A convergent Pd-catalyzed asymmetric allylic alkylation of dl- And meso-divinylethylene carbonate: Enantioselective synthesis of (+)-australine hydrochloride and formal synthesis of isoaltholactone

Article abstract of DOI:10.1002/chem.200700832

The use of a mixture of dl-and meso-divinylethylene carbonate as an electrophile in palladium-catalyzed asymmetric allylic alkylation reactions is reported. From the diastereomeric mixture of meso and chiral racemic starting materials, a single product is obtained in high optical purity employing either oxygen or nitrogen nucleophiles. The resulting dienes have proven to be versatile synthetic intermediates as each carbon is functionalized for further transformation and differentiated by virtue of the reaction. A mechanism for this intriguing transformation is proposed and a concise enantioselective total synthesis of (+)-australine hydrochloride is reported as well as a formal synthesis of isoaltholactone.

Full text of DOI:10.1002/chem.200700832

FULL PAPER
DOI: 10.1002/chem.200700832
A Convergent Pd-Catalyzed Asymmetric Allylic Alkylation of dl- and meso-
Divinylethylene Carbonate: Enantioselective Synthesis of (+)-Australine
Hydrochloride and Formal Synthesis of Isoaltholactone
Barry M. Trost,* Aaron Aponick, and Benjamin N. Stanzl[a]
Abstract: The use of a mixture of dl-
and meso-divinylethylene carbonate as
an electrophile in palladium-catalyzed
asymmetric allylic alkylation reactions
is reported. From the diastereomeric
mixture of meso and chiral racemic
starting materials, a single product is
obtained in high optical purity employ-
ing either oxygen or nitrogen nucleo-
philes. The resulting dienes have
proven to be versatile synthetic inter-
mediates as each carbon is functional-
ized for further transformation and dif-
ferentiated by virtue of the reaction. A
mechanism for this intriguing transfor-
mation is proposed and a concise enan-
tioselective total synthesis of (+)-aus-
traline hydrochloride is reported as
well as a formal synthesis of isoaltho-
lactone.
Keywords: asymmetric catalysis
·
asymmetric synthesis · natural prod-
ucts · palladium · total synthesis
Introduction
The development of catalytic asymmetric reactions that use
feedstock chemicals, or easily prepared starting materials, to
produce functionalized building blocks in high optical purity
continues to be at the forefront of modern synthetic organic
chemistry. To achieve this goal, our work in the area of pal-
ladium-catalyzed asymmetric allylic alkylation (AAA) has
focused on exploiting the well-known reaction mechanism
by targeting either the ionization or nucleophilic addition
steps as enantiodetermining.[1] Based on the successful palla-
dium-catalyzed dynamic kinetic asymmetric transformation
(DYKAT) of racemic butadiene monoepoxide,[2] we postu-
lated that a reasonable extension of this chemistry may be
realized by the addition of a second vinyl group to the sub-
strate providing a triene monoepoxide (hexatriene mono-
ACHTREUNGepoxide 1, Scheme 1). This structural modification, would
theoretically allow for both stereogenic centers to be epi-
merized by a metal catalyst and by such a mechanism, race-
mization of the starting material would be possible ((S,S)-1
! (R,R)-1 via meso-1). The success of the reaction would
Scheme 1. Potential DYKAT of triene monoepoxides.
then hinge upon the ability of each stereoisomer of the sub-
strate to be efficiently ionized and the resulting p-complexes
to equilibrate at appropriate rates. Nucleophilic attack
would then selectively provide one enantiomer of one of the
diastereomers that could possibly be formed. While triene
monoepoxides would be the simplest substrates, in principle
any substrate that incorporates a leaving group that may
also reversibly add to the p-complex may work in these
types of processes.
[a] Prof. B. M. Trost, A. Aponick, B. N. Stanzl
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.
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Table 1. Pd AAA using phthalimide as a nucleophile.
The functionalized dienes produced using heteroatom
nucleophiles would be monoprotected diols or N-pro-
tected amino alcohols with two adjacent stereocenters
set during the reaction. As these compounds would
have each atom of the framework differentiated by
virtue of the reaction, they should be well suited for fur-
ther selective transformations and find application in
natural product synthesis. Use of these diols in synthe-
ses has recently been reported,[3] but the starting materi-
als are derived from the chiral pool and required multi-
step preparations.[4] As both enantiomers of product
would be available using a catalytic enantioselective ap-
proach and the necessary substrates should be easily
prepared, we sought to test our hypotheses.
Entry
Carbonate
10 [mol%][a]
Product
Yield [%][b]
ee [%]
1[c]
2[c]
3[c]
4[c]
5[c]
6[c]
7[f]
7
7
7
8
8
8
5.0[d]
5.0
12
12
12
12
12
12
12
81
–
44 (88)[e]
43 (86)[e]
71
>99
>99
–
>99
>99
>99
2.0
5.0[d]
5.0
74
71
2.0
1.0
7+8[g]
74 (99)[e,h]
[a] (C3H5PdCl)2/11 1:3. [b] All yields based on mmol 7 and/or 8. [c] 0.5 mmol
scale, 16 h reaction time with 1.1 equiv 9. [ d]rac-11. [e] Based on a theoretic
maximum for 50% conversion of 7 as discussed below. [f] 5.0 mmol scale, 72 h
reaction time with 0.77 equiv 9. [g] 1:1 mixture 7:8. [h] 16% (R,R)-7 was also
recovered in 91% ee.
Results and Discussion
Optimization studies: Upon initial inspection, the
parent triene monoepoxide, hexatriene monoepoxide,
would seem to be the most atom economic choice of sub-
strate for the reaction. While this epoxide would certainly
incorporate all atoms of the starting material into the prod-
uct, previous reports indicated that it would be difficult to
prepare and handle, especially meso-1.[5] It was postulated
that 1,2-divinylethylene carbonate[6] (7 and 8) could be em-
ployed as a suitable surrogate. Use of the cyclic carbonate
would hopefully also function to tether the leaving group to
the substrate, a structural feature that is integral to the re-
versibly epimerizing nature of the necessary intermediates.
Furthermore, the carbonate was envisioned to derive readily
from a bulk chemical, acrolein (Scheme 2). Reductive dime-
rization[7] of acrolein 6 with zinc followed by cyclization in
neat diethyl carbonate[5a] provided the dl- and meso-isomers
7 and 8 on a large scale as a 1:1 mixture of separable diaste-
reomers in good yield.
Using 5 mol% ligand (R,R)-11 and 2 mol% 10 (entries 2,
3), 12 was again isolated as the sole product in >99% ee
but with 44 and 43% yield, respectively, due to the kinetic
resolution of racemic 7 (see below).
The reaction was next attempted with the cyclic carbonate
8 (entries 4–6) to determine how well the catalyst system
would work with an acyclic bisallylic meso compound, a
class of substrates that has not been explored in intermolec-
ular Pd AAA reactions.[9] To our delight, using both racemic
11 and (R,R)-11 the only product formed was the syn-diaste-
reomer 12 (entries 4 and 5). In both reactions the yield was
acceptable and in entry 5 the ee was >99%. The catalyst
loading could also be reduced (2 mol% 10, entry 6) while
both the yield and ee were maintained. These results provid-
ed preliminary evidence that a mechanistic scenario such as
that illustrated in Scheme 1 could be entered into from at
least two of the three substrates.
In an attempt to render this a high throughput process,
and since 7 and 8 are prepared in the same reaction and
both exclusively gave product 12 with excellent ee, the reac-
tion was carried out on a 1:1 mixture of 7 and 8 obtained
from 6. Under optimized conditions with prolonged reaction
time, the process performed equally well giving 12 with
>99% ee using 1 mol% 10 in 74% yield (based on charged
7+8) wherein the maximum theoretical yield is 75%. Inter-
estingly, the cyclic carbonate (R,R)-7, recovered in 16%
yield (theoretical max. 25%), has a 91% ee, indicative of a
kinetic resolution of racemic 7 present in the starting mate-
rial by the chiral catalyst system.
The relative configuration of 12 was initially determined
by conversion to the corresponding N-tosyl-oxazolidinone
and comparison to the known cis- and trans-N-tosyl-oxazoli-
dinones (14 and 15). Both compounds had been previously
prepared and demonstrate suitably different chemical shifts
for the labeled protons (d Ha/Hb in 14 = 4.54, 4.53 ppm
versus d Ha/Hb in 15 = 5.08, 4.93 ppm) that allowed for
facile identification.[10] The absolute configuration was later
determined to be S,S by conversion to the known saturated
Scheme 2. Preparation of 1,2-divinylethylene carbonate.
Preliminary studies focused on employing phthalimide 9
in the desired reaction. Neglecting the regiochemistry of the
nucleophilic addition, the products of the palladium-cata-
lyzed asymmetric allylic alkylation (Pd AAA) of 7 and 8 by
the well-established double inversion mechanism[8] would be
expected to be diastereomers 12 and 13, respectively
(Table 1). Using initial conditions that functioned well in
DYKAT reactions of butadiene monoepoxide as a starting
point,[2a] when the dl-carbonate 7 was allowed to react with
phthalimide in the presence of 5 mol% p-allylpalladium
chloride dimer 10, 15 mol% racemic 11, and 5 mol%
Na2CO3 in CH2Cl2,[2a] the only product isolated was the ex-
pected amino alcohol 12 in 81% yield (entry 1, Table 1).
