Development of a chiral propionaldehyde homoenolate equivalent which reacts with imines with excellent stereoselectivity: Efficient and practical synthesis of optically active γ-amino carbonyl compounds [12]

Full text of DOI:10.1021/ja9933487

11916
J. Am. Chem. Soc. 1999, 121, 11916-11917
Scheme 1. Reaction of Allyltitaniums Derived from 1 and
Acrolein Acetals with Carbonyl Compounds
Development of a Chiral Propionaldehyde
Homoenolate Equivalent Which Reacts with Imines
with Excellent Stereoselectivity: Efficient and
Practical Synthesis of Optically Active γ-Amino
Carbonyl Compounds
Xin Teng, Yuuki Takayama, Sentaro Okamoto, and
Fumie Sato*
Department of Biomolecular Engineering
Tokyo Institute of Technology
4259 Nagatsuta-cho, Midori-ku, Yokohama
Kanagawa 226-8501, Japan
ReceiVed September 15, 1999
Equivalents of a homoenolate synthon belong to the syntheti-
cally important group of umpoled reagents,1 and recently, much
effort has been made for the preparation of their chiral form.2
However, so far, a chiral homoenolate equivalent which reacts
with imines, thus allowing a straightforward access to optically
active γ-amino carbonyl compounds, has not been reported.3 We
have now succeeded in developing a chiral propionaldehyde
homoenolate equivalent that reacts with imines with excellent
selectivity.4
Recently, we have reported an efficient method for preparing
allyltitanium complexes by the reaction of allylic alcohol deriva-
tives with a divalent titanium reagent (η2-propene)Ti(O-i-Pr)2 (1),
derived from Ti(O-i-Pr)4 and 2 equiv of i-PrMgX, which proceeds
via an oxidative addition pathway.5,6 The resulting allyltitaniums
react with aldehydes at the γ-position exclusively to provide the
corresponding homoallylic alcohols. During these studies we
found that, while the allyltitanium 2 (R ) Et) obtained from 1
and acrolein diethyl acetal reacts with benzaldehyde to afford a
γ-addition product (â-ethoxy homoallyl alcohol) exclusively, the
complex 2 (R ) CH2CH2O-) derived from acrolein ethylene
acetal provides a mixture of the R- and γ-addition products7
(Scheme 1). With these results in hand, we searched for a proper
acetal which would afford the R-addition product highly pre-
dominantly, thus serving as a propionaldehyde homoenolate
equivalent. We found that the corresponding dicyclohexylethylene
acetal 3 gives a satisfactory result; thus, the corresponding 2
derived from 3 reacts with alkyl and aryl aldehydes and ketones
with good to excellent R-selectivity (see Scheme 1). In all cases,
the R-addition product consists of a mixture of inseparable E-
and Z-enol ethers; however, the 13C NMR analysis of the mixture
indicated that the chiral induction at the newly generated
asymmetric center was low (see Supporting Information).
As allyltitaniums also react with imines smoothly, we then
turned our attention to the reaction of allyltitaniums derived from
1 and 3 with imines, in anticipation of developing a propion-
aldehyde homoenolate equivalent which can react with imines
for the first time.3 Furthermore, we had some expectation of
attaining high chiral induction because the reaction of allyltita-
niums with imines proceeds with far better stereoselectivity than
that of the reaction with aldehydes.5b,d
The reaction of 2 derived from (R,R)-3 with imine 4c, prepared
from 2-methylpropanal and benzylamine, proceeds smoothly and
in a regiospecific way to afford 85% yield of the R-addition
product 5c as a mixture of E- and Z-enol ethers in a ratio of 94:
6, and from which pure (E)-5c was isolated in 70% yield by
column chromatography (entry 3 in Table 1). The mixture of (E)-
and (Z)-5c itself as well as the pure (E)-5c was respectively
converted into methyl 3-amino-4-methylpentanoate (6c) by
conventional methods (vide infra), and its enantiomeric excess
(ee) was determined. To our surprise as well as to our delight,
the ee of 6c derived from the mixture was 88% and that of pure
(E)-5c was very high, reaching 98%.
