Synthesis of α-hydroxyalkyl dehydroazepanes via catalytic enantioselective borylative migration of an enol nonaflate

Article abstract of DOI:10.1016/j.tetlet.2018.10.053

A Pd-catalyzed borylative migration methodology for cyclic enol perfluorosulfonates was applied to the synthesis of the corresponding 7-membered, azepane ring system. Throughout the optimization, it was shown that the reaction is sensitive to the nitrogen protecting group as well as the type of base and solvent. The resulting cyclic allylboronate reacts stereoselectively with aldehydes for the synthesis of novel α-hydroxyalkyl dehydroazepanes in good yield and enantioselectivity over two steps. We highlight the utility of this methodology with an efficient synthesis of the de novo 7-membered ring analogue of the piperidine alkaloid β-conhydrine.

Full text of DOI:10.1016/j.tetlet.2018.10.053

Accepted Manuscript
Synthesis of α-hydroxyalkyl dehydroazepanes via catalytic enantioselective
borylative migration of an enol nonaflate
Helen A. Clement, Dennis G. Hall
PII:
S0040-4039(18)31286-3
https://doi.org/10.1016/j.tetlet.2018.10.053
TETL 50363
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Accepted Date:
17 September 2018
24 October 2018
Please cite this article as: Clement, H.A., Hall, D.G., Synthesis of α-hydroxyalkyl dehydroazepanes via catalytic
enantioselective borylative migration of an enol nonaflate, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/
j.tetlet.2018.10.053
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Synthesis of α-hydroxyalkyl dehydroazepanes via
Leave this area blank for abstract info.
catalytic enantioselective borylative migration of an
enol nonaflate
Helen A. Clement and Dennis G. Hall*
ONf
Bpin
Pd(OAc)2, L*
HBpin, NR3
R
CHO
R
N
N
N
H
t-Boc
t-Boc
OH
tBoc
51% yield (2 steps), 84% ee
Tetrahedron Letters
journal homepage: www.elsevier.com
Synthesis of α-hydroxyalkyl dehydroazepanes via catalytic enantioselective
borylative migration of an enol nonaflate
Helen A. Clementa and Dennis G. Halla,*
a Department of Chemistry, 4-010 CCIS, University of Alberta, Edmonton, Alberta T6G 2G2, Canada
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A Pd-catalyzed borylative migration methodology for cyclic enol perfluorosulfonates was
applied to the synthesis of the corresponding 7-membered, azepane ring system. Throughout the
optimization, it was shown that the reaction is sensitive to the nitrogen protecting group as well
as the type of base and solvent. The resulting cyclic allylboronate reacts stereoselectively with
aldehydes for the synthesis of novel α-hydroxyalkyl dehydroazepanes in good yield and
enantioselectivity over two steps. We highlight the utility of this methodology with an efficient
synthesis of the de novo 7-membered ring analogue of the piperidine alkaloid β-conhydrine.
Available online
Keywords:
Allyllic boronates
Allylboration
2009 Elsevier Ltd. All rights reserved.
Azepanes
Enantioselective catalysis
Chiral boronates
Non-aromatic nitrogen-containing heterocycles are structural constituents of a vast number of natural products and pharmaceutical
drugs.1 Therefore, the development of stereocontrolled methodologies to access new sub-classes of non-aromatic heterocycles is an
important objective in order to help probe unexplored chemical space for medicinal chemistry purposes.2 In this regard, our laboratory
has previously developed a novel Pd-catalyzed enantioselective borylative migration reaction of 6-membered cyclic enol
perfluorosulfonates, leading to optically enriched piperidinyl and pyranyl allylic boronates.3 These products have proven to be versatile
synthetic intermediates in stereospecific aldehyde allylboration and regiocontrolled allylic Suzuki-Miyaura cross-coupling chemistry
(Figure 1).4,5
Figure 1. Catalytic enantioselective borylative migration for the preparation of various piperidine and pyran derivatives.
OSO2R
Bpin
X
HBpin, NR3
Pd(OAc)2, L*
RCHO
R
X
X
OH
X = O or NBoc
SO2R = Tf or Nf
up to 80% yield, 94% ee
(> 96% de)
Ar-Br
Pd(0)L
Base
Ar
L1
L2
X
Ar
X
-selective -selective
up to 93% yield, 93% ee
(> 49:1 :
up to 98% yield, 93% ee
(> 49:1 :

