Diastereoselective uncatalyzed conjugate addition of organoaluminum reagents: Efficient desymmetrization of (R)-[(p-Tolylsulfinyl)methyl]quinols

Full text of DOI:10.1021/jo961126a

6758
J . Org. Chem. 1996, 61, 6758-6759
one8 ) showing a prochiral dienone moiety, upon reaction
with organoaluminum reagents. We find that exclusive
1,4-addition proceeds without other metal catalysts in
good yields and mild conditions. The reaction occurs from
the face containing the OH with a total π-facial diaste-
reoselectivity and an effective desymmetrization of the
dienone moiety allowing the simultaneous generation of
two stereogenic centers.
Dia ster eoselective Un ca ta lyzed Con ju ga te
Ad d ition of Or ga n oa lu m in u m Rea gen ts:
Efficien t Desym m etr iza tion of
(R)-[(p-Tolylsu lfin yl)m eth yl]qu in ols
M. Carmen Carren˜o,* Manuel Pe´rez Gonza´lez, and
Mar´ıa Ribagorda
Departamento de Qu´ımica Orga´nica (C-I), Universidad
Auto´noma, Cantoblanco, 28049 Madrid, Spain
The results of reactions with a number of organoalu-
minum reagents are summarized in Table 1. We found
that better yields were obtained when 1 or 2 was added
J ean Fischer
over an excess of AlR2R3 (4 equiv). All reactions run in
2
CH2Cl2 led to compounds 3 and 4 resulting from the
exclusive 1,4-conjugate addition. Both 1 and 2 (a â,â-
disubstituted enone) behaved similarly toward trialkyl-
(Table 1, entries 1, 2, 6, and 7), alkinyl- (Table 1, entries
3, 4, 8, and 9), or vinylalanes (Table 1, entries 5 and 10),
giving rise to only one out of the four possible diastere-
omers in good yields. The unambiguous stereochemical
assignment of 3 and 4 was established on the basis of a
Laboratoire de Cristallochimie, UA 424, Universite´ Louis
Pasteur, 67070-Strasbourg, France
Received J une 17, 1996
The development of efficient enantioselective 1,4-
conjugate addition reactions has focused the interest of
several research groups in the past two decades. High
asymmetric inductions have been achieved by using
chiral electrophiles, nucleophiles, and to a lesser extent,
chiral catalysts.1 A number of reports demonstrated that
a sulfoxide on either the acceptor2 or the nucleophile3 can
efficiently control the diastereofacial selectivity of the
conjugate addition. To our knowledge, no reports dealing
with δ-sulfinyl-R,â-unsaturated carbonyl systems have
been published so far.
In the course of our investigations devoted to the use
of sulfoxides in asymmetric synthesis,4 we found that
DIBAL5 or alkylalanes6 reacted in a highly diastereose-
lective manner with â-keto sulfoxides. Thus, matching
sulfoxides with aluminum derivatives seemed to be
highly efficient in asymmetric reactions. Seeking to
further exploit this combination, we thought of conjugate
additions.
1
detailed H-NMR study and confirmed by X-ray diffrac-
tion of 4b.9
The high reactivity here reported is surprising because
such an easy reaction had only been found in a few cases
for simple alanes10 or in the presence of some transition
metals.11 In the absence of any other metal, the 1,4-
transfer was only possible via a free-radical process12 or
by using dialkylaluminum halides.13 In our case, we
could disregard a free-radical process based on a control
experiment in the presence of the radical scavenger
galvinoxyl with 1 and AlMe3. Even more remarkable are
the stereospecificity and the effective diastereotopic CdC
bond selection observed. A similar diastereoselective
process on p-quinols directed by the OH was found in
Recently, we synthesized (R)-4-hydroxy-4-[(p-tolylsulfi-
nyl)methyl]-2,5-cyclohexadienone (1)7 and observed an
intriguing diastereotopic CdC group selection for its
Diels-Alder cycloadditions. In the present work, we
investigate the behavior of p-quinols 1 and 2 (prepared
from 4,4-dimethoxy-2,6-dimethyl-2,5-cyclohexadien-1-
(8) Pelter, A.; Elgendy, S. Tetrahedron Lett. 1988, 29, 677.
(9) Crystal data for 4b revealed the associated structure shown:
* To whom correspondence should be addressed. E-mail:
carreno@ccuam3.sdi.uam.es.
(1) Reviews: (a) Schmalz, H. G. in Comprehensive Organic Synthe-
sis; Trost, B. M., Fleming, I, Eds.; Pergamon: Oxford, 1991; Vol. 4,
Chapter 1.5. (b) Rossiter, B. E.; Swingle, N. M. Chem. Rev. 1992, 92,
771. (c) Perlmutter, P. Conjugate Addition Reactions in Organic
Synthesis; Pergamon Press: Oxford, 1992. For recent references see:
(d) Urban, E.; Knu¨hl, G.; Helmchen, G. Tetrahedron 1996, 52, 971. (e)
Enders, D.; Kirchhoff, J .; Mannes, D.; Raabe, G. Synthesis 1995, 659.
