New alkylidenecyclopropane amino acid derivatives for an efficient construction of the 6H-pyrrolo[3,4-b]pyridine skeleton

Full text of DOI:10.1021/jo9709615

8276
J . Org. Chem. 1997, 62, 8276-8277
New Alk ylid en ecyclop r op a n e Am in o Acid
Der iva tives for a n Efficien t Con str u ction of
th e 6H-P yr r olo[3,4-b]p yr id in e Sk eleton
Karine Estieu, Rene´e Paugam, J ean Ollivier, and
J acques Salau¨n*
Laboratoire des Carbocycles (Associe´ au CNRS), Institut de
Chimie Mole´culaire d’Orsay Baˆt. 420, Universite´ de
Paris-Sud, 91405 Orsay, France
F igu r e 1. 6H-Pyrrolo[3,4-b]pyridine (1) and camptothecin (2).
Sch em e 1a
Franca M. Cordero, Andrea Goti, and
Alberto Brandi*
Dipartimento di Chimica Organica “UgoSchiff”,
Centro di Studio sulla Chimica e la Struttura dei Composti
Eterociclici e loro Applicazioni, CNR Universita` degli Studi
di Firenze, via G. Capponi 9, I-50121 Firenze, Italy
a
Received J une 2, 1997
Key: (a) 6 mol % Pd(dba)2, 7.2 mol % dppe, THF, rt; (b) 1 equiv
of 4a -c, 1 equiv of NaH, THF, rt, 1 h, 70-95%.
Alkylidenecyclopropanes form a peculiar class of
strained olefinic compounds, with remarkable synthetic
potential;1,2 thus, they undergo ring opening with pal-
ladium dichloride to produce π-allylpalladium com-
plexes,3 carbopalladation with vinyl and aryl halides in
the presence of Pd(0),4 regioselective Pd(0)-catalyzed [3
+ 2] cycloaddition with olefinic and acetylenic sub-
strates,1,5 and Pauson-Khand cyclization with dicobalt
hexacarbonyl complexes of acetylene.6,7 Most of these
reactions have been reported to occur both inter- and
intramolecularly.4,8 Moreover, alkylidenecyclopropanes
constitute the most suitable precursors for cyclobutanone
synthesis.9 As in the case for many cyclopropane deriva-
tives, they are also endowed with specific bioactivities.10
Optically active alkylidenecyclopropanes have recently
been prepared by the regio- and stereoselective Pd(0)-
catalyzed reduction of asymmetric 1-(1-alkenyl)cyclopro-
pyl esters by sodium formate.11
We report here a new and efficient synthesis of
optically pure diazabicycloheterocycles derived from 1.
Thus, Pd(0)-catalyzed nucleophilic substitution of the
1-vinyl-1-(tosyloxy)cyclopropane 314 (readily available
from vinylation and tosylation15 of cyclopropanone hemi-
acetal)16 by the methyl N-tosylglycinate (4a ) (R ) H), (S)-
(+)-alaninate (4b) (R ) Me), and (S)-(-)-phenylalaninate
(4c) (R ) PhCH2) in the presence of 1 equiv of NaH
produced the methyl N-(2-cyclopropylideneethyl)-N-to-
sylamino acid esters 5a , (S)-5b, and (S)-5c in 81, 95, and
77% yields, respectively; no significant epimerization of
the chiral center was observed for (S)-5b,c (ee >98%)
(Scheme 1).17 It must be noted that the Pd(0)-catalyzed
reaction of tosylate 3 with simple amines or imines led
exclusively to 2-cyclopropylideneethylamine derivatives;18
use of N-(diphenylmethylene)glycine esters as the nu-
cleophile, following the same process, was shown to
provide R-allyl-R-amino acids resulting from C-allyla-
tion.19
Partial reduction of ester 5a by 0.9 equiv of DIBAH
provided the 2-aminoethanal 6a , which was treated
directly with methylhydroxylamine hydrochloride in
ether in the presence of pyridine (1.1 equiv).20 The
resulting (Z)-nitrone 7a 20 was not isolated but underwent
ready intramolecular 1,3-dipolar cycloaddition8 to pro-
duce exclusively the spiro bicyclic isoxazolidine 8a , in
70% overall yield from 5a . Otherwise, (S)-5b,c were
reduced by 2.5 equiv of DIBAH, and the corresponding
alcohols were then oxidized under Swern conditions21 to
The 6H-pyrrolo[3,4-b]pyridine ring system 1 (Figure
1)12 is of current interest due to its presence in the
skeleton of very important antitumor agents such as
camptothecin 2 and to the biological properties of new
related compounds (e.g., antiretroviral activity, modula-
tion of protein synthesis, ...).13
(1) For a review see: Binger, P.; Bu¨ch, H. M. Cyclopropenes and
Methylenecyclopropanes as Multifunctional Reagents in Transition
Metal Catalyzed Reactions. Top. Curr. Chem. 1987, 135, 77-151.
