Chemoenzymatic formal synthesis of (−)- and (+)-epibatidine

Boyd, Derek R.; Sharma, Narain D.; Kaik, Magdalena; McIntyre, Peter B. A.; Stevenson, Paul J.; Allen, Christopher C. R.

doi:10.1039/c2ob06904k

Cited by 23 publications

(8 citation statements)

References 72 publications

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“…Therefore, the possibility of forming and separating crystalline derivatives from azidoacetates 8c , 9c , 11c , and 12c , which might be suitable for X‐ray crystallography, and the resulting unequivocal determination of structure and relative stereochemistry, was also investigated. As part of our earlier unpublished efforts, to synthesize the alkaloid epibatidine from cis ‐diols 2b and 2c , attempts were made to characterize the products ( 8c , 9c , 11c , and 12c ) through the formation of their derivatives. In order to solve the problem of product equilibration, the azide groups present in compounds 8c , 9c , 11c , and 12c were reduced with trimethyl phosphine, using a Staudinger reaction.…”

Section: Resultsmentioning

confidence: 99%

“…The cooled mixture was diluted with EtOAc (100 mL) and washed with brine containing 2% NaOH (3 × 50 mL) and saturated NH 4 Cl solution (75 mL). The organic phase was dried (Na 2 SO 4 ) and concentrated under reduced pressure, and the residue was purified by flash chromatography (pentane:EtOAc gradient 90:10 → 40:60) to afford compound 19c (1.1 g, 84%) as a white needles; mp 152-153°C (from EtOAc) (lit., mp 135°C) [32] ; (27), 67 (11).…”

Section: Methodsmentioning

confidence: 99%

“…3‐Chlorocyclohex‐3‐ene‐1,2‐dio1 3a , 3‐bromocyclohex‐3‐ene‐1,2‐diol 3b , ‘(1 S , 2 R )‐2‐bromo‐3‐chlorocyclohex‐3‐enyl acetate 4a , (1 S , 2 R )‐2,3‐dibromocyclohex‐3‐enyl acetate 4b , 2‐chloro‐7‐oxabicyclo[4.1.0]hept‐2‐ene 5a , 2‐bromo‐7‐oxabicyclo[4.1.0]hept‐2‐ene 5b , and 3‐phenyl‐2‐( p ‐toluenesulfonamido)cyclohex‐2‐enyl acetate 18c were available from earlier studies …”

Section: Methodsmentioning

confidence: 99%

“…R = Cl ( 2a ), Br ( 2b ), and Ph ( 2c ). To date, these compounds have been extensively used in the synthesis of homochiral natural products, including alkaloids, and of novel chiral ligands required for transition metal catalysis 6,7a‐d. The unsubstituted alkene bond in these cis ‐dihydrodiol bioproducts 2 can be regioselectively reduced by catalytic hydrogenation to give the much more stable, and easier to handle, cis ‐tetrahydrodiol precursors 3 , e.g .…”

Section: Introductionmentioning

confidence: 99%

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Reactions of nitrogen nucleophiles with enantiopure cyclohexenyl electrophiles: a stereo‐ and regio‐ selective study

