Synthesis of membranacin

Article abstract of DOI:10.1055/s-2004-825624

The synthesis of the Annonaceous acetogenin membranacin (2) has been achieved, using transition metal-oxo and transition metal-peroxy species in the key steps.

Full text of DOI:10.1055/s-2004-825624

LETTER
1437
Synthesis of Membranacin
S
ynthesis of Memb
e
ranacin offrey D. Head,a William G. Whittingham,b Richard C. D. Brown*a
a
School of Chemistry, University of Southampton, Highfield, Southampton S017 1BJ, UK
Fax +44(23)80596805; E-mail: rcb1@soton.ac.uk
b
Syngenta, Jealott’s Hill International Research Centre, Bracknell RG42 6EY, UK
Received 17 March 2004
With best wishes to Professor Clayton Heathcock upon his retirement from U.C. Berkeley
functionality to permit further elaboration. The lactone
ring would later facilitate introduction of the left hand
alkyl chain or the second THF ring, depending on whether
mono- or bis-THF were to be the target. Here we describe
the successful application of this strategy to the synthesis
of membranacin (2), a cytotoxic anti-tumor acetogenin
isolated from the seeds of the fruit tree Rollinia mucosa.5
Abstract: The synthesis of the Annonaceous acetogenin mem-
branacin (2) has been achieved, using transition metal-oxo and
transition metal-peroxy species in the key steps.
Key words: oxidations, asymmetric synthesis, natural products,
manganese, total synthesis
Annonaceous acetogenins are a large class of natural
products isolated from certain plants belonging to the
family Annonaceae.1–3 Their structures are characterised
by a core region consisting of one or more saturated oxy-
gen heterocycles (THF/THP), usually flanked on both
sides by hydroxyalkyl groups (Figure 1). One of these
alkyl chains usually carries a butenolide group at its end,
and either or both of the chains may possess unsaturation
or hydroxylation along their length. Major interest in the
acetogenins stems largely from their cytotoxic anti-tu-
mour activity, although insecticidal properties have also
received attention.1
Scheme 1 Synthesis of mono- or bis-THF acetogenins from
lactone 3
The required triene starting material 4 was prepared using
established procedures prior to introduction of the (2S)-
10,2-camphorsultam auxiliary (Scheme 2).4 Permangan-
ate oxidation of 4 followed by treatment of the crude reac-
tion mixture with NaIO4–SiO2 proceeded efficiently to
afford a single isolated diastereoisomeric lactone 3 in high
yield.4,6–8
A combination of BH3·DMS and NaBH4 provided the
most effective conditions for the selective reduction of the
acylsultam functionality present in 3, returning diol 7 in
reasonable yield.9 Other reductive conditions typically
gave mixtures including over reduced compounds. Addi-
tion of the C3–C13 chain required chemoselective reac-
tion at C14 with a cuprate reagent, which was achieved
after conversion of diol 7 to the corresponding epoxide 8.
Figure 1 Examples of Annonaceous acetogenin natural products
During our programme to develop routes to acetogenins
and related analogues, the lactone 3 was identified as a
versatile precursor to both mono- and bis-THFs
(Scheme 1). We had previously shown that racemic lac-
tones related to 3 could be prepared in six steps from ethyl
acetoacetate and 1,4-dibromobut-2-ene.4 Extension of the
methodology to the synthesis of acetogenins would rely
on the diastereoselective oxidation of 4 to provide 3, fol-
lowed by chemoselective reduction of the acylsultam
Protection of alcohol 9 as its TBS ether and reduction of
the lactone ring gave the corresponding lactol 11, which
underwent trans-selective olefination affording a,b-un-
saturated ester 12 in excellent yield (Scheme 3). DIBALH
reduction of the ester gave the E-allylic alcohol substrate
13 for a highly diastereoselective Sharpless asymmetric
epoxidation and in situ THF ring closure to provide the
bis-THF diol core of the natural product.10 This second
oxidative cyclisation process produced a single diastereo-
SYNLETT 2004, No. 8, pp 1437–1439
0
1.
0
7.
2
0
0
4
Advanced online publication: 08.06.2004
DOI: 10.1055/s-2004-825624; Art ID: Y02304ST
© Georg Thieme Verlag Stuttgart · New York

1438
G. D. Head et al.
LETTER
smaller amount of the uncyclised regioisomer (isolated
dr = 4:1).3d,11 Selective reduction of the C4–C5 double
bond with diimide completed the synthesis, affording a
compound giving spectroscopic data consistent with those
of membranacin (2).5a
In conclusion, the total synthesis of membranacin (2) has
been completed using metal-oxo and metal-peroxy-medi-
ated oxidative cyclisations as the key steps. The lactone
intermediate 3 should also prove useful for the synthesis
of other acetogenins and acetogenin analogues.
Acknowledgment
We thank the EPSRC (GDH), Syngenta (GDH) and the Royal
Society (RCDB) for financial support.
References
Scheme 2 Reagents and conditions: (a) NaOH, NaHCO3, MeOH,
H2O, 80 °C; (b) (COCl)2, DMF, CH2Cl2, then (2S)-10,2-camphorsul-
tam, NaH, THF; (c) KMnO4 (2.6 equiv), adogen 464 (5 mol%), ace-
tone–HOAc (3:2); (d) NaIO4–SiO2, CH2Cl2; (e) BH3·SMe2, NaBH4,
THF then CH2Cl2–MeOH; (f) Bu2SnO, TsCl, TBAB, PhH; (g) DBU,
CH2Cl2; (h) undec-10-enylmagnesiumbromide, CuI, THF, –50 °C;
(i) TBDMS-Cl, imidazole, CH2Cl2; (j) DIBALH, THF.
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and 14 in a lower ratio (15:1, NMR). Repeating the se-
quence of 1° alcohol activation, epoxide formation and
cuprate addition completed the C3–C34 region of the nat-
ural product. The butenolide portion of membranacin (2)
was introduced using Trost’s ruthenium-catalysed Alder–
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Scheme 3 Reagents and conditions: (a) Ph3P=CHCO2Et, PhMe;
(b) DIBALH, THF; (c) L-(+)-DET, Ti(Oi-Pr)4, t-BuOOH, 4 Å sieves,
CH2Cl2; (d) Bu2SnO, TsCl, TBAB, PhH; (e) DBU, CH2Cl2; (f)
CH3(CH2)8MgBr, CuI, THF; (g) CpRu(cod)Cl, MeOH, reflux; (h)
TsNHNH2, NaOAc, THF, H2O, reflux.
Synlett 2004, No. 8, 1437–1439 © Thieme Stuttgart · New York

LETTER
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Synthesis of Membranacin
1439
(8) A single diastereoisomer 3 was isolated from the reaction
mixture, although oxidative cyclisation of similar substrates
has been found to proceed with a diastereoselectivity of
approximately 6:1.
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Synlett 2004, No. 8, 1437–1439 © Thieme Stuttgart · New York