Enantioselective diels-alder reactions of chiral racemic acyclic dienes with (SS)-2-(p-tolylsulfinyl)-1,4-naphthoquinone

Article abstract of DOI:10.1016/S0957-4166(98)00323-1

Enantiopure sulfinylnaphthoquinone (+)-1 reacted with racemic acyclic dienes 2a-f bearing a stereogenic allylic center, through a tandem cycloaddition/pyrolytic sulfenic acid elimination, to afford enantio-enriched compounds 4a-f and 5a-f with good like:unlike selectivities (ca. 75:25) and good enantiomeric excesses (68-82%), arising from the partial kinetic resolution of the racemic dienes.

Full text of DOI:10.1016/S0957-4166(98)00323-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2965–2969
Enantioselective Diels–Alder reactions of chiral racemic acyclic
dienes with (SS)-2-(p-tolylsulfinyl)-1,4-naphthoquinone
M. Carmen Carreño,∗ Susana García-Cerrada, Antonio Urbano and Claudio Di Vitta †
Departamento de Química Orgánica (C-I), Universidad Autónoma, Cantoblanco, 28049 Madrid, Spain
Received 10 July 1998; accepted 10 August 1998
Abstract
Enantiopure sulfinylnaphthoquinone(+)-1 reacted with racemic acyclic dienes 2a–f bearing a stereogenic allylic
center, through a tandem cycloaddition/pyrolytic sulfenic acid elimination, to afford enantio-enriched compounds
4a–f and 5a–f with good like:unlike selectivities (ca. 75:25) and good enantiomeric excesses (68–82%), arising
from the partial kinetic resolution of the racemic dienes. © 1998 Elsevier Science Ltd. All rights reserved.
Among the stereochemical features of Diels–Alder reactions, π-facial diastereoselectivity has been
the subject of increasing attention in order to understand the factors responsible for the excellent
results observed and further develop stereocontrolled routes for the synthesis of natural products.
Both theoretical and experimental studies have focused on chiral dienophiles and/or chiral dienes1–4
bearing a single stereogenic center at the allylic position. Distinct works, concerned with three sets of
experimental results for cyclic,1a,2 semicyclic2b,3 and acyclic1a,2b,4 dienes, showed that good to excellent
π-facial diastereoselectivities could be achieved by the proper choice of allylic substituent and by the
introduction of an adequate cis-substituent at C-2 on the diene framework.4g In spite of such good
results, enantioselective synthetic applications of these kind of dienes are limited due to the difficulties
encountered in obtaining homochiral derivatives.4f
In connection with our work devoted to the use of enantiopure sulfoxides in asymmetric synthesis,5
we have shown the ability of the sulfinyl group situated on a quinonic framework to promote a double
induction in a Diels–Alder cycloaddition, leading to the efficient resolution of some chiral racemic
semicyclic dienes containing a stereogenic allylic carbon.6 The tandem Diels–Alder reaction/pyrolytic
sulfenic acid elimination, in addition to the resolution of semicyclic dienes occurring with optically pure
sulfinyl quinones, is now established as a general one-pot strategy to enantiomerically enriched polycyclic
hydroquinones.
In order to extend these excellent results, we decided to investigate if such a double asymmetric
induction process could also take place with acyclic dienes bearing a stereogenic allylic substituent. In
∗
†
Corresponding author. E-mail: carmen.carrenno@uam.es
On leave from Instituto de Química da Universidade de São Paulo, Brazil.
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00323-1
tetasy 2472 Communication

