Studies on the narciclasine alkaloids: Total synthesis of (+)- narciclasine and (+)-pancratistatin

Article abstract of DOI:10.1021/ja000930i

Enantioselective total syntheses of the antimmor alkaloids, (+)- narciclasine and (+)-pancratistatin, are reported. These syntheses feature a stereo- and regiocontrolled aryl enamide photocyclization to construct a common, advanced intermediate possessing a transfused BC substructure. Differential functional group interchange in the C-ring of this phenanthridone core structure allows for the production of the two target natural products in enantiomerically pure form.

Full text of DOI:10.1021/ja000930i

6624
J. Am. Chem. Soc. 2000, 122, 6624-6628
Studies on the Narciclasine Alkaloids: Total Synthesis of
(+)-Narciclasine and (+)-Pancratistatin
James H. Rigby,* Umar S. M. Maharoof, and Mary E. Mateo
Contribution from the Department of Chemistry, Wayne State UniVersity, Detroit, Michigan 48202-3489
ReceiVed March 15, 2000. ReVised Manuscript ReceiVed May 17, 2000
Abstract: Enantioselective total syntheses of the antitumor alkaloids, (+)-narciclasine and (+)-pancratistatin,
are reported. These syntheses feature a stereo- and regiocontrolled aryl enamide photocyclization to construct
a common, advanced intermediate possessing a trans-fused BC substructure. Differential functional group
interchange in the C-ring of this phenanthridone core structure allows for the production of the two target
natural products in enantiomerically pure form.
The Amaryllidaceae alkaloid (+)-pancratistatin (1a) was first
recently, Haseltine7 and Magnus8 have successfully achieved
syntheses of this alkaloid, as well. The pancratistatin congeners
7-deoxypancratistatin (1b),9 narciclasine (2a),10 and lycoricidine
(2b)11 have also garnered considerable attention from the
synthetic community. Despite the successes cataloged above,
it is clear from the considerable effort expended by numerous
research groups over many years that members of this family
of alkaloids remain particularly formidable targets for organic
synthesis.12 Indeed, they possess deceptively simple molecular
structures that present a number of challenges to the capabilities
of contemporary synthesis. The principal hurdles to synthesis
include elaboration of the fused BC ring system and the
stereocontrolled installation of the hydroxyl functions located
around the perimeter of the C-ring moiety. We now wish to
report on the successful synthesis of both (+)-pancratistatin (1a)
and (+)-narciclasine (2a) from a common advanced phenan-
thridone intermediate.13 Our strategy into these interesting target
molecules is depicted in Scheme 1.
isolated from the roots of Pancratium littorale by Pettit and
co-workers in 1984 as part of a systematic search for natural
products that exhibit anticancer activity.1 Recent studies have
shown that this substance exhibits a range of antineoplastic
properties, including activity against murine P-5076 ovarian
sarcoma and P-388 lymphocytic leukemia.2 No detailed exami-
nation of the molecular basis of this activity has been conducted,
but work on structurally related narciclasine (2a) has suggested
that these compounds could act by disrupting protein biosyn-
thesis in eukaryotic organisms.3
The key transformation upon which our entry into both
compounds is predicated is the hydrogen bond controlled aryl
enamide photocyclization (3 f 4), which should result in the
desired trans-locked advanced intermediate 4.14 The requisite
enamide precursor for this crucial reaction would be assembled
by addition of a metalated arene to the protected, enantiomeri-
The promising biological activity and limited availability of
this series of highly oxygenated phenanthridone alkaloids has
stimulated considerable synthetic work in which the first total
synthesis of (()-pancratistatin was recorded by Danishefsky and
Lee in 1989,4 and the first asymmetric synthesis of the natural
enantiomer of this material was reported in 1995 by Hudlicky,5
followed in the same year by work by Trost and Pulley.6 More
(7) Doyle, T. J.; Hendrix, M.; Van Der veer, D.; Javanmard, S.; Haseltine,
J. Tetrahedron 1997, 53, 11153.
(8) (a) Magnus, P.; Sebhat, I. K. J. Am. Chem. Soc. 1998, 120, 5341.
(b) Magnus, P.; Sebhat, I. K. Tetrahedron 1998, 54, 15509.
(9) (a) Tian, X.; Maurya, R.; Ko¨nigsberger, K.; Hudlicky, T. Synlett 1995,
1125. (b) Keck, G. E.; McHardy, S. F.; Murry, J. A. J. Am. Chem. Soc.
