Stereoselective routes to substituted β-amino carbonyl compounds via heterodiene cycloadditions of an auxiliary-based C2-symmetric ketene acetal

Article abstract of DOI:10.1016/S0040-4039(00)00407-X

Heterodiene cycloadditions of (S,S)-4,5-bis(o-tolyl)-2-methylene-1,3- dioxolane 1 with a series of substituted β-amido-α,β-unsaturated carbonyl compounds are diastereoselective (dr ≥ 4:1). The cycloadducts from N-(2-(1- oxoethyl)-3-oxobut-1-enyl)ethanamide 2a can be purified by crystallisation and hydrolysed with acid to generate the corresponding β-amidoacetic esters, the sequence providing an auxiliary-based stereoselective route to such compounds. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00407-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3501–3504
Stereoselective routes to substituted β-amino carbonyl
compounds via heterodiene cycloadditions of an auxiliary-based
C2-symmetric ketene acetal
Colin A. Ray,a Timothy W. Wallace a,∗ and Richard A. Ward b
aDepartment of Chemistry, University of Salford, Salford M5 4WT, UK
bDevelopment Chemistry 3, Glaxo Wellcome Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK
Received 11 February 2000; accepted 7 March 2000
Abstract
Heterodiene cycloadditions of (S,S)-4,5-bis(o-tolyl)-2-methylene-1,3-dioxolane 1 with a series of substituted
β-amido-α,β-unsaturated carbonyl compounds are diastereoselective (dr ≥4:1). The cycloadducts from N-(2-(1-
oxoethyl)-3-oxobut-1-enyl)ethanamide 2a can be purified by crystallisation and hydrolysed with acid to generate
the corresponding β-amidoacetic esters, the sequence providing an auxiliary-based stereoselective route to such
compounds. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: cycloadditions; ketene acetals; diastereoselection; amino acids and derivatives.
The [4π+2π] cycloaddition of α,β-unsaturated carbonyl compounds (1-oxabutadienes) to alkenes
can be an efficient route to dihydropyrans1 and the process has been exploited in synthesis.2 We have
developed a series of auxiliary-based C2-symmetric ketene acetals, e.g. 1, for use as the 2π components
of such reactions,3,4 and herein describe the results of a recently initiated study of their potential as a
source of homochiral β-amino acid derivatives (Scheme 1), which are valued synthetic intermediates.5
Related heterodiene cycloadditions have been used en route to racemic aminosugars6 and carbapenem
precursors,7 but a variant capable of providing useful levels of asymmetric induction remains an attractive
target.
Scheme 1.
∗
Corresponding author. Fax: +44 0 161-295-5111; e-mail: t.w.wallace@salford.ac.uk (T. W. Wallace)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00407-X
tetl 16687

3502
Our study was initiated with the simple amidodiene 2a,8 whose reaction with 1 equivalent of the
ketene acetal 14 in THF at −15°C over 5 days yielded a mixture of the cycloadducts 3a and 4a in
1
fair yield and a diastereoisomeric ratio (dr) of ca. 4:1 as judged by 250 MHz H NMR spectroscopy
(Table 1).9 Crystallisation of the mixture from isohexane (mainly 2-methylpentane) gave the cycloadduct
3a as colourless needles, m.p. 112–115°C. Cycloadditions of 1 with the β-acetamidoenoates 2b7 and
2c proceeded in similar fashion. Crystallisation of the mixed products from 2b yielded 3b as a single
isomer, while the purity of 3c was significantly improved by trituration with isohexane. The heterocyclic
aldehyde 5, prepared from 1,3-dimethyluracil by Vilsmeier formylation,10 was also found to react
diastereoselectively with 1, producing the fused spirocyclic pyrimidines 6+7 in moderate yield.
Scheme 2.
Table 1
The ortholactone function of the cycloadducts 3a+4a was hydrolysed upon brief treatment with acid
(0.1 M H2SO4, THF, 1 h), which generated the diastereoisomeric β-amidoesters 8 (56%) in essentially
1
the same ratio (4.25:1 by H NMR spectroscopy) as the educt mixture. In principle, the amidoesters 8
offer a second opportunity to isolate pure stereoisomers prior to the removal and recovery of the auxiliary
(S,S)-1,2-bis(o-tolyl)ethane-1,2-diol.4,11
The 4S configuration at the newly-generated stereocentre in the major products 3 is proposed on the
basis of the cycloaddition model 9, analogous to that advanced previously.3,4 The hydrogen-bonded
reacting conformations of the dienes (as depicted in Scheme 2) are supported for 2a by the results
of molecular modelling12 and for the esters 2b and 2c by the 13C NMR studies described by Bayles
et al.,7 which indicated that the preparative routes to these compounds predominantly gave rise to the
E-geometry shown. The preferential formation of 6 from the uracil-derived aldehyde 5 is tentatively
suggested on the basis of the results obtained using the structurally similar heterodiene, chromone-3-
carbaldehyde.3
The above results suggest that the sequence outlined in Scheme 1 could provide an effective stereo-
selective route to a variety of functionalised β-amino carbonyl systems based on a recyclable auxiliary

