Enantioselective Palladium-Catalyzed Alkenylation of Trisubstituted Alkenols to Form Allylic Quaternary Centers

Article abstract of DOI:10.1021/jacs.6b09649

In this report, we describe the generation of remote allylic quaternary stereocenters β, γ, and δ relative to a carbonyl in high enantioselectivity. We utilize a redox-relay Heck reaction between alkenyl triflates and acyclic trisubstituted alkenols of varying chain-lengths. A wide array of terminal (E)-alkenyl triflates are suitable for this process. The utility of this functionalization is validated further by conversion of the products, via simple organic processes to access remotely functionalized chiral tertiary acid, amine, and alcohol products.

Full text of DOI:10.1021/jacs.6b09649

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Communication
Enantioselective Palladium-Catalyzed Alkenylation of
Trisubstituted Alkenols to form Allylic Quaternary Centers
Harshkumar H. Patel, and Matthew S Sigman
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b09649 • Publication Date (Web): 21 Oct 2016
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Harshkumar H. Patel and Matthew S. Sigman*
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Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112, United States.
Supporting Information Placeholder
ABSTRACT: In this report, we describe the generation of remote
allylic quaternary stereocenters β, γ, and δ relative to a carbonyl in
high enantioselectivity. We utilize a redox-relay Heck reaction be-
tween alkenyl triflates and acyclic trisubstituted alkenols of varying
chain-lengths. A wide array of terminal (E)-alkenyl triflates are
suitable for this process. The utility of this functionalization is val-
idated further by conversion of the products, via simple organic
processes to access remotely functionalized chiral tertiary acid,
amine and alcohol products.
Figure 1. Proposed enantioselective redox-relay Heck
alkenylation of trisubstituted alkenols
Generation of enantiomerically enriched quaternary centers ad-
jacent to an alkenyl moiety in acyclic systems has recently received
considerable attention.1 This is in part due to the unique structural
features of quaternary centers for applications in synthesis, which
is further enabled by the resultant synthetic flexibility of the allylic
functional group.2 Existing approaches to access an allylic quater-
nary center utilize the precise proximity of a pre-existing functional
group or pre-installed stereocenter in the substrate of interest to en-
able the reactivity profile.3 Although many excellent methods have
been reported that allow for enantioselective installation of alkenyl
groups α4 or β5,6 to a functional group, approaches outlining such a
strategy to a quaternary chiral center γ or δ (or more remotely) di-
rectly have not been reported.7-9
At the outset of this project, a search for a suitable alkenyl cou-
pling partner was undertaken considering that electron deficient
alkenyl triflates, while successful in the reaction of disubstituted
alkenols (Figure 1b), were unreactive with the corresponding tri-
substituted alkenols.14 Initially, it was hypothesized that slow mi-
gratory insertion of the electron-poor alkenyl triflate (Table 1, entry
1) into the more hindered system was responsible for the failure to
observe product, which is consistent with previous report of re-
duced yields with electron-poor aryl boronic acids using hindered
alkenols.15 Considering this, an electron rich alkenyl triflate (Table
1, entry 2) containing a cyclohexenyl group, was submitted to the
reaction with trisubstituted alkenol 2a. Unfortunately, complete re-
covery of starting material resulted. Presumably, the cyclohexenyl
unit prevents migratory insertion of the trisubstituted alkene due to
its size. This hypothesis is consistent with poorer yields observed
previously with ortho-substituted arenes with trisubstituted al-
kenes.10 Therefore, a range of less hindered electron-rich reagents
were evaluated. Initially, alkenyl boronic acids were investigated
due to their commercial availability, stability, and the ease with
which one can vary the electronic nature of the alkenyl substituent.
