A biocatalytic route to enantioenriched, sulfanyl aldol products

Article abstract of DOI:10.1016/j.tet.2004.06.033

The aldol products derived from sulfur- or selenium containing acceptors were prepared by kinetic resolution in the presence of antibody 84G3 with enantiomeric excesses ranging from 56 to 70%. Much higher level of enantioselectivity was obtained (enantiomeric excesses all superior to 96%) for sulfanyl aldol products derived from thiomethoxyacetone with three different acceptors.

Full text of DOI:10.1016/j.tet.2004.06.033

Tetrahedron 60 (2004) 7607–7619
A biocatalytic route to enantioenriched, sulfanyl aldol products
C. Baker-Glenn,a R. Ancliffb and V. Gouverneura
,
*
aChemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
bGlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK
Received 13 April 2004; revised 3 June 2004; accepted 4 June 2004
Available online 17 July 2004
Abstract—The aldol products derived from sulfur- or selenium containing acceptors were prepared by kinetic resolution in the presence of
antibody 84G3 with enantiomeric excesses ranging from 56 to 70%. Much higher level of enantioselectivity was obtained (enantiomeric
excesses all superior to 96%) for sulfanyl aldol products derived from thiomethoxyacetone with three different acceptors.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
enantiomers could be accessed through aldol or retro-adol
reactions using the same antibody. Herein, we report that
antibody 84G3 has also the ability to catalyse aldol reactions
involving sulfur containing acceptors and the corresponding
retroaldolisation processes. In addition, we have investi-
gated the sense and level of regioselectivity for the
antibody-mediated aldol reactions of thiomethoxyacetone
with two acceptors other than para-nitrobenzaldehyde and
the corresponding retroaldolisations. We have also deter-
mined the enantioselectivity for the forward and reverse
aldol reactions allowing the preparation of various sulfanyl
aldols and the assignment of their absolute configurations.
Finally, we are reporting the kinetic parameters for selected
reactions.
The development of strategies for the preparation of
enantiomerically pure heterocycles remains a very import-
ant area of research. Recently, Warren and House have
reviewed the effectiveness of using the sulfanyl group as a
tool for the construction of various heterocyclic compounds
with in most cases total control over the product stereo-
chemistry.1 The sulfanyl migration of several enantiopure
1,3-diols has been studied and allowed the preparation of
various heterocycles, including heavily substituted tetra-
hydrofurans with excellent level of diastereo- and enantio-
control.2 In addition, sulfanyl 1,3-diols have been
transformed into the corresponding b,g-epoxy alcohols
upon methylation of the sulfide functionality followed by
cyclization under basic conditions.3 Therefore, numerous
strategies are reported in the literature for the synthesis of
sulfanyl-based cyclization precursors, including organo-
metallic addition to aldehydes, Sharpless asymmetric
dihydroxylation or asymmetric aldol reaction.4 In this
contribution, we report the first abzymatic route to various
enantioenriched sulfanyl aldols that are direct precursors of
sulfanyl 1,3-diols and the corresponding heterocyclic
targets. We recently described aldolase antibody 84G3 as
a highly efficient catalyst for the regio- and enantioselective
aldol reaction of various unsymmetrical methyl ketones
with para-nitrobenzaldehyde.5,6 This study revealed that in
the presence of this antibody, the catalysed reaction of
thiomethoxyacetone with para-nitrobenzaldehyde was
highly regioselective with the preferential formation of the
otherwise disfavoured linear regioisomer resulting from an
addition at the less substituted carbon. Both linear aldol
2. Results and discussion
2.1. Antibody-catalysed forward aldol reactions of
acetone, 2-pentanone and 3-pentanone with various
sulfur and selenium containing aldehydes and antibody-
mediated retroaldolisation of the corresponding racemic
aldols
First, we set out to study the ability of ab84G3 to catalyse
the forward aldol reactions of three representative donors
with sulfur- and selenium containing acceptors, and for the
unsymmetrical donor 2-pentanone, the degree of regio-
control that antibody 84G3 could exercise on the aldol
process (Table 1).
For all experiments, the product assignment and the product
distribution were proven unambiguously by comparison of
the retention times with independently chemically
synthesized standards using high performance liquid
chromatography (HPLC).7 To screen for catalytic activity,
Keywords: Catalytic antibodies; Aldol additon; Sulfur.
*
Corresponding author. Tel./fax: þ44-1865-275-644;
e-mail address: veronique.gouverneur@chem.ox.ac.uk
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.033

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C. Baker-Glenn et al. / Tetrahedron 60 (2004) 7607–7619
Table 1. Aldol reactions of S- and Se-containing acceptors with acetone, 2-pentanone and 3-pentanone
Entry
Acceptor and donor
Conditionsa
Conversion (%)
Product
1
2
PBS, 20 h
0
þacetone
Ab84G3, 20 h
24
3
4
PBS, 3 h
Ab84G3, 3 h
0
48
þ2-pentanone
þ3-pentanone
þacetone
5
6
PBS, 20 h
Ab84G3, 20 h
0
3
7
8
PBS, 20 h
Ab84G3, 20 h
0
27
9
10
PBS, 18 h
Ab84G3, 18 h
0
0
þacetone
a
All reactions at pH¼7.4, rt.
we performed the reactions under the following defined
conditions: 90 mM of donor, 130 mM of acceptor and
9 mol% antibody in PBS (pH¼7.4) at room temperature.
Control experiments revealed that, in the absence of
antibody, no reactions take place under these conditions
(entries 1, 3, 5, 7, 9). For the antibody-mediated reactions,
we found that all the reactions were taking place in the
presence of ab84G3 with the exception of the reaction of
acetone with 2-phenylthiobutyraldehyde8 (entry 10).
Indeed, this latter reaction did not produce any detectable
amount of aldol product after 18 h in the presence of up to
9 mol% ab84G3 suggesting that 2-phenylthiobutyraldehyde
is not a suitable donor for this antibody. The data collected
in Table 1 revealed that the best-catalysed antibody
transformation is the aldol reaction of phenylthioacetalde-
hyde9 with 2-pentanone (entry 4). For this reaction, only the
linear regioisomer was formed with no trace of the branched
regioisomer detectable by HPLC. The reaction of phenyl-
thioacetaldehyde with acetone was less efficient with 24%
of the desired aldol product formed after 20 h at room
temperature (entry 2). The aldol reaction of phenylseleno-
acetaldehyde10 was also successfully catalysed by antibody
84G3 but the use of the selenoaldehyde did not present any
significant advantage in comparison with the ‘thioanalogue’
(entry 8). Finally, we have found that only 3% of the
branched anti regioisomer was detected by HPLC for the
antibody-mediated aldol reaction involving 3-pentanone,
suggesting that this antibody-mediated transformation has
no synthetic utility. For all the antibody-catalysed reactions
(entries 2, 4, 6, 8), another compound was detected by
HPLC in addition to the desired aldol product. The structure
of this side product is unclear but we hypothesised that this
compound is arising from a self-condensation aldol reaction
of the S- or Se-containing aldehyde, which are both prone to
enolisation. This hypothesis is supported by the observation
that the retention time (HPLC analysis) of this side-product
was the same for all aldol reactions involving phenylthio-
acetaldehyde independent of the structure of the donors
examined herein. In addition, a control experiment revealed
that this same product was formed upon incubation of
phenylthioacetaldehyde as the sole substrate in the presence
of ab84G3.11
In addition to these experiments, we also assessed the ability
of ab84G3 to catalyse the retroaldolisation of racemic
sulfanyl aldols 1-5 all prepared according to standard
literature procedures (Table 2).7 The racemic aldols
(228 mM) were treated with ab84G3 (10 mol%) in aqueous
buffer (PBS, pH¼7.4, at room temperature). Analysis by
high-performance liquid chromatography (HPLC) indicated
that no reaction takes place in the absence of the antibody.
In contrast, the antibody-mediated retro-aldolisation reac-
tions of compounds 1, 2 and 4 halted at approximately 50%
conversion, auguring an efficient kinetic resolution for these
substrates. As expected from our results on the correspond-
ing forward aldol reactions, the antibody-catalysed retro-
aldolisation of the anti-3 was slow with 26% conversion of
the starting material after 90 h and no reaction was observed
for the syn-3 stereoisomer. No retroaldolisation was
observed with compound 5 suggesting that the binding
pocket of 84G3 does not tolerate the presence of the
quaternary carbon.
Table 2. Retro-aldolisation of compounds 1-4 in the presence of antibody
84G3
Entry
Substrate
Conditions
PBS, rt, 20 h
10 % ab84G3, rt, 20 h
Conversion
1
2
(^)-1
(^)-1
0
49
3
4
(^)-2
(^)-2
PBS, rt, 3.5 h
10 % ab84G3, rt, 3.5 h
0
45
5
6
(^)-anti-3
(^)-anti-3
PBS, rt, 90 h
10 % ab84G3, rt, 90 h
0
26
7
8
(^)-syn-3
(^)-syn-3
PBS, rt, 90 h
10 % ab84G3, rt, 90 h
0
0
9
10
(^)-4
(^)-4
PBS, rt, 20 h
10 % ab84G3, rt, 20 h
0
47

