Catalytic, asymmetric, and stereodivergent synthesis of non-symmetric β,β-Diaryl-α-Amino Acids

Article abstract of DOI:10.1021/ja511872a

We report a concise, enantio- and diastereoselective route to novel nonsymmetrically substituted N-protected β,β-diaryl-α-amino acids and esters, through the asymmetric hydrogenation of tetrasubstituted olefins, some of the most challenging examples in the field. Stereoselective generation of an E- or Z-enol tosylate, when combined with stereoretentive Suzuki-Miyaura cross-coupling and enantioselective hydrogenation catalyzed by (NBD)₂RhBF₄ and a Josiphos ligand, allows for full control over the two vicinal stereogenic centers. High yields and excellent enantioselectivities (up to 99% ee) were obtained for a variety of N-acetyl, N-methoxycarbonyl, and N-Boc β,β-diaryldehydroamino acids, containing a diverse and previously unreported series of heterocyclic and aryl substituted groups (24 examples) and allowing access to all four stereoisomers of these valuable building blocks.

Full text of DOI:10.1021/ja511872a

Article
pubs.acs.org/JACS
Catalytic, Asymmetric, and Stereodivergent Synthesis of
Non-Symmetric β,β-Diaryl-α-Amino Acids
Carmela Molinaro,*,† Jeremy P. Scott,*,‡ Michael Shevlin,*,† Christopher Wise,‡ Alain Menard,§
́
Andrew Gibb,‡ Ellyn M. Junker,‡ and David Lieberman‡
†Department of Process Chemistry, Merck & Co. Inc., Rahway, New Jersey 07065, United States
‡Department of Process Chemistry, Merck Sharp and Dohme Ltd., Hertford Road, Hoddesdon EN11 9BU, United Kingdom
S
* Supporting Information
ABSTRACT: We report a concise, enantio- and diastereose-
lective route to novel nonsymmetrically substituted N-protected
β,β-diaryl-α-amino acids and esters, through the asymmetric
hydrogenation of tetrasubstituted olefins, some of the most
challenging examples in the field. Stereoselective generation of
an E- or Z-enol tosylate, when combined with stereoretentive
Suzuki-Miyaura cross-coupling and enantioselective hydroge-
nation catalyzed by (NBD)2RhBF4 and a Josiphos ligand, allows
for full control over the two vicinal stereogenic centers. High
yields and excellent enantioselectivities (up to 99% ee) were
obtained for a variety of N-acetyl, N-methoxycarbonyl, and
N-Boc β,β-diaryldehydroamino acids, containing a diverse and
previously unreported series of heterocyclic and aryl substituted groups (24 examples) and allowing access to all four stereo-
isomers of these valuable building blocks.
Scheme 1. Synthesis of N-Acetyl and N-Methoxycarbonyl
Dehydroamino Acids via Vinyl Bromides
INTRODUCTION
■
a
The β,β-diarylalanine structural motif is an important pharma-
cophore in molecular agents that target many diseases, including
atherosclerosis,1 cancer,2 diabetes insipidus,3 diabetes mellitus
type 2,4 HIV,5 and thrombosis6 (Figure 1). Additionally, this
a
Conditions: (a) 1.05 equiv SOCl2, 2.1 equiv Et3N, 10 equiv MeOH,
DCM, 0 °C; (b) 1.1 equiv NBS, 1.1 equiv Et3N, DCM, 88%; (c) Chroma-
tographic separation; and (d) 15 mol % Pd(OAc)2, 15 mol % DavePhos,
1.3 equiv ArB(OH)2, 2.5 equiv K3PO4H2O, THF/H2O, 70 °C.
tandem Aza-Darzens/ring opening reactions in the presence of a
chiral reagent.14 Recently, palladium-catalyzed CH function-
alizations of alanine derivatives have been reported under
the direction of auxiliary15 or ligand control.16 Despite all these
efforts, the requirement for exotic protecting groups, directing
groups or ligands, stoichiometric silver, high palladium catalyst
loadings, expensive chirality sources or narrow substrate scope
limits their practicality.
