A synthetic approach to the phorboxazoles – A strategy for the synthesis of the C1–C19 polyketide fragment

Article abstract of DOI:10.1016/j.tetlet.2017.12.007

A synthetic approach to the C1–C19 polyketide fragment of the phorboxazoles is disclosed here. While an initial two-directional approach was efficient, it did not proceed in a high enough yield to justify moving forward. A subsequent successful strategy for the generation of the C11–C15 pyrans of both of the phorboxazoles was achieved, and the installation of the C9 stereocenter was able to be demonstrated. Furthermore, an efficient route for the preparation of the C1–C8 fragment with suitable functionality to allow for elaboration into the complete C1–C19 fragment, with the capricious C2–C3 Z-geometry installed, was also achieved.

Full text of DOI:10.1016/j.tetlet.2017.12.007

Tetrahedron Letters xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A synthetic approach to the phorboxazoles – A strategy for the synthesis
of the C1–C19 polyketide fragment
d
d
James W. Leahy a,b,c, , David C. Carroll , Kate E. McElhone
⇑
a Department of Chemistry, University of South Florida, CHE 205, 4202 E. Fowler Avenue, Tampa, FL 33620, United States
b Florida Center of Excellence for Drug Discovery and Innovation, University of South Florida, 3720 Spectrum Boulevard, Suite 303, Tampa, FL 33612, United States
c Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, MDC 7, 12901 Bruce B. Downs Boulevard, Tampa, FL 33612, United States
d Department of Chemistry, University of California, Berkeley, CA 94720, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A synthetic approach to the C1–C19 polyketide fragment of the phorboxazoles is disclosed here. While an
initial two-directional approach was efficient, it did not proceed in a high enough yield to justify moving
forward. A subsequent successful strategy for the generation of the C11–C15 pyrans of both of the phor-
boxazoles was achieved, and the installation of the C9 stereocenter was able to be demonstrated.
Furthermore, an efficient route for the preparation of the C1–C8 fragment with suitable functionality
to allow for elaboration into the complete C1–C19 fragment, with the capricious C2–C3 Z-geometry
installed, was also achieved.
Received 1 August 2017
Revised 27 November 2017
Accepted 1 December 2017
Available online xxxx
Keywords:
Phorboxazoles
Total synthesis
Two-directional synthesis
Ó 2017 Elsevier Ltd. All rights reserved.
The phorboxazole family of natural products, including phorbx-
azoles A (1) and B (2)1,2 as well as hemiphorboxazole (3),3 are mar-
ine macrolides isolated from an Indian Ocean sponge (Phorbas spp.)
that have attracted considerable interest for their unique structural
features as well as their biological properties (Fig. 1).4,5 Interest-
ingly, while 1 and 2 possess potent cytostatic properties presum-
ably tied to their ability to interact with cyclin-dependent kinase
(CDK) 4,6 3 is effectively inactive despite containing the entire
macrolide portion of 1.3 As part of a broad program aimed at the
total synthesis of this family of natural products, we have previ-
ously reported our synthetic efforts toward this molecule, specifi-
cally our approach to prospective intermediates 4 and 5.7,8 We
wish to report here our approach to the bis-pyran fragment 6 of
the phorboxazoles.
In our initial synthetic approach to this fragment, we envisioned
using Schreiber’s two-directional synthesis strategy,9 something
that had been applied beautifully by Burke in his total synthesis
of 2.10 We felt that Smith’s anion relay chemistry would be ideal
in this regard.11 Deprotonation of 2-t-butyldimethylsilyldithiane
(7) followed by addition of excess expoxide 8 resulted in the
desired Brook rearrangement and double addition to give 9
(Scheme 1). Copper mediated liberation of the ketone proceeded
with concomitant deprotection of the silyl ether, and silylation of
both of the secondary alcohols was achieved with TIPS triflate fol-
lowed by reduction of the ketone gave 10 in good overall yield and
only 4 steps. With an eye toward using the desymmetrization to
effectively set the remaining stereocenter, we liberated the pri-
mary alcohols and explored a variety of selective oxidation condi-
tions. Unfortunately, every condition tried returned a complex
mixture of products. Despite exploring a myriad of various protect-
ing groups and conditions, our ‘‘best” result was from dialdehyde
14, from which we were able to isolate pyran 15 (phorboxazole
numbering designations included for 12 and 15) in 10% yield. We
therefore sought an alternative approach to this fragment.
We felt that any revised pathway should also be sure to address
an approach that would allow access to either 1 or 2 from a similar
pathway, which we initially felt we would have been able to do
from 12. We recognized that we should be able to use the single
stereocenter that would correspond to C11 to set the stereochem-
istry at what would eventually become C13 of the phorboxazoles
depending on the conditions we chose. The only concern, then,
would be whether both isomers would give the desired stereocen-
ter at C15. To test this, we generated model systems 16 and 18
(Scheme 2). Iodoetherification of either the 1,3-syn or the 1,3-anti
isomers,12 followed by reductive removal of the iodide, provided
good yields of the desired product, which could be confirmed by
NMR analysis of the methine protons. With this in hand, we pro-
ceeded to take on the real system.
Known ester 20,13 readily available in enantiopure form via
Noyori reduction of the corresponding b-ketoester, was converted
⇑
Corresponding author at: Department of Chemistry, University of South Florida,
CHE 205, 4202 E. Fowler Avenue, Tampa, FL 33620, United States.
E-mail address: jwleahy@usf.edu (J.W. Leahy).
https://doi.org/10.1016/j.tetlet.2017.12.007
0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Leahy J.W., et al. Tetrahedron Lett. (2017), https://doi.org/10.1016/j.tetlet.2017.12.007

