Catalytic enantioselective synthesis of α-substituted secondary allylic alcohols from terminal alkynes and aldehydes via vinylaluminum reagents

Article abstract of DOI:10.1002/chem.201303619

One-pot procedure: A general method for the highly enantioselective synthesis of α-substituted allylic alcohols has been developed starting from readily available terminal alkynes and aldehydes and proceeding via vinylaluminum reagents (see scheme, dppp=1,3-bis(diphenylphosphino)propane). The use of Me₂AlH is essential in the Ni-catalyzed hydroalumination step to generate vinylaluminum reagents that cannot reduce the aldehyde. Copyright

Full text of DOI:10.1002/chem.201303619

COMMUNICATION
DOI: 10.1002/chem.201303619
Catalytic Enantioselective Synthesis of a-Substituted Secondary Allylic
Alcohols from Terminal Alkynes and Aldehydes via Vinylaluminum
Reagents
Ravindra Kumar,[b] Hiroki Kawasaki,[a] and Toshiro Harada*[a]
Enantioenriched chiral secondary allylic alcohols are
among the most versatile chiral building blocks in asymmet-
ric synthesis. Considerable attention has been focused on
the catalytic enantioselective synthesis of these alcohols, es-
pecially through the stereocontrolled coupling of readily
available starting components.[1,2] Although chiral allylic al-
cohols with various substitution patterns are in demand, ad-
vances in this area have mostly been focused towards the
synthesis of b-substituted E allylic alcohols.[3,4] In contrast,
very few methods have been developed for the synthesis of
a-substituted allylic alcohols.[5,3f] Recently, Kishi and co-
workers reported an efficient method for the enantioselec-
tive coupling of aldehydes with vinyl iodides through the Ni/
The Ni-catalyzed hydroalumination of terminal alkynes
with iBu2AlH, providing a-substituted vinylaluminum re-
agents with high Markovnikov selectivity has been reported
recently by Hoveyda et al.[7] It occurred to us that the enan-
tioselective addition of the generated vinylaluminum re-
agents to aldehydes could provide an alternative route to al-
lylic alcohols by using easily accessible alkynes as staring
materials (Scheme 1). We now report a straightforward and
efficient method for the catalytic enantioselective synthesis
of a-substituted secondary allylic alcohols starting from ter-
minal alkynes and aldehydes via vinylaluminum reagents.
We have recently reported the versatility of a chiral titani-
um catalyst derived from DPP-H8-BINOL (DPP=3,5-di-
phenylphenyl, BINOL=1,1’-bi-2-naphthol) 8a and excess ti-
tanium tetraisopropoxide for the enantioselective addition
of a variety of organometallic reagents, such as Grignard,[8]
organoboron,[9] alkylzinc,[10] and aryltitanium reagents,[11] to
aldehydes. These results prompted us to apply the chiral ti-
tanium catalyst to the reaction of p-chlorobenzaldehyde 3a
with vinylaluminum reagent 2a’, which are generated from
4-phenyl-1-butyne 1a according to the protocol described by
Hoveyda et al.[7] (Scheme 2).[12,13] Thus, treatment of 1a
(1.5 equiv) in hexane with iBu2AlH (1.5 equiv), in the pres-
Cr-catalyzed
Nozaki–Hiyama–Kishi
(NHK)
reaction
(Scheme 1).[5] The efficiency and robustness of this reaction
for the synthesis of a-substituted allylic alcohols has been
well-demonstrated by its application in natural-product syn-
theses.[6]
ence of [NiACHTUNGRTNEUNG(dppp)Cl2] (dppp=1,3-bis(diphenylphosphino)-
propane, 3 mol% with respect to 1a), followed by the reac-
tion of the resulting vinylaluminum reagent, 2a’, with alde-
hyde 3a in the presence of ligand 8a (5 mol%) and titanium
tetraisopropoxide (1.5 equiv), in THF at 08C for 1 h, afford-
ed allylic alcohol 4aa in 18% yield and 77% enantiomeric
excess (ee). The major product of this reaction was p-chloro-
benzyl alcohol (6, 34%), suggesting that the formation of vi-
nylaluminum reagent 2a’, bearing isobutyl groups, resulted
in a preferential hydride reduction of the aldehyde.[14]
Scheme 1. Catalytic enantioselective synthesis of a-substituted secondary
allylic alcohols.
