Facile synthesis of (−)-6-acetoxy-5-hexadecanolide by size-selective ring-closing/cross metathesis

A total synthesis of (−)-6-acetoxy-5-hexadecanolide, in six steps and 37% overall yield from (2R,3S)-1,2-epoxy-4-penten-3-ol is reported. The key synthetic step is a size-selective ring-closing/cross metathesis reaction in which lactone formation and alkyl chain extension are accomplished in an efficient one-pot process.     

Synthetic Studies towards Pheromones by Cyanide-Catalyzed Ring Transformation of α-Hydroxy-β-oxoesters to δ-Valerolactones

The cyanide-catalyzed ring-transformation of α-hydroxy-β-oxoesters to δ-lactones with exocyclic ester moiety is the key transformation for the preparation of racemic 5-hexadecanolide (15 % over nine steps) and 6-acetoxy-5-hexadecanolide (22 % over eight steps), two insect pheromones. The benzyloxycarbonyl moiety is transformed via the acid chloride to the undecanoyl side chain. After reduction of the ketone to the secondary alcohol, this functional group was either reduced via the chloro compound to furnish the 5-hexadecanolide. On the other hand, stereoselective reduction of the ketone gave secondary alcohol with the wrong relative configuration, which was established by X-ray single-crystal structure. Inversion was achieved by reaction of the methanesulfonate with cesium acetate yielding (R*,S*)-6-acetoxy-5-hexadecanolide with the relative configuration also present in the natural product.     

Constrained cycloalkyl analogues of glutamic acid: stereocontrolled synthesis of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740) and its 6-phosphonic acid analogue

A new stereocontrolled synthesis of (+)-2-aminobicyclo[3.1.0]hexane-2.6-dicarboxylic acid (LY354740) 1, a potent and selective 2mGluR agonist, has been accomplished in four steps with an overall yield of 27% starting from the enantiopure (+)-(R)-2-(p-tolylsulfinyl)cyclopent-2-enone 3. The key steps include asymmetric cyclopropanation of 3 with (dimethylsulfuranylidene)acetate (EDSA) and removal of the chiral p-tolylsulfinyl auxiliary from the cycloadduct ent-4c upon treatment with iso-propylmagnesium chloride. The stereoselective hydantoin formation from the bicyclic ketone 6 formed (Bucherer–Bergs reaction) and subsequent hydrolysis completed the synthesis of 1. The same reaction sequence has been applied in the first synthesis of enantiopure (+)-2-amino-6-phosphonobicyclo[3.0.1]hexane-2-carboxylic acid 2, a structural 6-phosphono analogue of 1. The starting bicyclic ketophosphonates 9–11 have been obtained by asymmetric cyclopropanation of (?)-(S)-3 with phosphoryl sulfonium ylides, producing only two endo-isomers. The major endo-isomer (+)-11a containing the 6-diisopropoxyphosphoryl group has been converted in three steps into (+)-endo-2 in 46% overall yield.     

A versatile approach to cis-5-substituted 4-hydroxy-2-pyrrolidinones: asymmetric synthesis of angiogenesis inhibitor streptopyrrolidine

A concise, flexible, and highly diastereoselective approach to cis-5-alkyl-4-hydroxy-2-pyrrolidinones 1 is described. The key step is an ammonium acetate-assisted catalytic hydrogenation of the enamides 9, derived in two steps from malimides 6a,b as we have described previously. The method was applied to the asymmetric synthesis of streptopyrrolidine 5, a natural product, which exhibited significant anti-angiogenesis activity.     

Short synthesis of phenylpropanoid glycosides calceolarioside-B and eutigoside-A

A convenient 4-step synthesis of calceolarioside-B 1 and eutigoside-A 2 in high overall yield is described. The key step involved the regioselective, Me₂SnCl₂-catalyzed O-6 acylation of unprotected 2-phenylethyl-β-d-glucosides 5a–b with cinnamoyl chlorides 6a–b in excellent yields. Acylation at O-6 is selective with the acid chlorides used. This work serves as a model for the convenient synthesis of phenylpropanoid glycosides acylated at O-6.     

