Enantioselective Synthesis of γ-Lactams by Lewis Base Catalyzed Sulfenoamidation of Alkenes

Article abstract of DOI:10.1021/acs.orglett.9b04347

A method for the catalytic, enantioselective, intramolecular 1,2-sulfenoamidation of alkenes is described. Lewis base activation of a suitable sulfur electrophile generates an enantioenriched, thiiranium ion intermediate from a β,γ-unsaturated sulfonyl ca

Full text of DOI:10.1021/acs.orglett.9b04347

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enantioselective Synthesis of γ‑Lactams by Lewis Base Catalyzed
Sulfenoamidation of Alkenes
Jesse L. Panger and Scott E. Denmark*
Roger Adams Laboratory, University of Illinois, 600 South Mathews Avenue, Urbana, Illinois 61801, United States
S
* Supporting Information
ABSTRACT: A method for the catalytic, enantioselective,
intramolecular 1,2-sulfenoamidation of alkenes is described.
Lewis base activation of a suitable sulfur electrophile generates
an enantioenriched, thiiranium ion intermediate from a β,γ-
unsaturated sulfonyl carboxamide. This intermediate is
subsequently intercepted by the sulfonamide nitrogen
resulting in cyclization to form γ-lactams. Electron-poor
alkenes required the use of a new selenophosphoramidate
Lewis base catalyst. Subsequent manipulations of the products
harness the latent reactivity of both the amide and thioether functionality.
for lactamizations are rare owing to the intrinsic preference
for amide nucleophiles to react through the oxygen atom.4
Furthermore, a long-lived, configurationally stable iranium ion
must be generated that allows for N-cyclization. In 2014, a
preliminary report from these laboratories demonstrated the
use of sulfonamides and carbamates as nucleophiles in the
catalytic, enantioselective, intramolecular sulfenoamination of
unactivated alkenes (Scheme 1B).5,6 A single example
employed an amide nucleophile to give a δ-lactam, albeit
with moderate enantioselectivity and under strongly acidic
conditions. In 2015, Yeung and co-workers described an
enantioselective halolactamization catalyzed by a cinchona-
derived carbamate (Scheme 1C).7
lkenes serve as important building blocks for a variety of
1
Atransformations central to synthetic chemistry. Over the
past few decades, enantioselective alkene difunctionalization
has received considerable attention as a way to form new,
stereochemically defined motifs from simple and abundant
starting materials.2a−e Whereas the use of Group 16 and 17
electrophiles to activate alkenes has been extensively studied
in lactonization processes (Scheme 1A),2c,3 analogous reports
Scheme 1. Enantioselective Group 16 and 17 Initiated
Cyclizations
As part of a longstanding program on the enantioselective
difunctionalization of alkenes, our laboratories have devel-
oped the Lewis base activation of Group 16 Lewis acid
electrophiles to generate stereodefined thiiranium ions from
various classes of alkenes followed by diastereospecific
capture by a wide range of oxygen, nitrogen, and carbon
nucleophiles.8,9 In 2019, this strategy was exploited for the
intermolecular capture of anilines and benzyl amines using
hexafluoroisopropyl alcohol (HFIP) as a mildly acidic,
activating solvent.10 With HFIP as both solvent and a weak
acid source (pKa 9.3),11 we sought to re-examine amides as
nucleophiles. The pKa drop from sulfonamides (∼12.3)12 to
sulfonyl carboxamides (<2)13 should enable efficient N-
cyclization to the desired γ-lactams.
The γ-lactam ring is a privileged scaffold in medicinal
chemistry.14 In addition to expressing a range of biological
activities, γ-lactams are useful synthetic intermediates
possessing latent reactivity allowing for further diversifica-
tion.15 Various catalytic, enantioselective methods have been
Received: December 3, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04347
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
developed for the preparation of γ-lactams with NHCs16a−d
and transition-metal catalysis.17 Herein, we disclose a general,
enantioselective construction of γ-lactams using sulfenium
ion-initiated amidation, in which the reactivity of both
electron-rich and electron-poor alkenes have been successfully
engaged (Scheme 1D).
