Isidoro Izquierdo

Polyhydroxylated pyrrolizidines. Part 2: The first total synthesis of (+)-hyacinthacine A3☆

Abstract The first total synthesis for the (+)-hyacinthacine A 3 1 in a highly stereocontrolled manner, is reported herein. An appropriately protected polyhydroxylated pyrrolidine, such as (2 R ,3 R ,4 R ,5 R )-3,4-dibenzyloxy- N - tert -butyloxycarbonyl-2′- O - tert -butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine 2 , (DMDP protected), readily available from d -fructose, was chosen as the homochiral starting material. The absolute configuration of natural 1 is also unambiguously established.

Polyhydroxylated pyrrolizidines. Part I: Short and highly stereocontrolled syntheses of hyacinthacines

Abstract Two short and highly stereocontrolled syntheses for 7a- epi -hyacinthacine A 2 (7-deoxyalexine) 3 and 5,7a-di epi -hyacinthacine A 3 4 are, respectively, reported herein. An appropriately protected polyhydroxypyrrolidine, (2 R ,3 R ,4 R ,5 S )-3,4-dibenzyloxy- N -benzyloxycarbonyl-2′- O - tert- butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine 5 , readily available from d -fructose, was chosen as the chiral starting material.

Polyhydroxylated pyrrolidines. Part II: Highly stereoselective synthesis of partially protected DMDP derivatives from d-fructose

Abstract The readily available 3,4-di- O -benzyl-1,2- O -isopropylidene-β- d -fructopyranose 2 was straightforwardly transformed into 5-azido-3,4-di- O -benzyl-5-deoxy-1,2- O -isopropylide ne-β- d -fructopyranose 4 , after treatment under modified Gareggs conditions followed by reaction of the resulting 3,4-di- O -benzyl-5-deoxy-5-iodo-1,2- O -isopropylidene-α- l -sorbopyranose 3 with sodium azide in DMF. Cleavage of the acetonide of 4 to afford 6 followed by regioselective O - tert -butyldiphenylsilylation at C(1)OH afforded 7 . Hydrogenation of 7 proceeded with high stereoselectivity yielding 3,4-di- O -benzyl-1- O - tert -butyldiphenylsilyl-2,5-dideoxy-2,5-imino- d -mannitol 1 , confirmed by its O -desilylation to 8 . Compound 1 was subjected to different N -protection reactions to afford the corresponding N -allyl ( 1a ), N -benzyl ( 1b ), and N - tert -butyloxycarbonyl ( 1c ) derivatives.

CHIRAL BUILDING-BLOCKS BY CHEMOENZYMATIC DESYMMETRIZATION OF 2-ETHYL-1,3-PROPANEDIOL FOR THE PREPARATION OF BIOLOGICALLY ACTIVE NATURAL PRODUCTS

Abstract 2-Ethyl-1,3-propanediol 1 and its related di-O-acetate 2 were desymmetrized by partial chemoenzymatic acetylation and deacetylation, by Pseudomonas fluorescens lipase (Amano P.; PFL), to (R)-1-O-acetyl-2-ethyl-1,3-propanediol 3. On treatment of 3 with I2/Ph3P/imidazole the related (S)-1-O-acetyl-2-ethyl-3-iodopropanol 4 was obtained and transformed into the corresponding triphenylphosphonium salt 5. Reaction of [(S)-3-acetoxy-2-ethylpropylidene]triphenylphosphorane 6, prepared from 5, with 2,3:4,5-di-O-isopropylidene-β- d -arabino-hexos-2-ulopyranose 7 gave (Z)-3-C-acetoxymethyl-1,2,3,4,5-pentadeoxy-6,7:8,9-di-O-isopropylidene-β- d -manno-dec-4-ene-6-ulo-6,10-pyranose 8 which was hydrogenated to 9 and subsequently deacylated to 10. Treatment of 10 with Me2CO/H+ caused a rearrangement to (3R,4R,5S,6R,9R)-9-ethyl-5-hydroxy-3,4-isopropylidenedioxy-1,7-dioxaspiro[5.5]undecane 11, which closely matched the skeleton of the talaromycins.

An efficient and highly stereoselective synthesis of nucleoside derivatives from furanoid 1,2=diols

Abstract Reaction between suitably protected furanoid glycals 1b–4b , readily obtained from furanoid 1,2-diols ( 1a–4a ), and different silylated pyrimidine bases, gave the corresponding 3′,5′- and 3′,5′,6′- O -protected 2′-deoxy-2′-β- d - xylo -pentofuranosyl 5–10 and β- d - gluco -hexofuranosyl 11 nucleosides, respectively. Compound 5 has been transformed into its 2′-deoxy 12 and 2′,3′- anhydro 14 derivatives. The high stereoselectivity of the reaction is discussed.

