Remarkable stereocontrol in the synthesis of 1,2,3,5-tetrasubstituted tetrahydropyrans via an asymmetric heterocycloaddition of a ketone-derived enol ether

Article abstract of DOI:10.1016/S0040-4039(03)00162-X

The synthesis of chiral 1,2,3,5-substituted tetrahydropyrans has been realized via an asymmetric hetero Diels-Alder (HDA) reaction. The key step that involved a trisubstituted chiral enol ether derived from (R)-mandelic acid as the dienophile promoted the

Full text of DOI:10.1016/S0040-4039(03)00162-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2141–2144
Remarkable stereocontrol in the synthesis of
1,2,3,5-tetrasubstituted tetrahydropyrans via an asymmetric
heterocycloaddition of a ketone-derived enol ether
Junfang Gong,a Eric Bonfand,b Eric Brown,b Gilles Dujardin,b,* Ve´ronique Micheleta,* and
Jean-Pierre Geneˆta
aLaboratoire de Synthe`se Se´lective Organique et Produits Naturels, E.N.S.C.P., UMR 7573, 11 rue P. et M. Curie,
F-75231 Paris Cedex 05, France
bLaboratoire de Synthe`se Organique, UPRES-A 6011 CNRS, Universite´ du Mans, Faculte´ des Sciences, BP 535, avenue Olivier
Messiaen, 72017 Le Mans Cedex, France
Received 18 December 2002; revised 13 January 2003; accepted 15 January 2003
Abstract—The synthesis of chiral 1,2,3,5-substituted tetrahydropyrans has been realized via an asymmetric hetero Diels–Alder
(HDA) reaction. The key step that involved a trisubstituted chiral enol ether derived from (R)-mandelic acid as the dienophile
promoted the creation of three stereogenic centers with a remarkable and unprecedented endo and facial stereocontrol. The
hydrogenation of the heteroadduct 2 was optimized by using Pd on charcoal and diisopropylethylamine, leading to a unique
isomer. The chiral inductor was cleanly and stereoselectively removed via an acetal reduction, which demonstrated the potential
of this methodology for the efficient construction of key intermediate of biologically active molecules. © 2003 Elsevier Science
Ltd. All rights reserved.
Carba-analogues of glycosides have attracted consider-
able interest over the last three decades in view of their
hydrolytic stability and potential enzyme inhibitory
properties.1 Moreover, C-glycosides have proven to be
exceedingly useful building blocks for the synthesis of
natural products with important pharmacological pro-
perties, which has stimulated the development of new
synthetic methodologies.2 During the course of our
synthetic studies toward ambruticin,3 a fascinating
antibiotic4 which came back in the front scene with
three recent total syntheses,5 we have been interested in
the synthesis of chiral tetrahydropyrans. Moreover,
functionalizations could be introduced at carbon C-6
(Scheme 1). The tetrasubstituted tetrahydropyran 1
could result from heteroadduct 2, via a stereoselective
hydrogenation of the double bond and reduction at
carbon C-1. The dihydropyran 2 was expected to be
stereoselectively and asymmetrically delivered by means
of an inverse-electron demand hetero Diels–Alder
(HDA) reaction10 between the activated heterodiene 3
and the enol ether 4.
1,2,5-trialkyl-3-hydroxy-tetrahydropyrans
constitute
important key intermediates for other molecules such as
lasonolide A,6 polycavernoside A,7 ratjadone,8 or con-
canamycin A.9
We turned our attention to the preparation of (L)-2,4-
dideoxy-C-glycoside derivatives and wish to describe a
novel approach to chiral ester 1, from which diverse
Keywords: asymmetric hetero Diels–Alder; chiral C-glycosides; stereo-
controlled hydrogenation; acetal reduction; ketone-derived enol ether.
