The use of chiral dithianes for the synthesis of chiral α-oxo-β-alkyl and chiral α-oxo-β-aryl esters

Article abstract of DOI:10.1055/s-2002-32574

A number of chiral dithianes were synthesised using chiral auxiliary technology. These were then used as acyl anion equivalents in the synthesis of chiral α-oxo-β-alkyl and chiral α-oxo-β-aryl esters.

Full text of DOI:10.1055/s-2002-32574

LETTER
1073
The Use of Chiral Dithianes for the Synthesis of Chiral -Oxo- -Alkyl and
Chiral -Oxo- -Aryl Esters
Use of Chiral
D
l
ithiane
i
s
zabeth Tyrrell,* George A. Skinner, John Janes, Greig Milsom
Kingston University, Penrhyn Road, Kingston Upon Thames, Surrey KT1 2EE, UK
E-mail: e.tyrrell@kingston.ac.uk
Received 7 May 2002
Abstract: A number of chiral dithianes were synthesised using
chiral auxiliary technology. These were then used as acyl anion
equivalents in the synthesis of chiral -oxo- -alkyl and chiral
oxo- -aryl esters.
-
Key words: non-racemising oxidation, chiral aldehyde, chiral 1,3-
dithiane, acyl anion equivalent, dethioacetalisation
Scheme 1
Unmasking the dithiane moiety then provides the corre-
sponding -oxocarboxylic acid ester 3. We reasoned that
if the lithiodithiane 1 originated from an -chiral aldehyde
then, provided the resulting chemical transformations
could be effected with a minimal loss in optical activity,
we should achieve our goal and form a chiral -oxo-ester.
Chiral -oxo and -hydroxy acids and their derivatives
not only serve as important intermediates in natural prod-
uct synthesis1 but they also play a crucial role in a number
of biochemical pathways in both plants and animals.2
We became interested in the synthesis of nature identical
-oxo and -hydroxy acid derivatives due to their impor-
tance as food flavourings.
The use of 1,3-dithiane derivatives in stereoselective syn-
theses have been reported, however, in most cases these
have been restricted to compounds with the stereogenic
centre in a or relationship to the dithiane moiety.9 A
recent example did however feature a stereogenic centre
adjacent to the dithiane.10
We envisaged using chiral oxazolidinone technology11 for
the synthesis of a range of chiral aldehydes. Importantly,
as both enantiomers of 2-methyl-1-butanol and the corre-
sponding aldehydes have recorded optical data we would
be able to explore the effects of both the oxidation steps
and the dithiane chemistry on the optical purity of the re-
sulting products Scheme 2.
Since the first recorded preparation of pyruvic acid, by
Berzelius in 1835,3 many methods have appeared in the
literature for the synthesis of -oxo acids and their deriv-
atives.4 Despite the wide variety of methods available not
all of the procedures described are compatible with the
presence of an enolisable asymmetric centre.
Shortly before our studies commenced Enders5 revealed
his strategy for the enantioselective synthesis of 3-substi-
tuted 2-ketoesters that utilised his SAMP/RAMP-hydra-
zone technology.6 In order to achieve azaenolate
formation, directly from the hydrazone, and avoiding self-
acylation in the process his approach was limited to the
synthesis of 2,6-di-tert-butyl-4-methoxyphenyl ester de-
rivatives only.
We needed a more flexible approach in order to synthesise
simple methyl ester derivatives as well as others.
Although we have investigated a variety of methods,7 the
focus of this communication involves the chemistry of
dithianes.
Scheme 2 Reagents: (i) LiAlH4. (ii) NaOCl–TEMPO, cat. KBr.
Corey was first to recognise that sulfur-stabilised anions,
such as 1, may act as masked nucleophilic acylating re-
agents.8 Thus acylation of a lithiodithiane, such as 1,
would provide a 1,2-dicarbonyl in which one of the carbo-
nyl moieties was masked as a dithiane 2 (Scheme 1).
The synthesis of (2S)-(+)-2-methylbutanal
6 was
achieved in three steps and with high levels of selectivity
via the oxidation of (S)-(–)-2-methylbutan-1-ol 5. Cleav-
age of the chiral auxiliary provided the known alcohol14
(S)-(–)-2-methyl-1-butanol 5 (75%) which was oxidised,
without significant racemisation, to the aldehyde 6
(Scheme 2).15 We found that this oxidation procedure16
provided the desired chiral aldehydes in the highest yield
and the greatest levels of optical purity with enantiomeric
excesses (ee) of between 91–95% (Table 1).
Synlett 2002, No. 7, Print: 01 07 2002.
Art Id.1437-2096,E;2002,0,07,1073,1076,ftx,en;D04202ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1074
E. Tyrrell et al.
LETTER
Table 1 Oxidation of 5 to 6
%Yielda
20
[ ]20
ee[%]f
%Yieldg
[ ]D
ee[%]k
D
R = C2H5
R1 = CH3
R2 = H
R = C2H5
R1 = CH3
R2 = H
a
b
c
75%
67%
70%
79%
72%
–4.5b
4.4c
95
92
82
70
78
68
76
31.3h
–29.9
–2.10i
2.20
93
92
91
92
95
R = C2H5
R1 = H
R = C2H5
R1 = H
R2 = CH3
R2 = CH3
R = CH3
R1 = Bn
R2 = H
R = CH3
R1 = Bn
R2 = H
10.3d
–9.9d
–3.2e
95
R = CH3
R1 = H
R = CH3
R1 = H
d
e
90
95
R2 = Bn
R2 = Bn
R = C3H7
R1 = H
R = C3H7
R1 = H
–5.29j
R2 = C2H5
R2 = C2H5
Notes: a Yield for the formation of the N-acyl-oxazolidinone, alkylation and hydrolysis steps. b Lit. value –4.8 (neat) [ref.14]. c Lit. value 4.8
(neat) [ref.12]. d Lit. value 11.0 (c.1.15, benzene) [ref.13]. e Lit. Value –3.36 (neat) [ref.12]. f Ee data were obtained from the 1H NMR spectra of
the corresponding MTPA esters [ref.19]. g The oxidation was carried out with NaOCl–TEMPO, cat KBr. h Lit. value 33.2 (c. 2 in acetone)
[ref.12]. i (c 1.43 in DCM). j Lit. value –5.54 (c. 6 in chloroform). k Ee values were determined by reduction to the alcohol, using borane-methyl
sulphide complex [ref.12] and analysed as the MTPA esters.
At this stage we were keen to establish whether dithiane should not lead to any notable scrambling at the stereo-
formation of the chiral aldehydes synthesised, as well as genic centre either.
the acylation step and the subsequent dethioacetalization
step would occur without the loss of stereointegrity that
the aldehydes encompassed. In order to confirm this we
(2S)-(+)-2-Methylbutanal, 6, was readily converted to
the dithiane 10 (92%) (Scheme 4). Metalation of 10, with
n-butyllithium, and treatment of the anion with methyl
compared the specific rotation of the chiral alcohols, 7,
chloroformate gave the optically active dithiane 11 (63%).
with the values obtained as a result of these reactions and
Cleavage of the dithiane moiety, via an S-alkylative
obtained the following results. Oxidation of the chiral al-
cleavage procedure,20 provided the chiral -oxo-ester 12
cohols to the aldehydes, 8, followed by thioacetalisation,
(86%) [ ]D20 = +36 (c 2.05, CHCl3). The enantiomeric ex-
9, metalation/quenching, dethioacetalisation and finally
cess of this compound (92%), was established by 1H NMR
reduction back to the alcohol under non-racemising
shift experiments21 using Eu(hfc)3. The ee data obtained
conditions18 (Scheme 3). NMR studies of the correspond-
were consistent with the value we obtained from the ear-
ing Mosher ester,19 formed from the chiral alcohols, con-
lier experiments detailed above.
firmed an approximate 5% reduction in ee when R was an
alkyl group; however a lower, 1%, reduction in the enan-
tiomeric excess was observed when the R group was ben-
zyl.
Scheme 4 Reagents: (i) HSCH2CH2CH2SH, pTSA. (ii) BuLi in
THF, ClCO2CH3. (iii) NaHCO3, CH3I, MeCN–H2O (8:1).
Scheme 3 Reagents: (i) HSCH2CH2CH2SH, pTSA. (ii) NaHCO3,
CH3I, MeCN–H2O (8:1). (iii) Borane THF complex, THF, 0 °C.
With the knowledge that we could produce chiral -oxo-
esters, such as 12, from the corresponding chiral alde-
It was gratifying to observe such a small reduction in op-
tical activity as a result of these chemical transformations
hyde, without observing any significant losses in optical
and we were therefore confident that the key acylation
activity, we applied the same procedures to all of the alde-
step, (the conversion of compound 10 to compound 11),
hydes synthesised.22 The outcomes of these experiments
Synlett 2002, No. 7, 1073–1076 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Use of Chiral Dithianes
1075
Synthesis of (3S)-(+)-3-Methyl-2-oxo-pentanoic Acid Methyl
Ester (12) from 2-[(1S)-1-Methylpropyl]-1,3-dithiane (10)
To a stirred solution of 2-[(1S)-1-methylpropyl]-1,3-dithiane (10)
(1.76 g, 10.00 mmol) dissolved in anhydrous THF (30 mL) and
maintained at a temperature of –40 °C under an atmosphere of ni-
trogen was added, dropwise, n-butyllithium (1.6 M in hexane; 6.56
mL, 10.50 mmol). The mixture was stirred for 2 hours at a temper-
ature of –20 °C and then cooled to –78 °C whereupon a 1:1 solution
of methyl chloroformate (3.95 mL, 50.99 mmol) and THF was de-
livered, via cannula, over a period of 10 minutes. The mixture was
stirred for a further 2 hours, until it reached an ambient temperature,