(2) Review: Posner, G. H. In The Chemistry of Sulfones and
Sulfoxide; Patai, S., Rappoport, Z., Stirling, C. J . M., Eds.; J ohn Wiley
& Sons: New York, 1988; Chapter 16.
(3) (a) Review: Hua, H. D. In Advances in Carbanion Chemistry;
Snieckus, V., Ed.; J AI Press: London, 1992; Vol. 1, p 249. (b) Haynes,
R. K.; Katsifis, A. G.; Vowiller, S. C.; Hambley, T. W. J . Am. Chem.
Soc. 1988, 110, 5423. (c) Marco, J . L.; Ferna´ndez, I.; Khiar, N.;
Ferna´ndez, P.; Romero, A. J . Org. Chem. 1995, 60, 6678.
(4) For an overview of our work see: (a) Carren˜o, M. C. Chem. Rev.
1995, 95, 1717. (b) Solladie´, G.; Carren˜o, M. C. Organosulphur
Chemistry: Synthetic Aspects; Page, P. C. B.,Ed.; Academic Press: New
York, 1995; Chapter 1.
(5) (a) Carren˜o, M. C.; Garc´ıa Ruano, J . L.; Mart´ın, A. M.; Pedregal,
C.; Rodr´ıguez, J . H.; Rubio, A.; Sa´nchez, J .; Solladie´, G. J . Org. Chem.
1990, 55, 2120. (b) Bueno, A. B.; Carren˜o, M. C.; Garc´ıa Ruano, J . L.;
Pen˜a, B.; Rubio, A.; Hoyos, M. A. Tetrahedron 1994, 50, 9355.
(6) Carren˜o, M. C.; Garc´ıa Ruano, J . L.; Maestro, M. C.; Pe´rez
Gonza´lez, M. Tetrahedron 1993, 49, 11009. Bueno, A. B.; Carren˜o, M.
C.; Garc´ıa Ruano, J . L. Tetrahedron Lett. 1995, 36, 3737. Et2AlCN also
produced cyanhidrines diastereoselectively; see: Escribano, A. M.;
Garc´ıa Ruano, J . L.; Mart´ın-Castro, A. M.; Rodr´ıguez, J . H. Tetrahedron
1994, 50, 7567.
This hydrogen bonding association should be maintained in solution
to account for the low chemical shift observed for the CH3 of the ethyl
substituent (δ ) 0.78 ppm) as a consequence of the anisotropic effect
exerted by the spatially close aromatic ring. A similar effect could be
observed in the proton or methyl group situated on the pro-R double
bond of p-quinols 1 and 2.
(10) (a) Pappo, R.; Collins, P. W. Tetrahedron Lett. 1972, 2627. (b)
Collins, P. W.; Dajani, E. Z.; Bruhn, M. S.; Brown, C. H.; Palmer, J .
R.; Pappo, R. Tetrahedron Lett. 1975, 4217. Hooz, J .; Layton, R. B. J .
Am. Chem. Soc. 1971, 93, 7320.
(11) For recent references see: (a) Flemming, S.; Kabbara, J .;
Nickisch, K.; Neh, H.; Westermann, J . Synthesis 1995, 317. (b)
Kabbara, J .; Flemming, S.; Nickisch, K.; Neh, H.; Westermann, J .
Tetrahedron 1995, 51, 743. (b) Westermann, J .; Nickisch, K. Angew.
Chem., Int. Ed. Engl. 1993, 32, 1368.
(12) Kabalka, G. W.; Daley, R. F. J . Am. Chem. Soc. 1973, 95, 4428.
(13) (a) Ashby, E. C.; Noding, S. A. J . Org. Chem. 1979, 44, 4792.
(b) Ru¨ck, K.; Kunz, H. Synlett 1992, 343. (c) Ru¨ck, K.; Kunz, H. Angew.
Chem., Int. Ed. Engl. 1991, 30, 694.
(7) Carren˜o, M. C.; Pe´rez Gonza´lez, M.; Fischer, J . Tetrahedron Lett.
1995, 36, 4893.
S0022-3263(96)01126-7 CCC: $12.00 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 20, 1996 6759
Ta ble 1. Con ju ga te Ad d ition s of AlR2R3 to 1 a n d 2
2
F igu r e 1. Associated species leading to high site and dias-
tereofacial selective 1,4-conjugate addition.
yield
mp
(°C)
a
substr
R2
R3 prod t (h) (%) [R]25
D
essential to the 1,4-addition. On the other hand, no
complete reaction was observed unless 4 equiv of AlMe3
was used (Table 2, entries 3-5).
