Total Synthesis of the NF-κB inhibitor (-)-cycloepoxydon: Utilization of tartrate-mediated nucleophilic epoxidation

Full text of DOI:10.1021/ja0169769

11308
J. Am. Chem. Soc. 2001, 123, 11308-11309
Total Synthesis of the NF-KB Inhibitor
(-)-Cycloepoxydon: Utilization of Tartrate-Mediated
Nucleophilic Epoxidation
Chaomin Li,† Emily A. Pace,§ Mei-Chih Liang,§
Emil Lobkovsky,‡ Thomas D. Gilmore,§ and
John A. Porco, Jr.*,†
Figure 1.
Scheme 1a
Department of Chemistry and Center for
Streamlined Synthesis and Department of Biology
Boston UniVersity, Boston, Massachusetts 02215
Department of Chemistry, Baker Laboratory
Cornell UniVersity, Ithaca, New York 14853-1301
ReceiVed August 30, 2001
ReVised Manuscript ReceiVed September 27, 2001
NF-κB is an inducible transcription factor that regulates the
expression of various cellular genes involved in immune and
inflammatory responses.1 The epoxyquinoid natural product
cycloepoxydon (1) (Figure 1) was isolated from fermentations
of a deuteromycete strain2 and shown to inhibit activation of NF-
κB. Due to our interest in the synthesis of epoxyquinoid natural
products,3 we have targeted cycloepoxydon for a total synthesis
effort. Herein, we report the first total synthesis and absolute
stereochemical assignment of (-)-cycloepoxydon utilizing a
tartrate-mediated nucleophilic epoxidation to introduce initial
stereocenters.
A retrosynthetic analysis for the synthesis of cycloepoxydon
is depicted in Figure 1 and is based on a “stereochemically linear”
strategy4 in which initial stereogenic centers associated with the
epoxide in conjunction with substrate control are used to establish
all remaining stereocenters. Key steps involve pyran formation
through endo-cyclization of epoxy alcohol precursor 2 and
reagent-controlled asymmetric nucleophilic epoxidation5 of quino-
ne monoketal 3.
a Reagents: (a) PhI(OAc)2, MeOH, rt, 30 min, 84%; (b) 2,2-diethyl-
1,3-propanediol, PPTS, benzene, 70 °C, 80 min, 89%; (c) nBuLi, L-DIPT,
Ph3COOH, PhCH3, rt, 24 h, 88% conversion (68% ee); (d) NaHMDS,
L-DIPT, Ph3COOH, PhCH3 (20% THF), -50 °C, 30 h, 97%, 96% ee;
(e) (E)-tributyl-1-pentenyl-stannane, Pd2dba3‚CHCl3, ClCH2CH2Cl, 60 °C,
40 h, 81%; (f) DIBAL-H, THF, -78 °C, 15 min, 88%; (g) 48% HF,
CH3CN, 0 °C, 5 min, 92%.
n-BuLi-(L) -diisopropyl tartrate (DIPT) employing tBuOOH,9 we
found trityl hydroperoxide (Ph3COOH) to be an effective peroxide
source. Optimization of reaction conditions [Ph3COOH (5 equiv),
n-BuLi (2.7 equiv), (L)-DIPT (1.0 equiv), toluene, rt] provided
monoepoxide 6 (68% ee). Interestingly, using NaHMDS, reactions
using (L)-DIPT were found to proceed at -50 °C and to afford
the opposite enantiomer 7.10 Use of KHMDS afforded moderate
conversion, but resulted in low ee ()10%). Production of 7 (97%
yield, 96% ee) from substrate 3 was optimized using NaHMDS-
(L)-DIPT [Ph3COOH (6.4 equiv), NaHMDS (5.2 equiv), (L)-DIPT
(1.6 equiv), 0.1 M in toluene, -50 oC, 30 h]. The absolute
stereochemistry of 7 was assigned by correlation with compounds
produced by diastereoselective epoxidation of a chiral quinone
monoketal (see Supporting Information for details).3b,11 Stille
coupling12 of 7 with (E)-tributyl-1-pentenyl-stannane13 afforded
8 which was reduced with Dibal-H in THF11b,14 to afford anti-
epoxy alcohol 9. Treatment of 9 with HF-CH3CN effected acetal
hydrolysis3 to provide epoxyquinol 10.
The synthesis was initiated by hypervalent iodine oxidation6
of 43b to afford dimethoxyketal 5 (Scheme 1). Transketalization
of 5 with 2,2-diethyl-1,3-propanediol afforded 1,3-dioxane 3,
which was found to be an improved substrate for nucleophilic
epoxidation relative to 5. Using 3, a number of methods for
asymmetric nucleophilic epoxidation were evaluated.5 We ob-
tained promising results using modifications of the tartrate-
modified7 nucleophilic epoxidation system reported by Jackson
and co-workers.8 Although reactions did not proceed using
A mechanistic proposal for tartate-mediated nucleophilic ep-
oxidations is shown in Figure 2. The asymmetric induction and
counterion dependency may be explained by preferential forma-
tion of complexes A (Li) or B (Na) in which 2 equiv of either
lithium or sodium tritylperoxide form bowl-shaped chelates with
either five- or six-membered ring hydrogen-bonded tartrate
conformers.15 The resulting bowl-shaped complexes may then
promote formation of two different epoxide enantiomers by
hydrogen-bond activation of the dienone and face-selective
conjugate addition of a peroxide anion.16 In both cases, the
substrate binds in an orientation such that the bulky Br and
† Department of Chemistry and Center for Streamlined Synthesis, Boston
University.
