Catalytic enantioselective synthesis of secondary allylic alcohols from terminal alkynes and aldehydes via 1-alkenylboron reagents

Article abstract of DOI:10.1021/ol1023213

A practical one-pot method has been developed for preparing enantioenriched secondary allylic alcohols starting from terminal alkynes and aldehydes. Hydroboration of terminal alkynes with dicyclohexylborane and subsequent reaction of the resulting alkenylboron reagents with aldehydes in the presence of a catalytic amount (5 mol %) of 3-(3,5-diphenylphenyl)-H₈-BINOL and excess titanium tetraisopropoxide afforded the corresponding allylic alcohols in high enantioselectivities up to 94% ee.

Full text of DOI:10.1021/ol1023213

ORGANIC
LETTERS
2010
Vol. 12, No. 22
5270-5273
Catalytic Enantioselective Synthesis of
Secondary Allylic Alcohols from
Terminal Alkynes and Aldehydes via
1-Alkenylboron Reagents
Takashi Shono and Toshiro Harada*
Department of Chemistry and Materials Technology, Kyoto Institute of Technology,
Matsugasaki, Sakyo-ku, Kyoto, Japan, 606-8585
harada@chem.kit.ac.jp
Received September 26, 2010
ABSTRACT
A practical one-pot method has been developed for preparing enantioenriched secondary allylic alcohols starting from terminal alkynes and
aldehydes. Hydroboration of terminal alkynes with dicyclohexylborane and subsequent reaction of the resulting alkenylboron reagents with
aldehydes in the presence of a catalytic amount (5 mol %) of 3-(3,5-diphenylphenyl)-H8-BINOL and excess titanium tetraisopropoxide afforded
the corresponding allylic alcohols in high enantioselectivities up to 94% ee.
Enantiomerically enriched chiral secondary allylic alcohols
are important synthetic precursors. They are also found in
numerous naturally occurring and biologically active com-
pounds. Much attention has been focused on their catalytic
enantioselective synthesis.1-3 Of several approaches, the one
based on alkyne hydroboration and subsequent catalytic
enantioselective alkenylation of aldehydes with the resulting
1-alkenylboron reagents is particularly attractive in view of
a wide availability of alkynes and aldehydes as well as
potential functional-group tolerance (Scheme 1). In 1992,
Scheme 1. Enantioselective Synthesis of Secondary Allylic
Alcohols from Terminal Alkynes and Aldehydes
(1) For kinetic resolution by the Sharpless epoxidation, see: (a) Gao,
Y.; Klunder, J. M.; Hanson, R. M.; Masamune, H.; Ko, A. Y.; Sharpless,
K. B. J. Am. Chem. Soc. 1987, 109, 5765–5780. (b) Johnson, R. A.;
Sharpless, K. B. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; Wiley-
VCH: Weinheim, 2000; p 231
.
(2) For early reports on enantioselective alkenylation of aldehydes, see:
(a) Oppolzer, W.; Radinov, R. N. Tetrahedron Lett. 1988, 29, 5645–5648.
(b) von dem Bussche-Hu¨nnefeld, J. L.; Seebach, D. Tetrahedron 1992, 48,
Oppolzer and Radinov developed an enantioselective alk-
enylation of aldehydes catalyzed by chiral amino alcohol
DAIB (3-exo-(dimethylamino)isoborneol), in which alkenyl-
boron reagents are used after converting to alkenylzinc
5719–5730
.
(3) For the Nozaki-Hiyama-Kishi Coupling, see: (a) Guo, H.; Dong,
C.-G.; Kim, D.-S.; Urabe, D.; Wang, J.; Kim, J. T.; Liu, X.; Sasaki, T.;
Kishi, Y. J. Am. Chem. Soc. 2009, 131, 15387–15393. (b) Hargadena, G. C.;
Guirya, P. J. AdV. Synth. Catal. 2007, 349, 2407–2424
.
10.1021/ol1023213  2010 American Chemical Society
Published on Web 10/29/2010

