Iridium-Catalyzed Asymmetric Allylic Alkylation of Deconjugated Butyrolactams

Article abstract of DOI:10.1021/acs.orglett.1c00697

Compared with the ever-growing list of nonprochiral nucleophiles in Ir-catalyzed asymmetric allylic substitution reactions, prochiral nucleophiles are less studied. We present a new prochiral nucleophile, namely, deconjugated butyrolactam, for Ir-catalyze

Full text of DOI:10.1021/acs.orglett.1c00697

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Letter
Iridium-Catalyzed Asymmetric Allylic Alkylation of Deconjugated
Butyrolactams
Sankash Mitra and Santanu Mukherjee*
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ABSTRACT: Compared with the ever-growing list of non-
prochiral nucleophiles in Ir-catalyzed asymmetric allylic substitu-
tion reactions, prochiral nucleophiles are less studied. We present a
new prochiral nucleophile, namely, deconjugated butyrolactam, for
Ir-catalyzed asymmetric allylic alkylation (AAA). This reaction
provides access to α-allyl deconjugated butyrolactams with a
moderate to good dr and an excellent er. This is the first AAA
reaction of deconjugated butyrolactams. Allyl transposition through Cope rearrangement appears to proceed stereospecifically to
form γ-allyl conjugated butyrolactams.
Scheme 1. Ir-Catalyzed Asymmetric Allylic Alkylation
(AAA) of Prochiral Nucleophiles
uring the past two decades, iridium-catalyzed asymmetric
allylic substitution (AAS) has established itself among
D
the most powerful carbon−carbon and carbon−heteroatom
bond-forming reactions.1 The regioselective formation of
branched allylic substitution products is the key feature of
the Ir-catalyzed AAS reaction, which sets it apart from the AAS
reaction under the more widely explored Pd catalysis.1,2 This
branched selectivity brings along an additional challenge while
using prochiral nucleophiles: Besides overcoming the steric
limitations, the relative stereochemistry of the two vicinal
stereocenters needs to be controlled. The latter challenge is
substantially trickier as it requires synchronized control of
facial selectivity both on the prochiral nucleophile as well as on
the π-allyl−Ir complex. Whereas an excellent level of face
selectivity on the allylic electrophile is achievable due to the
availability of well-understood catalyst systems,3 that on the
prochiral nucleophile is highly substrate-dependent.
Consequently, compared with the ever-growing list of
nonprochiral nucleophiles in Ir-catalyzed AAS reactions,4
prochiral nucleophiles are considerably less investigated.1d,5
The first ever example of a regio-, diastereo-, and
enantioselective Ir-catalyzed allylic alkylation (AA) of a
prochiral nucleophile was reported by Takemoto et al. in
2003 using imino glycinate as the nucleophile (Scheme 1A).6
Among the cyclic prochiral nucleophiles, the asymmetric allylic
alkylation (AAA) of azlactones was the first to be accomplished
by Hartwig et al. in 2013 (Scheme 1A).7 Whereas a number of
examples have appeared5 since these seminal reports with
varying levels of success, more reliable diastereoselective AAs
of prochiral nucleophiles have become possible only under
cooperative catalysis,8 pioneered by Carreira et al. in 2013.9
Nevertheless, the scope of cyclic prochiral nucleophiles
employed in Ir-catalyzed AAA reactions is still quite limited.
β,γ-Unsaturated γ-lactams (deconjugated butyrolactams)
have recently been introduced as the nitrogen analog of
Received: March 1, 2021
Published: April 6, 2021
https://doi.org/10.1021/acs.orglett.1c00697
© 2021 American Chemical Society
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deconjugated butenolides independently by Maruoka’s group10
and our laboratory11 in 2017. Depending on the nature of the
ring substituents, this prochiral nucleophile was found to
display either α- or γ-selectivity;10−12 however, its application
in enantioselective catalysis has so far been restricted mostly to
Michael and related reactions.
With the objective of broadening the scope of electrophiles
for deconjugated butyrolactams and considering the challenges
associated with the use of prochiral nucleophiles in Ir-catalyzed
AAA, we were intrigued by the possibility of applying
deconjugated butyrolactams as prochiral nucleophile in this
reaction.
Because of the presence of a reasonably acidic α-proton, the
β-alkoxycarbonyl-substituted deconjugated butyrolactam 1
could easily be enolized (Scheme 1B). The resulting stabilized
dienol X has been shown to display α-reactivity in our
previously explored sulfenylation11 and Michael additions to
α,β-unsaturated aldehydes and ketones.12b We envisioned that
the dienol X could be intercepted by the π-allyl−Ir
intermediate Y, generated in situ from a suitable allylic
electrophile.13
under either of these catalysts,14 the desired AA was found to
take place with branched allylic alcohol 2a in the presence of
only 3 mol % [Ir(COD)Cl]2 and 12 mol % (S)-L in 1,2-
dichloroethane at 25 °C. Using 20 mol % of Sc(OTf)3 as the
promoter, the α-allylic alkylation product 3aa was obtained
exclusively as a single regioisomer (>20:1 b/l (branched to
linear)) in 47% yield, albeit with a poor dr (entry 1). However,
both of the diastereomers were formed with a 98:2 er. An
attempt to improve the yield through the Brønsted-base-
assisted enolization of 1a was met with failure, as no reaction
took place (entry 2). Although switching the promoter to
Zn(OTf)2 led to an enhancement in the dr, it did so at the
expense of the reaction rate and the enantioselectivity (entry
3). Restoration of the er along with an increase in the dr was
observed when the reaction was carried out at 50 °C (entry 4).
The use of other Lewis-acidic or Brønsted-acidic promoters
proved detrimental to both the yield and stereoselectivity.14
A
solvent screening with 20 mol % of Zn(OTf)2 as the promoter
revealed toluene as the optimum to strike a balance between
the yield, dr, and er (entry 5). Lowering the initial
concentration to 0.2 M and using a little excess (1.5 equiv)
of allylic electrophile 2a, the product 3aa was isolated in 63%
yield with a 7.7:1 dr and a 98.5:1.5 er (entry 7). Tweaking of
other parameters to improve the yield and dr proved
unsuccessful.14
The conditions optimized for the regio-, diastereo-, and
enantioselective α-allylic alkylation of 1a with 2a (Table 1,
entry 7) were then extended to other substrate combinations.
We first checked the scope of branched allylic alcohols (2) for
the reaction with 1a. As shown in Table 2, allylic alcohols
Here we report the successful implementation of this
strategy, which culminated in the first catalytic asymmetric
allylic alkylation of deconjugated butyrolactams.
We began our investigation with the goal of identifying a
suitable combination of catalyst and allylic electrophile for the
AA of deconjugated butyrolactam 1a (Table 1).14 The
systematic screening of various combinations of allylic
electrophiles and Ir catalysts derived from either Feringa’s
phosphoramidite ligand15 or Carreira’s (phosphoramidite,ole-
fin)-ligand (S)-L1a was carried out. Although no reaction was
observed with either linear or branched allylic carbonates
a
Table 2. Scope of Allylic Alcohols
Table 1. Optimization of Reaction Parameters
a
b
c
promoter
solvent
t (h) yield (%)
dr
er
d
e
1
2
3
4
5
6
7
Sc(OTf)3
Sc(OTf)3
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
toluene
24
48
36
66
48
40
48
47
<5
35
39
49
53
63
1:1
n.d.
98:2
n.d.
96.5:3.5
98:2
97.5:2.5
98.5:1.5
98.5:1.5
f
d
2.5:1
3.6:1
3.6:1
7.7:1
7.7:1
g
toluene
toluene
gh
,
i
a
Yields were determined by 1H NMR spectroscopy with mesitylene as
b
the internal standard. Diastereomeric ratio (dr) was determined by
c
1H NMR analysis of the crude reaction mixture. Enantiomeric ratio
(er) of the major diastereomer as determined by HPLC analysis.
d
e
f
a
1
Reaction at 25 °C. Reaction with 1.0 equiv of DABCO. n.d. = not
Yields refer to the isolated product. dr is determined by H NMR
g
h
determined. Initial concentration 0.2 M. Using 1.0 equiv of 1a and
analysis of the crude reaction mixture. er corresponds to that of the
major diastereomer and was determined by HPLC analysis. dr of the
isolated product. Reaction at 25 °C.
i
b
1.5 equiv of 2a. Yield corresponds to the isolated product after
c
chromatographic purification.
