Synthesis of the C1-C17 segment of phorboxazole B

Article abstract of DOI:10.1021/ol0488800

(Equation Presented) The C1-C17 bis-oxane subunit 22 of phorboxazole B is efficiently synthesized by exploiting differential reactivities between similar substituents on the hydropyran rings in 4. Selective dihydroxylation of the equatorial vinyl group, h

Full text of DOI:10.1021/ol0488800

ORGANIC
LETTERS
2004
Vol. 6, No. 17
2965-2968
Synthesis of the C1−C17 Segment of
Phorboxazole B
Brian S. Lucas, Laura M. Luther, and Steven D. Burke*
Department of Chemistry, UniVersity of Wisconsin-Madison, 1101 UniVersity AVenue,
Madison, Wisconsin 53706-1396
burke@chem.wisc.edu
Received June 14, 2004
ABSTRACT
The C1−C17 bis-oxane subunit 22 of phorboxazole B is efficiently synthesized by exploiting differential reactivities between similar substituents
on the hydropyran rings in 4. Selective dihydroxylation of the equatorial vinyl group, hydroboration of the axial vinyl group, and intramolecular
Mitsunobu lactonization serve to fully differentiate the similar hydropyrans.
Recently, we reported a symmetry-based approach to the bis-
tetrahydropyran ring systems of phorboxazole A and B, the
key step being desymmetrization of meso tetraols by pal-
ladium-catalyzed, chiral-ligand-mediated double cycloetheri-
fication.1 Although we had achieved the formal desymme-
trization of these meso tetraol chains in greater than 98%
ee, we were left with the practical task of regioselectively
differentiating between the C5 and C15 vinyl groups, as well
as between the C7 and C13 ring hydroxyls, in the course of
installing the requisite phorboxazole functional groups. We
report herein the successful transformation of bis-tetrahy-
dropyran 4 to a fully functionalized C1-C17 segment of
phorboxazole B.
boxazoles have been the focus of numerous other efforts,7
SAR studies,8 and a recent overview.9 Discovered by
The cytotoxic macrolide phorboxazoles (Figure 1) have
been the subject of numerous synthetic efforts. In 1998, the
first total synthesis of phorboxazole A was completed by
Forsyth,2 with subsequent total syntheses by Evans3 (phor-
boxazole B), Smith,4 Pattenden,5 and Williams.6 The phor-
Figure 1. The phorboxazoles.
Molinski in 1995,10 phorboxazole A and its C13 epimer
phorboxazole B exhibit exceptional cytostatic activity. They
have shown a mean GI50 value of <1.6 × 10-9 M in vitro
against the NCI panel of 60 tumor cell lines.10b
(1) Lucas, B. S.; Burke, S. D. Org. Lett. 2003, 5, 3915.
(2) (a) Forsyth, C. J.; Ahmed, F.; Cink, R. D.; Lee, C. S. J. Am. Chem.
Soc. 1998, 120, 5597. (b) Cink, R. D.; Forsyth, C. J. J. Org. Chem. 1997,
62, 5672. (c) Lee, C. S.; Forsyth, C. J. Tetrahedron Lett. 1996, 37, 6449.
(d) Ahmed, F.; Forsyth, C. J. Tetrahedron Lett. 1998, 39, 183.
(3) (a) Evans, D. A.; Fitch, D. M.; Smith, T. E.; Cee, V. J. J. Am. Chem.
Soc. 2000, 122, 10033. (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.;
Cee, V. J.; Smith, T. E.; Santiago, K. J. Org. Lett. 1999, 1, 87.
(4) (a) Smith, A. B., III; Minbiole, K. P.; Verhoest, P. R.; Schelhaas, M.
J. Am. Chem. Soc. 2001, 123, 10942. (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; Verhoest, P. R.; Minbiole, K. P.; Lim, J. J. Org. Lett.
1999, 1, 909. (d) Smith, A. B., III; Minbiole, K. P.; Verhoest, P. R.;
Beauchamp, T. J. Org. Lett. 1999, 1, 913.
10.1021/ol0488800 CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/22/2004

