Ligand-controlled selectivity in the desymmetrization of meso cyclopenten-1,4-diols via rhodium(I)-Catalyzed addition of arylboronic acids

Article abstract of DOI:10.1021/jo100391e

A highly enantioselective desymmetrization of meso cyclopent-2-ene-1,4- diethyl dicarbonates has been developed using a Rh-catalyzed asymmetric allylic substitution. Depending on the type of ligand used, each of two regioisomeric products can be obtained in good yield and excellent enantioselectivity. Under rhodium(I) catalysis, bisphosphine P-Phos ligands form trans-1,2- arylcyclopentenols as the major product, whereas Segphos ligands lead predominantly to trans-1,4-arylcyclopentenols.

Full text of DOI:10.1021/jo100391e

pubs.acs.org/joc
Ligand-Controlled Selectivity in the Desymmetrization of meso
Cyclopenten-1,4-diols via Rhodium(I)-Catalyzed Addition of Arylboronic Acids
Frederic Menard, David Perez, Daniela Sustac Roman, Timothy M. Chapman, and
Mark Lautens*
Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street,
Toronto, Ontario, M5S 3H6, Canada
mlautens@chem.utoronto.ca
Received March 4, 2010
A highly enantioselective desymmetrization of meso cyclopent-2-ene-1,4-diethyl dicarbonates has been
developed using a Rh-catalyzed asymmetric allylic substitution. Depending on the type of ligand used,
each of two regioisomeric products can be obtained in good yield and excellent enantioselectivity. Under
rhodium(I) catalysis, bisphosphine P-Phos ligands form trans-1,2-arylcyclopentenols as the major
product, whereas Segphos ligands lead predominantly to trans-1,4-arylcyclopentenols.
Introduction
we looked at rhodium(I) complexes to catalyze the enantiose-
lective formation of C-C bonds with activated alkenes.
Transition-metal-catalyzed reactions have allowed us4 and
others5 to exploit this strategy successfully with symmetrical
activated alkenes (Figure 1). Although our work initially looked
at highly reactive alkenes I,6 II,7 and III,8 a systematic study led
us to explore the generality of the method. More specifically, we
sought to extend our methodology to alkenes lacking bicyclic
strain, e.g., IV, or even to simple linear allylic systems V.9
The extension to less strained alkenes brought our method
conceptually closer to asymmetric allylic substitution (AAS),
a field intensively studied with Pd catalysis.10 The use of this
Enantioselective desymmetrization strategies for the synth-
esis of small chiral molecules create highly valuable building
blocks from simple starting materials.1 This approach is attrac-
tive because it can achieve complete conversion of meso sub-
strates into the desired chiral products, whereas traditional
kinetic resolution reactions can lead only to a maximum
theoretical yield of 50%.2 Several catalytic protocols have been
developed to accomplish such desymmetrizations, many of
which make use of enzymatic processes.1,3 Focusing on the
development of new reactions to desymmetrize meso substrates,
(1) For excellent reviews, see: (a) Willis, M. C. J. Chem. Soc., Perkin Trans. 1 1999,
1765. (b) Mikami, K.; Yoshida, A. Synth. Chem. Jpn. 2002, 60, 732. (c) Hoffman, R.
W. Angew. Chem., Int. Ed. 2003, 42, 1096. (d) Rovis, T. In New Frontiers in
Asymmetric Catalysis; Mikami., K., Lautens, M., Eds.; Wiley, NJ, 2007; p 275.
(2) An elegant solution to this problem is dynamic kinetic resolution or
DYKAT: (a) Faber, K. Chem.;Eur. J. 2001, 7, 5004. (b) Martin-Matute, B.;
Edin, M.; Bogar, K.; Backvall, J.-E. Angew. Chem., Int. Ed. 2004, 43, 6535.
(3) (a) Martin-Matute, B.; Backvall, J.-E. Curr. Opin. Chem. Biol. 2007,
11, 226 and references therein. (b) Pellissier, H. Tetrahedron 2008, 64, 1563.
(4) (a) Chiu, P.; Lautens, M. Top. Curr. Chem. 1997, 190, 1–85.
(b) Lautens, M.; Fagnou, K.; Hiebert, S. Acc. Chem. Res. 2003, 36, 48.
(5) (a) Jacobsen, E. N. In Comprehensive Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: New York, 1999; p 1309. (b) Cole, B. M.;
Shimizu, K. D.; Krueger, C. A.; Harrity, J. P. A.; Snapper, M. L.; Hoveyda, A. H. Angew.
Chem., Int. Ed. 1996, 35, 1668. (c) Millward, D. B.; Sammis, G.; Waymouth, R. M.
J. Org. Chem. 2000, 65, 3902. (d) Bertozzi, F.; Crotti, P.; Macchia, F.; Pineschi, M.;
Arnold, A.; Feringa, B. L. Org. Lett. 2000, 2, 933. (e) Del Moro, G.; Crotti, P.; Di Bussolo,
V.; Macchia, F.; Pineschi, M. Org. Lett. 2003, 5, 1971. (f) Nishimura, T.; Kawamoto, T.;
Sasaki, K.; Tsurumaki, E.; Hayashi, T. J. Am. Chem. Soc. 2007, 129, 1492.
(6) (a) Lautens, M.; Rovis, T. Tetrahedron 1998, 54, 1107. (b) Lautens,
M.; Renaud, J.-P.; Hiebert, S. J. Am. Chem. Soc. 2000, 122, 1804. (c) Lautens,
M.; Fagnou, K. J. Am. Chem. Soc. 2001, 123, 7170. (d) Fagnou, K.; Lautens,
M. Angew. Chem., Int. Ed. 2002, 41, 26. (e) Lautens, M.; Hiebert, S. J. Am.
Chem. Soc. 2004, 126, 1437.
(7) (a) Menard, F.; Lautens, M. Angew. Chem., Int. Ed. 2008, 47, 2085.
(b) Panteleev, J.; Menard, F.; Lautens, M. Adv. Synth. Catal. 2008, 350, 2893.
(8) (a) Lautens, M.; Gajda, C.; Chiu, P. J. Chem. Soc., Chem. Commun. 1993,
1193. (b) Lautens, M.; Hiebert, S.; Renaud, J.-P. J. Am. Chem. Soc. 2001, 123,
6384. (c) Lautens, M.; Hiebert, S.; Renaud, J.-P. Org. Lett. 2001, 2, 1971.
(9) Yu, B.; Menard, F.; Isono, N.; Lautens, M. Synthesis 2009, 853.
(10) (a) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395.
(b) Tsuji, J. Palladium Reagents and Catalysts: Innovations in Organic Synth-
esis; Wiley: New York, 1996. (c) Pfaltz, A.; Lautens, M. In Comprehensive
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4056 J. Org. Chem. 2010, 75, 4056–4068
Published on Web 05/14/2010
DOI: 10.1021/jo100391e
r
2010 American Chemical Society

Menard et al.
JOCArticle
products,17 and excellent asymmetric methods exist for the
preparation of substituted products VI, VII and IX.18 It should
be noted that there is currently no enantioselective desymme-
trization protocol to obtain products such as VIII.19
We recently disclosed that a Rh(I)-catalyzed system could
achieve the desymmetrization of meso allylic diol derivatives
1a via a formal SN20 reaction to get 2a selectively (eq 1).20
Murakami also reported independently a closely related, elegant
approach that used unprotected alcohol 1 directly.21 Substituted
cyclopentenols such as 2 are useful building blocks, particularly
because of the alkene, allowing for further transformations.
FIGURE 1. Symmetrical substrates bearing decreasingly activated
alkenes (X = O, NR; LG = OR, NR2).
SCHEME 1. Substitution Patterns Accessible via AAS Reac-
tions
Herein, we present a comprehensive study aimed at under-
standing factors controlling regioselectivity and enantioselec-
tivity in the rhodium(I)-catalyzed desymmetrization of allylic
diols with boronic acids. Systematic investigations identified
sets of ligands that allow control over the regioselectivity of the
products. Moreover, we report conditions leading to improved
enantioselectivity compared to our preliminary report.20
transformation has been demonstrated many times in the
synthesis of a range of natural products.11 Metal-catalyzed
AAS reactions represent the state of the art in the addition of
soft nucleophiles such as enolates and heteroatoms to allylic
substrates.7,12,13 In contrast, the addition of hard nucleo-
philes has presented significant challenges with respect to
both functional group tolerance and selectivity. Recently,
efficient solutions were reported with Cu catalysts to effect
asymmetric allylic substitution with organomagnesium14 or
organozinc reagents,15 on both cyclic (IV) and acyclic (V)
substrates. Although these methods allow exceptional levels
of selectivity with alkyl nucleophiles, the addition of hard sp2
nucleophiles such as aryl and vinyl groups still remains a
limitation.16 Our goal was to develop a catalytic system that
would use organoboron reagents as hard nucleophiles pre-
cursors due to their commercial availability.
Cyclic meso allylic diol derivatives IV are challenging sub-
strates for the proposed reaction due to the possibility of
competing reaction pathways. Indeed, the allylic displacement
reaction may take place via an SN2 or SN20 type substitution,
with overall inversion or retention of stereochemistry in
both cases (Scheme 1). The resulting substitution motifs are
present in many biologically active compounds and natural
Results and Discussion
Desymmetrization of meso Cyclic Allylic Diols. Initial
desymmetrization reactions were attempted on the meso
diethyl dicarbonate 1a.22 The protocol that effected asym-
metric ring-opening reactions of oxabicyclic alkenes II23
failed to produce any desired product with substrate 1a,
and only unreacted starting material was observed (Table 1,
entry 1). We found that using [Rh(cod)OH]2 in combination
with BINAP,24 the trans-1,2-substituted product 2a was
obtained as the major product in a 2:1 ratio over the trans-
1,4-substituted product 3a (entry 2).25 Importantly, none of
the diastereomeric cis isomers VI or VIII were observed.
Despite low conversion of starting material, the reaction
profile was clean: only 2a, 3a, and unreacted starting ma-
terial were present in the mixture. Other metal complexes
such as [Ir(cod)Cl]2 or cationic [Rh(cod)2]OTf gave no
reaction or led to deboronation of the boronic acid. Increas-
ing the reaction temperature or using [Rh(cod)OH]2 in the
absence of a phosphine ligand led mostly to deboronation.
(11) For reviews see: (a) Trost, B. M. J. Org. Chem. 2004, 69, 5813.
(b) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921. (c) Graening,
T.; Schmalz, H.-G. Angew. Chem., Int. Ed. 2003, 42, 2580. (d) Trost, B. M.
Chem. Pharm. Bull. 2002, 50, 1.
(17) (a) Harre, M.; Raddatz, P.; Walenta, R.; Winterfeldt, E. Angew.
Chem., Int. Ed. Engl. 1982, 21, 480. (b) Spada, C. S.; Nieves, A. L.;
Woodward, D. F. Exp. Eye Res. 2002, 75, 155. (c) Acharya, H. P.;
Kobayashi, Y. Tetrahedron 2006, 62, 3329.
(12) With palladium: (a) Trost, B. M.; Machacek, M. R.; Aponick, A.
Acc. Chem. Res. 2006, 39, 747. (b) Basak, S.; Kazmaier, U. Eur. J. Org. Chem.
(18) (a) Legros, J. Y.; Fiaud, J.-C. Tetrahedron Lett. 1990, 31, 7453.
(b) Moriya, T.; Furuuchi, T.; Miyaura, N.; Suzuki, A. Tetrahedron 1994, 50,
7961. (c) Kobayashi, Y.; Mizojiri, R.; Ikeda, E. J. Org. Chem. 1996, 61, 5391.
(d) Bouyssi, D.; Gerusz, V.; Balme, G. Eur. J. Org. Chem. 2002, 2445.
(e) Kabalka, G. W.; Venkataiah, B.; Dong, G. Org. Lett. 2003, 5, 3803.
(19) An alternative method has been reported: Belardi, J. K.; Micalizio,
G. C. J. Am. Chem. Soc. 2008, 130, 16870.
(20) For an early report about this work, see: Menard, F.; Chapman, T.
M.; Dockendorff, C. J.; Lautens, M. Org. Lett. 2006, 8, 4569.
(21) Miura, T.; Takahashi, Y.; Murakami, M. Chem. Commun. 2007, 595.
€
2008, 4169. (c) Kazmaier, U.; Kramer, K. J. Org. Chem. 2006, 71, 8930.
(d) Kazmaier, U.; Stolz, D.; Kramer, K; Zumpe, F. Chem.;Eur. J. 2008, 14,
€
1322.
(13) With rhodium: (a) Evans, P. A.; Nelson, J. D. J. Am. Chem. Soc.
1998, 120, 5581. (b) Evans, P. A.; Nelson, J. D. Tetrahedron Lett. 1998, 39,
1725. (c) Evans, P. A.; Robinson, J. E.; Nelson, J. D. J. Am. Chem. Soc. 1999,
121, 6761. (d) Evans, P. A.; Kennedy, L. J. Org. Lett. 2000, 2, 2213. (e) Evans,
P. A.; Leahy, D. K. Chemtracts 2003, 16, 567.
ꢀ
~
(14) (a) Tissot-Croset, K.; Polet, D.; Alexakis, A. Angew. Chem., Int. Ed.
2004, 43, 2426. (b) Hoveyda, A. H.; Kacprzynski, M. A.
J. Am. Chem. Soc. 2004, 126, 10676. (c) Lopez, F.; van Zijl, A. W.; Minnaard,
A. J.; Feringa, B. L. Chem. Commun. 2006, 409.
(15) (a) Piarulli, U.; Claverie, C.; Daubos, P.; Gennari, C.; Minnaard, A.
J.; Feringa, B. L. Org. Lett. 2003, 5, 4493. (b) Piarulli, U.; Daubos, P.;
Claverie, C.; Roux, M.; Gennari, C. Angew. Chem., Int. Ed. 2003, 42, 234.
(16) In view of the number of synthetic targets that contain benzylic chiral
stereocenters, there is a need to develop more efficient methods. Alexakis, A.;
Malan, C.; Lea, L.; Tissot-Croset, K.; Polet, D.; Falciola, C. Chimia 2006, 60,
124.
(22) For preparation of 1a, see: Arnau, N.; Cortes, J.; Moreno-Manas,
M.; Pleixats, R.; Villarroya, M. J. Heterocycl. Chem. 1997, 34, 233.
(23) (a) Lautens, M.; Dockendorff, C.; Fagnou, K.; Malicki, A. Org. Lett.
2002, 4, 1311. (b) For a review of selected ring-openings prior to 2003, see:
Lautens, M.; Fagnou, K.; Hiebert, S. Acc. Chem. Res. 2003, 36, 48.
(24) (a) Kitamura, M.; Tokunaga, M.; Ohkuma, T.; Noyori, R. Tetra-
hedron Lett. 1991, 32, 4163. (b) Kitamura, M.; Tokunaga, M.; Ohkuma, T.;
Noyori, R. Org. Synth. 1993, 71, 1.
(25) (a) Kobayashi, Y.; Ainai, T.; Ito, M. Tetrahedron Lett. 2003, 44,
3983. (b) Stille, J. K.; Tueting, D. R.; Echavarren, A. M. Tetrahedron 1989,
45, 5052.
J. Org. Chem. Vol. 75, No. 12, 2010 4057

