A concise synthesis of butylcycloheptylprodigiosin

Article abstract of DOI:10.1021/ol070341i

A short and efficient total synthesis of the tripyrrole alkaloid butylcycloheptylprodigiosin is described. Key to the brevity of the approach is a two-step synthesis of macrocyclic formylpyrrole 4 from cyclononenone 6.

Full text of DOI:10.1021/ol070341i

ORGANIC
LETTERS
2007
Vol. 9, No. 10
1879-1881
A Concise Synthesis of
Butylcycloheptylprodigiosin
Jonathan T. Reeves*
Department of Chemical DeVelopment, Boehringer Ingelheim Pharmaceuticals, Inc.,
900 Old Ridgebury Road, P.O. Box 368, Ridgefield, Connecticut 06877
jreeVes@rdg.boehringer-ingelheim.com
Received February 9, 2007
ABSTRACT
A short and efficient total synthesis of the tripyrrole alkaloid butylcycloheptylprodigiosin is described. Key to the brevity of the approach is
a two-step synthesis of macrocyclic formylpyrrole 4 from cyclononenone 6.
The prodigiosins are a family of intensely pink/red alkaloids
with a common pyrrolylpyrromethene chromophore.1,2 These
natural products display a broad range of biological activity,
and synthetic analogues have shown promising immunosup-
pressive and anticancer effects.3 Butylcycloheptylprodigiosin
(1, Figure 1) was isolated in 1975 by Gerber from a strain
of bacteria (Streptomyces sp. Y-42) found in leaf and grass
compost.4 Ten years later, Floss and co-workers noted the
formation of 1 in the fermentation of mutant strains of
(1) For a review on the history, biology, and synthetic chemistry of the
prodigiosin alkaloids, see: Fu¨rstner, A. Angew. Chem., Int. Ed. 2003, 42,
Figure 1. Butylcycloheptylprodigiosin and Streptorubin B.
3582-3603.
(2) (a) Pe´rez-Toma´s, R.; Montaner, B.; Llagostera, E.; Soto-Cerrato, V.
Biochem. Pharm. 2003, 66, 1447-1452. (b) Manderville, R. A. Curr. Med.
Chem. Anti-Cancer Agents 2001, 1, 195-218.
Streptomyces coelicolor.5 In 1991, Weyland and co-workers
suggested 1 was actually the meta-bridged isomer streptoru-
bin B (2) on the basis of comparison of NMR data.6 Gerber’s
original structural assignment was confirmed, however, by
the pioneering total synthesis of 1 by Fu¨rstner and colleagues
in 2005.7 Although elegant, this synthesis required 16 linear
steps from 1,4-cyclononadien-3-one, thereby rendering the
(3) (a) Dairi, K.; Tripathy, S.; Attardo, G.; Lavallee, J.-F. Tetrahedron
Lett. 2006, 47, 2605-2606. (b) Stepkowski, S. M.; Erwin-Cohen, R. A.;
Behbod, F.; Wang, M. E.; Qu, X.; Tejpal, N.; Nagy, Z. S.; Kahan, B. D.;
Kirken, R. A. Blood 2002, 99, 680-689. (c) Stepkowski, S. M.; Nagy, Z.
S.; Wang, M.-E.; Behbod, F.; Erwin-Cohen, R.; Kahan, B. D.; Kirken, R.
A. Transplant. Proc. 2001, 33, 3272-3273. (d) D’Alessio, R.; Bargiotti,
A.; Carlini, O.; Colotta, F.; Ferrari, M.; Gnocchi, P.; Isetta, A.; Mongelli,
N.; Motta, P.; Rossi, A.; Rossi, M.; Tibolla, M.; Vanotti, E. J. Med. Chem.
2000, 43, 2557-2565. (e) Mortellaro, A.; Songia, S.; Gnocchi, P.; Ferrari,
M.; Fornasiero, C.; D’Alessio, R.; Isetta, A.; Colotta, F.; Golay, J. J.
Immunol. 1999, 162, 7102-7109. (f) Magae, J.; Miller, M. W.; Nagai, K.;
Shearer, G. M. J. Antibiot. 1996, 49, 86-90. (g) Nakamura, A.; Magae, J.;
Tsuji, R. F.; Yamasaki, M.; Nagai, K. Transplantation 1989, 47, 1013-
1016.
(4) (a) Gerber, N. N. J. Antibiot. 1975, 28, 194-199. (b) Gerber, N. N.;
Stahly, D. P. Appl. Microbiol. 1975, 30, 807-810.
(5) Tsao, S. W.; Rudd, B. A. M.; He, X. G.; Chang, C. J.; Floss, H. G.
J. Antibiot. 1985, 38, 128-131.
10.1021/ol070341i CCC: $37.00
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Published on Web 04/18/2007

