Expeditious synthesis of tri- and tetrahydroxyazepanes from D-(-)-quinic acid as potent glycosidase inhibitors

Article abstract of DOI:10.1021/jo070058x

(Chemical Equation Presented) Several new stereoisomers of 3,4,6-trihydroxyazepanes and 7-hydroxymethyl-3,4,5-trihydroxyazepanes as well as known 3,4,5-trihydroxyazepanes were synthesized as potent glycosidase inhibitors from D-(-)-quinic acid in an effic

Full text of DOI:10.1021/jo070058x

A number of tetra-,1,4c,6,7 tri-,7d,f,h,o and dihydroxy7d,f azepanes
thus have been prepared by different approaches. Among
trihydroxyazepanes, only a few methods were reported to
prepare 3,4,6-trihydroxyazepanes, such as the Lundt procedure
starting from 3-deoxysugars7d or the chemoenzymatic approach
developed by Wang et al.7h Meanwhile, a novel class of
azepanes containing an extra hydroxymethyl substituent are
considered not only to provide an additional interaction with
the active sites of glycosidases,4c but also to enhance the
conformational flexibility.7b,8 However, their syntheses were
described in a limited number of reports.4c,7k,n,9 In conjunction
with our interest in the syntheses of various glycosidase
inhibitors,10 we report herein an expeditious synthesis of new
stereoisomeric 3,4,6-trihydroxyazepanes and 7-hydroxymethyl-
3,4,5-trihydroxyazepanes from D-(-)-quinic acid.
Expeditious Synthesis of Tri- and
Tetrahydroxyazepanes from D-(-)-Quinic Acid as
Potent Glycosidase Inhibitors
Tzenge-Lien Shih,*,† Ru-Ying Yang,† Shiou-Ting Li,‡
Cheng-Fan Chiang,† and Chun-Hung Lin*,‡
Department of Chemistry, Tamkang UniVersity, Tamsui, Taipei
County 25137, Taiwan, and Institute of Biological Chemistry,
Academia Sinica, NanKang, Taipei 11529, Taiwan
tlshih@mail.tku.edu.tw; chunhung@gate.sinica.edu.tw
ReceiVed January 10, 2007
The synthesis of 3,4,6-trihydroxyazepanes 1, 2, and 3 is
depicted in Scheme 1. Protected 1,4,5-cyclohex-2-ene-triols 11,
12, and 17, previously prepared from D-(-)-quinic acid,11 were
subjected to dihydroxylation under RuCl3/NaIO4/phosphate
(4) (a) Cai, J.; Davison, B. E.; Ganellin, C. R.; Thaisrivongs, S.; Wibley,
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Stu¨tz, A. E.; Wrodnigg, T. M. Curr. Top. Med. Chem. 2003, 3, 513-523.
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Y.; Rodr´ıguez-Garc´ıa, E.; Vogel, P.; Jime´nez-Barbero, J.; Sinay¨, P. Org.
Biomol. Chem. 2004, 2, 1492-1499 and references cited therein.
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B.; Wilkiel, H.; Sharma, M.; Carpenter, N.; Fleet, G. W.; Bernacki, R. J.
Anticancer Res. 1992, 12, 161-166.
Several new stereoisomers of 3,4,6-trihydroxyazepanes and
7-hydroxymethyl-3,4,5-trihydroxyazepanes as well as known
3,4,5-trihydroxyazepanes were synthesized as potent gly-
cosidase inhibitors from D-(-)-quinic acid in an efficient
manner. The key step employs dihydroxylation of protected
chiral 1,4,5-cyclohex-2-enetriols under RuCl3/NaIO4/phos-
phate buffer (pH 7) condition, followed by reductive amino
cyclization. We found the choice of an appropriate protecting
group to C1-OH of chiral 1,4,5-cyclohex-2-enetriols would
increase the yields of cyclization. The preliminary biological
data indicate some of these azepanes possess potent inhibition
against R-mannosidase and R-fucosidase.
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237-241.
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PrakashaReddy, J. J. Org. Chem. 2004, 69, 4760-4766. (l) Painter, G. F.;
Eldridge, P. J.; Falshaw, A. Bioorg. Med. Chem. 2004, 12, 225-232. (m)
Painter, G. F.; Falshaw, A.; Wong, H. Org. Biomol. Chem. 2004, 2, 1007-
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Azepanes,1 the seven-membered-ring azasugars or iminocy-
clitols, along with five- and six-membered rings of azasugars
are well-known as glycosidase inhibitors.2 Their usage in the
treatment of diabetics,2b,3 viral infections,4 and cancer2c,5 has
attracted a great deal of attention due to good inhibitory potency.
* Address correspondence to these authors .T.-L.S.: phone/fax 886-2-
86315024. C.-H.L.: phone 886-2-27890110, fax 886-2-26514705.
† Tamkang University.
‡ Academia Sinica.
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Inhibitors: Nojirimycin and Beyond; Wiley-VCH: Weinheim, Germany,
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1924.
10.1021/jo070058x CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/05/2007
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J. Org. Chem. 2007, 72, 4258-4261

