Diastereoselective Synthesis of Highly Substituted Tetrahydropyran-4-ones

Article abstract of DOI:10.1021/ol027081j

(Matrix Presented) Aldol reactions of β-ketoesters with aldehydes followed by a tandem Knoevenagel condensation, with a further equivalent of aldehyde, and intramolecular Michael addition produces single diastereomers of highly substituted tetrahydropyran-4-ones.

Full text of DOI:10.1021/ol027081j

ORGANIC
LETTERS
2002
Vol. 4, No. 25
4527-4529
Diastereoselective Synthesis of Highly
Substituted Tetrahydropyran-4-ones
Paul A. Clarke* and William H. C. Martin
School of Chemistry, UniVersity of Nottingham, UniVersity Park,
Nottingham, NG7 2RD, United Kingdom
paul.clarke@nottingham.ac.uk
Received October 11, 2002
ABSTRACT
Aldol reactions of â-ketoesters with aldehydes followed by a tandem Knoevenagel condensation, with a further equivalent of aldehyde, and
intramolecular Michael addition produces single diastereomers of highly substituted tetrahydropyran-4-ones.
Tetrahydropyran (THP) rings are ubiquitous in the natural
product arena, and over the years many methods have been
developed for their construction. Some of the most widely
used methods are intramolecular epoxide opening, manipula-
tion of carbohydrates,1 hetero- Diels-Alder cyclizations,2,3
Prins reactions,4 and intramolecular Michael reactions.5
However, all of these procedures have drawbacks: for
example, the regiochemistry of epoxide opening, the many
protecting group manipulations and functional group inter-
conversions inherent in starting from a carbohydrate, restric-
tion to the use of E,E-dienes and activated aldehydes in the
hetero-Diels-Alder approach,3 the need for single double
bond isomers of homoallylic alcohols4 and product scram-
bling in the Prins reaction,6 and finally the reliance on
phenols in the Michael reaction.5
Our interest in the formation of THP rings arose from the
reports of Maitland and Japp7 and later Cornubert and
Robinet,8 who showed that a ketone and 2 molecules of
aldehyde could be condensed in a low- yielding process to
generate substituted THP rings. Much later both of these
reactions were found to generate single diasteromers of the
THP products (Scheme 1).9,10 We realized that with current
Scheme 1. The Maitland-Japp Reaction
(1) Hanessian, S. Total Synthesis of Natural Products: The ‘Chiron’
Approach; Baldwin, J. E., Ed.; Pergamon: Oxford, UK, 1983.
(2) For a treatise on the Hetero Diels-Alder reaction see: Boger, D.
L.; Weinreb, S. M. Hetero Diels-Alder Methodology in Organic Synthesis;
Academic Press: San Diego, CA, 1987.
synthetic technology it may be fruitful to revisit these
forgotten reactions. In this letter we wish to communicate
(3) For recent examples of asymmetric intermolecular reactions see:
Dossetter, A. G.; Jamison, T. F.; Jacobsen, E. N. Angew. Chem., Int. Ed.
1999, 38, 2398. Johannsen, M.; Jorgensen, K A. J. Org. Chem. 1995, 60,
5757. Schaus, S. E.; Branalt, J.; Jacobsen, E. N. J. Org. Chem. 1998, 63,
403.
(4) For several recent examples see: Jaber, J. J.; Mitsui, K.; Rychnovsky,
S. D. J. Org. Chem. 2001, 66, 4679. Cloninger, M. J.; Overman, L. E. J.
Am. Chem. Soc. 1999, 121, 1092. Kozmin, S. A. Org. Lett. 2001, 3, 755.
For a review see: Adams, D. R.; Bhaynagar Synthesis 1977, 661.
(5) For a review see: Little, R. D.; Masjedizadeh, M. R.; Wallquist, O.;
McLoughlin, J. I. Org. React. 1995, 47, 315.
(6) Snider, B. B. The Prins and Carbonyl Ene Reactions; Comprehensive
Organic Synthesis; Vol. 2, Chapter 2.1; Heathcock, C. H., Ed.; Pergamon:
Oxford, UK, 1992. For a recent report of the oxonia Cope complication
see: Crosby, S. R.; Harding, J. R.; King, C. D.; Parker, G. D.; Willis, C.
L. Org. Lett. 2002, 4, 577.
(7) Japp, F. R.; Maitland, W. J. Chem. Soc. 1904, 85, 1473.
(8) Cornubert, R.; Robinet, P. Bull. Chim. Soc. Fr. 1934, 90.
(9) Sivakumar, R.; Satyamurthy, N.; Ramalingam. K.; O’Donnell, D.
J.; Ramarajan, K.; Berlin, K. D. J. Org. Chem. 1979, 44, 1559.
(10) Baxter, C. A. R.; Whiting, D. A. J. Chem. Soc. C 1968, 1174.
10.1021/ol027081j CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/16/2002

