Tetrahydropyran rings from a Mukaiyama-Michael cascade reaction

Article abstract of DOI:10.1021/ja056483u

A new annulation reaction leading to tetrahydropyrans has been discovered. The reaction of homoallylic enol ethers (e.g., 1) with α,β-unsaturated ketones or esters begins with a Mukaiyama-Michael addition. The intermediate oxocarbenium ion undergoes a rap

Full text of DOI:10.1021/ja056483u

Published on Web 10/28/2005
Tetrahydropyran Rings from a Mukaiyama-Michael Cascade Reaction
Megan L. Bolla, Brian Patterson, and Scott D. Rychnovsky*
Department of Chemistry, UniVersity of California, IrVine, IrVine, California 92697-2025
Received September 21, 2005; E-mail: srychnov@uci.edu
Table 1. Mukaiyama-Michael Cascade Reaction with
3-Butene-2-one (MVK)
Reactions that form complex rings are vital tools in synthetic
chemistry. The significance of [4 + 2] cycloadditions, such as the
Diels-Alder reaction, cannot be overstated.1 We have discovered
a new annulation reaction that is formally a two-carbon plus four-
carbon ring-forming reaction, but it proceeds through a cationic
cascade. In the reaction, enones or acrylates combine with homo-
allylic enol ethers, such as 1, to produce tetrahydropyrans. The scope
and selectivity of the reaction have been elucidated in the
preliminary studies described below.
The Mukaiyama aldol-Prins cyclization, illustrated in eq 1, was
the starting point for this investigation.2 Ketones and aldehydes
react with homoallylic enol ethers, such as compound 1, to produce
tetrahydropyran 3 by an initial Mukaiyama aldol reaction and sub-
sequent Prins cyclization of the intermediate oxocarbenium ion.
We had observed that R,â-unsaturated aldehydes led to complex
mixtures in the reaction and decided to investigate enones. The re-
action of 3-butene-2-one (5) and enol ether 1 promoted by TiBr4
and 2,6-di-tert-butyl-4-methylpyridine (DTBMP)3 generated the
unexpected tetrahydropyran 7 in high yield and as a single
diastereomer.
The Mukaiyama-Michael cascade reaction of homoallylic enol
ethers and 3-butene-2-one (5) is successful with a variety of
substrates, and the scope of the reaction is outlined in Table 1. A
variety of homoallylic enol ethers reacted rapidly with the enone
at low temperature to produce tetrahydropyrans in 63-74% yields.
All of the products except 17 were single diastereomers by NMR
analysis, with all three substituents on the tetrahydropyran in
equatorial positions. Robust oxygen protecting groups (entries 2
and 3) were compatible with the reactions, although more labile
substituents, such as TBS, were cleaved under the strong Lewis
acidic conditions. Most examples incorporated secondary aliphatic
ethers, but both benzylic and tertiary ethers (entries 6 and 7) were
effective. The enol ethers were readily prepared by exchange
between ethyl vinyl ether and the corresponding homoallylic
alcohols derived from allylmetal additions to simple aldehydes.
Trisubstituted tetrahydropyrans are readily accessible by this new
synthetic strategy.
a The enone (2.0 equiv), enol ether (1.0 equiv), and DTBMP (1.5 equiv)
were combined in DCM at -78 °C, a solution of TiBr4 (2.0 equiv) was
added, and the reaction was stirred for 1 h before quenching. b Only a single
diastereomer was observed by NMR spectroscopy. c Isolated as an 88:12
mixture of epimers at the methyl ketone center.
Scheme 1. Mukaiyama-Michael Cascade Reaction with Ethyl
Acrylate
Ethyl acrylate (20) is a useful alkene component in the
Mukaiyama-Michael cascade reaction. Scheme 1 shows several
examples of the reaction of ethyl acrylate with a variety of enol
ethers substrates. The reaction conditions are more vigorous; the
temperature was increased to 23 °C during the course of the reaction
to ensure complete consumption of starting material. In each case,
a mixture of diastereomeric products was observed that were
epimeric at the carboethoxy center. The efficiency of the reaction
was more varied than with the enone, with yields ranging from
less than 20 to 75%. Both enones and acrylates are useful substrates
in the cascade cyclization reaction.