(2) For a review see: Goti, A.; Cordero, F. M.; Brandi, A. Cycload-
ditions onto Methylene- and Alkylidenecyclopropane Derivatives Top.
Curr. Chem. 1996, 178, 1-97.
(3) Donaldson, W. A.; Wang, J .; Cepa, V. G.; Suson, J . D. J . Org.
Chem. 1989, 54, 6056-6063.
(4) Fournet, G.; Balme, G.; Gore, J . Tetrahedron 1988, 44, 5809-
5820. Fournet, G.; Balme, G.; Barieux, J . J .; Gore, J . Tetrahedron 1988,
44, 5821-5832.
(13) (a) Priel, E.; Showalter, S. D.; Blair, D. G. AIDS Res. Hum.
Retroviruses 1991, 7, 65-72. (b) Pendrak, I.; Whittrock, R.; Kingsburg,
W. D. J . Org. Chem. 1995, 60, 2912-2915. (c) J anavs, J . L.; Florez, J .
C.; Pierce, M. E.; Takahashi, J . S. J . Neurosci. 1995, 15(1), 298-309
and references therein.
(14) Stolle, A.; Ollivier, J .; Piras, P. P.; Salau¨n, J .; de Meijere, A. J .
Am. Chem. Soc. 1992, 114, 4051-4067 and references therein.
(15) Salau¨n, J .; Ollivier, J . Nouv. J . Chem. 1981, 5, 587-594. One-
pot successive addition of vinylmagnesium chloride (2 equiv) and of
tosyl chloride (2 equiv) to cyclopropanone hemiacetal16 in THF provides
3 in 85% yield, after usual purification.
(16) Salau¨n, J .; Marguerite, J . Org. Synth. 1984, 63, 147-153. Fadel,
A.; Canet, J . L.; Salau¨n, J . Synlett 1990, 89-91. Salau¨n, J . Chem. Rev.
1983, 83, 619-632.
(17) Amino acid esters (S)-5b,c were obtained with 98% enantio-
meric excesses when 1 equiv of NaH was used, but use of more than
1 equiv of base caused their racemization.
(5) Lewis, R. T.; Motherwell, W. B.; Shipman, M. J . Chem. Soc.,
Chem. Commun. 1988, 948-950. Bapuji, S. A.; Motherwell, W. B.;
Shipman, M. Tetrahedron Lett. 1989, 30, 7107-7170. Motherwell, W.
B.; Shipman, M. Tetrahedron Lett. 1991, 32, 1103-1106. Yamago, S.;
Nakamura, E. Tetrahedron 1989, 45, 3081-3088.
(6) Smit, W. A.; Kireev, S. L.; Nefedov, O. M.; Tarasov, V. A.
Tetrahedron Lett. 1989, 30, 4021-4024.
(7) Stolle, A.; Becker, H.; Salau¨n, J .; de Meijere, A. Tetrahedron Lett.
1994, 35, 3517-3520 and 3521-3524.
(8) Brandi, A.; Cordero, F. M.; De Sarlo, F.; Goti, A.; Guarna, A.
