Enantioselective synthesis of siloxyallenes from alkynoylsilanes by reduction and a brook rearrangement and their subsequent trapping in a [4+2] cycloaddition

Article abstract of DOI:10.1002/anie.201102430

Two flavors of selectivity: An enantioselective Meerwein-Ponndorf-Verley- type reduction of alkynoylsilanes by a chiral lithium amide followed by a Brook rearrangement and S_E2′ electrophilic substitution provides the title compounds in a one-po

Full text of DOI:10.1002/anie.201102430

DOI: 10.1002/anie.201102430
Siloxyallenes
Enantioselective Synthesis of Siloxyallenes from Alkynoylsilanes by
Reduction and a Brook Rearrangement and Their Subsequent
Trapping in a [4+2] Cycloaddition**
Michiko Sasaki, Yasuhiro Kondo, Masatoshi Kawahata, Kentaro Yamaguchi, and Kei Takeda*
Enantioselective synthesis through the use of chiral allenes
has attracted much attention because of their capability to
transfer their axial chirality to one or more new stereogenic
centers.[1] A well-established approach to enantiomerically
enriched allenes relies on the SN2’ substitution of homochiral
propargylic derivatives with organocuprates.[2]
We became interested in developing new methodologies
for the synthesis of chiral, nonracemic allenes based on the
enantioselective Meerwein–Ponndorf–Verley-type reduction
of acylsilanes by chiral lithium amide that was developed by
us.[3] We envisaged that if alkynoylsilane 1 could be enantio-
selectively reduced by 2,[4] the resulting a-silyl alkoxide 3
would provide optically active siloxyallene derivatives
Scheme 1. Tandem process for the enantioselective formation of
siloxyallenes. El=electrophile.
through a Brook rearrangement;[5] subsequent SE2’ electro-
philic substitutions[6] of the silicate intermediate 4, would
result in the enantioselective preparation of 1-unsubstituted
siloxyallenes 5 or ent-5 depending on the mode of the SE2ꢀ
process (Scheme 1). We previously reported that the Brook
rearrangement mediated SE2ꢀ protonation of allylsilanes
having an oxygen substituent on the stereogenic center
proceeds in an anti fashion.[7]
We report here some preliminary results for the enantiose-
lective synthesis of 1-unsubstituted 1-siloxyallenes and their
trapping by [4+2] cycloaddition.
When 1a was treated with 2 at ꢀ808C in toluene for
30 min followed by addition of tBuOH (1.2 equiv) in THFand
then warming to ꢀ208C, siloxyallene (+)-6a[11] was obtained
in 52% yield and with e.r. 95:5 together with 7a (32%;
Table 1, entry 1).[12,13] The selectivity was markedly improved
by a change in the substituent X to a 3-phenylpropyl group
and the allene derivative (+)-6b was obtained in 86% yield
(Table 1, entry 2). Our initial choice of 1a as a substrate was
based on the assumed stabilization of the allene structure
owing to the a-anion-stabilizing nature of the silyl group. The
results showing that the less bulky alkyl derivative 1b
The synthesis of racemic siloxyallenes by a Brook
rearrangement was originally reported independently by the
Kuwajima[8] and Reich[9] groups. They generated a-hy-
droxypropargylsilane, a precursor for the Brook rearrange-
ment, by reactions of acylsilanes with lithium acetylides.
Scheidt et al. recently reported the synthesis of enantiomer-
ically enriched siloxyallenes by the treatment of a-hydrox-
ypropargylsilane, which was obtained by a catalytic asym-
metric addition of acetylide to acylsilane, with a catalytic
amount of nBuLi.[10] Consequently, their methods are limited
to the synthesis of 1-alkyl-substituted siloxyallene derivatives.
Table 1: Enantioselective formation of siloxyallenes (+)-6a–c from
alkynoylsilanes 1a–c by tandem reduction/Brook rearrangement/proto-
nation.
[*] Dr. M. Sasaki, Y. Kondo, Prof. Dr. K. Takeda
Graduate School of Medical Sciences, Hiroshima University
1-2-3 Kasumi, Minami-Ku, Hiroshima 734-8553 (Japan)
Fax: (+81)82-257-5184
E-mail: takedak@hiroshima-u.ac.jp
Homepage: http://home.hiroshima-u.ac.jp/takedake/index-e.html
Dr. M. Kawahata, Prof. Dr. K. Yamaguchi
Tokushima Bunri University, Sanuki (Japan)
[**] This research was partially supported by a Grant-in-Aid for Scientific
Research (B) 22390001 (K.T.) and a Grant-in-Aid for Young
Scientists (B) 22790011 (M.S.) from the Ministry of Education,
Culture, Sports, Science and Technology (MEXT). We thank the
Natural Science Center for Basic Research and Development (N-
BARD), Hiroshima University for the use of their facilities.
Starting
material, X
(+)-6
Yield [%]
7
Entry
e.r.
Yield [%]
1
2
3
1a, PhMe2Si
1b, PhCH2CH2CH2
1c, tBuPh2Si
52
86
37
95:5
98:2
92:8
32
3
54
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201102430.
Angew. Chem. Int. Ed. 2011, 50, 6375 –6378
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6375