Unfortunately, an alkenyl boronic acid (Table 1, entry 3) was an
ineffective coupling partner with alkenol 2a. Further, submission
of alternative coupling partners such as an alkenyl iodide (Table 1,
entry 4), and an alkenyl iodonium salt (Table 1, entry 5) were un-
successful. The main byproduct observed in this reaction is a diene
resulting from a homocoupling event. Apparently, after initial
transmetallation, palladium alkenyl species A does not undergo the
desired migratory insertion with the hindered alkenol but instead a
second transmetallation event competitively occurs to form palla-
dium bis-alkenyl species B (Table 1b). This intermediate can un-
dergo subsequent reductive elimination resulting in the formation
To address this challenge, we envisioned applying our recently
reported enantioselective redox-relay Heck tactic for functionaliza-
tion of trisubstituted alkenols containing various chain-lengths be-
tween the alkene and alcohol with an alkenyl reagent (Figure
1a).10,11 Successful development of such a method would provide
direct access to the desired functionalized alkenyl quaternary stere-
ocenter at remote positions (β, γ and δ) to a carbonyl group expand-
ing the methods by which to access these highly desirable chiral
building blocks. Additionally, such a reaction can be considered a
surrogate to the unresolved enantioselective alkylative Heck reac-
tion, since hydrogenation of the resultant double bond will furnish
the desired aliphatic Heck-type products.12 Compounds of this na-
ture are difficult to access using traditional approaches.13 Unfortu-
nately, while we have reported the arylation of trisubstituted
alkenols to establish quaternary stereocenters in high enantioselec-
tivity, initial efforts to promote the corresponding reaction using
alkenyl triflates was met with failure. Herein, we present the iden-
tification and application of a class of electron rich alkenyl triflates
to the redox-relay Heck reaction, to forge quaternary stereocenters
containing an alkene in high enantioselectivity.
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of the diene, which has deleterious effects on the reaction (vide in-
fra).
Table 2. Scope of alkenyl triflate in the redox-relay Heck
asymmetric alkenylation of trisubstituted alkenol.
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Table 1. Alkenyl coupling partner evaluation and reaction
optimization.
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styrenyl triflates (3a-3d) furnished the desired γ-alkenylated car-
bonyl products in good yields and high enantioselectivity. Simple
alkyl substituted alkenyl triflates 1e and 1f provided the desired
compounds 3e and 3f in excellent enantiomeric ratio of 97:3 and
75% and 79% yield, respectively. Notably, use of (E)-stereode-
fined alkenyl triflates is required since, a mixture of (E)- and (Z)-
1f (ratio of E/Z was 1:2.2) provides only 32% yield of 3f with a
reduction of er from 97:3 to 92:8. This suggests that the migratory
insertion is slowed with (Z)-alkenyl triflates due to increased steric
effects. Next, larger substrates such as β-disubstituted alkenyl tri-
flates were subjected to this reaction. Although, yields of the de-
sired γ-alkenylated products are generally good, the enantioselec-
tivity observed was highly dependent on the nature of the coupling
partner. For example, product 3g containing a β-disubstituted di-
phenyl group was formed in excellent yield and significantly re-
duced er (67:33). Similarly, the formation of 3h follows the same
trend, good yield and a modest 88:12 er. However, a reduction in
size of the alkenyl coupling partner to a β-disubstituted dimethyl
group, proved to be an excellent reagent with an enhanced er of
94:6 (3i). Linear alkenyl groups containing simple aliphatic sub-
stituents including a primary alkyl halide (3j-3l) are viable reagents
especially in terms of enantioselectivity albeit the incorporation of
a remote arene (3j) does cause a reduction in yield.
These unfortunate results suggested that a Pd(0) path might be a
more prudent approach to avoid a second transmetallation. There-
fore, we reconsidered a less hindered E-alkenyl triflate (Table 1,
entry 6), which was synthesized from the appropriate alkenyl io-
donium salt, using Gaunt’s procedure.16 Submitting this reagent
and trisubstituted alkenol 2a to Pd(0) and a chiral pyridine oxazo-
line ligand resulted in the formation of desired γ-substituted
alkenylated carbonyl product 3a in 45% yield and 88:12 enantio-
meric ratio (er). Surprisingly, approximately 20% yield of the diene
product was also observed. We surmised that the diene byproduct
in this case may arise from bimetallic transmetallation between two
palladium alkenyl species.17 To prevent such a process, excess
alkenol was used and further optimization of the solvent, concen-
tration, and chiral PyrOx ligand culminated in the formation of the
desired γ-alkenylated carbonyl product in high yield and enantiose-
lectivity (Table 1, entry 7). Of particular note, a more electrophilic
catalyst is introduced, replacing the CF3 with NO2 on the pyridine
moiety, which leads to significantly higher yields. Presumably, this
change enhances both the binding of the hindered alkene and rates
of migratory insertion.18
Using these optimized conditions, the scope of the alkenyl elec-
trophile was evaluated. A wide variety of β-substituted alkenyl tri-
flates were synthesized and reacted with acyclic trisubstituted
alkenol 2a under the optimal conditions. Electron-rich and poor
To explore the limits of the alkenol counterpart in this enantiose-
lective alkenylation of trisubstituted alkenols, various (E)- and (Z)-
stereodefined alkenols were synthesized and subjected to the Heck
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conditions with a range of alkenyl triflates. The (E)-allylic trisub-
Similarly, ozonolysis of 5, followed by treatment with tri-
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stituted alkenols gave the desired product in moderate to good
yields (3m-3o). While 3o was formed in good enantiomeric ratio of
94:6, 3m and 3n showed slightly lower er of 91:9 and 87:13 respec-
tively. Additionally, geraniol underwent migratory insertion at the
allylic position to provide 3p in moderate yield but an 84:16 er.
