Enantioselective organocatalytic aldehyde-aldehyde cross-aldol couplings. The broad utility of α-thioacetal aldehydes

Article abstract of DOI:10.1016/j.tet.2004.04.089

An asymmetric proline catalyzed aldol reaction with α-thioacetal aldehydes has been developed. Thioacetal bearing aldehydes readily participate as electrophilic cross-aldol partners with a broad range of aldehyde and ketone donors. High levels of reaction

Full text of DOI:10.1016/j.tet.2004.04.089

Tetrahedron 60 (2004) 7705–7714
Enantioselective organocatalytic aldehyde–aldehyde cross-aldol
couplings. The broad utility of a-thioacetal aldehydes
*
R. Ian Storer and David W. C. MacMillan
Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E California Blvd; Pasadena, CA 91125, USA
Received 6 April 2004; accepted 9 April 2004
Available online 15 July 2004
This manuscript is dedicated to Professor D. Seebach for his pioneering work in the area of asymmetric synthesis
Abstract—An asymmetric proline catalyzed aldol reaction with a-thioacetal aldehydes has been developed. Thioacetal bearing aldehydes
readily participate as electrophilic cross-aldol partners with a broad range of aldehyde and ketone donors. High levels of reaction efficiency as
well as diastereo- and enantiocontrol are observed in the production of anti-aldol adducts.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
enantioselective cross coupling allows access to highly
oxidized, stereodefined synthons of broad versatility. More-
over, the observed reactivity profile of ‘viable-electrophile,
non-nucleophile’ has established a-thioacetal aldehydes as
The aldol reaction is widely considered to be one of the most
important technologies for carbon–carbon bond formation
in chemical synthesis.1 Over the last thirty years, seminal
research from the laboratories of Evans,2 Heathcock,3
Masamune4 and Mukaiyama5 have established this vener-
able reaction as the principal chemical method for the
stereoselective construction of complex polyol architecture.
Recently, studies by Barbas,6 Evans,7 List,8 Shair,9
Shibasaki,10 and Trost11 have outlined the first examples
of enantioselective direct aldol reactions, an important class
of metal or proline catalyzed transformation that does not
require the pregeneration of enolates or enolate equivalents.
With these remarkable advances in place, a fundamental
goal for asymmetric aldol technology has become the
development of catalytic methods that would allow the
direct coupling of aldehyde substrates.12 In this context, our
laboratory has recently reported the first example of a direct
enantioselective aldehyde–aldehyde cross-aldol reaction
using small molecule catalysts (Scheme 1).13 Subsequently,
we described the enantioselective dimerization and cross
coupling of a-oxygenated aldehydes to provide erythrose
architecture of broad utility for the construction of hexose
carbohydrates.14 In this report, we further advance this
enamine catalysis concept to describe a highly stereo-
selective protocol for the cross coupling of aldehydes and
ketones with a-thioacetal aldehydes. Importantly, the
successful introduction of a-thioacetal functionality in this
Keywords: Aldol; Catalysis; Diastereoselection; Enantioselective;
Organocatalysis; Proline.
*
Corresponding author. Tel.: þ1-626-395-6044; fax: þ1-626-795-3658;
e-mail address: dmacmill@caltech.edu
Scheme 1. Proline-catalyzed cross aldehyde aldol.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.04.089

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R. Ian Storer, D. W. C. MacMillan / Tetrahedron 60 (2004) 7705–7714
preeminent substrates for highly selective cross aldol
reactions with prototypical aldehyde and ketone donors.
upon the design of aldehydic reagents that would
(i) selectively function as aldol donors or acceptors,
(ii) engender high levels of diastereocontrol, and
(iii) contain chemical functionality that is readily elaborated
and synthetically versatile. In this context, we selected
a-thioacetal aldehydes with the expectation that they would
be highly electrophilic yet sterically and electronically
deactivated towards enamine formation (Scheme 1 Eq. 3).
Moreover, the substantial steric demand of the a-dithane
was expected to enforce high levels of absolute and relative
stereocontrol in the aldol event. Lastly, the synthetic utility
of thioacetals as latent carbonyl and alkyl equivalents has
been widely established.15 Indeed, a variety of conditions
have been elucidated to transform dithianes to aldehydes,
alcohols or carboxylic acids. Alternatively, the reductive
extrusion of sulfur using transition metals is commonly
utilized for the conversion of thioacetals to saturated alkyl
substituents (Scheme 2).15 With regard to operational
advantages, it is important to note that a-thioacetal
aldehydes are readily accessible on large scale and can be
easily handled and stored.16
Traditionally, the enantioselective aldol coupling of non-
equivalent aldehydes has been viewed as a formidable
synthetic challenge on account of (i) the propensity of
aldehydes to polymerize under metal catalyzed conditions
and (ii) the mechanistic requirement that non-equivalent
aldehydes must selectively partition into two discrete
components, a nucleophilic donor and an electrophilic
acceptor. In our recent studies, however, we have
established that enamine catalysis can provide good levels
of chemo-differentiation and stereocontrol with non-
equivalent aldehydes, thereby establishing the aldehyde
cross-aldol as an operationally useful transformation. More
specifically, we have found that aldehydes containing a
methylene carbon (CH2R2) adjacent to the carbonyl have a
strong propensity to dimerize, via participation as both
nucleophile and electrophile (Scheme 1, Eq. 1).13 In
contrast, aldehydes that incorporate an a-methine carbon
(CHR3) generally do not homo-dimerize when exposed to
proline, instead behaving as electrophilic acceptors
exclusively (Scheme 1, Eq. 2). In this latter case, it is
presumed that the kinetic inaccessabilty of the a-methine
proton and the thermodynamic instability of the correspond-
ing enamine effectively prohibit nucleophile formation. As
a consequence, chemoselective partitioning of a-methylene
and a-methine aldehydes into nucleophilic and electrophilic
partners respectively can be accomplished via slow addition
of the enamine precursor to the a-methine aldehyde in the
presence of catalyst. With respect to stereoselectivity, it
should be noted that the bulky a,a-disubstituted aldehyde
acceptors consistently provide superior levels of anti-
diastereocontrol in crossed aldehyde aldol reactions in
comparison to their a-methylene counterparts (Scheme 1,
cf. Eqs. 1 and 3). This improvement in diastereocontrol as a
function of increasing steric demand of the electrophile is in
accord with a chair-like Zimmerman–Traxler transition
state that has been proposed for enamine aldol reactions.
Scheme 2. Manipulation of dithianes.
2. Results and discussion
The proposed organocatalytic cross aldol was first examined
using equimolar quantities of propanal and [1,3]-dithane-2-
carbaldehyde16 in the presence of catalytic proline (Table 1,
entry 1). Preliminary studies revealed that this aldol reaction
was indeed possible to provide the cross aldehyde adduct in
99% ee, however small quantities of the propanal dimer
were observed. Gratifyingly, the aldol union can be
Based on our knowledge of the chemo- and stereo-
differentiating features of the enamine cross aldol, we
recently sought to devise a new and generally useful class of
aldehyde cross coupling partner. Specifically we focused
Table 1. Enantioselective direct cross-aldol reaction: preliminary studies
Entry
Donor (equiv.a)
Acceptor (equiv.)
% Crossb (desired)
% Dimerb (undesired)
% ee Cross
1
2
3
1.0
2.0
1.0
1.0
1.0
0
1.0
1.0
2.0
4.0
2.0
1.0
90
65
100
100
10
35
0
0
10
—
99
99
99
99
99
—
4
5c
6
90
no thioacetal dimer
a
Donor added by syringe pump over 24 h.
1
Ratio of products determined by H NMR integration of reaction crude.
