Synthesis of fluorinated drimanes. Preparation of 9αF-drimenin

A stereoselective approach to the 9α-fluorinated analogue of the natural drimane sesquiterpene drimenin starting from β-ionone is described. β-Ionone is transformed into a bicyclic β-cetoester from which 9αF-drimenin is prepared through stereoselective electrophilic fluorination at the C-9 with N-fluorobenzenesulfonimide followed by Wittig methylenation, allylic bromination, bromine-hydroxyl exchange and γ-lactonization.     

A novel highly selective chiral auxiliary for the asymmetric synthesis of L- and D-alpha-amino acid derivatives via a multicomponent Ugi reaction

This paper describes the synthesis of a bicyclic beta-amino acid scaffold in both pure enantiomeric forms and its application as chiral auxiliary in an intramolecular version of the Ugi multicomponent reaction (U-5C-4CR) to prepare alpha-amino acid derivatives of both D- and L-series in a straightforward and very stereoselective manner. The mild conditions required for the Ugi condensation and for the removal of the chiral auxiliary make this method very attractive to prepare a wide range of differently structured N-alkylated and unalkylated amino acid derivatives.     

Iterative organometallic addition to chiral hydroxylated cyclic nitrones: highly stereoselective syntheses of alpha,alpha'- and alpha,alpha-substituted hydroxypyrrolidines

[reaction: see text]. Iteration of organometallic addition to chiral hydroxylated pyrroline N-oxides through an addition-oxidation-addition synthetic sequence allowed highly stereoselective double alkylation of pyrrolidine at C-2 or at C-2 and C-5 depending on the regioselectivity of the oxidation step. Application of this methodology has been exemplified by the synthesis of the all-substituted pyrrolidine alkaloid (-)-codonopsinine and of proline-type amino acid precursors possessing a quaternary stereogenic center, whose configuration can be controlled.     

Quaternary α,α-2-oxoazepane α-amino acids: synthesis from ornithine-derived β-lactams and incorporation into model dipeptides

To explore further the chemistry of amino acid-derived β-lactams, their conversion to α,α-heterocyclic quaternary amino acid derivatives is investigated. The latter derivatives, containing 2-oxoazepane as the α,α-substituent, are synthesized by a simple Pd-C-catalyzed hydrogenolysis of Orn(Z)-derived 2-azetidinones. The rearrangement from four- to seven-membered lactam ring is driven by the key intramolecular opening of the 1-Boc-β-lactam, initiated by 7-exotrig ring closure from the NH(2) of the Orn side chain. The synthetic route is applied to the stereoselective preparation of enantiomerically pure 4-amino-3-methyl-2-oxoazepane-4-carboxylate derivatives, for which the structure and configuration is confirmed by X-ray diffraction. Molecular modeling and NMR experiments indicate that these quaternary amino acids are able to drive the adoption of β-turn secondary structures when incorporated in model dipeptide derivatives.     

An enantioselective entry to cis-perhydroisoquinolines

An enantioselective route to cis-perhydroisoquinolines, involving a cyclocondensation reaction of (R)-phenylglycinol with a racemic oxoester, a stereoselective conjugate addition to an unsaturated bicyclic lactam, and the closure of the carbocyclic ring by a ring-closing metathesis as the key steps is reported. This route allows the preparation of 3-cyano derivatives as well as cis-octahydroisoquinolines bearing a quaternary center at the C4-position. [reaction: see text]     

Intramolecular cyclopropanation of unsaturated terminal epoxides and chlorohydrins

Lithium 2,2,6,6-tetramethylpiperidide (LTMP)-induced intramolecular cyclopropanation of unsaturated terminal epoxides provides an efficient and completely stereoselective entry to bicyclo[3.1.0]hexan-2-ols and bicyclo[4.1.0]heptan-2-ols. Further elaboration of C-5 and C-6 stannyl-substituted bicyclo[3.1.0]hexan-2-ols via Sn-Li exchange/electrophile trapping or Stille coupling generates a range of substituted bicyclic cyclopropanes. An alternative straightforward cyclopropanation protocol using a catalytic amount of 2,2,6,6-tetramethylpiperidine (TMP) allows for a convenient (1 g-7.5 kg) synthesis of bicyclo[3.1.0]hexan-2-ol and other bicyclic adducts. The synthetic utility of this chemistry has been demonstrated in a concise asymmetric synthesis of (+)-beta-cuparenone. The related unsaturated chlorohydrins also undergo intramolecular cyclopropanation via in situ epoxide formation.     

Reaction of aziridinecar☐ylic acids with thiols in aqueous solution. the formation of β-amino acid

Enantiomers of 3-methyl-2-aziridinecar☐ylic acids (1-d and 1-l) and 2-aziridinecar☐ylic acids (2-d and 2-l) reacted easily with thiophenol, cysteine and glutathione in aqueous solution or in sodium phosphate buffer solution at room temperature and gave predominantly β-amino acid derivatives with sulfur substituents at their α-position.From 1-d and thiophenol, (2S, 3R)-3-amino-2-phenylthiobutanoic acid (3-d) was produced predominantly. In order to confirm the structure, 3-d was converted to (3S, 4R)-3-phenylthio-4-methylazetidin-2-one (5) using the Ohno reaction. The configurations of 3-d and 6 were determined by X-ray diffraction and ¹³C NMR spectrum analysis, respectively. We concluded that the ring-opening reaction of unactivated aziridinecar☐yhc acids with thiols in aqueous solution occurred predominantly on C-2 of the aziridine ring with inversion of the configuration at this position. The reaction offers a good route for stereoselective synthesis of peptides or β-lactam derivatives.     

Stereoselective generation of vicinal stereogenic quaternary centers by photocycloaddition of 5-methoxy oxazoles to alpha-keto esters: synthesis of erythro beta-hydroxy dimethyl aspartates

The photocycloaddition of methyl pyruvate and methyl phenylglyoxylate, respectively, to 5-methoxy oxazoles bearing additional substituents at C-2 and C-4 leads to bicyclic oxetanes 2 and 3 with high to moderate (exo) diastereoselectivity that can be easily ring-opened to give bis-quaternary aspartic acid diester derivatives 4 and 5.     

The first total synthesis of (+/-)-scopadulin, an antiviral aphidicolane diterpene

[reaction: see text] The first total synthesis of (+/-)-scopadulin was accomplished by a stereoselective construction of a quaternary carbon at C-4, conversion of the hindered cyano group to a methyl group via our novel reaction for conversion of primary aliphatic amines into alcohols, and a highly chemo- and stereoselective methylation at C-16.     

A novel synthesis of (+)-biotin from L-cysteine

(+)-Biotin (1) was synthesized in 25% overall yield over 11 steps from L-cysteine. The contiguous asymmetric centers at C-3a and C-6a were formed through a novel and highly stereoselective Lewis base-catalyzed cyanosilylation of alpha-amino aldehyde 3 to provide anti-O-TMS-cyanohydrin 4 with high stereoselectivity and in high yield (anti/syn = 92:8, 96%). Treatment of 4 with a di-Grignard reagent, 1,4-bis(bromomagnesio)butane, followed by carbon dioxide, efficiently installed the 4-carboxybutyl chain at C-4 to give keto acid 5. The final cyclization to bicyclic compound 7b, a precursor to 1, was realized by a palladium-catalyzed intramolecular allylic amination of cis-allylic carbonate 6b that was elaborated from 5.     

The quest for new mild and selective modifications of natural structures: laccase-catalysed oxidation of ergot alkaloids leads to unexpected stereoselective C-4 hydroxylation

Laccase-catalysed oxidation of ergot alkaloids in the absence of chemical mediators allowed the unexpected isolation of the mono-hydroxylated derivatives of compounds 2-7. Structure determination by NMR techniques clearly indicated that hydroxylation took place at the C-4 benzylic position. Quite notably, the proposed protocol allowed, for the first time, functionalisation at the C-4 position of the ergoline skeleton. Depending on the absence or on the presence of a C-10 α-methoxy substituent, hydroxylation was either stereoselective (furnishing C-4α OH derivatives) or gave rise to a C-4α/C-4β OH mixture in a 2:1 ratio, respectively.     

Synthesis of densely functionalized cispentacin derivatives through selective aziridination and aziridine opening reactions: orthogonally protected di- and triaminocyclopentanecarboxylates

A novel substrate-directed synthetic route to a series of highly functionalized, orthogonally protected di- or triaminocyclopentanecarboxylate derivatives with multiple chiral centres from an unsaturated bicyclic β-lactam has been accomplished by applying stereoselective ring C–C double bond aziridination with chloramine-T and phenyltrimethylammonium tribromide, followed by regioselective aziridine opening with different N,O nucleophiles and hydrides. The functionalization strategy was successfully extended for access to enantiomerically pure orthogonally protected triaminocarboxylates.     

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.     

A 5-methylthiopenicillin analog and its transformation to novel bicyclic β-lactams

Reaction of methoxyacetyl chloride with 2-methylthio-2-thiazoline resulted in the stereoselective production of one isomer of 6-methoxy-5-methylthiopenam which underwent rearrangement to 6-methoxy-7-methylthio-5-oxo-2,3,4,5-tetrahydro-1,4-thiazepine when treated with trifluoroacetic acid. Subsequent thioamidation and alkylation with methyl iodide provided 5,7-bismethylthio-6-methoxy-2,3-dihydro-1,4-thiazepine which reacted with methoxyacetyl chloride and triethylamine to give a novel 1,4-thiazabicyclo[5.2.0]non-5-ene. Other substituted bicyclic β-lactams of similar structure have also been synthesized.     

Regio- and diastereoselective fluorination of alicyclic β-amino acids

A regio- and stereoselective approach to fluorinated β-aminocyclohexene or cyclohexane esters has been developed, starting from a bicyclic β-lactam (1). The procedure involves six or seven steps, based on regio- and stereoselective iodolactonization, lactone opening and hydroxy-fluorine exchange. The method has been extended to the synthesis of fluorinated amino ester enantiomers.     

Versatile route to centro-substituted triquinacene derivatives: synthesis of 10-phenyltriquinacene

[reaction: see text] A versatile route to prepare centro-substituted triquinacene derivatives (1, R = various substituents), as exemplified by the preparation of 10-phenyltriquinacene (1, R = Ph), is reported. The quaternary, centro substituent (C-10) was installed by a trimethylsilyl chloride-promoted conjugate addition reaction of an organocuprate, derived from phenylmagnesium bromide, and the protected bicyclic enone (11). The resultant trimethylsilyl enol ether was then converted regioselectively to the C-2-allylated conjugate addition products (13, R = Ph). The allyl moiety, following oxidative cleavage of the carbon-carbon double bond, was used to elaborate the tricyclic ring system by an intramolecular aldol/acetal deprotection reaction. The product of this reaction was then converted to the target compound using a standard series of functional group transformation reactions.     

Stereoselective synthesis of the right-hand segment of tubiferal A

Tubiferal A, a triterpenoid isolated from myxomycete Tubifera dimorphotheca, exhibits a reversal effect of vincristine (VCR) resistance against VCR-resistant KB cell lines. The compound possesses a complex structure involving the 6-7-6-5 polycyclic carbon framework with various functional groups. The stereoselective synthesis of the right-hand segment of tubiferal A was achieved on the basis of the cyclopentene annulation method and the semi-pinacol rearrangement reaction of an epoxy alcohol for constructing the trans-fused 6-5 bicyclic skeleton possessing two quaternary carbon atoms at the angular positions.     

A new stereocontrolled entry into the anthracyclinone families. Part 1: Synthesis of bicyclic precursors of 4-demethoxy-7-deoxy-derivatives

A new and versatile strategy to obtain enantiomerically pure bicyclic precursors of compounds belonging to different anthracyclinone families is reported. Completely stereoselective hydrocyanation of (R)-4-(2,5-dimethoxyphenyl)-1-p-tolylsulfinyl-2-butanone and further intramolecular capture of the Pummerer intermediate generated from the resulting sulfinylcyanohydrin are the key steps to obtain the bicyclic nitrile 2 with the proper configuration and functionality at C-9.     

Stereoselective Construction of Halogenated Quaternary Carbon Centers by Brønsted Base Catalyzed [4+2] Cycloaddition of α‐Haloaldehydes

Asymmetric construction of halogenated quaternary carbon centers under mild reaction conditions remains challenging. Reported here is an unprecedented and highly stereoselective Brønsted base catalyzed [4+2] cycloaddition between either α‐chloro‐ or α‐bromoaldehydes and cyclic enones. The key intermediate, an α‐halogenated enolate, is susceptible to dehalogenation and can be stabilized and stereochemically controlled using bifunctional tertiary amines. This method provides facile access to a collection of optically pure bicyclic dihydropyrans having three contiguous stereocenters, including a halogen‐bearing quaternary carbon center. Of note, the product can be transformed in situ into densely functionalized spirocyclopropanes in a highly efficient and stereoselective manner.     

An enantioselective synthesis of the bicyclic core of the marine natural product awajanomycin

A concise stereoselective synthesis of the N-benzylated bicyclic core of the marine natural product awajanomycin is described starting with naturally occurring l-alanine. Key steps in the synthesis include a ring-closing metathesis to establish a δ-lactam ring followed by a stereoselective hydroxylation to instal the quaternary centre.