Stereoselective Rh-catalyzed hydrogenation of cyclobutyl chiral enamides: Double stereodifferentiation vs catalyst-controlled diastereoselection

Article abstract of DOI:10.1021/jo048756u

The hydrogenation reactions of several cyclobutyl enamides derived from (-)-α-pinene or (-)-verbenone have been investigated by using different catalysts. The chiralities of both the substrate and the catalyst as well as the Z/E stereochemistry of the dou

Full text of DOI:10.1021/jo048756u

Stereoselective Rh-Catalyzed Hydrogenation of Cyclobutyl Chiral
Enamides: Double Stereodifferentiation vs Catalyst-Controlled
Diastereoselection
Gemma P. Aguado, Albertina G. Moglioni,† Elena Garc´ıa-Expo´sito, Vicenc¸ Branchadell, and
Rosa M. Ortun˜o*
Departament de Quı´mica, Universitat Auto`noma de Barcelona, 08193 Bellaterra, Barcelona, Spain
rosa.ortuno@uab.es
Received July 21, 2004
The hydrogenation reactions of several cyclobutyl enamides derived from (-)-R-pinene or (-)-
verbenone have been investigated by using different catalysts. The chiralities of both the substrate
and the catalyst as well as the Z/E stereochemistry of the double bond have been considered, and
the observed diastereoselectivity has been rationalized. For enamides with the double bond separated
from the cyclobutane by a methylene, the Wilkinson catalyst did not induce any diastereoselection,
but excellent diastereoselectivity was observed when using Et-DuPHOS-Rh and ChiraPHOS-Rh.
The configuration of the new stereogenic center was catalyst-dependent and can be rationalized
according to the Halpern mechanism. For (Z)-enamides with the double bond directly linked to the
cyclobutane ring, the chirality of the substrate governed the diastereoselection and the Halpern
mechanism seemed not to be operative in the hydrogenation with ChiraPHOS, with the configuration
of the new stereogenic center being determined by steric effects. On the contrary, the chirality of
the catalyst was the factor determining the stereochemistry of the major products with alkyl-
DuPHOS-Rh. Z/E stereochemistry influenced the stereodifferentiation, and a different behavior
for each Z or E stereoisomer was found. For both (Z)- and (E)-enamides, some instances of match/
mismatch between the chirality of the substrate and that of the catalyst were observed. As a result
of all of these studies, a series of new cyclobutyl R-amino acids has been synthesized. These products
are interesting to incorporate into conformationally constrained peptides.
Introduction
catalyst complex, which reacts with hydrogen faster than
the most stable one.2
Stereoselective catalytic hydrogenation is a very pow-
erful tool in organic synthesis for the preparation of
several types of products through the reduction of CdC
or CdO double bonds. The use of chiral ligands resulted
in a great improvement of this reaction with respect to
the use of achiral complexes such as the Wilkinson
catalyst.1 Among the chiral catalysts, rhodium phosphine
complexes have been the most studied, with (S,S)-
ChiraPHOS-Rh being the first catalyst whose mode of
action in the mechanism and whose stereochemical
outcome of the catalytic hydrogenation were investigated
and systematized. Halpern, indeed, studied the asym-
metric hydrogenation of achiral enamido esters (enam-
ides) to afford optically active R-amino acids and proposed
a mechanism to explain the stereoselectivity of the whole
process based on the kinetic control of the addition of
hydrogen to the substrate-catalyst complex. Halpern
showed that, in many cases, the resultant major stereo-
isomer is produced from the less stable substrate-
Later, Burk introduced the phospholane-based cata-
lysts, alkyl-DuPHOS-Rh, which also present C2 sym-
metry.3 In addition, some of these catalysts, such as
rhodium Et-DuPHOS, are commerically available in both
enantiomeric forms. These reagents have been used for
the asymmetric synthesis of R-, â-, and γ-amino acids. A
very recent example is the enantioselective synthesis of
(S)-(+)-3-aminomethyl-5-methylhexanoic acid (Pregaba-
lin) via the asymmetric hydrogenation of 3-cyano-5-
methylhex-3-enoic acid salt with [(R,R)-(Me-DuPHOS)-
Rh-(COD)]BF4 as a catalyst.4 Usually, these catalysts
allow the reactions to proceed quickly under mild tem-
perature and pressure conditions in such a way that the
N-Cbz amino protecting group remains unaltered.
(2) (a) Chan, A. S. C.; Pluth, J. J.; Halpern, J. J. Am. Chem. Soc.
1980, 102, 5952. (b) Halpern, J. Science 1982, 217. (c) Halpern, J. In
Asymmetric Synthesis; Morrison, J., Ed.; Academic Press: New York,
1985; Vol. 5, pp 41-68.
(3) For some leading works, see: (a) Burk, M. J. J. Am. Chem. Soc.
1991, 113, 8518. (b) Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow,
R. L. J. Am. Chem. Soc. 1993, 115, 10125. (c) Burk, M. J.; Gross, M.
F.; Harper, G. P.; Kalberg, C. S.; Lee, J. R.; Mart´ınez, J. P. Pure Appl.
Chem. 1996, 68, 37.
(4) (a) Garrett, H. J. Am. Chem. Soc. 2003, 125, 10219. (b) Burk,
M. J.; de Koning, P. D.; Grote, T. M.; Hoekstra, M. S.; Hoge, G.;
Jennings, R. A.; Kissel, W. S.; Le, T. V.; Lennon, I. C.; Mulhern, T. A.;
Ramsden, J. A.; Wade, R. A. J. Org. Chem. 2003, 68, 5731.
