Synthesis of Epibatidine Analogues by Pyrrole Diels–Alder Reactions: Rapid Access to Azabicyclo[2.2.1]heptane and 3,8-Diazabicyclo[3.2.1]octane Scaffolds for Library Synthesis

Article abstract of DOI:10.1002/ejoc.201601177

Analogues of the nicotinic acetylcholine antagonist epibatidine, suitable for diversification, were synthesized by application of a pyrrole Diels–Alder strategy, allowing rapid generation of azabicyclo[2.2.1]heptane bicyclic cores. Further molecular complexity could be accessed by using intramolecular Diels–Alder reactions, or ring expansion by ozonolysis–reductive amination chemistry. Scaffolds were designed such that they could be orthogonally deprotected, yielding three points of diversity for library synthesis, exemplified by 24 compounds synthesized from four cores.

Full text of DOI:10.1002/ejoc.201601177

A Journal of
Accepted Article
Title: Synthesis of epibatidine analogues by pyrrole Diels-Alder reactions: rapid ac-
cess to azabicyclo[2.2.1]heptane and 3,8-diazabicyclo[3.2.1]-octane scaffolds
for library synthesis
Authors: Alexander Murray; Emma Packard; Andrew Nortcliffe; William Lewis; Da-
niel Hamza; Geraint Jones; Christopher John Moody
This manuscript has been accepted after peer review and the authors have elected
to post their Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by using the Digital
Object Identifier (DOI) given below. The VoR will be published online in Early View as
soon as possible and may be different to this Accepted Article as a result of editing.
Readers should obtain the VoR from the journal website shown below when it is pu-
blished to ensure accuracy of information. The authors are responsible for the content
of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601177
Link to VoR: http://dx.doi.org/10.1002/ejoc.201601177
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201601177
COMMUNICATION
Synthesis of epibatidine analogues by pyrrole Diels-Alder reactions:
rapid access to azabicyclo[2.2.1]heptane and 3,8-diazabicyclo[3.2.1]-
octane scaffolds for library synthesis
[
a]
[a]
[a]
[a]
[b]
Alexander T. Murray, Emma Packard, Andrew Nortcliffe, William Lewis, Daniel Hamza, Geraint
[
b]
[a]
Jones, and Christopher J. Moody*
Abstract: Analogues of the nicotinic acetylcholine antagonist
approaches to analogues have been published, many of them
based on the key, less toxic isoxazolyl compound epiboxidine 2,
which has 10-fold lower analgesic activity than 1 but is at least
epibatidine, suitable for diversification, were synthesized by
application of
a pyrrole Diels-Alder strategy, allowing rapid
[
9]
generation of azabicyclo[2.2.1]heptane bicyclic cores. Further
molecular complexity could be accessed by use of intramolecular
Diels-Alder reactions, or ring expansion by ozonolysis-reductive
amination. Scaffolds were designed such that they could be
orthogonally deprotected, yielding three points of diversity for library
generation, exemplified by the synthesis of 24 compounds from four
cores.
20 times less toxic (Figure 1). Ring expansion of the six-
membered carbocyclic ring has also been shown to be an
effective strategy for synthesis of epibatidine-related analgesic
lead compounds, with 8-azabicyclo[3.2.1]octane isoxazole 3
[
10]
being still lower in toxicity than 2.
Me
Me
H
H
H
Cl
N
N
N
N
N
N
O
O
Introduction
1
2
3
The bicyclic alkaloid epibatidine 1 was discovered in 1974 from
Figure 1. Structures of epibatidine (1), epiboxidine (2) and homoepiboxidine
(3)
[
1]
skin extracts of the frog Phyllobates anthonyi. However, the
structure and presence of the unusual 2-chloropyridyl motif was
only unambiguously confirmed by 1H NMR and mass
[
2]
spectrometry in 1991, and by several total syntheses one year
Among the total syntheses of epibatidine, one method of
constructing the key azabicyclo[2.2.1]heptane core that was
demonstrated in both Shen and Regan’s routes to the natural
product involved a Diels-Alder reaction of a pyrrole and an
[
3]
later. Several further synthetic approaches to epibatidine have
[
4]
since been published. Epibatidine is considered an im-portant
lead compound in the development of novel classes of
analgesics via a non-narcotic mechanism of action, with its
antagonist effect at nicotinic acetylcholine receptors (nAChRs)
[
3d]
alkyne. N-Protected (activated) pyrroles can undergo a Diels-
Alder reaction with a sufficiently electron deficient dienophile to
form an azabicyclo[2.2.1]heptane scaffold. As well as the
aforementioned epibatidine syntheses, this approach has been
applied to the synthesis of the influenza antiviral drug,
[
5]
thought to be key to this action. However, its non-specific
activity as an agonist of both nicotinic and muscarinic
acetylcholine receptors means that epibatidine possesses
dangerous neurotoxic properties and thus possesses too low a
[11]
ostelamivir (Tamiflu®). We thus considered the application of
similar methodology, starting with commercially available N-Boc
protected pyrroles in order to access a diverse library of
epibatidine-like small nitrogenous saturated heterocycles as part
of our work under the European Lead Factory.
