Use of α-Allyloxy-Α-trimethylsilyloxyacetate for Reductive Imino Aldol Reaction Promoted by Titanium Tetraiodide: A Rapid Access to β-Amino-α-hydroxy Esters

Article abstract of DOI:10.1246/cl.2002.888

Under the influence of titanium tetraiodide the reductive imino aldol reaction of α-allyloxy-α-trimethylsiloxyacetate proceeded with imines to give β-amino-α-hydroxy esters in good yields.

Full text of DOI:10.1246/cl.2002.888

888
Chemistry Letters 2002
Use of ꢀ-Allyloxy-ꢀ-trimethylsiloxyacetate for Reductive Imino Aldol Reaction
Promoted by Titanium Tetraiodide: A Rapid Access to ꢁ-Amino-ꢀ-hydroxy Esters
Makoto Shimizuꢀ and Tetsuya Sahara
Department of Chemistry for Materials, Mie University, Tsu, Mie 514-8507
(Received June 26, 2002; CL-020536)
Under the influence of titanium tetraiodide the reductive
Table 1. Reductive aldol reaction of ꢀ; ꢀ-dialkoxyacetates 2:
Comparison of reaction conditionsa
imino aldol reaction of ꢀ-allyloxy-ꢀ-trimethylsiloxyacetate
proceeded with imines to give ꢁ-amino-ꢀ-hydroxy esters in
good yields.
In conjugation with an exploration into a short approach to
HIV protease inhibitors, selective preparation of ꢁ-amino-ꢀ-
hydroxy carboxylic acids 1 has been needed.1 One of the most
straightforward approaches to this kind of esters involves the
imino aldol reaction of ꢀ-hydroxy esters with imines, where
reductive formation of glyoxylate enolates may offer the requisite
enolate species.2 We have recently found that TiI4 is an excellent
reagent for selective reduction of several substrates.3 Recent
study has also revealed that TiI4 effects the reductive aldol
reaction of N-tosylimine derived from ethyl glyoxylate with
aldehydes to give ꢀ-amino-ꢁ-hydroxy esters stereoselectively in
good yields.4 In an analogous way to this methodology, a variety
of glyoxylates were subjected to the TiI4 mediated reductive
formation of enolate. However, this approach proved fruitless,
and only pinacol type homo-coupling products were obtained.5 In
an effort to generate enolate species in a chemoselective fashion,
the use of acetals derived from ethyl glyoxylate was investigated.
We have now found that the desired ꢁ-amino-ꢀ-hydroxy esters
are obtained in good to excellent yields using reaction of ꢀ; ꢀ-
dialkoxyacetates with imines promoted by TiI4. In particular, ꢀ-
allyloxy-ꢀ-trimethylsiloxyacetate (2f) underwent a selective
imino aldol reaction to give ꢁ-amino-ꢀ-hydroxy esters, where
deprotection of the alkoxy moiety was not needed for further
functional group transformations.
In an effort to find the most useful derivative for removal of
the protecting group, use of four types of ꢀ,ꢀ-dialkoxyacetates
2c–f was investigated. Among them, the use of the ꢀ-allyloxy-ꢀ-
trimethylsiloxy derivative 2f gave the adduct with a free hydroxy
group. The reductive imino aldol reaction of this particular acetal
2f was carried out with various aldimines under the optimum
reaction conditions found as in the case with entry 7 in Table 1,
and the results are summarized in Table 2.
O
OR1 c: R1 = Et, R2 = CH2CCl3
d: R1 = R2 = CH2CCl3
O
NH2
O
EtO
OR2
e: R1 = Me, R2 = CMe2OMe f: R1 = TMS, R2 = Allyl
OTMS
R = Ph, PhCH2
cyclo-C6H11 -C3H7
EtO
2
R
OH
,
i
O
OH
1
2f
Figure 2.
Figure 1.
The reaction of 2f with anisyl benzalimine in the presence of
TiI4 gave the desired ꢁ-amino-ꢀ-hydroxy ester 3b, where the
amount of TiI4 and the reaction temperature were found to be
crucial (entries 1–5). The reaction carried out with 3 equivalents
of TiI4 in EtCN at 0 ꢂC gave a satisfactory yield (entry 4).
Although the diastereoselectivity was not high, the aryl
benzalimines and its naphthyl analogue examined here all gave
good to excellent yields of the ꢁ-amino-ꢀ-hydroxy esters (entries
6–10).
The following scheme shows a possible reaction pathway.
The metal exchange reaction between TMS group and Ti(IV)
gives a titanium alkoxide, which in turn is attacked by an iodide
anion to form ꢀ-iodo ester. The subsequent reaction with another
iodide anion effects the formation of an enolate species. The
adduct is formed via a further reaction with imine.
In order to check the enolate formation, reduction of ethyl
ꢀ; ꢀ-diethoxyacetate with TiI4 (2.0 eq) in acetonitrile at ꢁ78 ꢂC
was carried out, and ethyl ꢀ-ethoxyacetate was obtained in
quantitative yield. We next examined the reductive imino aldol
reaction of ꢀ; ꢀ-dialkoxyacetates, and the results are summarized
in Table 1.
As shown in Table 1, ꢀ; ꢀ-dimethoxy derivative 2a gave the
desired adduct in 11% yield, whereas better results were obtained
using the diethoxy analogue 2b (entries 1 and 5). The reactions
carried out at lower reaction temperatures recorded reduced
yields of the products (entries 3–5). Use of an excess amount of
the acetal gave higher yields of the product (entries 6 and 7).
However, the difficulty to hydrolize the ethyl ether moiety of the
product called for the use of other substrates.
Copyright Ó 2002 The Chemical Society of Japan

