LA coMEdIA AnIMAdA dE PRIME TIME
2. LA AnIMAcIón
4.4. ubicación y espacialidad
The 2-methylnaphthyl group produces significantly lower yields in the Wittig reaction; however, this route from the -D-glucose is still the most viable path for generation of the vinyl bromide. At this stage in the project it became necessary to investigate a different protecting group for the 3-OH moiety.
Previous work has shown that the 3-OPMB and the 3-OTBS protected alcohols 184 and 185 are not appropriate for use at this stage since they would not survive the acidic conditions required to hydrolyse the 1,2-isopropylidene moiety. If they were used then the 1,2,3-triacetate 186 would be generated prior to addition of the nucleoside base thus making it necessary to be able to discriminate
between the 2’- and the 3’-position of the bis-acetate 187 at a later 1. AcOH aq. Base, BSA Base
184R= PMB 185R = TBS
2. Ac2O, pyr. TMSOTf, MeCN
186 187
Scheme 52. Use of the acid sensitive PMB or TBS protecting group leads to the bis-acetate nucleoside.
The tert-butyldiphenylsilane (TBDPS) group was the first option to be considered as it is an acid stable protecting group which can be removed by treatment with TBAF. Previous work by N. Solesbury has shown that the TBDPS group cannot be removed from the vinylphosphonate dimers140 therefore it would be necessary to deprotect and change the protecting group prior to the formation of the vinylphosphonate bond. Although this adds two extra steps to the synthesis, the TBDPS could be used, then cleaved and reprotected as the 2-methylnaphthyl ether after the vinyl halide has been installed but prior to the cross-coupling reaction.
Allofuranose 174 was protected using TBDPSCl and imidazole in dry DMF to form the TBDPS ether 188 in an excellent 94% yield (Scheme 53).189,190,191 The TBDPS ether is approximately 100 times more stable to acid hydrolysis than the TBS ether so should remain intact in the acid hydrolysis at a later stage.192
O
O O HO
O O
O
O O TBDPSO
O O
174 188 (94%)
imidazole, DMF TBDPSCl
Scheme 53. Addition of the TBDPS protecting group.
Unfortunately, as previously observed with the 2-methylnaphthyl compound 176 (Scheme 48), acid hydrolysis of the 5,6-isopropylidene of 188 using the standard aqueous acetic acid (80%
v/v) conditions181,182,183 was very slow so different methods were investigated. Previous work in the group has shown that if the reaction mixture was heated or left for too long (four days) then hydrolysis of the 1,2-isopropylidene would occur.140 Investigating different methods of hydrolysis led to the use of a catalytic amount (0.1 eq.) of dichloro-dicyanobenzoquinone (DDQ) in 9:1 v/v MeCN:H2O at r.t.184 In aqueous media, this is reduced to the bis-phenol (pKa of 3.42) by the acetone byproduct of the acetal hydrolysis.193 Hydrolysis did occur however, the reaction was slow and low yielding. Hydrolysis of the TBDPS acetonide 188 using acids with a similar pKa to the reduced DDQ was also investigated but once again the diol, 189 was a viscous syrup and was difficult to handle and purify by column chromatography or repeated evaporation with toluene.
O
O O TBDPSO
O O
O
O O TBDPSO
HO HO
188
conditions
189 Scheme 54. Acetal hydrolysis.
The hydrolysis was attempted using of 0.1 eq. of chloroacetic acid at r.t. in 9:1 v/v MeCN:H2O, however, after 19 hours only the unreacted acetonide 188 was observed. Warming the reaction to 40 oC or increasing the amount of acid (0.2 eq.) led to a complex mixture of products. Higher levels of the chloroacetic acid (0.5 eq.) had the undesired effect of cleavage of the TBDPS protecting group.
It is inferred from these results that the large steric bulk of the 2-methylnaphthyl and the TBDPS protecting groups is responsible for the very slow rates of hydrolysis of the diols. A solution to this problem is the use of a smaller protecting group.
