Enantioselective synthesis of glutarimide alkaloids cordiarimides A, B, crotonimides A, B, and julocrotine

Article abstract of DOI:10.1002/cjoc.201180248

Five glutarimide alkaloids cordiarimide A (5), cordiarimide B (6), crotonimide A (3), crotonimide B (4), and julocrotine (2) have been synthesized starting from Boc-L-glutamine (7). The benzylic alcohol chiral centre of cordiarimides B (6) has been established in 6:1 diastereoselectivity by catalytic asymmetric hydrogenation using Zhou's catalytic system Pd(CF ₃CO₂)₂/(R,R)-Me-DuPhos. Copyright

Full text of DOI:10.1002/cjoc.201180248

FULL PAPER
Enantioselective Synthesis of Glutarimide Alkaloids
Cordiarimides A, B, Crotonimides A, B, and Julocrotine
Teng, Bo(滕波)
Zheng, Jianfeng*(郑剑峰)
Huang, Huiying(黄慧英)
Huang, Peiqiang*(黄培强)
Department of Chemistry and Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and
Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, China
Five glutarimide alkaloids cordiarimide A (5), cordiarimide B (6), crotonimide A (3), crotonimide B (4), and
julocrotine (2) have been synthesized starting from Boc-L-glutamine (7). The benzylic alcohol chiral centre of cor-
diarimides B (6) has been established in 6∶ 1 diastereoselectivity by catalytic asymmetric hydrogenation using
Zhou’s catalytic system Pd(CF3CO2)2/(R,R)-Me-DuPhos.
Keywords glutarimides, alkaloids, asymmetric hydrogenation, diastereoselectivity, enantioselective synthesis
Introduction
MOLT-3 cell line, (S)-cordiarimides A (5) and
(3S,8S)-cordiarimides B (6) inhibited superoxide anion
radical formation in the xanthine/xanthine oxidase
(XXO) assay, with respective IC50 values of 54.1 and
Glutarimide derivatives are a class of compounds
possessing important bioactivities. Racemic thalidomide
(1) is the most well known glutarimide derivative, as it
has been introduced as a sedative drug in the late 1950s
(Figure 1). In 1961, it was withdrawn due to
teratogenicity and neuropathy. It has been revealed that
the R-enantiomer is effective against morning sickness
but the S-enantiomer is teratogenic. There is now a
growing clinical interest in thalidomide.1 It has been
discovered that thalidomide was a potent inhibitor of
new blood vessel growth (angiogenesis), and is
introduced as an immunomodulatory agent used
primarily, combined with dexamethasone, to treat
multiple myeloma.2 The FDA has also approved the
drug's use in the treatment of erythema nodosum lepro-
sum. There are studies underway to determine the drug's
effects on arachnoiditis and several types of cancers.3
Glutarimide derivatives were reported to be potent
aminopeptidase N (APN/CD13) inhibitors.4 Glutarimide
alkaloids were also found in some plants. For example,
(3S,11S)-julocrotine (2) was isolated from Julocroton
montevidensis;5 Croton membranaceus,6 and other spe-
cies;7,9 (S)-crotonimides A (3) and B (4) are found in
Croton pullei var. glabrior Lanj.9 Recently,
(S)-cordiarimides A (5) and (3S,8S)-cordiarimides B (6)
were isolated from the roots of Cordia globifera (Bo-
raginaceae), which is native to tropical America, Africa,
and Asia (Figure 1).10 Glutarimide alkaloids isolated
from Croton cuneatus were reported to exhibit cytotoxic
activity.8 While showed weak cytotoxicity against the
－
21.7 µmol•L , respectively.10 These radical scavenging
activities suggest that both 5 and 6 may have potential
for cancer chemoprevention. In connection with our
interest in the development of malimides and glutarim-
ides-based synthetic methodologies for the asymmetric
synthesis of N-containing bioactive compounds,11 we
undertook the synthesis of glutarimide alkaloids 2—6,
and the results are reported herein.
1
Figure 1 Structures of synthetic and naturally occurring bioac-
tive glutarimide derivatives.
*
E-mail: zjf485@xmu.edu.cn; pqhuang@xmu.edu.cn
Received January 21, 2011; revised February 24, 2011; accepted March 29, 2011.
Project supported by the National Natural Science Foundation of China (No. 20832005) and the National Basic Research Program (973 Program) of
China (No. 2010CB833200).