Considering the efficiency of this method in accessing 6-membered N- and O-containing heterocycles, our laboratory is interested in
expanding the scope of this reaction. Specifically, improving the generality of this useful methodology towards the preparation of other
ring sizes could provide a platform to access new chiral allylboronates and heterocycles for applications in drug discovery and natural
product synthesis. 6,7
HO2C
OMe
O
HO
O
OH
OH
F3C
OAc
O
N
O
NH
OH
N
H
O
HN
SQ-33351
(-)-Balanol
(protein kinase inhibitor)
(calcium channel blocker)
H
N
OH
HO
OH
HO
OH
N
N
H
HO2C
H
Clavicipitic Acid
(natural product)
Iminoheptitols
(glycosidase inhibitors)
Figure 2. Examples of azepane and tetrahydroazepine containing natural products and drugs.
A recent analysis of FDA-approved drugs revealed that, in addition to a large number of fused systems, single-ring azepanes and
tetrahydro azepines appeared in the top-5 of the most frequent 7-membered non-aromatic ring systems.1 Although these 7-membered
ring heterocycles are quite common components of pharmaceutical drugs and natural products (Figure 2), their stereoselective synthesis
has received much less attention than their piperidine and pyrrole counterparts.8 Furthermore, the synthesis of azepane analogues of
piperidine compounds can be potentially beneficial in regard to potency and toxicity due to increased ring flexibility. For example,
Sinaÿ and co-workers found that the azepane derivative of nojirimycin (an iminoheptitol, Figure 2) was found to be a potent α-
galactosidase inhibitor.9 Therefore, accessing 7-membered ring scaffolds using the borylative migration chemistry could allow access to
novel chemical space relevant for medicinal chemistry purposes.
A large number of methods and strategies for the preparation of polysubstituted 7-membered nitrogen heterocycles are based on the
cyclization of a linear precursor via N-alkylation10 or through a C–C bond forming process, such as ring-closing metathesis (RCM)11 or
ring-expansions.12 These unimolecular approaches employ a pre-functionalized acyclic precursor, which is usually prepared through a
multistep synthetic sequence. With this strategy, the stereochemical information must be embedded in the respective precursors or
introduced at a later step. An attractive, alternative approach consists of introducing the stereochemical information directly on a simple
azepane substrate to provide enantiomerically enriched products. Moreover, catalytic enantioselective borylation of a prochiral azepane
substrate would provide a chiral secondary boronate with several avenues for further derivatization via stereoselective transformations
of the resulting C–B bond.6
Herein, we describe our efforts to optimize the catalytic enantioselective borylation to access enantiomerically enriched 7-membered
nitrogen heterocycles. The allylboration products are obtained over only three steps from commercially available starting materials.
Furthermore, the products obtained have the potential to be probed for medicinal chemistry purposes in the future.
Table 1. Optimization of the nitrogen protecting group.a
ONf
Bpin
HBpin (1.4 equiv)
DMA (1.4 equiv)
Pd(OAc)2 (5 mol%)
(R)-TANIAPHOS (6 mol%)
N
N
Et2O, rt, 16 h
PG
PG
Bpin
1
2
PPh2
N
Entry PG
Substrate Conversion (%)b
Yield 2a–e (%)b eec
Fe
N
N
1
t-Boc
1a
1b
1c
1d
70
75
65
90
100
30
11
13
12
31
80
84
80
61
57
t-Boc
t-Boc
2
Cbz
(RP)-TANIAP
3
4
aAll reactions were performed on a 0.3 mmol scale. Estimated by crude H NMR
using 1,3,5-trimethoxy-benzene as an internal standard. cDetermined by chiral
b
1
3
C(O)Me
Ts
4d
5
d
HPLC after thermal allylboration with p-tolualdehyde. Reaction time: 24 h. Nf =
SO2C4F9; DMA = N,N-dimethylaniline.
C(O)CF3 1e
One new aspect to be considered when moving from a 6- to 7-
membered ring system is the potential for regioisomeric enolization during the preparation of the alkenyl nonaflate substrate; a potential

