Stereoselective synthesis of 2-substituted 3-azabicyclo[3.2.0]heptan-2-ones by [2+2]-cycloaddition of N-allyl-β-N-keteniminium salts derived from (R)-vinylglycinol

Article abstract of DOI:10.1016/S0957-4166(00)00237-8

A stereoselective synthesis of (1R,2R,5S)-2-benzyloxymethyl-3-azabicyclo[3.2.0]heptan-2-one was achieved, by intramolecular [2+2]-cycloaddition of (R)-vinylglycinol-derived N-allyl-β-N-keteniminium salts, with high facial diastereoselection. The regio- an

Full text of DOI:10.1016/S0957-4166(00)00237-8

Tetrahedron: Asymmetry 11 (2000) 2653±2659
Stereoselective synthesis of 2-substituted
3-azabicyclo[3.2.0]heptan-2-ones by [2+2]-cycloaddition of
N-allyl-b-N-keteniminium salts derived from (R)-vinylglycinol
Giuliano Delle Monache,a Domenico Misiti,b Patrizia Salvatore,b Giovanni Zappiab,*
and Marco Pierinic
aCentro di Studio per la Chimica dei Recettori e delle Molecole Biologicamente Attive-Istituto di Chimica,
Á
Universita Cattolica del S. Cuore, Largo F. Vito 1, 00168 Roma, Italy
Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Universita `La Sapienza',
b
Á
P.le A. Moro 5, 00185 Roma, Italy
cDip. Scienze del Farmaco, Via dei Vestini 31, 66013 Chieti, Italy
Received 8 May 2000; accepted 14 June 2000
Abstract
A
stereoselective synthesis of (1R,2R,5S)-2-benzyloxymethyl-3-azabicyclo[3.2.0]heptan-2-one was
achieved, by intramolecular [2+2]-cycloaddition of (R)-vinylglycinol-derived N-allyl-b-N-keteniminium
salts, with high facial diastereoselection. The regio- and stereochemical courses have been qualitatively
investigated by Molecular Mechanics calculations. # 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
The diastereoselective synthesis of natural or synthetic substituted pyrrolidines is an important
topic in organic synthesis because of their presence as constituents of biologically active com-
pounds. For instance, a-kainic acid1 and acromelic acids1 show remarkable neuroexcitatory
e€ects,2 although with di€erent modes of action.3 On the other hand, 2,3,4-trisubstituted
pyrrolidines are components of cyclic peptides4 or alkaloids.5 In particular, 3,4-dihydroxy-2-
hydroxymethyl pyrrolidines are inhibitors of several glycosidases.6 Therefore, chiral 2-sub-
stituted-3-azabicyclo[3.2.0]heptan-6-ones are useful intermediates for the synthesis of chiral het-
erocycles by elaboration of the four-membered ring.
The inter- and intramolecular [2+2]-cycloadditions of keteniminium salts to an ole®n were ®rst
introduced by Ghosez et al.7 as an alternative to the [2+2]-cycloaddition of a ketene8 with ole®ns.
Cyclobutanones,7a fused bicyclobutanones7b and azabicyclobutanones7c were prepared in good
* Corresponding author. E-mail: g.zappia@caspur.it
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00237-8

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G. Delle Monache et al. / Tetrahedron: Asymmetry 11 (2000) 2653±2659
yields by this method. Moreover, high enantioselectivity9 was observed in the inter- and
intramolecular [2+2]-cycloaddition of chiral keteniminium salts. Less attention,10 however, has
been paid to the stereochemical course of this [2+2]-cycloaddition when a stereogenic centre is
part of the ole®n compound.
Following our studies11 on the electrophile-mediated functionalization of chiral allyl amines,
we focused our interest on the intramolecular asymmetric [2+2]-cycloaddition of N-allyl-b-N-
keteniminium salts 1 derived from (R)-vinylglycinol as a way to prepare compounds 2. This
communication deals with our ®rst results.
