In silico inspired total synthesis of (-)-dolabriferol

Article abstract of DOI:10.1002/anie.201109080

Going retro: The diazabicycloundecane-induced retro-Claisen rearrangement of a linear precursor serves as the key step to form the hindered ester of the polypropionate dolabriferol (1, see scheme, PMB=p-methoxybenzyl, PMP=p-methoxyphenyl, TES=triethylsilyl). The rearrangement is thought to mimic the biosynthetic formation of 1. Copyright

Full text of DOI:10.1002/anie.201109080

Angewandte
Chemie
DOI: 10.1002/anie.201109080
Biomimetic Synthesis
In Silico Inspired Total Synthesis of (À)-Dolabriferol**
Russell H. Currie and Jonathan M. Goodman*
Dolabriferol (1) is a noncontiguous polypropionate isolated
from the anaspidean mollusc Dolabrifera dolabrifera.[1] Ever
since its initial discovery in 1996 by Gavagnin and co-workers,
dolabriferol has attracted significant synthetic interest.[2] The
challenging esterification had not been reported in synthetic
approaches towards dolabriferol,[2a,b,d] until the first total
synthesis reported by Vogel and co-workers.[2e]
The unusual connectivity of this highly substituted
polypropionate ester might originate either biosynthetically[1]
Scheme 2. Retrosynthesis—main disconnections. Tf=trifluoro-
methanesulfonyl.
or during isolation[3] through a mild base- or acid-catalyzed
retro-Claisen rearrangement of the intermediate hemiacetal 2
(Scheme 1). Recent computational work in our group has
shown this rearrangement to be an energetically favorable
pathway.[4]
ketoimide,[6] lactate aldol,[7] and MacMillanꢀs organocatalytic
cross-aldol[8] methodology.
A rapid and scalable synthesis of the C1 to C9 fragment
proceeded through exploitation of Evans b-ketoimide aldol
methodology (Scheme 3). Addition of the lithium enolate of
N-propionyl oxazolidinone (4) to propionyl chloride rapidly
Scheme 1. Proposed biosynthetic pathway.
Encouraged by the results of our calculations and the
related synthetic achievements of Perkins et al.,[2c] our retro-
synthetic planning (Scheme 2) focused on investigating and
replicating the rearrangement of such a linear precursor (3).
We anticipated that such a route would offer not only a robust
construction of the sensitive and hindered ester linkage, but
also offer significant insight into the biological construction of
noncontiguous polypropionates.
In line with our plan, the linear precursor 3 would be
assembled by a Sn(OTf)2-mediated aldol[5] coupling of two
fragments (C1 to C9 and C10 to C21). These two fragments
would be assembled by a combination of robust Evans b-
Scheme 3. Reagents and conditions: a) EtCOCl, LDA, MgBr2·Et2O,
À788C, THF, 52%; b) TiCl4, EtN(iPr)2, CH2Cl2, EtCHO, À788C, 92%;
c) Me4NBH(OAc)3, AcOH, MeCN, RT, 83% over 2 steps from 5;
d) PMP-CH(OMe)2, TsOH, 1.2 torr, 408C, 81%; e) LiBH4, MeOH, THF,
08C to RT, 78%; f) (COCl)2, DMSO, CH2Cl2, À788C, then Et3N.
Bn=benzyl, DMSO=dimethylsulfoxide, LDA=lithium diisopropyl-
amide, PMP=p-methoxy phenyl, THF=tetrahydrofuran, Ts=4-tolue-
nesulfonyl.
[*] R. H. Currie, Dr. J. M. Goodman
afforded the b-ketoimide 5 in high d.r. (24:1). Generation of
the titanium enolate of 5,[9] and subsequent addition to
propionaldehyde smoothly afforded 6 in 92% yield. Hydroxy
directed reduction of the unpurified 6 under Evans–Sak-
sena[10] conditions afforded the 1,3-anti-diol 7 in higher yields
than a separate two step procedure.
The highest yielding reaction conditions for the formation
of the strained anti-PMP acetal 8 were solvent free, thus
involving the in vacuo removal of methanol.[11] LiBH4
Unilever Centre for Molecular Science Informatics
Department of Chemistry, University of Cambridge
Lensfield Road, Cambridge CB2 8PH (UK)
E-mail: jmg11@cam.ac.uk
[**] Financial support for this work was provided by the EPSRC. We wish
to thank the EPSRC National Mass Spectrometry Service (Swansea)
for mass spectra.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201109080.
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cleavage of the auxiliary using the reaction conditions
reported by Li and Hale[12] cleanly afforded the alcohol 9.
Swern oxidation of 9 afforded the key C1 to C9 coupling
partner 10.
The diol 11, was derived by modification of the organo-
catalytic proline aldol protocol reported by Northrup and
MacMillan[8] using a one-pot NaBH4 reduction[13] (Scheme 4).
Scheme 5. a) Sn(OTf)2, Et3N, CH2Cl2, À788C, 83%; b) DMP, NaHCO3,
RT, CH2Cl2, 85%; c) HF·Py, Py, THF, RT; d) DBU, PhH, RT, 76%.
DMP=Dess–Martin periodinane, DBU=diazabicycloundecane,
Py=pyridine.
Scheme 4. a) PMP-CH(OMe)2, cat. TsOH, 1.2 torr, RT, 88%; b) DIBAL,
À108C, CH2Cl2, 98%; c) (COCl)2, DMSO, CH2Cl2, À788C, then Et3N;
d) Cy2BCl, À78 to À178C, Et3N, CH2Cl2, 69%; e) TESOTf, 2,6-lutidine,
CH2Cl2, À78 to 08C, 92%; f) SmI2, THF, MeOH, 08C, 94%. Cy=cyclo-
hexyl, DIBAL=diisobutylaluminum hydride, TES=triethylsilyl.
Formation of the PMP acetal 12 under acidic conditions
proceeded best when conducted neat and with the removal of
methanol. Regioselective cleavage of the PMP acetal with
DIBAL afforded the primary alcohol 13, and subsequent
Swern oxidation afforded the aldehyde 14. Addition of the
aldehyde to the E-boron enolate of the lactate 15 afforded the
aldol adduct 16, with the auxiliary overturning the inherent
Felkin bias of the aldehyde.[14] Protection of 16 as the silyl
ether (17), and subsequent SmI2 cleavage of the benzoate[15]
afforded the C10 to C21 fragment 18.
Union of the C1 to C9 fragment (10) and the C10 to C21
fragment (18) was achieved using the tin enolate of 18, thus
affording 19 in excellent yield and high d.r. (12.6:1;
Scheme 5).[5] The stereochemistry of 19 is tentatively assigned
based on similar reactions.[5,16] Oxidation of the C9 hydroxy
group afforded the desired linear precursor 20. There was no
evidence of the enol tautomer of the diketone in the 1H NMR
spectrum, and no epimerization at the stereogenic center at
C10 was observed. Removal of the silyl ether with HF/Py
followed by treatment with DBU[17a,b] effected the retro-
Claisen rearrangement, thus giving the desired connectivity
(21), whilst leaving the labile PMP acetal intact.
Scheme 6. a) CSA, MeOH, RT, 80%; b) DMP, NaHCO3, RT, CH2Cl2,
64%, c) DDQ, pH Buffer 7, CH2Cl2, RT, 49%. CSA=(Æ)-10-camphor-
sulfonic acid, DDQ=2,3-dichloro-5,6-dicyanobenzoquinone.
removal of the PMB protecting group in 46% yield to afford
the title compound dolabriferol (1).
This sequence constitutes the first biomimetic total syn-
thesis of dolabriferol, in 4.0% yield and 15 steps from
propionaldehyde. By completing this route, we have demon-
strated that a retro-Claisen rearrangement of a 1,3-diketone is
a feasible route for the biosynthetic formation of dolabriferol
and similar noncontiguous polypropionates.
Received: December 22, 2011
Published online: March 29, 2012
Keywords: aldol reaction · asymmetric synthesis ·
.
biomimetic synthesis · natural products · polyketides
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