An efficient and practical preparation of optically active syn-1-vinyl- 2-amino alcohol derivatives by the regio- and diastereoselective addition reaction of (γ-alkoxyallyl)titaniums with chiral imines. Formal synthesis of statine

Article abstract of DOI:10.1016/S0040-4039(00)00882-0

(γ-Alkoxyallyl)titaniums 1, generated by the reaction of acrolein dialkyl acetals and a divalent titanium reagent (η²-propene)Ti(O-i-Pr)₂, react readily with chiral imines 2, prepared from aldehydes and optically active 1-phenylethyl amine, in a regiospecific manner to give optically active syn-1-vinyl-2-amino alcohol derivatives 3 with diastereoselectivity of more than 80% in good yield. By using the adduct 3d thus obtained, statine was formally synthesized. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00882-0

Tetrahedron Letters 41 (2000) 5561±5565
An ecient and practical preparation of optically active
syn-1-vinyl-2-amino alcohol derivatives by the regio- and
diastereoselective addition reaction of (g-alkoxyallyl)titaniums
with chiral imines. Formal synthesis of statine
Sentaro Okamoto, Kohki Fukuhara and Fumie Sato*
Department of Biomolecular Engineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku,
Yokohama, Kanagawa 226-8501, Japan
Received 8 May 2000; accepted 26 May 2000
Abstract
(g-Alkoxyallyl)titaniums 1, generated by the reaction of acrolein dialkyl acetals and a divalent titanium
reagent (Z2-propene)Ti(O-i-Pr)2, react readily with chiral imines 2, prepared from aldehydes and optically
active 1-phenylethyl amine, in a regiospeci®c manner to give optically active syn-1-vinyl-2-amino alcohol
derivatives 3 with diastereoselectivity of more than 80% in good yield. By using the adduct 3d thus
obtained, statine was formally synthesized. # 2000 Elsevier Science Ltd. All rights reserved.
Synthesis of optically active 1-vinyl-2-amino alcohols and their derivatives has attracted much
interest because they can work as useful intermediates in organic synthesis.1 For example, they
can be readily converted into optically active a-hydroxy-b-amino acids1a and b-hydroxy-g-amino
acids1a,b,d as shown in Scheme 1, both skeletons of which are widely found as the main unit or
subunit in naturally occurring and man-made biologically important compounds.2
Scheme 1.
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00882-0

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The regio- and diastereoselective addition of a-alkoxyallylic anions to chiral imines seems to
a€ord a straightforward method for synthesizing chiral 1-vinyl-2-amino alcohols. However, no
report has appeared so far even for the reaction with an achiral imine.3 Herein, we report that this
type of transformation can be attained by using (alkoxyallyl)titaniums 1, thus opening up an
ecient entry to optically active 1-vinyl-2-amino alcohol derivatives with syn-stereochemistry.
Recently, we have reported an ecient method for generating allyltitanium compounds by the
reaction of allylic alcohol derivatives with a divalent titanium reagent (ꢀ2-propene)Ti(O-i-Pr)2
generated in situ from Ti(O-i-Pr)4 and 2 equiv. of i-PrMgCl, and their stereoselective addition
reaction with carbonyl compounds and imines.4,5 During these studies, as shown in Eq. (1), we
reported that the crotyltitanium complex thus prepared reacts with chiral imines 2, prepared from
aldehydes and optically active 1-phenylethylamine, to a€ord Cram-syn addition products highly
predominantly,4b where the reaction may proceed via a six-membered chair-like transition struc-
ture A which is based on the extended Cram's model proposed by Yamamoto.6
ꢀ1†
Quite recently, we found that (g-alkoxyallyl)-titaniums 1 can be prepared from (ꢀ2-propene)-
Ti(O-i-Pr)2 and acrolein dialkyl acetal and that their reaction with carbonyl compounds proceeds
regiospeci®cally to a€ord 1,2-diol derivatives with a diastereomeric ratio of 69:31, where the syn-
isomer is major, as shown in Eq. (2).4h With these results in hand, we anticipated that the reaction
of 1 with 2 might open up an ecient entry to optically active 1-vinyl-2-amino alcohols.
ꢀ2†
The results of the reaction of 1 with 2 (Eq. (3)) are summarized in Table 1.7 Allyltitanium
complex 1 prepared from acrolein dibenzyl8 or diethyl acetal reacts readily with methylimine 2a,
primary alkylimines 2b, 2c and 2d to a€ord the corresponding 1-vinyl-2-amino alcohol derivatives
regiospeci®cally in good yields; however, secondary alkylimine 2e and arylimine 2f scarcely react
presumably due to their steric requirement. Although four diastereomeric products are possible
for the reaction of 1 with 2, to our satisfaction, 1-vinyl-2-amino alcohol derivative 3 having an
anti-Cram-syn structure is produced, without exception, in a synthetically useful selectivity of more
than 80% ds (Eq. (3) and Table 1).9 Moreover, the major product 3, except for 3a, can be readily
separated from other diastereomers by column chromatography: thus pure 3 can be isolated in
good yield (Table 1).
ꢀ3†

