Formal total synthesis of (±)-γ-lycorane and (±)-1-deoxylycorine using the [4+2]-cycloaddition/rearrangement cascade of furanyl carbamates

Article abstract of DOI:10.1021/jo0014109

The total syntheses of γ-lycorane and (±)-1-deoxylycorine were accomplished using an intramolecular Diels-Alder cycloaddition of a furanyl carbamate as the key step. The initially formed [4+2]-cycloadduct undergoes nitrogen-assisted ring opening followed by deprotonation/reprotonation of the resulting zwitterion to give a rearranged hexahydroindolinone. The stereochemical outcome of the IMDAF cycloaddition has the side arm of the tethered alkenyl group oriented syn with respect to the oxygen bridge. The key intermediate used in both syntheses corresponds to hexahydroindolinone 20. Removal of the t-Boc group in 20 followed by reaction with 6-iodobenzo[1,3]dioxole-5-carbonyl chloride afforded enamide 22. Treatment of this compound with Pd(OAc)₂ employing the Jeffrey modification of the Heck reaction provided the galanthan tetracycle 24 in good yield. Compound 24 was subsequently converted into (±)-γ-lycorane using a four-step procedure to establish the cis-B,C-ring junction. A radical-based cyclization of the related enamide 33 was used for the synthesis of 1-deoxylycorine. Heating a benzene solution of 33 with AIBN and n-Bu₃SnH at reflux gave the tetracyclic compound 38 possessing the requisite trans fusion between rings B and C in good yield. After hydrolysis and oxidation of 38 to 40, an oxidative decarboxylation reaction was used to provide the C₂-C₃-C₁₂ allylic alcohol unit characteristic of the lycorine alkaloids. The resulting enone was eventually transformed into (±)-1-deoxylycorine via known synthetic intermediates.

Full text of DOI:10.1021/jo0014109

1716
J . Org. Chem. 2001, 66, 1716-1724
F or m a l Tota l Syn th esis of (()-γ-Lycor a n e a n d (()-1-Deoxylycor in e
Usin g th e [4+2]-Cycloa d d ition /Rea r r a n gem en t Ca sca d e of F u r a n yl
Ca r ba m a tes
Albert Padwa,* Michael A. Brodney,† and Stephen M. Lynch
Department of Chemistry, Emory Univeristy, Atlanta, Georgia 30322
Received September 25, 2000
The total syntheses of γ-lycorane and (()-1-deoxylycorine were accomplished using an intramolecular
Diels-Alder cycloaddition of a furanyl carbamate as the key step. The initially formed [4+2]-
cycloadduct undergoes nitrogen-assisted ring opening followed by deprotonation/reprotonation of
the resulting zwitterion to give a rearranged hexahydroindolinone. The stereochemical outcome of
the IMDAF cycloaddition has the side arm of the tethered alkenyl group oriented syn with respect
to the oxygen bridge. The key intermediate used in both syntheses corresponds to hexahydroin-
dolinone 20. Removal of the t-Boc group in 20 followed by reaction with 6-iodobenzo[1,3]dioxole-
5-carbonyl chloride afforded enamide 22. Treatment of this compound with Pd(OAc)2 employing
the J effrey modification of the Heck reaction provided the galanthan tetracycle 24 in good yield.
Compound 24 was subsequently converted into (()-γ-lycorane using a four-step procedure to
establish the cis-B,C-ring junction. A radical-based cyclization of the related enamide 33 was used
for the synthesis of 1-deoxylycorine. Heating a benzene solution of 33 with AIBN and n-Bu3SnH at
reflux gave the tetracyclic compound 38 possessing the requisite trans fusion between rings B and
C in good yield. After hydrolysis and oxidation of 38 to 40, an oxidative decarboxylation reaction
was used to provide the C2-C3-C12 allylic alcohol unit characteristic of the lycorine alkaloids. The
resulting enone was eventually transformed into (()-1-deoxylycorine via known synthetic intermedi-
ates.
The amaryllidaceae alkaloids constitute an important
(1), 1-deoxylycorine (2), and R-lycorane (3)), compounds
with a cis-B,C-ring juncture such as that found in
γ-lycorane (4) are also known (see also fortucine (5) and
siculinine (6)).7 Despite the apparent absence of useful
pharmaceutical properties, γ-lycorane (4) has become a
popular target for illustrating potential new strategies
for the synthesis of this family of alkaloids.8
Among the many approaches to the lycorine class of
alkaloids,9 the Diels-Alder cycloaddition reaction has
played a key role in the preparation of the C-ring of these
class of naturally occurring compounds.1 The lycorine-
type alkaloids, which are characterized by the presence
of the galanthan ring system, represent a significant
subclass within the amaryllidaceae family.2 This group
of compounds has attracted the attention of synthetic
chemists due to the interesting biological properties of
some of its members.3 Several of these alkaloids possess
antineoplastic and antimicotic activities, while others are
known to exhibit insect antifeedant activity.1 Lycorine
(1) was first isolated in 1877 and was shown to be a
powerful inhibitor of growth and cell division in higher
plants and also to possess antiviral activity.4,5 The
tetracyclic pyrrolo[d,e]phenanthridine (galanthan) skel-
eton has been of considerable interest to organic chemists
ever since the structure of lycorine was established by
Uyeo and Wildman in 1955.6 While many lycorine-type
alkaloids possess a trans-B,C-ring juncture (e.g., lycorine
(7) (a) Tokhtabaeva, G. M.; Sheichenko, V. I.; Yartseva, I. V.;
Talkachev, O. N. Khim. Prir. Soedin. 1987, 872. (b) Richomme, P.;
Pabuccuoglu, V.; Go¨zler, T.; Freyer, A. J .; Shamma, M. J . J . Nat. Prod.
1989, 52, 1150.
(8) (a) Ueda, N.; Tokuyama, T.; Sakan, T. Bull. Chem. Soc. J pn.
1966, 39, 2012. (b) Irie, H.; Nishitani, Y.; Sugita, M.; Uyeo, S. J . Chem.
Soc., Chem. Commun. 1970, 1313. (c) Iida, H.; Aoyagi, S.; Kibayashi,
C. J . Chem. Soc., Perkin Trans. 1 1975, 2502. (d) Umezawa, B.;
Hoshino, O.; Sawaki, S.; Sato, S.; Numao, N. J . Org. Chem. 1977, 42,
4272. (e) Iida, H.; Yuasa, Y.; Kibayashi, C. J . Am. Chem. Soc. 1978,
100, 3598. (f) Iida, H.; Yuasa, Y.; Kibayashi, C. J . Org. Chem. 1979,
44, 1074. (g) Sugiyama, N.; Narimiya, M.; Iida, H.; Kibuchi, T. J .
Heterocycl. Chem. 1988, 25, 1455. (h) Ba¨ckvall, J . E.; Andersson, P.
G.; Stone, G. B.; Gogoll, A. J . Org. Chem. 1991, 56, 2988. (I) Pearson,
W. H.; Scheryantz, J . M. J . Org. Chem. 1992, 57, 6783. (j) Grotjahn,
D. B.; Vollhardt, P. C. Synthesis 1993, 579. (k) Banwell, M. G.; Wu, A.
W. J . Chem. Soc., Perkin Trans. 1 1994, 2671. (l) Yoshizaki, H.; Satoh,
H.; Sato, Y.; Nukui, S.; Shibasaki, M.; Mori, M. J . Org. Chem. 1995,
60, 2016. (m) Angle, S. R.; Boyce, J . P. Tetrahedron Lett. 1995, 36,
6185. (n) Cossy, J .; Tresnard, L.; Pardo, D. G. Tetrahedron Lett. 1999,
40, 1125. (o) Rigby, J . H.; Mateo, M. E. Tetrahedron 1996, 32, 10569.
(9) (a) Martin, S. F.; Tu, C. Y.; Kimura, M.; Simonsen, S. H. J . Org.
Chem. 1982, 47, 3634. (b) Wang, C. L.; Ripka, W. C.; Confalone, P. N.
Tetrahedron Lett. 1984, 25, 4613. (c) Boeckman, R. K., J r.; Sabatucci,
J . P.; Goldstein, S. W.; Springer, D. M.; J ackson, P. F. J . Org. Chem.
1986, 51, 3740. (d) Stork, G.; Morgans, D. J . J . Am. Chem. Soc. 1979,
101, 7110. (e) Schultz, A. G.; Holoboski, M. A.; Smyth, M. S. J . Am.
Chem. Soc. 1993, 115, 7904. (f) Schultz, A. G.; Holoboski, M. A.; Smyth,
M. S. J . Am. Chem. Soc. 1996, 118, 6210. (g) Meyers, A. I.; Hutchings,
R. H. Tetrahedron Lett. 1993, 34, 6185.
* To whom correspondence should be addressed. E-mail:
chemap@emory.edu.
† Recipient of a Graduate Fellowship from the Organic Chemistry
Division of the American Chemical Society (1997-1998), sponsored
by Dupont Merck Pharmaceutical Co.
(1) Martin, S. F. In The Alkaloids; Brossi, A., Ed.; Academic Press:
New York, 1987; Vol. 30, pp 251-376.
(2) Lewis, J . R. Nat. Prod. Rep. 1994, 11, 329.
(3) (a) Leven, M.; Van den Berghe, D. A.; Vlietnck, A. J . Planta Med.
1983, 49, 109. (b) Pettit, G. R.; Gaddamidi, V.; Goswami, A.; Cragg,
G. M. J . Nat. Prod. 1984, 47, 796. (c) Rivera, G.; Gosalbez, M.; Ballesta,
J . P. G. Biochem. Biophys. Res. Commun. 1980, 94, 800.
(4) 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.
(5) Ghosal, S.; Saini, K. S.; Razdan, S. Phytochemistry 1985, 24,
2141.
(6) (a) Takagi, S.; Taylor, W. I.; Uyeo, S.; Yajima, H. J . Chem. Soc.
1955, 4003. (b) Fales, H. M.; Warnhoff, E. M.; Wildman, W. C. J . Am.
Chem. Soc. 1955, 77, 5885.