species through transmetalation with Me2Zn or Et2Zn.4
Following this report, several efficient catalytic systems have
been developed for the enantioselective alkenylation of
aldehydes via boron/zinc transmetalation of the alkenylboron
reagents.5,6 Despite these advances, the requirement of the
relatively expensive and pyrophoric dialkylzinc reagents in
transmetalation makes this approach less attractive in practi-
cal applications.7 Recently, Shibasaki and Kanai reported a
new approach, without involving the boron/zinc transmeta-
lation, using 1-alkenylboronic acid esters by the catalysis of
a chiral Cu(I)F complex.8 However, the boron reagents need
to be prepared beforehand and are not appropriate for a one-
pot synthesis starting from alkynes and aldehydes.
A recent report from our laboratory revealed that trieth-
ylborane can be used in the enantioselective alkylation of
aldehyde.9 In the presence of DPP-H8-BINOL (1d) (2 mol
%) and titanium tetraisopropoxide (3 equiv), triethylborane
reacts with aromatic and unsaturated aldehydes to give
ethylation products with high enantioselectivities. It occurred
to us that, with a similar catalyst system, 1-alkenylboron
reagents could be employed in the enantioselective alkeny-
lation without using the dialkylzinc reagents. We now report
a practical one-pot method for the catalytic enantioselective
synthesis of secondary allylic alcohols starting from terminal
alkynes and aldehydes via 1-alkenylboron reagents.
Table 1. Catalytic Enantioselective Synthesis of Alcohol 5aaa
ligand
Ti(OiPr)4
5aa
yield (%)
6
entry
(mol %)
(equiv)
ee (%)
yield (%)
1
2
3
4
-
-
-
3
3
3
3
3
3
1.5
4.5
3
17
51
71
56
59
62
72
42
61
8
-
-
41
22
27
27
26
23
25
20
22
37
22
1a (5)
1b (5)
1c (5)
1d (5)
1d (5)
1d (5)
1d (5)
1d (5)
1d (2)
75
82
71
89
91
86
89
0
5
6
7b
8
9
10c
11
3
67
86
a Unless otherwise noted, reactions were carried out with trans-(oct-1-
ennyl)BCy2 4a (1.5 equiv) in refluxing THF for 2-3 h. b 2 equiv of 4a
was employed. c The reaction was carried out at room temperature for 7 h.
out in the presence of titanium tetraisopropoxide (3 equiv),
alkenylation became a major process, affording rac-5aa in
51% yield (entry 2). Under these conditions, enantioselective
formation of (R)-5aa was observed by the addition of 5 mol
% of BINOL derivatives 1a-d (entries 3-6). Thus, for
example, upon heating 2a and 4 (1.5 equiv) in the presence
of (R)-1a (5 mol %) and titanium tetraisopropoxide (3 equiv)
in THF under reflux, (R)-5aa was obtained in 75% ee and
in 71% yield. Of these ligands, the best result was obtained
with (R)-DPP-H8-BINOL (1d), which provided (R)-5aa in
89% ee and in 62% yield (entry 6). The yield and the
enantioselectivity were improved by the increase of the
amount of the alkenylboron reagent 4 (2 equiv) (entry 7).
For the reaction employing 4 (1.5 equiv), decreasing the
Hydroboration of 1-octyne (3a) with dicyclohexylborane
in THF gave trans-1-octenylborane 4 regioselectively (Scheme
2).10 Upon heating 4 (1.5 equiv) with p-chlorobenzaldehyde
Scheme 2. Catalytic Enantioselective Synthesis of Alcohol 5aa
(5) (a) Soai, K.; Takahashi, K. J. Chem. Soc., Perkin Trans. 1 1994,
1257–1258. (b) Dahmen, S. D.; Bra¨se, S. Org. Lett. 2001, 3, 4119–4122.
(c) Chen, Y. K.; Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124,
12225–12231. (d) Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2003, 125,
10677–10683. (e) Ji, J.-X.; Qiu, L.-Q.; Yip, C. W.; Chan, A. S. C. J. Org.
Chem. 2003, 68, 1589–1590. (f) Lurain, A. E.; Maestri, A.; Kelly, A. R.;
Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2004, 126, 13608–13609. (g)
Jeon, S.-J.; Chen, Y. K.; Walsh, P. J. Org. Lett. 2005, 7, 1729–1732. (h)
Sprout, C. M.; Richmond, M. L.; Seto, C. T. J. Org. Chem. 2005, 70, 7408–
7417. (i) Richmond, M. L.; Sprout, C. M.; Seto, C. T. J. Org. Chem. 2005,
70, 8835–8840. (j) Lauterwasser, F.; Gall, J.; Ho¨fener, S.; Bra¨se, S. AdV.
Synth. Catal. 2006, 348, 2068–2074. (k) Wu, H.-L.; Wu, P.-Y.; Uang, B.-
J. J. Org. Chem. 2007, 72, 5935–5937. (l) Kerrigan, M. H.; Jeon, S.-J.;
Chen, Y. K.; Salvi, L.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2009,
131, 8434–8445. (n) Kim, H. Y.; Salvi, L.; Carroll, P. J.; Walsh, P. J. J. Am.
Chem. Soc. 2010, 132, 402–412.
(6) For a relevant approach based on hydrozirconylation of alkynes, see;
(a) Wipf, P.; Xu, W. Tetrahedron Lett. 1994, 35, 5197–5200. (b) Wipf, P.;
Ribe, S. J. Org. Chem. 1998, 63, 6454–6455.
(7) Catalytic enantioselective reductive coupling of alkynes and alde-
hydes is a promising alternative: (a) Miller, K. M.; Huang, W.-S.; Jamison,
T. F. J. Am. Chem. Soc. 2003, 125, 3442–3443. (b) Kong, J.-R.; Ngai, M.-
Y.; Krische, M. J. J. Am. Chem. Soc. 2006, 128, 718–719. (c) Chaulagain,
M. R.; Sormunen, G. J.; Montgomery, J. J. Am. Chem. Soc. 2007, 129,
9568–9569. (d) Yang, Y.; Zhu, S.-F.; Zhou, C.-Y.; Zhou, Q.-L. J. Am. Chem.
Soc. 2008, 130, 14052–14053. For review; see; (e) Bower, J. F.; Kim, I. S.;
Patman, R. L.; Krische, M. J. Angew. Chem., Int. Ed. 2009, 48, 34–46.
(8) Tomita, D.; Kanai, M.; Shibasaki, M. Chem. Asian J. 2006, 1-2,
161–166.
(2a) in THF under reflux for 3 h, dehydroboration11 of 4
took place preferentially to give reduction product 6 in 41%
yield with minor formation of alkenylation product rac-5aa
(Table 1, entry 1). When the reaction of 2a and 4 was carried
(9) Ukon, T.; Harada, T. Eur. J. Org. Chem. 2008, 4405–4407.
(10) Brown, H. C.; Mandal, A. K.; Kulkarni, S. U. J. Org. Chem. 1977,
42, 1392–1398.
(4) Oppolzer, W.; Radinov, R. N. HelV. Chim. Acta 1992, 75, 170–
173.
(11) Midland, M. M.; Petre, J. E.; Zderic, S. A.; Kazubski, A. J. Am.
Chem. Soc. 1982, 104, 528–531.
Org. Lett., Vol. 12, No. 22, 2010
5271

