Enantioselective Aza-Heck Cyclizations of N-(Tosyloxy)carbamates: Synthesis of Pyrrolidines and Piperidines

Article abstract of DOI:10.1021/jacs.8b12689

Pd(0)-systems modified with SPINOL-derived phosphoramidate ligands promote highly enantioselective aza-Heck cyclizations of alkenyl N-(tosyloxy)carbamates. The method provides versatile access to challenging N-heterocycles and represents the broadest scope enantioselective aza-Heck protocol developed to date.

Full text of DOI:10.1021/jacs.8b12689

Communication
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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Enantioselective Aza-Heck Cyclizations of N‑(Tosyloxy)carbamates:
Synthesis of Pyrrolidines and Piperidines
Xiaofeng Ma,† Ian R. Hazelden,† Thomas Langer,‡ Rachel H. Munday,‡ and John F. Bower*,†
†School of Chemistry, University of Bristol, Bristol, BS8 1TS, United Kingdom
‡Pharmaceutical Technology & Development, AstraZeneca, Charter Way, Macclesfield, SK10 2NA, United Kingdom
S
* Supporting Information
Scheme 1. Introduction
ABSTRACT: Pd(0)-systems modified with SPINOL-
derived phosphoramidate ligands promote highly enantio-
selective aza-Heck cyclizations of alkenyl N-(tosyloxy)-
carbamates. The method provides versatile access to
challenging N-heterocycles and represents the broadest
scope enantioselective aza-Heck protocol developed to
date.
here is a pressing demand for methods that provide
T
modular and stereocontrolled access to chiral N-
heterocyclic systems.1 To address this, we described recently
two-step protocols for the synthesis of pyrrolidines and
piperidines (4) that exploit bifunctional amino reagents 2′
(Scheme 1A).2,3 Here, Mitsunobu alkylation of 2′ with alkenyl
alcohols 1 precedes Pd(0)-catalyzed aza-Heck cyclization to
the target 4 (Scheme 1A). In this latter step, N−O oxidative
addition4 is followed by aza-palladation of the alkene,5
a
process that requires access to cationic intermediate Int-I.2
“Class 1” aza-Heck cyclizations were pioneered by Narasaka
and use pentafluorobenzoyl oxime esters as the N−O donor
(Scheme 1B).6−8 The “Class 2” processes shown in Scheme
1A,2 in combination with Watson’s “Class 3” methods,9 expand
the range of N−O donors available for aza-Heck chemistry.
Importantly, these newer processes offer significantly broader
scope than complementary aza-Wacker cyclizations of NH-
nucleophiles, while at the same time circumventing the use of
an external oxidant; a method comparison for carbamate-based
processes is shown in Scheme 1C.6,10a,b,e,g,h,j
In principle, the aza-Heck approach is much better suited to
enantioselective cyclizations than aza-Wacker processes.10,11
This is because (a) oxidatively sensitive and highly tunable
chiral P-ligands can be used and (b) alkene aza-palladation
occurs exclusively via a syn-addition pathway (Scheme
1C).2,6−9 However, these benefits are offset by the prescriptive
ligand requirements of the aza-Heck processes developed so
far. Indeed, only recently have efficient chiral ligands been
developed for certain subsets of Class 1 processes,8 and
enantioselective Class 2 and 3 cyclizations have not been
achieved. Herein, we address this issue by outlining highly
efficient enantioselective 5- and 6-exo Class 2 cyclizations. The
new method provides a range of challenging ring systems,
including α-tetrasubstituted variants, with high levels of
enantiocontrol. Two key advances underpin the work
described here: (1) the first examples of the use of N-
(tosyloxy)carbamates as N−O donors in aza-Heck cyclizations
and (2) the identification of SPINOL-derived phosphorami-
dates as effective ligand systems.12 The resulting processes
offer the most general enantioselective aza-Heck protocol
developed to date6,8 and, as such, provide an important
contribution to this emerging and topical field.
Our studies commenced by evaluating a range of chiral
ligands for the enantioselective cyclization of OFBz system 3a′.
As outlined in Table 1 chelating P,N- and P,P-systems L1 and
L2 were not effective and afforded only traces of target 4a
(entries 1−2). Conversely, the use of monodentate phosphor-
Received: November 27, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.8b12689
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Journal of the American Chemical Society
Communication
Table 1. Optimization of a 5-exo Aza-Heck Cyclization
Table 2. Enantioselective 5-exo Aza-Heck Cyclizations
a
b
c
Isolated yield. Determined by chiral SFC analysis. A concentration
of 0.07 M was used; n.d. = not determined.
