Formal [4 + 2] cycloaddition of donor-acceptor cyclobutanes and aldehydes: Stereoselective access to substituted tetrahydropyrans

Article abstract of DOI:10.1021/ja906755e

(Chemical Equation Presented) A highly diastereoselective synthesis of 2,6-cis-disubstituted tetrahydropyrans (THPs) via Lewis acid-catalyzed formal [4 + 2] cycloaddition of donor-acceptor cyclobutanes and aldehydes has been developed. THP products are fo

Full text of DOI:10.1021/ja906755e

Published on Web 09/18/2009
Formal [4 + 2] Cycloaddition of Donor-Acceptor Cyclobutanes and
Aldehydes: Stereoselective Access to Substituted Tetrahydropyrans
Andrew T. Parsons and Jeffrey S. Johnson*
Department of Chemistry, UniVersity of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290
Received August 10, 2009; E-mail: jsj@unc.edu
Table 1. Sc(OTf)3-Catalyzed Formal [4 + 2] Cycloaddition of
Donor-acceptor (D-A) cyclopropanes are an extensively studied
class of molecules due to their unique reactivity profile.1 Their value
as synthetic building blocks has been demonstrated by the preparation
of highly substituted carbo- and heterocyclic products via dipolar
cycloaddition.2 Despite the potential utility of homologous products,
reports that extend this methodology to D-A cyclobutanes are rare.3
This is particularly surprising since the strain energy of cyclobutane
(26.3 kcal/mol) is similar to that of cyclopropane (27.5 kcal/mol),4
suggesting that ring-opening reactions of cyclobutanes may be facile.
Aldehydes are competent dipolarophiles in Lewis acid-catalyzed
[3 + 2] cycloadditions with D-A cyclopropanes, furnishing
tetrahydrofuran derivatives in a stereoselective manner.2d,5 Given
this precedent, we sought to access tetrahydropyrans (THPs) through
Lewis acid-catalyzed formal [4 + 2] cycloaddition of malonate-
derived cyclobutanes and aldehydes (eq 1).6 The resulting THP
products are of interest because of their prevalence in biologically
relevant and structurally interesting molecules.7 To the best of our
knowledge, there are currently no reports of 1,4-dipolar cycload-
ditions using D-A cyclobutanes possessing a carbon-based donor
group. Herein we report the application of malonate-derived D-A
cyclobutanes as synthetic equivalents for all-carbon 1,4-dipoles.
Lewis acid-catalyzed formal [4 + 2] cycloaddition of these species
with aldehydes provides an efficient route to cis-2,6-disubstituted
tetrahydropyran products (eq 1).
Cyclobutanes with Cinnamyl and Aryl Aldehydesa
a Cyclobutane (1.0 equiv), aldehyde (3.0 equiv), Sc(OTf)3 (0.02
equiv), [1]0 ) 0.25 M in CH2Cl2. b Average isolated yield of two
independent trials. c dr was determined by 1H NMR spectroscopy.
d Hf(OTf)4 (0.02 equiv) was used as the catalyst.
(Table 2). The diastereomeric ratio of the THP products varied,
with branched and cyclic aldehydes providing the highest levels
of diastereoselectivity (up to 96:4 dr).
Table 2. MADNTf2-Catalyzed Formal [4 + 2] Cycloaddition of
Cyclobutanes with Aliphatic Aldehydesa
We began our studies by examining Lewis acid catalysts known
to activate malonate-derived molecules via coordination to the
dicarbonyl groups.5b Of those examined, Hf(OTf)4 and Sc(OTf)3
were the most effective catalysts, providing 2,6-cis-disubstituted
THPs in high yield and diastereoselectivity. The potential for
asymmetric catalysis prompted us to proceed with Sc(OTf)3, as
numerous enantioselective reactions have been reported using chiral
Sc(III) Lewis acids.8
Several malonate-derived cyclobutanes underwent cycloaddition
with cinnamyl and electronically diverse aryl aldehydes. Sc(OTf)3
proved to be a highly active catalyst in this system, requiring only
2 mol % loading to afford the desired THP cycloadducts in high
yield and stereoselectivity. In most cases, the 2,6-cis-diastereomer
was formed in greater than 94:6 selectivity; only cinnamaldehyde
and 2-chlorobenzaldehyde furnished products with a lower diaster-
eomeric ratio (Table 1).
Attempts to extend the Sc(OTf)3 system to aliphatic aldehydes
were not successful. Our group recently reported that MADNTf2
catalyzes dipolar cycloadditions of sensitive aldehydes while
avoiding decomposition.5d We examined this complex as a possible
alternative to Sc(OTf)3 and found it to be effective in catalyzing
the cycloaddition of linear, branched, and cyclic aliphatic aldehydes
a Cyclobutane (1.0 equiv), aldehyde (3.0 equiv), MADNTf2 (0.05
