Synthesis of differentially protected cyclopentitol: Its application towards the stereoselective synthesis of 5-epi-calditol

Article abstract of DOI:10.1016/j.tetlet.2004.02.020

The synthesis of differentially protected cyclopentitol derivative 5 is described using ring-closing metathesis of a diene derived from D-mannose. Subsequent chemical modifications such as catalytic osmylation and chain extension using glycidyl triflate c

Full text of DOI:10.1016/j.tetlet.2004.02.020

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2817–2819
Synthesis of differentially protected cyclopentitol: its application
towards the stereoselective synthesis of 5-epi-calditol
C. V. Ramana,* Bethi Sridhar Reddy and Mukund K. Gurjar
National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
Received 2 December 2003;revised 24 January 2004;accepted 5 February 2004
Abstract—The synthesis of differentially protected cyclopentitol derivative 5 is described using ring-closing metathesis of a diene
derived from D-mannose. Subsequent chemical modifications such as catalytic osmylation and chain extension using glycidyl triflate
completed the synthesis of 5-epi-calditol.
Ó 2004 Elsevier Ltd. All rights reserved.
Cyclopentitols are unique derivatives isolated frequently
as subunits of biologically active natural products (Fig.
1). Calditol (1) was isolated as a cell wall component of
the extreme thermoacidophile Sulfolobus solfatiricus (a
bacterium present in hot springs and responsible for the
production of sulfuric acid from elemental sulfur).1 Its
absolute structure was the subject of speculation for a
in the synthesis 1–4.2;5 Intrigued by the structural simi-
larity between the cyclopentitol moieties of 1–4, we ini-
tiated a programme directed towards the synthesis of
these subunits preferably using a common starting point.
Herein we report the synthesis of a differentially pro-
tected cyclopentitol derivative 5, its stereo- selective
dihydroxylation and conversion of the resulting diol into
5-epi-calditol 6.
€
long time and Sinay and co-workers resolved the issue
once and for all by the total synthesis of calditol and its
possible isomers.2 Trehazolin (2) and bacterohopanetriol
ethers 3 and 4 are some other natural products, which
contain cyclopentitol as a subunit.3;4 Samarium iodide
mediated intramolecular pinacol coupling of suitably
disposed ketoaldehydes seemed to be a popular strategy
The synthesis began with the one carbon Wittig olefin-
ation of the known lactol 7 (derived from the crossed
aldol reaction between diisopropylidene mannofuranose
and formaldehyde in the presence of K2CO3 in metha-
nol)6 using Ph3P@CH2 to procure the olefin 8 in 83%
OH
OH OH
R
HO
HO
OH
OH
O
HO
HO
OH
OH
OH
OH
OH
OH
OH
N
HO
O
HN
OH
O
Calditol (1)
Trehazolin (2)
BnO
O
HO
HO
HO
HO
HO
HO
OH
O
O
OH
R =
NH
NH
2
2
HO
O
O
HO
HO
OH
OBn
OH
OH
OH
5
5-epi-Calditol (6)
3
4
Figure 1.
Keywords: Calditol;Cyclopentitols;Ring closing metathesis;Second generation Grubbs Õ catalyst;Catalytic osmylation.
* Corresponding author. Tel./fax: +91-20-25893614;e-mail: chepuri@dalton.ncl.res.in
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.020

2818
C. V. Ramana et al. / Tetrahedron Letters 45 (2004) 2817–2819
1
yield. The structure of olefin 8 was confirmed by H
NMR spectroscopy, in which signals due to the olefinic
protons appeared at 5.32 and 5.92 ppm.
