Formal synthesis of (±)-roseophilin

Article abstract of DOI:10.1021/ol802329y

A formal synthesis of (±)-roseophilin is described. Scandium(lll)-catalyzed Nazarov cyclization of 2,5-disubstituted N-tosylpyrrole 19 gives a 5,5'-fused ketopyrrole, and ansa-bridge formation via π-allyl palladium macrocyclization gives 21.

Full text of DOI:10.1021/ol802329y

ORGANIC
LETTERS
2009
Vol. 11, No. 1
49-52
Formal Synthesis of (()-Roseophilin
Abdallah Y. Bitar and Alison J. Frontier*
Department of Chemistry, UniVersity of Rochester, Rochester, New York 14627
frontier@chem.rochester.edu
Received October 7, 2008
ABSTRACT
A formal synthesis of (()-roseophilin is described. Scandium(III)-catalyzed Nazarov cyclization of 2,5-disubstituted N-tosylpyrrole 19 gives a
5,5′-fused ketopyrrole, and ansa-bridge formation via π-allyl palladium macrocyclization gives 21.
Roseophilin (1), isolated from Streptomyces griseoViridis,
was identified as a potent cytotoxic agent against K562
human erythroid leukemia cells (chronic myeloid leukemia
model; IC50, 0.34 µM) and KB human epidermoid carcinoma
cells (nasopharyngeal carcinoma model; IC50, 0.88 µM).1
Unexpectedly, the unnatural enantiomer of 1, ent-roseophilin,
was shown to possess 2–10 fold greater potency than the
naturally occurring enantiomer.2
subunit. Its unique chemical structure coupled with its poorly
understood mechanism of cytotoxicity3 has led to the
development of several synthetic approaches targeting 1.2,4
Herein, we disclose our approach to the formal synthesis of
1 via macrotricycle 2, using a strategy involving the catalytic
Nazarov cyclization of polarized aryl vinyl ketones.5,6
Our retrosynthetic analysis of macrotricycle 2 is shown
in Scheme 1. Execution of a late-stage macrocyclization to
close the strained 13-membered ansa bridge was planned with
some trepidation. In most of the published approaches toward
this target, the final stages involved closure of either the
cyclopentenyl ring or the pyrrole ring within an existing
macrocyclic scaffold. In the few cases when a late-stage
macrocyclization was performed on the fused 5,5′-fused ring
system, bulky substituents on the side chain were needed to
conformationally induce ring closure.4d,h With greater con-
fidence, we planned to prepare macrocyclization precursor
3 from Nazarov cyclization of pyrrolylvinyl ketone 4,6 which
The structure of 1 contains an ansa-bridged macrocycle
that is connected to a pyrrolylfuran moiety via an azafulvene
(1) Hayakawa, Y.; Kawakami, K.; Seto, H.; Furihata, K. Tetrahedron
Lett. 1992, 33, 2701.
(2) Boger, D. L.; Hong, J. J. Am. Chem. Soc. 2001, 123, 8515.
(3) (a) Fürstner, A.; Grabowski, E. J. ChemBioChem 2001, 2, 706. (b)
Fürstner, A.; Reinecke, K.; Prinz, H.; Waldmann, H. ChemBioChem 2004,
5, 1575. (c) Manger, M.; Scheck, M.; Prinz, H.; von Kries, J. P.; Langer,
T.; Saxena, K.; Schwalbe, H.; Fürstner, A.; Rademann, J.; Waldmann, H.
ChemBioChem 2005, 6, 1749.
(4) For a review, see: (a) Fürstner, A. Angew. Chem., Int. Ed. 2003, 42,
3582 . Syntheses of Racemic 1: (b) Fürstner, A.; Weintritt, H. J. Am. Chem.
Soc. 1998, 120, 2817. (c) Fürstner, A.; Gastner, T.; Weintritt, H. J. Org.
Chem. 1999, 64, 2361. (d) Kim, S. H.; Figueroa, I.; Fuchs, P. L. Tetrahedron
Lett. 1997, 38, 2601. (e) Mochizuki, T.; Itoh, E.; Shibata, N.; Nakatani, S.;
Katoh, T.; Terashima, S. Tetrahedron Lett. 1998, 39, 6911. (f) Harrington,
P.; Tius, M. Org. Lett. 1999, 1, 649. (g) Robertson, J.; Hatley, R. J. D.;
Watkin, D. J. J. Chem. Soc., Perkin Trans. 1 2000, 3389. Asymmetric
Syntheses: (h) Bamford, S. J.; Luker, T.; Speckamp, W. N.; Hiemstra, H.
Org. Lett. 2000, 2, 1157. (i) Trost, B. M.; Doherty, G. A. J. Am. Chem.
Soc. 2000, 122, 3801. (j) Harrington, P. E.; Tius, M. A. J. Am. Chem. Soc.
2001, 123, 8509. (k) Occhiato, E. G.; Prandi, C.; Ferrali, A.; Guarna, A. J.
Org. Chem. 2005, 70, 4542. Approaches to the Roseophilin Core: (l)
Salamone, S. G.; Dudley, G. B. Org. Lett. 2005, 7, 4443. (m) Song, C.;
Knight, D. W.; Whatton, M. A. Org. Lett. 2006, 8, 163.
(5) For applications of different Nazarov cyclization strategies toward
roseophilin, see refs 4f, j, k, and m.
(6) (a) He, W.; Sun, X.; Frontier, A. J. J. Am. Chem. Soc. 2003, 125,
14728. (b) Malona, J. A.; Colbourne, J. M.; Frontier, A. J. Org. Lett. 2006,
8, 5661. (c) He, W.; Herrick, I. R.; Atesin, T. A.; Caruana, P. A.;
Kellenberger, C. A.; Frontier, A. J. J. Am. Chem. Soc. 2008, 130, 1003.
(7) (a) Padwa, A.; Kline, D. N.; Perumattam, J. Tetrahedron Lett. 1987,
23, 913. (b) Padwa, A.; Chiacchio, U.; Kline, D. N.; Perumattam, J. J. Org.
Chem. 1988, 53, 2238.
(8) (a) Canterbury, D. P.; Frontier, A. J.; Um, J. M.; Cheong, P. H.-Y.;
Goldfeld, D. A.; Huhn, R. A.; Houk, K. N. Org. Lett. 2008, 10, 4597. (b)
Canterbury, D. P.; Herrick, I. R.; Um, J. M.; Houk, K. N.; Frontier, A. J.
Tetrahedron, in press.
10.1021/ol802329y CCC: $40.75
Published on Web 11/26/2008
2009 American Chemical Society

