13 research outputs found
A Formal Synthesis of (−)-Englerin A by Relay Ring Closing Metathesis and Transannular Etherification
A bicyclization approach to englerin A has culminated in a formal asymmetric total synthesis. Key transformations in the 10-step sequence are a regiospecific epoxide opening and a relay ene-yne-ene metathesis that converts linear substrates specifically to Δ<sup>4,6</sup>-guaiadiene-9,10 diol derivatives. Regiospecific functionalization of the diene moiety installs the oxygen bridge required for the englerin tricyclic core
Five Easy Pieces. The Total Synthesis of Phosphoiodyn A (and Placotylene A)
The
convergent total synthesis of the marine natural product phosphoiodyn
A, a nanomolar agonist of human peroxisome proliferator-activated
receptor delta (hPPARδ), was achieved in five steps total from
commercially available and inexpensive starting materials. The synthesis
relies on the unprecedented regioselective hydrozirconation of a terminal
acetylene in the presence of a conjugated 1,3-diyne and on ammonolysis
of a β-chlorophosphonic acid monoester. The scheme also provides
the newly isolated placotylene A, an inhibitor of bone marrow-derived
macrophage (BMM) differentiation
Intermolecular Radical Cation Diels–Alder (RCDA) Reaction of Bicyclooctadienes: Biomimetic Formal Total Synthesis of Kingianin A and Total Syntheses of Kingianins D, F, H, and J
Three
endo bicyclooctadienol dimers corresponding to kingianins
A and H, D, and F and J were obtained by the intermolecular radical
cation Diels–Alder (RCDA) reaction. Each isomer was cleanly
isolated without the aid of preparative HPLC. Kingianins D, F, H,
and J were prepared by way of these intermediates from commercially
available materials in 10, 13, 9, and 17 steps, respectively. Kingianin
A has already been prepared from one of these compounds. Completion
of the synthesis of kingianin H relied on Manchand’s one-step,
three-carbon homologation
Total Synthesis of Kingianin A
A 12-step synthesis of kingianin A, an inhibitor of the antiapoptotic protein Bcl-xL, is based on a radical cation Diels–Alder reaction (RCDA). This approach is thought to be biomimetic. The use of a tether in the key RCDA step controls the regiochemistry of the cycloaddition, leading to the desired core structure and a separable diastereomer
Total Synthesis of Kingianin A
A 12-step synthesis of kingianin A, an inhibitor of the antiapoptotic protein Bcl-xL, is based on a radical cation Diels–Alder reaction (RCDA). This approach is thought to be biomimetic. The use of a tether in the key RCDA step controls the regiochemistry of the cycloaddition, leading to the desired core structure and a separable diastereomer
Asymmetric Induction in 8Ï€ Electrocyclizations. Design of a Removable Chiral Auxiliary
The pseudo <i>C</i><sub>2</sub> symmetric <i>trans</i> diphenyl oxazoline group acts as an effective chiral auxiliary in the 8Ï€, 6Ï€ tandem electrocyclization of a substituted tetraene 1-carboxylic acid. Assignment of absolute stereochemistry to the [4.2.0] bicyclooctadiene product supports a model in which both <i>s-cis</i> and <i>s-trans</i> conformations favor the transition states with the same helical twist. This assignment prefaces the development of analogs of SNF4435 C and D. These natural products demonstrate activity as androgen receptor antagonists and as multidrug resistance (mdr) reversal agents
Asymmetric Induction in 8Ï€ Electrocyclizations. Design of a Removable Chiral Auxiliary
The pseudo <i>C</i><sub>2</sub> symmetric <i>trans</i> diphenyl oxazoline group acts as an effective chiral auxiliary in the 8Ï€, 6Ï€ tandem electrocyclization of a substituted tetraene 1-carboxylic acid. Assignment of absolute stereochemistry to the [4.2.0] bicyclooctadiene product supports a model in which both <i>s-cis</i> and <i>s-trans</i> conformations favor the transition states with the same helical twist. This assignment prefaces the development of analogs of SNF4435 C and D. These natural products demonstrate activity as androgen receptor antagonists and as multidrug resistance (mdr) reversal agents
A Bicyclo[4.2.0]octene-Derived Monomer Provides Completely Linear Alternating Copolymers via Alternating Ring-Opening Metathesis Polymerization (AROMP)
Strained bicyclic carbomethoxy olefins
were utilized as substrates
in alternating ring-opening metathesis polymerization and found to
provide low-dispersity polymers with novel backbones. The polymerization
of methyl bicyclo[4.2.0]Âoct-7-ene-7-carboxylate with cyclohexene in
the presence of the fast-initiating Grubbs catalyst (H<sub>2</sub>IMes)Â(3-Br-Pyr)<sub>2</sub>Cl<sub>2</sub>Ruî—»CHPh leads to
a completely linear as well as alternating copolymer, as demonstrated
by NMR spectroscopy, isotopic labeling, and gel permeation chromatography.
In contrast, intramolecular chain-transfer reactions were observed
with [5.2.0] and [3.2.0] bicyclic carbomethoxy olefins, although to
a lesser extent than with the previously reported monocyclic cyclobutenecarboxylic
ester monomers [Song, A.; Parker, K. A.; Sampson, N. S. J. Am. Chem. Soc. 2009, 131, 3444]. Inclusion of cyclohexyl rings fused to the copolymer backbone
minimizes intramolecular chain-transfer reactions and provides a framework
for creating alternating functionality in a one-step polymerization
Total Synthesis of (±)-Bisabosqual A
The synthesis of the novel squalene synthase inhibitor,
bisabosqual
A, was completed in 14 steps (longest linear sequence) from commercially
available starting materials. The doubly convergent route employs
a tandem 5-exo, 6-exo radical cyclization as the key step. This reaction
assembles the fully functionalized tetracyclic core and introduces
three stereogenic centers. Other effective transformations are the
regioselective deoxygenation of an advanced enone intermediate and
the chemo- and diastereoselective addition of trimethylaluminum to
a ketone in the presence of esters
Importance of a 4‑Alkyl Substituent for Activity in the Englerin Series
The ring closing
metathesis/transannular etherification approach
to the englerin nucleus was adapted to provide two key intermediates
for analogue synthesis: the 4-desmethyl Δ<sup>5,6</sup> tricycle
and the 4-oxo Δ<sup>5,6</sup> tricycle. The former was elaborated
to 4-desmethyl englerin A and the latter served as a common precursor
for englerin A, 4-ethyl englerin A, and 4-isopropyl englerin A. 4-Desmethyl
englerin A was less active than the natural product by an order of
magnitude, but the 4-ethyl and 4-isopropyl analogues were comparable
in activity to englerin A. These results are consistent with the premise
that the 4-alkyl group enforces the binding conformation of the cinnamoyl
ester substituent. Furthermore, they suggest that 4-alkyl englerin
structures may prove to be useful tool compounds