A formal enantioselective acetate mannich reaction: The nitro functional group as a traceless agent for activation and enantiocontrol in the synthesis of β-amino acids

Article abstract of DOI:10.1021/ol801797h

(Chemical Equation) A two-step procedure involving the enantioselectlve addition of α-nitro esters to imines, followed by reductive denitration, provides a convenient new enantioselective synthesis of β-amino acids. Specifically, β-phenyl alanine derivatives with up to 98% ee are formed In good yield (64-88%) over two steps. The utility of the approach is demonstrated through the first enantioselective synthesis of the key β-amino acid of (+)-chaenorhine.

Full text of DOI:10.1021/ol801797h

ORGANIC
LETTERS
2008
Vol. 10, No. 20
4397-4400
A Formal Enantioselective Acetate
Mannich Reaction: The Nitro Functional
Group as a Traceless Agent for
Activation and Enantiocontrol in the
Synthesis of ꢀ-Amino Acids
Bo Shen and Jeffrey N. Johnston*
Department of Chemistry & Vanderbilt Institute of Chemical Biology, Vanderbilt
UniVersity, NashVille, Tennessee 37235-1822
jeffrey.n.johnston@Vanderbilt.edu
Received June 21, 2008
ABSTRACT
A two-step procedure involving the enantioselective addition of r-nitro esters to imines, followed by reductive denitration, provides a convenient
new enantioselective synthesis of ꢀ-amino acids. Specifically, ꢀ-phenyl alanine derivatives with up to 98% ee are formed in good yield (64-88%)
over two steps. The utility of the approach is demonstrated through the first enantioselective synthesis of the key ꢀ-amino acid of (+)-chaenorhine.
ꢀ-Amino acids are constituents of countless natural products,1
including several contemporary chemotherapeutics such as
Taxol.2 R-Unsubstituted ꢀ-amino acids, formally derived
from an “acetate” Mannich addition, are also expressed in
natural products that include edeines A and B,3 streptothricin
F,4 C-1027,5 and (+)-chaenorhine.6 These occurrences have
stimulated the development of addition reactions leading to
the ꢀ-amino acid motif. Recent preparations of R-unsubsti-
tuted ꢀ-amino acids include auxiliary-based methods such
as the addition of chiral nonracemic amines to unsaturated
esters.7 Enantioselective, catalytic approaches have also been
developed, including two-step procedures involving enol
silane formation and catalyzed addition,8 and a three-step
sequence involving Mannich addition of a malonate, hy-
drolysis, and decarboxylation.9 Beyond ꢀ-amino acid syn-
thesis, the general study of Mannich additions for the
(1) Juaristi, E. EnantioselectiVe Synthesis of ꢀ-Amino Acids; Wiley:
Hoboken, NJ, 2005.
(6) Bernhard, H. O.; Kompis, I.; Johne, S.; Groeger, D.; Hesse, M.;
Schmid, H. HelV. Chim. Acta 1973, 56, 1266. Badawi, M. M.; Bernauer,
K.; Van den Broek, P.; Groeger, D.; Guggisberg, A.; Johne, S.; Kompis,
I.; Schneider, F.; Veith, H. J.; et al. Pure Appl. Chem. 1973, 33, 81. Kompis,
I.; Hesse, M.; Schmid, H.; Johne, S.; Groger, D. Chimia 1970, 24, 450.
(7) Davies, S. G.; Mulvaney, A. W.; Russell, A. J.; Smith, A. D.
Tetrahedron: Asymmetry 2007, 18, 1554.
(2) Kingston, D. G. I. Anticancer Agents Natural Prod. 2005, 89.
Kingston, D. G. I. Chem. Commun. 2001, 867.
(3) Roncari, G.; Kurylo-Borowska, Z.; Craig, L. C. Biochemistry 1966,
5, 2153. Hettinger, T. P.; Craig, L. C. Biochemistry 1968, 7, 4147. Hettinger,
T. P.; Kurylo-Borowska, Z.; Craig, L. C. Biochemistry 1968, 7, 4153. Parry,
R. J.; Kurylo-Borowska, Z. J. Am. Chem. Soc. 1980, 102, 836.
(4) Gould, S. J.; Thiruvengadam, T. K. J. Am. Chem. Soc. 1981, 103,
6752.
(8) Wenzel, A. G.; Lalonde, M. P.; Jacobsen, E. N. Synlett 2003, 1919.
Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 12964. Itoh,
J.; Fuchibe, K.; Akiyama, T. Synthesis 2008, 1319.
(5) Lin, S.; VanLanen, S. G.; Shen, B. J. Am. Chem. Soc. 2007, 129,
12432.
(9) Marianacci, O.; Micheletti, G.; Bernardi, L.; Fini, F.; Fochi, M.;
Pettersen, D.; Sgarzani, V.; Ricci, A. Chem. Eur. J. 2007, 13, 8338.
10.1021/ol801797h CCC: $40.75
Published on Web 09/18/2008
2008 American Chemical Society

synthesis of chiral amines holds historic and continuing
importance in synthesis.10
acetates as acetate synthons in the enantioselective construc-
tion of ꢀ-amino acids.14,15
The feasibility of the denitration step in this setting was
first examined on ꢀ-amino-R-nitro esters 1 made from triethyl
amine-catalyzed aza-Henry reactions of tert-butyl nitroacetate
with N-Boc imines. That these substrates were racemates was
of no consequence at this stage. Numerous methods for
denitration have been developed,16 but stannane reductions
were particularly attractive for the mild, pH-neutral condi-
tions typical of these free radical-mediated reductive deni-
trations. Secondary nitroalkanes are suitable substrates,
particularly when one substituent further stabilizes the
intermediate carbon radical,17 as are tertiary nitroal-
kanes.17-19 As shown in Table 1, the use of standard reagents
Enantioselective Mannich reactions involving nitroalkanes
have been subjected to intensive study over the past
decade.11,12 We and others have also successfully employed
R-nitro esters in these additions,11 but the sole focus has
resided in the value of the nitro group as an amine
progenitor.13 We naturally wondered whether the nitro group,
which is critical for activation and stereocontrol in the
addition reaction, could be readily removed as part of a two-
step procedure leading ultimately to the R-unsubstituted
ꢀ-amino acid substructure (Figure 1). The strategy bears
Table 1. Reductive Denitration of R-Nitro Estersa
Figure 1. General design of an acetate Mannich equivalent.
entry
Ar
yield (%)b
analogy to malonate Mannich addition/hydrolysis/decar-
boxylation, but differs by the potentially mild, pH-neutral
conditions typical of stannane-mediated denitration. In this
Letter we describe the successful deployment of R-nitro
1
2
3
4
5
6
7
8
9
pMeC6H4
pMeOC6H4
pFC6H4
mMeC6H4
pPhC6H4
2Np
a
b
c
d
e
f
g
h
i
91
90
97
90
89
83
83
73
82
93
0
mPhOC6H4
pClC6H4
pAcOC6H4
2C4H3O
(10) Reviews: Verkade, J. M. M.; van Hemert, L. J. C.; Quaedflieg, P.;
Rutjes, F. Chem. Soc. ReV. 2008, 37, 29. Ting, A.; Schaus, S. E. Eur. J.
Org. Chem. 2007, 5797. Friestad, G. K.; Mathies, A. K. Tetrahedron 2007,
63, 2541. Guillena, G.; Ramon, D. J.; Yus, M. Tetrahedron: Asymmetry
2007, 18, 693. Pelissier, H. Tetrahedron 2006, 62, 2143. Sugiura, M.;
Kobayashi, S. Angew. Chem., Int. Ed. 2005, 44, 5176. Syamala, M. Org.
Prep. Proc. Intl. 2005, 37, 103. Ramon, D. J.; Yus, M. Angew. Chem., Int.
Ed. 2005, 44, 1602. Simon, C.; Constantieux, T.; Rodriguez, J. Eur. J. Org.
Chem. 2004, 4957. Arend, M.; Westermann, B.; Risch, N. Angew. Chem.,
Int. Ed. 1998, 37, 1044. Denmark, S.; Nicaise, O. J.-C. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Berlin, Germany, 1999; Vol. 2, p 923. Kobayashi, S.; Ueno, M.
In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, Germany, 2004; Vol. 1, p 143.
Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069.
10
11
j
k
3C4H3S
a All reactions were 0.10 M in substrate and proceeded to complete
conversion. b Isolated yields.
and stannyl radical-generating conditions provided the
desired ꢀ-amino ester products 2 in high isolated yield. Not
(11) Singh, A.; Yoder, R. A.; Shen, B.; Johnston, J. N. J. Am. Chem.
Soc. 2007, 129, 3466. Singh, A.; Johnston, J. N. J. Am. Chem. Soc. 2008,
130, 5866. Chen, Z.; Morimoto, H.; Matsunaga, S.; Shibasaki, M. J. Am.
(14) For a review of the use of nitroalkanes as alkyl anion equivalents,
see: Rosini, G.; Ballini, R. Synthesis 1988, 833
.
Chem. Soc. 2008, 130, 2170
.
(15) Enantioselective Brønsted acid catalyzed additions to azomethine,
selected references: Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed.
2006, 45, 1520. Nugent, B. M.; Yoder, R. A.; Johnston, J. N. J. Am. Chem.
Soc. 2004, 126, 3418. Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc.
2002, 124, 12964. Iyer, M. S.; Gigstad, K. M.; Namdev, N. D.; Lipton, M.
J. Am. Chem. Soc. 1996, 118, 4910. Corey, E. J.; Grogan, M. J. Org. Lett.
1999, 1, 157. Terada, M.; Yokoyama, S.; Sorimachi, K.; Uraguchi, D. AdV.
Synth. Catal. 2007, 349, 1863. Sigman, M. S.; Vachal, P.; Jacobsen, E. N.
Angew. Chem., Int. Ed. 2000, 39, 1279. Uraguchi, D.; Sorimachi, K.; Terada,
M. J. Am. Chem. Soc. 2004, 126, 11804. Rueping, M.; Sugiono, E.; Moreth,
S. A. AdV. Synth. Catal. 2007, 349, 759. Yamanaka, M.; Itoh, J.; Fuchibe,
K.; Akiyama, T. J. Am. Chem. Soc. 2007, 129, 6756. Reviews: Connon,
S. J. Angew. Chem., Int. Ed. 2006, 45, 3909. Akiyama, T.; Itoh, J.; Fuchibe,
K. AdV. Synth. Catal. 2006, 348, 999. Akiyama, T. Chem. ReV. 2007, 107,
(12) Reviews: Westermann, B. Angew. Chem., Int. Ed. 2003, 42, 151.
Friestad, G. K.; Mathies, A. K. Tetrahedron 2007, 63, 2541. Ting, A.;
Schaus, S. E. Eur. J. Org. Chem. 2007, 5797. Selected examples: Yamada,
K.; Harwood, S. J.; Groger, H.; Shibasaki, M. Angew. Chem., Int. Ed. 1999,
38, 3504. Adams, H.; Anderson, J. C.; Peace, S.; Pennell, A. M. K. J. Org.
Chem. 1998, 63, 9932. Nugent, B. M.; Yoder, R. A.; Johnston, J. N. J. Am.
Chem. Soc. 2004, 126, 3418. Okino, T.; Nakamura, S.; Furukawa, T.;
Takemoto, Y. Org. Lett. 2004, 6, 625. Palomo, C.; Oiarbide, M.; Laso, A.;
Lopez, R. J. Am. Chem. Soc. 2005, 127, 17622. Marianacci, O.; Micheletti,
G.; Bernardi, L.; Fini, F.; Fochi, M.; Pettersen, D.; Sgarzani, V.; Ricci, A.