For this purpose, compound 8 was prepared (Scheme 1) starting from l-serine, which was
converted into the known12 Weinreb amide 3. After protection of the hydroxyl group as a silyl
ether (t-BuPh2SiCl, imidazole, CH2Cl2; 89%), the a-amino amide was converted13 into the allyl
amine14 4, by treatment with LiAlH4 (1 M, THF; 0ꢀC), followed by Wittig methylation
(Ph3P+CH3Br^/KHMDS, ^78ꢀC!rt; 73% from 3).
Scheme 1.
The Boc-protecting group in 4 was removed (Scheme 1), according to the method of Ohfune et
al.,15 under neutral conditions (TBDMSOTf, 2,6-lutidine, CH2Cl2, rt, 20 min; NH4Cl; 98%) to
give the corresponding free amine, which in turn, by a Michael-type reaction with methyl acrylate
in MeOH, a€orded the a-amino ester16 5 in 94% yield. The secondary amine 5 was protected
(TsCl, CH2Cl2, Et3N, 0ꢀC!rt; 98%) as N-Ts 6, and the ester function was hydrolyzed (LiOH,
acetone/H2O; 86%). The coupling17 (BOPCl, DMAP cat., CH2Cl2, 80%) of acid 7 with
pyrrolidine ®nally a€orded the required amide 8.
Reaction of compound 8 with tri¯ic anhydride and 2,6-di-t-butyl-4-methylpyridine in 1,2-
dichloroethane under re¯ux for 3 h, followed by hydrolysis (H2O/CCl4, re¯ux), gave a complex
mixture of products. A cleaner reaction occurred when the cycloaddition reaction was carried out
at room temperature with ultrasound activation, but the main product (60% yield) was the
alcohol 9.

G. Delle Monache et al. / Tetrahedron: Asymmetry 11 (2000) 2653±2659
2655
To overcome these by-reactions we turned our attention to the use of benzyl ether as a pro-
tecting group for the hydroxyl. This switch was performed by treatment of 8 with TBAF (1 M
THF; 98% yield), followed by conversion (NaH, BnBr, TBAI, THF; 85%) of the free alcohol 9
into benzyl ether 10 (Scheme 2).
Scheme 2.
The results of the [2+2]-cycloaddition reaction on the allyl amine 10 under di€erent conditions
are reported in Table 1. A solution of Tf2O was added to a solution of substrate 10 and 2,6-di-t-
butyl-4-methylpyridine at room temperature. The resulting mixture was held under re¯ux or
sonicated. In both cases, compound 10 was converted into a mixture of (1R,2R,5S)-2-
benzyloxymethyl-N-(4-methylbenzenesulfonyl) 3-azabicyclo[3.2.0]heptan-6-one 11 and the [3.1.1]-
isomer 12 (Scheme 3).
Table 1
Results of intramolecular cycloaddition of keteniminium salt derived from protected (R)-vinylglycinol 10
Scheme 3.

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G. Delle Monache et al. / Tetrahedron: Asymmetry 11 (2000) 2653±2659
As shown in Table 1 the [3.2.0]-isomer 11 (dr=>95/5) was obtained as the major product,
when the reaction was run at room temperature under ultrasound activation (entry 2), although
similar results were obtained in CH2Cl2 under re¯ux (entry 3).
1
The two adducts were assigned the structures 11 and 12 on the basis of the H and 13C NMR
spectral data (Table 2), as well as COSY and HETCOR experiments. The assignments are in
agreement with the values reported in the literature for similar compounds.18
Table 2
1
Selected H- and 13C NMR spectral data for azabicyclo compounds 11 and 12
Table 2 shows that the signal of the 7-methylene in the 13C NMR in 11 is shifted down®eld due
to the proximity of the CˆO group. By contrast, in compound 12, the corresponding signal
appears to high®eld, whereas the resonance of the C-1 methine is now shifted down®eld by the
carbonyl group. In 11 the value of the J1,5 (7 Hz) established a cis-relationship between H-1 and
H-5 protons,18 while the small coupling ( J1,20) requires the dihedral angle between H-1 and H-2
to be close to 90ꢀ. The assignment of the structure was con®rmed by facile ring expansion of 11,
under Baeyer±Villiger19 conditions, to give the lactone 13. Notably, the long-range coupling
between 7-CH2 protons and H-5 in 11 (see Table 2) disappeared in the bicyclo compound 13.