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Pd-Catalyzed Asymmetric Allylic Alkylation
FULL PAPER
These results seemed to indicate that the rate of nucleo-
philic attack needed to be slowed to favor alkylation of one
specific p-allylpalladium complex. If the reaction is believed
to involve a kinetic resolution of the rac-7 and complete re-
action of meso-8, then only 75% of the starting material will
react. In an attempt to slow the rate of the nucleophilic
attack, a series of systematic changes of conditions was per-
formed. The concentration of the reaction was decreased to
0.1m, the amount of nucleophile decreased to 0.8 equiv
(75% required for all starting material to react, 5% to form
the active catalyst), the temperature lowered to 08C, the
phenol added over 5 h via syringe pump, and base was omit-
ted from the reaction mixture. These changes increased the
ratio to 2.3:1—only a modest change, but nevertheless in
the correct direction.
Another way to potentially slow the rate of nucleophilic
attack is to increase the steric hinderance of the nucleophile
and led to an examination of other types of substituted phe-
nols. The nucleophile 20 was designed to contain an ortho-
methyl group to slow down the nucleophilic attack and also
a p-methoxy group so oxidative deprotection of the product
could be effected. Under fairly standard conditions, with
2.5 mol% allylpalladium chloride dimer and 7.0 mol% race-
mic naphthyl ligand at 08C, 0.1m in CH2Cl2 the regioisomers
21 and 22 were obtained in a 7.5:1 ratio in 77% yield
(Table 3, entry 1). The ratio obtained using 20 is a substan-
amino alcohol 16[11] and comparison of the sign of the ob-
served optical rotation [a]2D5 = ꢀ23.2 (c=0.8, MeOH) to the
reported value [a]2D3 = ꢀ16.9 (c=0.8, MeOH).[12]
To probe the robustness of our system and explore the
scope of the reaction for future synthetic purposes, the use
of oxygen nucleophiles was explored in an effort to produce
monoprotected 1,2-diols. Initial efforts focused on using
easily deprotected simple alcohols such as p-methoxybenzyl
alcohol. Unfortunately, all attempts to use the alcohol in the
presence or absence of boron co-catalyst[2b,13] failed. Addi-
tionally, the stoichiometric use of borates,[2b] zinc alkox-
ides,[14] or inorganic carbonate[15] also failed to provide any
of the desired product.
Phenols represent another class of oxygen nucleophiles
that have been successfully employed in asymmetric allylic
alkylation reactions. Since p-methoxyphenol can be depro-
tected by oxidative means, its use was explored and this al-
cohol provided the first promising results, as seen in Table 2.
Table 2. Pd AAA using p-methoxyphenol as a nucleophile.
Table 3. Pd AAA using phenol 20 as a nucleophile.
Entry[a]
18/19
Entry[a]
18/19
1[b]
2[c]
3[d]
4[e]
5[f]
1.5:1
1.3:1
1.2:1
–
6[g]
1:2
7[h]
8[i,j]
9[i,k]
1.7:1
2.3:1
2.3:1
Entry
10 [%]a]
2.5[b]
2.5
2.5
2.5
Equiv 20
21/22
Yield 21+22 [%]
21 ee [%]
1
2
3
1.1
1.1
0.8
0.8
0.77
7.5:1
8.9:1
10.3:1
7.3:1
12:1
77
98
98
98
98
98
53 (71)[c]
55 (73)
54 (72)
64 (85)
1.3:1
4[d]
5[e]
[a] Reactions carried out under N2 with 1.1 equiv 17, 2.5 mol%
(C3H5PdCl)2, and 7.0 mol% 11. [ b]Rac-11; 18 + 19 obtained in 69%
combined yield. [c] (R,R)-11; 18 + 19 obtained in 59% combined yield
with 18 in 99% ee. [ d]dl-isomer only. [e] 2 equiv 17, 2 equiv AcOH (no
Na2CO3); only trace products. [f] 5.0 mol% Et3B added. [g] 1 equiv Et3B
added. [h] T = 0!48C, 0.8 equiv 17. [ i]17 added over 5 h [j] T 08C.
[k] No base added, T = 08C ! ambient. PMP = p-methoxyl.
1.0
[a] Reactions carried out under an atmosphere of N2 for 16 h using
(C3H5PdCl)2/11 1:3. [b] rac-11, ambient temperature. [c] Based on 75%
maximum yield as discussed below. [d] CO2 atmosphere. [e] 72 hour reac-
tion time.
tial improvement over that observed using p-methoxyphenol
17 (see Table 2, entry 1). Using (R,R)-10, 21 and 22 were ob-
tained in 53% yield as an 8.9:1 ratio with 98% ee for 21
(Table 3, entry 2). Decreasing the amount of phenol to 0.8
equivalents increased the ratio to 10.3:1, with a similar
chemical yield (entry 3). In an attempt to increase the mass
recovery, the reaction was run under an atmosphere of
carbon dioxide. As listed in entry 4 (Table 3) this modifica-
tion did not increase the yield and decreased the ratio of re-
gioisomers. On larger scale with decreased catalyst loading
(entry 5) and prolonged reaction time (72 h), a 64% yield of
a 12:1 ratio was obtained providing the branched isomer 21
with 98% ee. The increased chemical yield and the ratio of
Employing racemic naphthyl ligand under standard condi-
tions, alkylated product was obtained in a combined yield of
nearly 70% of a 1.5:1 ratio of branched to linear regioisom-
ers (entry 1). While this ratio leaves much to be desired, it is
important to note that only one diastereomer of the
branched isomer 18 was obtained. The syn stereochemistry
is assigned in analogy to results that will be discussed below.
When (R,R)-naphthyl ligand was employed, a slightly worse
regioisomeric ratio was observed in 59% yield, but impor-
tantly the branched isomer was obtained in 99% ee. Several
sets of conditions were tried, but were met with limited suc-
cess.
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9549

B. M. Trost et al.
regioisomers were deemed a satisfactory result. The ee of
the linear compound could not be determined by HPLC
analysis, although the optical rotation was nearly zero.
Since addition of the 2,3-dimethyl groups drastically in-
creased the ratio of observed regioisomers, it was postulated
that further increasing the steric bulk of the ortho group
may increase the ratio even further. To this end, the 2-tert-
butyl-4-methoxyphenol was utilized. Unfortunately, under
the standard reaction conditions only a 1:1 ratio of branched
to linear product was observed. It seems that when the
ortho group is too sterically bulky, that nucleophilic addition
to the internal carbon is slowed and alkylation at the termi-
nal carbon is increased.
To determine the relative and absolute configuration, we
sought to deprotect the aryl group to unmask the corre-
sponding diol which would either be meso or one of the dl
isomers whose rotations are known. Treatment of 21 with
ceric ammonium nitrate in the mixed acetonitrile/water sol-
vent system gave a quinone monoketal in nearly quantita-
tive yield. Hydrolysis, although sluggish, provided a sample
of the corresponding diol whose absolute configuration was
determined to be S,S by comparison of optical rotation of
our synthetic material {[a]2D2 = +82.6 (c=0.66, EtOH)} to
the known sugar derived material{[a]2D5 = ꢀ79.3 (c=0.64,
EtOH)}.[4a]
tent with the stereochemistry of the observed product 12,
which seems to arise from alkylation of 23. When the two
possible p-allylpalladium complexes formed by ionization of
meso-8 are examined, it seems that the matched ionization
to form 24 leads towards the unobserved product 13, while
in contrast, mismatched ionization to form 25 leads to the
observed product. When the four p-allylpalladium com-
plexes are compared, it is reasonable to believe that 26 is of
a higher energy than 24 and therefore 26 may not be attain-
able by direct ionization of (R,R)-7 and also may be the less
populated between 24 and 26. It is also reasonable that 25 is
of higher energy than 23 favoring conversion to 23 from 25.
Between the two sets of possibly interconvertible p-allylpal-
ladium complexes, the two that arise from matched ioniza-
tion events (23 and 24) are favored. What remains unclear is
why 23 is preferentially alkylated over any of the other
three complexes. It may be that 23 is the most stable com-
plex and the most highly populated state, which leads to in-
creased probability that it will be alkylated. This may have
something to do with the pendant carboxylate. If the carbox-
ylate ligates palladium in 23 the remaining vinyl group is
forced to point away from the ligand assembly, while liga-
tion of palladium in 24 orients the vinyl group toward the
ligand. It is then possible that 24 is in fact alkylated, but by
the pendent carboxylate, not an external nucleophile, lead-
ing back to meso-8. If the reaction between 24 and meso-8 is
rapid and reversible and (R,R)-7 is not ionized to a great
extent, then a situation that involves kinetic resolution of
the rac-7 and nonproductive matched ionization concurrent
with a productive mismatched ionization of meso-8 leading
to 12 is likely.
This rationale assumes that ionization occurs to give the
syn complexes, but another possibility is that ionization
occurs directly to give the anti complexes. As summarized in
Scheme 4, this scenario would allow for the matched ioniza-
tion of 8 to lead to the observed product after two p–s–p in-
terconversions occurring sequentially at the primary then
secondary carbon atoms. For the mechanism to produce the
observed product, the stereogenic allylic alcohol with the R
designation in the meso diol must be ionized and alkylated
with inversion to give the S product, while the S stereocen-
ter must be retained. At first glance it would appear to be
unfavorable to ionize in the anti fashion due to steric inter-
actions between the R group and the ligand assembly. How-
ever, the palladium-catalyzed asymmetric allylic alkylation
of cyclic meso substrates works exceedingly well using di-
phenylphosphinobenzoic acid based ligands.[18] These reac-
tions, by the cyclic nature of the substrates, “force” two
groups into the anti,anti configuration. After ionization, 28
can then undergo p–s–p interconversion to form 29 and
place the R group in a flap region. Further p–s–p intercon-
version, this time at the secondary carbon, would then form
the syn complex 23 and after alkylation 12.
