Kinetic resolution of hindered Morita-Baylis-Hillman adducts by Rh(I)-catalyzed asymmetric 1,4-addition/β-hydroxyelimination

Article abstract of DOI:10.1021/ol202069e

A kinetic resolution of hindered Morita-Baylis-Hillman adducts has been successfully achieved in excellent selectivities via Rh(I)-catalyzed asymmetric 1,4-addition/β-hydroxyelimination with the use of a chiral sulfinamide/olefin hybrid ligand. This study

Full text of DOI:10.1021/ol202069e

ORGANIC
LETTERS
2011
Vol. 13, No. 18
4954–4957
Kinetic Resolution of Hindered
MoritaꢀBaylisꢀHillman Adducts by
Rh(I)-Catalyzed Asymmetric
1,4-Addition/β-Hydroxyelimination
Yazhou Wang, Xiangqing Feng, and Haifeng Du*
Beijing National Laboratory of Molecular Sciences, CAS Key Laboratory of Molecular
Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences,
Beijing 100190, China
haifengdu@iccas.ac.cn
Received July 30, 2011
ABSTRACT
A kinetic resolution of hindered MoritaꢀBaylisꢀHillman adducts has been successfully achieved in excellent selectivities via Rh(I)-catalyzed
asymmetric 1,4-addition/β-hydroxyelimination with the use of a chiral sulfinamide/olefin hybrid ligand. This study provides a novel and efficient
access to both optically active hindered highly functionalized alkenes and MoritaꢀBaylisꢀHillman adducts.
Great progress has been made in the field of transition-
metal-catalyzed 1,4-additions of organometallic reagents
to electron-deficient alkenes. As one excellent subject of
such a transformation, Rh(I)-catalyzed asymmetric reac-
tions between organoboron reagents and R,β-unsaturated
substrates (HayashiꢀMiyaura reaction) have undergone ra-
pid growth and have become an extremely useful synthetic
tool to construct carbonꢀcarbon bonds selectively.1 Particu-
larly, some challenging reactions have been successfully rea-
lized with the use of lately emerging chiral alkene ligands,2ꢀ6
such as asymmetric additions to β,β-disubstituted R,β-unsa-
turated carbonyl compounds to construct all-carbon quatern-
ary stereocenters by Hayashi’s group.7 Although a wide range
(1) For leading reviews, see: (a) Hayashi, T. Synlett 2001, 879. (b)
Fagnou, K.; Lautens, M. Chem. Rev. 2003, 103, 169. (c) Hayashi, T.;
Yamasaki, K. Chem. Rev. 2003, 103, 2829. (d) Gennari, C.; Monti, C.;
Piarulli, U. Pure Appl. Chem. 2006, 78, 303. (e) Christoffers, J.;
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Koripelly, G.; Rosiak, A.; Rossle, M. Synthesis 2007, 1279. (f) Edwards,
H. J.; Hargrave, J. D.; Penrose, S. D.; Frost, C. G. Chem. Soc. Rev. 2010,
39, 2093.
(4) For selected examples of P/alkene hybrid ligands, see: (a) Maire,
€
H.; Grutzmacher, H. Chem.;Eur. J. 2004, 10, 4198. (b) Shintani, R.;
Duan, W.-L.; Nagano, T.; Okada, A.; Hayashi, T. Angew. Chem., Int.
Ed. 2005, 44, 4611. (c) Defieber, C.; Ariger, M. A.; Moriel, P.; Carreira,
E. M. Angew. Chem., Int. Ed. 2007, 46, 3139. (d) Stemmler, R. T.; Bolm,
C. Synlett 2007, 1365. (e) Minuth, T.; Boysen, M. M. K. Org. Lett. 2009,
11, 4212. (f) Shintani, R.; Naruo, R.; Tsutsumi, Y.; Hayashi, S.;
Hayashi, T. Chem. Commun. 2011, 47, 6123.
€
€
P.; Deblon, S.; Breher, F.; Geier, J.; Bohler, C.; Ruegger, H.; Schonberg,
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(2) For reviews on chiral olefin ligands, see: (a) Glorius, F. Angew.
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R.; Hayashi, T. Aldrichimica Acta 2009, 42, 31. (e) Feng, C.-G.; Xu,
M.-H.; Lin, G.-Q. Synlett 2011, 1345.
(3) For selected examples of chiral diene ligands, see: (a) Hayashi, T.;
Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am. Chem. Soc. 2003, 125,
11508. (b) Fischer, C.; Defieber, C.; Suzuki, T.; Carreira, E. M. J. Am.