C. Baker-Glenn et al. / Tetrahedron 60 (2004) 7607–7619
7609
2.2. Antibody-catalysed forward aldol reactions of
2.3. Enantioselectivity of the aldol and retro-aldol
products and assignment of absolute configurations
thiomethoxyacetone with benzaldehyde and para-
methoxycinnamaldehyde and the antibody-mediated
retro-aldolisations of the corresponding racemic aldols
To probe further the synthetic scope of these antibodies, we
studied the enantioselectivity of selected forward aldol and
retroaldol reactions. The enantiomeric excesses of the
products were determined by HPLC using chiral stationary
phases and are collected in Table 4.
Previous work from our laboratory has shown that the
reaction of thiomethoxyacetone with para-nitrobenzalde-
hyde 6 catalysed by ab84G3 is highly regioselective with
the preferential formation of the linear regioisomer 9
resulting from an addition at the less substituted carbon
(entry 2) (Table 3).5,6 We have now further investigated the
scope of this reaction and we have found that, in the
presence of antibody 84G3, thiomethoxyacetone also
undergoes the aldol condensation with benzaldehyde to
afford predominantly the linear regioisomer 10 with a
conversion of 12% after 3 h at room temperature (entry 4).
The sense and level of regioselectivity of these antibody-
mediated transformations suggest that in the presence of the
donor thiomethoxyacetone, ab84G3 catalyses predomi-
nantly the formation of the linear regioisomers
independent of the structure of the acceptors. We have
also found that no reaction was observed with the less
The data showed that the enantiomeric excesses of all aldol
products derived from sulfur- and selenium containing
acceptors ranged from 56% to 70%. As expected the ee
values of the forward aldol reaction correlate well with
the ee values of the corresponding retroaldolisations.
Gratifyingly, the catalyst was highly enantioselective and
allowed the recovery of the unreacted aldols 9-11 with ee
values typically greater than 96% for the retroaldolisation of
the racemic aldol products 9-11 derived from the reactions
of para-benzaldehyde, benzaldehyde or para-methoxy-
cinnamaldehyde with thiomethoxyacetone. These results
suggest that for antibody 84G3, the highest enantio-
selectivities (.96%) were observed for aldol reactions
where conjugated aldehydes served as acceptors. Lower
enantioselectivities were obtained when aldol acceptors
containing an sp3 center in the a-position are selected as
reaction partners. All the enantioenriched aldol products
formed via an antibody-mediated forward aldol reactions
possess the (R)-configuration and the recovered aldols
resulting from a retroaldolisation process possess the (S)-
configuration. To assign the absolute configurations
unambiguously, products 1, 2, 9 and 10 were prepared
independently by asymmetric synthesis or catalysis. The
absolute configurations of all other aldol products were
reactive acceptor para-methoxycinnamaldehyde
8
(entry 6). In contrast to the forward aldol reactions, the
corresponding antibody-mediated retroaldolisations were
much more efficient with a rapid reaction taking place with
the three racemic linear aldol products 9-11 (entries 8, 10,
12). The reactions were halting at approximately 50% as
expected for a kinetic resolution. The retroaldolisation of
compounds 10 and 11 derived from the less reactive
acceptors were the best-catalysed transformations as
reflected by the shorter reaction time required to reach
50% conversion.
Table 3. Aldolisation of thiomethoxyacetone with various acceptors and retro aldolisations
Entry
Acceptor and donor
Conditionsa
Conversion (%)
Ratio A/B
Aldolisation
1
2
6
6
PBS, 0 8C, 1 h 40
25% ab84G3, 0 8C, 1 h 40
9
56
10:90
98:2
3
4
7
7
PBS, rt, 3 h
9% ab84G3, rt, 3 h
1
12
0:100
92:8
5
6
8
8
PBS, 40 h
9% ab84G3, rt, 24 h
0
0
—
—
Retroaldolisation
Entry
Substrate
Conditions
Conversion (%)
7
8
(^)-9
(^)-9
PBS, rt, 2 h
10 % ab84G3, rt, 2 h
0
51
9
10
(^)-10
(^)-10
PBS, rt, 1 h
10 % ab84G3, rt, 1 h
0
50
11
12
(^)-11
(^)-11
PBS, rt, 1 h
10 % ab84G3, rt, 1 h
0
50

Table 4. ee Values for antibody-catalysed aldol and retro-aldol reactions
Entry
Product
Method conversion (%)
ee (%)
60
Entry
6
Product
Method conversion (%)
Retro-aldol (50%)
ee (%)
60
1
Aldol (30%)
2
Retro-aldol (50%)
56
7
Aldol (10%)
97
3
4
5
Aldol (65%)
64
66
70
8
9
Retro-aldol (50%)
Retro-aldol (50%)
Retro-aldol (50%)
96
98
99
Retro-aldol (54%)
Retro-aldol (37%)
10

C. Baker-Glenn et al. / Tetrahedron 60 (2004) 7607–7619
7611
Scheme 1. Independent asymmetric syntheses of enantioenriched aldols 1 and 2.
Scheme 2. Independent asymmetric syntheses of enantioenriched aldol 10.
assigned by analogy. It was anticipated that compounds 1
and 2 could be prepared in enantiomerically pure form from
a common precursor, the Weinreb amide 15 by functional
group manipulation of the methoxy-N-methylamide group
(Scheme 1).
pound 9 was already established correlating the absolute
configuration of the antibody-product with the enantiopure
sample prepared according to the Evans’s asymmetric aldol
methodology.14 Herein, we suggest an alternative route for
the preparation of enantioenriched 10 using L-proline as the
organocatalyst (Scheme 2).15 The (R)-aldol product 17
(ee¼71%) derived from acetone and benzaldehyde was
prepared in DMSO, in the presence of 20 mol% L-proline at
room temperature. Chlorination of the corresponding
protected terminal silyl enol ether followed by nucleophilic
substitution of the chlorine group of 18 with sodium
thiomethoxide in toluene at 0 8C proceeded smoothly to
afford, after deprotection, the enantioenriched compound 10
in 96% yield and with an ee of 71%. HPLC analysis
revealed that the retention time of the minor (S)-enantiomer
of this sample is identical to the retention time of the
antibody-product resulting from the retro-aldolisation
process, confirming that the antibody-product possess the
(S)-configuration.
The absolute configuration of the Weinreb amide 15 could
be easily secured through Bakers’ yeast reduction of the
corresponding ketoester according to a procedure described
in the literature.12 Although the Bakers’ yeast reduction of
the ethyl 4-phenylthio-3-oxobutanoate is reported to
produce the corresponding (R)-hydroxy ester 16 in 99%
ee, in our hands, this reaction gave the desired product with
a lower enantiomeric excess of 58% as determined by chiral
HPLC. Transamination of this enantioenriched compound
to give the N-methoxy-N-methylamide 15, followed by
addition of the Grignard reagent afforded the desired
enantioenriched compounds 1 and 2 with respective yields
of 84% and 52%. For the addition of n-PrMgBr on
compound 15, a side product resulting from elimination of
formaldehyde was observed and isolated with a chemical
yield of 34%.13 This side reaction was not observed when
compound 15 was treated with MeMgBr. Analysis of these
compounds by chiral HPLC revealed that no epimerisation
has occurred converting the Weinreb amide into the desired
ketones as these two compounds were obtained with an ee of
58%. Comparison of the retention times of these enantio-
enriched independently synthesised reference compounds
with the antibody-products established the (R) configuration
of the stereogenic center of the enantioenriched antibody
aldol products, which is consistent with preferential addition
of the ketone to the Si face of the aldehyde. For the retro-
aldol reactions, HPLC analysis confirmed that at approxi-
mately 50% conversion, the major enantiomer for the
recovered enantioenriched aldol products 1 and 2 possess
the (S)-configuration. For the aldol compounds derived from
thiomethoxyacetone, the absolute configuration of com-
2.4. Kinetic studies
The results of the kinetic studies of several retro-aldol
reactions are provided in Table 5. The kinetic parameters
are reported per antibody active site assuming that both
active sites of the antibody function independently. All the
Table 5. Kinetic parameters for selected retro-aldol reaction
Entry
Substrates
kcat
(min21
KM
(mM)
k
cat/kuncat
(kcat/KM)/kuncat
(M21
)
)
1
2
3
4
5
6
(^)-1
(^)-2
(^)-anti-3
(^)-4
(^)-9
0.031
0.604
0.006
0.053
0.81
474
148
390
584
69
—
—
—
—
—
—
—
—
4.3£105
1.9£106
6.2£109
(^)-10
3.17
56
3.3£1010

