Palladium-catalyzed asymmetric construction of vicinal all-carbon quaternary stereocenters and its application to the synthesis of cyclotryptamine alkaloids

Article abstract of DOI:10.1002/anie.201302805

A twofold Pd-DAAA Pd-catalyzed decarboxylative allylic alkylation (see scheme) was used to construct two vicinal all-carbon quaternary stereocenters (marked in red) in a diastereo- and enantioselective fashion. The products of the Pd-DAAA were further ela

Full text of DOI:10.1002/anie.201302805

Angewandte
Chemie
Communications
Palladium Catalysis
B. M. Trost,* M. Osipov
&&&& — &&&&
Palladium-Catalyzed Asymmetric
Construction of Vicinal All-Carbon
Quaternary Stereocenters and its
Application to the Synthesis of
Cyclotryptamine Alkaloids
A twofold Pd-DAAA Pd-catalyzed decar-
boxylative allylic alkylation (see scheme)
was used to construct two vicinal all-
carbon quaternary stereocenters (marked
in red) in a diastereo- and enantioselec-
tive fashion. The products of the Pd-
DAAA were further elaborated to com-
plete the formal syntheses of cyclotrypt-
amine alkaloids. The twofold Pd-cata-
lyzed transformation proceeds through
an initial matched allylation followed by
a second mismatched allylation to deliver
the desired product.
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DOI: 10.1002/anie.201302805
Palladium Catalysis
Palladium-Catalyzed Asymmetric Construction of Vicinal All-Carbon
Quaternary Stereocenters and its Application to the Synthesis of
Cyclotryptamine Alkaloids**
Barry M. Trost* and Maksim Osipov
The cyclotryptamine alkaloids are a diverse group of natural
products with a wide array of biological activities (Figure 1).[1]
This family of alkaloids consists of hexahydropyrroloindole
units linked to form oligomers of varying sizes. Cyclotrypt-
amine alkaloids are found in a number of different types of
plants and animals.
presence of this structural element greatly complicates the
asymmetric assembly of such molecular architectures because
of the steric congestion present when bringing four carbon
substituents together. Over the last several decades, extensive
research has been devoted to develop methods that can
assemble quaternary all-carbon stereocenters in an asymmet-
ric fashion, including cycloadditions, pericyclic reactions, and
metal-catalyzed alkylation strategies.[3] When a second vicinal
quaternary center is present in a synthetic target, the
asymmetric assembly is complicated further. In fact, the
construction of adjacent quaternary stereocenters has been
referred to as “a daunting challenge in natural product
synthesis”.[4] Currently, few methods exist for the construction
of vicinal quaternary carbon centers in a single synthetic
operation; hence each stereocenter is typically assembled
sequentially. Furthermore, relatively few examples have been
reported for the assembly of this structural motif in a catalytic
asymmetric manner.[5]
The Pd-catalyzed decarboxylative asymmetric allylic
alkylation (Pd-DAAA) has proven to be a mild, robust, and
functional-group-tolerant method for the construction of
stereocenters with high levels of diastereo- and enantioselec-
tivity.[6] This transformation has been performed with a variety
of nucleophiles, including ketones, b-ketoesters, acyl imid-
azoles, N-acyl oxazolidinones, and 2-oxindoles.[7] Recently,
the Pd-DAAA was used to construct two quaternary carbon
stereocenters bearing a 1,4 relationship.[8] We sought to test
the limits of the Pd-DAAA by constructing two vicinal
quaternary carbon stereocenters in a single operation. Unlike
two stereocenters in a distal 1,4 relationship, construction of
two vicinal quaternary carbon stereocenters leads to sterically
congested intermediates and products. Furthermore, the
stereochemistry of the second stereocenter would likely be
affected by the result of the first allylation; that is, substrate
control will compete with chiral-catalyst control.
Our retrosynthetic strategy to access the cyclotryptamine
core is outlined in Scheme 1. We envisioned that cyclotrypt-
amines (ꢀ)-chimonanthine (1), (ꢀ)-folicanthine, (2) (+)-caly-
canthine (3), (ꢀ)-WIN 64821 (4), and (ꢀ)-ditryptophenaline
(5) could be accessed by manipulation of the common
intermediate 6. This intermediate, which contains both vicinal
quaternary stereocenters, would arise from a Pd-DAAA of
dienol dicarbonate 7. Compound 7 would be formed by
treatment of bisoxindole 8 with allyl chloroformate under
basic conditions.
