Diastereodivergent additions of aluminum and magnesium reagents to [(S)S]-3,6-dimethoxy-2-(p-tolylsulfinyl)-benzaldehyde

Article abstract of DOI:10.1016/S0040-4039(03)01369-8

Enantiomerically pure [(S)S]-3,6-dimethoxy-2-(p-tolylsulfinyl)-benzaldehyde, prepared in two steps from commercially available 2,5-dimethoxybenzyl alcohol, reacted with organomagnesium and organoaluminum derivatives in a highly diastereodivergent way giving rise respectively to the (S) or (R) alkyl aryl or diaryl carbinols in excellent chemical and optical yields. Enantiopure (S) and (R)-2,5-dimethoxyphenyl methyl carbinols were obtained through a two-steps sequence comprising nucleophilic addition of MeMgBr or AlMe₃ and desulfinylation with n-BuLi.

Full text of DOI:10.1016/S0040-4039(03)01369-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5597–5600
Diastereodivergent additions of aluminum and magnesium
reagents to [(S)S]-3,6-dimethoxy-2-(p-tolylsulfinyl)-benzaldehyde
´
Antonio Almor´ın, M. Carmen Carren˜o,* Alvaro Somoza and Antonio Urbano*
Departamento de Qu´ımica Orga´nica (C-I), Universidad Auto´noma, Cantoblanco, 28049 Madrid, Spain
Received 29 May 2003; revised 2 June 2003; accepted 2 June 2003
Abstract—Enantiomerically pure [(S)S]-3,6-dimethoxy-2-(p-tolylsulfinyl)-benzaldehyde, prepared in two steps from commercially
available 2,5-dimethoxybenzyl alcohol, reacted with organomagnesium and organoaluminum derivatives in a highly diastereodi-
vergent way giving rise respectively to the (S) or (R) alkyl aryl or diaryl carbinols in excellent chemical and optical yields.
Enantiopure (S) and (R)-2,5-dimethoxyphenyl methyl carbinols were obtained through a two-steps sequence comprising
nucleophilic addition of MeMgBr or AlMe3 and desulfinylation with n-BuLi.
© 2003 Elsevier Ltd. All rights reserved.
Enantiopure chiral secondary carbinols are important
starting materials for the total synthesis of natural
products.1 Enzymatic resolution of racemic derivatives,2
catalytic asymmetric hydrogenation3 or asymmetric
reduction of prochiral ketones with chirally modified
hydrides4 are general methods for the synthesis of
optically enriched secondary alcohols. Although the
catalytic asymmetric dialkylzinc addition to benzalde-
hydes has also been successfully applied to the synthesis
of aryl alkyl carbinols,5 to the best of our knowledge,
2,5-dimethoxy benzaldehyde has only been used as
substrate in the quinine-catalyzed additions of
diethylzinc6 and di-n-propylzinc7 en route to a natural
pyranonaphthoquinone, but no addition of Me2Zn has
been described. Thus, the corresponding 2,5-
dimethoxyphenyl methyl carbinol is only available in
enantiomerically enriched form by asymmetric reduc-
tion of the substituted acetophenone,8–10 and by enzy-
matic resolution.11 In all cases but the last one, only
one enantiomer is available with a maximum enan-
tiomeric purity of 91%. The presence of a 2,5-
dimethoxy aryl moiety in such carbinol is of huge
interest for the synthesis of natural quinones1a,12 since
such aromatic moiety can be easily oxidized into the
quinone by a variety of mild procedures.
to benzaldehydes bearing a chiral auxiliary, has been
scarcely investigated.13 In our continous search for new
applications of sulfoxides in asymmetric synthesis,14 we
were interested in knowing whether enantiopure ortho-
sulfinylbenzaldehydes can control the diastereoselective
addition of organometallic reagents by a 1,4 asymmet-
ric induction process. Several reports have been pub-
lished concerning the addition of nucleophiles to
carbonyl groups in molecules containing a chiral sulfox-
ide, that posses the reaction site remote from the sulfi-
nyl group (1,>3 asymmetric induction). These studies
have mainly focused on acyclic,15 heterocyclic16 and
naphthalenic systems.17 In spite of the good diastereose-
lectivities achieved in general, only one recent
example13 dealt with molecules containing a simple
benzene ring. In that report the use of the bulky
2,4,6-triisopropylphenylsulfinyl group as chiral inductor
was necessary to obtain only one of the two possible
carbinols in a diastereoselective way.
