A synthetic approach to the phorboxazoles—synthesis of the exocyclic fragment

Article abstract of DOI:10.1016/j.tetlet.2016.08.090

A strategy for the total synthesis of the phorboxazoles, including the synthesis of the exocyclic fragment corresponding to the C33–C41 portion, is reported. The primary objective was to utilize a chelation-controlled addition to an α-alkoxyaldehyde to install the oxygen atom at the C38 position.

Full text of DOI:10.1016/j.tetlet.2016.08.090

Accepted Manuscript
A Synthetic Approach to the Phorboxazoles – Synthesis of the Exocyclic Frag-
ment
James W. Leahy, Linda Joy Brzezinski
PII:
S0040-4039(16)31128-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.08.090
TETL 48061
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
15 July 2016
26 August 2016
29 August 2016
Please cite this article as: Leahy, J.W., Brzezinski, L.J., A Synthetic Approach to the Phorboxazoles – Synthesis of
the Exocyclic Fragment, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.08.090
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A Synthetic Approach to the Phorboxazoles – Synthesis of the Exocyclic Fragment
a
b
James W. Leahy * and Linda Joy Brzezinski
a
Department of Chemistry, University of South Florida, CHE 205, 4202 E. Fowler Avenue,
Tampa, FL 33620; Florida Center of Excellence for Drug Discovery and Innovation, University
of South Florida, 3720 Spectrum Boulevard, Suite 303, Tampa, FL 33612 and Department of
Molecular Medicine, Morsani College of Medicine, University of South Florida, MDC 7, 12901
b
Bruce B. Downs Boulevard, Tampa, FL 33612. Department of Chemistry, University of
California, Berkeley, CA 94720
Abstract
A strategy for the total synthesis of the phorboxazoles, including a synthesis of the exocyclic
fragment corresponding to the C33-C41 portion, is reported. The primary objective was to utilize
a chelation-controlled addition to an -alkoxyaldehyde to install the oxygen atom at the C38
position.
Keywords
Phorboxazole; enantiospecific synthesis; chelation-controlled addition to α-alkoxyaldehyde
The phorboxazoles (1 and 2) are potent cytostatic and antifungal macrolides that have been
1
, 2
isolated from multiple Australian sponge sources. More recently, hemi-phorboxazole A (3)
3
was also isolated, and although it contains the full macrolide portion of 1, it is not biologically

4
active. The unique biological activity and structures of the phorboxazoles attracted the attention
5
6, 7
of the synthetic organic community even before the structure had been fully elucidated. These
efforts have resulted in a number of groups reporting on their total or partial syntheses which
8
, 9
were recently reviewed. This has prompted us to disclose our own synthetic approach to these
natural products.
We envisioned a disconnection of the macrolide about the ester at C1 as well as the C19-
C20 olefin, which we felt we could install via a modified Julia coupling, leading to our planned
intermediates 5 and 6, and the approaches to these molecules will be reported in due course. Our
plan for the exocyclic fragment 4 was to utilize the C33 hemiketal as an umpolung nucleophile
capable of displacing a leaving group at C32.

7
In our initial work that led to the structural elucidation of the exocyclic portion, we added
nucleophile 8 to the pyran aldehyde 7, which provided 9 and 10 as a 3:2 mixture of isomers at
the position that corresponded to C38. At the time that we conducted this work, we did not yet
know the absolute stereochemistry of the phorboxazoles, which led to these models being
prepared antipodal to the stereochemistry of the natural product. They did, however, allow for
the determination of the relative stereochemistry between C37 and C38, the latter of which had
been unequivocally established via Mosher ester analysis, thus completing the stereochemical
assignment for both 1 and 2. While this was invaluable in allowing us to determine the structure,
we were somewhat disappointed to observe that the addition to this aldehyde did not proceed
with good chelation control, which would have given us a preponderance of 10. We therefore
sought to modify our synthetic approach so that we would use a more chelation- friendly
1
0
substituent such as a p-methoxybenzyl ether to enhance the chelation control. It is noteworthy
that most of the synthetic approaches to this portion of the phorboxazoles either used an
1
1-18
available chiral pool reagent for this position
or set positions C37 and C38 via a Sharpless
1
9-23
24
25
asymmetric dihydroxylation.
Notable exceptions were the approaches of Evans, Paterson
2
6
and the first generation synthesis of Forsyth, all of which were conducted on the closed pyran

