Asymmetric Michael Addition Reaction of α-Aryl-Substituted Lactams Catalyzed by Chiral Quaternary Ammonium Salts Derived from Cinchona Alkaloids: A New Short Synthesis of (+)-Mesembrine

Article abstract of DOI:10.1055/s-0035-1560090

The enantioselective Michael addition reaction of α-aryl-substituted lactams with electron-deficient olefins was efficiently catalyzed using chiral quaternary ammonium salts derived from cinchona alkaloids. This method was highly useful for the construction of an all-carbon-substituted quaternary carbon stereogenic center at the α-position of lactams in good to high yields and with good enantiomeric excess and could be applied to the short synthesis of (+)-mesembrine.

Full text of DOI:10.1055/s-0035-1560090

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 2301–2305
letter
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S. Nunokawa et al.
Letter
Synlett
Asymmetric Michael Addition Reaction of α-Aryl-Substituted
Lactams Catalyzed by Chiral Quaternary Ammonium Salts
Derived from Cinchona Alkaloids: A New Short Synthesis of
(+)-Mesembrine
Shiori Nunokawa
Masamitsu Minamisawa
Keiji Nakano
O
Ar
NBoc
( )n
Br–
cat. (30 mol%)
Ag2O (30 mol%)
EWG
OR
Yoshiyasu Ichikawa
Hiyoshizo Kotsuki*
O
N+
+
EtOH (30 mol%)
toluene, –15 °C
Ar
NBoc
EWG
N
( )n
Laboratory of Natural Products Chemistry, Faculty of Science,
Kochi University, Akebono-cho, Kochi 780-8520, Japan
kotsuki@kochi-u.ac.jp
OMe
cat.: R = CO-1-adamantyl
(1.5 equiv)
up to 96% yield
up to 86% ee
Received: 02.07.2015
Accepted after revision: 16.07.2015
Published online: 01.09.2015
at the reaction center. Despite this fairly limited accessibili-
ty, we expected that the asymmetric Michael addition reac-
tion of α-substituted lactams would provide an expeditious
strategy for the construction of a potentially important
framework of biologically interesting natural products in
which an all-carbon-substituted quaternary carbon stereo-
genic center is a part of the stereoarray.1
However, our preliminary experiments showed that
commonly used primary, secondary, and tertiary chiral
amines were all unsatisfactory as organocatalysts for the
present purpose.6 This can be understood by considering
that they are not reactive enough to invoke enamine activa-
tion7 or to act as Lewis bases to abstract an α-methine pro-
ton of lactams.8 Therefore, we turned our attention to the
use of chiral phase-transfer catalysts derived from cinchona
alkaloids as relatively strong organobases.9 Herein, we re-
port a novel strategy using quaternary ammonium salts A
to H to achieve the required asymmetric Michael addition
reaction of α-aryl-substituted lactams (Figure 1).10
DOI: 10.1055/s-0035-1560090; Art ID: st-2015-u0495-l
Abstract The enantioselective Michael addition reaction of α-aryl-
substituted lactams with electron-deficient olefins was efficiently cata-
lyzed using chiral quaternary ammonium salts derived from cinchona
alkaloids. This method was highly useful for the construction of an all-
carbon-substituted quaternary carbon stereogenic center at the α-posi-
tion of lactams in good to high yields and with good enantiomeric ex-
cess and could be applied to the short synthesis of (+)-mesembrine.
Key words asymmetric organocatalysis, lactams, Michael addition,
cinchona alkaloids, mesembrine
All-carbon-substituted quaternary carbon stereogenic
centers are common structural units found in numerous bi-
ologically active natural products, and hence considerable
attention has been focused on the development of efficient
methodologies to construct these molecules.1 Among these,
recent advances in organocatalytic asymmetric synthesis
offer a highly useful and environment-friendly strategy.2
Most typically, the organocatalytic asymmetric Michael ad-
dition reaction has been accepted as a reliable and conve-
nient method, probably due to the versatility of designing
Michael donors and acceptors as well as the pool of avail-
able chiral organocatalysts.2,3
In contrast to the several reports that are available on
the use of normal aldehydes or ketones as Michael do-
nors,2,3 to the best of our knowledge, very little attention
has been paid to the use of α-substituted lactams or lac-
tones, except for benzene-fused homologues such as oxin-
doles.2b,4,5 Presumably, this might be due to the weak acidi-
ty of α-protons in connection with severe steric congestion
Br–
A: R = H, Ar = Ph
N+
B: R = COt-Bu, Ar = Ph
C: R = CO-1-Adm, Ar = Ph
D: R = CO-1-Adm, Ar = 4-MeOC6H4
Ar
OR
N
N
Br–
E: R = H, Ar = Ph
OR
F: R = COt-Bu, Ar = Ph
N+
Ar
G: R = CO-1-Adm, Ar = Ph
H: R = CO-1-Adm, Ar = 4-MeOC6H4
Figure 1 Cinchona alkaloid derivatives as catalyst
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2301–2305

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S. Nunokawa et al.