a−c
Table 2. Sulfenoamidation of Electron-Rich Styrenes
Initial optimization studies (Table 1) were performed with
(E)-N-tosylpent-3-enamide (1m), sulfenylating agent 3b,
catalyst (S)-2a, or tetrahydrothiophene (THT) in HFIP as
solvent. Without any Lewis base present, no reaction was
observed (entry 1). The use of achiral Lewis base THT
(entry 2) led to near-quantitative conversion to the desired
pyrrolidinone. However, using catalyst (S)-2a afforded much
lower conversion after 24 h (entry 3). To increase the
reaction rate a second set of experiments were conducted
with a less bulky sulfenylating agent and a more nucleophilic
styryl alkene (entries 4 and 5). In both cases, the yields of
the racemic and enantioenriched products were high, and an
er of 84:16 was obtained. A further increase to the steric bulk
of the sulfenylating agent (entry 6) did not appreciably erode
the yield, and there was a marked increase in er.
a
Table 1. Reaction Optimization
a
b
All reactions performed on a 1.00 mmol scale. Yield of isolated
b
sulfenylating
agent
concn
(M)
yield
(%)
c
analytically pure product. Enantiomeric ratio determined by CSP-
HPLC analysis.
c
entry
1
catalyst
er
1
2
3
4
5
6
1m
1m
1m
1a
1a
1a
3b
3b
3b
3a
3a
3b
0.2
0.2
0.2
0.5
0.5
0
THT
(S)-2a
THT
(S)-2a
(S)-2a
85 (93)
(12)
85 (88)
83 (83)
76 (85)
ND
Substitution at the ortho-position on the styryl arene with
an electron-rich group (4g) was efficiently accommodated,
and indole sulfonamide 1h was compatible under the reaction
conditions to afford lactam 4h in nearly quantitative yield and
98:2 er.
84:16
98:2
0.5
a
b
Reactions performed on 0.1 mmol scale. Yield in parentheses
determined by 1H NMR spectroscopic analysis using 1,1,2,2-
As was observed with aliphatic substrate 1m, electron-
deficient alkenes were much less reactive leading to low yields
even after extended reaction times. To address this problem,
two potential solutions were considered: (1) decrease the
electron density on the sulfenylating agent to facilitate
sulfenyl group transfer to the alkene, and (2) modify the
catalyst itself to enhance reactivity of the sulfenium group.
On the basis of previous studies, it was found that electronic
perturbations of sulfenylating agents had little impact on the
rate of sulfenium ion transfer.8g Instead, a catalyst
modification was envisioned such that a decrease in Lewis
basicity was postulated to increase the rate of the sulfenium
ion transfer. The justification for this counterintuitive
hypothesis was that the attenuated Lewis basicity would
increase the electrophilicity of the sulfenium ion so long as it
retained sufficient Lewis basicity to form the catalytically
active intermediate. To test this hypothesis, the simplest
modification was to change from a BINAM-derived catalyst
c
tetrachloroethane as an internal standard. Determined by CSP-
HPLC analysis.
Although yet fully optimized, the scope of the sulfeno-
lactamization with styryl-derived alkenes was explored using
catalyst (S)-2a along with sulfenylating agent 3b (Table 2).
Electron-rich styryl alkenes proved to be competent reaction
partners to generate highly enantioenriched γ-lactams. The
parent β,γ-unsaturated sulfonamide 1a gave product 4a in
92% yield and 97:3 er. Furthermore, electron-rich aryl groups
(4b−4d) led to similarly good yields and high enantiose-
lectivities. The (4R,5S)-configuration for the major enan-
tiomer of 4b was established by single-crystal X-ray analysis,
which is in agreement with the stereochemical model from
previous studies.8g 2-Naphthyl and 4-tolylsulfonamide 1e and
1f afforded cyclized pyrrolidinones 4e and 4f in slightly
reduced yields but maintained high enantioselectivity.
B
DOI: 10.1021/acs.orglett.9b04347
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Organic Letters
Letter
to one derived from BINOL.18 The synthesis began with
enantioenriched (R)-BINOL which was deprotonated with
NaH and then treated with diisopropylaminochlorophosphine
to generate the P(III) intermediate and then was immediately
oxidized with elemental selenium to form (R)-2b (Scheme
2). The preparation of this new Lewis base catalyst proved
advantageous in several ways: the starting material is readily
available, milder conditions are required for deprotonation,
and the catalyst itself could be obtained in nearly quantitative
yield after a simple filtration.
Table 3. Sulfenoamidation of Electron-Deficient Styrenes
and Alkenes
a−c
Scheme 2. Synthesis of BINOL-Derived Lewis Base
Catalyst (R)-2b
To test the viability of Lewis base (R)-2b, a comparison
experiment was performed in which sulfonamide 1b and (R)-
2b were combined to determine if (R)-2b would function
with a competent substrate. The BINOL-derived catalyst
delivered (4S,5R)-4b19 in 93% yield and 97:3 er, demonstrat-
ing that the two catalysts behave similarly with this substrate.