Scheme 1
could in turn be assembled via [3 + 2] cycloaddition/
Swern conditions provides aldehyde 8. Under standard
Horner-Wadsworth-Emmons conditions12 with methyl di-
ethylphosphonoacetate, aldehyde 8 was converted to the R,ꢀ-
unsaturated ester 9 in excellent yield.
chelotropic extrusion of the alkynyl ester 5, a sequence
discovered by Padwa7 and investigated further in our
laboratory.8
The synthesis began with ozonolytic desymmetrization9
of cyclohexene followed by Jones oxidation of the interme-
diate aldehyde to provide carboxylic acid 6 in excellent yield
(Scheme 2). Under refluxing conditions in the presence of
Vilsmeier-Haack formylation13 of 9 provided pyrrolylcar-
boxaldehyde 10 which was subjected to the first step of the
Corey-Fuchs transformation14 to arrive at gem-dibromoalkene
11 (Scheme 3). Reduction of the R,ꢀ-unsaturated ester moiety
of 11 with DIBAL-H and subsequent silyl protection of the
alcohol 12 yields gem-dibromoalkene 13. The rearrangement
step of the Corey-Fuchs sequence provided alkyne 14 in good
yield. Selective deprotonation of the acetylenic proton of 14
with lithium hexamethyldisilazide followed by addition of
methyl chloroformate yielded alkynyl ester 15. One-pot
formation of the alkynyl ester from 13 using organolithium
reagents followed by quenching with methyl chloroformate
was problematic due to orthometalation of the N-tosyl
protecting group.15 Crude alkynyl ester 15 underwent a [1,3]-
dipolar cycloaddition reaction with nitrone 16 at 80 °C in
toluene (1.6 M) to provide isoxazoline 17 in excellent yield
over two steps.
Scheme 2
To unveil the Nazarov cyclization precursor, isoxazoline
17 was exposed to a slight excess of m-CPBA at 0 °C,
standard conditions for a chelotropic extrusion of this type.7,8
The desired 2-pyrrolyl vinyl ketone was obtained along with
a byproduct resulting from epoxidation of the protected
allylic alcohol. If the rate of N-oxidation is slightly faster
than epoxidation, addition of a sacrificial alkene might
minimize unwanted epoxidation of valuable substrate 17.
Indeed, a protocol that involved alternating the addition of
(9) Claus, R. E.; Schreiber, S. L. Org. Synth. 1986, Coll. Vol. 7, 168.
(10) Song, C.; Knight, D. W.; Whatton, M. A. Tetrahedron Lett. 2004,
45, 9573.
trifluoroacetic anhydride and carboxylic acid 6, N-tosylpyr-
role was acylated selectively at the 2-position.10 Subse-
quently, the ketopyrrole formed was reductively deoxygen-
ated under mild conditions using zinc iodide and sodium
cyanoborohydride to provide ester 7 in good yield.11
Elaboration upon the alkyl side chain of ester 7 using the
high-yielding reduction/oxidation sequence of DIBAL-H and
(11) Lau, C. K.; Dufresne, C.; Bélanger, P. C.; Piétré, S.; Scheigetz, J.
J. Org. Chem. 1986, 51, 3038.
(12) Masanori, S.; Mori, K. Eur. J. Org. Chem. 2001, 503.
(13) Xu, R. X.; Anderson, H. J.; Gogan, N. J.; Loader, C. E.; McDonald,
R. Tetrahedron Lett. 1981, 22, 4899.
(14) Tietze, L. F.; Kettschau, G.; Heitmann, K. Synthesis 1996, 851.
(15) For similar difficulties with the N-tosyl group, see: Liu, J.; Yang,
Q.; Mak, T. C. W.; Wong, H. N. C. J. Org. Chem. 2000, 65, 3587.
50
Org. Lett., Vol. 11, No. 1, 2009

