A facile synthesis of a new trihydroxy piperidine derivative and (+)-proto-quercitol from D-(-)-quinic acid

Article abstract of DOI:10.1016/j.tetlet.2004.05.140

We described herein the new synthesis of a trihydroxy piperidine derivative (1,4,5-trideoxy-1,5-imino-D-ribo-hexitol) and (+)-proto-quercitol from D-(-)-quinic acid, both are considered as inhibitors for glycosidases.

Full text of DOI:10.1016/j.tetlet.2004.05.140

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5751–5754
A facile synthesis of a new trihydroxy piperidine derivative and
(+)-proto-quercitol from -())-quinic acid
D
Tzenge-Lien Shih,* Wei-Shen Kuo and Ya-Ling Lin
Department of Chemistry, Tamkang University, Tamsui 25 137, Taipei County, Taiwan, ROC
Received 22 March 2004; revised 5 May 2004; accepted 12 May 2004
Abstract—We described herein the new synthesis of a trihydroxy piperidine derivative (1,4,5-trideoxy-1,5-imino-
(+)-proto-quercitol from
Ó 2004 Elsevier Ltd. All rights reserved.
D
-ribo-hexitol) and
D
-())-quinic acid, both are considered as inhibitors for glycosidases.
The naturally occurring polyhydroxylated piperidines
(called azasugars or iminosugars) are known for their
diverse biological activity.1 The representative molecules
included 1-deoxynojirimycin (DNJ),2 1-deoxymannojiri-
mycin (DMJ),3 and fagomine4 (Fig. 1). In addition to
the above mentioned natural products, a trihydroxyl-
ated piperidine derivative 15 (1,4,5-trideoxy-1,5-imino-
cyclohexanepentols or deoxyinositols), are of interest
owing to their glycosidase inhibition activities.6 The
family of quercitols contained 16 stereoisomers7a but
only (+)-proto-, ())-proto-, and ())-vibo-quercitols were
found in plants.7b Among the 16 stereoisomers, the (+)-
proto-quercitol was discovered first, however, its syn-
thesis was not completed until 1968 by McCasland et al.
D
-lyxohexitol) has demonstrated potent inhibitions
from D
-(+)-chiro-inositol.6 Recently one of the appeared
against a-
D
-glucosidase, b-
D
-glucosidase, and b-
D
-
-
general strategies of synthesizing ( )-proto-quercitol
utilized the key intermediate, racemic 1,4,5-triacetoxy-
cyclohex-2-ene, which was derived from photooxygen-
ation of 1,4-cyclohexadiene followed by dihydroxylation
of the isolated double bond by Balci’s group.8
galactosidase.5a It was first synthesized from 3-deoxy-
D
ribo-hexose and required a glucose isomerase.5a Beside
the azasugars, the highly oxygenated cyclohexane
derivatives, such as quercitols (the generic term for
OH
OH
OH
OH
OH
HO
OH
OH
OH
HO
OH
OH
HO
HO
N
H
N
H
N
H
N
H
N
H
OH
OH
OH
DNJ
Fagomine
1
2
DMJ
OH
OAc
OAc
OH
OH
OAc
OAc
HO
AcO
AcO
OH
OAc
3
OAc
4
(+)-proto-quercitol
Figure 1.
Keywords: Azasugar; (+)-proto-Quercitol; D-Quinic acid.
* Corresponding author. Tel./fax: +886-2-8631-5024; e-mail: tlshih@mail.tku.edu.tw
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.140

5752
T.-L. Shih et al. / Tetrahedron Letters 45 (2004) 5751–5754
1
In conjunction with our ongoing project on the synthesis
of glycosidase inhibitors starting from -())-quinic acid,
we will present here a facile synthesis of 2 (1,4,5-trideoxy-
1,5-imino- -ribo-hexitol), which is the 2,3-epi analogue
of 1 (Scheme 1). During this study, we realized that we
could further utilize one of its intermediates 6 (vide infra,
Scheme 1) to synthesize (+)-proto-quercitol (Scheme 2).
and H5 were observed in their H NMR spectra.13 The
D
resolution of 6 and 7 was later confirmed by their
acetylation, respectively. The acetylated 7 showed the
NOE enhancement in NOESY experiment of H1 with
H4 and H5 but not acetylated 6.