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Chin. J. Chem. 2011, 29, 1312— 1318

Enantioselective Synthesis of Glutarimide Alkaloids
Results and discussion
of KI in acetone at reflux for 15 min produced com-
pound 9 in 87% yield. Removal of the Boc group (TFA,
10 equiv., CH2Cl2, 0.5 h), followed by acetylation
(Ac2O, CH2Cl2, 5 h) gave, in one-pot, (S)-cordiarimide
A (5) in 82% yield. The physical {[α]2D0 －32.8 (c 0.9,
CHCl3), lit.10 [α]D20 －29 (c 0.36, CHCl3)} and spectral
data of our synthetic product are in good agreement
with those reported,10 except the resonance at δ 1.96.
This resonance corresponds to that appears at δ 1.98 (for
compound 5) in reference 10, in which the interpretation
of this peak as a “ddd” with J＝4.7, 13.0, 26.2 Hz for
H-4 is not convincing. After a detailed NMR study, this
peak was interpreted as δ 1.96 (ddt, J＝13.0, 5.4, 13.0
Hz, 1H, H-4), and that for the natural product should be
revised accordingly.
Most methods reported so far for the synthesis of
glutarimide derivatives started from glutamic acid,12 and
that started from commercially available Boc-L-gluta-
mine appeared to be the most efficient, and was adopted
in our study.4b,4e Thus, treatment of Boc-L-glutamine (7)
with 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide
hydrochloride carbodiimide (EDCI), 1-hydroxybenzo-
triazole (HOBt) and NEt3 in dichloromethane gave the
desired glutarimide derivative 8 in 70% yield (Scheme
1). Reaction of glutarimide 8 with 2-bromoacetophe-
none in the presence of K2CO3 and a catalytic amount
Scheme 1 Synthesis of (S)-cordiarimide A (5)
With (S)-cordiarimide A (5) in hand, we proceeded
to investigate its diastereoselective reduction to prepare
(3S, 8S)-cordiarimide B (6) (Scheme 2). In an attempt to
perform a substrate-controlled reduction, we first tried
Pd(OH)2/C-catalyzed hydrogenation in MeOH. How-
ever, only deoxygenated product 10 was obtained in
95% yield. Alternatively, Pd/C-catalyzed hydrogenation
in MeOH afforded compound 11 as a 1 ∶ 1 di-
astereomeric mixture in 95% combined yield. This re-
sult showed that the chiral center in the glutarimide ring
had no impact on the diastereoselectivity of the reduc-
tion. We then tried the Corey-Bakshi-Shibata (CBS)
asymmetric reduction,15 unfortunately reaction of cor-
diarimide A with chiral methyl-substituted oxa-
zoborolidine and borane in either DCM or THF did not
give the desired product.15d The failure may be due to
reduction of the carbonyl group of imide by borane.13
Scheme 2 Synthesis of (3S,8S)-cordiarimide B (6)
Chin. J. Chem. 2011, 29, 1312— 1318
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Teng et al.
FULL PAPER
We next called for catalytic asymmetric hydrogen-
nation.16 In this context, many successful examples of
Pd(0)-catalyzed asymmetric hydrogenation methods
have been documented in the recent literatures,14 and
Zhou’s catalytic system14a was adopted. In Zhou’s
asymmetric catalytic system, ligand (R,R)-Me-DuPhos
was shown to produce R-benzylic alcohols. Thus, in the
presence of Pd(CF3CO2)2 and (S,S)-Me-DuPhos, cor-
diarimide A (5) was hydrogenised in dry 2,2,2-trifluo-
roethanol (TFE) under 15×105 Pa of hydrogen at 50 ℃
for 12 h to produce the corresponding benzylic alcohol
in 6∶1 diastereomeric ratio with 95% combined yield.
After decantation, pure major diastereomer was ob-
tained in 75% yield, and was shown to be the desired
one (6) with a C-8 S configuration. The physical {[α]D20
＋ 18.8 (c 0.71, CHCl3); lit.10 [α]D20 ＋ 20 (c 0.53,
CHCl3)} and spectral data of the synthetic product were
in good agreement with those reported.
We next turned to the synthesis of (S)-crotonimide A
(3) and (S)-crotonimide B (4) (Scheme 3). For this pur-
pose, glutarimide 8 was treated with (2-bromoethyl)-
benzene in acetone at reflux, which gave the desired
alkylated compound 12 in 55% yield. Unfortunately, no
optical rotation was observed for compound 12, which
indicated that a total racemization occurred. To avoid
the racemization, Mitsunobu reaction17 was envisioned.
