Angewandte
Chemie
It should be emphasized that the sterically congested
bicyclic skeleton, with contiguous quaternary methyl groups,
facilitated an unexpected but desirable selectivity during
these last few steps. The remaining steps for the completion of
the synthesis of (À)-norzoanthamine were: 1) coupling of
formyl ester 12 and ketophosphonate 6, and 2) formation of
the bisaminal framework at the very end of the synthesis
(Scheme 4).
We first attempted the reaction of formyl ester 12 and
ketophosphonate 6. However, all attempts failed and only
starting materials were recovered. The low reactivity of the
formyl group can be attributed to the presence of the
neighboring acetate and tert-butyldimethylsilyloxy groups.
Fortunately, selective removal of the TBS group on the C ring
Scheme 3. Synthesis of formyl ester 12. Reagents and conditions:
a) Me2CuLi, Et2O, À78–08C, 91%; b) NaBH4, MeOH, 08C–RT, 79%;
c) TBSOTf, 2,6-lutidine, CH2Cl2, 08C–RT, 95%; d) B-bromocatecholbor-
ane, CH2Cl2, À788C, 87%; e) DMP, CH2Cl2, 08C–RT, quant.; f) nBuLi,
TMSCl, THF, À78–08C; g) O3, CH2Cl2, MeOH, À788C, 79% (over 2
steps); h) Pb(OAc)4, benzene, MeOH, 08C–RT, 77%. DMP=Dess–
Martin periodinane, Tf=trifluoromethanesulfonyl, TMS=trimethylsilyl.
reduced with NaBH4 in MeOH to afford alcohol 10 in good
yield. Both the conjugate addition and the reduction reactions
proceeded in a highly stereoselective manner to afford 10 as a
single isomer. The assignment of the configuration was based
on NMR experiments.[7] Protection of the hydroxy group in 10
as the TBS ether, removal of the MOM group,[8] and
successive oxidation of the resulting hydroxy group afforded
the cyclopentanone derivative 7 in 83% overall yield.
To cleave the cyclopentanone moiety, 7 was subjected to
an a oxidation by using conventional procedures. However
the enolization step proved to be very difficult, probably
owing to the sterically encumbered carbonyl group resulting
from the buttressing effect of the angular methyl groups. We
were delighted that deprotonation proceeded cleanly to
afford the desired trimethylsilyl enol ether after successive
silylation reactions by using nBuLi as a base.[9]
Interestingly, ozonolysis of the silyl enol ether provided a-
hydroxy ketone 11 as a single diastereomer in 79% overall
yield from ketone 7, rather than the expected dicarbonyl
compound.[10] The configuration of the hydroxy group was
determined by use of the modified Mosher method.[11] To
obtain formyl ester 13, we next examined the oxidative
cleavage of hydroxy ketone 11 with the process established by
Criegee using Pb(OAc)4 in benzene/MeOH.[12] Surprisingly,
rather than the anticipated 13, the formyl ester 12 was
obtained in 77% yield as the sole product. A plausible
mechanism for this unprecedented oxidation process is out-
lined in the Supporting Information. Nonetheless, 12 is a
desirable intermediate because it can be directly employed as
a substrate for the Horner–Emmons reaction with 6.
Scheme 4. Completion of the total synthesis of (À)-norzoanthamine
(1). Reagents and conditions: a) TBAF, THF, 08C–RT, quant.; b) aq.
HF (4n), CH3CN, RT, quant.; c) TESCl, imidazole, CH2Cl2, RT, 76%;
d) 6, LiCl, iPr2NEt, CH3CN, 608C, 67% (94% based on the recovered
starting material); e) H2, Pd/C, EtOH, RT, 96%; f) AcOH, H2O, 508C,
56%; g) AlH3·EtNMe2, toluene, 508C, 59%; h) BzCl, NEt3, CH2Cl2,
08C–RT, 88%; i) DMP, CH2Cl2, RT, quant.; j) aq. HF (0.5N), CH3CN,
08C–RT, 94%; k) DMP, CH2Cl2, RT, quant.; l) LHMDS, TMSCl, THF,
À788C; m) cat. Pd(OAc)2, O2, DMSO, 608C, 74% (over 2 steps);
n) K2CO3, MeOH, RT; o) DMP, CH2Cl2, RT; p) NaClO2, NaH2PO4, 2-
methyl-2-butene, tBuOH, H2O, RT, 66% (over 3 steps); q) AcOH, H2O,
1008C, 92%. Bz=benzoyl, DMSO=dimethyl sulfoxide,
LHMDS=lithium hexamethyldisilazanide, TBAF=tetra-n-butylammo-
nium fluoride, TES=triethylsilyl.
Angew. Chem. Int. Ed. 2009, 48, 1404 –1406
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