Highly diastereo- and enantioselective reactions of enecarbamates with ethyl glyoxylate to give optically active syn and anti α-alkyl-β- hydroxy imines and ketones

Article abstract of DOI:10.1002/anie.200460165

The remarkably selective addition of enecarbamates 2 to ethyl glyoxylate (1) in the presence of a copper-dilmine catalyst (0.1 mol%) gives the corresponding imines 3 in high yields with excellent enantioselectivities. A concerted aza-enetype reaction mech

Full text of DOI:10.1002/anie.200460165

Angewandte
Chemie
Communications
The addition of enecarbamates to ethyl
glyoxylate in the presence of a copper–diimine
catalyst gives the corresponding imines in high yields with excellent
enantioselectivities. Whereas E enecarbamates give anti adducts, syn
adducts are obtained from Z enecarbamates. On the following pages,
Kobayashi and co-workers describe this novel reaction and propose a
concerted aza-ene-type reaction mechanism to explain the remarkable
stereochemical outcome.
Angew. Chem. Int. Ed. 2004, 43, 3257
DOI: 10.1002/anie.200460165
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Communications
Addition Reactions
worked well in this reaction, CuII–diamine complexes,[10]
which gave excellent results in Mannich-type reactions of
N-acylimino esters with enamides and enecarbamates,[5]
afforded the product with moderate enantioselectivity
(Table 1, entry 1). On the other hand, it was revealed that
Highly Diastereo- and Enantioselective Reactions
of Enecarbamates with Ethyl Glyoxylate To Give
Optically Active syn and anti a-Alkyl-b-Hydroxy
Imines and Ketones**
Table 1: Catalyzed reactions of ethyl glyoxylate (1) with enecarbamate 2a
(R1 =Ph, R2 =H, R3 =Bn).[a]
Ryosuke Matsubara, Yoshitaka Nakamura, and
Shu¯ Kobayashi*
Control of the absolute configuration of two adjacent stereo-
genic centers that include alkyl and hydroxy groups is among
the most important reactions for the synthesis of many
biologically active compounds.[1] For the relative stereochem-
istry issue (syn/anti), aldol,[2] allylation,[3] and related reactions
via six-membered transition states are powerful tools, and
diastereoselective reactions with chiral auxiliaries have
opened the way to optically active compounds. For asym-
metric catalysis, on the other hand, Mukaiyama-type reac-
tions of silicon reagents with chiral Lewis acids have been
investigated extensively.[4] However, the reactions proceed via
acyclic transition states to afford syn adducts in most cases,
and control of the relative stereochemistry by geometrical
isomers is difficult.
We recently investigated the use of enamides and
enecarbamates as nucleophiles.[5] In spite of their importance
in organic chemistry, examples of nucleophilic additions of
enamides or enecarbamates are few,[6] whereas there are
many reports on the use of enamines as nucleophiles.[7]
Herein we report the first highly diastereo- and enantiose-
lective addition reaction of enecarbamates with ethyl glyox-
ylate. This reaction proceeds smoothly in the presence of a
CuI–chiral diimine complex, and a-monosubstituted enecar-
bamates provide the corresponding adducts stereospecifi-
cally; that is, syn products are obtained from Z enecarbamates
and anti products are obtained from E enecarbamates with
high diastereo- and enantioselectivities.
Entry
Ligand
CuX
Yield [%][b]
ee [%][c]
1
2
3
4
3a
3b
3a
3b
3c
3c
Cu(OTf)2
Cu(OTf)2
CuClO4·4CH3CN
CuClO4·4CH3CN
CuClO4·4CH3CN
CuClO4·4CH3CN
93
65
90
94
93
96
55[d]
70[d]
35[d]
93
97
95
5
6[e]
[a] All reactions were performed in CH2Cl2 at 08C for 1 h in the presence
of CuX (10 mol%) and 3.[b] Yield of isolated 5a.[c] Determined by
HPLC (see Supporting Information).[d] The absolute configuration is R.
[e] Catalyst: 2 mol%.Tf =trifluoromethanesulfonyl.
much higher enantioselectivities were obtained when CuI–
diimine complexes[11] were used (Table 1, entries 4 and 5).
Among several chiral imines tested, CuI–diimine ligand 3c
gave the highest enantioselelctivity (97% ee). Furthermore,
lower loading of the catalyst (2 mol%) gave the same level of
reactivity and selectivity (96% yield, 95% ee; Table 1,
entry 6).