Menard et al.
JOCArticle
FIGURE 2. Ligand examined in the asymmetric allylic substitution reaction.
TABLE 1. Finding a Suitable Rhodium Precatalyst
A study of the impact of solvent showed that aprotic,
weakly coordinating solvents worked best, with THF being
the solvent of choice in terms of yield (Table 2, entries 1-6).
Regioisomeric ratios were not affected by the solvent. It is
noteworthy that, whereas enantioselectivity was constant for
2a, the solvent strongly influenced the ee of 1,4-product 3a
(entries 1-3). The nature of the base had a marked effect on
yield, product distribution, and on the enantioselectivity of
2a (entries 1, and 7-11). The absence of base showed a best
local maximum in terms of regioselectivity, but the yield was
unsatisfactory (entry 8). Since the primary goal was to
improve conversion, Cs2CO3 was used for further studies.
Substrates carrying different leaving groups were investigated
in the asymmetric allylic substitution reaction, but ethyl carbo-
nate appeared to be the best leaving group for the desired reac-
tion.29 The hexafluoroisopropyl carbonate leaving group
(HFIP), which had proved successful for the rhodium allylic
substitution reported by Evans, gave only trace conversion under
our conditions.30 The impact of ligands was then examined in
hope to modulate the intrinsic reactivity of the rhodium catalyst.
Biaryl bisphosphane ligands are the only class of ligands that
showed any appreciable activity (Figure 2).31 Two ligand
families proved to be unique in giving trans-2-phenylcyclopen-
tenyl carbonate (2a) with good regioselectivity: Chan’s P-PHOS
entry
catalyst
liganda
yield (%)b,c
ratio 2a:3a
1
2
3
4
[Rh(cod)OH]2
[Rh(cod)OH]2
[Rh(cod)Cl]2
[Rh(cod)OH]2
(R,S)-L18
(S)-L5
(S)-L5
None
0c
45
2:1
0c
10d
20:1
aSee Figure 2 for ligand structures. bDetermined by 1H NMR analysis
of crude mixture. cYield balance was recovered starting material.
dDeboronation observed.
Carbonate products 2a and 3a could not be separated at
this stage, but they were readily converted to the correspond-
ing alcohols 4a and 5a26 by simple hydrolysis (eq 2). The
resulting alcohols were easily separable by chromatography,
and their enantiomeric enrichment was determined by chiral
HPLC.27,28 The reaction was next investigated thoroughly to
identify key factors controlling selectivity.
ligands32 and Genet’s DiFluorPhos33 (entries 1-3, Table 3).34
^
(29) Amongotherleavinggroupstested,mostdidnotgiveanydesiredproduct
(carbonates: Me, Ph; acetate; benzoate; 4-nitrobenzoate; ethyl phosphonate). In
the case of HFIP carbonate, only trace of product was observed.
(30) Evans, P. A.; Uraguchi, D. J. Am. Chem. Soc. 2003, 125, 7158.
(31) For reviews on axially chiral biaryl diphosphines, see: (a) McCarthy,
M.; Guiry, P. J. Tetrahedron 2001, 57, 3809. (b) Tang, W.; Zhang, X. Chem.
Rev. 2003, 103, 3029.
Synthesis of Chiral trans-1,2-Arylcyclopentenols. The ini-
tial goal was to find reaction conditions to increase conver-
sion and regioselectivity of 1,2-arylcyclopentenol derivatives
2a, while at least maintaining the enantioselectivity.
(32) (a) Wu, J.; Kwok, W. H.; Lam, K. H.; Zhou, Z. Y.; Yeung, C. H.;
Chan, A. S. C. Tetrahedron Lett. 2002, 43, 1539. (b) Wu, J.; Chan, A. S. C.
Acc. Chem. Res. 2006, 39, 711.
(33) (a) Jeulin, S.; Duprat de Paule, S.; Ratovelomanana-Vidal, V.;
^
Genet, J.-P.; Champion, N.; Dellis, P. Angew. Chem., Int. Ed. 2004, 43,
(26) (a) Kobayashi, Y.; Murugesh, M. G.; Nakano, M.; Takahisa, E.;
Usmani, S. B.; Ainai, T. J. Org. Chem. 2002, 67, 7110. (b) Tueting, D. R.;
Echavarren, A. M.; Stille, J. K. Tetrahedron 1989, 45, 979. (c) Marino, J. P.;
ꢀ
Fernandez de la Pradilla, R.; Laborde, E. J. Org. Chem. 1987, 52, 4898.
^
(27) The absolute stereochemistry of (-)-4a was assigned by the prepara-
tion of its (þ)- and (-)-MTPA ester derivatives. Dale, J. A.; Mosher, H. S.
J. Am. Chem. Soc. 1973, 95, 512. Optical rotation measurements were also
correlated with literature reports (ref ).
(28) The stereochemistry of (1R,2S)-4a shown in eq 2 arose from (S)-
biaryl bisphospine ligands; that of (1R,4R)-5a was assigned by correlation.
320. (b) Jeulin, S.; Duprat de Paule, S.; Ratovelomanana-Vidal, V.; Genet, J.-
P.; Champion, N.; Dellis, P. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5799.
(34) Despite the promising ee obtained with Difluorphos (L3), we pur-
sued our studies with a ligand having comparable behaviour, namely,
P-PHOS (L1). The main reason was the prohibitive price of research
quantities of Difluorphos from its manufacturer.
4058 J. Org. Chem. Vol. 75, No. 12, 2010

Menard et al.
JOCArticle
TABLE 2. Variation of Solvent and Base with BINAP and Phenyl-
boronic Acida
TABLE 4. Optimization of Experimental Parameters with Xylyl-P-
PHOS
ee (%)d
entry
solvent
base
yield (%)b
ratio 2:3c
2
3
variation from
standard conditions
1
THF
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Na2CO3
45
21
19
9
0
0
15
26
29
16
12
2:1
2:1
2:1
2:1
76
74
76
nd
72
57
36
nd
entry
yield (%)a
ratio 2:3b
ee 4 (%)c
2e
3e
4e
5f
6
dioxane
toluene
DMF
MeCN
i-PrOH
THF
THF
THF
THF
THF
1
2
3
4
5
6
7
8
9
standard
substrate: 1y
substrate: 1z
70
74
41
0
73
79
79
70
87
>15:1
>15:1
1.2:1
90
90
82
0.5 equiv Cs2CO3
2.0 equiv Cs2CO3
5.0 equiv PhB(OH)2
L:Rh = 2.0:1
L:Rh = 1.2:1
L:Rh = 1.2:1;
7.5 mol % [Rh]2
P-PHOS, instead of
Xyl-P-PHOS,
L:Rh = 1.2:1
7
8
9
10
11
3:1
5:1
3:1
2.5:1
1:1
74
84
82
66
72
36
56
46
38
71
7:1
3.5:1
>20:1
>20:1
20:1
84
90
90
90
88
KOH
KF
DIPEA
aReactions performed using biscarbonate 1a (0.164 mmol), Rh
catalyst (5 mol % dimer), ligand (10 mol %), base (1.0 equiv), and
PhB(OH)2 (2.0 equiv) in THF (0.20 M) under Ar atmosphere. bIsolated
yield. cDetermined by 1H NMR analysis of crude mixture. dDetermined
by chiral HPLC analysis on deprotected alcohols. eReaction conducted
at 90 °C. fReaction conducted at 80 °C.
10
74
>20:1
82
aIsolated yield. bDetermined by 1H NMR analysis of crude mixture.
cDetermined by chiral HPLC analysis on deprotected alcohols.
gave good conversion and exceptional ee for both products 2
and 3, but in an almost equimolar mixture (entries 9 and 10). In-
triguingly, a dramatic difference in regioselectivity was observed
by replacing two hydrogens of L10 by two fluorine atoms on
the catecholic methylene of L3, a site remote from the reacting
groups (17:1 vs almost 1:1). Among several other chiral ligands
that were screened but are not shown, some returned only traces
of products (e.g., Monophos, C2-Ferriphos, KenPhos) or did
not react at all (i-Pr-PHOX, Me-DuPhos).
TABLE 3. Effect of Ligands on Regioselectivity of the Rh(I)-Catalyzed
AASa
Xylyl-SegPhos attracted our attention because it gave
exceptional ee for both products and gave good conversion
(L11, entry 10). As will be discussed below, this result was
later exploited in reactions aimed at synthesizing the com-
plementary 1,4-product 3.
ee (%)d
entry
ligand
L1, P-Phos
L2, Xyl-P-Phos
L3, DiFluorPhos
L4, Me-SoniPhos
L5, BINAP
L6, Tol-BINAP
L7, Xyl-BINAP
L9, C3-TunePhos
L10, SegPhos
L11, Xyl-SegPhos
L16, Cl-MeO-BIPHEP
L13, SolPhos
yield (%)b ratioc 2:3
2
3
1
2
3
4
5
6
7
8
74
65
58
16
45c
32
59
30
60
76
60
11
3
>20:1
13:1
17:1
10:1
2:1
1:1
2:1
1.5:1
2.3:1
1:1
82
88
92
nd
76
95
82
42
98
Optimization of Reaction Conditions. An optimization
study was undertaken to increase the yield and enantioselecti-
vity of the 1,2-product 2a with Xyl-P-Phos as ligand. A
summary of the most significant results is shown in Table 4.
A second look at the nature of the leaving group revealed that
small alkyl carbonates worked equally well, whereas aryl carbo-
nates led to a complete loss of regioselectivity (entries 1-3). The
amount of Cs2CO3 was found to significantly impact the reac-
tion, and the initial 1.0 equiv was best (entries 4 and 5). Increas-
ing the equivalents of phenylboronic acid gave higher conver-
sion, but at the expense of regioselectivity (entry 6). Increasing
the ratio of ligand to catalyst resulted in higher conversion and
increased selectivity (entries 7 and 8). This positive effect is pre-
sumed to arise from a higher concentration of the chiral active
complex, otherwise lower than expected due to ready oxidation
of ligand L2.35
72
32
60
80
9
92 >98
96 >98
10
11
12
13
14
15
1:1
nd
nd
90
98
L20, QUINAP
L19, ChiraPhos
L18, t-Bu-JosiPhos
2
nd
0
aReactions performed using biscarbonate 1a (0.164 mmol), 5 mol %
[Rh(cod)OH]2, ligand (10 mol %), Cs2CO3 (1.0 equiv), and ArB(OH)2
(2.0 equiv) in solvent (0.20 M) under Ar atmosphere. bIsolated yield.
cDetermined by 1H NMR analysis of crude mixture. dDetermined by
chiral HPLC analysis on deprotected alcohols.
The lower ratio of 1.2:1 was preferred for cost economy.
Increasing the amount of rhodium dimer led to significantly
Fortunately, they also showed reasonable enantioselectivity,
which could be improved upon further optimization.
Sterically, xylyl-substituted bisphosphanes gave enantio-
meric excesses 4-6% higher than those of their phenyl-
substituted analogues but did not increase regioselectivity
for 2a (entries 1 and 2; 5 and 7; 9 and 10). The SegPhos family
(35) 31P NMR analyses revealed that Xyl-P-PHOS is highly sensitive
to oxidation in solution. Phosphine oxides of Xyl-P-PHOS: 31P NMR
(THF-d8) = 27.1 ppm for dioxide; 25.3 and -14.2 for monoxide; -12.5
ppm for the free diphosphine.
J. Org. Chem. Vol. 75, No. 12, 2010 4059

