Total Synthesis of (+)-Narciclasine

Full text of DOI:10.1021/ja972950z

J. Am. Chem. Soc. 1997, 119, 12655-12656
12655
Communications to the Editor
Total Synthesis of (+)-Narciclasine
James H. Rigby* and Mary E. Mateo
Department of Chemistry
Wayne State UniVersity
Detroit, Michigan 48202-3489
of this endeavor was the ability to overcome the normal
propensity for o-alkoxy substituents on the arene moiety to
promote ipso bond formation during the photocyclization
event.7a This would be accomplished by exploiting possible
intramolecular hydrogen bonding between the C7 hydroxyl
group and the proximate enamide carbonyl oxygen to exert
conformational control during the cyclization as suggested in
intermediate A.7b
ReceiVed August 22, 1997
The Amaryllidaceae alkaloids have long been a source of
structurally intriguing target molecules that continue to challenge
the capabilities of contemporary organic synthesis.1 Within this
group, the phenanthridone alkaloids of the narciclasine family
have recently become the subject of intense synthetic study due
in large measure to their important antitumor activity.2 Indeed,
numerous syntheses of lycoricidine (1a)3 have been reported
in recent years, as have several approaches into 7-deoxypan-
cratistatin (2a).4 In contrast, synthetic successes into the closely
related congeners narciclasine (1b) and pancratistatin (2b) are
The synthesis began by preparing the syn-epoxy alcohol 58
in optically pure form from commercially available 3-cyclo-
hexene-1-carboxylic acid employing a modification of the
Berchtold sequence used previously for the synthesis of cho-
rismate derivatives (eq 1).9 In this instance, compound 5 serves
considerably fewer in number, perhaps reflecting the additional
level of preparative difficulty introduced by the presence of the
phenolic hydroxyl group at C7. The first synthesis of racemic
pancratistatin was completed by Danishefsky and Lee in 1989,5a
while asymmetric approaches into the compound have been
recorded by Hudlicky5b and Trost.5c Recently, a formal
synthesis of this compound was disclosed by Haseltine.5d To
date there has been no synthesis of narciclasine reported despite
several attempts.6 We now present the first total synthesis of
(+)-narciclasine in enantiomerically pure form.
The synthesis strategy reported in this document features a
late-stage construction of the critical C10a-C10b bond with
concomitant control of the relative stereochemistry of the
incipient trans-BC ring fusion. The key transformation for
achieving this objective is a hydrogen-bond-directed aryl
enamide photocyclization of a chiral, nonracemic seco precursor
(A) possessing intact A and C ring units. Critical to the success
as a masked form of diene C, since it has been previously
observed in our laboratory that unsaturation present at C3-C4
in these systems (narciclasine numbering) was incompatible with
the projected photocyclization conditions. The A ring fragment
was prepared in four steps from commercial 2,3-dihydroxyben-
zaldehyde employing known chemistry.10 Protection as the
ethoxyethyl ether afforded 6,8 which sets the stage for coupling
of the A and C ring fragments prior to cyclization.
(1) For an overview of the Amarylliclaceae alkaloids, see: Martin, S.
F. In The Alkaloids; Brossi, A. A., Ed.; Academic Press: New York, 1987;
Vol. 30, p 251.
(2) For a review of synthetic studies in this area, see: Polt, R. In Organic
Synthesis: Theory and Applications; Hudlicky, T., Ed.; JAI Press: Green-
wich, 1996; Vol. 3, p 109.
(3) (a) Ohta, S.; Kimoto, S. Chem. Pharm. Bull. 1976, 24, 2977. (b)
Paulsen, H.; Stubbe, M. Liebigs Ann. Chem. 1983, 535. (c) Chida, N.;
Ohtsuka, M.; Ogawa, S. Ibid. 1991, 32, 4525. (d) Hudlicky, T.; Olivo, H.
F. J. Am. Chem. Soc. 1992, 114, 9694. (e) Chida, N.; Ohtsuka, M.; Ogawa,
S. J. Org. Chem. 1993, 58, 4441. (f) Martin, S. F.; Tso, H.-H. Heterocycles
1993, 35, 85. (g) Hudlicky, T.; Olivo, H. F.; McKibben, B. J. Am. Chem.
Soc. 1994, 116, 5108.
(4) (a) Keck, G. E.; McHardy, S. F.; Murry, J. A. J. Am. Chem. Soc.
1995, 117, 7289. (b) Tian, X.; Maurya, R.; Ko¨nigsberger, K.; Hudlicky, T.
Synlett 1995, 1125. (c) Hudlicky, T.; Tian, X.; Ko¨nigsberger, K.; Maurya,
R.; Roudan, J.; Fan, B. J. Am. Chem. Soc. 1996, 118, 10752.
(5) (a) Danishefsky, S.; Lee, J. Y. J. Am. Chem. Soc. 1989, 111, 4829.
(b) Tian, X.; Hudlicky, T.; Ko¨nigsberger, K. Ibid. 1995, 117, 3643. (c)
Trost, B. M.; Pulley, S. R. Ibid. 1995, 117, 10143. (d) Doyle, T. J.; Hendrix,
M.; Vanderveer, D.; Javanmard, S.; Haseltine, J. Tetrahedron 1997, 53,
11153. (e) Friestad, G. K.; Branchaud, B. P. Tetrahedron Lett. 1997, 38,
5933.
Metalation of 6 (n-BuLi, -78 °C) followed by addition of
the isocyanate derived from 5 at -78 °C afforded the enamide
S0002-7863(97)02950-8 CCC: $14.00 © 1997 American Chemical Society

