Construction of Vicinal Quaternary Centers via Iridium-Catalyzed Asymmetric Allenylic Alkylation of Racemic Tertiary Alcohols

Article abstract of DOI:10.1021/jacs.1c00609

Enantioselective bond formation between sterically hindered fragments to furnish acyclic products with vicinal quaternary centers is a formidable challenge. We report a solution that involves cocatalysis between a chiral Ir-(phosphoramidite,olefin) complex and La(OTf)3. This robust catalytic system effects highly enantioconvergent and regioselective alkylation of racemic tertiary α-allenyl alcohols with tetrasubstituted silyl ketene acetals. The transformation displays broad functional group tolerance for both reaction components and allows efficient generation of β-allenyl ester products in good yield and with excellent enantioselectivity. Furthermore, both the allene and ester functionalities were leveraged to upgrade the structural complexity of the products via a series of stereoselective metal-catalyzed functionalization reactions.

Full text of DOI:10.1021/jacs.1c00609

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Communication
Construction of Vicinal Quaternary Centers via Iridium-Catalyzed
Asymmetric Allenylic Alkylation of Racemic Tertiary Alcohols
Mayuko Isomura, David A. Petrone, and Erick M. Carreira*
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ABSTRACT: Enantioselective bond formation between sterically hindered fragments to furnish acyclic products with vicinal
quaternary centers is a formidable challenge. We report a solution that involves cocatalysis between a chiral Ir−
(phosphoramidite,olefin) complex and La(OTf)3. This robust catalytic system effects highly enantioconvergent and regioselective
alkylation of racemic tertiary α-allenyl alcohols with tetrasubstituted silyl ketene acetals. The transformation displays broad
functional group tolerance for both reaction components and allows efficient generation of β-allenyl ester products in good yield and
with excellent enantioselectivity. Furthermore, both the allene and ester functionalities were leveraged to upgrade the structural
complexity of the products via a series of stereoselective metal-catalyzed functionalization reactions.
tertiary carbocation that underwent stereoselective reduc-
he asymmetric generation of quaternary stereocenters is
Tof particular interest due to their presence in scaffolds of tion.62
natural products and bioactive molecules.1,2 While the past
two decades have witnessed significant advances in this area,
they largely have addressed difficulties associated with setting
a single quaternary stereocenter.3−8 As such, direct access to
vicinal quaternary carbons stereoselectively remains a
formidable challenge9−11 that has inspired clever approaches,
involving cycloadditions,12−19 electrophilic substitutions,20−22
and allylations.23−30 In many methods reported, at least one of
the generated quaternary centers is endocyclic. By contrast,
the synthesis of fragments incorporating vicinal acyclic
quaternary carbons represents a more difficult task because
of the higher entropic and enthalpic penalties during bond
formation (Scheme 1A).31−33 Toward this end, Stoltz has
documented catalytic, enantioselective substitution of 3,3-
disubstituted allylic carbonates with substituted malonodini-
triles (Scheme 1B).34 Concurrently, Jørgensen reported
oxidative, stereoselective aldehyde homocoupling, furnishing
1,4-dialdehydes bearing vicinal quaternary stereocenters
(Scheme 1B).35−44
Tertiary carbocations represent convenient synthetic access
points for the asymmetric synthesis of quaternary centers.45−55
However, attempts to gain stereocontrol over these inter-
mediates have been scarce.56−58 In 2004, Braun showed that
chiral Ti(IV) complexes could be used to catalyze the
asymmetric allylation of tertiary-benzylic carbocations.56
Jacobsen has reported that chiral hydrogen-bond donor−
acceptor catalysts facilitate asymmetric allylation of tertiary
propargylic carbocations in 2018.57 Our group entered this
area with the substitutions of racemic secondary allenylic
alcohols by amines and organozinc reagents using a chiral Ir−
bis(phosphoramidite,olefin) complex.59−61 More recently, we
demonstrated that η2-coordination of the allene motifs in
racemic tertiary allenylic alcohols to a chiral Ir(I) catalyst led
to ionization and generation of an intermediate, metal-bound
We envisioned that by judicious choice of conditions, Ir-
stabilized, tertiary allenylic carbocations could act as
convenient linchpins for the enantioselective construction of
vicinal quaternary centers. Herein, we report the realization of
this goal with the enantioconvergent alkylation of racemic,
tertiary allenylic alcohols with fully substituted silyl ketene
acetals (Scheme 1C). This transformation represents the first
application of allenylic substitution in the enantioselective
construction of quaternary centers63 as well as the first
instance of its use for the enantioselective formation of vicinal
quaternary centers. Furthermore, exploiting our η2-coordina-
tion-induced SN1-type ionization mechanism allows unpro-
tected tertiary alcohols to be used as substrates in an Ir-
catalyzed asymmetric carbon−carbon formation for the first
time. This powerful methodology provides access to hindered,
acyclic β-allenyl ester products with good yields and excellent
regio- and enantioselectivity.
Our studies were initiated using α-allenyl alcohol ( )-1a as
a model substrate. Silyl ketene acetals were selected as
nucleophiles due to their synthetic versatility along with their
facile preparation.64−67 After extensive evaluation, a system
comprising [Ir(cod)Cl]2 (5 mol %), phosphorus−olefin ligand
(S)-L1 (20 mol %), TBS ketene acetal 2a (2.5 equiv), and
La(OTf)3 (7.5 mol %) in 1,4-dioxane ([( )-1a] 0.1 M) at 45
°C was found to be optimal. Under these conditions, β-allenyl
ester (R)-3a bearing vicinal quaternary carbons was isolated in
75% yield with 99% ee and >20:1 selectivity over the
Received: January 18, 2021
Published: March 1, 2021
https://dx.doi.org/10.1021/jacs.1c00609
J. Am. Chem. Soc. 2021, 143, 3323−3329
© 2021 American Chemical Society
3323

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Communication
a
Scheme 1. (A) Various Motifs of Quaternary and Vicinal
Quaternary Carbons; (B) Examples of Enantioselective
Synthesis of Acyclic Vicinal Quaternary Carbons; (C)
Enantioselective Generation of Vicinal Quaternary Carbons
via Allenylic Alkylation with Tetrasubstituted Silyl Ketene
Acetals
Table 1. Effect of Reaction Parameters
b
c
entry variation from “standard conditions” yield (R)-3a (%)
ee (%)
d
1
2
3
4
5
6
none
83(75)
92(88)
80
85
58
0
99
89
96
97
99
−
d
2b instead of 2a
2c instead of 2a
23 °C instead of 45 °C
60 °C instead of 45 °C
no La(OTf)3
7
8
9
10
11
12
13
14
Zn(OTf)2 instead of La(OTf)3
(S)-L2 instead of (S)-L1
no [Ir] nor (S)-L1
no [Ir]
73
0
3
1
1
39
3
73
99
−
−
−
−
78
−
99
no (S)-L1
1:1 [Ir]:L1
[Rh] instead of [Ir]
e
add 4 (10 mol %)
a
b
1
Reactions conducted on 0.4 mmol scale. Determined by H NMR
analysis of the unpurified reaction mixture using (CHCl2)2 as an
c
internal standard. Determined by HPLC with chiral stationary phase.
d
e
Isolated yield. [Rh(cod)Cl]2 in lieu of [Ir(cod)Cl]2. cod = 1,5-
cyclooctadiene; 2-Np = 2-naphthyl; OTf = O3SCF3; TBS = t-
BuMe2Si; TMS = Me3Si; TES = Et3Si; − = not determined.
was replaced by [Rh(cod)Cl]2 in this reaction, decomposition
of the allene substrate was observed under otherwise similar
reaction conditions (entry 13). It is well precedented that
triflic acid can be generated via the hydrolysis of metal triflate
salts in the presence of adventitious moisture.71−75 With this
in mind, we conducted an experiment with using 10 mol % of
2,6-di-tert-butyl-4-methyl-pyridine as a non-coordinating
Brønsted acid scavenger (entry 14).76 Therein essentially no
change in the reaction outcome was observed, which suggests
that the main role of La(OTf)3 is that of a Lewis acid.