7612
C. Baker-Glenn et al. / Tetrahedron 60 (2004) 7607–7619
retro-aldol reactions followed typical Michaelis–Menten
kinetics. The determination of kcat/kuncat was not determined
for compounds 1-4 as no product resulting from a retro-
aldolisation process was observed to be formed for the
uncatalysed reaction under our essay conditions, even after
prolonged reaction times. For compounds 1-4, the kinetic
data suggest that the linear aldol product 2 derived from
2-pentanone was processed by the antibody more efficiently
(kcat¼0.6 min21) than the aldol products 1 or 4 derived from
acetone. A similar trend was reported in the literature as it
was found that the retroaldolisation of a linear aldol product
derived from butanone was processed approximately 20
times more efficiently by antibody 84G3 than the corre-
sponding aldol product derived from acetone.16 We have
also found that the presence of the additional methyl group
of the branched aldol product anti-3 slowed down
considerably the antibody-mediated retroaldolisation of
this racemic substrate as reflected by the much lower rate
constant (kcat¼0.006 min21). The data also revealed that the
antibody-mediated retro-aldolisation of the aldol product
derived from the less reactive acceptor (benzaldehyde) is
significantly more efficient than the catalysed retroaldolisa-
tion of compounds derived from the more electron deficient
acceptor (para-nitrobenzaldehyde). The high catalytic
proficiencies of ab84G3 for both the retro-aldolisation of
aldols (^)-9 and (^)-10 suggest that these reactions are
synthetically valuable processes as the recovered aldol
products resulting from these kinetic resolutions were
formed with enantiomeric excesses superior to 98%.
methylene chloride (CH2Cl2) was obtained by distillation
over calcium hydride. Yields refer to chromatography and
spectroscopically (1H NMR) homogeneous materials.
Commercially available reagents were used without further
purification, unless otherwise stated. Reactions were
monitored by thin-layer chromatography (TLC) carried
out on Merck aluminum foil backed sheets precoated with
Kieselgel 60 F-254 using UV light as visualizing agent and
an ethanolic solution of potassium permanganate and heat as
developing agent. Merck Silica gel C60 (40–60 mM) was
used for flash column chromatography. NMR spectra were
recorded on a Bruker DPX-400 or Bruker AMX-500
spectrometer and calibrated using residual undeuterated
solvent as an internal reference. The following abbrevi-
ations were used to explain multiciplicities: s¼singlet,
d¼doublet, t¼triplet, q¼quadruplet, m¼multiplet, b¼
broad. The coupling constants J are given in hertz. IR
spectra were recorded on a Perkin–Elmer Paragon 1000 FT-
IR spectrometer. Mass spectra (m/z) and HRMS were
recorded on Micromass GCT using Chemical Ionisation
(NH3, CI), Electronic Impact (EIþ) or Field Ionization (FI).
Microanalyses were performed by ‘Elemental Micro-
analysis Limited’, Devon. Melting points were determined
in a capillary and are uncorrected.
HPLC information. Analytical HPLC and semi-preparative
HPLC were performed on a Waters HPLC system (626
Pump, 600 S Controller, 996 Photodiode Array Detector,
Millenium32 Software). Reactions were followed by
analytical RP-HPLC: Nova-pak Waters column, C-18,
˚
60 A pore size, 4 mm particle size, 3.9£150 mm, flow rate
1.0 ml/min. Enantiomeric excesses (ee) were determined by
chiral normal phase HPLC: Daicel Chiralpak AD or Daicel
Chiracel OJ, OD or OJ-H columns (4.6£250 mm), flow rate
1.0 ml/min. The solvent systems used for the retention times
provided for the donors, acceptors and aldol products
studied are defined as: solvent A: hexane; solvent B: iPrOH;
solvent C: EtOH.
3. Conclusion
Two major issues were under consideration. First was the
critical issue as to whether aldolase antibody 84G3 could
catalyse aldol reactions of all carbon donors with sulfur or
selenium-containing acceptors. Second, the possibility of
controlling simultaneously the regio- and enantioselectivity
of aldol reactions of thiomethoxyacetone with three
electronically and structurally different acceptors had to
be determined as well as the ability of ab84G3 to catalyse
the corresponding retro-aldolisations. It was found that the
antibody-aldol products derived from sulfur- or selenium
containing acceptors were obtained with enantiomeric
excesses ranging from 56 to 70%. In contrast, various
enantiopure (ee .96%) sulfanyl aldol products derived
from thiomethoxyacetone with three different acceptors
were obtained using antibody-catalysed aldolisation and
retro-aldolisations. The retro-aldolisations are synthetically
superior as reflected by the catalytic proficiency of ab84G3
for these reactions. Further exploration of ab84G3 to
produced enantioenriched precursors of various hetero-
cyclic systems is in progress in our laboratory.
4.2. Antibody assays
All antibody-catalysed reactions were performed in
phosphate buffered saline (10 mM phosphate, 16 mM
NaCl, pH 7.4). All antibody-catalysed reactions and back-
ground reactions were monitored by high-pressure liquid
chromatography (HPLC; Waters HPLC system (626 Pump,
600 S Controller, 996 Photodiode Array Detector,
Millenium32 Software) using a Nova-pak Waters column
˚
(C-18, 60 A pore size, 4 micrometer particle micrometer
size, 3.9£150 mm) and acetonitrile/water or methanol/water
mixtures (containing 0.1% trifluoroacetic acid) as eluents at
a flow rate of 1.0 ml/min.
4.3. Michaelis–Menten kinetics
Product formation or percent conversion of antibody-
catalysed reaction mixtures was monitored by HPLC. The
points were determined experimentally and the best fit value
of Vmax and Km were obtained by fitting the vi versus [S]0
data to hyperbolic saturation curves by weighted non-linear
regression. All data are reported per antibody active site. An
IgG antibody possesses 2 active sites per MW of
,150,000 g/mol.
4. Experimental
4.1. General
All reactions were carried out under an argon atmosphere
with dry solvents under anhydrous conditions, unless
otherwise noted. Dry tetrahydrofuran (THF) was obtained
by distillation over sodium and benzophenone, dry

C. Baker-Glenn et al. / Tetrahedron 60 (2004) 7607–7619
7613
4.4. Determination of enantiomeric excesses: forward
aldol reaction
4.7. General procedure 3: formation of Weinreb amide
from the corresponding ester
Antibody (64 nmol) was added to a stock solution contain-
ing the aldehyde (10 ml of 66 mM in 10% acetonitrile, 90%
PBS, 660 nmol), the ketone (100 ml of 65 mM in PBS,
6.5 mmol) and PBS (amount required to make the final
volume up to 2.11 ml). The reactions were monitored by
RP-HPLC using a Nova-pak Waters column. After reaching
a suitable conversion, the unreacted aldol was isolated by
semi-preparative reversed-phase HPLC, Hypersil ODS
column, 5 micrometer particle size, 7£250 mm, flow rate
2.0 ml min21 or Phenomenex Luna C18 column, 8.8
micrometer particle size, 15£250 mm, flow rate
8.0 ml min21. The fractions were freeze-dried, the residue
was redissolved in 200 ml of dichloromethane/hexane
(50:50) and the ee was determined by chiral normal-phase
HPLC.
To N,O-dimethylhydroxylamine hydrochloride (4 mmol) in
THF (13 ml) at 0 8C was added AlMe3 (2 M in DCM,
4 mmol). The mixture was stirred at 0 8C for 30 min and
room temperature for 20 min. The reaction mixture was then
cooled to 215 8C and ester (1.3 mmol) in THF (10 ml) was
added dropwise. The mixture was warmed to 0 8C and
stirred for a further 4 h. The reaction was then quenched
with 0.5 M HCl and the mixture extracted with EtOAc. The
organic layer was washed with water, dried over MgSO4 and
concentrated in vacuo.
4.8. General procedure 4: Grignard addition to the
Weinreb amide
The Grignard reagent (8.5 mmol) was added to a solution of
Weinreb amide (1.6 mmol) in THF (15 ml) at 240 8C. The
mixture was allowed to warm to 0 8C over 30 min and
stirred for a further 3–48 h. Sat. NH4Cl was added, and the
mixture allowed to warm to room temperature. The mixture
was extracted with DCM, dried over MgSO4 and the solvent
removed in vacuo.
Retro-aldol reactions. Antibody (32 nmol) was added to
racemic stock solution of aldol (10 ml of 80 mM in
acetonitrile, 800 nmol). The reactions were monitored by
RP-HPLC using using a Waters Nova-pak column. After
reaching 50% conversion, the unreacted aldol was isolated
by semi-preparative reversed-phase HPLC, Hypersil ODS
column, 5 micrometer particle size, 7£250 mm, flow rate
2.0 ml min21 or Phenomenex Luna C18 column, 8.8
micrometer particle size, 15£250 mm, flow rate
8.0 ml min21. The fractions were freeze-dried, the residue
was redissolved in 200 ml of dichloromethane/hexane
(50:50) and the ee was determined by normal-phase
HPLC.
4.9. General procedure 5: TBS protection
To the aldol product (20 mmol) in DMF (80 ml) at 0 8C was
added imidazole (98 mmol) and TBSCl (48 mmol). The
mixture was allowed to warm to room temperature and stir
for 18 h. The reaction was quenched with water. The
mixture was extracted with DCM, the combined organic
fractions dried over MgSO4, filtered under suction and the
solvent removed in vacuo.
4.5. General procedure 1: aldol reactions
To a solution of LDA [prepared by dropwise addition of
n-butyllithium (11.2 mmol, 2 M) to a solution of di-
isopropylamine (11.3 mmol) in dry THF (15 ml) at 0 8C]
at 278 8C was added the donor ketone (11.3 mmol) in dry
THF (7.5 ml) via cannula. The reaction was allowed to stir
at 278 8C for 30 min. The aldehyde acceptor (7.5 mmol) in
dry THF (7.5 ml) was then added via cannula, and the
mixture allowed to stir at 278 8C for 15 min. The reaction
was then quenched with saturated NH4Cl and allowed to
warm to room temperature. The aqueous layer was extracted
with EtOAc. The organic fractions were combined, dried
over MgSO4, filtered under suction and the solvent removed
in vacuo.
4.10. General procedure 6: TBS-deprotection of aldol
product
A stock solution was prepared by the addition of AcOH
(0.3 ml) to a solution of TBAF (5 ml, 1 M in THF). TBS
protected aldol (0.37 mmol) in THF (3.7 ml) was treated
with a portion of this stock solution (4 ml) and allowed to
stir at room temperature for 15 h. The reaction was then
quenched by addition of sat. NaHCO3 (10 ml). The mixture
was extracted with EtOAc, the combined organic fractions
dried over MgSO4, filtered under suction and the solvent
removed in vacuo.
4.11. General procedure 7: substitution of chloride with
sodium thiomethoxide
4.6. General procedure 2: formation of Weinreb amide
from the corresponding ester
To the chlorinated aldol (1.6 mmol) in toluene (35 ml) at
0 8C was added sodium thiomethoxide (3.2 mmol). The
mixture was allowed to slowly warm to room temperature,
stirred for 18 h and then quenched with saturated NH4Cl.
The mixture was extracted with DCM, the combined
organic fractions dried over MgSO4, filtered under suction
and the solvent removed in vacuo.
To N,O-dimethylhydroxylamine hydrochloride (43 mmol)
in dry toluene (50 ml) at 0 8C was added AlMe3 (39 mmol,
2 M in hexanes) dropwise. The mixture was allowed to
warm to room temperature and stirred for 30 min before
being cooled to 0 8C and ester (10.4 mmol) in dry toluene
(35 ml) added dropwise via cannula. The mixture was
allowed to warm to room temperature and stir for 2 h, then
poured in to aqueous tartaric acid and allowed to stir for a
further 1.5 h. The mixture was extracted with DCM. The
organic fractions were combined, dried over MgSO4,
filtered and the solvent removed in vacuo.
4.11.1. 4-Hydroxy-5-phenylsulfanyl-pentan-2-one (6)-1.
Synthesised from (phenylthio)-acetaldehyde (2 g, 13 mmol)
and dry acetone (1 ml, 14.5 mmol) using general procedure
1. Purification by column chromatography (1:1 hexane/

