Asymmetrized tris(hydroxymethyl)methane as precursor of iminosugars: Application to the synthesis of isofagomine

Article abstract of DOI:10.1016/S0040-4039(02)02492-9

A new synthetic application of asymmetrized tris(hydroxymethyl)methane (THYM*), readily obtained in both enantiomeric forms through a chemoenzymatic procedure, is reported. In this case THYM* precursor 3 was elaborated by ring closing metathesis into some enantiopure branched tetrahydropyridines, that have been used as precursors of the potent glycosidase inhibitor isofagomine 28.

Full text of DOI:10.1016/S0040-4039(02)02492-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 357–360
Asymmetrized tris(hydroxymethyl)methane as precursor of
iminosugars: application to the synthesis of isofagomine
Giuseppe Guanti* and Renata Riva*
Dipartimento di Chimica e Chimica Industriale, Via Dodecaneso 31, I-16146 Genova, Italy
Received 15 October 2002; revised 6 November 2002; accepted 7 November 2002
Abstract—A new synthetic application of asymmetrized tris(hydroxymethyl)methane (THYM*), readily obtained in both
enantiomeric forms through a chemoenzymatic procedure, is reported. In this case THYM* precursor 3 was elaborated by ring
closing metathesis into some enantiopure branched tetrahydropyridines, that have been used as precursors of the potent
glycosidase inhibitor isofagomine 28. © 2002 Elsevier Science Ltd. All rights reserved.
4
Asymmetrized tris(hydroxymethyl)methane 1 (THYM*)
Scheme 1) and its synthetic equivalent bis(hydroxy-
also intramolecularly, of suitable alkenes obtained
1
(
after olefination of BHYMA*. Now we report a new
methyl) acetaldehyde 2 (BHYMA*) constitute a family
application of THYM*, starting directly from 3. The
double bond was not oxidatively cleaved at an early
stage; on the contrary, it was used as functional group
for a cyclization reaction, performed through a ring
closing metathesis (RCM), after the substitution of one
hydroxy group of 3 with a N-Boc protected allylamine
of readily accessible chiral building blocks, that have
1
found many synthetic applications in our group. One
of the most useful precursors of 1 or 2 is represented by
monoacetate 3, whose synthesis in both enantiomeric
forms by asymmetrization of prochiral precursors cata-
2
5
lyzed by lipase from porcine pancreas (PPL) was
moiety. This transformation was realized following
3
already described by us.
two similar routes, differing by the order of introduc-
tion of the Boc protecting group and the terminal olefin
unit.
Actually, derivative 3 contains a masked aldehydic
functionality, that can be introduced by the oxidative
cleavage of the double bond without racemization and
can be successively reduced to the corresponding alco-
hol. THYM* and BHYMA* have been submitted to
several transformations involving: (a) the substitution
of one oxygenated moiety with a suitable nucleophile
In the first route (Scheme 2) the N-Boc protected
6
amines to be used as substrates in RCM reaction, were
prepared by nucleophilic substitution with allylamine of
7
a O-activated (as mesylate) derivative of 3, followed by
protection of N as Boc. This substitution was per-
1
without the formation of new stereocentres; (b) the
stereoselective functionalization of one or two branches
1
with the creation of new stereogenic centres; (c) the
stereoselective elaboration, which has been performed
Scheme 1.
Scheme 2. Reagents and conditions: (a) MsCl, Et N, CH Cl ,
3
2
2
−
30°C; (b) allylamine, 80°C; (c) KOH, MeOH, 0°C; (d) DHP,
*
Corresponding authors. Tel./fax: +39-010-3536105 (G.G.); Tel.: +
9-010-3536126; fax: +39-010-3536118 (R.R.); e-mail: guanti@
chimica.unige.it; riva@chimica.unige.it
p-TSA, CH Cl , 0°C; (e) TIPS-Cl, imidazole, DMF, rt; (f)
Boc O, 1,2-dichloroethane, reflux.
3
2
2
2
0
040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02492-9

3
58
G. Guanti, R. Ri6a / Tetrahedron Letters 44 (2003) 357–360
formed on three different O-protected mesylates with
satisfactory results only for the O-THP derivative 8
tion of the hydroxy group. No acyclic derivatives,
arising from intermolecular metathesis, could be
detected, thus allowing us to work also in solutions
more concentrated than usual.
(
90% yield). Since we were interested in defining an
efficient protocol for the preparation of different O-
protected analogous of 10 to be submitted to RCM
reaction, we decided to follow another route (Scheme
It is noteworthy that, although different unsaturated
six-membered nitrogen heterocycles, have been synthe-
sized in the last few years using a RCM for the cycliza-
3
), involving the transformation of 3 into the corre-
sponding carbamate, followed by the allylation of its
anion. For this purpose, 3 was transformed (via mesyl-
ate) into the corresponding azide 11, which was reduced
13
tion step, the synthesis of these new chiral building
blocks, obtained through an 8-step sequence in 62%
overall yield from (R)-3 (compound 22), represents, to
best of our knowledge, the only example in which the
8
with Staudinger method. However, while starting from
1
1 we were able to isolate only amide 12, deriving most
acyclic precursor has been prepared through
a
likely from an intramolecular acyl transfer during
9
chemoenzymatic procedure, involving an asymmetriza-
hydrolysis of the intermediate iminophosphorane, the
14
tion and not a kinetic resolution Moreover, with our
reduction of azido alcohol 13, obtained by Pseu-
domonas cepacia (PCL) catalyzed hydrolysis of 11, fur-
nished the expected amine which was transformed in
situ into N-Boc derivative 14, according to a modified
methodology, both configuration at the stereogenic cen-
2
tre are in principle available.
1
0
These tetrahydropyridines can be seen as useful inter-
mediates for the synthesis of iminosugars, a class of
sugar shaped compounds that have found a growing
interest in the last years for their properties as glycosi-
literature procedure. The free alcoholic function of
this intermediate was then protected in three different
1
1
ways (THP, TBDMS, TIPS) and the corresponding
carbamates were allylated under classical basic condi-
tions to give the required O-protected allyl derivatives
with an overall yield varying from 22% (10) to 92%
15
dase and glycosyltransferase inhibitors. Compounds
0–22 constitute actually a series of useful intermediates
for the synthesis of isofagomine 28, a mimic of glu-
2
1
2
(
19).
1
6,17
18
cose,
and of its ‘gulo’ stereoisomer 29, since very
19,20
similar racemic derivatives
have been transformed
With three different O-protected allyl carbamates in
hand, we started to study the RCM reaction. We
examined different reaction conditions and, at the end,
the best results were obtained using the protocol
described in Scheme 3. The excellent yields of the
obtained tetrahydropyridines (20–22) suggest that the
steric hindrance of the branched substrates used as
precursors and the formation of a substituted olefin
into the final products, by epoxidation of the double
bond, followed by hydrolysis of the oxirane ring and
protecting groups removal (Scheme 4). To demonstrate
the possibility to use THYM* as precursor of these
compounds, we converted 22, the intermediate easier to
be prepared in a multigram scale, into 28 and 29,
following the literature procedure. We were surprised
by the scarce reactivity of the double bond with respect
to the epoxidation, which required unusual harsh con-
ditions in order to go to completion with an apprecia-
ble rate. Compounds 23 and 24 were obtained only in
moderate yield and with modest diastereomeric ratio.
The best results, either in terms of rate, yield and d.r.
were obtained on the unprotected alcohol 25, thus
suggesting that the stereoselectivity can not be
attributed mostly to sterical reasons.
(
isopropylethylene) as by-product instead of classical
ethylene, do not influence negatively the course of this
reaction, which occurred smoothly whatever the protec-
Scheme 3. Reagents and conditions: (a) 1. MsCl, Et N,
3
CH Cl , −30°C; 2. NaN , DMF, 50°C; (b) PPh , THF/H O,
2
2
3
3
2
5
5°C; (c) PCL, THF/H O 1:3, pH 7, rt; (d) 1. PPh , THF/
2
3
H O, rt; 2. Boc-ON, Et N, rt; (e) DHP, p-TSA, CH Cl , 0°C
2
3
2
2
1
2
2
1
2
(
15) or R R SiCl, imidazole, rt [R =Me, R =tBu (16),
1
2
R =R =iPr (17)]; (f) allyl bromide, NaH, DMF, rt; (g)
Grubb’s catalyst, 0.028 M (20), 0.014 M (21) or 0.036 M (22)
in CH Cl , reflux.
Scheme 4. Reagents and conditions: (a) mCPBA, CH Cl ,
2
2
reflux; (b) Bu NF, THF, rt; (c) 3% HCIO in Me CO, rt; (d)
4
4
2
AcOEt/3 M HCI 2:1, rt; (e) 1% aq KOH, reflux.
2
2