[
6]
therapeutic index for safe administration as an analgesic.
Additionally, very low quantities of this molecule are isolable
from its natural source, with purification of the active alkaloid
[
7]
also proving problematic.
One promising feature of the proposed structure-activity
relationship of epibatidine in terms of scope for analogue
synthesis is that the pendant 2-chloropyridyl motif appears not to Results and Discussion
be necessary for analgesic activity. Additionally, both
[8]
enantiomers have similar nAChR agonist activity. Several
Building on our previous work on Diels-Alder reactions as key
[12]
transformations in natural product synthesis, as well as rapid
3
[13]
generation of sp -rich cores for library synthesis, we chose to
investigate the three scaffolds depicted in Figure 2 that could be
synthesized via pyrrole Diels-Alder reactions as key C-C bond
forming steps.
[
[
a]
b]
School of Chemistry
University of Nottingham
University Park, Nottingham, NG7 2RD, U.K.
c.j.moody@nottingham.ac.uk
http://www.nottingham.ac.uk/~pczcm3/
Sygnature Discovery
BioCity, Pennyfoot Street, Nottingham, NG1 1GF, U.K.
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601177
COMMUNICATION
[
14]
to give the key bicyclic system 5. Selective hydrolysis of one
of the esters gave carboxylic acid 6, which was condensed with
dimethylamine under HATU coupling conditions. Hydrogenation
gave the saturated endo-compound 8, the structure of which
was confirmed by X-ray crystallography (Figure 3), and the
amine could be deprotected and subjected to reductive
amination conditions to give 9.
Figure 2. General scaffold structures A, B and C, showing key bonds to form
via Diels-Alder cycloadditions.
The scaffold could be further diversified by initial alkaline
hydrolysis of the remaining ester to form carboxylic acid 10, with
concomitant epimerization. Further diversification was possible
by acid-mediated Boc-deprotection to give amine salts 11, or by
amide formation to give 12. Deprotection of the N-Boc
compound 12 gave the trifluoroacetate salt 13, the structure of
which was established by X-ray crystallography (Figure 3)
thereby confirming the earlier epimerization step. Finally
reductive amination yielded compound 14 as example of a
Boc
N
Boc
N
MeO C
CO Me
2
2
CO Me
2
9
0 ˚C, 18 h, 84%
COR
4
5
6
7
R = OMe
R = OH
THF, aq NaOH
rt, 18 h, 95%
[
15]
potential library compound (Scheme 1).
HNMe .HCl,
2
R = NMe2
HATU, DMF
DIPEA
Br
1
8 h, 76%
Pd/C, H , MeOH
2
rt,20 h, 71%
Boc
N
N
1
. HCl, dioxane, rt
CO Me
CO Me
2
2
2. 4-BrC H CHO
6
4
CONMe2
NaBH(OAc)3
DCE, rt
CONMe2
9
8
87% (2 steps)
aq NaOH, THF
rt, 24 h, 96%
Figure 3. X-Ray crystal structures of azabicyclo[2.2.1]-heptanes 8 (CCDC
511669) and 13 (CCDC 1511668). (TFA omitted for clarity)
1
Boc
H
N
•HX
HCl, dioxane
24 h
N
CO H
CO H
2
2
Secondly, we examined the utilization of an intramolecular
pyrrole Diels-Alder reaction in order to construct tricycle B. To
append the internal dienophile, N-Boc-pyrrole-2-carboxaldehyde
or TFA, CH Cl2
2
CONMe2
18 h
CONMe2
1
0
15 was firstly subjected to reductive amination with either
11a X = Cl, 97%
1
1b X = CF CO , 92%
benzylamine or isopropylamine to give amines 16a/b, followed
by coupling with monoethyl fumarate to give Diels-Alder
precursors 17a/b. In this instance, use of lithium triflimide
efficiently promoted the intramolecular cycloaddition to give 18a
3
2
4
-BrC H CH NH
6 4 2
Br
2
HATU, DIPEA
DMF, 84%
[
16]
and 18b at ambient temperature.
Saturation of the double
R
O
O
bond proceeded efficiently under hydrogenation conditions
yielding 19a/b, subsequently confirmed as the trans
diastereomers by X-ray crystallography as described below. The
ethyl esters were hydrolysed under basic conditions and the
resulting acids 20 reacted with 4-bromobenzylamine as an
example for a small amide library. The structures of acid 20a
and amide 21a were both confirmed by X-ray crystallography
(Figure 5).