In this communication, we report that the common
p-tolylsulfinyl group, easily accessible from commer-
cially available starting materials, is very efficient in
directing the nucleophilic addition of different
organometallic derivatives on the carbonyl group of
[(S)S]-3,6-dimethoxy-2-(p-tolylsulfinyl)-benzaldehyde
(1), and allows the diastereodivergent synthesis of the
corresponding sulfinyl-substituted (S) or (R) alkyl aryl
or diaryl carbinols, by simply choosing the appropriate
organometallic reagent. A final desulfinylation step on
methyl derivatives, illustrates the usefulness of the pro-
cess to synthesize in optically pure form both enan-
tiomers of 2,5-dimethoxyphenyl methyl carbinol in a
short and efficient manner.
The asymmetric approach to enantiopure carbinols
based on the simplest addition of the widely used
Grignard reagents or other organometallic compounds
Keywords: asymmetric synthesis; benzaldehydes; diastereoselection;
organometallic additions; sulfoxides.
* Corresponding
authors.
E-mail:
carmen.carrenno@uam.es;
antonio.urbano@uam.es
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01369-8

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A. Almor´ın et al. / Tetrahedron Letters 44 (2003) 5597–5600
The synthesis of [(S)S]-1, depicted in Scheme 1, started
from commercially available 2,5-dimethoxybenzyl alco-
hol (2). After many synthetic effort, we found that the
ortho-directed18 lithiation of 2 using n-BuLi in refluxing
THF followed by addition of (1R,2S,5R,SS)-(−)-men-
thyl p-toluenesulfinate19 at −78°C afforded exclusively
the 3-sulfinyl regioisomer [(S)S]-3 in 21% isolated yield
(58% based on recovered starting material 2) showing
90% ee.20 After one recrystallization, the optical purity
of 3 was shown to be 96%. When the lithiation step was
performed at rt, a 70:30 mixture of 3 and its 5-sulfinyl
substituted regioisomer was formed in 60% isolated
yield (85% based on recovered 2). PCC oxidation of
alcohol 3 (Scheme 1) gave aldehyde [(S)S]-1 in 75%
yield and 96% ee.20
With [(S)S]-1 in hand, we began the study of nucle-
ophilic additions by using different methyl substituted
organometallic reagents as models to determine the role
of the metal in the control of the diastereoselectivity.
The best results of this study are summarized in Table
1.
The addition of MeMgBr in THF at −78°C occurred in
4 h (entry 1) affording exclusively diastereoisomer 4
{[h]2D0=−129 (c 1, CHCl3)}, which was shown to be
enantiomerically pure from its Mosher’s esters,21 bear-
ing the (S) absolute configuration at the newly created
stereogenic center. This result was in agreement with
that reported by Toru13 in the Grignard addition on
unsubstituted 2-(2,4,6-triisopropylphenylsulfinyl)-ben-
zaldehyde but contrasted with the poor selectivity
achieved (67:33) by using the p-tolylsulfinyl analogue.
With the aim of inverting the diastereoselection, we
tried to mix ZnBr2 with [(S)S]-1, prior to the reaction
with MeMgBr, but an identical diastereoselectivity
resulted, being diastereomer [S,(S)S]-4 formed as major
(entry 2). Other Lewis acids such as TiCl4 (entry 3),
Ti(OiPr)3Cl (entry 4) or AlCl3 (entry 5), as well as the
methyl titanium reagent MeTi(OiPr)3 (entry 6), gave
22
poorer conversions and/or lower diastereoselections.