1
2
3
4
5
6
7
8
9
1b
1b
1
1
1
2
2
2
2
Me
Et
Me 3a
Et 3b
4
3
3
2
4
2
3
3
3
3
71
89
+236 120
+229 85
C4H9CtC-
TMSCtC-
(E)-C4H9CdC- Me 3e
Me 3c
Me 3d
56c +220 oil
69c +276 138
These results provided a basis for explaining both the
high reactivity of these systems and the desymmetriza-
tion of the dienone moiety observed. The stoichiometric
addition of AlMe3 produced the formation of an unreac-
tive aluminum alkoxide where the metal is associated
with the sulfinylic oxygen as shown in Figure 1. This
species has a frozen chairlike conformation by the
equatorial p-Tol. In such an arrangement the axial
methyl group linked to the aluminum atom is hindering
the pro-S double bond to any nucleophile approach from
the face containing the alkoxide group and renders only
the pro-R conjugate position available. This could be the
origin of the diastereotopic group selection. The second
alane equivalent should associate the carbonyl oxygen.
The use of an excess of aluminum reagent warrants the
completion, due to the association between the reagent
and the sulfinylic oxygen that could retard the intramo-
lecular transfer assisted by the alkoxide.
53c
82
71
87
67
55
oil
Me
Et
Me 4a
Et 4b
+228 150
+204 104.5
+208 oil
+226 145.5
+138 oil
C4H9CtC-
TMSCtC-
(E)-C4H9CdC- Me 4e
Me 4c
Me 4d
10
2
c ) 1, CHCl3. T ) -78 °C. c In the crude mixture 5-10% of
a
b
3a and 10-15% of 1 were present.
Ta ble 2. AlMe3 Ad d ition to p-Qu in ols 1, 5, a n d 6 a t -78 °C
Further support for our hypothesis was found in
experiments carried out by mixing AlMe3 (2 equiv) with
2 and subsequent addition of the resulting species into a
solution containing AlEt3 (1 equiv). Under these condi-
tions, the ethyl-substituted compound 4b was the major
component of the reaction mixture (4a /4b: 30/70).16
The mechanism proposed, based on the assisted in-
tramolecular transfer of the organoaluminum reagent,
could justify the easy and controlled formation of a
stereogenic tertiary center (from 1) and a quaternary one
(from 2) whatever the nature of the radical to be
transferred.
products
starting
substr
equiv/t (h) 1,4
1,2-syn
1,2-anti
material
1
2
3
4
5
5
6
1
1
1
4/4
8
87
2
90
4/4
2
11a
1/4
100
95
34
2/7
5
3/21
66
a
Wipf, P.; Kim, Y. J . Am. Chem. Soc. 1994, 116, 11678.
Grignard additions to their lithium alkoxides14 in racemic
series, but the dienone desymmetrization of an optically
active p-quinol had only been achieved in an intramo-
lecular conjugate addition.15
The lack of 1,4-addition of the methyl-protected p-
quinol 5 with AlMe3 (Table 2, entry 1) indicated that the
free OH should be present to assist the organoaluminum
reagent in the transfer of the R2 group. Compound 6
produced 1,2- and 1,4-adducts (Table 2, entry 2), the
latter being minor. Thus, the sulfoxide seems to be
Ack n ow led gm en t. We thank Direccio´n General de
Investigacio´n Cient´ıfica y Te´cnica (Grant Nos. PB92-
161 and PB95-174) and Comunidad Auto´noma de
Madrid (CAM Grant No. AE 244/95) for financial
support. One of us (M.P.G.) thanks CAM for a fellow-
ship.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for the synthesis and characterization data of 1, 2, 3a -e,
4a -e, and 5 (7 pages).
J O961126A
(14) (a) Solomon, M.; J amison, W. C. L.; McCormick, M.; Liotta, D.
C.; Cherry, D. A.; Mills, J . E.; Shah, R. D.; Rodgers, J . D.; Maryanoff,
C. A. J . Am. Chem. Soc. 1988, 110, 3702. (b) Swiss, K. A.; Liotta, D.
C.; Maryanoff, C. A. J . Am. Chem. Soc. 1990, 112, 9393. (c) Swiss, K.
A.; Hinkley, W.; Maryanoff, C. A.; Liotta, D. C. Synthesis 1992, 127.
(15) Fujioka, H.; Kitagaki, S.; Ohno, N.; Kitagawa, H.; Kita, Y.;
Matsumoto, K. Tetrahedron: Asymmetry 1994, 5, 333.
(16) Once 2 equiv of AlMe3 was added to 2, an aliquot was extracted.
At this stage, only 2% of 4a was formed. In a parallel experiment,
compound 2 was added over a mixture containing 2 equiv of AlMe3
and 1 equiv of AlEt3. In this way, a 45:55 mixture of 4a and 4b was
obtained. Thus, the result of the experience mentioned in the text
suggests the mechanism proposed.