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TABLE 5. Scope of Arylboronic Acids in the Rh(I)-Catalyzed Enan-
TABLE 6. Influence of Leaving Group, Solvent, and Concentration
using Xyl-SEGPHOS as Chiral Liganda
tioselective Desymmetrization with Xylyl-P-PHOSa
entry
1
solvent (conc, M) yield (%)b ratioc 3:2 ee (%)d 3 (2)
1
2
3
4
5
6
7
1a
1a
1a
1a
1a
1a
1a
THF (0.12)
THF (0.31)
26
56
63
60
80
70
70
1:1.2
1.5:1
99 (84)
99 (93)
99 (92)
99 (93)
99 (97)
99 (96)
99 (88)
dioxane (0.31)
benzene (0.31)
benzene (0.47)
benzene (0.69)
toluene (0.31)
1.3:1
1.7:1
2.0:1
1.8:1
1.5:1
aAll reactions were performed using 1 (0.135 mmol), catalyst (4 mol %),
Xyl-SegPhos (L11, 12 mol %), base (1 equiv), and solvent at the indicated
c
concentration of 1. bIsolated yield. Determined by 1H NMR of purified
mixture. dDetermined by chiral HPLC analysis of deprotected alcohol.
seemed detrimental to catalytic activity (e.g., N-Boc-4-amino-
phenylboronic acid, entry 10).36
The reaction showed a limitation with arylboronic acids
bearing ortho substituents as a marked decrease in both con-
version and selectivity was observed (entries 15 and 16). Other
cases where no conversion occurred included heterocyclic boro-
nic acids such as 4-pyridineboronic acid, 3-furanboronic acid,
3-thiopheneboronic acid, and 2-furanboronic acid. Electron-
deficient 3-nitrophenylboronic acid gave only very low conver-
sion (less than 10%). Also, sp3 nucleophiles such as methyl-
boronic acid gave no reaction.
Synthesis of Chiral trans-1,4-Arylcyclopentenols. The suc-
cessful enantioselective synthesis of 1,4-substituted cyclo-
pentenols was very recently reported by the group of Alexakis
using Cu catalysis with a new family of chiral phosphine ligands,
SimplePhos.37 The reaction was described with alkyl Grignard
reagents.
During the above studies, the fact that both regioisomers 2
and 3 were formed hinted at the possibility of developing a
complementary protocol to obtain 3 selectively. Ligand studies
identified bisphosphine ligand Xyl-SegPhos38 as the least selec-
tive for the 1,2-product 2a and hence the most promising for 3a
(eq 3). More importantly, Xyl-SegPhos showed exceptional
enantioselectivity for the 1,4-product 3a (98% ee), as well as
improved ee for 2a (96% ee). Encouraged by these observations,
the reaction was reinvestigated with the specific goal of finding
conditions that would allow selective preparation of trans-1,4-
arylcyclopentenols as useful chiral building blocks.
aProtocol A: reactions were performed using biscarbonate 1a (0.164
mmol), Rh catalyst (5 mol % dimer), (S)-L2 (12 mol %), Cs2CO3 (1.0
equiv), and ArB(OH)2 (2.0 equiv) in THF (0.20 M) under Ar atmo-
sphere. bIsolated yields of carbonates, average of at least two runs.
cDetermined by 1H NMR analysis of crude mixture. dDetermined by
chiral HPLC analysis on deprotected alcohol (4).
higher conversion (entries 7 and 8), but it was considered that
a loading above the already high 5 mol % of dimer (10 mol %
rhodium) was undesirable, so the catalyst loading was main-
tained at 5 mol % of dimer for further experiments. Finally, re-
examining P-Phos at a 1.2:1 Rh:L ratio showed better selectivity,
but the ee remained lower than with Xyl-P-Phos (entry 10).
Scope and Limitations of Arylboronic Acids. The enantio-
selective desymmetrization of dicarbonate 1a proved to be
efficient with a wide range of arylboronic acids (Table 5).
Some trends were observed when comparing sterics and
electronic effects. First, meta-substituted arylboronic acids
gave the best results in terms of both yield and ee (entries 11-14).
Then, within the para-substituted series, yields seem to
correlate with electron density of the substituents as indi-
cated by Hammett sigma constants, whereas ee was not
significantly affected (entries 2-9). In general, lower con-
version with electron-rich arylboronic acids was associated
by an increased amount of homocoupling products, which
The effect of solvent was examined using Xyl-SegPhos
(L11). Dioxane and benzene gave similar results for the
reaction, with benzene favoring slightly the desired regio-
isomer 3 (Table 6). Non-coordinating solvents like benzene
and toluene provided the highest yield and ratio of desired
(36) Control experiments showed that homocoupling of the boronic acid
occurs as a background reaction under the reaction conditions.
(37) Millet, R.; Alexakis, A. Synlett 2008, 1797.
(38) Shimizu, H.; Nagasaki, I.; Matsumura, K.; Sayo, N.; Saito, T. Acc.
Chem. Res. 2007, 40, 1385.
4060 J. Org. Chem. Vol. 75, No. 12, 2010

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TABLE 7. Effect of Bisphosphane Ligands on Regioselectivitya
and 5 can be prepared with unprecedented enantioselectivity
in a single operation from readily available starting materials
(i.e., entry 10).
Cl-MeO-BIPHEP was selected as optimal ligand to study
the influence of the boronic acid on the regioselectivity of the
reaction. While benzene is the solvent of choice to favor
formation of 3a, solubility issues arose when boronic acids
other than PhB(OH)2 were used. As we surveyed more
arylboronic acids, it became apparent that yields were gene-
rally low. Experimentally, the optimized reaction protocol
of Table 5 required canulating simultaneously 1a and the
boronic acid as a stock solution. Polar boronic acids would
often not fully solubilize in benzene and could not be added
this way. A solution to this issue was found by changing the
addition technique of reagents. Instead of adding the sub-
strate and boronic acid as a solution, dicarbonate 1a was
added while the premixed complex solution was still at 60 °C,
and the remaining solids were added by opening of the
reaction vessel. For instance, p-trifluoromethylphenylboro-
nic acid (6b) is insoluble in benzene, but the modified
procedure (protocol B) gave the arylcyclopentenes 2b and
3b in 87% yield as opposed to 18% when added at rt. (eq 4).
entry
L
ligand
yield (%)b ratioc 2a:3a ee (%)d 3a (2a)
1
2
3
4
none
L1 P-Phos
L2 Xyl-P-Phos
L3 DiFluorphos
L7 Xyl-BINAP
L5 BINAP
L10 SegPhos
L11 Xyl-Segphos
L11 Xyl-Segphos
10
74
87
58
43
42
60
26
56
80
76
60
73
82
20:1
20:1
18:1
17:1
12:1
2.5:1
2.3:1
1.2:1
98 (82)
nd (92)
nd (92)
nd (12)
95 (87)
98 (92)
99 (84)
99 (93)
99 (97)
99 (93)
>99 (93)
99 (94)
99 (95)
5e
6e
7
8
9e
1:1.4
10f L11 Xyl-Segphos
11e L12 SynPhos
1:2.0
1:1.7
1:2.0
1:2.5
1:2.8
12g L16 Cl-MeO-BIPHEP
13e L16 Cl-MeO-BIPHEP
14f L16 Cl-MeO-BIPHEP
aAll reactions were performed using 1a (0.135 mmol) with the listed
catalyst (8 mol % in Rh), ligand (12 mol %), and THF (0.12 M).
bIsolated yield. Determined by H NMR of purified mixture. Deter-
mined by chiral HPLC analysis of deprotected alcohols. eIn PhH (0.31
M). fIn PhH (0.47 M). gIn dioxane (0.47 M).
c
1
d
1,4-products as well as the highest ee for both regioisomers.
Toluene gave a yield similar to that of benzene, but the latter
was still preferred for its superior solubilizing ability.
The concentration of substrate was found to have a signifi-
cant effect on the regioselectivity with Xyl-SegPhos ligand
(L11). Increasing the concentration from 0.12 M to ∼0.5 M
favored the desired 1,4-product 3 (entries 4-6). Intriguingly, we
also observed that the ee of the 1,2-product is affected by the
concentration. A local maximum of concentration was observed
at 0.47 M and was selected as optimal concentration.
A second look was taken at ligands in solvents such as ben-
zene, dioxane, and THF. Again, only bidentate bisphophanes
were successful at giving the desymmetrized products 2 and 3.
The most significant results of the ligand study are summarized
in Table 7. An interesting general trend is observed as regio-
selectivity seems to correlate with the electronic density of the
phosphorus atoms. From the pyridine-based P-PHOS family,
which was shown to be selective for 2, an incremental ratio drift
can be seen toward the desired 1,4-substituted cyclopentene 3
(entries 2-12). The ligand Cl-MeO-BIPHEP39 gave the highest
3:2ratio. The noted dependence on concentration observed with
Xyl-SEGPHOS was also confirmed with Cl-MeO-BIPHEP
(entries 8-10 and 12-14, respectively).
Importantly, the electron-rich biphenyl-based ligands L10,
L11, L12, andL16 consistently gave outstanding ee values for 3a
(entries 7-14). It should also be noted that the ee of 1,2-sub-
stituted products 2 are notably higher with L10-L16 than those
we found previously with Xyl-P-PHOS (L2). Despite our best
efforts, the highest regioselectivity for 3 that could be achieved
was close to 3:1 (entry 14). However, the method is still synthe-
tically useful since once the carbonate is cleaved, the parent alco-
hols 4 and 5 are easily separated by chromatography. Further-
more, results from Table 7 indicate that both cyclopentenols 4
Scope of the Reaction with Cl-MeO-BIPHEP. The Rh-
catalyzed enantioselective desymmetrization was shown to
tolerate a wide range arylboronic acids and gave both
regioisomeric arylcyclopentenols cleanly. The results with
Cl-MeO-BIPHEP are summarized in Table 8. Importantly,
the 1,4-substituted products 3 were obtained with outstand-
ingly robust enantioselectivity. The regioisomeric ratio was
fairly constant at about 2:1, favoring the products 3. A
limitation was observed with ortho-substituted arylboronic
acids. In these cases, the reactivity is likely hampered by
steric factors, otherwise the regioselectivity and enantio-
selectivity is similar to that of the other examples.
Mechanistic Considerations. Our working hypothesis for
the mechanism of the reaction is depicted in Scheme 2. At
least two catalytic cycles can be considered. The first involves
a carborhodation of the alkene as the key step, whereas the
second involves an oxidative addition of the RhI catalyst to
generate RhIII σ-enyl intermediate. Our results suggest that
both may be operative and competitive, depending on the
ligands used.
The generation of the active catalyst is common to both
proposed pathways. In the premixing phase, [Rh(cod)OH]2
is heated in the presence of the bisphosphine ligand, and the
more labile 1,5-cyclooctadiene is displaced by the chiral
ligand to form A, which is presumably the active catalyst.40
Upon addition of the boronic acid, fast transmetalation of
the aryl moiety from boron to rhodium occurs to form B.
Binding the alkene of substrate 1 to the Rh(I) center leads to
C. The two proposed pathways diverge at this step.
(39) (a) Laue, C.; Schroeder, G.; Arlt, D. Eur. Pat. 749973 A1, 1996.
(b) Driesen-Holscher, B.; Kralik, J.; Agel, F.; Steffens, C.; Hu, C. Adv. Synth.
Catal. 2004, 346, 979.
(40) Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am.
Chem. Soc. 2002, 124, 5052.
J. Org. Chem. Vol. 75, No. 12, 2010 4061

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JOCArticle
TABLE 8. Scope of Arylboronic Acids in the Rh(I)-Catalyzed Enan-
complex G, from which a reductive elimination would lead to
the 1,4-substituted product 3. Accordingly, the rate of F/G
isomerization versus the rate of reductive elimination would be
pivotal in determining the regioselectivity of the reaction.
The regioselectivity of the reaction may therefore depend on
the relative rates of three steps: k1, k2, and k3/k-3. Exclusive
formation of the 1,2-products 2 would be observed if k1 is much
greater than k2. Alternatively, 2 may also be formed if condi-
tions either disfavor equilibration of F to G or force rapid
reductive elimination, k4 (e.g., by large steric demands on
complex F). On the other hand, to obtain selectively 1,4-
regiosomer 3, k2 must be accelerated relative to k1 to prevent
formation of 2. For instance, factors contributing to selective
formation of isomer 3 may include electron-rich phosphine
ligands stabilizing ionization of the complex to Rh(III) (this
seems to be what we observed in Table 7) and phosphines
favoring isomerization of intermediate F to G.
tioselective Desymmetrization with Cl-MeO-BIPHEPa
We were unable to gather direct evidence for a carbo-rhoda-
tion step (the selectivity problem might simply reflect the com-
peting formation of F and G). However, the observed ee of both
regioisomers 2 and 3 should be identical since irreversible
desymmetrization of the substrate takes place at k2. Yet, as
clearly shown in Tables 2, 3, 6, 7, and 8, the ee of 2 and 3 did not
correlate. We therefore conclude that both pathways must
occur, with the carbo-rhodation pathway potentially being less
enantioselective, and therefore affording 2 with an eroded ee.
In the substitution reaction, one of the carbonates is liberated
and is presumed to be ultimately trapped by boron byproducts
in the alkoxyde or carbonate ionic form. Nevertheless, the
potential of the alkoxide or carbonate to complex with the
rhodium catalyst could not be neglected. Indeed, our substrate
screening had shown that the nature of the carbonate had a
strong influence on both yield and enantioselectivity.
An experiment was conducted to probe whether the alkoxide
exerts a steric influence at the alkene attack or complexes to the
rhodium center. Ethyl dicarbonate 1a wassubmittedtothereac-
tion conditions in the presence of 1 equiv of 2-propanol (eq 5).
The results revealed that both factors are at play: the yield was
21% compared to 60%, but ee remained high (92/96% vs 93/
99% ee). When the substrates bore isopropyl carbonates, the
yield was poor, i.e., 20%, but enantioselectivity was the most
affected parameter. In this case, ee of both products was highly
eroded to 69% and 40% ee. These results suggest the released
alkoxide may complex to RhI and hinder catalyst turnover. In
addition, the size of the carbonate substituent may influence
enantiotopic discrimination.
aProtocol B: reactions were performed using 1a (0.135 mmol), Rh
catalyst dimer (4 mol %), (S)-L16 (12 mol %) in solvent (0.47 M), under
Ar; where 1a was added at 60 °C, followed by boronic acid and base
added as solids in one portion. bIsolated yield of mixed carbonates 2 and
3. cDetermined by 1H NMR of purified mixture. dDetermined by chiral
HPLC analysis of deprotected alcohols 4 and 5.
The carbo-rhodation pathway (i) shows a diastereo- and
enantioselective insertion of the alkene into the Rh-Ar
bond, which would generate the key intermediate D. Sub-
sequent antiperiplanar β-alkoxide elimination then yields the
1,2-product 2. This mechanism is based on our previous
work for Rh-catalyzed ring opening of oxabicyclic mole-
cules. In the present case, desymmetrization of the cyclic
dicarbonate yielded exclusively the trans products, whereas
with the previous ring-opening reaction, cis products were
observed exclusively. The relative stereochemistry in the
products is set by the carborhodation occurring on the face
of the olefin anti to the carbonate leaving groups.
The above mechanism cannot explain the formation of the
1,4-products 3. To account for the observed 1,4-product, we
need to consider at least partial contribution from an alter-
native pathway.
The oxidative addition pathway (ii) proceeds with an en-
antioselective ionization of the rhodium(I) catalyst to generate
a σ-enyl rhodium(III) complex intermediate F. The existence of
σ-enyl intermediates was demonstrated by Evans and co-
workers.13,41 They also showed that isomerization between
regioisomers was slow. Once the 1,2-σ-enyl complex F is
formed, it could reductively eliminate to yield the 1,2-substi-
tuted product 2 or equilibrate with the isomeric 1,4-σ-enyl
Two control experiments were conducted to further probe
the effect of free alkoxide in the reaction with BINAP
as ligand (eq 6).42 Adding 0.5 equiv of EtONa at the start of
the reaction led to only 10% conversion. Similarly, adding
0.5 equiv of t-BuOK showed no conversion at all. These
experiments suggest that the production of an alkoxide
(42) The reaction conditions are overall basic and may not favor dec-
arboxylation. Nevertheless, a large amount of boron reagents and byproduct
are present which may act as Lewis acids. Only a small concentration of
alkoxide is required to shut down the catalytic activity.
(41) (a) Evans, P. A.; Leahy, D. K. J. Am. Chem. Soc. 2003, 125, 8974. (b)
Evans, P. A.; Lawler, M. J. J. Am. Chem. Soc. 2004, 126, 8642.
4062 J. Org. Chem. Vol. 75, No. 12, 2010