A wide variety of racemic tertiary α-allenyl alcohols ( )-1
and silyl ketene acetals 2 were found to undergo the
transformation to afford products with high enantiomeric
excess and regiocontrol (Tables 2 and 3). The processes
scalability was tested by conducting the transformation on a 1
g scale using substrate 1a. This led to the desired product
being isolated in 76% yield with excellent selectivity (99% ee
and >20:1 rr). Substrates possessing a 2-naphthyl group
bearing electron-withdrawing or -donating substituents were
examined, and these led to products 3b and 3c in 77% and
73% yield with 92% and 97% ee, respectively. The
replacement of the 2-naphthyl motif with phenyl was tolerated
and led to the corresponding product being obtained in 65%
yield with 96% ee and >20:1 rr (3d). Substrates bearing
electron-withdrawing or -donating groups at the para-position
of the aryl substituent also participated in the transformation.
For example, products bearing halogens (3e, 3f), ester (3g),
trifluoromethoxy (3h), or alkyl groups (3i, 3j) were obtained
corresponding 1,3-diene regioisomer (Table 1, entry 1). The
effect of each parameter on the reaction outcome was also
examined. Less bulky TMS ketene acetal 2b afforded the
product in higher yield (88% vs 75%) but lower
enantioselectivity (89% vs 99% ee), while TES derivative 2c
resulted in lower enantiomeric excess with no improvement of
yield (entries 2 and 3).
When the reaction was conducted at 23 °C, product yield
remained unchanged and a slight attenuation of enantiocon-
trol was observed (97% ee) (entry 4), while a considerable
decrease in yield was observed at 60 °C (entry 5). Addition of
Lewis acid was found to be crucial, and only starting material
was recovered in the absence of La(OTf)3 (entry 6). When
Zn(OTf)2 was employed, the product was obtained in 73%
yield and 99% ee (entry 7). When the reduced ligand analog
(S)-L2 was employed, no product was observed, highlighting
the importance of the olefin ligand (entry 8). Control
experiments showed that the reaction fails in the absence of
[Ir(cod)Cl]2/(S)-L1 or either of its individual components
(entries 9−11). When the [Ir]:(S)-L1 ratio was changed from
1:2 to 1:1, a decrease in both yield (39%) and enantiomeric
excess (78% ee) were observed, in line with the notion that a
1:2 [Ir]:(phosphoramidite,olefin)-ligand complex is operative
(entry 12).68 You and co-workers reported that a catalyst
comprised of [Rh(cod)Cl]2 and (S)-L1 is effective for
enantioselective allylation of 1,3-diketones using racemic
allylic alcohol derivatives.69,70 However, when [Ir(cod)Cl]2
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Communication
a
Table 2. Scope of Racemic Electrophiles in the Ir-Catalyzed Enantioselective Alkylation Reaction
a
Reaction conditions: [Ir(cod)Cl]2 (5.0 mol %), (S)-L1 (20 mol %), ( )-1 (0.4 mmol), 2a (2.5 equiv), La(OTf)3 (7.5 mol %), 1,4-dioxane (c 0.1
M), and 45 °C unless otherwise noted. Isolated yields shown. Enantiomeric excess (ee) was determined by HPLC, SFC, or GC analysis using a
b
chiral stationary phase. Regiochemical ratios (rr) were determined by 1H NMR analysis of the unpurified reaction mixtures. Reaction conducted
c
d
e
f
using 2b (2.5 equiv). 20 mol % of La(OTf)3 was used. 10 mol % of La(OTf)3 was used. 4.0 equiv of 2a was used. Reaction was run at 23 °C.
in 52−82% yield with 91−98% ee and >20:1 rr. Substrates
bearing a pinacolborane group were also well-tolerated, and
the corresponding product (3k) could be obtained in 82%
yield with 93% ee and >20:1 rr. In contrast to our previously
reported asymmetric reductive deoxygenation reaction,
substrates bearing para-, meta-, or ortho-methoxy groups
(3l−3n) all provided the respective products with high
enantioselectivity (90−96% ee). Heteroaromatic substrates
were also examined, and products containing N-tosyl indole
(3o) and thiophene (3p) were obtained with 65% and 70%
yield with 93% and 93% ee and 20:1 and 7:1 rr, respectively.
