Protecting-group-free diastereoselective C-C coupling of 1,3-glycols and allyl acetate through site-selective primary alcohol dehydrogenation

Article abstract of DOI:10.1002/anie.201209863

Safe from protection! A pronounced kinetic preference for primary alcohol dehydrogenation enables the site-selective iridium catalyzed C-C coupling of polyols with allyl acetate in the absence of protecting groups, premetallated reagents, chiral auxiliaries, and discrete alcohol-to-aldehyde oxidation.

Full text of DOI:10.1002/anie.201209863

Angewandte
Chemie
DOI: 10.1002/anie.201209863
Synthetic Methods
À
Protecting-Group-Free Diastereoselective C C Coupling of 1,3-
Glycols and Allyl Acetate through Site-Selective Primary Alcohol
Dehydrogenation**
Anne-Marie R. Dechert-Schmitt, Daniel C. Schmitt, and Michael J. Krische*
The ability to discriminate between like functional groups, so
as to transform organic molecules in a site-selective or
chemoselective manner,[1] precludes the requirement of
protecting groups and, hence, carries the potential to dra-
matically enhance synthetic efficiency.[2] Though an excep-
tionally daunting challenge, systematic efforts toward cata-
lytic methods for the site-selective transformation of poly-
functional molecules have begun to emerge. For example, the
groups of Miller[3] and Taylor[4] report catalytic methods for
the site-selective manipulation of diols and higher polyols.
Site-selective metal-catalyzed cross-couplings have been
catalogued.[5] Further, in what is perhaps the most formidable
theatre for site selectivity, impressive advances in catalytic
lyzes the redox-triggered allylation[11,12] of unprotected diols
and higher polyols with a pronounced kinetic preference for
primary alcohol dehydrogenation. In this way, chemo- and
stereoselective carbinol CH-allylation of polyols is achieved
in the absence of protecting groups, chiral auxiliaries,
premetallated reagents, and discrete alcohol-to-aldehyde
oxidation (Scheme 1).
À
methods for C H functionalization have been achieved, as
illustrated in the seminal work of Barton,[6b] Murai and
Kakiuchi,[6a] and in more recent studies by the groups of
Davies,[6c] Sanford,[6d] Yu,[6e] Daugulis,[6f] Baran,[6g] and others.
Although methods for site-selective diol oxidation have
been reported, including iridium catalyzed methods,[7,8]
Scheme 1. Site-selective dehydrogenation enables the protecting-
group-free allylation of diols.
À
merged redox-C C bond construction events involving che-
moselective polyol oxidation are unknown.[9] In connection
À
with ongoing studies of C C bond forming hydrogenation, we
recently found that certain iridium and ruthenium complexes
catalyze hydrogen exchange between primary alcohols and
p-unsaturated reactants to generate organometal–aldehyde
pairs that combine to form products of carbonyl addition.[10]
In these transformations, primary alcohol reactants are
subject to oxidation, yet the secondary alcohol products are
not. This fact, and the ability to perform certain transfer
hydrogenative couplings in aqueous organic media, suggested
unprotected polyols might engage in site-selective carbinol
CH-functionalization. Herein, we report that the cyclometal-
lated p-allyliridium C,O-benzoate complex derived from (R)-
or (S)-segphos (segphos = 5,5’-bis(diphenylphosphino)-4,4’-
bi-1,3-benzodioxole) and 4-cyano-3-nitro-benzoic acid cata-
In an initial set of experiments, a series of chromato-
graphically isolated p-allyliridium complexes modified by (S)-
segphos and 4-substituted-3-nitro-C,O-benzoate moieties
were assayed in the allylation of diol 1 (Figure 1). The iridium
Figure 1. Cyclometallated iridium catalysts for site-selective allylation.
[*] Dr. A.-M. R. Dechert-Schmitt, Dr. D. C. Schmitt, Prof. M. J. Krische
University of Texas at Austin, Department of Chemistry and
Biochemistry, 1 University Station—A5300
Austin, TX 78712-1167 (USA)
E-mail: mkrische@mail.utexas.edu
complexes (R)-Ir-b-NO2 and (S)-Ir-a-CN, displayed roughly
equal effectiveness, with the latter providing the 1,3-syn-diol
2a in 67% yield with complete levels of catalyst-directed
diastereoselectivity[13] and without any detectable oxidation
of the unprotected secondary alcohol. Similarly, using the
enantiomeric catalyst (R)-Ir-CN, diol 1 was transformed into
the 1,3-anti-diol 2b in 59% yield without any detectable over-
oxidation. Inspired by these results, diols 3, 5, and 7 were
subjected to the enantiomeric catalysts (S)- and (R)-Ir-CN. In
[**] Acknowledgements is made to the Robert A. Welch Foundation
(F-0038) and the NIH-NIGMS (RO1-GM093905) for financial
support. The Cancer Prevention Research Institute of Texas (CPRIT)
is acknowledged for Postdoctoral Fellowship support (D.C.S.). Dr.
Taichiro Touge of Takasago is thanked for the generous donation of
