Enantioselective reductive aldol reaction using tertiary amine as hydride donor

Article abstract of DOI:10.1016/j.tetlet.2012.05.147

An efficient method was developed for the enantioselective reductive aldol reaction of α,β-unsaturated ketones with aldehydes in the presence of a Lewis base catalyst; conjugate reduction using a tertiary amine and trichlorosilyl triflate, followed by an aldol reaction with BINAP dioxide (BINAPO) as an organocatalyst, gave the corresponding product in high yield with high stereoselectivity.

Full text of DOI:10.1016/j.tetlet.2012.05.147

Tetrahedron Letters 53 (2012) 4199–4201
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Enantioselective reductive aldol reaction using tertiary amine
as hydride donor
Kazuki Osakama a, Masaharu Sugiura a, Makoto Nakajima a, , Shunsuke Kotani b,
⇑
⇑
a Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
b Priority Organization for Innovation and Excellence, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient method was developed for the enantioselective reductive aldol reaction of
a,b-unsaturated
Received 25 April 2012
Revised 28 May 2012
Accepted 30 May 2012
Available online 7 June 2012
ketones with aldehydes in the presence of a Lewis base catalyst; conjugate reduction using a tertiary
amine and trichlorosilyl triflate, followed by an aldol reaction with BINAP dioxide (BINAPO) as an organ-
ocatalyst, gave the corresponding product in high yield with high stereoselectivity.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Aldol reaction
Asymmetric catalysis
Conjugate reduction
Phosphine oxide
Tertiary amine
Reductive aldol reactions comprise a sequence of conjugate
reductions and aldol reactions that provide b-hydroxy carbonyl
compounds directly without isolation of the enolate intermediate.1
Reductive aldol reactions have great advantages in that they form
several bonds and create contiguous stereogenic centers in one pot.
To date, a number of catalysts based on metals and highly stereo-
selective transformations have been achieved,2 but there was no
example of organocatalyzed enantioselective reductive aldol reac-
tion until our group demonstrated an enantioselective reductive
aldol reaction with trichlorosilane catalyzed by chiral phosphine
oxides as organocatalysts.3
We recently developed a trichlorosilyl triflate/tertiary amine-
mediated conjugate reduction of a
,b-unsaturated ketones.4 Deute-
rium labeling experiments revealed that a trichlorosilyl enol ether
was generated and remained intact in the reaction media.5 This re-
sult supports the feasibility of enantioselective reductive aldol
reactions if aldehydes are used as the electrophile in the presence
of a Lewis base catalyst, such as phosphine oxide (Scheme 1).6,7
Here, we report a novel type of enantioselective reductive aldol
reaction of a,b-unsaturated ketones and aldehydes via a sequence
of conjugate reductions with trichlorosilyl triflate/tertiary amine
and aldol reactions catalyzed by a chiral phosphine oxide.
Initially, chalcone (1a) and benzaldehyde (2a) were chosen as the
substrates to study a reductive aldol reaction (Table 1). After treat-
ment of 1a with trichlorosilyl triflate and Cy2NiBu (2 equiv, each,
Cy = cyclohexyl) in dichloromethane at À40 °C, (S)-BINAPO (3) and
aldehyde 2a were successively added to the mixture (entry 1). A
small amount of the desired aldol adduct 4a was obtained, but the
major product was the reduced ketone. This result indicated that
the latter aldol reaction did not proceed extensively. We suspected
that acids, such as hydrogen chloride and/or trifluoromethanesulfo-
nic acid generated adventitiously from trichlorosilyl triflate
deactivated 2a or 3, resulting in low chemical and optical yields.
Therefore, decreasing the amount of trichlorosilyl triflate (1.5 equiv)
dramatically improved both the yield and stereoselectivity
Scheme 1. Reaction sequence of the conjugate reduction and aldol reaction.
⇑
Corresponding authors. Tel./fax: +81 96 371 4394.
E-mail addresses: nakajima@gpo.kumamoto-u.ac.jp (M. Nakajima), skotani@gpo.
kumamoto-u.ac.jp (S. Kotani).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.147

4200
K. Osakama et al. / Tetrahedron Letters 53 (2012) 4199–4201
Table 1
Table 2
Optimization of the reaction conditions for the reductive aldol reaction of chalcone
(1a) and benzaldehyde (2a) catalyzed by BINAPO (3)
Enantioselective reductive aldol reaction of a,b-unsaturated ketones 1 and aldehydes
a
2 catalyzed by BINAPOa
Entry
Temp., °C
Time, h
Yieldb, %
syn/antic
ee (syn) d, %
1e
2
À40
À40
À40
À40
À60
À78
24
1
1
1
18
24
30
83
85
32
87
22
17/83
95/5
97/3
95/5
97/3
90/10
5
95
89
93
93
84
3f
4g
5
6
a
Unless otherwise noted, the reactions were conducted using 2a (0.5 mmol), 1a
(1.2 equiv), Cy2NiBu (2.0 equiv), SiCl3OTf (1.5 equiv), and 3 (10 mol %) in CH2Cl2
Entry
1
2
Time, h
4
Yieldb, %
syn/antic
eed (syn), %
(5 mL).
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1a
1a
1a
1a
1a
1a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2f
1
1
1.5
1
1.5
1
1.5
4
4
0.5
2
0.25
1
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
83
84
86
82
69
83
56
73
79
81
87
57
83
50
68
95/5
97/3
96/4
95/5
74/26
97/3
89/11
94/6
70/30
96/4
95/5
97/3
97/3
96/4
99/1
95
93
93
80
81
88
84
89
32
90
95
90
84
89
70
b
Isolated yield.
c
Determined by 1H NMR analysis.
d
Determined by HPLC analysis.
e
SiCl3OTf (2.0 equiv).
iPr2NiBu (2.0 equiv) was used in place of Cy2NiBu.
f
iPr2NEt (2.0 equiv) was used in place of Cy2NiBu.
g
9
(entry 2).8 Varying the size of amines proved to have a large effect on
the reaction (entries 2–4). The enantioselection of the reaction
involving iPr2NiBu was similar to that involving Cy2NiBu (entry 3),
although iPr2NEt provided reduced product yields (entry 4). Lower-
ing the temperature slightly improved the product yield but pro-
longed the reaction time (entries 5 and 6).
10
11
12
13
14e
15e
1
1
2g
a
Unless otherwise noted, the reactions were conducted in the presence of 2
(0.5 mmol), 1 (1.2 equiv), Cy2NiBu (2.0 equiv), SiCl3OTf (1.5 equiv), and 3 (10 mol %)
With the optimal conditions in hand, reductive aldol reactions
of benzaldehyde (2a) with various types of
a,b-unsaturated ke-
in CH2Cl2 (5 mL).
b
tones 1 were performed (Table 2).9 All reactions with the chalcone
derivatives 1a–g proceeded smoothly to give the corresponding
products in good yields with high diastereo- and enantioselectivi-
ties (entries 2–7). Isopropyl ketone 1h provided the aldol product
in high yield and selectivity (entry 8), whereas the stereoselectivity
of the reaction with cyclopropyl ketone 1i was found to decrease
(entry 9).10
Isolated yield.
c
Determined by 1H NMR analysis.
d
Determined by HPLC analysis.
The reaction was conducted with ketone 1 (1.0 equiv), aldehyde 2 (1.5 equiv),
e
and SiCl3OTf (1.2 equiv).
SiCl3OTf (2.0 equiv)
O
OSiCl3
Next, reductive aldol reactions between various aldehydes 2
and chalcone (1a) were conducted (entries 10–15). The aromatic
aldehydes tended to give the aldol adducts 4j–l with good yields
and high stereoselectivities (entries 10–12). The conjugate alde-
hyde 2e, which provided a lower selectivity in the reductive aldol
reaction with trichlorosilane,3b furnished the product 4m in high
yield with high selectivity (entry 13). Strikingly, the aliphatic alde-
hydes 2f and 2g, which were generally less reactive in Lewis base-
catalyzed reactions,7,11 gave the corresponding aldol adducts in
good yields with high diastereoselectivities (entries 14 and 15).
As previous reports for phosphine oxide-catalyzed aldol
reaction,3b,7 the production of a syn-isomer indicated that the con-
jugate reduction of the chalcone derivatives predominantly pro-
duced (Z)-trichlorosilyl enol ether. To confirm the generation of
(Z)-trichlorosilyl enol ether, the conjugate reduction of ketone 1f
was examined in a NOESY experiment. A NOESY correlation was
observed between the two hydrogen atoms, as shown in Figure 1
(the spectrum is provided in the Supplementary data). This
Cy2NiBu (2.0 equiv)
Ph
Ph
CD2Cl2, –40 ºC
H
H
Br
Br
1f
Figure 1. NOESY 2D experiments of the silyl enol ether derived from 1f.
observation clearly demonstrated the generation of (Z)-trichlorosi-
lyl enol ether through the stereoselective reduction of ketone 1f
and the high syn-selectivity in the aldol step.