When the arene in the substrate was replaced with a
cyclopropyl group, product 3q was obtained in 54% yield
with 94% ee and >20:1 rr. The cyclopropyl group is thought
to provide the requisite stabilization for the tertiary
carbocation generated under the reaction conditions.77 In
stark contrast to this finding, no reaction was observed when
the arene was replaced by a cyclohexyl group (3r).
Furthermore, alkyl groups other than methyl could be
tolerated at the allenylic position. For example, subjecting
substrates containing ethyl or cyclopropyl group to the
reaction conditions furnished products 3s and 3t in 52%
and 55% yield with 90% and 94% ee, respectively.
Interestingly, the cyclopropyl-containing product 3t was
obtained with the absolute configuration opposite that of
parent methyl-containing product 3a.62
silyl ketene acetal 2d furnished 3u in 70% yield with 95% ee
and >20:1 rr. However, when the tert-butyl derivative was
employed, none of the desired β-allenyl ester was observed.78
A reaction employing the propionate derived silyl ketene
acetal 2e enriched in the E isomer (E:Z = 6.7:1) was also
examined. In the experiment, product 3v bearing a vicinal
tertiary-quaternary stereocenter arrangement was obtained in
72% yield and with 85% ee and >20:1 rr, albeit with a dr of
2.4:1.79 Danishefsky’s diene 2f was also found to be a
competent nucleophile, and its use resulted in the formation
of the corresponding α,β-unsaturated ketone product (3w) in
54% yield and 88% ee. Finally, silyl ketene acetals derived
from cyclohexane (2g), 4,4-difluorocyclohexane (2h), and
tetrahydropyran (2i) carboxylic acids were tested. Products
(3x−z) bearing unsubstituted, difluoro-substituted, and oxy-
gen-containing six-membered rings were obtained in good
yields (57−82%) with uniformly high enantioselectivities
(91−96%) and regioselectivities (>20:1 rr).
The retention of the allene unit in the products obtained
from the allenylic alkylation reaction makes them prime
candidates for synthetic diversification. As such, we examined
a series of metal-catalyzed functionalization reactions as a
means to increase their structural complexity (Scheme 2).
Asako and Takai’s Mo-catalyzed regioselective hydrosilylation
afforded allylsilane (Z)-5 in 73% yield with >20:1 rr and
>20:1 Z:E.80 Tsuji’s palladium-catalyzed arylamination also
worked well to give amine (Z)-6 in 70% yield with >20:1 rr
and >20:1 Z:E.81 After the transformation of ester to
carboxylic acid 7, Curtius rearrangement followed by
Encouraged by the wide substrate scope of racemic allenylic
electrophiles, we next investigated the silyl ketene acetal
component (Table 3). The use of the methyl ester-derived
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Communication
a
gent, regioselective alkylation of racemic tertiary α-allenyl
alcohols with tetrasubstituted silyl ketene acetal nucleophiles.
This intermolecular transformation displays broad functional
group tolerance for both reaction components, and it allows
rapid generation of sterically congested β-allenyl esters in
good yield (up to 82%) and excellent enantioselectivity (up to
99% ee). The reaction was shown to perform well even on a
gram-scale without any effect on efficiency or selectivity.
