Enantioselective synthesis of bicarbocyclic structures with an all-carbon quaternary stereocenter through sequential cross metathesis and intramolecular Rauhut-Currier reaction

A new extension of the Birch-Cope sequence is described which allows the efficient enantioselective construction of highly functionalized, fused bicarbocyclic structures with an all-carbon quaternary stereocenter in two steps. The two-step sequence includes a cross metathesis between a terminal alkene and a polarized alkene followed by an intramolecular Rauhut-Currier reaction with a trialkylphosphine catalyst.     

Concise formal synthesis of (-)-peduncularine via ring-closing metathesis

[reaction: see text] A synthesis of the 6-aza[3.2.1]bicyclooctene (-)-2 has been completed by a short sequence of reactions that required only six operations from (S)-malic acid and featured a novel ring-closing metathesis to form the bridged bicyclic ring. Because 2 was previously converted into (-)-peduncularine (1), its preparation constitutes a formal enantioselective synthesis of 1.     

Asymmetric cascade reaction sequences via chiral lithiated intermediates

The (-)-sparteine-mediated enantioselective intermolecular carbolithiation of (E)-2-propenylarylamines allows for the generation of chiral lithiated intermediates which have broad synthetic potential. These intermediates have been exploited in a series of further in situ reactions with electrophiles to generate a collection of products each containing a common stereogenic center. The stereogenic center, formed in high enantiomeric ratio in the first carbolithiation step, is carried through the cascade reaction sequence to the final products and is independent of electrophile used. The methodology is demonstrated by the synthesis of structurally diverse chiral anilines, indoles, and indolones all with an er of 92:8 (+/-1). The heterocyclic syntheses involve an enantioselective alkene carbolithiation and subsequent trapping of the intermediate organolithium with a suitable electrophile, followed by an in situ ring closure and dehydration to generate the indole or indolone rings.     

Intramolecular Heck cyclization to the galanthamine-type alkaloids: total synthesis of (±)-lycoramine

A novel approach towards the construction of the galanthamine skeleton was demonstrated by the total synthesis of (±)-lycoramine. The key steps include a Pd-catalyzed intramolecular cyclization to form the seven-membered azepane ring and a spontaneous intramolecular Michael addition to afford the five-membered furan ring. This synthetic route has also been demonstrated to be useful for the preparation of novel derivatives with simplified galanthamine skeletons.     

Diels-Alder reaction-aromatization approach toward functionalized ring C allocolchicinoids. Enantioselective total synthesis of (-)-7S-allocolchicine

Allocolchicinoids are analogues of the important antimitotic compound (-)-colchicine 1. A strategy is reported for the synthesis of ring C functionalized allocolchicinoids, which is based on a Diels-Alder reaction-aromatization sequence. This route is complementary to the previously disclosed benzannulation approach involving Fischer carbene complexes and alkynes. Dienes 12 and 14 incorporate the natural substitution pattern on ring A and undergo Diels-Alder reactions with various dienophiles. Subsequent aromatization affords the set of differently functionalized ring C allocolchicinoids 15-19, 23, and 25, with high regioselectively and in moderate to good yields. An intramolecular Diels-Alder reaction-aromatization sequence allows for access to allocolchicinoids with reversed regiochemical introduction of ring C substituents. The equilibria of the atropisomers of 15 and 19 are studied in three NMR solvents. Reactions of the dienes 12 and 14 with DMAD lead to the corresponding cycloadducts, but the subsequent aromatization is complicated. A regioselective Diels-Alder reaction-aromatization sequence is utilized as the key step in the first stereoselective total synthesis of (-)-allocolchicine 2. Asymmetric introduction of hydroxy group at C7 is achieved by the enantioselective reduction of ketone 29. The correct stereochemistry is then established by Mitsunobu inversion reaction using Zn(N(3))(2)-2Py.     