12656 J. Am. Chem. Soc., Vol. 119, No. 51, 1997
Communications to the Editor
Scheme 1
The requisite C3-C4 unsaturation was then revealed by
processing the epoxide in 9 using the Sharpless protocol12
followed by acylation of the resulting free hydroxyl functions
to give 10.8 Stereocontrolled, cis-dihydroxylation and protection
of the resultant diol as the acetonide proceeded without incident
to give 118 in 76% yield. The double bond required at C1 was
introduced by selective deprotection of the hydroxyl group at
this location followed by dehydration with the Burgess reagent13
in refluxing benzene to afford advanced intermediate 128 in good
yield.
The synthesis end-game involved a series of deprotection
steps, one of which was the removal of the lactam PMB group,
an operation that was viewed as being particularly challenging.
Several of the usual oxidative methods for PMB group removal
were explored for this purpose to no avail; however, an
interesting procedure for selective removal of amide N-benzyl
protection developed by Williams proved more successful.14 In
the event, routine saponification of the acetate groups in 12
followed by execution of the Williams protocol (n-BuLi/O2)
on the resultant diol provided the free amide, and acid-mediated
removal of the remaining acetonide function afforded (+)-
narciclasine ([R]25 141.8°, lit.15 [R]22 142.8°; mp: 248 °C
D
D
dec, lit.15 250-2 °C dec) in 37% overall yield. The synthetic
material was identical (1H NMR and 13C NMR) to a sample of
the natural product provided by the National Cancer Institute.
In summary, the application of a hydrogen-bond-directed aryl
enamide photocyclization provides access to the Amaryllidacene
alkaloid (+)-narciclasine in enantiomerically pure form. Minor
modification of the current synthetic sequence could permit the
preparation of pancratistatin, which will be reported in due time.
78 in 52% yield. A p-methoxybenzyl group was then installed
in virtually quantitative yield, and careful hydrolysis of the
ethoxyethyl group under mildly acidic conditions afforded the
free phenol 8 (Scheme 1).8 Irradiation of this material at 254
nm in benzene (Rayonet photochemical reactor) produced the
desired trans-fused phenanthridone 98 as a single diastereomer
in 46% yield based on recovered starting material along with
several minor products. A number of other solvents were
examined in this reaction, including cyclohexane, 1,2-dichlo-
roethane, and several mixed solvent systems. Unfortunately,
no yield improvement was observed under these conditions. The
regioisomeric cyclization product was obtained when methanol
was used as the solvent for this transformation, reinforcing the
notion that intramolecular hydrogen bonding is controlling the
course of reaction in compound 8.11
(6) (a) Krohn, K.; Mondon, A. Chem. Ber. 1976, 109, 855. (b) Banwell,
M. G.; Cowden, C. J.; MacKay, M. F. J. Chem. Soc., Chem. Commun.
1994, 61. (c) Khaldi, M.; Chretien, F.; Chapleur, Y. Tetrahedron Lett. 1995,
36, 3003. (d) Park, T. K.; Danishefsky, S. J. Ibid. 1995, 36, 195.
(7) (a) 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. (b) Rigby, J. H.; Gupta, V. Synlett 1995, 547.
(8) This compound exhibited spectral (1H NMR, 13C NMR, and IR) and
analytical (HRMS and/or elemental analysis) data consistent with the
assigned structure.
Acknowledgment. The authors thank the National Science Founda-
tion for their generous support of this work, as well as the Drug
Synthesis and Chemistry Branch, Developmental Therapeutics Program,
DCTDC, National Cancer Institute, for providing a sample of authentic
(+)-narciclasine.
Supporting Information Available: Experimental details and full
characterization data for key synthetic intermediates (8 pages). See
any current masthead page for ordering and Internet access instructions.
JA972950Z
(11) Unfortunately, efforts to apply this strategy to the synthesis of
pancratistatin via the corresponding trans-epoxy alcohol afforded the wrong
BC ring fusion stereochemistry.
(12) Sharpless, K. B.; Lauer, R. F. J. Am. Chem. Soc. 1973, 95, 2697.
(13) Burgess, E. M.; Penton, H. R., Jr.; Taylor, E. A. J. Org. Chem.
1973, 38, 26.
(14) Williams, R. M.; Kwast, E. Tetrahedron Lett. 1989, 30, 451.
(15) Ghosal, S.; Lochan, R.; Ashitosh; Kumar, Y.; Srivastava, R. S.
Phytochemistry 1985, 24, 1825.
(9) Pawlak, J. C.; Berchtold, G. A. J. Org. Chem. 1987, 52, 1765 and
references therein. Improved yields of 4 could be obtained using chromato-
graphic purification rather than crystallization.
(10) Brown, E.; Loriot, M.; Robin, J.-P. Tetrahedron Lett. 1982, 23, 949.