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To establish the optimal conditions, we first examined
the asymmetric Michael addition reaction of N-Boc-2-phe-
nyl-γ-butyrolactam (1a) with methyl vinyl ketone (2a) in
the presence of catalysts A–H under various conditions. The
results are summarized in Table 1.11
mol%) in toluene under lower temperatures (Table 1, entry
10 vs. entries 9, 11, and 12).13 In addition, we found that
Cs2CO3 and K2CO3 gave results comparable to those with in-
organic bases (Table 1, entries 15 and 16). The use of CH2Cl2
or THF as a solvent or CsOH·H2O as a base gave rather poor
results, probably due to a background reaction (Table 1, en-
tries 13, 14, and 17).
With our optimized reaction conditions in hand, we
then explored the general scope of the reaction, and the re-
sults are summarized in Scheme 1.11 All reactions were
performed in toluene containing 30 mol% EtOH in the pres-
ence of 30 mol% of the respective catalyst H and Ag2O.
Among several Michael acceptors, methyl vinyl ketone (2a)
and ethyl vinyl ketone (2b) reacted smoothly with lactam 1
to give the desired products in good to high yields (up to
96%) and with good enantioselectivity (up to 86% ee), while
methyl acrylate (2c) and acrylonitrile (2d) showed lower
reactivity in the present Michael addition system (3c and
3d).14 Lactam substrates containing an electron-donating
We found that a series of cinchonidine-type salts A–D
could smoothly promote the desired reaction, but the enan-
tioselectivity was not so high (Table 1, entries 1–4). When a
series of cinchonine-type salts E–H was used, the enantio-
selectivity improved considerably to form the Michael ad-
duct 3a, albeit with an opposite configuration (Table 1, en-
tries 5–8). In particular, favorable results could be attained
with the use of catalyst H, which contains the 9-hydroxy
protecting group with a sterically bulky 1-adamantoyl
group and a 4-methoxybenzyl group at the quinuclidine ni-
trogen center (Table 1, entry 8).12 After we screened various
inorganic base additives and reaction conditions, the best
results in terms of yield and enantioselectivity were ob-
tained with Ag2O (30 mol%) in combination with EtOH (30
Table 1 Catalytic Asymmetric Michael Addition Reactions: Optimizationa
O
O
O
Ph
catalyst (30 mol%)
+
*
NBoc
base (30 mol%)
O
Ph
NBoc
solvent
1a
2a
3a
Entry
Catalyst
Base
Ag2O
Conditions
Yield (%)b
ee (%)c
1
2
A
B
MeOH (30 mol%), toluene, r.t., 2.5 h
MeOH (30 mol%), toluene, r.t., 16 h
MeOH (30 mol%), toluene, r.t., 42 h
MeOH (30 mol%), toluene, r.t., 8.5 h
EtOH (30 mol%), toluene, r.t., 25 h
EtOH (30 mol%), toluene, r.t., 48 h
MeOH (30 mol%), toluene, r.t., 7 h
MeOH (30 mol%), toluene, r.t., 8 h
92
94
81
62
86
85
95
80
83
92
95
97
72
33d
97
76
97
12
29
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Cs2CO3
K2CO3
3
C
40
4
D
E
32
5
–11
–40
–60
–68
–83
–85
–77
–84
–60
–51
–78
–80
–33
6
F
7
G
H
H
H
H
H
H
H
H
H
H
8
9
MeOH (30 mol%), toluene, –15 °C, 15 h
EtOH (30 mol%), toluene, –15 °C, 28 h
i-PrOH (30 mol%), toluene, –15 °C, 10 h
n-BuOH (30 mol%), toluene, –15 °C, 78 h
EtOH (30 mol%), CH2Cl2, –15 °C, 8 h
EtOH (30 mol%), THF, –15 °C, 8 h
10
11
12
13
14
15
16
17
EtOH (30 mol%), toluene, –15 °C, 30 h
EtOH (30 mol%), toluene, –15 °C, 28 h
EtOH (30 mol%), toluene, –50 °C, 12 h
CsOH·H2O
a Reactions performed using 1.5 equiv of methyl vinyl ketone (2a) at a concentration of 0.17 M under the conditions listed. See the Supporting Information for
detailed experimental procedures.
b Isolated yield.
c Determined by chiral HPLC analysis.
d Unidentified polar substances were formed.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2301–2305

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S. Nunokawa et al.
