The synthesis of highly functionalized enantiomerically enriched cyclohexanes. An approach to carba-sugars and aminocarba-sugars

Article abstract of DOI:10.1055/s-1999-2539

Starting from bicyclic hemiesters obtained by enzymatic hydrolysis of meso diesters, polyfunctionalized cyclohexanes were prepared with high stereoselectivity in a synthetic strategy of few steps involving a Curtius reaction followed by a retro Michael ri

Full text of DOI:10.1055/s-1999-2539

LETTER
87
The Synthesis of Highly Functionalized Enantiomerically Enriched
Cyclohexanes. An Approach to Carba-Sugars and Aminocarba-Sugars.
Emmanuel Couché, Rachel Deschatrettes, Karine Poumellec, Michel Bortolussi, Gérard Mandville, Robert Bloch*
Laboratoire des Carbocycles (Associé au CNRS), Institut de Chimie Moléculaire d'Orsay, Bât. 420, Université de Paris-Sud,
91405 ORSAY, France
Fax +33(1) 69 15 62 78; E-mail: robbloch@icmo.u-psud.fr
Received 22 October 1998
Abstract : Starting from bicyclic hemiesters obtained by enzymatic
hydrolysis of meso diesters, polyfunctionalized cyclohexanes were
prepared with high stereoselectivity in a synthetic strategy of few
steps involving a Curtius reaction followed by a retro Michael ring
opening reaction and reductions. This sequence offers a versatile
approach to the synthesis of various aminocarba-sugars.
Key words: carba-sugars, aminocarba-sugars, functionalized
cyclohexanes, furan adducts
The terms pseudo-sugars1 and carba-sugars2 refer to car-
bocyclic analogues of monosaccharides in which the ring
oxygen atom is replaced by a methylene group. Owing to
their structurally close resemblance to sugars, it has been
suggested3 that carba-sugars might be accepted by en-
zymes or biological systems in place of true sugars and
may thus be excellent glycosidase inhibitors. It is now
well established that several glycosidase inhibitors dem-
onstrate promising therapeutic applications in the areas of
antibiotic activities, diabetes control or antiviral
chemotherapy4 and, for these reasons, considerable efforts
have been directed towards the development of syntheses
of carba-sugars and aminocarba-sugars. Different ap-
proaches to these compounds in either racemic or enanti-
omerically pure forms have been devised and include :
could be replaced by a hydroxy- or an amino-group. Then,
cleavage of the oxygen bridge under basic conditions14
would give functionalized cyclohexanes, interesting inter-
mediates for the synthesis of carba-sugars or aminocarba-
sugars. The feasibility of this method has been tested start-
ing from the more simple bicyclic compound 415.
It appeared rapidly that substitution of the carboxylic acid
group of 4 by a hydroxy or an acetoxy group was more
difficult than anticipated and until now we have not found
good solution to this modification which is hampered by
the proximity of the two functional groups. For example,
during our efforts to transform the carboxylic acid into a
methyl ketone followed by a Baeyer-Villiger oxidation,
we observed side reactions giving a good illustration of
this interference (Scheme 1).
– The modification of natural compounds such as carbo-
hydrates2,5, quinic acid6 or myo-inositol7
– The chemical transformations of microbial meta-
bolites8
– The ring opening of modified adducts of furan and
acrylic acid2,9
– The stereoselective conversions of 7-norbornenone (10)
or dienyl silanes11
It occurred to us that hemiesters 1, 2 or 3, easily available
in enantiomerically-pure form via an enzymatic hydroly-
sis of the corresponding meso diesters,12,13 might be excel-
lent intermediates for the synthesis of carba-sugars or
aminocarba-sugars.
