S,O-acetals as novel "chiral aldehyde" equivalents

Article abstract of DOI:10.1002/chem.200500919

Palladium-catalyzed asymmetric allylic alkylations (AAA) to form "chiral aldehyde" equivalents were investigated. α-Acetoxysulfones were formed in high enantiomeric excess as single regioisomers in AAA reactions of allylic geminal dicarboxylates with sodi

Full text of DOI:10.1002/chem.200500919

FULL PAPER
DOI: 10.1002/chem.200500919
S,O-Acetals as Novel “Chiral Aldehyde” Equivalents
[a]
BarryM. Trost,* Matthew L. Crawley, and Chul Bom Lee
Abstract: Palladium-catalyzed asym-
metric allylic alkylations (AAA) to
form “chiral aldehyde” equivalents
were investigated. a-Acetoxysulfones
were formed in high enantiomeric
excess as single regioisomers in AAA
reactions of allylic geminal dicarboxy-
lates with sodium benzenesulfinate.
The directing ability of this novel func-
tional group was highlighted by a series
of dihydroxylations, affording syn diols
exclusively anti to the acetoxy sulfone
as single diastereomers in excellent
yields. This is the first example of an
asymmetric dihydroxylation protocol
that gives the equivalent of reaction
with a simple enal. The synthetic value
of this process was exemplified by sub-
sequent transformations of the diols in-
cluding the development of a one-pot
dihydroxylation–deprotective acyl mi-
gration protocol to give differentially
protected 1,2-diols.
Keywords: allylation · allylic com-
pounds · asymmetric synthesis · chi-
ral aldehyde equivalents · palladium
Introduction
azlactones both enantio- and diastereoselectively. Both yield
substrates that allow for stereospecific functionalization of
the adjacent olefin.[5] This process is useful, though the ques-
tion remained if a versatile directing group, one that is read-
ily removed, transferred, or transformed could be installed
through an asymmetric allylic alkylation.
Stereospecific reactions of double bonds are an important
challenge in organic synthesis. In principle there are many
approaches to this problem. A particularly efficient solution
is to utilize enantioselective catalysis to set an allylic sp3
stereogenic center that can then direct functionalization of
the olefin in a highly diastereoselective fashion. The use of
asymmetric allylic alkylation (AAA) reactions has become a
vibrant area of research that has specifically addressed this
challenge in numerous total syntheses.[1] While there has
The flexibility of the functionality contained in an a,b-un-
saturated aldehyde led to the search for “chiral aldehyde”
equivalents. Simple a,b-unsaturated aldehydes have not
been observed to react in asymmetric dihydroxylations such
as the Sharpless AD presumably because the aldehyde
group is such a strong deactivator.[6] Rather, the correspond-
ing allylic alcohol or enoate must be employed followed by
subsequent oxidation or reduction. In some cases, this can
be incompatible with other functionality in the substrate.
Allylic acetals derived from chiral diols and enals have been
used to direct stereocontrolled reactions, including cuprate
additions, cyclopropanations, and additions of electrophiles
to the adjacent olefin in a number of cases.[7] To evaluate
the potential of these “chiral aldehyde” equivalents, two
questions needed to be addressed: 1) could such compounds
be easily accessed with high enantiopurity from AAA reac-
tions and 2) will such derivatives exercise differential reac-
tivity of the diastereotopic faces of the adjacent double
bond? Asymmetric allylic alkylation with sodium benzene-
sulfinate as nucleophile using gem-dicarboxylates as sub-
strates answered the first question through creation of chiral
allylic a-acetoxysulfones with high yields and enantiomeric
excess.[8] The requisite substrates for the AAA reaction
were readily available and their syntheses are reviewed. The
À
been considerable progress forming stereogenic carbon
carbon and carbon heteroatom bonds at a sp center in
3
À
AAA reactions,[2] successful installation of effective direct-
ing groups for acyclic substrates has been limited. An allylic
gem-diacetate substrate, having two prochiral leaving
groups, can undergo selective ionization in the presence of a
chiral ligand giving enantioselective addition of a nucleo-
phile.[3] The use of allylic geminal diacetates in the AAA re-
action has provided a solution to the selective directing
problem with carbon nucleophiles.[4] Addition of malonate
nucleophiles proceeds enantioselectively and in the case of
[a] Prof. B. M. Trost, Dr. M. L. Crawley, Prof. C. B. Lee
Department of Chemistry, Stanford University
Stanford, CA 94305-5080 (USA)
Fax : (+1)650-725-0002
E-mail: bmtrost@stanford.edu
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Chem. Eur. J. 2006, 12, 2171 – 2187
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2171

enantiopure substratesꢁ ability to efficiently direct dihydrox-
ylation of the a-olefin with complete stereocontrol is re-
vealed. Discussion of the conversion to functionalized deriv-
atives follows with one-pot dihydroxylation and unmasking
reactions highlighted.
allyl generated from ionization of 1 either regioisomer in
principle could be formed. However, only the “proximal”
pathway adduct is observed with carbon or heteroatom nu-
cleophiles when the steric bulk of R is larger than methyl.
(Scheme 2). Even when R = methyl the “proximal” adduct
3 is major with a variety of nucleophiles.[9] These concepts
were validated by the work of Trost and Lee who examined
a variety of carbon nucleophiles with gem-diacetates and es-
tablished the mechanism as outlined above and culminated
in a total synthesis of sphingofungins E and F.[10,11]
Concepts and Previous Work
The catalytic cycle of the AAA reaction with allylic gem-di-
acetates provides an opportunity for enantiotopic ionization
of one of the two prochiral acetates (Scheme 1). While the
syn,syn intermediate allyl complex should be formed kineti-
cally, either the syn,syn or syn,anti complex may be the
more reactive intermediate (Figure 1). Either complex can
give rise to two possible regioisomers as adducts.
Scheme 2. Regiochemistry of the nucleophilic addition to the p-allyl com-
plex.
Enantioselective synthesis of a-acetoxysulfones
Synthesis of gem-diacetates: The synthesis of geminal dicar-
boxylates from aldehydes is a developed process that has
been reported using protic acid catalysts[12] and more effi-
ciently with Lewis acid catalysts.[13,14] An efficient route to
the allylic diacetates starts with a,b-unsaturated aldehydes
5. These aldehydes are readily available via a number of
paths, that is, by purchase from commercial sources, through
Wittig reactions of commercial alkyl aldehydes 7 followed
by reduction–oxidation, through oxidation of E or Z allylic
alcohols 6 with pyridinium chlorochromate, and through
cross-metathesis reactions of terminal olefins 8 with enals 9
(Scheme 3).
Scheme 1. Catalytic cycle of Pd-catalyzed alkylation of gem-diacetates.
The gem-diacetates were generally prepared by reaction
of the enals with acetic anhydride catalyzed by ferric chlo-
ride in methylene chloride solution [Eq. (1)]. As summar-
ized in Table 1, most of the aldehydes reacted cleanly with
Figure 1. Palladium syn,syn and syn,anti ligand cartoons.
The alkylation adduct, a chiral allylic acetal equivalent,
can be a versatile building block for synthesis, particularly if
the newly formed stereogenic center can effectively direct
other reactions with high diastereoselectivity. Formation of
only one regioisomeric product resulting from a nucleophilic
attack on the carboxy-substituted terminus is required to
achieve this goal. Due to the unsymmetrical nature of the p-
Scheme 3. Synthesis of a,b-unsaturated aldehydes.
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Chem. Eur. J. 2006, 12, 2171 – 2187

Asymmetric Synthesis
FULL PAPER
Table 1. Preparation of allylic gem-1,1-diacetates using ferric chloride catalyst.
acetal proton that displayed
near d 7.0 as a singlet or as a
doublet with 5–8 Hertz cou-
pling constant. These com-
pounds displayed characteristic
strong carbonyl bands in IR
between 1760 and 1770 cmÀ1.
Entry
R
R’
Conditions
Product
Yield [%]
1Ph
2
3
4
5
6
7
8
9
H
4 equiv Ac
Me
H
2O, 1% FeCl3, 08C, 2 h
5 equiv Ac2O, 1% FeCl3, 08C, 2 h
4 equiv Ac2O, 1% FeCl3, 08C, 2 h
10a
10b
10c
10d
10e
10 f
10g
10h
10i[a]
87
83
91
61
73
94
64
50
85
Ph
(o-NO2)-Ph
(2-furyl)
Pr
Palladium-catalyzed AAA re-
actions with sodium benzene-
sulfinate: The versatility of al-
lylic sulfones has been demon-
strated by efficient control of
diastereoselectivity in addition
reactions to double bonds in
cyclic systems.[16] These allylic
sulfones are readily available
in enantiomerically enriched or
pure form by asymmetric allyl-
ic alkylations with sodium ben-
H
H
H
H
4 equiv Ac2O, 0.1% FeCl3, 08C, 0.5 h
3 equiv Ac2O, 0.5% FeCl3, 08C, 0.5 h
3 equiv Ac2O, 0.2% FeCl3, 08C, 1h
4 equiv Ac2O, 0.5% FeCl3, 08C, 0.5 h
5 equiv Ac2O, 1% FeCl3, RT, 1 0 h
5 equiv Ac2O, 0.5% FeCl3, 08C, 0.5 h
hexyl
iPr
-(CH2)4-
CH2OTBDPS
H
H
10
2 equiv Ac2O, 1% FeCl3, 08C, 3 h
3 equiv Ac2O, 1% FeCl3, 08C, 0.5 h
10j
79
99
11
CO2Et
Me
10k
[a] Prepared according to ref. [4].
acetic anhydride under these conditions to give the gem-di-
acetates in good to excellent yields. A variety of enals were
suitable, including aryl, alkyl, and ester substituted, both
with di- and trisubstituted substrates.
zenesulfinate. While simple cyclic allylic sulfones exhibit
high stereocontrol in the functionalization of the olefin, the
selectivity in similarly substituted acyclic systems has been
only modest.
The only instance where this method afforded a relatively
modest yield (50%) of gem-diacetate was in the conversion
of enal 5 to acetate 10h (Table 1, entry 8). In this case not
all of the starting material was converted at the specified
catalyst loading. Unfortunately, raising the catalyst load-
ing—while it did increase conversion—also resulted in the
formation of undesired side products and did not have a
positive effect on the overall yield.
While the most convenient route to access the gem-diace-
tates 10 was through the readily available (often commer-
cial) enals 5, some substrates were more easily accessible
through propargylic ester acetates using a palladium-cata-
lyzed redox isomerization–addition process.[15] One example
is the case of substrate 11, derived in four steps from cyclo-
pentanone. This material was converted to gem-diacetate
10l in 90% yield using three equivalents of acetic acid with
1% palladium dibenzylidene acetone catalyst loading
[Eq. (2)]. This method was more useful than the conversion
of the enal with ferric chloride as the ether of substrate 11 is
readily cleaved by a strong Lewis acid.
A strategy to create a better directing group for acyclic
systems was examined based on the observations that sulfi-
nate nucleophiles function well in the asymmetric allylic al-
kylation (AAA) reaction and that allylic geminal diesters
can be readily desymmetrized with carbon nucleophiles.[17] If
chiral a-acetoxysulfones were formed with high enantiomer-
ic excess they might subsequently direct a variety of desired
transformations of the olefin with good stereocontrol. The
observation that this asymmetric transformation could pro-
ceed using sodium benzenesulfinate on the prochiral diace-
tates with good ee was first made on a cinnamaldehyde de-
rivative 13a [Eq. (3); THAB = tetrahexylammonium bro-
mide]; the reaction demonstrated that good enantioselectivi-
ty could be achieved.
Expanding upon this promising lead observation, a wide
variety of substrates with different substitution patterns was
synthesized. Little improvement on the original conditions
was necessary. Under optimized conditions the ligand to pal-
ladium catalyst ratio was fixed at 3.0:1.0 (1.5:1.0 with re-
spect to palladium) to ensure excess phosphine was present
to avoid formation of palladium black. A catalyst load of 1
to 2.5% was necessary to get complete conversion of start-
ing diacetate to the product. Reaction of the gem-diacetates
These diacetates were mainly crystalline and air stable,
and could be stored indefinitely at room temperature under
an inert atmosphere. The compounds were stable to both
acidic (aqueous 1n hydrochloric acid) and mild basic (aque-
ous sodium bicarbonate) conditions. The derivatives were
1
readily distinguished in the H NMR spectrum by the allylic
Chem. Eur. J. 2006, 12, 2171 – 2187
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2173

B. M. Trost et al.
with this heteroatom nucleophile were performed under bi-
phasic conditions (methylene chloride/water) using tetraal-
kylammonium salts as phase-transfer catalysts. It was also
critical that the mixture be thoroughly deoxygenated to
avoid formation of an inert ligand–palladium complex in
which the amides are deprotonated and bound to palladium.
The original conversion issues, where 5% catalyst loading
was used, were resolved by this process. The reaction condi-
tions for each substrate varied only with respect to reaction
time, concentration, and temperature.
As was observed with carbon nucleophiles excellent con-
trol of regioselectivity was achieved (Table 2). Additionally,
further reaction of the a-acetoxysulfone did not occur under
the reaction conditions. The enantioselectivity of the reac-
tions was determined by examination of the products using
chiral high pressure liquid chromatography columns. Com-
parison of one enantiomer of adduct derived from chiral
ligand to the adduct derived from the opposite ligand clearly
established the selectivities. The C2-symmetric ligand 10 de-
rived from trans-1,2-diaminocyclohexane and 2-diphenyl-
phosphinobenzoic acid gave ee values higher than the other
ligands of this class. In some cases the other ligands gave no
reaction. For the examples shown both enantiomers of the
adduct were synthesized and in all cases similar ee values
and yields were obtained. The absolute configuration of the
products 13 was initially assigned by analogy to the previous
results with carbon and other heteroatom nucleophiles.
Later, derivatization studies and X-ray crystallography es-
tablished both the relative and absolute stereochemistry.
The exceptional enantioselectivity and high yields across
an array of substrates was notable for this AAA reaction.
Both di- and trisubstituted olefins with aryl, alkyl, and ester
substituents reacted without formation of byproducts. In all
cases where reaction occurred only the desired regioisomer
of product was observed. This was verified by 1H NMR
spectroscopy where the multiplicity and coupling patterns of
the olefinic protons were consistent with the desired addi-
tion product.
Adducts 13d, 13g, 13h, and 13k (Table 2) were formed
virtually enantiopure, with the minor enantiomer not detect-
able in all but one instance. The more sterically encumbered
alkenes in some cases did not react completely in 24 h at
Table 2. Alkylations of gem-diacetates with sodium benzenesulfinate.
Entry
R
R’
2 mol%
Conditions
21, 6 mol% 10a, 08C, 4 h
Product
Yield [%]
ee [%]
1Ph
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1
H
Ph
Ph
13a
ent-13a
13b
ent-13b
13c
ent-13c
13d
ent-13d
13e
ent-13e
13 f
ent-13 f
13g
ent-13g
13h
ent-13h
13i
89
85
98
96
95
95
85
77
>99
99
98
95
H
Me
Me
H
H
H
H
H
H
H
2 mol% 21, 6 mol% ent-10a, 08C, 4 h
2.5 mol% 21, 7.5 mol% 10b, RT, 24 h
2.5 mol% 21, 7.5 mol% ent-10b, RT, 24 h
2 mol% 21, 6 mol% 10c, 08C, 2 h
2 mol% 21, 6 mol% ent-10c, 08C, 2 h
2.5 mol% 21, 7.5 mol% 10d, RT, 24 h
2.5 mol% 21, 7.5 mol% ent-10d, RT, 24 h
2 mol% 21, 6 mol% 10e, 08C, 4 h
2 mol% 21, 6 mol% ent-10e, 08C, 4 h
2 mol% 21, 6 mol% 10 f, RT, 6 h
2 mol% 21, 6 mol% ent-10 f, RT, 6 h
2 mol% 21, 6 mol% 10g, 08C, 10 h
2 mol% 21, 6 mol% ent-10g, 08C, 10 h
2 mol% 21, 6 mol% 10h, RT, 48 h
2 mol% 21, 6 mol%, ent-10h, RT, 48 h
2 mol% 21, 6 mol% 10i, 08C, 4 h
2 mol% 21, 6 mol% ent-10i, 08C, 4 h
85[a]
86[a]
93
Ph
(o-NO2)-Ph
(o-NO2)-Ph
(2-furyl)
(2-furyl)
Pr
93
64
64
94
93
73
73
86
Pr
hexyl
hexyl
iPr
95
90
H
H
H
>99
97
>99
>99
94
iPr
85
-(CH2)4-
85[a]
80[a]
92
-(CH2)4-
2OTBDPSCH
2OTBDPSCH
7
8
H
H
1
ent-13i
9194
19
20
H
H
2 mol% 21, 6 mol% 10l, RT, 24 h
13l
76[a]
80
80
80
2 mol% 21, 6 mol% ent-10l, RT, 24 h
ent-13l
21
22
H
H
2 mol% 21, 6 mol% 10j, 08C, 4 h
13j
86
24:1 dr[b]
2:1 dr[b]
2 mol% 21, 6 mol% ent-10j, 08C, 4 h
ent-13j
89
23
24
CO2Et
CO2Et
Me
Me
2 mol% 21, 6 mol% 10k, 08C, 12 h
2 mol% 21, 6 mol% ent-10k, 08C, 12 h
13k
ent-13k
85[a]
83
99
98
1
[a] brsm = based on recovered starting material. [b] Diastereomeric ratio determined by H NMR integration.
2174
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Chem. Eur. J. 2006, 12, 2171 – 2187

Asymmetric Synthesis
FULL PAPER
ambient temperature. Notably, only two substrates (13c and
13l) gave ee values of <90%. This was presumably due to a
perturbation in the chiral pocket from adjacent steric en-
cumberance, as simple electron withdrawing substituents did
not cause a noticeable change in the enantioselectivity.
The effect of a pre-existing stereogenic center was exam-
ined. When the “matched” ligand was utilized, the resulting
a-acetoxysulfone dr was >20:1(Table 2, entry 21). Howev-
er, while the “mismatched” ligand case was able to reduce
the directing effect of the dimethylacetal (often 3:1to 5:1),
the result was still anti (with respect to the dimethylacetal)
Figure 2. Energy-minimized conformation of a-acetoxysulfone 20a.
substitution, though in
a modest 2:1ratio (Table 2,
entry 22). This was the only instance examined of a sub-
strate with a proximal chiral center.
allow a favorable p-orbital stacking interaction. Other low
energy conformations also favored p-orbital stacking. The
nearest low energy conformation that did not have signifi-
cant overlap of the phenyl ring and the olefin was
0.4 kcalmolÀ1 higher in energy.
The a-acetoxysulfone 13i was tested for its reactivity in
osmium tetroxide catalyzed dihydroxylation reactions. Using
N-methylmorpholine-N-oxide (NMO) as the stoichiometric
reoxidant, osmium tetroxide catalyzed dihydroxylations of
the a-acetoxysulfones in methylene chloride initially afford-
ed a modest dr of 6.5:1in Table 3, as shown with the alkoxy-
alkyl derivative 13i in its transformation to diols 14 and 15
[Table 3, Equation (5)]. Running the reaction at 08C com-
pared with ambient temperature improved the diastereose-
The a-acetoxysulfones in all cases were isolated by silica
gel chromatography after separation of the aqueous and or-
ganic phases of the reaction. The compounds could be
cleaved under basic conditions (using potassium carbonate
in methanol, see section on liberation of the aldehyde) but
were stable to various Lewis acids, even aqueous 1n hydro-
chloric acid. The compounds exhibited longer shelf life
when stored at 08C under inert atmosphere while storage in
solvent at ambient temperature resulted in slow decay to
the corresponding enal. The compounds were readily identi-
fied by 1H NMR spectroscopy. With respect to the a-acetoxy-
sulfone proton, all of the adducts with trisubstituted olefins
had a characteristic singlet be-
tween d 6.00 and 7.00; the di-
Table 3. Initial results for the dihydroxylation of the allyl sulfone 13i.
substituted adducts exhibited a
5 to 8 Hz doublet between d
6.00 and d 7.00 ppm. This shift
was always upfield (0.3–
0.7 ppm) from the correspond-
ing gem-diacetate proton.
Diastereoselective dihydroxy-
lations: The products from the
asymmetric allylic alkylations
of gem-diacetates with sodium
Entry
R
Conditions
Yield [%]
14:15[a]
1TBDPSOCH
2
3
(13i)
10 mol% OsO4, 3 equiv NMO, CH2Cl2, H2O, RT, 12 h
10 mol% OsO4, 3 equiv NMO, CH2Cl2, H2O, 0 8C, 12 h
5 mol% OsO4, 3 equiv NMO, CH2Cl2, H2O, 0 8C, 24 h
1
87
78
80
6.5:1
12.5:1
18:1
2
benzenesulfinate
have
a
TBDPSOCH2 (13i)
TBDPSOCH2 (13i)
unique S,O-mixed acetal struc-
ture. We predicted that the
[a] Diastereomeric ratio determined by H NMR integration.
electron-withdrawing
effect
and steric bulk of the phenyl-
sulfonyl group in combination with the electronic effect of
the acetoxy moiety together could effectively direct func-
tionalization of the adjacent olefin in a highly diastereose-
lective fashion. The ground state conformation of the allylic
a-acetoxysulfones as predicted by Macromodel using a con-
formation search with the MM2 force field in solution phase
with chloroform as solvent has the phenylsulfonyl moiety
nearly perpendicular to the plane of the double bond and
the acetoxy group in a syn orientation (analogous to the
“inside alkoxy” effect).[18] This suggested that high facial se-
lectivity involving attack of an electrophile anti to the sul-
fone would be expected (Figure 2). The phenyl ring of the
sulfone was oriented parallel to the olefin, which could
lectivity to 12.5:1. Decreasing the osmium tetroxide loading
from 10 to 5% further increased the dr to 18:1. Employing
catalyst loadings under 5 mol% led to incomplete conver-
sion after 24 h and did not further improve the selectivity.
Based upon the conformation depicted in Figure 1, the
major adduct 14 was tentatively assigned as the syn diol con-
figured anti to the a-acetoxysulfones; this speculation was
later confirmed. Under the optimized conditions (Table 3,
entry 3) the other a-acetoxysulfones were dihydroxylated
[Table 4, Equation (6)].
The dihydroxylations mainly afforded the expected anti
diols, though certain substrates either decomposed or rear-
ranged under the reaction conditions. The selectivity on a
Chem. Eur. J. 2006, 12, 2171 – 2187
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B. M. Trost et al.
Table 4. Dihydroxylations of a-acetoxysulfones using optimized conditions.
Entry
R
R’
Conditions[a]
Adduct
Yield [%]
dr[b]
1Ph
2
3
4
5
6
7
8
9
H (
13a)
H (ent-13a)
H (13a)
Me (13b)
H (13c)
H (13e)
standard
standard
standard + DABCO, tBuOH
standard
standard
standard
standard
14a
ent-14a
ent-14a
14b
77
68
>98:2
>98:2
>98:2
>98:2
Ph
Ph
Ph
78
57[c]
83
(o-NO2)-Ph
14c
14e
14 f
>98:2
[d]
Pr
hexyl
iPr
6195:5
84
81
82
811
711
H (13 f)
>98:2
>98:2
12:1
H (ent-13g)
H (ent-13i)
H (13i)
standard
ent-14g
ent-14i
14i8:1
ent-141i
CH2OTBDPS
2OTBDPS CH
CH2OTBDPS
standard[d]
1
11
0
standard
standard + DABCO, tBuOH:1
H (ent-13i)
12
H (13j)
standard
14j
85
6:1
13
1
H (13l)
standard
standard
14l
7196:4
94
4
2Et
CO
Me (13k)
16k
>98:2[e]
[a] Unless otherwise noted all reactions were run with 5 mol% osmium tetroxide, 3 equiv N-methylmorpholine-N-oxide, in 0.1m methylene chloride solu-
tion at 08C. [b] Diastereomeric ratio determined by 1H NMR integration. [c] 5% of the unmasked product formed and was inseparable from the major
adduct. [d] 10 mol% osmium tetroxide was used in this case. [e] Diasteromeric and enantiomeric ratio.
wide range of substrates was outstanding and often com-
plete. The conversions and yields were generally high, and
the products were isolated by silica gel chromatography.
While all adducts resulting from disubstituted olefin starting
material were stable for months when stored under argon at
08C, the adducts that were oils decomposed in a few days
upon standing at room temperature.
There were several notable trends in the dihydroxylation
reactions. The effect of DABCO and tert-butanol was negli-
gible or negative on both yield and selectivity (Table 4, en-
tries 1 vs 3 and 10 vs 11). As expected, smaller side chain
groups (Table 4, entries 6, 9, 10) gave good anti selectivity
though the selectivity was lower than that in the cases of
more bulky substrates. Lowering the osmium tetroxide cata-
lyst loading from 10 to 5% had a beneficial effect on dia-
steroeselectivity for substrate 13i (Table 4, entries 9 and 10).
The lower catalyst loading was then used for all other cases.
Trisubstituted olefin 13b (Table 4, entry 4) gave partial rear-
rangement to product 16b under the reaction conditions.
However, with the exception of substrate 13k (Table 4,
entry 14) which afforded 16k, none of the substrates fully
converted to a single rearranged product. This led to investi-
gation of additives to force the rearrangement of the initial
dihydroxylation adducts (see below).
toxysulfone was the dominant directing group in this case
displaying an energy preference of at least 2 kcalmolÀ1,
giving adduct 14j in 6:1 dr (syn to the dimethylacetal).
Using a Macromodel driven conformational search with
the MM2 force field in solution phase, the minimum energy
conformation of diol 14a was predicted to be consistent
with the conformation needed for 1,3-acyl migration. Thus,
a key observation from this model shows that the hydroxyl
group b to the a-acetoxysulfone had a dihedral angle of 528
with the acetate group, while the a-hydroxyl group was on
the opposite face (1608). Ultimately, the conformation that
was predicted is nearly identical to that of the X-ray diffrac-
tion crystal structure obtained for 14a (Figure 3). This helps
to explain the preference for 1,3 versus 1,2-acyl migration,
as discussed later.
Figure 3. Minimum energy conformation and X-ray structure of diol 14a.
Another question of interest was how the a-acetoxysul-
fones would compete against other directing groups.
Entry 13 in Table 4 highlights an internal competition for di-
recting the dihydroxylation. The dimethylacetal tends to be
modestly anti directing (3:1 to 11:1)[19] and was mismatched
with the strongly anti directing a-acetoxysulfone. The a-ace-
The utility of this strategy to make diols stereoselectively
was exemplified by diol ent-14g (Table 4, entry 8) obtained
enantiomerically pure compared with 70% ee in the asym-
metric dihydroxylation of methyl (E)-4-methyl-2-pente-
2176
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Chem. Eur. J. 2006, 12, 2171 – 2187

Asymmetric Synthesis
FULL PAPER
noate.[20] The dihydroxylated adduct was used as a key build-
ing block in the synthesis of a highly active analogue of
clasto-lactacystin b-lactone.
The value of this strategy becomes clearer considering
enals can not be directly dihydroxylated using the Sharpless
methodology.[6] The result from entry 14, Table 4, shows a
one pot protocol that afforded
the acetate group inside but on the opposite face of the
olefin (Vedejs) (Scheme 5). The Kishi model,[23] that would
align the hydrogen eclipsing the olefin with the sulfone
group on the same face as the approaching electrophile, pre-
dicts a conformation that was not compatible with the steric
demands of this system.
the dihydoxylated adduct of an
enal with the diol differentially
protected.
Determination of absolute
stereochemistry: X-ray crystal-
lography confirmed that the
relative configuration of the
diol to the a-acetoxysulfone
was indeed anti (see Support-
ing Information for a three di-
mensional representation and
crystal
report;
see
also
Scheme 5. Rationale for observed selectivity in the dihydroxylation reaction.
Figure 3). The absolute stereo-
chemistry of the diol from the
dihydroxylated adducts was established by derivatization to
a known compound. Diol 14a was protected as the dimethyl
ketal to 17a and reduced with diisobutylaluminum hydride
to afford known triol 18 (Scheme 4). Full characterization
data of enantiopure derivative 18 was previously established
by Zhou and co-workers and matched the observed optical
rotation and spectral data of the isolated product 18.[21]
Utilityof the a-acetoxysulfones: One advantage presented
by the acetoxysulfones for diastereoselective dihydroxyla-
tions is the possibility to selectively unmask and transform
the substrate. Liberation of the aldehyde before or after
protection of the diol, direct nucleophilic substitution on the
mixed acetal, and aldehyde formation in situ during the di-
hydroxylation with simultaneous acyl transfer were all
probed as methods to further functionalize the chiral ad-
ducts.
Derivatization to acetonides: Several of the ent-14 diols
were protected as the dimethyl ketal by treatment with 2,2-
dimethoxypropane and pyridinium p-toluenesulfonate in
acetone at ambient temperature (Scheme 6, method A).
More conveniently, the same protection was achieved by
direct treatment of the crude adduct of dihydroxylation with
2,2-dimethoxypropane using p-toluenesulfonic acid monohy-
drate as catalyst (Scheme 6, method B). Four acetonides 17
containing both di- and trisubstituted alkenes with both aryl
and alkyl substituents were formed in high yields (Table 5).
The acetonides were stable, amorphous solids that showed
no sign of decomposition after a significant time stored at
ambient temperature.
Scheme 4. Derivatization of diol 14a to known triol 18.
The establishment of the absolute stereochemistry of the
two stereogenic centers combined with the relative stereo-
chemistry of the three stereocenters as determined by X-ray
crystallography proved the absolute and relative conforma-
tion of adduct 14a. This result also verified that, as predict-
ed, the AAA reactions using sodium benzensulfinate as a
nucleophile did indeed proceed to give the same sense of
chirality as with stabilized carbon and heteroatom nucleo-
philes.
To rationalize the outcome of the dihydroxylation, it was
helpful to use both the Stork–Houk–Jaeger “inside alkoxy”
model[18] and the Vedejs model[22] for dihydroxylations of
chiral allylic ethers. Adaptation of these models to the a-
acetoxysulfone system predicts the osmium tetroxide ap-
proaching either directly anti to the sulfone with the acetate
on the same face of the olefin as the approaching electro-
phile (Houk) or along the same plane as the hydrogen, with
Scheme 6. Protection of the diols as acetonides.
Chem. Eur. J. 2006, 12, 2171 – 2187
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2177

B. M. Trost et al.
Table 5. Synthesis of acetonide derivatives.
Table 6. Addition of alkyl Grignard reactions to acetonide.
Entry
R
R’
Method
Compound
Yield [%]
Entry
RMgX
Additive
Yield [%]
dr[a]
[b]
1Ph
2
3
H
Ph
Pr
A
Me
H
17a
17b
ent-17c
17d
92
81[a]
95
1MeMgBr
–
87
87
74
88
84
1.5:1
1.5:1
2.2:1
1.5:1
1.5:1
[c]
B
A
A
2
3
4
5
MeMgBr
EtMgBr
MeMgBr
MeMgBr
–
–
[b]
4
iPr
H
83
CuBr[c]
MgCl2
[c]
[a] Two-step one-pot yield from the a-acetoxysulfone.
[a] Determined by 1H NMR integration. [b] Reaction run at 08C. [c] Re-
action run at À788C.
Liberation of the aldehyde: An obvious way to transform
the a-acetoxysulfone to a reactive functional group is direct
liberation to the aldehyde under basic conditions. With ad-
ducts derived from disubstituted olefins, the conditions for
direct liberation led to epimerization of the a-stereogenic
center and or elimination/decomposition. However, with tri-
substituted alkene 17b mild conditions (potassium carbon-
ate and methanol) gave a,b-acetonide aldehyde 19 in excel-
lent yield. Tetrasubstitution at the a-stereogenic center pre-
vented epimerization or elimination [Eq. (7)].
eochemistry of addition was tentatively assigned as shown
based on an a-alkoxy chelate controlled model via a five
membered-cyclic transition state for addition of the phenyl
magnesium bromide. The coupling constants of 5 to 7 Hz for
the protons a to the hydroxyl group was also consistent with
other syn adducts, though this correlation is not always accu-
rate.[18]
Separately, an attempted liberation of the aldehyde from
a-acetoxysulfone 17a in situ followed by addition of a
methyl group with trimethylaluminum did not proceed as
expected. The Lewis acidity of the aluminum derivatives
was strong enough to promote chemoselective cleavage of
the acetonide 17a to afford adduct 25 [Eq. (10)]. This reac-
tion is useful as the acetoxysulfone moiety was not labile
under these conditions and afforded a differentially protect-
ed triol as the adduct.
Direct addition of nucleophiles to the a-acetoxysulfone:
The dihydroxylation, protection, liberation sequence was
highly selective and proceeded in good yield. However, two
steps to the aldehyde are required to allow for nucleophilic
addition. An alternative envisions a one-pot dihydroxylation
protection protocol followed by direct reaction with a nucle-
ophile, one that unmasks and then reacts with the aldehyde
in situ.
Initial addition to the cinnamaldehyde derived acetonide
17a was attempted with alkyl Grignard reagents [Eq. (8)].
Nucleophilic addition of hydrides, such as utilized in the
protocol to establish the absolute stereochemistry, can also
directly unmask and subsequently reduce the a-acetoxysul-
fone to the corresponding alcohol 18. While only a handful
of nucleophiles were examined for direct addition, the re-
sults demonstrate the viability of a one-pot unmasking–addi-
tion sequence and suggest it may proceed with high diaster-
eoselectivity.
While excess nucleophile liberated the aldehyde in situ and
then subsequently added, the diastereoselectivity was poor
(Table 6). Variation of the temperature or addition of addi-
tives did not improve the result. Despite the low stereoselec-
tivity, this process allows useful access to various substituted
alkylketones with a chiral a,b-acetonide after oxidation.
A surprising result, given the poor selectivity the alkyl
Grignard reagents, was observed with phenylmagnesium
bromide as the nucleophile. Addition to acetoxysulfones
17a and 17c afforded only one diastereomeric alcohol, 23
and 24 respectively, in good yield [Eq. (9)]. The relative ster-
One-pot dihydroxylation–deprotective acyl migration pro-
tocol: An arguable disadvantage of the a-acetoxysulfone as
a “chiral aldehyde” equivalent is the extra step it takes to
prepare the sulfone compared with a direct enantioselective
reaction of the olefin.[24] However, it has been noted that
such a protocol fails with a,b-unsaturated aldehyde which is
2178
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Chem. Eur. J. 2006, 12, 2171 – 2187

