Rhodium-catalyzed asymmetric addition of arylboronic acids to β-nitroolefins: Formal synthesis of (S)-SKF 38393

Article abstract of DOI:10.1021/ol4027599

An efficient enantioselective addition of an array of arylboronic acids to various β-nitrostyrenes catalyzed by a novel and reactive rhodium-diene catalyst (S/C up to 1000) was developed, providing β,β- diarylnitroethanes in good to high yields (62-99%) with excellent enantioselectivities (85-97% ee). The method was extended to 2-heteroarylnitroolefins and 2-alkylnitroolefins similarly providing the desired products with high enantioselectivities and yields. The usefulness of this method was demonstrated in the formal synthesis of the enantiomer of the dopamine receptor agonist and antagonist, SKF 38393.

Full text of DOI:10.1021/ol4027599

ORGANIC
LETTERS
2013
Vol. 15, No. 22
5730–5733
Rhodium-Catalyzed Asymmetric Addition
of Arylboronic Acids to β‑Nitroolefins:
Formal Synthesis of (S)‑SKF 38393
Kung-Chih Huang,† Balraj Gopula,† Ting-Shen Kuo,‡ Chien-Wei Chiang,†
Ping-Yu Wu,§ Julian P. Henschke,§ and Hsyueh-Liang Wu*,†
Department of Chemistry and Instrumentation Center, Department of Chemistry, National
Taiwan Normal University, No. 88, Section 4, Tingzhou Road Taipei 11677, Taiwan,
Republic of China, and ScinoPharm Taiwan, No. 1, Nan-Ke eighth-Road Taiwan Science-
Based Industrial Park, Shan-Hua, Tainan County, 74144, Taiwan, Republic of China
hlw@ntnu.edu.tw
Received September 24, 2013
ABSTRACT
An efficient enantioselective addition of an array of arylboronic acids to various β-nitrostyrenes catalyzed by a novel and reactive rhodiumÀdiene
catalyst (S/C up to 1000) was developed, providing β,β-diarylnitroethanes in good to high yields (62À99%) with excellent enantioselectivities
(85À97% ee). The method was extended to 2-heteroarylnitroolefins and 2-alkylnitroolefins similarly providing the desired products with high
enantioselectivities and yields. The usefulness of this method was demonstrated in the formal synthesis of the enantiomer of the dopamine
receptor agonist and antagonist, SKF 38393.
4-Aryltetrahydroisoquinolines1 and 1-aryl-2,3,4,5-tetra-
hydro-1H-3-benzazepines2 are synthetic targets of consider-
able interest owing to their biological and pharmacological
activities. Cherylline is a type of 4-aryl-substituted tetra-
hydroisoquinoline that affects the central nervous system
(Figure 1),1a while SCH 23390 and SCH 39166 are typical
examples of potent benzazepine D1/D5 antagonists.2f
Common to both of these types of alkaloids is the β,β-diaryl-
ethylamine moiety. The enantioselective conjugate addition
of aryl nucleophiles to β-nitrostyrenes followed by the
reduction of nitro groups appears to be the most straightfor-
ward method for accessing such chiral β,β-diarylethylamines.
While organocatalytic FriedelÀCrafts-type conjugate
addition reactions efficiently provide the corresponding
adducts, good selectivity is achievedonly using certain sub-
strates.3 In pioneering work in the field of transition-metal-
catalyzed asymmetric conjugate addition reactions,4
Hayashi et al. reported a rhodiumÀBINAP5 catalyst for
† Department of Chemistry, National Taiwan Normal University.
‡ Instrumentation Center, Department of Chemistry, National Taiwan
Normal University.
§ ScinoPharm Taiwan.
(1) (a) Omer, L. M. Int. Clin. Pharmacol. Ther. Toxicol. 1982, 20, 320.
(b) The Chemistry and Biology of Isoquinoline Alkaloids; Phillipson, J. D.,
Roberts, M. F., Zenk, M. H., Eds.; Springer: Berlin, 1985. (c) Medicinal
Natural Products; Dewick, P. M., Ed.; Wiley-VCH: Weinheim, 2002; pp
315À346. (d) Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102, 1669.
