Angewandte
Chemie
[
11]
work up (NaBH4)
to afford the corresponding diol.
Protection of the hydroxy groups provided the bis(acetate
ester) 17 (77% yield, over 2 steps), thus allowing for
N acylation of the lactam with Boc O to furnish the bicyclic
2
imide 18 (99% yield). Further elaboration to a less-strained
advanced cyclopentane intermediate, with differentiation of
C13 and C6 oxygen functionalities, can also be accomplished
by saponification of both acetate esters, which is accompanied
by hydrolysis of the cyclic imide. Treatment of the resultant
diol carboxylic acid under acidic conditions effected an
intramolecular ester formation to afford lactone 19 (96%
yield, over 2 steps). The structure of 19 was verified by
extensive NOE analysis, from which the relative stereochem-
ical arrangement of its synthetic precursors could also be
inferred with confidence. Both the bridged (i.e., 18)and non-
bridged (i.e., 19)cyclopentane cores map directly onto the
originally proposed structure of palau’amine (1a). Indeed,
both have the potential to serve as useful advanced precursors
for future elaboration of the nitrogen-rich periphery of 1a.
However, the recent evidence supporting a revised
structural assignment for palauꢀamine (1b)challenged the
utility of this route in its ability to access the redefined target
structure. Nevertheless, the above-described Diels–Alder/
Scheme 7. Reagents and conditions: a) NaOH, EtOH, 238C, 98%;
b) (PhO) P(O)N , Et N, toluene, 238C; EtOH, 808C; c) HCl, EtOH,
2
3
3
9
4% (over 2 steps); d) HONH ·HCl, pyridine, EtOH, H O, 958C, 96%;
2
2
[
3,3]-rearrangement strategy could also be conveniently
e) SOCl , Et O, 238C, 59%; f) Boc O, Et N, DMAP, THF, reflux, 94%;
2
2
2
3
modified to accommodate the stereochemical inversions at
C12 and C17. This effort revisits the common early-stage
enone intermediate 10 (Scheme 4), which was found to exist
in a 72:28 isomeric ratio with its enoate counterpart 11. This
dynamic 10/11 mixture was subjected to selective Meerwein–
Verley–Pondorf reduction of the bridging ketone group in 11,
giving the secondary alcohol 20 in high yield (> 97%;
Scheme 6). This process again capitalizes on the Curtin–
g) OsO , NaIO , THF, H O, 238C; SiO , Et N, EtOAc, 238C, 86%;
4
4
2
2
3
h) O , MeOH, CH Cl ꢀ788C; NaBH , 238C; i) TsOH·H O, CH Cl
3
2
2
4
2
2
2,
238C; TIPSCl, imidazole, 238C, 91% (over 2 steps); j) Pd(OH)
/C, H ,
2
2
THF, 238C; k) TsOH·H O, PhCH(OMe) , toluene, 238C, 62% (over 2
2
2
steps); l) NaOH, MeOH, 238C; m) TMSCHN , benzene, MeOH,
2
2
38C; n) Dess–Martin periodinane, CH Cl , 238C; SiO , Et N, CH Cl ,
2 2 2 3 2 2
238C; 90% (over 3 steps). TIPS=triisopropylsilyl.
lowed by Boc protection of the resultant lactam to obtain
imide 23 (53% yield, over 3 steps). Upon cleavage of the
alkene in 23 by Lemieux–Johnson oxidation (Scheme 7)and
exposure to silica gel and Et N, C12 epimerization ensued to
3
provide the di-aldehyde 24 (86% yield)as the thermodynami-
cally favored diastereomer. The successful preparation of 24
constitutes a near-functional equivalent to the bridged
chlorocyclopentane 18 (see Scheme 5), with the key stereo-
chemical differences residing at C12 and C17. Moreover, an
alternate sequence by which to prepare an appropriately
functionalized non-bridging form of the chlorocyclopentane
core of 1b can be accomplished by direct ozonolysis of the
cyclopentene in 23 (Scheme 7), followed by reduction with
Scheme 6. Reagents and conditions: a) Al(OiPr) , iPrOH, reflux;
3
b) SOCl , CH Cl , 458C, 97% (over 2 steps).
2
2
2
Hammett energy profile of the system, only this time in the
opposite direction to advance 10 through sigmatropic rear-
rangement and reduction. The hydroxy group in 20 under-
went substitution with chloride resulting in net retention of
configuration at C17, presumably as a result of p-bond
NaBH and exposure to TsOH. This process led to sponta-
4
neous intramolecular alcoholysis of the imide to form the
C13–C19 lactone, whose C6 hydroxy group was protected as
the silyl ether 25 (91% yield, over 2 steps). Removal of the
C20 benzyl ether and tethering of the resultant hydroxy group
with the C16 carbamate (26; 62% yield, over 2 steps)
precluded unproductive aziridine formation at this junc-
[37]
anchimeric assistance, to afford the chloride 21 (97% yield,
over 2 steps), which constitutes the C17 epimer of 14 (see
Scheme 4).
Further derivatization of the tricyclo[5.2.1.0]decadiene 21
[38,39]
(
Scheme 7)followed a similar strategy to that of its
ture.
This strategy allowed for sequential lactone hydro-
C17 epimer. Removal of the ester carbon moiety was
accomplished through ester hydrolysis and Curtius rearrange-
ment to afford ketone 22 (92% yield, over 3 steps). The C16-
nitrogen functionality was introduced, as before (see
Scheme 5), by regioselective Beckmann rearrangement fol-
lysis, methyl ester formation, and C12 oxidation/epimeriza-
tion to afford aldehyde 27 (90% yield, over 3 steps), which is a
near-functional equivalent of the C12,C17 diastereomeric
counterpart to the chlorocyclopentane 19 (see Scheme 5).
Thus, stereoselective access to the advanced intermediates 24
Angew. Chem. Int. Ed. 2008, 47, 6821 –6824
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6823