Traceless Auxiliary Research Articles

Synthesis of Diverse γ-Lactams via Rh-Catalyzed C(sp2)-H Addition to Aliphatic Nitriles.

We herein report an unprecedented pathway to access γ-lactams using acetonitrile analogues as coupling partners without oxidants, ligands, and Lewis acids. The reaction undergoes Rh-catalyzed C(sp2)-H addition to carbon-bound nitriles with the aid of an amide traceless auxiliary followed by an annulation sequence, featuring a broad substrate scope, good functional group tolerance, and excellent chemo/stereoselectivity. Scale-up reactions and late-stage derivatizations highlight the potential synthetic utility of this methodology. A plausible mechanism is proposed based on mechanistic investigations.

Efficient asymmetric synthesis of aryl difluoromethyl sulfoxides and their use to access enantiopure α-difluoromethyl alcohols

The -CHF2 moiety has shown a growing interest in pharmaceutical and agrochemical applications over the last few years. Its introduction is therefore a current research topic for organic chemists. Several groups have reported the synthesis of difluoromethylated compounds. However, the more challenging enantioselective introduction of the difluoromethyl group has been scarcely described yet. We recently developed a new strategy, based on the use of an enantiopure difluoromethyl sulfoxide used as chiral and traceless auxiliary, for the synthesis of highly enantioenriched α-difluoromethyl alcohols. The first method developed in our laboratory aims to access highly stereoenriched α,α-difluoro-β-hydroxysulfoxides through the condensation of the enantiopure difluoromethyl sulfoxide on carbonyl derivatives. It is noteworthy that highly diastereo- and enantioenriched α,α-difluoro-β-hydroxysulfoxides can also be accessed after the diastereoselective reduction of highly enantioenriched α,α-difluoro-β-ketosulfoxides. Finally, the expected difluoromethyl-substituted alcohols can be obtained after removal of the chiral auxiliary with complete retention of stereoenrichment at carbon.

Direct Enantioselective and Regioselective Alkylation of β,γ-Unsaturated Carboxylic Acids with Chiral Lithium Amides as Traceless Auxiliaries.

Efficient asymmetric alkylation of β,γ-unsaturated carboxylic acids without prior functionalization is enabled by chiral lithium amides. Enantioselectivity is imparted by a putative mixed lithium amide-enediolate aggregate that acts a traceless auxiliary formed in situ, allowing for a direct asymmetric alkylation and a simple recovery of the chiral reagent.

MnI /AgI Relay Catalysis: Traceless Diazo-Assisted C(sp2 )-H/C(sp3 )-H Coupling to β-(Hetero)Aryl/Alkenyl Ketones.

An unprecedented MnI /AgI -relay-catalyzed C(sp2 )-H/C(sp3 )-H coupling of (vinyl)arenes with α-diazoketones is reported, wherein the diazo group was exploited as a traceless auxiliary for control of regioselectivity. Challenging β-(hetero)aryl/alkenyl ketones were obtained through this operationally simple approach. The cascade process merges denitrogenation, carbene rearrangement, C-H activation, and hydroarylation/hydroalkenylation. The robustness of this method was demonstrated at preparative scale and applied to late-stage diversification of natural products.

ChemInform Abstract: Direct Enantioselective Conjugate Addition of Carboxylic Acids with Chiral Lithium Amides as Traceless Auxiliaries.

AbstractA broad spectrum of carboxylic acids can be successfully added to α,β‐unsaturated esters after functionalization with optically active auxiliaries of type CPA‐1 and CPA‐2.

Organo-manganese η2-auxiliary directed reactions: a diastereoselective approach to 2,3-allenols.

Propargyl aldehydes underwent isomerization to allenyl aldehydes under mildly basic conditions when complexed to an organo-manganese auxiliary using methylcyclopentadienyl manganese tricarbonyl (MMT). This traceless auxiliary magnifies the axial chirality of the allene moiety, allowing for highly diastereoselective additions to the aldehyde carbonyl and subsequent access to an array of 2,3-allenols. Using this strategy, a nitrile-substituted 2,3-allenol was prepared and efficiently converted to Hagen's gland lactone.