Donor and acceptor premixed.
b
c

R. Ian Storer, D. W. C. MacMillan / Tetrahedron 60 (2004) 7705–7714
7707
comprehensively partitioned to a cross aldol mechanism via
the slow addition of propanal to an excess of the
electrophilic aldehyde (entries 3 and 4).
metric induction and efficiency obtained via slow addition
of the donor with excess dithiane acceptor (2 equiv.)
prompted us to select these catalytic conditions for further
exploration.
In these cases the corresponding cross aldol adduct was
obtained with excellent levels of anti diastereoselectivity
and enantiocontrol (entry 3, 16:1 anti–syn, 99% ee) without
production of dimeric propanal. As revealed in entries 3 and
5, the slow addition of the donor component is critical to the
kinetic circumvention of the undesired dimerization path-
way. The superior levels of cross-aldol selectivity, asym-
Experiments that probed the scope of the dithiane moiety
and the donor aldehyde are summarized in Table 2. In all
cases, slow addition of the donor aldehyde to a series of
thioacetal aldehydes in the presence of proline effectively
suppressed homodimerization, whilst providing good to
excellent yields of the desired cross-aldol products (entries
Table 2. Enantioselective direct cross-aldol reaction: scope studies
Entry
1
Temperature (8C)
Mol% cat.
10
Product
% Yield
85
anti–syna
% cc
4
16:1
.99b
2
4
10
10
10
10
77
70
41
75
8:1
99b
97b
98b
97b
3
23
23
4
10:1
8:1
4
5c
.20:1
6
23
23
23
10
20
20
10
73
52
91
88
.20:1
13:1
97b
7
70b
8d
—
96e
9d,f
23
.20:1
.99e
a
1
Ratio determined by H NMR analysis of the crude reaction mixtures.
b
c
d
e
f
Enantiomeric excess determined by chiral HPLC analysis of the 2,2-dimethyl-1,3-propanediol acetal derivatives.
Ratio of donor–acceptor was 1:1.5.
An excess of ketone donor was used.
Enantiomeric excess determined by chiral HPLC analysis.
Relative and absolute stereochemistry was confirmed by X-ray analysis.17

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1–7). Considerable variation in the steric demand of the
thioacetal substituent is possible without loss in enantio-
control (entries 1–4, 97 to 99% ee).16 However, couplings
performed with cyclic thioacetal aldehydes (Table 1, entries
1–2) were found to proceed more efficiently than with the
acyclic examples (Table 1, entries 3–4). In these cases, we
presume that the inherent reactivity of the acceptor
decreases with the relative steric demands of the proximal
acetal. To our delight, this chemo- and enantioselective
cross aldol is also tolerant to a wide range of donor systems
(entries 5–9, 97–99% ee). In the context of aldehyde
donors, propanal, octanal and hydrocinnamaldehyde
provide cross coupled adducts with [1,3]-dithane-2-carbal-
dehyde in 70–85% yield, .20:1 dr and 95–99% ee
(Table 2, entries 1,5,6). Moreover, the silyloxy glyco-
aldehyde donor enables the rapid construction of latent
erythrose architecture (entry 7, 95% yield, 13:1 anti–syn,
70% ee).
cannula. dimethylformamide (DMF) was purified according
to the method of Grubbs.21 Organic solutions were
concentrated under reduced pressure on a Bu¨chi rotary
evaporator. Chromatographic purification of products was
accomplished using forced-flow chromatography on ICN 60
32–64 mesh silica gel 63 according to the method of Still.22
Thin-layer chromatography (TLC) was performed on EM
Reagents 0.25 mm silica gel 60-F plates. Visualization of
the developed chromatograms was performed by ultra-
violet irradiation (254 nm) or stained using anisaldehyde or
aqueous acidic ammonium molybdate. 1H NMR spectra
were recorded in CDCl3, at ambient temperature on a Varian
300 spectrometer, at 300 MHz, with residual protic solvent
CHCl3 as the internal reference (dH¼7.26 ppm); Chemical
shifts (d) are given in parts per million (ppm), and coupling
constants (J) are given in Hertz (Hz). The proton spectra are
reported as follows: chemical shift (d/ppm) (multiplicity
(s¼singlet, d¼doublet, t¼triplet, q¼quartet, p¼pentet,
sept¼septet, m¼multiplet), coupling constant (J/Hz), num-
ber of protons, assignment). 13C NMR spectra were
recorded in CDCl3 at ambient temperature on the same
spectrometer at 75 MHz, with the central peak of CHCl3 as
the internal reference (dC¼77.3 ppm). Data for 13C NMR
are reported in terms of chemical shift. Two dimensional
COSY and HMQC NMR spectroscopy were used where
In accord with the studies of Hajos–Parrish18 and Barbas6–
List,7 ketone donors can also be accommodated without loss
in reaction efficiency or stereocontrol (Table 2, entries 8 and
9). More specifically, the rapid addition of acetone to [1,3]-
dithane-2-carbaldehyde in the presence of proline at room
temperature resulted in the corresponding cross aldol adduct
in 91% yield and 96% ee (entry 8). Of particular note was
the coupling of acetol in 88% yield, .20:1 dr, .99% ee
(entry 9) and the silyloxy glycoaldehyde donor (entry 7).
The successful implementation of these a-oxy substrates in
this cross aldol sequence should allow facile and rapid
access to biologically important polyol architectures, such
as hexose carbohydrates.
1
appropriate, to aid in the assignment of signals in the H
NMR spectra. Where a compound has been characterized as
an inseparable mixture of diastereoisomers, the NMR data
for the major isomer has been reported. IR spectra were
recorded on a Perkin Elmer Paragon 1000 spectrometer and
are reported in terms of frequency of absorption (cm21).
Mass spectra were obtained from the California Institute of
Technology Mass Spectral facility by electron ionisation,
chemical ionisation or fast atom/ion bombardment tech-
niques. Optical rotations were measured on a Jasco P-1010
polarimeter, and [a]D values are reported in 102-
1 deg cm2 g21; concentration (c) is in g/100 mL. High
performance liquid chromatography (HPLC) was performed
on Hewlett-Packard 1100 Series chromatographs using a
Chiralcel AD column (25 cm) and AD guard (5 cm), a
Chiralcel OJ column (25 cm) and OJ guard (5 cm), a
Chiralcel AS column (25 cm) and AS guard (5 cm), or a
Chiralcel ODH column (25 cm) and ODH guard (5 cm) as
noted. Syringe pump additions were made using a 10
syringe parallel pump (in all cases the syringe needle tip was
submerged below the surface of the liquid in the receiver
vessel to ensure continuous mixing).
Lastly, it is important to note that this dithiane-aldehyde
class provides the highest levels of diastereocontrol that
have been observed in aldehyde–aldehyde couplings to
date. As revealed in Table 2, formation of the anti-isomer is
accomplished with excellent selectivity for a range of
aldehyde donors and thio-acetal acceptors (entries 1–7, 8 to
20:1 anti–syn). The relative and absolute stereochemistry
observed is in accord with the previously proposed models
for proline catalyzed reactions.14,19
In summary, we have shown a-thioacetal aldehydes to be
versatile acceptor units for direct proline catalyzed aldol
reactions with a range of aldehyde and ketone donors.
Significantly, this reaction permits highly diastereoselective
and enantioselective access to b-hydroxy and a,b-di-
hydroxy aldehydes and ketones. Work is continuing to
apply these units in the synthesis of desymmetrized meso-
tartrate derivatives, hexose and pentose carbohydrates, and
to the total synthesis of polypropionate and polyacetate
natural products. A full account of these studies will be
presented in due course.
