[2,3]-Wittig rearrangement of enantiomerically enriched 3-substituted 1-propenyloxy-1-phenyl-2-propen-1-yl carbanions: Effect of heteroatoms and conjugating groups on planarization of an α-oxy-benzylcarbanion through a double bond

Article abstract of DOI:10.1002/chem.200802322

The effect of conjugating electron-withdrawing groups and α-anion-stabilizing heteroatom substituents on configurational stability of chiral carbanions through a double bond was examined on the basis of extent of chirality transfer in intramolecular trapp

Full text of DOI:10.1002/chem.200802322

FULL PAPER
DOI: 10.1002/chem.200802322
ACHTUNGTRENNUNG
Michiko Sasaki,[a] Hidaka Ikemoto,[a] Masatoshi Kawahata,[b] Kentaro Yamaguchi,[b] and
Kei Takeda*[a]
Abstract: The effect of conjugating electron-withdrawing groups and a-anion-sta-
bilizing heteroatom substituents on configurational stability of chiral carbanions
Keywords: carbanions · configura-
through a double bond was examined on the basis of extent of chirality transfer in
tion analysis · Wittig reactions
intramolecular trapping in [2,3]-Wittig rearrangement of chiral 3-substituted 1-pro-
penyloxy-1-phenyl-2-propen-1-yl carbanions.
Introduction
pending on the nature of the ethereal solvents used is note-
worthy. Thus, reactions in 1,4-dioxane and Et2O showed ex-
cellent and good asymmetric induction, respectively, in
sharp contrast to the reaction in THF, the most common sol-
vent for the rearrangement, in which almost complete race-
mization was observed. These findings led us to the general
idea that the rearrangement can be used as a tool for esti-
mation of the effect of substituents on the configurational
stability of chiral lithium compounds using substrates like 1,
in which a substituent X is a heteroatom or a conjugating
group such as a cyano and a carbonyl group (Scheme 1).
Thus, the extent of chirality transfer in the rearrangement
would reflect the difference in stereochemical stability of
chiral carbanions next to the substituent X. The Hoffmann
test may be less suitable particularly for electron-withdraw-
ing conjugating groups due to the relatively slower intermo-
lecular process. Although Brꢀckner has used [2,3]-thia-
Wittig rearrangement of diastereomeric organolithiums for
an estimation of the configurational stability of a-lithio sul-
fide[5] and Hammerschmidt has tested the microscopic con-
figurational stability of homochiral oxymethyllithium in
[1,2]-retro-Brook and [2,3]-Wittig rearrangement,[6] to the
best of our knowledge there have been no systematic studies
on the effects of conjugating groups including a cyano group
and the a-anion-stabilizing heteroatom substituents on the
configurational stability of chiral carbanions.
Because the enantioselective formation of a chiral carbanion
and its reaction with an electrophile in a stereodefined
manner is very attractive for asymmetric carbon carbon
À
bond formation, investigations on the relative configuration-
al stability of the anion would be important for the success-
ful preparative application of the process.[1] One of the most
widely used and elegant methods for evaluating configura-
tional stability of a chiral carbanion is the Hoffmann test,[2]
which is based on a kinetic resolution during the electrophil-
ic substitution step using racemic and enantioenriched alde-
hydes as an electrophile.
We have recently found that [2,3]-Wittig rearrangement
can trap a chiral carbanion generated between a double
bond and a phenyl group, which has been considered diffi-
cult to generate due to their high tendency toward racemiza-
tion, almost without racemization even at room tempera-
ture, indicating that the rearrangement is very fast.[3,4] The
finding that the asymmetric induction changes greatly de-
[a] Dr. M. Sasaki, H. Ikemoto, 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
[b] Dr. M. Kawahata, Prof. K. Yamaguchi
Tokushima Bunri University
Herein we report our results using vinylogous derivatives
2, in which a heteroatom or an electron-withdrawing conju-
gating group is placed at a vinylogous position. We chose 2
to remove any steric bias in 1 with respect to the difference
1314-1 Shido, Sanuki, Kagawa, 769-2193 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200802322.
