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

Article abstract of DOI:10.1021/jo060288w

Pd(OAc)₂ combined with nitrogen-containing ligands catalyzed the cyclization of (Z)-N-allylic 2-alkynamides in acetic acid to afford the α-(Z)-acetoxyalkylidene-γ-butyrolactams in high yield and high stereoselectivity. When chiral nitrogen-cont

Full text of DOI:10.1021/jo060288w

Palladium(II)-Catalyzed Asymmetric Synthesis of
(Z)-r-Alkylidene-γ-butyrolactams from (Z)-N-Allylic
2-Alkynamides. Total Synthesis of (-)-Isocynometrine
Wei Xu, Aidi Kong, and Xiyan Lu*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai, 200032, China
xylu@pub.sioc.ac.cn
ReceiVed February 11, 2006
Pd(OAc)2 combined with nitrogen-containing ligands catalyzed the cyclization of (Z)-N-allylic 2-alkyn-
amides in acetic acid to afford the R-(Z)-acetoxyalkylidene-γ-butyrolactams in high yield and high
stereoselectivity. When chiral nitrogen-containing ligands were used, the catalytic asymmetric protocol
was achieved with moderate enantioselectivity (up to 80 °C). The utility of this new methodology was
exemplified by the total synthesis of (-)-isocynometrine.
Introduction
variety of synthetically important carbo- and heterocycles with
high efficiency not normally accessible by traditional methods.5
Recently, we have developed the facile intramolecular enyne
cyclization of allylic 2-alkynoates or N-allylic 2-alkynamides
to build polysubstituted R-alkylidene-γ-butyrolactones6 or R-al-
kylidene-γ-butyrolactams7,8 via a Pd(II) catalyst, initiated by
halopalladation. In these reactions, halide ions serve not only
as nucleophiles but also as a ligand to inhibit the â-hydride
elimination reaction.9 However, there exist problems in the way
of developing the corresponding catalytic asymmetric process
while halides are used as a ligand. To solve these problems, a
new type of reaction to construct R-alkylidene-γ-butyrolactones
γ-Butyrolactam structures are widely spread in medicinal
chemistry.1 In particular, R-alkylidene-γ-butyrolactams show
important biological activities, such as cytotoxicity,2 antitumor,3
and antiinflamation activities but with lower toxicity4 as
compared with the corresponding lactones. Therefore, the
development of new methods for the stereoselective synthesis
of these kinds of molecules appears to be highly desirable.
The use of transition metal catalysts in the carbocyclization
of alkenes and alkynes offers the unique means to construct a
(1) (a) Nilsson, B. M.; Ringdahl, B.; Hacksell, U. J. Med. Chem. 1990,
33, 580. (b) Bergmann, R.; Gericke, R. J. Med. Chem. 1990, 33, 492. (c)
Shapiro, G.; Floersheim, P.; Boelsterli, J.; Amstutz, R.; Bolliger, G.;
Gammenthaler, H.; Gmelin, G.; Supavilai, P.; Walkinshaw, M. J. Med.
Chem. 1992, 35, 15. (d) Khuong-Huu, F.; Monseur, X.; Ratle, G.; Lukacs,
G.; Goutarel, R. Tetrahedron Lett. 1973, 1757. (e) Tchissambou, L.;
Benechie, M.; Khuong-Huu, F. Tetrahedron Lett. 1978, 1801. (f) Waterman,
P. G.; Faulkner, D. F. Phytochemistry 1981, 20, 2765. (g) Gammill, R. B.;
Wilson, C. A.; Bryson, T. A. Synth. Commun. 1975, 5, 245. (h) Lee, K. H.;
Hung, E. S.; Piantodosi, C.; Pagani, J.; Geissman, T. A. Cancer Res. 1971,
71, 1649.
(4) Patra, R.; Maiti, S. B.; Chatterjee, A.; Chakravarty, A. K. Tetrahedron
Lett. 1991, 32, 1363.
(5) (a) Trost, B. M.; Krische, M. J. Synlett 1998, 1. (b) Fru¨hauf, H.-W.
Chem. ReV. 1997, 97, 523. (c) Ojima, I.; Tzamarioudaki, M.; Li, Z.;
Donovan, R. J. Chem. ReV. 1996, 96, 635. (d) Moos, W. H.; Davis, R. E.;
Scwarz, R. D.; Gamzu, E. R. Med. Res. ReV. 1988, 8, 353.
