The first total syntheses of ircinol A, ircinal A, and manzamines A and D [13]

Full text of DOI:10.1021/ja981303k

J. Am. Chem. Soc. 1998, 120, 6425-6426
6425
Scheme 1
The First Total Syntheses of Ircinol A, Ircinal A, and
Manzamines A and D
Jeffrey D. Winkler* and Jeffrey M. Axten
Department of Chemistry, The UniVersity of PennsylVania
Philadelphia, PennsylVania 19104
ReceiVed April 17, 1998
In 1986, Higa, Jefford, and co-workers reported the isolation
of a structurally novel polycyclic alkaloid, manzamine A, 1, from
a sponge harvested near the coast of Okinawa.1 The unique
structure of 1 consists of a â-carboline heterocycle attached to a
novel pentacyclic diamine core containing both eight- and thirteen-
membered rings on a pyrrolo[2,3-i]isoquinoline framework. The
cytotoxic activity (IC50 ) 0.07 µg/mL against P-388 mouse
leukemia cells) and unique structure of 1 have stimulated
considerable interest and activity directed toward the total
synthesis of manzamine A which has not yet been successfully
achieved to date.2 The intramolecular vinylogous amide photo-
addition/fragmentation/Mannich closure sequence that we have
developed has been applied to the stereoselective synthesis of
complex structural types including mesembrine and the aspi-
dosperma alkaloids from simple precursors.3 We have described
the application of this methodology to the construction of the
tetracyclic core of the manzamine alkaloids, in which the single
stereocenter on the unsaturated eight-membered ring template 2
dictates all of the requisite stereochemical relationships embodied
in 3, which represents the tetracyclic core of manzamine A.4
Outlined herein is the extension of these preliminary investigations
to the first total synthesis of manzamine A.
The retrosynthetic analysis for our approach to the synthesis
of manzamine A is outlined in Scheme 1. Disconnection of the
â-carboline from 1 leads to ircinal A, 4, a naturally occurring
compound that has been converted to 1 by Pictet-Spengler
cyclization followed by DDQ oxidation.5 We anticipated that
ircinal A could be formed by B-ring functionalization and
macrocyclization of 5. The tetracyclic ring system of 5 would
result from the Mannich closure of ketoiminium 6, which is
derived by retro-Mannich fragmentation of 7, the product of
intramolecular cycloaddition of 8.
isomerization of 14 to the manzamine tetracycle 16 proceeded
on exposure of 14 to pyridinium acetate to give 16 as a single
stereoisomer in 20% overall yield from 11 (an average of 60%
yield/step for photoaddition, fragmentation, and Mannich closure).
The assignment of the relative stereochemistry shown in 16
follows from our published studies on the photocycloaddition of
24 and the conversion of 16 to manzamine A, as detailed below.
The unique stereochemistry of the C-12 substituent in 16, which
is not critical to the subsequent stereoselective introduction of
the C-12R hydroxyl moiety, was not established at this stage.
The elaboration of the B ring of 16 to include the functionality
present in manzamine A was achieved as follows: Carboxylation
of the kinetic enolate derived from 17, the silyl ether of 16, with
Mander’s reagent gave ketoester 18, with the C-10R ester on the
convex face of the AB ring system. Reduction of the C-11 ketone,
followed by elimination of the derived mesylate with DBU in
refluxing benzene, gave a 2:1 mixture of the R,â- and â,γ-
unsaturated esters 19 and 20, respectively. Equilibration of 19
to a 2:1 mixture of 19 and 20 could be achieved in quantitative
yield by reexposure of 19 to DBU in refluxing benzene.
Selenation of the conjugate base of 19 (LiTMP) led to the
formation of the R-selenated product 21 in ca. 40% yield, while
selenation of the deconjugated ester 20 led to the formation of
the same product in 78% yield. We attribute this difference in
reactivity to the relative difficulty of deprotonation of the C-12
hydrogen in 19. Oxidation of selenide 21 resulted in the formation
of the desired C-12R alcohol 22, the stereochemical assignment
of which was supported by the H bonding observed between the
hydroxyl hydrogen and the azocine nitrogen by 1H NMR (br s, δ
6.5, exchanges with D2O) and subsequently confirmed by the
conversion of 22 to manzamine A. The same product 22 could
be obtained more efficiently via epoxidation of the â,γ -unsatur-
ated ester 20 and treatment of the derived epoxide with sodium
methoxide (69% overall yield of 22 from 20). The closure of
the macrocyclic 13-membered ring to complete the synthesis of
the pentacyclic ring system of manzamine A proved challenging.