† Present address: Ca´tedra de Qu´ımica Medicinal, Facultad de
Farmacia y Bioqu´ımica, Universidad de Buenos Aires, Buenos Aires,
Argentina.
(1) See, for instance: Noyori, R. Asymmetric Catalysis in Organic
Synthesis; John Wiley and Sons: New York, 1993.
10.1021/jo048756u CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/21/2004
J. Org. Chem. 2004, 69, 7971-7978
7971

Aguado et al.
SCHEME 1
The influence of the Z/E stereochemistry of the ena-
mides on the stereoselectivity of the process has been
scarcely investigated. In general, (E)-olefins react slower
than their (Z)-olefin counterparts and afford saturated
products with lower enantiomeric excesses. In reference
to the asymmetric induction, results vary with the use
of different catalysts. Thus, for instance, the configura-
tion of the R-amino acids resulting from the hydrogena-
tion with BINAP-Rh depends on the Z/E configuration
of the substrate enamide.1 In contrast, Burk reported that
the configuration of the major isomer resulting from the
hydrogenation is not dependent on the Z/E geometry of
the double bond when a DuPHOS-Rh catalyst is used.5
Similar results have been described by other authors.6
Data found in the literature about asymmetric hydro-
genations mainly refer to the reduction of achiral sub-
strates. Nevertheless, only a few examples on the hydro-
genation of chiral substrates with chiral catalysts,
displaying double stereodifferentiation,7 have been re-
ported.8
In a preliminary communication, we described our first
results on the hydrogenation of some of the cyclobutyl
chiral (Z)-enamides shown in Scheme 1 using (Ph3P)3-
RhCl, Wilkinson catalyst, 1; [(S,S)-ChiraPHOS-Rh]ClO4,
2; and [(R,R)-(Et-DuPHOS)-Rh-(COD)]OTf, (R,R)-3, re-
spectively.9 The type I enamides were prepared from (-)-
R-pinene, and those of type II proceed from (-)-(S)-
verbenone. These substrates differ in that a methylene
group is intercalated between the double bond and the
cyclobutane moiety in type I substrates, whereas the
double bond is directly linked to the carbocyclic ring in
substrates of type II. This feature is crucial in the control
of the diastereoselectivity in addition reactions to the
double bond of these substrates, as has been previously
shown.
High diastereomeric ratios (dr) were obtained in the
hydrogenation of type II enamides by using 1, 2, and
(R,R)-3 as catalysts, affording amino acids with R con-
figuration for the new stereogenic center in all cases. On
the other hand, whereas no stereoselectivity was ob-
served in the hydrogenation of type I enamides with the
Wilkinson catalyst, R diastereoisomers were obtained as
major products (98:2 dr) when using (S,S)-ChiraPHOS.
Moreover, only one diastereomer resulted from the
hydrogenation with Et-DuPHOS-Rh, with the configu-
ration depending on the chirality of the catalyst used.9
In this article, we present the complete results of our
exhaustive study on the hydrogenation of types I and II
enamides with several catalysts. The chiralities of both
the substrate and the catalyst have been considered, as
well as the Z/E stereochemistry of the double bond. A
model based on theoretical calculations is proposed to
explain the stereochemistry of the produced compounds.
These hydrogenation reactions have allowed the synthe-
sis of a collection of new cyclobutyl R-amino acids useful
for their incorporation into conformationally constrained
peptidomimetics and other complex molecules.
(5) Burk, M. J.; Bienewald, F.; Harris, M.; Zanotti-Gerosa, A. Angew.
Chem., Int. Ed. 1998, 37, 1931.
(6) Tang, W.; Zhang, X. Org. Lett. 2002, 4, 4159.
Results and Discussion
(7) For definition and examples of double asymmetric induction or
double stereodifferentiation, see: (a) Horeau, A.; Kagan, H. B.;
Vigneron, J. P. Bull. Soc. Chim. Fr. 1968, 3795. (b) Masamune, S.;
Choy, W.; Petersen, J. S.; Sita, L. R. Angew. Chem., Int. Ed. Engl. 1985,
24, 1. (c) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic
Compounds; John Wiley and Sons: New York, 1994; pp 965-971.
(8) Schmidt, U.; Lieberknecht, A.; Kazmaier, U.; Griesser, H.; Jung,
G.; Metzger, J. Synthesis 1991, 49.
1. Synthesis of the Enamides. Compound (+)-4 was
synthesized from (+)-R-pinene as the chiral precursor
following the same route as that previously reported for
enantiomer (-)-4 from (-)-R-pinene (Scheme 1).10,11 The
(9) Aguado, G. P.; AÄ lvarez-Larena, AÄ .; Illa, O.; Moglioni, A. G.;
Ortun˜o, R. M. Tetrahedron: Asymmetry 2001, 12, 25.
