Synthetic studies toward phorboxazole A. stereoselective synthesis of the C(28)-C(46) side chain fragment.

Article abstract of DOI:10.1021/ol0063656

A stereoselective synthesis of the C(28)-C(46) fragment (3) of phorboxazole A is described. Key advances include an enantioselective allylation to establish the stereochemistry of the tetrahydropyran unit and a useful SmI(2)-mediated modification of the B

Full text of DOI:10.1021/ol0063656

ORGANIC
LETTERS
2000
Vol. 2, No. 19
3023-3026
Synthetic Studies toward Phorboxazole
A. Stereoselective Synthesis of the
C −C Side Chain Fragment
28
46
David R. Williams,* Michael P. Clark, Ulrich Emde, and Martin A. Berliner
Department of Chemistry, Indiana UniVersity, 800 East Kirkwood AVenue,
Bloomington, Indiana 47405-7102
williamd@indiana.edu
Received July 21, 2000
ABSTRACT
A stereoselective synthesis of the C −C46 fragment (3) of phorboxazole A is described. Key advances include an enantioselective allylation
28
to establish the stereochemistry of the tetrahydropyran unit and a useful SmI2-mediated modification of the Barbier reaction of iodomethyloxazole
15 with aldehyde 14.
Phorboxazoles A (1) and B (2) are unique macrolides isolated
from the Indian Ocean sponge Phorbas sp.1 These metabo-
lites possess exceptional cytostatic activity throughout the
panel of 60 NCI human tumor cell lines (mean GI50 < 1.6
× 10-9 M).2 Selective cytotoxicity at subnanomolar con-
centrations is found in a number of significant tumor cultures,
including leukemia CCRF-CBM, prostate PC-3, breast
MCF7, and colon HCT116 and HT29 cell lines.2c Moreover,
the phorboxazoles do not inhibit tubulin polymerization and
may offer a unique mechanism of action by arresting the
cell cycle in S phase.2 Biological studies are severely limited
by the scarcity of natural material. The unprecedented
structural features and extraordinary potency of 1 have
inspired several synthesis studies,3 and Forsyth and co-
workers have reported the first total synthesis.4a Very
recently, Evans and co-workers have also achieved a total
synthesis of this important target.4b Previously, we reported
the synthesis of the C1-C32 macrolactone of phorboxazole
A.3d,e Herein, we report the stereoselective synthesis of the
C28-C46 polyolefinic side chain fragment (3). Our retrosyn-
thetic analysis of 3 recognized a bond disconnection which
would provide for installation of the C39-C42 diene at late
stage events (Scheme 1). This strategy suggested sulfone 4
and R,â-unsaturated aldehyde 5 as fully functionalized
components of an E-selective Julia olefination reaction,5a as
an extension of our related efforts toward hennoxazole A.5b
Verhoest, P. R.; Minbiole, K. P.; Lim, J. J. Org. Lett. 1999, 1, 909. (j)
Smith, A. B., III; Minbiole, K. P.; Verhoest, P. R.; Beauchamp, T. J. Org.
Lett. 1999, 1, 913. (k) Evans, D. A.; Cee, V. J.; Smith, T. E.; Santiago, K.
J. Org. Lett. 1999, 1, 87. (l) Wolvers, P.; Hoffman, H. M. R. Synthesis
1999, 5, 797. (m) Wolbers, P.; Hoffman, H. M. R. Tetrahedron 1999, 55,
1905. (n) Wolbers, P.; Misske, A. M.; Hoffman, H. M. R. Tetrahedron
Lett. 1999, 40, 4527. (o) Schaus, J.; Panek, J. S. Org. Lett. 2000, 2, 469.
(p) Pattenden, G.; Plowright, A. Tetrahedron Lett. 2000, 41, 983. (q)
Rychnovsky, S.; Thomas, C. Org. Lett. 2000, 2, 1217.
(4) (a) Forsyth, C. J.; Ahmed, F.; Cink, R. D.; Lee, C. S. J. Am. Chem.
Soc. 1998, 120, 5597. (b) Evans, D. A.; Cee, V. J.; Smith, T. E.; Fitch, D.
M.; Cho, P. S. Angew. Chem., Int. Ed. 2000, 39, 2533. Evans, D. A.; Fitch,
D. M. Angew. Chem., Int. Ed. 2000, 39, 2536.
(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.; Antonio, J. J. Nat.
Prod. 1993, 56, 54. (c) Molinski, T. F. Tetrahedron Lett. 1998, 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) Williams, D. R.; Clark,
M. P.; Berliner, M. A. Tetrahedron Lett. 1999, 40, 2287. (e) Williams, D.
R.; Clark, M. P. Tetrahedron Lett. 1999, 40, 2291. (f) Pattenden, G.; Ye,
T. Tetrahedron Lett. 1998, 39, 319. (g) Pattenden, G.; Plowright, A. T.;
Tornos, J. A.; Ye, T. Tetrahedron Lett. 1998, 39, 6099. (h) Paterson, I.;
Arnott, E. A. Tetrahedron Lett. 1998, 39, 7185. (i) Smith, A. B., III;
(5) (a) Kocienski, P. J.; Blakemore, P. R.; Cole, W. J.; Morley, A. Synlett.
1988, 26. (b) Williams, D. R.; Brooks, D. A.; Berliner, M. A. J. Am. Chem.
Soc. 1999, 121, 4924.
10.1021/ol0063656 CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/30/2000