(e) Bentley, K. W. Nat. Prod. Rep. 2006, 23, 444.
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Ding, L. S.; Chen, Y. C. Chem. Commun. 2007, 2228. (b) Zhang, H.;
Liao, Y. H.; Yuan, W. C.; Zhang, X. M. Eur. J. Org. Chem. 2010, 3215.
(c) Sohtome, Y.; Shin, B.; Horitsugi, N.; Takagi, R.; Noguchi, K.;
Nagasawa, K. Angew. Chem., Int. Ed. 2010, 49, 7299.
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H. M.; Setler, P. E.; Bass, L. S. J. Med. Chem. 1982, 25, 697. (b)
Neumeyer, J. L.; Baindur, N.; Yuan, J.; Booth, G.; Seeman, P.; Niznik,
H. B. J. Med. Chem. 1990, 33, 521. (c) Petterson, I.; Liljefors, T.; Bogeso,
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Niznik, H. B.; Guan, H. C.; Seeman, P. J. Med. Chem. 1991, 34, 3366. (e)
Shah, J. H.; Izenwasser, S.; Geter-Douglass, B.; Witkin, J. M.; Newman,
A. H. J. Med. Chem. 1995, 38, 4284. (f) Wu, W.-L.; Burnett, D. A.;
Spring, R.; Greenlee, W. J.; Smith, M.; Favreau, L.; Fawzi, A.; Zhang,
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(4) (a) Conjugate Addition Reactions in Organic Synthesis; Perlmutter,
P., Ed.; Pergamon Press: Oxford, UK, 1992. (b) Schmalz, H.-G., Compre-
hensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon:
Oxford, UK, 1991; Vol. 4, Chapter 1.5. (c) Rossiter, B. E.; Swingle,
N. M. Chem. Rev. 1992, 92, 771. (d) Tomioka, K.; Nagaoka, Y.
Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto,
H., Eds.; Springer-Verlag: Berlin, 1999; Chapter 31.1 (e) Yamaguchi, M.
Comprehensive Asymmetric Synthesis; Jacobsen, E. N., Pfaltz, A., Yamamoto,
H., Eds.; Springer-Verlag: Berlin, 1999; Chapter 31.2. (f) Krause, N.; Hoffmann-
Roder, A. Synthesis 2001, 171.
r
10.1021/ol4027599
Published on Web 10/30/2013
2013 American Chemical Society

the asymmetric 1,4-addition of arylboronic acids to var-
ious electron-deficient olefins.6,7 Recently, enthusiasm for
the use of stable and optically active diene ligands as chiral
modifiers in the field of rhodium-catalyzed asymmetric
transformations has surged owing to the high catalytic
activity and enantioselectivity that they impart on the
catalyst.8 In the only example of catalysis of this reaction
using a rhodium complex of a chiral diene ligand, Lin et al.
described the high-yielding and enantioselective arylation
of a variety of β-nitrostyrenes.9 Like Lin’s C2-symmetric
chiral bicyclo[3.3.0]diene ligands, chiral sulfoxideÀ
phosphine10a,b and sulfoxideÀolefin ligands10c have proven
effective ligands in the conjugate addition of arylboronic
acids to β-nitrostyrenes.10
found to be effective in asymmetric arylation of R,β-
unsaturated carbonyl compounds.11 Both acyclic and cyclic
substrates were effective reaction partners with excellent
stereocontrol, reactivity, and efficiency (TON up to 2000)
when arylboronic acids were used as nucleophiles. In light of
the importance of chiral β,β-diarylnitroethanes as building
blocks, we herein report improvements upon the single
previously reported study9 of RhÀdiene ligand catalyzed
asymmetric arylation of nitroolefins using our own novel
ligands that allow significantly reduced catalyst loadings
and reaction temperature while exhibiting comparable re-
activity. This asymmetric arylation of β-nitrostyrenes was
epitomized by catalysis at 50 °C using only 0.25 mol % of a
rhodium dimer complex of chiral diene 1d (0.5 mol % of
Rh), yielding enantioenriched β,β-diarylnitroethanes with
up to 97% ee.
