•Quest for steroidomimetics from amino acids as chirons.•Novel steroidal and nonsteroidal architectures have been synthesized using amino acids.•New stereogenic center has been introduced and having potential for further functionalization.•Biological activity of some of the active compounds has been discussed.•Application of enantiomers of amino acids in steroidal backbone may generate exciting ligand-receptor interactions.The chiral pool amino acids have been utilized for the construction of steroidal and non-steroidal architectures in the quest for steroidomimetics. Chirality derived from amino acid-based architectures provides new and easy to incorporate chiral chemical space, which is otherwise very difficult to introduce and comprised of several synthetic steps for asymmetric steroids. The different and exciting ligand-receptor interactions may arise from the use of each amino acid enantiomer that was introduced into the chiral steroidal backbone. The A and D rings of steroidal architectures can be mimicked by the phenyl group of the amino acid tyrosine. The Mitsunobu reaction, nucleophilic substitution and elimination, etc. were utilized for constructing diverse tri- and tetracyclic steroidal skeletons as well as benzofused seco-steroids from amino acids. These benzofused, amino acid-derived steroidal and nonsteroidal molecules had promising biological activity in hormonal related disorders.Download high-res image (127KB)Download full-size image

Enantiomerically pure α-amino acids (α-AAs) are, for a long time, considered as a major class of chiral pools. Their employment in the enantioselective synthesis of natural products has made enormous impact in the general organic synthesis. This review is an effort to discuss the state of the art of synthetic methodologies in which the α-amino acids with electrically charged and polar uncharged side chains (i.e. Arginine, Histidine, Lysine, Aspartic acid, Glutamic acid, Serine, Threonine, Asparagine, Glutamine, Cysteine) have been transformed into final bioactive alkaloids and related diversity during the period 1996 to December 2013. In general, two principles are followed to harness the potential of the amino acids: one in which the original chiral center is preserved and the other in which the chiral center is resorted to create new stereocenters by stereoinduction. This article is arranged with individual amino acid in the alphabetical order as a source of starting material towards description of alkaloids. Key synthetic steps are mentioned in each description of an alkaloid for the benefit of future organic practitioners.Download high-res image (210KB)Download full-size image

Breast cancer cell proliferation is promoted by a variety of mitogenic signals. Classically estrogen is considered as most predominant mitogenic signal in hormone-dependent breast cancer and progesterone is primarily considered to have protective effect. However, it is suggested that some progesterone metabolite may promote breast cancer and progesterone metabolites like 5α-pregnane and 4-pregnene could serve as regulators of estrogen-responsiveness of breast cancer cells. Here, we estimated the potential of alternate targeting of breast cancer via progesterone signalling. l-Proline derived novel 14-azasteroid compounds were screened against MCF-7 and MDA-MB-231 cell lines using MTT assay. In silico studies, cell cycle, Annexin-V-FITC/PI, JC-1 mitochondrial assay, ROS analysis were performed to analyse the impact of hit compound 3b on breast cancer cells. Further, we analysed the impact of hit 3b on the progesterone, its metabolites and enzymes responsible for the conversion of progesterone and its metabolites using ELISA. Data suggests that compound 3b binds and down regulates of 5α-reductase by specifically inhibiting production of progesterone metabolites that are capable of promoting breast cancer proliferation, epithelial mesenchymal transition and migration. This study establishes the proof of concept and generation of new leads for additional targeting of breast cancer.Download high-res image (69KB)Download full-size image

The first examples of amino acid derived α,β-unsaturated esters to Z-alkylidene oxindoles via 3-aza-Cope rearrangement using In(OTf)3 are reported.

A highly efficient total synthesis of 3-epi-(+)-lycoricidine has been described for the first time from easily available (S)-Garner aldehyde with an overall yield of 7% in 20 steps. Stereoselective nucleophilic addition, Sharpless asymmetric dihydroxylation, Dess–Martin periodinane oxidation, intramolecular aldol cyclization, and Luche reduction are the salient features of this approach.