The regio- and stereochemical course of the cycloaddition was qualitatively investigated by
Molecular Mechanics calculations. Two possible transition state structures TS1 and TS2 were
envisaged. TS1 leads to the stereoisomers with a syn relationship between H-1 and H-2, i.e. the
products not experimentally observed. On the other hand, TS2 showed the correct geometry of
the keteniminium and ole®n fragments to give both the regioisomers 11 and 12.
0A conformational search20 was performed on the keteniminium salt structure 1 (R=Ts,
R =Bn). The analysis of the data showed that, within 6 kcal/mol from the global minimum,20
this structure exists only in conformations, such as C, leading to TS2 (Fig. 1).
A conformational search20 was also carried out on the regioisomers 11 and 12 and the relative
stability of the two isomers was obtained from the computed energies21 of their more stable
conformers. The results indicated a strong preference (^5.75 kcal/mol) for the [3.2.0]-isomer 11.

G. Delle Monache et al. / Tetrahedron: Asymmetry 11 (2000) 2653±2659
2657
Figure 1. Structure C describes one of the conformations found in the conformational search of 1 (R=Ts, R0=Bn).
Aromatic rings are omitted for the sake of clarity
In conclusion, this communication has shown that intramolecular [2+2]-cycloaddition of an
N-allyl-b-N-keteniminium salt derived from protected (R)-vinylglycinol 10, a€ords the azabicyclo
compounds 11 with high facial diastereoselectivity. Studies on the utilization of compounds 11
and 13 for the synthesis of biologically relevant 2,3,4-trisubstituted pyrrolidines are in progress.
Acknowledgements
This work was supported by MURST (Ministero dell'Universita e della Ricerca Scienti®ca,
Italy) and by CNR (Consiglio Nazionale delle Ricerche, Italy).
References
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Matsumoto, T. Tetrahedron Lett. 1983, 24, 939. (c) For a review, see: Parsons, A. F. Tetrahedron 1996, 4149.
2. See: (a) Excitatory Amino Acids; Simon, R. P., Ed.; Thieme Medical Publishers: New York, 1992. (b) Shinozaki,
H.; Ishida, M.; Okamoto, T. Brain Res. 1986, 399, 395. (c) Maruyama, M.; Takeda, K. Brain Res. 1989, 504, 328.
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1988, 53, 1298. (b) Benz, F.; Knusel, F.; Nuesch, J.; Treischler, H.; Voser, W.; Nyfeher, R.; Keller-Schierlein, W.
Helv. Chim. Acta 1974, 57, 2459. (c) Keller-Jushen, C.; Kuhn, M.; Loosli, H.-R.; Petcher, T. J.; Weber, H.; von
Wartburg, A. Tetrahedron Lett. 1976, 4147.
5. (a) Liddell, J. R. Natural Prod. Rep. 1999, 16, 419. (b) Takahata, H.; Momose, T. The Alkaloids; Cordell, G. A.,
Ed.; Academic Press: New York, 1993; Vol. 44.
6. Look, G. C.; Fotsch, C. H.; Wong, C.-H. Acc. Chem. Res. 1993, 26, 182.
7. (a) Sidani A.; Marchand-Brynaert, J.; Ghosez, L. Angew. Chem., Int. Ed. Engl. 1974, 13, 267; Org. Synth. 1990, 69,
199. (b) Marko, I.; Ronsmans, B., Hesbain-Frisque, A.-E.; Dumas, S.; Ghosez, L.; Ernst, B.; Grenter, H. J. Am.
Chem. Soc. 1985, 107, 2192; (c) Falmagne, J.-B.; Escudero, J.; Taleb-Sahraoni, S.; Ghosez, L. Angew. Chem., Int.
Ed. Engl. 1981, 20, 879. (d) Gobeaux, B.; Ghosez, L. Heterocycles 1989, 28, 29.