Mechanism: The methodology presented not only provides
products useful for synthetic purposes, but is intriguing from
a mechanistic standpoint also. Previously, either the ioniza-
tion or nucleophilic addition steps of the mechanism were
exploited independently as the enantiodetermining step.
Typically, different conditions are designed to either favor
rapid nucleophilic addition to the initially formed p-allylpal-
ladium complex or to promote equilibration of diastereo-
meric complexes. Under ideal conditions, coupling these
pathways may theoretically provide a suitable manifold for
both overall retention and inversion of product stereochem-
istry and thus a convergent pathway emanating from differ-
ent substrates may arise. The conditions necessary for this
type of process to occur must achieve a delicate balance be-
tween the relative rates of equilibration and nucleophilic ad-
dition. Based on the results outlined in Table 1, both types
of enantiodiscrimination are postulated to be occurring in
the present study.
Using the (R,R)-naphthyl ligand, the S,S product is ob-
tained from both dl- and meso-carbonates
7 and 8
(Scheme 3). This interesting result raises questions about
how the dl and meso compounds are converted to the same
product and what the origin of the enantioselectivity is. As
was previously reported, a mechanism involving all-syn-p-al-
lylpalladium complexes is possible (Scheme 3).[16] Using the
familiar wall and flap diagram to represent the chiral ligand
scaffold,[17] when (S,S)-7 and (R,R)-7 are ionized to give the
p-allylpalladium complexes 23 and 26, respectively, it is
clear that ionization to 23 is a matched case, whereas ioniza-
tion to give 26 is mismatched due to steric interactions be-
tween the ionized substrate and ligand walls. This is consis-
It is important to note that alkylation of complexes 27–29
at the primary carbon would lead to a Z olefin, while alkyla-
tion of any of the intermediates in Scheme 3 would lead to
E olefins. Since linear products are obtained with phenol nu-
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Pd-Catalyzed Asymmetric Allylic Alkylation
FULL PAPER
Scheme 3. Proposed mechanism involving all-syn complexes.
While the ee values of the
branched products were great-
er than 99% in both cases, the
most important observation,
1
easily determined by H NMR
in this case, was that the linear
product 36l contained an E
double bond derived from al-
kylation of a syn-complex. To
date, all linear products ob-
tained contain a single olefin
isomer whose geometry had
been obscured by overlapping
1H NMR signals at up to
600 MHz. If the assumption is
made that the linear products
are of the same double bond
geometry as 36l, this can be in-
terpreted as additional evi-
dence in favor of the all-syn
mechanism (Scheme 3).
Scheme 4. Proposed mechanism involving anti complexes.
cleophiles, experimental evidence in favor of or eliminating
one of the mechanisms may be obtained by determining the
olefin geometry. Unfortunately, as stated above, direct spec-
troscopic means of identification have been unsuccessful.
In addition to the use of the phenol 20 as a nucleophile
that functions as a protected alcohol in the product, it may
be desirable to use phenols whose structures are retained in
the final product. It was previously determined that the
ortho methyl group in 20 is necessary to improve the regio-
chemistry of nucleophilic addition to an acceptable ratio.
When other ortho-substituted aromatic alcohols such as
ortho-cresol 31 and 1-naphthol 32 were employed in the re-
action, the regiochemistry of the addition was eroded giving
only 47:16 and 5:2 ratios, respectively (based on isolated
yields, see Table 4). With the pure R,R ligand, the enantio-
pure monoarylated vicinal diols 33b and 35b were isolated
in 47 and 50%, respectively.
Table 4. Pd AAA using other phenols.
Entry
Phenol
Yield b [%]
Yield l [%]
1[a]
2[b]
50
15
16
47 (63)[c,d]
3[a]
4[b]
63
26
20
50 (67)[c,d]
[a] racemic ligand, RT, 1.1 equiv phenol. [b] (R,R)-11, 08C, 0.8 equiv
phenol. [c] >99% ee. [d] Based on 75% maximum yield.
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B. M. Trost et al.
Inspection of the two proposed mechanisms and the fact
that both the meso and dl compounds give the same product
may suggest that there may be an interconversion between
the dl and meso isomers. Since the reaction forms (S,S)-12
and leaves unreacted (R,R)-7 when employing the (R,R)-
naphthyl ligand, the product must be derived from both 8
and (S,S)-7. If it is assumed that the product is produced by
the standard p-allylpalladium inversion–inversion mecha-
nism,[8] (S,S)-12 is derived directly from (S,S)-7. The ques-
tion then arises as to whether the product can be produced
directly from 8 or if the meso compound can be converted
to (S,S)-7 which is then converted to product. To determine
the feasibility of converting 8 into one or both of the dl iso-
mers of 7, 8 was treated under the standard reaction condi-
tions, but with only enough phthalimide to generate the
active catalyst (Table 5). Under conditions employing
substrate catalyst pair, which usually gives higher ee values
at lower temperatures. This is the predicted result if the anti
mechanism (Scheme 4) is operating. Reaction by the path-
way illustrated in (Scheme 3), the all-syn mechanism, would
be predicted to exhibit an inverse temperature dependence,
that is, lower ee at lower temperature.
When 8 is allowed to react under conditions employing
10 mol% phthalimide, 5 mol% p-allylpalladium chloride
dimer, and 15 mol% (R,R)-naphthyl ligand but at ꢀ258C,
the trans isomer was isolated in 12% yield, with 8 recovered
in 64% yield (Table 5, entry 3). Most importantly, the ee of
isolated (S,S)-7 had dropped significantly to 53%. The re-
duced enantiomeric excess, due to this 508C change in tem-
perature is consistent with the all-syn mechanism.
To determine exact amounts of the starting materials and
products present upon completion of the reaction, the reac-
tion illustrated in Scheme 5 was tediously purified by repeat-
ed silica gel chromatography. Both the linear product 22 and
the branched alcohol 21 were isolated in 8 and 67% yield,
respectively, and 21% of the cyclic carbonate (R,R)-7 was
recovered.
Table 5. Substrate interconversion.
Entry
T [8C]
Yield 8 [%]
Yield 7 [%]
ee (S,S)-7 [%]
1[a]
2[b]
3[b]
25
25
ꢀ25
trace
21
64
14
21
12
nd
75
53
[a] N2, 1 atm. [b] CO2, 1 atm.
Scheme 5. Determination of the linear productꢁs absolute configuration.
10 mol% phthalimide, 5 mol% p-allylpalladium chloride
dimer, and 15 mol% (R,R)-naphthyl ligand at room temper-
ature, (S,S)-7 was recovered in 14% isolated yield, with 8
only observable in a trace amount by TLC (entry 1). In con-
trast, when the reaction is run under an atmosphere of CO2,
the mass recovery improves (entry 2). A 1:1 mixture of the
cis and trans cyclic carbonates were recovered in 42% com-
bined yield. By isolation and reduction of the trans com-
pound to the diol, it was determined by chiral GC analysis
and the sign of the optical rotation that the compound thus
obtained was (S,S)-7 in 75% ee. This result indicates that it
is possible to convert 8 into the dl-cyclic carbonate 7 under
the reaction conditions, and that the major enantiomer ob-
served is that which leads to product. The still relatively low
mass recovery is believed to be due to decomposition of the
p-allylpalladium complexes in the absence of nucleophile,
possibly through loss of CO2.
Upon inspection of the two proposed mechanisms, it
should be noted that in the anti mechanism (Scheme 4)
matched ionization of 8 is believed to lead to product in
contrast to the all-syn mechanism (Scheme 3) where a mis-
matched ionization is believed to give the product. It would
be predicted that the ee observed upon conversion of 8 to
(S,S)-7 in the absence of an external nucleophile may be de-
pendent on the reaction temperature. Under normal circum-
stances, the desired reaction is typically that of a matched
The ee values of 21 and 7 were determined by the normal
methods to be 98 and 91%. On a variety of chiral stationary
phase HPLC columns, the ee of 22 could not be determined
so the O-methyl mandalate method was used to assign the
absolute stereochemistry as S with 60% ee.[19] This result is
also consistent with the all-syn mechanism. The unreacted
starting material (R,R)-7 is recovered in high yield (25%
theoretical max), indicating a kinetic resolution of rac-7.
The remaining 75% of the starting cyclic carbonates are
nicely incorporated into the alkylation products 21 and 22,
which derive from p-allylpalladium complexes 23 and 25.
All experimental evidence collected to date points towards
the all-syn mechanism illustrated in Scheme 3.
The principle difference between the phenol and phthali-
mide reactions is the solubility of the nucleophile. Phthali-
mide is only partially soluble, while the phenols completely
dissolve under the reaction conditions. With phthalimide, a
proper balance between the relative rates of ionization,
equilibration, and nucleophilic addition is presumably ach-
ieved, but the higher concentration of phenol present in the
reaction mixture must increase the rate of nucleophilic addi-
tion relative to equilibration of the p-complexes and lead to
a less regioselective reaction.
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Pd-Catalyzed Asymmetric Allylic Alkylation
FULL PAPER
Total synthesis of (+)-australine hydrochloride: We have
previously reported the use of monoprotected diol 21 as a
convenient building block.[16] To demonstrate the utility of
the phthalimide derived product, we sought to employ the
N-protected aminoalcohol 12 in a synthesis of an alkaloid.