Enantiomerically enriched indolines and tetrahydroisoquinolines were synthesized within 5 min to 2 h in high yields from easily accessible (S)-amino acid derived chiral carbocations. The diastereoselective Friedel–Crafts reaction is promoted by a Lewis acid (AlCl3) offering trans-diastereoselectivity. The rate of the reaction and diastereoselectivity of the product are significantly influenced by steric hindrance of the amino acids substituents and aryl groups. The methodology can be applied for the synthesis of the enantiomerically enriched bioactive scaffold (3S,4R)-demethoxy-3-isopropyl diclofensine.

As a result of their easy availability in enantiomerically enriched form and their possession of synthetically transformable diverse functional groups, amino acids have been extensively used by synthetic organic and medicinal chemists as a chiral pool for access to heterocycles (monocycles, bicycles or polycycles, either bridged or fused). This review describes the syntheses of diverse asymmetric heterocycles with various membered rings (n = 3–9) followed by benzo or heteroannulated ones, for the period from 1996 to Dec. 2013. It details solution phase synthetic methodologies in which the naturally occurring α-amino acid is incorporated, totally or partially, into the final product.

An efficient, general and practical synthesis of diverse 3,4-dihydropyrazines, 6,7-dihydro-[1,2,3]triazolopyrazines and 7,8-dihydro-[1,2,3]triazolodiazepines through intramolecular 1,3-dipolar cycloaddition from amino acid derived common intermediates with high yields is described. Moreover, one-pot access to optically active 3-aryl substituted 6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazines in the palladium–copper co-catalytic system has also been achieved in this work. The easy substrate availability and operational simplicity make the process suitable for further exploration.

The intramolecular aminopalladation reaction of L-serine derived β-hydroxy-γ-alkenylamines undergoes 5-endo-trig cyclization to furnish pyrrolidine rings in high yields. The pyrrolidines thus obtained were used in the synthesis of (−)-8,8a-di-epi-swainsonine, a specific and competitive inhibitor (Ki value 2 × 10−6 M) of lysosomal α-mannosidases.

A microwave assisted efficient route to the synthesis of benzimidazole fused heterocycles through metal catalyzed endo-cyclization strategy involving imine and alkyne activation has been developed. In the presence of [RuCl2(p-cymene)2]2, a variety of 2-ethynyl aldehydes underwent cascade cyclization with substituted benzenediamines to afford the corresponding benzo[4,5]imidazo[2,1-a] pyridine scaffold in moderate to good yields.

We report easy access to carbohydrate derived diverse tricyclic skeletons which could be beneficial for exploring polyfunctionalized chiral alicycles. The key reaction to assemble a sugar fused tricyclic core is intermolecular tandem esterification and 1,3-dipolar cycloaddition. The framework was elaborated using amide forming reactions, opening of isoxazolidine rings followed by N and O-acylations. The sequences provide distinct, spatially separated and encoded chemical entities that may pave the way to investigate cell functions.

A synthetic approach toward xanthone and fluorenone derivatives through ruthenium catalyzed intra-molecular C–H bond functionalization using an external oxidant has been developed. In the presence of [RuCl2(p-cymene)2]2, a variety of substituted ortho-aryloxy/aryl benzaldehydes underwent cross dehydrogenative coupling to afford the corresponding analogs in moderate to good yields.

Two different stereoselective routes for the synthesis of Jaspine B and its C2 epimer are presented here, starting from easily available Garner aldehyde. The key synthetic steps involved iodocyclization, organocuprate addition, HWE olefination, regioselective α-tosylation and cross metathesis reaction. This is the first report to synthesize Jaspine B involving iodocyclization.

A series of trisubstituted methanes containing aryl and heteroaryl rings, as well as a sulfur spacer between the central methano-carbon and benzene ring, is reported. In an approach towards asymmetric tetrasubstituted methane with high enantioselectivity, chiral tertiary α-hydroxyaldehyde has been synthesized through a Sharpless dihydroxylation on a disubstituted olefin, followed by the chemoselective oxidation of the primary alcohol.

