Ryszard Lazny

N,N-Dialkylhydrazones in Organic Synthesis. From Simple N,N-Dimethylhydrazones to Supported Chiral Auxiliaries

The well-known properties of the carbonyl group render aldehydes and ketones prominent substrates in both C-C and C-heteroatom bond forming methodologies of organic synthesis. In practical syntheses, nitrogen analogues of aldehydes and ketones such as enamines, imines, or hydrazones, acting as synthetic equivalents of the carbonyl * To whom correspondence should be addressed. E-mail: lazny@uwb.edu.pl. Chem. Rev. 2010, 110, 1386–1434 1386

Triazenes as robust and simple linkers for amines in solid-phase organic synthesis☆

Abstract A new linker strategy for the attachment of aliphatic amines has been developed. Starting from Merrifield resin, an immobilized diazonium salt was prepared in two steps. Reaction of various amines gave rise to triazenes, which in turn were cleaved off upon treatment with mild acids. The triazenes have been proven to be base stable and were used in various types of transformations. The overall process is high-yielding and efficient.

Effect of lithium salts on enantioselective deprotonation of cyclic ketones

Abstract The influence of LiCl on deprotonation of 2- tert -butyl-2-methyl-1,3-dioxan-5-one 1 and tropinone 8 with chiral lithium amide bases is described. In most cases the enantioselectivity was much higher in the presence of 1 (or more) equivalent(s) of LiCl. In an extreme case the opposite enantiomers were obtained in the presence and in the absence of LiCl. The magnitude of LiCl effects and the optimal amount of LiCl varied with the ketone - lithium amide system. A new deprotonation procedure which utilizes the amine hydrochloride for generation of the chiral lithium amide is described. The effects of other lithium salts including LiBr, LiI, LiClO 4 were also briefly examined.

Application of triazenes for protection of secondary amines

Abstract Use of the phenyldiazenyl group, which serves as a protecting group for secondary amines is described in detail. The triazene protected amine is compatible with oxidative and reductive conditions as well as with strong bases (LDA, tert-butyllithium) and alkylating reagents. The amine is regenerated by action of trifluoroacetic acid and a suitable reducing agent (EtOH or NaH2PO2).

Synthesis of the host-selective phytotoxin destruxin B. Avoiding diketopiperazine formation from an N-methyl amino acid dipeptide by use of the Boc-hydrazide derivative

An efficient synthesis of the cyclic hexdepsipeptide destruxin B from its component residues is described that involves a [3+3] fragment coupling followed by cyclization via the azide method. A novel feature of the synthesis is the use of the Boc-hydrazide protecting group for the C-terminal N-methylalanine residue. This group serves both to inhibit facile diketopiperazine formation from the N-methylvalyl-N-methylalanine dipeptide and as a latent activating group for hexadepsipeptide cyclization.

Synthesis of pyranotropanes via enantioselective deprotonation strategy

Abstract Synthesis of tropane alkaloids darlingine, chalcostrobamine and isobellendine both in the racemic form and as unnatural enantiomers is described. Enantioselective deprotonation of tropinone, which proceeded with ca 90% ee, was the key step in each of the syntheses. Enantioselectivity was increased in the presence of LiCl.

Synthesis of polymeric supports with spacer-modified triazene linkers: aldol and Grignard reactions of immobilized nortropinone

Abstract Four new polymeric supports with 3- and 6-carbon atom spacers and triazene linkers derived from meta - and para -aminophenol were synthesized from commercial Merrifield polymer. The supports could be used for immobilization of secondary amines in SPOS. A new strategy based on the use of diethylamine triazenes as masked precursors for the generation of polymer-supported diazonium ions was used. The performance of the new linkers was tested on Grignard and aldol reactions of solid-phase immobilized nortropinone. The new supports with C 3 -T2 linkers gave products with better yields and purities than the classical T2 supports or the supports with the C 6 -T2 linkers.

Studies on Aldol Reactions of Nortropinone Derivatives in Solution and on Solid Phase

Polymer-anchored (Merrifield, trityl chloride, Wang p-nitrophenyl carbonate and triazene supports) nortropinone, or N-protected nortropinone derivatives in solution, were subjected to deprotonation with LDA or chiral lithium amides, and the resulting lithium enolates were trapped with an aldehyde. The aldols were obtained with moderate to good yields (44-84%) and enantioselectivities (44-86% ee).

Determination of the relative configuration of tropinone and granatanone aldols by using TBDMS ethers.

Summary The relative configurations of tert-butyldimethylsilyl (TBDMS) ethers of all four diastereomers of the aldols of tropinone (8-methyl-8-azabicyclo[3.2.1]octan-3-one), as well as of granatanone (9-methyl-9-azabicyclo[3.3.1]nonan-3-one), were determined from NMR data, and from the observed interconversion of the diastereomers (exo,anti to endo,syn and exo,syn to endo,anti). The exo forms invert to endo isomers in the presence of silica gel. The relative configuration of a new isomer of tropinone aldol accessible synthetically through the direct solventless reaction of tropinone and benzaldehyde in the presence of water was determined as exo,syn by comparison of NMR data of the aldol isomers, in particular vicinal coupling constants and shifts corresponding to the side-chain CH group, with data of related TBDMS derivatives and confirmed by single-crystal X-ray diffraction.