Menard et al.
SCHEME 2. Plausible Catalytic Cycles for the Rh-AAS Proceeding via Carborhodation and/or σ-Enyl Divergent Intermediates
JOCArticle
during the course of the reaction may be detrimental to the
conversion. Thus, as the reaction proceeds, even if decarboxy-
lation is slow, it may generate enough alkoxide to impede
reactivity. Potential trapping agents were examined with the
hope of sequestering the released ethoxide, but to no avail.43
SCHEME 3. Application of Methodology to the Synthesis of
NK1 Inhibitor Precursors
A competition experiment was performed with two different
nucleophiles. When 2.0 equiv of phenylboronic acid and
2.0 equiv of 4-methoxyphenylboronic acid were added together
to a reaction, the conversion achieved was only 50%, with a 2:1
ratio of products from the addition of the phenylboronic acid
and 4-methoxyphenylboronic acid, respectively (highly regiose-
lective for the 1,2-products, eq 7). These results suggest that the
presence of the 4-methoxyphenylboronic acid leads to a faster
deactivation of the catalyst than when only phenylboronic acid
is present (where 70% conversion is otherwise achieved). A slow
addition of the nucleophile was not beneficial for conversion.
current drug candidates.44 In particular, many tachykinin
receptor antagonists possess a triazole ring fused to a piper-
idine bearing a trans-3,4-arylhydroxy substitution motif. A
specific example is illustrated by 9, which is an analogue of
Aprepitant, an NK1 inhibitor from Merck (Scheme 3).45
Using our methodology to prepare compound (R,S)-4a
enantioselectively would provide an alternative method to
the chiral resolution reported in the patented synthesis.
The synthesis of the enantioenriched 3,4-trans disubstitut-
ed piperidine (R,S)-8 was effected by derivatizing (R,S)-7 to
an 3-arylpiperidine in 37% yield over three steps. Piperidine
8 was obtained in 91% ee and intercepts the patented
synthesis of 9. The synthesis of the NK1 inhibitor is reported
with five additional synthetic steps on the deprotected (R,S)-
8. Notably, the stereoselective synthesis of piperidines bear-
ing the particular substitution pattern displayed in 8 cannot
Synthetic Applications. trans-3,4-Disubstituted piperi-
dines are important building blocks that are present in
(44) (a) Humphrey, J. M. Curr. Top. Med. Chem. 2003, 3, 1423. (b) Saria,
A. Eur. J. Pharmacol. 1999, 375, 51.
(45) Devita, J. R.; Young, J. R. Patent WO/2007/081897, 2007.
˚
(43) ThetrappingagentstestedincludedTBSCl,4AMS, MgO/BaO, and BF3.
J. Org. Chem. Vol. 75, No. 12, 2010 4063

Menard et al.
JOCArticle
be accomplished easily using traditional methods. Thus, it
illustrates the value of the Rh-catalyzed AAS reaction.
and Cs2CO3 (80 mg, 0.26 mmol) were added together as solids,
by rapidly opening the deep vessel (minimizing exposition to
air). The tube was flushed with Ar at rt for 2-5 min, then put
back to heat at 60 °C for 16 h. Reaction showed full conversion
by TLC (vanillin stain). To the dark brown reaction mixture
were added 5 mL of Et2O (heavy precipitate formed) and 10 mL
of saturated NH4Cl aqueous solution. The decanted aqueous
layer was extracted with 3 ꢀ 20 mL of Et2O; the combined
organic phases were dried with brine and MgSO4, then filtered,
and concentrated under reduced pressure. The crude residue was
applied to the top of a column of silica gel and purified by
column chromatography (5-25% EtOAc/hexane as elution
gradient). Monocarbonates 2a and 3a were recovered together
as a colorless oil, 62 mg (82%). 1H NMR analysis revealed a 2:3
ratio of 1:2.8. Characterization and enantiomeric excess was
determined on the deprotected alcohols (see Procedure C).
General Deprotection of Alcohols (Procedure C). The com-
bined monocarbonate isomers 2 and 3 were dissolved in MeOH
(0.02 M), and K2CO3 (10-14 equiv) was added. The white
suspension was stirred at rt until complete conversion (typically
less than 3 h).48 One volume of saturated NH4Cl aqueous
solution was added and extracted three times with Et2O. The
combined organic layers were dried over MgSO4, filtered, and
concentrated under reduced pressure to yield a mixture of
alcohols. The 1,2- and 1,4-regioisomers 4 and 5 were separated
and purified by column chromatography on silica gel (10-40%
gradient of EtOAc/hexane). The yield was generally quantita-
tive and reflected the ratio of the crude carbonates mixture. The
enantioenrichment of each regioisomers was measured on the
isolated products and compared to racemic samples.49
Conclusions
We have reported a full study of the Rh(I)-catalyzed AAS
of symmetrical allylic diols. A new catalytic method has been
established to add stable sp2 C-nucleophiles to activated
alkenes. A range of chiral homoallylic alcohols can be
synthesized in unprecedented enantioselectivity from simple
cyclic allylic diol derivatives.
The regioselectivity of the products can be diverted by
changing the bisphosphine ligand and solvent system. This
work is complementary to existing methods in that it uses
aryl groups as nucleophiles. The application of this metho-
dology was demonstrated in the synthesis of enantioenriched
piperidine 8. The synthesis featured the rhodium-catalyzed
AAS as a key step to establish two neighboring trans stereo-
centers. Further work will aim at expanding the method to
other types of allylic diol derivatives.
Experimental Section
For general information see Supporting Information. Char-
acterization data for 2a-2p, 3a, 3b, 3l, 3m, 4a-4k, 4n-4p, and
5a was reported previously.20,46
Rhodium-Catalyzed Desymmetrization of cis-Cyclopent-2-
ene-1,4-diethyl Dicarbonate. Typical Preparation of the 1,2-
Regioisomeric Products 2 (Procedure A). To a 1 dram vial
equipped with a magnetic stir bar were added [Rh(cod)OH]2
(3.7 mg, 0.0082 mmol), (S)-Xyl-P-PHOS47 (14.9 mg, 0.020
mmol), and Cs2CO3 (53 mg, 0.164 mmol). The vial was sealed
and flushed with argon. Distilled THF (0.8 mL) was added, and
the mixture was stirred for 30 min on a 50-55 °C oil bath.
Dicarbonate 1a (40 mg, 0.164 mmol) and phenylboronic acid (40
mg, 0.32 mmol) were added together as a solution in distilled
THF (0.8 mL). The reaction mixture was heated on a 50-55 °C
oil bath. After 16 h, THF (5 mL) and hexanes (5 mL) were added
to the reaction mixture, and it was concentrated with silica gel,
then applied to the top of a column of silica gel, and purified by
column chromatography (5-20% EtOAc/hexane as elution
gradient). An inseparable mixture of the monocarbonates 2a
and 3a was recovered as a colorless oil, 33 mg (87%). 1H NMR
analysis revealed an isomer ratio of 92:8 favoring the 1,2-
product 2a. The enantiomeric excess was determined on the
deprotected alcohols (see Procedure C).
Rhodium-Catalyzed Enantioselectvie Desymmetrization of
meso Allylic Dicarbonates. (General Procedure B). Into a 13
mm ꢀ 135 mm screw-cap tube equipped with a magnetic stir bar
were weighed [Rh(cod)OH]2 (7.4 mg, 0.0164 mmol) and (S)-Cl-
MeO-BIPHEP47 (25.6 mg, 0.039 mmol). The tube was equipped
with a screw-cap septum and flushed with argon. Benzene (0.30
mL) was added, and the mixture was stirred in a 60 °C oil bath
for 15 min; the yellow solution turned to dark orange. Mean-
while, a solution of dicarbonate 1a (80 mg, 0.32 mmol) in 0.40
mL of benzene was prepared. The substrate solution was
canulated to the premixed complex solution at 60 °C; the reddish
solution darkened. Then phenylboronic acid (80 mg, 0.64 mmol)
(1R,2S)-trans-2-(40-Trifluoromethylphenyl)-cyclopent-3-enyl
Ethyl Carbonate (2b)20 and (1R,4R)-trans-4-(40-Trifluoromethyl-
phenyl)-cyclopent-2-enyl Ethyl Carbonate (3b).20. Prepared ac-
cording to Procedure B. The inseparable regioisomers were
obtained as a colorless oil in 81% yield (80 mg), showing a 1:2.8
1
ratio of 2:3 by H NMR spectroscopy. The regioisomers were
characterized as the free alcohols 4b and 5b. Major regioisomer 3b:
1H NMR (400 MHz, CDCl3): δ 7.55 (2H, d, J = 8.2 Hz), 7.24 (2H,
d, J = 8.7 Hz), 6.19-6.11 (2H, m), 5.76 (1H, ddd, J = 9.1, 4.0, 2.0
Hz), 4.25-4.16 (1H, m), 4.21 (2H, q, J = 7.1 Hz), 2.54-2.46 (1H,
m), 2.11 (2H, ddd, J = 14.6, 7.1, 5.6 Hz), 1.31 (3H, t, J = 7.1 Hz).
(1R,2S)-trans-2-(40-Trifluoromethylphenyl)-cyclopent-3-enol
(4b). Colorless oil. [R]28.7D=þ165 (c 0.80, CHCl3); enantiomeric
ratio was 96.4:3.6, as determined by HPLC analysis (Chiralcel
1
OD-H; 225 nm). H NMR (400 MHz, CDCl3): δ 7.56 (2H, d,
J = 8.2 Hz), 7.30 (2H, d, J = 8.1 Hz) 5.95 (1H, ddd, J = 5.9, 4.3,
2.2 Hz), 5.77 (1H, ddd, J=6.0, 4.2, 2.1 Hz), 4.28 (1H, dt, J=6.9,
4.3 Hz), 3.85-3.82 (1H, m), 2.82 (1H, dddd, J = 17.0, 6.8, 3.9,
2.0 Hz), 2.40 (1H, dddd, J = 17.0, 6.1, 4.3, 1.9 Hz), 1.83 (1H, br
s, alcohol). 13C NMR (100 MHz, CDCl3): δ 146.7, 131.4, 130.4,
127.7, 125.5 (q, J = 3.8 Hz, CF3), 122.9, 80.8, 60.4, 41.5. 19F
NMR (375 MHz, CDCl3): δ -63.1 (s, 3F).
(1R,4R)-trans-4-(40-Trifluoromethylphenyl)-cyclopent-2-enol
(5b). Colorless oil. [R]28.9D=þ210 (c 1.35, CHCl3); enantiomeric
ratio was 99.5:0.5, as determined by HPLC analysis (Chiralcel
1
OD-H; 225 nm). H NMR (400 MHz, CDCl3): δ 7.54 (2H, d,
J = 8.0 Hz), 7.24 (2H, d, J = 8.0 Hz), 6.09 (1H, dd, J = 5.7, 2.1
Hz), 6.03 (1H, ddd, J = 7.6, 2.2, 0.6 Hz), 5.09-5.03 (1H, m),
4.29-4.18 (1H, m), 2.32 (1H, ddd, J = 14.3, 8.0, 2.7 Hz), 2.08
(1H, ddd, J = 14.1, 6.9, 5.5 Hz), 1.57 (1H, brs). 13C NMR (100
MHz, CDCl3): δ 149.1 (d, J = 1.5 Hz), 138.3 (2), 135.1 (2),
128.7, 127.6 (2), 125.7 (q, J = 3.7 Hz, CF3), 77.5, 49.9, 44.1. 19
NMR (375 MHz, CDCl3): δ -62.8 (s, 3F).
F
(46) (a) Tueting, D. R.; Echavarren, A. M.; Stille, J. K. Tetrahedron 1989,
45, 979. (b) Kobayashi, Y.; Murugesh, M. G.; Nakano, M.; Takahisa, E.;
Usmani, S. B.; Ainai, T. J. Org. Chem. 2002, 67, 7110.
(47) (S)-Biarylphosphines ligands (BINAP, P-PHOS, and Cl-MeO-BI-
PHEP analogues) all lead to the (-)-enantiomers, which have the absolute
stereochemistry represented in this paper. The use of the (R)-biarylpho-
sphines yield the (þ)-enantiomers, having the opposite stereochemistry of
that represented. We arbitrarily opted to represent the (1R,2S)-2/4 and
(1R,4R)-3/5 stereochemistry for consistency.
(48) It was verified that longer reaction times did not affect the ee (up to 48
h at rt).
(49) Racemic products were obtained following the same procedure with
the achiral BIPHEP.
4064 J. Org. Chem. Vol. 75, No. 12, 2010

