Asymmetric Diels-Alder reactions of a new enantiomerically pure sulfinylquinone: A straightforward access to functionalized Wieland-Miescher ketone analogues with (R) absolute configuration

Article abstract of DOI:10.1021/jo060486n

An efficient and highly stereocontrolled preparation, on a large scale, of two new Wieland-Miescher-type diketones is described. The approach centers on a diastereoselective Diels-Alder reaction using a new enantiomerically pure sulfinylquinone. Mechanist

Full text of DOI:10.1021/jo060486n

Asymmetric Diels-Alder Reactions of a New Enantiomerically Pure
Sulfinylquinone: A Straightforward Access to Functionalized
Wieland-Miescher Ketone Analogues with (R) Absolute
Configuration
Don Antoine Lanfranchi and Gilles Hanquet*
Laboratoire de Ste´re´ochimie associe´ au CNRS, ECPM, ULP, 25 rue Becquerel, 67087 Strasbourg, France
ghanquet@chimie.u-strasbg.fr
ReceiVed March 6, 2006
An efficient and highly stereocontrolled preparation, on a large scale, of two new Wieland-Miescher-
type diketones is described. The approach centers on a diastereoselective Diels-Alder reaction using a
new enantiomerically pure sulfinylquinone. Mechanistic investigations of this cycloaddition on several
dienes are described.
Introduction
Since the pioneering works of Hajos1 and Eder,2 optically
active Wieland-Miescher-type diketones 1 (Figure 1) have been
employed as key starting materials for the total synthesis of
various natural products including terpenoids and steroids.3,4
Recently, the first total synthesis of the neoclerodane (-)-methyl
barbascoate from diketone (-)-(R)-1 (R ) Me) was reported
(Figure 1).3a The availability in large scale of more function-
alized Wieland-Miescher-type diketones such as 3 (Figure 2)
should open synthetic routes to more complex neoclerodanes
with attractive pharmacological properties (e.g., salvinorins5a
or salvinicins5b).
FIGURE 1. Wieland-Miescher-type diketones 1 and structure of (-)-
methylbarbascoate.
We recently initiated a program directed toward terpenoid
synthesis using diastereoselective Diels-Alder reactions of the
enantiomerically pure (SS)-5-methoxy-2-methyl-3-(p-tolylsul-
(1) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615.
(2) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl. 1971,
10, 496.
(3) See, for exemple: (a) Hagiwara, H.; Hamano, K.; Hoshi, T.; Suzuki,
T.; Kido, F. J. Org. Chem. 2005 70, 2250. (b) Ling, T.; Chowdhury, C.;
Kramer, B. A.; Vong, B. C.; Palladino, M. A.; Theodorakis, E. A. J. Org.
Chem. 2001, 66, 8843. (c) Katoh, T.; Nakatani, M.; Shikita, S.; Sampe, R.;
Ishiwata, A.; Ohmori, O.; Nakamura, M.; Terashima, S. Org. Lett. 2001,
3, 2701. (d) Banerjee, A. K.; Laya-Mimo, M. Stud. Nat. Prod. 2000, 175.
FIGURE 2. Wieland-Miescher-type triketone 3 and structure of
salvinorin A.
finyl)-1,4-benzoquinone 2 (Scheme 1) to construct a function-
alized skeleton with an angular methyl group.
10.1021/jo060486n CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/19/2006
4854
J. Org. Chem. 2006, 71, 4854-4861

Diels-Alder Reactions of an Enantiomerically Pure Sulfinylquinone
SCHEME 1
SCHEME 2. Synthesis of (+)-(SS)-5-Methoxy-2-methyl-3-
(p-tolylsulfinyl)-1,4-benzoquinone 2
The use of sulfinyl benzoquinones as dienophiles for Diels-
Alder reactions has experienced increased interest in recent
years.6,7 This methodology found its first synthetic application
in the enantioselective synthesis of angucyclinones using an
enantiomerically pure sulfinyl naphthaquinone as dienophile.8
Further investigations allowed the construction of enantiomeri-
cally pure angucyclinone-type skeletons via a tandem cycload-
dition/pyrolytic sulfoxide elimination sequence with kinetic
resolution of the racemic semicyclic dienes.9
The presence of a substituent in the starting quinone generally
influences the chemoselectivity of the cycloaddition. For
example, cycloaddition of (SS)-2-substituted 3-p-tolylsulfinyl-
1,4-benzoquinones with acyclic and cyclic dienes takes place
(4) Tokoroyama, T. Synthesis 2000, 5, 611. Advanced precursors of
natural products: (a) Kawano, H.; Itoh, M.; Katoh, T.; Terashima, S.
Tetrahedron Lett. 1997, 38, 7769. (b) Kawai, N.; Takao, K.-I.; Kobayashi,
S. Tetrahedron Lett. 1999, 40, 4193. (c) Nakatani, M.; Nakamura, M.;
Suzuki, A.; Inoue, M.; Katoh, T. Org. Lett. 2002, 4, 4483. (d) Coltart, D.
