Enantioselective synthesis of allenylenol silyl ethers via chiral lithium amide mediated reduction of ynenoyl silanes and their Diels-Alder reactions

Article abstract of DOI:10.1021/acs.orglett.5b00261

An enantioselective Meerwein-Ponndorf-Verley-type reduction of ynenoylsilanes by a chiral lithium amide followed by a Brook rearrangement and anti-mode protonation across conjugated 1,3-enynes provides allene derivatives bearing a 2-siloxyvinyl moiety in high enantioselectivity. The E/Z geometry of enol silyl ethers is controlled by the geometry of the starting enyne moiety. Thus, (E)- and (Z)-enol silyl ethers are obtained from (Z)- and (E)-ynenoylsilans, respectively. The 2-siloxyvinylallene products can participate in Diels-Alder reactions with reactive dienophiles such as PTAD, which can be achieved in a one-pot operation from ynenoylsilanes.

Full text of DOI:10.1021/acs.orglett.5b00261

Letter
pubs.acs.org/OrgLett
Enantioselective Synthesis of Allenylenol Silyl Ethers via Chiral
Lithium Amide Mediated Reduction of Ynenoyl Silanes and Their
Diels−Alder Reactions
Michiko Sasaki,*,† Yasuhiro Kondo,† Ta-ichi Moto-ishi,† Masatoshi Kawahata,‡ Kentaro Yamaguchi,‡
and Kei Takeda†
†Department of Synthetic Organic Chemistry, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi,
Minami-Ku, Hiroshima 734-8553, Japan
‡Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, 1314-1 Shido, Sanuki, Kagawa 769-2193, Japan
S
* Supporting Information
ABSTRACT: An enantioselective Meerwein-Ponndorf-Ver-
ley-type reduction of ynenoylsilanes by a chiral lithium
amide followed by a Brook rearrangement and anti-mode
protonation across conjugated 1,3-enynes provides allene
derivatives bearing a 2-siloxyvinyl moiety in high enantiose-
lectivity. The E/Z geometry of enol silyl ethers is controlled by
the geometry of the starting enyne moiety. Thus, (E)- and (Z)-
enol silyl ethers are obtained from (Z)- and (E)-ynenoylsilans,
respectively. The 2-siloxyvinylallene products can participate in Diels−Alder reactions with reactive dienophiles such as PTAD,
which can be achieved in a one-pot operation from ynenoylsilanes.
Scheme 1. Tandem Processes for the Enantioselective
Formation of Allenes
e have recently reported the enantioselective formation of
1
Wsiloxyallenes 4 bearing a vinyl substituent via Meer-
wein−Ponndorf−Verley-type reduction2 of enynoylsilanes 1
using chiral lithium amide 2 (Scheme 1).3,4 The enantioselec-
tivity observed is explained by anti-mode SE2′-type protonation
via a Brook rearrangement5 in a silicate intermediate 3 or a
silicate transition state.6 Thus, C−Si bond cleavage and
protonation in 3 occurs in a concerted fashion and in an anti-
mode while keeping a parallel alignment between the C−Si bond
and the π orbital of the triple bond. We became interested in
examining whether the stereoelectronic and/or steric prefer-
ences could be extended to a vinylogous system 5, in which a
double bond is introduced between the acylsilane moiety and the
triple bond, and enol silyl ethers 7 substituted by axially chiral
allenes can be formed as products. Although there are some
reports on syn-type intramolecular 1,4-addition across 1,3-
enynes,7 the stereochemical course of an anionic rearrangement
across the 1,3-enyne system leading to a 1,3,4-triene system has
never been explored. From a synthetic point of view,8 7 can serve
as a versatile chiral building block in C−C bond formation
reactions such as Diels−Alder reactions and aldol reactions by
taking advantage of an axis of chirality of the allene moiety.
Synthesis of allenylenol silyl ethers, however, is quite limited, and
there are only a few reports in the literature even in their racemic
form.9,10 In this paper, we report an enantioselective synthesis of
allenylenol silyl ethers using a tandem process that involves
Meerwein−Ponndorf−Verley-type reduction of ynenoylsilanes
by a chiral lithium amide, a Brook rearrangement in the resulting
α-silyl alkoxide, and protonation of a lithioallenyl carbanion.