D
Mesylation of 7 afforded allylic chloride 814 (87%) due to
the displacement of the mesylated group with chloride
through the SN2 reaction. Compound 8 was heated with
NaN3 in DMF through again the SN2 displacement to
furnish 915 in 85% yield. Compound 9 was subjected to
dihydroxylation and hydrogenation followed by pro-
tection with Cbz groupto afford 10.16 It was found that
Compound 5 was prepared in four steps from
D
-())-
quinic acid according to the literature procedure
(Scheme 1).9 The enone 5 was subjected to Luche
reduction10 at ambient temperature to afford 611 and 712
in 97% combined yield with a ratio of 1:1.4. The dis-
tinction between 6 and 7 was not so obvious since the
overlapping of a broad and multiple signals of H1, H4,
8
the employment of KMnO4/MgSO4 instead of OsO4/
NMO/TBOH conditions in dihydroxylation oxidation
OH
Cl
OH
N3
O
a
b
1
4
c
+
5
O
O
O
O
O
O
O
O
O
O
6
7
5
9
8
NHCbz
OH
OH
N
OH
d
e
HO
O
f
H
O
OH
O
OH
N
H
OH
O
OH
N
Cbz
OH
2
11
10
Cl
OH
steps
HO
6
O
N
H
O
OH
13
12
Scheme 1. Reagents and conditions: (a) NaBH4, CeCl3Æ7H2O, MeOH, rt, 97% (6+7); (b) 7, MsCl, pyr, 87%; (c) NaN3, DMF, 65 °C, 85%; (d) (i)
KMnO4, MgSO4, (ii) Pd/C, H2, MeOH, (iii) CbzCl, NaHCO3, (52%, three steps); (e) (i) NaIO4, MeOH, (ii) NaBH3CN, AcOH, MeOH, 76%; (f) H2,
Pd/C, 6 N HCl, 85%.
OH
O
OAc
OAc
OAc
OAc
a
c
d
b
O
O
O
AcO
HO
O
O
S
OAc
OAc
O
3
16
14
15
6
OH
OH
OAc
e
OH
OH
f
OAc
OAc
HO
AcO
OAc
4
(+)-proto-quercitol
Scheme 2. Reagents and conditions: (a) Ac2O, pyr, 93%; (b) (i) 80% AcOH, (ii) SOCl2, Et3N, 70% (two steps); (c) NaOAc, DMF, 90 °C, 72%; (d)
Ac2O, pyr, 90%; (e) (i) KMnO4, MgSO4, (ii) Ac2O, pyr, 34% (two steps); (f) NH3/MeOH, quantitative.

T.-L. Shih et al. / Tetrahedron Letters 45 (2004) 5751–5754
5753
199–210; (d) Look, G. C.; Fotsch, C. H.; Wong, C.-H.
Acc. Chem. Res. 1993, 26, 182–190; (e) Ganem, B. Acc.
Chem. Res. 1996, 29, 340–347; (f) Hudlicky, T.; Entwistle,
D. A.; Pitzer, K. K.; Thorpe, A. J. Chem. Rev. 1996, 96,
1195–1220; (g) Bols, M. Acc. Chem. Res. 1998, 31, 1; (h)
Sears, P.; Wong, C.-H. Angew. Chem., Int. Ed. 1999, 38,
2301–2324; (i) Lillelund, V. H.; Jensen, H. H.; Liang, X.;
Bols, M. Chem. Rev. 2002, 102, 515–554.
of 9 could eliminate the pale yellow color during the
subsequent purifications. A two-step conversion of 10
by oxidative cleavage with NaIO4 then reduced with
NaBH3CN afforded 1117 in 76% yield. Thus compound
11 was allowed to be hydrogenated in 6 N HCl over Pd/
C to provide the required azasugar 218 in 85% yield.
The structure of 2 was elucidated by HMBC and
HMQC experiments and the stereochemistry of H5 rel-
ative H2/H3 was further confirmed by no NOE obser-
vance of NOESY spectrum. Furthermore, efforts have
been made to synthesize 13, the enantiomer of 1, from
mesylation of 6 by the same manner of preparation of 2.
Unfortunately, it was proven fruitless. A tiny amount of
12 was received and most of 6 was recovered.
2. (a) Daigo, K.; Inamori, Y.; Takemoto, T. Chem. Pharm.
Bull. 1986, 34, 2243–2246; (b) Hughes, A. B.; Rudge, A. J.
Nat. Prod. Rep. 1994, 11, 135–162.
3. (a) Fellows, L. E.; Bell, E. A.; Lynn, D. G.; Pilkiewicz, F.;
Miura, I.; Nakanishi, K. J. Chem. Soc., Chem. Commun.
1979, 977–978; (b) Fuhrmann, U.; Bause, E.; Legler, G.;
Ploegh, H. Nature 1984, 307, 755–758; (c) Evans, S. V.;
Fellows, L. E.; Shing, T. K. M.; Fleet, G. W. J.
Phytochemistry 1985, 24, 1953–1955.
4. Kato, A.; Asano, N.; Kizu, H.; Matsui, K. J. Nat. Prod.
1997, 60, 312–314.
€
5. (a) Andersen, S. M.; Ekhart, C.; Lundt, I.; Stutz, A. E.
Carbohydr. Res. 2000, 326, 22–33; (b) Lemaire, M.; Veny,
With the accomplishment of the synthesis of 2, it is
obvious for us that 1R,4R,5R-triacetoxy-cyclohex-2-ene
3 can be easily prepared from the proper transforma-
tions of
D
-())-quinic acid (Scheme 2). Reports have
^
N.; Gefflaut, T.; Gallienne, E.; Chenevert, R.; Bolte, J.
Synlett 2002, 1359–1361.
6. McCasland, G. E.; Naumann, M. O.; Durham, L. J.
J. Org. Chem. 1968, 33, 4220–4227.
7. (a) McCasland, G. E.; Furuta, S.; Johnson, L. F.;
Shoolery, J. N. J. Am. Chem. Soc. 1961, 83, 2335–2343;
described the synthesis of ( )-proto-quercitol from the
racemic 3.8 Thus the chiral compound 3 can be used as a
crucial intermediate for synthesizing enantiomerically
pure (+)-proto-quercitol. Therefore, compound 6 was
acetylated to provide 14.19 The cyclohexyl groupof 14
was removed by 80% TFA (aq). Without further puri-
fication, the resulting diol was treated with thionyl
chloride20 to furnish 15 in 70% yield in a diastereomeric
mixture.21 Compound 1622 formed predominantly in
72% yield by heating 15 at 90 °C with sodium acetate in
DMF. It is noteworthy to mention that the elevated
temperature (>110 °C) and extended reaction time will
cause the low yields of 16 due to the aromatization of
15. The stereochemistry and regiochemistry of 16 were
further determined after its acetylation to provide 3 with
spectroscopic data in accordance with the reported
values.8b Therefore, our synthetic (+)-proto-quercitol23
was obtained by the known procedure, which converted
3 through 4.8b
€
(b) Maras, A.; Secen, H.; Sutbeyaz, Y.; Balci, M. J. Org.
Chem. 1998, 63, 2039–2041, and references cited therein.
€
8. (a) Secen, H.; Salamci, E.; Sutbeyaz, Y.; Balci, M. Synlett
1993, 609–610; (b) Salamci, E.; Secen, H.; Sutbeyaz, Y.;
€
€
Balci, M. J. Org. Chem. 1997, 62, 2453–2457; (c) Gultekin,
M. S.; Salamci, E.; Balci, M. Carbohydr. Res. 2003, 338,
1615–1619; For the synthesis of (+)-proto-quercitol see:
Hudlicky, T.; Thorpe, A. Synlett 1994, 899–901.
ꢀ
9. Colas, C.; Quiclet-Sire, B.; Cleophax, J.; Delaumeny,
J.-M.; Sepulchre, A.-M.; Gero, S. D. J. Am. Chem. Soc.
ꢀ
ꢀ
1980, 102, 857–858.
10. Chida, N.; Ohtsuka, K.; Nakazawa, K.; Ogawa, S. J. Org.
Chem. 1991, 56, 2976–2983.
11. Compound 6: clear syrup. 1H NMR (300 MHz, CDCl3): d
5.89 (br d, J ¼ 10:3 Hz, 1H), 5.71 (ddd, J ¼ 10:3, 4.4,
2.5 Hz, 1H), 4.35–4.50 (br m, 3H), 2.49 (dddd, J ¼ 13:9,
6.4, 3.7, 1.3 Hz, 1H), 1.66 (ddd, J ¼ 13:9, 9.5, 2.5 Hz, 1H),
1.48–1.60 (br m, 8H), 1.32–1.42 (br s, 2H). 13C NMR
(75 MHz, CDCl3): d 133.8, 127.4, 109.2, 72.2, 71.0, 63.3,
37.4, 35.8, 35.3, 25.1, 24.1, 23.9. MS (FAB) m=z 211
(Mþ+H, 38%), 193 (18%), 167 (32%), 99 (86%), 95 (100%).
12. Compound 7: clear syrup. 1H NMR (300 MHz, CDCl3): d
6.00 (dd, J ¼ 10:0, 4.7 Hz, 1H), 5.71 (dd, J ¼ 10:0, 2.2 Hz,
1H), 4.40–4.50 (m, 2H), 4.08 (dd, J ¼ 7:7, 4.1 Hz, 1H),
2.35 (dt, J ¼ 14:7, 3.9 Hz, 1H), 2.02 (ddd, J ¼ 14:7, 4.5,
2.3 Hz, 1H), 1.50–1.71 (m, 8H), 1.30–1.45 (br s, 2H). 13C
NMR (75 MHz, CDCl3): d 131.0, 127.3, 110.3, 72.6, 71.6,
62.8, 38.0, 35.9, 32.1, 25.0, 23.9, 23.8. MS (FAB) m=z 193
(Mþ+1)H2O, 55%), 147 (18%), 111 (33%), 70 (100%).
13. The determination of C-1 stereochemistry of both 6 and 7
has been reported while the isopropylidene group was used
In conclusion, we have accomplished the syntheses of a
new trihydroxy piperidine derivative 2 and (+)-proto-
quercitol from
Through the proper transformations of
acid, it is promising to synthesize not only this series of
piperidine derivatives but also the diastereomers of
quercitols in the future. The biological study of 2 and
employment of the key intermediates 6 and 7 for syn-
thesizing a variety of enantiomerically pure quercitols
are under investigation.
D
-())-quinic acid each in eleven steps.
-())-quinic
D
Acknowledgements
ꢀ
ꢀ
instead of the cyclohexyl group. Toth, Z. G.; Pelyvas, I. F.;
Szegedi, C.; Benke, P.; Magyar, E.; Miklovicz, T.; Batta,
G.; Sztaricskai, F. Carbohydr. Res. 1997, 300, 183–
189.
This work was financially supported from the National
Science Council (NSC92-2113-M-032-004) of the
Republic of China and Tamkang University.
14. Compound 8: pale yellow syrup. 1H NMR (300 MHz,
CDCl3): d 5.96 (dt, J ¼ 10:6, 2.5 Hz, 1H), 5.79 (dt,
J ¼ 10:6, 2.9 Hz, 1H), 4.60–4.69 (m, 1H), 4.40–4.53 (m,
2H), 2.51 (dt, J ¼ 14:0, 5.4 Hz, 1H), 2.10 (ddd, J ¼ 14:0,
8.4, 3.0 Hz, 1H), 1.53–1.60 (m, 8H), 1.32–1.45 (br s, 2H).
13C NMR (75 MHz, CDCl3): d 131.6, 128.0, 109.6, 71.7,
70.2, 51.6, 37.6, 35.8, 35.7, 25.0, 24.1, 23.8. MS (FAB) m=z
References and notes
1. (a) Paulsen, H. Angew. Chem., Int. Ed. Engl. 1966, 5, 495–
510; (b) Sinnott, M. L. Chem. Rev. 1990, 90, 1171–1202;
(c) Winchester, B.; Fleet, G. W. J. Glycobiology 1992, 2,

5754
T.-L. Shih et al. / Tetrahedron Letters 45 (2004) 5751–5754
1
191 (Mþ)1-HCl, 4%), 147 (6%), 111 (21%), 69 (88%), 57
(100%).
19. Compound 14: H NMR (300 MHz, CDCl3): d 5.75–5.85
(m, 2H), 5.44 (dd, J ¼ 8:5, 5.6 Hz, 1H), 4.40–4.52 (m, 2
H), 2.45 (dt, J ¼ 13:9, 4.9 Hz, 1H), 2.06 (s, 3H), 1.80 (ddd,
J ¼ 13:9, 8.8, 2.6 Hz, 1H), 1.50–1.62 (br m, 8H), 1.30–1.42
(br s, 2H). 13C NMR (75 MHz, CDCl3): d 170.4, 129.5,
128.9, 109.5, 71.7, 70.7, 66.4, 37.5, 35.8, 31.4, 25.1, 24.0,
23.9, 21.2. MS (FAB) m=z 252 (Mþ, 22%), 209 (20%), 155
(20%), 95 (100%), 69 (92%).
