Chemoenzymatic Synthesis of Unnatural Amino Acids <i>via</i> Modified Claisen Rearrangement of Glycine Enolates. Approach to Morphine Synthesis

González, David; Schapiro, Valeria; Seoane, Gustavo; Hudlický, Tomáš; Abboud, Khalil A.

doi:10.1021/jo962315w

Cited by 29 publications

(11 citation statements)

References 28 publications

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“…Thus, the reduced yield of cis-tetrahydrodiols 2d and 2e made the otherwise synthetically versatile bromo-and iodo-cis-dihydrodiol derivatives, 1d and 1e, less attractive chiral precursors. [6][7][8][9] In this context, earlier studies [6,9] showed that partial catalytic hydrogenation of cis-dihydrodiols 1c and 1d using Rh/Al 2 O 3 catalyst in THF or EtOH solvent resulted in good yields (85%) of adducts 2c, 2d with minimal evidence of hydrogenolysis of the carbon-halogen bond or aromatisation occurring. However, when these reaction conditions were applied to, arguably the most useful, cis-dihydrodiol 1e, yields of adduct 2e never exceeded [9] 55% and purification of the crude reaction mixture proved to be quite difficult.…”

Section: Introductionmentioning

confidence: 99%

Cycloalkenyl Halide Substitution Reactions of Enantiopure Arene cis‐Tetrahydrodiols with Boron, Nitrogen and Phosphorus Nucleophiles

et al. 2011

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Enantiopure arene cis-tetrahydrodiols of bromobenzene and iodobenzene have been obtained in good yields, from chemoselective hydrogenation (rhodium-graphite) of the corresponding cis-dihydrodiol metabolites. Palladium-catalysed substitution of the halogen, by hydrogen, boron, nitrogen and phosphorus nucleophiles, in the acetonide derivatives, has yielded highly functionalised products for application in synthesis with potential as scaffolds for chiral ligands.

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Section: Introductionmentioning

confidence: 99%

Cycloalkenyl Halide Substitution Reactions of Enantiopure Arene cis‐Tetrahydrodiols with Boron, Nitrogen and Phosphorus Nucleophiles

et al. 2011

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“…Then the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography on silica gel using CH 2 Cl 2 /MeOH (98:2) as eluent to provide 14 (10 mg, 0.03 mmol, 84%) as a colorless oil. 6,146.1,143.6,127.1,121.9,121.1,115.8,91.5,58.8,57.2,46.7,44.5,38.9,34.3,30.0,26.8,25.2. MS (EI): m/z (%) = 313 (21), 248 (100), 231 (59), 203 (18), 156 (18), 149 (13), 139 (18), 127 (10), 111 (16), 105 (13).…”

Section: Ethyl 2-{(1s6r)-1-(23-dimethoxyphenyl)-6-[(s)-3-methyl-2-omentioning

confidence: 99%

“…5 In 1997 we reported the Kazmaier-Claisen rearrangement of glycinate esters derived from diols of type 1 (R = Cl, Me, aryl). 6 This rearrangement provided a mixture of diastereomers at C-9 (morphine numbering) presumably because the rearrangement proceeded through both chair and boat transition states despite the fact that only the Zenolate species was generated from glycinates 2 (Scheme 1). Ireland reported that cyclohexenyl derivatives containing substituents on the ring frequently undergo the Ireland-Claisen rearrangement through both chair and boat transition states and therefore result in isomeric mixtures.…”

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confidence: 99%

Total Synthesis of Dihydrocodeine and Hydrocodone via a Double Claisen Rearrangement and C-10/C-11 Closure Strategy

Varghese¹,

Hudlický²

2013

Synlett

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Dihydrocodeine and hydrocodone were synthesized from bromobenzene in 16 and 17 transformations, respectively. The key steps involved the toluene dioxygenase-mediated dihydroxylation of bromobenzene by whole-cell fermentation with E. coli JM109(pDTG601A), Kazmaier-Claisen rearrangement of glycinate ester, Claisen rearrangement to set the C-13 quaternary center, and C-10-C-11 closure. Experimental procedures are provided for the key steps.The effort aimed at the total synthesis of morphine and related alkaloids has continued unabated over the 60 years since Gates's milestone preparation. 1 The more than 30 published total syntheses of morphine, codeine, and their congeners have been summarized in several reviews. 2 As creative as many of the published approaches are, none compare in efficiency to that reported by Rice in 1980; 3 however, even that one falls short of competing in price with morphine obtained from natural sources. Although morphine is not a particularly complex molecule, it is completely dissonant in its connectivity, and thus any synthetic strategy employed requires tactical adjustments to overcome these issues. Such adjustments invariably lead to longer sequences. We have pursued diverse approaches to morphine alkaloids for many years and have succeeded in several total syntheses; 4 however, we have not yet achieved a truly practical approach. Nevertheless, our exploitation of different strategies provides us with an opportunity for further improvements through multi-generational design. Herein we report an approach to hydrocodone and dihydrocodeine based on a sequential Claisen rearrangement and a C-10/C-11 closure, one that has not been extensively used for morphine alkaloids. 5 In 1997 we reported the Kazmaier-Claisen rearrangement of glycinate esters derived from diols of type 1 (R = Cl, Me, aryl). 6 This rearrangement provided a mixture of diastereomers at C-9 (morphine numbering) presumably because the rearrangement proceeded through both chair and boat transition states despite the fact that only the Zenolate species was generated from glycinates 2 (Scheme 1). Ireland reported that cyclohexenyl derivatives containing substituents on the ring frequently undergo the Ireland-Claisen rearrangement through both chair and boat transition states and therefore result in isomeric mixtures. 7When diol 1 (X = Br), 8 obtained by enzymatic dihydroxylation of bromobenzene with E. coli JM109 (pDTG601A), 9 was subjected to the sequence depicted in Scheme 1, two diastereomers of amino acid 4 were obtained in approximately 2:1 ratio. After esterification with diazomethane and separation of the isomers, 5b was subjected to base-catalyzed equilibration to provide a mixture of 5a (39%) and 5b (49%), which was separated by column chromatography. This process was repeated until all of the material was converted into pure 5a with the correct absolute configuration at C-9 (morphine numbering). We speculated that such equilibration is possible because of a more stable, weakly hydrogen-bonded, conformation in cases ...

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“…48 Fortunately, esters 103 were equilibrated under basic conditions to the (apparently) more stable isomer 103b. 51,52 A plausible explanation for this isomerization is that there is a hydrogen bond between the halogen and the carbamate proton. The C-9 ester (morphine numbering) is axial in 103a and equatorial in 103b ( Figure 5).…”

Section: Hudlickymentioning

confidence: 99%

Recent Progress in the Synthesis of Morphine Alkaloids

Zezula¹,

Hudlický²

2005

Synlett

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Chemoenzymatic Synthesis of Unnatural Amino Acids via Modified Claisen Rearrangement of Glycine Enolates. Approach to Morphine Synthesis

Cited by 29 publications

References 28 publications

Cycloalkenyl Halide Substitution Reactions of Enantiopure Arene cis‐Tetrahydrodiols with Boron, Nitrogen and Phosphorus Nucleophiles

Cycloalkenyl Halide Substitution Reactions of Enantiopure Arene cis‐Tetrahydrodiols with Boron, Nitrogen and Phosphorus Nucleophiles

Total Synthesis of Dihydrocodeine and Hydrocodone via a Double Claisen Rearrangement and C-10/C-11 Closure Strategy

Recent Progress in the Synthesis of Morphine Alkaloids

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