Dinuclear zinc-catalyzed asymmetric desymmetrization of acyclic 2-substituted-1,3-propanediols: A powerful entry into chiral building blocks

Article abstract of DOI:10.1002/chem.200800623

The asymmetric acylation of meso-2-substituted-1,3-propanediols by using an amphoteric chiral dinuclear zinc catalyst is described. It is has been demonstrated that both 2-alkyl- and 2-aryl-1,3-propanediols can be desymmetrized in high yields and enantioselectivities by using the same family of ligands. Given that both antipodes of the chiral catalyst are available, both enantiomers of the desymmetrized product can be obtained from the same starting material. The synthetic utility of the desymmetrized products has been demonstrated by the synthesis of several chiral building blocks with high enantiomeric purities.

Full text of DOI:10.1002/chem.200800623

DOI: 10.1002/chem.200800623
Dinuclear Zinc-Catalyzed Asymmetric Desymmetrization of Acyclic 2-
Substituted-1,3-Propanediols: A Powerful Entry into Chiral Building Blocks
Barry M. Trost,* Sushant Malhotra, Takashi Mino, and Naomi S. Rajapaksa[a]
Abstract: The asymmetric acylation of meso-2-substituted-1,3-propanediols by
using an amphoteric chiral dinuclear zinc catalyst is described. It is has been dem-
onstrated that both 2-alkyl- and 2-aryl-1,3-propanediols can be desymmetrized in
high yields and enantioselectivities by using the same family of ligands. Given that
both antipodes of the chiral catalyst are available, both enantiomers of the desym-
metrized product can be obtained from the same starting material. The synthetic
utility of the desymmetrized products has been demonstrated by the synthesis of
several chiral building blocks with high enantiomeric purities.
Keywords: asymmetric catalysis
chiral building blocks · desymmetri-
zation enantioselectivity
propanediol
·
·
·
Introduction
Differentiation of the enantiotopic alcohols in 2-substitut-
ed-1,3-propanediols is inherently difficult because the pro-
The ability to differentiate between two enantiotopic groups
of a symmetrical molecule is a powerful strategy for the syn-
thesis of chiral compounds. One such method, the asymmet-
ric desymmetrization through the enantiotopic acylation of
meso-1,3-diols, stands out as a versatile entry into a wide
range of chiral building blocks (Scheme 1). Although several
G
Scheme 1. Asymmetric desymmetrization of meso-1,3-propanediols.
efforts toward the desymmetrization of such diols have been
described,[1] there remains a need for a general process that
desymmetrizes a wide range of acyclic 2-substituted-1,3-pro-
panediols, particularly for cases in which either enantiomer
is accessible simply by reversing the chirality of the catalyst.
[a] Prof. B. M. Trost, S. Malhotra, T. Mino, N. S. Rajapaksa
Department of Chemistry, Stanford University
Stanford, California 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://dx.doi.org/10.1002/chem.200800623.
7648
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 7648 – 7657

FULL PAPER
Scheme 2. Mechanism for racemization of A to ent-A.
Scheme 3. Generation of the desymmetrization catalysts 1a and 2a.
ing material by simply reversing the chirality of the desym-
metrizing element.[10]
Fukumoto and co-workers developed the first synthetic
method to obtain desymmetrized 2-substituted-1,3-propane-
diols in high enantiomeric purity by employing chiral auxil-
iaries.[11,12] Oriyama and co-workers developed the first non-
enzymatic catalytic desymmetrization using a proline-de-
rived diamine to desymmetrize meso-2-alkyl-1,3-propane
diols.[13] In this reaction, the meso compound is first convert-
ed to the racemic monoacetate, which then undergoes a ki-
netic resolution to afford the desymmetrized products (21–
33% yields) along with a significant amount of the diester
(50–67%). Inspired by the discovery that a chiral amine can
be transiently acylated to generate a chiral acylating agent,
Fujimoto and co-workers developed a quinidine-based bi-
functional organocatalyst that can desymmetrize cyclic 1,3-
diols; however, only racemic products are obtained with
acyclic systems.[14]
Harada and co-workers developed a chiral oxazaborolidi-
none-catalyzed ring cleavage of 1,3-dioxane acetals as an
entry into desymmetrized meso-1,3-diols.[15] This process
provided several desymmetrized products containing mono-
substituted 2-aryl-1,3-propanediols in excellent enantioselec-
tivities (85–92% ee; ee=enatiomeric excess); however,
when this method was applied to 2-alkyl-1,3-propanediols,
lowered enantioselectivities were observed (56–67% ee).
More recently, Miller and co-workers have developed a
peptide-based catalyst that desymmetrizes glycerol deriva-
tives in high enantioselectivities (86–97% ee) and modest
yields (27–56% ee).[16] Nagao and co-workers have used a
chiral sulfonamide zinc catalyst that is effective at desymme-
trizing N-Boc-2-amino-2-alkyl-1,3-propanediols to provide
chiral tertiary amines with high conversions (70–92%) and
reasonable enantiomeric purity (70–88% ee).[17] Analogous-
ly, Kang and co-workers have developed a copper-based
system that catalyzes the asymmetric acylation of 2-substi-
tuted glycerols to give chiral tertiary alcohols in excellent
yields (85–98%) and enantioselectivities (80–94% ee).[18]
Given the disadvantages of enzymatic desymmetrizations
and the current limitations of synthetic catalysts, we set out
to develop a general method that permits the synthesis of a
range of chiral 2-monosubstituted alkyl, aryl, and alkoxy
1,3-propanediols. The underlying motivation for initially
taking on this challenge lay in our finding that a dinuclear
zinc catalyst derived from phenols 1 or 2 and Et2Zn can acti-
vate carbonyl groups by providing a chiral environment with
a basic zinc–alkoxide species and a Lewis acidic zinc–alkyl
species that is highly amphoteric in nature (Scheme 3).[19]
We have previously reported the effectiveness of catalyst
2a in desymmetrizing several 2-aryl-1,3-propanediols, 2-
methyl-1,3-propanediol, and cis-1,2-bis(hydroxymethyl)-
cyclohexane.[20] Despite promising results, improvements
were necessary to enhance the substrate scope of 2-alkyl-
1,3-propanediols and the enantioselectivities of 2-aryl-1,3-
propanediols that had previously proven to be problematic.
Further, we wished to demonstrate that chiral building
blocks with applications in complex molecule synthesis
could be rapidly generated from the desymmetrized prod-
ucts. Our goal was thus to develop a process that 1) affords
products in high enantioselectivities in which the yields re-
flect a true desymmetrization event (theoretical yield of
100%); 2) is practical, experimentally simple, and robust;
and 3) utilizes a commercially available ligand and acylating
agent. Herein we describe our work on the desymmetriza-
tion of a wide range of meso-2-monosubstituted alkyl, aryl,
and alkoxy 1,3-propanediols.
