Stereocontrolled approach to phenyl cyclitols from (SR)- [(p -tolylsulfinyl)methyl]-p-quinol

Article abstract of DOI:10.1021/jo900109p

Reactions of enantiopure (SR)-[(p-tolylsulfinyl)methyl]-p-quinol with ArAlMe₂ reagents allowed a highly diastereoselective 1,4-addition of the aryl group with an efficient desyrnmetrization of the prochiral cyclohexadienone moiety. The asymmetr

Full text of DOI:10.1021/jo900109p

Stereocontrolled Approach to Phenyl Cyclitols from
(SR)-[(p-Tolylsulfinyl)methyl]-p-quinol
Est´ıbaliz Merino,† Rosanne P. A. Melo,‡ Montserrat Ortega-Guerra, Mar´ıa Ribagorda,* and
M. Carmen Carren˜o*
Departamento de Qu´ımica Orga´nica (C-I), UniVersidad Auto´noma, Cantoblanco, 28049-Madrid, Spain
maria.ribagorda@uam.es; carmen.carrenno@uam.es
ReceiVed January 19, 2009
Reactions of enantiopure (SR)-[(p-tolylsulfinyl)methyl]-p-quinol with ArAlMe2 reagents allowed a highly
diastereoselective 1,4-addition of the aryl group with an efficient desymmetrization of the prochiral
cyclohexadienone moiety. The asymmetric synthesis of phenyl-substituted polyoxygenated cyclohexane
derivatives was achieved by combining this reaction with a stereoselective reduction and elimination of
the ꢀ-hydroxysulfoxide, after oxidation to sulfone, to recover a carbonyl group, and a stereoselective
epoxidation.
Introduction
reagents with enoates in the presence of enantiopure ligands5
or with homochiral vinyl sulfoximines as the acceptor.6
Rhodium-catalyzed 1,4-addition of aryl boronic acids to enones
in the presence of chiral ligands is nowadays recognized as an
efficient method to form C-aryl bonds with high enantioselec-
tivity.7 The synthesis of 3-aryl-substituted ketones was achieved
by Knochel through a copper-catalyzed process using function-
alized arylmagnesium compounds generated by metalation of
arylhalides by isopropyl magnesium chloride in the presence
of lithium chloride.8 Westermann9 reported in 1998 the nickel-
catalyzed 1,4-addition of aryl dialkyl aluminum reagents to
Asymmetric conjugate additions have been efficiently achieved
by using chiral electrophiles, nucleophiles,1 and chiral catalysts,1,2
including metal catalysts3 and organocatalysts.4 Extensive
studies have been devoted to 1,4-addition of alkyl organometallic
reagents. When dealing with aryl organometallics, high stereo-
selectivities can be achieved upon reactions of aryl lithium
† Current address: Departamento de Qu´ımica Fundamental, Universidade
Federal de Pernambuco, CCEN, Recife-PE, Brazil.
‡ Current address: Institute for Organic Chemistry and Chemical Biology,
Goethe University of Frankfurt, Max-von-Laue Strasse 7, 60438 Frankfurt am
Main, Germany.
(1) Reviews: (a) Harutyunyan, S. R.; Den Hartog, T.; Geurts, K.; Minnaard,
A. J.; Feringa, B. L. Chem. ReV. 2008, 108, 2824–2852, and references cited
therein. (b) Krause, N.; Hoffmann-Ro¨der, A. Synthesis 2001, 171–196. (c) Krause,
N. Modern Organocopper Chemistry; Wiley-VCH Verlag GmbH: Weinheim,
Germany, 2002. (d) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033–8061.
(e) Rossiter, B. E.; Swingle, N. M. Chem. ReV. 1992, 92, 771–806. (f) Perlmutter,
P. In Conjugate Addition Reactions in Organic Synthesis; Pergamon Press:
Oxford, 1992. (g) Schmalz, H. G. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 4, Chapter 1.5.
(2) (a) Lopez, F.; Minnaard, A. J.; Feringa, B. L. Acc. Chem. Res. 2007, 40,
179–188. (b) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002, 19, 3221–
3236. (c) Kanai, M.; Shibasaki, M. In Catalytic Asymmetric Synthesis, 2nd ed.;
Ojima, I., Ed.; Wiley-VCH: Weinheim, Germany, 2000; pp 569-592. (d)
Yamaguchi, M. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz,
A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol 3, pp 1121-1139. (e)
Tomioka, K.; Nagaoka, Y. In ComprehensiVe Asymmetric Catalysis; Jacobsen,
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1120.
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Chem. ReV. 2008, 108, 2796–2823. (b) Christoffers, J.; Koripelly, G.; Rosiak,
A.; Roessle, M. Synthesis 2007, 1279–1300.
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18, 299–365. (b) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701–1716. (c)
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2829–2844. (b) Fagnou, K.; Lautens, M. Chem. ReV. 2003, 103, 169–196. Recent
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Tetrahedron Lett. 2008, 49, 2106–2110. (d) Stemmler, R. T.; Bolm, C. Synlett
2007, 1365–1370. (e) Mauleo´n, P.; Alonso, I.; Rodr´ıguez Rivero, M.; Carretero,
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2824 J. Org. Chem. 2009, 74, 2824–2831
10.1021/jo900109p CCC: $40.75 2009 American Chemical Society
Published on Web 02/24/2009

Stereocontrolled Approach to Phenyl Cyclitols
SCHEME 1. 4-Hydroxy-4-Substituted
2,5-Cyclohexadienones as Starting Materials in Asymmetric
Synthesis
SCHEME 2. Conjugate Additions on Enantiopure
4-Hydroxy-4-[(p-tolylsulfinyl)methyl]-2,5-cyclohexadienone
(SR)-1 and Applications in Asymmetric Synthesis
enones en route to 3-aryl ketones. The procedure was applied
to trisubstituted enones and allowed the access to quaternary
centers at the ꢀ-position. More recently, Alexakis10 reported
the enantioselective copper-catalyzed 1,4-aryl transfer of ary-
laluminum reagents to trisubstituted cyclic enones in the
presence of chiral phosphoramidite ligands, leading to quaternary
stereocenters. In spite of the advances reached, the stereose-
lective introduction of alkyl or aryl groups to symmetrically
4,4-disubstituted cyclohexadienones or 4-hydroxy-4-alkyl-
substituted cyclohexadienones (p-quinols) remains a challenge
in asymmetric synthesis due to the symmetry of such prochiral
moieties, where up to four diastereomers can be formed during
the conjugate addition. The stereoselective differentiation of the
two diastereotopic conjugate positions (pro-R and pro-S) and
the two different faces for each conjugate attack poses a
challenging problem whose efficient solution is of huge synthetic
interest due to the multifunctional nature and potential synthetic
utility of the p-quinol unit (Scheme 1).11
Efficient desymmetrizations of cyclohexadienone moieties
have only been achieved by Feringa,12 using a BINOL phos-
phoramidite ligand, in the Cu-catalyzed enantioselective 1,4-
additions of dialkyl zinc derivatives to p-benzoquinone monoket-
als and 4-alkoxy-4-alkyl-substituted cyclohexadienones. We
have found that (SR)-[(p-tolylsulfinyl)methyl]-p-quinol deriva-
tives such as 1, bearing a CH2-sulfoxide substituent at C-4,13
reacted with organoaluminum reagents (alkyl, alkenyl, or
alkynyl), leading to the exclusive formation of 1,4-conjugate
addition products in the absence of any other metal catalyst,14
in a highly chemo- and π-facial diastereoselective manner
(Scheme 2). The efficient desymmetrization of the prochiral
dienone moiety, reacting exclusively from the pro-S double bond
syn to the face containing the C-4 OH, allowed the controlled
formation of two stereogenic centers in a single step. Further-
more, we observed that the ꢀ-hydroxysulfoxide present in the
resulting 1,4-adducts could be regarded as a chiral equivalent
of a ketone, which can be recovered after oxidation to sulfone
and mild basic treatment.15 Both findings allowed us to
synthesize different chiral nonracemic alkyl hydroxy-substituted
cyclohexenones such as phorenol,15 as well as different natural
polyoxygenated cyclohexane derivatives16 and C-4 oxygenated
angucyclinones.17
Despite the rich latent functionality of enantiopure cyclo-
hexadienones, they had never been used for the synthesis of
aryl-substituted polyhydroxycyclohexane derivatives,18,19 prob-
ably due to the lack of efficient desymmetrization methods,
allowing the introduction of aryl nucleophiles to the p-quinols
in a conjugate and stereoselective manner. The efficient con-
struction of such derivatives is of huge interest since these
moieties are present in a group of natural products, the
Amaryllidaceae family and analogues20 that show important
biological properties, including anticancer activity. The potential
usefulness of p-quinols as starting materials for such interest
chiral targets prompted us to extend the scope of the conjugated
additions of 4-[(p-tolylsulfinyl)methyl]-p-quinols to aryl orga-
nometallics. We now report our results evidencing that the
remote sulfoxide is able to direct the reaction of 1 with aryl
organoaluminum reagents, leading to the 1,4-conjugate addition
products in a stereocontrolled manner without adding any
catalyst. C-aryl-substituted polyoxygenated cyclohexanes were
obtained by further transforming the initial 1,4-adducts through
a series of stereoselective reactions and the elimination of the
ꢀ-hydroxysulfoxide, after oxidation to sulfone, to recover a
ketone. The overall sequence can be regarded as an umpolung
(15) Carren˜o, M. C.; Pe´rez-Gonza´lez, M.; Ribagorda, M.; Somoza, A.;
Urbano, A. Chem. Commun. 2002, 3052–3053.
(16) Synthesis of natural polyhydroxycyclohexanes: (a) Carren˜o, M. C.;
Merino, E.; Ribagorda, M.; Somoza, A.; Urbano, A. Chem.sEur. J. 2007, 13,
1064–1077. (b) Carren˜o, M. C.; Merino, E.; Ribagorda, M.; Somoza, A.; Urbano,
A. Org. Lett. 2005, 7, 1419–1422.
(17) Synthesis of angucyclinones: (a) Carren˜o, M. C.; Ribagorda, M.; Somoza,
A.; Urbano, A. Chem.sEur. J. 2007, 13, 879–890. (b) Carren˜o, M. C.; Ribagorda,
M.; Somoza, A.; Urbano, A. Angew. Chem., Int. Ed. 2002, 41, 2755–2757.
(18) (a) Posternak, T. The Cyclitols; Holden-Day: San Francisco, CA, 1962.
(b) Hudlicky, T.; Cebulak, M. Cyclitols and Their DeriVatiVes: A Handbook of
Physical, Spectral, and Synthetic Data; VCH: New York, 1993. (c) Delgado,
A. Eur. J. Org. Chem. 2008, 3893–3906. (d) Marco-Contelles, J.; Molina, M. T.;
Anjum, S. Chem. ReV. 2004, 104, 2858–2899.
(8) (a) Varchi, G.; Ricci, A.; Cahiez, G.; Knochel, P. Tetrahedron 2000, 56,
2727–2731. (b) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp,
F.; Korn, T.; Sapountzis, I.; Anh Vu, V. Angew. Chem., Int. Ed. 2003, 42, 4302–
4320, and references cited therein.
(9) Westermann, J.; Imbery, U.; Nguyen, A. T.; Nickisch, K. Eur. J. Inorg.