issue caused by the lack of symmetry of the ketone precursor. Fortunately, it was found that deprotonation of the corresponding N-Boc
azepinone occurred regioselectively using standard cryogenic conditions with lithium bis(trimethylsilyl)amide as the base.13,14 The
observed regioselectivity is proposed to originate from a long range inductive effect of the allylic carbamate nitrogen. Exposure of this
novel dehydroazepane N-Boc nonaflate 1a to our previously developed borylative migration conditions led to incomplete conversion of
the starting material and formation of the desired allylboronate in only 30% 1H NMR yield, yet with a reasonable enantioselectivity of
80% ee (Table 1, entry 1). Notably, a significant amount of two main side products were observed in this reaction; alkenyl boronate 3
along with the deborylated enamide 4.
1. Given these disappointing initial results, a short investigation on the effect of the nitrogen protecting group was
performed with the preposition that it could have a profound effect on the product distribution. For both the corresponding
benzyl (Cbz) and methyl carbamate substrates, a lower yield of 2b–c was observed with similar conversion and
enantioselectivitely (Table 1, entries 2–3). Use of tosylamide (1d) also led to a decreased yield of 2d relative to 2a, along with an
ee of only 61% (entry 4). The strongly electron-withdrawing trifluoroacetamide resulted in full conversion of 1e with a cleaner
reaction; 2e was formed in a relatively high yield (31%), along with the undesired alkenyl boronate side product in 51% yield.
Unfortunately, the enantioselectivity of 2e decreased to only 57% ee (entry 5). Considering the results in Table 1, it seems that a
carbamate nitrogen is important for maintaining a high enantioselectivity, however the rationalization of this effect is unclear at
this time. In the end, the N-Boc nonaflate substrate 1a was chosen for further reaction optimization due to the relatively high
yield and enantioselectivity observed, as well as the commercial availability of the corresponding N-Boc piperidinone starting
material.
Further optimization of the reaction conditions examining solvent, concentration and temperature is summarized in Table 2. The
reaction efficiency was found to be quite specific to diethyl ether as the solvent. Other ethereal solvents that were previously shown to
be effective with the piperidine ring system, 1b such as cyclopentyl methyl ether (CPME), dioxane, and tert-butyl methyl ether (MTBE),
did not work well with substrate 1a and led to a significantly decreased yield in all cases (entries 1–3, 5).
Table 2. Optimization of reaction solvent, concentration and temperature.a
ONf
Bpin
HBpin (1.4 equiv)
DMA (1.4 equiv)
Pd(OAc)2 (5 mol%)
(RP)-TANIAPHOS (6 mol%)
N
N
Solvent
, rt, 16 h
O
O
O
O
1a
2a
Entry
Solvent
Et2O
Conc. (M)
0.17
Conversion (%)b
Yield 2a (%)b
aAll reactions were performed on a 0.3 mmol scale. bEstimated by crude 1H
NMR (C6D6) using 1,3,5-trimethoxybenzene as an internal standard. cReaction
1
2
3
4
5
6c
70
58
70
89
77
78
30
temperature 40 °C.
CPME
Dioxane
Et2O
0.17
15
Fortuitously, a decrease in the reaction concentration slightly
increased the yield and conversion (entry 4). In contrast, increasing
the reaction temperature led to a diminished yield of 16% (entry 6).
0.17
trace
41
0.017
0.017
0.017
With the optimal solvent in hand, the effect of the base was
investigated (Table 3). On the basis of previous optimization of the
piperidine ring system,3 it was expected that the amine base should
MTBE
Et2O
trace
16
have
a
significant effect on the product distribution and
enantioselectivity. Compared to the use of N,N-dimethylaniline (DMA, entry 1), standard alkylamine bases such as N,N-
diisopropylethylamine (DIPEA) and triethylamine (TEA) led to diminished yields of 10 and 17%, respectively (entries 2–3).
Introduction of steric hindrance on the aniline nitrogen (N,N-diethylaniline, DEA) or near the nitrogen center (N,N-dimethyl-o-
toluidine, DMoT) lowered the reaction conversion and was detrimental to the yield of the desired product 2a (entries 4–5). Methyl
substitution at both meta positions (3,5,N,N-tetramethylaniline, TMA) led to a slightly lowered yield of 31% and had no significant
effect on the enantioselectivity (entry 6). Fortuitously, when a methyl group was introduced at the para position (N,N-dimethyl-p-
toluidine, DMpT), the reaction went to completion and the 1H NMR yield increased to 57% without eroding the enantioselectivity of the
process (entry 7). Further attempts to introduce para electron donating substituents on the aniline ring were unsuccessful in improving
the results; para dimethylamine substitution (N,N,N′,N′-Tetramethyl-p-phenylenediamine, TMpPD) led to a comparable yield of 30%,
however the enantioselectivity was decreased to only 55% (entry 8). Surprisingly, introduction of a methoxy group at the para position
(4-dimethylaminoanisole, DMAA) was found to be highly detrimental to the reaction and the desired product 2a formed in only 7% 1H
NMR yield (entry 9). Of further note, brief examination of the ligand and temperature was attempted with the newly optimized DMpT
base, but all attempts to increase the enantioselectivity and reaction efficiency were in vain.14
Table 3. Optimization of the base.a
ONf
Bpin
HBpin (1.4 equiv)
Base
(1.4 equiv)
Pd(OAc)2 (5 mol%)
(RP)-TANIAPHOS (6 mol%)
N
N
Et2O, rt, 16 h
O
O
O
O
1a
2a