In the case using ynenoylsilanes 5 as substrates, in contrast to
the case of 1, the E/Z geometries in 5 potentially affect the E/Z
geometry in the enol silyl ether moiety in the products 7,11 and
we therefore decided to conduct the reaction on both (E)- and
(Z)-derivatives. While (E)-5 was successfully prepared by
Sonogashira cross-coupling12 of β-iodoacryloyl silanes 8 with
the corresponding alkynes, some modifications in the case of
(Z)-5 were needed; thus, the coupling of 3-iodo-1-silyl-2-
propen-1-ol followed by oxidation was carried out, as shown in
Scheme 2.
Received: January 27, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00261
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Letter
Scheme 2. Syntheses of Ynenoylsilanes
Table 2. Enantioselective Formation of Allenylenol Silyl
Ethers 7 from Ynenoylsilanes 5
entry
5
R
7
yield (%)
er
1
2
3
4
5
6
(E)-5a
(E)-5b
(E)-5c
(E)-5d
(Z)-5a
(Z)-5b
PhCH2CH2CH2
PhOCH2CH2
PhOCH2
(Z)-7a
(Z)-7b
(Z)-7c
(Z)-7d
(E)-7a
(E)-7b
71
78
79
81
64
59
93:7
99:1
90:10
94:6
MeOCH2
PhCH2CH2CH2
PhOCH2CH2
97:3
>99:1
Table 1. Reduction of Ynenoylsilanes 5 Using Chiral Lithium
Amide 2
Scheme 3. Determination of Absolute Configuration of (Z)-7
and (E)-7
entry
5
R
yield (%)
er
1
2
3
4
5
6
(E)-5a
(E)-5b
(E)-5c
(E)-5d
(Z)-5a
(Z)-5b
PhCH2CH2CH2
PhOCH2CH2
PhOCH2
85
88
87
92
79
81
>99:1
>99:1
>99:1
>99:1
99:1
MeOCH2
PhCH2CH2CH2
PhOCH2CH2
>99:1
Figure 2. Rotamers of α-silyl alkoxide leading to (E)- and (Z)-7.
protonation across the enyne moiety. When (E)-5a was treated
with 2 in toluene followed by addition of a THF solution of t-
BuOH,17 (Z)-7a was obtained exclusively, in sharp contrast to
the result that (Z)-5a afforded only (E)-7a (Table 2). The same
stereoselectivity was also observed in reactions of the other
ynenoylsilanes (E)-5b−d and (Z)-5b. The absolute config-
urations of the allene derivatives (E)- and (Z)-7 were determined
to be both R by the fact that the known allene derivative (R)-
1118,19 was obtained from both of the isomers as shown in
Scheme 3.
The E/Z-geometry in the products is controlled by rotamers of
an α-silyl alkoxide, from which a Brook rearrangement occurs via
a pentacoordinate-silicate transition state or intermediate to give
enol silyl ethers as shown in Figure 2. This is based on the
stereoelectronic requirement that the C−Si bond cleaved should
be in a parallel arrangement to the π-bond of the double bond.
To obtain information about the origin of the strict E/Z-
selectivity observed, we performed DFT calculations on ground-
state conformations of α-silyl lithium alkoxides (E)-12a,b and
(Z)-12a,b leading to (Z)- and (E)-13, respectively (B3LYP/6-
311++G** level; see Supporting Information).20 These
calculations account for the stereoselectivity observed by
showing that (E)-12a and (Z)-12b leading to (Z)-13 and (E)-
13 are more stable than the corresponding intermediates leading
to (E)-13 and (Z)-13, respectively (Figure 3), although the
origin of the different stabilities of the rotamers is not clear at
present.
Figure 1. Transition state structures of the reduction.
