Stereocontrolled synthesis of 2,4,5-trisubstituted tetrahydropyrans

Article abstract of DOI:10.1039/b101414p

Cyclisation of homoallylic acetals under acidic conditions leads to the formation of 2,4,5-trisubstituted tetrahydropyrans with the creation of two new asymmetric centres with excellent stereocontrol. By varying the acid and the nucleophile, the reaction

Full text of DOI:10.1039/b101414p

Stereocontrolled synthesis of 2,4,5-trisubstituted tetrahydropyrans
Eiman H. Al-Mutairi,a Stuart R. Crosby,a Julia Darzi,a John R. Harding,b Rachael A. Hughes,a
Clare D. King,b Thomas J. Simpson,a Robert W. Smitha and Christine L. Willis*a
a School of Chemistry, University of Bristol, Cantock’s Close, Bristol, UK BS8 1TS.
E-mail: chris.willis@bristol.ac.uk
b AstraZeneca UK Ltd, Mereside, Alderley Park, Macclesfield, UK SK10 4TG
Received (in Cambridge, UK) 13th February 2001, Accepted 12th March 2001
First published as an Advance Article on the web 11th April 2001
Cyclisation of homoallylic acetals under acidic conditions
leads to the formation of 2,4,5-trisubstituted tetrahydropyr-
ans with the creation of two new asymmetric centres with
excellent stereocontrol. By varying the acid and the nucleo-
phile, the reaction may be adapted for the preparation of
2,4,5-trisubstituted tetrahydropyrans with either a halide,
alcohol, acetate or amide at C-4.
Substituted tetrahydropyrans are common features of many
natural products and biologically active compounds and many
strategies for their synthesis have been reported. One valuable
approach to the preparation of tetrahydropyrans is a Prins type
cyclisation in which treatment of a homoallylic acetal (or a
mixture of a homoallylic alcohol and carbonyl compound) with
Scheme 1
acid leads to formation of an oxocarbenium cation intermediate
which undergoes an intramolecular reaction with the alkene.1
cyclisations with varying success. These include the use of
Upon cyclisation, the fate of the resulting carbocation inter-
mediate is dependent upon the reaction conditions and sub-
strates employed. Thus, Thompson and coworkers have shown
that acetals derived from (E)- or (Z)-hex-3-en-1-ol cyclised in
the presence of titanium tetrabromide or tetrachloride to give
the trans- or cis-3-ethyl-4-halotetrahydropyrans respectively
with good stereocontrol.2 Prins type cyclisations have been
widely used for the synthesis of 2,4,6-trisubstituted tetra-
hydropyrans3 but examples of their use in the preparation of
tetrahydropyrans with other substitution patterns has been
rather more limited.4 In this paper we describe a direct method
for the preparation of 2,4,5-trisubstituted tetrahydropyrans from
homoallylic acetals5 which enables the creation of two
asymmetric centres with excellent stereocontrol and in which a
variety of functional groups may be introduced at C-4.
mercuric triflate,7 scandium triflate,8 BF3·Et2O–AcOH,3e,9 and
TFAA–AcOH.3f We investigated a range of methods to cyclise
homoallylic acetal 2 with the introduction of an oxygen
nucleophile into C-4 of a tetrahydropyran. One of the more
efficient procedures proved to be treatment of 2 with BF3·Et2O
in the presence of AcOH as the nucleophile and TMSOAc to act