An efficient stereoselective synthesis of aminocyclopentitols from (S)- and (R)-Garner aldehydes is presented here. The key steps involved diastereoselective addition of vinylmagnesium bromide to a Garner aldehyde, ring closing metathesis, diastereoselective dihydroxylation and stereoselective reduction of the keto functionality.

An efficient chiral pool approach using L-proline to access 14-azasteroids under mild reaction conditions has been described. The key step involves the intramolecular SN2′ cyclization reaction for the construction of critical C-ring in the nitrogen impregnated steroidal architectures bearing unsaturation at Δ9(11) position. In the endeavour to synthesize some new congeners, the remote electronic impact of the electron donating groups in A ring and heteroatoms like oxygen in B ring, on the propensity of C-ring cyclization was also observed.

An efficient synthetic strategy is described for the construction of amino acids derived enantiomerically pure cis-2,5-disubstituted chiral piperazines. Cu-catalyzed spontaneous regioselective ring opening and ring closing of non-activated N-tosyl aziridines as well as Pd-mediated N–C bond formation from N-tosyl halogenated amino-derivatives are the key steps for accessing disubstituted piperazines.

Diastereoselective trans-2,5-disubstituted amino acids derived diverse morpholines, piperazines and thiomorpholines were prepared in 30 min-1 h with high yields through iodine-mediated 6-exotrig type cyclization from a single common synthetic intermediate. The displacement of iodine with hydride ion gave a methyl substituent at the 2-position of morpholines which provides an additional opportunity for diversity oriented nucleophilic substitution on the rings as well as incorporation of substituents at the 5-position from amino acids constituents.Keywords: amino acids; diastereoselective reaction; morpholines; piperazines; thiomorpholines

An easy, efficient and concise approach to tetrahydrofluorene [6,5,6]ABC tricyclic core embedded new polycycles has been achieved under relatively mild and catalytic Nazarov type electrocyclization conditions, using 2 mol% of Sc(OTf)3 in anhydrous DCM (dichloromethane) at room temperature, with high yields. The generality of the reaction has been illustrated by synthesizing diverse polycycles embedded with rare heterotricyclic [6,5,5]ABC skeletons.

A new one-pot synthetic strategy is described for the synthesis of enantiomerically pure cis-3,5-disubstituted morpholines and 3,6-disubstituted 1,4-oxazepanes via tandem aziridine/epoxide ring opening sequences. This new strategy describes how epoxy alcohols could act as both a nucleophile and an electrophile in a tandem fashion and undergo intermolecular regioselective ring opening of chiral aziridines for the first time.

A series of amino acid-derived enantiomerically pure substituted benzo[d][1,2,3,6]oxatriazocine derivatives and 1-alkyl substituted benzotriazoles has been prepared by the diazotization of amino acid-derived benzo-fused alicycles. The first unprecedented diazo-oxygen bond formation in acidic medium led to an entirely new kind of substituted benzo[d][1,2,3,6]oxatriazocine heterocycles.

A new series of enantiomerically pure 2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxalines were synthesized for the first time in twelve steps from 1-fluoro-2-nitrobenzene and S-amino acids with 13–20% overall yields. First use of intramolecular Mitsunobu cyclization for 1,2,3,4-tetrahydroquinoxalines followed by PPh3/I2/imidazole mediated 6-exo-tet cyclization were the key steps.

A new series of ionone derived allylic alcohols have been evaluated for anti-ischemic activity. Out of them, 12f and 13b decreased infarct volume to 23.98 ± 4.7 mm3 and 93.98 ± 24.8 mm3 as compared to ischemic group.A new series of ionone derived allylic alcohols have been evaluated for anti-ischemic activity. Out of them, 12f and 13b decreased infarct volume to 23.98 ± 4.7 mm3 and 93.98 ± 24.8 mm3 as compared to ischemic group.

