hemi-phorboxazole A (1) in 85% yield for the two steps
(Scheme 1). Importantly, the spectral data of synthetic (+)-1
[cf. 1D and 2D NMR, UV, circular dichromism (CD), and
HRMS] were identical in all respects with the data derived
from natural hemi-phorboxazole A (1), thereby confirming
both the complete relative stereochemistry and assigned
absolute configuration.
Scheme 1
Figure 1. Natural products isolated from Phorbas sp.
With synthetic (+)-hemi-phorboxazole A (1) in hand, we
turned to the design, elaboration, and biological evaluation
of analogues, with the important goal of introducing synthetic
simplicity while maintaining the potentially important mac-
rolide ring conformation of the natural congener. At the
outset, we selected two analogues featuring macrolide ring
replacements on the basis of our earlier analogue studies of
(+)-phorboxazole A (5).8 In particular, we proposed: (i)
replacement of the C-ring tetrahydropyran with a cyclic
acetal and (ii) a bis-ring replacement comprising a similar
acetal for the C-ring tetrahydropyran and a phenyl ring for
the B-ring oxazole (Figure 2). Replacement of the tetrahy-
material to define the biological properties, recourse to total
synthesis was clearly required for forward progress.
Given that our laboratory has had a long-standing interest
in the phorboxazole area, with first- and second-generation
total syntheses of (+)-phorboxazole A (5) recorded in 20015
and 2005,6 we were intrigued with the diminutive form of
hemi-phorboxazole A (1). Indeed, a synthetic program
directed at hemi-phorboxazole A could take ready advantage
of the Petasis-Ferrier union/rearrangement,7 an effective
tactic specifically designed and developed for the stereocon-
trolled construction of the A and C cis-tetrahydropyran rings
inscribed within the parent phorboxazole macrolide. Equally
exciting was the potential for the design, synthesis, and
biological evaluation of hemi-phorboxazole A analogues, a
program that would fit nicely with our ongoing phorboxazole
analogue venture.8
With this as background, we envisioned that (+)-hemi-
phorboxazole A (1) could be readily elaborated by exploiting
the same late-stage vinyl iodide macrolide (+)-2, which was
constructed via a longest linear sequence of 20 steps (20%
yield) exploiting our now scalable second-generation phor-
boxazole A synthesis.6 Indeed, removal of the TBS group
at C(13) by treatment with tetrabutylammonium fluoride
(TBAF), followed by a palladium-catalyzed cyanation,9
employing tributyltin cyanide, provided totally synthetic (+)-
(5) Smith, A. B., III; Verhoest, P. R.; Minbiole, K. P.; Schelhaas, M.
J. Am. Chem. Soc. 2001, 123, 4834.
Figure 2. Phorboxazole analogues.
(6) (a) Smith, A. B., III; Razler, T. M.; Ciavarri, J. P.; Hirose, T.;
Ishikawa, T. Org. Lett. 2005, 7, 4399. (b) Smith, A. B., III; Razler, T. M.;
Ciavarri, J. P.; Hirose, T.; Ishikawa, T.; Meis, R. M. J. Org. Chem. 2008,
73, 1192.
dropyran ring with a synthetically simplified but geo-
metrically similar cyclic acetal (i.e., 1,3-dioxane) comprises
a tactic that was introduced and elegantly employed by
Wender et al. in their bryostatin analogue program.10 This
concept was also utilized with some success in our (+)-
(7) Smith, A. B., III; Fox, R. J.; Razler, T. M. Acc. Chem. Res. 2008,
41, 675.
(8) (a) Smith, A. B., III; Razler, T. M.; Pettit, G. R.; Chapuis, J.-C.
Org. Lett. 2005, 7, 4403. (b) Smith, A. B., III; Razler, T. M.; Meis, R. M.;
Pettit, G. R. Org. Lett. 2006, 8, 797. (c) Smith, A. B., III; Razler, T. M.;
Meis, R. M.; Pettit, G. R. J. Org. Chem. 2008, 73, 1201.
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