Chemoenzymatic Asymmetric Total Synthesis of (R)‐Lasiodiplodin Methyl Ether through a Sulfatase‐Based Deracemization Process

Abstract

(R)‐Lasiodiplodin methyl ether, a precursor of the antileukemic agent lasiodiplodin, was synthesized through a seven‐step linear sequence. Chirality was introduced through a sulfatase‐based deracemization process, in which a functionalized (rac)‐sec‐sulfate ester was enzymatically hydrolyzed with inversion of the stereocenter using an alkyl sulfatase. The remaining sulfate ester enantiomer was hydrolyzed with retention of configuration under acidic conditions, yielding the chiral key building block as the sole product in 93 % ee The total synthesis was completed through Negishi cross‐coupling and ring‐closing metathesis.

Enantiopure 2,9‐Dideuterodecane – Preparation and Proof of Enantiopurity

“…to furnish the title compound ( S )‐ 11 (5.51 g, 55.0 mmol, 68 %, based on 82 % purity established by 1 H NMR) after column chromatography (SiO 2 , n ‐pentane/Et 2 O 3 : 2, R f =0.26) as a colorless liquid. The spectroscopic data were in accordance with the literature and with those of the racemic compound [39] . [α] D 20 =+13° (CH 2 Cl 2 , 1.0 g L −1 ).…”

Inverting hydrolases and their use in enantioconvergent biotransformations

“…A chemoenzymatic deracemization protocol requiring medium change (Figure 2, type 3a) using Pisa1 (in the first step) and acidic hydrolysis ( p -toluenesulfonic acid, MTBE/H 2 O 98:2) in the second step, could be developed (Table 1) [16]. This protocol was successfully applied to 5-hexen-2-yl sulfate as the key step in the total asymmetric synthesis of ( R )-lasiodiplodin methyl ether, a precursor of the anti-leukemic agent lasiodiplodin [42]. An analogous one-pot two-step protocol was developed for 2-octyl sulfate [41], but its applicability was limited by the strongly acidic reaction conditions.…”

Why Leave a Job Half Done? Recent Progress in Enzymatic Deracemizations

“…[126] This enzyme was also employed to successfully deracemize hex-5-en-2-ol into the (S)-enantiomer, precursor of a lasiodiplodin derivative, which displays antileukemia activity. [127] Recently, an elegant report for the one-pot deracemization of various sec-alcohols was described in the presence of two stereocomplementary sulfatases (Scheme 22). [128] This study was possible due to the combination of the retaining and inverting features of two sulfatases by sequential or simultaneous enantioconvergent hydrolysis of the corresponding sulfate esters.…”