475301-86-1

Usage

General Description

(+)-Sparteine Surrogate

Upstream product

• 125109-97-9 (1S,5S)-N-methoxycarbonyl-1,2,3,4,5,6-hexahydro-1,5-methanopyrido-[1,2-a][1,5]diazocin-8-one 
• 2739-99-3 2-ethoxycarbonylmethylpiperidine 
• 2739-98-2 ethyl 2-(pyridinyl-2)acetate 
• 23581-42-2 octahydro-2H-quinolizine-2-one 
• 50-00-0 formaldehyd 
• 478798-07-1 (1S,5R)-Decahydro-1,5-methano-pyrido[1,2-a][1,5]diazocine 
• 2935-34-4 tetrahydrodeoxocytisine 

Relevant academic research and scientific papers

Gram-Scale Synthesis of the (?)-Sparteine Surrogate and (?)-Sparteine

An 8-step, gram-scale synthesis of the (?)-sparteine surrogate (22 % yield, with just 3 chromatographic purifications) and a 10-step, gram-scale synthesis of (?)-sparteine (31 % yield) are reported. Both syntheses proceed with complete diastereocontrol and allow access to either antipode. Since the syntheses do not rely on natural product extraction, our work addresses long-term supply issues relating to these widely used chiral ligands.

The First Modular Route to Core-Chiral Bispidine Ligands and Their Application in Enantioselective Copper(II)-Catalyzed Henry Reactions

The first modular and flexible synthesis of core-chiral bispidines was achieved by using an "inside-out" strategy. The key intermediate, a NBoc-activated bispidine lactam, was constructed in enantiomerically pure form from a chirally modified β-amino acid and 2-(acetoxymethyl)acrylonitrile in just five steps and good 48% yield. A simple addition-reduction protocol permitted a highly endo-selective introduction of substituents and, thus, a fast and variable access to 2-endo-substituted and 2-endo,N-fused bi- and tricyclic bispidines. The new diamines were evaluated as the chiral ligands in asymmetric Henry reactions. Excellent enantioselectivities of up to 99% ee and good diastereomeric ratios of up to 86:14 were reached with a copper(II) complex modified by a 2-endo,N-(3,3-dimethylpyrrolidine)-annelated bispidine. Its performance is superior to that of the well-known bispidines (-)-sparteine and the (+)-sparteine surrogate.

Revisiting the sparteine surrogate: Development of a resolution route to the (-)-sparteine surrogate

The improved performance of the sparteine surrogate compared to sparteine in a range of applications has highlighted the need to develop an approach to the (-)-sparteine surrogate, previously inaccessible in gram-quantities. A multi-gram scale, chromatography-free synthesis of the racemic sparteine surrogate and its resolution via diastereomeric salt formation with (-)-O,O′-di-p-toluoyl-l-tartaric acid is reported. Resolution on a 10.0 mmol scale gave the diastereomeric salts in 33% yield from which (-)-sparteine surrogate of 937 er was generated. This work solves a key limitation: either enantiomer of the sparteine surrogate can now be readily accessed.

Stereocontrolled synthesis and alkylation of cyclic β-amino esters: Asymmetric synthesis of a (-)-sparteine surrogate

A convenient method for the stereoselective synthesis of cyclic β-amino esters from an iodo αβ-unsaturated ester and α-methylbenzylamine is described. Subsequent enolate generation and alkylation proceeds with complete stereocontrol, with the two stereogenic centres working together. In this way, a functionalised piperidine suitable for alkaloid natural product synthesis was prepared. The usefulness of the methodology is exemplified with the concise synthesis of a (-)-sparteine surrogate. The Royal Society of Chemistry.

Chiral diamines for asymmetric synthesis: An efficient RCM construction of the ligand core of (-)- and (+)-sparteine

An efficient RCM-based approach was applied to the total asymmetric synthesis of a tricyclic diamine and, formally, of its enantiomer, widely known as efficient and versatile chiral ligands of the sparteine-like type.

Synthesis of sparteine-like chiral diamines and evaluation in the enantioselective lithiation-substitution of N-(tert-butoxycarbonyl)-pyrrolidine

Three chiral diamines were synthesised and evaluated as sparteine surrogates in the lithiation-substitution of N-(tert-butoxycarbonyl)pyrrolidine. The synthesis and attempted resolution of sparteine-like diamines {(1S*, 2R*, 8R*)-10-methyl-6,10-diazatricyclo [6.3.1.02,6]dodecane and (1S*, 2R*, 9R*)-11-methyl-7,11-diazatricyclo[7.3.1.02,7]tridecane} (via inclusion complex formation) are reported. Unfortunately, it was only possible to resolve the diazatricyclo-[7.3.1.02,7] tridecane compound. An alternative route to (1R,2S,9S)-11-methyl-7,11-diazatricyclo[7.3.1.02.7]tridecane starting from the natural product, (-)-cytisine, is described. This simple three-step route furnished gram-quantities of a (+)-sparteine surrogate. X-ray crystallography of an intermediate in the route, (1R,5S,12S)-3-methoxycarbonyl-decahydro-1,5-methanopyrido [1,2-a][1,5]diazocin-8-one, enabled the stereochemistry of all of the tricyclic diamines described in this paper to be unequivocally established. Two other diamines, starting from (S)-proline and resolved 2-piperidine ethanol, were prepared using standard methods. These diamines lacked the bispidine framework of (-)-sparteine and were found to impart vastly inferior enantioselectivity. It was concluded that, for the asymmetric lithiation-substitution of N-Boc pyrrolidine, a rigid bispidine framework and only three of the four rings of (-)-sparteine are needed for high enantioselectivity. Furthermore, it is shown that diamine (1R,2S,9S)-11-methyl-7,11-diazatricyclo [7.3.1.02,7]tridecane is the first successful (+)-sparteine surrogate.

Synthesis of enantiopure diamine ligands related to sparteine, via scandium triflate-catalyzed imino Diels-Alder reactions

Imino Diels-Alder reactions have been investigated as a new route to sparteine analogues. The first enantioselective synthesis of two diastereoisomeric tricyclic diamines, structurally equivalent to the ABC and BCD rings of the naturally occurring alkaloid, is reported, starting from enantiopure intermediates. The effectiveness of the diamines in the lithiation of N-Boc-pyrrolidine is discussed.

A readily-accessible (+)-sparteine surrogate

A "(+)-sparteine-like" chiral diamine, readily synthesized in three steps from (-)-cytisine, has been evaluated in four different asymmetric transformations; in each case, selectivity in an enantiocomplementary fashion to (-)-sparteine was observed. Copyright

Evaluation of a sparteine-like diamine for asymmetric synthesis

Evaluation of a sparteine-like diamine indicates that only the ABC rings of sparteine are required for high enantioselectivity in the lithiation-substitution of N-Boc pyrrolidine.

Synthesis and Stereochemistry of Some New Diazatricyclic Compounds

The diazatricyclic ketone 3 was synthesized by a double Mannich condensation starting from 2-quinolizidone (2).Reductions of 3 by complex hydrides and hydrazine gave a mixture of isomeric amino alcohols rac-4/5 and the diamine 6, respectively.Compounds rac-4 and rac-5 could be separated by selective acylation with 4-chlorobenzoyl chloride due to the fundamental steric differences in the N --> O acyl transfer interactions within the isomeric molecules.The cis- and trans-4-phenyl-2-quinolizidones (rac-10, rac-11) also underwent a Mannich condensation affording the same product rac-12 in both cases. - Key Words: 7,11-Diazatricyclo2,7>tridecanes / Cytisine analogues