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Enantiorecognition between a racemic reagent and a racemic substrate can be a valuable process in organic synthesis. This review highlights representative examples of this phenomenon and the use of mutual kinetic resolution as a method for screening of kinetic and/or parallel kinetic resolutions.

The SuperQuat (4-substituted 5,5-dimethyloxazolidine-2-one) family of chiral auxiliaries was first developed by us in the 1990s to address the shortcomings of the Evans (4-substituted oxazolidin-2-one) family of chiral auxiliaries. The incorporation of geminal dimethyl substitution at C(5) has two effects: (i) it induces a conformational bias on an adjacent, otherwise conformationally labile C(4)-substituent so that it projects towards the N-acyl fragment, thus offering superior diastereofacial selectivity in a range of transformations; and (ii) it hinders nucleophilic attack at the endocyclic carbonyl group, facilitating recovery and recyclability of the auxiliary, with enhanced cleavage properties. This review summarises the development and some of the most common uses of the SuperQuat family of chiral auxiliaries, particularly in the synthesis of natural products or other targets having bioloigcal interest. Where possible, comparisons with the performances of the corresponding Evans auxiliaries are presented.

Epoxidation of racemic trans -2-(N, N -dibenzylamino)cyclohex-3-en-1-ol, upon treatment with Cl 3 CCO 2 H then m -CPBA, proceeded with poor diastereoselectivity (ca. 60:40 dr), whilst epoxidation of racemic trans -2-(N -benzylamino)cyclohex-3-en-1-ol under the same conditions proceeded with high diastereoselectivity ( > 95:5 dr) and was followed by completely regioselective and stereospecific ring-opening in situ to give, after methanolysis of the intermediate trichloroacetate ester, (1 RS,2 SR,3 SR,4 SR)-2-(N -benzylamino)cyclohexane-1,3,4-triol. Use of aq HBF 4 as the acid protecting agent gave the amino triol directly. The differing diastereoselectivities of these epoxidation reactions may be due to a predilection towards formation of an intramolecular hydrogen-bond in the former substrate disrupting the ability of the in situ formed ammonium moiety to act as a directing group for the incoming oxidant; the presence of two potential hydrogen-bond donors (i.e., two N-H bonds) in the latter substrate circumvents this limitation. With the criterion for a highly diastereoselective (ammonium-directed) epoxidation in this system established, a synthesis of enantiopure trans -2-(N -benzylamino)cyclohex-3-en-1-ol ( > 99% ee) was developed and the ammonium-directed epoxidation was then employed as a key synthetic step to facilitate the asymmetric syntheses of enantiopure dihydroconduramines (-)-A-2, (-)-B-2, (-)-C-3 and (+)-F-3 ( > 98% ee in each case) from 1,3-cyclohexadiene.

α,β-Unsaturated hydroxamates derived from the ‘chiral Weinreb amide’ auxiliary (S)-N-1-(1'-naphthyl)ethyl-O-tert-butylhydroxylamine consistently adopt a defined conformation and undergo highly diastereoselective conjugate addition reactions with lithium amide reagents. The configuration of the N-1-(1'-naphthyl)ethyl group dictates the position of the O-tert-butyl group and also the configuration adopted by the pyramidal nitrogen atom via a ‘chiral relay’ effect. Conjugate addition of lithium amide reagents to these substrates proceeds on the face opposite to both the O-tert-butyl group and nitrogen lone-pair with high levels of diastereoselectivity.Dedicated to the memory of Professor Howard D. Flack (1943–2017).

The diastereoselectivities and rates of epoxidation (upon treatment with Cl3CCO2H then m-CPBA) of a range of cis- and trans-4-aminocycloalk-2-en-1-ol derivatives (containing five-, six-, and seven-membered rings) have been investigated. In all cases where the two potential directing groups can promote epoxidation on opposite faces of the ring scaffold, evidence of competitive epoxidation pathways, promoted by hydrogen-bonding to either the in situ formed ammonium moiety or the hydroxyl group, was observed. In contrast to the relative directing group abilities already established for the six-membered ring system (NHBn ≫ OH > NBn2), an N,N-dibenzylammonium moiety appeared more proficient than a hydroxyl group at directing the stereochemical course of the epoxidation reaction in a five- or seven-membered system. In the former case, this was rationalized by the drive to minimize torsional strain in the transition state being coupled with assistance from hydrogen-bonding to the ammonium moiety. In the latter case, this was ascribed to the steric bulk of the ammonium moiety disfavoring conformations in which hydrogen-bonding to the hydroxyl group results in direction of the epoxidation to the syn face. In cases where the two potential directing groups can promote epoxidation on the same face of the ring scaffold, an enhancement of epoxidation diastereoselectivity was not observed, while introduction of a second, allylic heteroatom to the substrate results in diminishment of the rate of epoxidation in all cases. Presumably, reduction of the nucleophilicity of the olefin by the second, inductively electron-withdrawing heteroatom is the dominant factor, and any assistance to the epoxidation reaction by the potential to form hydrogen-bonds to two directing groups rather than one is clearly unable to overwhelm it.

The 1H and 13C NMR data of synthetic samples of (S)-N(1)-methyl-2-[2'-(3″-hydroxy-4″-methoxyphenyl)ethyl]-1,2,3,4-tetrahydroquinoline, the originally proposed structure of the Hancock alkaloid (-)-galipeine, do not match those of the natural product. Herein, the preparation of the regioisomer (S)-N(1)-methyl-2-[2'-(3″-methoxy-4″-hydroxyphenyl)ethyl]-1,2,3,4-tetrahydroquinoline is reported, the 1H and 13C NMR data of which are in excellent agreement with those of (-)-galipeine. Comparison of specific rotation data enables assignment of the absolute (S)-configuration of the alkaloid, and together, these data engender the structural revision of (-)-galipeine to (S)-N(1)-methyl-2-[2'-(3″-methoxy-4″-hydroxyphenyl)ethyl]-1,2,3,4-tetrahydroquinoline.