Menard et al.
JOCArticle
(1R,2S)-trans-2-(30-Methoxyphenyl)-cyclopent-3-enyl Ethyl
Carbonate (2l)20 and (1R,4R)-trans-4-(30-Methoxyphenyl)-cyclo-
pent-2-enyl Ethyl Carbonate (3l).20. Prepared according to Pro-
cedure B. The regioisomers were obtained as a colorless oil in
(1R,4R)-trans-4-(30-Methylphenyl)-cyclopent-2-enol (5m).
Colorless oil. [R]28.1D = þ172 (c 1.00, CHCl3); enantiomeric
ratio was 99.5:0.5, as determined by HPLC analysis (Chiralcel
OD-H; 225 nm). 1H NMR (400 MHz, CDCl3): δ 7.18 (1H, t, J =
8.2 Hz), 7.01 (1H, d, J = 7.7 Hz), 6.95-6.92 (2H, m) 6.06-6.01
(2H, m), 5.07-5.03 (1H, m), 4.13-4.08 (1H, m), 2.33 (3H, s),
2.27 (1H, ddd, J = 14.1, 8.0, 2.6 Hz), 2.10 (1H, ddd, J = 14.1,
7.0, 5.5 Hz), 1.56 (1H, br s, alcohol). 13C NMR (100 MHz,
CDCl3): δ 144.7, 139.3, 138.2, 133.9, 128.5, 127.8, 127.1, 124.1,
77.5, 49.8, 44.1, 21.4. IR (NaCl, neat film): 3348 (br), 3055, 3024,
2962, 2924, 1705, 1604, 1589, 1489, 1435, 1257, 1172, 1111, 1026,
779, 702 cm-1. MS (EIþ) m/z (rel intensity): 174.1 (Mþ, 22), 156
(100), 141 (52), 128 (33), 115 (49), 91 (11), 84 (16). HRMS (EIþ)
calcd for C12H14O [Mþ]: 174.1045, found 174.1046.
1
80% yield (69 mg), showing a 1:1.8 ratio of 2:3 by H NMR
spectroscopy. The regioisomers were characterized as the free
1
alcohols 4l and 5l. Major regioisomer 3l: H NMR (400 MHz,
CDCl3): δ 6.80-6.65 (3H, m), 7.31-7.20 (1H, m), 6.18 (1H, dd,
J = 5.6, 1.9 Hz), 6.10-6.05 (1H, m), 5.74 (1H, dd, J = 7.2, 5.2,
2.6 Hz), 4.20 (2H, q, J = 7.2 Hz), 4.16-3.98 (1H, m), 3.79 (3H,
s), 2.47-2.42 (1H, m), 2.13 (1H, ddd, J = 13.0, 7.0, 5.9 Hz), 1.31
(3H, t, J = 7.1 Hz).
(1R,2S)-trans-2-(30-Methoxyphenyl)-cyclopent-3-enol (4l).
Colorless oil. [R]28.2 = þ160 (c 1.00, CHCl3); enantiomeric
D
ratio was 94.6:5.4, as determined by HPLC analysis (Chiralcel OD-
H; 225 nm). The characterization data was fully concordant with
the literature.46 1H NMR (400 MHz, CDCl3): δ 7.13 (1H, t, J =
7.4), 6.70-6.62 (3H, m) 5.80 (1H, ddd, J = 6.0, 4.4, 2.2 Hz), 5.67
(1H, ddd, J = 6.1, 4.1, 2.1 Hz), 4.18 (1H, dt, J=6.7, 4.2 Hz), 3.70
(3H, s), 3.64 (1H, sp, J=1.9 Hz), 2.70 (1H, dddd, J=16.9, 6.7, 3.9,
(1R,2S)-trans-2-(30-Bromophenyl)-cyclopent-3-enyl Ethyl
Carbonate (2q) and (1R,4R)-trans-4-(30-Bromophenyl)-cyclo-
pent-2-enyl Ethyl Carbonate (3q). Prepared according to Proce-
dure B. The inseparable regioisomers were obtained as a colorless
oil in 89% yield (89 mg), showing a 1:2.3 ratio of 2:3 by 1H NMR
spectroscopy. The regioisomers were characterized as the free
2.1 Hz), 2.27 (1H, dd, J=16.9, 2.1 Hz), 1.80 (1H, br s, alcohol). 13
C
alcohols 4q and 5q. Minor regioisomer 2q: H NMR (400 MHz,
1
NMR (100 MHz, CDCl3): δ 160.1, 144.3, 132.2, 129.8, 128.7,
120.1, 113.2, 112.1, 81.2, 60.8, 55.3, 41.6. IR (NaCl, neat film): 3323
CDCl3): δ 7.39-7.03 (4H, m), 5.96 (1H, ddd, J = 5.8, 4.0, 2.0 Hz),
5.80-5.75 (1H, m), 5.00 (1H, ddd, J = 6.6, 2.6, 3.1 Hz), 4.20 (2H,
q, J = 7.1 Hz), 3.96 (1H, brs), 2.54-2.45 (1H, m), 2.91 (1H, dddd,
J=17.8, 6.3, 3.9, 2.1 Hz), 1.31 (3H, t, J=7.1 Hz). Major regioiso-
mer 3q: 1H NMR (400 MHz, CDCl3): δ 7.39-7.03 (4H, m), 6.15
(1H, dd, J = 5.6, 1.7 Hz), 6.10 (1H, ddd, J = 7.7, 5.6, 2.2 Hz),
5.77-5.72 (1H, m), 4.20 (2H, q, J = 7.1 Hz), 4.15-4.08 (1H, m),
2.46 (1H, dt, J = 6.8, 2.2 Hz), 2.10 (1H, ddd, J = 14.7, 7.1, 5.9 Hz),
1.31 (3H, t, J=7.1 Hz).
(br), 3055, 3023, 2909, 2842, 1588, 1484, 1406, 1073, 1010 cm-1
.
MS m/z (rel intensity): 190 (Mþ, 100), 172 (20), 162 (50), 147 (41),
134 (63), 129 (27), 121 (38), 115 (32), 91 (32).
(1R,4R)-trans-4-(30-Methoxyphenyl)-cyclopent-2-enol (5l).
Colorless oil. [R]28.8 = þ220 (c 1.00, CHCl3); enantiomeric
D
ratio was 99.4:0.6, as determined by HPLC analysis (Chiralcel
OD-H; 225 nm). 1H NMR (400 MHz, CDCl3): δ 7.21 (2H, t, J =
7.9 Hz), 6.77-6.67 (3H, m) 6.06-6.01 (2H, m), 5.08-5.02 (1H,
m), 4.15-4.10 (1H, m), 3.79 (3H, s), 2.28 (1H, ddd, J = 14.1, 8.0,
(1R,2S)-trans-2-(30-Bromophenyl)-cyclopent-3-enol (4q). Color-
less oil. [R]26.3D = þ146 (c 1.00, CHCl3); enantiomeric ratio
was 96.8:3.2, as determined by HPLC analysis (Chiralcel OD-H;
2.8 Hz), 2.11 (1H, ddd, J = 14.1, 6.9, 6.0 Hz), 1.48 (1H, br s). 13
C
1
NMR (100 MHz, CDCl3): δ 159.8, 146.5, 138.9, 134.1, 129.6,
119.5, 112.9, 111.5, 77.5, 55.2, 49.9, 44.0. IR (NaCl, neat film):
3333 (br), 3055, 3001, 2963, 2939, 2839, 1604, 1489, 1458, 1435,
1319, 1265, 1157, 1041, 1026, 771 cm-1. MS (EIþ) m/z (rel
intensity): 190.1 (Mþ, 30), 172 (100), 157 (47), 129 (33), 128 (38),
127 (29), 115 (18), 85 (21), 84 (30). HRMS (EIþ) calcd for
C12H14O2 [Mþ]: 190.0994, found 190.0991.
225 nm). H NMR (400 MHz, CDCl3): δ 7.35-7.28 (2H, m),
7.15 (1H, t, J = 7.6 Hz), 7.09 (1H, dd, J = 7.6, 1.4 Hz), 5.90 (1H,
ddd, J = 6.1, 4.3, 2.2 Hz), 5.71 (1H, ddd, J = 6.1, 4.1, 2.0 Hz),
4.28-4.19 (1H, m), 3.74-3.66 (1H, m), 2.77 (1H, ddd, J = 17.0,
3.0, 1.8 Hz), 2.34 (1H, ddd, J = 17.0, 3.9, 1.8 Hz), 2.08 (1H, brs).
13C NMR (100 MHz, CDCl3): δ 144.4, 131.2, 130.0, 129.9,
129.8, 129.4, 125.8, 122.5, 81.4, 61.3, 42.8. IR (NaCl, neat film):
3331 (br), 3057, 2906, 2843, 1592, 1564, 1475, 1426, 1287, 1265,
1163, 1072, 1052, 996, 950, 780, 720 cm-1. MS (EIþ) m/z (rel
intensity): 240 (Mþ, 14), 238 (17), 222 (33), 184 (40), 182 (44),
141 (65), 131 (75), 128 (44), 115 (100), 91 (14). HRMS (EIþ)
calcd for C11H11BrO [Mþ]: 237.9993, found 237.9996.
(1R,2S)-trans-2-(30-Methylphenyl)-cyclopent-3-enyl Ethyl Car-
bonate (2m)20 and (1R,4R)-trans-4-(30-Methylphenyl)-cyclopent-
2-enyl Ethyl Carbonate (3m).20. Prepared according to Proce-
dure B. The regioisomers were obtained as a colorless oil in 99%
1
yield (81 mg), showing a 1:2.2 ratio of 2:3 by H NMR spec-
troscopy. The regioisomers were characterized as the free alcohols
4m and 5m. Major regioisomer 3m: 1H NMR (400 MHz, CDCl3): δ
7.22-7.16 (1H, m), 7.07-7.00 (2H, m), 6.92 (1H, d, J=6.9 Hz),
6.18 (1H, dd, J=5.6, 1.9 Hz), 6.07 (1H, ddd, J=5.0, 4.8, 2.3 Hz),
5.79-5.75 (1H, m), 4.20 (2H, q, J=7.1 Hz), 4.15-4.08 (1H, m),
2.46 (1H, ddd, J=14.7, 7.7, 2.3 Hz), 2.33 (3H, s), 2.12 (1H, ddd, J=
14.6, 7.1, 5.9 Hz), 1.31 (3H, t, J=7.1 Hz).
(1R,4R)-trans-4-(30-Bromophenyl)-cyclopent-2-enol (5q). Color-
less oil. [R]27.0 = þ181 (c 1.00, CHCl3); enantiomeric ratio
D
was 99.5:0.5, as determined by HPLC analysis (Chiralcel OD-H;
225 nm). 1H NMR (400 MHz, CDCl3): δ 7.33 (1H, dd, J = 6.1,
1.2 Hz), 7.26 (1H, t, J = 2.2 Hz), 7.15 (1H, t, J = 7.8 Hz), 7.05
(1H, dd, J = 7.6, 1.2 Hz), 6.08-6.05 (1H, m), 6.01 (1H, dd, J =
4.7, 2.0 Hz), 5.12-5.01 (1H, m), 4.16-4.08 (1H, m), 2.28 (1H,
ddd, J = 14.1, 8.0, 2.6 Hz), 2.07 (1H, ddd, J = 14.0, 7.0, 5.4 Hz),
1.57 (1H, br s). 13C NMR (100 MHz, CDCl3): δ 146.6, 137.8,
134.3, 129.8, 129.7, 129.1, 125.6, 122.5, 77.9, 50.8, 45.2. IR
(NaCl, neat film): 3328 (br), 3057, 2963, 2930, 2876, 1592, 1476,
1424, 1350, 1110, 1072, 1052, 937, 791, 778, 743, 692 cm-1. MS
(EIþ) m/z (rel intensity): 240 (Mþ, 6), 238 (16), 222 (72), 141
(100), 139 (23), 115 (67), 86 (22), 84 (27). HRMS (EIþ) calcd for
C11H11BrO [Mþ]: 237.9993, found 237.9990.
(1R,2S)-trans-2-(30-Methylphenyl)-cyclopent-3-enol (4m).
Colorless oil. [R]27.5D = þ197 (c 1.00, CHCl3); enantiomeric
ratio was 96.4:3.6, as determined by HPLC analysis (Chiralcel
OD-H; 225 nm). The characterization data was fully concordant
with previous reports from the literature.46 1H NMR (400 MHz,
CDCl3): δ 7.21 (1H, t, J = 7.5 Hz), 7.06-6.97 (3H, m), 5.89 (1H,
ddd, J = 5.0, 4.4, 2.2 Hz), 5.77 (1H, ddd, J = 6.0, 4.2, 2.1 Hz),
4.31-4.26 (1H, m), 3.73 (1H, sp, J = 1.9 Hz), 2.81 (1H, dddd,
J = 16.9, 6.5, 4.1, 2.0 Hz), 2.37 (1H, dddd, J = 16.9, 6.3, 4.1, 2.0
Hz), 2.34 (3H, s), 1.88 (1H, br s, alcohol). 13C NMR (100 MHz,
CDCl3): δ 142.5, 138.2, 132.4, 129.4, 128.5, 128.1, 127.4, 124.4,
81.0, 60.7, 41.3. IR (NaCl, neat film): 3323 (br), 3336 (br), 3056,
(1R,2S)-trans-2-(40-Fluoro-3-methylphenyl)-cyclopent-3-enyl
Ethyl Carbonate (2r) and (1R,4R)-trans-4-(40-Fluoro-3-methyl-
phenyl)-cyclopent-2-enyl Ethyl Carbonate (3r). Prepared accord-
ing to Procedure B. The inseparable regioisomers were obtained
as a colorless oil in 69% yield (60 mg), showing a 1:2.3 ratio of
3022, 2921, 2863, 1650, 1607, 1490, 1456, 1272, 1161, 1054 cm-1
.
MS m/z (rel intensity): 174 (Mþ, 93), 156 (25), 146 (55), 131 (69),
128 (47), 118 (100), 115 (41), 105 (50), 91 (42). HRMS (ESI)þ
calcd for C12H14O [Mþ]: 174.104465, found 174.104256.
2:3 by H NMR spectroscopy. The regioisomers were charac-
1
terized as the free alcohols 4r and 5r. Minor regioisomer 2r: 1H
NMR (400 MHz, CDCl3): δ 7.03-6.96 (1H, m), 6.95-6.88 (2H,
J. Org. Chem. Vol. 75, No. 12, 2010 4065

