Gold and BINOL-phosphoric acid catalyzed enantioselective hydroamination/N-sulfonyliminium cyclization cascade

Article abstract of DOI:10.1021/ol401784h

A highly enantioselective hydroamination/N-sulfonyliminium cyclization cascade is reported using a combination of gold(I) and chiral phosphoric acid catalysts. An initial 5-exo-dig hydroamination and a subsequent phosphoric acid catalyzed cyclization proc

Full text of DOI:10.1021/ol401784h

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Gold and BINOL-Phosphoric Acid
Catalyzed Enantioselective
Hydroamination/N‑Sulfonyliminium
Cyclization Cascade
Alex W. Gregory,† Pavol Jakubec,† Paul Turner,‡ and Darren J. Dixon*,†
Department of Chemistry, Chemistry Research Laboratory, University of Oxford,
Mansfield Road, Oxford OX1 3TA, U.K., and AstraZeneca R&D, Macclesfield,
Mereside, Alderley Park, Cheshire SK10 4TG, U.K.
darren.dixon@chem.ox.ac.uk
Received June 25, 2013
ABSTRACT
A highly enantioselective hydroamination/N-sulfonyliminium cyclization cascade is reported using a combination of gold(I) and chiral phosphoric acid catalysts.
An initial 5-exo-dig hydroamination and a subsequent phosphoric acid catalyzed cyclization process provide access to complex sulfonamide scaffolds in
excellent yield and high enantiocontrol. The method can be extended to lactam derivatives, with excellent yields and enantiomeric excesses of up to 93% ee.
Enantioselective cascade processes exploiting one-pot
combinations of gold and chiral binol phosphoric acid
(BPA) catalysts to govern both the reaction pathway and
stereocontrol are becoming useful in synthesis. Recently,
reactions exploiting the ability of gold to facilitate cyclo-
isomerization, isomerization, and tautomerism in combi-
nation with phosphoric acid or phosphate catalyzed
hydrogenation, PictetÀSpengler, or (N-acyl) iminium ion
cyclization processes have been reported.1,2 To this end,
our group recently described a cascade process comprising
alkynoic acid and tryptamine starting materials giving rise
to polycyclic products with high enantioselectivities.3 In
continuation of this work, we wished to examine the
compatibility of a gold catalyzed hydroamination with
an enantioselective phosphoric acid catalyzed N-sulfonyl-
iminium cyclization, a sequence that has no precedent.
† University of Oxford.
‡ AstraZeneca R&D.
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r
10.1021/ol401784h
XXXX American Chemical Society