(-)-Pseudodistomin E has been prepared for the first time, allowing its structure and absolute configuration to be confirmed. The established conjugate addition of lithium (S)-N-allyl-N-(α-methyl-p-methoxybenzyl)amide to methyl (E,E)-hepta-2,5-dienoate generated the C(2)-stereocenter, and iodolactonisation of a derivative generated the remaining two stereogenic centers. Ensuing iodide displacement was achieved using a tethering strategy, to introduce the nitrogen atom to C(5). Decarboxylative coupling of a carboxylic acid with a dialkylzinc reagent completed construction of the tridecadienyl chain.

d -Fagomine (1,2,5-trideoxy-1,5-imino-d-arabino-hexitol), a naturally occurring polyhydroxylated piperidine (iminosugar), and its stereoisomers display important biological activities such as glycosidase inhibition. This review delineates both de novo asymmetric and enantiospecific syntheses of fagomine and its stereoisomers.

The key step in our synthetic strategy towards (S,S)-methylphenidate hydrochloride employs the ring-opening of an in situ formed aziridinium intermediate. Treatment of an α-hydroxy-β-amino ester with methanesulfonic anhydride promoted aziridinium formation and the subsequent addition of phenylmagnesium bromide resulted in stereospecific and regioselective ring-opening to give the corresponding α-phenyl-β-amino ester with overall retention of configuration. Subsequent functional group manipulation followed by N-deprotection and cyclisation generated the piperidine ring within the target compound, and transesterification gave (S,S)-methylphenidate hydrochloride, in only 8 steps from 1,5-pentanediol, in 15% overall yield. These results demonstrate the synthetic utility of enantiopure aziridinium intermediates as substrates for the generation of stereodefined C–C bonds, and crucially this methodology provides access to α-substituted-β-amino ester substrates that are not accessible via enolate alkylation chemistry. The strategy reported herein is potentially applicable to all possible stereoisomers of methylphenidate as well as differentially substituted analogues.

A method to enable the synthesis of conduramines and theirN-substituted derivatives (enantiopure or racemic form) in six steps (five steps forN-substituted derivatives) from cyclohexa-1,4-diene is reported. Key features of this reaction sequence include a preparation of benzene oxide that is amenable to multigram scale, and its efficient ring-opening upon treatment with a primary amine. Epoxidation of the resultant amino alcohols (40% aq HBF4thenm-CPBA) is accompanied by hydrolytic ring-opening in situ to give the correspondingN-substituted conduramine derivatives directly. These may undergo subsequentN-deprotection to give the parent conduramines, as demonstrated by the preparation of enantiopure (−)-conduramine A1, (−)-conduramine A2, and (−)-conduramine E2 (the latter two for the first time). The selectivity of the epoxidation reaction is proposed to be the result of competitive ammonium-directed and hydroxyl-directed epoxidation processes, followed by either direct (SN2-type) or conjugate (SN2′-type) ring-openings of the intermediate epoxides.

The reported characterization data for the allocolchicinoid alkaloid suhailamine, isolated fromColchicum decaisneiand known to have an erroneous structure, have been reanalyzed. This analysis has led to the current proposal that suhailamine has the same structure asN-acetylcolchinol methyl ether (NCME), an assertion that is supported by comparison with previously reported data for NCME. Suhailamine is therefore a phantom natural product, while NCME represents a naturally occurring allocolchicinoid rather than a purely synthetic entity.

A review of the isolation, reported methods for the synthesis (up to the end of 2018), and spectroscopic data of angustureine, cuspareine, galipinine, and galipeine, members of the Hancock family of alkaloids based upon a 2‐substituted N(1)‐methyl‐1,2–3,4‐tetrahydroisolquinoline scaffold, is presented.

An asymmetric synthesis of microcosamine A, microgrewiapine A and microgrewiapine B (Microcos paniculata alkaloids) is reported. Conjugate addition of lithium (S)-N-benzyl-N-(α-methylbenzyl)amide to tert-butyl crotonate followed by enolate oxidation generates the C(2) and C(3) stereogenic centres of the targets, with subsequent diastereoselective intramolecular reductive amination being used to form the piperidine ring, simultaneously producing the C(6) stereogenic centre. 1H NMR 3J coupling constant and nOe analyses allow unambiguous assignment of relative configuration of the alkaloids. Comparison of specific rotation data for microcosamine A and microgrewiapine B is consistent with both possessing the absolute (2S,3R,6S)-configuration. For microgrewiapine A, conflicting data regarding the absolute configuration are revealed: in the isolation study a Mosher’s analysis concludes a (2S,3R,6S)-configuration, but comparison of specific rotation data suggests a (2R,3S,6R)-configuration. Thus it is promulgated it is imprudent to suggest the absolute configuration of this natural product; its re-isolation is required for resolution of this problem.

The asymmetric syntheses of pyrrolizidine, indolizidine and quinolizidine alkaloids have been achieved using the diastereoselective conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to α-alkenyl-α,β-unsaturated esters followed by diastereoselective protonation of the resultant enolates as the key stereodefining steps. The azabicyclic scaffolds were then efficiently constructed upon sequential oxidative cleavage of the olefinic units within the resultant β-amino esters and hydrogenolytic N-debenzylation of the corresponding dialdehydes, which occurs with concomitant double reductive cyclisation. Subsequent reduction of the ester moieties with LiAlH4 gave (+)-trachelanthamidine, (+)-tashiromine, (1S,8aR)-1-(hydroxymethyl)octahydroindolizine and (+)-epilupinine in 4.9, 4.1, 3.0 and 5.9% overall yield, respectively, in only six steps from commercially available starting materials.