Based on the above observation and our previous results,3 we
proposed the reaction mechanism, as shown in Scheme 2. The con-
jugate reduction of chalcone (1a) gave the (Z)-trichlorosilyl enol
ether stereoselectively. The latter aldol reaction of (Z)-trichlorosilyl
enol ether with aldehyde (2a) proceeded via a six-membered tran-
sition state involving hypervalent silicon species,6a,6d to afford the

K. Osakama et al. / Tetrahedron Letters 53 (2012) 4199–4201
4201
2312; (d) Bocknack, B. M.; Wang, L.-C.; Krische, M. J. Proc. Natl. Acad. Sci. 2004,
101, 5421–5424; (e) Nishiyama, H.; Shiomi, T.; Tsuchiya, Y.; Matsuda, I. J. Am.
Chem. Soc. 2005, 127, 6972–6973; (f) Fuller, N. O.; Morken, J. P. Synlett 2005,
1459–1461; (g) Lam, H. W.; Joensuu, P. M. Org. Lett. 2005, 7, 4225–4228; (h)
Deschamp, J.; Chuzel, O.; Hannedouche, J.; Riant, O. Angew. Chem. 2006, 118,
1314–1319. Angew. Chem., Int. Ed., 2006, 45, 1292–1297; (i) Zhao, D.; Oisaki, K.;
Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2006, 47, 1403–1407; (j) Zhao, D.;
Oisaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 14440–14441;
(k) Chuzel, O.; Deschamp, J.; Chausteur, C.; Riant, O. Org. Lett. 2006, 8, 5943–
5946; (l) Ito, J.; Shiomi, T.; Nishiyama, H. Adv. Synth. Catal. 2006, 348, 1235–
1240; (m) Shiomi, T.; Ito, J.; Yamamoto, Y.; Nishiyama, H. Eur. J. Org. Chem.
2006, 5594–5600; (n) Shiomi, T.; Nishiyama, H. Org. Lett. 2007, 9, 1651–1654;
(o) Bee, C.; Han, S. B.; Hassan, A.; Iida, H.; Krische, M. J. J. Am. Chem. Soc. 2008,
130, 2746–2747; (p) Lipshutz, B. H.; Amorelli, B.; Unger, J. B. J. Am. Chem. Soc.
2008, 130, 14378–14379; (q) Shiomi, T.; Adachi, T.; Ito, J.; Nishiyama, H. Org.
Lett. 2009, 11, 1011–1014; (r) Deschamp, J.; Riant, O. Org. Lett. 2009, 11, 1217–
1220; (s) Kato, M.; Oki, H.; Ogata, K.; Fukuzawa, S. Synlett 2009, 1299–1302.
3. (a) Sugiura, M.; Sato, N.; Kotani, S.; Nakajima, M. Chem. Commun. 2008, 4309–
4311; (b) Sugiura, M.; Sato, N.; Sonoda, Y.; Kotani, S.; Nakajima, M. Chem. Asian
J. 2010, 5, 478–481.
Scheme 2. Stereochemistry of the reductive aldol reaction.
4. Kotani, S.; Osakama, K.; Sugiura, M.; Nakajima, M. Org. Lett. 2011, 13, 3968–
3971.
corresponding aldol adduct with high syn-diastereo- and
enantioselectivities.
5. Quenching the reaction with D2O provided
(>99%, D).
a-deuterized product in 98% yield
In conclusion, we demonstrated a novel type of the enantiose-
lective reductive aldol reaction using a tertiary amine-mediated
conjugate reduction and an organocatalyzed aldol reaction. The
present reaction offered the aldol products with high diastereo-
and enantioselectivities. The NOESY analysis verified the (Z)-selec-
tive generation of trichlorosilyl enol ethers, which ensured high
syn-selectivity in reductive aldol reaction. This is the first example
of the enantioselective sequential reaction involving a tertiary
amine-mediated reduction. Efforts in our laboratory continue to
extend this strategy to other asymmetric reactions.
