Asymmetric reductive coupling of dienes and aldehydes catalyzed by nickel complexes of spiro phosphoramidites: Highly enantioselective synthesis of chiral bishomoallylic alcohols

Article abstract of DOI:10.1021/ja0693183

A highly efficient nickel-catalyzed asymmetric reductive coupling of dienes and aldehydes has been realized by using bulky spirobiindane phosphoramidite ligands, affording bishomoallylic alcohols in high yields with excellent diastereoselectivities and en

Full text of DOI:10.1021/ja0693183

Published on Web 02/02/2007
Asymmetric Reductive Coupling of Dienes and Aldehydes Catalyzed by
Nickel Complexes of Spiro Phosphoramidites: Highly Enantioselective
Synthesis of Chiral Bishomoallylic Alcohols
Yun Yang, Shou-Fei Zhu, Hai-Feng Duan, Chang-Yue Zhou, Li-Xin Wang, and Qi-Lin Zhou*
State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai UniVersity, Tianjin 300071, China
Received December 27, 2006; E-mail: qlzhou@nankai.edu.cn
Scheme 1
Alkenylation and allylation of aldehydes for preparing allylic
and homoallylic alcohols are fundamental processes in organic
synthesis, and many efficient methods, including asymmetric
versions, have been well developed.1 However, homoallylation of
aldehydes in the preparation of bishomoallylic alcohols, which are
important intermediates for preparing heterocyclic compounds and
various 1,4- or 1,5-difunctional molecules, has hitherto achieved
less progress. In fact, the available methods for the synthesis of
bishomoallylic alcohols are very limited. Homoallylation of car-
bonyl groups with homoallylic metal reagents is one of the few
reliable strategies for preparing bishomoallylic alcohols, but the
homoallylating reagents are restricted to highly electropositive
metals such as Mg and Ti, which are sensitive to atmospheric
conditions and moisture.2 To avoid using homoallylic metal
reagents, a nickel-catalyzed reductive coupling reaction of 1,3-
dienes and carbonyl groups employing commercially available
organometallic compounds or silanes as reducing reagents has been
developed for the preparation of bishomoallylic alcohols.3 In 1994,
being the most enantioselective ligand (45% ee) (Table 1).
Mori et al.4 disclosed that the nickel-catalyzed cyclization of 1,3-
Optimizing the reaction conditions such as solvents, reducing
dienes with tethered carbonyl groups in the presence of Bui2Al-
reagents, Ni precursors, and reaction temperatures made no
(acac) or silanes afforded a mixture of bishomoallylic alcohols and
homoallylic alcohols. Soon after that Tamaru et al.5 realized both
intermolecular and intramolecular reductive coupling reactions of
1,3-dienes and carbonyl compounds by using ZnEt2 or BEt3 as
reducing reagents to produce bishomoallylic alcohols with high
regio- and stereoselectivities. Although the nickel-catalyzed reduc-
tive coupling of 1,3-dienes and carbonyl compounds has attracted
much attention, the asymmetric version of this reaction is limited.
Recently, the Mori group6 reported an intramolecular nickel-
catalyzed asymmetric reductive coupling (cyclization) of 1,3-dienes
with aldehydes in the presence of silanes employing a 2,5-dimethyl-
1-phenylphospholane ligand, giving a mixture of bishomoallylic
and homoallylic cyclic alcohols with good enantioselectivities (up
to 86% ee). However, an example of intermolecular catalytic
asymmetric reductive coupling of 1,3-dienes and carbonyl groups,
to the best of our knowledge, has not been documented.7 Here we
report a nickel-catalyzed asymmetric reductive coupling of 1,3-
dienes and aldehydes, providing a useful method for preparing chiral
bishomoallylic alcohols in excellent diastereoselectivity (anti/syn:
>99/1) and enantioselectivity (up to 96% ee).
We recently developed various monophosphorus ligands based
on the chiral spirobiindane scaffold (Scheme 1). These ligands have
been demonstrated to be highly efficient for asymmetric hydrogena-
tion8 and other asymmetric catalysis.9 When these chiral spiro
monophosphorus ligands were tested in the nickel-catalyzed asym-
metric reductive coupling reaction of 1,4-diphenylbuta-1,3-diene
(1) and benzaldehyde in the presence of Et2Zn, the chiral bisho-
moallylic alcohol 3a was produced in high yields (92-99%) and
excellent diastereoselectivities (anti/syn: >99/1). However, the
enantioselectivities were low, with spiro phosphoramidite SIPHOS