production of large quantities of 1 (and analogues) for further
biological evaluation challenging. It appeared that our
recently disclosed methodology for preparation of 2-formyl-
4,5-disubstituted pyrroles could enable a much shorter
synthesis of 1.8 Herein is described the application of this
procedure to a concise (five steps from cyclononenone)
synthesis of 1.
The retrosynthetic analysis of 1 was guided by the efficient
three-step sequence employed by Fu¨rstner and co-workers
for late stage pyrrolylpyrromethene installation.7,9,10 Thus,
an O-triflation/Suzuki cross-coupling simplifies 1 to lactam
3, from which a condensation transform leads to the key
formylpyrrole 4 (Figure 2).
D. The application of this transform to 4 gives the aldol 5,
which could be derived from a conjugate addition/aldol
trapping reaction of cyclononenone 6 with n-BuMgCl and
4-formyloxazole 7.
Cyclononenone (6) was obtained by oxidation of com-
mercially available cyclononanone with IBX (o-iodoxyben-
zoate) as described by Nicolaou and co-workers.11 4-Formyl-
oxazole (7) was obtained as previously described by partial
reduction of commercially available ethyl 4-oxazolecarboxy-
late.8 With building blocks 6 and 7 in hand, investigation of
the conjugate addition/aldol reaction was initiated. Although
numerous variations of reaction conditions (organocopper
reagent, solvent, additive) have been described for conjugate
addition/enolate trapping reactions, it was found that simple
CuI-catalyzed addition of n-BuMgCl to 6 proceeded ef-
ficiently in THF at -40 °C in the absence of additives
(Scheme 1).12 The resultant enolate was trapped with 7 to
Scheme 1. Two-step Synthesis of Macrocyclic Formylpyrrole
4
Figure 2. Retrosynthetic analysis.
In our previous report, we described a novel synthesis of
4,5-disubstituted-2-formylpyrroles from aldol adducts of
ketones and 4-formyloxazole.8 This one-pot conversion,
illustrated in Figure 3, involves initial dehydration to give a
give crystalline adduct 5 in 78% yield as a single diastere-
omer by 1H NMR and HPLC analysis of the crude reaction
mixture. While the expected trans relationship of the n-butyl
and (4-oxazolyl)hydroxymethyl groups was evident from 1H
NMR and NOESY data, the relative stereochemistry of the
exocyclic carbinol (which is ultimately of no consequence)
could not be definitively assigned from NMR methods.13
(6) Laatsch, H.; Kellner, M.; Weyland, H. J. Antibiot. 1991, 44, 187-
191.
(7) (a) Fu¨rstner, A.; Radkowski, K.; Peters, H. Angew. Chem., Int. Ed.
2005, 44, 2777-2781. (b) Fu¨rstner, A.; Radkowski, K.; Peters, H.; Seidel,
G.; Wirtz, C.; Mynott, R.; Lehmann, C. W. Chem. Eur. J. 2007, 13, 1929-
1945.
(8) Reeves, J. T.; Song, J. J.; Tan, Z.; Lee, H.; Yee, N. K.; Senanayake,
C. H. Org. Lett. 2007, 9, XX-XX (ol070340q).
(9) D’Alessio, R.; Rossi, A. Synlett 1996, 513-514.
(10) (a) Fu¨rstner, A.; Grabowski, J.; Lehmann, C. W. J. Org. Chem.
1999, 64, 8275-8280. (b) Fu¨rstner, A.; Krause, H. J. Org. Chem. 1999,
64, 8281-8286. (c) Fu¨rstner, A.; Grabowski, J.; Lehmann, C. W.; Kataoka,
T.; Nagai, K. ChemBioChem 2001, 2, 60-68. (d) Fu¨rstner, A.; Reinecke,
K.; Prinz, H.; Waldmann, H. ChemBioChem 2004, 5, 1575-1579.
(11) Nicolaou, K. C.; Montagnon, T.; Baran, P. S.; Zhong, Y. L. J. Am.
Chem. Soc. 2002, 124, 2245-2258.
Figure 3. One-pot conversion of â-hydroxy-â-(4-oxazolyl) ketones
(A) to 4,5-disubstituted-2-formylpyrroles (D).
(12) (a) Stork, G.; d’Angelo, J. J. Am. Chem. Soc. 1974, 96, 7114-
7116. (b) Heng, K. K.; Smith, R. A. J. Tetrahedron 1979, 35, 425-435.
(c) Taylor, R. J. K. Synthesis 1985, 364-392. (d) Suzuki, M.; Kawagishi,
T.; Yanagisawa, A.; Suzuki, T.; Okamura, N.; Noyori, R. Bull. Chem. Soc.
Jpn. 1988, 61, 1299-1312. (e) Nicolaou, K. C.; Tang, W.; Dagneau, P.;
Faraoni, R. Angew. Chem., Int. Ed. 2005, 44, 3874-3879.
â-(4-oxazolyl)enone (B), which on treatment with aqueous
alkali undergoes hydrolysis of the oxazole ring to generate
C (or an equivalent tautomeric structure). Dehydrative
cyclization of the amino group yields the product pyrrole
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Org. Lett., Vol. 9, No. 10, 2007