Menard et al.
JOCArticle
m), 5.93 (1H, ddd, J = 5.9, 4.2, 2.1 Hz), 5.78 (1H, dd, J = 4.3,
2.2 Hz), 4.99 (1H, dt, J = 6.6, 2.7 Hz), 4.20 (2H, q, J = 7.1 Hz),
3.40 (1H, brs), 2.90 (1H, dddd, J = 17.8, 6.6, 4.0, 1.8 Hz),
2.51-2.44 (1H, m), 2.24 (3H, s), 1.31 (3H, t, J = 7.1 Hz). Major
regioisomer 3r: 1H NMR (400 MHz, CDCl3): δ 7.03-6.96 (1H,
m), 6.95-6.88 (2H, m), 6.14 (1H, dd, J = 5.6, 2.0 Hz), 6.07 (1H,
dt, J = 5.6, 2.3 Hz), 5.74 (1H, dd, J = 6.9, 4.0, 2.1 Hz), 4.20 (2H,
q, J = 7.1 Hz), 4.09 (1H, dddd, J = 7.8, 5.7, 4.2, 2.1 Hz), 2.45
(1H, ddd, J = 14.6, 7.9, 2.1 Hz), 2.24 (3H, s), 2.08 (1H, ddd, J =
14.6, 7.1, 1.3 Hz), 1.31 (3H, t, J = 7.1 Hz).
19F NMR (375 MHz, CDCl3): δ -112.2 (t, J = 9.8 Hz, 1F). IR
(NaCl, neat film): 3332 (br), 3055, 3010, 2963, 2938, 28340, 1604,
1502, 1457, 1318, 1255, 1229, 1045, 1024, 821, 765 cm-1. MS (EIþ)
m/z (rel intensity): 208.1 (Mþ, 97), 190 (99), 180 (100), 175 (33), 152
(35), 146 (50), 139 (32), 86 (27), 84 (45). HRMS (EIþ) calcd for
C12H13O2F [Mþ]: 208.0900, found 208.0905.
(1R,4R)-trans-4-(30-Fluoro-50-methoxyphenyl)-cyclopent-2-enol
(5s). Colorless oil. 1H NMR (400 MHz, CDCl3): δ 6.42-6.34 (3H,
m), 5.97 (1H, ddd, J=5.5, 3.3, 2.1 Hz), 5.93 (1H, dd, J=5.5, 2.0
Hz), 4.97 (1H, ddd, J = 7.0, 4.6, 2.1 Hz), 4.06-3.97 (1H, m), 3.70
(3H, s), 2.19 (1H, ddd, J = 14.1, 8.1, 2.7 Hz), 2.00 (1H, ddd, J =
14.1, 8.7, 5.4 Hz), 1.62 (1H, br s). 13C NMR (100 MHz, CDCl3): δ
163.8 (d, J = 244.8 Hz), 161.0 (d. J = 11.4 Hz), 148.1 (d. J = 8.8
Hz), 138.2, 134.7, 108.9 (d, J = 2.6 Hz), 106.1 (d, J = 21.7 Hz),
(1R,2S)-trans-2-(40-Fluoro-30-methylphenyl)-cyclopent-3-enol
(4r). Colorless oil. [R]28.2D=þ187 (c 0.50, CHCl3); enantiomeric
ratio was 97.1:2.9, as determined by HPLC analysis (Chiralcel OD-
H; 215 nm). 1H NMR (400 MHz, CDCl3): δ 6.96 (1H, d, J = 8.0
Hz), 6.94-6.86 (2H, m), 5.87 (1H, dd, J = 5.9, 2.3 Hz), 5.71 (1H,
dd, J = 6.0, 2.0 Hz), 4.20 (1H, dt, J = 6.6, 4.1 Hz), 3.70-3.64 (1H,
m), 3.76 (1H, ddd, J = 16.9, 6.7, 2.0 Hz), 3.34 (1H, ddd, J = 16.8,
4.1, 2.1 Hz), 2.23 (3H, d, J=2.0Hz), 2.04(1H, brs).13CNMR(100
MHz, CDCl3): δ 160.0 (d, J = 243.1 Hz), 138.1 (d. J = 3.8 Hz),
132.4, 130.5 (d, J=5.2 Hz), 129.7, 126.1 (d, J=7.9 Hz), 125.0 (d,
J=17.2 Hz), 115.1 (d, J=22.1 Hz), 81.2, 60.1, 41.5, 14.7. 19F NMR
(375 MHz, CDCl3): δ -121.4 (dd, J = 7.6, 1.9 Hz, 1F). IR (NaCl,
neat film): 3337 (br), 3056, 3017, 2962, 2844, 1501, 1252, 1236, 1207
1118, 1051, 949, 819, 756 cm-1. MS (EIþ) m/z (rel intensity): 192.1
(Mþ, 47), 174 (51), 159 (43), 146 (48), 136 (100), 133 (44), 123 (30),
109 (30). HRMS (EIþ) calcd for C12H13OF [Mþ]: 192.0950, found
192.0950.
99.3 (d, J = 25.3 Hz), 77.3, 55.5, 49.9 (d, J = 2.1 Hz), 43.8. 19
F
NMR (375 MHz, CDCl3): δ -112.2 (t, J = 9.7 Hz, 1F). IR (NaCl,
neat film): 3334 (br), 3053, 3010, 2959, 2843, 1601, 1499, 1254,
1237, 1116, 1052, 949, 789 cm-1. MS(EIþ) m/z(rel intensity): 208.1
(Mþ, 7), 190 (100), 175 (23), 147 (20), 146 (51), 133 (17), 127 (13),
86 (14), 84 (28). HRMS (EIþ) calcd for C12H13O2F [Mþ]:
208.0900, found 208.0903.
(1R,2S)-trans-2-(40-Methoxy-30-methylphenyl)-cyclopent-3-
enyl Ethyl Carbonate (2t) and (1R,4R)-trans-4-(40-Methoxy-30-
methylphenyl)-cyclopent-2-enyl Ethyl Carbonate (3t). Prepared
according to Procedure B. The inseparable regioisomers were
obtained as a colorless oil in 66% yield (60 mg), showing a 1:1.3
1
ratio of 2:3 by H NMR spectroscopy. The regioisomers were
(1R,4R)-trans-4-(40-Fluoro-30-methylphenyl)-cyclopent-2-enol
characterized as the free alcohols 4t and 5t. Major regioisomer 3t:1H
NMR (400 MHz, CDCl3): δ 7.03-6.97 (1H, m), 6.94-6.88 (1H,
m), 6.74 (1H, d, J = 6.7 Hz), 6.16 (1H, dd, J = 5.6, 2.0 Hz), 6.05
(1H, dt, J = 5.6, 2.3 Hz), 5.72 (1H, ddd, J = 6.9, 3.8, 2.1 Hz), 4.20
(2H, q, J = 7.1 Hz), 4.10-4.04 (1H, m), 3.81 (3H, s), 2.45 (1H, ddd,
J= 14.5, 7.8, 2.0 Hz), 2.20 (3H, m), 2.10 (1H, ddd, J= 14.6, 7.1, 5.8
Hz), 1.31 (3H, t, J = 7.1 Hz). Minor regioisomer 2t: 1H NMR (400
MHz, CDCl3): δ 7.03-6.97 (1H, m), 6.94-6.88 (1H, m), 6.76 (1H,
d, J = 3.8 Hz), 5.90 (1H, ddd, J = 5.9, 4.1, 2.1 Hz), 5.81-5.76 (1H,
m), 5.00 (1H, ddd, J = 6.6, 3.7, 2.7 Hz), 4.16 (2H, q, J = 7.1 Hz),
3.92 (1H, brs), 3.81 (3H, s), 2.91 (1H, dddd, J = 17.7, 6.6, 4.0, 1.8
Hz), 2.49-2.43 (1H, m), 2.20 (3H, s), 1.31 (3H, t, J = 7.1 Hz).
(1R,2S)-trans-2-(40-Methoxy-30-methylphenyl)-cyclopent-3-
enol (4t). Colorless oil. [R]28.5D = þ172 (c 1.00, CHCl3); enantio-
meric ratio was 89.7:10.3, as determined by HPLC analysis
(Chiralcel OD-H; 235 nm). 1H NMR (400 MHz, CDCl3): δ
6.93-6.85 (2H, m), 6.69 (1H, d, J=7.9 Hz), 5.78 (1H, ddd, J=
5.9, 4.4, 2.2 Hz), 5.68 (1H, ddd, J=5.9, 4.1, 2.1 Hz), 4.22-4.14
(1H, m), 3.74 (3H, s), 3.63-3.59 (1H, m), 2.71 (1H, dddd, J=
23.6, 6.7, 3.9, 1.8 Hz), 2.27 (1H, ddt, J = 16.8, 4.1, 2.0 Hz), 2.13
(3H, s), 1.75 (1H, brs). 13C NMR (100 MHz, CDCl3): δ 156.6,
134.1, 132.7, 129.7, 129.1, 126.8, 125.4, 110.0, 81.1, 59.9, 55.4,
41.2, 16.2. IR (NaCl, neat film): 3348 (br), 3055, 2993, 2916,
(5r). Colorless oil. [R]28.1 = þ204 (c 1.00, CHCl3); enantio-
D
meric ratio was 99.3:0.7, as determined by HPLC analysis
(Chiralcel OD-H; 215 nm). 1H NMR (400 MHz, CDCl3): δ
6.95-6.86 (3H, m), 6.06-5.98 (2H, m), 5.09-5.00 (1H, m),
4.14-4.06 (1H, m), 2.27 (1H, ddd, J=14.1, 8.0, 2.6 Hz), 2.24
(3H, d, J = 2.0 Hz) 2.05 (1H, ddd, J=14.2, 6.8, 5.5 Hz), 1.58
(1H, br s). 13C NMR (100 MHz, CDCl3): δ 160.7 (d, J = 243.1
Hz), 140.3 (d. J = 3.7 Hz), 139.3, 134.2, 130.1 (d, J = 5.9 Hz),
125.9, 125.8, 115.1 (d, J = 22.4 Hz), 77.6, 49.3, 44.4, 14.7 (d, J =
3.8). 19F NMR (375 MHz, CDCl3): δ -121.7 (dd, J = 13.3, 5.7
Hz, 1F). IR (NaCl, neat film): 3326 (br), 3055, 3018, 2962, 2927,
2891, 1501, 1325, 1245, 1205, 1118, 1028, 882, 790, 756 cm-1
.
MS (EIþ) m/z (rel intensity): 192.1 (Mþ, 5), 175 (15), 174 (100),
159 (82), 146 (29), 133 (54), 109 (11). HRMS (EIþ) calcd for
C12H13OF [Mþ]: 192.0950, found 192.0949.
(1R,2S)-trans-2-(30-Fluoro-50-methoxyphenyl)-cyclopent-3-enyl
Ethyl Carbonate (2s) and (1R,4R)-trans-4-(30-Fluoro-50-methoxy-
phenyl)-cyclopent-2-enyl Ethyl Carbonate (3s). Prepared according
to Procedure B. The inseparable regioisomers were obtained as a
colorless oil in 78% yield (72 mg), showing a 1:2.4 ratio of 2:3 by 1H
NMR spectroscopy. The regioisomers were characterized as the
free alcohols 4s and 5s. Minor regioisomer 2s: 1H NMR (400 MHz,
CDCl3): δ 6.59-6.40 (3H, m), 5.95 (1H, ddd, J = 5.9, 4.1, 2.1 Hz),
5.79-5.73 (1H, m), 5.02 (1H, dt, J = 6.6, 2.7 Hz), 4.20 (2H, q, J =
7.1 Hz), 3.94 (1H, brs), 3.77 (3H, s), 2.90 (1H, dddd, J=17.8, 6.6,
3.9, 1.8 Hz), 2.52-2.43 (1H, m), 1.31 (3H, t, J=7.1 Hz). Major
regioisomer 3s: 1H NMR (400 MHz, CDCl3): δ 6.59-6.40 (3H, m),
6.15 (1H, dd, J = 5.6, 1.8 Hz), 6.09 (1H, ddd, J = 5.6, 3.2, 2.2 Hz),
5.76-5.71 (1H, m), 4.20 (2H, q, J = 7.1 Hz), 4.13-4.05 (1H, m),
3.77 (3H, s), 2.45 (1H, ddd, J = 14.6, 7.8, 2.2 Hz), 2.11 (1H, ddd,
J = 14.6, 7.1, 5.8 Hz), 1.31 (3H, t, J = 7.1 Hz).
(1R,2S)-trans-2-(30-Fluoro-50-methoxyphenyl)-cyclopent-3-enol
(4s). Colorless oil. 1H NMR (400 MHz, CDCl3): δ 6.55-6.43 (3H,
m), 5.91 (1H, ddd, J = 12.2, 5.8, 2.4 Hz), 5.73 (1H, ddd, J = 8.0,
6.1, 1.9 Hz), 4.25 (1H, ddd, J = 8.2, 6.6, 3.1 Hz), 3.77 (3H, s),
3.74-3.68 (1H, m), 2.79 (1H, ddd, J = 17.0, 6.9, 2.1 Hz), 2.36 (1H,
ddd, J = 17.0, 4.1, 2.2 Hz), 1.98 (1H, br s). 13C NMR (100 MHz,
CDCl3):δ163.8 (d, J= 245.0 Hz), 161.0 (d. J= 11.4 Hz), 145.8 (d,
J = 8.9 Hz), 131.5, 130.2, 109.0 (d, J = 2.6 Hz), 106.4 (d, J = 21.7
Hz), 99.6 (d, J = 25.7 Hz), 80.7, 60.6 (d, J = 2.0 Hz), 55.5, 41.4.
2839, 1612, 1504, 1465, 1257, 1219, 1134, 1033, 949, 810 cm-1
.
MS (EIþ) m/z (rel intensity): 204.1 (Mþ, 14), 172 (8), 161 (35),
148 (100), 128 (49), 115 (43), 91 (23), 71 (22). HRMS (EIþ) calcd
for C13H16O2 [Mþ]: 204.1150, found 204.1147.
(1R,4R)-trans-4-(40-Methoxy-30-methylphenyl)-cyclopent-2-
enol (5t). Colorless oil. [R]28.6D=þ228 (c 1.00, CHCl3); enantio-
meric ratio was 99.6:0.4, as determined by HPLC analysis
(Chiralcel OD-H; 225 nm). 1H NMR (400 MHz, CDCl3): δ
6.95-6.86 (2H, m), 6.74 (1H, d, J = 8.2 Hz), 6.05-5.96 (2H, m),
5.04 (1H, ddd, J=7.0, 3.7, 2.2 Hz), 4.09-4.03 (1H, m), 3.80 (3H,
s), 2.25 (1H, ddd, J=14.1, 8.1, 2.6 Hz), 2.19 (3H, s), 2.07 (1H,
ddd, J = 14.2, 7.0, 5.6 Hz), 1.69 (1H, brs). 13C NMR (100 MHz,
CDCl3): δ 156.5, 139.9, 136.6, 133.7, 129.6, 126.9, 125.3, 110.2,
77.7, 55.6, 49.3, 44.5, 16.4. IR (NaCl, neat film): 3348 (br), 3055,
2993, 2947, 2831, 1705 (w), 1612, 1504, 1465, 1249, 1219, 1134,
1111, 1033, 910, 810 cm-1. MS (EIþ) m/z (rel intensity): 204.1
(Mþ, 22), 186 (88), 171 (100), 127 (11), 115 (45), 84 (5). HRMS
(EIþ) calcd for C13H16O2 [Mþ]: 204.1150, found 204.1154.
4066 J. Org. Chem. Vol. 75, No. 12, 2010

