Asymmetric synthesis of β-substituted γ-lactams via rhodium/diene-catalyzed 1,4-additions: Application to the synthesis of (R)-baclofen and (R)-rolipram

Article abstract of DOI:10.1021/ol103054a

An efficient rhodium/diene-catalyzed asymmetric addition of arylboronic acids to α,β-unsaturated γ-lactams has been developed. The power of this methodology is further demonstrated by the concise synthesis of (R)-baclofen and (R)-rolipram.

Full text of DOI:10.1021/ol103054a

ORGANIC
LETTERS
2011
Vol. 13, No. 4
788–791
Asymmetric Synthesis of β-Substituted
γ-Lactams via Rhodium/Diene-Catalyzed
1,4-Additions: Application to the
Synthesis of (R)-Baclofen and
(R)-Rolipram
Cheng Shao,†,‡ Hong-Jie Yu,† Nuo-Yi Wu,† Ping Tian,† Rui Wang,‡ Chen-Guo Feng,*,†
and Guo-Qiang Lin*,†
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032,
China, and State Key Laboratory of Applied Organic Chemistry and Institute of
Biochemistry and Molecular Biology, Lanzhou University, Lanzhou 730000, China
fengcg@sioc.ac.cn; lingq@sioc.ac.cn
Received December 16, 2010
ABSTRACT
An efficient rhodium/diene-catalyzed asymmetric addition of arylboronic acids to r,β-unsaturated γ-lactams has been developed. The power of
this methodology is further demonstrated by the concise synthesis of (R)-baclofen and (R)-rolipram.
γ-Lactams have attracted considerable attention due to
their presence in a large variety of biologically active
compounds1 as well as the synthetic precursors of inhibi-
tory neurotransmitters γ-aminobutyric acids (GABA).2
Significant efforts have been devoted to the asymmetric
synthesis of chiral γ-lactams, and a variety of methods
toward introducing C-4 chirality have been developed.3
However, most existing methods utilize properly substi-
tuted acyclic intermediates for lactam formation and
usually require multiple structural modifications in the
synthesis. A highly enantioselective and straightforward
method is still of great interest.
(3) Selected examples, see: (a) Corey, E. J.; Zhang, F. Y. Org. Lett.
2000, 2, 4257. (b) Thakur, V. V.; Nikalje, M. D.; Sudalai, A. Tetrahe-
dron: Asymmetry 2003, 14, 581. (c) Becht, J. M.; Meyer, O.; Helmchen,
G. Synthesis 2003, 2805. (d) Craig, D.; Hyland, C. J. T.; Ward, S. E.
Chem. Commun. 2005, 3439. (e) Enders, D.; Niemeier, O. Heterocycles
2005, 66, 385. (f) Paraskar, A. S.; Sudalai, A. Tetrahedron 2006, 62, 4907.
(g) Wee, A. G. H.; Duncan, S. C.; Fan, G. J. Tetrahedron: Asymmetry
2006, 17, 297. (h) Hynes, P. S.; Stupple, P. A.; Dixon, D. J. Org. Lett.
2008, 10, 1389. (i) Bantreil, X.; Prestat, G.; Madec, D.; Fristrup, P.; Poli,
G. Synlett 2009, 1441. (j) Wang, J.; Li, W.; Liu, Y. L.; Chu, Y. Y.; Lin,
L. L.; Liu, X. H.; Feng, X. M. Org. Lett. 2010, 12, 1280.
† Shanghai Institute of Organic Chemistry.
‡ Lanzhou University.
(1) Enz, A.; Feuerbach, D.; Frederiksen, M. U.; Gentsch, C.; Hurth,
K.; Muller, W.; Nozulak, J.; Roy, B. L. Bioorg. Med. Chem. Lett. 2009,
19, 1287.
(2) For reviews, see: (a) Trabocchi, A.; Guarna, F.; Guarna, A. Curr.
ꢀ~
Org. Chem. 2005, 9, 1127. (b) Ordonez, M.; Cativiela, C. Tetrahedron:
Asymmetry 2007, 18, 3.
r
10.1021/ol103054a
Published on Web 01/19/2011
2011 American Chemical Society

