C and then further heating the reaction mixture at
75 °C for 1 h where the diastereomeric ratio was >17:1
(34) Casensky, B.; Machacek, J .; Abrham, K. Collect. Czech. Chem.
Commun. 1971, 36, 2648.
(35) The addition of less than 1.5 total equiv of Red-Al results in
incomplete conversion of starting material to products, while the
addition of more than 1.5 equiv of Red-Al results in significantly more
over-reduction product 21.
J . Org. Chem, Vol. 67, No. 17, 2002 5997

Kuethe et al.
SCHEME 11
Exp er im en ta l Section
Melting points are uncorrected. All solvents and reagents
were used as received from commercial sources. Analytical
samples were obtained by chromatography on silica gel using
an ethyl acetate-hexane mixture as the eluent unless specified
otherwise. Elemental analyses were performed by Quantitative
Technologies, Inc., Whitehouse, NJ . The water content (KF)
was determined by Karl Fisher titration.
P r ep a r a tion of 3-Meth oxy-2-(4-flu or op h en yl)-2-cyclo-
p en ten -1-on e (8). To a solution of 10.0 g (52.4 mmol) of 7,
14.5 g (105.0 mmol) of anhydrous K2CO3, and 9.52 g (68.1
mmol) of 4-fluorophenylboronic acid suspended in 100 mL of
toluene were added 0.479 mg (0.524 mmol) of Pd2(dba)3 and
274 mg (1.05 mmol) of PPh3. The resulting mixture was heated
at reflux for 12 h, cooled to 20 °C, and then washed with 75
mL of 0.33 M K3PO4. The resulting toluene layer was then
concentrated under reduced pressure, and the residue was
purified by flash silica gel chromatography to provide 9.61 g
(89%) of 8 as a white solid: mp 91-92 °C (MTBE/hexane); 1H
NMR (CDCl3, 400 MHz) δ 2.59 (m, 2H), 2.80 (m, 2H), 4.02 (s,
3H), 7.05 (t, 2H, J ) 8.9 Hz), 7.75 (dd, 2H, J ) 8.9 and 5.6
Hz); 13C NMR (CDCl3, 100 MHz) δ 24.7, 33.9, 57.1, 115.0 (d, J
) 20 Hz), 117.8, 127.0, 130.1, 161.8 (d, J ) 240 Hz), 184.8,
203.0. Anal. Calcd for C12H11FO2: C, 69.89; H, 5.38. Found:
C, 69.77; H, 5.46.
TABLE 1
27
30
Gen er a l P r oced u r e for Cou p lin g of 1,3-Cyclop en -
ta n ed ion es a n d 1,3-Cycloh exa n ed ion es w ith Ar yl Ch lo-
r id es. Meth od A in 1,4-Dioxa n e. To a 100 mL round-bottom
flask were sequentially added Pd(OAc)2 (0.25 mmol), 2-(di-tert-
butylphosphino)biphenyl (0.55 mmol), the appropriate 1,3-
dione (25.24 mmol), and powdered K3PO4 (50.5 mmol). The
resulting mixture was degassed (three times) by vacuum/N2
backfills. The vessel was then charged with 26 mL of 1,4-
dioxane and the appropriate aryl chloride (32.8 mmol). The
vessel was degassed (three times) with vacuum/N2 backfills.
The resulting slurry was heated to reflux for 12 h and cooled
to room temperature, and water (75 mL) was added. To the
homogeneous solution was added concentrated HCl to adjust
the pH to 1 and the slurry stirred for 2.5 h. The slurry was
then filtered and the cake washed with 1 bed volume of water
and 1 bed volume of toluene. The solid was then dried under
vacuum at 60 °C for 48 h. An analytical sample was obtained
by recrystallization from acetone/hexane.