3.2. Synthesis and characterization
3.2.1. [1,3]Dithiane-2-carbaldehyde. The title compound
was obtained from 1,3-dithiane and ethyl formate using the
procedure outlined by Page.16b The product was initially
purified by flash chromatography (3:1 pentane–diethyl
ether) to remove any residual 1,3-dithiane and yield a pale
yellow oil. The aldehyde was then purified by distillation in
vacuo (78 8C, 0.15 mm Hg, 135 8C bath temp.)16a to yield a
colorless oil. The aldehyde could be successfully stored
under anhydrous conditions at ca. 220 8C (mp ,0 8C) as a
white crystalline solid.
3. Experimental
3.1. General
Commercial reagents were purified prior to use following
the guidelines of Perrin and Armarego.20 Non-aqueous
reagents were transferred under nitrogen via syringe or
3.2.2. (2S,3R)-3-[1,3]Dithiane-2-yl-3-hydroxy-2-methyl-
propionaldehyde (Table 2, entry 1). A solution of freshly

R. Ian Storer, D. W. C. MacMillan / Tetrahedron 60 (2004) 7705–7714
7709
distilled propionaldehyde (100 mL, 1.35 mmol) in 1.35 mL
DMF pre-cooled to 4 8C was added slowly over the course
of 24 h to a stirring suspension of [1,3]dithiane-2-carbalde-
hyde (400 mg, 2.70 mmol), L-proline (16 mg, 0.139 mmol)
and 1.35 mL DMF at 4 8C. After 46 h, the resulting solution
was diluted with diethyl ether and washed successively with
water and brine. The combined aqueous layers were
extracted with five portions of ethyl acetate. The organic
layers were combined, dried over anhydrous MgSO4, and
concentrated in vacuo. Analysis of the crude reaction
boxylic acid ethyl ester (2.5 g, 14.0 mmol) in CH2Cl2
(21 mL) at 278 8C. The reaction mixture was stirred at
278 8C for 1 h, quenched with MeOH (2 mL) and allowed
to slowly warm to room temperature. A solution of Rochel
salts (20 mL) and CH2Cl2 (30 mL) were added and stirring
continued for 3 h. The mixture was extracted three times
with CH2Cl2. The combined organics were washed with
brine, dried over MgSO4, filtered and concentrated to yield a
pale yellow oil. Purification by flash chromatography (4:1
pentane–diethyl ether) yielded a colorless clear oil in 85%
yield (1.59 g, 11.9 mmol). The title aldehyde could be
successfully stored under anhydrous conditions below 0 8C
(278 8C for long term storage).
1
mixture by H NMR revealed a 16:1 anti–syn mixture of
diastereoisomers. Flash chromatography (1:1 pentane–
diethyl ether) afforded the title compound as a mixture of
diastereoisomers as a clear, colorless oil in 85% yield
(236 mg, 1.15 mmol). The enaniomeric excess (ee) was
measured by HPLC analysis of the acetal derived from 2,2-
dimethylpropane-1,3-diol (see below). IR (film) 3456, 2902,
1717, 1422, 1277, 986, 908, 783 cm21; 1H NMR (300 MHz,
CDCl3) d 9.73 (d, J¼1.2 Hz, 1H, CHO), 4.24 (dd, J¼7.2,
4.8 Hz, 1H, CHOH), 3.87 (d, J¼7.2 Hz, 1H, SCHS), 3.05–
2.78 (m, 3H, CHCH3, SCH2CH2CH2S), 2.74–2.60 (m, 2H,
SCH2CH2CH2S), 2.15–1.95 (m, 2H, SCH2CH2CH2S), 1.25
(d, J¼7.5 Hz, 3H, CH3), no OH signal observed; 13C NMR
(75 MHz, CDCl3) d 203.4, 73.7, 48.5, 47.9, 27.7, 26.9, 25.4,
10.4; HRMS (EIþ) exact mass calcd for [M]þ (C8H14O2S2)
requires m/z 206.0435, found m/z 206.0432; [a]D¼215.3
(c¼1.0, CHCl3).
3.2.5. (2S,3R)-[1,3]Dithiolane-2-yl-3-hydroxy-2-methyl-
propionaldehyde (Table 2, entry 2). A solution of freshly
distilled propionaldehyde (123 mL, 1.69 mmol) in 1.75 mL
DMF pre-cooled to 4 8C was added slowly over the course
of 24 h to a stirring suspension of [1,3]dithiolane-2-
carbaldehyde (453 mg, 3.38 mmol), L-proline (19.5 mg,
0.169 mmol) and 1.75 mL DMF at 4 8C. After 28 h, the
resulting solution was diluted with diethyl ether and washed
successively with water and brine. The combined aqueous
layers were extracted with five portions of ethyl acetate. The
organic layers were combined, dried over anhydrous
MgSO4, and concentrated in vacuo. Analysis of the crude
reaction mixture by 1H NMR revealed an 8:1 anti–syn
mixture of diastereoisomers. Flash chromatography (2:1
pentane–diethyl ether) afforded the title compound as a
mixture of diastereoisomers as a clear, colorless oil in 77%
yield (251 mg, 1.31 mmol). The ee was measured by HPLC
analysis of the acetal derived from 2,2-dimethylpropane-
1,3-diol (see below). IR (film) 3440, 2972, 2928, 2877,
2730, 1715, 1456, 1423, 1380, 1279, 1101, 1035 cm21; 1H
NMR (300 MHz, CDCl3) d 9.80 (d, J¼2.1 Hz, 1H, CHO),
4.71 (d, J¼5.7 Hz, 1H, SCHS), 3.74 (ddd, J¼5.7, 5.7,
4.5 Hz, 1H, CHOH), 3.40–3.14 (m, 4H, SCH2CH2S), 2.85
(d, J¼4.4 Hz, 1H, OH), 2.78–2.66 (m, 1H, CHCH3), 1.19
(d, J¼7.2 Hz, 3H, CHCH3); 13C NMR (75 MHz, CDCl3) d
203.9, 76.6, 57.3, 50.3, 39.3, 38.5, 11.4; HRMS (EIþ) exact
mass calcd for [M]þ (C7H12O2S2) requires m/z 192.0279,
found m/z 192.0279; [a]2D2¼22.4 (c¼1.0, CHCl3).
3.2.3. (1R,2S)-2-(5,5-Dimethyl-[1,3]dioxan-2-yl)-1-
[1,3]dithian-2-yl-propan-1-ol. A solution of 2,2-dimethyl-
propane-1,3-diol (21.0 mg, 0.202 mmol) and pyridinium
p-toluenesulfonate (5 mg, 0.02 mmol) in acetonitrile
(0.2 mL) were added to
a solution of (2S,3R)-3-
[1,3]dithiane-2-yl-3-hydroxy-2-methyl-propionaldehyde
(17.0 mg, 0.083 mmol) in acetonitrile (0.2 mL) at room
temperature. The mixture was stirred for 16 h before
filtration through a pad of silica (2:1 pentane–diethyl
ether) and concentration in vacuo. Flash chromatography
(5:1 pentane–diethyl ether) afforded the title compound as a
mixture of diastereoisomers as a clear, colorless oil in 82%
yield (20 mg, 0.068 mmol) 99% ee. The product ee was
measured by chiral HPLC (OJ column, 2% EtOH in
hexanes) relative to a racemic sample; (1R,2S) anti isomer
tr¼39.3 min, (1S,2R) anti isomer tr¼33.7 min, syn isomers tr
major¼25.1 min, tr minor¼21.4 min. IR (film) 3446, 2954,
3.2.6. (1R,2S)-2-(5,5-Dimethyl-[1,3]dioxan-2-yl-1-
[1,3]dithiolan-2-yl-propan-1-ol.
