The first asymmetric synthesis of (1R,1′S)-1-[1′-(benzyloxycarbonyl-methylamino)-2′-phenylethyl] oxirane: A promising building block for the synthesis of peptide mimics

Article abstract of DOI:10.1055/s-1998-1558

The threo N-methyl oxirane 5 was prepared from (S)-N-methyl phenylalanine by bromoketone reduction or by epoxidation routes. The unexpected stereochemical result of the reduction of bromoketone 7 leading to the threo isomer is discussed.

Full text of DOI:10.1055/s-1998-1558

January 1998
SYNLETT
41
The First Asymmetric Synthesis of (1R,1’S)-1-[1’-(Benzyloxycarbonyl-methylamino)-2’-
phenylethyl]oxirane: a Promising Building Block for the Synthesis of Peptide Mimics
a
,a
b
Christian Beier , Ernst Schaumann* and Gunadi Adiwidjaja
a
Institut für Organische Chemie, Technische Universität Clausthal , Leibnizstraße 6, D-38678 Clausthal-Zellerfeld, Germany
Fax +49(5323)722858; E-mail: ernst.schaumann@tu-clausthal.de
b
Mineralogisch-Petrographisches Institut, Universität Hamburg , D-20146 Hamburg, Germany
Received 19 September 1997
Abstract:
5
The threo N-methyl oxirane was prepared from (S)-N-
methyl phenylalanine by bromoketone reduction or by epoxidation
routes. The unexpected stereochemical result of the reduction of
7
bromoketone leading to the threo isomer is discussed.
In recent years the synthesis of enantiomerically pure N-protected
1
1,
aminoalkyl epoxides, e.g. has been intensively investigated . Usually
they are used as key-building blocks for the synthesis of
hydroxyethylamine (HEA) or hydroxyethylene (HEI) dipeptide
2
3
isosteres , potent inhibitors of aspartic acid proteases such as renin or
4
HIV-protease . In the course of our studies on the use of amino
epoxides for natural product synthesis we became interested in the
5
,
2
diastereoselective synthesis of so far unknown N-methyl derivatives
1
of
.
Scheme 1
The most extensively used pathways for the synthesis of amino
epoxides are the epoxidation of the corresponding allyl amine for the
1a,b,c,g,4a,6e
threo isomer
, and the diastereoselective reduction of the
1d,e,f,h,4a
haloketone for the erythro isomer
, both derived from natural
2
amino acids. Our goal in the synthesis of was to introduce the N-
methyl substituent already with the amino acid. However, this may
create problems in diastereoselectivity as the transition from an NH to a
NMe unit changes the relative steric influence of the substituents on the
approach of the nucleophile and removes the possibility of hydrogen
6
bonding as stereochemical control element . Experimentally, starting
7
1e,f
3
from , the Albeck procedure
for the erythro nor-compound when
3
applied to gave a single diastereomer in excellent yield as shown by
Scheme 2
1
the presence of only one set of signals in the H NMR spectrum of the
crude product (Scheme 2).
4
The opposite result of the reduction of leading to the threo and not to
the expected erythro isomer may be explained by the Felkin-Anh and
the chelated Cram models for addition reactions to α-chiral carbonyl
1b
In contrast, applying the Luly protocol for the analogous synthesis of
the N-methylated threo oxirane was uneventful only to the stage of
9a
compounds (Scheme 3). In the case of the unmethylated α-
bromoketone the erythro selectivity is controlled by the formation of a
chelate intermediate from the α-heterosubstituted carbonyl compound
and the organometallic reagent. In contrast, the formation of
accord with the Felkin-Anh model, in which the N-methyl amido group
7
allylamine . Epoxidation of this material gave the same diastereomer
2b
as before in only 39% yield along with considerable decomposition.
Similar side reactions leading to oxazolidinones and particularly
decomposition had been observed by Rich on oxidation of an N-Boc-
N-methyl derivate. To establish the relative configuration of the isolated
2b
is in
6c
rather than the benzyl group takes the role of larger substituent. In this
2b
oxirane, epoxide
was treated with sodium thiophenoxide leading to
9b,c
conformation, the antiperiplanar effect
leads to attack of the hydride
8
substituted N-methyl-oxazolidinone . The chemical shifts of ring
ion on the carbonyl group from the si face leading to the threo
protons (H-4 = 3.77, H-5 = 4.23), the value of the coupling constant (J
configuration.
1b,h
8
and NOE experiments on (H-5/CH Ph 3.5 %,
2
(H-4/H-5) = 4.6 Hz)
Synthetically, our work demonstrates that the bromoketone route allows
convenient access to threo - , whereas in synthesis requiring the
corresponding erythro unit the N-methyl substituent has to be
H-5/H-4 1.7 %) strongly suggest trans configuration between H-4 and
H-5 and consequently the threo configuration of the isolated products.
2
Finally, the absolute proof of configuration was achieved by an X-ray
introduced at a later stage.
8
8
analysis of
.