Meth od B in THF . To a solution of THF (41 mL) were
added sequentially powdered K3PO4 (50.5 mmol), the ap-
propriate 1,3-dione (25.24 mmol), 2-(di-tert-butylphosphino)-
biphenyl (0.55 mmol), Pd(OAc)2 (0.25 mmol), and the appro-
priate aryl chloride (32.78 mmol). The sides of the flask were
washed with an additional 10 mL of THF, and the reaction
vessel was purged (three times) with vacuum/N2 backfills. The
heterogeneous reaction mixture was stirred at 110 °C for 12
h, cooled to room temperature, and diluted with 75 mL of
water. The resulting homogeneous solution was distilled to
remove THF and then heated to 50 °C. The aqueous solution
was then slowly acidified with 6 N HCl until a final pH of 1.
The slurry was cooled to room temperature and filtered. The
wet cake was washed with 1 bed volume of water, 1 bed volume
of toluene, and dried under vacuum at 60 °C for 48 h.
2-(4-F lu or op h en yl)-1,3-cyclop en ta n ed ion e (13). White
solid (92%): mp 243-244 °C (THF/hexane); 1H NMR ((CD3)2-
CO, 400 MHz) δ 2.57 (s, 4H), 7.05 (m, 2H), 7.97 (m, 2H), 12.5
(br s, 1H); 13C NMR ((CD3)2CO, 100 MHz) δ 30.3, 113.9, 114.3
(d, J ) 21 Hz), 128.4, 129.5, 161.1 (d, J ) 243 Hz), 209.1. Anal.
Calcd for C11H9FO2: C, 68.74; H, 4.72. Found: C, 68.63; H,
4.60.
ketone 26
R
yield (%)a
ee (%)b
yield (%)c
a n ) 1d
b n ) 1
c n ) 1
d n ) 2
e n ) 2
f n ) 2
Me
82
94
98
92
89
84
96
90
90
90
91
89
67
68
60
70
60
66
Ph
o-tolyl
Me
Ph
4-F-Ph
a
b
Isolated yield after column chromatography. Enantiomeric
excess was determined by chiral supercritical fluid chromatogra-
phy on either the Chiralcel OJ or Chiralcel OF chiral stationary
phase (4.6 × 250 mm) using a standard gradient of 4-40% meth-
anol in carbon dioxide at a flow rate of 1.5 mL/min at a pressure
of 300 bar with a column temperature of 30 °C and UV detection
at 215 nm. c Isolated yield after crystallization. See ref 37.
d
logues 27d -f gave the anti-syn cyclohexanes 28d -f as
the major products (28:29 > 20:1) where the stereochem-
istry was confirmed by NOE experiments on 28f.36
Epimerization with NaOMe and saponification afforded
hydroxyacids 30d -f in good yield and in >99% ee.
In conclusion, a practical method for the synthesis of
2-substituted cyclopentenone and cyclohexenones has
been developed. Asymmetric reduction of the enone leads
to cyclic allylic alcohols, which in conjunction with Red-
Al and epimerization/saponification allows for a highly
stereoselective synthesis of anti,anti-1,2,3-trisubstituted
cyclopentanes and cyclohexanes. These systems can be
elaborated to novel NK1 receptor antagonists.7,8
(36) Observed NOE data for compound 28f:
Gen er a l P r oced u r e for Br om in a tion of 3-Alk oxy-2-
su bstitu ted Cyclop en ten -1-on es a n d 3-Alk oxy-2-su bsti-
tu ted Cycloh exen -1-on es. To a solution of the appropriate
3-alkoxy-2-substituted cyclopenten-1-one or cyclohexen-1-one
(10 mmol) in 20 mL of 1,2-dichloroethane was added PBr3 (15
mmol). The resulting mixture was heated to reflux for 1 h,
cooled to 20 °C, and poured over cracked ice. The organic layer
(37) Newman, M. S.; McPherson, J . L. J . Org. Chem. 1954, 19, 1717.
5998 J . Org. Chem., Vol. 67, No. 17, 2002

Asymmetric Synthesis of Cyclopentanes and Cyclohexanes
was separated, washed with saturated aqueous NaHCO3, and
dried over MgSO4. The solvent was removed under reduced
pressure and the residue purified over a plug of silica gel.
3-Br om o-2-(4-flu or op h en yl)-2-cyclop en t en -1-on e (9).
White solid (65%): mp 57-58 °C (MTBE/hexane); 1H NMR
(CDCl3, 400 MHz) δ 2.72 (m, 2H), 3.10 (m, 2H), 7.13 (m, 2H),
7.51 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 35.8, 36.3, 115.4
(d, J ) 20 Hz), 126.1, 131.0, 142.1, 156.0, 162.9 (d, J ) 250
Hz), 202.2. Anal. Calcd for C11H8BrFO: C, 51.79; H, 3.16.
Found: C, 51.72; H, 3.25.
Gen er a l P r oced u r e for th e Br om in a tion of 2-Su bsti-
tu ted 1,3-Cyclop en ta n ed ion es a n d 2-Su bstitu ted 1,3-
Cycloh exa n ed ion es. To a slurry of the appropriately sub-
stituted cyclopentanedione or cyclohexanedione (10 mmol) and
solid Na2HPO4 (5 mmol) in 15 mL of dry CH3CN was added
dropwise POBr3 (7.5 mmol) in 5 mL of dry CH3CN. The
resulting mixture was heated to 65 °C for 1 h and cooled to
room temperature. To the mixture was added slowly 1 N KOH
until a final pH of 6.5-7.5 was obtained. The bottom aqueous
layer was separated and the CH3CN layer concentrated to a
final volume of 15 mL. To the solution was added 37.5 mL of
water, which precipitated the product. The product was
collected by filtration.
2.67 (m, 2H), 2.98 (m, 2H), 3.68 (s, 3H), 6.98 (d, 1H, J ) 7.6
Hz), 7.25 (m, 3H); 13C NMR (CDCl3, 100 MHz) δ 20.0, 27.2,
34.7, 52.4, 125.5, 128.7, 128.9, 130.1, 131.0, 136.1, 149.3, 157.4,
165.7, 207.6.
Met h yl 2-Met h yl-3-oxo-1-cycloh ex-1-en eca r b oxyla t e
(26d ). Colorless oil: 1H NMR (CDCl3, 400 MHz) δ 1.94 (t, 3H,
J ) 2.1 Hz), 2.20 (m, 2H), 2.47 (m, 2H), 2.57 (m, 2H), 3.82 (s,
3H); 13C NMR (CDCl3, 100 MHz) δ 12.9, 22.4, 27.5, 35.4, 38.0,
52.3, 137.5, 144.4, 169.1, 199.6.
Met h yl 2-P h en yl-3-oxo-1-cycloh ex-1-en eca r b oxyla t e
(26e). White solid: mp 44-45 °C (MTBE/hexane); 1H NMR
(CDCl3, 400 MHz) δ 2.18 (m, 2H), 2.62 (t, 2H, J ) 6.7 Hz),
2.73 (t, 2H, J ) 6.0 Hz), 3.48 (s, 3H), 7.10 (m, 2H), 7.32 (m,
3H); 13C NMR (CDCl3, 100 MHz) δ 22.2, 27.7, 38.2, 51.9, 127.8,
123.0, 129.0, 134.4, 139.4, 147.5, 169.0, 197.8. Anal. Calcd for
C
14H14O3: C, 73.03; H, 6.13. Found: C, 73.14; H, 5.99.
