Asymmetric syntheses of α-methyl γ-amino acid derivatives

Article abstract of DOI:10.1021/jo201215c

This project was undertaken to demonstrate the potential of asymmetric hydrogenations mediated by the chiral, carbene-oxazoline analogue of Crabtree's catalyst "cat" in asymmetric hydrogenations of allylic amine derivatives of amino acids. Peripheral feat

Full text of DOI:10.1021/jo201215c

ARTICLE
pubs.acs.org/joc
Asymmetric Syntheses of r-Methyl γ-Amino Acid Derivatives
Ye Zhu, Sakunchai Khumsubdee, Amber Schaefer, and Kevin Burgess*
Department of Chemistry, Texas A & M University, Box 30012, College Station, Texas 77841, United States
S Supporting Information
b
ABSTRACT: This project was undertaken to
demonstrate the potential of asymmetric hy-
drogenations mediated by the chiral, carbene-
oxazoline analogue of Crabtree’s catalyst “cat”
in asymmetric hydrogenations of allylic amine
derivatives of amino acids. Peripheral features
of the substrates (protecting groups, functional
groups related by redox processes, and alkene
geometries) were varied to optimize the stere-
ochemical vectors exerted by the substrate and
align them with the catalyst vector. N-Acetyl-protected, O-TBDPS-protected allylic substrates 9aÀe emerged as the best for this
reaction; syn-products were formed from the E-alkenes, while the Z-isomers gave anti-target materials, both with high
diastereoselectivities. This study featured asymmetric catalysis to elaborate optically active substrates into more stereochemically
complex chirons; we suggest that the approach used, optimization of stereocontrol by varying peripheral aspects of the substrate,
tends to be easier than de novo catalyst design for each substrate type. In other words, optimization of the substrate vector is likely to
be more facile than enhancement of the catalyst vector via ligand modifications.
’ INTRODUCTION
γ-Amino acids are important in medicinal chemistry. For
instance, γ-aminobutyric acid (GABA) has pivotal neurological
functions as a modulator of synaptic responses; these relate to
its interactions with various types of receptors, even ones in
different catagories, including ligand-gated ion channels1À3 and
some G-coupled protein receptors.4 Several neurological dis-
eases can be attributed to imbalances of GABA levels in the
central nervous system, and hence analogues of GABA have
therapeutic potential.5,6 Lipophilic analogues of GABA have
better bioavailabilities, particularly with repect to permeation of
the bloodÀbrain barrier, than GABA itself.7À9 Chiral deriva-
tives of GABA with side-chains appropriate for interactions
with protein surfaces can selectively interact with some of
the receptors modulated by GABA and thus have useful
pharmacological properties.10 Consequently, lipophilic, chiral
analogues of GABA have emerged as important pharma-
ceuticals such as (R)-baclofen,11À13 (S)-pregabalin,14À16 and
(S)-vigabatrin.10,17,18
This paper is specifically about R-substituted γ-amino acids.
Consistent with the discussion above, these fragments are found
in some experimental therapeutics, including those shown in
Figure 1. Important compounds containing optically active γ-amino acids.
Figure 1. R-Substituted γ-amino acids are also found in natural
products in the tubulysin series. Baclofen,19À21 pregabalin,22
somewhat classical and dated approaches like resolutions and
vigabatrin,10 the experimental therapeutics in Figure 1, and the
diastereoselective reactions involving chiral auxiliaries.23À25
tubulysins all feature one particular enantiomeric form. Conse-
quently, asymmetric syntheses of these fragments are potentially
important for design of CNS pharmaceuticals and in natural product
syntheses. Literature preparations of these materials tend to feature
Received: June 10, 2011
Published: August 18, 2011
r
2011 American Chemical Society
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Here we describe how chiral analogues of Crabtree’s catalyst26,27
can be used to prepare compounds 1 in this series. Chiral
analogues of Crabtree’s catalyst are special insofar as they can
mediate hydrogenations of alkenes without an obvious coordi-
nating functional group.26 Interactions of chiral Crabtree’s
catalysts analogues with the requisite substrates have never been
studied before, so there are two ways to approach this type of
situation. The first is to modify the catalyst so that it gives high
stereoselectivities for each substrate. Catalyst development is slow
and ideal ligand structures and conditions cannot be predic-
ted with certainty, so this is a poor strategy. We hypothesized that
a more effective approach would be to modify the substrate (alkene
geometries and protecting/functional groups) so that stereoselectiv-
ities obtained from a good catalyst become better. Thus our objective
in this research was to modify optically pure amino acid derivatives
into alkenes that could be hydrogenated with high stereoselectivities
by matching the influence of our chiral catalyst cat28,29 with the
stereochemical vectors exerted by the substrate (Figure 2).
Scheme 1. (a) Preparation and (b) Asymmetric Hydrogena-
tion of γ-Aminobutenoate Esters
Figure 2. Proposed asymmetric hydrogenation of optically pure allyl
amines from amino acids.
’ RESULTS AND DISCUSSION
To begin this project, amino acids with tert-butyloxycarbonyl,
phthalyl, or nosyl (here 2-nitrophenylsulfonyl, Ns) N-protecting
groups were converted to known30 Weinreb amide31 derivatives and
then reduced to aldehydes.30 These stereochemically delicate inter-
mediates were not isolated, but instead they were immediately
converted to the allyl amines 2. These alkenes were then subjected
to hydrogenations mediated by cat; the best stereoselectivity ob-
tained in this series was good (13:1.0; Scheme 1), but there were
possibilities for further improvements, and these were explored next.
One of our previous studies on acyclic stereocontrol using
cat featured chiral allylic alcohol substrates derived from lac-
tic acid.32 That research showed cat delivered hydrogen to the
ester A with only moderate diastereofacial selectivity, but
the allylic diol substrates B and C were reduced with much
higher selectivities. Extrapolating those observations suggested
substrates D, having similar structural modifications, would give
better stereoselectivies in the hydrogenation reactions (Figure 3).
Scheme 2 shows how the concept outlined in Figure 3 was
tested. Ester 2a (R = Bn) was reduced to the allylic alcohol 3a,
and then several substrates with different N- and O-protection
modalities were prepared and hydrogenated using cat. These
experiments showed a modest stereoselectivity for the N-Boc
substrate 3a, while the free amine 5a gave no significant conversion.
