An efficient and stereoselective construction of the C(9)-C(17) dihydropyran segment of swinholides A-C via a novel reductive cleavage of an epoxy aldehyde

Article abstract of DOI:10.1016/S0040-4039(99)02169-3

An efficient and highly stereoselective construction of the C(9)-C(17) dihydropyran segment of swinholides A-C, which involves a novel reductive cleavage of an epoxy aldehyde by an organoselenium reagent and the intramolecular conjugate addition of an ace

Full text of DOI:10.1016/S0040-4039(99)02169-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 707–711
An efficient and stereoselective construction of the C(9)–C(17)
dihydropyran segment of swinholides A–C via a novel reductive
cleavage of an epoxy aldehyde
Hiroyuki Hayakawa and Masaaki Miyashita ∗
Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
Received 27 September 1999; accepted 12 November 1999
Abstract
An efficient and highly stereoselective construction of the C(9)–C(17) dihydropyran segment of swinholides
A–C, which involves a novel reductive cleavage of an epoxy aldehyde by an organoselenium reagent and the
intramolecular conjugate addition of an acetal alkoxide anion of δ-hydroxy-α,β-unsaturated ester as the key steps,
is described. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: swinholides; pyrans; stereocontrol; reduction; epoxides; aldehydes.
The marine natural products swinholides A (1), B (2) and C (3), 44-membered dimeric macrolides
isolated from the Okinawan marine sponge Theonella swinhoei,1 have been revealed to exhibit potent
cytotoxicity against a variety of human carcinoma cell lines, as well as a broad spectrum of antifungal
activity.1–3
Their structures are characterized by the C2-symmetrical dimeric macrolides in which two
polypropionate-derived chains, including a gigantic lactone ring, take axial orientation on a
tetrahydropyran ring. Their unique structures and potent anticancer activities have elicited much
attention from synthetic organic chemists.4,5
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02169-3
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708
As part of our synthetic program toward the polypropionate-derived bioactive compounds possessing
characteristic sequences of alternating methyl- and hydroxyl-substituted carbons,6 we undertook asym-
metric total synthesis of the swinholide family. We report here an efficient and highly stereoselective
synthetic route to the C(9)–C(17) dihydropyran segment of swinholides A–C (1–3) which involves the
chemo- and regio-selective reductive cleavage of an epoxy aldehyde by an organoselenium reagent and
the intramolecular conjugate addition of an acetal alkoxide anion of δ-hydroxy-α,β-unsaturated ester as
the key steps.
The starting material 4, a chiral allylic alcohol easily available from (S)-3-benzyloxy-2-
methylpropanol,7 was subjected to the Katsuki–Sharpless asymmetric epoxidation8 with D-(−)-ethyl
tartrate to give the β-epoxy alcohol 5 in 83% yield (Scheme 1). The resulting alcohol 5 was converted to
the epoxy aldehyde 6 by Swern oxidation, which was directly submitted to the regioselective reductive
cleavage of an epoxide, a key step in the present synthesis, in order to lead to the β-hydroxy aldehyde
7. Although the reductive cleavage of an epoxide in the presence of an aldehyde function seems very
difficult, this key step was carried out by the organoselenium-mediated reduction methodology recently
developed by us.9 Thus, on treatment of the epoxy aldehyde 6 with sodium (phenylseleno)triethylborate9
(5 equiv.), a selenium reagent easily prepared by reduction of diphenyldiselenide with sodium
borohydride in ethanol, and acetic acid (7 equiv.) in ethanol at 0°C for 1 h, chemoselective reductive
cleavage of the epoxide occurred cleanly and regioselectively, giving rise to the desired β-hydroxy
aldehyde 7, which was directly subjected to Horner–Emmons reaction with triethyl phosphonoacetate
to afford the δ-hydroxy-α,β-unsaturated ester 8 in 90% isolated yield for the three steps. Subsequent
conversion of 8 into the benzylidene acetal 9 was successfully performed according to the Evans
protocol,10 namely, by treatment with benzaldehyde and t-BuOK in THF at 0°C, in 79% yield. The
acetal ester 9 thus obtained was transformed into the cis-unsaturated ester 11 by a three-step reaction
sequence: (i) reduction with lithium aluminum hydride in Et2O; (ii) Swern oxidation; (iii) Z-selective
Horner–Emmons reaction of the resulting aldehyde 10 with ethyl (di-o-tolylphosphono)acetate, the
Ando reagent11 in 92% overall yield. In this Horner–Emmons reaction, the desired cis-unsaturated ester
11 was exclusively formed.
With the key intermediate 11 in hand, we presumed that subsequent lactonization to 12 would readily