7614
C. Baker-Glenn et al. / Tetrahedron 60 (2004) 7607–7619
EtOAc) afforded 1 (1.9 g, 70%) as an oil. RF (1:1 hexane/
1
EtOAc): 0.25; d H NMR (400 MHz): 2.12 (3H, s, CH3),
argon. Dry THF (12 ml) was added. A single crystal of
iodine was added and a solution of propyl bromide (2.2 ml,
2.95 g, 24 mmol) in dry THF (12 ml) was added dropwise.
The mixture was allowed to stir until it cooled to room
temperature. The mixture was then added to a solution of
Weinreb amide (1.02 g, 4 mmol) in dry THF (8 ml) at
240 8C via cannula. The mixture was allowed to warm to
0 8C over 30 min and allowed to stir for a further 1.5 h.
Saturated ammonium chloride solution (25 ml) was added
and the mixture extracted with DCM. The organic fractions
were combined, dried over MgSO4, filtered under suction
and the solvent removed in vacuo. Purification by column
chromatography (5:1 hexane/EtOAc) afforded 2 (520 mg,
2.67 (1H, dd, J¼8.0, 17.5 Hz, CHAHBCHO), 2.75 (1H, dd,
J¼4.0, 17.5 Hz, CHAHBCHO), 3.04 (1H, dd, J¼6.5,
14.0 Hz, CHAHBS), 3.05 (1H, dd, J¼6.0, 14.0 Hz, CHAHBS),
3.40 (1H, br s, OH), 4.10–4.18 (1H, m, CH), 7.1.5–7.38 (5H,
m, Ar);d 13C NMR(100 MHz): 30.7(CH3), 40.0(CH2S), 48.4
(CH2CO), 66.2 (CH), 126.4 (Ar–C), 129.1 (Ar–C, 2C), 129.5
(Ar–C, 2C), 135.3 (Ar–C, quarternary), 208.7 (CvO); nmax
(neat): 3418.0 (br, O–H), 1710.9 (s, CvO); m/z (autospec,
CIþ): 207 ([M2OH]þ, 100%), 225 ([MþH]þ, 51%), 242
([MþNH4]þ, 26%); (HRMS, autospec CIþ): found 211.0800
([MþH]þ), C11H15SO2 requires 211.0793.
1
55%) as an oil. Rf (1:1 hexane/EtOAc): 0.16; d H NMR
4.12. Synthesis of the two aldol regioisomers derived
from 2-pentanone and phenylthioacetaldehyde
(400 MHz): 0.91 (3H, t, J¼7.6 Hz, CH3), 1.59 (2H, tq,
J¼7.6, 7.6 Hz, CH2CH3), 2.39 (2H, t, J¼7.6 Hz, CH2CH2-
CH3), 2.67 (1H, dd, J¼17.4, 7.9 Hz, CHAHBCHO), 2.76
(1H, dd, J¼17.4, 3.9 Hz, CHAHBCHO), 3.05 (1H, dd,
J¼13.9, 6.4 Hz, CHAHBS), 3.06 (1H, dd, J¼13.9, 6.4 Hz,
CHAHBS), 3.28 (1H, d, J¼2.2 Hz, OH), 4.11–4.20 (1H, m,
CHOH), 7.18–7.24 (1H, m, Ar), 7.27–7.33 (2H, m, Ar),
7.36–7.41 (2H, m, Ar); d 13C NMR (100 MHz): 13.6 (CH3),
17.0 (CH2CH3), 40.0 (CH2S), 45.5 (CH2CH2CH3), 47.3
(CH(OH)CH2CHO), 66.4 (CHOH), 126.5 (Ar–C), 129.1
(2C, Ar–C), 129.6 (2C, Ar–C), 135.3 (Ar–C, quarternary),
211.2 (CvO); nmax (neat): 3445.5 (br, O–H), 1706.7
(s, CvO); m/z (autospec, CIþ): 221 ([M2OH]þ, 100%),
239 ([MþH]þ, 87%), 256 ([MþNH4]þ, 45%); (HRMS,
GCT, FI): found 238.1026 ([Mz]), C13H18SO2 requires
238.1028.
4.12.1. (6)-3-Hydroxy-4-phenylsulfanyl-butyric acid
ethyl ester. Synthesised from (phenylthio)acetaldehyde
(4.365 g, 28.7 mmol) and ethyl acetate (4.17 ml, 43 mmol)
using general procedure 1. Purification by column chroma-
tography (4:1 hexane/EtOAc) afforded the desired com-
pound (5.6 g, 82%) as an oil. Rf (4:1 hexane/EtOAc): 0.50; d
1H NMR (500 MHz): 1.27 (3H, t, J¼7.2 Hz, CH3), 2.58
(1H, dd, J¼16.4, 8.1 Hz, CHAHBCHO), 2.67 (1H, dd,
J¼16.4, 4.1 Hz, CHAHBCHO), 3.07 (1H, dd, J¼13.8,
7.0 Hz, CHAHBS), 3.11 (1H, dd, J¼13.8, 5.7 Hz), 3.21
(1H, d, J¼3.9 Hz, OH), 4.11–4.17 (1H, m, CHOH), 4.17
(2H, q, J¼7.0 Hz, CH2CH3), 7.19–7.24 (1H, m, Ar), 7.28–
7.33 (2H, m, Ar), 7.37–7.42 (2H, m, Ar); d 13C NMR
(125 MHz): 14.0 (CH3), 39.8 (CH2CHO), 40.1 (CH2S), 60.8
(CH2CH3), 66.5 (CHOH), 126.5 (Ar–C), 129.0 (Ar–C, 2C),
129.7 (Ar–C, 2C), 135.1 (Ar–C, quarternary), 172.0
(CvO); nmax (neat): 3458.4 (br, O–H), 1729.5 (s, CvO);
m/z (autospec, CIþ): 223 ([M2OH]þ, 100%), 241
([MþH]þ, 21%), 258 ([MþNH4]þ, 34%); (HRMS, GCT,
FI): found 240.0821 ([Mz]), C12H16SO3 requires 240.0820.
4.12.4. (6)-2-Ethyl-3-hydroxy-4-phenylsulfanyl-butyric
acid ethyl ester. Synthesised from (phenylthio)acetalde-
hyde (88 mg, 6.5 mmol) and ethyl butanoate (1.2 ml,
9.8 mmol) using general procedure 1. Purification by
column chromatography afforded the desired compound
(1.1 g of a mixture of diastereomers, 64% yield, 44% de) as
an oil. Major diastereomer (isomer 1): d 1H NMR
(500 MHz): 0.92 (3H, t, J¼7.7 Hz, CH3CH2CH), 1.27
(3H, t, J¼7.2 Hz, CH3CH2O), 1.69–1.80 (2H, m, CHCH2-
CH3), 2.40 (1H, ddd, J¼5.1, 6.8, 9.0 Hz, CHEt), 2.87 (1H,
br s, OH), 2.95 (1H, dd, J¼13.8, 8.5 Hz, CHAHBS), 3.18
(1H, dd, J¼13.8, 3.4 Hz, CHAHBS), 3.87–3.91 (1H, m,
CHOH), 4.12–4.24 (2H, m, OCH2CH3), 7.19–7.24 (1H, m,
Ar), 7.27–7.33 (2H, m, Ar), 7.37–7.41 (2H, m, Ar); d 13C
NMR (125 MHz): 11.6 (CH3CH2CH), 14.1 (CH3CH2O),
21.1 (CHCH2CH3), 39.1 (CH2S), 51.7 (CHEt), 60.5
(CH2O), 69.5 (CHOH), 126.5 (Ar–C), 128.9 (Ar–C, 2C),
129.6 (Ar–C, 2C), 134.9 (Ar–C, quarternary), 174.2 (CO);
4.12.2. (6)-3-Hydroxy-N-methoxy-N-methyl-4-phenyl-
sulfanyl-butyramide. Synthesised from 3-hydroxy-4-
phenylsulfanyl-butyric acid ethyl ester (2.5 g, 10.4 mmol)
using general procedure 2. Purification by column chroma-
tography (1:1 hexane/EtOAc) afforded the desired com-
pound (2.1 g, 78%) as a white solid. Rf (1:1 hexane/EtOAc):
0.16; d 1H NMR (500 MHz): 2.65 (1H, dd, J¼16.8, 8.5 Hz,
CHAHBCHO), 2.86 (1H, dd, J¼16.8, 2.2 Hz CHAHBCHO),
3.09 (1H, dd, J¼13.4, 6.7 Hz, CHAHBS), 3.17 (1H, dd,
J¼13.4, 5.0 Hz), 3.19 (3H, s, CH3N), 3.67 (3H, s, CH3O),
3.97 (1H, d, J¼3.0 Hz, OH), 4.14–4.22 (1H, m, CHOH),
7.18–7.22 (1H, m, Ar), 7.27–7.32 (2H, m, Ar), 7.39–7.42
(2H, m, Ar); d 13C NMR (125 MHz): 31.7 (CH3N), 36.6
(CH2CO), 39.6 (CH2S), 61.2 (CH3O), 66.9 (CHOH), 126.2
(Ar–C), 128.9 (Ar–C, 2C), 129.3 (Ar–C, 2C), 135.5
(Ar–C, quarternary), 172.9 (CvO); nmax (neat): 3430.1 (br,
O–H), 1643.7 (s, CvO); m/z (autospec, CIþ): 238
([M2OH]þ, 52%), 256 ([MþH]þ, 100%); (HRMS, GCT,
CIþ): found 256.1018 ([MþH]þ), C12H18SO3N requires
256.1007. Analysis for C12H17SO3N: calculated C: 56.45,
H: 6.71, N: 5.49; found C: 56.61, H: 6.87, N: 5.53.
1
minor diastereomer: d H NMR (500 MHz): 0.92 (3H, t,
J¼7.7 Hz, CH3CH2CH), 1.28 (3H, t, J¼7.3 Hz, CH3CH2O),
1.60–1.69 (2H, CHCH2CH3), 2.60 (1H, ddd, J¼5.4, 5.4,
8.9 Hz, CHEt), 2.87 (1H, br s, OH), 3.05 (1H, dd, J¼13.7,
7.7 Hz, CHAHBS), 3.12 (1H, dd, J¼13.7, 5.0 Hz, CHAHBS),
3.82–3.86 (1H, m, CHOH), 4.12–4.24 (2H, OCH2CH3),
7.19–7.24 (1H, m, Ar), 7.27–7.33 (2H, m, Ar), 7.37–7.41
(2H, m, Ar); d 13C NMR (125 MHz): 11.6 (CH3CH2CH),
14.1 (CH3CH2O), 22.3 (CHCH2CH3), 39.6 (CH2S), 50.9
(CHEt), 60.5 (CH2O), 70.4 (CHOH), 126.5 (Ar–C), 128.9
(Ar–C, 2C), 129.9 (Ar–C, 2C), 135.2 (Ar–C, quarternary),
174.6 (CO); nmax (neat): 3468.3 (br, O–H), 1725.7 (s,
CvO); m/z (HRMS, GCT, FI): found 268.1146 ([Mz]),
C14H20O3S requires 268.1133.
4.12.3. 2-Hydroxy-1-phenylsulfanyl-heptan-4-one (6)-2.
Magnesium turnings (1.75 g, 72 mmol) were stirred
vigorously in a round-bottomed flask overnight under