Meth yl 2-(4-F lu or op h en yl)-3-oxo-1-cycloh ex-1-en eca r -
boxyla te (26f). White solid: mp 51-52 °C (MTBE/hexane);
1H NMR (CDCl3, 400 MHz) δ 2.19 (m, 2H), 2.61 (t, 2H, J )
6.7 Hz), 2.72 (t, 2H, J ) 6.1 Hz), 3.46 (s, 3H), 7.18 (m, 2H),
7.21 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 22.3, 27.5, 38.2,
51.9, 115.1 (d, J ) 20 Hz), 119.6, 129.3, 132.4, 136.0, 161.5 (d,
J ) 240 Hz), 197.5. Anal. Calcd for C14H13FO3: C, 67.73; H,
5.28. Found: C, 67.77; H, 5.29.
Gen er a l P r oced u r e for th e P r ep a r a tion of (1R,2R,3S)-
2-Su bstitu ted 3-Hyd r oxycyclop en ta n e-1-ca r boxylic Ac-
id s a n d (1R,2R,3S)-2-Su bstitu ted 3-Hyd r oxycycloh exa n e-
1-ca r boxylic Acid s. To a solution of (R)-2-methyl-CBS-oxa-
zaborolidine (18, 10 mmol) in 75 mL of toluene was added 60
mmol of BH3‚SMe3 (60 mmol). The resulting mixture was
cooled to -20 °C, and the appropriate ketone (100 mmol) in
360 mL of toluene was added dropwise while maintaining the
internal temperature below -15 °C. After 2 h, the mixture was
quenched with 60 mmol of MeOH and allowed to warm to room
temperature. The resulting mixture was washed with 234 mL
of 1 N HCl and the toluene layer azeotropically dried to a KF
< 120 and a final volume of 250 mL. An analytical sample
can be obtained by removal of the toluene under reduced
pressure and purification of the residue by silica gel chroma-
tography.
To the above dry toluene stream was added 170 mL of THF
and the mixture cooled to -40 °C. To the cooled solution was
added dropwise over 15 min 70% Red-Al (150 mmol) in toluene
while maintaining the internal temperature at <-35 °C. The
reaction mixture was allowed to slowly warm to -25 °C over
2.5 h and then added to a solution of 300 mL of 2 M NaHSO4.
The organic layer was then washed with 300 mL of water and
azeotropically dried to a KF < 130 and a final volume of 250
mL. An analytical sample can be obtained by removal of the
solvent under reduced pressure and purification of the residue
by silica gel chromatography.
To the above toluene solution was added 25 wt % NaOMe
in MeOH (40 mmol) and the mixture heated to 75 °C for 1 h.
The reaction was cooled to 50 °C; to the cooled mixture were
added 6 N NaOH (350 mmol), 300 mL of water, and MeOH
(300 mmol), and the mixture was stirred at room temperature
for 3 h. The layers were allowed to separate, and the aqueous
layer was washed with 230 mL of MTBE. The aqueous layer
was then made acidic (pH ∼1-1.5) with concentrated HCl and
extracted with 610 mL of isopropyl acetate. The isopropyl
acetate solution was treated with activated carbon, filtered,
and concentrated to a final volume of 220 mL and KF < 200.
To the isopropyl acetate solution was added 640 mL of heptane.
The slurry was cooled to -10 °C and filtered, and the wet cake
was washed with 1:5 isopropyl acetate/heptane and then
heptane.
cis-1-F lu or o-4-(2,3,5)-t r ib r om ocyclop en t -1-en ylb en -
zen e (15). Light yellow solid: mp 71-72 °C (MTBE/hexane);
1H NMR (CDCl3, 400 MHz) δ 3.04 (d, 1H, J ) 16.4 Hz), 3.32
(dt, 1H, J ) 16.4 and 6.9 Hz), 5.13 (d, 1H, J ) 6.2 Hz), 6.28
(d, 1H, J ) 6.2 Hz), 7.14 (m, 2H), 7.64 (m, 2H); 13C NMR
(CDCl3, 100 MHz) δ 43.8, 51.8, 56.7, 115.7 (d, J ) 20 Hz),
124.6, 128.4, 130.4, 143.7, 163.2 (d, J ) 250 Hz). Anal. Calcd
for C11H8Br3F: C, 33.12; H, 2.02. Found: C, 33.02; H, 1.70.
tr a n s-1-F lu or o-4-(2,3,5)-tr ibr om ocyclop en t-1-en yl-ben -
1
zen e (16). Unstable brown oil: H NMR (CDCl3, 400 MHz) δ
3.24 (m, 2H), 5.22 (m, 1H), 5.34 (m, 1H), 7.11 (m, 2H), 7.58
(m, 2H).
