X. Li et al. / Tetrahedron Letters 56 (2015) 3220–3224
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Scheme 4. Selective synthesis of four requisite epoxides. Reagents and conditions:
MPM-series: (a) (1) MPM-Cl, La(OTf)3, or use 5 obtained from 4. (2) LiBH4. (3) TIPS-
Cl, imidazole (91% for 2 steps). (4) NaOH, MeOH (69%); (b) (1) p-TsCl, n-Bu2SnO (cat.
amount), then K2CO3. (2) TBAF. (3) TEMPO, NaClO (76% for 3 steps). MEM-series: (a)
(1) MEM-Cl, Hünig’s base (90%), and follow the reactions indicated for the MPM-
series.
Scheme 2. Retrosynthetic analysis of photo-mycolactone A1.
cyclopropanation of C to B, pioneered by Hodgson.10 With the prec-
edent given by Hodgson, we anticipate that the four diastereomers
of C at C40 and C60 should selectively yield the corresponding four
diastereomers of B—note the stereogenic centers at C120, C130, and
C150.11 We expect the four diastereomers of C to be obtainable
from the corresponding four stereoisomers of D, respectively. In
connection with this plan, we note that A and its stereoisomers
have already been converted into photo-mycolactones A1, A2, B1,
and B2, respectively.9
Our first task was to secure all of the possible stereoisomers of D
in a stereochemically-defined, optically active form. Initially, we
planned to apply asymmetric epoxidation or dihydroxylation on
an optically active mono-protected 2-allyl-2-methylpropane-1,3-
diol. However, we could not secure a practical route to the requi-
site substrate via a chemical or enzymatic resolution of racemic
mono-protected 2-allyl-2-methylpropane-1,3-diol.
We recognized the possibility that methylation of a suitably
functionalized c-lactone could predominantly yield a product syn-
thetically equivalent to 6a. However, for a practical reason, we
opted to take a slightly different approach. On protection and then
coupling with diethyl methylmalonate, (R)-3 gave c-lactone 7 as a
1.5:1 diastereomeric mixture, which was converted into a readily
separable mixture of primary alcohols 8 and 9 via hydrolysis of
ethyl ester, activation of the resultant acids, and then NaBH4 reduc-
tion. MPM protection of 8 and 9 gave the major and minor diaste-
reomers 5a and 6a obtained in the previous route. In addition, we
should note that the major and minor
c-lactone series were
interconvertible.14
With use of the same synthetic sequence, ent-8 and ent-9 were
obtained from (S)-glycidol.
We then studied a synthesis of D from commercially available
(R)- and (S)-glycidols (Scheme 3). After protection of the primary
alcohol, (R)-glycidol was treated with t-butyl propionate under
Scheme 4 summarizes the transformation of 8 into epoxide-
aldehyde 11a. After protection of the primary alcohol, 8a was
subjected to LiBH4 reduction, followed by TIPS protection and
then selective TBDPS deprotection,15 to yield diol 10a. 10a was
then converted into 11a in 3 synthetic steps, that is, (1) p-TsCl,
n-Bu2SnO (cat. amount), to activate selectively the primary alcohol
under the Martinelli protocol;16 (2) TBAF, to remove the TIPS-
protecting group; (3) TEMPO,17 to oxidize the resultant primary
alcohol to the aldehyde. Although unstable, 11a was isolated in
ca. 48% overall yield from 10a and fully characterized.
the condition reported by Taylor, to give
meric mixture.12 On treatment with LDA, then MPMOCH2Cl, 4 gave
a readily separable 4–6:1 diastereomeric mixture of -lactones. We
c-lactone 4 as a diastereo-
c
assumed that the alkylation took place preferentially from the con-
vex face of 4 and tentatively assigned the stereochemistry of the
major diastereomer as 5a, which was confirmed via an X-ray anal-
ysis of the 3,5-dinitrobenzoate derived from 5a.13
With use of the same sequence of reactions, 9, ent-8, and ent-9
were converted into the corresponding epoxide-aldehydes 12a,
ent-11a, and ent-12a, respectively. 1H and 13C NMR analysis dem-
onstrated that the four epoxide-aldehydes thus obtained were
stereochemically homogeneous and have no cross-contamination.
With four stereochemically-defined and -homogeneous epox-
ide-aldehydes in hand, we studied the final phase of synthesis
(Scheme 5). In order to test the feasibility of the key Hodgson cycli-
zation, we desired to have E-olefin epoxide such as 15a. To achieve
this goal, we chose the one-pot version of Julia olefination for two
reasons.18 First, this process is well validated for the stereoselec-
tive synthesis of E-olefins. Second, allyl alcohol 13, one of the syn-
thetic intermediates in our previous work, should serve as the
starting material for synthesis of the requisite aryl sulfone;7
indeed, benzothiazole sulfone 14 was uneventfully obtained
from 13.
The one-pot version Julia olefination of epoxide-aldehyde 11a
with benzothiazole sulfone 14 under a standard condition fur-
nished epoxide-E-olefin 15a in 86% yield. Epoxide 15a was found
to be relatively unstable, particularly under acidic conditions, yet
stable enough to isolate and characterize. A 1H and 13C NMR anal-
ysis confirmed that 15a was stereochemically homogeneous and
also that the newly formed olefin was E (J = 16.2 Hz).
Scheme 3. Selective synthesis of c-lactones 5a and 6a. Reagents and conditions: (a)
(1) TBDPS-Cl, imidazole. (2) MeCH2CO2Bu-t, LiHMDS, AlEt3, then p-TsOH (91%); (b)
LDA, ClCH2OMPM (71%), followed by SiO2-chromatography; (c) (1) Same as step a-
1. (2) MeCH(CO2Et)2, LiHMDS, AlEt3, then p-TsOH (88%); (d) (1) aq KOH. (2) ClCO2Et.
(3) NaBH4 (68%); (e) MPM-Cl, La(OTf)3 (87%).