segphos ligands.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201209863.
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Table 1: Protecting-group-free catalyst-directed diastereoselective C C
each case, the corresponding products of allylation, 4a and
4b, 6a and 6b, and 8a and 8b, respectively, were formed in
good to excellent yields with exceptional control of diaste-
reoselectivity and without oxidation of the unprotected
secondary hydroxy moieties. Notably, the preparation of 4b
in four steps through iterative redox-triggered allylation
represents a synthesis of the C11–C18 fragment of the
oxopolyene macrolide RK-397, which was previously pre-
pared in seven steps from the same starting material
(Scheme 2).[14] Finally, even the unprotected triol 9 is con-
verted into adducts 10a and 10b using the enantiomeric
catalysts (S)- and (R)-Ir-CN, respectively, in good yields and
with high levels of catalyst-directed diastereoselectivity
(Table 1).
coupling of chiral diols 1, 3, 5, 7, and 9 with allyl acetate.[a]
Entry
Diol
Ir catalyst
Product[b]
1
(S)-Ir-a-CN
2
(R)-Ir-a-CN
3
4
5
6
(S)-Ir-a-CN
(R)-Ir-a-CN
(S)-Ir-a-CN
(R)-Ir-a-CN
7
8
(S)-Ir-a-CN
(R)-Ir-a-CN
Scheme 2. Synthesis of the C11–C18 fragment of RK-397, as described
in Table 1. Bn=benzyl, Bz=benzoyl, Cl,MeO-biphep=2,2’-bis(diphe-
nylphosphanyl)-5,5’-dichloro-6,6’-dimethoxy-1,1’-biphenyl, cod=1,5-
cyclooctadiene, DMF=dimethylformamide.
An even more challenging class of substrate is represented
by the unprotected chiral b,g-stereogenic alcohols 11 and 13.
Exposure of 1,3-glycol 11 to the catalyst (S)-Ir-NO2 under
standard conditions delivers the product of allylation 12a as
a 9:1 mixture of diastereomers. In this case, the diastereofacial
bias of the catalyst matches the preference of the transient
aldehyde for Felkin–Anh addition.[15] In the mismatched case
using the enantiomeric catalyst (R)-Ir-NO2, the diastereo-
meric product 12b is formed as a 3:1 mixture of diastereo-
mers. Similarly, the 1,3-glycol 13 is converted into diastereo-
meric allylation products 14a (5:1 d.r.) and 14b (3:1 d.r.)
using (S)-Ir-NO2 and (R)-Ir-NO2, respectively. For the allyla-
tion of unprotected chiral b,g-stereogenic alcohols 11 and 13,
the minor diastereomer obtained principally stems from
epimerization of the transient a-stereogenic aldehyde
(Table 2). Although the levels of catalyst-directed diastereo-
selectivity are modest, these results are significant in view of
the intractability of unprotected b-hydroxy-a-substituted
aldehydes. Whereas substrate-directed allylation of unpro-
tected b-hydroxyaldehydes is possible with allylindium
reagents to provide anti-1,3-diols,[16a] the corresponding 1,3-
syn-allylation is only possible using stoichiometric allyltita-
nium–taddol complexes.[16b]
9
(S)-Ir-a-CN
(R)-Ir-a-CN
10
[a] Reaction conditions: allyl acetate (200 mol%), diol (100 mol%), Ir
catalyst (5 mol%), 4-cyano-3-nitro-benzoic acid (10 mol%), and Cs2CO3
(100 mol%) in THF/H2O (14:1, 0.4 m) at 100 8C for 24 h. [b] Cited yields
are of diastereomeric mixtures isolated by silica gel chromatography.
Stereoisomeric ratios were determined by 1H NMR analysis of crude
reaction mixtures (major diastereomer/sum of two minor diastereo-
mers). See the Supporting Information for further experimental details.
Ac=acetyl, Bn=benzyl, c-Hex=cyclohexyl.
À
catalytic C C bond constructions that occur through the
addition, transfer, or removal of hydrogen potentially provide
a direct means of accessing native molecule structure in an
atom-efficient manner. Site selectivity further enhances
synthetic efficiency by dispensing with the need to install
and remove protecting groups. The site-selective redox-
allylations described herein, which occur by virtue of the
strong kinetic preference of the iridium catalyst for primary
alcohol dehydrogenation, allow chemo- and stereoselective
In conclusion, it has been posited, and generally appre-
ciated, that an ideal synthesis would be composed solely of
construction events.[9,17] As organic compounds, by their very
definition, are compounds composed of carbon and hydrogen,
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Angewandte
Chemie
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Table 2: Protecting-group-free catalyst-directed diastereoselective C C
coupling of chiral b,g-stereogenic alcohols 11 and 13 with allyl acetate.[a]
À
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Entry
1
Diol
Ir catalyst
Product[b]
(S)-Ir-b-NO2
2
3
4
(R)-Ir-b-NO2
(S)-Ir-b-NO2
(R)-Ir-b-NO2
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À
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Received: December 10, 2012
Published online: January 31, 2013
Keywords: allylation · diastereoselectivity · iridium ·
.
polyketides · transfer hydrogenation
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