3503
strategy. Further synthetic and X-ray diffraction studies,13 which should confirm stereochemical assign-
ments, are in progress and will be described in due course.
Acknowledgements
We are grateful to the EPSRC and Glaxo Wellcome for a CASE studentship, and warmly thank Ron
Galt (ICI Pharmaceuticals) for a valuable discussion and experimental details. We extend our thanks to
Ruth Howard and Steve Simpson (Salford), and to Peter Moore (Glaxo Wellcome) for mass, X-ray and
NMR data, respectively.
References
1. For a review, see: Desimoni, G.; Tacconi, G. Chem. Rev. 1975, 75, 651–692.
2. Boger, D. L.; Weinreb, S. M. Hetero Diels–Alder Methodology in Organic Synthesis; Academic Press: London, 1987; pp.
167–213.
3. Wallace, T. W.; Wardell, I.; Li, K.-D.; Leeming, P.; Redhouse, A. D.; Challand, S. R. J. Chem. Soc., Perkin Trans. 1 1995,
2293–2308.
4. Hayes, R.; Li, K.-D.; Leeming, P.; Wallace, T. W.; Williams, R. C. Tetrahedron 1999, 55, 12 907–12 928.
5. For reviews, see: Juaristi, E.; Quintana, D.; Escalante, J. Aldrichimica Acta 1994, 27, 3–11; Cole, D. C. Tetrahedron 1994,
50, 9517–9582; Cardillo, G.; Tomasini, C. Chem. Soc. Rev. 1996, 25, 117–128; Enantioselective Synthesis of Beta-Amino
Acids; Juaristi, E., Ed.; Wiley: New York, 1997. For recent examples, see: Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999,
64, 12–13; Evans, D. A.; Wu, L. D.; Wiener, J. J. M.; Johnson, J. S.; Ripin, D. H. B.; Tedrow, J. S. J. Org. Chem. 1999, 64,
6411–6417; Roche, D.; Prasad, K.; Repic, O. Tetrahedron Lett. 1999, 40, 3665–3668; Kawakami, T.; Ohtake, H.; Arakawa,
H.; Okachi, T.; Imada, Y.; Murahashi, S.-I. Org. Lett. 1999, 1, 107–110; Miyabe, H.; Fujii, K.; Naito, T. Org. Lett. 1999, 1,
569–572.
6. For examples and leading references, see: Tietze, L. F.; Voss, E. Tetrahedron Lett. 1986, 27, 6181–6184; Tietze, L. F.;
Hartfiel, U. ibid. 1990, 31, 1697–1700. See also: De Gaudenzi, L.; Apparao, S.; Schmidt, R. R. Tetrahedron 1990, 46,
277–290, and references cited therein.
7. Bayles, R.; Flynn, A. P.; Galt, R. H. B.; Kirby, S.; Turner, R. W. Tetrahedron Lett. 1988, 29, 6341–6344; idem., ibid. 1988,
29, 6345–6348.
8. Claisen, L. Justus Liebigs Ann. Chem. 1897, 297, 1–98.
9. New compounds gave satisfactory analytical data. Typical procedure: A solution of ketene acetal 1 (0.6 mmol) and the
diene 2 (0.6 mmol) in THF (10 mL) was kept at −15°C until analysis by HPLC or TLC indicated that the reaction was
complete. The reaction mixture was then concentrated and the residue analysed by 250 or 300 MHz NMR spectroscopy
(in each case the dr at this stage was estimated to be ca. 4:1). The isolated materials described in Table 1 were obtained
as follows. Entry 1: The residue was taken up in CH2Cl2 (1 mL), filtered through a plug of basic alumina using more
CH2Cl2 and the filtrate concentrated to obtain the isolated product (dr by NMR). Entry 2: The residue was taken up in
CH2Cl2 and filtered through a plug of basic alumina using ethyl acetate:isohexane (1:4). Concentration and crystallisation
from ether:isohexane (1:1) gave the isolated product (dr by NMR). Entry 3: The residue was taken up in CH2Cl2, filtered
through a plug of basic alumina using ether:isohexane (2:1) and the filtrate concentrated to obtain the isolated product (dr
by HPLC). Trituration with isohexane gave material with dr 14:1 by HPLC. Entry 4: The residue was crystallised from
isohexane (dr by HPLC). Selected 1H NMR data (signals tentatively attributed to minor products in square brackets): 3a
[4a] (400 MHz) 1.70 [1.67] (3H, s, ArMe), 1.79 [1.76] (3H, s, ArMe), 1.93 [1.94] (3H, s, MeCON), 2.28 (3H, s, MeCOC),
2.37 (3H, s, 6-Me), 2.42–2.56 (2H, m, 3-H2), 5.27 [5.34] (1H, d, J=9 Hz, 40 or 50-H), 5.36–5.46 (1H, m, 4-H), 5.55 (1H,
d, J=9 Hz, 40 or 50-H), 6.17 [6.06] (1H, d, J=10 Hz, NH), 7.03–7.09 (2H, m, 3,30-ArH), 7.20–7.35 (4H, m, 4,40,5,50-ArH),
7.57 (2H, dd, J=2, 8 Hz, 6,60-ArH); 3b [4b] (250 MHz) 1.68 [1.65] (3H, s, ArMe), 1.78 [1.74] (3H, s, ArMe), 1.89 (3H,
s, MeCON), 2.44 (3H, s, 2-Me), 2.40–2.50 (2H, obscured m, 5-H2), 3.74 (3H, s, CO2Me), 5.28 (1H, d, J=9 Hz, 40-H or
50-H), 5.30–5.40 (1H, m, 4-H), 5.54 (1H, d, J=9 Hz, 40-H or 50-H), 6.00 (1H, d, J=9 Hz, NH), 7.06 (2H, d, J=7.5 Hz,
3,30-ArH), 7.20–7.35 (4H, m, 4,40,5,50-ArH), 7.57 (2H, d, J=8 Hz, 6,60-ArH); 3c [4c] (400 MHz) 1.69 (3H, s, ArMe), 1.77
(3H, s, MeCON), 1.79 (3H, s, ArMe), 2.20 (3H, s, Me), 2.39–2.48 (2H, m, 5-H2), 2.45 (3H, s, 2-Me), 5.06 (1H, d, J=12
Hz, OCHPh), 5.29 (1H, d, J=9 Hz, 50-H), 5.33 (1H, d, J=12 Hz, OCHPh), 5.37–5.45 (1H, m, 4-H), 5.54 [5.55] (1H, d, J=9