Asymmetric Synthesis
FULL PAPER
the equivalent of the process reported herein. Furthermore,
if, in a one-pot protocol the dihydroxylation, aldehyde un-
masking, and differential protection of the diol were possi-
ble, an additional advantage to this protocol accrues.
The observation that the diols derived from trisubstituted
olefins are relatively unstable led to speculation that slow
but spontaneous acyl transfer was occurring. The minimum
energy conformation of the dihydroxylated a-acetoxysulfone
from Macromodel and X-ray crystal structure indicated the
acyl group was nicely aligned for a 1,3-migration. Using in-
tramolecular transesterification catalysts, several direct
transformations of acetoxysulfones 13 to differentiated diol
16 were achieved [Table 7, Equation (11)]. While in some
Summary
A versatile “chiral aldehyde” equivalent with exceptional di-
recting ability has been discovered and is readily accessible
through an asymmetric allylic alkylation of gem-diacetates
using sodium benzenesulfinate as the nucleophile. The gem-
diacetate precursors to the sulfones were available in high
yields from the corresponding enals or propargylic acetates;
those substrates were commercially available or derived in
one to two steps. The enantioselectivity created in the a-ace-
toxysulfone adducts was remarkable, almost always in
excess of 95%. The directing ability of this “chiral alde-
hyde” equivalent was exemplified in diastereoselective dihy-
droxylations that in all cases
proceeded with high diastereo-
selectivity and often with com-
Table 7. Selective one-pot dihydroxylation–differential protection unmasking.
plete control. The diol deriva-
tives were readily and some-
times
spontaneously
un-
masked, and the unmasking
could take place as a one-pot
operation with the dihydroxy-
lation. The protocol for che-
moselective 1,3-acyl transfer
giving a one pot dihydroxyla-
tion, differential protection,
and aldehyde unmasking was
particularly useful as it gave
products that the Sharpless
Entry
1
Substrate
Additive
Product
Yield [%][a]
31
dr
nBu2SnO
ent-16b
>98:2
2
3
4-DMAP
4-DMAP
ent-16b
92
–
>98:2
1,2- and 1,3-acyl transfer,
and decomposition products
–
asymmetric
dihydroxylation
could not form from the corre-
sponding enals. The high con-
formational bias of the acetoxy
sulfones provides an opportu-
nity for other diastereoselec-
tive elaborations of the adja-
cent double bond as well as
ease of unmasking of the alde-
hyde. Combined with its ro-
4
5
–
16k
16k
94
98
>98:2
>98:2
4-DMAP
[a] With the exception of entry 7, these reactions were run at O8C for 12 h, the additive added, and then at
RT for 12 h. The reaction in entry 7 only required 1 h at RT after the dihydroxylation was complete.
instances longer reaction time or dibutyltin oxide were suffi-
cient to promote the acyl migration, the most effective
method involved the use of 4-dimethylaminopyridine.
bustness to numerous electrophilic reagents, this new type
of “chiral aldehyde” complements the use of chiral acetals
which typically involve nucleophilic additions rather than
electrophilic additions as in the case here.
Most of these transformations proceeded to give a single
adduct with no byproducts. The adducts in entries 1and 2
(Table 7) were identical to those obtained by a stepwise di-
hydroxylation and the deprotective acyl-migration protocol.
One exception was the case of the cyclic sulfone ent-13i
(Table 7, entry 3), where both 1,2- and 1,3-acyl transfer oc-
curred along with decomposition. It is notable that the over-
all yields for these processes were significantly higher than
for dihydroxylation alone, presumably due to acyl migration
during isolation of the free diol. While 4-dimethylaminopyri-
dine was not necessary to facilitate the 1,3-acyl-migration in
the case of substrate 16k (Table 7, entries 4 and 5), it did in-
crease the rate of reaction (completed in 4 h versus 16 h).
Experimental Section
General methods: PE = petroleum ether b.p. 40–608C.
General procedure for ferric chloride catalyzed preparation of gem-diace-
tates: An aldehyde, neat or dissolved in a minimal amount of methylene
chloride at 08C, was added to freshly distilled acetic anhydride. After
5 min, a catalytic amount of anhydrous ferric chloride was added to the
solution, and stirring was continued at 08C or RT. The progress of the re-
action was monitored by TLC. After the complete conversion of the
starting aldehyde, the reaction mixture was poured into water and ex-
tracted with Et2O. The combined organic extracts were washed with
water and dried over anhydrous sodium sulfate. The solution was concen-
Chem. Eur. J. 2006, 12, 2171 – 2187
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2179

B. M. Trost et al.
trated in vacuo and the residue was purified by silica gel flash chromatog-
raphy or recrystallization.
1202, 1008 cmÀ1; elemental analysis calcd (%) for C10H16O4: C 59.98, H
8.05; found: C 59.76, H 8.15.
1-(1’,1’-Diacetoxy)-1-cyclohexene (10h): Following the general proce-
dure, 1-cyclohexene-1-carboxaldehyde (5h; 990 mg, 9.00 mmol) and
acetic anhydride (4.59 g, 45.0 mmol) were stirred in the presence of ferric
chloride (14.5 mg, 0.09 mmol) at 08C for 10 h. Flash chromatography
(PE/Et2O 4:1) afforded diacetate 10h as a clear oil (0.947 g, 50%). The
characterization data matched known values. 1H NMR (200 MHz,
CDCl3): d = 7.02 (s, 1H), 6.00 (s, 1H), 2.09–2.00 (m, 8H), 1.67–1.60 (m,
6H); 13C NMR (75 MHz, CDCl3): d = 168.7, 132.0, 128.6, 91.6, 24.6,
22.3, 21.8, 20.8; IR (CHCl3): n˜ = 2934, 1764, 1438, 1372, 1240, 1206,
1008 cmÀ1; HRMS: m/z: calcd for C9H14O3: 170.0943; found: 170.0940
[M +ÀC2H2O].
(E)-1,1-Diacetoxy-2-methyl-3-phenyl-2-propene (10b): Following the
general procedure, acetic anhydride (15.3 g, 150 mmol) and a-methyl-
trans-cinnamaldehyde (5b; 4.39 g, 30.0 mmol) in methylene chloride
(50 mL) were stirred in the presence of ferric chloride (64.8 mg,
0.400 mmol) at 08C for 2 h. Flash chromatography (PE/ethyl acetate 8:1)
afforded product 10b as
a
colorless oil (6.29 g, 83%). 1H NMR
(200 MHz, CDCl3): d = 7.32–7.25 (m, 5H), 7.20 (s, 1H), 6.75 (s, 1H),
2.12 (s, 6H), 1.96 (s, 3H); 13C NMR (75 MHz, CDCl3): d = 168.8, 136.0,
131.2, 130.9, 129.2, 128.3, 127.4, 92.9, 20.8, 12.3; IR (film): n˜ = 2990,
1765, 1493, 1444, 1372, 1241, 1203, 1072, 1007 cmÀ1; elemental analysis
calcd (%) for C14H16O4: C 67.73, H 6.50; found: C 67.52, H 6.40.
(S)-2,2-Dimethyl-4-(3’,3’-diacetoxy-1’-(E)-propenyl)-1,3-dioxolane (10j):
Following the general procedure, aldehyde 5j[25] (469 mg, 3.00 mmol) and
acetic anhydride (612 mg, 6.00 mmol) were stirred in the presence of
ferric chloride (4.8 mg, 0.030 mmol) at 08C for 120 min. Flash chromatog-
raphy (PE/Et2O 2:1) afforded diacetate 10j as a clear oil (614 mg, 79%).
[a]D = +42.5Æ0.2 (c=1.00, CHCl3); 1H NMR (300 MHz, CDCl3): d =
7.16 (d, J=5.5 Hz, 1H), 5.99 (dd, J=15.8, 5.6 Hz, 1H), 5.82 (dd, J=15.8,
5.7 Hz, 1H), 4.55 (q, J=7.0 Hz, 1H), 4.15 (dd, J=7.5, 6.4 Hz, 1H), 3.62
(dd, J=7.5, 6.5 Hz, 1H), 2.09 (s, 6H), 1.44 (s, 3H), 1.39 (s, 3H);
13C NMR (100 MHz, CDCl3): d = 168.5, 133.9, 125.8, 109.7, 88.3, 75.3,
69.0, 26.4, 25.6, 20.7; IR (film): n˜ = 2898, 1765, 1372, 1238, 1203, 1127,
1060 cmÀ1; elemental analysis calcd (%) for C12H18O6: C 55.81, H 7.02;
found: C 55.91, H 6.88.
(E)-1,1-Diacetoxy-3-(2-nitrophenyl)-2-propene (10c): Following the gen-
eral procedure, trans-2-nitrocinnamaldehyde (5c; 1.77 g, 10.0 mmol) and
acetic anhydride (4.08 g, 40.0 mmol) in methylene chloride (10.0 mL)
were stirred in the presence of ferric chloride (16.2 mg, 0.100 mmol) for
1 h at 08C. Flash chromatography (PE/Et2O 3:1) afforded diacetate 10c
as a white solid (2.54 g, 91%). M.p. 73.5–74 8C; 1H NMR (300 MHz,
CDCl3): d = 8.00 (d, J=8.2 Hz, 1H), 7.62–7.60 (m, 2H), 7.52–7.35 (m,
3H), 6.18 (dd, J=15.7, 5.5 Hz, 1H), 2.15 (s, 6H); 13C NMR (75 MHz,
CDCl3): d = 168.6, 148.0, 133.3, 131.2, 130.6, 129.2, 128.9, 126.9, 124.7,
88.4, 20.6; IR (film): n˜ = 2986, 1765, 1608, 1526, 1347, 1240, 1202, 1150,
1009 cmÀ1; HRMS: m/z: calcd for C9H10NO4: 220.0611; found: 220.0605
[M +ÀC2H3O2].
(E)-1,1-Diacetoxy-3-(2-furyl)-2-propene (10d): Following the general
procedure, trans-3-(2-furyl)-acrolein (5d; 1.22 g, 10.0 mmol) and acetic
anhydride (4.08 g, 40.0 mmol) in methylene chloride (10.0 mL) was stir-
red with a few drops of H2SO4 for 1h. Flash chromatography (PE/Et 2O
3:1) afforded the diacetate product 10d as a clear oil (1.31 g, 61%).
Note: the product decomposes at RT in a matter of days to a brown tar.
(E)-Ethyl 3-methyl-4-diacetoxycrotonate (10k): Following the general
procedure, ethyl 3-methyl-4-oxocrotonate (5k; 1.42 g, 10.0 mmol) and
acetic anhydride (3.06 g, 30.0 mmol) were stirred in the presence of ferric
chloride (16.2 mg, 0.100 mmol) at 08C for 30 min. Flash chromatography
(PE/Et2O 4:1) afforded product 10k as a clear oil (2.66 g, 99%).
1H NMR (300 MHz, CDCl3): d = 7.08 (s, 1H), 6.07 (s, 1H), 4.19 (q, J=
7.1 Hz, 2H), 2.18 (s, 3H), 2.13 (s, 6H), 1.29 (t, J=7.1Hz, 3H); 13C NMR
(75 MHz, CDCl3): d = 168.5, 165.8, 148.4, 120.1, 90.5, 60.2, 20.6, 14.1,
13.2; IR (film): n˜ = 2984, 1770, 1722, 1667, 1435, 1372, 1225, 1163, 1046,
1008 cmÀ1; HRMS: m/z: calcd for C9H16O4: 185.0809; found: 185.0808
[M +ÀC2H3O2].
1H NMR (300 MHz, CDCl3): d
= 7.39 (brs, 1H), 7.27 (d, J=6.4 Hz,
1H), 6.66 (d, J=16.0 Hz, 1H), 6.40–6.39 (m, 2H), 6.10 (dd, J=16.0,
6.4 Hz, 1H), 2.11 (s, 6H); 13C NMR (75 MHz, CDCl3): d = 168.8, 151.0,
143.2, 123.3, 119.8, 111.6, 111.0, 89.4, 20.8; IR (film): n˜ = 2990, 1762,
1664, 1489, 1374, 1239, 1205, 1139, 1051 cmÀ1
.
(E)-1,1-Diacetoxy-2-hexene (10e): Following the general procedure, 2-
hexenal (5e; 1.96 g, 20.0 mmol) and acetic anhydride (6.12 g, 60.0 mmol)
were stirred in the presence of ferric chloride (16.2 mg, 0.10 mmol) at
08C for 30 min. Flash chromatography (PE/Et2O 8:1) afforded product
10e as a clear oil (2.94 g, 73%). The characterization data matched
(E)-1,1-Diacetoxy-3-(1’-methoxycyclopentyl)-2-propene
(10l):
[Pd2dba3]·CHCl3 (47.0 mg, 0.040 mmol) and PPh3 (105 mg, 0.400 mmol)
were added to a flame dried flask which was then vacuum degassed and
filled with argon. Toluene (10 mL) was added and the solution was de-
gassed under vacuum. Acetic acid (720 mg, 12.0 mmol) was added and
the solution was stirred for 5 min under argon. A degassed solution of
alkyne 11 (786 mg, 4.00 mmol) in toluene (10 mL) was added under
argon and the mixture was heated to 1108C for 4 h. Flash chromatogra-
phy (PE/Et2O 5:1) afforded diacetate 10l as a clear oil (922 mg, 90%).
1H NMR (300 MHz, CDCl3): d = 7.16 (d, J=5.8 Hz, 1H), 6.03 (d, J=
15.8 Hz, 1H), 5.67 (dd, J=15.8, 6.1 Hz, 1H), 3.12 (s, 3H), 2.10 (s, 6H),
1.88–1.57 (m, 8H); 13C NMR (75 MHz, CDCl3): d = 168.8, 139.7, 122.9,
89.3, 86.1, 50.9, 35.7, 23.0, 20.8; IR (film): n˜ = 2965, 1765, 1436, 1373,
1241, 1203, 1068 cmÀ1; elemental analysis calcd (%) for C13H20O: C 60.92,
H 7.87; found: C 60.82, H 7.71.
1
known values. H NMR (300 MHz, CDCl3): d = 7.10 (d, J=6.5 Hz, 1H),
6.00 (dt, J=15.5, 2.3 Hz, 1H), 5.55 (dd, J=15.5, 6.5 Hz, 1H), 2.23–2.00
(m, 8H), 1.48–1.34 (m, 2H), 0.84 (t, J=6.2 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d = 168.7, 138.8, 123.3, 89.7, 33.8, 26.4, 20.7, 13.4; IR (film): n˜ =
2962, 1763, 1676, 1372, 1242, 1205, 1051 cmÀ1; elemental analysis calcd
(%) for C10H16O4: C 59.98, H 8.05; found: C 60.00, H 7.96.
(E)-1,1-Diacetoxy-2-nonene (10 f): Following the general procedure,
trans-2-nonenal (5 f; 2.80 g, 20.00 mmol) and acetic anhydride (6.13 g,
60.0 mmol) were stirred in the presence of ferric chloride (32.4 mg,
0.200 mmol) at 08C for 1h. Flash chromatography (PE/Et 2O 6:1) afford-
ed diacetate 10 f as a clear yellow oil (4.57 g, 94%). 1H NMR (300 MHz,
CDCl3): d = 7.09 (d, J=6.3 Hz, 1H), 6.00 (dt, J=15.5, 7.5 Hz, 1H), 5.51
(dd, J=15.5, 7.5 Hz, 1H), 2.08 (s, 6H), 2.08–2.06 (m, 2H), 1.31–1.18 (m,
8H), 0.85 (t, J=9.0 Hz, 3H); 13C NMR (75 MHz, CDCl3): d = 168.8,
General procedure for asymmetric alkylation of allylic geminal dicarbox-
ylates with sodium benzenesulfinate: A solution of allylic diacetate 10, p-
allylpalladium chloride dimer, and ligand in methylene chloride was
added at 08C or RT to a degassed solution of sodium benzenesulfinate
and tetraalkylammonium bromide in water. After stirring at 08C or RT
under argon until TLC indicated the reaction was complete, the mixture
was poured into water. The solution was extracted with diethyl ether and
the combined organic phases were washed with brine the organic phase
dried over magnesium sulfate, and concentrated in vacuo. The residue
was purified by silica gel flash chromatography.
138.3, 123.0, 89.8, 31.8, 31.5, 28.6, 28.2, 22.4, 20.8, 13.9; IR (film): n˜
=
2929, 1765, 1676, 1459, 1435, 1372, 1241, 1206, 1120 cmÀ1; HRMS: m/z:
calcd for C11H19O2: 183.1378; found: 183.1303 [M +ÀC2H3O2].
1,1-Diacetoxy-4-methyl-2-(E)-pentene (10g): Following the general pro-
cedure, 4-methyl-2-pentenal (5g; 1.20 g, 12.2 mmol) and acetic anhydride
(5.10 g, 50.0 mmol) were stirred in the presence of ferric chloride
(32.4 mg, 0.200 mmol) at 08C for 0.5 h. Flash chromatography (PE/Et2O
6:1) afforded product 10g as a colorless oil (1.58 g, 64%). 1H NMR
(E,S)-1-Acetoxy-1-phenylsulfonyl-3-phenyl-2-propene (13a): Following
the general procedure, a solution of diacetate 10a (108 mg, 0.462 mmol),
p-allylpalladium chloride dimer (3.38 mg, 0.0092 mmol), and ligand 12
(19.0 mg, 0.028 mmol) in methylene chloride (1.00 mL) was added at 08C
to sodium benzenesulfinate (114.9 mg, 0.700 mmol) and tetrahexylammo-
nium bromide (39.14 mg, 0.0920 mmol) in water (1.00 mL). The reaction
(300 MHz, CDCl3): d
= 7.09 (d, J=6.3 Hz, 1H), 5.99 (dd, J=15.8,
6.3 Hz, 1H), 5.47 (ddd, J=15.7, 6.3, 1.4 Hz, 1H), 2.40–2.28 (m, 1H), 2.08
(s, 6H), 1.03 (d, J=6.8 Hz, 6H); 13C NMR (75 MHz, CDCl3): d = 168.8,
144.6, 120.4, 89.8, 30.5, 21.5, 20.9; IR (film): n˜ = 1766, 1675, 1372, 1240,
2180
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 2171 – 2187

Asymmetric Synthesis
FULL PAPER
mixture was stirred at 08C for 2 h. Flash chromatography (PE/ethyl ace-
tate 6:1) afforded 13a a white solid (140 mg, 89%). M.p. 116–1178C;
[a]D = À19.9Æ0.1( c=1.32, CHCl3); tr(S)=12.85 min, tr(R)=15.24 min,
98% ee, (Chiralcel OD, l=254 nm, heptane/iPrOH 9:1); 1H NMR
(300 MHz, CDCl3): d = 7.92–7.89 (m, 2H), 7.68 (t, J=7.4 Hz, 1H), 7.54
(t, J=8.1Hz, 2H), 7.36–7.31 (m, 5H), 6.75 (dd, 15.9, 0.9 Hz, 1H), 6.40
(dd, J=7.3, 1.0 Hz, 1H), 6.17 (dd, J=16.1, 7.2 Hz, 1H), 2.09 (s, 3H);
13C NMR (75 MHz, CDCl3): d = 168.1, 139.4, 135.8, 134.9, 134.5, 129.8,
129.2, 128.8, 127.2, 115.9, 86.8, 20.4; IR (film): n˜ = 1765, 1448, 1372,
1324, 1204, 1151, 1082, 1032 cmÀ1; elemental analysis calcd (%) for
C13H16O4S: C 64.54, H 5.10; found: C 64.60, H 5.28.
1153 cmÀ1; elemental analysis calcd (%) for C17H15NO6S: C 64.54, H
5.10; found C 64.36, H 5.20.
(E,R)-1-Acetoxy-1-phenylsulfonyl-3-(2-nitrophenyl)-2-propene (ent-13c):
Following the general procedure, a solution of allylic diacetate 10c
(140 mg, 0.500 mmol), p-allylpalladium chloride dimer (3.66 mg,
0.0100 mmol), and ligand ent-12 (20.7 mg, 0.0300 mmol) in methylene
chloride (1.00 mL) was added at 08C to sodium benzenesulfinate
(123 mg, 0.750 mmol) and tetrahexylammonium bromide (43.4 mg,
0.100 mmol) in water (1.00 mL). The reaction mixture was stirred at 08C
for 2 h. Flash chromatography (PE/Et2O 1:1) afforded ent-13c as a white
solid (168 mg, 93%). M.p. 163–1668C; [a]D
CHCl3); tr(S)=21.93 min, tr(R)=23.11 min, 77% ee, (Chiralcel OD, l=
230 nm, heptane/iPrOH 9:1).
=
À7.8Æ0.2 (c=1.30,
(E,R)-1-Acetoxy-1-phenylsulfonyl-3-phenyl-2-propene (ent-13a): Follow-
ing the general procedure,
a solution of diacetate 10a (108 mg,
0.462 mmol), p-allylpalladium chloride dimer (3.38 mg, 0.0092 mmol),
and ligand 12 (19.0 mg, 0.028 mmol) in methylene chloride (1.00 mL) was
added at 08C to sodium benzenesulfinate (114.9 mg, 0.700 mmol) and tet-
rahexylammonium bromide (39.14 mg, 0.0920 mmol) in water (1.00 mL).
The reaction mixture was stirred at 08C for 2 h. Flash chromatography
(PE/ethyl acetate 6:1) afforded ent-13a as a white solid (134 mg, 85%).
(E,S)-1-Acetoxy-1-phenylsulfonyl-3-(2-furyl)-2-propene (13d): Following
the general procedure, a solution of furan 10d (112 mg, 0.500 mmol), p-
allylpalladium chloride dimer (3.66 mg, 0.010 mmol), and ligand 12
(20.7 mg, 0.030 mmol) in methylene chloride (1.00 mL) was added at RT
to sodium benzenesulfinate (123 mg, 0.750 mmol) and tetrahexylammoni-
um bromide (43.5 mg, 0.100 mmol) in water (1.00 mL). The reaction mix-
ture was stirred at RT for 24 h. Flash chromatography (PE/Et2O 2:1) af-
M.p. 116.5–1178C; [a]D
12.92 min, tr(R)=15.00 min, 96% ee, (Chiralcel OD, l=230 nm, heptane/
iPrOH 9:1).
=
+20.6Æ0.3 (c=1.10, CHCl3); tr(S)=
forded 13d as a white solid (99 mg, 64%). M.p. 89–89.58C; [a]D
=
À70.9Æ0.1( c=1.05, CHCl3); tr(S)=11.46 min, 100% ee, (Chiralcel OD,
l=230 nm, heptane/iPrOH 9:1); 1H NMR (300 MHz, CDCl3): d = 7.92–
7.89 (m, 2H), 7.68 (dd, J=6.0, 1.2 Hz, 1H), 7.59–7.54 (m, 2H), 7.39 (brs,
1H), 6.57 (d, J=15.0 Hz, 1H), 6.40–6.34 (m, 3H), 6.08 (dd, J=15.0,
7.0 Hz, 1H), 2.07 (s, 3H); 13C NMR (75 MHz, CDCl3): d = 167.9, 150.8,
143.5, 135.6, 134.4, 129.7, 129.0, 126.5, 113.7, 111.7, 111.6, 86.6, 20.5; IR
(film): n˜ = 2927, 1766, 1653, 1325, 1202, 1152, 1012 cmÀ1; HRMS: m/z:
calcd for C13H15O2: 247.0249; found: 247.0427 [M +ÀC2H3O2].
(E,S)-1-Acetoxy-2-methyl-1-phenylsulfonyl-3-phenyl-2-propene
(13b):
Following the general procedure, a solution of diacetate 13b (248 mg,
1.00 mmol), p-allylpalladium chloride dimer (9.10 mg, 0.025 mmol), and
ligand 12 (51.0 mg, 0.075 mmol) in methylene chloride (2.50 mL) was
added at RT to sodium benzenesulfinate (492 mg, 3.00 mmol) and tetra-
methylammonium bromide (30.8 mg, 0.200 mmol) in water (2.50 mL).
The reaction mixture was stirred at RT for 24 h. Flash chromatography
(PE/Et2O 3:1) to afford starting material (161 mg) and product as a
white solid (97 mg, 30%, 85% based on recovered material (brsm)).
Both the IR and 1H NMR characterization data matched known values.
The sign of rotation was opposite to that of 13b; the magnitude of the ro-
tation was similar. M.p. 95–968C; [a]D = +45.7Æ0.1( c=1.06, CHCl3);
tr(S)=15.05 min, tr(R)=19.69 min, 95% ee, (Chiralcel OD, l=230 nm,
heptane/iPrOH 95:5); 1H NMR (300 MHz, CDCl3): d = 7.93–7.89 (m,
2H), 7.70 (t, J=7.4 Hz, 1H), 7.59–7.54 (m, 2H), 7.36–7.19 (m, 5H), 6.48
(s, 1H), 6.24 (s, 1H), 2.12 (s, 3H), 2.09 (s, 3H); 13C NMR (75 MHz,
CDCl3): d = 168.1, 135.9, 135.8, 134.5, 134.4, 129.8, 129.1, 128.3, 127.7,
127.0, 124.8, 124.7, 90.3, 20.4, 15.3; IR (film): n˜ = 2965, 1760, 1586, 1493,
1447, 1323, 1204, 1150, 1058 cmÀ1; elemental analysis calcd (%) for
C18H18O4S: C 65.47, H 5.49; found: C 65.59, H 5.57.
(E,R)-1-Acetoxy-1-phenylsulfonyl-3-(2-furyl)-2-propene (ent-13d): Fol-
lowing the general procedure,
a solution of furan 10d (112 mg,
0.500 mmol), p-allylpalladium chloride dimer (3.66 mg, 0.010 mmol), and
ligand 10 (20.7 mg, 0.030 mmol) in methylene chloride (1.00 mL) was
added at RT to sodium benzenesulfinate (123 mg, 0.750 mmol) and tetra-
hexylammonium bromide (43.5 mg, 0.100 mmol) in water (1.00 mL). The
reaction mixture was stirred at RT for 24 h. Flash chromatography (PE/
Et2O 2:1) afforded ent-13d as a white solid (99 mg, 64%). M.p. 88–898C;
[a]D = +69.6Æ0.1( c=0.81, CHCl3); tr(S)=11.46 min, tr(R)=14.30 min,
97% ee, (Chiralcel OD, l=230 nm, heptane/iPrOH 9:1).
(E,S)-1-Acetoxy-1-phenylsulfonyl-2-hexene (13e): Following the general
procedure, a solution of substrate 10e (100 mg, 0.500 mmol), p-allylpalla-
dium chloride dimer (3.66 mg, 0.0100 mmol), and ligand 12 (20.7 mg,
0.0300 mmol) in methylene chloride (1.00 mL) was added at RT to
sodium benzenesulfinate (123 mg, 0.750 mmol) and tetrahexylammonium
bromide (43.4 mg, 0.100 mmol) in water (1.00 mL). The reaction mixture
was stirred at RT for 4 h. Flash chromatography (PE/Et2O 4:1) afforded
(E,R)-1-Acetoxy-2-methyl-1-phenylsulfonyl-3-phenyl-2-propene
(ent-
13b): Following the general procedure, a solution of diacetate 10b
(248 mg, 1.00 mmol), p-allylpalladium chloride dimer (9.10 mg,
0.025 mmol), and ligand ent-12 (51.0 mg, 0.075 mmol) in methylene chlo-
ride (2.50 mL) was added at RT to sodium benzenesulfinate (492 mg,
3.00 mmol) and tetramethylammonium bromide (30.8 mg, 0.200 mmol) in
water (2.50 mL). The reaction mixture was stirred at RT for 24 h. Flash
chromatography (PE/Et2O 3:1) to afford starting material (93 mg) and
product ent-13b as a white solid (130 mg, 54%, 86% brsm). M.p. 95–
13e as a clear oil (133 mg, 94%). [a]D
=
+20.9Æ0.1( c=1.5, CHCl3);
tr(R)=8.50 min, tr(S)=9.81min, 98% ee, (Chiralcel OD, l=230 nm, hep-
tane/iPrOH 95:5); 1H NMR (300 MHz, CDCl3): d = 7.90 (d, J=8.4 Hz,
2H), 7.72–7.52 (m, 3H), 6.19 (d, J=7.3 Hz, 1H), 6.00 (dt, J=15.5 Hz,
8.4 Hz, 1H), 5.50 (dd, J=15.5, 7.4 Hz, 1H), 2.13–2.02 (m, 5H), 1.44–1.33
(m, 2H), 0.87 (t, J=7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3): d = 168.5,
142.8, 135.9, 129.8, 117.4, 86.6, 34.4, 21.4, 20.4, 13.4; IR (film): n˜ = 2960,
1764, 1659, 1448, 1325, 1205, 1153, 1083 cmÀ1; elemental analysis calcd
(%) for C14H18O4S: C 59.55, H 6.43; found: C 59.65, H 6.62.
968C; [a]D
=
À48.8Æ0.1( c=2.10, CHCl3); tr(S)=14.36 min, tr(R)=
17.88 min, >95% ee, (Chiralcel OD, l=254 nm, heptane/iPrOH 95:5).
(E,S)-1-Acetoxy-1-phenylsulfonyl-3-(2-nitrophenyl)-2-propene (13c): Fol-
lowing the general procedure, a solution of allylic diacetate 10c (140 mg,
0.500 mmol), p-allylpalladium chloride dimer (3.66 mg, 0.0100 mmol),
and ligand 12 (20.7 mg, 0.0300 mmol) in methylene chloride (1.00 mL)
was added at 08C to sodium benzenesulfinate (123 mg, 0.750 mmol) and
tetrahexylammonium bromide (43.4 mg, 0.100 mmol) in water (1.00 mL).
The reaction mixture was stirred at 08C for 2 h. Flash chromatography
(PE/Et2O 1:1) afforded 13c as a white solid (168 mg, 93%). M.p. 162–
(E,R)-1-Acetoxy-1-phenylsulfonyl-2-hexene (ent-13e): Following the
general procedure, a solution of substrate 10e (100 mg, 0.500 mmol), p-
allylpalladium chloride dimer (3.66 mg, 0.0100 mmol), and ligand ent-12
(20.7 mg, 0.0300 mmol) in methylene chloride (1.00 mL) was added at
RT to sodium benzenesulfinate (123 mg, 0.750 mmol) and tetrahexylam-
monium bromide (43.4 mg, 0.100 mmol) in water (1.00 mL). The reaction
mixture was stirred at RT for 4 h. Flash chromatography (PE/Et2O 4:1)
afforded ent-13e as a clear oil (131 mg, 93%). [a]D = À22.9Æ0.2 (c=
1.0, CHCl3); tr(R)=8.10 min, tr(S)=9.71min, 95% ee, (Chiralcel OD, l=
230 nm, heptane/iPrOH 95:5).
1638C; [a]D
=
+8.6Æ0.6 (c=1.30, CHCl3); tr(S)=21.80 min, tr(R)=
23.05 min, 85% ee, (Chiralcel OD, l=230 nm, heptane/iPrOH 9:1).
1H NMR (300 MHz, CDCl3): d = 8.02–7.90 (m, 3H), 7.72–7.49 (m, 6H),
7.25 (d, J=4.5 Hz, 1H), 6.48 (d, 6.9 Hz, 1H), 6.28 (dd, J=9.5, 6.2 Hz,
1H), 2.13 (s, 3H); 13C NMR (75 MHz, CDCl3): d = 167.8, 147.8, 135.5,
134.7, 133.7, 133.5, 131.0, 129.7, 129.6, 129.1, 129.0, 124.8, 121.5, 85.8,
(E,S)-1-Acetoxy-1-phenylsulfonyl-2-nonene (13 f): Following the general
procedure, a solution of alkyl diacetate 10 f (484 mg, 2.00 mmol), p-allyl-
palladium chloride dimer (14.6 mg, 0.040 mmol), and ligand 12 (82.8 mg,
20.2; IR (film): n˜
= 3069, 2926, 1770, 1608, 1524, 1448, 1327, 1202,
Chem. Eur. J. 2006, 12, 2171 – 2187
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2181

