Toward the total synthesis of phorboxazole B: An efficient synthesis of the C20-C46 segment

Article abstract of DOI:10.1021/ol048275x

(Chemical Equation Presented) An efficient synthesis of the C20-C46 segment of phorboxazole B is described. The key steps involved Hg(OAc) ₂/I₂-induced cyclization to construct the cis-tetrahydropyran moiety, the coupling of the meta

Full text of DOI:10.1021/ol048275x

ORGANIC
LETTERS
2004
Vol. 6, No. 23
4261-4264
Toward the Total Synthesis of
Phorboxazole B: An Efficient Synthesis
of the C20−C46 Segment
De Run Li, Cai Yun Sun, Ce Su, Guo-Qiang Lin,* and Wei-Shan Zhou
Shanghai Institute of Organic Chemistry, 354 Fenglin Rd,
Shanghai 200032, P.R. China
lingq@mail.sioc.ac.cn
Received August 28, 2004
ABSTRACT
An efficient synthesis of the C20−C46 segment of phorboxazole B is described. The key steps involved Hg(OAc)2/I2-induced cyclization to
construct the cis-tetrahydropyran moiety, the coupling of the metalated 2-methyloxazole 7 with lactone 6, and Julia olefination to furnish the
conjugated diene moiety.
Phorboxazole A (1) and its epimer phorboxazole B (2),
isolated from the sponge Phorbas sp. collected in the Indian
Ocean, are novel 21-membered macrolides accommodating
four heavily functionalized oxanes and two 2,4-disubstituted
oxazoles.1 The relative and absolute stereochemistries of
phorboxazoles were determined by extensive NMR analysis,
degradation studies, and synthetic correlation.2 These me-
tabolites are ranked among the most cytostatic natural
products ever known, exhibiting extraordinary potency (mean
GI50 < 1.6 × 10-9 M) when bioassayed against 60 human
tumor cell strains at the National Cancer Institute (NCI).1
The unprecedented structural features and remarkable anti-
tumor activities of phorboxazoles have attracted great atten-
tion in the synthetic community,3 and several excellent
achievements of their total synthesis have been reported by
Forsyth,4 Evans,5 Smith,6 Pattenden,7 and Williams.8
double bonds, which combined the features of the Evans5
and Pattenden7 syntheses and led to the key building blocks
(3) (a) Paterson, I.; Arnott, E. A. Tetrahedron Lett. 1998, 39, 7185. (b)
Wolbers, P.; Misske, A. M.; Hoffman, H. R. Tetrahedron Lett. 1999, 40,
4527. (c) Wolber, P.; Hoffman, H. M. R. Tetrahedron 1999, 55, 1905. (d)
Misske, A. M.; Hoffman, H. M. R. Tetrahedron 1999, 55, 4315. (e) Wolbers,
P.; Hoffman, H. M. R. Synthesis 1999, 40, 2291. (f) Wolbers, P.; Hoffman,
H. M. R.; Sasse, F. Synlett 1999, 11, 1808. (g) Greer, P. B.; Donaldson,
W. A. Tetrahedron Lett. 2000, 41, 3801. (h) Rychovsky, S. D.; Thomas,
C. R. Org. Lett. 2000, 2, 1217. (i) Williams, D. R.; Clark, M. P.; Emde,
V.; Berliner, M. A. Org. Lett. 2000, 2, 3023. (j) Schaus, J. V.; Panek, J. S.
Org. Lett. 2000, 2, 469. (k) Huang, H.; Panek, J. S. Org. Lett. 2001, 3,
1693. (l) White, J. D.; Kranemann, C. L.; Kuntiyong, P. Org. Lett. 2001, 3,
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6018. (n) Paterson, I.; Luckhurst, C. A. Tetrahedron Lett. 2003, 44, 3749.
(o) Liu, B.; Zhou, W.-S. Tetrahedron Lett. 2003, 44, 4933. (p) Zhang, D.-H
and Zhou, W.-S. Synlett 2003, 15, 1817. (q) Li, D. R.; Tu, Y.-Q.; Lin,
G.-Q.; Zhou, W.-S. Tetrahedron Lett. 2003, 44, 8729. (r) Lucas, B.; Luther,
L. M.; Burke, S. D. Org. Lett. 2004, 6, 2965.
(4) (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) Forsyth, C. J.; Ahmed,
F.; Cink, R. D.; Lee, C. S. J. Am. Chem. Soc. 1998, 120, 5597.