as the application on the synthesis of (R)-baclofen and (R)-
rolipram.
Scheme 1. Chiral γ-Lactams Prepared via 1,4-Addition
Table 1. Influence of N-Protective Group of 7 on the Asym-
metric Rhodium-Catalyzed 1,4-Addition Reactiona
The asymmetric rhodium-catalyzed 1,4-addition of or-
ganometallic reagents to an R,β-unsaturated lactam is one
of the most attractive strategies from a synthetic point of
view (Scheme 1). Since the discovery by Miyaura and
Hayashi in 1998,4 rhodium catalyzed asymmetric 1,4-
addition of organometallic reagents has been rapidly
developed into a powerful tool for the stereoselective
formation of a C-C bond.5 Although Hayashi and co-
workers reported asymmetric 1,4-addition reaction to R,β-
unsaturated pyridinones in 2001,6 surprisingly, few reports
has been devoted to the addition of R,β-unsaturated γ-
lactams, probably due to the problematic isomerization of
the carbon-carbon double bond in 1 (Scheme 1).7 In 2006,
He and co-workers reported the asymmetric addition of
arylboronic acid to R,β-unsaturated γ-lactams using a
rhodium/(R)-binap complex as a catalyst.8 The reaction
usually proceeded in moderate yields with less than 90%
ee. Therefore, a more effective catalyst system is still highly
desirable for this transformation.
The advent of chiral diene ligands offers new opportu-
nities for asymmetric transition-metal catalysis.9 Com-
pared with phosphane ligands, chiral dienes provide
higher reactivities and enantioselectivities in a variety of
rhodium-catalyzed asymmetric reactions.10 Since 2007,
our group has developed various diene ligands based on
a [3.3.0]-bicyclooctadiene or dicyclopentadiene (DCP)
backbone (Figure 1) and successfully applied them in the
rhodium-catalyzed enantioselective arylation of imines11
and the 1,4-addition of arylboronic acids to electron
deficient olefins.12a-c Herein we describe our new efforts
in this catalytic system to R,β-unsaturated γ-lactams to
access highly optically pure β-substituted γ-lactams as well
time
(h)
yieldb
(%)
ee of 9c
entry
substrate
product
(%)
1
2
3
4
5
7a R = Bn
7b R = PMB
7c R = PMP
7d R = Boc
7e R = H
6
10
10
6
9aaþ10aa
9baþ10ba
9ca
96d
95e
98
94
94
89
97
-
9da
99
10
9ea
n.d.
a The reaction was carried out with 7 (0.2 mmol), phenylboronic acid
8a (0.4 mmol), [RhCl(C2H4)2]2 (0.0030 mmol), diene 3a (0.0066 mmol,
1.1 equiv to Rh), and KHF2 (0.8 mmol) in toluene/H2O (10/1) at 60 °C
for 6-10 h. b Yield of isolated product. c Determined by chiral HPLC
analysis. d Isolated as a 3.3:1 inseparable mixture of 9aa and 10aa.
e Isolated as a 2.9:1 inseparable mixture of 9ba and 10ba. n.d. = not
detected.
Initially, we examined the influence of the protective
grouponnitrogen. Several R,β-unsaturated γ-lactamswith
different N-protective groups were prepared and evaluated
in the rhodium-catalyzed addition of phenylboronic acid
under the reaction conditions recently developed for
nitroalkenes.12c The reactions of 7a and 7b gave the cor-
responding addition products with 94% ee accompanied
with inseparable byproduct 10 which may be attributed to
a Mizoroki-Heck-type reaction (Table 1, entries 1 and 2).
A slight decrease in enantioselectivity (89% ee) occurred
when PMP (p-methoxyphenyl) was used as a protecting
group (Table 1, entry 3). To our delight, the best result (99%
(4) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura, N.
J. Am. Chem. Soc. 1998, 120, 5579.
(5) For 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) Christoffers, J.; Koripelly, G.;
€
Rosiak, A.; Rossle, M. Synthesis 2007, 1279. (e) Hayashi, T.; Yoshida,
K. In Modern Rhodium-Catalyzed Organic Reactions; Evans, P. A., Ed.;
Wiley-VCH: Weinheim, 2004; pp 55-78.
(6) Senda, T.; Ogasawara, M.; Hayashi, T. J. Org. Chem. 2001, 66,
6852.
(7) (a) Baker, J. T.; Sifniades, S. J. Org. Chem. 1979, 44, 2798. (b)
Sonesson, C.; Larhed, M.; Nyqvist, C.; Hallberg, A. J. Org. Chem. 1996,
61, 4756. (c) Meyer, O.; Becht, J. M.; Helmchen, G. Synlett 2003, 1539.
(8) He, Y.; Woodmansee, D.; Choi, H.; Wang, Z.; Wu, B.; Nguyen,
T. (Irm Llc) WO2006081562, 2006.
(9) For seminal work, 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.
€
(10) For reviews, see: (a) Defieber, C.; Grutzmacher, H.; Carreira,
E. M. Angew. Chem., Int. Ed. 2008, 47, 4482. (b) Johnson, J. B.; Rovis, T.
Angew. Chem., Int. Ed. 2008, 47, 840. (c) Shintani, R.; Hayashi, T.
Aldrichimica Acta 2009, 42, 31.
(11) (a) Wang, Z.-Q.; Feng, C.-G.; Xu, M.-H.; Lin, G.-Q. J. Am.
Chem. Soc. 2007, 129, 5336. (b) Shao, C.; Yu, H.-J.; Wu, N.-Y.; Feng,
C.-G.; Lin, G.-Q. Org. Lett. 2010, 12, 3820.
Figure 1. Chiral Dienes Used in This Study.
Org. Lett., Vol. 13, No. 4, 2011
789