B. M. Trost et al.
0.120 mmol) in methylene chloride (5.00 mL) was added at RT to sodium
benzenesulfinate (492 mg, 2.00 mmol) and tetrahexylammonium bromide
(173.8 mg, 0.400 mmol) in water (5.00 mL). The reaction mixture was stir-
red at RT for 6 h. Flash chromatography (PE/Et2O 5:1) afforded 13 f as a
white solid (476 mg, 73%). M.p. 42–43.58C; [a]D = +22.3Æ0.1( c=1.20,
CHCl3); tr(S)=7.69 min, tr(R)=8.87 min, 95% ee, (Chiralcel OD, l=
230 nm, heptane/iPrOH 95:5); 1H NMR (300 MHz, CDCl3): d = 7.91–
7.86 (m, 2H), 7.69–7.52 (m, 3H), 6.18 (d, J=7.3 Hz, 1H), 5.97 (dt, J=
8.8, 7.3 Hz, 1H), 5.50 (dd, J=8.5, 7.3 Hz, 1H), 2.16–20.7 (m, 2H), 2.04 (s,
3H), 1.34–1.26 (m, 8H), 0.85 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d = 168.0, 143.0, 135.7, 134.3, 129.7, 129.0, 117.1, 86.6, 32.4, 31.5,
28.6, 28.1, 22.4, 20.3, 13.9; IR (film): n˜ = 2929, 2857, 1767, 1664, 1448,
1327, 1206, 1154, 1084, 1026 cmÀ1; elemental analysis calcd (%) for
C17H24O4S: C 62.93, H 7.46; found: C 62.93, H 7.45.
1-((E,R)-1’-Acetoxy-1’-phenylsulfonyl)-1-cyclohexene (ent-13h): Follow-
ing the general procedure,
a solution of diacetate 10h (210 mg,
1.00 mmol), p-allylpalladium chloride dimer (9.1mg, 0.025 mmol), and
ligand ent-12 (51.0 mg, 0.075 mmol) in methylene chloride (5.00 mL) was
added at RT to sodium benzenesulfinate (492 mg, 3.00 mmol) and tetra-
hexylammonium bromide (130 mg, 0.300 mmol) in water (5.00 mL). The
reaction mixture was stirred at RT for 24 h. Flash chromatography (PE/
Et2O 4:1) afforded diacetate 10h (131 mg, 62%) and product ent-13h as
a white solid (94 mg, 30%, 80% brsm). M.p. 82–83.58C; [a]D = À41.6Æ
0.2 (c=2.60, CHCl3); tr(S)=6.66 min, tr(R)=6.66 min, 100% ee, (Chiral-
cel OD, l=254 nm, heptane/iPrOH 9:1).
(E,S)-1-Acetoxy-1-phenylsulfonyl-4-(tert-butyldiphenylsilyloxy)-2-butene
(13i): Following the general procedure,
a solution of substrate 10i
(100 mg, 0.230 mmol), p-allylpalladium chloride dimer (1.60 mg,
0.0047 mmol), and ligand 12 (9.7 mg, 0.014 mmol) in methylene chloride
(1.00 mL) was added at 08C to sodium benzenesulfinate (67.3 mg,
0.410 mmol) and tetrahexylammonium bromide (20.3 mg, 0.047 mmol) in
water (1.00 mL). The reaction mixture was stirred at 08C for 2 h. Flash
chromatography (PE/ethyl acetate 10:1) afforded 13i as a clear oil
(E,R)-1-Acetoxy-1-phenylsulfonyl-2-nonene (ent-13 f): Following the
general procedure, a solution of alkyl diacetate 10 f (484 mg, 2.00 mmol),
p-allylpalladium chloride dimer (14.6 mg, 0.040 mmol), and ligand ent-12
(82.8 mg, 0.120 mmol) in methylene chloride (5.00 mL) was added at RT
to sodium benzenesulfinate (492 mg, 2.00 mmol) and tetrahexylammoni-
um bromide (173.8 mg, 0.400 mmol) in water (5.00 mL). The reaction
mixture was stirred at RT for 6 h. Flash chromatography (PE/Et2O 5:1)
afforded ent-13 f as a white solid (476 mg, 73%). M.p. 41.5–42.58C; [a]D
= À16.9Æ0.1( c=1.20, CHCl3); tr(S)=7.70 min, tr(R)=8.85 min, 90% ee,
(Chiralcel OD, l=230 nm, heptane/iPrOH 95:5).
(110 mg, 92%). [a]D
=
+2.7Æ0.1( c=6.00, CHCl3); [a]D
= +3.0 (c=
6.00, CHCl3); tr(S)=7.05 min, tr(R)=7.98 min, 94% ee, (Chiralcel OD,
l=230 nm, heptane/iPrOH 9:1); 1H NMR (300 MHz, CDCl3): d = 7.92–
7.87 (m, 2H), 7.67–7.61(m, 5H), 7.54–7.49 (m, 2H), 7.45–7.38 (m, 6H),
6.32 (d, J=6.3 Hz, 1H), 6.00 (dt, J=15.5, 3.3 Hz, 1H), 5.95–5.91 (m,
1H), 4.21 (brs, 2H), 2.09 (s, 3H), 1.04 (s, 9H); 13C NMR (75 MHz,
CDCl3): d = 168.1, 139.9, 135.7, 135.5, 134.3, 133.1, 133.0, 129.9, 129.8,
129.0, 127.8, 116.6, 86.2, 62.8, 26.6, 20.4, 19.1; IR (CHCl3): n˜ = 1767,
(E,S)-1-Acetoxy-4-methyl-1-phenylsulfonyl-2-pentene (13g): Following
the general procedure, a solution of acetate 10g (100 mg, 0.500 mmol), p-
allylpalladium chloride dimer (3.66 mg, 0.010 mmol), and ligand 12
(20.7 mg, 0.030 mmol) in methylene chloride (1.00 mL) was added at 08C
to sodium benzenesulfinate (123 mg, 0.750 mmol) and tetrahexylammoni-
um bromide (43.4 mg, 0.100 mmol) in water (1.00 mL). The reaction mix-
ture was stirred for 10 h at RT. Flash chromatography (PE/Et2O 3:1) af-
forded 13g as a clear oil (122 mg, 86%). [a]D = À34.0Æ0.1( c=5.00,
CHCl3); tr(S)=7.81min, tr(R)=8.65 min, >99% ee, (Chiralcel OD, l=
1672, 1588, 1327, 1206, 1153, 1113 cmÀ1
; HRMS: m/z: calcd for
C24H23O5SSi: 451.1035; found: 451.1048 [M ++C4H9].
(E,R)-1-Acetoxy-1-phenylsulfonyl-4-(tert-butyldiphenylsilyloxy)-2-butene
(ent-13i): Following the general procedure, a solution of diacetate 10i
(100 mg, 0.230 mmol), p-allylpalladium chloride dimer (1.6o mg,
0.0047 mmol), and ligand ent-12 (9.7 mg, 0.014 mmol) in methylene chlo-
ride (1.00 mL) was added at 08C to sodium benzenesulfinate (67.3 mg,
0.410 mmol) and tetrahexylammonium bromide (20.34 mg, 0.047 mmol)
in water (1.00 mL). The reaction mixture was stirred at RT for 2 h. Flash
chromatography (PE/ethyl acetate 10:1) afforded ent-13i as a clear oil
(108 mg, 91%). [a]D = À2.5Æ0.7 (c=1.05, CHCl3); [a]D = À3.0 (c=
5.93, CHCl3); tr(S)=7.17 min, tr(R)=8.05 min, 94% ee, (Chiralcel OD,
l=230 nm, heptane/iPrOH 9:1).
1
230 nm, heptane/iPrOH 95:5); H NMR (300 MHz, CDCl3): d = 7.87 (d,
J=7.3 Hz, 2H), 7.68–7.66 (m, 1H), 7.55 (d, J=7.3 Hz, 2H), 6.19 (d, J=
7.1Hz, 1H), 5.90 (dd, J=15.6, 5.6 Hz, 1H), 5.45 (dd, J=15.6, 6.9 Hz,
1H), 2.37–2.30 (m, 1H), 2.07 (s, 3H), 0.96 (d, J=6.9 Hz, 6H); 13C NMR
(75 MHz, CDCl3): d = 168.0, 148.8, 135.6, 134.3, 129.7, 128.9, 114.7, 86.5,
31.0, 21.5, 21.3, 20.5; IR (film): n˜ = 2962, 1766, 1662, 1448, 1372, 1326,
1207, 1154, 1084 cmÀ1
; HRMS: m/z: calcd for C12H15O2S: 223.0788;
(E,S)-1-Acetoxy-1-phenylsulfonyl-3-(1’-methoxycyclopentyl)-2-propene
(13l): Following the general procedure, a solution of allylic diacetate 10l
(256 mg, 1.00 mmol), p-allylpalladium chloride dimer (7.32 mg,
0.020 mmol), and ligand 12 (41.4 mg, 0.060 mmol) in methylene chloride
(2.00 mL) was added at RT to sodium benzenesulfinate (246 mg,
1.50 mmol) and tetrahexylammonium bromide (86.8 mg, 0.200 mmol) in
water (2.00 mL). The reaction mixture was stirred at RT for 4 h. Flash
chromatography (PE/Et2O 2:1) afforded starting material (138 mg) and
found: 223.0792 [M ++C2H3O2].
(E,R)-1-Acetoxy-4-methyl-1-phenylsulfonyl-2-pentene (ent-13g): Follow-
ing the general procedure,
a solution of acetate 10g (100 mg,
0.500 mmol), p-allylpalladium chloride dimer (3.66 mg, 0.010 mmol), and
ligand ent-12 (20.7 mg, 0.030 mmol) in methylene chloride (1.00 mL) was
added at 08C to sodium benzenesulfinate (123 mg, 0.750 mmol) and tet-
rahexylammonium bromide (43.4 mg, 0.100 mmol) in water (1.00 mL).
The reaction mixture was stirred for 10 h at RT. Flash chromatography
13l as a clear oil (118 mg, 35%, 76% brsm). [a]D
=
+24.2Æ0.1( c=
(PE/Et2O 3:1) afforded ent-13g as a clear oil (119 mg, 85%). [a]D
=
1.20, CHCl3); tr(S)=11.23 min, tr(R)=12.93 min, 80% ee, (Chiralcel OD,
l=230 nm, heptane/iPrOH 95:5); 1H NMR (300 MHz, CDCl3): d = 7.89
(d, J=7.4 Hz, 2H), 7.69–7.66 (m, 1H), 7.59–7.54 (m, 2H), 6.28 (d, J=
7.4 Hz, 1H), 5.93 (d, J=16.1 Hz, 1H), 5.67 (dd, J=15.9, 6.7 Hz, 1H),
3.05 (s, 3H), 2.09 (s, 3H), 1.85–1.47 (m, 8H); 13C NMR (75 MHz,
CDCl3): d = 168.1, 143.8, 135.7, 134.5, 129.8, 129.1, 117.2, 86.3, 86.2, 51.0,
35.8, 35.6, 23.0, 22.9, 20.4; IR (film): n˜ = 2962, 1768, 1447, 1372, 1326,
+42.6Æ0.1( c=4.00, CHCl3); tr(S)=7.80 min, tr(R)=8.65 min, 97% ee,
(Chiralcel OD, l=230 nm, hepꢂtane/iPrOH 95:5).
1-((E,S)-1’-Acetoxy-1’-phenylsulfonyl)-1-cyclohexene (13h): Following
the general procedure, a solution of diacetate 10h (420 mg, 2.00 mmol),
p-allylpalladium chloride dimer (18.2 mg, 0.050 mmol), and ligand 12
(103 mg, 0.150 mmol) in methylene chloride (5.00 mL) was added at RT
to sodium benzenesulfinate (985 mg, 6.00 mmol) and tetrahexylammoni-
um bromide (261mg, 0.600 mmol) in water (5.00 mL). The reaction mix-
ture was stirred at RT for 24 h. Flash chromatography (PE/Et2O 4:1) af-
forded diacetate 10h (168 mg, 40%) and product 13i as a white solid
1203, 1153, 1081 cmÀ1
; HRMS: m/z: calcd for C15H19O3S: 279.1058;
found: 279.1053 [M ++C2H3O2].
(E,R)-1-Acetoxy-1-phenylsulfonyl-3-(1’-methoxycyclopentyl)-2-propene
(ent-13l): Following the general procedure, a solution of allylic diacetate
10l (128 mg, 0.50 mmol), p-allylpalladium chloride dimer (3.60 mg,
0.010 mmol), and ligand ent-12 (41.4 mg, 0.060 mmol) in methylene chlo-
ride (2.00 mL) was added at RT to sodium benzenesulfinate (123 mg,
0.750 mmol) and tetrahexylammonium bromide (43 mg, 0.100 mmol) in
water (1.00 mL). The reaction mixture was stirred at RT for 4 h. Flash
chromatography (PE/Et2O 2:1) afforded starting material (68 mg, 53%)
and a clear oil ent-13l (57 mg, 34%, 80% brsm). The sign of rotation was
(291mg, 51%, 85% brsm). M.p. 82.5–83.5 8C; [a]D
=
+48.5Æ0.4 (c=
0.750, CHCl3); tr(S)=6.66 min, 100% ee, (Chiralcel OD, l=254 nm, hep-
tane/iPrOH 9:1); 1H NMR (300 MHz, CDCl3): d = 7.88 (d, J=7.0 Hz,
2H), 7.69–7.52 (m, 3H), 6.03 (s, 1H), 5.84 (s, 1H), 2.14–2.03 (m, 2H),
2.03–2.00 (m, 5H), 1.65–1.58 (m, 4H); 13C NMR (75 MHz, CDCl3): d =
168.1, 136.1, 134.2, 133.6, 129.6, 128.9, 127.6, 89.0, 25.3, 22.1, 21.5, 20.4;
IR (film): n˜ = 2965, 1762, 1445, 1323, 1213, 1153, 1083 cmÀ1; HRMS:
m/z: calcd for C15H18O4: 295.0976; found: 295.1000 [M ++H].
opposite to that of 13l and the magnitude of rotation was similar. [a]D
=
2182
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 2171 – 2187