equiv), [1]0 ) 0.25 M in (CH2)2Cl2. b Average isolated yield of two
independent trials. c dr was determined by 1H NMR spectroscopy.
d Reaction temperature: 0 °C.
Since the cyclobutane starting materials can themselves arise from
a Lewis acid-catalyzed cycloaddition of dimethyl 2,2-methylidene
malonate (DMM) and a nucleophilic olefin,9 we became interested in
testing the notion that the title THP synthesis could be streamlined
into a one-pot operation. A sequenced alkene/alkene [2 + 2]
cycloaddition-cyclobutane/aldehyde [4 + 2] cycloaddition could in
principle directly deliver THP products from simple linear starting
materials with no processing of intermediates (eq 2).
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10.1021/ja906755e CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
The initial [2 + 2] cycloaddition was achieved by slow addition
of DMM and 4-methoxystyrene to a suspension of Sc(OTf)3 in
CH2Cl2 at -78 °C. Formation of cyclobutane 1b was confirmed
by thin-layer chromatography, and subsequent addition of the
aldehyde resulted in the formation of the desired THP products
(Table 3). This one-pot method furnishes THPs in greater overall
Table 3. Sc(OTf)3-Catalyzed [[2 + 2] + 2] Cycloaddition of
4-Methoxystyrene, Dimethyl Methylidene Malonate, and Aldehydesa
Figure 1. Stereochemical analysis of the Sc(OTf)3-catalyzed formal [4 +
2] cycloaddition of (+)-1a and benzaldehyde.
cyclopropanes. Further study is necessary to elucidate the mech-
anism of this transformation.
We have developed a formal [4 + 2] cycloaddition of D-A
cyclobutanes and aldehydes to furnish cis-2,6-disubstituted THP
derivatives. We streamlined this methodology by developing a [[2
+ 2] + 2] cycloaddition where in situ generation of the cyclobutane
allows access to THPs directly from DMM, 4-methoxystyrene, and
an aldehyde. Current work seeks to expand the scope of the [[2 +
2] + 2] and [4 + 2] cycloadditions to accommodate a range of
substrates and provide access to other carbo- and heterocyclic
molecules. Mechanistic studies and the development of an enan-
tioselective variant are underway.
a 4-methoxystyrene (1.3 equiv), DMM (1.0 equiv), aldehyde (3.0
equiv), [1b] ) 0.15 M in CH2Cl2 at the time of aldehyde addition; see
the Supporting Information for additional experimental details.
b Average isolated yield of two independent trials.
yield than the two-step cyclobutane formation/[4 + 2] cycloaddition
sequence. By circumventing cyclobutane isolation, we hope to
expedite the exploration of these and related reagents in more
complex reaction manifolds. Extension of this methodology to a
diverse array of substrates is currently underway.
Acknowledgment. This work was supported by the NSF (CHE-
0749691) and Novartis.
In contrast to aldehyde cycloadditions with D-A cyclopro-
panes,5b electron-poor aldehydes react more rapidly with D-A
cyclobutanes (e.g., formation of 2e was complete in 4.5 h vs 6.5 h
for 2i; Table 1); however, a direct competition experiment between
electronically differentiated aldehydes revealed that there is a
preference for reaction with electron-rich aldehydes (eq 3). These
seemingly conflicting results may indicate an increased propensity
of electron-rich aldehydes to coordinate to the Sc(III) catalyst,
causing a decrease in Lewis acidity [via (RCHO)nSc(OTf)3]. Thus,
reaction times are not necessarily indicative of native aldehyde
reactivity; the difference in reaction rates may be due to varying
degrees of catalyst inhibition.
Supporting Information Available: Experimental details and
characterization data for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
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We subjected (+)-1a (98:2 er) to the standard reaction conditions
using benzaldehyde as the dipolarophile and monitored the er’s of
1a and 2i as functions of conversion (Figure 1). At 12% conversion,
(-)-2i was formed with a 59.5:40.5 er while (+)-1a remained highly
enriched (93:7 er). Moreover, while slow loss of cyclobutane
enantioenrichment occurred over time, the product enantiomer ratio
remained surprisingly constant. The electronic profiling (eq 3)
appears to indicate that there is a nucleophilic substitution com-
ponent5 to the reaction, but Figure 1 reveals that the issue of
chirality transfer is more ambiguous than for the analogous D-A
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