Chem. 1998, 295–298.
(10) (a) Hawner, C.; Li, K.; Cirriez, V.; Alexakis, A. Angew. Chem., Int.
Ed. 2008, 47, 8211–8214. (b) Vuagnoux-D’Augustin, M.; Alexakis, A.
Chem.sEur. J. 2007, 13, 9647–9662. (c) Alexakis, A.; Albrow, V.; Biswas, K.;
D’Augustin, M.; Prieto, O.; Woodward, S. Chem. Commun. 2005, 2843–2845.
(11) Magdziak, D.; Meek, S. J.; Pettus, T. R. R. Chem. ReV. 2004, 104, 1383–
1429.
(12) (a) Imbos, R.; Minnaard, A. J.; Feringa, B. L. Tetrahedron 2001, 57,
2485–2489. (b) Imbos, R.; Brilman, M. H. G.; Pineschi, M.; Feringa, B. L. Org.
Lett. 1999, 1, 623–625.
(13) (a) Carren˜o, M. C.; Pe´rez-Gonza´lez, M.; Ribagorda, M.; Houk, K. N.
J. Org. Chem. 1998, 63, 3687–3693. (b) Carren˜o, M. C.; Pe´rez Gonza´lez, M.;
Ribagorda, M.; Fischer, J. J. Org. Chem. 1996, 61, 6758–6759.
(14) For the enantioselective asymmetric conjugate additions of trialkyl
aluminum reagents to trisubstituted enones in the presence of chiral Cu catalysts,
see ref 10.
(19) For synthesis of polyhydroxylated cyclohexanes, see for example: (a)
Ley, S. V. Pure Appl. Chem. 1990, 62, 2031–2034. (b) Motherwell, W. B.;
Williams, A. S. Angew. Chem., Int. Ed. Engl. 1995, 34, 203–213. (c) Hudlicky,
T.; Gonzalez, D.; Gibson, D. Aldrichimica Acta 1999, 32, 35–62. (d) Angelaud,
R.; Babot, O.; Charvat, T.; Landais, Y. J. Org. Chem. 1999, 64, 9613–9624. (e)
Crich, D.; Grant, D.; Wink, D. J. J. Org. Chem. 2006, 71, 4521–4524.
(20) (a) Kornienko, A.; Evidente, A. Chem. ReV. 2008, 108, 1982–2014. (b)
Rinner, U.; Hudlicky, T. Synlett 2005, 365–387. (c) Martin, S. F. In The Alkaloids;
Brossi, A. R., Ed.; Academic Press: New York, 1987; Vol. 40, pp 251-376. (d)
Polt, R. L. In Organic Synthesis: Theory and Applications; HudlickyT., Ed.;
JAI Press: New York, 1997; Vol. 3, pp 109-148. (e) Hoshino, O. In The
Alkaloids; Cordell, G. A., Ed.; Academic Press: New York, 1998; Vol. 51, pp
323-424. (f) Kireev, A. S.; Nadein, O. N.; Agustin, V. J.; Bush, N. E.; Evidente,
A.; Manpadi, M.; Ogasawara, M. A.; Rastogi, S. K.; Rogelj, S.; Shors, S. T.;
Kornienko, A. J. Org. Chem. 2006, 71, 5694–5707.
J. Org. Chem. Vol. 74, No. 7, 2009 2825

Merino et al.
SCHEME 3. Synthesis of Phenyl Organoaluminum
Reagents
SCHEME 4. Reaction of Phenyl Organoaluminum Reagents
with (SR)-1
R-arylation of the keto group recovered after the elimination of
methyl p-tolylsulfone.
Results and Discussion
over Ph2AlMe under the conditions indicated in Scheme 4 (entry
2), the conjugate addition product 2 was formed with a
conversion of 55% as a 75:25 mixture of diastereomers. The
absolute configuration of the phenyl adducts was determined
to be (4R,5R,SR)-2a and (4S,5S,SR)-2b (see below). The major
diastereomer (4R,5R,SR)-2a resulted from the 1,4-transfer of
the phenyl group from the organoaluminum reagent to the pro-S
conjugate position syn to the face containing the hydroxyl
substituent. We finally found that the reaction of 1 with
PhAlMe2, generated by transmetalation of PhLi (5 equiv) with
AlMe2Cl (5 equiv), gave the 1,4-addition product (4R,5R,SR)-
2a in a highly diastereoselective manner (dr: 96:4) and excellent
yield (98% for the mixture of diastereomers) (table in Scheme
4, entry 3).
It is worth mention that we did not observe the formation of
the product resulting from the transfer of a methyl group.28 The
use of such a high excess of PhAlMe2 was necessary for
the rapid completion of the reaction since with 1 or 2 equiv the
starting material remained unchanged and with 3 or 4 equiv
the conversion was not complete. To disregard PhLi as the
phenyl source in this reaction, we treated 1 with an excess of
PhLi. Under the same reaction conditions, using CH2Cl2 as
solvent and 5 equiv of PhLi, the p-quinol 1 was recovered
unchanged. The 1,2-addition products were formed in a poorly
stereoselective manner when the solvent for the PhLi addition
was changed to THF. The high reactivity shown by the
dimethylphenyl alane with our 4-hydroxy-4-[(p-tolylsulfinyl)-
methyl]-substituted cyclohexadienone had been already observed
for other alanes13,15,16 as well as the need of an excess of the
reagent to complete the 1,4-additions. The existence of the free
OH at C-4 in these substrates had been previously shown to be
essential to increase the otherwise poor reactivity of trialkyla-
lanes in uncatalyzed conjugate additions.13 In order to demon-
strate the role of the OH in the conjugate addition of the phenyl
aluminum reagent, we effected the reaction of 4-methoxy-
substituted cyclohexadienone (SR)-313b with PhAlMe2 under the
conditions used above (PhLi, AlMe2Cl, 0 °C). As shown in
Scheme 5, a mixture of diastereomers 4 and 5,29 resulting from
1,2-addition of the phenyl to the carbonyl group of 3, was
formed, from which both 4 and 5 could be isolated pure in 70
and 12% yield, respectively. The major diastereomer 4 resulted
from the attack of the phenyl aluminum reagent from the face
Enantiopure [(p-tolylsulfinyl)methyl]-p-quinol (SR)-1 was
synthesized from (SR)-methyl p-tolyl sulfoxide and p-benzo-
quinone dimethyl monoketal, as previously described.21 We
initially focused in the asymmetric conjugate addition of a
phenyl group. Reactions of p-quinols22,23 and their ethers22,24
with alkyl organometallic reagents had been shown to give
mixtures of 1,2- and 1,4-addition products, depending on the
nature of the reagent and/or the presence of the free OH in the
cyclohexadienone. In light of this background and our findings
on alkyl organoaluminum conjugated additions,13,25,26 we first
explored the reactivity of p-quinol 1 with phenyl alanes.
