Iterative synthesis of semicorrins, tripyrrolines, and higher analogues [3]

Full text of DOI:10.1021/ja983698d

1958
J. Am. Chem. Soc. 1999, 121, 1958-1959
Iterative Synthesis of Semicorrins, Tripyrrolines, and
Higher Analogues
,†
Peter A. Jacobi* and Hui Liu
Department of Chemistry, Wesleyan UniVersity
Middletown, Connecticut 06459-0180
Burke Chemical Laboratory, Dartmouth College
HanoVer, New Hampshire 03755
ReceiVed October 23, 1998
Hydroporphyrins of the chlorin, bacteriochlorin, and corrin
families are ubiquitous chromophores in nature, and they play
important roles in many biological processes. Also, chlorins and
In principle, cyclizations of type 8 f 9 might be employed in
an iterative synthesis of hydroporphyrins, taking advantage of the
high reactivity of iminoyl derivatives of general structure 13
(X ) Cl, OTf, etc.). We expected that intermediates 13 could be
derived from enamides 9 (R ) H) by initial double bond
1
bacteriochlorins are promising substrates for use in tumor photo-
2
dynamic therapy (PDT). The most complex members of this
group are the corrins, which incorporate up to 10 stereogenic
centers within the macrocycle. A noteworthy accomplishment in
this area was the elegant synthesis of cobyric acid (6) by
3
protection with KCN, followed by activation of the lactam
carbonyl group. Pd(0)-mediated coupling of 13 with a second
alkyne amide 14 should then yield the corresponding pyrroli-
noalkyne 15 (not shown),6 which upon 5-exo-dig ring closure
would give semicorrin 16. Finally, repetition of this three-step
sequence of enamide activation, alkyne coupling, and cyclization
could afford tripyrrolines and ultimately secocorrins. This strategy
complements the sulfide contraction methodology involving
oxidative coupling of thiolactams 17 and enamides 18, followed
3
a
Eschenmoser et al.
a,7
by PR
3
-induced extrusion of sulfur.4
Recently we have shown that alkyne acids 7 are versatile
precursors to cyclic enamides of type 9 (R ) Bn), via initial
amidation to alkyne amides 8, followed by 5-exo-dig cyclization.5
As one example, enantiomerically pure enamides 9a and ent-9a
,6
(
A,B ) Me; R ) Bn) were obtained in ∼90% yield upon brief
warming of 8a or ent-8a, respectively, with 1.0 M TBAF/THF
(
ent ) mirror image of structure shown). In analogous fashion,
racemic enamide (()-12a (R ) Bn) was prepared in two steps
starting with the bis-ketene silyl acetal 10 and alkyne cobalt
This concept was first tested with the enamide derivative 21b,
5a
complex 11 (∼75% overall yield). Enamide (()-12a has the
substitution pattern found in ring-C of vitamin B12, and it was
cleanly debenzylated to the parent enamide (()-12b (R ) H)
itself derived by 5-exo-dig cyclization of the alkyne acid 20a
8
(PdCl
2
, 100%), followed by aminolysis (NH
3
, -78 °C, vacuum
9
dehydration, 87%). (Scheme 1). Enamide 21b was then readily
converted to the iminoyl chloride 23 by initial protection with
KCN (90%), followed by chlorination using Ph P/CCl (85%).
3 4
3
with Na/NH (98% yield).
3
10
†
Current address: Department of Chemistry, Dartmouth College, Hanover,
NH 03755.
(
Finally, we were pleased to find that Sonogashira coupling of 23
with the alkyne amide 8c (R ) H; A,B ) Me) afforded a 70%
1) (a) Montforts, F.-P.; Gerlach, B.; H o¨ per, F. Chem. ReV. 1994, 94, 327
and references therein. (b) Flitsch, W. In AdVances in Heterocyclic Chemistry;
Katritzky, A. R., Ed.; Academic Press: San Diego, California, 1988; Vol. 43,
p 74.
7
yield of the pyrrolinoalkyne 24, which underwent clean cycliza-
6
a
2
tion with TBAF to afford the semicorrin 25 (epimers at C ).
(
2) (a) Bonnett, R. Chem. Soc. ReV. 1995, 19 and references therein. (b)
Cyclization of 24 occurs readily at rt due to the activating
influence of the ring-A imine.
