Highly enantioselective alkenylation of cyclic α,β-unsaturated carbonyl compounds as catalyzed by a rhodium-diene complex: Application to the synthesis of (S)-pregabalin and (-)-α-kainic acid

Article abstract of DOI:10.1002/chem.201202660

Rhod to addition: An efficient asymmetric conjugate-addition reaction of alkenyltrifluoroborates and α,β-unsaturated carbonyl compounds, as catalyzed by a rhodium-diene complex, was developed. The products were obtained in high yield and high levels of enantioselectivity. The methodology was applied to a concise synthesis of (S)-pregabalin and (-)-α-kainic acid (see scheme).

Full text of DOI:10.1002/chem.201202660

COMMUNICATION
DOI: 10.1002/chem.201202660
Highly Enantioselective Alkenylation of Cyclic a,b-Unsaturated Carbonyl
Compounds as Catalyzed by a Rhodium–Diene Complex: Application to the
Synthesis of (S)-Pregabalin and (À)-a-Kainic Acid
Hong-Jie Yu, Cheng Shao, Zhe Cui, Chen-Guo Feng,* and Guo-Qiang Lin*[a]
Rhodium-catalyzed asymmetric conjugate addition of or-
ganometallic reagents to a,b-unsaturated carbonyl com-
pounds is a powerful tool to construct stereogenic carbon
centers.[1] Among the organometallic reagents used in this
transformation, organoboron reagents are the most popular
because of their suitable reactivity, easy accessibility, low
toxicity, and high stability toward air and water.[2] Since the
appearance of the seminal report of Miyaura, Hayashi, and
co-workers, both aryl- and alkenylboron species have been
recognized as valuable coupling reagents for rhodium-cata-
lyzed conjugate-addition reactions.[3] However, compared to
arylboron reagents, which are the subject of intensive re-
search and have many applications, the use of alkenylboron
reagents is much less explored in this field, with most exam-
ples featuring only simple a,b-unsaturated ketones as reac-
tion substrates.[4] Conjugate-addition reactions involving less
reactive a,b-unsaturated esters and amides tends to be more
difficult, and as such, has not been reported often. To the
best of our knowledge, only the research group of Fꢀrstner
has reported on the conjugate addition of alkenylboronates
to [5H]-furan-2-one; using a range of alkenylboronates,
yields in the range of 17–65% and ee values as high as 82%
were observed in studies toward the total synthesis of the
ecklonialactones and hybridalactone.[5] The conjugate addi-
tion of alkenylboron reagents to a,b-unsaturated amides re-
mains unexplored. Obviously, the versatility of alkenes in
synthetic chemistry makes the conjugate-addition reaction
of alkenylboron reagents to a wider range of Michael ac-
ceptors in high yields and high levels of enantioselectivity
an attractive research target.[6,7]
Pucheault found that potassium alkenyltrifluoroborates can
be successfully used in the rhodium-catalyzed conjugate ad-
dition to cyclic enones with high yields and high levels of
enantioselectivity.[9] On the other hand, the superior per-
formance of chiral diene ligands in rhodium-catalyzed con-
jugate-addition reactions may offer new opportunities for
highly efficient and stereoselective alkenylation reactions
for various Michael acceptors.[10]
Recently, our group reported an efficient rhodium-cata-
lyzed reaction using arylboronic acids to prepare chiral 4-
aryl lactams (Scheme 1).[11] Attempts to introduce alkenyl
Scheme 1. Rhodium–diene-catalyzed asymmetric conjugate-addition reac-
tions. Boc=tert-butoxycarbonyl.
groups using the corresponding alkenylboronic acids were
unsuccessful; low levels of enantioselectivity and low yields
were obtained under the reaction conditions that were opti-
mized for arylboronic acids. As part of our continuing ef-
forts in the development of methods for the synthesis of
chiral g lactams and the development of new asymmetric
rhodium-catalyzed reactions, we herein report a highly
enantioselective conjugate-addition of potassium alkenyltri-
fluoroborates to cyclic a,b-unsaturated carbonyl compounds,
and the successful application of this method to the synthe-
sis of (S)-pregabalin and (À)-a-kainic acid.
