Remote induction of stereoselective 1,2-addition of aryl Grignard reagents to β-sulfinyl enones

Article abstract of DOI:10.1016/j.tetlet.2013.12.108

Optically active tert-allylic alcohols constitute important and often challenging targets in organic synthesis. In this work, we employed a β-sulfinyl moiety as a remote chiral auxiliary to effect asymmetric 1,2-addition of aryl Grignard reagents to enones to form a variety of optically active tert-allylic alcohols. The absolute configuration of a representative alcohol product was determined by X-ray crystallography.

Full text of DOI:10.1016/j.tetlet.2013.12.108

Tetrahedron Letters 55 (2014) 1090–1092
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Remote induction of stereoselective 1,2-addition of aryl Grignard
q
reagents to b-sulfinyl enones
a
a,
⇑
a
a
Toshinori Nakakita , Motofumi Miura , Masaharu Toriyama , Shigeyasu Motohashi ,
Mikhail V. Barybin
a
b
School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi-shi, Chiba 274-8555, Japan
Department of Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045, United States
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Optically active tert-allylic alcohols constitute important and often challenging targets in organic
synthesis. In this work, we employed a b-sulfinyl moiety as a remote chiral auxiliary to effect asymmetric
Received 29 October 2013
Revised 20 December 2013
Accepted 25 December 2013
Available online 3 January 2014
1,2-addition of aryl Grignard reagents to enones to form a variety of optically active tert-allylic alcohols.
The absolute configuration of a representative alcohol product was determined by X-ray crystallography.
Ó 2014 The Authors. Published by Elsevier Ltd. All rights reserved.
Keywords:
Chiral sulfoxide
Diastereoselectivity
Arylation
Grignard reagent
Tertiary alcohol motifs are known to exert a broad gamut of bio-
logical activities and are found in the structures of numerous nat-
ural products and pharmaceuticals, such as various prostaglandin
(Luche reduction),10 an asymmetric 2,3-sigmatropic rearrange-
1
1
ment of
a-sulfinyl enones under mild conditions, and a remote
stereocontrolled reduction of b-sulfinyl enones using NaBH
4
or
1
12
derivatives, (+)-sydonol tetrodotoxicin, etc. Given that many bio-
DIBAL (diisobutylaluminum hydride) with LaCl
To date, numerous examples of asymmetric transformations of
-sulfinyl ketones and -sulfinyl enones have been reported. In
3
.
active compounds feature a chiral quaternary carbon within a ter-
tiary alcohol moiety, the development of new and/or improved
methods for accessing enantiopure tertiary alcohols constitutes
an important challenge in synthetic organic chemistry. The strate-
gies that have been considered thus far in this regard include ster-
eoselective nucleophilic addition to ketones,2 rearrangements,
a
a
these reactions, the formation of a six-membered ring via interac-
tion of the sulfoxide’s oxygen atom and the carbonyl’s oxygen
atom with a Lewis-acidic metal ion has been invoked as a key tran-
sition state. However, only a few examples of remotely induced
asymmetric reactions of b-sulfinyl ketones and b-sulfinyl enones
have been documented. Herein, we describe the use of a remote
b-sulfinyl chiral auxiliary in stereoselective 1,2-addition of aryl
Grignard reagents to b-sulfinyl enones to afford optically pure ter-
tiary and secondary chiral allylic alcohols.
3
4
stereospecific insertion of carbenes into secondary alcohols, and
5
asymmetric oxidation.
Stereoselective transformations facilitated by a chiral sulfoxide
auxiliary have proven useful in a variety of synthetic applications
and the ability to prepare such compounds with high enantiomeric
excess offers significant practical benefit. In particular, optically
active sulfinyl aldehydes, sulfinyl ketones, and sulfinyl enones have
been employed to effect a range of asymmetric reduction transfor-
mations, Diels–Alder reactions,7 1,2-additions,8 and aldol reac-
Optically active (Z)-b-sulfinyl enones 1 were readily prepared
12
from l-menthyl-(À)-(S)-toluenesulfinate in four steps. Table 1
summarizes the results of 1,2-addition of different Grignard re-
agents to enone (Ss)-1a in the presence or absence of a Lewis acid.
An analogous 1,2-addition of PhMgI to (Ss)-1a was considered as
well. Combining 1a with 1.0 equiv of PhMgI at À78 °C produced
no reaction and led to the complete recovery of the starting material
6
9
tions. We have previously reported on a highly stereoselective
4 3
reduction of a-sulfinyl enones using NaBH with YbCl in methanol
1
a (entry 1). However, employing 2 equiv of the Grignard reagent
q
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Commons Attribution-NonCommercial-No Derivative Works License, which per-
mits non-commercial use, distribution, and reproduction in any medium, provided
the original author and source are credited.
under otherwise identical conditions afforded, after workup, the
corresponding tertiary alcohol 2a in a moderate yield with a high
stereoselectivity (entry 2). Encouraged by this observation, we in-
creased the amount of PhMgI used to 5 equiv, which afforded 2a
in a good yield while maintaining the high stereoselectivity of the
⇑
Corresponding author. Tel./fax: +81 47 465 6362.
E-mail address: miura.motofumi@nihon-u.ac.jp (M. Miura).
0
040-4039/$ - see front matter Ó 2014 The Authors. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.12.108