However, an excellent stereoselectivity was obtained for 6a, a
substrate that has a bulky N-silyl protecting group and a free
hydroxyl; the only drawback with this reaction was that the
catalyst loading, 5 mol %, was a little high. Consequently, several
more substrates were prepared and tested. Those experiments
showed that the potentially coordinating formamide group of
10a correlated with poor conversion and selectivity. Interest-
ingly, the N-Boc and silyl alcohol 7a gave a good selectivity in
favor of the anti-product; this is opposite to all the other
substrates discussed so far. The best stereoselectivity in the series
was eventually obtained from the acetamido silyl ether (E)-9a.
Hydrogenation of this compound was highly syn-selective, and only
2 mol % of cat was required. High syn-selectivity was also observed
for the corresponding N-trifluoroacetate, but slightly more catalyst
was necessary to obtain 100% conversion. In summary, hydrogena-
tion of the acetamido silyl ether (E)-9a provided the answer to the
challenge of obtaining the syn-isomer in the phenylalanine series,
and hence we turned our attention to the anti-isomers.
Review of the data accumulated so far indicated substrate control
for most, though not all, of the alkenes hydrogenated using cat.
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Scheme 2. (a, b) Synthesis and (c) Asymmetric
Hydrogenation of N- or O-Protected Amino
Alcohol Derivatives
Figure 3. Proposed substrate modifications for enhancing the stereo-
selectivities in asymmetric hydrogenations.
This was not predicted on the basis of most of our previous
studies,32À36 but it is not surprising either. Most of the allylic amines
used in these experiments have substituents that are very large, capable
of coordination, or both. As a guide, it seemed that 1,3-allylic strain
effects37 in the substrate were dominant in most of these reactions
(Figure 4a and b). Influences of 1,3-allylic strain are enhanced for
Z-alkenes relative to their E-isomers, so we saw hydrogenation of the
cis-alkenes as a gateway to anti-isomers (Figure 4c).
Figure 4. Hypothesis for obtaining the anti-skeletons of R-methyl
γ-amino acid derivatives.
Scheme 3 shows the syntheses and hydrogenations of the
Z-allylic alcohol derivative 9a, formed via the StillÀGennari reac-
tion,38 to test the thesis presented in Figure 4. Gratifyingly, a high
stereoselectivity was obtained without modification of the substrate
and using only 2 mol % catalyst. Thus the anti-skeleton of the target
materials was obtained for the phenylalanine derivative (series a).
Other substrates were prepared in the final phase of this project to
test if syntheses of the syn- and antiisomers of the phenylalanine
derivatives 1a (Schemes 2 and 3) could be extrapolated to the allylic
amines from other amino acids. Preparations of the substrates follow
the sequences already outlined here, and full details are given in the
Supporting Information. Table 1 shows the results obtained for
eight more substrates, specifically the E- and Z-forms of 9bÀe.
Throughout excellent stereoselectivities were obtained, the con-
versions were complete, and only 2 mol % of catalyst was used.
’ CONCLUSIONS
Review of the products indicated in Table 1 shows that we
have made carbon frameworks corresponding to appropriate
chirons for all of the significant molecules shown in Figure 1 and
an epimer of each. Perhaps more importantly, however, is a
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Scheme 3. Synthesis and Hydrogenation of (Z)-9a
Table 1. Hydrogenation of Varying r-Substituted Alkene
Substrates Using (S)-cat
philosophical conclusion about the tactics used to reach this goal.
Many organic methodology papers emphasize how a particular
catalyst can transform a variety of substrate types with high stereo-
selectivities. This approach is fine for enantioselective reactions, and it is
wholly justifiable if the products have intrinsic value. However,
researchers wishing to apply new catalysts for stereocontrolled reactions
of chiral substrates will usually find it easier to modify peripheral
features of a new substrate (e.g., protecting groups, functional groups
related via oxidation levels, alkene geometries) than the catalyst. That
strategy was used here, and our experience indicates that in the
process of elaborating structures of stereochemically complex mol-
ecules, substrate modifications are more rewarding than the some-
what arbitrary process of catalyst discovery and optimization.28,39,40 In
other words, it is easier to optimize substrate vectors than catalyst
vectors. Several established concepts (protecting group size,
1,3-allylic strain, etc.) can be used to understand and predict
the effects of changes in the substrate, whereas similar
perturbations to the catalyst are harder to make and have
effects that are less predictable. This should not be taken to
mean that substrate modifications and the substrate vector
always correlate in readily understable ways, as examples in
this work demonstrate. However, substrate vectors tend to be
the ones to optimize first because they are easier to make, and
sometimes they do correlate in rational ways with substrate struc-
tures. It follows that accounts such as this, showing the strengths and
limitations of the catalyst with respect to a range of substrates, are
most useful to potential practioners of the method.
a Determined via HPLC on an unbonded silica 300 Å. b Stereochemistry
was determined by comparison with known compound (see Supporting
Information).
anhydrous conditions. Glassware for anhydrous reactions was dried in an
oven at 140 °C for a minimum of 6 h prior to use. Dry solvents were
obtained by passing the previously degassed solvents through activated
alumina columns. Reagents were purchased at a high commercial quality
(typically 97% or higher) and used without further purification, unless
otherwise stated. High field NMR spectra were recorded at 300 MHz for
1
1H and 75 MHz for 13C. Chemical shifts of H and 13C spectra were
referenced to the NMR solvents. Flash chromatography was performed
using silica gel (230À600 mesh). Thin layer chromatography was
performed using glass plates coated with silica gel 60 F254.
The following abbreviations were used to explain the multiplicities:
s = singlet, d = doublet, t = triplet, q = quartet, dd = double doublet,
dq = double quartet m = multiplet, br = broad.
Synthesis of r-Methyl γ-Amino Acid Derivatives 2.