Communications
provided better allene selectivity, however, led us to consider
the contribution of a steric factor to the selectivity. This was
supported by the reaction using 1c, bearing a bulkier tert-
butyldiphenylsilyl (TBDPS) group, which afforded (+)-6c
and 7c in a 37:54 ratio (Table 1, entry 3).
To demonstrate the synthetic utility of the method, we
examined the possibility of a tandem process using enynylsi-
lanes that would involve trapping of the generated homo-
chiral siloxyallene by a [4+2]-type cycloaddition (10 + 11!
12). The high reactivity and facial selectivity of the vinylallene
system in cycloadditions has been well documented.[14,9b]
Alkynoylsilane 8a was treated with 2 in toluene at ꢀ808C
for 30 min followed by addition of tBuOH (1.2 equiv) in THF
as an electrophile; subsequent reaction with maleic anhydride
in the presence of CF3COOH (3.6 equiv) at room temper-
ature provided the tandem reaction product 13a in 66% yield
and with e.r. 97:3 as a single isomer (Table 2, entry 1).[15] The
Figure 1. ORTEP drawing of 14a; ellipsoids are drawn at the 50%
probability.
Table 2: [4+2] Cycloaddition of vinylallenes generated from the tandem
sequence.
Scheme 2. Trapping of vinylallenes by [4+2] cycloaddition.
Entry
8
Dienophile[a]
t [h]
Product
Yield [%]
e.r.
1
2
3
4
5
6
7
8
9
8a
8a
8a
8b
8b
8b
8c
8c
8c
MA
NMM
NQ
MA
NMM
NQ
MA
NMM
NQ
5
3
13a
14a
15a
13b
14b
15b
13c
14c
15c
66
97:3
98:2
95:5
99:1
98:2
98:2
97:3
95:5
88:12
73
NMM or between 14a and maleic anhydride. To gain further
insight into the unusual facial selectivity, we decided to
conduct a [4+2] cycloaddition with NMM using siloxy,
methoxy, and alkyl derivatives 16a–c (Table 3). While the
reaction of 16a gave only the Z derivative 14a, reaction of the
methoxy derivative 16b[16] afforded both (Z)- and (E)-17 in
31% and 41% yield, respectively. In contrast, the reaction of
alkyl derivative 16c gave (E)-18 exclusively. The unexpected
facial selectivity[14f] depending on the substituents at the
terminal position of the vinylallenes seems to be consistent as
a whole with the trend in the energies of the transition states
leading to the model systems 19a–c and 20a–c, calculated at
5.5
5
3.5
4.5
5
51[b]
54
60
54[c]
56
5
7.5
62[d]
57
[a] MA=maleic anhydride, NMM=N-methylmaleimide, NQ=naph-
thoquinone. [b] E/Z mixture (1:3.7); both 95:5 e.r. [c] E/Z mixture
(1:4.4); (E)-15b 99:1 e.r. and (Z)-15b 98:2 e.r. [d] Since hydrolysis of
the enol silyl ether occurred during purification on silica gel, 14c was
isolated as a mixture with the corresponding aldehyde (20%).
same tandem reaction was also achieved with N-methyl-
maleimide and naphthoquinone, affording 14a and 15a,
respectively. Their relative and absolute configurations were
determined on the basis of single-crystal X-ray analysis of 14a
(Figure 1). It is formed by an endo addition and an attack
from the more hindered face of the vinylallenes, the same face
as the siloxy group (Scheme 2). The unprecedented facial
selectivity and endo selectivity were also observed in reac-
tions of 8b and 8c, which afforded 13b–15b and 13c–15c
respectively.
Table 3: [4+2] Cycloaddition of 16a–c with NMM.
T [8C]
t [h]
Product
Z [%]
E [%]
When (E)-15a (Table 2, entry 3), a minor product in the
reaction, was exposed to conditions similar to those employed
in the reaction of 8a, an E-to-Z isomerization was not
detected. Also, there was no crossover between 13a and
16a
16b
16c
0
5
20
14
48
23
14a
17
18
42
31
–
–
41
30
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Angew. Chem. Int. Ed. 2011, 50, 6375 –6378

