The first asymmetric total syntheses of (+)-lycorine and (+)-1-deoxylycorine

Article abstract of DOI:10.1021/ja9606440

The first asymmetric total syntheses of (+)-1-deoxylycorine (2a) and (+)-lycorine (2b), the unnatural enantiomer of lycorine (1), are described. Construction of lactam 12, a key intermediate in the synthesis of both 2a and 2b, began by Birch reduction-alk

Full text of DOI:10.1021/ja9606440

6210
J. Am. Chem. Soc. 1996, 118, 6210-6219
The First Asymmetric Total Syntheses of (+)-Lycorine and
(+)-1-Deoxylycorine
Arthur G. Schultz,* Mark A. Holoboski, and Mark S. Smyth
Contribution from the Department of Chemistry, Rensselaer Polytechnic Institute,
Troy, New York 12180-3590
ReceiVed February 26, 1996X
Abstract: The first asymmetric total syntheses of (+)-1-deoxylycorine (2a) and (+)-lycorine (2b), the unnatural
enantiomer of lycorine (1), are described. Construction of lactam 12, a key intermediate in the synthesis of both 2a
and 2b, began by Birch reduction-alkylation of the chiral benzamide 3 with 2-bromoethyl acetate followed by ester
saponification to give the 6-(2-hydroxyethyl)-1-methoxy-1,4-cyclohexadiene 6a in 96% yield as a single diastereomer.
This material was converted to the radical cyclization substrates 11a and 11b. Both 11a and 11b gave 12 and the
reduced enamide 11c on treatment with AIBN and Bu3SnH in refluxing benzene solution. Lactam 12 also was
obtained by photocyclization of enamide 11c. The allylic alcohol unit characteristic of the C ring of the lycorine
alkaloids was fashioned by a radical induced decarboxylation-epoxide fragmentation of the N-hydroxy-2-thiazoline
ester 21b. The resulting (+)-2-epi-deoxylycorine (22) was subjected to Mitsunobu inversion followed by LiAlH4
reduction to give (+)-1-deoxylycorine (2a). The synthesis of (+)-lycorine (2b) involved the conversion of 12 to
allylic alcohol 32 followed by a Torssell rearrangement of 32 to give the rearranged allylic acetate 35. Epoxidation
of 35 with dimethyldioxirane gave 36a, which set the stage for a decarboxylation-epoxide fragmentation of carboxylic
acid 36b to give 37 by photolysis of 36b in the presence of acridine and tert-BuSH. Reduction of 37 with LiAlH4
gave (+)-lycorine (2b).
Lycorine (1) is the most abundant alkaloid in plants of the
reported until we communicated the first asymmetric synthesis
of (+)-1-deoxylycorine (2a).9 Herein we report the details of
the synthesis of 2a along with the first asymmetric synthesis of
(+)-lycorine (2b), the unnatural enantiomer of 1.
Amaryllidaceae. It is said that as much as 1% of the dry weight
of daffodil bulbs may consist of lycorine.1 From the time of
its initial isolation in 1877 lycorine was recognized as a potent
emetic;2 more recent studies have shown that lycorine inhibits
protein and DNA synthesis in murine cells and in ViVo growth
of a murine transplantable ascite tumor.3 Lycorine is a powerful
inhibitor of growth and cell division in higher plants, algae,
and yeast4 and has antiviral activity.5
Results and Discussion
The lycorine ring system 2 was assembled by utilization of
three structural components as shown below. Stereoselective
development of the C ring centered on the reductive alkylation
of chiral benzamide 310 with the two-carbon alkylation reagent
4 to give a 1,4-cyclohexadiene. It was expected that the C(1)
hydroxy group of 2 would be introduced by bis-allylic oxidation
of the intermediate 1,4-cyclohexadiene;11 however, this oxidation
was ineffective, and an alternative process had to be developed.
Introduction of the hydroxy group at C(2) was accomplished
by a halolactonization (see 10a).
Much of the determination of structure for lycorine was
accomplished by Kondo and co-workers2,6 by utilization of
classical chemical studies; proof of structure was provided by
X-ray crystallographic analysis of dihydrolycorine hydrobro-
mide.7 Although several syntheses of racemic lycorine alkaloids
have been developed,8 an asymmetric synthesis had not been
X Abstract published in AdVance ACS Abstracts, June 15, 1996.
(1) Dalton, D. R. The Alkaloids: The Fundamental Chemistry -- A
Biogenetic Approach; Marcel Dekker: New York, 1979.
(2) Cook, J. W.; Loudon, J. D. In The Alkaloids; Manske, R. H. F.,
Holmes, H. L., Eds; Academic Press: New York, 1952; Vol. 2, p 331.
(3) (a) Mineshita, T.; Yayaguchi, K.; Takeda, K.; Kotera, K. Ann. Rep.
Shinogi Res. Lab. 1956, 6, 119. (b) Chattopadhyay, U.; Chaudhuri, L.; Das,
S.; Kumar, Y.; Ghosal, S. Pharmazie 1984, 39, 855.
(4) Leo De, P.; Dalessandro, G.; De Santis, A.; Arigoni, O. Plant Cell
Physiol. 1973, 14, 487.
(5) For a review of the chemistry and biological effects of lycorine and
related Amaryllidaceae alkaloids, see: Ghosal, S.; Saini, K. S.; Razdan, S.
Phytochem. 1985, 24, 2141.
The methoxy group on 3 and the acetoxy group on 4 provided
the means to introduce the nitrogen atom in 2, while the bromine
atom on the aroyl component 5 enabled the C(14)-C(15) bond
to be fashioned by a completely stereoselective aryl radical
(6) Kondo, H.; Uyeo, S. Chem. Ber. 1935, 68, 1756.
(7) Shiro, M.; Sato, T.; Koyama, H. Chem. Ind. 1966, 1229.
(8) For recent reviews of the Amaryllidaceae alkaloids, see: (a) Martin,
S. M. In The Alkaloids; Brossi, A., Ed.; Academic Press: New York, 1987;
Vol. 30, p 251. (b) Lewis, J. R. Nat. Prod. Rep. 1995, 12, 339.
(9) Schultz, A. G.; Holoboski, M. A.; Smyth, M. S. J. Am. Chem. Soc.
1993, 115, 7904.
S0002-7863(96)00644-0 CCC: $12.00 © 1996 American Chemical Society

Syntheses of (+)-Lycorine and (+)-1-Deoxylycorine
J. Am. Chem. Soc., Vol. 118, No. 26, 1996 6211
Scheme 1a
a Reaction conditions: (a) K, NH3, tert-BuOH (1 equiv) -78 °C;
BrCH2CH2OAc (2 equiv) -78 to 25 °C; KOH, MeOH; (b) DEAD,
PPh3, (PhO)2P(O)N3, THF; (c) HCl, MeOH; (d) I2, THF, H2O; (e) PPh3,
THF, reflux; (f) ArCOCl (1 equiv) Et3N, CH2Cl2; (g) BnOH, THF,
n-BuLi, -78 to 25 °C.
Figure 1. Qualitative transition state structures 13a and 13b for the
radical cyclization of 12 showing a more favorable orbital overlap in
13a and a steric interaction resulting from passage of C(14) near the
C(15)-H bond during R-facial attack in 13b.
addition reaction (see 10a). With the ring system completely
assembled, a decarboxylative elimination reaction unveiled the
ring C allylic alcohol unit characteristic of the lycorine alkaloids.
Construction of the Lycorine Ring System. The prepara-
tion of 12, a key intermediate in the asymmetric syntheses of
both (+)-1-deoxylycorine (2a) and (+)-lycorine (2b), is shown
in Scheme 1. Birch reduction-alkylation of 312 with 2-bromo-
ethyl acetate followed by ester saponification gave the 6-(2-
hydroxyethyl)-1-methoxy-1,4-cyclohexadiene 6a in 96% yield
as a single diastereomer. Diastereomeric purity of the product
of reductive alkylation of 3 was determined by direct 1H NMR
comparison to a 1:1 diastereomeric mixture prepared by
reductive alkylation of o-anisic acid with 2-bromoethyl acetate
and coupling of the resulting cyclohexadienecarboxylic acid to
L-prolinol (methyl ether).13 In comparison, alkylations of the
enolate derived from 3 with methyl iodide and ethyl iodide have
provided diastereoselectivities of 260:1 as determined by
quantitative gas chromatographic analysis.12a
Alcohol 6a was converted to azide 6b, which was subjected
to enol ether hydrolysis to give 7. Iodolactonization of 7
provided 8, and treatment of 8 with triphenylphosphine gave
the enantiomerically pure imine 9 in ∼50% overall yield from
6a. The racemate of 9 was prepared (see supporting informa-
tion), and a chiral HPLC analysis was developed to give near
base line resolution of the enantiomers. Examination of 9
prepared from 3 demonstrated that 9 had been prepared with
g99% ee.
10b with the lithium salt of benzyl alcohol afforded radical
cyclization substrates 11a and 11b. Both 11a and 11b
underwent cyclization on treatment with AIBN and Bu3SnH in
refluxing benzene solution to give the highly crystalline lactam
12 (53% and 51% yields); a single-crystal X-ray structure
determination provided the molecular structure of 12.9
The only other material isolated from the radical cyclizations
of 11a and 11b was the reduced enamide 11c (45%). Enamide
11c might be formed by direct reduction of the radical derived
from 11a and 11b with Bu3SnH or by way of an intramolecular
R-amidoyl to aryl 1,5-hydrogen atom transfer followed by
reduction.14
Precedence for formation of a trans BC ring junction in a
radical cyclization of an achiral substrate related to 11 is
available in the work of Rigby and co-workers.15 Thus, the
most remarkable feature of the conversions of 11a and 11b to
12 is the outstanding facial selectivity exhibited by the
intermediate aryl radical. Qualitative transition state structures
13a and 13b for aryl radical addition to the â- and R-face of
the C(15)-C(16) double bond are shown in Figure 1. These
models were obtained by minimization of a simplified precursor
of the intermediate aryl radical, wherein the benzyl ester was
replaced by a methyl group. From inspection of these models,
it is clear that the observed â-facial addition is a result of more
favorable orbital overlap as shown in 13a as well as an obvious
steric interaction that would result from passage of C(14) near
the C(15)-H bond during R-facial attack as shown in 13b.
Reduction of the intermediate tertiary radical 14 at C(16) by
Bu3SnH also occurs from the â-face despite the presence of
the relatively bulky (benzyloxy) carbonyl group at C(12). This
Acylation of imine 9 with 2-bromo- and 2-iodopiperonyloyl
chloride gave enamides 10a and 10b. Treatment of 10a and
(10) For prior consideration of the development of the C ring of lycorine
by way of a Birch reduction, see: (a) Hendrickson, J. B.; Alder, R. W.;
Dalton, D. R.; Hey, D. G. J. Org. Chem. 1969, 34, 2667. (b) Schultz, A. G.
Acc. Chem. Res. 1990, 23, 207.
(11) Schultz, A. G.; Taveras, A. G.; Harrington, R. E. Tetrahedron Lett.
1988, 29, 3907.
(12) (a) Schultz, A. G.; Macielag, M.; Sundararaman, P.; Taveras, A.
G.; Welch, M. J. Am. Chem. Soc. 1988, 110, 7828. (b) Benzamide 3 is
prepared by procedures described in ref 12a or may be purchased from
Aldrich Chemical Co. (34,836-8).
(13) For the genesis of this procedure, see ref 12a.
(14) (a) Cohen, T.; McMullen, C. H.; Smith, K. J. Am. Chem. Soc. 1968,
90, 6866. (b) Snieckus, V.; Cuevas, J.-C.; Sloan, C. P.; Liu, H.; Curran, D.
P. J. Am. Chem. Soc. 1990, 112, 896.
(15) Rigby, J. H.; Qabar, M. J. Am. Chem. Soc. 1991, 113, 8975.
(16) Molecular modeling studies were carried out with MacroModel
(MM2, Version 3.0).

6212 J. Am. Chem. Soc., Vol. 118, No. 26, 1996
Schultz et al.
stereoselectivity reflects the greater stability of the product 12,
which has a trans BC ring fusion and a cis CD ring fusion
compared to the epimer 15 which has cis BC and trans CD
ring fusions; molecular modeling16 demonstrated that 15 is ∼11
kcal/mol less stable than 12. Radical transfer reactions are
generally considered to occur by way of early transition states.