1995, 117, 7289. (c) Chida, N.; Sitsuoka, M.; Yamamoto, Y.; Ohtsuka,
M.; Ogawa, S. Heterocycles 1996, 43, 1385. (d) Keck, G. E.; Water, T. T.;
McHardy, S. F. J. Org. Chem. 1998, 63, 9164.
(1) (a) Pettit, G. R.; Gaddamidi, V.; Cragg, G. M.; Herald, D. L.; Sagawa,
Y. J. Chem. Soc., Chem. Commun. 1984, 1693. (b) Pettit, G. R.; Gaddamidi,
V.; Cragg, G. M. J. Nat. Prod. 1984, 47, 1018.
(2) 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.
(10) (a) Gonzalez, D.; Martinot, T.; Hudlicky, T. Tetrahedron Lett. 1999,
40, 3077. (b) Reference 13.
(11) (a) Paulsen, H.; Stubbe, M. Justus Liebigs Ann. Chem. 1983, 535.
(b) Chida, N.; Ohtsuka, M.; Ogawa, S. Tetrahedron Lett. 1991, 32, 4525.
(c) Hudlicky, T.; Olivo, H. F. J. Am. Chem. Soc. 1992, 114, 9694. (d) Martin,
S. F.; Tso, H.-H. Heterocycles 1993, 35, 85. (e) Chida, N.; Ohtsuka, M.;
Ogawa, S. J. Org. Chem. 1993, 58, 4441. (f) Hudlicky, T.; Olivo, H. F.;
McKibben, B. J. Am. Chem. Soc. 1994, 116, 5108. (g) Keck, G. E.; Wage,
T. T. J. Org. Chem. 1996, 61, 8366.
(12) For an informative discussion of the synthetic problems presented
by pancratistatin and its congeners, see: Polt, R. In Organic Synthesis
Theory and Applications; Hudlicky, T., Ed.; JAI Press: Greenwich, CT,
1996; Vol. 3, p 109.
(3) (a) Carrasco, L.; Fresno, M.; Vazquez, D. FEBS Lett. 1975, 52, 236.
(b) Jimenez, A.; Sanchez, L.; Vazquez, D. FEBS Lett. 1975, 55, 53. (c)
Mondon, A.; Keohn, K. Chem. Ber. 1975, 108, 445. (d) Jimenez, A.; Santos,
A.; Alonso, G.; Vazquez, D. Biochim. Biophys. Acta 1976, 425, 342. (e)
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., Cutter, H. G., Eds.; Plenum: New York, 1992; p 121.
(4) Danishefsky, S.; Lee, J. Y. J. Am. Chem. Soc. 1989, 111, 4829.
(5) (a) Tian, X.; Hudlicky, T.; Ko¨nigsberger, K. J. Am. Chem. Soc. 1995,
117, 3643. (b) Hudlicky, T.; Tian, X.; Ko¨nigsberger, K.; Maurya, R.;
Rouden, J.; Fan, B. J. Am. Chem. Soc. 1996, 118, 10752.
(13) For a preliminary account of the first synthesis of (+)-narciclasine,
see: Rigby, J. H.; Mateo, M. E. J. Am. Chem. Soc. 1997, 119, 12655.
(6) Trost, B. M.; Pulley, S. R. J. Am. Chem. Soc. 1995, 117, 10143.
10.1021/ja000930i CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/29/2000

Total Synthesis of (+)-Narciclasine and (+)-Pancratistatin
J. Am. Chem. Soc., Vol. 122, No. 28, 2000 6625
Scheme 1
the commercially available ene ester 8 was transformed into
the racemic syn-epoxy alcohol 9 in serviceable overall yield.
Esterification followed by enzymatic resolution of the resultant
butyryl ester with cholesterol esterase gave the corresponding
enantiomerically pure syn-epoxy alcohol 10 in 40% isolated
yield. Inversion of the alcohol under Mitsunobu conditions
provided the protected trans-epoxy alcohol 7 after ester saponi-
fication.