* Corresponding authors. E-mail: dujardin@univ-lemans.fr; michelet
@ext.jussieu.fr
Scheme 1. Retrosynthesis.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00162-X

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J. Gong et al. / Tetrahedron Letters 44 (2003) 2141–2144
The key [4+2] heterocycloaddition was particularly
tricky as it involved a trisubstituted dienophile. Indeed,
despite the tremendous recent progress achieved in the
area of HDA reactions with the use of CuII and CrIII-
based asymmetric catalysis,10e,11 the simultaneous con-
trol of endo/exo and facial selectivity remains a difficult
challenge when the dienophile is a dialkyl ketone-
derived enol ether. Considering our previous results and
expertise concerning the Eu(fod)3-catalyzed heterocy-
cloaddition of vinyl chiral ethers,12 we chose to investi-
gate enol ethers derived from (R)-mandelic acid as
chiral dienophiles. The preparation of the heterodienes
The key heterocycloaddition was thus investigated
under Eu(fod)3-catalyzed conditions. It was found that
reaction of enol ether 4c with heterodiene 3b in the
presence of 5 mol% Eu(fod)3 in refluxing petroleum
ether was particularly effective and led to the function-
alized dihydropyran 2b with 83% yield (Scheme 3).
Moreover, we were pleased to find that 2b was isolated
as a single endo isomer:15 the major Z isomer of 4c thus
underwent a very clean endo-selective and asymmetric
HDA reaction, meanwhile its E isomer was recovered
unchanged after the reaction. The lack of reactivity of
the E isomer of 4c with 3b could be explained by severe
steric interaction in the Eu(fod)3-chelated, favored,
endo-transition state. This fact agrees with previous
findings concerning the Eu(fod)3-catalyzed heterocy-
cloaddition of cyclanone-derived enol ethers when using
the same heterodiene.16 To our knowledge, the obten-
tion of adduct 2b as a sole diastereomer affords an
unprecedented example of total endo and asymmetric
control in an inverse-electron demand HDA reaction
involving a dialkylketone-derived enol ether as the
dienophile.
3a–b (Fig. 1) was based on previous methodology.12b
A
model study involving 3a towards various O-isopro-
penyl mandelic esters13 (4a-type) as the dienophile,
under typical Eu(fod)3-catalyzed conditions led to the
expected adducts in good yields with a high level of
endo control. However, the major endo adducts were
obtained with a moderate diastereofacial selectivity,
which
confirmed
some
previously
disclosed
observations.11e
Figure 1.
Scheme 3. [4+2] Heterocycloaddition.
The preparation of chiral enol ethers derived from
3-pentanone (R1=Me) was thus investigated. Applica-
tion of our previous method involving regiocontrolled
elimination of a mixed acetal with TMSOTf and
triethylamine13 gave poor results. Access to 4-type com-
pounds was envisaged via a regiocontrolled ethylidena-
tion, namely a Takai reaction14 of the corresponding
diester 5 (Scheme 2). Firstly applied to the methyl ester
5a, the Takai reaction using Zn/TiCl4 reagents and
1,1-dibromoethane proved to be non-selective: enol
ether 4b and its regioisomer 4%b were produced in a 4/1
ratio. In contrast, the same conditions applied to the
bulkier t-butyl ester 5b gave rise to the desired enol
ether 4c with a total regiocontrol. Alkene 4c was iso-
lated in 54% yield as a 9/1 Z/E mixture identified by 1H
NMR NOe measurements. The two stereoisomers
could be separated by careful chromatography on silica
gel, but the mixture was engaged directly in the next
step.