15. Compound 9: pale yellow syrup. 1H NMR (300 MHz,
CDCl3): d 6.00 (ddd, J ¼ 10:0, 3.2, 1.8 Hz, 1H), 5.90 (dd,
J ¼ 10:0, 2.6 Hz, 1H), 4.40–4.48 (m, 1H), 4.29 (ddd,
J ¼ 10:2, 8.6, 4.5 Hz, 1H), 3.75–3.85 (m, 1H), 2.19 (dt,
J ¼ 13:2, 4.9 Hz, 1H), 1.88 (dt, J ¼ 13:2, 8.2 Hz, 1H),
1.50–1.75 (m, 8H), 1.32–1.45 (m, 2H). 13C NMR (75 MHz,
CDCl3): d 129.5, 128.2, 110.6, 71.0, 70.0, 54.2, 38.1, 35.5,
31.5, 25.1, 24.0, 23.7. MS (EI) m=z 235 (Mþ, 26%), 206
(31%), 192 (95%), 178 (56%), 57 (100%).
20. Kim, C. U.; Lew, W.; Liu, H.; Zhang, L.; Swaminathan,
S.; Bischofberger, N.; Chen, M. S.; Mendel, D. B.; Tai, C.
Y.; Laver, W. G.; Stevens, R. C. J. Am. Chem. Soc. 1997,
119, 681–690.
16. A diastereomeric mixture was obtained as a clear syrup. It
is not necessary to determine or purify each of them at this
stage.
17. Compound 11 was isolated as a clear syrupby simple
filtration and used for the next step.
21. Compound 15, a pale yellow syrup, was isolated as a
diastereomeric mixture.
1
22. Compound 16: H NMR (300 MHz, CDCl3): d 5.80–5.93
(m, 1H), 5.74 (dd, J ¼ 10:0, 2.3 Hz, 1H), 5.35 (dd, J ¼ 7:7,
3.8 Hz, 1H), 5.10–5.18 (m, 1H), 4.03 (ddd, J ¼ 11:0, 7.3,
3.8 Hz, 1H), 2.11 (s, 3H), 2.05–2.09 (m, 1H), 2.03 (s, 3H),
1.93 (ddd, J ¼ 14:0, 11.0, 4.4 Hz, 1H). 13C NMR (75 MHz,
CDCl3): d 171.5, 170.3, 129.7, 127.9, 75.0, 66.9, 66.8, 66.7,
34.0, 21.1. MS (FAB) m=z 197 (Mþ)H2O, 16%), 155
18. Compound 2: clear syrup. Column chromatography (230–
400 mesh SiO2, CH2Cl2–MeOH–10% NH4OH ¼ 2:1:0.5).
1H NMR (500 MHz, D2O+CD3OD): d 3.99 (dd, J ¼ 6:0,
3.0 Hz, 1H), 3.58 (ddd, J ¼ 9:8, 6.0, 2.9 Hz, 1H), 3.50 (dd,
J ¼ 11:0, 4.9 Hz, 1H), 3.36 (dd, J ¼ 11:0, 7.1 Hz, 1H),
2.95–3.03 (m, 1H), 2.85–2.90 (m, 2H), 1.79 (dt, J ¼ 14:0,
3.0 Hz, 1H), 1.40 (ddd, J ¼ 14:0, 11.8, 2.4 Hz, 1H). 13C
NMR (125 MHz, D2O+CD3OD): d 70.3, 68.7, 66.2, 52.4,
(96%), 95 (100%).
21
D
23. For synthetic (+)-proto-quercitol in this article: ½aꢀ +25.3
(c 0.2, H2O) lit.7a +26 (H2O). Its spectroscopic data (1H
and 13C NMR) are all consistent with the reported
values.8b
46.8, 35.1. HRMS (FAB) calcd for C6H14NO3 (Mþ+H)
21
D
148.0974. Found 148.0978. ½aꢀ )49.2 (c 0.3, H2O).