Scheme 1. Concept of Dual Catalytic Gold and Organic
Phosphoric Acid Enantioselective Cyclization Cascade
Scheme 2. Proof of Principle Study in the N-Sulfonyliminium
Cyclization Cascade
TheproposedconceptisdepictedinScheme1foraninternal
alkyl sulfonamide residue possessing a terminal alkyne 1. Our
initial choice of sulfonamide over carboxylic acid amide was
influenced in part by their abundance in medicinally relevant
compounds4 and by the lack of such motifs in enantioselective
cascade processes. We envisaged a novel alkyne hydro-
amination process to form isothiazolidine-1,1-dioxide (2),
which could take place under gold(I) catalysis.5,6 Protonation
would then afford the N-sulfonyliminium intermediate 3,
which through tight ion pairing/general base catalysis with
the conjugate base of the chiral phosphoric acid would facili-
tate an enantiofacially selective cyclization, thus providing a
novel route to polycyclic isothiazolidine-1,1-dioxide moieties
of type 4 (Scheme 1).7À10 Herein we report our findings.
Proof of principle was first established after a brief
screen of metal complexes by adding [P(OPh)3]AuCl
(2 mol %) and AgOTf (2 mol %) in one portion to a mixture
of sulfonamide 5a and BPA-1A (10 mol %, Table 1) in
toluene at 50 °C (Scheme 2). The reaction furnished the
cascade products 6a and 7a (5-exo and 6-endo respectively
in 9:1 ratio) with quantitative mass return at a faster rate
than previously reported in N-acyliminium cyclization
cascades.3 Unfortunately, no enantioselectivity was wit-
nessed. However, we later confirmed that this was due to a
competing gold catalyzed background reaction;11 treat-
ment of sulfonamide 5a with [P(OPh)3]AuCl (3 mol %)
and AgOTf (3 mol %) at 60 °C in toluene afforded
cyclization products 6a and 7a in quantitative yield as a
9:1 mixture of regioisomers respectively.12 A range of
alternative alkynophilicLewisacidicmetal complexes were
screened in an attempt to slow the undesirable background
process. Pleasingly, with Echavarren’s catalyst13 (8), 6a
was afforded in 56% yield and 73% ee (Table 1, entry 4). A
brief solvent screen (Table 1, entries 4À8) identified tol-
uene as the best solvent for enantioselectivity when com-
pared with other aprotic solvents.14 To further minimize
the competitive gold catalyzed background reaction and
improve efficiency, the loading of gold catalyst 8 was
decreased to 2 mol % (Table 1, entry 9), which indeed
resulted in an increase in product enantiomeric excess.
Performing the reaction at 60 °C, rather than at 100 °C,
afforded higher yields of the desired reaction product but
with reduced enantiomeric excess (Table 1, entries 9 and 11).
However, due to the increased lifespan of the gold catalyst
under these conditions we were able to lower the gold
catalyst loading even further to 0.5À1.0 mol %, which proved
beneficial to both reaction yield and enantioselectivity
(Table 1, entries 12 and 13). A subsequent screen of chiral
BPA derivatives provided no enhancement in enantioselec-
tivity (Table 1, entries 15À17) and confirmed BPA-1A was
optimal for the enantioselective cascade process.
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With optimized conditions in hand a variety of substi-
tuted indole sulfonamide derivatives were cyclized with
good to excellent yields and enantioselectivities up to
96% ee (Figure 1). The reaction was found to tolerate
electron-withdrawing halides at various positions around
the ring (6b to 6f) and the electron-deficient 5-nitrile
derivative (6g), albeit at a slower reaction rate in the latter
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resulted in no reaction and showed only pure starting material.
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D. J.; Bunuel, E.; Nevado, C.; Echavarren, A. M. Angew. Chem., Int. Ed.
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B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Optimization Studies
entrya
LA cat.
LA (mol %)
BPA (mol %)
acid (mol %)
solvent
temp (°C)
yield (%)b
ee (%)
1
[P(OPh)3]AuOTf
2
1A
1A
1A
1A
1A
1A
1A
1A
1A
1A
1A
1A
1A
1A
1B
1C
1D
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
toluene
toluene
toluene
toluene
(CH2Cl)2
MeCN
100
100
100
100
60
26
71
54
56
83
77
14
83
68
68
82
84
78
21
83
85
79
17
52
17
73
46
53
27
0
2c
3e
4f
5
[NHC]AuOTfd
7
Cu(OTf)2
20
5
8
8
8
8
8
8
8
8
8
8
8
8
8
8
5
6
5
60
7
5
hexane
THF
60
8
5
60
9
2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
100
95
87
85
81
88
88
92
45
71
45
10
11
12
13
14
15
16
17
2
2
60
1
60
0.5
0.1
1
60
60
60
1
60
1
60
a All reactions proceeded for 20 h at 7 mM concentration (with respect to 5a) unless otherwise stated. No change in regioselectivity (9:1, 6a:7a) was
witnessed throughout optimization. b Isolated yield. c Initial LA catalyst loading of 2 mol %; after 48 h additional LA was charged (5 mol %) and reacted
for a further 12.5 h. d [NHC]AuOTf = {Au[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]OTf}. e 52 h reaction. f Reaction complete after 1 h.
case due to its poor solubility in the reaction solvent.