During the course of our research to support discovery and
clinical evaluation of a candidate molecule, we required rapid,
modular access to enantioenriched, differentially substituted
β,β-diarylalanine derivatives. We envisioned that the synthesis
of differentially substituted dehydro-β,β-diarylalanine derivatives
Figure 1. Representative β,β-diarylalanine derivatives.
structural class appears in synthetic intermediates in natural
product synthesis.7 Due to this broad utility, β,β-diarylalanine
derivatives have attracted considerable interest and a number
of approaches for synthesizing derivatives with two identical
β-aryl substituents have been reported.8 The synthesis of β,β-
diarylalanines, where both β-aryl substituents are nonidentical
represents a considerable synthetic challenge due to the for-
mation of a second, vicinal stereogenic center. These compounds
have been synthesized by diastereoselective SN1 reactions on
phenylalanine derivatives,9 opening of aziridines,10 alkylations
employing a chiral auxiliary,11 alkylation of glycine derivatives12
and nitroacrylates13 in the presence of a chiral catalyst, and
Received: November 25, 2014
© XXXX American Chemical Society
A
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Table 1. Suzuki-Miyaura Cross-Coupling Results with E- and Z-Vinyl Bromides
a
b
c
Conditions. 15 mol % Pd(OAc)2, 15 mol % DavePhos, 1.3 equiv ArB(OH)2, 2.5 equiv K3PO4−H2O, THF/H2O, 70 °C. Isolated yield. Isomer
d
e
f
g
Z-1 was used. Isomer E-1 was used. 15 mol % dppf used. E/Z mixture of 1 was used. 84% of a 1:3 E/Z mixture of isomers was obtained and then
separated. 64% of a 3:2 E/Z mixture of isomers was obtained and then separated.
h
a
Scheme 2. Retrosynthetic Analysis
Scheme 3. One-Pot Telescoped β-Ketoester Synthesis
followed by asymmetric hydrogenation17,18 could provide rapid
access to any stereoisomer of a given β,β-diarylalanine derivatives
in high optical purity. Surprisingly, the asymmetric hydro-
genation of such nonsymmetrically tetrasubstituted olefins has
not been previously reported.19 Herein, we report our results
in (1) identifying a catalyst system that can enantioselectively
reduce such highly congested systems without loss of olefin
geometric integrity; and (2) stereoselectively configuring the
E- or Z-double bond geometry of the hydrogenation substrates
from a common synthetic precursor.
a
Conditions: (a) Et3N, ArCOCl, 2-MeTHF, <10 °C; Boc2O, DMAP,
2-MeTHF, 20 °C; (b) t-BuOK, 2-MeTHF, <10 °C; and (c) LHMDS,
DMPU, 2-MeTHF, −78 °C. Yields are of isolated products 7 obtained
via direct crystallization.
propenoic acid 4a or 4b (Scheme 1). Esterification under
standard conditions and treatment with NBS with triethylamine
gave the corresponding β-bromo-β-substituted dehydroamino
esters 1 in 88% combined yield as a 1.5:1 mixture of E- and
Z-isomers.20 The isomers were separable by flash chromatog-
raphy and could be individually coupled under Suzuki-Miyaura
conditions with commercially available arylboronic acids. A cata-
lyst complex of Pd(OAc)2 and DavePhos21,22 provided alkenes 2
in yields ranging from 45 to 89% (Table 1). Alternatively, in
some instances, the E/Z mixture of 1 could be directly coupled
RESULTS AND DISCUSSION
■
Preparation of N-Acetyl and N-Methoxycarbonyl
Protected Dehydroamino Acids. Our study began with
targeting nonsymmetric N-acetyl and N-methylcarbamate
protected β,β-diarylamino acids. Initially, dehydroamino acids 2
were prepared in 3 steps from commercially available substituted
B
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Table 2. Stereocontrolled Z- and E-Enol Tosylate Synthesis
a
b
c
d
e
Conditions. LDA, Ts2O, THF, −50 °C. Et3N, Ts2O, CH3CN, 25 °C. LHMDS, Ts2O, THF, −50 °C. iPr2NEt, Ts2O, CH3CN, 25 °C. E/Z ratios
f
determined by HPLC of unpurified reaction mixtures. Yields are of isolated products obtained via direct crystallization.
Table 3. Suzuki-Miyaura Cross-Coupling Results with E- and Z-Tosylates
a
b
Conditions. 1.01 equiv ArB(OH)2, Pd(OAc)2 (0.5 mol %), dppb (1.1 mol %), 1.0 equiv K3PO4, 2-MeTHF, H2O, 70 °C. Yields are of isolated
c
d
products obtained via crystallization. Isomer E-6 was used. Isomer Z-6 was used.
and the product isomers separated subsequently by flash chro-
matography.23 Although this approach allowed for an expedient
preparation of a variety of dehydroamino acids 2a−2o containing
heterocyclic and substituted aryl groups primed for asymmetric
reduction, it suffered in the ability to control the E/Z geometry of
the tetrasubstituted alkene. We sought to address this limitation
and thereby increase the overall synthetic efficiency. Moreover, a
more readily removable nitrogen protecting group was highly
desirable to increase the utility of the resulting β,β-diarylamino
acid ester synthons.