Results and Discussion
It has been shown that a desymmetrized 2-methyl-1,3-pro-
panediol structural motif can be accessed from commercially
available methyl (S)-(+)-3-hydroxy-2-methylpropionate
(Roche Ester).[10] To demonstrate our method as a general
entry into other 2-substituted-1,3-propanediols we chose to
optimize our desymmetrization protocol on the next sim-
plest diol, 2-ethyl-1,3-propanediol (3; Scheme 4), the ester
Scheme 4. Catalytic asymmetric desymmetrization study outline.
analogue of which is not commercially available. Further-
more, the enzymatic desymmetrization of diol 3 has proven
to be problematic.[7] For our initial studies, vinyl benzoate
was the electrophile of choice, as the byproduct (acetalde-
hyde) cannot participate in the reverse reaction. Further, it
has been observed that the acyl transfer that led to product
racemization is slower in the benzoyl, relative to the acetyl
derivatives (Scheme 2, R=Ph vs. R=CH3).[22]
Chem. Eur. J. 2008, 14, 7648 – 7657
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7649

B. M. Trost et al.
To examine the solvent dependence of the reaction, the
desymmetrization of 1,3-propanediol 3 was attempted by
using 5 mol% catalyst 1a and vinyl benzoate as the electro-
phile at 38C. These experiments (Table 1) show that toluene
Table 1. The influence of solvent on the asymmetric benzoylation of 3.
Figure 1. Enantioselectivity vs. time for the asymmetric desymmetrization
of 3 at ꢀ208C and 38C.
Entry
Solvent
Yield [%]
ee [%]
1
2
3
4
CH3CN
CH2Cl2
THF
66
89
80
96
73
77
80
81
mental effects on both the yield and the enantioselectivity
(Scheme 6).
To alter the electronic nature of the benzoyl donor
moiety, electrophiles 7–11 were synthesized by means of a
PhCH3
gave a combination of both the
best yields and enantioselectivi-
ties.[23]
The influence of the tempera-
ture and the reaction time was
investigated next. A tempera-
ture of ꢀ208C gave the highest
yield and the greatest enantio-
Scheme 5. Synthesis of alkenyl benzoates 5 and 6.
selectivity (Table 2). Lowering the temperature below
ꢀ208C had little effect on the enantioselectivity, but the iso-
lated yield was significantly less due to low reaction conver-
Table 2. The influence of temperature on the asymmetric desymmetriza-
tion of 3.
Scheme 6. Influence of electrophiles 5 and 6 on the asymmetric desym-
metrization of 3.
Pd-catalyzed trans-vinylation reaction of vinyl acetate with
the appropriate carboxylic acids (Scheme 7).[25] O-Methoxy
vinylbenzoate 7 was synthesized to determine if incorporat-
Entry
T [8C]
Yield [%]
ee [%]
1
2
3
4
ꢀ30
ꢀ20
3
29
84
93
60
85
86
81
65
RT
Scheme 7. Synthesis of alkenyl benzoates 7–11.
sion. We also found that the enantiomeric ratio remains con-
stant during the course of the reaction and that catalyst 1a
does not promote the intramolecular benzoyl transfer at
ꢀ208C and 38C (Figure 1).
ing a group capable of coordinating to the catalyst would in-
fluence the enantioselectivity.
To study the influence of the structure of the electrophile
on the enantioselectivity of the reaction, we began by re-
placing the vinyl group with other alkenyl groups. Electro-
philes 5 and 6 were synthesized from 1-hexyne and benzoic
acid by using a ruthenium-catalyzed addition of the corre-
sponding carboxylic acids to alkynes (Scheme 5).[23] When
the asymmetric desymmetrization reaction was conducted
with such electrophiles, these structural changes had detri-
Replacing vinyl benzoate with electrophiles 7 and 8 af-
forded esters 12 and 13, respectively, in slightly higher enan-
tioselectivities (Table 3). When electrophiles 9 and 11 were
employed in the desymmetrization of 1,3-propanediol 3 to
afford the desymmetrized products 14 and 16, respectively,
lower enantioselectivities were observed. Unfortunately,
electrophile 10 failed to give any desired desymmetrized
product 15. Given that only a negligible improvement was
7650
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 7648 – 7657

Asymmetric Catalysis
FULL PAPER
lyst 1a.[20] This was, however, not the case for the 2-alkyl-
1,3-propanediols 3 and 17 (Table 5). Both catalysts give simi-
lar enantioselectivities for diol 3 (Table 5, entries 1 and 2).
Table 3. The influence of electrophiles 7–11 on the desymmetrization of
3.[a]
Table 5. The influence of catalyst on the asymmetric desymmetrization
of 3 and 17.
Entry
R
Electrophile/
Product
T [8C]
Yield [%]
ee [%]
1
2
3
4
5
6
7
o-C6H4OCH3
o-C6H4OCH3
p-C6H4OCH3
p-C6H4OCH3
p-C6H4Br
7/12
7/12
8/13
8/13
9/14
3
RT
3
RT
3
3
ꢀ20
88
94
88
90
28
0
82
72
83
76
68
Entry
R
Substrate/
Product
Catalyst
t [h]
Yield [%]
ee [%]
1
2
3
4
CH2CH3
CH2CH3
CH3
3/4
3/4
17/18
17/18
1a
2a
1a
2a
24
24
24
20
86
66
88
89
86
86
90
82
p-C6H4NO2
2-furyl
10/15
11/16
NA
68
82
CH3
[a] All reactions were run in toluene at the specified temperature using
0.31 mmol of 3 for 24 h with [3]=0.125m and [1a]=0.006m.
achieved with electrophiles 7 and 8, we continued our stud-
ies using commercially available vinyl benzoate.
Interestingly, higher enantioselectivities were obtained for 2-
methyl-1,3-propanediol (17) by using catalyst 1a (Table 5,
entries 3 and 4). Given that there was no advantage to
switching to 2a, we continued our studies with the catalyst
derived from the commercially available ligand 1 and Et2Zn.
The studies outlined above demonstrate that the asym-
metric desymmetrization of diol 3 can be achieved in im-
pressive yields and in high enantiomeric selectivities when
run with catalyst 1a in toluene at ꢀ208C for 24 h
(Scheme 8). Although other vinyl benzoates may be
Concentrations of both diol 3 and catalyst 1a were also
optimized. To understand the influence of the concentration
of catalyst 1a, we maintained the concentration of the diol
at 0.125m and tested various catalyst concentrations (en-
tries 1, 2, 4, and 5 in Table 4). Decreasing the catalyst load-
Table 4. Influence of concentration of 3 and 1a on the asymmetric de-
symmetrization of 3.
Entry
Catalyst [%]
[3][a]
[1a][a]
t [h]
Yield [%]
ee [%]
1
2
3
4
5
6
2.5
5
2.5
7.5
10
0.125
0.125
0.25
0.125
0.125
0.25
0.002
0.006
0.006
0.009
0.012
0.012
24
24
72
24
24
24
26
84
51
70
53
55
81
86
75
84
84
87
Scheme 8. Summary of optimized conditions for asymmetric desymmetri-
zations of diol 3.
