A first convergent synthesis of the polyolic fragment of the antifungal pentaene macrolide strevertene A

Article abstract of DOI:10.1016/j.tetlet.2008.07.022

The C(4-14) polyolic segment of antifungal macrolide strevertenes has been synthesized for the first time in protected form, incorporating four stereogenic centers. The synthetic strategy developed is based on the connection of two subunits prepared start

Full text of DOI:10.1016/j.tetlet.2008.07.022

Tetrahedron Letters 49 (2008) 5455–5457
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Tetrahedron Letters
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A first convergent synthesis of the polyolic fragment of the antifungal
pentaene macrolide strevertene A
*
*
Carlo Bonini , Lucia Chiummiento , Maria Funicello, Paolo Lupattelli, Valeria Videtta
Dipartimento di Chimica, Università degli Studi della Basilicata, Via N. Sauro 85, 85100 Potenza, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The C(4–14) polyolic segment of antifungal macrolide strevertenes has been synthesized for the first time
in protected form, incorporating four stereogenic centers. The synthetic strategy developed is based on
the connection of two subunits prepared starting from the same chiral building block.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 26 May 2008
Revised 30 June 2008
Accepted 2 July 2008
Available online 6 July 2008
Keywords:
Strevertene A
1,3-syn Diol
Oxymercuration
Polyols
Macrolide
Strevertenes A–G, architecturally interesting antifungal polyene
macrolides, were isolated from fermentations with Streptoverticilli-
um sp. LL-30F848 in 1999.1 These natural products exhibit inhibi-
tory activity against ergosterol production, and are a magnitude
more potent than nystatin A, a clinically important drug. The major
product of this new family of pentaene macrolides, strevertene A,
as well as the complex, was determined to inhibit the growth of
phytopathogenic fungi with MIC’s between 5 and 25 lg/mL. How-
ever, the physicochemical liabilities of this class have precluded so
far further studies and developments. The absolute and relative
configuration of all the 10 stereogenic centers of strevertenes has
been subsequently established,2 and it is represented in the re-
ported structures (see Fig. 1).
Figure 1. Strevertenes’ A–G structures.
The intriguing structure, the low natural abundance, and their
clinical potential prompted us to develop a synthesis of the major
component, Strevertene A. Herein, we report a first convergent ste-
reocontrolled synthesis of the C(4–14) polyol fragment for strever-
tene A (1), appropriately functionalized for future incorporation
into the macrolide skeleton.
As shown in retrosynthetic analysis in Scheme 1, the key step
involves the assembly of C(4–9) segment and C(10–14) segment
by olefination reaction followed by chemoselective reduction of
the newly formed double bond.
This final assembly to the advanced C(4–14) fragment 2, a pseu-
do meso compound, was envisioned to involve coupling of alde-
hyde 3 with the anion derived from sulfone 4 or phosphonium
salt 5. Aldehyde 3, sulfone 4, and phosphonium salt 5, each pos-
sessing two stereocenters, would arise from functional group
transformation of the common parent compound 6. Consequently
6 can be prepared from the homoallylic alcohol 7 readily available
from commercial (S)-benzyl glycidyl ether (8) via cross-metathesis
reaction.
The synthetic strategy is based on our recently developed meth-
odologies: (a) the intramolecular oxymercuration on
a,b-unsatu-
rated esters3a for d-lactones syntheses and (b) the one-pot
functionalization of alcohols to sulfides and subsequently to
sulfones.4
* Corresponding authors. Tel.: +39 0971 202254; fax: +39 0971 202223 (C.B.);
tel.: +39 0971 202255; fax: +39 0971 202223 (L.C.).
E-mail addresses: bonini@unibas.it (C. Bonini), lucia.chiummiento@unibas.it
(L. Chiummiento).
Synthesis of compound 6 began with the addition of vinylmag-
nesium bromide to epoxide 8 to give the reported homoallylic
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.022

