(+)-Phorboxazole a synthetic studies. A highly convergent, second generation total synthesis of (+)-phorboxazole A

Article abstract of DOI:10.1021/ol051584i

(Chemical Equation Presented) A second generation total synthesis of the potent antitumor agent (+)-phorboxazole A (1) has been achieved. The cornerstone of this approach comprises a more convergent strategy, involving late-stage Stille union of a fully e

Full text of DOI:10.1021/ol051584i

ORGANIC
LETTERS
2005
Vol. 7, No. 20
4399-4402
(+)-Phorboxazole A Synthetic Studies.
A Highly Convergent, Second
Generation Total Synthesis of
(+)-Phorboxazole A
Amos B. Smith, III,* Thomas M. Razler, Jeffrey P. Ciavarri, Tomoyasu Hirose, and
Tomoyasu Ishikawa
Department of Chemistry, Monell Chemical Senses Center, and Laboratory for
Research on the Structure of Matter, UniVersity of PennsylVania, Philadelphia,
PennsylVania 19104
smithab@sas.upenn.edu
Received July 6, 2005
ABSTRACT
A second generation total synthesis of the potent antitumor agent (
comprises a more convergent strategy, involving late-stage Stille union of a fully elaborated C(1
The second generation synthesis entails the longest linear sequence of 24 steps, with an overall yield of 4.2%.
+
)-phorboxazole A (1) has been achieved. The cornerstone of this approach
−
28) macrocycle with a C(29 46) side chain.
−
In 1995, Searle and Molinski1 isolated two architecturally
complex macrolides, (+)-phorboxazole A and B [epimeric
at C(13)], from the Indian ocean sponge Phorbas sp.,
endemic to the waters near the western coast of Australia.
The phorboxazoles displayed extraordinary biological prop-
erties, including high cell growth inhibitory activity against
both fungal and human tumor cell lines, rendering these
architecturally complex natural products potentially important
pharmacological lead structures. For example, in vitro
bioassay of both 1 and 2 against the National Cancer
Institute’s (NCI) panel of 60 human tumor cell lines reveals
a mean GI50 of 1.58 × 10-9 M. Not surprisingly, the
phorboxazoles have attracted considerable attention from the
synthetic community. To date, four total syntheses of
phorboxazole A (1)2 and one of phorboxazole B [the C(13)
epimer]3 have been reported, along with numerous related
synthetic studies.4
In 2001, we disclosed our first generation synthesis of (+)-
phorboxazole A, relying on the Petasis-Ferrier union/
rearrangement tactic, specifically developed to assemble the
two highly substituted, cis-tetrahydropyran rings embedded
in the phorboxazole macrocycle.5,6 Seven steps were, how-
(2) (a) Forsyth, C. J.; Ahmed, F.; Cink, R. D.; Lee, C. S. J. Am. Chem.
Soc. 1998, 120, 5597. (b) Smith, A. B., III; Verhoest, P. R.; Minbiole, K.
P.; Schelhaas, M. J. Am. Chem. Soc. 2001, 123, 4834. (c) Smith, A. B., III;
Minbiole, K. P.; Verhoest, P. R.; Schelhaas, M. J. Am. Chem. Soc. 2001,
123, 10942. (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. (f) Williams, D. R.; Kiryanov, A. A.; Emde, U.; Clark, M. P.; Berliner,
M. A.; Reeves, J. T. Angew. Chem., Int. Ed. 2003, 42, 1258.
(1) (a) Searle, P. A.; Molinski, T. F. J. Am. Chem. Soc. 1995, 117, 8126.
(b) Searle, P. A.; Molinski, T. F.; Brzezinski, L. J.; Leahy, J. W. J. Am.
Chem. Soc. 1996, 118, 9422. (c) Molinski, T. F. Tetrahedron Lett. 1996,
37, 7879.
(3) (a) Evans, D. A.; Cee, V. J.; Smith, T. E.; Fitch, D. M.; Cho, P. S.
Angew. Chem., Int. Ed. 2000, 39, 2533. (b) Evans, D. A.; Fitch, D. M.
Angew. Chem., Int. Ed. 2000, 39, 2536. (c) Evans, D. A.; Fitch, D. M.;
Smith, T. E.; Cee, V. J. J. Am. Chem. Soc. 2000, 122, 10033.
10.1021/ol051584i CCC: $30.25
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Published on Web 09/01/2005