We then examined several other enecarbamates, and the
results are summarized in Table 2. a-Unsubstituted enecar-
bamates 2b–e reacted smoothly to afford the desired adducts
in high yields with excellent enantioselectivities (Table 2,
entries 1–4). For the reactions with a-substituted enecarba-
mates, remarkable results were obtained. The reactions
proceeded stereospecifically: E enecarbamates gave anti
adducts, whereas Z enecarbamates produced syn adducts
with both excellent diastereo- and enantioselectivities in most
cases. These selectivities are in contrast to Lewis acid
catalyzed asymmetric aldol-type reactions of silicon enolates
with aldehydes, which give mostly syn adducts, regardless of
the geometry of the enolates.[4,12] The asymmetric reactions
discussed herein also proceeded smoothly in the presence of
0.1 mol% of the CuI catalyst. Moreover, it was found that
under the same conditions as those shown in Table 1, entry 5,
comparable yield and enantioselectivity were obtained when
using an undistilled polymer-form ethyl glyoxylate solution in
Initially, the reaction of ethyl glyoxylate (1), which was
freshly distilled from a commercially available polymer-form
solution in toluene, with enecarbamate 2a[8] was investigated
in the presence of various chiral Lewis acids. It was found that
some Lewis acids were effective and afforded the corre-
sponding imine-type adducts 4 in high yields. For determining
the ee values of the products, 4 was converted into the
corresponding ketones 5.[9] Although some copper salts
[*] R.Matsubara, Y.Nakamura, Prof.Dr.S.Kobayashi
Graduate School of Pharmaceutical Sciences
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax:(+81)3-5684-0634
E-mail: skobayas@mol.f.u-tokyo.ac.jp
[**] This work was partially supported by CREST, SORT, and ERATO,
Japan Science Technology Agency (JST), and a Grand-in-Aid for
Scientific Research from Japan Society for the Promotion of
Sciences (JSPS).RM. .is grateful for a JSPS fellowship for Japanese
Junior Scientists.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200460165
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Angewandte
Chemie
Table 2: CuI–3c-catalyzed reactions of 1 with 2 (R3 =Bn).[a]
Entry
2
5
Yield [%][b] syn/
ee [%][d]
anti[c]
1
2
3
4
5
2b (R1 =PMP, R2 =H)
2c (R1 =PCP, R2 =H)
2d (R1 =PMeP, R2 =H)
2e (R1 =2-Nap, R2 =H)
(E)-2 f (R1 =Ph, R2 =Me)
5b 94
5c 97
5d quant
5e 91
5 f 83
5 f 95
5 f 82
5 f 96
–
–
–
–
1:99
1:99
98:2
98:2
2:98
98:2
3:97
93
97
96
96
98
98
98
98
98
98
96
Scheme 2. Determination of the relative configuration of 5 f.
6[e,f] (E)-2 f
(Z)-2 f
8[f] (Z)-2 f
The fact that a-monosubstituted enecarbamates provided
products stereospecifically led us to propose a concerted aza-
ene-type reaction mechanism outlined in Figure 1.[17,18] This
7
9
10
11
(E)-2g (R1 =PMP, R2 =Me) 5g 96
(Z)-2g
5g 97
5g 82
(E)-2h (R1 =PMP,
R2 =Me)[g]
(Z)-2h[g]
12
13
14
15
16
5g 96
99:1
2:98
99:1
1:99
98
98
98
98
98
97
98
94
(E)-2i (R1 =PCP, R2 =Me) 5i 85
(Z)-2i
5i 79
5j 58
5j 92
5k 83
5k 89
5l 85
(E)-2j (R1 =Ph, R2 =Et)[h]
(Z)-2j
99:1
17[e] (E)-2k (R1 =Et, R2 =Me)
18[e] (Z)-2k
19
3:97[i]
92:8[i]
16:84[i]
1
2
À
À
2l (R , R = (CH2)4 )
Figure 1. Proposed transition-state models.
[a] All reactions were performed in CH2Cl2 at 08C in the presence of the
catalyst (10 mol%, unless otherwise noted).Reaction time was 05. –2 h
in most cases.[b] Yield of isolated product.[c] Determined by HPLC.
[d] Major diastereomer, ee value determined by HPLC (see Supporting
proposed mechanism does not contradict the result that the
reaction of N-methylated enecarbamate 2m with ethyl
glyoxylate gave no adduct with almost all the
starting materials left unconverted. TS-1 should be
a predominant transition state since the other
candidate, TS-2, has unfavourable steric interac-
tion between the bulky R group of the enecarba-
mate and the ester group of ethyl glyoxylate and/or
the bulky copper catalyst. The TS-1 model would account for
the stereochemical outcome of the reaction.
In summary, novel highly enantioselective copper–di-
imine-catalyzed addition reactions of enecarbamates with
ethyl glyoxylate have been developed. It was demonstrated
that high yields and high enantioselectivities were obtained,
even when using 0.1 mol% of the catalyst. a-Monosubstituted
enecarbamates also reacted with glyoxylate stereospecifically
to give the corresponding adducts in high yields with excellent
diastereo- and enantioselectivities. Further investigations into
the precise mechanism of this reaction as well as the use of
enecarbamates as nucleophiles in other reactions are in
progress.
