A stereoselective route toward polyhydoxylated piperidines. A total synthesis of (±)-deoxymannojirimycin

Article abstract of DOI:10.1021/ol051745i

(Chemical Equation Presented) A chemo- and stereoselective palladium-catalyzed amination of silylated butenediol dicarbonates has allowed for the introduction of a glycine moiety to obtain a desired functionalized epoxysilane. A stereoselective aldolizati

Full text of DOI:10.1021/ol051745i

ORGANIC
LETTERS
2005
Vol. 7, No. 22
4851-4854
A Stereoselective Route toward
Polyhydoxylated Piperidines. A Total
Synthesis of (±)-Deoxymannojirimycin
Ce´cile Boglio, Sebastian Stahlke, Serge Thorimbert,* and Max Malacria*
Institut de chimie mole´culaire (FR 2769), Laboratoire de chimie organique (UMR
CNRS 7611), UniVersite´ Pierre et Marie Curie, 4 place Jussieu, 75005 Paris, France
max.malacria@upmc.fr; serge.thorimbert@upmc.fr
Received July 22, 2005
ABSTRACT
A chemo- and stereoselective palladium-catalyzed amination of silylated butenediol dicarbonates has allowed for the introduction of a glycine
moiety to obtain a desired functionalized epoxysilane. A stereoselective aldolization then delivered the piperidine ring which may be used as
a precursor for the synthesis of a variety of polyhydroxylated azasugars. This efficient approach has been illustrated by the synthesis of
1-deoxymannojirimycin including a stereoselective reduction with LAH and a Tamao−Fleming oxidation of a C−SiMe2Ph bond.
For nearly half a century, glycosidase inhibitors have been
the subject of intense interest.1 Polyhydroxylated derivatives
of nitrogen heterocycles are one class of active compounds
that can be used as potential drugs to treat diabetes, hepatitis,
or various cancers.2 At physiological pH, their ammonium
salts have been recognized to act as transition-state analogues
of the enzymes. Moreover, as has been pointed out by Bols,3
“The best glycosidase inhibitors are compounds that have a
nitrogen in place of the exo- or endocyclic oxygen or
anomeric carbon...It is more important to mimic the charge
development in the transition state than the shape.” Some
polyhydroxylated piperidines which have been well studied
for their inhibiting properties are 1-deoxymannojirimycin (1),
1-deoxynojirimycin (2), and fagomine (3) (Figure 1).
Substituted piperidines, in general,4 and polyhydroxylated
derivatives,5 more precisely, have been the targets of a large
number of synthetic approaches6 due to their potential as
therapeutic agents and the need to find efficient access to
biologically active analogues. Herein, we propose a general
approach for the synthesis of 1-deoxyazasugars as well as
some silylated derivatives.7
Scheme 1 illustrates our retrosynthetic analysis. Access
to the desired polyhydroxylated piperidines could be achieved
(1) (a) Cai, G.; Salonikidis Petrus, S.; Fei, J.; Schwarz, W.; Schu¨le-in,
R.; Reutter, W.; Fan, H. FEBS J. 2005, 272, 1625-1638. (b) Karaveg, K.;
Siriwardena, A.; Tempel, W.; Liu, Z.-J.; Glushka, J.; Wang, B.-C.;
Moremen, K. W. J. Biol. Chem. 2005, 280, 16197-16207. (c) Zechel, D.
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Tetrahedron: Asymmetry 2000, 11, 1645-1680. (b) Kato, A.; Kato, N.;
Kano, E.; Adachi, I.; Ikeda, K.; Yu, L.; Okamoto, T.; Banba, Y.; Ouchi,
H.; Takahata, H.; Asano, N. J. Med. Chem. 2005, 48, 2036-2044.
(3) Lillelund, V. H.; Jensen, H. H.; Liang, X.; Bols, M. Chem. ReV. 2002,
102, 515-553.
(4) For some recent reviews, see: (a) Bailey, P. D.; Millwood, P. A.;
Smith, P. D. Chem. Commun. 1998, 633-640. (b) Laschat, S.; Dickner, T.
Synthesis 2000, 1781-1813. (c) Weintraub, P. M.; Sabol, J. S.; Kane, J.