In this communication we disclose our preliminary results
in this field and describe, starting from 4, a highly diaste-
reoselective synthesis of the functionalized cyclohexane
12, a strategy which, when applied to the transformations
of norbornane derivatives 1, 2 or 3 may lead to the synthe-
sis of various 4-amino-4-deoxy carba-sugars. We envis-
aged that the carboxylic acid group of substrates 1 - 4
Scheme 1
The amide 5 reacts with methylmagnesium bromide to
give the usual chelated intermediate16 which, upon hy-
drolysis, does not decompose to the expected methyl ke-
Synlett 1999, No. 1, 87–89 ISSN 0936-5214 © Thieme Stuttgart · New Yorkrk

88
E. Couché et al.
LETTER
tone but led via intramolecular reactions to the keto amide Catalytic hydrogenation of the double bond was per-
6 and to the lactone 7.
formed in the presence of a catalytical amount of 10%
Pd(C) under slight pressure (3 bars) of hydrogen at room
temperature. The reaction was very slow and only com-
plete after six days to give a unique diastereomer 11. It is
usually assumed that hydrogen adds to the olefin from the
least hindered side of the molecule, leading in our case to
a cis-1,2, cis-2,3 configuration. This cis,cis-configuration
is supported by the small coupling constants (J1,2 = 3.9 Hz
and J2,3 = 5.5 Hz) determined from the 1H NMR spectrum
of 11 by irradiation experiments. Finally, reduction of the
carbomethoxy group of the ester was selectively achieved
with tri (tert-butoxy) lithium aluminum hydride and af-
forded the cyclohexane 12 in modest yield.
Replacement of the carboxylic acid group by an amino
group appears to be more successful and our strategy is
outlined in Scheme 2.
In conclusion a simple and short method for preparing the
functionalized cyclohexane 12 has been established. Ap-
plication of this methodology to the synthesis of various
4-amino, 4-deoxy carba-sugars, starting from compounds
1, 2 or 3, are currently underway in our laboratory.
References and Notes
(1) McCasland, G.E.; Furuta, S.; Durham, L.J. J. Org. Chem
1966, 31, 1516-1521.
(2) For an excellent review concerning carba-sugars and amino
carba-sugars see : Suami, T.; Ogawa, S. Adv. Carbohydr.
Chem. Biochem. 1990, 48, 21-90.
(3) McCasland, G.E.; Furuta, S.; Durham, L.J. J. Org. Chem
1968, 33, 2835-2841.
Scheme 2
(4) For a review see : Ganem, B. Acc. Chem. Res. 1996, 29, 340-
347.
Enantiomerically pure (ee ≥98%) mono ester 4, obtained
by Pig Liver Esterase - catalyzed hydrolysis of the corre-
sponding meso diester,(12) was activated via a mixed
anhydride17 and treated with sodium azide18 to afford the
desired acyl azide 8 in quantitative yield. Subsequent re-
arrangement in refluxing toluene and trapping of the inter-
mediate isocyanate with methanol gave rise to the bicyclic
amino compound 9 with excellent stereoselectivity (de >
(5) a) Sudma, A.V.R.L.; Nagarajan, M. J. Chem. Soc., Chem.
Commun. 1998, 925-926. b) Letellier, P.; Ralainairina, R.; Be-
aupere, D.; Uzan, R. Synthesis 1997, 925-930. c) Lygo, B.;
Swiatyj, M.; Trabsa, H.; Voyle, M. Tetrahedron Lett. 1994,
35, 4197-4200. d) Park, T.K.; Danishefsky, S.J. Tetrahedron
Lett. 1994, 35, 2667-2670.
(6) a) Shing, T.K.M.; Wan, L.H. Angew. Chem., Int. Ed. Engl.
1995, 34, 1643-1645. b) Shing, T.K.M.; Tai, V.W.F. J. Org.
Chem. 1995, 60, 5332-5334. c) McComsey, D.F.; Maryanoff,
B.E. J. Org. Chem. 1994, 59, 2652-2654. d) Shing, T.K.M.;
Tang, Y. Tetrahedron 1991, 47, 4571-4578.
(7) Verduyn, R.; Van Leeunen, S.H.; Van Der Marel, G.A.; Van
Boom, J.H. Recl. Trav. Chim. Pays Bas 1996, 115, 67-71.
(8) a) Hudlicky, T.; Abboud, K.A.; Entwistle, D.A.; Fan, R.;
Maurya, R.; Thorpe, A.J.; Bolonick, J.; Myers, B. Synthesis
1996, 897-911. b) Hudlicky, T.; Entwistle, D.A. Tetrahedron
Lett. 1995, 36, 2591-2594. c) Dingli, L.; Van de Walle, M.
Synlett 1994, 228-230. d) Ley, S.V.; Yeung, L.L. Synlett 1992,
291-292.