Photodynamic Therapy of Neoplastic Disease; Kersel, D., Ed.; CRC Press:
Boca Raton, 1990; Vol. 2. (c) Bonnett, R. Proc. SPIE 1994, 74.
(
3) (a) Eschenmoser, A.; Wintner, C. E. Science 1977, 196, 1410 and
We next studied the coupling of the iminoyl chloride 23 with
the alkyne amide 20b, which was accomplished in 89% yield
using the reagent system Pd(0)/CuI. The resultant pyrrolinoalkyne
26 was then cleanly converted to the Z-semicorrin 27 upon treat-
ment with TBAF in THF (96% yield). Both of these transforma-
tions were effected at rt and under essentially neutral conditions
(Scheme 2). Furthermore, repetition of this sequence of enamide
references therein. See also: (b) Yamada, Y.; Miljkovic, D.; Wehrli, P.;
Golding, B.; L o¨ liger, P.; Keese, R.; M u¨ ller, K.; Eschenmoser, A. Angew.
Chem., Int. Ed. Engl. 1969, 8, 343. (c) Eschenmoser, A. Angew. Chem., Int.
Ed. Engl. 1988, 27, 5. For an alternative synthetic approach to Vitamin B12
,
see: (d) Stevens, R. V.; Beaulieu, N.; Chan, W. H.; Daniewski, A. R.; Takeda,
T.; Waldner, A.; Williard, P. G.; Zutter, U. J. Am. Chem. Soc. 1986, 108, 8.
1
039. See also: (e) Mulzer, J.; List, B.; Bats, J. W. J. Am. Chem. Soc. 1997,
19, 5512.
1
(
4) (a) Bishop, J. E.; O’Connell, J. F.; Rapoport, H. J. Org. Chem. 1991,
5
6, 5079. (b) G o¨ tschi, E.; Hunkeler, W.; Wild, H.-J.; Schneider, P.; Fuhrer,
(7) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16,
4467.
(8) See, for example: Arcadi, A.; Burini, A.; Cacchi, S.; Delmastro, M.;
Marinelli, F.; Pietrono, B. R. J. Org. Chem. 1992, 57, 976 and references
therein.
(9) See, for example: Micklefield, J.; Mackman, R. L.; Aucken, C. J.;
Beckmann, M.; Block, M. H.; Leeper, F. J.; Battersby, A. R. J. Chem. Soc.
Chem. Commun. 1993, 275 and references therein.
(10) Appel, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 801.
W.; Gleason, J.; Eschenmoser, A. Angew. Chem., Int. Ed. Engl. 1973, 12,
9
10. See also ref 3e.
5) (a) Jacobi, P. A.; Brielmann, H. L.; Hauck, S. I. J. Org. Chem. 1996,
1, 5013 and references therein. See also: (b) Jacobi, P. A.; Buddhu, S. C.;
(
6
Fry, D.; Rajeswari, S. J. Org. Chem. 1997, 62, 2894.
(6) (a) Jacobi, P. A.; Guo, J.; Rajeswari, S.; Zheng, W. J. Org. Chem. 1997,
6
3
2, 2907. (b) Koseki, Y.; Kusano, S.; Nagasaka, T. Tetrahedron Lett. 1998,
9, 3517.
1
0.1021/ja983698d CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/20/1999

Communications to the Editor
J. Am. Chem. Soc., Vol. 121, No. 9, 1999 1959
Scheme 1
of 35, since concomitant coupling and cyclization of terminal
alkynes is not observed with nonchelating substrates (Note: CuI
was not employed in the coupling of 28 with 20b, above, which
afforded exclusively the alkyne 29). In any event, acid-catalyzed
2 3
Dimroth rearrangement of 36 with TsOH/H O/CHCl then gave
a 65% yield of the desired tripyrroline 37 as an inseparable mix-
ture of E- and Z-isomers.12 In analogous fashion, Pd(0)/CuI-medi-
ated coupling of semicorrin 35 with the alkyne amide 20b led
directly to the tricyclic iminolactone 38 (60%). As in the case
with 36, iminolactone 38 was cleanly converted to the target tri-
pyrroline 39 upon acid-catalyzed isomerization (60%; Z:E ) 3:1).