Our retrosynthetic analysis of phorboxazole B (Scheme
1) disconnected the structure at the C2-C3 and C19-C20
(5) (a) Evans, D. A.; Cee, V. J.; Smith, T. E.; Santiaga, K. J.Org. Lett.
1999, 1, 87. (b) Evans, D. A.; Cee, V. J.; Smith, T. E.; Fitch, D. M.; Cho,
P. S. Angew. Chem., Int. Ed. 2000, 39, 2533. (c) Evans, D. A.; Fitch, D.
M. Angew. Chem., Int. Ed. 2000, 39, 2536. (d) Evans, D. A.; Fitch, D. M.;
Smith, T. E.; Cee, V. J. J. Am. Chem. Soc. 2000, 122, 10033.
(1) Searle, P. A.; Molinski, T. F. J. Am. Chem. Soc. 1995, 117, 8126.
(2) (a) Molinski, T. F. Tetrahedron Lett. 1996, 37, 7879. (b) Searle, P.
A.; Molinski, T. F.; Brzeainski, L. J.; Leahy, J. W. J. Am. Chem. Soc. 1996,
118, 9422.
10.1021/ol048275x CCC: $27.50
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the lactone 6 with 7, using the procedure described by the
Evans group5 and subsequent Julia olefination reaction with
sulfone 5, would lead to the formation of the C20-C46
segment 3.
Scheme 1. Retrosynthesis of Phorboxazole B
As shown in Scheme 3, the route to lactone 6 started from
our previous reported compound 8, which was synthesized
Scheme 3. Synthesis of Lactone 6
3 and 4. We envisaged coupling 3 and 4 at C19-C20 using
an E-selective Wittig reaction. An intramolecular Z-selective
Wadsworth-Emmons olefination reaction at C2-C3 would
then lead to completion of the total synthesis of phorboxazole
B.
The synthesis of the C3-C19 segment 4 has been reported
in a previous publication from our group.3p Herein, we now
describe our efficient synthesis of the segment 3 of
phorboxazole B.
from 1,3-propanediol using a Witttig reaction, a Sharpless
AD, and a Mukaiyama aldol reaction as key steps.3q
Deprotection of the acetoxy group from 8 with K2CO3/EtOH9
afforded alcohol 9 in 97% yield. When compound 9 was
treated with 10% CF3CO2H in CH2Cl2,10 the PMB protecting
groups were smoothly removed and the resultant triol
concomitantly cyclized to afford the lactone 10. Since lactone
10 is highly soluble in water, the reaction mixture was
directly neutralized with Et3N, concentrated, and purified by
SiO2 flash column chromatography without extraction.
Selective protection of the primary hydroxyl group in 10 with
TBSCl/Et3N11 delivered the mono-TBS ether 11. Protection
of 11 with a TIPS (triisopropylsilyl) group under routine
conditions (TIPSCl, imidazole, cat. DMAP, DMF)12 was not
From a retrosynthetic perspective (Scheme 2), disconnec-
tion of the C32-C33 bond and the C41-C42 double bond
Scheme 2. Retrosynthesis of the C20-C46 Segment 3 of
Phorboxazole B
13
successful, but the use of TIPSCl/AgNO3 afforded the
desired lactone 6.
The synthesis of the THP-oxazole segment 7 commenced
from diol 12, which was readily accessible from D-glycer-
(6) (a) Smith, A. B., III; Verhoest, P. R.; Minbiole, K. P.; Lim, J. J.
Org. Lett. 1999, 1, 909. (b) Smith, A. B., III; Minbiole, K. P.; Verhoest, P.
R.; Beauchamp, T. J. Org. Lett. 1999, 1, 913. (c) Smith, A. B., III; Verhoest,
P. R.; Minbiole, K. P.; Schelhaas, M. J. Am. Chem. Soc. 2001, 123, 4834.
(d) Smith, A. B., III; Minbiole, K. P.; Verhoest, P. R.; Schelhaas, M. J.
Am. Chem. Soc. 2001, 123, 10942.
(7) (a) Pattenden, G.; Plowright, A. T.; Tornos, J. A.; Ye, T. Tetrahedron
Lett. 1998, 39, 6099. (b) Ye, T.; Pattenden, G. Tetrahedron Lett. 1998, 39,
319. (c) Pattenden, G.; Plowright, A. T. Tetrahedron Lett. 2000, 41, 983.