Since 12 contains the heteroatoms in a 1,2-syn arrangement
with the remaining carbons in an oxidation state suitable for
further functionalization, alkaloid glycosidase inhibitors
seemed to be a logical target. More specifically, the poten-
tial use of 12 in the preparation of the polyhydroxylated pyr-
rolizidine alkaloid australine 40 was investigated.
Scheme 6. Retrosynthetic analysis of australine.
Australine[20] is a particularly interesting target for a mul-
titude of reasons, not the least of which is its highly oxygen-
ated bicyclic core structure containing five contiguous ste-
reogenic centers. In addition, several structurally related al-
kaloids mainly differing in the stereochemical orientation of
the substituents appended to the core have been isolated.[21]
While alexine (38) was the first of this family to be isolated,
other epimeric natural products such as 39 and 40 soon fol-
lowed. These compounds are potent and specific glycosidase
Previous studies from our group have demonstrated that ox-
azolidines are good substrates for these reactions,[24] but 4,5-
disubstituted-oxazolidinones hadnꢁt been explored. The key
issues involved the diastereoselectivity of the reaction. It
needed to be determined if the reaction would be catalyst
or substrate controlled, if 43 can be formed selectively, and
how well will the ring-closing metathesis (RCM) reaction of
43 would perform. To answer these questions, the conditions
previously established were employed using both enantio-
mers of the naphthyl ligand (Scheme 7).
inhibitors. For example, australine was isolated from the
rainforest tree Castanospermum australe[20] and is a mm in-
hibitor of a-glucosidase amyloglucosidase.[22] These com-
pounds and synthetic analogues thereof are attractive drug
targets in the therapeutic areas of cancer, diabetes, and obe-
sity and may potentially be used as antiviral agents. While
several syntheses of australine 40 and its corresponding hy-
drochloride salt have been reported,[23] it was hoped that ap-
plication of compounds derived from 12 in further palladi-
um-catalyzed reactions may lead to a general synthetic strat-
egy to access multiple diastereomeric natural products.
Our retrosynthetic strategy is outlined in Scheme 6 and
relies on a late stage epoxide ring opening to set the all-
trans orientation of the substituents. Based on our previous
work on similar systems, we believed that ring opening of
both of the diastereomeric intermediates corresponding to
41 should yield a single diastereomer.[24] This intermediate
would then be cyclized to form australine. Pyrrolidines 41
should be accessible from the oxazolidinone 42 by function-
alization of the monosubstituted olefin and epoxidation of
the remaining 3-pyrroline. It was believed that 42 should be
readily available from 43 by a chemoselective ring-closing
metathesis reaction, and that 43 should be accessible by the
palladium-catalyzed DYKAT reaction of 44 with nitrogen
nucleophile 45. The oxazolidinone 45 should be easily pre-
pared from 12.
Scheme 7. Diastereoselective alkylation of butadiene monoepoxide.
i) H2NCATHER(UGN CH2)2NH2, EtOH, 96%; ii) triphosgene, pyr., CH2Cl2, 78%;
iii) 0.5 mol% [Pd2dba3]·CHCl3, 1.5 mol% 11, 10 mol% DBU, CH2Cl2,
(R,R)-11: 95:5 dr 46/47, 99%, (S,S)-11: 4:96 dr 46/47, 98%; iv) 1 mol%
Grubbs 2nd-generation catalyst, CH2Cl2, 48: 77%, 49: 73%; v) TBSCl,
imidazole, CH2Cl2, 50:91%, 51:99%.
The requisite oxazolidinone 45 was easily prepared in two
steps from 12 in high yield. Under optimized conditions,
when 45 was allowed to react with 44 in the presence of
0.5 mol% [Pd2dba3]·CHCl3, 1.5 mol% ligand, and 10 mol%
DBU in CH2Cl2, a mixture of ring-opened products 46 and
47 was formed. After subsequent transformation, it was de-
termined that employing the R,R-naphthyl ligand, diastereo-
mer 46 was preferentially formed along with 47 as an insep-
arable mixture in a 95:5 ratio as determined by GC while
the S,S-naphthyl ligand gave a 4:96 ratio favoring 47. As de-
termined in initial experiments with higher catalyst loadings
(2.0 mol% [Pd2dba3]·CHCl3, 6.0 mol% ligand), the S,S-
naphthyl ligand and (S,S)-45 seem to be the matched pair.
This reaction gives a higher diastereomeric ratio and yield
(95 vs 83%) in a shorter reaction time (2.5 vs 5.5 h as
Initial studies sought to answer questions about the feasi-
bility of the palladium-catalyzed ring opening of 44 with 45.
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B. M. Trost et al.
judged by a characteristic color change from the yellow re-
action color to an orange resting catalyst color).
Preliminary experiments focused on first protecting the al-
cohols 46 and 47 as their TBS ethers followed by ring-clos-
ing metathesis using Grubbs first-generation catalyst[25] to
provide 50 and 51, at which stage their relative configura-
Scheme 8. Completion of the synthesis. i) Benzyl 2,2,2-trichloroacetimi-
date, TfOH, 94%, ii) 9-BBN, THF; NaBO3·H2O, H2O, 74%; iii) Oxone,
trifluoroacetone, NaHCO3, MeCN/aqueous EDTA, 08C, 67%;
iv) Dowex 1X8-50, BnOH, 1008C, 51%; v) MsCl, Et3N, CH2Cl2, 74%;
vi) H2, PdCl2, MeOH, 98%.
tions (and therefore those of 46 and 47) were determined by
NOE DIFF and NOESY experiments. It was later found, as
illustrated in Scheme 7, that using the unprotected alcohols
46 and 47 directly, RCM could be effected in good yield em-
ploying Grubbs second-generation catalyst. Protection of
the resultant primary alcohols gave the TBS ethers in high
yield. It was also fortuitous that 48 and 49 were separable
by careful chromatographic purification, whereas none of
the other sets of diastereomers could be cleanly separated.
With one of the two pyrrolizidine rings now formed and
three of the stereogenic centers established, the two main
objectives were to introduce the remaining oxygenated ste-
reocenters and to transform the remaining terminal olefin
into a group suitable for the formation of the fused ring. It
was decided to first try to take advantage of the free hy-
droxyl group in 48 and to do a directed epoxidation of the
proximal disubstituted olefin. While it is postulated that the
diastereoselectivity of the reaction is irrelevant, the forma-
tion of a single diastereomer is preferable for characteriza-
tion purposes and for further transformations. The chemose-
lectivity of the reaction was of some concern as both the de-
sired olefin and the monosubstituted olefin were both elec-
tron deficient and predicted to react sluggishly. At pro-
longed reaction times, using mCPBA buffered with
NaHCO3 in CH2Cl2, no reaction is observed. Using the
more reactive trifluoroperacetic acid, a myriad of products
was observed. The use of methyltrioxorhenium (MTO) with
urea hydrogen peroxide adduct as the terminal oxidant did
provide the epoxide in good yield as one diastereomer, but
was difficult to reproduce.
with in situ generated methyl trifluoromethyl dioxirane[24] to
give 53 as a single diastereomer in 67% yield.
To finish the synthesis, it was necessary to remove the ox-
azolidinone carbonyl group, open the epoxide, and cyclize
to form the pyrrolizidine. Solvolysis of the oxazolidinone
was first attempted by using resin bound base.[28] Under the
reported conditions (Dowex 1X8-50, HOꢀ form in methanol
at room temperature) no reaction occurred. The heteroge-
neous mixture was heated to 658C overnight where partial
conversion to a single additional compound was observed
by 1H NMR spectroscopy.
After considerable experimentation, it was determined
that both the oxazolidinone and epoxide moieties of 53 had
been solvolyzed under the reaction conditions, forming a
single adduct that had incorporated a molecule of methanol.
It would be beneficial to do both the hydrolysis and epoxide
ring opening in a single step; however, incorporation of a
methoxy group would certainly need to be avoided. While
there are no reports of the same conditions using alcohols
other than methanol, the obvious choice was to employ
benzyl alcohol because, in addition to solvolyzing the oxazo-
lidinone and opening the epoxide, it would also serve as a
protecting group. Under similar conditions, using benzyl al-
cohol at 1008C for 9 h, the desired reaction was effected,
forming 54 in 67% yield as a single diastereomer assigned
the all-trans stereochemistry illustrated in Scheme 8. Based
on analogy to our previous experience opening 3-pyrroline
oxides,[24] this assumption seemed reasonable and conversion
to the natural product after two additional steps would later
confirm the stereochemistry.
