An efficient procedure for the preparation of (1S,3R)- and (1S,3S)-1-amino-3-(hydroxymethyl)cyclopentanes.

Enantiomerically pure (1S,3S)- and (1S,3R)-1-amino-3-(hydroxymethyl)cyclopentanes have been efficiently synthesized from L-aspartic acid. The title compounds are isosteres of ribose and may be used to construct nucleoside analogs with important antiviral and antineoplastic activities as demonstrated by a concise total synthesis of (+)-4'-deoxycarbapentostatin nucleoside.

An efficient procedure for the preparation of 4-substituted 5-aminoimidazoles.

The preparation of O-methylimidates from alpha-aminonitriles and their subsequent co-cyclization with primary amines to afford 4-substituted 5-aminoimidazoles was studied. It was found that the mildly acidic pyridinium p-toluenesulfonate efficiently catalyzed each stage of the reaction sequence: (a) the formation of the O-methylimidates, (b) their co-cyclization with a variety of primary amines, and (c) certain derivatizations of the resultant heterocycles. The developed reaction conditions tolerate a wide variety of alpha-aminonitriles and primary amine co-reactants. Thus, it is possible to easily prepare a diverse array of substituted heterocyclic compounds in good yield. The requisite alpha-aminonitriles were synthesized either from amino acids or by phase-transfer alkylation of a glycine anion equivalent. The unstable free 5-aminoimidazoles were normally protected in situ to provide derivatives (methyl imidates or N,N-dimethylamidines) that were amenable to characterization.

Enantiospecific synthesis of carbapentostatins.

In this paper we describe enantioselective syntheses of (+)-carbapentostatin (8) and its cyclopentyl analogue 12b. A new and efficient one-pot, two-step preparation of aldehyde 15 has been developed, based on the borane reduction of N-Pf-protected L-aspartic acid gamma-methyl ester (13) and Swern oxidation of the resulting alcohol. Homologation to diester 18 and ring formation by Dieckman cyclization, followed by reduction and dehydration steps, afford the 4-amino-1-cyclopentenemethanol derivative 22. Hydroboration and oxidation transform this compound stereospecifically into aminocyclopentanol 26, the key aminocyclitol component for an asymmetric synthesis of (+)-carbapentostatin.

Formal enantiospecific synthesis of (+)-FR900482.

The enantiospecific synthesis of FK973, and thus a formal enantiospecific synthesis of the antitumor antibiotic (+)-FR900482, is reported. Addition of aniline 8 to chiral epoxide 9, prepared from l-vinylglycine, afforded amino alcohol 12. After protection of the aliphatic nitrogen with the 9-phenylfluoren-9-yl group, to preserve the acidic stereocenter from racemization, formation of the aziridine 14 and intramolecular condensation under basic conditions gave azocinone 15. Hydroxymethylation at the benzylic position was achieved by a process involving methylenation, epoxidation, and hydrogenolysis; the absolute stereochemistry of the resulting alcohol 23 was determined by X-ray crystallographic analysis. The hydroxyl group of 23 was carbamoylated, and the aromatic amine was deprotected electrochemically and then oxidized to give an unstable hydroxylamine that was immediately protected as acetate 26. Oxidation of 26 with DMP, followed by hydrazinolysis of the acetyl group led to spontaneous closure of the resulting N-hydroxyamino ketone to hemiketal 28, which can be considered as a fully protected precursor of FR900482 and derivatives. Acid treatment to remove the protecting groups and acetylation afforded the triacetate FK973.

Asymmetric synthesis of the carbapenam core from serine.

The stereospecific synthesis of the functionalized carbapenam core 16 from the serine-derived trisubstituted pyrrolidine 9 is reported. The synthetic strategy relies on synthesizing an appropriately functionalized pyrrolidine, followed by an intramolecular azetidone formation utilizing a modified Mukiyama reagent. The efficient one-pot conversion of the benzenesulfonamide-protected pyrrolidine 9 to the Cbz-protected pyrrolidine 10 is also reported.

Synthesis of chiral pilocarpine analogues via a C-8 ketone intermediate.

The synthesis of a chiral pilocarpine analogue 3 in which the lactone ring is replaced by an oxazolidinone and the bridging methylene group is in the ketone oxidation state has been accomplished. The utility of this compound as a key intermediate for the preparation of more complex structures was demonstrated by its reduction to two alcohol epimers and its reaction with a methylene ylide.

Chlorxanthomycin, a fluorescent, chlorinated, pentacyclic pyrene from a Bacillus sp.

A gram-positive Bacillus sp. that fluoresces yellow under long-wavelength UV light on several common culture media was isolated from soil samples. On the basis of carbon source utilization studies, fatty acid methyl ester analysis, and 16S ribosomal DNA analysis, this bacterium was most similar to Bacillus megaterium. Chemical extraction yielded a yellow-orange fluorescent pigment, which was characterized by X-ray crystallography, mass spectrometry, and nuclear magnetic resonance spectroscopy. The fluorescent compound, chlorxanthomycin, is a pentacyclic, chlorinated molecule with the molecular formula C22H15O6Cl and a molecular weight of 409.7865. Chlorxanthomycin appears to be located in the cytoplasm, does not diffuse out of the cells into the culture medium, and has selective antibiotic activity.