(d) Gonza´lez, M. A.; Pattenden, G. Angew. Chem., Int. Ed. 2003, 42, 1255.
(e) Pattenden, G.; Gonza´lez, M. A.; Little, P. B.; Millan, D. S.; Plowright,
A. T.; Tornos, J. A.; Ye, T. Org. Biomol. Chem. 2003, 1, 4173.
(8) (a) Williams, D. R.; Clark, M. P. Tetrahedron Lett. 1999, 40, 2291.
(b) Williams, D. R.; Clark, M. P.; Berliner, M. A. Tetrahedron Lett. 1999,
40, 2287. (c) Williams, D. R.;. Kiryanov, A. A.; Emde, U.; Clark, M. P.;
Berliner, M. A.; Reeves, J. T. Angew. Chem., Int. Ed. 2003, 42, 1258.
(9) Plattner, J. J.; Gless, R. D.; Rapoport, H. J. Am. Chem. Soc. 1972,
94, 8613.
(10) Yan, L.; Kahne, D. Synlett 1995, 523.
(11) Chaudhary, S. K.; Hernandez, O. Tetrahedron Lett. 1979, 99.
(12) Cunico, R. F.; Bedell, L. J. Org. Chem. 1980, 45, 4797.
separates 3 into the known sulfone 5,3q lactone 6, and the
tetrahydropyranyl oxazole 7. It was envisaged that coupling
4262
Org. Lett., Vol. 6, No. 23, 2004

aldehyde by reiterative application of asymmetric crotyla-
tion.3° To construct the cis-tetrahydropyran unit of 7, the
iodocyclization14 reaction of 12 was first explored. As shown
in Table 1, iodocyclization of diol 12 with iodine in
Scheme 4. Synthesis of Oxazole 7
Table 1. Construction of cis-Tetrahydropyran Moiety of 7
entry
conditions
13/14a yieldb (%)
1
2
3
4
I2, CH3CN, -35 °C to 0 °C
I2, NaHCO3, CH3CN, 0 °C
NIS, CH2Cl2, 30 °C
c
2.6:1
7.7:1
5:1
46
52d
86
Hg(OAc)2, toluene, 0 °C; I2, 30 °C
a Product ratio was determined by 1H NMR spectral analysis (300 MHz).
b Isolated yield. c Complex mixture. d Based on recovery of 40% starting
material.
acetonitrile yielded a complex mixture (entry 1), probably
due to the lability of the acetonide to the HI generated during
the process of cyclization. Therefore, NaHCO3 was added
to the reaction mixture (entry 2). To our delight, the desired
cis-tetrahydropyran 13, along with the minor trans-isomer
14, were obtained in 46% overall yield (13/14 ) 2.6:1). To
optimize the stereochemical outcome, NIS (N-iodosuccin-
imide) was used (entry 3). Although the ratio of 13 and 14
increased to 7.7:1, the overall yield was still low (52% based
on recovery of 40% starting material). We next turned our
attention to Hg(OAc)2-induced cyclization, which is also a
general method for preparing tetrahydropyran systems.15
After screening various solvents and reaction conditions, we
eventually found that when diol 12 was treated with
Hg(OAc)2 in dry toluene at 0 °C and the organomercurial
was treated with iodine, the cis-tetrahydropyran 13 was
formed in 86% yield with 5:1 dr.16 The configuration of 13
was later confirmed by 2D NOSEY analysis on the oxazole
7.
the hydroxyl group in 17 with BPSCl (tert-butyldiphenylsilyl
chloride)19 gave the ether 18, which was converted to
aldehyde 19 by the action of periodic acid.20 MeLi addition
to the aldehyde 19 followed by Dess-Martin oxidation21
afforded methyl ketone 20.
To complete the synthesis of oxazole 7, an E-selective
olefination reaction was required to construct the C27-C28-
trisubstituted double bond. Although the Wittig reaction22
and Julia olefination23 have been successfully employed to
construct E-double bonds, methyl ketone 20 reacted slug-
gishly under these reaction conditons. Ultimately, we resorted
to the procedure described by Pattenden, in which the oxazole
phosphonate ester 21 was used.7e We were delighted that,
when phosphonate ester 21 was deprotonated with LDA at
-78 °C followed by treatment with methyl ketone 20, the
desired THP-oxazole segment 7 was obtained in 78% yield
24
(based on the recovery of 20% starting material).