10.1021/jo0014109 CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/13/2001

Synthesis of (()-γ-Lycorane and (()-1-Deoxylycorine
J . Org. Chem., Vol. 66, No. 5, 2001 1717
Sch em e 1
natural products.10,11 Application of the intramolecular
Diels-Alder reaction to the construction of azapolycyclic
compounds has been practiced for more than two de-
cades,12,13 and interest in this methodology has been
reinforced over the past several years.14 Heterocycles
such as furan, thiophene, and pyrrole undergo Diels-
Alder reactions despite their stabilized 6-π aromatic
electronic configuration.15 The furan ring generally shows
low reactivity toward unactivated dienophiles, and the
competing retro-Diels-Alder reaction often becomes a
problem from a synthetic point of view.15 However,
placement of the furan ring and the dienophile in the
same molecule can often circumvent these problems.16
Several years ago we began a synthetic program to
provide general access to a variety of alkaloids by [4+2]-
cycloaddition chemistry of furanyl carbamates.17 Our
synthetic strategy directed toward the lycorine-type
alkaloids was to take advantage of an intramolecular
Diels-Alder reaction of an alkenyl-substituted furanyl
carbamate derivative (IMDAF),16 as had been outlined
in earlier reports from these laboratories.18 In our ap-
proach to the hexahydroindoline skeleton, we chose to
explore the ring-opening reaction of an aza-substituted
oxabicyclo[2.2.1]heptene derivative. Oxabicyclic com-
pounds are known to be valuable intermediates19 for the
synthesis of a variety of molecules of biological interest.20
We found that the [4+2]-oxabicyclic adduct 8, initially
formed from the intramolecular Diels-Alder cycloaddi-
tion of a suitably substituted furanyl carbamate such as
7, underwent a nitrogen-assisted ring opening. A subse-
quent hydrogen shift of the resulting zwitterion 9 gave
Sch em e 2
the hexahydroindolinone ring system 10 (Scheme 1). To
highlight the method, we applied the synthetic strategy
to the synthesis of (()-γ-lycorane (4). This cycloaddition
approach may also prove to be useful for the synthesis
of more complex lycorine-type alkaloids possessing the
cis-B,C-ring juncture (i.e., 5 and 6). In the present paper
we document the results of these studies.
(10) For some leading references, see: Gonza´lez, C.; Pe´rez, D.;
Guitia´n, E.; Castedo, L. J . Org. Chem. 1995, 60, 6318.
(11) (a) Hill, R. K.; J oule, J . A.; Loeffler, L. J . Am. Chem. Soc. 1962,
84, 4951. (b) Tsuda, Y.; Sano, T.; Taga, J .; Isobe, K.; Toda, J .; Irie, H.;
Tanaka, H.; Takagi, S.; Yamaki, S.; Murata, M. J . Chem. Soc., Chem.
Commun. 1975, 933. (c) Hwang, G.; Magnus, P. J . Chem. Soc., Chem.
Commun. 1983, 693.
(12) (a) Oppolzer, W. Angew. Chem., Int. Ed. Engl. 1977, 16, 10. (b)
Oppolzer, W. Synthesis 1978, 793. (c) Oppolzer, W. Heterocycles 1980,
14, 1615. (d) Brieger, G.; Bennett, J . N. Chem. Rev. 1980, 80, 63.
(13) Craig, D. Chem. Soc. Rev. 1987, 16, 187.
(14) Kappe, C. O.; Murphree, S. S.; Padwa, A. Tetrahedron 1997,
53, 14179 and references therein.
(15) Lipshutz, B. Chem. Rev. 1986, 86, 795.
(16) (a) Sternbach, D. D.; Rossana, D. M.; Onan, K. D. J . Org. Chem.
1984, 49, 3427. (b) Klein, L. L. J . Org. Chem. 1985, 50, 1770. (c) J ung,
M. E.; Gervay, J . J . Am. Chem. Soc. 1989, 111, 5469.
(17) Padwa, A.; Brodney, M. A.; Dimitroff, M. J . Org. Chem. 1998,
63, 5304.
(18) Padwa, A.; Brodney, M. A.; Satake, K.; Straub, C. S. J . Org.
Chem. 1999, 64, 4617.
Resu lts a n d Discu ssion
Our initial retrosynthetic approach to (()-γ-lycorane
(4), as briefly outlined in Scheme 2, was to utilize a
Pd(0)-catalyzed Heck cyclization of carbamate 13 to
produce the cyclic aminofuran 14. Removal of the t-Boc
group of 14 followed by reaction with either a butenyl
halide or the corresponding acid chloride was expected
to give the desired cyclization precursor 15. Thermolysis
of 15 should provide the cyclic enamino ketone 16, which
would then be processed to γ-lycorane. Indeed, the
requisite furanyl carbamate 14 could be prepared in 57%
yield by treating carbamate 11 with the iodo-substituted
benzyl bromide 12 in the presence of base. Heck cycliza-
tion of the resulting aryl iodide 13 occurred smoothly and
(19) (a) Vogel, P.; Fattori, D.; Gasparini, F.; Le Drian, C. Synlett
1990, 173. (b) Vogel, P. Bull. Soc. Chim. Belg. 1990, 99, 395. (c)
Lautens, M. Synlett 1993, 177.
(20) (a) Cox, P. J .; Simpkins, N. S. Synlett 1991, 321. (b) Bimwala,
R. M.; Vogel, P. J . Org. Chem. 1992, 57, 2076.

1718 J . Org. Chem., Vol. 66, No. 5, 2001
Padwa et al.
Sch em e 3a
produced 14 in 75% yield. Unfortunately, all attempts
to convert 14 into 15 failed to give any characterizable
product. The hydrolytic lability of the intermediate N-H
amine most likely interferes with both the alkylation and
acylation steps.
In view of this disappointing result, we decided to
approach the synthesis of 16 via an alternative strategy
wherein a Pd(0)-induced cyclization of an iodoaryl amide
became the key B-ring assembly step. The Heck reaction
of vinyl or aryl halides with alkenes catalyzed by pal-
ladium is well recognized as a powerful tool for carbon-
carbon bond formation.22 In recent years the intramolec-
ular version of the palladium-catalyzed arylation of
alkenes has also emerged as a potent method for the
construction of a variety of complex nitrogen hetero-
cycles.23 Although intramolecular Heck cyclizations gen-
erally show a preference for the exo mode of cyclization,24
recent results by Rigby and co-workers show that the
judicious choice of the Pd(0)-mediated cyclization condi-
tions can lead to products derived from either a 6-endo
pathway or a 5-exo mode.25 For example, hydroindolone
substrates afforded products derived from a 5-exocyclic
mode of addition under “standard” Heck conditions,22
while endo addition products were isolated using the
Jeffrey catalyst system (Pd(OAc)2, Bu4NCl, KOAc, DMF).26
The potential of this methodology for the synthesis of
various lycorine alkaloids prompted us to first carry out
some model studies to probe the likelihood of Heck
cyclization for B-ring assemblage. Initial feasibility stud-
ies were conducted with hexahydroindolinone 19 derived
from the thermolysis of furanyl carbamate 17. Acid
hydrolysis of 19 followed by conversion of the resulting
imine into enamide 21 proceeded in 72% overall yield.
By following the Rigby protocol,25 we found that treat-
ment of 21 using the J effrey palladium catalyst provided
only pentacycle 23 derived from the 6-endo mode of
addition in 66% yield. The endo-selective cyclization
pathway was extended to the more highly functionalized
hexahydroindolinone 22. In a similar fashion, reaction
of the carbomethoxy-substituted enamide 22, derived
from hexahyroindolinone 20, under the J effrey palladium
cyclization conditions produced the galanthan derivative
24 in 68% yield (Scheme 3).
a
Reagents: (a) HCl, CH2Cl2; (b) pyridine, 6-iodobenzo[1,3]dioxole-
5-carbonyl chloride; (c) Pd(OAc)2, [(Bu)4N]+Cl-, KOAc, DMF.
reaction.27 This was accomplished by converting carbox-
ylic acid 27 into the corresponding N-hydroxy-2-thiazo-
line thione ester 28 via a DCC/DMAP coupling. Heating
ester 28 in benzene at 80 °C with slow addition of a
solution of 2,2′-azobis(isobutyronitrile) (AIBN) and tribu-
tyltin hydride afforded the decarboxylated benzopyridone
29 in 71% overall yield (Scheme 4).
A major difficulty with any approach to the γ-lycorane
ring system has been in the control of stereochemistry
at the B,C-ring juncture. Our initial approach to (()-
lycorane (4) involved the catalytic reduction of 29 to 30.
Since 30 had already been converted to 4, this would
constitute a formal total synthesis of this alkaloid.
Unfortunately, all of our attempts to hydrogenate the
tetrasubstituted π-bond of enamide 29 under a variety
of catalytic hydrogenation conditions proceeded only in
very poor yield.
Because of the low yield associated with the catalytic
hydrogenation reaction, we decided to alter our approach
toward (()-γ-lycorane (4). We decided that the simplest
adjustment of our synthetic scheme would be first to
reduce the amido carbonyl group with LAH and then
carry out a subsequent enamine reduction using NaC-
NBH3 in the presence of HCl/MeOH. We were pleased
to find that this set of reducing conditions afforded (()-
γ-lycorane (4) in 74% yield as a single diastereomer.28
Presumably, the initially formed enamine derived from
reduction of the carbonyl group was protonated on the
â-face, and the resulting iminium ion 31 reacted further
with hydride from the least crowded face to produce (()-
γ-lycorane (4).
The synthesis of (()-γ-lycorane (4) from 24 was com-
pleted by conversion to its thioketal derivative 25 and
subsequent Ra-nickel reduction to 26 in 78% overall yield.
Substrate 26 was hydrolyzed to the corresponding car-
boxylic acid 27, which was decarboxylated using a
modification of the Barton-McCombie deoxygenation
(21) (a) Lythgoe, D. J .; McClenaghan, I.; Ramsden, C. A. J . Hetero-
cycl. Chem. 1993, 30, 113. (b) Bite, P.; Bamonczai, J .; Vargha, L. J .
Am. Chem. Soc. 1948, 70, 371. (c) Edwards, W. R., J r.; Singleton, H.
M. J . Am. Chem. Soc. 1938, 60, 540. (d) Marquis, R. Ann. Chim. Phys.
1905, 4, 196.
(22) (a) Heck, R. F. Acc. Chem. Res. 1979, 12, 146. (b) Heck, R. F.
Org. React. (N.Y.) 1982, 27, 345.
After the successful synthesis of (()-γ-lycorane (4), we
turned our attention to construction of the more compli-
cated 1-deoxylycorine (2) system using the IMDAF-
rearrangement strategy. As outlined in Scheme 5, we
envisioned that the galanthan skeleton 32, containing the
(23) (a) Larock, R. C.; Yong-de, L.; Bain, A. C. J . Org. Chem. 1991,
56, 4589. (b) Zhang, Y.; Wu, G. Z.; Angel, G.; Negishi, E. J . Am. Chem.
Soc. 1990, 112, 8590. (c) Carpenter, N. E.; Kucera, D. J .; Overman, L.
E. J . Org. Chem. 1989, 54, 5846. (d) Grigg, R.; Sridharan, V.;
Sukirthalingam, S. Tetrahedron Lett. 1991, 32, 3855. (e) Trost, B. M.;
Shi, Y. J . Am. Chem. Soc. 1991, 113, 701. (f) Harris, G. D.; Herr, R. J .;
Weinreb, S. M. J . Org. Chem. 1992, 57, 2528.
(24) (a) Grigg, R.; Santhakumar, V.; Sridharan, V.; Thornton-Pett,
M.; Bridge, A. W. Tetrahedron 1993, 49, 5177. (b) Overman, L. E. Pure
Appl. Chem. 1994, 66, 1423.
(25) Rigby, J . H.; Hughes, R. C.; Heeg, M. J . J . Am. Chem. Soc. 1995,
117, 7834.
(26) (a) J effrey, T. J . Chem. Soc., Chem. Commun. 1984, 1287. (b)
J effrey, T. Synthesis 1987, 70.
(27) (a) Barton, D. H. R.; McCombie, S. W. J . Chem. Soc., Perkin
Trans. 1 1975, 1574. (b) Barton, D. H. R.; Crich, D.; Motherwall, W.
B. Tetrahedron 1985, 41, 3901. (c) Barton, D. H. R.; Crich, D.;
Kretzcschmar, G. J . Chem. Soc., Perkin Trans. 1 1986, 39.
(28) The spectral data for 4 were consistent with those reported in
ref 8c.

Synthesis of (()-γ-Lycorane and (()-1-Deoxylycorine
J . Org. Chem., Vol. 66, No. 5, 2001 1719
Sch em e 4a
Sch em e 6
the C,D-rings of the galanthan skeleton and to control
the 2-hydroxy stereochemistry and (2) use of an oxidative
decarboxylation reaction of the C12-ester group as a way
to introduce the C2-C3-C12 allylic alcohol unit character-
istic of the lycorine alkaloids.
As delineated in our synthetic plan (Scheme 3), ther-
molysis of carbamate 18 afforded the rearranged hexahy-
droindolinone 20 in 87% yield. This reaction has been
proposed to proceed via zwitterion 9, which undergoes a
subsequent deprotonation/reprotonation to give 20.17
Unfortunately, all of our attempts to selectively reduce
the keto group in 20 with a variety of hydride reducing
agents invariably led to a mixture (ca. 1:1) of diastere-
omeric alcohols which proved to be extremely difficult to
separate. It occurred to us that we might circumvent this
troublesome stereochemical issue if we could induce a
conjugate 1,4-reduction of iminium ion 9 with NaCNBH3
(Scheme 6). Earlier results in our laboratory had dem-
onstrated that the IMDAF cycloaddition proceeds by a
transition state where the side arm of the tethered
alkenyl group is oriented exo with respect to the oxygen
bridge.18 Products resulting from an endo side arm
transition state were neither detected nor isolated. As a
consequence of this preferred exo orientation, the car-
bomethoxy and alkoxy groups are disposed in an anti
relationship. Thus, trapping of the vinylogous iminium
ion 9 in a 1,4-conjugate fashion should produce alcohol
34. Unfortunately, all of our attempts to obtain a sample
of 34 by conjugate reduction of 9 proceeded only in poor
yield (ca. 15%), and we eventually chose to abandon this
approach.
We next investigated the thermolysis of 18 (65 °C)
using benzyl alcohol as the solvent and were pleased to
find that benzyl ether 35 was obtained as the major
diastereomer (80%) in 62% overall yield. The structure
of the trans-alcohol 35 was based on a comparison of
NMR signals of the C5,C6-hydrogens with the related
methoxy ether synthesized in this laboratory whose
structure had been confirmed by X-ray crystallography.18
Mechanistically, this result can be explained in terms of
selective trapping of the zwitterion intermediate 9 with
the solvent from the R-face. Apparently, the preferred
mode of attack takes place on the side opposite the
alcohol functionality that corresponds to the less con-
gested face of the π-bond. This selective trapping of
a
Reagents: (a) HSCH2CH2SH, ∆; (b) Ra-Ni; (c) NaOH, MeOH,
H2O; (d) DCC, DMAP, HONC4H4S2; (e) Bu3SnH, AIBN, C6H6; (f)
LiAIH4, THF; (g) NaCNBH3, HCl, MeOH.
Sch em e 5
anti stereochemistry between the C12-ester and the C2-
benzoate, could be produced from the IMDAF reaction
of furanyl carbamate 18. We had previously demon-
strated that the thermolysis of 18 in methanol afforded
mostly a trans-methoxy-substituted alcohol (vide infra).18
Our intention was to use this unique cycloaddition as a
key step in the synthesis of deoxylycorine, thereby
avoiding additional steps to install the C-ring oxygen
functionality late in the synthesis. With 1-deoxylycorine
(2) as the target, cyclization of aryl iodide 33 across the
enamide π-bond would be carried out using free radical
conditions. Although precedence for the formation of a
trans-B,C-ring junction in a radical cyclization of an
achiral substrate related to 33 is available from inde-
pendent work of Rigby29 and Schultz,9f our approach to
1-deoxylycorine (2) has two novel synthetic aspects: (1)
the [4+2]-cycloaddition of a furanyl carbamate to create
(29) Rigby, J . H.; Qabar, M. J . Am. Chem. Soc. 1991, 113, 8975.

1720 J . Org. Chem., Vol. 66, No. 5, 2001
Padwa et al.
Sch em e 7
Sch em e 8a
iminium ion 9 to give trans-alcohol 35 was a welcome
discovery. The previous need for selective reduction of
the keto group in 20 was now eliminated, since this single
step equipped our system with the desired regio- and
stereochemistry. Subsequent protection of alcohol 35
using DCC/DMAP provided the benzoate ester 36 in 90%
yield. Catalytic hydrogenolysis of the benzyl ether func-
tionality with Pd/C afforded 37 in 85% yield, which
turned out to be identical to the benzoate ester obtained
from the small quantity of trans-alcohol 34 that we had
previously prepared from 18. Deprotection of the tert-
butyl carbamate functionality and acylation with 6-iodo-
benzo[1,3]dioxole-5-carbonyl chloride provided us with
the radical cyclization precursor 33 in 81% yield.
Exposure of 33 to n-Bu3SnH in benzene at reflux in
the presence of AIBN afforded the anticipated tetracyclic
product 38 in 51% yield, exhibiting the crucial trans-B,C-
ring fusion (Scheme 7). The trans stereochemistry was
confirmed in part by a large coupling (J ) 13.2 Hz)
between H15 and H16. The relative stereochemistry be-
tween the remaining centers was unequivocally assigned
by a single X-ray analysis that clearly fixes the cis
relationship of the carbomethoxy and neighboring hy-
drogen.30 The formation of the trans-B,C- and cis-C,D-
ring fusion is consistent with SYBYL force field calcula-
tions, which suggest that this stereochemistry corresponds
to the most stable isomer, and is also in agreement with
the earlier literature reports of Rigby29 and Schultz.9f
Compound 38 was also accompanied by a somewhat
lesser quantity (46%) of the reduced amide 39. Enamide
39 might be formed by direct reduction of the radical
derived from 33 or by way of an intramolecular R-amidoyl
to aryl 1,5-hydrogen atom transfer followed by reduc-
tion.31 Efforts to suppress the formation of 39 by changing
the reaction conditions proved futile.
a
Reagents: (a) NaOCH3, CH3OH; (b) Dess-Martin oxidation;
(c) NaOH, MeOH, H2O; (d) Pb(OAc)4, Cu(OAc)2, pyridine; (e)
NaBH4, MeOH.
intermediate and so bring about elimination, possibly
through a six-membered transition state. We reasoned
that the most straightforward synthesis of 1-deoxylyco-
rine from 38 would involve deprotection of the benzoyl
ester followed by an oxidative decarboxylation. However,
all of our attempts to promote this sequence of reactions
were unsuccessful. Various conditions were investigated
to effect the oxidative decarboxylation of the alcohol
derived from 38, but only complex mixtures of products
were obtained. Having been thwarted in attempts to use
benzoate ester 38 as a precursor to 1-deoxylycorine, we
turned our attention to a procedure developed by Mc-
Murry and Blaszczak33 that made use of γ-keto acids for
the oxidative decarboxylation reaction.
These workers made the interesting discovery that when
a carboxy group was located in a position γ to a second
carbonyl group, R,â-unsaturated carbonyl compounds
were readily formed. This procedure provides an easy
route to some molecules that otherwise would be difficult
to access. Indeed, we found that this reaction scheme does
proceed in good yield and can be applied toward the
synthesis of 1-deoxylycorine. The application of this
method required the hydrolysis/oxidation of 38 to 40,
which occurred in 89% overall yield (Scheme 8). The
oxidative decarboxylation reaction of 40 using Pb(OAc)4
and Cu(OAc)2 then gave enone 41 as the sole product
in 70% yield. Thus, the key oxidative decarboxylation
step worked quite well when a keto group was present
in the γ position. Reduction of 41 with NaBH4 provided
the crystalline 2-epi-1-deoxylycorin-7-one 42 (80%
yield), which had previously been converted into (()-1-
Oxidative decarboxylation of carboxylic acid derivatives
is a classical procedure in synthetic organic chemistry
and is well-known in scope and mechanism.32 This
reaction is best achieved by treatment of the acid with
lead tetraacetate in the presence of a catalytic amount
of copper(II) acetate. The latter served to trap the radical
(30) We have deposited atomic coordinates for compound 38 with
the Cambridge Data Centre. The coordinates can be obtained, on
request, from the Director, Cambridge Crystallographic Data Centre,
12 Union Rd., CB2 1EZ, U.K.
(31) Snieckus, V.; Cuevas, J . C.; Sloan, C. P.; Liu, H.; Curran, D. P.
J . Am. Chem. Soc. 1990, 112, 896.
(32) Sheldon, R. A.; Kochi, J . K. Org. React. (N.Y.) 1972, 19, 279.
(33) McMurry, J . E.; Blaszczak, L. C. J . Org. Chem. 1974, 39, 2217.

Synthesis of (()-γ-Lycorane and (()-1-Deoxylycorine
J . Org. Chem., Vol. 66, No. 5, 2001 1721
deoxylycorine.9f,34 The spectroscopic data of 42 were
identical to those reported in the literature.9f Thus, the
conversion of 41 to 42 represents the final step of a formal
total synthesis of (()-1-deoxylycorine (2).
to warm to rt and stirred at 25 °C for an additional 3 h. The
mixture was chromatographed on a silica gel column and
recrystallized from ethyl acetate/pentane to give 7.5 g (94%)
of the title compound as a white solid: mp 112-113 °C; IR
(KBr) 1758, 1666, 1602, 1488, 1260 cm-1 1H NMR (CDCl3,
;
In summary, a new strategy for the synthesis of the
amaryllideace alkaloid family has been developed based
in part on an intramolecular Diels-Alder reaction of a
furanyl carbamate for initial construction of the hexahy-
droindolinone core. By using either a 6-endo Heck cy-
clization or a 6-endo free radical closure, either the cis-
B,C- or trans-B,C-ring junction could be prepared. The
IMDAF cycloaddition-rearrangement cascade was suc-
cessfully used in the total synthesis of (()-γ-lycorane and
(()-1-deoxylycorine. We plan to use this and related
methodology in approaches to other alkaloidal targets.
400 MHz) δ 6.08 (s, 2H), 7.33 (s, 1H), 7.36 (s, 1H), 9.87 (s,
1H); 13C NMR (CDCl3, 100 MHz) δ 93.6, 102.9, 109.1, 119.6,
129.8, 149.4, 153.8, 194.7. Anal. Calcd for C8H5O3I: C, 34.81;
H, 1.83. Found: C, 34.80; H, 1.87.
6-Iod oben zo[1,3]d ioxole-5-ca r boxylic Acid . To a solu-
tion containing 9.6 g (56 mmol) of silver nitrate in 100 mL of
H2O at rt was added 4.5 g (113 mmol) of powdered NaOH.
The mixture was allowed to stir at 25 °C for 45 min, and then
7.4 g (27 mmol) of the above aldehyde in 15 mL of EtOH was
added. The solution was stirred for 2.5 h and filtered through
a pad of Celite. The aqueous layer was extracted with ether
and acidified using a 3 M HCl solution. Filtration of the
aqueous layer provided a white solid which was taken up in
ether and dried over MgSO4. Removal of the solvent under
reduced pressure provided 7.0 g (89%) of the title compound
as a white solid: mp 216-217 °C; IR (KBr) 2911 (br), 1694,
1616, 1346 cm-1; 1H NMR (CDCl3, 400 MHz) δ 3.40 (br s, 1H),
6.12 (s, 2H), 7.31 (s, 1H), 7.49 (s, 1H); 13C NMR (CDCl3, 100
MHz) δ 84.9, 102.6, 110.2, 119.9, 129.1, 147.8, 150.5, 167.0.
Anal. Calcd for C8H5O4I: C, 32.90; H, 1.73. Found: C, 32.93;
H, 1.79.
To a solution containing 5.0 g (17.1 mmol) of the above
carboxylic acid in 150 mL of benzene were added 4.3 g (34.2
mmol) of oxalyl chloride and 4 drops of DMF. The solution was
allowed to stir at rt for 5 h and concentrated under reduced
pressure to give 4.8 g (90%) of 6-iodo-benzo[1,3]dioxole-5-
carbonyl chloride. The acid chloride was used in the next step
without further purification.
1-(6-Iodoben zo[1,3]dioxole-5-car bon yl)-3a-m eth yl-1,2,3,-
3a ,4,6-h exa h yd r oin d ol-5-on e (21). To a solution containing
2.0 g (8 mmol) of tert-butyl-3a-methyl-5-oxo-2,3,3a,4,5,6-
hexahydroindol-1-carboxylate (19)18 in 100 mL of CH2Cl2 was
added 20 mL of a 3 M HCl solution. The mixture was stirred
at rt for 12 h, quenched with a 50% NaOH solution, and
extracted with ether. The combined organic extracts were dried
over MgSO4 and concentrated under reduced pressure. The
crude residue was subjected to flash silica gel chromatography
to provide 3a-methyl-2,3,3a,4,6,7-hexahydroindol-5-one imine
as a colorless oil which rapidly decomposed upon standing: IR
(neat) 2961, 1709, 1652, 1303 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 1.08 (s, 3H), 1.79-1.91 (m, 2H), 2.48-2.54 (m, 4H), 2.59-
2.69 (m, 1H), 2.80-2.86 (m, 1H), 3.69-3.78 (m, 1H), 3.89-
3.96 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 23.6, 26.8, 30.5,
39.4, 40.2, 54.5, 58.6, 178.4, 208.6; HRMS calcd for C9H13NO
151.0997, found 151.1005.
To a solution containing 1.2 g (8 mmol) of the above imine
in 125 mL of CH2Cl2 at 0 °C was added 1.3 g (16 mmol) of
freshly distilled pyridine. To this mixture was added 4.9 g (16
mmol) of 6-iodobenzo[1,3]dioxole-5-carbonyl chloride over a 5
min period. After being stirred at rt for 10 h, the reaction
mixture was quenched with 50 mL of H2O and extracted with
ethyl acetate. The combined organic extracts were dried over
MgSO4 and concentrated under reduced pressure. The crude
residue was purified by flash silica gel chromatography to give
2.4 g (72%) of 21 as a white solid: mp 193-194 °C; IR (KBr)
2904, 1790, 1724, 1610, 1504 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 1.12 (s, 3H), 1.77-1.91 (m, 2H), 2.50 (d, 1H, J ) 14.4 Hz),
2.56 (d, 1H, J ) 14.4 Hz), 3.01 (d, 2H, J ) 3.6 Hz), 3.40-3.64
(m, 1H), 3.79-4.13 (m, 1H), 5.98 (s, 2H), 6.60 (s, 1H), 7.18 (s,
1H), 7.46 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 24.8, 36.5,
38.0, 38.6, 44.4, 47.6, 50.1, 53.6, 103.2, 103.9, 104.4, 108.2,
113.0, 119.6, 122.9, 126.1, 145.1, 149.4, 149.8, 153.5, 169.4,
210.4. Anal. Calcd for C17H16NO4I: C, 48.02; H, 3.79; N, 3.29.
Found: C, 47.95; H, 3.77; N, 3.23.
Exp er im en ta l Section
Melting points are uncorrected. Mass spectra were deter-
mined at an ionizing voltage of 70 eV. Unless otherwise noted,
all reactions were performed in flame-dried glassware under
an atmosphere of dry argon. Solutions were evaporated under
reduced pressure with a rotary evaporator, and the residue
was chromatographed on a silica gel column using an ethyl
acetate/hexane mixture as the eluent unless specified other-
wise. All solids were recrystallized from ethyl acetate/hexane
for analytical data.
ter t-Bu tyl N-(6-Iod o-1,3-ben zod ioxolo-5-ylm eth yl)-N-
(2-fu r yl)ca r ba m a te (13). A solution containing 0.38 g (2
mmol) of furan-2-ylcarbamic acid tert-butyl ester (11),18 0.6 g
(4 mmol) of K2CO3, 0.3 g (7 mmol) of powdered NaOH, and
0.14 g (0.4 mmol) of tetrabutylammonium hydrogen sulfate
in 20 mL of benzene was heated at reflux for 30 min. Solid
5-(bromomethyl)-6-iodo-1,3-benzodioxole35 was added in one
portion, and the mixture was heated at reflux for an additional
1 h. The mixture was cooled to rt, quenched with 20 mL of
water, and extracted with CH2Cl2. The combined organic layers
were dried over MgSO4 and concentrated under reduced
pressure. The residue was subjected to flash silica gel chro-
matography to afford 0.88 g (95%) of 13 as a colorless oil: IR
(neat) 2975, 1716, 1609, 1474 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 1.44 (s, 9H), 4.70 (s, 2H), 5.95 (s, 3H), 6.30 (dd, 1H, J ) 2.0
and 0.8 Hz), 6.87 (s, 1H), 7.15 (dd, 1H, J ) 2.0 and 0.8 Hz),
7.21 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 28.4, 49.7, 82.3,
101.3, 103.1, 106.3, 107.1, 107.2, 122.9, 123.9, 138.2, 145.8,
145.9, 147.5, 151.8. Anal. Calcd for C17H18INO5: C, 46.07; H,
4.09; N, 3.16. Found: C, 46.26; H, 4.17; N, 2.95.
ter t-Bu tyl 5H-3,7,9-Tr ioxa-4-azadicyclopen ta[a ,g]n aph -
th a len e-4-ca r ba m a te (14). A solution containing 0.5 g (1.2
mmol) of iodide 13, 0.6 g (6 mmol) of KOAc, 0.6 g (2 mmol) of
tert-butylammonium chloride, and 0.1 g (0.4 mmol) of pal-
ladium acetate in 40 mL of freshly distilled DMF was heated
to 100 °C for 1.5 h. The reaction mixture was cooled to rt,
quenched with water, and extracted with ethyl acetate. The
combined organic layers were washed several times with
water, then dried over MgSO4, and concentrated under reduced
pressure. The residue was subjected to flash silica gel chro-
matography to give 0.21 g (57%) of 14 as a white solid: mp
89-91 °C; IR (neat) 2976, 1709, 1624, 1510, 1360 cm-1 1H
;
NMR (CDCl3, 400 MHz) δ 1.52 (s, 9H), 4.82 (s, 2H), 5.94 (s,
2H), 6.56 (d, 1H, J ) 2.0 Hz), 6.69 (s, 1H), 6.78 (s, 1H), 7.17
(d, 1H, J ) 2.0 Hz); 13C NMR (CDCl3, 100 MHz) δ 28.3, 57.2,
81.9, 85.8, 101.8, 108.2, 109.3, 111.1, 118.7, 133.4, 138.4, 147.7,
148.1, 148.8, 153.9; HRMS calcd for C17H17NO5 315.1107, found
315.1092.
6-Iod oben zo[1,3]d ioxole-5-ca r ba ld eh yd e. To a solution
containing 8.0 g (29 mmol) of 6-iodo-1,3-benzodioxole-5-
methanol35 and 300 mL of CH2Cl2 at 0 °C was added 12.4 g
(58 mmol) of pyridinium chlorochromate. The mixture allowed
3a-Meth yl-3,3a,4,5-tetr ah ydr o-1H-[1,3]dioxolo[4,5-j]pyr -
r olo[3,2,1-d e]p h en a n th r id in e-2,7-d ion e (23). To a solution
containing 0.15 g (0.4 mmol) of iodide 21 in 3 mL of dry DMF
in a sealed tube were added 8 mg (0.03 mmol) of Pd(OAc)2,
0.2 g (0.7 mmol) of tetrabutylammonium chloride, and 0.19 g
(2 mmol) of KOAc. The mixture was deoxygenated under
(34) Torssell, K. Tetrahedron Lett. 1974, 623.
(35) Abelman, M. M.; Overman, L. E.; Tran, V. D. J . Am. Chem.
Soc. 1990, 19, 6959.

1722 J . Org. Chem., Vol. 66, No. 5, 2001
Padwa et al.
vacuum, sealed under argon, and heated at 100 °C for 12 h.
The solution was concentrated under reduced pressure, and
the crude residue was purified by flash silica gel chromatog-
raphy to give 0.5 g (66%) of 23 as a yellow solid: mp 214-215
24 h and quenched with 10 mL of NaHCO3. The aqueous layer
was extracted with CH2Cl2, and the combined organic layers
were dried over MgSO4 and concentrated under reduced
pressure. The crude residue was purified by flash silica gel
chromatography to give 0.2 g (85%) of 25 as a white solid: mp
270-271 °C; IR (neat) 2980, 1726, 1676, 1616, 1482 cm-1; 1H
NMR (CDCl3, 400 MHz) δ 2.14 (dt, 1H, J ) 12.0 and 8.4 Hz),
2.23 (d, 1H, J ) 14.0 Hz), 2.60 (dd, 1H, J ) 12.4 and 5.6 Hz),
3.22 (d, 1H, J ) 14.0 Hz), 3.34-3.46 (m, 6H), 3.67 (s, 3H),
3.90 (dt, 1H, J ) 11.8 and 5.6 Hz), 4.32 (dd, 1H, J ) 12.2 and
8.0 Hz), 6.08 (s, 2H), 6.91 (s, 1H), 7.84 (s, 1H); 13C NMR (CDCl3,
100 MHz) δ 37.9, 38.8, 39.2, 40.1, 46.0, 47.5, 53.2, 54.5, 64.9,
100.7, 102.1, 106.4, 108.3, 121.9, 133.9, 137.4, 147.4, 152.3,
160.2, 174.3. Anal. Calcd for C20H19NO5S2: C, 57.54; H, 4.59;
N, 3.35. Found: C, 57.35; H, 4.65; N, 3.33.
°C; IR (KBr) 2925, 1733, 1669, 1640, 1479 cm-1 1H NMR
;
(CDCl3, 400 MHz) δ 1.25 (s, 3H), 2.14-2.19 (m, 1H), 2.20-
2.24 (m, 1H), 2.65 (d, 1H, J ) 14.4 Hz), 2.84 (d, 1H, J ) 14.4
Hz), 3.36 (d, 1H, J ) 21.4 Hz), 3.48 (d, 1H, J ) 21.4 Hz), 4.03-
4.14 (m, 1H), 4.46 (dd, 1H, J ) 12.4 and 8.4 Hz), 6.09 (s, 2H),
6.77 (s, 1H), 7.83 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 24.4,
36.5, 37.9, 43.9, 46.2, 52.8, 100.1, 102.1, 106.6, 121.5, 134.0,
143.8, 147.5, 152.4, 160.0, 207.8. Anal. Calcd for C17H15NO4:
C, 68.68; H, 5.09; N, 4.71. Found: C, 68.87; H, 5.32; N, 4.53.
1-(6-Iodoben zo[1,3]dioxole-5-car bon yl)-5-oxo-1,2,3,4,5,6-
h exa h yd r oin d ole-3a -ca r boxylic Acid Meth yl Ester (22).
A solution of 0.1 g (0.34 mmol) of 2-[2-(tert-butoxycarbonylfu-
ran-2-ylamino)ethyl]acrylic acid methyl ester18 (18) in 10 mL
of benzene was heated at 150 °C for 12 h in a sealed tube under
an argon atmosphere. The solution was concentrated under
reduced pressure, and the residue was subjected to flash silica
gel chromatography to give 0.09 g (87%) of 5-oxo-2,3,5,6-
tetrahydro-4H-indole-1,3a-dicarboxylic acid 1-tert-butyl ester
3a-methyl ester (20) as a yellow solid.18 To a solution contain-
ing 3.8 g (13 mmol) of 20 and 5 mL of CH2Cl2 was added 20
mL of a 25% TFA/CH2Cl2 solution. The mixture was stirred
at rt for 1 h and was concentrated under reduced pressure.
The crude residue was diluted with 25 mL of CH2Cl2 and cooled
to 0 °C, and 12 mL (86 mmol) of triethylamine was added. To
the resultant residue was added dropwise a solution of 4.4 g
(14 mmol) of 6-iodobenzo[1,3]dioxole-5-carbonyl chloride in 10
mL of CH2Cl2. The solution was allowed to stir for 4 h, the
mixture was quenched with 50 mL of NaHCO3, and the
aqueous layer was extracted with ethyl acetate. The combined
organic layers were dried over MgSO4 and concentrated under
reduced pressure. The crude residue was subjected to flash
silica gel chromatography to provide 4.7 g (78%) of amide 22
as a white solid: mp 176-177 °C; IR (KBr) 1725, 1669, 1641,
1488, 1034 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.90-1.98 (m,
1H), 2.43 (d, 1H, J ) 16.0 Hz), 2.57 (dd, 1H, J ) 12.4 and 6.4
Hz), 2.99 (d, 1H, J ) 16.0 Hz), 3.05 (dd, 1H, J ) 22.8 and 5.6
Hz), 3.22 (dd, 1H, J ) 22.8 and 2.0 Hz), 3.52 (t, 1H, J ) 8.8
Hz), 3.75 (s, 3H), 3.77-3.90 (m, 1H), 6.06 (s, 2H), 6.79 (s, 1H),
6.95 (d, 1H, J ) 2.8 Hz), 7.22 (s, 1H); 13C NMR (CDCl3, 100
MHz) δ 34.0, 37.0, 48.1, 50.6, 53.1, 53.2, 102.3, 107.3, 107.9,
118.8, 118.9, 136.8, 138.3, 148.8, 149.2, 168.5, 172.5, 206.5.
Anal. Calcd for C18H16NO6I: C, 46.08; H, 3.44; N, 2.99.
Found: C, 45.86; H, 3.41; N, 2.95.
7-Oxo-2,3,4,5-tetr a h yd r o-1H,7H-[1,3]d ioxolo[4,5-j]p yr -
r olo[3,2,1-d e]p h en a n th r id in e-3a -ca r boxylic Acid Meth yl
Ester (26). To a solution containing 0.6 g (1.5 mmol) of
thioketal 25 in 100 mL absolute ethanol was added 2 g of Ra/
Ni. The suspension was heated at reflux for 4 h, cooled to rt,
and filtered through Celite with 200 mL of ethanol. The solid
was recrystallized from ethyl acetate to give 0.46 g (93%) of
26 as a white solid: mp 214-215 °C; IR (neat) 2949, 1728,
1
1678, 1619, 1478 cm-1; H NMR (CDCl3, 400 MHz) δ 1.46-
1.53 (m, 1H), 1.67-1.79 (m, 1H), 1.99-2.08 (m, 1H), 2.09-
2.17 (m, 1H), 2.48-2.54 (m, 1H), 2.56 (dd, 1H, J ) 12.0 and
5.6 Hz), 2.65 (dt, 1H, J ) 12.8 and 3.2 Hz), 2.74 (dd, 1H, J )
16.4 and 6.4 Hz), 3.68 (s, 3H), 3.91 (ddd, 1H, J ) 18.0, 12.0,
and 5.6 Hz), 4.33 (dd, 1H, J ) 12.4 and 8.4 Hz), 6.07 (s, 2H),
6.92 (s, 1H), 7.84 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 20.4,
22.0, 31.9, 36.4, 45.9, 52.9, 53.6, 100.6, 101.9, 106.2, 108.2,
121.9, 135.0, 138.4, 147.4, 152.0, 160.1, 174.2. Anal. Calcd for
C
18H17NO5: C, 66.05; H, 5.23; N, 4.28. Found: C, 65.98; H,
5.30; N, 4.20.
7-Oxo-2,3,4,5-tetr a h yd r o-1H,7H-[1,3]d ioxolo[4,5-j]p yr -
r olo[3,2,1-d e]p h en a n th r id in e-3a -ca r boxylic Acid (27). To
a solution containing 0.2 g (0.6 mmol) of ester 26 in 3 mL of
methanol was added 20 mL of a 3 M NaOH. The reaction was
heated to 50 °C for 4 h, cooled to rt, and acidified with 3 M
HCl. The aqueous layer was extracted with ether, and the
combined organic layers were dried over MgSO4 and concen-
trated under reduced pressure to give 0.19 g (98%) of 27 as a
white solid which was used without further purification: mp
228-229 °C; IR (neat) 3420, 2955, 1675, 1600 cm-1; 1H NMR
(DMSO, 400 MHz) δ 1.43 (t, 1H, J ) 12.0 Hz), 1.53-1.62 (m,
1H), 1.98-2.06 (m, 2H), 2.37-2.45 (m, 3H), 2.65 (dd, 1H, J )
16.8 and 6.8 Hz), 3.69 (ddd, 1H, J ) 12.0, 11.8, and 5.6 Hz),
4.09 (dd, 1H, J ) 12.0 and 8.8 Hz), 6.12 (d, 2H, J ) 1.6 Hz),
7.03 (s, 1H), 7.51 (s, 1H); 13C NMR (DMSO, 100 MHz) δ 19.9,
21.3, 30.3, 35.1, 45.6, 52.8, 100.7, 101.9, 104.6, 106.7, 120.7,
2,7-Dioxo-2,3,4,5-tetr a h yd r o-1H,7H-[1,3]d ioxolo[4,5-j]-
pyr r olo[3,2,1-de]ph en an th r idin e-3a-car boxylic Acid Meth -
yl Ester (24). To a solution containing 2.0 g (4 mmol) of iodide
22 in 30 mL of dry DMF were added 0.38 g (1.7 mmol) of Pd-
(OAc)2, 2.4 g (8 mmol) of tetrabutylammonium chloride, and
2.3 g (23 mmol) of KOAc. The mixture was deoxygenated and
heated at 100 °C for 1 h. The reaction was cooled to rt,
quenched with 10 mL of H2O, and extracted with ethyl acetate.
The combined organic layers were dried over MgSO4 and
concentrated under reduced pressure. The crude residue was
purified by flash silica gel chromatography to give 0.95 g (66%)
of 24 as a white solid: mp 229-230 °C; IR (neat) 1730, 1673,
134.5, 139.3, 146.7, 151.5, 158.5, 174.6. Anal. Calcd for C17H15
-
NO5: C, 65.16; H, 4.83; N, 4.47. Found: C, 65.08; H, 4.67; N,
4.32.
1,2,3,3a ,4,5-Hexa h yd r o[1,3]d ioxolo[4,5-j]p yr r olo[3,2,1-
d e]p h en a n th r id in -7-on e (29). To a solution of 0.2 g (0.6
mmol) of carboxylic acid 27 in 20 mL of CH2Cl2 were added
0.16 g (0.8 mmol) of DCC, 0.11 g (0.8 mmol) of 3-hydroxy-4-
methyl-2(3H)-thiazoethione, and 0.02 g (0.2 mmol) of DMAP.
The reaction mixture was allowed to stir at rt for 6 h and
filtered through a pad of silica gel with ethyl acetate. The
organic layer was concentrated under reduced pressure, and
the resulting thione ester 28 was diluted with 25 mL of
benzene. To this solution were added 0.03 g (0.2 mmol) of AIBN
and 0.5 g (1.7 mmol) of tributyltin hydride, and the mixture
was heated at reflux for 2 h. The reaction was allowed to cool
to rt, and the solvent was removed under reduced pressure.
The organic residue was partitioned between acetonitrile and
hexane, and the acetonitrile layer was washed with hexane.
The combined acetonitrile layers were concentrated under
reduced pressure, and the residue was purified by flash silica
gel chromatography to give 0.13 g (73%) of 29 as a white
solid: mp 151-152 °C; IR (neat) 3065, 3020, 1680, 1483, 1241
1
1616, 1481, 1246 cm-1; H NMR (CDCl3, 400 MHz) δ 2.10-
2.19 (m, 1H), 2.51 (d, 1H, J ) 15.6 Hz), 2.91 (dd, 1H, J ) 12.8
and 6.0 Hz), 3.17 (d, 1H, J ) 16.0 Hz), 3.44 (s, 2H), 3.68 (s,
3H), 4.21 (ddd, 1H, J ) 16.8, 11.2, and 6.4 Hz), 4.45 (dd, 1H,
J ) 12.2 and 8.4 Hz), 6.08 (d, 1H, J ) 11.2 Hz), 6.09 (d, 1H,
J ) 1.2 Hz), 6.79 (s, 1H), 7.79 (s, 1H); 13C NMR (CDCl3, 100
MHz) δ 35.1, 36.6, 48.6, 49.0, 54.3, 54.7, 101.2, 103.1, 106.3,
107.3, 122.9, 134.4, 137.8, 148.9, 153.3, 160.7, 172.8, 205.9.
Anal. Calcd for C18H15NO6: C, 63.34; H, 4.43; N, 4.10. Found:
C, 63.19; H, 4.47; N, 4.07.
7-Oxo-2-d ith ia -[4,5]sp ir o-2,3,4,5-tetr a h yd r o-1H,7H-[1,3]-
d ioxolo[4,5-j]p yr r olo[3,2,1-d e]p h en a n th r id in e-3a -ca r box-
ylic Acid Meth yl Ester (25). To a solution containing 0.2 g
(0.6 mmol) of ketone 24 in 20 mL of dry CH2Cl2 were added
0.3 g (3.0 mmol) of 1,2-ethanedithiol and 0.3 g (2.3 mmol) of
boron trifluoride etherate. The mixture was stirred at rt for
1
cm-1; H NMR (CDCl3, 400 MHz) δ 1.29-1.39 (m, 1H), 1.70
(dd, 1H, J ) 12.0 and 8.4 Hz), 1.74-1.83 (m, 1H), 2.18-2.25
(m, 2H), 2.40 (ddd, 1H, J ) 12.0, 6.4, and 5.6 Hz), 2.46-2.52

Synthesis of (()-γ-Lycorane and (()-1-Deoxylycorine
J . Org. Chem., Vol. 66, No. 5, 2001 1723
(m, 1H), 2.70 (dd, 1H, J ) 16.0 and 6.8 Hz), 3.00-3.05 (m,
1H), 3.82 (ddd, 1H, J ) 12.0, and 11.8, and 5.6 Hz), 4.37 (dd,
1H, J ) 12.0 and 8.4 Hz), 6.06 (s, 2H), 6.89 (s, 1H), 7.82 (s,
1H); 13C NMR (CDCl3, 100 MHz) δ 22.4, 23.0, 28.3, 31.3, 40.5,
47.1, 100.2, 101.8, 106.2, 106.7, 121.3, 135.4, 141.4, 146.8,
151.9, 160.2. Anal. Calcd for C16H15NO3: C, 71.36; H, 5.61; N,
5.20. Found: C, 71.15; H, 5.59; N, 5.14.
6.31 (br s, 1H), 7.31-7.37 (m, 5H); 13C NMR (CDCl3, 100 MHz)
δ 28.5, 34.2, 38.9, 47.0, 52.9, 69.3, 69.9, 77.4, 80.9, 81.9, 103.5,
127.8, 128.1, 128.6, 138.8, 141.1, 152.3, 174.0. Anal. Calcd for
C
22H29NO6: C, 65.48; H, 7.25; N, 3.47. Found: C, 65.37; H,
7.18; N, 3.31.
In addition to the trans-alcohol, a smaller quantity (0.15 g,
20%) of the cis-isomer was also obtained as a colorless oil: IR
(()-γ-Lycor a n e (4). To a solution of 0.03 g (0.12 mmol) of
pyridone 29 in 20 mL of THF was added 0.01 g (0.3 mmol) of
LiAlH4, and the reaction was heated at reflux for 1 h. The
solution was cooled to rt, quenched with 0.5 mL of water and
then 1 mL of a 3 M NaOH solution, and extracted with ether.
The combined organic layers were dried over MgSO4 and
concentrated under reduced pressure. To the crude organic
residue were added 10 mL of methanol, a crystal of bromo-
cresol green, and 0.01 g (0.2 mmol) of NaCNBH3. To this
solution was added 3 M methanolic/HCl until a yellow color
persisted, and the solution was allowed to stir at rt for 4 h.
The reaction mixture was quenched by the addition of 2 mL
of 3 M KOH solution, and the aqueous layer was extracted
with CH2Cl2. The combined organic layers were dried over
MgSO4 and concentrated under reduced pressure. The crude
residue was subjected to flash silica gel chromatography to
provide 0.022 g (74%) of γ-lycorane (4): IR (CCl4) 2930, 1505,
1480, 1320, 1245, 1230, 1045 cm-1; 1H NMR (CDCl3, 400 MHz)
1.23-1.54 (m, 4H), 1.58-1.80 (m, 3H), 1.94-2.07 (m, 1H),
2.08-2.23 (m, 2H), 2.36 (dd, 1H, J ) 5.0 and 4.0 Hz), 2.73
(ddd, 1H, J ) 11.5, 5.0 and 1.0 Hz), 3.20 (d, 1H, J ) 14.0 Hz),
3.37 (ddd, 1H, J ) 9.0, 9.0 and 3.5 Hz), 4.05 (d, 1H, J ) 14.0
Hz), 5.88 (br s, 2H), 6.49 (s, 1H), 6.61 (s, 1H); 13C NMR δ 25.2,
29.2, 30.4, 31.7, 37.3, 39.4, 53.7, 57.1, 62.8, 100.6, 106.2, 108.3,
127.3, 133.1, 145.6, 146.0. The spectral data are in agreement
with those reported in the literature.8c
(neat) 3530, 1730, 1709, 1666, 1388 cm-1 1H NMR (CDCl3,
;
400 MHz) δ 1.50 (s, 9H), 1.67 (t, 1H, J ) 12.4 Hz), 1.76-1.84
(m, 1H), 2.27 (dd, 1H, J ) 12.4 and 6.0 Hz), 2.43 (dd, 1H, J )
12.0 and 3.6 Hz), 2.82 (br s, 1H), 3.41 (dt, 1H, J ) 11.4 and
6.0 Hz), 3.66-3.67 (m, 1H), 3.69 (s, 3H), 3.74-3.80 (m, 1H),
4.12 (m, 1H), 4.48-4.54 (m, 1H), 4.70-4.79 (m, 1H), 6.44 (br
s, 1H), 7.27-7.37 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ 28.5,
33.8, 36.9, 46.6, 52.9, 66.7, 71.6, 73.0, 77.5, 81.1, 103.4, 128.1,
128.2, 128.7, 138.3, 142.4, 152.5, 174.0; HRMS calcd for C22H29
NO6 403.1995, found 403.2003.
-
6-Ben zoyloxy-5-(1-ph en ylm eth an oyloxy)-2,3,4,5-tetr ah y-
d r o-4H-in d ole-1,3a -d ica r boxylic Acid 1-ter t-Bu tyl Ester
3a -Meth yl Ester (36). To a solution of 0.47 g (1.2 mmol) of
trans-alcohol 35 in 30 mL of CH2Cl2 were added 0.2 g (1.6
mmol) of benzoic acid, 0.3 g (1.4 mmol) of 1,3-dicyclohexylcar-
bodiimide, and 0.04 g (0.3 mmol) of 4-(dimethylamino)pyridine.
The reaction was allowed to stir at rt for 6 h, and the white
precipitate that formed was removed by filtration. The filtrate
was concentrated under reduced pressure, and the crude
residue was purified by flash silica gel chromatography to give
0.53 g (90%) of 36 as a white foam: IR (neat) 2929, 1710, 1649,
1
1449, 1388 cm-1; H NMR (CDCl3, 400 MHz) δ 1.53 (s, 9H),
1.69-1.79 (m, 2H), 2.31 (dd, 1H, J ) 12.0 and 6.0 Hz)), 2.82
(dd, 1H, J ) 12.0 and 4.0 Hz), 3.53 (td, 1H, J ) 11.2 and 6.0
Hz), 3.69-3.74 (m, 1H), 3.80 (s, 1H), 4.51 (dd 1H, J ) 7.2 and
4.0 Hz), 4.58-4.68 (m, 2H), 5.43 (ddd, 1H, J ) 12.0, 7.2 and
4.8 Hz), 6.35 (br s, 1H), 7.21-7.30 (m, 5H), 7.41-7.45 (m, 2H),
7.52-7.58 (m, 1H), 8.00 (d, 2H, J ) 7.6 Hz); 13C NMR (CDCl3,
100 MHz) δ 28.6, 34.2, 37.3, 47.2, 49.8, 52.9, 53.2, 69.6, 72.3,
81.0, 103.9, 128.1, 128.4, 128.5, 129.9, 130.4, 131.0, 133.2,
138.8, 141.8, 152.3, 166.0, 173.4; HRMS calcd for C29H33NO7-
Li 514.2417, found 514.2433.
5-Hyd r oxy-2,3,4,5-tetr a h yd r o-4H-in d ole-1,3a -d ica r box-
ylic Acid 1-ter t-Bu t yl E st er 3a -Met h yl E st er (34). To a
solution of 1.0 g (3.4 mmol) of carbamate 18 in 50 mL of THF
was added 0.9 g (13 mmol) of NaCNBH3. After being heated
at reflux for 24 h, the reaction mixture was quenched with 5
mL of H2O and extracted with CH2Cl2. The combined organic
extracts were dried over MgSO4 and concentrated under
reduced pressure. The crude residue was purified by flash
silica gel chromatography to give 0.15 g (15%) of the trans-
alcohol 34 as a clear oil: IR (neat) 3443, 1730, 1708, 1671,
5-Ben zoyloxy-2,3,4,5-tetr a h yd r o-4H-in d ole-1,3a -d ica r -
boxylic Acid 1-ter t-Bu tyl Ester 3a -Meth yl Ester (37). To
a solution of 0.05 g (0.1 mmol) of the above benzoate 36 in 15
mL of ethanol and 5 mL of THF in a high-pressure bottle under
argon was added 0.05 g of 5% Pd on carbon. The mixture was
shaken on a Parr hydrogenation apparatus under a 20 psi
hydrogen atmosphere for 12 h and then filtered through a pad
of Celite. The filtrate was concentrated under reduced pres-
sure, and the crude residue was subjected to flash silica gel
chromatography to afford 0.035 g (85%) of 37 as a white solid:
1
1455 cm-1; H NMR (CDCl3, 400 MHz) δ 1.47 (s, 9H), 1.69-
1.78 (m, 1H), 2.01 (ddd, 1H, J ) 17.1, 9.0, and 3.2 Hz), 2.18-
2.23 (m, 2H), 2.57 (dd, 1H, J ) 12.0 and 3.6 Hz), 2.64 (br s,
1H), 3.39 (dt, 1H, J ) 11.2 and 3.6 Hz), 3.58-3.62 (m, 1H),
3.67 (s, 3H), 3.68-3.71 (m, 1H), 3.90-3.92 (m, 1H), and 5.97
(br s, 1H); 13C NMR (CDCl3, 100 MHz) δ 28.5, 33.7, 34.3, 41.1,
46.6, 52.8, 52.9, 65.4, 80.4, 104.4, 137.3, 152.6, 174.7; HRMS
calcd for C15H23NO5 297.1576, found 297.1578.
mp 124-125 °C; IR (neat) 2927, 1721, 1687, 1456, 1388 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 1.50 (s, 9H), 1.69 (t, 1H, J )
12.0 Hz), 1.78 (ddd, 1H, J ) 12.4, 12.2, and 8.8 Hz), 2.25 (ddd,
1H, J ) 14.0, 8.4, and 3.2 Hz), 2.31 (dd, 1H, J ) 12.8 and 6.0
Hz), 2.78 (dd, 1H, J ) 12.0 and 4.0 Hz), 2.86 (dt, 1H, J ) 17.6
and 4.8 Hz), 3.47 (ddd, 1H, J ) 17.2, 11.2, and 6.0 Hz), 3.67
(dd, 1H, J ) 10.0 and 8.8 Hz), 3.76 (s, 3H), 5.20-5.30 (m, 1H),
6.08 (br s, 1H), 7.42 (t, 2H, J ) 7.6 Hz), 7.53-7.56 (m, 1H),
8.00-8.03 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 28.6, 30.1,
34.4, 37.5, 46.7, 52.5, 53.0, 68.7, 80.6, 103.7, 128.5, 129.8, 130.5,
133.1, 137.5, 152.6, 166.1, 174.1. Anal. Calcd for C22H27NO6:
C, 65.82; H, 6.78; N, 3.49. Found: C, 65.85; H, 6.64; N, 3.38.
A sample of 37 was also prepared from alcohol 34. To a
solution of 0.1 g (0.3 mmol) of trans-alcohol 34 in 10 mL of
CH2Cl2 were added 0.08 g (0.4 mmol) of DCC, 0.05 g (0.4 mmol)
benzoic acid, and 0.01 g (0.01 mmol) of DMAP. The reaction
mixture was allowed to stir for 6 h at rt and concentrated
under reduced pressure. The crude residue was purified by
flash silica gel chromatography to give 0.13 g (93%) of 37,
which was identical in all respects with a sample obtained from
the catalytic reduction of 36.
Another minor product isolated from the silica gel column
contained 0.3 g (30%) of 4-(tert-butoxycarbonylfuran-2-ylamino)-
2-methylbutyric acid methyl ester as a colorless oil: IR (neat)
2982, 1741, 1704, 1610, 1454 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 1.44 (s, 9H), 1.48-1.50 (m, 1H), 1.85-1.93 (m, 1H), 2.05-
2.14 (m, 1H), 2.67-2.71 (m, 2H), 2.79-2.85 (m, 1H), 3.61-
3.69 (m, 2H), 3.74 (s, 3H), 6.02 (br s, 1H), 6.34 (dd, 1H, J )
2.8 and 2.4 Hz), 7.18-7.19 (m, 1H); 13C NMR (CDCl3, 100
MHz) δ 19.5, 28.3, 28.6, 30.2, 38.9, 45.9, 52.8, 81.9, 111.3,
117.7, 138.6, 148.0, 172.8; HRMS calcd for C15H23NO5 297.1576,
found 297.1574.
6-Ben zyloxy-5-h yd r oxy-2,3,5,6-t et r a h yd r o-4H -in d ole-
1,3a -d ica r b oxylic Acid N-t er t -Bu t yl E st er 3a -Met h yl
Ester (35). A solution of 1.0 g (3.4 mmol) of furanyl carbamate
18 in 20 mL of benzyl alcohol was heated at 65 °C for 4 h. The
solvent was removed under reduced pressure, and the residue
was subjected to flash silica gel chromatography to give 0.8 g
(62%) of trans-alcohol 35 as a colorless oil: IR (neat) 3480,
1730, 1709, 1666, 1388 cm-1 1H NMR (CDCl3, 400 MHz) δ
;
1.51 (s, 9H), 1.62 (t, 1H, J ) 12.4 Hz), 1.71-1.81 (m, 1H), 2.23
(dd, 1H, J ) 12.6 and 6.0 Hz), 2.42 (br s, 1H), 2.58 (dd, 1H, J
) 12.4 and 4.0 Hz), 3.46 (dt, 1H, J ) 11.6 and 6.0 Hz), 3.65-
3.69 (m, 1H), 3.70 (s, 3H), 3.85-3.90 (m, 1H), 4.12 (dd, 1H, J
) 7.4 and 3.2 Hz), 4.51 (d, 1H, J ) 11.2 Hz), 4.73 (m, 1H),
5-Ben zoyloxy-1-(6-iod oben zo[1,3]d ioxole-5-ca r bon yl)-
1,2,3,4,5,6-h exa h yd r oin d ole-3a -ca r b oxylic Acid Met h yl
Ester (33). A 0.1 g (0.25 mmol) sample of 37 in 5 mL of a 25%
TFA/CH2Cl2 solution was stirred at rt for 6 h and concentrated
under reduced pressure. The crude residue was diluted with

1724 J . Org. Chem., Vol. 66, No. 5, 2001
Padwa et al.
10 mL of CH2Cl2 and cooled to 0 °C, and 1.5 g (1.5 mmol) of
triethylamine was added. To this mixture was added 0.09 g
(0.3 mmol) of 6-iodobenzo[1,3]dioxole-5-carbonyl chloride. The
solution was allowed to stir for 10 h and concentrated under
reduced pressure. The crude residue was subjected to flash
silica gel chromatography to provide 0.12 g (81%) of amide 33
as a white solid: mp 86-87 °C; IR (neat) 2953, 1719, 1636,
at rt and quenched with 10 mL of NaHCO3. The aqueous layer
was extracted with CH2Cl2, and the combined organic layers
were dried over MgSO4 and concentrated under reduced
pressure. The crude residue was purified by flash silica gel
chromatography to give 0.1 g (89%) of 40 as a white solid: mp
219-220 °C; IR (neat) 2889, 1736, 1648, 1607, 1460 cm-1; 1H
NMR (CDCl3, 400 MHz) δ 1.94 (ddd, 1H, J ) 12.4, 12.4, and
8.0 Hz), 2.29 (dd, 1H, J ) 18.6 and 13.6 Hz), 2.59 (d, 1H, J )
15.6 Hz), 2.77 (dd, 1H, J ) 12.8 and 5.6 Hz), 2.92 (d, 1H, J )
3.6 Hz), 2.97 (d, 1H, J ) 3.6 Hz), 3.35 (ddd, 1H, J ) 13.4, 13.2,
4.0 Hz), 3.42 (ddd, 1H, J ) 11.6, 11.6, and 6.0 Hz), 3.72 (s,
3H), 3.92 (d, 1H, J ) 13.2 Hz), 4.24 (dd, 1H, J ) 12.0 and 8.0
Hz), 6.02 (s, 2H), 6.61 (s, 1H), 7.51 (s, 1H); 13C NMR (CDCl3,
100 MHz) δ 36.3, 37.2, 37.7, 44.7, 47.2, 51.7, 53.4, 63.6, 102.1,
104.3, 109.0, 124.6, 134.2, 147.4, 151.1, 161.9, 174.7, 206.5.
Anal. Calcd for C18H17NO6: C, 62.97; H, 4.99; N, 4.08. Found:
C, 62.81; H, 4.97; N, 3.99.
1478, 1419 cm-1 1H NMR (DMSO, 50 °C, 400 MHz) δ 1.78
;
(dd, 1H, J ) 12.4 and 12.0 Hz), 1.86-1.94 (m, 1H), 2.28-2.34
(m, 2H), 2.65 (d, 1H, J ) 12.0 Hz), 2.82 (d, 1H, J ) 17.6 Hz),
3.30-3.32 (m, 2H), 3.74 (s, 3H), 5.20 (br s, 1H), 6.10 (s, 2H),
6.52 (br s, 1H), 6.91 (br s, 1H), 7.39 (s, 1H), 7.53 (dd, 2H, J )
7.6 and 7.2 Hz), 7.66 (dd, 1H, J ) 7.6 and 7.2 Hz), 7.96 (d, 2H,
J ) 7.6 Hz); 13C NMR (DMSO, 50 °C, 100 MHz) δ 29.3, 33.7,
36.3, 48.3, 51.9, 52.6, 59.5, 67.9, 80.9, 101.9, 106.9, 117.8, 128.5,
129.0, 129.6, 133.2, 136.6, 137.5, 147.9, 148.3, 165.0, 166.9,
173.0. Anal. Calcd for C25H22NO7I: C, 52.19; H, 3.85; N, 2.43.
Found: C, 52.09; H, 3.79; N, 2.36.
12b,12c-Dim eth yl-4,5,12b,12c-tetr a h yd r o-1H-[1,3]d iox-
olo[4,5-j]p yr r olo[3,2,1-d e]p h en a n th r id in e-2,7-d ion e (41).
To a solution of 0.05 g (0.12 mmol) of ester 40 in 0.5 mL of
methanol was added 10 mL of a 3 M NaOH solution. The
mixture was heated to 50 °C for 4 h and then acidified by the
addition of 3 M HCl. The aqueous layer was extracted with
ether, and the combined organic layers were dried over MgSO4
and concentrated under reduced pressure to provide the
corresponding carboxylic acid, which was used in the next step
without further purification. The crude carboxylic acid was
taken up in 15 mL of benzene, and 0.06 g (0.35 mmol) of
copper(II) acetate and 0.1 mL (1.3 mmol) of pyridine were
added. The solution was stirred until the it turned green, and
then 0.15 g (0.35 mmol) of lead(IV) acetate was added. The
reaction mixture was stirred at rt for 30 min and then heated
at reflux for 3 h. The mixture was diluted with CH2Cl2 and
washed with 2 M HCl and a saturated NaHCO3 solution, and
the combined organic layers were dried with MgSO4 and
concentrated under reduced pressure. The crude residue was
purified by flash silica gel chromatography to give 0.02 g (70%)
of 41 as a white solid: mp 193-194 °C; IR (neat) 2915, 1653,
1605, 1477, 1364 cm-1; 1H NMR (CDCl3, 400 MHz) δ 2.40 (dd,
1H, J ) 16.8 and 13.6 Hz), 3.01-3.09 (m, 3H), 3.26 (ddd, 1H,
J ) 12.8 and 4.0 Hz), 3.86-3.93 (m, 1H), 3.97-4.02 (m, 1H),
4.20 (d, 1H, J ) 12.4 Hz), 6.04-6.06 (m, 3H), 6.62 (s, 1H),
7.57 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 29.9, 38.4, 40.9,
43.6, 61.3, 102.1, 103.8, 109.1, 123.3, 125.3, 129.0, 134.7, 147.4,
151.2, 164.2, 197.1. Anal. Calcd for C16H13NO4: C, 67.83; H,
4.63; N, 4.95. Found: C, 67.71; H, 4.57; N, 4.86.
2-Hydr oxy-12b,12c-dim eth yl-1,2,4,5,12b,12c-h exah ydr o-
[1,3]d ioxolo[4,5-j]p yr r olo[3,2,1-d e]p h e n a n t h r id in e -7-
on e (42). To a solution of 0.01 g (0.04 mmol) of ketone 41 in
10 mL of methanol was added 5 mg (0.13 mmol) of NaBH4
dissolved in 0.5 mL of H2O at rt. The reaction mixture was
allowed to stir at rt for 1 h, quenched with 5 mL of H2O, and
extracted with CH2Cl2. The combined organic extracts were
dried over MgSO4 and concentrated under reduced pressure.
The crude residue was purified by flash silica gel chromatog-
raphy to give 0.008 g (80%) of 42: mp 193-194 °C; IR (CHCl3)
3600, 1640 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.52 (ddd, 1H,
J ) 12.5, 12.5, and 9.5 Hz), 1.76 (d, 1H, J ) 6.8 Hz), 2.75 (m,
4H), 3.73 (m, 1H), 3.82 (m, 1H), 3.89 (d, 1H, J ) 12.0 Hz),
4.67 (m, 1H), 5.66 (m, 1H), 6.02 (s, 2H), 6.72 (s, 1H), 7.55 (s,
1H); 13C NMR (CDCl3, 75 MHz) δ 28.1, 32.2, 40.0, 43.3, 60.2,
68.6, 101.6, 103.4, 108.3, 122.7, 125.3, 135.9, 140.3, 146.6,
150.7, 163.2. The spectral data are in agreement with those
reported in the literature.9f
2-Ben zoyloxy-12b ,12c-d im et h yl-7-oxo-2,3,4,5,12b ,12c-
h e xa h yd r o-1H ,7H -[1,3]d ioxolo[4,5-j]p yr r olo[3,2,1-d e]-
p h en a n th r id in e-3a -ca r boxylic Acid Meth yl Ester (38). To
a solution of amide 33 in 50 mL of benzene were added 0.01 g
(0.1 mmol) of AIBN and 0.1 g (0.3 mmol) of tributyltin hydride.
The mixture was heated at reflux for 2 h, and the solvent was
removed under reduced pressure. The organic residue was
partitioned between acetonitrile and hexane, and the aceto-
nitrile layer was washed with hexane. The combined acetoni-
trile layers were concentrated under reduced pressure, and
the residue was purified by flash silica gel chromatography to
give 0.06 g (51%) of 38 as a white solid: mp 171-172 °C; IR
(neat) 2926, 1720, 1650, 1604, 1454 cm-1 1H NMR (CDCl3,
;
400 MHz) δ 1.33-1.38 (m, 2H), 2.03-2.15 (m, 2H), 2.34 (dt,
1H, J ) 13.6 and 4.8 Hz), 2.57 (ddd, 1H, J ) 12.4, 12.4, and
4.8 Hz), 3.15 (ddd, 1H, J ) 13.0, 12.8, and 4.8 Hz), 3.34 (ddd,
1H, J ) 12.0, 12.0, and 5.6 Hz), 3.78 (s, 3H), 4.01 (d, 1H, J )
13.2 Hz), 4.17 (d, 1H, J ) 12.0 and 8.0 Hz), 5.39-5.45 (m, 1H),
6.00 (d, 1H, J ) 1.2 Hz), 6.07 (d, 1H, J ) 1.2 Hz), 6.66 (s, 1H),
7.46 (dd, 2H, J ) 8.0 and 7.6 Hz), 7.49 (s, 1H), 7.57-7.61 (m,
1H), 8.02-8.04 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 28.1,
29.6, 34.9, 36.8, 44.4, 51.3, 53.3, 62.7, 68.7, 101.9, 104.2, 108.8,
125.1, 128.7, 129.8, 130.1, 133.5, 136.2, 147.0, 150.9, 162.8,
166.0, 175.5. Anal. Calcd for C25H23NO7: C, 66.81; H, 5.16; N,
3.12. Found: C, 66.72; H, 5.12; N, 3.08.
The minor product isolated from the silica gel chromatog-
raphy column contained 0.045 g (46%) of 1-(benzo[1,3]dioxole-
5-carbonyl)-5-benzoyloxy-1,2,3,4,5,6-hexahydroindole-3a-car-
boxylic acid methyl ester (39) as a white solid: mp 60-61 °C;
1
1
-
IR (neat) 2955, 1720, 1633, 1437, 1275 cm ; H NMR (CDCl3,
400 MHz) δ 1.34-1.44 (m, 2H), 1.71 (dd, 1H, J ) 12.4 and
12.2 Hz), 1.82-1.89 (m, 1H), 2.12-2.26 (m, 1H), 2.44-2.52 (m,
1H), 2.68-2.78 (m, 1H), 2.80 (dd, 1H, J ) 12.0 and 3.6 Hz),
3.67 (ddd, 1H, J ) 12.0, 11.2, and 6.8 Hz), 3.85 (s, 3H), 5.23-
5.26 (m, 1H), 6.01 (s, 2H), 6.81 (s, 1H, J ) 8.0 Hz), 7.08 (br s,
1H), 7.14 (d, 1H, J ) 7.2 Hz), 7.43 (dd, 2H, J ) 8.0 and 7.8
Hz), 7.56 (dd, 1H, J ) 7.8 and 7.2 Hz), 8.01 (d, 2H, J ) 7.8
Hz); 13C NMR (CDCl3, 100 MHz) δ 28.9, 30.3, 34.3, 37.6, 52.9,
53.2, 68.4, 101.5, 101.7, 107.6, 108.4, 108.9, 120.7, 122.5, 128.6,
129.8, 130.4, 133.3, 138.1, 147.6, 149.4, 166.1, 174.0. Anal.
Calcd for C25H23NO7: C, 66.81; H, 5.16; N, 3.12. Found: C,
66.75; H, 5.24; N, 3.17.
12b,12c-Dim eth yl-2,7-d ioxo-2,3,4,5,12b,12c-h exa h yd r o-
1H,7H-[1,3]-dioxolo[4,5-j]pyr r olo[3,2,1-de]ph en an th r idin e-
3a -ca r boxylic Acid Meth yl Ester (40). To a solution con-
taining 0.15 g (0.3 mmol) of ester 38 in 15 mL of methanol
was added 0.18 g (3.3 mmol) of NaOH. The mixture was heated
at 60 °C for 4 h, cooled to rt, and quenched with 10 mL of
H2O. The aqueous layer was extracted with CH2Cl2, and the
combined organic layers were dried over MgSO4 and concen-
trated under reduced pressure. The crude alcohol was taken
up in 20 mL of CH2Cl2, and 0.17 g (0.4 mmol) of Dess-Martin
reagent36 was added. The mixture was allowed to stir for 3 h
Ack n ow led gm en t. We gratefully acknowledge the
National Science Foundation (Grant CHE-9806331) for
generous support of this work.
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra for new compounds lacking analyses together
with an ORTEP drawing for compond 38. This material is
available free of charge via the Internet at http://pubs.acs.org.
(36) Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277.
Ireland, R. E.; Liu, L. J . Org. Chem. 1993, 58, 2899.
J O0014109