Stereospecific synthesis of 2,3-dihydro-4H-pyran-4-ones by Hg(II)- catalyzed rearrangement of 1-alkynyl-2,3-epoxy alcohols

Full text of DOI:10.1021/jo9715837

3798
J . Org. Chem. 1998, 63, 3798-3799
Ster eosp ecific Syn th esis of
2,3-Dih yd r o-4H-p yr a n -4-on es by Hg(II)-
Ca ta lyzed Rea r r a n gem en t of
1-Alk yn yl-2,3-ep oxy Alcoh ols
Charles M. Marson,*,1 Steven Harper,2 and
Catriona A. Oare
Department of Chemistry, The University of Sheffield,
Sheffield S3 7HF, U.K.
Timothy Walsgrove
SmithKline Beecham, Old Powder Mills, nr. Leigh, Tonbridge,
Kent TN11 9AN, U.K.
natural products, including stegobiol,7a vallartanones A and
B,7b and the pheromone of the male swift moth.7c The best
known route to 2,3-dihydro-4H-pyran-4-ones, the Lewis acid-
catalyzed hetero Diels-Alder reaction of siloxy 1,3-dienes
with aldehydes,3g,7d-f permits the introduction of 2,3-cis
disubstitution. However, it does not afford pure trans 2,3-
disubstitution, and indeed, appreciable quantities of both
cis and trans products are often obtained.7g,h Nor may alkyl
or other groups be readily introduced at the 6-position
(Scheme 1). In the context of increasing the range of
stereoselective syntheses of pyranoids, we report here the
first examples of 1-alkynyl-2,3-epoxy alcohol rearrangements
to give 3-substituted-2,3-dihydropyran-4-ones (Scheme 1,
Table 1), a ring system readily adaptable to the synthesis
of the above classes of natural products. The reactions
proceed with additional 2- and/or 6-substituents and tolerate
a variety of sensitive functionality.
1-Alkynyl-2-alken-1-ols10 were epoxidized using either
tert-butyl hydroperoxide-VO(acac)2 or m-CPBA (for 1e) to
give the corresponding 1-alkynyl-2,3-epoxyalcohols10 (Scheme
1). The alkene required for the preparation of 1g was
prepared as follows: reduction of (Z)-ethyl 2,4-dimethyl-2-
pentenoate11 with DIBAH gave 2,4-dimethyl-2-penten-1-ol,
which was treated with TBHP and VO(acac)2 to give a
diastereoisomeric mixture of epoxy alcohols that underwent
Swern oxidation to give 2,4-dimethyl-2,3-oxiranylpentanal,
which was reacted with 1-heptynyllithium. The 1-alkynyl-
2,3-epoxy alcohols were treated with 1.7 mol % Hg(II) in 4.0
mM aqueous sulfuric acid.12 After neutralization, extraction,
and chromatography, the corresponding 2,3-dihydropyran-
4-ones were isolated (Table 1). Coupling constants and
NOESY experiments (involving the methine hydrogen atoms
at the 2- and 3-positions) confirmed the relative configura-
tions of 2d -g. The reaction proceeds for alkyl and aryl
substituents at C-3, but when this position is not substituted,
one example gave only a 2,5-disubstituted furan.14 Position
2 need not be substituted, but if it is, the stereochemistry
at C-2 is retained. The relative configuration of the 2,3-
Received August 26, 1997
The stereocontrolled assembly of substituents on a pyra-
noid ring is of continuing importance.3-7 The tetrahydro-
pyran ring3-6 is found in a wide variety of natural products,
many possessing useful pharmacological and therapeutic
properties. Examples of compounds containing a 3-meth-
yltetrahydropyran unit include numerous spiroketals,3a the
avermectins and the milbemycins,8 broad-spectrum anti-
parasitic and insecticidal agents, the potent antitumor
agents spongistatin 1,5a and serricornin, the sex pheromone
of the cigarette beetle.3b Syntheses of avermectins and
milbemycins require assembly of a spiroketal subunit,3a as
do the oligomycin, rutamycin and cytovaricin family of
antibiotics3c and the phyllanthostatins, a group of antine-
oplastic glycosides.3d The 3-methyltetrahydropyran unit in
monensin3e,f is common in polyether antibiotics and is also
present in the mycalamides, potent antiviral and antitumor
agents that also possess 4-oxygenated substituents.9
2,3-Dihydro-4H-pyran-4-ones are key intermediates7 in
the synthesis of a wide range of tetrahydropyrans and
carbohydrates. Additionally, the ring is present in several
(1) New address: Department of Chemistry, Queen Mary and Westfield
College, University of London, London E1 4NS, U.K.
(2) Current address: IRBM, via Pontina km 30, 600, 00040 Pomezia,
Rome, Italy.