Triphenyl aluminum can be easily prepared by the addition of
a commercially available solution of PhLi (2.0 M in dibutylether,
3 equiv) over a suspension of AlCl3 in hexane at -78 °C to rt
(table in Scheme 3, entry 1).27 On the basis of the work by
Westermann,9 we envisaged also generating other phenyl
aluminum reagents, such as methyldiphenyl aluminum
(Ph2AlMe) or dimethylphenyl aluminum reagent (PhAlMe2).
Both alanes can be easily prepared by treating a solution of
MeAlCl2 or AlMe2Cl in hexane with PhLi (2 or 1 equiv,
respectively) (see table in Scheme 3, entries 2 and 3).
Freshly prepared phenyl organoaluminum reagents were
directly used in the reaction with p-quinol 1. We first tested
the behavior of Ph3Al. Taking into account the presence of the
free OH in the p-quinol 1, we used an excess of Ph3Al (5 equiv).
When a solution of 1 in CH2Cl2 was added over freshly prepared
Ph3Al at 0 °C, no reaction was observed, even after leading the
reaction mixture to warm to room temperature (table in Scheme
4, entry 1). The use of THF instead of CH2Cl2 did not give the
addition product either. By adding a solution of 1 in CH2Cl2
(21) Carren˜o, M. C.; Pe´rez Gonza´lez, M.; Fischer, J. Tetrahedron Lett. 1995,
36, 4893–4896.
(22) Wipf, P.; Kim, Y. J. Am. Chem. Soc. 1994, 116, 11678–11688.
(23) (a) Solomon, M.; Jamison, W. C. L.; McCormick, M.; Liotta, D.; Cherry,
D. A.; Mills, J. E.; Shah, R. D.; Rodgers, J. D.; Maryanoff, C. A. J. Am. Chem.
Soc. 1988, 110, 3702–3704. (b) Swiss, K. A.; Liotta, D. C.; Maryanoff, C. A.
J. Am. Chem. Soc. 1990, 112, 9393–9394. (c) Swiss, K. A.; Hinkley, W.;
Maryanoff, C. A.; Liotta, D. C. Synthesis 1992, 127–131.
(24) Stern, A. J.; Rohde, J. J.; Swenton, J. S. J. Org. Chem. 1989, 54, 4413–
4419.
(25) For reactions using organoaluminum reagents without added catalysts
in conjugate additions with enones, see: (a) Ru¨ck, K.; Kunz, H. Synlett 1992,
343–344. Nitrolefins see: (b) Pecunioso, A.; Menicagli, R. J. Org. Chem. 1988,
53, 45–49. (c) Fleming, I.; Moses, R. C.; Tercel, M.; Ziv, J. J. Chem. Soc, Perkin
Trans. 1 1991, 617–626.
(26) Account on synthetic applications on organoalanes: Woodward, S. Synlett
2007, 1490–1500.
(27) (a) Wu, K.-H.; Gau, H.-M. J. Am. Chem. Soc. 2006, 128, 14808–14809.
(b) Ku, S.-L.; Hui, X.-P.; Chien-An, C.; Kuo, Y.-Y.; Gau, H.-M. Chem. Commun.
2007, 3847–3849. (c) Bumagin, N. A.; Ponomaryov, A. B.; Beletskaya, I. P.
Tetrahedron Lett. 1985, 26, 4819–4822. (d) Gonza´lez-Ortega, A.; Pedrosa, R.;
Vicente, M. Synthesis 1984, 238–240.
(28) Upon reaction with alkenyl or alkynyldimethylaluminum reagents,
compound 1 gave 10-15% of the corresponding 5-methylcyclohexenone product;
see ref 13.
(29) The stereochemistry of the minor carbinol 5 was unequivocally
established by X-ray diffraction: CCDC 712061, Mr C21H22O3S, unit cell
parameters: a ) 7.36750(10), b ) 32.5836(6), c ) 7.58820(10) Å, ꢀ )
101.6190(10)°, space group P21; see Supporting Information for details.
2826 J. Org. Chem. Vol. 74, No. 7, 2009

Stereocontrolled Approach to Phenyl Cyclitols
SCHEME 5. Reaction of Phenyl Dimethyl Aluminum with 3
if the process could be general enough to introduce a wide range
of aryl and heteroaryl groups in the p-quinol 1. The in situ
transmetalation between an ArLi reagent and AlMe2Cl to
produce the ArAlMe2 required the previous formation of the
ArLi when not commercially available. Such aryl or heteroaryl
lithium reagents were generated by halogen-metal exchange
between an aryl or heteroaryl halide and n-BuLi or by directed
orthometalation from the adequately substituted aromatic pre-
cursor, depending on the availability of the starting material
(eq 1).
of the carbonyl opposite to the one bearing the more electro-
negative OMe substituent at C-4. This stereoselectivity was not
unexpected since precedent work by Wipf30 had evidenced that
remote dipolar interactions could control the π-facial diaste-
reoselectivity of 1,2-additions on 4-alkoxy-substituted 2,5-
cyclohexadienones. This result corroborates the essential role
of the free OH directing the conjugate addition on the p-quinol
1. It is worth mention that the analogue reaction of methoxy
derivative 3 with commercially available AlMe3 occurred much
more slowly, with a conversion of only 10% after 4 h.13b The
high reactivity observed when PhAlMe2, generated from PhLi
and AlMe2Cl, was the reagent can be due to presence of LiCl
in the reaction medium that could activate the cyclohexadienone
acceptor. With the commercially available AlMe3, the absence
of salts could be in the origin of the decreased reactivity.
A possible mechanistic pathway explaining the chemo- and
diastereoselective 1,4-addition of PhAlMe2 on p-quinol (SR)-1
is summarized Scheme 6. The stoichiometric addition of
PhAlMe2 led to an unreactive aluminum alkoxide A, where the
metal is associated with the sulfinylic oxygen. Although this
initial acid-base reaction could give two differently substituted
aluminum alkoxides, the formation of A must be favored on
the basis of the lower acidity of the conjugate acid lost (CH4:
pKa ∼55). This species, with a methyl and a phenyl substituent
at the aluminum, has a frozen chairlike conformation due to
the preferred equatorial disposition of the p-Tol and phenyl
groups. In such an arrangement, the axial methyl substituent
linked to the aluminum atom is hindering the pro-R double bond
to any nucleophile approach from the face containing the
alkoxide group and renders only the pro-S conjugate position
available. This could be the origin of the diastereotopic group
selection. The second alane equivalent, acting as a Lewis acid,
should associate the carbonyl oxygen increasing the reactivity
of the system (B). The use of an excess of aluminum reagent
warrants the completion, due to the associated nature of the
organoaluminum reagent,31 that could retard the intramolecular
transfer assisted by the alkoxide. A plausible explanation for
the lack of reactivity observed in the case of Ph3Al could be
the unfavorable formation of an aluminum alkoxide similar to
A, whose chairlike conformation has two bulky phenyl groups
at the aluminum atom. The high π-facial diastereoselectivity
directed by the OH could be expected considering the similar
diastereoselective 1,4-addition found in Grignard additions to
the lithium alkoxides of p-quinols in racemic series.23
The freshly prepared alane was directly used in the reaction
with the p-quinol 1. The results of the reactions with differently
substituted aryl dimethyl aluminum reagents are indicated in
Table 1. Starting from 4-trifluoromethyl bromobenzene 6, the
bromo-lithium exchange (n-BuLi, THF, -78 °C, 10 min) was
followed by the addition of a hexane solution of Me2AlCl (30
min). After evaporation of the solvents under vacuum, CH2Cl2
was added on the resulting aluminum reagent 12, followed by
a solution of (SR)-1 in CH2Cl2 at 0 °C and then warming the
reaction to room temperature. Under these conditions, a 60:40
mixture of diastereomers 18a and 18b was isolated in a poor
12% yield, which could not be improved even after long reaction
times (Table 1, entry 1). This experimental protocol was applied
to obtain all the aryl dimethyl aluminum reagents 13-17. The
p-quinol 1 was recovered unchanged when the aluminum reagent
13 was derived from p-nitrobromobenzene 7 (Table 1, entry
2). The poor yield obtained from the p-trifluoromethylphenyl-
substituted alane 12 and the lack of reaction with p-nitrophenyl
dimethyl aluminum 13 indicated that the electron-poor aryl
groups were not nucleophilic enough to be efficiently transferred.
Better results were obtained from p-methyl iodobenzene 8,
whose sequential treatment with n-BuLi and Me2AlCl to
generate the aluminum reagent 14, followed by addition of the
p-quinol 1, afforded a 95:5 mixture of compounds 19a/19b,
which was isolated in a 60% yield (Table 1, entry 3). The major
diastereomer 19a also resulted from the 1,4-addition on the pro-S
double bond of 1 from the face bearing the OH. A slightly lower
selectivity was observed in the reaction of compound 1 with
p-dimethylaminophenyl dimethyl aluminum 15 generated from
p-dimethylamino bromobenzene 9. A 90:10 mixture of diaster-
eomers 20a/20b resulted in 85% yield (Table 1, entry 4). The
alkoxy-substituted aryl aluminum reagents 16 and 17 were
formed from p-bromoanisol 10 and 3,4-methylenedioxy bro-
mobenzene 11, respectively, by sequential reaction with n-BuLi
and Me2AlCl. Their reaction with p-quinol 1 led to the 1,4-
addition products 21 and 22 in 95:5 (21a/21b) and 75:25 (22a/
22b) diastereomeric ratios (Table 1, entries 5 and 6). Taking
into account the frequent presence of the methylenedioxyphenyl
Once the experimental conditions for the transfer of the Ph
group from PhAlMe2 were optimized, we decided to investigate
SCHEME 6. Associated Species Explaining the High Site and Diastereofacial Selective 1,4-Addition
J. Org. Chem. Vol. 74, No. 7, 2009 2827

Merino et al.
TABLE 1. Reactions of Aryldimethyl Aluminum Reagents with (SR)-p-Quinol 1a
a THF was used as solvent.