2
J.W. Leahy et al. / Tetrahedron Letters xxx (2017) xxx–xxx
Fig. 1. Structures and retrosynthetic analysis of the phorboxazoles.
Scheme 1. Two-directional approach to the bis-pyran fragment.
also used for the installation of the exocyclic oxazole in our C20-
C32 fragment,8 provided olefin 23 after liberation of the free sec-
ondary alcohol. We were now set to install the C13 stereocenter,
and reduction under either directed or Narasaka-Prasad conditions
gave the requisite diols (26 and 24, respectively).14,15 To ensure
that each of these reductions proceeded as expected, we converted
both into their corresponding acetonides using Rychnovsky’s pro-
tocol and confirmed that each reduction indeed formed the desired
products.16 Iodoetherification proceeded in both cases to give the
desired product as the major isomer (Scheme 4), though we did
also isolate some of the undesired isomer 31 in the reaction with
26. Following reductive removal of the iodide, the remaining sec-
ondary alcohol could be protected and the primary alcohol liber-
ated under standard conditions.
Scheme 2. Iodoetherification approach to the pyran.
into the requisite Weinreb amide and silylated to give 21
(Scheme 3). Following generation of the desired b-ketophospho-
nate, Horner Wadsworth Emmons olefination with 22, which we
In order to maintain flexibility with respect to our eventual cou-
pling of the two fragments, we also pursued a slightly truncated
approach, as outlined with the synthesis of 35 in Scheme 5. How-
Please cite this article in press as: Leahy J.W., et al. Tetrahedron Lett. (2017), https://doi.org/10.1016/j.tetlet.2017.12.007