M.; Danishefsky, S. J. Org. Lett. 2003, 5, 1289. (e) Ling, T.; Rivas, F.;
Theodorakis, E. A. Tetrahedron Lett. 2002, 43, 9019. (f) Marko´, I. E.;
Wiaux, M.; Warriner, S. M.; Giles, P. R.; Eustace, P.; Dean, D. Bailey, M.
Tetrahedron Lett. 1999, 40, 5629. (g) Takao, K.-I.; Kobayashi, S.
Tetrahedron Lett. 1997, 38, 6685. Total synthesis of (+)-atisirene: (h) Ihara,
M.; Toyota, M.; Fukumoto, K. Kametani, T. J. Chem. Soc., Perkin Trans.
1 1986, 2151. Total synthesis of antibacterial clerodane: (i) Hagiwara, H.;
Inome, K.; Uda, H. Tetrahedron Lett. 1994, 35, 8189. Total synthesis of
(+)-dysideapalaunic acid: (j) Hagiwara, H.; Uda, H. J. Chem. Soc., Perkin
Trans. 1 1991, 1803. Total synthesis of (-)-ilimaquinone: (k) Bruner, S.
D.; Radeke, H. S.; Tallarico, J. A.; Snapper, M. L. J. Org. Chem. 1995, 60,
1114. Total synthesis of (+)-avarol and (+)-avarone: (l) An, J.; Wiemer,
D. F. J. Org. Chem. 1996, 61, 8775.(m) Ling, T.; Xiang, A. X.; Theodorakis,
E. Angew. Chem., Int. Ed. 1999, 38, 3089. Total synthesis of (-)-
ilimaquinone analogues: (n) Radeke, H. S.; Digits, C. A.; Bruner, S. D.;
Snapper, M. L. J. Org. Chem. 1997, 62, 2823. Total synthesis of
(-)-dysidiolide: (o) Corey, E. J.; Roberts, B. E. J. Am. Chem. Soc. 1997,
119, 12425. Sesquiterpenes: (p) Poigny, S.; Guyot, M.; Samadi, M. J. Org.
Chem. 1998, 63, 5890. Total synthesis of nakijiquinones: (q) Stahl, P.;
Waldmann, H. Angew. Chem., Int. Ed. 1999, 38, 3710. Total synthesis of
(+)-aureol: (r) Suzuki, A.; Nakatani, M.; Nakamura, M.; Kawaguchi, K.;
Inoue, M.; Katoh, T. Synlett 2003, 329
(5) (a) Salvinorins A and B: Ortega, A.; Blount, J. F.; Manchand, P. S.
J. Chem. Soc., Perkin Trans. 1 1982, 2505. Valde´s, L. J., III; Butler,
W. M.; Hatfield, G. M.; Paul, A. G.; Koreeda, M. J. Org. Chem. 1984,
49, 4716. Salvinorin C: Valde´s, L. J., III; Chang, H.-M.; Visger, D. C.;
Koreeda, M. Org. Lett. 2001, 3, 3935. Salvinorins D-F: Munro, T. A.;
Rizzacasa, M. A. J. Nat. Prod. 2003, 66, 703. (b) Harding, W. W.;
Tidgewell, K.; Schmidt, M.; Shah, K.; Dersch, C. M.; Snyder, J.; Parrish,
D.; Deschamps, J. R.; Rothman, R. B.; Prisinzano, T. E. Org. Lett. 2005,
7, 3017.
(6) (a) Carren˜o, M. C.; Garcia Ruano, J. L.; Toledo, M. A.; Urbano, A.;
Remor, C. Z.; Stefani, V.; Fischer, J. J. Org. Chem. 1996, 61, 503. (b)
Carren˜o, M. C.; Garcia Ruano, J. L.; Urbano, A.; Remor, C. Z.; Fischer, J.
Tetrahedron Lett. 1997, 38, 9077. (c) Carren˜o, M. C.; Urbano, A.;
Hernandez-Sanchez, R.; Mahugo, J. J. Org. Chem. 1998, 64, 1387. (d)
Carren˜o, M. C.; Garcia Ruano, J. L.; Toledo, M. A.; Lafuente, C.
Tetrahedron: Asymmetry 1999, 10, 1119. (e) Carren˜o, M. C.; Garcia Ruano,
J. L.; Toledo, M. A. Chem. Eur. J. 2000, 6, 288.-
preferentially on the unsubstituted dienophilic double bond.10
In light of the preceding work6,7,9 on sulfinylquinone cycload-
ditions, we reasoned that the presence of a methoxy group at
the C-5 position should modify the behavior of the new
dienophile and that the sulfinyl group should control the
stereochemical course of the cycloaddition.
Here, we report an efficient synthesis11 on a multigram scale
of the previously unknown (SS)-5-methoxy-2-methyl-3-(p-
tolylsulfinyl)-1,4-benzoquinone 2 and a straightforward access
to highly functionalized and enantiomerically pure Wieland-
Miescher-type triketone (-)-(R)-3 and diketone (-)-(R)-4
via a Diels-Alder reaction between 2 and dienes 5 and 6
(Scheme 1).