Thus, it is believed that radical 14 has geometry at C(16)
analogous to 12 and that inversion to a radical resembling 15
is virtually impossible because of ring strain. On the basis of
this analysis, it is noteworthy that aryl radical addition to the
R-face of the enamide double bond followed by reduction of
the tertiary radical corresponding to 14 would have generated
17 with cis BC and CD ring fusions (overall trans radical
addition) rather than the less stable epimer 16 required for a
lycorine synthesis.17
Scheme 2
Scheme 3a
a Reaction conditions: (a) 10% Pd/C, H2, EtOH (1 atm); (b) DCC,
4-pyrrolidinopyridine, HONC4H4S2, CH2Cl2; (c) AIBN, Bu3SnH, PhH,
reflux; (d) DEAD, PPh3, AcOH, THF; (e) DEAD, PPh3, PhCO2H, THF;
(f) LiAlH4, THF, reflux.
the 1H NMR spectra of crude photoreaction mixtures indicated
that regioisomeric photoproducts also had formed. In an attempt
to eliminate the formation of the dehydrogenated photoproduct
20, irradiation of 11c was carried out in the presence of 5.5
equiv of thiophenol. Inhibition of the oxidative pathway leading
to 20 occurred and a 2:1 mixture of 12 and 17 was obtained in
60% yield. Control experiments demonstrated that 20 did not
convert to 12 or 17 on irradiation in the presence of thiophenol.
Thus, the byproduct from radical cyclizations of 11a and 11b
also can be converted to 12, although the facial selectivity for
the photocyclization of enamide 11c is poor. The unexpected
formation of cis-dihydro 17 rather than 16 may be a result of
the relative instability calculated for 16 compared to 17 (∼6
kcal/mol). Perhaps another mechanism for hydrogen atom
transfer in zwitterion 19 competes with the expected suprafacial
1,5-hydrogen migration to give the more stable product.21 It is
noteworthy that thiophenol was found to be an effective additive
to avert the formation of 20.
We have examined the photochemistry of enamide 11c.18
Related enamides undergo photocyclization to six-membered
nitrogen heterocycles19 by conrotatory cyclization of the enamide
to an intermediate zwitterion which undergoes a suprafacial 1,5-
hydrogen atom migration.20 As shown for enamide 11c, a
conrotatory photocyclization would generate zwitterion 18, from
which suprafacial 1,5-hydrogen migration would give 12.
Alternative facial selectivity for the conrotatory photocyclization
was expected to provide the diastereomeric trans-dihydro 16
via zwitterion 19.
The Synthesis of (+)-1-Deoxylycorine (2a). The radical
cyclization 11 f 12 effectively transfers the stereogenicity
developed at pro-C(12) during reductive alkylation of the chiral
benzamide 3 to C(15) of 12. With this transfer accomplished,
the synthesis of (+)-1-deoxylycorine (2a) was completed as
shown in Scheme 3.
Successful debenzylation of the benzyl ester in 12 depended
on the source of palladium catalyst. Utilization of Johnson-
Matthey 10% Pd/C (steam reduced) gave carboxylic acid 21a
in 84% yield. Attempts to decarboxylate 21a directly by
photolysis in the presence of acridine and tert-BuSH in benzene
solution22 resulted in decomposition. It is unclear why this
method for decarboxylation is ineffective, especially in light of
Irradiation of 11c in deoxygenated benzene solution (0.02
M) through Pyrex glass gave a mixture of 12, 20, and 17 (1.1:
2.7:1.0) in 80% yield (Scheme 2). Characteristic doublets in
(17) For a more complete discussion of the facial, regio- and stereose-
lectivity of radical cyclizations of chiral enamides, see: Schultz, A. G.;
Guzzo, P. R.; Nowak, D. M. J. Org. Chem. 1995, 60, 8040.
(18) Enamide 11c also was prepared via acylation of 9 with piperonyloyl
chloride to give 10c.
(19) (a) Lenz, G. R. Synthesis 1978, 489. (b) Ninomiya, I.; Naito, T. In
The Alkaloids; Brossi, A., Ed.; Academic Press: New York, 1983; Vol.
22, p 189.
(21) For an alternative mechanism involving intermolecular hydrogen
atom migration, see (a) Schultz, A. G.; Lucci, R. D. J. Chem. Soc., Chem.
Commun. 1976, 925. (b) Schultz, A. G.; Lucci, R. D.; Fu, W. Y.; Berger,
M. H.; Erhardt, J.; Hagmann, W. K. J. Am. Chem. Soc. 1978, 100, 2150.
(22) (a) Okada, K.; Okubo, K.; Oda, M. J. Photochem. Photobiol. A:
Chem. 1991, 57, 265. (b) Okada, K.; Okubo, K.; Oda, M. Tetrahedron Lett.
1989, 30, 6733.
(20) For an approach to the lycorine alkaloids involving photocyclizations
of enamides to dehydrogenated photoproducts, see: Iida, H.; Aoyagi, S.;
Kibayashi, C. J. Chem. Soc., Perkin Trans. 1 1975, 2502.

Syntheses of (+)-Lycorine and (+)-1-Deoxylycorine
J. Am. Chem. Soc., Vol. 118, No. 26, 1996 6213
Scheme 4
with sodium borohydride in ethanol (Scheme 4). This is
significant considering that independent syntheses of racemic
25 have been reported by Muxfeldt30 and Seebach31 and that
the assignment of structure for the reduction product had not
been previously determined.32
One additional observation deserves comment. It was thought
that carboxylic acid 21a might undergo a decarboxylative
fragmentation to allylic alcohol 22 via the hypothetical zwit-
terionic intermediate 26. Instead, 21a rearranged to the lactone
alcohol 28 in 80% yield on heating a solution of 21a in water
to reflux. This rearrangement may occur by way of trans diaxial
hydrolysis of the epoxide ring in 26 to give diol 27 initially in
a chair conformation followed by relaxation to a boat conforma-
tion and lactonization involving displacement of the C(2) alcohol
group.
a related successful conversion (Vide infra). In any event,
conversion of 21a to either the N-hydroxy-2-thiopyridone
ester23a (not shown) or the N-hydroxy-2-thiazoline thione ester
21b23b with DCC24 and treatment of either ester with AIBN
and Bu3SuH in refluxing benzene solution provided the crystal-
line (+)-2-epi-1-deoxylycorine (22).25,26
Inversion of the allylic alcohol of 22 under classic Mitsunobu
conditions with glacial acetic acid gave a 50% yield (44%
recovered starting material) of acetate 23a which was identical
(TLC, 1H NMR, 13C NMR, CIMS) to authentic racemic material
prepared from (()-1-deoxylycorine-7-one27 provided by Profes-
sor Kurt Torssell. A higher yield of ester 23b (73%) was
obtained when benzoic acid was used in the Mitsunobu
inversion. Reduction of either 23a or 23b with LiAlH4 provided
(+)-1-deoxylycorine (2a) in good yield, identical to racemic
1
material prepared from (()-1-deoxylycorine-7-one (TLC, H
NMR).
The Synthesis of (+)-Lycorine (2b). The remaining chal-
lenge to development of the first asymmetric synthesis of 2b
was the incorporation of the C(1) hydroxy substituent. This
substitution proved to be somewhat more difficult than initially
expected.
Although the relative configuration of 2a was known for
certain, the absolute configuration was not. Reduction of 2-epi-
1-deoxylycorin-7-one (22) with LiAlH4 gave 24 in 77% yield
28
(Scheme 4). Oxidation of 24 with MnO2 provided 1-deoxy-
lycorin-2-one (25) which exhibited an optical rotation ([R]24
D
Introduction of C(1) oxygenation prior to radical or photo-
chemical formation of the C(14)-C(15) bond could not be
accomplished.33 As a first alternative, the hydroxylation of an
enolate derived from (+)-1-deoxylycorin-2-one (25) was ex-
amined. Unfortunately, treatment of 25 with either tert-
+164° with mp 157-8 °C) opposite to that of 25 ([R]24D -169°
with mp 157-8 °C) prepared from natural lycorine (1) by
Kotera.29 These data confirm that 2a has absolute configuration
opposite to that of the natural lycorine alkaloids. In addition,
the stereochemical sense of alkylation of the enolate derived
from 3 with 2-bromoethyl acetate is confirmed to be the same
as that observed under identical reaction conditions for less
highly functionalized alkylation reagents.12
34
butyldimethylsilyl triflate at 0 °C in CH2Cl2 or sodium
hexamethyldisilylamide followed by tert-butyldimethylsilyl
chloride gave dienol silyl ether 29 rather than the desired C(1)
analogue.35
It is of interest to note that 1-deoxylycorin-2-one (25) provides
2-epi-1-deoxylycorine (24) with only a trace of 2 upon reduction
(23) (a) Barton, D. H. R.; Crich, D.; Motherwell, W. B. Tetrahedron
1985, 41, 3901. (b) Barton, D. H. R.; Crich, D.; Kretzschmar, G. J. Chem.
Soc., Perkin Trans. 1 1986, 39.
(24) Hassner, A.; Alexanian, V. Tetrahedron Lett. 1978, 4475.
(25) For earlier examples of radical-induced epoxide fragmentations,
see: (a) Sabatino, E. C.; Gritter, R. J. J. Org. Chem. 1963, 28, 3437. (b)
Barton, D. H. R.; Motherwell, R. S. H.; Motherwell, W. B. J. Chem. Soc.,
Perkin Trans. 1 1981, 2363. (c) Rawal, V. H.; Newton, R. C.; Krishna-
murthy, V. J. Org. Chem. 1990, 55, 5181. (d) Kim, S.; Lee, S.; Koh, J. S.
J. Am. Chem. Soc. 1991, 113, 5106. (e) Rawal, V. H.; Krishnamurthy, V.
Tetrahedron Lett. 1992, 33, 3439. (f) Rawal, V. H.; Iwasa, S. Tetrahedron
Lett. 1992, 33, 4687. (g) Dang, H.-S.; Roberts, B. P. Tetrahedron Lett. 1992,
33, 6169.
An effective solution to the C(1)-oxidation problem is shown
in Schemes 5 and 6. The conversion of epoxide 12 to selenide
30 was carried out by utilization of standard Sharpless conditions
at room temperature.36 Prolonged reaction or elevated temper-
atures resulted in transesterification by the solvent (ethanol).
Oxidation with hydrogen peroxide produced epoxide 31 rather
(26) For a nonstereoselective synthesis of racemic 22, see: Torssell, K.
Tetrahedron Lett. 1974, 623.
(27) Moller, O.; Steinberg, E.-M.; Torssell, K. Acta Chem. Scand. B 1978,
32, 98.
(28) Salmond, W. G.; Barta, M. A.; Havens, J. L. J. Org. Chem. 1978,
43, 2057.
(33) Holoboski, M. A. Ph.D. Thesis, Rensselaer Polytechnic Institute,
1995.
(34) Emde, H.; Domsch, D.; Feger, H.; Frick, U.; Gotz, A.; Hergott, H.
H.; Hofmann, K.; Kober, W.; Krageloh, K.; Oesterle, T.; Steppan, W.; West,
W.; Simchen, G. Synthesis 1982, 1.
(29) Kotera, K. Tetrahedron 1961, 12, 240.
(30) Muxfeldt, H.; Bell, J. P.; Baker, J. A.; Cuntze, U. Tetrahedron Lett.
1973, 4587.
(31) Weller, T.; Seebach, D. Tetrahedron Lett. 1982, 23, 935.
(32) Baker, J. A. Ph.D. Thesis, Cornell University, 1970.
(35) Unexpected problems associated with the oxidation of 22 with MnO2
to the corresponding enone made the study of dienol silyl ether formation
impractical; see ref 33.
(36) Sharpless, K. B.; Lauer, R. F. J. Am. Chem. Soc. 1973, 95, 2697.

6214 J. Am. Chem. Soc., Vol. 118, No. 26, 1996
Schultz et al.
Scheme 5a
represented an unfortunate turn of events in an otherwise
completely stereoselective synthesis. For this reason, a study
of an allylic substitution42 of alcohol 32 or acetate 34 gained
considerable appeal. Esterification of 32 with acetic anhydride,
triethylamine, and 4-dimethylaminopyridine gave the allylic
acetate 34 in 92% yield.
Effective reaction conditions for the rearrangement of 34 to
35 (Scheme 6) could not be found; however, treatment of allylic
alcohol 32 with a mixture of acetic acid, acetic anhydride, and
sulfuric acid at 50 °C, conditions first described by Torssell
and co-workers27 for rearrangement of a closely related analogue
of 32, provided a mixture consisting of the desired allylic acetate
35, the unrearranged allylic acetate 34, and a minor amount of
a substance tentatively identified as the C(1) diastereomeric
allylic acetate corresponding to 35. Chromatography on silica
gel provided crystalline 35 in 34% yield. The overall yield of
35 could be considerably improved by recycling operations that
involved hydrolysis of the recovered mixture of isomeric allylic
acetates followed by re-exposures to the Torssell reaction
conditions.
a Reaction conditions: (a) NaBH4, EtOH, PhSeSePh; (b) 30% H2O2,
THF; (c) NaIO4, H2O, THF; (d) TFAA, UHP, CH2Cl2; (e) Ac2O,
DMAP.
Scheme 6a
Allylic acetate 35 was converted to epoxide 36a on treatment
with dimethyldioxirane.43 It is noteworthy that m-chloroper-
benzoic acid did not react with 35 and that CF3CO3H gave only
a trace of 36a after an extended reaction period. The stereo-
selectivity of epoxidation was determined by observation of a
coupling constant of 2.7 Hz for H(1) and H(2). A coupling of
∼6 Hz would have been expected had the epoxidation of 35
occurred syn to the benzyl ester group; cf., epoxide 12.
Debenzylation of ester 36a occurred uneventfully to give
carboxylic acid 36b. While preparation of the desired ester for
radical fragmentation proved to be problematic, Okada’s direct
procedure for photochemical decarboxylation cleanly afforded
allylic alcohol 37.22 Acetylation of 37 gave diacetate 38 (mp
1
114 °C) for which the IR, H NMR, and mass spectra agreed
with data published for the racemate.44 Reduction of 37 with
LiAlH4 gave (+)-lycorine (2b) which was identical to a sample
of natural (-)-lycorine provided by Professor George Pettit
1
(TLC, H NMR). Because of general insolubility of lycorine
in organic solvents, 2b was converted to its diacetate [mp 207-9
°C dec, [R]23D -25° (c 0.16, CHCl3)] which was identical (TLC,
1H NMR, CIMS, IR, HPLC) to the diacetate (mp 207-13 °C)44a
prepared from natural (-)-lycorine (1) [[R]23D +25.6° (c 0.39,
CHCl3)].
a Reaction conditions: (a) AcOH, Ac2O, H2SO4, 50 °C; (b) di-
methyldioxirane, acetone, 0 °C; (c) 10% Pd/C, H2 (1 atm) EtOH; (d)
hν, Pyrex, acridine, PhH, tert-BuSH; (e) LiAlH4, THF, reflux; (f) Ac2O,
DMAP.
Conclusion
than the desired allylic alcohol 32.37 Oxidation of selenide 30
with sodium periodate gave allylic alcohol 32 in 81% overall
yield from 12.
The first asymmetric total syntheses of (+)-1-deoxylycorine
(2a) and (+)-lycorine (2b) have been achieved. The synthesis
of 2a required 13 steps from the readily available chiral
benzamide 3,12b while (+)-lycorine (2b) was obtained in 15
steps. Both 2a and 2b were prepared in enantiomerically pure
form via Birch reduction-alkylation of 3. The iodolactonization
7 f 8 accomplished the dual functions of introduction of the
hydroxy group at C(2) with complete stereocontrol and release
of the chiral auxiliary.
Epoxidation of allylic alcohol 3238 with trifluoroperacetic
acid39 generated from the reaction of trifluoroacetic anhydride
and urea hydrogen peroxide complex40 gave a 1:1 mixture of
31 and 33. Epoxidation of 32 with m-chloroperbenzoic acid
or VO(acac)2/tert-BuOOH provided even less of the desired
epoxide 33. Molecular models of 32 show that the pseudoequa-
torial C(3) hydroxyl group on the boat cyclohexene C ring is
poorly oriented for stereodirected peracid and VO(acac)2/tert-
BuOOH epoxidations.41
A key step in the synthesis of both 2a and 2b is the
completely regio- and stereoselective radical cyclization reaction
to give 12. Companion studies17 suggest that this type of chiral
Although the conversion of epoxide 33 to (+)-lycorine (2b)
might be possible, the absence of stereocontrol for its formation
(42) Stork, G.; White, W. N. J. Am. Chem. Soc. 1956, 78, 4609.
(43) (a) Adam, W.; Chan, Y.; Cremer, D.; Gauss, J.; Scheutzow, D.;
Schindler, M. J. Org. Chem. 1987, 52, 2800. (b) Adam, W.; Curci, R.;
Edwards, J. O. Acc. Chem. Res. 1989, 22, 205. (c) Murray, R. W. Chem.
ReV. 1989, 89, 1187.
(44) (a) Tsuda, Y.; Sano, T.; Taga, J.; Isobe, K.; Toda, J.; Takagi, S.;
Yamaki, M.; Murata, M.; Irie, H.; Tanaka, H. J. Chem. Soc., Perkin Trans.
1 1979, 1358. (b) Kotera, K.; Hamada, K.; Tori, Y.; Aono, K.; Kuriyama,
K. Tetrahedron Lett. 1966, 2009.
(37) For a discussion of this type of oxidation, see: Hori, T.; Sharpless,
K. B. J. Org. Chem. 1978, 43, 1689.
(38) Henbest, H. B.; Wilson, R. A. L. J. Chem. Soc. 1959, 1958.
(39) McKittrick, B. A.; Ganem, B. Tetrahedron Lett. 1985, 26, 4895.
(40) Cooper, M. S.; Heaney, H.; Newbold, A. J.; Sanderson, W. R.
Synlett. 1990, 533.
(41) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93,
1307.

Syntheses of (+)-Lycorine and (+)-1-Deoxylycorine
J. Am. Chem. Soc., Vol. 118, No. 26, 1996 6215
ylphosphoryl azide (7.18 g, 0.0261 mol) in THF (33 mL) was added
slowly, and the mixture was allowed to warm to room temperature
overnight. Evaporation of the solvent provided a dark brown oil (27.75
g) which was flash chromatographed (hexanes/ethyl acetate 2:1) to
afford 6b (6.15 g, 73%) as a pale yellow oil: 1H NMR (CDCl3) δ 5.93
(m, 1 H), 5.41 (dt, 1 H, J ) 10.0 Hz, 2.0 Hz), 4.80 (t, 1 H, J ) 3.20
Hz), 4.30 (m, 1 H), 3.61-3.55 (m, 2 H), 3.53 (s, 3 H), 3.35-3.32 (m,
1 H), 3.34 (s, 3 H), 3.27-3.09 (m, 3 H), 2.95-2.79 (m, 2 H), 2.41 (m,
1 H), 2.03 (m, 1 H), 1.93-1.70 (m, 4 H); IR (CHCl3) 2940, 2110,
enamide cyclization will have substantial application to the
stereocontrolled synthesis of other alkaloids.
While our earlier applications of the Birch reduction-
alkylation to asymmetric synthesis focused on target structures
with a quaternary stereocenter derived from C(1) of the starting
benzoic acid derivative,10b the syntheses of 2a and 2b rather
convincingly demonstrate that the methodology is applicable
to the synthesis of chiral six-membered rings containing only
tertiary and trigonal carbon atoms. The development of
synthetic strategies that illustrate a more versatile Birch reduc-
tion-alkylation will continue to be the subject of future publica-
tions from this laboratory.
1610 cm-1 13C NMR (CDCl3) 169.15, 152.14, 126.51, 125.74, 92.91,
;
71.72, 58.71, 58.08, 54.02, 50.48, 47.66, 45.77, 34.88, 26.49, 26.12,
24.73; CIMS, m/z (rel intensity) 321 (M+ + 1, 100). Anal. Calcd for
C16H24N4O3: C, 59.98; H, 7.55. Found: C, 59.71; H, 7.41.
(2′S,2R)-2-(2-Azidoethyl)-2-[[2′-(methoxymethyl)pyrrolidinyl]car-
bonyl]-3-cyclohexen-1-one (7). To 6b (6.15 g, 0.0191 mol) in MeOH
(192 mL) was added 6 M HCl (71 mL), and the clear yellow solution
was stirred at room temperature overnight. After removing the MeOH
under reduced pressure, water was added (30 mL), and the mixture
was extracted with methylene chloride (5 × 50 mL). The combined
organic layers were washed with NaHCO3 (saturated), dried (MgSO4),
and concentrated. Flash chromatography (hexanes/ethyl acetate, 1:1)
afforded 7 (5.57 g, 95%) as a pale yellow oil. 1H NMR (CDCl3) δ
6.04 (dt, 1 H, J ) 9.8 Hz, 4.2 Hz), 5.67 (d, 1 H, J ) 9.6 Hz), 4.27 (m,
1 H), 3.62 (dd, J ) 9.5, 3.1 Hz, 1 H), 3.48 (m, 1 H), 3.39-3.30 (m, 3
H), 3.36 (s, 3 H), 3.10-3.05 (m, 1 H), 2.66-2.60 (m, 3 H), 2.54 (m,
1 H), 2.31 (m, 1 H), 2.02 (m, 1 H), 1.75 (m, 1 H), 1.95-1.86 (m, 3
Experimental Section
1H and 13C NMR spectra were obtained on either a Varian XL-200
(200 MHz) or Unity 500 (500 MHz) spectrometer employing tetra-
methylsilane as an internal standard. Infrared spectra were recorded
on a Perkin-Elmer 298 Model spectrometer. Mass spectral data were
obtained on a Hewlett-Packard Model 5987-A GC-MS system employ-
ing methane or isobutane as chemical ionization gases or utilizing direct
electron impact. Optical rotations were taken on a Perkin-Elmer Model
241 polarimeter with a 0.5 mL (L ) 0.1 dm) cell. Elemental analyses
were performed by either Spang Microanalytical Laboratories, Eagle
Harbor, MI or Quantitative Technologies Inc., Whitehouse, NJ. Melting
points were determined in open capillary tubes on a Thomas Hoover
apparatus and were uncorrected. Column chromatography was per-
formed on Baker 40 µm silica gel. Radial chromatography was
performed with EM Science silica gel 60 (PF254) containing Gypsum.
All reactions were performed under an inert atmosphere of nitrogen
unless otherwise noted. HPLC analyses were performed on a Waters
Associates Model 6000A instrument equipped with a Model R401
differential refractometer and a Hewlett Packard Model HP3394
integrator using a 25 cm Daicel OD or a 25 cm Partisil 5 column. The
300 nm light source was a medium pressure 450W Hanovia mercury
arc lamp.
H); IR (CHCl3) 2950, 2110, 1710, 1625 cm-1 13C NMR (CDCl3)
;
207.12, 167.59, 128.43, 128.29, 71.55, 59.87, 58.83, 57.84, 47.68, 46.53,
36.15, 35.48, 26.48, 25.57, 24.34. CIMS, m/z (rel intensity) 307 (M+
+ 1, 100). Anal. Calcd for C15H22N4O3: C, 58.81; H, 7.24. Found:
C, 58.83; H, 7.25.
(2R,3R,4R)-1-Oxo-2-(2-azidoethyl)-3-iodocyclohexane-2,4-carbo-
lactone (8). To a solution of amide 7 (2.22 g, 7.25 mmol) and THF
(45 mL) were added H2O (45 mL) and iodine (11 g, 43 mmol). The
reaction was stirred 12 h and Na2S2O3 (sat) was added until the black
reaction turned yellow. The THF was evaporated and the aqueous phase
was washed with CH2Cl2 (5 × 20 mL). The combined organic phase
was dried (Na2SO4) and concentrated. Flash chromatography (EtOAc/
hexanes; 1:2) afforded lactone 8 as a colorless solid (2.0 g, 82%). Mp
69-72 °C; [R]18D -161.5° (c 6.76, CHCl3). 1H NMR (CDCl3) δ 2.05
(m, 1 H), 2.25 (m, 1 H), 2.46 (m, 1 H), 2.56-2.77 (m, 3 H), 3.41 (m,
2 H), 4.96 (d, J ) 1.4 Hz, 1 H), 5.00 (m, 1 H). 13C NMR (CDCl3)
197.13, 169.27, 77.46, 62.46, 46.28, 32.73, 27.26, 23.87, 23.82. IR
6-Bromopiperonylic acid was prepared45 and recrystallized from
water. 6-Iodopiperonal was prepared according to a literature proce-
dure46 and oxidized to 6-iodopiperonlyic acid.47 The corresponding
acid chlorides were prepared with thionyl chloride.
(2′S,6R)-1-Methoxy-6-(2-hydroxyethyl)-6-[[2′-(methoxymethyl)-
pyrrolidinyl]carbonyl]-1,4-cyclohexadiene (6a). A solution of 312
(7.08 g, 0.0284 mol) in THF (40 mL) was cooled to -78 °C and
ammonia (400 mL) and tert-butyl alcohol (2.11 g, 0.0284 mol) were
added. Potassium was added in small pieces until a blue color persisted
for 15 min. 2-Bromoethyl acetate (12.0 g, 0.071 mol) was added, and
the yellow solution was stirred 0.5 h. After evaporation of the ammonia,
methanol (42 mL) and 10% potassium hydroxide (14 mL) were added,
and the resulting solution stirred 6 h at room temperature. The mixture
was concentrated, CH2Cl2 (50 mL) and water (20 mL) were added, the
layers separated, and the aqueous solution was extracted with CH2Cl2
(3 × 20 mL). The combined organic layers were washed with brine
and dried (MgSO4), and the solvent was removed in Vacuo to afford a
yellow oil. Chromatography over silica gel (1:1 hexanes/ethyl acetate;
then ethyl acetate) provided pure 6a (8.05 g, 96%) as a pale yellow
oil: 1H NMR (CDCl3) δ 5.91 (dt, 1 H, J ) 9.8, 3.7, 1.2 Hz), 5.61 (d,
1 H, J ) 9.88 Hz), 4.72 (t, 1 H, J ) 3.50 Hz), 4.30 (m, 1 H), 3.70-
3.56 (m, 4 H), 3.53 (s, 3 H), 3.35 (s, 3 H), 3.38-3.20 (m, 3 H), 2.99-
2.75 (m, 2 H), 2.33 (m, 1 H), 2.08 (m, 1 H), 1.95-1.70 (m, 4 H); IR
(CDCl3) 2120, 1780, 1725 cm-1. CIMS m/z (rel intensity) 336 (M+
+
1, 100), 308 (50). Anal. Calcd for C9H10N3O3I: C, 32.26; H, 3.01;
N, 12.54. Found: C, 32.63; H, 2.95; N, 12.49.
(3aR,4R,5R)-4-Iodo-2,3,6,7-tetrahydroindole-3a,5-carbolactone (9).
To a solution of lactone 8 (6.35 g, 19.0 mmol) in THF (250 mL) was
added triphenylphosphine (5.0 g, 19 mmol), and the reaction was
refluxed (9 h), cooled, and concentrated. Flash chromatography (Et2O/
hexane; 1:1) afforded imine 9 (4.97 g, 90%) as a colorless solid. Mp
130 °C; [R]20 -170.6° (c 2.18, CHCl3). 1H NMR (CDCl3) δ 1.91
D
(m, 1 H), 2.50 (m, 4 H), 2.83 (dd, J ) 16.5, 7.5 Hz, 1 H), 4.00 (m, 2
H), 4.70 (d, J ) 5 Hz, 1 H), 4.90 (s, 1 H); 13C NMR (CDCl3) 170.33,
167.00, 77.93, 65.20, 60.23, 28.67, 25.42, 24.66, 22.63; IR (CHCl3)
2940, 1785, 1665 cm-1; CIMS m/z (rel intensity) 292 (M+ + 1, 100),
166 (66). Anal. Calcd for C9H10NO2I: C, 37.14; H, 3.46. Found:
C, 37.20; H, 3.46.
(3aR,4R,5R)-N-(6-Bromopiperonyloyl)-5,6-dihydro-4H-indoline-
3a,5-carbolactone (10a). A solution of imine 9 (0.526 g, 1.81 mmol)
and Et3N (0.37 g, 3.6 mmol) in CH2Cl2 (50 mL) was cooled to 0 °C,
and then a solution of 6-bromopiperonyloyl chloride (0.477 g, 1.81
mmol) in CH2Cl2 (25 mL) was added slowly. The reaction was allowed
to gradually warm to room temperature while stirring (12 h). The
mixture was washed with 10% HCl (20 mL), saturated NaHCO3 (30
mL), and dried (Na2SO4); solvent evaporation and flash chromatography
(CHCl3) 3360, 3000, 1610 cm-1; CIMS, m/z (rel intensity) 296 (M+
1, 100). An acceptable elemental analysis could not be obtained.
(2′S,6R)-1-Methoxy-6-(2-azidoethyl)-6-[[2′-(methoxymethyl)pyr-
rolidinyl]carbonyl]-1,4-cyclohexadiene (6b). To a solution of 6a (7.72
g, 0.0261 mol) in THF (130 mL) at 0 °C was added triphenylphosphine
(6.86 g, 1 equiv) and diethyl azodicarboxylate (4.55 g, 0.0261 mol),
and stirring was continued for 20 min. Then a solution of diphen-
+
(EtOAc/hexane; 1:4) provided enamide 10a (0.915 g, 98%) as a
1
colorless solid. Mp 131 °C; [R]25 -4.3° (c 0.46, CHCl3); H NMR
D
(45) Auerbach, J.; Weissman, S. A.; Blacklock, T. J.; Angeles, M. R.;
Hoogsteen, K. Tetrahedron Lett. 1993, 34, 931.
(46) Semmelhack, M. F.; Chong, B. P.; Stauffer, R. D.; Rogerson, T.
D.; Chong, A.; Jones, L. D. J. Am. Chem. Soc. 1975, 97, 2507.
(47) CA 55:3594c.
(CDCl3) δ 2.10 (m, 1 H), 2.25 (m, 1 H), 2.77 (d, J ) 19 Hz, 1 H), 2.97
(d, J ) 19 Hz, 1 H), 3.50 (m, 2 H), 4.64 (d, J ) 4.9 Hz, 1 H), 4.82 (m,
1 H), 6.03 (s, 2 H), 6.60 (s, 1 H), 6.78 (s, 1 H), 7.01 (s, 1 H). IR
(CDCl3) 1780, 1640 cm-1; CIMS m/z (rel intensity) 520 (M+ + 1, 21),

6216 J. Am. Chem. Soc., Vol. 118, No. 26, 1996
Schultz et al.
518 (M+ + 1, 22), 248 (100). Anal. Calcd for C17H13NO5BrI: C,
39.41; H, 2.53; N, 2.70. Found: C, 39.26; H, 2.70; N, 2.55.
101.60, 67.57, 60.04, 53.96, 53.81, 53.44, 43.80, 36.57, 32.50, 25.05.
IR (CHCl3) 1732, 1641 cm-1. CIMS m/z (rel intensity) 420 (M+ + 1,
100), 330 (24), 286 (25). Anal. Calcd for C24H21NO6: C, 68.73; H,
5.05; N, 3.34. Found: C, 68.38; H, 5.14; N, 3.10.
(3aR,4R,5R)-N-(6-Iodopiperonyloyl)-5,6-dihydro-4H-indoline-
3a,5-carbolactone (10b). A solution of imine 9 (1.76 g, 6.06 mmol)
and Et3N (1.23 g, 12.1 mmol) in CH2Cl2 (150 mL) was cooled to 0
°C, and then a solution of 6-iodopiperonyloyl chloride (1.88 g, 6.06
mmol) in CH2Cl2 (50 mL) was added slowly. The reaction was allowed
to gradually warm to room temperature while stirring (12 h). The
mixture was washed with 10% HCl (70 mL) and saturated NaHCO3
(100 mL) and dried (Na2SO4); solvent evaporation and flash chroma-
(3aS,4S,5R)-N-(Piperonyloyl)-4,5-epoxy-5,6-dihydro-4H-3a-(ben-
zyloxycarbonyl)indoline (11c). 1H NMR (CDCl3) δ 1.98 (ddd, J )
9.5, 11, 20.5 Hz, 1 H), 2.50 (m, 2 H), 2.66 (dd, J ) 7, 12.5 Hz, 1 H),
3.38 (m, 1 H), 3.47 (d, J ) 4 Hz, 1 H), 3.50 (m, 1 H), 3.88 (m, 1 H),
5.24 (d, J ) 12 Hz, 1 H), 5.29 (d, J ) 12.5 Hz, 1 H), 5.97 (s, 2 H),
6.65 (d, J ) 8 Hz, 1 H), 7.1-7.5 (m, 7 H). γ ) 300 nm (ꢀ ) 5246,
PhH) γmax ) 295 nm (ꢀ ) 5485, PhH). IR (CHCl3) 1730, 1630 cm-1
.
tography (EtOAc/hexane; 1:4) provided enamide 10b (3.4 g, 99%) as
1
a colorless solid, mp 200-202 °C; [R]24 -0.3° (c 3.26, CHCl3); H
D
CIMS m/z (rel intensity) 420 (M+ + 1, 100), 149 (16). CI HRMS
(methane) m/z 420.1444 (M + 1). Calcd for C24H22NO6: 420.1447.
NMR (CDCl3) δ 2.10 (m, 1 H), 2.25 (m, 1 H), 2.76 (d, J ) 19 Hz, 1
H), 2.96 (d, J ) 19 Hz, 1 H), 3.50 (m, 2 H), 4.63 (d, J ) 5 Hz, 1 H),
4.82 (m, 1 H), 6.01 (s, 2 H), 6.59 (s, 1 H), 6.76 (s, 1 H), 7.21 (s, 1 H).
IR (CDCl3) 1780, 1640 cm-1; CIMS m/z (rel intensity) 566 (M+ + 1,
14), 440 (37), 394 (94), 314 (98), 312 (80).
Alternate Procedure. A solution of ester 11b (600 mg, 1.10 mmol),
Bu3SnH (476 mg, 1.65 mmol), AIBN (18 mg, 0.11 mmol), and benzene
(120 mL) was degassed for 15 min and then refluxed for 5 h (until the
complete disappearance of starting material was observed by TLC).
The solvent was evaporated, and the organic residue was partitioned
between MeCN and hexane. The MeCN layer was washed with hexane
(four times), and after solvent removal, flash chromatography (EtOAc/
hexane; 1:1) afforded lactam 12 (235 mg, 51%) as a colorless solid.
1H NMR analysis of the crude reaction mixture indicated that 12 and
11c were present in a ratio of ∼1:1.
(3aS,4S,5R)-N-(6-Bromopiperonyloyl)-4,5-epoxy-5,6-dihydro-4H-
3a-(benzyloxycarbonyl)indoline (11a). A solution of BnOH (1.03 g,
9.61 mmol) in THF (60 mL) was cooled to -78 °C and a 2.5 M solution
of BuLi (2.60 mL, 6.5 mmol) in hexanes was added. The mixture
was allowed to stir for 5 min, and then enamide 10a (3.33 g, 6.43
mmol) in THF (20 mL) was added. The reaction was stirred at -78
°C (5 min), 0 °C (3 h), and room temperature (2 h). The reaction was
quenched with excess NH4Cl (saturated) and concentrated in Vacuo.
The aqueous phase was washed with CH2Cl2 (5 × 25 mL), and the
combined organic phase was dried (Na2SO4). Flash chromatography
(EtOAc/hexane; 1:4) afforded benzyl ester 11a (2.29 g, 73%) as a
colorless solid. Mp 68-72 °C; [R]24D +85° (c 2.0, CHCl3). 1H NMR
δ 2.05 (m, 1 H), 2.45 (m, 1 H), 2.65 (m, 2 H), 3.35 (m, 1 H), 3.45 (m,
1 H), 3.62 (m, 1 H), 3.92 (m, 1 H), 4.52 (s, 1 H), 5.22 (d, J ) 12.2 Hz,
1 H), 5.26 (d, J ) 12 Hz, 1 H), 6.0 (m, 2 H), 6.70-7.50 (m, 7 H). IR
(CHCl3) 1730, 1630 cm-1. CIMS m/z (rel intensity) 500 and 498 (M+
+ 1, 4), 420 (5), 266 (15), 133 (40), 107 (45), 91 (100). Anal. Calcd
for C24H20NO6Br: C, 57.85; H, 4.05; N, 2.81. Found: C, 57.86; H,
4.39; N, 2.65.
Photolysis of Enamide 11c. A solution of enamide 11c (50 mg,
0.12 mmol) and benzene (6 mL) in a Pyrex test tube was degassed
with nitrogen for 15 min. The mixture was irradiated (7 h) and then
concentrated. Flash chromatography (EtOAc/hexanes, 1:1) afforded a
colorless solid (40 mg, 80%) which consisted of lactams 12, 20, and
1
17 (1.1:2.7:1 ratio by 500 MHz H NMR). Analytical samples were
obtained by radial chromatography (EtOAc/hexanes, 1:1).
(2R,3S,12S)-2,3-Epoxy-12-(benzyloxycarbonyl)-15,16-didehydro-
9,10-[methylenebis(oxy)]galanthan-7-one (20). Mp 118 °C. 1H NMR
(CDCl3) δ 2.30 (m, 1 H), 2.92 (m, 2 H), 3.20 (dd, J ) 5.8, 17.6 Hz,
1 H), 3.60 (d, J ) 3.1 Hz, 1 H), 3.70 (m, 1 H), 3.78 (ddd, J ) 5.6, 12,
12 Hz, 1 H), 4.39 (dd, J ) 8.5, 12.5 Hz, 1 H), 5.18 (d, J ) 12.2 Hz,
1 H), 5.22 (d, J ) 12.2 Hz, 1 H), 6.1 (m, 2 H), 6.93 (s, 1 H), 7.82 (s,
1 H), 7.32 (m, 5 H). IR (CH2Cl2) 1730, 1675, 1600 cm-1. CIMS m/z
(rel intensity) 418 (M+ + 1, 55), 266 (65), 147 (25), 91 (100). CI
HRMS (methane) m/z 418.1291(M + 1). Calcd for C24H20NO6:
418.1291.
(3aS,4S,5R)-N-(6-Iodopiperonyloyl)-4,5-epoxy-5,6-dihydro-4H-
3a-(benzyloxycarbonyl)-indoline (11b). A solution of BnOH (1.90
g, 17.7 mmol) in THF (75 mL) was cooled to -78 °C and a 2.5 M
solution of BuLi (5.20 mL, 13 mmol) in hexanes was added. The
mixture was allowed to stir for 5 min and then enamide 10b (6.67 g,
11.8 mmol) in THF (35 mL) was added. The reaction was stirred at
-78 °C (5 min), 0 °C (3 h), and room temperature (2 h). The reaction
was quenched with excess NH4Cl (saturated) and concentrated in Vacuo.
The aqueous phase was washed with CH2Cl2 (5 × 25 mL), and the
combined organic phase was dried (Na2SO4). Flash chromatography
(EtOAc/hexane; 1:4) afforded benzyl ester 11b (5.92 g, 92%) as a
2R,3S,12S,15S,16R)-2,3-Epoxy-12-(benzyloxycarbonyl)-9,10-
[methylenebis(oxy)galanthan-7-one (17). 1H NMR (CDCl3) δ 1.78
(dd, J ) 11, 15 Hz, 1 H, H1ax), 2.20 (ddd, J ) 2.5, 6, 16 Hz, 1 H,
H
1eq), 2.32 (m, 2 H), 3.03 (m, 1 H, H15), 3.34 (d, J ) 4 Hz, 1 H, H3),
3.38 (m, 1 H, H2), 3.60 (m, 1 H, H5), 3.93 (m, 1 H, H5), 4.35 (d, J )
3 Hz, 1 H, H16), 5.25 (d, J ) 12.5 Hz, 1 H), 5.29 (d, J ) 10.5 Hz, 1
H), 6.00 (s, 1 H), 6.01 (s, 1 H), 6.61 (s, 1 H), 7.47 (s, 1 H), 7.38 (m,
5 H). CIMS m/z (rel intensity) 420 (M+ + 1, 100), 330 (12), 286
(20). CI HRMS (methane) m/z 420.1442 (M + 1). Calcd for C24H22-
NO6: 420.1447.
colorless solid. Mp 57-63 °C; [R]23 +73.5° (c 2.45, CHCl3). 1H
D
NMR δ 2.05 (m, 1 H), 2.45 (m, 1 H), 2.65 (m, 2 H), 3.35 (m, 1 H),
3.45 (m, 1 H), 3.62 (m, 1 H), 3.92 (m, 1 H), 4.49 (s, 1 H), 5.23 (d, J
) 12 Hz, 1 H), 5.26 (d, J ) 12.5 Hz, 1 H), 5.99 (s, 2 H), 6.70-7.50
(m, 7 H). IR (CDCl3) 1739, 1630 cm-1. CIMS m/z (rel intensity) 546
(M+ + 1, 4), 420 (25), 266 (40), 133 (55), 107 (70), 91 (100).
(2R,3S,12S,15R,16R)-2,3-Epoxy-12-(benzyloxycarbonyl)-9,10-
[methylenebis(oxy)]galanthan-7-one (12). A solution of ester 11a
(1.10 g, 2.2 mmol), Bu3SnH (960 mg, 3.30 mmol), AIBN (40 mg, 0.24
mmol), and benzene (240 mL) was degassed for 15 min and then
refluxed for 16 h (until the complete disappearance of starting material
was observed by TLC). The solvent was evaporated, and the organic
residue was partitioned between MeCN and hexane. The MeCN layer
was washed with hexane (four times) and after solvent removal, flash
chromatography (EtOAc/hexane; 1:1) afforded lactam 12 (490 mg,
53%) as a colorless solid (mp 203 °C, recrystallized from EtOAc/
Photolysis of Enamide 11c in the Presence of Thiophenol.
A
solution of enamide 11c (70 mg, 0.17 mmol), benzene (8.5 mL), and
thiophenol (0.1 mL) in a Pyrex test tube was degassed with nitrogen
for 15 min. The mixture was irradiated (7 h) and then concentrated.
Flash chromatography (EtOAc/hexanes, 1:1) afforded a colorless solid
(42 mg, 60%) which consisted of lactams 12 and 17 (2:1 ratio by 500
1
MHz H NMR).
(2R,3S,12S,15R,16R)-2,3-Epoxy-12-(hydroxycarbonyl)-9,10-
[methylenebis(oxy)]galanthan-7-one (21a). A mixture of lactam 12
(260 mg, 0.62 mmol), abs. EtOH (26 mL) and 10% Pd/C (260 mg;
Alfa) was stirred under (1atm) H2 for 3 h. The mixture was filtered
through Celite, and the Celite was rinsed with CH2Cl2. The combined
filtrate was concentrated to give acid 21a (172 mg, 84%) as a colorless
solid (mp 214-219 °C, -CO2), which was used without further
purification. 1H NMR (CDCl3) δ 1.65 (dd, J ) 15.9, 14.2 Hz, 1 H),
2.17 (ddd, J ) 7.8, 11.0, 12.4 Hz, 1 H), 2.55 (dd, J ) 5.2, 12.5 Hz, 1
H), 2.67 (m, 2 H), 3.34 (ddd, J ) 5.6, 12.2, 11.2 Hz, 1 H), 3.47 (d, J
) 3.4 Hz, 1 H), 3.60 (dd, J ) 3.4, 6.4 Hz, 1 H), 4.03 (d, J ) 12.7 Hz,
1 H), 4.20 (dd, J ) 7.8, 11.2 Hz, 1 H), 6.01 (s, 2 H), 6.63 (s, 1 H),
7.42 (s, 1 H); IR (KBr) 3420, 1715, 1625 cm-1; CIMS m/z (rel intensity)
330 (M+ + 1, 16), 315 (40), 262 (80), 232 (100).
hexane) and enamide 11c (45%). (12): [R]24 +86° (c 1.0, CHCl3);
D
1H NMR (CDCl3) δ 1.66 (dd, J ) 15.1, 14.7 Hz, 1 H, H1ax), 2.12 (ddd,
J ) 12.5, 12.2, 7.3 Hz, 1 H, H4), 2.47 (dd, J ) 4.9, 12.7 Hz, 1 H, H4),
2.66 (m, 2 H, H15, H1eq), 3.21 (ddd, J ) 12.5, 11.2, 4.9 Hz, 1 H, H5),
3.45 (d, J ) 3.9 Hz, 1 H, H3), 3.58 (m, 1 H, H2), 4.09 (d, J ) 12.2 Hz,
1 H, H16), 4.16 (dd, J ) 7.3, 11.7 Hz, 1 H, H5), 5.25 (d, J ) 12.2 Hz,
1 H), 5.30 (d, J ) 12.2 Hz, 1 H), 6.01 (s, 2 H), 6.64 (s, 1 H), 7.25-
7.38 (m, 5 H), 7.44 (s, 1 H). 13C NMR (CDCl3) 172.26, 162.65, 150.59,
146.83, 135.38, 135.11, 128.60, 128.42, 128.10, 124.82, 108.46, 103.62,

Syntheses of (+)-Lycorine and (+)-1-Deoxylycorine
J. Am. Chem. Soc., Vol. 118, No. 26, 1996 6217
(2R,3S,12S,15R,16R)-2,3-Epoxy-12-(3-hydroxy-4-methyl-2(3H)-
thiazolethione)carbonyl-9,10-[methylenebis(oxy)]galanthan-7-one
(21b). The acid 21a (266 mg, 0.809 mmol) was combined with DCC
(253 mg, 1.23 mmol), 4-pyrrolidinopyridine (61 mg, 0.41 mmol),
3-hydroxy-4-methyl-2(3H)-thiazolethione (180 mg, 1.2 mmol), and CH2-
Cl2 (50 mL) and stirred for 12 h in the dark. The mixture was
concentrated and flash chromatography (EtOAc/hexane; 1:1) afforded
ester 21b (318 mg, 86%) as a colorless solid. 1H NMR (CDCl3) δ
1.69 (m, 1 H, H1ax), 2.25 (s, 3 H), 2.40 (m, 1 H, H4), 2.74 (m, 2 H,
H15, H1eq), 3.36 (dd, J ) 5.4, 12.9 Hz, 1 H, H4), 3.59 (ddd, J ) 4.9,
12.5, 11.2 Hz, 1 H, H5), 3.65 (d, J ) 3.5 Hz, 1 H, H3), 3.69 (m, 1 H,
H2), 4.04 (d, J ) 12.5 Hz, 1 H, H16), 4.28 (dd, J ) 8.1, 12.5 Hz, 1 H,
H5), 6.02 (s, 2 H), 6.26 (m, 1 H), 6.65 (s, 1 H), 7.47 (s, 1 H).
was evaporated. Flash chromatography (EtOAc/hexanes, 1:4 then 1:1)
afforded (()-23a as a colorless solid (12 mg, 91%). A solution of
(()-23a (11 mg, 0.034 mmol), LiAlH4 (13 mg, 0.34 mmol), and THF
(2 mL) was refluxed for 3 h and then quenched by sequential dropwise
addition of H2O (0.013 mL), 15% NaOH (0.013 mL), and H2O (0.039
mL). Filtration of the mixture followed by flash chromatography of
the concentrated filtrate (10% MeOH/EtOAc) afforded (()-1-deoxy-
lycorine (2a) (7 mg, 76%) as a colorless solid, mp 153 °C.
(+)-1-Deoxylycorine (2a). A solution of acetate 23a (15 mg, 0.046
mmol), LiAlH4 (15 mg, 0.39 mmol), and THF (1 mL) was refluxed
for 3 h and then quenched by sequential dropwise addition of H2O
(0.015 mL), 15% NaOH (0.015 mL), and H2O (0.045 mL). Filtration
of the mixture followed by flash chromatography of the concentrated
filtrate (10% MeOH/EtOAc) afforded (+)-1-deoxylycorine (2a) (9 mg,
73%) as a colorless solid, which was recrystallized from CH2Cl2/CHCl3/
hexanes. Mp 155 °C; [R]25D +48° (c 0.46, CHCl3). 1H NMR (CDCl3)
δ 1.64 (ddd, J ) 4.9, 13.4, 13.4 Hz, 1 H, H1ax), 2.35 (m, 2 H, H15),
2.44 (d, J ) 13.9 Hz, 1 H, H1eq), 2.58 (m, 2 H), 2.63 (m, 1 H, H15),
3.32 (m, 1 H), 3.53 (d, J ) 14.1 Hz, 1 H, H7), 4.14 (d, J ) 13.9 Hz,
1 H, H7), 4.41 (s, 1 H, H2), 5.56 (s, 1 H, H3), 5.92 (s, 1 H), 5.93 (s, 1
H), 6.57 (s, 1 H), 6.75 (s, 1 H). 13C NMR (CDCl3) 146.38, 145.95,
143.93, 130.99, 128.69, 119.73, 107.14, 105.14, 100.88, 67.43, 66.30,
56.84, 53.63, 34.87, 34.00, 28.62. IR (CHCl3) 3600 cm-1. CIMS m/z
(rel intensity) 272 (M+ + 1, 100), 254 (90).
(2R,15R,16R)-2-Hydroxy-3,12-didehydro-9,10-[methylenebis-
(oxy)]galanthan-7-one (22). To ester 21b (318 mg, 0.694 mmol) were
added benzene (56 mL), Bu3SnH (303 mg, 1.03 mmol), and AIBN (11
mg, 0.067 mmol). The mixture was purged with nitrogen gas and then
refluxed for 2 h. The reaction was recharged with Bu3SnH (202 mg,
0.69 mmol) and AIBN (11 mg, 0.067 mmol), refluxed for 1 h, and
then the solvent was evaporated. The organic residue was partitioned
between MeCN and hexane, and the MeCN layer was washed with
hexane (five times). The combined MeCN solution was concentrated
and flash chromatography (MeOH/EtOAc; 1:9) afforded alcohol 22 as
a colorless solid (98 mg, 50%). Mp 231 °C. [R]27 +80.6° (c 1.65,
D
THF). 1H NMR (CDCl3) δ 1.52 (ddd, J ) 9.5, 12.5, 12.5 Hz, 1 H,
Alternate Procedure. A solution of benzoate 23b (20 mg, 0.05
mmol), LiAlH4 (12 mg, 0.31 mmol), and THF (1 mL) was refluxed
for 3 h and then quenched by sequential dropwise addition of H2O
(0.012 mL), 15% NaOH (0.012 mL) and H2O (0.036 mL). Filtration
of the mixture followed by flash chromatography of the concentrated
filtrate (10% MeOH/EtOAc) afforded (+)-1-deoxylycorine (2a) (10.2
mg, 76%).
H1ax), 1.76 (d, J ) 6.8 Hz, 1 H, OH), 2.75 (m, 4 H, H15, H4, H4, H1eq),
3.73 (m, 1 H, H5), 3.82 (m, 1 H, H5), 3.89 (d, J ) 12 Hz, 1 H, H16),
4.67 (m, 1 H, H2), 5.66 (m, 1 H, H3), 6.02 (s, 2 H), 6.72 (s, 1 H), 7.55
(s, 1 H). 13C NMR (CDCl3, MeOH; 9:1) 163.42, 150.67, 146.60,
140.30, 135.86, 125.29, 122.67, 108.31, 103.36, 101.60, 68.55, 60.23,
43.31, 39.99, 32.15, 28.08. IR (CHCl3) 3600, 1640 cm-1. CIMS m/z
(rel intensity) 286 (M+ + 1, 100), 268 (40).
(+)-2-epi-1-Deoxylycorine (24). A solution of alcohol 22 (143 mg,
0.502 mmol), LiAlH4 (0.19 g, 5.0 mmol), and THF (25 mL) was
refluxed for 6 h and then quenched by sequential dropwise addition of
H2O (0.19 mL), 15% NaOH (0.19 mL), and H2O (0.57 mL). Filtration
of the mixture followed by flash chromatography of the concentrated
filtrate (10% MeOH/EtOAc) afforded (+)-2-epi-1-deoxylycorine 24
(2S,15R,16R)-2-Acetyloxy-3,12-didehydro-9,10-[methylenebis-
(oxy)]galanthan-7-one (23a). To a solution of alcohol 22 (9 mg, 0.03
mmol) and THF (1.5 mL) were added PPh3 (12 mg, 0.045 mmol),
AcOH (3 mg, 0.05 mmol) and DEAD [(8 mg, 0.05 mmol) in THF (0.5
mL)]. The mixture was stirred (24 h) and concentrated, and flash
chromatography (EtOAc/hexane; 1:1) afforded acetate 23a (5 mg, 50%)
as a colorless solid (mp 223 °C) and recovered starting material (44%).
1H NMR (CDCl3) δ 1.84 (ddd, J ) 5.2, 13.2, 13.1 Hz, 1 H, H1ax), 2.08
(s, 3 H), 2.43 (dd, J ) 14.6, 1.7 Hz, 1 H, H1eq), 2.80 (m, 2 H, H4, H4),
2.85 (ddd, J ) 2.9, 12.7, 12.5 Hz, 1 H, H15), 3.72 (d, J ) 12.3 Hz, 1
H, H16), 3.82 (m, 2 H, H5, H5), 5.57 (m, 1 H, H2), 5.65 (m, 1 H, H3),
6.02 (s, 2 H), 6.70 (s, 1 H), 7.56 (s, 1 H). IR (CHCl3) 1720, 1640
(105 mg, 77%) as a colorless solid. Mp 60-64 °C; [R]23 +105° (c
D
0.21, CHCl3). 1H NMR (CDCl3) δ 1.41 (ddd, J ) 9.1, 12.2, 12.2 Hz,
1 H, H1ax), 2.43 (m, 1 H), 2.60 (m, 4 H, H15), 2.73 (m, 1 H, H1eq), 3.26
(m, 1 H), 3.56 (d, J ) 14.1 Hz, 1 H, H7), 4.08 (d, J ) 13.9 Hz, 1 H,
H7), 4.64 (m, 1 H, H2), 5.52 (s, 1 H, H3), 5.92 (d, J ) 1.2 Hz, 1 H),
5.93 (d, J ) 1.5 Hz, 1 H), 6.57 (s, 1 H), 6.73 (s, 1 H). IR (CHCl3)
3600 cm-1 13C NMR (CDCl3) 146.28, 145.87, 142.91, 130.56, 128.53,
.
cm-1
.
13C NMR (CDCl3) 170.44, 163.01, 150.56, 146.74, 143.68,
121.28, 107.12, 104.89, 100.80, 69.59, 66.90, 56.63, 53.65, 39.82, 34.59,
28.30. CIMS m/z (rel intensity) 272 (M+ + 1, 50), 254 (100).
(+)-1-Deoxylycorin-2-one (25). A solution of alcohol 24 (104 mg,
0.38 mmol), MnO2 (330 mg, 3.80 mmol), and CHCl3 (25 mL) was
stirred at room temperature for 6 h. The mixture was filtered through
Celite, and the filtrate was concentrated and chromatographed (EtOAc)
to give enone 25 as a colorless solid (65 mg, 63%). Mp 157-8 °C
(dec); [R]24D +164° (c 0.33, dioxane). Reported for (-)-25: mp 157-8
°C; [R]D24 -169° (c 0.490, dioxane).29 1H NMR (CDCl3) δ 2.28 (dd,
J ) 13.5, 16.4 Hz, 1 H, H1ax), 2.53 (dd, J ) 8.5, 17.1 Hz, 1 H, H4),
2.84 (m, 3 H, H16, H4, H5), 3.05 (dd, J ) 4.4, 16.6 Hz, 1 H, H1eq), 3.12
(m, 1 H, H15), 3.43 (m, 1 H, H5), 3.63 (d, J ) 13.9 Hz, 1 H, H7), 4.18
(d, J ) 13.9 Hz, 1 H, H7), 5.94 (s, 1 H), 5.94 (s, 1 H), 5.97 (m, 1 H,
H3), 6.59 (s, 1 H), 6.64 (s, 1 H). 13C NMR (CDCl3) 198.63, 167.73,
146.47, 146.31, 129.48, 128.06, 122.14, 107.09, 104.90, 100.97, 67.28,
135.52, 126.04, 117.48, 108.80, 103.51, 101.65, 67.87, 60.50, 43.53,
35.83, 29.05, 28.60, 21.31. CIMS m/z (rel intensity) 328 (M+ + 1,
100), 268 (80).
(2S,15R,16R)-2-Benzyloxy-3,12-didehydro-9,10-[methylenebis-
(oxy)]galanthan-7-one (23b). To a solution of alcohol 22 (27 mg,
0.095 mmol) and THF (4 mL) were added PPh3 (35 mg, 0.13 mmol),
BzOH (16 mg, 0.13 mmol) and DEAD [(24 mg, 0.13 mmol), in THF
(2 mL)]. The mixture was stirred (24 h) and concentrated, and flash
chromatography (EtOAc/hexane; 1:1) afforded benzoate 23b (27 mg,
73%) as a colorless solid (mp 199-203 °C). [R]24 -195° (c, 0.22,
D
1
CHCl3); H NMR (CDCl3) δ 1.96 (ddd, J ) 5.4, 13.2, 13.2 Hz, 1 H,
H1ax), 2.59 (dd, J ) 14.7, 2.9 Hz, 1 H, H1eq), 2.84 (m, 2 H, H4, H4),
2.98 (ddd, J ) 2.6, 12.7, 12.4 Hz, 1 H, H15), 3.79 (d, J ) 12.4 Hz, 1
H, H16), 3.85 (m, 2 H, H5, H5), 5.78 (m, 1 H, H2), 5.84 (m, 1 H, H3),
6.01 (s, 1 H), 6.02 (s, 1 H), 6.72 (s, 1 H), 7.4-8.1 (m, 6 H). IR (CHCl3)
56.19, 53.20, 40.40, 39.97, 29.70. IR (CHCl3) 1655 cm-1
.
1710, 1640 cm-1 13C NMR (CDCl3) 165.91, 163.03, 150.58, 146.74,
.
Alternate Procedure. A solution of (+)-1-deoxylycorine (2a) (4.0
mg, 0.015 mmol), MnO2 (13 mg, 0.15 mmol), and CHCl3 (2 mL) was
stirred at room temperature for 6 h. The mixture was filtered through
Celite, and the filtrate was concentrated and chromatographed (EtOAc)
to give enone 25 as a colorless solid (2.6 mg, 63%). Mp 157-8 °C.
Reduction of (+)-1-Deoxylycorin-2-one (25). A solution of enone
25 (4 mg, 0.015 mmol), NaBH4 (2 mg, 0.053 mmol), and EtOH (2
mL) were stirred at room temperature for 30 min. The reaction was
quenched by dropwise addition of NH4Cl (saturated), concentrated in
vacuo, diluted with NaHCO3 (5 mL, saturated), and extracted with CH2-
Cl2 (5 × 2 mL). The combined organic phase was dried (Na2SO4),
concentrated, and chromatographed (10% MeOH/EtOAc) to give (+)-
143.85, 135.52, 133.19, 130.07, 129.65, 128.40, 126.03, 117.51, 108.80,
108.73, 103.57, 103.50, 101.63, 68.34, 60.58, 43.53, 35.94, 29.15, 28.59.
CIMS m/z (rel intensity) 390 (M+ + 1, 2), 268 (6), 266 (28), 123 (100).
.
Anal. Calcd for C23H19NO5 0.5 H2O: C, 69.34, H. 5.06, N, 3.52.
Found: C, 69.72; H, 4.90; N, 3.40.
(()-1-Deoxylycorine (2a). (()-1-Deoxylycorin-7-one (10 mg, 0.04
mmol) was dissolved in CH2Cl2 (1 mL), and 4-(dimethylamino)pyridine
(1 mg, 0.008 mmol), triethylamine (4 mg, 0.04 mmol), and acetic
anhydride (4 mg, 0.04 mmol) were added. The solution was stirred at
room temperature for 1 h and was washed with 10% HCl followed by
NaHCO3 (sat). The organic phase was dried (Na2SO4) and the solvent

6218 J. Am. Chem. Soc., Vol. 118, No. 26, 1996
Schultz et al.
2-epi-1-deoxylycorine (24) and 2a as a 10:1 mixture of diastereomers
by 500 MHz H NMR (3 mg, 75%). Mp 98 °C.
31 as a colorless solid (45 mg, 67%). 1H NMR (CDCl3) δ 1.87 (ddd,
J ) 8.3, 12.4, 12.4 Hz, 1 H), 2.63 (dd, J ) 4.6, 14.4 Hz, H15), 2.88
(dd, J ) 5.6, 12.7 Hz, 1 H), 3.41 (ddd, J ) 5.6, 11.7, 12 Hz, 1 H),
3.46 (m, 2 H, H3, H2), 3.78 (d, J ) 3.4 Hz, 1 H, H1), 4.12 (d, J ) 14.4
Hz), 4.19 (dd, J ) 7.8, 11.7 Hz, 1 H), 5.18 (d, J ) 12.4 Hz, 1 H), 5.23
(d, J ) 12.2 Hz), 6.03 (s, 2 H), 6.92 (s, 1 H), 7.31 (m, 5 H), 7.45 (s,
1 H). 13C NMR (CDCl3) δ 173.19, 161.54, 151.04, 147.39, 134.95,
133.06, 128.74, 128.61, 128.19, 124.24, 108.69, 105.13, 101.89, 78.36,
67.72, 64.74, 59.68, 57.43, 52.41, 45.85, 41.82, 34.19. IR (CHCl3)
1
(2R,3S,12S,15R,16R)-3-Hydroxy-7-keto-9,10-[methylenebis(oxy)]-
galanthan-12,2-carbolactone (28). A solution of acid 21a (5 mg, 0.02
mmol) and water (10 mL) was refluxed for 5 h. The solution was
cooled to room temperature and extracted with CH2Cl2 (5×). The
organic phase was dried (Na2SO4) and concentrated to afford lactone
28 as a colorless solid (4 mg, 80%). Mp 144 °C. 1H NMR (CDCl3)
δ 2.09 (dd, J ) 12.7, 15.1 Hz, 1 H, H1ax), 2.38 (m, 1 H, H4), 2.61 (m,
2 H, H4, H1eq), 3.21 (ddd, J ) 6.8, 13.2, 13.2 Hz, 1 H, H15), 3.67 (d,
J ) 13.7 Hz, 1 H, H16), 3.82 (m, 1 H, H5), 3.92 (m, 1 H, H5), 4.71 (s,
1 H, H3), 4.88 (d, J ) 5.9 Hz, 1 H, H2), 6.02 (s, 2 H), 6.53 (s, 1 H),
3370, 1725, 1645, 1260 cm-1
.
(3R,12S,15R,16R)-1,2-Didehydro-3-hydroxy-12-(benzyloxycarbo-
nyl)-9,10-[methylenebis(oxy)]galanthan-7-one (32). To a solution of
selenide 30 in THF/water (1.2:1, 25 mL) was added sodium periodate
(0.47 g, 0.22 mmol), and the mixture was stirred at room temperature
for 12 h. The THF was evaporated, and the aqueous remains were
extracted with CH2Cl2 (3×). The combined organic phase was dried
(Na2SO4), the solvent evaporated, and flash chromatography (EtOAc/
hexanes, 1:3, then EtOAc) of the residue afforded alcohol 32 as a light
tan solid (40 mg, 87%). Mp 138-140 °C. 1H NMR (CDCl3) δ 2.10
(ddd, J ) 8.3, 11.7, 11.7 Hz, 1 H, H4), 2.76 (dd, J ) 5.9, 12.9 Hz, 1
H, H4), 3.36 (dd, J ) 1.5, 12 Hz, 1 H, H15), 3.54 (ddd, J ) 5.9, 11.5,
11.5 Hz, 1 H, H5), 3.79 (d, J ) 12 Hz, 1 H, H16), 4.25 (dd, J ) 8.1,
11.7 Hz, 1 H, H5), 4.30 (m, 1 H, H2), 5.13 (d, J ) 12.2 Hz, 1 H), 5.20
(d, J ) 12.5 Hz, 1 H), 6.03 (s, 2 H), 6.26 (dt, J ) 2.7, 9 Hz, 1 H), 6.31
(dt, J ) 2.7, 9.5 Hz, 1 H), 6.31 (dt, J ) 2.7, 9.5 Hz, 1 H), 6.88 (s, 1
H), 7.24-7.38 (m, 5 H), 7.53 (s, 1 H). 13C NMR (1:9 CD3OD/CDCl3)
173.36, 162.25, 150.85, 146.82, 138.13, 135.15, 134.08, 128.42, 128.15,
127.80, 124.18, 123.23, 108.59, 104.13, 101.67, 75.48, 67.14, 65.22,
60.68, 45.35, 39.17, 34.08. IR (CHCl3) 3400, 1710, 1640 cm-1; CIMS
(m/z) 420 (M+ + 1, 13), 402 (2), 330 (2), 315 (1), 286 (5), 266 (14).
FAB HRMS m/z 420.1439 (M + H)+. Calcd for C24H22NO6: 420.1447.
7.48 (s, 1 H). IR (film) 3350, 1775, 1625 cm-1
. CIMS m/z (rel
intensity) 330 (M+ + 1, 68), 286 (30), 156 (100).
(15R,16R)-2-(tert-Butyldimethylsilyloxy)-2,3,4,12-tetrahydro-9,10-
[methylenebis(oxy)]galanthan (29). To a solution of enone 25 (20
mg, 0.07 mmol), triethylamine (0.24 g, 2.4 mmol), and CH2Cl2 (5 mL)
was added tert-butyldimethylsilyl triflate (0.26 g, 1.2 mmol) at 0 °C.
The reaction was allowed to warm and stirred for 1 h at room
temperature. The solvent was evaporated, and the residue was
partitioned between Et2O and NaHCO3 (aq). The aqueous layer was
extracted (3×) with Et2O, and the combined organic phase was dried
(Na2SO4). Evaporation of the solvent and flash chromatography
(EtOAc) of the residue afforded enol ether 29 (26 mg, 93%) as a
colorless oil. 1H NMR (CDCl3) δ 0.22 (s, 3 H), 0.21 (s, 3 H), 0.96 (s,
9 H), 2.40 (dd, J ) 12.7, 15.2 Hz, 1 H, H1ax), 2.67 (dd, J ) 16.8, 5.1
Hz, 1 H, H1eq), 2.90 (ddd, J ) 5.1, 11.5, 11.5 Hz, 1 H, H15), 3.14 (m,
1 H, H16), 3.66 (m, 1 H), 3.83 (d, J ) 13.4 Hz, 1 H), 3.89 (d, J ) 13.4
Hz, 1 H, H7), 3.97 (d, J ) 13.2 Hz, 1 H, H7), 5.31 (s, 1 H, H4), 5.61
(d, J ) 5.31 Hz, 1 H, H4), 5.61 (d, J ) 1.7 Hz, 1 H, H3), 5.92 (s, 1 H),
5.93 (s, 1 H), 6.65 (s, 1 H), 6.68 (s, 1 H).
Alternate Procedure. A flask was cooled to -78 °C and charged
with NaN(SiMe3)2 (1 M in THF; 0.1 mL). Enone 25 (8 mg, 0.03 mmol)
was dissolved in THF (1 mL) and added to the flask via syringe. The
reaction stirred at -78 °C for 10 min, and then a solution of TBDMSCl
(7 mg, 0.05 mmol) in THF (1 mL) was rapidly added. The reaction
was allowed to warm to room temperature and was quenched with NH4-
Cl (saturated). The solvent was evaporated, and the mixture was
partitioned between CH2Cl2 and NaHCO3 (saturated), and the aqueous
layer was extracted with CH2Cl2 (3×). The combined organic phase
was dried (Na2SO4) and concentrated. 1H NMR (500 MHz) analysis
of the crude reaction mixture showed enol ether 29 as the only product.
(2S,3S,12S,15R,16R)-2-Phenylseleno-3-hydroxy-12-(benzyloxycar-
bonyl)-9,10-[methylenebis(oxy)]galanthan-7-one (30). Epoxide 12
(50 mg, 0.1 mmol) was stirred as a suspension in absolute EtOH (25
mL). Diphenyldiselenide (93 mg, 0.30 mmol) was added in one portion,
and stirring continued for 15 min at room temperature. Sodium
borohydride (23 mg, 0.61 mmol) was added slowly [CAUTION,
exothermic], and the mixture was stirred for 1 h at room temperature.
The reaction was quenched with NH4Cl (aq), and the EtOH was
evaporated. The aqueous layer was extracted with CH2Cl2 (3×) and
the combined organic phase was dried (Na2SO4). Evaporation of the
solvent and flash chromatography (EtOAc/hexanes, 1:3) afforded
selenide 30 as a colorless solid (64 mg, 93%). Mp 124 °C. 1H NMR
(CDCl3) δ 1.88 (ddd, J ) 8.3, 10.7, 11.9 Hz, 1 H), 2.38 (m, 1 H, H1ax),
2.59 (m, 1 H, H1eq), 2.71 (ddd, J ) 5.8, 13.1, 13.1 Hz, 1 H, H15), 3.05
(dd, J ) 5.4, 13 Hz, 1 H), 3.23 (ddd, J ) 5.6, 12.2, 12.2 Hz, 1 H),
3.87 (m, 1 H, H2), 3.95 (d, J ) 13.5 Hz, 1 H, H16), 4.15 (dd, J ) 7.5,
11.7 Hz, 1 H). 13C NMR (CDCl3) 172.59, 161.83, 150.64, 146.74,
135.64, 135.52, 135.18, 129.41, 128.66, 128.46, 128.11, 126.28, 124.46,
108.39, 103.93, 101.61, 75.97, 67.51, 64.07, 57.50, 44.47, 43.54, 35.61,
(1R,2R,3S,12S,15R,16R)-1,2-Epoxy-3-hydroxy-12-(benzyloxycar-
bonyl)-9,10-[methylenebis(oxy)]galanthan-7-one (33). To a stirred
mixture of allylic alcohol 32 (4 mg, 0.01 mmol), urea hydrogen peroxide
complex (10 mg, 0.1 mmol), and Na2HPO4 (13 mg, 0.09 mmol) in
CH2Cl2 (2 mL) was added trifluoroacetic anhydride (6 mg, 0.03 mmol).
The reaction was stirred 1.5 h and water was added. The aqueous layer
was extracted with CH2Cl2 (3×) the combined organic phase was dried
(Na2SO4), and the solvent evaporated. Flash chromatography (EtOAc)
afforded epoxide 31 (1.6 mg, 40%) and epoxide 33 (1.8 mg, 45%) as
colorless solids. Mp 128 °C. (33): 1H NMR (CDCl3) δ 2.27 (m, 1
H), 2.41 (dd, J ) 6.6, 13.7 Hz, 1 H), 3.20 (d, J ) 12.7 Hz, 1 H, H15),
3.45 (ddd, J ) 6.6, 11.7, 11.7 Hz, 1 H), 3.61 (d, J ) 4.7 Hz, 1 H),
3.80 (d, J ) 4.7 Hz, 1 H), 4.09 (d, J ) 12.9 Hz, 1 H, H16), 4.08 (m,
1 H), 4.13 (m, 1 H, H3), 5.09 (d, J ) 12.2 Hz, 1 H), 5.31 (d, J ) 12.2
Hz, 1 H), 6.04 (s, 2 H), 6.95 (s, 1 H), 7.24-7.38 (m, 5 H), 7.52 (s, 1
H). 13C NMR (CDCl3) 175.34, 162.13, 150.79, 147.21, 134.73, 133.22,
128.80, 128.72, 128.23, 125.01, 109.10, 103.12, 101.87, 76.45, 67.53,
61.05, 55.11, 53.15, 48.38, 43.75, 38.11, 35.94. IR (CHCl3) 3450, 1705,
1640, 1275 cm-1. CIMS m/z (rel intensity) 436 (M+ + 1, 2), 420 (1),
374 (4), 343 (1), 137 (4), 107 (25), 91 (100). Anal. Calcd for C24H21-
NO7: C, 66.20; H, 4.86; N, 3.22. Found: C, 66.02; H, 5.57; N, 2.81.
(3R,12S,15R,16R)-1,2-Didehydro-3-acetyloxy-12-(benzyloxycar-
bonyl)-9,10-[methylenebis(oxy)]galanthan-7-one (34). Alcohol 32
(35 mg, 0.084 mmol) was dissolved in CH2Cl2 (10 mL), and
4-(dimethylamino)pyridine (1 mg, 0.008 mmol), triethylamine (29 mg,
0.25 mmol), and acetic anhydride (22 mg, 0.17 mmol) were added.
The solution was stirred at room temperature for 1 h and was washed
with 10% HCl followed by NaHCO3 (saturated). The organic phase
was dried (Na2SO4), and the solvent was evaporated. Flash chroma-
tography (EtOAc/hexanes, 1:4 then 1:1) afforded acetate 34 as a
colorless solid (36 mg, 92%). Mp 133-7 °C. 1H NMR (CDCl3) δ
1.88 (s, 3 H), 1.98 (ddd, J ) 7.5, 12.5, 12.5 Hz, 1 H, H4), 2.93 (dd, J
) 5.5, 13 Hz, 1 H, H4), 3.27 (ddd, J ) 5.5, 12, 12 Hz, 1 H, H5), 3.39
(dd, J ) 1.5, 12 Hz, H15), 3.96 (d, J ) 12 Hz, 1 H, H16), 4.21 (dd, J
) 7.5, 11.5 Hz, 1 H, H5), 5.07 (d, J ) 12 Hz, 1 H), 5.25 (d, J ) 12
Hz, 1 H), 5.43 (m, 1 H, H3), 6.02 (s, 2 H), 6.08 (dt, J ) 2.5, 9.5 Hz,
1 H), 6.36 (dt, J ) 3, 9.5 Hz, 1 H), 6.90 (s, 1 H), 7.2-7.4 (m, 5 H),
7.50 (s, 1 H). 13C NMR (CDCl3) 171.34, 169.99, 161.70, 150.82,
147.02, 135.34, 133.63, 133.48, 128.56, 128.42, 128.31, 125.04, 124.85,
109.04, 104.15, 101.74, 75.69, 67.36, 64.56, 59.60, 45.24, 39.56, 34.29,
20.54. IR (CHCl3) 1740, 1730, 1640 cm-1. CIMS m/z (rel intensity)
34.44, 30.86. IR (CHCl3) 3450, 1720, 1640 cm-1
. CIMS m/z (rel
intensity) 578 (M+ + 1, 1), 420 (2), 330 (4), 286 (8), 315 (17), 313
(15), 213 (16), 215 (15), 159 (30). Anal. Calcd for C30H27NO6Se: C,
62.50; H, 4.72; N, 2.43. Found: C, 62.53; H, 5.09; N, 2.32.
(1S,2S,3S,12S,15R,16R)-1,2-Epoxy-3-hydroxy-12-(benzyloxycar-
bonyl)-9,10-[methylenebis(oxy)]galanthan-7-one (31). A solution of
selenide 30 (91 mg, 1.6 mmol), THF (50 mL), and 30% H2O2 (17 mL)
was stirred at room temperature for 2 h. The solution was concentrated
and partitioned between H2O and CH2Cl2. The aqueous phase was
extracted with CH2Cl2 (3×) and the combined organic phase was dried
(Na2SO4). Concentration and flash chromatography afforded epoxide

Syntheses of (+)-Lycorine and (+)-1-Deoxylycorine
J. Am. Chem. Soc., Vol. 118, No. 26, 1996 6219
462 (M+ + 1, 13), 266 (23), 223 (3), 191 (13), 177 (10), 123 (20).
Anal. Calcd for C26H23NO7. C, 67.67; H, 5.02; N, 3.04. Found: C,
66.76; H, 5.01; N, 2.98.
mixture. [R]23 +130° (c 0.2, CH2Cl2). 1H NMR (CDCl3) δ 2.03 (s,
D
3 H), 2.81 (m, 2 H), 3.02 (dd, J ) 1, 12.4 Hz, 1 H, H15), 3.80 (m, 2
H), 4.19 (d, J ) 12.3 Hz, 1 H, H16), 4.31 (m, 1 H, H2), 5.62 (m, 1 H,
H1), 5.66 (m, 1 H, H3), 6.01 (s, 1 H), 6.02 (s, 1 H), 6.60 (s, 1 H), 7.55
(s, 1 H). 13C NMR (CDCl3) 170.62, 162.72, 150.79, 147.01, 141.99,
132.38, 128.24, 118.68, 108.94, 103.38, 101.73, 70.66, 69.39, 55.34,
43.60, 39.40, 28.52, 20.93. IR (CHCl3) 3590, 1730, 1643 cm-1. CIMS
m/z (rel intensity) 344 (M+ + 1, 100), 284 (50), 266 (44). CI HRMS
m/z 344.1128 (M+ + 1) calcd for C18H18NO6: 344.1134.
(1S,12R,15R,16R)-1-Acetyloxy-2,3-didehydro-12-(benzyloxycar-
bonyl)-9,10-[methylenebis(oxy)]galanthan-7-one (35). Alcohol 33
(10 mg, 0.02 mmol) was dissolved in glacial AcOH (2 mL) and heated
to 50 °C. A solution of acetic anhydride (2 mL) and H2SO4 (4 drops)
was added dropwise and heating continued for 15 min. The solution
was neutralized with NaHCO3 (saturated) and extracted with CH2Cl2
(3×). The solvent was dried (Na2SO4) and evaporated, and the residue
was passed through a short column of silica gel (EtOAc/hexanes, 1:1)
to remove polar impurities. Radial chromatography (EtOAc/hexanes,
2:3) afforded the acetate 35 (3.1 mg, 34%) as a colorless solid. 1H
NMR (CDCl3) δ 1.87 (s, 3 H), 1.93 (ddd, J ) 12.5, 12.5, 7.8 Hz, 1 H),
2.61 (dd, J ) 5.4, 12.7 Hz, 1 H), 2.97 (dd, J ) 2.7, 13.2 Hz, 1 H, H15),
3.32 (ddd, J ) 5.1, 11.9, 11.9 Hz, 1 H), 4.17 (dd, J ) 7.6, 12 Hz, 1
H), 4.69 (d, J ) 13.2 Hz, 1 H, H16), 5.14 (d, J ) 12.4 Hz, 1 H), 5.25
(d, J ) 12.2 Hz, 1 H), 5.59 (dd, J ) 2.9, 6.1 Hz, 1 H, H1), 6.01 (d, J
) 1.5 Hz, 1 H), 6.02 (d, J ) 1.5 Hz, 1 H), 6.16 (d, J ) 9.8 Hz, 1 H,
H3), 6.32 (dd, J ) 6.1, 9.8 Hz, 1 H, H2), 6.55 (s, 1 H), 7.3-7.4 (m, 5
H), 7.50 (s, 1 H). 13C NMR (CDCl3) 172.42, 170.68, 162.10, 150.75,
147.00, 135.23, 132.54, 131.68, 128.69, 128.56, 128.08, 126.46, 125.23,
108.86, 103.93, 101.66, 67.71, 62.40, 57.08, 54.90, 44.26, 40.92, 34.55,
20.64. IR (CH2Cl2) 1730, 1640 cm-1. CIMS m/z (rel intensity) 462
(M+ + 1, 50), 404 (25), 314 (20), 268 (100). FAB HRMS m/z 462.1543
(M + H)+. Calcd for C26H24NO7: 462.1553.
(1R,2R,15R,16R)-1,2-Bis(acetyloxy)-3,12-didehydro-9,10-[meth-
ylenebis(oxy)]galanthan-7-one (38). A solution of alcohol 37 (2.0
mg, 0.0058 mmol), acetic anhydride (3 mg, 0.029 mmol), triethylamine
(3 mg, 0.029 mmol), and CH2Cl2 (2 mL) were stirred at room
temperature for 3 h. The mixture was washed with 10% HCl followed
by NaHCO3 (saturated). The organic layer was dried (Na2SO4) and
concentrated, and flash chromatography afforded diacetate 38 (2.2 mg,
100%) as a colorless solid. Mp 114 °C. [R]23 -27° (c 0.22, CH2-
D
Cl2). Reported: mp 114 °C.44 1H NMR (CDCl3) δ 2.04 (s, 3 H), 2.10
(s, 3 H), 2.82 (m, 2 H), 3.06 (ddd, J ) 12.4, 2.2, 1.3 Hz, 1 H, H15),
3.81 (m, 2 H), 4.24 (d, J ) 12.5 Hz, 1 H, H16), 5.29 (m, 1 H, H2), 5.63
(m, 1 H, H3), 5.76 (m, 1 H, H1), 6.02 (m, 2 H), 6.69 (s, 1 H), 7.57 (s,
1 H). 13C NMR (CDCl3) 169.86, 169.52, 162.60, 150.83, 147.10,
143.70, 131.88, 126.38, 115.46, 109.04, 103.55, 101.75, 70.22, 67.37,
55.17, 43.54, 40.46, 28.58, 21.01, 20.84. IR (CHCl3) 1735, 1643 cm-1
.
CIMS m/z (rel intensity) 386 (M+ + 1, 96), 326 (32), 266 (100).
(+)-Lycorine (2b) and Its Diacetate. Alcohol 38 (5 mg, 0.01
mmol), LiAlH4 (30 mg, 0.8 mmol), and THF (3 mL) were refluxed 4
h. Dropwise addition of H2O (0.03 mL), 15% NaOH (0.03 mL), and
H2O (0.09 mL) followed by filtration and concentration afforded (+)-
lycorine (2b) (3 mg, 70%). Rf 0.5 EtOAc/CH2Cl2/MeOH (2:2:1).
Reported: Rf 0.35 EtOAc/CH2Cl2/MeOH (2:2:1). 1H NMR (DMSO-
d6) 2.22 (m, 1 H), 2.44 (m, 1 H), 2.60 (m, 1 H), 3.19 (m, 1 H), 3.32 (d,
J ) 11.5 Hz, 1 H), 3.97 (m, 1 H), 4.02 (d, J ) 14.2 Hz, 1 H), 4.27 (m,
1 H), 4.79 (m, 1 H), 4.89 (m, 1 H), 5.37 (m, 1 H), 5.94 (s, 1 H), 5.96
(s, 1 H), 6.68 (s, 1 H), 6.81 (s, 1 H). (+)-Lycorine (2b) in DMSO-d6
(0.5 mL), acetic anhydride (0.5 mL), CH2Cl2 (2 mL), and 4-(dimethyl-
amino)pyridine (2 mg, 0.02 mmol) was stirred at room temperature
for 3 h. NaHCO3 (saturated) was added and stirred for 30 min. The
mixture was partitioned and the organic layer was washed with water
(5×). The organic layer was dried (Na2SO4) and concentrated, and
flash chromatography (EtOAc/hexane; 1:1 then 1:0) afforded lycorine
diacetate (2 mg, 54%) as a colorless solid. [R]D23 -25° (c 0.16, CHCl3),
mp 207-209 °C (dec). Reported mp 207-13 °C.44a 1H NMR (CDCl3)
δ 1.95 (s, 3 H), 2.08 (s, 3 H), 2.42 (dd, J ) 9, 17.6 Hz, 1 H), 2.66 (m,
2 H), 2.79 (d, J ) 11.4 Hz, 1 H, H16), 2.88 (d, J ) 10.3 Hz, 1 H, H15),
3.38 (m, 1 H), 3.54 (d, J ) 14.1 Hz, 1 H, H7), 4.17 (d, J ) 13.9 Hz,
1 H, H7), 5.25 (m, 1 H, H2), 5.53 (m, 1 H, H3), 5.74 (m, 1 H, H1), 5.92
(s, 2 H), 6.58 (s, 1 H), 6.75 (s, 1 H). IR (CHCl3) 1735 cm-1; CIMS
m/z (rel intensity) 372 (M+ + 1, 18), 312 (52), 252 (100).
(1R,2R,3R,12S,15R,16R)-1-Acetyloxy-2,3-epoxy-12-(benzyloxycar-
bonyl)-9,10-[methylenebis(oxy)]galanthan-7-one (36a). Acetate 35
(13 mg, 0.028 mmol) was added to a solution of dimethyldioxirane in
acetone (11 mL, 0.1 M), and the reaction was stirred at 0 °C for 96 h.
The solution was concentrated and passed through a short column of
silica gel (EtOAc/hexanes, 1:1). Radial chromatography (ethyl acetate/
hexanes, 1:1) afforded epoxide 36a as a colorless solid (6.0 mg, 46%).
Recovered acetate 35 was resubjected to epoxidation to provide an
additional 2.5 mg (19%) of epoxide 36a. Mp 110-112 °C. 1H NMR
(CDCl3) δ 1.88 (s, 3 H), 2.31 (ddd, J ) 8.3, 12.7, 12.7 Hz, 1 H), 2.52
(dd, J ) 5.7, 12.7 Hz, 1 H), 3.26 (dd, J ) 2.2, 13 Hz, 1 H, H15), 3.40
(ddd, J ) 5.9, 12.2, 12.2 Hz, 1 H), 3.63 (m, 2 H, H2, H3), 4.13 (dd, J
) 8, 12.2 Hz, 1 H), 4.23 (d, J ) 13.2 Hz, 1 H, H16), 5.21 (d, J ) 12.2
Hz, 1 H), 5.25 (d, J ) 12.2 Hz, 1 H), 5.97 (dd, J ) 2.5, 2.4 Hz, 1 H,
H1), 6.00 (s, 1 H), 6.01 (s, 1 H), 6.53 (s, 1 H), 7.3-7.4 (m, 5 H), 7.48
(s, 1 H). IR (CHCL3) 1723, 1642 cm-1 13C NMR (CDCl3) 172.34,
.
170.63, 161.87, 150.81, 146.98, 134.97, 132.36, 128.81, 128.77, 128.28,
125.50, 108.94, 103.25, 101.70, 67.87, 64.68, 57.12, 54.12, 52.60, 51.30,
43.68, 36.62, 31.88, 20.52. CIMS m/z (rel intensity) 478 (M+ + 1,
0.5), 452 (0.5), 266 (3). FAB HRMS m/z 478.1491 (M + H)+. Calcd
for C26H24NO8: 478.1501.
(1R,2R,3R,12S,15R,16R)-1-Acetyloxy-2,3-epoxy-12-hydroxycar-
bonyl-9,10-[methylenebis(oxy)]galanthan-7-one (36b). Benzyl ester
36a (6 mg, 0.01 mmol), absolute EtOH (1 mL), and 10% Pd/C (2 mg)
were stirred under 1 atm of H2 for 2 h. The mixture was filtered through
Celite, the retained solid was rinsed with CH2Cl2, and the combined
solvent was evaporated to provide acid 36b as a colorless solid (3.5
mg, 90%). Mp 225 °C (dec). 1H NMR (CDCl3) δ 2.07 (s, 3 H), 2.33
(m, 1 H), 2.53 (m, 1 H), 3.26 (d, J ) 13.2 Hz, 1 H, H15), 3.43 (m, 1
H), 3.65 (dd, J ) 3.1, 3.0 Hz, 1 H, H2), 3.72 (d, J ) 3.1 Hz, 1 H, H3),
4.09 (m, 1 H), 4.31 (d, J ) 13.1 Hz, 1 H, H16), 5.98 (m, 1 H, H1), 6.00
(m, 2 H), 6.55 (s, 1 H), 7.41 (s, 1 H). IR (CH2Cl2) 3500, 1727, 1640
cm-1. CIMS m/z (rel intensity) 388 (M+ + 1, 2), 344 (65), 284 (25),
266 (65).
(1R,2R,15R,16R)-1-Acetyloxy-2-hydroxy-3,12-didehydro-9,10-
[methylenebis(oxy)]galanthan-7-one (37). A solution of carboxylic
acid 36b (13 mg, 0.034 mmol), benzene (10 mL) tert-butyl thiol (0.2
mL), and acridine (12 mg, 0.068 mmol) in a 25 mL Pyrex flask was
degassed (N2) for 5 min and then irradiated (300 nm) for 105 min.
The flask was 6 inches from the light source and the contents were
stirred during the irradiation. The benzene was evaporated, and the
residue was dissolved in CH2Cl2 and washed with 10% HCl. The
organic phase was dried (Na2SO4) and concentrated. Flash chroma-
tography (EtOAc) afforded alcohol 37 (6 mg, 50%) as a colorless solid;
mp 236 °C (dec). The remaining material was judged to be decom-
position material by 500 MHz 1H NMR analysis of the crude reaction
Lycorine Diacetate from Natural (-)-Lycorine. (-)-Lycorine (1)
(4 mg, 0.014 mmol) in DMSO (0.5 mL), acetic anhydride (0.5 mL),
CH2Cl2 (2 mL), and 4-(dimethylamino)pyridine (2 mg, 0.02 mmol) was
stirred at room temperature for 3 h. NaHCO3 (saturated) was added
and stirred for 30 min. The mixture was partitioned, and the organic
layer was washed with water (5×). The organic layer was dried (Na2-
SO4) and concentrated, and flash chromatography (EtOAc/hexane; 1:1
then 1:0) afforded lycorine diacetate (4 mg, 80%) as a colorless solid.
23
[R]D +25.6° (c 0.39, CHCl3), mp 207-209 °C (dec).
Acknowledgment. This work was supported by the National
Institutes of Health (GM 26568). We thank Professor Kurt
Torssell for a sample of (()-1-deoxylycorine-7-one, Professor
George Pettit for a sample of (-)-lycorine together with 1H and
13C NMR spectra, and Degussa AG for a generous gift of
L-proline.
Supporting Information Available: Procedures for prepa-
ration of rac-9 and a description of the enantiomer assay for
(-)-9 (6 pages). See any current masthead page for ordering
and Internet access instructions.
JA9606440