Pd‐Catalyzed Stereospecific Azide Substitution of α,β‐Unsaturated γ,δ‐Epoxy Esters with Double Inversion of Configuration

Abstract

Over recent years, much interest has been focused on the development of not only a stereoselective but also a practical methodology for the synthesis of chiral b-amino alcohols, [1] aamino acids, [2] and a,a-disubstituted amino acids [2][3][4] (including natural and unnatural congeners) in the context of medicinal chemistry. Although many synthetic approaches to these biologically important compounds have been reported, [1][2][3][4] there is still a need for a new type of methodology that allows the stereospecific synthesis of functionalized amino alcohols and amino acids that bear contiguous chiral centers. We report herein an approach that permits the highly stereoselective synthesis of a variety of amino alcohols, amino acids, and quaternary amino acids, including acyclic and cyclic congeners. This methodology involves the palladium-catalyzed stereospecific azide substitution reaction of a,b-unsaturated g,d-epoxy esters with a double inversion of configuration as the key step.In connection with our recent studies on the palladiumcatalyzed stereospecific hydroxy substitution reactions of unsaturated g,d-epoxy esters with phenylboronic acid [5] and boric acid [6] with a double inversion of configuration, we anticipated that the palladium-catalyzed azide substitution reaction of a,b-unsaturated g,d-epoxy esters with an appropriate azide reagent might occur by a similar p-allyl palladium species to afford an azide substitution product with double inversion of configuration, as shown in Scheme 1. Namely, this new method involves two consecutive S N 2 processes to afford a substitution product with double inversion of configuration in contrast with the normal S N 2 epoxideopening reactions. [7] Initially, we chose ethyl trans-4,5-epoxy-(2E)-octenoate (1) [5] as a model substrate and examined its palladiumcatalyzed reaction with TMSN 3 to confirm whether such a reaction indeed takes place. Thus, first TMSN 3 (2 equiv) then a palladium catalyst ([Pd(PPh 3 ) 4 ] (10 mol %)) was added to a solution of 1 in THF and the mixture was stirred at room temperature for 20 minutes. The reaction was then quenched with a solution of citric acid in MeOH. The azide substitution reaction of 1 with double inversion of configuration did occur at the g-position to afford a single syn azido alcohol 2 in 90 % yield of the isolated product after purification by chromatography on silica gel (Scheme 2). The configuration of the product was unambiguously determined by NOE interaction studies of its d-lactone derivative 3, which was readily derived from 2 by catalytic hydrogenation in the presence of di-tertbutyl dicarbonate (Boc 2 O) [8] followed by lactonization with PPTS in dichloroethane (Scheme 2). It should be noted that the present palladium-catalyzed azide substitution reaction took place not only in high yield but also with complete stereoselectivity, thus giving rise to the single product with a double inversion of configuration.

Synthesis of (S)-FTY720 vinylphosphonate analogues and evaluation of their potential as sphingosine kinase 1 inhibitors and activators

“…With γ,δ-epoxy-α,β-unsaturated esters, nucleophilic attack at the γ position has been shown to predominate. 20-24 As shown in Scheme 3, we employed two different azide sources. Surprisingly, as shown in Scheme 3, we found that azidolysis of 15 and 16 with NaN 3 /NH 4 Cl in EtOH 25 afforded the highly δ-selective regioisomers 17 (68% yield) and 19 (72% yield), respectively.…”

Asymmetric Formal Synthesis of (+)‐Lactacystin

“…(+)‐Lactacystin ( 1 ) can be obtained from the known key pyroglutamic ester 3 ,8u which is formed from a one‐pot reductive cyclization of azido derivative 4 by using a hydrogenation reaction in presence of palladium on activated charcoal. This crucial azide 4 can be synthesized by employing a tetrakis(triphenylphosphine)palladium(0)‐catalyzed syn ‐selective ring opening of the epoxide of α,β‐unsaturated γ,δ‐epoxy ester 5 by treatment with an azide through Miyashita's approach (with double inversion of epoxide) 10. Ester 5 can be obtained by a Sharpless asymmetric epoxidation of alcohol 6 , which in turn can be synthesized through a Baylis–Hillman reaction from commercially available isobutyraldehyde 7 and ethyl cinnamate 8 .…”

“…The stage was now ready for the deliberate stereo‐ and regioselective epoxide ring‐opening reaction. In this regard, epoxy ester 5 was treated with TMSN 3 , according to the procedure of Miyashita,10 in the presence of a catalytic amount of tetrakis(triphenylphosphine)palladium(0) in THF to afford quaternary azide 4 with a dr of 100 % (by LC–MS analysis15).…”

Azidotrimethylsilane

“…The palladium-catalyzed stereospecific azide substitution reaction of α,β-unsaturated γ,δ-epoxides with TMSA has been shown to yield azido alcohols with double inversion of configuration. 31 Reactions catalyzed by (salen)Cr(III) complexes (1) provide high enantioselectivity, e.g., opening of a variety of meso-epoxides with TMSA using catalyst 1 gave β-silyloxy or hydroxyl azides in 65-90% yields with 82-98% enantiomeric excess (eq 14). 32, 33 On the contrary, reactions using chiral titanium and aluminum complexes, while viable, were shown to provide only modest enantioselectivity.…”

“…109 Allylic azides are also obtained directly from allylic alcohols using azidotrimethylsilane and silver(I) triflate (eq 31), 110 or iron(III) chloride. 111 (31) Nitriles 112 and amides 108 are produced respectively from primary and secondary allylic alcohols using azidotrimethylsilane in the presence of DDQ, acetic acid, and copper(II) perchlorate (eqs 32 and 33). In the absence of acetic acid, the same reaction conditions afford the corresponding tetrazole (eq 34).…”