In initial experiments, we examined the MPV-type reduction
of ynenoylsilanes (E)-5a with 2 in toluene at −80 °C. Although
the corresponding silyl alcohol (E)-10a was obtained in an
excellent enantioselectivity (er >99:1) with the absolute
configuration being assigned as R on the basis of the modified
Mosher method,13 recovery of the starting material (7−37%)
was inevitable under various conditions. The use of 2, however,
generated from MeLi·LiBr and not from n-BuLi, solved this
problem to provide (R,E)-10a in 85% yield (Table 1, entry
1).14,15 The enantioselectivity observed can be explained by
invoking a deformed six-membered transition state in which a
steric interaction between the 1′-methylene group and the
carbonyl-carbon substituents due to the increased double-bond
character of the C-1 nitrogen bond controls the selectivity
(Figure 1). That has been previously proposed for the reduction
of corresponding silylimines on the basis of the results of density
functional theory (DFT) calculations.16 Similar results were
obtained with (Z)-5a,b as well as other (E)-substrates (Table 1).
Having established the applicability of enantioselective MPV-
type reduction to ynenoylsilanes, we proceeded to examine the
viability of the tandem process that involves MPV-type
reduction, a Brook rearrangement in the resulting α-silyl
alkoxide, and the formation of an allenylenol silyl ether by
B
DOI: 10.1021/acs.orglett.5b00261
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Table 3. Diels−Alder Reactions of Allenylenol Silyl Ethers Achieved in a One-Pot Operation from Ynenoylsilanes 5
(E)-14−16
(Z)-14−16
entry
ab
5
dienophile
product
yield (%)
er
yield (%)
er
,
1
2
3
4
5
6
7
8
9
(Z)-5a
(Z)-5a
(Z)-5a
(Z)-5b
(Z)-5b
(Z)-5b
(E)-5a
(E)-5b
(E)-5c
(E)-5d
PTAD
NMM
MA
15a
14a
16a
15a
14a
16a
15a
15b
15c
15d
80
61
43
62
57
43
51
37
35
51
99:1 (R)
99:1 (R)
>99:1 (R)
99:1 (R)
99:1 (R)
99:1 (R)
96:4 (S)
97:3 (S)
>99:1 (S)
96:4 (S)
16
−
−
98:2 (S)
−
−
ab
,
PTAD
NMM
MA
26
99:1 (S)
−
−
11
32
56
30
−
−
a
a
a
a
PTAD
PTAD
PTAD
PTAD
97:3 (R)
94:6 (R)
99:1 (R)
96:4 (R)
10
a
b
PTAD (0.5 equiv), −80 °C, 1 h. TFA (0.9 equiv).
Scheme 5. Diels−Alder Reactions of Allenylenol Silyl Ethers 7
Figure 3. Relative energies of α-silyl lithium alkoxides.
Scheme 4. Stereochemical Pathway for Protonation of α-Silyl
Lihium Alkoxides
The correlation between absolute configurations of the
stereogenic centers of 10 and allene moieties of 7 indicates
that the protonation proceeds in an anti-mode to the C−Si bond
across the 1,3-enyne system (Scheme 4). Our previous studies on
alkynoyl silanes showed that protonation on the triple bond
occurs in an anti-mode to the C−Si bond probably because of
stereoelectronic and/or steric effects.3 If stereoelectronic effects
operate also in the 1,3-enyne system, overall syn-protonation
(anti, anti) products should be produced across the 1,3-enyne
system. A possible explanation for the overall anti protonation
observed is that the protonation is caused by t-BuOH(s)
precomplexed with a lithium atom bound to an oxygen atom of a
silicate or a silyl alkoxide,6b consequently from the same side as
the oxygen atom and thus from the opposite side to the C−Si
bond. However, a detailed understanding of the origin of the
stereochemical preference for the protonation must await further
mechanistic study.
(PTAD). The latter was selected in view of its extremely high
reactivity toward a diene that allows a D−A reaction with (Z)-
dienes under mild conditions.21 The reaction of (R,E)-7b with
NMM proceeded smoothly to give (R,E)-14b, while (R,Z)-7b
resulted in recovery of the starting materials (Scheme 5). In
contrast, the reactions of both (R,Z)- and (R,E)-7b with PTAD
proceeded even at −80 °C to give (S,E)- and (R,Z)-15b and
(R,E) and (S,Z)-14b, respectively. Their stereochemical assign-
ments were made on the basis of the results of the X-ray analysis
of (R,Z)-15c (vide infra).
These stereochemical outcomes can be rationalized by
invoking that the reaction proceeds through transition states,
the geometries of which are governed by a combination of steric
interactions between the dienophile and the allene substituent R,
and the E/Z-geometry of the enol silyl ether, as shown in Figure
4. The low E/Z selectivity in the reactions with PTAD is
attributed to the extremely high reactivity of the dienophile.
We next examined whether it is possible to bypass the isolation
of 1,3,4-trienol silyl ethers 7. As a result, we developed a one-pot
procedure that enables the direct conversion of ynenoylsilanes 5
into 14−16 (Table 3).
To evaluate the synthetic potential of (Z)- and (E)-enol silyl
ethers having an axially chiral allene moiety, we examined Diels−
Alder (D−A) reactions of (R,Z)- and (R,E)-7b with N-
methylmaleimide (NMM) and N-phenyl-1,2,4-triazolinediones
C
DOI: 10.1021/acs.orglett.5b00261
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Letter
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In conclusion, the significant points arising from the study
outlined here are as follows: (1) the reduction of ynenoylsilanes
via an MPV-type hydride transfer from a chiral lithium amide
provides α-silyl alkoxides that undergo protonation across
conjugated 1,3-enynes after a Brook rearrangement to give
allene derivatives bearing a 2-siloxyvinyl moiety enantioselec-
tively; (2) the stereoselective formation of (E)- and (Z)-enol silyl
ethers depending on the geometry of the starting enyne moiety
can be attributed to the difference between the stabilities of the
rotamers leading to the Brook rearrangement; (3) the correlation
between absolute configurations of the α-silyl alkoxide and the
allene moiety indicates that an anionic rearrangement across the
1,3-enyne system followed by protonation proceeds in an anti-
mode to the C−Si bond; (4) the 2-siloxyvinylallene products can
participate in Diels−Alder reactions with reactive dienophiles,
which can be achieved in a one-pot operation from
ynenoylsilanes.
́
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̈
ASSOCIATED CONTENT
* Supporting Information
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■
S
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Experimental procedure, characterization, and spectral data. This
material is available free of charge via the Internet at http://pubs.
acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: misasaki@hiroshima-u.ac.jp.
Notes
́
1975, 50, 4467. (b) Chinchilla, R.; Najera, C. Chem. Rev. 2007, 107, 874.
The authors declare no competing financial interest.
(13) Ohtani, I.; Kusumi, T.; Kashman, Y. J. Am. Chem. Soc. 1991, 113,
4092.
ACKNOWLEDGMENTS
■
(14) For a similar description of LDA generated from MeLi·LiBr, see:
Reich, H. J. J. Org. Chem. 2012, 77, 5471.
This research was partially supported by a Grant-in-Aid for
Scientific Research (C) 25460015 (M.S.) from the Ministry of
Education, Culture, Sports, Science and Technology (MEXT),
the Hoan Sha Foundation (M.S.), the Takeda Science
Foundation (M.S.) and the Naito Foundation Natural Science
Scholarship (M.S.). We thank the staff of Natural Science Center
for Basic Research and Development (N-BARD), Hiroshima
University for the use of their facilities.
(15) In experiments under conditions using a common solvent system
(toluene−Et2O−n-hexane) for both of the two alkyllithiums, the same
trend was observed, thus excluding the contribution of the Et2O
originating from a MeLi solution to an enhancement in yield.
(16) Kondo, Y.; Sasaki, M.; Kawahata, M.; Yamaguchi, K.; Takeda, K. J.
Org. Chem. 2014, 79, 3601.
(17) The addition of THF was essential for a facile Brook
rearrangement as in the case of alkynoylsilanes.3
(18) Mori, K. Tetrahedron 2012, 68, 1936.
(19) The decline in the enantiopurity of 11 was attributed to partial
racemization at the stage of the aldehyde.
(20) Calculations were performed on the Spartan ‘14 (Ver. 1.1.4 for
Mac), Wave function, Inc., Irvine, CA. Calculations of the transition
structures for the formation of (E)- and (Z)-7 were not attempted due to
the difficulty associated with several mechanistic possibilities.
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(b) Moody, C. J. Adv. Heterocycl. Chem. 1982, 30, 1. (c) Chen, J. S.;
Houk, K. N.; Foote, C. S. J. Am. Chem. Soc. 1998, 120, 12303.
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DOI: 10.1021/acs.orglett.5b00261
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