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this paper we report the study of Diels–Alder reactions of enantiomerically pure (SS)-2-(p-tolylsulfinyl)-
1,4-naphthoquinone 17 with several chiral racemic open-chain dienes 2a–f, showing a carbinol and a
different type of substitution at the allylic position.
Hexadiene derivatives 2b8 and 2c4a were prepared from known dienol 2a9 following conven-
tional procedures in 63% and 71% yields, respectively (Scheme 1). The synthesis of 5-phenyl sub-
stituted pentadienes 2d–f was carried out starting from phenylketone 3.10 Luche reduction with
NaBH4/CeCl3 allowed the carbinol 2d12 to be obtained, whose treatment with MOMCl–DIPEA and
11
TBDMSCl–imidazole afforded dienes 2e8 and 2f8 in 66% and 67% yields, respectively (Scheme 1).
Scheme 1.
Diels–Alder cycloadditions of (+)-1 and 2 were carried out in CH2Cl2 and the results are collected
in Table 1. As can be seen, methylsubstituted dienes 2a–c and phenylcarbinol 2d reacted at rt (48–72
h) whereas phenyl-substituted dienes 2e,f only proceeded under reflux of the solvent. In all cases,
after pyrolytic elimination of the sulfinyl group in the initially formed cycloadducts, we obtained a
diastereoisomeric mixture of compounds 4 and 5.
Cycloaddition between (+)-1 and dienol 2a afforded a non separable 70:30 mixture of 4a8,13 and
5a8,13 in enantio-enriched 31% yield. The ee of both adducts was determined after transformation into
the separable mixture of OMOM ethers 4b and 5b [CH2(OMe)2, P2O5, CHCl3, rt, 1 h, 22%],14 by
using Pr(hfc)3 (70% for 4a) and Eu(hfc)3 (74% for 5a) as chiral lanthanide shift reagents.15 These
enantio-purities were the result of the partial kinetic resolution of the racemic diene partner. In the
Table 1
Diels–Alder reactions of enantiopure sulfinylquinone (+)-1 and chiral racemic dienes 2a–f

M. C. Carreño et al. / Tetrahedron: Asymmetry 9 (1998) 2965–2969
2967
Fig. 1.
same way, reaction of (+)-1 and diene 2b yielded a 75:25 mixture of compounds (+)-4b8,13 (ee=82%)
and (+)-5b8,13 (ee=80%). In this case, we could recover unreacted diene (+)-2b in optically active form
{[α]D20=+19.3 (c 2.4, CHCl3)}. Finally, cycloaddition of (+)-1 with diene 2c, gave a non separable 75:25
mixture of compounds 4c8,13 and 5c8,13 in 45% yield. The enantio-purity of these derivatives could not
be determined at this stage and thus, we transformed the mixture of 4c and 5c into the corresponding
mixture of OMOM derivatives 4b and 5b (i. HF, CH3CN, rt, 1 h; ii. CH2(OMe)2, P2O5, CHCl3, rt, 1 h,
24%). After chromatographic separation, we could establish a 68% of ee for 4c and 72% for 5c.
Diels–Alder reactions of (+)-1 with phenyl-substituted dienes 2d–f followed a similar pattern. Cyclo-
addition with dienol 2d afforded a 75:25 mixture of 4d8,13 and 5d8,13 that could be separated by flash
chromatography. The ee of both adducts was determined after transformation into the OMOM ethers 4e
and 5e by using Pr(hfc)3 (74% for 4d) and Eu(hfc)3 (66% for 5d) as chiral lanthanide shift reagents.
Reaction of (+)-1 and diene 2e yielded a nonseparable 75:25 mixture of compounds 4e8,13 (ee=68%) and
5e8,13 (ee=68%). Finally, cycloaddition of (+)-1 with diene 2f, gave a 76:24 mixture of compounds 4f8,13
and 5f8,13 in 51%. The enantio-purity of these derivatives could only be determined after transformation
of the mixture of 4f and 5f into the epoxides 68,13 and 78,13 (m-CPBA, CH2Cl2, 68%). We could determine
an ee of 68% for 4f and 72% for 5f by using Pr(hfc)3 as a chiral lanthanide shift reagent.
In accordance with our previous results from other cycloadditions with similar dienophiles,5,6 the ma-
jor evolution of sulfinylnaphthoquinone 1 through the less hindered upper face of the S-cis conformation
represented in Fig. 1, accounts for the (S) configuration at C-1 of the resulting 1,4-dihydroanthraquinones
4 and 5 (Table 1), assuming a complete endo addition.
Compounds 4, resulting from the unlike16 (R=Me) and like16 approaches (R=Ph), are the major
products in all cycloadditions. To account for this preferred evolution, we must consider the confor-
mational arguments already invoked for this kind of reaction,4a,h as well as the interactions emerging
in the transition states: cycloadditions must take place through conformers which are staggered with
respect to forming bonds.17 As represented in Fig. 1, three transition states A, B and C, giving rise to
diastereoisomers 4, result from an unlike approach (R=Me).18 The most favored situation corresponds to
A where the largest R group of the allylic center of the diene is oriented anti, being the smallest H on the
same face of the attacking sulfinyl dienophile. In approaches B and C, the R and OR groups are situated
at the same side of the approaching dienophile giving rise to unfavourable steric and/or electrostatic
interactions. Thus, approach A would explain the favored reaction of the (R) enantiomer of the diene
(R=Me) through the matched pair and the observed resolution to give the major isomer 4.19
A similar analysis for like approaches (R=Me) D–F yielding derivatives 5, reveals that D and F show
similar destabilizing interactions, (OR in D and R in F are situated on the same side of the approaching