Our retrosynthetic strategy for the C1-C17 subunit of
phorboxazole B is outlined in Scheme 1. We anticipated that
It is well-known that the reaction rate of functional groups
on six-membered rings is influenced by conformation.11
Examples of the attenuated reactivity of axially disposed
groups can be found in studies of conformationally con-
strained cyclohexanes,12 as well as in the steroid literature.13
Our design for achieving the differentiation of the pendant
vinyl groups (Scheme 2) was based on the selective dihy-
Scheme 1. Retrosynthesis of C1-C17 Segment of
Phorboxazole B
Scheme 2. Differentiation of the C5 and C15 Vinyl Groups
an oxazole-containing subunit such as 1 could be obtained
from the key 2,6-dioxabicyclo[3.3.1]nonan-3-one intermedi-
ate 2, itself available from an intramolecular Mitsunobu
reaction of acid diol 3. The proximity of the C3 carboxylic
acid group to the C7 alcohol in 3 would serve to differentiate
the ring hydroxyls. The strategy ultimately relied on finding
a suitable way to distinguish between the C5 (axial) and the
C15 (equatorial) vinyl groups of bis-tetrahydropyran 4,
previously synthesized in >98% ee and 75% yield from meso
tetraol 5.1
droxylation of bis-tetrahydropyran diacetate 6 at the less
hindered, equatorial C15 vinyl group.14 Commercially avail-
able AD-mix â15 yielded diol 7 in 76% yield after 3 h at 0
°C.16,17 We found that quenching the reaction after 3 h and
recycling unreacted 6 avoided exhaustive dihydroxylation
to give a 96% yield of 7 based on recovered starting material
(BORSM). Protection of the diol using 2,2-dimethoxypro-
pane (DMP) and PPTS in 1,2-dichloroethane afforded the
acetonide 8 in quantitative yield. Hydroboration/oxidation
of the remaining vinyl group using disiamyl borane/sodium
perborate gave the primary alcohol 9, thereby completing
the differential potentiation of the vinyl groups in 4.
(5) (a) 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.
(b) Gonza´lez, M. A.; Pattenden, G. Angew. Chem., Int. Ed. 2003, 42, 1255.
(c) Ye, T.; Pattenden, G. Tetrahedron Lett. 1998, 39, 319. (d) Pattenden,
G.; Plowwright, A. T.; Tornos, J. A.; Ye, T. Tetrahedron Lett. 1998, 39,
6099. (e) Plowright, A. T.; Pattenden, G. Tetrahedron Lett. 2000, 41, 983.
(6) (a) Williams, D. R.; Kiryanov, A. A.; Emde, U.; Clark, M. P.;
Berliner, M. A.; Reeves, J. T. Angew. Chem., Int. Ed. 2003, 42, 1258. (b)
Williams, D. R.; Clark, M. P.; Emde, U.; Berliner, M. A. Org. Lett. 2000,
2, 3023. (c) Williams, D. R.; Clark, M. P.; Berliner, M. A. Tetrahedron
Lett. 1999, 40, 2287.
(7) (a) Li, D. R.; Tu, Y-Q.; Lin, G.-Q.; Zhou, W.-S. Tetrahedron Lett.
2003, 44, 8729. (b) Liu, B.; Zhou, W.-S. Tetrahedron Lett. 2003, 44, 4933.
(c) Paterson, I.; Luckhurst, C. A. Tetrahedron Lett. 2003, 44, 3749. (d)
Greer, P. B.; Donaldson, W. A. Tetrahedron 2002, 58, 6009. (e) Huang,
H.; Panek, J. S. Org. Lett. 2001, 3, 1693. (f) Greer, P. B.; Donaldson, W.
A. Tetrahedron Lett. 2000, 41, 3801. (g) Rychnovsky, S. D.; Thomas, C.
R. Org. Lett. 2000, 2, 1217. (h) Schaus, J. V.; Panek, J. S. Org. Lett. 2000,
2, 469. (i) Wolbers, P.; Hoffmann, H. M. R.; Sasse, F. Synlett 1999, 1808.
(j) Wolbers, P.; Misske, A. M.; Hoffmann, H. M. R. Tetrahedron Lett. 1999,
40, 4527. (k) Wolbers, P.; Hoffmann, H. M. R. Synthesis 1999, 797. (l)
Misske, A. M.; Hoffmann, H. M. R. Tetrahedron 1999, 55, 4315. (m)
Wolbers, P.; Martin, H.; Hoffmann, H. M. R. Tetrahedron 1999, 55, 1905.
(n) Rychnovsky, S. D.; Hu, Y.; Ellsworth, B. Tetrahedron Lett. 1998, 39,
7271. (o) White, J. D.; Kranemann, C. L.; Kuntiyong, P. Org. Lett. 2001,
3, 4003.
(11) (a) Eliel, E. L.; Wilen, S. M.; Mander, L. N. Stereochemistry of
Organic Compounds; Wiley: New York, 1994; Chapter 11, pp 720-754.
(b) Eliel, E. L.; Allinger, N. L.; Angyal, S. J.; Morrison, G. A. Conforma-
tional Analysis; Wiley: New York, 1965.
(12) (a) Eliel, E. L.; Haubenstock, H.; Acharya, R. V. J. Am. Chem.
Soc. 1961, 83, 2351. (b) Chapman, N. B.; Shorter, J.; Toyne, K. J. J. Chem.
Soc. 1964, 1077.
(13) Smith, P. B.; McKenna, J. Tetrahedron 1964, 20, 1933.
(14) Campbell, J. E., Ph.D. Dissertation, University of Wisconsin,
Madison, WI, 2003.
(15) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu,
D.; Zhang, X.-L. J. Org. Chem. 1992, 57, 2768.
(16) Although the stereochemistry at C16 is ultimately destroyed, a single
diastereomer is desirable in the context of a multistep synthesis. AD-Mix
â was chosen to provide the matched case of ligand and substrate control
as defined by the Sharpless mnemonic (ref 15) and Kishi’s empirical rule
for dihydroxylation of allylic ether systems. See: Cha, J. K.; Christ, W. J.;
Kishi, Y. Tetrahedron 1984, 40, 2247.
(8) (a) Uckun, F. M.; Forsyth, C. J. Bioorg. Med. Chem. Lett. 2001, 11,
1181. (b) Hansen, T. M.; Engler, M. M.; Forsyth, C. J. Bioorg. Med. Chem.
Lett. 2003, 13, 2127.
(9) Haustedt, L. O.; Hartung, I. V.; Hoffmann, H. M. R. Angew Chem.,
Int. Ed. 2003, 42, 2711.
(10) (a) Searle, P. A.; Molinski, T. F. J. Am. Chem. Soc. 1995, 117,
8126. (b) Molinski, T. F. Tetrahedron Lett. 1996, 37, 7879. (c) Searle, P.
A.; Molinski, T. F.; Brzezinski, L. J.; Leahy, J. W. J. Am. Chem. Soc. 1996,
118, 9422.
(17) In a related system, OsO4 alone provided signficantly less regio-
selectivity and overall yield than AD-Mix; see ref 14.
2966
Org. Lett., Vol. 6, No. 17, 2004

