Asymmetric platinum group metal-catalyzed carbonyl-ene reactions: Carbon-carbon bond formation versus isomerization

Article abstract of DOI:10.1021/jo062023n

A comparative study of the carbonyl-ene reaction between a range of 1,1′-disubstituted or trisubstituted alkenes and ethyl trifluoropyruvate catalyzed by Lewis acid-platinum group metal complexes of the type [M{(R)-BINAP}]²⁺ (M = Pt, Pd, Ni; BI

Full text of DOI:10.1021/jo062023n

Asymmetric Platinum Group Metal-Catalyzed Carbonyl-Ene
Reactions: Carbon-Carbon Bond Formation versus Isomerization
Simon Doherty,* Julian G. Knight,* Catherine H. Smyth, Ross W. Harrington, and
William Clegg
School of Natural Sciences, Chemistry, Bedson Building, Newcastle UniVersity, Newcastle upon Tyne, NE1
7RU, United Kingdom
simon.doherty@ncl.ac.uk; j.g.knight@ncl.ac.uk
ReceiVed September 30, 2006
A comparative study of the carbonyl-ene reaction between a range of 1,1′-disubstituted or trisubstituted
alkenes and ethyl trifluoropyruvate catalyzed by Lewis acid-platinum group metal complexes of the
type [M{(R)-BINAP}]2+ (M ) Pt, Pd, Ni; BINAP is 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) revealed
subtle but significant differences in their reactivity. For instance, the palladium-based Lewis acid [Pd-
{(R)-BINAP}]2+ catalyzes the ene reaction between methylene cycloalkane to afford the expected
R-hydroxy ester in good yield and excellent diastereo- and enantioselectivity. In contrast, under the same
conditions, the corresponding [M{(R)-BINAP}]2+ (M ) Pt, Ni) catalyzes isomerization of methylene
cycloalkane and the ene reaction of the resulting mixture of methylene cycloalkane and 1-methylcy-
cloalkene at similar rates to afford a range of R-hydroxy esters in high regioselectivity, good
diastereoselectivity, and good to excellent enantioselectivity. In addition, [Pt{(R)-BINAP}]2+ also catalyzes
postreaction isomerization of the ene product as well as consecutive ene reactions to afford a double
carbonyl-ene product. The sense of asymmetric induction has been established by single-crystal X-ray
crystallography, and a stereochemical model consistent with the formation of (S)-configured R-hydroxy
ester has been proposed; the same model also accounts for the observed exo-diastereoselectivity as well
as the level of diastereoselectivity.
Introduction
unsaturated R-hydroxy esters (eq 1, R3 ) H).2 This transforma-
tion has traditionally been catalyzed by a high-valent electro-
philic early transition metal, a main group or lanthanide metal
coordinated by a chiral multidentate protic nitrogen, and/or an
oxygen-based ligand.3 Since the first catalytic enantioselective
variant of this reaction,4 which used a chiral aluminum complex
of enantiopure BINOL, a host of Lewis acids including those
The asymmetric carbonyl-ene reaction between a glyoxylate
ester and an R-olefin is a powerful CsC bond forming reaction1
that provides access to nonracemic synthetically versatile â,γ-
(1) For general reviews of enantioselective ene reactions see: (a) Mikami,
K.; Shimizu, M. Chem. ReV. 1992, 92, 1021. (b) Dias, L. Curr. Org. Chem.
2000, 4, 305. (c) Berrisford, D. J.; Bolm, C. Angew. Chem., Int. Ed. Engl.
1995, 34, 1717. (d) Mikami, K.; Terada, M. ComprehensiVe Asymmetric
Catalysis; Springer-Verlag: Berlin, Heidelberg, 1999; Vol. III, p 1143.
(e) Mikami, K.; Nakai, T. Catalytic Asymmetric Synthesis; Wiley-VCH:
New York, 2000; pp 543-568. For selected relevant articles on carbonyl-
ene-type reactions see: (f) Evans, D. A.; Wu, J. J. Am. Chem. Soc. 2005,
127, 8006. (g) Evans, D. A.; Aye, Y.; Wu, J. Org. Lett. 2006, 8, 2071. (h)
Ho, C.-Y.; Ng, S.-S.; Jamison, T. F. J. Am. Chem. Soc. 2006, 128, 5362.
(2) Coppola, G. M.; Schuster, H. F. R-Hydroxy Acids in EnantioselectiVe
Syntheses; VCH: Weinheim, 1997.
(3) (a) Yamamoto, Y., Ed. Lewis Acids in Organic Synthesis; Wiley-
VCH: New York, 1994. (b) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H.
ComprehensiVes Asymmetric Catalysis; Springer-Verlag: Berlin, 1999; pp
912-1306. (c) Noyori, R. Asymmetric Catalysis in Organic Synthesis;
Wiley: New York, 1994.
10.1021/jo062023n CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/18/2006
J. Org. Chem. 2006, 71, 9751-9764
9751