A
solution of 2,2-
1471, 1394, 1108, 1081, 1040, 983 cm21
;
1H NMR
dimethylpropane-1,3-diol (10.8 mg, 0.104 mmol) and
pyridinium p-toluenesulfonate (5 mg, 0.02 mmol) in aceto-
nitrile (0.2 mL) were added to a solution of (2S,3R)-
[1,3]dithiolane-2-yl-3-hydroxy-2-methyl-propionaldehyde
(10.0 mg, 0.052 mmol) in acetonitrile (0.2 mL) at room
temperature. The mixture was stirred for 26 h before
filtration through a pad of silica (2:1 pentane–diethyl
ether) and concentration in vacuo. Flash chromatography
(4:1 pentane–diethyl ether) afforded the title compound as a
mixture of diastereoisomers as a clear, colorless oil in 76%
yield (11 mg, 0.04 mmol) 99% ee. The product ee was
measured by chiral HPLC (ODH column, 2% EtOH in
hexanes) relative to a racemic sample; (1R,2S) anti isomer
tr¼22.2 min, (1S,2R) anti isomer tr¼40.6 min, syn isomers tr
major¼16.6 min, tr minor¼18.7 min. IR (film) 3487, 2954,
(300 MHz, CDCl3) d 4.60 (d, J¼3.6 Hz, 1H, OCHO), 4.17
(d, J¼4.2 Hz, 1H, SCHS), 4.00–3.90 (m, 1H, CHOH), 3.63
(d, J¼11.1 Hz, 2H, OCH2C(CH3)2CH2O), 3.42 (d,
J¼11.1 Hz, 2H, OCH2C(CH3)2CH2O), 3.02–2.70 (m, 4H,
SCH2CH2CH2S), 2.21 (qdd (app. pd), J¼7.2, 7.2, 4.2 Hz,
1H, CHCH3), 2.15–1.86 (m, 2H, SCH2CH2CH2S), 1.18 (s,
3H, CH3CCH3), 0.87 (d, J¼7.2 Hz, 3H, CHCH3), 0.72 (s,
3H, CH3CCH3), no OH signal observed; 13C NMR
(75 MHz, CDCl3) d 104.2, 77.7, 77.5, 76.2, 51.9, 40.1,
30.7, 30.6, 29.8, 26.4, 23.3, 22.1, 12.0; HRMS (FABþ)
exact mass calcd for [M2H]þ (C13H23O3S2) requires m/z
291.1089, found m/z 291.1098; [a]2D2¼213.5 (c¼1.0,
CHCl3).
3.2.4. [1,3]Dithiolane-2-carbaldehyde.16c A solution of
DIBAL-H (1.0 M hexanes, 14.1 mL, 14.0 mmol) was added
dropwise to a stirred solution of [1,3]dithiolane-2-car-
2860, 1471, 1394, 1108, 1017, 990, 924 cm21; H NMR
1
(300 MHz, CDCl3) d 4.80 (d, J¼5.7 Hz, 1H, SCHS), 4.63
(d, J¼3.3 Hz, 1H, OCHO), 3.64 (m, 1H, CHOH), 3.62 (d,

7710
R. Ian Storer, D. W. C. MacMillan / Tetrahedron 60 (2004) 7705–7714
J¼11.0 Hz, 2H, CH2C(CH3)2CH2), 3.42 (d, J¼11.0 Hz, 2H,
CH2C(CH3)2CH2), 3.34–3.13 (m, 4H, SCH2CH2S), 2.09
(qdd, J¼6.9, 6.6, 3.0 Hz, 1H, CHCH3), 1.17 (s, 3H,
CH3CCH3), 1.06 (d, J¼6.9 Hz, 3H, CHCH3), 0.71 (s, 3H,
CH3CCH3), no OH signal observed; 13C NMR (75 MHz,
CDCl3) d 103.5, 77.5, 77.4, 57.8, 41.6, 39.2, 38.8, 30.5,
23.3, 22.0, 12.0, one signal obscured; HRMS (EIþ) exact
mass calcd for [M2H]þ (C12H22O3S2) requires m/z
277.0932, found m/z 277.0919; [a]2D4¼þ17.6 (c¼1.0,
CHCl3).
(24 mg, 0.078 mmol) 97% ee. The product ee was measured
by chiral HPLC (ODH column, 2% EtOH in hexanes)
relative to a racemic sample; (2R,3S) anti isomer
tr¼8.0 min, (2S,3R) anti isomer tr¼13.6 min, syn isomers
tr major¼5.4 min, tr minor¼6.5 min. IR (film) 3490, 2957,
2929, 2870, 2852, 1455, 1393, 1265, 1154, 1108, 1080,
1
1018, 976, 923 cm21; H NMR (300 MHz, CDCl3) d 4.65
(d, J¼3.0 Hz, 1H, OCHO), 3.94 (d, J¼3.3 Hz, 1H,
CH(SEt)2), 3.91–3.83 (m, 1H, CHOH), 3.62 (d,
J¼11.1 Hz, 2H, CH2O), 3.44 (d, J¼10.8 Hz, 1H, CH2O),
3.43 (d, J¼10.5 Hz, 1H, CH2O), 2.80–2.60 (m, 4H,
(SCH2CH3)2), 2.28 (qdd, J¼7.2, 7.2, 3.0 Hz, 1H,
CHCH3), 1.27 (t, J¼7.8 Hz, 6H, (SCH2CH3)2), 1.18 (s,
3H, CH3CCH3), 0.99 (d, 3H, J¼7.2 Hz, CHCH3), 0.71 (s,
3H, CH3CCH3), no OH signal observed; 13C NMR
(75 MHz, CDCl3) d 103.7, 77.6, 77.5, 75.4, 55.9, 40.6,
30.6, 25.8, 25.3, 23.3, 22.0, 14.9, 14.8, 11.3; HRMS
(FABþ) exact mass calcd for [M]þ (C14H28O3S2) requires
m/z 308.1480, found m/z 308.1490; [a]D¼233.2 (c¼1.0,
CHCl3).
3.2.7. Bis-ethylsulfanyl-acetaldehyde (Table 2, entry 3).
The title compound was obtained from glyoxal and ethane
thiol using the procedure outlined by Bates.16d The product
can be purified by flash chromatography (40:1 pentane–
diethyl ether) or by vacuum distillation (60 8C, 0.1 mm Hg)
to yield a colorless clear oil. The title aldehyde could be
successfully stored under anhydrous conditions below 0 8C
(278 8C for long term storage).
3.2.8. (2S,3R)-4,4-Bis-ethylsulfanyl-3-hydroxy-2-methyl-
butyraldehyde. A solution of freshly distilled propionalde-
hyde (98 mg, 123 mL, 1.69 mmol) in 1.75 mL DMF was
added slowly over the course of 24 h to a stirring suspension
of bis-ethylsulfanyl-acetaldehyde (554 mg, 3.38 mmol),
L-proline (19.5 mg, 0.17 mmol) and 1.75 mL DMF room
temperature. After 38 h, the resulting solution was diluted
with diethyl ether and washed successively with water and
brine. The combined aqueous layers were extracted with
five portions of ethyl acetate. The organic layers were
combined, dried over anhydrous MgSO4, and concentrated
in vacuo. Analysis of the crude reaction mixture by 1H NMR
revealed an 10:1 anti–syn mixture of diastereoisomers.
