Enantioselective protonation of a lithium enolate derived from 2-methyl-1-tetralone using chiral sulfonamides

Article abstract of DOI:10.1246/bcsj.78.906

The synthesis of enantiomerically enriched (R)-2-methyl-1-tetralone (1) with 77% e.e. was achieved through protonation of its lithium enolate (3) using a C₂-symmetric tris-sulfonamide (6) as an internal chiral proton source. Access to the complementary (S)-enantiomer 1 with 33% e.e. was achieved using a related C₂-symmetric bis-sulfonamide (9) as the chiral proton source.

Full text of DOI:10.1246/bcsj.78.906

906 Bull. Chem. Soc. Jpn., 78, 906–909 (2005)
Ó 2005 The Chemical Society of Japan
Enantioselective Protonation of a Lithium Enolate Derived
from 2-Methyl-1-tetralone Using Chiral Sulfonamides
ꢀ
Michael J. Suggate, and Michael Watkinson
Gregory S. Coumbarides, Jason Eames, J. Erik W. Scheuermann, Kevin F. Sibbons,
ꢀ
Department of Chemistry, Queen Mary, University of London, Mile End Road, London E1 4NS, UK
Received October 27, 2004; E-mail: j.eames@qmul.ac.uk
The synthesis of enantiomerically enriched (R)-2-methyl-1-tetralone (1) with 77% e.e. was achieved through pro-
tonation of its lithium enolate (3) using a C2-symmetric tris-sulfonamide (6) as an internal chiral proton source. Access
to the complementary (S)-enantiomer 1 with 33% e.e. was achieved using a related C2-symmetric bis-sulfonamide (9) as
the chiral proton source.
The synthesis of optically active ꢀ-substituted carbonyl
compounds by the enantioselective protonation of enolic and
enolate species, derived from racemic carbonyl compounds,
is very well documented.1 The majority of these studies have
focussed on the use of chelating chiral proton donors. These
chiral proton donors have generally contained an heteroatomic
acid, such as O-based carboxylic acids,2 phenols,3 alcohols,4
and water,5 N-based amides,6 anilines,7 oxazolidinones,8
sulfonamides,9 succinimides,10 ammonium salts,11 amines,12
and S-based thiols.13 The success of these types of proton
donors is largely due to their mild acidity14 and efficient proton
transfer.15
sulfonamide (6), derived from the corresponding N-tosyl azir-
idine17 as our chiral proton source (Scheme 2). We have al-
ways preferred to use (ꢁ)-2-methyl-1-tetralone (1) as our pa-
rent compound due to its UV activity, predictable enolate ster-
eochemistry and known enantiomeric separability.18 We chose
to use enol acetate (2)19 as our pro-enolate precursor due to its
improved thermal stability over other related enol derivatives
(Scheme 1). This enol acetate (2) was efficiently synthesized
in 94% yield by the addition of acetic anhydride and HClO4
to a solution of (ꢁ)-2-methyl-1-tetralone (1) in CCl4 at room
temperature.20 The required lithium enolate complex (3) was
liberated from enol acetate (2) using House and Trost’s ap-
We have recently become interested in the use of chiral C2-
symmetric bis-sulfonamides,16 such as (R,R)-(4), as potential
chiral proton donors, since they have been shown to lead to
moderate-to-good levels of enantioselectivity for the proton-
ation of lithium enolate (3) [derived from the enol acetate
(2) of racemic 2-methyltetralone (1)] to give the corresponding
enantiomerically enriched 2-methyltetralone (R)-(1) with 64%
enantiomeric excess (Scheme 1). We now wish to report our
study on the use of a related class of conformationally flexible
C2-symmetric sulfonamides as potential chiral proton donors
for the enantioselective protonation of enol(ate)s derived from
racemic 2-methyltetralone (1). For this study, we focussed on
the use of chiral bis-sulfonamides (5), (7), and (8–10) and tris-
R1
N
R2
Ts
R2
Ts
NH
HN
5
6
7
8
9
10
R1
R2
Ac
Ts
Bn
H
Bn
H
i-Pr i-Pr i-Pr i-Pr i-Bu Bn
Scheme 2.
OLi-t-BuOLi
Me
O
OAc
H
MeLi.LiBr
(2 molar amounts)
Me
Me
Ac2O, HClO4
CCl4
2 × LiBr
THF, -78 °C
2; 94%
3
(rac)-1
O
S
N
O
H
OLi-t-BuOLi
O
Me
H
1. (R,R)-4, -78 °C
2. Me3SiCl
Me
H
(R,R)-4
H
N
S
H
O
3
(R)-1; 64% e.e.; 57%
O
Scheme 1.
Published on the web May 6, 2005; DOI 10.1246/bcsj.78.906