10
employed, we determined that commercially available vinyl
benzoate gave comparable results to o- and p-methoxy-sub-
stituted vinyl benzoates. Further, it was determined that a
catalyst loading of 5 mol% with concentrations of 0.125m in
diol and 0.006m in catalyst were optimal. Having these con-
ditions in hand the next step was to determine if the opti-
mized conditions were suitable for the desymmetrization of
other 2-substituted-1,3-propanediols that contain functional-
ity that could be further elaborated.
ing to 2.5% reduced yields dramatically, though no change
in enantiomeric excess was observed (entry 1 in Table 4). In-
creasing the catalyst loading past 5 mol% (entries 4–6 in
Table 4) resulted in no improvement in the enantioselectivi-
ty and reduced the yields for the transformation. As a
result, a catalyst loading of 5 mol% was, to this point, the
upper threshold for the desymmetrization process.
Given that a catalyst concentration of 0.006m was opti-
mal, we initiated experiments to lower the catalyst loading
by maintaining [1a]=0.006m and doubling the concentration
of diol 3. Unfortunately, this resulted in both lowered yields
and enantioselectivities (entry 3 in Table 4).
We have previously reported that catalyst 2a gives an in-
crease in the enantioselectivity for the asymmetric desym-
metrization of 2-phenyl-1,3-propanediol compared to cata-
The desymmetrization of meso-2-alkyl and meso-2-alkoxy-
1,3-propanediols: The optimized conditions shown in
Scheme 5 were applied to a range of meso-2-alkyl and meso-
2-alkoxy-1,3-propanediols that can serve as synthetically
useful precursors. The optimized conditions proved to be a
general and robust method to enantioselectively desymme-
trize 2-alkyl-1,3-propanediols with high yields and enantio-
selectivities (Table 6). For example, the desymmetrization of
Chem. Eur. J. 2008, 14, 7648 – 7657
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7651

B. M. Trost et al.
Table 6. The desymmetrization of 2-alkyl-1,3-propanediols and 2-alkoxy-
1,3-propanediols.[a]
(Table 7, entry 1 and 2). Similar to observations made with
diol 3, lowering the temperature for reactions with meso-2-
phenyl-1,3-propanediol 29 from room temperature to
Table 7. The desymmetrization of 2-aryl-1,3-propanediols.[a]
Entry
R
Substrate/
Product
Yield [%]
ee [%]
1
2
3
4
5
6
7
R=CH3
17/18
3/4
88
86
84
90
90
86
84
80
90
40
60
R=CH2CH3
R=CH2CHCH2
R=CH2CCH
R=Bn
R=OBn
R=OTIPS
19/20
21/22
23/24
25/26
27/28
85
36
22(54)[b]
Entry Substrate/Product Mol% cat. T [oC] Yield [%] ee [%]
[a] All reactions conducted using optimized conditions shown in
Scheme 8. [b] Yield based on recovered starting material.
1
2
3
4
5
6
7
8
9
29/30
29/30
29/30
31/32
33/34
35/36
37/38
39/40
39/40
41/42
43/44
45/46
5% 1a
5% 2a
5% 2a
5% 2a
5% 2a
RT
RT
85
98
94
94
99
89
83
74
83
91
91
93
ꢀ15
ꢀ15
ꢀ15
ꢀ15
ꢀ15
ꢀ20
ꢀ20
ꢀ15
ꢀ15
ꢀ15
substrate 17 afforded benzoate 18 in 88% yield and 90% ee
(Table 6, entry 1).
10% 2a
10% 2a
5% 1a
ent 5% 2a
10% 2a
10% 2a
5% 2a
90
86
Previous work on the addition of terminal alkynes to al-
dehydes demonstrated that catalyst 1a has the ability to de-
protonate and bind to alkynes.[19g] Yet diol 21, which con-
tains a terminal alkyne, did not poison the catalyst or react
with the acetaldehyde that is generated during the course of
the reaction, instead affording product 22 in 90% yield and
80% ee (Table 6, entry 4). Further, substrate 23 afforded the
desymmetrized product 24 in 85% yield and 90% ee
(Table 6, entry 5). A close analogue of product 24, which
contains a benzyl ether instead of the benzoyl ester, has re-
cently been synthesized in three steps and 55% yield using
a chiral auxiliary.[26] The auxiliary approach has been em-
ployed in the synthesis of (E)-alkene peptide isosteres.[27]
The method presented here, therefore, provides a more
direct route to such structures.
Although excellent results were achieved with 2-alkyl-1,3-
propanediols, the desymmetrization of 2-alkoxy-1,3-pro-
panediols 25 and 27 gave both lowered isolated yields and
enantioselectivities (Table 6, entries 6 and 7). These 1,3-pro-
panediols are unique in that they contain an electron-with-
drawing group on the b-carbon atom that lowers the nucleo-
philicity of the primary alcohols compared to the 2-alkyl-
1,3-propanediols discussed above. It is conceivable that the
lowered enantioselectivity and yield observed is due to the
fact that this class of 1,3-diols are intrinsically poorer ligands
for the zinc catalyst and possess a reduced propensity to un-
dergo acylation by the vinyl benzoate.
56(95)[b]
80
97
88
78
80[c]
ꢀ67[c]
93
10
10
11
74
70
[a] Reactions were performed at 0.1m except as indicated elsewhere.
[b] Yield based on recovered starting material. [c] Reaction performed
with optimized conditions shown in Scheme 8.
ꢀ158C also resulted in increased enantioselectivity (Table 7,
entry 2 and 3).
The results presented in Table 7 show that the catalyst 2a
desymmetrizes both 2-aryl (Table 7, entries 1–9) and 2-thien-
yl-1,3-propanediols (Table 7, entries 10 and 11), giving enan-
tiomeric excesses ranging from 80 to 93%. The 1-naphthyl
substrate 39 is structurally unique, because it contains an ad-
ditional benzene ring in close proximity to the pronucleo-
phile. Enzymatic catalysis affords the desymmetrized prod-
uct 40 in 40% ee;[28] however, the desymmetrized product
can be obtained in 67% ee with catalyst 2a and in 80% ee
with catalyst 1a. Additionally, changing the positioning of
the 1,3-propanediol to the 2-naphthyl substrate gave an en-
antiomeric excess of 93% using catalyst 2a. The results pre-
sented in Table 7 demonstrate that either catalyst effects the
desymmetrization of 2-aryl-1,3-propanediols in high enantio-
selectivities. An added advantage to this process is that
either enantiomer of the desymmetrized product can be ac-
cessed by switching to the other enantiomer of the chiral
catalyst.