Deprotection of silyl ether 22, followed by tosylation of the
The preparation and reaction of the requisite photosubstrate is
outlined in Scheme 2.6 Reaction of the previously described
secondary amine 97 with acetylenic ketone 108 gave the requisite
vinylogous amide photosubstrate 11 in 99% yield from 9.
Photoaddition and retro-Mannich fragmentation of 11 led, via
O-closure of the ketoiminium intermediate 13, to aminal 14. The
(1) (a) Sakai, R.; Higa, T.; Jefford, C. W.; Bernardinelli, G. J. Am. Chem.
Soc. 1986, 108, 6404. (b) Nakamura, H.; Deng, S.; Kobayashi, J.; Ohizumi,
Y.; Tomotake, Y.; Matsuzaki, T.; Hirata, Y. Tetrahedron Lett. 1987, 28, 621.
(2) For an excellent review of synthetic efforts in this area, see: Matzanke,
N.; Gregg, R. J.; Weinreb, S. M.Org. Prep. Proc. Int. 1998, 30, 1 and
references therein. For synthetic approaches disclosed since 1996, see: (a)
Brands, K. M. J.; DiMichele, L. M. Tetrahedron Lett. 1998, 39, 1677. (b) Li,
S.; Yamamura, S. Tetrahedron Lett. 1998, 39, 2597. (c) Li, S.; Yamamura,
S.; Hosomi, H.; Ohba, S. Tetrahedron Lett. 1998, 39, 2601. (d) Baldwin, J.
E.; Bischoff, L.; Claridge, T. D. W.; Heupel, F. A.; Spring, D. R.; Whitehead,
R. C. Tetrahedron 1997, 53, 2271. (e) Li, S.; Ohba, S.; Kosemura, S.;
Yamamura, S. Tetrahedron Lett. 1996, 37, 7365. (f) Baldwin, J. E.; Claridge,
T. D. W.; Culshaw, A. J.; Heupel, F. A.; Smrckova, S.; Whitehead, R. C.
Tetrahedron Lett. 1996, 37, 6919. (g) Torisawa, Y.; Hosaka, T.; Tanabe, K.;
Suzuki, N.; Motohashi, Y.; Hino, T.; Nakagawa, M. Tetrahedron 1996, 52,
10597. (h) Martin, S. F.; Chen. H.-J.; Courtney, A. K.; Liao, Y.; Pa¨tzel, M.;
Ramser, M. N.; Wagman, A. S. Tetrahedron 1996, 52, 7251. (i) Pandit, U.
K.; Borer, B.; Bieraugel, H. Pure Appl. Chem. 1996, 68, 659.
(3) Winkler, J. D.; Mazur Bowen, C.; Liotta, F. Chem. ReV. 1995, 95, 2003.
For application to the manzamines, see: (a) Winkler, J. D.; Siegel, M. G.;
Stelmach, J. E. Tetrahedron Lett. 1993, 34, 6509. (b) Winkler, J. D.; Stelmach,
J.; Siegel, M. G.; Haddad, N.; Axten, J. M.; Dailey, W. P., III. Isr. J. Chem.
1997, 37, 47.
(4) Winkler, J. D.; Axten, J. M.; Hammach, A.; Kwak, Y.-S.; Lucero, M.;
Houk, K. N. Tetrahedron, in press (honoring Professor M. Joullie´).
(5) Kondo, K.; Shigemori, H.; Kikuchi, Y.; Ishibashi, M.; Sasaki, T.;
Kobayashi, J. J. Org. Chem. 1992, 57, 2480.
(6) All compounds were fully purified (>95%) and characterized by 1H
and 13C NMR, IR, HRMS, and specific rotation. See the Supporting
Information for experimental procedures, tabulated data, and copies of spectra.