(3) For general syntheses of tetrahydropyrans, see: (a) Perron, F.;
Albizati, K. F. Chem. Rev. 1989, 89, 1617. (b) Kobayashi, Y.; Kitano, Y.;
Takedo, Y.; Sato, F. Tetrahedron 1986, 42, 2937. (c) Evans, D. A.; Rieger,
D. L.; J ones, T. K.; Kaldor, S. W. J . Org. Chem. 1990, 55, 6260. (d) Smith,
A. B., III; Rivero, R. A.; Hale, K. J .; Vaccaro, H. A. J . Am. Chem. Soc. 1991,
113, 2092. (e) Fukuyama, T.; Wang, C.-L. J .; Kishi, Y.; J . Am. Chem. Soc.
1979, 101, 259. (f) Walba, D. M.; Thurmes, W. N.; Haltiwanger, R. C. J .
Org. Chem. 1988, 53, 1046. (g) Danishefsky, S. J .; De Ninno, M. P. Angew.
Chem., Int. Ed. Engl. 1987, 26, 15.
(4) For syntheses of tetrahydropyrans by the ring closure of 4,5-epoxy
alcohols, see: (a) Adiwijaja, G.; Florke, H.; Kirschning, A.; Schaumann, E.
Tetrahedron Lett. 1995, 36, 8771. (b) Fujiwara, K.; Tokiwano, T.; Murai, A.
Tetrahedron Lett. 1995, 36, 8063. (c) Suzuki, T.; Sato, O.; Hirama, M.
Tetrahedron Lett. 1990, 31, 4747.
(5) For isolation and/or structural elucidation of tetrahydropyrans, see:
(a) Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Herald, C. L.; Boyd, M. R.; Schmidt,
J . M.; Hooper, J . N. A. J . Org. Chem. 1993, 58, 1302. (b) Lynn, D. G.;
Phillips, N. J .; Hutton, W. C.; Shabanowitz, J .; Fennell, D. I.; Cole R. J . J .
Am. Chem. Soc. 1982, 104, 7319.
(10) All new compounds have been fully characterized (see the Supporting
Information). Configurations depicted refer to racemic materials. For further
details see the Supporting Information.
(11) Kinstle, T. H.; Mandanas, B. Y. J . Chem. Soc., Chem. Commun. 1968,
1699.
(12) General procedure for the preparation of dihydropyranones 2: To a
stirred solution of the epoxy alcohol 1 (1.5 mmol) in propanone (30 mL;
HPLC grade) at 20 °C was added 0.25 mL of a freshly prepared Hg(II)
solution, made by dissolving yellow mercury(II) oxide in dilute sulfuric acid,
such that a stock solution 0.1 M in mercury(II) and 2.5 vol % of sulfuric
acid was obtained. The optimum time of the reaction (TLC monitoring) was
typically between 5 and 20 min.
(13) Marson, C. M.; Benzies, D. W. M.; Hobson, A. D. Tetrahedron 1991,
47, 5491. This paper provides an explanation and definition of syn and anti
as used herein.
(6) For syntheses of tetrahydropyrans by the ring closure of 5-alkenols,
see: Evans, D. A.; Bender, S. L.; Morris, J . J . Am. Chem. Soc. 1988, 110,
2506. (b) Hartung, J .; Gallou, F. J . Org. Chem. 1995, 60, 6706.
(7) For syntheses of dihydro-4H-pyran-4-ones, see: (a) Mori, K.; Ebata,
T. Tetrahedron 1986, 42, 4685. (b) Manker, D. C.; Faulkner, D. J . J . Org.
Chem. 1989, 54, 5374. (c) Mori, K.; Kisida, H. Tetrahedron 1986, 42, 5281.
(d) Keck, G. E.; Li, X.-Y.; Krishnamurthy, D. J . Org. Chem. 1995, 60, 5998.
(e) Bednarski, M.; Danishefsky, S. J . Am. Chem. Soc. 1983, 105, 3716. (f)
Danishefsky, S. J . Chemtracts: Org. Chem. 1989, 2, 273. (g) Paterson, I.;
Osborne, S. Tetrahedron Lett. 1990, 31, 2213. (h) Maruoka, K.; Itoh, T.;
Shirasaka, T.; Yamamoto, H. J . Am. Chem. Soc. 1988, 110, 310.
(8) (a) Davies, H. G.; Green, R. H. Nat. Prod. Rep. 1986, 87. (b)
Danishefsky, S. J .; Armistead, D. M.; Wincott, F. E.; Selnick, H. G.; Hungate,
R. J . Am. Chem. Soc. 1989, 111, 2967.
(9) Perry, N. B.; Blunt, J . W.; Munro, M. H. G.; Thompson, A. M. J . Org.
Chem. 1990, 55, 223.
(14) Marson, C. M.; Harper, S.; Wrigglesworth, R. J . Chem. Soc., Chem.
Commun. 1994, 1879.