Flash chromatography (3:1 pentane–diethyl ether) afforded
the title compound as a mixture of diastereoisomers as a
clear, colorless oil in 70% yield (262 mg, 1.18 mmol). The
ee was measured by HPLC analysis of the acetal derived
from 2,2-dimethylpropane-1,3-diol (see below). IR (film)
3468, 2970, 2929, 2872, 2728, 1722, 1455, 1455, 1377,
1266, 1108, 1051, 976 cm21; 1H NMR (300 MHz, CDCl3) d
9.80 (d, J¼1.5 Hz, 1H, CHO), 3.93 (d, J¼6.3 Hz, 1H,
CH(SEt)2), 3.86 (dd, J¼6.3, 7.2 Hz, 1H, CHOH), 3.17 (br s,
1H, CHOH), 2.93 (qdd, J¼7.2, 7.2, 1.5 Hz, 1H, CHCH3),
2.80–2.50 (m, 4H, S(CH2CH3)2), 1.27 (t, J¼7.2 Hz, 3H,
SCH2CH3), 1.26 (t, J¼7.2 Hz, 3H, SCH2CH3), 1.19 (d,
J¼7.2 Hz, 3H, CHCH3); 13C NMR (75 MHz, CDCl3) d
204.1, 74.5, 56.3, 48.8, 25.8, 24.7, 14.9, 14.7, 11.1; HRMS
(FABþ) exact mass calcd for [M]þ (C9H18O2S2) requires
m/z 222.0748, found m/z 222.0758; [a]2D1¼þ23.3 (c¼1.0,
CHCl3).
3.2.10. Bis-isopropylsulfanyl-acetaldehyde (Table 2,
entry 4). A biphasic mixture of an aqueous 40% solution
of glyoxal (12.5 g solution, ca. 5 g glyoxal, 86 mmol),
isopropanethiol (13.1 g, 16.0 mL, 172 mmol) and 2 N HCl
(10 mL) in CH2Cl2 was stirred vigorously for 24 h. The
phases were separated and the aqueous phase extracted two
times with CH2Cl2. The organic phases were combined,
washed once with an aqueous solution of Na2CO3, dried
over MgSO4, and concentrated to yield a pale yellow oil.
The product was purified by flash chromatography (10:1
pentane–diethyl ether) to yield the title compound as a
colourless clear oil in 38% yield (6.4 g, 33 mmol). The title
aldehyde could be successfully stored under anhydrous
conditions below 0 8C (278 8C for long term storage). IR
(film) 2963, 2927, 2867, 2813, 2707, 1715, 1590, 1455,
1384, 1367, 1247, 1155, 1128, 1040 cm21 1H NMR
;
(300 MHz, CDCl3) d 9.07 (d, J¼5.6 Hz, 1H, CHO), 4.18
(dd, J¼5.6, 0.6 Hz, 1H, CH(SiPr)2), 3.05 (sep, J¼6.9 Hz,
2H, (CH(CH3)2)2), 1.32 (d, J¼6.6 Hz, 6H, CH2(CH3)2),
1.28 (d, J¼6.6 Hz, 6H, CH2(CH3)2); 13C NMR (75 MHz,
CDCl3) d 190.5, 53.6, 36.2, 23.8, 23.6; HRMS (EIþ) exact
mass calcd for [M]þ (C8H16OS2) requires m/z 192.0643,
found m/z 192.0636.
3.2.11. (2S,3R)-3-Hydroxy-4,4-bis-isopropylsulfanyl-2-
methyl-butyraldehyde. A solution of freshly distilled
propionaldehyde (20 mg, 25 mL, 1.69 mmol) in 0.35 mL
DMF was added slowly over the course of 24 h to a stirring
suspension of bis-isopropylsulfanyl-acetaldehyde (130 mg,
0.68 mmol), L-proline (3.9 mg, 0.034 mmol) and 0.35 mL
DMF room temperature. After 40 h, the resulting solution
was diluted with diethyl ether and washed successively with
water and brine. The combined aqueous layers were extracted
with five portions of ethyl acetate. The organic layers were
combined, dried over anhydrous MgSO4, and concentrated in
3.2.9. (2R,3S)-3-(5,5-Dimethyl-[1,3]dioxan-2-yl)-1,1-bis-
ethylsulfanyl-butan-2-ol. A solution of 2,2-dimethyl-
propane-1,3-diol (20.0 mg, 0.193 mmol) and pyridinium
p-toluenesulfonate (5 mg, 0.02 mmol) in acetonitrile
(0.2 mL) were added to a solution of (2S,3R)-4,4-bis-
ethylsulfanyl-3-hydroxy-2-methyl-butyraldehyde (21.4 mg,
0.096 mmol) in acetonitrile (0.2 mL) at room temperature.
The mixture was stirred for 36 h before filtration through a
pad of silica (10:1 pentane–diethyl ether) and concentration
in vacuo. Flash chromatography (10:1 pentane–diethyl
ether) afforded the title compound as a mixture of
diastereoisomers as a clear, colorless oil in 81% yield
1
vacuo. Analysis of the crude reaction mixture by H NMR
revealed an 8:1 anti–syn mixture of diastereoisomers. Flash
chromatography (3:1 pentane–diethyl ether) afforded the title
compound as a mixture of diastereoisomers as a clear,
colorless oil in 41% yield (34.2 mg, 0.14 mmol). The ee was
measured by HPLC analysis of the acetal derived from 2,2-
dimethylpropane-1,3-diol (see below). IR (film) 3470, 2962,

R. Ian Storer, D. W. C. MacMillan / Tetrahedron 60 (2004) 7705–7714
7711
2927, 2864, 1723, 1454, 1367, 1243, 1154, 1051 cm21; H
NMR (300 MHz, CDCl3) d 9.80 (d, J¼1.8 Hz, 1H, CHO),
4.01 (d, J¼5.4 Hz, 1H, CH(SiPr)2), 3.86 (dd (app. t), J¼5.7,
5.7 Hz, 1H, CHOH), 3.23 (br s, 1H, CHOH), 3.22–3.04 (m,
2H, (SCH(CH3)2)2), 2.93 (qdd, J¼7.5, 5.7, 1.8 Hz, 1H,
CHCH3), 1.32 (d, J¼6.6 Hz, 3H, SCH(CH3)2), 1.31 (d,
J¼6.6 Hz, 3H, SCH(CH3)2), 1.30 (d, J¼6.6 Hz, 3H,
SCH(CH3)2), 1.27 (d, J¼6.6 Hz, 3H, SCH(CH3)2), 1.17 (d,
J¼7.5 Hz, 3H, CHCH3); 13C NMR (75 MHz, CDCl3) d 204.4,
74.7, 54.5, 48.7, 35.6, 35.3, 24.1, 24.0, 23.7, 23.5, 11.0; HRMS
(FABþ) exact masscalcd for [M]þ (C11H22O2S2) requiresm/z
250.1061, found m/z 250.1071; [a]2D2¼28.2 (c¼1.0, CHCl3).
(70 mg, 0.25 mmol). The ee was measured by HPLC
analysis of the acetal derived from 2,2-dimethylpropane-
1,3-diol (see below). IR (film) 3460, 2927, 2856, 1718,
1
1
1465, 1422, 1378, 1277, 1244, 1051, 910, 787 cm21; H
NMR (300 MHz, CDCl3) d 9.72 (d, J¼2.1 Hz, 1H, CHO),
4.20 (ddd, J¼8.1, 2.7, 2.1 Hz, 1H, CHOH), 3.86 (d,
J¼8.1 Hz, 1H, SCHS), 3.02–2.60 (m, 6H, CHC6H13, OH,
SCH2CH2CH2S), 2.14–1.94 (m, 2H, SCH2CH2CH2S),
1.88–1.60 (m, 2H, CH2(CH2)4CH3), 1.46–1.22 (m, 8H,
(CH2)4CH3), 0.88 (t, J¼6.6 Hz, 3H, CH3); 13C NMR
(75 MHz, CDCl3) d 204.1, 72.9, 53.3, 48.2, 31.9, 29.6,
27.8, 27.5, 26.7, 26.3, 25.4, 22.8, 14.3; HRMS (EIþ) exact
mass calcd for [M]þ (C13H24O2S2) requires m/z 276.1218,
found m/z 276.1224; [a]2D2¼216.3 (c¼1.0, CHCl3).
