A new convenient route to enantiopure 2-coumarinyloxypropanals: Application to the synthesis of optically active geiparvarin analogues

Article abstract of DOI:10.1016/j.tetlet.2006.01.151

A new convenient route to enantiopure 2-coumarinyloxypropanals is described: Rosenmund reduction of (R)- or (S)-2-coumarinyloxypropanoyl chlorides afforded in good yields the corresponding 2-coumarinyloxypropanals. Their subsequent aldolic condensation with 3(2H)-furanones, followed by dehydration, led to enantiopure geiparvarin analogues now being investigated as promising antitumoral compounds.

Full text of DOI:10.1016/j.tetlet.2006.01.151

Tetrahedron Letters 47 (2006) 2405–2408
A new convenient route to enantiopure 2-coumarinyloxypropanals:
application to the synthesis of optically active geiparvarin analogues
a,
b
c
Stefano Chimichi,a,* Marco Boccalini, Giancarlo Cravotto and Ornelio Rosati
*
aDipartimento di Chimica Organica ‘U. Schiff’, via della Lastruccia 13, I-50019 Sesto F.no (Firenze), Italy
bDipartimento di Scienza e Tecnologia del Farmaco, via P. Giuria 9, I-10125 Torino, Italy
cDipartimento di Chimica e Tecnologia del Farmaco, via del Liceo 1, I-06123 Perugia, Italy
Received 22 December 2005; revised 27 January 2006; accepted 30 January 2006
Available online 14 February 2006
Abstract—A new convenient route to enantiopure 2-coumarinyloxypropanals is described: Rosenmund reduction of (R)- or (S)-2-
coumarinyloxypropanoyl chlorides afforded in good yields the corresponding 2-coumarinyloxypropanals. Their subsequent aldolic
condensation with 3(2H)-furanones, followed by dehydration, led to enantiopure geiparvarin analogues now being investigated as
promising antitumoral compounds.
Ó 2006 Elsevier Ltd. All rights reserved.
In our previous paper, we reported the synthesis of a ser-
ies of geiparvarin analogues in which a hydrogen atom
replaced the 30-methyl group on the unsaturated alken-
yloxy bridge, as well as geiparvarin (1) itself and evalu-
ated their activities both against several human
tumoral cell lines in vitro1 and as powerful and highly
selective monoamino oxidase-B (MAO-B) inhibitors.2
Our study clearly showed that the elimination of the
methyl group on the double bond remarkably increased
the cytotoxic activity against all of the tumoral cell lines
as well as the inhibitory power on MAO-B in compari-
son with the natural compound 1. Although further
experiments are needed, these results led us to hypothe-
size that a specific target might be involved in both phar-
macological effects. At any rate, they suggested the need
for a more thorough investigation of the potentiality of
geiparvarin and its analogues as antitumoral drugs as
well as of the related mechanism leading to apoptosis.
synthesis of the first optically active geiparvarin deme-
thylated at the 30 position (compounds 2 and 3).
We wish to report here a new, efficient method for the
preparation of 2-[(coumarin-7-yl)-oxy]propanals 4 and
5, key intermediates for the synthesis of optically active
geiparvarin analogues 2 and 3.
The ability of these compounds to act as alkylating
agents by means of conjugate addition (Michael accep-
tors) is well known and seems to be related to their bio-
logical activity.3 In order to study the structure–activity
relationships of geiparvarin analogues we undertook the
The preparation of optically active 2-aryloxypropanals
may be approached in two distinct ways, viz. the asym-
metric hydroformylation of aryl vinyl ethers4 or the
elaboration of functional groups as alcohols,5 esters,6
amides7 and acetals8 that have no practical application
due to the difficulty of their preparation.
Keywords: Enantiopure 2-coumarinyloxypropanals; Geiparvarin
analogues; Antitumoral compounds.
*
Corresponding authors. Tel.: +39 055 457 3537; fax: +39 055 457
3568; e-mail: stefano.chimichi@unifi.it
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.151