Initially, a model conjugate addition reaction of phenyl-
boronic acid (3a) to β-arylnitroalkene 2a was investigated
in the presence of 3 mol % of Rh-1a catalyst that was
prepared in situ (Table 1). When our previously deter-
mined optimized reaction conditions for asymmetric 1,4-
addition reactions to carbonyl compounds were used here-
in toeffectthistransformation, none of the desiredproduct
was observed (entries 1 and 2).11,12 The use of KHF2 as an
additive,9 however, successfully promoted the conjugate
addition, giving the adduct 4aa in 67% chemical yield and
moderate asymmetric induction (50% ee) (entry 3). Pleas-
ingly, while the previous report using a RhÀbicyclo-
[3.3.0]diene complex required 100 °C, our RhÀdiene
complex was effective at only 50 °C indicating improved
kinetics. While the role of KHF2 remains unknown, the
corresponding potassium organotrifluoroborate, formed
in situ from the reaction of the organoboronic acid and
KHF2, was speculated to be the active nucleophilic species
in the catalytic cycle;9 however, only a trace amount of
product 4aa was obtained when potassium phenyltrifluor-
oborate was used as a nucleophile (entry 4).13,14 Subse-
quently, the use of our novel 2,5-diarylsubstituted ligands
1bÀh was examined in conjuction with KHF2 as an
additive (entries 5À11). Ligand 1d, with 1-naphthyl sub-
stituents, was the most stereoselective among those tested.
The addition reaction, catalyzed by 3 mol % of Rh-1d,
generated in situ from 1.5 mol % of [RhCl(C2H4)2]2 and
3.6 mol % of chiral diene 1d, was completed at 50°C within
1.5 h in toluene to yield compound 4aa in 85% yield with
92% ee (entry 7). Solvent screening using ligand 1d and
KHF2 as an additive showed that while xylenes and THF
gave comparable results (entries 12 and 13, respectively),
Figure 1. Biologically active compounds.
During recent development of rhodium-catalyzed asym-
metric transformations for the synthesis of biologically
active compounds, we discovered and developed a novel
family of stable chiral C1-symmetric 2,5-diarylbicyclo-
[2.2.1]dienes 1, derived from (À)-bornyl acetate, that were
(5) (a) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura,
N. J. Am. Chem. Soc. 1998, 120, 5579. (b) Takaya, Y.; Senda, T.;
Kurushima, H.; Ogasawara, M.; Hayashi, T. Tetrahedron: Asymmetry
1999, 10, 4047. (c) Sakuma, S.; Sakai, M.; Itooka, R.; Miyaura, N.
J. Org. Chem. 2000, 65, 5951. (d) Senda, T.; Ogasawara, M.; Hayashi, T.
J. Org. Chem. 2001, 66, 6852.
(6) (a) Miyaura, N. Organoboranes for Syntheses; Ramachandran,
P. V., Brown, H. C., Eds.; American Chemical Society: Washington, D.C.,
2001; pp 94À107. (b) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103,
2829. (c) Hayashi, T. Pure. Appl. Chem. 2004, 76, 465.
(7) (a) Hayashi, T.; Senda, T.; Ogasawara, M. J. Am. Chem. Soc.
2000, 122, 10716. (b) Dong, L.; Xu, Y. J.; Cun, L. F.; Cui, X.; Mi, A. Q.;
Jiang, Y. Z.; Gong, L. Z. Org. Lett. 2005, 7, 4285. (c) Dong, L.; Xu, Y. J.;
Yuan, W. C.; Cui, X.; Cun, L. F.; Gong, L. Z. Eur. J. Org. Chem. 2006,
4093.
(8) For seminal reviews, see: (a) Glorius, F. Angew. Chem., Int. Ed.
€
2004, 43, 3364. (b) Defieber, C.; Grutzmacher, H.; Carreira, E. M.
Angew. Chem., Int. Ed. 2008, 47, 4482. (c) Shintani, R.; Hayashi, T.
