Synthesis of a Gln-Phe hydroxy-ethylene dipeptide isostere

[structure: see text] The protected Gln-Phe hydroxyethylene dipeptide isostere 1 was synthesized as a precursor for preparation of potential inhibitors of Botulinum neurotoxin B metalloprotease. The method allows for the synthesis of additional hydroxyethylene dipeptide isosteres such as 2 with functionalized P1 side chains. The isosteres prepared were coupled with a dipeptide to produce protected pseudotetrapeptide derivatives.     

Stereoselective Synthesis of Hydroxyethylene Dipeptide Isostere from Sugar

Regioselective opening of the aziridine ring in the carbohydrate-based precursor led to the stereoselective synthesis of N-Boc-O-benzyl-(4S,5S)-5-amino-4-hydroxy-6-phenylhexanoic acid methyl ester, the hydroxyethylene dipeptide isostere moiety of potent HIV-1 protease inhibitor.     

A short approach to the synthesis of the ritonavir and lopinavir core and its C-3 epimer via cross metathesis

A short synthesis of hydroxyethylene dipeptide isostere, a core unit of the HIV-protease inhibitors ritonavir and lopinavir, its C-3 epimer and C₂ symmetric diamino diol is described. The crucial aspects of the synthesis are self-cross metathesis and exploitation of C₂-symmetric of the metathesis product 8 to obtain the required skeleton.     

An efficient, stereoselective synthesis of the hydroxyethylene dipeptide isostere core for the HIV protease inhibitor A-792611

A stereoselective synthesis of the hydroxyethylene dipeptide isostere 1 is described. The route employs a substrate-directed kinetic protonation of an alpha/gamma-substituted lactone to afford the desired stereochemistry. A method for converting the diastereomerically enriched intermediate lactone to the ring-open form with retention of stereochemistry is demonstrated. A novel procedure for utilizing N,N-dibromo-5,5-dimethylhydantoin in Hofmann rearrangements is disclosed. This route was used to prepare amino alcohol 1, the core portion of the HIV protease inhibitor A-792611, in 46% yield from phenylalanine-derived epoxide 2.     

Quinazolines. XI. Synthesis of 2,4-diamino-5, 10-diliydrobenzo[g] quinazolines

An unequivocal synthesis of 2,4-diamino-5,10-dihydrobenzo[g]quinazolines is described, starting from methyl 2-tetralone-3-carboxylates. Condensation with guanidine yielded 2-amino-4-hydroxy derivatives, which were thiated with phosphorus pentasulfide and S-alkylated with dimethyl sulfate. The resultant 2-amino-4-methylthio compounds were converted into 2,4-diamino derivatives by amination at elevated temperature and pressure. Attempted synthesis from 3-cyano-1,4-dihydro-2-methoxynaphthalene and guanidine was unsuccessful.     

Total synthesis of (+/-)-scopadulin.

The first total synthesis of (+/-)-scopadulin, an aphidicolane diterpene, is described. The core structure (A/B/C/D ring system) was constructed by an initial synthesis of the B/C/D ring system by our reported methods and a subsequent A ring cyclization by intramolecular aldol condensation. A highly stereoselective cyanation of the tetracyclic enone by Et2AlCN gave a trans-fused A/B ring system with a beta-cyanide at C-4. Stereoselective construction of a quaternary carbon at C-4 was achieved by alpha-alkylation of the cyano group and conversion of the sterically hindered cyano group to a methyl group via our novel reaction for conversion of primary aliphatic amines into alcohols. Finally, the total synthesis of (+/-)-scopadulin was accomplished by a highly chemo- and stereoselective methylation at C-16 and modification of the C-4 alpha-functionality. The stereoselectivity observed in the MeTi(O-i-Pr)3-mediated methylation for the generation of a tertiary axial alcohol at C-16 is extremely high.     

