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axially disposed and, hence, the transition state for
cyclization is anticipated to be higher in energy due
to developing 1,3-diaxial interactions with the rela-
tively large metal-bound vinyl moiety. Hence, reac-
tions that form the 2,6-cis-diastereomers are intrinsi-
cally more facile. Energetic partitioning of the diaste-
reomeric reactive conformers B and D is dependent
on the structural features of the chiral metal frag-
ment. As reflected by the observed diastereoselectivi-
ties and isolated yields, one can infer that the palladi-
um p-allyl intermediates are more reactive and,
hence, less selective than the corresponding iridium
p-allyl intermediates.
Conclusion
In summary, we report the protecting group-free syn-
thesis of 4-hydroxy-2,6-cis- or trans-pyrans through
successive nucleophilic and electrophilic allylations of
chiral 1,3-diols 1a–1c. Using a cyclometalated iridium
catalyst generated in situ from commercial compo-
nents, the redox-triggered C-allylation of chiral 1,3-
diols 1a–1c occurs with complete levels of catalyst-
directed diastereoselectivity in the absence protect-
ing groups to deliver chiral homoallylic diols syn-2a,
2b, 2c and anti-2a, 2b, 2c, which are converted to
Scheme 4. Cross-metathesis of chiral diols syn-2a, 2b, 2c and anti-2a, 2b, 2c to form al-
lylic acetates syn-3a, 3b, 3c and anti-3a, 3b, 3c.[a] [a] Cited yields are of diastereomeric
mixtures isolated by silica gel chromatography. See Supporting Information for further
experimental details.
the allylic acetates syn-3a, 3b, 3c and anti-3a, 3b, 3c using
the second-generation Grubbs catalyst. Electrophilic allylation,
that is, Tsuji–Trost cyclization, of the allylic acetates syn-3a, 3b,
3c and anti-3a, 3b, 3c, using a chiral palladium catalyst, deliv-
ers the 4-hydroxy-2,6-cis-disubstituted pyrans 2,6-cis-4a–4c
and 4-epi-2,6-cis-4a-4c with complete levels of catalyst-direct-
ed diastereoselectivity. Formation of the corresponding 4-hy-
droxy-2,6-trans-disubstituted pyrans 2,6-trans-4a–4c and 4-epi-
2,6-trans-4a–4c was more challenging, but serviceable diaste-
reoselectivities could be obtained upon use of chiral palladium
or chiral iridium catalysts. The pyran 2,6-trans-4a represents
a synthetic intermediate in an ongoing total synthesis of the
polyketide natural product swinholide, which will be reported
in due course.
Figure 1. Structures of (S,S,aS)-L and (S,S)-DPPBA.
reoselectivity. Ultimately, it was found that the cyclometalated
iridium complex modified by the indicated chiral phosphorami-
dite ligand (S,S,aS)-L (Figure 1) provided optimal results. In sev-
eral cases, incomplete conversion was observed. It has been re-
ported that certain additives, such as tetrahydrothiophene,
and triphenylphosphine with copper(I) iodide or PbII acetate,
can enhance both stereoselectivity and conversion in such iri-
dium catalyzed Tsuji–Trost allylations.[19] However, in our hands,
these additives completely suppressed the reaction.
Experimental Section
Representative procedure for iridium-catalyzed diol C-allylation
(2S,4R)-Hept-6-ene-2,4-diol (syn-2a): To a sealed tube under an
argon atmosphere charged with (S)-butane-1,3-diol 1a (18 mg,
0.20 mmol, 100 mol%), [{Ir(cod)Cl}2] (3.4 mg, 0.005 mmol,
2.5 mol%), (R)-Cl, MeO-BIPHEP (6.5 mg, 0.01 mmol, 5 mol%),
Cs2CO3 (13.0 mg, 0.04 mmol, 20 mol%), and 4-Cl-3-NO2-BzOH
(4.0 mg, 0.02 mmol, 10 mol%) was added freshly distilled THF
(1 mL) and allyl acetate (0.22 mL, 2.0 mmol, 10 equiv). The septum
was quickly replaced with a screw cap and the reaction mixture
was allowed to stir in an oil bath at 1008C for 40 h. The reaction
mixture was allowed to cool to ambient temperature, and was
concentrated in vacuo. The residue was subjected to flash column
chromatography (hexanes/EtOAc=1:1) to furnish title compound
as a light yellow oil in 70% yield (18.3 mg, 0.14 mmol, dr= >20:1).
The trends in diastereoselectivity observed in the present
cyclizations can be understood on the basis of the indicated
stereochemical model, as illustrated in the cyclization of anti-
3a (Scheme 7). Rapid interconversion of the diastereomeric p-
allyl intermediates A/B and C/D is anticipated.[18] For the dia-
stereomers A/B, the reactive conformer B is pseudo-equatorial-
ly disposed, and cyclization occurs readily to furnish 2,6-cis-4a.
For the diastereomers C/D, the reactive conformer D is pseudo-
Chem. Eur. J. 2014, 20, 13382 – 13389
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