Communications
(chemoenzymatic or chromatographic separation of derived
unexpected,[11] and we decided to employ two consecutive
Claisen rearrangements to install the quaternary center. The
rearrangement was expected to occur on the sterically more
accessible face of the olefin, which is differentiated by the
presence of the pendant alkyl chain at C(6). Alkylation of the
potassium enolate with tosylate 9 (prepared in 4 steps from
(R)-cyclohex-2-enol, see the Supporting Information) in the
presence of [18]crown-6 afforded the corresponding enol
ether 10 in 89% yield. Gratifyingly, thermal rearrangement in
strictly degassed nonane at 1558C afforded ketone 11 in good
yield (d.r. = 10:1. 86%).[12] It is worth noting that although the
stereogenic centers at C(9) and C(10) in ketone 11 are absent
in the natural product, dramatic differences were observed in
the behavior of the various diastereoisomers in the subse-
quent allylation reaction (11!12). For example, the ketone
analogous to 11 but epimeric at C(10) was wholly unproduc-
tive.
Ketone 11 was subjected to allylation with KHMDS
(Scheme 4), [18]crown-6, and allyl bromide to give the
corresponding allyl enol ether (83%), which in turn under-
went a rearrangement at 1658C in o-xylene to afford ketone
12 as the only isolable compound in 40% yield. The poor mass
balance is caused by the formation of significant amounts of
polymeric material during the reaction. Hydroboration/oxi-
dation (9-BBN, then NaBO3·4H2O) of the sterically more
accessible olefin in 12 afforded a primary alcohol (60%),
which was acetylated (Ac2O, DMAP) and treated with TBAF
to remove the TBDPS group (86% over 2 steps). Dehydra-
tion of the unveiled primary alcohol according to Griecoꢀs
protocol[13] afforded olefin 13 (94%) and set the stage for
exploring ways for the installation of the stereogenic center at
C(18) and generation of a suitable precursor for the amine
found in daphmanidin E.
diastereomers)[4a,b] of the racemate, which is readily available
in a one-pot operation from diethyl succinate.[5] The inherent
C2 symmetry of 3 renders the ketones homotopic; conse-
quently, subsequent elaboration of 3 only necessitates oper-
ation on one ketone.[4c] Exhaustive ketalization of 3 with 1,3-
propanediol followed by hydrolysis afforded monoketal 4 in
88% yield. This compound was then converted into enol
triflate 5 by quenching the corresponding potassium enolate
with Cominsꢀ reagent[6] (87%). B-alkyl Suzuki cross-coupling
=
with the borane generated from 9-BBN and H2C
CHCH2OTBDPS proceeded smoothly in the presence of
[Pd2(dba)3] (2 mol%), AsPh3 (16 mol%), and K3PO4 in DMF
at 458C to afford 6 in excellent yield (89%).[7] The addition of
AsPh3 was crucial to suppress the reductive detriflation of 5
which was observed (up to 30%) when using standard
phosphine ligands such as dppf (1,1’-bis(diphenylphospha-
nyl)ferrocene) or PPh3.
The diastereoselective hydroboration of 6 was slow and
required a high concentration (ꢁ 1m BH3 in THF) and excess
of BH3 to proceed at a reasonable rate.[8] Under these
conditions we observed the partial reduction of the carboxylic
ester at C(18). Given that the esters must ultimately undergo
reduction, we decided to subject the mixture obtained after
oxidative workup[9] to excess DIBAL to afford triol 7 as a
single diastereoisomer (72% over 2 steps). X-ray crystallo-
graphic analysis of 7 verified the facial selectivity of the
hydroboration and the correct relative configuration at C(6)
and C(7).[10] The hydroxy groups were differentiated by
masking the 1,3-diol as an acetonide (acetone, pTsOH) with
concomitant hydrolysis of the 1,3-dioxane moiety. Finally,
protection of the remaining primary alcohol with benzoyl
chloride afforded 8 in 95% yield over 2 steps.
With ketone 8 in hand, the installation of the quaternary
center at C(8) was investigated (Scheme 4). Preliminary
studies indicated that O-alkylation of the enolate with allyl
electrophiles was preferred under all the conditions exam-
ined. This behavior of sterically congested enolates was not
Extensive experimentation on model systems revealed
that conjugate addition of a methyl carbanion to a nitroalkene
15 would constitute a viable way to install the stereogenic
center at C(18) (Scheme 5). The required nitroalkene 15 was
accessed by hydrolysis of the acetonide in 13 (CeCl3·xH2O,
oxalic acid, 98%),[14] differentiation of the primary and
secondary alcohols (90% overall yield),[15] and oxidation to
form aldehyde 14 (DMP, 99%).[16] A subsequent Henry
condensation of 14 with nitromethane was found to be
surprisingly difficult, but could be brought about by heating
14 in the presence of NH4OAc in MeNO2 (75%).[17] Most of
the established procedures failed to induce dehydration of the
Henry adduct to 15. Model studies showed that when
nitroalkenes similar to 15 were subjected to ZnMe2/CuCN·-
(LiCl)2 or other reagent combinations,[18] addition products
were routinely formed as a mixture of isomers (3:1–1:9) in
favor of the undesired epimer. The inherent preference of the
substrate for the undesired diastereomer at C(18) could be
overridden by external reagent/catalyst control. Treatment of
15 with Me2Zn and 20 mol% of the catalyst generated in situ
from [Cu(OTf)]2·toluene and L1[19] in toluene at ꢀ30–08C
afforded 16 in 90% yield as a 5:1 mixture of epimers, as
Scheme 4. Reagents and conditions: a) KHMDS, [18]crown-6, 9, THF,
ꢀ208C, 89%; b) 1558C, nonane, d.r.=10:1, 86%; c) KHMDS,
[18]crown-6, allyl bromide, THF, ꢀ208C, 83%; d) o-xylene, 1658C,
40%; e) 9-BBN, THF, RT; then NaBO3·4H2O, 60% f) Ac2O, pyridine,
DMAP, CH2Cl2, RT; TBAF·3H2O, THF, RT, 86% g) 2-NO2-C6H4SeCN,
PBu3, THF, RT; H2O2, pH 7 buffer, CH2Cl2, RT, 94%. TBAF=tetra-n-
butyl ammonium fluoride.
1
determined by H NMR spectroscopy.
The mixture of epimers at C(18) in 16 could not be
separated by chromatography on silica gel at this stage.
Reduction of 16 with Zn/NH4Cl(aq) in EtOH[17] afforded an
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 11501 –11505