The asymmetric syntheses of (–)-ADMJ and (+)-ADANJ, the 2-deoxy-2-amino analogues of (–)-1-deoxymannojirimycin and (+)-1-deoxyallonojirimycin, are described herein. Methodology for the ring-closing iodoamination of bishomoallylic amines followed by in situ ring-expansion (via intramolecular ring-opening of the corresponding aziridinium intermediates with a tethered carbamate moiety) to give oxazolidin-2-ones was initially optimised on a model system. Subsequent application of this methodology to two enantiopure bishomoallylic amines (which were produced via aminohydroxylation of an α,β-unsaturated ester, partial reduction and reaction of the corresponding aldehyde with vinylmagnesium bromide) also proceeded with concomitant N-debenzylation to afford the corresponding diastereoisomerically pure (>99:1 dr) oxazolidin-2-ones. Subsequent deprotection of these enantiopure templates gave (–)-ADMJ and (+)-ADANJ as single diastereoisomers in 16 and 24% overall yield, respectively.

The regioselectivity of the Friedel-Crafts-type cyclisation of a range of γ-aryl-β-benzoylamido acids, bearing oxy substituents at the C(3)- and C(4)-positions of the γ-aryl ring, has been investigated. In all of the cases examined (with 3,4-dimethoxy, 3,4-methylenedioxy and 3-hydroxy-4-methoxy substituents) the Lewis acid promoted cyclisation proceeds with exclusive regioselectivity for attack at the C(6)-position rather than at the C(2)-position, and furnishes the corresponding N - and O -protected 3-amino-6,7-dihydroxy-1-tetralone derivatives. This inherent regioselectivity can be overturned by the regioselective introduction of chlorine as a blocking group for the C(6)-position; subsequent Lewis acid promoted cyclisation then proceeds with exclusive regioselectivity for attack at the C(2)-position to deliver the corresponding N - and O -protected 3-amino-5-chloro-7,8-dihydroxy-1-tetralone derivative. These complementary cyclisation protocols represent useful methods for the preparation of these benzo-fused carbocyclic ring systems, which are the functionalised AB-rings of a range of morphinan alkaloids.

All rights reserved.A range of enantiopure 1,2,3,4-tetrahydroisoquinolines have been prepared directly from α-hydroxy-β-amino esters. Activation of the α-hydroxy group upon treatment with Tf2O and 2,6-di-tert-butyl-4-methylpyridine promotes aziridinium formation, which is then followed by rupture of the C(3)-N bond and Friedel-Crafts alkylation-type cyclisation of an N-benzyl moiety onto the resultant benzylic carbenium ion. The nature of the N-protecting group was varied and it was found that superior yields were obtained for reactions employing two benzylic groups. In the cases where two different N-benzyl groups were used, the regioselectivity resulting from competitive cyclisation of either N-benzyl group was addressed by the introduction of a p-trifluoromethyl group on one of the N-benzyl moieties, which retarded the rate of cyclisation via this electron poor aryl ring. This methodology was employed in the asymmetric synthesis of a range of enantiopure 1,2,3,4-tetrahydroisoquinolines, which were isolated in good yields as single diastereoisomers.

The asymmetric synthesis of a range of 1,2-anti-1,5-syn-transpentacins, bearing either alkyl, phenyl or hydroxymethyl substituents at the C(5)-position, has been achieved using the diastereoselective conjugate additions of Grignard reagents to an enantiopure β′-amino-α,β-unsaturated ester as the key step. In addition, the doubly diastereoselective conjugate addition of an enantiopure lithium amide reagent to the β′-amino-α,β-unsaturated ester provided access to the corresponding β,β′-diamino ester, which was subsequently converted to both (S,S)-(2,5-diaminocyclopent-1-yl)methanol and (S,S)-2,5-diaminocyclopentane-1-carboxylic acid. In each case, the final enantiopure products were obtained as single diastereoisomers (>99:1 dr) in good yields over five steps or fewer from commercially available starting materials.

Unambiguously corrected 1H NMR data for the originally isolated sample of microconine [N-methyl-2-methyl-3-methoxy-6-(deca-l’,3′,5′-trienyl)piperidine], an alkaloid found in Microcos paniculata, are reported. The asymmetric synthesis of the (2S,3R,6S)- and (2S,3S,6S)-stereoisomeric forms [epimeric at C(3)] of this compound allows the unambiguous assignment of the relative 2,3-cis-3,6-cis-configuration of the natural product. The synthesis uses the conjugate addition of enantiopure lithium (S)-N-benzyl-N-(α-methylbenzyl)amide to tert-butyl crotonate and ensuing enolate oxidation with (+)-camphorsulfonyloxaziridine to generate the requisite C(2) and C(3) stereogenic centres found within the target. After elaboration, an intramolecular reductive amination was used to form the piperidine ring, with concomitant formation of the C(6) stereogenic centre. Comparison of specific rotation data is consistent with the alkaloid having the absolute (2R,3R,6R)-configuration.

Conjugate addition of heteroaryl substituted lithium amides to a range of α,β-unsaturated esters followed by in situ enolate oxidation with (–)-(camphorsulfonyl)oxaziridine gave the corresponding α-hydroxy-β-amino esters. Subsequent Friedel-Crafts type cyclisation of these α-hydroxy-β-amino esters gave a range of heteroarene-fused azacycles in good yields and high diastereoselectivities.

