Structure elucidation and absolute stereochemistry of isomeric monoterpene chromane esters

Six novel monoterpene chromane esters were isolated from the aerial parts of Peperomia obtusifolia (Piperaceae) using chiral chromatography. This is the first time that chiral chromane esters of this kind, ones with a tethered chiral terpene, have been isolated in nature. Due to their structural features, it is not currently possible to assess directly their absolute stereochemistry using any of the standard classical approaches, such as X-ray crystallography, NMR, optical rotation, or electronic circular dichroism (ECD). Herein we report the absolute configuration of these molecules, involving four chiral centers, using vibrational circular dichroism (VCD) and density functional theory (DFT) (B3LYP/6-31G*) calculations. This work further reinforces the capability of VCD to determine unambiguously the absolute configuration of structurally complex molecules in solution, without crystallization or derivatization, and demonstrates the sensitivity of VCD to specify the absolute configuration for just one among a number of chiral centers. We also demonstrate the sufficiency of using the so-called inexpensive basis set 6-31G* compared to the triple-ζ basis set TZVP for absolute configuration analysis of larger molecules using VCD. Overall, this work extends our knowledge of secondary metabolites in plants and provides a straightforward way to determine the absolute configuration of complex natural products involving a chiral parent moiety combined with a chiral terpene adduct.     

Verticilide: elucidation of absolute configuration and total synthesis

Verticilide (1) is a 24-membered cyclic depsipeptide isolated from the culture broth of Verticillium sp. FKI-1033. It inhibits ryanodine binding to ryanodine receptor (RyR) and has insecticidal activity. The stereochemistry of 2-hydroxyheptanoic acid in verticilide was elucidated by chiral HPLC analysis of the degradation product 6 and synthetic (+) and (-)-6. We also describe the practical total synthesis of verticilide. [reaction: see text].     

Assignment of absolute stereochemistry and total synthesis of (-)-spongidepsin

[structure: see text] An enantioselective total synthesis of (-)-spongidepsin (2) and elucidation of the absolute stereochemistry of its four stereocenters are described. Spongidepsin (2), a 13-membered depsipeptide isolated from the Vanuatu marine sponge Spongia sp., has shown potent antitumor properties against a variety of NCI tumor cell lines. Our synthesis is convergent, and the absolute stereochemistry of four of the five chiral centers was assigned through synthesis.     

Total synthesis and absolute configuration of (-)-gummiferol

Stereoselective synthesis of two possible diastereomers of (-)-gummiferol was accomplished by the stepwise epoxidation and Cadiot-Chodkiewicz reaction as the key transformations. Detailed comparison of their (1)H and (13)C NMR data and specific rotation with those of the natural product led to the absolute structural elucidation of (-)-gummiferol.     

Synthesis and absolute configuration of (-)-meridinol and (-)-3-epimeridinol

The first synthesis of (-)-meridinol and (-)-3-epimeridinol was accomplished from (S)-malic acid. This synthesis unambiguously established the absolute stereochemistry of meridinol.     

The absolute configuration and circular dichroism of (+)-(1,5)-diamino-triptycene

The absolute configuration of(+)-(1,5)-diamino-triptycene has been determined by calculation of the CD spectrum of the molecule and comparison with the experimental results of Tanaka et al.⁴ To achieve this the exciton theory of Weigang and Nugent³ has been extended to include terms representing the retardation of the electro-magnetic wave in the chromophores. The final results of the present study are in contradiction with those of Tanaka et al.^4a,b,c     

Asymmetric synthesis,stereochemistry, and absolute configuration of 1,2-5-trimethyl-5-(2-cyanoethyl)- and 1,2,5-trimethyl-4-piperidinones

The asymmetric Michael alkylation of (–)-1,2,5-trimethyl-4-(1S-phenylethylimino)piperidine by electrondeficient alkenes proceeds with the formation of(+)-cis-(2S,5S)- and (–)-trans-(2R,5S) diastereomers of 1,2,5-trimethyl-5-(2-cyanoethyl)- and 1,2,5-trimethyl-5-(2-methoxycarbonylethyl)-4-piperidinones containing a chiral quaternary center C(₅). The spatial structure of these new chiral 4-piperidinones has been established on the basis of ¹H and ¹³C NMR spectroscopic data. The absolute configuration of the C(₂) and c(₅) chiral centers in the diastereomers has been determined by stereochemical correlation on the basis of circular dichroism data.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1369–1378, October, 1992.     

Synthesis,stereochemistry and absolute configuration of deodarols and deodarones

The stereochemistry and absolute configuration of the four deodarols and two deodarones derived from R-(+)-limonene is described.     

