Synthesis of chiral 1-(imidazol-2-yl)alkanamines using neomenthanethiol as a chiral auxiliary

Diastereomeric N-(imidazol-2-ylmethylidene)neomenthane-3-sulfinamides were obtained from enantiomerically pure neomenthanethiol in three steps. The compounds obtained added Grignard reagents at the C=N bond. After separation of diastereomers, an acid resolution gave enantiomerically pure primary 1-(imidazol-2-yl)alkanamines. In this scheme, the neomenthane fragment played the role of a chiral auxiliary.     

Beta-silylated homopropargylic amines via the asymmetric allenylboration of aldimines

The asymmetric synthesis of alpha-trimethylsilylpropargylic carbamines (7) through the addition of allenylboranes 4 to N-H aldimines is reported. The insertion of TMSCHN2 into enantiomerically pure B-alkynyl-10-TMS-9-borabicyclo[3.3.2]decanes 3 followed by a sterically driven 1,3-suprafacial borotropic shift proceeds with complete stereospecificity to produce 4 in diastereomerically and enantiomerically pure form. These reagents give 7 (51-85%, syn/anti >99%, 92-9% ee) permitting the recovery of 8 (53-63%). Allenylboranes 4 also provide a convenient route to optically pure allenylsilanes 13 (55-94%) through their protonolysis. [reaction: see text]     

Synthesis of new N-quaternary-3-benzamidoquinuclidinium salts

The synthesis of racemic and enantiomerically pure N-p-methylbenzyl-3- and N-p-chlorobenzylbenzamidoquinuclidinium bromides (6-8 and 9-11, respectively) is described. These compounds were prepared from racemic or enantiomerically pure 3-benzamidoquinuclidines 3-5 using the appropriate quaternization reagents: p-methyl- benzyl bromide (1) and p-chlorobenzyl bromide (2).     

Biocatalytic organic synthesis of optically pure (S)-scoulerine and berbine and benzylisoquinoline alkaloids

A chemoenzymatic approach for the asymmetric total synthesis of the title compounds is described that employs an enantioselective oxidative C-C bond formation catalyzed by berberine bridge enzyme (BBE) in the asymmetric key step. This unique reaction yielded enantiomerically pure (R)-benzylisoquinoline derivatives and (S)-berbines such as the natural product (S)-scoulerine, a sedative and muscle relaxing agent. The racemic substrates rac-1 required for the biotransformation were prepared in 4-8 linear steps using either a Bischler-Napieralski cyclization or a C1-Cα alkylation approach. The chemoenzymatic synthesis was applied to the preparation of fourteen enantiomerically pure alkaloids, including the natural products (S)-scoulerine and (R)-reticuline, and gave overall yields of up to 20% over 5-9 linear steps.     

An access to 3,4-(aminomethano)proline in racemic and enantiomerically pure form

Protected racemic and enantiomerically pure 3,4-(aminomethano)prolines rac-9 and (2S,2'R,3R,4R)-9 have been prepared applying a titanium-mediated reductive cyclopropanation as a key step. Thus, cyclopropanations of N,N-dibenzylformamide with titanacyclopropanes generated in situ from racemic or enantiomerically pure tert-butyl N-Boc-3,4-dehydroprolinates rac-8 or (S)-8 proceed diastereoselectively, and furnish the protected racemic and enantiomerically pure diamino acid 9. The latter was incorporated into three tripeptides containing glycyl, alanyl and phenylalanyl moieties.     

Enantioselective synthesis of ansa-zirconocenes

The reaction of the chiral chelated bis-amide complex Zr{(2R,4R)-PhNCHMeCH2CHMeNPh}Cl2(THF)2 (R,R-7) with lithium ansa-bis-indenyl reagents Li2[SBI](Et2O) (8a, SBI = (1-indenyl)2SiMe2) or Li2[EBI](Et2O) (8b, EBI = 1,2-(1-indenyl)2ethane) in THF affords the corresponding ansa-zirconocenes S,S-(SBI)Zr{(2R,4R)-PhNCHMeCH2CHMeNPh} (S,S,R,R-9a) or S,S-(EBI)Zr{(2R,4R)-PhNCHMeCH2CHMeNPh} (S,S,R,R-9b) in >95% isolated yield and >99% enantiomeric excess. Compound 9b was converted to the corresponding enantiomerically pure dichloride S,S-(EBI)ZrCl2 (S,S-10b) in 91% isolated yield by reaction with HCl in Et2O. The chiral diamine (2R,4R)-HPhNCHMeCH2CHMeNHPh (R,R-5) was recovered from this reaction.     