Scheme 3
portions of cyclohexene and oxidant at -30 °C did protect
to inhibit catalyst turnover. Further heating resulted in
decomposition. After exchanging the silyl protecting group
for an acetyl protecting group, the Nazarov substrate 19 was
heated in the presence of catalytic amounts of scandium(III)
triflate and 1 equiv of lithium perchlorate to provide Nazarov
product 20 in good yield (Scheme 4).6b Furthermore, the
reaction was relatively rapid with complete conversion
observed in under 2 h.
17 from overoxidation (Scheme 4). Further optimization of
this reaction is required. With ꢀ-ketoester 18 in hand, we
turned our attention to the Nazarov cyclization.
Initial attempts at cyclization of ꢀ-ketoester 18 were
unsuccessful. The silyl protecting group was cleaved under
the reaction conditions, and the exposed alcohol appeared
Initial attempts to cyclize structures similar to 3 (see
Scheme 1) using a mild base in a polar aprotic solvent16
were unsuccessful. Since intramolecular alkylation of the
ꢀ-ketoester by SN2 displacement was not possible, alkylation
with the appropriate π-allyl palladium species was ex-
plored.17 We sought to carry out the macrocyclization under
Scheme 4
Table 1. Optimization of the π-Allyl Palladium
Macrocyclizationa
ligand
(mol %)
overall yield
(%)
entry catalyst
ratio 21:Ab
1
2
3
4
Pd(PPh3)4
-
56
73
4:1
3:1
4:1
-
Pd(OAc)2 dpppc (48 mol %)
Pd(OAc)2 dpped (48 mol %)
Pd(OAc)2 dppbe (48 mol %)
82
f
a Reaction conditions: 20 mol % catalyst, ligand, NaH (1.1 equiv), reflux,
THF (0.001 M). b Based on 1H NMR integration. c dppp ) 1,3-bis(diphenyl-
phosphino)propane. d dppe ) 1,2-bis(diphenylphosphino)ethane. e dppb )
1,4-bis(diphenylphosphino)butane. f Decomposition was observed.
Org. Lett., Vol. 11, No. 1, 2009
51

Scheme 5
the macrocyclization and adapting the strategy to the
asymmetric synthesis of 2.
Figure 1. ORTEP drawing of macrocycle 21.
Acknowledgment. We are grateful to the NSF (CAREER:
CHE-0349045), the NIH (NIGMS R01 GM079364), and the
University of Rochester for generous financial support. We
thank Prof. Robert K. Boeckman, Jr. (University of Roch-
ester) and Prof. David W. C. MacMillan (Princeton Univer-
sity) for helpful discussions. We are also grateful to Dr.
William Brennessel (University of Rochester) for solving the
structure of 21 by X-ray crystallography and Dr. Alice
Bergmann (University of Buffalo) for carrying out high-
resolution mass spectroscopy.
dilute and controlled conditions using a suitable palladium (0)
catalyst system (Table 1). Our initial attempt relied upon
slow addition of the sodium enolate of 20 to a refluxing THF
solution of tetrakis(triphenylphosphine)palladium (entry 1).18
The reaction provided a 4:1 mixture of macrocycle 21 to a
product resulting from ꢀ-hydride elimination (A). The two
products were difficult to separate via flash chromatography.
Fortunately, macrocycle 21 could be recrystallized, and an
X-ray crystal structure was obtained as shown in Figure 1.
By preforming the Pd(0) catalyst using palladium acetate in
the presence of dppp, we were pleased to find the overall
yield increased to 73% (entry 2). The ratio was improved to
4:1 with the use of dppe (entry 3). Decomposition was
observed when dppb was employed (entry 4).
Supporting Information Available: Experimental pro-
cedures, characterization data, X-ray crystal structure coor-
dinates, and files for compound 21 in CIF format. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Functional group modification was required to complete
the formal synthesis of 1 (Scheme 5). Hydrogenation
followed by deprotection of the pyrrolyl nitrogen under basic
conditions furnished macrocyclic ꢀ-ketoester 22. Krapcho
dealkoxycarbonylation of 22 delivered 2 in good yield.
Future work will focus on developing a more efficient
synthesis of Nazarov cyclization precursor 19, optimizing
OL802329Y
(16) (a) Casadei, M. A.; Galli, C.; Mandolini, L. J. Am. Chem. Soc.
1984, 106, 1051. (b) Brillon, D.; Deslongchamps, P. Can. J. Chem. 1987,
65, 56.
(17) For a review, see: Trost, B. M. Angew. Chem., Int. Ed. 1989, 28,
1173.
(18) Kitagawa, Y.; Itoh, A.; Hashimoto, S.; Yamamoto, H.; Nozaki, H.
J. Am. Chem. Soc. 1977, 99, 3864.
52
Org. Lett., Vol. 11, No. 1, 2009