A Noncarbohydrate Based Approach to Polyhydroxylated Pyrrolidizines:  Total Syntheses of the Natural Products Hyacinthacine A₁ and 1-Epiaustraline

Abstract

[reaction: see text] A flexible route to polyhydroxylated pyrrolizidine alkaloids is described, starting from commercially available N-Boc pyrrole and using a partial reduction as the key step. Tactics for varying the stereochemistry around the ring by choice of partial reduction conditions are discussed and methods for constructing the bicyclic ring system of the pyrrolizidine targets are examined. Intramolecular S(N)2 type displacement reactions were found to be an efficient way of forming the requisite bicyclo ring systems while iodine-promoted cyclizations proved unsuitable. A first synthesis of hyacinthacine A1 is described that also confirmed the structure of the natural product, and a short stereoselective synthesis of 1-epiaustraline is also discussed in detail.

Synthesis of hyacinthacine B3and purported hyacinthacine B7

“…7 The synthesis of epimers 8 and a racemic synthesis have also been reported. 9 A recent study has revealed that the proposed structure of hyacinthacine C 3 is incorrect.…”

Total Synthesis of (+)‐Alexine by Utilizing a Highly Stereoselective [3+2] Annulation Reaction of an N‐Tosyl‐α‐Amino Aldehyde and a 1,3‐Bis(silyl)propene

“…It has recently been reported that MsCl (MsCl = mesyl chloride) also effects this cyclization in other similar systems, with the reaction proceeding by a selective mesylation of the primary hydroxy group followed by ring closure. [4] However, treatment of 16 with MsCl at 0 8C only gave a complex mixture of products, perhaps indicating that, for the present case, the mesylation suffers from poor chemoselectively. Instead, the cyclization could be accomplished by converting the primary hydroxy moiety in 16 into the corresponding alkylbromide followed by cyclization to afford the pyrrolizidine 17 in good yields.…”

“…The combined organic phases were successively washed with an aqueous solution of NaHCO 3 (5 % w/w, 10 mL) and brine (10 mL) and dried over MgSO 4 . Filtration and evaporation of the solvents yielded a white solid (400 mg, 99 %), which was used in the following allylation without further purification.…”

“…[2] Noteworthy members of this important class of compounds are (+)-alexine ((+)-1), (+)-australine ((+)-2), (+)-casuarine ((+)-3), and hyacinthacine A 1 (4), which are all structurally related and differ only in relative stereochemistry (compare 1 and 2) and the level of hydroxylation (compare 3 and 4). Formally, compounds 1-4 can be derived from the monocyclic glycosidase inhibitors 2,5-dideoxy-2,5-imino-d-mannitol, DMDP (5) and 2,5-dideoxy-2,5-imino-dglucitol, DGDP (6).…”

“…Keywords: annulation · asymmetric synthesis · natural products · nitrogen heterocycles · silanes higher synthetic efficiency, focused and divergent asymmetric routes from achiral starting materials have been developed that, to date, mainly rely on stereoselective reductions of pyrroles, [4] Sharpless asymmetric amino-hydroxylations [5] and dihydroxylations, [6] ring-closing metathesis, [7] and tandem [4+2]/A C H T U N G T R E N N U N G [3+2] cycloaddition reactions of nitroalkenes. [8] Recently, a synthesis of polyhydroxylated pyrrolidine alkaloids based on asymmetric allylic alkylations of butadiene epoxide with amines was reported by Trost et al [9] The Lewis acid promoted addition of allylsilanes to aldehydes (Sakurai-Hosomi allylation) is an important method for stereoselective CÀC bond formation.…”