Stereoselective Se2′ protonation of α- hydroxyallylsilanes mediated by a brook rearrangement

Article abstract of DOI:10.1002/chem.200802499

Stereoselective S_E2' protonation of α-hydroxyallylsilanes mediated by a Brook Re-arrangement was demonstrated. The study involved trapping of α-silyl alkoxide derivatives as alcohols by quenching the reaction at lower temperatures to gain information about the stereochemical pathway of the S_E2' reaction in allylsilicates. It was observed that the isolation can be performed by the reaction in Et₂O at a lower temperature. The protonation in allylsilanes with an oxygen substituent on the sterogenic center resulted allylic carbanion planarized by a neighboring CN group, which preceded in an anti fashion to afford enantiomerically enriched nitril derivatives. The study concluded that this process was similar to trapping of an enantioenriched C-chiral α-nitrile carbanion, which had a low inversion barrier.

Full text of DOI:10.1002/chem.200802499

COMMUNICATION
DOI: 10.1002/chem.200802499
Stereoselective SE2’ Protonation of a-Hydroxyallylsilanes Mediated by a
Brook Rearrangement
Michiko Sasaki,[a] Yuri Shirakawa,[a] Masatoshi Kawahata,[b] Kentaro Yamaguchi,[b] and
Kei Takeda*[a]
ꢀ
We have recently reported that enantioselective C C
bond formation at an a-position of a cyano group with an
external electrophile (1!2!3!4; Scheme 1) can be realiz-
reochemical discussion concerning SE2’ reaction in allylsili-
cates, derived from allylsilanes with an oxygen substituent
on the stereogenic center, as in 3, by means of a Brook rear-
rangement,[2,3] in sharp contrast to the extensive body of
knowledge concerning the corresponding reactions of allylsi-
lanes.[4]
After extensive experimentation, it proved possible to iso-
late 5 (M=H) by performing the reaction in Et2O at a
lower temperature.[5] Thus, treatment of 6a[1] with LDA at
ꢀ988C in Et2O afforded (E)-7 in 59% yield together with
(E)- and (Z)-8 (Scheme 2). A similar result was obtained
Scheme 1. Chirality transfer in epoxysilane rearrangement.
ed, although in modest enantiomeric excess (ee), with the
aid of both the concerted process of epoxysilane rearrange-
ment and a carbamoyl group (R=Cb).[1] During the course
of stereochemical studies of the reaction, we attempted to
trap a-silyl alkoxide derivatives 5 (M=Li), possible inter-
mediates in the reaction pathway, as alcohols 5 (M=H) by
quenching the reaction at lower temperatures, with the ex-
pectation that isolation of the alcohol would allow us to
obtain useful information regarding the stereochemical
pathway of the SE2’ reaction in allylsilicates such as 3. To
the best of our knowledge, there is no precedent for a ste-
Scheme 2. Preparation of (E)- and (Z)-7.
with 6b[1] to give (Z)-7. The observed stereospecificity was
consistent with a syn-attack ring-opening (e.g., 6a’) of the
epoxide, although we have suggested an anti-attack ring-
opening for similar reactions using the corresponding OTBS
derivatives in THF.[6,7] The geometry of 7 was determined
on the basis of result of X-ray analysis of (Z)-7.
With the desired alcohol derivatives (E)- and (Z)-7 in
hand, we examined their benzylation by exposure to LDA
in the presence of BnBr (Scheme 3). When LDA was added
to a solution of (E)-7 in Et2O at ꢀ808C in the presence of
BnBr and the reaction was quenched after 1 h, (Z)- and
(E)-9 were obtained in 85% and 8% yields, respectively, to-
[a] Dr. M. Sasaki, Y. Shirakawa, 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. Dr. K. Yamaguchi
Tokushima Bunri University
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.200802499.
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Table 1. Reaction of (E)-7 with LDA.
LDA
[equiv]
G
(Z,S)-8
(E)-7
Yield [%]
G
ee [%]
ee [%]
0.1
0.3
0.6
1.0
5
20
13
7
69
29
25
0
4
34
32
38
35
9
8
33
–
–
0
–
Table 2. Reaction of (Z)-7 with LDA.
Scheme 3. Reaction of (E)- and (Z)-7 with LDA in the presence of
benzyl bromide.
gether with protonated product (Z)-8. In contrast to the re-
sults obtained in the reaction of 6a (30–40% ee),[1] the eeꢁs
of almost all products were low. Reaction of (Z)-7 provided
(E)- and (Z)-9 with low ee in a reversed ratio.