yield, 97% ee) was obtained for 7d in which the nitrogen was
protected by a Boc (tert-butoxycarbonyl) group (Table 1,
entry 4). When the nitrogen was not masked, the compound
7e was relatively unstable7a and no desired product was
observed under the standard conditions (Table 1, entry 5).
Et3N as an additive. Replacement of toluene by dioxane
gave the same yield and enantioselectivity (Table 2, entry 14).
Table 3. Rhodium-Catalyzed Asymmetric 1,4-Addition Reac-
tion of Arylboronic Acids to 7da
Table 2. Optimization of the Experimental Conditionsa
time
(h)
yieldb
(%)
eec
entry
Ar
Ph (8a)
9
(%)
1
6
9da 99
9db 99
98
98
98
98
98
99
99
99
98
time
(h)
yieldc
(%)
eed
(%)
2
4-MeOC6H4 (8b)
4-MeC6H4 (8c)
3-MeOC6H4(8d)
3-MeC6H4 (8e)
2-MeOC6H4 (8f)
2-MeC6H4 (8g)
1-naphthyl (8h)
2-naphthyl (8i)
4-CF3C6H4 (8j)
4-ClC6H4 (8k)
4-BrC6H4 (8l)
5
5
6
6
8
8
6
5
entry
diene
solvent
additiveb
3
9dc
99
4
9dd 99
9de 98
1
3a
3a
3b
3c
3d
3e
3f
4
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
dioxane
KHF2
KHF2
KHF2
KHF2
KHF2
KHF2
KHF2
KHF2
KHF2
KHF2
K3PO4
KOH
6
24
5
99
52
99
99
99
98
99
99
35
69
65
58
99
99
97
97
2e
3
5
6
9df
99
94
7
9dg 99
9dh 99
4
5
96
8
5
6
96
9
9di
99
6
6
96
10d
11d
12d
24 (10) 9dj
56 (97) 98 (97)
9dk 78 (99) 98 (97) (R)
9dl 72 (99) 97 (97)
7
5
69
24 (6)
24 (6)
8
2
-51
37
9
5
24
24
24
24
6
10
11
12
13
14
6
27
a The reaction was carried out with 7d (0.2 mmol), arylboronic acid 8
(0.4 mmol), [RhCl(C2H4)2]2 (0.0030 mmol), diene (0.0066 mmol, 1.1
equiv to Rh), and Et3N (4 equiv) in toluene/H2O at 60 °C, unless
otherwise noted. b Yield of isolated product. c Determined by chiral
HPLC analysis. d The data in the brackets are results when KHF2 was
used as additive (0.8 mmol, 4 equiv).
3a
3a
3a
3a
81
71
Et3N
98
Et3N
10
98
a The reaction was carried out with 7d (0.2 mmol), phenylboronic
acid 8a (0.4 mmol), [RhCl(C2H4)2]2 (0.0030 mmol), diene (0.0066 mmol,
1.1 equiv to Rh), and additive in toluene/H2O at 60 °C. b Used 4 equiv for
entries 1-10, 13, and 14 and 2 equiv for entries 11 and 12. c Yield of
isolated product. d Determined by chiral HPLC analysis. e The reaction
was carried out at 40 °C.
With the optimal reaction conditions in hand, the scope
ofrhodium-catalyzed1,4-addition wasinvestigatedusing a
variety of boronic acids with diverse steric and electronic
properties. The results are summarized in Table 3. All
arylboronic acids with an electron-donating group on the
phenyl ring were added successfully to 7d, giving the
desired products in excellent yields (98-99%) and enan-
tioselectivities (98-99% ee) (Table 3, entries 2-7). Ex-
cellent ee’s (98-99%) and yields (99%) were also obtained
when 1-naphthyl or 2-naphthyl boronic acid was used
(Table 3, entries 8 and 9). When the phenyl ring was
substituted with electron-withdrawinggroups, the reaction
afforded the addition products in moderate yields even
after prolonged reaction time, but enantioselectivies were
still excellent (Table 3, entries 10-12). A possible reason
may be attributed to the relatively lower reactivity and
faster hydrolysis of the electron-deficient boronic acids.6
To our delight, this problem was solved by applying the
original reaction conditions (with KHF2 as an additive).
The yields were greatly improved to 99% (Table 3, entries
10-12, data in brackets). The absolute configuration of
9dk was assigned as R by comparing the optical rotation
of its deprotected product 11 (see below, Scheme 2) with
the literature value,13 which is consistent with the stereo-
chemical model proposed by Hayashi.9a
Next, several reaction parameters including ligand, tem-
perature, additive, and solvent were screened in order to
further improve the enantioselectivity. Some representa-
tive results are shown in Table 2. The application of dienes
3b-e as ligands, which bear two more sterically hindered
aromatic groups on the double bonds than 3a, resulted in a
small erosion of the enantioselectivity (Table 2, entries
3-6). When a flexible benzyl substituted diene 3f was used,
a significant loss of enantioselectivity was observed
although the high reactivitywas maintained(Table 2, entry
7). Low stereoselectivity were also observed using diene 4,
5, or 6 as a ligand (Table 2, entries 8-10). The reduction of
temperature to 40 °C gave a lower yield albeit keeping the
sameenantioselectivity (Table 2, entry 2). Itwas foundthat
a base or acid additive had a significant impact on both
yields and enantioselectivities (Table 2, entries 11-13).
The best result (99% yield, 98% ee) was achieved with
(12) (a) Feng, C.-G.; Wang, Z.-Q.; Shao, C.; Xu, M.-H.; Lin, G.-Q.
Org. Lett. 2008, 10, 4101. (b) Feng, C.-G.; Wang, Z.-Q.; Tian, P.; Xu,
M.-H.; Lin, G.-Q. Chem.;Asian J. 2008, 3, 1511. (c) Wang, Z. Q.; Feng,
C. G.; Zhang, S. S.; Xu, M. H.; Lin, G. Q. Angew. Chem., Int. Ed. 2010,
49, 5780. (d) Helbig, S.; Sauer, S.; Cramer, N.; Laschat, S.; Baro, A.;
Freya, W. Adv. Synth. Catal. 2007, 349, 2331.
(13) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y.
J. Am. Chem. Soc. 2005, 127, 119.
790
Org. Lett., Vol. 13, No. 4, 2011

