Generation and asymmetric Michael addition reaction of chirally N- protected α-aminoalkyl cyanocuprates

Article abstract of DOI:10.1016/S0040-4039(99)02059-6

Enantio-enriched α-aminopropylcyanocuprates, generated from the chirally N-protected α-aminopropylstannane (racemic at the Sn-bearing stereocenter) via Pearson's Sn/Li transmetalation protocol followed by treatment with copper cyanide, is shown to undergo an addition reaction to α,β-unsaturated aldehydes and ketones to give the γ-amino carbonyl compounds in higher stereoselective fashion. Of special interest is the reaction with acrolein and 2-cyclohexenone which affords the adducts as a single stereoisomer.

Full text of DOI:10.1016/S0040-4039(99)02059-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 345–349
Generation and asymmetric Michael addition reaction of chirally
N-protected α-aminoalkyl cyanocuprates
Takahiro Tomoyasu,† Katsuhiko Tomooka and Takeshi Nakai ∗
Department of Applied Chemistry, Tokyo Institute of Technology, Meguro-ku, Tokyo 152-8552, Japan
Received 4 October 1999; revised 27 October 1999; accepted 29 October 1999
Abstract
Enantio-enriched α-aminopropylcyanocuprates, generated from the chirally N-protected α-
aminopropylstannane (racemic at the Sn-bearing stereocenter) via Pearson’s Sn/Li transmetalation protocol
followed by treatment with copper cyanide, is shown to undergo an addition reaction to α,β-unsaturated aldehydes
and ketones to give the γ-amino carbonyl compounds in higher stereoselective fashion. Of special interest is the
reaction with acrolein and 2-cyclohexenone which affords the adducts as a single stereoisomer. © 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: asymmetric synthesis; amino ketones; copper reagents; transmetalation; Michael reaction.
The Michael reaction of organocopper reagents to α,β-unsaturated carbonyl compounds is a useful
C–C bond-forming reaction, and hence the development of its asymmetric versions is a subject of current
extensive studies.1 While two types of asymmetric versions have been developed which employ either
a Michael acceptor having a chiral auxiliary or a copper reagent having a chiral but nontransferable
ligand, little is known about another type of asymmetric version which employs a copper reagent
having an enantio-enriched transferable ligand. Recently, Linderman et al. have shown the feasibility
of this approach in the Michael addition reactions of enantio-enriched α-alkoxy organocopper reagents.2
However, no example of the successful generation of enantio-enriched α-amino alkylcuprates from chiral
organolithium precursors has been reported,3–5 mainly due to the considerable difficulty encountered
in the enantioselective generation of α-amino organolithiums and their configurational instability.6 To
overcome these difficulties, we were interested in the use of Pearson’s chirally N-protected chiral α-
aminoalkyllithiums (B) as cuprate precursors which can be generated diastereoselectively from the
chirally N-protected α-aminoalkylstannanes (A) in which the Sn-bearing stereocenter is racemic (Eq.
(1)).7,8 Herein disclosed are the preliminary results on the generation of the chirally N-protected chiral
∗
†
Corresponding author.
Present address: Nutrition Research Institute, Otsuka Pharmaceutical Factory, Co. Inc., Muya-cho, Naruto, Tokushima 772-
8601, Japan.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02059-6
tetl 15987

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α-aminoalkyl cyanocuprates (C) and their Michael reactions to α,β-unsaturated aldehydes and ketones
to afford the γ-amino carbonyl compounds (D) in enantio-enriched form.
(1)
The enantio-enriched α-aminoalkyl cyanocuprates 3 and 4 required for this study were generated
from the corresponding α-aminopropylstannane 1 which was prepared as a racemic form at the Sn-
bearing stereocenter from the racemic α-hydroxy propylstannane according to our reported procedure.8
Transmetalation of 1 with n-BuLi at −78°C occurred, to lead initially to an epimeric mixture of α-
amino alkyllithiums 2, which quickly equilibrated to the thermodynamically more stable (R)-2.7,8 The
doubly chiral lithium species thus formed was then added to a suspension of CuCN (1.0 or 0.5 equiv.) in
THF to generate the chiral ‘lower-order’ cyanocuprates 3 or ‘higher-order’ cyanocuprates 4, respectively,
as homogeneous solutions. The chiral cyanocuprates 3 and 4 thus generated were reacted with α,β-
unsaturated aldehydes in the presence of TMSCl at −78°C (Scheme 1).9 In the reaction with acrolein,
both of the cuprates 3 and 4 provided 1,4-adduct 5a as a single diastereomer in 78 and 97% yields,
respectively.10,11 The reaction of 3 with trans-crotonaldehyde was found to afford the 1,4-adducts 5b as
a 71:29 mixture of the two epimers due to the C-1 chiral center.12 These results reveal that the present
double transmetalation protocol permits ready access to enantio-enriched α-amino alkylcyanocuprates
which are otherwise difficult to generate.
Scheme 1.
We next examined the reaction of chiral cuprates 3 and 4 to α,β-unsaturated ketones (Table 1). The
results reveal that the reactions with cyclic ketones (entry 2–4, 6) proceed with higher diastereoselectiv-
ities at the C-1 chiral center as compared with the reaction with 3-penten-2-one (entry 1). The highest
diastereoselectivity was obtained in the reaction of higher-order cuprate 4 with 2-cyclohexenone (entry
4). Adduct 8 was obtained in a stereochemically pure form (>95% de) in 95% yield.10 The absolute
configuration of 8 was confirmed to be (S,S,S) by X-ray analysis of a crystal obtained from a diethyl ether
solution (Fig. 1).13 Based on these results, it is safe to conclude that both the Li→Cu transmetalation