N
N
N
N
H
H
Br
-BrC H CHO
Br
CONMe2
CONMe2
4
12 R = Boc
TFA
6
4
NaBH(OAc)3
CH Cl2
2
1
4
13 R = H•TFA
>95%
DCE, rt
70% (from 12)
Scheme 1. Synthesis of scaffold A and demonstration of ability to diversify in
several vectors.
Firstly, scaffold A was synthesized starting with the Diels-Alder
reaction of N-Boc pyrrole 4 with dimethyl acetylenedicarboxylate
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601177
COMMUNICATION
RNH2
NaBH(OAc)3
Boc
N
CO H
2
Boc
N
EtO C
2
O
R
Cl(CH ) Cl
N
2
2
H
HATU
DIPEA,
DMF
rt, 18 h
1
6a R = Bn >95%
1
5
i
1
6b R = Pr >95%
rt, 24 h
Boc
Boc
N
N
NR
LiNTf , Et O, rt
R
N
2
2
O
O
CO Et
2
EtO C
2
1
1
8a R = Bn 58%
17a R = Bn 60%
i
i
8b R = Pr 67%
17b R = Pr 55%
Figure 4. Library compounds 23a-n synthesized via high-throughput methods.
H , Pd
2
MeOH, rt
N-Deprotection under acidic conditions gave a pair of amines 22
that could be diversified into a small example library of 14
compounds 23a-n (Figure 4) (see Supporting Information for
details) of tertiary amines (by reductive amination), amides (by
coupling mediated by HATU) and sulfonamides (by reaction with
a sulfonyl chloride).
Boc
Boc
N
NR
O
N
NR
1
M LiOH (aq)
O
o
THF, 40 C
CO Et
CO2H
2
1
1
9a R = Bn 76%
20a R = Bn >95%
The final scaffold examined was the 3-aza analogue of
homoepiboxidine 3. This scaffold was proposed to be
synthesized via a ring expansion reaction, and particularly
interested us because it additionally bears similarities to the HIV
entry inhibitor Maraviroc®. The synthesis proceeded via an
initial Diels-Alder reaction between N-Boc-pyrrole 4 and methyl
3-bromopropiolate 24, followed by the reduction of the adduct 25
i
i
9b R = Pr 91%
20b R = Pr 70%
ArNH , HATU
2
DIPEA, DMF
[
17]
rt, 24 h
Boc
H
N
2
TFA, CH Cl2
NR
N
NR
rt
with NaBH
4
in acetonitrile to give ester 26 (Scheme 3). Although
O
O
2
3a-n
the analogous ethyl ester has been reported as a stable
then
Ar SCX column
[
11]
compound, in our hands methyl ester 26 was prone to retro-
N
H
N
H
Ar
O
O
Diels-Alder reaction upon concentration or storage. Direct
2 2
ozonolysis of a CH Cl solution of 26 was therefore necessary,
2
2a R = Bn 92%
21a R = Bn 81%
i
i
without concentration of the unstable material. After reductive
work-up with dimethyl sulfide, reductive amination of dialdehyde
with benzylamine afforded 3,8-diazabicyclo[3.2.1]octane 27. The
yield was unfortunately lower on larger scales, but 27 could
nevertheless be isolated in reasonable yield over three steps as
a separable ca. 5:1 mixture of diastereomers. The major
diastereomer was isolated and confirmed by X-ray
crystallographic analysis to be endo compound 27a (Figure 5).
2
2b R = Pr 98%
21b R = Pr 84%
Scheme 2. Synthesis of scaffold B (Ar = 4-bromophenyl).
20a
27a
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601177
COMMUNICATION
21a
the separable diastereomers of key amide intermediates 29a
and 29b upon coupling with morpholine using HATU. NOE
analysis of the two diastereomers of amide 29 gave
a
characteristic cross-peak between the N-Boc group of 29b and
the morpholine protons, which was absent for 29a. We therefore
propose that 29b is the exo isomer, and 29a endo. N-Boc
deprotection could be followed by direct sulfonamide formation
or amide coupling to give sulfonamides 30a and 30b and amides
31a and 31b in order to demonstrate library synthesis potential
from the free nitrogen, for either diastereomer.
As a variant on scaffold C that was more scalable and
involved less arduous chromatographic separation of
diastereomers, we decided to generate a homoepiboxidine-like
scaffold that was not prone to epimerization. The major (endo)
Figure 5. X-Ray crystal structures of azabicyclo[2.2.1] heptanes 20a (CCDC
511670) and 21a (CCDC 1511667) and azadiazabicyclo[3.2.1]octane 27a
1
4
diastereomer 27a was subjected to LiBH -mediated reduction,
(
CCDC 1511666).
which proceeded in quantitative yield to give primary alcohol 32.
This was used to synthesize three example compounds; a
sulfonamide, amine and amide (33-35) in reasonable yields over
two steps.