4-Octulose Derivatives as Key Intermediates in a New and Short Synthesis of Polyhydroxyindolizidines

Reaction of 3 with (cyanomethylene)triphenylphosphorane in refluxing dichloromethane or methanol gave mixtures of 4a and 4b in ratios of about 3:1 and 1:3, respectively. The same reaction performed with the furanoid isomer 5 afforded 6a and 6b in (E)/(Z) ratios of approximately 9:1 and 1:2, respectively. Catalytic hydrogenation of the α,β-unsaturated nitriles 4 and 6 with either 10% Pd-C or Raney nickel afforded the saturated nitriles 7 and 9, or the 1-amino-1,2,3-trideoxy-4-octulose derivatives 8 and 10, respectively. In an attempt to transform 6a into the appropriate polyhydroxylated branched-chain pyrrolidine 15, (5R,8S,9R,10S)-8,9,10-trihydroxy-1-aza-6-oxaspiro[4.5]decane, which was identified as its peracylated derivative 16, was isolated. Following an alternative synthetic strategy, partial hydrolysis of compound 9 afforded 17 which was regioselectively transformed into the corresponding derivative 22 via its 8-O-p-toluenesulfonyl derivative 18. Removal of the 4,5-O-isopropylidene group in 22 with aqueous trifluroacetic acid gave the free octulose 23, which was hydrogenated in the presence of 10% Pd-C, to afford the expected (6S,7R,8R,8aR)-6,7,8-trihydroxyindolizidine (1-deoxycasta-nospermine, 11).

A NEW AND HIGHLY STEREOSELECTIVE SYNTHESIS OF POLYHYDROXYINDOLIZIDINES FROM 4-OCTULOSE DERIVATIVES

Abstract (1 S ,2 S ,6 R ,7 R ,8 R ,8a R )-1,2,6,7,8-Pentahydroxyindolizidine 12 and (1 R ,6 R ,7 R ,8 R ,8a R )-1,6,7,8-tetrahydroxyindolizidine (1,6-diepicastanospermine, 24 ) have been stereoselectively synthesized from the important key intermediates l,4-dideoxy-1,4-imino- d - erythro - l - altro -octitol 7 and 1,2,4-trideoxy-1,4-imino- d - glycero - d - talo -octitol 20 in three steps. Compounds 7 and 20 were readily obtained from 2,3:4,5:6,7-tri- O -isopropylidene-β- d - glycero - d - galacto -oct-4-ulo-4,8-pyranose 1 and 2-deoxy-4,5:6,7-di- O -isopropylidene-β- d - manno -oct-4-ulo-4,8-pyranose 13 in four steps, respectively.

Polyhydroxylated Pyrrolizidines. Part 7. Stereoselective Synthesis of Unnatural Analogs of (+)‐Casuarine from Partially Protected DGDP

A new synthetic approach to analogs of (+)‐casuarine (2a and 2b), a natural pentahydroxylated pyrrolizidinic alkaloid in a highly stereocontrolled manner, is reported herein. An orthogonally protected polyhydroxylated pyrrolidine, such as (2S,3R,4R,5R)‐3,4‐dibenzyloxy‐2′‐O‐tert‐butyldiphenylsilyl‐2,5‐bis(hydroxymethyl)pyrrolidine [3, protected DGDP (2,5‐dideoxy‐2,5‐imino‐d‐glucitol)], easily available from d‐fructose, was chosen as the source of chirality and functionalization. †For Part 6 of the series, see Ref. 1.

Highly stereocontrolled alkylation of protected 'diacetone hexulose aldehydes'

Abstract Claisen–Schmidt aldol condensation (with acetone, catalysed by l - and d -proline), Knoevenagel reaction with acetoacetic acid and the modified Reformatsky reaction with bromoacetone of the ‘diacetone hexulose aldehydes’ 2 and 7 gave the corresponding β-hydroxyketones 3–4 and 8–9 as well as the (E)-α,β-enones 5 and 10, respectively. The highest chemo- and stereoselectivities were obtained with the Knoevenagel procedure using l -proline as the catalyst.

Lipase-mediated partial resolution of 1,2-diol and 2-alkanol derivatives: towards chiral building-blocks for pheromone synthesis

Abstract 1,2-Propanediol 5 , 1-chloro-2-propanol 8 and its related 2- O -acetate 9 were partially resolved by chemoenzymatic acetylation and deacetylation, in the presence of Pseudomonas fluorescens lipase (Amano P.; PFL), to ( R )-(−)-1-acetoxy-2-propanol 6 , ( R )-(+)-2-acetoxy-1-chloropropane 9 and ( R )-(−)-1-chloro-2-propanol 8 , respectively. On the other hand, treatment of (2 RS )- 2 with vinyl acetate in ether and Chirazyme ® L-2 gave 2- O -acetyl-1,3,4-trideoxy-5,6:7,8-di- O -isopropylidene-β- d - manno -non-5-ulo-5,9-pyranose 1 and 1,3,4-trideoxy-5,6:7,8-di- O -isopropylidene-β- d - gluco -non-5-ulo-5,9-pyranose 11 , respectively. Compound 10 was subsequently deacylated to 12 . Both alcohols 11 and 12 were treated with Me 2 CO/H + to cause their rearrangement to (2 S ,5 R ,8 R ,9 R ,10 S )-10-hydroxy-8,9-isopropylidenedioxy-2-methyl-1,6-dioxaspiro[4.5]decane 3 and its (2 R)- epimer 4 , which closely matched the skeleton of the odour bouquet minor components of Paravespula vulgaris (L.).