347
concerned and the Michael addition reaction proceed with complete retention of configuration at the
carbanion center.14,15
Table 1
Conjugate addition reaction of α-amino alkylcyanocuprate with α,β-unsaturated ketones
Fig. 1. X-Ray crystal structure of (S,S,S)-8
The oxazolidinone moiety of 8 was successfully deprotected by using the Birch condition.8 Thus, 8
was treated with sodium in liquid ammonia followed by reprotection of the liberated primary amine
with benzyloxycarbonyl chloride (Cbz–Cl) to afford the Cbz-protected amino alcohol 10 as a single
stereoisomer in good yield (Eq. (2)).10,16

348
(2)
In conclusion, we have shown that the enantio-enriched α-aminoalkyl cyanocuprate generated from
Pearson’s doubly chiral α-amino alkyllithium undergoes asymmetric Michael addition reactions with
overall retention of configuration at the carbanionic stereocenter. Of particular interest is the finding that
the reaction of the chiral higher-order cuprate with 2-cyclohexenone afforded the 1,4-adduct as a single
stereoisomer. Thus, the present type of asymmetric reaction provides an efficient method for asymmetric
synthesis of γ-amino carbonyl compounds. Further investigation to expand the scope of this approach is
in progress.
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education,
Science, Sports and Culture, Japan, and by the Research for the Future Program, administered by the
Japan Society of the Promotion of Science.
References
1. For reviews, see: (a) Krause, N.; Gerold, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 186–204. (b) Rossiter, B. E.; Swingle, N.
M. Chem. Rev. 1992, 92, 771–806. (c) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis; Pergamon Press:
Oxford, 1992.
2. (a) Linderman, R. J.; Griedel, B. D. J. Org. Chem. 1991, 56, 5491–5493. (b) Linderman, R. J.; Griedel, B. D. J. Org. Chem.
1990, 55, 5428–5430.
3. To our knowledge, only a few examples of racemic α-amino alkylcyanocuprate are reported: (a) Dieter, R. K.; Sadanandan,
E. V. J. Org. Chem. 1997, 62, 3798–3799. (b) Dieter, R. K.; Alexander, C. W. Synlett 1993, 407–409. (c) Dieter, R. K.;
Alexander, C. W. Tetrahedron Lett. 1992, 33, 5693–5696.
4. Schöllkopf et al. have reported the asymmetric conjugate addition reaction of chiral bislactim–ether cuprates: Schöllkopf,
U.; Pettig, D.; Schulze, E.; Klinge, M.; Egert, E.; Benecke, B.; Noltemeyer, M. Angew. Chem., Int. Ed. Engl. 1988, 27,
1194–1195.
5. Beak et al. have reported the asymmetric conjugate addition reactions of enantio-enriched N-Boc anilino benzylic and allylic
organolithium species: Park, Y. S.; Weisenburger, G. A.; Beak, P. J. Am. Chem. Soc. 1997, 119, 10537–10538.
6. (a) Gawley, R. E.; Zhang, Q. J. Org. Chem. 1995, 60, 5763–5769. (b) Burchat, A. F.; Chong, J. M.; Park, S. B. Tetrahedron
Lett. 1993, 34, 51–54. (c) Chong, J. M.; Park, S. B. J. Org. Chem. 1992, 57, 2220–2222. (d) Gawley, R. E.; Rein, K. In
Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol 1, pp. 459–485. (e)
Gawley, R. E.; Rein, K. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol 3, pp. 65–83.
7. (a) Pearson, W. H.; Lindbeck, A. C.; Kampf, J. W. J. Am. Chem. Soc. 1993, 115, 2622–2636. (b) Pearson, W. H.; Lindbeck,
A. C. J. Am. Chem. Soc. 1991, 113, 8546–8548.
8. Recently, we have reported the synthetic utility of the chiral α-amino organolithiums (B) in the context of asymmetric
synthesis of α-amino ketones and β-amino alcohols: Tomoyasu, T.; Tomooka, K.; Nakai, T. Synlett 1998, 1147–1149.
9. The presence of TMSCl is essential for this reaction. In the absence of TMSCl, only a destannylated product was obtained.
For a TMSCl effect on the conjugate addition, see: Bertz, S. H.; Miao, G.; Rossiter, B. E.; Snyder, J. P. J. Am. Chem. Soc.
1995, 117, 11023–11024, and references cited therein.
10. All the compounds were characterized by 1H and 13C NMR. Data for selected products are as follows. Compound 5a: 1H
NMR (CDCl3, 300 MHz) δ 0.84 (t, J=7.4 Hz, 3H), 1.23–1.45 (m, 2H), 1.79–1.90 (m, 1H), 2.02–2.15 (m, 1H), 2.38 (ddd,