Versatile use of acid-catalyzed ring-opening of β-aziridinyl-α,β-enoates to stereoselective synthesis of peptidomimetics

Treatment of N-arylsulfonylaziridines bearing α,β-unsaturated esters with alcohols, thiols or weak acids such as AcOH in the presence of catalytic amount of Lewis acids affords regio- and stereoselectively ring-opened products, such as δ-aminated γ-alkoxy-(alkylthio or acetoxy)-α,β-enoates. In addition, the regio- and stereoselective ring-opening reactions can be performed on solid supports and applied to stereoselective synthesis of (E)-alkene dipeptide isosteres.     

Efficient synthesis of trifluoromethyl and related trisubstituted alkene dipeptide isosteres by palladium-catalyzed carbonylation of amino acid derived allylic carbonates

A novel stereoselective synthetic approach to (Z)-trifluoromethylalkene dipeptide isosteres (CF(3)-ADIs) is described. Starting from readily available N-Boc-L-phenylalanine, Phe-Gly type CF(3)-ADIs were obtained through palladium-catalyzed carbonylation of allylic carbonates under CO. While the reaction of N-Boc derivatives proceeds in excellent yields but lower stereoselectivity (E: Z = 62:38-43:57), the reaction of the N, N-diBoc derivative exclusively affords the desired (Z)-isomer in 61% yield. We also present a highly stereoselective synthesis of several Phe-Gly type trisubstituted alkene dipeptide isosteres by palladium-catalyzed carbonylation.     

Stereocontrolled construction of tetrasubstituted tetrahydrofurans: synthesis of 2,5-anhydro d-glucitol

A highly stereoselective construction of 2,3,4,5-tetrasubstituted tetrahydrofurans has been accomplished by an unusual intramolecular 5-endo-tet cyclization of 2,3-epoxy alcohols involving hydroxyl nucleophile. The method has been utilized for the synthesis of 2,5-anhydro d-glucitol through two different approaches starting from the chiral molecule, l(+)-diethyl tartarate or from the non-chiral compound, allyl bromide or cis-but-2-ene-1,4-diol. This synthetic method is a useful example of 5-endo-tet cyclization of 2,3-epoxy alcohols.     

Regio- and stereoselective synthesis of (E)-alkene trans-Xaa-Pro dipeptide mimetics utilizing organocopper-mediated anti-S(N)2' reactions

Proline dipeptides (Xaa-Pro) exist as an equilibrium mixture of cis- and trans-rotamers, which depends on the energy barriers for imide isomerization. This conformation mixture contributes to both structure and function of proline-containing peptides and proteins. Structural motifs resembling these cis- or trans-conformers have served as useful tools for elucidating contributions of proline residues in the physicochemical and biological profiles of structures which contain them. Among such motifs are alkene dipeptide isosteres which mimic cis- or trans-imide using (Z)- or (E)-alkene, respectively. In this report, the first regio- and stereoselective syntheses of (E)-alkene dipeptide isosteres (20, 31, and 35) corresponding to trans-proline dipeptides are described. Key to the synthesis of these mimetics is the anti-S(N)2' reaction of vinyl aziridines such as 15 or vinyl oxazolidinones such as 28 and 32 with organocopper reagents "RCu" (R = CH(2)SiMe(2)(Oi-Pr)). Reaction of cis-vinylaziridine 15 derived from L-serine with organocopper reagent gave a precursor of the trans-L-Ser-D-Pro type alkene isosteres 20, accompanied by an S(N)2 side product. One limitation with the use of such aziridine-mediated methodology is formation of the corresponding trans-aziridine 22, which leads to L-L type isosteres, that is unstable and obtainable only in low yield. On the other hand, both isomers of oxazolidinone derivatives can be easily obtained from N-Boc-protected amino alcohols. The reaction of trans- 28 or cis-oxazolidinone derivative 32 with organocopper reagents proceeds quantitatively with high regio- and diastereoselectivities in anti-S(N)2' fashion. Subsequent oxidative treatment of the newly introduced isopropoxydimethylsilylmethyl group yields trans-L-Ser-L-Pro 31 or trans-L-Ser-D-Pro type isosteres 35, respectively. Of note, synthesized isostere 31 can also be converted to trans-phosphoSer-Pro 42 and trans-Cys-Pro mimetics 44. The present synthetic methodology affords trans-Xaa-Pro alkene-type dipeptide isosteres in high yield with relatively simple manipulation.     

