Total synthesis of the interleukin-1β converting enzyme inhibitor EI-1941-2 using tandem oxa-electrocyclization/oxidation

Article abstract of DOI:10.1021/ol060954f

The total synthesis of the interleukin-1β converting enzyme inhibitor EI-1941-2 was achieved utilizing tandem oxidation/oxa-electrocyclization/ oxidation to access a key α-pyrone intermediate. Support for the tandem reaction mechanism was obtained by eval

Full text of DOI:10.1021/ol060954f

ORGANIC
LETTERS
2006
Vol. 8, No. 13
2847-2850
Total Synthesis of the Interleukin-1
â
Converting Enzyme Inhibitor EI-1941-2
Using Tandem Oxa-electrocyclization/
Oxidation1
Andrew S. Kleinke, Chaomin Li,† Nicolas Rabasso,‡ and John A. Porco, Jr.*
Department of Chemistry and Center for Chemical Methodology and
Library DeVelopment (CMLD-BU), Boston UniVersity, 590 Commonwealth AVenue,
Boston, Massachusetts 02215
porco@bu.edu
Received April 20, 2006
ABSTRACT
The total synthesis of the interleukin-1
â
converting enzyme inhibitor EI-1941-2 was achieved utilizing tandem oxidation/oxa-electrocyclization/
oxidation to access a key
oxidation protocol.
r-pyrone intermediate. Support for the tandem reaction mechanism was obtained by evaluation of a stepwise
Koizumi and co-workers recently reported the isolation2 and
structure elucidation3 of the interleukin-1â converting en-
zyme (ICE) inhibitors EI-1941-2 (1) and EI-1941-1 (2)
(Figure 1). ICE is a cysteine protease which functions to
cleave the biologically inactive precursor of interleukin-1â,
an enzyme implicated in inflammatory disease.4 In light of
our interest5 in the synthesis of epoxyquinoid natural
products,6 we have targeted these compounds for synthesis.
Recently, the Hayashi group7 reported the enantioselective
synthesis of both 1 and 2, and Mehta and Roy8 completed
an enantioselective synthesis of 1. Herein, we report the
enantioselective synthesis of EI-1941-2 (1) utilizing a tandem
oxidation/oxa-electrocyclization/oxidation cascade to access
a key R-pyrone intermediate.
Our synthetic approach to 1 arose serendipitously during
studies toward the synthesis of epoxyquinol A (3)5f and
related natural products (Scheme 1).5 In these studies,
selective oxidation of primary alcohol 4 to the corresponding
aldehyde 5 was attempted. Previous work in our group
showed that dienal 5 should readily undergo 6π-oxa-
electrocyclization9,10 to the corresponding diastereomeric 2H-
pyrans (6/6′) and further dimerization to 3.5c,f However, when
† Current address: Department of Chemistry, Columbia University, 3000
Broadway, New York, NY 10027.
‡ Current address: Universite´ de Paris-sud, Le´quipe des Carbocycles,
91405 ORSAY Cedex, France.
(1) Presented in part at the 231st American Chemical Society National
Meeting, Atlanta, GA, March 26-30, 2006; ORGN abstract 072.
(2) Koizumi, F.; Matsuda, Y.; Nakanishi, S. J. Antibiot. 2003, 56, 464.
(3) Koizumi, F.; Takahashi, Y.; Hiroki, I.; Rieko, T.; Shizuo, O.; Mayumi,
Y.; Nakanishi, S.; Ikeda, S. Tetrahedron Lett. 2004, 45, 7419.
(4) Cerretti, D. P.; Kozlosky, B. M.; Nelson, N.; Van Ness, K.;
Greenstreet, T. A.; March, C. J.; Kronheim, S. R.; Druck, T.; Cannizzaro,
L. A.; Huebner, K.; Black, R. A. Science 1992, 256, 97.
Figure 1. EI-1941 natural products.
10.1021/ol060954f CCC: $33.50
© 2006 American Chemical Society
Published on Web 05/27/2006