Results and Discussion
(+)-(SS)-Sulfinyl benzoquinone 2 was synthesized by using
aldehyde 7, which was easily prepared in two steps12 from
inexpensive 2-methylhydroquinone, according to the sequence
given in Scheme 2.
Initial attempts to introduce bromine directly on aldehyde 7
led to a mixture of regioisomers. The transformation was carried
out successfully by releasing the ortho-directing phenol group.
Selective demethylation of 7 using regioselective conditions
(AlCl3/NaI, reflux in MeCN) proceeded smoothly to give phenol
8 in quantitative yield. Ortho-bromination followed by protection
of the free alcohol afforded the bromide 10 in 94% yield for
two steps. A Baeyer-Villiger/hydrolysis process followed by
protection of the resulting phenol group provided the bromide
12 in high yield. It should be observed that this precursor 12
could be prepared easily within one week from aldehyde 7 in
batches larger than 100 g using only crystallizations for
purifications. Furthermore, the use of crude products from 7 to
12 is possible, but in this case a chromatography of the final
bromide 12 is necessary.
(7) Hanquet, G.; Colobert, F.; Lanners, S.; Solladie´, G. ARKIVOC 2003,
(Vii), 328.
(8) Carren˜o, M. C.; Urbano, A.; Fischer, J. Angew. Chem., Int. Ed. Engl.
1997, 36, 1621.
(9) (a) Carren˜o, M. C.; Urbano, A.; Di vitta, C. J. Org. Chem. 1998, 63,
3, 8320; Chem. Eur. J. 2000, 6, 906. (b) For racemic sulfinylquinone
resolution using enantiopure semicyclic dienes, see: Carren˜o, M. C.;
Urbano, A.; Ribagorda, M.; Somoza, A. Angew. Chem., Int. Ed. 2002, 41,
2755.
(10) Carren˜o, M. C.; Garcia Ruano, J. L.; Toledo, M. A.; Urbano, A.
Tetrahedron Lett. 1994, 35, 9759.
(11) For the difference between an “efficient” and an “effective” synthesis
see: Heathcock, C. H. Angew. Chem., Int. Ed. Engl. 1992, 31, 665.
(12) Standridge, R. T.; Howell, H. G.; Gylys, J. A.; Partyka, R. A.;
Shulgin, A. T. J. Med. Chem. 1976, 19, 1400.
J. Org. Chem, Vol. 71, No. 13, 2006 4855

Lanfranchi and Hanquet
SCHEME 3. Synthesis of rac-5-Methoxy-2-methyl-3-(p-tolylsulfinyl)-1,4-benzoquinone 2
SCHEME 4. Self-Condensation of p-Tolylsulfenic Acid to p-Tolyl Disulfide Oxide
SCHEME 5. Hagiwara’s Procedure to Diketone (-)-(R)-1
SCHEME 6. Cycloaddition of Sulfinylquinone 2 with
Dienes 5 and 6
Metalation and sulfinylation13 of 12 with (-)-(SS)-menthyl-
p-toluenesulfinate afforded sulfoxide 13 in 65% yield after
trituration in diethyl ether. Finally, direct oxidative demethyl-
ation using cerium ammonium nitrate (CAN) afforded the
desired (SS)-5-methoxy-2-methyl-3-(p-tolylsulfinyl)-1,4-benzo-
quinone 2 in high yield as orange needles after crystallization
in methanol. The enantiomeric purity (>98%) of the sulfinyl
1
quinone 2 has been measured by H NMR spectroscopy using
Eu(tfc)3 as a chiral lanthanide shift reagent. The racemic
compound (()-2, necessary for such a determination, was
synthesized from 12 in three steps (Scheme 3).
We next investigated the reactivity of the enantiomerically
pure dienophile 2 toward the diene 5 obtained from ethylvinyl
ketone,14 or piperylene 6 in order to prepare functionalized
Wieland-Miescher-type triketone 3 and diketone 4. Our goal
was to use the simplest chemistry applicable in large scale
providing large quantities of chiral starting material for total
synthesis of complex neoclerodanes. The best results were
achieved working in CH2Cl2 at -20 °C for 5 and at room
temperature for 6. Under these conditions, Diels-Alder reaction
between quinone (+)-2 and 2 equiv of dienes 5 and 6 gave rise
within 10 days respectively to mixtures of cycloadduct 14 or 4
(ee >97%) and p-tolyl disulfide oxide resulting from the
spontaneous pyrolytic elimination of the sulfinyl group of the
initially formed cycloadduct in the reaction mixture (Scheme
6). This elimination produced sulfenic acid which self-condensed
to p-tolyl disulfide oxide quite slowly at room temperature
(Scheme 4).15
The p-tolyl disulfide oxide is recovered after chromatography
of the crude mixture. Despite the quite long reaction time
required to obtain a total conversion, we point out that the
preparation of the less functionalized Wieland-Miescher di-
ketone (-)-(R)-1 from 2-methyl-1,3-cyclohexanedione using
optimized Hagiwara’s protocol requires 5 days (for the anne-
lation step) and also stoechiometric amounts of chiral catalyst
(Scheme 5).16
(13) (a) Andersen, K. K.; Gaffield, W.; Papanikolaou, N. E. J. Am. Chem.