ever, required to complete the total synthesis after Stille union
of the macrocyclic precursor and side chain. We, therefore,
sought in a second generation approach a more convergent,
scalable route, comprising an advanced macrocycle, ap-
propriately functionalized for ready attachment of a more
fully elaborated side chain. Success with this venture would
reduce the number of post-Stille coupling steps, and thereby
increase the overall efficiency. In this, the first of two Letters,
we report the successful realization of this goal: a more
effective, convergent, and potentially scalable total synthesis
of (+)-phorboxazole A (1). In the second Letter, we
demonstrate the utility of the second generation approach
with the design and synthesis of a series of potent phorbox-
azole congeners possessing structurally modified side chains,
one of which proved significantly more active than phor-
boxazole A.7
tricyclic fragment 6, which in the forward sense would be
united via a stereoselective Wittig olefination. The requisite
tricycle 6 would be available via a three-step Petasis-Ferrier
union/rearrangement of oxazole aldehyde 8 with â-hydroxy
acid 7, the latter assembled via hetero-Diels-Alder8 and
acetate aldol tactics.9
Construction of macrocycle 4 began with the synthesis of
â-hydroxy acid 7 (Scheme 2). Condensation of known
Scheme 2
From the synthetic perspective, we trace our second
generation approach to the side chain oxazole 3 and a fully
elaborated macrocyclic vinyliodide 4 (Scheme 1).2b,c Discon-
Scheme 1
aldehyde 910 with the Danishefsky diene11 catalyzed by Ti-
(O-i-Pr)4/(R)-Binol furnished the hetero-Diels-Alder8 adduct
(-)-10 in 75% yield, with 92% enantioselectivity. Scandium
triflate-promoted axial delivery of the TMS-thiol enol ether
derived from ethylthioacetate led next to trans-tetrahydro-
pyranone (-)-11 as a single diastereomer in excellent yield.12
Importantly, this reaction was found to be highly reliable
on preparative scales up to 50 g.
Chemoselective olefination of (-)-11 utilizing the Petasis/
Tebbe reagent13 and 10 mol % of ethyl pivalate furnished
thiolester (-)-12 in 76% yield. The ethyl pivalate was
employed to prevent deleterious [2+2] side reactions of Cp2-
Lett. 2001, 3, 1693. (k) Greer, P. B.; Donaldson, W. A. Tetrahedron Lett.
2000, 41, 3801. (l) Greer, P. B.; Donaldson, W. A. Tetrahedron 2002, 58,
6009. (m) White, J. D.; Kranemann, C. L.; Kuntiyong, P. Org. Lett. 2001,
3, 4003. (n) Paterson, I.; Luckhurst, C. A. Tetrahedron Lett. 2003, 44, 3749.
(o) Paterson, I.; Steven, A.; Luckhurst, C. A. Org. Biomol. Chem. 2004, 2,
3026. (p) Lucas, B. S.; Burke, S. D. Org. Lett. 2003, 5, 3915. (q) Lucas, B.
S.; Luther, L. M.; Burke, S. D. Org. Lett. 2004, 6, 2965. (r) Liu, B.; Zhou,
W.-S. Tetrahedron Lett. 2003, 44, 4933. (s) Li, D. R.; Tu, Y. Q.; Lin, G.-
Q.; Zhou, W.-S. Tetrahedron Lett. 2003, 44, 8729.
(5) Smith, A. B., III; Verhoest, P. R.; Minbiole, K. P.; Lim, J. J. Org.
Lett. 1999, 1, 909.
(6) Smith, A. B., III; Minbiole, K. P.; Verhoest, P. R.; Beauchamp, T. J.
Org. Lett. 1999, 1, 913.
(7) Smith, A. B., III; Razler, T. M.; Pettit, G. R.; Chapuis, J.-C. Org.
Lett. 2005, following Letter.
(8) Keck, G. E.; Li, X.-Y.; Krishnamurthy, D. J. Org. Chem. 1995, 60,
5998.
nections of 4 in turn at the C(2-3) and C(19-20) olefins
reveal a central tetrahydropyran aldehyde 5 and an eastern
(4) (a) Rychnovsky, S. D.; Hu, Y.; Ellsworth, B. Tetrahedron Lett. 1998,
39, 7271. (b) Rychnovsky, S. D.; Thomas, C. R. Org. Lett. 2000, 2, 1217.
(c) Jasti, R.; Vitale, J.; Rychnovsky, S. D. J. Am. Chem. Soc. 2004, 126,
9904. (d) Wolbers, P.; Hoffmann, H. M. R.; Sasse, F. Synlett 1999, 1808.
(e) Wolbers, P.; Misske, A. M.; Hoffmann, H. M. R. Tetrahedron Lett.
1999, 40, 4527. (f) Wolbers, P.; Hoffmann, H. M. R. Synthesis 1999, 797.
(g) Wolbers, P.; Hoffmann, H. M. R. Tetrahedron 1999, 55, 1905. (h)
Misske, A. M.; Hoffmann, H. M. R. Tetrahedron 1999, 55, 4315. (i) Schaus,
J. V.; Panek, J. S. Org. Lett. 2000, 2, 469. (j) Huang, H.; Panek, J. S. Org.
(9) Nagao, Y.; Yamada, S.; Kumagai, T.; Ochiai, M.; Fujita, E. J. Chem.
Soc., Chem. Commun. 1985, 1418.
(10) Boeckman, R. K., Jr.; Charette, A. B.; Asberom, T.; Johnston, B.
H. J. Am. Chem. Soc. 1987, 109, 7553.
(11) (a) Danishefsky, S. Acc. Chem. Res. 1981, 14, 400. (b) Danishefsky,
S. Chemtracts: Org. Chem. 1989, 2, 273.
(12) Yamashita, Y.; Saito, S.; Ishitani, H.; Kobayashi, S. J. Am. Chem.
Soc. 2003, 125, 3793.
(13) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392.
4400
Org. Lett., Vol. 7, No. 20, 2005