Enantioselective total synthesis of Wieland-Gumlich aldehyde and (-)-strychnine

A total synthesis of (-)-strychnine in 15 steps from 1,3-cyclohexanedione in 0.15% overall yield is described. The sequence followed in the assembling of rings is: E-->AE [2-(2-nitrophenyl)-1,3-cyclohexanedione]-->ACE (3a-aryloctahydroindol-4-one)-->ACDE (arylazatricyclic core)-->ABCDE (strychnan skeleton)-->ABCDEF (Wieland-Gumlich aldehyde)-->ABCDEFG (strychnine). The key steps of the synthesis are the enantioselective construction of the 3a-(2-nitrophenyl)-octahydroindol-4-one ring system and the closure of the piperidine ring by a reductive Heck cyclization to generate the pivotal intermediate (-)-14. In contrast, a Lewis acid promoted a-alkoxypropargylic silane-enone cyclization did not lead to synthetically useful azatricyclic ACDE intermediates. The introduction of C-17 and the closure of the indoline ring by reductive amination of the alpha-(2-nitrophenyl) ketone moiety complete the strychnan skeleton from which, via the Wieland-Gumlich aldehyde, the synthesis of (-)-strychnine is achieved.     

Total synthesis of (+)-laurencin: an asymmetric alkylation-ring-closing metathesis approach to medium ring ethers

[formula: see text] The enantioselective total synthesis of (+)-laurencin 1 is achieved in 18 steps from (S)-(+)-4-benzyl-3-benzyloxyacetyl-2-oxazolidinone. The key steps in this synthesis are an asymmetric glycolate alkylation leading to acyl oxazolidinone 2 and a subsequent ring-closing olefin metathesis to construct the oxocene core of 1. The approach to medium ring ethers utilized in this synthesis provides a general and efficient route to the cyclic core of other marine natural products.     

Enantioselective synthesis of (-)-jiadifenin, a potent neurotrophic modulator

The first enantioselective synthesis of (-)-jiadifenin (1), a potent neurite outgrowth promoter isolated from the Illicium species, is described. The synthetic strategy builds upon bicyclic motif 6, which represents the AB ring of the natural product and proceeds in 19 steps and 1.1% overall yield. Key to our approach is a Mn(III)-mediated oxidation reaction of A ring that, following a regio- and diastereoselective α-hydroxylation and methylation sequence, produces the desired functionalities of (-)-jiadifenin. The effect of synthetic 1 in NGF-mediated neurite outgrowth was also measured in PC-12 cells.     

The enantioselective Birch-Cope sequence for the synthesis of carbocyclic quaternary stereocenters. Application to the synthesis of (+)-mesembrine

A synthetic technique for generating carbocyclic quaternary stereocenters with exceptionally high levels of enantioselectivity is described. A sequence of three reactions, enantioselective Birch reduction-allylation, enol ether hydrolysis, and Cope rearrangement, is used to stereoselectively generate chiral quaternary centers on a 2-cyclohexen-1-one ring. The products of the sequence are 4,4-disubstituted-2-carboxamide-2-cyclohexen-1-one structures which are versatile intermediates in complex natural product synthesis. An application of the sequence to the synthesis of (+)-mesembrine illustrates the utility of these intermediates.     

Total synthesis and proof of relative stereochemistry of (-)-aureonitol

Two trisubstituted epimeric tetrahydrofurans, 1 and 2, have been synthesized in order to confirm the relative stereochemistry in the natural product aureonitol. The key step in the synthesis of 1 and 2 involved a stereoselective intramolecular allylation of an allylsilane with an aldehyde, which introduced the stereotriad in the five-membered ring. The major tetrahydrofuran diastereoisomer 18 from this cyclization reaction was subsequently elaborated to tetrahydrofuran 1. Its 3-epimer (2) was then prepared from 1 via an oxidation-reduction sequence. Compound 1 exhibits identical (1)H NMR data to those reported for aureonitol, which was isolated from Helichrysum aureonitons by Bohlmann in 1979, whereas the (1)H NMR data for 2 are markedly different. The (1)H NMR data (in CDCl3, CD3OD, and C6D6) and (13)C NMR data (in CDCl3) for 1 are also identical with those reported for a natural product isolated from various Chaetomium sp. by Abraham, Seto, and Teuscher. These findings support Abraham's conclusion that the structure of aureonitol should be revised from 2 to 1. The enantioselective synthesis of 1 has also confirmed that (-)-aureonitol isolated by Abraham contains the (2S,3R,4S) absolute configuration of stereocenters on the tetrahydrofuran ring.     