These results collectively suggest that the enantioselectivity is not
only affected by the nature of the alkenyl triflate, but also mitigated
by the stereochemistry of the alkenol substrate. To probe this, (E)-
and (Z)-4-methyloct-3-en-1-ol (2q) were subjected to the reaction
with styrenyl triflate 1a, providing 3q in high yields. However,
reaction of (Z)-alkenol led to aldehyde 3q in significantly higher er
(95:5 as compared to 13:87 for (E)-alkene). This suggests that (Z)-
alkenols are superior to their (E)-counterparts. An alkene bearing
another oxygen substituent and having a secondary alcohol is also
tolerable, enabling the delivery of alkenyl group to a more remote
δ position with respect to the carbonyl (3r). A bis-homoallylic al-
cohol gave the desired δ-alkenylated product 3s in good er, albeit
in modest yield. Lastly, a more demanding trisubstituted alkenol
bearing butyl and ethyl substituents required slightly higher cata-
lyst loading and reaction times to provide the aldehyde 3t in 65%
yield and a moderate enantiomeric ratio.
phenylphosphine furnished tertiary aldehyde (not shown), and sub-
sequent Baeyer-Villiger oxidation20 and hydrolysis of the formate
ester yielded chiral tertiary alcohol 5c. The enantioselectivity was
effectively preserved in all of these functional group transfor-
mations. Thus, from a simple alkenylated product, one can access
a diverse range of remote tertiary functionalized alkyl products.21
Scheme 1. Derivatization of alkenylated products.
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Table 3. Evaluation of trisubstituted alkenols
In conclusion, we have reported a new method to form quater-
nary chiral centers remotely from a carbonyl in high enantioselec-
tivity. This process utilizes simple to access starting materials, a
conveniently prepared chiral ligand, and is performed under mild
conditions. High enantioselectivity is predicated on using a (Z)-
trisubstituted alkene and a relatively unhindered alkenyl triflate.
The olefin introduced in the products offers a flexible handle for
further synthetic manipulations as highlighted by the transfor-
mation of the alkene to an alcohol, protected amine, and a carbox-
ylic acid – all remote from the carbonyl in the product. Finally,
hydrogenation of the alkenylated products provides access to a qua-
ternary center bearing four unique alkyl groups. Further efforts are
focused on expanding the scope to other coupling partners as well
as applying this method in synthetic endeavors.
To take advantage of the alkenyl functional group in this unique
transformation, the resulting products were processed to various at-
tractive building blocks. As envisioned, this alkenylation reaction
can be a surrogate for the long-standing challenge of intermolecular
enantioselective alkyl Heck reactions as showcased by a hydro-
genation of 3l to furnish 3la in excellent yield (Scheme 1a). Indeed,
products of this sort would be difficult to access using traditional
strategies. Additionally, the aldehyde group in product 3f was re-
duced to the alcohol and appropriately protected to provide 5 (not
shown). Ozonolysis of alkene 5 followed by treatment with the
Jones reagent provided enantiomerically enriched acid 5a (Scheme
1b).5c This carboxylic acid was subjected to a Curtius rearrange-
ment19 yielding an isocyanate, which was trapped insitu by the ad-
dition of allyl alcohol to provide chiral tertiary protected amine 5b.
Experimental procedures and characterization data for new com-
pounds. This material is available free of charge via the Internet at
http://pubs.acs.org.
sigman@chem.utah.edu
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The authors declare no competing financial interests.
The work was supported by National Institute of Health (NIGMS
R01GM063540).
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