Studies of diastereoselectivity in Diels-Alder reactions of enantiopure (SS)-2-(p-tolylsulfinyl)-l,4-naphthoquinone and chiral racemic acyclic dienes

Article abstract of DOI:10.1021/jo000210u

Enantiopure sulfinylnaphthoquinone (+)-5 reacted with racemic acyclic dienes 1a-f bearing a stereogenic allylic center, through a tandem cycloaddition/pyrolytic sulfoxide elimination, to afford optically enriched compounds 8a-f and 9a-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. The opposite diastereoselection (8g-i: 9g- i, up to 5:95)was observed in reactions with dienes 1g-i, having an additional methyl group at C-3, the enantiomeric purities being moderate (14- 25%). Steric effects and torsional interactions in the corresponding approaches account for the observed diastereoselectivities.

Full text of DOI:10.1021/jo000210u

J . Org. Chem. 2000, 65, 4355-4363
4355
Stu d ies of Dia ster eoselectivity in Diels-Ald er Rea ction s of
En a n tiop u r e (SS)-2-(p-Tolylsu lfin yl)-1,4-n a p h th oqu in on e a n d
Ch ir a l Ra cem ic Acyclic Dien es
M. Carmen Carren˜o,* Susana Garc´ıa-Cerrada, Antonio Urbano, and Claudio Di Vitta†
Departamento de Quı´mica Orga´nica (C-I), Universidad Auto´noma, Cantoblanco, 28049-Madrid, Spain
carmen.carrenno@uam.es
Received February 14, 2000
Enantiopure sulfinylnaphthoquinone (+)-5 reacted with racemic acyclic dienes 1a -f bearing a
stereogenic allylic center, through a tandem cycloaddition/pyrolytic sulfoxide elimination, to afford
optically enriched compounds 8a -f and 9a -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. The opposite diastereoselection (8g-i: 9g-i, up to 5:95) was observed in reactions with
dienes 1g-i, having an additional methyl group at C-3, the enantiomeric purities being moderate
(14-25%). Steric effects and torsional interactions in the corresponding approaches account for
the observed diastereoselectivities.
In tr od u ction
ability and predictive value of the proposed explanations
are not obvious at this stage and each system has to be
considered separately. Incorporation of a single stereo-
genic center in an allylic position of either a dienophile10
or a diene,11-13 particularly when a heteroatom is present,
also imparts sufficient perturbation to control the π-facial
The π-facial diastereoselectivity of Diels-Alder reac-
tions is a topic of current interest, from both synthetic
and theoretical points of view, which has been the subject
of several very recent reviews.1 Most part of the studies
focused on π-facially perturbed dienes2 and to a lesser
extent on dienophiles.3 The observed selectivities have
been accounted for in terms of steric,4 electronic5 or
torsional6 effects, product stability,7 orbital interactions,8
or hyperconjugation.9 Nevertheless, the general applic-
(8) See ref 3b and the following: (a) Gleiter, R.; Paquette, L. A. Acc.
Chem. Res. 1983, 16, 328. (b) Ishida, M.; Beniya, Y.; Inagaki, S.; Kato,
S. J . Am. Chem. Soc. 1990, 112, 8980. (c) Ishida, M.; Aoyama, T.;
Beniya, Y.; Yamabe, S.; Kato, S.; Inagaki, S. Bull. Chem. Soc. J pn.
1993, 66, 3430. (d) Ishida, M.; Kakita, S.; Inagaki, S. Chem. Lett. 1995,
469.
(9) (a) Chung, W.-S.; Turro, N. J .; Srivastava, S.; Li, H.; Le Noble,
W. J . J . Am. Chem. Soc. 1988, 110, 7882. (b) Macaulay, J . B.; Fallis,
A. G. J . Am. Chem. Soc. 1990, 112, 1136. (c) Li, H.; le Noble, W. J .
Recl. Trav. Chim. Pays-Bas 1992, 115, 199. (d) Coxon, J . M.; McDonald,
D. Q. Tetrahedron Lett. 1992, 33, 651. (e) Poirier, R. A.; Pye, C. C.;
Xidos, J . C.; Burnell, D. J . J . Org. Chem. 1995, 60, 2328.
(10) See ref 5a and the following. (a) Paquette, L. A.; Lin, H. S.;
Gunn, B. P.; Coghlan, M. J . J . Am. Chem. Soc. 1988, 110, 5818. (b)
Haller, J .; Niwayama, S.; Duh, H. Y.; Houk, K. N. J . Org. Chem. 1997,
62, 5728.
(11) See refs 4f, 5a, 9b, and the following: (a) Macaulay, J . B.; Fallis,
A. G. J . Am. Chem. Soc. 1988, 110, 4074. (b) Macaulay, J . B.; Fallis,
A. G. J . Am. Chem. Soc. 1990, 112, 1136. (c) Winterfeldt, E. Chem.
Rev. 1993, 93, 827. (d) Burry, L. C.; Miller, D. O.; Burnell, D. J . J .
Chem. Soc., Perkin Trans. 1 1998, 3825. (e) Xidos, J . D.; Poirier, R. A.;
Burnell, D. J . Tetrahedron Lett. 2000, 41, 995.
(12) See ref 9b and the following: (a) Fisher, M. J .; Overman, L. E.
J . Org. Chem. 1988, 53, 2630. (b) Fisher, M. J .; Hehre, W. J .; Kahn, S.
D.; Overman, L. E. J . Am. Chem. Soc. 1988, 110, 4625. (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. (d) Lee, J .; Li, J . H.;
Oya, S.; Snyder, J . K. J . Org. Chem. 1992, 57, 5301. (e) Larsen, D. S.;
O’Shea, M. D. J . Chem. Soc., Perkin Trans. 1 1995, 1019.
(13) See refs 5a, 9b, and the following: (a) Franck, R. W.; Argade,
S.; Subramanian, C. S.; Frechet, D. M. Tetrahedron Lett. 1985, 26,
3187. (b) McDougal, P. G.; Rico, J . G.; Van Derveer, D. J . Org. Chem.
1986, 51, 4492. (c) Reitz, A. B.; J ordan, A. D., J r.; Maryanoff, B. E. J .
Org. Chem. 1987, 52, 4800. (d) Kozikowski, A. P.; Nieduzak, T. R.;
Konoike, T.; Springer, J . P. J . Am. Chem. Soc. 1987, 109, 5167. (e)
Tripathy, R.; Franck, R. W.; Onan, K. D. J . Am. Chem. Soc. 1988, 110,
3257. (f) Trost, B. M.; Lee, D. C. J . Org. Chem. 1989, 54, 2271. (g)
McDougal, P. G.; J ump, J . M.; Rojas, C.; Rico, J . G. Tetrahedron Lett.
1989, 30, 3897. (h) Kaila, N.; Franck, R. W.; Dannenberg. J . J . J . Org.
Chem. 1989, 54, 4206. (i) Barluenga, J .; Gonza´lez, F. J .; Fustero, S.;
Garc´ıa-Granda, S.; Pe´rez-Carren˜o, E. J . Org. Chem. 1991, 56, 4459.
(j) Bloch, R.; Chaptal-Gradoz, N. J . Org. Chem. 1994, 59, 4162. (k)
Adam, W.; Gla¨ser, J .; Peters, K.; Prein, M. J . Am. Chem. Soc. 1995,
117, 9190. (l) Crisp, G. T.; Gebauer, M. G. J . Org. Chem. 1996, 61,
8425.
† On leave from Instituto de Quimica da Universidade de Sa˜o Paulo,
Brazil.
(1) (a) Coxon, J . M.; Froese, R. D. J .; Ganguly, B.; Marchand, A. P.;
Morokuma, K. Synlett. 1999, 1681. (b) Cieplak, A. S. Chem. Rev. 1999,
99, 1265. (c) Ohwada, T. Chem. Rev. 1999, 99, 1337.
(2) (a) Watson, W. H. Stereochemistry and Reactivity of Systems
Containing π Electrons; Verlag Chemie International: Deerfield Beach,
FL, 1983. (b) Trost, B. M.; Fleming, I., Eds.; Paquette, L. A., 5th Volume
Ed. Comprehensive Organic Synthesis; Pergamon Press: Oxford, U.
K., 1991; Vol. 5, Chapter 4. For recent references, see: (c) Tsuji, M.;
Ohwada, T.; Shudo, K.; Tetrahedron Lett. 1998, 39, 403. (d) Mehta,
G.; Uma, R.; J agadeesh, M. N.; Chandrasekhar, J . Chem. Commun.
1998, 1813. (e) Marchand, A. P.; Ganguly, B.; Shukla, R. Tetrahedron
1998, 54, 4477. (f) Mehta, G.; Uma, R. J . Org. Chem. 2000, 65, 1685.
(3) See, for instance: (a) Mehta, G.; Padma, S.; Pattabhi, V.;
Pramanik, A.; Chandrasekhar, J . J . Am. Chem. Soc. 1990, 112, 2942.
(b) Okamoto, I.; Ohwada, T.; Shudo, K. J . Org. Chem. 1996, 61, 3155.
(c) Carren˜o, M. C.; Garc´ıa Ruano, J . L.; Urbano, A.; Lo´pez-Solera, M.
