Synthesis of some members of the hydroxylated phenanthridone subclass of the Amaryllidaceae alkaloid family

Article abstract of DOI:10.1021/jo0626111

The total synthesis of several members of the hydroxylated phenanthridone subclass of the Amaryllidaceae alkaloid family has been carried out. (±)-Lycoricidine and (±)-7-deoxypancratistatin were assembled through a one-pot Stille/intramolecular Diels-Alder cycloaddition cascade to construct the core skeleton. The initially formed [4 + 2]-cycloadduct undergoes nitrogen-assisted ring opening followed by a deprotonation/reprotonation of the resulting zwitterion to give a rearranged hexahydroindolinone on further heating at 160 °C. The stereochemical outcome of the IMDAF cycloaddition has the side arm of the tethered vinyl group oriented exo with respect to the oxygen bridge. The resulting cycloadduct was used for the stereocontrolled installation of the remaining functionality present in the C-ring of the target molecules. Key features of the synthetic strategy include (1) a lithium hydroxide induced tandem hydrolysis/decarboxylation/elimination sequence to introduce the required π-bond in the C-ring of (±)-lycoricidine, and (2) conversion of the initially formed Diels-Alder adduct into an aldehyde intermediate which then undergoes a stereospecific decarbonylation reaction mediated by Wilkinson's catalyst to set the trans-B-C ring junction of (±)-7-deoxypancratistatin.

Full text of DOI:10.1021/jo0626111

Synthesis of Some Members of the Hydroxylated Phenanthridone
Subclass of the Amaryllidaceae Alkaloid Family
Albert Padwa* and Hongjun Zhang
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
chemap@emory.edu
ReceiVed December 19, 2006
The total synthesis of several members of the hydroxylated phenanthridone subclass of the Amaryllidaceae
alkaloid family has been carried out. (()-Lycoricidine and (()-7-deoxypancratistatin were assembled
through a one-pot Stille/intramolecular Diels-Alder cycloaddition cascade to construct the core skeleton.
The initially formed [4 + 2]-cycloadduct undergoes nitrogen-assisted ring opening followed by a
deprotonation/reprotonation of the resulting zwitterion to give a rearranged hexahydroindolinone on further
heating at 160 °C. The stereochemical outcome of the IMDAF cycloaddition has the side arm of the
tethered vinyl group oriented exo with respect to the oxygen bridge. The resulting cycloadduct was used
for the stereocontrolled installation of the remaining functionality present in the C-ring of the target
molecules. Key features of the synthetic strategy include (1) a lithium hydroxide induced tandem hydrolysis/
decarboxylation/elimination sequence to introduce the required π-bond in the C-ring of (()-lycoricidine,
and (2) conversion of the initially formed Diels-Alder adduct into an aldehyde intermediate which then
undergoes a stereospecific decarbonylation reaction mediated by Wilkinson’s catalyst to set the trans-
B-C ring junction of (()-7-deoxypancratistatin.
Introduction
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 (2), 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), siculinine (6)).7 The history of the
related hydroxylated phenanthridones of the Amaryllidaceae
group, their biological profiles, and various syntheses have been
reviewed on several occasions,8 most recently by Hudlicky and
Rinner in 2005.9 Lycoricidine (7),10 the structurally related
The Amaryllidaceae alkaloids constitute an important class
of naturally occurring compounds.1 The lycorine-type alkaloids,
which are characterized by the presence of the galanthan ring
system (1), represent a significant subclass within the Amaryl-
lidaceae family.2 This group of compounds has attracted the
attention of synthetic chemists due to the interesting biological
properties of some of its members (Figure 1).3 Several of these
alkaloids possess antineoplastic and antimicotic activities, while
others are known to exhibit insect antifeedant activity.1 Lycorine
(2) 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) skeleton has been of considerable
(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. Phytochem. 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.
(1) Martin, S. F. The Amaryllidaceae Alkaloids. In The Alkaloids; Brossi,
A., Ed.; Academic Press: New York, 1987; Vol. 30, Chapter 3, p 251.
(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.
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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.
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T., Ed.; JAI Press: Greenwich, CT, 1997; Vol. 3, p 109. (b) Hoshino, O.
In The Alkaloids; Cordell, G. A., Ed.; Academic Press: New York, 1998;
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10.1021/jo0626111 CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/06/2007
2570
J. Org. Chem. 2007, 72, 2570-2582

Synthesis of Phenanthridone Subclass of Amaryllidaceae
SCHEME 1. Key Disconnections for the Synthesis of
(-Lycoricidine
Among the many approaches to the Amaryllidaceae alka-
loids,9,16 the Diels-Alder cycloaddition reaction has played a
key role in the preparation of the C-ring of these natural
products.17,18 Application of the intramolecular Diels-Alder
reaction for the construction of aza-polycyclic compounds has
been practiced for more than two decades,19,20 and interest in
this methodology has been reinforced over the past several
years.21 Heterocycles such as furan, thiophene, and pyrrole
undergo Diels-Alder reactions despite their stabilized 6-π
aromatic electronic configuration.22 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.22 However, placement of the
furan ring and the dienophile in the same molecule can often
circumvent these problems.23,24 Our synthetic strategy directed
toward the hydroxylated phenanthridone type alkaloids was to
take advantage of the intramolecular Diels-Alder reaction of
an alkenyl-substituted 2-amidofuran (IMDAF), as had been
outlined in earlier reports from this laboratory.25 Our retrosyn-
thetic analysis of (()-lycoricidine (7) is shown in Scheme 1
FIGURE 1. Some representative lycorine-type alkaloids.
narciclasine (8),11 as well as pancratistatin (9)12 and 7-deoxy-
pancratistatin (10)13 are popular synthetic targets primarily
because their heterocyclic framework provides a means to
demonstrate the utility of new synthetic strategies.9 In addition,
the narcissus alkaloids are available only in small quantities
from natural sources,14 and their use as therapeutic agents15
depends on their ready availability.
(9) Rinner, U.; Hudlicky, T. Synlett 2005, 365.
(10) For syntheses of lycoricidine, see: (a) Ohta, S.; Kimoto, S. Chem.
Pharm. Bull. 1976, 24, 2977. (b) Paulsen, H.; Stubbe, M. Tetrahedron Lett.
1982, 23, 3171. (c) Paulsen, H.; Stubbe, M. Liebigs Ann. Chem. 1983, 535.
(d) Chida, N.; Ohtsuka, M.; Ogawa, S. Tetrahedron Lett. 1991, 32, 4525.
(e) Hudlicky, T.; Olivo, H. F. J. Am. Chem. Soc. 1992, 114, 9694. (f) Chida,
N.; Ohtsuka, M.; Ogawa, S. J. Org. Chem. 1993, 58, 4441. (g) Martin, S.
F.; Tso, H. H. Heterocycles 1993, 35, 85. (h) Hudlicky, T.; Olivo, H. F.;
McKibben, B. J. Am. Chem. Soc. 1994, 116, 5108. (i) Keck, G. E.; Wager,
T. T. J. Org. Chem. 1996, 61, 8366. (j) Elango, S.; Yan, T. H. Tetrahedron
2002, 58, 7375.
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Tetrahedron Lett. 1972, 13, 2085. (b) Mondon, A.; Krohn, K. Chem. Ber.
1975, 108, 445. (c) Krohn, K.; Mondon, A. Chem. Ber. 1976, 109, 855. (d)
Rigby, J. H.; Mateo, M. E. J. Am. Chem. Soc. 1997, 119, 12655. (e) Rigby,
J. H.; Maharoof, U. S. M.; Mateo, M. E. J. Am. Chem. Soc. 2000, 122,
6624. (f) Gonzalez, D.; Martinot, T.; Hudlicky, T. Tetrahedron Lett. 1999,
40, 3077.
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58, 37.
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Boyd, M. R.; Williams, G. R.; Pettit, G. R., III; Doubek, D. L. Anti-Cancer
Drug Des. 1995, 10, 243. (b) Pettit, G. R.; Orr, S.; Ducki, S. Anti-Cancer
Drug Des. 2000, 15, 389. (c) Pettit, G. R.; Pettit, G. R., III; Backaus, R.
A.; Boyd, M. R.; Meerow, A. W. J. Nat. Prod. 1993, 56, 1682. (d) Hudlicky,
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Martinot, T. A.; Pettit, G. R. J. Org. Chem. 2002, 67, 8726.
(16) Hudlicky, T. J. Heterocycl. Chem. 2000, 37, 535.
(12) For syntheses of pancratistatin, see: (a) Danishefsky, S.; Lee, J. Y.
J. Am. Chem. Soc. 1989, 111, 4829. (b) Tian, X.; Hudlicky, T.; Ko¨nigs-
berger, K. J. Am. Chem. Soc. 1995, 117, 3643. (c) Trost, B. M.; Pulley, S.
R. J. Am. Chem. Soc. 1995, 117, 10143. (d) Keck, G. E.; McHardy, S. F.;
Murry, J. A. J. Am. Chem. Soc. 1995, 117, 7289. (e) Hudlicky, T.; Tian, X.
R.; Ko¨nigsberger, K.; Mauray, R.; Rouden, J.; Fan, B. J. Am. Chem. Soc.
1996, 118, 10752. (f) Chida, N.; Jitsuoka, M.; Yamamoto, Y.; Ohtsuka,
M.; Ogawa, S. Heterocycles 1996, 43, 1385. (g) Doyle, T. J.; Hendrix, M.;
VanDerveer, D.; Javanmard, S.; Haseltine, J. Tetrahedron 1997, 53, 11153.
(h) Magnus, P.; Sebhat, I. K. Tetrahedron 1998, 54, 15509. (i) Magnus, P.;
Sebhat, I. K. J. Am. Chem. Soc. 1998, 120, 5341. (j) Pettit, G. R.; Melody,
N.; Herald, D. L. J. Org. Chem. 2001, 66, 2583. (k) Kim, S.; Ko, H.; Kim,
E.; Kim, D. Org. Lett. 2002, 4, 1343. (l) Ko, H. J.; Park, J. E.; Kim, S. J.
Org. Chem. 2004, 69, 112.
(13) (a) Akgun, H.; Hudlicky, T. Tetrahedron Lett. 1999, 40, 3081. (b)
Rinner, U.; Siengalewicz, P.; Hudlicky, T. Org. Lett. 2002, 4, 115. (c) Tian,
X.; Maurya, R.; Ko¨nigsberger, K. Synlett 1995, 1125. (d) Keck, G. E.;
Wager, T. T.; McHardy, S. F. J. Org. Chem. 1998, 63, 9164. (e) Keck, G.
E.; McHardy, S. F.; Murry, J. A. J. Am. Chem. Soc. 1995, 117, 7289. (f)
Acena, J. L.; Arjona, O.; Leon, M. L.; Plumet, J. Org. Lett. 2000, 2, 3683.
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E.; Castedo, L. J. Org. Chem. 1995, 60, 6318.
(18) (a) Hill, R. K.; Joule, 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.
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Commun. 1983, 693.
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Oppolzer, W. Synthesis 1978, 793. (c) Oppolzer, W. Heterocycles 1980,
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(20) Craig, D. Chem. Soc. ReV. 1987, 16, 187.
(21) Kappe, C. O.; Murphree, S. S.; Padwa, A. Tetrahedron 1997, 53,
14179 and references cited therein.
(22) Lipshutz, B. Chem. ReV. 1986, 86, 795.
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1984, 49, 3427. (b) Klein, L. L. J. Org. Chem. 1985, 50, 1770. (c) Jung,
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63, 5304. (b) Padwa, A.; Brodney, M. A.; Satake, K.; Straub, C. S. J. Org.
Chem. 1999, 64, 4617.
J. Org. Chem, Vol. 72, No. 7, 2007 2571