5456
C. Bonini et al. / Tetrahedron Letters 49 (2008) 5455–5457
Scheme 3. Synthesis of aldehyde 3.
Scheme 1. Retrosynthetic analysis of strevertene A.
Scheme 4. Synthesis of sulfone 4 and phosphonium salt 5.
accomplished by heating the iodide 16 with 10 equiv of triphenyl-
phosphine (22 h, 85 °C) to afford, after crystallization, quantitative
yield of the phosphonium salt in two steps.11
To obtain the key compound 2, we tried firstly the one-pot Julia
olefination12 with sulfone 4 in order to generate the C(9–10) dou-
ble bond (Scheme 5). The best conditions for obtaining compound
17 were found by using LiHMDS in DME at ꢀ78 °C in the presence
of 18-crown-6-ether, in a 35% yield and a E/Z ratio of 57:43.
When the olefination was carried out under the Wittig condi-
tions,13 the coupling between the ylide of salt 5 and the aldehyde
3 afforded compound 17 in low yield but with excellent stereose-
lectivity (17% of yield and only Z isomer). Unfortunately, high ster-
ical hindrance of precursors seems to limit this coupling
efficiency.14 However, finally chemoselective reduction of the
C(9–10) double bond on compound 17, performed with H2 on
Pd/C 10% in EtOAc in a good 75% yield, completed the synthesis
of the target compound 2.15
Scheme 2. Synthesis of tetrol 6.
alcohol 9 in high yield (Scheme 2).5 Treatment of 9 in a cross-
metathesis reaction, with methyl acrylate 10 and second genera-
tion Grubbs catalyst, afforded the expected compound 76 in high
yield and stereoselectivity (94% yield, E/Z >99:1).7 The 1,3-syn diol
moiety of tetrol 6 was introduced by the oxymercuration reaction3
on homoallylic alcohol 7, generating the mercurium diol 11 with
high diasteroselectivity. This adduct was subsequently reduced
with LiAlH4 in THF to afford alcohol 6 in 50% yield in two steps.8
The common tetrol 6 was converted into aldehyde 3 and sulfo-
nyl derivative 4 and the phosphonium salt analog 5 as shown in
Schemes 3 and 4. To this end, silylation of primary alcohol followed
by debenzylation of 12, using Pearlman’s catalyst in EtOAc, pro-
vided alcohol 13 in 69% yield.9 Aldehyde 3 was subsequently ob-
tained from 13 in quantitative yield according to Dess–Martin
oxidation conditions.10
The functionalization of compound 6 as sulfonyl or phospho-
nium salt was initiated with the one-pot iodination, and
subsequent nucleophilic substitution with heteroarylthiol (phen-
yltriazolylthiol PT-SH) (Scheme 4) afforded sulphur derivative 15
in quantitative yield. Oxidation of the thioether with m-CPBA affor-
ded sulfone 4 in very high yield (93% after column chromatogra-
phy).4 The alternative synthesis of the phosphonium salt 5 was
Scheme 5. Coupling reactions and synthesis of 2.

