Highly Enantioselective Synthesis of 1,2-Amino Alcohol Derivatives via Proline-Catalyzed Mannich Reaction

Article abstract of DOI:10.1055/s-2003-41491

Here we report a new catalytic asymmetric synthesis of oxazolidin-2-ones 4 and Cbz-protected 1,2-amino alcohols 5. Our sequence is based on the chemistry of previously unknown 5-acyloxy-oxazolidin-2-ones, which are obtained via proline-catalyzed direct asymmetric three-component Mannich reaction and Baeyer-Villiger oxidation.

Full text of DOI:10.1055/s-2003-41491

CLUSTER
1903
Highly Enantioselective Synthesis of 1,2-Amino Alcohol Derivatives via
Proline-Catalyzed Mannich Reaction
E
nantioselecti
e
t
s
of 1, 2
e
-Amino A
l
r
cohol
D
erivativ
P
es ojarliev, William T. Biller, Harry J. Martin, Benjamin List*1
Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Fax +1(858)7847028; E-mail: blist@scripps.edu
Received 28 February 2003
Our strategy for a new organocatalytic synthesis of chiral
Abstract: Here we report a new catalytic asymmetric synthesis of
1,2-amino alcohols is based on our proline-catalyzed
asymmetric Mannich reaction with hydroxyacetone as the
oxazolidin-2-ones 4 and Cbz-protected 1,2-amino alcohols 5. Our
sequence is based on the chemistry of previously unknown 5-
acyloxy-oxazolidin-2-ones, which are obtained via proline-
donor component. We expected the produced a-hydroxy-
catalyzed direct asymmetric three-component Mannich reaction b-amino ketones (1, R2 = OH, Scheme 1) to be useful
and Baeyer–Villiger oxidation.
precursors of 1,2-amino alcohols via straightforward
redox processes. These could involve an oxidative PMP-
removal and a-hydroxy ketone cleavage,9 followed by
a reduction. Our first generation approach was developed
to determine the absolute configuration of the Mannich
products and was based on a lead tertaacetate mediated
glycol cleavage.2a The sequence, starting from the
Mannich product to give N-BOC-protected valinol,
required seven chemical operations. Later we developed
an improved synthesis by using a Baeyer–Villiger-
oxidation-based approach that gave N-BOC-protected
1,2-amino alcohols in high yields and in five chemical
operations.2b This second-generation approach worked
well with aliphatic and aromatic substituents. However,
we found that the use of aromatic aldehydes with electron-
withdrawing groups, which gave excellent ee’s in the
Mannich reaction, led to extensive racemization in the
final reduction step. We now report a significantly
improved, high-yielding, and racemization-free third-
generation approach that gives oxazolidin-2-ones 4 and
Cbz-protected 1,2-amino alcohols 5 in only three steps
from Mannich products 1. Further, we use previously
undescribed 5-acetoxy substituted oxazolidin-2-ones 3 as