amidate systems was more promising, such that L3−L7
promoted chemically efficient cyclizations (entries 3−7). Of
these, L7 was most effective and provided 4a in 74% yield and
80.5:19.5 e.r. (entry 7). At this stage, the influence of the
leaving group (LG) was explored leading to the observation
that OTs analogue 3a cyclizes with higher levels of
enantioselectivity to form 4a in 96.5:3.5 e.r. (entry 8). Further
optimization was achieved by variation of reaction temper-
ature, concentration, and Et3N loading. Ultimately, this led to
the conditions outlined in entry 10 which deliver 4a in 95%
yield and 97.5:2.5 e.r. The efficient use of OTs activated
system 3a is significant because the tosylate unit is cheaper, less
mass intensive, and easier to install than the pentafluor-
obenzoate leaving group used in previous work.2,6−8
The scope of the process for the construction of pyrrolidines
is outlined in Table 2. Both N-Boc and N-Cbz protected
systems can be used, with the latter offering marginally lower
enantioselectivities; for example, cyclization of 3b provided 4b
in 95:5 e.r. vs 97.5:2.5 e.r. for 3a to 4a. Note that 3a and 3b
were readily prepared by Mitsunobu alkylation of BocNHOTs
(2a) and CbzNHOTs (2b), respectively (see the Supporting
Information (SI)). Using N-Boc protected systems 3c−l, we
have found that high levels of enantioinduction are maintained
for cyclizations involving a range of sterically diverse
trisubstituted alkenes.13 Even system 3e, which has a bulky
isopropyl substituent at R1, cyclized efficiently to provide 4e in
97.5:2.5 e.r. The generality of the method for the construction
of pyrrolidines bearing tetrasubstituted α-stereocenters is
a
Run at 0.2 M.
significant; prior methodologies for accessing ring systems of
this type do not offer the same level of scope and versatility.14
The protocol also extends to 1,2-disubstituted alkenes, such
that cyclization of N-Boc protected substrates 3m−p generated
4m−p in good to excellent yield and high enantioselectivity.
Conversely, cyclization of N-Cbz system 3q provided 4q in
only 91:9 e.r. To improve the enantioselectivity of this process
we evaluated replacement of the tosylate leaving group of 3q
with other variants. These studies revealed that more electron-
poor aryl sulfonates improve reaction efficiency, such that p-
nitro system 3qd generated 4q in 93% yield and 94:6 e.r.15
Accordingly, where required, fine-tuning of enantioselectivity
can be achieved by variation of the leaving group (vide infra).
Absolute stereochemical assignments of the products in Table
2 were made by comparison of specific rotation values of 4p
and 4q to literature data and by single crystal X-ray diffraction
analysis of the p-bromophenylsulfonamide derivative of 4a (see
the SI).
B
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Communication
Extension of the enantioselective aza-Heck protocol to the
provision of piperidines via 6-exo cyclization proved to be
challenging. Exposure of 3r to the conditions outlined in Table
1, entry 10 provided 4r in 94.5:5.5 e.r., but in only 55% yield.
Extensive efforts to improve reaction efficiency by variation of
solvent, concentration, or base were not fruitful (see the SI).
Ultimately, we found that this more demanding cyclization
could be achieved efficiently by replacement of L7 with the less
sterically demanding ligand (S)-SIPHOS-IP (L8; see Table 1).
Under these conditions, cyclization of 3r provided 4r in 81%
yield and 95.5:4.5 e.r. (Table 3). N-Boc system 3s also
prepared 3z in 81% yield by Mitsunobu alkylation of
bifunctional amino-reagent 2a with (E)-hept-5-en-1-ol 1z
(Scheme 2). Note that the N−O bond of 2a facilitates the
Scheme 2. Caulophyllumine B via a Tandem Aza-Heck/
Heck Strategy
Table 3. Enantioselective 6-exo Aza-Heck Cyclizations
Mitsunobu reaction.17 Enantioselective cyclization of 3z under
optimized aza-Heck conditions provided piperidine 4z. This
product was not isolated, and instead the Pd(0)-catalyst was
harnessed for a subsequent Heck reaction, wherein addition of
aryl iodide 5 effected C−H arylation to provide 6 in 96.5:3.5
e.r. and 55% yield for the one-pot two-step process.
Conversion of 6 to the natural product caulophyllumine B
has been achieved previously in one step.18 The absolute
stereochemical assignment of 6 was made by comparison of its
specific rotation value to literature data. Similar analyses for 4u
and 4z support the stereochemical assignments in Table 3.19
We have also evaluated the protocols described here in the
diastereodivergent assembly of more heavily substituted
pyrrolidines (Scheme 3). Exposure of stereodefined 3aa
a
Et3N (500 mol %) was added, and L7 was used in place of L8.
Scheme 3. Diastereoselective Cyclizations under Catalyst
Control
participated smoothly to generate 4s in 98:2 e.r. and 84% yield.