G. S. Coumbarides et al.
Bull. Chem. Soc. Jpn., 78, No. 5 (2005)
907
R1
R1
N
O
OSiMe3
Me
OAc
Me
1. MeLi.LiBr
Me
MeLi.LiBr
(2 molar amounts)
H
N
R2
Ts
R2
Ts
R2
Ts
R2
Ts
2 × LiBr
2. sulfonamides 5-10
THF, -78 °C
3. Me3SiCl
THF, -78 °C
NLi LiN
NH
HN
2
(R)-1
11
% Yield
5-10
12-17
Silyl Enol
Entry
% e.e.
Sulfonamides Ketone
% Yield
Ether
Scheme 4.
1
2
3
4
5
6
7
8
(R)-1
(R)-1
(R)-1
(R)-1
4
77
5
40
58
70
60
11
11
11
11
25
26
5
R1
N
R2
Ts
13
Ts Bn
R2
Ts
15
5
11
NLi LiN
5
6
9
(S)-1
(R)-1
33
2
52
60
11
11
7
10
18
12
Ac
14
16 17
Scheme 3.
R1
R2
H
Bn
H
proach,21 by the simple addition of MeLi LiBr complex in
THF (2 molar amounts) (Scheme 1).22
We initially screened a series of structurally related C2-sym-
metric bis-sulfonamides (5), (7), and (8–10), and tris-sulfon-
amide (6) as potential chiral Brønsted acids against the lithium
enolate complex (3) to determine their relative facial proton-
ation preference (Scheme 3). The addition of these sulfon-
i-Pr i-Pr i-Pr i-Pr i-Bu Bn
ꢂ
Scheme 5.
R1
N
R2
Ts
R2
ꢄ
amides to a stirred solution of enolate (3) in THF at ꢃ78 C,
NLi LiN
18
gave after quenching the resulting solution after 1 h with
Me3SiCl [to remove any unreacted enolate (3) in the form of
the corresponding silyl enol ether 11] the required enantiomer-
ically enriched 2-methyl-1-tetralone (1) in moderate yield
(Scheme 3). The facial preference and levels of enantioselec-
tivity were found to vary considerably depending on the struc-
tural nature of the sulfonamide used. The highest level of enan-
tioselectivity was obtained using the tris-sulfonamide (6),
which gave the 2-methyltetralone (1) enriched in its (R)-enan-
tiomer with 77% e.e. (Scheme 3, Entry 2). In the majority of
these cases, protonation occurred on the same face, leading
to the (R)-enantiomer. This was presumably due to the same
relative configuration being present in all of these substituted
sulfonamides (Scheme 3). However, a notable exception to this
was bis-sulfonamide (9), which preferred to protonate on the
opposite face, leading to the complementary (S)-enantiomer
(1) with 33% e.e. (Scheme 3).
Ts
OLi.LiBr
Me
Scheme 6.
OLi.LiBr
Me
1.
R1
O
H
N
3, -78 °C
Me
R2
Ts
R2
Ts
2. acetic acid, -78 °C
3. Me3SiCl
NLi LiN
12-17
(rac)-1; 41-69%
Yield
Lithium sulfonamide
Ketone
(rac)-1
(rac)-1
(rac)-1
(rac)-1
(rac)-1
(rac)-1
12
13
14
15
16
17
53%
69%
66%
52%
41%
47%
Our attention next turned to probing the use of these substi-
tuted lithium sulfonamides (12–17) as potential chiral scaf-
folds for the enantioselective protonation of enolate (3) using
acetic acid as an external mild achiral proton source
(Schemes 4 and 5). The formation of the required chiral lithi-
um enolate complex, such as (18), was achieved by deprotona-
tion of the chiral sulfonamides (5–10) with a solution of
MeLi LiBr complex in THF, followed by the addition of a
solution of pre-formed lithium enolate (3) [derived from the
ꢂ
Scheme 7.
corresponding enol acetate (2) and MeLi LiBr complex]
ꢂ
From this study it is evident that a co-ordinating chiral acid,
like a chiral sulfonamide, gives far superior enantiocontrol
than using a combination of chiral sulfonamide and an external
acid (acetic acid). The reasons for this are not clear; however,
there appear to be subtle effects within these chiral proton
sources that have a dramatic effect on the level and facial pref-
erence of protonation. Whilst the effect of changing the alkyl
substituent R2 appears to be slight, the stereoelectronic nature
of the substituent R1 has a dominant affect (e.g., Scheme 3,
(Schemes 6 and 7). The treatment of the enol acetate (2) with
MeLi LiBr in THF (2 molar amounts), followed by a slow ad-
ꢂ
dition of the lithium sulfonamides (12–17) and quenching the
resulting chiral ensemble (18) after 1 h with acetic acid, inter-
estingly gave no level of enantiocontrol (Schemes 5 and 6).
However, simple protonation of the resulting achiral lithium
enolate of 2-methyltetralone may have occurred to give race-
mic 2-methyltetralone (1).

