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We report broad guidance on how to catalyze enantioselective aldehyde additions to nitroalkene or maleimide Michael electrophiles in the presence of unprotected acidic spectator groups, e.g., carboxylic acids, acetamides, phenols, catechols, and maleimide NH groups. Remarkably, these L-threonine and L-serine potassium salt catalyzed reactions proceed even when the nucleophilic and electrophilic Michael partners simultaneously contain acidic spectator groups. These findings begin to address the historical non-compatibility of enantioselective catalytic reactions in the presence of acidic moieties and simultaneously encroach on the reaction capabilities normally associated with cellular environments. A carboxylate salt bridge, from the catalyst enabled enamine, to the Michael electrophile is thought to facilitate the expanded Michael substrate profile. A practical outcome of these endeavors is a new synthetic route to (R)-Pristiq, (-)-O-desmethylvenlafaxine, an antidepressant, in the highest yield known to date because no protecting groups are required.

Site-selectivity, differentiating members of the same functional group type on one substrate, is an emerging tactic for shortened advanced building block and biomolecule synthesis. Despite its potential, site-selectivity remains less studied and especially so for ketone-based substrates. During this work ketone site-selectivity has been coupled with the chiral amine-catalyzed aldol desymmetrization of 4-keto-substituted cyclohexanones, allowing three stereogenic centers to form in the aldol product while leaving the acyclic ketone unreacted. Unique here, compared to all previous 4-substituted cyclohexanone desymmetrizations, is the first access to synthetically useful quantities of an epimeric (remote stereogenic center) aldol product. To demonstrate the value of these aldol products, we show their elaboration into eight keto-acetonide and one keto-lactone products. All compounds were isolated as single diastereomers and in high ee (≥96%). These efforts represent the first full characterization of aldol products with type III, Figure 2, relative stereochemistry, regardless of the enantiomer formed.

Routes to enantioenriched amines are outlined that employ reductive amination and carbanion addition methods. The strategies require either one or two reaction steps from prochiral carbonyl compounds for the synthesis of the corresponding chiral primary amines.

Site selectivity, differentiating instances of the same functional group type on one substrate, represents a forward-looking theme within chemistry: reduced dependence on protection/deprotection protocols for increased overall yield and step-efficiency. Despite these potential benefits and the expanded tactical advantages afforded to synthetic design, site selectivity remains elusive and especially so for ketone-based substrates. Herein, site-selective intermolecular mono-aldolization has been demonstrated for an array of prochiral 4-keto-substituted cyclohexanones with concomitant regio-, diastereo-, and enantiocontrol. Importantly, the aldol products allow rapid access to molecularly complex ketolactones or keto-1,3-diols, respectively containing three and four stereogenic centers. The reaction conditions are of immediate practical value and general enough to be applicable to other reaction types. These findings are applied in the first enantioselective, formal, synthesis of a leading Alzheimer's research drug, a γ-secretase modulator (GSM), in the highest known yield.

The review examines the chiral amine literature from 2000-2009 (May) concerning enantioselective and diastereoselective methods for N-acylenamide and enamine reduction, reductive amination, and imine reduction. The reaction steps for each strategy, from ketone to primary chiral amine, are clearly defined, with best methods and yields for starting material preparation and final deprotection noted. Categories of chiral amines have been defined in Section 1 to allow the reader to quickly understand whether their specific target amine falls within a difficult to synthesize, or not, structural class. Amino acids are not considered in this work.

Reductive amination of keto esters 1 with α-methylbenzylamine (α-MBA) in the presence of hydrogen and Raney-Ni allows direct access to diastereomeric amino esters 2 in good to high de (72–94 %). For the α-keto ester 1d and the β-keto esters 1a, 1b and 1c the reaction is optimally performed in the presence of AcOH, while the γ-keto ester 1h requires Ti(OiPr)4. The reductive amination product of 1d is an advanced homophenylalanine building block for Angiotensin Converting Enzyme (ACE) inhibitor drugs. The reductive amination product of 1h is converted in two additional steps to a protected chiral 2-methylpyrrolidine 4h, which is an advanced amine intermediate for pharmaceutical drugs, e.g. ABT-239. The strategy presented here obviates the need for preforming enamine or imine intermediates for amino ester synthesis.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