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group on the aromatic ring were found to be suitable sub-
strates compared with those having an electron-withdraw-
ing group (compare 3e–h with 3i and 3j). Unfortunately,
2-phenyl-substituted δ-valerolactam reacted only very
slowly under these conditions, and the product 3k was ob-
tained in only 9% yield with 26% ee (–15 °C, 100 h). This can
be ascribed to the severely decreased acidity of an α-
methine proton of this substrate.15 Finally, the absolute
configurations of the newly formed Michael adducts were
deduced by analogy to 3g after its conversion into (+)-
mesembrine (6, vide infra).
EWG
O
cat. H (30 mol%)
O
Ar
+
EWG
NBoc
( )n
Ag2O (30 mol%)
EtOH (30 mol%)
toluene
Ar
NBoc
( )n
1
2a: EWG = COMe
2b: EWG = COEt
2c: EWG = CO2Me
2d: EWG = CN
3
COEt
O
CO2Me
O
NBoc
NBoc
Upon evaluation of this synthetic methodology, we de-
cided to pursue the synthesis of (+)-mesembrine (6). Due to
its interesting biological activity and its unique structure of
a hexahydroindole skeleton bearing a sterically congested
aryl-substituted quaternary carbon center, this alkaloid has
attracted considerable attention from synthetic chemists
over the past several decades.16 Our new short synthesis of
6 was developed as shown in Scheme 2.
3b, –15 °C, 20 h
85%, 86% ee
3c, r.t., 100 ha
51%, 9% ee
CN
O
COMe
O
NBoc
NBoc
First, a two-step strategy based on intramolecular aldol
condensation of the Michael adduct 3g by treatment with
2.0 equivalents of KOt-Bu in THF at room temperature fol-
lowed by exposure to a catalytic amount of PTSA in reflux-
ing toluene gave bicyclic cyclohexenone 4 in around 50%
yield, which was increased to >99% enantiomeric excess by
recrystallization from hexane–Et2O. Boc-deprotection of 4
in (CF3)2CHOH under microwave irradiation conditions17
followed by N-methylation gave 516d in 86% yield.
Me
3d, r.t., 100 ha
8%, 67% ee
3e, –15 °C, 23 h
85%, 78% ee
COMe
O
COMe
O
MeO
MeO
NBoc
NBoc
MeO
O
3f, –15 °C, 70 h
3g, –15 °C, 28 h
60%, 76% ee
95%, 70% ee
(i)
(iii)
(iv)
COMe
COMe
O
3g
MeO
MeO
NBoc
(ii)
O
NBoc
NBoc
4
Cl
O
O
3h, –15 °C, 24 h
3i, –15 °C, 51 h
96%, 68% ee
89%, 65% ee
(v)
MeO
MeO
MeO
NMe
NMe
COMe
O
COMe
O
MeO
NBoc
5
6
NBoc
Scheme 2 Reagents and conditions: (i) KOt-Bu, THF, r.t., 30 min; (ii) cat.
PTSA·H2O, MS 4 Å, toluene, Δ, 11 h; (iii) (CF3)2CHOH, MW, 150 °C, 40
min; (iv) MeI, NaH, THF, r.t.; (v) Li/liq NH3, t-BuOH, THF, –78 °C, 30 min.
Cl
3j, r.t., 84 ha
26%, 23% ee
3k, –15 °C, 100 ha
9%, 26% ee
Scheme 1 Catalytic asymmetric Michael addition reactions: Generality.
Reactions performed using 1.5 equiv of Michael acceptor 2 at a concen-
tration of 0.17 M under the conditions listed. Isolated yields are shown.
The absolute configuration of the products was surmised in analogy
with 3g. The ee was determined by chiral HPLC analysis. See the Sup-
porting Information for detailed experimental procedures. a Unreacted
starting material was recovered.
Finally, Birch reduction using Li/liq. NH3 in THF–t-BuOH
according to Zhang’s method16d led to (+)-mesembrine (6)
in 77% yield with 99% enantiomeric excess. This sample
gave IR, 1H NMR, and 13C NMR data identical to the respec-
tive literature values.16 On the other hand, the optical rota-
19
tion was [α]D +42.2 (c 0.15, MeOH), which is consistent
with the literature value, [α]D20 +43 (c 0.8, MeOH), reported
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2301–2305

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S. Nunokawa et al.