(10) Moglioni, A. G.; Garc´ıa-Expo´sito, E.; Moltrasio, G. Y.; Ortun˜o,
R. M. Tetrahedron Lett. 1998, 39, 3593.
7972 J. Org. Chem., Vol. 69, No. 23, 2004

Stereoselective Hydrogenation of Enamides
SCHEME 2
CHART 1
TABLE 1. Hydrogenation of Enamides (+)- and (-)-4
and Diastereomeric Ratios (dr)a of Products with
Catalysts Wilkinson, 1; (S,S)-ChiraPHOS-Rh, 2; (R,R)-
Et-DuPHOS-Rh, (R,R)-3; and (S,S)-Et-DuPHOS-Rh, (S,S)-3
pair (+)- and (-)-6 were synthesized from (-)-(S)-
verbenone as the only chiral starting material through
the selective manipulation of functional groups.12 The
other enamides, 5 and 7-9, were also synthesized from
this precursor. Compounds 512 and (Z)-811 have previ-
ously been described. (E)-8, resulting as a minor isomer
in the preparation of the Z counterpart, as well as 7,
prepared from (Z)-8 by hydrolysis of the ketal, has not
been reported. The synthesis of the new product 9 is
shown in Scheme 2. The known alcohol 1011 was pro-
tected as a benzyl ether, and then ketal was removed
under mild conditions by treatment of 11 with PPTS in
acetone. The resultant ketone was submitted to Lieben
degradation with sodium hypobromite in aqueous diox-
ane, affording a carboxylic acid that was methylated with
diazomethane. Ester 13 was reduced with lithium boro-
hydride to give alcohol 14, which was oxidized to alde-
hyde with PDC in dichloromethane. We had found in our
laboratory that direct reduction of esters such as 13 to
aldehydes was not satisfactory because it provided mix-
tures of products.11 Finally, Wittig-Horner condensation
of the prepared aldehyde with a suitable phosphonate,13
in the presence of potassium tert-butoxide as a base,
allowed the obtainment of enamide 9.
entry substrate catalyst product configurationb
% drc
1
2
3
4
5
6
7
(-)-4
(-)-4
(-)-4
(-)-4
(+)-4
(+)-4
(+)-4
1
2
15a/15b
R/S
R
<50.5:49.5
96:4
>99.9:0.1
>99.9:0.1
85:15
>99.9:0.1
>99.9:0.1
15a
(R,R)-3 15a
(S,S)-3 15b
2
(R,R)-3 16a
(S,S)-3 16b
R
S
16a
R
R
S
a Determined by high-resolution 1H NMR. b Refers to the new
stereogenic center in the major diastereomer. c At 100% conver-
sion.
2. Hydrogenation Reactions and Stereochemical
Assignment. The produced amino acids are shown in
Chart 1.
(a) Type I Enamides. Table 1 summarizes the reac-
tions performed on substrates (+)- and (-)-4. With
achiral catalyst 1, no diastereoselectivity was observed
(entry 1). In contrast, moderate to excellent diastereo-
meric ratios were observed with chiral catalysts. The
isomer ratio was determined from the 500-MHz 1H NMR
spectra of the reaction crudes by considering the area of
the signals for the gem-dimethyl group at δ 0.79/1.27 and
0.80/1.28, respectively. The major diastereomers from the
hydrogenation of both (-)- and (+)-4 with (S,S)-Chira-
PHOS, 2, presented the R configuration in the newly
created stereogenic center (entries 2 and 5). The config-
(11) Moglioni, A. G.; Garc´ıa-Expo´sito, E.; Aguado, G. P.; Parella, T.;
Branchadell, V.; Moltrasio, G.; Ortun˜o, R. M. J. Org. Chem. 2000, 65,
3934.
(12) Aguado, G. P.; Moglioni, A. G.; Ortun˜o, R. M. Tetrahedron:
Asymmetry 2003, 14, 217.
(13) Schmidt, U.; Lieberknecht, A.; Wild, J. Synthesis 1984, 53.
J. Org. Chem, Vol. 69, No. 23, 2004 7973

Aguado et al.
TABLE 2. Hydrogenation of Enamides 5-9 and
Diastereomeric Ratios (dr)a of Products with Catalysts
Wilkinson, 1; (S,S)-ChiraPHOS-Rh, 2;
(R,R)-Et-DuPHOS-Rh, (R,R)-3; (S,S)-Et-DuPHOS-Rh,
(S,S)-3; and (R,R)-Me-DuPHOS-Rh, 21
entry substrate catalyst product configurationb
% drc
FIGURE 1. Assignment of cis stereochemistry on the basis
of NOEDIFF experiments on 22a.
1
2
5
1
2
17b
17b
R
R
R
R
R
R
S
75:25
5
95:5
3
5
(R,R)-3 17b
18b
(R,R)-3 18b
21 18b
(S,S)-3 18a
21a
(R,R)-3 21b
21 21b
(S,S)-3 21a
85:15
90:10
88:12
83:17
80:20
90:10
83:17
81:19
90:10
80:20
83:17
80:20
77:23
68:32
87:13
85:15
80:20
d
4
(+)-6
(+)-6
(+)-6
(+)-6
(-)-6
(-)-6
(-)-6
(-)-6
7
2
with ChiraPHOS but the stereochemistry of the new
products is governed by the configuration of the catalyst
in the reductions with DuPHOS. The predominance of
the chirality of the substrate in the diastereoselectivity
of the reactions with 1 and 2 is also pointed out in entries
15 and 16, which refer to the hydrogenation of enamide
9 with the same chirality as that of (-)-6 (compare entries
8 and 16) but the reverse of (+)-5, 6, 7, and (Z)-8.
5
6
7
8
2
S
9
R
R
S
10
11
12
13
14
15
16
17
18
19
20
21
22
1
2
19b
19b
R
R
R
S
7
7
(R,R)-3 19b
Results from the hydrogenation of (Z)-8 (entries 17-
19) and (E)-8 (entries 20-22) do not agree with those
previously reported in the literature. In the reaction with
2, the configuration of the products was dependent on
the Z/E stereochemistry of the starting material and dr
was very different in both cases. Thus, 20b was obtained
from (Z)-8 in 87:13 dr, favoring the R configuration (entry
17). Hydrogenation of (E)-8 afforded a complex mixture
of substances, with 20a, with the S configuration, being
the major identified product (entry 20). Otherwise, a
mixture of compounds 20b and 20a in 85:15 dr resulted
from the hydrogenation of (Z)-8 with (R,R)-3 (entry 18),
but no diastereoselectivity was observed in the reduction
of the E isomer with the same catalyst (entry 21). Finally,
amino acid 20a was the major isomer resulting from the
hydrogenation of both (Z)- and (E)-8 with (S)-3 (80:20 and
87:13 dr, respectively). In all of these cases, dioxolane
removal under the reaction conditions was observed. In
a separate experiment, hydrolysis of the ketal in (Z)-8
followed by hydrogenation with (R,R)-3 also afforded
compound 20b.
9
1
2
2
22a
22a
20b
9
S
(Z)-8
(Z)-8
(Z)-8
(E)-8
(E)-8
(E)-8
R
R
S
(R,R)-3 20b
(S,S)-3 20a
2
(R,R)-3 20a/20b
(S,S)-3 20a
20a
S
R/S
S
<50.5:49.5
87:13
a Determined by high-resolution 1H NMR. b Refers to the new
stereogenic center in the major diastereomer. c At 100% conver-
sion. d Complex mixture showing isomer 20a as the major product.
uration was catalyst-dependent when the two enanti-
omers were hydrogenated by using (R,R)- and (S,S)-Et-
DuPHOS, 3, respectively (entries 3, 4, 6, and 7). In all
cases, the methyl ketone was deprotected under the
hydrogenation conditions but no epimerization was observ-
ed. The stereochemistry of the new stereogenic centers
was determined by X-ray structural analysis of 15a.9
(b) Type II Enamides. Table 2 shows the reactions
performed on enamides 5-9 with catalysts 1-3 and
(R,R)-Me-DuPHOS-Rh, 21. In some instances reported
in the literature, this last catalyst afforded better dias-
tereoselection than Et-DuPHOS-based reagents when
sterically hindered substrates were hydrogenated.14
In the hydrogenation of enamides 5, (+)- and (-)-6, 7,
and (Z)-8, Wilkinson catalyst, 1; (S,S)-ChiraPHOS-Rh,
2; (R,R)-Et-DuPHOS-Rh, (R,R)-3; and (R,R)-Me-DuPHOS-
Rh, 21, behave similarly, affording saturated amino acids
with the R configuration and variable dr. (S,S)-Et-
DuPHOS-Rh, (S,S)-3, induced the opposite S configura-
tion in these substrates. Diastereomeric ratios were lower
when (R,R)-Me-DuPHOS was used with respect to those
in the reactions catalyzed by (R,R)-Et-DuPHOS (compare
entries 6 and 10 with entries 5 and 9 in Table 2). The
comparison of the results from the hydrogenations of the
enantiomers (+)-6 (entries 4-7) and (-)-6 (entries 8-11)
with chiral catalysts allowed us to conclude that the
configuration is substrate-dependent in the reactions
The stereochemical assignment of a and b diastereo-
1
mers was made by comparison of the H NMR pattern
for the different products with that of 19b, whose
configuration was unambiguously assigned by X-ray
structural analysis.9 Diastereomeric ratios were deter-
mined on the basis of significant peaks in the respective
1
high-resolution H NMR spectra of the reaction crudes.
The signals of the gem-dimethyl group at 0.4-0.7 ppm
and of HC2 at 4.0-4.2 ppm were mainly considered. The
cis relationship between the two side chains of the
cyclobutane ring showing that epimerization did not take
place was established by NOEDIFF experiments. As an
example, Figure 1 shows the results for amino acid 22a.
3. Stereochemical Outcome of These Reactions:
Double Stereodifferentiation or Catalyst-Substrate-
Governed Diastereoselection. In enamides (+)- and
(-)-4, a methylene group is intercalated between the
double bond and the bulky cyclobutane moiety containing
the gem-dimethyl group and the two stereogenic centers.
Thus, the achiral Wilkinson catalyst did not induce any
diastereoselectivity (entry 1 in Table 1). In contrast, with
(S,S)-ChiraPHOS-Rh, 2, a major diastereomer was ob-
tained. The predominant induced R configuration can be
interpreted on the basis of the Halpern mechanism, as
depicted in Scheme 3. The major diastereomer comes
from the presumably less stable catalyst-substrate
(14) (a) Albrecht, J.; Nagel, U. Angew. Chem., Int. Ed. Engl. 1996,
24, 407. (b) Burk, M. J.; Gross, M. F.; Harper, T. G. P.; Kalberg, C. S.;
Lee, J. R.; Mart´ınez, J. P. Pure Appl. Chem. 1996, 68, 37. (c) Burk, M.
J.; Gross, M. E.; Mart´ınez, J. P. J. Am. Chem. Soc. 1995, 117, 9375.
(d) Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R. L. J. Am.
Chem. Soc. 1993, 115, 10125. (e) Debenhamm, S. D.; Debenham, J.
S.; Burk, M. J.; Toone, E. J. J. Am. Chem. Soc. 1997, 119, 9897. (f)
Hoermer, R. S.; Askin, D.; Volante, R. P.; Reider, P. J. Tetrahedron
Lett. 1998, 39, 3455.