C. Bonini et al. / Tetrahedron Letters 49 (2008) 5455–5457
4. Bonini, C.; Chiummiento, L.; Videtta, V. Synlett 2005, 3067–3070.
5457
Studies to improve the final coupling reactions to the C(4–14)
polyol fragment 17 of strevertene A are ongoing in our laboratory.
In summary, we have achieved a convergent synthesis of com-
pound 2, an advanced C(4–14) polyol fragment toward the total
synthesis of natural macrolide strevertene A (1). Highlights of the
synthesis include the intramolecular oxymercuration–reduction
sequence with the direct formation of the protected syn 1,3-diol
and reductive demercuration to alcohol 6. This important building
block was prepared in only four steps in high yield and
diastereoselectivity.
5. Bonini, C.; Chiummiento, L.; Lopardo, M. T.; Pullez, M.; Colobert, F.; Solladié, G.
Tetrahedron Lett. 2003, 44, 2695–2697.
6. Pak, C. S.; Lee, E.; Lee, G. H. J. Org. Chem. 1993, 58, 1523–1530.
7. For recent reviews see: (a) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem.,
Int. Ed. 2005, 44, 4490–4527; (b) Schmidt, B.; Hermanns, J. Top. Organomet.
Chem. 2004, 7, 223–267; (c) Fuerstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012–
3043; (d) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413–4450.
8. For previous syntheses of alcohol 6 see: (a) Nicolaou, K. C.; Daines, R. A.;
Uenishi, J.; Li, W. S.; Papahatjis, D. P.; Chakraborty, T. K. J. Am. Chem. Soc. 1988,
110, 4672–4685; (b) Mohr, P. Tetrahedron Lett. 1992, 33, 2455–2458; (c)
Anderson, C. A.; Rychnovsky, S. D. Org. Lett. 2002, 4, 3075–3078; For ent-6 see:
(d) Escudier, J. M.; Baltas, M.; Gorrichon, L. Tetrahedron 1993, 49, 5253–5266;
(e) Solladié, G.; Hutt, J. Tetrahedron Lett. 1987, 28, 797–800.
Progress toward the total synthesis of strevertene A will be
reported in due course.
9. Hydrogenation of 12 with several protocols (Pd/C 5% and 10% in MeOH or in
EtOAc, PhSSiMe3 in CH2Cl2) gave always competitive deprotection of acetonide
or degradation of the substrate.
10. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–7287.
11. Phosphonium salt was prepared as reported: Paquette, L. A.; Chang, S.-K. Org.
Lett. 2005, 7, 3111–3114.
12. (a) Bonini, C.; Chiummiento, L.; Videtta, V. Synlett 2006, 2079–2082; (b)
Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563; (c) Baudin, J. B.;
Hareau, G.; Julia, S. A.; Lorne, R.; Ruel, O. Bull. Soc. Chim. Fr. 1993, 130, 336.
13. Wittig reaction was performed as reported for a similar aldehyde: Evans, D. A.;
Dow, R. L.; Shih, T. L.; Takacs, J. M.; Zahler, R. J. Am. Chem. Soc. 1990, 112, 5290–
5313.
Acknowledgment
Financial support was provided by USB.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.07.022.
14. Several reaction conditions were tested for the olefination. When KHMDS,
NaHMDS, and LiHMDS as bases in THF as solvent were used in Julia reaction,
nearly no conversion was observed. Instead when BuLi and LiHMDS were used
in THF for the Wittig reaction, only by-products were observed.
References and notes
15. Spectroscopic data of compound 2: ½a D20
ꢁ
+1.4 (c 0.97, CHCl3); 1H NMR (500 MHz,
CDCl3): d 7.66 (m, 5H), 7.40–7.34 (m, 10H), 4.62 (d, J = 12.5 Hz, 1H) 4.58 (d,
J = 12.5 Hz, 1H), 4.14–4.04 (m, 2H), 3.88–3.76 (m, 2H), 3.72–3.60 (m, 2H), 3.54–
3.46 (m, 1H), 3.42–3.34 (m, 1H), 1.73–1.67 (m, 4H), 1.46, 1.44, 1.43, 1.42 (4s,
12H), 1.05, 0.94–0.82 (m, 8H); 13C NMR (100 MHz, CDCl3): d 138.2, 135.5,
134.0, 133.9, 129.7, 129.6, 128.4, 127.8, 127.6, 127.6, 125.5, 98.5, 98.4, 73.7,
73.5, 68.8, 68.6, 68.5, 65.7, 59.7, 39.3, 37.1, 36.3, 33.8, 31.9, 30.3, 29.7, 26.8,
22.7, 20.3, 19.8, 19.2. Anal. Calcd for C41H58O6Si: C, 72.96; H, 8.66. Found: C,
72.98; H, 8.68.
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