T. Nakakita et al. / Tetrahedron Letters 55 (2014) 1090–1092
1091
Table 1
1
,2-Addition of (Z)-b-sulfinyl enone 1a
R
OH
O
O
S
HO
R
O
S
O
RM
S
+
THF
0.5 h
(
Ss)-1a
(Ss, R)-2a
(Ss,S)-2a
Entrya
1
RM
PhMgI
1.0 equiv)
PhMgI
2.0 equiv)
PhMgI
5.0 equiv)
PhMgI
5.0 equiv)
PhMgBr
5.0 equiv)
PhMgI
5.0 equiv)
PhMgI
5.0 equiv)
PhLi
5.0 equiv)
MeMgI
5.0 equiv)
i-PrMgBr
5.0 equiv)
Temp
Lewis acid
D.r. (R:S)b
Yieldc (%)
0
À78 °C
À78 °C
À78 °C
rt
(
2
3
4
5
6
7
8
9
99.5:0.5
99.1:0.9
98.0:2.0
98.5:1.5
98.3:1.7
97.2:2.8
99.5:0.5
23:77
59
88
81
85
27
37
6
(
(
(
Figure 1. X-ray crystal structure of 2g.
À78 °C
À78 °C
À78 °C
À78 °C
À78 °C
À78 °C
(
LaCl
3
(
poor yield (entry 8). Interestingly, attempts to use alkyl Grignard re-
agents, namely MeMgI and iPrMgBr, gave good yields of 2a but were
accompanied by inversion or essentially complete loss of the diaste-
reoselectivity of the addition (entries 9 and 10). The above observa-
tions provide some mechanistic hints regarding the interaction of
YbCl
3
(
(
86
71
(
1
a with PhMgI. It is reasonable to postulate that the phenyl ring of
1
0
49:51
(
PhMgI may engage in noncovalent interaction with the para-to-
p–p
lyl moiety by approaching 1a from the side opposite to sulfur’s lone
pair. The magnesium atom is then chelated by sulfoxide’s oxygen
and carbonyl’s oxygen atoms, which facilitates the insertion of the
C@O moiety into the aryl–Mg bond.
a
b
c
Reactions were carried out on a 50 mg scale at 0.19 mmol of (Ss)-1a.
1
The diastereoisomeric ratio was determined by H NMR of the crude product.
1
The yield was determined by H NMR analysis of the crude product using
2 2
CH Br as an internal standard.
We further investigated the scope of this reaction by consider-
ing variously substituted substrates 1 and the results of the series
of experiments are given in Table 2. Enones 1b–l were synthesized
following the general protocol developed for the preparation of
reaction (entry 3). Conducting the reaction at room temperature or
using the bromide- instead of iodide-containing Grignard reagent
caused a slight decrease in the stereoselectivity of the addition
1
2
1
a. The 1,2-addition of PhMgI proved to be almost completely
stereoselective in all cases and provided good yields of the corre-
sponding alcohols with the exception of entry 10 in Table 2. Com-
pound 1j features a phenyl group at the R position in its structure.
(
entries 4 and 5). The presence of a Lewis acid in the reaction mix-
ture had a critically detrimental effect on the yield of the alcohol
product (entries 6 and 7). Finally, employing 5 equiv of PhLi instead
of PhMgI afforded 2a with an excellent diastereomeric ratio but in a
2
This phenyl ring may compete with the para-tolyl moiety of 1j for
Table 2
Diastereoselective 1,2-addition reactions of (Ss)-1a–1l
Ph
HO
HO
O
R1
R2
R1
R2
Ph
R1
R2
O
S
PhMgI (5.0 equiv)
THF
O
O
S
S
+
-
78 oC / 0.5 h
(
Ss)-1a-1l
(Ss,R)-2a-2l
(Ss,S)-2a-2l
Entry
Substrate
R1
Product
R2
D.r. (R:S)a
Yieldb (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
n-Bu
H
H
Me
Me
Me
2a
2b
2c
2d
2e
2f
2g
2h
2i
99.1:0.9
91.0:9.0
91.0:9.0
100:0
85
74
70
84
80
76
86
76
66
33
63
71
i-Pr
n-Bu
Me
i-Pr
n-Bu
Et
Et
i-Pr
Ph
100:0
Me
Me
99.7:0.3
99.4:0.6
99.0:1.0
99.8:0.2
100:0
n-Bu
n-Bu
n-Bu
n-Bu
i-Bu
10
11
12
1j
1k
1l
2j
2k
2l
n-Bu
n-Bu
99.3:0.7
99.0:1.0
a
The diastereoisomeric ratio was determined by 1H NMR analysis of the crude product.
Isolated yield, average of two runs.
b

