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Enantioselective Synthesis of ( R)--Vinylamino Acids.

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Table I . Data for compounds (6)-(12): Yields, physical and spectroscopic
properties. IR [cm- '1; NMR (CDCII): 6 values rel. TMS (all signals are singlets); UV (cyclohexane) [nm] (€). All substances gave correct elemental analyses.
(6): 65%; colorless oil, b.p. 5O"C/lO-' torr.-IR (Film): 1853, 1815, 1760
(anhydride); 'H-NMR: -0.13 (9H), 6.72 ( I H); "C-NMR: 2.42, 145.28,
157.54, 166.98, 169.80
(7): 80%; colorless crystals, m.p. 54"C.-IR (Film): 1840, 1760 (anhydride);
'H-NMR: 0.24 (27H). 3.72 ( I H); "C-NMR: 0.77, 2.36, 2.60, 55.55, 58.80,
170.35, 172.58, 177.16 (2C); UV: 220 (1290), 240 (850)
(8). 32%; red-orange oil.-IR (Film): 1690 ( C 4 ) ; 'H-NMR: 0.27 (18H),
0.35 (9H), 5.80 ( I H); "C-NMR: 0.47, 1.38, 1.61, 133.30, 143.61, 169.18.
174.87, 210.16; UV: 230 (sh), 395 (190)
(9): 13%: red-orange crystals, m.p. 36-37"C.-IR
(Film): 1690 (C=O),
1570 (C=C); 'H-NMR: 0.16 (9H), 0.22 (9H), 0.28 (9H). 7.28 ( I H); "CNMR: - 1.28, -0.15, 0.84, 133.23, 145.86, 160.60, 167.61, 210.61; UV: 227
(1040), 400 (180)
(10); 17%; red crystals, m.p. 81--83"C.-IR
(CDCI,): 1700 ( C 4 ) . 1530
(C=C); 'H-NMR: 0.25 (9H), 0.35 (9H), 0.40 (9H); '"C-NMR: 0.31, 0.76,
1.64, 129.13, 145.65, 162.66, 181.34, 198.31; UV: 250(sh), 445 (350)
(11): 41%; yellow-orange crystals, m.p. 50"C.-IR (CDCI,): 1685 (C=O),
1545 ( C 4 ) ; 'H-NMR: 0.30 (18H), 0.46 (9H); "C-NMR: 0.77, 1.66, 2.23,
130.65, 148.57, 161.49, 168.40, 206.06; UV: 250 (6590), 405 (495)
(12): 49%; orange crystals, m.p. 132--133"C.--IR (KI): 1670 ( C - 0 ) ; ' H NMR: 0.24 (ISH), 0.35 (18H); "C-NMR: 1.13, 2.36, 146.82, 181.09, 204.81;
UV: 423 (290)
Bromination of (8) with pyridinium perbromide at
- 78 "C in pentane and subsequent dehydrobromination
affords 2-bromowith 1,5-diazabicyclo[5.4.0]undec-5-ene
3,4,5-tris(trimethylsilyl)cyclopentadienone (10). while
bromination of (9) at 0 ° C followed by HBr-elimination
furnishes the structurally isomeric bromodienone ( I I ) .
The fourth trimethylsilyl group can be incorporated by
reaction of the reactive Michael acceptor (11)[9"1with
LiSiMe3 in the presence of C U I ' ~ ~ ] .
The resulting tetrakis(trimethylsilyl)cyclopentadienone
(12) behaves completely different compared to the analogous fourfold tert-butyl substituted derivative[5b1on photochemical excitation. The final product of the photolysis
(Hg low-pressure lamp, Rigisolve matrix, 77 K, 200 h) is
not the tetrahedrane (1.5)['01, but tetrakis(trimethylsi1yl)butatriene (13) (65%)["'. On irradiation in an argon matrix (10
K, 35 h) with 313-nm light, the allenylketene (14) (IR:
1890, 2080 cm-') can be detected as intermediate. Further
irradiation at a wavelength of 254 nm (10 K, 10 h) leads to
loss of C O and formation of the butatriene (13) (1543
cm-I).
The new trimethylsilyl compounds (9) and (12) constitute the first cyclopentadienone-equivalents available as
synthons, which are stable at room temperature.
Received: January 22, 1981 [Z 908 IE]
supplemented: May 29, 1981
German version: Angew. Chem. 93. 1010 (1981)
[ I ] G. Maier. H. P. Reisenauer. L. H. Franz, unpublished. 1R spectrum of
(4): 1727, 1724, 1332, 1136, 822, 632 c m - ' (cf. G. Maier. H.-G. Harlan,
T. Sayrap, Angew. Chem. 88. 252 (1976); Angew. Chem. Int. Ed. Engl.
15. 226 (1976): footnote [13]). UV spectrum: Am,,x= 195 (s), 360 (vw)
nm.