The lack of research on the use of alkenylboron reagents
may be partially attributed to the low stability of alkenylbor-
onic acids compared with that of arylboronic acids. The de-
velopment of more stable potassium trifluoroborates seems
to be a good solution to this problem.[8] Darses, Genet, and
[a] H.-J. Yu, C. Shao, Z. Cui, Dr. C.-G. Feng, Prof. G.-Q. Lin
Key Laboratory of Synthetic Chemistry of Natural Substances
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032 (P. R. China)
Fax : (+86)21-6416-6263
E-mail: fengcg@sioc.ac.cn
At the outset, using reaction conditions from the literatur-
e,[4 g] we screened a variety of chiral ligands in the conju-
gate-addition reaction of trifluoroborate 2a and lactam 1a;
the rhodium catalysts were generated in situ from the reac-
lingq@sioc.ac.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202660.
tion of [{RhClACHTUNTRGNEUNG(C2H4)2}2] and chiral ligands. When the phos-
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phine ligands, BINAP (L1), MeO-BIPHEP (L2), and
SIPHOS-PE (L3), were examined, low yields (<15%) and
low levels of enantioselectivity (23–61% ee) were observed
(Table 1, entries 1, 3, and 5). When the reactions were car-
ried out at 1008C, a common reaction temperature for reac-
tions involving phosphine ligands, the results were worse
(Table 1, entries 2, 4, and 6). Then we turned our attention
to the chiral diene ligands. The use of chiral diene L4 gave
the product with a very high ee value (99%), albeit in mod-
erate yield (50%; Table 1, entry 7). High yields could be ob-
tained by using chiral ligands L5 and L6, however, low
levels of enantioselectivity were obtained (<65% ee;
Table 1, entries 8 and 9). Using diene L4, attempts to further
improve the yield by varying solvent, base, and temperature
proved unsuccessful (Table 1, entries 10–15). We reasoned
that the low yield probably originates from the deactivation
of the rhodium catalyst, through its binding to the alkene
moiety of adduct 3aa, and the side products generated
through the hydrolysis of trifluoroborate 2a. To our delight,
when freshly prepared [{Rh(OH)(L4)}2] was used as a more
active catalyst,[12] the yield significantly improved and
reached 97% (Table 1, entry 16). Even with the use of a
lower catalyst loading (1 mol% Rh), the product was still
obtained in 79% yield with 99% ee (Table 1, entry 18).
With optimized reaction conditions established (Table 1,
entry 17), the reaction scope was examined (Scheme 2). The
reactions of a variety of alkenyltrifluoroborates with lactam
1a were successful and products were obtained in moderate
to excellent yields (43–97%), with excellent levels of enan-
tioselectivity (97–99% ee). Both steric and electronic prop-
erties of alkenyltrifluoroborates affected the yield and the
enantioselectivity. The use of substituted alkenyltrifluorobo-
rates gave products that were generally obtained in higher
yield, therefore showing that increased steric hindrance is
beneficial to the reaction. For example, very high yields
were observed in the conjugate addition reaction of 2,2-di-
methyl-substituted and 1,2,2-trimethyl-substituted alkenyltri-
fluoroborates (3aa and 3ac). Alkenyltrifluoroborates that
were relatively electron rich gave higher yields. In compari-
son with the conjugate addition reaction of 2-phenyl-alke-
nyltrifluoroborate, the reaction of a substrate containing an
electron-donating methoxy group on the phenyl ring gave a
slightly higher yield (85%; compare 3ah with 3ai); however,
reaction of a substrate containing an electron-withdrawing
chloride group on the phenyl ring gave a lower yield (66%;
compare 3ah with 3aj). When a six-membered lactam was
used, the levels of enantioselectivity were slightly lower al-
though the yields remained high (3ba, 3bb, and 3bh). When
the reaction of a,b-unsaturated lactones was investigated, a
different combination of solvent and base was found to be
optimal. The combination of toluene and Et3N was replaced
by the combination of dioxane and KF and in doing so, the
yields were satisfactory, and again the levels of enantioselec-
tivity observed for 5-membered lactones were higher than
those observed for 6-membered lactones (compare 3ch with
3dh). As expected, the use of the more reactive a,b-unsatu-
rated ketones led to high yields, although only the 5-mem-
bered 2-cyclopentenone gave excellent levels of enantiose-
lectivity (98–99%; compare 3ed, 3eh, and 3 fh).