ring. While Evans was able to elicit exquisite stereocontrol on the fully elaborated skeleton in the
penultimate step of his synthesis, Forsyth and Paterson’s addition to a pyran fragment gave
27
predominantly the undesired Felkin-Ahn product. This would suggest that the variation in the
size of the R substituent impacts this selectivity. We therefore sought to prepare an acyclic
precursor that we felt would allow for greater and more predictable stereocontrol upon the
formation of the intended C38 stereocenter.
2
8
Borane reduction of (R)-malic acid gave the corresponding triol, which could be
selectively protected as dioxane 12. The remaining primary alcohol was converted into the
triisopropylsilyl ether, and DIBAL reduction of the acetal smoothly proceeded at the primary
2
9
position to give 14. Swern oxidation then provided aldehyde 15.

With a lack of an -substituent, we were unlikely to achieve much substrate-derived
stereocontrol, and indeed achiral nucleophile addition proceeded to give little to no
diastereomeric excess. In our hands, we found that Keck’s BINOL-mediated allylation afforded
3
0
the best yield and diastereomeric ratio, which provided access to 16. Upon methylation of this
alcohol, the olefin was converted into an aldehyde via the osmylation/periodate protocol,
followed by formation of 1,3-dithiane umpolung 19 using standard conditions. Fluoride-
mediated deprotection of the TIPS ether followed by Swern oxidation of the alcohol thus
provided aldehyde 21.
There have been several elegant approaches to the exocyclic triene portion of the
phorboxazoles, many of which could be used to add to 21. However, we wanted to evaluate the
3
1
selectivity of addition to our substrate, so we prepared 23 from known alcohol 22. Metallation

of 23 and addition to 21 ultimately proceeded in quite reasonable yield, and the desired
chelation-control product was the major isomer formed. Unfortunately, the level of selectivity
was meager at best.
We initially explored simply using the lithiated species derived from 23 via lithium-halogen
exchange. The reaction proceeded with modest selectivity (1.6:1) and modest yield (65 %). We
explored a series of additives (e.g. LiClO
4
, TiCl
4
, Me
2
AlCl, MeAlCl
2
, BF
3
•OEt
2
, SnCl
4
, ZnCl )
2
in an effort to improve on these results, though typically these led to incomplete consumption of
starting material or decomposition, and without any improvement in the diastereomeric ratio.
Our initial concern was that these conditions might have resulted in the epimerization of the C37
stereocenter that might contribute to our limited success, but we were able to independently
oxidize both crude 24 and 25 to the same ketone, and neither showed the presence of any
diastereomers – thus indicating that epimerization was not likely an issue. Ultimately the best
result we obtained was through the auspices of magnesium bromide as Evans had previously
2
4
observed, suggesting that moving away from the pyran does not provide a significant
improvement over most of the previous fragment endeavors.
The synthesis of 24 completes a fully elaborated C33-C41 fragment of the phorboxazoles
with functionality in place for the further elaboration to the natural products, and the use of a