(1) Reviews: Kuwajima, I.; Nakamura, E. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 2,
p 441. Kuwajima, I.; Nakamura, E. Top. Curr. Chem. 1990, 155, 1. Ryu, I.;
Sonoda, N. J. Synth. Org. Chem., Jpn. 1985, 43, 112. Werstiuk, N. H.
Tetrahedron 1983, 39, 205. Katritzky, A. R.; Piffl, M.; Lang, H.; Anders, E.
Chem. ReV. 1999, 99, 665. See also: Hoppe, D. Angew. Chem., Int. Ed. Engl.
1984, 23, 932.
(2) Review: Ahlbrecht, H.; Beyer, U. Synthesis 1999, 365.
(3) Even in achiral form, to our best knowledge, only one precedent of
homoenolate equivalents which react with imines (but not a propionaldehyde
homoenolate equivalent) has been reported: Fang, J.-M.; Chen, S. T.; Chen,
I.-H. J. Organomet. Chem. 1990, 398, 219.
(4) For the asymmetric nucleophilic addition reactions to imines, see
reviews: Enders, D.; Reinhold: U. Tetrahedron: Asymmetry 1997, 8, 1895.
Denmark, S. E.; Nicaise, O. J.-C. Chem. Commun. 1996, 999. Bloch, R. Chem.
ReV. 1998, 98, 1407. Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069.
Kleinman, E. F.; Volkmann, R. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 2, p 893. Most recent
examples: Cogan, D. A.; Liu, G.; Ellman, J. Tetrahedron 1999, 55, 8883.
Fang, X.; Johannsen, M.; Yao, S.; Gathergood, N.; Hazell, R. G.; Jφrgensen,
K. A. J. Org. Chem. 1999, 64, 4844. Nakamura, K.; Nakamura, H.; Yamamoto,
Y. J. Org. Chem. 1999, 64, 2614. Itsuno, S.; Watanabe, K.; Matsumoto, T.;
Kuroda, S.; Yokoi, A.; El-Shehawy, A. J. Chem. Soc., Perkin Trans. 1 1999,
2011.
(5) (a) Kasatkin, A.; Nakagawa, T.; Okamoto, S.; Sato, F. J. Am. Chem.
Soc. 1995, 117, 3881. (b) Gao, Y.; Sato, F. J. Org. Chem. 1995, 60, 8136. (c)
Kasatkin, A.; Sato, F. Angew. Chem., Int. Ed. Engl. 1996, 35, 2848. (d) Hikichi,
S.; Gao, Y.; Sato, F. Tetrahedron Lett. 1997, 38, 2867. (e) Teng, X.; Kasatkin,
A.; Kawanaka, Y.; Okamoto, S.; Sato, F. Tetrahedron Lett. 1997, 38, 8977.
(f) Teng, X.; Okamoto, S.; Sato, F. Tetrahedron Lett. 1998, 39, 6927. (g)
Matsuda, S.; An, D. K.; Okamoto, S.; Sato, F. Tetrahedron Lett. 1998, 39,
7513.
As shown in Table 1, the reaction appears to have wide
generality. Thus, in addition to secondary alkylimines, meth-
ylimines (entry 1) and primary alkylimines (entry 2) and
arylimines (entry 4) underwent the addition reaction with similar
excellent stereoselectivity. Regarding the N-substituent R2 in 4,
alkyl and aryl groups are acceptable in addition to benzyl group
(entries 5 and 6).
In several cases the separation of (E)- and (Z)-5 is difficult
(entry 1) or not as easy, although possible (entries 2, 4, and 5);
(7) It has been reported that allylzirconium compounds derived from Cp2-
Zr(n-Bu)2 and acrolein diethyl acetal or ethylene acetal react with aldehydes
to afford â-alkoxy homoallylic alcohols: Ito, H.; Taguchi, T.; Hanzawa, Y.
Tetrahedron Lett. 1992, 33, 7873.
(6) Reviews for the synthetic utility of 1: Sato, F.; Urabe, H.; Okamoto,
S. J. Synth. Org. Chem., Jpn. 1998, 56, 424. Sato, F.; Urabe, H.; Okamoto, S.
Synlett, in press.
