Communication
macrolactonization reactions.[4d] In our preliminary
investigation of these precursors, low yields
were obtained when we tried to scale up
(~100 mg), which was presumably caused by the
competing ketene polymerization.[7g] To address this
issue, we explored the use of a thioester substrate VI
activated by a thiophilic metal salt,[8] allowing the
corresponding ketene to be generated under compa-
ratively mild conditions.
Figure 2. Retrosynthetic analysis of lynbyaloside C.
Synthesis of b-keto ester fragment 16 started from
the Mukaiyama aldol reaction of dienol ether 10 with
acrolein,[9] followed by Sharpless kinetic resolution,[10] to afford
chiral, non-racemic allylic alcohol 12. Desired ester 13 was ac-
cessed by trapping the acetylketene intermediate of 12 with
methanol. Utilization of intramolecular hydride delivery[11] pro-
vided the 1,3-anti diol, which was subsequently silylated to
afford ester 14. Reduction of the aforementioned ester with
DiBALH gave the corresponding aldehyde, which was then
treated with tert-butylthiol diazoacetate 15[12] in the presence
of tin(II) chloride to successfully afford b-keto-thioester 16
(Scheme 2).
With the two requisite building blocks of 1 in hand, we
turned our attention to developing a robust and scalable
ketene esterification reaction. After screening numerous condi-
tions, silver trifluoroacetate was found to affect gram-scale
one-pot intermolecular ketene esterification in which the terti-
ary ester and pyran are formed consecutively to afford 17
(Scheme 3). The formation of the methyl ketal was achieved by
refluxing with dry MeOH in the presence of citric acid, and
subsequent protection of the secondary alcohol provided
diene 18a. The ensuing RCM proceeded smoothly upon treat-
ment with Hoveyda–Grubbs 2nd generation catalyst[13] in the
presence of benzoquinone[14] to yield 19a exclusively as the E
isomer. Regioselective hydrogenation of the disubstituted
olefin and deprotection of the benzyl ether was accomplished
by using activated Raney nickel, which was followed by Grieco
olefination conditions[15] to provide 20a. At this point, we at-
tempted to prepare the diene side chain through the method
of Fuwa et al.[4f] Alkene 20a was converted to the aldehyde via
two-step oxidation cleavage. Unfortunately, Takai olefination[16]
conditions yielded vinyl iodide 21 but also resulted in an unex-
pected double elimination, a problem that could not be re-
solved.
Scheme 1. Synthesis of tertiary alcohol 9a by electrophilic ether transfer re-
action. Reagents and conditions: a) Z-crotyl-trichlorosilane, Leighton catalyst
(R,R)-3, DBU, CH2Cl2, 08C, 1 h; TBAF, HCl, 93%, 99%ee; b) chloromethyl-2-
naphthylmethyl ether 5, DIPEA, TBAI, CH2Cl2, 408C, 12 h, 70%; c) CH3PPh3Br,
nBuLi, THF, 08C to RT, overnight, 71%; d) ICl, PhCH3, À958C, 1 min; DIPA/
H2O, 3 h, 76%, d.r.=10:1; e) TBSOTf, 2,6-lut., CH2Cl2, 08C, 30 min, 95%;
f) DDQ, CH2Cl2, pH 7 phosphate buffer, RT, 1 h, 93%; g) NaH, THF, 08C to RT,
overnight, 86%; h) 3-benzoxylpropyl magnesium bromide, CuI, THF, À78 to
À158C, 2 h, 65%. DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; TBAI: tetrabutyl-
ammonium iodide; DIPA: diisopropylamine; TBSOTf: trimethylsilyl trifluoro-
methanesulfonate; 2,6-lut.: 2,6-lutidine; DDQ: 2,3-dichloro-5,6-dicyano-p-
benzoquinone; RT: room temperature.
1,3-syn diol monoether 7 in 76% yield with reasonable diaste-
reoselectivity (10:1 syn:anti). Interestingly, no reactivity was ob-
served at the monosubstituted olefin, representing the first
report of a regioselective ether transfer in the presence of two
reactive olefins. The resulting diol monoether 7 was then con-
verted to epoxide 8 via the three-step functional group manip-
ulation, followed by ring opening with the corresponding
Grignard reagent in the presence of copper(I) iodide to afford
tertiary alcohol 9a.
With tertiary alcohol 9a in hand, we then turned our focus
towards the synthesis of the ketene precursor fragment. The
application of ketene chemistry for the synthesis of
sterically encumbered esters has been investigated.[7]
On the basis of these prior studies, several ketene
precursors, such as carboxylic acid I,[7a–f] acid halides
II, and alkynyl ether IV[7g–l] were explored (Figure 3).
Unfortunately, none of these ketene precursors
proved to be efficient for generating the desired ter-
tiary ester moiety. We believe that this is the result of
the instability of the ketene intermediates and a pref-
erence for degradative over productive pathways.
However, b-keto esters V have been shown to
The unexpected elimination process was successfully circum-
vented by use of
a cross-metathesis homologation and
generate stabilized b-keto ketenes in the context of Figure 3. Ketene precursor fragments for esterification reaction.
Chem. Eur. J. 2015, 21, 10681 – 10686
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