Total synthesis of (+)-phorboxazole A

Full text of DOI:10.1021/ja0105055

4834
J. Am. Chem. Soc. 2001, 123, 4834-4836
Scheme 1
Total Synthesis of (+)-Phorboxazole A
Amos B. Smith, III,* Patrick R. Verhoest,
Kevin P. Minbiole, and Michael Schelhaas
Department of Chemistry, Monell Chemical Senses Center
and Laboratory for Research on the Structure of Matter
UniVersity of PennsylVania, Philadelphia, PennsylVania 19104
ReceiVed February 26, 2001
In 1995 Searle and Molinski reported the isolation of phor-
boxazoles A (1) and B (2), isomeric oxazole-containing mac-
rolides, from the marine sponge Phorbas sp. endemic to the
western coast of Australia (Scheme 1).1 The relative and absolute
stereochemistries of the phorboxazoles were secured via a
combination of NMR analysis, degradation studies, and synthetic
correlation.2 When tested against the NCI panel of 60 human
tumor cell lines, the phorboxazoles displayed virtually unsurpassed
cytotoxicity, exhibiting a mean GI50 of 1.58 × 10-9 M. Although
the exact mechanism of action remains unknown, studies dem-
onstrate that phorboxazole A (1) arrests the cell cycle at the S
phase and does not affect tubulin. Given the potent cytotoxicity
and the possibility of a new mechanism of action, the phorbox-
azoles were selected by the NCI for in vivo trials.2a
The combination of the outstanding antimitotic activity,
architectural complexity, and extreme scarcity has led to wide
interest in the synthetic community.3 The first total synthesis of
phorboxazole A was reported by Forsyth and co-workers in 1998;4
shortly thereafter Evans and Fitch reported the completion of
phorboxazole B.5 In 1997 we embarked on the synthesis of these
challenging marine natural products; subsequently we disclosed
assembly of two subtargets exploiting a modified Petasis-Ferrier
union-rearrangement tactic for the stereocontrolled construction
of the two cis-fused tetrahydropyrans.3n,o In this communication,
we describe the synthesis of the C(3-28) vinyl stannane, the
C(33-46) lactone, their union via a bifunctional oxazole linchpin,
and completion of the phorboxazole A synthetic venture.
From the retrosynthetic perspective, disconnections of phor-
boxazole A (1) at the C(1) macrolactone, the C(2-3) and C(28-
29) linkages led to side chain subtarget 3 and macrolide precursor
4 (Scheme 1). A Wittig transform at C(19-20) further dissected
4 into aldehyde 56 and salt 6, the syntheses of which were
described previously.3n,o Continuing with this analysis, discon-
nection of subtarget 3 at C(32-33) and C(40-41) revealed vinyl
stannane 7, vinyl iodide 8, and the bifunctional oxazole 9.
Construction of the C(40-41) linkage would entail a Stille
coupling, while oxazole 9, possessing the pseudobenzylic bromide
and the triflate moieties, was envisaged as a novel bidirectional
linchpin to unite the side chain with the macrocycle. Importantly,
the coupling strategy possessed considerable flexibility from the
tactical perspective (vide infra).
Assembly of the side chain of phorboxazole began with known
Brown allylation7 adduct (+)-10 (Scheme 2).8,9 Methylation of
the hydroxyl [MeOTf, 2,6-di-tert-butyl-4-methylpyridine (DT-
BMP)],10 followed by ozonolysis furnished aldehyde (-)-11 in
81% yield for two steps. Although Wittig olefination of (-)-11
with methyl alkyne 12a (R ) Me) led to a disappointing mixture
of olefins (E/Z ca. 2.2:1), condensation with the commercially
available phosphonate salt 12b (R ) TMS) in THF afforded enyne
(-)-13 in good yield with acceptable selectivity (97%, 5.5:1 E/Z).