our attempts at developing an alternative, yet complementary,
diastereoselective method for the synthesis of THP rings,
based on the Maitland-Japp reaction,7 starting from com-
mercial or readily available starting materials.
Table 1.
To widen the scope of the reaction and enable the
installation of different substituents in the 2 and 6 positions
of the THP ring, we decided to move away from ketones
such as pentan-2-one and, instead, investigate the use of
dienolates of â-ketoesters. The marked difference in the
reactivity of the two enolate carbons11,12 should enable the
selective incorporation of different aldehydes, thus providing
THP rings with different substituents in the 2 and 6 positions.
1
R
R1
Ph
Pr
Pr
hexyl
Pr
Ph
yield (%)a
ratiob 2/3
b
c
d
e
f
hexyl
hexyl
i-Pr
i-Pr
Ph
80
80
55
55
78
68
1:2
12:1
1:1
1:1.4
only keto
only keto
Methyl acetoacetate was treated with NaH in THF at 0
°C and then with BuLi at -78 °C. The resulting dianion
was then treated with 1 equiv of benzaldehyde and the
resulting aldol product isolated (1a, Scheme 2). If we were
g
Ph
a Isolated yields after flash column chromatography, calculated over two
steps from methyl acetoacetate. b 1H NMR (400 MHz).
aryl, alkyl, and branched alkyl aldehydes can all be used in
either position without any reduction in diastereoselectivity
or yield.
Scheme 2
It is of interest that the keto and enol tautomers (2 and 3)
could be isolated by careful flash column chromatography.
In these cases it was found that upon standing in CHCl3 the
enol tautomer would slowly convert to the keto tautomer.
Under identical conditions the keto tautomer was unaffected.
This can be explained when one considers that the 1H NMR
spectra for the keto tautomers indicate that they exist in a
boat conformation, and hence there is little overlap between
C5-H5â σ-bonding orbital and the CdO π* orbital. The
boat conformation is evident from a W-coupling between
H3â and H5â of 0.8 Hz, and from the gradient nOe
enhancements of the THP ring protons (Figure 1). It is
to generate THP rings we would now have to develop a
tandem Knoevenagel-Michael reaction. We rationalized that
as both reactions have been promoted by Lewis acids,5,12
simply mixing the aldol product with a second aldehyde in
the presence of BF3‚OEt2 might be successful. As retro-
Michael reactions have hampered the formation of THP rings
in nonphenolic systems,5 we were optimistic that the relative
pKa values of the starting hydroxyl proton and the â-ketoester
proton in the THP product would favor Michael cyclization
and drive the equilibrium over to THP products. Indeed,
when aldol product 1a was subjected to BF3‚OEt2 in the
presence of furaldehyde in CH2Cl2, the THP ring was formed
rapidly as a mixture of keto and enol tautomers in 66% yield
over the two steps. Gratifyingly, only one diastereomer could
1
be detected in the H NMR of the crude reaction mixture.
Figure 1.
This diastereomer was identified as the C2-C6 cis, C5-C6
trans isomer, implying that the reaction was under thermo-
dynamic control.
possible that this boat conformation is stabilized relative to
the chair conformation by the donation of a lone pair of the
ring oxygen into the CdO π* orbital.
It has also proved possible to use cyclohexanone in the
Knoevenagel/Michael reaction to gain access to spiro-fused
THP products such as 4 in an unoptimized 48% yield over
the two steps (Scheme 3). Additionally, when the dianion
of methyl propionyl acetate was treated with isobutanal and
the product subjected to the BF3‚OEt2 conditions, pyran 5
We next investigated the scope of the pyran forming
reaction by surveying a number of different aldehydes in
both the initial aldol and the BF3‚OEt2 promoted reactions.
These results are summarized in Table 1. As can be seen,
(11) For the pioneering work of Weiler see: Huckin, S. N.; Weiler, L.
Tetrahedron Lett. 1971, 50, 4835. Huckin, S. N.; Weiler, L. Can. J. Chem.
1974, 52, 2157.
(12) For a review see: Jones, G. Org. React. 1967, 15, 204.
4528
Org. Lett., Vol. 4, No. 25, 2002

Scheme 3
Scheme 5
was formed rapidly in 78% yield. Extended reaction times
or resubmission of 5 to the reaction conditions resulted in
the partial epimerisation of the C3 position to generate
quantitatively a 1:3 ratio of pyrans 5 and 6 (Scheme 4). This
via standard Knoevenagel conditions reported by Tietze13
(Scheme 5). When 7 was submitted to the BF3‚OEt2
conditions it was rapidly converted (∼1 min) to THP 8,
which was isolated as a single diastereomer in 92% yield.
When 8 was resubjected to the reaction conditions it was
found to be converted to furan 9. This presumably occurs
via retro-Michael reaction followed by cyclization onto the
unactivated double bond. As the Lewis acid mediated
cyclization of alcohols onto unactivated double bonds is
somewhat rare, we believe that this cyclization is promoted
by trace amounts of HF present in the BF3‚OEt2 solution.
In summary, we have developed a general and convergent
diastereoselective synthesis of highly substituted THP rings
from readily available starting materials. We are now actively
engaged in the attempt to include the initial aldol reaction
in the same pot as the tandem Knoevenagel/Michael reactions
and in the possibility of making this THP forming procedure
enantioselective. These results will be reported in due course.
Scheme 4
result can be rationalized if the reaction is assumed to be
under thermodynamic control. The initial Knoevenagel
reaction generated a mixture of E and Z double bond isomers.
Each of these isomers undergoes rapid Michael/retro-Michael
reaction via the appropriate enol to place both the C2 and
C6 THP substituents equatorial, regardless of the original
double bond geometry. Enolization of the C3 position under
the reaction conditions ultimately results in the formation
of the more stable diastereomer.
Acknowledgment. We thank the EPSRC and the Uni-
versity of Nottingham (DTA studentship to W.H.C.M) for
financial support.
Supporting Information Available: Experimental details
for the pyran-4-one forming reaction and representative
examples of spectroscopic data (compounds 2b, 3b, and 2f).
This material is available free of charge via the Internet at
http://pubs.acs.org.
Further evidence to support this hypothesis was obtained
by the synthesis of Michael precursor 7, with pendant
unsaturation, as a 1:1 mixture of E/Z double bond isomers,
OL027081J
(13) Tietze, L. F.; Geissler, H.; Fennen, J.; Brumby, T.; Brand, S.; Schulz,
G. J. Org. Chem. 1994, 59, 182.
Org. Lett., Vol. 4, No. 25, 2002
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