Stereoselective synthesis of 3,4,5,6-tetrahydroxycyclohexyl β-amino acid derivatives

Article abstract of DOI:10.1016/j.tetlet.2008.07.094

Stereoselective syntheses of racemic (1S,2R,3R,4R,5S,6R)- and (1S,2R,3R,4S,5S,6R)-3,4,5,6-tetrahydroxy derivatives of 2-aminocyclohexanecarboxylic acid have been achieved by a stereospecific Diels-Alder reaction between furan and maleic anhydride, a Curtius rearrangement and hydroxylation reactions.

Full text of DOI:10.1016/j.tetlet.2008.07.094

Tetrahedron Letters 49 (2008) 5680–5682
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Tetrahedron Letters
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Stereoselective synthesis of 3,4,5,6-tetrahydroxycyclohexyl
b-amino acid derivatives
*
Joshua Chola, Ishmael B. Masesane
Chemistry Department, University of Botswana, P/bag 00704, Gaborone, Botswana
a r t i c l e i n f o
a b s t r a c t
Article history:
Stereoselective syntheses of racemic (1S,2R,3R,4R,5S,6R)- and (1S,2R,3R,4S,5S,6R)-3,4,5,6-tetrahydroxy
derivatives of 2-aminocyclohexanecarboxylic acid have been achieved by a stereospecific Diels–Alder
reaction between furan and maleic anhydride, a Curtius rearrangement and hydroxylation reactions.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 10 May 2008
Revised 7 July 2008
Accepted 16 July 2008
Available online 22 July 2008
The stereoselective synthesis of cyclic b-amino acids has at-
tracted the attention of chemists due to their biological activities
and the interesting structural properties of their oligomers.1–5
These compounds in which both the amino and the acid function-
alities are vicinally attached to an aliphatic ring still present a
demanding challenge to synthetic chemists. One of the major rea-
sons for this challenge is the difficulty associated with controlling
the absolute and relative stereochemistry of two adjacent stereo-
centres. The difficulty in controlling the relative stereochemistry
is exacerbated by the introduction of other stereocentres on the
ring carbon atoms.
In view of the challenges involved in the synthesis of cyclic b-
amino acids, we have been exploring the use of oxanorbornene ad-
ducts derived from the Diels–Alder reaction of ethyl (E)-3-nitroac-
rylate and furan as versatile intermediates in the synthesis of a
range of novel mono-, di- and trihydroxy derivatives of 2-aminocy-
clohexanecarboxylic acid (ACHC).6,7 In this Letter, we report the
use of an oxanorbornene adduct derived from the Diels–Alder reac-
tion of furan and maleic anhydride as a useful intermediate in the
synthesis of novel 3,4,5,6-tetrahydroxy derivatives of ACHC.
Our synthesis of tetrahydroxy cyclohexyl b-amino acid deriva-
tives began with the Diels–Alder reaction of furan 1 and maleic
anhydride 2. When maleic anhydride was suspended in furan
and the mixture stirred for 16 h at room temperature, bicyclic ad-
duct 3 was isolated exclusively in 98% yield, Scheme 1. This reac-
tion can be considered to be green as no solvents were used. The
stereochemistry of adduct 3 was assigned by 2D NMR experiments
and by comparison with the relative stereochemistry of subse-
quent products. It is known from the literature that the Diels–Alder
reaction between furan and maleic anhydride is reversible and
gives the more thermodynamically stable exo-adduct.8 A prerequi-
site for the Curtius rearrangement on adduct 3 is solvolysis of the
anhydride functionality. In the event, stirring a solution of adduct 3
in methanol at room temperature afforded half-ester 4 in 87% yield
(Scheme 1).
Next, half-ester 4 was converted into a form amenable to the
crucial Curtius reaction. To this end, the free acid was activated
using methyl chloroformate and then treated with sodium azide
at 0 °C to give acyl azide 5. To effect the Curtius rearrangement,
acyl azide 5 was stirred at 50 °C in toluene for 10 h, cooled to room
temperature, treated with methanol and stirred at room tempera-
ture to give carbamate 6 in 63% yield from 4 (Scheme 2).
We next set out to fragment the oxabicyclic adduct 6 by elimi-
nation of the oxygen bridge. There is extensive literature on both
acid- and base-mediated elimination of the oxygen bridge of oxa-
bicyclic rings.6,7,9,10 In our earlier work, we used a base for opening
O
O
O
O
O
CO2Me
CO2H
i
ii
O
+
O
O
O
1
2
3
4
Scheme 1. Reagents and conditions: (i) 25 °C, 98%; (ii) MeOH, 25 °C, 87%.
* Corresponding author. Tel.: +267 3552495; fax: +267 3552836.
E-mail address: Masesane@mopipi.ub.bw (I. B. Masesane).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.094

