Exercising regiocontrol in palladium-catalyzed asymmetric prenylations and geranylation: Unifying strategy toward flustramines A and B

Article abstract of DOI:10.1021/ja2020873

Pd-catalyzed asymmetric prenylation of oxindoles to afford selectively either the prenyl or reverse-prenyl product has been demonstrated. Control of the regioselectivity in this transformation is governed by the choice of ligand, solvent, and halide additive. The resulting prenylated and reverse-prenylated products were transformed into ent-flustramides and ent-flustramines A and B. Additionally, control of the regio-and diastereoselectivity was obtained using π-geranylpalladium complexes.

Full text of DOI:10.1021/ja2020873

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pubs.acs.org/JACS
Exercising Regiocontrol in Palladium-Catalyzed Asymmetric
Prenylations and Geranylation: Unifying Strategy toward
Flustramines A and B
Barry M. Trost,* Sushant Malhotra, and Walter H. Chan
Department of Chemistry, Stanford University, Stanford, California 94305-5080, United States
S Supporting Information
b
ABSTRACT: Pd-catalyzed asymmetric prenylation of oxi-
ndoles to afford selectively either the prenyl or reverse-
prenyl product has been demonstrated. Control of the
regioselectivity in this transformation is governed by the
choice of ligand, solvent, and halide additive. The resulting
prenylated and reverse-prenylated products were trans-
formed into ent-flustramides and ent-flustramines A and B.
Additionally, control of the regio- and diastereoselectivity
was obtained using π-geranylpalladium complexes.
Figure 1. Regio- and stereoselective prenylation and geranylation of
3-alkyloxindoles.
an extreme case, since attack at the more substituted terminus
with carbon nucleophiles involves formation of a quaternary
center.12 This regioselectivity issue becomes magnified when
the prochiral nucleophile is tertiary, since this would lead to
the formation of adjacent quaternary centers, a truly sterically
demanding event.
renylated, reverse-prenylated, and geranylated hexahydro-
pyrrolo[2,3-b]indole natural products exhibit a broad spec-
P
trum of biological activities.1 Current methods for accessing such
motifs include the organotin-mediated diastereo- and regio-
selective reverse prenylation of organoselenides derived from
tryptophan,2 the sigmatropic rearrangement of chiral
2-prenyloxyindoles,3 the electrophilic prenylation of Witkop’s
indole,4 and the enantioselective FriedelꢀCrafts alkylation of
tryptamine and R,β-unsaturated aldehydes employing iminium
catalysis.5 We envisioned the direct incorporation of either the
prenyl or reverse-prenyl group via catalytic asymmetric addition
of oxindoles to π-prenyl organometallic species I (Figure 1).
Additionally, in the nucleophilic attack using π-geranylmetal
species II, we thought that simultaneous regio- and diastereo-
control could potentially selectively afford any of the four
isomeric products. However, control of the regio-, enantio-,
and diastereoselectivity in the generation of quaternary stereo-
centers, especially vicinal quaternary stereocenters, using such
electrophilic species remains to be achieved.6
Beginning our investigation using ligands L1 and L2 in Pd-
catalyzed AAA resulted in promising levels of enantiocontrol
(85ꢀ97% ee). While ligand L2 favored attack at the more
substituted terminus, biasing the regioselectivity toward product
3a, L1 offered complementary regioselectivity toward product 4a
(Table 1, entries 1 and 2).13 Previous work on Pd-catalyzed AAA
demonstrated that the solvent and halide additive (by promoting
πꢀσꢀπ equilibration) can influence the regio- and enantio-
selectivity.11 Indeed, evaluation of several solvents revealed that
CH2Cl2 and 30 mol % tetrabutylammonium difluorotriphenylsi-
licate (TBAT) employing ligand L2 afforded the desired product
3a in 88% yield with 87% ee and 18:1 regioselectivity for the
branched product (entries 3ꢀ6). In contrast, the use of ligand L1
with toluene as the solvent favored the formation of the linear
product 4a in 66% yield with 96% ee and 3.2:1 selectivity favoring
the linear isomer 4a (entries 7ꢀ10). The regioselectivity differ-
ences afforded by L1 and L2 may be attributed to the greater
steric demands of L2, which favor coordination of the Pd(0)ꢀL2
complex to the less substituted alkene in the transition state of
the nucleophilic attack and thus result in the branched product
(as opposed to a Pd(0)ꢀL2 complex with the trisubstituted
alkene, which would lead to the linear product).
Danishefsky and co-workers2 previously proposed a cationic
prenyl species for accessing prenylated indole alkaloids, but the
use of this synthon in the context of an enantioselective
transformation has remained undeveloped.7 We previously de-
scribed Mo-catalyzed asymmetric allylic alkylation (AAA) to give
3,30-disubstituted oxindoles in high ee,8 but this process is not
applicable to 1,1-disubstituted allylating agents such as prenyl.
