Angewandte
Communications
Chemie
Scheme 4. REOs of various b-epoxy functionalized substrates (7 mol%
cat., 1.5 equiv Lut·HCl, 1.5 equiv Mn, 2.2 equiv Bu3SnH, 0.3m in THF,
3 days, 258C).
hydroxy substituent a slight decrease of catalyst control
(regioselectivity 92:8–89:11) was observed in the case of
epoxides with the (S,R) configuration (Scheme 4) and cat-Cl2
as well as (R,S) configuration at the epoxide and ent-cat-Cl2.
The minor product is in all cases easily removed by
chromatography.
Arguably, the most common and therefore most relevant
building blocks that can be prepared via the REO described
here are 1,3- and 1,4-diols and their derivatives.[2] These
functional units are ubiquitous in biologically active substan-
ces, especially antibiotics, and have therefore been in the
focus of synthetic studies for many years. We studied the
performance of the reaction in the opening of racemic b-
hydroxy and b-alkoxy substituted epoxides (Scheme 5) in
parallel resolution reactions first. In this manner, the perfor-
mance of the REO with both enantiomers of the substrate can
be evaluated in a single experiment. We chose methyl
substitution at the b-substituent in the second set of substrates
because in many 1,3-diols (part of) the polyol framework is O-
methylated.[13]
The results demonstrate that for the “anti-substrates”
almost perfect parallel resolutions take place [for 11 (OH):
the following numbers reproduce the experimental results
well: (R,S) epoxide to 1,3-diol: rr= 97:3 and (S,R) epoxide to
1,4-diol: rr= 99:1]. Therefore, the “anti-epoxides” seem to be
highly attractive substrates for the synthesis of anti-1,3-diols
and their O-methylated derivatives. For the “syn-substrates”
the resolution is very efficient [for 10 (OMe): (R,S) epoxide to
1,3-diol: rr= about 95:5 and (S,R) epoxide to 1,4-diol: rr=
about 99:1] but not quite as excellent as for the “anti-
substrates”. For 9 and 10, the ent-cat-Cl2/Lut·HBr system
resulted in high yields and almost identical selectivities (9:
90%, 1,3:1,4-diol = 48:52, 1,4-diol: e.r. of 94:6, 1,3-diol: e.r. of
91:9, 10: 92%, 1,3:1,4-product = 48:52, 1,4-diol: e.r. of 94:6,
1,3-diol: e.r. of 97:3) but with a much shorter reaction time
(3 h).
The opening of enantiomerically pure substrate 13
proceeds with high regioselectivity for both enantiomers of
the catalyst. The reaction to the 1,4-diol is more selective and
higher yielding than the opening to the 1,3-diol. The minor
isomer is easily removed. As expected, the combination
(weighted by yield) of both reactions of the enantiomerically
pure substrate 13 (88% yield, 1,3:1,4-diol = 47:53, 1,4-diol:
Scheme 5. Performance of the REO in the synthesis of 1,3- and 1,4-
diols (7 mol% cat., 1.5 equiv Lut·HCl, 1.5 equiv Mn, 2.2 equiv
Bu3SnH, 0.3m in THF, 3 days, 258C). Yield=combined yield of
separated opening products. Regioisomeric ratios (rr): from isolated
yields.
e.r. of 95:5, 1,3-diol: e.r. of 100:0) reproduces the parallel
resolution of the racemic substrate 11 (87%, 1,3:1,4-diol =
49:51; 1,4-diol: e.r. = 97:3; 1,3-diol: 99:1) reasonably well. The
slight discrepancy is due to the error of 13C-NMR spectros-
copy used for the determination of the regioselectivity of the
REOs of 13.
The 1,3-diols shown in Scheme 5 can also be prepared by
an aldol reaction of acetone with n-undecanal and further
manipulation. Aldol reactions with acetone and unbranched
aldehydes result in relatively low enantioselectivities.[14] Thus,
our method is an attractive alternative to this classical
approach.
To demonstrate the usefulness of the REO in the synthesis
of diol-containing compounds we prepared two natural
products [(À)-massioalactone (18) and (+)-3-hydroxy-5-dec-
anolide (17)][15] and employed a functionalized building block
derived from citrollenol (Scheme 6).[16] Epoxyester (14) is
opened to the desired enantiomerically pure 1,3-diol (16) by
ent-cat-Cl2 with excellent selectivity and with cat-Cl2 to the
enantiomerically pure 1,4-diol (15) in equally high selectivity.
From 16 both natural products 17 and 18 can be prepared in
high yield by pTsOH-mediated lactonization under the
appropriate conditions.
The citrollenol-derived epoxides (19) are opened to the
corresponding 1,3- or 1,4-diols with excellent reagent control
according to Scheme 2. These reactions amply highlight the
power of combining our modular substrate synthesis with the
REO in the preparation of functionalized 1,3- and 1,4-diols.
In summary, the regiodivergent epoxide opening is an
excellent and the only method to transform b-functionalized
cis-2,3-difuntionalized epoxides into 1,3- or 1,4-difunctional-
ized building blocks containing at least one hydroxy group.
Both the REO and the modular substrate synthesis tolerate
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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