2
4
nucleophile such as Evans’ 26 would be expected to give the complete exocyclic fragment. In
concert with our synthetic approach to the macrocycle, this would provide a route to 1 and 2.
Additional efforts toward the synthesis of the phorboxazoles will be reported.
Acknowledgements
We gratefully acknowledge the National Science Foundation (NSF Career Award CHE-
9
502149) and the Research Corporation (Cottrell Scholar Award) for financial assistance.
References
1
2
1
3
4
5
6
7
8
9
1
1
1
1
1
1
Searle, P. A.; Molinski, T. F. J. Am. Chem. Soc. 1995, 117, 8126.
Capon, R. J.; Skene, C.; Liu, E. H.; Lacey, E.; Gill, J. H.; Heiland, K.; Friedel, T. Nat. Prod. Res. 2004,
8, 305.
Dalisay, D. S.; Molinski, T. F. Org Lett 2009, 11, 1967.
Smith, A. B., III; Liu, Z.; Hogan, A.-M. L.; Dalisay, D. S.; Molinski, T. F. Org. Lett. 2009, 11, 3766.
Lee, C. S.; Forsyth, C. J. Tetrahedron Lett. 1996, 37, 6449.
Molinski, T. F. Tetrahedron Lett. 1996, 37, 7879.
Searle, P. A.; Molinski, T. F.; Brzezinski, L. J.; Leahy, J. W. J. Am. Chem. Soc. 1996, 118, 9422.
Haustedt, L. O.; Hartung, I. V.; Hoffmann, H. M. R. Angew Chem Int Ed Engl 2003, 42, 2711.
Shultz, Z.; Leahy, J. W. J. Antibiot. 2016, 69, 220.
Kahn, S. D.; Keck, G. E.; Hehre, W. J. Tetrahedron Lett. 1987, 28, 279.
Pattenden, G.; Plowright, A. T.; Tornos, J. A.; Ye, T. Tetrahedron Lett. 1998, 39, 6099.
Williams, D. R.; Clark, M. P.; Emde, U.; Berliner, M. A. Org. Lett. 2000, 2, 3023.
Li, R. D.; Tu, Y. Q.; Lin, G.-Q.; Zhou, W.-S. Tetrahedron Lett. 2003, 44, 8729.
White, J. D.; Kuntiyong, P.; Lee, T. H. Org. Lett. 2006, 8, 6039.
0
1
2
3
4
5
Wang, B.; Hansen, T. M.; Wang, T.; Wu, D.; Weyer, L.; Ying, L.; Engler, M. M.; Sanville, M.;
Leitheiser, C.; Christmann, M.; Lu, Y.; Chen, J.; Zunker, N.; Cink, R. D.; Ahmed, F.; Lee, C.-S.; Forsyth, C. J.
J. Am. Chem. Soc. 2011, 133, 1484.
1
1
7
1
1
2
2
2
2
2
2
2
2
2
2
6
7
559.
8
9
0
Lucas, B. S.; Gopalsamuthiram, V.; Burke, S. D. Angew. Chem., Int. Ed. 2007, 46, 769.
Matsunaga, S.; Kinoshita, T.; Okada, S.; Harada, S.; Shibasaki, M. J. Am. Chem. Soc. 2004, 126,
Raju, K. B.; Kumar, B. N.; Kumar, B. S.; Nagaiah, K. Helv. Chim. Acta 2015, 98, 386.
Smith, A. B., III; Verhoest, P. R.; Minbiole, K. P.; Schelhaas, M. J. Am. Chem. Soc. 2001, 123, 4834.
Smith, A. B., III; Razler, T. M.; Ciavarri, J. P.; Hirose, T.; Ishikawa, T.; Meis, R. M. J. Org. Chem.
008, 73, 1192.
1
2
3
4
5
6
7
8
Yadav, J. S.; Rajaiah, G. Synlett 2004, 1743.
Wolbers, P.; Hoffmann, H. M. R. Synthesis 1999, 797.
Kumar, S. P.; Nagaiah, K. Tetrahedron Lett. 2007, 48, 1391.
Evans, D. A.; Fitch, D. M. Angew. Chem., Int. Ed. 2000, 39, 2536.
Paterson, I.; Steven, A.; Luckhurst, C. A. Org. Biomol. Chem. 2004, 2, 3026.
Ahmed, F.; Forsyth, C. J. Tetrahedron Lett. 1998, 39, 183.
Mengel, A.; Reiser, O. Chem. Rev. (Washington, D. C.) 1999, 99, 1191.
Hanessian, S.; Ugolini, A.; Dube, D.; Glamyan, A. Can. J. Chem. 1984, 62, 2146.

29
30
31
Takano, S.; Akiyama, M.; Sato, S.; Ogasawara, K. Chem. Lett. 1983, 1593.
Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993, 115, 8467.
Baker, R.; Castro, J. L. J. Chem. Soc., Perkin Trans. 1 1990, 47.

Graphical Abstract

A synthetic approach to the phorboxazoles is disclosed
An enantiospecific synthesis of the C33-C41 exocyclic portion is described
The chelation-controlled addition to an -alkoxyaldehyde is examined