Doherty et al.
based on Ti,5 Cr,6 Co,7 Cu,8 various lanthanides,9 and most
recently Sc1f have proven to be highly efficient catalysts for
this transformation, often giving excellent levels of regio-,
enantio-, and diastereocontrol.
nates.23 The properties of such complexes are inherently different
from those of conventional Lewis acids, unique to the late
transition metals, and include well-defined coordination geom-
etries, high carbophilicity, functional group tolerance, slow rates
of ligand exchange, and rational control of stereoelectronic
properties through ligand modification. In this regard, Gagne´
et al. have investigated the thermodynamic and kinetic relation-
ship between Lewis acid-Lewis base complexes relevant to
the platinum(II)-catalyzed Diels-Alder reaction and have shown
that the activity of late transition metal Lewis acid catalysts is
controlled by ligand substitution rates rather than electrophilicity
and that, despite being considered “soft”, the late transition metal
Lewis acids are highly electrophilic.24
Recently, square planar cationic metal complexes of the type
[(diphosphine)M]2+ (M ) Pt, Pd, Ni) have emerged as an
alternative and highly efficient class of Lewis acid catalyst10
for a host of important enantioselective transformations includ-
ing Diels-Alder11 and hetero Diels-Alder reactions,12 the
enantioselective alkylation of R-imino esters,13 1,3-dipolar
cycloadditions,14 asymmetric Prins cyclizations,15 the Conia-
ene reaction,16 and conjugate addition of amines to R,â-
unsaturated N-alkenylimides,17 as well as asymmetric reactions
via palladium enolates18 such as Michael reactions with
enones,19 Mannich-type reactions,20 and the enantioselective
fluorination of oxindoles,21 â-ketoesters,22 and â-keto phospho-
These platinum group metal Lewis acids have also proven
to be highly efficient catalysts for the carbonyl-ene reaction. In
the first report, Hao et al. examined the influence of ligand,
counterion, solvent, and temperature on the palladium-catalyzed
glyoxylate-ene reaction and demonstrated that [Pd{(S)-Tol-
BINAP}(MeCN)2][SbF6]2 (BINAP is 2,2′-bis(diphenylphos-
phino)-1,1′-binaphthyl, Chart 1) is a highly efficient catalyst at
relatively high reaction temperatures.25 Following this, Gagne´
reported that the platinum(II)-catalyzed ene reaction between
methylene cyclohexane and ethyl glyoxylate was subject to
marked anion dependent additive effects and that achiral acidic
phenol additives accelerate the reaction of the triflate-based
catalyst by disrupting contact ion pairs and sequestering traces
of water.26 While these early examples relied on the use of an
enantiopure atropisomeric diphosphine such as BINAP or MeO-
BIPHEP (BIPHEP is 2,2′-bis(diphenylphosphino)biphenyl) for
efficient control of the stereochemistry, platinum group metal
complexes of conformationally flexible diphosphines such as
BIPHEP,27 1,1′-bis(diphenylphosphino)ferrocene (dppf), and
NUPHOS28 have also been used to control the stereochemical
outcome of the carbonyl-ene reaction. For example, the enan-
tiopure Lewis acid λ-[(BIPHEP)Pt](OTf)2 catalyzes the carbo-
nyl-ene reaction between methylene cyclohexane and ethyl
glyoxylate to afford an enantiomeric excess (ee) of 72%
compared to that of 74% obtained with [{(S)-MeO-BIPHEP}-
Pd](OTf)2.29 Interestingly, control of axial and helical chirality
in palladium complexes of the tropos diphosphine 2,4′,6′,2′′-
tetrakis(diphenylphosphino)-[1,1′,3′,1′′]terphenyl (tetraphos) re-
sulted in higher enantioselectivities and yields compared to those
obtained with the corresponding BINAP-based catalyst.30 In the
case of Ni, Pd, and Pt complexes of dppf, which require
coordination of enantiopure 2,2′-diamino-1,1′-binaphthyl for
control of the axial chirality, the Ni/dppf combination proved
to be significantly more efficient and enantioselective than either
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Asymmetric Platinum Group Reactions
CHART 1
its palladium or its platinum counterparts.31 In a related
approach, we have resolved platinum metal complexes of
conformationally flexible NUPHOS-diphosphines32 [NUPHOS
) 1,4-bis(diphenylphosphino)-1,2,3,4-tetrasubstituted-1,3-buta-
diene] and have shown the corresponding enantiopure Lewis
acids δ- or λ-[(NUPHOS)Pt](SbF6)2 to be highly efficient
catalysts for the carbonyl-ene reaction between various 1,1′-
disubstituted alkenes and phenyl glyoxal or ethyl glyoxylate,
giving ee’s that either rival or exceed those obtained with their
atropisomeric counterparts.33
Although the carbonyl-ene reaction with glyoxylate esters has
been thoroughly studied, the corresponding transformation with
R-keto esters is less documented (eq 1, R3 ) CH3, CF3), which
is somewhat surprising since it provides a straightforward route
to nonracemic homoallylic tertiary alcohols. Evans et al. has
reported that [Cu{(S,S)-t-Bu-box}][SbF6]2 catalyzes an enanti-
oselective version of the ene reaction with pyruvate esters to
afford excellent ee’s, although acceptable yields were obtained
only after careful optimization.8a Interestingly, Mikami and co-
workers recently demonstrated that the “soft” Lewis acid [Pd-
{(S)-SEGPHOS}]2+ [SEGPHOS ) 4,4′-bi-1,3-benzodioxole-
5,5′-diylbis(diarylphosphine)] possesses a favorable combination
of electrophilicity and ligand substitution rates since it catalyzes
the carbonyl-ene reaction of trifluoropyruvate to give high
yields, E-alkene selectivity, anti-diastereoselectivity, and high
enantioselectivities.34
of significant and interesting discoveries including (i) highly
efficient Lewis acid catalysis of the carbonyl-ene reaction by
each member of the triad [M{(R)-BINAP}]2+ (M ) Ni, Pd,
Pt), (ii) competitive Lewis acid-catalyzed isomerization of the
ene substrate to afford a mixture of homoallylic products, (iii)
Lewis acid-catalyzed isomerization of the resulting R-hydroxy
esters, (iv) facile addition of the ene product to a second
equivalent of R-keto ester to afford the product of a “double”
carbonyl-ene reaction, and (v) highly efficient catalysis of the
carbonyl-ene reaction with enantiopure Lewis acid complexes
of the conformationally flexible NUPHOS diphosphine 1,2-bis-
((1-diphenylphosphino)propylidene)cyclohexane (1,4-Et2-cyclo-
C6H8-NUPHOS), with ee’s and yields that rival those obtained
with their BINAP-based counterparts.
Results and Discussion
Since the carbonyl-ene reaction has been catalyzed by a host
of Lewis acids, it was considered an ideal transformation to
evaluate the relative merits of “soft” late transition metal
catalysts. In this study, the addition of a range of mono-, di-,
and trisubstituted alkenes to ethyl trifluoropyruvate has been
investigated, the results of which are summarized in Tables 1-7.
The Lewis acids [M{(R)-BINAP}]2+ (M ) Pt, 2a; Pd, 2b; Ni,
2c) and δ-[Pt(1,4-Et2-cyclo-C6H8-NUPHOS}]2+ δ-(4) were all
generated in situ by the addition of 2 equiv of a silver salt to a
dichloromethane solution of the corresponding dichloride 1a-c
and δ-3, respectively (eqs 2 and 3). After stirring for 30 min at
ambient temperature, the dienophile and alkene were added, and
the progress of the reaction was monitored by GC. Although
these reactions proceed in THF, 1,2-dichloroethane, and toluene,
the ee’s were all consistently lower than those obtained in
dichloromethane, which was adopted as the solvent of choice.
During our ongoing investigations into the platinum group
chemistry of NUPHOS diphosphines,35 we had cause to
investigate and compare the efficiency of [M(BINAP)]2+ (M
) Ni, Pd, Pt) as catalysts for the enantioselective carbonyl-ene
reaction with ethyl trifluoropyruvate. Herein, we report the
results of a systematic and detailed study which led to a number
(30) (a) Aikawa, K.; Mikami, K. Angew. Chem., Int. Ed. 2003, 42, 5458.
See also (b) Aikawa, K.; Mikami, K. Angew. Chem., Int. Ed. 2003, 42,
5455.
(31) Mikami, K.; Aikawa, K. Org. Lett. 2002, 4, 99.
(32) Doherty, S.; Newman, C. R.; Rath, R. K.; van den Berg, J. A.;
Hardacre, C.; Nieuwenhuyzen, M.; Knight, J. G. Organometallics 2004,
23, 1055.
(33) Doherty, S.; Goodrich, P.; Hardacre, C.; Luo, H. K.; Nieuwenhuyzen,
M.; Rath, R. K. Organometallics 2005, 24, 5945.
(34) (a) Mikami, K.; Aikawa, K.; Kainuma, S.; Kawakami, Y.; Saito,
T.; Sayo, N.; Kumobayashi, H. Tetrahedron: Asymmetry 2004, 15, 3885.
(b) Aikawa, K.; Kainuma, S.; Hatano, M.; Mikami, K. Tetrahedron Lett.
2004, 45, 183. (c) Mikami, J.; Kakuno, H.; Aikawa, K. Angew. Chem., Int.
Ed. 2005, 44, 7257.
(35) (a) Doherty, S.; Newman, C. R.; Rath, R. K.; Luo, K. K.;
Nieuwenhuyzen, M.; Knight, J. G. Org. Lett. 2003, 5, 3863. (b) Doherty,
S.; Knight, J. G.; Hardacre, C.; Luo, H. K.; Newman, C. R.; Rath, R. K.;
Campbell, S.; Nieuwenhuyzen, M. Organometallics 2004, 23, 6127. (c)
Doherty, S.; Goodrich, P.; Hardacre, C.; Luo, H.-K.; Rooney, D. W.; Seddon,
K. R.; Styring, P. Green Chem. 2004, 6, 63. (d) Doherty, S.; Knight, J. G.;
Rath, R. K.; Clegg, W.; Harrington, R. W.; Newman, C. R.; Campbell, R.;
Amin, H. Organometallics 2005, 24, 2633. (e) Doherty, S.; Newman, C.
R.; Hardacre, C.; Nieuwenhuyzen, M.; Knight, J. G. Organometallics 2003,
22, 1452.
In the first instance, the ene reaction between allyl benzene
and ethyl trifluoropyruvate to afford R-hydroxy ester 5 was
investigated using conditions similar to those developed by
Mikami et al.,34 the results of which are listed in Table 1. Each
of the catalysts, 2a-c, gave good conversions (76-92%) which
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Doherty et al.
TABLE 1. Asymmetric Carbonyl-Ene Reaction between Allyl
1-methylcyclohexene, the catalyst-pyruvate complex must
discriminate between the methyl substituent and the R-CH2 of
the cyclohexyl ring. High levels of regioselective discrimination
of substituents in 1,1-disubstituted alkenes have recently been
achieved with Lewis acid scandium catalysts based on pyridine
bis(oxazolines), which also gave excellent regio- and diaste-
reoselectivities with trisubstituted alkenes.1f Similar levels of
regioselectivity have also been obtained for carbonyl-ene
reactions catalyzed by optically active cationic cobalt(III)
complexes of â-ketoimines.6
Benzene and Ethyl Trifluoropyruvate Catalyzed by 2a-c in CH2Cl2
catalyst
(mol %)
time
(min)
conversionb
(%)
% eec
(config)
entrya
1
2
3
2a (5)
2b (5)
2c (5)
30
30
30
92
76
78
99 (S)
97 (S)
92 (S)
While the 6b:6c ratio of 4.7:1 may correspond to the
regioselectivity of the carbonyl-ene reaction, we must consider
that 6b could subsequently isomerize to 6c and/or undergo a
further ene reaction to afford 6d (Scheme 1), both of which
would lead to an artificially low regioselectivity. To investigate
this possibility, a dichloromethane solution of Lewis acid 2a
(5 mol %), R-hydroxy ester 6b (ca. 0.3 M), and ethyl
trifluoropyruvate (1.5 equiv) was stirred at room temperature,
and the composition was monitored as a function of time. The
48:7:45 distribution of 6b-d present after 2 h confirms that
while 6b isomerizes to 6c, it undergoes a much faster addition
to ethyl trifluoropyruvate to afford the double ene product 6d.
Since isomerization of 6b is relatively slow, the reaction between
methylene cyclohexane and ethyl trifluoropyruvate was sampled
and analyzed after 1 min, and the 6b:6c ratio of 46:1 should be
taken as a more reliable measure of the regioselectivity (Table
2, entry 7). Lewis acid 2a also catalyzed the ene reaction
between 6a and ethyl trifluoropyruvate, albeit much more slowly
than 6b as evidenced by the 6a:6d ratio of 96:4 present after 2
h, thereby confirming that the primary pathway to 6d is via the
addition of 6b to a second equivalent of ethyl trifluoropyruvate.
The (2S,3′S,1′′S) configuration of the major diastereoisomer of
6d (Table 2) is based on approach of (1′S,2S)-6b (an assignment
based on the X-ray structure determinations of 10 and 8b) to
the preferred face of the platinum-coordinated ethyl trifluoro-
pyruvate. The composition of a typical reaction mixture,
monitored as a function of time (Figure 1), clearly shows that
6b slowly isomerizes to 6c and eventually approaches equilib-
rium and that the double ene product 6d gradually increases to
a maximum level, which presumably corresponds to the
complete consumption of ethyl trifluoropyruvate. Examination
of the product distribution from this experiment also revealed
that the major exo-diastereoisomer of 6b with (1′S,2S) config-
uration isomerizes to (1′S,2S)-6c, which corresponds to the
minor endo-diastereoisomer from the ene reaction between
1-methylcyclohexene and ethyl trifluoropyruvate (note, the
major exo-diastereoisomer of 6c from the ene reaction of
1-methylcyclohexene has a (1′R,2S) configuration). Thus, the
exo:endo ratio of 6:4 determined after 1 min most likely reflects
the intrinsic diastereoselectivity of this addition (Table 2, entry
7), whereas the ratio of 1:2 after 30 min (Table 2, entry 1) is
artificially high in favor of the endo-diastereoisomer because
of the isomerization of (1′S,2S)-6b. In this regard, the relative
stereochemistry and absolute configurations of these products,
assigned by analogy with the single-crystal X-ray structures of
8b and 10, are entirely consistent with the transition state models
used to rationalize the stereochemical outcome of these trans-
formations (vide infra). Interestingly, there was no evidence for
isomerization of 6b in the absence of ethyl trifluoropyruvate
which suggests that [2a-pyruvate]2+ is the active isomerization
catalyst. As expected, higher yields of the double ene product
were obtained when the amount of ethyl trifluoropyruvate was
a Reaction conditions: 5 mol % catalyst, allyl benzene (0.4 mmol), and
ethyl trifluoropyruvate (0.6 mmol) in 2.0 mL of CH2Cl2, room temperature.
b Conversions determined by GC using a Supelco Beta DEX column.
c Enantiomeric excess determined by chiral GC using a Supelco Beta DEX
column. Average of three runs.
increase in the order Pt > Ni ≈ Pd, complete E selectivity, and
excellent enantioselectivity (92-99% ee). This order of reactiv-
ity is interesting since Gagne´ et al. have recently commented
on the relative activity of [P2Pd]2+ and [P2Pt]2+ (P2 ) dppe,
BINAP) Lewis acid catalysts for transformations such as the
Diels-Alder reaction and reasoned that catalyst activity is
determined by ligand substitution rates rather than by electro-
philicity.24 In such cases, [P2Pd]2+ Lewis acids are more active
than their platinum counterparts because ligand substitution rates
are faster and not because the metal center is more electrophilic.
Therefore, intuitively for reactions in which ligand exchange is
rate-limiting, it should be possible to control catalyst activity
by reducing the electrophilicity of the Lewis acid and conse-
quently the strength of the metal-product bonding. This appears
to be the case for the Lewis acid platinum-catalyzed glyoxylate-
ene reaction in which activity was found to increase with
increasing phosphine basicity.26
Lewis acids 2a-c also catalyze the addition of methylene
cyclohexane to ethyl trifluoropyruvate, full details of which are
provided in Table 2. Surprisingly, 2a catalyzed the ene reaction
between methylene cyclohexane and ethyl trifluoropyruvate to
afford the expected R-hydroxy ester 6a together with three
unanticipated byproducts, 6b-d, which were separated by
column chromatography and identified by a combination of 1H
and 13C NMR spectroscopy, mass spectrometry, and elemental
analysis. While R-hydroxy ester 6a is the product of an ene
reaction between ethyl trifluoropyruvate and methylene cyclo-
hexane, 6b and 6c are regioisomers that result from the
corresponding ene reaction with 1-methylcyclohexene, generated
in situ via Lewis acid-catalyzed isomerization of methylene
cyclohexane, and 6d is a double ene product formed by addition
of 6a and/or 6b to ethyl trifluoropyruvate (Scheme 1). Thus,
the distribution of R-hydroxy esters obtained from the reaction
between methylene cyclohexane and ethyl trifluoropyruvate
most likely reflects the relative rates of isomerization versus
ene reactivity. The data in Table 2 reveal that catalyst 2a exhibits
good enantioselectivity (77% ee) for the expected R-hydroxy
ester 6a. For the mono-ene products derived from the isomerized
alkene, catalyst 2a gives moderate regioselectivity in favor of
6b (ca. 4.7:1), low to high diastereoselectivity, and excellent
enantioselectivity for 6b and 6c (Table 2, entry 1). The double
ene product, 6d, is formed in high diastereoselectivity (91%
diastereomeric excess (de)). The moderate regioselectivity is
not surprising since Evans et al. have demonstrated that steric
considerations are an important factor in determining selectivity
for copper complexes of bis(oxazolines) with bulkier substituents
on the alkene leading to increased selectivities.8a In the case of
9754 J. Org. Chem., Vol. 71, No. 26, 2006