Table 1. Optimization of reaction conditions.[a]
Entry Catalyst
T [8C] Base
Yield [%][e] ee [%][f]
1
2
3
4
5
6
7
8
L1/
N
G
Et3N
Et3N
8
4
4
23
53
9
–
61
–
99
64
15[g]
95
95
96
95
96
71
99
99
99
L1/
L2/
L2/
L3/
L3/
L4/
L5/
L6/
L4/
L4/
L4/
L4/
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
DIEA
pyridine
KOH
Et3N
Et3N
Et3N
Et3N
–
trace
13
trace
50
69
92
46
8
43
38
9
10
11
12
13
14
15[b]
16[c]
17[c]
18[d]
L4/
L4/
37
58
97
42
[{Rh(OH)(L4)}2]
[{Rh(OH)(L4)}2]
[{Rh(OH)(L4)}2]
RT
RT
RT
Et3N
79
[a] Unless noted otherwise, reactions were carried out with 1a
(0.2 mmol), 2a (0.4 mmol), [{RhCl(C2H4)2}2] (0.005 mmol), ligand
AHCTUNGTRENNUNG
(0.011 mmol), catalytic amount of KOH (0.011 mmol) and 2 equiv of
base in toluene/H2O (10/1, 2.2 mL). [b] 1,4-Dioxane was used instead of
toluene. [c] [{Rh(OH)(L4)}2] (0.005 mmol) was used as rhodium catalyst
and without adding KOH. [d] [{Rh(OH)(L4)}2] (0.001 mmol) was used as
rhodium catalyst and without adding KOH. [e] Yield of isolated product.
[f] Determined by HPLC analysis, using a chiral stationary phase. [g] The
sense of asymmetric induction was opposite that observed in reactions as-
sociated with other entries in this table. DIEA=N,N-diisopropylethyla-
mine.
The absolute configurations of 3ch, 3eh, and 3 fh were as-
signed as R by comparison of their optical rotation with
those in the literature;[13] the configuration of the products
is in agreement with the stereochemistry-defining model for
the arylation of enones that was described by Hayashi
et al.[14] Using the conjugate addition reaction of potassium
2-(E)-phenylethenyltrifluoroborate and [5H]-furan-2-one in
the presence of the rhodium catalyst bearing the ligand
(S,S)-L4 as an example, the alkenylrhodium intermediate
prefers to coordinate to the Re face of the lactone to mini-
mize steric repulsions between the phenyl groups on the
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Alkenylation of Cyclic a,b-Unsaturated Carbonyl Compounds
COMMUNICATION
Scheme 3. Possible stereochemistry-defining pathway.
phatic pain.[15] Starting from conjugate-addition product
3aa, a hydrogenation reaction followed by hydrolysis using
6M HCl afforded the desired (S)-pregabalin hydrochloride
(5) in 96% yield over two steps (Scheme 4).
Scheme 4. Synthesis of (S)-pregabalin. Reaction conditions: a) 15 atm H2,
Pd/C, MeOH, RT (100%); b) 6M HCl, reflux (96%).
