Angewandte
Communications
Chemie
This analyses converged upon (2R,3R,14R,15R,16S) as
the most likely configuration of natural rakicidin A,[11,12] and
we initially targeted this particular isomer. Recently, two
reports appeared, both claiming assignment of the con-
figuration of rakicidin A.[13,14] Through synthesis of a com-
pound with spectroscopic data matching those of the
natural product, Chen and co-workers arrived at
a (2S,3S,14S,15S,16R) configuration,[13] whereas Igarashi
and co-workers paradoxically concluded the stereochemistry
to be (2R,3R,14S,15S,16R) by direct degradation of the
natural product and comparison with authentic standards
(Figure 1A).[14] This latter assignment, however, was cor-
rected earlier this year to corroborate a (2S,3S,14S,15S,16R)
configuration for rakicidin A, and it was thus clear that our
initial synthesis in fact had targeted ent-rakicidin A. Herein,
we report our unique route to the natural isomer of
rakicidin A, along with biological evaluation and the discov-
ery of a simplified bioactive rakicidin A analogue.
Although we have previously demonstrated in a model
system that the APD group can be constructed directly by
a Horner–Wadsworth–Emmons (HWE) reaction between
a b-amidophosphonate and a 2-amidoacrolein-derivative,[10] it
was deemed too challenging to handle this sensitive function-
ality during several synthetic steps. Consequently, dehydra-
tion would be delayed to the final step of the synthesis
(Figure 1B).[15] Considering macrocyclization sites to access 2,
we finally opted for pursuing an intramolecular HWE
reaction for building the trans-C9–C10 double bond because
of the relatively unhindered setup and the potential templat-
ing effects of the required metalloenolate intermediate. The
cyclization precursor would be constructed by three fragment
couplings, the first of which being an intermolecular ester
coupling reaction[16] between a b-hydroxyaspartate-building
block 5 and the secondary carbinol of b-hydroxy ester 4. The
(14S,15S,16R) isomer of 4 constitutes an anti-aldol-Felkin
motif that should be accessible through asymmetric aldol
methodology. The threo-(2S,3S) enantiomer of b-hydroxyas-
partic acid can be accessed through a known enantioresolu-
tion of the commercial racemate.[17]
We first devised an efficient route from 1,12-dodecanediol
to chiral aldehyde 13 (Scheme 1). The first stereogenic center
at the C4 position of fragment 4 (C16 in 1) was installed
through an asymmetric methylation employing Evans (R)-
oxazolidinone.[18] This was followed by reductive cleavage of
the auxiliary and Parikh–Doering oxidation[19] to give enan-
tiopure aldehyde 13. Working initially on ent-4, we found that
an Oppolzer aldol reaction[20] using superstoichiometric TiCl4
could be employed to selectively prepare the desired anti-syn
stereotriad. In our hands, however, this method lacked
reproducibility, notably on a large scale, resulting occasionally
in drastically reduced yields and selectivity. Poor solubility of
13 at low temperature was a major issue. We therefore
considered alternatives,[21] and to our delight, we found that
the proline-catalyzed cross-aldol reaction[22] between propa-
nal and 13, despite the double stereocontrol, proceeded with
high diastereoselectivity. The typical yields ranged from 30–
40% after chromatography, however, owing to its operational
simplicity, relative step-economy, and cost-effectiveness, this
solution is superior to the Oppolzer aldol reaction sequence,
Scheme 1. Synthesis of b-hydroxyester 4. Reagents and conditions:
a) 48% aq. HBr (1.7 equiv), toluene, reflux, 65 h; b) iBuMgBr
(3.0 equiv), Li2CuCl4 (0.013 equiv), THF, À788C to RT, 100 min;
c) H5IO6 (3.0 equiv), CrO3 (0.012 equiv), aq. CH3CN, 08C to RT, 8 h;
d) PivCl (1.1 equiv), NEt3 (3.0 equiv), THF, 08C to RT, 50 min; then
DMAP (0.3 equiv), (R)-4-Benzyl-2-oxazolidinone (1.2 equiv), THF,
508C, 5 h; e) NaHMDS (1.2 equiv), THF, À788C, 1 h; then MeI
(5.0 equiv), À788C, 3 h; f) LiBH4 (2.0 equiv), MeOH (1.5 equiv), THF,
08C to RT, 7 h; g) SO3-Pyr (4.0 equiv), NEt3 (5.0 equiv), CH2Cl2/DMSO,
08C 1 h; h) propanal (2.0 equiv, syringe pump), l-proline (0.2 equiv),
DMF, 08C, 64 h; i) NaClO2 (4.0 equiv), isoamylene (10 equiv),
t-BuOH/H2O, 08C, 17 h; j) BnBr (2.5 equiv), K2CO3 (3.0 equiv), DMF/
CH2Cl2, RT, 48 h. iBuMgBr=isobutyl magnesium bromide, PivCl=pi-
valoyl chloride, DMAP=4-dimethylaminopyridine, NaHMDS=sodium
hexamethyldisilazide, Pyr=pyridine, THF=tetrahydrofuran, DMF=di-
methylformamide, DMSO=dimethylsulfoxide.
at least for this particular target structure. Pinnick oxidation
and benzyl ester formation completed an efficient route to b-
hydroxy ester 4.
Proceeding with the key ester coupling, we encountered
serious problems and came up short trying to achieve the
coupling between various protected forms of (2S,3S)-b-
HOAsn or (2S,3S)-b-HOAsp with hindered alcohol 4. We
had anticipated challenges in this reaction,[16] but not even
traces of product could be isolated. Searching for ways to
reduce steric crowding as much as possible, we discovered
that tying together the b-OH and b-COOH groups as a lactone
ketal[23] uniquely enabled reactivity in this coupling
(Scheme 2).
Angew. Chem. Int. Ed. 2016, 55, 1030 –1035
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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