Soc. 1964, 56, 5635. (b) Carren˜o, M. C.; Garcia Ruano, J. L.; Urbano, A.
Synthesis 1992, 651. (c) Girardin, A.; Hutt, J.; Solladie´, G. Synthesis 1987,
173. (d) Hajipour, A. R.; Falahati, A. R.; Ruoho, E. Tetrahedron Lett. 2006,
47, 2717.
(14) Belanger, J.; Landry, N. L.; Pare, J. R.; Jankowski, K J. Org. Chem.
1982, 47, 3649.
Chromatography of the reaction mixture on demetalated silica
gel17 delivered cycloadducts 14 and 4 in 90% yield. Subsequent
(15) (a) Barrett, G. C. In The chemistry of sulphenic acids and their
deriVatiVes; Pata¨ı S, Ed.; John Wiley and Sons: Chichester, 1990; p 1. (b)
Hogg, D. R. In The chemistry of sulphenic acids and their deriVatiVes;
Pata¨ı S, Ed.; John Wiley and Sons: Chichester, 1990; p 361. (c) Davies, F.
A.; Jenkins, L. A.; Billmeis, R. L. J. Org. Chem. 1986, 51, 1033.
(16) Hagiwara, H.; Uda, H. J. Org. Chem. 1988, 53, 2308.
(17) Chromatography of reaction mixtures using standard silica gel
afforded (R)-4 in 75% yield and a mixture of (R)-3 and (R)-14 in only 15
and 20% yield, respectively. For demetalated silica gel preparation, see:
Hubbard, J. S.; Harris, T. M. J. Org. Chem. 1981, 46, 2566.
4856 J. Org. Chem., Vol. 71, No. 13, 2006

Diels-Alder Reactions of an Enantiomerically Pure Sulfinylquinone
TABLE 1. Cycloaddition of Sulfinylquinone 2 with Dienes 5, 6, and 15-17 in CH2Cl2
a Isolated yields of diastereoisomers 18a and 18b mixture. b Sulfenic acid elimination from minor diastereoisomer 19b occurred in the reaction mixture.
1
c Time for total disappearance of sulfinylquinone 2 on H NMR spectra of the crude mixture.
treatment of compound 14 with TBAF led in high yield to
triketone 3 which can be crystallized in ether. The enantiomeric
excess (>97%) of triketone 3 and diketone 4 were determined
by 1H NMR spectroscopy using Eu(tfc)3 as a chiral lanthanide
shift reagent.18
As expected, the presence of a methoxy group at the C-5
position led to an exclusive reaction through C-2-C-3 sulfinyl
substituted double bond in these reactions, and the very high
π-facial diastereoselectivities observed agrees with previous
results reported in the literature.20,7 To rationalize the stereo-
chemical outcome of this reaction, we chose three other dienes
15-17 and compared their reactivity toward the sulfinyl-quinone
(S
and 6 (Table 1).
S)-2 in CH2Cl2 at room temperature or -20 °C with dienes 5
For all dienes we observed that cycloadditions performed at
-20 °C led to stable adducts bearing the sulfinyl moiety. The
pyrolysis process depended on the structure of the cycloadducts
and occurred only at room temperature (entries 6 and 8).
Under these conditions, Diels-Alder reactions between
quinone (SS)-2 and 2 equiv of dienes 16 and 17 gave rise to the
optically active cycloadducts 19a and 21 as major or exclusive
diastereoisomer in excellent yields (entries 3, 4, and 9). No
spontaneous sulfoxide moiety elimination was observed at room
temperature for the major diastereoisomer 19a, and attempts to
initiate the sulfenic acid elimination under various conditions
(refluxing in toluene, heating in basic or acidic medium) were
ineffective. In sharp contrast, this elimination occurred spon-
taneously with the minor diastereoisomer 19b in the reaction
(18) Racemic triketone (()-3 and diketone (()-4 were prepared from
racemic sulfinyl benzoquinone 2.
(19) VCD/IR measurements and analysis were performed by Prof. T.
Freedman.
(20) Freedman, T. D.; Nafie, L. A.; Cao, X. Dukor, K. Chirality 2003,
15, 734.
(21) Carren˜o, M. C. Chem. ReV. 1995, 95, 1717.
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Lanfranchi and Hanquet
FIGURE 3. Qualitative energy minimization (MM2) of 19a and 19b.
mixture at room temperature (entry 4). The corresponding adduct
20 resulting from the cycloaddition/sulfenic acid elimination
process was recovered in 7% yield after chromatography. We
suppose that in the case of cycloadduct 19a, none of the
hydrogen atoms R to the sulfinyl group were in a favorable
conformation to allow a syn-elimination (Figure 3).
The results collected in Table 1 showed that the stereochem-
ical course of the reaction was correlated with temperature for
acyclic dienes. Decrease of the temperature increased reaction
time and increased diastereoselectivity. For example, the reac-
tions of dienes 5 and 16 were moderately selective at 20 °C
(entries 3 and 7) and became totally diastereoselective at -20
°C to deliver compounds 3 (after sulfenic acid elimination at
room temperature) and 19a as single products (entries 3 and
7). Totally diastereoselective cycloaddition with quinone (SS)-2
occurred with dienes 6 and 17 even at 20 °C (entries 5 and 9).
The C-5 methoxy-induced chemoselectivity toward the C2-
C3 double bond was clearly illustrated when the cycloaddition
was performed with cyclopentadiene. Carren˜o described few
years ago6a a chemoselective cycloaddition of (SS)-2-p-tolyl-
sulfinyl-1,4-benzoquinone with cyclopentadiene exclusively on
C5-C6 double bond. In our case, despite the presence of an
unfavorable methyl substituant at the C-2 position, no cycload-
duct resulting from C5-C6 double bond reaction was observed.
Only clean mixture of 18a and 18b was formed. The diastereo-
isomeric ratio 18a/18b was determined directly from the crude
reaction mixture by 1H NMR analysis, and 18a/18b were readily
separated by flash chromatography. Unexpectedly, this ratio was
inverted at -20 °C (entry 2).
FIGURE 4. X-ray crystal structure of cycloadduct 18a.
and 6 only at room temperature within few hours. A flash
chromatography using demetalated silica gel afforded quanti-
tatively the p-tolyl disulfide oxide and the corresponding
pyrolized cyclodducts 3 and 4.
Configurationnal Assignments. The absolute configuration
of adduct 18a has been unambiguously assigned as (4aS,5S,8R,-
8aR) from its X-ray crystal structure (Figure 4).
The (R)-absolute configuration of the angular stereogenic
center was confirmed for 3 and 4 from comparison of
experimental with calculated VCD/IR spectra of pure samples.19
On the basis of the stereochemistry unambiguously assigned
to (-)-(R)-3, (-)-(R)-4, and (-)-(R)-18a, the comparison of
the different 1H NMR parameters and the previously described
model approaches for (SS)-2-p-tolylsulfinyl-1,4-benzoquinone,6
we established the configuration of 21 as (4aS,8S,8aS). The
absolute configuration (4aS, 8aR) could be assigned to adduct
19a on the basis of the precedent evidences and 1H-1H NOESY
experiments (Figure 5). Assuming that the lone pair of the
known (SS)-sulfinyl moiety was directed to the angular methyl
group to minimize steric interaction, and that the corresponding
oxygen-atom could not adopt a favorable conformation to allow
the stereospecific syn-elimination of sulfenic acid (Figure 3),
In sharp contrast with cyclopentadiene, acyclic dienes 5, 6,
and 16 afforded highly diastereoselective cycloadditions at -20
°C, leading exclusively to adducts bearing the sulfinyl moiety.
A rapid work up of the reaction mixtures gave these cycload-
ducts as solids stable upon storage at -20 °C. The sulfinyl syn-
elimination occurred for the adducts proceeding from dienes 5
4858 J. Org. Chem., Vol. 71, No. 13, 2006

Diels-Alder Reactions of an Enantiomerically Pure Sulfinylquinone
TABLE 2. Lewis Acid Reaction of Sulfinylquinone 2 in CH2Cl2 with 2 equiv of Piperylene 6
isolated
ee (%)
(abs config)
entry
Lewis acid
equiv
time
T (°C)
yieldsa (%)
1
2
3
4
5
6
7
8
9
ZnBr2
ZnBr2
ZnBr2
SnCl4
TiCl4
TiCl4
BF3.OEt2
InCl3
TMSOTf
1
2
2b
1
1
2
1
1
1
3 days
12 h
4 h
12 h
4 days
1 h
15 days
20 days
1.5 h
-20
89
92
91
80
90 (-) (R)
90 (-) (R)
95 (-) (R)
60 (-) (R)
97 (-) (R)
-20
-40
-20
-20
91
-20
degradation
49
72
-20
84 (-) (R)
80 (-) (R)
-20
-78 to -20
degradation
a Isolated yields after purification on demetalated silica gel. The use of standard silica gel decreased the given yields by 12-18%. b This reaction has been
performed with a large excess of diene (20e´q.).