Since epoxidation of 48 was problematic, it was decided
that it would likely be easier to change the order of the
transformations, that is, to first install a group suitable for
forming the second ring. The monosubstituted olefin of 48
would be predicted to be selectively hydroborated in the
presence of the disubstituted olefin and the resulting alcohol
could be transformed into a variety of leaving groups. To
this end, the free alcohol of 48 was first protected as a
benzyl ether in 94% yield using the benzyl 2,2,2-trichloro-
With a good source of 54 in hand, the final stages re-
quired cyclization of the free amine with loss of the primary
alcohol to form the pyrrolizidine and deprotection of the
two benzyl groups to form australine. Cyclization was pro-
moted by selective formation of the primary mesylate by
using standard conditions at ꢀ308C with concomitant dis-
placement by the secondary amine to form the pyrrolizidine
in 74% yield (Scheme 8). It was decided to remove the
ACHTREUNG
imidate method.[26] Hydroboration followed by sodium per-
borate oxidation[27] then smoothly provided the primary al-
[25]
cohol 52 (Scheme 8). The remaining olefin was epoxidized
benzyl groups using PdCl2/H2 because it would give the
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Pd-Catalyzed Asymmetric Allylic Alkylation
FULL PAPER
HCl salt directly. This was desirable because literature re-
ports indicated that free australine was not nearly as stable
as its hydrochloride salt.[23f] In the event, (+)-australine hy-
ring or the five-membered butenolide. To probe this issue,
an acryloyl group was easily introduced in good yield to
form 61 (Scheme 10), and RCM experiments followed. At-
tempts to use the standard Grubbs first-generation catalyst
1
drochloride was formed in 98% yield whose H, 13C and IR
spectra as well as optical rotation matched the literature
data.[23f]
Formal synthesis of isoaltholactone by chemoselective meta-
thesis reactions: In addition to the use of the phthalimide
derived product, we were also interested in exploring che-
moselective reactions of the monoprotected diene diol in
the context of a synthesis. We were first attracted to the nat-
ural product goniotriol 56 because of the readily apparent
syn diol motif flanked by an alkene and an additional diol
that could potentially be derived from oxidation of an
olefin. Goniotriol is part of a family of so-called styryl lac-
tones and shares structural similarity to many natural prod-
ucts including altholactone 57 and isoaltholactone 58.[29] This
family of natural products has a diverse biological activity,
with altholactone 58 being one of the most cytotoxic com-
Scheme 10. Initial selectivity experiments. i) Acryloyl chloride, DMAP,
Et3N, CH2Cl2, 08C!RT, 71%; ii) 10 mol% Grubbs 2nd-generation cata-
lyst, CH2Cl2, reflux 2.5 h, 70%.
failed even at prolonged reaction times, while the second-
generation catalyst provided the butenolide 62 in 2.5 h. The
five-membered lactone was formed completely selectively
over the six-membered ring. During the course of our initial
investigation, similar observations were reported.[33]
Since the butenolide was so easily formed, it was decided
to move forward and try to introduce the phenyl group and
later expand the ring. The desired ring system would hope-
fully be obtained once the alcohol is deprotected and ex-
posed to equilibrating conditions to “walk” the ester one al-
cohol over and form the desired six-membered ring. The
triene 21 was exposed to the previous conditions that pro-
vided the butenolide followed by introduction of styrene
and prolonged reaction time to hopefully do cross-metathe-
sis (CM) on the remaining monosubstituted olefin. Surpris-
ingly, 62, which is the product of only RCM, resulted as the
major product along with the desired styrene 63 in a com-
bined yield of 75% (Scheme 11).
pounds in general while isoaltholactone is selective for HT-
29 colon cancer cells.[30] There has been significant interest
in these compounds due to their cytotoxicity and many total
syntheses have appeared largely relying on the chiral pool
for starting materials.[31] The development of a synthetic
strategy that relies on a catalytic enantioselective method to
set the initial stereochemistry would provide a facile entry
to this class of compounds, and we set our sights on isoaltho-
lactone.
Our initial retrosynthetic analysis relied upon the known
conversion of the protected styrene 59 to isoaltholactone 58
by chemoselective epoxidation of the styryl olefin with con-
comitant TBS deprotection and cyclization of the resulting
free alcohol to form the natural product (Scheme 9).[32] It
was believed that the a,b-unsaturated lactone could be
formed by RCM of a suitable protected acrylic ester 60, and
that the necessary compound would be readily available by
a chemoselective phenylation of the monoprotected diol 21.
At the outset of this work, it was unclear whether RCM
of a triene such as 61 would form the desired six-membered
Scheme 11. Attempted tandem RCM/CM.
This result was fairly unexpected as a relatively high cata-
lyst loading and styrene concentration as well as a long reac-
tion time afforded only a small percentage of the product in-
corporating a phenyl group. Additionally, it is in contrast to
a previous report where the alcohol is protected as a TBS
ether and the tandem RCM/CM process works well.[23b] It
was postulated that the electron-rich aryl ether was some-
how responsible for the lack of reactivity of the monosubsti-
tuted olefin.[34] To test this, the ether was oxidatively cleaved
using CAN in aqueous acetonitrile to provide 64 in 70%
yield (Scheme 12). CM with dodecene under our standard
conditions did indeed smoothly provide 65 which also led to
a synthesis of muricatacin 66 after hydrogenation.[35]
Scheme 9. Retrosynthetic analysis of isoaltholactone.
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B. M. Trost et al.
remove this group to date is on compounds that have a
styryl double bond.
Since the CM and RCM of 21 are both highly chemose-
lective reactions, cross-metathesis of phthalimide 12 with do-
decene was attempted to determine if this is a general trend
of this type of diene. Under the conditions illustrated in
Scheme 14, the desired product 70 was obtained along with
Scheme 12. Synthesis of muricatacin. i) CAN, CH3CN/H2O, 70%;
ii) 5 equiv dodecene, 10 mol% Grubbs 2nd-generation catalyst, CH2Cl2,
reflux 1 h, 84%; iii) H2, Pd/C, 93%.
Since such difficultly was being encountered in attempts
to introduce the phenyl group on the allylic aryl ether, it
was postulated that the aryl moiety was somehow slowing
the reaction at this position and that a chemoselective cross-
metathesis reaction may be possible with the acyclic precur-
sor 21. Under our standard initial conditions, the styryl
group was then selectively introduced in 72% yield to the
free alcohol allylic double bond as one geometrical isomer
(Scheme 13). To form the desired synthetic intermediate 62,
Scheme 14. CM of N-protected amino diene.
a trace of the doubly reacted product 71. When five equiva-
lents of olefin and 10 mol% Grubbs second-generation cata-
lyst was used, our standard initial conditions, 70 was isolated
in 62% yield along with 12% of 71. So clearly the second
olefin of 12 is much more reactive towards metathesis than
21, further evidence that the electron-rich arene plays a
major role in deactivating the olefin.
Since the absolute configuration of 21 is S,S, it does not
matter which olefin the phenyl group is appended to and
consequently which olefin is used to form the lactone. As
long as the sequence is chemoselective for one of the ole-
fins, and the molecule is suitably protected, the penultimate
intermediate 59 should be accessible. With this in mind, and
due to difficulty encountered in attempts to cleanly remove
the aryl ether, it was then postulated that 59 should be ac-
cessible by isomerization of the trans-a,b-unsaturated
double bond of an intermediate such as 72 (Scheme 15) to
cis followed by lactone formation. This compound could
hopefully be prepared by two selective cross-metathesis re-
actions on 21 with the introduction and removal of the aryl
group to allow for protecting groups to be introduced in the
proper order.
Scheme 13. Attempted RCM. i) 10 mol% Grubbs 2nd-generation cata-
lyst, 10 equiv styrene, CH2Cl2, reflux 2.5 h, 72%; ii) acryloyl chloride,
DIPEA, CH2Cl2, 08C, 88%; iii) 10 mol% Grubbs 2nd-generation cata-
lyst, CH2Cl2, reflux 16 h, then 10 additional mol% cat. reflux 24 h, 69:
27%, mixture of 62 and 63: 30%.
the free alcohol was acylated to append the acryloyl group
and RCM attempted. At this point, it was thought that the
RCM reaction of 68 should smoothly produce the desired
product because the reaction is between two monosubstitut-
ed olefins. Unfortunately, in the event, what was observed
under forcing conditions was a mixture of three compounds
including the desired product 69 in 27% and the two previ-
ously prepared butenolides 62 and 63 in a combined yield of
30%.
Scheme 15. Revised retrosynthetic analysis.
Since in the attempted RCM of 68, the disubstituted
olefin competes with the monosubstituted aryl ether olefin,
cross-metathesis between styrene and 21 selectively reacts
with the non-aryl allylic alkene to provide 67, and cross-
metathesis of 62 effectively fails, the difficulty must be due
to the aryl moiety. This fact should prove useful when it is
necessary to protect an allylic alcohol from ruthenium-cata-
lyzed metathesis reactions. In the present case it would then
follow that deprotection of the aryl group should eliminate
the current problems. Unfortunately all attempts to oxida-
tively deprotect 67 to the free alcohol were unsuccessful. It
is noteworthy that the only time it has proven difficult to
Initial studies were focused on selectively functionalizing
the termini via chemoselective cross-metathesis reactions.
Although the CM between a secondary allylic alcohol and
an acrylate may not be predicted to be a good reaction,[36]
the acrylate 73 was isolated in 60% yield as the E olefin
with no reaction observed on the allylic ether olefin. The
free alcohol was then protected as its TBS ether and the
aryl ether oxidatively cleaved using ceric ammonium nitrate
to give 74 in 68% over two steps (Scheme 16). Cross-meta-
thesis of 74 with styrene using Grubbs second-generation
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Pd-Catalyzed Asymmetric Allylic Alkylation
FULL PAPER
AHCTREUNG
In order to lactonize the acyclic methyl ester to form the
precursor to 77, the products were taken up in toluene and
heated at reflux for 4 h. This, however, did not lead to disap-
pearance of the methyl ester or additional formation of lac-
tone. Oteraꢁs tin catalyst[38] was added and after 2 h at reflux
in toluene all acyclic methyl ester 76 had lactonized in 85%.
Without separation of products, running this two-step se-
quence in succession resulted in a combined yield of 77%.
The next step involved another cross-metathesis to intro-
duce the styryl functionality. Treating 14 with styrene and
Grubbs second-generation catalyst in refluxing methylene
chloride overnight gave compound 77 in 90% yield. Elimi-
nation of benzenethiol with DBU in CH2Cl2 also proceeded
uneventfully, to complete the formal synthesis providing 59
in 89% yield.