3.2.12. (2R,3S)-3-(5,5-Dimethyl-[1,3]dioxan-2-yl)-1,1-
bis-isopropylsulfanyl-butan-2-ol.
A solution of 2,2-
dimethylpropane-1,3-diol (14.2 mg, 0.136 mmol) and
pyridinium p-toluenesulfonate (5 mg, 0.02 mmol) in aceto-
nitrile (0.2 mL) were added to a solution of (2S,3R)-3-
hydroxy-4,4-bis-isopropylsulfanyl-2-methyl-butyraldehyde
(17.0 mg, 0.068 mmol) in acetonitrile (0.2 mL) at room
temperature. The mixture was stirred for 51 h before
filtration through a pad of silica (5:1 pentane–diethyl
ether) and concentration in vacuo. Flash chromatography
(10:1 pentane–diethyl ether) afforded the title compound as
a mixture of diastereoisomers as a clear, colorless oil in 83%
yield (19.1 mg, 0.057 mmol) 98% ee. The product ee was
3.2.14. (1R,2S)-2-(5,5-Dimethyl-[1,3]dioxan-2-yl)-1-
[1,3]dithian-2-yl-octan-1-ol. A solution of 2,2-dimethyl-
propane-1,3-diol (20.4 mg, 0.20 mmol) and pyridinium
p-toluenesulfonate (5 mg, 0.02 mmol) in acetonitrile
(0.2 mL) were added to
a
solution of (2S,20R)-2-
([1,3]dithian-2-yl-hydroxy-methyl)-octanal (27 mg, 0.098
mmol) in acetonitrile (0.2 mL) at room temperature. The
mixture was stirred for 49 h before filtration through a pad
of silica (5:1 pentane–diethyl ether) and concentration in
vacuo. Flash chromatography (4:1 pentane–diethyl ether)
afforded the title compound as a mixture of diastereoisomers
as a clear, colorless oil in 95% yield (33.5 mg, 0.092 mmol)
97% ee. The product ee was measured by chiral HPLC
(ODH column, 2% EtOH in hexanes) relative to a racemic
sample; (1R,2S) anti isomer tr¼24.7 min, (1S,2R) anti
isomer tr¼16.7 min, syn isomers tr major¼27.6 min, tr
minor¼31.5 min. IR (film) 3490, 2953, 2928, 2855, 1469,
1422, 1394, 1113, 1018 cm21; 1H NMR (300 MHz, CDCl3)
d 4.71 (d, J¼3.3 Hz, 1H, OCHO), 4.25 (d, J¼6.8 Hz, 1H,
SCHS), 4.00 (dd, J¼6.8, 5.4 Hz, 1H, CHOH), 3.63 (d,
J¼11.0 Hz, 2H, OCH2C(CH3)2CH2O), 3.42 (d, J¼11.0 Hz,
2H, OCH2C(CH3)2CH2O), 2.99–2.72 (m, 4H, SCH2CH2-
CH2S), 2.19–2.01 (m, 2H, CH(C6H13), CH2(CH2)4CH3),
2.00–1.85 (m, 1H, CH2(CH2)4CH3), 1.62–1.46 (m, 2H,
SCH2CH2CH2S), 1.36–1.22 (m, 8H, (CH2)4CH3), 1.18 (s,
3H, CH3CCH3), 0.87 (t, J¼6.6 Hz, 3H, (CH2)5CH3), 0.72 (s,
3H, CH3CCH3), no OH signal observed; 13C NMR
(75 MHz, CDCl3) d 103.4, 77.7, 77.5, 74.0, 51.7, 43.6,
32.0, 30.6, 29.9, 29.8, 29.3, 27.5, 26.4, 26.2, 23.4, 22.9,
22.0, 14.4; HRMS (FABþ) exact mass calcd for [M]þ
(C18H34O3S2) requires m/z 362.1950, found m/z 362.1937;
[a]2D2¼þ0.71 (c¼1.0, CHCl3).
i
measured by chiral HPLC (ODH column, 2% PrOH in
hexanes) relative to a racemic sample; (2R,3S) anti isomer
tr¼10.2 min, (2S,3R) anti isomer tr¼11.7 min, syn isomers tr
major¼8.4 min, tr minor¼9.7 min. IR (film) 3494, 2957,
2928, 2867, 1461, 1393, 1365, 1244, 1154, 1107, 1040, 989,
923 cm21
;
1H NMR (300 MHz, CDCl3) d 4.69 (d,
J¼3.3 Hz, 1H, OCHO), 4.03 (d, J¼3.0 Hz, 1H, SCHS),
3.82 (dd, J¼8.5, 3.0 Hz, 1H, CHOH), 3.61 (d, 2H, CH2O),
3.51–3.37 (m, 2H, CH2O), 3.18 (sept, J¼6.6 Hz, 1H,
SCH(CH3)2), 3.10 (sept, J¼6.9 Hz, 1H, SCH(CH3)2), 2.33–
2.19 (m, 1H, CHCH3), 1.31 (d, J¼6.6 Hz, 3H, CH(CH3)2),
1.30 (d, J¼6.6 Hz, 3H, CH(CH3)2), 1.28 (d, J¼6.6 Hz, 3H,
CH(CH3)2), 1.25 (d, J¼6.6 Hz, 3H, CH(CH3)2), 1.18 (s, 3H,
CH3CCH3), 1.00 (d, J¼7.2 Hz, 3H, CHCH3), 0.71 (s, 3H,
CH3CCH3), no OH signal observed; 13C NMR (75 MHz,
CDCl3) d 103.2, 77.53, 77.47, 74.7, 53.9, 40.3, 35.1, 34.9,
30.6, 24.1, 23.9, 23.5, 23.4, 23.3, 22.0, 10.6; HRMS
(FABþ) exact mass calcd for [M]þ (C16H32O3S2) requires
m/z 336.1793, found m/z 336.1794; [a]2D2¼242.9 (c¼1.0,
CHCl3).
3.2.13. (2S,20R)-2-([1,3]Dithian-2-yl-hydroxy-methyl)-
octanal (Table 2, entry 5). A solution of freshly distilled
octanal (65 mg, 79 mL, 0.34 mmol) in 0.35 mL DMF was
added slowly over the course of 15 h to a stirring suspension
of [1,3]dithiane-2-carbaldehyde (50 mg, 0.34 mmol),
L-proline (3.9 mg, 0.034 mmol) and 0.35 mL DMF at
room temperature. After 36 h, the resulting solution was
diluted with diethyl ether and washed successively with
water and brine. The combined aqueous layers were
extracted with five portions of ethyl acetate. The organic
layers were combined, dried over anhydrous MgSO4, and
concentrated in vacuo. Analysis of the crude reaction
mixture by 1H NMR revealed a .20:1 anti–syn mixture of
diastereoisomers. Flash chromatography (3:1 pentane–
diethyl ether) afforded the title compound as a mixture of
diastereoisomers as a clear, colorless oil in 75% yield
3.2.15. (2S,3R)-2-Benzyl-3-[1,3]dithian-2-yl-3-hydroxy-
propionaldehyde (Table 2, entry 6). A solution of freshly
distilled hydrocinnamaldehyde (45 mg, 45 mL, 0.34 mmol)
in 0.35 mL DMF was added slowly over the course of 24 h
to a stirring suspension of [1,3]Dithiane-2-carbaldehyde
(100 mg, 0.68 mmol), L-proline (3.9 mg, 0.034 mmol) and
0.35 mL DMF at room temperature. After 46 h, the resulting
solution was diluted with diethyl ether and washed
successively with water and brine. The combined aqueous
layers were extracted with five portions of ethyl acetate. The
organic layers were combined, dried over anhydrous
MgSO4, and concentrated in vacuo. Analysis of the crude
1
reaction mixture by H NMR revealed a .20:1 anti–syn
mixture of diastereoisomers. Flash chromatography (1:1
pentane–diethyl ether) afforded the title compound as a

7712
R. Ian Storer, D. W. C. MacMillan / Tetrahedron 60 (2004) 7705–7714
mixture of diastereoisomers as a clear, colorless oil in 75%
yield (71 mg, 0.25 mmol). The ee was measured by HPLC
analysis of the acetal derived from 2,2-dimethylpropane-
1,3-diol (see below). IR (film) 3436, 2903, 1719, 1496,
1422, 1049, 747, 701 cm21; 1H NMR (300 MHz, CDCl3) d
9.80 (d, J¼0.6 Hz, 1H, CHO), 7.34–7.16 (m, 5H, Ph), 4.11
(dd, J¼9.3, 2.7 Hz, 1H, CHOH), 3.88 (d, J¼9.3 Hz, 1H,
SCHS), 3.28 (m, 1H, CHBn), 3.17 (dd, J¼13.6, 7.5 Hz, 1H,
CH2Ph), 3.04 (dd, J¼13.6, 7.8 Hz, 1H, CH2Ph), 2.86 (ddd,
J¼13.1, 8.7, 2.7 Hz, 1H, SCH2), 2.64–2.50 (m, 3H, SCH2,
SCH2), 2.10–1.85 (m, 2H, SCH2CH2CH2S), no OH signal
observed; 13C NMR (75 MHz, CDCl3) d 203.3, 138.6,
129.4, 129.0, 126.9, 71.5, 54.0, 47.8, 32.6, 26.7, 26.1, 25.3;
HRMS (FABþ) exact mass calcd for [M]þ (C14H18O2S2)
requires m/z 282.0748, found m/z 282.0762; [a]D¼þ29.5
(c¼1.0, CHCl3).