Total synthesis of (-)-stemonine

[reaction: see text] An enantioselective total synthesis of (-)-stemonine (1) is reported via a convergent assembly of the acyclic precursor 2. Key transformations include a Staudinger-aza-Wittig reaction to form the central perhydroazepine ring system and an iodine-induced tandem cyclization to construct the pyrrolidino-butyrolactone framework.     

Concise total synthesis of (+)-carpamic acid

We report herein an efficient enantioselective synthesis of (+)-carpamic acid, with nine steps as the longest linear sequence, the key strategy being based on a novel sequence of a cross-metathesis (CM) reaction and a subsequent cyclizing reductive amination to form the piperidine ring.     

A concise enantioselective entry to the synthesis of deoxy-azasugars

[reaction: see text] A concise enantioselective preparation of oxazolidinylpiperidine 4, a key intermediate in the synthesis of glycosidase inhibitors such as 1-deoxymannojirimycin or 1-deoxygalactostatin, has been developed. Sharpless catalytic asymmetric epoxidation of (E)-2,4-pentadienol followed by treatment with allyl isocyanate afforded epoxy carbamate 8. Regioselective intramolecular ring opening promoted by sodium bis(trimethylsilyl)amide and ring-closing metathesis provided the bicyclic intermediate 4 in high enantiomeric purity. The four-step sequence takes place in 51% overall yield.     

Synthesis of 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane, 2-(pyridin-3-yl)-1-azabicyclo[2.2.2]octane, and 2-(pyridin-3-yl)-1-azabicyclo[3.2.1]octane, a class of potent nicotinic acetylcholine receptor-ligands

In an attempt to generate nicotinic acetylcholine receptor (nAChR) ligands selective for the alpha4beta2 and alpha7 subtype receptors we designed and synthesized constrained versions of anabasine, a naturally occurring nAChR ligand. 2-(Pyridin-3-yl)-1-azabicyclo[2.2.2]octane, 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane, and several of their derivatives have been synthesized in both an enantioselective and a racemic manner utilizing the same basic synthetic approach. For the racemic synthesis, alkylation of N-(diphenylmethylene)-1-(pyridin-3-yl)methanamine with the appropriate bromoalkyltetrahydropyran gave intermediates which were readily elaborated into 2-(pyridin-3-yl)-1-azabicyclo[2.2.2]octane and 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane via a ring opening/aminocyclization sequence. An alternate synthesis of 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane via the alkylation of N-(1-(pyridin-3-ylethylidene)propan-2-amine has also been achieved. The enantioselective syntheses followed the same general scheme, but utilized imines derived from (+)- and (-)-2-hydroxy-3-pinanone. Chiral HPLC shows that the desired compounds were synthesized in >99.5% ee. X-ray crystallography was subsequently used to unambiguously characterize these stereochemically pure nAChR ligands. All compounds synthesized exhibited high affinity for the alpha4beta2 nAChR subtype ( K i < or = 0.5-15 nM), a subset bound with high affinity for the alpha7 receptor subtype ( K i < or = 110 nM), selectivity over the alpha3beta4 (ganglion) receptor subtype was seen within the 2-(pyridin-3-yl)-1-azabicyclo[2.2.2]octane series and for the muscle (alpha1betagammadelta) subtype in the 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane series.     