Letter
Synlett
for (+)-mesembrine.16j Therefore, it can be concluded that
the initial step for the Michael addition reaction on a lactam
framework should preferably form the adduct 3g with an R
configuration.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560090.
S
u
p
p
o
nrtogI
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
Based on these experimental findings, we could pro-
pose a crucial structure in the transition state to explain the
observed asymmetric induction (Figure 2). The contact ion
pair between the negatively charged enolate of the nucleo-
phile and the ammonium cation of the catalyst makes the
donor molecule well-defined within the catalyst major
groove. The presence of a sterically crowding adamantoyl
substituent effectively blocks the approach of the incoming
electrophile to the enolate from the bottom Re-face, thus
making the Si-face attack more favorable.
References and Notes
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‡
Ar
N
O
Ar
N
NBoc
O
O
(3) Organocatalytic Enantioselective Conjugate Addition Reactions;
Vicario, J. L.; Badía, D.; Carrillo, L.; Reyes, E., Eds.; RSC Publish-
ing: Cambridge, 2010.
Figure 2 Plausible transition-state model
(4) Reviews: (a) Zhou, F.; Liu, Y.-L.; Zhou, J. Adv. Synth. Catal. 2010,
352, 1381. See also: (b) Zhong, F.; Dou, X.; Han, X.; Yao, W.; Zhu,
Q.; Meng, Y.; Lu, Y. Angew. Chem. Int. Ed. 2013, 52, 943; and ref-
erences cited therein.
In summary, we have developed a highly enantioselec-
tive method for the asymmetric Michael addition reaction
of α-aryl-substituted lactams with electron-deficient ole-
fins catalyzed by chiral quaternary ammonium salts de-
rived from readily available cinchona alkaloids. This meth-
od proved to be particularly useful for the construction of
an all-carbon-substituted quaternary carbon stereogenic
center at the α-position of lactams and highlighted its utili-
ty in a highly concise route to the asymmetric synthesis of
(+)-mesembrine (6). Further studies on the application of
this method to natural product synthesis are now in prog-
ress in our laboratory
(5) An alternative approach using Pd-catalyzed allylation has been
developed by Stoltz and co-workers, see: (a) Behenna, D. C.; Liu,
Y.; Yurino, T.; Kim, J.; White, D. E.; Virgil, S. C.; Stoltz, B. M. Nat.
Chem. 2012, 4, 130. (b) Numajiri, Y.; Jiménez-Osés, G.; Wang, B.;
Houk, K. N.; Stoltz, B. M. Org. Lett. 2015, 17, 1082. (c) Liu, Y.;
Han, S.-J.; Liu, W.-B.; Stoltz, B. M. Acc. Chem. Res. 2015, 48, 740.
(6) See the chiral organocatalysts used in our preliminary experi-
ments: (a) Ishii, T.; Fujioka, S.; Sekiguchi, Y.; Kotsuki, H. J. Am.
Chem. Soc. 2004, 124, 9558. (b) Inokoishi, Y.; Sasakura, N.;
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(c) Moritaka, M.; Miyamae, N.; Nakano, K.; Ichikawa, Y.;
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N.; Moritaka, M.; Nakano, K.; Ichikawa, Y.; Kotsuki, H. Org.
Biomol. Chem. 2014, 12, 5847.
Acknowledgment
(7) Reviews: (a) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B.
Chem. Rev. 2007, 107, 5471. (b) Cheong, P. H.-Y.; Legault, C. Y.;
Um, J. M.; Celebi-Ölcüm, N.; Houk, K. N. Chem. Rev. 2011, 111,
5042. (c) Nielsen, M.; Worgull, D.; Zweifel, T.; Gschwend, B.;
Bertelsen, S.; Jørgensen, K. A. Chem. Commun. 2011, 47, 632.
(8) For a review, see: Denmark, S. E.; Beutner, G. L. Angew. Chem.
Int. Ed. 2008, 47, 1560.
(9) For selected reviews, see: (a) Jew, S.-s.; Park, H.-g. Chem.
Commun. 2009, 7090. (b) Marcelli, T.; Hiemstra, H. Synthesis
2010, 1229. (c) Yeboah, E. M. O.; Yeboah, S. O.; Singh, G. S. Tetra-
hedron 2011, 67, 1725. (d) Park, H.-g. Science of Synthesis; Asym-
metric Organocatalysis 2,; Maruoka, K., Ed.; Thieme: Stuttgart,
2012, Chap. 2.3.1, 499–549. (e) Brak, K.; Jacobsen, E. N. Angew.
Chem. Int. Ed. 2013, 52, 534. (f) Shirakawa, S.; Maruoka, K.
