Iridium-Catalyzed Stereoselective Allylic Alkylation Reactions with Crotyl Chloride

Article abstract of DOI:10.1002/anie.201609960

The development of the first enantio-, diastereo-, and regioselective iridium-catalyzed allylic alkylation reaction of prochiral enolates to form an all-carbon quaternary stereogenic center with an aliphatic-substituted allylic electrophile is disclosed. The reaction proceeds with good to excellent selectivity with a range of substituted tetralone-derived nucleophiles furnishing products bearing a newly formed vicinal tertiary and all-carbon quaternary stereodyad. The utility of this protocol is further demonstrated via a number of synthetically diverse product transformations.

Full text of DOI:10.1002/anie.201609960

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201609960
German Edition: DOI: 10.1002/ange.201609960
Enantioselective Synthesis
Iridium-Catalyzed Stereoselective Allylic Alkylation Reactions with
Crotyl Chloride
+
+
J. Caleb Hethcox , Samantha E. Shockley , and Brian M. Stoltz*
Dedicated to Professor Stephen F. Martin on the occasion of his 70th birthday
Abstract: The development of the first enantio-, diastereo-, and
regioselective iridium-catalyzed allylic alkylation reaction of
prochiral enolates to form an all-carbon quaternary stereo-
genic center with an aliphatic-substituted allylic electrophile is
disclosed. The reaction proceeds with good to excellent
selectivity with a range of substituted tetralone-derived nucle-
ophiles furnishing products bearing a newly formed vicinal
tertiary and all-carbon quaternary stereodyad. The utility of
this protocol is further demonstrated via a number of syntheti-
cally diverse product transformations.
T
he synthesis of singular all-carbon quaternary stereocenters
has been a long-standing challenge in the synthetic commun-
[
1]
ity. Significant progress in this area over the past few
decades has recently shifted the forefront of investigation
toward the more difficult task of constructing vicinal stereo-
dyads bearing at least one quaternary stereocenter. This
nascent field is beset with difficulties not only arising from the
increased sterics in the bond-forming event, but also the
additional requirement of diastereocontrol. Among the
Figure 1. Enantio-, diastereo-, and regioselective iridium-catalyzed
allylic alkylation reactions.
[
2,3]
available methodologies tailored for this challenge,
dium-catalyzed allylic alkylations represent some of the most
iri-
[4]
selective strategies, yet remain underdeveloped.
The first iridium-catalyzed enantio-, diastereo-, and
regioselective allylic alkylation was disclosed by Takemoto
in 2003 and remained the sole report of such a transformation
[5]
for a decade. Of the ten published accounts of enantio- and
[4]
diastereoselective iridium-catalyzed allylic alkylation since,
only five reports provide access to vicinal tertiary and all-
[
6]
carbon quaternary stereocenters. However, none of these
protocols tolerate the use of aliphatic-substituted electro-
philes (Figure 1a). Conversely, the four singular examples
employing aliphatic-substituted electrophiles in two pub-
lished papers failed to enable construction of all-carbon
quaternary stereocenters (Figure 1b). While these protocols
provide access to valuable chiral synthons, a wide variety of
synthetic targets require the installation of aliphatic-substi-
tuted stereodyads between neighboring tertiary and quater-
Figure 2. Select natural products bearing aliphatic-substituted vicinal
tertiary and quaternary stereocenters.
[
7]
nary carbon atoms (Figure 2). To the best of our knowledge,
no transition-metal-catalyzed process allows for the creation
of this desired motif. Herein, we report the first method for
the iridium-catalyzed synthesis of alkyl-substituted vicinal
tertiary and all-carbon quaternary stereogenic centers via
allylic alkylation of prochiral enolates (Figure 1c).
