Divergent total syntheses of (-)-aspidospermine and (+)-spegazzinine

Divergent total syntheses of (+)-spegazzinine (1) and (-)-aspidospermine (2) and their extensions to the synthesis of C19-epi-aspidospermine and C3-epi-spegazzinine are detailed, confirming the relative stereochemistry and establishing the absolute configuration of (+)-spegazzinine. A powerful intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of a 1,3,4-oxadiazole provided the pentacyclic skeleton and all the requisite stereochemistry of the natural products in a single reaction that forms three rings, four C-C bonds, and five stereocenters.     

Enantioselective total syntheses of (+)-arborescidine A, (-)-arborescidine B, and (-)-arborescidine C

Described are the first enantioselective total syntheses of (+)-arborescidine A ((+)-1), (-)-arborescidine B ((-)-2), and (-)-arborescidine C ((-)-3), via routes that proceeded in five steps and 50% overall yield, eight steps and 61% overall yield, and nine steps and 51% overall yield, respectively, from 6-bromotryptamine (7). The syntheses feature the use of the Noyori catalytic asymmetric hydrogen-transfer reaction to introduce chirality in dihydro-beta-carbolines 6 and 8. On the basis of an ample precedent from Noyori's work, the reduction produces dihydro-beta-carbolines, and ultimately the natural products, possessing the R absolute configuration. The synthetic arborescidines displayed optical rotations that were opposite in sign those of the natural products, thereby supporting the S configuration for natural arborescidines A (1) and B (2) and the (3S,17S) configuration for natural arborescidine C (3). Our results are in agreement with the initial stereochemical assignment by Pa?s and co-workers, and are counter to their recently revised assignment.     

Stereoselective synthesis and relative configuration assignment of gabosine J

The first total synthesis of (+)-gabosine J and that of the epimer at C4 of its enantiomer have been accomplished through an enantioselective approach from a common intermediate 1. These syntheses have allowed us to establish the correct relative configuration of the natural metabolite, which was originally misassigned. This work, together with our former syntheses of other gabosines and related compounds, validates enone 1 as a general synthetic precursor for this kind of carbasugars.     

Total syntheses of cladoacetals A and B: confirmation of absolute configurations

The first enantioselective syntheses of cladoacetals A (1a, overall yield: 16%) and B (1b, overall yield: 34%) from crotonaldehyde in nine and seven steps, respectively, have been accomplished. Sharpless asymmetric dihydroxylation, Suzuki coupling, and acid-catalyzed intramolecular acetalization were the key steps in the syntheses. The absolute configuration of natural (+)-cladoacetal A was affirmed to be 1S,3S,4R, whereas that of (-)-cladoacetal B was affirmed to be 1R,3S,4S.     

Stereoselective total synthesis and absolute configuration of the natural decanolides (-)-microcarpalide and (+)-lethaloxin. Identity of (+)-lethaloxin and (+)-pinolidoxin

[reaction: see text] Convergent, stereoselective syntheses of the pharmacologically active, naturally occurring lactones (-)-microcarpalide and (+)-lethaloxin have been achieved from the commercially available, chiral reagents (R)-glycidol, (S,S)-tartaric acid, and d-ribose as the starting materials. These syntheses have further served to establish the hitherto unknown absolute configuration of (+)-lethaloxin and to show its identity with (+)-pinolidoxin.     

Total Synthesis of Rishirilide B by Organocatalytic Oxidative Kinetic Resolution: Revision of Absolute Configuration of (+)-Rishirilide B

Described herein is the enantioselective syntheses of (+)- and (−)-rishirilide B from the corresponding optically active β-substituted tetralones, which were obtained by oxidative kinetic resolution based on α-hydroxylation in the presence of a chiral guanidine-bisurea bifunctional organocatalyst. Benzylic oxidation of the tetralones at C1 followed by regioselective isomerization of the oxabenzonorbornadiene structure led to rishirilide B. Our findings lead to the revision of the previously proposed (2R,3R,4R) absolute configuration of (+)-rishirilide B to (2S,3S,4S).     

Synthesis and Biological Evaluation of Bromo‐ and Fluorodanicalipin A

We disclose the syntheses of (+)‐bromodanicalipin A as well as (±)‐fluorodanicalipin A. The relative configuration and ground‐state conformation in solution of both molecules was secured by J‐based configuration analysis which revealed that these are identical to natural danicalipin A. Furthermore, preliminary toxicological investigations suggest that the adverse effect of danicalipin A may be due to the lipophilicity of the halogens.     

Synthesis of both enantiomers of akolactone B and (+)-ancepsenolide

The syntheses of (+)- and (−)-akolactone B and (+)-ancepsenolide were accomplished using a Pd-catalyzed carbonylation. As to the absolute configuration of akolactone B, making a comparison of the specific rotation of both enantiomers of synthetic akolactone B and the natural compound suggests that the absolute configuration at the 4-position of akolactone B is (R).     

