New Synthesis and Chirality of (−)‐4,4,4,4′,4′,4′‐Hexafluorovaline

Abstract

( -)-(R)-4,4,4,4,4,4'-Hexafluorovaline hydrochloride ((R)-5) of 98 % ee is prepared from /l,/l-bis(trifluoromcthy1)acrylic acid (= benzyl 4,4,4-trifluoro-3-(trifluoromethyl)but-2-enoate; 1) in 4 steps with ail overall yield of 9.6%. Key step is the separation of the TsOH salts of the diastereoisomers obtained by unti-Michael addition of (+)-(R)-I-phenylethylamine (2) to 1 ( + (R,R)-3). In contrast to the published (S)-chirality, the X-ray structure analysis of (R,S)-6 reveals, that (R)-chirality has to be assigned to the levorotatory (-)-4,4,4,4',4,4'-hex~fluorova-line hydrochloride.

Stereoselective Synthesis of [5‐[4,4,4,4′,4′,4′‐Hexafluoro‐N‐(2‐hydroxyethoxy)‐D‐valine]]‐ and [5‐[4,4,4,4′,4′,4′‐Hexafluoro‐N‐(2‐hydroxyethoxy)‐L‐valine]cyclosporin A

“…These were assigned to the three N-substituted C(a)-atoms adding further support to the formation of the tripeptide 11a. These results are in agreement with and represent the first example of an anti-Michael addition of NH 3 to a b,b-bis(trifluoromethyl)acrylamide moiety as in 10a (see also [7]). The formation of a second diastereoisomer was not observed.…”

“…Furthermore, it was our hope that the chiral centers in MeLeu-Ala would enhance the chiral induction in the addition step. We considered such a selectivity to be more likely than the formation of a 1 : 1 mixture of diastereoisomers observed in the reaction of (1R)-1-phenylethylamine with benzyl b,b-bis(trifluoromethyl)acrylate [7].…”

“…We described the synthesis of (À)-(4,4,4,4',4',4'-hexafluoro-d-valine )) in high enantiomer excess by means of the addition of (þ)-(R)-1-phenylethylamine (¼ (þ)-(aR)-a-methylbenzenemethanamine) to the a-position of benzyl b,b-bis(tri-fluoromethyl)acrylate (¼ benzyl 4,4,4-trifluoro-3-(trifluoromethyl)but-2-enoate) as key step [7]. Similarly, (þ)-4,4,4,4',4',4'-hexafluoro-l-valine (Val(F 6 )) was prepared in high enantiomer excess (see below).…”

“…Cyclosporin (1a) and some derivatives MeLeu-Ala-OR. In view of the rather high sensitivity of hexafluoro-d-valine benzyl ester towards Na 2 CO 3 , leading to rapid racemization [7], the use of activated esters of enantiomerically pure Val(F 6 ) was considered to give the tripeptide as a mixture of epimers. We, therefore, favored the preparation of the desired tripeptide from the Nterminal b,b-bis(trifluoromethyl)acrylamide of an ester Leu-Ala-OR 1 via addition of NH 3 or amines to the a-position of the C¼C bond of the acrylamide moiety.…”

“…-(þ)-4,4,4,4',4',4'-Hexafluoro-l-valine (Val(F 6 )). First, we prepared the hitherto unreported (þ)-4,4,4,4',4',4'-hexafluoro-l-valine (7b) via separation of the diastereoisomers obtained from the addition of (þ)-(1R)-1-phenylethylamine (5) to benzyl b,b-bis(trifluoromethyl)acrylate (4) [7] (Scheme 2). Treatment of this 1 : 1 mixture of diastereoisomeric adducts with TsOH in Et 2 O led to 6a and 6b and subsequently to the rapid precipitation of the (R,R)-adduct 6a.…”