Figure 1. Representative cyclotryptamine alkaloids.
From a structural perspective, cyclotryptamines are found
in both meso and optically active form. Because of their
diverse biological profiles and unique structural features, the
cyclotryptamine alkaloids have gained extensive attention
from the synthetic community. Many elegant strategies have
been devised to assemble these targets in enantiopure form.[2]
A pronounced feature found in these natural products is
the presence of two vicinal quaternary stereocenters. Quater-
nary all-carbon stereocenters are present in a variety of
natural products and biologically active compounds. The
[*] Prof. B. M. Trost, M. Osipov
Department of Chemistry, Stanford University
Stanford, CA 94305-5580 (USA)
E-mail: bmtrost@stanford.edu
[**] We thank the NSF (CHE-1145236) and the NIH (GM 033049) for
their generous support of our programs. M.O. thanks The John
Stauffer Memorial Fellowship and Stanford Graduate Fellowship for
financial support. We thank Johnson-Matthey for their generous
gifts of palladium salts.
To determine whether the Pd-DAAA could be used to
access the cyclotryptamine core in an enantio- and diastereo-
selective fashion, dienol dicarbonate 7 was prepared as
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201302805.
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Table 1: Selected optimization studies.[a]
Entry
Ligand
Solvent
d.r.[b]
ee [%][c]
1[d]
2[d]
3
4
5
6
7
8
9
10
11
12
13[e]
14[f]
15[e,f]
PPh3
(2-furyl)3P
tBu-XPhos
dppf
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
dioxane
DME
THF
THF
THF
2.0:1
5.4:1
5.8:1
6.0:1
1.7:1
7.0:1
1.6:1
1.6:1
3.3:1
3.0:1
2.7:1
3.0:1
2.8:1
3.5:1
3.2:1
–
–
–
–
Xantphos
iPr-PHOX
(S,S)-L1
(S,S)-L2
(S,S)-L3
(S,S)-L4
(S,S)-L3
(S,S)-L3
(S,S)-L3
(S,S)-L3
(S,S)-L3
–
Scheme 1. Retrosynthesis of cyclotryptamine alkaloids. Boc=tert-
butoxycarbonyl.
24
89
26
87
47
58
83
86
88
92
outlined in Scheme 2. Condensation of oxindole (9) and isatin
(10) afforded isoindigo in 82% yield.[9] Isoindigo was treated
with di-tert-butyl dicarbonate in THF followed by hydro-
[a] All reactions were performed with [Pd2(dba)3·CHCl3] (2.5 mol%),
ligand (7.5 mol%), and dienol dicarbonate 7 (0.02 mmol) in the
indicated solvent. All reactions proceeded with more than 95%
conversion (determined by 1H NMR spectroscopy of the crude reaction
mixture). [b] d.r. determined by 1H NMR spectroscopy of the crude
reaction mixture. [c] ee value determined by HPLC on a chiral stationary
phase. [d] 22.5 mol% of ligand was used. [e] Reaction was conducted at
08C. [f] (n-hex)4NBr (10 mol%) was used as additive. Entry in bold
highlights optimized reaction conditions. dba=dibenzylideneacetone,
DME=1,2-dimethoxyethane, dppf=1,1’-Bis(diphenylphosphino)ferro-
cene.
Scheme 2. Synthesis of dienol carbonate 7. Reagents and conditions:
a) HCl, HOAc, reflux, 82%; b) Boc2O, DMAP, NEt3, THF, 08C!RT,
89%; c) 10 wt% Pd(OH)2/C, EtOH, RT, 96%. d) allyl chloroformate,
NEt3, THF, 08C!RT, 90%. DMAP=4-dimethylaminopyridine.
genation with Pearlmanꢀs catalyst to provide bisoxindole 8.