Aldrichimica Acta 2009, 42, 31. (d) Tian, P.; Dong, H.-Q.; Lin, G.-Q.
ACS Catal. 2012, 2, 95. For pioneering research work employing chiral
diene ligands for asymmetric catalysis, see: (e) Hayashi, T.; Ueyama, K.;
Tokunaga, N.; Yoshida, K. J. Am. Chem. Soc. 2003, 125, 11508. (f)
Fischer, C.; Defieber, C.; Suzuki, T.; Carreira, E. M. J. Am. Chem. Soc.
2004, 126, 1628. For the substituent effects of chiral diene ligands on ee,
see: (g) Gendrineau, T.; Chuzel, O.; Eijsberg, H.; Genet, J.-P.; Darses, S.
Angew. Chem., Int. Ed. 2008, 47, 7669. (h) Gendrineau, T.; Genet, J.-P.;
Darses, S. Org. Lett. 2009, 11, 3486.
(11) (a) Wei, W.-T.; Yeh, J.-Y.; Kuo, T.-S.; Wu, H.-L. Chem.;Eur.
J. 2011, 17, 11405. (b) Liu, C.-C.; Janmanchi, D.; Chen, C.-C.; Wu,
H.-L. Eur. J. Org. Chem. 2012, 2503. (c) Chung, Y.-C.; Janmanchi, D.;
Wu, H.-L. Org. Lett. 2012, 14, 2766. (d) Wu, H.-L.; Chen, C.-C.; Liu,
C.-C.; Wei, W.-T.; Fang, J.-H. U.S. Pat. Appl. 2013/0096348 A1.
(12) Under the same conditions, raising the reaction temperature to
100 °C provided no desired product after 24 h.
(13) Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf,
M. R. J. Org. Chem. 1995, 60, 3020.
(14) For reviews, see: (a) Molander, G. A.; Figueroa, R. Aldrichimica
Acta 2005, 38, 49. (b) Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007,
40, 275. (c) Stefani, H. A.; Cella, R.; Vieira, A. S. Tetrahedron 2007, 63,
3623. (d) Darses, S.; Genet, J.-P. Chem. Rev. 2008, 108, 288.
(9) Wang, Z. G.; Feng, C. G.; Zhang, S. S.; Xu, M. H.; Lin, G. Q.
Angew. Chem., Int. Ed. 2010, 49, 5780.
(10) (a) Lang, F.; Chen, G.; Li, L.; Xing, J.; Han, F.; Cun, L.; Liao, J.
Chem.;Eur. J. 2011, 17, 5242. (b) Xing, J.; Chen, G.; Cao, P.; Liao, J.
Eur. J. Org. Chem. 2012, 1230. (c) Xue, F.; Wang, D. P.; Li, X. C.; Wan,
B. S. J. Org. Chem. 2012, 77, 3071. (d) Boiteau, J. G.; Imbos, R.;
Minnaard, A. J.; Feringa, B. L. Org. Lett. 2003, 5, 681. (e) Duursma, A.;
Hoen, R.; Schuppan, J.; Hulst, R.; Minnaard, A. J.; Feringa, B. L. Org.
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B. L. Tetrahedron: Asymmetry 2005, 16, 1901.