A two-step procedure for producing optically active, high value primary amines has been developed. The first and key step is the asymmetric reductive amination of a prochiral alkyl alkyl (acyclic or cyclic) or aryl alkyl (acyclic or cyclic) ketone with (R)- or (S)-a-methylbenzylamine (a-MBA). The normally stepwise excessive procedures of chiral auxiliary approaches are avoided by simultaneously incorporating the auxiliary and a new stereogenic center at the former carbonyl carbon of the ketone during step one. Specifically, step one is the hydrogenation (4-8 bar) of a prochiral ketone substrate in the presence of α-MBA, a Lewis acid [Ti(O-i-Pr) 4 , B(O-i-Pr) 3 , Al(O-i-Pr) 3 , or Zr(O-i-Pr) 4 ], and a heterogeneous hydrogenation catalyst (Raney-Ni, Pt-C, Pd-C, Ru-C, or Rh-C), providing the amine diastereomers 2 in good to excellent yield and diastereoselectivity. Depending on the ketone examined (acyclic vs. cyclic, alkyl alkyl vs. aryl alkyl, sterically encumbered vs. unencumbered), the correct combination of heterogeneous hydrogenation catalyst, solvent, and temperature is crucial for allowing high yield and de with practical reaction times (generally 6-20 h). Performing the reaction in the absence of one of the indicated Lewis acids results in the formation of large amounts of alcohol by-product (>25%). Step two, hydrogenolysis, allows smooth removal of the chiral auxiliary providing α-chiral primary amines in good overall yield (5 examples 71-78%, 1 example 64%) and in 66-98% enantiomeric excess. This two-step strategy is noteworthy because: 1) it is yield and stepwise efficient; 2) all the reagents are inexpensive and already used by the pharmaceutical industry; 3) a broad range of ketone substrates are suitable; 4) either enantiomeric form of the α-chiral amine product can be produced; 5) the reaction conditions are mild; and 6) the process is amenable to scale-up.

Many substance P antagonists have a core structure based on the quinuclidine skeleton. Manufacture of these drug antagonists proceeds through the advanced intermediate (2S,3S)-cis-2-benzhydryl-3-aminoquinuclidine 1, and all previous syntheses of 2S,3S-1 proceed through quinuclidinone 2. The synthesis described herein provides a 40% improved synthetic yield of (2S,3S)-1 from quinuclidinone 2, when compared to all previously reported syntheses. The key process improvements originate from: (1) dynamic kinetic resolution of ketone rac-4, producing ketone (2S)-4 and (2) the subsequent reductive amination of ketone (2S)-4 without epimerization. The former dynamic kinetic resolution, the first demonstrated for this ketone (quinuclidinone) architecture, uses inexpensive (natural) l-tartaric acid to provide ketone (2S)-4 in high yield (90%) and enantiopurity (95% ee). The latter demonstrates the first use of Ti(OiPr)4/Pt-C/H2 for reductive amination and is especially noteworthy for its ability to preserve the α-l...

Sulfone 2 was initially prepared using a zinc-mediated one-pot coupling procedure. A traditional sodium sulfite-mediated two-pot procedure was found to eliminate a major impurity, yet modest yields...

Advantageous use of homochiral cyclohexadiene-cis-1,2-diol 2, available by means of biocatalytic oxidation of chlorobenzene with toluene dioxygenase, has enabled the synthesis of all four enantiomerically pure C(18)-sphingosines 1. The four requisite diastereomers of azido alcohols 4a-d were accessed by regioselective opening of epoxides 7 and 8 with either azide or halide ions. The configuration of C4 and C5 in azides 4 defines the stereochemistry of the incipient sphingosine chain, liberated from 4 by the oxidative cleavage of the C1-C6 olefin. For L-threo-sphingosine (1b), lactol 20b generated by this cleavage was converted by periodate oxidation to azido deoxy L-threose 22b, which gave 1b upon Wittig olefination and reduction. Similarly, D-erythro-sphingosine (1a) and L-erythro-sphingosine (1c) were generated from 4a,c, respectively. The last sphingosine (1d) was synthesized from the silyl-protected azido alcohol 29d. Subsequent transformations provided silyl-protected azido deoxy D-threose 32d, which upon Wittig olefination and reduction gave D-threo-sphingosine (1d). Experimental and spectral data are provided for all new compounds.