J. Chola, I. B. Masesane / Tetrahedron Letters 49 (2008) 5680–5682
5681
O
O
O
CO2Me
CON3
CO2Me
CO2H
CO2Me
NHCO2CH3
ii
i
4
5
6
Scheme 2. Reagents and conditions: (i) ClCO2Me, NEt3, THF then NaN3, H2O, 0 °C; (ii) toluene, 50 °C then CH3OH, 25 °C, 63% from 4.
OAc
OAc
O
CO2Me
AcO
AcO
CO2Me
CO2Me
NHCO2CH3
i
ii, iii
NHCO2Me
NHCO2Me
OAc
7
OAc
8
6
Scheme 3. Reagents and conditions: (i) BF3ÁEt2O, Ac2O, 0 °C, 61%; (ii) OsO4, Me3NOÁH2O, acetone; (iii) Ac2O, py, 76% from 7.
related oxabicyclic compounds.6,7 In this project, we investigated
the ability of the Lewis acid BF3ÁEt2O in the presence of a nucleo-
phile to open the oxabicyclic adduct 6. In the event, a solution of
carbamate 6 in acetic anhydride was treated with BF3ÁEt2O at
0 °C to afford cyclohexene 7 in 61% yield (Scheme 3).
Elaboration of cyclohexene 7 through OsO4-mediated dihydr-
oxylation followed by acylation afforded racemic (1S,2R,3R,4R,
5S,6R)-3,4,5,6-tetraacetoxycyclohexyl b-aminocarboxylate 811 as
the only detectable isomer in 76% yield over the two steps. The rel-
ative stereochemistry of the product was assigned using NOESY
NMR experiments (Fig. 1). The ability of cyclic homoallylic carba-
mates to give high levels of syn selectivity in osmium-mediated
dihydroxylation reactions is well documented,6,7,12 therefore our
results were not surprising.
cyclohexene 7 was treated with MCPBA, two isomeric epoxides 9
and 10 were isolated in 78% yield and 9:1 ratio with isomer 9 in
excess. The epoxides were separated by column chromatography.
The selectivity of the epoxidation reaction was consistent with
reported literature.6,7,13,14 The major epoxide 9 was treated with
perchloric acid followed by acylation to give racemic (1S,2R,3R,
4S,5S,6R)-tetraacetoxycyclohexyl b-amino acid derivative 1111 as
the only detectable product in 64% yield (Scheme 4). The relative
stereochemistry of the product was assigned using NOESY NMR
experiments (Fig. 2).
In conclusion, a stereoselective and effective route to tetrahydr-
oxy derivatives of ACHC has been developed based on the oxabi-
cyclic adduct derived from the Diels–Alder reaction of furan and
maleic anhydride,
a
Curtius reaction and dihydroxylation
An alternative oxygenation route involved an epoxidation reac-
tion followed by acid-catalysed opening of the epoxide. Thus, when
reactions. On-going work in our laboratory includes testing these
compounds for biological activity against bacteria.
H
H
H
H
R
R
H
H
R
R
CO2Me
CO2Me
H
R
H
H
R
R
R
NHCO2Me
H
NHAc
R = OAc
R = OAc
Figure 1. Selected NOESY interactions in 8.
Figure 2. Selected NOESY interactions in 11.
OAc
CO2Me
O
OAc
OAc
CO2Me
CO2Me
i
+
O
NHCO2Me
NHCO2Me
NHCO2Me
OAc
10
OAc
7
OAc
9
ii, iii, iv
OAc
AcO
AcO
CO2Me
NHAc
OAc
11
Scheme 4. Reagents and conditions: (i) MCPBA, CH2Cl2, 25 °C (9:10, 9:1) 78%; (ii) chromatography; (iii) HClO4, H2O/acetone; (iv) Ac2O, pyridine, 64% from 9.