We then turned our attention to the use of Me2AlH, in-
stead of iBu2AlH, with the expectation that the vinylalumi-
num reagent 2a, bearing methyl groups, would not be able
to reduce the aldehyde. The aluminum hydride reagent, in
hexane, was prepared in quantitative yield by the reaction
of Me2AlCl with NaH by following the reported procedure
with some modification.[15,16] Me2AlH exhibited similar effi-
ciency and regioselectivity to that of iBu2AlH for the hydro-
alumination of alkyne 1a. Treatment of 1a with Me2AlH
[a] H. Kawasaki, Prof. Dr. T. Harada
Department of Chemistry and Materials Technology
Kyoto Institute of Technology
Matsugasaki, Sakyo-ku, Kyoto 606-8585 (Japan)
Fax : (+81)75-724-7514
E-mail: harada@chem.kit.ac.jp
[b] Dr. R. Kumar
Venture Laboratory
Kyoto Institute of Technology
Matsugasaki, Sakyo-ku, Kyoto 606-8585 (Japan)
(1.7 equiv), in the presence of [NiACTHNUTRGNEG(NU dppp)Cl2] (3 mol%), in
THF/hexane (08C–room temperature), followed by quench-
ing the reaction mixture with D2O, gave a 11:1 mixture of
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201303619.
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conditions, reactions were also carried out with BINOL de-
rivatives 8b–e as ligands. H8-BINOL 8b exhibited a relative-
ly high selectivity of 84% ee (Table 1, entry 7). A high ee
value of 93% was observed for 3,5-di-(tert-butyl)phenyl de-
rivative 8c (Table 1, entry 8). On the other hand, the enan-
tioselectivity of the reaction when BINOL 8d or DPP-
BINOL 8e were used was inferior to that obtained when oc-
tahydro derivatives 8b and 8a were used (Table 1, entries 9
and 10). a-Substituted vinylaluminum reagent 2a, in the ab-
sence of titanium tetraisopropoxide and ligand 8a, was
much less reactive towards the aldehyde (Table 1, entry 11);
however, 2a did undergo carbonyl addition in the absence
of ligand 8a when titanium tetraisopropoxide was present
(Table 1, entry 12). Notably, the activity of the titanium cata-
lyst, derived from 8a, is high enough to overwhelm the
background racemic reaction between reagent 2a and titani-
um tetraisoproxide.[17] Reducing the catalyst loading to
2 mol% unfortunately resulted in lower selectivity (82% ee,
Table 1, entry 6).
Under the optimized conditions (Table 1, entry 5), the
scope of the catalytic enantioselective alkenylation was stud-
ied for a range of aldehydes by using aluminum reagent 2a
(Scheme 3). The reaction of para- and meta-substituted ben-
zaldehyde derivatives (3a and 3c–f) afforded the corre-
sponding alkenylation products 4 in good yields and high se-
lectivities (91–93% ee, Table 2, entries 1–5). On the other
hand, only moderate enantioselectivity was observed for
ortho-substituted derivative 3g (Table 2, entry 6). High se-
lectivities (88–91% ee) were also observed for the reaction
of heteroaromatic aldehyde 3i and a,b-unsaturated alde-
hydes 3j and 3k (Table 2, entries 7–9). The reaction of ali-
phatic aldehyde 3m, however, resulted in a moderate selec-
Scheme 2. Enantioselective preparation of allylic alcohol 4aa from
alkyne 1a and aldehyde 3a.
PhCH2CH2CD=CH2 and PhCH2CH2CH=C(D)H in 82%
yield.
When vinylaluminum reagent 2a, generated from 1a
(1.5 equiv), was employed in the subsequent reaction with
aldehyde 3a, in the presence of ligand 8a (5 mol%) and ti-
tanium tetraisopropoxide (1.5 equiv), 4aa was obtained as
a major product in 50% yield and 92% ee (Table 1, entry 1).
In this reaction, methyl adduct 7 (10%) and regioisomeric
alkenyl adduct 5 (<2%) were obtained as by-products, but
no reduction product, 6, was detected. To improve the yield
of 4aa, the molar ratio of 1a/Me2AlH/titanium tetraisoprop-
oxide was optimized (Table 1, entries 2–5). A yield of 75%
and an ee value of 93% were obtained when 3 equivalents
of each reagent were used (Table 1, entry 5). Under these
Table 1. Optimization of reaction conditions for hydroalumination and
enantioselective alkenylation leading to 4aa.[a]
Entry 1a
[equiv]
Me2AlH Ti
G
7 yield
E
A
ACHTUNGTRENNUNG
1
2
3
4
1.5
2
2.5
2.5
3
3
3
3
3
2.6
2.6
2.6
2.6
3
3
3
3
3
1.5
2
2.5
3
3
3
3
3
3
3
8a
8a
8a
8a
8a
8a
8b
8c
8d
8e
–
50 92
10
8
10
15
4
6
4
10
3
4
63 92
67 91
61 90
75 93
74 82
74 84
68 93
74 65
75 80
5
6[b]
7
8
9
10
11
12
3
1.5
3
3
2.6
3
0
3
trace
50
–
–
trace
11
–
[a] Unless otherwise noted, reactions were carried out with 5 mol% of
ligand 8. [b] 2 Mol% of 8a was employed as a ligand.
Scheme 3. Catalytic enantioselective synthesis of a-substituted secondary
allylic alcohols from terminal alkynes 1 and aldehydes 3.
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Chem. Eur. J. 2013, 19, 17707 – 17710

Synthesis of a-Substituted Secondary Allylic Alcohols
COMMUNICATION
Table 2. Catalytic enantioselective synthesis of 1,1-disubstituted allylic alcohols
from aldehyde 2 and alkynes 3.
5
agents prepared in situ from terminal alkynes 1a–k
by the Ni-catalyzed hydroalumination reaction
with Me2AlH. Aluminium reagents generated from
3-phenylprop-1-yne 1b and 5-methylhex-1-yne 1c
exhibited high enantioselectivity and good reactivi-
ty towards aromatic aldehydes (Table 2, entries 11–
13). The size of the a-substituent of the vinylalumi-
num reagents affected the reactivity, but not the
enantioselectivity of the reactions. Hence, the reac-
tion of 3a with the cyclohexyl-substituted reagent,
generated from 1d, resulted in a low yield of corre-
sponding product 4da (90% ee, Table 2, entry 14),
whereas the reaction of 3a with a reagent bearing
a less sterically demanding cyclopropyl group, gen-
erated from 1e, afforded corresponding product
4ea (94% ee) in good yield (Table 2, entry 15).
Moderate enantioselectivity was observed in the
reaction of 3a with a reagent derived from phenyl-
acetylene (1 f, Table 2, entry 17). Under the opti-
mized conditions, enyne 1g, as well as diyne 1h,
was successfully employed as an alkyne compo-
nent, as exemplified in the highly enantioselective
formation of dienyl carbinols 4ga and 4gh
(Table 2, entries 18 and 19) and en-ynyl carbinol
4ha (Table 2, entry 20). Notably, this reaction toler-
ates alkynes with chloride and silyloxy substituents
(Table 2, entries 21–25). The corresponding func-
tionalized allylic alcohols (4ia, 4il, 4ja, 4ka, and
4kd) were obtained with high enantioselectivities
(84–93% ee) and in good yields.