S0022-3263(97)01583-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/20/1998

Communications
J . Org. Chem., Vol. 63, No. 12, 1998 3799
Sch em e 1
Sch em e 2
Ta ble 1. Rea r r a n gem en t of 2,3-Ep oxy Alcoh ols To Give
2,3-Dih yd r o-4H-p yr a n -4-on esa
The tolerance of the process to a ring fused across the
epoxide function was tested by treatment of 1-(1,2-epoxycy-
clopentyl)-3-phenylprop-2-yn-1-ol with the acidic solution of
catalytic Hg(II); no dihydropyranone was isolated, but
instead 4-(5-phenyl-2-furyl)butanal was obtained (70%); such
furans that have been previously obtained, but principally
from tertiary alcohols.14
entry
epoxy alcoholb
productc
yieldd (%)
The stereospecificity of the reaction is shown by compari-
son of entry 7 with all other reactions in Table 1. In each
reaction, only a single dihydropyran-4-one diastereoisomer
was detected, the stereochemistry arising by exclusive
inversion at CR of the epoxide. The configuration at the
carbinol carbon atom is immaterial,15 free rotation enabling
both epimeric alcohols to deliver hydride anti to the C-O
bond of the epoxide undergoing cleavage. Since enol inter-
mediates would result in loss of stereochemical integrity at
CR, it is presumed that a 1,2-hydride shift occurs with
concomitant ring opening of the epoxide in a semipinacol
rearrangement.16 The rearrangement of alkynyl epoxy
alcohols into dihydropyranones contrasts markedly with
reactions of the analogous tertiary alcohols, from which
â-hydroxy ketones,16 cyclized products,17 and substituted
furans14 have been obtained.
The feasibility of an enantioselective variant of the
dihydropyran-4-one reaction was probed. Entry 4 was
repeated, but by asymmetric epoxidation of the correspond-
ing (()-alkynyl allylic alcohol under conditions of kinetic
resolution18 (TBHP, 10 mol % Ti(O-i-Pr)4, 15 mol % of (+)-
diisopropyl tartrate, -20 °C, 9 h). Chromatography of the
reaction mixture afforded two fractions: a 4:1 diastereoiso-
meric mixture of epoxy alcohols (42%) and unreacted enynol
(48%). The diastereoisomeric mixture of epoxy alcohols was
reacted with the acidic solution of catalytic Hg(II) to give
diastereoisomerically pure 2d (55%) in 60% ee (Chirex
column, phase 3014, 1:9 ethyl acetate/petroleum ether
eluent).
In summary, stereocontrolled routes to 2,3-dihydro-4H-
pyran-4-ones by the Hg(II)-catalyzed rearrangement of
1-alkynyl-2,3-epoxy alcohols in acidic media have been
demonstrated. The mild conditions are tolerant of a variety
of sensitive functionalities. The scope, mechanistic aspects,
and synthetic applications of these reactions are under
investigation.
a
All products depicted are racemic. b The major diastereoisomer
is shown, although syn/anti mixtures13 of 1 were used in the
rearrangements [for which the ratios are as follows (entry): 7:3
(1a ), 3:1 (1b), 6:1 (1c), 2:1 (1d ), 2:1 (1e, m-CPBA), 21:1 (1f), 1:1
(1g)]. c Conditions as in footnote 12. Isolated yields.
d
disubstituted dihydropyranones is determined solely by the
configuration of the alkene (in the initial enynol); thus, the
(Z)-alkene leads to epoxide 1g and, hence, only to the trans
product 2g. The alternative stereochemistry in entries 3-6
(Table 1) leads to the dihydropyranone with only cis 2,3-
disubstitution. This capability of stereocontrolled placement
of several substituents would be of use in the synthesis of
natural products such as the environmentally benign pes-
ticide serricornin,3b which possesses cis-2-ethyl-3-methyl
substitution, as obtained in entry 4 (Table 1).
Alkyl, aryl, and hydroxylated functionalities are tolerated
at C-6, provided the group is not substantially electron-
withdrawing. An electron-donating substituent at C-6 was
found to enhance markedly the formation of the dihydropy-
ranone ring, so much so that in the reaction of enynol 4 with
tert-butyl hydroperoxide in the presence of VO(acac)2 no
epoxide was isolated; instead, the reaction proceeded directly
to the 2,3-dihydro-6-ethoxypyranone 5, no Hg(II) catalysis
being necessary (Scheme 2).
Ack n ow led gm en t. We thank the EPSRC and Smith-
Kline Beecham for a CASE award (to C.A.O.).
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures and spectroscopic data are available for 1a -g, 2a -g, and
3, and 4 (6 pages).
J O9715837
(15) The epimers of 1e were separated and separately treated with
aqueous acidic Hg(II), each isomer affording the same dihydropyranone 2e.
(16) Marson, C. M.; Walker, A. J .; Pickering, J .; Hobson, A. D.; Wriggles-
worth, R.; Edge, S. J . J . Org. Chem. 1993, 58, 5944.
(17) Marson, C. M.; Harper, S.; Walker, A. J .; Pickering, J .; Campbell,
J .; Wrigglesworth, R.; Edge, S. J . Tetrahedron 1993, 49, 10339.
(18) Finn, M. G.; Sharpless, B. K. Asymmetric Synthesis 1985, 5, 247.