TiCH2 with the resultant exo-olefin.14 Reduction with 10%
Pd/C and triethylsilane next afforded aldehyde (-)-13 in
excellent yield.15 To establish the C(11) configuration
required in the C(11-15) tetrahydropyran, we employed the
Nagao acetate aldol protocol,9 promoted by tin triflate,
followed by treatment with lithium peroxide, to furnish
â-hydroxy acid (-)-7, with excellent diastereoselectivity (ca.
10:1) and in good yield.
mediated oxidative removal of the PMB protecting group
and mesylation of the corresponding primary alcohol led to
tricycle (-)-6, the requisite Wittig salt precursor for union
with 5.
Our next course of action called for the synthesis of the
C(22-26) cis-tetrahydropyran (5, Scheme 4), again employ-
With ample quantities of both â-hydroxy acid (-)-7 and
aldehyde 8 available, we turned to the Petasis-Ferrier union/
rearrangement (Scheme 3).5 Bis-silylation of (-)-7 followed
Scheme 4
Scheme 3
ing the three-step Petasis-Ferrier union/rearrangement tac-
tic.6 We began with construction of (+)-17 via an Evans’s
syn-aldol,19 employing BPS-protected aldehyde 9, followed
by hydrolysis of the resultant imide with lithium peroxide;
the yield for the two steps was 90%. Bis-silylation followed
by TMSOTf-promoted condensation with known aldehyde
18,20 buffered with 2,6-di-tert-butyl-4-methylpyridine, fur-
nished dioxanone (+)-19 both in excellent yield (ca. 93%)
and diastereoselectivity (ca. 20:1). Olefination with the
Petasis/Tebbe reagent,13 followed by exposure of the resultant
enol acetal to Me2AlCl at -78 °C, then led to tetrahydro-
pyranone (+)-20 in near quantitative yield.
Completion of the C(22-26) central tetrahydropyran (5,
Scheme 4) proceeded first by kinetic enolization of ketone
(+)-20 with LHMDS, followed by addition of MeI to furnish
the equatorial methyl ketone. Axial hydride delivery employ-
ing sodium borohydride, followed by protection of the
resultant equatorial alcohol with 3,4-dimethoxybenzyl chlo-
ride led to (+)-21, which upon removal of the BPS protecting
group with TBAF, followed by Parikh-Doering21 oxidation,
provided aldehyde (+)-5, the requisite coupling partner for
union with (-)-6.
by TMSOTf-promoted dioxanone formation16 with oxazole
aldehyde 85,17 furnished (-)-14 in 95% yield, with excellent
diastereoselectivity (ca. 10:1) at C(15). Conversion of (-)-
14 to the corresponding enol acetal was again achieved
employing the Petasis/Tebbe reagent; however, in this case,
a more concentrated solution of the reagent (ca. 0.7 M) was
employed, compared to that used in the construction of (-)-
12. This modification, in conjunction with the use of ethyl
pivalate, both shortened the reaction time and greatly reduced
side product formation. Execution of the Petasis-Ferrier
rearrangement was then achieved by introduction of the enol
acetal to a vigorously stirred solution of Me2AlCl and Cs2-
CO3 at room temperature; pleasingly, tetrahydropyranone
(-)-15 was produced in 66% yield for the two steps.18
Completion of fragment 6 involved reduction of the C(13)
carbonyl with K-Selectride, followed by TBS protection of
the resultant axial alcohol to furnish (-)-16; in turn, DDQ-
With aldehyde (+)-5 and mesylate (-)-6 in hand, we were
in position to effect their union (Scheme 5). The initial
capricious yields observed upon Wittig salt formation,
presumably due to the reactivity of the initially formed C(19)
primary chloride, led us to opt for the one-pot Wittig salt
formation/olefination protocol developed by Evans and Fitch
(14) Huffman, M. PCT. Int. Appl. 2000 WO 2000024723 A1.
(15) Fukuyama, T.; Tokuyama, H. Aldrichimica Acta 2004, 37, 87.
(16) Noyori, R.; Murata, S.; Suzuki, M. Tetrahedron 1981, 37, 3899.
(17) Williams, D. R.; Clark, M. P.; Berliner, M. A. Tetrahedron Lett.
1999, 40, 2287.
(19) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,
2127.
(18) Evans, W. J.; Giarikos, D. G.; Ziller, J. W. Organometallics 2001,
20, 5751.
(20) Ahmed, F.; Forsyth, C. J. Tetrahedron Lett. 1998, 39, 183.
(21) Parikh, J. R.; von E. Doering, W. J. Am. Chem. Soc. 1967, 89, 5505.
Org. Lett., Vol. 7, No. 20, 2005
4401

