A convenient entry to 5-(sp2)-substituted and 5,5-disubstituted tetronic acids

Article abstract of DOI:10.1055/s-2006-941596

A one-pot, convenient and general access to 5-sp²-substituted and 5,5-disubstituted tetronic acids is described. The protocol embodies two consecutive chemical events: a Michael addition of pyrrolidine on a secondary or tertiary γ-hydroxy-α,β-a

Full text of DOI:10.1055/s-2006-941596

LETTER
1607
A Convenient Entry to 5-(sp2)-Substituted and 5,5-Disubstituted Tetronic
Acids
2
5
-(sp )-Substituted
a
a
nd 5,5-D
i
v
substituted T
i
etronic
d
A
cids Tejedor,1 Alicia Santos-Expósito,1 Fernando García-Tellado*1
Instituto de Productos Naturales y Agrobiología, CSIC, Avda. Astrofísico Francisco Sánchez 3, 38206 La Laguna, Tenerife, Canary Islands,
Spain
Fax +34(922)260135; E-mail: fgarcia@ipna.csic.es
Received 2 February 2006
Michael addition of a secondary amine to generate the
Abstract: A one-pot, convenient and general access to 5-sp2-substi-
intermediate enamine 7 and an acid-catalyzed hydrolysis–
tuted and 5,5-disubstituted tetronic acids is described. The protocol
embodies two consecutive chemical events: a Michael addition of
pyrrolidine on a secondary or tertiary g-hydroxy-a,b-alkynyl ester
lactonization to generate the tetronic acid core
(Scheme 2).10
derivative to give the corresponding enamine, and the subsequent
acid-catalyzed hydrolysis–lactonization of this intermediate to af-
ford the tetronic acid derivative.
CO2Me
CO2Me
O
domino
O
O
R1
R2
Key words: alkynes, lactones, aminations, cyclizations, Michael
additions
R1
R2
R1
R2
Et3N (cat.)
4
acid-catalyzed
trans-acetalization–lactonization
Tetronic acids (4-hydroxy-2(5H)-furanones) form a sub-
class of b-hydroxybutenolydes with the generic structure
of 1. Vitamin C (2) and penicillic acid (3) are representa-
tive members of this family of compounds (Figure 1).
[HCl concd, i-PrOH, ∆]
O
O
O
O
R1
R1
R2
OH
O
O
5
R3
5
R2
OMe
OR
OH
Scheme 1
1
2
R = R1 = R2 = R3 = H
R = R2 = H; R1 = OH;
R3 = CH(OH)CH2OH
3
Secondary or tertiary g-hydroxy-a,b-alkynyl esters 6 are
suitable synthetic platforms to generate the 3-oxo-g-lac-
tone ring core of the tetronic acids with different pattern
and level of substitution at C-5. The required transforma-
tion involves a tandem triple bond oxidation–lactoniza-
tion to generate the 3-oxo function and the g-lactone ring,
respectively. This tandem transformation is well accom-
plished in a one-pot fashion by simple treatment of the
conjugated alkynol 6 with pyrrolidine to generate the cor-
responding enamine 7, followed by a thermally driven
acid-catalyzed enamine hydrolysis and lactonization.
While the enamine formation is an energetically favored
process (CH2Cl2, r.t.), the lactonization requires acidic
conditions and thermal activation (HCl, 2-PrOH, reflux).
Table 1 shows the general scope and effectiveness of this
transformation.
Figure 1
Tetronic acids and their metabolites exhibit a wide array
of biological properties2,3 and they have been object of
numerous synthetic studies.4 Two years ago, we reported
a simple and effective one-pot protocol to obtain 5-substi-
tuted tetronic acids 5 from alkyl propiolates and aldehydes
(Scheme 1; R1 = Alk, R2 = H).5 A serious limitation to
this method arises when either the aldehyde is a,b-unsat-
urated or aromatic, or a non-activated ketone is used. In
these cases, the required 1,3-dioxolane derivatives 4 can-
not be obtained by the triethylamine-catalyzed domino re-
action of methyl propiolate and the carbonyl derivative,6
and as a consequence, neither 5-sp2-substituted nor 5,5-
disubstituted tetronic acid derivatives can be accessed by
this methodology. In this communication, we report on a
one-pot synthesis of these derivatives from the readily
accessible g-hydroxy-a,b-alkynyl esters 6.7–9 The entire
process embodies two consecutive chemical events: a
g-Aryl-g-hydroxy-a,b-alkynols 6a–c are cleanly and effi-
ciently transformed into the corresponding 5-aryl tetronic
acids derivatives 5a–c, with independence of the electron-
ic nature of the aromatic ring (entries 1–3). Alkynol 6d
bearing an (E)-propenyl substituent at the g-position rear-
ranges to the corresponding 5-(E)-propenyl tetronic acid
derivative 5d in high yield and complete stereoselectivity
(entry 4). g,g-Disubstituted alkynols 6e–g, derived from
SYNLETT 2006, No. 10, pp 1607–1609
Advanced online publication: 12.06.2006
DOI: 10.1055/s-2006-941596; Art ID: D03306ST
© Georg Thieme Verlag Stuttgart · New York
2
1
.0
6
.2
0
0
6