A cyclopropanol-based approach to synthesis of Unit A of the cryptophycins

A new asymmetric synthesis of Unit A of the cryptophycins has been carried out yielding 13% of the target product over 14 steps. The key steps of the synthesis were diastereoselective hydroboration–oxidation reactions performed on the alkenyl moiety of a 1,3-dioxane derivative 8, which can be easily prepared via the Kulinkovich cyclopropanation of protected diethyl (S)-(−)-malate followed by transformation of the resulting small rings of the product 6 into the functional groups necessary for the synthesis of the target compound.     

Optically active 1-(benzofuran-2-yl)ethanols and ethane-1,2-diols by enantiotopic selective bioreductions

Enantiotopic selective reduction of 1-(benzofuran-2-yl)ethanones 1a–d, 1-(benzofuran-2-yl)-2-hydroxyethanones 4a–c and 2-acetoxy-1-(benzofuran-2-yl)ethanones 3a–c was performed by baker's yeast for preparation of optically active (benzofuran-2-yl)carbinols [(S)-5a–d, (S)-6a–c and (R)-6a–c, enantiomeric excess from 55 to 93% ee].     

A facile synthesis of (6S,1′S)-(+)-hernandulcin and (6S,1′R)-(+)-epihernandulcin

A facile total synthesis of (+)-hernandulcin (1) was accomplished from (−)-isopulegol in 6 steps with 15% overall yield. Epoxidation of (−)-isopulegol with m-chloroperbenzoic acid followed by opening of the epoxide 3a with prenyl Grignard afforded the tertiary alcohol 4a with correct C-6 and C-1′ stereochemistry as a major product. Oxidation of the secondary alcohol in compound 4a to the ketone 5a was accomplished in high yield by using TPAP and N-methylmorpholine N-oxide. Conversion of the ketone 5a to α,β-unsaturated ketone via organoselenium intermediate gave (+)-hernandulcin (1). This method was also successfully applied to the synthesis of (+)-epihernandulcin (2).     

An improved asymmetric total synthesis of (+)-biotin via the enantioselective desymmetrization of a meso-cyclic anhydride mediated by cinchona alkaloid-based sulfonamide

The highly enantioselective total synthesis of (+)-biotin 1 via the Hoffmann–Roche lactone–thiolactone strategy has been achieved starting from cis-1,3-dibenzyl-2-imidazolidone-4,5-dicarboxylic acid 2 with an overall yield of 35%. Two contiguous stereogenic centers at C-3a and C-6a were established through a rapid cinchona alkaloid-based sulfonamide-mediated enantioselective alcoholysis of meso-cyclic anhydride 3 to afford (4S,5R)-cinnamyl hemiester 4h, the direct precursor to (3aS,6aR)-lactone 5 with high enantioselectivity. A one-pot installation of the 4-carboxybutyl side chain was accomplished by a Fukuyama coupling reaction of (3aS,6aR)-thiolactone 6 with the organozinc reagent prepared from ethyl 5-bromopentanoate.     

Lipase-mediated kinetic resolution of cis-1,2-indandiol and the Ritter reaction of its mono-acetate

Lipase-mediated kinetic resolution of cis-1,2-indandiol 5 in the presence of lipase PS was examined. Enantiomerically enriched (1S,2R)-2-acetoxy-1-indanol 6a was obtained when cis-1,2-indandiol 5 was treated with one equivalent of vinyl acetate. Treatment of 5 with two equivalents of vinyl acetate furnished a mixture of (1R,2S)-2-acetoxy-1-indanol 6a and (1R,2S)-1-acetoxy-2-indanol 6b. A route to both enantiomers of 1 was also developed by using the enantiomerically enriched mono-acetate thus obtained.     

New total synthesis of (+)-ambrein

The convergent synthesis of (+)-ambrein 1 was achieved based on a modified Julia coupling reaction between aldehyde 14 corresponding to the left-half A and sulfone 25a or 25b corresponding to the right-half B. Aldehyde 14 was synthesized in 14% overall yield (nine steps) from the enzymatic resolution product, epoxy alcohol (8aS)-2. Sulfone 25a or 25b was synthesized in 11 steps (25a: 41% overall yield, 25b: 56% overall yield) from the enzymatic resolution product, (1S,6S)-2,2-dimethyl-6-hydroxyhexane-1-carboxylate 4.     

A general strategy for the formal synthesis of (−)-trans-kumausyne and total synthesis of (5R)-Hagen’s gland lactones from diacetone-d-glucose

A general strategy for the formal synthesis of (−)-trans-kumausyne 1 via the bicyclic lactone (3aR,5R,6aR)-4 and total synthesis of (5R)-Hagen’s gland lactones 2 and 3 via bicyclic lactone (3aR,5S,6aR)-5 starting from diacetone-d-glucose 6 is described. Syntheses of 4 and 5 were achieved by Wittig olefination–lactonization–Michael addition of the corresponding lactols 16 and 17, respectively.     

Formal synthesis of amphidinin B

An efficient, convergent, and highly stereoselective formal synthesis of amphidinin B (1) is reported herein. In Amphidinin B both C10–C21 (4) and C1–C9 (5) fragments were derived from geraniol 6 and mono-PMB ether of 1,4-butane diol 7 in 19 and 9 steps, respectively. The key steps involved in this synthesis are Sharpless asymmetric epoxidation, Evans aldol, Julia olefination, oxa-Michael, Keck allylation, Mannich reaction, Evans asymmetric alkylation, and Yamaguchi esterification.     

Asymmetric synthesis of novel 1,4-aminoalcohol ligands with norbornene and norbornane backbone: use in the asymmetric diethylzinc addition to benzaldehyde

The asymmetric synthesis of cis-1,4-aminoalcohols with norbornene and norbornane backbone was performed starting with (2S,3R)-(−)-cis-hemiester 1 (98% ee). Chemoselective amination with HMPTA followed by Grignard reactions and subsequent LAH reductions afforded compounds 5a–d. cis-Hemiester 1 was also transformed into chiral ligands 7a–f and 9a–d with the DCC coupling method followed by LAH reduction using acyclic, heterocyclic amines and various aniline derivatives and p-toluenesulfonamide, respectively. The chiral ligands were subjected to asymmetric diethylzinc addition to examine their effectiveness as chiral catalysts. Among these, arylamine and tosyl substituted chiral ligands 9a–d exhibited the highest selectivities (up to 97% ee).     

Enantioselective synthesis of benzomorphan analogues by intramolecular oxa-Pictet–Spengler cyclization

A new strategy toward biologically active enantiomerically pure benzomorphan analogues is described. The key steps in the synthesis are the l-proline catalyzed asymmetric α-aminooxylation of an aldehyde and the titanium tetrachloride promoted intramolecular oxa-Pictet–Spengler cyclization of (4R)-2-(bromomethyl)-4-(2,5-dimethoxybenzyl)-1,3-dioxolane. In the intramolecular oxa-Pictet–Spengler cyclization, cis-pyran 8a (71%) formed over the trans-pyran 8b (14%). Computational modeling studies provided an insight into the stereoselectivity of the products. Docking studies of benzomorphan derivatives indicated that compound 6c had the best binding efficiency, and that it formed extensive hydrogen bonding with TYR148 on transmembrane (TM) helix 3 and HIS297 on TM6 of the μ-opioid receptor, which belong to the G-protein coupled receptor super family.     