Chem. Soc. 2004, 126, 1628. (c) Aikawa, K.; Akutagawa, S.; Mikami, K.
J. Am. Chem. Soc. 2006, 128, 12648. (d) Wang, Z.-Q.; Feng, C.-G.; Xu,
M.-H.; Lin, G.-Q. J. Am. Chem. Soc. 2007, 129, 5336. (e) Gendrineau,
T.; Chuzel, O.; Eijsberg, H.; Genet, J.-P.; Darses, S. Angew. Chem., Int.
Ed. 2008, 47, 7669. (f) Brown, M. K.; Corey, E. J. Org. Lett. 2010, 12,
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€
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Breher, F.; Schonberg, H.; Grutzmacher, H. Organometallics 2005, 24,
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Chem., Int. Ed. 2010, 49, 1143.
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L. N.; Steib, A. K.; Raducan, M.; Karaghiosoff, K.; Mayer, P.; Knochel,
P. Org. Lett. 2011, 13, 3182. (b) Jin, S.-S.; Wang, H.; Xu, M.-H. Chem.
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r
10.1021/ol202069e
Published on Web 08/15/2011
2011 American Chemical Society

of electron-deficient alkenes have proven to be suitable
substrates for the asymmetric HayashiꢀMiyaura reactions,
nonactivated R,R,β-trisubstituted alkenes are still challenging
substrates for this type of reaction. Very recently, Darses and
co-workers described a Rh(I)-catalyzed 1,4-addition of aryl-
boronic acids 2 to hindered MoritaꢀBaylisꢀHillman
(MBH) adducts 1followed by a β-hydroxyelimination to fur-
nish functionalized alkenes 3 in up to 91% yield (Scheme 1).8
Two examples for the asymmetric version with C1-symmetric
chiral diene ligands3f developed by their own group gave
the desired products 3 in 25% yield with 84% ee, which
were still not satisfactory, while several well-established
chiral phosphane ligands showed little activity for this
transformation.8a To the best of our knowledge, this is the
only report for asymmetric additions to nonactivated R,R,
β-trisubstituted alkenes. Further studies on this type of
hindered substrates is therefore of great interest.
conversion was still very low. This promising enantioselec-
tivity encouraged us to search for the reason for the low
reactivity. Considering that MBH adduct 1a is a chiral
compound, we supposed that a kinetic resolution was possi-
ble to involve in the recognition process. The ee of recovered
1a was then determined to be 33% for the R configuration.
Calculated according to the reported method,10 the s-factor is
surprisingly as high as 127, which suggests that there indeed
exists an obvious kinetic resolution. Therefore, besides the
highly functionalized optically active alkenes, the current
study is also likely to provide a novel access to optically
active MBH adducts. As we know, MoritaꢀBaylisꢀHillman
reactions have achieved great success, and the resulting MBH
adducts have been widely applied in synthetic chemistry.11
However, the asymmetric reactions of cyclic enones with
aromatic aldehydes are still a challenge.12 Until very recently,
highly enantioselective reactions of cyclopentenone with
aromatic aldehydes were realized by Connell and co-workers
with the use of Fu’s chiral DMAP catalyst.13,14
Scheme 1. Rh(I)-Catalyzed Reactions of Hindered MBH Ad-
ducts
Scheme 2. Initial Studies on Rh(I)-Catalyzed Asymmetric 1,4-
Addition to Hindered MBH Adducts
As part of our interest in exploring novel chiral alkene
ligands for transition-metal-catalyzed asymmetric reactions,
a variety of acyclic chiral dienes as well as hybrid ligands
including P/alkene and sulfinamide/alkene ligands have been
developed.9 Inspired by Darses’s work, we envisaged that
with the use of our chiral alkene ligands, the difficulties for
the asymmetric transformation of nonactivated R,R,β-tri-
substituted alkenes can probably be overcome. Herein, we
wish to report our preliminary efforts on this subject.
Initially, Rh(I)-catalyzed asymmetric 1,4-addition of
phenylboronic acid (2a) to hindered MBH adduct 1a was
examined with the use of chiral diene ligand 49d to afford the
desired product 3aa in 38% conversion and 41% ee. We were
pleased to find that the enantioselectivity could be further
improved to 98% when a chiral sulfinamide/alkene hy-
brid ligand 5a9i was employed (Scheme 2). However, the
A variety of chiral sulfinamide/alkene ligands were sub-
sequently subjected to Rh(I)-catalyzed asymmetric kinetic
resolution of MBH adduct 1a with phenylboronic acid
(2a). As shown in Table 1, it was found that the ligands’
structures had an obvious impact on both activity and
(10) (a) Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1998, 18, 249. (b)
Keith, J. M.; Larrow, J. F.; Jacobsen, E. N. Adv. Syn. Catal. 2001, 343, 5.