908 Bull. Chem. Soc. Jpn., 78, No. 5 (2005)
Enantioselective Protonation
0.21 mmol) and MeLi LiBr (0.28 mL, 1.54 M in ether, 0.43
Entries 2 and 5). However, altering the Lewis basicity of the
amine donor (NR1) does not appear to influence the facial pro-
tonation. The sulfonamide donor (6) gave better levels of ster-
eoselectivity than an amine donor in (7) and (8) (Scheme 3,
Entry 2 versus Entries 3 and 4). Recently, there have been
some reports1 into the de-racemisation of 2-methyl-1-tetralone
(1) using other chiral Brønsted acids, such as chiral alcohols,23
ammonium salts,11 and amides.6b The associated levels of ster-
eocontrol were shown to be good to excellent (up to 94%
e.e.,23 40% e.e.,11 and 64% e.e.6b) for a wide range of structur-
ally different chiral acids. The results reported therein further
serve to substantiate the efficacy of chiral Brønsted acids in
the enantioselective protonation of lithium enolates derived
from 2-methyl-1-tetralone; however, as yet there is no clear
rationale between the levels of enentioselectivity, structure
of acids and their relative acidity. Investigations along these
lines are currently underway within our laboratories.
ꢂ
mmol)] in THF (2 mL) was added. The resulting solution was stir-
red for 1 h. The reaction was quenched by the dropwise addition
of acetic acid (1 mL). After a saturated solution of NaHCO3 (10
mL) was added, this solution was extracted with ether (2 ꢅ 20
mL). The organic phase was washed again with a saturated solu-
tion of NaHCO3 (10 mL) and the solvent was removed under a
vacuum. The residue was purified by flash chromatography on
silica gel, eluting with light petroleum:ether (9:1) to give 2-meth-
yl-1-tetralone (rac)-(1)18 (22 mg, 70%) as a colorless oil with 0%
enantiomeric excess (determined by chiral HPLC using a Chiral-
cel OD column18—solvent hexane:isopropyl alcohol (98:2); flow
rate: 0.70 mL/min; retention time (S)-enantiomer 10.95 min,
(R)-enantiomer 11.89 min).
We are grateful to Queen Mary, University of London for a
studentship (to JEWS), The Royal Society and The University
of London Central Research Fund for financial support, and
the EPSRC National Mass Spectrometry Service (Swansea)
for accurate mass determination.
Experimental
Typical Procedure for a Co-ordinating Acid. A solution of
MeLi LiBr (0.21 mL, 1.54 M in ether, 0.32 mmol) was added
ꢂ
References
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Typical Procedure for the Use of a Conjugate Base and Ex-
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ꢂ
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´
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