Concise and stereocontrolled synthesis of polysubstituted tetrahydropyrans

Article abstract of DOI:10.1016/S0040-4039(00)01179-5

A range of polysubstituted tetrahydropyrans can be readily assembled by a novel methodology involving a metallo-ene reaction coupled with an intramolecular Sakurai cyclisation (IMSC). (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01179-5

Tetrahedron Letters 41 (2000) 7225±7230
Concise and stereocontrolled synthesis of polysubstituted
tetrahydropyrans
Istvan E. Marko* and Bernard Leroy
 Â
Ã
Universite Catholique de Louvain, Departement de Chimie, Batiment Lavoisier, Place Louis Pasteur 1, B-1348,
Louvain-la-Neuve, Belgium
Received 14 June 2000; accepted 12 July 2000
Abstract
A range of polysubstituted tetrahydropyrans can be readily assembled by a novel methodology involving
a metallo-ene reaction coupled with an intramolecular Sakurai cyclisation (IMSC) # 2000 Elsevier Science
Ltd. All rights reserved.
Keywords: allylation; cyclisation; Sakurai reactions; ene reactions; carbamates.
Numerous biologically active natural products contain, embedded in their complex
architectural framework, a polysubstituted tetrahydropyran subunit. The widespread occurrence
of tetrahydropyrans, coupled with their key role as pharmacophores, has stimulated the
development of a plethora of elegant methodologies for their stereocontrolled assembly.1 As part
of a synthetic programme aimed at the ecient preparation of tetrahydropyran-containing
natural products, we required a rapid, stereocontrolled and stereodivergent route to the three
diastereomeric diols 1±3 (Fig. 1).
Figure 1.
In a previous communication, we have reported on a novel, three-component methodology,
that provided us with an easy access to isomerically pure tetrahydropyrans 1 and 2.2 This
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01179-5

7226
protocol involves an initial, abnormal, ene reaction between allylsilane 4 and an aldehyde, a€ording
silylenol ether 5 solely as the (E)-geometric isomer.3 Subsequent intramolecular cyclisation via
oxocarbenium ion 7 generated diastereomerically pure exo-methylene tetrahydropyran 6. The
2,3-anti, 2,6-syn-stereochemistry derived from the preferred pseudo-equatorial arrangement of
the substituents in intermediate 7. Oxidative cleavage of the exocyclic C±C double bond, followed
by stereoselective reduction with the appropriate hydrides, ultimately provided diols 1 and 2 in
high overall yields (Fig. 2).4
Figure 2.
Unfortunately, the subsequent transformation of 1 or 2 into isomer 3 proved to be lengthy and
cumbersome. We envisioned that a rapid access to the desired tetrahydropyrans 3 could be
realised starting from the (Z)-isomer of enol ether 5. In this article, we wish to report our
preliminary results on the successful implementation of this strategy.
With the desired (Z)-silylenol ethers being unattainable by the previous methodology, we
selected the corresponding carbamate derivatives 10. These compounds should be readily
available by the the elegant allyl-metallation protocol reported by Hoppe (Fig. 3).5
Figure 3.
Thus, allyl alcohol 8 was transformed into carbamate 9 by condensation with diisopropyl
carbamoyl chloride in excellent yield. Metallation of 9 proved unexpectedly dicult and
proceeded only under the conditions described in Fig. 3. Gratifyingly, addition of Ti(OPri)4 to a
solution of the in situ generated allyllithium reagent, followed by an aldehyde led in high yield to
the desired (Z)-enolcarbamate 10 as a single geometric isomer.6 A collection of representative
examples is displayed in Table 1.
Primary, secondary and tertiary aliphatic aldehydes reacted smoothly (Entries 1±3) and so did
unsaturated aldehydes (Entry 4). Whilst in some cases, the allylation reaction displayed complete
diastereoselectivity (Entry 5), in other cases, it proceeded with modest stereocontrol (Entry 6).

7227
Table 1
Metallo-ene reaction of allylcarbamate 9
With ready access to the desired (Z)-enolcarbamates at hand, we next turned our attention to
the crucial intramolecular Sakurai cyclisation (IMSC).7 To the best of our knowledge, the IMSC
reactions of substrates such as 10 have never been reported before.
.
After some experimentation, we were delighted to ®nd that, in the presence of BF3 Et2O, a
range of enol carbamates smoothly underwent IMSC condensation with a variety of aldehydes,
a€ording the corresponding exo-methylene tetrahydropyrans 11 in excellent yields. Even more
pleasing was the obtention, in all cases, of a single diastereoisomer possessing the expected
C3-axial alkoxy-substituent (Table 2).
The presence of the C3-substituent in the axial position was clearly revealed by comparing the
values of the coupling constants between the previously prepared, equatorially disposed, pyran
derivative 13 with the newly obtained axial isomer 12 (Fig. 4).8
Subsequent transformations of 12 into diols such as 3 proceeded smoothly. Ozonolysis of the
exo-methylene double bond a€orded ketone 14 which was reduced by L-Selectride1, providing
the syn-hydroxycarbamate 15 as a single diastereoisomer. Deprotection of the carbamate
function was accomplished smoothly using LiAlH4.9 It is interesting to note that these two separate
operations could be eciently combined in a single step. Indeed, treatment of ketocarbamate 14
with LiAlH4 not only resulted in the stereoselective reduction of the ketone function but also in the
unravelling of the protecting group, a€ording directly syn-diol 16 in 98% overall yield (Fig. 5).