b
1
Entry
Base
Conversion (%)b
Yield 2a (%)b
eec
79
--
aAll reactions were performed on a 0.3 mmol scale. Estimated by crude H NMR
(C6D6) using 1,3,5-trimethoxybenzene as an internal standard.
1
2
3
4
5
6
7
8
9
DMA
DIPEA
TEA
89
41
10
17
trace
7
100
87
DMoT: R1, R3 = H, R2 =
N
DMpT: R1, R2 = H, R3 =
TMA: R1, R2, R3 = Me
TMpPD: R1, R2 = H, R3 =
DMAA: R1, R2 = H, R3 =
R1
R2
--
DEA
50
--
R3
DMoT
TMA
49
--
cDetermined by chiral HPLC after thermal allylboration with p-tolualdehyde.
95
31
57
30
7
81
81
55
--
With the reaction conditions optimized to an acceptable yield and
enantioselectivity, the utility of novel allylboronate 2a was displayed
in the synthesis of a small set of α-hydroxyalkyl dehydroazepanes via
subsequent thermal allylboration of typical aldehydes (Table 3).15
Representative aromatic (5), hetero-aromatic (6) and linear (7–8)
aldehydes were applicable in this chemistry, leading to consistently
DMpT
TMpPD
DMAA
100
100
49
moderate yields of 44–51% and good enantioselectivities (81–83%). Increasing the reaction scale slightly from a 0.3 to 0.5 mmol scale
led to similar results of 5. The absolute stereochemistry of compound 5 was confirmed by X-ray crystal diffraction of the corresponding
hydrochloride salt (5•HCl) after N-Boc deprotection. To our surprise, it was found that the linear allylboration products 7 and 8 from
aliphatic aldehydes were obtained as a mixture of diastereomers (d.r. ≈ 5.5 : 1). Separation of the diastereomers of 7 was successfully
achieved by semi-preparative HPLC purification. The relative stereochemistry of each diastereomer was confirmed by 1D and 2D
ROESY NMR experimentation of the corresponding carbamate derivatives 9 and 10 (Table 4).14
Table 4. Scope of the borylative migration, aldehyde allylboration sequence.a
ONf
HBpin (1.2 equiv)
DMpT (1.2 equiv)
Pd(OAc)2 (5 mol%)
R
CHO (1.1 equiv)
R
2a
N
(RP)-TANIAPHOS (6 mol%)
N
Toluene, 80 °C
16 h
H
O
Et2O, rt, 16 h
OH
O
O
O
1a
5 8

N
O
N
H
O
H
O
OH
OH
O
O
5
6
44% yield (38%)b
81% ee (81%)b
5 HCl

48% yield
83% ee
N
N
N
H
H
O
H
H
H
OH
O
OH
O
O
O
O
9
10

7
8
ROESY
51% yield
84% ee
 5.5 : 1 d.r.
44% yieldd
81% ee
 5.5 : 1 d.r.
aReaction sequence performed on a 0.3 mmol scale. Isolated yields reported over two steps. bResults from the reaction performed on a 0.5 mmol scale in
parentheses. cAllylboration conditions: C2H5CHO (5 equiv), toluene (1 M), 2 d.
Usually, the stereoselectivity of allylboration reactions are very high due to a tight B–O coordination of the aldehyde carbonyl to the
boron resulting in a compact six-membered chair-like transition state (Scheme 1, left).16 Although further investigation would be
required to rationalize the relatively low diastereoselectivity observed with linear aldehydes in this case, the small substrate scope in
Table 4 suggests that the stereoselectivity of the aldehyde allylboration is less efficient than that previously observed with the
corresponding piperidine analogue.3,4 It is proposed that the unexpectedly low diastereoselectivity is most likely due to a competing
minor chair-like transition state with the aldehyde substituent placed in a pseudo-axial orientation to avoid steric interaction with the N-
Boc group (Scheme 1, middle). Such a transition state would be more accessible with aliphatic aldehydes due to the smaller substituent
size compared to aromatic ones. However the corresponding twist boat-like transition states cannot be ruled out at this point (Scheme 1,
right). Only one example of a 7-membered ring allylboration reaction was found in the literature.16,17 Furthermore, a few examples do
exist involving relatively low diastereoselecivities (9:1 d.r.) with cyclic substrates.18

O
O
H
H
O
H
O
B
B
B
O
O
O
O
O
O
H
N
H
N
O
N
O
O
O
O
Chair-like TS
major diastereomer
Chair-like TS
minor diastereomer
Twist boat-like TS
minor diastereomer
Scheme 1. The potentially competing transition states during the aldehyde allylboration step with aliphatic aldehydes.
As a further demonstration of the developed methodology, a short synthesis of the 7-membered ring homolog of β-conhydrine was
performed (Scheme 2). The piperidine-based 1,2-amino alcohol is a natural product obtained from hemlock and although it is of interest
for displaying broad biological activity, its well-documented toxicity is a limiting factor. Surprisingly, even though the stereoselective
synthesis of β-conhydrine has been completed numerous times with multiple different strategies,19 the stereoselective synthesis of the 7-
membered azepane homolog appears to be lacking. Presumably, the additional conformational flexibility of the larger 7-membered ring
could lead to changes, and potentially improvements, in the therapeutic window of these compounds. The stereoselective synthesis of
analogue 11 was obtained in high overall yield via standard hydrogenation using Crabtree’s catalyst and N-Boc deprotection with
excess hydrochloric acid.4 The accomplishment of the synthesis of a diastereomeric mixture of ring-expanded β-conhydrine 11 in only 5
steps from commercially available starting materials emphasizes how little these chiral α-hydroxyalkyl azepane scaffolds have been
explored in the literature to-date, and suggests a potential for this borylative migration reaction to be utilized in alkaloid synthesis and
drug discovery.
In conclusion, the Pd-catalyzed enantioselective borylative migration methodology has been successfully optimized to the
corresponding 7-membered ring scaffold in order to provide α-hydroxyalkyl dehydroazepanes in a low step count with good
enantioselectivities and yields over two steps. The nitrogen protecting group proved to be a contributing factor to the product
distribution, with carbamates being essential to avoid erosion of enantioselectivity. The optimization of this reaction allowed the
preparation of novel α-hydroxyalkyl dehydroazepanes, with the azepane derivative of β-conhydrine highlighting the new chemical
space that can be accessed with the developed methodology. Further study into the mechanistic intricacies of the catalytic
enantioselective borylative migration reaction is currently underway in our group and will be reported in due course.
1) Crabtree's cat.
(5 mol%)
H
2 (1 atm)
DCM rt, 48 h
8
N
H
HCl
N
2) HCl (10 equiv)
MeOH, rt, 1 h
H
H
H
OH
OH
-conhydrine
11
81% yield (2 steps)
[]D20 : 1.56 (c, 0.100 MeOH)
Scheme 2. Synthesis of compound 11; the azepane derivative of β-conhydrine.
Acknowledgments
This research was generously funded by the Natural Science and Engineering Research Council of Canada (Discovery Grant to
D.G.H., Canada Graduate Scholarship-Master’s to H.C.) and the University of Alberta. We would also like to thank Ed Fu for his
support with the HPLC work, Tasmin Adel for her assistance with the preparation of alkenyl nonaflates (NSERC – Undergraduate
Student Research Awards recipient), Dr. Michael J. Ferguson for X-ray crystallographic analysis and Mark Miskolzie for his help with
the ROESY NMR studies.
A. Supplementary Material
Supplementary material that may be helpful in the review process should be prepared and provided as a separate electronic file. That
file can then be transformed into PDF format and submitted along with the manuscript and graphic files to the appropriate editorial
office.
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2.
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Highlights
• Seven-membered enol nonaflate undergoes Pd-catalyzed borylative migration
• Dehydroazepane allylic boronate product is obtained in high enantioselectivity
• Aldehyde allylboration occurs with high diastereoselectivity to provide alpha-hydroxyalkyl dehydroazepanes
• Homolog of coniine, a piperidine alkaloid, was synthesized in high diastereoselectivity