7974 J. Org. Chem., Vol. 69, No. 23, 2004

Stereoselective Hydrogenation of Enamides
SCHEME 3
FIGURE 2. Energy curve corresponding to the rotation
around the C3-C4 bond obtained at the AM1 level of calcula-
tion for a model (Z)-enamide with R ) H.
complex and results from the addition of hydrogen to the
si face of the double bond. The chirality of the substrate
also influences the π-facial diastereoselection because the
diastereomeric ratios from (-)- and (+)-4 were 96:4 and
85:15, respectively, favoring the R isomer in both cases
(entries 2 and 5 in Table 1). On the contrary, the con-
figuration of the reduction products using Et-DuPHOS
as a catalyst was determined exclusively by the chirality
of the catalyst, affording saturated amino acids with 99.9:
0.1 dr in all cases (entries 3, 4, 6, and 7 in Table 1).
In enamides 5-9, the double bond is directly linked to
the cyclobutane ring and both steric hindrance and the
chirality of the substrate were expected to exert influence
on the π-facial discrimination. In other addition reactions
to the double bond in these substrates, we had previously
observed that the major induced configuration could be
explained by assuming that the reagent attacks the less
hindered π face opposite to the gem-dimethyl group in a
preferential conformation for the substrate.15 To provide
a more accurate model to explain the diastereoselectivity
observed in the hydrogenation reactions, we carried out
theoretical calculations by considering the rotation around
the C3-C4 bond of a model (Z)-enamide with R ) H. The
FIGURE 3. Minimum energy structure of (Z)-8 obtained at
the BPW91/6-31G(d) level of calculation.
corresponding potential energy curve obtained at the
AM1 level of calculation is shown in Figure 2. We can
observe that there is a very flat region in the 150-250°
range with two energy minima at Φ ) 168 and 228° with
an energy difference of only 0.2 kcal mol-1. Beyond this
region, energy rapidly increases so that the rotation is
hindered. Two energy minima have also been located at
the BPW91/6-31G(d) level of calculation at Φ ) 224.1 and
236.9°, with the latter being 0.4 kcal mol-1 higher in
energy than the former. We have also located the most
stable conformers for (Z)-enamides 5 (R ) COOMe, Φ )
224.7°), 7 (R ) Ac, Φ ) 224.6°), and (Z)-8 (R ) dioxolane,
Φ ) 223.5°). The structure of the most stable conformer
of the latter is shown in Figure 3.
Assuming that this is the preferred conformation for
the (Z)-enamides, the reaction is favored by the C2 si face,
leading to b stereoisomers with R configuration in the
new stereogenic center (Chart 1).
For the model (E)-enamide (R ) H), only one conforma-
tional minimum was found corresponding to a dihedral
angle Φ ) 246.6°, which also favors the production of b
stereoisomers. For (E)-8, the most stable structure cor-
responds to Φ ) 236.9° (see the Supporting Information).
(15) (a) Moglioni, A. G.; Garc´ıa-Expo´sito, E.; AÄ lvarez-Larena, AÄ .;
Branchadell, V.; Moltrasio, G. Y.; Ortun˜o, R. M. Tetrahedron: Asym-
metry 2000, 11, 4903. (b) Moglioni, A. G.; Muray, E.; Castillo, J. A.;
AÄ lvarez-Larena, AÄ .; Moltrasio, G. Y.; Branchadell, V.; Ortun˜o, R. M.
J. Org. Chem. 2002, 67, 2402. (c) Moglioni, A. G.; Brousse, B. N.;
AÄ lvarez-Larena, AÄ .; Moltrasio, G. Y.; Ortun˜o, R. M. Tetrahedron:
Asymmetry 2002, 13, 451.
J. Org. Chem, Vol. 69, No. 23, 2004 7975

Aguado et al.
SCHEME 4
with (R,R)- and (S,S)-3 (entries 5, 7, 9, and 11), we can
deduce that (+)-6/(R,R)-3 and (-)-6/(S,S)-3 are matching
pairs. In these cases, the configurations of the major
stereoisomers result from a cooperative effect of the
chiralities in the substrate and in the catalyst, also called
double stereodifferentiation. On the contrary, (+)-6/
(S,S)-3 and (-)-6/(R,R)-3 are the mismatching pairs.
Diastereoselectivity decreased when catalyst 21 was
employed (entries 6 and 10 in Table 2). In general, the
determined dr for the obtained products was lower than
that for the reduction of enamides (+)- and (-)-4 and the
values reported in the literature for the hydrogenation
of achiral olefins with DuPHOS catalysts. Nevertheless,
we have recently reported the hydrogenation of a chiral
cyclobutyl dehydrodipeptide with (R,R)-Et-DuPHOS to
afford a major product in >99.9:0.1 dr showing a clearly
defined instance of double asymmetric induction.16
The behaviors of (Z)- and (E)-enamides toward (S,S)-
ChiraPHOS, 2 (entries 17 and 20 in Table 2), were
similar because in both cases the chirality of the sub-
strate governed the diastereoselection. With DuPHOS
catalysts, the match/mismatch is not very marked for
(Z)-8 (compare 85:15 vs 80:20 dr in entries 18 and 19 in
Table 2). This effect is noteworthy, however, for (E)-8
because the chiralities of the substrate and (R,R)-3 are
strongly mismatching (entry 21). These results contrast
with others previously reported in the literature, ac-
counting for a similar behavior of achiral Z and E
substrates toward DuPHOS catalysts.5,6
Conclusions
All of these results shed light on the use of chiral cata-
lysts in the stereoselective hydrogenation of chiral olefins.
