The olefin metathesis reaction is
finding increasing use in drug
discovery and process chemistry, with a number of applications now
implemented at commercial manufacturing scale. Catalyst improvements
over the past decade have allowed use of the metathesis reaction with
highly functionalized substrates, allowing chemists to access increasingly
diverse chemical space, including most notably macrocycles, constrained
small ring spirocycles, and fused-ring systems. For scientists employed
in the pharmaceutical industry, the patent literature is the primary
avenue for communication of synthetic routes to drug candidates. While
most examples of the metathesis reaction in the patent literature
offer only sketchy experimental details and provide little context
on reaction development, the wide scope of substrates within the pharmaceutical
patent literature provides a true indication of reaction scope and
functional group compatibility. The current article reviews applications
of the metathesis reactions in drug discovery and development in the
pharmaceutical industry disclosed in the patent literature from January
2016 to August 2017.
Individual enantiomers of substituted cyclohexyl diazoacetates or
2-octyl diazoacetates matched with a
configurationally suitable chiral dirhodium(II) carboxamidate
catalyst provide an effective methodology for the
synthesis of lactones with exceptional diastereo- and regiocontrol.
Enantiomerically pure
(1S,2R)-cis-2-methylcyclohexyl diazoacetate forms the
all-cis-(1R,5R,9R)-9-methyl-2-oxabicyclo[4.3.0]nonan-3-one
with complete diastereocontrol in reactions catalyzed by dirhodium(II)
tetrakis[methyl
1-(3-phenylpropanoyl)-2-oxoimidazolidine-4(R)-carboxylate], Rh2(4(S)-MPPIM)4,
but the configurational mismatch results in a mixture of products.
The same
diazoacetate produces
(1S,5R)-5-methyl-2-oxabicyclo[4.3.0]nonan-3-one
with virtually complete selectivity by catalysis
with dirhodium(II) tetrakis[methyl
2-oxopyrrolidine-5(S)-carboxylate],
Rh2(5(S)-MEPY)4. Similarly
high stereo- and
regiocontrol is also achieved with enantiomerically pure
trans-2-methylcyclohexyl diazoacetates. Product
control
from insertion reactions of d- or l-menthyl
diazoacetate and (+)-neomenthyl diazoacetate from the
configurational
match with dirhodium(II) catalyst results in the formation of one
C−H insertion product in high yield. The exceedingly high product diastereoselection observed in these reactions is
consistent with virtually exclusive insertion
into equatorial C−H bonds. The catalyst-dependent selective
formation of a cis-disubstituted γ-butyrolactone or
a
β-lactone from 2-octyl diazoacetate has been achieved. Control
of product diastereoselectivity and regioselectivity
in C−H insertion reactions is explained by conformational suitability
in configurational match/mismatch of catalyst
and carbene.
1,3-Dioxan-5-yl diazoacetates are valuable substrates for highly diastereoselective and enantioselective carbon-hydrogen insertion reactions. trans-2-(tert-Butyl)-1,3-dioxan-5-yl diazoacetate is a direct precursor to 2-deoxyribono-1,4-lactone in up to 81% ee, whereas cis-2-(tert-butyl)-1,3-dioxan-5-yl diazoacetate yields only the protected 2-deoxyxylono-1,4-lactone in up to 96% ee. However, trans-2-aryl-1,3-dioxan-5-yl diazoacetate (aryl = phenyl or 2-naphthyl) forms the precursor to 2-deoxyxylono-1,4-lactone in up to 95% ee but with the mirror image configuration of that produced from the trans-2-(tert-butyl) analogue. The catalysts that are most suitable for these carbon-hydrogen insertion reactions are chiral dirhodium(II) carboxamidates. 1,3-Dialkoxy-2-propyl diazoacetates give mainly 2-deoxyxylono-1,4-lactone derivatives (>90:10) with generally high enantiocontrol, but replacement of hydrogen at the 2-position of these 2-propyl diazoacetates led to a mixture of products.
Catalytic intramolecular cyclopropanation by diazoacetates onto a
remote carbon−carbon double bond
resulting in the formation of 9- to 20-membered ring lactones is
reported. When competition exists between proximal
allylic and remote olefinic cyclopropanation, macrocyclization is
favored by catalysts of increasing electrophilicity:
Rh2(pfb)4 > Rh2(OAc)4,
Cu(MeCN)4PF6 > Rh(cap)4,
and Cu(acac)2. Terpene systems,
cis-nerolidyl diazoacetate
and related structures, malonic ester derivatives, and those with
1,2-benzenedimethanol, pentaerythritol, and
cis-2-buten-1,4-diol linkers all undergo cyclopropanation onto the most remote
carbon−carbon double bond in good yield.
Generally, only one cyclopropane diastereoisomer is observed, but
increasing ring size allows stereochemistries in
macrocyclization reactions that resemble those of their intermolecular
cyclopropanation counterparts. In one system
(25) macrocyclic addition is accompanied by ylide
formation/[2,3]-sigmatropic rearrangement resulting in the
formation
of a 10-membered ring lactone. Overall, few limits to macrocycle
formation are evident, and the methodology
appears to have general applicability.
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