Padwa and Zhang
SCHEME 3. Cycloaddition/Rearrangement Cascade
SCHEME 2. Synthesis of a Model 2-Amidofurana
a Reagents: (a) MeO2CCH2P(O)(OEt)2, NaH, CuI, DMF, 100 °C, 61%;
(b) NaH, CH2O, THF, 25 °C, 83%; (c) NaClO2, H2O2, NaH2PO4, acetone,
10 °C, 93%; (d) (COCl)2, CH2Cl2, n-BuLi, BocNHfuran, 65% (2 steps).
SCHEME 4. An Unusual Acid-Catalyzed Rearrangement
and makes use of a tandem cascade sequence consisting of a
Stille coupling26 followed by a spontaneous intramolecular [4
+ 2]-cycloaddition of an amidofuran. The resulting cycloadduct
13 is then used for the stereocontrolled installation of the other
functionality present in the C-ring of (()-lycoricidine. The
carbomethoxy substituent would be utilized as the critical control
element not only to facilitate the [4 + 2]-cycloaddition but also
to provide a handle for the introduction of the required π-bond
and to set the stereochemistry at the C4a ring junction. In the
present paper, we document the results of our studies making
use of this methodology.27
C-ring with the correct stereochemistry. The first step in our
conceived synthesis of (()-lycoricidine (7) requires a stere-
ochemically controlled dihydroxylation of the π-bond present
in the Diels-Alder cycloadduct. This tactic was easily tested
using the readily available cycloadduct 16. Treatment of 16 with
catalytic OsO4 in the presence of 4-methylmorpholine-N-oxide
furnished the desired diol 19 in 95% yield (Scheme 4). The
dihydroxylation reaction occurred exclusively from the less
hindered exo face. In our attempts to convert diol 19 into the
corresponding acetonide, a rather unusual acid-catalyzed rear-
rangement occurred when the reaction was performed in
methanol containing a trace amount of p-toluenesulfonic acid.
The major and unexpected product obtained from this reaction
(81% yield) was identified as enone 20 on the basis of its
spectral data. This unusual reorganization can be rationalized
by the cascade pathway proposed in Scheme 5.
We assume that the first step proceeds by an acid-catalyzed
oxabicyclic ring opening which is assisted by the electron pair
of the amido nitrogen. A subsequent deprotonation would
generate enol 22 which might very well transfer the Boc group
on the adjacent carbamate, followed by loss of water to produce
23 as a transient species. This step is not essential for the overall
reaction to occur since some variation in timing is certainly
possible. Addition of methanol to the highly reactive imino
functionality present in 23 would lead to tert-butyl vinyl
carbonate 24. Hydrolysis of the acid-sensitive carbonate with
simultaneous elimination of water accounts for the formation
of the observed product 20.
Results and Discussion
Model Studies. As a prelude to the total synthesis of (()-
lycoricidine (7), we initially set out to prepare the core
hydroxylated phenanthridone skeleton in order to test the
viability of our approach as well as to probe specific reactions
to be used in a total synthesis effort. With this in mind, we first
investigated the thermolysis of the prototypic system 15 prepared
according to the sequence of reactions outlined in Scheme 2.
The thermolysis of 2-amidofuran 15 at 160 °C resulted in a
major reorganization that gave rise to dihydrophenanthridine
dione 18 in 70% yield. When the thermolysis was carried out
at 80 °C, we were pleased to discover that the desired Diels-
Alder cycloadduct 16 was formed in quantitative yield. This
IMDAF cycloaddition proceeded by a transition state where the
side arm of the tethered vinyl group is oriented exo with respect
to the oxygen bridge.24 Consequently, the carbomethoxy group
and oxy bridge in the product are disposed in an anti relation-
ship. Further heating of cycloadduct 16 at 160 °C resulted in a
smooth reorganization to afford the rearranged product 18 in
high yield. This reaction cascade can be accounted for by a
nitrogen-assisted ring opening of 16 to give zwitterion 17 as a
transient intermediate. A subsequent deprotonation/reprotonation
of 17 accounts for the formation of 18.
In our planned approach toward (()-lycoricidine (7), we
needed to install the other functional groups present on the
As a consequence of the acid lability of diol 19, we decided
to replace the Boc with a benzyl group in order to avoid the
acid-catalyzed cascade reaction encountered with 19. The
synthesis of the N-benzyl cycloadduct 25 proceeded along
similar lines to that described above. In this case, the methyl
acrylate moiety was introduced by means of a Stille coupling26
using methyl 2-tri-n-butyl stannylacrylate.28 The optimal condi-
tions for this reaction were eventually determined to be those
described by Baldwin.29 The expected cross-coupled amidofuran,
(25) (a) Wang, Q.; Padwa, A. Org. Lett. 2004, 6, 2189. (b) Padwa, A.;
Ginn, J. D. J. Org. Chem. 2005, 70, 5197. (c) Padwa, A.; Bur, S. K.; Zhang,
H. J. Org. Chem. 2005, 70, 6833. (d) Wang, Q.; Padwa, A. Org. Lett. 2006,
8, 601. (e) Padwa, A.; Wang, Q. J. Org. Chem. 2006, 71, 7391.
(26) Farina, V.; Krishnamurphy, V.; Scott, W. J. Org. React. 1997, 50,
1.
(27) For a preliminary report, see: Zhang, H.; Padwa, A. Org. Lett. 2006,
8, 247.
2572 J. Org. Chem., Vol. 72, No. 7, 2007

Synthesis of Phenanthridone Subclass of Amaryllidaceae
SCHEME 5. A Proposed Mechanism for the
Rearrangement
SCHEME 6. Dihydroxylation of the IMDAF Cycloadduct
Since the â-face of the double bond in compound 29 is
blocked by the bulky acetonide, the dihydroxylation reaction
was expected to take place from the less hindered R-face, syn
to the carbomethoxy group, thereby setting the correct stereo-
chemistry of the C2-hydroxyl group needed for an eventual
synthesis of (()-lycoricidine (7). Indeed, when 29 was treated
with OsO4/NMO, the desired diol 30 was formed as a transient
species but underwent spontaneous cyclization with the adjacent
carbomethoxy group to deliver γ-lactone 31 (Scheme 7). A
subsequent mesylation reaction afforded mesylate 32 in 74%
yield for the two-step sequence starting from 29. With com-
pound 32 in hand, we hoped that we could induce a domino
fragmentation cascade which would involve (a) lactone hy-
drolysis using LiOH to deliver the carboxylate anion, and (b) a
subsequent decarboxylation/elimination of the mesylate group
to introduce the critical double bond in the C-ring.31 Gratify-
ingly, this desired cascade proceeded quite smoothly and
afforded the allylic alcohol 35 in near quantitative yield. This
reaction presumably proceeds by an initial opening of the lactone
ring with hydroxide to give carboxylate anion 33. A subsequent
decarboxylation would generate anion 34 which, in turn, would
induce the elimination of the mesylate anion ultimately affording
the observed alcohol 35.
however, was not isolated as it spontaneously underwent an
intramolecular [4 + 2]-cycloaddition to furnish cycloadduct 25
in 55% overall yield for the two-step cascade. The increased
reactivity of the N-benzyl amidofuran (55 °C) when compared
to the Boc analogue (80 °C) is probably related to a higher lying
HOMO of the furanyl 4π-system. The subsequent dihydroxy-
lation reaction proceeded as expected with exclusive exo-
stereoselectivity to give diol 26 (Scheme 6). In order to minimize
acid degradation pathways, we chose to induce the opening of
the oxabicyclic ring prior to the protection of the C3,C4-hydroxyl
groups. The expected N-acyliminium ion was generated by
treating 26 with BF3•OEt2, and the incipient cation was reduced
in situ using Et3SiH to give triol 27 in 74% yield. The presence
of the angular carbomethoxy group directs the hydride delivery
from the less hindered â-face and sets the correct stereochem-
istry at C4a that is needed for (()-lycoricidine (7). Selective
esterification of the C2-hydroxyl group with AcCl/NEt3 followed
by protection of the remaining two hydroxyl groups with 2,2-
dimethoxypropane in the presence of p-TsOH provided ac-
etonide 28 whose structure was unequivocally established by
X-ray crystallography. The acetoxy group present in compound
28 was hydrolyzed with NaOMe, and the resulting alcohol was
then treated with NaH followed by the addition of CS2 and MeI
to afford the corresponding xanthate. Heating the xanthate in
1,2-dichlorobenzene for 12 h afforded the expected olefin 29
derived from a Chugaev elimination30 in 92% yield.
(()-Lycoricidine. Having been encouraged by the prelimi-
nary cycloaddition experiments involving furanyl carbamate 15,
we turned our attention to the preparation of amidofuran 40
which we hoped to use for the eventual synthesis of (()-
lycoricidine (7). The synthesis of 40 began by coupling the
known acid chloride 3632 with the lithiated carbamate 37b
derived by treating furan-2-ylcarbamic acid tert-butyl ester (37a)
with n-BuLi. Removal of the Boc-protecting group from the
(28) (a) Zhang, H. X.; Guiibe, F.; Balavoine, G. J. Org. Chem. 1990,
55, 1857. (b) Miyake, H.; Yamamura, K. Chem. Lett. 1989, 981. (c) Cochran,
J. C.; Bronk, B. S.; Terrence, K. M.; Philips, H. K. Tetrahedron Lett. 1990,
31, 6621.
(29) Mee, P. H.; Lee, V.; Baldwin, J. E. Angew. Chem., Int. Ed. 2004,
43, 1132.
(31) For a related fragmentation reaction, see: Khim, S.; Dai, M.; Zhang,
X.; Chen, L.; Pettus, L.; Thakkar, K.; Schultz, A. G. J. Org. Chem. 2004,
69, 7728.
(30) Nace, H. R. Org. React. 1962, 12, 57.
(32) McIntosh, M. C.; Weinreb, S. M. J. Org. Chem. 1993, 58, 4823.
J. Org. Chem, Vol. 72, No. 7, 2007 2573

Padwa and Zhang
SCHEME 7. Decarboxylation/Elimination Sequence
SCHEME 9. Stereocontrolled Reduction of N-Acyliminium
Ion Precursor
combination of CuCl/Pd(0)/LiCl for the key coupling.34 The
use of DMSO with rigorous exclusion of oxygen and moisture
at 60 °C gave the best results. The expected cross-coupled
amidofuran 40, however, was not isolated as it spontaneously
underwent an intramolecular [4 + 2]-cycloaddition to furnish
cycloadduct 13 in 82% overall yield for the two-step cascade.
The increase in reactivity of 40 when compared to the related
furanyl carbamates24 (>150 °C) is due to the placement of the
carbonyl center within the dienophilic tether as well as the
presence of the carbomethoxy group, which lowers the LUMO
energy of the π-bond, thereby facilitating the cycloaddition.
Dramatic effects on the rate of the Diels-Alder reaction were
previously noted to occur when an amido group was used to
anchor the diene and dienophile.35 Our ability to isolate
oxabicyclic adduct 13 is presumably a result of the lower
reaction temperature employed (i.e., 60 °C) as well as the
presence of the amido carbonyl group, which diminishes the
basicity of the nitrogen atom, thereby retarding the ring cleavage/
rearrangement reaction generally encountered with these sys-
tems.24
SCHEME 8. Intramolecular Diels-Alder Reaction
With the rapid construction of the lycoricidine framework in
hand, installation of the other functional groups present on the
C-ring with the correct relative stereochemistry was investigated.
To continue the synthesis, cycloadduct 13 was transformed to
diol 41 by reaction with catalytic OsO4 in the presence of
4-methylmorpholine-N-oxide. The dihydroxylation reaction oc-
curred exclusively from the less hindered exo face, producing
41 in 98% yield (Scheme 9). Having introduced the correct cis-
stereochemistry of the hydroxyl groups at the C3,C4 positions,
we then proceeded to set the stereochemistry at the C4a position,
insert the remaining R-hydroxyl group at C2, and ultimately
introduce the required π-bond. All of these operations were
facilitated by making use of the available carbomethoxy group
(vide infra). First, diol 41 was converted to the corresponding
acetonide 42 in 80% yield by treatment with 2,2-dimethox-
ypropane and catalytic pyridinium p-toluenesulfonate. The
uniquely functionalized oxabicyclic adduct 42 contains a
resulting carbamate 38 with Mg(ClO4)2 afforded NH amide 39
in 75% yield, and this was followed by reaction with NaH and
p-methoxybenzyl chloride to give 11 in 83% yield.33 The methyl
acrylate moiety was introduced by means of a Stille coupling26
using methyl 2-tri-n-butyl stannylacrylate (12)28 (Scheme 8).
The optimal conditions for this reaction were eventually
determined to be those described by Corey which utilized a
(34) Han, X.; Stoltz, B. M.; Corey, E. J. J. Am. Chem. Soc. 1999, 121,
7600.
(35) (a) Oppolzer, W.; Fro¨stl, W. HelV. Chim. Acta 1975, 58, 590. (b)
White, J. D.; Demnitz, F. W. J.; Oda, H.; Hassler, C.; Snyder, J. P. Org.
Lett. 2000, 2, 3313. (c) Padwa, A.; Ginn, J. D.; Bur, S. K.; Eidell, C. K.;
Lynch, S. M. J. Org. Chem. 2002, 67, 3412. (d) Tantillo, D. J.; Houk, K.
N.; Jung, M. E. J. Org. Chem. 2001, 66, 1938.
(33) Replacement of the Boc group with the PMB functionality was
necessary for the subsequent Stille reaction.
2574 J. Org. Chem., Vol. 72, No. 7, 2007

Synthesis of Phenanthridone Subclass of Amaryllidaceae
SCHEME 10. Final Steps in the Synthesis of
SCHEME 11. Preference for the cis-Isomer
(()-Lycoricidine
THF induced the tandem hydrolysis/decarboxylation/elimination
sequence,31 previously encountered with the model substrate 32,
to furnish allylic alcohol 47 in 93% yield. Finally, deprotection
of the acetonide with TFA afforded (()-lycoricidine (7) in 90%
yield.
(()-7-Deoxypancratistatin. The potent antiviral properties
associated with the hydroxylated phenanthridone 7-deoxypan-
cratistatin (10)38 coupled with its limited availability from natural
resources and decreased toxicity relative to pancratistatin (9)39
have prompted significant efforts toward its total synthesis.40
The main challenge toward designing any synthetic strategy
toward deoxypancratistatin lies in the control of the trans-fused
B-C ring junction (C4a, C10b) and with the stereocontrolled
installation of continuous hydroxy functionalities located around
the perimeter of the C-ring moiety. The trans-B-C ring junction
is believed to be critical for its anticancer activity15 but is much
more difficult to generate than the thermodynamically more
stable cis ring junction.8 For example, Rigby and co-workers
have observed a decided preference for the cis fusion in the
related pancratistatin intermediate 49 which was readily formed
by epimerization of the less stable trans-isomer 48 at room
temperature (Scheme 11).41
Our plan for the synthesis of 7-deoxypancratistatin (10) was
to convert alcohol 14, which had previously been used as an
intermediate in the total synthesis of (()-lycoricidine (7), into
the corresponding aldehyde 50. We reasoned that the trans-
B-C ring junction could be established through a RhCl(PPh3)3-
promoted decarbonylation reaction of this aldehyde.42 Under
the influence of transition metal compounds, aldehydes are
known to readily undergo decarbonylation and produce the
“masked” N-acyliminium ion which can be released by treatment
with a Lewis acid such as TMSOTf. When the resulting ring-
opened iminium ion was treated with Zn(BH4)2,36 alcohol 14
was obtained with complete diastereoselectivity in 74% yield.
What was required for the end game leading to (()-
lycoricidine (7) was to invert the stereochemistry of the C2-
hydroxyl group, remove the carbomethoxy moiety, and generate
a double bond between the C1-C10b position of the C-ring. To
this end, compound 14 was treated with NaH followed by the
addition of CS2 and MeI to give the corresponding xanthate
ester which, upon heating at reflux in 1,2-dichlorobenzene for
12 h, afforded the expected olefin 43 derived from a Chugaev
elimination30 in 94% yield (Scheme 10). Since the â-face of
the π-bond of 43 was blocked by the bulky acetonide, a
dihydroxylation reaction was expected to take place from the
less hindered R-face (syn to the carbomethoxy group), thereby
setting the correct stereochemistry of the C2-hydroxyl group.
Indeed, when 43 was treated with OsO4/NMO, the desired diol
44 was formed as a transient species but underwent spontaneous
cyclization with the adjacent carbomethoxy group to deliver
γ-lactone 45. A subsequent mesylation reaction afforded me-
sylate 46 in 76% yield for the two-step sequence starting from
43. The γ-lactonization of 44 to 45 permits the selective
activation of the C1-hydroxyl group. The PMB group was
removed by the reaction of 46 with PdCl2 in the presence of
acetic acid37 to furnish the deprotected amide in 65% yield.
Gratifyingly, the reaction of this amide with LiOH in aqueous
(38) (a) Pettit, G. R.; Gaddamidi, V.; Herald, D. L.; Singh, S. B.; Cragg,
G. M.; Schmidt, J. M. J. Nat. Prod. 1986, 46, 995. (b) Gabrielson, B.;
Monath, T. P.; Huggins, J. W.; Kirsi, J. J.; Hollingshead, M.; Shannon, W.
M.; Pettit, G. R. In Natural Products as AntiViral Agents; Chu, C. K., Cutler,
H. G., Eds.; Plenum: New York; 1992, p 121. (c) Ghosal, S.; Singh, S.;
Kumar, Y.; Srivastava, R. S. Phytochemistry 1989, 28, 611.
(39) (a) Gabrielsen, B.; Monath, T. P.; Huggins, J. W.; Pettit, G. R.;
Kirsi, J. J.; Schubert, E. M.; Dare, J.; Ussery, M. A. J. Nat. Prod. 1992,
55, 1569. (b) Pettit, G. R.; Pettit, G. R., III; Groszek, R. A.; Backhaus, R.
A.; Doubek, D. L.; Barr, R. J.; Meerow, A. W. J. Nat. Prod. 1995, 58,
756.
(40) For some selected examples, see: (a) Fleet, G. W. J.; Ramsden, N.
G.; Witty, D. R. Tetrahedron 1989, 45, 319. (b) Arjona, O.; Iradier, F.;
Plumet, J.; Martnez-Alcazar, M. P.; Hernandez-Cano, F.; Fonseca, I.
Tetrahedron Lett. 1998, 39, 6741. (c) Rinner, U.; Siengalwicz, P.; Hudlicky,
T. Org. Lett. 2001, 4, 115. (d) Hudlicky, T.; Rinner, U.; Gonzalez, D.;
Akgun, H.; Schilling, S.; Siengalewicz, P.; Martinot, T. A.; Pettit, G. R. J.
Org. Chem. 2002, 67, 8726. (e) Rinner, U.; Hillebrenner, H.; Adams, D.
R.; Hudlicky, T.; Pettit, G. R. Bioorg. Med. Chem. Lett. 2004, 14, 2911. (f)
McNulty, J.; Mao, J.; Gibe, R.; Mo, R.; Wolf, S.; Pettit, G. R.; Herald, D.
L.; Boyd, M. R. Bioorg. Med. Chem. Lett. 2001, 11, 169. (g) Schilling, S.;
Rinner, U.; Chan, C.; Ghiviriga, I. Can. J. Chem. 2001, 79, 1659. (h) Ibn-
Ahmed, S.; Khaldi, M.; Chretien, K.; Chapleur, Y. J. Org. Chem. 2004,
69, 6722. (i) Zhang, H.; Padwa, A. Tetrahedron Lett. 2006, 47, 3905.
(41) (a) Rigby, J. H.; Maharoof, U. S. M.; Mateo, M. E. J. Am. Chem.
Soc. 2000, 122, 6624. (b) For a somewhat related example, see: Thompson,
R. C.; Kallmerten, J. J. Org. Chem. 1990, 55, 6078.
(36) Gensler, W. J.; Johnson, F.; Sloan, A. D. B. J. Am. Chem. Soc.
1960, 82, 6074.
(37) Keck, G. E.; Boden, E.; Sonnewald, U. Tetrahedron Lett. 1981,
22, 2615.
(42) (a) Tsuji, J.; Ohno, K. Synthesis 1969, 157. (b) Walborsky, H. M.;
Allen, L. E. J. Am. Chem. Soc. 1971, 93, 5465.
J. Org. Chem, Vol. 72, No. 7, 2007 2575

Padwa and Zhang
SCHEME 13. Synthesis of (()-7-Deoxypancratistatin
SCHEME 12. Use of Wilkinson’s Catalyst to Control
Stereochemistry
corresponding saturated hydrocarbons.42 Rhodium complexes
such as Wilkinson’s catalyst RhCl(PPh3)3 are most often
employed in both stoichiometric and catalytic reactions to effect
the decarbonylation.42,43 The earlier seminal studies by
Walborsky42b demonstrated that the decarbonylation reaction
using Wilkinson’s catalyst proceeds with retention of config-
uration, and this finding has been used by others in complex
natural product synthesis.43 With this in mind, we set out to
convert the carbomethoxy group present in 14 to the corre-
sponding aldehyde. Our first attempt to prepare aldehyde 50
involved the reduction of 14 with DIBAL. However, the
expected aldehyde (or alcohol) was not produced, but instead
amine 51 was obtained in high yield as the exclusive product
(Scheme 12). The increased reactivity of the amido carbonyl
group over the ester toward DIBAL reduction is probably related
to a significant decrease in the strain energy of ring B by
changing the hybridization from sp2 to sp3 at the C6 position.44
This undesired reduction could be circumvented by converting
the ester group into the corresponding acid chloride after
protecting the free OH group as the benzyl ether. Selective
reduction of the acid chloride with Zn(BH4)2 followed by a
subsequent oxidation of the resulting alcohol using Ley’s
procedure45 afforded the desired aldehyde 50. When a solution
of 50 and RhCl(PPh3)3 was heated in benzonitrile at reflux, the
decarbonylation reaction proceeded to give the desired trans-
fused lactam 52 in 63% yield.
hydroxyl group and also to invert the stereochemistry at the C2
position. To this end, a transient double bond between C1 and
C2 was installed by carrying out a debenzylation under hydro-
genolysis conditions followed by a Chugaev elimination30 of
the xanthate ester which proceeded in 85% overall yield
(Scheme 13). Since the presence of the bulky acetonide moiety
partially blocked the â-face of the π-bond of 53, dihydroxylation
occurred preferentially from the less hindered R-face to furnish
two easily separable diol isomers (3:1) in almost quantitative
yield. A subsequent regioselective inversion of the stereochem-
istry at the C1-hydroxyl group of the major diol 54 was achieved
through a three-step sequence.12c Treatment of diol 54 with
thionyl chloride followed by oxidation of the resulting sulfite
with NaIO4 in the presence of catalytic RuCl3 furnished sulfate
55 in 82% yield.46 Reaction of sulfate 55 with cesium benzoate
followed by acid hydrolysis resulted in the formation of triol
56 in 75% yield. The final ester hydrolysis and amide depro-
tection proceeded uneventfully to furnish 7-deoxypancratistatin
(10) in 80% yield.
In conclusion, we have developed a new type of cross-
coupling/cycloaddition cascade which has been successfully
utilized in the total synthesis of several members of the
hydroxylated phenanthridone subclass of the Amaryllidaceae
alkaloid family. These alkaloids were assembled by a one-pot
Stille/intramolecular Diels-Alder cycloaddition cascade to
construct the core skeleton. The resulting cycloadduct was then
used for the stereocontrolled installation of the other functional-
ity present in the C-ring of the target molecules. Key features
of the synthetic strategy include (1) a lithium hydroxide induced
tandem hydrolysis/decarboxylation/elimination sequence to
introduce the required π-bond in the C-ring of (()-lycoricidine,
With the rapid construction of the trans-fused lactam in hand,
installation of the other functional groups present on the C-ring
with the correct relative stereochemistry was next investigated.
What was required for the end game was to introduce a C1-
(43) (a) Ziegler, F. E.; Belema, M. J. Org. Chem. 1997, 62, 1083. (b)
Kato, T.; Hoshikawa, M.; Yaguchi, Y.; Izumi, K.; Uotsu, Y.; Sakai, K.
Tetrahedron 2002, 58, 9213. (c) Harmata, M.; Wacharasindhu, S. Org. Lett.
2005, 7, 2563. (d) Malerich, J. P.; Maimone, T. J.; Elliott, G. I.; Trauner,
D. J. Am. Chem. Soc. 2005, 127, 6276.
(44) A related finding had been made by the Hudlicky group in their
elegant total synthesis of (+)-pancratistatin. In an attempted deprotection
of a N-tosyl amide using Na(Hg), it was observed that reduction of the
lactam carbonyl group preferentially occurred, and this finding was attributed
to relief of ring strain.12b
(45) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.
(46) (a) Gao, Y.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 7538.
(b) Lohray, B. B. Synthesis 1992, 1035.
2576 J. Org. Chem., Vol. 72, No. 7, 2007

