Chemoenzymatic Synthesis of Racemic and Enantiomerically Pure Phosphaaspartic Acid and Phosphaarginine

Abstract

Diisopropyl allyloxymethylphosphonate prepared by a one‐pot procedure was isomerized to give racemic 1‐hydroxy‐3‐butenylphosphonate with LDA by a [2,3]‐sigmatropic rearrangement. Chloroacetylation delivered an ester, which was resolved in a two‐phase system by using the lipase from Thermomyces lanuginosus. Racemic and (S)‐α‐hydroxyphosphonate 6 were converted to (±)‐ and (R)‐phosphaaspartic acid by functional‐group manipulation. (±)‐, (R)‐ and (S)‐6 were first esterified with 4‐nitrobenzenesulfonyl chloride before hydroboration to transform the double bond into a hydroxyethyl group. The hydroxyl group was manipulated to give a guanidinyl group and the 4‐nitrobenzenesulfonyloxy to give an amino group. Global deprotection of the α‐aminophosphonates yielded the desired phosphaamino acids.

Preparation of Phosphonic Acid Analogues of Proline and Proline Analogues and Their Biological Evaluation as δ1-Pyrroline-5-carboxylate Reductase Inhibitors

“…Hydroxyphosphonate (±)- 7 was resolved by lipase-catalyzed kinetic hydrolysis of the chloroacetic ester and delivered the enantiomers with ee >97%. 18 The enantiomer ( S )- 7 was transformed into ( R )- 1 , ( R )- 2 , and ( R )- 6 and the enantiomer ( R )- 7 into phosphaproline ( S )- 1 by functional group manipulation. Furthermore, (±)- and ( S )- 7 were already converted to phosphaaspartic acids via azides (±)- and ( S )- 8 prepared by Mitsunobu reaction.…”

“…Furthermore, (±)- and ( S )- 7 were already converted to phosphaaspartic acids via azides (±)- and ( S )- 8 prepared by Mitsunobu reaction. 18 Evans and Weber 19 and later others 20,21 described the formation of pyrrolidines from homoallyl azides upon hydroboration with dicyclohexylborane. As we hoped that azides 8 prepared by the Mitsunobu reaction 18,22 would undergo the same cylization, we reacted them with dicyclohexylborane.…”

“…14 The synthesis of analogues 6 was accomplished starting from 4-hydroxybutylphosphonates 16 , derived from nosylates (±)- and ( S )- 11 (ee 85%) by hydroboration with H 3 B × tetrahydrofuran (THF), followed by oxidative cleavage of the B–C bond with H 2 O 2 /NaHCO 3 (Scheme 3). 18 The Mitsunobu reaction and the ensuing cyclization induced by hydrazine hydrate were similarly performed for the transformation of 12 into 15 in Scheme 2 and delivered 1,2-oxazinanes (±)- and ( R )- 18 , cyclic oxime ethers. 27 However, this time the hydroxylamine derivatives, the two 1,2-oxazinan-3-ylphosphonates (±)- and ( R )- 18 , were first isolated as homogeneous compounds by flash column chromatography, fully characterized and finally deprotected.…”

“…The resulting suspension of dicyclohexylborane 23 was again cooled at 0 °C. Racemic 1-azido-3-butenylphosphonate (±)- 8 18 (475 mg, 1.82 mmol) dissolved in dry DME (1 mL) was added. After stirring for 1 h at 0 °C and 2 h at room temperature, the reaction was quenched with concd HCl (2 mL) and water (5 mL).…”

“…Fractions containing the product (TLC: i PrOH/H 2 O/NH 3 (25%), 6:3:1, R f = 0.25) were pooled and concentrated under reduced pressure to furnish racemic phosphaproline [(±)- 1 ] (179 mg, 65%) as colorless crystals; mp 270–273 °C (H 2 O/EtOH). Similarly, ( R )-(−)-1-azido-3-butenylphosphonate ( R )- 8 18 {533 mg, 2.04 mmol; [α] D 20 −31.3 ( c 1.2, acetone)} was converted to ( R )-phosphaproline [( R )- 1 ] (191 mg, 62%); [α] D 22 −46.6 ( c 0.5, 1 M NaOH) {lit. : 14 [α] D 21 −49.1 ( c 1.1, 1 M NaOH); lit.…”