Asymmetric Platinum Group Reactions
TABLE 2. Asymmetric Carbonyl-Ene Reaction between Methylene Cyclohexane and Ethyl Trifluoropyruvate Catalyzed by 2a-c in CH2Cl2
product ratioc
exo:endo ratiod
% eee
6b
% def,g
6d
entrya
catalyst (mol %)
X-
time (min)
convb (%)
6a:6b:6c:6d
6b
6c
6a
6c
1
2
3
4
5
6
7
8
8
2a (5)
2b (5)
2c (5)
2a (1)
2a (0.5)
2a (0.2)
2a (5)
2b (5)
2c (5)
2a (5)
2a (5)
2a (5)
δ-4 (5)
SbF6
SbF6
SbF6
SbF6
SbF6
SbF6
SbF6
SbF6
SbF6
BF4
30
30
30
30
30
120
1
1
1
30
30
30
10
100
100
100
79
68
80
>99
>99
>99
82
38:47:10:5
100:0:0:0
57:40:2:1
36:49:10:5
37:48:10:5
36:49:10:5
53:46:1:0
100:0:0:0
59:40:1:0
61:36:2:0
29:71:0:0
nd
>99:1
1:2
77
93
74
76
76
77
77
94
75
82
53
nd
70h
99
99, 98
91
>99:1
>99:1
>99:1
>99:1
>99:1
1:2
2:1
1:2
1:1
6:4
99
99
99
99
99
86, 82
99, 98
99, 98
99, 96
99, 96
92
99
99
99
>99:1
>99:1
nd
nd
>99:1
1:1
4:6
nd
nd
3:2
99
99
99
nd
99h
86,83
99, 87
9
10
11
12
ClO4
OTf
SbF6
8
3
100
nd
nd
43:55:1:1
99h, 99h
77h
a Reaction conditions: 5 mol % catalyst, methylene cyclohexane (0.4 mmol), and ethyl trifluoropyruvate (0.6 mmol) in 2.0 mL of CH2Cl2, room temperature.
b Conversions determined by GC using a Supelco Beta DEX column. c Product ratios determined by 1H NMR spectroscopy. d exo:endo ratio determined by
1H NMR spectroscopy and chiral GC and assigned by analogy with the X-ray crystal structure of 8b. e Enantiomeric excess determined by chiral GC using
a Supelco Beta DEX column and listed either as % ee exo in cases where the ee of the minor endo diastereoisomer was not determined or as % ee exo, %
ee endo. f Diastereoisomeric excess determined by chiral GC using a Supelco Beta DEX column. g Minor enantiomers were not detected. h Opposite enantiomer
to that shown in the table figure. Average of three runs; nd ) not determined.
SCHEME 1
increased, but in general, reactions were performed with 1.5
equiv of enophile.
marked improvement on those of 77 and 74% obtained with
2a and 2c, respectively (Table 2, entry 2). The different product
distributions obtained with catalyst 2b compared with 2a,c are
most likely associated with a change in the relative rates of
isomerization and ene reactivity, particularly since a comparative
study has shown Lewis acid 2a to be a more efficient
isomerization catalyst than 2b. In this regard, [Pd{(S)-SEG-
PHOS}]2+ has previously been reported to catalyze the ene
reaction between methylene cyclohexane and ethyl trifluoro-
pyruvate to afford 6a as the sole product in 96% ee.34
Unfortunately, the corresponding reaction catalyzed by [Pt{(S)-
Table 2 shows that the product distribution also depends on
the metal center. Lewis acid 2c (M ) Ni) gave R-hydroxy ester
6a in good yield and moderate enantioselectivity (74% ee) and
gave 6b in high diastereoselectivity and enantioselectivity, as
the major components, together with minor amounts of 6c as a
near 1:1 mixture of diastereoisomers in good enantioselectivity
and double addition product 6d in high diastereoselectivity
(Table 2, entry 3). In stark contrast, catalyst 2b (M ) Pd) gave
R-hydroxy ester 6a as the sole product in 93% ee, which is a
J. Org. Chem, Vol. 71, No. 26, 2006 9755

Doherty et al.
FIGURE 1. Variation of the percent composition for the carbonyl-
ene reaction between methylene cyclohexane and ethyl trifluoropyruvate
catalyzed by [Pt{(R)-BINAP}][SbF6]2 (2a) in dichloromethane with
respect to time at room temperature.
FIGURE 2. Asymmetric unit of (R)-1-(1-naphthyl)ethylammonium
(2S)-3-(cyclohexen-1-yl)-2-(trifluoromethyl)-2-hydroxypropanoate dichlo-
romethane solvate (10), with 40% probability displacement ellipsoids,
showing the absolute stereochemistry of C(2) to be of S configuration.
Hydrogen bonds within the asymmetric unit are shown as dashed lines.
SEGPHOS}]2+ was not reported for comparison. The absolute
configuration of 6a was determined by hydrolysis to the free
acid (9) and a single-crystal X-ray structure determination of
its (R)-1-naphthylethylammonium salt (10), shown in Figure 2.36
The relative stereochemistry and absolute configurations of
R-hydroxy esters 6b-d are based on analogy with this structure
and that of 8b, which was also determined by single-crystal
X-ray crystallography (see below).
ene reaction with methylene cyclohexane. The enantioselectivity
improved at low temperatures, and at -78 °C, the ee of 80%
was marginally higher than that of 77% obtained at room
temperature.
1
A low temperature 31P and H NMR study (213 K) on a
A limited study of the influence of the counterion on the
Lewis acid-catalyzed reaction between methylene cyclohexane
and ethyl trifluoropyruvate revealed a marked effect on conver-
sion and enantioselectivity with catalyst performance generally
dichloromethane solution containing [Pt{(R)-BINAP}][SbF6]2
and 10 equiv of ethyl trifluoropyruvate identified the catalyst-
substrate complex [Pt{(R)-BINAP}‚(pyruvate)]2+. Two doublets
at 4.8 and 2.7 ppm with a JPP value of 25.0 Hz and Pt-P
coupling constants of 4190 and 4039 Hz indicate that the
dienophile binds to platinum in the expected κ(O),κ(O) bidentate
manner through its carbonyl oxygen atoms and that one of the
PtsOdC bonds is stronger than the other. In addition, two sharp
-
increasing in the order SbF6 ≈ BF4- > ClO4- > TfO- (Table
2, entries 9-11); this is consistent with previous reports
including the platinum-catalyzed glyoxylate-ene reaction26 and
the ruthenium-catalyzed Diels-Alder reaction between meth-
acrolein and cyclopentadiene.37 In an examination of the catalyst
loading using methylene cyclohexane and [Pt{(R)-BINAP}]-
[SbF6]2 (Table 2, entries 4-6), it was found that loadings as
low as 0.2 mol % may be used (80% conversion in 2 h);
however, reactions were routinely performed with 5 mol %
catalyst, for practical reasons. The effect of temperature on the
performance of catalyst 2a was also investigated since it
consistently gave the lowest enantioselectivity in the carbonyl-
1
triplets at δ 1.33 and 1.13 in the low temperature H NMR
spectrum correspond to free and coordinated ethyl trifluoropy-
ruvate, respectively, and confirm that exchange is slow on the
NMR time scale. A minor resonance at 1.8 ppm was associated
with residual [Pt{(R)-BINAP}][SbF6]2 and corresponds to a Keq
of approximately 100 calculated via integration of the 31P
resonances. These data are similar to those recently reported24
for [Pt{(R)-BINAP}(acryloyl-N-oxazolidinone)]2+ and are con-
sistent with activation of the dienophile via a traditional Lewis
acid mechanism, as proposed in the transition model used to
rationalize the stereochemical outcome of these transformations
(vide infra). Addition of methylene cyclohexane to the solution
used for these NMR studies resulted in a rapid reaction to afford
R-hydroxy esters 6a-d in the same ratio and with enantiose-
lectivities and diastereoselectivities similar to those listed in
Table 2, suggesting that we may be observing the active
catalyst-substrate complex.
A comparative study between Lewis acid 2a and the
enantiopure NUPHOS-based catalyst δ-[(1,4-Et2-cyclo-C6H8-
NUPHOS)Pt]2+ δ-(4) was carried out for the ene reaction
between methylene cyclohexane and ethyl trifluoropyruvate to
evaluate the relative merits of atropos and tropos diphosphines.
Under similar conditions, Lewis acid δ-4 afforded R-hydroxy
ester 6a in a 71% ee, regioisomeric ene products 6b and 6c in
moderate-to-high diastereoselectivity and excellent enantiose-
lectivity, and double ene product 6d in moderate diastereose-
lectivity (77% de, Table 2, entry 12). Moreover, the regiose-
(36) Crystal data for (S)-6a: C12H14N+‚C10H12F3O3-‚CH2Cl2, Mr
)
494.4, monoclinic, space group P21, a ) 12.8271(18), b ) 6.6780(7), c )
15.6221(18) Å, â ) 113.549(8)°, V ) 1226.7(3) Å3, Z ) 2, Fcalcd ) 1.338
g cm-3, T ) 150 K; crystal size 0.42 × 0.10 × 0.10 mm3, Mo KR radiation,
λ ) 0.710 73 Å, µ ) 0.31 mm-1, transmission 0.880-0.970 by multi-scan
methods, 2θmax ) 25°, Nonius Kappa CCD diffractometer, 14 780 measured
data, 4155 unique reflections, Rint ) 0.039; standard direct methods and
full-matrix least-squares refinement on all unique F2 values, NH and OH
H atoms freely refined, CH H atoms riding, R (3463 F values with F2 >
2σ) ) 0.048, Rw (all F2 values) ) 0.121, goodness-of-fit ) 1.10, 2-fold
disorder resolved for solvent molecule, final difference map extremes +0.30
and -0.28 e Å-3, absolute structure parameter 0.01(9). Programs: Nonius
COLLECT and EvalCCD, Bruker SADABS and SHELXTL. CCDC 615959
(S-6a), CCDC 615960 (S,S-8b), and CCDC 615961 (1a) contain the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif (or from the Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, U.K.; fax
(+44) 1223-336.-033; or deposit@ccdc.cam.uk).
(37) (a) Ku¨ndig, E. P.; Suadan, C. M.; Bernardinelli, G. Angew. Chem.,
Int. Ed. 1999, 38, 1220. (b) Kumar, P. G. A.; Pregosin, P. S.; Vallet, M.;
Bernardinelli, G.; Jazzar, R. F.; Viton, F.; Ku¨ndig, E. P. Organometallics
2004, 23, 5410.
9756 J. Org. Chem., Vol. 71, No. 26, 2006

Asymmetric Platinum Group Reactions
TABLE 3. Asymmetric Carbonyl-Ene Reaction between 1-Methylcyclohexene and Ethyl Trifluoropyruvate Catalyzed by 2a-c in CH2Cl2
product ratioc
exo:endo ratiod
% eee
% de
entrya
catalyst (mol %)
time (min)
convb (%)
6a:6b:6c:6d
6b
6c
6a
6b
6c
6d
1
2
3
4
5
2a (5)
2a (5)
2b (5)
2c (5)
δ-4 (5)
30
1
30
30
30
>99
98
93
100
100
2:91:7:0
3:92:5:0
1:81:18:0
1:98:1:0
4:95:1:0
>
99:1
>99:1
>99:1
>99:1
>99:1
1:2
2:1
3:1
3:1
2:1
78
75
96
77
74f
>99
>99
99
99, 96
99, 97
96, 94
79, 84
95f, 92f
>99
>99f
a Reaction conditions: 5 mol % catalyst, 1-methylcyclohexene (0.4 mmol), and ethyl trifluoropyruvate (0.6 mmol) in 2.0 mL of CH2Cl2, room temperature.
b Conversions determined by GC using a Supelco Beta DEX column. c Product ratios determined by 1H NMR spectroscopy. d exo:endo ratio determined by
1H NMR spectroscopy and chiral GC and assigned by analogy with the X-ray crystal structure of 8b e Enantiomeric excess determined by chiral GC using
a Supelco Beta DEX column and listed either as % ee exo in cases where the ee of the minor endo diastereoisomer was not determined or as % ee exo, %
ee endo. f Opposite enantiomer to that shown in the table figure. Average of three runs.
lectivity of 55:1 is comparable to that of 46:1 obtained with its
(R)-BINAP counterpart (Table 2, entry 7). Comparison of the
GC retention times revealed that δ-[(1,4-Et2-cyclo-C6H8-
NUPHOS)Pt]2+ δ-(4) gave R-hydroxy esters 6a-d with the
opposite absolute stereochemistry to that obtained with (R)-
BINAP; that is, NUPHOS-type diphosphines with a δ confor-
mation behave in much the same manner as (S)-BINAP.
Gratifyingly, this study shows that Lewis acid catalysts based
on conformationally flexible NUPHOS-type diphosphines can
compete with their enantiopure BINAP counterparts.
ethyl glyoxylate and 1-methylcyclohexene was catalyzed by 2a
and afforded regioisomer 6′c in excellent enantioselectivity (99%
ee) and moderate diastereoselectivity (2:1), together with a minor
amount of 6′b (<2%). Thus, since isomerization of R-hydroxy
esters has been shown to be relatively slow (vide supra), the
Lewis acid-catalyzed addition of 1-methylcyclohexene to ethyl
glyoxylate and ethyl trifluoropyruvate must occur with opposing
regioselectivity, ethyl glyoxylate forming the thermodynamically
favored regioisomer 6′c while ethyl trifluoropyruvate affords
the less favored R-hydroxy ester 6b. It is reasonable to suggest/
speculate that the transition state involving the R-CH2 is more
favored for the less hindered ethyl glyoxylate, whereas the
corresponding transition state for pyruvate would experience
unfavorable steric interactions between the CF3 group and the
cyclohexyl ring.
Reasoning that the product distribution obtained from the
Lewis acid-catalyzed ene reaction between methylene cyclo-
hexane and ethyl trifluoropyruvate reflected the finely balanced
kinetics of alkene isomerization relative to ene reactivity, we
also investigated the corresponding reaction with 1-methylcy-
clohexene, the results of which are summarized in Table 3.
Reassuringly, the performance of catalysts 2a-c for the addition
of 1-methylcyclohexene to ethyl trifluoropyruvate paralleled that
obtained in the corresponding reaction with methylene cyclo-
hexane in that (i) the enantioselectivities of R-hydroxy esters
6a-c are similar to those obtained with methylene cyclohexane,
(ii) catalyst 2b gave R-hydroxy ester 6a in 96% ee (Table 3,
entry 3) whereas its platinum and nickel counterparts gave
markedly lower ee’s of 78 and 77%, respectively (Table 3,
entries 1, 4), and (iii) each of the catalysts gave high levels of
regioselectivity to afford 6b as the dominant product, which
corresponds to effective discrimination in favor of the methyl
substituent compared to the cyclohexyl R-CH2. As expected,
the performance of δ-4 for the addition of 1-methylcyclohexene
to ethyl trifluoropyruvate compares favorably with that of 2a
in that a similar distribution of R-hydroxy ester 6a and
regioisomers 6b,c was obtained, with comparable levels of
enantioselectivity and diastereoselectivity (Table 3, entry 5).
Evans et al. have reported that copper complexes of bis-
(oxazolines) catalyze the addition of 1-methylcyclohexene to
ethyl glyoxylate to afford a single regioisomer, 6′c, which
corresponds to the opposite sense of regioselectivity, that is,
discrimination favoring the cyclohexyl R-CH2 (eq 4).7 Since it
would not be reliable to compare catalyst selectivities for
reactions involving different enophiles, the reaction between
For comparison, the addition of methylene cyclopentane and
1-methylcyclopentene to ethyl trifluoropyruvate was also cata-
lyzed by 2a-c, details of which are summarized in Tables 4
and 5, respectively. Not surprisingly, the reactivity patterns and
trends in catalyst selectivity obtained with these substrates are
qualitatively similar to those of their six-membered counterparts.
First, Lewis acids 2a,c catalyze the addition of methylene
cyclopentane to ethyl trifluoropyruvate to afford mixtures of
7a-d (Table 4, entries 1 and 4), whereas 2b was highly selective
for R-hydroxy ester 7a (Table 4, entry 3). The similarity in
catalyst performance between methylene cyclopentane and
methylene cyclohexane also extends to trends in enantioselec-
tivity in that Lewis acid 2b gave R-hydroxy ester 7a in excellent
J. Org. Chem, Vol. 71, No. 26, 2006 9757