Reactions of the mono-epoxy derivatives, 4–7, of the cis-1,2-dihydrocatechols 1 and 2 with various oxygen-, nitrogen-, carbon- and halogen-centred nucleophiles have been studied. In both direct and acid-catalysed processes these epoxides react exclusively by the pathway involving nucleophilic attack at 5a-C of the substrate and such regioselectivity has been exploited in a synthesis of the fluoro-deoxy-conduritol 32. Palladium-catalysed nucleophilic additions to epoxide 4 proceed in the same regiochemical sense (attack at 5a-C) but with overall retention of configuration. A competing process associated with palladium-catalysed addition of phthalimide to epoxide 4 is isomerisation of the substrate to cyclohexenone 41. Product structures have been established by single-crystal X-ray analyses and chemical correlation studies.

A chromatography-free synthesis of chiral primary amines via a one-pot reaction (imine formation, imine reduction, and hydrogenolysis of the auxiliary) is presented.

A three component catalyst system entailing an amino acid (O(t)Bu-L-threonine), a hydrogen bond donor (sulfamide), and an amine base (DMAP) allows α-branched aldehyde addition to nitroalkenes in good to high yield and excellent ee. Importantly, the lowest reported catalyst loading (5.0 mol%) and aldehyde stoichiometry (1.2-2.0 equiv) is demonstrated and in most instances the best current product profile is observed.

An approach to several conduritols, both naturally occurring and unnatural derivatives, is described. The key strategy of this potentially exhaustive approach relies on the bio-oxidation of chloro- or bromobenzene to their corresponding cis-diols. Subsequent synthetic manipulations enjoy extensive use of symmetry considerations in the introduction of functionalities. Complete stereo- and enantio-control is achieved in the preparation of conduritols E 5 and F 6, aminoconduritols A-1 7 and F-4 9, fluorodeoxyconduritol F 13, chlorodeoxyconduritol F 14, and deoxyconduritol E 15. A detailed discussion of the stereoelectronic parameters that control opening of epoxy alkenes of type 33 or 37 is advanced. Full experimental details are provided for all compounds.

The review examines the chiral amine literature from 2000-2009 (May) concerning enantioselective and diastereoselective methods for N-acylenamide and enamine reduction, reductive amination, and imine reduction. The reaction steps for each strategy, from ketone to primary chiral amine, are clearly defined, with best methods and yields for starting material preparation and final deprotection noted. Categories of chiral amines have been defined in Section 1 to allow the reader to quickly understand whether their specific target amine falls within a difficult to synthesize, or not, structural class. Amino acids are not considered in this work.

