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was formed in 62% yield and 92% ee, as determined by SFC
analysis. Opening of the b–lactone with methyl acetate
enolate gave b-ketoester 9 in 77% yield. This ester was
subjected to sequential diazotization and protection as the
corresponding triethylsilyl ether. An initial foray into the Rh-
À
catalyzed C H insertion reaction using [Rh2(OAc)4] gave the
cyclized product resulting from insertion into the homoallylic
À
C H bond; the product was obtained as a 4:1 mixture of
diastereomers as determined by analysis of the crude NMR
spectra,[13] which revealed a preference for the desired C11
C12 cis product (81%).
À
Analysis of putative competing transition states[13] for the
reaction prompted us to screen sterically more demanding Rh
catalysts in order to obtain better cis/trans selectivity. In
agreement with this hypothesis, with [Rh2(esp)2] (esp =
a,a,a’,a’-tetramethyl-1,3-benzenedipropionate) as catalyst
the reaction afforded an improved 6:1 ratio of products,
whereas the use of [Rh2(S-PTAD)4] (13) furnished 11 in 71%
yield with an improved diastereomer ratio of 9:1 cis/trans.
Krapcho decarboxylation of 11 resulted in the triethylsilyl-
protected b-hydroxyketone, allowing facile separation of the
major cis-diastereomer from the minor trans-cyclization
product by chromatography on silica gel. Subsequent elimi-
nation of triethylsilanol promoted by DBU in CH2Cl2 at 08C
gave cyclopentenone 12 in 60% yield over two steps.
Installation of the C8 side chain of the cyclopentenyl ring
was conducted using a modification of a procedure by
Kobayashi,[9a] involving the aldol addition of cyclopentenone
12 and epoxyaldehyde 15, followed by a trans-selective
elimination to obtain dienone 16 (Scheme 5). Epoxyaldehyde
Scheme 3. Retrosynthesis of PEIPC (4) and strategy analysis.
that the novelty of the approach along with the efficiency
gained warranted its examination in the context of the total
synthesis project, especially since 6 would be accessible in
fewer steps than I or II. Furthermore we envisioned EC (1) as
a direct precursor of EI (3), provided hydration of the
À
endocyclic enone in 1 (C10 C11) could be effected in
a diastereo- and regioselective manner.
The synthesis commenced with exposure of commercially
available (Z)-decenal (7)[11] to ketene following the condi-
tions disclosed by Nelson et al. (Scheme 4).[12] b-Lactone 8
Scheme 4. Reagents and conditions: a) LiClO4 (3 equiv), Me3Si-quini-
dine (12 mol%), iPr2NEt (2.5 equiv), AcCl (2.5 equiv, addition by
syringe pump over 4 h), Et2O/CH2Cl2, À788C, 62%, 92% ee (deter-
mined by SFC analysis); b) iPr2NLi (3.8 equiv), methyl acetate
(3.8 equiv), THF, À788C, 77%; c) p-ABSA (1.3 equiv), Et3N (2 equiv),
MeCN, 08C to RT, 97%; d) Et3SiCl (1.5 equiv), imidazole (2 equiv),
DMF, 08C to RT, 98%; e) [Rh2(S-PTAD)4] (13; 1 mol%), CH2Cl2, reflux,
d.r.=9:1, 71%; f) NaCl (30 equiv), Me2SO, 1408C, 65%; g) DBU
(10 equiv), CH2Cl2, 08C, 93%. p-ABSA=para-acetamidoben-
zenesulfonyl azide, S-PTAD=S-(1-adamantyl)-(N-phthalimido)acetato,
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene.
Scheme 5. Reagents and conditions: a) O3, NaHCO3 (0.3 equiv),
MeOH/CH2Cl2, À788C then Et3N (2 equiv), Ac2O (2 equiv), PhH, 08C;
b) Ph3PCHCHO (2.1 equiv), toluene, 708C, d.r.=5:1, 55%; c) (S)-2-
(diphenyl[(trimethylsilyl)oxy]methyl)pyrrolidine (10 mol%), H2O2
(1.3 equiv), CH2Cl2, RT, d.r.=10:1, 51%, 92% ee; d) LiN(SiMe3)2
(1.2 equiv), then 15 (2 equiv), THF, À788C; e) MeSO2Cl (3 equiv),
Et3N (6 equiv), CH2Cl2, À788C then Al2O3, CH2Cl2, RT, 64% over two
steps; f) Novozyme, buffer pH 7/THF, 70%; g) 2,4,6-Cl3C6H2COCl
(10 equiv), 4-Me2NC5H4N (10 equiv), lyso-PC (3 equiv), CHCl3, 69%.
Novozyme=lipase from Candida antarctica on acrylic resin, lyso-
PC=1-palmitoyl-sn-glycero-3-phosphatidylcholine.
2
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
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