The A-ring building block common to both pancratistatin and
narciclasine was prepared in straightforward fashion from
commercial 2,3-dihydroxybenzaldehyde using a literature pro-
cedure.19 The choice of phenol protection was particularly
critical at this stage of the synthesis, since it had to be robust
enough to survive the subsequent metalation-addition steps and
yet be removed under conditions sufficiently mild to not
jeopardize the relatively fragile enamide function prior to
photocyclization. After some experimentation it was found that
the ethoxy ethyl group satisfied both of these criteria. With each
of the segments of the cyclization precursor now in hand,
coupling was achieved in the following fashion. Compound 11
was metalated with n-BuLi at -78 °C and then combined with
a solution of the preformed vinyl isocyanate derived from acid
7 to afford enamide 12 in 62% yield (eq 3).
cally pure vinyl isocyanate 5,15 which in turn would be derived
from (-)-chorismic acid (6) or one of its derivatives. The
production of the correct relative stereochemistry at C4a-C10b
during the photocyclization was anticipated based on several
observations made by Haslam and co-workers indicating that
external reagents often attack the R,â-unsaturated acid moiety
of chorismate from the â-direction.16 This assumption was
destined not to be tested directly during our investigations since
it was quickly established in early model studies that the diene
unit of chorismate was not compatible with the photocyclization
conditions required for the B-ring assembly.17 Instead, a
surrogate for chorismate, epoxy acid 7, in which the diene
functionality was present in masked form, was selected for this
purpose. This material was expected to participate in the key
B-ring forming event without incident and then be amenable to
tetraol elaboration at a later point in the synthesis. Indeed, 7
was a key intermediate used by Berchtold in his excellent
synthesis of (-)-chorismic acid itself.18
At this juncture in the synthesis, several significant features
of the projected photocyclization step had to be addressed. Of
paramount importance to the success of our endeavor was the
notion of controlling the regiochemical course of the ring
forming event by exploiting a hydrogen bond between the
phenolic alcohol and the amide carbonyl oxygen that would
restrict rotation around the aryl-amide carbonyl bond as depicted
(14) For a review of aryl enamide photocyclizations, see: Ninomiya, I.;
Naito, T. In The Alkaloids; Brossi, A., Ed.; Academic Press: New York,
1983; Vol. XXII, p 189.
(15) For an overview of vinyl isocyanate chemistry, see: Rigby, J. H.
Synlett 2000, 1.
(16) Ife, R. J.; Ball, L. F.; Lowe, P.; Haslam, E. J. Chem. Soc., Perkin
Trans 1 1976, 1776.
(17) Gupta, V., WSU. Unpublished results.
(18) (a) McGowen, D. A.; Berchtold, G. A. J. Org. Chem. 1981, 46,
2381. (b) Hoare, J. H.; Policastro, P. P.; Berchtold, G. A. J. Am. Chem.
Soc. 1983, 105, 6264. (c) Pawlak, J. L.; Berchtold, G. A. J. Org. Chem.
1987, 52, 1765.
Following a sequence essentially as described by Berchtold,18
(19) Brown, E.; Loriot, M.; Robin, J. P. Tetrahedron Lett. 1982, 32, 949.

6626 J. Am. Chem. Soc., Vol. 122, No. 28, 2000
Rigby et al.
Scheme 2
Scheme 3
in Scheme 1. This type of conformational control was necessary
because ample literature precedent indicated that photocycliza-
tion of related o-alkoxy-substituted enamides resulted in a bond
formation that occurred at the ipso arene carbon (Scheme 2).14
Indeed, early model studies in our own laboratory confirmed
that this reaction pathway prevailed in phenanthridone precursors
possessing o-alkoxy-substituents on the arene moiety.20 In
addition to these concerns, model studies from our laboratory
also revealed that it was necessary for the amide nitrogen to
exhibit a non-hydrogen substituent for successful photocycliza-
tion to occur, presumably due to unfavorable rotamer popula-
tions in the secondary amide.20 It is also possible that N-alkyl
substitution also serves to stabilize putative intermediates in the
photocyclization process. In light of these observations, com-
pound 12 was processed to give cyclization precursor 13 as
shown in eq 4. Although a number of candidates for this
C-ring precursor 16 and the stage was set for a second attempt
at the key photocyclization.
Conversion of carboxylic acid 16 into the corresponding
isocyanate via Curtius rearrangement of the corresponding acyl
azide as before followed by addition of the aryllithium derivative
of bromide 11 gave enamide 17 in 52% yield, and further
conversion into the requisite photosubstrate 18 proceeded
without incident (Scheme 3). Irradiation of 18 followed under
standard conditions to give phenanthridone 19 in 30% yield
(60% based on recovered starting material), which possessed
the desired trans relationship between the C4a and C10b centers.