3504
Hz, 40-H), 5.97 [6.02] (1H, d, J=9.5 Hz, NH), 7.02–7.07 (2H, m, 3,30-ArH), 7.18–7.40 (9H, m, ArH), 7.57 (2H, br d, J=8
Hz, 6,60-ArH); 6 [7] (300 MHz) 1.66 (3H, s, ArMe), 1.77 (3H, s, ArMe), 2.27 (1H, t, J=12 Hz, 8-Hax), 2.75 (1H, dd, J=5,
12 Hz, 8-Heq), 3.07 [3.08] (3H, s, NMe), 3.23 [3.21] (3H, s, NMe), 4.40 (1H, ddd, J=2, 5, 12 Hz, 8-Ha), 5.31 (1H, d, J=9
Hz, 40-H), 5.58 [5.43] (1H, d, J=9 Hz, 50-H), 6.95–7.10 (2H, m, 3,30-ArH), 7.15–7.30 (4H, m, 4,40,5,50-ArH), 7.50–7.60
(2H, m, 6,60-ArH), 7.70 [7.62] (1H, d, J=2 Hz, 5-H); 8 (300 MHz) 1.80 (3H, s, ArMe), 1.87 (3H, s, ArMe), 1.92 (3H, s,
MeCON), 2.15 (3H, s, 20-Me), 2.24 (3H, s, 6-Me), 2.60 (1H, dd, J=7, 15 Hz, 2-H), 2.70 (1H, dd, J=7, 15 Hz, 2-H), 4.07
[4.24] (1H, d, J=6 Hz, 4-H), 5.10–5.20 (1H, m, 3-H), 5.24 (1H, d, J=9 Hz, 200-H), 6.11 (1H, d, J=9 Hz, 100-H), 6.74 (1H,
d, J=10 Hz, NH), 6.90–7.00 (2H, m, 3,30-ArH), 7.07–7.23 (4H, m, 4,40,5,50-ArH), 7.46 (1H, br d, J=8 Hz, 6-ArH), 7.60
(1H, br d, J=8 Hz, 60-ArH).
10. Botta, M.; Saladino, R.; Lamba, D.; Nicoletti, R. Tetrahedron 1993, 49, 6053–6070.
11. The ester 8 was readily hydrolysed with 5% NaOH in EtOH (20°C, 1 h) and the auxiliary diol recovered intact by adding
water and extracting with CH2Cl2.
12. The various possible reacting (s-cis) conformations of the heterodiene 2a were generated with CAChe 4.1.1 (Oxford
Molecular) and their geometries optimised using an augmented MM3 force field. The results indicate that the H-bonded
arrangement depicted in Scheme 2 is >4.9 kcal/mol more stable than the closest alternative.
13. A preliminary crystallographic investigation of a poorly diffracting crystal of 3a has confirmed the gross structure and
4S-configuration depicted.