10.1021/ja9933487 CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/04/1999

Communications to the Editor
J. Am. Chem. Soc., Vol. 121, No. 50, 1999 11917
Scheme 2a
Table 1. Asymmetric Addition Reaction of the Allyltitanium
Compound Derived from 1 and 3 with Imines
adducts 5a
isolated yield, %
EZ pure
ee at C-4, %c
pure
imine 4
R1
entry
R2 E:Zb mixture (E)-5 overalld (E)-5
1
2
3
4
5
6
4a; Me Bn
4b; n-Pr Bn
4c; i-Pr Bn
92:8
94:6
94:6
93:7
84
81
85
82
85
71
83
85
88
70
40
98
96
4d; Ph
4e; Ph
4f; Ph
Bn
n-Pr 95:5
Ph 95:5
86
88
>85e
a (i) (Boc)2O, Et3N, THF; (ii) O3, Me2S, CH2Cl2; (iii) NaClO2,
NaH2PO4, 2-methyl-2-butene, t-BuOH-H2O; (iv) Mel, NaHCO3, DMF;
(v) Ac2O, pyr., cat. DMAP; (vi) cat. p-TsOH, MeOH; (vii) TFA, CH2Cl2-
H2O.
a No γ-addition product was observed. b Determined by H NMR
analysis. c ee (for entries 1-5) and absolute configuration (for entries
1-4) were determined by converting into the corresponding â-amino
ester 6 (see Scheme 2 and Supporting information). d ee of 6 derived
from the mixture of (E)- and (Z)-5. e For determination, see Supporting
Information.
1
Scheme 3
however, use of the mixture for further synthetic elaboration might
be useful since the enantiomeric purity of the mixture is very
high.
By taking advantage of the versatility of the enol ether
functionality, the product 5 could be readily transformed into a
variety of γ-aminocarbonyl compounds, including γ-amino acids,
as represented by Scheme 2.8 The compound 5 can also be
converted to â-amino ester 6 as is also shown in Scheme 2 and
in Table 1.
The predominant production of (E)-5 with the absolute con-
figuration depicted in Table 1 can be explained by assuming that
the allyltitanium complex generated from 1 and 3 would exist
mostly as an internal titanium derivative, which can be stabilized
by chelation, rather than as the primary derivative,9 and the
reaction with imines proceeds preferentially via the most stable
transition state depicted in Scheme 3, which has a trans-fused
chair-chair conformation.10
In summary, we have now succeeded in developing, for the
first time, a chiral homoenolate equivalent which reacts with
imines with excellent stereoselectivity, thus allowing an efficient
preparation of optically active γ-amino carbonyl compounds.
Since the reagent is easy to prepare from readily available and
inexpensive starting materials, the reaction is practical and will
find numerous applications in organic synthesis. The application
of the reaction as well as further study to clarify the scope and
limitations of the reaction is now in progress.
(8) Synthesis of optically active γ-amino acids attracts current interest: See
(a) Smrcina, M.; Majer, P.; Majerova´, E.; Guerassina, T. A.; Eissenstat, M.
A. Tetrahedron 1997, 53, 12867 and references therein. For biological
importance of γ-amino acids, see: (b) Nanavati, S. M.; Silverman, R. B. J.
Am. Chem. Soc. 1991, 113, 9341. (c) Burke, J. R.; Silverman, R. B. J. Am.
Chem. Soc. 1991, 113, 9329. See also ref 8a and references therein.
(9) A similar stabilization of allyltitaniums by intramolecular chelation or
coordination has been reported, see: Hanko, R.; Hoppe, D. Angew. Chem.
1982, 94, 378. Weidmann, B.; Seebach, D. Angew. Chem. 1983, 95, 12. Roder,
H.; Helmchen, G.; Peters, E.-M.; Peters, K.; Schnering, H.-G. Angew. Chem.,
Int. Ed. Engl. 1984, 23, 898. Zubaidha, P. K.; Kasatkin, A.; Sato, F. Chem.
Commun. 1996, 197. See also ref 5f.
Supporting Information Available: Experimental procedure and
spectral data (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
JA9933487
(10) Yamamoto, Y.; Nishii, S.; Maruyama, K.; Komatsu, T.; Itoh, W. J.
Am. Chem. Soc. 1986, 108, 7778.