C. Baker-Glenn et al. / Tetrahedron 60 (2004) 7607–7619
7615
4.12.5. (6)-2-Ethyl-3-hydroxy-N-methoxy-N-methyl-4-
phenylsulfanyl-butyramide. To N,O-dimethylhydroxyl-
amine hydrochloride (840 mg, 8.6 mmol) in dry toluene
(10 ml) at 0 8C was added trimethylaluminium (3.9 ml,
7.8 mmol, 2 M in hexanes) dropwise. The mixture was
allowed to warm to room temperature and stirred for
30 min. The mixture was then cooled to 0 8C and 2-ethyl-3-
hydroxy-4-phenylsulfanyl-butyric acid ethyl ester (500 mg
of mixture of diastereomers, 2.1 mmol) in dry toluene (7 ml)
was added dropwise via cannula. The mixture was heated to
reflux for 2.5 h. The mixture was then allowed to cool, and
poured into aqueous tartaric acid (250 ml, 1 M) and allowed
to stir for 1.5 h. The mixture was extracted with Et2O. The
organic fractions were combined, dried over MgSO4,
filtered and the solvent removed in vacuo. Purification by
column chromatography (4:1 hexane/EtOAc) afforded anti-
isomer (254 mg, 43%) and syn-isomer (96 mg, 16%) as oils
(46% de). Analysis syn-isomer: Rf (1:1 hexane/EtOAc):
0.32; d 1H NMR (400 MHz): 0.88 (3H, t, J¼7.6 Hz,
CH3CH2), 1.62–1.85 (2H, m, CH2CH3), 3.07 (1H, dd,
J¼13.8, 7.5 Hz, CHAHBS), 3.13 (1H, dd, J¼13.8, 5.8 Hz,
CHAHBS), 3.15–3.24 (1H, m, CHEt), 3.21 (3H, s, CH3N),
3.49 (1H, br s, OH), 3.68 (3H, s, CH3O), 3.88–3.95 (1H, m,
CHOH), 7.16–7.21 (1H, m, Ar), 7.26–7.31 (2H, m, Ar),
7.35–7.39 (2H, m, Ar); d 13C NMR (100 MHz): 11.9
(CH3CH2), 20.1 (CH2CH3), 31.9 (CH3N), 37.8 (CH2S), 45.1
(CHEt), 61.5 (CH3O), 70.5 (CHOH), 126.3 (Ar–C), 129.0
(2C, Ar–C), 129.3 (2C, Ar–C), 135.3 (Ar–C, quarternary),
176.1 (CO); nmax (neat): 3426.5 (br, O–H), 1643.6 (s,
CvO); m/z (autospec, ESIþ): 589 ([2MþNa]þ, 78%), 306
([MþNa]þ, 100%);m/z (HRMS, autospec, ESIþ): found
306.1131 ([MþNa]þ): C14H21NO3SNa requires 306.1140.
C), 134.8 (Ar–C, quarternary), 212.1 (CO); nmax (neat):
3437.5 (br, O–H), 1784.3 (s, CvO); m/z (HRMS, GCT, FI):
found 238.1038 ([Mz]), C13H18O2S requires 238.1028; anti-
isomer synthesised from the corresponding 2-ethyl-3-
hydroxy-N-methoxy-N-methyl-4-phenylsulfanyl-butyramide
(30 mg, 0.1 mmol) using general procedure 4 with a reaction
time of 6 h. Purification by column chromatography (4:1
hexane/EtOAc) afforded the product (10 mg, 42%) as an oil.
1
Rf (1:1 hexane/EtOAc): 0.44; d H NMR (500 MHz): 0.91
(3H, t, J¼7.7 Hz, CH3CH2), 1.57–1.73 (2H, m, CH2Me), 2.18
(3H, s, CH3CO), 2.71–2.77 (1H, m, CHEt), 3.01 (1H, dd,
J¼13.7, 7.7 Hz, CHAHBS), 3.13 (1H, dd, J¼13.7, 5.1 Hz,
CHAHBS), 3.15 (1H, br s, OH), 3.78–3.85 (1H, m, CHOH),
7.21–7.25 (1H, m, Ar), 7.28–7.33 (2H, m, Ar), 7.37–7.41
(2H, m, Ar); d 13C NMR (125 MHz): 11.7 (CH3CH2), 21.8
(CH2CH3), 31.3 (CH3CO), 39.8 (CH2S), 56.9 (CHEt), 70.4
(CHOH), 126.6 (Ar–C), 129.0 (2C, Ar–C), 130.0 (2C, Ar–
C), 134.9 (Ar–C, quarternary), 213.2 (CO); nmax (neat):
3413.9(br, O–H), 1704.7(s, CvO);m/z(GCT, FI):238([Mz],
100%); m/z (HRMS, autospec, CIþ): found 239.1106
([MþH]þ), C13H19SO2 requires 239.1106.
4.12.7. (6)-5-Hydroxy-4-methyl-6-phenylsulfanyl-
hexan-3-one 3. Formed from (phenylthio)-acetaldehyde
(447.5 mg, 2.9 mmol) and 3-pentanone (0.45 ml, 376 mg,
4.4 mmol) using general procedure 1. Purification by
column chromatography (2:1 40–60 petrol/Et2O) afforded
the two diastereomers: anti-3: oil, (70 mg, 10.1%); Rf (2:1
40–60 petrol/Et2O): 0.27; d 1H NMR (500 MHz): 1.04 (3H,
t, J¼7.2 Hz, CH3CH2), 1.15 (3H, d, J¼7.3 Hz, CH3CH),
2.38–2.47 (1H, m, CHAHBCH3), 2.50–2.59 (1H, m,
CHAHBCH3), 2.88 (1H, dq, J¼7.0, 7.2 Hz, CHMe), 2.98
(1H, dd, J¼13.9, 8.5 Hz, CHAHBCHOH), 3.17 (1H, dd,
J¼13.9, 5.0 Hz, CHAHBCHOH), 3.18 (1H, d, J¼5.5 Hz,
OH), 3.76–3.83 (1H, m, CHOH), 7.20–7.54 (1H, m, Ar),
7.26–7.33 (2H, m, Ar), 7.37–7.41 (2H, m, Ar); d 13C NMR
(125 MHz): 7.3 (CH3CH2), 13.8 (CH3CH), 35.9 (CH3CH2),
39.3 (CH2S), 48.8 (CH3CH), 71.9 (CHOH), 126.6 (Ar–C),
129.0 (2C, Ar–C), 129.8 (2C, Ar–C), 135.0 (Ar–C,
quarternary), 215.6 (CvO); nmax (KBr disk): 3339.6 (br,
O–H), 1708.4 (s, CvO); m/z (autospec, CIþ): 221
([M2OH]þ, 100%), 239 ([MþH]þ, 48%), 256 ([MþNH4]þ,
15%); (HRMS, autospec, CIþ): found 239.1104 ([MþH]þ),
C13H19SO2 requires 239.1106; HPLC OD: 80% solvent
A/20% solvent B: 7.4 min (5R, 4S), 8.4 min (5S, 4R); syn-3:
oil, 375 mg, 54.3%); Rf (2:1 40–60 petrol/Et2O): 0.23; d 1H
NMR (500 MHz): 1.04 (3H, t, J¼7.3 Hz, CH3CH2), 1.17 (3H,
d, J¼7.0 Hz, CH3CH), 2.40–2.50 (1H, m, CHAHBCH3),
2.52–2.61 (1H, m, CHAHBCH3), 2.84 (1H, dq, J¼4.5, 7.0 Hz,
CHCH3), 2.98 (1H, dd, J¼13.9, 7.5 Hz, CHAHBCH3S), 3.04
(1H, dd, J¼13.9, 5.5 Hz), 3.00 (1H, d, J¼3.0 Hz, OH), 3.98–
4.02 (1H, m, CHOH), 7.20–7.25 (1H, m, Ar), 7.25–7.33 (2H,
m, Ar), 7.37–7.40 (2H, m, Ar); d 13C NMR (125 MHz): 8.0
(CH3CH2), 11.4 (CH3CH), 35.7 (CH3CH2), 38.5 (CH2S), 49.2
(CH3CH), 70.0 (CHOH), 127.0 (Ar–C), 129.6 (2C, Ar–C),
130.1 (2C, Ar–C), 135.5 (Ar–C, quarternary), 215.8 (CvO);
nmax (neat): 3437.4 (br, O–H), 1704.0 (s, CvO); m/z
(autospec, CIþ): 221 ([M2OH]þ, 100%), 239 ([MþH]þ,
60%); (HRMS, autospec, CIþ): found 239.1110, ([MþH]þ),
C13H19SO2 requires 239.1106.
1
Analysis for anti-isomer: (1:1 hexane/EtOAc): 0.28; d H
NMR (400 MHz): 0.91 (3H, t, J¼7.6 Hz, CH3CH2),1.68–
1.82 (2H, m, CH2CH3),2.99–3.26 (3H, m, CH2S and OH),
3.22 (3H, s, CH3N), 3.76 (3H, s, CH3O), 3.80–3.90 (1H, m,
CHOH), 4.11–4.17 (1H, m, CHEt), 7.17–7.22 (1H, m, Ar),
7.27–7.31 (2H, m, Ar), 7.35–7.39 (2H, m, Ar); d 13C NMR
(100 MHz):11.9 (CH3CH2), 22.7 (CH2CH3), 31.8 (CH3N),
39.3 (CH2S), 44.3 (CHEt), 61.6 (CH3O), 70.8 (CHOH),
126.4 (Ar–C), 129.0 (2C, Ar–C), 129.5 (2C, Ar–C), 135.5
(Ar–C, quarternary), 176.4 (CO); nmax (neat): 3415.8 (br,
O–H), 1635.2 (s, CvO); m/z (autospec, ESIþ): 589
([2MþNa]þ, 42%), 306 ([MþNa]þ, 100%); m/z (HRMS,
autospec, ESIþ): found 306.1131 ([MþNa]þ): C14H21NO3-
SNa requires 306.1140.
4.12.6. (6)-3-Ethyl-4-hydroxy-5-phenylsulfanyl-pentan-
2-one. syn-Isomer synthesised from the corresponding
2-ethyl-3-hydroxy-N-methoxy-N-methyl-4-phenylsulfanyl-
butyramide (120 mg, 0.42 mmol) using general procedure 4
and a reaction time of 1.5 h. Purification by column
chromatography afforded the product (69 mg, 69%) as an
1
oil. Rf (1:1 hexane/EtOAc): 0.46; d H NMR (400 MHz):
0.87 (3H, t, J¼7.6 Hz, CH3CH2), 1.59–1.69 (1H, m,
CHAHBMe), 1.71–1.84 (1H, m, CHAHBMe), 2.17 (3H, s,
CH3CO), 2.76–2.81 (1H, m, CHEt), 2.89 (1H, dd, J¼11.1,
2.4 Hz, CHAHBS), 2.90 (1H, br s, OH), 3.14 (1H, dd,
J¼11.1, 3.9 Hz, CHAHBS), 3.87–3.92 (1H, m, CHOH),
7.17–7.22 (1H, m, Ar), 7.26–7.31 (2H, m, Ar), 7.35–7.40
(2H, m, Ar); d 13C NMR (100 MHz): 11.7 (CH3CH2), 22.6
(CH2CH3), 31.6 (CH3CO), 39.1 (CH2S), 57.5 (CHEt), 69.1
(CHOH), 126.7 (Ar–C), 129.1 (2C, Ar–C), 129.8 (2C, Ar–
4.12.8. 4-Hydroxy-5-phenylselenyl-pentan-2-one (6)-4.
Formed from (phenylselenyl)-acetaldehyde (100 mg,