7228
Table 2
Intramolecular Sakurai cyclisation of enol carbamates
Figure 4.
In summary, we have developed an ecient and stereocontrolled access to a variety of
polysubstituted tetrahydropyrans by a unique combination of the Hoppe allylmetallation of the
novel carbamate derivative 9 with an intramolecular Sakurai cyclisation.10 The tetrahydropyran
derivatives 11, obtained by this methodology, are stereocomplementary to those prepared earlier
according to our previously reported ene-IMSC protocol.

7229
Figure 5.
Acknowledgements
Financial support of this work by the Universite catholique de Louvain, the Actions de
Recherche Concertees (convention 96/01-197), the Fonds pour la Formation a la Recherche dans
l'Industrie et dans l'Agriculture (FRIA) and the Fonds de la Recherche Fondamentale Collective
(dossier no 2.4571.98) is gratefully acknowledged. I.E.M. is thankful to Merck for its continuous
support and for receiving the Merck Young Investigator Award.
References
1. For excellent reviews, see: (a) Perron, F.; Albizati, K. M. Chem. Rev. 1989, 89, 1617. (b) Boivin, T. L. B.
Tetrahedron 1987, 43, 3309.
2. (a) Marko, I. E.; Bayston, D. J. Tetrahedron Lett. 1993, 34, 6595. (b) Marko, I. E.; Bayston, D. J. Tetrahedron
1994, 50, 7141. (c) Marko, I. E.; Bayston, D. J. Synthesis 1996, 297. (d) Feneau-Dupont, J.; Declercq, J. P.;
Bayston, D. J.; Marko, I. E. Bull. Soc. Chim. Belg. 1997, 106, 173.
3. For related ene-reactions of allylsilanes, see: (a) Mikami, K.; Loh, T.-P.; Nakai, T. J. Am. Chem. Soc. 1990, 112,
6737. (b) Mikami, K.; Shimizu, M.; Nakai, T. J. Org. Chem. 1991, 56, 2952. For a study on the in¯uence of an
allylic alkoxy-substituent on ene-reactions, see: (c) Tanino, K.; Nakamura, T.; Kuwajima, I. Tetrahedron Lett.
1990, 31, 2165. (d) Shoda, H.; Nakamura, T.; Tanino, K.; Kuwajima, I. Tetrahedron Lett. 1993, 34, 6281.
4. For synthetic applications, see: Marko, I. E.; Plancher, J.-M. Tetrahedron Lett. 1999, 40, 5259, and references cited
therein.
5. (a) Hoppe, D.; Kramer, T.; Schwark, J.-R.; Zschage, O. Pure Appl. Chem. 1990, 62, 1999. (b) Zschage, O.;
Schwark, J.-R.; Kramer, T.; Hoppe, D. Tetrahedron 1992, 48, 8377. (c) Berque, I.; Le Menez, P.; Razon, P.;
Mahuteau, J.; Ferezou, J.-P.; Pancrazi, A.; Ardisson, J.; Brion, J.-D. J. Org. Chem. 1999, 64, 373.
6. The geometry of the enolcarbamate was established by NMR spectroscopy and corroborates the results published
earlier by Hoppe (Ref. 5a, b).
7. For selected examples of IMSC reactions, see: (a) Marko, I. E.; Chelle, F. Tetrahedron Lett. 1997, 38, 2895.
(b) Marko, I. E.; Dobbs, A. P.; Scheirmann, V.; Chelle, F.; Bayston, D. J. Tetrahedron Lett. 1997, 38, 2899.
(c) Langkopf, E.; Schinzer, D. Chem. Rev. 1995, 95, 1375, and references cited therein.
8. The sole formation of the axial isomer reinforce our proposed chair-like transition state 7 for the IMSC
cyclisation. It is also interesting to note that in these IMSC reactions, no competing [3,3]-sigmatropic
rearrangements, that would lead to equatorial products, took place. (a) Semeyn, C.; Blaauw, R. H.; Hiemstra,
H.; Speckamp, W. N. J. Org. Chem. 1997, 62, 3426. (b) Knight, S. D.; Overman, L. E.; Pairaudeau, G. J. Am.
Chem. Soc. 1995, 117, 5776.