The first total synthesis of lactonamycin, a hexacyclic antitumor antibiotic

The total synthesis of lactonamycin has been achieved. The synthesis includes sequential intramolecular conjugate addition of alcohols to the acetylenic ester, stereoselective glycosylation of the tertiary alcohol, and Michael-Dieckmann type cyclization with the thioester, by which the highly convergent route has been established.     

Short stereoselective synthesis of alpha-substituted gamma-lactams

A concise, stereoselective synthesis of alpha-substituted gamma-lactams is reported. gamma-Lactam scaffolds 2 and 3, possessing an Evans' chiral auxiliary and two types of N substituents, were successfully alkylated with different electrophiles to give alpha-substituted gamma-lactams with reasonable diastereoselectivities. The use of a masked carboxymethyl function off the lactam nitrogen provided a convergent means to alpha-substituted gamma-lactam dipeptide isosteres.     

Diastereoselective synthesis of enantioenriched homopropargyl amino alcohols from α-dibenzylamino aldehydes and their use as chiral synthons

Homochiral α-dibenzylamino aldehydes, prepared from the corresponding α-amino acids, react with propargyl bromide and zinc in DMF/THF (1:1) or DMF/Et₂O (1:1) at 20 °C to afford, in good yields and dr, homopropargylic 1,2-amino alcohols. anti Diastereomers were always formed as major products in this reaction. These compounds are versatile intermediates for a variety of synthetic targets: γ-amino-β-hydroxy-ketones, 4-amino-1,3-diols, 1,7-diamino-2,6-diols, and ω-amino-δ-hydroxy esters.     

Synthesis of the macrolactone core of (+)-neopeltolide by transannular cyclization

The synthesis of the macrolactone core of (+)-neopeltolide has been achieved. The key synthetic strategy involves the highly diastereoselective synthesis of the 2,6-cis-disubstituted tetrahydropyran ring by a transannular cyclization of δ-hydroxy alkene using mercuric trifluoroacetate. Two of the six stereocenters C-5 and C-11 were realized from L-malic acid, while the remaining stereocenters C-3 (Sharpless asymmetric epoxidation), C-7 (transannular cyclization), C-9 (regioselective epoxide opening) and C-13 (chelation controlled reduction) were derived by asymmetric synthesis. The macrolactone ring was synthesized by macrocyclization using a RCM protocol.     

An approach to sequence-specific antibody proteases

We describe here a novel strategy for the isolation of antibodies with sequence-specific protease activity: the synthesis of dipeptide haptens in which the targeted peptide bond has been replaced by a ring-strained or torsionally strained hydroxyethylene transition-state analog. Thus, the analogs mimic both a peptide bond in a distorted, reactive conformation and the transition state for peptide bond hydrolysis. In order to obtain sequence-specific antibody proteases, these analogs have been flanked with additional amino acid residues in preparation for immunization. In particular, we have synthesized peptides containing analogs such as 2-cis-amino-3-cis-hydroxycyclobutane carboxylic acid andendo-(3-amino-2-hydroxy)bicyclo[2.2.1]heptane-7-anti-carboxylic acid. We have also prepared a series of peptide derivatives containing analogs, such as 2-[3-amino-2-oxo-1-azetidinyl]-3-methylbutanoic acid, in which the targeted peptide bond has been incorporated into a β-lactam ring. Since the “peptide bond” has been left intact, these species mimic only a distorted ground state. At present, antibodies are being elicited against a number of the above peptide derivatives.     

An alternate synthesis of 6-substituted-5-deazapteridines

A procedure for synthesis of 2,4-diamino-6-substituted-5-deazapteridines (pyrido[2,3-d]pyrimidines) is described. Condensation of 1-piperidino-1-propene with ethoxymethylenemalononitrile afforded an enamino malononitrile adduct, which when treated with ammonia yielded 2-amino-3-cyano-5-methylpyridine. Cyclization to 2,4-diamino-6-methyl-5-deazapteridine could be effected with guanidine. Similar condensation of piperidinopropene with ethyl methoxymethylenecyanoacetate followed by cyclization with hydroxylamine gave 2-amino-3-carbethoxy-6-methylpyridine 1-oxide. Reduction with phosphorus trichloride afforded the pyridine base, however, attempts to cyclize the amino ester to 2-amino-4-hydroxy-6-methyl-5-deazapteridine were unusccessful.     