R-Methyl γ-amino acid alkene derivatives (E)-2 and (Z)-2 were
synthesized via a known procedure.1À6
(S)-E-Methyl 4-((tert-Butoxycarbonyl)amino)-2-methyl-5-
phenylpent-2-enoate (E-2a). 1H NMR (300 MHz, CDCl3)
δ 7.28À7.08 (5H, m), 6.56 (1H, d, J = 12 Hz), 4.72À4.54 (2H, br),
3.75 (3H, s), 2.98 (1H, dd, J = 6.0, 14 Hz), 2.79 (1H, dd, J = 12, 18 Hz),
1.71 (3H, d, J = 1.1 Hz), 1.43 (9H, s); 13C NMR (75 MHz, CDCl3)
δ 155.4, 138.0, 137.9, 129.9, 128.5, 126.6, 125.0, 79.9, 52.2, 50.4, 41.4,
’ EXPERIMENTAL SECTION
General Procedures. All reactions were carried out under an inert
atmosphere (nitrogen or argon where stated) with dry solvents under
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28.6, 12.9. HRMS (ESI): exact mass calcd for C18H25LiNO4 [M + Li]+
326.1944, found 326.2052.
General Procedure for Syntheses of Compounds (E)-7,
Illustrated for 7a.
General Procedure for Syntheses of Compounds (E)-3,
Illustrated for 3a.
Imidazole (0.7 g, 10 mmol) was added to a stirred solution of Boc-
protected allylic amine 3a (2.7 g, 9.4 mmol) in CH2Cl2 (20 mL). tert-
Butyldiphenylsilyl chloride (2.5 mL, 9.9 mmol) was then added slowly, and
the resulting mixture was stirred for 24 h. Water (30 mL) was added to the
reaction, and the layers were separated. The aqueous layer was extracted
using CH2Cl2 (3 Â 20 mL). The combined organic extracts were dried
over Na2SO4 and concentrated in vacuo. The residue was purified by
column chromatography using 10% EtOAc/hexanes as eluent giving
(S)-E-tert-butyl (5-((tert-butyldiphenylsilyl)oxy)-4-methyl-1-phenylpent-
The phenylalanine derivative 2a (0.9 g, 2.7 mmol) was dissolved in
CH2Cl2 (20 mL), and the solution was cooled to À50 °C. A DIBAL
solution (1 M in hexane) (8.1 mL, 8.1 mmol) was added slowly, and then
the reaction was stirred at À50 °C for 5 h and then quenched by addition
of EtOAc (0.5 mL). Saturated potassium sodium tartrate solution
(20 mL) was added, and the mixture was warmed to 25 °C and stirred
for 1 h. The layers were separated, and the aqueous layer was extracted
with CH2Cl2 (3 Â 30 mL). The combined organic extracts were dried
over Na2SO4 and concentrated in vacuo. The residue was purified by
column chromatography using 30% EtOAc/hexanes as eluent giving
(S)-E-tert-butyl (5-hydroxy-4-methyl-1-phenylpent-3-en-2-yl)carbamate
1
3-en-2-yl)carbamate (7a) (4.1 g, 82%) as a colorless oil. H NMR (300
MHz, CDCl3) δ 7.68À7.66 (4H, m), 7.48À7.37 (6H, m), 7.29À7.19 (5H,
m), 5.41 (1H, d, J = 9.3 Hz), 4.72À4.50 (1H, br), 4.50À4.39 (1H, br), 4.01
(2H, s), 3.05À2.90 (1H, m), 2.75 (1H, dd, J = 7.5, 13 Hz), 1.47 (9H, s),
1.44 (3H, s), 1.09 (9H, s); 13C NMR (75 MHz, CDCl3) δ 155.1, 137.8,
137.2, 135.6, 135.5, 133.6 (2 peaks), 129.8, 129.7, 128.2, 127.7, 126.2, 123.0,
79.2, 67.8, 49.6, 42.2, 28.5, 26.9, 19.3, 13.8. HRMS (ESI): exact mass calcd
for C33H43LiNO3Si [M + Li]+ 536.3172, found 536.3175.
1
(3a) as a colorless oil (0.7 g, 2.4 mmol, 90%). H NMR (300 MHz,
CDCl3) δ 7.32À7.18 (5H, m), 5.31 (1H, dq, J = 1.5, 9.0 Hz), 4.55 (2H,
br), 3.97 (2H, s), 2.94 (1H, dd, J = 6.0, 13 Hz), 2.73 (1H, dd, J = 7.2, 13
Hz), 1.51 (3H, d, J = 1.5Hz), 1.43 (9H, s); 13C NMR (75MHz, CDCl3) δ
155.4, 138.0, 137.9, 129.9, 128.5, 126.6, 125.0, 79.6, 76.9, 68.1, 50.0, 42.3,
28.7, 14.2. HRMS (ESI): exact mass calcd for C17H25NNaO3 [M + Na]+
314.1732, found 314.1768.
General Procedure for Syntheses of Compounds (E)-8,
Illustrated for 8a.
Synthesis of Phenylalanine Derivative (E)-5a.
A dioxane solution of 4 M HCl (3.0 mL, 12 mmol) was added to the
Boc-protectedamine7a(0.5 g, 1.0 mmol) inEt2O 30 mL, and the mixture
was stirred at 25 °C for 4 h. The mixture was made basic by addition of a
10% NaOH solution, and the layers were separated. The aqueous layer
was extracted with Et2O (3 Â 20 mL). The combined organic extracts
were dried over Na2SO4 and concentrated in vacuo. The product 8a was
used without further purification. 1H NMR (300 MHz, CDCl3) δ
7.69À7.65 (4H, m), 7.43À7.34 (6H, m), 7.30À7.18 (5H, m), 5.43
(1H, dd, J = 1.2, 8.8 Hz), 5.30 (1H, s), 4.01 (2H, s), 3.87 (1H, q), 2.69
(2H, t, J = 6.3Hz), 1.52À1.31 (1H, br), 1.48 (3H, d, J = 0.9Hz), 1.05 (9H,
s); 13C NMR(75MHz, CDCl3) δ 140.4, 136.6, 135.8, 135.7, 133.7, 133.6,
130.1, 129.9, 128.8, 128.0, 127.1, 120.4, 68.6, 50.8, 44.8, 27.1, 19.6, 14.0.
HRMS (ESI): exact mass calcd for C28H36NOSi [M + H]+ 430.2566,
found 430.2502.
The Boc-protected allylamine 3a (1.4 g, 4.9 mmol) was dissolved in
30 mL of CH2Cl2 and cooled to 0 °C. Trifluoroacetic acid (25 mL) was
added in one portion, and then the mixture was warmed to 25 °C and
stirred for 3 h. Solvent was evaporated under a stream of nitrogen, and
the residue was dissolved in 20 mL of CH2Cl2 and washed with 20 mL of
saturated NaHCO3. The aqueous layer was extracted with CH2Cl2 (2 Â
10 mL). The combined organic layers were dried over Na2SO4, and solvent
was removed in vacuo. The residue 4a was used without further purification.