1608
D. Tejedor et al.
LETTER
Typical Procedure for the Synthesis of 5-(sp2)-Substituted and
5,5-Disubstituted Tetronic Acids from g-(sp2)-Substituted and
g,g-Disubstituted g-Hydroxy-a,b-alkynols
R1
R1
R2
OH
R2
OH
N
Alkynol 6d (68.8 mg, 0.446 mmol) in CH2Cl2 (1 mL) was stirred
with freshly distilled pyrrolidine (0.038 mL, 0.446 mmol) at r.t. for
1 h. Concd HCl (10 drops), H2O (10 drops) and 2-PrOH (7 mL)
were added and the reaction mixture was heated at reflux for 2 h.
Evaporation of the solvent to reduced pressure and short flash chro-
matography (elution gradient: EtOAc–hexane from 2:8 to 6:4)
yielded pure tetronic acid derivative 5d in 83% yield (51.9 mg); mp
100–102 °C (white needles, CH2Cl2–hexanes).
CO2Me
N
H
7a–g
5a–g
CO2Me
acid-catalyzed
6a–g
hydrolysis–lactonization
[HCl, H2O, i-PrOH, ∆]
Scheme 2
1H NMR (400 MHz, CDCl3 the product exists in equilibrium as a
mixture of the enol and the b-ketoester): d (enol) = 1.76 (d, 3 H,
J = 6.6 Hz), 5.07 (s, 1 H), 5.16 (d, 1 H, J = 7.7 Hz), 5.38 (ddq, 1 H,
J = 1.9, 7.7, 15.4 Hz), 5.98 (ddq, 1 H, J = 0.8, 6.6, 15.4 Hz); d (b-
ketoester) = 1.76 (d, 3 H, J = 6.9 Hz), 3.20 (s, 2 H), 5.46 (ddq, 1 H,
J = 1.6, 6.1, 15.4 Hz), 5.97 (ddq, 1 H, J = 1.3, 6.9, 15.4 Hz).
13C NMR (50.3 MHz, CDCl3): d (enol) = 18.3, 81.8, 89.1, 123.6,
134.9, 178.0, 182.9; d (b-keto ester) = 18.2, 37.1, 86.8, 122.0, 133.6,
170.2, 203.5.
aliphatic or aromatic ketones, are efficiently transformed
into the corresponding 5,5-disubstituted tetronic deriva-
tives (entries 5–7). Remarkably, this protocol is easily
extended to the synthesis of 5,5-spiro-tetronic acid deriv-
atives (i.e. 5g, entry 7), a very important subclass 5,5-di-
substituted tetronic acids.4,11
Finally, although we were concerned with the possibility
of an amine-catalyzed rearrangement of g-aryl-g-hy-
droxy-a,b-alkynyl esters to the corresponding g-aryl-g-
oxo-a,b-unsaturated alkenoates,12 this was not observed
under our reaction conditions. Alkynols 6a–d were clean
and efficiently transformed into the tetronic acids deriva-
tives 5a–d, via formation of the corresponding enamine
intermediates 7a–d.
IR (CHCl3): 3018.5, 1806.1, 1763.2, 1712.8, 1621.2, 1224.7,
1025.8, 1002.5 cm–1.
Anal. Calcd for C7H8O3: C, 59.99; H, 5.75. Found: C, 60.15; H,
5.88.
MS: m/z (rel. int.) = 140 (5.8) [M+], 112 (66), 84 (22), 71 (28), 69
(100).
Acknowledgment
In summary, we have shown that the g-hydroxy-a,b-alky-
nyl ester functionality is an excellent scaffold to gain
access to a diverse set of 5-aryl or 5-vinyl substituted
and 5,5-disubstituted tetronic acid derivatives. As an ad-
ditional extrinsic reaction value, the processing is a one-
pot procedure and bench-friendly; it utilizes simple and
readily available starting materials. Furthermore, because
the chiral access to g-sp2-substituted g-hydroxy-a,b-
alkynoates has been very recently established, the actual
protocol opens a new avenue for the enantioselective syn-
thesis of the corresponding tetronic derivatives.13
This research was supported by the Spanish Ministerio de Educa-
ción y Ciencia and the European Regional Development Fund
(CTQ2005-09074-C02-02). F.G.T. thanks the Instituto Canario de
Investigación del Cáncer for financial support (ICIC-GI no 10/2005;
ISCiii, RTICCC C03/10).
References and Notes
(1) Associate researcher at the Instituto Canario de
Investigación del Cáncer, www.icic.es.
(2) Haynes, L. J.; Plimmer, J. R. Q. Rev. Chem. Soc. 1960, 14,
292.
(3) (a) Sodeoka, M.; Sampe, R.; Kojima, S.; Baba, Y.; Usui, T.;
Ueda, K.; Osada, H. J. Med. Chem. 2001, 44, 3216.
(b) Bühler, H.; Bayer, A.; Effenberg, F. Chem. Eur. J. 2000,
6, 2564; and references cited therein.
(4) For a recent review, see: Tejedor, D.; García-Tellado, F.
Org. Prep. Proced. Int. 2004, 36, 33.
(5) Tejedor Aragón, D.; López, G. V.; García-Tellado, F.;
Marrero-Tellado, J. J.; de Armas, P.; Terrero, D. J. Org.
Chem. 2003, 68, 3363.
(6) (a) Tejedor, D.; González-Cruz, D.; Sántos-Expósito, A.;
Marrero-Tellado, J. J.; Armas, P.; García-Tellado, F. Chem.
Eur. J. 2005, 11, 3502. (b) Tejedor, D.; García-Tellado, F.;
Marrero-Tellado, J. J.; de Armas, P. Chem. Eur. J. 2003, 9,
3122. (c) de Armas, P.; García-Tellado, F.; Marrero-
Tellado, J. J.; Tejedor, D.; Maestro, M. A.; González-Platas,
J. Org. Lett. 2001, 3, 1905.
Table 1 Transformation of g-Hydroxy-a,b-alkynols 6 into Tetronic
Acid Derivatives 5
Entry
R1
R2
H
Product
5a
Yield (%)a
1
2
3
4
5
6
7
Ph
74
79
86
83b
78
73
80
4-OMeC6H4
2-ClC6H4
(E)-Propenyl
Me
H
5b
H
5c
H
5d
Me
Ph
5e
Me
5f
Cyclopentanone
5g
(7) Midland, M. M.; Tramontano, A.; Cable, J. R. J. Org. Chem.
1980, 45, 28.
(8) Shahi, S. P.; Koide, K. Angew. Chem. Int. Ed. 2004, 43,
2525.
a Yields of isolated, analytically pure products.
b Only the E-isomer is detected.
Synlett 2006, No. 10, 1607–1609 © Thieme Stuttgart · New York