Synthesis of Phenanthridone Subclass of Amaryllidaceae
4a-Methoxy-4,6-dioxo-4,4a,5,6-tetrahydro-1H-phenanthridine-
10b-carboxylic Acid Methyl Ester (20). To a solution containing
0.05 g (0.14 mmol) of cycloadduct 16 in 2 mL of a 2:1:1 mixture
of THF/H2O/t-BuOH) was added 0.03 g (0.23 mmol) of NMO (N-
methylmorpholine-N-oxide) and catalytic OsO4. After stirring for
1 h at rt, the mixture was diluted with H2O and extracted with
CH2Cl2. The combined organic extracts were washed with H2O
and brine and dried over MgSO4. Concentration under reduced
pressure provided the expected diol 19 in 95% yield as a clear oil
which was used in the next step without further purification: 1H
NMR (CDCl3, 400 MHz) δ 1.48 (s, 9H), 2.48 (dd, 1H, J ) 13.2
and 6.8 Hz), 3.06 (d, 1H, J ) 13.2 Hz), 3.57 (s, 3H), 4.06 (d, 1H,
J ) 6.0 Hz), 4.40 (d, 1H, J ) 6.4 Hz), 4.92 (d, 1H, J ) 6.0 Hz),
7.09 (s, 1H), 7.16 (d, 1H, J ) 7.6 Hz), 7.40 (dt, 1H, J ) 7.6 and
1.2 Hz), 7.52 (dt, 1H, J ) 7.6 and 1.2 Hz), 8.15 (d, 1H, J ) 7.6
Hz); 13C NMR (CDCl3, 100 MHz) δ 27.8, 39.4, 53.2, 53.7, 71.8,
75.8, 77.4, 83.8, 93.9, 126.7, 127.0, 128.3, 128.9, 133.8, 140.4,
152.6, 164.0, and 170.9.
and (2) conversion of the initially formed Diels-Alder adduct
into an aldehyde intermediate which is then induced to undergo
a stereospecific decarbonylation reaction using Wilkinson’s
catalyst to set the trans-B-C ring junction of (()-7-deoxypan-
cratistatin. We plan to use this and related cascade methodology
in approaches to other natural product targets, the results of
which will be disclosed in due course.
Experimental Section
2-[2-(tert-Butoxycarbonylfuran-2-ylaminocarbonyl)phenyl]-
acrylic Acid Methyl Ester (15). To a suspension of 0.40 g (1.9
mmol) of 2-(1-methoxycarbonylvinyl)benzoic acid47 in 4 mL of
CH2Cl2 at rt were added dropwise 0.25 mL (2.9 mmol) of oxalyl
chloride and several drops of DMF as a catalyst. The reaction
mixture was stirred at rt for 3 h and then concentrated under reduced
pressure. The residue was taken up in 4 mL of THF and was used
for the next step without further purification. In a separate flask
containing 0.39 g (2.1 mmol) of furan-2-ylcarbamic acid furan-2-
tert-butyl ester (37a) and 5 mL of THF at 0 °C was added 0.9 mL
(2.3 mmol) of n-BuLi (2.5 M in hexane). After stirring for 20 min,
the solution was added dropwise to the above acid chloride solution
at 0 °C. The reaction mixture was stirred at 0 °C for 20 min, diluted
with H2O, and extracted with EtOAc. The combined organic extracts
were washed with H2O and brine, dried over MgSO4, and
concentrated under reduced pressure. The residue was subjected
to flash silica gel chromatography to give 0.46 g (64%) of
The crude diol 19 was taken up in 1.5 mL of 2,2-dimethoxypro-
pane, and catalytic p-toluene sulfonic acid was added. The mixture
was stirred at rt for 30 min, quenched with a saturated NaHCO3
solution, and extracted with EtOAc. The organic extracts were
washed with H2O and brine and dried over MgSO4. After
concentration under reduced pressure, the residue was subjected
to preparative TLC to give 0.032 g (81%) of 20 as a white solid:
1
mp 200-202 °C; IR (neat) 1734, 1677, and 1056 cm-1; H NMR
(CDCl3, 600 MHz) δ 3.03 (s, 3H), 3.21 (dt, 1H, J ) 18.0 and 2.4
Hz), 3.41 (dd, 1H, J ) 18.0 and 6.0 Hz), 3.54 (s, 3H), 6.14 (dd,
1H, J ) 10.2 and 2.4 Hz), 7.02 (ddd, 1H, J ) 10.2, 6.0, and 2.4
Hz), 7.33 (br s, 1H), 7.45 (d, 1H, J ) 7.8 Hz), 7.48 (t, 1H, J ) 7.8
Hz), 7.62 (dt, 1H, J ) 7.8 and 1.2 Hz), and 8.11 (d, 1H, J ) 7.8
Hz); 13C NMR (CDCl3, 150 MHz) δ 32.9, 50.4, 53.5, 83.5, 125.8,
125.9, 127.9, 128.6, 128.7, 133.4, 136.7, 147.1, 163.7, 170.7, and
188.7. Anal. Calcd for C16H15NO5: C, 63.78; H, 5.02; N, 4.65.
Found: C, 63.22; H, 4.98; N, 4.57.
1
amidofuran 15: IR (neat) 1748, 1724, 1238, and 1153 cm-1; H
NMR (CDCl3, 600 MHz) δ 1.28 (s, 9H), 3.75 (s, 3H), 5.86 (s,
1H), 6.23 (d, 1H, J ) 3.0 Hz), 6.39 (s, 1H), 6.57 (s, 1H), 7.30 (d,
1H, J ) 7.8 Hz), 7.33 (s, 1H), 7.39 (t, 1H, J ) 7.8 Hz), 7.46 (t,
1H, J ) 7.8 Hz), and 7.55 (d, 1H, J ) 7.8 Hz); 13C NMR (CDCl3,
150 MHz) δ 27.7, 52.3, 84.2, 106.4, 111.5, 128.0, 128.1, 129.5,
130.6, 130.9, 135.5, 136.1, 140.4, 140.8, 143.8, 151.4, 166.3, and
170.9.
5-Benzyl-2,4a-Epoxy-6-oxo-2,4a,5,6-tetrahydro-1H-phenan-
thridine-10b-carboxylic Acid Methyl Ester (25). To a solution
containing 4.0 g (9.9 mmol) of N-benzyl-N-furan-2-yl-2-iodoben-
zamide47 and 5.2 g (14 mmol) of methyl 2-tri-n-butyl stannylacry-
late28 in 40 mL of DMF under argon atmosphere were added 1.2
g (0.99 mmol) of Pd(PPh3)4 and 0.57 g (3.0 mmol) of CuI. The
reaction mixture was stirred at rt for 20 min, followed by the
addition of 2.3 g (15 mmol) of CsF. After stirring at rt for 30 min,
the reaction mixture was heated at 55 °C for 8 h. The mixture was
cooled to rt, diluted with EtOAc and H2O, and filtered over a pad
of Celite. The organic layer was separated, and the aqueous layer
was extracted with EtOAc. The combined organic layers were
washed with H2O and brine and dried over MgSO4. After removing
the solvent under reduced pressure, the residue was subjected to
flash silica gel chromatography to give 1.9 g (55%) of cycloadduct
25 as a white solid: mp 183.5-185 °C; IR (neat) 1736, 1664, 1398,
2,4a-Epoxy-6-oxo-2,4a-dihydro-1H,6H-phenanthridine-5,10b-
dicarboxylic Acid 5-tert-Butyl Ester 10b-Methyl Ester (16). A
solution containing 0.43 g (1.2 mol) of amidofuran 15 in 2 mL of
toluene was heated at 80 °C for 3 h. After cooling to rt, the reaction
mixture was concentrated under reduced pressure to give cycload-
duct 16 in 98% yield as a white solid: mp 133-134 °C; IR (neat)
1
1735, 1684, 1369, 1256, and 1150 cm-1; H NMR (CDCl3, 600
MHz) δ 1.58 (s, 9H), 2.53 (dd, 1H, J ) 12.0 and 4.8 Hz), 2.80 (d,
1H, J ) 12.0 Hz), 3.60, (s, 3H), 4.95 (dd, 1H, J ) 4.8 and 1.8
Hz), 6.35 (d, 1H, J ) 5.4 Hz), 6.50 (dd, 1H, J ) 5.4 and 1.8 Hz),
7.33 (d, 1H, J ) 7.8 Hz), 7.40 (dt, 1H, J ) 7.8 and 1.2 Hz), 7.53
(dt, 1H, J ) 7.8 and 1.2 Hz), and 8.20 (dd, 1H, J ) 7.8 and 1.2
Hz); 13C NMR (CDCl3, 150 MHz) δ 28.0, 41.8, 53.1, 54.9, 75.7,
84.8, 97.4, 126.4, 128.3, 128.6, 129.8, 133.8, 134.3, 136.1, 139.8,
152.1, 162.5, and 171.4. Anal. Calcd for C20H21NO6: C, 64.68; H,
5.70; N, 3.77. Found: C, 64.61; H, 5.78; N, 3.81.
1
1347, and 1257 cm-1; H NMR (CDCl3, 600 MHz) δ 2.60 (dd,
2,6-Dioxo-2,3-dihydro-1H,6H-phenanthridine-5,10b-dicar-
boxylic Acid 5-tert-Butyl Ester 10b-Methyl Ester (18). In a sealed
tube were added 0.03 g (0.09 mmol) of cycloadduct 16 and 1.5
mL of benzene. The mixture was purged with argon, sealed, and
heated at 160 °C for 4 h. After cooling to rt, the solvent was
removed under reduced pressure and the residue was subjected to
flash silica gel chromatography to give 0.03 g (80%) of 18 as a
1H, J ) 11.4 and 4.8 Hz), 2.84 (d, 1H, J ) 11.4 Hz), 3.45 (s, 3H),
4.39 (d, 1H, J ) 15.6 Hz), 4.89 (dd, 1H, J ) 4.8 and 1.8 Hz), 5.58
(d, 1H, J ) 15.6 Hz), 6.13 (d, 1H, J ) 5.4 Hz), 6.56 (dd, 1H, J )
5.4 and 1.8 Hz), 7.25 (t, 1H, J ) 7.2 Hz), 7.32-7.44 (m, 6H),
7.52 (dt, 1H, J ) 7.2 and 1.8 Hz), and 8.27 (dd, 1H, J ) 7.2 and
1.8 Hz); 13C NMR (CDCl3, 150 MHz) δ 42.0, 49.0, 52.6, 54.2,
74.6, 100.5, 126.9, 127.1, 127.3, 128.2, 128.3, 128.6, 129.5, 133.0,
133.1, 138.6, 139.3, 139.6, 164.4, and 171.4. Anal. Calcd for C22H19-
NO4: C, 73.12; H, 5.30; N, 3.88. Found: C, 73.19; H, 5.22; N,
3.91.
5-Benzyl-2,4a-epoxy-3,4-dihydroxyl-6-oxo-2,4a,5,6-tetrahydro-
1H-phenanthridine-10b-carboxylic Acid Methyl Ester (26). To
a solution containing 1.0 g (2.8 mmol) of cycloadduct 25 in 40
mL of acetone and 4 mL of H2O at rt was added 0.54 g (4.6 mmol)
of NMO (N-methylmorpholine-N-oxide) and catalytic OsO4. The
mixture was stirred at rt for 12 h, diluted with H2O, and extracted
with CH2Cl2. The organic extracts were washed with H2O and brine
1
clear oil: IR (neat) 1766, 1733, 1244, and 1147 cm-1; H NMR
(CDCl3, 600 MHz) δ 1.59 (s, 9H), 2.77 (d, 1H, J ) 15.0 Hz), 3.13
(d, 1H, J ) 3.9 Hz), 3.59 (d, 1H, J ) 15.0 Hz), 3.64 (s, 3H), 5.61
(t, 1H, J ) 3.9 Hz), 7.28 (dd, 1H, J ) 7.8 and 1.5 Hz), 7.48 (td,
1H, J ) 7.8 and 1.5 Hz), 7.60 (td, 1H, J ) 7.8 and 1.5 Hz), 8.21
(dd, 1H, J ) 7.8 and 1.5 Hz); 13C NMR (CDCl3, 100 MHz) δ
27.8, 37.8, 47.0, 50.3, 53.9, 85.4, 111.0, 124.9, 126.7, 128.9, 129.5,
132.4, 134.1, 137.6, 151.3, 160.6, 170.4, and 203.5.
(47) See accompanying Supporting Information for experimental details.
J. Org. Chem, Vol. 72, No. 7, 2007 2577

Padwa and Zhang
and dried over MgSO4. Concentration under reduced pressure
Methyl Ester (29). To a solution of 0.70 g (1.5 mmol) of ketal 28
in 10 mL of THF at rt was added 0.22 g (3.8 mmol) of NaOMe in
several portions. After stirring for 20 min, the mixture was quenched
with a saturated NH4Cl solution and extracted with EtOAc. The
organic extracts were washed with H2O and brine and dried over
MgSO4. Concentration under reduced pressure gave the corre-
sponding alcohol derived from acetate hydrolysis in quantitative
yield which was used in the next step without further purification:
1H NMR (CDCl3, 400 MHz) δ 2.08 (dd, 1H, J ) 13.4 and 10.4
Hz), 2.38 (br s, 1H), 2.84 (dd, 1H, J ) 13.4 and 5.2 Hz), 3.31 (s,
3H), 4.02-4.12 (m, 2H), 4.49 (t, 1H, J ) 5.6 Hz), 4.87 (d, 1H, J
) 15.6 Hz), 4.89 (dd, 1H, J ) 8.8 and 5.6 Hz), 5.46 (d, 1H, J )
15.6 Hz), 7.19-7.32 (m, 5H), 7.43 (d, 1H, J ) 7.6 Hz), 7.47 (t,
1H, J ) 7.6 Hz), 7.56 (td, 1H, J ) 7.6 and 1.4 Hz), and 8.18 (dd,
1H, J ) 7.6 and 1.4 Hz).
To a solution containing 0.45 g (1.0 mmol) of the above alcohol
in 18 mL of THF was added 0.08 g (2.1 mmol) of NaH (60%
dispersion in mineral) at 0 °C. After stirring for 10 min, the mixture
was warmed to rt and was stirred for an additional 30 min. The
mixture was cooled to 0 °C, and 0.25 mL (4.2 mmol) of CS2 was
added. The solution was stirred for 1 h at this temperature, and
then 0.5 mL (8.3 mmol) of methyl iodide was added. After stirring
for 10 min, the mixture was warmed to rt and was stirred for an
additional 30 min. The solution was quenched with a saturated NH4-
Cl solution and extracted with EtOAc. The combined organic
extracts were washed with H2O and brine and dried over MgSO4.
After concentration under reduced pressure, the residue was taken
up in 20 mL of 1,2-dichlorobenzene and was heated at reflux for
12 h. After cooling to rt, the mixture was subjected to flash silica
gel chromatography to give 0.4 g (92%) of alkene 29 as a pale
yellow oil: IR (neat) 1734, 1654, and 1210 cm-1; 1H NMR (CDCl3,
600 MHz) δ 1.41 (s, 3H), 1.43 (s, 3H), 3.24 (s, 3H), 3.97 (d, 1H,
J ) 9.0 Hz), 4.79 (d, 1H, J ) 15.6 Hz), 4.81-4.83 (m, 1H), 4.50
(t, 1H, J ) 8.4 Hz), 5.58 (d, 1H, J ) 15.6 Hz), 6.20 (dd, 1H, J )
10.2 and 3.0 Hz), 6.43 (d, 1H, J ) 10.2 Hz), 7.21 (t, 1H, J ) 7.2
Hz), 7.25-7.33 (m, 4H), 7.47-7.50 (m, 2H), 7.57 (t, 1H, J ) 7.2
Hz), and 8.22 (d, 1H, J ) 7.8 Hz); 13C NMR (CDCl3, 150 MHz)
δ 24.8, 27.4, 46.3, 52.6, 53.1, 64.2, 72.2, 73.0, 109.4, 124.4, 126.5,
127.0, 127.8, 28.5, 128.6, 129.8, 129.9, 130.0, 132.3, 138.1, 140.4,
166.5, and 170.7. HRMS calcd for [(C25H25NO5) + H]+: 420.1806.
Found: 420.1804.
furnished diol 26 as a white solid in 98% yield: IR (neat) 3384,
1
1733, 1654, and 1242 cm-1; H NMR (CDCl3, 400 MHz) δ 2.40
(dd, 1H, J ) 12.8 and 6.4 Hz), 3.01 (d, 1H, J ) 12.8 Hz), 3.15 (d,
1H, J ) 6.0 Hz), 3.33 (d, 1H, J ) 5.6 Hz), 3.63 (s, 3H), 3.95 (t,
1H, J ) 6.0 Hz), 4.04 (t, 1H, J ) 5.6 Hz), 4.27 (d, 1H, J ) 6.4
Hz), 5.21 (d, 1H, J ) 16.0 Hz), 5.45 (d, 1H, J ) 16.0 Hz), 7.17 (d,
1H, J ) 7.6 Hz), 7.18-7.23 (m, 1H), 7.29-7.35 (m, 4H), 7.40
(dt, 1H, J ) 7.6 and 0.8 Hz), 7.53 (dt, 1H, J ) 7.6 and 1.2 Hz),
and 8.18 (dd, 1H, J ) 8.0 and 1.2 Hz); 13C NMR (CDCl3, 150
MHz) δ 39.2, 48.6, 53.4, 55.6, 73.0, 73.5, 77.2, 96.5, 126.0, 126.1,
126.2, 126.6, 128.3, 128.7, 129.3, 133.6, 139.5, 140.3, 165.8, and
171.6.
5-Benzyl-2,3,4-trihydroxy-6-oxo-2,3,4,4a,5,6-hexahydro-1H-
phenanthridine-10b-carboxylic Acid Methyl Ester (27). To a
suspension containing 1.8 g (0.49 mmol) of diol 26 in 100 mL of
CH2Cl2 at -78 °C was added 7.8 mL (4.9 mmol) of Et3SiH,
followed by the slow addition of 3.1 mL (2.5 mmol) of BF3‚Et2O.
After stirring for 1 h, the reaction mixture was allowed to warm to
rt and was stirred until the color of the reaction mixture turned
into green (ca. 20 min). The reaction mixture was quenched with
a saturated NH4Cl solution and extracted with CHCl3. The combined
organic extracts were dried over MgSO4 and concentrated under
reduced pressure. The residue was subjected to flash silica gel
chromatography to give 1.26 g (74%) of triol 27 as a clear oil: IR
(neat) 3383, 1729, and 1634 cm-1; 1H NMR (CDCl3, 400 MHz) δ
2.16 (t, 1H, J ) 12.8 Hz), 2.62 (dd, 1H, J ) 12.8 and 4.0 Hz),
3.43 (s, 3H), 3.98-4.03 (m, 1H), 4.09 (d, 1H, J ) 10.4 Hz), 4.15
(t, 1H, J ) 2.8 Hz), 4.72 (dd, 1H, J ) 10.4 and 3.6 Hz), 4.95 (d,
1H, J ) 16.0 Hz), 5.25 (d, 1H, J ) 16.0 Hz), 7.19-7.40 (m, 7H),
7.55 (dt, 1H, J ) 7.6 and 1.2 Hz), and 8.09 (dd, 1H, J ) 7.6 and
1.2 Hz); 13C NMR (CDCl3, 100 MHz) δ 33.4, 47.5, 50.4, 52.9,
62.4, 66.9, 67.8, 72.8, 124.6, 126.8, 127.0, 128.4, 128.5, 128.9,
129.1, 132.6, 139.5, 141.2, 166.8, and 172.2. HRMS calcd for
[(C22H23NO6) + H]+ 398.1598. Found: 398.1594.
12-Acetoxy-7-benzyl-16,16-dimethyl-6-oxo-7,8,11,12,13,14-
hexahydro-6H-15,17-dioxa-7-aza-cyclopenta[a]phenanthrene-9-
carboxylic Acid Methyl Ester (28). To a solution containing 0.90
g (2.3 mmol) of triol 27 in 20 mL of CH2Cl2 at 0 °C was added
0.9 mL (12 mmol) of pyridine, followed by the addition of 0.17
mL (2.4 mmol) of acetyl chloride in 2 mL of CH2Cl2. The reaction
mixture was stirred at 0 °C for 20 min, quenched with a saturated
NaHCO3 solution, and extracted with CHCl3. The organic extracts
were dried over MgSO4 and concentrated under reduced pressure.
The residue was taken up in 10 mL of THF and was concentrated
under reduced pressure in order to completely remove pyridine.
The residue was dissolved in 3 mL of DMF, followed by the
addition of 1.0 mL of 2,2-dimethoxypropane, and a catalytic amount
of p-toluene sulfonic acid was added. The reaction mixture was
stirred at rt for 12 h, quenched with a saturated NaHCO3 solution
and extracted with EtOAc. The combined organic layers were
washed with H2O and brine and dried over MgSO4. After removing
the solvent under reduced pressure, the residue was subjected to
flash silica gel chromatography to give 0.78 g (71%) of ketal 28
as a white solid: mp 206.5-207.5 °C; IR (neat) 1739, 1654, 1239,
and 1060 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.37 (s, 3H), 1.40
(s, 3H), 2.14 (s, 3H), 2.22 (dd, 1H, J ) 13.2 and 12.0 Hz), 2.79
(dd, 1H, J ) 13.2 and 4.8 Hz), 3.34 (s, 3H), 4.04 (d, 1H, J ) 8.8
Hz), 4.55 (t, 1H, J ) 4.4 Hz), 4.89 (d, 1H, J ) 15.6 Hz), 4.95 (dd,
1H, J ) 8.8 and 5.2 Hz), 5.26 (dt, 1H, J ) 12.0 and 4.4 Hz), 5.44
(d, 1H, J ) 15.6 Hz), 7.19-7.41 (m, 6H), 7.48 (dt, 1H, J ) 7.6
and 1.2 Hz), 7.56 (dt, 1H, J ) 7.6 and 1.6 Hz), and 8.19 (dd, 1H,
J ) 7.6 and 1.6 Hz); 13C NMR (CDCl3, 100 MHz) δ 21.4, 26.6,
28.5, 31.4, 46.5, 50.6, 53.0, 63.6, 67.4, 74.0, 75.0, 110.5, 124.6,
126.9, 128.0, 128.4, 128.6, 129.0, 129.3, 132.6, 139.4, 140.0, 166.0,
170.4, and 171.6. Anal. Calcd for C27H29NO7: C, 67.63; H, 6.10;
N, 2.92. Found: C, 67.50; H, 6.17; N, 2.88.
7-Benzyl-12-hydroxy-16,16-dimethyl-8,12,13,14-tetrahydro-
7H-15,17-dioxa-7-aza-cyclopenta[a]phenanthren-6-one (35). To
a solution of 0.30 g (0.7 mmol) of ketal 29 in 15 mL of acetone
and 1.5 mL of H2O was added 0.12 g (1.0 mmol) of NMO (N-
methylmorpholine-N-oxide) and catalytic OsO4. The mixture was
stirred at rt for 12 h, quenched with a saturated Na2S2O3 solution,
and extracted with EtOAc. The combined organic layers were
washed with H2O and brine, dried over MgSO4, and concentrated
under reduced pressure. To the residue were added 20 mL of THF,
0.5 mL (3.5 mmol) of Et3N, and 0.14 mL (1.8 mmol) of mesyl
chloride. The mixture was stirred at rt for 12 h, quenched with a
saturated NaHCO3 solution, and extracted with EtOAc. The organic
extracts were washed with H2O and brine and dried over MgSO4.
After concentration under reduced pressure, the residue was
subjected to flash silica gel chromatography to give 0.26 g (74%)
of mesylate 32 as a white solid: mp 231-232 °C; IR (neat) 1793,
1
1653, 1361, and 1182 cm-1; H NMR (CDCl3, 400 MHz) δ 1.35
(s, 3H), 1.51 (s, 3H), 3.23 (s, 3H), 4.32 (d, 1H, J ) 5.2 Hz), 4.48-
4.54 (m, 2H), 4.70 (d, 1H, J ) 16.8 Hz), 5.16 (d, 1H, J ) 3.6 Hz),
5.44 (d, 1H, J ) 16.8 Hz), 5.71 (s, 1H), 7.20-7.32 (m, 5H), 7.54-
7.58 (m, 2H), 7.80-7.91 (m, 1H), and 8.33-8.36 (m, 1H); 13C
NMR (CDCl3, 150 MHz) δ 25.6, 27.7, 39.7, 47.1, 50.7, 65.9, 73.2,
74.5, 79.4, 81.1, 113.1, 126.4, 126.5, 127.2, 128.9, 129.7, 130.1,
130.2, 131.2, 132.8, 138.6, 165.2, and 170.1. Anal. Calcd for C25H25-
NO8S: C, 60.11; H, 5.04; N, 2.80. Found: C, 59.87; H, 4.99; N,
2.85.
7-Benzyl-16,16-dimethyl-6-oxo-7,8,13,14-hexahydro-6H-15,-
17-dioxa-7-aza-cyclopenta[a]phenanthrene-9-carboxylic Acid
To a solution of 0.15 g (0.3 mmol) of the above mesylate 32 in
6 mL of THF was added a solution of 0.05 g (1.2 mmol) of LiOH
2578 J. Org. Chem., Vol. 72, No. 7, 2007

Synthesis of Phenanthridone Subclass of Amaryllidaceae
in 1 mL of H2O. The mixture was stirred at rt for 20 min and then
heated at 60 °C for 10 min. After cooling to rt, the mixture was
diluted with a saturated NH4Cl solution and EtOAc. The organic
extracts were washed with H2O and brine and dried over MgSO4.
Concentration under reduced pressure afforded 0.1 g (90%) of
alcohol 35 as a white solid: mp 246-247 °C; IR (neat) 3398 and
147.8, 148.7, 159.3, and 170.3. Anal. Calcd for C20H16INO5: C,
50.33; H, 3.38; N, 2.93. Found: C, 50.21; H, 3.34; N, 2.81.
5-(4-Methoxybenzyl)-2,4a-epoxy-6-oxo-2,4a,5,6-tetrahydro-
1H-[1.3]dioxolo-[4,5-j]phenanthridine-11b-carboxylic Acid Meth-
yl Ester (13). A Schlenk tube charged with 0.3 g (6.3 mmol) of
LiCl was dried with a flame under vacuum. Upon cooling, 0.12 g
(0.10 mmol) of Pd(PPh3)4 and 0.5 g (0.5 mmol) of CuCl were
added, and the mixture was degassed three times under vacuum
using an argon purge. To this mixture were added 8.4 mL of
anhydrous DMSO, 0.5 g (1.0 mmol) of iodide 11, and 0.47 g (1.3
mmol) of methyl 2-tri-n-butyl stannylacrylate.28 The resulting
mixture was vigorously degassed by several freeze-thaw cycles
(-78 to 25 °C). After stirring at rt for 1 h, the reaction mixture
was heated at 60 °C for 20 h. The mixture was then cooled to rt,
diluted with 200 mL of EtOAc, 50 mL of a saturated NaHCO3
solution, and 150 mL of H2O, and filtered over a Celite pad. The
organic layer was separated, washed with H2O and brine, and dried
over MgSO4. After removal of the solvent under reduced pressure,
the residue was subjected to flash silica gel chromatography with
a hexane/EtOAc/Et3N mixture to give 0.37 g (82%) of 13 as a pale
1
1627 cm-1; H NMR (CDCl3, 400 MHz) δ 1.28 (s, 3H), 1.56 (s,
3H), 2.65 (br s, 1H), 3.95 (t, 1H, J ) 7.6 Hz), 4.23 (dt, 1H, J )
8.0 and 2.4 Hz), 4.28-4.36 (m, 2H), 4.87 (d, 1H, J ) 14.8 Hz),
5.56 (d, 1H, J ) 14.8 Hz), 6.55 (t, 1H, J ) 2.8 Hz), 7.19-7.35
(m, 5H), 7.39 (dt, 1H, J ) 7.6 and 1.2 Hz), 7.48 (dt, J ) 7.6 and
1.2 Hz), and 8.30 (dd, 1H, J ) 7.6 and 1.2 Hz); 13C NMR (CDCl3,
150 MHz) δ 24.7, 27.3, 47.8, 59.7, 72.6, 79.8, 79.9, 111.7, 121.7,
125.7, 126.3, 127.3, 128.3, 128.5, 128.6, 128.9, 129.5, 131.8, 132.6,
137.8, and 162.7. Anal. Calcd for C23H23NO4: C, 73.19; H, 6.14;
N, 3.71. Found: C, 73.20; H, 6.10; N, 3.77.
6-Iodobenzo[1.3]dioxole-5-carboxylic Acid Furan-2-yl Amide
(39). To a solution of 4.5 g (25 mmol) of furan-2-ylcarbamic acid
2-tert-butyl ester (37a)48 in 40 mL of THF at 0 °C was added 11
mL (27 mmol) of a 2.5 M n-BuLi in hexane solution. The reaction
mixture was stirred for 20 min and was then added dropwise through
a cannula to a solution containing 6.4 g (21 mmol) of 6-iodobenzo-
[1.3]dioxole-5-carbonyl chloride (36)49 in 40 mL of THF at 0 °C.
The resulting solution was stirred at 0 °C for 20 min, diluted with
200 mL of H2O, and extracted with EtOAc. The combined extracts
were washed with H2O and brine, dried over MgSO4, and
concentrated under reduced pressure to afford carbamate 38 as a
brown oil.
yellow oil: IR (neat) 1733, 1655, 1513, 1447, 1383, and 1249 cm-1
;
1H NMR (CDCl3, 600 MHz) δ 2.51 (dd, 1H, J ) 12.0 and 4.8
Hz), 2,76 (d, 1H, J ) 12.0 Hz), 3.46 (s, 3H), 3.79 (s, 3H), 4.32 (d,
1H, J ) 15.6 Hz), 4.87 (dd, 1H, J ) 4.8 and 1.5 Hz), 5.43 (d, 1H,
J ) 15.6 Hz), 6.01 (s, 2H), 6.14 (d, 1H, J ) 5.4 Hz), 6.54 (dd, 1H,
J ) 5.4 and 1.5 Hz), 6.73 (s, 1H), 6.85 (d, 2H, J ) 8.4 Hz), 7.32
(d, 2H, J ) 8.4 Hz), and 7.67 (s, 1H); 13C NMR (CDCl3, 150 MHz)
δ 42.1, 48.4, 52.7, 54.3, 55.4, 74.4, 100.5, 102.1, 107.7, 108.9,
113.9, 121.6, 128.6, 130.7, 133.4, 134.7, 139.4, 147.9, 151.5, 158.8,
163.9, and 171.6. HRMS calcd for [(C24H21NO7) + H]+: 436.1391.
Found: 436.1395.
To this oil were added 50 mL of CH3CN and 1.9 g (6.2 mmol)
of Mg(ClO4)2. The reaction mixture was heated to 50 °C for 1 h,
cooled to rt, diluted with 300 mL of H2O, and extracted with EtOAc.
The combined organic layers were washed with H2O and brine and
dried over MgSO4. After removing the solvent under reduced
pressure, the residue was recrystallized from EtOAc to give 3.4 g
(46%) of the titled compound 39 as a white solid. The filtrate was
subjected to silica gel chromatography to give an additional 2.1 g
for an overall yield of 75%: mp 192-193 °C; IR (neat) 3228, 1660,
4-(4-Methoxybenzyl)-3b,12-epoxy-2,2-dimethyl-5-oxo-3a,4,5,-
11,12,12a-hexahydro-3bH-1,3,7,9-tetraoxa-4-aza-dicyclopenta-
[a,h]phenanthrene-10b-carboxylic Acid Methyl Ester (42). To
a solution of 0.90 g (2.1 mmol) of alkene 13 in 30 mL of CH3CN
and 3 mL of H2O was added 0.4 g (4.4 mmol) of 4-methylmor-
pholine-N-oxide and a catalytic amount of OsO4. The reaction
mixture was stirred at rt overnight and was then diluted with 200
mL of H2O and extracted with CH2Cl2. The organic extracts were
washed with H2O and brine and dried over MgSO4. Removal of
the solvent afforded diol 41 which was immediately taken up in 2
mL of DMF and 4 mL of 2,2-dimethoxypropane, and 0.1 g (0.4
mmol) of pyridinium p-toluenesulfonate was added. The reaction
mixture was stirred at rt overnight, quenched with a saturated
NaHCO3 solution, and extracted with EtOAc. The organic layer
was washed with H2O and brine and dried over MgSO4. After
concentration under reduced pressure, the residue was subjected
to flash silica gel chromatography to afford 0.9 g (80%) of 42 as
a pale yellow oil: IR (neat) 1731, 1655, 1513, 1484, 1448, and
1
1531, 1476, and 1243 cm-1; H NMR (acetone-d6, 600 MHz) δ
6.12 (s, 2H), 6.40 (d, 1H, J ) 2.4 Hz), 6.46 (t, 1H, J ) 2.4 Hz),
7.10 (s, 1H), 7.23 (dd, 1H, J ) 2.4 and 1.2 Hz), 7.36 (s, 1H), and
10.07 (br s, 1H); 13C NMR (acetone-d6, 150 MHz) δ 82.5, 95.5,
97.8, 103.5, 109.6, 112.2, 119.8, 136.4, 147.5, 149.2, 150.7, and
165.5. Anal. Calcd for C12H8INO4: C, 40.36; H, 2.26; N, 3.92.
Found: C, 40.51; H, 2.12; N, 3.93.
6-Iodobenzo[1.3]dioxole-5-carboxylic Acid Furan-2-yl-(4-
methoxybenzyl) Amide (11). To a solution of 0.70 g (1.9 mmol)
of the above amide 39 in 8 mL of DMF at 0 °C was added 0.09 g
(2.3 mmol) of NaH (60% in mineral oil) in several portions. After
stirring for 10 min, the reaction mixture was warmed to rt and was
stirred for an additional 30 min. The reaction mixture was cooled
to 0 °C, and 0.4 mL (2.8 mmol) of 4-methoxybenzyl chloride was
added dropwise. After stirring for 15 min, the cooling bath was
removed and the reaction mixture was stirred at rt for 4 h. The
mixture was quenched with H2O and extracted with EtOAc. The
combined extracts were washed with H2O and brine and dried over
MgSO4. After concentration under reduced pressure, the residue
was subjected to silica gel chromatography to give 0.7 g (83%) of
iodide 11 as a white solid: mp 119.5-120.5 °C; IR (neat) 1671,
1610, 1512, 1478, and 1237 cm-1; 1H NMR (CDCl3, 400 MHz) δ
3.79 (s, 3H), 4.90 (s, 2H), 5.76 (d, 1H, J ) 3.2 Hz), 5.91 (s, 2H),
6.07 (dd, 1H, J ) 3.2 and 2.4 Hz), 6.62 (s, 1H), 6.83 (d, 2H, J )
8.8 Hz), 7.08 (s, 1H), 7.08-7.10 (br m, 1H), and 7.29 (d, 2H, J )
8.8 Hz); 13C NMR (CDCl3, 150 MHz) δ 51.1, 55.4, 82.2, 102.0,
105.8, 108.0, 111.1, 113.9, 118.7, 128.8, 130.6, 135.7, 140.0, 147.3,
1
1246 cm-1; H NMR (CDCl3, 600 MHz) δ 1.19 (s, 3H), 1.37 (s,
3H), 2.26 (dd, 1H, J ) 12.6 and 6.0 Hz), 2.92 (d, 1H, J ) 12.6
Hz), 3.56 (s, 3H), 3.77 (s, 3H), 4.14 (d, 1H, J ) 4.8 Hz), 4.30 (d,
1H, J ) 6.6 Hz), 4.42 (d, 1H, J ) 5.4 Hz), 5.18 (d, 1H, J ) 15.6
Hz), 5.37 (d, 1H, J ) 15.6 Hz), 6.00 (s, 2H), 6.50 (s, 1H), 6.80 (d,
2H, J ) 8.4 Hz), 7.23 (d, 2H, J ) 8.4 Hz), and 7.61 (s, 1H); 13C
NMR (CDCl3, 150 MHz) δ 25.1, 25.8, 39.2, 46.9, 53.4, 54.9, 55.5,
74.9, 80.6, 82.6, 96.5, 102.1, 105.5, 108.5, 112.6, 113.4, 120.9,
128.2, 132.2, 135.6, 147.8, 152.0, 158.1, 164.7, and 171.4. HRMS
calcd for [(C27H27NO9) + H]+: 510.1759. Found: 510.1756.
12-Hydroxy-4-(4-methoxybenzyl)-2,2-dimethyl-5-oxo-3a,4,5,-
11,12,12a-hexahydro-3bH-1,3,7,9-tetraoxa-4-aza-dicyclopenta-
[a,h]phenanthrene-10b-carboxylic Acid Methyl Ester (14). To
a solution of 0.20 g (0.4 mmol) of acetonide 42 in 6 mL of CH2Cl2
at -78 °C were added 3.1 mL (0.8 mmol) of a 0.25 M solution of
Zn(BH4)2 in Et2O36 and 0.14 mL (0.8 mmol) of TMSOTf,
respectively. After stirring for 20 min at -78 °C, the reaction
mixture was allowed to warm to rt and was stirred for an additional
4 h. The mixture was quenched with a saturated NH4Cl solution,
and the aqueous layer was extracted with CH2Cl2. The combined
(48) Padwa, A.; Brodney, M. A.; Lynch, S. M. Org. Synth. 2002, 78,
202.
(49) McIntosh, M. C.; Weinreb, S. M. J. Org. Chem. 1993, 58, 4823.
J. Org. Chem, Vol. 72, No. 7, 2007 2579