The desymmetrization of meso-2-aryl-1,3-propanediols:
Given the prevalence of aromatic functionality in both natu-
ral products and pharmaceuticals, a general method that
would provide either enantiomer of the desymmetrized 2-
aryl-1,3-propanediols would also be of significant value. Al-
though the dinuclear zinc catalyst 1a desymmetrized meso-
2-aryl-1,3-propanediols in yields and enantioselectivities
comparable to the 2-alkyl-1,3-propanediols, extending the
chiral pocket by using a larger biphenyl-based catalyst 2a
enhanced the enantioselectivities for 1,3-propanediol 29
Synthetic utility—the rapid generation of chiral building
blocks: The asymmetric desymmetrization of 2-substituted-
1,3-propanediols provides several chiral building blocks that
can be potentially employed in total synthesis. There are
two challenges that needed to be addressed in order to dem-
onstrate a broad applicability of this methodology. First, as
described in Scheme 2, either an acid- or base-catalyzed in-
7652
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 7648 – 7657

Asymmetric Catalysis
FULL PAPER
tramolecular acyl transfer that may lead to erosion in enan-
tiomeric excess must be avoided. Second, in the oxidation of
the desymmetrized alcohol to an aldehyde or carboxylic
acid, the b-elimination of the benzoate must be minimized.
The latter issue was specifically relevant to an ongoing proj-
ect involving the total synthesis of a marine macrolide for
which the aldehyde was required.
tives, this methodology provides a general entry into other
2-alkyl and 2-aryl derivatives, for which the chiral precursors
are not commercially available.
To further enhance the utility of our methodology, prod-
uct 22 was transformed into structurally diverse chiral build-
ing blocks (Scheme 10). Ruthenium-catalyzed regioselective
The formation of the p-toluenesulfonate 47 (path a) from
substrate 18 using standard conditions gave a minimal ero-
sion of the enantiomeric ratio (Scheme 9). This compound
Scheme 10. Synthesis of complex chiral building blocks from 22.
hydrosilylation[33] transformed alkyne 22 into vinyl silane 52
in high yields and with minimal degradation in the enantio-
meric excess. Vinyl silanes have shown great utility in the
[33]
[35]
[36]
ꢀ
ꢀ
C C,
ꢀ
formation of C H,
and C O
bonds and pro-
vide a route to more elaborated chiral building blocks. The
desymmetrized alkyne 22 can also undergo ruthenium-cata-
lyzed oxidative cyclizations and cycloisomerizations to
afford lactone 53 and dihydropyran 54. The acetate deriva-
tive of lactone 53 has been used for the enantioselective
total synthesis of the natural product tacamonie,[37] and this
method provides a more efficient way to access this inter-
mediate. Interestingly, no degradation of enantiomeric
excess is observed when electron-rich phosphanes are used
to access lactone 53. However, with electron-deficient phos-
phanes, the electrophilicity of the metal is enhanced, and
this may account for the degradation of the enantiomeric
excess from 80% to 71% during the formation of dihydro-
pyran 54.
Scheme 9. Synthesis of chiral building blocks from 18 as a representative
example. a) TsCl, Et3N, CH2Cl2, RT; b) NaCN, DMSO, 808C;
c) [Zn(N3)2·Py], DIAD, PPh3, PhCH3; d) TIPSCl, imidazole, DMF; e) Ph-
ACHTREUNG
ACHTREUNG
has been previously synthesized from the Roche ester in
five steps (compared to two steps from inexpensive commer-
cially available diol 17) and served as an essential intermedi-
ate in determining the absolute stereochemistry of benzoate
18.[29] Building block 47 proved to be a useful intermediate
for the formation of nitrile 48 (path b).[29] Azide 49 (path c)
can be accessed directly from the desymmetrized product 18
from a Mitsunobu reaction.[30] The desbenzoyl derivatives
for both substrates 48 and 49 have been accessed from com-
mercially available chiral 3-bromo-2-methyl-1-propanol[31]
and have been employed in the total synthesis of natural
products.[32] However, to access analogues that contain 2-
substitution other than a methyl group, multistep sequences
have been employed.[32c] The orthogonally protected asym-
metric 1,3-propanediol (path d) 50 provides another poten-
tially useful chiral building block. Initial attempts to oxidize
primary alcohol 18 to aldehyde 51 proved problematic due
to subsequent elimination of the benzoyl group. Gratifying-
ly, TEMPO and bisacetoxy iodosobenzene provided mild re-
action conditions for the formation of aldehyde 51, with no
erosion of the enantiomeric selectivity. Although these ex-
amples represent entries into 2-methyl substituted deriva-
Proposed mechanism and stereochemical proof: In the pro-
posed mechanism, the reaction between a 1,3-propanediol
and the zinc catalyst 1a furnishes the zinc alkoxide
(Scheme 11, I). Coordination of the vinyl benzoate can
occur from either face of the C2 symmetric ligand, away
from the two phenyl groups that are almost perpendicular
to the plane of the catalyst. This mode of binding activates
the carbonyl carbon atom to give intermediate II. Catalyst-
directed benzoylation could then proceed via transition
state III, for which a proton transfer is followed by acylation
by the activated ester within the coordination sphere of the
catalyst. Ligand exchange on IV with another molecule of
diol decomplexes the desymmetrized product and then pro-
tonates the zinc–enolate, leading to the release of acetalde-
hyde.
Chem. Eur. J. 2008, 14, 7648 – 7657
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7653

B. M. Trost et al.
In comparison to enzymatic
desymmetrizations, this process
does not require the screening
of enzymes and it incorporates
a benzoyl group that is less
prone to intramolecular acyl
transfer.[38] Usually enzymatic
acylation and enzymatic hydro-
A
give opposite enantiomers, but
this is not always the case. For
example, the desymmetrization
of 1,3-propanediol 3 to product
4 gave superior enantioselectiv-
ities compared to enzymatic
acylation, which affords the R-
configured product in 72%
yield and 46% ee.[7] Although
the enzymatic hydrolysis of the
diacetylated product derived
from diol 3 gives higher enan-
tioselectivities (94% ee), only
the R enantiomer can be direct-
ly accessed by this method.[7]
With our asymmetric desym-
metrizations, both antipodes of
the desymmetrized product are
accessible in high enantioselec-
tivities by switching the chirali-
ty of the ligand.[7] The substrate
scope of these reactions extends
to both 2-alkyl- and 2-aryl-1,3-
propanediols. The reactions are
operationally simple and the
product can be obtained in ex-
Scheme 11. Proposed catalytic cycle for the desymmetrization of meso-2-substituted-1,3-propanediols.
The absolute stereochemistry was assigned by comparison
of the optical rotation of desymmetrized products 18[5] and
47[29] with known literature values. It was found that the
(S,S)-1 ligand gives products with S stereochemistry for 2-
alkyl, 2-alkoxy, and 2-(hetero)aryl-1,3-propanediols. The ste-
reochemical outcome can be rationalized based on transition
state III depicted in Scheme 11, in which the prochiral alco-
hol proximal to the vinyl benzoate is benzoylated.
cellent purities by directly loading the crude reaction mix-
ture onto silica gel. An added benefit of this procedure is
that both ligand 1 and vinyl benzoate are commercially
available.