1
092
T. Nakakita et al. / Tetrahedron Letters 55 (2014) 1090–1092
Table 3
substrates 2 were treated with magnesium mono perphthalate
MMPP) followed by desulfurization from sodium amalgam (Na–
Diastereoselective 1,2-addition reactions of (Ss)-1d
(
R
HO
Hg), and the corresponding optically active tertiary allylic alcohols
were obtained in good yield. When the oxidation reaction was car-
ried out using MCPBA as a oxidation reagent, the quaternary car-
bon was somewhat racemized and afforded the allylic alcohol
with slightly decreased enantiomeric ratio (S:R = 80:20; data not
shown).
In conclusion, we have developed the highly stereoselective 1,2-
addition of aryl Grignard reagents to b-sulfinyl enones to afford the
corresponding chiral tertiary alcohols in excellent diastereomeric
O
HO
R
O
S
O
S
O
S
RMgI (5.0 equiv)
THF
+
78 oC / 0.5 h
-
(
Ss)-1d
(
Ss, R)-3a-3d
(Ss, S)-3a-3d
Yieldb (%)
Entry
R
D.r. (R:S)a
Product
1
2
3
4
4-H
4-ClC
4-H
3-H
3
COC
H
4
6
H
4
93:7
98:2
92:8
93:7
3a
3b
3c
3d
69
77
80
69
6
3
CC
CC
6
H
H
4
purity. The reaction is considered to be facilitated by the p–p inter-
3
6
4
action between the para-tolyl substituent of the sulfinyl enone
with the aryl moiety of the Grignard reagent and to involve forma-
tion of the seven-membered Mg-chelate ring. These results provide
a new useful synthetic strategy that can be applied to the prepara-
tion of various natural products and other bioactive compounds
containing chiral alcohol building blocks.
a
The diastereoisomeric ratio determined by 1H NMR analysis of the crude
product.
b
Isolated yield, average of two runs.
Table 4
Removal of sulfoxide moiety
Acknowledgments
Ph
HO
R
1
O
1. MMPP
OH
1Ph
H2C
R2
The authors thank the Analytical Center of the School of
Pharmacy, Nihon University and the Center for Analytical Instru-
mentation, Chiba University for the X-ray crystallographic
assistance.
S
R2
2
. Na-Hg
R
2a, 2c, 2d, 2f
4a, 4c, 4d, 4f
Entry
1
Substrate (d.r.)
R1
R2
2 Steps yielda (%)
76
E.r. (S:R)b
Supplementary data
2a
n-Bu
H
Me
n-Bu
Me
Et
97:3
(99.1:0.9)
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.12.
2
3
4
2c
81
65
78
86:14
96:4
92:8
(91.0:9.0)
2d
Me
1
08.
(100:0)
2h
n-Bu
References and notes
(99.0:1.0)
a
Isolated yield.
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electron-withdrawing groups in the para-position of the Grignard
reagent’s aromatic ring led to somewhat decreased diastereoiso-
meric ratios for the products 3a–3d under identical reaction condi-
tions. Nevertheless, the chiral sulfoxide auxiliary was still quite
effective in controlling the stereoselectivity of 1,2-addition to b-
sulfinyl enones thereby providing a new useful method for the syn-
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alcohols. These results are shown in Table 4. Variously substituted