Angewandte
Chemie
Scheme 3. a) tBuOCl, CH2Cl2, À788C; then 16, iPrOH, EtMgBr, 08C to
RT, 74%,>95:5 d.r.; b) TsOH·H2O, MeOH, 92%; c) triphosgene, py,
CH2Cl2, À788C to 08C, 97%; d) Raney-Ni, B(OH)3, H2, MeOH/H2O
(5:1), 88%; e) Me4NBH(OAc)3, AcOH/MeCN (1:1), À58C, 74%,
4.3:1 d.r.; f) TsOH·H2O, 2,2-dimethoxypropane, 99%; g) aq. LiOH
(1n), 92%; h) NaIO4 on silica gel, CH2Cl2, 99%. Tr=trityl, Ts=4-
toluenesulfonyl.
followed by hydrolysis of the carbonate. The resulting 1,2-diol
was cleaved with NaIO4/silica gel to provide aldehyde 5 in
90% yield (over 3 steps).
With the two key subunits in hand, our attention turned to
the zinc-mediated addition of enyne 4 to aldehyde 5
(Scheme 4).[14] Treatment of 13 with Zn(OTf)2, (+)-NME,
and iPr2NEt in toluene led to the formation of propargylic
alcohol 3 in 91% yield as a single diastereomer, as determined
Scheme 2. a) LDA, LiCl, THF, À788C to 08C, 87%, 97:3 d.r.; b) LDA,
BH3·NH3, THF, 87%; c) Dess–Martin periodinane, py, CH2Cl2, 99%;
d) 10, Cy2BOTf, NEt3, CH2Cl2, À788C, 90%, >95:5 d.r.; e) TESCl,
DMAP, imidazole, DMF, 98%; f) DIBAL-H, CH2Cl2, À788C, 95%;
g) TPAP, NMO, M.S. (4 ꢁ), CH2Cl2; h) Ph3PC(Me)CO2Et, toluene,
658C, 87% (over 2 steps), >95:5 d.r.; i) DIBAL-H, CH2Cl2, À788C,
98%; j) TMSCꢀCH, CuI, [Pd(PPh3)4], pyrrolidine, 96%; k) MnO2,
CH2Cl2, 94%; l) KHMDS, [18]crown-6, (iPrO)2P(O)CH(OMe)CO2Me,
THF, >95:5 d.r.; m) K2CO3, MeOH, 96% (over 2 steps). Bn=benzyl,
Cy =cyclohexyl, DIBAL-H=diisobutylaluminum hydride, DMAP=4-
dimethylaminopyridine, DMF=N,N-dimethylformamide, HMDS=
hexamethyldisilazane, LDA=lithium diisopropylamide, Mes=2,4,6-tri-
methylphenyl, M.S.=molecular sieves, NMO=4-methylmorpholine N-
oxide, py=pyridine, Tf=trifluoromethanesulfonyl, TMS=trimethylsilyl,
TPAP=tetra-n-propylammonium perruthenate.
1
by H NMR spectroscopy.[23] This report constitutes the first
example of an enyne/aldehyde coupling reaction in the
context of complex fragment assembly. Conversion of the
enyne into the trans,trans-diene was now critical for successful
evolution of the route. Importantly, if realizable it would offer
an alternative to the traditional palladium-catalyzed cross-
coupling approaches for the introduction of the C10–C13
diene subunit in all previous syntheses of bafilomycin A1.[7–10]
Scheme 4. a) Zn(OTf)2, (+)-NME, iPr2NEt, toluene, RT, 91%, >95:5 d.r.; b) (EtO)3SiH, [Cp*Ru(NCMe)3]PF6, CH2Cl2, 08C to RT; c) TBAF, CuI,
THF, 08C, 72% (over 2 steps); d) MeI, NaH, THF/DMF (1:1), 89%; e) HF·py, THF, 91%; f) AcO(O)CH, DMAP, CH2Cl2, 99%; g) CSA, MeOH;
then K2CO3, MeOH, 68% (79% brsm); h) aq. LiOH (1n), THF/MeOH/H2O (5:1:1); i) 2,4,6-trichlorobenzoylchloride, iPr2NEt, toluene, 60% (over
2 steps); j) TASF, H2O, DMF, 90%; k) TEMPO, PhI(OAc)2, CH2Cl2, 71%; l) TMSCl, NEt3, LiHMDS, THF, À788C; m) 2, BF3·OEt2, M.S. (4 ꢁ),
CH2Cl2, À788C; n) TASF, H2O, DMF, 35% (over 3 steps, 76% brsm). brsm=based on recovered starting material, Cp*=C5Me5, CSA=camphor-
sulfonic acid, (+)-NME=(+)-N-methyl ephedrine, TASF=tris(dimethylamino)sulfonium difluorotrimethylsilicate, TBAF=tetra-n-butylammonium
fluoride, TEMPO=2,2,6,6-tetramethylpiperidin-1-yloxyl.
Angew. Chem. Int. Ed. 2009, 48, 578 –581
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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