(11) For leading reviews on MBH reaction, see: (a) Langer, P. Angew.
Chem., Int. Ed. 2000, 39, 3049. (b) Basavaiah, D.; Rao, A. J.; Satyanarayana,
T. Chem. Rev. 2003, 103, 811. (c) Masson, G.; Housseman, C.; Zhu, J.
Angew. Chem., Int. Ed. 2007, 46, 4614. (d) Singh, V.; Batra, S. Tetrahedron
2008, 64, 4511. (e) Declerck, V.; Martinez, J.; Lamaty, F. Chem. Rev. 2009,
109, 1. (f)Wei, Y.;Shi, M. Acc. Chem. Res. 2010, 43, 1005. (g) Basavaiah, D.;
Reddy, B. S.; Badsara, S. S. Chem. Rev. 2010, 110, 5447.
(7) (a) Shintani, R.; Duan, W.-L.; Hayashi, T. J. Am. Chem. Soc. 2006,
128, 5628. (b) Shintani, R.; Tsutsumi, Y.; Nagaosa, M.; Nishimura, T.;
Hayashi, T. J. Am. Chem. Soc. 2009, 131, 13588. (c) Shintani, R.; Takeda,
M.; Nishimura, T.; Hayashi, T. Angew. Chem., Int. Ed. 2010, 49, 3969.
(8) (a) Gendrineau, T.; Genet, J.-P.; Darses, S. Org. Lett. 2010, 12, 308.
For selected related references, see:(b) Navarre, L.; Darses, S.; Genet, J.-P.
Chem. Commun. 2004, 1108. (c) Navarre, L.; Darses, S.; Genet, J.-P. Adv.
Synth. Catal. 2006, 348, 317. (d) Gendrineau, T.; Demoulin, N.; Navarre,
L.; Genet, J.-P.; Darses, S. Chem.;Eur. J. 2009, 15, 4710.
(9) For chiral diene ligands, see: (a) Hu, X.; Zhuang, M.; Cao, Z.; Du,
H. Org. Lett. 2009, 11, 4744. (b) Hu, X.; Cao, Z.; Liu, Z.; Wang, Y.; Du,
H. Adv. Synth. Catal. 2010, 352, 651. (c) Cao, Z.; Du, H. Org. Lett. 2010,
12, 2602. (d) Wang, Y.; Hu, X.; Du, H. Org. Lett. 2010, 12, 5482. For
P/alkene ligands, see:(e) Liu, Z.; Du, H. Org. Lett. 2010, 12, 3054. (f)
Cao, Z.; Liu, Y.; Liu, Z.; Feng, X.; Zhuang, M.; Du, H. Org. Lett. 2011,
13, 2164. (g) Cao, Z.; Liu, Z.; Liu, Y.; Du, H. J. Org. Chem. 2011, 76,
6401. (h) Liu, Z.; Cao, Z.; Du, H. Org. Biomol. Chem. 2011, 9, 5369. For
sulfinamide/alkene ligands, see:(i) Feng, X.; Wang, Y.; Wei, B.; Yang, J.;
Du, H. Org. Lett. 2011, 13, 3300. (j) Feng, X.; Wei, B.; Yang, J.; Du, H.
Org. Biomol. Chem. 2011, 9, 5927.
(12) For selected examples of MBH reactions of cyclic enones with
aromatic aldehydes, see: (a) McDougal, N. T.; Schaus, S. E. J. Am. Chem.
Soc. 2003, 125, 10294. (b) McDougal, N. T.; Trevellini, W. L.; Rodgen, S. A.;
Kliman, L. T.; Schaus, S. E. Adv. Synth. Catal. 2004, 346, 1231. (c) Sohtome,
Y.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K. Tetrahedron Lett. 2004, 45,
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Lattanzi, A. Synlett 2007, 2106. (g) Shi, M.; Liu, X.-G. Org. Lett. 2008, 10,
1043. (h) Sohtome, Y.; Takemura, N.; Takagi, R.; Hashimoto, Y.; Nagasawa,
K. Tetrahedron 2008, 64, 9423.
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(14) Fu, G. C. Acc. Chem. Res. 2004, 37, 542.
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Org. Lett., Vol. 13, No. 18, 2011
4955

Table 1. Evaluation of Ligandsa
Table 3. Rh(I)-Catalyzed 1,4-Addition/Hydroxyelimination
Reactionsa
ee (3aa)
(%)b
ee
conversion
(%)c
entry ligand
(recovered 1a) (%)b
s-factor10
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
98
98
94
81
80
69
76
90
33
21
10
30
10
18
17
33
25
18
10
27
11
21
18
27
137
122
36
13
9.9
6.5
8.7
13
5g
5h
a All reactions were carried out with 1a (0.20 mmol), 2a (0.40 mmol),
[RhCl(C2H4)2]2 (0.005 mmol), KOH (0.015 mmol), and ligand (0.012 mmol)
in dioxane/MeOH (2/1) (0.60 mL) at 60 °C for 8 h. b The ee was determined
by chiral HPLC. c The conversion was calculated by the following equation:
conversion = ee (recovered 1a)/[ee (recovered 1a) þ ee (3aa)].
selectivity. All of the reactions gave the desired product 3aa
with 76ꢀ98% ee, but the conversions were very low, which
resulted in low ee for recovered MBH adduct 1a (entries
1ꢀ8). Overall, ligand 5a proved to be the most suitable ligand
for this kinetic resolution (Table 1, entry 1).
With the use of chiral ligand 5a, the ee of product 3aa and
the s-factor have already reached a high level. The key point
is how to improve the reactivity. Therefore, various reaction
conditions were further optimized. We were pleased to find
that by increasing the amount of KOH from 7.5 mol % to
50 mol % the conversion can be improved from 25% to
Table 2. Optimization of Reaction Conditionsa
temp
KOH
ee for 3aa ee for 1a
conv
s-
entry (°C)
(mol %)
(%)e
(%)e
(%)f factor10
1
60
60
60
60
60
50
30
16
30
30
7.5
25
98
98
97
90
97
98
97
99
97
92
33
40
55
26
65
69
83
48
87
64
25
29
36
22
40
42
46
33
47
41
137
147
114
24
2
3
50
4
100
50
5
129
207
172
321
188
46
6
50
7b
8b
9c
10c,d
50
a All reactions were carried out with 1 (0.40 mmol), 2a (0.80 mmol),
[RhCl(C2H4)2]2 (0.010 mmol), KOH (0.20 mmol), and 5a (0.024 mmol)
in dioxane/MeOH (10/1) at 30 °C under argon for 24 h unless other stated.
b The reaction was carried out in 0.2 mmol scale for 21 h. c Yield based on 1.
d The ee was determined by chiral HPLC. e The absolute configuration was
tentatively assigned by analogy with 3ea. f The absolute configuration was
determined by comparing the optical rotation with the reported one.
50
50
50
a All reactions were carried out with 1a (0.20 mmol), 2a (0.40 mmol),
[RhCl(C2H4)2]2 (0.005 mmol), and 5a (0.012 mmol) for 8 h unless other
stated. For entries 1ꢀ4, dioxane/MeOH (2/1) (0.60 mL) was used as
solvent; for entries 5ꢀ10, dioxane/MeOH (10/1) (0.60 mL) was used as
solvent. b The reaction time was 16 h. c The reaction time was 21 h.
d Ligand 5a (55/45 dr) was used. e The ee was determined by chiral
HPLC. f The conversion was calculated by the following equation:
conversion = ee (recovered 1a)/[ee (recovered 1a) þ ee (3aa)].
36% (Table 2, entries 1 vs 3). However, when the amount of
KOH was further increased to 100 mol %, both the con-
version and ee dropped (Table 2, entry 4). Temperature was
4956
Org. Lett., Vol. 13, No. 18, 2011

another key factor to affect the reactivity. When the tem-
perature was lowered from 60 to 30 °C, the conversion was
improved to 47%, and accordingly, excellent ee values for
product 3aa and recovered 1a were afforded (Table 2, entry 9).