Asymmetric Synthesis
FULL PAPER
À24.6Æ0.2 (c=1.20, CHCl3); tr(S)=11.47 min, tr(R)=13.02 min, 80% ee,
(Chiralcel OD, l=230 nm, heptane/iPrOH 95:5).
poured into ethyl acetate and the organic phase was washed with 1n
aqueous sodium bisulfite solution. The organic phase was dried over
magnesium sulfate and concentrated in vacuo. The residue was purified
by flash chromatography.
(S,S)-2,2-Dimethyl-4-(3’-acetoxy-3’-phenylsulfonyl-1’(E)-propenyl)-1,3-di-
oxolane (13j): Following the general procedure, a solution of diacetate
10j (103 mg, 0.400 mmol), p-allylpalladium chloride dimer (2.92 mg,
0.0040 mmol), and ligand 12 (16.6 mg, 0.024 mmol) in methylene chloride
(2.00 mL) was added at 08C to sodium benzenesulfinate (98.4 mg,
0.400 mmol) and tetrahexylammonium bromide (34.8 mg, 0.080 mmol) in
water (2.00 mL). The reaction mixture was stirred at 08C for 4 h. Flash
chromatography (PE/Et2O 1:1) afforded 13j as a white solid (107 mg,
(1S,2R,3S)-1-Acetoxy-1-phenylsulfonyl-3-phenyl-2,3-propandiol
(14a):
Following the general procedure, a-acetoxysulfone ent-13a (40 mg,
0.126 mmol), 4% aqueous osmium tetroxide solution (40 mL, 1.60 mg,
0.0063 mmol), and NMO (44.4 mg, 0.379 mmol) in methylene chloride
(1.50 mL) were stirred at 0–58C for 12 h. Flash chromatography (PE/
ethyl acetate 3:1) afforded product ent-14a as a white solid (29.0 mg,
66%). 1H NMR indicated the product was a single diastereomer. M.p.
1
79%). H NMR indicated a diastereomeric ratio >20:1in favor of “ anti”
134–136 (decomp); [a]D
=
+57.3Æ0.2 (c=1.14, CHCl3); 1H NMR
based on separated peaks for the acetate methyl protons (major peak
2.09 ppm, minor peak 2.06 ppm). M.p. 110–1118C; [a]D
=
+69.9Æ0.2
(200 MHz, CDCl3): d = 7.93–7.90 (m, 2H), 7.68–7.66 (m, 1H), 7.59–7.54
(m, 2H), 7.36–7.29 (m, 5H), 5.97 (d, J=8.5 Hz, 1H), 4.77 (brs, 1H),
4.36–4.35 (m, 1H), 3.15 (d, J=5.3 Hz, 1H), 2.77 (d, J=6.4 Hz, 1H), 1.96
(c=3.10, CHCl3); 1H NMR (300 MHz, CDCl3): d = 7.89 (d, J=7.8 Hz,
2H), 7.71–7.53 (m, 3H), 6.30 (d, J=3.2 Hz, 1H), 5.91–5.87 (m, 2H),
4.55–4.50 (m, 1H), 4.07 (dd, J=9.2, 8.2 Hz, 1H), 3.50 (dd, J=9.1, 8.5 Hz,
1H), 2.09 (s, 3H), 1.39 (s, 3H), 1.37 (s, 3H); 13C NMR (75 MHz, CDCl3):
d = 167.8, 137.6, 135.4, 134.5, 129.8, 129.1, 120.0, 110.0, 85.3, 75.2, 68.9,
26.4, 25.6, 20.3; IR (film): n˜ = 2986, 1768, 1448, 1372, 1326, 1205, 1153,
1060 cmÀ1; HRMS: m/z: calcd for C12H12O4: 325.0752; found: 325.0733
[M +ÀCH3].
(s, 3H); 13C NMR (50 MHz, CDCl3): d
= 167.8, 139.8, 137.0, 134.6,
129.4, 129.3, 128.7, 128.6, 128.2, 126.3, 84.8, 72.5, 20.1; IR (film): n˜
=
3490, 3064, 3030, 2935, 1777, 1448, 1372, 1309, 1210, 1151, 1049 cmÀ1; ele-
mental analysis calcd (%) for: C 58.27, H 5.18; found: C 58.36, H 5.30.
(1R,2S,3R)-1-Acetoxy-1-phenylsulfonyl-3-phenyl-2,3-propandiol
(ent-
14a): Method A: Following the general procedure, acetoxysulfone 13a
(40.0 mg, 0.1264 mmol), 4% aqueous osmium tetroxide solution (40 mL,
1.60 mg, 0.0063 mmol), NMO (44.4 mg, 0.379 mmol), DABCO (0.86 mg,
0.0076 mmol), and tert-butanol (one drop) were stirred in methylene
chloride (1.50 mL) at 0–58C for 24 h. Flash chromatography (PE/ethyl
acetate 3:1) afforded product ent-14a as a white solid (34.0 mg, 77%).
1H NMR indicated the product was a single diastereomer. M.p. 134–
(S,S+R)-2,2-Dimethyl-4-(3’-acetoxy-3’-phenylsulfonyl-1’(E)-propenyl)-
1,3-dioxolane (ent-13j): Following the general procedure, a solution of di-
acetate 10j (51.6 mg, 0.200 mmol), p-allylpalladium chloride dimer
(1.46 mg, 0.0040 mmol), and ligand ent-12 (8.3 mg, 0.012 mmol) in meth-
ylene chloride (1.00 mL) was added at 08C to sodium benzenesulfinate
(49.2 mg, 0.200 mmol) and tetrahexylammonium bromide (17.4 mg,
0.040 mmol) in water (1.00 mL). The reaction mixture was stirred at 08C
for 4 h. Flash chromatography (PE/Et2O 1:1) afforded ent-13j as a clear
oil (59 mg, 86%). 1H NMR indicated a diastereomeric ratio of 2:1in
favor of “anti” on separated peaks for the acetate protons. Minor adduct:
[a]D = +53.9Æ0.1( c=4.80, CHCl3); 1H NMR (300 MHz, CDCl3): d =
7.89 (d, J=7.8 Hz, 2H), 7.71–7.53 (m, 3H), 6.30 (d, J=3.2 Hz, 1H), 5.91–
5.87 (m, 2H), 4.55–4.50 (m, 1H), 4.07 (dd, J=9.2, 8.2 Hz, 1H), 3.50 (dd,
J=9.1, 8.5 Hz, 1H), 2.06 (s, 3H), 1.39 (s, 3H), 1.37 (s, 3H); IR (film):
1368C; [a]D
=
À58.3Æ0.1( c=1.12, CHCl3); 1H NMR (300 MHz,
CDCl3): d = 7.93–7.90 (m, 2H), 7.68–7.66 (m, 1H), 7.59–7.54 (m, 2H),
7.36–7.29 (m, 5H), 5.97 (d, J=8.5 Hz, 1H), 4.77 (brs, 1H), 4.36–4.35 (m,
1H), 3.15 (d, J=5.3 Hz, 1H), 2.77 (d, J=6.4 Hz, 1H), 1.96 (s, 3H); IR
(film): n˜ = 3490, 3064, 3030, 2935, 1777, 1448, 1372, 1309, 1210, 1151,
1049 cmÀ1
.
Method 2: Following the general procedure, acetoxysulfone 13 (40.0 mg,
0.1264 mmol), 4% aqueous osmium tetroxide solution (40 mL, 1.60 mg,
0.0063 mmol), and NMO (44.4 mg, 0.379 mmol) were stirred in methyl-
ene chloride (1.50 mL) at 0–58C for 24 h. Flash chromatography (PE/
ethyl acetate 3:1) afforded product ent-14a as a white solid (35.0 mg,
n˜ = 2987, 1768, 1448, 1372, 1326, 1205, 1154, 1060 cmÀ1
.
(E,S)-Ethyl 4-acetoxy-3-methyl-4-phenylsulfonylcrotonate (13k): Follow-
ing the general procedure, a solution of allylic diacetate 10k (134 mg,
0.500 mmol), p-allylpalladium chloride dimer (3.66 mg, 0.0100 mmol),
and ligand 12 (20.7 mg, 0.0300 mmol) in methylene chloride (1.00 mL)
was added at RT to sodium benzenesulfinate (123 mg, 0.750 mmol) and
tetrahexylammonium bromide (43.4 mg, 0.100 mmol) in water (1.00 mL).
The reaction mixture was stirred for 12 h at 08C. Flash chromatography
(PE/Et2O 2:1) afforded starting diacetate 10k (163 mg, 40%) and prod-
uct 13k as a clear oil (252 mg, 51%, 85% brsm). [a]D = +68.1Æ0.1( c=
1.20, CHCl3); tr(S)=8.08 min, tr(R)=11.17 min, 98% ee, (Chiralcel OD,
1
78%). H NMR indicated the product was a single diastereomer.
(1S,2R,3S)-1-Acetoxy-2-methyl-1-phenylsulfonyl-3-phenyl-2,3-propandiol
(14b): Following the general procedure, acetoxysulfone 13b (33.0 mg,
0.100 mmol), 4% aqueous osmium tetroxide solution (30 mL, 1.20 mg,
0.0050 mmol), and NMO (35.1mg, 0.300 mmol) in methylene chloride
(1.00 mL) were stirred at 0–58C for 12 h. Flash chromatography (PE/
ethyl acetate 3:1) afforded product 14b as a colorless stick oil (20.6 mg,
57%). 1H NMR indicated the product was a single diastereomer. [a]D
=
l=254 nm, heptane/iPrOH 90:10); 1H NMR (300 MHz, CDCl3): d
=
1
+80.1Æ0.2 (c=0.610, CHCl3); H NMR (200 MHz, CDCl3): d = 7.98 (d,
J=7.2 Hz, 2H), 7.66–7.58 (m, 3H), 7.39–7.33 (m, 5H), 6.16 (s, 1H), 4.57
(d, J=5.5 Hz, 1H), 3.59 (s, 1H), 2.81 (d, J=5.5 Hz, 1H), 2.01 (s, 3H),
1.29 (s, 3H); 13C NMR (50 MHz, CDCl3): d = 196.9, 168.2, 134.4, 129.2,
129.1, 128.4, 128.2, 128.1, 86.4, 76.3, 68.7, 28.8, 20.1, 19.3. IR (film): n˜ =
3498, 2938, 1766, 1448, 1371, 1309, 1202, 1149, 1050 cmÀ1; HRMS: m/z:
calcd for C18H20O6S: 347.0981; found: 347.0955 [M +ÀOH].
7.89 (d, J=7.5 Hz, 2H), 7.71–7.55 (m, 3H), 6.13 (s, 1H), 5.87 (s, 1H),
4.16 (q, J=7.1Hz, 2H), 2.31 (s, 3H), 2.07 (s, 3H), 1.27 (t, J=7.2 Hz,
3H); 13C NMR (75 MHz, CDCl3): d = 167.6, 165.0, 144.7, 134.6, 129.6,
129.4, 129.1, 123.5, 88.7, 60.3, 20.3, 16.6, 14.1; IR (film): n˜ = 2984, 1771,
1719, 1652, 1448, 1372, 1329, 1202, 1158, 1065 cmÀ1; HRMS: m/z: calcd
for C13H15O4: 267.0691; found: 267.0686 [M +ÀC2H3O2].
(E,R)-Ethyl-4-acetoxy-3-methyl-4-phenylsulfonylcrotonate
(ent-13k):
Following the general procedure, a solution of allylic diacetate 10k
(134 mg, 0.500 mmol), p-allylpalladium chloride dimer (3.66 mg,
0.0100 mmol), and ligand ent-12 (20.7 mg, 0.0300 mmol) in methylene
chloride (1.00 mL) was added at RT to sodium benzenesulfinate (123 mg,
0.750 mmol) and tetrahexylammonium bromide (43.4 mg, 0.100 mmol) in
water (1.00 mL). The reaction mixture was stirred for 12 h at 08C. Flash
chromatography (PE/Et2O 2:1) afforded starting diacetate 10k (160 mg,
38%) and product ent-13k as a clear oil (251mg, 50%, 83% brsm). [ a]D
(1S,2R,3S)-1-Acetoxy-1-phenylsulfonyl-3-(2-nitrophenyl)-2,3-propandiol
(14c): Following the general procedure, acetoxysulfone 13c (72.3 mg,
0.200 mmol), 4% aqueous osmium tetroxide solution (63 mL, 2.54 mg,
0.010 mmol), and NMO (70.3 mg, 0.600 mmol) in methylene chloride
(2.00 mL) were stirred at 0–58C (cold room) for 12 h. Flash chromatogra-
phy (PE/Et2O 1:3) afforded product 14c as a white solid (64.0 mg, 81%).
1H NMR indicated the product was a single diastereomer. M.p. 94–
95.58C; [a]D
=
+31.0Æ0.2 (c=1.00, CH3OH); 1H NMR (200 MHz,
=
+69.1Æ0.1( c=1.20, CHCl3); tr(S)=8.07 min, tr(R)=11.13 min, 98%
CD3OD): d = 7.88–7.81(m, 4H), 7.62–7.40 (m, 5H), 5.96 (d, J=9.4 Hz,
1H), 5.16 (s, 1H), 4.21 (d, J=9.5 Hz, 1H), 2.01 (s, 3H); 13C NMR
(50 MHz, CD3OD): d = 169.7, 149.0, 139.0, 138.5, 135.4, 134.0, 132.1,
130.6, 130.3, 129.4, 125.2, 86.9, 72.2, 68.6, 20.2; IR (film): n˜ = 3489, 2925,
1776, 1610, 1525, 1344, 1200, 1151, 1052 cmÀ1; HRMS: m/z: calcd for
C11H12NO6: 254.0664; found: 254.0651[ M +ÀC6H5SO2].
ee, (Chiralcel OD, l=254 nm, heptane/iPrOH 90:10).
General procedure for osmium catalyzed diastereoselective dihydroxyla-
tions: a-Acetoxysulfone, 4% aqueous osmium tetroxide solution, and N-
methylmorpholine-N-oxide (NMO) were stirred at 0–58C for 24 h. In
some cases DABCO and tert-butanol were added. The crude mixture was
Chem. Eur. J. 2006, 12, 2171 – 2187
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2183