new chiral a-amino aldehyde equivalents.
Key words: multicomponent reactions, organocatalysis, oxa-
zolidinones, aminoalcohols
The proline-catalyzed direct asymmetric three-
component Mannich reaction between ketones,
aldehydes, and p-anisidine produces b-amino ketones 1 in
enantio- and diastereoselectivities of up to >99%
(Scheme 1).2,3 A useful application of our reaction would
be a general synthesis of a-amino acid derivatives. We
pursue a route that centers on the oxidative glycol- or
Baeyer–Villiger-type a-cleavage of products 1 with R2 =
OH.4 Combined with an oxidative removal of the N-pro-
tecting group such a sequence could result in a short and
practical catalytic asymmetric synthesis of a-amino acids.
Here we present significant progress towards this goal
with an efficient conversion of Mannich products 1 (R1 =
Me, R2 = OH) into 1,2-amino alcohol derivatives via pre-
viously unknown 5-acyloxy-oxazolidin-2-ones.
O
O
p-Anisidine
(S)-Proline
O
NHPMP
R3
NHPMP
R3
HO
+
R1
H
R3
R1
R2
R2
O
The required diastereomerically pure syn-a-hydroxy-b-
aminoketones 1a–d were synthesized in good yields and
in high diastereoselectivities and enantioselectivities via
proline-catalyzed three-component Mannich reaction of
hydroxyacetone with p-anisidine, and aldehydes as
described earlier.2b Reacting Mannich products 1a–d with
triphosgene followed by cerium ammonium nitrate
(CAN) gave oxazolidinones 2 in good yields (Scheme 2).
Baeyer–Villiger oxidation of 5-acyl-oxazolidinones 2
with in situ generated trifluoroperacetic acid10 then gave
5-acetoxy oxazolidin-2-ones 3 (trans-stereochemistry
assigned from 1H NMR). Although Baeyer–Villiger
oxidations of such a-carbamoyl-oxyketones are
unprecedented, the observed complete regioselectivity
was expected and is based on the high migratory aptitude
of oxyalkyl groups.11
1
up to 99 % de, ee
Scheme 1 The proline-catalyzed direct asymmetric three-compo-
nent Mannich reaction (PMP = p-methoxyphenyl)
Chiral 1,2-amino alcohol derivatives are useful precursors
of important non-racemic compounds such as drugs,
amino acids, and chiral auxiliaries and ligands. The
development of new efficient methods for their
asymmetric synthesis is of high current interest.5 In this
regard, the Sharpless catalytic asymmetric amino-
hydroxylation is one of the most powerful procedures
previously described.6,7 In addition, several other
interesting methods have been reported.8
SYNLETT 2003, No. 12, pp 1903–1905
2
9
.0
9
.2
0
0
3
To explore the utility of 5-acetoxy substituted oxazolidin-
2-ones (3) as chiral a-amino aldehyde equivalents we
Advanced online publication: 19.09.2003
DOI: 10.1055/s-2003-41491; Art ID: Y00203ST
© Georg Thieme Verlag Stuttgart · New York