We attributed the loss of enantiomeric excess in the prod-
ucts to the result of competition between benzylation and
C-protonation by 7 in a-silyl alkoxide 7’; the latter process
leading to 8 should be much faster than the former
(Scheme 4). Compound 8 can be racemized to give the a-ni-
trile carbanion 8’ by deprotonation with LDA even if the
protonation of 7’ by 7 (7’!8) proceeds stereoselectively by
a concerted process.
LDA
[equiv]
(E,S)-8
(Z)-7
Yield [%]
E
Yield [%]
ee [%]
0.1
0.3
0.6
1.0
54
77
78
18
68
55
38
4
25
–
–
13
The absolute configurations of the major enantiomer (E)-
and (Z)-8 were determined as shown in Scheme 5 after deri-
vatization of (E)- and (Z)-8 separately to the Mosher esters
Scheme 5. Determination of absolute configurations of (E,Z)-8.
11[8] through the reduction of the nitrile group followed by
an O-to-N migration[1] of the carbamoyl group. It should be
noted that the stereogenic centers of the major enantiomers
of (E)- and (Z)-8 obtained from (E)-7 were enantiomeric
with each other and the stereogenic center of (E)-8 obtained
from (E)-7 was enantiomeric with that of (E)-8 from (Z)-7.
Next we examined the effects of the solvent and base on
enantioselectivity using (Z)-7 (Table 3). Addition of hexane
resulted in enhancement of ee at the expense of chemical
Scheme 4. A plausible pathway of racemization in the reactions in
Scheme 3.
If this explanation is correct, use of a catalytic amount of
LDA should give 8 in increased enantioselectivity, because
the hydroxyl group in 7 can be a proton source and mini-
mize the formation of 8’ by LDA. The results are shown in
Tables 1 and 2. As expected, the enantiomeric excess in-
creased with decreasing amount of LDA in the reactions of
both (E)-and (Z)-7; thus, use of 0.1 equiv and 1.0 equiv of
LDA gave the best and poorest results in terms of ee, re-
spectively, and with regard to chemical yield the best result
was obtained when 0.3 equiv of the base was used. The
lower chemical yields when using stoichiometric amounts of
the base may stem from base-induced decomposition in 8.
yield (entries 1 and 2). 1,8-DiazabicycloACTHNUTRGNE[NUG 5.4.0]undec-7-ene
(DBU) and LiOtBu (entries 3–8) were used with anticipa-
tion that as they are less basic, the deprotonation of 8 can
be suppressed and the generation of a conjugate acid of
DBU and of tBuOH can accelerate the protonation of the
a-nitrile carbanion. Although use of DBU in DMSO result-
ed in significant decomposition, reactions using LiOtBu pro-
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Asymmetric Synthesis
COMMUNICATION
Table 3. Reaction of (Z)-7 with a catalytic amount of base.
hols 7 and lithium alkoxide 7’ by means of the Hartree–
Fock calculations (Scheme 7). The two local minima (E)-
7a,b for (E)-7 were identified by subjection of conformers
that were located by both MMFF94s and Conflex methods
A
(Z)-7
Entry Base
(equiv)
Solvent
T
Yield
[%] [%]
N
1
2
3
4
5
6
7
8
LDA (0.1)
LDA (0.1)
DBU (0.1)
tBuOLi (0.1)
tBuOLi (0.1)
tBuOLi (0.1)
tBuOLi (0.1)
Et2O–hexane (1:1) ꢀ80 20
Et2O–hexane (1:2) ꢀ80 25
77
77
74
61
76
70
52
75
72
56
10
64
50
20
–
DMSO
Et2O
RT 14
ꢀ80 25
Et2O–hexane (1:1) ꢀ80 36
Et2O–hexane (1:1)
Et2O–hexane (1:1)
0
64
RT 85
RT 86
tBuOLi (0.05) tBuOH
–
vided comparable ee values and much better chemical yields
than those in the case of LDA in Et2O/hexane (entries 6–8).
To understand the stereochemical outcome in the reac-
tions of (E,Z)-7, the origin of the stereospecificity depend-
ing on the E/Z geometry of 7 should be rationalized. The
E/Z geometry in 8 would be solely controlled by the confor-
mation of silicate intermediates 12, which are generated by
deprotonation by a base, assuming that no E/Z isomeriza-
tion occurs in the products 8 under the conditions used and
ꢀ
that C Si bond cleavage in the silicates occurs in a concert-
ed fashion, while keeping a parallel alignment between the
ꢀ
C Si bond and the p orbital. Thus, conformers 12a and 12b
Scheme 7. Stereochemical pathways for reactions of (E)- and (Z)-7.
give (Z)-8 and (E)-8, respectively (Scheme 6). On the other
hand, the stereochemistry at the C2 position would be regu-
lated by both the double bond geometry and a syn/anti
ꢀ
mode protonation to the C Si bond in 12. For example, (E)-
12a would afford (Z,R)-8 and (Z,S)-8 in syn and anti forms,
respectively.
