Conjugate reduction-initiated tandem cyclization of a chiral α,β,χ,ψ-unsaturated bisphosphine oxide

Article abstract of DOI:10.1016/S0040-4039(02)00787-6

Conjugate reduction-initiated cyclization of a chiral α,β,χ,ψ-unsaturated bisphosphine oxide was developed by treating with lithium tri-siamylborohydride (LS-selectride) as a reducing agent to afford efficiently and selectively a carbocycle bearing bispho

Full text of DOI:10.1016/S0040-4039(02)00787-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4355–4359
Conjugate reduction-initiated tandem cyclization of a chiral
a,b,x,c–unsaturated bisphosphine oxide
Yasuo Nagaoka,b Nawal El-Koussi,a Shinichi Uesatob and Kiyoshi Tomiokaa,*
aGraduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
bDepartment of Biotechnology, Faculty of Engineering, Kansai University, Suita, Osaka 564-8680, Japan
Received 3 April 2002; revised 15 April 2002; accepted 19 April 2002
Abstract—Conjugate reduction-initiated cyclization of a chiral a,b,x,c-unsaturated bisphosphine oxide was developed by treating
with lithium tri-siamylborohydride (LS-selectride®) as a reducing agent to afford efficiently and selectively a carbocycle bearing
bisphosphine appendage. © 2002 Elsevier Science Ltd. All rights reserved.
Construction methodology of a functionalized carbocy-
cle has been a topic of recent synthetic organic chem-
istry.1 We have been engaged in this field for a number
of years and succeeded in Michael–Aldol tandem
cyclization of a c-oxoenoate2,3 and Michael–Michael
tandem cyclization of a a,b,x,c-unsaturated bisphos-
phonate.4,5 A recent report from this laboratory proved
the versatile utility of the process in providing an
efficient methodology for synthesis of a chiral carbocy-
cle bearing bisphosphine appendages.6 Upon treatment
with LDA a chiral bisphosphine oxide 1a (R=Me)
underwent lithiation to 2 and subsequent Michael
cyclization through 3 to give 4 as a major product in
60% yield (Scheme 1). Reduction of an olefin moiety of
4 with lithium aluminium hydride or diimide gave
stereoselectively trans- and cis-5a, respectively. Subse-
quent deoxygenation of 5a afforded the chiral bisphos-
phine 5b applicable as a chiral ligand in an efficient
catalytic asymmetric hydrogenation. However, concep-
tual drawback of the carbocycle synthesis lies on a
stepwise formation of 5a. Simultaneous reduction of 1
and generation of a-anion 7 provide a more efficient
way than the separate stepwise procedure starting from
1 to 4 via 2. We describe herein that the reaction of
1b (R=Bn) with lithium tri-siamylborohydride (LS-
selectride®) directly and stereoselectively afforded the
corresponding reduction-Michael tandem cyclization
products 8.7
We chose a benzyl ether 1b (R=Bn) as a starting
bisphosphine oxide because a benzyl protecting group
is easily removal and hence convertible to another
group. The chiral 1b was conveniently prepared in 48%
yield through partial reduction of a dibenzyl ether of
ethyl
-tartrate 6b8 with DBALH to a dialdehyde and
L
subsequent Horner–Wadsworth–Emmons olefination.6
We began our study with evaluation of a variety of
hydride reagents as a reduction and carbanion-forming
agent. Treatment of 1b with a molar equivalent of
LiAlH4 in THF at 0°C for 5 min afforded, after
aqueous workup and purification by silica gel column
chromatography, all of possible four 5-membered car-
bocycles 8a–d in 53% combined yield. Over reduction
product and reduced-but-not-cyclized product were not
isolated in this reaction. The ratio of these carbocycles
8a–d was determined by isolation and 31P NMR analy-
sis of the crude product to be 58:23:16:3 (Table 1, entry
1). The relative stereochemistry of 8a–d was assigned
based on the NOESY analysis.6
Other aluminium hydride, Red-Al (Na(O(CH2)2OMe)2-
AlH2), was not reactive enough to afford 8 in 26% yield
(entry 2). Although DIBAL-H gave a relatively good
60% combined yield of 8, the selectivity was not high,
giving all four isomers in nearly equal amounts (entry
3). Fortunately, borane-based hydrides behaved satis-
factorily affording stereoselectively 8. Thus, super-
hydride® (LiEt3BH) reduced 1b in THF to give 8a and
8b as major two diastereomers in good yield (entry 4).
* Corresponding author. Tel.: +81-75-753-4553; fax: +81-75-753-4604;
e-mail: tomioka@pharm.kyoto-u.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00787-6