as a fluoride trap to prevent competing formation of the 4-fluoro
derivative 7. Under these conditions, acetate 8 was obtained in
53% yield. Alternatively, treatment of 2 with anhydrous
trifluoroacetic acid gave diol 9 in 72% yield after hydrolysis of
the resultant 4-trifluoroacetate with potassium carbonate in
MeOH, (Scheme 2). Again these reactions proceeded with good
stereocontrol and only the all equatorial diastereomer was
isolated.
The substrate used for our initial cyclisation studies was the
homoallylic acetal 2 which was readily prepared in 4 steps from
ethyl 3-hydroxybutanoate 1 (readily available in both enantio-
meric forms) by MEM (methoxyethoxymethyl) protection of
the alcohol, DIBAL-H reduction to the aldehyde followed by
Horner Wadsworth Emmons chain extension with triethyl
phosphonoacetate and finally a further DIBAL-H reduction of
the resultant (E)-a,b-unsaturated ester. In the first cyclisation
study, homoallylic acetal 2 was treated with titanium tetrachlo-
ride in CH2Cl2 giving the 2,5-disubstituted 4-chlorotetrahy-
Scheme 2
To further examine the use of TFA for the cyclisation of
homoallylic acetals to give 2,4,5-trisubstituted tetrahydropyr-
ans, a series of substrates with a cis double bond and a SEM,
MEM or MOM group were prepared from pent-4-yn-2-ol 10
(Scheme 3). The hydroxy group of 10 was converted to the
acetal prior to reaction of the alkyne with butyllithium,
BF3·Et2O and propylene oxide giving a mixture of diaster-
eomeric alcohols 11. Catalytic hydrogenation of 11 in the
presence of Lindlar’s catalyst gave the (Z)-alkenols 12 and then
oxidation under Swern conditions gave the three required
homoallylic acetals 13. Treatment of the SEM acetal 13 with
aqueous TFAA gave three products in which the tetra-
hydropyran 14 was formed in only 18% yield. The major
products were the diastereomeric tetrahydrofurans 15 and 16
formed via rearrangement of the double bond into conjugation,
hydrolysis of the acetal and an intramolecular conjugate
addition to the resultant enone.
1
dropyran 3 in 63% yield (Scheme 1). From the H and 13C-
NMR spectra and NOE studies it was apparent that a single
product had been isolated in which all three substituents were in
an equatorial position.6 When the primary alcohol of 2 was
protected as the TBDPS ether 4, the TiCl4 mediated reaction
gave an improved 74% yield of the cyclic product 5 again as a
single diastereomer. By using other Lewis acids, further halides
could be introduced at C-4 of the tetrahydropyran. Thus,
treatment of 4 with titanium tetrabromide gave the 4-bromo
derivative 6 in 85% yield and reaction of 2 with BF3·Et2O in
CH2Cl2 gave a 55% yield of the 2,5-disubstituted 4-fluoro-
tetrahydropyran 7.
The synthetic utility of these cyclisations would be greatly
extended if functional groups other than a halide could be
introduced at C-4. Several methods have been reported for the
introduction of oxygenated substituents at C-4 in Prins type
However, treatment of each of the acetals 13 with anhydrous
TFA in dichloromethane gave, after hydrolysis of the initially
formed trifluoroacetate, the 2,5-disubstituted-4-hydroxytetra-
DOI: 10.1039/b101414p
Chem. Commun., 2001, 835–836
This journal is © The Royal Society of Chemistry 2001
835

In conclusion, Prins type cyclisation of homoallylic acetals
provides a versatile approach to the synthesis of 2,4,5-trisub-
stituted tetrahydropyrans. Our initial investigations indicate that
excellent stereocontrol may be achieved with both cis and trans
alkenes giving the all equatorial product and this merits further
investigation. By varying the acid and nucleophile a halide
(bromide, chloride or fluoride), oxygenated group (hydroxy,
ether or ester) or a nitrogen containing substituent may be
introduced at C-4 of the tetrahydropyran.
We are grateful to the following for funding: AstraZeneca
and the EPSRC (R. A. H.), Glaxo Wellcome (R. W. S.) and the
BBSRC (S. C.).
Notes and references
1 Review: B. B. Snider, in Comprehensive Organic Synthesis, ed. B. M.
Trost and I. Fleming, Pergamon Press, 1991, vol. 2, p. 527.
2 R. C. Winstead, T. H. Simpson, G. A. Lock, M. D. Schiavelli and D. W.
Thompson, J. Org. Chem., 1986, 51, 275.
Scheme 3
3 For example: (a) L. Coppi, A. Ricci and M. Taddei, Tetrahedron Lett.,
1987, 28, 973; (b) Z. Y. Wei, J. S. Li and D. Wang, Tetrahedron Lett.,
1987, 28, 3441; (c) L. Coppi, R. Ricci and M. Taddei, J. Org. Chem.,
1988, 53, 913; (d) I. E. Marko and F. Chelle, Tetrahedron Lett., 1997, 38,
2895; (e) G. S. Vismanathan, J. Yang and C.-J. Li, Org. Lett., 1999, 1,
993; (f) S. D. Rychnovsky, G. Yang, Y. Hu and U. R. Khire, J. Org.
Chem., 1997, 62, 3022; (g) S. D. Rychnovsky, Y. Hu and B. Ellsworth,
Tetrahedron Lett., 1998, 39, 7271; (h) J. Yang, G. S. Viswanathan and C.-
J. Li, Tetrahedron Lett., 1999, 40, 1627; (i) M. J. Cloninger and L. E.
Overman, J. Am. Chem. Soc., 1999, 121, 1092.
4 For example: 3,4-Disubstitution, P. R. Stapp, J. Org. Chem., 1969, 34,
479; 2,4-disubstitution, I. T. Kay and E. G. Williams, Tetrahedron Lett.,
1983, 24, 5915; C. Chen and P. S. Mariano, J. Org. Chem., 2000, 63,
3252; 2,5,6-trisubstitution, P. Mohr, Tetrahedron Lett., 1995, 36, 2453;
2,3,4,5,6-pentasubstitution, S. D. Rychnovsky and C. R. Thomas, Org.
Lett., 2000, 2, 1217.
hydropyran 14 in 50–60% yield with all three substituents again
in an equatorial position. Interestingly the stereochemical
outcome of this reaction differs from that reported for the
cyclisation of MEM protected (Z)-hex-3-en-1-ol with TiCl4 in
which a cis relationship of the vicinal halide and alkyl group
predominated.2 In addition, Rychnovsky and co-workers have
shown that although the TiCl4 mediated cyclisation of an (E)-
unsaturated homoallylic acetal gives an all equatorial 2,5,6-tri-
substituted 4-chlorotetrahydropyran, the reaction on the analo-
gous (Z)-isomer leads to a mixture of diastereomers in which the
4-chloro-5-alkyl substituents are cis in the major isomer.9 Thus
the MEM acetal 13 was cyclised using TiCl4 and the product 17
was obtained in 92% yield again with all the substituents
equatorial.
To the best of our knowledge Prins type cyclisations of
homoallylic acetals to tetrahydropyrans have never been
conducted in the presence of nitrogen nucleophiles although
products from such reactions would be of great general value in
synthesis. It would be expected that the acidic reaction
conditions required for formation of the oxocarbenium cation
would not be compatible with the use of amines as nucleophiles.
Indeed we found this to be the case. However, on treatment of
homoallylic acetal 4 with triflic acid in acetonitrile the 4-amido
derivative 18 was obtained in excellent yield (Scheme 4).
5 The only other example of the preparation of a 2,4,5-trisubstituted
tetrahydropyran via a Prins cyclisation of a homoallylic acetal is that of
I. T. Kay and D. Bartholomew, Tetrahedron Lett., 1984, 25, 2035.
6 All compounds were fully characterised, spectroscopic data for
4-chlorotetrahydropyran 3: dH(300 MHz, CDCl3) 1.22 (3H, d, J 6.3,
2-CH3), 1.69 (1H, dt, J 13.0 and 11.5, 3-Hax), 1.92 (1H, m, 5-H), 2.04
(1H, br s, OH), 2.21 (1H, ddd, J 13.0, 4.5 and 2.0, 3-Heq), 3.40 (1H, t, J
12.0, 6-Hax), 3.46 (1H, m, 2-H), 3.79 (2H, m, 5-CH2OH), 4.03 (1H, dt, J
11.5 and 4.5, 4-H), 4.09 ( 1H, dd, J 12.0 and 4.5, 6-Heq); dC(75 MHz,
CDCl3) 21.3 (2-CH3), 44.2 (C-3), 47.0 (C-5), 57.6 (C-4), 61.0
(5-CH2OH), 69.6 (C-6), 73.5 (C-2); m/z (CI) 167 and 165 (MH+, 4 and
14%), 149 (5), 147 (15), 129 (75), 111 (48) and 85 (100). (Found: MH+
165.0685 C7H14O2Cl requires 165.0682).
7 M. Nishizawa, T. Shigaraki, H. Takao, H. Imagawa and T. Sugihara,
Tetrahedron Lett., 1999, 40, 1153.
8 W.-C. Zhang, G. S. Viswanathan and C.-J. Li, Chem. Commun., 1999,
291; W.-C. Zhang and C.-J. Li, Tetrahedron, 2000, 56, 2403.
9 Y. Hu, D. J. Skalitzky and S. D. Rychnovsky, Tetrahedron Lett., 1996,
37, 8679.
Scheme 4
836
Chem. Commun., 2001, 835–836