4
Boc
N
Boc
N
PhMe
NaBH4
MeCN
Br
0 o
C
8
CO Me
CO Me
2
2
Boc
N
R
o
N
5
days
5%
-15 C
LiBH4
Br
CO Me
2
1. HCl, dioxane
4
90 min
THF
2
4
25
26
27a
H
H
o
1
2
3
. O , -78 C
2.function-
alize
3
rt, 40 h BnN
BnN
. Me S, rt
OH
OH
2
>95%
32
. BnNH2,
NaBH(OAc)3,
DCE, rt
33 R = SO2C6H4Br, 50%
34 R = COC6H4Br, 65%
3
5 R = CH C H Br, 29%
Boc
Boc
2 6 4
N
N
LiOH,
Scheme 4. Reduction of 27a and library synthesis examples
THF:MeOH:H O
2
BnN
CO2Me
BnN
CO2H
0%, 1:1 dr
morpholine
(4:1:1), rt
2
8
27a endo
27b exo
0% (100 mg scale)
Conclusions
9
6
3
0% (5 g scale)
In conclusion, we have synthesized three new scaffolds suitable
for library synthesis inspired by the analgesic alkaloid
epibatidine, and based on pyrrole Diels-Alder reactions as key
steps to rapidly build three-dimensional molecular complexity
from simple, often commercially available, precursors. Library
synthesis based on cores A and B has afforded 13 discrete
scaffolds and delivered a total of 1233 compounds with an
average molecular weight of 454 and average logP of 1.44.
from 25
HATU, DIPEA
DMF, rt
~
5:1 dr endo:exo
Boc
1. HCl/dioxan, rt
. 4-BrC H SO Cl
R
N
N
2
6
4
2
O
Et N, py
O
3
CH Cl (A)
2
2
N
N
*
BnN
*
BnN
or 4-BrC H CO H,
2
2
8
9a endo
9b exo
9%, 1:1 dr,
O
6
4
2
O
HATU, DIPEA
DMF (B)
A, R = SO C H Br
B, R = COC H Br
2 6 4
6
4
Experimental Section
separable
from diastereomer 29a (endo)
A = 90% (30a)
For general experimental procedures, see the supporting Information.
B = 49% (31a)
from diastereomer 29b (exo)
A = 77% (30b)
(
1R*,4S*)-7-tert-Butyl
2,3-dimethyl
7-azabicyclo[2.2.1]hepta-2,5-
diene-2,3,7-tricarboxylate 5 N-Boc-pyrrole 4 (5.00 g, 30 mmol) and
dimethyl acetylenedicarboxylate (31.0 mL, 250 mmol) were combined
and heated at 90 C for 18 h. The mixture became dark brown. The
reaction mixture was cooled to rt and some excess alkyne was removed
under high vacuum. The dark brown oil (37 g) was purified by flash
B = 33% (31b)
Scheme 3. Synthesis of scaffold C and example library compound synthesis
a, exo-diastereomer; b, endo-diastereomer)
(
column chromatography (10–25% ether in light petroleum, R
f
0.34 in 50%
ether in light petroleum. The Diels-Alder adduct 5 was isolated as a pale
[
14]
Upon saponification of ester 27a/b with LiOH, a 1:1 mixture of
epimers of acid 28 was obtained, which allowed access to both
yellow solid (7.82 g, 25.3 mmol, 84%). MP 71–72 °C (lit., MP 71 °C).
+
+
6
HRMS m/z (ESI ) Found 332.1111 [M+Na] , C15H19NNaO requires
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601177
COMMUNICATION
-
1
3
1
32.1105. max (CHCl
714, 1522, 1477, 1424, 1334, 1239, 1017, 929, 850, 662, 627. H NMR
)  7.14 (br s, 2H), 5.46 (br s, 2H), 3.83 (s, 6H), 1.42 (s,
3
)/cm 3776, 3685, 3606, 3012, 2413, 2245, 1884,
for 24 h. The volatiles were removed under reduced pressure to give 8a
as a colorless oil (160 mg, 0.61 mmol, quantitative) that required no
1
+
+
(400 MHz; CDCl
3
H
further purification. HRMS m/z (ESI ) Found 227.1383 [M+H] ,
13
-1
9
H). C NMR (100 MHz, CDCl
) 
3 C
163.3, 153.9, 143.4, 142.5, 81.5,
C H N O
11 19 2 3
requires 227.1390. max (CHCl
2696, 2548, 2361, 1741, 1653, 1602, 1500, 1361, 1158, 1106. H NMR
400 MHz; CDCl )  9.90 (br s, 1H), 9.77 (br s, 1H), 4.47–4.34 (m, 2H),
4.07 (dd, J 11.2, 4.1, 1H), 3.66 (s, 3H), 3.60 (dd, J 11.2, 4.1, 1H), 3.07 (s,
3
)/cm 3061, 2980, 2850,
1
69.1, 52.3, 28.1.