7616
C. Baker-Glenn et al. / Tetrahedron 60 (2004) 7607–7619
0.53 mmol) and acetone (0.06 ml, 0.80 mmol) using general
procedure 1. Purification by column chromatography (1:1
hexane/EtOAc) afforded 4 (95 mg, 70%) as an oil. Rf (1:1
(301 mg, 14%) as an oil. anti-13 (from mixture with linear
regioisomer): Rf (1:1 hexane/EtOAc): 0.43; d 1H NMR
(400 MHz): 1.82 (3H, CH3S), 2.34 (3H, s, CH3CO), 3.43
(1H, d, J¼9.7 Hz, CHS), 3.46 (1H, br s, OH), 4.91 (1H, d,
J¼9.7 Hz, CHOH), 7.24–7.38 (5H, m, Ar); d 13C NMR
(100 MHz): 13.3 (CH3S), 28.0 (CH3CO), 59.6 (CHS), 73.2
(CHOH), 126.9 (2C, Ar–C), 128.3 (Ar–C), 128.4 (2C, Ar–
C), 140.8 (Ar–C, quarternary), 204.7 (CO); nmax (neat):
3436.1 (br, O–H), 1700.2 (s, CvO); m/z (GCT, FI): found
209.0640 ([Mz]), C11H13O2S requires 209.0636; syn-13: Rf
(1:1 hexane/EtOAc): 0.46; d 1H NMR (400 MHz): 2.06 (3H,
CH3S), 2.13 (3H, s, CH3CO), 3.28 (1H, br s, OH), 3.51 (1H,
d, J¼8.6 Hz, CHS), 4.97 (1H, d, J¼8.6 Hz, CHOH), 7.25–
7.40 (5H, m, Ar); d 13C NMR (100 MHz): 12.3 (CH3S), 29.1
(CH3CO), 60.5 (CHS), 69.8 (CHOH), 126.9 (2C, Ar–C),
128.2 (Ar–C), 128.4 (2C, Ar–C), 140.4 (Ar–C, quartern-
ary), 202.7 (CO); nmax (neat): 3448.3 (br, O–H), 1700.4 (s,
CvO); m/z (GCT, FI): found 209.0634 ([Mz]), C11H13O2S
requires 209.0636.
1
hexane/EtOAc): 0.30; d H NMR (400 MHz): 2.14 (3H, s,
CH3), 2.71 (1H, dd, J¼17.5, 7.9 Hz, CHAHBCHO), 2.77
(1H, dd, J¼17.5, 4.0 Hz, CHAHBCHO), 3.02 (1H, dd,
J¼12.7, 6.8 Hz, CHAHBSe), 3.06 (1H, dd, J¼12.7, 5.9 Hz,
CHAHBSe), 3.25 (1H, br s, OH), 4.12–4.21 (1H, m, CH)
7.25–7.30 (3H, m, Ar) 7.50–7.55 (2H, m, Ar); d 13C NMR
(100 MHz): 30.7 (CH3), 34.5 (CH2Se), 48.8 (CH2CO), 66.8
(CH), 127.3 (Ar–C, quarternary), 127.3 (Ar–C), 129.2 (2C,
Ar–C), 132.7 (2C, Ar–C), 208.7 (CvO); nmax (neat):
3422.8 (br, O–H), 1710.7 (s, CvO); m/z (HRMS, autospec,
ESIþ) found 281.0061 ([MþNa]þ), C11H14O2SeNa requires
281.0057; HPLC OJ–H: 93% solvent A/7% solvent C:
24.2 min (S), 23.2 min (R).
4.12.9. 4-Hydroxy-5-methyl-5-phenylsulfanyl-hexan-2-
one (6)-5. 2-Methyl-2-phenylsulfanyl-propionaldehyde
(200 mg, 1.1 mmol) and acetone (0.22 ml, 3.2 mmol)
using general procedure 1. Purification by column chroma-
tography (2:1 hexane/EtOAc) afforded 5 (250 mg, 95%) as
an oil. Rf (1:1 hexane/EtOAc): 0.34; d 1H NMR (400 MHz):
1.21 (3H, s, CH3CMe) 1.26 (3H, s, CH3CMe), 2.23 (3H, s,
CH3CO), 2.65 (1H, dd, J¼16.5, 10.1 Hz, CHAHBCHO),
2.80 (1H, dd, J¼16.5, 1.9 Hz, CHAHBCHO), 3.19 (1H, d,
OH), 3.91 (1H, ddd, J¼2.4, 2.4, 10.1 Hz, CHOH), 7.30–
7.40 (3H, m, Ar), 7.50–7.55 (2H, m, Ar); d 13C NMR
(100 MHz): 23.9 (CH3CMe), 24.7 (CH3CMe), 31.0
(CH3CO), 44.9 (CH2CO), 53.1 (CH2S), 72.1 (CH), 128.8
(2C, Ar–C), 129.2 (Ar–C), 130.4 (Ar–C, quarternary),
137.5 (2C, Ar–C), 185.8 (CO); nmax (neat): 3418.0 (br, O–
H), 1710.9 (s, CvO); m/z (autospec, CIþ): 239 ([MþH]þ,
12%), 221 ([M2OH]þ, 100%); m/z (HRMS, autospec,
CIþ): found 239.1109 ([MþH]þ) C13H19SO2 requires
239.1106.
4.12.12. 4-Hydroxy-6-(4-methoxy-phenyl)-1-methyl-
sulfanyl-hex-5-en-2-one (6)-11. Formed from 4-methoxy-
cinnamaldehyde (1.62 g, 10 mmol) and methylthioacetone
(1.5 ml, 15 mmol) using general procedure 1. The product
was formed as a mixture (11/syn-14/anti-14 69:8:23).
Purification by column chromatography afforded 11 (1.1 g
of mix with anti product, 37%) as an oil; Rf (1:1 hexane/
1
EtOAc): 0.38; d H NMR (400 MHz): 2.06 (3H, s, CH3S),
2.89 (1H, dd, J¼15.2, 4.8 Hz, CHAHBCH), 2.93 (1H, dd,
J¼15.2, 7.3 Hz, CHAHBCH), 3.20 (2H, s, CH2S), 3.79 (3H,
s, CH3O), 4.71–4.76 (1H, m, CHOH), 6.07 (1H, dd, J¼6.3,
15.9 Hz, CHvCHAr), 6.57 (1H, d, J¼15.9 Hz, CHAr), 6.80
(2H, d, J¼8.7 Hz, Ar), 7.26 (2H, d, J¼8.8 Hz, Ar); d 13C
NMR (100 MHz): 15.6 (CH3S), 43.7 (CH2S), 46.9
(CH2CH), 55.2 (CH3O), 69.0 (CH), 114.0 (2C, Ar–C),
127.7 (2C, Ar–C), 127.9 (CHvCHAr), 129.2 (Ar–C,
quarternary), 129.9 (CHAr), 159.3 (Ar–C, quarternary),
204.9 (CO); nmax (neat):1700.4 (s, CvO), 1606.3 (s, CvC);
m/z (GCT, FI): 266.0987 ([Mz]), C14H18O3S requires
266.0977; HPLC OD: 85% solvent A/15% solvent C:
17.3 min (S), 19.1 min (R).
4.12.10. 4-Hydroxy-1-methylsulfanyl-4-phenyl-butan-2-
one (6)-10. Formed from benzaldehyde (1 ml, 10 mmol)
and methylthioacetone (1.5 ml, 15 mmol) using general
procedure 1. The product was formed as a mixture (linear
regioisomer
10/branched-syn
13/branched-anti
13
15:15:14). Purification by column chromatography (4:1
hexane/EtOAc) afforded 10 (622 mg of 1:1 mix with anti
regioisomer 13, 15%) as an oil; linear isomer:Rf (1:1
4.12.13. 4-Hydroxy-6-(4-methoxy-phenyl)-3-methyl-
sulfanyl-hex-5-en-2-one (6)-14. Formed from 4-methoxy-
cinnamaldehyde (1.62 g, 10 mmol) and methylthioacetone
(1.5 ml, 15 mmol) using general procedure 1. The product
was formed as a mixture (11/syn-14/anti-14 69:8:23).
Purification by column chromatography afforded anti-14
(1.1 g of mix with linear regioisomer, 4%) as an oil and syn-
14 (213 mg, 8%) as an oil; anti-14; Rf (1:1 hexane/EtOAc):
0.38; d 1H NMR (400 MHz): 1.99 (3H, s, CH3S), 2.36 (3H,
s, CH3CO), 3.29 (1H, d, J¼9.1 Hz, CHS), 3.79 (3H, s,
CH3O), 4.61 (1H, app t, J¼7.9 Hz, CHOH), 6.20 (1H, dd,
J¼6.8, 15.8 Hz, CHCHAr), 6.63 (1H, d, J¼15.9 Hz, CHAr),
6.84 (2H, d, J¼8.7 Hz, Ar), 7.33 (2H, d, J¼8.7 Hz, Ar); d
13C NMR (100 MHz): 12.9 (CH3S), 28.0 (CH3C), 55.3
(CH3O), 58.1 (CHS), 71.3 (CHOH), 114.0 (2C, Ar–C),
125.9 (CHvCHAr), 128.0 (2C, Ar–C), 129.2 (Ar–C,
quarternary), 131.8 (CHAr), 159.4 (Ar–C, quarternary),
204.5 (CO); nmax (neat):1700.1 (s, CvO), 1606.8 (s, CvC);
m/z (GCT, FI): 266.0965 ([Mz]), C14H18O3S requires
266.0977; syn-14: Rf (1:1 hexane/EtOAc): 0.40; d 1H
NMR (400 MHz): 2.06 (3H, s, CH3S), 2.32 (3H, s, CH3C),
1
hexane/EtOAc): 0.43; d H NMR (400 MHz): 2.04 (3H, s,
SCH3), 3.00 (1H, dd, J¼17.2, 3.4 Hz, CHAHBCH), 3.09
(1H, dd, J¼17.2, 9.0 Hz, CHAHBCH), 3.16 (2H, s, CH2S),
3.19 (1H, br s, OH), 5.18 (1H, dd, J¼3.4, 9.0 Hz, CHOH),
7.24–7.41 (5H, m, Ar); d 13C NMR (100 MHz): 15.6
(SCH3), 43.6 (CH2S), 48.6 (CH2CH), 70.3 (CH), 125.7 (2C,
Ar–C), 127.8 (Ar–C), 128.6 (2C, Ar–C), 142.7 (Ar–C,
quarternary), 205.3 (CO); nmax (neat): 3430.0 (br, O–H),
1700.5 (s, CvO); m/z (GCT, FI): found 209.0640 ([Mz]),
C11H13O2S requires 209.0636.
4.12.11. 4-Hydroxy-3-methylsulfanyl-4-phenyl-butan-2-
one (6)-13. Formed from benzaldehyde (1 ml, 10 mmol)
and methylthioacetone (1.5 ml, 15 mmol) using general
procedure 1. The product was formed as a mixture (linear/
syn/anti 15:15:14). Purification by column chromatography
(4:1 hexane/EtOAc) afforded anti-13 (622 mg of 1:1 mix
with linear regioisomer 10, 15%) as an oil and syn-13