The reaction of bisoxindole 8 with allyl chloroformate and
triethylamine facilitated smooth formation of dienol dicar-
bonate 7 in 90% yield.[10] Surprisingly, dienol dicarbonate 7
proved to be a bench-stable intermediate that could be
accessed on a scale of more than 16 g in an overall yield of
63% from inexpensive commercially available starting mate-
rials 9 and 10 using the shown sequence.
symmetric product 6 (Table 1, entry 3). Bidentate ligands
(Figure 2) were studied next in the transformation; utilizing
dppf improved the d.r. to 6:1, still favoring the chiral product
6 (Table 1, entry 4). Xantphos led to a reduced 1.7:1 d.r., in
favor of the chiral product 6 (Table 1, entry 5).
With key dienol dicarbonate 7 in hand, the Pd-DAAAwas
explored. Initial studies were performed using achiral ligands
to determine the influence of the ligand structure on the
diastereoselectivity of the reaction. Ideally, ligand control
would override substrate control and could be used to favor
either the d/l (6) or meso (11) products. This would provide
access to both chiral and meso cyclotryptamine natural
products. Treatment of the dienol dicarbonate 7 with [Pd2-
(dba)3·CHCl3] and PPh3 facilitated the desired allylation with
greater than 95% conversion, but in a mere 2:1 d.r., favoring
the chiral product 6 (Table 1, entry 1). Switching to the
electron-deficient ligand tri-2-furylphosphine led to an
improvement in the diastereoselectivity of the transformation
and delivered the products in a 5.4:1 d.r., still favoring the C2
symmetric product 6 (Table 1, entry 2). Employing the bulky
tBu-XPhos ligand resulted in further enhancement of the
diastereoselectivity to 5.8:1, but continued to favor the C2
Figure 2. Ligands employed in the optimization studies.
Based on the results obtained by employing achiral
ligands (Table 1, entries 1–5), it appeared that substrate
control was favoring the C2 symmetric product 6 over the
meso product 11, but the ligand structure still influenced this
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selectivity as can be deduced from the varying diastereomeric
ratios. With this bias, we were interested in determining if
chiral ligands could provide the C2 symmetric product 6 with
high levels of enantioselectivity. Employing iPr-PHOX[11] in
the transformation provided the products 6 and 11 with an
excellent 7:1 d.r., but in only 24% ee (Table 1, entry 6). A
screening of our modular ligands L1–L4 (Table 1, entries 7–
10) showed that (S,S)-L3, which contains a stilbene backbone,
performed best, both in terms of diastereo- and enantiose-
lectivity, thus facilitating the allylation, which resulted in 3.3:1
d.r. and 87% ee (Table 1, entry 9). Continuing with (S,S)-L3
as the ligand, a solvent screen revealed that the Pd-DAAA
was best performed in THF (Table 1, entries 9, 11, and 12).
Temperature and additives were examined for the effect on
the diastereo- and enantioselectivity of the transformation.
Performing the reaction at reduced temperature led to
a slightly diminished diastereoselectivity, but a slight increase
in enantioselectivity (Table 1, entry 13). The addition of (n-
hex)4NBr (10 mol%) to the reaction led to an increase in both
diastereoselectivity and enantioselectivity (Table 1, entry 14).
It has been demonstrated that addition of (n-hex)4NBr to the
Pd-catalyzed allylic alkylations can have a beneficial effect on
enantioselectivity by decreasing the rate of the nucleophilic
attack.[12] In the hope of seeing a synergistic effect on
selectivity, the Pd-DAAA was conducted at 08C in the
presence of (n-hex)4NBr (10 mol%). To our delight, running
the reaction under these conditions resulted in greater than
95% conversion, 3.2:1 d.r., and 92% ee (Table 1, entry 15).
With optimized conditions in hand, the scalability of the
Pd-DAAA was explored. The transformation proved quite
amenable to scale-up, and was easily conducted on a scale of
more than 9 g [Eq. (1)]. When conducted on this scale, the Pd
Scheme 3. Completion of the formal syntheses. Reagents and condi-
tions: a) TFA, CH2Cl2, RT; b) NaH, DMF, 08C, then BnBr and warming
to RT, 95% over two steps; c) OsO4, NaIO4, 2,6-lutidine, dioxane/H2O,
RT; d) NaBH4, MeOH, 08C, 52% over two steps. DMF=N,N-dimethyl-
formamide, TFA=trifluoroacetic acid.
