Synthesis of carba-sugars from (-)-quinic acid

Article abstract of DOI:10.1016/S0040-4039(01)00601-3

(1S,2R,3R,4S,5R)- (3a) and (1S,2S,3S,4S,5R)-1,2,3,4,5-pentahydroxy-1-hydroxymethylcyclohexane (4a), (1R,2R,3R,4S,5R)- (3b) and (1R,2S,3S,4S,5R)-1,2,3,4,5-pentahydroxycyclohexan-1-carboxylic acid (4b) are reported. The syntheses exploit the diastereoselective oxidation of the 5,6-double bond of the quinic acid-derived lactone 2 with osmium tetroxide.

Full text of DOI:10.1016/S0040-4039(01)00601-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3973–3976
Synthesis of carba-sugars from (−)-quinic acid
Montserrat Carballido, Luis Castedo* and Concepcio´n Gonza´lez*
Departamento de Qu´ımica Orga´nica y Unidad Asociada al CSIC, Facultad de Qu´ımica, Universidad de Santiago de Compostela,
15706 Santiago de Compostela, Spain
Received 12 February 2001; accepted 9 April 2001
Abstract—(1S,2R,3R,4S,5R)- (3a) and (1S,2S,3S,4S,5R)-1,2,3,4,5-pentahydroxy-1-hydroxymethylcyclohexane (4a), (1R,2R,3R,
4S,5R)- (3b) and (1R,2S,3S,4S,5R)-1,2,3,4,5-pentahydroxycyclohexan-1-carboxylic acid (4b) are reported. The syntheses exploit
the diastereoselective oxidation of the 5,6-double bond of the quinic acid-derived lactone 2 with osmium tetroxide. © 2001
Elsevier Science Ltd. All rights reserved.
Carba-sugars are cyclic monosaccharide analogues in
which the endocyclic oxygen atom is replaced by a
methylene group.1 As a consequence of this substitu-
tion, carba-sugars are hydrolytically stable analogues of
their parent sugars towards degradation of glycosi-
dases. The discovery of carba-sugars in natural prod-
ucts and their potential in biochemical studies of
specific enzyme inhibition, particularly as glycosidase
inhibitors,2 have resulted in considerable attention
being focused on their synthesis.
HO X
HO
2
O
RO
HO CO2H
3
HO
OH
OH
6
5
3
O
a X= CH2OH
b X= CO2H
HO X
HO
OH
HO
HO
OR'
OH
2
2
3
(-)-Quinic acid (1)
OH
OH
4
Scheme 1.
iii
O
O
O
RO
R1O
R1O
HO CO2H
CO2Me
OH
ii
i
O
+
HO
OH
OBz
OR2
OR2
OH
1
5 R = TBS
6 R = H
7 R1 = TBS; R2 = H
8 R1 = TBS; R2 = H
9 R1 = TBS; R2 =Bn
iv
v
Scheme 2. Reagents and conditions: (i) Ref. 4; (ii) K2CO3, MeOH, rt (94%); (iii) NaH, THF, 0°C (83%); (iv) TBAF, AcOH, THF,
rt (94%); (v) (1) NaH, THF, 0°C, (2) BnBr, Bu4NI, rt (79%).
* Corresponding authors. Fax: 34 981 595012; e-mail: cgb1@lugo.usc.es
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00601-3

3974
M. Carballido et al. / Tetrahedron Letters 42 (2001) 3973–3976
O
O
O
R1O
HO
R1O
HO
O
H
OsO4 cat
H
+
O
O
R1O
H
OR2
OH
R3O
H
11
10
OR2
OR2
5: R1= TBS; R2= Bz
6: R1= H; R2= Bz
8: R1= TBS; R2= H
9: R1= TBS; R2= Bn
a: R1= TBS; R2= Bz; R3= H
b: R1= TBS; R2= H; R3= H
c: R1= TBS; R2= Bn; R3= H
d: R1= H; R2= Bz; R3= H
e: R1= TBS; R2= H; R3= Bz
f: R1= H; R2= H; R3= Bz
a: R1= TBS; R2= Bz
b: R1= TBS; R2= H
c: R1= TBS; R2= Bn
d: R1= H; R2= Bz
Scheme 3.
In this communication, we report the synthesis of
carba-sugars 3 and 4 starting from a cheap and com-
mercially available (−)-quinic acid (1) as a chiral tem-
plate,3 by cis-hydroxylation of the 5-cyclohexene
derivative 2 (Scheme 1).
Kishi noted that osmium tetroxide approaches prefer-
entially to the face of the double bond opposite to the
pre-existing allylic hydroxyl or alkoxyl group.8 How-
ever, if there is more than one allylic substituent, the
stereochemical results are not so easily predicted. In our
case, the cis-hydroxylation also depends on the reaction
conditions. Intrigued by this result, we turned our
attention to study the osmylation reaction with a series
of alkenes and with different co-oxidants for the regen-
eration of the osmium tetroxide.
The cyclohexene derivative 5 was obtained in three
steps and 47% overall yield from (−) quinic acid (1), as
described by Bartlett et al. (Scheme 2).4 Treatment of
the benzolactone 5 with sodium methoxide or potas-
sium carbonate in methanol afforded, in both cases, a
mixture of the methyl ester 75 and the hydroxycarbolac-
tone 8.5 The main product during the reaction course
was the methyl ester 7; however, after work-up, the
reaction mixture was equilibrated to an approximate
1:1 mixture of 7 and 8. Treatment of diol 7 with an
equivalent of sodium hydride yielded lactone 8 in 83%
yield.
The major product arising from the diprotected ben-
zoylalkene 5 arose from Si-hydroxylation when NaIO4
or NMO were the co-oxidants (entries 1 and 2, Table
1), whereas OsO4/M3NO oxidation gave predominantly
Re-hydroxylation. In the latter case, compound 12 was
also formed. This is an intermediate in the equilibrium
process in acid media between lactones 11a and 13
(Scheme 4). TBS deprotection of 5 afforded hydroxy-
alkene 6, which was subjected to osmylation and gave
an approximately 1:1 mixture of Re- and Si-hydroxyla-
tion in low yield (entries 4 and 5, Table 1). Benzylation
of 8 afforded 9. This compound was not hydroxylated
with OsO4/NaIO4, but afforded mainly the Re-hydroxy-
lation product using NMO as co-oxidant (entry 11,
Table 1). Finally, removal of the lactone bridge, as in 7,
The key step of the synthesis of 3 and 4 is the introduc-
tion of the hydroxyl groups in the 2- and 3-positions
using osmium tetroxide (Scheme 3). This paper
describes a study of various conditions and reagents.
The results are summarized in Table 1.6 Different co-
oxidants for the regeneration of osmium tetroxide were
investigated (potassium ferrocyanide, N-methylmor-
pholine oxide, N-trimethylamine oxide and sodium
periodate). No reaction was observed when potassium
ferrocyanide, ADmix-a or ADmix-b was used. Sodium
periodate gave cleaner reaction mixtures than both
N-methylmorpholine oxide and N-trimethylamine
oxide.
Table 1. Osmium tetroxide oxidationa
Entry
Substrate
Method
Hydroxylation
Si (%) Re (%)
Hydroxylation of the allylic alcohol 8 (entries 7, 8 and
9, Table 1) gave a mixture of two hydroxylated prod-
ucts, 10b and 11b, resulting from the reaction of the Si
and Re faces, respectively. When the addition occurs
from the Re face, migration of the carbolactone from
the 1,5- to the 1,3-position was also observed. Surpris-
ingly, the proportional ratio of Si and Re cis-hydroxy-
lation was very dependent on the co-oxidant.
Hydroxylated lactone 11b was the major diastereoiso-
mer in the OsO4/NaIO4 oxidation (entry 7, Table 1)
proceeding from the sterically more congested face of
the molecule, which has been demonstrated to be the
more sterically hindered one.7 In contrast, hydroxylated
lactone 10b was the major diastereoisomer in the OsO4/
NMO oxidation (entry 8, Table 1).
1
2
3
4
5
6
7
8
5
5
5
6
6
6
8
8
8
9
9
A
B
C
A
B
C
A
B
C
A
B
71
64
19
22
23
–
26
B5
57
19
24
–
b
b
12
61
36
–
55
18
18
–
9
10
11
c
c
B5
80
a Ratio determined from isolated compounds. Method A: NaIO4; B:
NMO; C: Me3NO.
b Complex mixture of products.
c No reaction.