Scheme 1. Serendipitous R-Pyrone Formation
Scheme 2. Proposed Mechanism for R-Pyrone Formation
4 was treated with oxoammonium salt 7 (Bobbitt’s Reagent,
Scheme 1, inset),11 R-pyrone12,13 8 was obtained unexpectedly
in 85% yield.14
A proposed mechanism for the formation of R-pyrone 8
involves initial oxidation of primary alcohol 4 to aldehyde
5 followed by oxa-electrocyclization to afford 2H-pyrans 6/6′
(Scheme 2). The electrophilic oxoammonium salt 7 may then
react with the 2H-pyran15 moiety, resulting in intermediate
10 which may undergo elimination generating pyrylium salt
11. Alternate pathways for pyrylium generation may entail
an ene-type mechanism16 or direct hydride abstraction.17,18
Nucleophilic hydroxylamine 9, the reduced form of 7
generated in the initial oxidation step (4 f 5),19 may then
condense20 with 11, resulting in formation of intermediate
12 followed by elimination21 to provide the observed
R-pyrone 8. Mehta and Roy8 have proposed an alternate
mechanism for a related R-pyrone formation involving initial
oxidation with an oxoammonium species to a carboxylic acid
followed by electrophilic cyclization-elimination.
On the basis of the oxa-electrocyclization/oxidative R-py-
rone formation process, a retrosynthetic analysis of EI-1941-2
was developed (Scheme 3). EI-1941-2 (1) may be derived
(5) (a) Li, C.; Lobkovsky, E.; Porco, J. A., Jr. J. Am. Chem. Soc. 2000,
122, 10484. (b) Li, C.; Pace, E.; Liang, M.-C.; Lobkovsky, E.; Gilmore, T.
D.; Porco, J. A., Jr. J. Am. Chem. Soc. 2001, 123, 11308. (c) Li, C.; Bardhan,
S.; Pace, E. A.; Liang, M.-C.; Gilmore, T. D.; Porco, J. A., Jr. Org. Lett.
2002, 4, 3267. (d) Li, C.; Johnson, R. P.; Porco, J. A., Jr. J. Am. Chem.
Soc. 2003, 125, 5095. (e) Li, C.; Porco, J. A., Jr. J. Am. Chem. Soc. 2004,
126, 1310. (f) Li, C.; Porco, J. A., Jr. J. Org. Chem. 2005, 70, 6053.
(6) (a) Marco-Contelles, J.; Molina, M. T.; Anjum, S. Chem. ReV. 2004,
104, 2857. (b) Miyashita, K.; Imanishi, T. Chem. ReV. 2005, 105, 4515.
(7) (a) Shoji, M.; Uno, T.; Kakeya, H.; Onose, R.; Shiina, I.; Osada, H.;
Hayashi, Y. J. Org. Chem. 2005, 70, 9905. For synthesis of ent-EI-1941-2
and epi-ent-EI-1941-2, see: (b) Shoji, M.; Uno, T.; Hayashi, Y. Org. Lett.
2004, 6, 4535.
Scheme 3. Retrosynthetic Analysis for EI-1941-2
(8) Mehta, G.; Roy, S. Tetrahedron Lett. 2005, 46, 7927.
(9) For recent, elegant examples of 6π-oxa-electrocyclization in complex
natural product synthesis, see: (a) Malerich, J. P.; Maimone, T. J.; Elliott,
G. I.; Trauner, D. J. Am. Chem. Soc. 2005, 127, 6276. (b) Tambar, U. K.;
Kano, T.; Stoltz, B. M. Org. Lett. 2005, 7, 2413. (c) Shoji, M.; Imai, H.;
Mukaida, M.; Sakai, K.; Kakeya, H.; Osada, H.; Hayashi, Y. J. Org. Chem.
2005, 70, 79. (d) Kurdyumov, A. V.; Hsung, R. P. J. Am. Chem. Soc. 2006,
128, 6272.
(10) Recent reviews of 6π-oxa-electrocyclization: (a) Beaudry, C. M.;
Malerich, J. P.; Trauner, D. Chem. ReV. 2005, 105, 4757. (b) Hsung, R. P.;
Kurdyumov, A. V.; Sydorenko, N. Eur. J. Org. Chem. 2005, 70, 23.
(11) (a) Ma, Z.; Bobbitt, J. M. J. Org. Chem. 1991, 56, 6110. (b)
Merbouh, N.; Bobbitt, J. M.; Brueckner, C. Org. Prep. Proc. Int. 2004, 36,
1. (c) Bobbitt, J. M.; Merbouh, N. Org. Synth. 2005, 82, 80.
(12) For a recent review of R-pyrone formation and reactivity, see: Ram,
V. J.; Srivastava, P. Curr. Org. Chem. 2001, 5, 571.
from hydrogenation of the C5-C6 olefin of R-pyrone 13.
Compound 13 may be prepared by R-pyrone formation from
diol 14 utilizing the tandem oxa-electrocyclization/oxidation
protocol. Epoxyquinol 14 may result from global deprotec-
tion of 15, followed by selective reduction of the resulting
C2 carbonyl. The unsaturated side chain in 14 may be
installed by Stille cross-coupling of vinyl bromide 15 and
the corresponding E-vinylstannane. The antipode of 15 has
been previously reported by our laboratory.5b
(13) See Supporting Information for experimental details.
(14) Li, C. Studies Toward the Synthesis of Torreyanic Acid and Related
Epoxyquinoid Natural Products. Ph.D. Thesis, Boston University, 2005.
(15) For 1,2-addition of oxoammonium salts to electron-rich olefins,
see: Takata, T.; Tsujino, Y.; Nakanishi, S.; Nakamura, K.; Yoshida, E.;
Endo, T. Chem. Lett. 1999, 9, 937.
The synthesis was initiated beginning with the known
quinone monoketal 16 (Scheme 4). Tartrate-mediated nu-
(16) Pradhan, P. P.; Bailey, W. F.; Bobbitt, J. M. Abstracts of Papers,
230th ACS National Meeting, Washington, DC, United States, August 28-
September 1, 2005; ORGN abstract 109.
(17) Breton, T.; Liaigre, D.; Belgsir, E. M. Tetrahedron Lett. 2005, 46,
2487.
(18) For the reaction of 2H-pyrans with trityl perchlorate to afford
pyrylium salts, see: Roedig, A.; Renk, H. A.; Schaal, V.; Scheutzow, D.
Chem. Ber. 1974, 107, 1136.
(19) (a) Bobbitt, J. M.; Flores, M. C.; Ma, Z.; Tang, H. Heterocycles
1990, 30, 1131. (b) Ma, Z. Chiral and Achiral Oxoammonium Salts:
Syntheses and Applications. Ph.D. Thesis, University of Connecticut, 1991.
(20) Patil, N. T.; Yamamoto, Y. J. Org. Chem. 2004, 69, 5139.
(21) For the related decomposition of R-(2,2,6,6-tetramethylpiperidinyl-
oxy)ketone to a Vic-diketone, see: Liu, Y. C.; Ren, T.; Guo. Q. X. Chin.
J. Chem. 1996, 14, 252.
2848
Org. Lett., Vol. 8, No. 13, 2006

