Metathesis access to monocyclic iminocyclitol-based therapeutic agents

Abstract

By focusing on recent developments on natural and non-natural azasugars (iminocyclitols), this review bolsters the case for the role of olefin metathesis reactions (RCM, CM) as key transformations in the multistep syntheses of pyrrolidine-, piperidine- and azepane-based iminocyclitols, as important therapeutic agents against a range of common diseases and as tools for studying metabolic disorders. Considerable improvements brought about by introduction of one or more metathesis steps are outlined, with emphasis on the exquisite steric control and atom-economical outcome of the overall process. The comparative performance of several established metathesis catalysts is also highlighted.

Keywords: Ru-alkylidene catalysts; azasugars; iminocyclitols; natural products; olefin metathesis.

Scheme 1

Well-defined Mo- and Ru-alkylidene metathesis catalysts.

Scheme 2

Representative pyrrolidine-based iminocyclitols.

Scheme 3

Synthesis of (±)-(2R*,3R*,4S*)-2-hydroxymethylpyrrolidin-3,4-diol (18), (±)-2-hydroxymethylpyrrolidin-3-ol (19) and (±)-(2R*,3R*,4R*)-2-hydroxymethylpyrrolidin-3,4-diol (20).

Scheme 4

Synthesis of enantiopure iminocyclitol (−)-(2S,3R,4S,5S)-2,5-dihydroxymethylpyrrolidin-3,4-diol (23).

Scheme 5

Synthesis of 1,4-dideoxy-1,4-imino-D-allitol (29) and formal synthesis of (2S,3R,4S)-3,4-dihydroxyproline (30).

Scheme 6

Synthesis of iminocyclitols 35 and 36.

Scheme 7

Total synthesis of iminocyclitols 40 and 44.

Scheme 8

Synthesis of 2,5-dideoxy-2,5-imino-D-mannitol [(+)-DMDP] (49) and (−)-bulgecinine (50).

Scheme 9

Synthesis of (+)-broussonetine G (53).

Scheme 10

Structural features of broussonetines 54.

Scheme 11

Synthesis of broussonetines by cross-metathesis.

Scheme 12

Representative piperidine-based iminocyclitols.

Scheme 13

Total synthesis of 1-deoxynojirimycin (62) and 1-deoxyaltronojirimycin (65).

Scheme 14

Synthesis by RCM of 1-deoxymannonojirimycin (63) and 1-deoxyallonojirimycin (66).

Scheme 15

Total synthesis of (+)-1-deoxynojirimycin (62).

Scheme 16

Synthesis of ent-1,6-dideoxynojirimycin (83) and 5-amino-1,5,6-trideoxyaltrose (84).

Scheme 17

Synthesis of 1-deoxygalactonojirimycin (64), 1-deoxygulonojirimycin (91) and 1-deoxyidonojirimycin (93) [Step c: m-CPBA, NaH₂PO₄, CH₂Cl₂, 0 °C to r.t. Step d: 2,2-dimethoxypropane, PPTS, acetone, r.t. Step e: H₂SO₄, 1,4-dioxane, H₂O, reflux. Step f: K₂OsO₄·2H₂O, NMO, acetone, H₂O, r.t. Step g: HCl, MeOH. Step h: Oxone, CF₃COCH₃, NaHCO₃, aqueous Na₂·EDTA, CH₃CN, 0 °C. Step i: 0.3 M KOH, 1,4-dioxane, H₂O, reflux].

Scheme 18

Synthesis of L-1-deoxyaltronojirimycin (96).

Scheme 19

Synthesis of 1-deoxymannonojirimycin (63) and 1-deoxyaltronojirimycin (65).

Scheme 20

Synthesis of 5-des(hydroxymethyl)-1-deoxymannonojirimycin (111) and 5-des(hydroxymethyl)-1-deoxynojirimycin (114).

Scheme 21

Synthesis of D-1-deoxygulonojirimycin (91) and L-1-deoxyallonojirimycin (122).

Scheme 22

Total synthesis of fagomine (129), 3-epi-fagomine (126) and 3,4-di-epi-fagomine (130).

Scheme 23

Total synthesis of (+)-adenophorine (135).

Scheme 24

Total synthesis of (+)-5-deoxyadenophorine (138) and analogues 142–145.

Scheme 25

Synthesis by RCM of 1,6-dideoxy-1,6-iminoheptitols 148 and 149.

Scheme 26

Synthesis by RCM of oxazolidinyl azacycles 152 and 154.

Scheme 27

Representative azepane-based iminocyclitols.

Scheme 28

Synthesis of hydroxymethyl-1-(4-methylphenylsulfonyl)azepane 3,4,5-triol (169).

Scheme 29

Synthesis by RCM of tetrahydropyridin-3-ol 171 and tetrahydroazepin-3-ol 173.