Doherty et al.
TABLE 4. Asymmetric Carbonyl-Ene Reaction between Methylene Cyclopentane and Ethyl Trifluoropyruvate Catalyzed by 2a-c in CH2Cl2
product ratioc
exo:endo ratiod
% eee
% def,g
entrya
catalyst (mol %)
time (min)
convb (%)
7a:7b:7c:7d
7b
7c
7a
7b
7c
7d
1
2
3
4
2a (5)
2a (5)
2b (5)
2c (5)
30
1
30
30
100
100
100
98
7:68:15:10
10:64:17:9
98:2:0:0
>99:1
>99:1
>99:1
>99:1
3:1
7:1
72
71
96
73
>99
>99
>99
>99
97, 95
97, 96
92
91
45:26:19:10
7:3
95, 94
89
a Reaction conditions: 5 mol % catalyst, methylene cyclopentane (0.4 mmol), and ethyl trifluoropyruvate (0.6 mmol) in 2.0 mL of CH2Cl2, room temperature.
b Conversions determined by GC using a Supelco Beta DEX column. c Product ratios determined by 1H NMR spectroscopy. d exo:endo ratio determined by
1H NMR spectroscopy and chiral GC and assigned by analogy with the X-ray crystal structure of 8b. e Enantiomeric excess determined by chiral GC using
a Supelco Beta DEX column and listed either as % ee exo in cases where the ee of the minor endo diastereoisomer was not determined or as % ee exo, %
ee endo. f Diastereoisomeric excess determined by chiral GC using a Supelco Beta DEX column. g Minor enantiomers were not detected. Average of three
runs.
TABLE 5. Asymmetric Carbonyl-Ene Reaction between 1-Methylcyclopentene and Ethyl Trifluoropyruvate Catalyzed by 2a-c in CH2Cl2
product ratioc
exo:endo ratiod
% eee
% def,g
7d
entrya
catalyst (mol %)
time (min)
convb (%)
7a:7b:7c:7d
7b
7c
7a
69
70
>99
76
7b
7c
1
2
3
4
2a (5)
2a (5)
2b (5)
2c (5)
30
1
30
30
100
100
100
98
4:75:16:5
1:80:19:0
4:89:8:0
>99:1
>99:1
>99:1
>99:1
3:1
9:1
4:1
3:1
>99
>99
>99
>99
96, 95
96, 95
92, 91
98, 96
89
1:54:32:14
80
a Reaction conditions: 5 mol % catalyst, 1-methylcyclopentene (0.4 mmol), and ethyl trifluoropyruvate (0.6 mmol) in 2.0 mL of CH2Cl2, room temperature.
b Conversions determined by GC using a Supelco Beta DEX column. c Product ratios determined by 1H NMR spectroscopy. d exo:endo ratio determined by
1H NMR spectroscopy and chiral GC and assigned by analogy with the X-ray crystal structure of 8b. e Enantiomeric excess determined by chiral GC using
a Supelco Beta DEX column and listed either as % ee exo in cases where the ee of the minor endo diastereoisomer was not determined or as % ee exo, %
ee endo. f Diastereoisomeric excess determined by chiral GC using a Supelco Beta DEX column. g Minor enantiomers were not detected. Average of three
runs.
enantioselectivity (96% ee), whereas 2a,c gave significantly
lower enantioselectivities of 72 and 73%, respectively. A
comparison of Tables 4 and 5 reveals that R-hydroxy esters 7b,c
are both formed with uniformly high enantioselectivities, >99%
and 92-99%, respectively, regardless of the catalyst and
substrate. As for methylene cyclohexane, the formation of
R-hydroxy esters 7b,c must occur via a rapid Lewis acid-
catalyzed isomerization of methylene cyclopentane followed by
a moderately regioselective and highly enantioselective and
diastereoselective addition of the resulting 1-methylcyclopentene
to ethyl trifluoropyruvate (Scheme 1). In addition, the exo:endo
ratio of 7c gradually decreases with increasing reaction time,
from 7:1 after 1 min to 3:1 after 30 min (Table 4, entries 1 and
2) because of the isomerization of (1′S,2S)-7b to (1′S,2S)-7c,
the product from the minor endo transition state of the direct
ene reaction between 1-methylcyclopentene and ethyl trifluo-
ropyruvate (vide infra). This isomerization and the associated
artificial change in the exo:endo ratio are clearly evident in
Figure 3, which shows the composition of (1′S,2S)-7b, (1′S,2S)-
7c, and (1′R,2S)-7c as a function of time for the reaction between
methylene cyclopentane and ethyl trifluoropyruvate. The results
in Table 5 also show that these parallels in reactivity and
selectivity also apply to 1-methylcyclopentene, which is most
evident from the catalyst-dependent enantioselectivities of
R-hydroxy ester 7a.
By analogy with our studies on 6b, a dichloromethane
solution of Lewis acid 2a (5 mol %), R-hydroxy ester 7b, and
ethyl trifluoropyruvate (1.5 equiv) gave a 25:47:28 mixture of
7b, isomerization product 6c, and double ene product 7d, after
2 h. A qualitative comparison with the corresponding ratio of
48:7:45 obtained from 6b suggests that isomerization of 7b is
faster than that of 6b while the rates of addition to ethyl
trifluoropyruvate remain comparable. In a more detailed study,
the variation in composition with respect to time for the reaction
between 1-methylcyclopentene and ethyl trifluoropyruvate
catalyzed by 2a (Figure 4) clearly shows that R-hydroxy ester
9758 J. Org. Chem., Vol. 71, No. 26, 2006

Asymmetric Platinum Group Reactions
diastereoselectivity, via the addition of 1-ethylcyclohexene to
ethyl trifluoropyruvate (Table 6, entry 1). The identity of each
of these R-hydroxy esters was established by 1H and 13C NMR
spectroscopy and mass spectrometry. The identity of 8b, the
relative stereochemistry of the two stereocenters, and the
stereochemistry of the trisubstituted double bond were un-
equivocally confirmed by a single-crystal X-ray structure
determination.38 A perspective view of the molecular structure
is shown in Figure 5. The structure reveals that 8b is formed
with E stereochemistry and that the carbonyl-ene reaction occurs
with exo selectivity (vide infra). The 8b:8c regioselectivity of
17:1 in favor of the ethylidene-based ene product 8b is
significantly lower than that of 44:1 obtained in the correspond-
ing reaction with 1-methylcyclohexene and is consistent with a
more difficult discrimination between the ethyl and cyclohexyl
R-CH2 relative to a methyl and the same R-CH2. In contrast,
2b catalyzed the ene reaction with ethylidene cyclohexane to
afford 7a exclusively and in an excellent enantioselectivity and
high diastereoselectivity (exo 96%, endo 89% ee; exo:endo 9:1).
Although 1-ethylcyclohexene is not commercially available, a
comparative study of catalyst performance and a scale-up
experiment to isolate R-hydroxy ester 8b for characterization
were undertaken using a 10:1 equilibrium mixture of 1-ethyl-
cyclohexene and ethylidene cyclohexane prepared via the acid-
catalyzed isomerization of ethylidene cyclohexane (Table 7).
Lewis acids 2a,b both catalyze the ene reaction with this mixture
to afford R-hydroxy ester 8b as the major regioisomer (ca. 61:4
and 81:2, respectively) in high diastereoselectivity (exo:endo
> 99:1) and excellent enantioselectivity (exo 99% ee), together
with minor amounts of 8c, also in high diastereoselectivity and
enantioselectivity (Table 7, entry 1). The reaction also generated
R-hydroxy ester 8a by virtue of the equilibrium mixture of
reactants, and as expected, the formation of 8a by catalysts 2a,b
was both highly diastereoselective and enantioselective
(93-96% ee). More conveniently, a similar product distribution
was obtained when Lewis acid 2a was used as the catalyst for
the in situ isomerization of ethylidene cyclohexane immediately
prior to the addition of ethyl trifluoropyruvate. GC analysis of
a dichloromethane solution of 2a (5 mol %) and ethylidene
cyclohexane revealed that isomerization was complete within
10 min and that addition of ethyl trifluoropyruvate to this
mixture resulted in rapid formation of ene products with
diastereo- and enantioselectivities similar to those obtained with
the preformed equilibrium mixture.
FIGURE 3. Composition of (1′S,2S)-7b, (1′S,2S)-7c, and (1′R,2S)-7c
as a function of time for the carbonyl-ene reaction between 1-meth-
ylcyclopentene and ethyl trifluoropyruvate catalyzed by [Pt{(R)-
BINAP}][SbF6]2 (2a) illustrating the artificial change in the exo:endo
ratio.
FIGURE 4. Variation of the percent composition for the carbonyl-
ene reaction between 1-methylcyclopentene and ethyl trifluoropyruvate
catalyzed by [Pt{(R)-BINAP}][SbF6]2 (2a) in dichloromethane with
respect to time at room temperature.
7c and double ene product 7d gradually increase at the expense
of 7b, while 7a remains constant. Just as that for 6b, the change
in composition with time, in particular the ratio 7b:7c, suggests
that isomerization is relatively slow and that the 7b:7c ratio of
80:19 obtained after 1 min (Table 5, entry 2) corresponds to
the intrinsic regioselectivity of the catalyst-pyruvate complex
for discrimination between the methyl substituent and the R-CH2
of the five-membered ring. Reassuringly, the corresponding
reaction between methylene cyclopentane and ethyl trifluoro-
pyruvate gave a similar composition-time relationship (Figure
S1, Supporting Information), which differed only in the initial
distribution of products.
The sense of asymmetric induction for the carbonyl-ene
reaction catalyzed by 2a-c can be accounted for on the basis
of a transition state model recently proposed by Oi et al.10,12b
and Ghosh and Matsuda.11a and used to justify the stereochem-
ical outcome of the [M{(S)-BINAP}](X2) (M ) Pd, Pt)
catalyzed asymmetric Diels-Alder reaction between N-acryloyl-
N-oxazolidinones and various dienes. In this model, the sense
(38) A single-crystal X-ray study established the relative configuration
of the stereocenters in 8b, and the absolute stereochemistry was assigned
by analogy with that for (S)-6a. Crystal data for (S,S)-8b: C13H19F3O3, Mr
) 280.3, orthorhombic, space group P212121, a ) 8.490(5), b ) 11.316-
(5), c ) 30.145(17) Å, V ) 2896(3) Å3, Z ) 8, Fcalcd ) 1.286 g cm-3, T
) 150 K; crystal size 0.50 × 0.10 × 0.10 mm3, Mo KR radiation, λ )
0.710 73 Å, µ ) 0.11 mm-1, transmission 0.945-0.989 by multi-scan
methods, 2θmax ) 25°, Nonius Kappa CCD diffractometer, 28 215 measured
data, 2892 unique reflections (Friedel pairs averaged), Rint ) 0.093; standard
direct methods and full-matrix least-squares refinement on all unique F2
values, OH H atoms freely refined, CH H atoms riding, R (2308 F values
with F2 > 2σ) ) 0.061, Rw (all F2 values) ) 0.145, goodness-of-fit )
1.15, final difference map extremes +0.35 and -0.34 e Å-3. Programs:
Nonius COLLECT and EvalCCD, Bruker SADABS and SHELXTL.
Finally, the addition of ethylidene cyclohexane to ethyl
trifluoropyruvate has been investigated since both substrates
simultaneously introduce two vicinal stereocenters and the
transformation of ethylidene cyclohexane is more challenging
than that of methylene cyclohexane as it requires regioselective
discrimination between nonequivalent R-CH2 groups (Table 6).
The addition of ethylidene cyclohexane to ethyl trifluoropyruvate
catalyzed by 2a gave R-hydroxy ester 8a as the dominant
product in excellent enantioselectivity and high diastereoselec-
tivity (exo 99%, endo 88% ee; 7:1 exo:endo) together with minor
amounts of 8b,c in excellent enantioselectivity and good
J. Org. Chem, Vol. 71, No. 26, 2006 9759

