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Enantio- and Diastereoselective Synthesis of Methyl (2R)-2-Amino-5-oxocarboxylates from Enones and Bislactim-Ether Cuprates.

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[I] a) R. J. Ternansky, D. W. Balogh, L. A. Paquette, J. Am. Chem. SOC.104
(1982) 4503; b) L. A. Paquette, R. J. Ternansky, D. W. Balogh, G. Kentgen, ibid. 105 (1983) 5446.
121 a) W.-D. Fessner, Bulusu A. R. C. Murty, H. Prinzbach, Angew. Chem.
99 (1987) 482; Angew. Chem. Int. Ed. Engl. 26 (1987) 451; b) W.-D.
Fessner, Bulusu A. R. C. Murty, J. Worth, D. Hunkler, H. Fritz, H.
Prinzbach, W. D. Roth, P. von R. Schleyer, A. B. McEwen, W. F. Maier,
ibid. 99 (1987) 484 and 26 (1987) 452, resp.
131 L. A. Paquette, R. A. Snow, J. L. Muthard, T. Cynkowski, J. Am. Chem.
SOC.100 (1978) 1600.
[4] P. Gund, T. M. Gund, J. Am. Chem. SOC.103 (1981) 4458.
[51 0. Ermer: Aspekte uon Kraflfeldrechnungen, Wolfgang-Baur-Verlag,
Munchen 1981, Chap. 4.6.3.
161 a) F. Harary in A. T. Balaban (Ed.): Chemical Applications of Graph Theory, Academic Press, London 1976, Chap. 2; b) A. T. Balaban, ibid.,
Chap. 3; c) J. Simon in R. B. King, D. H. Rouvray (Eds.): Graph Theory
and Topology in Chemistry, Elsevier, Amsterdam 1987, p. 43.
171 W. Luef, R. Keese, Helu. Chim. Acla 70 (1987) 543.
[8] a) H. E. Simmons 111, J. E. Maggio, Tetrahedron Left. 22 (1981) 287; b)
S. A. Benner, J. E. Maggio, H. E. Simmons Ill, J. Am. Chem. SOC.103
(1981) 1581.
[9] L. A. Paquette, M. Vazeux, Tetrahedron Lett. 22 (1981) 291.
[lo] For examples of the rare central coupling of five quaternary tetracoordinated but non-equivalent C atoms. See: a) L. F. Pelosi, W. T. Miller, J.
Am. Chem. SOC.98 (1976) 431 1 ; b) G. Maier, S. Pfriem, Angew. Chem. 90
(1978) 552; Angew. Chem. Int. Ed. Engl. 17 (1978) 520; c) J. E. Maggio,
H. E. Simmons 111, J. K. Kouba, J. Am. Chem. SOC.I03 (1981) 1579.
[I I] For a discussion of ideal tetrahedral coordination in hydrocarbons see:
a) A. Greenberg, J. F. Liebman: Strained Organic Molecules. Academic
Press, New York 1978, Chap. 6; b) [7].
1121 a) D. Kuck, Angew. Chem. 96 (1984) 515; Angew. Chem. Int. Ed. Engl. 23
(1984) 508.
113) a) D. Kuck, B. Paisdor, H.-F. Griitzmacher, Chem. Ber. 120 (1987) 589;
b) B. Paisdor, H.-F. Griitzmacher, D. Kuck, ibid. 121 (1988) 1307.
[14] D. Kuck, H. Bogge, J. Am. Chem. SOC.108 (1986) 8107.
[I51 a) B. R. Venepalli, W. C. Agosta, Chem. Rev. 87(1987) 399; b) K. Krohn,
Nachr. Chem. Tech. Lab. 35 (1987) 264.
[I61 1 and 7 gave satisfactory elemental analyses.
1171 ’H-NMR (300 MHz, CDCI,): 6=7.46 (m. 8H), 7.50 (m, 4H), 7.95 (d, 7.3
Hz, 4H). Even at 130°C (solvent CDClzCDC12) no coalescence is observed in the ‘H-NMR spectrum of 7.
salts, which have already proven useful for the preparation
of alkyl and alkenyl cup rate^,"^ we found that the bislactim-ether cuprates 3 can be obtained by reaction of 2 with
CuBr. S(CH3)2in the presence of dimethyl sulfide.