Enantioselective Total Synthesis of (−)‐Lansai B and (+)‐Nocardioazines A and B

The concise total syntheses of the bis(pyrroloindolines) (?)‐lansai B and (+)‐ nocardioazines A and B are reported. The key pyrroloindoline building blocks are rapidly prepared by enantioselective formal [3+2] cycloaddition reactions. The macrocycle of (+)‐nocardioazine A is constructed by an unusual intramolecular diketopiperazine formation.     

The absolute configuration of the pyrrolosesquiterpenoid glaciapyrrol A

The total syntheses of the structurally unique and moderately cytotoxic pyrrolosesquiterpenoid glaciapyrrol A that has been isolated from a marine streptomycete by Macherla et al. and of seven of its stereoisomers have been performed from geraniol or nerol, respectively, using a known diastereoselective Ru-catalysed approach for the synthesis of tetrahydrofurans previously reported by Stark and co-workers. Comparison of (1)H and (13)C NMR data unambiguously clarified the relative configuration of natural glaciapyrrol A that was previously only partly solved from the available NMR data. An enantioselective synthesis was carried out resulting in the unnatural enantiomer (11S,12R,15R)-(-)-glaciapyrrol A. These data establish the absolute configuration of the natural product as (11R,12S,15S)-(+)-glaciapyrrol A.     

Concise total synthesis and stereochemical revision of (+)-naseseazines A and B: regioselective arylative dimerization of diketopiperazine alkaloids

Concise and enantioselective total syntheses of (+)-naseseazines A and B are described. Our regioselective and directed dimerization of diketopiperazines provides their critical C3-C(sp(2)) linkages, an assembly with plausible biogenetic relevance. We revise the absolute stereochemistry of (+)-naseseazines A and B.     

Total Syntheses and Biological Evaluation of Both Enantiomers of Several Hydroxylated Dimeric Nuphar Alkaloids

Herein, we describe the first total syntheses of five members of the dimeric nuphar alkaloids: (+)‐6,6′‐dihydroxythiobinupharidine (+)‐ 1 a , (+)‐6‐hydroxythiobinupharidine (+)‐ 1 b , (?)‐6,6′‐dihydroxythionuphlutine (?)‐ 2 a , (?)‐6,6′‐dihydroxyneothiobinupharidine (?)‐ 3 a , and (+)‐6,6′‐dihydroxyneothionuphlutine (+)‐ 4 a . The latter two have not been found in nature. We have also made each of their enantiomers (?)‐ 1 a – b , (+)‐ 2 a , (+)‐ 3 a , and (?)‐ 4 a . The key step in these syntheses was the dimerization of an α‐aminonitrile (a hydrolytically stable surrogate for its corresponding hemiaminal) with chiral Lewis acid complexes. We have also reassigned the literature structures of (+)‐ 1 a – 1 b —for those instances in which the NMR spectra were obtained in CD₃OD—to their corresponding CD₃O‐adducts. Our efforts provide for the first time apoptosis data for (?)‐ 3 a , (+)‐ 4 a , and all five non‐natural enantiomers prepared. The data indicate high apoptotic activity regardless of the enantiomer or relative stereochemical configuration at C7 and C7′.     

Concise, asymmetric, stereocontrolled total synthesis of stephacidins A, B and notoamide B

Concise asymmetric total syntheses of the fungal metabolites (-)-stephacidin A, (+)-stephacidin B, and (+)-notoamide B are described. Key features of these total syntheses include (1) a facile synthesis of (R)-allyl proline methyl ester, (2) a revised route toward the pyranoindole ring system, (3) a novel cross-metathesis strategy for the introduction of important functional groups, and (4) an SN2' cyclization to form the [2.2.2] bridged bicyclic ring system. Furthermore, our synthesis has taken advantage of microwave heating to shorten reaction times as well as increase yields for the preparation of vital intermediates.     

Concise enantioselective syntheses of quinolactacins A and B through alternative Winterfeldt oxidation

Enantioselective total syntheses of (+)-quinolactacin B and (+)-quinolactacin A2 through asymmetric Pictet-Spengler cyclization and KO(2) oxidation-an alternative Winterfeldt condition-are described.     

Henrycinols A and B,Two Novel Indole Alkaloids Isolated from Melodinus henryi Craib

Henrycinols A ( 1 ) and B ( 2 ), two novel indole alkaloids, together with three known compounds, (+)‐Δ¹⁴‐vincamine ( 3 ), (+)‐16‐epi‐Δ¹⁴‐vincamine ( 4 ), and (+)‐isoeburnamine ( 5 ), were isolated from the roots of Melodinus henryi Craib . Their structures were established on the basis of 1D‐ and 2D‐NMR spectroscopic analysis. The relative configuration of henrycinols A and B was determined by NOESY analysis.     

