A new method for the synthesis of unsymmetrical bis-aldols by the samarium(II) iodide-mediated aldol reaction of aldehydes with aryl or alkyl oxiranyl ketones

Article abstract of DOI:10.1246/cl.2000.580

Unsymmetrieal alkyl or aryl 2-hydroxy-1-(1-hydroxyalkyl)-alkyl ketones (bis-aldols) were synthesized by the samarium(II) iodide-mediated aldol reaction of aldehydes with alkyl or aryl oxiranyl ketones. Bis-aldols were formed via the aldol reaction of aldehydes with samarium enolates generated by epoxy-fragmentation of oxiranyl ketones using two moles of samarium(II) iodide.

Full text of DOI:10.1246/cl.2000.580

580
Chemistry Letters 2000
A New Method for the Synthesis of Unsymmetrical Bis-Aldols by the Samarium(II) Iodide-
Mediated Aldol Reaction of Aldehydes with Aryl or Alkyl Oxiranyl Ketones
Teruaki Mukaiyama, Hidehiro Arai, and Isamu Shiina
Department of Applied Chemistry, Faculty of Science, Science University of Tokyo, Kagurazaka, Shinjuku-ku, Tokyo 162-8601
(Received February 21, 2000; CL-000181))
Unsymmetrical alkyl or aryl 2-hydroxy-1-(1-hydroxyalkyl)-
alkyl ketones (bis-aldols) were synthesized by the samarium(II)
iodide-mediated aldol reaction of aldehydes with alkyl or aryl oxi-
ranyl ketones. Bis-aldols were formed via the aldol reaction of
aldehydes with samarium enolates generated by epoxy-fragmenta-
tion of oxiranyl ketones using two moles of samarium(II) iodide.
oxiranyl ketones with SmI2 in the presence of a protic compound
such as methanol afforded mono-aldols probably via samarium
enolates III as shown in the following scheme.7 These interme-
diates, samarium alkoxides III, are considered to be the same
nucleophilic enolates formed from mono-aldols by deprotonation
at 1-position. These results led us to consider that the correspon-
ding bis-aldols would be yielded from alkyl or aryl oxiranyl
ketones on treatment with carbonyl compounds, electrophiles, in
aprotic solvent via the above mentioned samarium enolates III.
The aldol reaction has long been recognized to be one of
the most versatile tools for carbon-carbon bond formation.
Therefore, various types of aldol reactions have been developed
mostly by the promotion of acids and bases.1 It was considered
that alkyl or aryl 2-hydroxy-1-(1-hydroxyalkyl)alkyl ketones
(bis-aldols) were synthesized by the aldol reaction of aldehydes
with enolate anions I generated from alkyl or aryl 2-hydroxy-
alkyl ketones (mono-aldols) on treatment with a base.
However, it was reported that aldol reaction of aldehydes with
enolate anions II generated from mono-aldols by deprotonation
at 1'-position usually proceeded to afford the isomeric products,
2-hydroxyalkyl 2'-hydroxyalkyl ketones.
In the first place, the aldol reaction of (3SR,2RS)-3-methyl-
oxiran-2-yl phenyl ketone (1), an aryl oxiranyl ketone, with
several aldehydes was examined. The reaction of 1 with benz-
aldehyde gave the corresponding bis-aldols in good yields
along with a small amount of 2-hydroxypropyl phenyl ketone
(mono-aldol). Since these bis-aldol adducts have 1,3-diphenyl
structure, undesirable elimination of the hydroxyl group at 2-
position or retro-aldol reaction took place during the purifica-
tion according to the usual work up. The desired bis-aldols
were obtained up to 70% yield in total when the reaction was
carried out at -100 °C for 1 h and at -45 °C for 5 h; however,
these bis-aldol adducts were not stable enough to determine
their stereochemistry (Table 1, Entry 1). On the other hand, the
bis-aldol adducts prepared from 1 with aliphatic aldehydes were
relatively stable and their configurations were determined after
converting them to the corresponding acetonides (Entries 2-4).
When alkyl oxiranyl ketones, (3SR,2RS)-3-i-propyloxiran-2-yl
methyl ketone and (3SR,2RS)-3-phenyloxiran-2-yl methyl
ketone, were used as substrates for the generation of samarium
enolates, the corresponding bis-aldols were obtained in high
yields (Entries 7-9). In these cases, undesirable formation of
α,β-unsaturated ketones did not take place because bis-aldol
adducts were relatively stable.
Though several aldol reactions that formed 2-hydroxyalkyl
2'-hydroxyalkyl ketones were already known, only a few meth-
ods for synthesis of bis-aldols were reported because the gener-
ation of enolate anions from mono-aldols by selective deproto-
nation at 1-position using a base had troublesome problems.2
Namely, treatment of protected mono-aldols with bases usually
caused the formation of dehydrated products, α,β-unsaturated
ketones, and the treatment of free mono-aldols with strong
bases such as LDA also caused retro-aldol reaction. Masamune
et al. reported that symmetrical or unsymmetrical alkyl 3-
hydroxy-2-(1-hydroxyalkyl)alkanoates (bis-aldolates) were
formed by double aldol reaction using 1-phenyl-2-
[benzyl(phenylsulfonyl)amino]propyl acetate.3 In their report,
it was noted that alkyl acetates gave the bis-aldolates when in
situ-formed enol borates,4 originated from alkyl acetates, are
treated with 2-methylpropanal or benzaldehyde.
Concerning diastereoselectivities of the present reaction, it
was proven that the two stereoisomers A and D were produced
(Entries 2-9). For example, aldol reaction of 1 with propanal
afforded the corresponding A as a major stereoisomer and D as
a minor stereoisomer as shown in Table 1 (Entry 2, A / D = 67 /
33). The configurations of A and D were confirmed as syn,syn
It is known that a wide range of 1-hydroxy-, 1-acetoxy-, 1-
alkoxy-, 1-alkylthio- or 1-halo-alkyl ketones is reduced under
mild conditions with 2 molar amounts of SmI2 to form the corre-
sponding deoxygenated, desulfurated or dehalogenated ketones,
respectively.5,6 It is also reported that reduction of alkyl or aryl
1
and anti,anti by measuring H NMR of the corresponding ace-
tonide derivatives.
Copyright © 2000 The Chemical Society of Japan