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S. Chimichi et al. / Tetrahedron Letters 47 (2006) 2405–2408
Scheme 3. Reagents and conditions: (i) ethyl (2S)-hydroxypropanoate
or isobutyl (2R)-hydroxypropanoate, PPh3, DIAD, THF, rt; (ii)
NaOH 1.25 M, MeOH, rt; (iii) HCl 2.4 M.
Scheme 1. Hydroformylation of aryl vinyl ethers.
Although abundant work has been published on the
hydroformylation of aryl vinyl ethers, few enantioselec-
tive examples are reported. Among the more interesting
ones, we found a paper by Solinas4 (Scheme 1) on the
hydroformylation of aryl vinyl ethers 6 affording
branched 2-aryloxypropanals 7 with 63–70% regioselec-
tivity and 80% of enantiomeric excess but with low con-
version (50%).
ture is kept near the lowest value at which hydrogen
chloride starts to evolve, the aldehyde is obtained in very
good yields. Attempts to reduce the acyl chloride 12 at
higher temperatures, led to a mixture of the aldehyde,
7-hydroxycoumarin, 7-vinyloxycoumarin and 7-ethoxy-
coumarin as shown in Scheme 4.11
As reported,4 if the reaction was allowed to proceed
until conversion reached 99% the yield in the branched
aldehyde 7 was higher but the enantioselectivity became
very poor (30%). On the other hand, while it is easy to
obtain enantiopure alcohols, esters or amides, their con-
version to the corresponding aldehydes can be problem-
atic. In our hands, the oxidation of 2-hydroxyethoxy-
coumarins provided 2-oxoethoxycoumarins in no more
than 20% yield, while the chemical reduction with
NaBH4 or LiAlH4 of the ester, amide or acyl halide
failed to give the corresponding aldehyde (Scheme 2).
Thus, good overall yields (80–90%) of enantiopure alde-
hydes can be achieved by the classical Rosenmund
reduction of the corresponding acyl chlorides,12 avoid-
ing the drawback of enantioselective hydroformylation
of aryl vinyl ethers. In particular, we point out that
the reduction must be performed at a temperature close
to 125 °C (no reaction took place below 110 °C) and in
the absence of impurities such as thionyl chloride.
After acids 10 and 11 were converted into the corre-
sponding acyl chlorides, subsequent reduction in the
above conditions afforded aldehydes 4 and 513 in good
yields (Scheme 5).
Furthermore, the reaction of coumarin 8 with 2-chloro-
1,1-dimethoxypropane8 did give aldehyde 4 but in the
racemic form.
The enantiomeric purity of the aldehydes 4 and 5 was
determined by NMR spectroscopy14 as follows: com-
pound 4a was converted into the corresponding Schiff’s
base by reaction with (R)-a-methylbenzylamine in meth-
A few years ago, we described9 the facile and convenient
synthesis of 7-(2-oxoethoxy)coumarins from coumarin-
7-yloxyacetic acids in excellent overall yields (ꢀ97%)
starting from the easily available 7-hydroxycoumarins
8 or 9. On this basis, we now prepared the new enantio-
pure acids 10 and 1110 (Scheme 3).
1
anol and the H NMR spectrum was carefully exam-
ined. The presence of only one diastereoisomer
confirmed the general applicability of Rosenmund
reduction for the synthesis of enantiopure aldehydes
starting from 2-aryloxy propionic acids. It is interesting
to note that the enantiopure aldehyde obtained by this
procedure does not racemize during the reaction, con-
trary to what other authors observed for chiral non-
racemic aldehydes obtained by asymmetric hydroformyl-
ation of aryloxy ethylenes employing a chiral rhodium
complex.15
Application of our methodology to the synthesis of
2-[(coumarin-7-yl)-oxy]propanals 4 and 5 pointed out
that the temperature is a most important factor in the
reduction of the acyl chloride; if the reaction tempera-
Finally, the geiparvarin analogues 2 and 316 have been
obtained in good overall yield (70%) by condensation
of the anion of 2,2,5-trimethyl-3(2H)-furanone 1317 with
aldehyde 4 or 5 and subsequent Stork–Kraus dehydra-
tion (Scheme 6).
In conclusion, we demonstrated that the Rosenmund
reduction of (R)- or (S)-2-[(coumarin-7-yl)-oxy]propa-
noyl chlorides opens a novel path for the synthesis of
the corresponding enantiomerically pure aldehydes.
These are key intermediates for the synthesis of a new
class of geiparvarin analogues.
Scheme 2. Oxidations and reductions of coumarin derivatives.