I. J . Org. Chem. 1997, 62, 976.
(4) (a) Burnell, D. J .; Valenta, Z. Can. J . Chem. 1991, 69, 179. (b)
Tsuji, T.; Ohkita, M.; Nishida, S. J . Org. Chem. 1991, 56, 997. (c)
Ishihara, K.; Yamamoto, H. J . Am. Chem. Soc. 1994, 116, 1561. (d)
Mikami, K.; Motoyama, Y.; Terada, M. J . Am. Chem. Soc. 1994, 116,
2812. (e) Corey, E. J .; Sarshar, S.; Lee, D. H. J . Am. Chem. Soc. 1994,
116, 12089. (f) Xidos, J . D.; Poirier, R. A.; Pye, C. C.; Burnell, D. J . J .
Org. Chem. 1998, 63, 105.
(5) (a) Kahn, S. D.; Hehre, W. J . J . Am. Chem. Soc. 1987, 109, 663.
(b) Fotiadu, F.; Michel, F.; Buono, G. Tetrahedron Lett. 1990, 31, 4863.
(c) Roush, W.; Brown, B. B. J . Org. Chem. 1992, 57, 3380. (d) Coxon,
J . M.; Fong, S. T.; McDonald, D. Q.; Steel, P. J .Tetrahedron Lett. 1993,
34, 163. (e) Paquette, L. A.; Branan, B. M.; Rogers, R. D.; Bond, A. H.;
Lange, H.; Gleiter, H. J . Am. Chem. Soc. 1995, 117, 5992.
(6) (a) Brown, F. K.; Houk, K. N. J . Am. Chem. Soc. 1985, 107, 1971.
(b) Houk, K. N.; Li, Y.; Evanseck, J . D. Angew. Chem., Int. Ed. Engl.
1992, 31, 1, 682. (c) Houk, K. N.; Gonza´lez, J .; Li, Y. Acc. Chem. Res.
1995, 28, 81.
(7) (a) Avenati, M.; Vogel, P. Helv. Chim. Acta 1983, 66, 1279. (b)
Pinkerton, A. A.; Schwarzenbach, D.; Birbaum, J . L.; Carrupt, P. A.;
Schwager, L.; Vogel, P. Helv. Chim. Acta 1984, 67, 1136.
10.1021/jo000210u CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/13/2000

4356 J . Org. Chem., Vol. 65, No. 14, 2000
Carren˜o et al.
Sch em e 1a
diastereoselection, although the exact factors responsible
for the observed selectivities are still imperfectly under-
stood. Distinct works, concerned with three sets of
experimental results for cyclic,11 semicyclic12 and acyclic13
dienes, uplighted that good to excellent π-facial diaste-
reoselectivities could be achieved by proper choice of the
allylic substituent. Rationalization of the results obtained
with rigid cyclic and semicyclic dienes proposed steric and
electronic effects of heteroatom substituents as respon-
sible of differentiation between the diastereotopic π faces.
The conformational flexibility of open-chain dienes sig-
nificantly enhances the complexity of mechanistic and
stereochemical interpretations. This problem has been
partially circumvented13a-c,k by the introduction of a
substituent in the cis position adjacent to the stereogenic
center. Allylic strain14 emerging in such 1,2-substituted
dienes is able to fix a conformation of the stereogenic unit
in the transition state and, thus discriminate between
the diastereotopic faces, enhancing π-facial selectivities.
Despite the good results achieved, enantioselective syn-
thetic applications of this kind of dienes are limited due
to the difficulties encountered in the synthesis of optically
pure derivatives.13c,g,15
In connection with a research program devoted to the
use of enantiopure sulfoxides in asymmetric synthesis,
we found that the sulfinyl group situated on a quinonic
framework could control the regiochemistry, endo selec-
tivity, and π-facial diastereoselectivity of its Diels-Alder
cycloadditions with a wide range of cyclic and acyclic
dienes.16 We established the domino Diels-Alder reac-
tion/pyrolytic sulfoxide elimination as a general one-pot
strategy to enantiomerically enriched polycyclic quinones.
More recently, looking for an enantioselective approach
to angucyclinones,17 we uncovered the ability of the
sulfinyl group to promote a double asymmetric induc-
tion18 in the cycloaddition process, leading to the efficient
kinetic resolution of some chiral racemic vinylcyclo-
hexenes containing a stereogenic allylic carbon.19 This
methodology allowed the total enantioselective synthesis
of several angucyclinones.20
a
Key: (a) MOMCl, DIPEA, CH2Cl2, rt, 3 h; (b) TBDMSCl,
imidazole, DMF, rt, overnight; (c) NaBH4, CeCl3‚7H2O, MeOH, rt,
1 h; (d) (i) CH2dCHMgBr, THF, -78 °C to 0 °C; (ii) HCl 10%, rt,
1 h, 35%.
several chiral racemic open-chain dienes 1a -f, possesing
a carbinol22 and different sterically demanding substit-
uents at the allylic position, and 1g-i possessing an
additional methyl substituent at C-3.
Resu lts
Syn th esis of Dien es. Dienol 1a (Scheme 1), with a
methyl substituent at the allylic position, was prepared
according to a previously reported procedure.23 The
methoxymethyloxy (OMOM) derivative 1b was obtained
from 1a in 63% yield by reaction with MOMCl and
diisopropylethylamine (DIPEA). Treatment of 1a with
tert-butyldimethylsilyl chloride (TBDMSCl) and imida-
zole gave a 71% yield of diene 1c.13e Starting from known
phenylbutadienyl ketone 2,24 we synthesized 5-phenyl
substituted pentadienes 1d -f as follows. Luche reduc-
tion25 of 2 gave a 91% yield of carbinol 1d ,26 whose
treatment with MOMCl-DIPEA or TBDMSCl-imidazole
afforded dienes 1e and 1f in 66% and 67% yields,
respectively (Scheme 1).
The required 5-methyl substituted dienes 1g-i, bear-
ing an additional methyl group at C-3, were prepared as
outlined in Scheme 1. Addition of vinylmagnesium bro-
mide on commercially available 2,4-pentanedione 3 fol-
lowed by acidic treatment gave rise, after flash chroma-
tography, to a 35% yield of 4-methyl-3,5-hexadien-2-one
(4)27 as an inseparable 75:25 mixture of E and Z isomers.
Luche reduction of 4 afforded in 85% yield carbinol 1g,
which after protection with either MOMCl/DIPEA or
TBDMSCl/imidazole led respectively to derivatives 1h
(50% yield) and 1i (97% yield). All dienes 1g-i were used
in the cycloadditions as a 75:25 mixture of E and Z
isomers since a higher reactivity of E isomer in Diels-
Alder reaction was expected.
To extend these excellent results, we decided to inves-
tigate if such a double asymmetric induction process
could also take place with racemic acyclic dienes bearing
a stereogenic allylic substituent. In this paper,21 we
report the study of Diels-Alder reactions of enantiomeri-
cally pure (SS)-2-(p-tolylsulfinyl)-1,4-naphthoquinone with
(14) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841.
(15) (a) Hatakeyama, S.; Sugawara, K.; Takano, S. J . Chem. Soc.,
Chem. Commun. 1991, 1533. (b) Gebauer, M. G.; Crisp, G. T.
Tetrahedron 1996, 52, 12465. (c) Yu, C. M.; Lee, S. J .; J eon, M. J . Chem.
Soc., Perkin Trans 1 1999, 3557.
(16) For an overview, see: (a) Carren˜o, M. C. Chem. Rev. 1995, 95,
1717. For recent references, see: (b) Carren˜o, M. C.; Garc´ıa Ruano, J .
L.; Toledo, M. A.; Urbano, A.; Remor, C. Z.; Stefani, V.; Fischer, J . J .
Org. Chem. 1996, 61, 503. (c) Carren˜o, M. C.; Garc´ıa Ruano, J . L.;
Remor, C. Z.; Urbano, A.; Fischer, J .Tetrahedron Lett. 1997, 38, 9077.
(d) Carren˜o, M. C.; He´rnandez-Sa´nchez, R.; Mahugo, J .; Urbano, A. J .
Org. Chem. 1999, 64, 1387. (e) Carren˜o, M. C.; Garc´ıa Ruano, J . L.;
Urbano, A.; Remor, C. Z.; Arroyo, Y. J . Org. Chem. 2000, 65, 453.
(17) Carren˜o, M. C.; Urbano, A.; Fischer, J . Angew. Chem., Int. Ed.
Engl. 1997, 36, 1621.
Diels-Ald er Rea ction s. With the desired racemic
acyclic dienes in hand, we began the study of Diels-Alder
(18) Masamune, S.; Choy, W.; Petersen, J . S.; Sita, L. R. Angew.
Chem., Int. Ed. Engl. 1985, 24, 1.
(19) Carren˜o, M. C.; Urbano, A.; Di Vitta, C. J . Org. Chem. 1998,
63, 8320.
(22) For the sake of clarity, the numbered used for carbinols 1a , 1d
and 1g was the same as for the corresponding ethers.
(23) Shackelford, J . M.; Schwartzman, L. H. J . Org. Chem. 1962,
27, 1047.
(20) (a) Carren˜o, M. C.; Urbano, A.; Di Vitta, C. Chem. Commun.