High stereodifferentiation resulted in the hydrogenation
of type I enamides when ChiraPHOS or DuPHOS-Rh was
employed. Diastereoselection was substrate-dependent
when either Wilkinson catalyst or ChiraPHOS-Rh was
used in the hydrogenation of type II (Z)-enamides. Du-
PHOS catalyts, however, always controlled the configu-
ration of the amino acids resulting from both types of
substrates. In general, diastereoselectivity was lower in
the hydrogenation of type II enamides and, in some in-
stances, matching/mismatching effects have been found.
Finally, different behavior has been observed in the hy-
drogenation of a chiral (Z)-olefin with respect to the E
isomer toward different catalysts, contrary to the ex-
amples reported in the literature on the hydrogenation
of achiral olefins.
Inspection of Table 2 leads to the following consider-
ations. Moderate diastereoselectivity was induced when
Wilkinson catalyst, 1, was used (entries 1 and 12),
affording R diastereomers. When (S,S)-ChiraPHOS, 2,
was used in the hydrogenation of (Z)-enamides 5, (+)-6,
7, and (Z)-8, R diastereomers were also produced in
higher dr (entries 2, 4, and 13). On the contrary, S
diastereomers prevailed when both 1 and 2 were used
in the hydrogenation of substrates (-)-6 and 9 with
opposite chirality of the former enamides (entries 8, 15,
and 16). In all of these cases, (S,S)-ChiraPHOS, 2, does
not follow the Halpern mechanism. The formation of the
major adducts can be explained on the basis of the steric
congestion of the catalyst-substrate complexes favoring
the production of R diastereomers as the result of the si
attack to (R,R)-substrates 5, (+)-6, 7, and (Z)-8 (Scheme
4). Similarly, S diasteromers were the major products
resulting from (S,S)-enamides (-)-6 and 9.
Experimental Section
Methyl (1′R,3′R)-2-Acetylamino-3-(3′-acetyl-2′,2′-dim-
ethylcyclobutyl)-(Z)-2-propenoate, 7. Oil. [R]D: -9.2 (c
1.09, MeOH). IR (film): 3288, 1725, 1703, 1671 cm-1. 1H NMR
(acetone-d6): δ 0.89 (s, 3H), 1.31 (s, 3H), 1.87-2.30 (complex
absorption, 2H), 1.98 (s, 3H), 2.01 (s, 3H), 2.89-3.03 (complex
absorption, 2H), 3.67 (s, 3H), 6.46 (d, J ) 8.8 Hz, 1H), 8.26
(broad s, 1H). 13C NMR (acetone-d6): δ 18.6, 22.7, 23.6, 30.1,
30.7, 40.5, 45.8, 52.1, 54.1, 128.5, 137.4, 165.5, 169.1, 206.8.
Anal. Calcd for C14H21NO4: C, 62.90; H, 7.92; N, 5.24. Found:
C, 62.62; H, 7.87; N, 5.02.
Methyl (1′R,3′R)-2-Benzyloxycarbonylamino-3-[2′,2′-di-
methyl-3′-(2-methyl-1,3-dioxolan-2-yl)cyclobutyl]-(E)-2-
In contrast, when using DuPHOS-Rh, the stereochem-
istry is governed by the catalyst, which follows the
Halpern mechanism. From the reactions of (+)- and (-)-6
(16) Aguado, G. P.; Moglioni, A. G.; Brousse, B.; Ortun˜o, R. M.
Tetrahedron: Asymmetry 2003, 14, 2445.
7976 J. Org. Chem., Vol. 69, No. 23, 2004

Stereoselective Hydrogenation of Enamides
propenoate, (E)-8. Oil. [R]D: -14.3 (c 0.28, MeOH). IR
provide pure ester 13 (0.9 g, 95% yield). [R]D: -21 (c 0.67,
MeOH). IR (film): 1734 cm-1 1H NMR (acetone-d6): δ 0.92
1
(film): 3330, 1729, 1705 cm-1. H NMR (acetone-d6): δ 1.04
.
(s, 3H), 1.10 (s, 3H), 1.17 (s, 3H), 1.54-2.22 (complex absorp-
tion, 3H), 3.18 (m, 1H), 3.71 (s, 3H), 3.72-3.92 (complex
absorption, 4H), 5.09 (s, 2H), 6.15 (d, J ) 10.0 Hz, 1H), 7.20-
7.49 (complex absorption, 5 H), 7.90 (broad s, 1H). 13C NMR
(acetone-d6): δ 17.8, 23.0, 25.6, 30.7, 39.7, 43.8, 49.8, 51.0, 63.2,
65.0, 66.0, 109.2, 126.9, 127.8, 128.2, 129.9, 136.7, 153.7, 164.1.
Anal. Calcd for C22H29O6: C, 65.49; H, 7.24; N, 3.47. Found:
C, 65.24; H, 7.41; N, 3.17.
(s, 3H), 1.22 (s, 3H), 1.91 (complex absorption, 2H), 2.25 (m,
1H), 2.74 (dd, J ) 8.2 Hz, J′ ) 10.0 Hz, 1H), 3.33-3.52
(complex absorption, 2H), 3.60 (s, 3H), 4.45 (s, 2H), 7.31
(complex absorption, 5H). 13C NMR (acetone-d6): δ 17.6, 21.9,
31.0, 42.1, 42.6, 46.2, 51.1, 71.4, 73.3, 128.0, 128.2, 128.9, 139.9,
173.3. Anal. Calcd for C16H22O3: C, 73.20; H, 8.45. Found: C,
73.42; H, 8.58.