The derivatization of alcohols 18 and 22 demonstrates the
potential of this methodology to provide rapid access to a
range of chiral building blocks. The desymmetrized 2-
methyl-1,3-propanediol structural motif has been previously
synthesized from commercially available Roche ester. This
work presents a new way to access this common chiral start-
ing material in either fewer or a comparable number of in-
expensive synthetic steps from commercially available start-
ing materials. Additionally, for compounds that contain a
substituent other than a methyl group, this method provides
a direct entry into such desymmetrized structural motifs.
Conclusion
In summary, we have developed an efficient method to de-
symmetrize 2-alkyl- and 2-aryl-1,3-propanediols in excellent
yields and enantiomeric selectivites. The underlying ration-
ale for the success of a catalyst system such as 1a and 2a is
that it provides an amphoteric environment in which one
zinc atom generates an alkoxide of a 1,3-propanediol and
the other acts as a Lewis acid by activating the vinyl ben-
zoate. The result of this coordination is an enantioselective
benzoylation that affords a wide range of desymmetrized 2-
alkyl and 2-aryl-1,3-propanediols.
Experimental Section
General information: All reactions were carried out in flame-dried glass-
ware under a N2 atmosphere. Anhydrous acetonitrile, dichloromethane,
tetrahydrofuran, and toluene were obtained from a Seca solvent purifica-
7654
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 7648 – 7657

Asymmetric Catalysis
FULL PAPER
tion system by Glass Contour. Solvents and reagents were transferred by
means of a syringe, which had been oven dried and cooled in a dessica-
tor.
aqueous NaHCO3. The organic layer was dried (Na2SO4), filtered, and
concentrated. Silica gel chromatography with ethyl acetate/hexane mix-
tures gave compound 47 (0.27 g, 74%, 88% ee) as a white solid. Rf =0.45
(20% ethyl acetate/hexanes); [a]2D5 =ꢀ4.80 (88% ee, c=0.99 in CH2Cl2);
tr =18.57 (major) and 20.83 min (Chiralcel OD Chiral HPLC, l=254 nm,
heptane/iPrOH=95:5, 0.8 mLminꢀ1). The product 47 has been reported
Analytical thin-layer chromatography was preformed on precoated
250 mm layer thickness silica gel 60 F254 plates (EMD Chemicals Inc.).
Visualization was performed by ultraviolet light and/or by staining with
either ceric ammonium molybdate or potassium permanganate. Flash
column chromatography was performed over 32–63 mm silica gel (Sorb-
ent Technologies) and by using compressed air. The eluents employed for
flash chromatography are reported as volume: volume percentages.
1H NMR spectra were acquired using Varian Inova 500 MHz, Mercury
400 MHz, and Gemini 300 MHz spectrometers. Chemical shifts (d) are
reported in parts per million (ppm) and are calibrated to residual solvent
peaks: proton (CDCl3 7.26 ppm) and carbon (CDCl3 77.0 ppm). Coupling
constants (J) are reported in Hz. Multiplicities are reported using the fol-
lowing abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; m, mul-
tiplet. 13C NMR spectra were recorded using a Varian Unity INOVA
spectrometer at 125 MHz or a Varian Gemini at 75 MHz.
1
previously[29] was identified by comparison of H NMR and IR data.
(ꢀ)-3-Cyano-2-methylpropyl benzoate (48): Sodium cyanide (12.7 mg,
0.260 mmol) was added to a solution of (R)-2-methyl-3-(tosyloxy)propyl
benzoate (45 mg, 0.129 mmol) in [D6]DMSO (0.8 mL). The reaction mix-
ture was heated to 808C for 2.5 h. Upon completion (monitored by
1H NMR spectroscopy), the reaction was diluted with diethyl ether
(40 mL), washed five times with water, dried (MgSO4), filtered, and con-
centrated. The crude product was purified by silica gel column chroma-
tography (20% ethyl acetate/hexanes) to afford compound 48 (25 mg,
96%) as a clear oil. Rf =0.2 (20% ethyl acetate/hexanes); [a]2D5 =ꢀ14.65
(88% ee, c=0.39 in CH2Cl2); 1H NMR (500 MHz, CDCl3): d=8.04 (dd,
J=8.0, 1.0 Hz, 2H), 7.57 (tt, J=8.0, 1.0 Hz, 1H), 7.45 (dd, J=8.0, 8.0 Hz,
2H), 4.28 (dd, J=11.0, 5.6 Hz, 1H), 4.23 (dd, J=11.0, 6.5 Hz, 1H), 3.43
(dd, J=11.9, 5.8, 1H), 3.36 (dd, J=11.9, 6.3 Hz, 1H), 2.28–2.16 ppm (m,
1H), 1.1 (d, J=7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=166.2,
133.2, 129.6, 129.6, 128.5, 118.1, 66.4, 30.4, 21.7, 16.3 ppm; IR (neat):
n˜max =2967, 2935, 2101, 1721, 1460, 1452, 1272, 1111, 1071, 211 cmꢀ1; tr =
39.82 (major) and 41.23 min (Chiralcel OD Chiral HPLC, l=254 nm,
IR spectroscopic data was recorded on NaCl plates as thin films on a
Perkin–Elmer Paragon 500 FT-IR spectrophotometer using 0.1 mm path
length. The absorbance frequencies are recorded in wavenumbers (cmꢀ1).
Elemental analyses were performed by M-H-W Laboratories, Phoenix,
Arizona. High-resolution mass spectra were obtained from the Mass
Spectrometry Resource, School of Pharmacy, University of California-
San Francisco, supported by the NIH Division of Research Resource,
and are reported as m/z (relative ratio). Accurate masses are reported
for the molecular ion [M+] or a suitable fragment ion. Chiral HPLC anal-
yses were performed on Daicel Chiralpack columns (AD, AS, OB-H,
OC, OD, or OJ) using heptane/2-propanol mixtures. The respective ratio
of the eluent mixture, flow rate, detection wavelength, and column are in-
dicated within the experimental details. Retention times (Tr) are reported
in minutes (min). Optical rotations were determined using a JASCO
DIP-1000 digital polarimeter in 50 mm cells and the sodium D line
(589 nm) at the temperature, solvent, and concentration indicated.
heptane/iPrOH=4000:1, 0.8 mLminꢀ1); HRMS(EIS):
C12H14NNaO2 [M+Na+H]+: 227.0971; found: 227.0369.
m/z calcd for
(ꢀ)-2-Methyl-3-oxopropyl benzoate (51): (Diacetoxyiodo)benzene
(930 mg, 2.89 mmol) and TEMPO (41 mg, 0.26 mmol) was added to a so-
lution of (S)-3-hydroxy-2-methylpropyl benzoate (500 mg, 2.63 mmol,
90% ee) in dichloromethane (2.63 mL). The reaction mixture was stirred
for 1.5 h at room temperature, quenched with saturated aqueous
NaHCO3, and extracted into diethyl ether. The combined organic ex-
tracts were dried (Na2SO4), filtered, and concentrated. Silica gel chroma-
tography with 20% ethyl acetate/hexanes afforded compound 51
(470 mg, 93%, 90% ee) as a yellow oil. It is important to store this oil at
Representative procedure for asymmetric desymmetrizations
ꢀ208C away from light. Rf =0.24 (35% diethyl ether/hexanes); [a]D25
=
Preparation of the dinuclear zinc catalyst: Diethyl zinc (47 mL,
0.0312 mmol, 0.67m in toluene) was added dropwise to a solution of
(S,S)-Pro-phenol ligand 1 (9.96 mg, 0.0156 mmol) in anhydrous toluene
(553 mL) while stirring under nitrogen. The light yellow catalyst solution
(0.026m) was stirred for 30 min at room temperature and then transferred
to the appropriate reaction using a syringe.
