Stereoselective synthesis of δ-amino-β′-hydroxy-β, γ-unsaturated esters by the samarium(II) iodide-mediated aldol reaction of aldehydes with γ,δ-aziridiny-α,β-unsaturated esters

Article abstract of DOI:10.1246/cl.2005.372

δ-Amino-β′-hydroxy-β,γ-unsaturated esters were stereoselectively synthesized by the aldol reaction of aldehydes with samarium enolates generated by aziridine-fragmentation of γ,δ-aziridinyl- α,β-unsaturated esters using two moles of samarium(II) iodide. C

Full text of DOI:10.1246/cl.2005.372

372
Chemistry Letters Vol.34, No.3 (2005)
Stereoselective Synthesis of ꢀ-Amino-ꢁ0-Hydroxy-ꢁ,ꢂ-Unsaturated Esters by the Samarium(II)
Iodide-mediated Aldol Reaction of Aldehydes with ꢂ,ꢀ-Aziridiny-ꢃ,ꢁ-Unsaturated Esters
Yasuyuki Ogawa,y;yy Kiichi Kuroda,y;yy and Teruaki Mukaiyamaꢀy;yy
yCenter for Basic Research, The Kitasato Institute, 6-15-5 (TCI) Toshima, Kita-ku, Tokyo 114-0003
yyKitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641
(Received December 7, 2004; CL-041494)
ꢀ-Amino-ꢁ0-hydroxy-ꢁ,ꢂ-unsaturated esters were stereose-
P
N
SmI2
R2
P
N
lectively synthesized by the aldol reaction of aldehydes with sa-
marium enolates generated by aziridine-fragmentation of ꢂ,ꢀ-
aziridinyl-ꢃ,ꢁ-unsaturated esters using two moles of samari-
um(II) iodide.
O
SmI2
O
SmI2
R1
R1
P
R2
P
SmI2
SmI2
H3O+
NH
NH
O
N
O
R1
P
R2
R1
R2
Samarium(II) iodide (SmI2) is known as a powerful one-
electron reducing agent1 and is widely used in organic synthe-
sis.2 As shown in Scheme 1, it was reported that the reduction
of oxiranyl ketones or aziridinyl ketones with SmI2 in the pres-
ence of protic compounds such as methanol afforded mono-al-
dols or ꢁ-amino ketones through intermediate samarium eno-
lates.3 On the basis of these results, preparation of 3-hydroxy-
2-(1-hydroxyalkyl)alkyl ketones (double-aldols) or 3-amino-2-
(1-hydroxyalkyl)alkyl ketones (ꢁ-amino-ꢁ0-hydroxy ketones)
by SmI2-mediated aldol reaction of aldehydes with oxiranyl ke-
tones or aziridinyl ketones was studied,4,5 which were then suc-
cessfully applied to synthesis of taxane skeleton.6
Next, the use of ꢂ,ꢀ-aziridinyl-ꢃ,ꢁ-unsaturated esters in-
stead of the above mentioned oxiranyl ketones or aziridinyl ke-
tones was studied in order to explore new possibilities for their
application to synthetic chemistry. Aldol adducts thus formed
here were considered to be ꢀ-amino-ꢁ0-hydroxy-ꢁ,ꢂ-unsaturat-
ed esters (Scheme 2).
R3CHO
O
R1
R2
OH
R3
dipeptide analogue
Scheme 2.
3-(10-tosylaziridin-20-yl)acrylic methyl ester (1)7 with several al-
dehydes was examined (Table 1). Reaction of 1 with benzalde-
hyde gave the corresponding ꢀ-amino-ꢁ0-hydroxy-ꢁ,ꢂ-unsatu-
rated ester (1a) (27/73 mixture of syn and anti isomers)8 in good
yield along with a small amount of ꢀ-N-tosylamino-ꢁ,ꢂ-unsatu-
rated methyl ester (Entry 1). The yield of 1a slightly decreased
because the reduction of benzaldehyde took place at the same
time. On the other hand, reaction of 1 with aliphatic aldehydes
proceeded smoothly to give the corresponding ꢀ-amino-ꢁ0-
hydroxy-ꢁ,ꢂ-unsaturated esters (1b–1f) in excellent yields
(Entries 2–6).