Furthermore, by taking advantage of both the allene and ester,
we utilized a series of stereoselective transition metal-catalyzed
reactions to add additional complexity to the enantioenriched
allenylic alkylation products. We are currently in the process
of expanding the scope of enantioselective reactions with this
catalytic system. More broadly, the transformation we disclose
begins to expand the scope of asymmetric allenylic
substitution, which has otherwise lagged behind the more
extensively studied allylation counterpart.
Table 3. Scope of Silyl Ketene Acetal Nucleophiles
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c00609.
a
Reaction conditions: [Ir(cod)Cl]2 (5.0 mol %), (S)-L1 (20 mol %),
( )-1a (0.4 mmol), 2 (2.5 equiv), La(OTf)3 (7.5 mol %), 1,4-dioxane
(c 0.1 M), and 45 °C. Isolated yields shown. Enantiomeric excess
value (ee) was determined by HPLC or SFC analysis using a chiral
Experimental details of synthetic procedures, character-
ization data for all new compounds, NMR spectra,
crystal data, ORTEP diagrams (PDF)
1
stationary phase. Regiochemical ratios (rr) were determined by H
NMR analysis of the unpurified reaction mixtures. 10 mol % of
Accession Codes
b
c
d
e
CCDC 2056432, 2056443, 2056444, 2056454, and 2056457
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge via www.ccdc.ca-
m.ac.uk/data_request/cif, or by emailing data_request@ccdc.
cam.ac.uk, or by contacting The Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
+44 1223 336033.
La(OTf)3 was used. 2d was used. (E)-2e was used. 2f was used.
f
2g, 2h, or 2i was used.
quenching with BnOH furnished carbamate 8 in good yield.
Finally, Breit’s Rh-catalyzed intramolecular cyclization reaction
between carboxylic acid and allene delivered lactone 9 in 94%
yield with 5.2:1 dr.82 In all cases, no erosion of enantiomeric
purity was observed.
In conclusion, we have developed an enantioselective
method that permits facile access to the vicinal quaternary
carbon centers within acyclic motifs. This cocatalytic process
utilizes the simple and robust Ir−(phosphoramidite,olefin)
catalyst system and La(OTf)3 to afford highly enantioconver-
AUTHOR INFORMATION
■
Corresponding Author
Erick M. Carreira − ETH Zu
rich, 8093 Zurich, Switzerland;
̈ ̈
orcid.org/0000-0003-1472-490X;
Email: erickm.carreira@org.chem.ethz.ch
Scheme 2. Synthetic Application of the β-Allenyl Ester Products
a
b
c
DIBAL-H (3 equiv), DCM, −78 °C to rt, 30 min. DMP (1.5 equiv), DCM, 0 °C, 30 min. NaClO2 (3.0 equiv), KH2PO4 (3.0 equiv), 2-methyl-
d
t
2-butene (6.6 equiv), BuOH/H2O, 0 °C to rt, 11 h. Product was derived from (R)-3a possessing 99% ee.
3326
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Authors
pubs.acs.org/JACS
Communication
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Highly Stereoselective Olefin Cyclopropanation of Diazooxindoles
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Mayuko Isomura − ETH Zu
orcid.org/0000-0002-6235-5937
David A. Petrone − ETH Zurich, 8093 Zu
orcid.org/0000-0001-9867-9178
̈
rich, 8093 Zu
̈
rich, Switzerland;
̈
̈
rich, Switzerland;
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c00609
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
ETH Zu
̈
rich and the Swiss National Science Foundation
(200020_152898) are gratefully acknowledged for financial
support. M.I. thanks the Funai Foundation for a Funai
Overseas Scholarship. D.A.P. thanks the National Sciences and
Engineering Research Council of Canada for a postdoctoral
fellowship. The authors thank Michael Solar and Dr. N. Trapp
(ETH Zu
Zurich) is thanked for helpful discussion. Prof. Helma
Wennemers (ETH Zurich) is thanked for access to SFC
and HPLC instruments, and Greta Vastakaite (ETH Zurich)
̈
rich) for X-ray analysis. Roman C. Sarott (ETH
̈
̈
̈
is thanked for assistance with their operation.
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