ꢀ12.38 (90% ee, c=2.34 in CHCl3); 1H NMR (500 MHz, CDCl3): d 9.8
(d, J=1.0 Hz, 1H), 8.03 (dd, J=8.4, 1 Hz, 2H), 7.59 (td, J=8.4, 1.0 Hz,
1H), 7.45 (dd, J=8.4, 8.4 Hz, 2H), 4.58 (m, 2H), 2.89 (m, 1H), 1.28 ppm
(d, J=7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=201.8, 165.9, 132.9,
129.3, 128.2, 63.7, 45.6, 10.4 ppm; IR (neat): n˜max =3064, 2968, 2894, 1721,
1602, 1452, 1389, 1377, 1337, 1314, 1272, 1177, 1114, 1070, 1026, 982, 934,
850, 806, 711 cmꢀ1; tr =18.94 and 19.74 min (major) (Chiralcel OJ Chiral
HPLC, l=254 nm, heptane/iPrOH=95:5, 1.0 mLminꢀ1). This compound
has been previously reported.[40]
Asymmetric desymmetrization: Anhydrous toluene (1.9 mL) was added
to
a flame-dried tube containing 2-ethyl-propane-1,3-diol (32.5 mg,
0.312 mmol) and vinyl benzoate (231 mg, 1.56 mmol) at room tempera-
ture. A stock solution of catalyst (0.026m, 0.6 mL, 0.0156 mmol) was
added at ꢀ708C under a positive flow of nitrogen. The reaction was
sealed and stirred at ꢀ208C for 24 h (stirring was essential to the yield of
the reaction as the reaction is heterogeneous at this temperature, when
the reaction was conducted at ꢀ208C without stirring, similar enantiose-
lectivities were obtained; however, significantly lowered yields were ob-
served). The crude product was directly applied to a silica gel column,
and eluted with 20%!50% ethyl acetate/hexanes to give the desired
product (54.7 mg, 84% yield). Rf =0.44 (50% ethyl acetate/hexanes);
[a]2D5 =ꢀ1.89 (86% ee, c=1.0 in CH2Cl2); 1H NMR (500 MHz, CDCl3):
d=8.07 (dd, J=8.4, 1.4 Hz, 2H), 7.60 (tt, J=7.4, 1.4 Hz, 1H), 7.48 (dt,
J=8.4, 7.4 Hz, 2H), 4.51 (dd, J=11.2, 4.3 Hz, 1H), 4.39 (dd, J=11.2,
6.3 Hz, 1H), 3.71 (m, 1H), 3.63 (m, 1H), 2.05 (t, J=6.3 Hz, 1H), 1.90 (m,
1H), 1.50 (m, 2H), 1.02 ppm (t, J=7.6 Hz, 3H); 13C NMR (125 MHz,
CDCl3): d=167.4, 133.4, 130.3, 129.9, 128.7, 64.9, 62.6, 42.7, 21.1,
11.8 ppm; IR (neat): n˜max =3332, 2963, 2932, 2879, 1719, 1464, 1381, 1044,
1008, 969, 767 cmꢀ1; tr =31.4 and 37.6 min (major) (Chiralcel OBH Chiral
HPLC, l=254 nm, heptane/iPrOH=99:1, 0.8 mLminꢀ1); ee=86%; ele-
mental analysis calcd (%): C 69.21, H 7.74; found: C 69.19, H 7.60.
(ꢀ)-4-(Benzyldimethylsilyl)-2-(hydroxymethyl)pent-4-enyl benzoate (52):
[Ru
N
N
(S)-2-(hydroxymethyl)pent-4-yn-1-yl benzoate (20 mg, 0.092 mmol) and
benzyldimethyl silane (16 mg, 0.11 mmol) in acetone (1 mL). The reac-
tion was stirred at room temperature for 2 h, concentrated, and subjected
to chromatography (15% ethyl acetate/hexanes) to give compound 52
(32 mg, 94%, 78% ee) as a clear oil. Rf =0.35 (15% ethyl acetate/hex-
anes); [a]2D5 ꢀ12.86 (78% ee, c=0.3 in CH2Cl2); 1H NMR (125 MHz,
CDCl3): d=8.05 (m, 2H), 7.58 (tt, J=8.0, 1.5 Hz, 1H), 7.45 (m, 2H), 7.20
(m, 2H), 7.06 (m, 1H), 7.0 (d, J=7.0 Hz, 2H), 5.72 (m, 1H), 5.59 (d, J=
2.5 Hz, 1H), 4.45 (dd, J=11.2, 4.3 Hz, 1H), 4.29 (dd, J=11.2, 6.2 Hz,
1H), 3.60 (ddd, J=8.1, 5.1, 3.5 Hz, 2H), 2.3–2.0 (m, 5H), 0.11 (s, 3H),
0.10 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d=167.1, 147.6, 139.6,
133.1, 129.9, 129.6, 128.4, 128.2, 128.1, 127.9, 124.1, 64.3, 62.3, 39.5, 34.7,
25.5, ꢀ3.3 ppm; IR (neat): n˜max =3449, 3051, 3030, 2958, 2916, 2855, 1716,
1602, 1493, 1451, 1384, 1317, 1280, 1202, 1182, 1156, 1119, 1052, 1031,
927, 829, 756, 715, 699 cmꢀ1; tr =70.23 min (major) and 73.73 min (Chiral-
cel OD Chiral HPLC, l=220 nm, heptane/iPrOH=98:2, 0.8 mLminꢀ1);
HRMSEIS:
369.1891.