121 K. Hufner. K . Goliasch. Chem. Ber. 94, 2909 (1961); V. Osrerthun. E.
Winterjeldt, ibid. 110. 146 (1977).-We thank Prof. Winterfeldt for a
sample of (3).
I31 Cyclopentadienone (4) already dimerizes on thawing the argon matrix.
We were unable to confirm earlier data (0.L. Chapman, C. L. Mcintosh.
J. Chem. SOC.Chem. Commun. 1971. 770). according to which (4) was
obtained in the condensed phase at 77 K. Isolation on a cold (I0 K) window, without argon, yielded monomeric (4), but mainly the dimer was
recorded at 77 K.
I41 E. R. F. Gesing. J. P. Tone. K . P. C. Vollhardt. Angew. Chem. 92. 1057
(1980); Angew. Chem. Int. Ed. Engl. 19, 1023 (1980).
I51 I n analogy to a) G. Maier. S . Pfriem. Angew. Chem. 90. 551 (1978): Angew. Chem. In!. Ed. Engl. 17, 519 (1978); b) G. Maier. S . Pfiem. U .
Schufer. R . Marusch. ibid. 90. 552 (1978) and 17. 520 (1978).
Angew Chrm. Inr. Ed. Engl. 20 ( I Y X I ) No I t
[6] a) I. Bohm, H. Herrmann, K . Menke, H. Hopf: Chem. Ber. ill, 523
(1978); b) H. Okinoshima. K . Yamamoro, M. Kumada, J. Organomet.
Chem. 86, C27 (1975).
(71 a) Preparation according to the method of D. R. M. Walron, F. Waugh,
J. Organomet. Chem. 37, 45 (1972); b) Addition of (5) to maleic anhydride: K. Birkofer. D. Eichsfadl, ibid. 145. C29 (1978).
[S] A corresponding photoreaction in the tri-fert-butyl series has already
been reported: G. Maier, A . Aberreca, Angew. Chem. 85. 1056 (1973);
Angew. Chem. In!. Ed. Engl. 12, 1015 (1973).
191 a) G. Srork. B. Ganam. J. Am. Chem. SOC.95. 6152 (1973); b) D.J. Alger.
I . Fleming. J. Chem. SOC.Chem. Commun. 1978, 177.
[lo] Force-field calculations show that the "corset effect" [Sb] for the stabilization of the tetrahedrane skeleton no longer suffices in the case of fourfold substitution with trimethylsilyl groups. The trimethylsilyl group is
larger than the rerf-butyl group, but the decisive factor is the distance between Si and the ring C-atom (K. Mislow. private commurtication).
[ I 11 identified by comparison with authentic substance: J. R. Fritch. K . P. C.
Vollhardt. M. R . Thompson. V. W. Day. J. Am. Chem. SOC.101. 2768
(1979).
Enantioselective Synthesis of
(R)-a-Vinylamino Acids['*1
By Ulrich Schollkopf and Ulrich Grothr']
Dedicated to Professor Werner Reif on the occasion
ofhis 60th birthday
a-Vinylamino acids of type (6) have gained increasing
importance as potential enzyme inhibitors[''. Although several methods are available for their preparation in racemic
formL2],enantioselective syntheses, which would provide
access to these compounds in, if possible, the most optically pure form and with defined configuration have so far
not been described in the literature.
We describe here the enantioselective synthesis of almost optically pure (R)-2-arnino-3-phenyl-3-butenoic
acid
methyl ester (6) (p-methylenephenylalanine methyl ester),
which has previously been prepared in racemic form1".
This demonstrates that our bislactim-ether methodL4]is also
suitable for the asymmetric synthesis of a-vinylamino
acids. The bislactim ether
of cyclo-(L-Val-Gly) is converted with butyllithium into its lithium derivative (2).
which on reaction with acetophenone affords the adduct
(3)(ca. 90% yield) with extremely high diastereoselectivity.
The carbonyl compound enters trans to the isopropyl
group at C-6, i.e. the (R)-configuration is induced at C-3
(use of D-valine would result in the (S)-configuration). The
configuration was assigned on the basis of the 'H-NMR
spectrum. Since the adduct (3) has the "aryl-inner" conformation@],the hydrogen atom 6-H falls into the shielding
anisotropic region of the phenyl ring and its NMR signal
experiences a strong upfield shift.
