An enantioselective approach to trehazolin: A concise and efficient synthesis of the aminocyclopentitol core

Article abstract of DOI:10.1016/S0040-4039(00)02314-5

A concise and efficient synthesis of the aminocyclopentitol core of trehazolin is presented.

Full text of DOI:10.1016/S0040-4039(00)02314-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1471–1473
An enantioselective approach to trehazolin: a concise and
efficient synthesis of the aminocyclopentitol core
Mohindra Seepersaud and Yousef Al-Abed*
The Picower Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030, USA
Received 27 October 2000; revised 6 December 2000; accepted 7 December 2000
Abstract—A concise and efficient synthesis of the aminocyclopentitol core of trehazolin is presented. © 2001 Elsevier Science Ltd.
All rights reserved.
Several aminocyclopentitol containing natural products
have been discovered and found to display potent and
selective inhibitory effects on a variety of important
glycosidases.1,2 Examples include allosamidin 1, repre-
senting a new family of pseudotrisaccharide chitinase
inhibitors, mannostatins A 2a and B 2b, which are
selective mannosidase inhibitors and trehazolin 3 which
inhibits the trehalase-catalyzed breakdown of trehalose
into two molecules of glucose.
desymmetrization of substituted cyclopentene-4-meso-
diols, heterocycloadditions of cyclopentadienes, and
more recently the very efficient ketyl radical cyclizations
promoted by samarium diiodide.3
Recently ring closing metathesis (RCM) has emerged as
a powerful tool for the cyclizations of dienes.4 In
connection, we were the first to report the RCM on
substituted internal dienes, to give complex polyhydroxy-
lated cyclopentenes.5 Thus, an alternative strategy to
aminocyclopentitol core can be devised using an inter-
mediate polyhydroxylated cyclopentene. We have
recently reported a short and very efficient synthesis of
carba-arabinose precursor 4 in five steps (47% yield)
using RCM.6 This precursor 4 bears a striking struc-
tural similarity to ring A of 3. Logical retrosynthetic
analysis suggests that the target aminocyclopentitol
Different research groups have examined the chemical
and biological properties of these natural products and
interesting synthetic analogs as well as structure–activ-
ity relationships have been obtained.2 There have been
several strategies adopted towards the synthesis of the
aminocyclopentitol core present in these compounds.
These strategies2 include 1,3-dipolar cycloaddition, rad-
ical carbocyclizations of carbohydrate precursors,
Keywords: cyclopentenes; amino sugars; cyclitols; carbohydrate mimetics.
* Corresponding author. E-mail: yal-abed@picower.edu
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02314-5

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M. Seepersaud, Y. Al-Abed / Tetrahedron Letters 42 (2001) 1471–1473
moiety 5 could be readily assembled by elaboration of
precursor 4 (Scheme 1).
The NOE analysis of the epoxides 9 and 13 are shown
below. For epoxide 9, a 1% NOE was observed between
H3 and H4 and also for H4 and H5. This result confirms
a syn arrangement of the epoxide with the C4-OH
group. For epoxide 13, a 2% NOE was observed
between H3 and H4, a 0.3% NOE between H2 and
CH2OBn and no NOE between H4 and H5. This data
confirms an anti arrangement of epoxide with respect to
C4-OH.
Having our key cyclopentenes in hand, the p-methoxy-
benzyl (PMB) group of the b isomer (62%) 4b was
deprotected to give the allylic alcohol 8. Of note, the
corresponding a isomer (38%) 4a was deprotected and
inverted under standard Mitsunobu conditions to the b
allylic alcohol 8.7 The combined material was then
treated with mCPBA to afford an epoxide 9. Here a
single diastereomer was observed consistent with the
influence of the stereodirecting effect of the b hydroxy
group.8 Ring opening using NaN3 gave the diol 10. The
azide was then treated under Staudinger reduction
conditions9 to give the key aminocyclopentitol unit 11
in 69% overall yield from 4 (Scheme 2).
Confirmation of the stereochemistry around C-1 and
C-5 came from a comparison of the two diastereomeric
epoxides 9 and 13 (Scheme 3).10 The epoxide 13 was
prepared by treatment of 4b with mCPBA followed by
deprotective removal of the p-methoxybenzyl group. As
before, only one diastereomer was observed and this is
thought to arise from the steric crowding of the b-face
by the PMB group, thus making the a face more
accessible to epoxy approach.
The key aminocyclopentitol 11 can be converted in four
steps to trehazolin 3, via a procedure developed by
Storch de Gracia and co-workers.3 In their procedure
the pseudo anomeric centre C-4 was inverted using
triflic anhydride in the presence of pyridine at low
temperature to give the corresponding aminooxazoline,
Scheme 1.
Scheme 2. (a) DDQ, CH2Cl2, H2O, 84%; (b) (i) DDQ, CH2Cl2, H2O, 84%, (ii) PPh3, DEAD, C6H5COOH, NaOMe, 95%; (c)
mCPBA, CH2Cl2, 89%; (d) NaN3, DMF, 97%; (e) PPh3, THF, 98%.
Scheme 3. (a) mCPBA, CH2Cl2, 73%; (b) DDQ, CH2Cl2, 79%.