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4663

Scheme 1. ACHTUNGTRENNUNG[2,3]-Wittig rearrangement as a tool for estimation of the
effect of group X on the configurational stability of chiral carbanions.
in rate of the rearrangement arising from the difference in
the bulkiness of X. That is based on results of preliminary
experiments performed using 4 (Table 1).
Table 1. ACHTUNGTRENNUNG[2,3]-Wittig rearrangement of 4a–d.
Scheme 2. Preparation of 6a–g.
Wittig rearrangement of 6a–g was conducted using nBuLi
or LDA as a base[12] in 1,4-dioxane, Et2O, and THF at room
temperature. The results are shown in Table 2.[13]
4
R
Yield [%]
ee [%]
72
2
8
a
b
c
Ph
Me
o-tol
p-tol
70
21
33
88
Particularly notable is the fact that substrates bearing
electron-withdrawing groups such as a cyano group[10,14] can
partly retain their stereochemical information without com-
plete racemization. Regarding the relationship between sol-
vent and asymmetric induction, the same general trend as
that with the orginal system[3] was observed only for X=
phenyl and SiMe3 groups; that is, the enantiomeric excesses
in their reactions decreased in the order of 1,4-dioxane >
Et2O > THF. In the case of methyl and cyano groups or
other heteroatom substituents, a clear correlation was not
observed.
In principle, the major diastereomer of the rearrangement
products 7 and 7’, which is a faster rearrangement product,
should posses a higher ee value than that of the minor
isomer. This trend was observed in most cases but not all
cases. The latter may be due to the difference in stability of
the two diastereomers.
The noteworthy points from Table 2 are as follows: 1)
when X is an anion-unstabilizing group such as a methyl
group, little racemization was observed regardless of the sol-
vent used (entries 1–3); 2) in the case of conjugating groups,
phenyl and cyano groups (entries 4–6; 10–12), racemization
occurs depending on the extent of their electron-withdraw-
ing nature, and the phenyl group is very sensitive to changes
in solvent; and 3) a-carbanion-stabilizing heteroatom sub-
stituents other than the silyl group cause considerable race-
mization.
Studies on configurational stability of a-heteroatom-sub-
stituted carbanions using the Hoffmann test have shown
that organolithiums a to phosphorus[15] and silicon are con-
figurationally unstable on a microscopic timescale, while
lithiated sulfones[16] are configurationally stable on a micro-
scopic timescale.[17] The results of the Hoffmann test also
d
66
The reaction of a-methyl derivative 4b, in which there
should be much better asymmetric induction than that in
the reaction of the phenyl counterpart 4a, resulted in a
much poorer ee, which was speculated to be caused by de-
celeration of the rearrangement due to steric repulsion in
the transition state in the rearrangement. This assumption
was supported by the fact that o-tolyl derivative 4c afforded
the corresponding rearrangement product in a much smaller
ee than that in the case of p-tolyl derivative 4d. Further-
more, a pentyl group was introduced as the R in the allyl
group to enable us to distinguish whether the product 5 was
formed via [2,3]- or [1,2]-Wittig rearrangement, the latter
proceeding via a radical pathway. We envisioned that the
system can provide information about the effect of the sub-
stituent X on the configurational stability of chiral carban-
ions through a double bond.
Results and Discussion
The preparation of 6a–g is shown in Scheme 2. As a group
X we selected methyl, phenyl, trimethylsilyl, cyano, benze-
nesulfonyl, diethoxyphosphoryl and diphenylphosphinoyl
groups. Enantioenriched alcohol precursors were obtained
using Sharpless kinetic resolution,[8] (À)-B-chlorodiisopino-
camphenylborane reduction,[9] lipase-mediated kinetic reso-
lution,[10] or Sharpless asymmetric dihydroxylation.[11]
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Chem. Eur. J. 2009, 15, 4663 – 4666

ACHTUNGTRENNUNG[2,3]-Wittig Rearrangement
FULL PAPER
Table 2.