1904
P. Pojarliev et al.
CLUSTER
O
O
the synthesis of acetal 6 may be thermodynamic in nature
and is likely the result of a double SN2 reaction at the
labile acetal center. The intrinsic propensity of 5-acyloxy-
oxazolidin-2-ones 3 to undergo nucleophilic substitutions
at their acetal center is remarkable and contrasts the
known behavior of N-BOC-substituted oxazolidinones,
which invariably react with nucleophiles at their ring
carbonyl carbon.2,8b Presumably, the C–OAc-bond is
weakened by an anomeric effect of the ring oxygen atom.
O
NHPMP
i. Triphosgene
ii. CAN
CF3CO3H
85-90%
O
NH
R
O
NH
R
R
62-84 %
OH
Ac
AcO
1
2
3
a (R = biphenyl, 94 % ee)
b (R = p-NO2-C6H4, 99 % ee)
c (R = Ph, 93 % ee)
d (R = i-Pr, 65 → 99 % ee)
In conclusion, we have developed an efficient and highly
enantioselective synthesis of a-amino acid derivatives 3–
7. Our sequence is based on the proline-catalyzed asym-
metric three-component Mannich reaction, combined
with a Baeyer–Villiger oxidation to furnish previously
undescribed 5-acyloxy-oxazolidin-2-ones 3. All steps of
the developed sequence are operationally simple, rapid,
give good chemical yields, and provide the products in
high optical purity. Our methodology is best suited for the
synthesis of aryl glycine derivatives because the initial
Mannich reaction provides the highest steroselectivities
with aromatic aldehydes. As such, the presented scheme
nicely complements our recently developed catalytic
asymmetric aldehyde a-amination reaction, which fur-
nishes aliphatic a-amino acid derivatives in excellent
enantioselectivities.13 Future work will focus on the
intriguing yet underexplored chemistry of 5-acyloxy-ox-
azolidin-2-ones 3 and on the application of our
methodology to the synthesis of biologically active
compounds.
Scheme 2 Synthesis of 5-acetoxy oxazolidin-2-ones 3
studied their reactivity towards nucleophiles. Remark-
ably, NaBH4-reduction of acetals 3a–c did not provide the
expected 1,2-amino alcohols but oxazolidin-2-ones 4a–c
in high yields (Scheme 3). Evidently, instead of reducing
the ester functionality, the hydride source directly
substitutes OAc with hydrogen. The corresponding Cbz-
protected amino alcohols (5a–d) can also be obtained
after a work-up that consists of base-treatment followed
by in situ protection. That no racemization occurred
during the reduction was confirmed in all cases by
measuring the ee of the produced amino alcohols 5.12 The
preference of 5-acetoxy oxazolidin-2-ones 3 to react with
nucleophiles via substitution instead of nucleophilic
addition was further confirmed by treating ester 3a with
Na2CO3/MeOH, which gave methoxy derivative 6 as a
single stereoisomer (trans-stereochemistry assigned from
1H NMR). Moreover, if ester 3a was treated with a 1:1
mixture of ethynylmagnesium bromide and AlMe3,
alkyne 7 was obtained in 54% yield as a single
stereoisomer (cis-stereochemistry assigned from 1H
NMR).
Acknowledgment
Support by the NIH (GM-63914) is gratefully acknowledged. We
thank M. G. Finn and his group for sharing chemicals.
O
O
References
O
NH
R
O
NH
R
(1) New Address: Max-Plank-Institut für Kohlenforschung,
45470 Mülheim an der Ruhr, Germany.
MeO
MgBr
AlMe3, 54 %
MeOH, Na2CO3
95 %
E-mail: list@mpi-muelheim-mpg.de
6
7
O
(2) (a) List, B. J. Am. Chem. Soc. 2000, 122, 9336. (b) List, B.;
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2002, 124, 827.
R = biphenyl
R = biphenyl
O
NH
(3) List, B. Synlett 2001, 1675.
(4) An alternative strategy involves products 1 with R3 = CO2H
or equivalents such as CH2OBn (see ref. 1) or CO2R. This
interesting approach is limited to g-oxo functionalized a-
amino acid derivatives, see: Córdova, A.; Watanabe, S.;
Tanaka, F.; Notz, W.; Barbas, C. F. III J. Am. Chem. Soc.
2002, 124, 1866.
AcO
R
3
NHCbz
O
i. NaBH4
ii. NaOH
iii. CbzCl
NaBH4
R
O
NH
R
OH
4
5
(5) For excellent reviews on the synthesis and use of vicinal
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Rev. 1996, 96, 835.
(6) (a) Li, G.; Chang, H.-T.; Sharpless, K. B. Angew. Chem., Int.
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a (R = biphenyl, 87%)
a (R = biphenyl, 81%, 94 % ee)
b (R = p-NO2-C6H4, 85 %)
c (R = Ph, 84%)
b (R = p-NO2-C6H4,78 %, >99 % ee)
c (R = Ph, 80%, 93 % ee)
d (R = i-Pr,82 %,>99 % ee)
Scheme 3 Reactions of 5-acetoxy oxazolidin-2-ones 3
(7) (a) Reddy, K. L.; Sharpless, K. B. J. Am. Chem. Soc. 1998,
120, 1207. (b) O’Brien, P.; Osborne, S. A.; Parker, D. D. J.
Chem. Soc., Perkin Trans. 1 1998, 2519.
While the complete cis-stereoselectivity in this novel
carbon-carbon bond-forming reaction is consistent with
an SN2-type mechanism, the complete trans-selectivity in
Synlett 2003, No. 12, 1903–1905 © Thieme Stuttgart · New York

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Enantioselective Synthesis of 1,2-Amino Alcohol Derivatives
1905
(8) For selected other methods for the synthesis of 2-substituted
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Synlett 2003, No. 12, 1903–1905 © Thieme Stuttgart · New York