Doherty et al.
TABLE 6. Asymmetric Carbonyl-Ene Reaction between Ethylidene Cyclohexane and Ethyl Trifluoropyruvate Catalyzed by 2a and 2b in
CH2Cl2
product ratioc
exo:endo ratiod
% eee
8b
entrya
catalyst (mol %)
time (min)
convb (%)
8a:8b:8c
8a
8b
8c
8a
8c
1
2
2a (5)
2b (5)
30
30
100
100
82:17:1
100:0:0
7:1
9:1
>99:1
nd
99, 88
96, 89
99
nd
a Reaction conditions: 5 mol % catalyst, ethylidene cyclohexane (0.4 mmol), and ethyl trifluoropyruvate (0.6 mmol) in 2.0 mL of CH2Cl2, room temperature.
b Conversions determined by GC using a Supelco Beta DEX column. c Product ratios determined by 1H NMR spectroscopy. d exo:endo ratio determined by
1H NMR spectroscopy and chiral GC and assigned by analogy with the X-ray crystal structure of 8b. e Enantiomeric excesses determined by chiral GC using
a Supelco Beta DEX column and listed either as % ee exo in cases where the ee of the minor endo diastereoisomer was not determined or as % ee exo, %
ee endo. Average of three runs; nd ) not determined.
attack at the more accessible Re face, to afford an R-hydroxy
ester with (S)-configuration, more favorable.
The endo/exo selectivity of an ene reaction is commonly
accepted to be controlled by steric interactions.41 In a recent
study, Evans and co-workers investigated the [Cu(S,S)-t-Bu-
box)][SbF6]2-catalyzed glyoxylate ene reaction, proposed a
model invoking two-point catalyst dienophile binding to form
an adduct of the type [Cu(S,S)-t-Bu-box)(glyoxylate)][SbF6], and
speculated that an endo approach of the alkene was favored
because approach in an exo manner would result in severe steric
interactions between the tert-butyl group of the oxazoline and
the cyclohexene.8 By analogy and with reference to the
stereochemical model described in Figure 6, it is reasonable to
suggest that 1-methylcyclohexene (and ethylidene cyclohexane)
will preferentially approach the coordinated ethyl trifluoropy-
ruvate in an exo manner, as shown in Figure 8a, since an endo
approach would experience unfavorable steric interactions
between the alkene and the pseudo-equatorial phenyl ring
FIGURE 5. Two crystallographically independent molecules of ethyl
2-((E)-2-ethylidenecyclohex-1-yl)-3,3,3-trifluoro-2-hydroxypro-
attached to PB (Figure 8b). Thus, the combination of these
stereochemical models predicts that 1-methylcyclohexene (and
1-methylcyclopentene) and ethylidene cyclohexane add to ethyl
trifluoropyruvate in an exo manner to afford R-hydroxy esters
6b/7b and 8b, respectively, in high diastereoselectivity (exo:
endo > 99:1) and with (S,S) configuration, which is supported
by single-crystal X-ray structure determinations of 6a and 8b.
The same model can also be used to rationalize why
1-methylcycloalkenes and 1-ethylcyclohexene add to ethyl
trifluoropyruvate to afford 6c/7c and 8c with much lower
diastereoselectivity (2:1 to 4:1 exo:endo) since the corresponding
transition state models (Figure 9a,b) clearly show that the steric
differentiation associated with exo and endo approach is much
less pronounced than that experienced during the formation of
panoate (8b) in the asymmetric unit, illustrating the E stereochemistry
of the trisubstituted double bond, the relative stereochemistry of the
two stereocenters, and the pair of intermolecular hydrogen bonds
between the oxygen atoms of the carbonyls and the hydrogen atoms
of the R-hydroxy groups, which link the molecules into a discrete chiral
dimer, both molecules being of the same absolute configuration.
of asymmetric induction for the addition of methylene cyclo-
hexane to ethyl trifluoropyruvate catalyzed by [M{(R)-BI-
NAP}]2+ involves coordination of the dienophile through both
carbonyl oxygen atoms to form a square-planar catalyst-
substrate adduct similar to that formed between [Cu(S,S)-t-Bu-
box)][SbF6]2 and R-dicarbonyl substrates, proposed by Evans
and co-workers and used to explain the high level of enantioface
selection in Diels-Alder, hetero Diels-Alder, and aldol reac-
tions.39 The model illustrated in Figure 6 and the single-crystal
X-ray structure of 1a (Figure 7)40 both show the asymmetric
environment created by the alternating edge-face arrangement
of the P-Ph rings which is responsible for controlling the
stereochemical outcome of a transformation. It is clear that the
pseudo-equatorial phenyl ring on PA is orientated above the MP2
plane in such a manner that the Si face of the pyruvate is
protected from an attack by the nucleophilic alkene, rendering
(40) Crystal data for 1a: C44H32Cl2P2Pt‚2CH2Cl2, Mr ) 1058.5, orthor-
hombic, space group P212121, a ) 12.7463(15), b ) 14.9692(17), c )
22.258(3) Å, V ) 4253.0(8) Å3, Z ) 4, Fcalcd ) 1.653 g cm-3, T ) 150 K;
crystal size 0.54 × 0.50 × 0.50 mm3, Mo KR radiation, λ ) 0.710 73 Å,
µ ) 0.31 mm-1, transmission 0.880-0.970 by multi-scan methods, 2θmax
) 25°, Bruker SMART 1K diffractometer, 37 872 measured data, 10 223
unique reflections, Rint ) 0.037; standard direct methods and full-matrix
least-squares refinement on all unique F2 values, H atoms riding, R (9496
F values with F2 > 2σ) ) 0.027, Rw (all F2 values) ) 0.056, goodness-
of-fit ) 1.10, final difference map extremes +1.03 and -1.43 e Å-3
,
(39) (a) Evans, D. A.; Burgey, C. S.; Paras, N. A.; Vojkovsky, T.; Tregay,
S. W. J. Am. Chem. Soc. 1998, 120, 5824. (b) Evans, D. A.; Kozlowski,
M. C.; Burgeym, C. S.; MacMillan, D. W. C. J. Am. Chem. Soc. 1997,
119, 7893.
absolute structure parameter 0.004(4). Programs: Bruker SMART, SAINT,
SADABS, and SHELXTL.
(41) Snider, B. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, pp 527-561.
9760 J. Org. Chem., Vol. 71, No. 26, 2006

Asymmetric Platinum Group Reactions
TABLE 7. Asymmetric Carbonyl-Ene Reaction between 1-Ethylcyclohexenea and Ethyl Trifluoropyruvate Catalyzed by 2a and 2b in CH2Cl2
product ratiod
exo:endo ratioe
% eef
entryb
catalyst (mol %)
time (min)
convc (%)
8a:8b:8c
8a
8b
8c
8a
8b
8c
1
2
2a (5)
2b (5)
30
30
83
77
35:61:4
17:81:2
7:1
11:1
>99:1
>99:1
3:1
11:1
95, 93
96, 90
99
98
99, 96
99, 94
a 10:1 ratio of 1-ethylcyclohexane/ethylidene cyclohexane was used. b Reaction conditions: 5 mol % catalyst, 1-ethylcyclohexene (0.4 mmol), and ethyl
trifluoropyruvate (0.6 mmol) in 2.0 mL of CH2Cl2, room temperature. c Conversions determined by GC using a Supelco Beta DEX column. d Product ratios
determined by 1H NMR spectroscopy. e exo:endo ratio determined by 1H NMR spectroscopy and chiral GC and assigned by analogy with the X-ray crystal
structure of 8b. f Enantiomeric excess determined by chiral GC using a Supelco Beta DEX column. Average of three runs.
FIGURE 6. Stereochemical model showing the asymmetric environ-
ment created by the P-Ph rings of (R)-BINAP and the favored Re-
face attack of methylene cyclohexane to give R-hydroxy esters with
(S)-absolute configuration.
FIGURE 8. Stereochemical model showing exo/endo approaches of
1-methylcyclohexene to [Pt{(R)-BINAP}(pyruvate)]2+ to account for
the high exo-diastereoselectivity to afford (1′S,2S)-6b.
FIGURE 7. Molecular structure of [Pt{(R)-BINAP}Cl2] (1a) high-
lighting the noncrystallographic molecular C2 axis and the asymmetric
environment created by the alternating edge-face arrangement of the
P-Ph rings of BINAP. Ellipsoids are at the 30% probability level.
Bonds within the dinaphthyl unit and bonds to Pt are shown solid;
others are shown hollow.
FIGURE 9. Stereochemical model showing exo and endo approaches
of 1-methylcyclopentene to [Pt{(R)-BINAP}(pyruvate)]2+ to explain
the low level of exo-diastereoselectivity in favor of (1′R,2S)-7c.
6b-8b (cf. Figure 8). In this case, it is more difficult to predict
from the transition state models which diastereoisomer would
be favored. However, we are confident that exo approach to
afford the (R,S)-diastereoisomer will be the dominant pathway
since the addition of 1-methylcyclohexene to ethyl trifluoro-
pyruvate monitored as a function of time clearly showed that
the major diastereoisomer of 6b (assumed to be S,S stereo-
chemistry based on the structures of 6a and 8b) isomerizes to
the minor diastereoisomer of 6c (vide supra). Provided that
isomerization occurs with retention of stereochemistry, this
experiment confirms that the minor diastereoisomer of 6c has
S,S stereochemistry, which must result from endo approach,
according to the stereochemical model in Figure 9.
In conclusion, soft late transition metal Lewis acids of the
type [M{(R)-BINAP}]2+ are highly active catalysts for the
carbonyl-ene reaction between ethyl trifluoropyruvate and a
range of methylene cycloalkanes and trisubstituted alkenes.
J. Org. Chem, Vol. 71, No. 26, 2006 9761