monanthine,[2a,b] (+)-folicanthine,[2c] and (ꢀ)-calycanthi-
ne.[2a,b] Our synthetic sample of 14 had a rotation of ꢀ192
(c = 1.2 in CHCl3), indicating the formation of the shown
enantiomer. This result corresponds with the formal syntheses
of (ꢀ)-chimonanthine (1), (ꢀ)-folicanthine (2), and (+)-caly-
canthine (3).[2a] Likewise, bisaldehyde 13 has been used by
Overman and co-workers to complete the total synthesis of
(ꢀ)-WIN 64821 (4) and (ꢀ)-ditryptophenaline (5)[13] and
constitutes a formal synthesis of these targets with the same
absolute configuration.
The described Pd-DAAA is intriguing from a mechanistic
perspective, because the process proceeds through two
independent allylation steps (Scheme 4). The first allylation
(A) is enantiodetermining in the transformation, and gives
rise to two intermediates, 15 and ent-15, which are not
observed. Instead, the enantiomeric mixture of 15 and ent-15
and ligand loading could be reduced five-fold, and only
0.5 mol% of [Pd2(dba)3·CHCl3] and 1.5 mol% of (S,S)-L3
were needed to drive the transformation to completion.
Under these reaction conditions, the isolated products could
be obtained in a 96% yield, 3.3:1 d.r., and 91% ee.
With gram quantities in hand, chiral bisallyl oxindole 6
was transformed into diol 14 (Scheme 3). Treatment of
bisallyl oxindole 6 with TFA in CH2Cl2 followed by benzy-
lation with BnBr provided alkylated oxindole 12 in near
quantitative yield. Oxidative cleavage of the alkylated
oxindole 12 under modified Johnson–Lemieux conditions
afforded unstable bisaldehyde 13. Reduction of bisaldehyde
13 with NaBH4 provided diol 14. At this stage, optical rotation
was used to determine the absolute configuration of diol 14.
Previously, Overman and co-workers have used the (+)
enantiomer of diol 14 to complete the syntheses of (+)-chi-
Scheme 4. Mechanistic rationale for double Pd-DAAA.
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undergoes a second, diastereoselective allylation step (B),
which affords the observed products 6 and 11 in 95% yield,
3.3:1 d.r., and 91% ee [Eq. (1)].
Several outcomes for allylations A and B are possible that
can provide the enantio- and diastereoselectivity observed in
the double allylation process. For instance, the first allylation
(A) can proceed with lower levels of enantioselectivity than
what is observed at the end of the transformation (91% ee),
while the second allylation (B) can enhance the %ee to 91%
by transforming the minor intermediate enantiomer ent-15 to
the meso product 11. Conversely, the first allylation (A) can
proceed with higher levels of enantioselectivity than that
observed at the end of the transformation (91%), and the
second allylation (B) could be eroding the %ee observed by
transforming the major intermediate enantiomer 15 to the
meso product. Additionally, the second allylation step (B) can
occur in a matched sense, where the stereocenter constructed
in allylation step A reinforces the formation of the second
stereocenter in step B to favor the C2 symmetric product 6.
Conversely, the second allylation (B) can occur in a mis-
matched fashion, such that the first stereocenter leads to
unfavorable interactions in the transition state in step B,
which would disfavor the formation of the C2 symmetric
product 6.
To probe the effect the allylation step B has on the %ee
and d.r. of the transformation, monoallylated enol carbonates
15 and rac-15 were studied in the Pd-DAAA. Monoallylated
enol carbonate 15 is the intermediate obtained in the double
allylation process after the enantiodetermining allylation step
(A). Subjecting this intermediate (15) with known enantio-
purity to the reaction conditions of the Pd-DAAA would
reveal the effect the second allylation step (B) has on the
enantioselectivity and diastereoselectivity of the overall
reaction.
Scheme 5. Preparation of monoallyl enol carbonates 15 and rac-15.
Reagents and conditions: a) [Pd2(dba)3·CHCl3] (2.5 mol%), (rac)-L1
(7.5 mol%), allyl acetate, Cs2CO3, THF, RT; b) allyl chloroformate,
NEt3, THF, 08C, 95% over two steps; c) [Pd2(dba)3·CHCl3] (2.5 mol%),
(S,S)-L1 (7.5 mol%), allyl acetate, Cs2CO3, THF, RT; d) allyl chlorofor-
mate, NEt3, THF, 08C, 95% over two steps.