Scheme 16. Sequential functionalization of the termini. i) 5 equiv methyl
acrylate, 10 mol% Grubbs 2nd-generation catalyst, CH2Cl2, reflux 1 h,
60%; ii) TBS-OTf, 2,6-lutidine, CH2Cl2; iii) CAN, CH3CN/H2O, 68% (2
steps); iv) 5 equiv styrene, 10 mol% Grubbs 2nd-generation catalyst,
CH2Cl2, reflux 16 h, 59%.
catalyst then provided 75 in 59% yield, demonstrating that
the initial chain in 21 can be extended in both directions
with the introduction of functional groups that allow for fur-
ther differentiation.
While this sequence demonstrates that it is possible to in-
troduce the functional groups necessary for isoaltholactone,
further optimization was necessary to reduce the amount of
catalyst used and to provide enough material to complete
the synthesis. To this end, 73 was obtained in 69% yield
using 2 mol% Grubbs second-generation catalyst with five
equivalents of methyl acrylate by refluxing for 2 h in
CH2Cl2. The TBS group was then introduced using TBSCl
in 98% yield, and the aryl ether was deprotected using
CAN in acetonitrile and water to provide 74 in quantitative
yield. At this point the second CM was postponed until
after lactonization to avoid any potential for metathesis on
the undesired olefin. The lactone was then formed in a two
step process involving conjugate addition of benzenethiol
and cyclization. Initially, 74 was treated with benzenethiol
and piperidine in acetonitrile at 858C according to the pro-
cedure of Tanikaga.[37] Finally, we attempted the conjugate
addition of benzenethiol by simply stirring 74 (Scheme 17)
in benzenethiol as the solvent with a catalytic amount of tri-
Conclusion
In summary, we have developed a simple, three-step, catalyt-
ic enantioselective procedure to produce synthetically useful
monoprotected diols and N-protected aminoalcohols in high
ee from a mixture of dl- and meso-1,2-divinylethylene car-
bonate that is easily prepared from the commodity chemical
acrolein. Although the process did not proceed as was ini-
tially expected, an interesting mechanism involving both a
kinetic resolution and desymmetrization in a convergent
process is proposed. The present study demonstrates how
well a series of equilibrating intermediates can behave when
a proper balance of the relative variables is achieved and
may potentially lead to further examples where mismatched
substrate catalyst pairs also enter the reaction. Additionally,
the compounds produced have been demonstrated to be
useful synthons. Since each backbone atom in the product is
differentiated, further chemoselective transformations
should make a wide range of chiral compounds easily acces-
sible for future syntheses. (+)-australine hydrochloride and
isoaltholactone were easily prepared in a straightforward
manner using this methodology. These syntheses nicely dem-
onstrate further use of the products and feature a highly dia-
stereoselective Pd-catalyzed ring opening of butadiene mon-
oepoxide as well as a series of chemoselective ring-closing
and cross-metathesis reactions.
Scheme 17. Formal synthesis of isoaltholactone under optimized condi-
tions. i) 5 equiv methyl acrylate, 2 mol% Grubbs 2nd-generation catalyst,
CH2Cl2, reflux 2 h, 69%; ii) TBSCl, imidazole, CH2Cl2, 98%; iii) CAN,
CH3CN/H2O, quantitative; iv) PhSH, Et3N, 83%; v) Oteraꢁs cat. toluene,
85% (77% over two steps if products not separated); vi) 5 equiv styrene,
5 mol% Grubbs 2nd-generation catalyst, CH2Cl2, reflux 16 h, 90%;
vii) DBU, CH2Cl2, 89%.
Experimental Section[39]
cis- and trans-1,2-Divinylethylene carbonate (7 and 8): According to the
procedure of Hekmatshoar,[7] acrolein (10.0 mL, 150 mmol) was added to
a biphasic mixture of saturated aqueous ammonium chloride (225 mL)
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B. M. Trost et al.
and THF (375 mL). Zinc powder (1.95 g, 29.9 mmol) was then added in 1
portion and the biphasic mixture was allowed to stir overnight, at which
point TLC analysis indicated that the starting material had been con-
sumed. The crude reaction mixture was filtered over celite with CH2Cl2,
diluted with water, and extracted with CH2Cl2. The combined organic ex-
tract was dried over magnesium sulfate and the solvent removed in
vacuo. Two batches run at this scale were combined and flash chromatog-
raphy (gradient, 20 to 30% EtOAc/petroleum ether) afforded a colorless
oil (13.7 g, 80%) that was taken directly on.
According to the procedure of Braun,[5a] the diol (13.7 g, 120 mmol) was
dissolved in diethyl carbonate (18.2 mL, 1.25 equiv) and potassium car-
bonate (0.0498 g, 0.361 mmol) was added. The flask was equipped with a
shortpath distillation head, and the reaction mixture was heated to 1158C
and maintained for 2 h, during which time ethanol distilled off. The crude
product was cooled to RT and directly purified by flash chromatography
(gradient, 10 to 30% EtOAc/petroleum ether) to afford the title com-
pound as a pale yellow oil (14.4 g, 84%).
leum ether) to afford 12 (3.4200 g, 70%, 94% based on a maximum 75%
conversion).
AHCTRE(GNU S,S)-4-(4-Methoxy-2,3-dimethylphenoxy)hexa-1,5-dien-3-ol (21) and 6-
(4-methoxy-2,3-dimethylphenoxy)hexa-1,4-dien-3-ol (22): 4-Methoxy-2,3-
dimethylphenol (20; 0.5458 g, 3.6 mmol), (R,R)-11 (0.0851 g, 0.11 mmol),
and p-allylpalladium chloride dimer (0.0131 g, 0.036 mmol) were tared
into a 100 mL Schlenk flask. The reaction vessel was evacuated for a
period of 5 min, then backfilled with nitrogen. The procedure was repeat-
ed two additional times before CH2Cl2 (35 mL, degassed by freeze/pump/
thaw method) was added, and the resulting suspension allowed to stir for
15 min before being cooled to 08C in an ice bath. The cyclic carbonates 7
and 8 (0.6527 g of a 1:1 mixture, 4.66 mmol) were tared into a vial,
purged with nitrogen for 15 min, dissolved with CH2Cl2 (11.6 mL, de-
gassed by freeze/pump/thaw method), and slowly added to the reaction
mixture. The mixture was allowed to stir and slowly warm to 48C at am-
bient rate over 48 h before being poured into a separatory funnel con-
taining ether and 1m NaOH. The layers were then separated and the or-
ganic layer washed with two additional portions 1m NaOH and one
brine. The ethereal solution was then dried (MgSO4) and the solvent re-
moved in vacuo. Flash chromatography (gradient 2 to 25% EtOAc/petro-
leum ether) afforded 21 as a pale yellow oil (0.6580 g, 59%) and 22 as a
colorless oil (0.0569, 5%).
Pure samples of each compound were obtained by flash chromatography
(gradient, 1 to 20% EtOAc/petroleum ether):
trans-1,2-Divinylethylene carbonate (7): Rf =0.40 (20% EtOAc/petrole-
um ether); 1H (300 MHz, CDCl3): d = 5.93–5.82 (m, 2H), 5.48 (d, J=
16.8 Hz, 2H), 5.43 (d, J=10.2 Hz, 2H), 4.76–4.65 ppm (m 2H); 13C NMR
Data for 21: Rf =0.56 (20% EtOAc/petroleum ether); [a]2D2 = +1.44 (c=
(75 MHz, CDCl3): d = 153.9, 131.0, 121.7, 82.4 ppm; IR (neat): n˜
=
1.06, CH2Cl2); 1H (300 MHz, CDCl3): d = 6.65 (ABq, J=9.0 Hz, DnAB
=
3095, 2996, 2929, 1806 cmꢀ1; HRMS (EI): m/z: calcd for C6H7O3: 95.0497,
21.6 Hz, 2H), 5.97 (ddd, J=16.5, 10.5, 5.4 Hz, 1H), 5.84 (ddd, J=17.1,
10.8, 6.6 Hz, 1H), 5.47–5.25 (m, 4H), 4.43 (t, J=6.6 Hz, 1H), 4.32 (brs,
1H), 3.77 (s, 3H), 2.63 (d, J=3.6 Hz, 1H), 2.20 (s, 3H), 2.16 ppm (s,
3H); 13C NMR (75 MHz, CDCl3): d = 152.4, 149.5, 136.0, 134.4, 127.7,
126.6, 119.6, 117.4, 112.0, 107.7, 83.6, 74.8, 55.9, 12.6, 12.1 ppm; IR (neat):
n˜ = 3453 cm ꢀ1: HRMS (EI): m/z: calcd for C15H20O3: 248.1412, found
248.1401 [M +].
found 95.0496 [MꢀCO2H+].
cis-1,2-Divinylethylene carbonate (8): Rf =0.32 (20% EtOAc/petroleum
ether); 1H (300 MHz, CDCl3): d
=
5.81–5.70 (m, 2H), 5.47 (d, J=
17.7 Hz, 2H), 5.42 (d, J=11.1 Hz, 2H), 5.19–5.13 ppm (m 2H); 13C NMR
(75 MHz, CDCl3): d = 154.2, 129.8, 121.4, 80.0 ppm; IR (neat): n˜
=
3094, 2995, 1805 cmꢀ1; HRMS (EI): m/z: calcd for C6H7O3: 95.0497,
found 95.0489 [MꢀCO2H+].