B. M. Trost et al.
(1S,2R,3S)-1-Acetoxy-1-phenylsulfonyl-2,3-hexandiol (14e): Following
the general procedure, acetoxysulfone 13e (282 mg, 1.00 mmol), 4%
aqueous osmium tetroxide solution (318 mL, 12.7 mg, 0.050 mmol), and
NMO (352 mg, 3.00 mmol) in methylene chloride (5.00 mL) were stirred
at 0–58C (cold room) for 5 h. Flash chromatography (PE/Et2O 1:3) af-
forded product 14e as a white solid (194 mg, 61%). The diastereomeric
red at 0–58C for 12 h. Flash chromatography (PE/ethyl acetate 3:1) af-
forded product ent-14i as a colorless oil (27.4 mg, 71%). The diastereo-
meric ratio was 11:1 as determined by 1H NMR integration by compari-
son of the acetate protons (major d 2.04, minor 2.10 ppm).
(1S,2R,3S)-1-Acetoxy-1-phenylsulfonyl-4-(tert-butyldiphenylsilyloxy)-2,3-
butandiol (14i): Following the general procedure, acetoxysulfone 13i
(36.0 mg, 0.0707 mmol), 4% aqueous osmium tetroxide solution (22 mL,
0.915 mg, 0.0036 mmol), and NMO (26.0 mg, 0.220 mmol) in methylene
chloride (1.00 mL) were stirred at 0–58C for 24 h. Flash chromatography
(PE/ethyl acetate 3:1) afforded product 14i as a colorless oil (31.0 mg,
81%). The diastereomeric ratio was 18:1 as determined as determined by
1H NMR integration by comparison of the acetate protons (major d 2.04,
1
ratio was >95:5 as determined by H NMR integration by comparison of
the acetate protons (major d 2.03, minor 2.09 ppm). M.p. 88–898C; [a]D
= +20.5Æ0.2 (c=2.50, CHCl3); 1H NMR (300 MHz, CDCl3): d = 7.93
(d, J=8.1Hz, 2H), 7.72–7.56 (m, 3H), 5.93 (d, J=8.8 Hz, 1H), 4.09–4.02
(m, 1H), 3.59–3.56 (m, 1H), 3.36–3.28 (m, 1H), 2.15–2.07 (m, 1H), 2.03
(s, 3H), 1.76–1.31 (m, 4H), 0.92 (t, J=7.4 Hz, 3H); 13C NMR (50 MHz,
CDCl3): d = 167.9, 136.6, 134.5, 129.3, 129.2, 84.8, 70.4, 69.7, 35.5, 20.2,
18.9, 13.9; IR (film): n˜ = 3503, 2960, 1738, 1448, 1372, 1310, 1202, 1153,
1048 cmÀ1; elemental analysis calcd (%) for C14H20O6S: C 53.15, H 6.37;
found: C 53.27, H, 6.50.
minor 2.10 ppm). [a]D
(200 MHz, CDCl3): d
=
+20.9Æ0.4 (c=1.60, CHCl3); 1H NMR
=
7.94 (d, J=8.1Hz, 2H), 7.90–7.54 (m, 7H),
7.47–7.39 (m, 6H), 5.94 (d, J=8.8 Hz, 1H), 4.26 (dd, J=8.8, 5.9 Hz, 1H),
3.78–3.69 (m, 3H), 3.06 (d, J=5.9 Hz, 1H), 2.45 (d, J=6.3 Hz, 1H), 2.04
(s, 3H), 1.04 (s, 9H); IR (film): n˜ = 3510, 1776, 1428, 1310, 1202, 1152,
1113, 1053 cmÀ1; HRMS: m/z: calcd for C22H22O5SSi: 425.0642; found:
425.0879 [M +ÀC4H9ÀC2H3O2].
(1’R,2’R,3’S,4S)-2,2-Dimethyl-4-(3’-acetoxy-1’,2’-dihydroxy-3’-phenylsul-
fonyl-1’-propan)-1,3-dioxolane (14j): Following the general procedure,
acetoxysulfone 13j (170 mg, 0.500 mmol), 4% aqueous osmium tetroxide
solution (159 mL, 6.36 mg, 0.025 mmol) and NMO (176 mg, 1.50 mmol) in
methylene chloride (5.00 mL) were stirred at 0–58C for 12 h. Flash chro-
matography (PE/Et2O 1:3) afforded product 14j as a white solid (158 mg,
85%). The diastereomeric ratio was >6:1), as determined by 1H NMR
integration by comparison of the acetate protons, (major acetate peak d
2.02, minor acetate peak 2.11 ppm) favoring the typical “anti” product
(1S,2R,3S)-1-Acetoxy-1-phenylsulfonyl-2,3-nonandiol (14 f): Following
the general procedure, acetoxysulfone 13 f (32.4 mg, 0.100 mmol), 4%
aqueous osmium tetroxide solution (32 mL, 1.27 mg, 0.005 mmol), and
NMO (35.1mg, 0.300 mmol) in methylene chloride (1.00 mL) were stir-
red at 0–58C (cold room) for 12 h. Flash chromatography (PE/ethyl ace-
tate 1:1) afforded product 14 f as a white glass (30.2 mg, 84%). 1H NMR
indicated the product was a single diastereomer. M.p. 72–738C; [a]D
=
+30.7Æ0.2 (c=1.80, CHCl3); 1H NMR (200 MHz, CDCl3): d = 7.97–
7.92 (m, 2H), 7.74–7.54 (m, 3H), 5.93 (d, J=8.8 Hz, 1H), 4.12–4.03 (m,
1H), 3.60–3.57 (m, 1H), 3.20 (d, J=5.7 Hz, 1H), 2.03 (s, 3H), 1.94 (d, J=
8.8 Hz, 1H), 1.64–1.55 (m, 2H), 1.47–1.22 (m, 8H), 0.85 (t, J=6.8 Hz,
3H); 13C NMR (50 MHz, CDCl3): d = 167.9, 136.7, 134.6, 129.4, 129.3,
84.8, 70.4, 70.0, 33.5, 31.6, 29.1, 25.6, 22.5, 20.1, 14.0; IR (film): n˜ = 3497,
2929, 2858, 1779, 1448, 1373, 1310, 1203, 1153, 1051 cmÀ1; elemental anal-
ysis calcd (%) for C17H26O6S: C 57.00, H 7.31; found: C 57.22, H 7.50.
(1st cmpd.). M.p. 146–1488C; [a]D
=
+30.5Æ0.1( c=1.00, CH2Cl2);
1H NMR (200 MHz, CDCl3): d = 7.92 (d, J=7.0 Hz, 2H), 7.71–7.55 (m,
3H), 5.88 (d, J=8.7 Hz, 1H), 4.27–4.04 (m, 3H), 3.81 (dd, J=8.7, 7.0 Hz,
1H), 3.55–3.48 (m, 1H), 3.17 (d, J=5.2 Hz, 1H), 2.59 (d, J=7.7 Hz, 1H),
[2.11 (s, 0.43H), 2.02 (s, 2.58H)], 1.38 (s, 3H), 1.33 (s, 3H); 13C NMR
(50 MHz, CDCl3): d = 168.2, 137.8, 134.8, 129.8, 129.5, 110.4, 84.8, 77.6,
70.8, 69.4, 66.3, 26.5, 25.3, 20.3; IR (film): n˜ = 3490, 2397, 1778, 1448,
1373, 1310, 1203, 1153, 1063 cmÀ1; HRMS: m/z: calcd for C15H19O8S:
359.0801; found: 359.0792 [M +ÀCH3].
(1R,2S,3R)-1-Acetoxy-4-methyl-1-phenylsulfonyl-2,3-pentandiol
(ent-
14g): Following the general procedure, acetoxysulfone ent-13g (84.7 mg,
0.300 mmol), 4% aqueous osmium tetroxide solution (95 mL, 3.81mg,
0.015 mmol), and NMO (105 mg, 0.900 mmol) in methylene chloride
(3.00 mL) were stirred at 0–58C for 4 h. Flash chromatography (PE/Et2O
1:2) afforded product ent-14g as a white solid (76 mg, 81%). 1H NMR in-
dicated the product was a single diastereomer. M.p. 121–1228C; [a]D
=
1
(2R,3R)-Ethyl
2-acetoxy-3-hydroxy-3-methyl-4-oxodihydrocrotonate
À143.7Æ0.1( c=2.00, CHCl3); H NMR (300 MHz, CDCl3): d = 7.94 (d,
J=8.3 Hz, 2H), 7.72–7.67 (m, 1H), 7.60–7.55 (m, 2H), 5.94 (d, J=8.8 Hz,
1H), 4.31–4.27 (m, 1H), 3.31 (d, J=6.3 Hz, 1H), 3.16–3.10 (m, 1H), 2.22
(d, J=8.6 Hz, 1H), 2.01 (s, 3H), 1.92–1.85 (m, 1H), 1.00 (d, J=6.6 Hz,
3H), 0.91(d, J=6.6 Hz, 3H); 13C NMR (50 MHz, CDCl3): d = 167.9,
136.7, 134.5, 129.3, 129.2, 85.0, 75.3, 68.4, 30.6, 20.2, 19.2, 18.8; IR (film):
(14k): Following the general procedure, acetoxysulfone 13k (32.6 mg,
0.100 mmol), 4% aqueous osmium tetroxide solution (32 mL, 1.27 mg,
0.005 mmol) and NMO (35.1mg, 0.300 mmol) in methylene chloride
(1.00 mL) were stirred at 0–58C (cold room) for 12 h. Flash chromatogra-
phy (PE/Et2O 1:3) afforded product 14k as a clear oil (20.4 mg, 94%).
1H NMR indicated the product was
a single diastereomer. [a]D =
n˜ = 3613, 3354, 2966, 1781, 1473, 1450, 1370, 1302, 1194, 1150, 1045 cmÀ1
;
+11.6Æ0.2 (c=1.80, CHCl3); 1H NMR (300 MHz, CDCl3): d = 9.60 (s,
1H), 5.16 (s, 1H), 4.26 (q, J=6.0 Hz, 2H), 3.59 (s, 1H), 2.15 (s, 3H), 1.44
(s, 3H), 1.29 (t, J=6.1Hz, 3H); 13C NMR (50 MHz, CDCl3): d = 199.4,
169.6, 167.1, 74.9, 62.1, 52.0, 20.3, 19.3, 13.9; IR (film): n˜ = 3462, 2918,
1734, 1447, 1373, 1200, 1063 cmÀ1; HRMS: m/z: calcd for C9H15O6:
219.0798; found: 219.0868 [M ++H].
HRMS: m/z: calcd for C11H13O6S: 273.0433; found: 273.0435 [M +
ÀC3H7].
(1R,2S,3R)-1-Acetoxy-1-phenylsulfonyl-4-(tert-butyldiphenylsilyloxy)-
2,3-butandiol (ent-14i): Following the general procedure, acetoxysulfone
ent-13i (36.0 mg, 0.0707 mmol), 4% aqueous osmium tetroxide solution
(44 mL, 0.0071mmol), and NMO (26.0 mg, 0.2200 mmol) in methylene
chloride (1.00 mL) were stirred at 0–58C for 12 h. Flash chromatography
(PE/ethyl acetate 3:1) afforded product ent-14i as a colorless sticky oil
(31.5 mg, 82%). The diastereomeric ratio was 12.5:1 as determined as de-
termined by 1H NMR integration by comparison of the acetate protons
(major d 2.04, minor 2.10 ppm). [a]D = À20.6Æ0.4 (c=1.20, CHCl3);
1H NMR (200 MHz, CDCl3): d = 7.94 (d, J=8.1Hz, 2H), 7.90–7.54 (m,
7H), 7.47–7.39 (m, 6H), 5.94 (d, J=8.8 Hz, 1H), 4.26 (dd, J=8.8, 5.9 Hz,
1H), 3.78–3.69 (m, 3H), 3.06 (d, J=5.9 Hz, 1H), 2.45 (d, J=6.3 Hz, 1H),
2.04 (s, 3H), 1.04 (s, 9H); 13C NMR (50 MHz, CDCl3): d = 167.9, 136.9,
135.6, 135.5, 134.5, 132.7, 130.0, 129.5, 127.9, 84.5, 69.5, 68.4, 64.6, 26.7,
(4S,5R)-4-((1’R)-1’-Acetoxy-1’-phenylsulfonylmethyl)-2,2-dimethyl-5-
phenyl-1,3-dioxolane (17a): Diol ent-14a (170 mg, 0.485 mmol), 2,2-dime-
thoxypropane (2,2-DMP) (5.00 mL), acetone (5.00 mL), and PPTS (one
crystal) were mixed at RT and stirred for 24 h. The mixture was poured
into diethyl ether (20 mL), washed with 10% aqueous sodium bicarbon-
ate solution (20 mL), the organic phase dried over sodium sulfate, and
concentrated in vacuo. Flash chromatography (PE/Et2O 2:1) afforded
product 17a as a white solid (174 mg, 92%). 1H NMR indicated adduct
was a single diastereomer. M.p. 61–628C; [a]D = À13.6Æ0.1( c=2.00,
1
CHCl3); H NMR (300 MHz, CDCl3): d = 7.91(d, J=7.4 Hz, 2H), 7.67–
20.2, 19.0; IR (film): n˜
= 3510, 1776, 1428, 1310, 1202, 1152, 1113,
7.64 (m, 1H), 7.56–7.51 (m, 2H), 7.35–7.26 (m, 5H), 5.97 (d, J=8.0 Hz,
1H), 4.87 (d, J=7.6 Hz, 1H), 4.41–4.35 (m, 1H), 1.81 (s, 3H), 1.51 (s,
3H), 1.33 (s, 3H); 13C NMR (75 MHz, CDCl3): d = 168.0, 136.9, 136.8,
134.3, 129.6, 128.9, 128.8, 128.5, 127.2, 111.1, 84.9, 81.5, 78.7, 27.1, 26.3,
1053 cmÀ1
; HRMS: m/z: calcd for C22H22O5SSi: 425.0642; found:
425.0879 [M +ÀC4H9ÀC2H3O2].
Method B: Following the general procedure, acetoxysulfone ent-13i
(36.0 mg, 0.0707 mmol), 4% aqueous osmium tetroxide solution (44 mL,
0.0071mmol), DABCO (0.53 mg, 0.0047 mmol) tert-butanol (1drop), and
NMO (26.0 mg, 0.2200 mmol) in methylene chloride (1.00 mL) were stir-
20.3; IR (CHCl3): n˜
= 2988, 1772, 1448, 1373, 1328, 1198, 1155,
1057 cmÀ1; HRMS: m/z: calcd for C19H19O6S: 375.0896; found: 375.0920
[M +ÀCH3].
2184
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 2171 – 2187

Asymmetric Synthesis
FULL PAPER
(4R,5S)-4-((1’S)-1’-Acetoxy-1’-phenylsulfonylmethyl)-2,2-dimethyl-5-
phenyl-1,3-dioxolane (ent-17a): Diol ent-14a (170 mg, 0.485 mmol), 2,2-
DMP (5.00 mL), acetone (5.00 mL), and PPTS (one crystal) were mixed
at RT and stirred for 24 h. The mixture was poured into diethyl ether
(20 mL), washed with 10% aqueous sodium bicarbonate solution
(20 mL), the organic phase dried over sodium sulfate, and concentrated
in vacuo. Flash chromatography (PE/Et2O 2:1) afforded product 17a as a
white solid (176 mg, 93%). 1H NMR indicated adduct was a single dia-
À788C. The solution was allowed to warm to RT overnight with stirring.
The mixture was washed with 5% aqueous ammonium chloride solution
(10 mL), diluted with methylene chloride (20 mL), the organic phase
dried over sodium sulfate, and concentrated in vacuo. Flash chromatogra-
phy (PE/Et2O 1:1) afforded product as
a clear oil (12 mg, 58%).
1H NMR and optical rotation matched literature values.[26] [a]D
=
À22.1Æ0.3 (c=0.300, CHCl3); lit.:[26] [a]D
=
À19.5Æ0.3 (c=3.10,
CH2Cl2); 1H NMR (200 MHz, CDCl3): d = 7.41–7.32 (m, 5H), 4.92 (d,
J=8.5 Hz, 1H), 3.91–3.84 (m, 2H), 3.68–3.64 (m, 1H), 1.95–1.89 (m,
1H), 1.59 (s, 3H), 1.53 (s, 3H); IR (CHCl3): n˜ = 3451, 1605, 1372, 1240,
stereomer. M.p. 60–628C; [a]D
=
+14.5Æ0.1( c=2.00, CHCl3);
1H NMR (300 MHz, CDCl3): d = 7.91(d, J=7.4 Hz, 2H), 7.67–7.64 (m,
1H), 7.56–7.51 (m, 2H), 7.35–7.26 (m, 5H), 5.97 (d, J=8.0 Hz, 1H), 4.87
(d, J=7.6 Hz, 1H), 4.41–4.35 (m, 1H), 1.81 (s, 3H), 1.51 (s, 3H), 1.33 (s,
1056 cmÀ1
.
(3S,4S)-2,2-Dimethyl-4-(hydroxymethyl)-3-phenyl-1,3-dioxolane
(18):
3H); IR (CHCl3): n˜
1057 cmÀ1
= 2988, 1772, 1448, 1373, 1328, 1198, 1155,
DIBAL-H (1.0m in hexanes, 0.50 mL, 0.500 mmol) was added to a solu-
tion of acetal 17a (39.0 mg, 0.100 mmol) in THF (1 mL) at À788C. The
solution was allowed to warm to RT overnight with stirring. The mixture
was washed with 5% aqueous ammonium chloride solution (10 mL), di-
luted with methylene chloride (10 mL), the organic phase dried over
sodium sulfate, and concentrated in vacuo. Flash chromatography (PE/
Et2O 1:1) afforded product 18 as a clear oil (17 mg, 84%). 1H NMR and
.
(4S,5R)-4-((1’R)-1’-Acetoxy-1’-phenylsulfonylmethyl)-5-phenyl-2,2,4-tri-
methyl-1,3-dioxolane (17b): A 4% aqueous solution of osmium tetroxide
(0.12 mL, 0.0462 mmol) was added to a solution of substrate ent-13b
(305 mg, 0.923 mmol) and N-methylmorpholine-N-oxide (324 mg,
2.77 mmol) in methylene chloride (5.00 mL). The solution was stirred for
16 h at 08C. The organic layer was separated, the organic phase dried
over sodium sulfate, and treated with 2,2-dimethoxypropane (1.00 mL)
and 2 crystals of toluenesulfonic acid monohydrate. The solution was stir-
red for 8 h at RT. Flash chromatography (PE/Et2O 2:1) afforded aceto-
optical rotation matched literature values.[26] [a]D
=
+23.5Æ0.2 (c=
1.50, CHCl3); lit.:[26] [a]D
(300 MHz, CDCl3): d
=
+19.4Æ0.2 (c=3.00, CH2Cl2); 1H NMR
=
7.42–7.30 (m, 5H), 4.92 (d, J=8.5 Hz, 1H),
3.91–3.84 (m, 2H), 3.68–3.62 (m, 1H), 1.87 (brs, 1H), 1.60 (s, 3H), 1.54
(s, 3H); 13C NMR (50 MHz, CDCl3): d
137.6, 128.6, 128.3, 126.5,
109.3, 83.5, 78.6, 60.3, 27.2, 27.1; IR (CHCl3): n˜ = 3460, 2986, 2933, 1495,
1455, 1372, 1240, 1166, 1082, 1056 cmÀ1
nide 17b as a colorless oil (303 mg, 81%). [a]D
=
+0.8Æ0.1( c=2.60,
=
CHCl3); 1H NMR (500 MHz, CDCl3): d = 8.01(dd, J=6.4, 2.0 Hz, 2H),
7.68–7.66 (m, 1H), 7.59–7.56 (m, 2H), 7.36–7.32 (m, 5H), 5.76 (s, 1H),
5.31 (s, 1H), 2.04 (s, 3H), 1.55 (s, 3H), 1.16 (s, 3H), 1.13 (s, 3H);
13C NMR (125 MHz, CDCl3): d = 168.6, 138.8, 135.2, 134.0, 129.5, 128.9,
128.5, 128.2, 126.8, 109.0, 87.6, 84.0, 83.1, 28.3, 25.7, 20.4, 18.6; IR (film):
.
(4S,5R)-4-Formyl-5-phenyl-2,2,4-trimethyl-1,3-dioxolane (19): Acetoxy-
sulfone 17b (81mg, 0.200 mmol) and potassium carbonate (55.3 mg,
0.400 mmol) were stirred in methanol (1.00 mL) for 4 h at RT. The mix-
ture was filtered, concentrated in vacuo, diluted with methylene chloride
(5.0 mL) and water (5.0 mL), the organic layer separated, the organic
phase dried over magnesium sulfate, and concentrated in vacuo. Flash
chromatography (PE/Et2O 3:1) afforded aldehyde 19 as a colorless oil
(41mg, 93%). [ a]D = À82.7Æ0.3 (c=1.3, CHCl3); 1H NMR (500 MHz,
CDCl3): d = 9.82 (s, 1H), 7.37–7.31 (m, 5H), 5.30 (s, 1H), 1.67 (s, 3H),
1.52 (s, 3H), 0.86 (s, 3H); 13C NMR (125 MHz, CDCl3): d = 202.2, 135.4,
128.3, 128.1, 126.3, 109.6, 86.7, 78.9, 27.8, 26.0, 18.1; IR (film): n˜ = 2989,
2936, 1735, 1496, 1456, 1376, 1249, 1220, 1181, 1053, 995 cmÀ1; HRMS:
m/z: calcd for C12H15O2: 191.1073; found: 191.1067 [M +ÀCHO].
n˜
= ;
2990, 2937, 1764, 1602, 1448, 1375, 1326, 1203, 1153, 1055 cmÀ1
HRMS: m/z: calcd for C18H16O6S: 389.1059; found: 389.1065 [M +ÀCH3].
4R,5S)-4-((1’S)-1’-Acetoxy-1’-phenylsulfonylmethyl)-2,2-dimethyl-5-
propyl-1,3-dioxolane (17c): Diol 14c (63.3 mg, 0.200 mmol), 2,2-dime-
thoxypropane (2.00 mL), acetone (2.00 mL), and pyridinium p-toluene-
sulfonate (one crystal) were mixed at RT and stirred for 24 h. The mix-
ture was poured into diethyl ether (20 mL), washed with 10% aqueous
sodium bicarbonate solution (10 mL), the organic phase dried over
sodium sulfate, and concentrated in vacuo. Flash chromatography (PE/
Et2O 2:1) afforded acetonide 17c as a white solid (67.5 mg, 95%).
1H NMR indicated the product was a single diastereomer. M.p. 67–
(4R,5S)-2,2-Dimethyl-4-((1’R)-1’-hydroxyethyl)-5-phenyl-1,3-dioxolane
(22)—General procedure: Acetal 17a (39.0 mg, 0.100 mmol) in diethyl
ether (1.00 mL) was added at the stated temperature under argon to an
diethyl ether solution of methyl magnesium bromide (0.200 mL, 71.7 mg,
0.600 mmol) and additive (see Table 8). After stirring at the state temper-
ature for 1h, the mixture was allowed to warm to RT and diluted with di-
ethyl ether (10 mL). The mixture was then quenched with 10% aqueous
ammonium chloride solution (10 mL), the organic phase dried over
sodium sulfate, and concentrated in vacuo. Flash chromatography (PE/
Et2O 2:1) afforded alcohol 35 as a clear gel. [a]D = À36.0Æ0.3 (c=1.00,
CHCl3); 1H NMR (200 MHz, CDCl3): d = 7.45–7.30 (m, 5H), 4.91(dd,
J=12.4, 11.2 Hz, 1H), 4.06–3.69 (m, 2H), 2.16–2.10 (m, 1H), 1.58 (s,
3H), 1.51 (s, 3H), [1.14 (d, J=6.4 Hz, 1.3H), 1.08 (d, J=6.4 Hz, 1.8H)
68.58C; [a]D
=
À13.3Æ0.1( c=2.00, CHCl3); 1H NMR (200 MHz,
CDCl3): d = 7.93 (d, J=7.4 Hz, 2H), 7.70–7.65 (m, 1H), 7.59–7.54 (m,
2H), 5.90 (d, J=6.6 Hz, 1H), 4.25 (dd, J=6.6, 6.4 Hz, 1H), 4.10–4.04 (m,
1H), 2.07 (s, 3H), 1.71–1.40 (m, 6H), 1.37 (s, 3H), 1.16 (s, 3H), 0.94 (t,
J=7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3): d
= 168.0, 137.0, 134.4,
129.5, 110.1, 84.9, 78.2, 76.6, 36.1, 27.4, 26.5, 20.2, 19.0, 13.9; IR (CHCl3):
n˜ = 2968, 1756, 1450, 1380, 1316, 1215, 1168, 1062 cmÀ1; HRMS: m/z:
calcd for C17H24O6S: 341.1065; found: 341.1051 [M +ÀCH3].
(4S,5R)-4-((1’R)-1’-Acetoxy-1’-phenylsulfonylmethyl)-2,2-dimethyl-5-iso-
propyl-1,3-dioxolane (17d): Diol 14d (31.6 mg, 0.100 mmol), 2,2-dime-
thoxypropane (1.00 mL), acetone (1.00 mL), and pyridinium p-toluene-
sulfonate (one crystal) were mixed at RT and stirred for 24 h. The mix-
ture was poured into diethyl ether (20 mL), washed with 5% aqueous
sodium bicarbonate solution (20 mL), the organic phase dried over
sodium sulfate, and concentrated in vacuo. Flash chromatography (PE/
Et2O 2:1) afforded acetonide 17d as a clear oil (29 mg, 83%). 1H NMR
indicated the product was a single diastereomer. [a]D = +19.4Æ0.3 (c=
1.00, CHCl3); 1H NMR (300 MHz, CDCl3): d = 7.94 (d, J=7.1Hz, 2H),
7.67–7.64 (m, 1H), 7.56–7.53 (m, 2H), 7.35–7.26 (m, 5H), 5.85 (d, J=
8.1Hz, 1H), 4.42–4.38 (m, 1H), 3.75 (dd, J=5.6, 2.1Hz, 1H), 2.08 (s,
3H), 1.86–1.82 (m, 1H), 1.35 (s, 3H), 1.06 (s, 3H), 0.96–0.93 (m, 6H);
13C NMR (75 MHz, CDCl3): d = 168.1, 137.5, 134.3, 129.6, 129.0, 110.7,
85.4, 75.4, 31.1, 27.5, 26.8, 20.3, 19.4, 17.1; IR (CHCl3): n˜ = 2964, 1774,
1471, 1448, 1372, 1328, 1199, 1156, 1055 cmÀ1; elemental analysis calcd
(%) for C17H26O6S: C 57.29, H 6.79; found: C 57.22, H 6.91.
together 3H)]; 13C NMR (75 MHz, CDCl3): d
127.6, 127.0, 97.8, 86.7, 86.0, 79.5, 78.8, 66.7, 65.6, 27.2, 27.0, 18.2; IR
= 139.7, 128.6, 128.4,
(CHCl3): n˜
= ;
3468, 2985, 1604, 1456, 1372, 1239, 1169, 1060 cmÀ1
HRMS: m/z: calcd for C13H18O3: 222.1256; found: 222.1251 [M +].
Table 8. Additions of methyl magnesium bromide to acetal 17a.
Entry T [8C] Additive (wt./mg) Amount [mg]/% Yield dr (syn:
anti)[a]
1
2
3
0
none
CuBr (71.7)
MgCl2 (9.5)
19.3/87
19.6/88
18.7/84
1.5:1.0
1.5:1.0
1.5:1.0
À78
À78
(3R,4R)-2,2-Dimethyl-4-(hydroxymethyl)-3-phenyl-1,3-dioxolane
DIBAL-H (1.0m in hexanes, 0.300 mL, 42 mg, 0.300 mmol) was added to
a solution of acetal 17a (39.0 mg, 0.100 mmol) in hexanes (1 mL) at
(18):
[a] The dr was determined by proton NMR integration of the methyl
proton doublets (d 1.14, J=6.4 Hz, minor peak, d 1.08, J=6.4 Hz, major
peak).
Chem. Eur. J. 2006, 12, 2171 – 2187
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2185