Our studies commenced with an exploration of the
efficacy of additives, leaving groups, bases, and ligands on
the selectivity of the reaction between a-carboxymethyl
tetralone (4) and crotyl electrophile 5. Using our previously
[
+]
[+]
[
*] Dr. J. C. Hethcox, S. E. Shockley, Prof. Dr. B. M. Stoltz
The Warren and Katharine Schlinger Laboratory for Chemistry and
Chemical Engineering, Division of Chemistry and Chemical Engi-
neering, California Institute of Technology
1200 E. California Blvd, MC 101-20, Pasadena, CA 91125 (USA)
E-mail: stoltz@caltech.edu
reported conditions for iridium-catalyzed allylic alkylations
+
[6a,b]
[
] These authors contributed equally to this work.
with cinnamyl-derived electrophiles as a starting point,
the
reactivity of tetralone 4 was first investigated with crotyl
carbonate in the presence of catalytic phosphoramidite
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201609960.
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[
a]
Table 1: Optimization of reaction parameters.
effect of the chloride anions more
pronounced. To our delight, regio-
selectivity
was
dramatically
improved with the use of crotyl
chloride, albeit with diminished
diastereoselectivity (entry 5).
Previous work demonstrating
the marked effect of bases on
regio- and diastereoselectivity in
iridium-catalyzed allylic alkylations
prompted an extensive exploration
of bases (see Supporting Informa-
[
c]
Entry
L
Base
Additive
mol %)
LG
4:5 Yield of
6+7 [%]
6:7
dr of
6
ee of
6 [%]
[
b]
[c]
[d]
(
1
2
3
4
5
6
L1
L1
L1
L1
L1
–
LiBr (100) OCO Me 2:1
100
85
100
69
55:45 6.4:1
34:66 5.3:1
45:55 6.8:1
50:50 7.2:1
86:14 4.8:1
–
–
–
–
–
2
LiOt-Bu
LiOt-Bu
LiOt-Bu
LiOt-Bu
–
OCO Me 2:1
2
LiBr (100) OCO Me 2:1
LiCl (100) OCO Me 2:1
LiCl (100)
2
2
[
5–8]
tion for details).
We found that
Cl
Cl
2:1
2:1
94
100
L1 proton sponge LiCl (100)
93:7
7.9:1
66
the use of proton sponge in place of
LiOt-Bu afforded the desired
branched product 6 with high regio-
selectivity (93:7, 6:7) and diastereo-
selectivity (7.9:1 dr), though in
a modest 66% enantiomeric excess
7
8
9
L3 proton sponge LiCl (100)
L4 proton sponge LiCl (100)
L2 proton sponge LiCl (100)
Cl
Cl
Cl
2:1
2:1
2:1
79
91
46
69:31 2.4:1
52:48 1.5:1
95:5
–
–
96
6.0:1
1
0
L2 proton sponge
–
Cl
2:1 trace
–
–
–
(
entry 6). A brief study of ligand
1
1
L2 proton sponge LiCl (400)
Cl
2:1
78
94:6
6.7:1
97
[
9]
frameworks (entries 7–9) revealed
3,3’-diphenyl-phosphoramidite L2
to be optimal. Using L2, allylic
alkylation product 6 was obtained
1
1
2
3
L2 proton sponge LiCl (400)
L2 proton sponge LiCl (400)
Cl
Cl
1:1
1:2
55
76
95:5
>95:5
5.3:1
5.3:1
98
85
in
excellent
enantioselectivity
(96% ee) with comparable regio-
and diastereoselectivities to L1,
though in considerably lower yield
(entry 9). Efforts to increase the
yield revealed super-stoichiometric
levels of LiCl to be both essential
and correlative to the conversion
(entries 10 and 11). Ultimately, we
[
a] Reactions performed on 0.1 mmol scale using base (200 mol %), [Ir(cod)Cl] (2 mol %), L (4 mol %),
2
1
and TBD (10 mol %) in THF (0.1m) at 258C for 18 h. [b] H NMR yield of the mixture of diastereomers
based on internal standard. [c] Determined by H NMR analysis of the crude reaction mixture.