Doherty et al.
While [Pd{(R)-BINAP}]2+ consistently gave the expected
R-hydroxy esters in high diastereo- and enantioselectivity, its
platinum and nickel counterparts gave a mixture of products
resulting from a combination of pathways including (i) alkene
isomerization coupled with carbonyl-ene reactivity, (ii) isomer-
ization of the resulting R-hydroxy ester, and (iii) addition of
the primary R-hydroxy ester to a second molecule of ethyl
trifluoropyruvate to afford a double ene product. On the basis
of initial product distributions, the rates of isomerization appear
to increase in the order ethylidene cyclohexane < methylene
cyclohexane < methylene cyclopentane. Preliminary studies
have also shown that enantiopure platinum complexes of the
conformationally flexible NUPHOS diphosphine 1,4-Et2-cyclo-
C6H8-NUPHOS catalyze the carbonyl-ene reaction with trends
in reactivity and selectivity patterns that mirror those obtained
with its BINAP counterpart, with δ-NUPHOS diphosphines
behaving in much the same manner as (S)-BINAP. Further
studies are currently underway to understand the factors that
influence and control the relative rates of isomerization and ene
reactivity with the aim of coupling these transformations to
develop novel tandem reaction sequences. The application of
conformationally flexible NUPHOS diphosphines in a broad
range of platinum group metal-catalyzed asymmetric transfor-
mations is also being explored with the aim of assessing the
relative merits of tropos and atropos diphosphines.
CCH2), 123.9 (q, JC-F ) 286 Hz, CF3), 78.8 (q, JC-F ) 28 Hz,
CCF3), 64.0 (OCH2CH3), 40.1 (Cy), 30.3 (Cy), 25.9 (Cy), 23.4 (Cy),
22.5 (CH2CCF3OH), 14.4 (OCH2CH3); LRMS (EI) m/z 266 [M]+;
HRMS (EI) exact mass calcd for C12H17O3F3 [M]+ requires m/z
266.112979, found m/z 266.113319. Ee determined by GC using a
Supelco Beta DEX column (injection temp 135 °C; column
conditions 105 °C for 40 min ramp to 175 °C at 5 °C/min; hold 20
min, pressure 21 psi) major (2S)-enantiomer tR ) 40.8 min, minor
(2R)-enantiomer tR ) 38.2 min; 77% ee. Absolute stereochemistry
determined by single-crystal X-ray crystallography of the (R)-1-
(1-naphthyl)ethylammonium salt of the derived carboxylic acid.
(1′S,2S)-Ethyl 3,3,3-Trifluoro-2-hydroxy-2-(2′-methylenecy-
clohex-1′-yl)propanoate (6b). A sample was isolated as a single
20
diastereoisomer after purification by column chromatography. [R]D
1
) +41.9 (c 2.6, CH2Cl2); H NMR (300.0 MHz, CDCl3, δ) 4.77
(s, 1H, dCHaHb), 4.64 (s, 1H, dCHaHb), 4.39-4.19 (m, 2H, OCH2-
CH3), 3.87 (s, 1H, OH), 2.95 (t, J ) 5.2 Hz, 1H, CHCCF3OH),
2.41-2.32 (m, 1H, CysCH2), 2.13-1.85 (br m, 3H, CysCH2),
1.77-1.63 (m, 2H, CysCH2), 1.54-1.40 (m, 2H, CysCH2), 1.31
(t, J ) 7.2 Hz, 3H, OCH2CH3); 13C{1H} NMR (125.7 MHz, CDCl3,
δ) 170.9 (CdO), 147.8 (CdCH2), 124.0 (q, JC-F ) 288 Hz, CF3),
111.1 (CdCH2), 82.1 (q, JC-F ) 27 Hz, CCF3), 64.2 (OCH2CH3),
44.4 (Cy), 35.5 (Cy), 28.4 (Cy), 28.3 (Cy), 23.6 (Cy), 14.3
(OCH2CH3); LRMS (EI) m/z 266 [M]+; HRMS (EI) exact mass
calcd for C12H17O3F3 [M]+ requires m/z 266.112979, found m/z
266.111816. Anal. Calcd for C12H17F3O3: C, 54.13; H, 6.44.
Found: C, 54.27; H, 6.78. Ee determined by GC using a Supelco
Beta DEX column (injection temp 135 °C; column conditions 105
°C for 40 min ramp to 175 °C at 5 °C/min; hold 20 min, pressure
21 psi) major (1′S,2S)-enantiomer tR ) 27.5 min, minor (1′R,2R)-
enantiomer tR ) 29.5 min; 99% ee. Absolute and relative stereo-
chemistry assigned by analogy.
Experimental Section
Typical Procedure for Lewis Acid-Catalyzed Ene Reaction.
A flame-dried Schlenk flask charged with [{(R)-BINAP)MCl2] (0.02
mmol), AgSbF6 (15 mg, 0.044 mmol), and CH2Cl2 (2.0 mL) was
stirred at room temperature for 30 min. After this time, ethyl
trifluoropyruvate (80 µL, 0.6 mmol) was added followed by
methylene cyclohexane (48 µL, 0.4 mmol). The resulting mixture
was stirred for a further 30 min, after which time the solution was
flushed through a short plug of silica with CH2Cl2, the solvent was
removed, and the resulting residue was purified by column
chromatography, eluting with hexane/CH2Cl2 (3:2). The products
were analyzed by 1H NMR spectroscopy, and the ee’s were
determined by chiral GC.
Ethyl E-2-(Trifluoromethyl)-2-hydroxy-5-phenylpent-4-enoate
(5). A sample was isolated as a colorless oil after purification by
column chromatography. [R]D20 ) -46.9 (c 1.0, CH2Cl2); 1H NMR
(300.0 MHz, CDCl3, δ) 7.20-7.09 (m, 5H, Ph), 6.41 (d, J ) 15.8
Hz, 1H, PhCHdCH), 5.98 (ddd, J ) 15.0, 8.1, 6.6 Hz, 1H, CHd
CHCH2), 4.22 (m, 2H, OCH2CH3), 3.82 (s, 1H, OH), 2.81-2.67
(m, 2H, CHCH2), 1.20 (t, J ) 7.1 Hz, 3H, OCH2CH3); 13C{1H}
NMR (125.7 MHz, CDCl3, δ) 169.8 (CdO), 137.2 (Ph), 136.1 (Ph),
129.1 (Ph), 126.9 (Ph), 128.3 (CdC), 123.9 (q, JC-F ) 286 Hz,
CF3), 121.0 (CdC), 78.2 (q, JC-F ) 29 Hz, CCF3), 64.4 (OCH2-
CH3), 36.1 (dCHCH2), 14.6 (OCH2CH3); LRMS (EI) m/z 288
[M]+; HRMS (EI) exact mass calcd for (C14H15O3F3) [M]+ requires
m/z 288.097329, found m/z 288.096703; ee determined by GC using
a Supelco Beta DEX column (injection temp 170 °C; column
conditions 140 °C for 45 min ramp to 180 °C at 3 °C/min, pressure
21 psi) major (S)-enantiomer tR ) 37.7 min, minor (R)-enantiomer
tR ) 35.4 min.
(1′R,2S)-Ethyl 3,3,3-Trifluoro-2-hydroxy-2-(2′-methylcyclo-
hex-2′-en-1′-yl)propanoate (6c). A sample was formed as a 3:1
exo:endo mixture of diastereoisomers which can be partially
separated by careful column chromatography to afford a 97:3 exo:
20
endo mixture. [R]D ) +12.1 (c 0.93, CH2Cl2). Major exo-
diastereoisomer: 1H NMR (300.0 MHz, CDCl3, δ) 5.70 (br s, 1H,
dCH), 4.41-4.31 (m, 2H, OCH2CH3), 3.69 (s, 1H, OH), 2.78 (t,
J ) 5.4 Hz, 1H, CHCCF3OH), 2.03-1.99 (m, 2H, CysCH2), 1.93-
1.80 (m, 1H, CysCH2), 1.77 (br s, 3H, CHdCCH3), 1.73-1.71
(m, 1H, CysCH2), 1.55-1.51 (m, 1H, CysCH2), 1.50-1.39 (m,
1H, CysCH2), 1.34 (t, J ) 7.2 Hz, 3H, OCH2CH3); 13C{1H} NMR
(125.7 MHz, CDCl3, δ) 170.4 (CdO), 130.7 (CHdCCH3), 129.8
(CHdCCH3), 124.0 (q, JC-F ) 287 Hz, CF3), 81.1 (q, JC-F ) 28
Hz, CCF3), 64.1 (OCH2CH3), 42.2 (Cy), 31.5 (Cy), 26.4 (Cy), 25.3
(Cy), 25.3 (Cy), 19.6 (CHdCCH3), 14.4 (OCH2CH3). Minor endo-
diastereoisomer: 1H NMR (300.0 MHz, CDCl3, δ) 5.73 (br s, 1H,
dCH), 4.47-4.26 (m, 2H, OCH2CH3), 3.50 (s, 1H, OH), 2.88-
2.86 (m, 1H, CHCCF3OH), 2.20-2.13 (m, 2H, CysCH2), 1.98
(br s, 3H, CHdCCH3), 1.94-1.88 (m, 1H, CysCH2), 1.62-1.43
(m, 3H, CysCH2), 1.35 (t, J ) 7.1 Hz, 3H, OCH2CH3); 13C{1H}
NMR (125.7 MHz, CDCl3, δ)169.9 (CdO), 132.8 (CHdCCH3),
131.7 (CHdCCH3), 124.0 (q, JC-F ) 287 Hz, CF3), 81.5 (q, JC-F
) 28 Hz, CCF3), 63.8 (OCH2CH3), 40.6 (Cy), 35.8 (Cy), 26.3 (Cy),
24.7 (Cy), 17.6 (CHdCCH3), 14.4 (OCH2CH3); LRMS (EI) m/z
266 [M]+; HRMS (EI) exact mass calcd for C12H17O3F3 [M]+
requires m/z 266.112979, found m/z 266.112595. Anal. Calcd for
C12H17F3O3: C, 54.1; H, 6.44. Found: C, 54.44; H, 6.82. Ee’s of
both diastereoisomers were determined by GC using a Supelco Beta
DEX column (injection temp 135 °C; column conditions 105 °C
for 40 min ramp to 175 °C at 5 °C/min; hold 20 min, pressure 21
psi). Major exo-diastereoisomer: major (1′R,2S)-enantiomer tR )
36.7 min, minor (1′S,2R)-enantiomer tR ) 35.2 min; 99% ee. Minor
endo-diastereoisomer: (1′S,2S)-enantiomer tR ) 42.9 min, minor
(1′R,2R)-enantiomer tR ) 46.3 min; 98% ee. exo:endo ) 3:1.
Absolute and relative stereochemistry assigned by analogy.
(2S,3′S,1′′S)-Ethyl 2-(Trifluoromethyl)-2-hydroxy-3-[3′-(1′′-
ethoxycarbonyl-2′′,2′′,2′′-trifluoro-1′′-hydroxyethyl)cyclohex-1′-
(2S)-Ethyl 3-(Cyclohexen-1′-yl)-2-(trifluoromethyl)-2-hydrox-
ypropanoate (6a). A sample was isolated as a colorless oil after
20
purification by column chromatography. [R]D ) -19.2 (c 1.0,
CH2Cl2); 1H NMR (300.0 MHz, CDCl3, δ) 5.54 (br s, 1H, dCH),
4.40-4.24 (m, 2H, OCH2CH3), 3.76 (s, 1H, OH), 2.59 (d, J )
13.9 Hz, 1H, CHHCCF3OH), 2.43 (d, J ) 14.0 Hz, 1H, CHHCCF3-
OH), 2.12-1.75 (br m, 4H, CysCH2), 1.60-1.45 (br m, 4H, Cys
CH2), 1.33 (t, J ) 7.1 Hz, 3H, OCH2CH3); 13C{1H} NMR (125.7
MHz, CDCl3, δ) 170.2 (CdO), 131.4 (CHdCCH2), 128.2 (CHd
9762 J. Org. Chem., Vol. 71, No. 26, 2006