The asymmetric syntheses of all members of the Hancock alkaloid family based upon a 2-substituted N-methyl-1,2,3,4-tetrahydroquinoline core are delineated. The conjugate addition of enantiopure lithium N-benzyl- N-(α-methyl- p-methoxybenzyl)amide to 5-( o-bromophenyl)- N-methoxy- N-methylpent-2-enamide is used to generate the requisite C-2 stereogenic center of the targets, while an intramolecular Buchwald-Hartwig coupling is used to form the 1,2,3,4-tetrahydroquinoline ring. Late-stage diversification completes construction of the C-2 side chains. Thus, (-)-cuspareine, (-)-galipinine, (-)-galipeine, and (-)-angustureine were prepared in overall yields of 30%, 28%, 15%, and 39%, respectively, in nine steps from commercially available 3-( o-bromophenyl)propanoic acid in all cases. Unambiguously corrected 1H and 13C NMR data for the originally isolated samples of (-)-cuspareine, (-)-galipinine, and (-)-angustureine are also reported, representing a valuable reference resource for these popular synthetic targets.

A divergent strategy for the asymmetric syntheses of d -fagomine and three of its diastereoisomers has been developed. The diastereoselective conjugate addition of an enantiopure lithium amide to an α,β-unsaturated ester was used as the key step to install the correct configuration required for the C(5)-stereogenic centre within the targets. In situ enolate oxidation generated the corresponding anti-α-hydroxy-β-amino ester, which possessed the correct configuration required for the C(4)-stereogenic centre within both d -fagomine and d -3-epi-fagomine. Subsequent epimerisation of this key anti-α-hydroxy-β-amino ester upon oxidation and diastereoselective reduction gave the corresponding syn-α-hydroxy-β-amino ester, which possessed the correct configuration required for the C(4)-stereogenic centre within both d -4-epi-fagomine and d -5-epi-fagomine. Elaboration of both α-hydroxy-β-amino esters upon reduction to the corresponding aldehydes followed by aldol reaction generated the requisite C(3)-stereogenic centres within the target compounds, then cyclisation and deprotection gave the enantiopure iminosugars in good overall yields, as single diastereoisomers (>99:1 dr).

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Epoxidations (40% aq HBF4 then m-CPBA) of racemic cis-2-(N-benzylamino)cyclohex-3-en-1-ol and racemic cis-2-(N,N-dibenzylamino)cyclohex-3-en-1-ol proceed with very high levels of diastereoselectivity (>95:5 dr). The latter is in direct contrast to the epoxidation of the corresponding trans-diastereoisomer (which proceeds with essentially no selectivity), showing that the relative configuration of the substrate dramatically influences the diastereoselectivity in these instances. Meanwhile, epoxidations of enantiopure (1R,2S,αR)-2-[(N-α-methylbenzyl)amino]cyclohex-3-en-1-ol and (1S,2R,αR)-2-[(N-α-methylbenzyl)amino]cyclohex-3-en-1-ol [surrogates for the enantiomers of cis-2-(N-benzylamino)cyclohex-3-en-1-ol] proceed with complete diastereoselectivity (>95:5 dr) under the same conditions, showing that neither the presence of the α-methyl group nor the relative configuration of the α-methylbenzyl stereocenter have an effect upon the established level of diastereoslectivity in these cases. In contrast, epoxidations of enantiopure (1R,2S,αR)-2-[N-benzyl-N-(α-methylbenzyl)amino]cyclohex-3-en-1-ol and (1S,2R,αR)-2-[N-benzyl-N-(α-methylbenzyl)amino]cyclohex-3-en-1-ol [surrogates for the enantiomers of cis-2-(N,N-dibenzylamino)cyclohex-3-en-1-ol] proceed with lower diastereoselectivity (∼70:30 dr). Thus, the presence of the α-methyl group has a detrimental effect on the established level of diastereoselectivity in these cases (although again the relative configuration of the α-methylbenzyl stereocenter is unimportant). The diastereoselective epoxidation pathway is used to enable the asymmetric syntheses of six hitherto unknown, enantiopure dihydroconduramines (+)-C-2, (−)-C-2, (+)-D-2, (+)-E-2, (+)-F-2, and (−)-F-2 (>99% ee in each case).

Two synthetic routes have been developed for the asymmetric syntheses of (2 R,3 S)- and (2 S,3 S)-3-hydroxyproline. The key synthetic step in each of these strategies is the conversion of protected α,δ-dihydroxy-β-amino esters (either 2,3- anti- or 2,3- syn-configured) into β,δ-dihydroxy-α-amino esters (protected forms thereof), via the intermediacy of the corresponding aziridinium ions. The products of these stereospecific rearrangements were then cyclized and deprotected to afford (2 R,3 S)-3-hydroxyproline and (2 S,3 S)-3-hydroxyproline as single diastereoisomers (99:1 dr) in26% overall yield.

A total of nine enantiopure syn-β-substituted-α-amino acids have been synthesised, comprising both syn-β-hydroxy-α-amino acids and syn-β-fluoro-α-amino acids. The key step in the synthetic strategy towards these syn-β-substituted-α-amino acids involves a stereospecific rearrangement, which proceeds via the intermediacy of the corresponding aziridinium ions. The requisite enantiopure syn-α-hydroxy-β-amino esters were prepared via asymmetric aminohydroxylation of the corresponding α,β-unsaturated esters followed by epimerisation of the resultant anti-α-hydroxy-β-amino esters at the C(2)-position. Subsequent activation of the α-hydroxy moiety as a leaving group followed by displacement by the β-amino substituent gave the corresponding aziridinium species. Regioselective in situ ring-opening of the aziridinium intermediates with either water or fluoride gave the corresponding syn-β-hydroxy-α-amino ester or syn-β-fluoro-α-amino ester, respectively, and N-deprotection and ester hydrolysis afforded the target syn-β-substituted-α-amino acids as single diastereoisomers in good overall yield.