N-protection was considered, PMB protection was ultimately
selected so as to provide for maximum flexibility during the
removal process in the eventual “end-game” of the synthesis.
The crucial B-ring formation was now at hand.
1
High-field H NMR analysis revealed that the proton at C10b
Irradiation of a dilute (0.2 M) solution (benzene) of 13
(Rayonet reactor at 254 nm; 5 °C) afforded a cyclized product
14 in which the incorrect trans ring fusion had been formed
exclusively. This disappointing result indicated that the notion
of extending the chorismate conformational behavior to the very
different trans-epoxy alcohol system of compound 13 was, in
fact, faulty, and a new plan of attack had to be devised.
This problem was quite easily remedied since it was
anticipated that the corresponding syn-epoxy alcohol would lead
to the correct ring fusion stereochemistry during the photolysis.
Furthermore, it was expected that the R-oriented hydroxyl group
present at C1 in the resulting phenanthridone product could be
inverted to provide the correct â-configuration at that center.
A related inversion was performed in the Trost/Pulley synthesis
of pancratistatin.6 It was also reasoned that a syn relationship
between the C1 hydroxyl and the proton at C10b would facilitate
dehydration to give the corresponding unsaturated intermediate
from which narciclasine could be prepared. Thus, protection
and saponification of 10 gave the requisite enantiomerically pure
exhibited the expected trans diaxial coupling with both C1 and
C4a (13 and 9 Hz), confirming that the necessary ring junction
had been obtained. It should be noted that considerable effort
was expended to identify an alternative solvent system in which
to conduct this reaction, since it was believed that the low
conversions observed above were due to preferential light
absorption by benzene. Unfortunately, no other satisfactory
solvent surfaced during this study and attempts to improve
conversion efficiency using other wavelengths of light also
failed. Consequently, the recovered starting material had to be
recycled. With the successful production of 19, the stage was
now set to effect separate conversions from this common
intermediate into the (+)-pancratistatin and (+)-narciclasine
targets.
The preparation of narciclasine was pursued first (Scheme
4). Thus, treatment of phenanthridone 19 with diphenyldis-
21
elenide/NaBH4 and then H2O2 installed the requisite C3-C4
unsaturation, and acylation of the free hydroxyl groups in this
material furnished compound 20. Stereoselective cis-dihydroxy-
(20) Rigby, J. H.; Gupta, V. Synlett 1995, 547 and references therein.
(21) Sharpless, K. B.; Lauer, R. F. J. Am. Chem. Soc. 1973, 95, 2697.

Total Synthesis of (+)-Narciclasine and (+)-Pancratistatin
J. Am. Chem. Soc., Vol. 122, No. 28, 2000 6627
Scheme 4
Scheme 5
oxygen at C1 could also be an unwanted outcome of this
oxidation-reduction approach.26 In the event, 24 was treated
with the Dess-Martin reagent to give the ketone 25a, which
slowly, but inexorably, epimerized to the more stable cis-isomer
25b on standing for a few hours as expected. In an effort to
prevent this isomerization the sequence of events was modified
slightly. Thus, the alcohol in 24 was again oxidized as before,
but now it was immediately treated with NaBH4 at -20 °C.
This action proved successful and provided the desired axial
alcohol in good yield, and the newly installed hydroxyl group
was protected as a benzyl ether to give compound 26. The
structural assignment made for this compound was supported
lation and protection of the resultant diol as the acetonide
followed to give 21 in 75% yield. The alkene function required
at C1 was then introduced by selective deprotection of the
hydroxyl group at C1 with fluoride followed by dehydration
mediated by the Burgess reagent22 in refluxing benzene. This
set of transformations afforded compound 22 in good yield.
The synthesis end-game consisted of a series of deprotection
steps, the most difficult of which proved to be the removal of
the PMB group from the lactam nitrogen. Several of the usual
oxidative methods for this purpose failed; however, an intriguing
procedure for selective removal of amide N-benzyl protection
devised by Williams23 proved to be more successful. Thus,
saponification of the acetates in 21 followed by treatment of
the resultant product with excess BuLi and dry oxygen provided
the free amide after workup. Routine acid hydrolysis of the
acetonide gave (+)-narciclasine ([R]25 141.8°, lit.24 [R]25
1
by relevant H NMR coupling patterns.