On the other hand, Pd-catalyzed processes work well with such
allylating agents; however, the typical regioselectivity involves
nucleophilic addition to the less substituted terminus.9 Despite
this, previous work on Pd-catalyzed AAA has demonstrated that
with heteroatom and malonate nucleophiles and monosubsti-
tuted allyl electrophiles, this regioselectivity can be reversed to
favor the branched products.10,11 However, prenylation represents
The scope of the regio- and enantioselective reverse prenyla-
tion was then evaluated (Table 2).14a Substrate selection was
Received: March 7, 2011
Published: April 26, 2011
r
2011 American Chemical Society
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Table 1. Selected Optimization Studies
Table 2. Regioselective Pd-Catalyzed Asymmetric Reverse
Prenylationa
entrya ligand
solvent
3a:4ab
% yieldc 3a,4a % eed 3a,4a
1
2
L1
L2
THF
THF
1:1.6
2:1
33,56
59,29
93,97
85,95
Tuning the Branched Selectivity
3
4
5
6
L2
L2
L2
L2
dioxane
3.1:1
5.6:1
5.1:1
18:1e
3a: 29
3a: 80
3a: 75
3a: 91
3a: 87
DCE
3a: 58
3a: 82
3a: 88
DCM
DCM
Tuning the Linear Selectivity
7
8
L1
L1
L1
L1
cyclohexane
1:3.7
1:3.4
1:2.4
1:3.2
NDf
NDf
4a: 66
4a: 84
4a: 94
4a: 96
hexane
9
benzene
4a: 57
10
toluene
4a: 66
a Reactions were conducted on a 0.034 mmol scale using 1.5 equiv of
carbonate and 1.0 equiv of nucleophile at 0.17 M. b Based on 1H NMR
analysis of the crude reaction mixture. c Isolated yields. d Determined by
chiral HPLC. e 30 mol % TBAT was added. f ND = not determined.
a Reactions were conducted on a 0.034 mmol scale using 1.5 equiv of
carbonate and 1.0 equiv of nucleophile at 0.17 M. b Unless otherwise
inspired by the development of a general strategy for accessing
diverse prenylated hexahydropyrrolo[2,3-b]indoles for the
broader investigation of the biological activity of such com-
pounds in enantioenriched form.15 Substitution at nitrogen was
well-tolerated: N-allyl, N-prenyl, N-p-methoxybenzyl (N-PMB),
and N-methoxymethyl (N-MOM) groups all afforded products
with high regio- and enantiocontrol (3aꢀc). The non-N-sub-
stituted derivative 1h, however, resulted in low selectivity.
Incorporation of an electron-donating or -withdrawing group
or a phenyl group on the oxindole carbocycle had minimal
influence on the selectivity. From the standpoint of enantio-
and regiocontrol, the nitrile-containing oxindole derivatives
1aꢀg proved to be superior. Modification of this group by
employing ester 1i and secondary amide 1j also afforded the
desired products with high enantiocontrol but slightly lowered
regiocontrol.
The prenylation of the same oxindoles was investigated with
the aim of obtaining the linear regioisomers (Table 3). All of the
N-protecting groups examined afforded linear prenylated pro-
ducts with high enantiocontrol, and non-N-substituted oxindole
1h afforded the product 4h in 62% yield with 86% ee. Substitu-
tion on the oxindole carbocycle and at the 3-position of the
oxindole was well-tolerated. Although the regiocontrol in the
formation of linear products 4aꢀi was lower than that of reverse-
prenylated compounds 3aꢀi, the regioisomers were separable by
silica gel chromatography in all cases.
c
specified. Isolated yield of major product only. d Regioselectivity was
determined by 1H NMR analysis of the crude reaction mixture.
hexahydropyrrolo-[2,3-b]indoles.6 This electrophile poses the
added challenge of diastereocontrol. Employing 1a and race-
mic linalyl carbonate 5 (Scheme 1) afforded a 15:15:1 mixture
of linalylated 6, geranylated 8, and nerylated 10 as products.
Gratifyingly, 6 was formed as a single diastereomer with 90%
ee, albeit in 46% yield.14b On the basis of this result, we
hypothesized that the reaction with branched electrophile 5
partitions equally through slowly equilibrating syn and anti π-
allyl complexes to afford equal amounts of products 6 and 8.16
To test this hypothesis, we investigated the use of geometri-
cally defined linear carbonates 7 and 9. The ionization of these
more hindered carbonates was achieved by conducting the
reaction at 40 °C and switching to the more reactive Pd-
(Cp)allyl precatalyst. Indeed, under these conditions, geranyl
carbonate 7 exclusively afforded the geranylated product 8 in
76% yield with 91% ee. Furthermore, neryl 2,2,2-trichloroethyl
(Troc) carbonate 9 in CH2Cl2 afforded the linalylated product
6 as a single diastereoisomer in 92% yield with 91% ee and 13:1
selectivity versus the neryl isomer.17 Switching the solvent to
dioxane afforded the neryl isomer 10 with 94% ee but in only
41% yield, a result of the modest regioselectivity (1.5:1 over the
linalyl isomer, with a small amount of the geranyl isomer also
being formed).