The mechanism of the cascade reaction is outlined in Figure 1.
The first step is assumed to be a Mukaiyama-Michael reaction
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10.1021/ja056483u CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Influence of Substituents on the Cyclization Pathway
Yields
entry
R
34
35
36
-
1
2
3
PhCH2CH2
Ph-
ClCH2
2%
46%
43%
37%
39%
-
68%
Figure 1. Proposed mechanism for the Mukaiyama-Michael cascade
cyclization leading to 7 and the Mukaiyama-Michael Prins cyclization
reaction leading to 28, which was not observed with substrates 1 and 5.
Mukaiyama-Michael Prins adduct 36. Both the Prins product and
cascade cyclization product were observed in the reactions of
different enol ethers with 2-cyclohexenone, but the outcome
responds to substrate modifications in a predictable manner.
We have discovered a new annulation reaction that leads to
complex tetrahydropyrans from very simple substrates. The
Mukaiyama-Michael cascade cyclization and the related Prins
cyclization will be useful new tools for the synthesis of complex
natural products.
Scheme 2. Mukaiyama-Michael Cascade Reaction Leads to
Inversion of Configuration but Retention of Optical Purity
Acknowledgment. We thank the National Institutes of Health
(CA-081635) for their financial support. Fellowship support was
provided to B.P. by the NIGMS (GM-68971) under the Minority
Opportunities Program.
between reactants 1 and 5, leading to zwitterion 25.4 Rapid
equilibration of 25 and 26 by way of a 2-oxonia-Cope rearrange-
ment5 sets up the final cyclization between the oxocarbenium ion
and the enolate in 27 to produce the tetrahydropyran 7.6 Bromo
tetrahydropyran 28 might be formed by Prins cyclization of the
initial Mukaiyama-Michael adduct 25, but it was not observed in
this case. We have demonstrated in model studies that the 2-oxonia-
Cope rearrangement is very rapid for oxocarbenium ions related
to 25.5j The proposed sequence is conceptually related to an oxonia-
Cope Prins sequence that we described recently.7 Unlike that
sequence, the current reaction was developed from a fortuitous
observation and involves very simple substrates.
The sequence from oxocarbenium ion 25 to 26 to 27 suggests
that the stereogenic center in the enol ether should be inverted in
the product. The observations in Scheme 2 demonstrate that this is
the case. A normal segment-coupling Prins cyclization of ester (R)-
30 leads to (S,S)-29, whereas the Mukaiyama-Michael cascade
reaction of enol (R)-1 leads to (R,R)-29 in high optical purity.
Substituted enones also can be employed, but the outcome is
more complicated. Table 2 outlines the reaction of several enol
ethers with 2-cyclohexenone. The phenethyl enol ether (entry 1)
reacts to give the expected cascade product 35 with high dia-
stereoselectivity along with significant amounts of the Mukaiyama-
Michael Prins adduct 36 (e.g., 28, Figure 1). Previous work has
demonstrated that the rate and equilibrium in 2-oxonia-Cope
rearrangements are strongly influenced by the electronic properties
of the R group.5f An R group favoring the rearranged oxocarbenium
ion (e.g., 26, Figure 1) would promote the cascade product, whereas
a substituent favoring the starting oxocarbenium ion (i.e., 25) would
favor Prins products. The phenyl substituent stabilizes the rearranged
oxocarbenium ion and leads to the diastereomeric cascade products
34 and 35 in good yield (entry 2). In contrast, chloromethyl
substituent (entry 3) inhibits Cope rearrangement5f and favors the
Supporting Information Available: Experimental data for the
synthesis and characterizations of the compounds described. This
material is available free of charge via the Internet at http://pubs.acs.org.
References
(1) Cycloaddition Reactions in Organic Synthesis; Kobayashi, S., Jorgensen,
K. A., Eds.; Wiley-VCH Verlag: Weinheim, Germany, 2002.
(2) (a) Patterson, B.; Marumoto, S.; Rychnovsky, S. D. Org. Lett. 2003, 5,
3163-3166. (b) Patterson, B.; Rychnovsky, S. D. Synlett 2004, 543-
545.
(3) TiCl4 and 2,6-DTBMP also promote the reaction between 4 and 5 to give
6, but in reduced yield (53%). Stoichiometric TiBr4 was required for high
conversion. Both Ti(O-i-Pr)4 and TiF4 were ineffective.
(4) (a) Narasaka, K.; Soai, K.; Mukaiyama, T. Chem. Lett. 1974, 1223-1224.
(b) Narasaka, K.; Soai, K.; Aikawa, Y.; Mukaiyama, T. Bull. Chem. Soc.
Jpn. 1976, 49, 779-783. (c) Saigo, K.; Osaki, M.; Mukaiyama, T. Chem.
Lett. 1976, 163-164. (d) Heathcock, C. H.; Norman, M. H.; Uehling, D.
E. J. Am. Chem. Soc. 1985, 107, 2797-2799. (e) Giuseppone, N.;
Courtaux, Y.; Collin, J. Tetrahedron Lett. 1998, 39, 7845-7848. (f) Evans,
D. A.; Rovis, T.; Kozlowski, M. C.; Tedrow, J. S. J. Am. Chem. Soc.
1999, 121, 1994-1995. (g) Paulsen, H.; Antons, S.; Brandes, A.; Logers,
M.; Muller, S. N.; Naab, P.; Schmeck, C.; Schneider, S.; Stoltefuss, J.
Angew. Chem., Int. Ed. 1999, 38, 3373-3375. (h) Jaber, N.; Assie, M.;
Fiaud, J.-C.; Collin, J. Tetrahedron 2004, 60, 3075-3083.
(5) (a) Lolkema, L. D. M.; Semeyn, C.; Ashek, L.; Hiemstra, H.; Speckamp,
W. N. Tetrahedron 1994, 50, 7129-7140. (b) Nokami, J.; Yoshizane,
K.; Matsuura, H.; Sumida, S. J. Am. Chem. Soc. 1998, 120, 6609-6610.
(c) Roush, W. R.; Dilley, G. J. Synlett 2001, 955-959. (d) Loh, T.-P.;
Hu, Q.-Y.; Ma, L.-T. J. Am. Chem. Soc. 2001, 123, 2450-2451. (e) Alder,
R. W.; Harvey, J. N.; Oakley, M. T. J. Am. Chem. Soc. 2002, 124, 4960-
4961. (f) Crosby, S. R.; Harding, J. R.; King, C. D.; Parker, G. D.; Willis,
C. L. Org. Lett. 2002, 4, 577-580. (g) Loh, T.-P.; Hu, Q.-Y.; Ma, L.-T.
Org. Lett. 2002, 4, 2389-2391. (h) Hussain, I.; Komasaka, T.; Ohga,
M.; Nokami, J. Synlett 2002, 640-642. (i) Nokami, J.; Nomiyama, K.;
Matsuda, S.; Imai, N.; Kataoka, K. Angew. Chem., Int. Ed. 2003, 42,
1273-1276. (j) Jasti, R.; Anderson, C. D.; Rychnovsky, S. D. J. Am.
Chem. Soc. 2005, 127, 9939-9945.
(6) Pastine, S. J.; McQuaid, K. M.; Sames, D. J. Am. Chem. Soc. 2005, 127,
12180-12181.
(7) (a) Dalgard, J. E.; Rychnovsky, S. D. J. Am. Chem. Soc. 2004, 126,
15662-15663. (b) Dalgard, J. E.; Rychnovsky, S. D. Org. Lett. 2005, 7,
1589-1591.
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