42
LETTERS
SYNLETT
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Scheme 3
Acknowledgment
We thank the Deutsche Forschungsgemeinschaft (Sch 231/7-2) and the
Fonds der chemischen Industrie for generous support.
References and Notes
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(8) Crystal Structure Analysis of 9: C
H NO S, M = 313.40,
18 19 2
monoclinic, space group P2(1), crystal dimensions 0.76 x 0.44 x
0.04 mm, cell dimensions: a = 6.021(1), b = 7.397(1), c =
18.308(1) Å; β = 93.49(1)°; V = 813.9(2) Å , Z = 2, Further crystal
structure data are available from the Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.
Requests should be accompanied by a full citation of this paper.
3
(9) a) Mulzer, J. In Houben-Weyl Methods of Organic Chemistry, 4th
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(10) All new compounds gave satisfactory spectroscopic and analytical
25
data. Selected data of (2b): colorless oil, [α]
-32.3 (c=1.37,
D
1
CHCl ). H NMR (400 MHz, DMSO-d , 77°C): δ =2.50 (dd, J =
3
6
2.4, 5.0, 1H, CH O); 2.72 (dd, J = 4.4, 5.0, 1H, CH O); 2.81 (s,
2
2
3H, NCH ); 2.88 (dd, J = 6.6, 14.4, 1H, CH Ph); 2.93 (dd, J = 8.8,
3
2
14.4, 1H, CH Ph); 3.20 (ddd, J = 2.4, 4.4, 6.6, 1H, CHO); 4.01 (dt,
2
J = 6.6, 8.8, 1H, NCH); 4.96, 5.01 (each d, J = 13.2, 2H, OCH );
2
13
7.13 - 7.31 (m, 10H, H
). - C NMR (100 MHz, DMSO-d ,
aromat.
6
77°C): δ = 30.3 (NCH ); 34.3 (CH Ph); 45.4 (ring-CH ); 51.5
3
2
2
(ring-CH); 59.3 NCH); 66.0 (OCH Ph); 26.1, 127.0, 127.4, 128.0,
2
(2) a) Hellen, C. U. T.; Kraeusslich, H.-G.; Wimmer, E. Biochemistry
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der Helm, K.; Rippmann, F. Kontakte (Darmstadt) 1993(2), 48.
128.1, 128.7 (CH
Anal. Calcd for C
73.29; H, 6.96; N, 4.41.
(8): colorless prisms, mp 106°C; [α]
NMR (400 MHz, CDCl ): δ = 2.72 (dd, J = 8.0, 14.0, 1H, CH Ph);
); 136.9, 137.6 (C
NO : C, 73.29; H, 6.80; N, 4.50. Found: C,
3
); 155.4 (C=O). );
aromat.
aromat.
H
19 21
23
1
+8.4 (c = 1.00, CHCl ). H
3
D
3
2
2.82 (dd, J = 7.6, 14.0, 1H, CH SPh); 2.86 (s, 3H, NCH ); 3.01
(dd, J = 5.0, 14.0, 1H, CH SPh); 3.04 (dd, J = 5.0, 14.0, 1H,
2
3
2
(3) a) Greenlee, W. J. Pharmaceutical Res. 1987, 28, 263.
b) Greenlee, W. J. Med. Res. Rev. 1990, 10, 173. c) Doherty, A.
M.; Kaltenbronn, J. S.; Hudspeth, J. P.; Repine, J. P.; Roark, W.
H.; Sircar, I.; Tinney, F. J.; Connolly, C. J.; Hodges, J. C.; Taylor,
M. D.; Batley, B. L.; Ryan, M. J.; Essenburg, A. D.; Rapundalo, S.
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1991, 34, 1258. d) Rich, D. H. in Comprehensive Medicinal
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CH Ph); 3.77 (dt, J = 4.6, 8.0, 1H, H-4); 4.23 (dt, J = 4.6, 7.6, 1H,
2
H-5); 7.02-7.30 (m, 10H, H
). H,H-COSY-90 (400 MHz,
aromat.
CDCl ) crosspeaks: δ /δ = 2.72/3.04, 2.72/3.77, 2.82/3.01, 2.82/
3
x y
13
4.23, 3.01/4.23, 3.04/3.77, 3.77/4.23.
C NMR (50 MHz,
CDCl ): δ = 29.5 (NCH ); 37.5, 38.4 (CH ); 62.4 (C-4); 75.6 (C-
3
3
2
5); 126.9, 127.1, 128.8, 129.1, 129.3, 130.2 (CH
); 134.1,
aromat.
135.1 (C
); 157.0 (C=O). Anal. Calcd for C H NO S: C,
18 19 2
aromat.
68.98; H, 6.11; N; 4.47. Found: C, 68.97; H, 6.10; N, 4.38.