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An approach is developed for the syntheses of the Boc-monoprotected derivatives of the cyclobutane diamines, which is aimed at the preparation of multigram amounts of the compounds. These novel synthetic schemes have used classical malonate alkylation chemistry for the construction of cyclobutane rings.

A new approach for a facile and versatile synthesis of functionalized quinolines from 3-formylchromone and substituted anilines is discussed. The methodology is shown to be extremely useful for the synthesis of diverse sets of functional drug-like quinolines.

An efficient synthesis (up to a 200 g scale) of 3-hydroxypyrrolidin-2-ones bearing alkyl substituents or functional groups at the C-5 position is described. The reaction sequence started from 1,3-dipolar cycloaddition of in situ generated nitrile oxides with (meth-)acrylates into 3-substituted isoxazoline-5-carboxylates. The catalytic hydrogenolysis of the isoxazoline N-O bond was optimal upon using H 2 (1 atm) at rt, with the following order of the catalyst activity: Pd-C > Pd(OH) 2 -C > Pt-C. The reactions with Pt-C were more selective for the synthesis of pyrrolidones, while Pd-C provided the fastest conversion rates. The stirring efficiency had a positive impact on conversion rather than elevated temperatures (up to 40 °C) or pressure (up to 50 atm). The diastereoselectivity was governed mainly by steric factors, with a dr of 1:1 to 3:1 ( cis- and trans -isomers could be separated). Higher homologues (isoxazolinylacetates and -propanoates) were suitable for the synthesis of 6- or 7-substituted 4-hydroxypiperidones and 5-hydroxyazepanones, respectively. The proposed methods are tolerant to functional groups, including CF 3 (but not CHF 2 or CH 2 Cl), ester, and most N -Boc-protected amines. The utility of hydroxyl groups in lactams was shown by functional group transformations. Hydrogenolysis of C(5)-functionalized isoxazolines, bearing trimethylsilyl, phosphonate, or sulfone groups, was also studied to demonstrate limitations.

Structural restriction of the sulfonamide bond was used to design sultams with abnormal geometric parameters. Based on analysis of tertiary aliphatic sulfonamides published in the Cambridge crystallographic database, Paquette's sultams (i.e., bridged bicyclic sultams with a bridgehead nitrogen atom) were outlined, and a number of these compounds (including the novel smallest representative, 2-thia-1-azabicyclo[2.1.1]hexane 2,2-dioxide) were synthesized by cyclization of the corresponding amino sulfonyl fluorides. A series of tertiary aliphatic sulfonamides was studied by crystallographic and quantum chemical methods. It was found that the s-character of the nitrogen lone pair is the most important factor defining properties of the S-N bond. Thus, going from the sp 3 -hybrid lone pair in common sulfonamides to the sp-like lone pair in the smallest Paquette's sultam resulted in an increase in S-N bond length by ca. 0.06 Å. The strain energy of ca. 30 kcal/mol was predicted for the latter compound, which was higher than for any existing sulfonamides studied.

We experimentally verified an assumption that the substitution of a carbon atom with a pentavalent phosphorus atom in 1-alkoxy (dialkylamino) hexatrienes will not hamper its ability to electrocyclize. A series of 1-, 3-, and 5-phosphahexatrienes were synthesized. It was shown that parent λ(5)-phosphinines could be synthesized by electrocyclization of the 3- and 5-phosphahexatrienes. The resultant electrocyclization is a convenient method for the synthesis of parent λ(5)-phosphinines bearing different substituents on the phosphorus atom.