A tandem synthesis of polypropionate chains. Highly stereo< selective construction of the C(13)-C(25) segment containing nine contiguous chiral centers of swinholides A-C based on the stereospecific methylation of y, 5-epoxy acrylates by trimethylaluminiu

Article abstract of DOI:10.1039/a908342a

The highly stereoselective synthesis of the common C(13)C(25) segment containing nine contiguous chiral centers of swinholides A-C and misakinolide A has been achieved by tandem methodology which involves the stereospecific methylation of y, o-epoxy acryl

Full text of DOI:10.1039/a908342a

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A tandem synthesis of polypropionate chains. Highly stereo-
selective construction of the C(13)–C(25) segment containing nine
contiguous chiral centers of swinholides A–C based on the stereo-
specific methylation of ꢀ,ꢁ-epoxy acrylates by trimethylaluminium
Hiroyuki Hayakawa and Masaaki Miyashita*
Division of Chemistry, Graduate School of Science, Hokkaido University, Hokkaido 060-0810,
Japan
Received (in Cambridge, UK) 13th September 1999, Accepted 19th October 1999
The highly stereoselective synthesis of the common C(13)–
C(25) segment containing nine contiguous chiral centers of
swinholides A–C and misakinolide A has been achieved
by tandem methodology which involves the stereospecific
methylation of ꢀ,ꢁ-epoxy acrylates with trimethyl-
aluminium and the novel reductive cleavage of an epoxy
aldehyde with an organoselenium reagent as key steps.
attention from synthetic organic chemists.4,5 As part of our syn-
thetic program toward the polypropionate-derived bioactive
compounds possessing characteristic sequences of alternating
methyl- and hydroxy-substituted carbons,6 we set about asym-
metric total synthesis of the swinholide family. We report here
the highly stereoselective construction of the common C(13)–
C(25) segment of swinholides A–C (1–3) and misakinolide A
(4) containing nine contiguous chiral centers by the tandem
methodology which involves the stereospecific methylation of
γ,δ-epoxy acrylates with trimethylaluminium7 and the novel
reductive cleavage of an epoxy aldehyde with an organo-
selenium reagent as key steps.
The marine natural products swinholides A (1), B (2) and C (3),
The starting material 5, a chiral α-epoxy alcohol easily avail-
able from (S)-3-benzyloxy-2-methylpropanol,8 was subjected
to Swern oxidation followed by Horner–Emmons reaction
with triethyl phosphonoacetate to give the γ,δ-epoxy acrylate
6† in 88% yield, Scheme 1. Upon treatment of 6 with excess
trimethylaluminium in the presence of water in dichlorometh-
ane at Ϫ30 ЊC,7 methylation took place at the γ-position with
complete regio- and stereo-selectivity to afford the alcohol 7 as
the sole product in 92% isolated yield. No isomeric products
were formed. After protection of the hydroxy group of 7 with
chlorotriethylsilane (TESCl), reduction of the ethyl ester with
diisobutylaluminium hydride (DIBAL-H) gave the allylic alco-
hol 8, which was subjected to epoxidation with MCPBA in
dichloromethane to furnish the desired β-epoxy alcohol 9 as the
sole product in 76% overall yield. As we have recently reported,9
epoxidation of such a 4-methyl-5-(triethylsilyl)oxyallyl alcohol
system with MCPBA in dichloromethane occurs highly stereo-
selectively from the opposite side of the C(5) triethylsilyloxy
group regardless of the stereochemistry of an adjacent methyl
group. The β-epoxy alcohol 9 thus obtained was transformed
into the γ,δ-epoxy ester 10 by Swern oxidation followed
by Horner–Emmons reaction in 94% yield. After removal of
the triethylsilyl group of 10 with tetrabutylammonium fluoride
(Bu4NF) in THF, the resulting epoxy acrylate 11 was subjected
again to the crucial methylation reaction. Thus, the treatment
of 11 with excess trimethylaluminium in the presence of
water at Ϫ30 ЊC produced the dihydroxy ester 12 having five
contiguous chiral centers in 97% isolated yield. In this case
too, the methylation reaction occurred in complete diastereo-
selectivity.
The dihydroxy ester 12 was transformed into the allylic alco-
hol 13 by the same sequence of reactions for 7 to 8: protection
of the hydroxy groups with TESCl followed by reduction with
DIBAL-H. Subsequent epoxidation of 13 with MCPBA in
dichloromethane gave a single α-epoxy alcohol 14, as expected
(vide supra),9 in 85% overall yield from 12. The epoxy alcohol 14
thus obtained was converted to the epoxy aldehyde 15 by Swern
oxidation, which was submitted to the regioselective reductive
cleavage of an epoxide, a crucial step in the present synthesis,
in order to lead to the β-hydroxy aldehyde 16. Although the
reductive cleavage of an epoxide in the presence of an aldehyde
seems very difficult, this key step was overcome by the organo-
44-membered dimeric macrolides, isolated from the Okinawan
