Enantioenriched dihydropyrones from beta-lactone templates.

Article abstract of DOI:10.1021/ol025607u

[reaction: see text] Optically active 4-substituted 2-oxetanones provide conduits for preparing 2,3-dihydro-4H-pyrone heterocycles. Enantioenriched beta-lactones are prepared by asymmetric catalytic acyl halide-aldehyde cyclocondensation reactions. Hydraz

Full text of DOI:10.1021/ol025607u

ORGANIC
LETTERS
2002
Vol. 4, No. 11
1823-1826
Enantioenriched Dihydropyrones from
â-Lactone Templates
G. Greg Zipp, Mark A. Hilfiker, and Scott G. Nelson*
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
sgnelson@pitt.edu
Received January 23, 2002
ABSTRACT
Optically active 4-substituted 2-oxetanones provide conduits for preparing 2,3-dihydro-4H-pyrone heterocycles. Enantioenriched â-lactones
are prepared by asymmetric catalytic acyl halide-aldehyde cyclocondensation reactions. Hydrazone anion-mediated â-lactone ring opening
and ensuing cyclization−dehydroamination of the derived â-ketohydrazone afford the desired dihydropyrones (68−81%). Optimized lactone
ring-opening−cyclization reaction conditions render a variety of optically active 4-substituted-2-oxetanones as effective precursors to
enantioenriched 2,3-dihydro-4H-pyrones.
Optically active dihydropyrones constitute generally useful
building blocks for numerous synthesis activities, proving
especially useful for accessing the structurally diverse pyran
rings that characterize the ionophore family of natural
products.1,2 The chemotherapeutic potential of these pyran-
containing natural products has inspired the development of
numerous reaction technologies for preparing the dihydro-
pyrone progenitors of the targeted pyran subunits. Hetero
Diels-Alder (HDA) reactions stand out among these reaction
technologies as affording the most direct entry to optically
active 2,3-dihydro-4H-pyrones 1.3,4 Strategic decisions pur-
sued within complex molecule syntheses ongoing in our
group inspired us to investigate functional alternatives to
HDA-based dihydropyrone syntheses that would, none-
theless, retain the considerable efficiency that characterizes
these reactions (Figure 1). To this end, we have explored
optically active 4-substituted 2-oxetanones 2 as conduits for
preparing 2,3-dihydro-4H-pyrone heterocycles. Specifically,
the â-keto aldehyde 3 emerging from acetaldehyde enolate-
mediated ring opening of â-lactone 2 was anticipated to
undergo facile lactol formation and ensuing dehydration to
afford the corresponding enantioenriched dihydropyrone 1
(eq 1).
(1) Faul, M. M.; Huff, B. E. Chem. ReV. 2000, 100, 2407-2473.
(2) For reviews, see: (a) Danishefsky, S. J.; Bilodeau, M. T. Angew.
Chem., Int. Ed. Engl. 1996, 35, 1380-1419. (b) Fleming, I.; Barbero, A.;
Walter, D. Chem. ReV. 1997, 97, 2063-2192.
(3) (a) Bednarski, M.; Danishefsky, S. J. Am. Chem. Soc. 1983, 105,
6968-6969. (b) Bednarski, M.; Danishefsky, S. J. Am. Chem. Soc. 1986,
108, 7060-7067.
Figure 1. Synthesis of enantioenriched 2,3-dihydro-4H-pyrones.
10.1021/ol025607u CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/30/2002

