Efficient Total Synthesis of Pulchellalactam, a CD45 Protein Tyrosine Phosphatase Inhibitor

Abstract

A new approach to a CD45 protein tyrosine phosphatase inhibitor, pulchellalactam, is described. The key step of the sequence involves addition and elimination of an enolic lactam in a single step and 70% yield, employing an organocuprate reagent. The resulting alpha,beta-unsaturated lactam could be condensed with isobutyraldehyde to produce Z-pulchellalactam or converted into siloxypyrrole, which was subjected to the BF(3) x Et(2)O-promoted coupling reaction with isobutyraldehyde to afford E-pulchellalactam after E1-cB elimination and TFA deprotection. This first total synthesis afforded Z-pulchellalactam in six steps and 32% overall yield from Boc-glycine. The same sequence of reactions could also be applied to the liquid- or solid-phase synthesis of trifunctionalized pulchellalactam derivatives.

The Vinylogous Aldol and Related Addition Reactions: Ten Years of Progress

“…The reactions proceeded with good Z-selectivity, and several candidates were evaluated for their antithrombotic activity in a rat arterial thrombosis model. Adaptation of this dual VAR/elimination procedure to a soluble polymer-supported execution was described by Li et al, 162 targeting Z-pulchellalactam (395), a CD45 protein tyrosine phosphatase inhibitor. Indeed, when pegylated lactam 394 was reacted with isobutyraldehyde (67) in the presence of sodium hydride in THF, Z-pulchellalactam (395) was directly accessed in high purity via vinylogous addition and formal E1cB dehydration (Scheme 70, eq 2).…”

Tetramic acids and derivatives by telluride-triggered Dieckmann cyclizations

“…The procedure reported previously for an N-Boc tetramic acid was followed. 32 Diisopropyl ethylamine (0.5 mL, 2.9 mmol) and freshly recrystallized ptoluenesulfonyl chloride (0.27 g, 1.45 mmol) was added to a stirred solution of tetramic acid 6e (0.40 g, 1.45 mmol) in dry CH 2 Cl 2 (5 mL). The reaction mixture was stirred at room temperature (16 h) and quenched with saturated aqueous ammonium chloride (3 x 5 mL), extracted with methylene chloride (3x10 mL), dried (anhydrous Na 2 SO 4 ), and concentrated to near dryness.…”

CC Bond‐Forming Reactions

“…Particularly intriguing, in a system presented by Li et al [383], is the possibility of generating diverse reactive species sequentially under controlled conditions, allowing in principle a dramatic gain in molecular complexity by performing only few steps. Methods like this are needed when hypothetical MCRs are not possible.…”