Highly enantioselective synthesis of (E)-allylic alcohols

Article abstract of DOI:10.1021/jo0709403

(Chemical Equation Presented) The asymmetric addition of alkenylzincs to aromatic and a-branched aliphatic aldehydes catalyzed by 1 generated the corresponding (E)-allylic alcohols with >95% ee and good to excellent chemical yields, especially >99.5% ee w

Full text of DOI:10.1021/jo0709403

has drawn the attention of organic chemists. The advantages of
this methodology include the following: (1) the alkenylzinc
reagents could be prepared in situ with simple operations either
by metal exchange of zinc chloride with alkenyl magnesium
bromide, zinc bromide with alkenyllithium,5 or by reaction of
dialkylzinc with alkenylzirconium reagents6 or alkenylboranes;7
and (2) a regioselective synthesis of E-double bonds as well as
an asymmetric carbon-carbon bond formation occurred during
the course of reaction, and chiral allylic alcohols thus obtained
are important intermediates for the preparation of numerous
natural products and biologically active compounds.8 Employ-
ment of various categories of ligands such as â-amino alco-
hols,9,10 paracyclophane-based ketimines,11 â-amino thiols,12
γ-amino naphthols,13 and dipeptide ligands14,15 for such purposes
have been studied. However, the exploration of efficient chiral
ligands to synthesize allylic alcohols in good enantioselectivities
still remains a challenge that requires considerable and intensive
investigation. Additionally, it has been demonstrated that further
Highly Enantioselective Synthesis of (E)-Allylic
Alcohols†
Hsyueh-Liang Wu, Ping-Yu Wu, and Biing-Jiun Uang*
Department of Chemistry, National Tsing Hua UniVersity,
Hsinchu, Taiwan, 300, Republic of China
bjuang@mx.nthu.edu.tw
ReceiVed May 11, 2007
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(b) Recently, it has been demonstrated that alkenylzinc reagents could be
prepared from alkenylboronic acids; see: Schmidt, F.; Rudolph, J.; Bolm,
C. Synthesis 2006, 3625.
(8) For recent selected examples, see: (a) Tarnowski, A.; Retz, O.; Ba¨r,
T.; Schmidt, R. R. Eur. J. Org. Chem. 2005, 1129. (b) Niida, A.; Oishi, S.;
Sasaki, Y.; Mizumoto, M.; Tamamura, H.; Fujii, N.; Otaka, A. Tetrahedron
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A.; Kawai, H.; Suzuki, T. Tetrahedron 2005, 61, 7392. (d) Brenna, E.;
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Sayed, E. J. Org. Chem. 2001, 66, 4766.
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P. J.; Walsh, P. J. J. Am. Chem. Soc. 2005, 127, 13138.
The asymmetric addition of alkenylzincs to aromatic and
R-branched aliphatic aldehydes catalyzed by 1 generated the
corresponding (E)-allylic alcohols with >95% ee and good
to excellent chemical yields, especially >99.5% ee was
observed in the case of 4-CF3-benzaldehyde. Notably, 1 is
an effective ligand to catalyze the addition of disubstituted
(R2 ) R3 ) ethyl) and bulky substituted (R2 ) H, R3 )
tert-butyl) alkenylzincs to benzaldehyde, affording the cor-
responding allylic alcohols both with 96% ee.
Since the discovery of Et2Zn,1 the preparation2 of organozinc
reagents and their applications3 in C-C bond formation have
been well-investigated. Unlike the enantioselective addition of
alkyllithium and Grignard reagents, addition of alkylzincs to
aldehydes in the presence of chiral catalysts4 affords chiral
secondary alcohols, possessing diversity of functionality, in high
enantioselectivities. Catalytic asymmetric addition of organozinc
reagents to carbonyl compounds has been widely studied for
over two decades, and successful examples of catalysts with
various ligand scaffolds have been reported.4 Recently, the
enantioselective addition of alkenylzinc reagents to aldehydes
† In memory of Professor Yoshihiko Ito who passed away on December 23,
2006.
(1) Frankland, E. Justus Liebigs Ann. Chem. 1849, 71, 171.
(2) Knochel, P.; Singer, R. D. Chem. ReV. 1993, 93, 2117.
(3) For application of organozinc reagents in organic synthesis, see: (a)
Carruthers, W. In ComprehensiVe Organometallic Chemistry; Wilkinson,
G., Ed.; Pergamon Press: Oxford, 1982; Chapter 49. (b) Langer, F.;
Schwink, L.; Devasagayaraj, A.; Chavant, P. Y.; Knochel, P. J. Org. Chem.