Table 2: Pd-DAAA of monoallyl enol carbonate 15.[a]
Entry
ee [%] of 15
Ligand
d.r.[b]
ee [%][c] of 6
1
2
3
4
62
62
62
0
(S,S)-L3
(R,R)-L3
(rac)-L3
(S,S)-L3
3.6:1
6.5:1
5.4:1
4.0:1
57
69
62
-8
[a] All reactions were performed with [Pd2(dba)3·CHCl3] (2.5 mol%),
ligand (7.5 mol%), (n-hex)4NBr (10 mol%), and dienol dicarbonate 7
(0.02 mmol) in THF (0.1m) at 08C. All reactions proceeded with more
than 95% conversion (determined by 1H NMR spectroscopy of the crude
reaction mixture). [b] d.r. determined by 1H NMR spectroscopy of the
crude reaction mixture. [c] ee value determined by HPLC on a chiral
stationary phase.
Enantioenriched (62% ee) monoallylated enol carbonate
15 was prepared by treatment of oxindole dimer 8 with
a single equivalent of allyl acetate and (S,S)-L1[14] under Pd
catalysis followed by enol carbonate formation with allyl
chloroformate (Scheme 5). Racemic monoallylated enol
carbonate rac-15 was prepared in an analogous fashion.
Both enol carbonates 15 and rac-15 were subjected to the
Pd-DAAA reaction conditions using different enantiomers of
L3 (Table 2). The reaction of enantioenriched monoallyl enol
carbonate 15 under optimized conditions employing (S,S)-L3,
which is the enantiomer of the ligand that is present in the
double allylation, resulted in formation of the desired product
6 with greater than 95% conversion, 3.6:1 d.r., and 57% ee
(Table 2, entry 1). The d.r. obtained in this reaction was
comparable to the d.r. obtained in the double Pd-DAAA
[compare to Eq. (1)], and the ee value decreased by 5% in
comparison to the starting material. The result in Table 2,
entry 1, suggests that the first allylation step (A) proceeds
with higher enantioselectivity (> 91%) than what is observed
at the end of the double allylation process (91%), because the
ee value decreased by 5% from 15 to 6. Enantioenriched
monoallyl enol carbonate 15 was next treated under the
optimized reaction conditions with (R,R)-L3, the antipode of
the ligand present in the Pd-DAAA. This reaction resulted in
formation of the desired product 6 with greater than 95%
conversion, 6.5:1 d.r., and 69% ee (Table 2, entry 2). The d.r.
obtained in this reaction was significantly higher than the d.r.
obtained in the Pd-DAAA [compare Table 2, entry 2, to
Eq. (1)], and a 7% increase in the ee value was observed. The
increased enantiopurity of the product observed in Table 2,
entry 2 supports the notion that the first allylation step (A)
proceeds with greater than 91% ee. Additionally, the results
in Table 2, entry 2, suggest that the second allylation step (B),
is mismatched with (S,S)-L3, the enantiomer of the ligand that
is present in the double Pd-DAAA, because the d.r. is
improved when (R,R)-L3 is used. The reaction of enantioen-
riched monoallyl enol carbonate 15 employing (rac)-L3
resulted in formation of the desired product with greater
than 95% conversion, 5.4:1 d.r., and 62% ee (Table 2,
entry 3). In this reaction, the d.r. was slightly higher than
the d.r. obtained in the double Pd-DAAA [compare Table 2,
entry 3, with Eq. (1)], and no change in the ee value was
observed. Finally, treatment of racemic monoallyl enol
carbonate rac-15 under optimized conditions employing
(S,S)-L3 resulted in formation of the desired product 6 with
greater than 95% conversion, 4:1 d.r., and ꢀ8% ee, favoring
the opposite enantiomer to the one that is observed in the
double allylation process with (S,S)-L3 (Table 2, entry 4). This
result supports the notion that the second allylation (B) is
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mismatched, because the minor enantiomer of the product is
favored from what is expected when (S,S)-L3 is used for the
double Pd-DAAA.
the end of the transformation (91% ee). The second allylation
(B) is more substrate controlled than ligand controlled and
occurs in a mismatched fashion. This event reduces the
enantiopurity of intermediate 15 to that of product 6 from
93% to 91% ee. This occurs because the second mismatched
allylation step (B) proceeds at different rates for 15 and ent-15
to give the meso and chiral products. Both 15 and ent-15 react
in the second allylation to form the chiral products 6 and ent-6
with a greater rate than the meso product.
To gain further insight into the first allylation (A) of the
double Pd-DAAA process, we were interested in isolating
and assaying the intermediate monoallyl enol carbonate 15 by
stopping the double Pd-DAAA reaction at partial conversion.
Monoallyl enol carbonate 15 could be observed using TLC
analysis after running the double Pd-DAAA reaction for
10 min. However, attempts to stop the reaction at partial
conversion after 5, 10, 15, 30, and 60 min by dilution of
reaction aliquots with oxygenated diethyl ether led only to the
double allylation products 6 and 11, which were observed by
1H NMR spectroscopy. This unexpected result indicated that
the double Pd-DAAA was occurring more quickly than the
catalyst oxidation with molecular oxygen. To overcome this
limitation, aliquots of the reaction mixture were loaded
directly onto preparatory TLC plates at 0, 5, 10, and 15 min
reaction times (Table 3), and the monoallyl enol carbonate 15
However, the relative rate of the formation of ent-6 to 11
is greater than the rate of formation for 6 to 11, which leads to
a greater portion of meso product to come from 15, and leads
to the observed reduction in enantiopurity in the product
from monoallyl enol carbonate intermediate 15. These
conclusions are supported by the result shown in Table 2,
entry 1, where the starting material 15 (62% ee) was treated
under the optimized reaction conditions with (S,S)-L3, the
same enantiomer of the ligand that is present under the
optimized reaction conditions in Eq. (1), and produced the
product with a reduced 57% ee. The result shown in Table 2,
entry 2, also supports this conclusion, because treatment of
the monoallyl enol carbonate 15 with (R,R)-L3, the opposite
enantiomer of the ligand that is present in the reaction
mixture, resulted in an improvement in enantiopurity from
62% to 69% ee. The result shown in Table 2, entry 4, also
supports these conclusions, because treatment of racemic
monoallyl enol carbonate rac-15 with (S,S)-L3 produced
a product with ꢀ8% ee, favoring the opposite enantiomer of
that observed under the optimized reaction conditions
employing (S,S)-L3 as the ligand [Eq. (1)]. Finally, direct
isolation of the monoallyl enol carbonate 15 from the double
Pd-DAAA also supports this conclusion, because this inter-
mediate was observed in 93% ee, which is higher than the
91% ee obtained in product 6.
Based on the mechanistic experiments in Tables 2 and 3,
several conclusions can be drawn about the diastereoselec-
tivity of the Pd-DAAA. Under the optimized reaction
conditions, monoallyl enol carbonate 15 reacts with the
catalyst in a mismatched fashion and produces a greater
quantity of meso product 11 than the reaction of catalyst with
ent-15. This occurs because the monoallyl enol carbonate
intermediate 15 is present in much greater quantity than ent-
15. (at 62% ee, the ratio of 15 to ent-15 is 81:19) This
conclusion is supported by the results shown in Table 2,
entry 2, where the monoallyl enol carbonate was treated with
(R,R)-L3 to produce the chiral product 6 in a 6.5:1 d.r., which
is higher than the 3.3:1 d.r. observed under the optimized
reaction conditions [Eq. (1)]. Under the conditions shown in
Table 2, entry 2, the allylation is conducted with the opposite
enantiomer of the ligand that is present under the optimized
reaction conditions, and is therefore matched for monoallyl
enol carbonate 15 and is mismatched for the enantiomer ent-
15. Because the matched monoallyl enol carbonate 15 is now
present in much greater quantity than the mismatched
monoallyl enol carbonate ent-15, the diastereoselectivity of
the reaction increases from what is observed under the
optimized reaction conditions [Eq. (1)].
Table 3: Isolation of monoallyl enol carbonate 15.
