Formal synthesis of (±)-clausenamide by nhc-catalyzed γ-lactam formation

Article abstract of DOI:10.3987/COM-12-S(N)128

(±)-Clausenamide is a biologically active γ-lactam isolated as a racemic mixture from Clausena lansium. Reported medicinal properties include hepatoprotective effects as well as neuroprotective and nootropic activity. In order to improve synthetic access

Full text of DOI:10.3987/COM-12-S(N)128

HETEROCYCLES, Vol. 86, No. 2, 2012
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HETEROCYCLES, Vol. 86, No. 2, 2012, pp. 1689 - 1696. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 4th October, 2012, Accepted, 12th October, 2012, Published online, 22nd October, 2012
DOI: 10.3987/COM-12-S(N)128
FORMAL SYNTHESIS OF (±)-CLAUSENAMIDE BY NHC-CATALYZED
!-LACTAM FORMATION
Ming He, Michael Rommel, and Jeffrey W. Bode*
Laboratory of Organic Chemistry, Department of Chemistry and Applied
Biosciences, ETH-Zurich, Wolfgang Pauli Strasse 10, Zurich 8093, Switzerland
bode@org.chem.ethz.ch
Dedicated to Professor Ei-ichi Negishi on the occasion of his 77th birthday.
Abstract – (±)-Clausenamide is a biologically active !-lactam isolated as a
racemic mixture from Clausena lansium. Reported medicinal properties include
hepatoprotective effects as well as neuroprotective and nootropic activity. In order
to improve synthetic access to this molecule and its analogues, and to devise a
route amenable to asymmetric catalysis, we have developed a new formal
synthesis of (±)-clausenamide based on an N-heterocyclic carbene (NHC)
catalyzed annulation of cinnamaldehyde and an unsaturated imine. The key
!-lactam forming annulation proceeds at room temperature in good yield and
excellent diastereoselectivity. Preliminary efforts towards an enantioselective
variant are also reported.
Chinese folk medicine uses teas made from Clausena lansium to treat both acute and chronic hepatitis.
Subsequent studies have attributed these hepatoprotective effects to the !-lactam natural product
(±)-clausenamide, which was isolated from this source in 1984 as about 0.04% of the dry leaf weight.1,2
Preliminary biological evaluations showed that clausenamide (1) showed a marked hepatoprotective
effect against chemical toxins, such as carbon tetrachloride and thioacetamide. More recently, interest in
clausenamide has focused on its potential neuroprotective and nootropic effects.3 Numerous studies have
identified a protective effect of (–)-clausenamide on memory and neuronal DNA damage upon induced
cerebral artery occlusion (i.e. stroke).4 Several other members of the clausenamide family, including
neoclausenamide (2)5 and homoclausenamide (3)6 have been isolated and have begun to attract attention
(Scheme 1).7

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HETEROCYCLES, Vol. 86, No. 2, 2012
O
O
Me
Me
OH
N
N
OH
HO
OH
(–)-clausenamide (1)
(+)-clausenamide (ent-1)
(±)-clausenamide (natural product)
O
O
Me
N
Me
HO
OH
N
OH
(±)-neoclausenamide (2) (±)-homoclausenamide (3)
Scheme 1. Clausenamide and enantiomers.
These promising biological activities have inspired several groups to develop synthetic routes to
clausenamide with the aim of providing access to analogues by a concise, scalable approach. Unusual for
a chiral, naturally occurring substance, clausenamide is isolated as a racemic mixture. Separation of the
enantiomers and examination of their biological properties has revealed that only the (3R,4S,5S)
enantiomer is neurologically active. Therefore, while racemic clausenamide can be obtained from natural
sources, a synthetic, enantioselective route would be highly desirable. At least three reports of its
synthesis or formal synthesis have already appeared,8 along with the synthesis of neoclausenamide and
homoclausenamide.
In this report, we document the NHC-catalyzed synthesis of lactam 8 and its elaboration into
(±)-clausenamide core 5, which has been previously converted into the natural product by a short
synthetic sequence.5 Our studies provide an improved, straightforward route to racemic clausenamide as
well as the framework for a catalytic, enantioselective synthesis through the use of chiral N-heterocyclic
carbene catalysts.9
The most obvious synthetic disconnection of clausenamide is opening of the !-lactam to reveal a !-amino
acid. The synthesis of this densely functionalized stereochemical array presents a considerable challenge
and most researchers have instead elaborated preformed !-lactams en route to clausenamide. Two
syntheses, including the work of Hartwig and Born that serves as our inspiration have passed through
lactam 5, which we believed to be accessible by our previously reported NHC-catalyzed annulations of
imines and ",#-unsaturated aldehyde.10 Our retrosynthetic analysis of clausenamide therefore took

HETEROCYCLES, Vol. 86, No. 2, 2012
1691
advantage of our ability to form lactam 8 by NHC-catalyzed homoenolate addition and our conviction
that this product could be converted to lactam 5 (Scheme 2).
O
O
O
Me
O
Me
Me
N
N
N
OH
OH
OH
1
5
6
O
O
Me
ArO2S
O
SO2Ar
N
N
N
H
H
H
O
Ph
Ph
8
7
10
9
Scheme 2. Retrosynthesis of (±)-clausenamide 1 with lactams 5 and 8 as key intermediates. Lactam 8 can
be formed by an NHC-catalyzed annulation of cinnamaldehyde with unsaturated imine 10.
As a starting point for our synthetic approach to clausenamide, we selected the annulation of
cinnamaldehyde (9) and N-sulfonylimine 10 (Scheme 3). By performing this reaction at room
temperature, we found that we could produce lactam 8 in good yield and on a gram scale as an 8:1
mixture of diasteroisomers. After the deprotection of the sulfonamide protecting group, the minor
diastereomer was easily removed by column chromatography and the desired cis isomer 11 was obtained
in excellent yield. This cis-lactam was methylated by deprotonation with sodium hydride followed by
trapping with methyl iodide to give N-Me lactam 12 in 60% overall yield from annulation product 8.
O
Cl–
O
O
ArO2S
SO2Ar
H
N
N
Mes
Mes
N
N
HN
H
15 mol %
Na/Naphthalene
DME, rt
H
10 mol % DBU
tBuOH, 23 °C, 12 h
Ph
Ph
Ph
61 % yield
61 % yield
10
9
8 (8:1 dr)
11 (single isomer)
(Ar = p-MeC6H4)
MeI, NaH
DMF, rt
93% yield
O
O
O
Me
O
Me
N
Me
N
Me
N
N
O3, CH2Cl2
then, DMS
PhMgBr
OH
ref. 8
Ph
H
CH2Cl2, 0 °C
OH
O
Ph
3 steps
63%
(two steps)
OH
7
1 (±)-clausenamide
13 (single isomer)
12 (single isomer)
Scheme 3. Formal synthesis of (±)-clausenamide by an NHC-catalyzed !-lactam forming annulation.

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HETEROCYCLES, Vol. 86, No. 2, 2012
To complete the formal synthesis of clausenamide, lactam 12 was subjected to ozonolysis followed by the
addition of phenylmagnesium bromide to the unpurified aldehyde afforded, as a single diastereomer,
secondary alcohols 13 in 63% yield. This material has been previously prepared by Hartwig and Born by
an 8-step route and its conversion to (±)-clausenamide has been described. The preparation of 13
therefore constitutes a formal synthesis of this natural product.
Overall, our improved access to 13 occurs in a 5-step sequence from cinnamaldehyde and features a
diastereoselective, NHC-catalyzed annulation to form the key lactam structure by a simple, scalable
reaction. Both of the reaction components are derived from readily available cinnamaldehyde.
With the longer term goal of developing a catalytic, enantioselective approach to the biologically active
(–)-clausenamide in mind, we have briefly evaluated the feasibility of conducting the NHC-catalyzed
!-lactam formation with a chiral catalyst. As we have previously documented,11 this !-lactam forming
annulation proceeds only with imidazolium-derived N-heterocyclic carbenes; triazolium-derived catalyst
14 that has proven to be outstanding for numerous highly enantioselective annulations are unfortunately
unreactive in this process.12 When the annulations were attempted in CH2Cl2 and with Hünig’s base,
which are the more usual conditions for the use of triazolium salts, the only observed product was small
amounts of the hetero-Diels-Alder adduct 15 (Scheme 4). We therefore examined the use of
(S,R)-aminoindanol-derived imidazolium precatalyst 16,13 but found that this catalyst was also
non-productive in our initial studies.
O
N
Cl–
O
N
SO2Ar
H
N
O
N
Mes
H
ArO2S
H
H
15 mol % 14
N
Ph
10 mol % iPr2NEt
CH2Cl2, 23 °C, 12 h
Ph
Ph
9
15 trace
10
O
Me
–ClO4
O
N
SO2Ar
H
N
N
Mes
H
H
15 mol % 16
no !-lactam product
10 mol % DBU
tBuOH, 23 °C, 12 h
Ph
9
10
Scheme 4. Failure of aminoindanol-derived precatalysts.