Information).[e] À208C.[f] Catalyst: 10.mol%.[g] R
3 =Et.[h]
1
(1.0 equiv) and 2 (2.0 equiv). [i] Determined by NMR analysis. PMP=
p-methoxyphenyl, PCP=p-chlorophenyl; PMeP=p-methylphenyl; 2-
Nap=2-naphthyl.
toluene, which indicates that the CuI–diimine complex both
depolymerizes the glyoxylate as well as catalyzes the follow-
ing asymmetric addition reaction.[13]
The reactions with enecarbamates are more atom eco-
nomical than those with enolates; the initial imine-type
products 4 contain all the atoms that compose both substrates
(ethyl glyoxylate and enecarbamates). After the enecarba-
mate addition, the following diastereoselective reduction was
conducted in the same pot to afford N-Cbz-protected a-
hydroxy-g-amino acid ester
6
with high selectivity
(Scheme 1).[14] For anti-5 f (d.r. = 99:1), the reduction of the
Received: March 31, 2004 [Z460165]
Published Online: May 17, 2004
Keywords: asymmetric catalysis · aza-ene reaction · copper ·
N ligands · synthetic methods
Scheme 1. Conversion into N-Cbz a-hydroxy g-amino acid ester 6.
Cbz=benzyloxycarbonyl.
.
[1] For recent examples, see: T. Wakabayashi, K. Mori, S. Kobaya-
shi, J. Am. Chem. Soc. 2001, 123, 1372, and references therein.
[2] Reviews: a) C. H. Heathcock in Comprehensive OrganicSyn-
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b) R. Mahrwald, Chem. Rev. 1999, 99, 1095; c) E. M. Carreira in
Modern Carbonyl Chemistry (Ed.: J. Otera), Wiley-VCH,
Weinheim, 2000, p. 227.
ketone moiety with NaBH4 followed by cyclization gave
lactone 7 as a diastereomeric mixture (Scheme 2).[15] One
diastereomer of 7 was obtained as a crystalline compound,
which was characterized by X-ray crystallography.[16] From
the knowledge of the relative configuration of 7, the relative
configuration of 5 f was determined.
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Communications
[3] Reviews: a) Y. Yamamoto, N. Asao, Chem. Rev. 1993, 93, 2207;
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[5] R. Matsubara, Y. Nakamura, S. Kobayashi, Angew. Chem. 2004,
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[7] a) Y. Hayashi, K. Otaka, N. Saito, K. Narasaka, Bull. Chem. Soc.
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[8] Enecarbamates are readily prepared (see Supporting Informa-
tion).
[9] The absolute configuration of 5a was determined by the
comparison of HPLC retention time: P. Herold, A. F. Indolese,
M. Studer, H. P. Jalett, U. Siegrist, H. U. Blaser, Tetrahedron
2000, 56, 6497; the absolute configuration of 5 f was also
determined by the Mosher esterification method (see Support-
ing Information).
[10] S. Kobayashi, R. Matsubara, Y. Nakamura, H. Kitagawa, M.
Sugiura, J. Am. Chem. Soc. 2003, 125, 2507.
[11] Z. Li, K. R. Conser, E. N. Jacobsen, J. Am. Chem. Soc. 1993, 115,
5326.
[12] For Mukaiyama-type catalytic asymmetric aldol reactions of
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1993, 115, 7039; b) K. Mikami, S. Matsukawa, J. Am. Chem. Soc.
1994, 116, 4077; c) D. A. Evans, D. W. C. MacMillan, K. R.
Campos, J. Am. Chem. Soc. 1997, 119, 10859; d) D. A. Evans,
C. E. Masse, J. Wu, Org. Lett. 2002, 4, 3375.
[13] The CuII–box catalyst is known to have the same activity for
depolymerization of ethyl glyoxylate; see: D. A. Evans, S. W.
Tregay, C. S. Burgey, N. A. Paras, T. Vojkovsky, J. Am. Chem.
Soc. 2000, 122, 7936.
[14] K.-M. Chen, G. E. Hardtmann, K. Prasad, O. Repic, M. J.
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[15] S. Kanemasa, N. Nakagawa, H. Suga, O. Tsuge, Bull. Chem. Soc.
Jpn. 1989, 62, 171.
[16] See also Supporting Information.
[17] A cncerted aza-ene-type reaction was proposed for the Michael
reaction with a chiral enamine: a) L. Ambroise, D. Desmaꢁle, J.
Mahuteau, J. dꢀAngelo, Tetrahedron Lett. 1994, 35, 9705; b) M. J.
Lucero, K. N. Houk, J. Am. Chem. Soc. 1997, 119, 826; c) S.
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[18] The reactions with imines did not proceed stereospecifically; see
reference [5].
3260
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