Thus, treatment of glutarimide 8 with DIAD, PPh3, and
2-phenylethanol at r.t. gave the N-alkylated product 12
in 55% yield {[α]2D0 －15 (c 1.0, CHCl3)}. Successive
treatment of compound 12 with TFA and propionic an-
hydride (NEt3, DMAP (cat.), CH2Cl2) provided
(S)-crotonimide A (3) in 80% yield {m.p. 101—102 ℃
(EtOAc/P.E.), lit.9 m.p. 98.5—99.5 ℃; [α]2D0 －10.8 (c
0.6, CHCl3), lit.9 [α]D20 －9.8 (c 0.1, CHCl3)}. Similarly,
successive treatment of compound 12 with TFA and
isobutyric anhydride produced (S)-crotonimide B (4) in
77% yield {m.p. 126—127 ℃ (EtOAc/P.E.), lit.9 m.p.
127.5.5—128.5 ℃; [α]2D0 －12.8 (c 0.42, CHCl3), lit.9
[α]2D0 －12.5 (c 0.10, CHCl3)}. The spectral data of our
synthetic products are in accordance with that reported.9
Alternatively, we also undertook the synthesis of
(S)-crotonimide A (3) from compound 9 by another
route (Scheme 4). Treatment of compound 9 with TFA
and propionic anhydride provided compound 13 in 75%
yield. Pd(OH)2/C-catalyzed hydrogenation of compound
13 in MeOH gave (S)-crotonimide A (3) in 95% yield.
The overall yield by this route increased to 43% com-
paring with the first one (30%, cf. Scheme 3).
The syntheses of (3S, 11S)-julocrotine (2) were next
undertaken (Scheme 5). Successive treatment of com-
pound 12 with TFA and (S)-2-methylbutyric anhydride
(NEt3, DMAP (cat.), CH2Cl2) produced (3S,11S)-ju-
locrotine (2) in 79% yield. The physical and spectral
data of our synthetic (3S,11S)-julocrotine (2) {[α]D20
－9.2 (c 1.2, CHCl3); lit.5 [α]D20 －9 (c 1.0, CHCl3)} are
in good agreement with the reported ones.7
In summary, concise and efficient enantioselective
syntheses of five glutarimide alkaloids cordiarimides A
(5), cordiarimides B (6), crotonimide A (3), crotonimide
B (4), and julocrotine (2) have been achieved for the
first time. The benzylic alcohol chiral centre of cor-
diarimides B (6) was established in 6∶1 diastereose-
Scheme 3 Syntheses of (S)-crotonimide A (3) and (S)-crotonimide B (4)
Scheme 4 Synthesis of (S)-crotonimide A (3)
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© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 1312— 1318

Enantioselective Synthesis of Glutarimide Alkaloids
Scheme 5 Synthesis of (3S,11S)-julocrotine (2)
lectivity by catalytic asymmetric hydrogenation using
Zhou’s catalytic system Pd(CF3CO2)2/(R,R)-Me-
DuPhos. The overall yields from Boc-L-glutamine were
49%, 47%, 43%, 29%, and 30%, respectively. The syn-
theses of these natural products confirmed their struc-
tures.
MS (ESI) m/z: 229 (M＋H＋).
tert-Butyl (S)-2,6-dioxo-1-(2-oxo-2-phenylethyl)-
piperidin-3-ylcarbamate (9) To a mixture of 8 (315
mg, 1.38 mmol), K2CO3 (152 mg, 1.1 mmol) and KI
(130 mg, 0.77 mmol) in dry acetone (40 mL) was added
2-bromoacetophenone (272 mg, 1.38 mmol). The reac-
tion mixture was then refluxed for 15 min and filtered.