SCHEME 1. Synthesis of 3,4,5- and 3,4,6-Trihydroxyazepanes
TABLE 1. Yields of Dihydroxylation under Different Conditions
TABLE 2. Yields of Reductive Amino Cyclization with Different
Reducing Agents
condition time (min) 20 f 22 (%) 21 f 23 (%) 26 f 27 (%)
condition
22 f 24:29 (%)
23 f 25:29 (%)
27 f 28:30 (%)
a
b
c
120
30
<10
69
27
65
69
43
69
52
64
64
a
b
36:9
40:11
29:16
30:12
33:13
52:13
a KMnO4, MgSO4, EtOH:H2O (1:1), rt. b RuCl3‚3H2O, NaIO4, EtOAc:
CH3CN:H2O (3:3:1), 0 °C. c RuCl3‚3H2O, NaIO4, EtOAc:CH3CN:H2O:
Na2HPO4‚2H2O (3:3:1:1), 0 °C.
a BnNH2 (6.1 equiv), NaBH(OAc)3 (3.3 equiv), CH2Cl2, rt. b BnNH2
(1.0 equiv), NaBH3CN (1.0 equiv), AcOH (1.0 equiv), MeOH, 0 °C to rt.
materials 20, 21, and 26 were hydroxylated under the condition
of KMnO4/MgSO4 to give moderate yields (52-69%, Table 1,
condition a).11,12 Lower yields were obtained under the condition
of RuCl3/NaIO4/H2O, which was attributed to the undesired
deprotection of cyclohexyl ketal at the resulting low pH
(condition b). The additional presence of phosphate buffer13 led
to improved yields with significant reduction of the reaction
time (condition c). Phosphate buffer thus helped to maintain
the reaction solution at a neutral pH. The stereochemistry of
buffer (pH 7) condition to afford 13 (80%), 14 (73%), and 18
(83%), respectively. The resulting diols 13, 14, and 18 were
oxidatively cleaved by NaIO4 to provide the corresponding
dialdehydes. Subsequent reductive amino cyclization was
optimized by using benzylamine (6.1 equiv) and NaBH(OAc)3
(3.3 equiv) to afford 15 (63%), 16 (76%), and 19 (80%),
followed by hydrogenation with 10% Pd/C in MeOH-2 N HCl
to afford the target molecules 1 (67%), 2 (99%), and 3 (99%),
respectively. The synthesis took four steps from protected
cyclohexenetriols 11, 12, and 17 with overall yields of 33-
66%, or ten steps from D-(-)-quinic acid with 17-34% yields.
(12) Salamci, E.; Secen, H.; Su¨tbeyaz, Y.; Balci, M. J. Org. Chem. 1997,
62, 2453-2457.
(13) (a) Shing, T. K. M.; Tai, V. W.-F.; Tam, E. K. W. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 2312-2313. (b) Shing, T. K. M.; Tam, E. K. W.
J. Org. Chem. 1998, 63, 1547-1554. (c) Plietker, B.; Miggemann, M. Org.
Biomol. Chem. 2004, 2, 2403-2407.
A similar route was studied to synthesize the same products
1, 2, and 3, in which the aforementioned benzyl ether was
substituted with an acetate as the protecting group. The starting
J. Org. Chem, Vol. 72, No. 11, 2007 4259

