Stereoselective synthesis of the C21-C27 fragment of the phorboxazoles

Article abstract of DOI:10.1016/S0040-4039(03)01099-2

A stereoselective synthesis of the C21-C27 fragment of phorboxazoles A and B was achieved in 12 linear steps via an intramolecular cyclization induced by mercury acetate, to afford a functionalized tetrahydropyran.

Full text of DOI:10.1016/S0040-4039(03)01099-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4933–4935
Stereoselective synthesis of the C21ꢀC27 fragment of
the phorboxazoles
Bo Liu and Wei-Shan Zhou*
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, PR China
Received 31 December 2002; revised 27 February 2003; accepted 15 April 2003
Abstract—A stereoselective synthesis of the C21ꢀC27 fragment of phorboxazoles A and B was achieved in 12 linear steps via an
intramolecular cyclization induced by mercury acetate, to afford a functionalized tetrahydropyran. © 2003 Elsevier Science Ltd.
All rights reserved.
Phorboxazoles A (1) and B (2),1 isolated from the
Indian Ocean sponge Phorbas sp., exhibit potent cyto-
static activity against human tumor cell lines in the
NCI panel.2 The complex structure consists of four
oxane rings, two oxazole rings, fifteen stereogenic cen-
ters and a conjugated diene segment (Fig. 1).
been employed in the synthesis of carbohydrates.6 It
was further shown that cis-2,6-disubstituted tetra-
hydropyrans could be thus generated in the course of
Masamune’s synthesis of the bryostatins7 and Yoshii’s
synthesis of tetronomycin.8 Accordingly, we hoped that
this methodology would find utility in the synthesis of
the phorboxazoles.
The novel structure and potent biological activities of
the phorboxazoles have attracted tremendous attention
in the synthetic community,3 and several examples of
successful total syntheses have been reported.4 In this
letter, our work on the synthesis of the C21ꢀC27 seg-
ment of the phorboxazoles is described.
The synthesis of the C21ꢀC27 fragment commenced
from
D
-glyceraldehyde acetonide 3, which was readily
accessible from
D
-mannitol.9 Asymmetric crotyl addi-
tion to 3 with chiral boronate (−)-4 under Roush’s
conditions10 afforded homoallylic alcohol 5, which was
transformed to its acetate 6 according to the standard
procedure.11 Asymmetric crotylation using (+)-4 of
aldehyde 7 obtained from the ozonolysis of 6, was
followed by treatment with sodium hydroxide. To our
It has been reported that the intramolecular alkoxymer-
curation of unsaturated alcohols and phenols provide a
general synthesis of five- and six-membered ring ethers.5
This intramolecular alkoxymercuration chemistry has
1
surprise, H NMR spectroscopy of the product indi-
cated that the BꢀO bond of the compound from asym-
metric crotylation was not cleaved using the usual
workup procedure.10 However this could be achieved
by treatment with base overnight in ether instead of
toluene, resulting in the simultaneous hydrolysis of the
acetate to provide 8 (Scheme 1).
To complete the synthesis of the fully functionalized
tetrahydropyran of the phorboxazoles, a stereoselective
intramolecular cyclization to construct the stereogenic
center of C22 was required. We anticipated that suit-
able facial bias could be imposed in the transitional
state which would result in a stereoselective cyclization.
Figure 1.
To our delight, diol 8 was converted to pyran 9 using
mercury acetate with good diastereoselectivity and in
excellent yield, while compound 10, the isomer of 9,
* Corresponding author. Tel.: +86-21-64163300; fax: +86-21-
64166128; e-mail: zhws@pub.sioc.ac.cn
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01099-2

4934
B. Liu, W.-S. Zhou / Tetrahedron Letters 44 (2003) 4933–4935
the selective methylation of the aldehyde in the presence
of the ester with organometallic agents. In fact, methyl
addition to aldehyde 14 proved sluggish with dimethyl
zinc, and unreactive with methyltripropoxyl titanium,
despite both agents having been extensively employed
as nucleophilic reagents for addition to aldehydes.16,17
Ultimately, selective addition was realized using
trimethyl aluminum to afford alcohol 15.18 Having
secured the requisite carbon skeleton, Dess–Martin oxi-
dation afforded the desired ketone, 16 (Scheme 2).19
In summary, construction of the C21ꢀC27 subunit 16
for the phorboxazoles has been achieved via a mercury-
mediated cyclization. The synthesis proceeded in an
efficient and stereocontrolled fashion in 12 linear steps
(17% overall yield). The synthesis of other subunits of
the phorboxzoles is in progress in our group.
,
Scheme 1. Reagents and conditions: (i) (−)-4, 4 A MS, toluene,
−78°C, 7 h, 65%. (ii) Ac2O, Et3N, DMAP (cat.), CH2Cl2, rt,
overnight, 95%. (iii) O3, CH2Cl2, −78°C, 2 h; then Me2S, rt,
,
overnight. (iv) (+)-4, 4 A MS, toluene, −78°C, 6 h, then rt,
overnight. (v) 1 M NaOH, Et2O, rt, overnight, 60% for three
steps.
Acknowledgements
was obtained in 13% yield. Acetylation of the free
hydroxyl group of 9, followed by oxidative
demercuration7,8,12 led to alcohol 12. Benzoylation13of
12 afforded 13, which was converted to aldehyde 14 in
the presence of periodic acid14 at 0°C. Although di-
azomethane had been successfully employed to trans-
form aldehydes to methyl ketones in excellent yield,15
treatment of 14 with diazomethane provided a mixture
of complex products without formation of the desired
ketone despite our considerable efforts to optimize the
reaction conditions. In the event, we had to resort to
This work was supported by the National Natural
Science Foundation of China.
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