Fortunately, a solution to the 3-protection was found with the acetate group. The 3-OH of the allofuranose 174 was protected using acetic anhydride (1.56 eq.) in the presence of triethylamine (3 eq.) and a catalytic quantity of DMAP (0.1 eq.), stirring at room temperature in dry CH2Cl2 to obtain 190 in a 86% yield as a crystalline solid (Scheme 55).194
DMAP, CH2Cl2, r.t.
Scheme 55. Acetate protection of the 3-OH.
The next challenge was the hydrolysis of the 5,6-acetonide 190 to form diol 191 and oxidative cleavage to access aldehyde 192 (Scheme 56); hydrolysis using a 70% aqueous solution v/v of acetic acid is a reliable method of cleaving the 5,6-acetonide.182 However, in the subsequent oxidative cleavage process, it was not desirable to use sodium periodate which requires an aqueous reaction mixture (e.g. EtOH:H2O).195 Due to the high polarity of the diol 38, and aldehyde 39, an aqueous reaction mixture resulted in the significant loss of product due to its solubility in the aqueous phase and formation of the aldehyde hydrate.
O
Scheme 56. Reagents & conditions: a. 70% AcOH, r.t.; b. NaIO4, 4:1 v/v EtOH:H2O, r.t.
To reduce the problem of hydrate formation, a single organic phase could be used instead of the aqueous system. However, this approach would impede the progress of the NaIO4 mediated oxidative cleavage of diol 191 due to the poor solubility. The
presence of silica is often reported to aid such reactions but in this case, no benefit was seen.196 One-pot procedures for the hydrolysis and subsequent oxidative cleavage of the diol to the aldehyde 192 have also been published in the literature (Scheme 57).169,196 Different methods were attempted with varying degrees of conversion (Table 13).
Scheme 57. One-pot hydrolysis-oxidative cleavage of the 5,6-isopropylidene.
Conditions Observations Ref.
NaIO4.SiO2, CH2Cl2, 4 ½ d. Recovered 190 (50%) 196
NaIO4 (1.0 eq.), H5IO6 (0.5
eq.), EtOAc, 5 d. Aldehyde 192 and hydrate (92%) 169
H5IO6(1.1 eq.), EtOAc, 4 h. Aldehyde 192 and hydrate (98%) 176 197 H5IO6(1.25 eq.), THF, 4 h. Aldehyde 192 and hydrate (71%)
Table 13. Conditions used in the one pot hydrolysis-oxidative cleavage of the 5,6-acetonide of 190.
Using the method of periodic acid in THF, spectroscopic analysis 1H NMR of the crude product showed a mixture of the aldehyde 192 and the corresponding hydrate. The method of Yang et al. uses a combination of periodic acid and sodium periodate in dry ethyl acetate (dried over CaCl2) to obtain the aldehyde 192.169 However, the most successful results were obtained using a variation of the
method of Agrofoglio et al. using solely periodic acid (1.2 eq.) in dry EtOAc.197 Once the aldehyde 192 was obtained, it was used without further purification; it was found that purification did not increase the yield of the Wittig reaction and column chromatography often led to loss of material.
While investigating the formation of aldehyde 192 and the subsequent olefination and regioselective reduction steps, the unreliable nature of the earlier PDC oxidation prompted the exploration of a model system. Using the glucofuranose 172, this approach would involve the inversion of the 3-OH stereochemistry at a later stage in the synthesis; removing the capricious PDC oxidation of the 1,2:5,6-diisopropylidene--D-glucofuranose (Scheme 10). Glucofuranose 172 was protected as the acetate 193 using the same conditions in an excellent 93% yield (Scheme 58).194 Aldehyde 194 was then produced using the one-pot hydrolysis-oxidative cleavage procedure using 1:1 v/v EtOAc-THF as the solvent.
Conditions Observations
NaIO4.SiO2, CH2Cl2, 7 d.196 Recovered 193 (34%) NaIO4(1.0 eq.), H5IO6(0.5 eq.), EtOAc, 3 d.169 Aldehyde 194 (73%) H5IO6(1.5 eq.), EtOAc, 3 h. Aldehyde 194 (75%) H5IO6(1.25 eq.), 1:1 v/v EtOAc-THF, 2½ h. Aldehyde 194 (83%)
Table 14. Conditions used in the one pot hydrolysis-oxidative cleavage of the 5,6-acetonide of 193.