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Enantioselective Synthesis of (R)-N-Boc-1-amino-2-arylcyclopropene-1-carboxylic Acid Methyl Ester.

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readily soluble in benzene and toluene, but only moderately soluble in
aliphatic solvents. M.p.=58"C. 'H-NMR: 6 ~ 6 . 8 - 8 . 0(m); "Se-NMR
(57.24 MHz, Me2Se/Cc,D6 standard), in CnDo: 6=477.7, in CH,CN/
C'<,D,,( 3 : I ) . 6=470.4, i n CDCI?: &=485.3; shifts concentrdtion-depend:nt. MS (70 eV, D I R , 55°C): m/z [%] 314 (4, PhzSe?), 284 (10, PhSel@),
254 (100. I:),
234 (2, Ph2Se"), 157 (14, PhSe'), 127 (36, Is), 77 (13,
(-,,HI( ).
3c crystallizes triclinically, space group PT, a=975.6(4), b=991.0(4),
:.= 10096(4) p ~ a=
,
116.04(2), pl=91.77(2), y = 115.26(2)", V =
7 6 4 . 0 4 ~10" pm , Z = 2 , based o n the formula Ph2Se2.12; 2227 symmetry-dependent reflections, 1875 observed ( 1 > 2 o ( I ) ; R,. =0.0296
(measurement. Siemens-Stoe AED 2; solution SHELX 76). Further details of the crystal structure investigation are available on request from
the Fachinformationszentrum Energie, Physik, Mathematik GmbH, D75 14 kggenstein-Leopoldshafen 2 (FRG), o n quoting the depository
number CSD-52950, the names of the authors, and the journal citation.
R. E. Marsh. Acro Cry.sta1logr. 5 (1952) 458.
H. Krehs, A n g w . Chem. 70 (1958) 615; F. van Bolhuis, P. P. Koster, T.
Michel\en, Actn Cri,.s<a/logr.23 (1967) 90.
G. Y C'hao, J . D. McCullough, Acra Crystallogr. 14 (1961) 940; H.
Hope, J . I). McCullough, ibid. 17 (1964) 712: H. D. Maddox, J. D.
McCullough. /norg Chem. 5 (1966) 522.
A. J. Aahe 111, E. G. Ludwig, J. Oleksyszyn, J. C. Huffmann, Organometal/ic,i 3 ( 1984) 337; 0. Mundt, M. Riffel. G. Becker, A. Simon, Z. Narurforccft. B 3 9 (1984) 317.
P. Laur. Sth In!. S-vmposium on the Chemistry ofSelenium and Tellurium.
Oak Ridge, TN (USA) 1987; Abstract 10.
H. Krehr, Angew. Chem. 62 (1953) 293.
2
3
H
7, x
=
HCI
R
a,R =
H; b, R
= CH3; c .
R
=
CL
pound and the 2-diazo compound into the bislactim ether
carbene 3,l6] which is trapped with the arylethyne 4.
Within analytical accuracy only one diastereomer is
formed, namely ( R ) - 5 . The configuration was confirmed
by an X-ray structure analysis of 5a (Fig. l).I7]
Enantioselective Synthesis of
(R)-N-Boc-l-amino-2-arylcyclopropene-l-carboxylic
Acid Methyl Ester**
By Ulrich Schollkopf,* Bernd Hupfeld, Stephan Kuper,
Ernst Egert, * and Michael Dyrbusch
Dedicated to Professor Emanuel Vogel on the occasion of
his 60th birthday
P,y-Unsaturated amino acids of the p-methylenephenylalanine type l"]are of special interest as suicide-inhibitorsLZ1
for pyridoxal phosphate-dependent enzymes. I-Amino-2-aryl-cyclopropene- 1-carboxylic acids (Type 7)13]-
NH,
II I
H5C6-C-CH-C0,H
*
Fig. I . Structure of the carbene adduct 5a in the crystal 171; 0 = N, @ =O.