Org. Lett., Vol. 15, No. 22, 2013
5731

Table 1. Asymmetric Conjugate Addition of PhB(OH)2 to
β-Nitroalkene 2a Catalyzed by Rh-1a
Table 2. Asymmetric Conjugate Addition to Substituted
β-Nitrostyrenes 2 Catalyzed by [RhCl(1d)]2
a
entry
2
Ar
time (h)
yieldb (%)
eec (%)
1
2a C6H5 (3a)
4
6.5
23
21
72
5
99 (S-4aa)
94 (R-4ab)
81 (R-4ac)
96 (R-4ad)
83 (R-4ae)
90 (R-4af)
82 (R-4ag)
68 (R-4ah)
67 (R-4ai)
99 (R-4aj)
90 (R-4ak)
77 (R-4al)
71 (R-4am)
90 (R-4an)
70 (R-4ao)
85 (R-4aa)
94 (R-4bb)
81 (S-4ab)
93 (S-4dp)
71 (S-4ea)
89 (R-4fp)
62 (R-4fl)
92 (R-4fe)
99 (R-4gp)
70 (R-4gl)
94 (R-4ge)
81 (R-4ha)
86 (R-4hl)
93 (R-4ia)
82 (R-4il)
92
93
94
94
94
93
95
91
93
89
91
97
95
96
91
90
93
89
91
95
89
90
92
91
91
92
95
91
89
85
entry ligand time (h) additive solvent yieldb (%) eec (%)
2d
3
2a 4-ClC6H4 (3b)
2a 3-NO2C6H4 (3c)
2a 4-NO2C6H4 (3d)
2a 4-CNC6H4 (3e)
2a 4-CF3C6H4 (3f)
2a 4-FC6H4 (3g)
2a 3-ClC6H4 (3h)
2a 3-CF3C6H4 (3i)
2a 4-tBuC6H4 (3j)
2a 3-MeOC6H4 (3k)
2a 4-MeOC6H4 (3l)
2a 4-PhC6H4 (3m)
2a 1-naphthyl (3n)
2a 2-naphthyl (3o)
2b 4-MeC6H4 (3p)
2b 4-ClC6H4 (3b)
2c 4-MeC6H4 (3p)
2d 4-MeC6H4 (3p)
2e C6H5 (3a)
1
1a
1a
1a
1a
1b
1c
1d
1e
1f
23
23
23
23
23
23
KOHd
Et3Ne
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
xylenes
THF
n.r.
n.r.
67
n.d.
n.d.
50
n.d.
54
55
92
60
45
52
44
90
88
83
90
87
80
92
92
92
91
4
2
f
5
3
4g
KHF2
KOHd
6
trace
85
f
7
6
5
KHF2
KHF2
KHF2
KHF2
KHF2
KHF2
KHF2
KHF2
KHF2
KHF2
KHF2
KHF2
KHF2
KHF2
KHF2
KHF2
KHF2
f
f
f
f
f
f
f
f
f
f
f
f
f
f
f
f
8
9e
6
6
56
18
24
18
6
7
1.5
85
10
11e
12
13
14
15
16f
17g
18f
19
20e
21
22
23
24
25h
26i
27e
28e
29e
30e
8
23
23
23
23
8
79
9
90
10
11
12
13
14
15
16
17
18h,i
19h,j
20h,k
21h,l
1g
1h
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
95
6
98
5
90
8
8
87
24
51
24
48
18
72
6
8
dioxane
glyme
71
8
66
8
diglyme
CH2Cl2
toluene
toluene
toluene
toluene
43
8
>99
>99
94
1.5
2f
2f
2f
4-MeC6H4 (3p)
4-MeOC6H4 (3l)
4-CNC6H4 (3e)
2.5
4
99
20
48
18
59
9
23
97
2g 4-MeC6H4 (3p)
2g 4-MeOC6H4 (3l)
2g 4-CNC6H4 (3e)
2h C6H5 (3a)
a The reaction was conducted on a 0.2 mmol scale in the presence of
[RhCl(C2H4)2]2 (3.0 μmol) with ligand 1 (7.2 μmol) under an Ar atmo-
sphere at 50 °C; n.r. means no reaction; n.d. means not determined.
b Isolated yield. c Determined by chiral HPLC; see the Supporting
Information. d 1.5 M KOH(aq) (0.13 mL) was added. K2CO3, NaOH,
CsOH, i-Pr2NH, and K3PO4 were found to be ineffective. e 0.48 mmol of
Et3N was added. f 3.0 M KHF2(aq) (0.2 mL) was added. g Potassium
phenyltrifluoroborate was used instead of PhB(OH)2. h Preformed
[RhCl(1d)]2 was used. i 1.5 mol % of [RhCl(1d)]2 (3.0 mol % Rh).
j 0.5 mol % of [RhCl(1d)]2 (1.0 mol % Rh). k 0.25 mol % of [RhCl(1d)]2
(0.5 mol % Rh). l 0.05 mol % of [RhCl(1d)]2 (0.1 mol % Rh).
