19 research outputs found
Diastereo- and Enantioselective Synthesis of Bi- and Tricyclic <i>N</i>‑Heterocycle-Fused β‑Lactones
The utility of the nucleophile-catalyzed
(Lewis base) aldol lactonization
(NCAL) process for the diastereo- and enantioselective synthesis of <i>N</i>-heterocycle-fused-β-lactones from <i>N</i>-linked ketoacids is described. A series of bi- and tricyclic, <i>N</i>-heterocycle-fused, β-lactones were first synthesized
in racemic fashion via the NCAL process with excellent diastereoselectivity
(>19:1) utilizing 4-pyrrolidinopyridine as an effective achiral
Lewis
base. A catalytic, enantioselective version of this NCAL process using
isothiourea catalysts provided access to bicyclic β-lactone-fused, <i>N</i>-heterocycles in moderate to good yields (up to 80%) with
high enantiocontrol (up to >99:1 er). An unusual diastereodivergent
NCAL process was discovered that leads to two different products;
a tricyclic <i>N</i>-heterocycle-fused β-lactone and
a bicyclic enamine derived from in situ decarboxylation of the diastereomeric
tricyclic β-lactone. The reactivity of these adducts was briefly
explored
Multicomponent, Enantioselective Michael–Michael-Aldol-β-Lactonizations Delivering Complex β‑Lactones
Optically active,
tertiary amine Lewis bases react with unsaturated
acid chlorides to deliver chiral, α,β-unsaturated acylammonium
salts. These intermediates participate in a catalytic, enantioselective,
three-component process delivering bi- and tricyclic β-lactones
through a Michael–Michael-aldol-β-lactonization. In a
single operation, the described multicomponent, organocascade process
forms complex bi- and tricyclic β-lactones by generating four
new bonds, two rings, and up to four contiguous stereocenters. In
the racemic series, yields of 22–75% were achieved using 4-pyrrolidinopyridine
as Lewis base. In the enantioselective series employing isothiourea
catalysts, a kinetic resolution of the initially formed racemic Michael
adduct appears operative, providing yields of 46% to quantitative
(based on 50% max) with up to 94:6 er. Some evidence for a dynamic
kinetic asymmetric transformation for tricyclic-β-lactone <b>1d</b> was obtained following optimization (yields up to 61%,
94:6 er) through a presumed reversible Michael
Concise Synthesis of the Isothiourea Organocatalysts Homobenzotetramisole and Derivatives
A concise approach to the synthesis
of homobenzotetramisole and
derivatives is described. Our strategy features a one-pot acylation–cyclization
of 2-aminobenzothiazole with α,β-unsaturated acid chlorides
to afford annulated pyrimidones. Subsequent Grignard addition followed
by acid-promoted dehydration and reduction provides good overall yields
of the title compounds in three steps and in quantities up to 10 g.
The synthesis employs low-cost and readily available starting materials
and enables access to both optical antipodes of these increasingly
useful nucleophilic catalysts following chiral separation
A Diastereoselective, Nucleophile-Promoted Aldol-Lactonization of Ketoacids Leading to Bicyclic-β-Lactones
An improved, tandem acid activation/aldol-lactonization
process
is described. This more practical protocol shortens reaction times
for the construction of bicyclic β-lactones from ketoacids and
implements the use of commercially available reagents <i>p</i>-toluenesulfonyl chloride (<i>p</i>-TsCl) as activator
and 4-dimethylaminopyridine (4-DMAP) as nucleophilic promoter (Lewis
base). Substrates with β-substituents, with respect to the carboxylic
acid, consistently showed excellent levels of diastereoselectivity
during the bis-cyclization event
Acylammonium Salts as Dienophiles in Diels–Alder/Lactonization Organocascades
α,β-Unsaturated acylammonium
salts, generated <i>in situ</i> from commodity acid chlorides
and a chiral isothiourea
organocatalyst, comprise a new and versatile family of chiral
dienophiles for the venerable Diels–Alder (DA) cycloaddition.
Their reactivity is unveiled through a highly diastereo- and enantioselective
Diels–Alder/lactonization organocascade that generates <i>cis</i>- and <i>trans</i>-fused bicyclic γ-
and δ-lactones bearing up to four contiguous stereocenters.