M.; Borcherding, D. R. Tetrahedron 2003, 59, 2953-2989. (d) Felpin, F.-
X.; Lebreton, J. Eur. J. Org. Chem. 2003, 3693-3712. (e) Buffat, M. G. P.
Tetrahedron 2004, 60, 1701-1729.
Figure 1. Structure of 1-deoxymannojirimycin (DMJ) (1), 1-deoxy-
nojirimycin (DNJ) (2), and fagomine (3).
(5) For a recent review, see: Pearson, M. S. M.; Mathe´-Allainmat, M.;
Fargeas, V.; Lebreton, J. Eur. J. Org. Chem. 2005, 2159-2191.
10.1021/ol051745i CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/28/2005

level of stereoselectivity in 5 due, in part, to the presence of
the three-membered ring.
Scheme 1. Retrosynthetic Analysis of Polyhydroxypiperidines
Finally, the preparation of the desired allylamine 6 from
the easily accessible silylated bis-allylic derivatives 7 would
nicely illustrated the chemo- and stereoselective silicon
directed palladium-catalyzed alkylation we have recently
published.15
Our synthesis began with the preparation of the model
diacetate 7a bearing the triethylsilyl group. We found it to
react with N-tosylglycine methyl ester in the presence of
palladium catalyst and i-PrOH as solvent (Scheme 2).16,17
Scheme 2. Preparation and Palladium-Catalyzed Amination of
Silylated Allylic Derivatives 7
in a divergent way from the bicyclic system 4. The nitrogen
heterocycle bearing the epoxysilane function was considered
to be of great interest, as it could be functionalized following
selected reactions such as nucleophilic attacks on the
epoxysilane8 or Brook-type rearrangements,9 with or without
migration of the silicon group.10 For example, from 4,
chemoselective reduction of the ester and epoxysilane
functionalities should deliver the silyl analogue of DMJ.
Further reaction utilizing a Tamao-Fleming oxidation of the
C-Si bond should yield the protected form of 1.11 On the
other hand, direct oxidation of the epoxysilane12 should give
a keto alcohol, which can be stereoselectively reduced to
yield DNJ 2. Our synthetic approach to the piperidine
skeleton would be based on an intramolecular aldol conden-
sation of the acyclic precursor 5.13 Previously, we reported
a strategy for the enantioselective preparation of silylated
epoxy cyclopentanols via a stereoselective aldolization to
build the five-membered cycle.14 We expected the same high
Unfortunately, due to the low reactivity of the intermediate
π-allylic palladium complex, a competing â-elimination also
occurred to give the corresponding diene 9a in 40% yield.
We therefore prepared a more reactive precursor 7b having
two allylic carbonate functionalities. This turned out to be
advantageous, the desired product 8b being produced in 75%
yield with only a trace amount of the diene 9b. Careful
control of the reaction temperature was required for good
reproducibility. We noticed similar reactivity with the bis-
carbonate 7c, bearing a functionalizable Me2PhSi group. In
this instance, we were able to isolate the allylic amine 8c in
71% yield as a 95/5 mixture of two stereoisomers.
Treatment of 8c with a catalytic amount of potassium
carbonate in MeOH allowed for a smooth deprotection to
provide the corresponding allylic alcohol 6 in excellent yield
(Scheme 3). Epoxidation was next performed in a classic
manner with 2 equiv of m-CPBA. The epoxy alcohol 10, so
obtained was isolated in 75% yield after purification.
(6) For selected recent approaches, see: (a) Wang, R.-W.; Quing, F.-L.
Org. Lett. 2005, 7, 2189-2192. (b) Segraves, N. L.; Crews, P. J. Nat. Prod.
2005, 68, 118-121. (c) Goodenough, K. M.; Raubo, P.; Harrity, J. P. A.
Org. Lett. 2005, 7, 2993-2996. (d) Mart`ın, R.; Murruzzu, C.; Perica`s, M.
A.; Riera, A. J. Org. Chem. 2005, 70, 2325-2328. (e) Lemire, A.; Charette,
A. B. Org. Lett. 2005, 7, 2747-2750. (f) Legault, C. Y.; Charette, A. B. J.
Am. Chem. Soc. 2005, 127, 8966-8967. (g) Thomassigny, C.; Barroso, M.
T.; Greck, C. Lett. Org. Chem. 2005, 2, 316-318. (h) McDonnell, C.;
Cronin, L.; O’Brien, J. L.; Murphy, P. V. J. Org. Chem. 2004, 69, 3565-
3568. (i) Takahata, H.; Banba, Y.; Sasatani, M.; Nemoto, H.; Kato, A.;
Adachi, I. Tetrahedron 2004, 60, 8199-8205. (j) Adelbrecht, J. C.; Craig,
D.; Dymock, B. W.; Thorimbert, S. Synlett 2002, 467-470.
(7) For some silyl analogues of natural compounds, see: (a) Tacke, R.;
Schmid, T.; Merget, M. Organometallics 2005, 24, 1780-1783. (b) Bains,
W.; Tacke, R. Curr. Opin. Drug DiscoV. DeV. 2003, 6, 526-543. (c)
Cavelier, F.; Vivet, B.; Martinez, J.; Aubry, A.; Didierjean, C.; Vicherat,
A.; Marraud, M. J. Am. Chem. Soc. 2002, 124, 2917-2923.
(8) (a) Heffron, T. P.; Jamison, T. F. Org. Lett. 2003, 5, 2339-2342.
(b) Mordini, A.; Bindi, S.; Capperucci, A.; Nistri, D.; Reginato, G.; Valacchi,
M. J. Org. Chem. 2001, 66, 3201-3205.
(9) For two reviews on the Brook rearrangement, see: (a) Moser, W. H.
Tetrahedron 2001, 57, 2065-2084. (b) Brook, A. G. Acc. Chem. Res. 1974,
7, 77-84.
(10) (a) Achmatowicz, B.; Jankowski, P.; Wicha, J.; Zarecki, A. J.
Organomet. Chem. 1998, 558, 227-230. (b) Kira, K.; Isobe, M. Chem.
Lett. 2001, 432-433. (c) Courillon, C.; Thorimbert, S.; Malacria, M. C. R.
Chimie 2004, 7, 797-807.
(14) (a) Humilie`re, D.; Thorimbert, S.; Malacria, M. Synlett 1998, 1255-
1257. (b) Thorimbert, S.; Taillier, C.; Bareyt, S.; Humilie`re, D.; Malacria,
M. Tetrahedron Lett. 2004, 45, 9123-9126.
(15) (a) Thorimbert, S.; Malacria, M. Tetrahedron Lett. 1996, 37, 8483-
8486. (b) Thorimbert, S.; Malacria, M. Tetrahedron Lett. 1998, 39, 9659-
9660. (c) Commandeur, C.; Thorimbert, S.; Malacria, M. J. Org. Chem.
2003, 68, 5588-5592.
(11) Jones, G. R.; Landais, Y. Tetrahedron 1996, 52, 7599-7662.
(12) Trost, B. M.; Ball, Z. T.; Jo¨ge, T. Angew. Chem., Int. Ed. 2003, 42,
3415-3418.
(13) For related intramolecular aldolisations, see: (a) Danieli, B.; Lesma,
G.; Palmisano, G. Tetrahedron Lett. 1981, 22, 1827-1828. (b) Chandrakala,
P. S.; Katz, A. M.; Carell, H. L.; Sailaje, P. R.; Podile, A. R.; Nangia, A.;
Desiraju, G. R. J. Chem. Soc., Perkin Trans. 1 1998, 2597-2608. (c) Bravin,
F. M.; Busnelli, G.; Colombo, M.; Gatti, F.; Manzoni, L.; Scolastico, C.
Synthesis 2004, 353-358.
(16) For the reactivity of silylated acetate alcohols with benzylamine
,see: Thorimbert, S.; Giambastiani, G.; Commandeur, C.; Vitale, M.;
Malacria, M.; Poli, G. Eur. J. Org. Chem. 2003, 2702-2708.
(17) For a DFT study, see: Branchadell, V.; Moreno-Man˜as, M.; Pleixats,
R.; Thorimbert, S.; Commandeur, C.; Boglio, C.; Malacria, M. J. Organo-
met. Chem. 2003, 687, 337-345.
4852
Org. Lett., Vol. 7, No. 22, 2005

(46%). We reasoned that the free hydroxyl might first be
chelating to the reducing agent, thus disminishing the
regioselectivity of the reduction of the epoxysilyl function.