Transformation of an optically active decahydro-6-isoquinolone scaffold: perfect Felkin-Anh diastereoselectivity

Diastereomerically and enantiomerically pure decahydro-6-isoquinolone derivative 7 (>99% de, 97% ee) was obtained from the Michael addition product 3. Interestingly, aldehyde 7 reacted with a number of different Grignard reagents to give the secondary alcohols 9 in good yields as single diastereomers. This result can be explained by taking the Felkin-Anh model into account.     

Asymmetric Synthesis of Aryl 2-Piperidyl Methanols from a Chiral α-Aminonitrile Precursor

Synthesis of enantiomerically pure phenyl 2-piperidyl methanols from a convenient chiral α-aminonitrile 1 is described. Reaction with aldehydes of the anion generated from 1 leads to threo (αR, 2R) products, whereas treatment of 1 with organolithium reagents affords erythro (αR, 2S) compounds.     

L-cysteine, a versatile source of sulfenic acids. Synthesis of enantiopure alliin analogues

[reaction: see text] l-Cysteine is a stimulating starting product for the generation of transient sulfenic acids, such as 4, 6, 9, and 15, which add to suitable acceptors, allowing formation of sulfoxides showing a biologically active residue. These sulfoxides are easily isolated in enantiomerically pure form. For instance, N-(tert-butoxycarbonyl)-l-cysteine methyl ester (1a) furnished in few steps sulfenic acid 9a, which was readily converted into (R,S(S))-(2-tert-butoxycarbonylamino-2-methoxycarbonyl-ethylsulfinyl)ethene (22), the methyl ester of Boc-protected nor-alliin. Moreover, the addition of 9a to 2-methyl-1-buten-3-yne has led to a sulfur epimeric and separable mixture of (R)-2-(2-tert-butoxycarbonylamino-2-methoxycarbonyl-ethylsulfinyl)-3-methyl-buta-1,3-dienes 10a and 11a, still possessing a "masked" sulfenic acid function, producible from their cysteine moieties once the dienes have been converted into the desired derivatives.     

Efficient synthesis of enantiomerically pure 2-acylaziridines: Facile syntheses of N-Boc-safingol, N-Boc-D-erythro-sphinganine, and N-Boc-spisulosine from a common intermediate

Various enantiomerically pure 2-acylaziridines were prepared efficiently from the corresponding aziridine-2-carboxylate via Weinreb's amide and the subsequent treatment of organometallic compounds. The carbonyl group of those 2-acylaziridines was stereoselectively reduced by NaBH4in the presence of ZnCl2 to give erythro-1,2-amino alcohols with high diastereoselectivities and chemical yields. Using this methodology, we prepared (1R,2S)-N-Boc-norephedrine 5, N-Boc-safingol 8, N-Boc-D-erythro-sphinganine 9, and N-Boc-spisulosine 10 in high yields.     

Stereoselective synthesis of a potent thrombin inhibitor by a novel P2-P3 lactone ring opening

The concise synthesis of a potent thrombin inhibitor was accomplished by a mild lactone aminolysis between an orthogonally protected bis-benzylic amine and a diastereomerically pure lactone. The lactone was synthesized by the condensation of l-proline methyl ester with an enantiomerically pure hydroxy acid, which in turn was synthesized by a highly stereoselective (>500:1 er) and productive (100,000:1, S/C) enzymatic reduction of an alpha-ketoester. In addition, a second route to the enantiomerically pure lactone was accomplished by a diastereoselective ketoamide reduction.     

Fluorination-free synthesis of a 4,4-difluoro-3,3-dimethylproline derivative

A Claisen rearrangement/iodolactamization sequence starting from commercially available trifluoroacetaldehyde methyl hemiacetal, followed by a classical chemical resolution, provided enantiomerically pure 4,4-difluoro-3,3-dimethylproline (S)-1. No hazardous fluorination reagents were used, and the overall yield over 12 steps was greater than 28%.     

Generation of chiral boron enolates by rhodium-catalyzed asymmetric 1,4-addition of 9-aryl-9-borabicyclo[3.3.1]nonanes (B-Ar-9BBN) to alpha,beta-unsaturated ketones

Asymmetric 1,4-addition of 9-phenyl-9-borabicyclo[3.3.1]nonane (2m) to 2-cyclohexenone (1a) proceeded with high enantioselectivity in toluene at 80 degrees C in the presence of 3 mol % of a rhodium catalyst generated from [Rh(OMe)(cod)]2 and (S)-binap to give a high yield of boron enolate (S)-3am, which is 98% enantiomerically pure. Reaction of the boron enolate 3am with electrophiles, methanol-d, propanal, and allyl bromide, gave the corresponding 2-substituted (3S)-3-phenylcyclohexanones with perfect regio- and diastereoselectivity.     