Gen er a l P r oced u r e for Ca r bon yla tion of 3-Br om o-2-
su bstitu ted Cyclop en ten -1-on es a n d 3-Br om o-2-su bsti-
tu ted Cycloh exen -1-on es. Meth od A. A solution of the
corresponding bromide (10 mmol), Pd(PPh3)2Cl2 (0.30 mmol),
and n-tributylamine (20 mmol) in 20 mL of MeOH was heated
at 60 °C under 40 psi CO for 16 h. The mixture was cooled to
room temperature; the catalyst was filtered over Celite, and
the MeOH was removed under reduced pressure. The residue
was redissolved in 35 mL of EtOAc and washed with 35 mL
of 1 N HCl. The organic layer was dried over MgSO4 and the
solvent removed under reduced pressure. The residue was
purified by chromatography on silica gel.
Meth od B. A solution of the corresponding bromide (10
mmol), 5% Pd/C (0.10 mmol), and n-tributylamine (20 mmol)
in 20 mL of dimethylacetamide was heated at 60 °C under 10
psi CO for 12 h. The mixture was cooled to room temperature;
the catalyst was filtered over Celite, and the MeOH was
removed under reduced pressure. The mixture was slowly
titrated with 1 N HCl (20 mL) while keeping the temperature
below 25 °C. The product was then collected by filtration,
washed with water until the filtrate pH was >5, and dried.
Met h yl 2-(4-F lu or op h en yl)-3-oxo-1-cyclop en t -1-en e-
ca r boxyla te (5). Colorless solid: mp 70-71 °C (MTBE/
1
hexane); H NMR (CDCl3, 400 MHz) δ 2.67 (m, 2H), 2.94 (m,
2H), 3.77 (s, 3H), 7.09 (t, 2H, J ) 8.9 Hz), 7.35 (dd, 2H, J )
8.9 and 5.6 Hz); 13C NMR (CDCl3, 100 MHz) δ 27.2, 34.7, 52.5,
115.3 (d, J ) 20 Hz), 126.2, 131.2, 145.6, 156.5, 163.3 (d, J )
250 Hz), 166.2. Anal. Calcd for C13H11FO3: C, 66.66; H, 4.73.
Found: C, 66.47; H, 4.92.
Meth yl 2-P h en yl-3-oxocyclopen t-1-en ecar boxylate (26b).
White solid: mp 56-57 °C; 1H NMR (CDCl3, 400 MHz) δ 2.67
(m, 2H), 2.95 (m, 2H), 3.75 (s, 3H), 7.33 (m, 2H), 7.40 (m, 3H);
13C NMR (CDCl3, 100 MHz) δ 27.1, 34.6, 52.2, 128.0, 128.9,
129.0, 130.2, 146.4, 156.4, 207.2. Anal. Calcd for C13H12O3: C,
72.21; H, 5.59. Found: C, 72.20; H, 5.34.
Met h yl (3S)-2-(4-F lu or op h en yl)-3-h yd r oxycyclop en t -
1-en eca r boxyla te (4). White solid (94%): [R]D -186.6 (c 0.01,
1
MeOH); mp 43-44 °C; H NMR (CDCl3, 400 MHz) δ 1.72 (br
s, 1H), 1.89 (m, 1H), 2.45 (m, 1H), 2.67 (m, 1H), 2.92 (m, 1H),
3.63 (s, 3H), 5.14 (m, 1H), 7.04 (t, 2H, J ) 8.9 Hz), 7.35 (dd,
2H, J ) 8.9 and 5.6 Hz); 13C NMR (CDCl3, 100 MHz) δ 31.6,
Met h yl 2-(2-Tolyl)-3-oxocyclop en t -1-en eca r b oxyla t e
(26c). Colorless oil: 1H NMR (CDCl3, 400 MHz) δ 2.12 (s, 3H),
J . Org. Chem, Vol. 67, No. 17, 2002 5999

Kuethe et al.
32.0, 51.5, 80.6, 115.1 (d, J ) 20 Hz), 130.1, 130.7, 131.4, 152.3,
162.6 (d, J ) 250 Hz), 166.3. Anal. Calcd for C13H13FO3: C,
66.09; H, 5.55. Found: C, 65.81; H, 5.61.
(1R,2R,3S)-2-P h en yl-3-h yd r oxycyclop en ta n e-1-ca r box-
ylic Acid (30b). White solid: [R]D -30.3 (c 0.001, MeOH); mp
1
98-99 °C (isopropyl acetate/heptane); H NMR (CD3CN, 400
Meth yl (1S,2R,3S)-2-(4-F lu or op h en yl)-3-h yd r oxycyclo-
p en ta n e-1-ca r boxyla te (19). Colorless oil: [R]D +74.9 (c
MHz) δ 1.73 (m, 1H), 2.09 (m, 3H), 2.11 (br s, 1H), 2.91 (m,
1H), 3.05 (m, 1H), 4.12 (q, 1H, J ) 7.0 Hz), 7.31 (m 5H), 9.00
(br s, 1H); 13C NMR (CD3CN, 100 MHz) δ 26.2, 33.5, 49.1, 57.7,
79.3, 126.6, 127.8, 128.4, 138.0, 162.0. Anal. Calcd for
1
0.0064, MeOH); H NMR (CDCl3, 400 MHz) δ 1.71 (m, 2H),
2.10 (m, 2H), 2.37 (m, 1H), 3.30 (s, 3H), 3.32 (m, 2H), 4.62 (q,
1H, J ) 6.9 Hz), 7.01 (m, 2H), 7.19 (m, 2H); 13C NMR (CDCl3,
100 MHz) δ 24.9, 48.1, 51.3, 56.0, 77.0, 115.2 (d, J ) 30 Hz),
129.7 (d, J ) 10 Hz), 134.7, 161.7 (d, J ) 240 Hz), 174.7. Anal.
Calcd for C13H15FO3: C, 65.53; H, 6.35. Found: C, 65.58; H,
6.30.
C
12H14O3: C, 69.88; H, 6.84. Found: C, 69.82; H, 6.67.
(1R,2R,3S)-2-(2-Tolyl)-3-h yd r oxycyclop en t a n e-1-ca r -
boxylic Acid (30c). White solid: [R]D -9.00 (c 0.002, MeOH);
mp 198-199 °C (isopropyl acetate/heptane); 1H NMR ((CD3)2-
SO, 400 MHz) δ 1.61 (m, 1H), 1.96 (m, 3H), 2.29 (s, 3H), 2.73
(q, 1H, J ) 8.6 Hz), 3.35 (t, 1H, J ) 8.7 Hz), 3.95 (m, 1H),
4.75 (m, 1H), 7.12 (m, 3H), 7.19 (d, 1H, J ) 7.6 Hz), 11.9 (s,
1H); 13C NMR ((CD3)2SO, 100 MHz) δ 20.2, 27.2, 34.6, 50.4,
52.8, 80.3, 126.1, 126.6, 130.2, 137.1, 142.0, 176.8. Anal. Calcd
for C13H16O3: C, 70.87; H, 7.33. Found: C, 70.47; H, 7.50.
(1R,2R,3S)-2-Meth yl-3-h yd r oxycycloh exa n e-1-ca r boxy-
lic Acid (30d ). White solid: [R]D -8.4 (c 0.004, MeOH); mp
139-140 °C (isopropyl acetate/hexane); 1H NMR (CD3CN, 400
MHz) δ 0.96 (d, 3H, J ) 6.4 Hz), 1.25-1.45 (m, 5H), 1.65 (br
s, 1H), 1.75 (m, 2H), 1.85 (m, 1H), 1.95 (m, 1H), 3.05 (ddd,
1H, J ) 10.0 and 4.1 Hz); 13C NMR (CD3CN, 100 MHz) δ 16.6,
24.7, 30.6, 36.0, 42.5, 50.5, 75.0, 176.9. Anal. Calcd for
C8H14O3: C, 60.74; H, 8.92. Found: C, 60.82; H, 9.18.