Menard et al.
JOCArticle
(1R,2S)-trans-2-(40-Methylsulfanylphenyl)-cyclopent-3-enyl
Ethyl Carbonate (2u) and (1R,4R)-trans-4-(40-Methylsulfanyl-
phenyl)-cyclopent-2-enyl Ethyl Carbonate (3u). Prepared accord-
ing to Procedure B. The inseparable regioisomers were obtained
as a colorless oil in 80% yield (72 mg), showing a 1:2.6 ratio of
7.10-7.02 (3H, m), 5.95 (1H, ddd, J=5.9, 4.4, 2.2 Hz), 5.75
(1H, ddd, J = 5.9, 4.3, 2.2 Hz), 4.35 (1H, dt, J=6.6, 3.3 Hz), 4.10
(1H, brs), 2.80 (1H, dddd, J = 17.2, 6.7, 4.1, 2.1 Hz), 2.39 (1H,
ddt, J=17.2, 3.6, 2.0 Hz), 1.97 (1H, brs). 13C NMR (100 MHz,
CDCl3): δ 161.2 (d, J = 245.0 Hz), 130.7 (d, J=9.7 Hz), 129.4
(d, J = 15.0 Hz), 128.4 (d, J = 4.5 Hz), 128.3 (d, J=8.2 Hz),
124.3 (d, J=3.4 Hz), 115.6, 115.4, 79.8, 54.1 (d, J=1.5 Hz),
41.5. 19F NMR (375 MHz, CDCl3): δ -118.3 (d, J = 8.6 Hz, F).
IR (NaCl, neat film): 3348 (br), 3055, 2993, 2924, 2847, 1720 (w),
1581, 1489, 1450, 1226, 1041, 949, 864, 756 cm-1. MS (EIþ) m/z
(rel intensity): 178.1 (Mþ, 3), 146 (21), 135 (44), 133 (51), 122
(100), 115 (14), 109 (45), 75 (30), 63 (24). HRMS (EIþ) calcd for
C11H11FO [Mþ]: 178.0794, found 178.0800.
1
2:3 by H NMR spectroscopy. The regioisomers were charac-
terized as the free alcohols 4u and 5u. Minor regioisomer 2u: 1H
NMR (400 MHz, CDCl3): δ 7.20 (2H, dd, J=5.6, 3.3 Hz), 7.05
(2H, dd, J=8.3, 1.8 Hz), 5.93 (1H, ddd, J=5.8, 4.1, 2.1 Hz), 5.80
(1H, dd, J=4.3, 2.1 Hz), 5.00 (1H, dt, J=6.6, 2.7 Hz), 4.20 (2H,
q, J=7.1 Hz), 3.96 (1H, brs), 2.89 (1H, dddd, J = 17.7, 6.6, 3.9,
1.8 Hz), 2.46 (3H, s), 2.52-2.48 (1H, m), 1.31 (3H, t, J=7.1 Hz).
Major regioisomer 3u: 1H NMR (400 MHz, CDCl3): δ 7.24 (2H,
dd, J=11.4, 1.6 Hz), 7.14 (2H, dd, J=8.4, 1.8 Hz), 6.16 (1H, dd,
J=5.6, 1.9 Hz), 6.08 (1H, ddd, J=5.5, 3.1, 2.3 Hz), 5.75 (1H,
ddd, J=7.0, 3.9, 2.1 Hz), 4.20 (2H, q, J=7.1 Hz), 4.15-4.08 (1H,
m), 2.46 (3H, s), 2.48-2.42 (1H, m), 2.09 (1H, ddd, J=14.6, 7.1,
5.9 Hz), 1.31 (3H, t, J = 7.1 Hz).
(1R,4R)-trans-4-(20-Fluorophenyl)-cyclopent-2-enol (5v). Color-
less oil. [R]28.5D=þ98 (c 0.82, CHCl3); enantiomeric ratio was
98.2:1.8, as determined by HPLC analysis (Chiralcel OD-H;
1
215 nm). H NMR (400 MHz, CDCl3): δ 7.22-7.14 (1H, m),
7.10-6.97 (3H, m), 6.09-6.00 (2H, m), 5.08-5.01 (1H, m),
4.48-4.40 (1H, m), 2.31 (1H, ddd, J = 14.1, 8.1, 2.8 Hz), 2.11
(1H, ddd, J=13.8, 6.8, 5.5 Hz), 1.58 (1H, brs). 13C NMR (100
MHz, CDCl3): δ 161.0 (d, J = 245.3 Hz), 137.7, 134.8, 131.7 (d,
J = 14.7 Hz), 128.1 (d, J = 2.6 Hz), 128.0, 124.4 (d, J = 3.3 Hz),
115.6, 115.4, 77.3, 42.8 (d, J = 2.6 Hz), 42.7. 19F NMR (375 MHz,
CDCl3): δ -119.0 to -119.1 (m, rotamers). IR (NaCl, neat film):
3317 (br), 3063, 2963, 2931, 1581, 1489, 1450, 1350, 1226, 1111,
1026, 756 cm-1. MS (EIþ) m/z (rel intensity): 178.1 (Mþ, 20), 160
(100), 159 (72), 133 (75), 122 (19), 109 (34), 86 (24), 84 (44). HRMS
(EIþ) calcd for C11H11FO [Mþ]: 178.0794, found 178.0791.
(1R,2S)-trans-2-(Thiophen-30-yl)-cyclopent-3-enyl Ethyl Car-
bonate (2w) and (1R,4R)-trans-4-(Thiophen-30-yl)-cyclopent-2-
enyl Ethyl Carbonate (3w). Prepared according to Procedure
B. The inseparable regioisomers were obtained as a colorless oil
in 31% yield (24 mg), showing a 1:3.5 ratio of 2:3 by 1H NMR
spectroscopy. The regioisomers were characterized as the free
alcohols. Minor regioisomer 2w: 1H NMR (400 MHz, CDCl3): δ
7.23-7.18 (1H, m), 6.97-6.91 (2H, m), 5.85-5.76 (2H, m), 4.99
(1H, dt, J = 6.5, 2.3 Hz), 4.13 (2H, q, J = 7.1 Hz), 4.00 (1H, brs),
2.82 (1H, dddd, J = 17.8, 6.5, 3.8, 1.8 Hz), 2.45-2.36 (1H, m),
1.24 (3H, t, J = 7.1 Hz). Major regioisomer 3w: 1H NMR (400
MHz, CDCl3): δ 7.22-6.98 (1H, m), 6.89-6.86 (1H, m), 6.81
(1H, dd, J = 4.9, 1.1 Hz), 6.14 (1H, dd, J = 5.6, 2.0 Hz), 5.96
(1H, dt, J = 5.6, 2.3 Hz), 5.67 (1H, ddd, J = 7.1, 4.1, 2.1 Hz),
4.21-4.14 (1H. m), 4.13 (2H, q, J = 7.1 Hz), 2.37 (1H, dd, J =
14.5, 7.8, 2.4 Hz), 2.10 (1H, ddd, J = 14.1, 7.1, 5.7 Hz), 1.24 (3H,
t, J = 7.1 Hz).
(1R,2S)-trans-2-(40-Methylsulfanylphenyl)-cyclopent-3-enol
(4u). Colorless oil. [R]28.9D=þ205 (c 1.00, CHCl3); enantiomeric
ratio was 95.6:4.4, as determined by HPLC analysis (Chiralcel
OD-H; 262 nm). 1H NMR (400 MHz, CDCl3): δ 7.22 (2H, ddd,
J = 8.4, 4.3, 2.2 Hz), 7.11 (1H, ddd, J = 8.2, 4.1, 2.2 Hz), 5.90 (1H,
ddd, J = 5.8, 2.4, 2.2 Hz), 5.75 (1H, ddd, J = 5.9, 2.2, 2.0 Hz), 4.24
(1H, ddd, J=6.6, 5.8, 4.3Hz), 3.74-3.72 (1H, m), 2.80 (1H, dddd,
J = 15.3, 6.8, 3.9, 2.2 Hz), 2.47 (3H, s), 2.37 (1H, dddd, J = 17.0,
6.1, 4.1, 2.0 Hz), 1.81 (1H, brs). 13C NMR (100 MHz, CDCl3): δ
139.8, 136.6, 132.3, 129.9, 128.1 (2C), 127.4 (2C), 81.2, 60.4, 41.6,
16.4. IR (NaCl, neat film): 3348 (br), 3055, 3016, 2962, 2916, 2839,
1489, 1435, 1404, 1319, 1049, 949, 817, 732 cm-1. MS(EIþ) m/z(rel
intensity): 206.1 (Mþ, 25), 188 (8), 150 (100), 129 (34), 128 (53), 116
(39), 115 (51), 91 (17), 89 (9). HRMS (EIþ) calcd for C12H14OS
[Mþ]: 206.0765, found 206.0760.
(1R,4R)-trans-4-(40-Methylsulfanylphenyl)-cyclopent-2-enol
(5u). Colorless oil. [R]28.1D=þ298 (c 1.00, CHCl3); enantiomeric
ratio was 99.5:0.5, as determined by HPLC analysis (Chiralcel
OD-H; 262 nm). 1H NMR (400 MHz, CDCl3): δ 7.20 (2H, dd,
J=9.4, 1.8 Hz), 7.05 (2H, dd, J = 8.2, 1.8 Hz), 6.06-5.97 (2H,
m), 5.08-5.01 (1H, m), 4.15-4.05 (1H, m), 2.46 (3H, s), 2.27
(1H, ddd, J = 14.0, 8.0, 2.8 Hz), 2.06 (1H, ddd, J = 14.2, 7.2, 4.6
Hz), 1.66 (1H, brs). 13C NMR (100 MHz, CDCl3): δ 142.1,
139.2, 136.2, 134.4, 127.8 (2C), 127.4 (2C), 77.6, 49.6, 44.3, 16.5.
IR (NaCl, neat film): 3333 (br), 3055, 3016, 2962, 2931, 2885,
1489, 1435, 1411, 1319, 1026, 817, 732 cm-1. MS (EIþ) m/z (rel
intensity): 206.1 (Mþ, 5), 150 (15), 142 (41), 128 (40), 115 (100),
102 (31), 89 (42), 63 (41). HRMS (EIþ) calcd for C12H14OS
[Mþ]: 206.0765, found 206.0766.
(1R,2S)-trans-2-(Thiophen-30-yl)-cyclopent-3-enol (4w). Color-
less oil. [R]27.6D=þ108 (c 0.40, CHCl3); enantiomeric ratio was
94.4:5.6, as determined by HPLC analysis (Chiralcel OD-H; 235
nm). 1H NMR (400 MHz, CDCl3): δ 7.28 (1H, dd, J = 4.9, 3.0
Hz), 6.99-6.96 (1H, m), 6.95 (1H, dd, J = 4.1, 1.2 Hz), 5.87 (1H,
ddd, J = 5.9, 4.1, 2.0 Hz), 5.82 (1H, ddd, J = 5.9, 4.0, 2.0 Hz),
4.31 (1H, dt, J = 6.9, 3.7 Hz), 3.89-3.84 (1H, m), 2.80 (1H, ddd,
J = 6.5, 3.6, 1.8 Hz), 2.35 (1H, ddt, J = 17.0, 3.7, 1.8 Hz), 1.84
(1H, brs). 13C NMR (100 MHz, CDCl3): δ 143.3, 133.2, 129.8,
127.3, 126.1, 120.3, 80.0, 56.1, 41.5. IR (NaCl, neat film): 3333
(br), 3101, 3055, 2916, 2847, 1527, 1411, 1319, 1257, 1157, 1049,
940, 841, 779, 748, 640 cm-1. MS (EIþ) m/z (rel intensity): 166.0
(Mþ, 37), 148 (27), 147 (53), 138 (38), 135 (42), 123 (54), 110
(100), 97 (58), 91 (19), 84 (30), 77 (17). HRMS (EIþ) calcd for
C9H10OS [Mþ]: 166.0452, found 166.0452.
(1R,2S)-trans-2-(20-Fluorophenyl)-cyclopent-3-enyl Ethyl Car-
bonate (2v) and (1R,4R)-trans-4-(20-Fluorophenyl)-cyclopent-2-
enyl Ethyl Carbonate (3v). Prepared according to Procedure B.
The inseparable regioisomers were obtained as a colorless oil in
1
16% yield (13 mg), showing a 1:1.3 ratio of 2:3 by H NMR
spectroscopy. The regioisomers were characterized as the free
alcohols 4v and 5v. Minor regioisomer 2v: 1H NMR (400 MHz,
CDCl3): δ 7.24-7.16 (1H, m), 7.10-6.98 (3H, m), 5.93 (1H, ddd,
J=5.9, 4.3, 2.2 Hz), 5.77 (1H, dd, J = 4.1, 2.2 Hz), 5.16 (1H, dt,
J = 6.8, 2.9 Hz), 4.28 (1H, brs.), 4.20 (2H, q, J = 7.1 Hz), 2.96
(1H, dddd, J = 17.9, 6.8, 4.0, 2.1 Hz), 2.55-2.49 (1H, m), 1.31
(3H, t, J = 7.1 Hz). Major regioisomer 3v: 1H NMR (400 MHz,
CDCl3): δ 7.24-7.16 (1H, m), 7.10-6.98 (3H, m), 6.18 (1H, dd,
J = 5.6, 2.0 Hz), 6.10 (1H, ddd, J = 5.6, 3.2, 2.4 Hz), 5.74 (1H,
ddd, J = 7.9, 4.4, 2.3 Hz), 4.44 (1H, dddd, J = 13.7, 7.9, 4.3, 2.2
Hz), 4.20 (2H, q, J = 7.1 Hz), 2.53-2.47 (1H, m), 2.14 (1H, ddd,
J = 14.6, 7.2, 5.8 Hz), 1.31 (3H, t, J = 7.1 Hz).
(1R,4R)-trans-4-(Thiophen-30-yl)-cyclopent-2-enol (5w). Color-
less oil. [R]27.8 = þ269 (c 0.50, CHCl3); enantiomeric ratio
D
was 99.6:0.4, as determined by HPLC analysis (Chiralcel OD-H;
1
235 nm). H NMR (400 MHz, CDCl3): δ 7.30-7.20 (1H, m),
(1R,2S)-trans-2-(20-Fluorophenyl)-cyclopent-3-enol (4v). Color-
6.97-6.82 (2H, m), 6.07 (1H, brs), 5.99 (1H, brs), 5.02 (1H, brs),
4.22 (1H, brs), 2.30-2.08 (2H, m), 1.58 (1H, brs). 13C NMR (100
MHz, CDCl3): δ 145.5, 138.9, 133.9, 127.1, 126.1, 119.6, 77.5,
45.2, 43.2. IR (NaCl, neat film): 3317 (br), 3101, 3055, 2962,
less oil. [R]28.8 = þ150 (c 0.30, CHCl3); enantiomeric ratio
D
was 94.1:5.9, as determined by HPLC analysis (Chiralcel OD-H;
1
215 nm). H NMR (400 MHz, CDCl3): δ 7.23-7.17 (1H, m),
J. Org. Chem. Vol. 75, No. 12, 2010 4067