Entry
ACHTUNGTRENNUNG[2,3]-Wittig rearrangement of 6a–g.
X
Solvent
Base[a]
Yield [%]
7/7’
ee [%]
7
7’
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
6a
6a
6a
6b
6b
6b
6c
6c
6c
6d
6d
6d
6e
6e
6e
6 f
6 f
6 f
6g
6g
6g
Me
Me
Me
Ph
Ph
Ph
SiMe3
SiMe3
SiMe3
CN
1,4-dioxane
Et2O
THF
1,4-dioxane
Et2O
THF
1,4-dioxane
Et2O
THF
1,4-dioxane
Et2O
THF
1,4-dioxane
Et2O
THF
1,4-dioxane
Et2O
THF
1,4-dioxane
Et2O
THF
A
A
A
A
A
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
77
79
87
70
64
61
80
78
79
31
31
40
49
71
75
18
27
8
32:68
38:62
31:69
45:55
51:49
43:57
47:53
51:49
47:53
50:50
44:56
50:50
63:37
49:51
60:40
76:24
49:51
75:25
57:43
33:67
65:35
94
95
93
84
60
3
85
82
56
8
8
2
5
7
0
2
1
12
5
98
100
96
92
71
4
86
79
62
9
CN
CN
6
3
SO2Ph
SO2Ph
SO2Ph
P(O)
P(O)
P(O)
P(O)Ph2
P(O)Ph2
P(O)Ph2
12
17
7
14
18
7
12
4
22
G
E
G
58
52
50
10
14
[a] A: nBuLi; B: LDA.
are consistent with the calculated inversion energies
(ÀCH2SiH3: 0.8 kcalmolÀ1 ÀCH2SH: 2.8 kcalmolÀ1).[18] Con-
anion moiety by an external electrophile, and 2) allows in-
ference from stereochemical analysis of the products wheth-
er a configurational loss occurs on the time scale of that cap-
ture, the method using [2,3]-Wittig rearrangement 1) cap-
tures the carbanion moiety by an internal allyl transfer and
2) allows inference from stereochemical analysis of the
products how much configurational loss occurs on the time
scale of that capture.
;
sequently, the results showing that more racemization oc-
curred in the sulfonyl derivative 6e than in the silyl deriva-
tive 6c deserve some comments. This suggests that in allyl
carbanion 3, the contribution of the resonance form 3B
should be more significant in the sulfone derivative 6e than
in the silyl derivative 6c, which is consistent with the expect-
[19]
ation based on pKa values of their a-proton, and that the
carbanion in 3B can be rather planarized. In other words,
the chirality of b-heteroatom-substituted allylic carbanions
would not be transferred into the a-position to the heteroa-
tom through a double bond in the above system. This is sup-
ported by the fact that an obvious solvent effect was ob-
served only for the phenyl and trimethylsilyl derivatives,
which have a less electron-withdrawing nature than that of
the cyano group and other heteroatom substituents. We pre-
viously proposed that the origin of the excellent enantiose-
lectivity observed in 1,4-dioxane is the decreased rate of rac-
emization by chelation of the lithium cation with the two
oxygens. Increased contribution of the resonance form 3B
and of the planar structure of the anion a to the group X
would make chelation by the 1,4-dioxane in 3 A less impor-
tant.
Conclusion
We have examined the possibility that the extent of chirality
transfer in [2,3]-Wittig rearrangement employing a chiral b-
substituted allyl benzyl carbanion is used as a tool for evalu-
ation of the effect of substituents on the configurational sta-
bility of a chiral carbanion through a double bond, and
found that in the behavior of the conjugative electron-with-
drawing groups and a-anion-stabilizing heteroatoms on the
configurational stability of chiral carbanions, there is no
direct correlation between the groups themselves and their
vinylogous variants.
The method described herein offers an advantage com-
pared with the Hoffmann test. The surprisingly high reaction
rates of [2,3]-Wittig rearrangements make the method a par-
ticular sensitive test for highly configurationally labile car-
banions. This is based on the logical differences between the
two methods. While the Hoffmann test 1) captures the carb-
Experimental Section
General methods and additional procedures are available in the Support-
ing Information.