(
3
H
(
[
1R*,4S*)-7-(tert-Butoxycarbonyl)-3-(methoxycarbonyl)-7-azabicyclo
2.2.1]hepta-2,5-diene-2-carboxylic acid 6 To a solution of 5 (7.80 g,
1
3
3 C
3H), 2.95 (s, 3H), 2.20–1.99 (m, 4H). C NMR (100 MHz, CDCl ) 
25.3 mmol) in THF (51 mL) was added NaOH (aq) (101 mL, 0.25 M, 25.3
169.3, 167.4, 61.0, 60.7, 51.8, 45.1, 42.4, 37.6, 35.9, 23.6, 22.4.
mmol), and the solution gradually became pale yellow. The reaction
mixture was stirred at rt for 18 h then acidified by 1 M HCl (50 mL) and
extracted with ethyl acetate (2 × 50 mL). The organic phase was washed
with water (70 mL), then with sat. NaHCO (aq) (70 mL). The latter was
3
extracted with ether (50 mL), separated and acidified to pH 1 with 1 M
HCl. This was extracted with ethyl acetate (80 mL). The organic layer
(1S*,2S*,3R*,4R*)-Methyl 3-(dimethylcarbamoyl) -7- azabicyclo
[2.2.1]heptane-2-carboxylate, 2,2,2-trifluoroacetate 8b Adduct 8 (298
mg, 0.9 mmol) was dissolved in dichloromethane (1.5 mL), cooled to 0 ºC
and TFA (0.8 mL) added dropwise over 30 sec. The reaction mixture
was then stirred at rt for 1.5 h. The volatiles were removed under
reduced pressure to give 8b as a colorless oil (275 mg, 0.8 mmol, 88%)
was dried over Na
2 4
SO and concentrated to give mono acid 6 as a bright
+
yellow oil (7.10 g, 24.1 mmol, 95%) which required no further purification.
that required no further purification. HRMS m/z (ESI ) Found 227.1380
+
+
+
-1
HRMS m/z (ESI ) Found 318.0943 [M+Na] , C14
H
17NNaO
)/cm 3012, 2983, 2772, 2668, 2361, 2342, 1729,
714, 1682, 1617, 1441, 1413, 1371, 1337, 1240, 1120,1024, 927, 851.
6
requires
[M+H] , C11
H N O
19 2 3
requires 227.1390. max (CHCl
3
)/cm 3011, 2955,
-
1
1
3
18.0948. max (CHCl
3
2720, 2564, 2362, 1741, 1676, 1654, 1438, 1192, 1065, 837. H NMR
1
3 H
(400 MHz; CDCl )  3.78 (dt, J 9.9, 4.6, 2 H), 3.58 (s, 3H), 3.38 (ddd, J
1
H NMR (400 MHz; CDCl
H), 5.59 (br s, 1H), 3.98 (s, 3H), 1.39 (s, 9H). C NMR (100 MHz,
CDCl )  166.4, 161.0, 160.7, 154.0, 153.9, 142.8 (2 C), 81.9, 69.7, 68.4,
4.2, 28.0. The data were in agreement with the literature.
) 
3 H
7.16 (br, s, 1H), 7.13 (br s, 1H), 5.65 (br s,
11.3, 4.8, 1.1, 1H), 2.98 (s, 3 H), 2.86 (s, 3H), 2.84 (dd, J 4.3, 1.8, 1H),
2.18 (ddd, J 12.4, 8.9, 4.3, 1H), 1.91 (br s, 1H), 1.76 (ddd, J 12.4, 8.9, 4.3,
13
1
13
3
C
1H), 1.60–1.46 (m, 1H), 1.45–1.32 (m, 1H). C NMR (100 MHz, CDCl
C
 172.2, 170.4, 59.6, 59.2, 51.1, 49.0, 46.6, 37.1, 35.5, 26.7, 24.9.
3
)
[
18]
5
(
[
2
1S*,4R*)-7-tert-Butyl 2-methyl 3-(dimethylcarbamoyl)-7-azabicyclo-
2.2.1]hepta-2,5-diene-2,7-dicarboxylate 7 To a solution of 6 (7.10 g,
4.1 mmol), in dichloromethane (130 mL) and dimethylformamide (130
(1S*,2S*,3R*,4R*)-Methyl 7-(4-bromobenzyl)-3-(dimethylcarbamoyl)-
7-azabicyclo[2.2.1]heptane-2-carboxylate 9 Amine hydrochloride 8a
(53 mg, 0.23 mmol) and 4-bromobenzaldehyde (47 mg, 0.25 mmol),
were dissolved in 1,2-dichloroethane (2 mL) and stirred for 30 min until
complete dissolution occurred. Sodium triacetoxyborohydride (146 mg,
0.69 mmol) was added and the solution stirred at rt for 16 h. Following
dilution with dichloromethane (10 mL), the solution was washed with
water (2 × 10 mL). The organics were separated and dried over Na SO
2 4
and concentrated to give a colorless oil (93 mg). Purification by flash
column chromatography (10–30% ethyl acetate in light petroleum with
mL) was added dimethylamine hydrochloride (2.40 g, 28.9 mmol),
followed by HATU (13.7 g, 36.2 mmol) then N,N-diisopropylethylamine
(
21 mL, 120.5 mmol). The solution gradually turned orange to dark green.