The filtrate was concentrated under reduced pressure to
obtain a yellow solid, which was dissolved in 20 mL
EtOAc and then washed with water (10 mL) and brine
(5 mL). The organic phases were dried over Na2SO4,
filtered and concentrated under reduced pressure. The
residue was purified by flash column chromatography
on silica gel (eluent: EtOAc∶PE＝1∶2, volume ratio)
to afford 9 (185 mg, 87%) as a white foam. [α]2D0 －36
(c 0.6, MeOH); 1H NMR (CDCl3, 400 MHz) δ: 1.37 (s,
9H), 1.94 (ddt, J＝13.0, 5.1, 13.0 Hz, 1H, H-4),
2.39—2.44 (m, 1H, H-4), 2.68—2.90 (m , 2H, H-5),
4.36—4.48 (m, 1H, H-3), 5.08 (d, J＝17.0 Hz, 1H,
H-7), 5.15 (d, J＝17.0 Hz, 1H, H-7), 5.44 (d, J＝5.1 Hz,
1H, NHBoc), 7.39—7.86 (m, 5H, ArH); 13C NMR
(CDCl3, 100 MHz) δ: 24.5, 28.1, 31.4, 46.3, 52.1, 80.0,
127.8, 128.6, 133.7, 134.4, 155.4, 171.0, 171.6, 191.3;
IR (film) vmax: 3381, 2977, 1707, 1512, 1365, 1222,
Experimental
General methods
Melting points were determined on a micro melting
point apparatus and were uncorrected. Infrared spectra
were measured with a FT-IR spectrometer using film
1
KBr pellet techniques. H NMR and 13C NMR spectra
were recorded in CDCl3 at 400 MHz and 100 MHz re-
spectively. Chemical shifts (δ) are expressed downfield
from TMS. Mass spectra were recorded with a liquid
chromatography-mass spectrum apparatus (direct injec-
tion). Optical rotations were measured with a polarime-
ter. Silica gel (300—400 mesh) was used for flash
column chromatography, eluting (unless otherwise
stated) with ethyl acetate/petroleum ether (PE) (60—90
℃) mixture. Ether and THF were distilled over sodium
benzophenone ketyl under N2. Dichloromethane was
distilled over calcium hydride under N2.
－1
＋
1156 cm ; MS (ESI) ＋m/z: 347 (M＋H ). HRMS calcd
for [C18H22N2O5＋Na] 370.1460, found 370.1456.
[(S)-N-(2,6-Dioxo-1-(2-oxo-2-phenylethyl)piperi-
din-3-yl)acetamide] (S)-cordiarimide A (5) To a
solution of 9 (107 mg, 0.31 mmol) in DCM (4 mL) was
slowly added trifluoroacetic acid (0.5 mL). The mixture
was stirred at room temperature for 30 min and concen-
trated under reduced pressure to give a yellow solid,
which was dissolved in DCM (4 mL) and then added
Ac2O (0.25 mL, 2.4 mmol). The mixture was stirred at
room temperature for 5 h. The solution was concentra-
ted under reduced pressure. The residue was purified by
flash column chromatography on silica gel (eluent:
EtOAc ∶ PE ＝ 3 ∶ 1, volume ratio) to afford
(S)-cordiarimide A (5) (73 mg, 82%) as a white foam.
[α]2D0 －32.8 (c 0.9, CHCl3) {lit.10 amorphous solid,
tert-Butyl (S)-2,6-dioxopiperidin-3-ylcarbamate
(8) To a solution of Boc-L-glutamine (Boc-L-Gln)
(S)-7 (284 mg, 1.15 mmol), HOBt (234 mg, 1.70 mmol)
and EDCI (332 mg, 1.70 mmol) in dry DCM (15 mL)
was added TEA (0.32 mL, 2.5 mmol) at 0 ℃. The
mixture was stirred at 0 ℃ for 1 h and at room tem-
peratur－e for 48 h. The reaction was quenched with 2
1
mol•L
HCl (5 mL). The resulting mixture was
washed with sat. aqueous solution of NaHCO3 (5 mL)
and brine (5 mL). The organic phases were dried over
MgSO4, filtered and concentrated under reduced pres-
sure. The residue was purified by flash column chro-
matography on silica gel (eluent: EtOAc∶PE＝1∶1,
volume ratio) to afford 8 (185 mg, 70%) as a white
solid. m.p. 215—216 ℃ (EtOAc/PE) [lit.4b m.p.
212—214 ℃]; [α]D20 －61.0 (c 0.95, MeOH) {lit.4b
1
[α]2D6 －29 (c 0.36, CHCl3)}; H NMR (CDCl3, 600
1
[α]2D5 －58.2 (c 1.05, MeOH)}; H NMR (CDCl3, 400
MHz) δ: 1.96 (ddt, J＝13.0, 5.4, 13.0 Hz, 1H, H-4),
2.05 (s, 3H, CH3), 2.50—2.58 (ddt, J＝13.0, 3.0, 5.4 Hz,
1H, H-4), 2.86 (ddd, J＝13.0, 5.4, 18.0 Hz, 1H, H-5),
2.93 (ddd, J＝5.4, 3.0, 18.0 Hz, 1H, H-5), 4.74 (ddd,
J＝13.0, 5.4, 5.4 Hz, 1H, H-3), 5.17 (d, J＝17.0 Hz, 1H,
H-7), 5.26 (d, J＝17.0 Hz, 1H, H-7), 6.57 (d, J＝5.4 Hz,
1H, NH, D2O exchangeable), 7.52—8.05 (m, 5H, ArH);
MHz) δ: 1.43 (s, 9H), 1.80—2.00 (m, 1H, H-4),
2.45—2.56 (m, 1H, H-4), 2.61—2.82 (m, 2H, H-5),
4.38—4.42 (m, 1H, H-3), 5.37—5.45 (m, 1H, NHBoc),
8.48 (s, 1H, NH)); 13C NMR (CDCl3, 100 MHz) δ: 25.4,
28.2, 31.2, 51.9, 80.5, 155.5, 171.6; IR (film) vmax
3357, 3186, 3086, 2963, 1757, 1736, 1527, 1355 cm ;
:
－1
Chin. J. Chem. 2011, 29, 1312— 1318
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Teng et al.