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Table 1
Reaction of (g-alkoxyallyl)titaniums 1 with chiral imines 2 shown in Eq. (3)
Since both enantiomers of 2 are readily available and the auxiliary group is easily removed, the
present ®nding opens an easy and practical route to both enantiomers of syn-1-vinyl-2-amino
alcohol derivatives. Noteworthy here is the fact that 3 has an anti-Cram-syn structure, and not
Cram-syn, which was the structure of the major product for the reaction of Eq. (1). Predominant
production of 3 can be explained by assuming that allyltitaniums 1 may exist as its Z-form B
which is stabilized by the chelation between the alkoxy group and the titanium,10 and the reaction
proceeds via an open-chain transition state C11 or, alternatively, via a six-membered boat-like
transition structure D12 (Fig. 1).
Figure 1.
The compound 3d thus obtained was converted to 4-(2-hydroxy)ethyl-5-(2-methyl)propyl-2-
oxazolidone (5),1b,d the known synthetic precursor of statine which is a key element of pepstatin,
a naturally occurring aspartic protease inhibitor, as shown in Scheme 2. The product 3d, after
protection of the amino group as its methyl carbamate, was successively treated with 9-BBN and
y
The stereochemistry of 3a was con®rmed by converting to the known compound, 4-methyl-5-ethyl-2-oxazolidone, by
reaction sequences shown below. The absolute con®guration was con®rmed to be R,R by comparing its [ꢁ]D value with
that reported for the (S,S)-isomer.13

5564
H2O2/NaHCO3 to a€ord primary alcohol 4 in 69% yield. The compound 4 was then converted to
5 in 70% yield by debenzylation under Birch reduction conditions and the following cyclization
using NaH in THF. Spectroscopic data of 5 thus obtained was in good agreement with those
reported in the literature1b and its absolute con®guration was con®rmed to be R,R based on its
25
D
20
D
[ꢁ]D value (‰ꢁŠ +73.2 (c 0.531, CHCl3), lit.1b for (S,S)-5: ‰ꢁŠ ^75.2 (c 1.76, CHCl3)).
Scheme 2.
In summary, we have developed an ecient method for preparing optically active syn-1-vinyl-
2-amino alcohol derivatives 3 from g-alkoxy allyltitaniums 1 and chiral imines 2. Since 1 is easy
to prepare from readily available and inexpensive starting materials, and both enantiomers of 2
are readily accessible, the reaction is highly practical and will ®nd applications in organic synthesis
such as the preparation of a-hydroxy-b-amino- and b-hydroxy-g-amino acids.
References
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Mizuno, K.; Oda, H.; Masaki, Y. Bull. Chem. Soc. Jpn. 1996, 69, 1737. (c) Barrett, A. G. M.; Seefeld, M. A.;
White, A. J. P.; Williams, D. J. J. Org. Chem. 1996, 61, 2677. (d) Sakaitani, M.; Ohfune, Y. J. Am. Chem. Soc.
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3. The Lewis acid mediated stereoselective addition reactions of g-alkoxyallylic stannanes with N-acyliminium
intermediates providing 1-alkenyl-2-amino alcohol derivatives have been reported: (a) Yamamoto, Y.; Schmid,
M. J. Chem. Soc., Chem. Commun. 1989, 1311. (b) Marshall, J. A.; Gill, K.; Seletsky, B. M. Angew. Chem., Int. Ed.
2000, 39, 953. Intramolecular cyclization of chiral imines having g-alkoxyallylstannyl moiety in the presence of
Lewis acid a€ording a-vinyl-b-amino cyclic ethers has been reported: (c) Park, J.-Y.; Kadota, I.; Yamamoto, Y.
J. Org. Chem. 1999, 64, 4901.
4. (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,
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Appl. Chem. 1999, 71, 1511. (b) Sato, F.; Urabe, H.; Okamoto, S. Synlett 2000, 753. (c) Sato, F.; Urabe, H.;
Okamoto, S. J. Synth. Org. Chem. Jpn. 1998, 56, 424.
6. Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207.
7. Typical reaction procedure: To a solution of acrolein dibenzyl acetal (254 mg, 1.9 mmol) and Ti(O-i-Pr)4 (675 mL,
2.28 mmol) in diethyl ether (14 mL) was added i-PrMgCl (4.38 mL, 1.04 M in ether, 4.56 mmol) at ^50ꢁC. The
resulting mixture was stirred for 1.5 h at ^50 to ^40ꢁC. To this was added imine 2b (161 mg, 1.0 mmol) at
^40ꢁC. The resulting mixture was allowed to warm to room temperature over 8 h. After addition of aq. sat.
NaHCO3 (0.5 mL), NaF (1.2 g) and Celite (1.2 g), the mixture was ®ltered though a pad of Celite. The ®ltrate was

5565
concentrated in vacuo and passed through a short silica gel column to give a mixture of adducts (270 mg) in 69%
total yield. Pure 3b (169 mg) was isolated in 55% yield by column chromatography on silica gel.
8. Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21, 1357.
9. Although it seemed that the reactions using 1 derived from the diethyl acetal would give somewhat better
diastereoselectivity as observed in the reaction with 2b, we mainly carried out the reaction of 1 derived from the
dibenzyl acetal because the benzyl group of the resulting products 3 can be easily deprotected.
10. Yamamoto, Y.; Nishii, S. J. Org. Chem. 1988, 53, 3597. Ito, H.; Taguchi, T.; Hanzawa, Y. Tetrahedron Lett. 1992,
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