1996, 61, 8229. (c) Knochel, P.; Perea, J. J. A.; Jones, P. Tetrahedron 1998,
54, 8275. (d) Boudier, A.; Bromm, L. O.; Lotz, M.; Knochel, P. Angew.
Chem., Int. Ed. 2000, 39, 4414. (e) Hupe, E.; Calaza, M. I.; Knochel, P. J.
Organomet. Chem. 2003, 680, 136.
(4) For reviews, see: (a) Noyori, R.; Kitamura, M. Angew. Chem., Int.
Ed. Engl. 1991, 30, 49. (b) Soai, K.; Niwa, S. Chem. ReV. 1992, 92, 833.
(c) Soai, K.; Shibata, T. ComprehensiVe Asymmetric Catalysis; Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag: Berlin, Germany,
1999; Vol. 2, p 911. (d) Pu, L.; Yu, H. B. Chem. ReV. 2001, 101, 757. (e)
Pu, L. Tetrahedron 2003, 59, 9873.
(11) (a) Dahmen, S.; Bra¨se, S. Org. Lett. 2001, 3, 4119. (b) Bra¨se, S.;
Dahmen, S.; Ho¨fener, S.; Lauterwasser, F.; Kreis, M.; Ziegert, R. E. Synlett
2004, 2647. (c) Lauterwasser, F.; Gall, J.; Ho¨fener, S.; Bra¨se, S. AdV. Synth.
Catal. 2006, 348, 2068.
(12) (a) Tseng, S.-L.; Yang, T.-K. Tetrahedron: Asymmetry 2005, 16,
773. (b) Ko, D. H.; Kang, S. W.; Kim, K. H.; Chung, Y.; Ha, D. C. Bull.
Korean Chem. Soc. 2004, 25, 35.
(13) Ji, J.-X.; Qiu, L.-Q.; Yip, C. W.; Chan, A. S. C. J. Org. Chem.
2003, 68, 1589.
(14) (a) Sprout, C. M.; Richmond, M. L.; Seto, C. T. J. Org. Chem.
2004, 69, 6666. (b) Sprout, C. M.; Richmond, M. L.; Seto, C. T. J. Org.
Chem. 2005, 70, 7408. (c) Richmond, M. L.; Sprout, C. M.; Seto, C. T. J.
Org. Chem. 2005, 70, 8835.
(15) For other selected examples, see: (a) Bussche-Hu¨nnefeld, J. L. von
dem; Seebach, D. Tetrahedron 1992, 48, 5719. (b) Soai, K.; Takahashi, K.
J. Chem. Soc., Perkin Trans. 1 1994, 1257.
10.1021/jo0709403 CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/27/2007
J. Org. Chem. 2007, 72, 5935-5937
5935

TABLE 1. Optimization of the Reaction for the Asymmetric
Alkenylation of Benzaldehyde Catalyzed by 1
SCHEME 1. Asymmetric Arylation of Aldehydes Catalyzed
by 1
entry
solvent
temp (°C)
yield (%)a
ee (%)b
1
2
hexane
toluene
toluene
toluene
toluene
toluene
toluene
-30
-30
-30
-20
-40
-30
-30
91
88
86
88
70
81
85
91
93
94
89
90
90
96
3c
4c
5c
6c,d
7c,e
manipulations of the chiral allylic alcohols to synthetically useful
and valuable enantioenriched R-amino acids,10b γ-unsaturated
â-amino acids,10d epoxy alcohols,10e,f and â-hydroxyaldehydes10g
could be achieved, and these methods represent advances in
terms of synthetic efficiency and selectivity.
a Isolated yield. b Determined by chiral HPLC; see Supporting Informa-
tion. c DMS was removed following the preparation of alkenylborane. d 5
mol % of 1 was used. e Me2Zn was used instead of Et2Zn.
As part of our efforts on the development and scrutiny of
camphor-derived chiral ligands for catalytic asymmetric reac-
tions,16 (-)-2-exo-morpholinoisoborne-10-thiol (1) was found
to be an effective chiral ligand in the arylation of aldehydes
with up to >99.5% ee (Scheme 1).17 To study the scope and
catalytic ability of 1, we investigate the application of 1 in
alkenylation reaction, and herein, we describe the optimization
of reaction conditions and scope of 1 in the alkenylation of
aldehydes.
The in situ preparation of reactive alkenylzinc species starts
from hydroboration of 1-octyne with dicyclohexylborane,7a
followed by boron-zinc exchange reaction with Et2Zn to yield
active ethyl 1-octenylzinc. At the outset, reaction of 1-octe-
nylzinc with benzaldehyde catalyzed by 10 mol % of 1 in hexane
was examined at -30 °C, and (R,E)-1-phenyl-2-nonene-1-ol (2a)
was obtained with 91% yield and 91% ee (Table 1, entry 1).
Allylic alcohol 2a was obtained with slightly better ee when
the reaction was conducted in toluene (entry 2). To examine
the influence of dimethyl sulfide (DMS), from BH3‚DMS
complex in the preparation of dicyclohexylborane, DMS was
removed after preparation of 1-octenylborane, and with that, a
slight improvement of the enantioselectivity was observed (entry
3). Lowering reaction temperature did not improve enantiose-
lectivity, and decreasing catalytic loading of 1 diminished the
enantioinduction (entries 4-6). Finally, transmetalation using
dimethylzinc provided a better selectivity than using diethylzinc
(entry 7).
In light of the above observations, addition of 1-octenylzinc
to various aldehydes was examined. As shown in Table 2,
addition of 1-octenylzinc reagent to substituted benzaldehydes
with either electron-donating or electron-withdrawing groups
gave the corresponding allylic alcohols 2a-2j with high
enantioselectivities and yields (entries 1-10), while catalytic
addition of methyl 1-hexenylzinc to benzaldehyde and 3-CF3-
benzaldehyde provided 2k and 2l with 97 and 98% ee,
respectively (entries 11 and 12). Notably, in the case of 4-CF3-
benzaldehyde, >99.5% ee of the allylic alcohol 2j was observed
(entry 10).
TABLE 2. Asymmetric Alkenylation of Various Aldehydes
allylic
entry
R1
R2
R3
alcohol yield (%)a ee (%)b
1
2
3
4
5
6
7
8
H
C6H13
C6H13
C6H13
C6H13
C6H13
C6H13
C6H13
C6H13
C6H13
C6H13
C4H9
Ph
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
85
85
88
90
88
83
83
81
87
90
83
82
89
91
80
96
95
97
96
96
96
95
95
98
>99.5
97
98
96
96
97
H
H
H
H
H
H
H
H
H
H
H
2-Cl-Ph
3-Cl-Ph
4-Cl-Ph
3-F-Ph
2-Me-Ph
4-Me-Ph
3-MeO-Ph
3-CF3-Ph
4-CF3-Ph
Ph
9
10
11
12
13
14
15
C4H9
3-CF3-Ph
Ph
Ph
C2H5 C2H5
H
H
tBu
Ph(CH2)3 cyclohexyl
a Isolated yield. b Determined by chiral HPLC; see Supporting
Information.
To further study the scope of the reaction, we investigated
addition of bulky substituted and disubstituted alkenylzincs to
aromatic and R-branched aliphatic aldehydes. Excellent enan-
tioselectivities and chemical yields were also observed in the
cases of addition of benzaldehyde with alkenylzincs that were
prepared from tert-butylethyne, a bulky alkyne, or 3-hexyne,
an internal alkyne (entries 13 and 14). Catalytic asymmetric
alkenylation of cyclohexane carboxaldehyde yielded 2o with
97% ee18 (entry 15). To the best of our knowledge, 1 is one of
the effective and efficient ligands to achieve enantioselective
alkenylation of both bulky and internal alkenylzincs with
benzaldehyde.6e,10b,11b,12,14b,c
Additionally, ent-1 was easily prepared from (1R)-(-)-10-
camphorsulfonic acid17 and that provides access to both (R) and
(S)-chiral allylic alcohol.
(16) (a) Hwang, C.-D.; Uang, B.-J. Tetrahedron: Asymmetry 1998, 9,
3979. (b) Hwang, C.-D.; Hwang, D.-R.; Uang, B.-J. J. Org. Chem. 1998,
63, 6762. (c) Chang, C.-W.; Yang, C.-T.; Hwang, C.-D.; Uang, B.-J. Chem.
Commun. 2002, 54. (d) Wu, H.-L.; Uang, B.-J. Tetrahedron: Asymmetry
2002, 13, 2625. (e) Uang, B.-J.; Fu, I.-P.; Hwang, C.-D.; Chang, C.-W.;
Yang, C.-T.; Hwang, D.-R. Tetrahedron 2004, 60, 10479.
In conclusion, we have achieved a highly enantioselective
alkenylation of aromatic and R-branched aliphatic aldehydes
(18) All chiral allylic alcohols show the same configuration. In the cases
of 2a-2n, they were designated as (R)-alcohol, whereas 2o was assigned
as (S)-alcohol due to the change in priorities.
(17) Wu, P.-Y.; Wu, H.-L.; Uang, B.-J. J. Org. Chem. 2006, 71, 833.
5936 J. Org. Chem., Vol. 72, No. 15, 2007

to the reaction mixture for 1 h using a syringe pump. After being
stirred at -30 °C for 20 h, the reaction was quenched by adding
saturated ammonium chloride (5 mL). The aqueous solution was
extracted with ether (3 × 10 mL). The combined ether extracts
were dried and concentrated in vacuo. The crude product was
purified by column chromatography (EtOAc/hexanes ) 1:8) to yield
(R,E)-1-phenylnon-2-en-1-ol 2a (182 mg, 85%) as a colorless oil.
The enantioselectivity was measured by HPLC (Chiralcel OB,
catalyzed by 1 with alkenylzincs that were prepared either from
internal or terminal alkynes. Our method produced chiral allylic
alcohols, bearing R-configuration,18 in 95 to >99.5% ee19 and
80-92% yield. This finding offers a useful synthetic route to
highly functionalized (E)-chiral allylic alcohols.
Experimental Section
24
2-propanol/hexanes ) 1:99, 1.0 mL/min) to be 96% ee: [R]D
A representative example for the alkenylation of aldehydes was
conducted as follows: cyclohexene (300 µL, 3.0 mmol) was slowly
added to a flask that contained hexanes (1.0 mL) and BH3‚DMS
(1.5 mmol) at 0 °C. After being stirred at 0 °C for 3 h, 1-octyne
(220 µL, 1.5 mmol) was added to the flask, and the mixture was
slowly warmed to room temperature. The mixture was stirred at
room temperature for 1 h, and the volatile was evaporated in vacuo.
Toluene (1.0 mL) was added to the residue, and the resulting
mixture was cooled to -78 °C. Dimethylzinc solution (1.5 mmol,
2.0 M solution in toluene) was added to the above mixture followed
by a solution of 1 (25 mg, 0.098 mmol in 0.5 mL of toluene). The
mixture was warmed to -30 °C over a period of 1 h, and
benzaldehyde (100 µL, 0.98 mmol) in toluene (4.0 mL) was added
1
-32.8 (c 1.9, CHCl3); H NMR (500 MHz, CDCl3) δ ) 7.48-
7.14 (m, 5H), 5.75 (dt, J ) 14.7, 6.5 Hz, 1H), 5.65 (ddd, J ) 14.7,
6.5, 1.5 Hz, 1H), 5.14 (d, J ) 6.5 Hz, 1H), 2.04 (dt, J ) 6.5, 6.5
Hz, 2H), 1.46-1.14 (m, 9H), 0.87 (t, J ) 6.0 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ ) 143.4 (C), 132.8 (CH), 132.2 (CH), 128.5
(CH), 127.4 (CH), 126.1 (CH), 75.2 (CH), 32.2 (CH2), 31.6 (CH2),
28.9 (CH2), 28.8 (CH2), 22.6 (CH2), 14.0 (CH3); IR (neat) 3362,
3085, 3062, 3029, 2956, 2926, 1668, 1492 cm-1; HRMS calcd for
C15H22O 218.1671, found 218.1665.
Acknowledgment. The authors would like to thank the
National Science Council of the Republic of China, Taiwan,
for financial support of this research.
Supporting Information Available: Experimental details and
full characterizations of new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(19) For the proposed mechanism regarding highly enantioselective
addition of Et2Zn to aldehydes, see: (a) Kitamura, M.; Okada, S.; Suga,
S.; Noyori, R. J. Am. Chem. Soc. 1989, 111, 4028. (b) Kitamura, M.; Suga,
S.; Niwa, M.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 4832. (c) Kitamura,
M.; Suga, S.; Oka, H.; Noyori, R. J. Am. Chem. Soc. 1998, 120, 9800.
JO0709403
J. Org. Chem, Vol. 72, No. 15, 2007 5937