The catalytic hydrogenation was then studied and
proved to be very difficult. The formation of compound
6 was expected as it is well established that the addition
of hydrogen generally occurs on the less hindered face
of the alkenes. Nevertheless, even though many 1,3,5-
substituted dihydropyrans were stereoselectively hydro-
genated using 10% palladium on activated charcoal
under 1–3 bar hydrogen pressure,17,18 no relevant exam-
ples were described starting from 1,1%,2,3,5-substituted
dihydropyrans. As shown in Table 1 (entry 1), the
above mentioned conditions proved to be non selective
and gave a mixture of tetrahydropyrans 6, epi-6 and
alcohol 7.19,20 The use of Pd 5% on carbon under one
atmosphere of hydrogen, in 95% aqueous ethanol, at
room temperature (entry 2) also afforded a complex
mixture, in which the major adduct was the deprotected
3-hydroxy compound 7. Higher catalyst loading (entry
3) shortened the reaction time but did not give better
results. In contrast, the use of 50% wet palladium on
carbon restricted to 5% the deprotection ratio and led
to pure crystallized tetrahydropyran 6 in moderate iso-
lated yield (entry 4). X-Ray analysis of compound 6
proved the overall syn relationship of OR* at C-1, Me
at C-2, Ot-Bu at C-3 and CO2Me at C-5. The relation-
ship between inducing and induced stereogenic centers
definitively established the absolute configuration of 6
(and 2b, Scheme 3). Further experiments were per-
formed to enhance the selectivity in the formation of 6.
Scheme 2. Synthesis of enol ethers 4.

J. Gong et al. / Tetrahedron Letters 44 (2003) 2141–2144
Table 1. Hydrogenation of dihydropyran 2b
2143
Entry
Catalyst (% weight)
t (h)
Isomer ratio (%)a
6/epi-6/7
Overall conversion/2b
(isolated yield of 6)
1
2
3
4
5
6
Pd 10% on C (10)b
Pd 5% on C (10)
Pd 5% on C (15)
wet Pd 5% on C (25)
PtO2 (10)
Pd 5% on C (15), i-Pr2NEt (15)
3
21
5
15
44
5
50:25:25
37:13:50
17:16:67
76:19:5
100:0:0
100:0:0
100
100
100
100 (56)
20
100 (83)
a Measured by 1H NMR, based on the benzylic proton of the mandelic ester moiety (Ref. 19).
b 3 bar.
18
access to 1,2,3,5-substituted tetrahydropyrans. The key
step, that involved the Eu(fod)3-catalyzed HDA re-
action of a trisubstituted chiral enol ether derived from
(R)-mandelic acid and an activated heterodiene, pro-
moted the creation of three stereogenic centers with
unprecedented endo and facial controls. Stereoselective
hydrogenation of the 1-alkoxydihydropyran thus
obtained was optimized by using Pd on charcoal and
diisopropylethylamine. The subsequent acetal reduc-
tion, performed with BH3·Me2S/TMSOTf, achieved to
demonstrate the potential of this approach for the
ready construction of complex tetrahydropyranic inter-
mediates for biologically active molecules. Further
studies are directed at exploring new applications of
this methodology toward the total synthesis of natural
products and analogues.
The use of PtO2 as the catalyst (entry 5) afforded a
clean hydrogenation with a high selectivity despite 80%
of starting material being recovered. Meanwhile, sus-
pecting that the formation of 7 was due to catalyst
acidity, we added 15% weight of diisopropylethyl-
amine.18c We were grateful to find that the Pd-catalyzed
hydrogenation was much cleaner, faster and led to the
unique isomer 6 in 83% isolated yield (entry 6). More-
over, the reaction could be scaled up to 1.4 g of
substrate 2b.21
The next crucial step consisted in the reduction of the
acetal 6. We had envisaged the cleavage of the chiral
inductor to form the lactol followed by a Kishi
reaction22 which proved particularly efficient for the
preparation23 of C-glycosides. The selective reduction
of simple ketals using BH3·Me2S/TMSOTf, described
by Bartels et al. drew our attention.24 We were grateful
to find that it could be applied in target-oriented
synthesis.
Acknowledgements
J.G. is grateful to the Ministe`re de l’Education et de la
Recherche and the C.N.R.S. for a grant (2001–2002).
We thank Dr. Vincent Maisonneuve (Laboratoire des
Fluorures UMR CNRS 6010, Universite´ du Maine, Le
Mans) for performing the X-ray crystallography of
compound 6.