8. Snider, B. B. Chem. Rev. 1988, 88, 793.
9. (a) Houge, C.; Frisque-Hesbain, A-M.; Mockel, A.; Ghosez, L. J. Am. Chem. Soc. 1982, 104, 2920. (b) Chen, L.;
Ghosez, L. Tetrahedron Lett. 1990, 31, 4467. (c) Chen, L.; Ghosez, L. Tetrahedron: Asymmetry 1991, 2, 1181.
(d) Genicot, C.; Ghosez, L. Tetrahedron Lett. 1992, 33, 7357.
10. Cholerton, T. J.; Collington, E. W.; Finch, H.; Williams, D. Tetrahedron Letters 1988, 29, 3369.

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11. For an account of our work in this ®eld, see: (a) Delle Monache, G.; Misiti, D.; Zappia, G. Tetrahedron:
Asymmetry 1999, 10, 2961. (b) Delle Monache, G.; Di Giovanni, M. C.; Misiti, D.; Zappia, G. Tetrahedron:
Asymmetry 1997, 8, 231. (c) Di Giovanni, M. C.; Misiti, D.; Zappia, G.; Delle Monache, G. Gazz. Chim. Ital.
1997, 127, 475. (d) Di Giovanni, M. C.; Misiti, D.; Villlani, C.; Zappia, G. Tetrahedron: Asymmetry 1996, 7, 2277.
(e) Misiti, D.; Delle Monache, G.; Zappia, G. Liebigs Ann. Chem. 1996, 235.
12. Campbell, A. D.; Raynham, T. M.; Taylor, R. J. K. Synthesis 1988, 1707.
13. Fehrentz, J.-A.; Castro, B. Synthesis 1983, 676.
1
14. Melting points were determined in open capillaries and are uncorrected. H (300 MHz) and 13C NMR (75 MHz)
were run in CDCl3, unless otherwise reported. Coupling constants are given in hertz. The proton and carbon
signals of the protecting groups (t-BuPh2Si, Ts) are not reported. Optical rotations were determined at 23ꢀC
(concentration g/100 ml). Compound 4: m.p. 41±42ꢀC; [ꢀ]D=+25.4 (c 1.7, CHCl3); anal. calcd for C25H35NO3Si:
C, 70.55; H, 8.29; N, 3.29; found: C, 70.56; H, 8.30; N, 3.28; 1H NMR ꢁ: 5.84 (1H, ddd, J=17.0, 10.0, 5.0, ˆCH),
P
5.22 (1H, dt, J=17.0, 1.5, ˆCHAHB), 5.16 (1H, dt, J=10.0, 1.5, ˆCHAHB), 4.24 (1H, m, J=25.0, CHN), 3.74
(1H, dd, J=10.0, 4.5, CHCHDOSi), 3.64 (1H, dd, J=10.0, 4.5, CHCHDOSi); 13C NMR ꢁ: 155.45 (s, NCO), 136.49
1
(d, CHˆ), 115.65 (t, ˆCH2), 66.06 (t, CH2OSi), 64.30 (d, CHN). Compound 5: [ꢀ]D=^2.2 (c 2.0, CHCl3); H
NMR ꢁ: 5.56 (1H, ddd, J=17.0, 10.0, 8.0, CHˆ), 5.16 (1H, br d, J=17.0, ˆCHAHB), 5.13 (1H, br d, J=10.0,
ˆCHAHB), 3.68 (3H, s, OCH3), 3.62 (1H, dd, J=10.0, 5.0, CHCHDSi), 3.57 (1H, dd, J=10.0, 9.0, CHCHDSi),
3.22 (1H, td, J=8.5, CHN), 2.91 (1H, dt, J=12.0, 6.5, CHEHFN), 2.79 (1H, dt, J=12.0, 6.5, CHEHFN), 2.57 (1H,
dt, J=17.0, 6.5, CHGHLCO), 2.49 (1H, J=17.0, 6.5, CHGHLCO); 13C NMR ꢁ: 173.07 (s, COO), 137.22 (d, ˆCH),
117.97 (t, ˆCH2), 66.64 (t, CH2OSi), 61.10 (d, CHN), 51.58 (q, OCH3), 42.37 (t, CH2N), 34.43 (t, CH2CO).