The replacement of amide bond in bioactive peptides with a
trans-double bond has long been a topic of interests in biologi-
cal, theoretical, and synthetic areas. ꢀ-Amino-ꢁ0-hydroxy-ꢁ,ꢂ-
unsaturated esters have been considered as important analogues
of dipeptide and are expected to be used for building blocks to
synthesize various biologically important polypeptides. In this
communication, we would like to describe a new and efficient
method for the stereoselective synthesis of ꢀ-amino-ꢁ0-hy-
droxy-ꢁ,ꢂ-unsaturated esters.
A characteristic point of this aldol reaction is that it
proceeded with complete ꢃ-regioselectivity and formed (E)-ole-
fin selectively whereas no diastereoselectivity was observed
(syn=anti ¼ 27=73{57=43).
Then, the same reaction was examined by using other unsat-
urated aziridines (ketone, amide, and imide) in order to improve
Table 1. SmI2-mediated aldol reaction of ꢂ,ꢀ-aziridinyl-ꢃ,ꢁ-un-
saturated ester (1) and various aldehydes
In the first place, SmI2-mediated aldol reaction of (20R,2E)-
NHTs
O
NHTs
O
SmI
2
Ts
N
O
O
SmI / THF
2
O
SmI
2
OMe
OH
OMe
X
X
+
OMe
RCHO
R
R
2
R
R
2
1
1
R
R
OH
−78 °C
1
X = O, NR
syn
anti
SmI
2
Aldehyde
R
Yield/%
O
XH
Entry
Product
I Sm
2
SmI
2
(syn/anti)
O
XH
O
X
+
R CHO
H O
3
R
R
2
3
1
1
2
3
4
5
6
Ph
Et
Ph(CH2)2
i-Pr
c-Hex
Piv
1a
1b
1c
1d
1e
1f
63 (27/73)
92 (55/45)
96 (51/49)
86 (56/44)
94 (54/46)
97 (57/43)
R
R
2
R
1
R
2
1
HO
R
3
X = O; mono-aldol
X = NR; β-amino ketone
X = O; double-aldol
X = NR; β-amino β'-hydroxy
ketone
Scheme 1.
Copyright Ó 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.3 (2005)
373
Table 2. SmI2-mediated aldol reaction of unsaturated aziridines
and 3-phenylpropanal
NHTs
O
O
NHTs
O
NaOMe / MeOH
(85%)
OMe
OH
N
O
NHTs
O
NHTs
O
Ts
N
O
Ph
Ph
OH
SmI2 / THF
CHO
−78 °C
R
R
Bn
+
R
5a
(−)-1c
R1
OH
R1
syn
OH
Ph
Scheme 4.
anti
saturated aziridines were used (Entries 2–4).
Aziridine
Yield/%
Entry
Product
The mechanism of this reaction is shown in Scheme 3. The
first step of this reaction involves reduction of the aziridinyl un-
saturated imide to cause both fragmentation of an aziridine ring
and migration of a double bond and to form the samarium imide
enolate, which in turn nucleophilically attacks the aldehyde.
Stereochemistry of the reaction could be explained by the chelat-
ed six-membered transition state model which contains an addi-
tional chelation between oxazolidinone to samarium.
R
(syn/anti)
1
2
3
2
3
4
Ph
NEt2
2-oxazolidinone
2a
3a
4a
61 (58/42)
83 (60/40)
81 (>95/<5)
the diastereoselectivity (Table 2). Reactions between other un-
saturated aziridines and 3-phenylpropanal also proceeded
smoothly and afforded the corresponding ꢀ-amino-ꢁ0-hydroxy-
ꢁ,ꢂ-unsaturated carbonyl compounds in high yields. It is noted
that the high syn diastereoselectivity was observed (syn=anti ¼
>95=<5) when unsaturated imide 4 was used (Entry 3).
Prompted by this result, we applied the aldol reaction to the
asymmetric one by introducing a suitable chiral auxiliary to the
unsaturated aziridine. In the first place, the reaction of
(20R,400R,2E)-400-Benzyl-300-[3-(10-tosylaziridin-20-yl)acryloyl]-
oxazolidin-200-one (5) with 3-phenylpropanal was examined
(Table 3, Entry 1)9. This asymmetric aldol reaction proceeded
smoothly and afforded the corresponding product 5a in high
yield with high syn diastereoselectivity (syn=anti ¼ >95=
<5).10 In addition, the corresponding products were obtained
in high yields with high diasteoselectivities also when other un-
Next, 5a was converted to enantiomerically pure ꢀ-amino-
ꢁ0-hydroxy-ꢁ,ꢂ-unsaturated ester (–)-1c, ½ꢃꢁD ꢂ27ꢃ (c 0.26,
21
CHCl3) by methanolysis without accompanying detectable epi-
merization or double bond conjugation (Scheme 4).