Chemistry Letters 2000
581
bined organic layer was dried over anhydrous Na2SO4. After
evaporation of the solvent under reduced pressure, crude prod-
uct was purified by silica gel chromatography to give a mixture
of the corresponding bis-aldols (124 mg, 83%) as a colorless oil
(Table 1, Entry 3).
In the next place, reaction of a chiral aryl oxiranyl ketone
with an aldehyde was tried in the presence of SmI2. The chiral
oxiranyl ketone, (3S,2R)-3-propyloxiran-2-yl phenyl ketone (2),
was prepared according to the following procedure: epoxida-
t
tion of (E)-2-hexen-1-ol with Ti(OiPr)4 / BuOOH / L-(+)-
diethyl tartrate led to 79% isolated yield of ((2S,3S)-3-propyl-
oxiran-2-yl)methanol according to Sharpless method.8 The
subsequent Swern oxidation gave (3S,2R)-3-propyloxirane-2-
carbaldehyde, which was in turn treated with phenyllithium to
afford the corresponding secondary alcohol. The second Swern
oxidation led to the desired ketone 2 (92% ee by HPLC analysis).
Treatment of the mixture of optically active 2 and 3-
phenylpropanal with SmI2 under the standard reaction conditions
gave two separable diastereomers of 2-hydroxy-1-(1-hydroxy-3-
phenylpropyl)pentyl phenyl ketone (90%, syn,syn (A) / anti,anti
(D) = 35 / 65). It was noteworthy that the excellent optical puri-
ty of produced bis-aldols was preserved through the present
protocol (determined by HPLC; 92% ees, respectively).
It is assumed then that a mixture of two isomeric disamari-
um alkoxy enolates III is generated from alkyl or aryl oxiranyl
ketones by the reduction with SmI2 at first. The reaction is con-
sidered to proceed through Zimmermann-type transition states;
therefore, syn,syn-bis-aldol A would be produced from cis-III
via TS-A while anti,anti-bis-aldol D would be produced from
trans-III via TS-D as shown in Scheme 3.
A typical experimental procedure is described for the reac-
tion of 1 and 3-phenylpropanal: to a mixture of 1 (81 mg, 0.50
mmol) and 3-phenylpropanal (74 mg, 0.55 mmol) in THF (5
mL) at -78 °C under an argon atmosphere was added a solution
of SmI2 in THF (0.1 M, 11 mL, 1.1 mmol). After the reaction
mixture was stirred for 1 h at -78 °C and for 5 h at -45 °C, the
reaction mixture was quenched with water and was diluted with
ethyl acetate. It was filtered through a short pad of silica gel
and the filtrate was extracted with ethyl acetate, and the com-
Thus, a convenient method was developed for the synthesis
of unsymmetrical bis-aldols from alkyl or aryl oxiranyl ketones
and aldehydes by using 2 moles of SmI2 via the disamarium
alkoxy enolates.
This work was supported by Grant-in-Aids for Scientific
Research from the Ministry of Education, Science, Sports, and
Culture.
References and Notes
1
B. M. Trost and I. Fleming, “Comprehensive Organic Synthesis,”
Pergamon Press, Oxford (1991), Vol. 2.
2
Morris et al. reported two examples of bis-aldol formation by the
reaction of alkyl 2-hydroxyalkyl ketones and 2-methylpropanal
using 1 molar amount of dichlorophenylborane or trichloroborane
and 2 molar amounts of ethyldiisopropylamine. G. P. Luke and J.
Morris, J. Org. Chem., 60, 3013 (1995). See also: P. A.
McCarthy and M. Kageyama, J. Org. Chem., 52, 4681 (1987).
A. Abiko, J.-F. Liu, D. C. Buske, S. Moriyama, and S.
Masamune, J. Am. Chem. Soc., 121, 7168 (1999).
3
4
5
6
T. Mukaiyama and T. Inoue, Chem. Lett., 1976, 559.
G. A. Molander and G. Hahn, J. Org. Chem., 51, 1135 (1986).
Aldol-type C-glycosidation of phenyl 3,4,6-tri-O-benzyl-1-thio-
β-D-arabino-hexopyranosid-2-ulose was reported in 1998 by uti-
lizing SmI2. The reaction probably proceeded through the initial
formation of samarium enolate by the desulfurization at C-1 posi-
tion with SmI2, which in turn reacted with carbonyl compounds
to form the corresponding aldol-type products. S. Ichikawa, S.
Shuto, and A. Matsuda, Tetrahedron Lett., 39, 4525 (1998).
G. A. Molander and G. Hahn, J. Org. Chem., 51, 2596 (1986).
T. Katsuki and K. B. Sharpless, J. Am. Chem. Soc., 102, 5974
(1980).
7
8