Preface STEREOSELECTIVE SYNTHESIS OF ALPHA-BRANCHED AMINES BY NUCLEOPHILIC ADDITION OF UNSTABILIZED CARBANIONS TO IMINES Introduction Overview of the Methods for the Preparation of Imines Chiral Auxiliary-Based Approaches Catalytic Asymmetric Nucleophilic Addition to Achiral Imines Conclusion ASYMMETRIC METHODS FOR RADICAL ADDITION TO IMINO COMPOUNDS Background and Introduction Intermolecular Radical Addition Chiral N-Acylhydrazones Asymmetric Catalysis of Radical Addition Closing Remarks ENANTIOSELECTIVE SYNTHESIS OF AMINES BY CHIRAL BRONSTED ACID CATALYSTS Introduction Carbon-Carbon Bond Forming Reactions Carbon-Hydrogen Bond Forming Reactions Carbon-Heteroatom Bond Forming Reactions Conclusion REDUCTION OF IMINES WITH TRICHLOROSILANE CATALYZED BY CHIRAL LEWIS BASES Introduction Formamides as Lewis-Basic Organocatalysts in Hydrosilylation of Imines Other Amides as Organocatalysts in Hydrosilylation of Imines Sulfinamides as Organocatalysts in Hydrosilylation of Imines Supported Organocatalysts in Hydrosilylation of Imines Mechanistic Considerations Synthetic Applications Conclusions Typical Procedures for the Catalytic Hydrosilylation of Imines CATALYTIC, ENANTIOSELECTIVE VINYLOGOUS MANNICH REACTIONS Introduction Vinylogous Mukaiyama-Mannich Reactions of Silyl Dienolates Direct Vinylogous Mannich Reactions of Unmodified Substrates Miscellaneous Conclusion CHIRAL AMINES FROM TRANSITION-METAL-MEDIATED HYDROGENATION AND TRANSFER HYDROGENATION Scope and Related Publications Chiral Amines with a Disubstituted Nitrogen Atom, HNRR1 Chiral Amines with Trisubstituted Nitrogen, NRR1R2 Conclusion ASYMMETRIC REDUCTIVE AMINATION Introduction Transition Metal-Mediated Homogenous Reductive Amination Enantioselective Organocatalytic Reductive Amination Diastereoselective Reductive Amination Conclusions ENANTIOSELECTIVE HYDROGENATION OF ENAMINES WITH MONODENTATE PHOSPHORUS LIGANDS Introduction Asymmetric Hydrogenation of Enamides Asymmetric Hydrogenation of N,N-Dialkyl Enamines Conclusion and Outlook BIDENTATE LIGANDS FOR ENANTIOSELECTIVE ENAMIDE REDUCTION Introduction Catalytic Enantioselective Hydrogenation of Enamides Conclusions ENANTIOSELECTIVE REDUCTION OF NITROGEN-BASED HETEROAROMATIC COMPOUNDS Asymmetric Hydrogenation of Quinolines Asymmetric Hydrogenation of Isoquinolines Asymmetric Hydrogenation of Pyrroles Asymmetric Hydrogenation of Quinoxalines Asymmetric Hydrogenation of Pyridine Derivatives Summary and Outlook ASYMMETRIC HYDROAMINATION Introduction: Synthesis of Amines via Hydroamination Hydroamination of Simple, Nonactivated Alkenes Hydroamination of Dienes, Allenes, and Alkynes Hydroamination with Enantiomerical Pure Amines Synthesis of Chiral Amines via Tandem Hydroamination/Hydrosilylation Conclusions Experimental Section ENANTIOSELECTIVE C-H AMINATION Introduction Background Racemic C-H Amination Substrate-Controlled Chiral Amine Synthesis via C-H Amination Enantioselective C-H Amination of Achiral Substrates Conclusion CHIRAL AMINES DERIVED FROM ASYMMETRIC AZA-MORITA-BAYLIS-HILLMAN REACTION Introduction Recent Mechanistic Insights Asymmetric Aza-MBH Reaction Chiral Auxiliary-Induced Diastereoselective Aza-MBH Reaction Chiral Teriary Amine Catalysts Chiral Phosphine Catalysts Chiral Bifunctional N-Heterocyclic Carbenes Chiral Ionic Liquids as Reaction Medium Aza-MBH-Type Reaction to Obtain Chiral Amines Strategies for the Removal of Protecting Groups Selected Typical Experimental Procedures Summary and Outlook BIOCATALYTIC ROUTES TO NONRACEMIC CHIRAL AMINES Introduction Kinetic Resolution of Racemic Amines DKR and Deracemization of Amines Asymmetric Synthesis of Amines Using Transaminases Conclusions and Future Perspectives

An efficient, four step synthesis of chiral enone 2a [(+)-2,3-(isopropylidenedioxy)-4-cyclopentenone]from diol 1a (X = Cl), available from microbial oxidation of chlorobenzene, is described. This synthesis is a vast improvement over that previously reported and compares very favorably with others in the literature.

Reductive amination of prochiral unhindered 2-alkanones 1 with (R)- or (S)-α-MBA in the presence of Yb(OAc)3 (50−110 mol %), Raney-Ni, and hydrogen (120 psi) results in increased diastereoselectivity for the amine products 2 (80−89% de) with good yield (80−87%). The increased de is based on comparison with the best previously reported de's when using (R)- or (S)-α-MBA, regardless of the strategy employed [stepwise (isolation of ketimines) or one-pot (reductive amination)], reducing agent examined, or achiral Lewis acid or Bronsted acid examined. An in situ cis- to trans-ketimine isomerization mechanism, promoted by Yb(OAc)3, has been proposed to account for the observed increase in diastereoselectivity and suggests a new entry into the control of ketimine geometry.