Finally, we have evaluated both iminoyl chlorides and triflates
as substrates for Pd(0)-mediated coupling. Once in hand, these
species generally serve equally well (cf. 31, above). However,
triflate formation is occasionally complicated by competing
reaction at nitrogen. For example, treatment of Z-semicorrin 34
3 4
activation (27 f 28, Ph P/CCl ), alkyne coupling (28 f 29, Pd°,
no CuI) and cyclization (29 f 30, TBAF) led directly to the Z,Z-
tripyrroline 30, which had identical physical and spectral proper-
ties as the material previously reported by Eschenmoser in his
model studies for the synthesis of cobyric acid (6).3b,11
2
with Tf O/2,6-di-tert-butyl-4-methylpyridine led directly to the
N,O-ditriflate derivative 40, obtained exclusively as the E-isomer
due to steric repulsion. Interestingly, however, bis-triflation did
not forestall subsequent elaboration. Thus, Sonogashira coupling
Scheme 2
Scheme 4
It was important to explore the effect of adjacent substituents
on both the coupling and cyclization steps. Steric crowding turned
out not to be a problem, as demonstrated for the case of iminoyl
triflate 31 and alkyne amide 32. Once again, Sonogashira coupling
of 31 with 32 afforded an excellent yield of the corresponding
pyrrolinoalkyne 33 (not shown, 93%), which underwent cycliza-
tion at rt with TBAF to give a 96% yield of the Z-semicorrin 34
of 40 with the acetylenic amide 32, followed by 5-exo-dig
cyclization, gave an excellent yield of the corresponding tripyr-
roline 42, whose E,Z-geometry was confirmed by X-ray analysis
3 4
(X ) OH). Chlorination of 34 with Ph P/CCl then gave an 81%
yield of the iminoyl chloride 35 (X ) Cl). Interestingly, Pd(0)-
mediated coupling of 35 with the alkyne amide 32 produced a
variable product mixture, dependent mainly upon the presence
or absence of CuI. With no added CuI, this reaction was sluggish
and was accompanied by considerable decomposition. However,
in the presence of CuI, coupling of 35 with 32 led directly to the
iminolactone 36 (Y ) O, Z ) NH), which was isolated in 46%
yield as the Z,Z-isomer (Scheme 3). This divergence in reaction
(
hydrogen bond between rings B and C).13 Repetition of this
sequence of activation, coupling, and cyclization then afforded
the secocorphin derivative 45 (Scheme 4). In 45, the E,E,Z-
geometry derives from hydrogen bonding between rings C and
D and steric repulsion between rings A-C.
Complications of the type described in Scheme 4 are unlikely
in the cobyric acid (6) series, where both the C-7 and C-12
positions bear geminal alkyl groups. Currently we are extending
this methodology to the incorporation of meso-substituents, and
also to the synthesis of semicorrins having the oxidation state of
Scheme 3
14,15
ring-D in vitamin B12
.
Acknowledgment. This paper is dedicated to my good friend and
mentor, Professor Edward C. Taylor, on the occasion of his 75th birthday.
Supporting Information Available: Copies of H and/or 13C NMR
1
spectra and experimental procedures for compounds 23-28, 30, 31, and
3
3-39, crystallographic data for compound 42 (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
JA983698D
(
12) Katritzky, A. R.; Lagowski, J. M. In ComprehensiVe Heterocyclic
Chemistry; Katritzky, A. R., Rees, Charles W., Eds.; Pergamon Press Inc.:
New York, 1984; Vol. 5, p 94.
(13) We are grateful to Dr. Victor G. Young, X-ray Crystallographic
Laboratory, Department of Chemistry, University of Minnesota, for carrying
out this analysis (cf. Supporting Information).
pathway might be due to complexation of Cu with the A,B-rings
(14) Satisfactory analytical and spectral data were obtained for all new
compounds reported.
(
11) We are grateful to Professor Doctor Albert Eschenmoser, ETH-Z, for
(15) Financial support of this work by the National Institutes of Health,
NIGMS Grant No. GM38913, and the National Science Foundation, Grant
No. CHE-9424476, is gratefully acknowledged.
providing us with experimental details and spectral data for several unpublished
procedures.