and the solvent was removed in vacuo. Chromatography on silica
using light petroleum–diethyl ether (9:1) provided (–)2-methyl car-
boxylate-2-(1R)-( )(1)-methylpropyl)-1,3-dithiane, 11, as a colour-
are summarised in (Table 2) and serve to confirm the re-
producibility of our approach.
To supplement the ee data obtained via chiral shift re-
agents we also attempted to determine the optical purity of
the chiral -oxo-esters, via their conversion to known de-
rivatives. The outcomes from these experiments were,
however, thwarted by the tendency for the substrates to ei-
ther undergo rapid decomposition or to undergo loss of
optical activity under the prevailing reaction conditions.
For example, selective reduction of 12, to the correspond-
ing -hydroxy ester, using Midland’s reagent23 was met
with slow conversion rates and low selectivities. A similar
result had been reported earlier for analogous substrates
less oil, (1.48 g, 63%); [ 20] –4.67 (c 2.57, CH2Cl2).
D
containing branches to the carbonyl group.24 This was To a solution of the dithiane, 11, (0.55 g, 2.35 mmol) in a mixture
of acetonitrile–water 8:1 (18 mL) was added sodium hydrogen car-
bonate (0.98 g, 11.67 mmol) and iodomethane (1.47 mL, 23.61
mmol). The mixture was stirred at an ambient temperature for about
18 hours. After this period diethyl ether (10 mL) was added and the
an unfortunate outcome as we had previously made
(2S,3S)-(+)-methyl-2-hydroxy-3-methylpentanoate, for
comparative purposes, by an alternative route starting
from L-isoleucine.25
mixture poured into a separating funnel. The mixture was extracted
with water (10 mL) followed by a saturated solution of brine (10
mL). The organic phase was dried over anhydrous magnesium sul-
fate, filtered and the solvent removed in vacuo. The crude product
was purified by chromatography on silica using (light petroluem bp
40–60 and diethyl ether, 1:4) to afford the title compound, 12, as a
colourless oil (0.29 g, 86%).
In summary this communication describes the application
of chiral dithianes for the synthesis of chiral -oxo-esters.
In these studies we noted that NaOCl-TEMPO efficiently
oxidised chiral primary alcohols to the corresponding al-
dehyde with a minimal loss of optical activity.
20] +36.00 (c 2.05, CHCl3). FTIR (cm–1): 2970, 1729,1460,
Using the chiral aldehydes synthesised, we were able to
[
D
effect dithiane formation, acylation and dethioacetalisa- 1268, 1052. 1 NMR (CDCl3, 300 MHz): 0.67 (3 H, t, J = 6 Hz,
CH3); 0.89 (3 H, d, J = 8 Hz, CH3); 1.45 (2 H, m, CH2); 2.9 (1 H, m,
tion with a minimal loss of optical activity in order to af-
CH); 3.62 (3 H, s, OCH3). 13C NMR (CDCl3, 75.45 MHz): 11.27
ford a range of chiral -oxo-esters.
(q), 14.51 (q), 24.84 (t), 43.48 (d), 57.75 (q), 162.22 (s), 198.19 (s).
MS (EI, 70 eV) m/z 144 (M+), 85, 57 (100), 47. Anal. Calcd for
C7H12O3: C, 58.32; H, 8.39. Found: C, 58.21; H, 8.31.
Table 2 Oxidation of Chiral Aldehydes to Chiral -Oxo-esters
%Yielda
[ ]20
%Yieldg
[ ]20
ee[%]l
D
D
R = C2H5
R1 = CH3
R2 = H
R = C2H5
R1 = CH3
R2 = H
a
b
c
58%
52%
58%
57%
58%
–4.87b
4.91c
86
74
84
75
82
36.0g
–35.5h
–22.8i
–21.3j
–24.2k
92
90
95
92
92
R = C2H5
R1 = H
R = C2H5
R1 = H
R2 = CH3
R2 = CH3
R = CH3
R1 = Bn
R2 = H
R = CH3
R1 = Bn
R2 = H
–13.65d
13.44e
6.77f
R = CH3
R1 = H
R = CH3
R1 = H
R2 = Bn
d
e
R2 = Bn
R = C3H7
R1 = H
R = C3H7
R1 = H
R2 = C2H5
R2 = C2H5
Notes: a Yield includes dithiane and acylation reactions. b c 2.57. c c 2.61. d c 2.63. e c 2.58. f c 2.60. g c 2.05. h c 2.00. i c 2.00. j c 1.97. k 2.05. l
this was determined by NMR experiments using shift reagents [ref.21].
Synlett 2002, No. 7, 1073–1076 ISSN 0936-5214 © Thieme Stuttgart · New York

1076
E. Tyrrell et al.
LETTER
(16) Other methods for the oxidation of (2S)-(–)2-methylbutan-1-
ol 5 to (2S)-(+)-2-methylbutanal (6; Table 3).
Acknowledgement
The author wishes to thank Bush Boake Allen Ltd. for financial
support in the form of a studentship to GM and for performing
NMR experiments on our behalf and to the EPSRC National Mass
Spectroscopy Service Centre, University of Swansea for High
Resolution Mass Spectra.
Table 3 Preparation of (2S)-(+)-2-Methylbutanol (6)
Procedure
PCC
%Yield
45
%ee17
55
Parikh–Moffatt
Swern
56
87
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Synlett 2002, No. 7, 1073–1076 ISSN 0936-5214 © Thieme Stuttgart · New York