Chemistry of Ethanediyl S,S-Acetals. VII. A Stereoselective Synthesis of Allylic Alcohols with cis-Configurated Double Bond

A new high yielding coupling reaction of C-2 monosubstituted 5,6-dihydro-1,4-dithiins with aldehydes is reported. In this way allylic alcohols having the cis-substituted double bond tied up by a sulfur-containing ring can be readily prepared. Subsequent stereoselective sulfur removal then affords allylic alcohols with cis-configurated double bond.     

Diastereoselective synthesis of psi[(E)-CMe=CH]- and psi[(E)-CMe=CMe]- type dipeptide isosteres based on organocopper-mediated anti-S(N)2' reaction

[reaction: see text] A straightforward synthetic route for the synthesis of diastereomerically pure psi[(E)-CMe=CH]- and psi[(E)-CMe=CMe]-type dipeptide isosteres was developed on the basis of regio- and stereoselective anti-S(N)2' alkylation of 3-(N-Boc-5-methyl-4-substituted-oxazolidin-2-on-5-yl)acrylates with organocopper reagents.     

Total synthesis of aspergillide B and structural discrepancy of aspergillide A

Fourteen-membered cytotoxic macrolides 1 and 2 were synthesized from alcohol 10 in 15 steps utilizing stereospecific Pd(II)-catalyzed cyclization of ζ-hydroxy chiral allylic alcohol 7. Aspergillides A and B were isolated from marine fungus, and their structures were proposed as 1 and 2, respectively. The synthetic 1 was not matched with aspergillide A but matched with aspergillide B. The chiral center at C-13 position of aspergillide B was revised to be (S)-configuration. The key steps of the stereoselective synthesis include the Sharpless asymmetric dihydroxylation, cross-metathesis, stereospecific construction of tetrahydropyran ring of 16 using Pd^II catalyst, and the Yamaguchi macrolactonization.     

SmI2-mediated reduction of gamma,gamma-difluoro-alpha,beta-enoates with application to the synthesis of functionalized (Z)-fluoroalkene-type dipeptide isosteres

A samarium diiodide (SmI(2))-mediated reduction of gamma,gamma-difluoro-alpha,beta-enoates (15, 29, and 34) was successfully applied to the synthesis of (Z)-fluoroalkene dipeptide isosteres (23, 30, and 35), which have served as potential dipeptide mimetics. Reduction of the gamma,gamma-difluoro-alpha,beta-enoates by SmI(2) proceeded via successive two-electron transfers to form dienolate species which upon kinetically controlled trapping with t-BuOH yielded Xaa-Gly-type fluoroalkene isosteres exemplified by 23, 30, and 35. Replacement of the t-BuOH kinetic trapping agent with aldehydes or ketones provided access to alpha-substituted fluoroalkene isosteres (43 and 45) through aldol reactions of Sm-dienolates with the carbonyl compounds. Of particular note, the use of the SmI(2)-HCHO reagent system with chiral enoate 34 provided D-Phe-psi[(Z)-CF[double bond]CH]-D/L-Ser isosteres (45), which could be converted to enantiomerically pure isosteres (49-52) that bore a variety of side chain functionalities at the alpha-position. This was achieved by a sequence of manipulations consisting of beta-lactone formation followed by chromatographic separation and ring-opening with soft nucleophiles. Included in the present work is the first utilization of a Rh-catalyzed Reformatsky reaction of chiral imines for the stereoselective preparation of alpha,alpha-difluoro-beta-amino acid derivatives (28 and 33). The appropriate choice of reagents (carbonyl compounds for kinetic trapping or ring-opening nucleophiles and imines for Reformatsky reactions) allows the presented methodology to yield various fluoroalkene isosteres possessing a wide range of side chain functionalities.