Thus, we protected the alcohol 4 as its TBDMS ether 12 in
96% yield. To our delight, this protection proved to be
beneficial for the reduction. After one night in Et2O at rt,
we observed the clean formation of two compounds. Direct
conversion of the crude mixture to the corresponding acetates
greatly simplified the purification (Scheme 4).
Scheme 3. Preparation of the Piperidine Skeleton
Scheme 4. Chemoselective Reduction of the Ester and
Epoxide and N-Tosyl Functions
However, the crude product was sufficiently pure to be used
directly for the next step.
Based on some of our past work, we used the iodoxy-
benzoic acid (IBX) to oxidize the primary alcohol. We also
tested SIBX,18 a stabilized form of IBX, and obtained the
desired aldehyde 5 in a comparable yield of 65%. Signifi-
cantly, these three consecutive steps could be performed
without purification of the intermediates to give 5 from 8c
in 85% yield. The acyclic epoxy aldehyde 5 reacted smoothly
in the presence of DBU to give the piperidine ring in 92%
yield.19 This aldolization proved highly stereoselective, giving
mainly one of the four possible diastereomers (Scheme 3).
As expected, the trans relationship between the oxirane and
the created hydroxyl was totally controlled.14 The two
diastereomers 4 and 11, obtained in an 85/15 ratio, cor-
responded to the two epimers at the C-R of the cyclic amino-
ester. In the major product 4, the ester functionality was trans
relative to the hydroxyl group. Attempts to improve the
diastereoselectivity by lowering the temperature, with or
without catalytic Yb(OTf)3, were unsuccessful. The two
diastereomers 4 and 11 could be separated by careful SiO2
flash chromatography. However, we reasoned that under our
basic conditions 11 could give the corresponding dehy-
droamino ester by dehydration. Indeed, from 5 after a
reaction time of 12 h, we obtained an 85/15 mixture of 4
and the expected dehydroamino ester deriving from 11. This
allowed for an easy isolation of pure 4 in 78% yield.
With the piperidine ring system in hand, we attempted
reduction of both the ester and the epoxide functionalities.
At first, the use of an excess of lithium aluminum hydride
reduced both the ester and the epoxide in moderate yield
We isolated the expected diacetate 13 in 54% yield, as
well as 6% of the triacetate 14 resulting from the removal
of the N-tosyl protecting group. The formation of 14 was
quite surprising in view of past literature.20 Indeed, the N-Ts
bond is usually cleaved under more drastic conditions such
as DIBAL in refluxing toluene, or by the use of various
radical anions, such as sodium naphthalemide. Finally, we
took advantage of this result and were able to cleanly convert
12 into the triacetate 14 in 78% yield (Scheme 4).
To explain the clean deprotection of the secondary amine,
we propose that the ester of 12 is first reduced into an
aluminate, which then assists in the cleavage of the N-Ts
bond. The resulting alumino amino-alcoholate could form a
stable 5-membered cycle A (Figure 2). This proposition is
Figure 2. Proposed intermediates during the reduction of 4 or 12.
(18) Ozane, A.; Pouyse´gu, L.; Depernet, D.; Franc¸ois, B.; Quideau, S.
Org. Lett. 2003, 5, 2903-2906.
(19) For related intermolecular alkylations or aldolizations of amino
esters, see: (a) Keynes, M. N.; Earle, M. A.; Sudharshan, M.; Hultin, P. G.
Tetrahedron 1996, 52, 8685-8702. (b) Kazmaier, U.; Grandel, R. Eur. J.
Org. Chem. 1998, 1833, 3-1840. (c) Zumpe, F. L.; Kazmaier, U. Synlett
1998, 1199-1200. (d) Kazmaier, U.; Zumpe, F. L. Angew. Chem., Int. Ed.
1999, 38, 1468-1470. (e) Kazmaier, U.; Maier, S.; Zumpe, F. L. Synlett
2000, 1523-1535. (f) Kummeter, M.; Kazmaier, U. Eur. J. Org. Chem.
2003, 3330-3334. (g) De Nicola, A.; Einhorm, C.; Einhorm, J.; Luche, J.