Menard et al.
JOCArticle
2931, 2893, 1527, 1411, 1319, 1157, 1111, 1026, 779 cm-1. MS
(EIþ) m/z (rel intensity): 166.0 (Mþ, 32), 148 (99), 147 (91), 135
(21), 123 (23), 121 (52), 115 (100), 97 (29), 63 (30). HRMS (EIþ)
calcd for C9H10OS [Mþ]: 166.0452, found 166.0451.
3-(tert-butyldimethylsilyloxy)-2-phenylpentane-1,5-diyl dimetha-
nesulfonate. Following a literature protocol,52 the above diol
(55 mg, 0.31 mmol) was dissolved in dry DCM (8 mL) under N2
at 0 °C. Triethylamine (0.18 mL 1.3 mmol) and methanesulfonyl
chloride (0.05 mL. 0.67 mmol) were added to the flask and the
reaction was allowed to warm up to room temperature and
stirred for 16 h. Water (30 mL) was added to quench the
reaction, and the aqueous layer was extracted with DCM (5 ꢀ
20 mL). The combined organic layers were dried with MgSO4,
filtered, and the solvent was removed under reduced pressure to
give the desired bissulfonate as a brown oil (135 mg, 100%),
which was used without further purification in the next step.
1-Benzyl-4-(tert-butyldimethylsilyloxy)-3-phenylpiperidine (8).
The above bissulfonate (135 mg, 0.29 mmol) was dissolved in
dry dioxane (15 mL). Benzylamine (0.473 mL, 4.34 mmol) and
triethylamine (0.081 mL, 0.58 mmol) were added and the reaction
was allowed to stir at 80 °C overnight. The reaction was washed
with H2O (20 mL) and 3 M NaOH (2 mL). The aqueous layer was
extracted with Et2O (3 ꢀ 25 mL). The combined organic layers
were washed with brine, dried with MgSO4, and filtered, and the
solvent was removed under reduced pressure to give a red oil,
which was purified using column chromatography (40% EtOAc/
Hex) to give piperidine 8 as a red oil (35 mg, 32%). 1H NMR (300
MHz, CDCl3) δ: 7.84-7.64 (m, 10H), 4.12 (td, 1H, J = 9.8, 4.8
Hz), 4.04 (d, 2H, J = 2.8 Hz), 3.44 (dt, 2H, J = 11.4, 1.7 Hz),
3.32-3.24 (m, 2H), 2.78-2.60 (m, 2H), 2.43-2.19 (m, 2H), 1.18
(s, 9H), 0.33 (s, 6H) ppm. 13C NMR (75 MHz, CDCl3) δ: 147.8,
134.6, 134.2, 133.8, 133.6, 132.6, 132.0, 80.0, 68.3, 64.0, 57.8, 56.7,
40.8, 31.2, 23.4, 0.9 ppm. IR (CHCl3) υ: 3029, 2627, 2855, 2801,
1495, 1472, 1361, 1252, 1108, 835 cm-1. HRMS (EIþ) calcd for
C24H35NOSi [M]þ: 381.2488, found 381.2469.
tert-Butyldimethyl((1R,2S)-2-phenylcyclopent-3-enyloxy)silane
(7). On the basis of a literature protocol,50 a solution of 4a
(100 mg, 0.62 mmol) in dry DCM (10 mL) was stirred at 0 °C
under N2. tert-Butyldimethylsilyl chloride (207 mg, 1.37 mmol)
and imidazole (127 mg, 1.87 mmol) were added. The reaction
was allowed to stir overnight at room temperature. Water
(5 mL) was added, and the layers were decanted. The aqueous
layer was extracted with DCM (3 ꢀ 15 mL), the combined orga-
nic layers were washed with brine, dried with MgSO4, and
filtered, and the solvent was removed under reduced pressure
to give an oil. The product was purified by column chromatog-
raphy (10% EtOAc/Hex) to afford a colorless oil (152 mg,
90%). 1H NMR (400 MHz, CDCl3) δ: 7.43-7.28 (m, 5H),
5.90 (ddd, 1H, J = 6.1, 4.0, 2.1 Hz), 5.84 (ddd, 1H, J = 6.0,
4.0, 2.0 Hz), 4.35-4.31 (m, 1H), 3.86-3.83 (m, 1H), 2.82 (dddd,
1H, J = 16.2, 9.4, 7.0, 2.4 Hz), 2.47 (dddd, 1H, J = 16.4, 7.6, 5.5,
2.4 Hz), 0.96 (s, 9H), 0.14 (s, 6H) ppm. 13C NMR (100 MHz,
CDCl3) δ: 143.7, 132.7, 129.6, 127.8, 127.7, 126.6, 82.6, 60.6,
26.1, 26.0, 18.3, -4.7 ppm. IR (CHCl3) υ: 3060, 3029, 2956,
2929, 2857, 1471, 1361, 1252, 1113, 897 cm-1. HRMS (EIþ)
calcd for C13H17OSi [Mþ]: 217.1049; found: 217.1051.
3-(tert-Butyldimethylsilyloxy)-2-phenylpentane-1,5-diol. Accord-
ing to a modified literature protocol,51 cyclopentene 7 (162 mg,
1.12 mmol) was dissolved in dry DCM (36 mL) and MeOH (40 mL)
and cooled down to -78 °C. A stream of ozone was bubbled
throughuntil solution turned blue, and then N2 was bubbled through
until all blue color disappeared. Sodium borohydride (212 mg, 5.6
mmol) was added in four equal portions every 15 min for the
duration of 1 h, while maintaining the temperature at -78 °C. The
reaction was left to stir at room temperature until complete by TLC
analysis. The solvent was removed under reduced pressure; the
residue was retaken in EtOAc (25 mL) and was washed with brine.
The aqueous wash was extracted with EtOAc (5 ꢀ 25 mL), the
combined organic layers were dried with MgSO4 and filtered, and the
solvent was removed under reduced pressure to give an oil, which
was purified using column chromatography (50-100% EtOAc/
Hex, then 5% MeOH/DCM) to give the diol as a white solid (100
mg, 55%). 1H NMR (300 MHz, CDCl3) δ: 7.27-7.17 (m, 5H), 4.14
(ddd, 1H, J = 9.8, 5.1, 1.6 Hz), 4.03 (dd, 1H, J = 10.9, 7.4 Hz), 3.86
(dd, 1H, J = 10.9, 7.4 Hz), 3.60 (td, 2H, J = 7.4, 1.4 Hz), 3.01 (ddd,
1H, J = 11.6, 7.3, 4.4 Hz), 0.084 (s, 9H), 0.03 (s, 6H) ppm. 13CNMR
(75 MHz, CDCl3) δ: 143.9, 133.8, 133.2, 131.7, 77.3, 68.2, 64.5, 57.4,
40.4, 30.6, 22.7, -0.5 ppm. IR (CHCl3) υ: 3338, 2956, 2925, 2883,
2852, 1473, 1251, 1098, 1031, 915 cm-1. HRMS (EIþ) calcd for
C13H19O2Si [M-75]þ: 235.1154; found 235.1165.
Acknowledgment. The authors thank Dr. Chris Dockendorff
for helpful advice in the initial phases of this work, Dr.
Alistair Boyer for reviewing the manuscript, and Prof.
Michael Krische for insightful discussions. This work was
funded by the NSERC of Canada and Merck though an
Industrial Research Chair, and the University of Toronto.
We also gratefully acknowledge Solvias, Takasago and
Digital Chemical Specialties for generous gifts of chiral
ligands. F.M. thanks the Ontario Government for a graduate
scholarship (OGS).
Supporting Information Available: General experimental
methods, reaction procedures, complete characterization data,
1
and copies of H and 13C NMR spectra for compounds 1, 1a,
1aa, 2a, 2b, 2l, 2m, 2q-2w, 3a, 3b, 3l, 3m, 3q-3w, 4a, 4b, 4l, 4m,
4q-4w, 5a, 5b, 5l, 5m, 5q-5w, 7, and 8. This material is available
free of charge via the Internet at http://pubs.acs.org.
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4068 J. Org. Chem. Vol. 75, No. 12, 2010