Asymmetric Platinum Group Reactions
en-2′-yl]propanoate (6d). A sample was isolated as a single
diastereoisomer after purification by column chromatography. [R]D
OH), 2.38-2.26 (m, 1H, CysCH2), 2.23-2.11 (m, 1H, CysCH2),
2.08-1.99 (m, 2H, CysCH2), 1.78 (br s, 3H, CHdCCH3), 1.33
(t, J ) 7.1 Hz, 3H, OCH2CH3); 13C{1H} NMR (125.7 MHz, CDCl3,
δ) 170.6 (CdO), 137.9 (CHdCCH3), 131.9 (CHdCCH3), 124.0
(q, JC-F ) 287 Hz, CF3), 80.4 (q, JC-F ) 28 Hz, CCF3), 64.2
(OCH2CH3), 51.5 (Cy), 31.5 (Cy), 27.4 (Cy), 17.2 (CHdCCH3),
14.4 (OCH2CH3). Minor (1′S,2S)-diastereoisomer: 1H NMR (300.0
MHz, CDCl3, δ) 5.59 (br s, 1H, dCH), 4.47-4.40 (m, 2H, OCH2-
CH3), 3.76 (s, 1H, OH), 3.36 (t, J ) 5.8 Hz, 1H, CHCCF3OH),
2.35-2.20 (m, 1H, CysCH2), 2.20-2.11 (m, 1H, CysCH2), 2.09-
2.03 (m, 2H, CysCH2), 1.75 (br s, 3H, CHdCCH3), 1.37 (t, J )
7.2 Hz, 3H, OCH2CH3); 13C{1H} NMR (125.7 MHz, CDCl3, δ)
170.5 (CdO), 136.7 (CHdCCH3), 132.0 (CHdCCH3), 123.9 (q,
JC-F ) 287 Hz, CF3), 80.4 (q, JC-F ) 28 Hz, CCF3), 64.1 (OCH2-
CH3), 50.7 (Cy), 30.3 (Cy), 26.5 (Cy), 16.0 (CHdCCH3), 14.4
(OCH2CH3). LRMS (EI) m/z 252 [M]+; HRMS (EI) exact mass
calcd for C11H15O3F3 [M]+ requires m/z 252.097329, found m/z
252.097076. Anal. Calcd for C11H25F3O3: C, 52.38, H; 5.99.
Found: C, 52.67; H, 6.22. Ee’s of both diastereoisomers were
determined by GC using a Supelco Beta DEX column (injection
temp 135 °C; column conditions 100 °C for 45 min ramp to 170
°C at 5 °C/min; hold 10 min, pressure 21 psi). Major exo-
diastereoisomer: major (1′R,2S)-enantiomer tR ) 21.8 min, minor
(1′S,2R)-enantiomer tR ) 22.1 min; 97% ee. Minor endo-diastere-
oisomer: major (1′S,2S)-enantiomer tR ) 28.3 min, minor (1′R,2R)-
enantiomer tR ) 34.1 min; 95% ee. exo:endo ) 3:1. Absolute and
relative stereochemistry assigned by analogy.
20
) -51.3 (c 1.45, CH2Cl2); 1H NMR (300.0 MHz, CDCl3, δ) 6.09
(br s, 1H, dCH), 4.46-4.19 (m, 4H, OCH2CH3), 3.91 (s, 1H, OH),
3.77 (s, 1H, OH), 2.74 (m, 1H, CHCCF3OH), 2.42 (d, J ) 14.3
Hz, 1H, CHHCCF3OH), 2.17 (d, J ) 13.7 Hz, 1H, CHHCCF3-
OH), 2.12-1.97 (m, 4H, CysCH2), 1.50-1.39 (m, 2H, CysCH2),
1.35 (t, J ) 6.9 Hz, 3H, OCH2CH3), 1.33 (t, J ) 6.9 Hz, 3H,
OCH2CH3); 13C{1H} NMR (75.5 MHz, CDCl3, δ) 170.9 (CdO),
169.5 (CdO), 136.4 (CHdCCH2), 124.6 (CHdCCH2), 123.8 (q,
JC-F ) 287 Hz, CF3), 123.4 (q, JC-F ) 286 Hz, CF3), 79.9 (q, JC-F
) 28 Hz, CCF3), 77.6 (q, JC-F ) 27 Hz, CCF3), 63.8 (OCH2CH3),
63.7 (OCH2CH3), 41.0 (Cy), 36.7 (Cy), 25.2 (Cy), 24.7 (Cy), 16.9
(CH2CCF3OH), 13.6 (OCH2CH3), 13.4 (OCH2CH3); LRMS (EI)
m/z 437 [M + H]+; HRMS (EI) exact mass calcd for C17H23O6F6
[M + H]+ requires m/z 437.139883, found m/z 437.140808. Anal.
Calcd for C17H22F6O6: C, 46.79; H, 5.08. Found: C, 47.02; H,
5.21. Ee determined by GC using a Supelco Beta DEX column
(injection temp 135 °C; column conditions 105 °C for 40 min ramp
to 175 °C at 5 °C/min; hold 20 min, pressure 21 psi) major
(2S,3′S,1′′S)-diastereoisomer tR ) 62.1 min, minor (2R,3′S,1′′S)-
diastereoisomer tR ) 61.9 min; 91% de.
(2S)-Ethyl 3-(Cyclopenten-1′-yl)-2-(trifluoromethyl)-2-hy-
droxypropanoate (7a). A sample was isolated as a colorless oil
20
after purification by column chromatography. [R]D ) -18.8 (c
1
1.21, CH2Cl2); H NMR (300.0 MHz, CDCl3, δ) 5.53 (br s, 1H,
dCH), 4.38-4.28 (m, 2H, OCH2CH3), 3.79 (s, 1H, OH), 2.86 (d,
J ) 14.4 Hz, 1H, CHHCCF3OH), 2.67 (d, J ) 15.0 Hz, 1H,
CHHCCF3OH), 2.36-2.17 (m, 4H, CysCH2), 1.87-1.77 (m, 2H,
CysCH2), 1.33 (t, J ) 7.1 Hz, 3H, OCH2CH3); 13C{1H} NMR
(125.7 MHz, CDCl3, δ) 170.2 (CdO), 137.0 (CHdCCH2), 130.6
(CHdCCH2), 123.9 (q, JC-F ) 286 Hz, CF3), 78.3 (q, JC-F ) 28
Hz, CCF3), 64.2 (OCH2CH3), 36.6 (Cy), 33.6 (Cy), 33.0 (Cy), 24.1
(CH2CCF3OH), 14.5 (OCH2CH3); LRMS (EI) m/z 251 [M - H]+;
HRMS (EI) exact mass calcd for C11H14O3F3 [M - H]+ requires
m/z 251.089504, found m/z 251.090229. Ee determined by GC using
a Supelco Beta DEX column (injection temp 135 °C; column
conditions 100 °C for 45 min ramp to 170 °C at 5 °C/min; hold 10
min, pressure 21 psi) major (2S)-enantiomer tR ) 26.8 min, (2R)-
minor enantiomer tR ) 24.6 min; 72% ee. Absolute stereochemistry
assigned by analogy.
(2S,3′S,1′′S)-Ethyl 2-(Trifluoromethyl)-2-hydroxy-3-[3′-(1′′-
ethoxycarbonyl-2′′,2′′,2′′-trifluoro-1′′-hydroxyethyl)cyclopent-1′-
en-2′-yl]propanoate (7d). A sample was isolated as a single
20
diastereoisomer after purification by column chromatography. [R]D
) +1.96 (c 0.92, CH2Cl2); 1H NMR (300.0 MHz, CDCl3, δ) 5.73
(br s, 1H, dCH), 4.50-4.22 (m, 4H, OCH2CH3), 3.86 (s, 1H, OH),
3.80 (s, 1H, OH), 3.51-3.49 (br m, 1H, CHCCF3OH), 2.83 (d, J
) 14.6 Hz, 1H, CHHCCF3OH), 2.38 (d, J ) 13.8 Hz, 1H,
CHHCCF3OH), 2.44-2.33 (m, 1H, CysCH2), 2.27-2.18 (m, 1H,
CysCH2), 2.15-2.04 (m, 1H, CysCH2), 2.02-1.90 (m, 1H, Cys
CH2), 1.36 (t, J ) 7.2 Hz, 3H, OCH2CH3), 1.32 (t, J ) 7.2 Hz,
3H, OCH2CH3); 13C{1H} NMR (125.7 MHz, CDCl3, δ) 171.2 (Cd
O), 169.9 (CdO), 137.0 (CHdCCH2), 134.2 (CHdCCH2), 124.2
(q, JC-F ) 287 Hz, CF3), 123.7 (q, JC-F ) 287 Hz, CF3), 79.5 (q,
JC-F ) 27 Hz, CCF3), 79.4 (q, JC-F ) 28 Hz, CCF3), 64.5 (OCH2-
CH3), 64.4 (OCH2CH3), 50.7 (Cy), 31.6 (Cy), 31.3 (Cy), 26.7 (CH2-
CCF3OH), 14.5 (OCH2CH3), 14.1 (OCH2CH3); LRMS (EI) m/z 423
[M + H]+; HRMS (EI) exact mass calcd for C16H21O6F6 [M +
H]+ requires m/z 423.124233, found m/z 423.122650. Anal. Calcd
for C16H20F6O6: C, 45.50; H, 4.77. Found: C, 45.87; H, 5.03. Ee
determined by GC using a Supelco Beta DEX column (injection
temp 135 °C; column conditions 100 °C for 45 min ramp to 170
°C at 5 °C/min; hold 10 min, pressure 21 psi) major (2S,3′S,1′′S)-
diastereoisomer tR ) 65.2 min, minor (2R,3′S,1′′S)-diastereoisomer
tR ) 64.8 min; 92% ee.
(1′S,2S)-Ethyl 3,3,3-Trifluoro-2-hydroxy-2-(2′-methylenecy-
clopent-1′-yl)propanoate (7b). A sample was isolated as a single
20
diastereoisomer after purification by column chromatography. [R]D
1
) +44.4 (c 1.0, CH2Cl2); H NMR (300.0 MHz, CDCl3, δ) 4.99
(br s, 1H, dCHaHb), 4.55 (br s, 1H, dCHaHb), 4.49-4.26 (m, 2H,
OCH2CH3), 3.79 (s, 1H, OH), 3.17 (t, J ) 8.2 Hz, 1H, CHCCF3-
OH), 2.30-2.24 (m, 1H, CysCH2), 2.12-1.92 (m, 1H, CysCH2),
1.55-1.43 (m, 1H, CysCH2), 1.37 (t, J ) 7.2 Hz, 3H, OCH2CH3);
13C{1H} NMR (125.7 MHz, CDCl3, δ) 170.6 (CdO), 151.2 (Cd
CH2), 124.1 (q, JC-F ) 288 Hz, CF3), 108.4 (CdCH2), 80.3 (q,
JC-F ) 27 Hz, CCF3), 64.1 (OCH2CH3), 45.3 (Cy), 36.0 (Cy), 27.6
(Cy), 25.5 (Cy), 14.4 (OCH2CH3); LRMS (EI) m/z 253 [M + H]+;
HRMS (EI) exact mass calcd for C11H16O3F3 [M + H]+ re-
quires m/z 253.105154, found m/z 253.105782. Anal. Calcd for
C11H15F3O3: C, 52.38; H, 5.99. Found: C, 52.46; H, 6.12. Ee
determined by GC using a Supelco Beta DEX column (injection
temp 135 °C; column conditions 100 °C for 45 min ramp to 170
°C at 5 °C/min; hold 10 min, pressure 21 psi) major (1′S,2S)-
enantiomer tR ) 23.3 min, minor (1′R,2R)-enantiomer tR ) 29.6
min; 99% ee. Absolute and relative stereochemistry assigned by
analogy.
(3S,2S)-Ethyl 3-(Cyclohexen-1′-yl)-2-(trifluoromethyl)-2-hy-
droxybutanoate (8a). A sample was isolated as a 98:2 exo:endo
mixture of diastereoisomer after purification by column chroma-
tography. [R]D20 ) -18.6 (c 1.0, CH2Cl2); H NMR (300.0 MHz,
1
CDCl3, δ) 5.58-5.53 (br s, 1H, dCH), 4.37-4.20 (m, 2H, OCH2-
CH3), 3.72 (s, 1H, OH), 2.86-2.79 (q, J ) 7.0 Hz, 1H, CHCH3),
2.01-1.92 (m, 4H, CysCH2), 1.57-1.47 (br m, 4H, CysCH2),
1.32 (t, J ) 7.2 Hz, 3H, OCH2CH3), 1.21 (dd, J ) 7.0 Hz, 1.2 Hz,
3H, CHCH3); 13C{1H} NMR (125.7 MHz, CDCl3, δ) 170.9 (Cd
O), 138.1 (CdCCHCH3), 126.2 (CdCCHCH3), 124.0 (q, JC-F
)
(1′R,2S)-Ethyl 3,3,3-Trifluoro-2-hydroxy-2-(2′-methylcyclo-
pent-2′-en-1′-yl)propanoate (7c). A sample was formed as a 3:1
288 Hz, CF3), 81.2 (q, JC-F ) 27 Hz, CCF3), 64.0 (OCH2CH3),
43.7 (Cy), 26.8 (Cy), 25.9 (Cy), 23.5 (Cy), 22.8 (CHCH3), 14.5
(OCH2CH3), 13.8 (CHCH3); LRMS (EI) m/z 279 [M - H]+; HRMS
(EI) exact mass calcd for C13H18O3F3 [M - H]+ requires m/z
279.120804, found m/z 279.121300. Ee’s of both diastereoisomers
were determined by GC using a Supelco Beta DEX column
(injection temp 135 °C; column conditions 105 °C for 40 min ramp
exo:endo mixture of diastereoisomers and isolated as a 10:1 exo:
20
endo mixture after purification by column chromatography. [R]D
)
+13.4 (c 1.17, CH2Cl2). Major (1′R,2S)-diastereoisomer: 1H NMR
(300.0 MHz, CDCl3, δ) 5.59 (br s, 1H, dCH), 4.38-4.31 (m, 2H,
OCH2CH3), 3.81 (s, 1H, OH), 3.18 (t, J ) 5.8 Hz, 1H, CHCCF3-
J. Org. Chem, Vol. 71, No. 26, 2006 9763