5682
J. Chola, I. B. Masesane / Tetrahedron Letters 49 (2008) 5680–5682
11. Satisfactory spectroscopic and analytical data have been obtained for all new
compounds. Compound 8: white gum; max (KBr disk): 3248, 2937, 1755, 1664,
Acknowledgements
m
1563 cmÀ1; dH (500 MHz, CDCl3): 2.01 (3H, s, CH3CO), 2.03 (6H, s, 2 Â CH3CO),
2.11 (3H, s, CH3CO), 2.57 (1H, dd, J = 3.5 and 12.3 Hz, H-1), 4.12 (3H, s, OCH3),
4.15 (3H, s, OCH3), 4.33 (1H, m, H-2), 4.88 (1H, dd, J = 3.5 and 12.4 Hz, H-5),
4.96 (1H, t, J = 3.5 Hz, H-3), 5.21 (1H, br, H-4), 5.26 (1H, t, J = 12.3, H-6) 5.49
(1H, d, J = 10.0 Hz, NH); dC (125 MHz, CDCl3): 20.8, 20.9 and 21.1 (4 Â CH3CO),
44.7 (C-1), 53.5 (C-2), 62.8 (OCH3), 65.1 (OCH3), 70.6 (C-5), 72.9 (C-4), 73.2 (C-
3), 75.3 (C-6), 169.8, 170.4, 170.8, 171.3 and 171.9 (carbonyls); m/z (CI): 448
(MH+, 100%); HRMS (ES+): C18H25NO12Na requires M+, 470.1277. Found:
470.1267. Compound 11: colourless gum; mmax (KBr disk): 3271, 2986, 1747,
1651, 1556 cmÀ1; dH (500 MHz, CDCl3): 1.91 (3H, s, CH3CO), 1.97 (3H, s,
CH3CON), 2.03 (6H, s, 2 Â CH3CO), 2.16 (3H, s, CH3CO), 2.77 (1H, dd, J = 3.7 and
12.7 Hz, H-1), 4.12 (3H, s, OCH3), 4.50 (1H, m, H-2), 5.05 (2H, m, H-4 and 5),
5.50 (1H, t, J =12.4 Hz, H-3), 5.53 (1H, t, J = 11.9 Hz, H-6), 5.56 (1H, d, J = 8.0 Hz,
NH); dC (125 MHz, CDCl3): 20.8 (CH3CO), 21.2 (CH3CO), 21.2 (CH3CO), 21.3
(CH3CO), 23.3 (CH3CON), 42.7 (C-1), 49.6 (C-2), 61.7 (OCH3), 68.5 (C-5), 71.5 (C-
3), 71.8 (C-4), 73.6 (C-6), 169.3, 169.9, 170.0, 170.1, 171.4, 171.7 (carbonyls);
m/z (ES+): 454 (MNa+). HRMS (ES+): C18H25NO11Na requires M+, 454.1328.
Found: 454.1336.
We thank the Royal Society of Chemistry (RSC) for financial
support, Dr. M. Bezabir for NMR experiments, Mr. D. Mosimaneth-
ebe for mass spectra and Dr. P. G. Steel for donating chromatogra-
phy columns to our laboratory.
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