FIGURE 6. Favored approaches of cyclic and acyclic dienes in Diels-
Alder reactions of (SS)-5-methoxy-2-methyl-3-(p-tolylsulfinyl)-1,4-
benzoquinone 2.
a large excess of diene was used (entry 3). All other tested Lewis
acids allowed the formation of the cycloadduct (-)-(R)-4 with
moderate π-facial selectivity, except TMSOTf which rapidly
destroyed the (Ss)-sulfinyl-quinone 2 (entry 9). As we can see,
the unvariable sign of the specific rotation of the isolated
FIGURE 5. NOE observed by the 1H-1H NOESY experiment of 19a.
samples demonstrated that the stereochemical course of the
reaction was identical with or without Lewis acids.
The catalytic activity of ZnBr2 was then explored during
cycloaddition of the other dienes with (SS)-sulfinylquinone 2.
the experimentally observed NOE depicted in Figure 5 was only
consistent with (4aS,8aR) absolute configuration for adduct 19a.
This 1H-1H NOESY experiment showed a relationship between
one of the proton of the methylene R to the sulfinyl group and
With a 1:2:2 (SS)-2/ZnBr2/substrate ratio in dichloromethane at
-20 °C, we observed that ZnBr2 caused a dramatic decrease of
reaction time and enhanced stereoselectivity to very high level
(Table 3). The case of cyclopentadiene (entry 1) illustrated this
catalytic activity in a spectacular way. The reaction time was
reduced to 2 h and only one cycloadduct (18a) was detected in
the crude mixture and isolated. In a similar way, cycloadduct
19a was obtained diastereoselectively as pure product after 12
h (entry 2). Unfortunately, diene 5 was not stable under these
conditions, even when stoechiometric amounts of Lewis acid
were used.
the more deshielded aromatic protons of the p-tolyl group.
The influence of several Lewis acids on the cycloaddition
with quinone (SS)-2 has also been evaluated. Cycloaddition with
diene 6 in dichloromethane at -20 °C has been selected as a
probe reaction. In fact, this diene was a good candidate as its
cycloaddition occurred with the same stereoselectivity at +20
and -20 °C. For all experiments, quinone (SS)-2 and Lewis
acid were mixed in dichloromethane at -78 °C and then stirred
for10 min before addition of the diene. Finally, the reaction
mixture was stored in freezer at -20 °C. The results are
summarized in Table 2.
All the observed stereochemical outcomes in thermal condi-
tions could be rationalized using the transition states previously
proposed by Carren˜o6,7 where the most favored endo approach
of the diene occurred from the face of the sulfinylquinone
containing the less sterically demanding lone pair at sulfur in
the more reactive s-cis conformation (Figure 6). Thus, consider-
ing the (R) absolute configuration induced at the angular methyl
group in all cycloadducts, the resulting enantiomers must arise
from the attack of the diene on the top face of (SS)-2.
The different diastereoselectivity observed in the cycloaddi-
tion of sulfinyl-quinone (SS)-2 with cyclic diene 15, 1-substituted
acyclic dienes 6, 17, and 2-substituted acyclic diene 5 could be
As expected, Lewis acid-catalyzed reactions were always
faster than their thermal analogues. Concerning asymmetric
induction, the best Lewis acid was TiCl4 (entry 5) used
stoechiometrically (97% ee). Nevertheless, the reaction remained
quite slow (4 days for total conversion), and the use of 2 equiv
of TiCl4 afforded unidentified decomposition products. Finally,
ZnBr2 (entries 1-3) proved to be the most efficient Lewis acid.
The reaction was much faster (12 h) with 2 equiv of Lewis
acid and the good enantioselectivity (90% ee) observed at -20
°C (entry 2) was enhanced up to 95% when the cycloaddition
was performed at -40 °C. At this temperature, cycloaddition
required longer reaction time but could be reduced to 4 h when
J. Org. Chem, Vol. 71, No. 13, 2006 4859

Lanfranchi and Hanquet
TABLE 3. ZnBr2 Cycloaddition of Sulfinylquinone 2 with Dienes 5, 6, and 15-17 in CH2Cl2
a 2 equiv of ZnBr2 was used.
FIGURE 7. Expected major conformations of (SS)-2 in the presence
of 1 equiv of Lewis acid.
FIGURE 8. Expected major conformation of (SS)-2 in the presence
of 2 equiv of ZnBr2.
explained by assuming the steric interaction between the
methylene bridge of the former or the substituant of the latter
with the quinone which develop in the transition state (1A and
1C). This interaction must be more severe with 2,3-disubstituted
diene 16 and does not exist with 1-substituted diene (1B), which
led to the better diastereoselectivity.
species such as 2D should be expected when a second equivalent
of Lewis acid was introduced (Figure 8).
Conclusions
The same π-facial diastereoselectivity observed in cycload-
ditions under thermal or Lewis acid conditions suggested the
existence of a similar reactive conformation of the sulfinyl
quinonic system in all the cases. This was in sharp contrast with
the previously described results obtained with 2-substituted
3-sulfinylquinones lacking the methoxy group at C-5 position
which afforded cycloadducts with opposite absolute configu-
ration when the reaction was performed under thermal conditions
or in the presence of chelating Lewis acid.6,7,9,10 A detailed
examination of the three possible situations (Figure 7) allowed
us to propose that, under Lewis acid conditions and assuming
preferred chelation with ZnBr2, 2B could be the reactive
conformation responsible of the favored approach of dienes from
the less hindered top face of (SS)-2 to afford cycloadducts with
the (R) absolute configuration at the angular methyl group.