B3LYP/6-311 + G** using SPARTAN 08[17] (Table 4).[18] Thus,
energies of the transition states for the siloxy and methoxy
derivatives 19a’ and 19b’ leading to (Z)-19a and (Z)-19b are
approximately 2,23 and 1.47 kcalmolꢀ1 lower than the corre-
sponding energies for the transition states leading to (E)-20a’
10 mL) and extracted with Et2O (10 mL ꢁ 3). The combined organic
phases were successively washed with saturated aqueous NaHCO3
solution (5 mL) and saturated brine (5 mL), dried, and concentrated.
The residual oil was subjected to column chromatography (silica gel,
5 g, elution with hexane/CH2Cl2/Et2O = 15:10:1) to give 14a (49.6 mg,
76%).
Received: April 8, 2011
Published online: May 31, 2011
Table 4: B3LYP/6-311+G** Optimized geometries of transition-state
structures 19a’ and 20a’ and relative energies of 19a–c’ and 20a–c’.
Keywords: cumulenes · cycloadditions · synthetic methods
.
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[a]
Entry
19’
G298
20’
G298
DG298
[a]
[a]
1
2
3
a
b
c
ꢀ688137.15
ꢀ456334.41
ꢀ409128.42
ꢀ688133.92
ꢀ456332.94
ꢀ409130.53
3.23
1.47
ꢀ2.11
[a] Zero point energy corrected free energies are given in kcalmolꢀ1
.
and (E)-20b’. This is in sharp contrast to the results with the
methyl derivatives 19c’ and 20c’, in which the latter transition
state leading to the E product is more stable.
In conclusion, we have developed a consecutive process
for the enantioselective formation of siloxyallenes from
alkynoylsilanes, taking advantage of reduction by a chiral
lithium amide followed by stereoselective SE’-type process
through a Brook rearrangement of an alkynyl silicate
intermediate. In the case of enynoylsilanes, the resulting
vinylallenes undergo in situ [4+2] cycloaddition to afford
highly functionalized polycyclic compounds with excellent
enantiomeric ratios. We are continuing to explore the scope,
limitations, generality, and synthetic applications of these
transformations.
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2009, 1749 – 1756.
Experimental Section
[11] For the determination of the absolute configuration of (+)-6a
and the stereochemical pathway of the process, see the
Supporting Information.
[12] For regioselectivity in an allenyllithium reagent, see: a) H. J.
Reich, J. E. Holladay, J. D. Mason, W. H. Sikorski, J. Am. Chem.
Soc. 1995, 117, 12137 – 12150; also, see: b) H. J. Reich, J. E.
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121, 9769 – 9779.
[13] When 1a was treated with 2 in THF, which is our original
protocol, a complex mixture was obtained. However, the
reduction proceeds in toluene at ꢀ808C to give the correspond-
ing alcohol in 79% yield and with e.r. 99:1. Addition of THF was
essential to effect the Brook rearrangement.
Synthesis of 14a: To a cooled (ꢀ808C) solution of 2, generated from
(S)-2,2-dimethyl-N-(2-(4-methylpiperazin-1-yl)-1-phenylethyl)pro-
pan-1-amine (76.1 mg, 0.263 mmol) and nBuLi (1.67m in n-hexane,
157 mL, 0.263 mmol) in toluene (1.0 mL) at 08C, was added dropwise
a solution of 8a (51.3 mg, 0.219 mmol) in toluene (0.8 mL). The
reaction mixture was stirred at the same temperature for 30 min
before a solution of tBuOH (25 mL, 0.263 mmol) in THF (5.5 mL) was
added. The reaction mixture was allowed to warm to ꢀ208C over
10 min, and then trifluoroacetic acid (0.5m in THF, 1.58 mL,
0.788 mmol) and N-methylmaleimide (29.2 mg, 0.263 mmol) were
added to the solution. The reaction mixture was stirred at room
temperature for 3 h, and then diluted with hydrochloric acid (1%,
Angew. Chem. Int. Ed. 2011, 50, 6375 –6378
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6377

Communications
[14] a) M. Murakami, T. Matsuda in Modern Allene Chemistry, Vol. 2
[15] The reaction without the addition of CF3COOH proceeded well
but required the use of an excess of the dienophile, presumably
owing to the presence of nitrogen nucleophiles originating from
2.
[16] Allene 16b was prepared by base-catalyzed isomerization of 1-
(3-methoxyprop-1-yn-1-yl)cyclopent-1-ene, which was obtained
from the Sonogashira coupling of iodocyclopentene and prop-
argyl alcohol.
(Eds.: N. Krause, A. S. K. Hashmi), Wiley-VCH, Weinheim,
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[17] SPARTAN 08; Wave function Inc.: Irvine, CA, www. wave-
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[18] For theoretical studies of the [4+2] cycloaddition of vinylallenes,
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