to geometry optimization at HF/6-31+G* level and then re-
finement at RI-MP2/6-31+G* level; the former was found
to be more stable.[9] In both conformers, the silyl group is
aligned almost perpendicularly to the plane of the olefin. In
the case of lithium alkoxide, the conformations obtained
were similar to those of the alcohol, but the stability was re-
versed. Thus, an internally chelated conformation (E)-7b’
was found to be more stable than (E)-7a’. In the case of the
Z derivatives, only alcohol conformers (Z)-7c in which the
hydroxyl group was almost perpendicular to the plane of the
olefin and formed intramolecular hydrogen bonding to the
carbonyl group was found. Both (Z)-7a, which is similar to
that obtained from X-ray analysis of (Z)-7, and a conformer
corresponding to (Z)-7b were not found. In the case of the
lithium alkoxide Z derivatives, a local minimum identified
was only (Z)-7c’, in which the lithium ion was chelated with
the carbonyl oxygen. On the basis of this analysis and the
absolute configuration of the products 8, there is a possible
explanation for the results shown in Tables 1 and 2. Thus,
(E)-7 affords (E,R)-8 and (Z,S)-8 through anti-attack proto-
nation of silicate intermediates (E)-12a and (E)-12b derived
from (E)-7a’ and (E)-7b’, respectively, according to the
least motion principle,[10] while (Z)-7 gives only (E,S)-8 via
(Z)-12a derived from (Z)-7c’. The origin for the observed
anti-attack protonation might be related to steric effects of
the bulky silyl group, to steroelectronic effects in the con-
Consequently, it is important to know in which conforma-
tion (E)- and (Z)-7 react to give which silicates. This led us
to search for stable ground-state conformations of silyl alco-
Scheme 6. Stereochemical pathways for the formation of (Z)- and (E)-8
and for (Z,R)- and (Z,S)-8.
Chem. Eur. J. 2009, 15, 3363 – 3366
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3365

K. Takeda et al.
York, 1980, pp. 149–221; c) A. G. Brook, Acc. Chem. Res. 1974, 7,
77–84; for the use of the Brook rearrangement in tandem bond for-
mation strategies, see; d) W. H. Moser, Tetrahedron 2001, 57, 2065–
2084. Also, see: e) A. Ricci, A. Degl’Innocenti, Synthesis 1989, 647–
660; f) P. C. B. Page, S. S. Klair, S. Rosenthal, Chem. Soc. Rev. 1990,
19, 147–195; g) H. Qi, D. P. Curran in Comprehensive Organic
Functional Group Transformations (Eds. A. R. Katritzky, O. Meth-
Cohn, C. W. Rees, C. J. Moody), Pergamon, Oxford, 1995, pp. 409–
431; h) P. F. Cirillo, J. S. Panek, Org. Prep. Proced. Int. 1992, 24,
553–582; i) A. F. Patrocinio, P. J. S. Moran, J. Braz. Chem. Soc. 2001,
12, 7–31.
certed process involving Brook rearrangement and protona-
tion, and to electronic effects of the carbamoyloxy group. In
any case, the interesting results are the subject of more de-
tailed investigations.
In conclusion, we have demonstrated that the SE2’ proto-
nation in allylsilanes, with an oxygen substituent on the ste-
reogenic center, mediated by a Brook rearrangement, in
which the resulting allylic carbanion is potentially planarized
by a neighboring CN group, proceeds in an anti fashion to
afford enantiomerically enriched nitrile derivatives. This
means that the overall process is equivalent to trapping of
an enantioenriched C-chiral a-nitrile carbanion, which has a
very low inversion barrier,[11,12] in up to 77% ee with the aid
of both the concerted process of the protonation and a car-
bamoyl group.[13]
[3] We have discussed the stereochemical pathway of reactions involv-
ing allylsilicates and related system; a) K. Tanaka, H. Masu, K. Ya-
maguchi, K. Takeda, Tetrahedron Lett. 2005, 46, 6429–6432; b) Y.
Nakai, M. Kawahata, K. Yamaguchi, K. Takeda, J. Org. Chem. 2007,
72, 1379–1387.
[4] a) M. J. C. Buckle, I. Fleming, S. Gil, K. L. C. Pang, Org. Biomol.
Chem. 2004, 2, 749–769; b) C. E. Masse, J. S. Panek, Chem. Rev.
1995, 95, 1293–1316; c) I. Fleming, A. Barbero, D. Walter, Chem.
Rev. 1997, 97, 2063–2192; d) I. Fleming, J. Dunoguꢃs, R. Smithers,
Org. React. 1989, 37, 57–575.
Experimental Section
[5] We have sometimes observed that the rate of Brook rearrangement
in Et2O is much slower than that in THF.
[6] a) K. Takeda, E. Kawanishi, M. Sasaki, Y. Takahashi, K. Yamaguchi,
Org. Lett. 2002, 4, 1511–1514; b) M. Sasaki, E. Kawanishi, Y. Nakai,
T. Matsumoto, K. Yamaguchi, K. Takeda, J. Org. Chem. 2003, 68,
9330–9339.
[7] We have recently found that the mode of a base-induced ring-open-
ing of epoxysilanes can change depending on solvents, which will be
reported in future publication.
[8] a) I. Ohtani, T. Kusumi, Y. Kashman, H. Kakisawa, J. Am. Chem.
Soc. 1991, 113, 4092–4096; b) T. Kusumi, J. Synth. Org. Chem. Jpn.
1993, 51, 462–470.
A solution of tBuOLi (0.5m in tBuOH, 14.8 mL, 0.0074 mmol) was added
to a solution of (Z)-7 (50.4 mg, 0.148 mmol) in tBuOH (1.7 mL) at 258C.
The mixture was stirred at the same temperature for 15 min before addi-
tion of CH3COOH (1.0m in Et2O, 15 mL, 0.015 mmol). After being stirred
at the same temperature for 5 min, the reaction mixture was diluted with
10% aqueous NH4Cl solution (5 mL) and extracted with Et2O (5 mLꢂ3).
Combined organic phases were washed with water (5 mL) and saturated
brine (5 mL), dried, and concentrated. The residual oil was subjected to
column chromatography (silica gel 8 g, elution with hexane: Et2O=6:1)
to give (E)-8 (43.1 mg, 86%, 75% ee).
[9] Calculations were performed on the Spartan 06 and Conflex pro-
grams: Spartan 06 (Ver. 1.0.1 for Mac), Wavefunction, Inc, Irvine,
CA; Conflex (Ver. 6.2 for Mac), H. Goto, K. Ohta, T. Kamakura, S.
Obata, Nakayama, T. Matsumoto, E. Osawa, Conflex Corporation,
Tokyo (Japan), 2004.
Acknowledgements
[10] J. Hine, Adv. Phys. Org. Chem. 1978, 15, 1–61.
This research was partially supported by the Ministry of Education, Cul-
ture, Sports, Science and Technology (MEXT) by a Grant-in-Aid for Sci-
entific Research (B) 19390006 (K.T.) and a Grant-in-Aid for Young Sci-
entists (B) 20790011 (M.S.), and the Uehara Memorial Foundation
(M.S.). We thank the Research Center for Molecular Medicine, Faculty
of Medicine, Hiroshima University and N-BARD, Hiroshima University
for the use of their facilities.
[11] For a-nitrile carbanions, see: a) F. F. Fleming, B. C. Shook, Tetrahe-
dron 2002, 58, 1–23; b) S. Arseniyadis, K. S. Kyler, D. S. Watt, Org.
React. 1984, 31, 1–364; c) F. F. Fleming, S. Gudipati, Z. Zhang, W.
Liu, O. W. Steward, J. Org. Chem. 2005, 70, 3845–3849.
[12] a) E. Buncel; M. J. Dust, Carbanion Chemistry: Structures and
Mechanisms, ACS, Washington, 2003; b) J. Kaneti, P. von R. Schley-
er, T. Clark, A. J. Kos, G. W. Spitznagel, . J. G. Andrade, J. B.
Moffat, J. Am. Chem. Soc. 1986, 108, 1481–1492; c) P. R. Carlier,
Chirality 2003, 15, 340–347; d) P. R. Carlier, Y. Zhang, Org. Lett.
2007, 9, 1319–1322; e) W. Zarges, M. Marsch, K. Harms, G. Boche,
Angew. Chem. 1989, 101, 1424; Angew. Chem. Int. Ed. Engl. 1989,
28, 1392.
Keywords: asymmetric synthesis · carbanions · chirality ·
enantioselectivity · silicates
[13] We believe that the effect of the carbamoyloxy group is not so large
because the corresponding O-TBS derivatives afforded the proton-
ated products in ca. 40% ee. Details will be reported in a full paper.
Also, see: ref. [1].
[1] M. Sasaki, E. Kawanishi, Y. Shirakawa, M. Kawahata, H. Masu, K.
Yamaguchi, K. Takeda, Eur. J. Org. Chem. 2008, 3061–3064.
[2] For reviews on the Brook rearrangement, see: a) M. A. Brook, Sili-
con in Organic, Organometallic, and Polymer Chemistry, Wiley, New
York, 2000; b) A. G. Brook, A. R. Bassindale in Rearrangements in
Ground and Excited States (Ed.: P. de Mayo), Academic Press, New
Received: November 29, 2008
Published online: February 16, 2009
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