In summary, we have reported a large-scale preparation of a
new enantiomerically pure sulfinyl quinone as dienophile for
highly chemo- and diasteroselective Diels-Alder cycloadditions.
This sulfinyl quinone is easily prepared in laboratory in 50-g
scale and is stable for years on storage in freezer. The
asymmetric synthesis of new enantiopure (ee >97%) Wieland-
Miescher-type ketones with differentiated functionalizations of
potential interest for the total synthesis of natural products have
been presented. Enantiomerically pure building blocks (-)-(R)-3
and (-)-(R)-4 can be prepared in 3 weeks on large scale using
very simple conditions and cheap reagents. This delay can be
reduced to 2 weeks for (-)-(R)-4 if ZnBr2 is used as catalyst
for the cycloaddition step.
Experimental Section
When 2 equiv of ZnBr2 was used, the reaction time decreased
and the sign of the specific rotation of isolated cycloadducts
remained the same. Assuming the formation of the chelated
species 2B from (SS)-2 and 1 equiv of ZnBr2, a bimetallic
Preparation of (+)-(S)S-5-Methoxy-2-methyl-3-(toluene-4-
sulfinyl)[1,4]benzoquinone (2). An aqueous solution (720 mL) of
ammonium cerium(IV) nitrate (CAN) (68.27 g; 124.52 mmol; 2.5
equiv) was added rapidly (<30 s) to a solution of sulfoxide 13
4860 J. Org. Chem., Vol. 71, No. 13, 2006

Diels-Alder Reactions of an Enantiomerically Pure Sulfinylquinone
(14.46 g; 45.16 mmol; 1.0 equiv) in MeCN (720 mL) at room
temperature. After stirring for 40 mn, the 1H NMR analysis
indicated that the oxidative demethylation was complete (extended
reaction time tends to decrease frankly the yield). The solvent was
evaporated and the mixture extracted with CH2Cl2 (2 × 400 mL).
The combined extracts were washed with water (400 mL) and brine
(400 mL) and dried over MgSO4. The solvent was evaporated in a
vacuum leaving the sulfinylquinone as an orange solid. Recrystal-
lization of the sulfinylquinone (+)-2 from boiling MeOH (100 mL)
gave pure (+)-2 (12.049 g; 92%) as bright orange needles. This
sulfinylquinone is stable on storage (4-8 °C, protected from light)
To a solution of quinone (+)-2 (1.0 g; 3.445 mmol; 1.00 equiv)
in 15 mL of dry CH2Cl2 under argon was added diene 5 (0.108 g;
6.890 mmol; 2.01 equiv) at -20 °C. The reaction flask was put
into the freezer (-20 °C) for 10 days. Flash chromatography on
demetallated silica gel (gradient elution 9/1 f 3/1 cyclohexane/
EtOAc) afforded pure (-)-14 as a yellow oil (0.960 g, 91%) which
crystallized on standing. (Note: chromatography of the reaction
mixture using standard silica gel afforded (-)-14 and (-)-4 in only
1
15 and 20% yield, respectively). H NMR (300 MHz; CDCl3): δ
0.26 (s, 9H); 1.29 (s, 3H). 2.29 (s, 3H); 2.53 (d, J ) 2 Hz, 1H);
2.55 (d, J ) 1 Hz, 1H); 3.82 (s, 3H); 5.35 (m, 1H); 5.91 (s; 1H).
13C NMR (75 MHz; CD2Cl2): δ 0.3 (SiMe3); 15.7; 25.3; 31.3; 53.1;
55.1; 107.5; 108.5; 131.4; 145.7; 149.3; 164.0; 180.9; 199.2. IR
(cm -1): 1652; 1604; 1536; 1213. TLC Rf: 0.30 (cyclohexane/
EtOAc 3/1). Mp: 117-118 °C (Et2O/pentane). Anal. Calcd for
1
for more than 2 years. H NMR (400 MHz; CDCl3): δ 2.39 (s,
3H); 2.51 (s, 3H); 3.79 (s, 3H); 5.96 (s, 1H); 7.30 (d, 3J ) 8.3 Hz,
3
2H); 7.64 (d, J ) 8.1 Hz, 2H). 13C NMR (75 MHz; CDCl3): δ
9.4; 21.4; 56.5; 107.9; 124.9; 130.1; 139.4; 144.5; 148.1; 157.8;179.1;
185.2. IR (cm-1): 1668; 1626; 1591; 1205. Mp: 133-134 °C
(MeOH) (mp racemic: 132-133 °C from MeOH). Anal. Calcd for
C15H14O4S: C, 62.05; H, 4.86; S, 11.04. Found: C, 61.89; H, 4.80;
C16H22O4Si: C, 62.75; H, 7.18. Found: C, 62.63; H, 7.39. [R]20
-160.7 (c ) 0.42; CH2Cl2).