N-Benzyloxymalimide for an easy access to 5-alkyl-3-pyrrolin-2-ones: asymmetric synthesis of the mixed imide substructure of the potent immunosuppressant microcolin B

O-Benzyl-N-benzyloxymalimide 12 has been synthesized as a useful variant of the chiral building blocks 9. The advantage of the malimide 12 over 9 was demonstrated by mild and high-yielding reductive N-deprotection of N-benzyloxylactams 18a–i to give a series of (4R,5S)-5-alkyl-4-hydroxy-pyrrolidin-2-ones, which are key intermediates for the asymmetric synthesis of pyrrolidines, pyrrolizidines, and indolizidines, as well as β-hydroxy γ-amino acids. Lactam ent-11a has been applied to the synthesis of the mixed imide 25, a key intermediate for the total synthesis of microcolin B, which also demonstrated that lactam ent-11a or 11a can serve as a latent form of the 5-methyl-3-pyrrolin-2-one substructure of majusculamide D 4, deoxymajusculamide D, and the jamaicamides A–C.     

Synthesis of tubuphenylalanine and epi-tubuphenylalanine via regioselective aziridine ring opening with carbon nucleophiles followed by hydroboration-oxidation of 1,1-substituted amino alkenes

An efficient synthesis of N-Boc-tubuphenylalanine benzyl ester (N-Boc-Tup-OBn, 1a) and N-Boc-epi-tubuphenylalanine benzyl ester (N-Boc-epi-Tup-OBn, 1b) is reported herein. Regioselective aziridine 4 ring opening with carbon nucleophiles followed by hydroboration of 1,1-substituted aminoalkene 3 using 9-BBN and subsequent oxidation in an alkaline medium are used as the key steps to provide N-tosyl 1,4-aminoalcohols. The 1,4-aminoalcohols are successfully transformed into the desired products with an overall yield of 23% for 1a and 11% for 1b over 8 consecutive steps separately.     

Catalytic asymmetric syntheses of (−)-oudemanisin A and its diastereomer

The first asymmetric catalytic synthesis of (?)-oudemanisin A 1a and its diastereomer 1b has been achieved. The key steps of our strategy involved the asymmetric alkynylation of an unsaturated aliphatic aldehyde catalyzed by Trost’s ProPhenol ligand, chemoselective oxidation of the olefinic diol, base-induced ring opening of the lactone, and acylation–alkylation of the ester.     

Diastereoselective synthesis of 4-substituted 5-(p-tolylsulfinyl)-5,6-dehydropiperidin-2-ones. A new approach to methyl l-(2S,4S)-4-methyl-6-oxopipecolate

The sulfoxide-mediated diastereoselective Michael reaction of homochiral α-sulfinylketimines 1a–d and β-substituted ene esters 2a–d (Hua's reaction) was explored. Straightforward cyclization of the open-chain adducts take place under the reaction conditions to provide the 4-substituted 5-(p-tolylsulfinyl)-5,6-dehydropiperidin-2-ones 3 and 7–12, whose stereochemistry is formed in the prior step. Furthermore, the role of the metal ion of the aza-enolate reagents and the steric demands of the O-alkyl ester group have been examined. It seems that the anti-diastereoselectivity depends on metal chelation by the oxygen of the ester as well as the oxygen of the sulfinyl group and the nitrogen in the aza-enolate ((Z)-configuration). In addition, the synthesis of methyl l-(2S,4S)-4-methyl-6-oxopipecolate has been achieved from the suitably functionalized 2-sulfinylketimine 1a (five steps; overall yield: 53–65%).     

First total synthesis of (−)-(3S,6R)-3,6-dihydroxy-10-methylundecanoic acid

The first total synthesis of (3S,6R)-3,6-dihydroxy-10-methylundecanoic acid was accomplished from commercially available 1-bromo-3-methylbutane in 11 steps and 25.8% overall yield. The key steps were asymmetric allylic alkylations via allyldiisopinocampheylborane and hydroboration-oxidation.