Acyclic stereoselective boron alkylation reactions for the asymmetric synthesis of β-substituted α-amino acid derivatives

Article abstract of DOI:10.1021/ja0298794

Optically active syn- or anti-β-substituted-α-amino acid derivatives are prepared in 94 to ≥99% ee and 66-98% ds by reaction of the Schiff base acetate of glycine tert-butyl ester with chiral, nonracemic B-alkyl-9-BBN derivatives in the presence of the Cinchona alkaloid, cinchonidine (CdOH) or cinchonine (CnOH), base, and lithium chloride. Copyright

Full text of DOI:10.1021/ja0298794

Published on Web 02/08/2003
Acyclic Stereoselective Boron Alkylation Reactions for the Asymmetric
Synthesis of â-Substituted r-Amino Acid Derivatives
Martin J. O’Donnell,* Jeremy T. Cooper, and Mary M. Mader
Department of Chemistry, Indiana UniVersity Purdue UniVersity Indianapolis, Indianapolis, Indiana 46202, and
Lilly Research Laboratories, A DiVision of Eli Lilly and Company, Indianapolis, Indiana 46285
Received December 22, 2002 ; E-mail: odonnell@chem.iupui.edu
The enantioselective synthesis of R-amino acid derivatives via
organoboranes was recently reported from this laboratory.1 The
methodology involves reaction of the R-acetoxy derivative of the
benzophenone imine of glycine tert-butyl ester (1) with an achiral
B-alkyl-9-BBN (2) in the presence of a Cinchona alkaloid and added
lithium chloride (eq 1). Either enantiomer of the product R-amino
of 1 with racemic B-(s-butyl)-9-BBN [(()-6] in the presence of an
achiral proton source.6 The product racemic diastereomers 7 were
obtained with low syn-diastereoselectivity [60% ds, 3:2 dr of
(7a+7d):(7b+7c)], which is not surprising due to the similar size
of ethyl vs methyl.7 Replacement of the ethyl with a larger phenyl
group7 in the B-alkyl-9-BBN (()-8 increased the syn-diastereo-
selectivity substantially (91% ds, 10:1 dr) for products 9.6
Matteson asymmetric homologation chemistry8 with DICHED
boronic esters (10) was used to establish the latent â-stereocenter
in the enantiomers of 6 [R1,R2 ) Et,Me for (R)-6; or Me,Et for
(S)-6] (eq 3) because of the potential for the homologation
acid (5) was prepared by simply changing the alkaloid: cinchoni-
dine (3, CdOH) gave (S)-5, while cinchonine (4, CnOH) led to
(R)-5. The highest enantioselectivity (95% ee) was obtained in the
preparation of the â-substituted R-amino acid derivative of cyclo-
pentylglycine [(S)-5, R ) c-C5H9]. We hypothesized that the
enantioselective protonation was controlled by complexation of the
enolate to the alkaloid, with delivery of the proton from the less
sterically hindered face.
â-Substituted R-amino acids, of interest as conformationally
constrained R-amino acid analogues,2 have been the focus of
numerous synthetic studies.3 We report a novel route to these
important targets, the stereoselective boron alkylation of 1 with
chiral, nonracemic B-substituted-9-BBN’s4 (eq 2).
methodology to be applied to the construction of R-amino acid
derivatives containing multiple stereogenic centers in the side-chain.
Boronic esters (10) were converted to the B-alkyl-9-BBN derivatives
(6) for use in the asymmetric boron alkylation reaction by the
reduction/hydroboration methodology of Brown and Singaram.9 The
organoborane alkylation reaction with an expected poor selectivity
was chosen as a test case. Thus, use of cinchonine, which typically
gives 2R stereochemistry,1 together with the (R)-organoborane 6
gave the inherently disfavored (2R,3R)-anti-product 7b in high
enantio- and diastereoselectivity (eq 3 and Table 1, entry b). The
other stereoisomers of 7 were formed in equally high stereoselec-
tivity (Table 1, entries a, c, and d).6
Rhodium-catalyzed asymmetric hydroboration of styrene10 was
used to establish the stereogenic center in the preparation of 8. Once
again (eq 4 and Table 1, entry f), the case with an expected poor
Two representative â-alkyl-substituted R-amino acid targets were
chosen for this study, the isoleucines (7) and the â-methylpheny-
lalanines (9). Stereochemical control in the preparation of each of
the four stereoisomers of the two targets will depend on: (a)
stereoselective preparation of the latent â-center via the corre-
sponding chiral, nonracemic organoborane (6 or 8) and (b) final
protonation of the boron enolate intermediate to set the R-stereo-
center, which follows the organoborane alkylation to form the CR-
Câ bond.1
stereoselectivity, the formation of the anti-diastereomer, was studied.
In this case, an eroded diastereoselectivity (66% ds) was observed
while an excellent enantioselectivity (97%) was maintained. The
other three stereoisomers of 9 (Table 1, entries e, g, and h) were
prepared with high enantioselectivity but variable diastereoselec-
tivity. In the case of the syn-products (9a and 9d) the diastereo-
selectivity was high (98% and 97% ds, respectively), while for the
other anti-product (9c) the diastereoselectivity was again moderate.6
The inherent diastereoselectivity5 in the final protonation step
of the boron alkylation sequence was addressed first by reaction
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J. AM. CHEM. SOC. 2003, 125, 2370-2371
10.1021/ja0298794 CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Stereoselective Alkylation of 1 with Organoboranes 6 or