1
98%) and enantioselectivity (ee > 95%) as shown by H
NMR in the presence of chiral Eu(hfc)3. Basic ring open-
ing of the bicycle 9 proved fairly sensitive to reaction con-
ditions, due to side reactions involving either
epimerization of the carbomethoxy group (9 → 13) or an
intramolecular reaction leading from 10 to the oxazolidi-
none 14.
(9) a) Tran, C.H.; Crout, D.H.G. J. Chem. Soc., Perkin Trans 1
1998, 1065-1068. b) Acena, J.L.; Arjona, O.; Plumet, J. J.
Org. Chem. 1997, 62, 3360-3364. c) Acena, J.L.; Arjona, O.;
Fernandez de la Pradilla, R.; Plumet, J.; Viso, A. J. Org.
Chem. 1994, 59, 6419-6424. d) Acena, J.L.; Arjona, O.; Fern-
andez de la Pradilla, R.; Plumet, J.; Viso, A. J. Org. Chem.
1992, 57 , 1945-1946. e) Vogel, P.; Fattori, D.; Gasparini, F.;
Le Drian, C. Synlett 1990, 173-185 and references there in.
(10) Mehta, G.; Mohal, N. Tetrahedron Lett. 1998, 39, 3285-3286.
(11) Angelaud, R.; Landais, Y. Tetrahedron Lett. 1997, 38, 8841-
8844.
Under the best conditions found (LiHMDS 2.2 equiva-
lents, THF, -10°C, 3 hours) the reaction was clean but the
conversion was incomplete and the cyclohexene 1019 was
formed in 41% yield (53% yield based on recovered 9).
(12) Bloch, R.; Guibé-Jampel, E.; Girard, C. Tetrahedron Lett.
1985, 26, 4087-4090.
Synlett 1999, No. 1, 87–89 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
The Synthesis of Enantiomerically Enriched Cyclohexanes
89
(13) Ohno, M.; Ito, Y.; Arita, M.; Shibata, T.; Adachi, K.; Sawai,
H. Tetrahedron 1984, 40, 145-152.
Procedure for the synthesis of 11 : A solution of compound 10
(229 mg, 1 mmol) in a mixture of ethyl alcohol (5 mL) and
ethylacetate (5 mL) was introduced in to a pressure bottle. Af-
ter addition of 30 mg of 10% palladium on activated carbon
the bottle was filled with hydrogen under 3.3 bar pressure in a
Parr hydrogenator. After six days the catalyst was removed by
filtration. The filtrate was concentrated and the residue was
purified by flash chromatography on silica gel (ethyl acetate/
petroleum ether 1/1) to yield 202 mg (87%) of 11.
(14) See for example: a) Evans, D.A.; Barnes, D.M. Tetrahedron
Lett. 1997, 38, 57-58. b) Gustafsson, J.; Sterner, O. J. Org.
Chem. 1994, 59, 3994-3997. c) Leung-Toun, R.; Liu, Y.;
Muchowski, J.M.; Wu, Y.L. Tetrahedron Lett. 1994, 35,
1639-1642. d) Yang, W.; Koreeda, M. J. Org. Chem. 1992, 57,
3836-3839. e) Campbell, M.M.; Mahon, M.F.; Sainsbury, M.;
Searle, P.A. Tetrahedron Lett. 1991, 32, 951-954 and refe-
rences there in. f) Keay, B.A.; Rajapaksa, D.; Rodrigo, R. Can
J. Chem. 1984, 62, 1093-1098. g) Brion, F. Tetrahedron Lett.
1982, 23, 5299-5302.
(15) Compound 4 is irritant for the skin and must be handled with
gloves.
(16) a) Nahm, S.; Weinreb, S.M. Tetrahedron Lett. 1981, 22, 3815-
3818. b) Guingant A. Tetrahedron: Asymmetry 1991, 2, 415-
418.
11 : IR (neat) 3450, 1720 cm-1. 1H NMR (250 MHz, CDCl3) d
1.7 (m, 6H), 2.94 (m, 1H, H3), 3.68 (s, 3H, OCH3), 3.71 (s, 3H,
OCH3), 3.85 (m, 1H, H1), 4.03 (m, 1H, H2), 5.48 (m, 1H, NH)
;
13C NMR (63 MHz, CDCl3) d 18.8, 23.9, 29.4, 43.7, 51.8,
52.0, 52.5, 69.5, 157.2, 174.5 ; CIMS (NH3) m/z (relative in-
tensity): 232 (MH+, 100), 217 (100), 200 (46) ; [a]D20)) +36 (c
0.99, MeOH). Anal. calcd for C10H17O5N: C, 51.95 ; H, 7.36.