References
Scheme 4. Ketal reduction of tetrahydropyran 6.
Indeed, reduction of ketal 6 provided a mixture of 1a25
and epi-1a in an optimized 90/10 ratio with 86% yield
(Scheme 4). Each epimer could be isolated by chro-
matography on silica gel. The relative and then abso-
lute stereochemistry of the newly created center of
1. Suhadolnik, R. J. Nucleoside Antibiotics; Wiley-Inter-
science: New York, 1970.
2. (a) Du, Y.; Linhardt, R. J.; Vlahov, I. R. Tetrahedron
1998, 54, 9913–9959; (b) Nicotra, F. Topics Curr. Chem.
1997, 187, 55–83; (c) Sinay¨, P. Pure Appl. Chem. 1997, 69,
459–463; (d) Beau, J.-M.; Gollagher, T. Topics Curr.
Chem. 1997, 187, 1–54; (e) Postema, M. H. D. C-Gly-
coside Synthesis; CRC Press: Boca Raton, 1995; (f) Levy,
D. E.; Tang, C. The Chemistry of C-Glycosides; Perga-
mon: Oxford, 1995.
1
pyrans 1a and epi-1a was confirmed by H NMR NOE
measurements.
In conclusion we have disclosed a highly stereocon-
trolled three-step sequence for the efficient asymmetric

2144
J. Gong et al. / Tetrahedron Letters 44 (2003) 2141–2144
D. E.; Jacobsen, E. N. Angew.Chem., Int. Ed. 2002, 41,
3. Michelet, V.; Adiey, K.; Bulic, B.; Geneˆt, J.-P.; Dujardin,
G.; Rossignol, S.; Brown, E.; Toupet, L. Eur. J. Org.
3059–3061.
Chem. 1999, 2885–2892 and references cited therein.
12. (a) Dujardin, G.; Rossignol, S.; Brown, E. Tetrahedron
Lett. 1996, 37, 4007–4010; (b) Dujardin, G.; Rossignol,
S.; Brown, E. Synthesis 1998, 763–770.
4. (a) Ringel, S. M.; Greenough, R. C.; Roemer, S.; Con-
nor, D.; Gutt, A. L.; Blair, B.; Kanter, G.; von Strandt-
mann, M. J. Antibiot. 1977, 30, 371–375; (b) Levine, H.
B.; Ringel, S. M. Proceeding of the Third International
Coccidioidomycosis Symposium, June 1977, pp. 318–322;
(c) Knauth, P.; Reichenbach, H. J. Antibiot. 2000, 53,
1182–1190; (d) Kende, A. S.; Fujii, Y.; Mendoza, J. S. J.
Am. Chem. Soc. 1990, 112, 9645–9646; (e) Kende, A. S.;
Mendoza, J. S.; Fujii, Y. Tetrahedron 1993, 49, 8015–
8038; (f) Mendoza, J. S.; Kende, A. S. Recent Prog.
Chem. Synth. Antibiot. Relat. Microb. Prod. 1993, 405–
433.
5. (a) Kirkland, T. A.; Colucci, J.; Geraci, L. S.; Marx, M.
A.; Schneider, M.; Kaelin, D. E., Jr.; Martin, S. F. J. Am.
Chem. Soc. 2001, 123, 12432–12433; (b) Lee, E.; Choi, S.
J.; Kim, H.; Han, H. O.; Kim, Y. K.; Min, S. J.; Son, S.
H.; Lim, S. M.; Jang, W. S. Angew. Chem., Int. Ed. 2002,
41, 176–178; (c) Liu, P.; Jacobsen, E. N. J. Am. Chem.
Soc. 2001, 123, 10772–10773.
13. Dujardin, G.; Rossignol, S.; Brown, E. Tetrahedron Lett.
1995, 36, 1653–1656.
14. (a) Takai, K.; Kakiuchi, T.; Kataoka, Y. J. Org. Chem.