The methyl glycosides of 3-deoxy-3-amino- d - glycero - l - gulo -heptose, 3-deoxy-3-amino- d - glycero - d - galacto -heptose, 3-deoxy-3-amino- d - glycero - l - allo -heptose and 3-deoxy-3-amino- d - glycero - d - allo -heptose were prepared from the corresponding d -aldopentoses via a seven step synthetic sequence. The doubly diastereoselective conjugate additions of the requisite antipode of lithium N -benzyl- N -(α-methylbenzyl)amide to four diastereoisomeric d -aldopentose-derived α,β-unsaturated esters and in situ enolate oxidation with the requisite antipode of camphorsulfonyloxaziridine (CSO) were used as the key, stereodefining steps. Sequential protection of the C(2)-hydroxyl group within the resultant α-hydroxy-β-amino esters and partial reduction of the ester functionality furnished the corresponding β-amino aldehydes. Subsequent N- and O-deprotection gave the target compounds (as the corresponding methyl pyranosides and/or methyl furanosides) in good yields and high diastereoisomeric purity.

Complementary protocols for the diastereoselective syn- and anti-dihydroxylations of enantiopure dihydropyrrole scaffolds were used as the key steps in the asymmetric syntheses of several polysubstituted homoprolines and homoprolinols. The requisite dihydropyrroles were prepared in three steps from commercially available sorbic acid via either hydroamination or aminohydroxylation of the corresponding tert-butyl ester, followed by ring-closing metathesis. Subsequent olefinic oxidation and deprotection gave access to the corresponding enantiopure homoprolines [(2S,3S,4R)-dihydroxyhomoproline, (2S,3R,4R)-dihydroxyhomoproline and (S,S,S)-3-amino-4-hydroxy-homoproline], enantiopure α-hydroxy-homoprolines [3,6-dideoxy-3,6-imino- d -allonic acid and 3,6-dideoxy-3,6-imino- d -gulonic acid] and enantiopure homoprolinols [1,4-dideoxy-1,4-imino- l -allitol and (S,S,S)-3-amino-4-hydroxyhomoprolinol] as single diastereoisomers in good overall yields.

In the last 10 years, since Merck’s discovery and development of (R)-sitagliptin phosphate as a treatment for type 2 diabetes, numerous efforts towards efficient synthesis of (R)-sitagliptin have been reported. In this review, several total syntheses of (R)-sitagliptin are described, highlighting the key stereoselective and stereospecific strategies employed.

The conjugate additions of alkyllithium reagents to alkoxycarbene cations of the iron chiral auxiliary [(η5-C5H5)Fe(CO)(PPh3) C(OMe)CH CHR]+ proceeded with moderate to excellent diastereoselectivity. The resultant methoxyvinyl complexes were transformed into the corresponding iron acyl complexes following a sequence of protonation and demethylation. The overall transformation yields iron acyl complexes of opposite relative configuration to those which result from the conjugate addition of the same nucleophile to the corresponding α,β-unsaturated iron acyl complex.

Diastereoselective syn- and anti-dihydroxylations of enantiopure tetrahydropyridine and tetrahydroazepine scaffolds have been used in total asymmetric syntheses of the polyhydroxylated azacycles (−)-fagomine, (−)-3-epi-fagomine, (−)-5-epi-fagomine and two related polyhydroxylated azepanes. In each case, the target compounds were isolated as single diastereoisomers (>99:1 dr) in fewer than eight steps from the commercially available starting materials, sorbic acid and the requisite α-methylbenzylamine.

2-Azido-4-aminocyclohexane-1,3-diols 12, 14 and 16 were synthesised and their crystal structures were studied by X-ray diffraction. Compound 12 crystallizes in the monoclinic space group P2 1 /n with cell parameters of a = 13.7059(2) A, b = 10.8861(2) A, c = 13.8675(3) A, β = 117.2365(10)°, V = 1839.67(6) A3 and Z = 4. Compound 14 crystallizes in the orthorhombic space group Pcab with cell parameters of a = 9.9508(1) A, b = 10.9839(2) A, c = 24.7035(4) A, V = 2700.06(7) A3 and Z = 8. Compound 16 crystallizes in the triclinic space group $$\text{P}\bar{\it{1}}$$ with cell parameters of a = 10.9511(3) A, b = 11.3148(3) A, c = 15.9545(5) A, α = 86.3487(11)°, β = 87.4723(11)°, γ = 89.3398(10)°, V = 1970.91(10) A3 and Z = 4. All three structures were characterised by arrays of hydrogen bonding interactions and these crystallographic studies also revealed their conformations, which gave valuable information into the regioselectivity of epoxide ring-opening during their formation. Three 2-azido-4-aminocyclohexane-1,3-diols 12, 14 and 16 were synthesised and their crystal structures were studied by X-ray diffraction. All three structures were characterised by arrays of hydrogen bonding interactions and these crystallographic studies also revealed valuable conformational data which was used to rationalise the regioselectivity of epoxide ring-opening during their formation.

