Enantioselective alkylation of aldehydes using functionalized alkylboron reagents catalyzed by a chiral titanium complex

Article abstract of DOI:10.1021/ol4019248

A practical method is developed for the synthesis of enantioenriched functionalized secondary alcohols through catalytic enantioselective alkylation of aldehydes. Functionalized alkylboron reagents, [FG-(CH₂) _n]₃B (FG = Br, TIPSO, PhtN, CO₂ⁱPr, and CN) prepared from terminal olefin precursors by hydroboration, undergo enantioselective addition to aldehydes in the presence of a catalytic amount (5 mol %) of 3-(3,5-diphenylphenyl)-H₈-BINOL and excess titanium tetraisopropoxide to afford the corresponding functionalized alcohols in high enantioselectivities up to 99% ee.

Full text of DOI:10.1021/ol4019248

ORGANIC
LETTERS
2013
Vol. 15, No. 16
4198–4201
Enantioselective Alkylation of Aldehydes
Using Functionalized Alkylboron
Reagents Catalyzed by a Chiral
Titanium Complex
Ravindra Kumar,† Hiroki Kawasaki,‡ and Toshiro Harada*,‡
Venture Laboratory and Department of Chemistry and Materials Technology,
Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto, 606-8585, Japan
harada@chem.kit.ac.jp
Received July 9, 2013
ABSTRACT
A practical method is developed for the synthesis of enantioenriched functionalized secondary alcohols through catalytic enantioselective
i
alkylation of aldehydes. Functionalized alkylboron reagents, [FGÀ(CH2)n]3B (FG = Br, TIPSO, PhtN, CO2 Pr, and CN) prepared from terminal olefin
precursors by hydroboration, undergo enantioselective addition to aldehydes in the presence of a catalytic amount (5 mol %) of 3-(3,5-diphenylphenyl)-
H8-BINOL and excess titanium tetraisopropoxide to afford the corresponding functionalized alcohols in high enantioselectivities up to 99% ee.
A variety of methods have been developed for the
catalytic enantioselective alkylation of aldehydes1 ever
since the seminal report of a chiral amino alcohol catalyzed
reaction with dialkylzinc reagents by Noyori and co-
workers.2 However, the scope of alkyl groups that can be
introduced is relatively limited. The situation is in good
contrast to a wide range of aryl groups that can be
introduced by a relevant catalytic enantioselective aryla-
tion reaction.3 In particular, very few methods have been
developed for the enantioselective addition of functiona-
lized alkylgroups that would provide anefficiententry into
chiral polyfunctional alcohols,4,5 despite recent significant
advances in the chemistry of the functionalized organome-
tallic reagents.6 Taking advantage of the easy access by the
hydroboration of alkene precursors and high functional
group tolerance, an alkylboron reagent would serve as one
of the optimal reagents for the alkylation of aldehydes
(Scheme 1). Indeed, Knochel and co-workers have reported
a highly enantioselective method for aldehyde alkylation
using alkylboron reagents.5 In this method, functionalized
† Venture Laboratory.
‡ Department of Chemistry and Materials Technology.
(1) (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley:
New York, 1994; pp 225À297. (b) Noyori, R.; Kitamura, M. Angew.
Chem., Int. Ed. Engl. 1991, 30, 49–69. (c) Soai, K.; Niwa, S. Chem. Rev.
1992, 92, 833–856. (d) Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101, 757–824.
(e) Hatano, M.; Miyamoto, T.; Ishihara, K. Curr. Org. Chem. 2006, 11,
127–157. (f) Hatano, M.; Ishihara, K. Synthesis 2008, 1647–1675. For
leading references, see also: (g) Tanaka, T.; Sano, Y.; Hayashi, M.
Chem.;Asian J. 2008, 3, 1465–1471. (h) Kanehira, S.; Tanigawa, M.;
Miyawaki, Y.; Harada, T. Bull. Chem. Soc. Jpn. 2010, 83, 19–32. (i)
Hatano, M.; Gouzu, R.; Mizuno, T.; Abe, H.; Yamada, T.; Ishihara, K.
Catal. Sci. Technol. 2011, 1, 1149–1158.
€
(4) (a) Rozema, M. J.; Eisenberg, C.; Lutjens, H.; Ostwald, R.; Belyk,
K.; Knochel, P. Tetrahedron Lett. 1993, 34, 3115–3118. (b) Eisenberg,
C.; Knochel, P. J. Org. Chem. 1994, 59, 3760–3761. (c) Lutz, C.;
Knochel, P. J. Org. Chem. 1997, 62, 7895–7898.
(5) Langer, F.; Schwink, L.; Devasagayaraj, A.; Chavant, P.-Y.;
Knochel, P. J. Org. Chem. 1996, 61, 8229–8243.
(6) Knochel, P.; Leuser, H.; Gong, L.-Z.; Perrone, S.; Kneisel, F. F.
In The Chemistry of Organozinc Compounds; Rappoport, Z., Marek, I.,
Eds.; John Wiley & Sons: Chichester, U.K., 2006; pp 287À393.
(2) Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J. Am. Chem. Soc.
1986, 108, 6071–6072.
(3) For a review, see: (a) Bolm, C.; Hildebrand, J. P.; Muniz, K.;
~
Hermanns, N. Angew. Chem., Int. Ed. 2001, 40, 3284–3308. (b) Schmidt,
F.; Stemmler, R. T.; Rudolph, J.; Bolm, C. Chem. Soc. Rev. 2006, 35,
454–470. For leading references, see also: Uenishi, A.; Nakagawa, Y.;
Osumi, H.; Harada, T. Chem.;Eur. J. 2013, 19, 4896–4905.
r
10.1021/ol4019248
Published on Web 07/29/2013
2013 American Chemical Society