M. Seepersaud, Y. Al-Abed / Tetrahedron Letters 42 (2001) 1471–1473
1473
Scheme 4.
which was then subjected to hydrogenolysis to afford
trehazolin 3 (Scheme 4).
1179; (f) Crimmins, M. T.; King, B. W. J. Org. Chem.
1996, 61, 4192.
5. (a) Seepersaud, M.; Al-Abed, Y. Org. Lett. 1999, 1, 1463;
(b) Seepersaud, M.; Bucala, R.; Al-Abed, Y. Z. Natur-
forsch. 1999, 54b, 565.
6. Seepersaud, M.; Al-Abed, Y. Tetrahedron Lett. 2000, 41,
7801.
Of note, the a-allylic alcohol 4a is the right candidate
for the direct synthesis of trehazolamine, however, all
attempts at diastereoselective epoxidation failed, and an
inseparable mixture of epoxides were obtained.
7. Arco, M. J.; Trammel, M. H.; White, J. D. J. Org. Chem.
1976, 2075.
8. Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev.
1993, 93, 1307.
9. Shiozaki, M.; Arai, M.; Kobayashi, Y.; Kasuya, A.;
Miyamoto, S.; Furukawa, Y.; Takayama, T.; Haruyama,
H. J. Org. Chem. 1994, 59, 4450.
Overall this is the first use of the RCM in the construc-
tion of trehazoline intermediates. This method repre-
sents
a
simple and direct preparation of the
aminocyclopentitol core. The synthesis involved nine
steps with an overall yield of 32%. The strategy allows
for the stereocontrolled preparation of a series of
diverse analogs of trehazaloamine.
10. Selected spectroscopic data for compounds are as fol-
1
lows. Epoxide 9: H NMR (CDCl3, 500 MHz) l 2.86 (d,
J=10.8 Hz, O-H), 3.43 (d, J=11.6 Hz, CH2-OBn), 3.54
(s, H5), 3.74 (d, J=7.3 Hz, H3), 4.04 (s, H2), 4.20 (d,
J=11.6 Hz, CH2-OBn), 4.28 (ABq, J=11.4 Hz, Dl=0.07
ppm, 2H), 4.44 (dd, J=7.3, 10.8 Hz, H4), 4.47 (d, J=13.5
Hz, 2H), 4.48 (ABq, J=12.0 Hz, Dl=0.17 ppm, 2H),
7.28 (m, 15H). 13C NMR (CDCl3, 67.5 MHz) l 62.3,
64.8, 66.7, 71.7, 72.6, 73.2, 73.3, 79.1, 81.0, 127.8–128.7
(several signals), 137.3, 137.5, 138.0. MS (ES) m/z (M+
Na+), 455, (M+NH+4), 450 (base peak). Epoxide 13: 1H
NMR (CDCl3, 500 MHz) l 2.56 (bs, O-H), 3.58 (d,
J=11.2 Hz, CH2-OBn), 3.59 (s, H5), 3.84 (dd, J=5.2, 6.0
Hz, H3), 3.94 (d, J=11.2 Hz, CH2-OBn), 4.20 (d, J=5.2
Hz, H4), 4.28 (d, J=6.0 Hz, H2), 4.55 (ABq, J=11.8 Hz,
Dl=0.08 ppm, 2H), 4.56 (s, 2H), 4.7 (ABq, J=11.8 Hz,
Dl=0.03 ppm, 2H). 13C NMR (CDCl3, 67.5 MHz) l
60.2, 64.3, 66.8, 70.0, 72.6, 73.1, 73.2, 81.8, 82.5, 127.8–
128.7 (several signals), 137.2, 137.7, 138.2. MS (ES) m/z
(M+Na+), 455, (M+NH+4), 450 (base peak). Aminocy-
clopentitol 11: 1H NMR (C6D6, 270 MHz) l 3.17 (d,
J=6.0 Hz, H5), 3.65 (ABq, J=9.4 Hz, Dl=0.2 ppm, 2H,
CH2-OBn), 3.93 (dd, J=6.0, 7.0 Hz, H4), 4.07 (dd, J=
6.0, 7.0 Hz, H3), 4.15 (d, J=6.0 Hz, H2), 4.21 (s, 2H),
4.45 (ABq, J=11.6 Hz, Dl=0.06 ppm, 2H), 4.70 (ABq,
J=11.9 Hz, Dl=0.14 ppm, 2H), 7.31 (m, 15H). 13C
NMR (CDCl3, 67.5 MHz). l 66.0, 69.2, 72.9 (two sig-
nals), 73.9, 75.3, 79.8, 81.4, 89.0, 127.8–128.6 (several
signals), 137.6, 137.8, 138.3. MS (ES) m/z (M+H+), 450
(base peak), 391, 279.
Acknowledgements
The authors would like to thank the Patterson founda-
tion for their support.
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