B. M. Trost et al.
(4S,5R)-2,2-Dimethyl-4-((1’R)-1’-hydroxypropyl)-5-phenyl-1,3-dioxolane
(22): Acetal 17a (39.0 mg, 0.100 mmol) in diethyl ether (1.00 mL) was
added at À788C under argon to an 1.0m diethyl ether solution of ethyl-
magnesium bromide (0.600 mL, 80 mg, 0.600 mmol). After stirring for
1h, the mixture was allowed to warm to RT and diluted with diethyl
ether (20 mL). The mixture was then quenched with 10% aqueous am-
monium chloride solution (20 mL), the organic phase dried over sodium
sulfate, and concentrated in vacuo. Flash chromatography (PE/Et2O 2:1)
afforded alcohol 22 as a clear gel (17.5 mg, 74%). The product was a 2:1
mixture of diastereomers as determined by 1H NMR integration of the
methyl protons (triplet) of the ethyl group (d = 0.91, J=7 Hz, minor
peak, d = 0.85, J=6.8 Hz, major peak). [a]D = À14.2Æ0.1( c=1.00,
128.9, 128.3, 127.9, 127.1, 85.6, 76.1, 73.9, 73.0, 28.7, 20.3; IR (CHCl3): n˜
= 3511, 2974, 1774, 1448, 1370, 1310, 1201, 1152, 1054 cmÀ1; HRMS: m/z:
calcd for C17H17O5S (M+- C4H9O): 333.0791; found: 333.0796.
127.1, 85.6, 76.1, 73.9, 73.0, 28.7, 20.3; HRMS: m/z: calcd for C17H17O5S:
333.0791; found: 333.0796 [M +ÀC4H9O].
(2S,3R)-2-Hydroxy-2-methyl-3-acetoxy-3-phenylpropanal (ent-16b):
A
4% aqueous osmium tetroxide solution (31 mL, 0.005 mmol) was added
at 08C to a solution of substrate ent-14b (33.0 mg, 0.100 mmol) and
NMO (35.1 mg, 0.300 mmol) in methylene chloride (1.00 mL). After 12 h
at 08C 4-dimethylaminopyridine (12.2 mg, 0.100 mmol) was added and
the solution was stirred for 6 h at RT. Flash chromatography (PE/Et2O
1:1) afforded aldehyde ent-16b as a colorless oil (20.5 mg, 92%). [a]D
=
1
À4.6Æ0.1( c=1.3, CHCl3); 1H NMR (500 MHz, CDCl3): d = 9.68 (s,
1H), 7.41–7.36 (m, 5H), 5.90 (s, 1H), 3.36 (s, 1H), 2.08 (s, 3H), 1.22 (s,
3H); 13C NMR (125 MHz, CDCl3): d = 201.3, 169.6, 134.4, 128.8, 128.2,
79.6, 76.9, 20.9, 19.6; IR (film): n˜ = 3488, 2935, 1736, 1496, 1456, 1373,
1234, 1107, 1026, 926 cmÀ1; HRMS: m/z: calcd for C12H14O4: 223.0970;
found: 223.0968 [M ++H].
CHCl3); H NMR (200 MHz, CDCl3): d = 7.44–7.36 (m, 10H), 5.00–4.96
(m, 1H), 3.99–3.93 (m, 1H), 3.82–3.76 (m, 1H), 2.07 (d, J=2.4 Hz, 1H),
1.58 (s, 3H), 1.56 (s, 3H), 1.45–1.33 (m, 2H), [0.91 (t, J=7.1Hz, 1H)
(minor), 0.85 (t, J=6.8 Hz, 1H) (major)]; 13C NMR (75 MHz, CDCl3): d
= 138.5, 128.7, 128.6, 128.4, 127.8, 126.9, 108.9, 85.3, 85.3, 85.1, 79.4, 78.7,
72.3, 70.2, 28.2, 27.3, 27, 25.5, 10.1; IR (CHCl3): n˜ = 3461, 2984, 2934,
1457, 1371, 1236, 1168, 1062 cmÀ1; HRMS: m/z: calcd for C13H17O3:
221.1181; found: 221.1183 [M +ÀCH3].
(4S,5R)-2,2-Dimethyl-4-((1’R)-1’-hydroxy-1’-phenyl)-5-phenyl-1,3-dioxo-
lane (23): Acetal 17a (58.5 mg, 0.150 mmol) in diethyl ether (2.00 mL)
was added at À788C under argon to an diethyl ether solution of phenyl-
magnesium bromide (0.90 mL, 163 mg, 0.900 mmol). After stirring for
1h, the mixture was allowed to warm to RT and diluted with diethyl
ether (20 mL). The mixture was then quenched with 10% aqueous am-
monium chloride solution (20 mL), the organic phase dried over sodium
sulfate, and concentrated in vacuo. Flash chromatography (PE/Et2O 2:1)
afforded alcohol 23 as a clear gel (28 mg, 66%). 1H NMR indicated that
Acknowledgements
We thank the National Institutes of Health (GM-13598) and the National
Science Foundation for their generous support of our programs. Mass
spectra were provided by the Mass Spectrometry Regional Center of the
University of California, San Francisco supported by the NIH Division of
Research Resources.
the product was a single diastereomer. [a]D
=
À0.83Æ0.1( c=1.00,
CHCl3); 1H NMR (300 MHz, CDCl3): d = 7.38–7.16 (m, 10H), 4.96 (d,
J=8.3 Hz, 1H), 4.68 (dd, J=7.0, 3.8 Hz, 1H), 4.12 (dd, J=8.3, 3.9 Hz,
1H), 2.77 (d, J=7.1Hz, 1H), 1.57 (s, 6H); 13C NMR (75 MHz, CDCl3): d
= 140.5, 137.8, 128.5, 128.2, 128.1, 126.9, 126.8, 121.1, 109.9, 86.5, 79.8,
72.6, 27.3, 27.1; IR (CHCl3): n˜ = 3451, 2986, 2917, 1604, 1495, 1454,
1380, 1238, 1164, 1052 cmÀ1; HRMS: m/z: calcd for C17H17O3: 269.1178;
found: 269.1168 [M +ÀCH3].
[1] For a recent discussion on AAA reactions in synthesis see: B. M.
Trost, Chem. Pharm. Bull. 2002, 50, 1 .
[2] For recent reviews see: a) B. M. Trost, M. L. Crawley, Chem. Rev.
2003, 103, 2921; b) B. M. Trost, C. B. Lee, “Catalytic Asymmetric
Synthesis” (Ed.: I. Ojima), 2nd ed., Wiley-VCH, New York, 2000,
Chapter 8E, pp. 503–650; c) B. M. Trost, D. L. Van Vranken, Chem.
Rev. 1996, 96, 395.
(4S,5R)-2,2-Dimethyl-4-((1’R)-1’-hydroxy-1’-phenyl)-5-isopropyl-1,3-diox-
olane (24): Acetal 17c (17.8 mg, 0.050 mmol) in diethyl ether (1.00 mL)
was added at À788C under argon to an diethyl ether solution of PhMgBr
(0.300 mL, 54.5 mg, 0.300 mmol). After stirring for 1h, the mixture was
allowed to warm to RT and diluted with diethyl ether (10 mL). The mix-
ture was then quenched with 10% aqueous ammonium chloride solution
(10 mL), the organic phase dried over sodium sulfate, and concentrated
in vacuo. Flash chromatography (PE/Et2O 2:1) afforded alcohol 24 as a
clear gel (10.2 mg, 82%). 1H NMR confirmed the product was a single di-
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K. M. Hasegawa, H. Yamamoto, J. Am. Chem. Soc. 1984, 106, 5004;
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7247.
astereomer. [a]D
=
+49.9Æ0.4 (c=0.25, CHCl3); 1H NMR (200 MHz,
CDCl3): d = 7.37–7.32 (m, 5H), 4.59 (dd, J=5.5, 5.2 Hz, 1H), 3.97 (dd,
J=6.2, 6.1Hz, 1H), 3.73 (dd, J=6.1, 5.6 Hz, 1H), 2.90 (d, J=4.6 Hz,
1H), 1.49 (s, 3H), 1.42 (s, 3H), 0.85 (d, J=6.4 Hz, 3H), 0.69 (d, J=
6.1Hz, 3H); 13C NMR (50 MHz, CDCl3): d = 140.5, 128.5, 128.2, 126.9,
109.4, 83.2, 83.0, 75.2, 30.6, 27.7, 19.2, 17.2; IR (CHCl3): n˜ = 3457, 2962,
1605, 1451, 1370, 1243, 1166, 1039 cmÀ1; HRMS: m/z: calcd for C14H19O3:
235.1330; found: 235.1328 [M +ÀCH3].
(1R,2S,3R)-1-Acetoxy-3-tert-butylhydroxy-1-phenylsulfonyl-3-phenyl-2-
propanol (25): Trimethylaluminum (2.0m in toluene, 0.300 mL, 43.2 mg,
0.600 mmol) was added at 08C to a degassed solution of trifluorometh-
anesulfonic acid (135.0 mg, 0.900 mmol). After the reaction mixture was
stirred for 20 min, a solution of acetal 17a (39.0 mg, 0.100 mmol) in tolu-
ene (0.50 mL) was added at 08C and the solution was stirred for 1h. The
mixture was washed with water (25 mL), diluted with methylene chloride
(20 mL), the organic phase dried over sodium sulfate, and concentrated
in vacuo. Flash chromatography (PE/Et2O 2:1) afforded the unexpected
product 25 as a clear oil (22 mg, 48%). [a]D
=
À54.5Æ0.7 (c=0.70,
1
CHCl3); H NMR (200 MHz, CDCl3): d = 7.92 (d, J=5.8 Hz, 2H), 7.65–
7.60 (m, 3H), 7.34–7.26 (m, 5H), 5.81(d, J=7.3 Hz, 1H), 4.66 (d, J=
3.5 Hz, 1H), 4.00 (m, 1H), 2.86 (d, J=7.1Hz, 1H), 2.05 (s, 3H), 1.06 (s,
9H); 13C NMR (50 MHz, CDCl3): d = 168.2, 141.4, 139.7, 134.0, 129.6,
2186
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Chem. Eur. J. 2006, 12, 2171 – 2187

Asymmetric Synthesis
FULL PAPER
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Received: July 29, 2005
Published online: January 10, 2006
Chem. Eur. J. 2006, 12, 2171 – 2187
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2187