Compound 6: [ꢀ]D=^3.4 (c 3.5, CHCl3); anal. calcd for C31H39NO5SSi: C, 65.81; H, 6.95; N, 2.48; found: C,
65.80; H, 6.97; N, 2.49; 1H NMR ꢁ: 5.60 (1H, ddd, J=17.0, 10.0, 6.0, CHˆ), 5.11 (1H, dt, J=10.5, 1.5,
ˆCHAHB), 4.98 (1H, dt, J=17.0, 1.5, ˆCHAHB), 4.48 (1H, qt, J=6.0, 1.5, CHN), 3.74 (1H, dd, J=11.0, 6.0,
CHCHDOSi), 3.70 (1H, dd, J=11.0, 7.0, CHCHDOSi), 3.62 (3H, s, OCH3), 3.51 (1H, ddd, J=16.0, 10.0, 6.0,
CHEHFN), 3.37 (1H, ddd, J=16.0, 10.0, 6.0, CHEHFN), 2.82 (1H, ddd, J=16.0, 10.0, 6.0, CHGHLCO), 2.71 (1H,
ddd, J=16.0, 10.0, 6.0, CHGHLCO); 13C NMR ꢁ: 171.95 (s, COO), 133.24 (d, ˆCH), 119.11 (t, ˆCH2), 64.64 (t,
CH2OSi), 61.36 (d, CHN), 51.54 (q, OCH3), 40.59 (t, CH2N), 35.70 (t, CH2CO). Compound 7: [ꢀ]D=^2.4 (c 1.1,
CHCl3); 1H NMR ꢁ: 5.60 (1H, br d, J=17.0, 10.0, 6.0, CHˆ), 5.07 (1H, br d, J=17.0, ˆCHAHB), 4.97 (1H, br d,
J=10.0, ˆCHAHB), 4.41 (1H, br q, J=6.0, CHN), 3.70 (2H, d, J=6.0, CH2OSi), 3.49 (1H, dt, J=15.0, 7.0,
CHCHDN), 3.37 (1H, dt, J=15.0, 7.0, CHCHDN), 2.71 (1H, dt, J=17.0, 7.0, CHEHFCO), 2.64 (1H, dt, J=17.0,
7.0, CHEHFCO); 13C NMR ꢁ: 177.10 (s, COOH), 133.45 (d, CHˆ), 64.43 (t, CH2OSi), 61.34 (d, CHN), 40.94 (t,
CH2N), 36.64 (t, CH2CO). Compound 8: [ꢀ]D=^9.5 (c 3.0, CHCl3); anal. calcd for C34H44N2O4SSi: C, 67.51; H,
7.33; N, 4.63; found: C, 67.50; H, 7.35; N, 4.60; 1H NMR ꢁ: 5.56 (1H, ddd, J=17.0, 10.0, 6.0, CHˆ), 5.08 (1H, dt,
J=10.5, 1.5, ˆCHAHB), 4.95 (1H,dt, J=17.0, 1.5, ˆCHAHB), 4.53 (1H, qt, J=6.0, 5.0, 1.5, CHN), 3.75 (1H, dd,
J=11.0, 6.5, CHCHDOSi), 3.71 (1H, dd, J=11.0, 6.5, CHCHDOSi), 3.49 (1H, ddd, J=16.0, 10.0, 6.0,
CHCHDOSi), 3.40 (1H, ddd, J=16.0, 10.0, 6.0, CHEHFNSO2), 3.38 (2H, m, CH2NCO), 3.31 (1H, dt, J=10.0,
6.5, CHGHLNCO), 3.17 (1H, ddd, J=10.0, 7.0, 6.0, CHGHLNCO), 2.82 (1H, ddd, J=16.0, 10.0, 6.0,
CHMHNNCO), 2.66 (1H, ddd, J=16.0, 10.0, 6.0, CHMHNCO), 1.73^1.94 (4H, m, 2ÂCH2); 13C NMR ꢁ: 169.53
(s, NCO), 133.15 (d, CHˆ), 119.09 (t, ˆCH2), 64.60 (t, CH2OSi), 61.64 (d, CHN), 46.35 (t, CH2NCO), 45.40 (t,
CH2NCO), 41.05 (t, CH2NSO2), 36.55 (t, CH2CO), 25.95 (t, CH2), 24.35 (t, CH2). Compound 9: [ꢀ]D=^59.5 (c
1
1.1, CHCl3); anal. calcd for C18H26N2O4SSi: C, 58.99; H, 7.15; N, 7.64; found: C, 60.04; H, 7.19; N, 7.60; H