Hydroxylated pyrrolidines. Enantiospecific synthesis of all-cis 2,3,4,5-substituted pyrrolidine derivatives from serine.

We report the enantiospecific synthesis of the sterically congested all-cis 2,3,4,5-substituted pyrrolidines 4, 5, and 6, from either D- or L-serine. Hemiaminal intermediate 13 is converted to the fully substituted pyrrolidine 15 by way of a tandem Wittig-Michael reaction. The endo stereochemistry of the C-3 methyl group of compound 15 is set by stereoselective reduction of the double bond in 11, driven by a preference for hydrogenation from the rear side of the molecule. The all-cis configuration of these fully substituted pyrrolidines has been established by X-ray analysis of compound 6. Removal of the benzenesulfonyl group from the highly substituted and functionalized intermediate 15 is successfully accomplished by sodium naphthalenide reduction.

Enantiospecific Synthesis of (R)-4-Amino-5-oxo-1,3,4,5-tetrahydrobenz[cd]indole, an Advanced Intermediate Containing the Tricyclic Core of the Ergots.

We report a new strategy for the enantiospecific synthesis of (R)-4-amino-5-oxo-1,3,4,5-tetrahydrobenz[cd]indole. This compound is an advanced intermediate which contains the tricyclic core of many of the tetracyclic ergot alkaloids. Our method involves the initial synthesis of D-4-bromotryptophan from the coupling of an indolyllithium species with a masked serinal. The alpha-amino position was protected with an N-trityl group, ensuring the enantiomeric integrity of this position during the ensuing organometallic cyclization reaction. Stabilization of the tricycle was accomplished by protecting the indole nitrogen with a BOC group or by reducing the alpha-amino ketone to the corresponding beta-amino alcohol.

Conformationally Constrained 7-Azabicyclo[2.2.1]heptane Amino Acids. Synthesis of a Glutamic Acid Analogue.

We report the synthesis of 2-substituted 7-azabicyclo[2.2.1]heptane glutamic acid analogue 27 from L-serine. Hemiaminal intermediate 2 can be converted to the 2S,3S,5S-trisubstituted pyrrolidine 3 by a tandem Wittig/Michael reaction or to the 2S,3S,5R-trisubstituted pyrrolidine 4 via an iodosulfonamidation reaction. The key transannular alkylation step to form the [2.2.1] ring system involves a beta-elimination of a silyl ether followed by cyclization to afford tert-butyl 7-benzyloxycarbonyl-7-azabicyclo[2.2.1]-2-heptene-1-carboxylate (20). Selective functionalization at C-2 was accomplished by the direct reduction with SmI(2) of 2-keto-3-silyl ether 23 to the C-2 ketone 24, which was converted to alpha,beta-unsaturated ester 25. Stereospecific reduction of the double bond from the exo face leads to a single protected glutamate analogue, tert-butyl (1S,2R,4R)-7-benzyloxycarbonyl-2-(methoxycarbonylmethyl)-7-azabicyclo[2.2.1]heptane-1-carboxylate (27).

Chirospecific Syntheses of Conformationally Constrained 7-Azabicycloheptane Amino Acids by Transannular Alkylation.

A new method is reported for the chirospecific preparation of optically pure 1-carboxy-7-azabicycloheptane amino acids for the generation of peptidomimetics as conformational probes. The method allows for the multigram preparation of these amino acid analogues through use of a thiolactam sulfide contraction and a transannular alkylation sequence as the key C-C bond-forming steps, starting from L-glutamic acid. The route provides access to two common intermediates, 7-(benzyloxycarbonyl)-1-carboxy-7-azabicyclo[2.2.1]-3-heptane and (1S,4R)-7-(benzyloxycarbonyl)-1-carboxy-7-azabicyclo[2.2.1]-3-heptanone tert-butyl ester, for elaboration to symmetrical and chiral amino acid homologues, respectively. Decarboxylation of the C-1 carboxy unit of the latter intermediate also demonstrated the applicability of the method for a short, chirospecific preparation of a (+)-epibatidine intermediate, (1S,4R)-7-(tert-butyloxycarbonyl)-1-carboxy-7-azabicyclo[2.2.1]-3-heptanone.

Synthesis of Anisolylated Aspartyl and Glutamyl Tripeptides.

A process has been developed for transforming the beta-carboxyl of aspartate and the gamma-carboxyl of glutamate into anisolyl ketones. These ketones are occasional byproducts in peptide synthesis, resulting from deprotection or resin-removal processes in the presence of anisole as a scavenger. The ketone amino acids have been incorporated in a tripeptide by coupling with CBMIT. During peptide bond formation the keto group of the glutamyl residue required protection, which was provided as the ethylene dithioketal.