Representative procedure:
A solution of nBuLi (1.86m in hexane,
289 mL, 0.54 mmol) was added at room temperature to a solution of 6b
Chem. Eur. J. 2009, 15, 4663 – 4666
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www.chemeurj.org
4665

K. Takeda et al.
(>99% ee, 57.8 mg, 0.18 mmol) in dioxane (3.6 mL). After stirring at the
same temperature for 10 min, a few drops of saturated aqueous NH4Cl
solution was added. The mixture was diluted with Et2O, dried, and con-
centrated. The residual oil was subjected to column chromatography
(silica gel 7 g, elution with hexane/AcOEt 22:1) to give 7b and 7’b
(40.5 mg, 70%, 7b/7’b 45:55).
[7] The absolute configuration of the alcohol in 5 was assigned by anal-
ogy with our previous results.[3] It has been reported that [2,3]-
Wittig rearrangement of lithiated allyl ethers and lithiated diallyl
ethers proceeds with inversion of configuration at the lithium-bear-
ing carbon atom. a) E. J. Verner, T. Cohen, J. Am. Chem. Soc. 1992,
114, 375–377; b) R. Hoffmann, R. Brꢀckner, Angew. Chem. 1992,
104, 646–648; Angew. Chem. Int. Ed. Engl. 1992, 31, 647–649; c) K.
Tomooka, T. Igarashi, M. Watanabe, T. Nakai, Tetrahedron Lett.
1992, 33, 5795–5798.
Acknowledgement
[8] P. R. Carlier, W. S. Mungall, G. Sohrçder, K. B. Sharpless, J. Am.
Chem. Soc. 1988, 110, 2978–2979.
This research was partially supported by a Grant-in-Aid for Scientific Re-
search (B) 19390006 (K.T.) and a Grant-in-Aid for Young Scientists (B)
20790011 (M.S.) from the Ministry of Education, Culture, Sports, Science
and Technology (MEXT), and the Uehara Memorial Foundation (M.S.).
We thank the Research Center for Molecular Medicine, Faculty of Medi-
cine, Hiroshima University and N-BARD, Hiroshima University for the
use of their facilities. We thank the Research Center for Molecular Medi-
cine, Faculty of Medicine, Hiroshima University and N-BARD, Hiroshi-
ma University for the use of their facilities.
[9] H. C. Brown, J. Chandrasekharan, P. V. Ramachandran, J. Am.
Chem. Soc. 1988, 110, 1539–1546.
[10] M. Sasaki, E. Kawanishi, Y. Shirakawa, M. Kawahata, H. Masu, K.
Yamaguchi, K. Takeda, Eur. J. Org. Chem. 2008, 3061–3064.
[11] H. C. Kolb, M. S. VanNieuwenhze, K. B. Sharpless, Chem. Rev. 1994,
94, 2483–2547.
[12] Although the choice of the base was based on best conversion,
almost the same amounts of hexanes originating from nBuLi solu-
tion was used in the reactions with both of the bases.
[13] Since the relative configurations of 7a–g and 7’a–g could not be as-
signed except 7’b, that of which was determined by an X-ray analy-
sis, the more polar isomer and the less polar isomer were referred to
as 7 and 7’, respectively, on the basis of the polarity in the MPLC.
[14] a) H. M. Walborsky, J. M. Motes, J. Am. Chem. Soc. 1970, 92, 2445–
2450; b) H. M. Walborsky, A. A. Youssef, J. M. Motes, J. Am. Chem.
Soc. 1962, 84, 2465–2466; c) H. M. Walborsky, F. M. Hornyak, J.
Am. Chem. Soc. 1955, 77, 6026–6029; d) P. R. Carlier, Y. Zhang,
Org. Lett. 2007, 9, 1319–1322. e) P. R. Carlier, Chirality 2003, 15,
340–347.