Reaction of thionyl chloride/2,6-lutidine with (3) affords a mixture (80:20) of the two olefins (4) and (5).
which on hydrolysis with hydrochloric acid give, aside
from L-V~I-OCH,,the (R)-a-vinylamino acid ester (6) and
the a-keto ester (7). The keto ester (7) can be extracted
from the acidic aqueous solution. The amino acid ester (6),
which can be separated from L-V~I-OCH,by distillation,
is > 95% optically
[*I Prof. Dr. U.Schollkopf, Dipl.-Chem. U. Groth
[**I
Organisch-chemisches Institut der Universitat
Tammannstrasse 2, D-3400 Gottingen (Germany)
Asymmetric Synthesis via Heterocyclic Intermediates, Part 9.-Part
141.
0 Verlag Chemie GmbH. 6940 Weinheim. 1981
0570-0833/81/1111-0977 $02.50/0
8:
977
. .Q
IPr N,
HT
OMe
,,,,%H
AM:ox:Fe
soc,z
iPr
O
iPr
2,6 lufidine
Ph
N$OH Me
____,
0.25 N HCI
the p H was 8 - 10. The ether phase was separated off and
the aqueous phase extracted a further three times with ether. The combined ether extracts were dried over MgS04,
the ether removed under reduced pressure, and (6) distilled
in a Kugelrohr apparatus. Yield 0.22 g (64% referred to the
isomeric mixture of (4) and (S)), b.p. 100-11O"C/0.1 torr,
[a]g=- 62.1 (c = 0.6, ethanol), enantiomeric purity
>95%"'; 'H-NMR (CDCI,): 6=1.83 (s, NHJ, 3.71 (s,
OCH,), 4.54 (s, a-H), 5.34 and 5.43 (2 s, C=CH2), 7.257.49 (m, C,H,).
Me
Ph
T .+,H
: H z
- L - V ~ I - O C H ~ HzN
Ph
C02Me
H Y S 2 +
CH2
0 11
y+-Ph
Me02C
Me
The bislactim ether (8)['] of [(S)-(0,O-dimethyl-a-methyldopa)-Gly] is also suitable as starting compound for
the enantioselective synthesis of a-vinylamino acids. Reaction of the lithium compound of (8) with acetone, followed
by elimination of water and hydrolysis, affords the (R)-2amino-3-methyl-3-butenoic acid methyl ester (type (6). Me
instead of Ph)L9' with e x . i= 88% (determined 'H-NMR
spectroscopically with Eu(hfc), on the OCH, signal.
Procedure
(3): A 1 . 5 5 ~solution of n-butyllithium (4.2 mmol) in
hexane (2.7 mL) was added dropwise (under N2, injection
needle) at - 70°C to a solution of
(0.74 g, 4 mmol) in
dimethoxyethane (8 mL). The mixture was stirred for ca.
10 min at -70°C and then treated with the solution of
acetophenone (0.50 g, 4.2 mmol) in dimethoxyethane ( 5
mL). After ca. 4 h the mixture was rendered neutral with a
solution of glacial acetic acid (0.25 g, 4.2 mmol) in dimethoxyethane (2 mL), allowed to warm to room temperature, and the solvent removed under reduced pressure. The
residue was taken u p in ca. 10-15 mL of ether, washed
with about 20 mL of water, and the aqueous phase extracted twice with 20 mL of ether. The combined ether extracts were dried over MgS04, the ether removed under reduced pressure, and (3) was distilled in a Kugelrohr apparatus. Yield 1.1 g (91%) (3), b.p. 140-150°C/0.1 torr.
(4) and (5): A solution of SOC12 (0.37 g, 3.1 mmol) in toluene (4 mL) was added to a solution of (3) (0.91 g, 3
mmol) and 2,6-lutidine (0.66 g, 6.2 mmol) in toluene (10
mL) at room temperature. After 16 h the mixture was
treated with ca. 20 mL of ether, washed with ca. 15-20
mL of water, dried over MgSO,, the solvent removed under reduced pressure, and the residue distilled in a Kugelrohr apparatus. Yield 0.75 g (88%) (4) and (5) in the ratio
80 :20, b.p. 13O-14O0C/O.1 torr.