(7) The eight-membered ring of 9 was prepared by intramolecular alkylation
of the corresponding N-Alloc O-tosylate using NaH (82%), followed by
nitrogen deprotection (Pd0, 90%) as described in ref 4.
S0002-7863(98)01303-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/13/1998

6426 J. Am. Chem. Soc., Vol. 120, No. 25, 1998
Communications to the Editor
Scheme 2
derived alcohol 23, gave 24. Removal of the Boc protecting group
and exposure of the secondary amine to Hu¨nig’s base under high
dilution conditions (1 mM) led to the formation of methyl ircinate
25 in a disappointing 12% yield. We were delighted to find that
cyclization of the acetylenic substrate 269 under the same reaction
conditions led to the formation of the desired macrocyclic product
in 89% yield, which on Lindlar reduction gave 25 in 94% yield.
Reaction of the unsaturated ester 25 with DIBAL-H resulted
in the first total synthesis of ircinol A, 27, [R]D ) -18° (c )
0.30, MeOH), in 83% yield, the isolation of which was recently
reported by Kobayashi and co-workers.10 Oxidation of 27 with
the Dess-Martin reagent gave a 90% yield of ircinal A, 4, ([R]D
) +46° (c ) 0.23, CHCl3); lit.5 [R]D ) +48° (c ) 2.9, CHCl3)),
the transformation of which to manzamine A has been reported
by Kobayashi.5 Following that procedure, reaction of 4 with
tryptamine in the presence of trifluoroacetic acid gave manzamine
D, 28, in 58% yield, which on oxidation with DDQ provided
manzamine A, 1 (50% yield), which was identical in all respects
with an authentic sample kindly provided to us by Professor
Kobayashi.
The completion of the first total synthesis of manzamine A in
17 steps from the readily available bicyclic precursor 9 (which
was prepared in 14 steps from pyridine-3-methanol)4 underscores
the utility of the vinylogous amide photoaddition/ fragmentation/
Mannich closure sequence that we have developed for the
synthesis of complex structures from simple precursors. The
establishment of all of the stereochemical relationships in 1 from
the single stereogenic center in 9 further attests to the remarkable
levels of stereochemical control that are possible using this
photochemical cascade in organic synthesis.
Acknowledgment. J.M.A. is the recipient of a Division of Organic
Chemistry Graduate Fellowship, sponsored by Abbott Laboratories and
administered by the American Chemical Society. We thank Professor J.
Kobayashi (Hokkaido University) for helpful discussions and a generous
sample of manzamine A. We also warmly acknowledge the invaluable
contributions of Dr. Miles G. Siegel and Dr. John E. Stelmach to the
early stages of this work and Dr. Abdelhakim Hammach for his assistance
in the preparation of 9. The generous financial support of the National
Institutes of Health (Grant CA40250), SmithKline Beecham, Wyeth-
Ayerst, and Pfizer is gratefully acknowledged.
(8) The acetylenic ketone 10 was prepared in three steps from the known
methyl 10-hydroxy-5-decynoate (Nowak, W.; Gerlach, H. Liebigs Ann. Chem.
1993, 153) by the following sequence: (1) formation of the Weinreb amide
(Me3Al, MeNHOMe-HCl, 94%); (2) semi-hydrogenation (Lindlar, 99%); (3)
reaction with ethynylmagnesium bromide (79%).
(9) The acetylenic substrate 26 was prepared from 9 and the diynone
corresponding to 10 (which was available by the route outlined in ref 8, albeit
without semi-hydrogenation of the intermediate alkyne) by the same reaction
sequence employed for the preparation of 24 from 9 and 10.
(10) The levorotatory rotation that we observe for ircinol A, which differs
in sign from that of the previously published report (Tsuda, M.; Kawasaki,
N.; Kobayashi, J. Tetrahedron 1994, 50, 7957), is consistent with data recently
obtained by Professor Kobayashi (personal communication).
Supporting Information Available: Preparation pocedures for 1, 11,
14, and 16-28 with spectral data (21 pages, print/PDF). See any current
masthead page for ordering and Web access instructions.
JA981303K