Padwa and Zhang
organic extracts were washed with H2O and brine and dried over
MgSO4. After removing the solvent under reduced pressure, the
residue was dissolved in 5 mL of THF, and this was followed by
the addition of 0.4 mL (0.4 mmol) of TBAF (1.0 M in THF) at rt.
After stirring for 5 min, the mixture was diluted with a saturated
NH4Cl solution and EtOAc. The organic layer was separated, and
the aqueous layer was extracted with EtOAc. The combined organic
extracts were washed with brine and dried over MgSO4. After
concentration under reduced pressure, the residue was subjected
to flash silica gel chromatography to afford 0.15 g (74%) of alcohol
14 as a white solid: mp 204.5-205.5 °C; IR (neat) 3396, 1728,
1639, 1512, 1456, and 1244 cm-1; 1H NMR (CDCl3, 400 MHz) δ
1.39 (s, 3H), 1.43 (s, 3H), 2.04 (dd, 1H, J ) 13.6 and 10.4 Hz),
2.24 (d, 1H, J ) 8.8 Hz), 2.69 (dd, 1H, J ) 13.6 and 5.2 Hz), 3.32
(s, 3H), 3.77 (s, 3H), 4.02 (d, 1H, J ) 8.8 Hz), 4.02-4.08 (m,
1H), 4.47 (dd, 1H, J ) 5.2 and 4.4 Hz), 4.73 (d, 1H, J ) 15.6 Hz),
4.88 (dd, 1H, J ) 8.4 and 5.6 Hz), 5.37 (d, 1H, J ) 15.6 Hz), 6.03
(d, 1H, J ) 1.2 Hz), 6.04 (d, 1H, J ) 1.2 Hz), 6.80 (d, 2H, J ) 8.8
Hz), 6.86 (s, 1H), 7.23 (d, 2H, J ) 8.8 Hz), and 7.59 (s, 1H); 13C
NMR (CDCl3, 100 MHz) δ 26.4, 28.4, 35.4, 45.9, 50.2, 52.8, 55.4,
63.8, 65.6, 74.8, 75.9, 102.1, 105.1, 108.8, 109.9, 113.7, 123.7,
129.1, 132.2, 135.3, 147.9, 151.3, 158.6, 165.6, and 172. Anal.
Calcd for C27H29NO9: C, 63.4; H, 5.71; N, 2.74. Found: C, 63.0;
H, 5.60; N, 2.70.
4-(4-Methoxybenzyl)-2,2-dimethyl-5-oxo-3a,4,5,12a-tetrahy-
dro-3bH-1,3,7,9-tetraoxa-4-aza-dicyclopenta[a,h]phenanthrene-
10b-carboxylic Acid Methyl Ester (43). To a solution of 0.40 g
(0.7 mmol) of alcohol 14 in 7 mL of THF was added 0.09 g (2.2
mmol) of NaH (60% in mineral oil) at 0 °C. After stirring for 10
min, the mixture was warmed to rt and was stirred for an additional
30 min. The solution was cooled to 0 °C, and 0.26 mL (4.4 mmol)
of CS2 was added; the mixture was stirred for 1 h at this
temperature, and then 0.5 mL (8.8 mmol) of MeI was added. After
stirring for 10 min, the mixture was warmed to rt and was stirred
for an additional 20 min. The solution was quenched with a
saturated NH4Cl solution and then extracted with EtOAc. The
combined organic extracts were washed with H2O and brine and
dried over MgSO4. After concentration under reduced pressure, the
residue was dissolved in 20 mL of 1,2-dichlorobenzene and was
heated at reflux for 12 h. After cooling to room temperature, the
mixture was concentrated under reduced pressure and subjected to
flash silica gel chromatography to give 0.34 g (94%) of alkene 43
as a pale yellow oil: IR (neat) 1733, 1650, 1512, 1275, 1244, 1210,
and 1037 cm-1; 1H NMR (CDCl3, 600 MHz) δ 1.43 (s, 3H), 1.44
(s, 3H), 3.25 (s, 3H), 3.77 (s, 3H), 3.91 (d, 1H, J ) 9.0 Hz), 4.68
(d, 1H, J ) 15.6 Hz), 4.81 (dt, 1H, J ) 7.2 and 1.8 Hz), 4.99 (dd,
1H, J ) 9.0 and 7.2 Hz), 5.49 (d, 1H, J ) 15.6 Hz), 6.05 (s, 2H),
6.18 (dd, 1H, J ) 9.6, and 1.8 Hz), 6.26 (dd, 1H, J ) 9.6 and 1.2
Hz), 6.80 (d, 2H, J ) 9.0 Hz), 6.93 (s, 1H), 7.23 (d, 2H, J ) 9.0
Hz), and 7.64 (s, 1H); 13C NMR (CDCl3, 150 MHz) δ 24.8, 27.5,
45.6, 52.5, 53.1, 55.5, 64.3, 72.2, 72.9, 102.1, 105.0, 109.4, 109.5,
113.9, 124.7, 126.6, 129.1, 130.2, 132.7, 133.8, 147.8, 151.2, 158.6,
165.9, and 170.8. HRMS calcd for [(C27H27NO8) + H]+: 494.1809.
Found: 494.1805.
mmol) of Et3N, and 0.12 mL (1.5 mmol) of MsCl. The mixture
was stirred at room temperature for 6 h and was then quenched
with a saturated NaHCO3 solution and extracted with EtOAc. The
organic layer was washed with H2O and brine and dried over
MgSO4. After removing the solvent under reduced pressure, the
residue was subjected to flash silica gel chromatography to give
0.22 g (76%) of 46 as a white solid: mp 179-180 °C; IR (neat)
1
1788, 1653, 1608, 1508, 1245, 1179, and 1037 cm-1; H NMR
(CDCl3, 600 MHz) δ 1.35 (s, 3H), 1.52 (s, 3H), 3.22 (s, 3H), 3.76
(s, 3H), 4.27 (d, 1H, J ) 5.4 Hz), 4.48-4.51 (m, 2H), 4.57 (d, 1H,
J ) 16.2 Hz), 5.12 (d, 1H, J ) 3.6 Hz), 5.37 (d, 1H, J ) 16.2 Hz),
5.63 (s, 1H), 6.04 (s, 1H), 6.06 (s, 1H), 6.82 (d, 2H, J ) 8.4 Hz),
7.13 (d, 2H, J ) 8.4 Hz), 7.31 (s, 1H), and 7.75 (s, 1H); 13C NMR
(CDCl3, 150 MHz) δ 25.7, 27.7, 39.7, 46.3, 50.8, 5.4, 66.0, 73.2,
74.3, 79.4, 81.4, 102.4, 106.6, 109.8, 113.1, 114.3, 125.4, 126.2,
127.7, 130.7, 148.7, 151.5, 158.8, 164.6, and 170.1. Anal. Calcd
for C27H27NO11S: C, 56.54; H, 4.74; N, 2.44. Found: C, 56.29;
H, 4.55; N, 2.18
Methanesulfonic Acid 2,2-Dimethyl-5,10b-dioxo-3a,3b,4,5,-
10b,11,12,12a-octanhydro-1,3,7,9,12-pentaoxa-4-aza-dicyclopen-
ta[a,h]phenanthren-11-yl Ester. To a solution of 0.07 g (0.12
mmol) of mesylate 46 in 1.0 mL of EtOAc were added 1.0 mL of
CH3COOH and 0.04 g (0.24 mmol) of PdCl2. The resulting
suspension was stirred under a hydrogen atmosphere (80 psi)
overnight. The mixture was diluted with EtOAc and filtered over
a Celite pad. After concentration under reduced pressure, the residue
was subjected to flash silica gel chromatography to give 0.04 g
(65%) of the titled compound as a white solid: mp 240-241 °C;
IR (neat) 1793, 1678, 1180, and 1035 cm-1; 1H NMR (CDCl3, 400
MHz) δ 1.42 (s, 3H), 1.56 (s, 3H), 3.25 (s, 3H), 4.04 (d, 1H, J )
6.8 Hz), 4.22 (t, 1H, J ) 6.4 Hz), 4.73 (dd, 1H, J ) 5.6 and 4.4
Hz), 5.24 (d, 1H, J ) 4.4 Hz), 5.59 (s, 1H), 5.98 (br s, 1H), 6.05
(d, 1H, J ) 1.2 Hz), 6.08 (d, 1H, J ) 1.2 Hz), 7.28 (s, 1H), and
7.69 (s, 1H); 13C NMR (CDCl3, 150 MHz) δ 26.0, 28.0, 39.8, 50.6,
60.1, 60.6, 73.7, 79.7, 81.8, 102.6, 107.3, 109.4, 114.3, 124.8, 127.1,
148.8, 152.0, 164.4, and 169.6. HRMS calcd for [(C19H19NO10S)
+ H]+: 454.0802. Found: 454.0803.
12-Hydroxy-2,2-dimethyl-3b,4,12,12a-tetrahydro-3aH-1,3,7,9-
tetraoxa-4-aza-dicyclopenta[a,h]phenanthren-5-one (47). To a
solution containing 5 mg (0.01 mmol) of the above compound in
2 mL of THF was added a solution of 2 mg (0.1 mmol) of LiOH
in 0.5 mL of H2O. The reaction mixture was stirred at rt for 20
min and then heated to 60 °C for 10 min. After cooling to rt, the
mixture was diluted with a saturated NH4Cl solution and EtOAc
was added. The organic layer was washed with H2O and brine and
dried over MgSO4. Concentration under reduced pressure afforded
3.4 mg (93%) of alcohol 47 as a white solid whose spectral
properties were identical to that reported in the literature:50 IR (neat)
1
3350, 1653, 1475, 1257, 1059, and 1035 cm-1; H NMR (CDCl3,
600 MHz) δ 1.38 (s, 3H), 1.53 (s, 3H), 1.64 (br s, 1H), 4.13-4.15
(m, 3H), 4.38-4.40 (m, 1H), 6.03 (d, 1H, J ) 1.8 Hz), 6.04 (d,
1H, J ) 1.8 Hz), 6.25 (br s, 1H), 7.04 (s, 1H), and 7.60 (s, 1H);
13C NMR (CDCl3, 150 MHz) δ 24.9, 27.2, 56.2, 73.2, 79.1, 79.7,
101.6, 102.2, 107.9, 111.7, 121.0, 124.1, 127.8, 128.5, 148.9, 152.1,
and 162.6.
(()-Lycoricidine (7). To a flask containing 3 mg (0.01 mmol)
of alcohol 47 at 0 °C was added 0.3 mL of cold (-20 °C) TFA.
After stirring for 40 min, the solution was diluted with 2 mL of
cold dioxane and concentrated under reduced pressure. The residue
was subjected to flash silica gel chromatography to give 2.3 mg
(90%) of (()-lycoricidine (7) as a white solid whose spectral
properties were identical to those reported in the literature:50 1H
NMR (methanol-d4, 400 MHz) δ 3.89-3.92 (m, 2H), 4.24 (ddd,
1H, J ) 4.8, 2.0, and 1.6 Hz), 4.37 (ddd, 1H, J ) 8.0, 2.4, and 1.6
Hz), 6.04 (d, 1H, J ) 1.2 Hz), 6.05 (d, 1H, J ) 1.2 Hz), 6.16 (m,
1H), 7.15 (s, 1H), and 7.38 (s, 1H).
Methanesulfonic Acid 4-(4-Methoxybenzyl)-2,2-dimethyl-5,-
10b-dioxo-3a,3b,4,5,10b,11,12,12a-octahydro-1,3,7,9,12-pentaoxa-
4-aza-dicyclopenta[a,h]phenanthren-11-yl Ester (46). To a so-
lution of 0.25 g (0.5 mmol) of alkene 43 in 8 mL of acetone and
0.8 mL of H2O was added 0.08 g (0.7 mmol) of 4-methylmorpho-
line-N-oxide and a catalytic amount of OsO4. The reaction mixture
was stirred at rt for 12 h, quenched with a saturated Na2S2O3
solution, and extracted with EtOAc. The combined organic layer
was washed with H2O and brine and dried over MgSO4. After
concentration under reduced pressure, the residue was dissolved
in 10 mL of THF and a catalytic amount of NaOMe was added.
After stirring for 20 min, the mixture was quenched with 50 mL
of H2O and extracted with EtOAc. The combined organic layer
was dried over MgSO4 and concentrated under reduced pressure.
To the resulting residue were added 20 mL of THF, 0.4 mL (3.1
(50) Keck, G. E.; Wager, T. T.; Rodriquez, J. F. D. J. Am. Chem. Soc.
1999, 121, 5176.
2580 J. Org. Chem., Vol. 72, No. 7, 2007