The use of a PhCH3/THF (1:1) solvent system improved the E/Z
ratio at the expense of both yield and reproducibility (72%, 7.5:1
E/Z). Removal of the TMS group (K2CO3), followed by Sharpless
dihydroxylation11 of the enyne12,13 (AD-Mix â; 7:1 dr) and
acetonide formation then provided (+)-14. Terminal methylation
(1) Searle, P. A.; Molinski, T. F. J. Am. Chem. Soc. 1995, 117, 8126.
(2) (a) Searle, P. A.; Molinski, T. F.; Brzezinski, L. J.; Leahy, J. W. J.
Am. Chem. Soc. 1996, 118, 9422. (b) Molinski, T. F. Tetrahedron Lett. 1996,
37, 7879.
(3) (a) Lee, C. S.; Forsyth, C. J. Tetrahedron Lett. 1996, 37, 6449. (b)
Cink, R. D.; Forsyth, C. J. J. Org. Chem. 1997, 62, 5672. (c) Ahmed, F.;
Forsyth, C. J. Tetrahedron Lett. 1998, 39, 183. (d) Ye, T.; Pattenden, G.
Tetrahedron Lett. 1998, 39, 319. (e) Pattenden, G.; Plowright, A. T.; Tornos,
J. A.; Ye, T. Tetrahedron Lett. 1998, 39, 6099. (f) Paterson, I.; Arnott, E. A.
Tetrahedron Lett. 1998, 39, 7185. (g) Wolbers, P.; Hoffman, H. M. R.
Tetrahedron 1999, 55, 1905. (h) Misske, A. M.; Hoffman, H. M. R.
Tetrahedron 1999, 55, 4315. (i) Williams, D. R.; Clark, M. P.; Berliner, M.
A. Tetrahedron Lett. 1999, 40, 2287. (j) Williams, D. R.; Clark, M. P.
Tetrahedron Lett. 1999, 40, 2291. (k) Wolbers, P.; Hoffman, H. M. R.
Synthesis, 1999, 5, 797. (l) Evans, D. A.; Cee, V. J.; Smith, T. E.; Santiago,
K. J. Org. Lett. 1999, 1, 87. (m) Wolbers, P.; Misske, A. M.; Hoffmann, H.
M. R. Tetrahedron Lett. 1999, 40, 4527. (n) Smith, A. B., III; Verhoest, P.
R.; Minbiole, K. P.; Lim, J. J. Org. Lett. 1999, 1, 909. (o) Smith, A. B., III;
Minbiole, K. P.; Verhoest, P. R.; Beauchamp, T. J. Org. Lett. 1999, 1, 913.
(p) Wolbers, P.; Hoffman, H. M. R.; Sasse, F. Synlett 1999, 11, 1808. (q)
Schaus, J. V.; Panek, J. S. Org. Lett. 2000, 2, 469. (r) Pattenden, G.; Plowright,
A. T. Tetrahedron Lett. 2000, 41, 983. (s) Rychnovsky, S. D.; Thomas, C. R.
Org. Lett. 2000, 2, 1217. (t) Williams, D. R.; Clark, M. P.; Emde, U.; Berliner,
M. A. Org. Lett. 2000, 2, 3023. (u) Greer, P. B.; Donaldson, W. A. Tetrahedron
Lett. 2000, 41, 3801. (v) Evans, D. A.; Cee, V. J.; Smith, T. E.; Fitch, D. M.;
Cho, P. S. Angew. Chem., Int. Ed. 2000, 39, 2533.
(6) Although aldehyde 5 was the original subtarget for the central pyran,
revised aldehyde (+)-23 was ultimately employed (Scheme 4).
(7) Brown, H. C.; Ramachandran, P. V. Pure Appl. Chem. 1991, 63, 307.
(8) Clive, D. L. J.; Keshava Murthy, K. S.; Wee, A. G. H.; Prasad, J. S.;
da Silva, G. V. J.; Majewski, M.; Anderson, P. C.; Haugen, R. D.; Heerze, L.