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having either electron-rich or electron-deficient aryl substitu-
ents were found suitable under the optimized reaction
conditions to furnish the α-allyl products (3) in moderate to
good yield and with a moderate to good dr and uniformly high
enantioselectivity (entries 1−15). In general, allylic alcohols
containing electron-rich aryl substituents afforded the products
with excellent enantioselectivity. Allylic alcohols bearing
heterocyclic (2p−q) as well as alkenyl (2r) substituents also
gave the products in moderate to good yield with excellent
enantioselectivity (entries 16−18). In the latter case, the
reaction had to be carried out at 25 °C. Unfortunately, no
reaction was observed in the case of allylic alcohols with
aliphatic substituents, which marks a limitation of this protocol.
Having demonstrated the scope and limitations of allylic
alcohol, we examined the effect of deconjugated butyrolactam
substituents on the outcome of this reaction. Deviation from
1a by replacing the N-protecting group with p-methoxybenzyl
(PMB; 1b) led to a significant drop in the enantioselectivity
when reacted with allylic alcohol 2a (Scheme 2, entry 1).
room for improvement. However, it must be mentioned that in
nearly all of the cases, the minor diastereomer of the products
was formed with either the same or a very similar level of er.14
In line with our previous studies,11,12a,b no α-allyl conjugated
butyrolactam or γ-allyl deconjugated butyrolactam product was
detected in any of our reactions, and exclusive regioselectivity
was observed.
During product isolation through column chromatographic
purification, we observed a significant erosion in the dr in some
cases. For example, the α-allyl-deconjugated butyrolactam 3ah,
which was formed as a 7:1 mixture of two diastereomers
(Table 2, entry 8), when subjected to purification through
silica gel column chromatography, was isolated as a 2:1 dr. The
presence of an enolizable α-proton in 3ah made us wonder
whether the dr of the isolated product reflects the
thermodynamic ratio. To verify this possibility, we carefully
isolated a fraction of 3ah with a 3.4:1 dr and treated it with 10
mol % of Na2CO3 in EtOH at 25 °C for 24 h (Scheme 3). The
Scheme 3. Product Epimerization in Silica Gel
a
Scheme 2. Scope of Deconjugated Butyrolactams
recovered 3ah showed a dr of 2:1, which remained unchanged
even after chromatographic purification. This experiment
indicates that the diastereomeric ratios determined from the
crude catalytic reaction mixture (e.g., 7:1 for 3ah) reflect the
catalyst-controlled kinetic ratios, whereas those obtained from
the purified products (e.g., 2:1 for 3ah) reveal the equilibrium
ratios of the two product diastereomers. Considering the
higher acidity of the α-proton (ring proton) compared with
that of the allylic proton of 3, the diastereomers are likely to
arise from the epimerization of the ring proton (vide infra).
The scalability of this Ir-catalyzed AAA protocol was
examined on a 10-fold scale compared with that used for
displaying the substrate scope. Using a slightly lower loading
(4 mol %) of the Ir/(S)-L complex, the reaction between 1a
and 2a, while taking somewhat longer, furnished the product
3aa in similar yield and with similar enantioselectivity but with
a slight increase in the diastereoselectivity (Scheme 4A).
The densely functionalized α-allyl-substituted deconjugated
butyrolactams obtained in this reaction were deemed suitable
for elaboration to potentially useful building blocks. For
example, the catalytic hydrogenation of 3aa led to the isolation
of the α-(1-phenylpropyl)-substituted deconjugated butyro-
lactam 4 in 93% yield with a 7:1 dr and a 99:1 er (Scheme 4B).
Olefin cross metathesis with methyl acrylate in the presence of
Grubbs second-generation catalyst produced 5 in modest yield
but with a diminished dr. Ir-catalyzed hydroboration16 of 3aa
followed by oxidation with sodium perborate led to an overall
anti-Markovnikov hydration. The resulting alcohol 6 is the
product isolated from our previously reported catalytic
enantioselective Michael reaction,12b and it helped in
establishing its relative and absolute configurations as well as
those of the AA product 3aa. The stereochemistry of the other
a
1
Yields refer to the isolated product. dr is determined by H NMR
analysis of the crude reaction mixture. er corresponds to that of the
major diastereomer and was determined by HPLC analysis.
However, an excellent level of enantioselectivity was preserved
when butyrolactams with other electron-rich N-protecting
groups such as 3,4-dimethoxybenzyl (1c) and 2,4-dimethox-
ybenzyl (1d) were employed (entries 2 and 3). Our protocol
was found to be tolerant to bulkier alkyl substituents at the C5
position of butyrolactam, and the products (3ea and 3fa) were
formed with an outstanding er (entries 4 and 5). Similarly, 4-
benzyloxycarbonyl-substituted butyrolactam (1g), even though
N-protected with PMB, furnished the product (3ga) with a
99:1 er (entry 6).
