Two Interrelated Strategies for Cephalotaxine Synthesis

Abstract

Studies of two interrelated strategies for the synthesis of members of the cephalotaxus alkaloid family have culminated in a concise route for the preparation of the parent member cephalotaxine (1). As part of efforts exploring the use of an SET-promoted photocyclization reaction of aryl-substituted silylallyliminium salts to generate the spirocyclic DE unit of the target, we noted that attempts to generate the pentacyclic amino ketone 23 by deacylation of the enol ester 20 led to production of a mixture of 23 and the macrocyclic amino enone 24. A rapid equilibrium was shown to exist between 23 and 24, favoring the latter ring-opened form. This contrasts with the behavior of desmethylcephalotaxinone (22), a key late intermediate in several earlier cephalotaxine syntheses, which is known to exist in a ring-closed form. These observations led to the design of a second generation strategy which relies on transannular cyclization of the macrocyclic amino enedione 28. In practice, the sequence following this design transforms the known iodopiperonylethanol derivative 4 to 22 in 13 steps and a 12% overall yield and, thus, corresponds to an efficient formal synthesis of cepahalotaxine.

Efficient Synthesis of Six-Membered Ring D Analogues of the Pentacyclic Alkaloid Cephalotaxine by Two Palladium-Catalyzed Reactions

“…In a similar way, 18c was obtained. [9,10] For the syntheses of 18d and 18e, the corresponding phenylpropanol derivatives were prepared from safrol applying a procedure described by Kabalka et al [11] Bromination and iodination, respectively, followed by conversion to the nosylates led to the desired substrates.…”

“…Ϫ 1 H NMR (200 MHz,CDCl 3 ): δ ϭ 3.01 (t, J ϭ 6.5 Hz, 2 H, ArCH 2 ), 4.35 (t, J ϭ 6.5 Hz, 2 H, OCH 2 ), 5.94 (s, 2 H, OCH 2 O), 6.57 (s, 1 H, 4-H), 6.86 (s,1 H,7.96 (d,J ϭ 8.8 Hz,2 H,8.31 (d,J ϭ 8.8 Hz,2 H,. (8/7) [9,10] To a stirred solution of 2-benzo [1,3]dioxol-5-ylethanol [20] (505 mg, 3.04 mmol) in CH 2 Cl 2 (30 mL) was added CF 3 COOAg (750 mg, 3.40 mmol, 1.1 equiv.) and iodine (940 mg, 3.70 mmol, 1.2 equiv.).…”

Characterization of select members of the Taxane family using Raman spectroscopy

“…) There have been several elegant studies of cephalotaxine because of its unique carbon skeleton. 23,24 Currently, there are numerous ongoing studies aimed at designing second-and third-generation drugs that will demonstrate even higher antitumor capabilities, be more water-soluble, available via oral intake and less cytotoxic. 25 -28 Raman spectroscopy is a rapid, simple and noninvasive technique that has previously been used widely for detailed structural analysis of nonbiological as well as biological compounds.…”

Synthesis of Antiproliferative Cephalotaxus Esters and Their Evaluation against Several Human Hematopoietic and Solid Tumor Cell Lines: Uncovering Differential Susceptibilities to Multidrug Resistance

“…Several elegant syntheses of 1 have been reported over the past three decades. The racemic approaches have embodied several key transformations, including Nazarov cyclization, [19] photo-stimulated S RN 1 cyclization, [20] Claisen rearrangement, [21,22] oxidative ring contraction, [23] acylnitroso Diels-Alder cycloaddition, [24,25] transannular N-conjugate addition, [26,27] intramolecular alkyne hydroamination, [28] and reductive ring expansion of tetrahydrosioquinoline intermediates. [29,30] Non-racemic routes have featured electrophilic aromatic substitution, [31] Heck arylation, [32,33] Pummerer-electrophilic aromatic substitution cascade, [34][35][36] and acid catalyzed ring expansion of cyclobutanol derivatives.…”