Diastereoselective syntheses of dihydroconduramines (±)-B-1, (±)-E-1, and (±)-F-1 have been achieved from N-protected 4-aminocyclohex-2-en-1-ols via two complementary procedures for epoxidation as the key step. Treatment of either trans- or cis-4-N-benzylaminocyclohex-2-en-1-ol with Cl3CCO2H and then m-chloroperoxybenzoic acid (m-CPBA) resulted in initial formation of the corresponding ammonium species, followed by epoxidation on the face syn to the ammonium moiety exclusively; chemoselective N-benzylation then provided either (1RS,2SR,3RS,4RS)- or (1RS,2RS,3SR,4SR)-2,3-epoxy-4-N,N-dibenzylaminocyclohexan-1-ol, respectively. Treatment of either trans- or cis-4-N,N-dibenzylaminocyclohex-2-en-1-ol with m-CPBA resulted in initial formation of the corresponding N-oxide, followed by epoxidation on the face syn to the hydroxyl group exclusively; reduction then provided either (1RS,2RS,3SR,4RS)- or an alternative route to (1RS,2RS,3SR,4SR)-2,3-epoxy-4-N,N-dibenzylaminocyclohexan-1-ol, respectively. In all cases, S(N)2-type ring opening of these epoxides upon treatment with aqueous H2SO4 proceeded by nucleophilic attack with inversion at C(2) preferentially, distal to the in situ formed ammonium moiety. Hydrogenolytic N-deprotection then gave the corresponding dihydroconduramines (±)-B-1, (±)-E-1, and (±)-F-1.

The incorporation of alkoxy ligands within a range of alkoxyfluoroboranes and dialkoxyfluoroboranes results in fluoroborane reagents with attenuated Lewis acidity and increased ability to donate fluoride ion(s) when compared to boron trifluoride itself. Pinacolatoboron fluoride (pinBF), prepared in situ from BF3·OEt2 and bis(O-trimethylsilyl)pinacol, has been identified as an efficient fluoride donor which allows highly stereoselective SN1-type epoxide ring-opening (with retention of configuration) of a range of trans-β-methyl-substituted aryl epoxides to give the corresponding syn-fluorohydrins. The substrate scope of this transformation is more broad than the analogous protocol using boron trifluoride alone.

Conjugate addition of enantiopure lithium ( R )- N -benzyl- N -(α-methylbenzyl)amide to a range of ω-aryl-α,β-unsaturated esters gives the corresponding ω-aryl-β-amino esters as single diastereoisomers in high yields. Friedel–Crafts cyclisation of the pendant carbonyl group onto the ω-aryl ring then gives a range of 3-amino-substituted 1-indanones, 1-tetralones, and 1-benzosuberones, representing an efficient and short protocol for the preparation of these benzo-fused carbocycles in enantiopure form.

The syn- and anti-diastereoisomeric forms of the reported structures of the marine alkaloids nakinadines D-F have been synthesized, for the first time in all cases, via an approach involving asymmetric Mannich-type (imino-aldol) reactions of methyl phenylacetate with N-tert-butylsulfinyl imines as the key steps to control the stereochemistry. Comparison of the (1)H and (13)C NMR spectroscopic data reported for the natural materials with those acquired for these synthetic samples confirms the initially assigned relative (RS,SR)-configurations of these three alkaloids. In the absence of specific rotation (or other diagnostic) data for the natural materials, it is not possible to unambiguously assign their absolute configurations, although given the absolute (2S)-configurations assigned to nakinadines B and C, and the absolute (2S,3R)-configuration previously established for nakinadine A, the data herein uphold our proposal that nakinadines D-F share the absolute (2S,3R)-configuration.

The asymmetric synthesis of N,O-diacetyl-3-epi-xestoaminol C is reported. The synthesis employs diastereoselective aminohydroxylation of tert-butyl crotonate [conjugate addition of lithium (S)-N-benzyl-N-(α-methylbenzyl)amide, then in situ enolate oxidation with (+)-camphorsulfonyloxaziridine (CSO)] and a diastereoselective reduction protocol as the key stereodefining steps. The synthetic sample of the natural product was isolated as its N,O-diacetyl derivative for ease of purification; this material was prepared in ten steps and 17% overall yield from commercially available tert-butyl crotonate. This synthesis confirms unambiguously both the assigned structure and absolute (S,S)-configuration of the natural product.

The asymmetric syntheses of the N-terminal α-hydroxy-β-amino acid components of microginins 612, 646 and 680 are reported. Conjugate addition of lithium ( R )- N -benzyl- N -(α-methylbenzyl)amide to the requisite ( E )-α,β-unsaturated ester followed by in situ enolate oxidation with (−)-(camphorsulfonyl)oxaziridne (CSO) gave the corresponding anti -α-hydroxy-β-amino esters. Sequential Swern oxidation followed by diastereoselective reduction gave the corresponding syn -α-hydroxy-β-amino esters. Subsequent N-debenzylation (i.e., hydrogenolysis for microginin 612, and NaBrO 3 -mediated oxidative N-debenzylation for microginins 646 and 680) followed by acid catalysed ester hydrolysis gave the corresponding syn -α-hydroxy-β-amino acids, the N-terminal components of microginins 612, 646 and 680, in good yield. An analogous strategy for elaboration of the enantiopure anti -α-hydroxy-β-amino esters facilitated the asymmetric synthesis of the corresponding C(2)-epimeric α-hydroxy-β-amino acids.

