Hyacinthacines, synthesis

Dipolarophiles D14. The 1,3-dipolar cycloaddition of nitrones to dimethyl maleate and dimethyl fumarate is widely used in the synthesis of polyhydroxy alkaloid derivatives of dihydroindolizidinone (81), pyrrolizidine (119), (—)-codonopsinine, and (+ )-hyacinthacines Ai and A2 (312). In cases of unstable nitrones, syntheses of cycloadducts are performed in situ (81). 

For the described approach, it is important to note that aldolases of different origin were tested and that, in contrast to L-rhamnulose-1-phosphate aldolase (RhuA), the D-fructose-1,6-biphosphate aldolase from rabbit muscle and L-fucu-lose-1-phosphate aldolase from E. coli were not active for DHAP/(R)-N- and (S)-iV-Cbz-prolinal condensation. Since RhuA accepts both, (S)-N- and (R)-N-Cbz prolinals, the chemo-enzymatic synthesis of both, hyacinthacines A and A2 isomers could be achieved. In conclusion, the origin and the particular enzyme itself... 

Py used a nitrone-alkene coupling in a short, asymmetric synthesis of (+ )-hyacinthacine A2 (Scheme 5.43).74 The key carbon-carbon bond-forming step in their approach involved the highly diastereoselective reductive coupling of the L-xylose-derived cyclic nitrone 66 to ethyl acrylate.74... 

Synthesis from o-fructose Syntheses of 7a-cp/-hyacinthacine A2 (7-deoxya-lexine, 139) and 5,7a-di-e/7/-hyacinthacine A3 (143) from D-fmctose have been reported (Scheme 10). Mesylation of 3-(9-benzoyl-4-(9-benzyl-l,2-0-isopropylidene-p-D-fructopyranose (128) followed by azidolysis gave 5-azido-3-(9-benzoyl-4-0-benzyl-... 

For the synthesis of 5,7a-di-cp/-hyacinthacine A3 (143), compound 133 was treated with l-triphenylphosphoranylidene-2-propanone to give 140, which underwent catalytic hydrogenation to afford 142 via the intermediate 141. Finally, removal of the protecting groups in 142 gave 143 (Scheme 1 i).256.2S7... 

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. 

Amino acids, which were also used as chiral natural starting materials for the synthesis of hyacinthacines, will also be discussed. Finally, a third part will cover the use of tartrate derivatives as precursors of hyacinthacines. 

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). 

A few years later, the same authors reported a second synthesis of hyacinthacine A2 starting from the same sugar-derived nitrone 31 [14]. This approach was very close to the one previously described by Martin et al. [12], the key step being based on the RCM of the same diolefin intermediate 29 (Scheme 5). The nucleophilic addition of vinylmagnesium bromide onto 31 led diastereoselectively to hydroxylamine 36, proceeding by the less... 

Recently, using the same 1,3-dipolar cycloaddition, Goti et al. reported the access to hyacinthacine Aj starting from commercially available 2,3,5-tri-O-benzyl-D-ribofuranose-derived nitrone 38 [15]. This approach relying exactly on the same synthetic pathway (Scheme 6), this synthesis will not be detailed herein. Hyacinthacine Aj was finally obtained in six steps from nitrone 38 and 17.8% overall yield. 

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... 

Other synthetic approaches to hyacinthacine skeleton using the xylose-derived nitrone were reported. In 2010, the synthesis of (—)-hyacinthacine A3 66 (the enantiomer of the naturally occurring (+)-hyacinthacine A3) was described by Hu et al. [20]. This member of the hyacinthacines family includes a chiral center at the C-5 position of the B-ring (Scheme 12). 

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],... 

In 2007, Izquierdo and colleagues reported the synthesis of hyacinthacines Ai and Ag starting from the same DALDP derivative. However, this work wiU not be commented here as this chapter was retracted in 2009 [30]. 

Concomitantly with Izquierdo s successive studies, Cao et al. [31] reported in 2008 a synthesis of hyacinthacine Ag, which starts from the o-glucose-deiived pyrrolidine 95. This strategy which is similar to the one developed by Izquierdo will not be discussed in details herein (Scheme 23). 

Recently, an elegant synthesis of hyacinthacine A2 was proposed by Fox and colleagues in which the pyrrolizidine skeleton was elaborated through a trans-annular hydroamination of a 5-aza-trans-cyclooctene such as XIV, in mm obtained via a diastereoselective photoisomerization of a c/s-octene XV (Scheme 24) [32]. The enantiopure cyclooctene was obtained from the chiral ketone 96, prepared via a three steps sequence from sucrose disaccharide [33]. 

In 2009, the same group reported the synthesis of hyacinthacines C2, C3, and their C-5 epimers, starting from a similar Af-Boc-lactam 107 (Scheme 30) [37]. This compound was submitted to a series of reaction to install the formyl functional group of 108 which would then be subjected to aUylation and subsequent dihydroxylation to provide the polyols 109 and 110. Natural pyrro-lizidine ring systems of 21, 22, and their nonnatural C-5 epimers could then be elaborated by cyclization of the polyol intermediates. 

In 2009, Marco et al. reported the synthesis of hyacinthacine A2 7 and A3 8 and unnatural isomer 5- p/-hyacinthacine A3 118 from the intermediate 119, issued from the (/ )-Gamer s aldehyde, a derivative of L-serine [38]. Alcohol 119, obtained in six steps from Gamer s aldehyde [39], was first protected as a TES ether, then submitted to an oxidative cleavage of the terminal alkene to provide the alcohol 121 after subsequent reducticm step. Desilylation followed by mesylation afforded the compound 123, which underwent a one-pot acidic cleavage of the Boc and aminoketal protective groups. Standard hydrogenoly-sis of benzyl ethers and cyclization under basic conditions achieved this linear but efficient synthesis of hyacinthacine A2 (14 steps from Gamer s aldehyde, 22% overall yield) (Scheme 34). 

The use of tartaric acid derivatives in the synthesis of hyacinthacines will conclude this part dealing with pool chiral derivative precursors. 

The synthesis of hyacinthacine A3 was devised following the same approach (Scheme 40). The imide 139 was treated with a Grignard reagent, which was... 

Total Synthesis of Hyacinthacines from Nonchiral Pool Sources... 

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