Allylic amine 4a was dissolved in CH2Cl2 (20 mL), and imidazole
(1.2 equiv) was then added. tert-Butyldiphenylsilyl chloride (1.1 equiv)
was then added slowly, and the resulting mixture was stirred for 1 h at
25 °C. The reaction was quenched with 20 mL of saturated NaHCO3,
and the aqueous layer was extracted with CH2Cl2 (3 Â 10 mL).
The combined organic extracts were dried over Na2SO4 and concen-
trated in vacuo. The residue was purified by column chromatography
using 5% MeOH/CH2Cl2 to give 25% of compound 5a as a colorless oil.
1H NMR (300 MHz, CDCl3) δ 7.69À7.65 (4H, m), 7.43À7.34 (5H,
m), 7.30À7.18 (6H, m), 5.43 (1H, dd, J = 1.2, 8.8 Hz), 5.30 (1H, s), 4.01
(2H, s), 3.06 (1H, m), 2.69 (2H, t, J = 6.3 Hz), 1.48 (3H, d, J = 0.9 Hz),
1.05 (9H, s); 13C NMR (75 MHz, CDCl3) δ 139.2, 135.8, 135.2, 134.0,
129.9, 129.8, 128.6, 128.3, 127.9, 126.4, 68.6, 50.8, 44.8, 27.1, 19.6, 14.0.
HRMS (ESI): exact mass calcd for C28H36NOSi [M + H]+ 430.2566,
found 430.2502.
General Procedure for Syntheses of Allylic Acetates
(E)-9.
Allylic amine 8 was dissolved in CH2Cl2 (0.1M), and pyridine
(1.5 equiv) was added to the solution. Acetic anhydride (1.1 equiv)
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was added and the mixture was stirred at 25 °C for 1 h. The solution was
washed with 1 M HCl(aq) (10 mL), saturated NaHCO3(aq) (10 mL),
and water (10 mL). The organic layers were dried over Na2SO4 and
concentrated in vacuo. The residue was purified by column chromatog-
raphy using 50% EtOAc/hexanes as eluent.
(75 MHz, CDCl3) δ 169.1, 138.4, 138.1, 135.6, 133.7, 133.6, 129.7,
128.5, 128.2, 127.7, 73.3, 72.5, 68.0, 46.9, 26.9, 23.5, 19.3, 14.0.
HRMS (ESI): exact mass calcd for C31H40NO3Si [M + H]+ 502.2777,
found 502.2801.
(S)-E-N-(1-(4-(Benzyloxy)phenyl)-5-((tert-butyldiphenyl-
silyl)oxy)-4-methylpent-3-en-2-yl)acetamide (E)-9e.
(S)-E-N-(5-((tert-Butyldiphenylsilyl)oxy)-4-methyl-1-phe-
nylpent-3-en-2-yl)acetamide (E)-9a.
Product was obtained as a colorless oil (95%). 1H NMR (300 MHz,
CDCl3) δ 7.67À7.63 (4H, m), 7.48À7.36 (6H, m), 7.30À7.17 (5H, m),
5.44 (1H, dd, J = 1.5, 9.0 Hz), 5.26 (1H, d), 5.01À4.90 (1H, m), 4.01
(2H, s), 2.96 (1H, dd, J = 4.8, 13 Hz), 2.79 (1H, dd, J = 7.5, 13 Hz), 1.97
(3H, s), 1.28 (3H, s), 1.08 (9H, s); 13C NMR (75 MHz, CDCl3) δ 169.2,
138.3, 137.8, 135.7, 133.9, 133.7, 130.1, 129.9, 128.5, 127.9, 126.5, 122.2,
67.8, 48.2, 41.7, 27.1, 23.7, 19.5, 14.1. HRMS (ESI): exact mass calcd for
C30H38NO2Si [M + H]+ 472.2672, found 472.2666.
Product was obtained as a colorless oil (83%). 1H NMR (300 MHz,
CDCl3) δ 7.70À7.67 (4H, m), 7.48À7.40 (11H, m), 7.12 (2H, dd, J =
13 Hz), 6.92 (2H, d, J = 8.0 Hz), 5.47 (1H, d, J = 0.9 Hz), 5.39 (1H, d, J =
6.0 Hz), 5.07 (2H, s), 5.01À4.89 (1H, m), 4.05 (2H, s), 2.92 (1H, dd, J =
3.0, 12 Hz), 2.85 (1H, dd, J = 0.9, 9.0 Hz), 2.00 (3H, s), 1.49 (3H, s), 1.12
(9H, s); 13C NMR (75 MHz, CDCl3) δ 169.0, 157.4, 138.0, 137.2,
135.6, 133.7, 133.5, 130.8, 130.0, 129.7, 128.6, 128.0, 127.7, 127.5, 122.2,
114.7, 70.0, 67.7, 48.2, 40.7, 26.9, 23.5, 19.3, 14.0. HRMS (ESI): exact
mass calcd for C37H44NO3Si [M + H]+ 578.3090, found 578.3075.
Synthesis of (Z)-9. (Z)-9 was synthesized from (Z)-2 by using the
same procedure as for synthesis of compounds (E)-9.
(S)-E-N-(5-((tert-Butyldiphenylsilyl)oxy)-4-methylpent-3-
en-2-yl)acetamide (E)-9b.
(S)-Z-N-(5-((tert-Butyldiphenylsilyl)oxy)-4-methyl-1-phe-
nylpent-3-en-2-yl)acetamide (Z)-9a.
Product was obtained as a colorless oil (89%). 1H NMR (300 MHz,
CDCl3) δ 7.72À7.68 (4H, m), 7.47À7.39 (6H, m), 5.40À5.38 (2H, m),
4.82À4.72 (1H, m), 4.08 (2H, s), 1.97 (3H, s), 1.66 (3H, s), 1.22 (3H, d,
J = 6.6 Hz), 1.11 (9H, s); 13C NMR (75 MHz, CDCl3) δ 168.8, 136.9,
135.6, 133.7, 133.6, 129.7, 127.7, 125.1, 68.0, 43.1, 26.9, 23.6, 21.9, 19.3,
13.9. HRMS (ESI): exact mass calcd for C24H34NO2Si [M + H]+
396.2359, found 396.2570.
