Yb(OTf)3-catalyzed Mannich-type reaction of a chiral non-racemic silyloxypyrrole

Article abstract of DOI:10.1016/S0040-4039(00)01055-8

A Yb(OTf)₃-catalyzed Mannich-type reaction of the chiral non-racemic silyloxypyrrole 2 is described. The three-component (silyloxypyrrole, aldehyde and amine) reaction allowed the use of aromatic as well as aliphatic enolisable aldehydes. The erythro selectivity was proved by chemical correlation and X-ray analysis. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01055-8

Tetrahedron Letters 41 (2000) 6355±6359
Yb(OTf)3-catalyzed Mannich-type reaction of a chiral
non-racemic silyloxypyrrole
Bruno Dudot,a Angele Chiaronia and Jacques Royera,b,
*
aInstitut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette cedex, France
b
Â
Â
Á
Â
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Laboratoire de Chimie Therapeutique associe au CNRS et a l'Universite Rene Descartes (UMR 8638),
Â
Faculte de Pharmacie, 4 avenue de l'Observatoire, 75270 Paris cedex 06, France
Received 16 May 2000; accepted 20 June 2000
Abstract
A Yb(OTf)3-catalyzed Mannich-type reaction of the chiral non-racemic silyloxypyrrole 2 is described.
The three-component (silyloxypyrrole, aldehyde and amine) reaction allowed the use of aromatic as well as
aliphatic enolisable aldehydes. The erythro selectivity was proved by chemical correlation and X-ray
analysis. # 2000 Elsevier Science Ltd. All rights reserved.
We have already reported on the reactivity of lactam 11 which was proved to be easily
substituted at several positions of the ®ve-membered ring.2,3 Alkylations at C-3, 1,4-additions at
C-4, as well as substitutions at C-5, were achieved with high diastereoselectivities.
Special attention was paid to the transformation of lactam 1 into the silyloxypyrrole 2 since the
latter undergoes a Lewis acid-catalyzed aldol-type reaction with various carbonyl derivatives
(Scheme 1).3 This reaction allowed access to interesting derivatives in good yield and with good
diastereoselectivity.
Scheme 1.
* Corresponding author. E-mail: jacques.royer@pharmacie.univ-paris5.fr
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01055-8

6356
Lanthanide tri¯ates, particularly Sc(OTf)3 and Yb(OTf)3, were recently described to be very
ecient and highly selective catalysts for the addition of various nucleophiles to imines.4 It has
been reported by Kobayashi that Yb(OTf)3-catalyzed addition of silyl enol ethers or ketene
acetals to aldimines proceeded very eciently and selectively while the reaction with aldehydes
did not occur under the same reaction conditions.4b We recently reported5 the reaction of 2 with
imines catalyzed by Yb(OTf)3. This reaction was found to be very ecient with aromatic imines
but failed with aliphatic enolisable imines.
In order to extend the scope of reactivity of lactam 1, we thus decided to investigate the
Yb(OTf)3-catalyzed Mannich-type reaction of silyloxypyrrole 2 in the one-pot three-component
condensation depicted in Scheme 2.
Scheme 2.
In a typical experiment, 5% mol. of Yb(OTf)3 was added to a solution of silyloxypyrrole 2
(1 equiv.) and aldehyde (1.5 equiv.) in CH3CH2CN containing molecular sieves at ^45ꢀC,
followed by the dropwise addition of aniline (1.5 equiv.). A very rapid reaction occurred (the
disappearence of starting materials was generally observed within 30 min) and the adducts 5±11
were easily obtained in high yields as mixtures of diastereomers as indicated in Table 1. Crude
1
reaction mixtures were examined by NMR (13C and H) and HPLC in order to determine the
diastereomeric ratios. As shown in Table 1, fair diastereoselectivities, very similar to those
observed using preformed imines,5 were obtained for aromatic aldehydes.
Table 1
Yb(OTf)3-catalyzed Mannich-type reaction of silyloxypyrrole 2 with aniline and various aromatic and
aliphatic aldehydes in CH3CH2CN at ^45ꢀC

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To our knowledge, such a one-pot Mannich reaction, described for silyl enol ethers4c,d was not
reported using silyloxydienes.6 It is also noteworthy that this three-component reaction was also
possible using aliphatic enolisable aldehydes giving rise to compounds 8±11 in good yields
(77±85%). The diastereoselectivities were better than that of imines derived from aromatic
aldehydes, the major isomer being formed in 73% (R=t-Bu) to 85% (R=CH2Ph).
The choice of the above reaction conditions was the result of a preliminary study. The reaction
was tested in various solvents and proved to be ecient at ^70ꢀC in CH2Cl2, THF or ether
and at ^23ꢀC in CH3CN. Under these conditions, the yields were in the range 65±80% and the
diastereoselectivities a little bit lower than in propionitrile as judged by NMR analysis of the
crude reaction mixture.
The determination of the relative con®guration of the di€erent diastereomers appeared to be a
1
very dicult task. In the H NMR spectra, the diagnostic protons H-5 and H-16 (see Scheme 2
for numbering) of the two major isomers, when visible, exhibited the same very small coupling
constant. An erythro (syn) con®guration for the two major isomers was then proposed, in
agreement with the stereochemical outcome observed with preformed non-enolisable imines.5
This has been proved unambiguously for adducts 8, derived from an enolisable aldehyde, after
chemical transformation and X-ray analysis of a derivative.
The crude reaction mixture of compounds 8a±d was submitted to hydrogenation (H2/Pd/C,
95% yield) followed by basic hydrolytic cleavage of the benzoyl ester (Scheme 3). At this stage,
the two major isomeric alcohols 12a7 and 12b8 were separated by ¯ash-chromatography and were
obtained in 66 and 17%, respectively. The minor isomer 12b was isolated as nice crystals suitable
for X-ray analysis.9 The crystal structure is depicted in Fig. 1 showing the erythro con®guration.
Reduction of the lactam function (LiAlH4 in THF, 91% yield) and hydrogenolysis of the chiral
appendage (H2, Pd(OH)2/C, 65% yield) were performed separately on each alcohol 12a and 12b
to furnish the diamines 13a and 13b.10 These two diamines were found to be enantiomeric
materials (13a.2HCl, [ꢀ]D +47 (CH3OH, c 0.4); 13b.2HCl, [ꢀ]D ^46 (CH3OH, c 0.3)). This clearly
proved that the two major isomers of the initial mixture 8 possess the same relative erythro
con®guration at C-5, C-16.
Scheme 3.

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Figure 1. Crystal structure of 12b showing the ellipsoꢀ ids displacement (30%) and the intramolecular hydrogen bond:
...
O8±H O15 (O8 O15:2.690(2) A, O8±H O15=157 )
...
...
In conclusion, we have described a diastereoselective one-pot Mannich reaction of
silyloxypyrrole 2. The reaction is very ecient and particularly useful for enolisable aldehydes.
The determination of the relative con®guration, clearly established in the case of acetaldehyde
and suggested in all cases by NMR data, showed a good erythro:threo selectivity ranging from
90:10 to 100:0 for enolisable aldehydes. This reaction could permit access to original diamines
useful as chiral ligands or could constitute a key step in the asymmetric synthesis of alkaloids.
These potential applications are under investigation in our laboratory.
Acknowledgements
The authors thank Professor H.-P. Husson for frequent fruitful discussions and interest to this
work.
References
1. Baussanne, I.; Chiaroni, A.; Husson, H.-P.; Riche, C.; Royer, J. Tetrahedron Lett. 1994, 35, 3931±3934.
2. (a) Baussanne, I.; Royer, J. Tetrahedron Lett. 1998, 39, 845±848; (b) Baussanne, I.; Travers, C.; Royer, J.
Tetrahedron: Asymmetry 1998, 9, 797±804.
3. (a) Baussanne, I.; Royer, J. Tetrahedron Lett. 1996, 37, 1213±1216); (b) Baussanne, I.; Schwardt, O.; Royer, J.;
Pichon, M.; Figadere, B.; Cave, A. Tetrahedron Lett. 1997, 38, 2259±2262; (c) Dudot, B.; Micouin, L.; Baussanne,
I.; Royer, J. Synthesis 1999, 688±694.
4. (a) Kobayashi, S.; Nagayawa, S. J. Am. Chem. Soc. 1997, 119, 10049±10053; (b) Kobayashi, S.; Nagayawa, S.
J. Am. Chem. Soc. 1998, 120, 2985±2986; (c) Kobayashi, S.; Araki, M.; Yasude, M. Tetrahedron Lett. 1995, 36,
5773±5776; (d) Annunziata, R.; Cinquini, M.; Cozzi, F.; Molteni, V.; Schupp, O. J. Org. Chem. 1996, 61, 8293±
8296.
5. Dudot, B.; Royer, J.; Sevrin, M.; George, P. Tetrahedron Lett. 2000, 41, 4367±4371.