When [(S)S]-1 was submitted to reaction with Me2Zn in
CH2Cl2 at rt for 16 h (entry 7), compound 4 was again
Scheme 1.
Table 1. Diastereoselective organometallic additions to [(S)S]-3,6-dimethoxy-2-(p-tolylsulfinyl)-benzaldehyde (1)
Entry
R-metal
Solvent
T (oC)
Time (h)
Carbinols (ratio)
D.e. (%)
Yield (%)
1
2
3
4
5
6
7
8
MeMgBr
THF
THF
CH2Cl2
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
−78
−48
−48
−48
−48
0
4
8
4 (>98):5 (<2)
4 (98):5 (2)
4 (92):5 (8)
4 (90):5 (10)
4 (64):5 (36)
4 (92):5 (8)
4 (98):5 (2)
4 (<2):5 (>98)
4 (3):5 (97)
8 (>98):9 (<2)
8 (<2):9 (>98)
10 (>98):11 (<2)
98
96
84
80
28
84
96
98
94
98
98
98
91
a
MeMgBr/ZnBr2
MeMgBr/TiCl4
MeMgBr/Ti(OiPr)3Cl
MeMgBr/AlCl3
MeTi(OiPr)3
Me2Zn
Me3Al
Me2AlCl
EtMgBr
Et3Al
a
b
c
3.5
4.5
5.5
4.5
16
0.3
1
5
1
8
d
20
90
92
84
68
64
76
−78
−78
−78
−78
−78
9
10
11
12
CH2Cl2
THF
PhMgBr
a Not determined.
b 11% conversion.
c 85% conversion.
d 10% conversion.

A. Almor´ın et al. / Tetrahedron Letters 44 (2003) 5597–5600
5599
generated with an excellent diastereoselectivity (98:2), in
90% yield. This high reactivity was noteworthy because
it is well documented that dialkylzinc reagents react
only sluggishly with aldehydes in the absence of cata-
lysts,23 and suggested an activation by the sulfoxide
which could interact with the organozinc reagent,
favoring the addition. This was confirmed by perform-
ing the reaction on 2,5-dimethoxybenzaldehyde, lacking
the sulfoxide. Under the same conditions (Me2Zn,
CH2Cl2, rt, 16 h), only a 5% of conversion was
observed.
generated in situ from AlCl3 and PhLi.24 When this
reagent was added over a solution of [(S)S]-1 in
CH2Cl2, no reaction occurred even at room tempera-
ture for 24 h. A similar negative result was observed
when [(S)S]-1 was treated with PhAlMe2, generated in
situ from a 1:1 mixture of Me2AlCl and PhLi.25 Under
the same conditions, 2,5-dimethoxybenzaldehyde disap-
peared in 24 h upon reaction with PhAlMe2 giving a
complex mixture where the addition products resulting
from the transfer of the Me and Ph groups could be
detected. This result suggested that the sulfoxide was
difficulting the reaction of bulky diphenylzinc or aryl
aluminum reagents with [(S)S]-1. Thus, the sulfinyl
group seems to play a crucial role facilitating the addi-
tion of alkyl groups from the organometallics and
difficulting the phenyl transfer.
Gratifyingly, when the reaction of [(S)S]-1 was carried
out with Me3Al in CH2Cl2 at −78°C, only diastereoiso-
mer 5 {[h]2D0=−156 (c 0.7, CHCl3)}, showing the (R)
configuration at the hydroxylic carbon was obtained
after 20 min (Table 1, entry 8). Carbinol 5 was isolated
with 92% yield in enantiomerically pure form (Mosher’s
esters).21 In the absence of the sulfoxide, the addition of
Me3Al to 2,5-dimethoxybenzaldehyde was compara-
tively slow (35% conversion after 20 min). This result
suggested an essential role of the sulfoxide controlling
both the diastereoselectivity and the reaction rate of the
process.