Protection of the hydroxyl group in 13 with p-methoxy-
benzyl trichloroacetimidiate17 in the presence of BF3‚OEt2
gave the PMB ether 15 (Scheme 4). Iodide 15 was converted
to the nitrile 16, and this was successively reduced with
DIBAL and NaBH4 to give the alcohol 17.18 Protection of
With segments 5-7 in hand, the stage was set to complete
the synthesis of the C20-C46 segment of phorboxazole B
(Scheme 5). Oxazole 7 was deprotonated with lithium
diethylamide at -78 °C5a and treated afterward with lactone
6, and the desired cyclic hemiketal 22 was obtained in 61%
yield as the sole isomer. Selective deprotection of the C41
TBS ether of 22 and spontaneous Fischer glycosidation of
the hemiketal was accomplished with PPTS/CH3OH and
(13) Nishino, S.; Nagato, Y.; Yamamoto, H.; Ishido, Y. J. Carbohydr.
Chem. 1986, 5, 199.
(14) Bernard, N.; Chemla, F.; Ferreira, F.; Mostefai, N.; Normant, J. F.
Chem. Eur. J. 2002, 8, 3139.
(15) (a) Pougny, J. R.; Nassr, M. A..; Sinay, P. J. Chem. Soc., Chem.
Commun. 1981, 375. (b) Blanchette, M. A.; Malamas, M. S.; Nantz, M.
H.; Roverts, J. C.; Somfai, P.; Whritenour, D. C.; Masamune, S. J. Org.
Chem. 1989, 54, 2817. (c) Hori, K.; Hikage, N.; Inagaki, A.; Mori, S.;
Nomura, K.; Yoshii, E. J. Org. Chem. 1992, 57, 2888. (d) Martin, O. R.;
Xie, F. Carbohydr. Res. 1994, 264, 141. (e) Koning, C. B.; Green, I. R.;
Michael, J. P.; Oliveira, J. R. Tetrahedron 2001, 57, 9623.
(16) Compound 13 could be isolated by flash chromatography using silica
gel in 71% yield as the major diastereomer.
(18) Hosokawa, S.; Isobe, M. J. Org. Chem. 1999, 64, 37.
(19) Guindon, Y.; Yoakim, C.; Bernstein, M. A.; Morton, H. E.
Tetrahedron Lett. 1985, 26, 1185.
(20) Li, L.; Wu, Y.; Wu, Y. J. Carbohydr. Chem. 1999, 18, 1067.
(21) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(22) Zhao, Z. C.; Scarlato, G. R.; Armstrong, R. W. Tetrahedron Lett.
1991, 32, 1609.
(17) Audia, J. E.; Boisvert, L.; Patten, A. D.; Villalobos, A.; Danishefsky,
S. J. J. Org. Chem. 1989, 54, 3738.
(23) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron Lett.
1991, 32, 1175.
Org. Lett., Vol. 6, No. 23, 2004
4263

Scheme 5. Synthesis of the C20-C46 Segment of Phorboxazole B
afforded the alcohol 23. Careful oxidation of the allylic
In summary, an efficient synthesis of the C20-C46
segment 3 of phorboxazole B has been developed using a
convergent strategy. The key steps involved Hg(OAc)2/
I2-induced cyclization to construct the cis-tetrahydropyran
unit, the employment of metalated 2-methyl oxazole chem-
istry to couple lactone 6 with oxazole 7, and Julia olefination
to furnish the conjugated diene moiety. The successful
synthesis of the C20-C46 segment 3 has laid a solid
foundation for the total synthesis of phorboxazle B, which
is in progress in our laboratory and will be reported in due
course.
primary alcohol of 23 with Dess-Martin periodinane,21
followed by Julia olefination23 of the crude aldehyde 24 with
sulfone 5, smoothly furnished the desired E-diene moiety
(51%, two steps; E/Z >95:5). The synthesis of the C20-
C46 segment of phorboxazole B was thus completed.
(24) The cis-configuration of the tetrahydropyran of the compound 7
was confirmed by the NOE effect among H22, H24, and H26. The NOE
effect among C27 methyl group and H30 confirmed E-configuration of
C27-C28 double bond.
Supporting Information Available: Selected experi-
mental procedures and spectroscopic data of compounds 3,
5-14, 16-18, and 20-23. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL048275X
4264
Org. Lett., Vol. 6, No. 23, 2004