Doherty et al.
to 175 °C at 5 °C/min; hold 20 min, pressure 21 psi). Major exo-
diastereoisomer: major (3S,2S)-enantiomer tR ) 41.6 min, minor
(3R,2R)-enantiomer tR ) 41.1 min; 99% ee. Minor endo-diastere-
oisomer: major (3R,2S)-enantiomer tR ) 47.5 min, minor (3S,2R)-
enantiomer tR ) 47.2 min; 88% ee. exo:endo ) 7:1. Absolute and
relative stereochemistry assigned by analogy.
Preparation of (2S)-3-(Cyclohexen-1′-yl)-2-(trifluoromethyl)-
2-hydroxypropanoic Acid (9). A solution of (2S)-ethyl 3-(cyclo-
hexen-1-yl)-2-(trifluoromethyl)-2-hydroxypropanoate (0.100 g, 0.376
mmol) and NaOH (0.300 g, 7.52 mmol) in methanol (3.0 mL) was
stirred at room temperature and monitored by TLC until all of the
starting materials had been consumed (ca. 18 h). The resulting
solution was diluted with water (25 mL) and washed with diethyl
ether, and the aqueous layer was acidified to pH 3 using 1 N HCl.
The product was extracted into diethyl ether (5 × 15 mL), the
organic layers were combined, washed with brine, and dried over
Na2SO4, and the solvent was removed in vacuo to afford the pure
product as an off-white solid in a 95% yield. Mp 121-124 °C;
[R]D20 ) -16.2 (c 1.0, CH2Cl2); 1H NMR (300.0 MHz, CDCl3, δ)
6.65 (br s, 2H, OH, CO2H), 5.61 (br s, 1H, dCH), 2.72 (d, J )
14.0 Hz, 1H, CHHCCF3OH), 2.53 (d, J ) 14.0 Hz, 1H, CHHCCF3-
OH), 2.08-1.86 (br m, 4H, CysCH2), 1.60-1.47 (br m, 4H, Cys
CH2); 13C{1H} NMR (75.5 MHz, CDCl3, δ) 173.0 (CdO), 130.9
(CHdCCH2), 129.0 (CHdCCH2), 123.6 (q, JC-F ) 287 Hz, CF3),
78.5 (q, JC-F ) 29 Hz, CCF3), 40.3 (Cy), 30.1 (Cy), 25.8 (Cy),
23.2 (Cy), 22.2 (CH2CCF3OH); LRMS (EI) m/z 238 [M + H]+;
HRMS (EI) exact mass calcd for C10H13O3F3 [M + H]+ requires
m/z 238.081679, found m/z 238.082451. Anal. Calcd for
C10H13F3O3: C, 50.42; H, 5.50. Found: C, 50.77; H, 5.81.
Preparation of (R)-1-(1-Naphthyl)ethylammonium (2S)-3-
(Cyclohexen-1-yl)-2-(trifluoromethyl)-2-hydroxypropanoate (10).
To a solution of (2S)-3-(cyclohexen-1-yl)-2-(trifluoromethyl)-2-
hydroxypropanoic acid (0.064 g, 0.27 mmol) in 5 mL of dichlo-
romethane was added (R)-1-(1-naphthyl)ethylamine (0.046 mL, 0.27
mmol). After stirring at room temperature for 5 min, the solvent
was removed in vacuo to afford a white solid which was washed
with 2 × 2 mL of hexane and subsequently crystallized by slow
diffusion of a concentrated dichloromethane solution layered with
hexane (89%). Mp 137-139 °C; [R]D20 -73.6 (c 1.0, acetone); 1H
NMR (300.0 MHz, CD2Cl2, δ) 7.84-7.73 (m, 3H, C10H7), 7.59-
7.57 (m, 1H, C10H7), 7.52-7.36 (m, 3H, C10H7), 7.25 (br s, 3H,
NH3), 5.23 (br s, 2H, dCH, OH), 5.07 (q, J ) 6.0 Hz, 1H, CHCH3),
2.17 (q, J ) 13.8 Hz, 2H, CHaHbCCF3OH), 1.76 (br s, 4H, Cys
CH2), 1.60 (d, J ) 6.6 Hz, 3H, CHCH3), 1.35-1.33 (m, 4H, Cys
CH2); 13C{1H} NMR (75.5 MHz, CD2Cl2, δ) 174.6 (CdO), 135.5
(C10H7), 134.8 (C10H7), 133.2 (CdCCH2), 130.8 (C10H7), 130.1
(C10H7), 130.0 (C10H7), 127.9 (CdCCH2), 127.0 (C10H7), 126.5
(C10H7), 126.2 (C10H7), 126.0 (q, JC-F ) 287 Hz, CF3), 123.9
(C10H7), 122.4 (C10H7), 78.6 (q, JC-F ) 26 Hz, CCF3), 47.8
(CHCH3), 40.9 (Cy), 30.5 (Cy), 26.2 (CHCH3), 23.9 (Cy), 22.9
(Cy), 21.1 (CH2CCF3OH); LRMS (EI) m/z 238 [M + H]+; HRMS
(EI) exact mass calcd for C10H13O3F3 [M + H]+ requires m/z
238.081679, found m/z 238.081833. Anal. Calcd for C22H26F3-
NO3: C, 64.54; H, 6.40; N, 3.42. Found: C, 64.78; H, 6.66; N,
3.49.
(1′S,2S)-Ethyl 2-((E)-2′-Ethylidenecyclohex-1′-yl)-3,3,3-trif-
luoro-2-hydroxypropanoate (8b). A sample was isolated as a
single diastereoisomer after purification by column chromatography
and crystallized by slow evaporation of a concentrated dichlo-
20
romethane solution at room temperature. [R]D ) +39.3 (c 1.0,
1
CH2Cl2); H NMR (300.0 MHz, CDCl3, δ) 5.23 (q, J ) 6.7 Hz,
1H, )CH), 4.37-4.21 (m, 2H, OCH2CH3), 3.82 (s, 1H, OH), 2.88-
2.85 (m, 1H, CHCCF3OH), 2.39-2.31 (m, 1H, CysCH2), 2.22-
2.08 (m, 2H, CysCH2), 2.04-1.89 (m, 1H, CysCH2), 1.79-1.70
(m, 1H, CysCH2), 1.66-1.45 (m, 3H, CysCH2), 1.54 (dd, J )
6.7 Hz, 1.2 Hz, 3H, CdCHCH3), 1.32 (t, J ) 7.1 Hz, 3H,
OCH2CH3); 13C{1H} NMR (75.5 MHz, CDCl3, δ) 170.9 (CdO),
138.1 (CdCCH3), 124.0 (q, JC-F ) 288 Hz, CF3), 120.7 (CHd
CCH3), 82.9 (q, JC-F ) 27 Hz, CCF3), 63.7 (OCH2CH3), 45.6 (Cy),
28.3 (Cy), 27.2 (Cy), 26.6 (Cy), 23.1 (Cy), 14.1 (OCH2CH3), 12.9
(CdCHCH3); LRMS (EI) m/z 280 [M]+; HRMS (EI) exact mass
calcd for C13H19O3F3 [M]+ requires m/z 280.128629, found m/z
280.127632. Anal. Calcd for C13H19F3O3: C, 55.71; H, 6.83.
Found: C, 55.97; H, 6.91. Ee determined by GC using a Supelco
Beta DEX column (injection temp 135 °C; column conditions 105
°C for 40 min ramp to 175 °C at 5 °C/min; hold 20 min, pressure
21 psi) major (1′S,2S)-enantiomer tR ) 41.2 min, minor (1′R,2R)-
enantiomer tR ) 45.9 min; 99% ee. Relative stereochemistry
determined by single-crystal X-ray crystallography and absolute
stereochemistry assigned by analogy.
(1′R,2S)-Ethyl 2-(2′-Ethylcyclohex-2′-en-1′-yl)-3,3,3-trifluoro-
2-hydroxypropanoate (8c). A sample was isolated as a colorless
oil after purification by column chromatography. Diastereoisomers
can be separated by column chromatography. Major exo-diastere-
20
oisomer: [R]D ) +5.6 (c 1.1, CH2Cl2). Minor endo-diastereoi-
20
somer: [R]D ) -36.1 (c 1.2, CH2Cl2). Major exo-diastereoiso-
1
mer: H NMR (300.0 MHz, CDCl3, δ) 5.74 (br s, 1H, dCH), 4.44-
4.26 (m, 2H, OCH2CH3), 3.61 (s, 1H, OH), 2.86 (t, J ) 4.5 Hz,
1H, CHCCF3OH), 2.18-2.00 (m, 4H, CysCH2), 1.95-1.84 (m,
1H, CysCH2), 1.83-1.72 (m, 1H, CysCH2), 1.70-1.62 (m, 2H,
CHdCCH2CH3), 1.35 (t, J ) 7.2 Hz, 3H, OCH2CH3), 0.99 (t, J )
7.3 Hz, 3H, CHdCCH2CH3). Minor endo-diastereoisomer: 1H
NMR (300.0 MHz, CDCl3, δ) 5.71 (br s, 1H, dCH), 4.46-4.22
(m, 2H, OCH2CH3), 3.68 (s, 1H, OH), 2.98 (br m, 1H, CHCCF3-
OH), 2.14-1.95 (m, 4H, CysCH2), 1.92-1.82 (m, 1H, CysCH2),
1.71-1.61 (m, 1H, CysCH2), 1.58 (br m, 2H, CHdCCH2CH3),
1.37 (t, J ) 7.2 Hz, 3H, OCH2CH3), 0.95 (t, J ) 7.4 Hz, 3H, CHd
CCH2CH3). Major exo-diastereoisomer: 13C{1H} NMR (125.7
MHz, CDCl3, δ) 170.2 (CdO), 136.7 (CdCH2CH3), 128.1 (Cd
CCH2CH3), 124.0 (q, JC-F ) 287 Hz, CF3), 81.4(q, JC-F ) 28 Hz,
CCF3), 64.0 (OCH2CH3), 39.5 (Cy), 29.9 (Cy), 26.9 (Cy), 25.0 (Cy),
18.9 (CdCCH2CH3), 14.5 (OCH2CH3), 13.9 (CdCCH2CH3);
LRMS (EI) m/z 279 [M - H]+; HRMS (EI) exact mass calcd for
C13H18O3F3 [M - H]+ requires m/z 279.120804, found m/z
279.122101. Ee’s of both diastereoisomers determined by GC using
a Supelco Beta DEX column (injection temp 135 °C; column
conditions 105 °C for 40 min ramp to 175 °C at 5 °C/min; hold 20
min, pressure 21 psi). Major exo-diastereoisomer: major (1′R,2S)-
enantiomer tR ) 45.3 min, minor (1′S,2R)-enantiomer tR ) 44.2
min; 99% ee. Minor endo-diastereoisomer: major (1′S,2S)-enan-
tiomer tR ) 45.8 min, minor (1′R,2R)-enantiomer tR ) 48.6 min;
92% ee. exo:endo ) 4:1. Absolute and relative stereochemistry
assigned by analogy.
Acknowledgment. We gratefully acknowledge the EPSRC
for funding (C.H.S.) and Johnson Matthey for generous loans
of palladium and platinum salts.
Supporting Information Available: General experimental
procedure, Figure S1, and for compounds 1a, 8b, and 10, details
of crystal data, structure solution and refinement, atomic coordi-
nates, bond distances, bond angles, and anisotropic thermal
parameters in CIF format. Observed and calculated structure factor
tables are available from the authors upon request. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO062023N
9764 J. Org. Chem., Vol. 71, No. 26, 2006