This was stirred at rt for 18 h then diluted with ethyl acetate (200 mL) and
extracted with sat. NH Cl (aq) (150 mL). The organic phase was washed
with sat. NaHCO (aq) (150 mL) followed by 5% aq LiCl solution (200
mL) then brine (150 mL). The organics were dried over Na SO and
concentrated to give a dark green oil (7.60 g). Purification by flash
column chromatography (30–40% ethyl acetate in hexane with 1% NH in
O, R 0.43 in 50% ethyl acetate in hexane with 0.1% NH in H O) gave
the desired compound 7 as a pale yellow oil (5.86 g, 18.2 mmol, 76%).
4
3
2
4
1% NH
NH in H
2 3
mmol, 87%). HRMS m/z (ESI ) Found 395.0971 [M+H] , C18H24 BrN O
3
2 f
in H O, R 0.13 in 50% ethyl acetate in light petroleum with 0.1%
3
3
2
O) gave the desired compound 9 as a colorless oil (79 mg, 0.20
+
+
79
H
2
f
3
2
-
1
requires 395.0965. max (CHCl
3
)/cm 3010, 1735, 1645, 1488, 1352,
+
+
1
HRMS m/z (ESI ) Found 323.1590 [M+H] ,
3
1
NMR (400 MHz; CDCl
5
NMR (100 MHz, CDCl
C
16
H
23
N O
2 5
requires
1192, 1071, 1013, 908, 870. H NMR (400 MHz; CDCl )  7.42 (d, J 8.3,
3
H
-
1
23.1601.max (CHCl
628, 1518, 1411, 1335, 1239, 1120, 1089, 1022, 928, 850, 662, 628. H
3
)/cm 3777, 3685, 3408, 3011, 2413, 2254, 1715,
2H), 7.22 (d, J 8.2 2H), 3.60 (s, 3H), 3.56 (s, 2H), 3.53 (dd, J 11.4, 4.0,
1H), 3.44 (dt, J 9.3, 4.3, 2H), 3.05 (dd, J 11.4, 4.0, 1H), 2.97 (s, 3H), 2.89
1
13
3
) 
H
7.20 (br s, 1H), 7.03 (br s, 1H), 5.53 (br s, 1H),
(s, 3H), 2.28–2.16 (m, 2H), 1.86–1.63 (m, 3H). C NMR (100 MHz,
CDCl )  172.5, 170.5, 138.4, 131.3, 130.0, 120.7, 62.5, 61.9, 51.1, 50.5,
47.3, 45.8, 37.1, 35.5, 23.5, 22.4.
13
.19 (br s, 1H), 3.73 (s, 3H), 3.04 (s, 3H), 2.97 (s, 3H), 1.41 (s, 9H).
C
3
C
) 
3 C
165.7, 162.6, 155.5, 151.5, 142.5 (2 C), 140.9,
95.6, 81.3, 70.2, 52.0, 34.1, 28.1.
(
1S*,2S*,3R*,4R*)-7-(tert-Butoxycarbonyl)-3-(dimethylcarbamoyl)-7-
(
1S*,2S*,3R*,4R*)-7-tert-Butyl 2-methyl 3-(dimethylcarbamoyl)-7-
azabicyclo[2.2.1]heptane-2-carboxylic acid 10 To a solution of 5b
(105.5 mg, 0.32 mmol) in THF (1.0 mL) was added NaOH (aq) (0.25 M,
0.32 mmol, 1.3 mL), the reaction mixture was stirred at rt for 18 h then
acidified by 1 M HCl (1 mL) and extracted with ethyl acetate (2 × 5 mL).
The organic phase was washed with water (10 mL) then with sat.