HETEROCYCLES, Vol. 86, No. 2, 2012
1693
We attributed the failure of the annulation to proceed with the imidazolium-precatalyst to inhibition by
the highly electrophilic imine 10. To modulate the electrophilicity, we prepared the N-sulfonyl imine of
para-methoxycinnamaldehyde (17), which was expected to be less electrophilic and therefore less
inclined to inhibit the chiral N-heterocyclic carbene catalyst. With this substrate, we observed modest
conversion to the desired !-lactam 18 with 25% ee (Scheme 5). The use of the imine derived from
"-methylcinnamaldehyde (19) offered modest improvements, with the product obtained in 53% ee.
Although further improvement is clearly needed, these studies establish that enantioselective
NHC-catalysis can be a viable approach to the asymmetric synthesis of clausenamide and analogues.
Emerging results in this area using alternative substrates and catalyst may be suitable for the synthesis of
clausenamide.14
O
O
ArO2S
Me
–ClO4
N
O
SO2Ar
H
N
N
N
Mes
15 mol % 16
H
H
10 mol % DBU
tBuOH, 23 °C, 16 h
OMe
MeO
10% yield
MeO
10
17
18 25% ee
(Ar = p-OMeC6H4)
O
Me
–ClO4
O
O
SO2Ar
N
N
ArO2S
N
N
Mes
15 mol % 16
H
Me
H
Me
Ph
10 mol % DBU
tBuOH, 23 °C, 16 h
Ph
16% yield
9
19
20 53% ee
Scheme 5. Preliminary studies of enantioselective NHC-catalyzed annulations.
In summary, we have documented a concise and facile synthesis of the natural product (±)-clausenamide
(1) featuring an NHC-catalyzed annulation. The key C–C bond forming annulation to access the !-lactam
core proceeds under mild, operationally friendly reaction conditions using commercially available IMesCl
as the catalyst. Varying the annulation partners or the aryl substituent introduced by nucleophilic addition
will allow access to clausenamide-analogs with the same synthetic route. We have also briefly explored
the use of chiral NHC precatalysts for affecting an enantioselective annulation. Although further studies
and improved catalysts are needed, this work established an NHC-catalyzed annulation that can serve as
an entry to the enantioselective synthesis of clausenamide.