709
Scheme 1. Reagents: (i) Ti(OiPr)4, D-(−)-DET, TBHP, CH2Cl2, −20°C; (ii) (COCl)2, DMSO, CH2Cl2, −78°C, then Et3N; (iii)
Na[PhSeB(OEt)3] (5 equiv.), AcOH (7 equiv.), EtOH, 0°C; (iv) (EtO)2P(O)CH2CO2Et, NaH, THF, 0°C, then aldehyde, 0°C;
(v) C6H5CHO, t-BuOK, THF, 0°C; (vi) LiAlH4, Et2O, 0°C; (vii) (o-CH3C6H4O)2P(O)CH2CO2Et, NaH, THF, −78∼0°C; (viii)
80% aq. AcOH, 60°C, 12 h; (ix) DIBAL-H, CH2Cl2, −78°C, then CSA in MeOH; (x) KH, CH3I, THF, 0°C∼rt
occur under normal hydrolytic conditions. However, this conversion was found to be susceptible to
the hydrolytic conditions since the lactone 12 formed in situ was readily transformed into the bicyclic
compound 14 under the conditions by way of the intramolecular conjugate addition of the hydroxyl
group. Therefore, we investigated minutely the conditions for lactonization. The results are listed in Table
1. As shown, the conversion of 11 to 12 was found to be highly dependent on the reaction temperature as
well as the reaction time. Eventually, we found that the reaction conditions in entry 4 were optimal for
the present lactonization, resulting in the formation of 90% isolated yield of the hydroxy lactone 12.
Conversion of 12 to the target molecule 16 was successfully performed by the following two-step
reaction sequence: (i) reduction with diisobutylaluminum hydride (DIBAL-H) in CH2Cl2 followed by
treatment with methanolic 10-camphorsulfonic acid; (ii) methylation with potassium hydride and MeI
in THF, in 85% overall yield. The product was a 4:1 anomeric mixture. Thus, an efficient and highly
stereoselective synthetic route to the C(9)–C(17) dihydropyran segment of swinholides A–C (1–3) has
been established.12 Stereoselective alkylation at the C(9) position has been reported by several groups.4,5

710
Table 1
Reaction of 11 with 80% aq. AcOH
The present method should also provide a facile entry to a variety of δ-hydroxy-α,β-unsaturated esters
and 1,3-syn-polyols as well as syn-7-hydroxy-α,β-unsaturated-δ-lactones.
Acknowledgements
This work was supported by a Grant-in-Aid for JSPS Fellows (no. 2709) and a Grant-in-Aid for
Scientific Research on Priority Areas (no. 706: Dynamic Control of Stereochemistry) from the Ministry
of Education, Science, Sports and Culture of Japan.
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1
12. Compound 12: H NMR (270 MHz, CDCl3): 0.95 (3H, d, J=7.2 Hz), 1.73 (1H, ddd, J=13.9, 7.3, 3.1 Hz), 1.95 (1H, m),
2.05 (1H, ddd, J=13.9, 10.1, 5.6 Hz), 2.44 (2H, m), 2.94 (1H, d, J=4.6 Hz), 3.51 (1H, dd, J=8.9, 6.6 Hz), 3.60 (1H, dd,
J=8.9, 4.3 Hz), 3.99 (1H, dddd, J=7.4, 5.6, 4.6, 3.1 Hz), 4.51 (2H, s), 4.69 (1H, dddd, J=10.1, 7.3, 6.9, 5.9 Hz), 6.02 (1H, dt,
J=9.7, 1.8 Hz) and 6.88 (1H, ddd, J=9.7, 5.2, 3.2 Hz).