marine sponge Theonella swinhoei,1 and misakinolide A (4), a
40-membered dimeric lactone, isolated from another Okinawan
marine sponge Theonella,2 have been revealed to exhibit potent
cytotoxicity against a variety of human carcinoma cell lines,
as well as broad-spectrum antifungal activity.1–3 The stereo-
structures of the monomeric units of swinholide A and mis-
akinolide A are remarkably similar to one another and only
the number of double bonds connected to a carboxy group is
different. The structures of these families are characterized by
the C2-symmetrical dimeric macrolides in which two poly-
propionate-derived chains including a gigantic lactone ring
are axially oriented on a tetrahydropyran ring. Their unique
structures and potent anticancer activities have elicited much
J. Chem. Soc., Perkin Trans. 1, 1999, 3399–3401
This journal is © The Royal Society of Chemistry 1999
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Scheme 1 Reagents and conditions: i, (COCl)2, DMSO, CH2Cl2, Ϫ78 ЊC, then Et3N; ii, (EtO)2POCH2CO2Et, NaH, THF, 0 ЊC, then aldehyde at
0 ЊC; iii, (CH3)3Al (10 equiv.), H2O (6 equiv.), CH2Cl2, Ϫ30 ЊC; iv, TESCl, ImH, DMAP, CH2Cl2; v, DIBAL-H, THF, 0 ЊC; vi, MCPBA, CH2Cl2, 0 ЊC;
vii, Bu4NF, THF; viii, Na[PhSeB(OEt)3], CH3CO2H, EtOH, 0 ЊC.
Scheme 2 Reagents and conditions: i, TESCl, ImH, DMAP, CH2Cl2; ii, DIBAL-H, THF, 0 ЊC; iii, Ti(OiPr)4, -(ϩ)-DET, TBHP, CH2Cl2, Ϫ23 ЊC; iv,
(COCl)2, DMSO, CH2Cl2, Ϫ78 ЊC, then Et3N; v, (EtO)2POCH2CO2Et, NaH, THF, 0 ЊC, then aldehyde at 0 ЊC; vi, Bu4NF, THF, 0 ЊC; vii, (CH3)3Al
(10 equiv.), H2O (6 equiv.), CH2Cl2, Ϫ30 to 10 ЊC; viii, TESOTf, 2,6-lutidine, CH2Cl2; ix, MCPBA, CH2Cl2, 0 ЊC.
selenium-mediated reduction methodology recently developed
by us.10 Thus, the reductive cleavage of the epoxy aldehyde 15
by the use of sodium (phenylseleno)triethylborate10 (3 equiv.)
and acetic acid (3 equiv.) in ethanol occurred cleanly and regio-
selectively giving rise to the desired β-hydroxy aldehyde 16,
which was directly subjected to Horner–Emmons reaction with
triethyl phosphonoacetate to afford the unsaturated ester 17 in
82% overall yield for the 3 steps. After protection of a hydroxy
group in 17 with TESCl, Scheme 2, the resulting ester 18
was converted to the α-epoxy alcohol 19 by treatment with
DIBAL-H followed by the Katsuki–Sharpless asymmetric
epoxidation with -(ϩ)-diethyl tartrate (78% for the 3 steps).
The α-epoxy alcohol 19 thus obtained was transformed into the
γ,δ-epoxy acrylate 20 again by a similar three-step reaction
sequence: 1) Swern oxidation; 2) Horner–Emmons reaction
with triethyl phosphonoacetate; 3) removal of the TES group
with Bu4NF, in 74% overall yield. The resulting epoxy acrylate
20 was subjected to a third methylation with trimethylalumin-
ium. The reaction took place again with complete diastereo-
selectivity to yield the trihydroxy ester 21 as the sole product,
albeit in modest yield (44%, 60% yield based on the consumed
substrate). In this way, the segment 21 having eight chiral
centers was efficiently and straightforwardly synthesized by
repeating three times the key methylation reaction with tri-
methylaluminium. Introduction of an asymmetric center at the
C(13) position was accomplished as follows. Protection of the
four hydroxy groups in 21 with triethylsilyl trifluoromethane-
sulfonate (TESOTf) and 2,6-lutidine in dichloromethane
resulted in the formation of a nearly quantitative yield of 22,
which was submitted to reduction with DIBAL-H followed by
oxidation with MCPBA to give a single β-epoxy alcohol 23, the
target molecule, in 69% overall yield. In this case too, epoxid-
ation with MCPBA occurred in complete diastereoselectivity
same as for 8 and 13.
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Smith, J. Am. Chem. Soc., 1994, 116, 9391; A. P. Patron, P. K.
In summary, a highly stereoselective synthesis of the com-
mon C(13)–C(25) segment containing nine contiguous chiral
centers of swinholides (1–3) and misakinolide A (4) has been
achieved by the tandem strategy which involves the stereo-
specific methylation of γ,δ-epoxy acrylates with trimethylalu-
minium and the regioselective reductive opening of an epoxy
aldehyde as key steps. It should be noted that the construction
of all the nine chiral centers in the target molecule 23 has
been achieved with complete stereoselectivity in the present
synthesis.
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 Stereo-
chemistry) from the Ministry of Education, Science, Sports and
Culture of Japan.
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† All new compounds exhibited satisfactory spectra (1H and 13C NMR,
IR) and elemental analyses.
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Communication 9/08342A
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