FULL PAPER
13C NMR (CDCl3, 150 MHz) δ: 23.1, 24.4, 31.5, 46.4,
51.4, 128.0, 128.9, 133.9, 134.6, 170.3, 170.9, 171.8,
191.4; IR (film) vmax: 3288, 3059, 2940, 1685, 1535,
tert-Butyl (S)-2,6-dioxo-1-phenethylpiperidin-3-
ylcarbamate (12) To a solution of 8 (448 mg, 1.96
mmol), PPh3 (562 mg, 2.15 mmol) and diisopropyl
azodicarboxylate (DIAD) (0.42 mL, 2.15 mmol) in dry
THF (10 mL) was added 2-phenylethanol (0.18 mL,
1.56 mmol). The mixture was stirred at room tempera-
ture for 24 h and then concentrated under reduced
pressure. The residue was purified by flash column
chromatography on silica gel (eluent: EtOAc∶PE＝
1∶2, volume ratio) to afford 12 (368 mg, 55%) as a
white solid. m.p. 127—129 ℃ (EtOAc/PE); [α]D20
＋
－1
1367, 1237, 1155 cm ; MS (ESI) m/z: 289 (M＋H ).
(S)-N-(2,6-Dioxo-1-phenethylpiperidin-3-yl)acet-
amide (10) To a mixture of (S)-cordiarimide A (5)
(100 mg, 0.35 mmol) and 20% Pd(OH)2/C (20 mg) was
added MeOH (5 mL). The mixture was stirred at room
temperature under an atmosphere of H2 for 12 h, fol-
lowed by filteration over Celite and concentrated under
reduced pressure to afford 10 (100 mg, 95%) as a white
solid. m.p. 123.1—124.5 ℃ (EtOAc/PE); [α]2D0 －8.2
1
－12.4 (c 0.8, CHCl3); H NMR (CDCl3, 400 MHz) δ:
1
1.38 (s, 9H), 1.65 (ddt, J＝12.6, 5.0, 12.6 Hz, 1H, H-4),
2.32—2.38 (m, 1H, H-4), 2.52—2.64 (m, 1H, H-5),
2.65—2.75 (m, 3H, C5-H, H-8), 3.84—3.97 (m, 2H,
H-7), 4.12—4.20 (m, 1H, H-3), 5.39 (d, J＝5.0 Hz, 1H,
(c 0.7, CHCl3); H NMR (CDCl3, 400 MHz) δ: 1.61
(ddt, J＝12.9, 4.6, 12.9 Hz, 1H, H-4), 1.98 (s, 3H),
2.45—2.52 (m, 1H, H-4), 2.60—2.80 (m, 4H, H-5,
H-8), 3.92—4.08 (m, 2H, H-7), 4.45 (ddd, J＝12.9, 4.6,
4.6 Hz, 1H, H-3), 6.48—6.52 (m, 1H, NH), 7.12—7.25
(m, 5H, ArH); 13C NMR (CDCl3, 100 MHz) δ: 23.0,
24.2, 31.5, 33.7, 41.4, 51.2, 126.5, 128.3, 128.8, 137.9,
170.2, 170.8, 171.6; IR (film) vmax: 3292, 3059, 3029,
13
NH), 7.11—7.25 (m, 5H, ArH); C NMR (CDCl3, 100
MHz) δ: 24.6, 28.1, 31.5, 33.7, 41.4, 51.2, 80.1, 126.4,
128.2, 128.8, 138.0, 155.4, 170.9, 171.5; IR (film) vmax
:
3347, 2981, 2929, 1702, 1671, 1494, 1367, 1241, 1148
＋
－1
－1
cm ; MS (ESI) m＋/z: 333 (M＋H ). HRIMS calcd for
2957, 1678, 1548, 1367 cm ; MS (ESI) m/z: 275 (M＋
＋
＋
[C18H24N2O4＋Na] 355.1634, found 355.1638.
H
). HRESIMS calcd for [C15H18N2O3 ＋ Na]
[(S)-N-(2,6-Dioxo-1-phenethylpiperidin-3-yl)pro-
pionamide] (S)-crotonimide A (3) To a solution of
12 (125 mg, 0.37 mmol) in DCM (4 mL) was slowly
added trifluoroacetic acid (0.5 mL). The mixture was
stirred at room temperature for 30 min and concentrated
under reduced pressure to give a yellow solid. The solid
was dissolved in DCM (4 mL) and then added propi-
onic anhydride (0.48 mL, 3.7 mmol). The mixture was
stirred at room temperature for 5 h, and then concen-
trated under reduced pressure. The residue was purified
by flash column chromatography on silica gel (eluent:
EtOAc ∶ PE ＝ 1 ∶ 1, volume ratio) to afford
(S)-crotonimide A (3) (85 mg, 80%) as a white solid.
m.p. 101—102 ℃ (EtOAc/PE) [lit.9 colorless solid,
m.p. 98.5—99.5 ℃]; [α]2D0 －13.8 (c 0.4, CHCl3) {lit.9
[α]D －9.8 (c 0.1, CHCl3)}; 1H NMR (CDCl3, 400 MHz)
δ: 1.11 (t, J＝7.6 Hz, 1H, CH3), 1.60 (ddt, J＝13.0, 5.1,
13.0 Hz, 1H, H-4), 2.35—2.40 (m, 1H, CH2CH3), 2.50
(ddt, J＝13.0, 2.3, 5.1 Hz, 1H, H-4), 2.60—2.65 (m, 1H,
H-5), 2.70—2.82 (m, 3H, C5-H, H-8), 3.93—4.05 (m,
2H, H-7), 4.60 (ddd, J＝13.0, 5.1, 5.1 Hz, 1H, H-3),
6.36 (d, J＝5.1 Hz, 1H, NH), 7.18—7.31 (m, 5H, ArH);
13C NMR (CDCl3, 100 MHz) δ: 9.5, 24.4, 29.5, 31.6,
33.9, 41.6, 57.7, 126.6, 128.4, 128.9, 138.1, 170.9,
171.8, 174.2; IR (film) vmax: 3336, 2957, 2926, 1712,
297.1215, found 297.1209.
{N-[(S)-1-[(S)-2-Hydroxy-2-phenylethyl]-2,6-di-
oxopiperidin-3-yl]acetamide} (3S,8S)-cordiarimide
B (6) To a mixture of (S,S)-Me-DuPhos (13 mg, 0.04
mmol) and Pd(CF3CO2)2 (13 mg, 0.04 mmol) in a dried
schlenk tube was added degassed anhydrous acetone
(0.5 mL) under nitrogen atmosphere in glove box. The
mixture was stirred at room temperature for 1 h and
then concentrated under reduced pressure to give the
catalyst (pure complex was directly used as the cata-
lyst). This catalyst and the substrate (S)-cordiarimide A
(5) (102 mg, 0.35 mmol) were dissolved in dry
2,2,2-trifluoroethanol (TFE) (1 mL) under nitrogen at-
mosphere in glove box, and then the mixture was
transferred into an autoclave. The reaction mixture in
autoclave was stirred under 15×105 Pa of hydrogen at
50 ℃. After 12 h, the hydrogen was carefully released.
The mixture was filtered over Celite and concentrated
under reduced pressure to give the corresponding ben-
zylic alcohol as a foam in 6∶1 diastereomeric ratio
(100 mg, 95%). The mixture was purified by decanta-
tion with a little of solvent (DCM∶PE＝1∶2, volume
ratio) several times, and was dried to give the pure di-
astereomer 6 (75 mg, 75%). [α]2D0 ＋18.8 (c 0.7, CHCl3)
{lit.10 amorphous solid, [α]D26 ＋20 (c 0.53, CHCl3)};
1H NMR (CDCl3, 400 MHz) δ: 1.73 (m, 1H, H-4), 2.00
(s, 3H), 2.44 (ddt, J＝13.0, 5.4, 13.0 Hz, 1H, H-4),
2.76—2.93 (m, 2H, H-5), 3.97 (dd, J＝13.7, 3.3 Hz, 1H,
H-7), 4.07 (dd, J＝13.7, 9.3 Hz, 1H, H-7), 4.48—4.90
(ddd, J＝13.0, 5.4, 5.4 Hz, 1H, H-3), 4.84 (m, 1H, H-8),
6.32 (d, J＝5.4 Hz, 1H, NH), 7.20—7.38 (m, 5H, ArH);
13C NMR (CDCl3, 100 MHz) δ: 23.0, 24.0, 31.6, 47.6,
51.3, 72.1, 125.8, 128.0, 128.5, 141.3, 170.7, 172.0,
172.8; IR (film) vmax: 3343, 1678, 1538, 1370, 1162,
－1
1675, 1511, 1372, 1148 cm ; MS (ESI) m/z: 289 (M＋
H＋).
(S)-N-(2,6-Dioxo-1-phenethylpiperidin-3-yl)iso-
butyramide) (S)-crotonimide B (4) To a solution of
12 (100 mg, 0.30 mmol) in DCM (4 mL) was slowly
added trifluoroacetic acid (0.5 mL). The mixture was
stirred at room temperature for 30 min and concentrated
under reduced pressure to give a yellow solid. The solid
was dissolved in DCM (4 mL) and then added iso-
butyric anhydride (0.47 mL, 3.0 mmol). The mixture
was stirred at room temperature for 5 h, and then con-
－1
＋
1029 cm ; MS (ESI) m/z: 291 (M＋H ).
1316
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© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 1312— 1318

Enantioselective Synthesis of Glutarimide Alkaloids
centrated under reduced pressure. The residue was pu-
rified by flash column chromatography on silica gel
(eluent: EtOAc∶PE＝1∶2, volume ratio) to afford
(S)-crotonimide B (4) (69 mg, 77%) as a white solid.
m.p. 126.0—127.0 ℃ (EtOAc/PE) [lit.9 colorless solid,
m.p. 127.5—128.5 ℃]; [α]2D0 －12.8 (c 0.4, CHCl3)
X. F.; Zhao, C. R.; Xu, F. W.; Li, Q. B.; Han, J. X. Cancer
Lett. 2010, 28, 153.
(d) Inagaki, Y.; Tang, W.; Zhang, L.; Du, G. H.; Xu, W. F.;
Kokudo, N. Biosci. Trends 2010, 4, 56.
(e) Zhang, X. P.; Fang, H.; Zhu, H. W.; Wang, X. J.; Zhang,
L.; Li, M. Y.; Li, Q. B.; Yuan, Y. M.; Xu, W. F. Bioorg.
Med. Chem. 2010, 18, 5981.
(a) Nakano, T.; Djerassi, C.; Corral, R. A.; Orazi, O. O. J.
Org. Chem. 1961, 26, 1184.
(b) Anastasi, C. Anales. Asoc. Quim. Argent. 1925, 13, 348.
Aboagye, F. A.; Sam, G. H.; Massiot, G.; Lavaud, C.
Fitoterapia 2000, 71, 461.
Moreira, R. Y. O.; Brasil, D. S. B.; Alves, C. N.; Guilhon,
G. M.; Santos, L. S.; Arruda, M. S. P. Int. J. Quantum.
Chem. 2008, 108, 513.
Suarez, A. I.; Blanco, Z.; Delle Monache, F.; Compagnone,
R. S.; Arvelo, F. Nat. Prod. Res. 2004, 18, 421.
(a) Barbosa, P. S.; Abreu, A. S.; Batista, E. F.; Guilhon, G.
M. S. P.; Müller, A. H.; Arruda, M. S. P.; Santos, L. S.;
Arruda, A. C.; Secco, R. S. Biochem. Syst. Ecol. 2007, 35,
887.
(b) Kutney, J. P.; Klein, F. K.; Eigendorf, G.; McNeill, D.;
Stuart, K. L. Tetrahedron Lett. 1971, 12, 4973.
(c) Stuart, K. L.; McNeill, D.; Kutney, J. P.; Eigendorf, G.;
Klein, P. K. Tetrahedron 1973, 29, 4071.
1
{lit.9 [α]D －12.5 (c 0.10, CHCl3)}; H NMR (CDCl3,
400 MHz) δ: 1.18 (d, J＝7.0 Hz, 3H, CH3), 1.19 (d, J＝
7.0 Hz, 3H, CH3), 1.66 (ddt, J＝13.0, 5.1, 13.0 Hz, 1H,
H-4), 2.38 [m, 1H, C(O)CH(CH3)2], 2.50 (ddt, J＝13.0,
2.3, 5.1 Hz, 1H, H-4), 2.60—2.68 (m, 1H, H-5),
2.72—2.81 (m, 3H, H-5, H-8), 3.88—4.07 (m, 2H,
H-7), 4.46 (ddd, J＝13.0, 5.1, 5.1 Hz, 1H, H-3), 6.35 (d,
J＝5.1 Hz, 1H, NH), 7.18—7.31 (m, 5H, ArH); 13C
NMR (CDCl3, 100 MHz) δ: 19.4, 19.5, 31.7, 33.9, 41.6,
51.3, 126.6, 128.4, 129.0, 138.1, 170.9, 171.8, 177.2;
IR (film) vmax: 3347, 2981, 2929, 1702, 1671, 1494,
5
6
7
8
9
＋
－1
1367, 1241, 1148 cm ; MS (ESI) m/z: 303 (M＋H ).
{(S)-N-[(S)-2,6-Dioxo-1-phenethylpiperidin-3-yl]-
2-methylbutanamide} (3S,11S)-Julocrotine (2) To a
solution of 12 (150 mg, 0.43 mmol) in DCM (4 mL)
was slowly added trifluoroacetic acid (0.5 mL). The
reaction was allowed to stir at room temperature for 30
min, and concentrated under reduced pressure to give a
yellow solid. The solid was dissolved in DCM (4 mL)
and then added (S)-2-methylbutyric anhydride (0.7 mL,
3.44 mmol), Et3N (0.12 mL, 0.86 mmol) and DMAP
(cat.). The mixture was stirred at room temperature for
3 h and the solution was concentrated under reduced
pressure. The residue was purified by flash column
chromatography on silica gel (eluent: EtOAc∶PE＝
3∶1, volume ratio) to afford (3S,11S)-julocrotine (2)
(78 mg, 79%) as a colorless oil. [α]2D0 －9.2 (c 1.2,
10 Parks, J.; Gyeltshen, T.; Prachyawarakorn, V.; Mahidol, C.;
Ruchirawat, S.; Kittakoop, P. J. Nat. Prod. 2010, 73, 992.
11 For an account, see:
(a) Huang, P.-Q. Synlett 2006, 1133.
For recent examples, see:
(b) Huang, P.-Q.; Fu, R.; Ye, J.-L.; Dai, X.-J.; Ruan, Y.-P. J.
Org. Chem. 2010, 75, 4230.
(c) Huang, P.-Q.; Yang, R.-F. Chem. Eur. J. 2010, 16,
10319.
1
CHCl3) {lit.5a [α]D －9 (c 1.0, CHCl3)}; H NMR
(CDCl3, 400 MHz) δ: 0.87 (t, J＝7.4 Hz, 3H, CH2CH3),
1.09 [d, J＝6.9 Hz, 3H, CH(CH3)], 1.40—1.51 (m, 1H,
H-12), 1.60—1.72 (m, 1H, H-12), 1.99 (ddt, J＝13.0,
5.3, 13.0 Hz, 1H, H-4), 2.14—2.21 (m, 1H, H-11),
2.44—2.55 (m, 1H, H-4), 2.60—2.82 (m, 4H, H-5,
H-8), 3.91—4.07 (m, 2H, H-7), 4.41 (ddd, J＝13.0, 5.3,
5.3 Hz, 1H, H-3), 6.23 (d, J＝5.3 Hz, 1H, NH),
7.10—7.24 (m, 5H, ArH); 13C NMR (CDCl3, 100 MHz)
δ: 11.8, 17.3, 24.4, 27.2, 31.7, 33.9, 41.6, 42.9, 51.1,
126.5, 128.4, 128.9, 138.1, 170.9, 171.8, 176.8; IR
(film) vmax: 3309, 2967, 2926, 1675, 1552, 1350, 1145
(d) Huang, P.-Q.; Liu, W.-J.; Ye, J.-L. Org. Biomol. Chem.
2010, 8, 2085.
12 (a) Luzzio, F. A.; Mayorov, A. V.; Ng, S. S.; Kruger, E. A.;
Figg, W. D. J. Med. Chem. 2003, 46, 3793.
(b) Zhu, X. X.; Giordano, T.; Yu, Q.-S.; Holloway, H. W.;
Perry, T. A.; Lahiri, D. K.; Brossi, A.; Gerig, N. H. J. Med.
Chem. 2003, 46, 5222.
(c) Capitosti, S. M.; Hansen, T. P.; Brown, M. L. Org. Lett.
2003, 16, 2865.
(d) Nakamura, T.; Noguchi, T.; Kobayashi, H.; Miachi, H.;
Hashimoto, Y. Chem. Pharm. Bull. 2006, 54, 1709.
(e) Robin, S. R.; Zhu, J. R.; Galons, H.; Pham-Huy, C.;
Claude, J. R.; Tomas, A.; Viossat, B. Tetrahedron: Asym-
metry 1995, 6, 1249.
＋
－1
cm ; MS (ESI) m/z: 317 (M＋H ).
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© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 1312— 1318