Synthesis of Phenanthridone Subclass of Amaryllidaceae
12-Benzyloxy-4-(4-methoxybenzyl)-2,2-dimethyl-5-oxo-3a,4,5,-
11,12,12a-hexahydro-3bH-1,3,7,9-tetraoxa-4-aza-dicyclopenta-
[a,h]phenanthrene-10b-carbaldehyde (50). To a solution of 1.6
g (3.0 mmol) of alcohol 14 in 60 mL of DMF at 0 °C was added
0.16 g (4.0 mmol) of NaH (60% dispersion in mineral oil). After
stirring for 10 min, the reaction mixture was warmed to rt and was
stirred for an additional 30 min. The reaction mixture was cooled
to 0 °C, and 0.5 mL (4.3 mmol) of benzyl bromide was added
dropwise. After stirring for 20 min, the reaction mixture was
warmed to rt and was stirred for an additional 5 h. The mixture
was quenched with a saturated NH4Cl solution and extracted with
EtOAc. The combined organic layers were washed with H2O and
brine and dried over MgSO4. After removal of the solvent under
reduced pressure, the residue was subjected to flash silica gel
chromatography to give 1.7 g (91%) of 12-benzyloxy-4-(4-
methoxybenzyl)-2,2-dimethyl-5-oxo-3a,4,5,11,12,12a-hexahydro-
3bH-1,3,-7,9-tetraoxa-4-aza-dicyclopenta[a,h]phenanthrene-10b-
carboxylic acid methyl ester as a colorless oil: IR (neat) 1731,
12-Hydroxy-4-(4-methoxybenzyl)-2,2-dimethyl-3a,4,5,11,12,-
12a-hexahydro-3bH-1,3,7,9-tetraoxa-4-aza-dicyclopenta[a,h]-
phenanthrene-10b-carboxylic Acid Methyl Ester (51). To a
solution of 0.05 g (0.1 mmol) of alcohol 14 in a mixture containing
2 mL of CH2Cl2 and 1 mL of THF at -78 °C was added dropwise
0.4 mL (0.4 mmol) of DIBAL (1.0 M in CH2Cl2). The reaction
mixture was stirred at this temperature for 1 h and was quenched
by the addition of 0.4 g of powdered Na2SO4‚10H2O and 0.4 g of
Celite. The reaction mixture was warmed to rt, stirred for an
additional 20 min, and filtered through a pad of anhydrous MgSO4.
The filtrate was concentrated under reduced pressure and subjected
to flash silica gel chromatography to give 0.04 g (91%) of 51 as a
colorless oil: IR (neat) 3400, 1727, 1511, 1487, 1240, and 1039
1
cm-1; H NMR (CDCl3, 400 MHz) δ 1.40 (s, 3H), 1.53 (s, 3H),
1.97 (dd, 1H, J ) 13.2 and 10.4 Hz), 2.23 (d, 1H, J ) 8.4 Hz),
2.66 (dd, 1H, J ) 13.2 and 5.0 Hz), 2.83 (d, 1H, J ) 8.8 Hz), 3.27
(d, 1H, J ) 13.6 Hz), 3.30 (d, 1H, J ) 15.6 Hz), 3.64 (s, 3H), 3.70
(d, 1H, J ) 15.6 Hz), 3.79 (s, 3H), 4.14-4.20 (m, 1H), 4.42 (d,
1H, J ) 13.6 Hz), 4.56 (dd, 1H, J ) 5.6 and 4.4 Hz), 4.92 (dd,
1H, J ) 8.8 and 5.6 Hz), 5.89 (d, 1H, J ) 1.4 Hz), 5.90 (d, 1H, J
) 1.4 Hz), 6.34 (s, 1H), 6.81 (d, 2H, J ) 8.8 Hz), 6.89 (s, 1H),
and 7.24 (d, 2H, J ) 8.8 Hz); 13C NMR (CDCl3, 100 MHz) δ
26.4, 28.5, 37.2, 51.8, 52.5, 55.4, 56.9, 57.3, 66.4, 67.0, 76.1, 76.6,
101.1, 105.9, 107.5, 109.1, 113.8, 128.8, 129.7, 130.5, 132.6, 146.3,
146.8, 158.6, and 174.3.
1
1648, 1512, 1453, 1244, and 1035 cm-1; H NMR (CDCl3, 400
MHz) δ 1.39 (s, 3H), 1.42 (s, 3H), 2.09 (t, 1H, J ) 12.4 Hz), 2.59
(dd, 1H, J ) 12.4 and 4.4 Hz), 3.19 (s, 3H), 3.70 (dt, 1H, J ) 12.4
and 4.4 Hz), 3.76 (s, 3H), 3.93 (d, 1H, J ) 8.8 Hz), 4.46 (t, 1H, J
) 4.4 Hz), 4.67 (s, 2H), 4.78 (d, 1H, J ) 15.6 Hz), 4.86 (dd, 1H,
J ) 8.8 and 4.4 Hz), 5.31 (d, 1H, J ) 15.6 Hz), 6.03 (d, 1H, J )
1.2 Hz), 6.04 (d, 1H, J ) 1.2 Hz), 6.79 (d, 2H, J ) 8.8 Hz), 6.85
(s, 1H), 7.22 (d, 2H, J ) 8.8 Hz), 7.28-7.38 (m, 5H), and 7.57 (s,
1H); 13C NMR (CDCl3, 100 MHz) δ 26.7, 28.6, 32.0, 45.9, 50.3,
52.6, 55.4, 63.9, 71.0, 71.4, 74.4, 75.0, 102.1, 105.0, 108.8, 110.2,
113.6, 123.7, 128.3, 128.4, 129.2, 132.2, 135.0, 137.7, 147.9, 151.3,
158.5, 165.5, and 171.6.
12-Benzyloxy-4-(4-methoxybenzyl)-2,2-dimethyl-3b,4,10b,11,-
12,12a-hexahydro-3aH-1,3,7,9-tetraoxa-4-aza-dicyclopenta[a,h]-
phenanthren-5-one (52). To a solution of 1.2 g (2.1 mmol) of
aldehyde 50 in 50 mL of benzonitrile was added 2.9 g (3.2 mmol)
of RhCl(PPh3)3. The mixture was heated at reflux in a preheated
oil bath for 24 h. After cooling to rt, the mixture was subjected to
flash silica gel chromatography to give 0.73 g (63%) of amide 52
as a pale yellow oil: IR (neat) 1647, 1512, 1457, 1245, and 1040
To a solution of 1.7 g (2.8 mmol) of the above benzyl ether in
30 mL of THF and 15 mL of MeOH was added a solution of 1.2
g (28 mmol) of LiOH in 15 mL of H2O. The reaction mixture was
heated at reflux for 12 h. After cooling to rt, the mixture was
acidified to pH of 3 with 3 N HCl and was extracted with EtOAc.
The organic extracts were dried over MgSO4 and concentrated under
reduced pressure. To the residue was added 10 mL of CH2Cl2,
followed by the addition of 0.4 mL (4 mmol) of (COCl)2 and several
drops of DMF as a catalyst. The resulting mixture was stirred at rt
for 2 h and then concentrated under reduced pressure. The residue
was taken up in 5 mL of CH2Cl2 and was concentrated under
reduced pressure in order to completely remove the excess HCl
and oxalyl chloride. The residue was taken up in 15 mL of CH2-
Cl2, cooled to 0 °C, and then 22 mL (5.6 mmol) of Zn(BH4) 2 (0.25
M in Et2O) was added. After stirring for 20 min, the reaction
mixture was warmed to rt and was stirred for an additional 6 h.
The solution was quenched with a saturated NH4Cl solution and
extracted with CH2Cl2. The combined organic extracts were washed
with brine, dried over MgSO4, and concentrated under reduced
pressure to 50 mL. To this crude solution were added 1.4 g 4 Å
molecular sieves and 0.5 g (4.2 mmol) of NMO (N-methylmor-
pholine-N-oxide), followed by the addition of 0.05 g (0.14 mmol)
of TPAP in several portions. The mixture was stirred at rt for 3 h
and filtered through a pad of Celite. The filtrate was concentrated
under reduced pressure, and the residue was subjected to flash
silica gel chromatography to give 1.2 g (77%) of aldehyde 50 as a
pale yellow oil: IR (neat) 1719, 1648, 1610, 1511, 1453, 1269,
1245, and 1036 cm-1; 1H NMR (CDCl3, 600 MHz) δ 1.35 (s, 3H),
1.45 (s, 3H), 1.98 (dd, 1H, J ) 12.6 and 10.8 Hz), 2.69 (dd, 1H,
J ) 12.6 and 5.4 Hz), 3.73-3.76 (m, 1H), 3.77 (s, 3H), 4.25-4.27
(m, 2H), 4.49 (dd, 1H, J ) 9.0 and 5.4 Hz), 4.65 (d, 1H, J ) 12.0
Hz), 4.68 (d, 1H, J ) 12.0 Hz), 4.79 (d, 1H, J ) 15.6 Hz), 5.44 (d,
1H, J ) 15.6 Hz), 6.04 (d, 1H, J ) 0.9 Hz), 6.06 (d, 1H, J ) 0.9
Hz), 6.70 (s, 1H), 6.81 (d, 2H, J ) 8.7 Hz), 7.22 (d, 2H, J ) 8.7
Hz), 7.29-7.36 (m, 5H), 7.68 (s, 1H), 9.40 (s, 1H); 13C NMR
(CDCl3, 100 MHz) δ 26.4, 28.3, 29.1, 45.9, 52.9, 55.4, 62.8, 71.1,
72.0, 74.1, 74.6, 102.3, 104.6, 109.5, 110.3, 114.0, 124.6, 128.2,
128.7, 128.9, 131.6, 131.7, 137.9, 148.6, 152.1, 158.7, 165.0,
197.9.
1
cm-1; H NMR (CDCl3, 600 MHz) δ 1.37 (s, 3H), 1.40 (s, 3H),
1.86 (q, 1H, J ) 12.6 Hz), 2.42 (dt, 1H, J ) 12.6 and 3.6 Hz),
2.63 (td, 1H, J ) 12.6 and 3.6 Hz), 3.65-3.72 (m, 2H), 4.20 (dd,
1H, J ) 8.4 and 4.8 Hz), 4.36 (t, 1H, J ) 4.8 Hz), 4.72 (s, 2H),
4.88 (d, 1H, J ) 15.6 Hz), 5.27 (d, 1H, J ) 15.6 Hz), 6.02 (s, 1H),
6.78(s, 1H), 6.80 (d, 2H, J ) 8.4 Hz), 7.20 (d, 2H, J ) 8.4 Hz),
7.29-7.32 (m, 1H), 7.34-7.39 (m, 4H), and 7.61 (s, 1H); 13C NMR
(CDCl3, 150 MHz) δ 26.6, 27.5, 28.3, 36.4, 46.0, 55.5, 62.7, 71.2,
73.5, 74.8, 76.6, 101.9, 104.1, 109.0, 110.3, 114.0, 123.5, 128.1,
128.2, 128.3, 128.8, 132.4, 134.9, 138.0, 147.2, 151.3, 158.5, and
165.7. HRMS calcd for [(C32H33NO7) + H]+ 544.2330. Found:
544.2320.
4-(4-Methoxybenzyl)-2,2-dimethyl-3b,4,10b,12a-tetrahydro-
3aH-1,3,7,9-tetraoxa-4-aza-dicyclopenta[a,h]phenanthren-5-
one (53). To a solution of 0.30 g (0.55 mmol) of 52 in 8 mL of
degassed EtOAc was added 0.15 g of Pearlman’s catalyst (20%
Pd(OH)2 on carbon). The reaction mixture was stirred at rt under
a H2 balloon for 6 h, filtered through a pad of Celite, concentrated
under reduced pressure, and the residue was taken up in 15 mL of
THF. To the above solution at 0 °C was added 0.07 g (1.6 mmol)
of NaH (60% dispersion in mineral oil) in several portions. After
stirring for 10 min, the cooling bath was removed and the solution
was stirred at rt for 40 min. The reaction mixture was cooled to 0
°C and 85 µL (3.3 mmol) of CS2 was added. After stirring at 0 °C
for 1 h, 0.2 mL (6.6 mmol) of methyl iodide was added and the
resulting mixture was stirred at 0 °C for 10 min and then at rt for
8 h. The reaction mixture was quenched with a saturated NH4Cl
solution and extracted with EtOAc. The combined organic layers
were washed with H2O and brine and dried over MgSO4. After
removing the solvent under reduced pressure, the residue was taken
up in 20 mL of o-dichlorobenzene and was heated at reflux for 24
h. After cooling to rt, the reaction mixture was subjected to flash
silica gel chromatography to give 0.21 g (85%) of alkene 53 as a
white solid: mp 171-173 °C; IR (neat) 2924, 1645, 1511, 1456,
1246, and 1038 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.34 (s, 6H),
3.46 (dd, 1H, J ) 11.6 and 3.0 Hz), 3.64 (dd, 1H, J ) 11.6 and
J. Org. Chem, Vol. 72, No. 7, 2007 2581