Scheme 4. Forward Synthesis of Intermediate 13
Scheme 5. Formation of a Novel, Polycyclic Dimer
ment was based on single-crystal X-ray analysis.13,14 The
formation of these dimeric compounds supports our initial
mechanistic rationalization for R-pyrone formation (Scheme
2) and the intermediacy of both 2H-pyrans 20/20′ and
pyrylium 22.
A rationalization for the formation of polycyclic dimer
21 is shown in Scheme 5. 2H-pyrans 20/20′ undergo
pyrylium formation (Scheme 2) generating intermediate 22.
Dimerization of 22 through attack of the pyrylium by the
secondary alcohol of another molecule of 22 provides bis-
2-alkoxy-2H-pyran 23, which may undergo intramolecular
[4 + 2]-cycloaddition24 to polycyclic dimer 21. The facial
selectivity of the [4 + 2]-cycloaddition appears to be
governed by the syn 1,3-ether tether, which directs the
cycloaddition away from the epoxide moiety.
We postulated that the suppressed formation of R-pyrone
13 observed in the two-step reaction sequence may be due
to reduced amounts of hydroxylamine 9 (Scheme 2). In
preliminary experiments, treatment of diastereomeric 2H-
pyrans 20/20′ with 1.0 equiv of 2,2,6,6,-tetramethylpiperidin-
1-oxyl25 24 and 3.0 equiv of 7 afforded 13 in 76% yield
without formation of polycyclic dimer 21 (Scheme 6).13 This
cleophilic epoxidation5b of 16 using diisopropyl D-tartrate,
trityl hydroperoxide, and NaHMDS in toluene at -50 °C
for 18 h produced the desired R-epoxide 15 in 70% yield
(97% ee). Stille cross-coupling22 with E-vinyltributylstannane
17, Pd2(dba)3, and AsPh3 in toluene afforded the protected
epoxyquinone monoketal 18 (89%). Global deprotection with
48% HF provided epoxyquinone 19 (80%) which was
reduced in a regioselective fashion with DIBAL-H to provide
14 in 77% yield with 9:1 anti:syn diastereoselectivity. For
R-pyrone formation, we employed the oxa-electrocyclization/
oxidation sequence (Scheme 1) which afforded a 56% yield
of R-pyrone 13 along with 20% of secondary alcohol
oxidation product 19.
Scheme 6. Alternate Synthesis of R-Pyrone 13
To further investigate our proposed mechanism for R-py-
rone formation (Scheme 2), we considered whether the 2H-
pyran derived from alcohol 14 may undergo further oxidation
with 7 to afford R-pyrone 13. Accordingly, treatment of 14
with TEMPO and CuCl under an oxygen atmosphere in
DMF5c,f,23 resulted in the formation of diastereomeric 2H-
pyrans 20/20′ (Scheme 5). Immediate treatment of 20/20′
with oxoammonium salt 7 resulted in the formation of the
desired R-pyrone 13 in 8% yield along with 21 (30%). An
analogous dimer was formed when 4 (Scheme 1) was
subjected to this series of conditions; the structural assign-
result highlights the likely importance of hydroxylamine
byproduct 9 in the R-pyrone formation pathway.
(22) For a review of the Stille reaction, see: Farina, V.; Krishnamurthy,
V.; Scott, W. J. Org. React. 1997, 50, 1.
(23) Semmelhack, M. F.; Schmid, C. R.; Corte˜s, D. A.; Chou, C. S. J.
Am. Chem. Soc. 1984, 106, 3374.
(24) For [4 + 2]-dimerization of 2-alkoxy-2H-pyrans, see: Zhuo, J. C.;
Wyler, H.; Schenk, K. HelV. Chim. Acta 1995, 78, 151.
(25) Fields, J. D.; Kropp, P. J. J. Org. Chem. 2000, 65, 5937.
Org. Lett., Vol. 8, No. 13, 2006
2849