LETTER
5-(sp2)-Substituted and 5,5-Disubstituted Tetronic Acids
1609
(9) An ammonium hydroxide catalyzed addition of ethyl
propiolate on cyclohexanal, cyclohexanone, 2-methyl-
cyclohexanone and isopropyl methyl ketone have been
reported. See: Ishikawa, T.; Mizuta, T.; Hagiwara, K.;
Aikawa, T.; Kudo, T.; Saito, S. J. Org. Chem. 2003, 68,
3702.
(10) For a previous example of this transformation related to the
synthesis of 5-methyl-5-cyclohexyl tetronic acid derivative,
see: Ballantine, J. A.; Ferrito, V.; Hassall, C. H.; Jones, V. I.
P. J. Chem. Soc. C 1969, 56.
(11) For a recent example, see: Rath, J. P.; Kinast, S.; Maier, M.
E. Org. Lett. 2005, 7, 3089.
(12) (a) Nineham, A. W.; Raphael, R. A. J. Chem. Soc. 1949,
118. (b) For a recent mechanistic study, see: Sonye, J. P.;
Koide, K. Org. Lett. 2006, 8, 199.
(13) Gao, G.; Wang, Q.; Yu, X.-Q.; Xie, R.-G.; Pu, L. Angew.
Chem. Int. Ed. 2006, 45, 122.
Synlett 2006, No. 10, 1607–1609 © Thieme Stuttgart · New York