diethyl ether) afforded the title compound as a mixture of
diastereoisomers as a clear, colorless oil in 52% yield
(283 mg, 0.88 mmol). The ee was measured by HPLC
analysis of the acetal derived from 2,2-dimethylpropane-
1,3-diol and confirmed by analysis of the corresponding
diol, obtained by reduction of the aldehyde (see below). IR
(film) 3468, 2945, 2910, 2892, 2847, 1714, 1466, 1422,
1
1373, 1253, 1129, 1005, 872, 836, 774 cm21; H NMR
(300 MHz, CDCl3) d; 9.53 (s, 1H, CHO), 4.37 (ddd, J¼9.5,
2.1, 1.9 Hz, 1H, CHOH), 4.33 (d, J¼2.1 Hz, 1H, CHOTBS),
3.59 (d, J¼9.5 Hz, 1H, SCHS), 3.07–2.83 (m, 2H, SCH2),
2.76 (s, 1H, OH), 2.55–2.42 (m, 1H, SCH2), 2.37–2.25 (m,
1H, SCH2), 2.13–1.88 (m, 2H, SCH2CH2CH2S), 0.90 (s,
9H, SiC(CH3)3), 0.092 (s, 3H, SiCH3), 0.089 (s, 3H, SiCH3);
13C NMR (75 MHz, CDCl3) d 200.5, 78.7, 73.7, 42.7, 26.0,
24.8, 24.7, 24.1, 18.4, 24.5, 24.8; HRMS (EIþ) exact mass
calcd for [M]þ (C13H26O3SiS2) requires m/z 322.1063,
found m/z 322.1070; [a]2D4¼29.9 (c¼1.0, CHCl3).
3.2.16. (1R,2S)-2-(5,5-Dimethyl-[1,3]dioxan-2-yl)-1-
[1,3]dithian-2-yl-3-phenyl-propan-1-ol. A solution of
2,2-dimethylpropane-1,3-diol (25.0 mg, 0.24 mmol) and
pyridinium p-toluenesulfonate (5 mg, 0.02 mmol) in aceto-
nitrile (0.2 mL) were added to a solution of (2S,3R)-2-
benzyl-3-[1,3]dithian-2-yl-3-hydroxy-propionaldehyde
(26 mg, 0.092 mmol) in acetonitrile (0.2 mL) at room
temperature. The mixture was stirred for 65 h before
filtration through a pad of silica (10:1 pentane–diethyl
ether) and concentration in vacuo. Flash chromatography
(5:1 pentane–diethyl ether) afforded the title compound as a
mixture of diastereoisomers as a clear, colorless oil in 90%
yield (31 mg, 0.084 mmol) .99% ee. The product ee was
measured by chiral HPLC (AD column, 2% EtOH in
hexanes) relative to a racemic sample; (1R,2S) anti isomer
tr¼40.7 min, (1S,2R) anti isomer tr¼66.7 min, syn isomers tr
major¼59.6 min, tr minor¼54.0 min. IR (film) 3480, 2955,
3.2.18. (1R,2S)-2-(tert-Butyl-dimethyl-silanyloxy)-2-(5,5-
dimethyl-[1,3]dioxan-2-yl)-1-[1,3]dithian-2-yl-ethanol. A
solution of 2,2-dimethylpropane-1,3-diol (102 mg,
0.975 mmol) and pyridinium p-toluenesulfonate (10 mg,
0.04 mmol) in acetonitrile (0.3 mL) were added to a solution
of (2S,3R)-3-[1,3]dithiane-2-yl-3-hydroxy-2-methyl-pro-
pionaldehyde (31.4 mg, 0.098 mmol) in acetonitrile
(0.2 mL) at room temperature. The mixture was stirred for
16 h before filtration through a pad of silica (10:1 pentane–
diethyl ether) and concentration in vacuo. Flash chroma-
tography (10:1 pentane–diethyl ether) afforded the title
compound as a mixture of diastereoisomers as a clear,
colorless oil in 46% yield (18.2 mg, 0.045 mmol) 70% ee.
The product ee was measured by chiral HPLC (AD column,
2% EtOH in hexanes) relative to a racemic sample; (1R,2S)
anti isomer tr¼6.3 min, (2S,3R) anti isomer tr¼7.7 min, syn
isomers tr major¼9.8 min, tr minor¼11.7 min. IR (film)
3485.7, 2954, 2927, 2900, 2856, 1470, 1395, 1249, 1124,
1100, 1027, 837, 778 cm21; 1H NMR (300 MHz, CDCl3) d
4.52 (d, J¼4.4 Hz, 1H, OCHO), 4.27 (d, J¼3.0 Hz, 1H,
SCHS), 4.15 (dd, J¼7.9, 3.0 Hz, 1H, CHOH), 3.87 (dd,
J¼7.9, 4.4 Hz, 1H, CHOTBS), 3.72–3.58 (m, 2H, CH2O),
3.45–3.35 (m, 2H, CH2O), 3.10–2.95 (m, 2H, SCH2CH2-
CH2S), 2.90–2.63 (m, 2H, SCH2CH2CH2S), 2.12–1.90 (m,
2H, SCH2CH2CH2S), 1.19 (s, 3H, C(CH3)2), 0.89 (s, 9H,
SiC(CH3)3), 0.73 (s, 3H, C(CH3)2), 0.14 (s, 3H, SiCH3),
0.11 (s, 3H, SiCH3), no OH signal observed; 13C NMR
(75 MHz, CDCl3) d 104.2, 77.5, 76.5, 72.8, 48.4, 30.7, 30.2,
29.3, 26.3, 26.2, 23.4, 22.1, 18.6, 24.0, 24.5, 1 signal
obscured; HRMS (EIþ) exact mass calcd for [M]þ
(C18H36O4SiS2) requires m/z 408.1824, found m/z
408.1827; [a]2D4¼221.2475 (c¼1.0, CHCl3).