7230
9. It is noteworthy that attempted deprotection of pyran derivative 12 could not be accomplished. In this case,
recourse to a modi®ed carbamate function proved mandatory (Leroy, B.; Marko, I. E., unpublished results). For
the synthesis of the protecting group, see: Derwing, C.; Hoppe, D. Synthesis 1996, 149.
10. Typical experimental procedure. Preparation of 12: To a solution of TMEDA (1.114 ml, 7.38 mmol) in dry diethyl
ether (15 ml) at ^78ꢀC was added sec-BuLi (1.3 M in hexanes, 5.677 ml, 7.38 mmol) and the mixture was stirred at
^78ꢀC for 30 min. A solution of allylsilane 9 (1 g, 3.69 mmol) in diethyl ether (15 ml) was then slowly added, and
the mixture stirred at ^78ꢀC for 30 min. Titanium tetraisopropoxide (3.268 ml, 11.07 mmol) was then quickly
added, and the mixture stirred at ^78ꢀC for 30 min. A solution of butyraldehyde (399 mg, 5.53 mmol) in diethyl
ether (15 ml) was then quickly added at ^78ꢀC and the temperature was allowed to warm to 0ꢀC. After stirring for
10 min, the reaction mixture was poured onto 1N HCl (40 ml) and extracted with diethyl ether. The organic layer
was washed with saturated NaHCO3 (40 ml), dried (MgSO4) and evaporated in vacuo. The residue was puri®ed by
column-chromatography (silica gel, petroleum ether:ethyl acetate, 8:1) to give the alcohol 10 as a colourless oil
(901 mg, 71%). 1H NMR (CDCl3, 300 MHz) ꢀ 6.79 (s, 1H), 3.75±3.94 (m, 3H), 2.36 (dd, J=13.2 Hz, 9.3 Hz, 1H),
2.09 (dd, J=13.4 Hz, 3.8 Hz, 1H), 1.78 (bs, 1H), 1.01±1.51 (m, 4H), 1.23 (d, J=6.5 Hz, 12H), 0.92 (t, J=6.1 Hz,
3H), 0.04 (s, 9H). 13C NMR (CDCl3, 75 MHz) ꢀ 153.94, 132.61, 119.00, 69.92, 46.92, 40.21, 39.31, 21.72, 21.60,
19.58, 14.82, ^0.49. IR (®lm) 3474, 2957, 1700 cm^1. MS (EI) m/z 343 (7%, M+). Anal. calcd for C18H37NO3Si:
C, 62.95%; H, 10.89%; N, 4.07%; found: C, 62.93%; H, 10.85%; N, 4.08%. To a ꢀsolution of alcohol 10 (855 mg,
.
2.49 mmol) and butyraldehyde (198 mg, 2.74 mmol) in dry CH2Cl2 (25 ml) at ^78 C was added slowly BF3 OEt2
(338 ml, 2.74 mmol). The temperature was allowed to warm to 0ꢀC over 3 h. The reaction mixture was poured onto
saturated NaHCO3 (25 ml) and the aqueous layer was extracted with CH2Cl2 (2Â25 ml). The combined organic
layers were dried (MgSO4) and evaporated in vacuo. The residue was puri®ed by column-chromatography (silica
gel, petroleum ether:ethyl acetate, 25:1) to give the tetrahydropyran 12 as a colourless oil (737 mg, 91%). 1H NMR
(CDCl3, 300 MHz) ꢀ 5.08 (bs, 2H), 4.89 (t, J=1.6 Hz, 1H), 3.90±4.23 (m, 1H), 3.59±3.72 (m, 1H), 3.34 (ddd,
J=8.2 Hz, 4.5 Hz, 1.4 Hz, 1H), 3.24±3.32 (m, 1H), 2.18 (tt, J=13.2 Hz, 1.6 Hz, 1H), 2.11 (dd, J=13.4 Hz, 3.5 Hz,
1H), 1.38±1.66 (m, 8H), 1.19 (d, J=6.8 Hz, 12H), 0.91 (t, J=7.1 Hz, 3H), 0.89 (t, J=7.2 Hz, 3H). 13C NMR
(CDCl3, 75 MHz) ꢀ 155.20, 143.23, 113.20, 79.99, 78.43, 74.12, 46.10 (b), 38.42, 37.52, 33.73, 21.20 (b), 18.89,
18.72, 14.03. IR (®lm) 2960, 1693 cm^1. MS (EI) m/z 325 (12%, M+). Anal. calcd for C19H35NO3: C, 70.00%; H,
10.81%; N, 4.36%; found: C, 70.11%; H, 10.84%; N, 4.30%.