349
J=1.2, 6.8, 14.5 Hz, 2H), 3.24–3.25 (m, 1H), 4.24 (dd, J=6.3, 8.7 Hz, 1H), 4.61 (dd, J=8.7, 8.9 Hz, 1H), 4.72 (dd, J=6.3, 8.9
Hz, 1H), 7.35–7.45 (m, 5H), 9.62 (t, J=1.2 Hz, 1H). 13C NMR (CDCl3, 75 MHz) δ 11.2, 23.2, 25.9, 40.8, 56.5, 59.8, 69.9,
1
127.6, 129.1, 129.2, 139.0, 158.0, 201.2. Compound 8: H NMR (CDCl3, 300 MHz) δ 0.82 (t, J=7.3 Hz, 3H), 1.00–1.26
(m, 2H), 1.34–1.48 (m, 1H), 1.50–1.66 (m, 1H), 1.79–2.07 (m, 3H), 2.12–2.43 (m, 3H), 3.19 (dt, J=3.3, 10.1 Hz, 1H), 4.29
(dd, J=6.0, 8.2 Hz, 1H), 4.65 (dd, J=8.2, 9.0 Hz, 1H), 4.68 (dd, J=6.0, 9.0 Hz, 1H), 7.31–7.43 (m, 5H). 13C NMR (CDCl3,
75 MHz) δ 10.8, 22.0, 24.4, 28.5, 40.0, 40.9, 45.3, 60.1, 61.1, 69.8, 127.9, 129.1, 129.4, 138.6, 158.5, 210.7. 10: 1H NMR
(CDCl3, 300 MHz) δ 0.08–2.00 (m, 12H), 0.91 (t, J=7.3 Hz, 3H), 3.41 (m, 2H), 4.57 (d, 1H), 5.08 (dd, J=12.2, 16.8 Hz,
2H), 7.26–7.40 (m, 5H). 13C NMR (CDCl3, 75 MHz) δ 10.6, 23.8, 25.1, 27.0, 35.6, 38.8, 40.6, 56.8, 66.6, 70.7, 127.9,
128.0, 128.4, 136.5, 156.3.
11. In the absence of CuCN, the reaction of alkyllithium (R)-2 with acrolein was found to afford 71% yield of the 1,2-adduct as
a mixture of the two epimers due to the α-hydroxy chiral center.
12. The stereochemistry of the diastereomers have not been determined yet; however, it is quite reasonable that these have
opposite configurations over C1 and C2, but the identical relative configuration at C2, because the similar reaction with
1
acrolein provides a single diastereomer. The diastereomers are easily distinguishable by H NMR (CDCl3): δ value for
CHO of 5b: 9.65 for the major isomer and 9.68 for the minor isomer; δ value for COCH3 of 6: 2.04 for the major isomer
and 2.13 for the minor isomer.
13. Crystal date for (S,S,S)-8 (C18H23NO3): monoclinic, P21 (#4), a=9.117(2) Å, b=7.311(1) Å, c=12.417(3) Å, β=97.07(2)°,
V=821.3(3) Å3, Z=2. A total of 1673 reflections (h,k,±l) were collected in the range 6°<2θ<50° with 1189 having
I>3.00σ(I) being used in the structural refinement by full-matrix least-squares techniques (198 variables) using the TEXSAN
crystallographic package from Molecular Structures Corporation.
14. Linderman et al. have reported that the addition reaction of enantio-defined α-alkoxyalkylcopper reagents with α,β-enones
occurs predominantly with retention of configuration at the carbanionic stereocenter (Ref. 2).
15. It is still hard to propose a transition-state model to rationalize the high diastereoselectivity over the double bond, because
the mechanism of the cuprate addition reaction itself remains unsettled.
16. The assignment of the configuration of the newly-formed chiral center of 10 has not been made yet, although R-configuration
is highly expected.