[
1
found that the combination of cata-
d] Determined by chiral SFC analysis. [e] TBD=1,3,5-triazabicyclo[4.4.0]dec-5-ene, proton
1
sponge=1,8-bis(dimethylamino)naphthalene.
lytic phosphoramidite L2· = [Ir-
2
(cod)Cl]2, 200 mol
%
proton
sponge, and 400 mol % LiCl deliv-
ered product 6 in 78% yield (entry 11) with an exceptional
branched to linear ratio (94:6, 6:7), diastereoselectivity (6.7:1
dr), and enantioselectivity (97% ee). Finally, it should be
noted that we observed optimal conversion and selectivity
using a 2:1 nucleophile to electrophile ratio; however, the
nucleophile and electrophile stoichiometry could be varied
(1:1 or 1:2) without dramatically affecting reaction conversion
or selectivity, rendering the reaction synthetically practical
1
[6a]
L1· = [Ir(cod)Cl] and either LiBr (Table 1, entry 1), LiOt-
2
2
[
6b]
Bu (entry 2),
or a combination of LiBr and LiOt-Bu
(
entry 3). Unfortunately, while these conditions resulted in
excellent conversion and good diastereoselectivity, low levels
of regioselectivity were observed. As our earlier work on
cinnamyl-derived electrophiles revealed that the regioselec-
tivity improved as carbocation stability increased (i.e.,
[6b]
increasingly electron-rich aromatic cinnamyl derivatives),
[
10]
we reasoned that the poor regioselectivity in this case was
likely due to the minimal stabilization of the carbocation
afforded by the methyl substituent of 5. Specifically, we
hypothesized that the attenuated carbocation stability could
be effecting slow equilibration between diastereomers of the
iridium p-allyl complex, translating into diminished regio-
selectivity. Previous reports have proposed that LiCl may
facilitate the equilibration leading to increased regio- and
(entries 12 and 13).
With the optimized conditions identified, we explored the
substrate scope of this enantio-, diastereo-, and regioselective
allylic alkylation reaction (Table 2). Generally, the process is
tolerant of a wide range of substituents and functionality on
[
12]
both the arene and ester groups. We found that increasing
the size of the ester moiety (ÀCO Me, ÀCO Et, ÀCO i-Pr)
2
2
2
resulted in formation of the corresponding products 6, 10a,
and 10b in increasingly improved regio- and diastereoselec-
tivity but moderately diminished yields. As a balance between
yield and selectivity, we moved forward in our investigation
using a-carboxyethyl tetralone derivatives. Moreover, we
were pleased to find that a (2-trimethylsilyl)ethyl substrate
underwent allylic alkylation to provide 10c with good
[
10]
enantioselectivity,
but we noted little improvement in
selectivity with the use of LiCl as compared to LiBr (entry 4).
We subsequently turned our attention to the nature of the
leaving group on the electrophile. We envisioned that switch-
ing from crotyl methyl carbonate to crotyl chloride would
render the anions in solution congruent and perhaps make the
2
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[
a,b]
Table 2: Substrate scope exploration.
Furthermore, during the course of our investigations we
found that the b-keto ester moiety was crucial to the reaction.
Substrates with this functionality replaced with either a nitrile
or ketone provided the corresponding products 10j and 10k
in decreased selectivities. No allylic alkylation was observed
with aliphatic-substituted allyl chloride derivatives other than
of crotyl chloride.
To demonstrate the synthetic utility of this method, we
carried out a number of transformations on allylic alkylation
products 6 and 10a (Figure 3). We found that the addition of
allylmagnesium chloride proceeded smoothly to furnish
alcohol 11 in 71% yield. In a two-step protocol, addition of
Figure 3. a) Allylmagnesium chloride, THF, À788C, 71%. b) HG-II,
[a] Reactions performed with 9 (0.2 mmol), 4 or 8 (200 mol %), proton
CH Cl , 81%. c) K OsO , NMO, THF/H O, 59%. d) DIBAL, THF,
2
2
2
4
2
sponge (200 mol %), [Ir(cod)Cl] (2 mol %), L2 (4 mol %), and TBD
À788C, 43%. e) K OsO , NMO, THF/H O, 65%. f) Me S(O)I, NaH,
2
2
4
2
3
1
(
10 mol %) in THF (0.1m) at 258C for 18 h. [b] H NMR yield of the
DMSO, 82%.