Aldol 5 was subjected to the previously optimized cond-
itions for pyrrole formation. Thus, treatment with MsCl/Et3N
in THF, addition of aqueous NaOH on completion of the
mesylation (as monitored by HPLC) and finally heating at
70 °C for 9 h produced the desired formylpyrrole 4 in 68%
isolated yield. The powerful combination of a conjugate
addition/aldol reaction and a one-pot dehydration/oxazole
hydrolysis/pyrrole formation had enabled a two-step synthesis
of 4 from cyclononenone 6. By way of comparison, prepara-
tion of N-Boc 4 required 13 steps from 1,4-cyclononadien-
3-one in the previous synthesis.7
Scheme 3. Completion of the Total Synthesis of 1
To ascertain the effect of olefin geometry of the intermedi-
ate enone on the rate of oxazole hydrolysis, 5 was dehydrated
to enone 8, formed as a 6:1 mixture of separable E/Z isomers
(Scheme 2). Olefin geometries were unambiguously assigned
Scheme 2. Convergent Hydrolysis of E-8 and Z-8 to 4
fonylation of 3 with Tf2O gave triflate 10 in 84% yield.
Suzuki cross-coupling of 10 with commercially available
boronic acid 11 with concomitant hydrolysis of the Boc
group furnished (()-butylcycloheptylprodigiosin (1) in 70%
1
yield.15 Spectral data of 1 (IR, H and 13C NMR, HRMS)
were in excellent agreement with data from Fu¨rstner’s
synthetic material7 and available data from the natural
product.5
In summary, a concise total synthesis of (()-butylcyclo-
heptylprodigiosin (1) has been described. The use of a
conjugate addition/aldol reaction in conjunction with the
application of our methodology for synthesis of 2-formyl-
4,5-disubstituted pyrroles from â-hydroxy-â-(4-oxazolyl)
ketones was key to the brevity of the route (five steps, 23%
overall yield versus 16 steps, 1.5% overall yield for the
previous synthesis).7 The approach outlined herein should
be of general use for the synthesis of other prodigiosin
alkaloids as well as analogues and may assist further
investigations of their medicinal potential.
from COSY and NOESY NMR analyses. Individual hy-
drolysis of the isomeric enones, monitored by HPLC analysis,
showed that E-8 converted more quickly to 4 than Z-8. The
attenuated reactivity of Z-8 may be attributable to poorer
conjugation of the ketone with the oxazole ring relative to
E-8 due to torsional strain and, thus, decreased electrophi-
licity of the oxazole toward hydrolytic attack at C2.14
Elaboration of 4 into 1 was accomplished in three steps
as outlined in Scheme 3. Condensation of 4 with commer-
cially available pyrrolinone 9 gave 3 as a bright yellow solid
in 75% yield.7 The preparation of 3 constituted a formal total
synthesis of 1, and conversion of 3 to 1 followed directly
from the procedures of Fu¨rstner and co-workers.7,9 O-Sul-
Acknowledgment. Prof. Heinz G. Floss (University of
1
Washington) is thanked for a copy of the H NMR spec-
trum of butylcycloheptylprodigiosin. Prof. Alois Fu¨rstner
(Max-Planck Institut fu¨r Kohlenforschung) is thanked for
helpful discussions. Mr. Scot J. Campbell and Dr. Heewon
Lee are thanked for assistance with 2-D NMR and HRMS
analysis, respectively.
Supporting Information Available: Experimental pro-
cedures, characterization data and copies of 1H and 13C NMR
spectra for 1, 3-5, 8 and 10. This material is available free
of charge via the Internet at http://pubs.acs.org.
(13) Kitamura, M.; Nakano, K.; Miki, T.; Okada, M.; Noyori, R. J. Am.
Chem. Soc. 2001, 123, 8939-8950.
(14) 1H NMR signals for the two oxazole hydrogens and the vinyl
hydrogen are significantly further downfield for E-8 than Z-8 (see the
Supporting Information for complete spectral data), which also suggests
lesser conjugation of the oxazole with the ketone carbonyl in Z-8.
OL070341I
(15) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483.
Org. Lett., Vol. 9, No. 10, 2007
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