Palladium(II)-catalyzed synthesis of α-alkylidene-γ-butyrolactams from N-allylic 2-alkynamides. Total synthesis of (±)-isocynodine and (±)-isocynometrine

Article abstract of DOI:10.1021/jo001704u

An efficient method for preparing α-alkylidene-γ-butyrolactams via the Pd(II)-catalyzed cyclization of acyclic N-allylic 2-alkynamides via halopalladation, intramolecular olefin insertion, and β-heteroatom elimination was developed. The reaction is less influenced by the leaving group and the concentration of the halide ions in comparison with the cyclization of acyclic alkynoates. The total syntheses of (±)-isocynodine and (±)-isocynometrine were realized using this method.

Full text of DOI:10.1021/jo001704u

J . Org. Chem. 2001, 66, 6545-6550
6545
P a lla d iu m (II)-Ca ta lyzed Syn th esis of r-Alk ylid en e-γ-bu tyr ola cta m s
fr om N-Allylic 2-Alk yn a m id es. Tota l Syn th esis of (()-Isocyn od in e
a n d (()-Isocyn om etr in e
Xu Xie, Xiyan Lu,* Yanyun Liu, and Wei Xu
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Lingling Lu, Shanghai 200032, China
xylu@pub.sioc.ac.cn
Received December 4, 2000
An efficient method for preparing R-alkylidene-γ-butyrolactams via the Pd(II)-catalyzed cyclization
of acyclic N-allylic 2-alkynamides via halopalladation, intramolecular olefin insertion, and
â-heteroatom elimination was developed. The reaction is less influenced by the leaving group and
the concentration of the halide ions in comparison with the cyclization of acyclic alkynoates. The
total syntheses of (()-isocynodine and (()-isocynometrine were realized using this method.
In tr od u ction
Resu lts a n d Discu ssion
γ-Butyrolactam structures are widely spread in me-
dicinal chemistry.1 In particular, R-alkylidene-γ-butyro-
lactams show important biological activities, such as
cytotoxicity,2 antitumor,3 and antiinflamation activities
but with lower toxicity4 as compared with the corre-
sponding lactones. Therefore, the development of new
methods for the stereoselective synthesis of this kind of
molecules appears to be highly desirable. Generally,
R-alkylidene-γ-butyrolactams are synthesized by R-alkyl-
idenation of preformed lactams5 or from functionalized
acyclic precursors.6
Transition metal-catalyzed cyclization reactions have
received much attention owing to the template effect of
the transition metal.7 Recently, we have developed the
facile intramolecular enyne cyclization of allylic alkynoates
to build polysubstituted R-alkylidene-γ-butyrolactones via
a palladium(II) catalyst.8 However, their use in lactam
synthesis was limitedly exploited.9 In this paper, we wish
to report our recent results on the palladium(II)-catalyzed
synthesis of R-alkylidene-γ-butyrolactams from N-allylic-
2-alkynamides and the total synthesis of (()-isocynodine
and (()-isocynometrine using this methodology.
Cycliza tion of Acyclic N-Allylic-2-Alk yn a m id es. In
our previous work, R-alkylidene-γ-butyrolactones have
been successfully synthesized from 4′-substituted allylic
alkynoates catalyzed by Pd(II) species.10a In this method,
the reaction was initiated by the halopalladation of the
triple bond first, followed by intramolecular carbon-
carbon double bond insertion, and the Pd(II) species is
regenerated via â-heteroatom elimination to make the
catalytic cycle possible. N-Allylic alkylamides (1a , 2a , and
3a ) with different substitutents (Br, OAc, and OH) were
tried using the reaction conditions similar to those
reported for the cyclization of allylic alkynoates.10 To our
surprise, the variation of leaving groups has less influ-
ence on the â-heteroatom elimination as compared with
the cyclization of allylic alkynoates10b (Table 1). Moreover,
the rate of cyclization, the yield, and the stereoselectivity
of the exocyclic double bond were less influenced by the
concentration of the halide ions11 (Table 2).
On the basis of the reaction conditions studied, N-(4′-
acetoxybut-2′-enyl)alk-2-ynamides 2 were treated with
10 mol % of Pd(OAc)2 and 6 equiv of lithium halide in
HOAc. The results are shown in Table 3. Variation of
the substituents on the nitrogen atom influenced the
cyclization greatly on the rate of the reaction (Table 3,
entries 1, 6, and 7). N-Benzyl-substituted amides are the
most reactive. In all cases, the reaction gives high
Z-selectivity of the exocyclic double bond. The Z-selectiv-
ity decreased with the increased bulkiness of R (Table 3,
entries 1-4), which is similar to our previous results on
the cyclization of allylic alkynoates.10
(1) Nilsson, B. M.; Ringdahl, B.; Hacksell, U. J . Med. Chem. 1990,
33, 580. Fergmann, H. P.; Gericke, R. J . Med. Chem. 1990, 33, 492.
(2) Belaud, C.; Roussakis, C.; Latouurnoux, Y.; Alami, N. E.;
Villieras, J . Synth. Commun. 1985, 15, 1233.
(3) Kornet, M. J . J . Pharm. Soc. 1979, 68, 350.
(4) Patra, R.; Maiti, S. B.; Chatterjee, A.; Chakravarty, A. K.
Tetrahedron Lett. 1991, 32, 1363
(5) Seidland, M. C.; Cook, K. S. J . Heterocycl. Chem. 1965, 2, 171.
Zimmer, H.; Armbruster, D. C.; Trauth, L. T. J . Heterocycl. Chem.
1965, 2, 171. Warnhoff, H.; Lohmar, R. Synthesis 1976, 331. Kametam,
T.; Ihara, M. J . Chem. Soc. C 1971, 999
(6) Alami, N. E.; Belaud, C.; Villieras, J . Tetrahedron Lett. 1987,
28, 59. Henin, F.; Muzart, J .; Pete, J . P. Tetrahedron Lett. 1986, 27,
6339. Brown, W. R.; Heaney, H.; J ordan, B. M. Tetrahedron Lett. 1988,
29, 6657. Tanaka, K.; Yoda, H.; Isob, Y.; Kaji, A. J . Org. Chem. 1986,
51, 1856.
(7) Nobels, A. F.; Graziani, M.; Hubert, A. J . Metal Promoted
Selectivity in Organic Synthesis; Kluwer Academic Publishers: Dor-
drecht, 1991. Trost, B. M. Pure Appl. Chem. 1992, 64, 315. Negishi,
E. Pure Appl. Chem. 1992, 64, 323. Ba¨ckvall, J .-E. Pure Appl. Chem.
1992, 64, 429. Kishi, Y. Pure Appl. Chem. 1992, 64, 343
(8) Lu, X.; Zhu, G.; Wang. Z. Synlett 1998, 115.