m/z calcd for C22H29O3S i M[ +H]+: 369.1886; found:
(R)-2-Methyl-3-(tosyloxy)propyl benzoate (47): A solution of (S)-3-hy-
droxy-2-methylpropyl benzoate (204 mg, 1.05 mmol, 91% ee) in dichloro-
methane (3 mL) was added to Et3N (1.06 g, 10.5 mmol) and p-toluenesul-
fonyl chloride (0.40 g, 2.10 mmol). The reaction was stirred at room tem-
perature for 15 h, diluted with diethyl ether, and washed with saturated
(ꢀ)-(3,4-Dihydro-2H-pyran-3-yl)methyl benzoate (54): (S)-2-(Hydroxy-
methyl)pent-4-yn-1-yl benzoate (52.4 mg, 0.24 mmol), RuCp(p-fluorotri-
phenylphoshine)2Cl (15 mg, 0.018 mmol), p-fluorotriphenylphoshine
Chem. Eur. J. 2008, 14, 7648 – 7657
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7655

B. M. Trost et al.
(22.8 mg, 0.072 mmol), N-hydroxysuccinimide (28 mg, 0.24 mmol), and
tetrabutylammonium hexafluorophosphate (21 mg, 0.055 mmol) were
combined in a flame-dried vial cooled under nitrogen. To this was added
DMF (0.6 mL) that had been degassed with argon (essential for high
yielding reaction). The mixture was placed in a pre-heated oil bath
(858C) and was stirred for 24 h under nitrogen. The reaction was then
cooled to room temperature, diluted with diethyl ether, and washed with
water (”3). The aqueous layer was re-extracted with diethyl ether and
the combined organic layers were dried with sodium sulfate, filtered, and
concentrated to dryness. Silica gel that was pretreated with 5% diethyl
ether/hexanes and 1% triethylamine was used for column chromatogra-
phy by eluting with the same solvent system to afford compound 54
(42 mg, 81%, 71% ee) as a yellow oil. Rf=0.52 (5% diethyl ether/hex-
anes); [a]2D5 =ꢀ4.5 (71% ee, c=0.34 in CH2Cl2); 1H NMR (500 MHz,
CDCl3): d=8.04 (dd, J=8.0, 1.0 Hz, 2H), 7.57 (tt, J=1.0 Hz, 1H), 7.45
(m, 2H), 6.40 (td, J=6.1, 2.0 Hz, 1H), 4.72 (ddd, J=6.2, 4.2, 3.3 Hz, 1H),
4.36 (dd, J=11.0, 5.8 Hz, 1H), 4.25 (dd, J=11.0 Hz, 1H), 4.15 (ddd, J=
10.5, 3.0, 1.5 Hz, 1H), 3.85 (dd, J=10.5, 8 Hz, 1H), 2.4 (m, 1H), 2.2 (m,
1H), 1.9 ppm (m, 1H); 13C NMR (125 MHz, CDCl3): d=166.4, 143.9,
Org. Lett. 2006, 8, 3441; d) A. B. Smith III; C. M. Adams, S. A.
Lodise Barbosa, A. P. Degnan, Proc. Natl. Acad. Sci. USA 2004,
101, 12042; C. M. Adams, S. A. Lodise Barbosa, A. P. Degnan, Proc.
Natl. Acad. Sci. USA 2004, 101, 12042.
[11] a) M. Ihara, M. Takahashi, N. Taniguchi, K. Fukumoto, T. Kametani,
J. Chem. Soc. Chem. Commun. 1987, 619; b) M. Ihara, T. Kawabu-
chi, Y. Tokunaga, K. Fukumoto, Tetrahedron: Asymmetry 1994, 5,
1041.
[12] M. Ihara, F. Setsu, M. Shohda, N. Taniguchi, Y. Tokunaga, K. Fuku-
moto, J. Org. Chem. 1994, 59, 5317.
[13] T. Oriyama, H. Taguchi, D. Terakado, T. Sano, Chem. Lett. 2002, 26.
[14] S. Mizuta, T. Tsuzuki, T. Fujimoto, I. Yamamoto, Org. Lett. 2005, 7,
3633.
[15] T. Harada, K. Shiraishi, Synlett 2005, 13, 1999.
[16] C. A. Lewis, B. R. Sculimbrene, Y. Xu, S. J. Miller, Org. Lett. 2005,
7, 3021.
[17] T. Honjo, M. Nakao, S. Sano, M. Shiro, K. Yamaguchi, Y. Sei, Y.
Nagao, Org. Lett. 2007, 9, 509.
[18] S. Mizuta, T. Tsuzuki, T. Fujimoto, I. Yamamoto, Org. Lett. 2005, 7,
3633.
[19] a) B. M. Trost, H. Ito, J. Am. Chem. Soc. 2000, 122, 12003; b) B. M.
Trost, H. Ito, E. R. Silcoff, J. Am. Chem. Soc. 2001, 123, 3367;
c) B. M. Trost, V. S. C. Yeh, Angew. Chem. 2002, 114, 889; Angew.
Chem. Int. Ed. 2002, 41, 861; d) B. M. Trost, L. R. Terrell, J. Am.
Chem. Soc. 2003, 125, 338; e) B. M. Trost, A. Fettes, B. T. Shireman,
J. Am. Chem. Soc. 2004, 126, 2660; f) B. M. Trost, S. Shin, J.A. Scla-
fani, J. Am. Chem. Soc. 2005, 127, 8602; g) B. M. Trost, A. H. Weiss,
A. Jacobi von Wangelin, J. Am. Chem. Soc. 2006, 128, 8; h) B. M.
Trost, J. Jaratjaroonphong, V. Reutrakul, J. Am. Chem. Soc. 2006,
128, 2778; i) B. M. Trost, S. Hisaindee, Org. Lett. 2006, 8, 6003.
[20] B. M. Trost, T. Mino, J. Am. Chem. Soc. 2003, 125, 2410.
[21] For representative examples see a) S. Canova, V. Bellosta, A. Bigot,
P. Mailliet, S. Mignani, J. Cossy, Org. Lett. 2007, 9, 145; b) J. Pospisil,
I. E. Marko, J. Am. Chem. Soc. 2007, 129, 3516; c) L. Ferrie, S. Rey-
mond, P. Capdevielle, J. Cossy, Org. Lett. 2006, 8, 3441; d) A. B.
Smith, III, C. M. Adams, S. A. Lodise Barbosa, A. P. Degnan, Proc.
Natl. Acad. Sci. USA 2004, 101, 12042.
133.0, 130.0, 129.5, 128.4, 99.2, 66.9, 65.2, 32.2, 22.5 ppm; IR (neat): n˜max
3063, 2926, 1722, 1651, 1602, 1584, 1451, 1392, 1379, 1344, 1315, 1274,
1245, 1196, 1177, 1118, 1071, 1027, 976, 921, 894, 878, 806, 736, 711 cmꢀ1
=
;
tr =36.51 min (major) and 39.82 min (Chiralcel AD Chiral HPLC, l=
220 nm, heptaneiPrOH=99.1:0.1 mLminꢀ1); HRMSESI: m/z calcd for
C13H15O3 [M+H]+: 219.1016; found: 219.1025.
Acknowledgements
We thank the National Science Foundation and the National Institutes of
Health (GM-33049) for their generous financial support. S.M. thanks Eli
Lilly & Company for a graduate fellowship. Mass spectra were provided
by the Mass Spectrometry Facility, University of San Francisco, support-
ed by the NIH division or Research Resources.