1999, 817. (b) Carren˜o, M. C.; Urbano, A.; Di Vitta, C. Chem. Eur. J .
2000, 6, 906.
(21) Part of this work was previously communicated: Carren˜o, M.
C.; Garc´ıa-Cerrada, S.; Urbano, A.; Di Vitta, C. Tetrahedron: Asym-
metry 1998, 9, 2965.
(24) Yu, Y.; Lin, R.; Zhang, Y. Tetrahedron Lett. 1993, 34, 4547.
(25) Gemal, A. L.; Luche, J . L. J . Am. Chem. Soc. 1981, 103, 5454.
(26) Kozima, S.; Ishii, T.; Tsuboi, T.; Kawanisi, M.; Mizuno, M.;
Hitomi, T. Chem. Express 1987, 2, 301.
(27) Adams, D. R.; Bhatnagar, S. P.; Cookson, R. C.J . Chem. Soc.,
Perkin Trans 1 1975, 1502.

Reactions of Chiral Racemic Acyclic Dienes
J . Org. Chem., Vol. 65, No. 14, 2000 4357
Ta ble 1. Diels-Ald er Rea ction s of En a n tiop u r e Su lfin yln a p h th oqu in on e (+)-5 a n d 2 Equ iv of Ra cem ic Acyclic Dien es
1a -i in CH2Cl2
entry
diene
T (°C)
t (h)
products ratio
yield (%)
enantiomeric ratios
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1e
1f
1g
1g
1h
1h
1i
20
20
20
20
40
20a
40
20
0
48
72
72
48
24
24
24
24
72
8a (70) + 9a (30)
8b (75) + 9b (25)
8c (75) + 9c (25)
8d (75) + 9d (25)
8e (75) + 9e (25)
8e (75) + 9e (25)
8f (76) + 9f (24)
8g (9) + 9g (91)
8g (5) + 9g (95)
8h (40) + 9h (60)
8h (33) + 9h (67)
8i (33) + 8i (67)
31
36
57
83
40
60
51
66
88b
25
55
33
8a (85:15) + 9a (87:13)
8b (91: 9) + 9b (90:10)
8c (84:16) + 9c (86:14)
8d (87:13) + 9d (84:16)
c
8e (84:16) + 9e (84:16)
8f (84:16) + 9f (86:14)
c
9g (75:25)
c
8h (76:24) + 9h (57:43)
8i (60:40) + 9i (60:40)
10
11
12
20
20a
20
240
40
168
a
b
Cycloaddition performed at high pressure (4 kbar). Isolated yield for 9g. c Not determined.
cycloadditions choosing enantiomerically pure (SS)-2-(p-
tolylsulfinyl)-1,4-naphthoquinone (+)-528 as a model of
chiral dienophile. The influence of an array of different
reactions conditions was studied. The use of Lewis acids
was prevented due to the fast decomposition of the
dienes. The best results were achieved working in CH2-
Cl2 at different temperatures. Under these thermal
conditions, Diels-Alder reactions between quinone (+)-5
and 2 equiv of racemic dienes 1a -i, gave rise to variable
mixtures of optically active 1,4-dihydro-9,10-anthraquino-
nes 8a -i and 9a -i resulting from the spontaneous
pyrolytic elimination of the sulfoxide in the initially
formed and not detected cycloadducts 6a -i and 7a -i
(Scheme 2, Table 1). The diastereoisomeric 8:9 ratios,
reflecting the like/unlike29 selectivity of the cycloaddition
with respect to the chiral dienic system, were determined
directly from the crude reaction mixtures by integration
of well separated signals in the 1H NMR spectra. The
enantiomeric excesses of compounds 8 and 9 were
measured by 1H NMR using chiral lanthanide shift
reagents, which required the preparation of each racemic
derivative (()-8 and (()-9 from naphthoquinone (()-5.28
These values reflect the π-facial diastereoselection of the
cycloaddition with respect to the chiral sulfinyl dienophile
and the efficiency of the kinetic resolution of the racemic
diene partner. In several reactions, we could recover
unreacted dienes in optically active form. All derivatives
8 and 9 proved to be very unstable and decomposed
rapidly on standing and in solution at room temperature,
evolving to 9,10-anthraquinone or 2-methyl-9,10-an-
thraquinone.
Sch em e 2a
As can be seen in Table 1, 5-methyl substituted dienes
1a -c, phenylcarbinol 1d and 3,5-dimethyl-substituted
dienes 1g-i, reacted at room temperature (entries 1-4,
8, 10, and 12) whereas phenyl-substituted analogues 1e,f
only reacted under reflux of the solvent (entries 5-7).
Cycloaddition between (+)-5 and dienol 1a (entry 1)
afforded, after flash chromatography, a 31% yield of the
nonseparable 70:30 mixture of optically active compound
8a , proceeding from the unlike approach, and 9a which
resulted from the like one. The optical purity of both
derivatives (70% ee for 8a and 74% ee for 9a ) was
determined after their transformation into the separable
mixture of OMOM ethers (+)-8b and (+)-9b [CH2(OMe)2,
P2O5, CHCl3, rt, 30 min, Scheme 3],30 by using Pr(hfc)3
a
Key: (a) CH2(OMe)2, P2O5, CHCl3, rt, 1 h; (b) HF, CH3CN,
rt,1 h; (c) m-CPBA, CH2Cl2.
and Eu(hfc)3 respectively, as chiral lanthanide shift
reagents. In the same way, reaction of (+)-5 and OMOM-
substituted racemic diene 1b (entry 2) gave a 36% yield
of a 75:25 mixture of compounds (+)-8b (ee ) 82%) and
(+)-9b (ee ) 80%), after flash chromatography. In this
reaction, we could recover unreacted diene (+)-1b in
(28) Carren˜o, M. C.; Garc´ıa Ruano, J . L.; Urbano, A. Synthesis 1992,
651.
(29) We follow Franck’s lead in utilising this nomenclature, see: ref
13e, ftnt 5. See also, Seebach, D.; Prelog, V. Angew. Chem., Int. Ed.
Engl. 1982, 21, 654.
(30) Fuji, K.; Nakano, S.; Fujita, E. Synthesis 1975, 276.

4358 J . Org. Chem., Vol. 65, No. 14, 2000
Carren˜o et al.
optically active form {[R]20 ) +19.3 (c 2.4, CHCl3)}.
D
Finally, cycloaddition of (+)-5 with OTBDMS-substituted
racemic diene 1c (entry 3), gave a non separable 75:25
mixture of compounds 8c and 9c in 57% yield, after flash
chromatography. Optical purity of these derivatives could
not be determined at this stage and thus, we transformed
the mixture of 8c and 9c into the corresponding mixture
of OMOM derivatives (+)-8b and (+)-9b as outlined in
Scheme 3. Thus, after desilylation of 8c and 9c (HF, CH3-
CN, rt, 1 h)31 and methoxymethylation of the resulting
alcohols 8a and 9a , compounds 8b and 9b were obtained
in 40% overall yield. Chromatographic separation of 8b
and 9b allowed to establish a 68% of ee for derivative 8c
and a 72% for 9c.
Diels-Alder reactions between quinone (+)-5 and
phenyl substituted dienes 1d -f followed a similar pat-
tern (Scheme 2, Table 1). Cycloaddition with racemic
dienol 1d (entry 4) afforded a 75:25 mixture of derivatives
8d , proceeding in this case from the like approach, and
9d , from the unlike one. The optical purity of both
compounds, which could be separated by flash chroma-
tography, was determined on their OMOM ethers 8e and
9e (Scheme 3), by using Pr(hfc)3 (74% ee for 8d ) and
Eu(hfc)3 (68% ee for 9d ). Reaction of (+)-5 and diene 1e
(entry 5) yielded a 40% of a non separable 75:25 mixture
of 8e and 9e. The yield of this reaction was enhanced up
to 60% working at high pressure (entry 6), affording
again a 75:25 mixture of 8e (ee ) 68%) and 9e (ee ) 68%).
Finally, cycloaddition of (+)-5 with diene 1f (entry 7),
gave a 76:24 mixture of derivatives 8f and 9f in 51%
yield. Optical purity of these compounds could only be
determined after transformation of the mixture of 8f and
9f into the corresponding inseparable mixture of epoxides
10f and 11f (m-CPBA, CH2Cl2, 0 °C, 4 d, 72%, Scheme
2), proceeding from the exclusive attack of the oxidant
on the less encumbered bottom face of the olefinic system.
We could thus determine a 68% ee for derivative 8f and
a 72% ee for 9f by using Pr(hfc)3 as chiral lanthanide shift
reagent.
F igu r e 1. Significant 1H NMR parameters used for configu-
rational assignments.
chromatographic separation. When the same reaction
was performed under high-pressure conditions (4 Kbar,
entry 11), a 33:67 mixture of diastereoisomers was
obtained in 55% yield. The optical purity of both deriva-
tives (52% ee for 8h and 14% ee for 9h ) was determined
by using Eu(hfc)3 and Pr(hfc)3, respectively. Finally,
Diels-Alder reaction between (+)-5 and diene 1i (entry
12), gave a non separable 33:67 mixture of derivatives
8i and 9i in 33% yield, after flash chromatography. The
enantiomeric purity of minor diastereoisomer 8i (ee )
20%) was established on the mixture of 8i and 9i by using
Pr(hfc)3 as chiral lanthanide shift reagent, whereas that
of major derivative 9i (ee ) 20%) could be determined
on epoxide 11i by using Pr(hfc)3, after oxidation of the
mixture of 8i and 9i (m-CPBA, CH2Cl2, 0 °C, 24 h, 47%,
Scheme 2) and chromatographic separation of the result-
ing epoxides 10i and 11i.