The next task was to differentiate the C7 and C13
substituents in 9, so that the C7 hydroxyl could be trans-
formed into an exo methylene with retention of the C13
hydroxyl. As shown in Scheme 3, after in situ generated
hydroxyl, which would lead to a 10-membered lactone ring,
was not observed.
With the C7 hydroxyl group now inverted and protected
as the lactone, the differentiation was completed by protect-
ing the C13 hydroxyl as the TBDPS ether 2. The required
Z-(R,â)-unsaturated ester was installed by a Dibal-H/Still-
Gennari olefination sequence23 using trifluoroethyl phos-
phonate 12 to give Z-13 in 71% yield. Finally, oxidation at
C7 using Dess-Martin periodinane24 to ketone 14 was
followed by selective methylenation of the ketone with
dimethyltitanocene,25 affording the fully differentiated exo
methylene 15.
Scheme 3. Differentiation of the C7 and C13 Hydroxyl Groups
To install the vicinal amino alcohol functionality and
complete the synthesis of the C1-C17 subunit of phorbox-
azole B, we chose a strategy analogous to that employed by
Forsyth in his synthesis of the C3-C17 subunit of phor-
boxazole A2b (Scheme 4). Acidic deprotection of the ac-
Scheme 4. Completion of the C1-C17 Segment of
Phorboxazole B
RuO4 oxidation18 of the 1° alcohol of 9 to the carboxylic
acid 10, the axially disposed acetic acid substituent was
uniquely situated for a intramolecular Mitsunobu19 reaction
with the C7 ring hydroxyl. Although SN2-type reactions of
equatorial leaving groups on six-membered rings are known
to be particularly difficult,20 we surmised that in this
intramolecular case, the steric “cost” of the backside approach
of the nucleophile had been partially paid via the covalent
positioning of the nucleophile. Indeed, after deprotection of
the ring hydroxyls using NaOH/MeOH and quenching with
the carboxylic acid resin Dowex CCR-3, the crude acid diol21
3 yielded the [3.3.1] oxabicyclic lactone 11 when subjected
to standard Mitsunobu conditions.22 Involvement of the C13
etonide of 15 was followed by monoprotection of the
resulting diol 16 to afford 1° TES ether 17. Mitsunobu
inversion of the free 2° alcohol using diphenyl phosphoryl
azide26 proceeded in excellent yield to give the azide 18.
Finally, Staudinger reduction27 of the azide to the amine
(22) For other transannular intramolecular Mitsunobu lactonizations,
see: (a) Boto, A. Betancor, C.; Prange´ T.; Sua´rez, E. J. Org. Chem. 1994,
59, 4393. (b) Smith, A. B., III; Sulikowski, G. A.; Sulikowski, M. M.;
Fujimoto, K. J. Am. Chem. Soc. 1992, 114, 2567.
(18) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J.
Org. Chem. 1981, 46, 3936.
(19) Mitsunobu, O. Synthesis 1981, 1.
(20) (a) Conant, J. B.; Hussey, R. E. J. Am. Chem. Soc. 1925, 47, 476.
(b) Goering, H. L.; Espy, H. H. J. Am. Chem. Soc. 1955, 77, 5023.
(21) The crude acid diol 3 proved difficult to purify because of its
extremely polar nature and was therefore taken on directly to 11.
(23) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
(24) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(25) (a) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392.
(b) Improved synthesis of dimethyltitanocene: Payack, J. F.; Hughes, D.
L.; Cai, D.; Cottrell, I. F.; Verhoeven, T. R. Org. Synth. 2002, 79, 19.
(26) Lal, B.; Pramanik, B. N.; Manhas, M. S.; Bose, A. K. Tetrahedron
Lett. 1977, 18, 1977.
Org. Lett., Vol. 6, No. 17, 2004
2967

