Angewandte
Chemie
Scheme 3. Synthesis of dihydrooxepine 23. Reagents and conditions:
a) TFAA, UHP, CH2Cl2, ꢀ208C, 53% total yield after 4 reaction cycles
(19% of 20 recovered; after a single reaction cycle: 23% yield, 65%
yield based on recovered starting material); b) KHMDS, PhNTf2, THF,
ꢀ788C, 77%; c) cat. Pd(OAc)2, PPh3, HCO2H, nBu3N, DMF, 658C,
94%. DMF=N,N-dimethylformamide, KHMDS=potassium hexame-
thyldisilazide, TFAA=trifluoroacetic anhydride, UHP=urea hydrogen
peroxide.
exclusively as a single isomer. After conversion to enol triflate
22, subjection to the palladium-catalyzed reduction condi-
tions gave dihydrooxepine 23 in excellent yield with the Cbz
group intact.
The stage was now set for dimerization of monomer 23
(Scheme 4). First, the Cbz group was removed by the
palladium-catalyzed hydrogenolysis to give secondary amine
Scheme 2. Synthesis of substrate 20 for Baeyer–Villiger oxidation.
Reagents and conditions: a) cat. DBU, CH2Cl2, RT, quant.; b) H2O2,
cat. NaOH, MeOH, 08C, 97%; c) NH2NH2·H2O, AcOH, CH2Cl2, 08C!
RT, 55%; d) DMP, CH2Cl2, 08C, 97%; e) TMSOTf, iPr2NEt, CH2Cl2, RT;
f) DMDO, CH2Cl2/acetone, ꢀ788C; evaporation; acidic silica gel, 56%
(over 2 steps); g) TBSOTf, 2,6-lutidine, CH2Cl2, 08C, 75%. Ac=acetyl,
Cbz=benzyloxycarbonyl, DBU=1,8-diazabicyclo[5.4.0]undec-7-ene,
DMDO=dimethyldioxirane, DMP=Dess–Martin periodinane,
TBS=tert-butyldimethylsilyl, Tf=trifluoromethanesulfonyl, TMS=tri-
methylsilyl.
rearrangement and Dess–Martin oxidation of the resulting
allyl alcohol proceeded smoothly to afford enone 16.
At this point, we investigated the oxidation of the allylic
position. Since the conventional oxidation reactions using
SeO2 or brominating agent[15] resulted in a complex mixture,
we devised an alternative method for this transformation. To
this end, we have successfully established a stepwise protocol,
including regioselective dienol silyl ether formation and
vinylogous Rubottom oxidation. Thus, treatment of 16 with
TMSOTf and Hꢀnigꢁs base gave dienol silyl ether 17 as an
exclusive product. Subsequent DMDO oxidation followed by
acidic workup with silica gel gave the desired g-hydroxyenone
19 as a sole product,[16] which was then protected as its TBS
ether 20. In contrast to the conventional Rubottom oxidation
that gives a-hydroxyketones, the result indicated that the
epoxidation occurred at the b,g-double bond to generate
epoxide 18.
Scheme 4. Dimerization of monomer. Reagents and conditions:
a) Et3SiH, cat. Pd(OAc)2, cat. Et3N, CH2Cl2, 458C, 91%; b) KOH, THF/
MeOH/H2O, RT, quant.; c) BOPCl, Et3N, CH2Cl2, RT, 83%; d) Et3SiH,
cat. Pd(OAc)2, cat. Et3N, CH2Cl2, 458C, 78%; e) TBAF, THF, RT, 74%.
BOPCl=bis(2-oxo-3-oxazolidinyl)phosphonyl chloride, TBAF=tetrabu-
tylammonium fluoride.
Surprisingly, the protected hydroxy group of compound 20
is located on the concave face, as determined by X-ray
crystallographic analysis for the advanced intermediate 27.[17]
Since further experiments showed unsuccessful condensation
of monomer units possessing the same configurations as
natural product 1,[18] we decided to invert the stereochemistry
of the hydroxy-bearing carbon center after dimerization and
continued further transformations using 20.
24, and the methyl ester was hydrolyzed to provide carboxylic
acid 25. The crucial condensation of 24 and 25 was then
carried out using BOPCl to afford amide 26 in high yield. The
diketopiperazine ring was then formed by removal of the Cbz
group and subsequent reaction of the generated amine with
the ester to give the corresponding amide. Finally, two TBS
groups were removed to give unprotected diol 28.
We then focused on the construction of the dihydroox-
epine skeleton using a Baeyer–Villiger oxidation[12] to form
enol lactone (Scheme 3). Thus, we examined a variety of
oxidants and found that a combination of TFAA/UHP
systems[12c] gave the best results. Gratifyingly, the expected
Baeyer–Villiger oxidation proceeded to give enol lactone 21
The remaining tasks for the total synthesis of acetylar-
anotin (1) were stereochemical inversion of the hydroxy-
bearing carbon centers at positions 5 and 13, and introduction
of the disulfide moiety (Scheme 5). Since the Mitsunobu
conditions provided a complex mixture of products, we
examined an oxidation–reduction sequence. Among a variety
Angew. Chem. Int. Ed. 2012, 51, 13062 –13065
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