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dienophile). For E approach, where the smallest H is on the bottom side of the diene, the bulky R group
is in a gauche disposition with respect to the C2–C3 double bond and also in the face of the approaching
dienophile. This could be the origin of the formation of minor compounds 5. The matched pair in this like
approach arose from the evolution of (S)-2a–c or (R)-2d–f dienes. According to previous results, π-facial
diastereoselectivity of cycloadditions with sulfinylquinones strongly increases with low temperatures.
Thus, the moderate reactivity of dienes 2, which reacted at rt or 40°C could justify the formation of a
minor amount (9–16%) of the corresponding enantiomers of 4 and 5 (see Table 1).
In summary, the enantioselective reaction of acyclic dienes bearing an allylic stereogenic center
with (S)-2-p-tolylsulfinyl-1,4-naphthoquinone is reported as a useful synthetic approach to chiral 1,4-
dihydro-9,10-anthraquinone derivatives which takes advantage of the kinetic resolution of racemic dienes
observed in these processes. The extension of this methodology to the synthesis of other quinones of
interest is under way.
Acknowledgements
We thank Dirección General de Investigación Científica y Técnica (Grant PB95-0174) for financial
support. CDV thanks FAPESP-Fundação de Amparo à Pesquisa do Estado de São Paulo for a post-
doctoral fellowship.
References
1. (a) Kahn, S. D.; Hehre, W. J. J. Am. Chem. Soc. 1987, 109, 663–666. (b) Paquette, L. A.; Lin, H. S.; Gunn, B. P.; Coghlan,
M. J. J. Am. Chem. Soc. 1988, 110, 5818–5826. (c) Haller, J.; Niwayama, S.; Duh, H. Y.; Houk, K. N. J. Org. Chem. 1997,
62, 5728–5731.
2. (a) Macaulay, J. B.; Fallis, A. G. J. Am. Chem. Soc. 1988, 110, 4074–4076. (b) Macaulay, J. B.; Fallis, A. G. J. Am. Chem.
Soc. 1990, 112, 1136–1144. (c) Winterfeldt, E. Chem. Rev. 1993, 93, 827–843. (d) Letourneau, J. E.; Wellman, M. A.;
Burnell, D. J. J. Org. Chem. 1997, 62, 7272–7277. (e) Xidos, J. D.; Poirier, R. A.; Pye, C. C.; Burnell, D. J. J. Org. Chem.
1998, 63, 105–112.
3. (a) Fisher, M. J.; Overman, L. E. J. Org. Chem. 1988, 53, 2630–2634. (b) Fisher, M. J.; Hehre, W. J.; Kahn, S. D.; Overman,
L. E. J. Am. Chem. Soc. 1988, 110, 4625–4633. (c) Datta, S. C.; Franck, R. W.; Tripathy, R.; Quigley, G. J.; Huang, L.;
Chen, S.; Sihaed, A. J. Am. Chem. Soc. 1990, 112, 8472–8478. (d) Lee, J.; Li, J. H.; Oya, S.; Snyder, J. K. J. Org. Chem.
1992, 57, 5301–5312. (e) Larsen, D. S.; O’Shea, M. D. J. Chem. Soc., Perkin Trans. 1 1995, 1019–1028.
4. (a) Tripathy, R.; Franck, R. W.; Onan, K. D. J. Am. Chem. Soc. 1988, 110, 3257–3262. (b) Trost, B. M.; Lee, D. C.
J. Org. Chem. 1989, 54, 2271–2274. (c) McDougal, P. G.; Jump, J. M.; Rojas, C.; Rico, J. G. Tetrahedron Lett. 1989,
30, 3897–3900. (d) Kaila, N.; Franck, R. W.; Dannenberg. J. J. J. Org. Chem. 1989, 54, 4206–4212. (e) Barluenga, J.;
González, F. J.; Fustero, S.; García-Granda, S.; Pérez-Carreño, E. J. Org. Chem. 1991, 56, 4459–4463. (f) Bloch, R.;
Chaptal-Gradoz, N. J. Org. Chem. 1994, 59, 4162–4169. (g) Adam, W.; Gläser, J.; Peters, K.; Prein, M. J. Am. Chem. Soc.
1995, 117, 9190–9193.
5. For an overview of our work, see: (a) Carreño, M. C. Chem. Rev. 1995, 95, 1717–1760. For more recent references, see: (b)
Carreño, M. C.; García Ruano, J. L.; Toledo, M. A.; Urbano, A.; Remor, C. Z.; Stefani, V.; Fischer, J. J. Org. Chem. 1996,
61, 503–509. (c) Carreño, M. C.; García Ruano, J. L.; Urbano, A.; Hoyos, M. A. J. Org. Chem. 1996, 61, 2980–2985. (d)
Carreño, M. C.; García Ruano, J. L.; Urbano, A.; López-Solera, M. I. J. Org. Chem. 1997, 62, 976–981. (e) Carreño, M.
C.; García Ruano, J. L.; Remor, C. Z.; Urbano, A.; Fischer, J. Tetrahedron Lett. 1997, 38, 9077–9080.
6. Carreño, M. C.; Urbano, A.; Fischer, J. Angew. Chem., Int. Ed. Engl. 1997, 36, 1621–1623.
7. Carreño, M. C.; García Ruano, J. L.; Urbano, A. Synthesis 1992, 651–653.
8. All new compounds were characterized on the basis of their 1H NMR (300 MHz, CDCl3) and 13C NMR (75 MHz, CDCl3)
spectral data.
9. Shackelford, J. M.; Schwartzman, L. H. J. Org. Chem. 1962, 27, 1047–1049.
10. Yu, Y.; Lin, R.; Zhang, Y. Tetrahedron Lett. 1993, 34, 4547–4550.