Boyd

Sharma

Belhocine

et al. 2013

J of Physical Organic Chem

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The reactions of enantiopure cyclohexene epoxides and trans-1,2-bromoacetates, derived from the corresponding substituted benzene cis-dihydrodiol metabolites, with nitrogen nucleophiles, were examined and possible mechanisms proposed. An initial objective was the synthesis of new 1,2-aminoalcohol enantiomers as potential chiral ligands and synthetic scaffolds for library generation. These apparently simple substitution reactions proved to be more complex than initially anticipated and were found to involve a combination of different reaction mechanisms.Allylic trans-1,2-azidohydrins were prepared by Lewis acid-catalysed ring-opening of cyclic vinyl epoxides with sodium azide via an S N 2 mechanism. On heating, these trans-1,2-azidohydrins isomerized to the corresponding trans-1,4-azidohydrins via a suprafacial allyl azide [3,3]-sigmatropic rearrangement mechanism. Conversion of a 1,2-azidohydrin to a 1,2-azidoacetate moved the equilibrium position in favour of the 1,4-substitution product. Allylic trans-1,2-bromoacetates reacted with sodium azide at room temperature to give C-2 and C-4 substituted products. A clean inversion of configuration at C-2 was found, as expected, from a concerted S N 2-pathway. However, substitution at C-4 was not stereoselective and resulted in mixtures of 1,4-cis and 1,4-trans products. This observation can be rationalized in terms of competitive S N 2 and S N 2′ reactions allied to a [3,3]-sigmatropic rearrangement. cis-1,2-Azidohydrins and cis-1,2-azidoacetates were much more prone to rearrange than the corresponding trans-isomers.Reaction of the softer tosamide nucleophile with trans-1,2-bromoacetates resulted, predominantly, in C-4 substitution via a syn-S N 2′ mechanism. One application of the reaction of secondary amines with allylic cyclohexene epoxides, to give trans-1,2-aminoalcohols, is in the synthesis of the anticholinergic drug vesamicol, via an S N 2 mechanism.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Reactions of nitrogen nucleophiles with enantiopure cyclohexenyl electrophiles: a stereo‐ and regio‐ selective study

Boyd

Sharma

Belhocine

et al. 2013

J of Physical Organic Chem

Self Cite

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“…Thanks to the high fidelity of the [1,3]‐transfer of chirality, the [3,3]‐sigmatropic rearrangement proved to be a powerful tool in natural product synthesis. Stevenson et al reported the synthesis of (–)‐epibatidine with use of this rearrangement as key step for the introduction of the amino group (Scheme ) . Dehydration of carbamate 38 , obtained from 37 under Appel's conditions, gave the isocyanate 39 , which was treated with t BuOH to form the diene 40 , an advanced precursor of the desired natural product.…”

Section: Applications In Natural Products Synthesismentioning

confidence: 99%

The Allyl Cyanate/Isocyanate Rearrangement: An Efficient Tool for the Stereocontrolled Formation of Allylic C–N Bonds

et al. 2017

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[3,3]‐Sigmatropic rearrangements represent powerful methods in the toolbox of synthetic organic chemists for the stereoselective construction of carbon–carbon as well as carbon–heteroatom bonds. Thus, the allyl cyanate/isocyanate rearrangement, although still underused for the preparation of allylamine derivatives, offers clear advantages over other similar methods. It usually occurs at or below ambient temperature with no need to use any metal catalyst, in a stereospecific way, and with a complete transfer of chirality. Moreover, combined with the high reactivity of the resulting isocyanates towards nucleophiles, this rearrangement gives access to various classes of compounds with wide structural and functional diversity. This microreview provides an overview of synthetic applications of this rearrangement since its discovery, with particular emphasis on its utility for the synthesis of complex nitrogen‐containing molecules such as natural products.

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Allyl Cyanate‐To‐Isocyanate Rearrangement: Preparation of tert ‐Butyl 3,7‐Dimethylocta‐1,6‐dien‐3‐ylcarbamate

Ichikawa

Kariya²,

Hasegawa³

2014

Organic Syntheses

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Geraniol Dichloromethane Trichloroacetyl isocyanate Trichloroacetyl carbamate Methanol Potassium carbonate ( E )‐3,7‐Dimethylocta‐2,6‐dien‐1‐ylcarbamate Triphenylphosphine Triethylamine Carbon tetrabromide t ‐Butyl 3,7‐dimethylocta‐1,6‐dien‐3‐ylcarbamate 3‐Isocyanato‐3,7‐dimethylocta‐1,6‐diene Tetrahydrofuran Lithium t ‐butoxide N‐Butanol

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Chemoenzymatic formal synthesis of (−)- and (+)-epibatidine

Cited by 23 publications

References 72 publications

Reactions of nitrogen nucleophiles with enantiopure cyclohexenyl electrophiles: a stereo‐ and regio‐ selective study

Reactions of nitrogen nucleophiles with enantiopure cyclohexenyl electrophiles: a stereo‐ and regio‐ selective study

The Allyl Cyanate/Isocyanate Rearrangement: An Efficient Tool for the Stereocontrolled Formation of Allylic C–N Bonds

Allyl Cyanate‐To‐Isocyanate Rearrangement: Preparation of tert ‐Butyl 3,7‐Dimethylocta‐1,6‐dien‐3‐ylcarbamate

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