(S)-E-N-(6-((tert-Butyldiphenylsilyl)oxy)-2,5-dimethylhex-
4-en-3-yl)acetamide (E)-9c.
Product was obtained as a colorless oil (83%). 1H NMR (300 MHz,
CDCl3) δ 7.67À7.63 (4H, m), 7.45À7.37 (6H, m), 7.25À7.17 (3H, m),
7.08À7.05 (2H, m), 5.23 (1H, d, J = 6.0 Hz), 5.08 (1H, d, J = 15 Hz),
4.74À4.62 (1H, m), 4.14 (1H, d, J = 7.2 Hz), 3.97 (1H, d, J = 13 Hz),
2.82 (1H, dd, J = 0.6, 3.0 Hz), 2.69 (1H, dd, J = 6.9, 13 Hz), 1.87 (3H, s),
1.80 (3H, s), 1.05 (9H, s); 13C NMR (75 MHz, CDCl3) δ 168.9, 138.4,
137.4, 135.6, 135.6, 133.5, 129.7, 129.6, 128.2, 127.8, 127.7, 126.3, 125.1,
62.5, 48.2, 41.4, 26.8, 23.4, 21.1, 19.3. HRMS (ESI): exact mass calcd for
C30H38NO2Si [M + H]+ 472.2672, found 472.2723.
Product was obtained as a colorless oil (71%). 1H NMR (300 MHz,
CDCl3) δ 7.70À7.63 (4H, m), 7.42À7.28 (6H, m), 5.42 (1H, d, J =
6.0 Hz), 5.22 (1H, d, J = 6.0 Hz), 4.59À4.45 (1H, m), 4.07 (2H, s), 1.97
(3H, s), 1.83À1.70 (1H, m), 1.63 (3H, s), 1.07 (9H, s) 0.89 (6H, dd, J =
6.3, 6.6 Hz); 13C NMR (75 MHz, CDCl3) δ 168.9, 138.3, 135.5
(2 peaks), 133.7, 133.6, 129.7, 127.7, 121.5, 67.9, 51.9, 32.9, 26.8,
23.6, 19.3, 18.7, 18.1, 14.2. HRMS (ESI): exact mass calcd for
C26H38NO2Si [M + H]+ 424.2672, found 424.2682.
(S)-Z-N-(5-((tert-Butyldiphenylsilyl)oxy)-4-methylpent-3-
en-2-yl)acetamide (Z)-9b.
(R)-E-N-(1-(Benzyloxy)-5-((tert-butyldiphenylsilyl)oxy)-4-
methylpent-3-en-2-yl)acetamide (E)-9d.
Product was obtained as a colorless oil (70%). 1H NMR (300 MHz,
CDCl3) δ 7.71À7.69 (4H, m), 7.46À7.41 (6H, m), 5.28À5.26 (1H, m),
5.12À5.09 (1H, m), 4.59À4.50 (1H, m), 4.30 (2H, dd, J = 12, 39 Hz),
1.88 (3H, s), 1.83 (3H, s), 1.08 (9H, s), 0.90 (3H, d, J = 7.5 Hz); 13C
NMR (75 MHz, CDCl3) δ 168.8, 135.6, 135.5, 134.8, 133.9, 129.6,
127.7, 63.2, 53.9, 43.6, 29.2, 26.8, 22.5, 21.8. HRMS (ESI): exact mass
calcd for C24H34NO2Si [M + H]+ 396.2359, found 396.2570.
Product was obtained as a colorless oil (78%). 1H NMR (300 MHz,
CDCl3) δ 7.73À7.70 (4H, m), 7.44À7.36 (11H, m), 5.82 (1H, d, J =
7.5 Hz), 5.69 (1H, dd, J = 3.0, 15 Hz), 5.05À4.92 (1H, m), 4.58 (2H,
d, J = 2.7 Hz), 4.11 (2H, s), 3.60 (1H, dd, J = 5.0, 7.5 Hz), 3.52 (1H,
dd, J = 5.0, 8.4 Hz), 2.00 (3H, s), 1.70 (3H, s), 1.12 (9H, s); 13C NMR
7454
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ARTICLE
(S)-Z-N-(6-((tert-Butyldiphenylsilyl)oxy)-2,5-dimethylhex-
4-en-3-yl)acetamide (Z)-9c.
Hz), 1.59 (2H, s), 1.47 (3H, d, J = 0.6 Hz), 1.08 (9H, s); 13C NMR
(75 MHz, CDCl3) δ 163.6, 160.0, 138.4, 138.0, 137.2, 136.5, 135.5 (2
peaks), 133.6, 133.5, 129.8, 129.7 (2 peaks), 126.9, 126.5, 122.3, 121.7, 67.5
(2 peaks), 61.3, 46.8, 43.4, 41.5, 26.8, 19.3, 13.8 (2 peaks). HRMS (ESI):
exact mass calcd for C29H36NO2Si [M + H]+ 458.2515, found 458.2577.
Synthesis of (S)-E-N-(5-((tert-Butyldiphenylsilyl)oxy)-4-
methyl-1-phenylpent-3-en-2-yl)-2,2,2-trifluoroacetamide (11a).
1
Product was obtained as a colorless oil (71%). H NMR (300 MHz,
CDCl3) δ 7.72À7.69 (4H, m), 7.48À7.38 (6H, m), 5.28 (1H, d, J =
8.7 Hz), 5.09 (1H, dd, J = 1.2, 9.4 Hz), 4.39À4.36 (1H, m), 4.34 (1H, s),
4.28 (1H, d, J = 12 Hz), 1.91 (3H, s), 1.86 (3H, d, J = 1.2 Hz), 1.79À1.69
(1H, m), 1.09(9H, s), 0.85(3H, d, J= 3.9 Hz), 0.83 (3H, d, J=3.9 Hz);13C
NMR (75 MHz, CDCl3) δ 168.8, 138.7, 135.7, 133.7 (2 peaks), 129.6,
127.7, 124.6, 62.8, 52.0, 32.7, 26.9, 23.5, 21.4, 19.4, 18.6, 18.3. HRMS (ESI):
exact mass calcd for C26H38NO2Si [M + H]+ 424.2672, found 424.2689.
(R)-Z-N-(1-(Benzyloxy)-5-((tert-butyldiphenylsilyl)oxy)-4-
methylpent-3-en-2-yl)acetamide (Z)-9d.