D. J. Am. Chem. Soc. 1988, 110, 6914 (see Supporting Information).
(9) The enantiomeric excess (ee) of alcohol (+)-10 was determined to be
94% via Mosher ester analysis: (a) Dale, J. A.; Mosher, H. S. J. Am. Chem.
Soc. 1973, 95, 512. (b) Sullivan, G. R.; Dale, J. A.; Mosher, H. S. J. Org.
Chem. 1973, 38, 2143. (c) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa,
H. J. Am. Chem. Soc. 1991, 113, 4092.
(10) The biphenyltertbutyl silyl (BPS) moiety had a tendency to migrate
to the secondary hydroxyl when more standard conditions (NaH, MeI) were
employed.
(11) Jacobsen, E. N.; Marko, I.; Mungall, W. S.; Schroder, G.; Sharpless,
K. B. J. Am. Chem. Soc. 1988, 110, 1968.
(4) Forsyth, C. J.; Ahmed, F.; Cink, R. D.; Lee, C. S. J. Am. Chem. Soc.
1998, 120, 5597.
(5) (a) Evans, D. A.; Fitch, D. M. Angew. Chem., Int. Ed. 2000, 39, 2536.
(b) Evans, D. A.; Fitch, D. M.; Smith, T. E.; Cee, V. J. J. Am. Chem. Soc.
2000, 122, 10033.
10.1021/ja0105055 CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/01/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 20, 2001 4835
of the alkyne (tBuLi; MeI) followed by desilylation (TBAF; 100%
yield, 2 steps) next led to alcohol (+)-15, which upon TEMPO
oxidation14 afforded an unstable carboxylic acid 16;15 immediate
hydrolysis of the acetonide with concomitant cyclization (FeCl3‚
6 H2O) and protection of the remaining secondary hydroxyl
(TIPSCl, imid) furnished (-)-17. A two-step palladium-promoted
hydrostannylation/iodination16 protocol completed construction of
the desired vinyl iodide (-)-8 (83% yield, 2 steps).17 Additionally,
10-15% of the internal stannane was recovered after iodination.
Scheme 3
Scheme 2
Extensive experimentation demonstrated the necessity of early
installation of the C(28) vinyl stannane; thus vinyl stannane 4
was prepared as outlined in Scheme 4. Toward this end, alcohol
(+)-213o was subjected to hydroxyl protection (DMBCl, KH) and
desilylation (TBAF); subsequent exposure to the tin cuprate
derived from hexamethylditin (MeLi, CuCN) followed by me-
thylation (MeI, DMPU) provided (+)-22 in excellent overall yield
(71%; 4 steps). Desilylation (TBAF), oxidation (SO3‚pyr), and
Wittig olefination of the derived aldehyde (+)-23 with (+)-6 then
proceeded smoothly to afford alkene (+)-4 (20:1 E:Z). Unfortu-
nately, all attempts to introduce the C(1-2) moiety, involving
removal of the BPS group and oxidation to the C(3) aldehyde,
proved unsuccessful due presumably to the sensitivity of the
trimethyl tin moiety to the oxidative conditions. We therefore
turned to the union of the side chain fragment (-)-20 with (+)-
4, exploiting the bifunctional oxazole linchpin 9. This possibility
nicely demonstrated the flexibility of the overall coupling strategy.
Assembly of the Stille coupling partner (-)-7 began with
known TBS-glycidol (+)-18 (Scheme 3).18 Exposure to lithium
TMS acetylide in the presence of BF3‚OEt2,19 methylation
(MeOTf, DTBMP), and selective removal of the TBS group in
the presence of the TMS alkyne (cat. HCl, MeOH) furnished
known alcohol (-)-1920 (69% yield, 3 steps). Parikh-Doering21
oxidation then provided the corresponding aldehyde without
epimerization; alternate oxidation protocols (i.e., Swern) led to
epimerization at C(43).22 Hodgson homologation23 (CrCl2, Bu3-
SnCHBr2, LiI, THF/DMF) of the derived aldehyde next afforded
vinyl stannane (-)-7 as a single isomer (77%). The crucial Stille
coupling24 of (-)-7 and vinyl iodide (-)-8 was then achieved
Scheme 4
25
with Pd2(dba)3‚CHCl3 in the presence of Ph2PO2NBu4 (DMF,
room temperature, 4 h) to furnish (-)-20 in near quantitative yield.
