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Asymmetric Synthesis of 3‐Oxacarbacyclin and 3‐Oxaisocarbacyclin by a Common Enantioselective Deprotonation Based Route
Author(s) -
Vaulont Irene,
Gais HansJoachim,
Reuter Norbert,
Schmitz Elmar,
Ossenkamp Rainer K. L.
Publication year - 1998
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/(sici)1099-0690(199805)1998:5<805::aid-ejoc805>3.0.co;2-r
Subject(s) - chemistry , enantioselective synthesis , ketone , deprotonation , lithium amide , allylic rearrangement , aldehyde , enol , silyl enol ether , medicinal chemistry , amide , enantiomeric excess , organic chemistry , stereochemistry , catalysis , ion
Asymmetric total syntheses of 3‐oxacarbacyclin ( 4 ) and 3‐oxaisocarbacyclin ( 5 ) have been achieved by a new and common route. The key step of these syntheses is an enantioselective deprotonation of the prochiral ketone 25 with lithium ( R , R )‐bis(phenylethyl)amide ( 12 ) in the presence of LiCl. Treatment of the thus formed enolate 26 with ClSiEt 3 gave the enol ether 27 of 92% ee in 94% yield. Deprotonation of the analogous prochiral ketone 9 with 12 in the presence of LiCl followed by reaction of the enolate 13 with ClSiEt 3 led to isolation of the silyl enol ether 8b of 92% ee in 95% yield. A study of the deprotonation of 9 with the chiral lithium amides 14−19 showed that 12 in combination with LiCl is the optimal base in terms of enantioselectivity and accessibility. The ω‐side chain in 4 and 5 was established by a Mukaiyama reaction of 27 with the unsaturated aldehyde 28 , leading to ketone 39 of 90% de , in combination with a stereoselective Pd‐catalyzed allylic rearrangement of acetate 47 to the isomeric acetate 48 and a Mitsunobu reaction of the allylic alcohol 49 . The key step in the construction of the α‐side chain in 4 is a Horner‐Wadsworth‐Emmons reaction of ketone 7c with the 8‐phenylnormenthol‐containing phosphonoacetate 56 which gave ester 60 of 90% de . Ester 60 was obtained diastereomerically pure by chromatography in 72% yield from 7c . Reduction of 60 furnished the allylic alcohol 62 which was converted to 4 in a standard fashion. It is at the stage of the α,β‐unsaturated ester 60 where divergence into synthesis of 5 was made. Selective isomerization of 60 to the β,γ‐unsaturated ester 66 of 97% ie in 91% yield was accomplished by deprotonation of 60 with 12 to enolate 65 and its subsequent regioselective protonation. By a similar reaction sequence the isomeric α,β‐unsaturated ester 61 was converted to the ß,γ‐unsaturated ester 69 of 97% ie in 88% yield. Reduction of 66 afforded the homoallylic alcohol 71 which was converted to 5 in a standard fashion.