(1R,3S)-3-Benzyloxymethyl-2,2-dimethylcyclobutyl-
methanol, 14. A 2 M solution of LiBH4 in THF (8 mL, 16
mmol) was added to a solution of ester 13 in freshly distilled
dry THF (10 mL), and the mixture was heated to reflux for 24
h under a nitrogen atmosphere. Then the reaction mixture was
cooled to room temperature, and the excess hydride was
destroyed by slow addition of methanol. Water was added, and
the resultant solution was extracted with EtOAc (4 × 25 mL).
The combined organic extracts were dried over MgSO4, and
the solvent was removed at reduced pressure. The residue was
purified by column chromatography (EtOAc) to give alcohol
14 (364 mg, 69% yield). Oil. [R]D: +8.9 (c 0.89, MeOH). IR
(1S,3R)-2,2-Dimethyl-3-(2′-methyl-1′,3′-dioxolan-2′-yl)-
cyclobutylmethanol Benzyl Ether, 11. Sodium hydride
(485 mg, 20.2 mmol) was added to a solution of the known
alcohol 1011 (570 mg, 2.8 mmol) in freshly distilled DMF (9.6
mL), and the mixture was stirred for 1 h under a nitrogen
atmosphere. Then benzyl bromide (2.7 g, 15.8 mmol) was
added dropwise, and the resultant solution was stirred at room
temperature for 96 h. The solvent and much of the excess
benzyl bromide were removed under reduced pressure, and
the residue was diluted with CH2Cl2 (35 mL). The solution was
washed with three 30-mL portions of water and dried over
MgSO4. The solvent was removed, and the residue was purified
by column chromatography (1:1 CH2Cl2-hexane, CH2Cl2, and
1:1 EtOAc-hexane as the successive eluents) to afford ether
11 (665 mg, 80% yield) as a pale yellow oil. [R]D: -12.54 (c
4.6, MeOH). IR (film): 2952, 2876, 1456, 1365, 1177, 1074
1
(film): 3510-3250 (broad) cm-1. H NMR (CDCl3): δ 0.97 (s,
3H), 1.16 (s, 3H), 1.23 (m, 1H), 1.91-2.25 (complex absorption,
3H), 3.30-3.64 (complex absorption, 5H), 4.45 (s, 2H), 7.30
(complex absorption, 5H). 13C NMR (CDCl3): δ 16.3, 23.3, 31.4,
39.1, 41.3, 44.1, 63.78, 71.1, 72.8, 127.4, 128.2, 138.6. Anal.
Calcd for C15H22O2‚1/2H2O: C, 74.04; H: 9.11. Found: C, 74.48;
H, 9.07.
1
cm-1. H NMR (acetone-d6): δ 1.06 (s, 3H), 1.14 (s, 3H), 1.15
(s, 3H), 1.48-1.61 (m, 1H), 1.72-1.82 (m, 1H), 2.05-2.15
(complex absorption, 2H), 3.31-3.50 (complex absorption, 2H)
3.74-3.94 (complex absorption, 4H), 4.44 (s, 2H), 7.31 (complex
absorption, 5H). 13C NMR (acetone-d6): δ 17.3, 22.4, 24.0, 32.4,
41.1, 42.4, 50.55, 64.2, 66.0, 71.9, 73.3, 110.3, 128.0, 128.2,
129.0, 140.1. Anal. Calcd for C18H26O3: C, 74.45; H, 9.02.
Found: C, 74.21; H, 8.99.
Methyl (1′S,3′S)-2-Acetylamino-3-(3′-benzyloxymethyl-
2′,2′-dimethylcyclobutyl)-(Z)-2-propenoate, 9. A mixture
of alcohol 14 (0.8 g, 3.4 mmol) and PDC (1.4 g, 3.6 mmol) in
dry CH2Cl2 (23 mL) was stirred at room temperature for 6 h
under a nitrogen atmosphere. Then a small portion of Florisil
was added, and stirring was continued for 30 min. The mixture
was filtered through Celite that was washed with ether (50
mL), and solvents were removed at reduced pressure to provide
a crude aldehyde (0.5 g, 70% yield), which was used in the
next step without further purification.
Methyl 2-N-acetylamino-2,2-dimethoxyphosphinyl acetate
(0.6 g, 2.6 mmol) in dry dichloromethane (5 mL) was slowly
added to a solution of KOtBu (0.3 g, 2.5 mmol) in dry
dichloromethane (6 mL) at -78 °C under a nitrogen atmo-
sphere. The resultant solution was stirred at -78 °C for 30
min, and aldehyde (0.2 g, 0.9 mmol) in dry dichloromethane
(3 mL) was added. The mixture was warmed to room temper-
ature and stirred for 6 days under a nitrogen atmosphere.
Then water (10 mL) was added, layers were separated, and
the aqueous phase was extracted with dichloromethane (4 ×
25 mL). The combined organic phases were dried over MgSO4,
and solvent was removed. The residue was chromatographed
(2:1 EtOAc-hexane) to give the enoate 9 (50 mg, 17% yield).
