Angewandte
Chemie
of 5-heptynal (11)[6] with acetyl bromide provided the
enantioenriched b-lactone 12 incorporating C17 carbinol
stereocenter (75%, ꢀ 95% ee). Amine-mediated lactone
ring opening was followed by installation of the C17 p-
methoxybenzyl ether; ensuing amide reduction provided b-
alkoxy aldehyde 13 representing C12–C17 of the algycone
(58% over three steps). Alkaloid catalysis provided the
conduit to the C7–C9 propionate relationship through
TMSQn-catalyzed cyclocondensation of 3-trimethylsilylpro-
pynal (14) with propionyl chloride to generate b-lactone 15
with near perfect absolute and relative stereocontrol. In this
instance, two-step thiolate-mediated conversion of lactone 15
to the corresponding b-silyloxy aldehyde 16 (10 mol%
KHMDS, EtSH; TBSOTf then iBu2AlH) (76% for two
steps) revealed the AAC-derived b-lactone as the requisite
syn propionate aldol equivalent.
Scheme 2. Iterative catalyzed aldol additions: a) 10 mol% 4, MeCOBr,
iPr2NEt, À608C. b) Me2AlCl, (MeO)MeNH2Cl. c) TBSOTf, 2,6-lutidine,
À608C. d) iBu2AlH, THF, À788C. e) 10 mol% TMSQd, EtCOCl, LiClO4,
iPr2NEt, À788C. f) Et3SiOTf, 2,6-lutidine, À608C. g) 10 mol% TMSQn,
EtCOCl, LiI, iPr2NEt, À788C. h) MeMgBr, THF, 08C. TBS=tert-butyl
dimethylsilyl, TMSQd=O-trimethylsilylquinidine, TMSQn=O-trime-
thylsilylquinine.
Assembling the lower C12–C28 fragment 2 was predi-
cated on the aldol coupling of ketone 10 and aldehyde 13
proceeding to correctly establish the, as yet, unaddressed C17
stereocenter (Scheme 4). To this end, the kinetic enol silane
ship in providing b-lactone 7 (78%, > 95% de). The last aldol
iteration was accomplished by Weinreb amide-mediated
refunctionalization of 7 to aldehyde 8 (79% for three steps)
and ensuing propionyl chloride AAC homologation, this time
using O-trimethylsilyquinine (TMSQn) as catalyst, to provide
the syn,anti,syn b-lactone 9 as a single stereoisomer (77%,
> 95% de). The C20–C28 fragment was completed by
converting b-lactone 9 to the methyl ketone 10 using the
same amine-mediated b-lactone refunctionaliztion proce-
dure, substituting MeMgBr addition to the intervening
amide for the typical terminal reduction step (71% over
three steps).[5]
Catalytic asymmetric AAC reactions similarly served as
aldol surrogates in establishing the isolated C17–C19 acetate
and C7–C9 propionte aldol relationships embedded in the
aglycone (Scheme 3). The AlIII-catalyzed cyclocondensation
Scheme 4. Synthesis of lower fragment 2: a) NaHMDS, THF; TMSCl,
2,6-lutidine. b) 13, BF3·OEt2 (1 equiv), CH2Cl2, À788C. c) 1. TFA, 1:1
MeOH:CH2Cl2; 2. TESOTf, 2,6-lutidine, À558C. d) DDQ, 2:1
CH2Cl2:pH 7 phosphate buffer. e) Me3OBF4, proton sponge, CH2Cl2.
f) [Cp2ZrHCl], 2,6-lutidine, THF then I2. Cp=cyclopentadienyl,
DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone, TFA=trifluoroacetic
acid.
17 derived from ketone 10 participated in highly 1,3-anti
selective Mukaiyama aldol addition to aldehyde 13
(BF3·OEt2, CH2Cl2, À788C) affording b-hydroxy ketone 18
as a single diastereomer (71%);[7] diastereoselection in this
aldol coupling is consistent with a matched pairing of
aldehyde and enolate facial biases according to the transi-
tion-state model 19.[8] Reacting 18 with acidic methanol
cleaved the C23 and C25 triethylsilyl ethers and elicited
concomitant hemiketal formation to generate pyran 20 as a
single b-anomer. Appropriately configuring both the tempo-
rary and permanent ether functionalities required for advanc-
Scheme 3. Catalytic asymmetric acetate and propionate aldols: a) 10
mol% ent-4, MeCOBr, iPr2NEt, À608C. b) Me2AlCl, (MeO)MeNH2Cl.
c) PMBOC(NH)CCl3, 15 mol% BF3·Et2O, CH2Cl2. d) iBu2AlH, THF,
À788C. e) 10 mol% TMSQd, EtCOCl, MgCl2, iPr2NEt, À788C. f) 10
mol% KHMDS, EtSH, THF then TBSOTf, 2,6-lutidine. PMB=p-
methoxybenzyl, KHMDS=potassium hexamethyldisilazide.
Angew. Chem. Int. Ed. 2010, 49, 8678 –8681
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim