¯
S. Omura, T. Sunazuka et al.
with DIBAL-H and a Horner–Wadsworth–Emmons reaction
with ethyl diethylphosphono acetate in the presence of
LiCl[43] to provide the (E)-a,b-unsaturated ethyl ester (+)-50
as
a sole isomer in good yield over all the steps
(Scheme 10). Subsequently, deprotection of the PMB group
with DDQ provided the g-hydroxy-a,b-unsaturated ethyl
Scheme 11. Reagents and conditions: a) NaBH4, MeOH, 08C, 10 min
(88%; d.r.=3:1); b) TsCl, Et3N, N-methylimidazole, PhCl, RT, 15 h
(96%); c) DBU, PhH, 808C, 2 h (79 and 19% for (À)-52 and (À)-53, re-
spectively); d) LiOH, THF/MeOH/H2O (3:1:1), RT, 2.5 h; e) EtOCOCl,
Et3N, THF, 08C, 45 min; NaBH4 in EtOH, 08C, 15 min (82% over
2 steps); f) DPPA, DEAD, PPh3, THF, RT, 2 h (85%); g) DIBAL-H,
THF, À788C, 2 h (51%); h) PivCl, pyridine, CH2Cl2, 08C, 3 h (79%);
i) Dess–Martin periodinane, CH2Cl2, RT, 30 min (98%; 97% ee).
DEAD=diethyl azodicarboxylate, DPPA=diphenyl phosphorazidate.
Scheme 10. Reagents and conditions: a) PMBOACTHNUTRGEN(UNG =NH)CCl3, cat. TfOH,
CH2Cl2/hexane (1:1 v/v), RT, 30 min (75%); b) DIBAL-H, CH2Cl2,
À788C, 1 h; c) ethyl diethylphosphonoacetate, iPr2NEt, LiCl, MeCN, RT,
1.5 h (63% over 2 steps); d) DDQ, CH2Cl2/pH 7.0 phosphate buffer (3:2
v/v), RT, 2.5 h (96%); e) diketene, DMAP, THF, RT, 2 h (quant.);
f) K2CO3, EtOH, RT, 5 h (91%). DMAP=4-dimethylaminopyridine,
DIBAL-H=diisobutylaluminium hydride, PMB=4-methoxybenzyl, Tf=
trifluoromethanesulfonyl.
tion of separable isomers (À)-52 and (À)-53 (E/Z=4.1:1) in
98% yield. The trisubstituted exo-cyclic olefin moieties of
each product were determined by means of NOE interac-
tions. The S configuration of the C3 center of (À)-52 was de-
termined by means of NOE and ROESY interactions for
the hydrogenated product of (À)-52[50] because it could not
be determined from NOE interactions for (À)-52. In the fol-
lowing steps, (À)-52 was transformed into the targeted
methylketone (+)-33. Selective hydrolysis of the ethyl ester
group under basic conditions afforded a carboxylic acid
functionality, followed by formation of the corresponding
carboxylic anhydride, which was immediately reduced with
NaBH4 to the desired primary alcohol in 82% yield over
the two steps.[51] Alternatively, the carboxylic acid group was
directly transformed into the primary alcohol by using
boron-mediated reduction,[52] although in an unsatisfactory
yield. Subsequently, the azidation of the hydroxy group
under Mitsunobu conditions[53] produced the azidolactone
(À)-54 in good yield. The lactone moiety was reduced to the
diol in 51% yield by using DIBAL-H in THF, followed by
the selective protection of the primary alcohol with a Piv
group to provide (+)-55. Next, oxidation of (+)-55 by using
the Dess–Martin periodinane provided the desired chiral
methylketone (+)-33 in excellent yield without racemiza-
tion. The optical purity of (+)-33 (S isomer; 97% ee) was
confirmed by means of chiral HPLC analysis with the com-
parable R isomer of (À)-33 (see the Supporting Informa-
tion), which was prepared in the same manner from (À)-(S)-
methyl lactate.
ester, the optical rotation of which was compared with that
of a reported enantiomer[44] to confirm the R configuration
of this secondary alcohol. Esterification of this alcohol with
diketene in the presence of DMAP[45] afforded the acetoace-
tyl ester (+)-48 in quantitative yield. We next attempted the
intramolecular chirality-transferring Michael reaction.
Through extensive optimization of comparative reaction
conditions,[46] we obtained acetylbutyrolactone (+)-47 under
simple basic conditions with K2CO3 in 91% yield as a single
diastereomer, the relative stereochemistry of which was as-
signed by comparison with related compounds for the cou-
pling constants[47] and NOE interactions between the a and
g protons of (+)-47. The effect of the alcoholic solvent,
which would stabilize the anticipated transition state,[41b] was
one of the key factors in the intramolecular chirality-trans-
ferring Michael reaction. In addition, the substrate benefit-
ted from the Thorpe–Ingold effect[41] by suitable methyl sub-
stitution at the g-position of the a,b-unsaturated ester to
promote kinetically favorable cyclization. This reaction can
be performed on a large scale (>9 g) without any side reac-
tions or decrease in the diastereoselectivity.
To construct the E-ethylidene function, the ketone of the
acetyl group of (+)-47 was reduced with NaBH4 to afford
the b-hydroxylactone as an inseparable diastereomixture
(d.r.=3:1), which was subjected to tosylation with TsCl in
the presence of Et3N and N-methylimidazole, as reported by
Tanabe and co-workers,[48] to provide 51 in excellent yield
(Scheme 11). Subsequently, heating of 51 in the presence of
DBU[49] facilitated b-elimination of the tosyl group and iso-
merization of the ethylidene group, thus resulting in produc-
In the final stage, chiral methylketone (+)-33 was convert-
ed into (+)-(15S,16R)-5 by using the same reaction sequen-
ces as in the synthesis of racemic 5 (Scheme 12). The optical
purity of the substrates after the 1,2-addition reaction was
checked for intermediate (À)-56 by means of chiral HPLC
analysis and confirmed as 97% ee (see the Supporting Infor-
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