The cuprate 3a reacts highly selectively with 2-enones 4
to give 1,4-adducts; the diastereofacial selectivity at the
heterocycle is extremely high (> 100 : 1 ; Table l), i.e. one
obtains almost exclusively the (2R,5S) epimers of the adducts, the precursors of the corresponding D-a-amino-6oxocarboxylic acids (type 14).
L
I
R3
0
I
.
1/2 CuBr S(CH&
>
H3C0
3
5
6
1-3: a , R1 = H;
b. R1 = CH3
5, 6: R1 = H
Table 1. Yields and configurations of the Michael adducts 5 , R’= H.
5
R2
R’
R4
Yield
(2R.I‘R) : (2R,l’S) [a][b]
5 :6
“1
Enantio- and Diastereoselective Synthesis of
Methyl (2R)-2-Amino-5-oxocarboxylatesfrom
Enones and Bislactim-Ether Cuprates**
a
b
c
d
By Ulrich Schollkopf;* Dagmar Pettig, Edda Schulze,
Michael Klinge, Ernst Egert,* Bernd Benecke, and
Mathias Noltemeyer
Dedicated 10 Professor Heinrich Noth on the occasion of
his 60th birthday
e
f
g
1194
0 VCH Verlagsgesellschaft mbH, 0-6940 Weinheim, 1988
H
H
H
CHj
Ph
2-Fury1
H
71
71
66
52
62
60
39
100
100
100
100
83
100
- [c]
:
:
:
:
:
:
2
6
12
100
100
64
- [c]
l o o : 51
100 : 3
100 : 5 1
100 : 19
100 : 6
100 : 22
100 : 5
[a] Determined by capillary chromatography and I3C-NMR spectroscopy. [b]
(2S)-epimers 5 1. [c] (2R) : ( 2 S ) > 100: I.
Lithiated bislactim ethers 2 react with enones to give
1,2- and 1,4-add~cts.[’~
In our studies on the asymmetric
synthesis of non-proteinogenic amino acids according to
the bislactim-ether method[21we were interested in finding
an entry to 1,Cadducts of the type 5 ;we therefore decided
to check whether and how the lithium compounds 2 are
convertible into cuprates of bislactim ethers. Numerous alkyl and alkenyl cuprates have already been de~cribed,’~]
whereas very few azaenolate-cuprates have been reported.I4l Heterocyclic azaenolate-cuprates are as yet unknown. After a number of abortive attempts with such Cu‘
[*I Prof. Dr. U. Schollkopf, Dr. D. Pettig, E. Schulze, M. Klinge
Institut fur Organische Chemie der Universitat
Tammannstr. 2, D-3400 Gottingen (FRG)
Dr. E. Egert, B. Benecke, M. Noltemeyer
lnstitut fur Anorganische Chemie der Universitat
Tammannstr. 4, D-3400 Gottingen (FRG)
[**I Asymmetric Synthesis via Heterocyclic Intermediates, Part 41.-Part 40:
K. Schollkopf, K.-0. Westphalen, J. Schroder, K. Horn, Liebigs Ann.
Chem. 1988, 781.
-(CH2)2-(CH2)3-(CH2)4-(CH2)2CH,
H
CH,
H
CH,
H
Simple cyclic enones such as cyclopentenone and cyclohexenone (4a and 4b, resp.) react also with high enantiofacial selectivity at the double bond. Of four possible diastereomers, almost only the (ZR,SS,l’R)-isorners 5a and 5b
are formed, i.e. two stereocenters are created highly selectively at the same time. The (2R,l’R) configuration of 5b
was confirmed by an X-ray structure analysis. Cyclic
enones with a substituent in the 3-position (e.g. 4d) react
with lesser enantiofacial selectivity. The same holds true
for conformationally flexible acyclic enones with substituents in the 3-position (e.g. 4e and 4f).[’I
Reaction of 3a with (-)-(R)-carvone 4h leads because
of favorable double stereoselection (matched case) and because of highly selective protonation at C-2’, almost exclusively to (2R,I‘R,2’R)-5h. The diastereomeric ratio is ca.
100 : 3 : 2 :1. The structure of 5h was confirmed by an Xray analysis. With ( + )-(S)-carvone (mismatched case) the
diastereomers are formed in the ratio 10 :5 : 1.5 : 1.5.
0570-0833/88/0909-1194 $ 02.50/0
Angew. Chem. Int. Ed. Engl. 27 (1988) No. 9
hydrolysis of (2R,l'S)-Sf leads as expected to the methyl
(2R,3S)-3-(2'-furyl)-3,4-dihydro-5-methyl-pyrrolecarboxy~
ate 16, whose C = N bond is so regiostable that it can be
purified by distillation.
p
4h
50. b
HQ/H,o
+
++H3C0,C
- (L-Val-OCH3)
XNH
14, X = H
15a, X = Boc,
n = 1(71%)
15b. X = Boc.
n = 2(68%)
H3C0
CHT
=/
0
8
7
S02Ph
Experimental
10
9
5 (8, 10): l a (1.00 g, 5.45 mmol) [S] was metalated with n-butyllithium in
Since the carbonyl group is a particularly useful functional group, the compounds of type 5 (or 14, cf. below)
open up an entry to numerous non-proteinogenic amino
acids that are stereoisomerically pure in the a- and partly
also in the fbposition (e.g. 14a and 14b). The cuprate 3a
reacts with the dienone 7 to give the 1,6-adduct 8 (together with ca. 10% 1,2-adduct), and again with high diastereoselectivity; only two diastereomers in the ratio 10 : l
are detectable I3C-NMR spectroscopically. Both have the
(2R)-configuration, whereas the 1 '-configuration is still unclear. Phenyl vinyl sulfone 9 also reacts with a high degree
of diastereospecificity with 3a (de>98%) to give the "Michael adduct" 10. Reaction of the lithium compound 2a
with 9, on the other hand, furnishes only polymeric products.
As expected cuprates of type 3 can also be alkylated.
Thus, reaction of 3a and 3b with ethyl 3-bromopropionate
l l a affords the alkylated products (2R,5S)-12a and 13a,
which are precursors of the corresponding (R)-glutamic
acid derivatives, in satisfactory yields and with a remarkably high de value of ca. 98%. The lithium compounds 2a
and 2b react with the bromopropionate lla,'7] not only
with alkylation but also with elimination. 3-Bromopropionitrile l l b reacts analogously with 3a and 3b to give
12b and 13b (de ca. 98%). Reaction of the lithium compound 2a with acetonitrile leads to polymerization. The
cuprates 3 are thus preferred over the lithium compounds
2 in the alkylation of the bislactim ethers if the alkylating
agent is base-labile or if very high de values are aimed
for.
12.13
12, R = H; 13, R = CHB
11, 12, 13: a , X = C02CH,CH3;
b , X = CN
The hydrolysis of the adducts 5a and 5b (two equivalents
of 0.25 N HCI, room temperature, 20 h) affords (besides LVal-OMe) the diastereomerically and enantiomerically
pure (2R,3R)-amino acid methyl esters 14. These are thermolabile and therefore cannot be separated from the Lvaline methyl ester by distillation. The separation can,
however, be accomplished readily by chromatography at
the stage of the N-Boc derivatives 15a, b. In contrast, the
Angew. Chem Int. Ed. Engl. 27 (1988) No. 9
THF (10mL) at -78°C. The solution of 2a was then added dropwise
through a Teflon tube to a solution of CuBr.S(CH3)2191 (0.56 g, 2.73 mmol)
and S(CH3)2( 5 mL) in THF (10 mL). After 0.5 h at -30°C the mixture was
treated with a solution of 4 (or 7, 9 ) (5.45 mmol) in T H F ( 5 mL) at -70°C
and stirred for 4-16 h at this temperature. After subsequent addition of glacial acetic acid (0.33 g, 5.45 mmol) the mixture was allowed to warm to room
temperature, transferred to a column of Silica gel 60 f20g; 0.05-0.2 mm, 70270 mesh ASTM; 200 x 60 mm') and eluted with ca. 500 mL of ether. After
removal of solvent the residue was distilled (Kugelrohr) or chromatographed.-5a: b.p. 1 lO"C/0.05 torr, m.p. 60-61 "C; 5b: b.p. 15O"C/O.O5 ton,
m.p. 95-97°C; 5c: b.p. 115"C/O.O5 torr, m.p. 71-72°C; 5 d : b.p. llO"C/O.O5
torr, Rr=0.16, ether/pentane (1 : 3 ) ; 5e: (2R,I'R)-5e: Rt=0.20, (2R.I'S)-Se:
R,=0.14, ethyl acetate/pentane (1 :6); 5f: (2R,I'R)-5f: R,=0.07, (2R,I'S)-Sf:
Rr=0.04, ether/pentane ( I :6); 5g: h.p. 12O0C/O.01 tom; 5h: b.p. 120"C/
0.05torr, m.p. 76-77°C; 8: Rt=0.05, ether/pentane ( I :8); 10: Rr=0.15, ethedpentane (1 :3).