G. Guanti, R. Ri6a / Tetrahedron Letters 44 (2003) 357–360
359
Other methods, tested in order to improve most of all
the stereoselectivity, like for example Jacobsen cata-
6. Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998,
371–388.
21
lyst in the presence of mCPBA or NaClO, or t-
7. All new compounds reported in this paper have been
22
25
D
1
13
BuOOH in the presence of VO(acac)2
were
fully characterized ([h] , IR, GC–MS, H and
C
absolutely unsatisfactory: with the first conditions
only traces of the desired epoxides were obtained
starting from 22, while, with the second reagent, an
extensive decomposition of the starting compound 25
was observed. The mixture of the diastereomeric
NMR).
8
9
. Banfi, L.; Guanti, G.; Riva, R. Tetrahedron: Asymmetry
999, 10, 3571–3592.
1
. We experienced an analogous behavior on very similar
compounds, as reported in Ref. 8.
2
3
epoxides could not be separated and was converted
as such, by acidic or basic hydrolysis, into the final
products, that were quite easily separated by chro-
matography. Under acidic conditions, compounds 28
and 29 were obtained in moderate overall yield but
with complete retention of the d.r. of the starting
epoxides. On the other hand, the basic hydrolysis of
1
1
0. Ariza, X.; Urp ´ı , F.; Viladomat, C.; Vilarrasa, J. Tetra-
hedron Lett. 1998, 39, 9101–9102.
1. The preparation of 15 by protection of 13 as THP ether,
followed by azide reduction and introduction of the
carbamate moiety, was less satisfactory giving an overall
yield of 71%.
1
1
2. While we are not able to explain the low yield of 10, the
moderate yield of 18 is in part due to the competitive
intramolecular silyl migration from oxygen to nitrogen,
as previously experienced on monosilyl ethers of
THYM*. This problem was however solved using a
bulkier silylated group.
3. (a) Miller, S. J.; Grubbs, R. H. J. Am. Chem. Soc.
1995, 117, 5855–5856; (b) Jo, E.; Na, Y.; Chang, S.
Tetrahedron Lett. 1999, 40, 5581–5582; (c) Schleich, S.;
Helmchen, G. Eur. J. Org. Chem. 1999, 2515–2521; (d)
Souers, A. J.; Ellman, J. A. J. Org. Chem. 2000, 65,
1222–1224; (e) Taniguchi, T.; Ogasawara, K. Org. Lett.
2000, 2, 3193–3195; (f) Kumareswaran, R.; Balasubrama-
nian, T.; Hassner, A. Tetrahedron Lett. 2000, 41, 8157–
8162; (g) Agami, C.; Couty, F.; Evano, G. Tetrahedron:
Asymmetry 2000, 11, 4639–4643; (h) Mues, H.; Kazmaier,
U. Synthesis 2001, 487–498; (i) Banba, Y.; Abe, C.;
Nemoto, H.; Kato, A.; Adachi, I.; Takahata, H. Tetra-
hedron: Asymmetry 2001, 12, 817–819; (j) Varray, S.;
Lazaro, R.; Martinez, J.; Lamaty, F. Eur. J. Org. Chem.
2
6 and 27, furnished 28 and 29 with and a remark-
able changement of the d.r., with stereoisomer 29 pre-
vailing in this case. These data suggest that, only
under acidic conditions, the epoxide opening is
regioselective. Finally, the spectroscopic data of both
17,19
triols agree with those reported in literature
and,
in particular, the optically rotatory value of 28 fits
24
well with the reported one, thus demonstrating that
the whole sequence proceeded without racemization.
We are now trying to investigate more in detail the
mechanistically aspects of the last reactions, that have
never been pointed out in similar projects. Further-
more, we are also studying other stereoselective addi-
tions to the double bond of 22 and 25 in order to
synthesize new highly functionalized piperidine deriva-
tives of great interest for their potential biological
activity. Our data will be reported in due course.
Acknowledgements
2002, 2308–2316.
1
4. Only recently the enzymatic kinetic resolution of a com-
pound similar to 20–22 has been reported Altenbach,
H.-J.; Blanda, G. Tetrahedron: Asymmetry 1998, 9, 1519–
The authors gratefully thank Amano for a generous
gift of lipase from Pseudomonas cepacia, the Univer-
sity of Genova and MURST (COFIN 00) for finan-
cial support and Ms Monica Paravidino for her help
in this work.
1524.
1
5. Lillelund, V. H.; Jensen, H. H.; Liang, X. F.; Bols, M.
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therein.
1
6. Several enantioselective synthesis of 28, passing through
different intermediates, are known. See: (a) Jespersen,
T. M.; Dong, W.; Sierks, M. R.; Skrydstrup, T.; Lundt,
I.; Bols, M. Angew. Chem., Int. Ed. Engl. 1994, 33,
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2
2
25
25
24. 28: [h]
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=+18 (c 0.16, EtOH); 29: [h] =+22 (c 0.11,
D
D
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