Chem. Eur. J. 2007, 13, 8338. Gomez-Bengoa, E.; Linden, A.; Lopez, R.;
Mugica-Mendiola, I.; Oiarbide, M.; Palomo, C. J. Am. Chem. Soc. 2008,
130, 7955. Rueping, M.; Antonchick, A. P. Org. Lett. 2008, 10, 1731. Yoon,
T. P.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2005, 44, 466
.
5744.
(13) For pioneering work to develop R-nitro esters as substrates for
enantioselective R-amino acid synthesis, see: Moreau, B.; Charette, A. B.
J. Am. Chem. Soc. 2005, 127, 18014. Li, H. M.; Wang, Y.; Tang, L.; Wu,
F. H.; Liu, X. F.; Guo, C. Y.; Foxman, B. M.; Deng, L. Angew. Chem., Int.
Ed. 2005, 44, 105. Knudsen, K. R.; Jorgensen, K. A. Org. Biomol. Chem.
2005, 3, 1362. ꢀ-Nitro ketone nucleophiles: Linton, B. R.; Reutershan,
M. H.; Aderman, C. M.; Richardson, E. A.; Brownell, K. R.; Ashley, C. W.;
Evans, C. A.; Miller, S. J. Tetrahedron Lett. 2007, 48, 1993.
(16) Ono, N. Wiley-VCB: New York, 2001; p 193. Ono, N. In The Nitro
Group in Organic Synthesis: Recent AdVances in Synthesis and Chemistry;
Feuer, H., Nielsen, A. T., Eds.; VCH: New York, 1990; p 1.
(17) Ono, N.; Miyake, H.; Tamura, R.; Kaji, A. Tetrahedron Lett. 1981,
22, 1705.
(18) Petrini, M.; Torregiani, E. Tetrahedron Lett. 2006, 47, 3501. Tanner,
D. D.; Blackburn, E. V.; Diaz, G. E. J. Am. Chem. Soc. 1981, 103, 1557
.
(19) Tormo, J.; Hays, D. S.; Fu, G. C. J. Org. Chem. 1998, 63, 5296
.
4398
Org. Lett., Vol. 10, No. 20, 2008

unexpectedly, a variety of functionalized aryl groups fur-
nished the denitrated products (2a-j) in good to excellent
yield (Table 1, entries 1-10). Fluorinated (1c) and chlori-
nated (1h) (Table 1, entries 3 and 8) substrates are tolerated,
as well as the electronically rich furyl-derived ꢀ-amino ester
1j. Unfortunately, thiophenyl substrates are unsuitable at the
present time (Table 1, entry 11).
Table 2. A Catalytic Asymmetric Acetate Mannich Reaction in
Two Stepsa
entry
Ar
ee (%)b
yield (%)c
1
2
3
4
5
6
7
8
9
pMeC6H4
pMeOC6H4
pFC6H4
mMeC6H4
pPhC6H4
2Np
mPhOC6H4
pClC6H4
pAcOC6H4
2C4H3O
a
b
c
d
e
f
g
h
i
94
85
93
87
92
95
89
98
91
85
80
88
85
87
81
77
67
73
68
64
The experiments in Table 1 merely confirmed the expectation
that denitration is possible, but did not prognosticate the
feasibility of the overall strategy with regard to enantioenriched
product formation. R-Nitro esters 1 are obtained as a thermo-
dynamic ratio of diastereomers at room temperature. The
enantiomeric ratio for each diastereomer, however, is at the 94:6
level (88% ee each, eq 1). We were gratified to find that
reductive denitration of this mixture resulted in convergence
to the desired amine with identical enantiomer enrichment (88%
ee). This finding indicated that stereocontrol to establish the
benzylic carbon proceeds with the same azomethine facial
selectivity regardless of the diastereomer produced. Furthermore,
the selectivity is at the same level in each case. Had the minor
diastereomer formed with R configurational selectivity and 88%
ee, the product of eq 1 would have been isolated in 29% ee.
10
j
a All reactions were 0.30 (step 1) and 0.10 M (step 2) in substrate and
proceeded to complete conversion. b Enantiomer ratios were measured using
chiral stationary phase HPLC. c Isolated yields (two steps).