Completion of the synthesis of 1 relied on our ability to
effect the selective reduction of the C5-C6 olefin of 13.
Protection of the secondary alcohol in 13 was achieved by
treatment with TBSOTf/2,6-di-tert-butyl-4-methyl pyridine
(80%, Scheme 7). As was the case in prior efforts by both
oxidation/oxa-electrocyclization/oxidation cascade for gen-
eration of a key R-pyrone intermediate. A two-step oxidation
sequence helped to elucidate the mechanism of this trans-
formation while also providing access to a novel polycyclic
dimer via [4 + 2]-dimerization. Further applications of the
oxa-electrocyclization/oxidation process are ongoing in our
laboratory and will be reported in due course.
Scheme 7. Completion of the EI-1941-2 Synthesis
Acknowledgment. Financial support from the American
Cancer Society (RSG-01-135-01), Bristol-Myers-Squibb, and
Merck Research Laboratories is gratefully acknowledged. We
thank Professor James M. Bobbitt (University of Con-
necticut) for providing reagent 7 and for helpful discussions,
and Dr. Fumito Koizumi (Kyowa Hakko Kogyo Co., Ltd.)
for providing a sample of natural EI-1941-2.
Hayashi7 and Mehta,8 we were unable to effect this reduction
in the presence of the C7 carbonyl and thus completed our
synthesis in an analogous fashion.13 Synthetic EI-1941-2 (1)
was found to be spectroscopically identical to the natural
product.3
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
In conclusion, the total synthesis EI-1941-2 (1) has been
achieved utilizing an oxoammonium salt-mediated tandem
OL060954F
2850
Org. Lett., Vol. 8, No. 13, 2006