C
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Preparation of N-Boc Protected Dehydroamino Acids.
In our revised analysis, we focused on the preparation of racemic
α-N-Boc-amino-β-ketoesters 7, which we expected to be readily
available by rearrangement of simple N-acylated-N-Boc glycine
methyl ester derivatives 8 (Scheme 2). In the forward sense,
sterecontrolled generation of either the Z-enol tosylate or the E-
isomer from 7, followed by stereoretentive Suzuki-Miyaura
cross-coupling with commercially available aryl boronic acids
would afford either tetrasubstituted double bond isomer. Early
on, we recognized that even if enolization (E vs Z) of 7 were
limited to accessing just one of the two possible enol tosylates
selectively, reversing the order in which the aryl groups were
introduced would still potentially allow for optional selection of
the β-amino acid stereogenic center.
We began with the preparation of the β-ketoesters 7a−c from
commercially available glycine methyl ester 9 (Scheme 3). A
telescoped through process for N-benzoylation, N-Boc protec-
tion, followed by base mediated aza-Chan N → C rearrangement
was developed and thereby avoided the need to isolate the inter-
mediates 8.24 Yields were good for the acid chlorides evaluated
(75−81%) and the products 7a−c were all crystalline solids.
The rearrangement of the electron rich intermediate 8c (Ar =
4-methoxyphenyl) was unsatisfactory using tBuOK and LHMDS
was the preferred base in this instance.
Next we evaluated our ability to control the enolization
selectivity of α-N-Boc-amino-β-ketoesters 7a−c. We focused on
the preparation of their enol tosylate derivatives due to the
documented use in Suzuki-Miyaura cross-couplings25 and an
expectation of advantageous chemical stability and crystallinity.
Following screening of conditions using substrate 7a, two com-
plementary reaction protocols emerged. Specifically, a tertiary
amine base (Et3N or iPr2NEt) with Ts2O in CH3CN was found
to be Z-selective (≥6:1) while the use of LDA or LHMDS
with Ts2O in THF favored the E-isomer preferentially (≥24:1)
(Table 2). Application of these conditions to 7a−c afforded
E- and Z-enol tosylates 6a−c and 6d−f in 50−86% isolated yield
by direct crystallization and with >99% geometric purity.26,27
With the enol tosylates in hand, attention turned to their Suzuki-
Miyaura coupling reactions with a variety of commercially
available arylboronic acids.
Table 4. Ligand Screen for the Enantioselective Rh-Catalyzed
Hydrogenation of Substrate 2l
a
b
c
d
d
entry
loading
ligand
conversion
%ee
1
2
20
20
20
20
20
20
20
20
20
20
20
20
10
5
T021−2
T025−2
W022−1
W016−1
W023−1
W017−1
J212−1
J012−1
J002−1
J014−1
J210−1
J011−1
J011−1
J011−1
J011−1
J011−1
81
96
85
93
e
3
97
92
e
e
e
4
96
92
95
96
5
100
95
6
7
100
100
97
80
88
93
94
96
97
97
97
96
93
8
9
10
11
12
99
100
98
f
13
100
100
95
f
14
f
15
2
f
16
1
69
a
Conditions: (NBD)2RhBF4, MeOH, 0.02M, 500 psi H2, 40 °C.
b
c
Mol% Rh. A ratio of 1.05:1 Ligand/Rh was used. See Figure 2 for
d
ligand structures. As determined by chiral SFC at 210 nm. Boc
deprotection of the aza-indole was observed during the screen. The
conversion were determined by fully deprotecting the products at the
end of the reaction. Absolute configuration (2S, 3S) unless otherwise
e
f
stated. (2R, 3R). 0.1 M concentration was used.
Early studies of the coupling of Z-tosylate 6d with
4-chlorophenylboronic acid indicated geometrical leakage was
a major issue such that a mixture (up to 80% of the isomer!) of
the two possible tetrasubstituted double bond isomeric products
could result. Subsequent hydrogenation would afford an un-
desirable mixture at the β-stereogenic center. Screening of phos-
phine ligand, Pd precatalyst, base and solvent in tandem with
DoE optimization identified the use of Pd(OAc)2 (0.5 mol %),
1,4-bis(diphenylphosphino) butane (dppb) (1.1 mol %) and
K3PO4 (100 mol %) in 2-MeTHF (10 vol) and water (5 vol) as
suppressing this undesired scrambling.28,29 Under these preferred
conditions, scrambling was limited to just 7% and crystalline
product 2v could be directly isolated from iPrOH and water in 79%
yield with >99:1 E/Z purity. A variety of further dehydroamino
acids 2w−2aa were then accessed in good to excellent yields using
these conditions (65−95%) (Table 3, entries 7−12).