Consequently, the stereoselective synthesis of ꢀ-amino-ꢁ0-
hydroxy-ꢁ,ꢂ-unsaturated esters from ꢂ,ꢀ-aziridinyl-ꢃ,ꢁ-unsatu-
rated esters and aldehydes was developed via the samarium eno-
lates by using two moles of SmI2. Further investigation of this
reaction is now in progress.
The present work was partially supported by Grant of
the 21st Century COE Program from the Ministry of Education,
Culture, Sports, Science and Technology (MEXT), Japan.
Table 3. SmI2-mediated asymmetric aldol reaction
References and Notes
1
a) G. A. Molander, Chem. Rev., 92, 29 (1992). b) G. A. Molander
and C. R. Haris, Chem. Rev., 96, 307 (1996). c) G. A. Molander,
Acc. Chem. Res., 31, 603 (1998). d) G. A. Molander and C. R. Haris,
Tetrahedron, 54, 3321 (1998).
G. A. Molander and G. Hahn, J. Org. Chem., 51, 1135 (1986).
a) G. A. Molander and G. Hahn, J. Org. Chem., 51, 2596 (1986). b)
G. A. Molander and P. J. Stengel, J. Org. Chem., 60, 6660 (1995). c)
G. A. Molander and P. J. Stengel, Tetrahedron, 53, 8887 (1997).
a) T. Mukaiyama, H. Arai, and I. Shiina, Chem. Lett., 2000, 580. b) T.
Mukaiyama, K. Pudhom, K. Yamane, and H. Arai, Bull. Chem. Soc.
Jpn., 76, 413 (2003).
T. Mukaiyama, Y. Ogawa, and K. Kuroda, Chem. Lett., 33, 1472
(2004).
a) K. Pudhom, K. Yamane, H. Arai, and T. Mukaiyama, Chem. Lett.,
2002, 87. b) J. Matsuo, Y. Ogawa, K. Pudhom, and T. Mukaiyama,
Chem. Lett., 33, 124 (2004).
Ts
O
O
O
NHTs
R
O
N
SmI / THF
2
R
N
O
R
1
N
O
1
R CHO
2
2
3
OH
2
Bn
Bn
−78 °C
Aldehyde
R2
Aziridine
R1
Yield/%
(syn/anti)
Entry
Product
4
1
2
3
4
5
H
H
Me
Me
Ph(CH2)2
i-Pr
Ph(CH2)2
i-Pr
5a
5b
6a
6b
93 (>95/<5)
81 (>95/<5)
86 (>95/<5)
76 (>95/<5)
5
6
6
7
8
9
N. Fujii, K. Nakai, H. Tamamura, A. Otaka, N. Mimura, Y. Miwa, T.
Taga, Y. Yamamoto, and T. Ibuka, J. Chem. Soc., Perkin Trans. 1,
1995, 359.
The stereochemistries of the diastereomers were determined by meas-
uring the coupling constants of their derivatives, which were formed by
DIBAL reduction and acetonide formation.
Typical experimental procedure is as follows (Table 3, Entry 1): to a
mixture of 5 (43.0 mg, 0.0976 mmol) and 3-phenylpropanal (14.5 mg,
0.117 mmol) in THF (3 mL) at ꢂ78 ꢃC under an argon atmosphere
was added a solution of SmI2 in THF (0.1 M, 2.40 mL, 0.240 mmol).
After the reaction mixture was stirred for 30 min at ꢂ78 ꢃC, the reac-
tion mixture was quenched with saturated aqueous ammonium chloride
and was diluted with ethyl acetate. It was extracted with ethyl acetate,
and the organic layer was washed with brine and dried over anhydrous
sodium sulfate. The crude product was obtained after evaporation of
the solvent under reduced pressure and purification by thin-layer chro-
matography afforded syn-adduct (51.3 mg, 93%).
Ts
N
SmI2
O
SmI2
O
O
TsN
O
RCHO
SmI2
N
O
N
O
Bn
O
Bn
O
Bn
O
O
NHTs
O
N
H
N
I2Sm
O
R
H
R
OH
O
Bn
R1
10 The absolute configuration of 5a was determined by the modified
Mosher method.
Scheme 3.
Published on the web (Advance View) February 12, 2005; DOI 10.1246/cl.2005.372