[15] a) S. E. Denmark, R. L. Dorow, J. Org. Chem. 1990, 55, 5926–5928;
b) P. OꢂBrien, H. R. Powell, P. R. Raithby, S. Warren, J. Chem. Soc.
Perkin Trans. 1 1997, 1031–1039.
[16] a) G. Boche, Angew. Chem. 1989, 101, 286–306; Angew. Chem. Int.
Ed. Engl. 1989, 28, 277–297; b) H.-J. Gais, J. Vollhardt, H. J. Lind-
ner, Angew. Chem. 1986, 98, 916–917; Angew. Chem. Int. Ed. Engl.
1986, 25, 939–941; c) H.-J. Gais, G. Hellmann, J. Am. Chem. Soc.
1992, 114, 4439–4440.
[1] a) The chemistry of organolithium compounds (Eds.: Z. Rappoport,
I. Marek), Wiley, New York, 2004; b) D. M. Hodgson, Organolithi-
ums in enantionselective synthesis, Springer, New York, 2003; c) J.
Clayden, Organolithiums: Selectivity for synthesis, Pergamon,
Oxford, 2002; d) V. K. Aggarwal, Angew. Chem. 1994, 106, 185–187;
Angew. Chem. Int. Ed. Engl. 1994, 33, 175–177.
[2] a) R. W. Hofmann, J. Lanz, R. Metternich, G. Tarara, D. Hoppe,
Angew. Chem. 1987, 99, 1196; Angew. Chem. Int. Ed. Engl. 1987, 26,
1145–1146; b) R. Hirsch, R. W. Hoffmann, Chem. Ber. 1992, 125,
975–982; c) R. W. Hoffmann, M. Julius, F. Chemla, T. Ruhland, G.
Frenzen, Tetrahedron 1994, 50, 6049–6060; d) A. Basu, D. Gallagh-
er, P. Beak, J. Org. Chem. 1996, 61, 5718–5719. Also, see: e) P.
Beak, A. Basu, D. J. Gallagher, Y. S Park, S. Thayumanavan, Acc.
Chem. Res. 1996, 29, 552–560.
[3] M. Sasaki, M. Higashi, H. Masu, K. Yamaguchi, K. Takeda, Org.
Lett. 2005, 7, 5913–5915.
[4] For reviews on [2,3]-Wittig rearrangement, see: a) T. Nakai, K.
Mikami, Chem. Rev. 1986, 86, 885–902; b) J. A. Marshall in Com-
prehensive Organic Synthesis, Vol. 3 (Eds.: B. M. Trost, I. Fleming),
Pergamon, Oxford, 1991, pp. 975–1014; c) K. Mikami, T. Nakai,
Synthesis 1991, 594–604; d) T. Nakai, K. Mikami, Org. React. 1994,
46, 105–209; e) T. Nakai, K. Tomooka, Pure Appl. Chem. 1997, 69,
595–600. f) D. M. Hodgson, Organolithiums in enantionselective syn-
thesis, Springer, New York, 2003, pp. 217–250.
[17] R. W. Hoffmann, T. Rꢀhl, J. Harbach, Liebigs Ann. Chem. 1992,
725–730.
[18] B. Boche, A. Opel, M. Marsch, K. Harms, F. Hallera, J. C. W Loh-
renz, C. Thꢀmmler, W. Koch, Chem. Ber. 1992, 125, 2265–2273.
[19] a) F. G. Bordwell, Acc. Chem. Res. 1998, 31, 456–463; b) R. W. Taft,
F. G. Bordwell, Acc. Chem. Res. 1998, 31, 463–469; c) S. Zhang, X.-
M. Zhang, F. G. Bordwell, J. Am. Chem. Soc. 1995, 117, 602–606.
[5] K. Brickmann, R. Brꢀckner, Chem. Ber. 1993, 126, 1227–1239.
[6] D. C. Kapeller, L. Brecker, F. Hammerschmidt, Chem. Eur. J. 2007,
13, 9582–9588.
Received: November 17, 2008
Revised: January 28, 2009
Published online: March 19, 2009
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