amount of titanium tetraisopropoxide to 1.5 equiv resulted
in a decrease of the product yield and enantioselectivity (entry
8), while 4.5 equiv of titanium tetraisopropoxide did not
afford better results (entry 9). At room temperature, the
reaction was sluggish, giving rac-5aa in low yield and 6 as
a major product (entry 10). At a 2 mol % catalyst loading,
the yield of (R)-5aa was comparable, while the enantiose-
lectivity was decreased to 86% ee (entry 11).
Table 2. Catalytic Enantioselective Synthesis of Secondary
Allylic Alcohols 5 from Aldehydes 2 and Alkynes 3a
Under the conditions employing ligand 1d (5 mol %) with
titanium tetraisopropoxide (3 equiv) in refluxing THF, the
scope of the present catalytic enantioselective synthesis of
secondary allylic alcohols was examined for a variety of
aldehydes 2a-h and alkynes 3a-h (Scheme 3). Hydrobo-
Scheme 3. Catalytic Enantioselective Synthesis of Secondary
Allylic Alcohols 5 from Aldehydes 2 and Alkynes 3
a Unless otherwise noted, reactions were carried out by refluxing a THF
solution of an alkenylboron reagent (1.5 equiv), prepared from alkyne 3
(1.65 equiv) and Cy2BH (1.5 equiv), aldehyde 2, ligand 1d (5 mol %), and
titanium tetraisopropoxide (3 equiv) for 2-3 h. b Determined by chiral
stationary phase HPLC or capillary GC analysis. c The reaction was carried
out with an alkenylboron reagent prepared from alkyne 3 (2.2 equiv) and
Cy2BH (2 equiv).
ration of alkyne 3a with dicyclohexylborane followed by the
reactions of the resulting alkenylboron reagent with aromatic
aldehydes 2a-e afforded 1-aryl-non-2-en-1-ols 5 in 60-72%
yields with high enantioselectivities (90-94% ee) (Table 2,
entries 1-6). The alkenylboron reagent also underwent enan-
tioselective addition to R,ꢀ-unsaturated aldehydes 2f,g to give
divinyl carbinol 5fa (93% ee) and 5ga (91% ee) (entries 7 and
8). Lower, still acceptable, enantioselectivity was obtained in
the reaction of aliphatic aldehyde 2h (entry 9).
The scope of the reaction was then examined by varying the
structure of the alkynes. High enantioselectivities (90-94% ee)
were obtained for branched alkyne 3b and phenyl-substituted
alkyne 3c in the reaction of aromatic aldehydes 2a,b (entries
10-12), while the reaction of cyclopropylethyne (3d) and
2b resulted in lower enantioselectivity (entry 13). The present
reaction conditions are compatible with a range of function-
alized alkynes, including those containing a chlorine atom,
a protected alcohol, a nitrile, and an amide. Thus, alkenyl-
boron reagents derived from 5-chloro-pent-1-yne (3e) and
4-trityloxy-but-1-yne (3f) underwent addition to 2a,b in high
enantioselectivities (87-91% ee) (entries 14-16). It should
be noted that hexynenitrile 3g and hexynamide 3h were also
successfully employed in the enantioselective alkenylation
despite the potential reactivity of a cyano and amide functional
groups (entries 17-20). The corresponding functionalized allylic
alcohols were obtained also in high enantioselectivities (87-94%
ee). To our knowledge, these reactions are the first examples
of enantioselective alkenylation starting from alkynenitriles and
alkynamides.
We speculate that alkenylboron reagent 4 undergoes boron/
titanium transmetalation with titanium tetraisopropoxide
selectively on the alkenyl group to produce alkenyltitanium
7 as an active intermediate (eq 1).12,13 The low-yield
formation of racemic product (rac-5aa) in the reaction at
(12) Alternatively, 7 would form an aggregate with concurrently
produced Cy2B(OiPr) and participate in the catalytic reaction. For a relevant
aggregation with ArAl(OiPr)2, see: Wu, K.-H.; Gau, H-.M. J. Am. Chem.
Soc. 2006, 128, 14808–14809
.
5272
Org. Lett., Vol. 12, No. 22, 2010

