B. Carbain et al. / Tetrahedron Letters 51 (2010) 2717–2719
2719
R2
R1
O
and effective route to phospha-isosteres of various bioactive mole-
cules such as shikimates or even neuraminidase inhibitors.7 A set
of ‘phospha’-shikimic acids was synthesized in good yield and will
be investigated for activity in a shikimate dehydrogenase assay in
due course.
COOR'
X
O
H.-B. decarbox.
60%
IBX, 88%
8
O
O
MeO
MeO
O
O
OMe
OMe
Acknowledgement
HP(O)(OMe)2
Pd(PPh3)4,
81%
16: R'=Me, R1=R2=O
17: R'=Me, R1=R2=
18: R'= H, R1=R2=
Br(CH2)2OH
t-BuOK, 65%
NaOH, 82%
19: X = I
20: X = PO3Me2
O
O
We thank Professor Jim Hanson, of our department, for helpful
advice.
1. TMSBr
lutidine
1. TFA 2. NaI, then
NH4CO3
O
2.TFA, then
NH4HCO3
O
O
Supplementary data
O
-
HO
P(OMe)
HO
P
O
Supplementary data (synthetic procedures, 1H, 13C and 31P NMR
and HR-ESI-MS data. Crystal data of cyclohexenephosphonate 7)
associated with this article can be found, in the online version, at
O
-
O
-
+
+
HO
2NH4
NH4
HO
3
4
Scheme 6. Synthesis of 3-dehydro-‘phospha’-shikimic acid via route B. H.-B.
decarbox. = Hunsdiecker–Barton decarboxylation.
References and notes
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published procedure (Scheme 5).15 Silylation of the 3-OH group to
give 9 followed by saponification of the methyl ester afforded acid
10 which could be readily iododecarboxylated to furnish 11. The
yield of the following phosphonylation to give 12 roughly tripled
compared to its acetyl-protected counterpart thus making this pro-
tecting group pattern the superior choice for the generation of 1
and 2 as well. Removal of the silyl group to give 13 and oxidation
to the ketone 14 with IBX proceeded in high yields and thus pro-
tected 3-dehydro-‘phospha’-shikimic acid 14 was obtained.
Following acid hydrolysis of the ketal to furnish 15 we success-
fully generated the monomethyl ester 4 by iodide-mediated O-al-
kyl cleavage followed by saponification (Scheme 5). TMSBr-
mediated hydrolysis to the phosphonate 3 proved difficult how-
ever, resulting in only very low yields.
Finally, we adopted strategy (B) involving oxidation and protec-
tion of the ketone before halodecarboxylation and phosphonyla-
tion. We expected to gain information on further improvement of
yields in the latter two steps and to allow for a more smooth
deprotection towards target 3 (Scheme 6). IBX-oxidation of pro-
tected shikimic acid 8 yielded the ketone 16 which could be readily
protected as its ethylene ketal to give 17. Saponification of the
methyl ester afforded acid 18 which was iododecarboxylated to
form 19 in a yield comparable to those obtained before. The yield
of the following phosphonylation to give 20 increased to 81% and
finally, target 3 was readily obtained from 20 by TMSBr-mediated
ester cleavage followed by removal of the ketal protecting group
with TFA. In addition, this route provides an alternative access to
monoester 4 as well.16
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16. Target compounds 3 and 4 could be isolated and purified without problems,
but decomposed slowly when stored, see also Supplementary data.
In conclusion, we have extended the scope of the Hunsdiecker–
Barton decarboxylation to vinyl-, in particular trihydroxy- and
dihydroxyketo-cyclohexenylcarboxylic acids carrying different
protecting groups. In combination with phosphonylation and
appropriate protecting groups, our approach represents a short