Evaluation of π-geranylpalladium complex II (Figure 1, M =
Pd) was motivated by the recent isolation of several geranylated
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COMMUNICATION
Table 3. Regioselective Pd-Catalyzed Asymmetric
Prenylationa
Scheme 1. Pd-Catalyzed AAA Using Carbonates (()-5, 7,
and 9
Scheme 2. Catalytic Asymmetric Synthesis of ent-Flustra-
mides and ent-Flustramines A and B
a Reactions were conducted on 0.034 mmol scale using 1.5 equiv of
carbonate and 1.0 equiv of nucleophile at 0.17 M. b Isolated yield of
major product only. c Regioselectivity was determined by 1H NMR
analysis of the crude reaction mixture.
To demonstrate the synthetic utility of this methodology and
assign the absolute configuration of the products, reverse-prenylated
oxindole 3j and the regioisomeric product 4j were converted to
ent-flustramide A {[R]2D5 þ62.2 [90% ee from (R,R)-L1, c 1.10,
EtOH]; lit.18 [R]1D8 ꢀ73.2, c 1.09, EtOH} and ent-flustramide B
minimizes the charge separation between the enolate and the
allyl cation, thereby rationalizing the change in enantiotopic faces
of the prochiral nucleophile when it approaches the two different
termini of the bound allyl unit.22,23
{[R]2D6 þ73.7 [76% ee from (S,S)-L1, c 1.78, EtOH]; lit. [R]D25
ꢀ
104.2, c 1.75, EtOH}, respectively, and to ent-flustramine A
{[R]2D5 þ126.9 [90% ee from (R,R)-L1, c 0.73, EtOH]; lit. [R]D18
ꢀ
139.4, c 0.73, EtOH} and ent-flustramine B {[R]2D4 þ74.2 [76% ee
from (S,S)-L1, c 1.50, EtOH]; lit. [R]2D3 ꢀ93.5 (c 1.5, EtOH)},
respectively, using literature procedures (Scheme 2).19 Flustramines
A and B possess skeletal and smooth muscle relaxant activity.20
Flustramine A has also been shown to have voltage-gated channel
blocking activity,21 while (ꢀ)-debromoflustramine B possesses
significant butyrylcholinesterase inhibitory activity when evaluated
as a single enantiomer.
In conclusion, regiocontrol in accessing prenylated and reverse-
prenylated C-3a oxindoles in high optical purities has been
achieved. These products are valuable building blocks leading
toward the flustramine family of natural products. Results from
the geranylation studies have presented for the first time the
asymmetric synthesis of vicinal all-carbon quaternary centers for
both reaction partners. The opposite regioselectivity observed
using isomeric π-geranyl- and π-nerylpalladium complexes al-
lows three of the four isomeric products to be accessed selec-
tively. This work demonstrates that unusual ligand-dependent
versatility can be observed in Pd-catalyzed AAA reactions and
presents new opportunities for directing nucleophilic attack to
the internal carbon more generally using π-allylpalladium
complexes.
The syntheses of ent-flustramides A and B revealed that
opposite enantiomers of the reverse-prenylated and prenylated
species were formed when the same enantiomer of the ligand was
used. This suggests that either face of the oxindole can approach
the π-prenylpalladium complex (Figure 2). In the context of
our working model, the depicted orientation of the oxindole
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COMMUNICATION
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Figure 2. Rationalizing the divergent absolute stereochemistries of the
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’ ASSOCIATED CONTENT
S
(13) Products 3a and 4a were separable by chromatography. Em-
ploying the isomeric electrophile had a minimal impact on the regiocon-
trol, but a significant decrease in conversion was observed.
(14) (a) See the Supporting Information for the preparation of
substrates. (b) The assignment of the relative stereochemistry of 6 is
detailed in the Supporting Information, and the absolute stereochem-
istry was assigned by analogy with the stereochemical outcome of the
asymmetric prenylation reactions.
Supporting Information. Experimental details and anal-
b
ytical data for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
bmtrost@stanford.edu
ꢀ
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(17) Regioselectivity differences between geranyl and neryl geome-
trical isomers have been reported previously in refs 7a and 7c.
(18) Kawasaki, T.; Shinada, M.; Kamimura, D.; Ohzono, M.; Ogawa,
A. Chem. Commun. 2006, 420.
’ ACKNOWLEDGMENT
This work was supported by the National Institutes of Health
(GM033049) and the National Science Foundation. S.M.
acknowledges Stanford University for a graduate fellowship.
Palladium salts were generously supplied by Johnson-Matthey.
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