Recent results in synthetic glycochemistry with iron salts at Orsay-Gif - Carbohydrate Chemistry: Chemical and Biological Approaches - page 123

1

6 6

O COOH

R 2 N

OH

cyclization

AcHN

functionalization

X 1

MeO
MeO

21

COOR 2

: X = OH

22

: X = NH 2

24

23 : X = guanidine

Petasis

COOR 2

(HO) 2 B

R 2 NH

O

MeO OMe

OH

26 25

Scheme 7 Retrosynthetic analysis of zanamivir congeners 21-23 from a -hydroxy-
aldehyde 25.

COO i -Pr O CO 2 i -Pr

(HO) 2 B CO 2 i -Pr

O
MeO

a

b,c

N

MeO OMe

27 28 26

SiMe 3

O

TIPSO
29

d OH e OH

HO O

MgBr

30 31 25

OH

f) R 2 N H

24a R = All

25 + 26

24b

R = Bn

CO 2 i -Pr

R 2 N

MeO OMe

Scheme 8 Synthesis of the anti aminoalcohols 24a-b. Reagents and conditions: a) Me 3-
SiCCLi, THF, 78 1 Cto0 1 C,3h,54%);b)i)CH(OMe) 3 ,cat.H 2 SO 4 ,rt,1h,quant.;ii)K 2 CO 3 ,
i-PrOH, 70 1 C, 12 h, quant.; c) i) 2,5-dimethylhexa-2-4-diene, BH 3 THF, THF, 0 1 C, 4 h,
ii) CH 2 O, H 2 O, 82%; d) i) cat. Li 2 CuCl 4 ,THF,40 1 C; ii) TBAF, THF, rt, 84%; e) cat. TEMPO, KBr,
NaOCl, CH 2 Cl 2 /aq. NaHCO 3 (7 : 3). f) HNR 2 ,CH 2 Cl 2 /HFIP (9 : 1), 80 1 CorCH 2 Cl 2, MW (120 1 C).
HFIP = hexafluoroisopropanol; TBAF = tetrabutylammonium fluoride; TEMPO = 2,2,6,6-tetra-
methylpiperidin-1-oxyl

of the lithiated monoanion, which was condensed on the Weinreb amide
27 as shown in Scheme 8. The a-hydroxyaldehyde 25 was prepared from
protected (R)-glycidol 29 by epoxide ring opening with Grignard reagent
30 in the presence of dilithium tetrachlorocuprate, 29 deprotection with
TBAF to diol 31 and selective oxidation at the primary position using the
NaOCl/KBr combination with a catalytic amount of TEMPO. 30 Aldehyde
25 was used directly in the next Petasis condensation.
The reaction using diallylamine, in the solvent system CH 2 Cl 2 /HFIP
(9 : 1) at 80 1C for 12 h, provided anti aminoalcohol 24a as a single diaster-
eoisomer in 95% yield. The reaction could also be performed in pure CH 2 Cl 2
using microwave (120 1C) allowing the reaction to be completed in only 15
minutes. This reaction, carried out with N,N-dibenzylamine in CH 2 Cl 2 under
microwave irradiation, led similarly to adduct 24b in 71% yield.
Deprotection of the dimethylketal in 24a or 24b proved to be very dif-
ficult with a number of acidic promoters (H 2 SO 4 ,TFA,CeCl 3 7H 2 O/NaI, 31