Noteworthy is that the phenyl ring and the cyclopropene double bond are
completely coplanar, thus indicating an effective conjugation of the two xsystems.
H2C
1
structural variants of 1 -should be particularly effective
inhibitors because of their extremely strained and thus
highly reactive double bond. Since-as ~ s u a l [ ~ ~ - o none
ly
enantiomer may be biologically active, each enantiomer
should be investigated separately. We describe here a n enantioselective synthesis of N-Boc-l-amino-2-phenyl-,
-(4methylpheny1)-, and -(4-chlorophenyl)cyclopropene-l-carboxylic acid methyl esters 7a, b and c utilizing the bislactim ether carbene 3 . The amino acid esters 7 are obtained
in almost enantiomerically pure form (ee>95%): with 3
the (R)-enantiomers and with ent-3 the (S)-enantiomers.
The synthesis starts from 2, the bislactim ether of cyclo(L-Val-Gly).I5' This is converted via the 2-lithium com["I
[**I
Prof. Dr U. Schollkopf, Dipl.-Chem. B. Hupfeld,
DipLChem. S Kuper
lnstitut fur Organische Chemie der Universitat
Tammann5trasse 2, D-3400 Gottingen (FRG)
Dr. E. Egert. M. Dyrbusch
lnstitut fur Anorganische Chemie der Universitat
Tdmmannstrasse 4, D-3400 Gottingen (FRG)
Asymmetric Syntheses via Heterocyclic Intermediates, Part 37.-Part
36: U. Schiillkopf, J. Schroder, Liebigs Ann. Chem. 1988, 87.
Anyen,. Chiw Inr. Ed Engl. 27 11988) Nri. 3
Hydrolysis of the carbene adducts 5 to 6, the hydrochlorides of the amino acid esters, was achieved with two
equivalents of 0.1 N HCI at room temperature. The salts 6
were transformed into the N-Boc derivatives 7. After separation from Boc-L-Val-OMe these were reconverted into
the compounds 6 by treatment with 0.5 N HCI in methanol
(6 h, 60°C).
Experimental
5 : A solution of 2 (0.55 g, 3.0 mmol) in T H F (7 mL) was treated dropwise at
- 78°C with a solution of nBuLi (3.0 mmol) in hexane. After 15 min stirring,
the resulting mixture was added via a Teflon tube (cooled with dry-ice) to a
solution of 0.53 g (3.0 mmol) of benzenesulfonyl azide in 7 m L of THF. Stirring was continued for 2.5 h at -78°C and then n-BuLi (3.0 mmol) was added to the mixture at such a rate that the temperature did not rise above
-7OOC. After 10 min the mixture was added dropwise within 15 min through
a Teflon tube (cooled with dry-ice) to 30 m L of 4, which was warmed to
50-60°C. After 30 min vigorous stirring, the mixture was allowed to cool to
room temperature, treated with 150 mL of Et20, and washed with 3 x 30 m L
of a 10"h NaCl solution. The organic phase was dried over magnesium sulfate and the solvent removed in vacuo. Excess 4 was distilled off at 3040"C/0.01 torr and the residue chromatographed o n silica gel (Kieselgel 60.
500 x 15 m m 2 column, petroleum ether/ether l5/l).- 5a: 0.43 g (50%), m.p.
112-113°C; 5b: 0.45 g (50%), m.p. 70-71°C; 5c: 0.62 g (65%), m.p. 103104°C. Diastereomeric iatio > 4 9 : I IS].