improvement on the enantioselectivity of the reaction. By com-
parison, the chiral MonoPhos ligand bearing a binaphthyl scaffold
was also tested under identical reaction conditions, and its enan-
tioselectivity (38% ee) was found to be not as good as that of its
spiro counterpart SIPHOS.
It has been proven that only one ligand coordinates with the
central nickel during the catalytic cycle in the reductive coupling
of 1,3-dienes with aldehydes, and a bulky phosphine ligand was
facilitated to stabilize the active catalyst in the reaction.10 We
therefore envisaged that increasing the bulkiness of the chiral
phosphorus ligand might also enhance its enantioselectivity in the
asymmetric reductive coupling of 1,3-dienes with aldehydes by
restricting the rotation of the P-Ni bond of the catalyst. The ligands
were improved by introducing substituents onto 6,6′-positions of
the spirobiindane backbone and by changing alkyl groups on the
nitrogen atom of the phosphoramidite ligand.11
As expected, the 6,6′-disubstituted spirobiindane phosphoramidite
ligands displayed higher enantioselectivities in the nickel-catalyzed
reductive coupling of a 1,3-diene with aldehydes. For example, the
SIPHOS ligand afforded the bishomoallylic alcohol 3a in 45% ee,
but by contrast, ligand 4b bearing two 6,6′-dimethyl groups on the
spirobiindane backbone showed 72% ee in the same reaction. An
even higher enantioselectivity (82% ee) was obtained by using
ligand 4c, which has 6,6′-phenyl groups. However, further increas-
ing the steric hindrance of groups at the 6,6′-position of the
spirobiindane ring from phenyl to 3,5-dimethylphenyl did not help
the enantioselectivity of the reaction. The second stage of ligand
improvement was carried out by modifying the amine moiety of
the phosphoramidite ligand based on the 6,6′-diphenyl spirobiindane
structure. When ethyl groups were substituted for the methyl groups
9
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J. AM. CHEM. SOC. 2007, 129, 2248-2249
10.1021/ja0693183 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Ni-Catalyzed Asymmetric Reductive Coupling of
1,4-Diphenylbuta-1,3-diene (1) with Benzaldehydea
Scheme 2
entry
ligand
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
10
11d
12e
13f
(R)-SIPHOS
(R)-ShiP
(R)-FuP
(R)-SITCP
(S)-MonoPhos
(R)-4b
(R)-4c
(R)-4d
(R)-4e
(R)-4f
99
95
92
93
95
99
99
96
96
99
95
99
89
45
5
37
40
38
72
82
76
78
96
88
92
90
enantioselective in this reductive coupling reaction. To extend the
scope of the reaction, ethyl 5-phenylpenta-2,4-dienoate was inves-
tigated. By coupling with benzaldehyde, the corresponding coupling
product was obtained in high yield, excellent anti selectivity, albeit
with moderate enantiomeric excess (Scheme 2).12
(R)-4f
(R)-4f
(R)-4f
In conclusion, we have disclosed the first catalytic asymmetric
intermolecular reductive coupling of 1,3-dienes and aldehydes. By
using nickel complexes with bulky spirobiindane phosphoramidite
ligands as catalysts and Et2Zn as a reducing reagent, chiral
bishomoallylic alcohols were produced in high yields with excellent
diastereoselectivities and enantioselectivities.
a Reaction conditions: Ni(acac)2/ligand/1/2a/Et2Zn ) 0.006/0.0072/ 0.12/
0.24/0.28 (mmol) in toluene (1.2 mL), 25 °C, under argon, 1.0 h. b Isolated
yield. The anti/syn ratio was >99/1 in all cases. c Enantioselectivity of the
anti-isomer was determined on HPLC using a Chiralpak AD-H column.d 1
mol % of catalyst was used, 8 h. e Ni(COD)2 was used. f NiBr2 was used.
Acknowledgment. We thank the National Natural Science
Foundation of China for financial support.
Table 2. Ni-Catalyzed Asymmetric Reductive Coupling of
1,4-Diphenylbuta-1,3-diene (1) with Different Aldehydes 2a
Supporting Information Available: Experimental procedures, the
characterizations of ligands and products, and the analysis of ee values
of products (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
entry
Ar
product
yield (%)
anti/syn
ee (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
99
95
98
94
99
95
94
85
92
98
94
96
96
98
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
99:1
>99:1
>99:1
98:2
>99:1
>99:1
>99:1
96
93
91
94
92
95
96
96
90
85
93
86
92
91
o-MeC6H4
o-MeOC6H4
m-MeC6H4
m-MeOC6H4
p-MeC6H4
p-MeOC6H4
p-Me2NC6H4
p-ClC6H4
p-CF3C6H4
1-naphthyl
2-naphthyl
2-furyl
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