O-TBDPS-allylic amine 8a (0.2 g, 0.5 mmol) was dissolved in 2 mL of
CH2Cl2 and cooled to 0 °C. Trifluoroacetic anhydride (76 μL, 0.6 mmol)
was added dropwise to this solution followed by pyridine (61 μL, 0.8
mmol). The mixture was stirred for 2 h at 25 °C, and then additional
aliquots of trifluoroacetic anhydride (38 μL, 0.3 mmol) and pyridine (30
μL, 0.4 mmol) were added to this solution, which was stirred for an
additional 1 h. The solvent was removed in vacuo, and the residue was
purified by flash chromatography using 10% EtOAc/hexanes giving
acetamide 11a as a colorless oil (0.3 g, 96%). 1H NMR (300 MHz, CDCl3)
δ 7.70À7.65 (4H, m), 7.49À7.37 (6H, m), 7.34À7.18 (5H, m), 6.30 (1H,
d, J = 8.0 Hz), 5.56À5.52 (1H, m), 5.02À4.97 (1H, m), 4.05 (2H, s), 3.01
(1H, dd, J = 5.4, 13 Hz), 2.88 (1H, dd, J = 7.8, 13 Hz), 1.48 (3H, d, J = 1.2
Hz), 1.12 (9H, s); 13C NMR (75 MHz, CDCl3) δ 156.4, 155.9, 140.1,
136.4, 135.5 (2 peaks), 133.5, 133.4, 129.8, 129.7, 128.6, 128.1, 127.8, 126.8,
120.2, 117.8, 114.0, 67.4, 48.9, 41.0, 26.9, 19.3, 13.9. HRMS (ESI): exact
mass calcd for C30H34F3LiNO2Si [M + H]+ 532.2471, found 532.2474.
General Catalytic Hydrogenation Conditions. The corre-
sponding alkenes (0.1 mmol) and (S)-1 (2 mol %) were dissolved in
CH2Cl2 (0.5 M). The resulting mixture was degassed by three cycles of
freezeÀpumpÀthaw and then transferred to a Parr bomb. The bomb
was pressurized to 50 bar with hydrogen, and the mixture was stirred at
300 rpm for 16 h. The bomb was then vented, and solvent was
evaporated. The crude product was passed through a short silica plug
using 50% EtOAc/hexanes as the eluent. The diastereomeric ratio was then
measured by HPLC analysis using an unbonded silica 300 Å column.
N-((2R,4R)-5-((tert-Butyldiphenylsilyl)oxy)-4-methyl-1-
phenylpentan-2-yl)acetamide (syn-1a).
Product was obtained as a colorless oil (83%). 1H NMR (300 MHz,
CDCl3) δ 7.73À7.68 (4H, m), 7.47À7.30 (11H, m), 5.69 (1H, d, J = 6.9
Hz), 5.30 (1H, dd, J = 1.5, 9 Hz), 4.71À4.66 (1H, m), 4.48 (2H, d, J = 2.1
Hz), 4.39 (1H, dd, J = 0.9, 12 Hz), 4.24 (1H, d, J = 13 Hz), 3.48À3.35 (2H,
m), 1.89 (3H, s), 1.85(3H, s), 1.08 (9H, s); 13CNMR(75MHz, CDCl3) δ
169.0, 138.8, 138.0, 135.6, 133.6 (2 peaks), 129.7, 128.5, 127.8, 127.7, 123.8,
73.2, 72.4, 62.8, 46.9, 26.9, 23.4, 21.4, 19.3. HRMS (ESI): exact mass calcd
for C31H40NO3Si [M + H]+ 502.2777, found 502.2758.
(S)-Z-N-(1-(4-(Benzyloxy)phenyl)-5-((tert-butyldiphenylsilyl)-
oxy)-4-methylpent-3-en-2-yl)acetamide (Z)-9e.
Product was obtained as a colorless oil (75%). 1H NMR (300 MHz,
CDCl3) δ 7.70À7.67 (4H, m), 7.48À7.40 (11H, m), 7.12 (2H, d, J = 13
Hz), 6.92 (2H, d, J = 8.0 Hz), 5.47 (1H, d, J = 0.9 Hz), 5.39 (1H, d, J = 6.0
Hz), 5.07 (2H, s), 5.01À4.89 (1H, m), 4.05 (2H, s), 2.92 (1H, dd, J =
3.0, 12 Hz), 2.85 (1H, dd, J = 0.9, 9.0 Hz), 2.00 (3H, s), 1.49 (3H, s), 1.12
(9H, s); 13C NMR (75 MHz, CDCl3) δ 169.4, 157.6, 138.1, 135.2
(2 peaks), 134.2, 134.0, 131.4, 129.7, 128.4, 127.4, 126.9, 126.3, 114.2,
70.1, 62.3, 48.7, 40.6, 26.2, 23.3, 20.9, 19.2. HRMS (ESI): exact mass
calcd for C37H44NO3Si [M + H]+ 578.3090, found 578.3077.
1H NMR (300 MHz, CDCl3) δ 7.67À7.62 (4H, m), 7.46À7.35 (6H,
m), 7.33À7.17 (5H, m), 5.17 (1H, d, J = 9.0 Hz), 4.39À4.21 (1H, m),
3.52À3.40 (2H, m), 2.83À2.80 (2H, m), 1.89 (3H, s), 1.78À1.64 (1H,
m), 1.55 (1H, s), 1.30À1.21 (1H, s), 1.07 (9H, s), 0.89 (3H, d, J = 6.9
Hz); 13C NMR (75 MHz, CDCl3) δ 169.6, 137.8, 135.6, 135.5, 133.9,
133.7, 129.6, 128.3, 127.8, 126.4, 69.2, 47.8, 41.4, 37.4, 32.7, 26.9, 23.4,
19.3, 16.4. HRMS (ESI): exact mass calcd for C30H40NO2Si [M + H]+
474.2828, found 474.2832.
Synthesis of (S)-E-N-(5-((tert-Butyldiphenylsilyl)oxy)-4-
methyl-1-phenylpent-3-en-2-yl)formamide (10a).
Formic acid (0.2 g, 5 mmol) in CH2Cl2 (2.5 mL) was added dropwise
to a solution of DCC (0.5 g, 2.5 mmol) in 3 mL of CH2Cl2 at 0 °C. The
mixture was stirred for 5 min and then added to an ice bath cooled solution
of O-TBDPS-allylic amine 8a (0.4 g, 1 mmol) in 3 mL of pyridine. The
mixture was then stirred in ice bath for 4 h. The solid was removed via
filtration and washed with Et2O (10 mL). The combined extracts were
evaporated and purified by flash chromatography using 40% EtOAc/
N-(2S,4R)-5-((tert-Butyldiphenylsilyl)oxy)-4-methylpentan-
2-yl)acetamide (syn-1b).
1
hexanes giving formamide 10a as a colorless oil (0.4 g, 78%). H NMR
(300 MHz, CDCl3) δ 7.18À7.63 (4H, m), 7.48À7.31 (6H, m), 7.29À7.19
(5H, m), 5.45 (1H, dd, J = 1.2, 9.1 Hz), 5.31 (1H, d, J = 6.0 Hz), 5.10À5.00
(1H, m), 4.02(1H, s), 2.98(1H, dd, J= 5.4, 13 Hz), 2.82 (1H, dd, J=7.5, 13
1H NMR (300 MHz, CDCl3) δ 7.67À7.63 (4H, m), 7.43À7.36 (6H,
m), 5.12 (1H, d, J = 8.7 Hz), 4.13À3.97 (1H, m), 4.06À4.01 (1H, m),
1.88 (3H, s), 1.79À1.60 (1H, m), 1.62 (1H, s), 1.25À1.13 (2H, m), 1.11
7455
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ARTICLE
(3H, d, J = 3.3 Hz), 1.08 (9H, s), 0.91 (3H, d, J = 6.5 Hz); 13C NMR (75
MHz, CDCl3) δ 135.6, 134.8, 129.6 (2 peaks), 127.7 (2 peaks), 68.1,
28.5, 26.9, 26.6, 22.0, 19.3, 13.7. HRMS (ESI): exact mass calcd for
C24H36NO2Si [M + H]+ 398.2515, found 398.2552.
N-((3R,5R)-6-((tert-Butyldiphenylsilyl)oxy)-2,5-dimethyl-
hexan-3-yl)acetamide (syn-1c).
137.9, 137.8, 136.3, 135.6, 135.4, 135.3, 133.8, 133.7, 130.0 (2 peaks),
129.6, 129.5, 128.3 (2 peaks), 127.9, 127.8, 127.7, 127.6, 126.4, 126.3,
113.7, 68.2, 48.0 (2 peaks), 40.2, 41.0, 38.0, 37.1, 32.8, 26.9, 26.5, 23.5,
23.4, 19.3, 19.2, 17.2, 12.9. HRMS (ESI): exact mass calcd for
C30H40NO2Si [M + H]+ 474.2828, found 474.2833.
N-((2S,4S)-5-((tert-Butyldiphenylsilyl)oxy)-4-methylpentan-
2-yl)acetamide (anti-1b).
1H NMR (300 MHz, CDCl3) δ 7.71À7.63 (4H, m), 7.53À7.13 (6H,
m), 4.10À3.95 (1H, m), 3.49À3.44 (2H, m), 2.60À2.51 (1H, m), 2.35
(3H, s), 1.97À1.62 (1H, m), 1.53 (3H, d, J = 6.0 Hz), 1.21 (3H, d, J = 9.0
Hz), 1.08 (9H, s), 0.97À0.79 (2H, m); 13C NMR (75 MHz, CDCl3) δ
135.6, 134.8, 129.7, 129.0, 128.2, 124.6, 95.4, 29.7, 26.8, 17.8. HRMS
(ESI): exact mass calcd for C24H36NO2Si [M + H]+ 398.2515 Found
398.2571.
1H NMR (300 MHz, CDCl3) δ 7.67À7.63 (4H, m), 7.41À7.38 (6H,
m), 5.00 (1H, d, J = 9.9 Hz), 3.91À3.88 (1H, m), 3.53À3.39 (2H, m),
1.91 (3H, s), 1.78À1.55 (1H, m), 1.56 (1H, s), 1.52À1.45 (1H, m),
1.19À1.10 (1H, m), 1.06 (9H, s), 0.91À0.84 (9H, m); 13C NMR (75
MHz, CDCl3) δ 135.6 (2 peaks), 129.6, 127.6 (2 peaks), 69.8, 51.9, 37.4,
33.1, 33.0, 26.9, 23.7, 19.8, 19.3, 19.1, 16.2. HRMS (ESI): exact mass
calcd for C26H40NO2Si [M + H]+ 426.2828, found 426.2851.
N-((2R,4R)-1-(Benzyloxy)-5-((tert-butyldiphenylsilyl)oxy)-
4-methylpentan-2-yl)acetamide (syn-1d).
N-((3R,5S)-6-((tert-Butyldiphenylsilyl)oxy)-2,5-dimethyl-
hexan-3-yl)acetamide (anti-1c).
1H NMR (300 MHz, CDCl3) δ 7.72À7.69 (4H, m), 7.48À7.38 (6H,
m), 4.92 (1H, d, J = 9.0 Hz), 3.98À3.91 (2H, m), 3.62À3.49 (2H, m),
1.96 (3H, s), 1.80À1.53 (2H, m), 1.40À1.20 (1H, m), 1.09 (9H, s),
0.96À0.81 (9H, m);13C NMR (75 MHz, CDCl3) δ 135.6, 133.8, 133.6,
132.3, 129.9, 127.8, 122.0, 67.9, 51.7, 35.2, 32.1, 26.3, 24.5, 21.8, 20.7,
19.8, 18.0. HRMS (ESI): exact mass calcd for C26H40NO2Si [M + H]+
426.2828, found 426.2842.
1H NMR (300 MHz, CDCl3) δ 7.67À7.63 (4H, m), 7.40À7.32
(11H, m), 5.47 (1H, d, J = 9.0 Hz), 4.50 (2H, dd, J = 12, 17 Hz),
4.24À4.12 (1H, m), 3.50À3.43 (4H, m), 1.89 (3H, s), 1.80À1.76 (1H,
m), 1.73À1.59 (1H, m), 1.27À1.20 (1H, m), 1.16 (9H, s), 0.93 (3H, d,
J = 6.6 Hz); 13C NMR (75 MHz, CDCl3) δ 135.6, 129.6, 128.4, 127.6
(2 peaks), 73.5, 72.8, 69.9, 47.0, 36.1, 33.2, 27.0, 23.8, 19.2, 18.0. HRMS
(ESI): exact mass calcd for C31H42NO3Si [M + H]+ 504.2934, found
504.2952.