azabicyclo-[2.2.1]heptane-2,7-dicarboxylate 8 Adduct 7 (2.60 g, 8.1
mmol) was dissolved in methanol (150 mL) and palladium on activated
carbon added (862 mg, 30% w/w). The solution was stirred under an
atmosphere of hydrogen at rt for 20 h. Filtration through Celite and
removal or methanol under reduced pressure gave the desired product 8
as a colorless solid (1.87 g, 5.7 mmol, 71%) that required no further
purification. MP 105–106 °C. HRMS m/z (ESI ) Found 349.1721 [M+Na] ,
C
2
1
3
NaHCO
separated and acidified to pH 1 with 1 M HCl. This was extracted with
ethyl acetate (20 mL). The organic layer was dried over Na SO and
3
(aq) (10 mL). The latter was extracted with ether (10 mL),
+
+
2
4
-
1
16
H
26
N
2
NaO
5
requires 349.1734. max (CHCl
3
)/cm 3006, 2982, 2954,
concentrated to give a colorless oil which was triturated with ether and
hexanes, solvents were removed under reduced pressure to give acid 10
as a white foamy solid (96.8 mg, 0.31 mmol, 96%) that required no
460, 1736, 1693, 1647, 1457, 1437, 1370, 1297, 1252, 1162, 1104,
1
055, 906, 874. H NMR (400 MHz; CDCl
3 H
)  4.36 (br s, 2H), 3.66 (s,
+
H), 3.62 (br s, 1H), 3.06 (s, 1H), 2.93 (s, 3H), 2.32 (br s, 1H), 1.89–1.71
further purification. MP 113–114 °C. HRMS m/z (ESI ) Found 335.1569
13
+
-1
(m, 1H), 1.71–1.55 (m, 1H), 1.46 (s, 9H). C NMR (100 MHz; CDCl
3
) 
71.6, 169.5, 155.2, 80.3, 60.3, 59.1, 51.3, 48.0, 45.8, 37.2, 35.6, 28.2,
5.7, 24.3.
C
[M+Na] , C15
H
24
N
2
NaO
5
requires 335.1577. max (CHCl
3
)/cm 3512, 2982,
1
1
2
2360, 1695, 1642, 1457, 1369, 1256, 1165, 1055, 904, 870. H NMR
(400 MHz; CDCl
3 H
)  4.60 (br s, 1H), 4.44 (br s, 1H), 3.75–3.70 (m, 1H),
3
.41 (d, J 4.9, 1h), 3.19 (s, 3H), 2.98 (s, 3H), 1.92–1.80 (m, 1H), 1.74–
13
(
[
1S*,2S*,3R*,4R*)-Methyl 3-(dimethylcarbamoyl) -7- azabicyclo
2.2.1]heptane-2-carboxylate hydrochloride 8a Adduct 8 (205 mg,
1.50 (m, 3H), 1.43 (s, 9H). C NMR (100 MHz, CDCl
3 C
)  176.9, 169.8,
154.9, 80.5, 60.6, 57.6, 50.8, 47.9, 37.2, 36.0, 29.3, 28.0, 24.1.
0.63 mmol) was dissolved in 4 M HCl in dioxane (6 mL) and stirred at rt
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601177
COMMUNICATION
13
(
1S*,2S*,3R*,4R*)-3-(Dimethylcarbamoyl)-7-
C NMR (100 MHz, DMSO-d
) 
6 C
171.3, 169.2, 167.0, 158.3 (q, JC,F
azabicyclo[2.2.1]heptane-2-carboxylic acid hydrochloride 11a
Adduct 10 (96 mg, 0.3 mmol) was dissolved in 4 M HCl in dioxane (6 mL)
and stirred at rt for 24 h over which time a white precipitate formed. The
volatiles were removed under reduced pressure to give a turbid gummy
solid that was triturated with ether, following evaporation 11a was
obtained as a colorless solid (72 mg, 0.3 mmol, 97%) that required no
35.3), 138.5, 131.2, 129.6, 119.9, 62.0, 58.3, 47.6, 46.2, 41.9, 36.7, 35.6,
26.3, 21.6.
2
3
3
(
[
1S,2S,3R,4R)-N ,7-Bis(4-bromobenzyl)-N ,N -dimethyl-7-azabicyclo-
2.2.1]heptane-2,3-dicarboxamide 14 Amine 13 (50 mg, 0.13 mmol)
and 4-bromobenzaldehyde (27 mg, 0.15 mmol), were dissolved in 1,2-
dichloroethane (2 mL) and 3 Å molecular sieves (powdered, 50 mg) were
+
further purification. MP 160–162 °C. HRMS m/z (ESI ) Found 213.1242
+
-1
[
M+H] , C10
H N O
17 2 3
requires 213.1234. max (CHCl
3
)/cm 3776, 3685,
added.
The solution was stirred at rt for 17 h.
Sodium
3
8
4
1
1
607, 3012, 2413, 2245, 1885, 1735, 1646, 1522, 1424, 1239, 1015, 929,
triacetoxyborohydride (83 mg, 0.39 mmol) was added and the solution
stirred at rt for 16 h. Following dilution with dichloromethane (5 mL), the
solution was washed with water (2 × 5 mL). The organics were
1
50, 662, 627. H NMR (400 MHz; D
2 H
O)  4.59–4.53 (m, 2H), 3.77 (t, J
.5, 1H), 3.47 (d, J 5.4, 1H), 3.11 (s, 3H), 2.93 (s, 3H), 2.06–1.92 (m, 1H),
13
2 C
.92–1.74 (m, 2H), 1.72–1.60 (m,1H). C NMR (100 MHz, D O)  175.1,
separated, dried over Na
103 mg). Purification by flash column chromatography (0.5–1%
methanol in chloroform with 1% NH in H O, R 0.23 in 2% methanol in
chloroform with 0.1% NH in H O) gave the desired compound 14 as a
2 4
SO and concentrated to give a pale yellow oil
68.5, 61.7, 59.2, 48.0, 47.3, 37.3, 36.3, 25.7, 21.8.