J.W. Leahy et al. / Tetrahedron Letters xxx (2017) xxx–xxx
3
Scheme 3. Control of the C13 stereocenter of the phorboxazoles.
Scheme 4. Installation of the pyran via iodoetherification.
Scheme 5. Alternative approach to oxazole pyran scaffold and controlled addition to generate the C9 stereocenter.
ever, with primary alcohols 29 and 32 in hand, we were able to oxi-
dize them to the corresponding aldehydes and show that we could
introduce a methallyl nucleophile under the auspices of chiral bor-
ane conditions, establishing the C9 center of 36 with excellent
stereocontrol (and confirmed via Mosher analysis).17 This provided
confidence that the use of a fully elaborated allyl nucleophile
would behave in our real system.
double bond set at the outset. Malate derived 37 (effectively the
protected enantiomer of 33, Scheme 6)18 was converted to the
Weinreb amide and treated with the lithiated methanol synthon
3819 to give ketone 39, which could be methylenated to provide
the latent methallylating agent for our eventual coupling. Follow-
ing liberation of the diol, in situ epoxidation and addition of a pro-
tected propargyl anion led to 40. The remaining alcohol could be
silylated, and the C2-C3 syn geometry created via reduction with
Lindlar’s catalyst.
We were fully aware of the difficulties associated with the
installation of the cis-alkene at C2–C3,5 so we wanted to have that
Please cite this article in press as: Leahy J.W., et al. Tetrahedron Lett. (2017), https://doi.org/10.1016/j.tetlet.2017.12.007

4
J.W. Leahy et al. / Tetrahedron Letters xxx (2017) xxx–xxx
Scheme 6. Synthesis of the C1-C8 fragment.
3. Smith III AB, Liu Z, Hogan A-ML, Dalisay DS, Molinski TF. Org Lett.
2009;11:3766.
4. Haustedt LO, Hartung IV, Hoffmann HMR. Angew Chem Int Ed Engl.
2003;42:2711.
5. Shultz Z, Leahy JW. J Antibiot. 2016;69:220.
6. Forsyth CJ, Lu Y, Chen J, La Clair JJ. J Am Chem Soc. 2006;128:3858.
7. Leahy JW, Brzezinski LJ. Tetrahedron Lett. 2016;57:4670.
8. Leahy JW, Boyer SJ. Tetrahedron Lett. 2017;58:3238.
9. Poss CS, Schreiber SL. Acc Chem Res. 1994;27:9.
10. Lucas BS, Gopalsamuthiram V, Burke SD. Angew Chem Int Ed. 2007;46:769.
11. Smith III AB, Wuest WM. Chem Commun (Cambridge, U. K.). 2008;5883.
12. Bailey AD, Cherney SM, Anzalone PW, Anderson ED, Ernat JJ, Mohan RS. Synlett.
2006;215.
In summary, we have synthesized two fragments that corre-
spond to the C1–C8 (41) and C9–C19 portions of both phorboxa-
zole A and B (29 and 32, respectively). We have also established
that we can install the eventual C9 stereocenter using an allylated
nucleophile. What remains is to achieve the addition of 41 to 29
and 32 with similar control of stereochemistry and to subsequently
couple this to the other phorboxazole fragments we have previ-
ously disclosed.
Acknowledgements
13. Claffey MM, Hayes CJ, Heathcock CH. J Org Chem. 1999;64:8267.
14. Evans DA, Chapman KT, Carreira EM. J Am Chem Soc. 1988;110:3560.
15. Chen KM, Hardtmann GE, Prasad K, Repic O, Shapiro MJ. Tetrahedron Lett.
1987;28:155.
16. Rychnovsky SD, Skalitzky DJ. Tetrahedron Lett. 1990;31:945.
17. The same sequence could be conducted on 32 to provide the corresponding C13
epimer (using the phorboxazole numbering system) in essentially the same
yields and diastereocontrol at the newly formed ‘‘C9” stereocenter.
18. Dias LC, Meira PRR. J Org Chem. 2005;70:4762.
We gratefully acknowledge the National Science Foundation
(NSF Career Award CHE-9502149) and the Research Corporation
(Cottrell Scholar Award) for financial assistance.
References
19. Evans DA, Carter PH, Carreira EM, Charette AB, Prunet JA, Lautens M. J Am Chem
Soc. 1999;121:7540.
1. Searle PA, Molinski TF, Brzezinski LJ, Leahy JW. J Am Chem Soc. 1996;118:9422.
2. Molinski TF. Tetrahedron Lett. 1996;37:7879.
Please cite this article in press as: Leahy J.W., et al. Tetrahedron Lett. (2017), https://doi.org/10.1016/j.tetlet.2017.12.007