N-((2R,4S)-1-(Benzyloxy)-5-((tert-butyldiphenylsilyl)oxy)-
4-methylpentan-2-yl)acetamide (anti-1d).
N-((2R,4R)-1-(4-(Benzyloxy)phenyl)-5-((tert-butyldiphenyl-
silyl)oxy)-4-methylpentan-2-yl)acetamide (syn-1e).
1H NMR (300 MHz, CDCl3) δ 7.76À7.63 (4H, m), 7.47À7.30
(11H, m), 5.73 (1H, d, J = 8.1 Hz), 4.52 (2H, s), 4.17À4.14 (1H, m),
3.60À3.44 (4H, m), 1.94 (3H, s), 1.89À1.55 (2H, m), 1.37À1.32 (1H,
m), 1.08 (9H, s), 0.97 (3H, d, J = 6.9 Hz); 13C NMR (75 MHz, CDCl3)
δ 158.7, 137.2, 135.1, 134.5, 132.7, 128.5, 127.7, 127.3, 71.3, 68.1, 42.7,
34.7, 32.8, 26.0, 22.5, 19.8, 17.2. HRMS (ESI): exact mass calcd for
C31H42NO3Si [M + H]+ 504.2934, found 504.2971.
1H NMR (300 MHz, CDCl3) δ 7.67À7.62 (4H, m), 7.45À7.37
(11H, m), 7.09 (2H, d, J = 8.4 Hz), 6.94 (2H, d, J = 8.4 Hz), 5.07 (2H, s),
4.32À4.19 (1H, m), 3.53À3.40 (2H, m), 2.76 (1H, s), 2.74 (1H, d, J =
2.1 Hz), 1.89 (3H, s), 1.78À1.60 (1H, m), 1.62 (1H, s), 1.59À1.46
(1H, m), 1.30À1.19 (1H, m), 1.06 (9H, s), 0.89 (3H, d, J = 6.6 Hz); 13C
NMR (75 MHz, CDCl3) δ 169.6, 157.5, 137.1, 135.6 (2 peaks), 130.6,
130.2, 129.7, 128.6, 128.0, 127.7, 127.5, 114.7, 70.0, 69.2, 47.9, 40.0, 37.4,
32.7, 26.9, 23.5, 19.3, 16.5. HRMS (ESI): exact mass calcd for
C37H46NO3Si [M + H]+ 580.3247, found 580.3253.
N-((2R,4S)-1-(4-(Benzyloxy)phenyl)-5-((tert-butyldiphenyl-
silyl)oxy)-4-methylpentan-2-yl)acetamide (anti-1e).
N-((2R,4S)-5-((tert-Butyldiphenylsilyl)oxy)-4-methyl-1-phenyl-
pentan-2-yl)acetamide (anti-1a).
1H NMR (300 MHz, CDCl3) δ 7.78À7.66 (4H, m), 7.65À7.36
(11H, m), 7.08 (2H, dd, J = 9.0 Hz), 6.91 (2H, d, J = 8.7 Hz), 5.05 (2H,
s), 4.25À4.18 (1H, m), 3.58À3.45 (1H, m), 2.78À2.72 (2H, m), 2.28
(2H, br), 1.89 (3H, s), 1.68À1.59 (1H, br), 1.11 (9H, s), 1.10 (2H, s),
0.95 (3H, d, J = 6.6 Hz); 13C NMR (75 MHz, CDCl3) δ 169.3, 137.1,
135.6, 135.3, 135.2, 134.8, 133.7, 130.0, 129.7, 128.6, 127.9, 127.8, 127.5,
121.1, 116.5, 114.7, 68.2, 53.5, 48.1, 39.2, 37.0, 32.8, 26.6, 23.5, 19.4,
17.2. HRMS (ESI): exact mass calcd for C37H46NO3Si [M + H]+
580.3247, found 580.3272.
1H NMR (300 MHz, CDCl3) δ 7.72À7.65 (4H, m), 7.48À7.38 (6H,
m), 7.33À7.11 (5H, m), 5.40 (1H, d, J = 8.7 Hz), 4.38À4.22 (1H, m),
3.59 (1H, dd, J = 5.4, 10 Hz), 3.49 (1H, dd, J = 5.6, 10 Hz), 2.85À2.75
(2H, m), 1.90 (3H, s), 1.88À1.70 (2H, m), 1.29À1.24 (1H, m), 1.08
(9H, s), 0.96 (3H, d, J = 6.6 Hz); 13C NMR (75 MHz, CDCl3) δ 169.3,
7456
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ARTICLE
(26) Cui, X.; Burgess, K. Chem. Rev. 2005, 105, 3272–3296.
’ ASSOCIATED CONTENT
(27) Roseblade, S. J.; Pfaltz, A. Acc. Chem. Res. 2007, 40, 1402–1411.
(28) Perry, M. C.; Cui, X.; Powell, M. T.; Hou, D.-R.; Reibenspies,
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(29) Powell, M. T.; Hou, D.-R.; Perry, M. C.; Cui, X.; Burgess, K.
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(30) Fehrentz, J. A.; Castro, B. Synthesis 1983, 676–678.
(31) Levin, J. L.; Turos, E.; Weinreb, S. M. Synth. Commun. 1982,
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Supporting Information. 1H and 13C NMR spectra for
S
b
compounds 2 and 5À11 and discussion of assignments of
absolute configuration of compounds 1. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
(32) Zhu, Y.; Burgess, K. J. Am. Chem. Soc. 2008, 130, 8894–8895.
(33) Zhao, J.; Burgess, K. J. Am. Chem. Soc. 2009, 131, 13236–13237.
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(35) Zhou, J.; Ogle, J. W.; Fan, Y.; Banphavichit, V.; Zhu, Y.; Burgess,
K. Chem.—Eur. J. 2007, 13, 7162–7170.
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Chem., Int. Ed. 1996, 35, 220–222.
Corresponding Author
*E-mail: burgess@tamu.edu.
’ ACKNOWLEDGMENT
We thank The National Science Foundation (CHE-0750193)
and The Robert A. Welch Foundation (A-1121) for financial
support for this work.
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