In all of the other Z-tosylate couplings, 6% or less of the
undesired olefin isomer was formed and the desired products can
be upgraded by direct crystallization. While a full understanding
of the mechanism for loss of geometric fidelity has not been
delineated at this time, some observations are possible. Control
reactions with dppb, K3PO4 and 4-ClC6H4B(OH)2 present
but in the absence of Pd(OAc)2 indicate no isomerization or
Figure 2. Ligands used in hydrogenation screening.
decomposition of 6d after 3 h at 70 °C. In addition, the Z/E ratio
of Suzuki-Miyaura product mixtures were stable to prolonged
aging. Thus, Pd appears to be required for scrambling and iso-
merization is not a simple result of base promoted conjugate
addition and elimination to the acrylate starting materials
or products. In contrast to the Z-tosylates, no double bond
scrambling was observed in the Suzuki-Miyaura coupling of the
E-tosylate counterparts 6a−c using the previously optimized
conditions and the coupling reactions were faster. Access to a
range of dehydroamino acids 2p−2u was possible with good to
excellent isolated yields (56−98%) (Table 3, entries 1−6).
Asymmetric Hydrogenation. With dehydroamino acids in
hand, we began our investigation of the asymmetric hydro-
genation using N-acetyl protected alkene 2l as a model substrate.
While ruthenium and iridium catalysts gave poor reactivity,
rhodium catalysts gave good reactivity and selectivity using
D
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Table 5. Enantioselective Hydrogenation of N-Ac, N-CO2Me, and N-Boc Protected β,β-Diaryl Dehydroamino Acids
a
b
Conditions: 5 mol % (NBD)2RhBF4, 5.25 mol % J011−1, 400 psi H2, MeOH, 0.1 M, 25 °C. Conditions: 10 mol % (NBD)2RhBF4, 10.5 mol %
J212−1, 120 psi H2, iPrOH, 0.5M, 80 °C, 22 h. Enantioselectivities were determined by chiral stationary phase HPLC of unpurified reaction mixtures.
c
d
Yields are of isolated products obtained via chromatography or crystallization and are unoptimized. J212−2 used instead of J212−1. 1.2 equiv HBF4·
e
OEt2 was added. 100% conversion to a mixture of 3j and partial Boc deprotection of the aza-indole was observed (∼1:1.5). Only yield of 3j is
f
reported. 100% conversion to a mixture of 3l and partial Boc protected aza-indole was observed. The mixture was fully deprotected and yield of 3l is
g
reported. 100% conversion to a mixture of 3m and partial Boc deprotection of the aza-indole was observed. Only yield of 3m is reported.
(NBD)2RhBF4 as the precatalyst in MeOH under 500 psi H2 at
40 °C (Table 4).30 Over 150 ligands were tested and the ligands
giving good conversion to product with excellent selectivity
were C1-symmetric planar chiral ferrocenes (Figure 2). Aryl-
substituted hydroxy-Taniaphos31 and aryl, norbornyl-substituted
Walphos ligands32 gave selectivities up to 96% ee (Table 4,
entries 1−6). However, since these ligands have limited com-
mercial availability, we turned to the related and more available
Josiphos ligand family. Gratifyingly, aryl, tert-butyl substituted
Josiphos ligands33 gave high levels of activity and selectivity
(Table 4, entries 7−12), with 4-trifluoromethylphenyl Josiphos
ligand J011−1 giving 97% ee (Table 4, entry 12). It is interesting
to note that while the Walphos and Josiphos ligands have the
same sense of chirality and similarly bulky alkyl substitution, the
phenyl spacer in the Walphos ligands results in an inversion of
enantioselectivity compared to Josiphos (Table 4, entries 3−6).
An examination of catalyst loading with the ligand J011−1
revealed that 5 mol % gave complete conversion and high
selectivity, while further reductions of catalyst loading led to
reduced activity and enantioselectivity (Table 4, entries 13−16).
