3 and 22 proceeds with low diastereoselectivity and with
preference for the undesired stereoisomer at C9 which must
be formed by means of pseudo-equatorial attack (Fig. 2b).
We assume that bicyclic intermediate 4 is conformationally
more rigid than cyclization precursors 17, such that transition
states B and C can compete without preference for a confor-
mation that clearly favours axial attack.13 The synthetic
strategy described here should facilitate the total synthesis of
natural products with B-seco limonoid scaffold and analogues
thereof and fuel investigations aimed at unraveling the
molecular basis for their manifold biological activity.
This research was supported by the European Research
Council (ERC European Advanced Investigator Grant to
H.W.), the Max Planck Society and the Fonds der Chemischen
Industrie (Kekule-stipend to H.S.).
´
Notes and references
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Scheme 3 Synthesis and Ireland–Claisen rearrangement of bicyclic
allyl ester precursor 4. Reagents and conditions: (a) LiHMDS, TMSCl,
THF, À78 1C to 0 1C, 45 min; (b) NBS, THF, 0 1C, 30 min, 68%
(2 steps); (c) allyltributyltin, AIBN, toluene, 80 1C, 18 h, 81%,
de = 80%; (d) KHMDS, THF, 30 min À78 1C, then MeI, 30 min
rt, 74%, de = 100%; (e) PdCl2(CH3CN)2, toluene, 65 1C, 2 days, 70%
(81% brsm); (f) paraformaldehyde, imidazole, THF/1 M NaHCO3
(2 : 1), rt, 19 h, 74%; (g) TFA/H2O (3 : 1), rt, 30 min, 84%; (h) TBSCl,
imidazole, DMF, rt, 18 h, 94%; (i) tetraallyltin, BuLi, THF, À78 1C to
rt, 30 min, 72%, dr = ca. 2 : 1; (j) Grubbs I, CH2Cl2, rt, 18 h;
(k) HF–pyridine, THF, 0 1C to rt, 20 h, 99%; (l) EDC–HCl, 4-oxocyclo-
hexyl carboxylic acid, DMAP, CH2Cl2, rt, 16 h, 80%; (m) DIPEA,
MOMCl, NaI, THF, 50 1C, 16 h, 62%; (n) LiHMDS, supernatant of a
centrifuged mixture of TMSCl/NEt3 (v/v = 1/1) and toluene, toluene,
À78 1C to 65 1C in 6 h, 60 h at 65 1C, 88% yield, dr = 1 : 2 (3 : 22).
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case the preference for axial attack predominates over the stereo-
directing influence of the b-hydroxy group.
Ring closing metathesis and subsequent selective deprotection
of the primary silyl ether successfully delivered bicyclic triol 21.
Esterification and protection of the remaining hydroxy groups as
MOM–ethers, which was accompanied by silyl migration, gave
rise to rearrangement precursor 4.
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13 Furthermore, MM2 conformational calculations indicate that the
C11–oxygen is within H-bonding distance to the terminal methyl
C–H of the C14 MOM group, thus blocking a pseudo-axial
approach.
For rearrangement of allyl ester 4 variation of the reaction
conditions was necessary. The Ireland–Claisen rearrangement
proceeds successfully upon gradual warming of the reaction
mixture from À78 1C to 65 1C over a period of 6 h. Also it was
crucial to employ the supernatant of a centrifuged mixture of
TMSCl, NEt3 and toluene instead of the unactivated TMSCl for
formation of both the required intermediate silyl ketene acetal and
the silyl enol ether of the cyclohexanone. Under these conditions
the Ireland–Claisen rearrangement proceeded smoothly to give
a 1 : 2 mixture of isomers 3 and 22 in 88% combined yield. The
configuration of the diastereomers was assigned based on the
coupling constants recorded for the protons at C9 and C11 and
nOe signal enhancements (Scheme 3).
In contrast to the high face-selectivity in the synthesis of
model systems 18a–c, the rearrangement to bicyclic products
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 6545–6547 6547