1
2867, 1472, 1422, 1394, 1131, 1096, 1024, 701 cm21; H
NMR (300 MHz, CDCl3) d 7.32–7.15 (m, 5H, Ph), 4.61 (d,
J¼3.0 Hz, 1H, OCHO), 4.18 (d, J¼6.9 Hz, 1H, SCHS), 3.92
(m, 1H, CHOH), 3.83 (br s, 1H, OH), 3.65 (m, 2H, CH2O),
3.39 (d, J¼11.4 Hz, 1H, CH2O), 3.38 (d, J¼11.4 Hz, 1H,
CH2O), 3.00–2.79 (m, 3H, CH2Ph, SCH2), 2.74–2.64 (m,
3H, SCH2CH2CH2S), 2.08–1.95 (m, 1H, SCH2CH2CH2S),
1.94–1.78 (m, 1H, SCH2CH2CH2S), 1.21 (s, 3H, CH3), 0.71
(s, 3H, CH3); 13C NMR (75 MHz, CDCl3) d 129.6, 128.7,
126.4, 102.5, 77.5, 77.3, 72.6, 51.3, 45.5, 33.2, 32.6, 30.6,
29.4, 28.8, 26.2, 23.4, 22.0; HRMS (FABþ) exact mass
calcd for [M2H]þ (C19H27O3S2) requires m/z 367.1402,
found m/z 367.1416; [a]2D2¼þ16.7 (c¼1.0, CHCl3).
3.2.17. (2S,3R)-2-(tert-Butyl-dimethyl-silanyloxy)-3-
[1,3]dithian-2-yl-3-hydroxy-propionaldehyde (Table 2,
entry 7). A solution of freshly purified (tert-butyl-dimethyl-
silanyloxy)-acetaldehyde (294 mg, 1.69 mmol) in 0.88 mL
DMF was added slowly over the course of 24 h to a stirring
suspension of [1,3]dithiane-2-carbaldehyde (500 mg,
3.38 mmol), L-proline (39 mg, 0.34 mmol) and 0.88 mL
DMF at room temperature. After 44 h, the resulting solution
was diluted with diethyl ether and washed successively with
water and brine. The combined aqueous layers were
extracted with five portions of ethyl acetate. The organic
layers were combined, dried over anhydrous MgSO4, and
concentrated in vacuo. Analysis of the crude reaction
3.2.19. (1R,2R)-2-(tert-Butyl-dimethyl-silanyloxy)-1-
[1,3]dithian-2-yl-propane-1,3-diol. (A reduction method
was used to provide an alternative enantiomeric excess
assay). A solution of (2S,3R)-2-(tert-butyl-dimethyl-silanyl-
oxy)-3-[1,3]dithian-2-yl-3-hydroxy-propionaldehyde (19.0
mg, 0.16 mmol) was added dropwise to a stirring suspension
of sodium borohydride (15.0 mg, 0.39 mmol) in ethanol at
0 8C. The effervescing mixture was slowly warmed to room
temperature and stirred for 30 min. A saturated solution of
ammonium chloride was added to quench the reaction,
followed by dilution with CH2Cl2 and water. The aqueous
1
mixture by H NMR revealed a 13:1 anti–syn mixture of
diastereoisomers. Flash chromatography (3:1 pentane–

R. Ian Storer, D. W. C. MacMillan / Tetrahedron 60 (2004) 7705–7714
7713
layer was washed three times with portions of CH2Cl2, and
the combined organics dried over MgSO4, filtered and
concentrated to yield a colourless oil. Purification by flash
chromatography (2:1 pentane–diethyl ether) gave the title
product as a colorless oil in 89% yield (17.0 mg,
0.052 mmol), 72% ee. The product ee was measured by
chiral HPLC (AD column, 4% EtOH in hexanes) relative to
a racemic sample; (1R,2R) anti isomer tr¼23.3 min, (1S,2S)
anti isomer tr¼29.1 min. IR (film) 3405, 2954, 2929, 2892,
1H NMR (300 MHz, CDCl3) d 4.44 (br s, 1H, SCHS), 3.99–
3.94 (m, J¼1.8 Hz, 2H, CHOH, CHOTBS), 3.86–3.66 (m,
2H, CH2OH), 2.99–2.88 (m, 3H, SCH2CH2CHHS), 2.84–
2.72 (m, 1H, SCH2CH2CH2S), 2.16–1.85 (m, 2H, SCH2-
CH2CH2S), 0.92 (s, 9H, SiC(CH3)3), 0.17 (s, 3H, SiCH3),
0.14 (s, 3H, SiCH3); 13C NMR (75 MHz, CDCl3) d 76.0,
72.1, 64.3, 50.0, 30.3, 29.4, 26.1, 26.0, 18.3, 24.2, 24.4;
HRMS (EIþ) exact mass calcd for [M]þ (C13H28O3SiS2)
requires m/z 324.1249, found m/z 324.1252.
column, 12% EtOH in hexanes) relative to a racemic
sample; (3S,4R) anti isomer tr¼108.0 min, (3R,4S) anti
isomer tr¼128.3 min, syn isomers not detected. The product
was recrystallized from boiling acetone. The resulting
crystals were analyzed by X-ray crystallogrphy to obtain
confirmation of both relative and absolute stereochemistry.
IR (film) 3370, 3304, 1673, 1386, 1357, 1262, 1222, 1126,
1
1060, 1005, 913 cm21; H NMR (300 MHz, C2D6SO) d
5.81 (d, J¼5.1 Hz, 1H, C(O)CHOH), 5.56 (d, J¼6.0 Hz, 1H,
CH(OH)C(S)S), 4.23 (d, J¼3.6 Hz, 1H, SCHS), 4.00 (m,
1H, C(O)CHOH), 3.90 (m, 1H, CH(OH)CS), 3.00–2.68 (m,
4H, SCH2CH2CH2S), 2.16 (s, 3H, CH3), 1.98 (m, 1H,
SCH2CH2CH2S), 1.82 (m, 1H, SCH2CH2CH2S); 13C NMR
(75 MHz, C2D6SO) d 210.7, 77.9, 76.0, 49.5, 29.5, 28.8,
27.6, 26.7; HRMS (EIþ) exact mass calcd for [M]þ
(C8H14O3S2) requires m/z 222.0385, found m/z 222.0382;
[a]D¼þ13.0 (c¼1.0, EtOH).
2847, 1461, 1422, 1253, 1253, 1091, 1040, 836, 778 cm21
;
Acknowledgements
3.2.20. (R)-4-[1,3]Dithian-2-yl-4-hydroxy-butan-2-one
(Table 2, entry 8). Acetone (395 mg, 0.5 mL, 6.80 mmol)
was added to a suspension of [1,3]dithiane-2-carbaldehyde
(37 mg, 0.25 mmol) and L-proline (5.8 mg, 0.05 mmol) in
2.0 mL DMF at room temperature. After stirring at room
temperature for 65 h, the resulting solution was diluted with
diethyl ether and washed successively with water and brine.
The combined aqueous layers were extracted with five
portions of ethyl acetate. The organic layers were combined,
dried over anhydrous MgSO4, and concentrated in vacuo.
Flash chromatography (1:2 pentane–diethyl ether) afforded
the title compound as a clear, colorless oil in 91% yield
(47 mg, 0.23 mmol) 96% ee. The product ee was measured
by chiral HPLC (ODH column, 5% EtOH in hexanes)
relative to a racemic sample; R-isomer tr¼28.9 min,
S-isomer tr¼26.5 min. IR (film) 3438, 2901, 1713, 1422,
Financial support was provided by kind gifts from Bristol-
Myers Squibb, Eli Lilly, and Merck Research Laboratories.
D.W.C.M is grateful for support from the Sloan Foundation
and Research Corporation.
References and notes
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1361, 1277, 1164, 1072, 909 cm21; H NMR (300 MHz,
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