A second-generation radical-based synthesis of (+)-7- deoxypancratistatin

Full text of DOI:10.1021/jo981890s

9164
J . Org. Chem. 1998, 63, 9164-9165
elegant process developed by Kim.4 This 6-exo cyclization,
with concomitant loss of nitrogen and styrene, would gener-
ate the same radical intermediate 4 previously shown to
cyclize efficiently to give a single diastereomer of product.
A Secon d -Gen er a tion Ra d ica l-Ba sed
Syn th esis of (+)-7-Deoxyp a n cr a tista tin †
Gary E. Keck,* Travis T. Wager, and
Stanton F. McHardy
Department of Chemistry, University of Utah,
Salt Lake City, Utah 84112
Received September 17, 1998
The Amaryllidaceae alkaloids continue to attract consid-
erable interest as targets for total synthesis, due to their
interesting biological activity and structural features.1 Some
time ago, we reported2 a total synthesis of the naturally
occurring alkaloid 7-deoxypancratistatin (1)3 via an approach
based upon the radical cyclization process indicated below.
Our original intent, namely to utilize a lactone containing
substrate 2, was thwarted by the ease with which the lactone
carbonyl suffered reduction by Bu3SnH under the radical
cyclization conditions. We thus completed the synthesis by
conducting the radical cyclization on the TBS protected lactol
3. Although this synthesis served to define the viability of
the critical radical cyclization event, difficulties encountered
in the construction of the requisite substrate and the
aforementioned lactone reduction problem resulted in a
sequence that was longer than we had envisioned.
We thus were led to reinvestigate the radical cyclization
process using the lactone 2. Despite extensive experimenta-
tion, no conditions for effecting this process in high yield
could be identified using Bu3SnH; however, the use of
Ph3SnH gave the desired lactone product 10 in 70% isolated
yield, with very little lactone reduction observed. This
finding thus set the stage for investigation of the double-
radical cyclization approach indicated above.
The route began by esterification of 115 with iodo piperon-
ylic acid.6 Selective reduction of the lactone carbonyl group
was accomplished using L-Selectride (Aldrich), and the
resulting lactol was converted to the O-benzyloxime 13.
Protection of the free hydroxyl group followed by desilylation
of the primary TBS group gave the corresponding alcohol,
which was oxidized and converted to the N-aziridinylimine
by stirring in ethanol with 1-amino-2-phenylaziridine.7
In considering more direct approaches to a key radical
intermediate such as 4, we became intrigued by the prospect
of generating such a radical intermediate directly via a prior
radical cyclization event. Thus, ignoring for a moment the
lactone reduction problem, it seemed possible that radical
intermediate 4 could itself be generated via cyclization of
an aryl radical onto an N-aziridinylimine, employing the
† Dedicated to Professor E. J . Corey on the occasion of his 70th birthday.
(1) For syntheses of pancratistatin see: (a) Danishefsky, S.; Lee, J . Y.
J . Am. Chem. Soc. 1989, 111, 4829. (b) Hudlicky, T.; Tian, X.; Ko¨nigsberger,
K.; Maurya, R.; Rouden, J .; Fan, B. J . Am. Chem. Soc. 1996, 118, 10752.
(c) Trost, B. M.; Pulley, S. R. J . Am. Chem. Soc. 1995, 117, 10143. (d) Doyle,
T. J .; Hendrix, M.; VanDerveer, D.; J avanmard, S.; Haseltine, J . Tetrahe-
dron, 1997, 53, 11153. (e) Magnus, P.; Sebhat, I. K. J . Am. Chem. Soc. 1998,
120, 5341. For syntheses of 7-deoxypancratistatin see: (f) Ohta, S.; Kimoto,
S. Chem. Pharm. Bull. 1976, 24, 2977. (g) Paulsen, H.; Stubbe, M. Liebigs
Ann. Chem. 1983, 535. (h) Tian, X.; Maurya, R.; Ko¨nigsberger, K.; Hudlicky,
T. Synlett 1995, 1125. (i) Chida, N.; Iitsuoka, M.; Yamamoto, Y.; Ohtsuka,
M.; Ogawa, S. Heterocycles 1996, 43, 1385. For a review of synthetic work
in this area, see: Polt, R. In Organic Synthesis: Theory and Application;
Hudlicky, T., Ed.; J AI Press: Greenwich, 1996; Vol. 3, p 109.
(2) Keck, G. E.; McHardy, S. F.; Murry, J . A. J . Am. Chem. Soc. 1995,
117, 7289.
Attempts at radical cyclization of 14 under the newly
discovered Ph3SnH protocol were unsuccessful, and no
(4) (a) Kim, S.; Cheong, J . H.; Yoon, K. S. Tetrahedron Lett. 1995, 36,
6069. (b) Kim, S.; Kee, I. S. Tetrahedron Lett. 1993, 34, 4213. (c) Kim, S.;
Kee, I. S.; Lee, S. J . Am. Chem. Soc. 1991, 113, 9882. (d) Kim, S.; Cheong,
J . H. Synlett 1997, 947. (e) Lee, H.-Y.; Kim, D.-I.; Kim, S. Chem. Commun.
1996, 1539.
(5) Fleet, G. W. J .; Ramsden, N. G.; Witty, D. R. Tetrahedron 1989, 45,
319.
(6) Bogucki, D. E.; Charlton, J . L. J . Org. Chem. 1995, 60, 588.
