A short route to enantiomerically pure benzophenanthridinone skeletons synthesis of lactone analogues of narciclasine and lycoricidine

Article abstract of DOI:10.1021/jo049153l

Condensation of functionalized o-toluamide anions on a carbohydrate-derived lactone, followed by intramolecular aldol cyclization, provides enantiomerically pure 2-arylcyclohexenones. Different approaches for the stereoselective transformation of the carb

Full text of DOI:10.1021/jo049153l

A Sh or t Rou te to En a n tiom er ica lly P u r e Ben zop h en a n th r id in on e
Sk eleton : Syn th esis of La cton e An a logu es of Na r cicla sin e a n d
Lycor icid in e
Said Ibn-Ahmed,† Mustapha Khaldi, Franc¸oise Chre´tien, and Yves Chapleur*
Groupe SUCRES, UMR 7565 CNRS-Universite´ Henri Poincare´ Nancy 1,
BP 239, F-54506 Nancy-Vandoeuvre, France
yves.chapleur@sucres.uhp-nancy.fr
Received May 19, 2004
Condensation of functionalized o-toluamide anions on a carbohydrate-derived lactone, followed by
intramolecular aldol cyclization, provides enantiomerically pure 2-arylcyclohexenones. Different
approaches for the stereoselective transformation of the carbonyl group of these key intermediates
into an amino group were unsuccessful. However 1,4-addition of thiolate and concomitant ring
closure to isocoumarine provided a useful method for the transformation of the tertiary amide
function. Opening of the isocoumarin with ammonia provided the corresponding amide and recovery
of the enone system. Subsequent reductive amination of this cyclohexenone was found to depend
on the nature of the protecting groups and led to the protected form of 4-epi- and -iso-narciclasine.
Oxo analogues of narciclasine and epi-narciclasine and lycoricidine were also obtained after reduction
of the enone and subsequent lactonization. They showed no biological activity as antitumor agents.
In tr od u ction
Lycoricidine 1 and narciclasine 2 are alkaloids ex-
tracted from different daffodil bulbs (Figure 1).1 In the
1970s, structural determination2,3 showed that these
inhibitors of protein synthesis4 are highly oxygenated
benzophenantridinone-type compounds. The antitumor
activity of these compounds has been also investigated
and seems to be related to the oxygenated cycle and to
the tricyclic system. Compounds lacking this rigid ar-
rangement failed to exhibit any biological properties.5
More recently, a related compound pancratistatin 36 and
its 7-deoxy analogue7 were isolated and exhibited very
promising antitumor activity.8 These intriguing and
F IGURE 1. Structures of natural compounds.
unique structures and the associated biological properties
have triggered synthetic studies culminating with the
syntheses of lycoricidine,9 narciclasine,3a,b,9m,n,10a-d pan-
cratistatin,10d,11 and some derivatives thereof.12 Synthetic
studies toward the natural compounds11h,13 and the
* To whom correspondence should be addressed. Phone: +33 383
68 47 73. Fax: + 33 383 68 47 80.
† Present address: Laboratoire de Synthe`se Organique et Proce´de´s
d’Extraction, Faculte´ des Sciences, Universite´ Ibn Tofail, BP 133, 14000
Kenitra, Morocco.
(8) Pettit, G. R.; Gaddamidi, V.; Herald, D. L.; Singh, S. B.; Cragg,
G. M.; Schmidt, J . M.; Boettner, F. E.; Williams, M.; Sagawa, Y. J .
Nat. Prod. 1986, 49, 995.
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10.1021/jo049153l CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/08/2004
6722
J . Org. Chem. 2004, 69, 6722-6731

Lactone Analogues of Narciclasine and Lycoricidine
SCHEME 1a
preparation of analogues have appeared over the
years.13b,14 In this context, we developed a program for
the synthesis of analogues.5,13h,15
From a retrosynthetic point of view, two main ap-
proaches can be envisioned. In one approach, a conver-
gent synthesis consisted of constructing two fragments
representing the A and C cycles which must be coupled
together to form the B ring. This approach implies the
formation of the 10a-10b carbon-carbon bond, which is
a crucial point of the synthesis. Heck reaction and other
palladium-based bond-forming reactions,16 radical cycli-
zation,9l,m,14d,g photocyclization,10d,13d and others proved to
be efficient for forming this bond.11c-e Our own work along
these lines showed that this synthetic operation is
strikingly dependent on the protecting groups present on
the C ring.17 For example, all attempts to construct the
B ring by an intramolecular process including Heck
reaction, radical cyclization, and others using benzyloxy
groups at positions 2, 3, and 4 failed. Ring B construction
can be achieved by coupling an aromatic anion easily
produced by an orthometalation process to the appropri-
ate precursor of the C ring.9d,11b This procedure needs an
a
s
Reagents and conditions: (a) BuLi, THF, -78 °C; (b) AcOH,
H2O, 60 °C; (c) NaIO4, MeOH, rt, then THF, Na2CO3, DBU, rt; (d)
Ac2O, pyridine, rt.
(11) (a) Danishefsky, S. J .; Lee, J . Y. J . Am. Chem. Soc. 1989, 111,
4829-4837. (b) Tian, X. R.; Hudlicky, T.; Konigsberger, K. J . Am.
Chem. Soc. 1995, 117, 3643-3644. (c) Trost, B. M.; Pulley, S. R. J .
Am. Chem. Soc. 1995, 117, 10143-10144. (d) Doyle, T. J .; Hendrix,
M.; VanDerveer, D.; J avanmard, S.; Haseltine, J . Tetrahedron 1997,
53, 11153-11170. (e) Magnus, P.; Sebhat, I. K. Tetrahedron 1998, 54,
15509-15524. (f) Pettit, G. R.; Melody, N.; Herald, D. L. J . Org. Chem.
2001, 66, 2583-2587. (g) Kim, S.; Ko, H.; Kim, E.; Kim, D. Org. Lett.
2002, 4, 1343-1345. (h) Nadein, O. N.; Kornienko, A. Org. Lett. 2004,
6, 831-834.
(12) For reviews, see: (a) Martin, S. F. The Amaryllidaceae Alka-
loids. In The Alkaloids; Brossi, A., Ed.; Academic Press: New York,
1987; Vol. 30, Chapter 3, pp 251-376. (b) Polt, R. Amaryllidaceae
alkaloids with antitumor activity. In Organic Synthesis: Theory and
Applications; Hudlicky, T., Ed.; J AI Press, Inc.: Greenwich, CT, 1996;
Vol. 3, pp 109-148. (c) Hudlicky, T. J . Heterocycl. Chem. 2000, 37,
535-539.
(13) (a) Lopes, R. S. C.; Lopes, C. C.; Heathcock, C. H. Tetrahedron
Lett. 1992, 33, 6775-6778. (b) Angle, S. R.; Louie, M. S. Tetrahedron
Lett. 1993, 34, 4751-4754. (c) McIntosh, M. C.; Weinreb, S. M. J . Org.
Chem. 1993, 58, 4823-4832. (d) Rigby, J . H.; Gupta, V. Synlett 1995,
547-548. (e) Doyle, T. J .; Vanderveer, D.; Haseltine, J . Tetrahedron
Lett. 1995, 36, 6197-6200. (f) Hudlicky, T.; Tian, X. R.; Konigsberger,
K.; Maurya, R.; Rouden, J .; Fan, B. J . Am. Chem. Soc. 1996, 118,
10752-10765. (g) Gauthier, D. R.; Bender, S. L. Tetrahedron Lett.
1996, 37, 13-16. (h) Ibn Ahmed, S.; Chre´tien, F.; Chapleur, Y.; Hajjaj,
N. Heterocycl. Commun. 1997, 3, 135-138. (i) Angle, S. R.; Wada, T.
Tetrahedron Lett. 1997, 38, 7955-7958. (j) Elango, S.; Wang, Y. C.;
Cheng, C. L.; Yan, T. H. Tetrahedron Lett. 2002, 43, 3757-3759.
(14) (a) Keck, G. E.; Fleming, S. A. Tetrahedron Lett. 1978, 4763-
4766. (b) Weller, T.; Seebach, D. Tetrahedron Lett. 1982, 23, 935-938.
(c) Pettit, G. R.; Melody, N.; Osullivan, M.; Thompson, M. A.; Herald,
D. L.; Coates, B. J . Chem. Soc., Chem. Commun. 1994, 2725-2726.
(d) Keck, G. E.; McHardy, S. F.; Murry, J . A. J . Am. Chem. Soc. 1995,
117, 7289-7290. (e) Tian, X. R.; Maurya, R.; Konigsberger, K.;
Hudlicky, T. Synlett 1995, 1125. (f) Chida, N.; J itsuoka, M.; Yamamoto,
Y.; M Ohtsuka, M.; Ogawa, S. Heterocycles 1996, 43, 1385-1390. (g)
Keck, G. E.; Wager, T. T.; McHardy, S. F. J . Org. Chem. 1998, 63,
9164-9165. (h) Akgun, H.; Hudlicky, T. Tetrahedron Lett. 1999, 40,
3081-3084. (i) Keck, G. E.; McHardy, S. F.; Murry, J . A. J . Org. Chem.
1999, 64, 4465-4476. (j) Acena, J . L.; Arjona, O.; Leon, M. L.; Plumet,
J . Org. Lett. 2000, 2, 3683-3686. (k) Hudlicky, T.; Rinner, U.; Gonzalez,
D.; Akgun, H.; Schilling, S.; Siengalewicz, P.; Martinot, T. A.; Pettit,
G. R. J . Org. Chem. 2002, 67, 8726-8743. (l) Rinner, U.; Siengalewicz,
P.; Hudlicky, T. Org. Lett. 2002, 4, 115-117. (m) Phung, A. N.;
Zannetti, M. T.; Whited, G.; Fessner, W. D. Angew. Chem., Int. Ed.
2003, 42, 4821-4824.
ortho directing group, obviously a tertiary amide, which
proved reluctant to further transformations.18
An alternate synthetic route would be the formation
of the C ring from a suitable precursor in which the 10a-
10b bond of the target would already be present. In this
context, the use of benzylic anions would provide a good
solution for the connection between the A ring and the
chiral residue needed for the C ring construction. Here
again, the use of a tertiary amide would be suitable for
the formation of the benzylic anion, but the above-
mentioned problems related to further transformations
of the tertiary amide group also need to be solved
efficiently.