Chaenorhine is a macrocyclic spermine alkaloid isolated from
C. origanifolium in which a ꢀ-amino acid is present as a key
constituent of the macrobicyclic core structure (Scheme 1).6
Scheme 1. Enantioselective Synthesis of Wasserman’s
Chaenorhine Protected ꢀ-Amino Acid Intermediate
We investigated the scope of this overall approach as a
two-step protocol as outlined in Table 2. Optimized
conditions for the aza-Henry step provided (S)-2a with
slightly improved selectivity after reductive denitration
(94% ee and 80% overall yield, Table 2, entry 1). The
ꢀ-amino tyrosine derivative (S)-2b was produced in 85%
ee and 88% yield overall with use of an identical protocol.
Substitutions of the aromatic ring, varing both electroni-
cally and by position, provided the derived ꢀ-amino acids
with good enantioselectivity and overall yield (87-98%
ee, 68-87% overall yield, Table 2, entries 3-9). Fur-
thermore, an electron rich heterocycle such as the furyl
ꢀ-amino acid (S)-2j was obtained in 85% ee and 64% yield
overall (Table 2, entry 10).
Wasserman has reported the only total synthesis of record, and
this provided access to racemic chaenorhine.20
Addition of tert-butyl nitroacetate to imine 3l, followed
by denitration, produced ꢀ-amino ester 2l in 88% ee and
75% yield overall (Scheme 1). Methanolysis and selective
Among the products in Table 2, protected ꢀ-tyrosines are of
particular note as they can be structural elements of natural
products. We targeted one additional ꢀ-tyrosine derivative
particularly for its relevance to natural product synthesis. (+)-
Org. Lett., Vol. 10, No. 20, 2008
4399

reprotection of the free amine then furnished the Wasserman
ꢀ-amino ester intermediate 5 in 85% yield (two steps), but
in enantioenriched form as the S enantiomer. Incidentally,
this methyl ester could be formed directly from commercially
available methyl nitroacetate, albeit with slightly diminished
enantiomeric excess (72% ee).
As a representative example, we examined the protocol
developed by Fu,19 which employs a substoichiometric
amount of stannane, in conjunction with a stoichiometric
amount of silane (eq 2). In our hands, this method worked
well to provide 2h in 70% isolated yield, requiring only a
longer reaction time when compared to the use of stannane
alone. Again, no loss in enantiomeric enrichment was
observed, as 2h was delivered in 97% ee (cf. Table 2,
entry 8).
to enantioenriched ꢀ-amino ester products is therefore
possible by stannyl radical-mediated denitration. The Man-
nich addition/denitration protocol can be considered an
equivalent to the analogous addition/decarboxylation se-
quence involving ꢀ-diesters. Whereas the latter requires ester
to carboxylic acid conversion under either acidic or basic
conditions,9 the free radical conditions used here for deni-
tration are considered pH-neutralsin the present work, for
example, the acetate in 2i/l was retained. The practitioner
can now choose from among this range of possibilities.
Moreover, the lower molecular weight of the nitro group
compared to an ester might render it more attractive when
employed as a disposable functional group. The utility of
the strategy and method was successfully applied to the
ꢀ-amino acid component of (+)-chaenorhine, which should
now be accessible in enantioenriched form following the
synthesis of Wasserman.
Acknowledgment. This work was initiated through funds
provided by the NSF (CHE-0415811), and continued through
the financial support of the Vanderbilt Institute of Chemical
Biology.
Supporting Information Available: Preparation and
analytical data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
In summary, the enantioselective synthesis of ꢀ-phenyl
alanine derivatives with use of a two-step procedure has been
developed. The successful application of this strategy is in
large part due to the ability of chiral proton catalyst 4 to
provide each intermediate R-nitro ester diastereomer with
high enantioselectivity and consistent configuration at the
benzylic amine carbon. Convergence of these diastereomers
OL801797H
(20) Wasserman, H. H.; Robinson, R. P.; Carter, C. G. J. Am. Chem.
Soc. 1983, 105, 1697.
4400
Org. Lett., Vol. 10, No. 20, 2008