Data for 22: Rf =0.30 (20% EtOAc/petroleum ether); [a]2D2 = ꢀ0.34 (c=
1.0, CH2Cl2); 1H (300 MHz, CDCl3): d = 6.64 (ABq, J=9.3 Hz, DnAB
=
ACHTREUNG
9
4.9 Hz, 2H), 6.00–5.87 (m, 3H), 5.30 (dt, J=15.9, 1.2 Hz, 1H), 5.81 (dt,
J=10.2, 1.5 Hz, 1H), 4.71 (t, J=4.8 Hz, 1H), 4.48 (d, J=4.2 Hz, 2H),
3.78 (s, 3H), 2.19 (s, 3H), 2.17 (s, 3H), 1.79 ppm (brs, 1H); 13C NMR
(0.1186 g, 0.15 mmol), and p-allylpalladium chloride dimer (0.0183 g,
0.05 mmol) were tared into a 100 mL flask. The reaction vessel was evac-
uated for a period of 5 min, then backfilled with nitrogen. The procedure
was repeated two additional times before CH2Cl2 (30.0 mL, degassed by
freeze/pump/thaw method) was added, and the resulting suspension al-
lowed to stir for 15 min. A 1:1 mixture of the cyclic carbonates 7 and 8
(0.7006 g, 5.0 mmol) was tared into a small flask, purged with argon for
15 min, dissolved with CH2Cl2 (10.0 mL, degassed by freeze/pump/thaw
method), and added to the reaction mixture. After stirring for 72 h at
room temperature, the solvent was removed in vacuo and the reaction
mixture was directly applied to a column and subjected to flash chroma-
tography on silica gel (gradient, 5 to 25% EtOAc/petroleum ether) to
afford 15 (0.9015 g, 74%). Rf =0.20 (20% EtOAc/petroleum ether); [a]D23
= ꢀ86.37 (c=1.0, CH2Cl2); 1H (300 MHz, CDCl3): d = 7.87–7.81 (m,
2H), 7.76–7.71 (m, 2H), 6.22 (ddd, J=17.3, 10.4, 6.9 Hz, 1H), 5.83 (ddd,
J=15.3, 10.5, 4.7 Hz, 1H), 5.43–5.15 (m, 4H), 4.89 (app t, J=6.6 Hz,
1H), 4.72–4.65 (m, 1H), 3.52 ppm (d, J=8.7 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d
= 152.1, 150.8, 139.1, 133.4, 127.3, 127.2, 126.7,
115.5, 109.7, 107.8, 73.2, 68.4, 56.0, 12.3, 12.1 ppm; IR (neat): n˜ = 3374,
1482, 1254, 1112 cmꢀ1. HRMS (EI): m/z: calcd for C15H20O3: 248.1412,
found 248.1405 [M +].
AHCTREUNG
a
100 mL flask. The reaction vessel was evacuated for a period of 5 min,
then backfilled with nitrogen. The procedure was repeated two additional
times before CH2Cl2 (54 mL, degassed by freeze/pump/thaw method) was
added, followed by a solution of oxazolidionone 45 (1.0222 g, 7.35 mmol)
in CH2Cl2 (20 mL), and the resulting solution was allowed to stir for
5 min before the DBU (0.1118 g, 0.73 mmol) was added. After five addi-
tional min, butadiene monoepoxide (0.5149 g, 7.3 mmol) was added and
the mixture was allowed to stir at ambient temperature for 16 h before
the solvent was removed in vacuo. Flash chromatography (gradient, 25 to
50% EtOAc/petroleum ether) afforded a mixture of diasteromers as a
yellow oil(1.5371 g, quantitative yield).
(75 MHz, CDCl3): d
= 168.8, 137.3, 134.2, 132.1, 131.6, 123.5, 118.8,
116.8, 72.7, 58.6 ppm; IR (neat): n˜ = 3463, 1707, 1387 cmꢀ1; HRMS (EI):
m/z: calcd for C11H6NO3: 186.0555, found 186.0545 [MꢀC3H5O+].
Data for 46: Rf =0.39 (50% EtOAc/petroleum ether); 1H (500 MHz,
CDCl3): d = 5.91–5.80 (m, 2H), 5.71 (ddd, J=9.0, 10.0, 17.0 Hz, 1H),
5.43–5.14 (m, 6H), 4.56 (dd, J=7.5, 6.5 Hz, 1H), 4.00–3.80 (m, 4H),
Large-scale preparation of 12: Sodium carbonate (0.1060 g, 1.0 mmol),
phthalimide (2.2364 g, 15.2 mmol, 0.76 equiv), (R,R)-naphthyl ligand
(0.2373 g, 0.30 mmol, 1.5 mol%), and p-allylpalladium chloride dimer
(0.0366 g, 0.10 mmol, 0.5 mol%) were tared into a 250 mL flask. The re-
action vessel was evacuated for a period of 5 min, then backfilled with ni-
trogen. The procedure was repeated two additional times before CH2Cl2
(120.0 mL, degassed by freeze/pump/thaw method) was added, and the
resulting suspension allowed to stir for 15 min. The cyclic carbonates 7
and 8 (2.803 g of a 1:1 mixture, 20.0 mmol) were tared into a flask,
purged with argon for 15 min, dissolved with CH2Cl2 (40.0 mL, degassed
by freeze/pump/thaw method), and added to the reaction mixture. After
stirring for 96 h at room temperature, the solvent was removed in vacuo
and the reaction mixture was directly applied to a column and subjected
to flash chromatography on silica gel (gradient, 10 to 30% EtOAc/petro-
3.57 ppm (brs, 1H); 13C NMR (125 MHz, CDCl3): d
= 157.8, 134.1,
132.6, 132.1, 122.3, 121.4, 119.8, 119.6, 119.0, 80.3, 65.6, 62.9, 59.4 ppm;
HRMS (EI): m/z: calcd for C11H13NO2: 191.0946, found 191.0946
[MꢀH2O+].
(2R,3R,4R,5R)-4-(Benzyloxy)-5-(benzyloxymethyl)-2-((S)-1,3-dihydroxy-
propyl)pyrrolidin-3-ol (54):[40] Dowex 1X8 (Clꢀ form) was activated in
the following manner: The resin (approximately 1 g) was loaded into a
Pasteur pipet and washed with 3m NaOH (20 mL) then water (10 mL).
The resin was then flushed with N2 for 15 min to remove excess water
before benzyl alcohol (10 mL) was passed over the column under a pres-
sure of N2. N2 was then blown over the resin for 5 min to remove excess
9558
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 9547 – 9560

Pd-Catalyzed Asymmetric Allylic Alkylation
FULL PAPER
solvent and facilitate its removal from the column. Approximately
300 mg (the amount necessary to make a thick slurry of resin in the de-
sired amount of solvent) of the resin was added to the oxazolidionone 53
(0.0296 g, 0.097 mmol) and the flask was evacuated and backfilled with
N2 four times. Benzyl alcohol (1.0 mL) was added and the heterogeneous
mixture heated to 1008C for 9 h, at which time TLC analysis indicated a
complete reaction. The mixture was cooled to RT and filtered over Celite
with MeOH. Rotary evaporation of the volatile organic material fol-
lowed by Kugelrohr distillation (0.1 mm Hg, 508C) to remove benzyl al-
cohol afforded a pale yellow oil. Flash chromatography (gradient 2–12%
MeOH/CH2Cl2) provided a pale yellow solid (19.3 mg, 51%). Rf =0.25
(10% MeOH/CH2Cl2); m.p. 95–978C; [a]2D4 = +25.51 (c=1.0, CH2Cl2);
1H (500 MHz, CDCl3): d = 7.36–7.29 (m, 10H), 4.67 (d, J=12.0 Hz, 1H),
4.57 (d, J=12.0 Hz, 1H), 4.53 (s, 2H), 4.08 (dd, J=5.5, 4.0 Hz, 1H),
3.80–3.78 (m, 2H), 3.22 (q, J=5.5 Hz, 1H), 3.10 (t, J=5.0 Hz, 1H), 3.03
(brs, 4H), 1.68–1.64 ppm (m, 2H); 13C NMR (125 MHz, CDCl3): d =
138.0, 137.8, 128.54, 128.53, 127.91, 127.88, 127.80, 127.80, 88.0, 79.0, 73.3,
[2] a) B. M. Trost, R. C. Bunt, R. C. Lemoine, T. L. Calkins, J. Am.
Chem. Soc. 2000, 122, 5968; b) B. M. Trost, E. J. McEachern, F. D.
Toste, J. Am. Chem. Soc. 1998, 120, 12702; c) B. M. Trost, R. C.
Bunt, Angew. Chem. 1996, 108, 70; Angew. Chem. Int. Ed. Engl.
1996, 35, 99; d) B. M. Trost, R. C. Lemoine, Tetrahedron Lett. 1996,
37, 9161; e) B. M. Trost, C. Jiang, J. Am. Chem. Soc. 2001, 123,
12907.
[3] a) S. D. Burke, G. M. Sametz, Org. Lett. 1999, 1, 71; b) K. J. Quinn,
I. K. Isaacs, J. M. Andres, Org. Lett. 2004, 6, 4143; c) K. J. Quinn,
I. K. Isaacs, B. A. DeChristopher, S. C. Szklarz, R. A. Arvary, Org.
Lett. 2005, 7, 1243; d) S. Michaelis, S. Blechert, Org. Lett. 2005, 7,
5513.
[4] a) R. Criegee, E. Hoger, G. Huber, P. Kruck, F. Marktscheffel, H.
Schellenberger, Justus Liebigs Ann. Chem. 1956, 599, 81–125; b) C.
Crombez-Robert, M. Benazza, C. Frechou, G. Demailly, Carbohydr.