C. Baker-Glenn et al. / Tetrahedron 60 (2004) 7607–7619
7617
3.34 (1H, d, J¼8.3 Hz, CHS), 3.79 (3H, s, CH3O), 4.58 (1H,
app t, J¼6.8 Hz, CHOH), 6.04 (1H, dd, J¼6.6, 15.9 Hz,
CHvCHAr),6.65 (1H, d, J¼15.8 Hz, CHAr), 6.84 (2H, d,
J¼8.8 Hz, Ar), 7.31 (2H, d, J¼8.7 Hz, Ar); d 13C NMR
(100 MHz): 12.4 (CH3S), 29.0 (CH3C), 55.3 (CH3O), 59.4
(CHS), 68.8 (CHOH), 113.9 (2C, Ar–C), 125.1
(CHvCHAr), 127.8 (2C, Ar–C), 129.1 (Ar–C, quartern-
ary), 132.3 (CHAr), 159.5 (Ar–C, quarternary), 203.0 (CO);
nmax (neat):1699.7 (s, CvO), 1606.7 (s, CvC); m/z
(HRMS, autospec, ESI2): 265.0894 ([M2H]2),
C14H17O3S requires 265.0898.
4.12.16. 4-Hydroxy-5-phenylsulfanyl-pentan-2-one (R)-
1. Synthesised from 3-hydroxy-N-methoxy-N-methyl-4-
phenylsulfanyl-butyramide (R)-15 (255 mg, 1 mmol) using
general procedure 4. Purification by column chromato-
graphy (4:1 hexane/EtOAc) afforded (R)-1 (176 mg, 84%)
as an oil. Analysis as described above for the racemic
compound. [a]D¼þ8.6 (c¼10, CHCl3). ee¼58%; HPLC
OD: 93% solvent A/7% solvent B: 15.5 min (S), 16.7 min
(R).
4.12.17. 2-Hydroxy-1-phenylsulfanyl-heptan-4-one (R)-
2. Magnesium turnings (438 mg, 18 mmol) were stirred
vigorously overnight. Dry THF (3 ml) was added. Iodine (a
single crystal) was added and a solution of propyl bromide
(0.55 ml, 6 mmol) in dry THF (3 ml) was added dropwise.
The mixture was allowed to stir until it cooled to room
temperature. The mixture was then added to a solution of
amide (22) (255 mg, 1 mmol) in dry THF (2 ml) at 240 8C
via cannula. The mixture was allowed to warm to 0 8C over
30 min and allowed to stir for a further 1.5 h. Saturated
ammonium chloride solution (15 ml) was added and the
mixture extracted with DCM. The organic fractions were
combined, dried over MgSO4, filtered under suction and the
solvent removed in vacuo. Purification by column chroma-
tography (4:1 hexane/EtOAc) afforded (R)-(c4) (123 mg,
52%) as an oil. Analysis as described above for the racemic
compound. [a]D¼þ14.4 (c¼10, CHCl3). ee¼58%; HPLC
OD: 85% solvent A/15% solvent B: 12.2 min (S), 10.2 min
(R).
4.12.14. (R)-3-Hydroxy-4-phenylsulfanyl-butyric acid
ethyl ester 16. To baker’s yeast (42 g) in distilled water
(420 ml) was added sucrose (50.4 g). The mixture was
allowed to stir for 30 min and then 3-oxo-4-phenylsulfanyl-
butyric acid ethyl ester (2 g, 8.3 mmol) in EtOH (42 ml)
added. The mixture was allowed to stir for 18 h and then the
mixture was filtered through celite. The celite was washed
with EtOAc (100 ml) and the layers separated. The aqueous
layer was extracted with EtOAc. The organic layers were
combined, dried over MgSO4, filtered under suction and the
solvent removed in vacuo. Purification by column chroma-
tography (4:1 hexane/EtOAc) afforded (R)-16 (1.08 g, 54%)
as an oil. Rf (4:1 hexane/EtOAc): 0.50; d 1H NMR
(500 MHz): 1.27 (3H, t, J¼7.2 Hz, CH3), 2.58 (1H, dd,
J¼16.4, 8.1 Hz, CHAHBCHO), 2.67 (1H, dd, J¼16.4,
4.1 Hz, CHAHBCHO), 3.07 (1H, dd, J¼13.8, 7.0 Hz,
CHAHBS), 3.11 (1H, dd, J¼13.8, 5.7 Hz), 3.21 (1H, d,
J¼3.9 Hz, OH), 4.11–4.17 (1H, m, CHOH), 4.17 (2H, q,
J¼7.0 Hz, CH2CH3), 7.19–7.24 (1H, m, Ar), 7.28–7.33
(2H, m, Ar), 7.37–7.42 (2H, m, Ar); d 13C NMR
(125 MHz): 14.0 (CH3), 39.8 (CH2CHO), 40.1 (CH2S),
60.8 (CH2CH3), 66.5 (CHOH), 126.5 (Ar–C), 129.0 (Ar–C,
2C), 129.7 (Ar–C, 2C), 135.1 (Ar–C, quarternary), 172.0
(CHO); nmax (neat): 3458.4 (br, O–H), 1729.5 (s, CvO);
m/z (autospec, CIþ): 223 ([M2OH]þ, 100%), 241
([MþH]þ, 21%), 258 ([MþNH4]þ, 34%); (HRMS, GCT,
FI): found 240.0821 ([Mz]), C12H16SO3 requires 240.0820;
[a]D¼þ5.8 (c¼10, CHCl3); ee¼58%.
4.12.18. 4-Hydroxy-4-phenyl-butan-2-one (R)-17. To
benzaldehyde (2 ml, 20 mmol) in DMSO (160 ml) and
acetone (40 ml) was added (L)-proline (690 mg, 6 mmol).
The mixture was allowed to stir for 3 h. Water (100 ml) was
added and the mixture extracted with EtOAc. The combined
organic fractions were dried over MgSO4, filtered under
suction and the solvent removed in vacuo. Purification by
column chromatography (4:1 hexane/EtOAc) afforded (R)-
17 (920 mg, 28%) as an oil; Rf (1:1 hexane/EtOAc): 0.38; d
1H NMR (400 MHz): 2.20 (3H, s, CH3), 2.83 (1H, dd,
J¼17.3, 3.3 Hz, CHAHB), 2.89 (1H, dd, J¼17.3, 9.1 Hz,
CHAHB), 3.33 (1H, br s, OH), 5.16 (1H, dd, J¼3.3, 9.1 Hz,
CH), 7.26–7.37 (5H, m, Ar); d 13C NMR (100 MHz): 30.8
(CH3), 52.0 (CH2), 69.8 (CH), 125.6 (2C, Ar–C), 127.7
(Ar–C), 128.6 (2C, Ar–C), 142.7 (Ar–C, quarternary),
209.1 (CO); nmax (neat): 3448.9 (br, O–H), 1708.1 (s,
CvO); m/z (HRMS, GCT, FI): found: 164.0833 ([Mz]),
C10H12O2 requires 164.0837; [a]D¼þ45.1 (c¼10, CHCl3).
ee¼71%.
4.12.15. 3-Hydroxy-N-methoxy-N-methyl-4-phenyl-
from
sulfanyl-butyramide
(R)-15.
Synthesised
3-hydroxy-4-phenylsulfanyl-butyric acid ethyl ester 16
(1 g, 4.16 mmol) using general procedure 2. Purification
by column chromatography (4:1 hexane/EtOAc) afforded
(R)-15 (863 mg, 81%) as an oil. Rf (1:1hexane/EtOAc):
0.16; d 1H NMR (500 MHz): 2.65 (1H, dd, J¼16.8, 8.5 Hz,
CHAHBCHO), 2.86 (1H, dd, J¼16.8, 2.2 Hz CHAHBCHO),
3.09 (1H, dd, J¼13.4, 6.7 Hz, CHAHBS), 3.17 (1H, dd,
J¼13.4, 5.0 Hz), 3.19 (3H, s, CH3N), 3.67 (3H, s, CH3O),
3.97 (1H, d, J¼3.0 Hz, OH), 4.14–4.22 (1H, m, CHOH),
7.18–7.22 (1H, m, Ar), 7.27–7.32 (2H, m, Ar), 7.39–7.42
(2H, m, Ar); d 13C NMR (125 MHz): 31.7 (CH3N), 36.6
(CH2CO), 39.6 (CH2S), 61.2 (CH3O), 66.9 (CHOH), 126.2
(Ar–C), 128.9 (Ar–C, 2C), 129.3 (Ar–C, 2C), 135.5
(Ar–C, quarternary), 172.9 (CvO); nmax (neat): 3430.1 (br,
O–H), 1643.7 (s, CvO); m/z (autospec, CIþ): 238
([M2OH]þ, 52%), 256 ([MþH]þ, 100%); (HRMS, GCT,
CIþ): found 256.1018 ([MþH]þ), C12H18SO3N requires
256.1007. Analysis for C12H17SO3N: calculated C: 56.45,
H: 6.71, N: 5.49; found C: 56.61, H: 6.87, N: 5.53;
[a]D¼þ39.3 (c¼10, CHCl3). ee¼58%.
4.12.19. (R)-4-(tert-Butyl-dimethyl-silanyloxy)-4-phenyl-
butan-2-one. Synthesised from 4-hydroxy-4-phenyl-butan-
2-one (850 mg, 5.2 mmol) using general procedure 5.
Purification by column chromatography (4:1 hexane/DCM)
afforded the desired compound (1.29g, 90%) as an oil. Rf
1
(1:1 hexane/Et2O): 0.70; d H NMR (400 MHz): 20.18
(3H, s, SiCH3), 0.02 (3H, s, SiCH3), 0.85 (9H, s, C(CH3)3),
2.55 (1H, dd, J¼14.9, 4.0 Hz, CHAHB), 2.95 (1H, dd,
J¼14.9, 8.9 Hz, CHAHB), 5.16 (1H, dd, J¼4.0, 8.8 Hz, CH),
7.22–7.36 (5H, m, Ar); d 13C NMR (100 MHz): 25.3
(SiCH3), 24.7 (SiCH3), 18.1 (SiC(CH3)3), 25.7 (3C,
C(CH3)3), 31.8 (CH3CO), 54.4 (CH2), 71.9 (CH), 125.8
(2C, Ar–C), 127.4 (Ar–C), 128.3 (2C, Ar–C), 144.4