Synlett 1993, 1-8. Cordero, F. M.; Brandi, A. Tetrahedron Lett. 1995,
36, 1343-1346.
(9) Salau¨n, J .; Champion, J .; Conia, J . M. Org. Synth. 1977, 57, 36-
40. Salau¨n, J . Rearrangements involving the cyclopropyl group. In The
Chemistry of the Cyclopropyl Group; Rappoport, Z., Ed.; Wiley: New
York, 1987; pp 809-878.
(18) Aufranc, P.; Ollivier, J .; Stolle, A.; Bremer, C.; Es-Sayed, M.;
de Meijere, A.; Salau¨n, J . Tetrahedron Lett. 1993, 34, 4193-4196.
(19) Voigt, K.; Stolle, A.; Salau¨n, J .; de Meijere A. Synlett 1995, 226-
228.
(20) DeShong, P.; Lauder, S. W., J r.; Leginus, J . M.; Dicken, C. M.
Adv. Cycloaddit. 1988, 1, 87-128.
(10) Salau¨n, J .; Baird, M. S. Curr. Med. Chem. 1995, 2, 511-542.
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S0022-3263(97)00961-4 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 24, 1997 8277
Sch em e 2a
Sch em e 4a
a
Key: (a) xylene reflux, 6 h, 43-64%.
selectivity ascribed to a steric effect.24 Fortunately,
cycloadducts 8b and 8′b as well as 8c and 8′c were
separable by flash chromatography, and their structures
1
were determined by H and 13C NMR spectroscopy. For
instance, after irradiation of the methyl on carbon 6′-C
at δ 1.35 ppm, the major isomer 8b showed a doublet at
δ 3.65 ppm (J ) 7.40 Hz) for the 6′-H proton, while the
minor isomer 8′b showed a doublet at δ 3.20 ppm (J )
5.36 Hz) for the same proton; as J cis is larger than J trans
in isoxazolidine and pyrrolidine rings,22 the observed
coupling constants supported the structure assignments.
On heating in xylene at reflux for 6 h, the N-O
isoxazolidine bond of the tricyclic isoxazolidines 8a -c
was cleft to produce the cyclopropyloxy diradicals
10a -c, which then readily underwent cyclopropane ring
opening with strain release into the diradicals 11a -c,
followed by ring reclosure, to afford the diazaheterocycles
12a (49%) and (1R,6S,9S)-12b,c (43-64%, Scheme 4).
The isoxazolidines 8′b,c underwent the thermal induced
ring expansion to give the diastereomeric (1S,6R,9S)-
diazaheterocycles. Epimerization of diamines 12b,c was
not observed under these conditions25 and the whole
process occurred with the maximum “atom economy” as
no added reagent or catalyst was required after nitrone
formation.
Now readily available, the derivatives of 2,4-
diazabicyclo[3.4]octan-7-ones 12a -c are specific sub-
stance P (SP) antagonists both in vitro and in vivo (IC50
ranges from 0.8 to 3 µM for the NK1 receptor of human
IM9 cells26,27); they appeared as promising therapeutic
agents for the treatment of important diseases (asthma,
inflammation and pain, migraine, and vascular head-
aches).28 Moreover, they constitute suitable precursors
of bioactive alkaloids such as camptothecin (2), for
instance, and analogous derivatives. Synthetic applica-
tions of these new diazaheterocycles are currently under
investigation.
aKey: (a) 0.9 equiv of DIBAH, CH2Cl2, -78 °C, 1 h or (i) 2.5
equiv of DIBAH, (ii) (COCl)2, DMSO, iPr2EtN; (b) 1.2 equiv of
MeNHOH-HCl, 1.4 equiv of pyridine, H2O, rt, 18 h, 70-76%
overall yield from 5a -c.