SCHEME 2. Synthesis of 7-Hydroxymethyl-3,4,5-trihydroxyazepanes
the diols of 22, 23, and 27 was rigorously determined in
accordance with our previous report.11 Compounds 22, 23, and
27 were further oxidized by NaIO4 and subjected to reductive
amino cyclization by treatment with BnNH2 under the reduction
azepanes 6, 7, and 8, respectively, in three steps, including
ozonolysis, reductive amination, and final deprotection. A
different route in the synthesis of hydrochloride salt forms of 6
and its C7 epimer furnished 9 and 10, respectively, derived from
37 which was prepared from D-(-)-quinic acid in six steps.22
The stereochemistry was lost at C7 while compound 37 was
subjected to dihydroxylation, oxidative cleavage, and reductive
aminocyclization.23 Therefore, two separable C7-epimeric prod-
14
condition of either NaBH(OAc)3 or NaBH3CN/AcOH.15
Consistent with the previous report that the reaction yield is
often affected by the choice of reducing agents,15 NaBH3CN/
AcOH (Table 2, condition b) was found to give slightly better
yields than NaBH(OAc)3 (condition a). The explanation of the
lower yields of 24 (40%), 25 (30%), and 28 (52%) was due to
the acyl migration from C1 to C3 in compounds 22, 23, and 27
upon the addition of NaIO4 to lead to the diastereomers 29 and
30 as the unexpected products. Compounds 24, 25, 28, 29, and
30 were finally deprotected by hydrogenolysis in the presence
of 10% palladium on charcoal under acidic conditions to give
116 (97%), 217 (99%), 318 (99%), 4 (50%), and 519 (41%),
respectively.
(21) Shing, T. K. M.; Cui, Y.-X.; Tang, Y. Tetrahedron 1992, 48, 2349-
2358.
(22) Valsecchi, E.; Tacchi, A.; Prosperi, D.; Compostella, F.; Panza, L.
Synlett 2004, 2529-2532.
(23) The resulting stereochemistry observed in the oxidation and
subsequent reductive amination of 33 and 37 could be explained by
following molecular models.
The synthesis of 7-hydroxymethyl-3,4,5-trihydroxyazepanes
6, 7, and 8 was carried out in an analogous manner
(Scheme 2). Protected 1-hydroxylmethyl-3,4,5-cyclohexene-
triols 31, 32, and 33, prepared from D-(-)-quinic acid according
to the reported procedure,20,21 were transformed to the desired
(14) Painter, G. F.; Eldridge, P. J.; Falshaw, A. Bioorg. Med. Chem.
2004, 12, 225-232.
(15) Baxter, E. W.; Reitz, A. B. J. Org. Chem. 1994, 59, 3175-3185.
(16) The synthesis of the enantiomer of compound 1 has been reported.
See ref 7d.
The imine intermediate likely adopts a twist-boat conformation due to the
protecting group of cyclohexyl ketal. As for the reduction of the intermediate
A, the benzyl ether at C6 is situated at the pseudoaxial position (i.e., endo-
cyclic), making it possible to coordinate the triacetoxyborohydride to have
the hydride transfer from the bottom face. On the other hand, the benzyl
ether of the intermediate B is located at the pseudoequatorial position (i.e.,
exo-cyclic), in which the oxygen unlikely interacts with the reducing agent
to deliver the hydride. The reducing agent thus attacks from both sides of
the imine group to lose stereoselectivity.
(17) The synthesis of compound 2 has been reported. See ref 7h.
(18) The synthesis of the enantiomer of compound 4 has been reported.
See ref 7h.
(19) The 1H NMR of compound 5 was taken in D2O instead of CD3OD.
See ref 7d.
(20) Alves, C.; Barros, M. T.; Maycock, C. D.; Ventura, M. R.
Tetrahedron 1999, 55, 8443-8456.
4260 J. Org. Chem., Vol. 72, No. 11, 2007