The required oxazole 9 was prepared exploiting a method
developed by Sheehan in 1949 (Scheme 5) for the synthesis of
oxazolones.26 Bromoacetyl bromide was exposed to silver iso-
cyanate (30 min, Et2O), filtered, and then subjected to alcohol-
free diazomethane;27 immediate triflation (Et3N, Tf2O, THF, -78
°C to room temperature)3q furnished triflate 9 in 48% overall
yield.28
(12) For use of the Sharpless AD reaction with enynes, see: Jeong, K.-S.;
Sjo, P.; Sharpless, K. B. Tetrahedron Lett. 1992, 33, 3833. Diminished
diastereoselectivity with homoallylic enynols has been reported: Caddick, S.;
Shanmugathasan, S.; Brasseur, D.; Delisser, V. M. Tetrahedron Lett. 1997,
38, 5735.
(13) Since the Z isomer was markedly less reactive than the E isomer in
the dihydroxylation reaction, the E/Z mixture could be used directly.
(14) Zhao, M.; Li, J.; Mano, E.; Song, Z.; Tschaen, D. M.; Grabowski, E.
J. J.; Reider, P. J. J. Org. Chem. 1999, 2564.
(15) Occasionally, the carboxylic acid would undergo cyclization to the
corresponding lactone during workup or chromatography.
(16) Zhang, H. X.; Guibe, F.; Balavoine, G. J. Org. Chem. 1990, 55, 1857.
(17) Exposure of alkyne (-)-17 to the Schwartz hydrozirconation and
subsequent exposure to NIS, I2, or NBS failed to afford the desired vinyl
halide; instead, starting material or decomposition was observed.
(18) Prepared in one step from S-glycidol; see: Cywin, C. L.; Webster, F.
X.; Kallmerten, J. J. Org. Chem. 1991, 56, 2953.
Scheme 5
The stage was now set for the union of (+)-4 with (-)-20
utilizing 9. After optimization we found that i-PrMgCl promoted
the coupling of bromide 9 with lactone (-)-20 to afford a single
hemiketal29 in excellent yield (Scheme 6). Presumably, Grignard
exchange generates the metalated oxazole that subsequently
attacks the lactone. Interestingly, premixing of the coupling
(19) Eis, M. J.; Wrobel, J. E.; Ganem, B. J. Am. Chem. Soc. 1984, 106,
3693.
(20) Alcohol (-)-19 was first prepared by Pattenden et al. from malic acid
in 11 steps (ref 3e); Williams later prepared (-)-19 (ref 3t).
(21) Parikh, J. R.; v. E. Doering, W. J. Am. Chem. Soc. 1967, 89, 5505.
(22) Epimerization was determined by reduction (BH3‚THF) to alcohol (-)-
19 and comparison of optical rotations.
(23) Hodgson, D. M.; Boulton, L. T.; Maw, G. N. Tetrahedron 1995, 51,
3713.
(24) (a) Farina, V.; Krishnamurthy, V.; Scott, W. J. Organic Reactions;
Wiley: New York, 1997. (b) Stille, J. Angew. Chem., Int. Ed. Engl. 1986,
25, 508.
(25) This salt was introduced by Liebeskind to remove Bu3SnI from the
reaction mixture and thereby accelerate the Stille coupling process: Srogl, J.;
Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1997, 119, 12376.
(26) Sheehan, J. C.; Izzo, P. T. J. Am. Chem. Soc. 1949, 71, 4059.
(27) (a) DeBoer, T. J.; Backer, H. J. Org. Synth. 1956, 36, 16. (b) Aldrich
Technical Bulletin AL-121.
(28) In this three-step process, intermediates were not purified or isolated;
thus, the assembly of 9 is possible in a matter of hours.