4356
Y. Nagaoka et al. / Tetrahedron Letters 43 (2002) 4355–4359
O
RO
MeO
MeO H
H
PPh2
OMe
CO2Et
RO
Li
MeO
R
Me
CO2Et
Li
Ph2P
6a
6b
PPh2
O
2
H
PPh2
O
Bn
3
O
i. DIBAH
LDA
ii.
POPh2
THF
–78 °C
Li
O
PO(OEt)2
MeO
MeO
MeO
O
PPh2
XPh2
H-
RO
PPh2
MeO
RO
PPh2
X
P=O
P
XPh2
5a
5b
PPh2
4
O
O
R
Me
Bn
O
1a
1b
O
BnO
BnO
PPh2
PPh2
H-
BnO
BnO
O
PPh2
PPh2
BnO
BnO
PPh2
8a
BnO
8c
BnO
O
O
O
O
PPh2
PPh2
PPh2
H
BnO
BnO
7
O
PPh2
PPh2
O
O
8b
8d
Scheme 1. Hydride and LDA-mediated cyclization of 1.
Table 1. Reduction-Michael cyclization of 1b in THF
Entry
Reagents
Temp. (°C)
Time (min)
Yield (%)f
Ratio of 8g a:b:c:d
1
2
3
4
5
6
7
8
LiAlH4
0
0
0
0
5
5
5
53
26
60
70
83
80
75
53
30
88
64
58:23:16:3
54:13:33:0
42:14:23:21
61:37:2:0
58:41:1:0
56:43:1:0
66:34:0:0
67:17:16:0
54:9:37:0
68:32:0:0
36:34:17:13
a
Na(O(CH2)2OMe)2AlH2
i-Bu2AlHb
LiEt3BHc
10
30
10
60
60
60
60
540
LiEt3BHc
−40
LiEt3BHc,d
0
0
0
60
0
Li(sec-Bu)3BHc
Na(sec-Bu)3BHc
K(sec-Bu)3BHc
Li(siamyl)3BHc
9
10
11
e
Zn(BH4)2
Reflux
a A 65% toluene solution.
b A 1 M hexane solution.
c A 1 M THF solution.
d Toluene was used as a solvent
e A 0.15 M THF solution prepared from NaBH4 and ZnCl2.
f Combined yield of the mixture.
g Determined by 31P NMR (202 MHz, CDCl3) analysis l: 8a (30.2 and 34.5), 8b (30.8 and 31.2), 8c (31.4 and 37.4), 8d (29.9 and 32.2).
Lower temperature (−40°C) and toluene solvent did not
affect greatly the yield and selectivity (entries 5 and 6).
Bulkier lithium trialkylborohydride, L-selectride®
(Li(sec-Bu)3BH) improved the selectivity to afford a
66:34 mixture of 8a,b in 75% yield (entry 7). Sodium and
potassium versions, N-Selectride® and K-Selectride®,
however, decreased the selectivity giving a mixture of
three diastereomers 8a,b,c in a decreased yield (entries 8
and 9). Although a non-alkaline metal hydride, zinc
borohydride,9 gave 8 under reflux for 9 h, the selectivity
was almost negligible giving possible all carbocycles
(entry 11). Finally we found that LS-selectride®
(Li(siamyl)3BH) behaved best to give a 68:32 mixture of
8a,b in 88% yield without formation of 8c,d (entry 10).