tetroxide and N-methylmorpholine N-oxide in acetone/
water solvent system and occurred exclusively from the
a-face giving the diol 11. For characterization, the diol
11 was converted to its diacetate 11-Ac by treatment
with acetic anhydride in pyridine. In the 1H NMR
spectrum of 11-Ac, H(1) and H(2) appeared downfield at
5.21 (d, J ¼ 5:2 Hz) and 5.29 (dd, J ¼ 7:3, 5.2 Hz) ppm,
respectively.12 The observed NOEÕs between H(1) and
H(6)/H(60), H(4) and H(1)/H(2) in the NOESY spectrum
of 11-Ac clearly indicated a syn-spacial relation between
these protons thus confirming its assigned structure
(Scheme 1). After confirming the configuration of the
resulting diol 11, we proceeded to accomplish the syn-
thesis of 5-epi-calditol. Treatment of the diol 11 with
NaH and benzyl bromide in DMF followed by depro-
tection of the acetonide group with 80% aq acetic acid
afforded 13 in 76% yield.
Protection of the diol 8 as the corresponding dibenzyl
ether using benzyl bromide and NaH in DMF, followed
by selective hydrolysis of the 5,6-isopropylidene group
using 0.8% H2SO4 in methanol, gave the diol 9 in 82%
overall yield. The resulting diol 9 was then treated with
methanesulfonyl chloride and triethylamine in CH2Cl2
to afford the bis-mesylated compound in quantitative
yield, which was subjected to elimination (by treating
with sodium iodide in refluxing 2-butanone) without any
further purification to afford the diene 10 in 70% yield.7
1
The structure of diene 5 was confirmed by its H NMR
spectrum, in which six olefinic proton signals were
present between 5.2–5.7 ppm.8 As expected, our initial
efforts to bring about the ring closing metathesis of
diene 10 using the first generation GrubbsÕ catalyst met
with failure. Although, Eustache and co-workers
reported the successful RCM of a similar diene using
SchrockÕs catalyst,9 however, because of the superior
stability as well as easy availability of the GrubbsÕ sec-
ond generation catalyst we intended to use it in the
present context. Gratifyingly, the RCM of 10 with sec-
ond generation GrubbsÕ catalyst (B) was facile and the
key cyclopentitol derivative 5 was obtained in 81% yield
along with the unreacted 10 (11%).10 The structure of
compound 5 was confirmed by its 1H NMR spectrum, in
which only two olefinic proton signals were present at
5.90 (dd, J ¼ 2:3, 5.8 Hz) and 6.05 (d, J ¼ 5:8 Hz).11
Our intended strategy for the installation of the glycidyl
ether unit was the selective allylation of HO-C(4) of 13
and the Sharpless asymmetric dihydroxylation of
resulting allyl ether. Selective allylation of 13 was carried
out by treatment with 1.2 equiv each of NaH and allyl
bromide in THF, the allyl ether 14 was obtained in 76%
yield. Attempted asymmetric dihydroxylation of 14
using ADmix-b gave poor diastereoselectivity (insepa-
rable 1:1 epimeric mixture).13 After being met with dis-
couraging results in the asymmetric dihydroxylation, we
next focused our attention on alkylation of the diol 13
directly with the corresponding glycerol derivative
(Scheme 2).
We next focused our attention on the diastereoselectivity
of the dihydroxylation of 5. Eustache and co-workers
reported the dihydroxylation of a similar cyclopentitol
derivative (albeit protected as its benzyl ethers) with an
ꢀ2:1 diastereomeric ratio, the major being the one in
which dihydroxylation occurred from the a-face.9 The
dihydroxylation of 5 was carried out using osmium
After initial investigations with different 2,3-O-isopro-
pylidine (R)-glyceryl halides as well as with the corre-
sponding 1-O-sulfonates, we found that 13 could be
selectively alkylated (63% yield) by using 2,3-O-isopro-
pylidine-(R)-glycerol-1-O-triflate and n-BuLi in THF.