Reductive amination of prochiral unhindered 2-alkanones 1 with (R)- or (S)-alpha-MBA in the presence of Yb(OAc)3 (50-110 mol %), Raney-Ni, and hydrogen (120 psi) results in increased diastereoselectivity for the amine products 2 (80-89% de) with good yield (80-87%). The increased de is based on comparison with the best previously reported de's when using (R)- or (S)-alpha-MBA, regardless of the strategy employed [stepwise (isolation of ketimines) or one-pot (reductive amination)], reducing agent examined, or achiral Lewis acid or Brønsted acid examined. An in situ cis- to trans-ketimine isomerization mechanism, promoted by Yb(OAc)3, has been proposed to account for the observed increase in diastereoselectivity and suggests a new entry into the control of ketimine geometry.

A one-pot asymmetric sequential amination-alkylation method has been developed for the synthesis of alkyl-alkyl′ α-chiral primary amines (aliphatic primary amines with a chiral center adjacent to the nitrogen atom) from aldehydes. In situ aldimine formation from non-branched, α-branched, and β-branched aliphatic aldehydes with (R)- or (S)-α-(methylbenzyl)amine [catalyzed by 5 mol-% Ti(OiPr)4] followed by reaction with a methyl, ethyl, or n-butyl cuprate complex in the presence of boron trifluoride or an allyl Grignard reagent provides good yield (77–88 %) and diastereomeric excess (77–92 %) for amines 2 or 5. To further demonstrate the usefulness of this method, several of the secondary amine products (2d, 2e, and 5) were hydrogenolyzed, providing the corresponding enantioenriched alkyl-alkyl′ α-chiral primary amines 3d, 3e, and 6 (86–96 % yield).(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

[reaction: see text] A new method for the one-pot asymmetric reductive amination of prochiral aliphatic ketones has been developed. The previously unexplored reagent combination of Ti(O(i)Pr)(4)/Raney Ni/H(2) in the presence of (R)- or (S)-alpha-methylbenzylamine provides good to excellent yield (76-90%) and diastereomeric excess (72-98%). The second step, hydrogenolysis, provides the corresponding primary amine in high yield (88-93%) and with uncompromised enantiomeric excess.

Here we report on inroads concerning increased substrate breadth via the picolylamine organocatalyst template, a vicinal chiral diamine based on a pyridine-primary amine motif. The addition of cyclohexanone to β-nitrostyrene has many catalyst solutions, but cyclopentanone and isobutyraldehyde additions continue to be challenging. PicAm-3 (10 mol%) readily allows the Michael addition of cyclopentanone or isobutyraldehyde (5.0 equiv.) to β-nitrostyrene derivatives. By contrast, PicAm-1 (7.0 mol%) is optimal for catalyzing the aldol reaction of cyclohexanone or cycloheptanone (3.3 equiv.) with aromatic aldehydes. Eighteen products are reported and for each reaction type new products are reported (4b-d, 9c). Very good yields and stereoselectivities are generally noted. The reactions, which require an acid additive, proceed via a transient chiral enamine and a mechanistic case is put forth for a bifunctional catalysis model.

A pyridine based 1,2-diamine containing only one stereogenic center has been identified for fast aldol reactions (16-48 h). Using 2-5 mol% of (R)- or (S)-PicAm-2, cyclohexanone (3.3 equiv) readily undergoes aldol reactions with o-, m-, and p-substituted aromatic aldehyde partners (limiting reagent), including the poor electrophile 4-methylbenzaldehyde (95-99% ee). Furthermore, functionalized cyclic ketone substrates have been converted into four aldol products 9-12 using the lowest catalyst loading (5.0 mol%) to date with the highest yield and enantioselectivity.

Urea–hydrogen peroxide complex in an organic solvent and in the presence of DBU and poly-(L)-leucine causes rapid asymmetric epoxidation of the enones 1a, b and d.

An approach to several conduritols, both naturally occurring and unnatural derivatives, is described. The key strategy of this potentially exhaustive approach relies on the bio-oxidation of chloro- or bromobenzene to their corresponding cis-diols. Subsequent synthetic manipulations enjoy extensive use of symmetry considerations in the introduction of functionalities. Complete stereo- and enantio-control is achieved in the preparation of conduritols E 5 and F 6, aminoconduritols A-1 7 and F-4 9, fluorodeoxyconduritol F 13, chlorodeoxyconduritol F 14, and deoxyconduritol E 15. A detailed discussion of the stereoelectronic parameters that control opening of epoxy alkenes of type 33 or 37 is advanced. Full experimental details are provided for all compounds.