Y. Nagaoka et al. / Tetrahedron Letters 43 (2002) 4355–4359
4357
Although borane and aluminium-based hydride
reagents were applicable in a conjugate reduction-ini-
tiated tandem cyclization, the selectivity was depen-
dent on the type of a metal cation. Especially, a
lithium cation is superior to sodium, potassium, and
zinc, as shown in Table 1.
the other hand, D, D%, and D%% are the most sterically
demanding structures and predict the least favorable
production of 8d, which is the most minor isomer
observed. The conformation presentations B and B%
suggest steric superiority to C, C%, and C%%. Other con-
trolling factors involve chelate formation of two
phosphine oxides with a metal cation, especially a
lithium cation. A chelate formation of two oxygen
atoms of bisphosphine oxide with lithium cation is
responsible for the high selectivity with use of lithium
reagents other than sodium, potassium, and zinc
hydride reagents.12 These analyses predict well and
explain the preferred formation of the isomer in the
order of 8a, 8b, 8c, and 8d by the reaction of 1b with
lithium trialkylborohydride.
The initial step of the tandem cyclization involves a
conjugate reduction of 1b to a carbanion 7 (Scheme
1). The regio- and stereochemical courses of this first
step were examined by reducing 1b with LiAlD4
under the conditions of entry 1, giving 8a,b,c-D in 34,
1
17, and 9% isolated yields. H NMR analysis of these
deuterated 8D clearly indicated stereoselective a-side
introduction of deuterium in the conjugate addition
manner as shown by the spectra of 8a and 8aD (Fig.
1),10 being the same stereochemical course with those
of lithium thiolate addition to a carboxylate ver-
sion.3a,11 A carbanion 7 is thus generated and under-
In summary, a conjugate reduction-initiated tandem
cyclization of a chiral a,b,x,c-unsaturated bisphos-
phine oxide afforded stereoselectively and in a single
step a five-membered carbocycle in 60% yield by
using lithium trialkylborohydride as a hydride source
as well as a carbanion forming agent. The methodol-
ogy is useful for the convenient synthesis of a chiral
bisphosphine ligand.
goes intramolecular Michael addition to
a
a,b-unsaturated phosphine oxide moiety.
Formation of diastereoisomers 8a,b,c-D bearing
stereospecifically substituted a-D suggests that
intramolecular Michael reaction of a carbanion is not
directly related to stereoselectivity of
reagent attack. Stereoselective formation of
a
hydride
is
4
Acknowledgements
ascribable to the sterically favorable conformation 3
(Scheme 1). Straightforward extension to the Newman
presentation A and A% predicts the preferred forma-
tion of 8a over other three isomers (Scheme 2). On
This research was supported by a Grant-in-Aid from
the Ministry of Education, Culture, Sports, Science
and Technology, Japan.
Figure 1. 1H NMR of 8a and deuterated 8aD in C6D6.

4358
Y. Nagaoka et al. / Tetrahedron Letters 43 (2002) 4355–4359
BnO
H
O
BnO H
BnO
H
BnO
BnO
OBn
PPh2
H
O
H
H
Ph2P
H
PPh2
PPh2
H
PPh2
O
O
PPh2
O
A
8a
A'
O
O
BnO
O
H
BnO
PPh2
OBn
BnO H
BnO
PPh2
O
BnO
PPh2
H
Ph2P
PPh2
O
H
H
PPh2
H
O
H
B
8b
B'
O
BnO
H
BnO
O
O
H
O
PPh2
BnO
PPh2
OBn
BnO H
PPh2
Ph2P
H
BnO
H
O
C'
BnO
PPh2
O
H
Ph2P
O
H
H
H
O
H
PPh2
C
8c
H
PPh2
H
BnO
O
C"
BnO
H
H
BnO
H
O
BnO H
BnO
H
Ph2P
D'
OBn
H
PPh2
O
BnO
PPh2
H
Ph2P
O
PPh2
O
BnO
H
H
PPh2
O
H
H
O
O
D
8d
H
PPh2
BnO
PPh2
D"
O
Scheme 2. The Newman presentation of 7 leading to 8.
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Ph). 8b (in CDCl3): 1.57 (1H, dd, J=13.5, 7.0 Hz, 5-Ha),
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