)
D
A solution of TBAF (1 M in THF 1.633 mL; 1.633 mmol; 1
equiv) was slowly added to a THF (10 mL) solution of 14 (500
mg; 1.633 mmol; 1 equiv) at 0 °C under argon. After 10 min,
aqueous ammonium chloride solution (20 mL) was added. The
aqueous layer was extracted with EtOAc (3 × 15 mL). The
combined organic phases were washed with water (20 mL) and
brine (20 mL), dried over MgSO4, and concentrated in a vacuum
to give crude (-)-3. The crude triketone may be purified by flash
chromatography on demetalled silica gel (eluent cyclohexane/EtOAc
4/1) or crystallized in Et2O/pentane at -20 °C to afford pure (-)-3
(363.15 mg; 95% from chromatography or 313.5 mg; 82% from
S, 11.06. [R]20 ) +445.5 (c ) 1.00; CH2Cl2)
D
Preparation of (-)-(R)-2-Methoxy-4a,7,8-trimethyl-4R,5-
dihydro[1,4]naphthoquinone (4). To a solution of sulfinylquinone
(+)-2 (2 g; 6.9 mmol; 1.0 equiv) in 100 mL of dry CH2Cl2, under
argon, was added piperylene (mixture of isomers; 1.38 mL; 940
mg; 13.8 mmol; 2.0 equiv). After 10 days at rt, the solvent was
evaporated leaving the crude cycloadduct. Flash chromatography
on demetalled silica gel (gradient elution 9/1 f 3/1 cyclohexane/
EtOAc) afforded pure (-)-4 as a yellow oil (1.42 g, 91%) which
crystallized on standing. (Note: chromatography of the reaction
mixture using standard silica gel and cyclohexane/EtOAc, 2/1 as
eluent afforded (-)-4 in 72-75% yield). 1H NMR (200 MHz;
CDCl3): 1.39 (s, 3H); 2.35 (s, 3H); 2.53 (d, J ) 2 Hz, 1H); 2.55
(d, J ) 1 Hz, 1H); 3.81 (s, 3H); 5.89 (s, 1H); 6.09 (m, 1H); 6.22
(m, 1H). 13C NMR (75 MHz; C6D6): δ 21.9; 26.0; 32.8; 45.5; 55.5;
107.7; 129.0; 131.0; 133.3; 145.5; 164.1; 180.9; 199.9. IR (cm -1):
1650; 1602; 1201. TLC Rf: 0.26 (cyclohexane/EtOAc 2/1). Mp:
132 °C. Anal. Calcd for C13H14O3: C, 71.58; H, 6.42. Found: C,
1
crystallization). H NMR (300 MHz; CDCl3): 1.51 (s, 3H); 2.03
(s, 3H); 2.29 (m, 2H); 2.61 (m, 2H); 3.88 (s, 3H); 5.99 (s,1H). 13
C
NMR (75 MHz; CDCl3): δ 12.8; 26.0; 29.5; 33.4; 49.3; 56.7; 109.4;
138.9; 146.5; 163.1; 185.1; 198.2; 198.5. IR (cm -1): 1656; 1638;
1603; 1154. TLC Rf: 0.21 (cyclohexane/CH2Cl2/acetone 10/10/1).
Mp: 150 °C (Et2O/pentane) (mp racemic: 125 °C from Et2O/
pentane). Anal. Calcd for C13H14O4: C, 66.66; H, 6.02. Found: C,
66.41; H, 5.96. [R]20 ) - 63.5 (c ) 0.41; acetone).
D
71.39; H, 6.31. [R]20 ) -114.5 (c ) 0.40; CHCl3).
D
Preparation of (-)-(R)-2-Methoxy-4a,8-dimethyl-7-trimeth-
ylsilanyloxy-4a,5-dihydro[1,4]naphthoquinone (14) and (-)-(R)-
3-Methoxy-5,8a-dimethyl-8,8a-dihydro-7H-naphthalene-1,4,6-
trione (3). Note: The dienoxysilane 5 can be kept for more than a
year under an inert atmosphere at - 20 τï +15 °C without apparent
decomposition (1H NMR). Nevertheless, before launching the
Diels-Alder reaction with sulfinylquinone 2 and a not freshly
prepared diene, the latter should be dissolved in Et2O, washed with
a saturated NaHCO3 solution, then with brine, dried over MgSO4,
and distilled (50 °C/30 mbar) as a white oil.
Acknowledgment. We thank Prof. T. D. Freedman and X.
Cao for VCD/IR measurements and analysis, Prof. M. Carmen
Carren˜o for useful discussions, and the Collectivite´ territoriale
de Corse for financial support to D.A.L.
Supporting Information Available: Experimental procedures
and spectroscopic and crystallographic data. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO060486N
J. Org. Chem, Vol. 71, No. 13, 2006 4861