2h 4-MeOC6H4 (3l)
18
11
18
2i
2i
C6H5 (3a)
4-MeOC6H4 (3l)
a The reaction was conducted on a 0.2 mmol scale, in the presence of
[RhCl(1d)]2 (0.5 μmol, 0.5 mol % Rh), under an Ar atmosphere at 50 °C.
b Isolated yield. c Determined by chiral HPLC; see the Supporting
Information. d 0.75 equiv of 4-Cl-phenylboronic acid was added after
4.5 h. e 1.5 equiv of arylboronic acid was added after 6 h. f 1.5 equiv of
arylboronic acid was added after 16 h. g 1.5 equiv of 4-Cl-phenylboronic
acid was added after 48 h. h 0.75 equiv of 4-MeO-phenylboronic acid was
added after 6 h. i 0.75 equiv of 4-CN-phenylboronic acid was added after 23 h.
ethereal solvents (entry 14À16) provided reduced yields
and lower enantioselectivities, apart from glyme (entry 15),
that gave comparable ee.15 While dichloromethane
(entry 17) gave excellent conversion, the selectivity was
only moderate. An improved chemical yield was obtained
without sacrificing the high ee when the reaction was
carried out in the presence of 1.5 mol % of preprepared
[RhCl(1d)]2 (3 mol % of Rh) (entry 18). Optimization of
the catalytic loading revealed that even in the presence of
0.5 and 0.25 mol % of [RhCl(1d)]2, the reaction proceeded
smoothly to give compound 4aa in 94À99% chemical
yields and 92% ee (entries 19À20). This contrasts that
reported previously,9 where 1.5 mol % of the correspond-
ing bicyclo[3.3.0]diene Rh dimer complexes were required
for similar substrates. This suggests that bicyclo[2.2.1]-
diene ligands provide more reactive Rh catalysts than
the bicyclo[3.3.0]diene ligands that rely on 50 °C higher
reaction temperature while using more catalyst. Notably,
with 0.05 mol % of [RhCl(1d)]2 (0.1 mol % of Rh; a S/C
ratio of 1000) the asymmetric reaction provided the
desired product without the loss of high catalytic
activity or enantioselectivity, but a longer reaction time
(15) In this study, only an amount of adduct 4aa was isolated from
reactions in alcohol solvents, which is at odds with our previous studies
that alcohol solvents were good reaction media; see ref 11.
5732
Org. Lett., Vol. 15, No. 22, 2013

(23 h) was required (entry 21). Low Rh loadings could be
benficial in pharmaceutical drug substance manufacture
where only ppm concentrations of residual Rh are allowed
by regulatory agencies. This further supports our observa-
tion that the bicyclo[2.2.1]diene ligands provide more
active (lower reaction temperature and catalyst loading)
Rh catalysts in conjugate additions to β-nitroolefins.
With the reaction conditions specified in Table 1, entry
20, as a starting point, we next investigated the asymmetric
addition of a range of arylboronic acids to a variety of
nitro-based Michael acceptors (Table 2). Under the opti-
mal conditions, theenantioselective conjugatedadditionof
arylboronic acids, substituted with electron-withdrawing
(entries 2À9) or electron-donating groups (entries 10À13),
to 4-methyl-β-nitrostyrene (2a) furnished products in good
yields with high enantio-induction (89À97% ee). The abso-
lute configuration of the stereogenic center was determined
to be R by X-ray crystallographic analysis of compound
4al.16 The utilization of both 1-naphthyl- and 2-naphthyl-
boronic acids (3n and 3o) had a negligible effect on the
outcome of the reaction, providing compounds 4an and 4ao
in comparable yield with a similar level of enantioselectivity,
respectively (entries 14 and 15). Subsequently, the enan-
tioselective addition of various arylboronic acids to
β-nitroalkenes 2bÀi was studied to elucidate this asymmetric
transformation further. Excellent enantioselectivities were
also observed from the reactions of β-nitrostyrenes regard-
less of whether the substituents were electron-withdrawing
or electron-donating (2bÀe) (89À95% ee) (entries 16À20).