Con figu r a tion a l Assign m en ts. The relative stereo-
chemistry of all compounds resulting from the cycload-
dition/kinetic resolution/pyrolytic sulfoxide elimination
process could be established on the basis of their spec-
troscopic parameters especially those of 1H NMR, includ-
ing NOESY experiments. The assignment of the absolute
configuration was mainly based on the usual behavior
of sulfinylquinones as dienophiles16 and the mechanistic
model proposed below.
Finally, we carried out the reactions with racemic
dienes 1g-i bearing the additional methyl group at C-3
(Scheme 2, Table 1), with the aim of evaluating the effect
of the allylic strain present in this type of dienes on the
diastereoselectivity of the process. Thus, Diels-Alder
reaction between sufinylnaphthoquinone (+)-5 and dienol
1g (entry 8) at room temperature for 24 h afforded a 9:91
mixture of optically active compounds 8g, proceeding
from a like approach, and 9g, from an unlike one, in 66%
yield after flash chromatography. When the same reac-
tion was performed at 0 °C (entry 9) the like/unlike
diastereoselectivity increased to a 5:95 mixture of dias-
tereoisomers, from which (+)-9g was isolated diastere-
oisomerically pure in 88% yield. This result corroborated
the observations of Prein13k which pointed out the
importance of 1,3-allylic strain in controlling the selectiv-
ity of Diels-Alder reactions with 5-hydroxy substituted
pentadienes. In this case we could also recover unreacted
In accordance with conformational studies on 1,4-
dihydronaphthalenes,32 1,4-dihydroanthraquinone de-
rivatives 8a -i and 9a -i prepared by us must exist as a
stable boatlike conformation such as I (Figure 1) with
the substituent at C-1 in axial disposition to avoid
destabilizing interactions with the R2 group at C-2 (R2 )
H or Me) and the adjacent carbonyl group, present in the
other possible conformer II (Figure 1).
diene 1g in optically active form {[R]20 ) +27 (c 0.1,
D
As mentioned earlier, all derivatives 8a -i and 9a -i
are very unstable and decompose quickly in CDCl3
solutions. This instability difficulted regristation of clean
CHCl3)}. The optical purity of compound 9g (50% ee) was
determined after its transformation into the OMOM
derivative (+)-9h (Scheme 3), by using Eu(hfc)3. Cycload-
dition of (+)-5 and diene 1h (entry 10) led to a 40:60
mixture of compounds 8h and 9h in 25% yield, after
(32) (a) Rabideau, P. W. Acc. Chem. Res. 1978, 11, 141. (b) Raber,
D. J .; Hardee, J . E.; Rabideau, P. W.; Lipkowitz, K. B. J . Am. Chem.
Soc. 1982, 104, 2843. (c) Rabideau, P. W. The Conformational Analysis
of Cyclohexenes, Cyclohexadienes, and Related Hydroaromatic Com-
pounds; VCH Publishers: New York, 1989.
(31) Newton, R. F.; Reynolds, D. P.; Finch, M. A. W.; Kelly, D. R.;
Roberts, S. M. Tetrahedron Lett. 1979, 3981.

Reactions of Chiral Racemic Acyclic Dienes
J . Org. Chem., Vol. 65, No. 14, 2000 4359
NMR spectra which would allow a detailed structural
study. For this reason, compounds 8b,c,f,h ,i and 9b,c,f-
,h ,i were transformed into the more stable epoxides
10b,c,f,h ,i and 11b,c,f,h ,i, which were used for the
structural assignment. Thus, a diastereoselective epoxi-
dation using m-CPBA occurred exclusively on the less
hindered bottom face of the double bond, opposite to
the axial substituent at C-1 of conformer I (Figure 1),
giving rise to the stereoselective formation of the desired
epoxides (Scheme 2). The relative stereochemistry of
these derivatives was established on the basis of the
observed long-range coupling constants existent between
H1 and H3, and H2 and H4 (J 1,3 ≈ J 2,4 ≈ 1 Hz), indicating
the equatorial disposition of all these hydrogens, which
is only possible if the epoxide and the substituent at C-1
are trans and adopt the boatlike conformation III similar
to that of the 1,4-dihydroanthraquinones I (Figure 1).
The relative stereochemistry of compounds 8a -f and
9a -f was deduced from that of epoxides 10c and 10f,
which in turn was determined from 1H-1H NOESY
experiments, since 8a -f and 9a -f had been previously
correlated through their OMOM derivatives (see Scheme
2). As depicted in Figure 1, epoxides 10c and 10f showed
NOE enhancements between the R group at the chiral
substituent and H1 and H2 protons as well as between
the OTBDMS group and H4′ hydrogen. This suggested
the (S) absolute configuration for the stereogenic oxygen-
ated carbon of 10c (R ) Me) as well as for its precursor
8c and the analogues 8a ,b, and the (R) configuration for
that of 10f (R ) Ph), as well as for derivatives 8d -f. As
a consequence, the opposite (R) configuration was as-
signed for the C-1′ stereogenic center in minor diastere-
oisomers 9a -c and (S) for the same carbon in 9d -f. This
F igu r e 2. Like/unlike approaches of acyclic dienes 1 in Diels-
Alder reactions with enantiopure (SS)-2-(p-tolylsulfinyl)-1,4-
naphthoquinone.
resolution process. The resulting like/unlike selectivities
(mixtures of 8 and 9) reflects the diastereofacial control
of the chiral diene.
In accordance with the results of other cycloadditions
with enantiopure (SS)-2-(p-tolylsulfinyl)-1,4-quinones,
the most favored endo approach of the diene occurs from
the top face of the dienophile (+)-5 containing the less
sterically demanding lone electron pair at sulfur in the
more reactive s-cis conformation (Figure 2).16 This ap-
proach accounts for the observed (S) absolute configura-
tion at C-1 in the resulting 1,4-dihydroanthraquinones
8 and 9 (see Scheme 2). Thus, derivatives 8a -c result
from an unlike approach and bear the (1S,1′S) absolute
configuration. The major diastereomers 8d -f formed from
dienes 1d -f have the (1S,1′R) absolute configuration as
a result of a like approach. Although the stereochemical
descriptor changes from R1 ) Me to R1 ) Ph, due to a
different priority order in the application of the CIP rules,
the relative stability of the transitions states are similar
for all dienes 1a -f. In the case of cycloadditions with 3,5-
dimethyl-substituted dienes 1g-i, the major diastereo-
isomers 9g-i formed show the (1S,1′R) absolute config-
uration, opposite to that induced at C-1′ in major
compounds 8a -c formed from dienes 1a -c lacking the
methyl substituent at C-3. Taking into account that
substitution at the stereogenic center in 1a -c and 1g-i
is the same, this must be a consequence of a change in
the type of approach of the diene. Compounds 9g-i must
then proceed from a like approach on the diene frame-
work.
1
was confirmed on epoxide 11f (see Figure 1) from the H
NMR chemical shift of H4′ which appeared very shielded
(δ ) 1.13 ppm) if compared with that of the same proton
in diastereoisomer 10f (δ ) 2.81 ppm). This notable
shielding must be due to the anisotropic effect of the close
aromatic ring, and was also observed for derivatives 9d -f
(see Supporting Information).
Finally, the relative stereochemistry of derivatives
8g-i and 9g-i, bearing the methyl substituent at C-2,
was deduced from the NOESY experiments effected on
epoxide 10h (Figure 1). In this case, we noticed evident
NOEs between the methyl group on the exocyclic center
and H4′ proton, as well as between the methyl group at
C-2 and the hydrogen situated at C-1′, suggesting the
(S) configuration for the stereogenic center of compound
10h and as a consequence for that of its precursor 8h
and the analogues 8g,i. The opposite (R) configuration
was then assigned for the chiral center C-1′ of major
diastereoisomers 9g-i proceeding from a like approach.
Interactions emerging in the like or unlike approaches
of the dienophile on the different conformations of the
diene resulting from free rotation around the single C4-
C5 bond account for the preferred evolution. According
to Houk’s work,34 allylic substituents must be staggered
with respect to forming bonds in cycloaddition transition
states to avoid torsional interactions. The presence of
eclipsing bonds increases their energetic contents in ca.
5 kcal/mol being such torsional interactions similar to
those involving formed bonds.
Discu ssion
To rationalize the results achieved in such a double
asymmetric induction process,33 we must differentiate the
diastereofacial selectivities of both chiral partners. The
observed enantiomeric purity of both 8 and 9 is a
consequence of the π-facial diastereoselectivity of the
cycloaddition with the homochiral sulfinyl group on the
quinone moiety and indicates the efficiency of the kinetic
(34) (a) Caramella, P.; Rondan, N. G.; Paddon-Row: M. N.; Houk,
K. N. J . Am. Chem. Soc. 1981, 103, 2438. (b) Rondan, N. G.; Paddon-
Row: M. N.; Caramella, P.; Mareda, J .; Mueller, P. H.; Houk, K. N. J .
Am. Chem. Soc. 1982, 104, 4974. (c) Paddon-Row: M. N.; Rondan, N.
G.; Houk, K. N. J . Am. Chem. Soc. 1982, 104, 7162. (d) Houk, K. N.;
Moses, S. R.; Wu, Y. D.; Rondan, N. G.; J a¨ger, V.; Schohe, R.; Fronczek,
F. R. J . Am. Chem. Soc. 1984, 106, 3880.
(33) We use this term in the conventional sense defined by Masam-
une (see ref 18), considering the kinetically favoured reaction occurring
between homochiral dienophile (+)-5 and one of the enantiomers of
chiral racemic dienes 1a -i.

4360 J . Org. Chem., Vol. 65, No. 14, 2000
Carren˜o et al.
Sch em e 3
justified on the basis of the moderate reactivity of dienes
1a -f which need temperatures ranging from 20 to 40 °C
to react. According to our previous work,16 π-facial
diastereoselectivity of cycloadditions with sulfinylquino-
nes improved strongly at low temperatures.
The relative stabilities of the transition states resulting
from dienes 1g-i are different due to the 1,3-allylic
strain14 existent between the methyl group at C-3 and
the substituents of the allylic center, which imposes
strong conformational preferences. According to Prein’s
proposal,13k rotamers B (R2 ) Me) in the unlike approach
and D (R2 ) Me) in the like one must be intrinsically
favored since the smallest hydrogen substituent is situ-
ated at the sterically most biased inside position to
minimize 1,3-allylic strain.35 A preference of ca. 3-4 kcal/
mol could be estimated for the ground and transition
states. A comparison of the relative stability of both
transition states B and D allowed us to conclude that
approach D with the less sterically demanding OX
substituent on the reactive face of the diene will be
favored over transition state B where this position is
occupied by the bulkiest R1 substituent. Thus, the major
evolution through a like approach for this type of dienes
is due to the main evolution through a transition state
such as D. Moreover, the higher like/unlike selectivity
achieved with dienol 1g (X ) H) is in accordance with
this model of approach since the free hydroxyl group is
the smallest one if compared with the other OX substit-
uents (OMOM and OTBDMS). Moreover, all cycloaddi-
tions have been performed in a non polar solvent such
as CH2Cl2 which could favor the formation of hydrogen
bonding13k,36 between the OH group of the diene and the
incoming dienophile enhancing the preference for like
attack and evolution through D transition state.
Due to the different behavior of dienes bearing and
lacking the methyl substituent at C-3, the mechanistic
discussion that follows is independent for each type of
diene. The major formation of diastereoisomers 8a -f,
resulting from the unlike approach of dienes 1a -c (R1 )
Me; R2 ) H) and from the like one of dienes 1d -f (R1 )
Ph; R2 ) H), could be explained considering the three
transition states A, B and C (R2 ) H) represented in
Figure 2. The most favored situation correspond to A,
where the largest R1 group of the allylic center is anti to
the attacking sulfinyl dienophile and the smallest H is
on the same face. In approaches B and C, where the R1
and OX groups are situated on the same side of the
approaching dienophile, unfavorable steric and/or elec-
trostatic interactions appear. Thus, the matched evolu-
tion of the (S) enantiomer of dienes 1a -c (R1 ) Me; R2
) H) and the (R) one of 1d -f (R1 ) Ph; R2 ) H) through
the approach A justifies the observed kinetic resolution
which gave the major isomers 8a -f.
A similar analysis for like approaches of dienes 1a -c
[(R)-enantiomers reacting] and unlike of 1d -f [(S)-
enantiomers reacting] yielding minor derivatives 9a -f
must focus in transition states D, E and F (R2 ) H)
represented in Figure 2. In this case, transition states D
and F show destabilizing interactions similar to B and
C, being OX group in D and R1 in F situated on the same
side of the approaching dienophile. The most favored
situation corresponds to E, where the smallest H is on
the bottom side of the diene. Nevertheless, the energetic
content of transition state resulting from approach A
must be lower to that of approach E where the bulky R1
group is in gauche disposition with respect to the C3-C4
double bond and also in the face of the approaching
dienophile. The matched pair in this case arose from the
reaction of the (S) enantiomer of dienes 1a -c and from
the (R) enantiomer of dienes 1d -f. The formation of a
minor amount (9-16%) of the enantiomers of 8a -f and
9a -f (see enantiomeric ratios in Table 1) could be
The lower enantiomeric ratios obtained in the cycload-
ditions with dienes 1g-i (see Table 1) if compared with
those of dienes 1a -f, lacking the additional methyl
substituent at C-3, were not easy to rationalize. We
reasoned that the presence of two alkyl substituents at
C-3 and C-4 of the diene moiety could compete in
directing the regiochemistry of the process. A decreased
regioselectivity would affect the final enantiomeric purity
of the resulting compounds since the chiral inductor
disappears during the reaction. To check this point, we
carried out the cycloaddition between 5-methoxy-2-(p-
tolylsulfinyl)-1,4-naphthoquinone (12)28 and diene 1h
(CH2Cl2, 40 °C, 4 days, Scheme 3), giving rise to a mixture
of derivatives 13 and 14 which, after chromatographic
purification, evolved on standing in CH2Cl2 at room
temperature for 5 days into a 78:22 mixture of regioiso-
meric 1-methoxy-6-methyl-9,10-anthraquinone (15)37 and
1-methoxy-7-methyl-9,10-anthraquinone (16).38 This could
be in the origin of the lower enantioselectivities achieved
in the cycloadditions of 3-methyl-substituted dienes 1g-i
with enantiopure sulfinylquinone (+)-5.
(35) Broeker, J . L.; Hoffmann, R. W.; Houk, K. N. J . Am. Chem.
Soc. 1991, 113, 5006.
(36) (a) Tripathy, R.; Carroll, P: J .; Thornton, E. R. J . Am. Chem.
Soc. 1990, 112, 6743. (b) Tripathy, R.; Carroll, P: J .; Thornton, E. R.
J . Am. Chem. Soc. 1991, 113, 7630.
(37) Krohn, K. Liebigs Ann. Chem. 1981, 2285.
(38) The structures of 15 and 16, which showed very similar 1H
NMR spectra, were assigned on the basis of the preferred regiodirecting
power of the alkyl substituent at C-1 over that at C-2 in the diene
partner.

Reactions of Chiral Racemic Acyclic Dienes
J . Org. Chem., Vol. 65, No. 14, 2000 4361
(E)-5-[(ter t-Bu tyldim eth ylsilyl)oxy]-1,3-h exadien e (1c).13e
1c was obtained from 1a 23 following method B (eluent: hexane)
as a colorless oil (71% yield): 1H NMR δ 0.06 (2s, 6H), 0.90 (s,
9H), 1.23 (d, 3H, J ) 6.5 Hz), 4.34 (quint, 1H, J ) 6.5 Hz),
5.05 (dd, 1H, J ) 10.0, 1.5 Hz), 5.17 (dd, 1H, J ) 17.0, 1.5
Hz), 5.70 (dd, 1H, J ) 15.0, 6.5 Hz), 6.08-6.42 (m, 2H); HRMS
calcd for C12H24OSi 212.15964, found 212.15931.
Con clu d in g Rem a r k s
The enantioselective reactions of racemic acyclic dienes
1 bearing an allylic stereogenic center with (SS)-2-(p-
tolylsulfinyl)-1,4-naphthoquinone gave rise, through a
one-pot domino cycloaddition/sulfoxide elimination pro-
cess which takes place with the kinetic resolution of the
racemic dienes, to enantiomerically enriched 1,4-dihydro-
9,10-anthraquinone derivatives 8 and 9.
The major observed evolution corresponded to the
matched pair resulting from the unlike (for dienes 1a -
c) and like (for dienes 1d -f) approaches, as a result of
steric effects in the transition states. The importance of
1,3-allylic strain in controlling these Diels-Alder reac-
tions has been also highlighted for dienes 1g-i.
(E)-1-P h en yl-2,4-p en t a d ien -1-ol (1d ). 1d was obtained
from 224 following method C at room temperature (91%
yield): 1H NMR δ 2.09 (s, 1H), 5.12-5.34 (m, 3H), 5.88 (m,
1H), 6.26-6.43 (m, 2H), 7.25-7.42 (m, 5H); HRMS calcd for
C
11H12O 160.08881, found 160.08850.
(E)-5-[(Met h oxym et h yl)oxy]-5-p h en yl-1,3-p en t a d ien e
(1e). 1e was obtained from 1d following method A (eluent:
hexane/EtOAc 95:5) as a colorless oil (66% yield): 1H NMR δ
3.39 (s, 3H), 4.62 and 4.74 (AB system, 2H, J ) 6.5 Hz), 5.12
(d, 1H, J ) 10.0 Hz), 5.16 (d, 1H, J ) 7.0 Hz), 5.25 (d, 1H, J
) 16.5 Hz), 5.81 (dd, 1H, J ) 14.0, 7.0 Hz), 6.26-6.42 (m, 2H),
7.27-7.37 (m, 5H); HRMS calcd for C13H16O2 204.11503, found
204.11552.