SCHEME 7. Preparation of Dimethyl Heteroaryl Aluminum
Reagents 24, 27, and 30
moiety in the structure of natural products, we tried to improve
the diastereoselectivity of the reaction of 1 with the aluminum
reagent 17. After different reactions at lower temperatures and
different solvents, a slight improvement could only be achieved
when the p-quinol 1, dissolved in THF, was added to the
previously generated aluminum reagent 17 (Table 1, entry 7,
22a/22b, 80:20).
We also studied the behavior of heteroaryl dimethyl aluminum
reagents 24, 27, and 30, which were easily prepared by the
addition of the corresponding heteroaryl lithium reagent to
AlMe2Cl in hexane at -78 °C. A commercially available
solution of 2-thienyl lithium 23 (1 M in THF, 5 equiv) was
used for the preparation of dimethyl 2-thienyl aluminum 24 (5
equiv, hexane solution) (Scheme 7). 2-Benzofuranyl lithium
reagent 26, prepared by directed orthometalation of benzofuran
25 with n-BuLi in THF at -78 °C, was the precursor of
2-benzofuranyl dimethyl aluminum 27, and the 3-pyridyl
dimethyl aluminum 30 could be generated in two steps by
halogen-lithium exchange between 3-bromopyridine 28 and
n-BuLi followed by reaction of the resulting 3-lithiumpyridine
29 with AlMe2Cl (Scheme 7).
The results of the conjugate addition of the resulting
heteroaryl alanes to 1 are shown in Table 2. In all cases, a
solution of p-quinol (SR)-1 in THF was added over a freshly
prepared solution of the alane at 0 °C and then warming the
reaction mixture to room temperature. Dimethyl 2-thienyl
aluminum 24 gave the desired conjugate addition product as
80:20 mixture of diastereoisomers 31a and 31b in 90% yield
(Table 2, entry 1). The conjugate addition of dimethyl 2-ben-
zofuranyl aluminum 27 was completed within 2 h to give a
80:20 mixture of diastereomers 32a and 32b in a 75% yield
(Table 2, entry 2). The reaction was not so efficient with the
heteroaryl dimethyl aluminum reagent 30 derived from 3-py-
ridine. In such case, the reaction with (SR)-1 led to a poor 20%
yield of the corresponding 1,4-addition products 33a and 33b
as a 60:40 mixture (Table 2, entry 3).
This result obtained from the pyridyl derivative corroborated
that the transfer of aryl or heteroaryl groups from the aryl or
heteroaryl dimethyl aluminum intermediate to our p-quinol 1
only produced good conversions when the aryl group to be
transferred is a good nucleophile due to its electron-rich aromatic
nature. When the reactivity of the aryl aluminum was high
2828 J. Org. Chem. Vol. 74, No. 7, 2009

Stereocontrolled Approach to Phenyl Cyclitols
TABLE 2. Reaction of Heteroaryldimethyl Aluminum 24, 27, and
30 with (SR)-p-quinol 1
of small hydrides such as DIBAL-H on rigid cyclohexanones
is known to be even higher in cyclohexenones.33 Considering
the structure of 34, conformation A represented in Scheme 8,
with the CH2SO2p-Tol and Ph substituents in pseudoequatorial
positions would be more stable than B. If A is the reactive
conformer, the axial attack of the small hydride DIBAL-H
explains the major formation of the 1,4-cis-diol 35a in the
reduction process. We could improve this stereoselectivity by
34
using NaBH4 in the presence of CeCl3 as reduction system.
Using MeOH as solvent, we obtained exclusively diastereomer
(1R,4R,6R)-35a in an almost quantitative yield. With the aim
of inverting the stereoselectivity of this reduction, we tried
cyclohexenone 34 with L-Selectride, a bulky hydride whose
preference for the equatorial approach on rigid cyclohexanone
derivatives is well established.35 Surprisingly, the reaction of
compound 34 with L-Selectride gave rise again to an 85:15
mixture of 35a and 35b. Although the presence of the pseudo-
axial OH at C-4 in conformation A of 34 could make the
equatorial approach of the hydride by electrostatic interactions
difficult,36 such a preference for the axial attack of the bulky
hydride was not expected. Taking into account that the con-
formational energies of 4-substituted cyclohexene derivatives
are smaller than those of the saturated analogues,37 if we assume
that, in this case, B is the reactive conformer, the exclusive
equatorial approach of L-Selectride would explain the experi-
mental observation. Thus, although in conformer B the CH2SO2p-
Tol and Ph groups are in a less favored disposition, the transition
state resulting from the equatorial attack of L-Selectride to B
could be preferred.
enough, the site selectivity ranged from 95 to 80%, with the
pro-S double bond always preferred for the conjugate attack on
a 4-hydroxy-4-[(p-tolylsulfinyl)methyl]-2,5-cyclohexadienone
having the R absolute configuration at the sulfoxide. The π-facial
diastereoselectivity of the process was always very high since
the conjugate addition occurred exclusively from the face of
the 4-hydroxy-2,5-cyclohexadienone system containing the OH
group. This must be a consequence of both the smaller size of
the OH compared to the CH2SOp-Tol substituent at C-4 and
the assistance given by the oxygen in the intermediate of type
C shown in Scheme 6 in the aryl transfer. This assistance also
explains such an easy process with the otherwise poorly reactive
aluminum reagents.
Stereoselective Transformations of the Conjugate Adducts.
Applications of these site and diastereoselective arylaluminum
1,4-additions with 4-hydroxy-4-[(p-tolylsulfinyl)methyl]-2,5-
cyclohexadienone to asymmetric synthesis of arylcyclitols
required the stereoselective transformation of the 1,4-adducts
into differently oxygenated systems, as well as the elimination
of the ꢀ-hydroxy sulfoxide to recover a carbonyl group at C-4.