Padwa and Zhang
9.0 Hz), 3.77 (s, 3H), 4.37 (dd, 1H, J ) 9.0 and 7.0 Hz), 4.59-
4.62 (m, 1H), 4.95 (d, 1H, J ) 15.6 Hz), 5.40 (d, 1H, J ) 15.6
Hz), 6.03 (s, 2H), 6.09 (dt, 1H, J ) 10.0 and 3.0 Hz), 6.32 (d, 1H,
J ) 10.0 Hz), 6.81 (d, 2H, J ) 8.8 Hz), 6.90 (s, 1H), 7.25 (d, 2H,
J ) 8.8 Hz), and 7.65 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ
25.4, 27.7, 38.7, 45.9, 55.4, 60.9, 72.0, 75.0, 101.9, 103.9, 109.3,
109.4, 113.8, 123.8, 126.2, 128.1, 128.4, 132.7, 133.8, 147.0, 151.2,
158.4, and 165.6. HRMS calcd for [(C25H25NO6) + H]+: 436.1755.
Found: 436.1757.
2,3,4-Trihydroxy-5-(4-methoxybenzyl)-6-oxo-1,2,3,4,4a,5,6,-
11b-octahydro[1,3]dioxolo[4,5-j]phenanthridine-1-carboxylic Acid
Phenyl Ester (56). To a solution of 0.02 g (0.04 mmol) of sulfate
55 in 1.5 mL of DMF at rt were added 9 mg (0.07 mmol) of benzoic
acid and 0.02 g (0.06 mmol) of Cs2CO3. After cooling to rt, 2 mL
of THF and 3 mL of a 40% H2SO4 solution were added and the
mixture was heated at 80 °C for 6 h, cooled to room temperature,
and diluted with H2O and EtOAc. The combined organic layer was
washed with a saturated NaHCO3 solution and brine and dried over
MgSO4. The solvent was removed under reduced pressure, and the
residue was subjected to flash silica gel chromatography to give
16 mg (75%) of 56 as a white solid: mp 230-231 °C; IR (neat)
11,12-Dihydroxy-4-(4-methoxybenzyl)-2,2-dimethyl-3b,4,10b,-
11,12,12a-hexahydro-3aH-1,3,7,9-tetraoxa-4-aza-dicyclopenta-
[a,h]phenanthren-5-one (54). To a solution of 0.15 g (0.34 mmol)
of 53 in 20 mL of acetone and 2 mL of H2O was added NMO
(N-methylmorpholine-N-oxide) and catalytic OsO4. The mixture was
stirred at rt for 24 h and then quenched with a saturated Na2S2O3
solution in EtOAc. The combined organic layers were washed with
brine, dried over MgSO4, and concentrated under reduced pressure.
The residue was subjected to flash silica gel chromatography to
give 0.11 g (68%) of diol 54 as a pale yellow oil: IR (neat) 3401,
1
3420, 1714, 1602, 1509, 1463, 1270, and 1034 cm-1; H NMR
(CDCl3, 600 MHz) δ 2.68 (d, 1H, J ) 4.2 Hz), 3.04 (d, 1H, J )
4.2 Hz), 3.37 (br s, 1H), 3.65 (dd, 1H, J ) 13.8 and 4.2 Hz), 3.79
(s, 3H), 3.96-4.30 (m, 3H), 4.95 (d, 1H, J ) 16.2 Hz), 5.36 (d,
1H, J ) 16.2 Hz), 5.62 (t, 1H, J ) 3.6 Hz), 5.93 (d, 1H, J ) 0.9
Hz), 5.95 (d, 1H, J ) 0.9 Hz), 6.57 (s, 1H), 6.85 (d, 2H, J ) 9.0
Hz), 7.31 (d, 2H, J ) 8.4 Hz), 7.40 (t, 2H, J ) 8.4 Hz), 7.57 (t,
1H, J ) 8.4 Hz), 7.68 (s, 1H), and 7.80 (d, 2H, J ) 9.0 Hz); 13C
NMR (DMSO-d6, 150 MHz) δ 38.9, 45.1, 55.0, 57.1, 67.4, 67.5,
70.4, 72.0, 101.7, 103.4, 107.7, 113.6, 123.8, 127.5, 128.6, 129.5,
129.7, 133.0, 133.4, 133.5, 146.3, 150.5, 157.6, 164.3, and 165.4.
(()-7-Deoxypancratistatin (10). To a solution of 13 mg (0.02
mmol) of ester 56 in 2 mL of THF at 25 °C was added 4 mg (0.06
mmol) of NaOMe. The reaction mixture was stirred at 25 °C for 6
h, and then the mixture was quenched with a saturated NH4Cl
solution and extracted with EtOAc. The combined organic layer
was washed with brine, dried over MgSO4, and concentrated under
reduced pressure. The residue was taken up in 3 mL of degassed
THF followed by the addition of 0.05 g (0.08 mmol) of Pearlman’s
catalyst (20% Pd(OH)2 on carbon). The mixture was stirred under
a H2 atmosphere at rt overnight, filtered through Celite, and
concentrated under reduced pressure. The crude residue was
subjected to flash silica gel chromatography to give 6 mg (80%)
of (()-7-deoxypancratistatin (10) as a colorless oil:13 1H NMR
(DMSO-d6, 600 MHz) δ 2.98 (dd, 1H, J ) 12.3 and 2.1 Hz), 3.67-
3.76 (m, 2H), 3.82-3.86 (m, 1H), 3.94-4.00 (m, 1H), 4.30-4.35
(m, 1H), 4.79 (d, 1H, J ) 7.4 Hz), 5.00-5.10 (m, 2H), 5.36 (d,
1H, J ) 4.0 Hz), 6.08 (s, 2H), 6.85 (s, 1H), 6.91 (s, 1H), and 7.31
(s, 1H); 13C NMR (DMSO-d6, 150 MHz) δ 40.1, 50.4, 68.7, 70.2,
70.3, 73.3, 101.5, 105.5, 106.7, 123.8, 135.3, 145.8, 150.5, and
164.0.
1
1642, 1610, 1511, 1462, 1247, and 1036 cm-1; H NMR (CDCl3,
400 MHz) δ 1.24 (s, 3H), 1.51 (s, 3H), 2.60 (d, 1H, J ) 2.0 Hz),
3.01 (dd, 1H, J ) 14.8 and 7.2 Hz), 3.23 (s, 1H), 3.73 (ddd, 1H,
J ) 10.8, 5.2, and 2.0 Hz), 3.77 (s, 3H), 3.85 (dd, 1H, J ) 14.8
and 7.2 Hz), 4.22 (dd, 1H, J ) 10.8 and 7.2 Hz), 4.30 (dd, 1H, J
) 7.2 and 5.2 Hz), 4.38 (t, 1H, J ) 7.2 Hz), 4.67 (d, 1H, J ) 15.2
Hz), 5.29 (d, 1H, J ) 15.2 Hz), 6.01 (d, 1H, J ) 1.2 Hz), 6.02 (d,
1H, J ) 1.2 Hz), 6.80 (d, 1H, J ) 8.8 Hz), 7.24 (s, 1H), 7.26 (d,
1H, J ) 8.8 Hz), and 7.60 (s, 1H); 13C NMR (CDCl3, 100 MHz)
δ 25.6, 28.1, 41.9, 46.9, 55.4, 57.8, 69.5, 70.7, 75.0, 77.1, 101.8,
106.0, 108.2, 110.6, 113.8, 122.1, 128.7, 131.6, 134.6, 147.3, 151.7,
158.7, and 165.0. HRMS calcd for [(C25H27NO8) + H]+: 470.1809.
Found: 470.1808.
Preparation of Hexacyclic Cyclosulfate (55). To a solution of
0.05 g (0.11 mmol) of diol 54 in 3 mL of CH2Cl2 at 0 °C were
added 62 µL (0.44 mmol) of Et3N and 12 µL (0.17 mmol) of SOCl2.
After stirring at 0 °C for 5 min, the cooling bath was removed and
the reaction mixture was stirred at rt for 40 min. The mixture was
quenched with a saturated NaHCO3 solution and extracted with
CH2Cl2. The combined organic layer was washed with H2O and
brine and dried over MgSO4. After removal of the solvent under
reduced pressure, the residue was taken up in 4 mL of CH3CN,
followed by the addition of 2.2 mg of RuCl3‚3H2O (0.01 mmol).
A solution of 0.05 g (0.22 mmol) of NaIO4 in 1.0 mL of H2O was
added. The mixture was stirred at rt for 12 h and diluted with EtOAc
and H2O. The organic layer was washed with brine, dried over
MgSO4, and concentrated under reduced pressure. The residue was
subjected to flash silica gel chromatography to give 0.05 g of sulfate
55 (82%) as a white solid: mp 218-220 °C; IR (neat) 1648, 1511,
1460, 1396, 1248, and 1212 cm-1; 1H NMR (CDCl3, 400 MHz) δ
1.25 (s, 3H), 1.56 (s, 3H), 3.47 (dd, 1H, J ) 14.4 and 8.8 Hz),
3.77 (s, 3H), 3.81 (dd, 1H, J ) 14.4 and 7.2 Hz), 4.53 (t, 1H, J )
7.2 Hz), 4.60 (dd, 1H, J ) 9.6 and 7.2 Hz), 4.69 (d, 1H, J ) 15.2
Hz), 4.83 (dd, 1H, J ) 9.6 and 7.2 Hz), 5.23-5.29 (m, 2H), 6.07
(s, 2H), 6.81 (d, 2H, J ) 8.8 Hz), 6.94 (s, 1H), 7.23 (d, 2H, J )
8.8 Hz), 7.64 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 25.4, 27.9,
38.8, 47.1, 55.5, 56.8, 74.0, 81.6, 82.9, 102.4, 105.4, 108.9, 112.2,
114.0, 122.1, 128.7, 130.0, 148.4, 152.3, 159.0, and 164.0. Anal.
Calcd for C25H25NO10S: C, 56.49; H, 4.74; N, 2.64. Found: C,
56.78; H, 4.75; N, 2.64.
Acknowledgment. This research was supported by the
National Institutes of Health (GM 0539384) and the National
Science Foundation (CHE-0450779). We thank our colleague,
Dr. Kenneth Hardcastle, for his assistance with the X-ray
crystallographic studies.
Supporting Information Available: Spectroscopic and experi-
mental procedures for the preparation of the necessary precursors
1
for amidofurans 15 and 25. H and 13C NMR data of various key
compounds lacking CHN analyses together with an ORTEP drawing
for compound 28 as well as the corresponding CIF file. The authors
have deposited atomic coordinates for compound 28 with the
Cambridge Crystallographic Data Centre. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO0626111
2582 J. Org. Chem., Vol. 72, No. 7, 2007