Asymmetric allylation of aldehyde 9 was effected follow-
ing the tin to boron transmetalation of stannane 107 using
the boron bromide reagent derived from (R,R)-1,2-diamino-
1,2-diphenylethane bis-sulfonamide and boron tribromide
(Scheme 3).8 Formation of the C37 homoallylic alcohol was
Scheme 1
Scheme 3
achieved in 98% yield (10:1 dr).9 This is a significant
improvement for establishing the correct relative stereo-
chemistry at C37/C38 since previous efforts had required a
Mitsunobu inversion of the undesired C38 diastereomer.4a
Selective oxidative cleavage of the geminally disubstituted
olefin and a directed reduction of the resulting â-hydroxy
ketone (>95% de)10 provided a single diastereomeric product
after purification by flash chromatography. Treatment of this
diol with TBSOTf and collidine furnished the polyol deriva-
tive 12. Conversion to the fluoride-labile tert-butylmethoxy-
phenylsilyl (TBMPS) ether was necessary at this point in
the scheme because our plans for selective deprotection in
the corresponding MOM ether of 16 proved unworkable.
The synthesis of conjugated enal 5 began with aldehyde
9, which was prepared from optically active alcohol 66 in
seven steps (Scheme 2). Protection of the alcohol followed
Scheme 2
(6) Alcohol 6 is available from D-glyceraldehyde acetonide via a
stereoselective addition of 1-(trimethylsilyl)vinyl copper, followed by
protodesilylation. See: (a) Sato, F.; Kusakabe, M. Chem. Lett. 1986, 1473.
(b) Sato, F.; Tanaka, Y.; Sato, M. J. Chem. Soc., Chem. Commun. 1983,
165.
(7) Preparation of stannane 10 is conveniently carried out via deproto-
nation of 3-methyl-3-buten-1-ol with 2 equiv of Schlosser’s base (KOtBu/
nBuLi in hexanes) (see (a) Schlosser, M.; Hartmann, J. Angew. Chem., Int.
Ed. Engl. 1973, 12, 508. (b) Collum, D. B.; Mguirk, P. R. J. Org. Chem.
1989, 49, 843.) and quenching the resulting dianion with tributyltin iodide.
Protection of the resulting primary alcohol with trimethylacetyl chloride/
pyridine provided stannane 10.
(8) Corey, E. J.; Yu, C. M.; Kim, S. S. J. Am. Chem. Soc. 1989, 111,
5495.
(9) For more examples of asymmetric allylations being used for the
synthesis of complex homoallylic alcohols, see: Williams, D. R.; Brooks,
D. A.; Meyer, K. G.; Clark, M. P. Tetrahedron Lett. 1998, 39, 7251.
(10) Evans, D. A.; Carreira, E. J. Am. Chem. Soc. 1988, 110, 3560.
by reductive ozonolysis led to aldehyde 7. Wittig olefination
was followed by reduction (DIBAL) of the resulting ester,
and protection of the resulting allylic alcohol provided 8 in
excellent overall yield. Selective removal of the acetonide
protecting group with mild acid and cleavage of the diol with
sodium periodate gave the desired aldehyde 9.
3024
Org. Lett., Vol. 2, No. 19, 2000