As mentioned above (Scheme 2), the latter had been used by
us as a key step in the enantioselective synthesis of different
alkyl-substituted polyoxygenated cyclohexane derivatives.16
To evaluate the influence of the presence of an aryl group
on the stereoselectivity of different transformations en route to
the aryl cyclitols, we choose compound (4R,5R,SR)-2a as a
model. Having in mind our previous protocol, we first oxidized
the sulfoxide into sulfone 34 (Scheme 8). Reduction of 34 with
DIBAL-H afforded an 80:20 mixture of carbinols 35a and 35b,
from which 35a was isolated pure in a 73% yield. The
(1R,4R,6R) configuration of 35a was established on the basis
of its NMR parameters and secured by X-ray diffraction.32 This
structural determination also confirmed the configurational
assignment of the stereogenic C-4 and C-5 centers of the
precursor 2a, created during the conjugate addition of phenyl
dimethylaluminum on p-quinol (SR)-1. The preferred axial attack
In order to recover a carbonyl group at C-1 of 35a by
retroaddition of MeSO2p-Tol upon treatment with Cs2CO3,15
we first protected the secondary OH at C-4 as the TBDMS
derivative (Scheme 9). Under the reaction conditions previously
established by us, after treatment of compound 36 with Cs2CO3
in CH3CN, we observed the formation of MeSO2p-Tol 37, but
we were unable to isolate any other product. Fortunately, when
we changed the solvent to CH2Cl2, the treatment of 36 with
Cs2CO3, under heterogeneous conditions, allowed the isolation
of cyclohexenone (4R,6R)-38a in a 68% yield, together with a
13% yield of the C-6 diastereomer (4R,6S)-38b, formed by
epimerization of 38a under the basic reaction conditions.
Diastereoselective transformations on 38a were further re-
quired to validate our strategy to the phenyl cyclitol derivatives.
The anti epoxidation of 38a was achieved in a highly diaste-
reoselective manner using the bulky tert-butylhydroperoxide
(TBHP) as oxidant and benzyltrimethylammonium hydroxide
(triton B, 40% in MeOH)38 as base. Under these conditions,
the epoxide 39 was formed in excellent yield. Reduction of 39
with NaBH4 in the presence of CeCl339 afforded an unseparable
(33) For a review, see: (a) Gung, B. Tetrahedron 1996, 52, 5263–5301. (b)
Wu, Y.-D.; Houk, K. N.; Trost, B. M. J. Am. Chem. Soc. 1987, 109, 5560–
5561.
(34) Li, K.; Hamann, L. G.; Koreda, M. Tetrahedron Lett. 1992, 33, 6569–
6570.
(35) (a) Wigfield, D. C. Tetrahedron 1979, 35, 449–462. (b) Brown, H. C.;
Krishnamurthy, S. J. Am. Chem. Soc. 1972, 94, 7159–7161.
(36) Wu, Y.-D.; Tucker, J. A.; Houk, K. N. J. Am. Chem. Soc. 1991, 113,
5018–5027.
(37) Conformational energy in cyclic derivatives: difference in free energy
between axial and equatorial substituents, see: Eliel, E. L., Wilen, S. H. In
Stereochemistry of Organic Compounds; John Wiley & Sons: New York, 1994.
(38) Barros, M. T.; Matias, P. M.; Maycock, Ch. D.; Ventura, M. R. Org.
Lett. 2003, 5, 4321–4323.
(39) Li, K.; Hamann, L. G.; Koreda, M. Tetrahedron Lett. 1992, 33, 6569–
6570.
(30) Wipf, P.; Jung, J.-K. Chem. ReV. 1999, 99, 1469–1480, and references
cited therein.
(31) Ashby, E. C.; Smith, R. S. J. Organomet. Chem. 1982, 225, 71–85.
(32) X-ray diffraction of 35a: CCDC 711956, Mr C20H22O4S1, unit cell
parameters: a ) 9.7463(2), b ) 9.6804(2), c ) 19.1212(4) Å, ꢀ ) 92.5600(10)°,
space group P21; for details, see Supporting Information.
J. Org. Chem. Vol. 74, No. 7, 2009 2829

Merino et al.
SCHEME 8. Stereoselective Carbonyl Reduction Reaction of 34
SCHEME 9. Synthesis of Polyoxygenated Aryl Cyclitols
protecting carbonyl group. The overall process can be regarded
as an umpolung since a phenyl group has been introduced R to
the ketone using a nucleophilic aryl donor.
Experimental Procedures
(4R,5R,SR)-4-Hydroxy-5-phenyl-4-[(p-tolylsulfinyl)methyl]-2-cy-
clohexenone (2a). To a solution of PhLi (0.96 mL, 1.92 mmol, 2
M in nBu2O) was added AlMe2Cl (1.92 mL, 1.92 mmol 1 M in
hexane) at 0 °C. The mixture was stirred at room temperature for
30 min and diluted with CH2Cl2. A solution of (SR)-4-hydroxy-4-
[(p-tolylsulfinyl)methyl]-2,5-cyclohexadienone 1 (100 mg, 0.38
mmol) in CH2Cl2 was then slowly added at 0 °C over the
organometallic solution. The reaction mixture was allowed to warm
to room temperature. After stirring for 30 min, the reaction was
quenched by the addition of saturated aqueous potassium sodium
tartrate. The mixture was then extracted with CH2Cl2, and the
organic layer was dried over anhydrous magnesium sulfate, filtered,
and concentrated in vacuo. The crude product (96:4 mixtures of
diastereomers) was purified by flash chromatography (eluent AcOEt/
hexane 3:1). Compounds 2 were obtained as colorless oil in 98%
mixture of epimeric carbinols 40a and 40b in a 80:20 ratio and
70% yield after column chromatography.