The protocol appears to be general for cyclizations involving
trans-1,2-disubstituted alkenes such that 4t−x were all formed
with acceptable levels of efficiency.16 Interestingly, L8 is not
especially effective for 5-exo cyclizations; for example, exposure
of 3a to the (S)-SIPHOS-IP system (L8) provided 4a in only
34% yield (vs 95% yield with L7). At the current level of
development, 6-exo cyclizations involving trisubstituted alkenes
are demanding. We have to date been unable to devise
acceptable conditions for conformationally flexible systems;
however, processes of this type can be realized for the
construction of challenging tetrahydroisoquinolines such as 4y,
which was accessed in 48% yield and 96:4 e.r. using L7. Here,
the use of L8 provided low levels of efficiency.
A key feature of the processes described here is that they are
redox neutral. This contrasts with related Wacker-type
processes, where the requirement for an external oxidant
limits the potential for using highly tunable (but oxidatively
sensitive) P-ligands to induce asymmetry.10,11 Further, as
noted in our earlier studies, nonenantioselective processes of
this type do not offer high levels of scope for carbamate-based
processes, especially with respect to ring size and alkene
substitution.2b,10e,g,h,j A further benefit of operating in a redox
neutral manifold is that the catalytic cycle is closed by release
of a Pd(0)-catalyst and this offers opportunities for the design
of powerful tandem processes. To demonstrate this, we
(>98:2 e.r.), which is substituted at C-2, to optimized aza-
Heck conditions using L7 as ligand provided 4aa in 73% yield
and 5:1 d.r. Conversely, use of the same conditions for the
cyclization of ent-3aa generated diastereomeric product 4aa′ in
6:1 d.r. Thus, the chiral Pd-catalyst can be used to enforce
diastereocontrol during the assembly of these challenging
pyrrolidine systems.20 Further investigations into the scope of
this approach are ongoing.
The mechanistic detail of the alkene aza-palladation step (cf.
Int-I to 4, Scheme 1A) that underpins the processes outlined
here merits comment. Our collective studies indicate that
alkene aza-palladation proceeds via a cationic pathway (e.g., via
Int-I) for previous Class 1 and 2 processes that use
C
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Communication
pentafluorobenzoate as the leaving group.2,7f In these processes
the equivalent of acid generated via the β-hydride elimination
step triggers protodecarboxylation of the pentafluorobenzoate
leaving group, thereby maintaining access to a cationic cycle.7f
Cationic Heck-like manifolds accommodate bidentate chiral
ligands, and this renders them ideal for enantioselective
reaction development.21 By contrast, optimal efficiencies are
achieved in the current processes with only a 1:1.2 ratio of Pd/
PR3 (see Table 1). This observation is consistent with
cyclization occurring via a neutral pathway, where the sulfonate
leaving group is ligated to the Pd-center during alkene aza-
palladation.22 In this scenario, the increased enantioselectivity
observed in the cyclizations of 3qd vs 3q can be attributed to
an electronic effect (see Table 2). This interpretation must be
treated with caution, and alternative rationalizations cannot be
discounted on the basis of available data.
In summary, we show that Pd(0)-systems modified with
SPINOL-derived phosphoramidate ligands promote highly
enantioselective 5- and 6-exo aza-Heck cyclizations of alkenyl
N-(tosyloxy)carbamates. The substrates are easily accessed by
Mitsunobu alkylation of bifunctional amino reagent
BocNHOTs (2a) or CbzNHOTs (2b), and this underpins a
direct route to enantioenriched pyrrolidines and piperidines
that are challenging or inaccessible using conventional
approaches. In particular, this new aza-Heck method is
complementary to related oxidative aza-Wacker cyclizations
(see Scheme 1C); highly enantioselective variants of the latter
are rare and, to our knowledge, have not been achieved for
carbamate-based nucleophiles.10,11 Ultimately, the aza-Heck
method described here is able to provide high enantioselec-
tivity because external oxidants are avoided, and this allows the
use of highly tunable chiral P-based ligands. These
considerations are one of several key benefits of the aza-
Heck approach,6a and the continued development of this
manifold is ongoing in our laboratory.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b12689.
Experimental details and characterization data (PDF)
Crystallographic data for a derivative of 4a (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*john.bower@bris.ac.uk
ORCID
Xiaofeng Ma: 0000-0001-8973-5377
John F. Bower: 0000-0002-7551-8221
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Royal Society for a URF (J.F.B.) and the
European Research Council for financial support via the EU’s
Horizon 2020 Programme (ERC Grant 639594 CatHet).
I.R.H. thanks AstraZeneca and EPSRC (EP/M506473/1) for a
PhD studentship. We thank the University of Bristol, School of
Chemistry X-ray crystallography service and Fiona Bell
(AstraZeneca) for analysis.
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(13) The geometry of the alkene is an important factor in
determining the enantioselectivity of the product. For example, the
(Z)-isomer of 3q provided 4q in only 76% yield and 75:25 e.r. under
the conditions shown in Table 2 (see the SI). At the present level of
development, 5-exo cyclizations involving tetrasubstituted alkenes are
not efficient; a representative example is given in the SI.
E
DOI: 10.1021/jacs.8b12689
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX