The design of efficient and selective routes to pyridyl analogues of 2,3-dihydro-1,4-benzodioxin-6-carbaldehyde

This Letter describes the synthetic routes to challenging pyridyl analogues of 2,3-dihydro-1,4-benzodioxin-6-carbaldehyde which were key intermediates for our antibacterial medicinal chemistry programme. All routes described started from kojic acid (8) and have been used to give multigram quantities of each aldehyde.     

Enantioselective addition of diethylzinc to aldehydes catalyzed by 5-cis-substituted proline derivatives

5-Cis-substituted prolinols, prolinamines, and prolinamine sulfonamides proved to be efficient ligands for the enantioselective addition of diethylzinc to aldehydes, providing up to 99% ee. The sense of asymmetric induction can be controlled by the nature of the exocyclic functional group (CPh₂OH vs. CH₂NHR vs. CH₂NHSO₃R). The additional 5-cis substituent exerts a strong beneficial effect on the chirality transfer since it rigidifies the catalyst structure. The stereochemical outcome of the reactions is discussed in detail on the respective transition states.     

The design of efficient and selective routes to pyridyl analogues of 3-oxo-3,4-dihydro-2H-1,4-(benzothiazine or benzoxazine)-6-carbaldehydes

This Letter describes the synthesis of challenging pyridyl analogues of 3-oxo-3,4-dihydro-2H-1,4-(benzothiazine or benzoxazine)-6-carbaldehydes. The six different routes described are high yielding, contain no major purification issues and have been used to give gram quantities of each aldehyde.     

Synthesis of ortho-substituted cyanopyridines through lithio intermediate trapping

Ortholithiation of 4-cyanopyridine using 2,2,6,6-tetramethylpiperidide (LiTMP) and trapping the lithio intermediate with electrophiles represents an efficient and straightforward access to ortho-substituted-4-cyanopyridines. The cyano group can be used as an ortho-directing group and allows the preparation of 3-halogeno-4-cyanopyridines. Reactivity of 2- and 3-cyanopyridines is also investigated and seems to give similar results.     

Highly efficient racemisation of a key intermediate of the antibiotic moxifloxacin

N-Chlorination by sodium dichloroisocyanurate and dehydrochlorination by TEA, followed by hydrogenation, allowed (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane to be quantitatively racemised and the resulting trans-free cis racemate to be recycled into the resolution process to yield (1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane, a key intermediate of moxifloxacin.     

The construction of novel perylenequinone core via efficient synthesis of versatile ortho-naphthoquinone as a key intermediate

The novel perylenequinone core, 1,12-diacetonitrile-3,10-perylenequinone, was successfully prepared from the dimerization of the key intermediate, 3-acetonitrile-1,2-naphthoquinone, which was synthesized by an efficient synthetic route in relatively short reaction steps (seven steps) and satisfactory overall yield. The perylenequinone core containing the acetonitrile functionality is notable in the sense that the versatile acetonitrile group could be utilized to prepare various compounds at a later synthetic stage for the development of new and novel perylenequinone derivatives as potential photodynamic agents.     

Enantioselective synthesis of an aziridinomitosane and selective functionalizations of a key intermediate

An enantioselective synthesis of mitosane core (-)-1 has been achieved. Key steps include a rapid assembly of a key eight-membered-ring intermediate employing ring-closing metathesis. Kinetic resolution of an advanced secondary alcohol was then accomplished by using a peptide-based asymmetric acyl transfer catalyst that was discovered from a parallel screen of catalyst candidates. Optically pure material was then converted to the mitosane core, which was the subject of additional studies on the selective modification to produce several substituted compounds containing a mitosane ring system.     

A short and efficient enantioselective route to a key intermediate for the total synthesis of forskolin

A simple route for the enantioselective synthesis of key intermediates (11 and 12) for the total synthesis of forskolin has been developed starting from acid 6 and (S)-alcohol 5. The latter is prepared by enantioselective catalytic CBS reduction of dienone 3, and is converted by an intramolecular Diels-Alder reaction to tricyclic lactone 9.     

C3-triiodocyclotriveratrylene as a key intermediate to fluorescent probes: application to selective choline recognition

A new strategy to obtain fluorescent cyclotriveratrylene (CTV) probes is proposed. The key intermediate, a triiodo CTV, is prepared in 3 steps with 47% overall yield. The whole synthesis requires only one purification step. The potential of this triiodo CTV as an intermediate is illustrated through the synthesis of a fluorescent phosphorylated probe that is able to bind choline and acetylcholine in pseudo-physiological conditions, with selectivity towards choline. As a consequence, this intermediate should allow us to rapidly form a library of probes in order to highlight the most promising ones.     

A general and efficient route to enantioselective synthesis of pumiliotoxin A alkaloids via a common key intermediate

A general and efficient formal synthesis of pumiliotoxins and allopumiliotoxins has been achieved via a common key intermediate 3a. Our route featured a novel one-pot substitution-ring-opening sequence and an efficient Claisen-type condensation. This method is also applicable to quinolizidine derivative 2b.     

Carbocyclic analogs of C-nucleosides: a key intermediate via a novel and efficient CC ring scission

Treatment of hydroxymethylene ketone $\text{6}$ with trimethylene dithiotosylate according to literature conditions,^3b led to the novel CC ring scission product $\text{7}$ in high yield; also, the hydroxide-initiated cleavage⁴ of $\text{1}$ gave the β-elimination product $\text{13}$ which underwent a highly stereospecific addition of diazomethane to provide $\text{15}$.     

The conversion of 3,4-cis- to 3,4-trans-cannabinoids

An investigation of the conversion of Δ¹-3,4-cis-THC 1a to Δ⁶-3,4-trans-THC 2a with BBr₃ is described. By use of 1a of known optical purity it was determined that the main epimerization occurs at C-4. The small loss of optical purity observed during formation of 2a results from either competitive epimerization at C-3 or a racemization process. The conversion of 3,4-cis- to 3,4-trans-HHCs proceeds with exclusive C-4 inversion.     

Simple and efficient synthetic routes to d-cycloserine

d-Cycloserine has been successfully synthesized in good yields through three new synthetic routes from a readily available d-serine. In each synthesis, cyclization served as the key step, and two of the routes employed one-pot operations for the preparation of the target product. These methods featured the use of mild reaction conditions and simple treatments.     

A general synthesis of N-substituted 1,4-benzoxazine- and 1,4-benzothiazine-2-carboxylates via copper-catalyzed intramolecular amination of arylbromides

Starting from ortho-bromosubstituted phenoxyacetates or (phenythio)acetates and primary amines, various N-substituted 4H-1,4-benzoxazine- and 4H-1,4-benzothiazine-2-carboxylates were synthesized in moderate to high yields by using a Cu(I)-catalyzed Ullmann-type cyclization as a key step. The method is simple to operate, tolerates many functional groups and does not require any additives.     

Highly efficient stereocontrolled synthesis of Danishefsky's taxol CD ring key intermediate

Danishefsky's taxol CD ring key intermediate is synthesized in 15 steps and 11.4% overall yield from a readily available starting material. Absolute stereochemistry of the starting material and stereocontrolled steps determine the absolute configuration of the five requisite contiguous stereocenters.     

Mild, efficient and rapid O-debenzylation of ortho-substituted phenols with trifluoroacetic acid

The mild and efficient deblocking of aryl benzyl ethers with TFA is reported. Cleavage was fastest with ortho-electron-withdrawing groups on the phenolic ring, which we have attributed to a proton chelation effect, furnishing the deprotected phenols in excellent yields. The corresponding para-methoxybenzyl, allyl and iso-propyl ethers were also cleanly removed under these conditions. In addition, the selective aryl benzyl ether debenzylation in the presence of benzyl ester, Cbz carbamate and Boc carbamate functionalities was also observed.     

Rapid and efficient routes to phosphatidylinositol 3,4,5-trisphosphates via myo-inositol orthobenzoate

Efficient routes to two phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P₃] analogues with different acyl chains have been developed by using cheaply available myo-inositol as the starting material. The high yield of the orthobenzoate derivative, preferential formation of the required protected inositol diastereomer in its desymmetrization and ease of separation make the synthesis expedient, economical and high yielding. Due to the inherent problem of racemization of diacylglycerol (DAG), the synthesis of phosphatidylinositol phosphates [PIPns] with unambiguous stereochemical purity has always been difficult. Our methodology excludes the possibility of racemization in the DAG unit and thus provides access to PtdIns(3,4,5)P₃ of high optical purity. Since the acyl functionalities are introduced last, the methodology reported is amenable to the synthesis of PtdIns(3,4,5)P₃ with any acyl chain (or even a library of analogues).     

Dienamines as diels-alder dienes. An efficient synthesis of a key intermediate for drimane-related sesquiterpenes

An efficient synthesis of dienediester 3, a key intermediate for drimane-related sesquiterpenes, is described starting from enal 4.     

Synthesis of a key intermediate of novel galbonolide analogues via efficient construction of a conjugated diene system

The development of an efficient synthetic method enabled multi-gram synthesis of a key intermediate, which is useful for the modification at the C6-functional group of galbonolide analogues. The structure of a key intermediate including a conjugated diene was afforded by Horner-Emmons reaction, alkylation of Weinreb amide with alkyl lithium and a subsequent Wittig reaction.