Azomethine ylide cycloaddition/reductive heterocyclization approach to oxindole alkaloids: asymmetric synthesis of (-)-horsfiline.

The intermolecular [3 + 2] annulation of azomethine ylides with 2(2-nitrophenyl)acrylate dienophiles followed by reductive heterocyclization affords the spiro(indole-pyrrolidine) ring system. Hence, this enable us to accomplish a concise and highly enantioselective synthesis of (-)-horsfiline 1, based on chiral auxiliary-directed pi-face discrimination in the 1,3-dipolar cycloaddition of (1S,2R)-2-phenyl-1-cyclohexyl ester 4f with N-methylazomethine ylide.     

Synthesis of the C1-C12 acid fragment of amphidinolide T marine macrolides via SmI2-mediated enantioselective reductive coupling of aldehydes with a chiral crotonate

A new strategy for enantioselective assembly of the trisubstituted tetrahydrofuran ring has been established for synthesis of the C1-C12 acid fragment of amphidinolide T series marine macrolides. The key steps involve the SmI₂-mediated highly enantioselective reductive coupling of an aldehyde with the (1S,2R)-N-methylephedrine-derived crotonate to form the cis-3,4-disubstituted γ-butyrolactone and the subsequent BF₃-mediated 1,3-anti-selective allylation of the five-membered-ring oxocarbenium ion with allyltrimethylsilane. The desired C1-C12 acid fragment was obtained in >25% overall yield via a 9-step sequence.     

Enantioselective synthesis of marine indole alkaloid hamacanthin B

An enantioselective total synthesis of hamacanthin B (1) is described. This synthesis is based on the asymmetric synthesis of (S)-2-azido-(indol-3-yl)ethylamine 7, which is coupled with the 3-indolyl-alpha-oxoacetyl chloride 8 and subsequently used in a successful intramolecular Staudinger-aza Wittig cyclization to form the central dihydropyrazinone ring. The stereochemistry of naturally isolated hamacanthin B is revealed as the (S)-configuration.     

Concise enantioselective synthesis of (−)-lasubine II

An enantioselective synthesis of the quinolizidine alkaloid (−)-lasubine II 1 is reported. Two different pathways to the key intermediate 2 are described. The first case involving a sequence of ring rearrangement metathesis (RRM), simple functional group interconversion operations, followed by a stereoselective cross metathesis (CM) and in the second case a domino ring opening-/ring closing-/cross metathesis step is involved. In both cases, following the metathesis reactions, exclusively the E-isomer was obtained. The final cyclisation towards the quinolizidine skeleton is achieved by an intramolecular Michael reaction. This concept represents the first example of a highly stereoselective RRM-CM combination in the synthesis of a natural product.     

Enantioselective total synthesis of clavirolide C. Applications of Cu-catalyzed asymmetric conjugate additions and Ru-catalyzed ring-closing metathesis

The first enantioselective total synthesis of clavirolide C, a member of the dolabellane family of diterpenes isolated from Pacific soft coral Clavularia viridis, is disclosed. The total synthesis features the application of chiral amino acid based ligands in Cu-catalyzed asymmetric conjugate addition (ACA) reactions and a relatively rare application of catalytic ring-closing metathesis to access an 11-membered ring structure. The total synthesis effort has spawned the development of a new protocol for NHC.Cu-catalyzed ACA of alkylaluminum reagents to beta-substituted cycloalkenones. The enantioselective clavirolide C synthesis requires 17 steps (longest linear sequence), affords the target molecule in 3.5% overall yield, and confirms the stereochemical assignment for the natural product.     

Formal synthesis of (-)-apicularen A

[reaction: see text] A formal synthesis of (-)-apicularen A has been completed. The synthesis features a cyanohydrin acetonide coupling as a convergent approach to the C9-C18 segment and an intramolecular Diels-Alder addition sequence to create both the 10-membered macrocycle and the aromatic ring.