Here, we describe the details of our investigations of
this second strategy.15 This led to a viable route to
narciclasine derivatives suitable for biological evaluation.
En route to the natural compounds, we also prepared the
lactone analogues of narciclasine, lycoricidine, and their
4-epi derivatives for biological evaluation as antitumor
agents.
Resu lts
Our model compound for the A-ring was the penta-
substituted orthotoluamide 4 prepared according to a
standard procedure.15,19 The chiral part of the future
C-ring was taken from the chiral pool, and D-gulonolac-
tone was easily recognized as a suitable starting mater-
ial14d,g because all of the chiral centers, with the correct
configuration, are present in 5.
Condensation of the lithium anion derived from 4 (s-
BuLi, -78 °C) with 5 gave the expected lactol in 70%
yield as a mixture of anomers 6 (Scheme 1). The extra
carbon of the sugar residue was then excised by selective
hydrolysis of one acetal ring followed by Malaprade
(15) Khaldi, M.; Chre´tien, F.; Chapleur, Y. Tetrahedron Lett. 1995,
36, 3003-3006.
(16) Grubb, L. M.; Dowdy, A. L.; Blanchette, H. S.; Friestad, G. K.;
Branchaud, B. P. Tetrahedron Lett. 1999, 40, 2691-2694.
(17) Chapleur, Y.; Chre´tien, F.; Khaldi, M. Recent Developments in
the Enantiospecific Synthesis of Amaryllidacae Alkaloids In Antibiotics
and Antiviral Compounds; Krohn, K., Kirst, E., Maas, H., Eds.; Verlag
Chemie: Weinheim, 1993; pp 380-388.
(18) Park, T. K.; Danishefsky, S. J . Tetrahedron Lett. 1995, 36, 195-
196.
(19) Khaldi, M.; Chre´tien, F.; Chapleur, Y. Tetrahedron Lett. 1994,
35, 401-404.
J . Org. Chem, Vol. 69, No. 20, 2004 6723

Ibn-Ahmed et al.
SCHEME 2a
a
Reagents and conditions: (a) NaBH4, CeCl3, EtOH, rt; (b) Tf2O, pyridine, -30 °C then NaN3, DMF.
SCHEME 3a
a
Postulated mechanism for the formation of lactones 13 and 14.
cleavage of the resulting diol 7 to provide the correspond-
ing aldehyde. This crude aldehyde was then involved in
the Knoevenagel-type cyclization. Extensive experimen-
tation led to efficient conditions (Na2CO3, DBU cat., THF)
for this cyclization, giving a mixture of the aldol com-
pound 8 (mixture of epimers) and cyclohexenone 9 in 70%
yield. The purified mixture of 8 and 9 can be treated with
acetic anhydride to give a single acetate 10. This com-
the intermediate iminium salt hydrolyzed to the corre-
sponding lactone on workup.21 This mechanism explained
well the formation of 14 with inversion of configuration
at C-4a. However, this pathway did not account for the
formation of 13. A more likely mechanism accounting for
the formation of both 13 and 14 would take into account
the presence of the allylic acetate in the intermediate
triflate 15. Anchimeric assistance of the ester triggers
the expulsion of the triflate yielding the intermediate
dialkoxycarbenium ion 16 in equilibrium with the allylic
cation 17 (Scheme 3).
The latter can undergo nucleophilic attack of the hard
oxygen atom from both faces of the cycle to give 13 and
14. The synthetic route described here had the merit to
furnish an excellent solution to the problem of tertiary
amide transformation. An indirect proof supporting the
proposed mechanism could be obtained by the use of a
nonparticipating protecting group at O-2. Starting from
alcohol 9, several ethers were tested such as MOM,
MEM, and BOM. Bad results were observed in the
introduction of these groups in basic medium, but tet-
rahydropyran formation proceeded well yielding 18 in
90% yield as a diastereoisomeric mixture (Scheme 4).
Carbonyl reduction of 18 gave two alcohols 19 and 22.
The structure of these compounds was established after
THP removal to give 20 and 23, respectively. Formation
of triflate 24 from 22 proceeded uneventfully, but at-
tempts to substitute the triflate group with an azide
group gave the corresponding lactone in poor yield. At
low temperature in DMF, only formate 26 was formed
in good yield. These results confirmed two important
1
pound was actually a 1:2 mixture of atropoisomers in H
NMR due to a restricted rotation around the amide bond.
With compound 10 in hand, the reduction of the
carbonyl group was next examined using Luche’s condi-
tions.20 A mixture of two diastereoisomers 11 and 12 was
obtained in a 1:1 ratio (Scheme 2). Alcohol 11 seemed to
be an ideal substrate to study the introduction of the
nitrogen atom at C-4a in the proper configuration using
an SN2-type reaction. Attempts to introduce an azido
group using diphenylphosphoryl azide completely failed.
This could be attributed to a severe crowding of the
hydroxyl group preventing the initial formation of the
expected oxyphosphonium salt. The use of a less sterically
demanding activating group such as a triflate was
investigated. Treatment of 11 with triflic anhydride in a
CH2Cl2/pyridine mixture gave the corresponding triflate,
immediately engaged in an SN2 reaction with sodium
azide. A 1:1 mixture of epimeric lactones 13 and 14 in
equal amounts was isolated, and their structures were
easily established by spectroscopy. The formation of these
products should be explained by internal displacement
of the triflate by the oxygen of the amide carbonyl to form
(20) Gemal, A. L.; Luche, J . L. J . Am. Chem. Soc. 1981, 103, 5454-
5459.
(21) Chre´tien, F.; Chapleur, Y. J . Org. Chem. 1988, 53, 3615-3617.
6724 J . Org. Chem., Vol. 69, No. 20, 2004

Lactone Analogues of Narciclasine and Lycoricidine
SCHEME 4a
a
Reagents and conditions: (a) MeONa, MeOH, rt; (b) DHP, TsOH, rt; (c) NaBH4, CeCl3, EtOH, rt; (d) THF, Dowex H+ resin; (e) Ac2O,
pyridine, 70 °C; (f) Tf2O, CH2Cl2, pyridine, -30 °C; (g) from 22 Tf2O, DMF, -30 °C, 1 h then NaN3.
SCHEME 5a
a
Reagents and conditions: (a) NH2OMe, HCl, THF, reflux; (b) L-Selectride, THF, -30 °C.
points: the prominent role of the acetate group in 13 and
the easy transformation of the unreactive tertiary amide
function into a lactone. Furthermore, the steric hindrance
around the C-4a atom, which impedes the approach of
external nucleophiles on this position, was also con-
firmed. This led to the conclusion that internal nucleo-
philic displacement would be an acceptable solution to
this issue.
The introduction of the nitrogen function using the
carbonyl group of the enone was next considered as an
alternative, presumably nonstereoselective, route. Many
attempts to prepare benzylimine from ketone 10 gave
untractable mixtures. A more rewarding reaction was
treatment of 10 with O-methylhydroxylamine hydrochlo-
ride, which did not provide the expected oxime but the
two isocoumarins 27 and 28 upon heating (Scheme 5).
This result opened a second way to an intramolecular
chemical manipulation of the tertiary amide group.
Moreover, it gave the possibility of achieving our goal by
providing a way for the completion of the aminocyclitol
synthesis. J udicious choice of the starting sugar is
necessary to provide the correct configuration involved
of the pancratistatin C ring.
All of the above results clearly showed that an excellent
solution to the unavoidable chemical transformation of
the tertiary amide group could be based on an intramo-
lecular reaction. It was clear that nucleophilic attack by
the oxygen atom led to an iminium species which was
easily hydrolyzed to the lactone. Another way to achieve
this goal should be the trapping of an enolate intermedi-
ate by the amide group, which would afford an isocou-
marin. On this basis, reduction of the enone system of
10 with L-Selectride was carried out giving the isocou-
Introduction of an azido group at C-4a of alcohols 19
and 22 using Murahashi’s method was investigated.22
Acetylation of 19 and 22 with acetic anhydride in
pyridine at 70 °C in the presence of DMAP gave the
corresponding acetates 21 and 25, respectively. Treat-
ment of either 21 or 25 with sodium azide in a water-
THF mixture in the presence of Pd(dba)2-CHCl3 complex
and bis[2(diphenylphosphino)ethyl]phenylphosphine failed
to give any product. Again, the severe crowding of the
4a position whatever the absolute configuration was used
to explain these failures. A further confirmation was also
given by the rather drastic conditions needed to introduce
the acetyl groups.
(22) Murahashi, S. I.; Tanigushi, Y.; Imada, Y.; Tanigawa, Y. J . Org.
Chem. 1989, 54, 3292-3303.
J . Org. Chem, Vol. 69, No. 20, 2004 6725

Ibn-Ahmed et al.
SCHEME 6a
SCHEME 7a
a
Reagents and conditions: (a) TFA, THF/H2O, reflux; (b)
MOMCl, iPr2NEt, CH2Cl2, rt; (c) NH3, MeOH, 0 °C then rt; (d)
NaBH3CN, HCO2H, CH3CN, reflux.
coupling constant between H-4 and H-4a of 6.5 Hz
indicating a cis arrangement of these protons in the
C-ring in a boat conformation.
The structure of compound 36 was also deduced from
its NMR spectrum which exhibited an allylic methylene
signal. Moreover, comparison with known derivatives
prepared by Krohn and Mondon from natural narci-
clasine supported our hypothesis.3a,b Finally, this com-
pound was expected from a 1,4-reduction of the inter-
mediate iminium 33 (path b). It is obvious that this
reduction is favored over the “normal” pathway leading
to 34 because of a possible steric hindrance in the hydride
approach (path a) which does not exist in path b.
The formation of the intriguing structure 38 can be
explained by the intramolecular addition of the hydroxyl
group at C-2 on the activated double bond in 33 (path c).
The formation of minute amounts of the isocoumarin 37
probably results from 1,4-reduction of the enone of 32 to
give the corresponding enolate, which undergoes facile
intramolecular lactonization.
From this first set of experiments it appeared that this
synthetic sequence is probably one of the shortest routes
to the benzophenantridinone skeleton described so far.
However, in the context of a narciclasine total synthesis,
this route suffered some drawbacks: the wrong stereo-
chemistry obtained in the reduction of the iminium ion
and the formation of byproducts. It was clear that 38
would no longer be formed using an OH-2-protected
derivative of 32. It could also be hypothesized that a more
favorable and stereoselective reduction should be carried
out on a less rigid cycle. This led us to examine a slightly
different route using methoxymethyl ethers as protecting
groups. Thus, compound 30 (major isomer) was treated
with trifluoroacetic acid in a water/THF mixture to
remove the acetate and the acetal group. The resulting
triol 39 was treated with a large excess of MOMCl in the
presence of diisopropylethylamine in dichloromethane
giving 40 in 70% yield. As for 30, treatment of 40 with
ammonia gave the primary amide 41. Finally, reductive
amination of the latter gave in this case only two
compounds in a 8/2 ratio, the isonarciclasine derivative
42 being the major one (Scheme 7).
a
Reagents and conditions: (a) PhSH, NEt3, THF, reflux; (b)
NH3, MeOH, 0 °C then rt; (c) NaBH3CN, HCO2H, CH3CN, reflux;
(d) Ac2O, pyridine, rt.
marin 29 in modest yield. A more efficient procedure for
isocoumarine was found by using a powerful nucleophile
such as thiophenol in the presence of triethylamine,
which cleanly added to the double bond of 10 to provide
the corresponding isocoumarin in 86% yield as a sepa-
rable 4:1 mixture of two epimers 30 and 31 (Scheme 6).
All attempts to prepare the tetraisoquinoline ring system
by treatment of isocoumarins 29, 30, and 31 with
benzylamine as described by Thompson and Kallmerten
failed.9f Upon treatment of 30 with ammonia in methanol
the amide 32 was formed. Thus, this two-step synthetic
sequence led formally to the hydrolysis of the amide
group and conversion to a primary amide group. Despite
its length, the efficiency of the sequence was sufficient
and allowed introduction of the amino group at C-4a.
Obviously, reductive animation of the keto group of 32
using the primary amide function as the amine donor
would afford a good solution. If the reductive amination
of ketones is well precedented, the reductive amination
of an enone is less documented and could be troublesome.
Indeed, it was, as shown by treatment of 32 with sodium
cyanoborohydride in acetonitrile in the presence of formic
acid. Under these conditions, a mixture of four products
was formed (8/10/2/1) which consisted of the 4a-epi-
narciclasine derivative 34 and the isonarciclasine deriva-
tive 36 as the main product. Two minor compounds 38
and 37 were also isolated from the mixture. The structure
of these compounds was established by 1H NMR and
mass spectrometry.
The epi-narciclasine derivative 34 was clearly a com-
pound resulting from the expected reductive amination.
Not unexpectedly, the reduction of the intermediate
iminium derivative (path a) 33 occurs from the less
hindered face placing the nitrogen cis to the isopropyl-
idene ring. The structure of 34 was deduced from the
From these results, it can be concluded that the
stereoselective introduction of the nitrogen atom at C-4a
6726 J . Org. Chem., Vol. 69, No. 20, 2004

Lactone Analogues of Narciclasine and Lycoricidine
SCHEME 8a
tricyclic system and the amide function at least are
required for biological activity.
Exp er im en ta l Section
1-Deoxy-1-[6-[(d ieth yla m in o)ca r bon yl]-7-m eth oxy-1,3-
ben zod ioxol-5-yl]-3,4:6,7-bis-O-(1-m eth yleth ylid en e)-â-D-
gu lo-2-h ep tu lofu r a n ose (6). A 1.1 M solution of s-BuLi in
cyclohexane (30 mL) was slowly added to a -78 °C cooled
solution of amide 4 (7 g, 26 mmol) in dry THF (400 mL). After
the dark solution was stirred for 30 min at this temperature,
a solution of lactone 5 (10 g, 38.7 mmol) was added. The
mixture was stirred for 1 h at -78 °C and quenched by
addition of a saturated aqueous ammonium chloride solution
(120 mL). The solvent was removed in vacuo, and the residue
was extracted with CH2Cl2 (3 × 250 mL). The organic phase
was washed with 3 N HCl solution (20 mL) and water until
neutral, dried over magnesium sulfate, and concentrated under
reduced pressure. The residue was purified by silica gel flash
chromatography with hexane/EtOAc (3:2) to give 14.2 g of 6
as a mixture of anomers in 70% yield: Rf 0.22 and 0.44
(hexane/EtOAc 3:2); mp 150-152 °C; IR νmax 3220, 1650, 1370,
a
Reagents and conditions: (a) MeONa, MeOH, rt; (b) AcOH,
1
1390 cm-1; H NMR δ 0.98 (t, 3H, J ) 7 Hz), 1.24 (t, 3H, J )
H2O 9/1, TFA, reflux.
7 Hz), 1.33 (s, 3H), 1.40 (s, 3H), 1.45 (s, 3H), 1.50 (s, 3H), 2.82
(d, 1H, J ) 14.5 Hz), 3.12 (m, 3H), 3.30 (d, 1H, J ) 14.5 Hz),
3.69 (m, 1H, J ) 8.5, 7.5 Hz), 3.98 (m, 4H), 4.11 (dd, 1H, J )
4.5, 8.5 Hz), 4.20 (dd, 1H, J ) 6.5, 8.5 Hz), 4.31, (m, 2H, J )
5.5 Hz), 4.71 (dd, 1H, J ) 5.5, 4.5 Hz), 5.90 (d, 1H, J ) 1.5
Hz), 5.96 (d, 2H, J ) 1.5 Hz), 6.90 (s, 1H); 13C NMR δ 12.4,
13.9, 25.0, 25.1, 26.2, 26.7, 36.4, 39.8, 42.7, 59.6, 60.0, 76.1,
80.6, 80.8, 83.9, 101.3, 104.9, 106.2, 109.6, 112.6, 123.0, 129.3,
138.9, 150.0, 169.3. Anal. Calcd for C26H27NO10: C, 59.66; H,
7.00; N, 2.68. Found: C, 59.86; H, 7.00; N, 2.78.
1-Deoxy-1-[6-[(d ieth yla m in o)ca r bon yl]-7-m eth oxy-1,3-
ben zod ioxol-5-yl]-3,4-O-(1-m eth yleth ylid en e)-â-D-gu lo-2-
h ep tu lofu r a n ose (7). To a stirred solution of hemiacetal 6
(10.14 g, 20 mmol) in THF (20 mL) was added an aqueous
solution of acetic acid 3:7 v/v (300 mL). This mixture was
heated at 60 °C. The reaction was monitored by TLC. After
complete disappearance of starting material, the solvents were
removed under vacuum, and the residue was codistilled several
times with toluene (10 mL each time) to remove water. The
residue was purified by column chromatography (hexane/
EtOAc 1:4) to give 7 as a mixture of anomers (7.69 g, 90%):
Rf 0.4 (EtOAc); mp 154-156 °C; [R]D +3.17 (c 1.8, CHCl3); IR
νmax 3334, 1650, 1173 cm-1; 1H NMR δ 1.29 (t, 3H, J ) 7 Hz),
1.37 (s, 3H), 1.40 (t, 3H, J ) 7 Hz), 1.55 (s, 3H), 2.45 (s, 1H),
2.67 (d, 1H, J ) 14.5 Hz), 3.32 (m, 4H), 3.98 (s, 3H), 4.10 (m,
2H), 4.35 (d, 1H, J ) 6 Hz), 4.85 (dd, 1H, J ) 4, 6 Hz), 5.95
(m, 3H), 6.80 (2s, 2H); 13C NMR δ 12.7, 14.0, 24.5, 26.0, 36.5,
39.8, 43.3, 60.1, 64.1, 70.8, 77.2, 81.4, 84.2, 101.5, 104.7, 104.9,
remains difficult. It is clear that the protecting groups
used here play an important role in the reductive
amination reaction. Changing the isopropylidene acetal
for the more bulky MOM group did affect dramatically
the course of the reaction.
The easy formation of the lactone ring system from the
tertiary amide led us to explore the synthesis of lactone
analogues of narciclasine and lycoricidine. In the narci-
clasine series, we started from compounds 11 or 12,
deacetylated in the usual way to afford the corresponding
alcohols 23 and 20 (Scheme 8). Attempts to cyclize these
compounds under basic conditions proved difficult. Fi-
nally, it was found that treatment under acidic conditions
led to the removal of the acetal protecting groups and
promoted lactone formation in satisfactory yields.
The same sequence was used for the synthesis of a
lycoricidine analogue starting from D-gulonolactone de-
rivative 5 and the orthotoluamide derivative 46.23 Lac-
tones 47 and 48 were thus obtained. The four lactones
were assayed as antitumor agents against L1210 cell
lines but none showed any significant biological activity.
Con clu sion
112.7, 123.0, 129.0, 134.6, 150.0, 169.4. Anal. Calcd for C23H33
NO10: C, 57.13; H, 6.88; N, 2.95. Found: C, 57.12; H, 6.86; N,
2.90.
-
In conclusion, we have developed a very short route to
the benzophenanthridinone skeleton of Amaryllidaceae
alkaloids using the o-toluamide anion condensation onto
gulonolactone. The synthetic route described also makes
use of a facile transformation of tertiary amide into
lactone, thus solving the problem associated with these
useful metalation-directing groups. This opens the way
to iso-narciclasine and many other analogues of narci-
clasine. Lactone analogues of narciclasine and lycorici-
dine and their epi derivatives have also been obtained
by this route, but no biological activities as antitumor
agents were found for these analogues. Since we have
shown before5 that seco analogues of Amaryllidaceae
alkaloids bearing the amide bond are not biologically
active, we can now draw the conclusion that both the
(3′a R,7′S,7′a R)-N,N-Diet h yl-3′a ,4′,7′,7′a -t et r a h yd r o-7′-
h yd r oxy-7-m eth oxy-2′,2′-d im eth yl-4′-oxo[5,5′-bi-1,3-ben -
zod ioxole]-6-ca r boxa m id e (9) a n d 2-Deoxy-2-[6-[(d ieth -
yla m in o)ca r bon yl]-7-m eth oxy-1,3-ben zod ioxol-5-yl]-5,6-
O-(1-m eth yleth ylid en e)-1-in osose (8). To a solution of diol
7 (465 mg, 1 mmol) in methanol (10 mL) was added, at room
temperature, sodium periodate (278 mg, 1.3 mmol). The
mixture was stirred for 1 h; after that time, no starting
material was present (TLC monitoring with EtOAc). Methanol
was removed in vacuo, and the residue was taken up in CH2-
Cl2 (100 mL). The organic phase was washed with water, dried,
and concentrated. The resulting aldehyde was dissolved in
anhydrous THF (20 mL). To this solution were added solid
sodium carbonate (252 mg, 3 mmol) and one or two drops of
DBU. The suspension turned red as the reaction proceeded.
After 6 h, aqueous 3 N HCl was cautiously added to neutrality.
The residue was extracted with diethyl ether (2 × 50 mL). The
organic phase was washed, dried, and concentrated in vacuo.
(23) Khaldi, M.; Chre´tien, F.; Chapleur, Y. Bull. Soc. Chim. Fr. 1996,
133, 7-13.
J . Org. Chem, Vol. 69, No. 20, 2004 6727

Ibn-Ahmed et al.
The residue was purified by column chromatography (hexane/
EtOAc 2:3) to afford 8 (81 mg, 18%) and 9 (303 mg, 70%).
Compound 8: Rf 0.38 (EtOAc); [R]D -29.1 (c 0.9 CHCl3); IR ν
2H), 3.98 (s, 2.H, 3H atropoisomer A), 4.00 (s, 1H, 3H
atropoisomer B), 4.19 (dd, 1H, J ) 2.5, 4.5 Hz), 4.23 (dd, 1H,
J ) 5.5, 7.5 Hz), 4.39 (dd, 1H, J ) 4.5, 7.5 Hz), 5.21 (dd, 1H,
J ) 2.5, 5.5 Hz), 5.30 (s, 1H), 5.48 (t, 1H, J ) 2.5 Hz), 5.98 (d,
1.3H, J ) 2 Hz, atropoisomer A), 6.00 (d, 0.7H, J ) 2 Hz,
atropoisomer B), 6.30 (s, 0.7H, atropoisomer A), 6.40 (s, 0.3H,
atropoisomer B); 13C NMR δ 12.5, 13.7, 21.2, 24.9, 27.2, 39.1,
43.2, 60.0, 72.1, 73.7, 75.9, 79.0, 101.5, 104.8, 110.5, 121.9,
125.0, 131.9, 135.6, 138.9, 144.4, 149.9, 168.8, 170.68. Anal.
Calcd for C24H31NO9: C, 60.37; H, 6.54; N, 2.93. Found: C,
60.01; H, 6.20; N, 2.88.
3400, 1740, 1600, 1380, 1390 cm-1; 1H NMR δ 0.80 (t, 3H,
max
J ) 7 Hz), 1.20 (t, 3H, J ) 7 Hz), 1.35 (s, 3H), 1.50 (s, 3H),
3.1-3.7 (m, 4H), 3.98 (s, 3H), 4.20 (m, 1H), 4.46 (d, 1H, J ) 6
Hz), 4.50 (t, 1H, J ) 6 Hz), 4.73 (m, 2H), 5.98 (d, 2H, J ) 1.5
Hz), 6.04 (s, 1H). Compound 8 was not further characterized
but transformed into 10. Standard acetylation (pyridine Ac2O)
and workup of the 9 and 8 mixture gave only acetate 10 in
92% yield. This compound was purified by column chroma-
tography (hexane/EtOAc, 1:4) and isolated as a 34/66 mixture
of atropoisomers A and B.
[3a R-(3a r,3b r,12â,12a r)]-3a ,3b,12,12a -Tetr a h yd r o-12-
a cetyloxy-6-m eth oxy-2,2-d im eth yl-2H-[1,3]ben zod ioxolo-
[5,6-c]-1,3-d ioxolo[4,5-h ][1]b en zop yr a n -5-on e (13) a n d
[3aR-(3ar,3bâ,12â,12ar)]-3a,3b,12,12a-Tetr ah ydr o-12acetyl-
oxy-6-m eth oxy-2,2-d im eth yl-2H-[1,3]ben zod ioxolo[5,6-c]-
1,3-d ioxolo[4,5-h ][1]ben zop yr a n -5-on e (14). To a solution
of allylic alcohol 11 or 12 (477 mg, 1 mmol) in anhydrous CH2-
Cl2 (10 mL) at -30 °C was added pyridine (0.6 mL) and then
triflic anhydride (0.4 mL). After being stirred for 30 min at
-30 °C, the solution was allowed to warm to room temperature
for 2 h. The mixture was poured into chilled sodium bicarbon-
ate solution. The compounds were extracted with dichlo-
romethane (2 × 50 mL). The organic phase was washed with
water, dried, and concentrated. High-pressure chromatography
allowed separation of 14 (109 mg, 27%) and 13 (110 mg, 27%).
Compound 13: Rf 0.38 (hexane/EtOAc, 2:3); [R]D + 3.69 (c 0.5,
Compound 9: Rf 0.51(EtOAc); mp 200 °C; [R]D -39.3 (c 1,-
CHCl3); IR νmax 3350, 1740, 1600, 1380, 1390 cm-1; 1H NMR δ
0.90 (t, 3H, J ) 7 Hz), 1.30 (t, 3H, J ) 7 Hz), 1.40 (s, 6H),
2.80-3.80 (m, 4H), 4.00 (s, 3H), 4.54 (m, 2H), 4.57 (dd, 1H, J
) 3, 4 Hz), 5.98 (s, 2H), 6.28 (s, 0.33H, atropoisomer A), 6.45
(s, 0.66H, atropoisomer B), 6.81 (d, 0.33H, J ) 3 Hz, atropo-
isomer A), 6.93 (d, 0.66H, J ) 3 Hz, atropoisomer B); 13C NMR
δ 12.5, 13.5, 25.6, 27.3, 38.6, 43.3, 59.9, 66.4, 75.4, 78.9, 101.5,
105.0, 110.2, 126.3, 128.3, 136.2, 137.6, 139.4, 145.0, 149.5,
166.9, 193.7; EIMS (m/z) 433 [M]+. Anal. Calcd for C22H33
-
NO8: C, 60.95; H, 6.28; N, 3.23. Found: C, 60.75; H, 6.17; N,
3.36.
(3′a R,7′S,7′a R)-N,N-Dieth yl-7′-(a cetyloxy)-3′a ,4′,7′,7′a -
t et r a h yd r o-7-m et h oxy-2′,2′-d im et h yl-4′-oxo[5,5′-b i-1,3-
ben zod ioxole]-6-ca r boxa m id e (10): Rf 0.48 (EtOAc); [R]D
1
CHCl3); mp 154 °C; IR νmax 1725, 1708, 1483, 1373 cm-1; H
1
+ 25.2 (c 1, CHCl3); IR νmax 1760, 1700, 1630, 1380 cm-1; H
NMR δ 1.28 (s, 3H), 1.39 (s, 3H), 2.05 (s, 3H), 4.10 (s, 3H),
4.53 (dd, 1H, J ) 1.5, 6.5 Hz), 4.95 (dd, 1H, J ) 3.5, 6.5 Hz),
5.33 (dd, 1H, J ) 6.5, 1.5 Hz), 5.38 (dd, 1H, J ) 3, 3.5 Hz),
6.04 (d, 2H, J ) 4 Hz), 6.55 (dd, 1H, J ) 3, 6.5 Hz), 6.92 (s,
1H); 13C NMR δ 20.8, 24.7, 26.1, 60.9, 67.8, 73.9, 74.5, 75.7,
79.4, 102.3, 110.2, 110.5, 118.0, 131.8, 133.1, 139.5, 145.5,
153.6, 159.1, 169.9. Anal. Calcd for C20H20O9: C, 59.40; H, 4.99.
Found: C, 59.61; H, 5.19. Compound 14: Rf 0.53 (hexane/
EtOAc, 2:3); [R]D +222.15 (c 0.72, CHCl3); mp 198 °C; IR νmax
NMR δ 0.98 (t, 3H, J ) 7 Hz), 1.10 (t, 3H, J ) 7 Hz), 1.15 (s,
3H), 1.20 (s, 3H), 2.10 (s, 0.99, atropoisomer A), 2.18 (s, 2.1H,
atropoisomer B), 2.95, 3.15, 3.25, 3.40, 3.75 (m, 4H), 3.98 (s,
0.99H, atropoisomer A), 4.00 (s, 2.1H, atropoisomer B), 4.60
(m, 2H), 5.63 (m, 1H, J ) 3.5 Hz), 5.98 (s, 2H), 6.31 (s, 0.34H,
atropoisomer A), 6.48 (s, 0.66H, atropoisomer B), 6.68 (d,
0.66H, J ) 3 Hz, atropoisomer B), 6.83 (d, 0.34H, J ) 3 Hz,
atropoisomer B); 13C NMR δ 12.5, 13.4, 20.6, 25.5, 26.9, 38.3,
42.9, 59.8, 68.8, 75.4, 76.4, 101.4, 104.8, 100.8, 122.8, 125.3,
127.1, 137.5, 139.3, 142.4, 148.8, 166.1 169.8. Anal. Calcd for
1
1715, 1709, 1472, 1374 cm-1; H NMR δ 1.45 (s, 3H), 1.53 (s,
3H), 2.18 (s, 3H), 4.10 (s, 3H), 4.30 (dd, 1H, J ) 6, 7 Hz), 4.62
(dd, 1H, J ) 3.5, 7 Hz), 5.03 (t, 1H, J ) 2 Hz), 5.50 (dt, 1H, J
) 2.5, 2 Hz), 6.04 (d, 1H, J ) 1 Hz), 6.08 (d, 1H, J ) 1 Hz),
6.12 (dd, 1H, J ) 2.5, 2.5 Hz), 6.75 (s, 1H); 13C NMR δ 21.1,
25.6, 27.4, 60.7, 71.96, 73.9, 75.5, 76,5, 98.2, 102.3, 109.5, 110.2,
123.0, 129.9, 123.9, 138.7, 145.3, 153.8, 160.0, 170.5. Anal.
Calcd for C20H20O9: C, 59.40; H, 4.99. Found: C, 59.03; H,
4.75.
C
24H29NO9: C, 60.61; H, 6.15; N, 2.95. Found: C, 60.32; H,
6.08; N, 2.71.
(3′a R,4′S,7′S,7′a R)-N,N-Dieth yl-3′a ,4′,7′,7′a -tetr a h yd r o-
,7′-a cetyloxy-4′h yd r oxy-7-m eth oxy-2′,2′-d im eth yl[5,5′-bi-
1,3-ben zod ioxole]-6-ca r boxa m id e (11) a n d (3′a R,4′R,7′S,7′
a R)-N,N-Dieth yl-3′a ,4′,7′,7′a -tetr a h yd r o-,7′-a cetyoxy-4′h y-
d r oxy-7-m eth oxy-2′,2′-d im eth yl[5,5′-bi-1,3-ben zod ioxole]-
6-ca r boxa m id e (12). To a solution of enone 10 (1 g, 2.1 mmol)
in ethanol (6 mL) at 0 °C were added solid cerium chloride
hydrate (823 mg, 2.1 mmol) and sodium borohydride (50 mg,
2.1 mmol). After the mixture was stirred for 15 min, a few
drops of 3 N hydrochloric acid were added. Ethanol was
removed in vacuo, and the residue was taken up in 100 mL of
CH2Cl2. The organic phase was washed with water until
neutral, dried, and concentrated under vacuum. The two
isomers were separated by high-pressure column chromatog-
raphy (hexane/EtOAc, 3:2) to give 11 (350 mg, 35%) and 12
(561 mg, 56%). Compound 11: Rf 0.52 (EtOAc); [R]D +106.5 (c
(3′a R,7′S,7′a R)-N,N-Dieth yl-7′-tetr a h yd r op yr a n yloxy-
3′a ,4′,7′,7′a -t et r a h yd r o-7-m et h oxy-2′,2′-d im et h yl-4′-oxo-
[5,5′-bi-1,3-ben zod ioxole]-6-ca r boxa m id e (18). The start-
ing compound could be alcohol 9, but it was more useful to
start from acetate 10 resulting from the cyclization-acetyla-
tion sequence of 7. The acetate group of 10 was removed by
conventional treatment with sodium methoxide in methanol.
To a solution of 9 (1 g, 2.5 mmol) in dry CH2Cl2 (60 mL) were
added dry dihydropyran (0.75 mL, 7.5 mmol) and PTSA (50
mg). The mixture was stirred for 4 h at room temperature and
then diluted with CH2Cl2 (100 mL). Saturated aqueous sodium
bicarbonate (5 mL) was added. The organic phase was washed
with water, saturated ammonium chloride solution (10 mL),
and water and dried. The residue was purified by column
chromatography (hexane/EtOAc, 3:2) to provide 18 (1.1 g,
90%). This compound was a mixture of diastereoisomers, each
isomer being present as a mixture of atropoisomers. Compound
1
0.8, CHCl3); IR νmax 3419, 1737, 1609, 1471, 1373; H NMR δ
1.02 (t, 3H, J ) 7 Hz), 1.21 (t, 3H, J ) 7 Hz), 1.35 (s, 3H), 1.48
(s, 3H), 2.00 (s, 3H), 3.10, 3.40, 3.60 (m, 4H), 3.98 (s, 0.99,
atropoisomer A), 4.00 (s, 2.1H, atropoisomer B), 4.44 (dd, 1H,
J ) 2, 7 Hz), 4.56 (dd, 1H, J ) 1.5, 3.5 Hz), 4.77 (dd, 1H, J )
7, 3.5 Hz), 5.05 (s, 1H), 5.19 (dd, 1H, J ) 1.5, 6 Hz), 5.89 (dd,
1H), 5.94 (d, 1H, J ) 2 Hz), 5.98 (d, 1H, J ) 2 Hz), 6.40 (s,
1H); 13C NMR δ 12.7, 13.5, 20.8, 24.4, 25.4, 39.3, 43.2, 59.9,
67.5, 68.5, 76.1, 77.2, 101.4, 104.9, 109.5, 120.9, 123.2, 131.4,
18: Rf 0.45 (hexane/EtOAc, 2:3); IR νmax 1760, 1630, 1380 cm-1
;
1H NMR δ 1.02 (t, 3H, J ) 7 Hz), 1.14 (t, 3H, J ) 7 Hz), 1.42-
1.78 (m, 14H), 2.95-3.91 (m, 4H), 3.98 (s, 3H), 4.00 (s, 3H),
4.55-4.64 (m, 3H), 4.86 (m, 1H), 5.01 (m, 1H), 5.96 (s, 2H),
6.30, 6.32, 6.42, 6.49 (4s, 1H), 6.83, 6.95, 7.02 (3d, 1H, J ) 3
Hz).
135.5, 138.7, 149.3, 149.7, 168.7, 169.8. Anal. Calcd for C24H31
-
NO9: C, 60.37; H, 6.54; N, 2.93. Found: C, 60.09; H, 6.32; N,
2.78. Compound 12: Rf 0.73 (EtOAc); [R]D +15.0 (c 1.1, CHCl3);
IR νmax 3450, 1750, 1630, 1380 cm-1; 1H NMR δ 1.05 (t, 3H, J
) 7 Hz), 1.10 (t, 3H, J ) 7 Hz), 1.40 (s, 3H), 1.50 (s, 3H), 2.10
(s, 3H), 3.05 (q, 2H, J ) 7 Hz), 3.20 (q, 2H), 3.50-3.60 (m,
(3′aR,4′R,7′S,7′aR)-N,N-Dieth yl-7′-a cetyloxy-3′a ,4′,7′,7′a -
t et r a h yd r o-7-m et h oxy-2′,2′-d im et h yl-4′-h yd r oxy[5,5′-b i-
1,3-ben zod ioxole]-6-ca r boxa m id e (20) a n d (3′a R,4′S,7′S,7′
6728 J . Org. Chem., Vol. 69, No. 20, 2004

Lactone Analogues of Narciclasine and Lycoricidine
a R)-N,N-Diet h yl-7′-a cet yloxy-3′a ,4′,7′,7′a -t et r a h yd r o-7-
m eth oxy-2′,2′-d im eth yl-4′-h yd r oxy[5,5′-bi-1,3-ben zod iox-
ole]-6-ca r boxa m id e (23). The mixture 18 was directly pro-
cessed to enone reduction using the procedure already described
for the preparation of 11 and 12. Two compounds 19 and 22
were obtained in a 2/1 ratio. Here again, mixtures of isomers
and atropoisomers were obtained. To ascertain the configu-
ration at C4a, the THP group was removed according to the
following procedure: to a solution of 19 or 22 (26 mg, 0.05
mmol) in anhydrous THF (5 mL) was added Dowex-H+ resin
(30 mg). This suspension was gently stirred at room temper-
ature for 4 h. The resin was then filtered off, and the resulting
solution was concentrated to give 20 or 23 (20 mg, 90%). It
should be noted that the same compounds can be obtained from
deacetylation of 11 and 12 by NH3g in MeOH. Compound 20:
[3a R-(3a r,11â,12r,12a r)]-12-(Acet yloxy)-3a ,11,12,12a -
tetr a h ydr o-6-m eth oxy-2,2-dim eth yl-11-(O-m eth ylh yd r ox-
yla m in o)-5H-[1,3]ben zod ioxolo[5,6-c]-1,3-d ioxolo[4,5-h ]-
[1]ben zop yr a n -5-on e (27) a n d [3a R-(3a r,11r,12r,12a r)]-
12-(Acet yloxy)-3a ,11,12,12a -t et r a h yd r o-6-m et h oxy-2,2-
d im et h yl-11-(O-m et h ylh yd r oxyla m in o)-5H -[1,3]b en zo-
d ioxolo[5,6-c]-1,3-d ioxolo[4,5-h ][1]ben zop yr a n -5-on e (28).
To a solution of enone 10 (105 mg, 0.22 mmol) in THF (5 mL)
was added O-methylhydroxylamine hydrochloride (22 mg, 1.2
mmol). The reaction was stirred for 24 h at room temperature.
NMR monitoring of the reaction indicated an incomplete
reaction. The same amount of O-methylhydroxylamine was
added and the mixture heated at reflux for further 15 h. After
cooling, water (10 mL) was added and the mixture extracted
with CH2Cl2 (3 × 10 mL). The organic phase was dried over
sodium sulfate and concentrated in vacuo. Hydroxylamines
were separated by column chromatography (hexane/EtOAc,
2:3) giving 27 (15 mg, 15%) and 28 (20 mg, 20%). Compound
27: Rf 0.43 (hexane/EtOAc, 2:3); 1H NMR δ 1.46 (s, 3H), 1.55
(s, 3H), 2.25 (s, 3H), 3.70 (s, 3H), 4.08 (m, 1H), 4.13 (s,3H),
4.70 (dd, 1H, J ) 8.5, 6.5 Hz), 5.09 (d, 1H, J ) 6.5 Hz), 5.99
(d, 1H, J ) 6 Hz), 6.12 (d, 2H, J ) 2 Hz), 7.05 (s, 1H), 7.65 (s,
1
Rf 0.24 (EtOAc); [R]D -16.3 (c 0.7, CHCl3); H NMR δ 1.05 (t,
3H, J ) 7 Hz), 1.19 (m, 5H), 1.36 (s, 3H), 1.45 (s, 3H), 3.13-
3.62 (m, 4H), 3.99 (s, 3H), 4.15-4.30 (m, 4H), 4.50 (dd, 1H, J
) 7.5, 3 Hz), 4.64 (dd, 1H, J ) 7.5, 3 Hz), 5.85-5.95 (m, 3H),
6.38 (s, 1H); 13C NMR δ 12.6, 13.6, 24.4, 26.7, 39.1, 43.4, 59.9,
66.2, 69.8, 77.7, 79.0, 101.4, 104.5, 109.6, 121.8, 130.3, 133.9,
134.9, 138.8, 143.8, 149.7, 168.7. Anal. Calcd for C22H22NO8:
C, 60.65; H, 6.71; N, 3.22. Found: C, 60.81; H, 6.55; N, 3.09.
1
1H). Compound 28: Rf 0.73 (hexane/EtOAc, 3:2); H NMR δ
1.38 (s, 3H), 1.41 (s, 3H), 2.05 (s, 3H), 3.70 (s, 3H), 4.01 (s,
3H), 4.37 (dd, 1H, J ) 11, 2 Hz), 4.84 (ddd, 1H, J ) 3, 5.5, 1.5
Hz), 4.93 (d, 1H, J ) 5.5 Hz,), 6.03 (dd, 1H, J ) 2, 3 Hz), 6.13
(d, 2H, J ) 1.5 Hz), 6.16 (dd, 1H, J ) 1.5, 11 Hz), 7.20 (s, 1H),
7.65 (s, 1H).
1
Compound 23: Rf 0.40 (EtOAc); [R]D 23.5 (c 0.5, CHCl3); H
NMR δ 1.07 (t, 3H, J ) 7 Hz), 1.16 (t, 3H, J ) 7 Hz), 1.36, 146
(2s, 4.5H, atropoisomer A), 1.37, 1.51 (2s, 1.5H, atropoisomer
B), 3.15-3.30 (m, 3H), 3.66 (m, 3H), 3.96 (s, 3H), 4.27-4.35
(m, 2H), 4.45 (m, 1H), 4.57 (m, 1H), 5.85-5.94 (m, 3H), 6.45
(s, 0.75H, atropoisomer A), 6.47 (s, 0.25H, atropoisomer B);
13C NMR δ 12.4, 12.4, 24.3, 26.4, 38.8, 43.1, 59.9, 68.2, 69.2,
76.2, 79.2, 101.3, 104.0, 109.9, 121.6, 131.9, 133.9, 135.4, 138.9,
142.8, 149.4, 168.2. Anal. Calcd for C22H22NO8: C, 60.65; H,
6.71; N, 3.22. Found: C, 60.55; H, 6.76; N, 3.14.
[3aR-(3ar,12r,12ar)]-3a,11,12,12a-Tetr ah ydr o-12-acetyl-
oxy-6-m eth oxy-2,2-d im eth yl-5H-[1,3]ben zod ioxolo[5,6-c]-
1,3-d ioxolo[4,5-h ][1]ben zop yr a n -5-on e (29). To a solution
of enone 10 (238 mg, 0.5 mmol) in dry THF (5 mL) at -30 °C
was added L-Selectride (0.9 mL, 1.5 mmol). The mixture was
stirred for 15 min at this temperature. A few drops of 3 N HCl
were added and the products extracted with diethyl ether (3
× 15 mL). The organic phase was washed with water until
neutral, dried, and concentrated in vacuo. Compound 29 was
purified by column chromatography (36 mg, 18%): Rf 0.78
(EtOAc); [R]D +1.87 (c 1.7, CHCl3); 1H NMR δ 1.20 (s, 3H),
1.24 (s, 3H), 2.10 (s, 3H), 2.58 (dd, 1H, J ) 16.5, 6 Hz), 2.98
(dd, 1H, J ) 4.5, 16.5 Hz), 4.14 (s, 3H), 4.41 (dd, 1H, J ) 6.5,
6 Hz), 4.94 (d, 1H, J ) 6 Hz), 5.33 (ddd, 1H, J ) 6.5, 6, 4.5
Hz), 6.10 (s, 2H), 6.60 (s, 1H).
(3′a R,4′R,7′S,7′a R)-N,N-Dieth yl-7′-(tetr a h yd r op yr a n -2-
yloxy)-3′a ,4′,7′,7′a -t et r a h yd r o-7-m et h oxy-2′,2′-d im et h yl-
4′-a cetyloxy[5,5′-bi-1,3-ben zod ioxole]-6-ca r boxa m id e (21)
a n d (3′a R,4′S,7′S,7′a R)-N,N-Dieth yl-7′-(tetr a h yd r op yr a n -
2-yloxy)-3′a ,4′,7′,7′a -tetr a h yd r o-7-m eth oxy-2′,2′-d im eth yl-
4′-acetyloxy[5,5′-bi-1,3-ben zodioxole]-6-car boxam ide (25).
Standard acetylation of 19 or 22 using acetic anhydride in
pyridine gave 21 and 25, respectively, in 85% yield. For the
above-described reasons, these mixtures of isomers were not
fully characterized but used as such. Compound 21: Rf 0.70
(hexane/EtOAc, 3:2); IR νmax 1740, 1600, 1375 cm-1; 1H NMR
δ 1.00-1.2 (m, 6H), 1.38-1.90 (m, 14H), 2.10 (m, 3H), 2.90-
3.40 (m, 2H), 3.50-3.75 (m, 2H), 3.98-4.00 (3s, 3H), 4.30 (m,
1H), 4.45 (m, 1H), 6.65 (m, 1H), 4.80 (s, 0.5H, atropoisomer
A), 5.0 (s, 0.5H, atropoisomer B), 5.78 (m, 1H), 5.98 (m, 2H),
6.10 (m, 0.5H, atropoisomer A), 6.35 (m, 0.5H, atropoisomer
B), 6.50 (m, 1H). Compound 25: Rf 0.62 (hexane/EtOAc, 3:2);
IR νmax 1745, 1605, 1380 cm-1; 1H NMR δ 1.05-1.20 (m, 6H),
1.38-1.70 (m, 14H), 1.90 (2s, 1.2H, atropoisomer A), 2.05 (2s,
1.8H, atropoisomer B), 3.10 (m, 2H), 3.50, (m, 2H), 3.98-4.00
(m, 3H), 4.15 (m, 1H), 4.35 (m, 1H), 4.80 (m, 0.4H, atropoiso-
mer A), 5.0 (m, 0.6H, atropoisomer B), 5.53 (m, 1H), 5.8 (s,
1H), 5.95 (m, 2H), 6.05 (m, 0.4H, atropoisomer A), 6.15 (m,
0.6H, atropoisomer B), 6.45 (m, 1H).
[3a R-(3a r,11â,12r,12a r)]-12-(Acet yloxy)-3a ,11,12,12a -
tetr a h yd r o-6-m eth oxy-2,2-d im eth yl-11-(p h en ylth io)-5H-
[1,3]ben zod ioxolo[5,6-c]-1,3-d ioxolo[4,5-h ][1]ben zop yr a n -
5-on e (30) a n d [3a R-(3a r,11r,12r,12a r)]-12-(Acetyloxy)-
3a ,11,12,12a -t e t r a h y d r o-6-m e t h o x y-2,2-d im e t h y l-11-
(p h en ylth io)-5H-[1,3]ben zod ioxolo[5,6-c]-1,3-d ioxolo[4,5-
h ][1]ben zop yr a n -5-on e (31). To a solution of enone 10 (1.1
g, 2.3 mmol) in anhydrous THF (40 mL) were added thiophenol
(2.7 mL, 26 mmol) and triethylamine (1 mL, 11 mmol). The
mixture was then refluxed for 15 h. Removal of the solvents
in vacuo followed by three codistillations with toluene (15 mL)
gave the final residue purified over a silica gel column (hexane/
EtOAc, 2:3). Compounds 30 (825 mg, 70%) and 31 (188 mg,
16%) were isolated. Compound 30: Rf 0.68 (hexane/EtOAc, 2:3);
mp 205-208 °C; [R]D +118.1 (c 0.5, CHCl3); IR νmax 1730, 1720,
1
1483 cm-1; H NMR δ 1.40 (s, 3H), 1.50 (s, 3H), 1.65 (s, 3H),
(3′a R,4′R,7′S,7′a R)-N,N-Dieth yl-7′-(tetr a h yd r op yr a n -2-
yloxy)-3′a ,4′,7′,7′a -t et r a h yd r o-7-m et h oxy-2′,2′-d im et h yl-
4′-for m yloxy[5,5′-bi-1,3-ben zodioxole]-6-car boxam ide (26).
Due to the presence of two diastereoisomers (THP) and
atropoisomers, this compound was difficult to characterize
completely, especially the 13C NMR spectra: Rf 0.51 (hexane/
4.15 (s, 3H), 4.75 (d, 1H, J ) 4 Hz), 4.90 (m, 2H), 5.14 (dd,
1H, J ) 8.5, 4 Hz), 6.11 (d, 2H, J ) 10 Hz), 6.85 (s, 1H), 7.30
(m, 3H), 7.50 (m, 2H); 13C NMR δ 20.3, 25.5, 27.6, 44.5, 60.9,
61.9, 73.6, 73.8, 97.5, 102.5, 108.7, 109.9, 111.3, 145.4, 147.3,
154.8, 156.8, 170.9. Anal. Calcd for C26H24O9S: C, 60.93; H,
4.72; S, 6.25. Found: C, 60.77; H, 4.98; S, 6.17. Compound
31: Rf 0.58 (hexane/EtOAc, 2:3); [R]D -138.3 (c 0.9, CHCl3);
IR νmax 1725, 1600, 1610, 1480, 1390 cm-1; 1H NMR δ 1.41 (s,
3H), 1.51 (s, 3H), 2.00 (s, 3H), 4.05 (s, 3H), 4.25 (d, 1H, J )
2.5 Hz), 4.59 (dd, 1H, J ) 3, 6.5 Hz), 4.98 (d, 1H, J ) 6.5 Hz),
5.83 (dd, 1H, J ) 2.5, 3 Hz), 6.01 (AB, 2H, J ) 9 Hz), 6.34 (s,
1H), 7.30 (m, 3H), 7.50 (d, 2H, J ) 8 Hz); 13C NMR δ 20.9,
25.3, 27.3, 45.2, 60.9, 70.9, 71.6, 74.5, 76.5, 98.1, 102.3, 108.9,
1
EtOAc, 3:2); IR νmax 1772, 1605, 1380 cm-1; H NMR δ 1.10-
1.14 (m, 6H), 1.35-1.45 (m, 14H), 3.10 (m, 2H), 3.50 (m, 2H),
3.98 (s, 3H), 4.00 (s, 3H), 4.25-4.64 (m, 3H), 4.75 (m, 0.5H,
atropoisomer.A), 4.95 (s, 0.5H, atropoisomer B), 5.7 (s, 0.5H,
atropoisomer A), 5.8 (m, 0.5H, 1H), 5.96 (2s, 1H), 6.0 (2s, 1H),
6.05, 6.10 (2d, 0.5H, J ) 3 Hz, atropoisomer A), 6.25, 6.30 (2d,
0.5H, J ) 3 Hz atropoisomer B), 6.40 (s, 0.5H, atropoisomer
A), 6.45, 6.48 (2s, 0.5H, atropoisomer B), 8.15 (m, 1H).
J . Org. Chem, Vol. 69, No. 20, 2004 6729

Ibn-Ahmed et al.
109.1, 111.5, 127.7, 129.4, 131.3, 134.3, 136.5, 137.7, 145.2,
147.2, 154.5, 157.5, 169.8. Anal. Calcd for C26H24O9S: C, 60.93;
H, 4.72; S, 6.25. Found: C, 60.81; H, 4.81; S, 6.22.
[1R-(1â,2r,3â,4â)]-6-Meth oxy-2,3,4-tr i(m eth oxym eth yl)-
1,2,3,4-tetr a h yd r o-1-(p h en ylth io)-2H-[1,3]ben zod ioxolo-
[5,6-c]-[1]ben zop yr a n -6-on e (40). Compound 30 (540 mg,
1.05 mmol) was suspended in a water/THF mixture (44 mL,
3:1 v/v), and then TFA (2.4 mL) was added. The reaction
mixture was refluxed for 2 h and then concentrated to dryness
and coevaporated three times with toluene. The crude residue
was dissolved in dichloromethane (30 mL), diisopropylamine
(2 mL) and MOMCl (2 mL) were added, and the resulting
mixture was refluxed for 2 h. After the mixture was cooled to
room temperature, dichloromethane (50 mL) was added, and
the solution was washed twice with water. The organic phase
was dried and concentrated. The crude residue was chromato-
graphed on a silica gel column to give pure 40 (413 mg, 70%):
Rf 0.13 (hexanes/EtOAc, 3:2); [R]D +115.1 (c 0.4, CHCl3); IR
(3′a R,7′S,7′a R)-3′a ,4′,7′,7′a -Tet r a h yd r o-7′-h yd r oxy-7-
m et h oxy-2′,2′-d im et h yl-4′-oxo[5,5′-b i-1,3-b en zod ioxole]-
6-ca r boxa m id e (32). A solution of lactone 30 (496 mg, 1
mmol) in methanol (20 mL) was cooled at 0 °C. A stream of
gaseous ammonia was bubbled through the solution until
saturated. The mixture was then allowed to warm to room
temperature for 4 h while a gentle stream of ammonia was
maintained. Excess of ammonia was cautiously removed under
vacuum, and the solvent was then removed. The rather
instable amide 32 (301 mg) was not fully characterized but
used as such in the next step: Rf 0.3 (EtOAc); IR νmax 3847,
1
1650 cm-1; H NMR δ 1.40 (s, 3H), 1.60 (s, 3H), 4.05 (s, 3H),
1
νmax 3848, 1600, 1614 cm-1; H NMR δ 3.46 (s, 6H), 3.47 (s,
4.29-4.31 (m, 2H), 4.84 (dd, 1H, J ) 2, 5 Hz), 6.05 (s, 2H), 6.4
(s, 1H), 6.50 (d, 1H, J ) 2 Hz), 6.88 (s, 1H), 7.30 (s, 1H), 7.50
(s, 1H).
3H), 4.12 (s, 3H), 4.57 (m, 1H), 4.65-4.95 (m, 8H), 5.51 (dd,
1H, J ) 4, 10 Hz), 6.08 (s, 2H), 6.82 (s, 1H), 7.24-7.54 (m,
5H). Anal. Calcd for C27H30O11S: C, 57.64; H, 5.37; S, 5.70.
Found: C, 57.92; H, 5.42; S, 5.55.
[3a S-(3a r,3b r,12r,12a r)]-12-H yd r oxy-3b ,4,12,12a -t et -
r ah ydr o-6-m eth oxy-2,2-dim eth ylbis[1,3]dioxolo[4,5-c:4′,5′-
j]p h en a n th r id in -5(3a H)-on e (34), [3a S-(3a r,12r,12a r)]-
4,11,12,12a -Te t r a h yd r o-12-h yd r oxy-6-m e t h oxy-2,2-d i-
m eth ylbis[1,3]d ioxolo[4,5-c:4′,5′-j]p h en a n th r id in -5(3a H)-
on e (36), [1aS-(1ar,1bâ,4aâ,11cr)]-1b,4a,5,11c-Tetr ah ydr o-
7-m e t h o x y -3,3-d im e t h y lb is [1,3]d io x o lo [4,5-c:4′,5′-j]-
oxir en o[a ]p h en a n t h r id in -6(1a H )-on e (38), a n d [3a R-
(3a r,12r,12a r)]-3a ,11,12,12a -Tet r a h yd r o-12-h yd r oxy-6-
m et h oxy-2,2-d im et h yl-5H -[1,3]b en zod ioxolo[5,6-c]-1,3-
d ioxolo[4,5-h ][1]ben zop yr a n -5-on e (37). To a solution of 32
(301 mg, 0.8 mmol) in dry acetonitrile (8 mL) were added
formic acid (3 mL) and sodium cyanoborohydride (100 mg, 1.6
mmol). The mixture was heated at reflux for 24 h. After cooling
3 N hydrochloric acid (4 mL) and CH2Cl2 (50 mL) were added.
The organic phase was washed with saturated sodium bicar-
bonate solution and water and dried. After concentration, the
residue was chromatographed on a silica gel column to give
34 (74 mg, 20% further charactrized as its acetate 35), 36 (92
mg, 25%), 38 (15 mg, 5%), and 37 (28 mg, 10%). Compound
36: IR νmax 3849, 3741, 3212, 2922, 2359, 2339, 1644, 1480,
4-Meth oxy-6-[(3R,4S,5R)(3,4,5-tr is-m eth oxom eth oxy-6-
oxocycloh ex-1-en yl)]b en zo[1,3]d ioxole-5-ca r b oxa m id e
(41). A solution of lactone 40 (160 mg, 0.28 mmol) in methanol
(12 mL) was cooled to 0 °C. A stream of gaseous ammonia was
bubbled through the solution until saturation occurred. The
mixture was then allowed to warm to room temperature for 4
h while a gentle stream of ammonia was maintained. Excess
ammonia was cautiously removed under vacuum, and the
solvent was then removed. The crude residue was chromato-
graphed on a silica gel column to give pure 41 (98 mg, 73%):
Rf 0.21 (EtOAc); [R]D -112 (c 0.6, CHCl3); IR νmax 3323, 1731,
1668, 1609 cm-1; 1H NMR δ 3.37 (s, 3H), 3.38 (s, 3H), 3.55 (s,
3H), 4.04 (s, 3H), 4.12 (d, 1H, J ) 2 Hz), 4.23 (m, 1H), 4.34
(dd,1H, J ) 5, 4 Hz), 4.71-4.90 (m, 6H), 5.97 (s, 1H), 5.99 (s,
1H),6.08 (s, 2H), 6.10 (d, 1H, J ) 5 Hz), 6.76 (s, 1H). Anal.
Calcd for C21H27O11N: C, 53.70; H, 5.75; N, 2.98. Found: C,
53.4; H, 5.82; N, 2.68.
[2S-(2r,3â,4â)]-7-Meth oxy-2,3,4-tr i(m eth oxym eth oxy)-
1,3,4,5-t et r a h yd r o-2H-[1,3]d ioxolo[4,5-j]p h en a n t h r id in -
6-on e (42) an d [2R-(2r,3â,4â)]-6-m eth oxy-2,3,4-tr i(m eth oxy-
m e t h yl)-1,2,3,4-t e t r a h yd r o-2H -[1,3]b e n zod ioxolo[5,6-
c][1]ben zop yr a n -6-on e (43). To a solution of 41 (90 mg, 0.2
mmol) in dry acetonitrile (9 mL) were added formic acid (1
mL) and sodium cyanoborohydride (25 mg, 0.4 mmol). The
mixture was heated at reflux for 12 h. After cooling, 3 N
hydrochloric acid (1 mL) and CH2Cl2 (25 mL) were added. The
organic phase was washed with saturated sodium bicarbonate
solution and water and dried. After concentration, the residue
was chromatographed on a silica gel column to give 42 (54
mg, 62%) and 43 (12 mg, 13%). Compound 42: Rf 0.48 (CH2-
Cl2/MeOH 18/1); [R]D +52.7 (c 0.15, CHCl3); IR νmax 2924, 1649
1434, 1383 cm-1 1H NMR δ 1.40 (s, 3H), 1.50 (s, 3H), 2.60
;
(dd, 1H, J ) 15.5, 7.5 Hz), 2.96 (dd, 1H, J ) 4.5, 15.5 Hz),
3.98 (s, 3H), 4.17 (m, 1H), 4.33 (dd, 1H, J ) 7, 6 Hz), 4.95 (d,
1H, J ) 6 Hz), 6.02 (m, 2H), 6.75 (s, 1H); CIMS (methane)
negative mode (m/z) 346 (60) [M - CH3]-, 360 (100) [M - H]-,
361 (54) [M + 1 - H]-. Compound 37: IR νmax 3404, 2922, 1650,
1481 cm-1; 1H NMR δ 1.35 (s, 3H), 1.45 (s, 3H), 2.68 (dd, 1H,
J ) 11, 6 Hz), 3.00 (dd, 1H, J ) 4.5, 11 Hz), 4.1 (s, 3H), 4.45
(dd, 1H, J ) 6, 6 Hz), 4.96 (d, 1H, J ) 6 Hz), 5.39 (m, 1H),
6.10 (m, 2H), 6.75 (s, 1H). Compound 38: mp 258-260 °C, [R]D
+22.8 (c 0.6, MeOH); IR νmax 3404, 1650, 1479 cm-1; 1H NMR
(CD3OD)δ 1.45 (s, 3H), 1.50 (s, 3H), 3.85 (dd, 1H, J ) 4,5, 10
Hz), 4.05 (s, 3H), 4.30 (dd, 1H, J ) 6.5 Hz), 5.05 (d, 1H, J )
6.5 Hz), 5.37 (d, 1H, J ) 4.5 Hz), 6.00 (s, 1H), 6.03 (d, 2H, J
) 4.5 Hz), 6.92 (s, 1H), 13C NMR δ 24.06, 24.38, 44.38, 59.30,
69.88, 71.20, 74.90, 96.16, 101.51, 109.28, 109.77, 131.22,
134.66, 136.68, 142.73, 153.10, 160, 171.47. Anal. Calcd for
1
cm-1; H NMR δ 2.66 (dd, 1H, J ) 11, 8 Hz), 3.04 (dd, 1H, J
) 5, 11 Hz), 3.38 (s, 3H), 3.41 (s, 3H), 3.50 (s, 3H), 4.09 (s,
3H), 4.12 (dd, 1H, J ) 3.5, 5 Hz), 4.29 (m, 1H), 4.96 (d, 1H, J
) 3.5 Hz), 4.73-4.99 (m, 6H), 6.05 (s, 2H), 6.70 (s, 1H), 8.88
(s, 1H). Anal. Calcd for C21H27O10N: C, 55.63; H, 6.00; N, 3.09;
Found: C, 55.30; H, 6.16; N, 2.88. Compound 43: Rf 0.43 (CH2-
Cl2/MeOH 18/1); IR νmax 3344, 1643 cm-1; 1H NMR δ 2.55 (dd,
1H, J ) 10, 5 Hz), 3.12 (dd, 1H, J ) 7, 10 Hz), 3.43 (s, 3H),
3.45 (s, 3H), 3.48 (s, 3H), 3.88 (dd, J ) 6.5, 3.5 Hz), 4.07 (s,
3H), 4.32 (m, 1H), 4.52 (d, 1H, J ) 3.5 Hz), 4.72-4.94 (m, 6H),
6.05 (s, 2H), 6.70 (s, 1H).
C
18H17NO7: C, 60.17; H, 4.77; N, 3.90. Found: C, 59.98; H,
4.62; N, 3.85.
[3a S-(3a r,3b r,12r,12a r)]-12-(Acet yloxy)-3b ,4,12,12a -
tetr a h yd r o-6-m eth oxy-2,2-d im eth ylbis[1,3]d ioxolo[4,5-c:
4′,5′-j]p h en a n th r id in -5(3a H)-on e (35). Compound 34 was
acetylated under standard conditions (AC2O, pyridine) to give
35: Rf 0.30 (MeOH/EtOAc, 1:9), [R]D +44.6 (c 1.37, CHCl3);
IR νmax 1722, 1651, 1485; 1H NMR δ 1.38 (s, 3H), 1.45 (s, 3H),
2.05 (s, 3H), 3.96 (s, 3H), 4.62 (dd, 1H, J ) 1, 6.5 Hz), 5.03
(dd, 1H, J ) 4.5, 1 Hz), 5.17, (d, 1H, J ) 6.5 Hz), 5.56 (dd, 1H,
J ) 9, 4.5 Hz), 6.00 (s, 1H), 6.05 (s, 1H), 6.62 (d, 1H, J ) 9
Hz), 6.65 (s, 1H); 13C NMR δ 22.9, 25.6, 27.7, 44.3, 61.3, 71.8,
72.3, 72.9, 79.5, 102.3, 109.8, 111.4, 113.8, 131.7, 135.1, 137.7,
143.0, 153.7, 170.8, 171.0. Anal. Calcd for C20H21NO8: C, 59.55;
H, 5.25; N, 3.47. Found: C, 59.40; H, 5.18; N, 3.52.
[6aS-(6ar,7â,8â,9r)]-6a,7,8,9-Tetr ah ydr o-4m eth oxy-7,8,9-
tr ih yd r oxy-5H-[1,3]ben zod ioxolo[5,6-c][1]ben zop yr a n -5-
on e (44) a n d [6a R-(6a r,7â,8â,9r)]-6a ,7,8,9-Tetr a h yd r o-4-
m e t h oxy-7,8,9-t r ih yd r oxy-5H -[1,3]b e n zod ioxolo[5,6-
c][1]ben zop yr a n -5-on e (45). To a solution of 23 or 20 (477
mg, 1 mmol) in 95% acetic acid (20 mL) was added trifluoro-
acetic acid (1 mL). The mixture was heated under reflux for 8
h and then concentrated. The residue was coevaporated three
times with methanol (15 mL). Pure compounds 44 (158 mg,
49%) or 45 (174 mg, 54%) were obtained after silica gel column
6730 J . Org. Chem., Vol. 69, No. 20, 2004

Lactone Analogues of Narciclasine and Lycoricidine
chromatography using MeOH/EtOAc, 1:9 as eluent. Compound
44: Rf 0.3 (MeOH/EtOAc 1:9); mp 136-138 °C; [R]D +15 (c
0.2, MeOH); IR νmax 3379, 2920, 1702, 1606, 1480, 1368, 1254,
1090 cm-1; 1H NMR (CD3OD) δ 3.51 (dd, 1H, J ) 1.5, 8.5 Hz)
3.95 (s, 3H), 4.23 (dd, 1H, J ) 3.5, 1.5 Hz), 4.45 (ddd, 1H, J )
2, 1, 8.5 Hz), 5.05 (m, 1H), 6.00 (d, 2H, J ) 10 Hz), 6.22 (dd,
1H, J ) 1.5, 2 Hz), 6.85 (s, 1H); 13C NMR (CD3OD) δ 60.9,
69.3, 70.7, 73.4, 76.9, 102.1, 102.2, 116.9; 125.4, 126.8, 132.5,
139.3, 148.5, 153.1, 164.6. Anal. Calcd for C15H14O8: C, 55.90;
H, 4.38. Found: C, 56.12; H, 4.34. Compound 45: Rf 0.3
(MeOH/EtOAc 1:9); mp 116-118 °C; [R]D +102.1 (c 0.5,
MeOH); IR νmax 3379, 2920, 1702, 1606, 1480, 1368, 1254, 1090
cm-1; 1H NMR (CD3OD) δ 3.85 (ddd, 1H, J ) 1, 2, 3.5 Hz) 3.98
(s, 3H), 4.12 (dd, 1H, J ) 7.5, 2 Hz), 4.24 (dd, 1H, J ) 4.5, 3.5
Hz), 4.86 (dd, 1H, J ) 1.5, 7.5 Hz), 6.03 (d, 2H, J ) 12 Hz),
6.29 (dt, 1H, J ) 1, 1.5, 4.5 Hz), 6.86 (s, 1H); 13C NMR (CD3-
OD) δ 60.4, 70.0, 70.5, 74.4, 79.2, 99.7, 103.8, 110.9, 126.2,
131.4, 136.1, 139.1, 146.8, 155.5, 165.0. Anal. Calcd for
102.1, 102.2, 108.1, 116.9, 125.4, 126.8, 132.5, 139.3, 148.5,
153.1, 164.6. Anal. Calcd for C14H12O7: C, 57.54; H, 4.14;
Found: C, 57.69; H, 4.08.
[6a R-(6a r,7â,8â,9r)]-6a ,7,8,9-Tet r a h yd r o-7,8,9-t r ih y-
d r oxy-5H -[1,3]b en zod ioxolo[5,6-c][1]b en zop yr a n -5-on e
(48): Rf 0.44 (MeOH/EtOAc 1:10); mp 148-150 °C; [R]D +77.3
(c 0.5, MeOH); IR νmax 3370, 2360, 1694, 1483, 1270, 1033 cm-1
;
1H NMR (CD3OD) δ 3.96 (ddd, 1H, J ) 1, 3, 2.6 Hz), 4.22 (dd,
1H, J ) 7.5, 2.6 Hz), 4.31 (dd, 1H, J ) 4.5, 3 Hz), 5.08 (dd,
1H, J ) 2, 7.5 Hz), 6.10 (d, 2H, J ) 2.5 Hz), 6.33 (dt, 1H, J )
1, 2, 4.59 Hz), 7.16 (s, 1H), 7.40 (s, 1H); 13C NMR (CD3OD) δ
69.5, 69.8, 73.9, 69.6, 103.2, 103.6, 109.1, 118.1; 125.2, 130.2,
134.1, 149.7, 154.1, 164.0. Anal. Calcd for C14H12O7: C, 57.54;
H, 4.14. Found: C, 57.68; H, 4.10.
Ack n ow led gm en t. We gratefully acknowledge Lab-
oratoires Servier (Suresnes, France) for biological test-
ing and the Centre National de la Recherche Scienti-
fique for financial support.
C
15H14O8: C, 55.90; H, 4.38. Found: C, 55.98; H, 4.68.
[6a S-(6a r,7â,8â,9r)]-6a ,7,8,9-Tet r a h yd r o-7,8,9-t r ih y-
d r oxy-5H -[1,3]b en zod ioxolo[5,6-c][1]b en zop yr a n -5-on e
(47): Rf 0.35 (MeOH/EtOAc 1:10); [R]D -54.9 (c 0.7, MeOH);
IR νmax 3368, 2921, 1704, 1613, 1121, 1038 cm-1; 1H NMR (CD3-
OD) δ 3.63 (dd, 1H, J ) 2, 8 Hz), 4.34 (dd, 1H, J ) 2, 3 Hz),
4.54 (ddd, 1H, J ) 2.5, 3, 8 Hz), 5.25 (ddd, 1H, J ) 2, 2, 3 Hz),
6.09 (d, 2H, J ) 1.5 Hz), 6.30 (dd, 1H, J ) 2.5, 2 Hz), 7.16 (s,
1H), 7.38 (s, 1H); 13C NMR (CD3OD) δ 60.3, 70.7, 73.4, 76.9,
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal methods. Copies of NMR spectra of compound 6-14, 18,
20-22, 25, 26, 29-31, 35, 38, 41, 42, 44, 45, 47, and 48. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O049153L
J . Org. Chem, Vol. 69, No. 20, 2004 6731