[1] a) Enzymes Catalysis in Organic Synthesis, Vols. 1 and 2 (Eds.: K.
Drauz, H. Waldman), VCH, Weinheim, 1995; b) G. M. T. Tombo,
H. P. Schaer, F. X. Busquets, O. Ghisalba, Tetrahedron Lett. 1986, 27,
5707; c) G. Guanti, L. Banfi, R. Riva, Tetrahedron: Asymmetry 1994,
5, 9.
[2] K. Tsuji, Y. Terao, K. Achiwa, Tetrahedron Lett. 1989, 30, 6189.
[3] E. Santaniello, P. Ferraboschi, P. Grisenti, Tetrahedron Lett. 1990,
31, 5657.
[4] B. Wirz, R. Schmid, W. Walther, Biocatalysis 1990, 3, 159.
[5] E. Santaniello, S. Casati, P. Ciuffreda, L. Gamberoni, Tetrahedron:
Asymmetry 2004, 15, 3177.
[6] a) M. Kirihara, M. Kawasaki, T. Takuwa, H. Kakuda, T. Wakikawa,
Y. Takeuch, K. L. Kirk, Tetrahedron: Asymmetry 2003, 14, 1753;
b) A. Ghanem, H. Y. Aboul-Enein, Tetrahedron: Asymmetry 2004,
15, 3331.
[22] G. Reginato, A. Ricci, S. Roelens, S. Scapecchi, J. Org. Chem. 1990,
55, 5132.
[23] An added benefit of toluene as the reaction solvent was realized
upon completion of the reaction, in which the crude reaction mix-
ture could directly be poured onto silica gel, thus, obviating the
need for a workup procedure. This not only enhances the practicali-
ty of the procedure but also allows for the complete recovery of
starting diols; many of which have high solubilities in aqueous
media.
[24] L. J. Goossen, J. Paetzold, D. Koley, Chem. Commun. 2003, 6, 706.
[25] J. C. Vallejos, C. Yani, Eur, Pat. Appl. 494016, 1992.
[26] M. K. Edmonds, A. D. Abell, J. Org. Chem. 2001, 66, 3747.
[27] a) J. Xiao, B. Weisblum, P. Wipf, J. Am. Chem. Soc. 2005, 127, 5742;
b) N. G. Bandur, K. Harms, U. Koert, Synlett 2007, 1, 99.
[28] G. Guanti, E. Narisano, T. Podgorski, S. Thea, A. Williams, Tetrahe-
dron 1990, 46, 7081.
[29] T. Tachihara, S. Ishizaki, Y. Kurobayashi, H. Yamura, Y. Ikemoto,
A. Onuma, K. Yoshikawa, T. Yanai, T. Kitahara, Helvetica Chimica
Acta, 2003, 86, 274.
[30] O. Mitsunobu, M. Yamada, Bull. Chem. Soc. Jpn. 1967, 40, 2380.
[31] Currently available from Aldrich, CASNo. 325006, costs US$46.30/
gram for both enantiomers.
[32] For nitrile see a) E. de Lemos, F.-H. Poree, A. Commercon, J.-F.
Betzer, A. Pancrazi, J. Ardisson, Angew. Chem. 2007, 119, 1949;
Angew. Chem. Int. Ed. 2007, 46, 1917; b) M.A. Evans, J. P. Morken,
Org. Lett. 2005, 7, 3371; c) For azide see K. Sahasrabudhe, V. Gra-
cias, K. Furness, B. T. Smith, C. E. Katz, D. S. Reddy, J. Aubꢁ, J.
Am. Chem. Soc. 2003, 125, 7914.
[33] B. M. Trost, Z. T. Ball, J. Am. Chem. Soc. 2001, 123, 12726.
[34] For representative examples see B. M. Trost, Z. T. Ball, T. Joge, J.
Am. Chem. Soc. 2002, 124, 7922.
[7] I. Izquierdo, M. T. Plaza, M. Rodríguez, J. Tamayo, Tetrahedron:
Asymmetry 1999, 10, 449.
[8] E. Garcia-Urdiales, I. Alfonso, V. Gotor, Chem. Rev. 2005, 105, 313.
[9] a) D. H. G. Crout, V. S. B. Gaudet, K. Laumen, M. P. Schneider, J.
Chem. Soc. Chem. Commun. 1986, 808; b) Z.-F. Xie, I. Nakamura,
H. Suemune, K. Sakai, J. Chem. Soc. Chem. Commun. 1988, 9667;
c) K.-C. K. Liu, K. Nozaki, C.-H. Wong, Biocatalysis 1990, 3, 169–
177; d) B. Morgan, D. R. Dodds, A. Zaks, D. R. Andrews, R. Klesse,
J. Org. Chem. 1997, 62, 7736; e) N. Claudia, J. M. J. Williams, Adv.
Synth. Catal. 2003, 345, 835; f) 1-ethoxyvinyl 2-furanoate has been
used as an acylating agent to circumvent the intramolecular acyla-
tion by S. Akai, T. Naka, T. Fujita, Y. Takebe, T. Tsujino, Y. Kita, J.
Org. Chem. 2002, 67, 411.
[10] For representative applications to natural product synthesis see a) S.
Canova, V. Bellosta, A. Bigot, P. Mailliet, S. Magnani, J. Cossy, Org.
Lett. 2007, 9, 145; b) J. Pospisil, I. E. Marko, J. Am. Chem. Soc.
2007, 129, 3516; c) L. Ferrie, S. Reymond, P. Capdevielle, J. Cossy,
7656
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 7648 – 7657

Asymmetric Catalysis
FULL PAPER
[35] For representative examples see a) B. M. Trost, M. R. Machacek,
Z. T. Ball, Org. Lett. 2003, 5, 1895; b) B. M. Trost, Z. T. Ball, J. Am.
Chem. Soc. 2004, 126, 13942.
[36] For representative examples see a) B. M. Trost, Z. T. Ball, K. M.
Laemmerhold, J. Am. Chem. Soc. 2005, 127, 10028; b) B. M. Trost,
Z. T. Ball, T. Joge, Angew. Chem. 2003, 115, 3537; Angew. Chem.
Int. Ed. 2003, 42, 3415.
[38] The majority of examples currently in the literature have acetyl
groups.
[39] For an example in which only one enantiomer can be accessed in
high enantioselectivity with enzymatic desymmerization see D. B.
Kastrinsky, D. L. Boger, J. Org. Chem. 2004, 69, 2284.
[40] T. Rein, J. Anvelt, A. Soone, R. Kreuder, C. Wulff, O. Reiser, Tetra-
hedron Lett. 1995, 36, 2303.
[37] B. Danieli, G. Lesma, S. Macecchini, D. Passarella, A. Silvani, Tetra-
hedron: Asymmetry 1999, 10, 4057.
Received: April 3, 2008
Published online: July 24, 2008
Chem. Eur. J. 2008, 14, 7648 – 7657
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7657