Moreover, ligand 5a with55/45 dr was alsoeffective for the
kinetic resolution to give a slightly lower ee and conversion
(Table 2, entry 10), which indicated that it was the sulfur
chirality instead of the carbon chirality to determine the
process of recognition and asymmetric induction.9i
Under the optimized reaction conditions, we next exam-
ined the scope of hindered MBH adducts 1 for Rh(I)-
catalyzed kinetic resolution reactions with phenylboronic
acid (2a). As illustrated in Table 3, different substituents on
phenyl groups of MBH adducts 1 were well tolerated to
furnish the optically active alkenes in 26ꢀ44% yield with
95ꢀ99% ee, and the recovered MBH adducts 1 in 43ꢀ61%
yield with 44ꢀ97% ee as well (s-factor = 155ꢀ419, Table 3,
entries 1ꢀ9). Although MBH adducts derived from cyclo-
hexanone were good substrates in Darses’s work,8a disap-
pointingly, we found these substrates were less reactive for
the current kinetic resolution (<20% conversion). A variety
of arylboronic acids were also tolerated for Rh(I)-catalyzed
kinetic resolution reactions of MBH adducts 1a or 1e to give
the desired products 3 in 22ꢀ48% yield with 89ꢀ98% ee
(Table 4, entries 1ꢀ8). However, ortho-substituted MBH
adducts and arylboronic acids were not suitable substrates
for this type of transformation, which was possibly due to
the bulky steric hindrance. The absolute configurations
of product 3 were tentatively assigned by analogy with
compound (S)-3ea, which was determined by its X-ray
structure (see Supporting Information).
On the basis of the previously reported X-ray structure of
complex formed between chiral ligand 5a and [RhCl-
(C2H4)2]2,9i the absolute configurations of products and
recoveredMBH adducts, and somerelatedliterature,8d,15
a
plausible pathway for the asymmetric kinetic resolution is
outlined as Figure 1. According to the literature,8d,15 the
hydroxyl group of MBH adduct was supposed to coordi-
nate with rhodium. Because of the steric repulsions in B, C,
and D, only (S)-1a can coordinate with rhodium as A to
give the corresponding product with S configuration.
Figure 1. A plausible pathway for the asymmetric kinetic resolution.
Table 4. Rh(I)-Catalyzed 1,4-Addition/Hydroxyelimination
Reactions with Various Arylboronic Acidsa
In summary, highly enantioselective Rh(I)-catalyzed 1,
4-addition/β-hydroxyelimination reactions of nonactivated
hindered MBH adducts and arylboronic acids have been
successfully achieved with the use of a simple chiral sulfina-
mide/olefin ligand. Importantly, we found for the first time
that there existed a kinetic resolution with an s-factor of up to
419 in this transformation. Therefore, besides the highly
functionalized chiral alkenes (up to 99% ee), this work also
provides a novel access to optically active MBH adducts
(up to 97% ee), which are not easily prepared by catalytic
asymmetric MBH reactions. Further studies on expanding
the substrate scope, exploring more efficient catalysts, and the
application of chiral sulfinamide/olefin ligands in asymmetric
catalysis are underway in our laboratory.
3 ee (yield) recovered 1 ee
entry
ArB(OH)2
(%)b,c,d
(yield) (%)b,c,e s-factor10
1
2
3
4
5
2b: Ar = 4-MeC6H4 3ab: 96 (33) 1a: 67 (53)
2c: Ar = 2-Np 3ac: 89 (25) 1a: 38 (68)
2d: Ar = 4-tBuC6H4 3ed: 98 (44) 1e: 93 (45)
99
25
340
134
45
2e: Ar = 4-PhC6H4
2f: Ar =
3ee: 96 (43) 1e: 85 (37)
3ef: 93 (32) 1e: 50 (55)
4-HOCH2C6H4
6
7
8
2g: Ar = 3-MeC6H4 3eg: 95 (48) 1e: 94 (44)
2h: Ar = 3-ClC6H4 3eh: 98 (22) 1e: 32 (62)
2i: Ar = 3,5-Me2C6H3 3ei: 92 (39) 1e: 66 (50)
139
135
48
Acknowledgment. The authors are thankful for the finan-
cial support from the National Science Foundation of China
(20802079, 21072194) and 973 program (2010CB833300).
a All reactions were carried out with 1a (0.40 mmol) (for entries 1 and 2)
or 1e (0.4 mmol) (for entries 3ꢀ8), [RhCl(C2H4)2]2 (0.010 mmol), 2
(0.80 mmol), KOH (0.20 mmol), and 5a (0.024 mmol) in dioxane/MeOH
(10/1) at 30 °C under argon for 24 h unless other stated. b Yield based on 1.
c The ee was determined by chiral HPLC. d The absolute configuration
was tentatively assigned by analogy with 3ea. e The absolute config-
uration was determined by comparing the optical rotation with the
reported one.
Supporting Information Available. The procedure for
rhodium-catalyzed additions, characterization of products,
X-ray data, and data for the determination of enantiomeric
excesses. This material is available free of charge via the
Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 18, 2011
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