Scheme 2. Synthesis of (R)-Baclofen
Scheme 3. Synthesis of (R)-Rolipram
Notablely, the corresponding chiral β-substituted
γ-lactams are very useful building blocks for assembling
some bioactive compounds. For example, with the treat-
ment of 6 N HCl, 9dk underwent deprotection and
subsequent hydrolysis to afford a selective GABAB
receptor agonist, (R)-baclofen hydrochloride,14 in high
yield (Scheme 2).
The synthetic utility of this methodology is also demon-
strated by a two-step synthesis of antidepressant (R)-
rolipram.15 With the complex of rhodium/3a as catalyst,
the key enantioselective addition of 12 to 7d gave the
desired product 13 in 98% yield with 97% ee. A higher
ee value (>99%) for 13 was easily obtained after a single
recrystallization. Deprotection of 13 with TFA afforded
(R)-rolipram in quantitative yield (Scheme 3).
γ-lactams using chiral diene as ligands. Under optimal
conditions, the reaction proceeded with excellent yields
and enantioselectivities, affording a variety of synthetically
useful chiral β-substituted γ-lactams. The power of this
methodology is demonstrated by the concise synthesis of
(R)-baclofen and (R)-rolipram. Extension of the metho-
dology to other related substrates and further synthetic
applications are currently underway.
Acknowledgment. Financial support from the National
Natural Science Foundation of China (21002112), the
Major State Basic Research Development Program
(2010CB833302), and the Shanghai Municipal Committee
of Science and Technology (09JC1417300) is greatly ac-
knowledged.
In summary, we have developed a rhodium-catalyzed
asymmetric addition of arylboronic acids to R,β-unsaturated
(14) (a) Olpe, H. R.; Demieville, H.; Baltzer, V.; Bencze, W. L.;
Koella, W. P.; Wolf, P.; Haas, H. L. Eur. J. Pharmacol. 1978, 52, 133. (b)
Berthelot, P.; Vaccher, C.; Flouquet, N.; Debaert, M.; Luyckx, M.;
Brunet, C. J. Med. Chem. 1991, 34, 2557. (c) Kerr, D. I. B.; Ong, J. Med.
Res. Rev. 1992, 12, 593.
(15) (a) Seika, M. Drugs Future 1998, 23, 108. (b) Baures, P. W.;
Eggleston, D. S.; Erhard, K. F.; Cieslinski, L. B.; Torphy, T. J.;
Christensen, S. B. J. Med. Chem. 1993, 36, 3274. (c) Sommer, N.;
Loschmann, P. A.; Northoff, G. H.; Weller, M.; Steinbrecher, A.;
Steinbach, J. P.; Lichtenfels, R.; Meyermann, R.; Riethmuller, A.;
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Supporting Information Available. Experimental pro-
cedures and characterization data; copies of H and 13
NMR spectra and HPLC profiles. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
1
C
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