Oil. [R]D: -7.3 (c 0.82, MeOH). IR (film): 3267 (broad), 1725,
1668 cm-1. 1H NMR (acetone-d6): δ 1.00 (s, 3H), 1.11 (s, 3H),
1.56 (ddd, J ) J′ ) J′′ ) 10.2 Hz, 1H), 1.97 (s, 3H), 2.07-2.92
(complex absorption, 3H), 3.30-3.53 (complex absorption, 2H),
3.66 (s, 3H), 4.45 (s, 2H), 6.49 (d, J ) 8.8 Hz, 1H), 7.20-7.40
(complex absorption, 5H), 8.25 (broad s, 1H). 13C NMR
(acetone-d6): δ 17.5, 22.2, 26.3, 30.8, 40.8, 42.4, 42.9, 51.6, 71.1,
72.8, 127.6, 127.7, 128.5, 137.7, 139.5, 165.2, 168.6. Anal. Calcd
for C20H27O4N: C, 69.50; H, 7.88; N, 4.06. Found: C, 69.80; H,
7.87; N, 4.04.
(1R,3S)-3-Benzyloxymethyl-2,2-dimethylcyclobutylMeth-
yl Ketone, 12. A mixture of ketal 11 (140 mg, 0.48 mmol)
and PPTS (64 mg, 0.25 mmol) in wet acetone (6.5 mL) was
heated to reflux for 6 h. Then the reaction mixture was cooled
to room temperature, and the solvent was removed at reduced
pressure. The residue was diluted with 25 mL of ether, washed
twice with saturated aqueous NaHCO3, and dried over MgSO4.
The solvent was removed, and the crude ketone 12 was
purified by column chromatography (3:2 CH2Cl2-hexane) to
afford pure 12 (114 mg, 96% yield) as a pale yellow oil. Ot:
105-110 °C (0.03 Torr). [R]D: -42 (c 3.4, MeOH). IR (film):
1705 cm-1. 1H NMR (CDCl3): δ 0.87 (s, 3H), 1.34 (s, 3H), 1.71-
1.99 (complex absorption, 2H), 2.02 (s, 3H), 2.21-2.34 (m, 1H),
2.84 (dd, J ) 7.5 Hz, J′ ) 10.0 Hz, 1H), 3.31-3.43 (complex
absorption, 2H), 4.44 (s, 2H), 7.30 (complex absorption, 5H).
13C NMR (acetone-d6): δ 17.1, 20.3, 30.0, 31.2, 41.7, 43.0, 53.9,
71.4, 73.2, 128.0, 128.1, 128.9, 139.9, 206.9. Anal. Calcd for
C16H22O2‚1/2H2O: C, 75.26; H, 8.68. Found: C, 75.42; H, 8.67.
Methyl (1R,3S)-3-Benzyloxymethyl-2,2-dimethylcy-
clobutane-1-carboxylate, 13. An ice-cooled aqueous solution
of sodium hypobromite prepared from Br2 (1.25 mL, 25 mmol)
and NaOH (4.3 g, 107 mmol) was added to a stirred solution
of ketone 12 (2 g, 8.1 mmol) in dioxane (25 mL) cooled at -5
°C. The mixture was subsequently stirred at 0 °C for 3 h and
at room temperature for 4 h and was extracted with two 50-
mL portions of ether. Forty percent aqueous NaHSO3 and
concentrate HCl were subsequently added to reach pH 2. Then
the acid aqueous solution was extracted with ether (5 × 50
mL), and the organic extracts were dried over MgSO4. The
solvent was removed at reduced pressure, affording a crude
acid (0.9 g, 45% yield), which was used in the next step without
further purification. To an ice-cooled solution of this acid (0.9
g, 3.6 mmol) in ether (50 mL) was added a freshly distilled
ethereal solution of diazomethane. The mixture was stirred
at room temperature for 1 h, excess diazomethane was
destroyed by addition of benzoic acid, the resultant mixture
was filtered, and the solvent was removed to afford an oil that
was chromatographed on silica gel (3:1 hexanes-EtOAc) to
(1′S,2R,3′R)-2-Acetylamino-4-(3′-acetyl-2′,2′-dimethyl-
cyclobutyl)butanoate, 15a. Crystals. Mp: 127-131 °C (from
acetone-pentane). [R]D: -18.9 (c 0.79, MeOH). IR (film): 3303
1
(broad), 1746, 1702, 1659 cm-1. H NMR (500 MHz, acetone-
d6): δ 0.79 (s, 3H), 1.27 (s, 3H), 1.31-2.10 (complex absorption,
7H), 1.90 (s, 3H), 1.97 (s, 3H), 2.87 (dd, J ) 7.9 Hz, J′ ) 9.8
Hz, 1H), 3.65 (s, 3H), 4.35-4.40 (m, 1H), 7.32 (broad s, 1H).
13C NMR (acetone-d6): δ 16.7, 22.1, 23.1, 26.2, 30.1, 30.6, 30.4,
41.8, 42.9, 51.60, 52.6, 53.7, 169.5, 173.0, 206.4. Anal. Calcd
for C15H25NO4: C, 63.58; H, 8.89; N, 4.94. Found: C, 63.24;
H, 8.56; N, 4.86.
J. Org. Chem, Vol. 69, No. 23, 2004 7977

Aguado et al.
17b, 18a, 18b, 19a, 19b, 20a, 20b, 21a, 21b, 22a, and 22b;
computational details; Cartesian coordinates of all optimized
structures; and energy curve corresponding to rotation around
C3-C4 bond for a model (E)-enamide (R ) H). This material
is available free of charge at http://pubs.acs.org.
Acknowledgment. Financial support from MCyT
(BQU2001-1907) and Generalitat de Catalunya
(2001SGR 00182) is gratefully acknowledged.
Supporting Information Available: General experimen-
tal methods; full description of compounds 15b, 16a, 16b, 17a,
JO048756U
7978 J. Org. Chem., Vol. 69, No. 23, 2004