Chemistry Letters 2002
889
Table 2. Reductive aldol reaction of ꢀ-allyloxy-ꢀ-trimethylsi-
loxyacetate 2fa
2
3
4
a) F. Ramirez, N. Ramanathan, and N. B. Desai, J. Am. Chem.
Soc., 84, 1317 (1962). b) W. P. Newmann and A. Schwarz,
Angew. Chem., Int. Ed. Engl., 14, 812 (1975). c) A. G. Davies
and J. A. Hawari, J. Organomet. Chem., 224, C37 (1982). d) T.
Mukaiyama, J. Kato, and M. Yamaguchi, Chem. Lett., 1982,
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36, 5955 (1995).
a) R. Hayakawa, T. Sahara, and M. Shimizu, Tetrahedron Lett.,
41, 7939 (2000). b) M. Shimizu, K. Shibuya, and R. Hayakawa,
Synlett, 2000, 1437. c) R. Hayakawa and M. Shimizu, Org. Lett.,
2, 4079 (2000). d) R. Hayakawa, H. Makino, and M. Shimizu,
Chem. Lett., 2001, 756. e) M. Shimizu, T. Sahara, and R.
Hayakawa, Chem. Lett., 2001, 792. f) M. Shimizu, F.
Kobayashi, and R. Hayakawa, Tetrahedron, 57, 9591 (2001).
M. Shimizu, Y. Takeuchi, and T. Sahara, Chem. Lett., 2001,
1196.
5R. Hayakawa and M. Shimizu, Chem. Lett., 2000, 724, and
references therein.
6
A typical procedure is as follows: Propionitrile (0.5mL) was
added to TiI4 (198 mg, 0.356 mmol) at ambient temperature
under an argon atmosphere. After 10 minutes stirring, to the
solution of TiI4 was added p-anisyl benzalimine (25.0 mg,
ꢂ
0.119 mmol) in propionitrile (0.5mL) at 0 C. After stirring for
I
30 min at 0 ꢂC, a solution of ethyl 2-(2-propenyloxy)-2-
trimethylsiloxyacetate 2f (55.1 mg, 0.237 mꢂmol) in propioni-
trile (0.5mL) was added to the mixture at 0 C, and the whole
mixture was stirred for 2.5h. The reaction was quenched with
sat. aq NaHCO3, 10% NaHSO3, filtered through a Celite pad,
and extracted with ethyl acetate (10 mL ꢃ 3). The combined
organic extracts were dried over anhydrous Na2SO4 and
concentrated in vacuo. Purification by flush column chromato-
graphy (hexane : ethyl acetate ¼ 5 : 1 as an eluent) gave ethyl
2-hydroxy-3-phenyl-3-(4-methoxyphenylamino)-propionate
(29.9 mg, 80%) as a colorless oil.
O
O
TiI3
O
OTMS
OTiI3
TiI4
EtO
EtO
I
OTiI3
I-
O
O
EtO
-TMSI
Ti
I3
2f
I
NAr
I2
Ti
O
NHAr
I3TiO
EtO