D
D
142.8°; mp 248 °C dec, lit.24 mp 250-252 °C dec) in 37%
overall yield. In addition, the synthetic material was identical
(1H NMR and 13C NMR) to a sample of the natural product
provided by the National Cancer Institute.
The final C-ring functional group processing of 26 proceeded
as follows. Epoxide 26 was treated with (PhSe)2, NaBH4, and
then H2O2 at reflux as before to afford allylic alcohol 27 via
selective axial opening of the epoxide with phenylselenide anion
followed by facile selenoxide elimination. Routine cis-dihy-
droxylation gave 28 in good yield. All that remained at this
juncture were several deprotection steps, one of which caused
some initial difficulties. The principal goal at this stage of the
synthesis was to identify conditions that could cleanly remove
the PMB group from the lactam nitrogen. From the very outset
of the synthetic planning, this projected operation was a source
of considerable concern since nitrogen deprotections of this type
can be problematic. Unfortunately, the usual set of oxidative
conditions (i.e., DDQ or CAN) failed to deliver any of the
desired product as was the case with the narciclasine series
described previously. Furthermore, the Williams protocol, which
was so effective earlier, also failed in the current situation.
Finally, after considerable experimentation it was found that
exposure of 28 to Pd(OH)2/C-H2 in EtOH resulted in the
smooth removal of both the benzyl ether at C1 and the N-p-
methoxybenzyl group to give the penultimate intermediate 29
in good yield.27 The synthesis of (+)-pancratistatin was
With narciclasine in hand, our attention then turned to
completing the synthesis of pancratistatin. Each of the antici-
pated methods for addressing the projected inversion of the C1
alcohol in phenanthridone 19 would require prior protection of
the phenolic hydroxyl group and deprotection of the C1 hydroxyl
group. These two objectives were easily achieved in straight-
forward fashion on 19 to yield 24 as shown in Scheme 5, and
a detailed examination of the alcohol inversion process was then
initiated. Unfortunately, exposing compound 24 to the classic
Mitsunobu conditions (DEAD, PPh3, PhCO2H) provided only
starting material. However, an alternative approach was envi-
sioned that would involve initial oxidation to the corresponding
ketone followed by reduction to the desired inverted alcohol.
While potentially attractive, this approach was somewhat
dangerous in that the presence of a ketone directly adjacent to
the ring fusion could potentially compromise the relatively
strained trans-BC ring stereochemistry. Indeed, Kallmerten had
observed a decided preference for the cis-fusion in a related
phenanthridone intermediate.25 Furthermore, elimination of the
(22) Burgess, E. M.; Penton, H. R., Jr.; Taylor, E. A. J. Org. Chem.
1973, 38, 26.
(23) Williams, R. M.; Kwast, E. Tetrahedron Lett. 1989, 30, 451.
(24) Ghosal, S.; Luchan, R.; Kumar, Y.; Srivastava, R. S. Phytochemistry
1985, 24, 1825.
(25) Thompson, R. C.; Kallmerten, J. J. Org. Chem. 1990, 55, 6076.
(26) Khaldi, M.; Chretien, F.; Chapleur, Y. Tetrahedron Lett. 1995, 36,
3003.

6628 J. Am. Chem. Soc., Vol. 122, No. 28, 2000
Rigby et al.
Scheme 6
after a similar step in the Trost/Pulley synthesis.6 The resultant
product was shown to be identical in all respects with authentic
(+)-pancratistatin. In summary, the syntheses of (+)-pancrat-
istatin and (+)-narciclasine have been achieved from a common
phenanthridone intermediate starting from commercial 3-cy-
clohexene-1-carboxylic acid.
Acknowledgment. The authors wish to thank the National
Science Foundation for their generous support of this research.
They also wish to thank Professor G. R. Pettit for providing a
generous sample of authentic (+)-pancratistatin and the Drug
Synthesis and Chemistry Branch, Developmental Therapeutics
Program, DCTDC, National Cancer Institutes, for providing a
sample of narciclasine for comparison purposes.
Supporting Information Available: Experimental details
and full characterization data for key synthetic intermediates
(PDF). This material is available free of charge via the Internet
at http://pubs.acs.org.
JA000930I
completed by treatment of 29 with LiCl/DMF under reflux to
remove the C7 methyl group protection, a reaction patterned
(27) Bernotas, R. C.; Cue, R. U. Synth. Commun. 1990, 20, 1209. (b)
Pearlman, W. M. Tetrahedron Lett. 1967, 1663.