Synthesis of Enantiomerically Pure Bis(hydroxymethyl)-Branched Cyclohexenyl and Cyclohexyl Purines as Potential Inhibitors of HIV

The synthesis of the enantiomerically pure bis(hydroxymethyl)-branched cyclohexenyl and cyclohexyl purines is described. Racemic trans-4,5-bis(methoxycarbonyl)cyclohexene [(+/-)-6] was reduced with lithium aluminum hydride to give the racemic diol (+/-)-7. Resolution of (+/-)-7 via a transesterification process using lipase from Pseudomonas sp. (SAM-II) gave both diols in enantiomerically pure form. The enantiomerically pure diol (S,S)-7was benzoylated and epoxidized to give the epoxide 9. Treatment of the epoxide 9 with trimethylsilyl trifluoromethanesulfonate and 1,5-diazabicyclo[5.4.0]undec-5-ene followed by dilute hydrochloric acid gave (1R,4S,5R)-4,5-bis[(benzoyloxy)methyl]-1-hydroxycyclohex-2-ene (10). Acetylation of 10 gave (1R,4S,5R)-1-acetoxy-4,5-bis[(benzoyloxy)methyl]cyclohex-2-ene (11). (1R,4S,5R)-1-Acetoxy-4,5-bis[(benzoyloxy)methyl]cyclohex-2-ene (11) was converted to the adenine derivative 12 and guanine derivative 13 via palladium(0)-catalyzed coupling with adenine and 2-amino-6-chloropurine, respectively. Hydrogenation of 12 and 13 gave the correspondning saturated adenine derivative 14 and guanine derivative 15. (1R,4S,5R)-4,5-Bis[(benzoyloxy)methyl]-1-hydroxycyclohex-2-ene (10) was converted to the adenine derivative 16 and guanine derivative 17 via coupling with 6-chloropurine and 2-amino-6-chloropurine, respectively, using a modified Mitsunobu procedure. Hydrogenation of 16 and 17 gave the corresponding saturated adenine derivative 18 and guanine derivative 19. Compounds 12-19 were evaluated for activity against human immunodeficiency virus (HIV), but were found to be inactive. Further biological testings are underway.     

Synthesis of a new chiral source, (1R,2S)-1-Phenylphospholane-2-carboxylic acid, via a key intermediate alpha-phenylphospholanyllithium borane complex: configurational stability and X-ray crystal structure of an alpha-monophosphinoalkyllithium borane complex

A synthetic route to enantiomerically pure (1R,2S)-1-phenylphospholane-2-carboxylic acid (1), which is a phosphorus analogue of proline, has been established. A key step is the deprotonation-carboxylation of the 1-phenylphospholane borane complex 3 by using sBuLi/1,2-dipiperidinoethane (DPE). Configurational stability of the key intermediate, the amine-coordinated alpha-phosphinoalkyllithium borane complex 4, was investigated by employing lithiodestannylation-carboxylation of both diastereomers of the 1-phenyl-2-trimethylstannylphospholane borane complex 7 in the presence of several kinds of amines, and as a result, 4 was found to be configurationally labile even at -100 degrees C. The key intermediate, the DPE-coordinated trans-1-phenyl-2-phospholanyllithium borane complex 9, was isolated, and the structure was identified by X-ray crystal structure analysis. This is the first X-ray crystal structure determined for an alpha-monophosphinoalkyllithium borane complex. Remarkably, the alkyllithium complex is monomeric and tricoordinate at the lithium center with a slightly pyramidalized environment, and the existence of a Li--C bond (2.170 A) has been confirmed. Moreover, (1)H-(7)Li HOESY and (6)Li NMR analyses suggested the structure of 9 in solution as well as the existence of an equilibrium between 9, its cis isomer, and the ion pair 8 at room temperature, which was extremely biased towards 9 at -100 degrees C. Finally, 1 was used as a chiral ligand in a palladium-catalyzed allylic substitution, and the desired product was obtained in high yield with good enantioselectivity.     

Practical enantioselective synthesis of endothelin antagonist S-1255 by dynamic resolution of 4-methoxychromene-3-carboxylic acid intermediate

A practical multikilogram-scale synthesis of enantiomerically pure S-1255 (1), a potent and orally active ET(A) receptor antagonist, is described. Utilizing readily available starting materials and reagents, the entire sequence of reactions starting from 2,5-dihydroxyacetophenone 8 proceeded under mild conditions to give 1 in an excellent chemical yield (8 steps, 41% overall yield) and in a high enantiopurity (98% ee). The crucial step of the synthesis is a dynamic resolution of key intermediate 16. (R)-Methoxy acid (R)-16 having 97-99% ee was obtained in 83-84% yield from racemic 16 as a crystalline (1S,2R)-(+)-norephedrine or (+)-cinchonine salt by the dynamic resolution comprising concurrent crystallization and in situ racemization. A mechanism of the dynamic resolution through a ring-opened zwitterionic intermediate is discussed. In the final synthetic step, an effective carbon-carbon bond formation between the C4 carbon and the p-anisyl group was accomplished by a conjugate addition-elimination reaction of Grignard reagent 3 to (R)-16 to give 1 having 98% ee. Owing to high efficiencies of functional group transformations, carbon-carbon bond formations, and the dynamic resolution, the synthesis required no chromatographic purification and was amenable to a multikilogram-scale preparation. Several kilograms of 1 for clinical trials were successfully prepared by this process.     

Synthesis of a potent hNK-1 receptor antagonist via an SN2 reaction of an enantiomerically pure alpha-alkoxy sulfonate

The concise synthesis of a stereochemically rich hNK-1 receptor antagonist is described. The synthesis is highlighted by an S(N)2 reaction of an enantiomerically pure alpha-alkoxy sulfonate (orthogonally protected butane triol), which was prepared by utilizing salen-mediated hydrolytic kinetic resolution technology. A stereocontrolled acetalization was employed to connect two enantiomerically pure fragments with a high degree of diastereoselectivity.     

Flexible synthesis of enantiomerically pure 2,8-dialkyl-1,7-dioxaspiro[5.5]undecanes and 2,7-dialkyl-1,6-dioxaspiro[4.5]decanes from propargylic and homopropargylic alcohols

A new approach to enantiomerically pure 2,8-dialkyl-1,7-dioxaspiro[5.5]undecanes and 2,7-dialkyl-1,6-dioxaspiro[4.5]decanes is described and utilizes enantiomerically pure homopropargylic alcohols obtained from lithium acetylide opening of enantiomerically pure epoxides, which are, in turn, acquired by hydrolytic kinetic resolution of the corresponding racemic epoxides. Alkyne carboxylation and conversion to the Weinreb amide may be followed by triple-bond manipulation prior to reaction with a second alkynyllithium derived from a homo- or propargylic alcohol. In this way, the two ring components of the spiroacetal are individually constructed, with deprotection and cyclization affording the spiroacetal. The procedure is illustrated by acquisition of (2S,5R,7S) and (2R,5R,7S)-2-n-butyl-7-methyl-1,6-dioxaspiro[4.5]-decanes (1), (2S,6R,8S)-2-methyl-8-n-pentyl-1,7-dioxaspiro[5.5]undecane (2), and (2S,6R,8S)-2-methyl-8-n-propyl-1,7-dioxaspiro[5.5]undecane (3). The widely distributed insect component, (2S,6R,8S)-2,8-dimethyl-1,7-dioxaspiro[5.5]undecane (4), was acquired by linking two identical alkyne precursors via ethyl formate. In addition, [(2)H(4)]-regioisomers, 10,10,11,11-[(2)H(4)] and 4,4,5,5-[(2)H(4)] of 3 and 4,4,5,5-[(2)H(4)]-4, were acquired by triple-bond deuteration, using deuterium gas and Wilkinson's catalyst. This alkyne-based approach is, in principle, applicable to more complex spiroacetal systems not only by use of more elaborate alkynes but also by triple-bond functionalization during the general sequence.     

Useful dual Diels-Alder behavior of 2-azetidinone-tethered aryl imines as azadienophiles or azadienes: a beta-lactam-based stereocontrolled access to optically pure highly functionalized indolizidine systems

Imines derived from 4-oxoazetidine-2-carbaldehydes have been found to be versatile Diels-Alder reagents in that they exhibit two reactivity patterns. 2-Azetidinone-tethered imines undergo diastereoselective reaction with Danishefsky's diene in the presence of different Lewis acids. The effect of the amount of catalyst on the conversion rate as well as on the product ratio has been studied. Under standard reaction conditions, indium(III) chloride and zinc(II) iodide provided the best yields, and indium(III) triflate the highest diastereoselectivity in the Lewis acid promoted aza-Diels-Alder cycloaddition. Treatment of the aforementioned imines with cyclopentadiene, 2,3-dimethyl-1,3-butadiene or 3,4-dihydro-2 H-pyran led to cycloadducts arising from inverse electron-demand condensation involving the beta-lactam-tethered aryl imine as the heterodiene component. In addition, the first methodology for preparing indolizidines from beta-lactams has been developed. This process involves amide bond cleavage of the beta-lactam ring in the aza-Diels-Alder cycloadducts with concomitant cyclization. Full chirality transfer occurs when the reaction is performed with an enantiomerically pure substrate.     

2’，4”-O-双(三甲基硅)-6-O-甲基红霉素A 9-O-(1-甲氧基环己基)肟的区域选择性合成机理及其晶体结构

合成了化合物3的6-OH区域选择性甲基化产物, 即2',4"-O-双(三甲基硅)-6-O-甲基红霉素A 9-O-(1-甲氧基环己基)肟(4)的单晶, 以及化合物2的单晶, 并确定了其立体构型, 以期阐明区域选择性与大环内酯构象之间的关系.