RECENT PROGRESS AND PROSPECTS ON PLANT-DERIVED ANTI-HIV AGENTS AND ANALOGS - Medicinal Chemistry of Bioactive Natural Products - page 362

39 . R 1 =R 2 =Ac

46 . R 1 =H, R 2 =
47 . R 1 =Ac, R 2 =

O

O

40 . R 1 =R 2 =

SO 2 -

O

O O

O

48 . R 1 = R 2 =H

O

Br

OR 2

41 . R 1 =R 2 =

OR 1

SO 2 -

O

49 . R 1 = R 2 =H

O

42 . R 1 =R 2 = NH

O

O

50 . R 1 = R 2 =

O

O

43 . R 1 =R 2 =
44 . R 1 =H, R 2 =
45 . R 1 =Ac, R 2 =

O

O

O

Figure 9-4. Khellactone 3 0 R,4 0 R-substitutions (39-50).

and better pharmaceutical properties. DCK was synthesized through a four-step
route beginning with 7-hydroxycoumarin. 22 Osium oxide 26 and dioxane were
used for the dihydroxylation of seselin, which produced racemic cis-khellactones.
Isolation of pure 3 0 R,4 0 R-stereoisomer from the cis-racemic mixture is difficult and
inefficient; therefore, we turned to asymmetric synthesis for the solution. Xie et al. 30
synthesized DCK (2) in up to 86% ee via a catalytic Sharpless asymmetric dihy-
droxylation (AD) 27,28 of seselin. Seven different chiral ligands were used
for optimal enantioselectivity. Hydroquinidine (DHQD-R) type ligands 29 led to
3 0 S,4 0 S-configuration, and hydroquinine (DHQ-R) type ligands gave 3 0 R,4 0 R-configura-
tion as the main product. (DHQ) 2 PYR (hydroquinine 2,5-diphenyl-4,6-pyrimidine-
diyl diether) gave the highest R,R stereoselectivity. 30 Methanesulfonamide (1 equiv.)
was added to the reaction mixture to improve rate at 0 C. 27 In a solid-phase synthetic
route, 91% ee of the AD reaction was yielded by using OsO 4 as catalyst and
(DHQ) 2 -PHAL (hydroquinine 1,4-phthalazinediyl diether) as ligand at rt. 31 Scheme
9-1 describes the optimized synthetic route for DCK analogs. 25

9.2.3 Coumarin Skeleton Modification

9.2.3.1 Substituents on Coumarin Skeleton
9.2.3.1.1 Monosubstituted Analogs Xie et al. synthesized a series of monosub-
stituted derivatives at the coumarin 3, 4, 5, and 6 positions. 25,32,33 The data in Table
9-2 show that mono-methyl substitution at the 3, 4, or 5 position (51, 53, and 59)
greatly increased potency in comparison with 2. 3- and 4-Methoxy DCK analogs
(52 and 54) showed slightly less potency whereas 5-methoxy DCK (60) retained
activity. However, although methylation or methoxylation at the 3, 4, and 5 posi-
tions did not affect the antiviral activity of DCK analogs, these same substitutions at