The asymmetric syntheses of a range of N- and O-protected 3-deoxy-3-aminosphingoid bases have been achieved using two complementary approaches. dl-Serine was converted to a racemic N,N-dibenzyl-protected γ-amino-α,β-unsaturated ester which was resolved using a parallel kinetic resolution (PKR) strategy upon reaction with a pseudoenantiomeric mixture of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide and lithium (S)-N-3,4-dimethoxybenzyl-N-(α-methylbenzyl)amide, giving the corresponding enantio- and diastereoisomerically pure β,γ-diamino esters. Alternatively, elaboration of l-serine gave the corresponding enantiopure N,N-dibenzyl-protected γ-amino-α,β-unsaturated ester, and doubly diastereoselective conjugate addition of the antipodes of lithium N-benzyl-N-(α-methylbenzyl)amide was found to proceed under the dominant stereocontrol of the lithium amide reagent in both cases, thus augmenting the accessible range of β,γ-diamino esters. Both of these protocols were expanded to include in situ oxidation of the enolate formed upon conjugate addition, giving access to the corresponding α-hydroxy-β,γ-diamino esters. Elaboration of these β,γ-diamino and α-hydroxy-β,γ-diamino esters gave the protected forms of the 3-deoxy-3-aminosphingoid base targets.

The use of O -methyl- N -(α-methylbenzyl)hydroxylamine as a novel chiral auxiliary in asymmetric ortho -deprotonation of the (η 6 -arene) chromium tricarbonyl complexes is described. Upon quenching of the resultant ortho -lithiated complex with an electrophile, 1,2-disubstituted (η 6 -arene) chromium tricarbonyl complexes were obtained in good yield and excellent levels of diastereoselectivity.

This account describes an overview of the asymmetric syntheses of pyrrolizidines, indolizidines and quinolizidines via a common double reductive cyclisation protocol. The highly diastereoselective conjugate addition of an enantiopure lithium amide to an α,β-unsaturated ester incorporating a terminal C=C bond installed the nitrogen-bearing stereogenic centre and was followed by enolate functionalisation to introduce the second olefinic functionality. Alternatively, conjugate addition to the corresponding α-alkenyl α,β-unsaturated ester followed by α-protonation of the intermediate enolate may also be used to access the cyclisation precursor. After oxidation of the two terminal olefinic units to give the corresponding dialdehyde, tandem hydrogenolysis/hydrogenation was employed to efficiently construct the azabicyclic core of each target molecule. This double reductive cyclisation strategy was successfully utilised in the syntheses of 13 azabicyclic alkaloids or closely related analogues.1 Introduction2 Asymmetric Syntheses of (–)-Isoretronecanol and (–)-Trachelanthamidine3 Asymmetric Syntheses of (+)-Trachelanthamidine [(+)-Laburnine], (+)-Tashiromine and (+)-epi-Lupinine4 Asymmetric Syntheses of (–)-Hastanecine, (–)-Turneforcidine and (–)-Platynecine5 Asymmetric Syntheses of (–)-Macronecine, (–)-Petasinecine, (–)-1-epi-Macronecine, (+)-1-epi-Petasinecine and (+)-2-epi-Rosmarinecine6 Conclusion

The asymmetric syntheses of all eight tetraponerine alkaloids (T1–T8) were achieved using the diastereoselective conjugate additions of lithium amide reagents in the key stereodefining steps. Conjugate addition of either lithium (R)-N-allyl-N-(α-methylbenzyl)amide or lithium (R)-N-(but-3-en-1-yl)-N-(α-methylbenzyl)amide to tert-butyl sorbate was followed by ring-closing metathesis of the resultant N-alkenyl β-amino esters, reduction to the corresponding aldehydes, and reaction with tert-butyl (triphenylphosphoranylidene)acetate. Subsequent conjugate addition of the requisite antipode of lithium N-benzyl-N-(α-methylbenzyl)amide to the resultant α,β-unsaturated esters gave a range of diamines for elaboration to T1–T8 via a sequence involving reduction of the ester moiety to give the corresponding aldehyde, olefination, tandem hydrogenation/hydrogenolysis, and cyclization upon reaction with 4-bromobutanal to give the tricyclic skeleton.

A range of alkyl- or aryl-substituted iron succinoyl complexes, incorporating the iron chiral auxiliary [(η5-C5H5)Fe(CO)(PPh3)], were prepared in high regio- and diastereoselectivities by employing four successful strategies: (i) the alkylation of chiral enolate equivalents with tert-butyl bromoacetate; (ii) the mutual kinetic resolution of tert-butyl α-bromoacetate with a chiral acetate enolate equivalent; (iii) the alkylation of chiral succinoyl enolate equivalents; (iv) the conjugate addition of organolithium reagents or lithium amide reagents to chiral fumaroyl derivatives. Oxidative cleavage of the iron chiral auxiliary was shown to occur without compromising the stereochemical integrity of the succinoyl fragments.

A range of the methyl glycosides of 2-deoxy-2-aminohexoses, comprising d-allosamine, d-mannosamine, d-idosamine and d-talosamine, were prepared from the corresponding d-aldopentoses via a seven step synthetic sequence. The doubly diastereoselective conjugate addition of the requisite antipode of lithium N-benzyl-N-(α-methylbenzyl)amide and in situ enolate oxidation with the requisite antipode of camphorsulfonyloxaziridine (CSO) was used as the key, stereodefining step. Sequential reduction of the resultant α-hydroxy-β-amino esters and oxidative cleavage of the C(1)-C(2) diol unit furnished the corresponding α-amino aldehydes. Subsequent N- and O-deprotection gave the target compounds (as mixtures of anomers) in good yield and high diastereoisomeric purity. © 2014 Elsevier Ltd. All rights reserved.

An asymmetric synthesis of the allocolchicinoid N-acetylcolchinol methyl ether (NCME) from 3-methoxybenzaldehyde is reported. Comparison of 1H and 13C NMR spectroscopic data obtained for this sample of NCME provide further evidence for the assertion that this compound is congruous with the natural product that has been dubbed suhailamine, establishing NCME as a naturally-occurring allocolchicinoid. The single crystal X-ray diffraction structure of NCME is also reported for the first time, revealing a preference for adoption of the (7S,Ra,Z) form—i.e., describing the orientation of the biaryl axis and the amide N–CO bond as well as the configuration of the stereocenic centre—in the solid state. A preference for the same form in DMSO-d6 solution is revealed upon analysis by a range of NMR spectroscopic techniques, whilst an interconverting 69:24:7 mixture of the (7S,Ra,Z), (7S,Sa,Z) and (7S,Ra,E) forms is observed in CDCl3.