With optimized conditions in hand, a variety of N-acetyl and
N-methoxycarbonyl β,β-diaryl dehydroamino acids 2a−2o were
hydrogenated (Table 5). All the substrates tested afforded
excellent enantioselectivities (88−97%) independent of whether
the substituents on the phenyl ring were electron donating or
electron withdrawing (Table 5, entries 1−8).34 The hydro-
genation worked equally well with E- or Z-alkenes (Table 5,
entry 10 vs 13) and gratifyingly, in addition to substituted phenyl
E
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rings, benzofurans, azaindoles and pyridines were also tolerated
affording high enantioselectivities (Table 5, entries 9, 10,
12−15). Furthermore, methoxycarbonyl-protected substrates
also gave good results (Table 5, entries 14−15). In all cases, no
diastereomeric products were observed, indicating that there was
no isomerization of the olefin during the hydrogenation.35
We next turned our attention to N-Boc protected dehydro-
amino acid substrates 2p−2aa. We expected that asymmetric
hydrogenation of these substrates would be exceptionally
challenging due to the increase steric bulk around the olefin
and the reduced propensity of Boc vs acetyl to associate with the
metal catalyst; indeed, subjecting substrate 2v to the standard
conditions optimized for the N-acetyl protected substrates
provided no conversion to product.36 Moreover, attempts to
prepare racemic product using Pd/C (120 psi H2, 35 °C, MeOH)
led only to competitive dechlorination of the chlorophenyl ring
with the double bond untouched. Molecular modeling of N-Boc
β-phenyl- and β,β-diphenylalanine methyl esters illustrate the
steric congestion afforded by tetrasubstitution such that the
phenyl groups are twisted out of conjugation and effectively
shield both faces of the double bond (Figure 3).37
Table 6. Optimization of the Enantioselective Rh-Catalyzed
Hydrogenation of Substrate 2v
a
b
c
d
d
entry
cond
%Rh
ligand
solvent
conv
%ee
1
2
A
A
A
B
B
B
B
B
C
C
C
D
D
25
25
25
10
10
10
10
10
10
5
J011−1
J013−1
J212−1
J212−2
J212−2
J212−2
J212−2
J212−2
J212−2
J212−2
J212−2
J212−2
J212−2
MeOH
MeOH
MeOH
MeOH
EtOH
iPrOH
DCE
20
42
85
7
97
97
3
92
e
4
97
e
e
e
e
e
e
e
e
e
5
67
91
97
90
100
100
69
99
98
98
97
96
97
95
95
96
95
95
6
7
8
PhCl
9
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
10
11
12
13
2
2
1
a
Conditions: (NBD)2RhBF4, MeOH. A: 0.016M, 500 psi H2, 50 °C. B:
0.1M, 500 psi H2, 50 °C. C: 0.5M, 500 psi H2, 50 °C. D: 0.5M, 120 psi
b
c
H2, 80 °C. Mol% Rh. A ratio of 1.05:1 Ligand/Rh was used. See
Figure 1 for ligand structures. J212−2 is the enantiopode of J212−1.
d
As determined by chiral HPLC at 210 nm. Absolute configuration
(2S, 3S) unless otherwise stated. (2R, 3R).
e
stereoisomers for a given β,β-diaryl-α-amino acid is illustrated by
the preparation of the 3,5-difluorophenyl-4-methoxyphenyl
analogues (2S, 3S)-3q, (2R, 3R)-3q ≡ ent-3q and (2S, 3R)-3z
(entries 22, 23 and 24). Preparation of the diastereomeric
products (2S, 3R)-3p and (2S, 3S)-3v illustrate tolerance of a
chlorine substituent with no evidence of competitive dechlori-
nation under these more aggressive hydrogenation conditions
(Table 5, entries 16 and 19). The absolute and relative stereo-
chemistry was confirmed by the single crystal X-ray structure
determination of 3v (Figure 4).39
Figure 3. Ground state conformations of N-Boc β-phenylalanine and
β,β-diphenylalanine methyl esters.
We returned to screening using (NBD)2RhBF4 as precatalyst
and a variety of commercially available chiral phosphine
ligands (Table 6, entries 1−3). Under these high catalyst loading
conditions, previously identified ligand J011−1 gave high
enantioselectivity but poor conversion (Table 6, entry 1). Ligand
J013−1 and J212−1 gave good enantioselectivity and increased
levels of reactivity (Table 6, entries 2−3). An examination of
solvent effects with J212−1 showed a dramatic increase in reacti-
vity as the solvent was changed from MeOH to EtOH to iPrOH
(Table 6, entries 4−6); halogenated solvents DCE and PhCl also
provided good results, but we selected iPrOH as the solvent of
choice since it is more environmentally friendly.38
We were able to optimize the catalyst loading as low as 1 mol %
by raising the reaction temperature from 50 to 80 °C. The higher
temperature also allowed the reaction pressure to be lowered to a
more practical 120 psi (Table 6, entries 9−13).