M. Carballido et al. / Tetrahedron Letters 42 (2001) 3973–3976
3975
diastereoisomer 14 independent of the reaction condi-
tions (Scheme 5).
HO
O
O
O
OH
O
H+
TBSO
HO
In summary, it was found that the facial selectivity of
the hydroxylation with osmium tetroxide could be
reversed by changing the protecting groups on C-1 and
C-4, or in the case of compounds 5 and 8, by changing
the co-oxidant. It is notable in this comparison that
treatment of 5 with NaIO4 gave predominantly Si-
hydroxylation for 5, and use of Me3NO gave predomi-
nantly Re-hydroxylation, whereas the opposite was
observed with 8.
HO
12 OBz
11a
OBz
H+
O
O
HO
TBSO
HO
13
OBz
Scheme 4.
Reduction of the carbolactones 11b and 10b with
lithium borohydride followed by deprotection of the
hydroxyl group with aqueous acetic acid afforded poly-
hydroxycyclohexanes 3a and 4a in 45 and 63% overall
yield, respectively (Scheme 6).9 Treatment of hydroxy-
carbolactone 11b with aqueous acetic acid gave tetraol
15, whose X-ray structure is shown in Fig. 1.10 Hydroly-
sis of lactone 15 under basic conditions afforded the
hydroxy quinic acid derivative 3b in quantitative yield,
whereas treatment of hydroxycarbolactone 10b with
aqueous acetic acid gave analogue 4b directly in 64%
yield.
OH
OH
OH
OH
OsO4 cat
MeO2C
TBSO
MeO2C
TBSO
OH
OH
14
7
Scheme 5. Reagents and yields: (i) NMO (87%); (ii) NaIO4
(70%); (iii) Me3NO (89%).
O
HO
HO
RO
CO2H
OH
CH2OH
HO
HO
HO
HO
HO
i
iii
O
51%
99%
OH
OH
Acknowledgements
OH
OH
3a
OH
11b R=TBS
15 R=H
ii, 77%
3b
Financial support from the Xunta de Galicia under
project PGIDT99PX120904B is gratefully acknowl-
edged. M.C. would like to thank the Xunta de Galicia
for a scholarship. The authors would like to thank Dr.
Chris Abell (University of Cambridge) for his helpful
discussions. C.A. would like to thank the Iberdrola
Visiting Professorship Program.
O
HO
TBSO
HO
HO
CH2OH
CO2H
HO
HO
HO
i
ii
64%
O
82%
OH
HO
HO
OH
OH
OH
OH
4b
4a
10b
References
Scheme 6. Reagents and conditions: (i) (1) LiBH4, MeOH,
THF, D, (2) AcOH, H2O, D; (ii) AcOH, H2O, THF, 40°C; (iii)
(1) LiOH, 0°C, (2) Amberlite-IR 120.
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5. All new compounds gave satisfactory analytical and/or
spectroscopic data.
6. The stereochemistry of the osmylation products was
determined using 1H NMR NOE experiments of the
hydroxylated compounds or their corresponding O-
isopropilidenacetals.
7. Gonza´lez-Bello, C.; Manthey, M. K.; Harris, J. H.;
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Figure 1. X-Ray structure of 15.
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3976
M. Carballido et al. / Tetrahedron Letters 42 (2001) 3973–3976
1
9. Compound 3a: [h]D20 −2° (c 0.7, CH3OH); H NMR (500
NMR (250 MHz, CD3OD) l 4.12 (t, 1H, J 3.0), 4.05 (m,
MHz, CH3OD) l 3.76 (m, 2H), 3.64 (s, 2H), 3.45 (d, 1H,
J 11.2), 1.77 (dd, 1H, J 13.1 and 4.7) and 1.66 (dd, 1H, J
13.1 and 11.8); 13C NMR (125 MHz, DEPT, CH3OD) l
86.8 (CH), 84.2 (C), 82.6 (CH), 81.7 (CH), 78.4 (CH), 75.1
(CH2) and 31.7 (CH2); MS (+FAB) m/z (%) 195 (MH+);
HRMS calcd for C7H15O6: MH+, 195.0869. Found: MH+,
195.0875. Compound 3b: [h]2D0 −12° (c 0.7, H2O); 1H
NMR (250 MHz, D2O) l 3.59 (d, 1H, J 3.0), 3.41 (dd, 1H,
J 3.0 and 9.5), 3.33 (m, 1H), 3.22 (t, 1H, J 9.5) and 1.70
(m, 2H); 13C NMR (63 MHz, DEPT, D2O) l 177.5 (C),
76.0 (C), 74.5 (CH), 73.2 (CH), 71.2 (CH), 69.1 (CH) and
34.7 (CH2); MS (+FAB) m/z (%) 209 (MH+); HRMS
calcd for C7H13O7: MH+, 209.0661. Found: MH+,
1H), 3.66 (m, 2H), 3.64 (s, 2H), 3.32 (m, 1H), 1.98 (dd,
1H, J 13.6 and 4.9) and 1.56 (dd, 1H, J 13.6 and 11.7); 13
C
NMR (63 MHz, DEPT, CD3OD) l 78.1 (C), 77.1 (CH),
76.8 (CH), 70.4 (CH), 68.2 (CH), 67.5 (CH2) and 39.8
(CH2); MS (+FAB) m/z (%) 195 (MH+); HRMS calcd for
C7H13O7: MH+, 195.0869. Found: MH+, 195.0875. Com-
pound 4b: mp 210–212°C [20% ethyl acetate–methanol
(Lit.11 221°C, 25% aq. ethanol)]; [h]D20 −17° (c 2.6, H2O),
Lit.11 −16° (c 1.0, 50% aq. ethanol).
10. Crystallographic data have been deposited in the Cam-
bridge Crystallographic Data Centre (CCDC No.
157890).
11. Adlersberg, M.; Bondinell, W. E.; Sprinson, D. B. J. Am.
Chem. Soc. 1973, 95, 887.
1
209.0666. Compound 4a: [h]2D0 −20° (c 1.1, CH3OH); H
.