(6) (a) Ma, S.; Lu, X. J. Org. Chem. 1991, 56, 5120. (b) Lu, X.; Zhu,
G.; Wang, Z. Synlett 1998, 115.
(7) Jiang, H.; Ma, S.; Zhu, G.; Lu, X. Tetrahedron 1996, 52, 10945.
(8) Xie, X.; Lu, X.; Liu, Y.; Xu, W. J. Org. Chem. 2001, 66, 6545.
(9) (a) Wang, Z.; Zhang, Z.; Lu, X. Organometallics 2000, 19, 775. (b)
Lu, X.; Wang, Z. Polyhedron 2000, 19, 577. (c) Zhang, Z.; Lu, X.; Xu, Z.;
Zhang, Q.; Han, X. Organometallics 2001, 20, 3724.
(2) Belaud, C.; Roussakis, C.; Letourneux, Y.; Alami, N. E.; Villieras,
J. Synth. Commun. 1985, 15, 1233.
(3) Kornet, M. J. J. Pharm. Sci. 1979, 68, 350.
10.1021/jo060288w CCC: $33.50 © 2006 American Chemical Society
Published on Web 04/21/2006
3854
J. Org. Chem. 2006, 71, 3854-3858

Synthesis of (Z)-R-Alkylidene-γ-butyrolactams
TABLE 1. Cyclization of N-(Z)-(4′-X-2′-butenyl)-2-butynamides (X
) leaving group)a
SCHEME 1
substrate
entrya
R
X
time (h)
productb
yield (%)c,d
1
2
3
4
5
6
7
H
OBz
OBz
OBz
OAc
OBz
OAc
OBz
1a
1b
1c
1c′
1d
1d′
1e
24
28
23
23
45
42
24
2a
2b
2c
2c
2d
2d
2e
e
70
90
90
80
82
e
Me
Bn
Bn
Ts
Ts
Boc
TABLE 2. Cyclization of
N-(Z)-(4′-Benzoyloxybut-2′-enyl)butynamides in the Absence of the
Nitrogen Ligands
a Reaction conditions: A mixture of 1 (0.5 mmol), Pd(OAc)2 (0.025
mmol), and bpy (0.038 mmol) in HOAc (2.0 mL) was stirred at 80 °C; the
reaction was monitored by TLC. b The products were identified by 1H NMR,
IR, MS, and elemental analysis or HRMS. c Isolated yield. d Z/E > 97:3
e No anticipated product was observed
entrya
substrate R
productb
yield (%)c,d
has been developed in which the acetoxy anion served as the
nuleophile and the nitrogen-containing ligands were employed
to inhibit the â-hydride elimination reaction.10 The stoichio-
metric reactions strongly demonstrated that the nitrogen-
containing ligands, like halides, serve to favor â-heteroatom
elimination over â-hydride elimination.10 Also a similar strategy
was used in the cycloisomerization of the electron-rich 1,6-
enynes.11 The asymmetric version of this acetoxypalladation-
initiated enyne-coupling reaction was achieved while chiral
nitrogen-containing ligands were employed.10 Herein we wish
to report the asymmetric construction of R-alkylidene-γ-
butyrolactams from palladium(II)-catalyzed intramolecular enyne
cyclization of N-allylic 2-alkynamides based on the above
methodology.
1
2
3
Me
Bn
Ts
1b
1c
1d
2b
2c
2d
37
45
24
a Reaction conditions: A mixture of 1 (0.5 mmol) and Pd(OAc)2 (0.025
mmol) in HOAc (2.0 mL) was stirred at 80 °C and the reaction was
monitored by TLC. b The products were identified by H NMR, IR, MS,
1
and elemental analysis. c Isolated yield. d Z/E > 97:3
Further experiments were carried out to study the difference
of the cyclization of allylic alkynoates and N-allylic alkyna-
mides. As mentioned in the acetoxypalladation-initiated cy-
clization of allylic butynoates,10a,b the cyclization reaction can
occur only in the presence of bipyridine as the ligands. When
the reaction was carried out in the absence of the nitrogen
ligands, only the hydroacetoxylation byproduct was observed
(Scheme 1),10 while in the case of N-allylic alkynamides, the
cyclization product could be isolated in noticeable yield even
in the absence of the nitrogen ligands (Table 2). Combined with
the electronic effect of the substituents on nitrogen atom
mentioned above, these results revealed that the nitrogen atom
of the N-allylic alkynamides, to some extent, may also play the
role of nitrogen-containing ligand in stabilizing the carbon-
palladium bond, inhibiting the â-hydride elimination and
promoting the â-heteroatom elimination.10b,c,13
Results and Discussion
We initially examined the reaction of N-(Z)-(4′-X-2′-butenyl)-
2-butynamides (X ) leaving group) using the reaction conditions
for the corresponding esters10 (Table 1).