N-Boc amino acid esters 15: A mixture of 5a or 5b (3.0 mrnol) and 0.25 N
HCI (24 mL, 6.0 mmol) was vigorously stirred for 20 h. After removal of solvent under vacuum, the residue (hydrochlorides of the amino acid esters) was
treated with CHCI, (20mL), NaCl (1.8 h) and Boc-anhydride (1.53 g,
7.0 mmol) and then with 8 mL of a saturated NaCO, solution. The mixture
was heated under reflux for 3 h, the phases separated, and the aqueous phase
extracted with 2 x 20 mL of ether, dried over MgS04 and the solvent removed under vacuum. The residue was chromatographed on ca. 70 g of silica
gel (Silica gel 60, 5OOx 15 mm2 column, ether/pentane (1 :1).-15a: R t =
0.13, m.p. 104-105°C; 15b: Rt=0.18, m.p. 85-86°C.
Correct C,H analyses were obtained for all compounds
Received: April 20, 1988 [Z 2712 IE]
German version: Angew. Chem. 100 (1988) 1238
[I] D. Pettig, Diplomarbeit. Universitat Gottingen 1984.
[2] U. Schollkopf, Pure Appl. Chem. 55 (1983) 1799; Chem. Scr. 25 (1985)
105; U. Schollkopf in J. Streith, H. Prinzbach, G. Schill (Eds.): Organic
Synthesis: An Interdisciplinary Challenge, Blackwell, Oxford 1985,
p. 101.
[3] G . H. Posner, Org. React. N . Y. I9 (1972) I ; ibid. 22 (1975) 253; J. F.
Normant, Synthesis 1973, 63; H. 0. House, W. L. Respess, G. M. Whitesides, J. Org. Chem. 31 (1966) 3128; Gmelin: Handbook of Inorganic
Chemistry, Cu. Organocopper Compounds, Part 2, Springer, Berlin 1983.
[4] a) E. J. Corey, D. Enders, Tetrahedron Lett. 1976, I 1 ; b) Chem. Ber. III
(1978) 1362; C) K. Yamamoto, M. Iijima, Y. Ogimura, Tetrahedron Lett.
23 (1982) 371 1; d) K. Yamamoto, M. Kanoh, N. Yamamoto, J . Tsuji, ibid.
28 (1987) 6347.
[5] We attribute the high enantiofacial selectivity in the case of 4a and 4b to
the rigid "transoid" enone arrangement. The situation is analogous to the
Michael addition to acrylic acid esters [6]. In the case of "transoid" fixed
5,6-dihydropyran-2-one the enantiofacial selectivity at the double bond is
> 90%; in the case of the open-chain, flexible crotonic acid methyl esters,
however, it is only ca. 50%.
161 U. Schollkopf, D. Pettig, Synthesis 1986. 737.
171 For the alkylation of Zb see: U. Schollkopf, K.-0. Westphalen, U. Groth,
Chuanzheng Deng, Synthesis 1981, 969; U. Schollkopf, U. Busse, R.
Lonsky, R. Hinrichs, Liebigs Ann. Chem. 1986, 2150.
181 U. Schollkopf, U. Groth, C. Deng, Angew. Chem. 93 (1981) 791; Angew.
Chem. Int. Ed. Engl. 20 (1981) 798; l a and Ib and en/-la and ent-lb are
commercially available from Merck-Schuchardt.
191 CuBr-S(CH,), is recrystallized: G . H. Posner: An Introduction to Synthesis Using Organocopper Reagents, Wiley, New York 1980.
0 VCH Verlagsgesellschaft mbH, 0-6940 Weinheim. 1988
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methyl, diastereoselective, synthesis, cuprates, ethers, enones, amin, oxocarboxylates, bislactim, enantio
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