0 VCH Verlag.sgesei1schaJi mhH. 0 - 6 9 4 0 Weinherm. 1988
0570-0833/88/0303-0433 $ 02.50/0
433
Boc
7 : A solution of 5 (2.0 mmol) in MeCN ( I S mL) was treated with 40 m L of
0 I N HCI and the resulting mixture stirred for 2 days. The solution was
extracted twice with Et,O and the extracts discarded. The aqueous phase was
evaporated to dryness under vacuum and the amino acid ester hydrochlorides subsequently suspended in 25 m L of CHIC12. The suspension was
treated at 0°C with 1.1 g (5.0 mmol) of Boc,O and 1.5 g (15.0 mmol) of Et,N
and, after 4 h, the mixture was poured into 20 m L of water, the phases separated, and the organic phase rewashed with 2 x 10 m L of water and dried
over magnesium sulfate. The solvent was removed in vacuo and the residue
chromatographed on silica gel (Kieselgel 60, 300x 10 mm2 column, ether/
petroleum ether l/l).- 7a: 0.34 g (58"/0), m.p. 133-134"C, [a]$:'=
+53 4,
+51.4, R,=0.294: 7c:
R,=0.304: 7b: 0 3 6 g (59"/0), m.p 103-104"C, [a]?:'=
0.39g (60"h), m.p. 90-91 "C. [u]$'=Sl.O, Rl=0.275: recrystallized from etherlpentane 112: optical rotation: c = 1 in CCI,. All the compounds described
gave correct elemental analyses.
Received: October 12, 1987 [Z 2475 IE]
German version: Angew. Chem. 100 (1988) 438
[ I ] R. V. J. Chari, J. Wemple, Tetrahedron Lett. 1979, 11 I.
121 a) R. R. Rando, Acc. Chem. Res. 8 (1975) 281: b) R. H. Abeles, A. L.
Maycock, ibid. 9 (1976) 313: c) R. H. Abeles, Pure Appl. Chem. 53 (1981)
149; d) C. Walsh, Tetrahedron 38 (1982) 871
[3] For the synthesis of the achiral l-amino-2,3-drphenylcyclopropeneI-carboxylic acid methyl ester via the I-methoxycarbonyl-2,3-diphenylcyclopropenylium ion, see I. N. Domnin, E. F. Zhuravleva, M. 1. Komendantov, A. 1. Ritari, Zh. Org. Khim. 13 (1977) 1789.
[41 E. J. Ariens, W. Soudijn, W. M. Timmermann: Stereochembtry and Biological Actimty of Drugs, Blackwell, Oxford 1983.
[5] U. Schollkopf, U. Groth, C . Deng, Angew. Chem. 93 (1981) 791: Angew.
Chem. Int. Ed. Engl. 20 (1981) 798: 2 and ent-2 are commercially available: Merck-Schuchardt, D-6100 Darmstadt, MS-Info 85-14.
161 U.Schollkopf, M. Hauptreif, J. Dippel, Angew. Chem. 98 (1986) 187; Angew. Chem. Ini. Ed. Engl. 25 (1986) 192.
[7] 5 a : space group P2,2,2,, a=861.4(1), b=1209.1(1), c = 1577.2(1) pm,
V = 1.643 nm3, 2 = 4 , p=0.07 m m - ' (MoKn); crystal dimensions:
0.3 x0.3 x0.5 mm'; 2367 measured intensities, 28,,, =SO", 1537 symmetry-independent reflections with IF > 3 o ( f l used for the structure solution (direct methods) a n d refinement; C, N a n d 0 atoms refined anisotropically, H atoms located by difference electron density determination and
refined with a riding model, R=0.062 (R,=0.052, w - ' = 0 2 ( ~ + 0 . 0 0 0 3
P ) . Further details of the crystal structure investigation are available on
request from the Fachinformationszentrum Energie, Physik, Mathematik
GmbH, D-75 14 Eggenstein-Leopoldshafen 2 (FRG), on quoting the depository number CSD-52781, the names of the authors, and the journal
citation.