Entry
Allylic alcohol
Yield[a]
[%]
ee[b]
[%]
1
2
3
4
5
6
7
8
9
4aa; R1 =p-ClC6H4
4ac; R1 =p-CF3C6H4
4ad; R1 =p-CNC6H4
4ae; R1 =p-CO2MeC6H4
4af; R1 =m-MeOC6H4
4ag; R1 =o-BrC6H4
4ai; R1 =2-thienyl
75
77
61
65
74
73
69
74
39
62
93[c]
91
91
91
92
68
91
88
88
68
4aj; R1 =1-cyclohexenyl
4ak; R1 =CH2 =C(Me)
4am; R1 =Cy
10
11
12
4ba; R1 =p-ClC6H4
4bb; R1 =p-BrC6H4
69
70
91
92
13
14
4ca
4da
62
33
91
90
15
16
4ea; R1 =p-ClC6H4
63
68
94
71
4en; R1 =PhCH2CH2
17
4 fa
50
77
In summary, we have developed a general one-
pot method for the highly enantioselective synthe-
sis of a-substituted allylic alcohols starting from
readily available terminal alkynes and aldehydes
and proceeding via vinylaluminum reagents. The
use of Me2AlH is essential in the Ni-catalyzed hy-
droalumination step to generate vinylaluminum re-
agents that cannot reduce the aldehyde starting
material. High enantioselectivities were achieved
at a low catalyst loading (5 mol%) in the subse-
quent addition reaction. The present study shows
the applicability of the DPP-H8-BINOL derived ti-
tanium catalyst for the enantioselective carbonyl
addition of organoaluminum reagents and demon-
strates the versatilty of this catalytic system.
18
19
4ga; R1 =p-ClC6H4
4gh; R1 =1-naphthyl
62
78
91
92
20
4ha
58
95
21
22
4ia; R1 =p-ClC6H4
4il; R1 =PhCH=CH
72
51
92
84
23
4ja
70
93
24
25
4ka; R1 =p-ClC6H4
4kd; R1 =p-CNC6H4
60
60
93
93
[a] Isolated yield. [b] Determined by HPLC analysis by using a chiral column. [c] The
absolute configuration was determined by the method described by Mosher et al.[18]
TBDPS=tert-butyldiphenylsilyl, TBS=tert-butyldimethylsilyl.
Experimental Section
General procedure for catalytic enantioselective synthesis of
a-substituted secondary allylic alcohols: A hexane solution of
Me2AlH (1.1m, 1.4 mL, 1.5 mmol) was added to a stirred solu-
tion of [NiACTHUNGTRENNUNG
tivity of 68% ee (Table 2, entry 10). Notably, the reaction
tolerated aldehydes that possessed potentially reactive
cyano and ester substituents (Table 2, entries 3 and 4).
To further investigate the scope for vinylaluminum re-
agents 2, reactions were carried out with vinylaluminum re-
Chem. Eur. J. 2013, 19, 17707 – 17710
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www.chemeurj.org
17709

T. Harada et al.
added to the resulting solution of vinylaluminum reagent 2 at 08C. After
being stirred for 1 h at 08C, the reaction mixture was poured into a two-
phase mixture of ethyl acetate (10 mL) and aqueous 1n HCl (30 mL)
and extracted three times with ethyl acetate. The combined organic
layers were washed successively with aqueous 5% NaHCO3 and brine,
dried (Na2SO4), and concentrated in vacuo. The residue was purified by
flash chromatography on silica gel, eluting with ethyl acetate/toluene or
ethyl acetate/hexane, to give allylic alcohols 4. The ee values of 4 were
determined by HPLC analysis by using a chiral column.
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Acknowledgements
This work was supported by KAKENHI (20550095 and 24550118) from
Ministry of Education, Culture, Sports, Science, and Technology
(MEXT), Japan and by Kyoto Institute of Technology Research Fund.
Keywords: allylic alcohols
·
asymmetric catalysis
·
asymmetric synthesis · hydrometalation · titanium
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Received: September 13, 2013
Published online: November 14, 2013
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