The high reactivity and stereochemical outcome of
R3Al (R=Me, Et) additions to [(S)S]-1 could be
explained through the initial formation of a species
such as A (Fig. 1), where the aluminum is associated to
the sulfinylic oxygen. The most favored disposition of
sulfur substituents is the one shown in A where the
small non-bonding electron pair is situated in the s-cis
disposition close to the carbonyl oxygen, which is
forced to be far from the ortho-methoxy group to avoid
electronic repulsions. The intramolecular transfer of the
alkyl R group to the most accesible Re-face of the
aldehyde, through a seven-membered cyclic transition
state, explains the formation of (R) carbinols.
Finally, Me2AlCl also showed
a high reactivity
(CH2Cl2, −78°C, 1 h) as nucleophile (Table 1, entry 9)
for the transfer of a methyl group, and its addition to
[(S)S]-1 followed a similar pattern. Compound 5 was
again formed with an excellent diastereoselectivity (de
94%). The same reaction on 2,5-dimethoxybenzalde-
hyde at −78 °C for 9 h took place with only a 40%
conversion.
The opposite diastereoselection observed in the addi-
tions of Mg or Zn derivatives, is explained from the
evolution of a chelate such as B (Fig. 1), where the
metal is associated to the sulfinyl and carbonyl oxygens.
The attack of a second equivalent of the organometallic
reagent to the Si-face of the carbonyl, justifies the
formation of the (S)-carbinols. A key structural feature
of B is the disposition of the non-bonding electron pair
at sulfur which could also interact with the electrophilic
organometallic reagent favoring the Si face attack.
Both mechanistic proposals explain the enhanced reac-
tivity observed for R3Al (favored intramolecular trans-
fer) and Me2Zn or Grignard reagents (activation of the
carbonyl group by chelation) due to the presence of the
sulfoxide. The lack of reactivity observed for the aryl
zinc or aluminum reagents could be due to their bulky-
ness and lower electrophilicity. This avoids the assoca-
Cleavage of the sulfoxide of 4 and 5 was achieved with
n-BuLi at −78°C (Scheme 1) through the dilithiated
intermediates (S)-6 and (R)-6 which were trapped with
H2O to give enantiomerically pure (Mosher%s esters)21
aryl methyl carbinols (S)-7 and (R)-79a (88% yield).
This desulfinylation step is of huge interest since inter-
mediates 6 could be trapped by other electrophiles
opening access to differently tetrasubstituted aromatic
carbinols.
With the aim of determining the generality of this
diastereodivergent
process,
we
added
other
organometallic reagents to [(S)S]-1. Thus, EtMgBr
(Table 1, entry 10) gave exclusively diastereomer
[S,(S)S]-8 {[h]2D0=−107 (c 0.4, CHCl3)}, whereas AlEt3
afforded the [R,(S)S] epimer 9 {[h]2D0=−146 (c 0.2,
CHCl3)}, as a sole diastereomer (entry 11). Phenyl
magnesium bromide (entry 12) reacted with [(S)S]-1
leading to the exclusive formation of diaryl carbinol
[S,(S)S]-10 {[h]2D0=−173 (c 0.5, CHCl3). Upon treat-
ment of [(S)S]-1 with Ph2Zn at rt for 24 h in CH2Cl2,
the starting material was recovered unchanged. This
lack of reactivity was surprising tacking into account
that diphenylzinc is able to react with benzaldehydes
even without catalysts.5a
In order to check if a phenyl aluminum derivative was
able to invert the diastereoselectivity of the process, we
tried to perform the nucleophilic addition of Ph3Al
Figure 1.

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A. Almor´ın et al. / Tetrahedron Letters 44 (2003) 5597–5600
tion to the basic centers of [(S)S]-1, essential for the
effective transfer of aryl groups.
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sulfinylcarbinols 4–5 and 8–9, as well as the [S,(S)S]
diastereomer of diarylcarbinol 10 in excellent chemical
and optical yields, simply by selecting the organometal-
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Acknowledgements
We thank MCYT (Grant BQU2002-03371) for financial
support and Comunidad Auto´noma de Madrid for a
fellowship to AS.
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