Expeditious Racemic and Enantiodivergent Synthesis of 1‐Deoxymannojirimycin and 1,4‐Dideoxymannojirimycin

Abstract

The racemic and enantiodivergent syntheses of 1‐deoxymannojirimycin (DMJ) and 1,4‐dideoxymannojirimycin have been realized through key enamide ester intermediates obtained by converting cis‐4,5‐dihydroxylated δ‐valerolactam derivatives into the corresponding enol phosphates and subjecting them to Pd‐catalyzed methoxycarbonylation. Further elaborations of these intermediates included stereocontrolled catalytic hydrogenation, for the synthesis of racemic 1,4‐dideoxymannojirimycin, and hydroboration/oxidation, for the synthesis of DMJ. Enantiodivergency was attained by optical resolution before exhaustive functional group deprotection, through the formation of diastereomeric camphanic esters. As the key racemic intermediate esters were easily prepared in a few steps on a large scale, and the final chromatographic separation of the camphanic esters was straightforward, this approach represents a convenient way to obtain both enantiomers of DMJ for medicinal chemistry studies.

Complementary and Stereodivergent Approaches to the Synthesis of 5‐Hydroxy‐ and 4,5‐Dihydroxypipecolic Acids from Enantiopure Hydroxylated Lactams

“…This methodology requires enantiopure hydroxylated‐lactams as starting materials or, as an alternative, a racemate resolution at any stage of the synthesis. We used both approaches for the synthesis of 4‐hydroxypipecolic acids27 and various piperidine alkaloids, such as glycosidase inhibitors fagomine27b,28 and 1‐deoxymannojirimycin 29…”

“…For the synthesis of 4,5‐ cis ‐4,5‐dihydroxypipecolic acid 10 and 11 , cis ‐4,5‐dihydroxylated lactam 15 (Figure 3) is required. Despite being a simple compound (and a potentially useful polyfunctionalized chiral synthon), the isolated enantiomers of cis isomer 15 are unknown, and only the synthesis of the racemic compound has been reported 29. For the synthesis of 4,5‐ trans pipecolic acid 9 , we envisaged a complementary route starting from enantiopure 5‐hydroxy δ‐valerolactam 16 , which was synthesised by Herdeis from glutamic acid,30 and in which the required 4‐OH group could be installed at a later stage of the process.…”

“…With lactam (4 S ,5 R )‐ 15 in hand, we proceeded with the synthesis of 2,4‐ cis ‐4,5‐ cis ‐4,5‐dihydroxypipecolic acid ( 10 ; Scheme ) by converting the lactam into enantiopure enecarbamate ester 25 according to the procedure we reported for the corresponding racemic compound 29. Thus protection of (4 S ,5 R )‐ 15 as acetonide (–)‐ 22 (92 %), and then N ‐protection as carbamate (–)‐ 23 (84 %) set the stage for the quantitative generation of corresponding enol phosphate 24 by treatment of the lactam with potassium bis(trimethylsilyl)amide (KHMDS) at –78 °C in tetrahydrofuran (THF) followed by the addition of diphenylchlorophosphate.…”

“…(4 S ,5 R )‐4,5‐Dihydroxypiperidin‐2‐one [(–)‐15]: Azide 21 (840 mg, 5.35 mmol) was dissolved in anhydrous methanol (35 mL) under a nitrogen atmosphere. Then, 10 % Pd/C catalyst (3 mol‐%) was added and the reaction flask flushed first with N 2 and then with hydrogen and left under a hydrogen atmosphere (balloon) at room temperature for 24 h. The suspension was filtered through a Celite pad and the filtrate concentrated under vacuum, affording pure lactam 15 as a white solid (638 mg, 91 %) with spectroscopic data identical to those of the racemic compound 29. M.p.…”

From synthetic control to natural products: a focus on N‐heterocycles

“…54 The stereoselective synthesis of 1-deoxymannojirimycin (DMJ) has been realized through the key enamide ester intermediate 41 obtained by converting cis 4,5-dihydroxylated -valerolactam into the corresponding vinyl phosphates and subjecting it to Pd-catalysed methoxycarbonylation as described above. 69 Further elaborations of this intermediate included its conversion into more rigid, cyclic urethane 57; stereo-controlled hydroboration/oxidation of the latter followed by exhaustive hydrolysis gave target DMJ (−)-60. Enantiodivergency was attained by optical resolution of racemic 58 (Scheme 9) before exhaustive functional group deprotection, through the formation of diastereomeric camphanic esters.…”