4-(Arylsulfonyl)glycals in synthesis. Cation-mediated synthesis of 2,6- disubstituted dihydropyrans

Article abstract of DOI:10.1055/s-1999-2540

4-(Arylsulfonyl)glycal 9, easily prepared from phenylsulfinic acid, acrolein and 2-phenyloxirane, undergoes efficient, stereoselective S(N)1' reactions on exposure to Lewis acidic reagent systems. Treatment of syn-9 with dimethyldioxirane gives a single glycal epoxide, which also is a substrate for intermolecular C-glycosidation reactions.

Full text of DOI:10.1055/s-1999-2540

132
LETTER
4-(Arylsulfonyl)glycals in Synthesis. Cation-Mediated Synthesis of
2,6-Disubstituted Dihydropyrans
Jennifer M. Bailey,a Donald Craiga* and Peter T. Gallagherb
aCentre for Chemical Synthesis, Department of Chemistry, Imperial College of Science, Technology and Medicine, London SW7 2AY, UK
bEli Lilly and Co., Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK
Fax +44 171-594 5804; E-mail: dcraig@ic.ac.uk
Received 27 October 1998
treatment of the crude product effected cyclisation, giving
Abstract: 4-(Arylsulfonyl)glycal 9, easily prepared from phenyl-
a four-component mixture of methyl lactol ethers. Simple
sulfinic acid, acrolein and 2-phenyloxirane, undergoes efficient,
treatment of this mixture with potassium tert-butoxide3
effected clean, rapid isomerisation to the diastereomers 8a
stereoselective SN1’ reactions on exposure to Lewis acidic reagent
systems. Treatment of syn-9 with dimethyldioxirane gives a single
glycal epoxide, which also is a substrate for intermolecular C-gly- and 8b possessing the equatorially-disposed C-2 phenyl
cosidation reactions.
and C-4 tosyl groups. Finally, removal of the elements of
methanol from 8a,b was achieved by reaction with TMSI
in acetonitrile, followed by quenching with hexamethyl-
disilazane (Scheme 2).9 This procedure gave exclusively
syn-9 in good yield; its syn-configuration was assigned by
X-ray crystallographic analysis10 (Figure 1).
Key words: sulfone, dihydropyran, cation-mediated, synthesis,
SN1’, glycal
We recently described cation-mediated reactions of 1,4-
bis(arylsulfonyl)-1,2,3,4-tetrahydropyridines 1, which
upon treatment with Lewis acids and nucleophiles under-
went SN1’reaction to give 2,6-dialkyl-1,2,5,6-tetrahydro-
pyridines
2 in good yields and with excellent
stereoselectivities (Scheme 1).1 We have been investigat-
ing also the analogous reactions of 4-(arylsulfonyl)glycals
3, which we anticipated would yield dihydropyrans 4 by a
similar dissociative mechanism. We had previously pre-
pared analogue 5 as an intermediate in a synthesis of the
enzyme inhibitor2 2,3-dideoxy-D-manno-2-octulopyran-
osonic acid.3 This letter reports the results of these inves-
tigations.4,5
As with our analogous work on bis(arylsulfonyl)tetrahy-
dropyridines, initial studies of cation-mediated reactions
of 9 involved aluminium-based Lewis acidic reagents.
Treatment of dichloromethane solutions of syn-9 with tri-
methylaluminium or chlorodimethylaluminium at ambi-
ent temperature gave [2R*,6S*]-6-methyl-2-phenyl-3,6-
dihydro-2H-pyran (10a) in high yield, with greater than
10:1 selectivity for the anti-isomer. An analogous trans-
formation could be realised using i-Bu3Al, with 10b being
formed as a 10:1 mixture with the syn-diastereomer. Sim-
ilarly, reaction of 1-hexynyldimethylalane11 with syn-9
gave the alkynyl-substituted dihydropyran 10c, again with
high (≥ 10:1) anti-selectivity; treatment with dimethyl[2-
(±)-2-Phenyl-4-(4-tolylsulfonyl)-3,4-dihydro-2H-pyran
(9) was chosen as the substrate on which to develop the C–
C bond-forming reactions. This was easily synthesised
from acrolein and racemic 2-phenyloxirane as depicted in
Scheme 2. Thus, addition of sodium 4-tolylsulfinate to
acrolein in acetic acid followed by protection of the alde-
hyde function using HC(OMe)3–K-10 montmorillonite
clay6 gave the known7 sulfonylacetal 6.8 Addition of 2-
phenyloxirane to a cold THF solution of the lithio-anion
of 6 followed by warming to ambient temperature gave
the alcohol 7 as a diastereomeric mixture; Brønsted acid
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LETTER
Cation-Mediated Synthesis of 2,6-Disubstituted Dihydropyrans
133
(trimethylsilyl)ethynyl]alane gave 10d in a similar reac-
tion. Treatment of a mixture of allyltrimethylsilane and
syn-9 with tin(IV) chloride gave the anti-allylated ana-
logue 10e. Finally, a Mukaiyama-type aldol reaction12
was achieved by addition of tin(IV) chloride to syn-9 in
the presence of the TBDMS enol ether of pinacolone, giv-
ing ketone 10f. The structural assignments for all of the
major products were inferred from the observation of a
6.8% n.O.e. between the C-6 Me group and H-2 in 10a.