mixture of diastereomers based on internal standard; combined isolated
yield of branched and linear products given in parentheses; regioselec-
tivity of the crude reaction mixture; ee’s determined by chiral SFC or
HPLC analysis. [c] Absolute stereochemistry determined via single-
crystal X-ray analysis.
allyl Grignard with subsequent ring-closing metathesis
allowed rapid access to tricycle 12 bearing three contiguous
stereocenters in 58% yield over two steps. The resultant
cyclohexene moiety underwent dihydroxylation to provide
triol 13 bearing five contiguous stereogenic centers in 59%
yield. Both the ester and the ketone functionalities of 10a
were reduced to provide 1,3-diol 14 in 43% yield. Dihydroxy-
lation of the pendant olefin of 10a proceeded with concom-
itant lactonization to provide highly functionalized g-butyro-
lactone 15 in 65% yield. Functionalized g-butyrolactone
moeites are highly prevalent and estimated to be present in
about 10% of all natural products. Additionally, Corey-
Chaykovsky epoxidation proceeded smoothly, furnishing 16
in 82% yield. Notably, all six of these derivatizations proceed
with excellent diastereoselectivity to facilitate the synthesis of
at least three contiguous stereogenic centers, demonstrating
the ease with which complexity can be added to these high-
value products.
selectivity, albeit in modest yield. Alkylation product 10c may
undergo subsequent fluoride-triggered allylic alkylation
mediated by palladium to provide either diastereomer of
[
13]
the bis-alkylation product with catalyst control.
We sought to further examine the scope of the reaction by
exploring the diversity of substitution permitted on the
tetralone aromatic ring. Gratifyingly, a wide variety of both
electron-donating and withdrawing groups were tolerated at
varying positions, though an electronic effect was noted on
enantioselectivity. We observed that substrates bearing elec-
[
14]
tron-donating groups (MeOÀ, Me NÀ) at the 6-position gave
2
products 10d and 10e with slightly diminished enantioselec-
tivity (84–86% ee). Conversely, substrates with electron-
withdrawing groups (7-MeOÀ, 7-NO À, 6-BrÀ) afforded the
2
corresponding products 10 f, 10g, and 10h in excellent
enantioselectivity (94–98% ee). Additionally, 5,7-dimethyl-
substituted tetralone 10i was furnished in comparable selec-
tivity to unsubstituted a-carboxyethyl tetralone 10a. In all
examples, good regio- and diastereoselectivity was observed.
In summary, we have developed the first enantioselective
transition-metal-catalyzed allylic alkylation reaction forming
vicinal tertiary and all-carbon quaternary stereocenters
between prochiral enolates and an aliphatic-substituted
electrophile. Critical to the success of this new reaction is
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addition to the use of proton sponge, the combination of
which affords excellent regio- and enantioselectivities along
with good yields and diastereoselectivities. Additionally,
a number of transformations were carried out on the
alkylation products to demonstrate the value of this method
in rapidly accessing highly functionalized, stereochemically
rich polycyclic scaffolds. Further explorations to expand this
chemistry to include additional aliphatic-substituted electro-
philes and to broaden the nuclophile scope are currently
underway and will be reported in due course.
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Final Article published: && &&, &&&&
4
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Angewandte
Communications
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Communications
Enantioselective Synthesis
J. C. Hethcox, S. E. Shockley,
B. M. Stoltz*
&&&& — &&&&
Iridium-Catalyzed Stereoselective Allylic
Alkylation Reactions with Crotyl Chloride
Sponge worthy: The unique combination
of crotyl chloride, LiCl, and proton sponge
has delivered the first enantio-, diastereo-
aliphatic-substituted electrophile. The
reaction proceeds with good to excellent
selectivity for a range of substituted
tetralones providing products bearing
a newly formed vicinal tertiary and all-
carbon quaternary stereodyad.
,
and regioselective iridium-catalyzed
allylic alkylation reaction to form an all-
carbon quaternary stereocenter with an
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5
These are not the final page numbers!