Entry
t [min]
ee [%][b] of 15
ee [%][b] of 6
1
2
3
4
0[c]
5
10
15
–
–
93
93
93
91
91
91
[a] All reactions were performed with [Pd2(dba)3·CHCl3] (2.5 mol%),
ligand (7.5 mol%), (n-hex)4NBr (10 mol%), and dienol dicarbonate 7
(0.02 mmol) in THF (0.1m) at 08C. [b] ee value determined by HPLC on
a chiral stationary phase. [c] Only traces of 15 and 6 were observed.
and the double allylation products 6 and 11 were separated
from the active catalyst species. The enantiopurities of 15 and
6 were assayed by HPLC on a chiral stationary phase to
determine if the conclusions drawn from Table 2 were valid.
At t = 0 min, only traces of 15 and 6 were observed. At t = 5,
t = 10, and t = 15 min on the other hand, 15 and 6 could be
isolated and assayed by HPLC on a chiral stationary phase. At
these time intervals, both the intermediate monoallyl enol
carbonate 15 and the double allylation products 6 and 11 were
detected, indicating that the second, mismatched allylation
step (B) had a rate comparable to the first, enantiodetermin-
ing allylation (A). Monoallyl enol carbonate 15 was observed
in 93% ee at t = 5, t = 10, and t = 15 min, while the double
allylation product 6 was isolated with 91% ee at t = 5, t = 10,
and t = 15 min. As suggested by the result shown in Table 2,
the enantiopurity of monoallyl enol carbonate 15 is higher
than the ee value of the double allylation product 6.
Based on the results obtained from Tables 2 and 3, several
conclusions can be drawn about enantioselectivity of the
double allylation process (Scheme 4). The first, enantiode-
termining allylation (A) provides intermediates 15 and ent-15
with greater enantiopurity ( ꢁ 93% ee) than that observed at
The observed stereochemical outcome for the double Pd-
DAAA can be rationalized using a “wall and flap” mnemonic,
6
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Angewandte
Chemie
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which represents the chiral p-allyl palladium species
(Scheme 6).[15] Approach of the oxindole enolate under the
“flap” of the chiral-ligand environment in trajectory I is
favored and minimizes steric clash with the “walls”. On the
other hand, approach of the oxindole enolate from the
opposite face as depicted in trajectory II leads to several
unfavorable steric interactions. Trajectory I leads to the
formation of monoallyl enol carbonate 15, the enantiomer
observed in the double Pd-DAAA.
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In conclusion, we have successfully developed a scalable
twofold Pd-DAAA of oxindole dienol dicarbonate 7 to
construct two vicinal carbon quaternary stereocenters in
near quantitative yield and high levels of diastereo- and
enantioselectivity. The bisoxindole product (6) of this chal-
lenging transformation was elaborated into known intermedi-
ates to complete the formal synthesis of the cyclotryptamine
alkaloids (ꢀ)-chimonanthine (1), (ꢀ)-folicanthine, (2)
(+)-calycanthine (3), (ꢀ)-WIN 64821 (4), and (ꢀ)-ditrypto-
phenaline (5). Detailed mechanistic studies on the twofold
allylation process showed that the reaction proceeds through
an enantiodetermining allylation step (A) in 93% ee followed
by a mismatched second allylation step (B) to arrive at the
chiral product in 3.3:1 d.r. and 91% ee.
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dimer can undergo the Pd-catalyzed decarboxylative allylation
to construct two vicinal quaternary stereocenters in racemic
form. See C. Menozzi, P. I. Dalko, J. Cossy, Heterocycles 2007, 72,
199.
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Received: April 4, 2013
Published online: && &&, &&&&
Keywords: alkaloids · allylic alkylation · asymmetric catalysis ·
.
palladium · quaternary stereocenters
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b) B. M. Trost, G. M. Schroeder, J. Org. Chem. 2000, 65, 1569.
[13] L. E. Overman, D. V. Paone, J. Am. Chem. Soc. 2001, 123, 9465.
[14] (S,S)-L1 and (S,S)-L3 provide the same enantiomer of product
11 when employed in the double allylation process.
[15] a) B. M. Trost, F. D. Toste, J. Am. Chem. Soc. 1999, 121, 4545;
b) B. M. Trost, M. R. Machacek, A. Aponick, Acc. Chem. Res.
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Angew. Chem. Int. Ed. 2013, 52, 1 – 7
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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These are not the final page numbers!