M. C. Carreño et al. / Tetrahedron: Asymmetry 9 (1998) 2965–2969
2969
11. Gemal, A. L.; Luche, J. L. J. Am. Chem. Soc. 1981, 103, 5454–5459.
12. Kozima, S.; Ishii, T.; Tsuboi, T.; Kawanisi, M.; Mizuno, M.; Hitomi, T. Chem. Express 1987, 2, 301–304.
13. Configurational assignments of derivatives 4a–f and 5a–f were established from NOE experiments.
14. Fuji, K.; Nakano, S.; Fujita, E. Synthesis 1975, 276–277.
15. The racemic compounds necessary for such evaluation were prepared from the corresponding racemic sulfinylquinone
(ꢀ)-1 (see Ref. 7).
16. We follow Franck’s lead in utilizing this nomenclature, see: Ref. 4a, ftnt 5. See also, Seebach, D.; Prelog, V. Angew. Chem.,
Int. Ed. Engl. 1982, 21, 654–660.
17. (a) Caramella, P.; Rondan, N. G.; Paddon-Row, M. N.; Houk, K. N. J. Am. Chem. Soc. 1981, 103, 2438–2440. (b) Paddon-
Row, M. N.; Rondan, N. G.; Houk, K. N. J. Am. Chem. Soc. 1982, 104, 7162–7166.
18. The discussion is focused on methyl substituted dienes 2a–c. Although the stereochemical descriptor changes from R=Me
to R=Ph, the relative stability of the transition states is similar in both cases.
19. For phenyl substituted dienes 2d–f, the (S) enantiomer reacts faster.