1994, 59, 2668–2670; (b) Postema, M. H. D.; Calimente,
D.; Liu, L.; Behrmann, T. L. J. Org. Chem. 2000, 65,
6061–6068.
1
15. No other isomers were detected by H NMR (400 MHz)
on the crude material.
16. Martel, A.; Leconte, S.; Dujardin, G.; Brown, E.;
Maisonneuve, V.; Retoux, R. Eur. J. Org. Chem. 2002,
514–525.
17. (a) Boger, D. L.; Robarge, K. D. J. Org. Chem. 1988, 53,
5793–5796; (b) Werschkun, B.; Thiem, J. Synthesis 1999,
121–137.
18. (a) Bennasar, M.-L.; Zulaica, E.; Juan, C.; Llauger, L.;
Bosch, J. Tetrahedron Lett. 1999, 40, 3961–3964; (b)
Tietze, L. F.; Hartfiel, U. Tetrahedron Lett. 1990, 31,
1697–1700; (c) Bach, P.; Lohse, A.; Bols, M. Tetrahedron
Lett. 1999, 40, 367–370.
6. (a) Horton, P. A.; Koehn, F. E.; Longley, R. E.;
McConnell, O. J. J. Am. Chem. Soc. 1994, 116, 6015–
6016; (b) Lee, E.; Song, H. Y.; Kang, J. W.; Kim, D.-S.;
Jung, C.-K.; Joo, J. M. J. Am. Chem. Soc. 2002, 124,
384–385.
19. All isomeric ratios indicated in this work were determined
1
by H NMR (400 MHz) on the crude material. For each
hydrogenation assay (Table 1), the evaluation of the
6/epi-6/7 ratio was based on the integration of the ben-
zylic proton of the mandelic ester moiety: H NMR (400
7. (a) Yotsu-Yamashita, M.; Haddock, R. L.; Yasumoto, T.
J. Am. Chem. Soc. 1993, 115, 1147–1148; (b) Fujiwara,
K.; Murai, A.; Yotsu-Yamashita, M.; Yasumoto, T. J.
Am. Chem. Soc. 1998, 120, 10770–10771; (c) Paquette, L.
A.; Barriault, L.; Pissarnitski, D.; Johnston, J. N. J. Am.
Chem. Soc. 2000, 122, 619–631; (d) White, J. D.; Black-
more, P. R.; Browder, C. C.; Hong, J.; Lincoln, C. M.;
Nagornyy, P. A.; Robarge, L. A.; Wardrop, D. J. J. Am.
Chem. Soc. 2001, 123, 8593–8595.
8. (a) Christmann, M.; Bhatt, U.; Quitschalle, M.; Claus, E.;
Kalesse, M. Angew. Chem., Int. Ed. 2000, 39, 4364–4366;
(b) Bhatt, U.; Christmann, M.; Quitschalle, M.; Claus,
E.; Kalesse, M. J. Org. Chem. 2001, 66, 1885–1893; (c)
Williams, D. R.; Ihle, D. C.; Plummer, S. V. Org. Lett.
2001, 3, 1383–1386.
1
MHz, CDCl3) l 5.46 (6), 5.26 (epi-6), 5.14 (7) ppm. The
relative stereochemistry of alcohol 7 was not established.
20. A lack of selectivity was recently observed in the catalytic
hydrogenation of bicyclic 1,1%,2,3,5-substituted dihydro-
pyrans: Martel, A.; Dujardin, G.; Brown, E. Synthesis
2003, in press.
21. Tetrahydropyran 6: Mp=150–152°C; [h]2D0 −2.8 (c 1.0,
1
acetone); H NMR (400 MHz, CDCl3): l 7.54 (m, 2H),
7.28 (m, 3H), 5.46 (s, 1H), 4.19 (dd, J=11.2, 4.0 Hz, 1H),
3.79 (ddd, J=10.2, 5.1, 5.1 Hz, 1H), 3.51 (s, 3H), 2.12
(qd, J=6.8, 5.1 Hz, 1H), 1.74 (m, 2H), 1.89 (m, 2H), 1.39
(s, 9H), 1.19 (s, 9H), 0.99 (d, J=6.9 Hz, 3H), 0.98 (t,
J=7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3): l 171.4,
138.3, 127.8, 127.3, 127.0, 104.3, 80.9, 73.6, 72.3, 69.9,
65.8, 51.8, 38.4, 31.5, 28.3, 27.8, 26.4, 8.4, 8.3; Microanaly-
sis: calcd for C26H40O7: C, 67.22 H, 8.68, Found: C, 67.45
H, 8.73.
9. Ingenhorst, G.; Bindseil, K. U.; Boddien, C.; Dro¨se, S.;
Gassel, M.; Altendorf, K.; Zeeck, A. Eur. J. Org. Chem.
2001, 4525–4532.
10. (a) Boger, D. L.; Weinreb, S. N. Hetero Diels–Alder
Methodology in Organic Synthesis; Academic Press: San
Diego, 1987; (b) Waldmann, H. Synthesis 1994, 535–555;
(c) Tietze, L. F.; Kettschau, G. Top. Curr. Chem. 1997,
189, 1–120; (d) Ru¨ck-Braun, K.; Kunz, H. Chiral Auxil-
iaries in Cycloadditions; Wiley-VCH: Weinheim, 1999; (e)
Carmona, D.; Lamata, P. M.; Oro, L. A. Coord. Chem.
Rev. 2000, 717–772; (f) Jorgensen, K. A. Angew. Chem.,
Int. Ed. 2000, 39, 3558–3588.
22. Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc.
1982, 104, 4976–4977.
23. (a) Lasterra Sanchez, M. E.; Michelet, V.; Besnier, I.;
Geneˆt, J.-P. Synlett 1994, 705–708; (b) Michelet, V.;
Dujardin, G.; Geneˆt, J.-P. Tetrahedron Lett. 1997, 38,
7741–7744.
24. Bartels, B.; Hunter, R. J. Org. Chem. 1993, 58, 6756–
6765.
25. Tetrahydropyran 1a: [h]2D0 +39.8 (c 1.0, CHCl3). 1H NMR
(400 MHz, CDCl3): l 4.01 (dd, J=12.0, 2.8 Hz, 1H), 3.76
(s, 3H), 3.68 (dt, J=11.4, 4.9 Hz, 1H), 3.27 (ddd, J=7.7,
6.1, 1.8 Hz, 1H), 1.85–1.65 (m, 4H), 1.50–1.40 (m, 1H),
1.20 (s, 9H), 0.91 (t, J=7.5 Hz, 3H), 0.89 (d, J=7.0 Hz,
3H); 13C NMR (50 MHz, CDCl3): l 171.3, 81.2, 75.5,
73.6, 70.0, 52.0, 37.8, 32.0, 28.4, 25.3, 10.2, 5.1. HRMS-
DCI/CH4: [M+H]+ calcd for C14H27O4: 259.1909, found:
259.1915.
11. (a) Thorhauge, J.; Johannsen, M.; Jorgensen, K. A.
Angew. Chem., Int. Ed. 1998, 37, 2404–2406; (b) Evans,
D. A.; Olhava, E. J.; Johnson, J. S.; Janey, J. M. Angew.
Chem., Int. Ed. 1998, 37, 3372–3375; (c) Zhuang, W.;
Thorhauge, J.; Jorgensen, K. A. Chem. Commun. 2000,
459–460; (d) Audrain, H.; Thorhauge, J.; Hazell, R. G.;
Jorgensen, K. A. J. Org. Chem. 2000, 65, 4487–4497; (e)
Evans, D. A.; Johnson, J. S.; Olhava, E. J. J. Am. Chem.
Soc. 2000, 122, 1635–1649; (f) Gademann, K. G.; Chavez,