This report describes the successful implementation of this
dihydropyrone synthesis relying on catalytic asymmetric acyl
halide-aldehyde cyclocondensation (AAC) reactions as the
source of the requisite â-lactone electrophiles.5
aldehyde-derived â-lactone 2a (eq 3). Reacting 2a with the
lithium enolate of acetaldehyde (2 equiv) at temperatures
ranging from -78 to 0 °C afforded complex product mixtures
and only trace amounts of the desired â-keto aldehyde.
Failure in these efforts was ultimately traced to our inability
to rigorously control the quality and purity of the lithium
enolate generated by the decomposition of 2-lithio tetrahy-
drofuran.9
Ring strain imparts considerable activation to â-lactones
toward nucleophile-mediated ring opening. Among several
ring opening modes available to â-lactones, strongly basic
nucleophiles promote ring opening derived from carbonyl
addition-elimination.6,7 Consistent with this observation, we
anticipated that enolate nucleophiles would express similar
regiochemical preferences in opening optically active 4-sub-
stituted 2-oxetanones 2 (eq 2). Furthermore, we expected
the â-alkoxy ketone intermediate 4 emerging from this
process to be protected from further carbonyl addition by
rapid deprotonation of the transient â-dicarbonyl intermedi-
ate.8
These preliminary investigations focused our attention on
identifying an actealdehyde enolate equivalent that could be
generated under more carefully controlled reaction condi-
tions. Alkanal hydrazones were thus selected as aldehyde
surrogates, offering the advantage that the requisite anions
could be generated under typical enolization conditions
(LDA). Acetaldehyde hydrazone was conveniently prepared
by condensing acetaldehyde with the appropriate N,N-
dialkylhydrazine.10 Reacting the lithiated hydrazone 5 with
lactone 2a at -78 °C provided regioselective carbonyl
addition and ensuing ring opening to afford the â-keto
hydrazone 6 as the only component in the crude product
mixture (100% conversion) (eq 3).11 The piperidine-derived
hydrazone afforded a lithium anion 5 offering greater
reproduciblity in the ring-opening reaction as compared to
the N,N-dimethyl acetaldehyde hydrazone anion.
The efficiency of the hydrazone-mediated lactone openings
presented the cyclization-dehydroamination sequence as the
Evaluating this hypothesis in the context of the proposed
dihydropyrone synthesis led us to examine the reactivity of
the acetaldehyde lithium enolate toward the hydrocinnam-
(7) (a) Arnold, L. D.; Kalantar, T. H.; Vederas, J. C. J. Am. Chem. Soc.
1985, 107, 7105. (b) Griesbeck, A.; Seebach, D. HelV. Chim. Acta 1987,
70, 1326. (c) Arnold, L. D.; May, R. G.; Vederas, J. C. J. Am. Chem. Soc.
1988, 110, 2237. (d) Castagnani, R.; De Angelis, F.; De Fusco, E.; Giannessi,
F.; Misiti, D.; Meloni, D.; Tinti, M. O. J. Org. Chem. 1995, 60, 8318. (e)
Bernabei, I.; Castagnani, R.; De Angelis, F.; De Fusco, E.; Giannessi,
F.; Misiti, D.; Muck, S.; Scafetta, N.; Tinti, M. O. Chem. Eur. J. 1996, 2,
826. (f) Nelson, S. G.; Spencer, K. L. Angew. Chem. 2000, 39, 1323. (g)
Wan, Z.; Nelson, S. G. J. Am. Chem. Soc. 2000, 122, 10470-10471. (h)
Ref 5b.
(8) For the aldol polymerization of acetaldehyde enolate equivalents,
see: (a) Murahashi, S.; Nozakura, S.; Sumi, M. J. Polym. Sci., Polym. Lett.
1965, 3, 245-249. (b) Nozakura, S.-I.; Ishihara, S.; Inaba, Y.; Matsumura,
K.; Murahashi, S. J. Polym. Sci. 1973, 11, 1053-1067. (c) Sogah, D. Y.;
Webster, O. W. In Recent AdVances in Mechanistic and Synthetic Aspects
of Polymerization; Fontanille, M., Guyot, A., Eds.; D. Reidel: Dordrecht,
The Netherlands, 1987; pp 61-72. (d) Charleux, B.; Pichot, C. Polymer
1993, 34, 195-203.
(4) (a) Corey, E. J.; Cywin, C. L.; Roper, T. D. Tetrahedron Lett. 1992,
33, 6907-6910. (b) Keck, G. E.; Li, X.-Y.; Krishnamurthy, D. J. Org.
Chem. 1995, 60, 5998-5999. (c) Ghosh, A. K.; Mathivanan, P.; Cappiello,
J.; Krishnan, K. Tetrahedron: Asymmetry 1996, 7, 2165-2168. (d) Schaus,
S. E.; Brånalt, J.; Jacobsen, E. N. J. Org. Chem. 1998, 63, 403-405. (e)
Yao, S.; Johannsen, M.; Audrain, H.; Hazell, R. G.; Jorgensen, K. A. J.
Am. Chem. Soc. 1998, 120, 8599-8605. (f) Dossetter, A. G.; Jamison, J.
F.; Jacobsen, E. N. Angew. Chem., Int. Ed. 1999, 38, 2398-2400. (g)
Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325-335 and
references therein. (h) Jorgensen, K. A. Angew. Chem., Int. Ed. 2000, 39,
3558-3588 and references therein. (i) Qian, C.; Wang, L. Tetrahedron Lett.
2000, 41, 2203-2206. (j) Aikawa, K.; Irie, R.; Katsuki, T. Tetrahedron
2001, 57, 845-851. (k) Huang, Y.; Rawal, V. Org. Lett. 2000, 2, 3321-
3323.
(9) Bates, R. B.; Kroposki, L. M.; Potter, D. E. J. Org. Chem. 1972, 37,
560.
(10) Corey, E. J.; Enders, D. Chem. Ber. 1978, 111, 1337-1339.
(11) â-Keto hydrazone intermediates 6 can be isolated and purified by
column chromatography; however, crude â-keto hydrazones emerging from
the â-lactone ring openings were routinely used in the subsequent cyclization
reactions.
(5) (a) Nelson, S. G.; Peelen, T. J.; Wan. Z. J. Am. Chem. Soc. 1999,
121, 9742-9743. (b) Nelson, S. G.; Wan, Z. Org. Lett. 2000, 2, 1883-
1886. See also: (c) Nelson, S. G.; Spencer, K. L. J. Org. Chem. 2000, 65,
1227. (d) Nelson, S. G.; Wan. Z.; Peelen, T. J.; Spencer, K. L. Tetrahedron
Lett. 1999, 40, 6535-6540.
(6) Pommier, A.; Pons, J.-M. Synthesis 1993, 441-459.
1824
Org. Lett., Vol. 4, No. 11, 2002