Subsequent removal of the pivaloate of 13 (DIBAL) and
oxidation11 afforded the desired C33 aldehyde (14).
Scheme 5
Limited methodology has been described for the successful
nucleophilic addition of C-2 metalated oxazoles to carbonyl
compounds. These procedures utilize zinc,12 chromium,13 or
lithium diethylamide3k to circumvent issues arising from the
instability and reactivity of 5-lithiooxazoles. Herein, we
report a new and convenient method for the generation of
â-hydroxy ketones from the reaction of iodomethyloxazoles14
and aldehydes with SmI2 under Barbier-type conditions.15
To this end, addition of 4 equiv of SmI2 to a mixture of
aldehyde 14 and iodomethyloxazole 15 proceeded to give
the â-hydroxyoxazole as a 1:1 mixture of diastereomers in
71% yield (Scheme 4). This mixture was immediately
Scheme 4
using silver oxide in methyl iodide, and selective desilylation
of the primary TBMPS group18 followed by oxidation19
provided the R,â-unsaturated aldehyde fragment 5.
Scheme 5 incorporates the straightforward preparation of
the appropriately functionalized sulfone 4. Thus, the Lewis
acid-catalyzed opening of the (R)-glycidol derivative with
lithium trimethylsilylacetylide and methylation followed by
removal of the THP-protecting group gave primary alcohol
18. Activation of the alcohol and displacement with 1-phenyl-
1H-tetrazole-5-thiol20 was followed by introduction of the
vinyl bromide functionality via hydrozirconation of the
alkyne with Schwartz’s reagent21 and a NBS quench.
Oxidation of the heterocyclic sulfide with ammonium mo-
lybdate provided the desired sulfone 4.
Adaptation of the Kocienski modification5 of the Julia
condensation utilized the potassium carbanion of the N-
phenyltetrazole sulfone 4 for in situ elimination (Scheme 5).
Reaction with aldehyde 5 provided diene 19 in 60% yield22
and resulted in unexpected Z-selectivity (>8:1 Z:E). This
result was surprising considering that our model studies had
demonstrated the stereoselective formation of E,E-dienes
converted to the desired C33 ketone using the trifluoroacetic
anhydride variant of the Swern oxidation.16 The â-ketooxa-
zole was directly cyclized under mildly acidic conditions to
afford the mixed ketal ring system 16 in 58% yield, along
with 23% of the allylic alcohol 17 as single diastereomers.17
Methylation of the C35 alcohol was efficiently carried out
(11) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43,
2380.
(12) Helquist, P.; Gangloff, A. R.; Akermark, B. J. Org. Chem. 1992,
57, 4797.
(13) Uguen, D.; Breuilles, P. Tetrahedron Lett. 1998, 39, 3149.
(14) Oxazole 15 was conveniently prepared from the amide of serine
methyl ester shown below in four operations: (a) DAST, K2CO3, CH2Cl2
(92%); (b) BrCCl3, DBU (81%); (c) DDQ, CH2Cl2 (90%); and (d) PPh3,
I2, imid, CH2Cl2 (85%).
(17) The allylic alcohol 17 was easily converted to 16 with TBMPSBr,
Et3N, and CH2Cl2 (91% yield).
(18) Guindon, Y.; Fortin, R.; Yoakim, C.; Gillard, J. W. Tetrahedron
Lett. 1984, 25, 4717.
(19) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(20) Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017.
(21) Hart, D.; Schwartz, J. J. Am. Chem. Soc. 1974, 96, 8115.
(22) Additionally, small quantities of tetraene 20 have been observed in
the Julia olefination reaction resulting from subsequent elimination of
methanol.
(15) For reviews, see: (a) Krief, A.; Laval, A.-M. Chem. ReV. 1999, 99,
745. (b) Kinishima, M.; Hioki, K.; Kono, K.; Sakuma, T.; Tani, S. Chem.
Pharm. Bull. 1994, 42, 2190.
(16) The oxalyl chloride Swern procedure (see ref 12) gave a side product
resulting from dichlorination at the C(32) position (72% yield).
Org. Lett., Vol. 2, No. 19, 2000
3025

when sulfone 4 was reacted with R,â-unsaturated aldehydes.23
Fortunately, we discovered that the undesired C41-C42
Z-alkene could be isomerized to the E-alkene.24 Thus, after
removal of the C38 silyl protecting group, treatment of the
Z,E-diene 19 with a crystal of iodine followed by irradiation
with a sun lamp (250 W) resulted in complete isomerization
to the desired E,E-diene 3. Our spectral data for the
phorboxazole side chain were consistent with a detailed
analyses of 1H and 13C NMR spectra of the natural product.
In summary, we have described an efficient, enantiose-
lective synthesis of the C28-C46 side chain of phorboxazole
A. Our work features significant methodology for enantio-
controlled allylation and a useful Barbier procedure for a
samarium-mediated incorporation of the intact oxazole unit
which may have important implications for heterocyclic
chemistry. Progress toward the completion of phorboxazole
A (1) is underway and will be reported in due course.
Acknowledgment. The authors gratefully acknowledge
the National Institutes of Health (GM-41560) for generous
support of our work. We thank Professor Evans for a preprint
of his total synthesis (ref 4b).
(23) For example, reaction of sulfone 4 with cinnamaldehyde resulted
in an 8:1 ratio of (E,E) to (E,Z) dienes.
Supporting Information Available: Experimental pro-
cedures and spectral data for compounds 3, 11, and 16 and
a listing of H NMR data for compounds 4, 5, 14, and 19.
1
This material is available free of charge via the Internet at
http://pubs.acs.org.
(24) Roelofs, W.; Comeau, A.; Hill, A.; Milicevic, G. Science 1971, 174,
297.
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