§ Department of Biology, Boston University.
‡ Department of Chemistry, Baker Laboratory, Cornell University.
(1) (a) Baeuerle, P. A.; Baltimore, D. Cell 1996, 87, 13-20. (b) Umezawa,
K.; Ariga, A.; Matsumoto, N. Anti-Cancer Drug Des. 2000, 15, 239-244.
(2) (a) Gehrt, A.; Erkel, G.; Anke, H.; Anke, T.; Sterner, O. Nat. Prod.
Lett. 1997, 9, 259-264. (b) Gehrt, A. Erkel, G.; Anke, T.; Sterner, O. J.
Antibiotics 1998, 51, 455-463.
(3) (a) Li, C.; Lobkovsky, E.; Porco, J. A., Jr. J. Am. Chem. Soc. 2000,
122, 10484-10485. (b) Hu, Y., Li, C.; Kulkarni, B.; Strobel, G.; Lobkovsky,
E.; Torczynski, R. M.; Porco, J. A., Jr. Org. Lett. 2001, 3, 1649-1652.
(4) For a review, see: Smith, A. B., III; Empfield, J. R. Chem. Pharm.
Bull. 1999, 47, 1671-1678.
(5) For a recent review on asymmetric epoxidation of electron-deficient
olefins, see: Porter, M. J.; Skidmore, J. Chem. Commun. 2000, 1215-1225.
(6) (a) Pelter, A.; Elgendy, S. Tetrahedron Lett. 1988, 29, 677-80. (b)
Fleck, A. E.; Hobart, J. A.; Morrow, G. W. Synth. Commun. 1992, 22, 179-
187.
(9) Epoxidations using catalytic or stoichiometric amounts of DIPT/Bu2-
Mg using either tBuOOH as described in ref 8 or Ph3COOH were unsuccessful.
(10) A reversal of facial selectivity in tartrate-mediated nucleophilic
epoxidation with change of metal ion (Li to Mg) was reported in ref 8.
(11) Diastereoselective epoxidation of quinone monoketals using chiral
acetals: (a) Wipf, P.; Kim, Y.; Jahn, H. Synthesis 1995, 12, 1549-1561. (b)
Corey, E. J.; Wu, L. I. J. Am. Chem. Soc. 1993, 115, 9327-9328.
(12) Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50,
1-652.
(7) For representative asymmetric reactions employing tartaric acid esters,
see: (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974-
5976. (b) Yamashita, H.; Mukaiyama, T. Chem. Lett. 1985, 1643-1646. (c)
Hayashi, M.; Ono, K.; Hoshimi, H.; Oguni, N. Tetrahedron 1996, 52, 7817-
7832. (d) Ukaji, Y.; Shimizu, Y.; Kenmoku, Y.; Ahme, A.; Inomata, K. Chem.
Lett. 1997, 1, 59-60.
(13) Eisch J. J.; Galle, J. E. J. Organomet. Chem. 1988, 341, 293-313.
(14) Ragot, J. P.; Steeneck, C.; Alcaraz, M.-L.; Taylor, R. J. K. J. Chem.
Soc., Perkin Trans. 1 1999, 1073-1082.
(8) Elston, C. L.; Jackson, R. F. W.; MacDonald, S. J. F.; Murray, P. J.
Angew. Chem., Int. Ed. Engl. 1997, 36, 411-412.
10.1021/ja0169769 CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/23/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 45, 2001 11309
Figure 3.
enone 11. The stereochemistry of 11 was tentatively assigned
using conformational analysis20 which showed minimum energies
for s-trans conformers of 10 (cf. Scheme 2, inset), indicating that
the directed epoxidation should proceed to afford the diastereomer
shown. The s-trans conformation of 10 was also confirmed using
NOE experiments (15% NOE between H1 and H2). Final synthesis
of (-)-cycloepoxydon was achieved by tandem deprotection and
cyclization by treatment of 11 with HF/CH3CN, which provided
endo-epoxide opening product (-)-cycloepoxydon 1 and exo-
epoxide opening product 12 (“iso-cycloepoxydon”) in 53 and 35%
yields, respectively.21 The relative stereochemistries of 1 and 12
were further confirmed by single X-ray crystal structure analysis.22
Synthetic 1 was confirmed to be identical to data reported for
natural (-)-cycloepoxydon2a by 1H and 13C NMR and
[R]D (-139°, c ) 1.0, CDCl3:CD3OD 95:5).
Figure 2.
Scheme 2a
As shown in Figure 3a, 50 µM (-)-1 inhibited tumor necrosis
factor (TNF)-induced NF-κB DNA binding in mouse 3T3 cells.
Furthermore, (-)-1 blocked degradation of IκBR, a required
upstream event in the activation of NF-κB (Figure 3b). The
enantiomer (+)-1 also inhibited TNF-induced NF-κB DNA
binding and degradation of IκBR (Figure 3, a and b).
a Reagents: (a) m-CPBA, CH2Cl2, rt, 4 h, 85%; (b) 48% HF, CH3CN,
rt, 2 h, 1 (53%), 12 (35%).
In summary, the first total synthesis and absolute stereochemical
assignment of the NF-κB inhibitor (-)-cycloepoxydon has been
achieved employing a tartrate-mediated asymmetric nucleophilic
epoxidation of a quinone monoketal. The enantioselectivity in
this epoxidation system has been rationalized by the formation
of hydrogen-bonded chelates of tartrate and hydroperoxide anion.
Further studies on epoxyquinoids and mechanistic studies regard-
ing the tartrate-mediated epoxidation of electron-deficient olefins
are in progress.
protected hydroxymethyl group are positioned in the convex face
of the chelated complex. For complex A, this positioning of the
substrate results in addition of the peroxide anion from the R-face
of the dienone, while addition to the â-face is observed for B.17
Preferred formation of B in the case of the sodium counterion
may result from a combination of energetic preference for five-
membered ring hydrogen bonding15 coupled with the increased
atomic radius of sodium favoring a six-membered metal chelate.
Completion of the synthesis of cycloepoxydon required regio-
and diastereoselective epoxidation of epoxyquinol 10 (Scheme
2). Although electrophilic epoxidations of conjugated dienone
substrates generally provide γ,δ-epoxy enones,18 the hydroxyl-
directing19 group effects of 10 were unclear at the outset. In the
event, treatment of 10 with m-CPBA cleanly afforded γ,δ-epoxy
Acknowledgment. This research was supported by the American
Cancer Society (RSG-01-135-01-CDD, J.A.P, Jr.) and the NIH (grant
CA47763, T.D.G). M-C.L. was partially supported by the Ministry of
Education, Taiwan. E.A.P. was supported in part by the Boston University
Undergraduate Research Opportunities Program. We thank Mr. X. Wang,
Mr. D. Kalaitzidis, Professor J. Snyder, and Professor S. E. Schaus for
helpful discussions.
(15) For theoretical calculations of five- and six-membered intramolecular
hydrogen bonds in tartaric acid esters, see: (a) Polavarapu, P. L.; Ewig, C.
S.; Chandramouly, T. J. Am. Chem. Soc. 1987, 109, 7382-7386. (b)
Gawronski, J.; Gawronska, K.; Skowronek, P.; Rychlewska, U.; Warzajtis,
B.; Rychlewski, J.; Hoffmann, M.; Szarecka, A. Tetrahedron 1997, 53, 6113-
6144. (c) Rychlewska, U.; Warzajtis, B.; Hoffmann, M.; Rychlewski, J.
Molecules 1997, 2, 106-113.
Supporting Information Available: Chemical and biological pro-
cedures and characterization data for all new compounds, including X-ray
structural analyses of 1 and 12 (PDF). X-ray crystallographic data (CIF).
This material is available free of charge via the Internet at http://pubs.acs.org.
(16) For examples of hydrogen bond activation of carbonyls, see: (a)
Hiemstra, H. Wynberg, H. J. Am. Chem. Soc. 1981, 103, 417-430. (b) Agami,
C.; Meynier, F.; Puchot, C.; Guilhem, J.; Pascard, C. Tetrahedron 1984, 40,
1031-1038. (c) Cokley, T. M.; Harvey, P. J.; Marshall, R. L.; McCluskey,
A.; Young, D. J. J. Org. Chem. 1997, 62, 1961-1964.
JA0169769
(19) For a review on directed reactions, see: Hoveyda, A. H.; Evans, D.
A.; Fu, G. C. Chem. ReV. 1993, 93, 1307-1370.
(20) A conformational search was performed using PC Spartan Pro, ver.
1.0.6; Wavefunction: Irvine, CA.
(21) Efforts to enhance endo-cyclization by treatment of 2 with La(OTf)3
(cf. Tokiwano, T.; Fujiwara, K.; Murai, A. Chem. Lett. 2000, 272-273)
favored formation of 12 (11:1).
(22) See the Supporting Information for further details on X-ray structures
and coordinates.
(17) Reduced ee in the case of LiOOTr-DIPT relative to the NaOOTr-
DIPT reactions may be explained by the presence of a complex of type B (cf.
Figure 2, B, M ) Li) in addition to complex A.
(18) For select examples, see: (a) Burdett, J. E., Jr.; Rao, P. N.; Kim, H.
K.; Karlen, M. T.; Blye, R. P. J. Chem. Soc., Perkin Trans. 1 1982, 2877-
2880. (b) Ley, S. V.; Cox, L. R.; Meek, G.; Metten, K.-H.; Pique, C.; Worrall,
J. M. J. Chem. Soc. Perkin Trans. 1 1997, 3299-3314.