Table 1. â-Lactone-to-Dihydropyrone Interconversion
Merging the optimized lactone ring opening and cycliza-
tion-dehydroamination reaction conditions rendered a va-
riety of optically active 4-substituted-2-oxetanones 2a-d as
effective precursors to enantioenriched 2,3-dihydro-4H-
pyrones (Table 1). Acetaldehyde hydrazone anion reacts with
â-lactones incorporating simple alkyl chains, ether function-
ality, as well as unsaturated alkyl groups to effect the lactone-
to-pyranone conversion in good yields (68-81%). We
anticipated that these reaction conditions would have no
effect on the resident stereogenic center and would proceed
with complete stereochemical integrity; the veracity of this
prediction was unambiguously confirmed for the known
pyranones 7a4a and 7d.4b Differentially substituted dihydro-
pyrones were prepared by analogous heterocycle intercon-
version employing other aldehyde and ketone hydrazone
anions to effect â-lactone ring opening; lithium anions
a Lactones 2 were prepared as described in ref 5a. b The absolute
configuration of dihydropyrones 7a and 7d was unambiguously established;
see ref 4a and b. The configuration of the remaining dihydropyrones was
assigned by analogy to these determinations.
last barrier to completing the envisioned dihydropyrone
synthesis. Hydrazone protonation was expected to elicit facile
cyclic aminal formation upon subjecting the â-keto hydra-
zone to simple acids. In practice, the efficiency of the
cyclization-dehydroamination sequence proved to be par-
ticularly sensitive to the nature of the acid reagent (eq 4).
Relatively weak acids (pTsOH, CSA, pPTS) at ambient
temperatures (∼23 °C) afforded mixtures of the desired
pyranone 7 and the lactol 8. While 8 was considered a
precursor to the desired unsaturated pyranone 7, effecting
dehydration of 8 without isolation and resubmission to the
reaction conditions resulted in partial decomposition of the
dihydropyrone 7 and commensurately low isolated yields.
These results suggested that extended reaction times under
even mildly acidic conditions were detrimental to reaction
efficiency. Thus, reaction conditions that would shorten
reaction times, including more strongly acidic media and
elevated temperatures, were next evaluated. These investiga-
tions led to amberlyst-15 acidic resin (Am-15) and refluxing
THF solvent being identified as the reaction conditions
affording maximum yields in the cyclization-dehydroami-
nation sequence. Thus, treating the crude â-ketohydrazone
6 with Am-15 resin in refluxing THF afforded the desired
dihydropyrone 7, uncontaminated with the lactol, in consis-
tently good yields.
derived from hydrazones 10 and 11 provided the enantioen-
riched 2,5- or 2,6-disubstituted dihydropyrones 12 and 13a-
c, respectively (eq 5, Table 1). The optically active 3,4-
disubstituted 2-oxetanone 14 also undergoes analogous
lactone-to-dihydropyrone interconversion to afford the 2,3-
disubstituted dihydropyrone 15 (eq 6); however, partial
epimerization of the C3 stereocenter during pyranone forma-
tion led to 15 being obtained as ∼3:1 (syn:anti) diastereo-
meric mixture.12
Org. Lett., Vol. 4, No. 11, 2002
1825

Despite the power of asymmetric catalyzed bond construc-
tions, rigorous uncoupling of reaction enantioselection and
substrate structure cannot always be assured. Thus, multiple
strategies for accessing target synthons are often desirable.
The â-lactone-to-dihydropyrone interconversions provide
convenient access to structurally diverse, enantioenriched
dihydropyrone synthons. As a result, these transformations
are expected to complement the highly efficient hetero
Diels-Alder-based routes widely employed in preparing
these versatile synthons.
(12) A representative experimental procedure for converting optically
active â-lactones to the corresponding 2,3-dihydro-4H-pyrones involved
adding the hydrazone (1.5 mmol) to a 0 ïC solution of lithium diisopro-
pylamide (1.5 mmol) in THF (7 mL) and stirring for 1 h. The resulting
heterogeneous mixture was cooled to -78 °C; a solution of â-lactone 2
(1.0 mmol) in THF (1 mL) was added, and the resulting solution was
maintained at -78 °C for 3 h before warming to ambient temperature and
stirring for 12 h. The reaction was quenched with H2O (0.5 mL), and the
mixture was diluted with Et2O (20 mL), dried (MgSO4), filtered, and
concentrated. The resulting residue was dissolved in THF (10 mL), and
amberlyst-15 acidic resin (500 mg) was added; the reaction was heated at
reflux for 3 h. Upon cooling to ambient temperature, the mixture was filtered,
concentrated, and purified by flash chromatography.
Acknowledgment. The American Cancer Society (RPG
CCD 99031) and the Bristol-Myers Squibb Foundation are
gratefully acknowledged for their support.
Supporting Information Available: Experimental pro-
cedures, compound characterization data, and representative
spectra are provided. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL025607U
1826
Org. Lett., Vol. 4, No. 11, 2002