Sch em e 3. Tr a n sition Sta tes of th e 1,3-Dip ola r
Cycloa d d ition of (Z)-Nitr on es 7a -c
provide the 2-aminoethanal (S)-6b,c. Upon treatment
with MeNHOH-HCl, (S)-6b gave the (Z)-nitrone (S)-
7b,20 which underwent cycloaddition to give a 55/45
diastereomeric mixture of the fused cycloadducts
(3′aR,6′S,6′aR)-8b and (3′aS,6′S,6′aS)-8′b in 76% overall
yield from the amino ester (S)-5b, while the aldehyde (S)-
6c (R ) PhCH2) led after reaction with MeNHOH-HCl
via the nitrone (Z)-7c20 to a 62/38 diastereomeric mixture
of fused cycloadducts (3′aR,6′S,6′aR)-8c and (3′aS,
6′S,6′aS)-8′c in 70% overall yield (Scheme 2).
The regioselectivity of the cycloaddition, i.e., the ex-
clusive formation of the fused adducts 8a -c and the lack
of bridged adducts 9a -c,22 is supported by simple mo-
lecular mechanics calculations (MAD).23 Thus, the dif-
ference of total steric energies between the optimized
geometries of the conformations of the transition states
leading to cycloadducts 8a -c or 9a -c (∆E ) -15 kcal/
mol) suggests kinetic control of the reaction. The forma-
tion of the two diastereomeric cycloadducts 8b and 8′b
observed from the (Z)-nitrone (S)-7b (R ) Me) and of the
two diastereomeric cycloadducts 8c and 8′c from the (Z)-
nitrone (S)-7c (R ) PhCH2) probably results from the two
possible approaches of the dipolarophile by the (Z)-
nitrone moieties, either from above (transition state 7A)
or from below (transition state 7A′) the plane of the
alkylidenecyclopropane (Scheme 3). Analogous MAD
calculations of the difference of energies between the
conformations of the transition states leading to cyclo-
adducts 8b and 8′b (∆E ) -1.5 kcal/mol) or to 8c and
8′c (∆E ) -3.6 kcal/mol), respectively, confirm that the
presence of a methyl or benzyl substituent on carbon 6′-C
did not induce in these cases any significant diastereo-
Ack n ow led gm en t. This work was financially sup-
ported by the CNRS (France) and the CNR (Italy) within
a French-Italian Cooperation Program and through
grants from the ERASMUS European Program. We are
grateful to Dr. J ean-Franc¸ois Peyronel (Rhone-Poulenc
Rohrer, France) for helpful discussions concerning the
SP antagonists.
Su p p or tin g In for m a tion Ava ila ble: Full experimental
procedures and complete spectral data for all reaction products
(8 pages).
J O9709615
(24) Cordero, F. M.; Brandi, A. Tetrahedron Lett. 1995, 36, 1343-
1346.
(25) No interconversion was observed between 8b,c and 8′b,c
respectively, during the radical rearrangement step.
(26) Unpublished results. Private communication from Dr. J . F.
Peyronel (Medicinal Chemistry Department, Rhone-Poulenc Rohrer
Central Research, France).
(27) Fardin, V.; Foucault, F.; Bock, M. D.; J olly, A.; Flamand O.;
Clerc, F.; Garret, C. Neuropeptides 1994, 26, 34.
(21) Mancuso, A. J .; Swern, D. Synthesis 1981, 165-185.
(22) Brandi, A.; Cordero, F. M.; De Sarlo, F.; Gandolfi, R.; Rastelli,
A.; Bagatti, M. Tetrahedron 1992, 48, 3323-3334.
(23) Molecular mechanics calculations have been performed with
the MAD (Molecular Advanced Design) version 2.3, using a MM2-type
force field, available from Oxford Molecular, Ecole Polytechnique,
Palaiseau (France). The minima were found through
geometrical optimization of the structure for which the distances
between the atoms C3′-O2′ and C2′a-C6′a were constrained to 3 Å.
a
complete
(28) Peyronel J . F.; Tabart, M.; Achard, D.; Malleron, J . L.; Grisoni,
S.; Carruette, A.; Montier, F.; Moussaoui, S.; Fardin, V.; Garret, C.
Eur. J . Med. Chem. 1995, 30 (Suppl.), 576s-585s.