S. Chimichi et al. / Tetrahedron Letters 47 (2006) 2405–2408
2407
Scheme 4. Catalytic hydrogenation of 12.
2. Carotti, A.; Carrieri, A.; Chimichi, S.; Boccalini, M.;
Cosimelli, B.; Gnerre, C.; Carotti, A.; Carrupt, P. A.;
Testa, B. Bioorg. Med. Chem. Lett. 2002, 12, 3551–3555.
3. Smith, A. B., III; Levenberg, P. A.; Jerris, P. J.; Scarbo-
rough, R. M.; Wovkulich, P. M. J. Am. Chem. Soc. 1981,
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4. Solinas, M.; Gladiali, S.; Marchetti, M. J. Mol. Catal. A:
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0.1-23; Chem. Abstr. 1963, 59, 5080.
Scheme 5. Reagents and conditions: (i) SOCl2, CHCl3; (ii) H2, Pd/
BaSO4, toluene.
8. Vasudevan, A.; Wodka, D.; Verzal, M. K.; Souers, A. J.;
Gao, J.; Brodjian, S.; Fry, D.; Dayton, B.; Marsh, K. C.;
Hernandez, L. E.; Ogiela, C. A.; Collins, C. A.; Kym, P.
R. Bioorg. Med. Chem. Lett. 2004, 14, 4879–4882.
9. Chimichi, S.; Boccalini, M.; Cosimelli, B. Tetrahedron
2002, 58, 4851–4858.
10. Compound 11a was obtained by reaction of 7-hydroxy-4-
methylcoumarin with ethyl (2S)-hydroxypropanoate in
Mitsunobu conditions and subsequent hydrolysis of the
corresponding ester; Mitsunobu, O. Synthesis 1981, 1–28.
11. Tsuji, J.; Ohno, K. J. Am. Chem. Soc. 1968, 90, 94–98;
Tsuji, J.; Ohno, K.; Kajimoto, T. Tetrahedron Lett. 1965,
6, 4565–4568.
12. Schregenberger, C.; Seebach, D. Tetrahedron Lett. 1984,
25, 5881–5884.
13. (2R)-[(4-Methyl-2-oxo-2H-chromen-7-yl)oxy]propanal (5a):
A mixture of acid 11a (1 mmol) and thionyl chloride
(0.5 mL, 7 mmol) was refluxed for 2 h in dry chloroform
(25 mL). Excess of thionyl chloride and chloroform are
then removed under reduced pressure to obtain the pure
acyl chloride (quantitative yield). Anhydrous toluene
(10 mL) and 5% palladium–barium sulfate catalyst
(0.050 g) were placed in a round-bottomed flask equipped
with a reflux condenser and a gas inlet tube. A slow stream
of hydrogen was passed through the stirred mixture while
the temperature was raised to 125 °C for 30 min. After
cooling to room temperature, the acyl chloride (1 mmol)
was added. The mixture was then kept at 125 °C for 3 h
under hydrogen flow. After the reaction had cooled to
room temperature, the suspension was diluted with ethyl
acetate and filtered on Celite to remove the catalyst.
Removal of the solvent gave a crude product that was
purified by flash chromatography (petroleum ether/ethyl
Scheme 6. Reagents and conditions: (i) LDA, THF, ꢁ78 °C. (ii) 4 or 5,
THF; (iii) MeSO2Cl, Et3N, THF, 0 °C.
Acknowledgements
Financial support from MIUR ‘Sviluppo di processi
ecocompatibili nella sintesi organica’ (COFIN 2004,
prot. 2004037895) is gratefully acknowledged.
References and notes
`
1. Viola, G.; Vedaldi, D.; Dall’Acqua, F.; Basso, G.; Disaro,
S.; Spinelli, M.; Cosimelli, B.; Boccalini, M.; Chimichi, S.
Chem. Biodivers. 2004, 1, 1265–1280.