Meth yl (1S,2S,3S)-2-(4-F lu or op h en yl)-3-h yd r oxycyclo-
p en ta n e-1-ca r boxyla te (20). Colorless oil: [R]D -45.6 (c
1
0.0026, MeOH); H NMR (CDCl3, 400 MHz) δ 2.05 (m, 2H),
2.07-2.18 (m, 2H), 3.35 (m, 1H), 3.45 (m, 1H), 3.50 (s, 3H),
3.74 (d, 1H, J ) 10.6 Hz), 4.55 (m, 1H), 6.99 (m, 2H), 7.36 (m,
2H); 13C NMR (CDCl3, 100 MHz) δ 27.4, 35.5, 47.1, 52.0, 52.1,
74.7, 115.0 (d, J ) 20 Hz), 130.5, 133.4, 161.6 (d, J ) 240 Hz),
178.3. Anal. Calcd for C13H15FO3: C, 65.53; H, 6.35. Found:
C, 65.42; H, 6.26.
Meth yl (1R,2R,3S)-2-(4-F lu or op h en yl)-3-h yd r oxycyclo-
p en ta n e-1-ca r boxyla te (3). Colorless oil: [R]D -103.3 (c 0.01,
MeOH); 1H NMR (CDCl3, 400 MHz) δ 1.83 (m, 1H), 1.95 (br s,
1H), 2.13 (m, 3H), 2.91 (q, 1H, J ) 8.5 Hz), 3.22 (dd, 1H, J )
18.2 and 8.5 Hz), 3.62 (s, 3H), 4.17 (m, 1H), 7.01 (m, 2H), 7.21
(m, 2H); 13C NMR (CDCl3, 100 MHz) δ 26.3, 33.1, 49.3, 51.9,
56.7, 79.6, 115.5 (d, J ) 20 Hz), 129.0, 136.7, 161.8 (d, J )
240 Hz), 175.6. Anal. Calcd for C13H15FO3: C, 65.53; H, 6.35.
Found: C, 65.15; H, 6.05.
(1S,2S,3R)-2-(4-F lu or op h en yl)-3-h yd r oxym eth ylcyclo-
p en ta n ol (21). Colorless oil: 1H NMR (CDCl3, 400 MHz) δ
1.72 (m, 2H), 1.96 (m, 3H), 2.10 (m, 1H), 2.12 (m, 1H), 2.64
(dd, 1H, J ) 9.5 and 7.4 Hz), 3.50 (dd, 1H, J ) 10.6 and 6.2
Hz), 3.59 (dd, 1H, J ) 10.6 and 6.2 Hz), 4.12 (q, 1H, J ) 6.8
Hz), 7.01 (m, 2H), 7.18 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ
25.2, 33.2, 47.2, 56.5, 65.2, 80.4, 115.5 (d, J ) 20 Hz), 138.1,
161.7 (d, J ) 240 Hz). Anal. Calcd for C12H15FO2: C, 68.55;
H, 7.19. Found: C, 68.42; H, 7.10.
(1R,2R,3S)-2-(4-Flu or oph en yl)-3-h ydr oxycyclopen tan e-
1-ca r boxylic Acid (2). White solid: [R]D -67.0 (c 0.01,
MeOH); mp 142-143 °C (isopropyl acetate/heptane); 1H NMR
(CDCl3, 400 MHz) δ 1.89 (m, 1H), 2.01 (2.10 br s, 1H), 2.17
(m, 3H), 2.96 (m, 1H), 3.23 (dd, 1H, J ) 9.8 and 7.6 Hz), 4.19
(q, 1H, J ) 7.0 Hz), 7.03 (m, 2H), 7.22 (m, 2H), 10.9 (br s, 1H);
13C NMR (CDCl3, 100 MHz) δ 25.9, 33.2, 49.0, 56.7, 79.2, 115.0
(d, J ) 20 Hz), 129.5, 138.0, 161.7 (d, J 240 Hz), 176.3. Anal.