NMR ꢁ: 5.52 (1H, ddd, J=17.0, 10.5, 6.0, CHˆ), 5.13 (1H, dt, J=10.5, 1.5, ˆCHAHB), 5.09 (1H, dt, J=17.0, 1.5,
ˆCHAHB), 4.51 (1H, dddt, J=8.0, 6.0, 5.0, 1.5, CHN), 4.06 (1H, s, OH), 3.82 (1H, br dd, J=12.0, 8.0,
CHCHDOSi), 3.73 (1H, dd, J=12.0, 5.0, CHCHDOSi), 3.49 (1H, ddd, J=15.0, 9.0, 6.0, CHEHFNTs), 3.41 (1H,
ddd, J=15.0, 6.5, 5.0, CHEHFNTs), 3.38 (2H, m, CH2NCO), 3.33 (2H, t, J=6.5, CH2NCO), 2.99 (1H, ddd,
J=16.0, 9.0, 6.5, CHGHLCO), 2.53 (1H, ddd, J=16.0, 6.0, 5.0, CHGHLCO), 1.92 (2H, m, CH2), 1.82 (2H, m,
CH2); 13C NMR ꢁ: 169.71 (s, CO), 132.39 (d, CHˆ), 119.35 (t, ˆCH2), 62.68 (t, CH2OSi), 62.47 (d, CHN), 45.75,
45.55 (t, each, 2ÂCH2NCO), 40.11 (t, CH2NTs), 34.95 (t, CH2CO), 25.91, 24.28 (t each, 2ÂCH2). Compound 10:
[ꢀ]D=^27.3 (c 1.9, CHCl3); anal. calcd for C25H32N2O4S: C, 65.76; H, 7.06; N, 6.14; found: C, 65.68; H, 7.16; N,
6.11; 1H NMR ꢁ: 7.5±7.3 (5H, m, C6H5), 5.60 (1H, ddd, J=17.0, 11.0, 6.0, CHˆ), 5.13 (1H, br d, J=11.0,
ˆCHAHB), 5.08 (1H, br d, J=17.0, ˆCHAHB), 4.65 (1H, br q, J=6.0, CHN), 4.51 (1H, d, J=12.0, OCHAHBC6H5),
4.44 (1H, d, J=12.0, OCHAHBC6H5), 3.63 (1H, dd, J=10.0, 7.0, OCHGHD), 3.58 (1H, dd, J=10.0, 6.0,
OCHCHD), 3.48 (1H, ddd, J=15.0, 9.0, 6.0, CHEHFNSO2), 3.42 (1H, ddd, J=15.0, 9.0, 5.5, CHEHFNSO2), 3.37
(2H, br t, J=6.0 Hz, CH2N), 3.35 (1H, dt, J=10.5, 6.5, CHGHLN), 3.23 (1H, dt, J=10.5, 6.0, CHGHLCO), 2.76

G. Delle Monache et al. / Tetrahedron: Asymmetry 11 (2000) 2653±2659
2659
(1H, ddd, J=15.0, 9.0, 6.0, CHMHNCO), 2.65 (1H, ddd, J=15.0, 9.0, 6.0, CHMHNCO), 2.01 (2H, m, CH2), 1.99
(2H, m, CH2). 13C NMR ꢁ: 169.55 (s, CON), 137.33 (s, C6H5), 133.40 (d, CHˆ), 128.30 (2Âd, C6H5), 127.57 (3Âd,
C6H5), 118.93 (t, ˆCH2), 72.86 (t, OCH2), 70.47 (t, OCH2C6H5), 59.28 (d, CHN), 46.38, 45.41 (t each, CH2N),
40.95 (t, CH2NSO2), 36.38 (t, CH2CO), 25.91 (t, CH2), 24.32 (t, CH2). Compound 11: m.p.=72±73ꢀC; [ꢀ]D=^6.4
1
(c 0.9, CHCl3); anal. calcd for C21H23NO4S: C, 65.43; H, 6.01; N, 3.63; found: C, 65.44; H, 6.02; N, 3.63; H and
13C NMR spectral data are in Table 2. Compound 12: [ꢀ]D=29.6 (c 0.7, CHCl3); anal. calcd for C21H23NO4S: C,
65.43; H, 6.01; N, 3.63; found: C, 65.37; H, 5.90; N, 3.55; 1H and 13C NMR spectral data are in Table 2.
