Functionalized gem-difluoro beta- and gamma-lactams were synthesized through a novel intramolecular hydroamination reaction of difluoropropargyl amides. beta-Lactams were obtained via a Baldwin disfavored 4-exo-digonal cyclization using palladium acetate as the catalyst, whereas gamma-lactams were produced under basic conditions. Acid hydration of gamma-lactams produced ketoamides or hemiaminals selectively.

Asymmetric conjugate addition of α-heterosubstituted aldehydes such as α-amido and α-alkoxy aldehydes to vinyl sulfone was effected under the influence of structurally rigid trans-diamine-based Tf-amido organocatalyst (S,S)-2 with a dihydroanthracene framework to furnish α,α-dialkyl(amido)aldehydes and α,α-dialkyl(alkoxy)aldehydes with high enantioselectivity. The chiral efficiency of the structurally unique catalyst (S,S)-2 is apparent in comparison with (S,S)-1 and (S,S)-4 with similar functionality.

From a practical point of view, the development of a novel approach for the asymmetric synthesis of both enantiomeric products through catalytic asymmetric transformations with the same chiral catalyst would be very useful.[1] Various types of chiral metal complexes have already been introduced. [2] However, strictly speaking, many of these examples have employed a distinct three-dimensional association between a chiral ligand and different metals, or vice versa. In marked contrast, an initial effort for the synthetic application of chiral organocatalysts has appeared very recently, but has not been developed to a synthetically useful level. [3] In this context, we explored the capability of an additive to induce an unexpected inversion in catalyst selectivity for certain asymmetric transformations catalyzed by a single chiral organocatalyst. Herein we present the first practical example of such a system, employing achiral, organic acids as reliable additives in asymmetric, direct aldol reactions catalyzed by a chiral, cisdiamine-based, Tf-amido organocatalyst of type 1 (Tf = trifluoromethanesulfonyl Scheme 1). [4][5][6][7] Initally, the asymmetric direct aldol reaction of cyclohexanone and a-keto ester 3 a was carried out with organocatalyst 1 a to establish the optimum reaction conditions. The treatment of cyclohexanone 2 a and a-keto ester 3 a with 20 mol % of 1 a in methanol at 0 8C gave the corresponding aldol products 4 a in moderate yields; the major isomer, syn-4 a, was obtained with high enantioselectivity (Table 1, entry 1). We had previously observed a remarkable enhancement in enantioselectivity for the asymmetric conjugate addition of heterosubstituted aldehydes to vinyl sulfones by using bulky benzoic acid additives under the influence of a structurally rigid, trans-diamine-based, Tf-amide catalyst with a dihydroanthracene framework. [8] This finding prompted us to test a series of benzoic acid derivatives to probe their potential for the reversal of enantioselectivity in these products as well. [a]Entry Additive [b] Yield [c] [%] d.r. [d] (syn/anti) aldol ee [e] [%]

The transition metal-catalyzed direct activation of electron deficient triple bonds was investigated by using the combined electron withdrawing effects of two fluorine atoms to modulate the electronic density of the triple bond. With use of catalytic amounts of AgNO3 (10 mol %) the synthesis of substituted 3,3-difluoro-4,5-dihydrofurans from gem-difluorohomopropargyl alcohols occurred in excellent NMR yields. Treatment of these dihydrofurans with SiO2 or Pd/H2 yielded the corresponding 3-fluorinated furans and 3,3-difluorotetrahydrofurans.

A scalable synthesis of 2,2-difluorohomopropargyl esters was achieved using a magnesium-promoted Barbier reaction of substituted difluoropropargyl bromides with alkyl chloroformates. These 2,2-difluorohomopropargyl esters were effective precursors in the synthesis of homopropargylic amides-by aminolysis using AlMe3, as well as of ketones-through the reaction of the corresponding Weinreb amides with Grignard reagents. Ring closing metathesis using difluorinated 1,7-enyne carbonyl compounds furnished six-membered diene products, which were used as susbstrates in a Diels-Alder reaction to afford 4,4-difluoroisoquinolin-3-ones. The [2 + 2 + 2] cycloaddition of alkynes with fluorinated 1,7-diyne amides gave 4,4-difluoro-1,4-dihydro-3(2H)-isoquinolinone derivatives regioselectively.

Fluorination of dienamines generated by α-branched enals and 6′-hydroxy-9-amino-9-deoxy-epi-quinidine (30 mol %) with NSFI show excellent α-regioselectivity to construct allylic fluorides containing a highly stereocontrolled quaternary fluorinated carbon (E/Z ≥ 20/1 and up to 93% enantiometric excess (ee)). By DFT calculation, the quinuclidine moiety of the catalyst was shown to function as a coordinating group to promote a reaction at the proximal α-position, and the nonclassical CH hydrogen bond plays an important role in the high enantioselectivity.

The iodocyclization of gem-difluorohomoallenyl and gem-difluorohomopropargyl alcohols with I2 and ICl, respectively, produced the corresponding fluorinated iodofuran analogues in good yields. The iodo substituent in fluorinated 4-iodofurans was utilized as a synthetic handle to prepare multi-substituted 3-fluorofurans using a Suzuki cross-coupling reaction. The yields of both iodocyclization of gem-difluorohomopropargyl alcohol and subsequent Suzuki coupling were dramatically enhanced by microwave irradiation.

An indium-mediated Barbier-type reaction of difluoropropargyl bromide with several aldehydes in aqueous media was enhanced by a catalytic amount of a lanthanide triflate (5 mol %). The reaction gave the corresponding beta,beta-difluorohomopropargyl alcohols with high regioselectivity. The [2 + 2 + 2] alkyne cyclotrimerization of beta,beta-difluorohomopropargyl alcohols with monosubstituted acetylenes produced 4,4-difluoroisochromans in good yields with moderate regioselectivity.