Moreover, the first examples of DA-initiated, stereodivergent
organocascades are described delivering complex scaffolds found
in bioactive compounds. The origins of stereoselectivity are
rationalized through computational studies. In addition, the utility
of this methodology is demonstrated through a concise approach to
the core structure of glaciolide and formal syntheses of fraxinellone,
trisporic acids, and trisporols
Cyclopropanations of Olefin-Containing Natural Products for Simultaneous Arming and Structure Activity Studies
Cyclopropanations of alkene-containing natural products that proceed under mild conditions are reported for simultaneous arming and structure–activity relationship studies. An alkynyl diazo ester under Rh(II) catalysis is employed for cyclopropanations of electron-rich olefins while an alkynyl sulfonium ylide is used for electron-poor olefins. This approach enables simultaneous natural product derivatization for SAR studies and arming (i.e., via alkyne attachment) for subsequent conjugation with reporter tags (e.g., biotin, fluorophores, photoaffinity labels) for mechanism of action studies including cellular target identification and proteome profiling experiments
Mechanistic Investigations of the ZnCl<sub>2</sub>-Mediated Tandem Mukaiyama Aldol Lactonization: Evidence for Asynchronous, Concerted Transition States and Discovery of 2-Oxopyridyl Ketene Acetal Variants
The ZnCl<sub>2</sub>-mediated tandem Mukaiyama aldol
lactonization
(TMAL) reaction of aldehydes and thiopyridyl ketene acetals provides
a versatile, highly diastereoselective approach to <i>trans</i>-1,2-disubstituted β-lactones. Mechanistic and theoretical
studies described herein demonstrate that both the efficiency of this
process and the high diastereoselectivity are highly dependent upon
the type of ketene acetal employed but independent of ketene acetal
geometry. Significantly, we propose a novel and distinct mechanistic
pathway for the ZnCl<sub>2</sub>-mediated TMAL process versus other
Mukaiyama aldol reactions based on our experimental evidence to date
and further supported by calculations (B3LYP/BSI). Contrary to the
commonly invoked mechanistic extremes of [2+2] cycloaddition and aldol
lactonization mechanisms, investigations of the TMAL process suggest
a concerted but asynchronous transition state between aldehydes and
thiopyridyl ketene acetals. These calculations support a boat-like
transition state that differs from commonly invoked Mukaiyama “open”
or Zimmerman–Traxler “chair-like” transition-state
models. Furthermore, experimental studies support the beneficial effect
of pre-coordination between ZnCl<sub>2</sub> and thiopyridyl ketene
acetals prior to aldehyde addition for optimal reaction rates. Our
previously proposed, silylated β-lactone intermediate that led
to successful TMAL-based cascade sequences is also supported by the
described calculations and ancillary experiments. These findings suggested
that a similar TMAL process leading to β-lactones would be possible
with an oxopyridyl ketene acetal, and this was confirmed experimentally,
leading to a novel TMAL process that proceeds with efficiency comparable
to that of the thiopyridyl system
Dyotropic Rearrangements of Fused Tricyclic β‑Lactones: Application to the Synthesis of (−)-Curcumanolide A and (−)-Curcumalactone
Dyotropic rearrangements of fused, tricyclic β-lactones
are
described that proceed via unprecedented stereospecific, 1,2-acyl
migrations delivering bridged, spiro-γ-butyrolactones. A unique
example of this dyotropic process involves a fused bis-lactone possessing
both β- and δ-lactone moieties which enabled rapid access
to the core structures of curcumanolide A and curcumalactone. Our
current mechanistic understanding of the latter dyotropic process,
based on computational studies, is also described. Other key transformations
in the described divergent syntheses of (−)-curcumanolide A
and (−)-curcumalactone from a common intermediate (11 and 12
steps from 2-methyl-1,3-cyclopentanedione, respectively), include
a catalytic, asymmetric nucleophile (Lewis base)-catalyzed aldol-lactonization
(NCAL) leading to a tricyclic β-lactone, a Baeyer–Villiger
oxidation in the presence of a β-lactone, and highly facial-selective
and stereocomplementary reductions of an intermediate spirocyclic
enoate. The described dyotropic rearrangements significantly alter
the topology of the starting tricyclic β-lactone, providing
access to complex spirocyclic cyclopentyl-γ-lactones and bis-γ-lactones
in a single synthetic operation
Dyotropic Rearrangements of Fused Tricyclic β‑Lactones: Application to the Synthesis of (−)-Curcumanolide A and (−)-Curcumalactone
Dyotropic rearrangements of fused, tricyclic β-lactones
are
described that proceed via unprecedented stereospecific, 1,2-acyl
migrations delivering bridged, spiro-γ-butyrolactones. A unique
example of this dyotropic process involves a fused bis-lactone possessing
both β- and δ-lactone moieties which enabled rapid access
to the core structures of curcumanolide A and curcumalactone. Our
current mechanistic understanding of the latter dyotropic process,
based on computational studies, is also described. Other key transformations
in the described divergent syntheses of (−)-curcumanolide A
and (−)-curcumalactone from a common intermediate (11 and 12
steps from 2-methyl-1,3-cyclopentanedione, respectively), include
a catalytic, asymmetric nucleophile (Lewis base)-catalyzed aldol-lactonization
(NCAL) leading to a tricyclic β-lactone, a Baeyer–Villiger
oxidation in the presence of a β-lactone, and highly facial-selective
and stereocomplementary reductions of an intermediate spirocyclic
enoate. The described dyotropic rearrangements significantly alter
the topology of the starting tricyclic β-lactone, providing
access to complex spirocyclic cyclopentyl-γ-lactones and bis-γ-lactones
in a single synthetic operation
Chemical Mechanism of the Phosphotriesterase from <i>Sphingobium</i> sp. Strain TCM1, an Enzyme Capable of Hydrolyzing Organophosphate Flame Retardants
The mechanism of action of the manganese-dependent
phosphotriesterase
from <i>Sphingobium</i> sp. strain TCM1 that is capable
of hydrolyzing organophosphate flame retardants was determined. The
enzyme was shown to hydrolyze the <i>R</i><sub>P</sub>-enantiomer
of <i>O</i>-methyl <i>O</i>-cyclohexyl <i>p</i>-nitrophenyl thiophosphate with net inversion of configuration
and without the formation of a covalent reaction intermediate. These
results demonstrate that the enzyme catalyzes the hydrolysis of substrates
by activation of a nucleophilic water molecule for direct attack at
the phosphorus center