Res. 1997, 303, 359.
[5] a) R. A. Braun, J. Org. Chem. 1963, 28, 1383; b) S. Holand, R. Ep-
sztein, Synthesis 1977, 10, 706.
72.0, 71.0, 69.7, 66.2, 63.6, 60.7, 36.1 ppm; IR (neat): n˜
= ;
3357 cmꢀ1
HRMS (EI): m/z: calcd for C22H30NO5: 388.2124, found 388.2136 [M+H+
[6] 1,2-Divinylethylene carbonate is used in the preparation of hexa-
triene monoepoxide by pyrolysis, see ref. [5].
].
Australine hydrochloride (55): Mesyl chloride (6.2 mg, 0.054 mmol) was
added to a solution of 54 (19.0 mg, 0.049 mmol) and Et3N (10.9 mg,
0.11 mmol) in CH2Cl2 (1.0 mL) at ꢀ308C. The temperature was main-
tained for 1 h then allowed to slowly warm to 08C over 1 h then to RT
for 20 min. The solvent was removed in vacuo and flash chromatography
(gradient 2 to 10% MeOH, CH2Cl2) afforded a pale yellow oil (13.4 mg,
[7] R. Hekmatshoar, I. Yavari, Y. S. Beheshtiha, M. M. Heravi, Mon-
atsh. Chem. 2001, 132, 689.
[8] a) B. M. Trost, L. Weber, J. Am. Chem. Soc. 1975, 97, 1611; b) B. M.
Trost, T. R. Verhoeven, J. Am. Chem. Soc. 1976, 98, 630; c) T. Haya-
shi, T. Hagihara, M. Konishi, M. Kumada, J. Am. Chem. Soc. 1983,
105, 7767; d) J. C. Fiaud, L. Y. Legros, J. Org. Chem. 1987, 52, 1907;
e) I. Stary, J. Zajicek, P. Kocovsky, Tetrahedron 1992, 48, 7229.
[9] To the best of our knowledge, only one Pd AAA of an acyclic meso
bis-electrophile has been reported and it was in an intramolecular
cyclization: L. Jiang, S. D. Burke, Org. Lett. 2002, 4, 3411.
[10] M. Kimura, S. Tanaka, Y. Tamaru, Bull. Chem. Soc. Jpn. 1995, 68,
1689.
[11] J. M. Andres, N. de Elena, R. Pedrosa, A. Perez-Encabo, Tetrahe-
dron 1999, 55, 14137.
[12] The difference in magnitude of the optical rotation may be due to
differing water content. The value reported in the present study was
recorded using anhydrous methanol.
74%). Rf =0.36 (10% MeOH/CH2Cl2); [a]D24
=
ꢀ9.9240 (c=1.0,
CH2Cl2); 1H (500 MHz, CDCl3): d = 7.37–7.26 (m, 10H), 4.71 (d, J=
12.0 Hz, 1H), 4.60 (d, J=12.0 Hz, 1H), 4.56 (d, J=12.0 Hz, 1H), 4.53 (d,
J=12.0 Hz, 1H), 4.28 (dd, J=7.0, 6.0 Hz, 1H), 4.16–4.12 (m, 2H), 3.63–
3.54 (m, 2H), 3.45 (dd, J=5.5, 4.0 Hz, 1H), 3.20–3.12 (m, 1H), 2.91 (q,
J=6.5 Hz, 1H), 2.77–2.72 (m, 1H), 1.99–1.90 ppm (m, 3H); 13C NMR
(125 MHz, CDCl3): d = 138.5, 138.1, 128.5, 128.45, 127.82, 127.80, 127.72,
127.70, 81.4, 81.1, 73.5, 73.0, 72.5, 72.1, 71.1, 70.6, 52.4, 36.9 ppm; IR
(neat): n˜ = 3385 cmꢀ1; HRMS (EI): m/z: calcd for C16H20NO4: 278.1392,
found 278.1394 [MꢀPhH2+].
Based on the previously reported procedure,[25] palladium chloride
(8.0 mg) was added to
a solution of the dibenzyl ether (8.0 mg,
[13] B. M. Trost, T. Zhang, Org. Lett. 2006, 8, 6007.
0.022 mmol) in MeOH (1 mL) and the heterogeneous mixture was stirred
rapidly for 20 min. The flask was evacuated under a gentle vacuum and
backfilled with H2 (5”), then allowed to stir for 1.25h. The crude reac-
tion mixture was then evacuated under a gentle vacuum and backfilled
with air (5”) and filtered over Celite with MeOH. Evacuation of the sol-
vent provided an extremely pure sample of the title compound as an
opaque white oil (4.8 mg, 98%) that satisfactorily matched all previously
reported data.[23f] [a]D24 = +22.35 (c=0.3, H2O), lit.[23f] [a]2D0 = +22.2
(c=0.50, H2O); 1H (600 MHz, D2O reference set to 4.78 ppm): d = 4.68
(dd, J=6.6, 4.2Hz, 1H), 4.84 (t, J=7.8Hz, 1H), 4.15 (dd, J=10.2, 7.8Hz,
1H), 3.99 (dd, J=13.2, 3.6Hz, 1H), 3.92–3.88 (m, 2H), 3.81 (ddd, J=
11.4, 7.8, 3.0Hz, 1H), 3.42–3.35 (m, 2H), 2.33–2.29 (m, 1H), 2.26–
2.19 ppm (m, 1H); 13C NMR (150 MHz, CDCl3): d = 75.4, 72.6, 71.4,
[14] H. Kim, C. Lee, Org. Lett. 2002, 4, 4369.
[15] B. M. Trost, E. J. McEachern, J. Am. Chem. Soc. 1999, 121, 8649.
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[17] B. M. Trost, F. D. Toste, J. Am. Chem. Soc. 1999, 121, 4545; for a
recent review covering the use of the wall and flap diagram see ref.
[1].
[18] a) B. M. Trost, Acc. Chem. Res. 1996, 29, 355; b) B. M. Trost, Chem.
Pharm. Bull. 2002, 50, 1.
[19] B. M. Trost, J. L. Belletire, S. Godleski, P. G. McDougal, J. M. Balko-
vec, J. Org. Chem. 1986, 51, 2370.
[20] R. J. Molyneaux, M. Benson, R. Y. Wong, J. E. Tropea, A. D. Elbein,
J. Nat. Prod. 1988, 51, 1198.
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Asano, R. J. Molyneux, R. J. Nash, Phytochemistry 2001, 56, 265;
b) N. Asano, R. J. Nash, R. J. Molyneux, G. W. J. Fleet, Tetrahedron:
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[22] a) J. E. Tropea, R. J. Molyneaux, G. P. Kaushal, Y. T. Pan, M. Mitch-
ell, A. D. Elbein, Biochemistry 1989, 28, 2027; b) R. J. Nash, L. E.
Fellows, J.V. Dring, G. W. J. Fleet, A. Girdhar, N. G. Ramsden, J. M.
Peach, M. P. Hegarty, A. M. Scofield, Phytochemistry 1990, 29, 111.
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b) W. H. Pearson, J.V. Hines, J. Org. Chem. 2000, 65, 5785; c) J. D.
White, P. Hrnciar, A. F. T. Yokochi, J. Am. Chem. Soc. 1998, 120,
7359; d) J. D. White, P. Hrnciar, J. Org. Chem. 2000, 65, 9129; e) A.
Romero, C.-H. Wong, J. Org. Chem. 2000, 65, 8264; f) S. E. Den-
mark, E. A. Martinborough, J. Am. Chem. Soc. 1999, 121, 3046;
g) C. Ribes, E. Falomir, M. Carda, J.A. Marco, Org. Lett. 2007, 9,
77; h) Prepared from castanospermine: R. H. Furneaux, G. J. Gain-
sford, J. M. Mason, P. C. Tyler, Tetrahedron 1994, 50, 2131.
70.6, 68.0, 55.7, 52.1, 34.3 ppm; IR (neat): n˜ = 3355 cmꢀ1
.
Acknowledgements
We thank the National Science Foundation and National Institutes of
Health (GM 33049) for their generous support of our programs. A.A. is
supported by an NIH postdoctoral fellowship. B.N.S. thanks Pfizer and
Stanford University for summer research fellowships. 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. We thank Johnson Matthey for their generous gift of palladi-
um salts.
[1] B. M. Trost, M. R. Machacek, A. Aponick, Acc. Chem. Res. 2006,
39, 747, and references therein.
Chem. Eur. J. 2007, 13, 9547 – 9560
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9559

B. M. Trost et al.
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R. A. Arvary, Org. Lett. 2005, 7, 1243.
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but the selectivity is attributed to sterics, for leading references see:
S. BouzBouz, R. Simmons, J. Cossy, Org. Lett. 2004, 6, 3465.
[35] During our work in this area a similar strategy appeared in the liter-
ature in a synthesis of muricatacin, see ref. [33a].
[36] A.K. Chatterjee, T. Choi, D. P. Sanders, R. H. Grubbs, J. Am. Chem.
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[39] See Supporting Information for full experimental details and spec-
tra.
[31] For a review with leading references see: G. Zhao, B. Wu, X. Y. Wu,
Y. Z. Zhang, Mini-Rev. Org. Chem. 2005, 2, 333.
[40] Procedure adapted from that of ref. [28].
Received: June 1, 2007
[32] J. M. Harris, G. A. OꢁDoherty, Tetrahedron 2001, 57, 5161.
Published online: September 11, 2007
9560
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Chem. Eur. J. 2007, 13, 9547 – 9560