6359
6. (a) Rassu, G.; Zanardi, F.; Battistini, L.; Casiraghi, G. Synlett 1999, 1333±1350; (b) Rassu, G.; Zanardi, F.;
Battistini, L.; Casiraghi, G. Chem. Soc. Rev. 2000, 29, 109±118.
1
7. Compound 12a: white amorphous solid; [ꢀ]D +44 (CHCl3, c 1); I.R. (cm^1): 3444, 1667; H NMR (300 MHz,
CDCl3), ꢁ (ppm), J (Hz): 7.4±7.2 (m, 5H), 7.1 (dd, 2H, J=J0=7.9), 6.7 (t, 1H, J=7.3), 6.35 (d, 2H, J=7.9), 4.75
(dd, 1H, J=4.1, J0=8.1), 4.15 (dd, 1H, J=8.1, J0=11.7), 3.95 (dd, 1H, J=4.1, J0=11.7), 3.8 (ddd, 1H, J=J0=3.4,
J00=9.2), 3.6±3.45 (qd+broad s overlapped, 2H, J=6.4, J0=2.4), 3.4±3.1 (broad s, 1H), 2.65 (ddd, 1H, J=8.7,
J0=9.9, J00=17.4), 2.6±2.4 (ddd, 1H, J=4.6, J0=10.6, J00=17.4), 2.15±2.05 (m, 1H), 1.95±1.8 (m, 1H), 0.95 (d, 3H,
J=6.3); 13C NMR (62.5 MHz, CDCl3), ꢁ (ppm): 177.8, 146.2, 137.1, 129.0, 128.4, 127.7, 127.5, 117.6, 113.3, 63.9,
63.0, 62.0, 50.6, 30.9, 19.8, 15.7; HRMS (IC): calcd for C20H24N2O2: [MH]+ 325.19155; found: 325.19206.
8. Compound 12b: colourless crystals, mp 131ꢀC (1,2-dimethoxyethan); [ꢀ]D ^53 (CH3OH, c 1); I.R. (cm^1): 3331,
1662; 1H NMR (300 MHz, CDCl3) ꢁ (ppm), J (Hz): 7.25±7.1 (m, 7H), 6.7 (t, 1H, J=J0=7.3), 6.55 (d, 2H, J=7.9),
4.5 (dd, 1H, J=3.4, J0=8.0), 4.3 (dd, 1H, J=8.2, J0=12.2), 3.8 (dd, 2H, J=3.4, J0=12.2), 3.75 (qd, 1H, J=3,
J0=6.4), 3.7±3.3 (broad s+ddd overlapped, 2H, J=3, J0=4.5, J00=7.9), 2.7±2.55 (ddd, 1H, J=7.6, J0=9.6,
J00=17.3), 2.55±2.4 (ddd, 1H, J=5.6, J0=10.2, J00=17.3), 2.2±2.05 (m, 1H), 1.95±1.85 (m, 1H), 1.15 (d, 3H,
J=6.3); 13C NMR (62.5 MHz, CDCl3), ꢁ (ppm): 177.7, 146.8, 137.4, 129.4, 128.7, 127.8, 127.3, 118.0, 113.5, 63.5,
62.4, 61.8, 50.0, 31.5, 20.3, 16.5; anal. calcd for C20H24N2O2: C, 74.04; H, 7.46; N, 8.64; found: C, 73.85; H, 7.37;
N, 8.55.
9. Crystal data: C20H24N2O2, Mw=324.41, colourless crystal of 0.36Â0.33Â0.26 mm, orthorhombic, space group P
21 21 21, Z=4, a=8.235(4), b=12.401(5), c=17.481(8) A, V=1785.2(14) A3, dcalc=1.207 g cm^3, F(000)=696,
l=1.54180 A (CuKa), ꢂ 0.620, Nonius CAD4 di€ractometer, theta range: 4.37±67.86, 3493 collected re¯exions,
3247 unique (Rint=0.0614), 2830 observed (I>2ꢃ(I)), Full-matrix least-squares (SHELXL93), R=0.0474 for 2830
observed re¯exions, wR2=0.1331 for 3247 unique re¯exions, goodness of ®t=1.034, residual electron density
between: ^0.123 and 0.135 eA^3. In the crystal the amino group N18 is linked by hydrogen bond with the oxygen
atom O8 of a neighbourhood molecule (X+1, Y, Z).
1
10. Compounds 13: amorphous solid: I.R. (cm^1): 3293, 1601, 1498; H NMR (250 MHz, CDCl3), ꢁ (ppm), J (Hz):
7.15 (dd, 2H, J=7.5, J0=8.5), 6.7 (t, 1H, J=7.3), 6.65 (d, 2H, J=8.7), 3.6±3.5 (qd, 1H, J=J0=6.2), 3.25±3.1 (m,
1H), 3.05±2.85 (m, 2H), 1.95±1.7 (m, 3H), 1.55±1.4 (m, 1H), 1.2 (d, 3H, J=6.3); 13C NMR (62.5 MHz, CDCl3) ꢁ
(ppm): 147.8, 129.4, 117.3, 113.6, 63.3, 51.8, 47.3, 27.8, 26.0, 17.6; MS (ESI): [MH]+Á=191. 13a.2HCl: [ꢀ]D +47
(CH3OH, c 0.4); anal. calcd for C12H20N2Cl2: C, 54.76; H, 7.66, N, 10.61; found: C, 54.14, H, 7.51, N, 10.13.
13.2HCl: [ꢀ]D ^46 (CH3OH, c 0.3).