A concise and general route to synthesize a new class of [6-5-6] tricyclic core embedded polyheterocycles has been accomplished using diastereoselective Nazarov cyclization with an overall yield of 35–40%. Versatility of this synthetic route has also been demonstrated by accessing a variety of [6-5-5] tricyclic core incorporated polycycles. It was observed that the efficiency of cyclization depends upon the impact of polarization on the reacting systems. Amongst the various Lewis and Brønsted acids screened for cyclization, triflic acid was found to be the most effective catalyst.

The first examples of amino acid derived α,β-unsaturated esters to Z-alkylidene oxindoles via 3-aza-Cope rearrangement using In(OTf)3 are reported.

A concise and general route to synthesize a new class of [6-5-6] tricyclic core embedded polyheterocycles has been accomplished using diastereoselective Nazarov cyclization with an overall yield of 35–40%. Versatility of this synthetic route has also been demonstrated by accessing a variety of [6-5-5] tricyclic core incorporated polycycles. It was observed that the efficiency of cyclization depends upon the impact of polarization on the reacting systems. Amongst the various Lewis and Brønsted acids screened for cyclization, triflic acid was found to be the most effective catalyst.

As a result of their easy availability in enantiomerically enriched form and their possession of synthetically transformable diverse functional groups, amino acids have been extensively used by synthetic organic and medicinal chemists as a chiral pool for access to heterocycles (monocycles, bicycles or polycycles, either bridged or fused). This review describes the syntheses of diverse asymmetric heterocycles with various membered rings (n = 3–9) followed by benzo or heteroannulated ones, for the period from 1996 to Dec. 2013. It details solution phase synthetic methodologies in which the naturally occurring α-amino acid is incorporated, totally or partially, into the final product.

Enantiomerically enriched indolines and tetrahydroisoquinolines were synthesized within 5 min to 2 h in high yields from easily accessible (S)-amino acid derived chiral carbocations. The diastereoselective Friedel–Crafts reaction is promoted by a Lewis acid (AlCl3) offering trans-diastereoselectivity. The rate of the reaction and diastereoselectivity of the product are significantly influenced by steric hindrance of the amino acids substituents and aryl groups. The methodology can be applied for the synthesis of the enantiomerically enriched bioactive scaffold (3S,4R)-demethoxy-3-isopropyl diclofensine.

A new series of enantiomerically pure 2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxalines were synthesized for the first time in twelve steps from 1-fluoro-2-nitrobenzene and S-amino acids with 13–20% overall yields. First use of intramolecular Mitsunobu cyclization for 1,2,3,4-tetrahydroquinoxalines followed by PPh3/I2/imidazole mediated 6-exo-tet cyclization were the key steps.

An easy, efficient and concise approach to tetrahydrofluorene [6,5,6]ABC tricyclic core embedded new polycycles has been achieved under relatively mild and catalytic Nazarov type electrocyclization conditions, using 2 mol% of Sc(OTf)3 in anhydrous DCM (dichloromethane) at room temperature, with high yields. The generality of the reaction has been illustrated by synthesizing diverse polycycles embedded with rare heterotricyclic [6,5,5]ABC skeletons.

A new one-pot synthetic strategy is described for the synthesis of enantiomerically pure cis-3,5-disubstituted morpholines and 3,6-disubstituted 1,4-oxazepanes via tandem aziridine/epoxide ring opening sequences. This new strategy describes how epoxy alcohols could act as both a nucleophile and an electrophile in a tandem fashion and undergo intermolecular regioselective ring opening of chiral aziridines for the first time.

An efficient, general and practical synthesis of diverse 3,4-dihydropyrazines, 6,7-dihydro-[1,2,3]triazolopyrazines and 7,8-dihydro-[1,2,3]triazolodiazepines through intramolecular 1,3-dipolar cycloaddition from amino acid derived common intermediates with high yields is described. Moreover, one-pot access to optically active 3-aryl substituted 6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazines in the palladium–copper co-catalytic system has also been achieved in this work. The easy substrate availability and operational simplicity make the process suitable for further exploration.