Calcd for C12H13FO3: C, 64.28; H, 5.84. Found: C, 64.00; H,
6.04.
(1R,2R,3S)-2-P h en yl-3-h yd r oxycycloh exa n e-1-ca r box-
ylic Acid (30e). White solid: [R]D -12.73 (c 0.0033, MeOH);
1
mp 176-177 °C (isopropyl acetate/hexane); H NMR ((CD3)2-
CO, 400 MHz) δ 1.35-1.61 (m, 4H), 1.85 (m, 1H), 1.94 (m, 1H),
2.06 (m, 1H), 2.66 (m, 2H), 3.67 (m, 1H), 7.12 (m, 1H), 7.23
(m, 4H), 11.9 (br s, 1H); 13C NMR ((CD3)2CO, 100 MHz) δ 23.8,
30.1, 35.3, 49.1, 54.4, 72.9, 126.2, 127.9, 128.8, 142.0, 174.6.
Anal. Calcd for C13H16O3: C, 70.89; H, 7.32. Found: C, 70.89;
H, 7.32. Found: C, 70.75; H, 7.43.
(1R,2R,3S)-2-(4-F lu or op h en yl)-3-h yd r oxycycloh exa n e-
1-ca r boxylic Acid (30f). White solid: [R]D -16.0 (c 0.002,
MeOH); mp 137-138 °C (EtOAc/hexane); 1H NMR ((CD3)2CO,
400 MHz) δ 1.51 (m, 4H), 1.83 (m, 1H), 1.96 (m, 1H), 2.02 (m,
1H), 2.65 (m, 2H), 3.65 (m, 1H), 6.96 (m, 2H), 7.26 (m, 2H),
11.1 (br s, 1H); 13C NMR ((CD3)2CO, 100 MHz) δ 23.7, 30.0,
35.3, 49.1, 53.7, 72.8, 114.3 (d, J ) 30 Hz), 130.3 (d, J ) 10
Hz), 138.2, 161.5 (d, J ) 20 Hz), 174.4. Anal. Calcd for C13H15
FO3: C, 65.54; H, 6.35. Found: C, 65.23; H, 6.23.
-
Ack n ow led gm en t. We thank Mr. Louis Matty, Dr.
Aaron Moment, Mr. Paul Fernandez, Dr. Thorsten
Rosner, and Dr. Yuri Bereznitski of Merck & Co., Inc.,
for their valuable experimental assistance.
(1R,2R,3S)-2-Meth yl-3-h yd r oxycyclop en ta n e-1-ca r box-
ylic Acid (30a ). White solid: [R]D -15.26 (c 0.0019, MeOH);
mp 87-88 °C (isopropyl acetate/heptane); 1H NMR (CDCl3, 400
MHz) δ 1.12 (t, 3H, J ) 6.9 Hz), 1.77 (m, 1H), 1.95-2.29 (m,
5H), 2.44 (q, 1H, J ) 8.0 Hz), 3.83 (q, 1H, J ) 5.6 Hz), 11.3
(br s, 1H); 13C NMR (CDCl3, 100 MHz) δ 17.7, 25.9, 33.4, 49.4,
51.9, 79.7, 176.3; Anal. Calcd for C7H12O3: C, 58.32; H, 8.39.
Found: C, 58.30; H, 8.45.
Su p p or tin g In for m a tion Ava ila ble: Characterization
data for synthetic intermediates used in the synthesis of 26b-
f, 1H NMR data for 16, and 1H and 13C NMR data for
compounds 26c, d . This material is available free of charge
via the Internet at http://pubs.acs.org.
J O025883M
6000 J . Org. Chem., Vol. 67, No. 17, 2002