Regiochemistry‐Directed Syntheses of Polyhydroxylated Alkaloids from Chiral Aziridines

Abstract

In this study,t wo possible regiochemical pathways of aziridine ring opening, termed" regiochemistry-directed branches for 2-substituteda ziridines"a re described, providing easy access to two classes of compound from ac ommons ynthetic intermediate. Application of this synthetic strategy,w ith stereoselective dihydroxylation and reductive amination as the key steps, allowed the asymmetric synthesis of natural and unnatural polyhydroxylated alkaloids including the calyculin fragment C 33 -C 37 ,1 ,4-dideoxy-1,4-imino-l-ribitol and analogueso fh yacinthacine, swainsonine, castanospermine, and deoxynojirimycin. The initial domino reactions consisted of aziridine ring openinga nd debenzylation, and reductived oublea nnulations were established for the preparationo fb icyclic pyrrolizidine and indolizidine-represented by 8-deoxyhyacinthacine and (3R)methyl-8-deoxyswainsonine-with remarkable stereoselectivity and in high yield.[a] Dr.Scheme3.Brønsted-acid-controlled cyclization.Reagents and conditions: i) AcOH/H 2 O2:1, 60 8C, 4h;i i) Ts OH, AcOH,P d/C (20 mol %), H 2 (1 atm), MeOH, RT,12hthen TFA, RT,2h; iii)Et 3 SiH, TFA/CH 2 Cl 2 /H 2 O(75:25:5), RT, 12 h; iv) conc. HCl, MeOH, reflux, 2h;v )Amberlite 410 Cl (OH À form); vi)TFA/H 2 O( 2:1), RT,2d; vii)Pd/C (20 mol %), MeOH/PMHS (10:1), reflux,1h.

N-(1-Phenylethyl)aziridine-2-carboxylate esters in the synthesis of biologically relevant compounds

“…Aziridine aldehydes 6 are in most instances prepared from the corresponding alcohols 7 by Swern oxidation [28–33]. Procedures relying on DIBAL-H reduction of esters 5 are less frequent [34]. Although aziridine aldehydes 6 are chemically stable enough to be chromatographed on silica gel and can later be stored at −10 °C they are normally prepared before use and applied as crude materials.…”

“…An interesting structural feature of calyculins is a C33–C37 fragment γ-amino acid (2 S ,3 S ,4 S )- 159 . Its stereocontrolled synthesis involved cis -dihydroxylation of the aziridine cis -acrylate (2 R ,1' R )- 156a which led to the formation of a 91:9 mixture of diastereoisomeric diols with 160 preponderating (Scheme 41) [34]. The regioselective aziridine ring opening with methanol and catalytic hydrogenation in the presence of formalin gave the final product (2 S ,3 S ,4 S )- 159 .…”

“…Since the pyrrolidine (2 S ,3 S ,4 R )- 182 has three stereogenic centers of the same configuration as in (2 S ,3 S ,4 S )- 159 its synthesis started from the common intermediate diol 160 (Scheme 41) with the aziridine ring opening to produce the pyrrolidin-2-one (3 S ,4 S ,5 S ,1' R )- 183a (Scheme 47) [34]. The amide bond reduction and N -debenzylation gave 1,4-dideoxy-1,4-imino-ʟ-ribitol (2 S ,3 S ,4 R )- 182 which was isolated as the hydrochloride salt.…”

“…Enantioselective syntheses of 1-deoxy-ᴅ- galacto -homonojirimycin ((2 R ,3 S ,4 R ,5 S )- 211 ) as well as pyrrolizidine alkaloids were completed from the cis -acrylate (2 S ,1' S )- 156a (Scheme 54) [34]. Dihydroxylation of Weinreb amide (2 S ,1' S )- 212 gave the diol 213 with excellent diastereoselectivity (>99:1) which already had the correct configurations at C3 and C4 of the final product (3 S ,4 R ).…”

Bicyclic Aziridinium Ions in Azaheterocyclic Chemistry – Preparation and Synthetic Application of 1‐Azoniabicyclo[n.1.0]alkanes

“…Additional factors (such as steric interactions) might come in play in this particular transformation, accounting for the opposite reactivity as observed for the formation of 3‐chloropiperidine 114 (Nu=Cl). This type of ring expansion with 1‐azoniabicyclo[1.1.0]hexane as an intermediate was further utilized for the synthesis of the hydroxylated alkaloid hyacinthacin …”