Most of the reactions proceeded smoothly to afford the
γ-butyrolactams in high yields with high stereoselectivity with
respect to the exocyclic double bonds (Z/E > 97:3).12 The
variation of leaving groups has little influence on the â-hetero-
atom elimination reaction, which is similar to the reaction
initiated by halopalladation.12b Change of the substituents on
the nitrogen atom of the N-allylic 2-alkynamides influenced the
cyclization greatly on the yield of the reaction (Table 1, entries
1-3, and 5). The alkynamides with electron-withdrawing
substituents on the nitrogen atom required longer reaction time
and gave lower yield than those with electron-donating sub-
stituents (Table 1, compare entry 3 with 5, and entry 4 with 6).
N-Benzyl-substituted amides led to the best results. However,
no product could be isolated when N-Boc is the substituent
(Table 1, entry 7) or there is no substituent on the nitrogen atom
of the N-allylic 2-alkynamides (Table 1, entry 1).
Variation of the substituted group R1 on the alkyne of the
N-allylic 2-alkynamides influenced the cyclization moderately
on the yield of the reaction. However, attempts to cyclize the
N-(Z)-(4′-acetoxy-2′-butenyl)propynamide (1f) met with failure,
which was in accord with Pd(OAc)2-catalyzed hydroacetoxy-
lation of 2-alkynoates14 and might be attributed to the possible
formation of (alkynyl)palladium species15 (Table 3, entry 1).
When R1 is methyl, the yield of the enyne-coupling product is
the highest (Table 3, entry 2). For larger R1 groups, the yield is
(13) Similar results related to stabilizing the carbon-transition metal bond
and inhibiting the â-hydride elimination by coordination have been
reported: (a) Sole´, D.; Cancho, Y.; Llebaria, A.; Moreto´, J. M.; Delgado,
A. J. Am. Chem. Soc. 1994, 116, 12133. (b) Devasagayaraj, A.; Stu¨demann,
T.; Knochel, P. Angew. Chem., Int. Ed. Engl. 1995, 34, 2723. (c) Giovannini,
R.; Stu¨demann, T.; Dussin, G.; Knochel, P. Angew. Chem., Int. Ed. 1998,
37, 2387. (d) Giovannini, R.; Knochel, P. J. Am. Chem. Soc. 1998, 120,
11186. (e) Jensen, A. E.; Knochel, P. J. Org. Chem. 2002, 67, 79.
(14) Lu, X.; Zhu, G.; Ma, S. Tetrahedron Lett. 1992, 33, 7205.
(10) (a) Zhang, Q.; Lu, X. J. Am. Chem. Soc. 2000, 122, 7604. (b) Zhang,
Q.; Lu, X.; Han, X. J. Org. Chem. 2001, 66, 7676. (c) Lu, X.; Zhang, Q.
Pure Appl. Chem. 2001, 73, 247.
(11) Zhang, Q.; Xu, W.; Lu, X. J. Org. Chem. 2005, 70, 1505.
(12) Zhu, G.; Lu, X. Organometallics 1995, 14, 4899.
J. Org. Chem, Vol. 71, No. 10, 2006 3855

Xu et al.
TABLE 3. Cyclization of N-(Z)-(4′-X-2′-butenyl)-2-alkynamides (X
) leaving group)
TABLE 4. Asymmetric Cyclization of
N-Benzyl-N-(Z)-(4′-acetoxyl-2′-butenyl)-2-butynamide (1c′) with
Different Chiral Ligandsa
substrate
entrya
R1
X
productb
yield (%)c,d
1
2
3
4
5
6
7
8
9
H
Me
n-Bu
MeOCH2
Ph
OBz
OBz
OBz
OBz
OBz
OAc
OAc
OAc
OAc
1f
2f
e
90
71
81
74
90
77
86
80
1c
1g
1h
1i
1c′
1g′
1h′
1i′
2c
2g
2h
2i
2c
2g
2h
2i
Me
n-Bu
MeOCH2
Ph
a Reaction conditions: A mixture of 1 (0.5 mmol), Pd(OAc)2 (0.025
mmol), and bpy (0.038 mmol) in HOAc (2.0 mL) was stirred at 80 °C; the
reaction was monitored by TLC. b The products were identified by 1H NMR,
IR, MS, and elemental analysis or HRMS. c Isolated yield. d Z/E > 97:3.
e No product was observed.
a little lower (except for Ph). In all cases, the reaction gave
high Z-selectivity of the exocyclic double bond without the
detection of E-exocyclic double bonds.12 In addition, the reaction
of N-(E)-(4′-benzoyloxy-2′-butenyl)-2-butynoamide was inef-
fective under the same reaction conditions, and the starting
material remained intact after 24 h even at elevated temperature
(100 °C). This result is similar to the cyclization of enyne esters
initiated by acetoxypalladation,10 but is different from that
initiated by halopalladation.16 The stronger coordinating ability
of (Z)-olefins compared to (E)-olefins may account for the
discrepancy.17
With these results in hand, we made an effort to develop an
asymmetric version of this reaction. In the work on the
asymmetric cyclization of alkynoates, the employment of
pymox-Ph or phenyl-substituted bisoxazoline as the ligands led
to the remarkable yield and high enantioselectivity (up to 92%
ee).10 Thus, 1c′ was selected to examine the asymmetric
cyclization leading to γ-butyrolactams (Table 4).
Unfortunately, low enantioselectivity (8-59% ee) was achieved
when the substrates were N-benzyl-substituted alkynamides.
Based on the supposition discussed above that the nitrogen atom
of the alkynamide may also coordinate with the palladium atom,
there might exist competition between the alkynamides and the
chiral nitrogen-containing ligands in coordination with the
palladium18 resulting in a low enantioselectivity. When an
alkynamide with an electron-withdrawing group on the nitrogen
atom was used as the substrate, the enantioselectivity did
increase as shown in Table 5. Finally, a moderate enantio-
selectivity up to 72% ee was obtained for a tosyl group
substituted alkynamide, using pymox-Ph as the ligand.
The results show that not only the substituted groups on the
nitrogen atom of alkynamides but also the leaving groups have
a Reaction conditions: Pd(OAc)2 (0.025 mmol), substrate (0.5 mmol),
L* (0.038 mmol) in HOAc (2 mL) at 60 °C. b Isolated yield. c Z/E>97:3.
d Determined by chiral HPLC, using the chiral AD column eluting with
hexane/2-propanol (95/5) (λ ) 254 nm).
much influence on the enantioselectivity. Despite using pymox
(pyridyl monooxazoline)19 or bisoxazoline20 as the chiral ligand,
the enantioselectivities of the reaction of N-tosylalkynamides
are much better than those of the reaction of N-benzylalkyn-
amides. The bulky leaving group is led to further enhancement
in the enantioselectivity of this reaction. Both the electron-
withdrawing group on the nitrogen atom of alkynamides and
the bigger leaving group had a positive effect on the asymmetric
cyclization of alkynamides initiated by acetoxypalladation.
Further experiments showed that if the ratio of ligand and Pd-
(OAc)2 was increased, not only was the yield enhanced a little,
but the enantioselectivity improved as well (Table 6).
The plausible mechanism for this transformation is believed
to be analogous to that of the halopalladation-initiated cycliza-
(18) Lee, C.-W.; Oh, K. S.; Kim, K. S.; Ahn, K. H. Org. Lett. 2000, 2,
1213.
(15) (a) Trost, B. M.; Sorum, M. T.; Chan, C.; Harms, A. E.; Ru¨hter, G.
J. Am. Chem. Soc. 1997, 119, 698. (b) Melikyan, G. G.; Nicholas, K. M.
In Mordern Acetylene Chemistry; Stang, P. J., Diederich, F., Eds.; VCH:
New York, 1995; p 79.
(16) Zhu, G.; Ma, S.; Lu, X. J. Chem. Res. (S) 1993, 366.
(17) Hartley, F. R. The Chemistry of Platinum and Palladium; Applied
Science Publishers Ltd: London, UK, 1973; p 377.
(19) (a) Brunner, H.; Obermann, U. Chem. Ber. 1989, 122, 499. (b)
Ichiyanagi, T.; Shimizu, M.; Fujisawa, T. J. Org. Chem. 1997, 62, 7937.
(c) Cheng, J.; Deming, T. J. Macromolecules 1999, 32, 4745.
(20) (a) Corey, E. J.; Imai, N.; Zhang, H. J. Am. Chem. Soc. 1991, 113,
728. (b) Mu¨ller, D.; Umbricht, G.; Weber, B.; Pfaltz, A. HelV. Chim. Acta
1991, 74, 232.
3856 J. Org. Chem., Vol. 71, No. 10, 2006

Synthesis of (Z)-R-Alkylidene-γ-butyrolactams
TABLE 5. Asymmetric Cyclization of Alkynamidesa
SCHEME 2. The Plausible Mechanism
SCHEME 3. Total Synthesis of (-)-Isocynometrine (10)
a Reaction conditions: Pd (OAc)2 (0.025 mmol), substrate (0.5 mmol),
L* (0.038 mmol) in HOAc (2 mL) at 60 °C. b Isolated yield. c Z/E > 97:3.
d Determined by chiral HPLC when R ) Bn, using the chiral AD column
eluting with hexane/2-propanol (95/5) (λ ) 254 nm), when R ) Ts, using
the chiral AS column eluting with 60:40 hexane:2-propanol (λ ) 254 nm).
TABLE 6. Asymmetric Cyclization of 1da
tenyl)-3-phenylpropynamide (3) was selected as the starting
compound. The asymmetric cyclization of 3 with our catalytic
system using (S)-pymox-Ph as the ligands gave a mixture of 4
and 5. This implies that the hydrolysis of the vinyl acetate in 4
is much easier than that of the vinyl bromide as reported.8 After
hydrolysis without separation, an 80% yield of 5 was isolated
with 53% ee. Reduction of 5 with NaBH4 gave a pair of
diastereisomers 6a and 6b in a 2.5:1 ratio, which could be
separated by column chromatography. Compound 6a was
regarded as the required intermediate in our synthesis according
to its spectral data.8 Protection the hydroxy group of 6a with
the benzoyl group gave 7 (yield 87%, 80.5% ee) and then
ozonolysis of the double bond at -78 °C produced the
corresponding aldehyde 8. The aldehyde 8 was treated succes-
sively in three steps without purification to construct the
imidazole ring to obtain 9 according to the literature8 and then
deprotected to give the target molecule (-)-isocynometrine (10),
a Reaction conditions: Pd(OAc)2 (0.025 mmol), substrate (0.5 mmol),
L* in HOAc (2 mL) at 60°C. b Isolated yield. c Z/E > 97:3. d Determined
by chiral HPLC, using the chiral AS column eluting with hexane/2-propanol
(60/40) (λ ) 254 nm).
tion of enyne amides.8 This will involve intramolecular insertion
of the olefin into the vinyl-palladium intermediate formed by
trans-acetoxypalladation of the carbon-carbon triple bond,
followed by â-heteroatom elimination to give the γ-butyrolactam
and the Pd(II) species making the catalytic cycle possible
(Scheme 2).
On the basis of these results, we turned our attention to the
total synthesis of the natural product, (-)-isocynometrine,21 to
demonstrate the synthetic utility of the asymmetric protocol
(Scheme 3). Similar to our reported work of the synthesis of
(()-isocynometrine,8 N-methyl N-(Z)-(4′-benzoyloxy-2′-bu-
mp 177-179 °C, yield 62% with 98.1% ee ([R]20 -63.7 (c
D
0.7, CHCl3) [lit.21 [R]20 -66 (c 1.0, CHCl3)]).
D
In summary, we developed the synthesis of γ-butyrolactams
from the cyclization of enyne amides initiated by acetoxypal-
ladation in the presence of nitrogen-containing ligands under
(21) (a) Chiaroni, A.; Riche, C.; Tchissambou, L.; Khuong-Huu, F. J.
Chem. Res. (S) 1981, 182; J. Chem. Res. (M) 1981, 2116. (b) Tchissambou,
L.; Benechie, M.; Khuong-Huu, F. Tetrahedron 1982, 38, 2687.
J. Org. Chem, Vol. 71, No. 10, 2006 3857

Xu et al.
1760, 1672, 1639, 1189, 920 cm-1. Anal. Calcd for C11H15NO3:
C, 63.14; H, 7.23; N, 6.69. Found: C, 62.84; H, 7.58; N, 6.53.
For the data for other starting materials, see the Supporting
Information.
The procedure for the asymmetric cyclization of N-(Z)-(4′-X-
2′-butenyl)-2-alkynoamides (2c or 2c′) (X ) OBz or OAc) was
similar as above. The percent ee values were determined by HPLC,
using the chiralcel AD column eluting with hexane:2-propanol (v/v
95/5) (λ ) 254 nm) when R ) Bn and the chiralcel AS column
eluting with hexane:2-propanol (v/v 60/40) (λ ) 254 nm) when R
) Ts.
Pd(II) catalysis with high efficiency and stereoselectivity.
Employing the nitrogen-containing chiral ligands, the catalytic
asymmetric protocol was established with moderate enantio-
selectivity (up to 80% ee). The nitrogen atom of the N-allylic
alkynamides might compete with the nitrogen-containing chiral
ligands in coordination with palladium, which might be the
reason for the low enantioselectivity as compared with that of
γ-butyrolactones. The synthetic utility of this asymmetric
cyclization was exemplified by the total synthesis of (-)-
isocynometrine. Further studies for the asymmetric reaction are
in progress.
The synthesis of (-)-isocynometrine was similar to the reported
method of the synthesis of (()-isocynometrine. See the Supporting
Information.
Experimental Section
10: mp 177-179 °C; yield 62% with 98.1% ee; IR (KBr) ν
1
3097, 2837, 1687, 706 cm-1; H NMR (CDCl3) δ 7.29-7.21 (m,
Materials. The chiral ligands were prepared by literature
methods.18,19 The amide starting materials were prepared according
to the literature procedure.8 Procedures and data for the starting
materials were available in the Supporting Information.
5 H), 7.10 (s, 1 H), 6.69 (s, 1 H), 5.05 (br, 1 H), 4.84 (d, J ) 8.4
Hz, 1 H), 3.45 (t, J ) 9.6 Hz, 1 H), 3.24 (dd, J ) 9.6, 6.3 Hz, 1
H), 3.15-3.08 (m, 1 H), 3.10 (s, 3 H), 2.99 (t, J ) 8.1 Hz, 1 H),
2.92 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 174.4, 139.6, 137.6,
132.4, 128.3, 126.9, 125.9, 75.2, 54.9, 54.8, 30.9, 29.7, 29.6; MS
Cyclization of N-(Z)-(4′-X-2′-butenyl)alk-2-ynamides (X )
leaving group): Typical Procedure. To a solution of Pd(OAc)2
(0.025 mmol) and ligand (0.038 mmol) in HOAc (2 mL) was added
the substrate (0.5 mmol). The reaction was carried out at 80 (for
nonchiral ligands) or 60 °C (for chiral ligands). After the reaction
was completed as monitored by TLC, ether was added. The mixture
was washed with saturated NaHCO3 and brine and dried (Na2SO4).
The solvent was evaporated, and the residue was purified by flash
chromatography (300-400 mesh silica gel, petroleum ether/ethyl
acetate) to give the cyclization product.
N-Methyl-R-(Z)-(1′-acetoxyethylidene)-â-vinyl-γ-butyrolac-
tam (2b). Oil; 1H NMR (300 MHz CDCl3) δ 5.82-5.76 (m, 1H),
5.25-5.13 (m, 2H), 3.63 (m, 2H), 3.06 (dd, J1 ) 1.6 Hz, J2 ) 9.3
Hz, 1H), 2.84 (s, 3H), 2.25 (s, 3H), 1.92 (s, 3H); MS m/z 210 (M+
+ 1), 168, 167, 140, 124 (100), 98, 96, 44, 43; IR (neat) ν 2920,
(ESI) m/z 286 (M+ + 1); [R]20 -63.7 (c 0.7, CHCl3).21
D
Acknowledgment. The authors thank the Major State Basic
Research Program (Grant G20000077502-A). We also thank
the National Natural Sciences Foundation of China (20072045)
and the Chinese Academy of Sciences for the financial support.
Supporting Information Available: Synthetic procedures and
data for the starting materials, the cyclization lactams, the asym-
metric cyclization products, and the total synthesis of (-)-
isocyanometrine. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO060288W
3858 J. Org. Chem., Vol. 71, No. 10, 2006