Also, hydrogenation of the isolated double bond in 10a
using diimide13 gave material which showed 1H nmr char-
acteristics identical to those reported.4 Anti-9 gave an the basis of our earlier work,3 we anticipated that epoxida-
identical product profile in the Me3Al-mediated transfor- tion of the double bond would be an efficient and stereo-
mation, pointing towards a dissociative mechanism for the selective process, and that the product oxiranes would be
SN’ process. Further evidence for cationic intermediates reactive substrates in nucleophile- and Lewis acid-medi-
was provided by the reactions of more highly substituted ated reactions. Treatment of syn-9 with a 0.08M acetone
analogues of 9. Alkylation of 9 proceeded highly regio- solution of dimethyldioxirane (DMDO)15 gave quantita-
and stereoselectively, and in good yield upon treatment tively the unstable epoxide 12 as a single diastereomer, as
with n-BuLi followed by addition of reactive electro- evidenced by 1H nmr. Reaction of crude 12 with methanol
philes; introduction of the C-4 alkyl group in the products gave a single methyl glycoside 13, whose all-equatorial
11 occurred predominantly syn to the 2-phenyl substitu- stereochemistry was confirmed by single-crystal X-ray
ent. The X-ray crystal structure of 11b is shown in Figure crystallography (Figure 3).10 Compound 13 could be des-
2.10 In general, these more substituted substrates under- ulfonylated by the action of sodium naphthalide in THF,
went accelerated reactions with the Lewis acid–nucleo- furnishing the deoxysugar 16 in an unoptimised yield of
phile combinations investigated earlier, indicative of the 47%.16 Reaction of 12 with trimethyl-aluminium effected
greater stability of the intermediate cation, and of the re- syn-delivery of the methyl group to give the sulfonyl-sub-
lief of strain taking place upon ionisation. As before, C–C stituted hydroxytetrahydropyran 14 (Figure 4).10 This se-
bond formation took place with double bond transposi- lectivity could be reversed by the use of lithium
tion, to give anti-2,6-disubstituted dihydropyrans 10g,h. dimethylcuprate as the methyl source, which resulted in
Thus, both the SN1' and 4-alkylation reactions of 9 showed the formation of the isomer 15 in good yield. It seems like-
stereochemical preferences opposite to those of the nitro- ly that whilst formation of 14 is a consequence of internal
gen analogues reported in our earlier work,1 and we again delivery of CH3 from the -ate complex formed by Me3Al-
explain this tendency in terms of an axial trajectory of nu-
cleophilic attack on the unsaturated oxonium intermedi-
ate. The cation-mediated reactions of syn-9, and the
synthesis and reactions of the 4-substituted analogues 11
are depicted in Scheme 3 and in the Table.14
The final part of this phase of our investigation sought to
explore the utility of glycal epoxides derived from 9. On
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134
J. M. Bailey et al.
LETTER
Dewey, R. S.; Timmons, R. J. J. Am. Chem. Soc. 1961, 83,
3725-3726.
mediated ring-opening of the epoxide, compound 15 aris-
es through an SN2-like mechanism17 involving inversion
at the anomeric centre (Scheme 4).18
(14) Experimental procedure for the preparation of 10a.
To a solution of syn-9 (0.5 g, 1.6 mmol) in dry CH2Cl2 (14.5
ml) at rt under a N2 atmosphere was added Me3Al (1.6 ml of a
2M solution in hexanes, 3.2 mmol, 2 equiv). After 1 h tlc
indicated complete consumption of starting material, and the
reaction was quenched by the addition of MeOH (20 ml)
followed by saturated aqueous Rochelle salt (20 ml). The mix-
ture was stirred for a further 30 min, and then extracted with
EtOAc (3 x 20 ml). The combined organic extracts were
washed with H2O (10 ml), brine (10 ml), and then dried
(MgSO4). Removal of solvents under reduced pressure follo-
wed by chromatography of the oily residue (SiO2, 10% Et2O–
petrol) gave [2R*,6S*]-6-methyl-2-phenyl-3,6-dihydro-2H-
pyran (10a) (0.25 g, 91%) as a colourless oil; nmax (film) 3087,
3062, 3031, 2971, 2925, 2893, 2845, 2830, 1658, 1603, 1494,
1450, 1425, 1391, 1365, 1298, 1190, 1124, 1080, 1059 cm-1;
dH (300 MHz, CDCl3) 7.41-7.16 (5H, m, Ph), 5.92-5.88 (1H,
m, H-4), 5.76 (1H, d, J 11.5 Hz, H-5), 4.73 (1H, dd, J 8.5, 4.5
Hz, H-2), 4.46 (1H, m, H-6), 2.35-2.21 (2H, m, H-3), 1.32
(3H, d, J 6.5 Hz, CH3); dC (75 MHz, CDCl3) 124.6, 131.2,
128.3, 127.4, 126.3, 123.7, 76.6, 69.5, 32.0, 20.0; m/z (CI) 192
[M+NH4]+, 175 [M+H]+, 157 [M-OH]+ (Found: C, 82.75; H,
8.14. C12H14O requires C, 82.71; H, 8.09%).
In summary, we have demonstrated that a 2-substituted 4-
(4-tolylsulfonyl)glycal 9 enters into highly stereoselective
SN1’ reactions, giving anti-2,6-disubstituted 3,6-dihydro-
2H-pyrans in good to excellent yields. Compounds 9 are
readily alkylated at the 4-position, and syn-9 undergoes
completely selective epoxidation to give an intermediate
which may react further with carbon and oxygen nucleo-
philes. We are currently investigating cycloaddition and
electrophilic substitution reactions of 9, and the results of
these studies will be reported in due course.
Acknowledgement
We thank the EPSRC and Lilly Research Centre (CASE Stu-
dentship to J. M. B.) for financial support of this research. We thank
Sarah Elton-Farr (undergraduate research participant, 1995) for
some preliminary experiments.
References and Notes
(15) Halcomb, R. L.; Danishefsky, S. J. J. Am. Chem. Soc. 1989,
111, 6661-6666.
(16) Neither sodium amalgam nor SmI2 effected the conversion of
13 into 16. Samarium(II) iodide was similarly unreactive to-
wards the acetate derivative from 13.
(1) Craig, D.; McCague, R.; Potter, G. A.; Williams, M. R. V.
Synlett 1998, 55-57.
(2) Sarabia-García, F.; López-Herrera, F. J.; Pino-González, M.
S. Tetrahedron Lett. 1994, 35, 6709-6712.
(17) For recent examples of organocopper-mediated ring-opening
reactions of glycal epoxides, see: Hayward, M. M.; Roth, R.
M.; Duffy, K. J.; Dalko, P. I.; Stevens, K. L.; Guo, J.; Kishi,
Y. Angew. Chem. Int. Ed. Engl. 1998, 37, 193-196.
(3) Craig, D.; Pennington, M. W.; Warner, P. Tetrahedron Lett.
1995, 36, 5815-5818.
(4) For related reactions of the vinylogous 2-(phenylsulfonyl)
tetrahydro-2H-pyrans, see: Brown, D. S.; Bruno, M.; Daven-
port, R. J.; Ley, S. V. Tetrahedron 1989, 45, 4293-4308.
(5) For recent studies of related reactions of glycal esters with
organocopper and organozinc reagents, see: Thorn, S. N.;
Gallagher, T. Synlett 1996, 856-858; Dorgan, B. J.; Jackson,
R. F. W. Synlett 1996, 859-861.
(6) Taylor, E. C.; Chiang, C.-S. Synthesis 1977, 467.