(7) Mu¨ller, R. K.; J oos, R.; Felix, D.; Schreiber, J .; Wintner, C.; Eschen-
moser, A. Org. Synth. 1976, 6, 56.
(3) Ghosal, S.; Singh, S.; Kumar, Y.; Srivastava, R. S. Phytochemistry
1989, 28, 611.
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Communications
J . Org. Chem., Vol. 63, No. 25, 1998 9165
Sch em e 1a
product corresponding to the desired tandem cyclization
event could be isolated. Instead, products that appeared to
derive from two independent events (Ar-I reduction and
Ph3Sn• addition to the N-aziridinylimine) were obtained.
Thus, for example, in one reaction product 16 was isolated
in 16% yield.
One possible reason for the failure to obtain the desired
cyclization product in this reaction, which we had, in fact,
considered as a potential complication, was the presence of
the ester linkage in the tether connecting the two reactive
moieties. Thus, the preferred conformation of esters is well-
known to be s-trans, whereas a s-cis conformation is required
for cyclization. This type of problem has been previously
noted in other intramolecular reactions.8
We therefore chose to investigate a parallel sequence
using an ether linkage in place of the ester, with the idea of
installing the requisite carbonyl group after conducting the
cyclization event. To this end, iodopiperonol6 was converted
to the corresponding trichloroacetimidate in the normal way
(NaH, Cl3CCN) and used to alkylate alcohol 11. Reduction
of the lactone to the lactol with L-Selectride and O-benzyl-
oxime formation gave 21 (96% yield over two steps), which
was successively silylated (TBSOTf) and desilylated (HF‚
pyridine) to give the alcohol 22. Oxidation (TPAP, NMO) and
formation of the aziridinylimine then gave 23 in 83% yield
(Scheme 1).
a
Key: (a) L-Selectride, CH2Cl2, -78 °C; (b) HCl‚H2NOBn, pyridine;
(c) TBSOTf, 2,6-ludidine, CH2Cl2, 0 °C; (d) HF‚pyridine, THF; (e) TPAP,
NMO, 4 Å MS; (f) 1-amino-2-phenylaziridine, EtOH, 0 °C.
The key radical cyclization event required some optimiza-
tion but ultimately proceeded very cleanly to afford 24 as a
single diastereomer in 78% isolated yield. The optimal
conditions again involved the use of Ph3SnH and AIBN in
benzene at 80 °C; somewhat lower yields were obtained
using Bu3SnH. Cleavage of the N-O bond using SmI2 in
THF9 and direct quenching with TFAA gave the trifluoro-
acetamide 25 in 88% isolated yield. Installation of the
carbonyl group was accomplished quite easily using PCC in
CH2Cl2 at 55 °C,10 to give lactone 26 in 83% isolated yield.
This intermediate differs from the one used in our
previous synthesis only by the nature of the protecting group
at the C2 hydroxyl, TBS in the present case and MOM in
the former. In the previous synthesis, both the MOM and
acetonide protecting groups were easily removed using
DOWEX-H+ resin in methanol at 70 °C. We were most
surprised to find that these conditions were ineffective in
the present case, as were more forcing conditions utilizing
higher temperatures and longer reaction times. Although
the acetonide was hydrolyzed readily, the silyl ether linkage
proved to be unusually robust. Eventually we found that
to lactam rearrangement was then effected using K2CO3 in
dry methanol as before to give 7-deoxypancratistatin.
The route described herein thus marks a considerable
improvement over our earlier synthesis, which required 21
steps and afforded a 7% overall yield. The present synthesis
is 13 linear steps from 6-iodopiperonol and proceeds in 21%
overall yield. Moreover, the present synthesis quite nicely
demonstrates the power of the Kim methodology in a rather
highly functionalized and demanding case, given that the
bimolecular rate constant for reaction of phenyl radicals with
Bu3SnH has been reported to be 5.9 × 108 M-1 s-1 at 30
°C12 and that reasonable intramolecular hydrogen abstrac-
tion pathways are also present. Finally, the dramatic
differences between reactions using Bu3SnH versus those
using Ph3SnH with lactone 2 may prove useful in other
circumstances.
Ack n ow led gm en t. Financial assistance provided by
the National Institutes of Health (through grant GM-
28961) and Pfizer Inc. is gratefully acknowledged.
11
both groups could be removed using BF3‚OEt2 in CH2Cl2
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures and full characterization data for compounds used in the
main synthesis and copies of NMR spectra (33 pages).
to give the same triol lactone as previously prepared; lactone
(8) Boeckman, R. K., J r.; Demko, D. M. J . Org. Chem. 1982, 47, 1792.
(9) Keck, G. E.; McHardy, S. F.; Wager, T. T. Tetrahedron Lett. 1995,
36, 7419.
(10) Bonadies, F.; Di Fabio, R.; Bonini, C. J . Org. Chem. 1984, 49, 1647.
(11) For the cleavage of TBS ethers with BF3‚OEt2, see: Kelly, D. R.;
Roberts, S. M.; Newton, R. F. Synth. Commun. 1979, 9, 295.
J O981890S
(12) J ohnston, L. J .; Lusztyk, J .; Wayner, D. D. M.; Abeywickreyma, A.
N.; Beckwith, A. L. J .; Scaiano, J . C.; Ingold, K. U. J . Am. Chem. Soc. 1985,
107, 4594.