L. J. Chem. Soc., Chem. Commun. 1994, 879-880. (h) Lorthiois, E.; Marek,
I.; Normant, J. F. J. Org. Chem. 1998, 63, 566-574.
supported by the fact that we never observed N-Ts bond
cleavage for 4. For this compound, the aluminum is com-
plexed by the initially free alcohol early before any reductions
and finally gives the stable intermediate B.
(20) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; John Wiley & Sons: New York, 1999.
Org. Lett., Vol. 7, No. 22, 2005
4853

Final oxidation of the C-Si bond in 13 and 14 was
performed according to the Tamao-Fleming procedure21,22
(Scheme 5). Initial attempts at oxidation with the KBr/
tions of Han.24 Finally, the stereochemical assignment of the
formed compounds have been confirmed by an X-ray
structure analysis of 15 (Figure 3).25
Scheme 5. Tamao-Fleming Oxidation of the C-Si Bond
Figure 3. X-ray Analysis of 15.
In conclusion, we have reported a complementary,
highly selective, and efficient synthesis of polyhydroxylated
piperidines that rivals previous preparations (36%, 7 steps
from the acyclic precursor 8c). Our approach allows for the
differentiation of all the hydroxy groups, which we believe
offer a great potential for the elaboration of more complex
racemic molecules. A task which is under active investigation
in our laboratory, as well as an asymmetric version of this
synthetic approach.26
AcOOH mixture in a buffered AcONa/AcOH solution gave
the desired secondary alcohols 15 in a moderate conversion
of 50% after 15 h. Upon treatment with 1.6 equiv of
Hg(OAc)2 in a AcOOH/AcOH solution, both 13 and 14 were
oxidized into 15 and 16 in 65 and 78% yield, respectively.
Interestingly, these polyhydroxylated piperidines are or-
thogonally protected, which could be helpful for further
modifications. Finally, after selective removal of the TBS
protecting group, we acetylated the intermediate diol to
isolate in a quantitative yield, the known penta-acetylated
Acknowledgment. We gratefully acknowledge financial
support from UPMC, CNRS, and Institut Universitaire de
France of whom M.M. is a senior member. C.B. thanks the
Ministe`re de l’Education for financial support. S.S. from the
University of Go¨ttingen, thanks the Erasmus program. We
also wish to thank SIMAFEX and Dr. D. Depernet
(dominique.depernet@simafex.fr) for a gift of SIBX.
1
form of (()-DMJ 17. Our H NMR spectrum was not in
accordance with the one described by O’Doherty, but quite
similar to the description of Hutchinson.23 We fully depro-
tected 17 with 6 N HCl aqueous solution and obtained the
1
expected product in a quantitative yield. The H and 13C
Supporting Information Available: Full experimental
procedures, characterization of all new products, and refer-
ences to known compounds. Crystallograpic data for com-
pound 15 (CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
NMR spectra were in perfect accordance with the descrip-
(21) (a) Fleming, I.; Henning, R.; Plaut, H. J. Chem. Soc., Chem.
Commun. 1984, 29-31. (b) Tamao, K.; Ishida, N.; Tanaka, T.; Kumada,
M. Organometallics 1983, 2, 1694-1696. (c) See also a serie of papers
from Fleming in: J. Chem. Soc., Perkin Trans. 1 1992, 3295-3369.
(22) For some Tamao-Fleming oxidations applied in piperidine syn-
thesis, see: (a) Singh, R.; Ghosh, S. K. Tetrahedron Lett. 2002, 43, 7711-
7715. (b) Vanecko, J. A.; West, F. G. Org. Lett. 2002, 4, 2813-2816.
(23) (a) Hardick, D. J.; Hutchinson, D. W.; Trew, S. J.; Wellington, M.
H. Tetrahedron 1992, 48, 6285-6296. (b) Haukass, M. H.; O’Doherty, G.
A. Org. Lett. 2001, 3, 401-404.
OL051745I
(24) Singh, O. V.; Han, H. Tetrahedron Lett. 2003, 44, 2387-2391.
(25) The authors have deposited the atomic coordinates for the structure
of 15 at the Cambridge Crystallographic Data Centre, CCDC no. 279056.
(26) Adams, C. E.; Walker, F. J.; Sharpless, K. B. J. Org. Chem. 1985,
50, 420-422.
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Org. Lett., Vol. 7, No. 22, 2005