Deprotection of 5-epi-calditol 16 followed by peracetyl-
ation using acetic anhydride in pyridine and catalytic
O
OBn
OBn
OH
OH
OBn
OBn
O
O
ref. 6
a)
b), c)
d)
O
O
D-Mannose
O
O
HO
O
O
O
O
HO
O
O
OH
OH
9
7
8
10
e)
BnO
BnO
RO
OBn
OBn
OBn
OBn
OR
BnO
BnO
BnO
BnO
h)
i)
f)
HO
O
O
O
OBn
OBn
HO
O
O
O
11 R = H
11-Ac R = Ac
13
12
5
g)
H
H '
6
6
N
N
H
OBn H
BnO
1
Mes
Cl
Cl
Mes
Ph
H
2
4
Ru
OAc
O
OAc
PCy
H C
3
O
3
H
3
CH
3
B
NOE' s found in 11-Ac
Scheme 1. Reagents and conditions: (a) PPh3CH3þIÀ, NaNH2, THF/EtO2, 0 °C–rt, 10 h, 83%;(b) NaH, BnBr, DMF, 0 °C–rt, 4 h, 90%;(c) 0.8% w/v
H2SO4/H2O, MeOH, rt, 6 h, 91%;(d) MsCl, Et 3N, CH2Cl2, rt, 4 h, then NaI, 2-butanone, reflux, 6 h, 70% (overall);(e) B (2 mol%), C6H6, reflux, 6 h,
81%;(f) OsO 4, NMO, acetone/H2O, rt, 12 h, 80%;(g) Ac 2O, pyridine, DMAP (cat), rt, 4 h, 89%;(h) NaH, BnBr, DMF, 0 °C–rt, 6 h, 95%;(i) 80%
acetic acid/H2O, 60 °C, 4 h, 80%.

C. V. Ramana et al. / Tetrahedron Letters 45 (2004) 2817–2819
2819
63, 5883–5889;(c) Storch de Gracia, I.;Bobo, S.;Martin-
BnO
BnO
OBn
OBn
OBn
Ortega, M. D.;Chiara, J. L. Org. Lett. 1999, 1, 1705–1708;
(d) Kobayashi, Y. Carbohydr. Res. 1999, 315, 3–15.
6. (a) Ho, P. T. Can. J. Chem. 1979, 57, 381–383;(b) Wxzak,
I.;Whistler, R. L. Carbohydr. Res. 1984, 133, 235–245.
7. Gurjar, M. K.;Patil, V. J.;Pawar, S. M. Carbohydr. Res.
1987, 165, 313–317.
BnO
BnO
BnO
HO
a)
b)
HO
OBn
(1:1)
O
O
BnO
OBn
OBn
14
16
15
HO
OH
BnO
HO
HO
BnO
AcO
OBn
OBn
OAc
OAc
25
D
1
AcO
AcO
8. Spectral data of diene 10: ½aꢁ +30.6 (c 1.1, CHCl3); H
c)
d)
HO
NMR (CDCl3, 500 MHz): d 1.49, 1.56 (2s, 6H), 3.44 (d,
J ¼ 10:5 Hz, 1H), 3.47 (d, J ¼ 10:5 Hz, 1H), 3.88 (t,
J ¼ 8:3 Hz, 1H), 4.38 (d, J ¼ 8:3 Hz, 1H), 4.49 (d,
J ¼ 12:4 Hz, 1H), 4.52 (d, J ¼ 12:4 Hz, 1H), 4.62 (d,
J ¼ 12:3 Hz, 1H), 4.64 (d, J ¼ 12:3 Hz, 1H), 5.20 (dd,
J ¼ 1:8, 10.8 Hz, 1H), 5.27–5.32 (m, 2H), 5.46 (dd,
J ¼ 1:8, 17.1 Hz, 1H), 5.64 (ddd, J ¼ 8:3, 10.8, 17.1 Hz,
1H), 5.77 (dd, J ¼ 10:8, 17.1 Hz, 1H), 7.23–7.35 (m, 10H);
13C NMR (CDCl3, 50 MHz): d 26.5, 27.8, 70.0, 72.9, 73.5,
79.5, 80.3, 84.0, 108.2, 116.4, 120.2, 127.1, 127.5, 128.0,
128.2, 134.0, 136.2, 138.1, 138.5. Anal. Calcd for
C25H30O4: C, 76.11, H, 7.66. Found: C, 76.32, H, 7.55.