A Concise Total Synthesis of (+)‐Tetrabenazine and (+)‐α‐Dihydrotetrabenazine

Highly concise asymmetric total syntheses of (+)‐tetrabenazine ( 1 ), a drug for the treatment of chorea associated with Huntington’s disease, and of (+)‐α‐dihydrotetrabenazine ( 2 ), an active metabolite of 1 , have been accomplished. Our synthetic route features a trans‐selective enol etherification, followed by an unprecedented cation‐dependent aza‐Claisen rearrangement to establish the carbon framework and two stereogenic centers of tetrabenazine. The syntheses consist of seven steps (34 % overall yield) for (+)‐ 2 and eight steps (22 % overall yield) for (+)‐ 1 .     

The first asymmetric total syntheses and determination of absolute configurations of xestodecalactones B and C

The first efficient asymmetric total syntheses of xestodecalactones B and C have been accomplished in 10 steps with an overall yield of 22 and 20.2%, respectively. The key steps involve the utility of Evans oxazolidinone-mediated syn-aldol condensations to establish the C-9 configuration and the macrolide ring formation by intramolecular acylation. The absolute configurations of xestodecalactones B and C have been determined via these syntheses.     

Palladium-catalyzed DYKAT of butadiene monoepoxide: enantioselective total synthesis of (+)-DMDP, (-)-bulgecinine, and (+)-broussonetine G

Palladium catalyzed asymmetric allylic alkylation reaction of an amine with two equivalents of butadiene monoxide allows for the expedient synthesis of trans- and cis-2,5-dihydropyrroles. The versatility of these chiral synthons towards the synthesis of a wide variety of iminosugar natural products was demonstrated with the short and high yielding asymmetric syntheses of (+)-DMDP, and (-)-bulgecinine. In addition, the first total synthesis of (+)-broussonetine G, a potent glycosidase inhibitor, is described along with the assignment of its relative and absolute stereochemical configuration.     

The lyconadins: enantioselective total syntheses of (+)-lyconadin A and (-)-lyconadin B

A full account of the enantioselective total syntheses of (+)-lyconadin A (1) and (-)-lyconadin B (2) is presented. Central to this venture was recognition and deployment of a key strategy-level intramolecular aldol/conjugate addition cascade that led, in a single operation, to two new carbon-carbon sigma-bonds, three new stereogenic centers, and two new rings, albeit with the incorrect stereogenicity at C(12) for the lyconadins. Correction of the C(12) stereogenicity was achieved via innovative use of a protonated intramolecular aminal. An aminoiodo olefin cyclization, in conjunction with alpha-pyridinone and 3,4-dihydropyridinone annulation protocols, permitted completion of the syntheses of (+)-lyconadin A (1) and (-)-lyconadin B (2), respectively.     

Diastereoselective reactions at enantiomerically pure, sterically congested cyclohexanes as an entry to wailupemycins A and B: total synthesis of (+)-wailupemycin B

Wailupemycin A (1) and B (2) are polyketide natural products with a highly substituted cyclohexanone core. Three different routes for the syntheses of these compounds were pursued, which commenced from either (R)-(-)-carvone (ent-5) or (S)-(+)-carvone (5). In the first approach it was attempted to construct the skeleton of wailupemycin A from triol 19 (nine steps from ent-5; 19 % yield) by a sequence of diastereoselective epoxidation, nucleophilic ring opening at C-13 and carbonyl addition at C-5. The synthetic plan failed at the stage of the carbonyl addition to aldehyde 27, which had been obtained in seven steps (18 % yield) from triol 19. The second route included an epoxide ring opening at C-13 and a carbonyl addition at C-7 as key steps. It could have led to either wailupemycin A or B depending on the diastereoselectivity of the addition step. Starting from allylic alcohol 30 (six steps from ent-5; 59 % yield) the cyclohexanone 28 was obtained in five steps (54 % yield). Unfortunately, the carbonyl addition failed also in this instance. In the eventually successful third attempt the skeleton of wailupemycin B was built from cyclohexanone 43 (eight steps from 5; 53 % yield) by highly diastereoselective carbonyl addition reactions at C-7 and C-12. The phenyl group at C-14 was introduced at a late stage of the synthetic sequence. Careful protecting group manipulation finally allowed for the total synthesis of (+)-wailupemycin B. The absolute and relative configuration of the natural product was unambiguously confirmed. The total yield of wailupemycin B amounted to 6 % over 23 steps starting from (S)-(+)-carvone (5).