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S. Chimichi et al. / Tetrahedron Letters 47 (2006) 2405–2408
20
acetate = 1:1, as an eluant) to afford 5a as waxy solid
2-one (3a): white waxy solid; ½aꢂD +272.1 (c 1.07, CHCl3);
20
1
(90%): ½aꢂD +57.4 (c 0.87, CHCl3); IR (CH2Cl2) 1735,
IR (CH2Cl2) 1731, 1702, 1643, 1555, 1278, 1125 cmꢁ1; H
1614, 1389 cmꢁ1
;
1H NMR (400 MHz, CDCl3) d 9.52
NMR (400 MHz, CDCl3) d 7.52 (d, 1H, 3J = 7.9 Hz, H-5)
3
4
(d, 1H, 3J = 1.6 Hz, H-10), 7.565 (d, 1H, 3J = 8.8 Hz, H-5),
6.88 (dd, 1H, J = 7.9 Hz and J = 2.7 Hz, H-6), 6.80 (d,
1H, 4J = 2.7 Hz, H-8), 6.785 (dd, 1H, 3J = 16.1 Hz and
3J = 4.4 Hz, H-20), 6.435 (dd, 1H, 3J = 16.1 Hz and
4J = 1.5 Hz, H-30), 6.15 (q, 1H, 4J = 1.2 Hz, H-3), 5.47
6.91 (dd, 1H, 3J = 8.8 Hz and 4J = 2.5 Hz, H-6), 6.83
4
4
(d, 1H, J = 2.5 Hz, H-8), 6.20 (d, 1H, J = 1.3 Hz, H-3),
4.78 (qd, 1H, 3J = 6.8 Hz and J = 1.6 Hz, H-20), 2.44
4
(d, 3H, 4J = 1.3 Hz, 4-Me), 1.58 (d, 3H, 3J = 6.8 Hz,
(s, 1H, H-300), 5.06 (qdd, 1H, J = 6.4 Hz and J = 4.4 Hz
3
3
13
4
20-Me); C NMR (100.58 MHz, CDCl3) d 200.7 (C-10),
and J = 1.5 Hz, H-10), 2.40 (d, 3H, 4J = 1.2 Hz, 4-Me),
3
161.3 (C-2), 160.4 (C-7), 155.5 (C-8a), 152.7 (C-4), 126.4
(C-5), 114.9 (C-4a), 113.0 (C-3), 112.9 (C-6), 103.8 (C-8),
78.5 (C-20), 19.2 (4-Me), 15.8 (20-Me); MS (EI) m/z (%):
232 (35, M+), 203 (100), 175 (20), 159 (12), 91 (37). Anal.
Calcd for C13H12O4: C, 67.23; H, 5.21. Found: C, 67.56;
H, 4.92.
1.57 (d, 3H, J = 6.4 Hz, 10-Me), 1.40 (s, 6H, 500-Me); 13C
NMR (100.58 MHz, CDCl3) d 206.0 (C-400), 180.0 (C-200),
161.1 (C-2), 160.4 (C-7), 155.2 (C-8a), 152.4 (C-4), 140.4
(C-20), 125.8 (C-5), 119.6 (C-30), 114.1 (C-4a), 113.3 (C-6),
112.3 (C-3), 102.6 (C-8), 102.5 (C-300), 88.6 (C-500), 73.6 (C-
30), 23.1 (500-Me), 20.8 (10-Me), 18.7 (4-Me); MS (EI) m/z
(%): 340 (12, M+), 176 (17), 165 (71), 91 (15), 77 (53), 69
(100). Anal. Calcd for C20H20O5: C, 70.57; H, 5.92.
14. Parker, D. Chem. Rev. 1991, 91, 1441–1457.
15. Basoli, C.; Botteghi, C.; Cabras, M. A.; Chelucci, G.;
Marchetti, M. J. J. Organomet. Chem. 1995, 488, C20–
C22.
16. Data of 7-{[(1R,2E)-3-(5,5-dimethyl-4-oxo-4,5-dihydro-2-
furanyl)-1-methyl-2-propenyl]oxy}-4-methyl-2H-chromen-
20
Found: C, 70.23; H, 6.23. The (S)-enantiomer 3b has ½aꢂD
ꢁ272.0 (c 1.08, CHCl3).
17. Chimichi, S.; Boccalini, M.; Cosimelli, B.; Dall’Acqua, F.;
Viola, G. Tetrahedron 2003, 59, 5215–5223.