Direct enantioselective conjugate addition of carboxylic acids with chiral lithium amides as traceless auxiliaries.

Michael addition is a premier synthetic method for carbon–carbon and carbon–heteroatom bond formation. Using chiral dilithium amides as traceless auxiliaries, we report the direct enantioselective Michael addition of carboxylic acids. A free carboxyl group in the product provides versatility for further functionalization, and the chiral reagent can be readily recovered by extraction with aqueous acid. The method has been applied in the enantioselective total synthesis of the purported structure of pulveraven B.

Amine‐Promoted Asymmetric (4+2) Annulations for the Enantioselective Synthesis of Tetrahydropyridines: A Traceless and Recoverable Auxiliary Strategy

Gone, without a trace: The in situ reaction of 2-(acetoxymethyl)buta-2,3-dienoate and a secondary amine produces a 2-methylene-3-oxobutanoate equivalent that can be used in asymmetric [4+2] annulations with N-tosylimines to provide tetrahydropyridines in good to excellent yields and enantioselectivities. The amine is easily recovered and acts as a traceless auxiliary.

ChemInform Abstract: Highly Enantioselective Direct Alkylation of Arylacetic Acids with Chiral Lithium Amides as Traceless Auxiliaries.

A direct, highly enantioselective alkylation of arylacetic acids via enediolates using a readily available chiral lithium amide as a stereodirecting reagent has been developed. This approach circumvents the traditional attachment and removal of chiral auxiliaries used currently for this type of transformation. The protocol is operationally simple, and the chiral reagent is readily recoverable.

Highly Enantioselective Direct Alkylation of Arylacetic Acids with Chiral Lithium Amides as Traceless Auxiliaries

A direct, highly enantioselective alkylation of arylacetic acids via enediolates using a readily available chiral lithium amide as a stereodirecting reagent has been developed. This approach circumvents the traditional attachment and removal of chiral auxiliaries used currently for this type of transformation. The protocol is operationally simple, and the chiral reagent is readily recoverable.

ChemInform Abstract: Enders′ SAMP‐Hydrazone as Traceless Auxiliary in the Asymmetric 1,4‐Addition of Cuprates to Enones.

AbstractThe method involves both the addition reaction and the cleavage of the hydrazone auxiliary under hydrolysis and work‐up conditions by use of CuSO4/NH4Cl.

Enders’ SAMP‐Hydrazone as Traceless Auxiliary in the Asymmetric 1,4‐Addition of Cuprates to Enones

AbstractConjugate additions of Gilman cyanocuprates to (S)‐N‐amino‐2‐(methoxymethyl)pyrrolidine (SAMP)‐hydrazones 4, 5 derived from cyclic and acyclic α,β‐unsaturated ketones were investigated. A protocol utilizing copper(II) sulfate/ammonium chloride was evolved, which allowed cleavage of SAMP (S)‐1 under the hydrolysis and work‐up conditions, followed by recovery of the auxiliary with ethylenediaminetetraacetic acid (EDTA). The enantioselectivity of cuprate additions was dominated for cyclic SAMP‐hydrazones 4 by the cuprate alkyl substituent and the ring size, in the case of acyclic arylidene SAMP‐hydrazones 5, however, by the nature of the aryl substituent. Electron‐donating substituents gave poor enantiomeric excesses, whereas electron‐withdrawing groups provided excellent ee values of 98–99%. The configuration of the new stereocenter was determined to be (R). Moreover, a reaction sequence was developed which integrates a tandem 1,4‐addition/methylation and traceless hydrolytic cleavage of the auxiliary (S)‐1 in a one‐pot reaction, resulting in enantiomerically pure methyl ketones 11–13, each of them with>99% ee.