(7) Bonete, P.; Nájera, C. Tetrahedron 1995, 51, 2763-2776.
(8) All yields cited herein are of isolated, purified materials which
gave satisfactory 1H, 13C nmr and ir spectra, and which
showed low-resolution ms and either elemental combustion
analysis or high-resolution ms characteristics in accord with
the assigned structures.
(9) Paquette, L. A.; Oplinger, J. A. J. Org. Chem. 1988, 53, 2953-
2959.
(10) We have not prepared isomerically pure samples of anti-9. We
thank Professor David J. Williams and Dr Andrew J. P. White
of this department for the X-ray crystallographic determina-
tions.
(11) Carreño, M. C.; González, M. P.; Ribagorda, M. J. Org.
Chem. 1996, 61, 6758-6759.
(12) Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem. Soc.
1974, 96, 7503-7509.
(13) Treatment of 11a with dipotassium azodicarboxylate (20
equiv) and AcOH (40 equiv) in CH2Cl2 (0.1M) at rt for 12 h
followed by heating under reflux for 12 h gave 20% of
[2R*,6S*]-6-methyl-2-phenyltetrahydropyran, together with
80% unreacted starting material. See: Van Tamelen, E. E.;
(18) Data for [2R*,3S*,4S*,6S*]-2-Methyl-6-phenyl-4-(4-tolylsul-
fonyl)tetrahydropyran-3-ol (14); mp 150-152°C; nmax
(CH2Cl2) 3512, 2954, 2926, 2877, 2857, 1597, 1496, 1451,
1403, 1380, 1311, 1301, 1288, 1141, 1093, 676 cm-1; dH (300
MHz, CDCl3) 7.75 (2H, d, J 8.5 Hz, ortho-Tol), 7.39-7.18 (7H,
m, meta-Tol and Ph), 4.68 (1H, dd, J 11.5, 2.5 Hz, H-6), 4.44
(1H, quintet, J 6.5 Hz, H-2), 4.27 (1H, dd, J 9.0, 6.0 Hz, H-3),
4.15 (1H, d, J 1.0 Hz, -OH), 3.50 (1H, ddd, J 14.0, 10.0, 4.0
Hz, H-4), 2.49 (3H, s, Ts-CH3), 2.02 (1H, dt, J 13.0, 3.0 Hz,
H-5eq), 1.64 (1H, q, J 12.5 Hz, H-5ax), 1.41 (3H, d, J 7.0 Hz,
C-2 CH3); m/z (CI) 364 [M+NH4]+, 347 [M+H]+, 191, 173,
104 (Found: [M+NH4]+, 364.1584. C19H22O4S requires
[M+NH4]+, 364.1583).
Data for [2R*,3R*,4R*,6R*]-2-Methyl-6-phenyl-4-(4-tolyl-
sulfonyl)tetrahydropyran-3-ol (15); mp 138-140°C; nmax
(CH2Cl2) 3508, 3063, 2959, 2927, 2859, 1598, 1493, 1451,
1402, 1376, 1292, 1214, 1180, 1141, 1090, 994, 815, 758,
734, 701, 670 cm-1; dH (300 MHz, CDCl3) 7.77 (2H, d, J 8.5
Hz, ortho-Tol), 7.41-7.26 (7H, m, meta-Tol and Ph), 4.42 (1H,
dd, J 11.0, 2.0 Hz, H-6), 4.24 (1H, br s, -OH), 3.69 (1H, t, J 9.0
Hz, H-3), 3.57-3.50 (1H, m, H-2), 3.40 (1H, ddd, J 13.0, 10.0,
4.0 Hz, H-4), 2.49 (3H, s, Ts-CH3), 2.08 (1H, ddd, J 13.5, 4.0,
2.0 Hz, H-5eq), 1.75 (1H, q, J 13.0 Hz, H-5ax), 1.41 (3H, d, J
7.0 Hz, C-2 CH3); m/z (CI) 364 [M+NH4]+, 347 [M+H]+, 210,
189, 173 (Found: [M+NH4]+, 364.1584. C19H22O4 requires
[M+NH4]+, 364.1572).
(19) Yield based on recovery of 8% unreacted starting material.
Synlett 1999, No. 1, 132–134 ISSN 0936-5214 © Thieme Stuttgart · New York