Angew. Chem. Int. Ed. 2013, 52, 4312.
We thank Prof. Y. Fukuyama of Tokushima Bunri University for
MS/HRMS measurements. The authors are also grateful to Ms. Megu-
mi Kosaka and Mr. Motonari Kobayashi at the Division of Instrumen-
tal Analysis, Department of Instrumental Analysis & Cryogenics,
Advanced Science Research Center, Okayama University for the ele-
mental analyses. This work was supported in part by a Grant-in-Aid
for Scientific Research on Innovative Areas ‘Advanced Molecular
Transformations by Organocatalysts’ from the MEXT (Japan) (No.
24105523 & 26105743).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2301–2305

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S. Nunokawa et al.
Letter
Synlett
(10) The quaternary ammonium catalysts were prepared by an anal-
ogous procedure as reported by Jørgensen and co-workers:
Poulsen, T. B.; Bernardi, L.; Bell, M.; Jørgensen, K. A. Angew.
Chem. Int. Ed. 2006, 45, 6551.
(11) General Procedure for the Asymmetric Michael Addition
Reaction of Lactams
(12) We briefly examined the attachment on a quinuclidine nitro-
gen, but no improvements were observed using an anthracenyl-
methyl or 4-nitrobenzyl group.
(13) When the temperature was lowered to –30 °C, the reaction
using Ag2O as an inorganic base was completely impeded. Fur-
thermore, the use of H2O in place of EtOH caused only the
racemic background reaction, and in the absence of EtOH no
reaction was observed. The results imply that alcohol additives
can effectively mix both the reagents and catalysts in the reac-
tion medium.
(14) Unfortunately, the use of phenyl vinyl ketone as a Michael
acceptor gave only a complex mixture of products.
(15) In accordance with this observation, no reaction was observed
for the 2-alkyl-substituted γ-butyrolactam even after prolonged
reaction (r.t., 100 h).
(16) For recent synthesis of mesembrine, see: (a) Arns, S.; Lebrun,
M.-E.; Grisé, C. M.; Denissova, I.; Barriault, L. J. Org. Chem. 2007,
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The chiral ammonium catalyst was prepared by mixing a cin-
chona amine (0.06 mmol) and freshly distilled 4-methoxyben-
zyl bromide (0.06 mmol) in toluene (0.2 mL) at r.t. for 1 h. Then,
Ag2O (0.06 mmol) and EtOH (0.06 mmol) were added, and the
mixture was stirred at r.t. for 20 min. After cooling to –15 °C,
lactam (0.2 mmol) in toluene (0.8 mL) followed by the Michael
acceptor (1.5 equiv) were added, and the reaction progress was
monitored by TLC. After completion of the reaction, the mixture
was directly purified by silica gel column chromatography
(eluted with benzene–acetone, 12:1) to give the desired adduct.
The ee of this compound was determined by chiral HPLC analy-
sis.
(R)-N-Boc-2-(3-oxobutyl)-2-phenyl-γ-butyrolactam (3a)
Colorless needles; mp 97–99 °C (from hexane–Et2O); Rf = 0.17
19
(hexane–acetone, 4:1). [α]D +83.2 (c 1.0, EtOH, 79% ee). FTIR
(KBr): ν = 1773, 1715, 1365, 1313, 1164 cm–1.1H NMR (500
MHz, CDCl3): δ = 1.53 (9 H, s), 2.03 (3 H, s), 2.10–2.16 (2 H, m),
2.19–2.29 (2 H, m), 2.41–2.45 (1 H, m), 2.53–2.62 (1 H, m), 3.48
(1 H, ddd, J = 10.0, 8.5, 8.0 Hz), 3.75 (1 H, ddd, J = 10.0, 8.0, 3.0
Hz), 7.26–7.41 (5 H, m). 13C NMR (125.8 MHz, CDCl3): δ = 28.00
(3×), 29.91, 31.55, 32.17, 38.78, 42.95, 52.93, 83.02, 126.43 (2×),
127.37, 128.78 (2×), 139.04, 150.18, 175.56, 208.10. Anal. Calcd
for C19H25NO4: C, 68.86; H, 7.60; N, 4.23. Found: C, 68.76; H,
7.60; N, 4.09. The ee of the product was determined by chiral
HPLC analysis (Chiralpak AD-H column, 0.46 × 25 cm, hexane–
2-PrOH = 90:10, 0.3 cm3/min): tR (major) = 39.4 min; tR (minor)
= 43.0 min.
(17) Choy, J.; Jaime-Figueroa, S.; Jiang, L.; Wagner, P. Synth. Commun.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2301–2305