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EXPERIMENTAL
(E)-4-Methoxy-N-((E)-3-phenylallylidene)benzenesulfonamide (10) Cinnamaldehyde dimethyl acetal
(1.0 equiv) and the arylsulfonamide (1.0 equiv) were mixed in a flask equipped with a Dean-Stark
condenser. The neat mixture was heated to 180 °C for 30 min. The resulting melt was cooled to room
1
temperature and the solid was crystallized from toluene to yield the product. mp 125–190 °C; H NMR
(400 MHz, CDCl3) $ 8.74 (d, 1H, J = 9.5 Hz), 7.89 (d, 2H, J = 8.9 Hz), 7.54–7.40 (m, 6H), 7.00–6.93 (m,
3H,), 3.85 (s, 3H); 13C NMR (100 MHz, CDCl3) $ 170.5, 163.7, 153.8, 134.2, 131.7, 130.2, 129.7, 129.3,
128.7, 124.7, 114.5, 55.8; IR (thin film) v 3054, 2987, 2305, 1581, 1499, 1421, 1266, 1153, 1092, 896,
857, 807, 743, 705 cm-1; ESI-MS: 302.1 (M+H)+.
cis-1-(4-Methoxyphenylsulfonyl)-4-phenyl-5-(2-para-tolylethylidene)pyrrolidin-2-one (8). Into an
oven dried flask was weighed cinnamaldehyde (0.90 g, 6.8 mmol, 1.0 equiv), imine 10 (2.05 g, 6.8 mmol,
1.0 equiv) and IMesCl (0.35 g, 1.0 mmol, 0.15 equiv). The flask was evacuated and back-filled with
t
argon. To this mixture was added 68 mL of BuOH followed by the addition of DBU (0.10 mL, 0.68
mmol, 0.10 equiv). The resulting mixture was allowed to stir at rt for 14 h, concentrated under reduced
pressure, and purified by flash chromatogrphay (4:1 hexanes/EtOAc) to afford the lactam product as an
1
8:1 mixture of diastereomers (1.8 g, 4.2 mmol, 61% yield). mp 135–136 °C; H NMR (400 MHz, CDCl3)
$ 7.96 (d, 2H, J = 8.9 Hz), 7.28–7.21 (m, 3H), 7.15–7.04 (m, 2H), 6.86 (d, 2H, J = 8.1 Hz), 6.39 (d, 1H, J
= 15.7 Hz), 5.58 (dd, 1H, J = 15.7, 8.2 Hz), 5.31 (m, 1H), 4.93* (m, 1H), 3.99 (m, 1H), 3.34* (m, 1H),
3.83 (s, 3H), 3.86* (s, 3H), 2.98 (dd, 1H, J = 17.2, 13.2 Hz), 3.15* (dd, 1H, J = 17.6, 8.4 Hz), 2.72 (dd,
1H, J = 17.2, 7.2 Hz), 2.61* (dd, 1H, J = 17.6, 3.2 Hz), 2.51 (s, 3H), 2.61* (s, 3H), 2.22 (s, 3H), 2.37* (s,
13
3H); C NMR (100 MHz, CDCl3) $172.1, 164.1, 135.8, 135.7, 134.7, 131.3, 131.1, 130.3, 129.4, 128.9,
128.7, 128.1, 127.9, 126.9, 126.7, 126.6, 123.2, 114.1, 65.8, 55.8, 43.5, 35.2; IR (thin film) v 3054, 2987,
2305, 1735, 1654, 1596, 1498, 1421, 1265, 1166, 1092, 898, 835, 739 cm-1; ESI-MS: 434.1 (M+H)+.
(*indicates peaks assigned to the minor diastereomer).
cis-4-Phenyl-5-styrylpyrrolidin-2-one (11). Naphthalene (1.8 mmol, 0.24 g, 12 equiv) was dissolved in
2.0 ml DME. Na (0.043 g, 1.8 mmol, 12 equiv) was added to the solution, and the mixture was stirred at
room temperature for 2 h to form a dark green solution. The protected lactam (0.065 g, 0.15 mmol, 1.0
equiv) dissolved in 1.0 mL of DME was added to the solution at 0 °C, and the mixture was warmed up
slowly to room temperature. After 1 h, water was added and the mixture was extracted with Et2O. The
combined extracts were washed with brine, dried over MgSO4, and concentrated. Purification by flash
chromatography (1:1 hexane/EtOAc) afforded the desired product (24 mg, 0.092 mmol, 61% yield). mp
1
70–71 °C; H NMR (400 MHz, CDCl3) $ 7.34–7.11 (m, 10 H), 6.46 (d, 1H, J = 16.0 Hz), 6.32 (s, 1H),