Found: C, 51.52, H, 7.61.
(17) Attempted formation of the acid chloride gave rise to the an-
hydride by an intramolecular reaction.
Procedure for the synthesis of 12 : To a stirred solution of
lithium aluminum hydride (820 mg, 21.5 mmol) in dry THF
(20 mL) kept at room temperature under argon was added
slowly a solution of t-butanol (5 g, 67.5 mmol) in dry THF
(20 mL). The mixture was cooled at 0°C and a solution of
compound 11 (155 mg, 0.675 mmol) in dry THF (20 mL) was
added dropwise. The mixture was stirred at 0°C for 12 hours
and a saturated aqueous solution of Na2SO4 (10 mL) was
added. The organic layer was separated and the organic phase
was extracted with ether (3x10 mL) and ethyl acetate (2x10
mL). The combined organic layers were dried over magnesi-
um sulfate and concentrated in vacuo. The residue was puri-
fied by flash chromatography on silica gel (ethyl acetate/
petroleum ether 8/2) to yield 65 mg (47%) of compound 12.
12 : IR (neat) 3400, 3320, 1700 cm-1. 1H NMR (200 MHz,
CDCl3) d 0.95 (m, 1H), 1.35 (m, 3H), 1.80 (m, 3H), 2.10 (bs,
1H, OH), 3.45 (m, 2H, CH2-OH), 3.73 (s, 3H, OCH3), 3.78 (m,
(18) Weinstock, J. J. Org. Chem. 1961, 26, 3511.
(19) Procedure for the synthesis of 10 : To a solution of freshly
distilled hexamethyldisilazane (890 ml, 4.2 mmol) in dry THF
(15 mL) under argon was added at 0°C a solution of n-butyl-
lithium (1.6M) in hexane (2.4 mL, 3.85 mmol). The mixture
was stirred for 20 minutes and then was added dropwise to a
solution of compound 9 (400 mg, 1.75 mmol) in dry THF (20
mL) kept at -10°C under an argon atmosphere. After two
hours, brine (5 mL) and a 1M aqueous solution of HCl (10
mL) were added successively at -10°C. The organic layer was
separated and the aqueous solution was extracted with ethyl
acetate (3x10 mL). The combined organic layers were dried
over magnesium sulfate, concentrated in vacuo and the resi-
due was purified by flash chromatography on silica gel (petro-
leum ether/ethyl acetate 1/1) to give 163 mg of 10 (41%) as a
viscous oil and 93 mg of 9.
2H, OH and H1), 4.20 (m, 1H, H2), 4.88 (m, 1H, NH) ; 13
C
10 : IR (neat) 3315, 1725, 1705, 1655 cm-1. 1H NMR (250
MHz, CDCl3) d 1.53 (m, 1H, H6), 1.85 (m, 1H, H6’), 2.30 (m,
2H, H5, H5’), 3.60 - 3.80 (m, 1H, OH), 3.71 (s, 3H, OCH3),
3.78 (s, 3H, OCH3), 3.86 (m, 1H, H1), 4.76 (m, 1H, NH), 4.82
(m, 1H, H2), 7.14 (t, J = 3.6 Hz, 1H, H4) ; 13C NMR (63 MHz,
CDCl3) d 23.9, 24.8, 48.7, 51.9, 52.4, 69.3, 128.4, 143.7,
158.2, 166.0 ; CIMS (NH3) m/z (relative intensity): 230 (MH+,
100), 215 (19), 198 (35) ; [a]D20)) +148 (c 0.92, MeOH). Anal.
calcd for C10H15O5N: C, 52.40 ; H, 6.59. Found: C, 52.17, H,
6.56.
NMR (50 MHz, CDCl3) d 23.9, 24.7, 30.1, 43.5, 54.2, 54.7,
65.2, 73.1, 162.1 ; CIMS (NH3) m/z (relative intensity): 204
(MH+, 100). Anal. calcd for C9H17O4N: C, 53.19 ; H, 8.43.
Found: C, 53.59, H,8.54.
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