Compound 13: [ꢀ]D=95.3 (c 1.1, CHCl3); anal. calcd for C21H23NO5S: C, 62.83; H, 5.77; N, 3.49; found: C, 62.77;
H, 5.71; N, 3.44; 1H NMR (CD3COCD3) ꢁ: 7.77 (2H, d, J=8.0, C6H4CH3), 7.42±7.20 (7H, m, C6H5+C6H4CH3),
5.07 (1H, ddd, J=6.5, 3.5, 1.5, CHO), 3.89 (1H, dt, J=5.0, 3.5, CHN), 3.85 (1H, dd, J=13.0, 1.5, CHAHBN), 3.76
(1H, dd, J=13.0, 4.0, CHAHBN), 3.73 (1H, dd, J=9.5, 3.5, CHCHCHDO), 3.69 (1H, dd, J=9.5, 5.0,
CHCHCHDO), 3.28 (1H, ddt, J=9.5, 6.5, 3.5, CH), 2.82 (1H, dd, J=18.0, 9.5, CHEHFCO), 2.43 (3H, s,
C6H4CH3), 2.27 (1H, dd, J=18.0, 3.5, CHEHFCO); 13C NMR ꢁ: 178.40 (s, CO), 144.49 (s, 40-C6H4SO2), 139.25
(s, C6H5), 134.04 (s, 10-C6H4SO2), 130.58 (2Âd, 20,60-C6H4SO2), 129.09 (2Âd, C6H5), 128.30 (d, C6H5), 128.25
(2Âd, 30,50-C6H4SO2), 127.94 (2Âd, C6H5), 83.71 (d, CHO), 73.76 (t, OCH2C6H5), 73.08 (t, CHCH2O), 66.86 (d,
CHN), 55.12 (t, CH2N), 43.36 (d, CHN), 34.83 (t, CH2CO), 21.41 (q, CH3).
15. Sakaitani, M.; Ohfune, Y. J. Org. Chem. 1990, 55, 870.
16. Bis alkylated product (3%) was isolated.
17. (a) Diago-Meseguer, J.; Palomo-Coll, A. L. Synthesis 1980, 547. (b) Cabre, J.; Palomo, A. L. Synthesis 1984, 413.
18. See, for instance: (a) Rey, M.; Roberts, S. M.; Dreiding, A. S.; Roussel, A.; Vanlierde, H.; Toppet, S.; Ghosez, L.
Helvetica Chim. Acta 1982, 65, 703. (b) Snider, B. B.; Hui, R. A. H. F. J. Org. Chem. 1985, 50, 5167. (c) Snider,
B. B.; Allento€, A. J.; Walner, M. B. Tetrahedron 1990, 46, 8031.
19. Krow, G. R. Oganic Reactions 1993, 43, 251.
20. Batchmin of Macromodel Version 4.5 (Columbia Univ. New York), Amber* Force Field, united atoms, Monte
Carlo stocastic algorithm with 5000 generated structures, minimization by PR conjugate gradient, energy window
12 kcal/mol. All the rotatable bonds were explored.
21. Structures generated by the conformational search were further optimized with the MMX force ®eld (PC Model
4.0, Serena Software, Bloomington, IN). Energy comparison refers to MMX computed structures.