8
the anti-product. The preferred formation of the anti-product demon-
strates substantial reagent control is obtained in these reactions.
In summary, the stereoselective organoborane alkylation for the
synthesis of optically active â-substituted R-amino acids has been
realized. This novel reaction, in combination with demonstrated
methodology8-10 for the preparation of chiral, nonracemic orga-
noboranes, will provide access to a variety of R-amino acids
containing multiple stereogenic centers. Future studies will focus
on application of this methodology, improvement of the diastereo-
stereoselectivity in the mismatched case, and gaining further insight
into the mechanistic details of the reaction.
ratio of
entry
â-R*-9-BBN
alkaloid
producta
stereoisomers % eeb %ds
7a:7b:7c:7d
CdOH (3) 7a (syn)
CnOH (4) 7b (anti)
CdOH (3) 7c (anti) 0.5:0:98.5:1 g99 98
CnOH (4) 7d (syn) 0.5:0:1:98.5
a
(R)-6
(R)-6
(S)-6
(S)-6
97:1:2:0
0:97:0:3
g99 97
g99 97
b (eq 3)
c
d
99 99
9a:9b:9c:9d
e
(R)-8
(R)-8
(S)-8
(S)-8
CdOH (3) 9a (syn)
CnOH (4) 9b (anti) 23:65:1:11
CdOH (3) 9c (anti)
CnOH (4) 9d (syn)
96:1:1:2
96 98
97 66
97 66
94 97
f (eq 4)
g
h
9:1:65:25
3:2:1:94
Acknowledgment. This work is dedicated to Professor Donald
Matteson on the occasion of his 70th birthday. We acknowledge
the National Institutes of Health (GM 28193) and Eli Lilly and
Company for support. We thank Professors B. Singaram and P. V.
Ramachandran for helpful discussions. M.M.M. thanks the Depart-
ment of Organic Chemistry at the Danish Technical University for
computing time.
a % yield, not optimized, for entries a-h: 27%, 67%, 33%, 53%, 65%,
70%, 70%, 63%. b % ee of major stereoisomer.
The stereochemical outcome of the boron alkylation reaction is
dependent on two key factors. First, the inherent diastereoselectivity
(substrate control) favors formation of the syn-products (vide supra).
This is in contrast with studies11 of the diastereoselective reaction
of simple acyclic alkenes containing a â-stereogenic center with
electrophiles (in this case, protonation of lithium enolates) where
anti products are favored. These earlier results were rationalized
using the “Houk model,” in which the electrophile approached from
the least hindered face of the most stable enolate conformation.
Calculations predicted that, to minimize A1,3-strain, the smallest
group (H) on the â-stereogenic center eclipsed the alkene or enolate
double bond.11 In the present case, with the bulky diphenylketimine
group at the R-carbon, the Houk conformer (12) was calculated to
be less stable than the anti-conformer (13), in which steric
interaction between the two non-hydrogen groups on the â-center
and the R-Ph2CdN has been minimized.12,13 Protonation of the more
stable conformer (13) from the least hindered top face then leads
to the observed syn-products (eq 5). Calculations of the 9-BBN
boron enolates by semiempirical methods [PM3 and MNDO(d)]
predicted the same preference for conformation 13.
Supporting Information Available: Full experimental procedures
and analytical data as well as stereoviews and Cartesian coordinates
of 12 and 13 (M ) Li, 9-BBN), and absolute energies of 12 and 13
(M ) Li) (PDF). This material is available free of charge via the Internet
at http://pubs.acs.org.
References
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2001, 57, 6329-6650.
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(4) Use of chiral, nonracemic, and achiral B-alkyl-9-BBN’s in the B-alkyl
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(6) See Supporting Information for full experimental details.
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H. Stereochemistry of Organic Compounds; Wiley-Interscience: New
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(12) A conformational search of the lithium enolates corresponding to (3S)-9
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energy conformers spanning an energy range of 12 kJ/mol were refined
independently at PM3 and MNDO(d), and the geometries were then
optimized at B3LYP/6-31G* using Jaguar. See Supporting Information
for full details.
(13) The lithium enolate generated by addition of (S)-6 to 1 was calculated,
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computational treatments.
The second important factor in determining the stereochemistry
of the products in these reactions is the relative importance of the
two steric control elements in the chiral protonation: the stereogenic
â-center (substrate control) and the Cinchona alkaloid (reagent
control). Insight into this is gained from the â-methylphenylalanine
products 9 (eq 4 and Table 1, entries e-h). In the matched case
for formation of syn-products (entries e and h), the diastereoselec-
tivity is high because the inherent preference for syn-diastereo-
selectivity is reinforced by the preference of cinchonine to yield
2S- and cinchonidine to give 2R-products. In contrast, for the mis-
matched case to yield anti-products (entries f and g), these two
factors are in opposition; the preference of the substrate is for forma-
tion of the syn-product, while the reagent (Cinchona alkaloid) favors
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