Asymmetric N-sulfinyl dienophile Diels-Alder cycloadditions using chiral T1(IV)-based Lewis acids

Article abstract of DOI:10.1016/S0040-4039(00)00480-9

Enantioselective Diels-Alder reactions of 1,3-cyclohexadiene with N- sulfinylbenzyl carbamate (1a) or N-sulfinyl-p-toluenesulfonamide (1b) promoted by chiral Ti(IV)-based Lewis acids are reported. The endo-adducts were obtained in 15-76% ee. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00480-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3743–3746
Asymmetric N-sulfinyl dienophile Diels–Alder cycloadditions
using chiral Ti(IV)-based Lewis acids
Annette Bayer and Odd R. Gautun ∗
Department of Chemistry, Faculty of Science, University of Tromsø, NO-9037 Tromsø, Norway
Received 16 February 2000; accepted 21 March 2000
Abstract
Enantioselective Diels–Alder reactions of 1,3-cyclohexadiene with N-sulfinylbenzyl carbamate (1a) or N-
sulfinyl-p-toluenesulfonamide (1b) promoted by chiral Ti(IV)-based Lewis acids are reported. The endo-adducts
were obtained in 15–76% ee. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: asymmetric inductions; Diels–Alder reactions; N-sulfinyl compounds; titanium and compounds.
Hetero [4+2]-cycloadditions of N-sulfinylaniline to conjugated dienes were first described by Wich-
terle and Rocek in 1953.1 Since then a number of Diels–Alder reactions for various types of N-
sulfinyl compounds have been reported.2–8 The resulting heterocyclic products can be further transform-
ed into synthetically useful derivatives, e.g. homoallyl amines and vicinal aminoalcohols, by well-
established techniques.7 Stereoselective Diels–Alder reactions with chiral N-sulfinyl dienophiles9,10 or
chiral dienes11 have given optically active adducts with high diastereoselectivity (>97%). However, no
reports of Diels–Alder reactions with N-sulfinyl dienophiles utilising chiral Lewis acid catalysts to induce
enantioselectivity have been found. Herein, we present enantio- and diastereoselective Diels–Alder
reactions of 1,3-cyclohexadiene and N-sulfinyl compounds 1a12 or 1b3 promoted by chiral Ti(IV)-based
Lewis acids (Table 1).
Initial studies using titanium catalysts prepared in situ from titanium sources such as TiCl2(O-i-Pr)2,13
TiCl4 or Ti(O-i-Pr)4 and the bidentate ligands 3a,14 3c,15 and 3d16 following established methods,14,16,17
afforded low and/or not reproducible yields of the Diels–Alder products 2. However, by turning to the
thermally labile precursor Me2TiCl2,18 more reliable results were obtained.
18
In general, the chiral catalyst was prepared by mixing Me2TiCl2 (approximately 5.0 mmol) and a
solution of the chiral diols 3a–c (5.0 mmol) in dry toluene (15 ml) under argon atm at −75°C. For the
ligands 3d–e, dichloromethane was used as solvent. The resulting solution was then allowed to reach
room temperature and thereafter diluted with toluene or dichloromethane (ca. 0.2 M, quantitative yield
was assumed). This solution was stored in the freezer (−20°C) in a sealed flask for up to 1 month without
detectable deterioration.
∗
Corresponding author. Tel: +47 77 64 40 69; fax: +47 77 64 47 37; e-mail: odd-reidar.gautun@chem.uit.no (O. R. Gautun)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00480-9
tetl 16759

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Table 1
Asymmetric Diels–Alder reactions of N-sulfinyl dienophiles 1a and 1b with 1,3-cyclohexadiene
promoted by chiral Ti(IV) Lewis acids
A typical experiment for the asymmetric Diels–Alder reaction using stoichiometric amounts of the
Ti(IV) complex was as follows: to a stirred solution of the chiral Ti(IV) complex (0.4 mmol) in toluene
(2 ml) a solution of 1a (0.4 mmol) in dry dichloromethane (0.34 ml) was added at −70°C and argon
atm. After 20 min a precooled solution of 1,3-cyclohexadiene (1.0 mmol) in toluene was added. The
reaction mixture was stirred for 20 h and then quenched with phosphate buffer (2 ml, pH=7). The
resultant mixture was heated to room temperature, the layers separated, and the aqueous phase extracted
with dichloromethane (3×5 ml, p.a. quality). The combined organics were dried (MgSO4), filtered and
1
concentrated in vacuo. The crude product was analysed by H NMR (400 MHz) to determine the
diastereomeric ratio and then purified by flash chromatography (ethyl acetate:n-pentane, 50:50). The
diastereomers were separated and the enantiomeric excess determined by chiral HPLC (Chiracel OJ;
2-PrOH:n-hexane, 35:65; 0.5 ml/min; UV detector, 230 nm).
The results of the enantioselective Diels–Alder reactions of the dienophiles 1a or 1b with 1,3-