Notwithstanding the excellent level of enantioselectivity
observed in most of the examples shown above, the yield and
diastereoselectivity generally remained modest, thereby leaving
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Scheme 4. (A) Scale-Up Experiment and (B) Synthetic
Elaboration of α-Allyl-Deconjugated Butyrolactam 3aa
Scheme 5. Allylic Transposition through Cope
Rearrangement
In summary, we have presented a new class of prochiral
nucleophile for the Ir-catalyzed asymmetric allylic alkylation
reaction and, in the process, accomplished the first catalytic
AAA of deconjugated butyrolactams. This reaction is catalyzed
by the Ir(I)/(phosphoramidite,olefin) complex and utilizes
easy-to-prepare branched allylic alcohols as the allylic electro-
phile in combination with a substoichiometric amount of
Zn(OTf)2 as the Lewis acid promoter. The resulting α-allyl-
substituted deconjugated butyrolactams, bearing two vicinal
tertiary stereogenic centers, were obtained with exclusive
branched selectivity in moderate to good yield with moderate
to good diastereoselectivity and excellent enantioselectivity.
The densely functionalized products were transformed into a
few interesting building blocks. Allyl transposition through
Cope rearrangement appears to proceed stereospecifically, and
hence the enantiopurity of the ensuing γ-allyl-substituted
conjugated butyrolactam varies with the diastereopurity of the
starting material.
products (3), shown in Table 2 and Scheme 2, was inferred by
analogy.
The alcohol 6 was converted to a tetrahydropyranopyrrole
derivative 7 in good yield by cyclization via the corresponding
mesylate derivative (Scheme 4B). It must be noted that during
this cyclization, both of the diastereomers of 6 converged into
a single enantiomer of 7, as evident from the retention of
enantiopurity. From these observations, it can be concluded
that the diastereomers (of 6 and hence those) of 3 are epimeric
at the C3 of butyrolactam, as shown in Scheme 3.
Intrigued by the presence of the 1,5-hexadiene core in the α-
allyl deconjugated butyrolactams, we envisaged a α- to γ-
transposition of the allylic unit via a [3,3]-sigmatropic (Cope)
rearrangement.17 Such an allylic transposition was indeed
found to take place when 3aa was refluxed in toluene (Scheme
5A). However, starting from a purified sample of 3aa with a 3:1
dr, γ-allyl conjugated butyrolactam 8, consisting of a
quaternary stereogenic center, was obtained with a poor er.
This erosion in enantiopurity possibly originates from the
divergence in stereochemistry at the C3 of the diastereomers of
3aa (Scheme 5B). Whereas the major diastereomer (S,R)-3aa
is expected to generate the γ-allyl product (R)-8 through a
plausible boat-like transition state (boat-TS-I), the Cope
rearrangement of the minor diastereomer (R,R)-3aa is likely to
proceed through a chairlike transition state (chair-TS-II) to
form the other product antipode (S)-8.
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00697.
Experimental details and characterization data, NMR
spectra, and HPLC chromatograms (PDF)
AUTHOR INFORMATION
Corresponding Author
■
As a support of this mechanistic hypothesis, a sample of
unpurified 3aa (with an 8:1 dr), obtained from the Ir-catalyzed
AAA reaction, when subjected to the same Cope rearrange-
ment conditions, furnished the γ-allyl product 8 with much
improved enantioselectivity (Scheme 5A).
Santanu Mukherjee − Department of Organic Chemistry,
Indian Institute of Science, Bangalore 560012, India;
orcid.org/0000-0001-9651-6228; Email: sm@iisc.ac.in
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Author
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Sankash Mitra − Department of Organic Chemistry, Indian
Institute of Science, Bangalore 560012, India; orcid.org/
0000-0002-5159-0763
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5767−5772. (i) Hethcox, J. C.; Shockley, S. E.; Stoltz, B. M.
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00697
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Science and Engineering Research
Board (SERB) (grant no. EMR/2016/005045) and the
Council of Scientific and Industrial Research (CSIR) (grant
no. 02(0385)/19/EMR-II) is gratefully acknowledged. S.M.
thanks the Indian Institute of Science, Bangalore for a doctoral
fellowship. High-resolution mass spectra (HR-MS) were
recorded on equipment procured under the Department of
Science and Technology (DST)-FIST grant (grant no. SR/
FST/CS II-040/2015).
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