Exp er im en ta l Section
Melting points were obtained in open capillary tubes and
are uncorrected. 1H- and 13C NMR spectra were recorded in
CDCl3 at 300 and 75 MHz, respectively. NOESY experiments
were performed in CDCl3 or C6D6 at 500 MHz. Diastereoiso-
meric ratios were established by integration of well-separated
signals in the crude reaction mixtures and are listed in Table
1. Mass spectra (MS and HRMS) were recorded in the electron
impact mode at 70 eV. All reactions were monitored by thin-
layer chromatography that was performed on precoated sheets
of silica gel 60, and flash chromatography was done with silica
gel 60 (230-400 mesh) of Macherey-Nagel. Eluting solvents
are indicated in the text. The apparatus for inert atmosphere
experiments was dried by flaming in a stream of dry argon.
Dry THF was distilled from sodium/benzophenone ketyl. CH2-
Cl2 was dried over P2O5. For routine workup, hydrolysis was
carried out with water, extractions with CH2Cl2, and solvent
dryness with Na2SO4. High-pressure reactions were performed
in a Unipress Equipment 101LV 30/16 in polyethylene vials.
Hexadiene 1a 23 and phenyl ketone 224 were prepared according
to previously reported procedures.
(E)-5-[(ter t-Bu tyld im eth ylsilyl)oxy]-5-p h en yl-1,3-p en -
ta d ien e (1f). 1f was obtained from 1d following method B
(eluent: hexane/CH2Cl2 85:15) as a colorless oil (67% yield):
1H NMR δ 0.03 (s, 3H), 0.10 (s, 3H), 0.95 (s, 9H), 5.10 (m, 1H),
5.23 (d, 1H, J ) 15.0 Hz), 5.25 (d, 1H, J ) 6.5 Hz), 5.80 (dd,
1H, J ) 14.0, 6.5 Hz), 6.23-6.40 (m, 2H), 7.23-7.38 (m, 5H);
HRMS calcd for C17H26OSi 274.1759, found 274.17465.
4-Meth yl-3,5-h exa d ien -2-on e (4).27 To a solution of vinyl-
magnesium bromide 1 M in THF (60 mL, 60 mmol), 2,4-
pentanedione (3.00 g, 30 mmol) in 90 mL of dry THF was
added at -78 °C under argon. After 2 h at -78 °C and 2 h at
room temperature, the mixture was added dropwise to a
solution of HCl 10%, stirred for 1.5 h and extracted with ethyl
ether. The organic layer was washed with water and dried with
MgSO4. After evaporation of the solvent and flash chromatog-
raphy (eluent: hexane/EtOAc 85:15), 4 was obtained as an
inseparable 75:25 mixture of E:Z isomers, in 35% yield: 1H
NMR (E isomer) δ 2.20 (s, 3H), 2.22 (s, 3H), 5.44 (d, 1H, J )
11.0 Hz), 5.66 (d, 1H, J ) 17.0 Hz), 6.14 (s, 1H), 6.35 (dd, 1H,
J ) 17.0, 11.0 Hz).
Gen er a l P r oced u r e for th e Syn th esis of OMOM De-
r iva tives, Meth od A. To a solution of 1.5 mmol of the
corresponding alcohol in 5 mL of CH2Cl2, 817 µL (4.7 mmol)
of DIPEA and 712 µL (9.4 mmol) of MOMCl were added. The
mixture was stirred at room temperature for 3 h and hydro-
lyzed with a cold aqueous solution of NaHCO3. After workup
and flash chromatography, the pure OMOM derivative was
obtained.
Gen er a l P r oced u r e for th e Syn th esis of OTBDMS
Der iva tives, Meth od B. To a solution of 5.4 mmol of the
corresponding alcohol in 8 mL of DMF, 0.96 g (6.4 mmol) of
TBDMSCl and 0.92 g (13.5 mmol) of imidazole were added.
The mixture was stirred at room temperature overnight,
hydrolyzed with an aqueous saturated solution of NH4Cl, and
extracted with ethyl ether. The organic layer was washed with
a saturated solution of NH4Cl and brine and dried with MgSO4.
After evaporation of the solvent and flash chromatography,
the pure OTBDMS derivative was obtained.
Gen er a l P r oced u r e for th e Red u ction of Keton es,
Meth od C. To a solution of 1.6 mmol of the corresponding
ketone and 596 mg (1.6 mmol) of CeCl3‚7H2O in 5 mL of MeOH
at the temperature indicated in each case, 60 mg (1.6 mmol)
of solid NaBH4 were added in small portions. The mixture was
stirred for 15 min, hydrolyzed with water and extracted with
ethyl ether. The organic layer was dried with MgSO4 and, after
evaporation of the solvent, crude alcohol was obtained and
used without further purification.
(E)-5-[(Meth oxym eth yl)oxy]-1,3-h exa d ien e (1b). 1b was
obtained from 1a 23 following method A (eluent: hexane/EtOAc
90:10) as a colorless oil (63% yield): 1H NMR δ 1.28 (d, 3H, J
) 6.5 Hz), 3.36 (s, 3H), 4.21 (quint, 1H, J ) 6.5 Hz), 4.56 and
4.67 (AB system, 2H, J ) 6.5 Hz), 5.09 (dd, 1H, J ) 10.5, 1.2
Hz), 5.20 (dd, 1H, J ) 17.0, 1.2 Hz), 5.59 (dd, 1H, J ) 15.0,
6.5 Hz), 6.19 (dd, 1H, J ) 15.0, 10.5 Hz), 6.32 (ddd, 1H, J )
17.0, 10.5, 10.5 Hz).
4-Meth yl-3,5-h exa d ien -2-ol (1g). 1g was obtained from 4
following method C at 0 °C, as an inseparable 75:25 mixture
of E:Z isomers in 85% yield: 1H NMR (E isomer) δ 1.27 (d, 3H,
J ) 6.0 Hz), 1.56 (broad s, 1H), 1.79 (broad s, 3H), 4.69 (m,
1H), 5.05 (d, 1H, J ) 11.0 Hz), 5.20 (d, 1H, J ) 17.0 Hz), 5.49
(d, 1H, J ) 8.5 Hz), 6.35 (dd, 1H, J ) 17.0, 11.0 Hz).
5-[(Meth oxym eth yl)oxy]-3-m eth yl-1,3-h exa d ien e (1h ).
1h was obtained from 1a following method A (eluent: hexane/
EtOAc 95:5) as an inseparable 75:25 mixture of E:Z isomers,
1
in 50% yield: H NMR (E isomer) δ 1.26 (d, 3H, J ) 6.5 Hz),
1.79 (broad s, 3H), 3.36 (s, 3H), 4.52 and 4.63 (AB system, 2H,
J ) 7.0 Hz), 4.63 (m, 1H), 5.05 (d, 1H, J ) 11.0 Hz), 5.20 (d,
1H, J ) 17.0 Hz), 5.37 (broad d, 1H, J ) 9.0 Hz), 6.37 (dd, 1H,
J ) 17.0, 11.0 Hz).
5-[(ter t-Bu t yld im et h ylsilyl)oxy]-3-m et h yl-1,3-h exa d i-
en e (1i). 1i was obtained from 1g following method B as an
inseparable 75:25 mixture of E:Z isomers in 97% yield and
used without further purification: 1H NMR (E isomer) δ 0.03
(s, 3H), 0.04 (s, 3H), 0.87 (s, 9H), 1.20 (d, 3H, J ) 6.5 Hz),
1.74 (broad s, 3H), 4.65 (dq, 1H, J ) 8.5, 6.5 Hz), 5.00 (d, 1H,
J ) 11.0 Hz), 5.14 (d, 1H, J ) 17.0 Hz), 5.48 (broad d, 1H, J
) 8.5 Hz), 6.34 (dd, 1H, J ) 17.0, 11.0 Hz).
Gen er al P r ocedu r e for Diels-Alder Reaction s, Meth od
D. To a solution of (SS)-2-(p-tolylsulfinyl)-1,4-naphthoquinone
(+)-528 (80 mg, 0.27 mmol) in 2 mL of dry CH2Cl2 under argon,
the corresponding racemic diene 1a -i (0.54 mmol, 2 equiv) was
added. After the time required in each case (see Table 1 for
reaction conditions) and evaporation of the solvent, crude
dihydroanthraquinones 8a -i and 9a -i were obtained and
purified by flash chromatography.
Gen er a l P r oced u r e for th e Tr a n sfor m a tion of Alco-
h ols in to OMOM Der iva tives, Meth od E. To a solution of
0.2 mmol of the corresponding alcohol in 2 mL of CHCl3 (dried
over P2O5), 1.3 mL of dimethoxymethane and a catalytic
amount of P2O5 were added. After stirring 30 min at room

4362 J . Org. Chem., Vol. 65, No. 14, 2000
Carren˜o et al.
temperature and dilution with 20 mL of CH2Cl2, the mixture
was poured into a precooled saturated aqueous solution of
NaHCO3. After workup, the crude mixture of OMOM deriva-
tives was purified by flash chromatography.