6. For reviews on Lewis base organocatalysts, see: (a) Denmark, S. E.; Beutner, G.
L. Angew. Chem. 2008, 120, 1584–1663. Angew. Chem., Int. Ed. 2008, 47, 1560–
1638; (b) Orito, Y.; Nakajima, M. Synthesis 2006, 1391–1401; (c) Malkov, A. V.;
ˇ
´
Kocovsky, P. Eur. J. Org. Chem. 2007, 29–36; (d) Benaglia, M.; Rossi, S. Org.
Biomol. Chem. 2010, 8, 3824–3830.
7. For phosphine oxide-catalyzed enantioselective aldol reactions, see: (a) Kotani,
S.; Hashimoto, S.; Nakajima, M. Synlett 2006, 1116–1118; (b) Kotani, S.;
Hashimoto, S.; Nakajima, M. Tetrahedron 2007, 63, 3122–3132; (c) Kotani, S.;
Shimoda, Y.; Sugiura, M.; Nakajima, M. Tetrahedron Lett. 2009, 50, 4602–4605;
(d) Kotani, S.; Aoki, S.; Sugiura, M.; Nakajima, M. Tetrahedron Lett. 2011, 52,
2834–2836; (e) Rossi, S.; Benaglia, M.; Genoni, A.; Benincori, T.; Celentano, G.
Tetrahedron 2011, 67, 158–166; (f) Rossi, S.; Benaglia, M.; Cozzi, F.; Genoni, A.;
Benincori, T. Adv. Synth. Catal. 2011, 353, 848–854.
8. The acidic condition might diminish the activity of the Lewis base catalyst. A
slight excess amount of the amine kept the reaction media basic to increase the
catalyst activity, leading to high yield and stereoselectivity.
Acknowledgement
9. Representative procedure for the reductive aldol reaction of ketone 1a and
aldehyde 2a: A solution of trichlorosilyl triflate in dichloromethane (2.0 M,
0.38 mL, 0.75 mmol, 1.5 equiv) was added dropwise to the solution of ketone
1a (125.0 mg, 0.6 mmol, 1.2 equiv) and dicyclohexylisobutylamine (237.4 mg,
1.0 mmol, 2.0 equiv) in dichloromethane (5 mL) at À40 °C. (S)-BINAPO
(32.7 mg, 0.05 mmol, 10 mol%) and aldehyde 2a (0.05 mL, 0.5 mmol,
1.0 equiv) were successively added to the mixture, which was further stirred
for 1 h. The reaction was quenched with sat. NaHCO3 (5.0 mL) and stirred for
1 h. After filtration through celiteÒ, the aqueous layer was extracted with EtOAc
(2 Â 30 mL) and the combined organic layers were successively washed with
15% HCl (3 Â 20 mL), water (20 mL), sat. NaHCO3 (20 mL), and brine (20 mL),
and dried over Na2SO4. After filtration and evaporation, the obtained crude
product was purified by column chromatography (hex/EtOAc = 8:1, SiO2 10 g)
to furnish the aldol product as a diastereomeric mixture. The enantiomeric
excess was determined by chiral HPLC.
This work was financially supported by The Sasakawa Scientific
Research Grant from Japan Science Society.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.05.
147.
References and notes
10. The conjugate reductions of enones bearing aliphatic substituents on R2 (Me,
iPr, tBu) resulted in low yields, see Ref. 4.
1. For reviews on reductive aldol reaction, see: (a) Guo, H.-C.; Ma, J.-A. Angew.
Chem. 2006, 118, 362–375. Angew. Chem., Int. Ed. 2006, 45, 354–366; (b)
Nishiyama, H.; Shiomi, T. Top. Curr. Chem. 2007, 279, 105–137.
2. For enantioselective reductive aldol reaction, see: (a) Taylor, S. J.; Duffey, M. O.;
Morken, J. P. J. Am. Chem. Soc. 2000, 122, 4528–4529; (b) Zhao, C.-X.; Duffey, M.
O.; Taylor, S. J.; Morken, J. P. Org. Lett. 2001, 3, 1829–1831; (c) Russell, A. E.;
Fuller, N. O.; Taylor, S. J.; Aurriset, P.; Morken, J. P. Org. Lett. 2004, 6, 2309–
11. Low reactivity of non-conjugated aldehydes has been observed for Lewis base-
catalyzed reactions with trichlorosilylated reagents due to the formation of the
corresponding O-silylated chlorohydrins, see: Denmark, S. E.; Wynn, T.;
Beutner, G. L. J. Am. Chem. Soc. 2002, 124, 13405–13407.