room temperature (Table 1, entry 10) suggests that the boron/
titanium transmetalation would be very slow at the low
temperature and require THF reflux conditions to proceed.
The result of a control experiment in the absence of ligand
(Table 1, entry 2) implies that alkenyltitanium 7 would
undergo facile addition in refluxing THF to give rac-5
without the catalysis. The high enantioselectivities observed
in the present reactions even at a relatively low catalyst
loading could be rationalized not only by superior activity
of the catalyst14 but also by a relatively low concentration
of alkenyltitanium 7 due to the slow rate of the transmeta-
lation step.
alcohols starting from readily available 1-alkynes and alde-
hydes via 1-alkenylboron reagents. The reaction can be
carried out by a one-pot operation without employing
dialkylzinc reagents at a low catalyst loading (5 mol %).
The reaction is applicable to a variety of functionalized
alkynes, including those containing a chlorine atom, a
protected alcohol, a nitrile, and an amide.
Acknowledgment. This work was supported by KAKENHI
(20550095) and by Kyoto Institute of Technology Research
Fund.
Supporting Information Available: Experimental pro-
cedures and characterization of products. This material is
available free of charge via the Internet at http://pubs.acs.
org.
OL1023213
In summary, we have developed a practical method for
the highly enantioselective synthesis of secondary allylic
(14) (a) Harada, T.; Kanda, K. Org. Lett. 2006, 8, 3817–3819. (b)
Harada, T.; Ukon, T. Tetrahedron: Asymmetry 2007, 18, 2499–2502. (c)
Muramatsu, Y.; Harada, T. Angew. Chem., Int. Ed. 2008, 47, 1088–1090.
(d) Muramatsu, Y.; Harada, T. Chem.sEur. J. 2008, 14, 10560–10563. (e)
Muramatsu, Y.; Kanehira, S.; Tanigawa, M.; Miyawaki, Y.; Harada, T. Bull.
Chem. Soc. Jpn. 2010, 83, 19–32.
(13) For mechanistic aspects of BINOLate-Ti catalysis, see: Baisells,
J.; Davis, T. J.; Carroll, P.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124,
10336–10348.
Org. Lett., Vol. 12, No. 22, 2010
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