Substrates containing electron-donating groups (6h to 6k)
were also found to work well. These derivatives demon-
strated that all the possible positions around the carbocycle
of the indole ring could be substituted without significant
detriment to enantioselectivity or yield.
To further test the flexibility of this new methodology,
attempts were made to perform the reaction cascade on the
chain extended amide analogue 9a. Pleasingly, using
5 mol % of 8 and 10 mol % BPA-1A in refluxing toluene
gave desired product10a in50%eeand79%yieldasasingle
regioisomer. Successful optimization of the enantioselectiv-
ity was achieved through lowering the loading of the gold
catalyst (see Supporting Information); with 1 mol % of gold
catalyst 8, lactam 10a was formed in 86% yield and 66% ee.
A collection of examples were examined to test the effects
of electron withdrawing (10b) and donating (10c and 10d)
substituents in this variant of our cascade process. Pleas-
ingly the reactions proceeded with good to excellent yields
and with enantiomeric excesses up to 93% (Figure 2).
From the data collected during the development of our
method (Table 1) and literature precedent, we propose the
Figure 1. Substrate scope. aIn all examples products of
5-exocyclization (6) were separated from 6-endo cyclization
mechanism of the reaction proceeds through two sequential
and independent catalyzed transformations (Scheme 3).
A gold(I) complex activates alkyne 5 through π acid/base
interactions lowering the energy of the alkyne LUMO,15
which allows the sulfonamide to attack selectively in a
5-exo fashion, presumably due to the gold alkyne bond
being skewed toward the terminal end of the alkyne due
regioisomers (7) by FCC (9:1 crude ratio). Compound 7a was
fully characterized in order to confirm the structure of the minor
regioisomer. b Reaction time 60 h.
to sterics.16 Protodeauration forms enesulfonamide 11. At
this juncture intermediate 11 can take two potential path-
ways: (i) gold catalyzed nonenantioselective N-sulfonylimi-
nium cyclization via 1217,18 or (ii) the enantioselective BPA
catalyzed N-sulfonyliminium cyclization via 13. Evidence
(15) Schmidbaur, H.; Schier, A. Organometallics 2010, 29, 2.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. Evidence for N-Sulfonyliminium Intermediate
Figure 2. Application to δ-lactam synthesis via a 6-exo-cycliza-
tion cascade.
Scheme 3. Proposed Cascade Mechanism
Figure 3. Thermal ellipsoid plot of 15a and 10b determined using
single crystal X-ray diffraction data (1 equiv of 15a and solvent (10b)
omitted for clarity). C, gray; Br, green; N, blue; O, red; S, yellow.
the remaining derivatives were assigned by analogy and
match the configuration of our previous findings.3
In conclusion we have developed a highly enantioselec-
tive N-sulfonyliminium cyclization cascade that allows
access to complex and unusual sulfonamide scaffolds in
excellent yield. We have also proven that this methodology
can be used to create different ring systems of various sizes
with most cases providing excellent yields and enantiomeric
excesses. Mechanistic understanding has allowed us to con-
trol the background gold catalyzed reaction. Investigations
into the development of more diverse cores possessing a
range of different tethered nucleophiles are underway in our
laboratory, and the results will be disclosed in due course.
that the enantioselective reaction pathway passes through an
N-sulfonyliminium intermediate (not a gold(I) phosphate
catalyzed intermediate19) came from an independent study
(Scheme 4). Ketone 14 was prepared and treated with
BPA-1A at 10 mol % in refluxing toluene. Product 6a was
obtained in quantitative yield in 92% ee. That the sense and
magnitude of the enantioselectivity in this reaction were the
same as those in the cascade (Table 1, entry 14) points to a
common intermediate 13.
The absolute stereochemistry was assigned by single
crystal X-ray diffraction of the 3-bromobenzylated com-
pound, 15a (derived from 6a) and the lactam 10b
(Figure 3). The absolute stereochemical configurations of
Acknowledgment. We gratefully acknowledge the EPSRC
(Leadership fellowship to D.J.D.; studentship to A.W.G.;
postdoctoral fellowship to P.J.) and AstraZeneca for
funding. We thank David M. Barber and Alison Hawkins
of the Department of Chemistry for X-ray structure
determination and the Oxford Chemical Crystallography
Service for the use of the instrumentation.
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Yang, T.; Campbell, L.; Dixon, D. J. J. Am. Chem. Soc. 2007, 129,
12070.
Supporting Information Available. Experimental pro-
cedures and characterization of compounds are available
1
with copies of H and 13C NMR spectra for all new
compounds, as well as HPLC and X-ray data where
applicable. This material is available free of charge via
the Internet at http://pubs.acs.org.
(19) Raducan, M.; Moreno, M.; Boura, C.; Echavarren, A. M. Chem.
Commun. 2012, 48, 52.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX