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Angewandte
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Scheme 4. Conversion of 15 into 4. Reagents and conditions: a) 16,
TiCl4, (+)-sparteine, NMP, CH2Cl2, 08C, 90%; b) PIFA, MeOH/H2O,
78%; c) 40% HF, MeCN, 96%. NMP=N-methyl-2-pyrrolidinone,
PIFA=phenyliodine(III) bis(trifluoroacetate).
Scheme 3. Synthesis of 15. Reagents and conditions: a) EtCO2H,
EDCI, DMAP, CH2Cl2, 96%; b) TiCl4, (ꢀ)-sparteine, acrolein, CH2Cl2,
08C, 86%; c) 1) DIBAL-H, CH2Cl2, ꢀ788C; 2) HS(CH2)3SH, BF3·Et2O,
69% from 8; d) TBSOTf, Et3N, CH2Cl2, 08C, 90%; e) tBuLi, THF,
HMPA, ꢀ788C, 71%; f) BnBr, NaHMDS, THF, DMF, 90%; g) CSA,
MeOH, ꢀ108C, 93%; h) SO3-py, DMSO, Et3N, CH2Cl2, 90%. CSA=
camphorsulfonic acid, DIBAL-H=diisobutylaluminum hydride,
DMAP=4-dimethylaminopyridine, DMF=N,N-dimethylformamide,
DMSO=dimethyl sulfoxide, EDCI=1-ethyl-3-(3-dimethylaminopropyl)-
carbodiimide hydrochloride, HMPA=hexamethylphosphoramide,
NaHMDS=sodium hexamethyldisilazide, py=pyridine, TBS=tert-
butyldimethylsilyl, Tf=trifluoromethanesulfonyl.
Benzyl protection of the newly formed hydroxy group at
C6 was unexpectedly difficult. The etherification with BnBr in
the presence of NaH resulted in unwanted side products in
pure DMSO or DMF. Fortunately, this problem was later
satisfactorily solved by using a 5:1 mixture of THF/DMF as
the solvent and performing the alkylation at ꢀ108C.
Furthermore, the incorporation of the C1/C2 unit was
planned by an Evans aldol reaction. Thus, the C3 atom had to
be transformed into an aldehyde first. To this end, the TBS
protecting group at the primary OH group (C3) was
selectively cleaved with MeOH in the presence of a catalytic
amount of CSA, while the TBS group on the secondary OH
group (C10) remained intact. The resulting alcohol 14 was
then treated with SO3·py in CH2Cl2 to deliver the expected
terminal aldehyde 15, thus setting the stage for the incorpo-
ration of the first two carbon atoms in the C1 to C11 fragment
(4).
The aldol reaction was achieved (Scheme 4) under the
conditions described by Crimmins et al.[8] including TiCl4/
sparteine/NMP. The enantiomerically pure 17 was then
treated with PIFA[9] to deprotect the thioketal protecting
group. Finally, removal of the TBS group with HF afforded
alkene 4, which is needed for the later catenation with 5.
The synthesis of fragment 5 was started with the
installation of the C16/C17 stereogenic centers (Scheme 5).
The aldol reaction of 19 with 20 gave 21 in 99% yield. TBS
protection of the hydroxy group with TBSOTf/2,6-lutidine
followed by cleavage of the oxazolidinethione auxiliary with
DIBAL-H gave the intermediate aldehyde.
Scheme 5. Synthesis of 5. Reagents and conditions: a) TiCl4, (+)-spar-
teine, NMP, CH2Cl2, 08C, 99%; b) TBSOTf, 2,6-lutidine, CH2Cl2, 08C,
95%; c) 1) DIBAL-H, CH2Cl2, ꢀ788C, 88%; 2) 23, TiCl4, iPr2NEt,
CH2Cl2, ꢀ788C, 77%; d) 1) MeNH(OMe)·HCl, Me3Al, CH2Cl2;
=
2) (CH2 CH)4Sn, MeLi, THF; 3) Me4NBH(OAc)3, AcOH, MeCN,
ꢀ158C, 71% from 24; e) 1) Me2C(OMe)2, acetone, p-TsOH;
2) nBu4NF, THF, 93% from 25. Ts=toluenesulfonyl.
To extend the chain by two carbon units and install a new
stereogenic center at C15, an asymmetric acetate aldol
reaction that was induced by an oxazolidinethione auxiliary
was performed next. Generally speaking, the diastereoselec-
tivity for such reactions is less satisfactory than that for the
corresponding propionate aldol condensations under similar
conditions. Several elegant protocols[10] for dealing with these
types of problems have been reported. However, the advan-
tages of using these protocols appear to be somewhat
counterbalanced by, for instance, the extra efforts required
for gaining access to the special auxiliaries (with sterically
more hindered substituents at the stereogenic centers). In
hope to find an alternative that is more suitable to us, we
2
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
These are not the final page numbers!