NMR (125 MHz, D2O + CD3OD) δ 71.1, 70.8, 65.9, 53.4, 49.7,
37.7. HRMS (FAB) calcd for C6H14NO3 ([M + H]+) 148.0974,
found 148.0975.
ucts, 38 and 39, were isolated in 34% and 41% total yields.
The stereochemistry of 38 and 39 was then distinguished by
NOESY and other spectra.
(3S,4R,6R)-Trihydroxyazepane (2). Flash column chromatog-
raphy (230-400 mesh SiO2, MeOH/CH2Cl2/10% NH4OH ) 1/15/
0.1 then 1/3/0.5) afforded a pale yellow syrup. [R]23D -0.5 (c 0.3,
H2O). 1H NMR (300 MHz, D2O) δ 4.24 (ddd, J ) 9.6, 6.3,
3.2 Hz, 1H), 4.20-4.10 (m, 1H), 4.07 (ddd, J ) 9.6, 3.9, 2.2 Hz,
1H), 3.34 (dd, J ) 13.8, 3.0 Hz, 1H), 3.30-3.20 (m, 2H), 3.16
(dd, J ) 13.8, 5.7 Hz, 1H), 2.09 (ddd, J ) 14.6, 9.7, 3.3 Hz, 1H),
1.93 (ddd, J ) 14.6, 6.5, 3.9 Hz, 1H). 13C NMR (75 MHz, D2O +
CD3OD) δ 69.8, 69.2, 63.6, 51.4, 47.6, 36.6. HRMS (FAB) calcd
for C6H14NO3 ([M + H]+) 148.0974, found 148.0979.
In summary, the new 1 (3S,4R,6R)-, 2 (3S,4R,6S)-, and 3
(3R,4R,6S)-trihydroxyazepanes accompanying with known 4
(3R,4R,5R)- and 5 (3R,4S,5R)-trihydroxyazepanes each have
been efficiently synthesized from D-(-)-quinic acid in ten steps.
The benzyl group at the C1 position is superior to the acyl group
when using protected 1,4,5-cyclohex-2-enetriols as starting
materials. The protecting group plays an important role not only
in the yields of dihydroxylation reactions, but also in the
efficiency of reductive aminocyclization. Obviously, the acyl
groups in 22, 23, and 27 were sensitive to the acidic condition
that made acyl migration possible to cause low reaction yields.
Among these synthetic tri- and tetrahydroxyazepanes, the
preliminary result indicated that compound 3 is a potent inhibitor
against R-mannosidase (from jack bean) and R-fucosidase (from
Thermotoga maritima) with Ki values of 21.1 and 14.9 µM,
respectively.24 The potency is considered to be equivalent or
even better to other reported tri- and tetrahydroxyazepanes.7d,9b
(3R,4R,6S)-Trihydroxyazepane (3). Flash column chromatog-
raphy (230-400 mesh SiO2, MeOH/CH2Cl2/10% NH4OH ) 1/15/
0.1 then 1/3/0.5) afforded a pale yellow syrup. [R]21D -6.4 (c 0.3,
1
H2O). H NMR (300 MHz, D2O) δ 4.10-3.90 (m, 1H), 3.78 (td,
J ) 7.4, 3.4 Hz, 1H), 3.70 (td, J ) 7.4, 3.4 Hz, 1H), 3.19 (dd, J )
14.4, 3.2 Hz, 1H), 3.13 (dd, J ) 13.8, 4.4 Hz, 1H), 2.90 (dd, J )
14.4, 7.0 Hz, 1H), 2.84 (dd, J ) 13.8, 7.6 Hz, 1H), 2.08 (dt, J )
14.3, 3.4 Hz, 1H), 1.82 (dt, J ) 14.3, 9.2 Hz, 1H). 13C NMR
(75 MHz, D2O + CD3OD) δ 75.3, 73.7, 67.5, 55.1, 51.8, 41.2.
HRMS (FAB) calcd for C6H14NO3 ([M + H]+) 148.0974, found
148.0968.
Experimental Section
(3S,4R,6S)-Trihydroxyazepane (1). Flash column chromatog-
raphy (230-400 mesh SiO2, MeOH/CH2Cl2/10% NH4OH ) 1/15/
Acknowledgment. This work was supported by the National
Science Council (NSC93-2113-M-032-007 and NSC94-2113-
M-032-006), Tamkang University, and Academia Sinica, Tai-
wan.
0.1 then 1/3/0.5) afforded a pale yellow syrup. [R]19 +18.6 (c
D
1
0.5, H2O). H NMR (500 MHz, D2O) δ 3.96-3.85 (m, 2H), 3.78
(ddd, J ) 10.1, 3.3, 2.4 Hz, 1H), 3.01 (dd, J ) 13.8, 4.2 Hz, 1H),
2.97 (dd, J ) 14.4, 5.7 Hz, 1H), 2.91-2.84 (m, 2H), 1.97 (ddd, J
) 14.0, 10.1, 8.9 Hz, 1H), 1.85 (dt, J ) 14.0, 3.8 Hz, 1H). 13C
Supporting Information Available: 1H and 13C NMR spectra
of all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(24) Regarding the conditions of R-mannosidase and R-fucosidase activity
assays, please see refs 10a and 10b for the details.
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