9. Sellier, O.;Weghe, P. V.;Eustache, J. Tetrahedron Lett.
1999, 40, 5859–5860.
13
O
O
O
AcO
O
OAc
6-Ac
Scheme 2. Reagents and conditions: (a) NaH, allyl bromide, THF,
0 °C–rt, 2 h, 76%;(b) ADmix- b, t-BuOH/H2O, 0 °C, 18 h, 78%;(c)
n-BuLi, 2,3-O-isopropylidene-(R)-glycerol-1-O-triflate, THF, )78–
0 °C, 6 h, 63%;(d) Pd/C, H 2, MeOH/AcOH (1:0.01), 6 h, then Ac2O,
pyridine, DMAP (cat), 12 h, 61% (overall).
dimethylaminopyridine gave the hepta-acetyl-5-epi-
calditol 6-Ac in 61% overall yield. The spectral and
analytical properties as well as the optical rotation of
6-Ac are comparable with the reported values.14
10. Trnka, T. M.;Grubbs, R. H. Acc. Chem. Res. 2001, 34,
18–29.
25
11. Spectral data of cyclopentene 5: ½aꢁ )41.7 (c 0.9, CHCl3);
D
1H NMR (CDCl3, 200 MHz): d 1.36, 1.42 (2s, 6H), 3.61 (d,
J ¼ 10:3 Hz, 1H), 3.66 (d, J ¼ 10:3 Hz, 1H), 4.42 (br s,
1H), 4.47 (d, J ¼ 2:3 Hz, 1H), 4.54 (d, J ¼ 11:8 Hz, 1H),
4.62 (s, 2H), 4.68 (d, J ¼ 12:1 Hz, 1H), 5.90 (dd, J ¼ 2:3,
5.8 Hz, 1H), 6.05 (br d, J ¼ 5:8 Hz, 1H), 7.28–7.35 (m,
10H); 13C NMR (CDCl3, 50 MHz): d 27.7, 28.1, 71.5, 73.5,
84.4, 87.4, 94.7, 112.2, 127.4, 127.5, 128.2, 128.3, 132.0,
137.6, 138.1, 138.2. Anal. Calcd for C23H26O4: C, 75.38, H,
To conclude, we have provided a simple preparative
procedure for the synthesis of differentially protected
cyclopentitol 5, and its application towards the diaste-
reoselective synthesis of 5-epi-calditol. Presently, work
towards the synthesis of naturally occurring aminocy-
clopentitol derivatives from 5 using the Overman aza-
Claisen rearrangement or epoxidation and subsequent
inter/intramolecular opening with amino-nucleophiles is
in progress.
7.15. Found: C, 75.14, H, 7.02.
25
12. Spectral data of diacetate 11-Ac: ½aꢁ : +47.6 (c 1.5,
D
CHCl3); 1H NMR (CDCl3, 500 MHz): d 1.35–1.47 (2s,
6H), 2.04–2.09 (2s, 6H), 3.60 (d, J ¼ 10:6 Hz, 1H), 3.61 (d,
J ¼ 10:6 Hz, 1H), 4.12 (dd, J ¼ 2:9, 7.3 Hz, 1H), 4.45 (d,
J ¼ 2:9 Hz, 1H), 4.58 (d, J ¼ 12:1 Hz, 1H), 4.59 (d,
J ¼ 12:0 Hz, 1H), 4.63 (d, J ¼ 12:1 Hz, 1H), 4.70 (d,
J ¼ 12:0 Hz, 1H), 5.21 (d, J ¼ 5:2 Hz, 1H), 5.29 (dd,
J ¼ 5:2, 7.3 Hz, 1H), 7.25–7.34 (m, 10H); 13C NMR
(CDCl3, 125 MHz): d 20.7, 20.8, 27.1, 27.4, 72.0, 72.9,
73.1, 73.9, 75.6, 85.0, 85.1, 86.6, 114.1, 127.6, 127.7, 127.8,
128.4, 128.5, 137.6, 137.8, 169.3, 169.5. Anal. Calcd for
C27H32O8: C, 66.93, H, 6.66. Found: C, 66.56, H, 6.42.