Notably, 2-(2-nitrovinyl)-furan (2f) and 2-(2-nitrovinyl)-
thiophene (2g) were good reaction partners, yielding addi-
tion products with a comparably high stereoselectivity
(89À92% ee) (entries 21À26). In addition to β-nitrosty-
renes, β-nitroolefins with alkyl substituents were tested as
acceptors in this asymmetric transformation. The conjugate
addition of phenylboronic acid (3a) and 4-methoxyphenyl-
boronic acid (3l) to (E)-3-methyl-1-nitrobut-1-ene (2h) and
(E)-(2-nitrovinyl)cyclohexane (2i) proceeded in a highly
enantiocontrolled manner (85À95% ee) to generate the
corresponding adducts in excellent yields (81À93%), re-
spectively (entries 27À30).
Scheme 1. Synthesis of ent-SKF 38393
underwent N-alkylation with 2-bromo-1,1-diethoxyethane
under basic conditions to give acetal 7 in good yield. A
three-step manipulation that involved the acid-mediated
Jackson-type cyclization19a,b of acetal 7, reduction,19c and
the removal of Ns-group furnished compound 8, a pre-
cursor of ent-SKF-38393, in 63% yield with 95% ee.
In conclusion, a highly efficient (S/C, substrate/catalyst,
up to 1000) and enantioselective rhodium-catalyzed addi-
tion reaction of arylboronic acids to β-nitroalkenes utilizing
a novel family of bicyclo[2.2.1]diene ligands was realized.
Generally, the asymmetric addition reactions, conducted at
only 50 °C in the presence of 0.25 mol % of [RhCl(1d)]2, of
various arylboronic acids with β-nitroolefins yielded enan-
tioenriched β,β-disubstituted nitroethanes in good to excel-
lent yields (up to 99%) with excellent enantioselectivity (up
to 97%). High catalytic activity and enantioselectivity can
also be observed in the reactions of 2-heteroarylnitroolefins
and 2-alkylnitroolefins using our RhÀ1d complex. In com-
parison to the use of bicyclo[3.3.0]diene ligands in the
asymmetric arylation reaction of some β-nitroolefins and
nucleophiles,9 our system allows lower catalyst loadings to
be realized while a significantly lower temperature can be
used while equal or better enantioselectivity can be obtained.
This method was employed to synthesize chiral 1-phenylte-
trahydro-1H-3-benzazepine 8 efficiently, which is the inter-
mediate of pharmacologically interesting ent-SKF 38393.
Further investigation and application of this methodology
and the development of catalytic systems for other asym-
metric synthesis are currently in progress.
By way of demonstration, chiral compound 4ea, as
synthesized using the catalytic asymmetric method
reported herein, was utilized in the formal synthesis of
ent-SKF 38393,17 the enantiomer of a dopamine receptor
agonist and antagonist (Scheme 1).2a The reduction of
compound 4ea with nickel boride produced primary amine
5,18 which was converted into sulfonamide 6. Compound 6
Acknowledgment. Financial support provided by the
National Science Council of Republic of China (NSC
100-2113-M-003-009-MY2) and National TaiwanNormal
University is gratefully acknowledged.
(16) See the Supporting Information.
(17) Neumeyer, J. L.; Kula, N. S.; Baldessarini, R.; Baindur, J. N.
J. Med. Chem. 1992, 35, 1466.
(18) Hynes, P. S.; Stupple, P. A.; Dixon, D. J. Org. Lett. 2008, 10,
1389.
(19) (a) Birch, A. J.; Jackson, A. H.; Shannon, P. V. R. J. Chem. Soc.,
Perkin Trans. 1 1974, 2185. (b) Ponzo, V. L.; Kaufman, T. S. Tetra-
hedron Lett. 1995, 36, 9105. (c) Kosciolowicz, A.; Rozwadowska, M. D.
Tetrahedron: Asymmetry 2006, 17, 1444.
Supporting Information Available. Experimental pro-
cedures and characterization of compounds are provided.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
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