Ab initio asymmetric syntheses of methyl N,O-diacetyl-D-3-epi-daunosaminide and methyl N,O-diacetyl-D-ristosaminide, employing diastereoselective epoxidation and dihydroxylation, respectively, of alkyl (3S,αR,Z)-3-[N-benzyl-N-(α-methylbenzyl)amino]hex-4-enoates as the key steps, are reported. The requisite substrates were readily prepared using the conjugate additions of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to methyl and tert-butyl (E)-hexa-2-en-4-ynoates followed by diastereoselective alkyne reduction. syn-Dihydroxylation using OsO4 proceeded under steric control on the 4Re,5Re face of the olefin to give the corresponding diol, which subsequently underwent lactonization. Meanwhile, epoxidation using F3CCO3H in conjunction with F3CCO2H proceeded on the opposite 4Si,5Si face of the olefin under hydrogen-bonding control from the in situ formed ammonium ion. Treatment of the intermediate epoxide with concd aq H2SO4 promoted highly regioselective ring-opening (distal to the in situ formed ammonium moiety) to give the corresponding diol (completing overall the formal anti-dihydroxylation of the olefin), which then underwent lactonization under the reaction conditions. Elaboration of these diastereoisomeric lactones through hydrogenolysis, N-Boc protection, reduction, methanolysis, and acetate protection gave methyl N,O-diacetyl-D-3-epi-daunosaminide and methyl N,O-diacetyl-D-ristosaminide.

Both diastereoisomers of 2-amino-3-hydroxybutanoic acid and 2-amino-3-hydroxy-3-phenylpropanoic acid have been prepared from enantiopure α-hydroxy-β-amino esters via the intermediacy of the corresponding cis- and trans-aziridines. Aminohydroxylation of two α,β-unsaturated esters produced enantiopure 2,3-anti-α-hydroxy-β-amino esters in >99:1 dr. Subsequent epimerisation at the C(2)-position via a sequential oxidation/diastereoselective reduction protocol gave the corresponding enantiopure 2,3-syn-α-hydroxy-β-amino esters in >99:1 dr. These syn- and anti-substrates were then converted into the corresponding N-Boc protected cis- and trans-aziridines, respectively, via a three step reaction sequence: (i) hydrogenolysis and in situ N-Boc protection; (ii) OH-activation; and (iii) aziridine formation. Subsequent regioselective ring-opening of the C(3)-methyl-aziridines with Cl3CCO2H proceeded with inversion of configuration to give the corresponding 2-amino-3-trichloroacetate esters, whereas the analogous reaction with the C(3)-phenyl-aziridines resulted in rearrangement to the corresponding oxazolidin-2-ones with retention of configuration. In each case, hydrolysis of the products from these ring-opening reactions produced the corresponding enantiopure β-hydroxy-α-amino acids as single diastereoisomers.

All three diastereomers are prepared in 11 steps starting from commercially available 2,2-dimethoxyacetaldehyde.

Efficient de novo asymmetric syntheses of (+)-preussin B, the C(2)-epimer of (−)-preussin B, and 3-deoxy-(+)-preussin B have been developed, using the diastereoselective conjugate addition of lithium (S)-N-benzyl-N-(α-methylbenzyl)amide to tert-butyl 4-phenylbut-2-enoate and diastereoselective reductive cyclizations of γ-amino ketones as the key steps to set the stereochemistry. Conjugate addition followed by enolate protonation generated the corresponding β-amino ester. Homologation using the ester functionality as a synthetic handle gave the corresponding γ-amino ketone. Hydrogenolytic N-debenzylation was accompanied by diastereoselective reductive cyclization in situ; reductive N-methylation then gave 3-deoxy-(+)-preussin B as the major diastereoisomeric product. Meanwhile, the same conjugate addition but followed by enolate oxidation with (+)-camphorsulfonyloxaziridine gave the corresponding anti-α-hydroxy-β-amino ester. α-Epimerization by oxidation and diastereoselective reduction then gave access to...

Homochiral (E)- and (Z)-enamides derived from SuperQuat (S)-4-phenyl-5,5-dimethyl-oxazolidin-2-one undergo highly diastereoselective epoxidation upon treatment with dimethyldioxirane. Subsequent epoxide opening with meta-chlorobenzoic acid proceeds via a stereoselective SN1-type process, with retention of configuration, to give the corresponding 1′-m-chlorobenzoyl-2′-hydroxy derivatives. Treatment of the SuperQuat enamides with mCPBA effects this two-step transformation in one pot. Reductive cleavage of the isolated 1′-m-chlorobenzoyl-2′-hydroxy derivatives (≥96% de) generates homochiral 1,2-diols in ≥96% ee. Alternatively, regioselective lithiation of the enamide at C(1′) with tBuLi followed by reaction with an aromatic aldehyde and in situ O-benzylation generates a 1′-(benzyloxy-aryl-methyl) substituted enamide with high diastereoselectivity. Subsequent oxidative cleavage of the enamide C{double bond, long}C bond with NaIO4/RuCl3 followed by methanolysis of the resultant N-acyl fragment furnishes an O-benzyl protected α-hydroxy methyl ester in high ee. © 2008 Elsevier Ltd. All rights reserved.