[XI In each case only one set of signals could be recognized in the "C-NMR
spectrum (200 MHz).
bis[ 1,2,5]thiadiazole-4,4,8,8-tetrayl)dimalononitrile,1 , a new
type of electron acceptor,"] play an important role in
decreasing Coulomb repulsion by delocalization of negative charge'31 and in forming two-dimensional networks by
intermolecular interactions between the h e t e r o a t ~ m s I. n~ ~ ~
this connection, bis([l,2,5]thiadiazolo)[3,4-b;3',4'-e]pyrazine, 2, is an interesting hypervalent sulfur-nitrogen heterocycle for which resonance structures such as 2a-c come
into considation. We have succeeded in preparing 2 and
found that it is a strong electron acceptor, in spite of its
being a 14n-electron heterocycle.
5,6-Diamino[ 1,2,5]thiadiazolo[3,4-b]pyrazine3a was prepared by reaction of the dichloro compound 3bl5]with potassium phthalimide followed by hydrolysis with hydrazine hydrate (yield 63%). Reaction of 3a with thionyl chloride in the presence of pyridine in dichloromethane afforded, after sublimation, stable red crystals of 2 in 66%
yield.[']
+
The half-wave reduction potentials ( E l = 0.10, E2=
-0.82 V vs. SCE) were measured by cyclic ~oltammetry.['~
The first reduction potential is more positive than that of 1
( - 0.02 v),[*]i.e. 2 is a stronger electron acceptor than 1,
even though it does not contain any electron-withdrawing
substituents. Moreover, the log K,,, value (15.86) is larger
than that for 1 (8.10),[81 indicating that the radical anion of
2 is thermodynamically more stable than that of 1. The
high electron affinity of 2 can possibly be attributed to the
generation of a new aromatic sextet in one thiadiazole ring
by one-electron reduction to give the radical anion 4. This
assumption is supported by the fact that the reduction potential of 5[91(El = yO.46 V vs. SCE) is less negative than
that of the dichloro compound 3b (El= -0.56 V vs.
SCE).
Bis(ll,2,5]thiadiazolo)l3,44 ;3',4'-e]pyrazine,
a Novel 14n-Electron Heterocycle
with High Electron Affinity
By Yoshiro Yamashita, * Kenichi Saito, Takanori Suzuki,
Chizuko Kabuto, Toshio Mukai, and Tsutomu Miyashi
Cyclic thiazyl compounds have recently attracted considerable attention because of the interesting redox properties of the sulfur-nitrogen linkage.lll We have already
shown that the thiadiazole rings in 2,2'-(benzo[1,2-~;4,5-c~-
~-
~~
["I
~
Dr. Y. Yamashita, K. Saito, T. Suzuki, Dr. C Kabuto,
Prof. Dr. T. Mukai, Prof. Dr. T. Miyashi
Department of Chemistry, Faculty of Science, Tohoku University,
Aramaki, Sendai 980 (Japan)
434
0 VCH Verlagsyesellschafl mbH, 0-6940 Weinheim, 1988
The single crystal required for an X-ray structure analysisl'"] was obtained by sublimation.'"' Figure I shows two
views of the crystal structure. In the crystal there exist two
different kinds of 2 (abbreviated as BTPY-I and BTPY-2);
the molecular structures, however, are almost identical.[lZ1
Figure 2 shows the molecular structure of BTPY-I, the
center of which is related with the unit cell (Fig. la). The
molecule is planar. The S-N bond lengths lie between
those of an S-N single bond (1.73 A)1131
and an S-N double bond in sulfur diimide (1.53 A).[l4]The C-N bonds and
C-C bonds also have intermediate n-bond orders,[I5. l 6 ] although significant differences in the C-N bond lengths of
the thiadiazole rings and a little bond alternation are observed. The calculated n-bond orders show a delocalization of the n-electrons.
From Figure 1 it is clear that the molecules form a threedimensional network via S-N contacts. The BTPY-2 molecules are linked by strong S-N contacts between the thiadiazole rings (3.19 A) to give a ribbon-like structure. The
0570-0833/88/0303-0434 $ 0Z.S0/0
Angew. Chem. Int. Ed. Enyl. 27 (1988) No. 3
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