85:15), in 88% yield: [R]20 +60 (c 0.15, CHCl3); 1H NMR δ
1.10 (d, 3H, J ) 6.5 Hz), 1.95 (broad s, 3H), 3.02 (m, 1H), 3.44
(m, 1H), 3.76 (m, 1H), 4.09 (dq, 1H, J ) 3.8, 6.5 Hz), 5.82 (m,
1H), 7.71 (m, 2H), 8.08 (m, 2H).
D
(1S,1′S)-1-[(1′-Hyd r oxy)eth yl)]-1,4-dih yd r o-9,10-a n th r a -
qu in on e (8a ) a n d (1S,1′R)-1-[(1′-Hyd r oxy)eth yl)]-1,4-d i-
h yd r o-9,10-a n th r a qu in on e (9a ). 8a and 9a were obtained
from 1a following method D (eluent: hexane/EtOAc 85:15) as
an inseparable 70:30 mixture, in 31% yield: 1H NMR (8a ) δ
1.26 (d, 3H, J ) 6.5 Hz), 2.04 (broad s, 1H), 3.09 (m, 1H), 3.42
(dt, 1H, J ) 24.0, 4.5 Hz), 3.79 (m, 1H), 4.09 (m, 1H), 5.93 (m,
1H), 6.17 (ddd, 1H, J ) 10.0, 4.5, 2.4 Hz), 7.71 (m, 2H), 8.09
(m, 2H). 8a and 9a were also obtained from desilylation of 8c
and 9c (0.21 mmol) in 15 mL of CH3CN, by adding 7 drops of
40% solution of HF. The mixture was stirred 10 min at room
temperature, diluted with CH2Cl2 and extracted with water.
After workup, crude alcohols 8a and 9a were obtained and
used without further purification.
(1S,1′R)-1-[(1′-Meth oxym eth yloxy)eth yl]-2-m eth yl-1,4-
d ih yd r o-9,10-a n th r a qu in on e (9h ). 9h was obtained from 1h
following method D (rt, 4 Kbar) after separation of the 33:67
mixture of 8h and 9h by flash chromatography (eluent:
hexane/EtOAc 90:10), in 41% yield: [R]20D +16 (c 0.19, CHCl );
3
1H NMR δ 1.02 (d, 3H, J ) 6.5 Hz), 1.94 (broad s, 3H), 2.98
(m, 1H), 3.39 (s, 3H), 3.41 (m, 1H), 3.89 (m, 1H), 4.01 (dq, 1H,
J ) 3.0, 6.5 Hz), 4.67 and 4.86 (AB system, 2H, J ) 7.0 Hz),
5.76 (m, 1H), 7.70 (m, 2H), 8.09 (m, 2H). 9h was also obtained
from 9g following method E (eluent: hexane/EtOAc 90:10):
[R]20 +84 (c 0.05, CHCl3).
D
(1S,1′S)-1-[(1′-ter t-Bu tyldim eth ylsilyloxy)eth yl]-2-m eth -
yl-1,4-d ih yd r o-9,10-a n th r a qu in on e (8i) a n d (1S,1′R)-1-
[(1′-ter t-Bu tyld im eth ylsilyloxy)eth yl]-2-m eth yl-1,4-d ih y-
d r o-9,10-a n th r a qu in on e (9i). 8i and 9i were obtained from
1i following method D (eluent: hexane/EtOAc 95:5) as an
inseparable 33:67 mixture, in 33% yield: 1H NMR (8i) δ -0.10
(s, 3H), 0.00 (s, 3H), 0.80 (s, 9H), 1.13 (d, 3H, J ) 6.5 Hz),
1.93 (broad s, 3H), 2.96 (m, 1H), 3.39 (m, 1H), 3.78 (m, 1H),
4.11 (m, 1H) 5.73 (m, 1H), 7.71 (m, 2H), 8.10 (m, 2H).
Gen er a l P r oced u r e for Ep oxid a tion s, Meth od F . To a
solution of the corresponding derivative 8 and 9 in dry CH2-
Cl2, 2 equiv of m-CPBA were added. After stirring at the
temperature and for the time indicated in each case, solid K2-
CO3 was added, and the mixture was filtered and washed with
CH2Cl2. After evaporation of the solvent, crude epoxides were
purified by flash chromatography.
(1S,1′S)-1-[(1′-Met h oxym et h yloxy)et h yl]-1,4-d ih yd r o-
9,10-a n th r a qu in on e (8b). 8b was obtained from 1b following
method D, after separation of the resulting 75:25 mixture of
8b and 9b by flash chromatography (eluent: hexane/EtOAc
1
85:15), in 27% yield: [R]20 +138 (c 0.05, CHCl3); H NMR δ
D
1.31 (d, 3H, J ) 6.5 Hz), 3.03 (s, 3H), 3.12 (ddt, 1H, J ) 24.0,
6.0, 2.5 Hz), 3.40 (dt, 1H, J ) 24.0, 4.5 Hz), 3.75 (m, 1H), 4.11
(dq, 1H, J ) 2.8, 6.5 Hz), 4.40 and 4.50 (AB system, 2H, J )
7.0 Hz), 6.00 (ddd, 1H, J ) 10.0, 4.5, 2.8 Hz), 6.12 (ddd, 1H, J
) 10.0, 4.5, 2.0 Hz), 7.72 (m, 2H), 8.10 (m, 2H). 8b was also
obtained from the mixture of 8a and 9a following method E
after separation by flash chromatography.
(1S,1′S)-1-[(1′-ter t-Bu tyld im eth ylsilyloxy)eth yl]-1,4-d i-
h yd r o-9,10-a n th r a qu in on e (8c) a n d (1S,1′R)-1-[(1′-ter t-
Bu t yld im et h ylsilyloxy)et h yl]-1,4-d ih yd r o-9,10-a n t h r a -
qu in on e (9c). 8c and 9c were obtained from 1c following
method D (eluent: hexane/EtOAc 9:1) as an inseparable 75:
25 mixture, in 57% yield: 1H NMR (8c) δ -0.36 (s, 3H), -0.12
(s, 3H), 0.71 (s, 9H), 1.27 (d, 3H, J ) 6.0 Hz), 3.05 (m, 1H),
3.36 (dt, 1H, J ) 24.0, 4.5 Hz), 3.64 (m, 1H), 4.19 (dq, 1H, J )
2.8, 6.0 Hz), 5.93 (ddd, 1H, J ) 10.0, 4.5, 2.8 Hz), 6.04 (ddd,
1H, J ) 10.0, 4.5, 2.4 Hz), 7.70 (m, 2H), 8.08 (m, 2H).
(1S,1′R)-1-[(1′-P h en yl-1′-h yd r oxy)m eth yl]-1,4-d ih yd r o-
9,10-a n tr a qu in on e (8d ). 8d was obtained from 1d following
method D, after separation of the resulting 75:25 mixture of
8d and 9d by flash chromatography (eluent: CH2Cl2/EtOAc
90:10), in 62% yield: 1H NMR δ 2.70 (d, 1H, J ) 7.0 Hz), 2.92
(ddt, 1H, J ) 24.0, 6.5, 2.5 Hz), 3.31 (dt, 1H, J ) 24.0, 4.5
Hz), 4.10 (m, 1H), 5.13 (d, 1H, J ) 7.0 Hz), 5.58 (dt, 1H, J )
10.0, 4.0 Hz), 6.12 (ddd, 1H, J ) 10.0, 4.0, 2.0 Hz), 7.32 (m,
5H), 7.72 (m, 2H), 8.08 (m, 2H).
(1S,1′R)-1-[(1′-P h en yl-1′-m et h oxym et h yloxy)m et h yl]-
1,4-d ih yd r o-9,10-a n th r a qu in on e (8e) a n d (1S,1′S)-1-[(1′-
P h en yl-1′-m eth oxym eth yloxy)m eth yl]-1,4-d ih yd r o-9,10-
a n th r a qu in on e (9e). 8e and 9e were obtained from 1e
following method D (eluent: hexane/EtOAc 90:10) as an
inseparable 75:25 mixture, in 40% yield (40 °C) or 60% yield
(rt, 4 Kbar): 1H NMR (8e) δ 2.98 (s, 3H), 3.16 (ddt, 1H, J )
24.0, 6.5, 2.8 Hz), 3.39 (ddt, 1H, J ) 24.0, 1.0, 4.8 Hz), 3.98
(m, 1H), 4.44 (s, 2H), 5.13 (d, 1H, J ) 2.8 Hz), 5.56 (m, 1H),
6.06 (m, 1H), 7.26-7.45 (m, 5H), 7.74 (m, 2H), 8.11 (m, 2H).
8e and 9e were also obtained from the 75:25 mixture of 8d
and 9d following method E.
(1S*,2S*,3R*,1′S*)-1-[(1′-Meth oxym eth yloxy)eth yl]-2,3-
ep oxy-1,2,3,4-tetr a h yd r o-9,10-a n th r a qu in on e (10b). 10b
was obtained from (()-8b following method F after 8 days at
-20 °C (eluent: hexane/EtOAc 85:15), in 51% yield: mp 101-
1
102 °C (methanol); H NMR δ 1.43 (d, 3H, J ) 6.5 Hz), 2.77
(dt, 1H, J ) 20.0, 2.0 Hz), 3.08 (s, 2H), 3.42 (m, 1H), 3.52 (m,
1H), 3.58 (m, 1H), 3.69 (broad s, 1H), 4.03 (dq, 1H, J ) 2.5,
6.5 Hz), 4.39 and 4.50 (AB system, 2H, J ) 7.0 Hz), 7.68 (m,
2H), 8.03 (m, 2H). Anal. Calcd for C18H18O5: C, 68.76; H, 5.78.
Found: C, 68.45; H, 5.79.
(1S*,2S*,3R*,1′S*)-1-[(1′-ter t-Bu t yld im et h ylsilyloxy)-
et h yl]-2,3-ep oxy-1,2,3,4-t et r a h yd r o-9,10-a n t h r a q u in on e
(10c). 10c was obtained from the 75:25 mixture of (()-8c and
(()-9c following method F after 9 days at -5 °C (eluent:
hexane/CH2Cl2 50:50), in 45% yield: 1H NMR (C6D6) δ -0.28
(s, 3H), -0.15 (s, 3H), 0.84 (s, 9H), 1.23 (d, 3H, J ) 6.5 Hz),
2.81 (dt, 1H, J ) 20.0, 2.0 Hz), 3.18 (m, 1H), 3.42 (broad d,
1H, J ) 4.0 Hz), 3.55 (broad d, 1H, J ) 20.0 Hz), 3.81 (broad
s, 1H), 4.27 (dq, 1H, J ) 2.5, 6.5 Hz), 7.07 (m, 2H), 8.06 (m,
2H); HRMS calcd for C22H28O4Si 384.17569, found 384.17618.
(1S*,2S*,3R*,1′R*)-1-[(1′-ter t-Bu tyld im eth ylsilyloxy-1′-
p h e n yl)m e t h yl]-2,3-e p oxy-1,2,3,4-t e t r a h yd r o-9,10-a n -
th r a qu in on e (10f) a n d (1S*,2S*,3R*,1′S*)-1-[(1′-ter t-Bu -
tyld im eth ylsilyloxy-1′-p h en yl)m eth yl]-2,3-ep oxy-1,2,3,4-
tetr a h yd r o-9,10-a n th r a qu in on e (11f). 10f and 11f were
obtained from a 76:24 mixture of (()-8f and (()-9f following
method F after 4 days at 0 °C as an inseparable 76:24 mixture
(eluent: hexane/EtOAc 85:15), in 74% yield: 1H NMR (10f) δ
-0.33 (s, 3H), -0.28 (s, 3H), 0.81 (s, 9H), 2.81 (dt, 1H, J )
20.0, 2.0 Hz), 3.29 (m, 1H), 3.39 (m, 1H), 3.48 (m, 1H), 3.88
(m, 1H), 5.19 (d, 1H, J ) 1.5 Hz), 7.0-8.1 (m, 9H); HRMS calcd
for C27H30O4Si 446.19134, found 446.19046.
(1S*,2S*,3R*,1′R*)-1-[(1′-Meth oxym eth yloxy)eth yl]-2,3-
ep oxy-2-m et h yl-1,2,3,4-t et r a h yd r o-9,10-a n t h r a q u in on e
(11h ). 11h was obtained from (()-9h following method F after
2 days at -15 °C, in 61% yield: mp 107-108 °C (methanol);
1H NMR δ 1.09 (d, 3H, J ) 6.5 Hz), 1.60 (s, 3H), 2.83 (m, 1H),
3.33 (m, 1H), 3.39 (s, 3H), 3.46 (m, 1H), 3.80 (m, 1H), 4.16
(dq, 1H, J ) 2.5, 6.5 Hz), 4.69 (s, 2H), 7.70 (m, 2H), 8.06 (m,
2H); HRMS calcd for C19H20O5 328.13107, found 328.13150.
(1S,2S,3R,1′R)-1-[(1′-ter t-Bu tyld im eth ylsilyloxy)eth yl]-
2,3-ep oxy-2-m eth yl-1,2,3,4-tetr a h yd r o-9,10-a n th r a qu in o-
n e (11i). 11i was obtained from the mixture of 8i and 9i
following method F (24 h at 0 °C) after separation by flash
(1S,1′R)-1-[(1′-ter t-Bu t yld im et h ylsilyloxy-1′-p h en yl)-
m eth yl]-1,4-dih ydr o-9,10-an th r aqu in on e (8f) an d (1S,1′S)-
1-[(1′-ter t-Bu t yld im et h ylsilyloxy-1′-p h en yl)m et h yl]-1,4-
d ih yd r o-9,10-a n th r a qu in on e (9f). 8f and 9f were obtained
from 1f following method D as an inseparable 76:24 mixture,
in 51% yield: 1H NMR (8f) δ -0.37 (s, 3H), -0.33 (s, 3H), 0.74
(s, 9H), 3.12 (ddt, 1H, J ) 24.0, 6.5, 2.7 Hz), 3.36 (dt, 1H, J )
24.0, 4.8 Hz), 3.90 (m, 1H), 5.17 (d, 1H, J ) 2.0 Hz), 5.41 (m,
1H), 6.00 (m, 1H), 7.29-7.46 (m, 5H), 7.75 (m, 2H), 8.13 (m,
2H).
(1S,1′R)-1-[(1′-H yd r oxy)et h yl)]-2-m et h yl-1,4-d ih yd r o-
9,10-a n th r a qu in on e (9g). 9g was obtained from 1g following
method D, after separation of the resulting 5:95 mixture of
8g and 9g by flash chromatography (eluent: CH2Cl2/EtOAc

Reactions of Chiral Racemic Acyclic Dienes
J . Org. Chem., Vol. 65, No. 14, 2000 4363
1
chromatography (eluent: hexane/EtOAc 85:15), in 32% yield:
(s, 3H); H NMR (16) δ 8.12 (d, 1H, J ) 8.0 Hz), 8.05 (d, 1H,
J ) 1.6 Hz), 7.96 (dd, 1H, J ) 7.7, 1.2 Hz), 7.71 (dd, 1H, J )
8.5, 7.7 Hz), 7.53 (dd, 1H, J ) 8.1, 2.0 Hz), 7.33 (dd, 1H, J )
8.5, 1.2 Hz), 4.05 (s, 3H), 2.52 (s, 3H).
mp 135-136 °C (methanol); [R]20 -17 (c 0.06, CHCl3); 1H
D
NMR δ 0.09 (s, 3H), 0.19 (s, 3H), 0.88 (s, 9H), 1.05 (d, 3H, J )
6.5 Hz), 1.60 (s, 3H), 2.82 (dt, 1H, J ) 20.0, 2.0 Hz), 3.30 (m,
1H), 3.44 (m, 1H), 3.72 (m, 1H), 4.21 (dq, 1H, J ) 2.8, 6.5 Hz),
7.70 (m, 2H), 8.08 (m, 2H); HRMS calcd for C23H30O4Si
398.19134, found 398.19083.
Ack n ow led gm en t. We thank Direccio´n General de
Investigacio´n Cient´ıfica y Te´cnica (Grant PB98-0062)
for financial support. C.D.V. thanks FAPESP-Fundac¸a˜o
de Amparo a` Pesquisa do Estado de Sa˜o Paulo for a
postdoctoral fellowship. S.G.C. thanks Comunidad Au-
to´noma de Madrid for a predoctoral fellowship.
1-Met h oxy-6-m et h yl-9,10-a n t h r a q u in on e (15)37 a n d
1-Meth oxy-7-m eth yl-9,10-a n th r a qu in on e (16). A solution
of 5-methoxy-2-(p-tolylsulfinyl)-1,4-naphthoquinone (12)28 (63
mg, 0.19 mmol) and diene 1h (75:25 E:Z mixture) (60 mg, 0.38
mmol) in 5 mL of dry CH2Cl2 under argon was refluxed for 4
days. The resulting mixture was purified by flash chromatog-
raphy (eluent: hexane/EtOAc 65:35), and the residue was
dissolved in 1 mL of CH2Cl2 and stirred at room temperature
for 5 days. After flash chromatography (eluent: hexane/EtOAc
85:15), anthraquinones 15 and 16 were obtained as an
inseparable 78:22 mixture in 32% yield: 1H NMR (15) δ 8.16
(d, 1H, J ) 8.0 Hz), 8.02 (d, 1H, J ) 1.6 Hz), 7.96 (dd, 1H, J
) 7.7, 1.2 Hz), 7.71 (dd, 1H, J ) 8.5, 7.7 Hz), 7.57 (dd, 1H, J
) 8.1, 2.0 Hz), 7.34 (dd, 1H, J ) 8.5, 1.2 Hz), 4.05 (s, 3H), 2.51
Su p p or tin g In for m a tion Ava ila ble: Additional charac-
terization data for 1b-f, 4, 1g-i, 8b,d ,e, 9a ,c,e-i, 10b,c, and
11f,h ,i. Experimental procedures and characterization data
1
for 9b,d , 8h , 11b, and 10h ,i. Copies of H NMR spectra for
all compounds and 13C NMR for 1b,g,h ,i, 4, 8b,d , and
9b,d ,g,h . This material is available free of charge via the
Internet at http://pubs.acs.org.
J O000210U