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cyclohexadiene in the presence of the Ti(IV) complexes (1 equiv.) are shown in Table 1. The overall
yields of endo- and exo-isomers were 29–83% with the endo-isomer as the major product. The endo-
adduct 2 was formed with 15–76% ee. Interestingly, reactions promoted by the Ti(IV)–TADDOL-based
ligands 3a–c gave endo-2a (X=Cbz) and 2b (X=Ts) of opposite configuration. In addition, ligands 3a
and 3c behaved like ‘enantiomers’ in the way that they gave enantiomers of endo-2 as the predominant
product (compare entry 1 with 5, and entry 2 with 6). The best enantioselectivities, 76% ee for 1a (entry
5) and 74% ee for 1b (entry 6), were obtained with ligand 3c. In general, the 1,4-diol ligands 3a–c were
superior to the 1,2-diols 3d–e with respect to yield and selectivity. While 1,4-diols constitute the optimal
ligands for chelated titanium complexes, 1,2-diols most likely form aggregates to reduce ring strain.19
The relative configuration of the cycloadducts 2 were determined by considering the shielding effect
of the ‘S_O’ group similar to the work described by Zhang and Flann.20 The absolute configuration of
2a (X=Cbz) at C-3 and C-6 was established by chemical correlation with the known cyclic carbamate
721 using Weinreb’s methodology10 (see Scheme 1). The endo-2a obtained in entry 1 (Table 1) was
rearranged to hydroxy carbamate 5 and then cyclized to carbamate 6. Catalytic hydrogenation of 6
20
provided (1R,2S)-721 ([α] +17.9 (c 1.1, abs. EtOH)) and thus endo-2 (entry 1, Table 1) had the
D
(2S,3R,6S)-configuration.
Scheme 1. (a) PhMgBr, THF, −60°C, 0.5 h, 88%; (b) P(OMe)3, MeOH, 80°C, 93%; (c) t-BuOK, THF, 0°C, 1 h, 79%; (d) 5%
Rh–Al2O3, 1 atm H2, EtOAc:n-hexane (1:2), rt, 21 h, 47%
The absolute configuration of endo-2b (X=Ts) was determined by chemical correlation with endo-
2a (Scheme 2). The endo-2a obtained in entry 1 (Table 1) was rearranged to carbamate 8a followed
by deprotection and tosylation to yield tosylate (S)-8b. Compound endo-2b (entry 2) was rearranged to
tosylate (R)-8b, correspondingly. Comparison of the tosylates 8b by HPLC (Chiralpak AD column; abs.
EtOH:n-hexane, 1:9; 1.0 ml/min; UV detector, 230 nm) showed that endo-2b obtained in entry 2 had the
(2R,3S,6R) configuration.
Scheme 2. (a) (i) 1.25 M aq. NaOH, rt, 14 h; (ii) 0.5 M aq. HCl, 0°C, 10 min, 75% (Cbz), 34% (Ts); (b) (i) TMSI, MeCN, 0°C,
30 min; (ii) MeOH, rt, 10 min; (iii) TsCl, Et3N, CH2Cl2, rt, 21 h, 77%

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In summary, the first enantioselective hetero [4+2]-cycloaddition of N-sulfinyl dienophiles with 1,3-
cyclohexadiene have been achieved by using stoichiometric amounts of chiral titanium catalysts. Efforts
to develop new catalysts with the aim to increase the turnover and the enantioselectivities for these
reactions are now in progress.
Acknowledgements
We thank the Norwegian Research Council (grant 122792/410) for financial support.
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