In a further application of our method, we decided to
apply it in the synthesis (À)-a-kainic acid, a natural product
first isolated in 1953 from the Japanese marine algae dige-
nea simplex.[16] (À)-a-Kainic acid exhibits potent anthelmin-
tic and neuroexcitatory activity, and currently has been
widely used as a tool in neuropharmacology.[17] Because its
limited availability has severely hampered research using
this compound,[18] great efforts have been devoted to the
total synthesis of (À)-a-kainic acid.[19] Our synthesis com-
menced with asymmetric alkenylation of lactam 1a, as cata-
lyzed by [{Rh(OH)ACTHUNTRGNE(UNG (R,R)-L4)}2], to furnish lactam 6 in 82%
yield with 99% ee (Scheme 5). Next, alkylation of 6 gave
trans-3,4-substituted ester 7. The key syn relationship at C3/
C4 in (À)-a-kainic acid was then easily established by in-
verting configuration at C3 through a dynamic protonation
process. Treatment of 7 with LiHMDS followed by protona-
tion with (À)-CSA at À788C afforded the desired cis-ester 8
in 84% yield. Reduction of 8 by DIBAL-H followed by
treatment with MeOH generated 9, which when reacted
with TMSCN in the presence of BF3·OEt2 gave nitrile 10 as
a 5:1 mixture of diastereomers.[19g] While benefitting from
the epimerization of the undesired isomer during the basic
hydrolysis process,[19g] the crude diastereomeric mixture of
nitrile 10 was refluxed in 2M NaOH solution to afford the
natural product (À)-a-kainic acid 11 in 82% yield. The total
synthesis of (À)-a-kainic acid was therefore accomplished in
seven steps from commercially available lactam 1a in 40%
yield, thus representing one of the most concise and efficient
synthetic routes reported to date. Notably, the versatility of
this synthetic strategy provides a convenient and easy access
to a variety of kainic acid derivatives bearing different sub-
stitutions at the core pyrrolidine ring.
Scheme 2. Substrate scope of the rhodium-catalyzed asymmetric alkeny-
lation reaction. Unless noted otherwise, reactions were carried out with 1
(0.2 mmol), 2 (0.4 mmol), [{Rh(OH)ACHTNUGTRNEUNG((S,S)-L4)}2] (0.005 mmol), and Et3N
(56 mL) in toluene/H2O (10:1, 2.2 mL). Yields are given for isolated prod-
ucts after column chromatography. The ee values were determined by
HPLC analysis using a chiral stationary phase. [a] Toluene/H2O (50:1)
was used. [b] Toluene and Et3N were replaced by 1,4-dioxane and KF.
[c] 2 (0.8 mmol) was used. Bn=benzyl, Cy=cyclohexyl.
diene and the lactone, thus leading to the desired product
3ch with R configuration (Scheme 3). The configuration of
other adducts were assigned as R by assuming a similar
pathway.
The application of this method was demonstrated by a
concise synthesis of (S)-pregabalin. As a 3-substituted ana-
logue of g-aminobutyric acid (GABA), which is a neuro-
transmitter, (S)-pregabalin, with the brand name Lyrica, is
an anticonvulsant drug used to treat epilepsy and neuro-
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C.-G. Feng, G.-Q. Lin et al.
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Scheme 5. Synthesis of (À)-a-kainic acid. Reaction conditions: a) potassi-
um 2-propenyltrifluoroborate, [{Rh(OH)((R,R)-L4)}2] (2.5 mol%), Et3N,
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AHCTUNGTRENNUNG
toluene/H2O, RT (82%); b) LiHMDS, THF, À788C; tert-butyl 2-bromoa-
cetate, THF, À788C (91%); c) LiHMDS, THF, À788C; (À)-CSA, THF,
À788C (84%; with recovery of 7 15%); d) DIBAL-H,THF, À78oC;
e) PPTS, MeOH, 08C (78%, two steps); f) TMSCN, BF3·OEt2, CH2Cl2,
À78oC (99%); g) NaOH, H2O, reflux (82%). CSA=camphorsulfonic
acid, DIBAL-H=diisobutylaluminum hydride, TMS=trimethylsilyl,
LiHMDS=lithium hexamethyldisilazide, PPTS=pyridinium p-toluene-
sulfonate.
