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A direct spirocyclization approach for the chemical synthesis of spiro[cyclohexane-2-indoline] alkaloids is reported. The absolute stereochemistry was introduced by a desymmetrizing Dieckmann condensation, and the relative stereochemistry was controlled by the manipulation of the kinetic and thermodynamic pathways of the spirocyclization. By contrast to the biogenetic proposal involving the diester-type alkaloid as the precursor, we demonstrate that chemically a common lactone-type intermediate could bridge the chemical synthesis of this class of natural products.

Inspired by the biogenetic origin of goniomitine, new synthetic bio-inspired fragmentation strategies for the synthesis of functionalized 2-quinolinones and indolones have been developed. Remarkable synthetic efficiency was achieved by telescoping several transformations into one-pot reactions, allowing for the direct coupling of 2-alkynyl-anilines and diazo ketones. The synthetic utility was demonstrated by the 5-step asymmetric total synthesis of (-)-goniomitine from 2-ethyl-cyclopentanone.

Although the widespread usage of aza-pinacol and aza-semipinacol rearrangements as synthetic methods has not been found, these synthetic transformations offer novel tactics for the preparation of nitrogen-containing heterocycles and natural alkaloids. Herein, we briefly discuss the most recent developments in this area and present our strategy based on aza-pinacol rearrangements for the synthesis of indolines and indolenines. 1 Introduction 2 Recently Developed Aza-Pinacol and Aza-Semipinacol Rearrangements 3 Indoline/Indolenine Synthesis Employing Aza-Pinacol Rearrangements as the Key Strategy 4 Conclusion

An indoxyl-based strategy for the synthesis of indolines and indolenines via unprecedented aza-pinacol and aza-semipinacol rearrangements was developed. This method provides direct access to the core structures of several classes of indole alkaloids. The synthetic utility was demonstrated by the divergent synthesis of an array of functionalized polycyclic structures from a common intermediate and the formal total synthesis of the indoline natural product minfiensine. The reversed reactivity of indoxyl as a building block compared to that of indole offers a conceptually distinct disconnection strategy for indoline- and indolenine-containing heterocycles and natural products.

A distinct strategy via unprecedented semipinacol rearrangements for the synthesis of functionalized hydrodibenzofurans is reported. The versatile reactivity of benzofuran-3-one as a building block enabled the convergent coupling of simple starting materials and, thus, allowed for the facile variation of R group and the construction of hydrodibenzofurans with fused rings.

An efficient, organocatalytic, highly enantioselective, conjugate addition reaction of nitromethane with α,β-unsaturated aldehydes has been developed. The process serves as the key step for a practical 3-step synthesis of chiral baclofen, an anti-spastic drug.

A quinine-promoted, enantioselective Michael addition reaction of diphenyl phosphite with nitroalkenes has been developed. This methodology affords a facile access to enantiomerically enriched p-nitrophosphates, precursors for the preparation of synthetically and biologically useful β-amino-phosphonates.

A direct [3 + 2] annulation reaction between indoles and α,β-unsaturated ketones is reported, which allows for the efficient assembly of densely substituted, highly functionalized pyrrolo[1,2-a]indoles. Model reactions toward the originally assigned structure of yuremamine are also described, leading to the successful construction of the core with required functionality.

A mild and simple method for the direct C-H functionalization of the C-1 position of tetrahydrocarbazoles with good functional group tolerance is presented.

This one-step operation allows for the efficient assembly of highly substituted pyrrole ring systems from simple starting materials.

A convergent method to access the fused indoline ring system present in a multitude of bioactive molecules has been developed. The strategy involves the condensation of hydrazines with latent aldehydes to ultimately deliver indoline-containing products by way of an interrupted Fischer indolization sequence. The method is convergent, mild, operationally simple, broad in scope, and can be used to access enantioenriched products. In addition, our approach is amenable to the synthesis of furoindoline and pyrrolidinoindoline natural products as demonstrated by the concise formal total syntheses of physovenine and debromoflustramine B. The strategy will likely enable the synthesis of more complex targets such as the communesin alkaloids.

An unprecedented highly enantioselective cascade oxa-Michael−Michael reaction has been developed. The simple and practical process, efficiently catalyzed by chiral diphenylprolinol TMS ether, affor...

An unprecedented highly enantio- and diastereoselective cascade aza-Michael–Michael reaction of α,β-unsaturated aldehydes with trans-γ-Ts protected amino α,β-unsaturated ester has been developed; the simple and practical process, efficiently catalyzed by chiral diphenylprolinol TMS ether, serves as a powerful access to highly functionalized trisubstituted chiral pyrrolidines.

Fluorous (S) pyrrolidine sulfonamide serves as an efficient promoter for highly enantioselective aldol reactions of ketones and aldehydes with aromatic aldehydes on water. A notable feature of the organocatalyst is that it can be recovered from the reaction mixtures by simple fluorous solid-phase extraction and subsequently reused (up to seven cycles) without a significant loss of catalytic activity and stereoselectivity.

The first enantioselective conjugate addition reaction of 1 H-benzotriazole with a variety of enones has been developed. The process, catalyzed by a cinchona alkaloid thiourea, affords Michael adducts in good yields and with moderate to good enantioselectivities.

[reaction: see text] A novel organocatalytic, enantioselective domino double Michael addition reaction of alpha,beta-unsaturated aldehydes with ethyl 4-mercapto-2-butenoate has been developed. The process is promoted by chiral diphenylprolinol TMS ether to give chiral tetrahydrothiophenes in high to excellent levels of enantioselectivities.

Highly enantio- and diastereoselective tandem Michael−aldol reactions, efficiently catalyzed by a cinchona alkaloid thiourea via synergistic noncovalent hydrogen-bonding activation of both the Michael donor and acceptor, have been developed. The process affords a powerful means for the construction of versatile chiral thiochromanes with the formation of three stereogenic centers in a one-pot synthesis from simple achiral compounds.

An organocatalytic, enantioselective conjugate addition reaction of nitroalkanes with nitroolefins has been developed under neat conditions without using an organic solvent. The process, catalyzed by a modified Cinchona alkaloid, affords synthetically useful 1,3-dinitro compounds in good yields (70–82 %) with good degrees of enantioselectivity (67–88 % ee).

A recyclable and reusable (S) diphenylpyrrolinol silyl ether I organocatalyst bearing a n-C8F17 fluorous tag has been demonstrated for promoting the asymmetric Michael addition reactions of a wide range of aldehydes with both aryl and alkyl-substituted nitroolefins and excellent levels of enantio- and diastereoselectivities are achieved. The catalyst I can be conveniently recovered by fluorous solid-phase extraction and subsequently reused (up to eight cycles) without significant loss of its catalytic activity and stereoselectivity for the process.

Chiral (S)-pyrrolidine tri- fluoromethanesulfonamide has been shown to serve as an effective catalyst for direct Michael addition reactions of aldehydes and ketones with nitroole- fins. A wide range of aldehydes and ke- tones as Michael donors and nitroole- fins as acceptors participate in the process, which proceeds with high levels of enantioselectivity (up to 99 % ee) and diastereoselectivity (up to 50:1 d.r.). The methodology has been employed successfully in an efficient synthesis of the potent H3 agonist Sch 50917. In addition, a practical three-step procedure for the prepara- tion of (S)-pyrrolidine trifluorometh- AA has been developed. The high levels of stereochemical con- trol attending Michael addition reac- tions catalyzed by this pyrrolidine sul- fonamide, have been investigated by using ab initio and density functional methods. Transition state structures for the rate-limiting CC bond-forming step, corresponding to re- and si-face addition to the reactive conformation of the key enamine intermediates have been calculated. Analysis of these structures indicates that hydrogen bonding plays an important role in cat- alysis and that the energy barrier for si-face attack in reactions of aldehydes to form 2R,3S products is lower than that for the re-face attack leading to 2S,3R products. In contrast, the energy barrier for re-face addition is lower than that for si-face addition in reac- tions of ketones. The computational re- sults, which are in good agreement with the experimental observations, are discussed in the context of the stereo- chemical course of these Michael addi- tion reactions.

An enantioselective, organocatalytic Michael addition reaction of thioacetic acid with enones has been developed. The process, catalyzed by a chiral bifunctional amine thiourea, furnishes products in excellent yields with up to 63% ee.

A highly enantioselective, organocatalytic Michael addition reaction of unmodified ketones with chalcones has been developed for the first time. The process, catalyzed by (S)-N-(pyrrolidin-2-ylmethyl)-trifluoromethanesulfonamide, affords 1,5-diketones in high yields (73–89%) and with high degrees of enantio- and diastereoselectivity (86–97% ee, >30 : 1 dr).

[reaction: see text] A novel binaphthyl-derived amine thiourea organocatalyst has been developed and demonstrated to efficiently catalyze Michael addition reactions (using as low as 1 mol % loading) of diketones to nitroalkenes with remarkably high enantioselectivities.