On the Mechanism of the Asymmetric Aldol Addition of Chiral N-Amino Cyclic Carbamate Hydrazones: Evidence of Non-Curtin-Hammett Behavior.

he mechanistic details of the aldol addition of N-amino cyclic carbamate (ACC) hydrazones is provided herein from both an experimental and computational perspective. When the transformation is carried out at room temperature the anti-aldol product is formed exclusively. Under these conditions the anti- and syn-aldolate intermediates are in equilibrium and the transformation is under thermodynamic control.

Synthesis of 1,3-Diketones and β-Keto Thioesters via Soft Enolization.

Ketones and thioesters undergo soft enolization and acylation using crude acid chlorides on treatment with MgBr·OEt and -PrNEt to give 1,3-diketones and β-keto thioesters, respectively. The use of crude acid chlorides adds efficiency and cost reduction by avoiding the need to purify and/or purchase them. The process is conducted in a direct fashion that does not require prior enolate formation, further enhancing its efficiency and making it very easy to carry out.

The antimalarial drug mefloquine enhances TP53 premature termination codon readthrough by aminoglycoside G418.

Nonsense mutations constitute ~10% of TP53 mutations in cancer. They introduce a premature termination codon that gives rise to truncated p53 protein with impaired function. The aminoglycoside G418 can induce TP53 premature termination codon readthrough and thus increase cellular levels of full-length protein.

A Mismatch-Free Strategy for the Diastereoselective α,α-Bisalkylation of Chiral Nonracemic Methyl Ketones.

A chiral auxiliary-based diastereoselective transformation that entirely avoids the stereochemically mismatched pairing, providing equally high levels of asymmetric induction in the formation of each diastereomer is described. In particular, we show that chiral nonracemic methyl ketones undergo α,α-bisalkylation using phenylalanine-derived N-amino cyclic carbamate (ACC) auxiliaries with essentially perfect diastereoselectivity, as well as excellent yield and regioselectivity. Significantly, with the use of a single enantiomer of the auxiliary, either diastereomeric product can be synthesized with an equally high level of asymmetric induction.

Asymmetric Induction in Hydroacylation by Cooperative Iminium Ion-Transition-Metal Catalysis.

A new strategy for the rhodium-catalyzed enantioselective hydroacylation is described. This has been achieved through the merger of iminium ion catalysis and transition-metal catalysis such that asymmetric induction derives from a readily accessible, inexpensive chiral nonracemic secondary amine catalyst rather than a chiral nonracemic phosphine as is typical of conventional asymmetric hydroacylation methods.

Asymmetric Synthesis of (+)-anti- and (-)-syn-Mefloquine Hydrochloride.

The asymmetric (er > 99:1) total synthesis of (+)-anti- and (-)-syn-mefloquine hydrochloride from a common intermediate is described. The Sharpless asymmetric dihydroxylation is the key asymmetric transformation used in the synthesis of this intermediate. It is carried out on an olefin that is accessed in three steps from commercially available materials, making the overall synthetic sequence very concise.

Direct carbon-carbon bond formation via reductive soft enolization: a syn-selective Mannich addition of α-iodo thioesters.

The β-amino carboxylic acid moiety is a key feature of numerous important biologically active compounds. We describe a syn-selective direct Mannich addition reaction that uses α-iodo thioesters and sulfonyl imines and produces β-amino thioesters. Enolate formation is achieved by reductive soft enolization.

Diastereoselective addition of Grignard reagents to α-epoxy N-sulfonyl hydrazones.

The α-alkylation of ketones and their derivatives by the addition of their corresponding enolates to alkyl halides is a fundamental synthetic transformation, but its utility is limited because the key bond-forming step proceeds in a bimolecular nucleophilic substitution fashion. Here we describe how an umpolung strategy that involves the addition of Grignard reagents to α-epoxy N-sulfonyl hydrazones-directed by the alkoxide of the 1-azo-3-alkoxy propenes formed in situ via base-induced ring opening of the epoxide-leads to the syn-selective production of α-alkyl-β-hydroxy N-sulfonyl hydrazones with α-quaternary centres. This transformation is remarkable in its ability to incorporate an unprecedented range of carbon-based substituents, which include primary, secondary and tertiary alkyl, as well as alkenyl, aryl, allenyl and alkynyl groups.

A Concise and Highly Enantioselective Total Synthesis of (+)-anti- and (-)-syn-Mefloquine Hydrochloride: Definitive Absolute Stereochemical Assignment of the Mefloquines.

A concise asymmetric (>99:1 e.r.) total synthesis of (+)-anti- and (-)-syn-mefloquine hydrochloride from a common intermediate is described.

Asymmetric anti-aldol addition of achiral ketones via chiral N-amino cyclic carbamate hydrazones.

The asymmetric anti-aldol addition of ketone-derived donors and aldehyde acceptors is described. Asymmetric induction is achieved through the use of chiral N-amino cyclic carbamate (ACC) auxiliaries. The transformation exhibits essentially perfect anti-diastereoselectivity and enantioselectivity, and has the unusual feature of proceeding via thermodynamic, rather than kinetic control.

Catalytic asymmetric addition of thiols to nitrosoalkenes leading to chiral non-racemic α-sulfenyl ketones.

The first asymmetric organocatalytic sulfenylation of in situ derived nitrosoalkenes leading to chiral nonracemic α-sulfenylated ketones is described. The transformation proceeds in an umpolung fashion, relative to enolate/azaenolate methods, and uses simple thiols, thereby obviating the need for electrophilic sulfur reagents.

Asymmetric total synthesis of the antimalarial drug (+)-mefloquine hydrochloride via chiral N-amino cyclic carbamate hydrazones.

Mefloquine hydrochloride is an important antimalarial drug. It is currently manufactured and administered in racemic form; however there are indications regarding the biological activity of the two enantiomers that suggest the superiority of the (+)-form. The asymmetric total synthesis of the (+)-enantiomer of mefloquine hydrochloride is described.

Asymmetric total synthesis of (+)- and (-)-clusianone and (+)- and (-)-clusianone methyl enol ether via ACC alkylation and evaluation of their anti-HIV activity.

The total asymmetric synthesis of (+)- and (-)-clusianone and (+)- and (-)-clusianone methyl enol ether is reported. Asymmetric induction is achieved through the use of ACC alkylation, providing the key intermediates with an er of 99:1. The four synthetic compounds were evaluated for their anti-HIV activity.

Development of a strategy for the asymmetric synthesis of polycyclic polyprenylated acylphloroglucinols via N-amino cyclic carbamate hydrazones: application to the total synthesis of (+)-clusianone.

A broadly applicable asymmetric synthetic strategy utilizing N-amino cyclic carbamate alkylation that provides access to the various stereochemical permutations of a common structural motif found in many polycyclic polyprenylated acylphloroglucinols is described. The utility of this methodology is demonstrated through the first asymmetric total synthesis of the antiviral agent (+)-clusianone.

Direct carbon-carbon bond formation via soft enolization: aldol addition of α-halogenated thioesters.

α-Halo thioesters undergo soft enolization and syn-selective direct aldol addition to aldehydes in the presence of MgBr(2)·OEt(2) and i-Pr(2)NEt to produce α-halo-β-hydroxy thioesters.

Direct carbon-carbon bond formation via reductive soft enolization: a kinetically controlled syn-aldol addition of α-halo thioesters and enolizable aldehydes.

The direct addition of enolizable aldehydes and α-halo thioesters to produce β-hydroxy thioesters enabled by reductive soft enolization is reported. The transformation is operationally simple and efficient and has the unusual feature of giving high syn-selectivity, which is the opposite of that produced for (thio)esters under conventional conditions. Moreover, excellent diastereoselectivity results when a chiral nonracemic α-hydroxy aldehyde derivative is used.

Direct carbon-carbon bond formation via soft enolization: a biomimetic asymmetric Mannich reaction of phenylacetate thioesters.

An asymmetric Mannich reaction of phenylacetate thioesters and sulfonylimines using cinchona alkaloid-based amino (thio)urea catalysts is reported that employs proximity-assisted soft enolization. This approach to enolization is based on the cooperative action of a carbonyl-activating hydrogen bonding (thio)urea moiety and an amine base contained within a single catalytic entity to facilitate intracomplex deprotonation. Significantly, this allows thioesters over a range of acidity to react efficiently, thereby opening the door to the development of a general mode of enolization-based organocatalysis of monocarboxylic acid derivatives.

Copper(I)-catalyzed addition of Grignard reagents to in situ-derived N-sulfonyl azoalkenes: an umpolung alkylation procedure applicable to the formation of up to three contiguous quaternary centers.

The alpha-alkylation of N-sulfonyl hydrazones via in situ-derived azoalkenes provides an umpolung approach to ketone alpha-alkylation that has considerable potential with regard to catalysis and the direct incorporation of functionality not amenable to the use of enolate chemistry. Herein, we describe the first Cu(I)-catalyzed addition of Grignard reagents to in situ-derived N-sulfonyl azoalkenes. This method is remarkable in its ability to deliver highly sterically hindered compounds that would be difficult or impossible to synthesize via traditional enolate chemistry, including those having up to three contiguous quaternary centers.

Direct carbon-carbon bond formation via chemoselective soft enolization of thioesters: a remarkably simple and versatile crossed-Claisen reaction applied to the synthesis of LY294002.

Thioesters undergo chemoselective soft enolization and acylation by N-acylbenzotriazoles on treatment with MgBr2 x OEt2 and i-Pr2NEt to give beta-keto thioesters. Prior enolate formation is not required, and the reaction is conducted using untreated CH2Cl2 open to the air. The coupled products are stable synthetic equivalents of beta-keto acids and can be converted directly into beta-keto esters, beta-keto amides, and beta-diketones under mild conditions.