Claisen Rearrangements of Allylic and Propargylic Alcohols Prepared by an N-Boc-2-acyloxazolidine Methodology − Application to the Synthesis of Original Chiral Building Blocks

Abstract

Stereodefined alkenols prepared in two steps from a Weinreb amide derived from (R)-phenylglycinol undergo highly stereoselective Claisen rearrangements. The masked aldehyde moiety of the produced N-Boc-alkenyloxazolidines can then be recovered and reduced without epimerization, to yield new enantiopure chiral building blocks. Alternatively, epoxidation of these N-Boc-2-alkenyloxazolidines by a well-established intramolecular bromocarbamation involving the

Diaryl Thiourea Catalysts Promote the Formation of Propargyl Enol Ethers in the Claisen Rearrangement Sequence

“…This liability does not affect the classical ketone/aldehyde Claisen rearrangement, but the β,γ-unsaturated allenyl ketone 4 can isomerize to 5 by simple proton transfer (Scheme 1a) [7]. Unfortunately, the early studies on propargyl Claisen reactions do not always explicitly report the isomeric purity of the products [1,8,9]. In our hands, we found that the classical Saucy-Marbet conditions indeed promote the undesired isomerization, affording the product as a mixture of isomers 4 and 5 even with short reaction times.…”

Diaryl Thiourea Catalysts Promote the Formation of Propargyl Enol Ethers in the Claisen Rearrangement Sequence

“…This liability does not affect the classical ketone/aldehyde Claisen rearrangement, but the β,γ-unsaturated allenyl ketone 4 can isomerize to 5 by simple proton transfer (Scheme 1a) [7]. Unfortunately, the early studies on propargyl Claisen reactions do not always explicitly report the isomeric purity of the products [1,8,9]. In our hands, we found that the classical Saucy-Marbet conditions indeed promote the undesired isomerization, affording the product as a mixture of isomers 4 and 5 even with short reaction times.…”

Synthesizing Allenes Today (1982-2006)

“…Typically, the reaction conditions include heating propargyl alcohols, usually between 80-160°C, with triethyl orthoacetate in the presence of a catalytic amount of propionic acid (Scheme 9). Using this methodology, Couty and co-workers 43 were able to transform propargyl alcohols attached to oxazolidine rings into various allenyl esters. This rearrangement proved to be highly stereoselective and produced diastereomerically pure allenes in good yields, except when substituent R was a phenyl ring (Table 2).…”

Peptide Backbone Editing via Post-Translational O to C Acyl Shift

“…Attack of the carbon of enol 7 on the proximal carbonyl of the acyl-imide would yield compound 9, thus forging the key C−C bond of the rearrangement. This step is reminiscent of intramolecular Claisen rearrangements of allylic alcohols that are used to produce γ,δ-unsaturated esters stereoselectively 38 or the O to C acyl shift employed in the synthesis of benzofurans. 37 A second ring-opening step forms the diketone species 10, which tautomerizes to low-energy diketoamide 11 and enol 12.…”

“…Although pseudointramolecular decarboxylative Claisen reactions generate new C−C bonds via S to C acyl shifts during polyketide biosynthesis, in this case the carbon nucleophile is generated enzymatically and transiently while held in proximity to the electrophile. 36 Intramolecular Claisentype rearrangements and O to C acyl shifts to form C−C bonds have precedent in chemical synthesis, 37,38 but to our knowledge, there is no reported example of an acyl shift that generates a new C−C bond in a peptide backbone.…”

Diaryl Thiourea Catalysts Promote the Formation of Propargyl Enol Ethers in the Claisen Rearrangement Sequence

“…This liability does not affect the classical ketone/aldehyde Claisen rearrangement, but the β,γ-unsaturated allenyl ketone 4 can isomerize to 5 by simple proton transfer (Scheme 1a) [7]. Unfortunately, the early studies on propargyl Claisen reactions do not always explicitly report the isomeric purity of the products [1,8,9]. In our hands, we found that the classical Saucy-Marbet conditions indeed promote the undesired isomerization, affording the product as a mixture of isomers 4 and 5 even with short reaction times.…”

Synthesizing Allenes Today (1982-2006)

“…Typically, the reaction conditions include heating propargyl alcohols, usually between 80-160°C, with triethyl orthoacetate in the presence of a catalytic amount of propionic acid (Scheme 9). Using this methodology, Couty and co-workers 43 were able to transform propargyl alcohols attached to oxazolidine rings into various allenyl esters. This rearrangement proved to be highly stereoselective and produced diastereomerically pure allenes in good yields, except when substituent R was a phenyl ring (Table 2).…”

Peptide Backbone Editing via Post-Translational O to C Acyl Shift

“…Attack of the carbon of enol 7 on the proximal carbonyl of the acyl-imide would yield compound 9, thus forging the key C−C bond of the rearrangement. This step is reminiscent of intramolecular Claisen rearrangements of allylic alcohols that are used to produce γ,δ-unsaturated esters stereoselectively 38 or the O to C acyl shift employed in the synthesis of benzofurans. 37 A second ring-opening step forms the diketone species 10, which tautomerizes to low-energy diketoamide 11 and enol 12.…”

“…Although pseudointramolecular decarboxylative Claisen reactions generate new C−C bonds via S to C acyl shifts during polyketide biosynthesis, in this case the carbon nucleophile is generated enzymatically and transiently while held in proximity to the electrophile. 36 Intramolecular Claisentype rearrangements and O to C acyl shifts to form C−C bonds have precedent in chemical synthesis, 37,38 but to our knowledge, there is no reported example of an acyl shift that generates a new C−C bond in a peptide backbone.…”

Diaryl Thiourea Catalysts Promote the Formation of Propargyl Enol Ethers in the Claisen Rearrangement Sequence

“…This liability does not affect the classical ketone/aldehyde Claisen rearrangement, but the β,γ-unsaturated allenyl ketone 4 can isomerize to 5 by simple proton transfer (Scheme 1a) [7]. Unfortunately, the early studies on propargyl Claisen reactions do not always explicitly report the isomeric purity of the products [1,8,9]. In our hands, we found that the classical Saucy-Marbet conditions indeed promote the undesired isomerization, affording the product as a mixture of isomers 4 and 5 even with short reaction times.…”

Synthesizing Allenes Today (1982-2006)

“…Typically, the reaction conditions include heating propargyl alcohols, usually between 80-160°C, with triethyl orthoacetate in the presence of a catalytic amount of propionic acid (Scheme 9). Using this methodology, Couty and co-workers 43 were able to transform propargyl alcohols attached to oxazolidine rings into various allenyl esters. This rearrangement proved to be highly stereoselective and produced diastereomerically pure allenes in good yields, except when substituent R was a phenyl ring (Table 2).…”

Peptide Backbone Editing via Post-Translational O to C Acyl Shift

“…Attack of the carbon of enol 7 on the proximal carbonyl of the acyl-imide would yield compound 9, thus forging the key C−C bond of the rearrangement. This step is reminiscent of intramolecular Claisen rearrangements of allylic alcohols that are used to produce γ,δ-unsaturated esters stereoselectively 38 or the O to C acyl shift employed in the synthesis of benzofurans. 37 A second ring-opening step forms the diketone species 10, which tautomerizes to low-energy diketoamide 11 and enol 12.…”

“…Although pseudointramolecular decarboxylative Claisen reactions generate new C−C bonds via S to C acyl shifts during polyketide biosynthesis, in this case the carbon nucleophile is generated enzymatically and transiently while held in proximity to the electrophile. 36 Intramolecular Claisentype rearrangements and O to C acyl shifts to form C−C bonds have precedent in chemical synthesis, 37,38 but to our knowledge, there is no reported example of an acyl shift that generates a new C−C bond in a peptide backbone.…”