Hyacinthacine total synthesis

Due to their interesting structural features and promising pharmacological properties, much effort has been directed toward the stereoselective synthesis of these natural products. Moreover, as structure elucidation of hyacinthacines has relied mainly on NMR analysis, organic chemists have also focused their efforts on the total synthesis of these natural products to establish their absolute configuration. 

The first total synthesis of hyacinthacine using sugar in the chiral pool strategy was reported by Martin et al. in 2001 (Scheme 1) and concerned (+)-hyacinthacine A2 [12]. The key step was a ring-closing metathesis of the suitable allylpyrrolidine II which allowed the formation of the B-ring of the pyrrolizidine. 

SCHEME 2 Total synthesis of hyacinthacine A2 according to Martin et al. 

In 2003, Goti et al. [13] described the total synthesis of hyacinthacine A2 through cycloaddition between acrylic acid derivatives and a carbohydrate-derived nitrone 31, which was obtained firom L-xylose or D-arabinose (Scheme 3). 

SCHEME 6 Total synthesis of hyacinthacine according to Goti et al. 

In 2005, Py and colleagues reported an efficient total synthesis of hyacinthacine A2 based on a Sml2-induced nitrone umpolung [19]. This elegant... 

There has been no report so far of a synthesis of (+)-hyacinthacines Ci, C4, and C5 bearing substituents at each carlxMi of the pyrrolizidine skeleton. Therefore, their absolute configurations have yet to be determined. Yu and colleagues described recently the total synthesis of the proposed structure of ( )-hyacinthacine C5 [21] based on an original nucleophilic addition of a dithiane onto the xylose-derived nitrone 62 followed by a Cope-House cycli-zation (Scheme 13). 

In 2(X)5, Renaud and Landais reported the first enantioselective synthesis of hyacinthacine Ai and its epimer at the C-3 position using as a key step a stereocontrolled free-radical carboazidation of a chiral allylsilane XI (Scheme 15) [22]. Tamao-Fleming C—Si bond oxidation and reduction of the azide, with ring-closure achieved the total synthesis. 

The first total synthesis of (+)-hyacinthacine A3 was reported in 2002 starting from the pyrrolizidine XII which was further elaborated into the unsaturated ketone XIII (Scheme 17) [25]. 

In 2010, Izquierdo reported the total synthesis of natural (+)-hyacinthacine Ag 12, following the same strategy, but starting from the D-fructose-derived triorthogonally protected 2,5-dideoxy-2,5-imino-D-altritol (DALDP) 92 (Scheme 21) [28],... 

Total Synthesis of Hyacinthacines from Nonchiral Pool Sources... 

While most of the syntheses of hyacinthacines are based on the modification and elaboration of precursors from the chiral pool, less effort has been directed toward the construction of the pyrrolizidine skeleton using non-natural precursors. This chapter summarizes racemic as well as enantioselective total synthesis of hyacinthacines reported to date, which start from nonchiral pool sources. In this context, biocatalysis constitutes the most widely used alternative to the chiral pool approach. Enzymatic kinetic resolution using lipases but also aldolase-mediated reactions have been successfully employed to provide precursors that were later elaborated toward hyacinthacines. Synthetic chiral auxiliaries have also been used successfully in this context. 

Delair et al. [44] recently devised an elegant approach toward hyacinthacine Al 6 using their sterically hindered homochiral benzyl alcohol Stericol 150 [45] (Scheme 42). [2+2]-Cycloaddition between a dichloroketene and an enol ether flanked by the chiral auxiliary XVlll was used as one of the key steps in the total synthesis of hyacinthacine Ai 6. The CH2OH moiety at C-3... 

SCHEME 43 Total synthesis of hyacinthacine Ai according to Delair et at. 

SCHEME 44 Total synthesis of hyacinthacine Bi according to Delair et al. 

SCHEME 46 Total synthesis of hyacinthacine B3 according to Pyne et al. 

SCHEME 47 Total synthesis of (—)-7a-epi-hyacinthacine Ai according to Laschat et al. 

SCHEME 48 Total synthesis of stereomers of hyacinthacine Ai and A2 according to Clapes et al. 

SCHEME 52 Total synthesis of hyacinthacines Ae and A7 according to Donohoe et al. 

SCHEME 54 Total synthesis of hyacinthacine A2 accrading to Blechert el al. 

SCHEME 55 Total synthesis of hyacinthacine A2 accOTding to Blechrat et al. 

Total Synthesis of Unnatural Hyacinthacines Izquierdo and co-workers reported on a total asymmetric synthesis of unnatural hyacinthacines 163, potent glycosi-dase inhibitors, from D-fructose. " The compound 158 was treated with 10% Pd-C in the presence of H2 in methanol to afford the compound 161 in fully protected form. The... 

Izquieido L Plaza MT, Franco F. Polyhydroxylated pytrolizi-dines. Part 4 total asymmetric synthesis of unnatural hyacinthacines from a protected derivative of DGDP. Tetrahedron Asymm. 2004 15(9) 1465 1469. 

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