Scheme 5
Scheme 6
in their pioneering (+)-phorboxazole B synthesis.3,22 Specif-
ically, treatment of mesylate (-)-6 with tributylphosphine
for 36 h, followed by introduction of aldehyde (+)-5 and
DBU, yielded the C(19-20)-E-olefin in 96% yield, with
greater than 20:1, E:Z selectivity. Completion of macrocycle
4 was now in sight. Selective removal of the BPS group
with KOH and 18-crown-623 furnished the corresponding
primary alcohol, which upon oxidation under Dess-Martin
conditions,24 followed by oxidative removal of the DMB
protecting group with DDQ, led to alcohol (+)-23 in 95%
yield.
Arrival at (+)-phorboxazole A (1) and thereby a second
generation total synthesis closely followed our first genera-
tion approach. Specifically, conversion of TMS-protected
alkyne (+)-25 to the corresponding bromoalkyne with
AgNO3/NBS, followed by palladium-catalyzed hydrostan-
nylation,29 furnished a mixture (ca. 6:1) of external and
internal vinylstannanes, which were readily converted to the
corresponding vinylbromides using NBS/CH3CN at 0 °C.
Global deprotection enlisting 6% HCl furnished synthetic
(+)-phorboxazole A (1) in 35% over three steps after HPLC
separation of the regioisomeric vinyl bromides.
We next enlisted the Still-Genari-modified Horner-
Emmons25 olefination to construct the Z-macrolide 4 (Scheme
5). To this end, EDCI‚MeI/HOBT-mediated coupling of
alcohol (+)-23 with trifluoroethyl phosphonate acid 2426 led
to the corresponding phosphonate ester. Exposure of the latter
to K2CO3/18-crown-627 furnished macrocyclic enoate (+)-4
in excellent overall yield (ca. 89% for the two steps), albeit
with only modest 2.5:1, Z:E selectivity.
Completion of the phorboxazole skeleton now called for
union of the side chain stannane (-)-3 with (+)-4, utilizing
the Stille coupling protocol developed by the Liebeskind
group,28 which involves a combination of Pd2(dba)3‚CHCl3/
AsPh3, DIPEA, and Ph2PO2NBu4 in DMF at room temper-
ature; pleasingly, the coupled product (+)-25 was obtained
in 68% yield (Scheme 6).
In summary, we have developed an effective, second
generation total synthesis of (+)-phorboxazole A (1). Com-
pared to our first generation approach, which required 27
steps (longest linear sequence) and proceeded in 3.1% overall
yield, the second generation synthesis proceeds in 24 steps
(longest linear sequence) to furnish (+)-phorboxazole A (1)
in 4.2% overall yield. Importantly, completion of this
potentially scalable synthesis of (+)-phorboxazole A provides
access not only to 1 but also to significant quantities of
advanced intermediates for future analogue synthesis. In the
accompanying Letter, we disclose the syntheses and biologi-
cal evaluation of several structurally simplified analogues
which possess equal to or greater tumor cell growth inhibitory
activity compared to that of (+)-phorboxazole A (1).
(22) Liu, P.; Panek, J. S. J. Am. Chem. Soc. 2000, 122, 1235.
(23) Torisawa, Y.; Shibasaki, M.; Ikegami, S. Chem. Pharm. Bull. 1983,
31, 2607.
(24) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(25) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
(26) Pickering, D. A. Ph.D. Thesis, University of Minnesota, MN, 1996.
(27) (a) Aristoff, P. A. J. Org. Chem. 1981, 46, 1954. (b) Nicolaou, K.
C.; Seitz, S. P.; Pavia, M. R. J. Am. Chem. Soc. 1982, 104, 2030.
(28) Srogl, J.; Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1997,
119, 12376.
Acknowledgment. Support for this work was provided
by the NIH (CA-19033) and Takeda Chemical Company
(T.I.).
Supporting Information Available: Experimental pro-
cedures and spectroscopic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(29) Zhang, H. X.; Guibe´, F.; Balavoine, G. J. Org. Chem. 1990, 55,
1857.
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