7618
C. Baker-Glenn et al. / Tetrahedron 60 (2004) 7607–7619
(Ar–C, quarternary), 207.3 (CO); nmax (neat): 1720.6 (s,
CvO); m/z (GCT, CIþ): 279 ([MþH]þ, 7%), 221
([M2C4H9]þ, 15%), 164 ([M2OTBSþNH3]þ, 33%), 147
([M2OTBS]þ, 100%); [a]D¼þ65.9 (c¼10, CHCl3).
one (R)-10. Synthesised from 4-(tert-butyl-dimethyl-
silanyloxy)-1-methylsulfanyl-4-phenyl-butan-2-one (130 mg,
0.37 mmol) using general procedure 6. Purification by column
chromatography (4:1 hexane/EtOAc) afforded (R)-10 (40 mg,
66%) as an oil. Analysis as described above for the racemic
compound. [a]D¼þ43.7 (c¼10, CHCl3); HPLC OD: 90%
solvent A/10% solvent B: 15.6 min (S), 16.7 min (R).
4.12.20. 4-(tert-Butyl-dimethyl-silanyloxy)-1-chloro-4-
phenyl-butan-2-one (R)-18. To 4-(tert-butyl-dimethyl-
silanyloxy)-4-phenyl-butan-2-one (556 mg, 2 mmol) in dry
DCM (30 ml) at 0 8C was added DIPEA (1.7 ml, 12 mmol).
To this was added TMSOTf (1.5 ml, 4 mmol) dropwise. The
mixture was allowed to stir at 0 8C for 1.5 h. The reaction
was then cautiously quenched with sat. NH4Cl (50 ml). The
mixture was extracted with hexane, the organic fractions
combined, dried over Na2SO4, filtered under suction and the
solvent removed in vacuo. The residue was taken up in dry
DCM (2 ml) and added dropwise to a solution of SO2Cl2
(0.19 ml, 2.4 mmol) in DCM (10 ml) at 278 8C. The
mixture was allowed to warm to room temperature over
30 min and allowed to stir at room temperature for 30 min.
The reaction was then quenched with ice-cold water
(15 ml). The mixture was extracted with DCM, the organic
layers combined, dried over MgSO4, filtered under suction
and the solvent removed in vacuo. Purification by column
chromatography (4:1 hexane/DCM) afforded (R)-18
(221 mg, 35%) as an oil. Rf (1:1 hexane/DCM): 0.32; d
1H NMR (400 MHz): 20.18 (3H, s, SiCH3), 0.01 (3H, s,
SiCH3), 0.85 (9H, s, SiC(CH3)3), 2.65 (1H, dd, J¼14.6,
3.8 Hz, CHAHBCH), 3.05 (1H, dd, J¼14.6, 9.2 Hz, CHA-
HBCH), 4.10 (1H, dd, J¼16.0 Hz, CHAHBCl), 4.19 (1H, dd,
J¼16.0 Hz, CHAHBCl), 5.17 (1H, dd, J¼3.8, 9.1 Hz, CH),
7.24–7.37 (5H, m, Ar); d 13C NMR (100 MHz): 25.3
(SiCH3), 24.8 (SiCH3), 18.0 (SiC(CH3)3), 25.7 (3C,
SiC(CH3)3), 50.0 (CH2Cl), 50.7 (CH2CH), 72.2 (CH),
125.7 (2C, Ar–C), 127.7 (Ar–C), 128.4 (2C, Ar–C),
143.7 (Ar–C, quarternary), 200.3 (CO); nmax (neat):1736.5
(s, CvO); m/z (autospec, CIþ): 315 ([MþH]þ 37Cl, 1%)
313 ([MþH]þ 35Cl, 2.5%), 257 ([M2C(CH3)3]þ 37Cl,
18%), 255 ([M2C(CH3)3]þ 35Cl, 49%), 183 ([M2OTBS]þ
37Cl, 35%), 181 ([M2OTBS]þ 35Cl, 100%); m/z (autospec,
CIþ): 313.1389 ([MþH]þ(35Cl)), C16H26O2SiCl requires
313.1391; [a]D¼þ78.7 (c¼10, CHCl3).
Acknowledgements
This work was generously supported by GlaxoSmithKline
(Full Industrial Case to C.B.G.) and the Royal Society of
Chemistry (RSRG 20750 grant to V.G.). We are most
grateful to Professor Richard Lerner for providing all the
antibodies for this study and Diane Kubitz for preparing
them (The Scripps Research Institute, CA, USA).
References and notes
1. Fox, D. J.; House, D.; Warren, S. Angew. Chem., Int. Ed. 2002,
41, 2462.
2. Aggarwal, V. K.; Coldham, I.; McIntyre, S. M.; Sansbury,
F. H.; Villa, M. J.; Warren, S. Tetrahedron Lett. 1988, 29,
4885. Eames, J.; Jones, R. V. H.; Warren, S. Tetrahedron Lett.
1996, 37, 4823. Eames, J.; Delasheras, M. A.; Warren, S.
Tetrahedron Lett. 1996, 37, 4077. Eames, J.; Warren, S.
Tetrahedron Lett. 1996, 37, 3525.
3. Solladie, G.; Salom-Roig, X. J.; Hanquet, G. Tetrahedron Lett.
2000, 41, 551.
4. Carlisle, J.; Fox, D. J.; Warren, S. Chem. Commun. 2003, 21,
2696. and references therein.
5. Maggiotti, V.; Resmini, M.; Gouverneur, V. Angew. Chem.,
Int. Ed. 2002, 41, 1012. For other references covering the
generation and reactivity of aldolase antibodies, see for
example: Wagner, J.; Lerner, R. A.; Barbas, C. F., III. Science
¨
1995, 270, 1797. Bjornestedt, R.; Zhong, G.; Lerner, R. A.;
Barbas, C. F., III. J. Am. Chem. Soc. 1996, 118, 11720. Zhong,
G.; Hoffmann, T.; Lerner, R. A.; Danishefsky, S.; Barbas,
C. F., III. J. Am. Chem. Soc. 1997, 119, 8131. Barbas, C. F., III;
Heine, A.; Zhong, G.; Hoffmann, T.; Gramatikova, S.;
4.12.21. (R)-4-(tert-Butyl-dimethyl-silanyloxy)-1-methyl-
sulfanyl-4-phenyl-butan-2-one. Synthesised from 4-(tert-
butyl-dimethyl-silanyloxy)-1-chloro-4-phenyl-butan-2-one
(130 mg, 0.44 mmol) using general procedure 7. Purifi-
cation by column chromatography (4:1 hexane/DCM)
afforded the desired compound (137 mg, 96%) as an oil.
Rf (1:1 hexane/DCM): 0.25; d 1H NMR (400 MHz): 20.18
(3H, s, SiCH3), 0.01 (3H, s, SiCH3), 0.85 (9H, s,
SiC(CH3)3), 2.00 (3H, s, CH3S), 2.73 (1H, dd, J¼15.0,
4.2 Hz, CHAHBCH), 3.13 (1H, dd, J¼15.0, 8.8 Hz, CHA-
HBCH), 3.14 (1H, d, J¼13.9 Hz, CHAHBS), 3.21 (1H, d,
J¼13.9 Hz, CHAHBS), 5.18 (1H, dd, J¼4.2, 8.8 Hz, CH),
7.21–7.40 (5H, m, Ar); d 13C NMR (100 MHz): 25.2
(SiCH3), 24.7 (SiCH3), 15.4 (SCH3), 18.0 (C(CH3)3), 25.7
(3C, C(CH3)3), 44.5 (CH3SMe), 51.1 (CH2CH), 72.1 (CH),
125.8 (2C, Ar–C), 127.5 (Ar–C), 128.4 (2C, Ar–C), 144.2
(Ar–C, quarternary), 203.4 (CO); nmax (neat):1708.7 (s,
CvO); m/z (GCT, FI): 324.1592 ([Mz]), C17H28O2SiS
requires 324.1579; [a]D¼þ77.5 (c¼10, CHCl3).
¨
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