In conclusion, we have established a highly stereoselective
process to install an aryl substituent at the prochiral 2,5-
cyclohexadienone moiety of (SR)-4-hydroxy-4-[(p-tolylsulfi-
nyl)methyl]-2,5-cyclohexadienone 1 using an aryl organoalu-
minum reagent (ArAlMe2) in the absence of any other catalyst.
The aryl or heteroaryl aluminum reagents were generated in
situ by treatment of ArLi with AlMe2Cl, and an excess was
necessary to achieve the 1,4-addition at the conjugate pro-S
position in a highly site and π-facial diastereoselective manner
directed by both the OH and the sulfoxide. The study carried
out allowed us to establish that best yields and selectivities were
reached when the aryl nucleophiles bear electron-donating
substituents that increase the reactivity of the aluminum reagents.
With heteroaryl reagents, the π-excedent nature of the hetero-
cyclic moiety was also essential to give the 1,4-addition products
in good yields and stereoselectivities. The method opens an
efficient way to create C-aryl stereogenic centers from the
prochiral cyclohexadienone moiety. Further transformations of
product 2a, resulting from the reaction of 1 with PhAlMe2, were
carried out in order to know the stereoselectivity of reductions
and epoxidation reactions, en route to aryl cyclitols. A key step
with this aim was the elimination of the ꢀ-hydroxy sulfoxide,
after oxidation to sulfone, by retroaddition under basic condi-
tions (Cs2CO3, CH2Cl2), which allowed recovering a carbonyl
group. Thus, the ꢀ-hydroxy sulfoxide was used to direct the
stereoselective aryl conjugate addition and acted as a chiral
yield as a 96:4 mixture of (4R,5R,SR)-2a and (4S,5S,SR)-2b: [R]20
D
) +191 (c ) 0.55 in CHCl3); 1H NMR (300 MHz) δ ) 7.38-7.36
(AA′, 2H, p-Tol), 7.32-7.22 (m, 8H, Ph, H-3 and BB′ system of
p-Tol), 6.12 (d, J ) 10.2 Hz, 1H, H-2), 4.27 (s, OH), 3.39 (dd, X
part of ABX system, J ) 11.9 and 3.6 Hz, 1H, H-5), 3.21 (dd, A
part of ABX system, J ) 11.9 and 16.4 Hz, 1H, H-6), 2.89 and
2.70 (AB system, J ) 13.6 Hz, 2H, CH2p-Tol), 2.52 (dd, B part
of ABX system, J ) 16.4 and 3.6 Hz, 1H, H-6), 2.35 (s, 3H); 13
C
NMR δ ) 198.8, 148,6, 142.4, 139.5, 138.1, 130.3 (2C), 129.6
(2C), 129.4, 128.5 (2C), 127.8, 123.9 (2C), 70.7, 64.3, 50.1, 40.4,
21.4; MS (EI) m/z (%) 340 (8) [M]+, 324 (98), 306 (19), 236 (100);
HRMS calcd for C20H20O3S 340.1133, found 340.1131 [M]+.
(4R,5R)-4-Hydroxy-5-phenyl-4-[(p-tolylsulfonyl)methyl]-2-cyclo-
hexenone (34). To a solution of 2a (748 mg, 2.2 mmol, 1.0 equiv)
in CH2Cl2 (0.5 M) was added dropwise a solution of MCPBA,
predried over MgSO4 (475 mg, 2.7 mmol, 1.5 equiv) in CH2Cl2.
The resulting solution was stirred at 0 °C; once the reaction mixture
was completed by TLC, it was hydrolyzed with saturated Na2SO3
and extracted with CH2Cl2, then the organic layer was washed with
NaHCO3 and brine, dried over MgSO4, and the solvent was
evaporated under reduced pressure to afford compound 34 as a
yellowish solid which can be used without further purification (99%,
783 mg): mp 58-60 °C (AcOEt/CH2Cl2); [R]20D ) +4 (c ) 1.08,
acetone); 1H NMR (300 MHz, CDCl3) δ ) 2.36 (s, 3H, CH3), 2.47
(dd, part B of the ABX system, J ) 16.6 and 3.7 Hz, 1H, H6),
2830 J. Org. Chem. Vol. 74, No. 7, 2009

Stereocontrolled Approach to Phenyl Cyclitols
3.12-3.19 (m, 1H, H6′), 3.13 and 3.24 (AB system, J ) 14.3 Hz,
2H, CH2), 3.40 (dd, part X of the ABX system, J ) 12.4 and 3.7
Hz, 1H, H5), 3.70 (s, 1H), 6.20 (d, J ) 10.3 Hz, 1H, H2), 7.21-7.22
(m, 7H), 7.42 (d, J ) 10.3 Hz, 1H, H3), 7.62-7.65 (BB′ system,
2H, p-Tol); 13C NMR (75 MHz, CDCl3) δ 21.6, 40.5, 49.8, 62.5,
70.3, 127.6 (2C), 127.9, 128.7 (2C), 129.5, 129.6 (2C), 130.1 (2C),
137.5, 137.9, 145.4, 147.4, 198.5; MS (FAB) m/z (%) 357 (13) [M
+ 1]+, 341 (16), 307 (84); HRMS (FAB) calcd for C20H20O4S
357.1082, found 357.1076 [M + 1]+.
support. M.R. thanks MEC for a Ramo´n y Cajal contract. E.M.
and M.O.G. thank MEC for fellowships, and R.P.A.M. thanks
CAPES (Coordenac¸a˜o de Aperfeic¸oamento de Pessoal de N´ıvel
Superior) for financial support.
Supporting Information Available: Experimental details and
structural data (NMR spectra) for all compounds described
within the text and crystallographic data of compounds 5 and
35a. This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank MCYT (Grant CTQ2005-
02095) and MICINN (Grant CTQ2008-04691) for financial
JO900109P
J. Org. Chem. Vol. 74, No. 7, 2009 2831