OTiI3
O
O
R
H
EtO
R
or
OH
EtO
3b
7
After separation of diastereomers, the adduct 3a was hydro-
lyzed to the amino acid, which was cyclized using the
pyridinium salt9 to give the ꢁ-lactam. Examination of the
coupling constant between H3–H4 indicated the stereochem-
istry.
Scheme 1.
In conclusion, the reductive aldol reaction of ꢀ-allyloxy-ꢀ-
trimethylsiloxy ester promoted by TiI4 afforded ꢁ-amino-ꢀ-
hydroxy esters in good yields. Although the diastereoselectivity is
not high, the present methodology introduces the use of a new
readily removable acetal-type protecting group for reductive
enolate formations.
O
NHpAn
H H
1) NaOH, H2O/MeOH
rt
EtO
Ph
NpAn
EtO
Ph
2)
+
CH2Cl2, refl.
-
EtO
3a
O
N
This work was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports,
Science, and Technology, Japan, and a grant from the Nagase
Science and Technology Foundation.
I
53% J3,4 = 1.60 Hz
Me
8
The relative stereochemistry of the product was determined
using 1H NMR (NOESY) after transforming into the corre-
sponding imidazolidinone as in the following typical example,
in which the anti-isomer showed correlation, whereas the syn-
analogue did a very weak correlation:
References and Notes
1
a) A. H. Fray, R. L. Kaye, and E. F. Kleinman, J. Org. Chem., 51,
4828 (1986). b) K. Iizuka, T. Kamijo, H. Harada, K. Akahara, T.
Kubota, H. Umeyama, T. Ishida, and Y. Kiso, J. Med. Chem.,
33, 2707 (1990). c) A. M. Diedrich and D. M. Ryckman,
Tetrahedron Lett., 34, 6169 (1993). d) Y. Kiso, Biopolymers,
40, 235(1996). e) Y. X. Wong, D. I. Freedberg, P. T. Wingfield,
S. J. Stahl, J. D. Kaufman, Y. Kiso, T. N. Bhat, J. W. Erickson,
and D. A. Torchia, J. Am. Chem. Soc., 118, 12287 (1996). f) S.
Kobayashi, H. Ishitani, and M. Ueno, J. Am. Chem. Soc., 120,
431 (1998). g) M. Shimizu, Y. Ikari, and A. Wakabayashi, J.
Chem. Soc., Perkin Trans. 1, 2001, 2519.
O
O
Cl3COCOCl,
Et3N,
DMAP
O
NHpAn
Ph
NpAn
H
O
NpAn
Ph
O
+
EtO
anti
H
H
CH2Cl2, 0 ˚C
100%
OH
EtO2C
Ph
EtO2C
H
NOESY
cis
:
syn = 81 : 19
:
trans = 82 : 18
9
H. Huang, N. Iwasawa, and T. Mukaiyama. Chem. Lett., 1984,
1465.