In summary, we have developed a rhodium-catalyzed
asymmetric conjugate-addition reaction of potassium alke-
nyltrifluoroborates and a,b-unsaturated carbonyl com-
pounds by using a rhodium–diene complex as a catalyst.
Under optimized reaction conditions, the reactions gave
products with moderate to excellent yields with high levels
of enantioselectivity. The utility of this methodology was
demonstrated by a concise synthesis of (S)-pregabalin and
(À)-a-kainic acid. Further synthetic applications to the syn-
thesis of natural products and pharmaceutical agents are
currently in progress.[20]
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Experimental Section
[7] For copper-catalyzed asymmetric conjugate addition of alkenylme-
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Typical procedure for the conjugate addition of potassium trifluorobo-
rates: Under argon atmosphere, a mixture of 1 (0.2 mmol), potassium al-
kenyltrifluoroborate 2 (0.4 or 0.8 mmol), [{Rh(OH)ACHTUNTRGNE(UNG (S,S)-L4)}2] (1.9 mg,
0.005 mmol, 5 mol% Rh), H2O (0.2 mL) and Et3N (56 mL) in toluene
(2 mL) was stirred at room temperature for 2—24h. The reaction was
quenched with saturated aqueous NH4Cl and extracted with ethyl ace-
tate. The combined organic phases were washed with brine, dried, and
concentrated under reduced pressure. The residue was purified by silica-
gel column chromatography to afford the desired product 3. The ee value
was determined by HPLC analysis using a chiral stationary phase.
[9] a) M. Pucheault, S. Darses, J. P. Genet, Tetrahedron Lett. 2002, 43,
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Acknowledgements
[10] For reviews of chiral diene ligands, see: a) J. B. Johnson, T. Rovis,
Angew. Chem. 2008, 120, 852; Angew. Chem. Int. Ed. 2008, 47, 840;
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Xu, G.-Q. Lin, Synlett 2011, 1345.
We thank Dr. Han-Qing Dong for his help in the preparation of this
manuscript. This work was supported by National Natural Science Foun-
dation of China (21002112), the Major State Basic Research Develop-
ment Program (2010CB833302), and the Shanghai Municipal Committee
of Science and Technology (11431920300).
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[13] See the Support Information for details.
Keywords: alkenylation · asymmetric catalysis · conjugate
addition · diene ligands · rhodium
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Alkenylation of Cyclic a,b-Unsaturated Carbonyl Compounds
COMMUNICATION
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[20] During the preparation of this manuscript, a rhodium-catalyzed con-
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Received: July 26, 2012
Published online: && &&, 0000
Chem. Eur. J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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C.-G. Feng, G.-Q. Lin et al.
Asymmetric Alkenylation
H.-J. Yu, C. Shao, Z. Cui, C.-G. Feng,*
G.-Q. Lin* .................... &&&& — &&&&
Highly Enantioselective Alkenylation
of Cyclic a,b-Unsaturated Carbonyl
Compounds as Catalyzed by a
Rhodium–Diene Complex: Applica-
tion to the Synthesis of (S)-Pregabalin
and (À)-a-Kainic Acid
Rhod to addition: An efficient asym-
metric conjugate-addition reaction of
alkenyltrifluoroborates and a,b-unsatu-
rated carbonyl compounds, as cata-
lyzed by a rhodium–diene complex,
was developed. The products were
obtained in high yield and high levels
of enantioselectivity. The methodology
was applied to a concise synthesis of
(S)-pregabalin and (À)-a-kainic acid
(see scheme).
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www.chemeurj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!