alkylboranes [FGÀ(CH2)n]BEt2, prepared by hydrobora-
tion of the corresponding terminal alkenes with Et2BH, was
converted to dialkylzinc reagents [FGÀ(CH2)n]2Zn by a
B/Zn exchange reaction with Et2Znandused in the presence
of a chiral bis-triflylamide titanium complex for the enan-
tioselective synthesis of polyfunctional secondary alcohols.
Although the reaction exhibited high functional group
tolerance and excellent selectivity at an 8 mol % catalyst
loading, the use of pyrophoric neat Et2Zn in large excess and
its removal before use in the alkylation reaction make this
protocol practically less attractive.
Scheme 2. Optimization of Reaction Conditions
Scheme 1. Enantioselective Synthesis of Functionalized Sec-
ondary Alcohols from Terminal Alkenes and Aldehydes
Recently, we have reported an enantioselective alkyla-
tion of aldehydes using Et3B via direct boron to titanium
transmetalation through the catalysis of a chiral titanium
complex derived from 3-(3,5-diphenylphenyl)-H8-BINOL
(DPP-H8-BINOL 6a).7 In the present study, we examined
the application of the catalyst system to the enantioselec-
tive synthesis of polyfunctional chiral secondary alcohols
using functionalized trialkylboranes 3 prepared from termi-
nal alkenes 2.8
Treatment of 1-naphthaldehyde (1a) with Et3B (3a)
(1.5 equiv) in the presence of (R)-DPP-H8-BINOL 6a
(2 mol %) and Ti(OiPr)4 (3 equiv) in refluxing THF
afforded the corresponding ethylation product 4aa in
83% yield and in 96% ee (Scheme 2, entry 1).7 Under
these conditions, the reaction of 1a with Bu3B (3b) resulted
in the major formation of the reduction product 5a (49%)
(entry 2). Butyl adduct 4ab was obtained as a minor
product, while maintaining high enantioselectivity. When
5 mol % of 6awas employed, the yield of 4ab was improved
to 57% with retardation of the competing reduction (entry 3).
(R)-DPP-BINOL 6c (5 mol %) exhibited a slightly better
result with respect to the yield of 4ab but with lower enantios-
electivity (entry 4). (R)-H8-BINOL 6b afforded the major
reduction product even at 20 mol % loading (entry 5).
The undesirable reduction of aldehydes could proceed
through dehydroboration9 by alkylboranes 3 and/or
through MeerweinÀPonndorfÀVerley-type reduction10
by titanium tetraisopropoxide. We speculated that an
alkyltitanium [RTi(OiPr)3] is an active species for alkylation
of aldehydes. Its generation might be a rate-determining
step by unfavorable transmetalation of the alkylboranes
with titanium tetraisopropoxide, requiring THF refluxing
conditions. According to this mechanistic proposition, the
substrate aldehyde would be reduced by the coexisting
alkylboranes and/or titanium tetraisopropoxide during the
slow generation of the alkyltitanium reagents. To circum-
vent the problem, the reaction of p-chlorobenzaldehyde (1b)
with Hex3B (2c) was carried out under similar conditions of
entry 3 by slowly adding the aldehyde. In accord with our
expectation, the slow addition of 1b improved the yield of
corresponding product 3bc to 60% and 70% after 2 and 4 h,
respectively (entries 7 and 8 vs entry 6). In our recent study
on enantioselective alkenylation of aldehydes by using alk-
1-enyl dicyclohexylboranes (RCHdCHBCy2), addition
of the alkenyl groups took place selectively without the
(7) Ukon, T.; Harada, T. Eur. J. Org. Chem. 2008, 4405–4407.
(8) For nonenantioselective carbonyl addition of alkylboron re-
agents catalyzed by a nickel complex, see: (a) Hirano, K.; Yorimitsu,
H.; Oshima, K. Org. Lett. 2005, 7, 4689–4691. (b) Hirano, K.; Yorimitsu,
H.; Oshima, K. Adv. Synth. Catal. 2006, 348, 1543–1546. See, also: (c)
Takahashi, G.; Shirakawa, E.; Tsuchimoto, T.; Kawakami, Y. Chem.
Commun. 2005, 1459–1460.
(9) (a) Midland, M. M.; Petre, J. E.; Zderic, S. A.; Kazubski, A.
J. Am. Chem. Soc. 1982, 104, 528–531. (b) Midland, M. M.; McLoughlin,
J. I.; Gabriel, J. J. Org. Chem. 1989, 54, 159–165.
(10) Mahrwald, R.; Schick, H. Synthesis 1990, 592–595.
(11) Shono, T.; Harada, T. Org. Lett. 2010, 12, 5270–5273.
Org. Lett., Vol. 15, No. 16, 2013
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Table 1. Catalytic Enantioselective Alkylation of Aldehydes
Using Alkylboron Reagentsa
Scheme 3. Catalytic Enantioselective Alkylation of Aldehydes
by Using Alkylboron Reagents
(3c) (Scheme 3). The reaction of para and meta substituted
benzaldehyde derivatives (1bÀd) as well as 1-naphthalde-
hyde 1a afforded the corresponding products 4 in good
yields and in high selectivities (90À96% ee) (Table 1,
entries 1À4). On the other hand, moderate enantioselec-
tivity was observed for ortho substituted derivative 1e
(entry 5). The reaction exhibited high enantioselectivity
(91À94% ee) also for heteroaromatic aldehydes 1f,g
and R,β-unsaturated aldehyde 1h (entries 6À8). Aliphatic
aldehyde 1j was considerably less reactive, affording the
corresponding product 4ic in low yield with an inferior
selectivity (72% ee).
To clarify the scope for alkylboron reagents 3, reactions
werecarried out withthosepreparedfrom terminalalkenes
2 by hydroboration with BH3 SMe2. Boron reagents 3,
3
prepared from aryl substituted olefins 2d,e and ω-bromo-
1-alkenes 2f,g, underwent enantioselective addition to
aromatic, heteroaromatic, and R,β-unsaturated aldehydes
to give the corresponding alkylation products 4 in high
enantioselectivity (91À99%). Functionalized alkylboron
reagents prepared from TIPS protected olefinic alcohols
2h,i and the phthalimide derivative (2j) of pent-4-enyla-
mine also underwent enantioselective addition to aromatic
aldehydes to furnish the corresponding monoprotected
diols and amino alcohols, respectively, in 89À96% ee, with
the exception of the reaction of o-bromo derivative 1f
(entries 17À22). Alkylboron reagents bearing isopropyl
ester and cyano groups, derived from terminal functiona-
lized alkenes 2k,l, could be used successfully in the present
reaction (entries 23À26). The corresponding functiona-
lized secondary alcohols were obtained in good yields and
high enantioselectivities (93À97% ee).
a Reactions were carried out by adding aldehydes 1 (0.5 mmol) in
THF (0.7 mL) slowly for 4 h to a solution of boron reagents 3 (1.5 M)
(1.5 equiv), 6a (5 mol %), and Ti(OiPr)4 (3 equiv) in THF at 66 °C. The
reaction mixture was refluxed further for 1 h. b Isolated yield. c Deter-
mined by a chiral phase LC analysis. d The absolute configuration was
determined to be R. See Supporting Information for details.
participation of the cyclohexyl group.11 Based on this
observation, hexylation of 2b was examined by using
HexBCy2 (1.5 equiv) as a boron reagent (entry 9). Although
hexyl adduct 3bc was obtained as a sole alkylation product,
the reaction was sluggish and the reduction pathway
predominated (entry 9).
Recently, we have reported an alternative method for
enantioselective addition of functionalized alkyl groups to
Under the slow addition conditions (Scheme 2, entry 8),
the scope of the catalytic enantioselective alkylation was
studied first for a range of aldehydes 1aÀi by using Hex3B
(12) Kinoshita, Y.; Kanehira, S.; Hayashi, Y.; Harada, T. Chem.;
Eur. J. 2013, 19, 3311–3314.
4200
Org. Lett., Vol. 15, No. 16, 2013