(6): A solution of (4) plus (5)(0.52 g, 1.8 mmol) in 0.25 N
HCI (14.4 mL, 3.6 mmol) was stirred for 30 h and then extracted with ether. The aqueous phase was evaporated
down under reduced pressure to ca. 1-2 mL (bath temperature 6O-8O0C), covered with ca. 10 mL ether, and treated
with conc. ammonia solution with vigorous shaking until
97 8
0 Verlag Chemie GrnbH, 6940 Weinheim. 1981
Received: April 10, 1981 [Z891 IE]
German version: Angew. Chem. 93. 1022 (1981)
CAS Registry numbers:
(1). 78342-42-4;(3). 79435-70-4;(4). 79435-71-5;(5). 79435-72-6:(6). 7943579435-74-8;
73-7;(8). 79448-86-5;methyl (R)-2-amino-3-methyl-3-butenate,
PhCOMe, 98-86-2
[I] B. W . Metcalf, K. Jund. Tetrahedron Lett. 1977, 3689; R. R. Rando, Acc.
Chem. Res. 8. 281 (1975): G. Nass. K. Poralla. H. Zahner. Naturwissenschaften 58, 603 (1971); W. Trowitzsch, H. Sahm, 2. Naturforsch. 32c. I 8
(1977); R . H. Abeles. Pure Appl. Chem. 53, 149 (1980).
[21 Cf. W. 1. Greenlee. D. Taub, A. A. Patchett, Tetrahedron Lett. 1978. 3999;
B. W. Metcalf: E. Bonilauri. J. Chem. SOC.Chem. Commun. 1978. 914; W.
Steglich. H. Wegrnann. Synthesis 1980. 481; 1. Hoppe, U. Schollkopf: ;bid.
1981. 646.
131 R. V. J . Char;. J. Wemple. Tetrahedron Lett. 1979, 11 1.
[4] U. Schollkopf: U. Groth, K . - 0 . Westphalen. C. Deng. Synthesis 1981. 969,
a n d earlier communications of this series.
[5l U. Schollkopf: U. Grorh. C. Deng. Angew. Chem. 93. 193 (1981); Angew.
Chem. lnt. Ed. Engl. 20. 798 (1981).
[6]Cf. U. Schollkopf, W . Hartwig. U. Groth. K . - 0 . Westphalen, Liebigs Ann.
Chem. 1981. 696; U. Schollkopf, W . Hartwig. U . Groth. Angew. Chem. 91.
922 (1979);Angew. Chem. Int. Ed. Engl. 18. 863 (1979);A . K . Bose, M. S.
Manhas. R . V. Tawares. J. M. van der Veen. H. Fujiwara. Heterocycles 7.
1227 (1977).
[7] We assume >95%, if only o n e enantiomer is detectable ' H - N M R spectroscopically on the basis of its O C H x signal using Eu(hfc).>.
[8] U. Schollkopf. W. Hartwig. K.-H. Pospischil. Synthesis 1981, 966.
[91 For the synthesis o f this amino acid (D-isodehydrovaline) from methyl 2aminoacrylate with isomerization and its use in penicillin synthesis cf. 1.
E. Baldwin. M. A . Christie. S. B. Haber. L. I. Kruse. J. Am. Chem. SOC.
98. 3045 (1976).
CC-Coupling and Reversible y-H Abstraction
in the Tantalum Complex
C1(q5-Cp)(q3-C9H7)Ta(
CHCMe,)
By Anton W. Gal and Harry van der Heijded"
Coordinatively unsaturated cyclopentadienyl(Cp)-tantalum-neopentylidene complexes have been shown to be
useful precursors for reactive tantalum olefin compoundslIal.They generally react with olefins to give tantalacyclobutane intermediates, which rearrange via S,a hydrogen migration to give the corresponding tantalum olefin complexesL'a~cl.
However, coordinatively saturated neopentylidene
complexes,
such
as
Cl(qsCp),Ta(CHCMe,)IId1, d o not react with olefins. In an attempt to enhance the reactivity of CI(q5-Cp),Ta(CHCMe3)
we have now replaced one $-Cp group by an q3-indenyl
group (q3-C9H7)to obtain Cl(q5-Cp)(q3-C9H7)Ta(CHCMe3)
(2)[*1.
The q3-indenyl complex (2) is prepared by reaction of
one equivalent of indenylsodium with CI,CpTa(CHCMe,)
( I ) (molar ratio 1 : 1) in benzene[". If excess of indenylsodium ( > 2 : 1) is used (3) is the only product (Scheme 1).
['I Dr. A.
W. Gal, H. van d e r Heijden
Koninklijke/Shell-Laboratorium,
Amsterdam (Shell Research B. V.)
Badhuisweg 3, NL-1031 C M Amsterdam (The Netherlands)
0570-0833/81/1111-0978 $ 02.50/0
Angew. Chem. I n I . Ed. Engl 20 (1981) No. I 1
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