With revised conditions for N-Boc substrates defined, the
substrate scope was evaluated. Gratifyingly, high enantioselectiv-
ities (92−99% ee) and conversion (>99%) were realized with
good to excellent isolated yields (59−88%) obtained by direct
crystallization for all the dehydroamino acid reductions examined
(Table 5, entries 16−24). While we adopted 10 mol % of Rh and
J212 ligand to evaluate the substrate scope, successful multigram
scale reduction has been carried out at catalyst loadings as low
as just 1.0 mol %. The ability to optionally access all possible
Figure 4. X-ray structure ORTEP plot of 3v (thermal ellipsoids drawn at
the 30% level).
The nonsymmetrically substituted N-protected β,β-diaryl-α-
aminoesters reported in this paper are synthetically valuable
chiral building blocks. In order to facilitate their subsequent
coupling, we evaluated selectively hydrolyzing the esters reveal-
ing the corresponding acid. Initially, ester hydrolysis of 3v to
F
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afford the corresponding N-Boc amino acid 9v at first proved
challenging with up 27% epimerization of the amino acid center
when employing NaOH in aqueous THF (Scheme 4). DoE
Vazquez, Stephen Keen, Michael Boyd, and Ernest Lee for
technical assistance (Merck).
REFERENCES
■
a
Scheme 4. Hydrolysis of N-Boc Amino Acid Ester 3v
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a
Conditions: 3.0 equiv KOH, H2O/iPrOH, 50 °C then HCl.
optimization of temperature, concentration, and equivalents
using KOH in aqueous THF, followed by a further screen of
polar solvents, identified aqueous i-PrOH at 50 °C as preferred.
Application of these conditions to 3v afforded 9v as a crystalline
solid in 79% yield with <1% epimer (Scheme 4).40
CONCLUSIONS
■
We have demonstrated the first synthesis of nonsymmetrically
substituted β,β-diaryl α-amino acid esters through the asym-
metric hydrogenation of highly congested tetrasubstituted
olefins. The reaction conditions using (NBD)2RhBF4 and
Josiphos ligands, allowed for outstanding control over the two
vicinal stereogenic centers providing excellent enantioselectiv-
ities (88−99%) over a series of aryl and heteroaryl substituted
substrates with Ac, methoxycarbonyl and less reactive Boc pro-
tected amines. Furthermore, preparation of either the E- or the
Z- olefins was possible by the development of conditions to
suppress scrambling during the enol tosylate Suzuki-Miyaura
cross-coupling. This approach allowed for stereodivergent access
to all four possible stereochemical isomers and is ideally placed to
support drug discovery structure−activity relationship studies.
Finally, a controlled hydrolysis of the methyl ester significantly
enhances the practicality of the approach and the ability to
leverage these valuable synthons in amino acid coupling
chemistry.
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AUTHOR INFORMATION
■
Corresponding Authors
carmela_molinaro@merck.com
jeremy.scott@merck.com
michael_shevlin@merck.com
Notes
§The research described was partially carried out in 2010 at the
former Merck Frosst Canada, Department of Process Research,
́
Merck, 16711 Autoroute Transcanadienne, Kirkland, Quebec,
Canada, H9H 3L1.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors would like to acknowledge Dan Sorensen, Andrew
Kirtley, Robert Reamer, Simon Hamilton, Andy Brunskill, and
Tanja Brkovic for analytical support (Merck). The authors also
acknowledge Scott Shultz, Jess Eastwood, Alejandro Dieguez-
(9) Wilcke, D.; Herdtweck, E.; Bach, T. Chem. Asian. J. 2012, 7, 1372−
1382.
G
DOI: 10.1021/ja511872a
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(37) Geometry optimizations were performed using Spartan’10,
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density functional with 6-31G* basis sets.
(38) The increased reactivity observed in the series of solvents MeOH,
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hydrogen in the higher alcohols. Indeed, hydrogen is less soluble in
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yields were observed.
(23) Confirmation of the stereochemistry of the N-acetyldehydroa-
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corresponding amino acid hydrochloride salt.
mino acids 2 was made by NOE experiments.
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H
DOI: 10.1021/ja511872a
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