13. Kolb, H. C.;VanNieuwenhze, M. S.;Sharpless, K. B.
Chem. Rev. 1994, 94, 2483–2547;Wang, Z.-M.;Zhang,
X.-L.;Sharpless, K. B. Tetrahedron Lett. 1993, 34, 2267–
Acknowledgements
B.S.R. thanks CSIR for financial support in the form of
a research fellowship.
References and notes
1. (a) De Rosa, M.;De Rosa, S.;Gambacorta, A. Phyto-
chemistry 1977, 16, 1909–1912;(b) De Rosa, M.;De Rosa,
S.;Gambacorta, A.;Minale, L.;Bu ÕLock, J. D. Phyto-
chemistry 1977, 16, 1961–1965.
2. Bleriot, Y.;Untersteller, E.;Fritz, B.;Sinay, P. Chem. Eur.
J. 2002, 8, 240–246.
3. Ando, O.;Satake, H.;Itoi, K.;Sato, A.;Nakajima, M.;
Takahashi, S.;Haruyama, H.;Ohkuma, Y.;Kinoshita, T.;
Enekita, R. J. Antibiot. 1991, 44, 1165–1168.
4. (a) Renoux, J.-M.;Rohmer, M. Eur. J. Biochem. 1985,
151, 405–410;(b) Hermann, D.;Bisseret, P.;Connan, J.;
Rohmer, M. Tetrahedron Lett. 1996, 37, 1791–1794.
5. (a) Chiara, J. L.;Storch de Gracia, I.;Bastida, A. Chem.
Commun. 2003, 1874–1875;(b) Storch de Gracia, I.;
Dietrich, H.;Bobo, S.;Chiara, J. L. J. Org. Chem. 1998,
2270.
14. Spectral data of hepta-O-acetyl-5-epi-calditol (6-Ac): ½aꢁ
25
D
20
D
+16.2 (c 0.6, CHCl3);lit. 2 ½aꢁ : +17.9 (c 0.7, CHCl3); 1H
NMR (CDCl3, 500 MHz): d 2.06–2.12 (7s, 21H), 3.52 (dd,
J ¼ 4:3, 10.1 Hz, 1H), 3.78 (dd, J ¼ 0:8, 2.4 Hz, 1H), 3.88
(dd, J ¼ 4:8, 10.1 Hz, 1H), 4.13 (dd, J ¼ 6:9, 12.0 Hz, 1H),
4.17 (d, J ¼ 12:8 Hz, 1H), 4.29 (dd, J ¼ 3:9, 12.0 Hz, 1H),
4.87 (d, J ¼ 12:8 Hz, 1H), 5.10–5.18 (m, 1H), 5.20
(t, J ¼ 5:7 Hz, 1H), 5.32 (dd, J ¼ 2:8, 6.3 Hz, 1H), 5.61
(dd, J ¼ 0:8, 5.2 Hz, 1H); 13C NMR (CDCl3, 125 MHz): d
20.4, 20.7, 20.8, 20.9, 21.2, 61.9, 62.5, 69.2, 70.1, 71.7, 73.3,
80.5, 82.8, 83.2, 169.4, 169.6, 170.0, 170.1, 170.5. Anal.
Calcd for C23H32O15: C, 50.36, H, 5.88. Found: C, 50.52,
H, 5.72.