aldehydes by using alkylzinc bromide reagents [FGÀ(CH2)nÀ
and aldehydesvia alkylboron reagents. Thereaction can be
carried out at a low catalyst loading (5 mol %) and is
applicable to a variety of functionalized alkenes, including
those containing a bromine atom, a protected alcohol and
amine, an ester, and a nitrile.
ZnBr LiCl] in the presence of the DPP-H8-BINOL-derived
3
titanium catalyst.12 Notably, the two methods can be
employed in the preparation of enantiomerically enriched
functionalizedalcoholsin a complementary manner. Thus,
for example, starting from ω-bromo-1-alkene 2f,g, the
enantioselective addition of terminal alkenyl groups can
be achieved via the corresponding alkylzinc bromide
reagents (CH2dCH(CH2)nZnBr; n = 2, 3) while, on the
other hand, the application of the present method realizes
the enantioselective addition of ω-bromoalkyl groups
(entries 13À16).
Acknowledgment. This work was supported by
KAKENHI (No. 20550095) from the Ministry of Education,
Culture, Sports, Science, and Technology (MEXT), Japan
and by the Kyoto Institute of Technology Research Fund.
Supporting Information Available. Experimental proce-
dures and characterization of products. This material is
available free of charge via the Internet at http://pubs.acs.org.
In summary, we have developed a practical method for
the enantioselective synthesis of functionalized secondary
alcohols starting from readily available terminal alkenes
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 16, 2013
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