Next, electron-deficient alkenes 1i, 1j, and 1k were subjected
to the standard reaction conditions with (R)-2b and afforded
the corresponding cyclized products (4i, 4j, 4k) in syntheti-
cally acceptable yields and excellent enantioselectivities
(Table 3). The presence of an ortho substituent on the
styryl group resulted in the reduced yield and enantiose-
lectivity (4l). If a second o-methyl group was incorporated,
the reaction failed.
Next, catalyst (R)-2b was evaluated with the previously
refractory substrates (E)-alkenes bearing alkyl substituents.
Sulfenoamidation of alkenes 1m and 1n still proved sluggish
but nevertheless afforded products 4m and 4n in 55% and
57% yields, respectively, with a moderate drop in er for 4n. 3-
Butenamide substrate 1o also exhibited a further drop in
yield but maintained a 91:9 er. Prenyl sulfonamide 1p
performed better than its other alkyl counterparts in both
yield and enantioselectivity, matching that of aryl substrates.
Finally, the cyclic skipped diene 1q was afforded the
desymmetrized product 4q in 78% yield and 90:10 er. The
respectable enantioselectivity observed for this substrate was
unexpected in view of the generally poor selectivity seen
previously with (Z)-alkenes.8g Furthermore, given that the
opening of thiiranium ions is diastereospecifically anti, this
result demonstrates that (R)-2b is capable of enantiotopic
group differentiation.20
a
b
All reactions performed on a 1.00 mmol scale. Yield of isolated
c
analytically pure product. Enantiomeric ratio determined by CSP-
HPLC analysis.
one-pot procedure to generate a mixture of sulfoxides
followed by spontaneous elimination upon addition of
aqueous Na2S2O3 proceeded to form the unsaturated lactam
6. Deoxygenation of 4a proceeded smoothly with BH3·SMe2
to give enantiomerically enriched 2,3-disubstituted pyrrolidine
7 in 95% yield. Treatment with LiAlH4 resulted in formation
of ring-opened amino alcohol 8 in excellent yield. Conversely,
using DIBAL as a weaker reductant yielded a mixture of
diastereomeric hemiaminal products which epimerized on
silica gel to diastereomerically enriched intermediate 9 in
94% yield. The hemiaminal could undergo further trans-
formations such as stereoselective cyanation with TMSCN in
96% yield (10) and allylation with allyltrimethylsilane in 65%
yield (11) albeit in reduced yield owing to competitive
formation of a pyrrole side product. Lastly, treatment with
TFAA and lutidine allowed for the facile conversion of lactam
4a to highly enantioenriched 4,5-disubstituted-2-pyrroline 12
in 98% yield.
In summary, an enantioselective Lewis base catalyzed
sulfenolactamization of β,γ-unsaturated sulfonyl carboxamides
has been described. The reaction proceeds under mild
conditions through formation of an enantiomerically enriched
thiiranium ion followed by a diastereospecific capture with
nitrogen to afford highly functionalized γ-lactams. The
development of a new Lewis base catalyst has allowed for
an expanded substrate scope of less nucleophilic alkenes.
Moreover, the lactam products have been shown to undergo
To illustrate the utility of these products, synthetic
manipulations of enantioenriched γ-lactam 4a were explored
(Scheme 3) following recrystallization to ≥99:1 enantiopur-
ity. Detosylation was carried out with magnesium in
methanol in 85% yield to unveil deprotected lactam 5. A
C
DOI: 10.1021/acs.orglett.9b04347
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a variety of manipulations harnessing both the amide and
thioether functionality to reach valuable synthetic targets.
ACKNOWLEDGMENTS
■
We are grateful to the National Institutes of Health (GM
R35 127010) for generous financial support. We also thank
the UIUC SCS support facilities (microanalysis, mass
spectrometry, X-ray, and NMR spectroscopy) for their
assistance.
a
Scheme 3. Product Manipulations
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04347.
■
S
Experimental Procedures, characterization data for all
new compounds along with copies of spectra and
chromatograms (PDF)
Accession Codes
CCDC 1952721−1952722 contain the supplementary
crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.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.
AUTHOR INFORMATION
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Am. Chem. Soc. 2014, 136 (25), 8915−8918.
■
Corresponding Author
*E-mail: sdenmark@illinois.edu.
ORCID
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Scott E. Denmark: 0000-0002-1099-9765
Notes
The authors declare no competing financial interest.
D
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