Exploring symmetry-based logic for a synthesis of palau'amine

Abstract

A synthetic approach to palau'amine is described that exploits veiled symmetry in the structure. Bis-alkylidenes i have been prepared and found susceptible to halogenative desymmetrization using t-BuOCl. This oxidation forms the imbedded spirocyclopentane motif observed in the natural product. A host of atypical reactions and processes developed during these studies are discussed, as are plans for completing total syntheses of this compound class.

Scheme 1

Reaction conditions: a) 1 equiv NH₂NH₂, 10 equiv AcOH, MeOH / H₂O, rt to 62 °C (>95%). b) 1 equiv KHMDS; 1.2 equiv allyl bromide, THF, -35 °C (90%). c) 1.5 equiv LiOH, 2:1:1 THF / MeOH / H₂O; aq citric acid (>95%). d) 1.1 equiv 9, 1 equiv TBTU, 3 equiv (i-Pr)₂NEt, DMF, then concentrate in vacuo at 70 °C (72%). TBTU = 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate

Scheme 2

Reaction conditions: a) 1.05 equiv KHMDS, degassed THF, -78 °C, 30 min; add 1.1 equiv oxidant and stir for 1h at -78 °C. b) 0.02M 13 in degassed toluene, 95 °C, 1h (81%). c) hv (Rayonet - 254 nm bulb set), 0.01 M in deoxygenated phH, 2 h (36% 12 + 20% 14a/b) d) 12 isolated as ∼1:1 mixture of diastereomers. e) only dl form observed (ref 18). f) 14 isolated as an equal mixture of meso and racemic C₂ forms.

Scheme 3

Reaction conditions: a) KHMDS (1.1 equiv), deoxygenated THF, -78 °C, 30 min; then [R-Cp]₂TiCl₂ (1.15 equiv), -78 °C, 3h; then Cu(OTf)₂ (1.6 equiv), 3.5h, -78 °C. b) 20% yield of 12 and 10% recovered 11 also isolated in this experiment.

Scheme 4

Reaction conditions: a) 0.95 equiv 17, pyr, CH₃CN, rt (94%). b) LiOH, 1:1 THF / H₂O, 0 °C (95% - recrystallized). c) 1.05 equiv 9·Hl, 1.1 eq TBTU, 3 equiv (i-Pr)₂NEt, DMF, rt (>95%). d) 1.5 equiv HgCl₂, 3 equiv pyr, CH₃CN, reflux, 3h (70%).

Scheme 5

Reaction conditions: a) [i-PrCp]₂TiCl₂ (1.15 equiv), deoxygenated THF, 0 °C to -78 °C, 30 min; then KHMDS (1.1 equiv), -78 °C, 1.5h; then Cu(OTf)₂ (1.5 equiv) or FeCl₂(DMF)₃FeCl₄ (1 equiv), 3h, -78 °C to RT, 1.5h. b) 20% yield of α,γ dimers (analogous to 12) are isolated in this experiment. Meso 21 has been characterized by X-ray crystallography (ref 17).

Scheme 6

A) Initial strategy to parley dimers 21 into palau’amine intermediates with control of relative stereochemistry. B) Reaction condition: a) NH₄PF₆ pre-treatment; 20 mol% (Ph₃P)₃RhCl, PhMe₂SiH (1.1 equiv), CH₂Cl₂, 45 °C, 24h b) NH₄PF₆ pre-treatment; 5 mol% 31, 5 mol% 2-(dicyclohexylphosphino)-2′-(N,N-dimethylamino)biphenyl, PhMe₂SiH (1.1 equiv), Mgl₂ (0.8 equiv), CH₂Cl₂, 45 °C, 18h (60% 27 + 11% 28). c)same as (b) except NH₄PF₆ treatment omitted and MgBr₂·Et₂O (1.5 equiv) used in place of Mgl₂ (45% 28 + 30% 27). d) KHMDS (2.1 equiv), THF, -78 °C to RT, 1h, 85%. e) BF₃·Et₂O (5 equiv), CH₂Cl₂, 0 °C to RT, 3.5h; sat NaHCO₃, 80%. X-ray structure of 29 shown in ORTEP format (30% probability thermal ellipsoids, hydrogen atoms omitted for clarity).

Scheme 7

Reaction conditions: a)1.3 equiv DBU, 1.2 equiv LiCl, DMF, 50 °C 3h (70%).

Scheme 8

Reaction conditions: a) NH₄PF₆ pre-treatment; 5 mol% 31, 5 mol% 2-(dicyclohexylphosphino)-2′-(N,N-dimethylamino)biphenyl, PhMe₂SiH (2.1 equiv), Mgl₂ (0.5 equiv), CH₂Cl₂, 55 °C, 18h (33a+33b:33c = 4:1, 82%. b) 3 equiv Cy₂BOTf, 4.8 equiv KN(TMS)₂, THF, -78 °C to rt, 20 min. (50%). c) t-BuOCl (1.1 equiv), MgX₂ (1.5 equiv), THF / CH₂Cl₂, -78 °C, 2h [when X = Cl: 26% 36 + 8% 35 + 30% 34; when X = Br: 70% 38, 37 not detected]. d) Et₃BHLi (5 equiv), toluene, -78 °C (70%). e) TiF₄ (10 equiv), CH₂Cl₂, sealed vial, 80 °C, 30 min. (80%). Structure 33b has been characterized by X-ray crystallography.

Scheme 9

Reaction conditions a) NH₄PF₆ pre-treatment; 15 mol% 41, 17 mol% 2-(dicylohexylphosphino)-2′-(N,N-dimethylamino)biphenyl, phMe₂SiH (2.1 equiv), Lil (1.1 equiv), CH₂Cl₂, 55 °C, 72h (82%) (ref 38) b) 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosophabicyclo[3,3,3]undecane (10 equiv), CH₃CN/DMF, rt, 14h (40%). c) t-BUOCl (1.2 equiv) CH₂Cl₂, -78 °C, 1h (20-32%). One diastereomer of 40 has been characterized by X-ray crystallography (ref 17).

Figure 1

Original and revised palau’amine structures. In either case the imbedded spirocyclopentane motif can be viewed as a product of halogenative desymmetrization.