(9) J iang, H.; Ma, S.; Zhu, G.; Lu, X. Tetrahedron 1996, 52, 10945.
Xie, X.; Lu, X. Tetrahedron Lett. 1999, 40, 8415. Xie, X.; Lu, X. Synlett
2000, 707.
Taking into account of the fact that two types of
conformation are possible for an amide,12 a mechanism
slightly different from our previous publication10 was
proposed (Scheme 1).
Compound 2 first coordinates with Pd(II), and the
subsequent stereoselective halopalladation of carbon-
carbon triple bond in the presense of LiX may afford the
(10) (a) Ma, S.; Lu, X. J . Org. Chem. 1991, 56, 5120. (b) Zhu, G.;
Lu, X. Organometallics 1995, 14, 4899.
(11) Ma, S.; Zhu, G.; Lu, X. J . Org. Chem. 1993, 58, 3692.
(12) Stewart, W. E.; Siddall, T. H., III. Chem. Rev. 1970, 70, 517.
10.1021/jo001704u CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/12/2001

6546 J . Org. Chem., Vol. 66, No. 20, 2001
Xie et al.
Ta ble 1. P a lla d iu m (II)-Ca ta lyzed Cycliza tion of
elimination and regenerates the Pd(II) species. As there
exists a cis-trans isomer of amides A and B,12 the
insertion of a carbon-carbon double bond will be impos-
sible with the intermediate B. In the literature,13 it was
reported that the equilibrium distribution of two types
of conformation of alkynamides in solution depends
mainly upon the steric repulsion between the groups on
the carbonyl carbon atom and the nitrogen atom. Thus,
compounds 2 with bulkier benzyl group on nitrogen atom
have a stronger preference of A over B, which should be
responsible for the sharp difference of the cyclization rate
of substrates 2 with different substituents on the nitrogen
atom.
N-Allylic Alk yn a m id es w ith Differ en t Lea vin g Gr ou p sa
entry
X
substrate
time (h) yieldb (%) ratioc (Z/E)
1
2
3
Br
OAc
OH
1a
2a
3a
4
4
5
89.5
93.1
90.5
95:5
94:6
94:6
Ster eoch em istr y of P a lla d iu m -Ca ta lyzed Cycliza -
tion of N-(1′-Su bstitu ted -4′-a cetoxybu t-2′-en yl)a lk -
2-yn a m id es. Based on the cyclization reaction of 2, we
further studied the relative stereochemistry of the â,γ-
substituents in the cyclization products when 1′-sub-
situtent was introduced. The results are outlined in Table
4.
a
A mixture of substrate (0.5 mmol), Pd(OAc)2 (0.05 mmol), LiBr
(2 mmol), and HOAc (2 mL) was stirred at room temperature, and
b
the reaction was monitored by TLC. Isolated yield; the products
were confirmed by 1H NMR, IR, MS, and elemental analysis.
c Ratio determined by 1H NMR spectra of the isolated products.
Ta ble 2. P d (II)-Ca ta lyzed Cycliza tion of 2a w ith
Differ en t Con cen tr a tion of Br om id e Ion sa
Similar to the cyclization of allylic substituted alkuno-
ates,11 the cyclization of substituted alkynamides (Table
4, entries 1, 3, and 4, R) alkyl group) predominantly
afforded â,γ-cis products, which became the only product
in the case of N-unblocked amides (Table 4, entries 3 and
4, R′ ) H), while the cyclization of unsubstituted propy-
namide (Table 4, entry 2, R ) H) showed low diastereo-
selectivity.
entry
LiBr (equiv)
time (h)
yieldb (%)
ratioc (Z/E)
1
2
3
4
5
1
2
4
6
8
4
4
4
4
4
92
91
93
93
93
89:11
92:8
94:6
96:4
97:3
Syn th esis of (()-Isocyn om etr in e (7) a n d (()-Iso-
cyn od in e (13). The cyclization products 4 are polyfunc-
tional γ-lactams that can undergo further transformation
for the synthesis of natural products. Isocynometrine is
an imidazole alkaloid isolated from Cynometra species.
It has been used in Africa as a traditional folk medicine
with antitussive and analgesic activities.14 The structure
of isocynometrine was determined by Riche et al. as 7,15
and Khuong-Huu et al. reported its synthesis from
1-methyl-5-methoxycarbonylimidazole.16 Comparing the
structure of isocynometrine with our cyclization product
4f, we envisioned that 4f can be used as the key precursor
to achieve the synthesis of isocynometrine (Scheme 2).
a
A mixture of 2a (137 mg, 0.5 mmol), Pd(OAc)2 (11 mg, 0.05
mmol), and HOAc (2 mL) was stirred at room temperature, and
the reaction was monitored by TLC. Isolated yield. c The Z/E
b
ratios were determined by 1H NMR spectra.
Ta ble 3. Cycliza tion of
N-(4′-Acetoxybu t-2′-en yl)a lk -2-yn a m id esa
We first tried the hydrolysis of vinylic bromide in 4f
to 8. In our previous work toward the synthesis of (()-A
factor, the vinylic bromide in the γ-lactone was hydro-
lyzed by first reacting with Et2NH to form the enamine
followed by the acid hydrolysis of the latter to form the
enol or the ketone.17,18 In the case of the hydrolysis of 4f
using the same reaction conditions, the reaction did not
take place. Then we tried the hydrolysis of the vinylic
bromide in different kinds of lactones and lactams (Table
5) and found that the electron density of the nitrogen
atom in the lactams greatly influenced the reactivity of
the vinylic bromide. Only the vinylic bromide in lactams
time
yieldc (%)
(Z/E)
entry
R
R′ substrate
X
(h) productb
1
2
3
4
5
6
7
8
9
Me
n-Pr
C7H15 Bz
Ph
H
Bn
Bn
2a
2b
2c
2d
2e
2e
2f
2g
2h
2i
Br
Br
Br
Br
Br
Cl
Br
Br
4
4
9
6
1
4a
4b
4c
4d
4e
4e′
4f
94 (96:4)
98 (88:12)
88 (85:15)
95 (60:40)d
89 (100:0)e
61 (100:0)e
92 (55:45)d
96 (92:8)e
78 (92:8)e
79 (53:47)d
Bn
Bn
Bn
Me
Me
H
H
1
Ph
Me
Me
Ph
H
24
14
18
30
4g
4h
Br
Br
Br/Cl
10
11
H
4i
f
H
2j
-
a
A mixture of 1 (0.5 mmol), Pd(OAc)2 (0.05 mmol), and LiX (3
mmol) in HOAc (2 mL) was stirred at room temperature; the
b
reaction was monitored by TLC. The products were identified
(13) Laplanchc, L. A.; Rogers, M. T. J . Am. Chem. Soc. 1963, 84,
3728.
(14) Khuong-Huu, F, Monseur, X.; Ratle, G.; Lukacs, G.; Goutarel,
R. Tetrahedron Lett. 1973, 1757.
(15) Chiaroni, A.; Riche, C.; Tchissambou, L.; Khuong-Huu, F. J .
Chem. Res., Synop. 1981, 182.
(16) Tchissambou, L.; Benechie, M.; Khuong-Huu, F. Tetrahedron
1982, 38, 2687.
by 1H NMR, IR, MS, and elemental analysis or HRMS. c Isolated
yield. Determined by 1H NMR spectra. e Isolated ratio. f Disor-
d
dered reaction.
vinylpalladium intermediate A and B. The intramolecu-
lar insertion of the carbon-carbon double bond into the
carbon-palladium bond in A yields the cyclic intermedi-
ate C, which in turn gives product 4 via â-acetoxy
(17) J i, J .; Zhang, C.; Lu, X. J . Org. Chem. 1995, 60, 1160.
(18) Pappoport, A. Z.; Topol, A. J . Org. Chem. 1989, 54, 5967.

Total Synthesis of (()-Isocynodine and (()-Isocynometrine
Sch em e 1
J . Org. Chem., Vol. 66, No. 20, 2001 6547
Ta ble 4. P a lla d iu m (II)-Ca ta lyzed Cycliza tion of
reduction of 8 with NaBH4 gave a pair of diastereisomers
9 and 10 in a 5:1 ratio, which could be separated by
column chromatography. The major product 9 has the
same relative stereochemistry with isocynometrine,16 as
N-(1′-Meth yl-4′-a cetoxybu t-2′-en yl)a lk yn a m id es 5a
1
confirmed by comparing the H NMR and IR spectra and
by X-ray diffraction. Protection the hydroxy group of 9
with benzoyl group and then ozonolysis of the double
bond at -78 °C produced the corresponding aldehyde 12.
The aldehyde 12 was treated successively in three steps
without purification to construct the imidazole ring to
obtain (()-isocynodine (13) according to the literature20
and then deprotected to give the target molecule (()-
isocynometrine (7).
In summary, we developed an efficient method for
preparing γ-butyrolactams via the Pd(II)-catalyzed cy-
clization of acyclic N-allylic 2-alkynamides. Referring to
the reaction rate and the stereoselectivity of the exocyclic
double bond, the reaction is less influenced by the leaving
group and the concentration of the halide ions in com-
parison with the cyclization of acyclic allylic alkynoates.
Furthermore, the total syntheses of (()-isocynodine and
(()-isocynometrine were realized using the cyclized
product as the key intermediate.
time
(h)
yield %b
entry
R
R′
substrate
product
(cis/trans)c
1
2
3
4
Me
H
Me
n-Pr
Bn
Bn
H
5a
5c
5f
5i
4
1
16
18
6a
6c
6f
6i
89 (86:14)
87 (46:54)
70 (>98:2)
72 (>98:2)
H
a
Reaction conditions: substrate (0.5 mmol), Pd(OAc)2 (0.05
mmol), LiBr (3 mmol), and HOAc (2 mL) at room temperature.
Isolated yield. c The stereochemistry was determined by NOESY
b
spectra, and the ratio was determined by 1H NMR spectra.
with electron-deficient substituent on the nitrogen atom
can be easily hydrolyzed.
For the hydrolysis of 4f, 14b, and 14d , we still met
difficulties probably due to the presence of the phenyl
group (Table 5, entries 2, 4, and 5). Recently, Buchwald
and Hartwig independently reported the nucleophilic
substitution of aromatic halides with amines.19 It occurs
to us that it is possible to convert the vinylic bromide to
the enamine using the similar method. Fortunately,
compound 8 could be obtained by a palladium-catalyzed
amination of the vinylic bromide 4f with piperidine
followed by hydrolysis of the enamine formed. Further
Exp er im en ta l Section
Ma ter ia ls. The catalysts Pd2(dba)3‚CHCl321 and Pd(OAc)2
22
were prepared by literature methods. LiBr and LiCl were dried
at 120 °C under reduced pressure for 4 h before use.
Cycliza tion of N-(4′-Acetoxybu t-2′-en yl)a lk -2-yn a m id es
(2): Typ ica l P r oced u r e. To a solution of Pd(OAc)2 (11 mg,
(20) Naito, T.; Honda, Y.; Bhavakul, V.; Yamaguchi, S.; Fujiwara,
A.; Miyata, O.; Ninomiya, I. Chem. Pham. Bull. 1997, 45, 1932
(21) Ukai, T.; Kawazura, H.; Ishii, Y.; J . Organomet. Chem. 1974,
65, 253.
(22) Stephenson, T. A.; Morchouse, S. M.; Powell, A. R.; Hetter, J .
P.; Wilkinson, G. J . Chem. Soc. 1965, 3632.
(19) Wolfe, J . P.; Wagaw, S.; Buchwald, S. L. J . Am. Chem. Soc.
1996, 118, 7215. Driver, M. S.; Hartwig, J . F. J . Am. Chem. Soc. 1996,
118, 7217.

6548 J . Org. Chem., Vol. 66, No. 20, 2001
Xie et al.
Sch em e 2a
a
Reaction conditions: (a) (i) Pd2(dba)3‚CHCl3 (4 mol %), dppf (8 mol %), piperidine (1.2 equiv), t-BuOK (1 equiv), THF, 55 °C, (ii) 3 N
HCl; (b) NaBH4, MeOH, -40 °C; (c) BzCl, DMAP, pyridine; (d) (i) O3, MeOH-CH2Cl2, -78 °C, (ii) Me2S, -78 to 0 °C; (e) (i) TsCH2NC,
t-BuOK, THF, -10 °C, (ii) POCl3, Et3N, THF, (iii) MeNH2, MeOH; (f) NaOH-MeOH.
(81Br)], 305 [M+, (79Br)], 227, 226, 107, 91 (100.00). Anal. Calcd
for C15 H16NOBr: C, 58.84; H, 5.27; N, 4.57. Found: C, 58.56;
H, 5.35; N, 4.61.
Ta ble 5. Hyd r olysis of Vin yl Br om id es in γ-La cton es a n d
γ-La cta m s
N-Ben zyl-r-br om obu tylid en e-â-vin yl-γ-bu tyr ola cta m
(4b). Z-Isomer: oil; IR (neat) ν 2963, 1690, 1639, 1423, 1153,
701 cm-1 1H NMR (CDCl3) δ 7.24-7.16 (m, 5H), 5.63-5.57
;
(m, 1H), 5.03-4.97 (m, 2H), 4.57 (d, J ) 14.6 Hz, 1H), 4.32 (d,
J ) 14.6 Hz, 1H), 3.55-3.50 (m, 1H), 3.33 (dd, J ) 9.7, 7.8
Hz, 1H), 2.83 (dd, J ) 9.7, 1.7 Hz, 1H), 2.44 (t, J ) 7.8 Hz,
2H), 1.67-1.53 (m, 2H), 0.85 (t, J ) 7.3 Hz, 3H); MS (m/e)
335 [M+, (81Br)], 333 [M+, (79Br)], 334, 332, 255, 254, 135, 91.
Anal. Calcd for C17H20NOBr: C, 61.09; H, 6.03; N, 4.19.
Found: C, 61.32; H, 6.19; N, 4.38. E-Isomer: oil; IR (neat) ν
substrate
yield (%)
entry
Y
R
R′
time (d)
15
1
2962, 1687, 1645, 1424, 1275, 701 cm-1; H NMR (CDCl3) δ
1
2
3
4
5
6
O
O
N
N
N
N
H
(14a )10
(14b)10
(14c)
(14d )
(4f)
1
78
7.26-7.14 (m, 5H), 5.64-5.59 (m, 1H), 5.06-5.00 (m, 2H), 4.48
(d, J ) 14.7 Hz, 1H), 4.34 (d, J ) 14.7 Hz, 1H), 3.55-3.51 (m,
1H), 3.37 (dd, J ) 9.7, 7.5 Hz, 1H), 3.37-3.30 (m, 1H), 3.21-
3.11 (m, 1H), 2.90 (dd, J ) 9.8, 1.3 Hz, 1H), 1.61 (tq, J ) 7.3,
7.3 Hz, 2H), 0.90 (t, J ) 7.4 Hz, 3H); MS (m/e) 335 [M+, (81Br)],
333 [M+, (79Br)], 255, 254, 92, 91; HRMS calcd for C17H20NOBr
333.0728, found 333.0725.
Ph
Me
Ph
Ph
Me
no reaction
59
no reaction
no reaction
no reaction
BOC
BOC
Me
3
Me
(4g)
0.05 mmol) and LiX (3 mmol) in HOAc (2 mL) was added 2
(0.5 mmol). The reaction was carried out at room temperature.
After the reaction was complete as monitored by TLC, CH2-
Cl2 (50 mL) was added. The mixture was washed with
saturated NaHCO3 and brine and dried (MgSO4). The solvent
was evaporated, and the residue was purified by chromatog-
raphy (silica gel, petroleum ether/ethyl acetate) to give cy-
clization product 4.
N-Ben zyl-r-b r om ooct ylid en e-â-vin yl-γ-b u t yr ola ct a m
(4c): Z-Isomer: oil; IR (neat) ν 2928, 1691, 1638, 1423, 1276,
701 cm-1 1H NMR (CDCl3) δ 7.35-7.23 (m, 5H), 5.70-5.64
;
(m, 1H), 5.10-5.04 (m, 2H), 4.64 (d, J ) 14.6 Hz, 1H), 4.39 (d,
J ) 14.6 Hz, 1H), 3.59 (m, 1H), 3.41 (dd, J ) 9.8, 7.8 Hz, 1H),
2.90 (dd, J ) 9.8, 1.7 Hz, 1H), 2.56-2.50 (m, 2H), 1.63-0.87
(m, 13H); MS (m/e) 391 [M+, (81Br)], 389 [M+, (79Br)], 311, 310,
92, 91. Anal. Calcd for C21H28NOBr: C, 64.61; H, 7.23; N, 3.59.
Found: C, 64.92; H, 7.28; N, 3.33. E-Isomer: oil; IR (neat) ν
2928, 1689, 1646, 1424, 1276, 700 cm-1;1H NMR (CDCl3) δ
7.33-7.21 (m, 5H), 5.77-5.66 (m, 1H), 5.14-5.07 (m, 2H), 4.55
(d, J ) 14.7 Hz, 1H), 4.43 (d, J ) 14.7 Hz, 1H), 3.59 (m, 1H),
3.44 (dd, J ) 9.7, 7.5 Hz, 1H), 3.40 (m, 1H), 3.26 (m, 1H), 2.98
(dd, J ) 9.8, 1.3 Hz, 1H), 1.55-0.86 (m, 13H); MS (m/e) 392
[M+ + 1, (81Br)], 390 [M+ + 1, (79Br)], 311, 310, 93, 91.
N-Ben zyl-r-b r om oet h ylid en e-â-vin yl-γ-b u t yr ola ct a m
(4a ). Z-isomer: oil; IR (neat) ν 2918, 1689, 1651, 1424, 701
cm-1 1H NMR (CDCl3) δ 7.32-7.23 (m, 5H), 5.72-5.63 (m,
;
1H), 5.10-5.03 (m, 2H), 4.61 (d, J ) 14.6 Hz, 1H), 4.43 (d, J
) 14.6 Hz, 1H), 3.61-3.56 (m, 1H), 3.43 (dd, J ) 9.7, 7.9 Hz,
1H), 2.92 (dd, J ) 9.7, 1.7 Hz, 1H), 2.40 (d, J ) 0.7 Hz, 3H);
MS (m/e) 307 [M +, (81Br)], 305 [M+, (79Br)], 226, 91 (100), 79,
77. Anal. Calcd for C15 H16NOBr: C, 58.84; H, 5.27; N, 4.57.
Found: C, 58.65; H, 5.38; N, 4.39. E-Isomer: oil; IR (neat) ν
N -Be n zyl-r-b r om ob e n zylid e n e -â-vin yl-γ-b u t yr ola c-
2961, 1689, 1651, 1439, 701 cm-1; H NMR (CDCl3) δ 7.23-
ta m (4d ): oil; IR (neat) ν 2918, 1690, 1639, 1422, 700 cm-1
;
1
7.20 (m, 5H), 5.76-5.65 (m, 1H), 5.13-5.07 (m, 2H), 4.56 (d,
J ) 14.7 Hz, 1H), 4.41 (d, J ) 14.7 Hz, 1H), 3.61-3.56 (m,
1H), 3.45 (dd, J 1)9.7 Hz, J 2)7.7 Hz, 1H), 2.98 (dd, J 1)9.7 Hz,
J 2)1.2 Hz, 1H), 2.94 (d, J ) 1.2 Hz, 3H); MS (m/e) 307 [M+,
1H NMR (CDCl3) δ 7.44-7.22 (m, 10H), 5.82-5.77 (m, 0.4H,
E), 5.57-5.45 (m, 0.6H, Z), 5.29-5.18 (m, 1H), 4.82-4.28 (m,
3H), 3.81-3.76 (m, 0.4H), 3.57-3.50 (m, 1H), 3.40 (dd, J )
9.5, 7.5 Hz, 0.6H), 3.06 (d, J ) 9.9 Hz, 0.4H), 2.90 (dd, J )

Total Synthesis of (()-Isocynodine and (()-Isocynometrine
9.8, 0.8 Hz, 0.6H); MS (m/e) 368 [M+ + 1, (81Br)], 366 [M+ + 1,
J . Org. Chem., Vol. 66, No. 20, 2001 6549
15.0 Hz, 0.14H, trans), 3.65-3.50 (m, 1.72H), 3.16-3.13 (m,
0.28H), 2.39 (s, 3H), 1.17 (d, J ) 6.3 Hz, 0.42H, trans), 1.08
(d, J ) 6.3 Hz, 2.58H, cis); MS (m/e) 320 [M+ + 1, 81Br)], 318
[M+ + 1, (79Br)], 241, 240, 91 (100), 107, 79. Anal. Calcd for
C16H18NO2Br: C, 60.01; H, 5.67; N, 4.37. Found: C, 59.99; H,
5.70; N, 4.30.
(79Br)], 288, 169, 141, 115, 91 (100). Anal. Calcd for C20H18
-
NOBr: C, 65.23; H, 4.93, N, 3.80. Found: C, 65.26; H, 4.97;
N, 3.79.
N-Ben zyl-r-(Z)-br om om eth ylen e-â-vin yl-γ-bu tyr ola c-
ta m (4e): oil; IR (neat) ν 3061, 1692, 1636, 1424, 701 cm-1
;
1H NMR (CDCl3) δ 7.36-7.25 (m, 5H), 6.47 (d, J ) 2.3 Hz,
1H), 5.72-5.60 (m, 1H), 5.19-5.12 (m, 2H), 4.60 (d, J ) 14.6
Hz, 1H), 4.45 (d, J ) 14.6 Hz, 1H), 3.52-3.45 (m, 1H), 3.40
(dd, J ) 9.5, 8.5 Hz, 1H), 3.01 (dd, J ) 9.5, 5.3 Hz, 1H); MS
(m/e) 293 [M+, (81Br)], 291 [M+, (79Br)], 212, 93, 92, 91(100),
65; HRMS calcd for C14H14NOBr 291.0258, found 291.0278.
N-Ben zyl-r-(Z)-ch lor om et h ylen e-â-vin yl-γ-b u t yr ola c-
cis- a n d tr a n s-N-ben zyl-r-(Z)-(br om om eth ylid en e)-â-
vin yl -γ-m eth yl-γ-bu tyr ola cta m (6c): oil; IR (neat) ν 2972,
1
1693, 1413, 748 cm-1; H NMR (CDCl3) δ 7.27-7.18(m, 5H),
6.37 (d, J ) 2.4 Hz, 0.54H, trans), 6.32 (d, J ) 2.6 Hz, 0.46H,
cis), 5.72-5.53 (m, 1H), 5.23-5.08 (m, 2H), 5.05 (d, J ) 14.9
Hz, 0.46H), 4.93 (d, J ) 14.9 Hz, 0.54H), 3.91 (d, J ) 14.9 Hz,
0.54H), 3.91 (d, J ) 14.9 Hz, 0.46H), 3.51 (dq, J ) 6.6, 6.4 Hz,
0.46H), 3.39 (m, 0.46H), 3.13 (dq, J ) 6.1, 6.1 Hz, 0.54H), 2.89
(m, 0.54H), 1.12 (d, J ) 6.2 Hz, 1.62H), 1.00 (d, J ) 6.2 Hz,
1.38H); MS (m/e) 307 [M+, (81Br)], 305 [M+, (79Br)], 227, 226,
91 (100), 65. Anal. Calcd for C15H16NO2Br: C, 58.84; H, 5.27;
N, 4.57. Found: C, 58.76; H, 5.39; N, 4.58.
ta m (4e′): oil; IR (neat) ν 3063, 2925, 1693, 1425 cm-1 1H
;
NMR (CDCl3) δ 7.34-7.25 (m, 5H), 6.28 (d, J ) 2.4 Hz, 1H),
5.69-5.60 (m, 1H), 5.19-5.12 (m, 2H), 4.59 (d, J ) 14.7 Hz,
1H), 4.46 (d, J ) 14.7 Hz, 1H), 3.57-3.49 (m, 1H), 3.42 (dd, J
) 9.6, 8.6 Hz, 1H), 2.95 (dd, J ) 9.6, 5.5 Hz, 1H); MS (m/e)
249 [M+, (81Br)], 247 [M+, (100), (79Br)], 249, 248, 212, 92, 91;
HRMS calcd for C14H14NOCl 247.0764, found 247.0746.
N -Me t h yl-r-b r om ob e n zylid e n e -â-vin yl-γ-b u t yr ola c-
cis-r-(Z)-(Br om oeth ylid en e)-â-vin yl -γ-m eth yl-γ-bu ty-
r ola cta m (6f): mp 122-123 °C; IR (Nujol) ν 3187, 2978, 1692,
1641, 920 cm-1 1H NMR (CDCl3) δ 6.41(br, 1H), 5.73-5.61
;
ta m (4f): oil; IR (neat) ν 2961, 1688, 1638 cm-1
;
1H NMR
(m, 1H), 5.21-5.12 (m, 2H), 3.84 (dq, J ) 6.7, 6.7 Hz, 1H),
3.61 (m, 1H), 2.38 (s, 3H), 1.08 (d, J ) 6.5 Hz, 3H); MS m/e:
232 [M+ + 1, (81Br)], 230 [M+ + 1, (79Br)], 150 (100), 107, 79,
78, 77. Anal. Calcd for C9H12NOBr: C, 46.98; H, 5.26; N, 6.09.
Found: C, 47.01; H, 5.28; N, 6.05.
(CDCl3) δ 7.43-7.29 (m, 5H), 5.94-5.85 (m, 0.45H, E), 5.64-
5.55 (m, 0.55H, Z), 5.33 (d, J ) 17.0 Hz, 0.45H, E), 5.27 (d, J
) 10.1 Hz, 0.45 H, E), 4.86 (d, J ) 10.1 Hz, 0.55H, Z), 4.65 (d,
J ) 17.0 Hz, 0.55H, Z), 3.83-3.00 (m, 3H), 2.99 (s, 1.65H),
2.86 (s, 1.35H); MS (m/e) 293 [M+, (81Br)], 291 [M+, (79Br)], 212,
155, 141 (100), 115. Anal. Calcd for C14 H14NOBr: C, 57.55;
H, 4.83; N, 4.79. Found: C, 57.63; H, 4.66; N, 4.59.
cis-r-(Z)-(Br om ob u t ylid en e)-â-vin yl-γ-m et h yl-γ-b u t y-
r ola cta m (6i): mp 93-95 °C; IR (Nujol) ν 3178, 2958, 1697,
1629, 917 cm-1 1H NMR (CDCl3) δ 6.36(br, 1H), 5.76-5.65
;
N-Meth yl-r-br om oeth ylid en e-â-vin yl-γ-bu tyr ola cta m
(4g). Z-Isomer: mp 61-62 °C; IR (Nujol) 2926, 1680, 1647,
1398, 924 cm-1; 1H NMR (CDCl3) δ 5.78-5.67 (m, 1H), 5.12-
5.05 (m, 2H), 3.61-3.50 (m, 2H), 3.02-2.98 (m, 1H), 2.89 (s,
3H), 2.37(s, 3H); MS (m/e) 232 [M+ + 1, (81Br)], 230 [M+ + 1,
(79Br)], 150 (100), 107, 79, 77, 42. Anal. Calcd for C9H12NOBr:
C, 46.98; H, 5.26; N, 6.09. Found: C, 47.19; H, 5.41; N, 5.92.
(m, 1H), 5.22-5.12 (m, 2H), 3.82 (dq, J ) 6.5, 6.5 Hz, 1H),
3.64 (m, 1H), 2.53-2.48 (m, 2H), 1.73-1.59 (m, 2H), 1.14 (d,
J ) 6.5 Hz, 3H), 0.93 (t, J ) 7.4 Hz, 3H); MS (m/e) 261 [M+,
(81Br)], 259 [M+, (79Br)], 258, 178 (100), 135, 105, 91, 79. Anal.
Calcd for C11H16NOBr: C, 51.18; H, 6.25; N, 5.43. Found: C,
51.54; H, 6.25; N, 5.23.
N-Meth yl-tr a n s-(r-ben zoyl-â-vin yl)-γ-bu tyr ola cta m (8).
To a Schlenk tube was added successively 4f (292 mg, 1 mmol),
Pd2(dba)3‚CHCl3 (41 mg, 0.04 mmol), dppf (44 mg, 0.08 mmol),
and piperidine (0.15 mL, 1.2 mmol) in dried THF (8 mL) under
Ar. The mixture was stirred at room temperature for 10 min,
and then KOBut (169 mg, 1.5 mmol) was added. The reaction
mixture was stirred at 55 °C for 2 h and cooled to room
temperature, 3 N HCl (5 mL) was added, and the mixture was
stirred for an additional 3 h at room temperature. CH2Cl2 (50
mL) was added, and the solution was washed with saturated
brine, dried (MgSO4), and purified by chromatography (silica
gel, petroleum ether/ethyl acetate ) 7:3) to give 8 (125 mg,
E-Isomer: oil; IR (neat) ν 2928, 1680, 1640 cm-1 1H NMR
;
(CDCl3) δ 5.81-5.69(m, 1H), 5.18-5.13 (m, 2H), 3.64-3.54 (m,
2H), 3.08 (d, J ) 8.5 Hz, 1H), 2.96 (s, 3H), 2.95 (s, 3H); MS
(m/e) 232 [M+ + 1, (81Br)], 230 [M+ + 1, (79Br)], 150 (100), 107,
79, 77, 42; HRMS calcd for C9H12NOBr 229.0102, found
229.0117.
r-Br om oeth ylid en e-â-vin yl-γ-bu tyr ola cta m (4h ). Z-Iso-
mer: mp 102-103 °C; IR (Nujol) ν 3183, 1694, 1637, 1488
cm-1 1H NMR (CDCl3) δ 7.10-6.90 (br, 1H), 5.86-5.75 (m,
;
1H), 5.16-5.10 (m, 2H), 3.72 (m, 1H), 3.61 (m, 1H), 3.13 (d, J
) 9.3 Hz, 1H), 2.43 (s, 3H); MS (m/e) 218 [M+ + 1, (81Br)], 216
(M+ + 1, (79Br)], 188, 136 (100), 107, 79, 77. Anal. Calcd for C8
H10NOBr: C, 44.47; H, 4.66; N, 6.48. Found: C, 44.10; H, 4.52;
yield 54.6%): oil; IR (neat) ν 2929, 1698, 1677, 1260, 690 cm-1
;
1H NMR (CDCl3) δ 8.05 (d, J ) 7.3 Hz, 2H), 7.57-7.42 (m,
3H), 5.86-5.77 (m, 1H), 5.14-5.04 (m, 2H), 4.25 (d, J ) 6.2
Hz, 1H), 3.70-3.58 (m, 2H), 3.19 (dd, J ) 8.7, 5.2 Hz, 1H),
2.84 (s, 3H); MS (m/e) 230 (M+ + 1), 124, 105 (100), 83, 42;
HRMS calcd for C14H15NO2 229.1103, found 229.1099. The
relative stereochemistry of R- and â-substituents was assigned
as trans after determination of the relative configuration of 9
by X-ray diffraction analysis.
N, 6.33. E-Isomer: oil; IR (neat) ν 3101, 1686, 1642, 1488 cm-1
;
1H NMR (CDCl3) δ 6.50-6.30 (br, 1H), 5.87-5.76 (m, 1H),
5.22-5.15 (m, 2H), 3.76 (m, 1H), 3.62 (m, 1H), 3.40 (d, J ) 9.5
Hz, 1H), 2.95 (s, 3H); MS (m/e) 217 [M+, (81Br)], 215 [(M+, (79-
Br)], 188, 186, 137, 136(100), 79, 77; HRMS calcd for C8 H10
NOBr 214.9940, found 214.9948.
-
r-Br om oben zylid en e-â-vin yl-γ-bu tyr ola cta m (4i): oil;
IR (neat) ν 3191, 1691, 1630, 709 cm-1 1H NMR (CDCl3) δ
;
N-Meth yl-tr a n s-[r-(1-h yd r oxyben zyl)-â-vin yl]-γ-bu ty-
r ola cta m (9) + (10). A solution of 8 (51 mg, 0.22 mmol) in
MeOH (2 mL) was cooled to -40 °C, and then NaBH4 (12 mg,
0.33 mmol) was added. The mixture was stirred. After the
reaction was complete as monitored by TLC, a drop of HOAc
was added to quench the reaction and the mixture was allowed
to raise to room temperature. MeOH was evaporated, and CH2-
Cl2 (20 mL) was then added. The solution was washed with
saturated NaHCO3 solution and brine, dried (Na2SO4), con-
centrated, and purified by chromatography (silica gel, petro-
leum ether/ethyl acetate ) 7:3) to give 9 (35 mg) and 10 (7
mg). Total yield: 83.2%.
7.70 (br, 0.53H), 7.20 (br, 0.47H), 7.43-7.24 (m, 5H), 5.96-
5.85 (m, 0.47H, E), 5.69-5.58 (m, 0.53H, Z), 5.30 (d, J ) 17.0
Hz, 0.47H, E), 5.25 (d, J ) 10.1 Hz, 0.47H, E), 4.86 (d, J )
17.0 Hz, 0.53H, Z), 4.66 (d, J ) 10.1 Hz, 0.53H, Z), 3.88 (m,
0.47H, E), 3.68 (dd, J ) 9.8, 7.3 Hz, 0.47H, E), 3.60 (m, 0.53H,
Z), 3.51 (dd, J ) 9.6, 7.5 Hz, 0.53H, Z), 3.21 (d, J ) 9.8 Hz,
0.47H, E), 3.05 (d, J ) 9.1 Hz, 0.53H, Z); MS (m/e) 279 (M+,
(81Br)], 277(M+, (79Br)], 169, 155, 153, 141 (100), 115. Anal.
Calcd for C13H12NOBr: C, 56.14; H, 4.35; N, 5.04. Found: C,
56.09; H, 4.09; N, 4.79.
Cycliza tion of N-(1′-Meth yl-4′-a cetoxybu t-2′-en yl)a lk -
2-yn a m id es 5. The procedure is the same as that for cycliza-
tion of 2.
9: mp 98-100 °C; IR (KBr) ν 3378, 2926, 1662, 1505, 1430,
1
1401, 1259, 770, 707 cm-1, H NMR (CDCl3) δ 7.30-7.09 (m,
cis- a n d tr a n s-N-b en zyl-r-(Z)-(b r om oet h ylid en e)-â-
vin yl-γ-m eth yl-γ-bu tyr ola cta m (6a ): oil; IR (Nujol) ν 2978,
1690, 1650, 1404, 700 cm-1; 1H NMR (CDCl3) δ 7.33-7.23 (m,
5H), 5.64-5.55 (m, 1H), 5.21-5.07 (m, 2.14H), 4.97 (d, J )
15.0 Hz, 0.86H), 4.14 (d, J ) 15.0 Hz, 0.86H, cis), 3.96 (d, J )
5H), 5.43 (br, 1H), 5.14-5.02 (m, 1H), 4.64 (d, J ) 8.8 Hz, 1H),
4.52 (dt, J ) 10.2, 0.9 Hz, 1H), 4.44 (dt, J ) 17.0, 1.0 Hz, 1H),
3.27 (dd, J ) 9.8, 8.6 Hz, 1H), 3.02 (dd, J ) 9.8, 7.9 Hz, 1H),
2.81 (s, 3H), 2.62-2.45 (m, 2H); MS (m/e) 231(M+), 125 (100),
124, 110, 98, 77. Anal. Calcd for C14H17NO2: C, 72.70; H, 7.41;

6550 J . Org. Chem., Vol. 66, No. 20, 2001
Xie et al.
N, 6.06. Found: C, 72.50; H, 7.47; N, 5.95. The relative
stereochemistry of R and â-substituents was determined by
X-ray crystallography.
(8 mL) was added dropwise a MeOH solution of MeNH2 (1.67
M, 8 mL). After being stirred for 1 h, the mixture was
concentrated and purified by chromatography (silica gel, CH2-
Cl2/ethanol ) 98:2) to obtain a colorless solid 13 (98 mg, overall
yield from 12: 47%): mp 158-162 °C; IR (KBr) ν 1721, 1689,
1269, 714 cm-1; 1H NMR (CDCl3) δ 7.94-7.91 (m, 2H), 7.59-
7.54 (m, 1H), 7.46-7.30 (m, 8H), 6.98 (s, 1H), 6.60 (d, J ) 3.7
Hz, 1H), 3.45 (s, 3H), 3.44-3.33 (m, 2H), 3.26-3.21 (m, 1H),
3.13 (dd, J ) 9.6, 6.4 Hz, 1H), 2.82 (s, 3H); MS (m/e) 390 (M+
+ 1), 267, 211, 210 (100), 209, 195, 178, 105, 77.
10: mp 130-131 °C; IR (KBr) ν 3377, 3061, 1687, 1506, 1442,
1
1404, 1265, 709 cm-1; H NMR (CDCl3) δ 7.34-7.26 (m, 5H),
5.56-5.44 (m, 1H), 5.14 (dd, J ) 6.6, 3.6 Hz, 1H), 4.88-4.79
(m, 2H), 4.11 (d, J ) 6.6 Hz, 1H), 3.18 (dd, J ) 9.5, 8.6 Hz,
1H), 2.96 (dd, J ) 9.5, 7.2 Hz, 1H), 2.83 (s, 3H), 2.86-2.81 (m,
2H); MS (m/e) 232 (M+ + 1), 231(M+), 214, 125 (100), 124, 110,
98, 77. Anal. Calcd for C14H17NO2: C, 72.70; H, 7.41; N, 6.06.
Found: C, 72.76; H, 7.45; N, 6.07.
Syn th esis of (()-Isocyn om etr in e (7). To a solution of
NaOH (21 mg, 0.53 mmol) in MeOH (4 mL) was added
compound 13, and the mixture was stirred for 0.5 h and
concentrated. Water (2 mL) was added, and the resulting
mixture was extracted with CH2Cl2 (10 mL × 3), washed with
brine, dried (Na2SO4), and concentrated. The crude product
was purified by chromatography (silica gel, CH2Cl2/ethanol )
95:5) to yield colorless solid 7 (18 mg, yield: 82%) and
recrystallized from acetone-hexane to yield colorless
N-Meth yl-O-ben zoyl-tr a n s-[r-(1-h yd r oxyben zyl)-â-vi-
n yl]-γ-bu tyr ola cta m (11). To a solution of 9 (100 mg, 0.4
mmol) and a catalytic amount of DMAP in pyridine (2 mL)
was added dropwise under cooling benzoyl chloride (0.55 mL,
0.52 mmol). After being stirred at room temperature for 10 h,
the mixture was poured into water and extracted with CH2-
Cl2 (10 mL × 4). The organic layer was washed successively
with CuSO4 solution and brine, dried (Na2SO4), and concen-
trated. The residue was further purified by chromatography
(silica gel, petroleum ether/ethyl acetate ) 2:1) to give a
colorless solid (11) (110 mg, yield 80%): mp 95-97 °C; IR (KBr)
ν 3035, 1723, 1693, 1268, 1111, 713 cm-1; 1H NMR (CDCl3) δ
8.12-8.09 (m, 2H), 7.62-7.51 (m, 1H), 7.48-7.43 (m, 4H),
7.33-7.27 (m, 3H), 6.60 (d, J ) 3.8 Hz, 1H), 5.91-5.80 (m,
1H), 5.17 (dd, J ) 17.1, 0.5 Hz, 1H), 5.13 (dd, J ) 10.2, 0.5
Hz, 1H), 3.09-2.95 (m, 4H), 2.75 (s, 3H); MS (m/e) 335 (M+),
230, 105 (100), 86, 84, 77, 49. Anal. Calcd for C21H21NO3: C,
75.19; H, 6.31; N, 4.19. Found: C, 75.01; H, 5.93; N, 4.22.
N -Me t h yl-O-b e n zoyl-t r a n s-[r-(1-h yd r oxyb e n zyl)-â-
for m yl]-γ-bu tyr ola cta m (12). Ozone was bubbled into a
solution of 9 (479 mg, 1.4 mmol) in MeOH (30 mL) and CH2-
Cl2 (15 mL) at -78 °C. After the reaction was complete as
monitored by TLC, Ar was bubbled into the mixture for 5 min
and then Me2S (2.5 mL) was added. The mixture was stirred
for an additional 2 h then allowed the temperature raising to
room temperature, concentrated, and purified by chromatog-
raphy on silica gel (petroleum ether/ethyl acetate )1:1) to give
compound 12 (437 mg, yield: 91%): oil; IR (neat) ν 2928, 2885,
1725, 1687, 1269, 1110, 788, 773 cm-1; 1H NMR (CDCl3) δ 9.73
(s, 1H), 8.11-8.09 (dd, J ) 7.1, 1.6 Hz, 2H), 7.65-7.59 (m,
1H), 7.52-7.27 (m, 7H), 6.66 (d, J ) 4.4 Hz, 1H), 3.57-3.48
(m, 2H), 3.30-3.23 (m, 1H), 2.82-2.71 (m, 1H), 2.74 (s, 3H);
MS (m/e) 337 (M+), 232 (100), 202, 186, 131, 105, 91, 77; HRMS
calcd for C20H19NO4 337.1314, found 337.1319.
Syn th esis of (()-Isocyn od in e (13). Compound 12 was
treated according to the literature method to construct the
imidazole ring.20 A solution of tosylmethylisocyanide (104 mg,
0.5 mmol) in THF (10 mL) was added dropwise to a solution
of t-BuOK (81 mg, 0.7 mmol) in THF (5 mL) at -30 °C. After
the mixture was stirred for 10 min and cooled to -40 °C, a
solution of 12 (181 mg, 0.5 mmol) in THF (5 mL) was added
dropwise. The reaction mixture was stirred for 30 min and
poured into ice-water (20 mL). After being neutralized with
HOAc, the mixture was extracted with CH2Cl2, dried (Na2SO4),
and concentrated. The crude product was purified by a short
column of silica gel chromatography (petroleum ether/ethyl
acetate ) 1:1) to obtain an oil. To the solution of the crude oil
in THF (10 mL) was added first Et3N (0.38 mL) and then a
solution of POCl3 (0.05 mL, 0.59 mmol) in THF at -10 °C.
After being stirred for 30 min, the mixture was poured into
ice-water (20 mL), extracted with CH2Cl2, dried (Na2SO4), and
concentrated. To the solution of the crude product in MeOH
needles: mp 215-216 °C; IR (KBr) ν 1721, 1689, 706 cm-1
;
1H NMR (CDCl3) δ 7.27-7.21 (m, 5H), 7.10 (s, 1H), 6.69 (s,
1H), 4.85 (d, J ) 8.3 Hz, 1H), 3.42 (t, J ) 9.2 Hz, 1H), 3.22
(dd, J ) 9.6, 6.4 Hz, 1H), 3.16-3.09 (m, 1H), 3.12 (s, 3H), 2.98
(t, J ) 7.8 Hz, 1H), 2.90 (s, 3H); MS (m/e) 285 (M+), 206, 179
(100), 136, 135, 109, 108, 107, 95. The 1H NMR spectrum of
compound 7 is identical to the 1H NMR spectrum of original
synthetic isocynometrine.16 The X-ray crystallographic struc-
ture of 7 is identical to the structure of isocynometrine.15
Hydr olysis of Vin yl Br om ides in γ-Lacton es an d γ-Lac-
ta m s (14). Compounds 14 were hydrolyzed using the literature
procedure.17,18
r-F or m yl-â-vin yl-γ-bu tyr ola cton e (15a ) fr om r-(Z)-br o-
m om eth ylid in e -â-vin yl-γ-bu tyr ola cton e (14a ):10 mp 89-
90 °C; IR (Nujol) ν 2985-2750, 1723, 1677, 1415, 1200 cm-1
;
1H NMR (CDCl3) δ 10.15 (br, 0.53H), 9.85 (s, 0.47H), 6.96 (s,
0.53H), 5.82-5.71 (m, 1H), 5.31-5.16 (m, 2H), 4.59-4.46 (m,
1H), 4.10-4.03 (m, 1H), 3.81-3.60 (m, 1H), 3.49 (d, J ) 9.5
Hz, 0.47H); MS 140 (M+), 111, 81, 67, 54, 53 (100). Anal. Calcd
for C7H8O3: C, 60.00; H, 5.75. Found: C, 60.16; H, 5.71.
N-(ter t-Bu t yloxyca r b on yl)-r-a cet yl-â-vin yl-γ-b u t yr o-
la cta m (15c) fr om N-(t-Bu tyloxyca r bon yl)-r-br om oeth -
ylid en e-â-vin yl-γ-bu tyr ola cta m (14c): oil; IR (neat) ν 3274,
2985, 1700, 1361 cm-1; 1H NMR (CDCl3) δ 6.48 (br, 1H), 5.77-
5.71 (m, 1H), 5.16-5.06 (m, 2H), 3.62-3.49 (m, 2H), 3.34 (d,
J ) 8.0 Hz, 1H), 3.14-3.09 (m, 1H), 2.18 (s, 3H); MS (m/e)
154 (M+ + 1, 100), 111, 110, 81, 69. Anal. Calcd for C8H11
-
NO2: C, 62.73; H, 7.24; N, 9.14. Found: C, 62.25; H, 7.33; N,
9.30.
Ack n ow led gm en t. The Major State Basic Research
Program (Grant No. G2000077502-A). We thank the
National Natural Science Foundation of China and
Chinese Academy of Sciences for financial support.
Su p p or tin g In for m a tion Ava ila ble: Synthetic procedure
and analytical data of comounds 1a , 3a , 2a -j, 5a ,c,f,i, and
14c,d ; 1H NMR spectra of compounds 2a -2c,f,h ,i, 3a , (E)-
4b, (E)-4c, 4e, 4e′, 5c, 7, 8, 12, and 13; X-ray diffraction
analytical data of 7 and 9. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O001704U