Solid-phase Synthesis of Tertiary N-Methyl Amines Including Tropanes

Synthesis on solid phase is one of modern methodologies especially useful in parallel and combinatorial syntheses. Tertiary amine functionalities are found in many important classes of catalysts, reagents and biologically active compounds. The tertiary N-methyl group is also present in structures of tropane alkaloids and majority of synthetic tropane derivatives with potential biological activity. Despite of well-defined tropane scaffold structure, which is present in known or potentially bioactive functionalized tropane derivatives only a few approaches to tropanes libraries and supported synthesis have been studied. Our approach to supported synthesis of tropane derivatives is based on anchoring nortropinone (1, Scheme 1), a secondary amine which naturally required a postcleavage N-methylation with one of the known procedures. Although secondary amines can be anchored reversibly via several well-known linkers including activated Wang carbonate, and triazene T2, we also looked for other methods. The linkers preserving the amine character of the anchored nitrogen atom, such as REM (via Michael addition-Hofmann elimination), amino acetals (DSEM and POEM), BAL-type, BOBA and several widely available polymeric gels (Merrifield, trityl chloride), could offer certain advantages. The motivation for seeking such anchors was an observation that the reactions of lithium enolates of tropinone and N-benzylnortropinone (both tertiary amines) in solution were more stereoselective and higher yielding than reactions of corresponding N-diazaphenyl (triazene) or carbobenzyloxy (uretane) derivatives. Therefore, we undertook a study on anchoring, and cleavage of nortopinone (1) on various polymeric supports with emphasis on methods for conversion of immobilized nortropane scaffold to tertiary amines such as tropane (2, Scheme 1). Solid-phase methods for synthesis of tertiary amines including N-methyl amines have been reported by Andersson. Others reported solid-phase alkylation and cleavage of tertiary amines by Hofmann type elimination from REM-type resins. An interesting method for debenzylating cleavage of quaternized amines from the Merrifield support based on nucleophilic displacement was reported by Cai. In our report, we wish to describe a novel method for preparation of N-methylated tertiary amines, including tropanes, based on quaternization and nucleophilic debenzylation of so formed ammonium salts immobilized via benzyl amine linkage on a widely available solid support, the Wang gel. We also report results of our approaches to reversible immobilization of nortropinone on polystyrene type supports with MOM analogue, BOM analogue, Wang type, PAL-type, Merrifield, para-C3-T2 triazene, carbamate Wang, and trityl linkers (Figure 1). Reversible Anchoring of the Amino Ketone. The cyclic secondary amines like nortropinone (1) could, in principle, be immobilized in a form of a tertiary amine via several linkers such as REM, Wang, and BAL linkers. The REM linker could not be used for our purposes because of its incompatibility with the basic conditions of enolate reactions, such as the directed aldol reaction. The Wang and BAL type linkers are typically used for releasing amine derivatives, usually amides or sulfonamides. However, the recent reports prompted us to investigate their use for immobilization of amino ketones such as nortropinone. We found that even though nortropinone could be anchored to Wang polymer (to give 6) and the 2,6-dimethoxy Wang polymer (to give 10, PAL type linker) very effectively (87-100%, Table 1, Figure 1), cleavage of this amino ketone was not feasible. Attempted oxidative cleavage of the Wang linker 6 (with DDQ) and simple benzylamine linker 7 derived from Merrifield polymer (with ceric(IV) ammonium nitrate, CAN), in our hands, did not provide any amine products (Figure 1). Therefore, we investigated amino acetal linkers analogous to MOM and BOM protecting groups for amines (8 and 9, Figure 1). Preparation of similar linkers by two different methods was reported. Unfortunately, we were able to obtain only modest loadings of the test amine, 4-benzylpiperidine or nortropinone 1, via such linkers prepared by either method (Figure 1). The cleavage provided poor loadings of released amines (17 and 9%, Table 1) despite using trifluoroacetic acid (TFA) at different concentrations, addition of water, prolonged cleavage times, and ultrasound. The only practical method for reversible linking of the amino ketone 1 to polymers in the form of a tertiary amine was the reactions with Merrifield gel or trityl chloride gel to form loaded polymers 7 and 3, respectively (Figure 1). The amino ketone could however be cleaved off the Merrifield support only by the procedure of Leysen et al. (action of 1-chloroethyl chloroformate (ACE-Cl) in 1,2dichloropropane (DCP), followed by methanolysis) in an analogy to the known reactions in solution, albeit with moderate yield (37% of the theoretical loading). As expected, nortropinone was very efficiently anchored and cleaved from supports with trityl linker 3 and carbamate Wang linker 4, (ca. 100% of the theoretical loadings). Immobilization and