(29) Presumably, the sterochemical outcome is due to anomeric effects;
see: Bonner, W. A. J. Am. Chem. Soc. 1959, 81, 1448.

4836 J. Am. Chem. Soc., Vol. 123, No. 20, 2001
Communications to the Editor
Scheme 6
Scheme 7
partners before addition of i-PrMgCl was required to minimize
the dimerization of 9 (arising from the electrophilic nature of
unreacted 9).30 Methyl ketal formation (pTSA, MeOH, 35 °C)
completed the synthesis of the C(29-41) side chain triflate (-)-
3.
Stille coupling of (-)-3 with vinyl stannane (+)-4 [Pd(PPh3)4,
LiCl, 100 °C, 24 h] furnished adduct (+)-24 in a 72% yield
(Scheme 6). Selective removal of the BPS group (KOH, 18-cr-
6), oxidation (Dess-Martin), and removal of the DMB group
(DDQ) then afforded hydroxyaldehyde (+)-25. Appendage of a
C(1-2) phosphonate moiety31 at C(24), followed by a Still-
modified Horner-Emmons macrocyclization32 provided (+)-26;
interestingly the Z/E selectivity improved with higher tempera-
ture.33
Having arrived at the complete phorboxazole skeleton, access
to the terminal vinyl bromide proved to be an unexpected
challenge. Radical promoted hydrostannylation (Bu3SnH, AIBN,
∆; or Bu3SnH, Et3B, room temperature), although providing a
mixture of the external to internal vinyl stannanes (4:1), led to
isomerization at the C(2-3) olefin. Alternatively, palladium-
mediated hydrostannylation [PdCl2(PPh3)2, Bu3SnH; NBS] gave
predominately the internal [C(45)] bromide, albeit with no C(2,3)
isomerization. Success was eventually found in the three-step
procedure of Guibe,16 which exploited the terminal alkynyl
bromide for enhanced diastereoselectivity. Global deprotection
(6% HCl, THF, 72 h) then afforded (+)-phorboxazole A (1),
which displayed spectral data identical in all respects to that
reported for the natural material [1H NMR (600 MHz), COSY,
ROESY, HRMS, UV λ max, optical rotation).
of the synthetic venture include the use of modified Petasis-
Ferrier rearrangements for the effective assembly of both the
C(11-15) and C(22-26) cis-tetrahydropyan rings; the design,
synthesis, and application of a novel bifunctional oxazole linchpin;
and the preparation and Stille coupling of a C(28) trimethylstan-
nane. The longest linear sequence leading to (+)-phorboxazole
A (1) was 27 steps, with an overall yield of 3%.
Acknowledgment. Support was provided by the National Institutes
of Health (National Cancer Institute) through grant CA-19033. An
American Chemical Society, Division of Organic Chemistry Fellowship
(funded by DuPont Pharmaceuticals, Inc.) is also gratefully acknowledged
(K.P.M.).
In summary, a highly convergent, stereocontrolled total syn-
thesis of (+)-phorboxazole A (1) has been achieved. Highlights
(30) Dimerization was also observed under inverse addition conditions (i.e.,
slow addition of the oxazole to a -100 °C solution of tBuLi).
(31) Pickering, D. A. Ph.D. Thesis, University of Minnesota, 1996.
(32) (a) Stil, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405; (b) For
the use of K2CO3/18-crown-6 in Horner-Emmons reactions, see: Aristoff, P.
A. J. Org. Chem. 1981, 46, 1954. Also see: Nicolaou, K. C.; Seitz, S. P.;
Pavia, M. R. J. Am. Chem. Soc. 1982, 104, 2030.
(33) We suspect that higher temperatures accelerate collapse of the
intermediate oxaphosphatane, thereby minimizing equilibration to the more
stable E isomer.
Supporting Information Available: Spectroscopic and analytical data
for compounds 1, 4, 7-9, 20, and 22-26, and selected experimental
procedures (PDF). This material is available free of charge via the Internet
at http://pubs.acs.org.
JA0105055