by oxazole formation using the Wipf procedure.28 As our
subunit has the C1-C3 Z-R,â-unsaturated ester installed prior
to the oxazole formation, we performed a model study to
ascertain the stability of the Z double bond under the
relatively basic Wipf conditions. Scheme 5 illustrates our
oxazole formation using trans-crotonic acid as a model
coupling partner. Acylation of amine 19 using 1.1 equiv of
trans-crotonic acid gave the amide 20 in 76% yield. Initial
attempts at direct oxidation of the 1° TES ether to the C17
aldehyde under Swern conditions29 were unsuccessful;
therefore, we opted for acidic removal of the TES ether to
give 1° alcohol 21 followed by oxidation to the aldehyde
using Dess-Martin periodinane.24 The crude amide aldehyde
was successfully cyclodehydrated to furnish the desired
oxazole 22 using Wipf’s conditions.28
Scheme 5. Subunit Coupling Model Study
In conclusion, we have demonstrated that the similar
functional groups of bis-tetrahydropyran 4 can be efficiently
differentiated by relying on conformational preferences and
functional group proximities within the molecule. Selective
dihydroxylation of an equatorial vinyl group over an axial
vinyl group and intramolecular Mitsunobu lactonization were
the key tactics employed in the synthesis of a fully elaborated
C1-C17 bis-oxane subunit of phorboxazole B.
Acknowledgment. We thank Dr. John E. Campbell for
helpful discussions regarding selective dihydroxylation, Dr.
Charles G. Fry for assistance with NMR characterization of
11, and NIH grants CA074394 and CA108488 for generous
support. L.M.L. gratefully acknowledges the 2004-2005
Wisconsin/Hilldale Undergraduate/Faculty Research Award
for assistance.
produced the fully functionalized C1-C17 subunit of phor-
boxazole B 19 in 15 steps and 10.8% overall yield from 4.
Our strategy for future subunit coupling follows the
Forsyth precedent of acylation of the C16 amine, followed
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for compounds 2 and 6-22.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(27) Vaultier, M.; Knouzi, N.; Carrie´, R. Tetrahedron Lett. 1983, 24,
763.
(28) (a) Wipf, P.; Lim, S. J. Am. Chem. Soc. 1995, 117, 558. (b) Wipf,
P.; Graham, T. H. J. Org. Chem. 2001, 66, 3242.
(29) Rodr´ıguez, A.; Nomen, M.; Spur, B. W.; Godfroid, J. J. Tetrahedron
Lett. 1999, 40, 5161.
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