HETEROCYCLES, Vol. 86, No. 2, 2012
1695
5.59 (dd, 1H, J = 16.0, 6.9 Hz), 4.60 (t, 1H, J = 7.2 Hz), 3.94 (dd, 1H, J = 16.2, 8.3 Hz), 2.80–2.67 (m,
2H); 13C NMR (100 MHz, CDCl3) $ 177.7, 138.4, 136.3, 131.9, 128.7, 128.3, 128.0, 127.7, 127.5, 127.3,
126.6, 94.6, 60.2, 45.5, 35.4; IR (thin film) v 3424, 3055, 2987, 2306, 1702, 1422, 1265, 896, 739, 706
cm-1; EI-MS: 263.1 (M+).
cis-1-Methyl-4-phenyl-5-styrylpyrrolidin-2-one (12). To lactam 11 (20.0 mg, 0.074 mmol, 1.00 equiv)
in 0.5 mL of THF, was added NaH (2.1 mg, 0.088 mmol, 1.2 equiv), followed by the addition of MeI
(0.22 mmol, 0.14 mL, 3.0 equiv). The reaction mixture was stirred at room temperature for 40 min. Water
was added and the mixture was extracted with Et2O, washed with brine, and dried over Na2SO4. The
crude product was purified by flash chromatography (1:1 hexane/EtOAc) to provide the methylated
product 12 (0.069 mmol, 19 mg, 93% yield). mp 94–96 °C; 1H NMR (400 MHz, CDCl3) $ 7.33–7.11 (m,
10 H), 6.40 (d, 1H, J = 15.8 Hz), 5.52 (dd, 1H, J = 15.8, 8.1 Hz), 4.42–4.37 (m, 1H,), 3.84 (dd, 1H, J =
13
16.6, 8.5 Hz), 2.86 (dd, 1H, J = 16.0, 9.2 Hz), 2.86 (s, 3H), 2.57 (dd, 1H, J = 16.0, 8.5 Hz); C NMR
(100 MHz, CDCl3) $ 174.6, 138.5, 136.2, 133.5, 128.8, 128.7, 128.4, 128.2, 127.4, 126.7, 125.8, 76.9,
67.0, 43.2, 35.7, 28.6; IR (thin film) v 3055, 2986, 2306, 1686, 1421, 1266, 896, 748, 704 cm-1; EI-MS:
277.1 (M+).
cis-5-(Hydroxy(phenyl)methyl)-1-methyl-4-phenylpyrrolidin-2-one (13). Lactam 12 (44 mg, 0.16
mmol, 1.0 equiv) in 2.0 ml CH2Cl2 was treated with a stream of O3 in O2 for 30 min. After purging with
O2 for 20 min, DMS was added at –78 °C and the mixture stirred for 1 h at –78 °C and 2 h at 0 °C. To this
solution was added PhMgBr (3.0 equiv, 0.48 mmol) at 0 °C and stirred for 30 min at 0 °C. The mixture
was quenched by the addition of 2 N HCl and extracted with EtOAc. The combined extracts were washed
with brine, dried over Na2SO4, and concentrated. Purification by flash chromatography (1:1 hexane/
EtOAc) afforded the desired product (28 mg, 0.10 mmol, 63% yield over two steps). The spectral data
matched a previous report. mp 188–190 °C; 1H NMR (400 MHz, DMSO-d6) $ 7.46–7.17 (m, 10 H), 5.36
(d, 1H, J = 4.9 Hz), 4.26(d, 1H, J = 4.8 Hz), 4.16 (d, 1H, J = 8.0 Hz), 3.80 (m, 1H), 3.05 (dd, 1H, J = 15.0,
13.4 Hz), 2.26 (dd, 1H, J = 15.0, 8.4 Hz), 2.21 (s 3H); 13C NMR (100 MHz, CDCl3) $ 176.0, 142.4, 138.3,
129.0, 128.7, 128.3, 127.6, 125.4, 72.0, 70.6, 43.6, 35.2, 31.3; IR (thin film) v 3371, 3054, 2987, 2305,
1682, 1422, 1266, 896, 748, 704 cm-1; ESI-MS: 282.1 (M+H)+.
ACKNOWLEDGEMENTS
This work was conducted at the University of California–Santa Barbara and was supported by an NSF
CAREER award to J.W.B. M.R. received a postdoctoral fellowship from the German Academic
Exchange Service (DAAD). We thank Yi-Huang for assistance in the preparation of this manuscript.

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