Synthesis,resolution, and absolute stereochemistry of (-)-blestriarene C

A naturally occurring 1,1'-biphenanthrene, blestriarene C (1), was prepared in 13 steps and 30% overall yield. The key steps are the ester-mediated nucleophilic aromatic substitution on 2,6-di-tert-butyl-4-methoxyphenyl 5-isopropoxy-2-methoxybenzoate (4) by 2-methoxy-4-methoxymethoxy-6-methylphenylmagnesium bromide (5) and a novel intramolecular cyclization of the resulting 4-isopropoxy-2'-methoxy-4'-methoxymethoxy-6'-methylbiphenyl-2-carboxylic ester 14 to 7-isopropoxy-4-methoxy-2-(methoxymethoxy)phenanthren-9-ol (15). The racemic blestriarene C was optically resolved by chiral HPLC on a preparative scale to give several 10-mg yields of both the enantiomers in up to 95% ee. The absolute stereochemistry was determined to be S(a)-(-) by the axial chirality recognition method, which was based on the stereospecific formation of a 12-membered cyclic diester containing two biaryl-o,o'-diyl unites joined by ester -CO(2)- linkages. The validity of the method was confirmed by an X-ray crystallographic analysis and ab initio conformational analyses of such 12-membered cyclic diesters. It was found that blestriarene C and its 7,7'-diisopropyl ether 2 underwent rapid photoracemization even under ambient light exposure.     

The absolute configuration of (+)-(E)-4-phenylbut-3-ene-2-ol

A derivative of (+)-(E)-4-phenylbut-3-ene-2-ol is shown by X-ray crystallography to be of (R) configuration, confirming the assumption in the literature that the absolute configuration of (+)-(E)-4-phenylbut-3-ene-2-ol is (R).     

Complete stereochemistry of neamphamide A and absolute configuration of the beta-methoxytyrosine residue in papuamide B

The absolute stereochemistry of the three unresolved structural components in neamphamide A (1) was determined to be (R)-beta-methoxy-L-tyrosine, (2R,3R,4S)-4-amino-7-guanidino-2,3-dihydroxyheptanoic acid, and (2R,3R,4R)-3-hydroxy-2,4,6-trimethylheptanoic acid. Stereochemical assignments were made by chemical degradation of 1, derivatization of the resulting products, and then spectroscopic and chromatographic comparison of the derivatives with synthetically prepared standards. Using the same analytical protocol developed for 1, the beta-methoxytyrosine residue in papuamide B (2) was found to be (R)-beta-methoxy-D-tyrosine. This represents a rare example of divergent stereochemistry in an unusual amino acid residue that is present in two closely related classes of peptides.     

The absolute stereochemistry of grenadamide

3-(2S-Heptylcycloprop-1S-yl)propanoic acid 2-phenylethanamide was synthesised from cis-cyclopropan-1,2-dimethanol via enzymatic desymmetrisation of the dibutyrate; it gave identical NMR spectroscopic data to those reported for grenadamide but had an equal and opposite absolute rotation, indicating that the latter is the 2R,1R-enantiomer.     

Total synthesis of (-)-bitungolide F and determination of its absolute stereochemistry

A highly convergent total synthesis of bitungolide F leading to the assignment of its absolute stereochemistry is described. The key steps include a Horner-Wadsworth-Emmons olefination to construct the C7-C8 bond, a Wittig reaction to introduce the conjugate E,E-olefinic moiety in the molecule, and finally a ring-closing metathesis reaction to construct the six-membered alpha,beta-unsaturated delta-lactone of the molecule. Modified Evans's syn-aldol reaction, using Crimmins's protocol, was used to install the stereochemistries at the C4 and C5 centers. The stereochemistry at C9 was introduced by means of hydroxy-directed reduction of the C9 keto using Evans's protocol.     

The absolute stereochemistry of crotonitenone

The configuration at C—4 of the novel casbenoid diterpene, crotonitenone (3), was determined by Horeau's method as (R) — hence the absolute stereochemistry of the molecule is as written in (3).     

Final elucidation of the absolute configuration of the signal metabolite hormaomycin

The complete absolute configuration of hormaomycin 1 a has been established by HPLC and HPLC/MS experiments with appropriately derivatized 4-propylprolines, (2S,4S)-6 and (2R,4R)-6, as well as 4-(Z)-propenylprolines, cis-5 and trans-5, and also feeding experiments with enantiomerically pure samples of the deuterium-labeled 3-(2'-nitrocyclopropyl)alanine, (2S)-3,3-[D2]15 and (2S)-2,2'-[D2]15, and 4-(Z)-propenylproline 2',4-[D2]-(2S,4R)-5. The latter five amino acids were prepared for the first time and allowed one to unequivocally assign the hitherto unknown absolute configurations of the last four stereocenters in hormaomycin 1 a. As a bonus, some new information about the biosynthesis of this molecule has also been gathered.     

An enantioselective total synthesis of (+)- and (-)-saudin. Determination of the absolute configuration.

A short efficient enantioselective synthesis of both (+)- and (-)-saudin, a naturally occurring hypoglycemic diterpene, is described. This synthesis establishes the absolute configuration of natural (-)-saudin for the first time. The key steps include the enantioselective construction of a dimethyl Hagemann's ester by an asymmetric Michael reaction and establishment of the key 1,3 disposed quaternary centers by means of a novel Ti(IV) promoted Claisen rearrangement. The assembly of the polycyclic ketal skeleton was likely under kinetic control proceeding via formation of the C1oxygen-C7 bond through an oxonium ion intermediate in the final stage.