(
3
2
f
(
[
1
1S*,2S*,3R*,4R*)-3-
2.2.1]heptane -2-carboxylic acid, 2,2,2-trifluoroacetate 11b Adduct
0 (150 mg, 0.5 mmol) was dissolved in dichloromethane (2 mL), cooled
(Dimethylcarbamoyl)-
7-azabicyclo
3
2
+
turbid oil (50 mg, 0.09 mmol, 70%). HRMS m/z (ESI ) Found 548.0566
+
79
-1
[
M+H] , C24
H
2 3 2 3
28 Br N O requires 548.0543. max (CHCl )/cm 3445,
to 0 ºC and TFA (418 L) added dropwise over 15 sec. The reaction
mixture was then stirred at rt for 18 h. The volatiles were removed under
reduced pressure to give 11b as a white foamy solid (143 mg, 0.4 mmol,
3
1
1
8
293, 3011, 2967, 2930, 2856, 2361, 2342, 1647, 1515, 1489, 1403,
240, 1107, 1072, 1013. H NMR (400 MHz; d -DMSO)  8.30 (t, J 5.9,
6 H
H), 7.44 (d, J 8.5, 2H), 7.40 (d, J 8.4, 2H), 7.20 (d, J 8.4, 2H), 7.10 (d, J
.5, 2H), 4.30 (dd, J 15.2, 6.0, 1H), 4.10 (dd, J 15.2, 6.0 Hz, 1H), 3.73 (t,
1
+
9
2
2
2%) that required no further purification. HRMS m/z (ESI ) Found
+
-1
13.1240 [M+H] , C10
854, 1716, 1652, 1587, 1406, 1142, 1109, 836. H NMR (400 MHz; d
13.00 (br s, 1H), 9.11 (br s, 1H), 8.79 (br s, 1H), 4.47 (t, J 4.5,
H N O requires 213.1234. max (CHCl )/cm 2927,
1
7
2
3
3
J 4.1, 1H), 3.61 (t, J 4.1, 1H), 3.56 (d, J 14.0, 1H), 3.44 (d, J 14.0, 1H),
1
6
-
3.38 (d, J 4.7, 1H), 3.06 (s, 3H), 2.95 (d, J 4.7, 1H), 2.83 (s, 3H), 1.83–
DMSO) 
H
1
.72 (m, 1H), 1.66–1.54 (m, 1H), 1.37 (ddd, J 12.7, 9.0, 4.0, 1H), 1.28
1
3
1
4
H), 4.43 (d, J 4.8, 1H), 3.64 (t, J 5.0, 1H), 3.31 (d, J 5.8, 1H), 3.07 (s,
H), 2.89 (s, 3H), 1.92–1.78 (m, 1H), 1.77–1.61 (m, 2H), 1.58–1.47 (m,
H). C NMR (100 MHz, DMSO-d )  172.5, 166.8, 60.4, 58.4, 47.7,
6 C
6.5, 36.6, 35.6, 26.2, 21.4.
13
6 C
(ddd, J 12.7, 9.0, 4.0, 1H).* C NMR (100 MHz, DMSO-d )  172.7,
170.5, 142.0, 139.3, 131.0, 130.2, 129.4, 128.5, 119.7, 119.6, 63.6, 62.1,
13
61.5, 51.0, 49.5, 47.1, 41.7, 41.5, 36.7, 35.4. *With additional minor
signals due to the presence of inseparable 4-bromobenzaldehyde.
(
1S*,2S*,3R*,4R*)-tert-Butyl
2-((4-bromobenzyl)carbamoyl)-3-
tert-Butyl 2-((benzylamino)methyl)-1H-pyrrole-1-carboxylate 16a N-
Boc-pyrrole-2-carboxaldehyde 15 (2.0 g, 10.25 mmol) and benzylamine
(dimethylcarbamoyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate 12 To
a solution of 10 (223 mg, 0.7 mmol), in dichloromethane (4 mL) and
dimethylformamide (4 mL) was added 4-bromobenzylamine
hydrochloride (191 mg, 0.9 mmol), followed by HATU (407 mg, 1.1 mmol)
then N,N-diisopropylethylamine (622 L, 3.6 mmol). The solution was
stirred at rt for 18 h then diluted with ethyl acetate (10 mL) and extracted
(
1.23 mL, 11.27 mmol) were dissolved in 1,2-dichloroethane (90 mL),
sodium triacetoxyborohydride (6.9 g, 30.75 mmol) was added and the
solution stirred at rt for 16 h. Following dilution with dichloromethane (90
mL), the solution was washed with sat. NaHCO (aq) (60 mL). The
3
organics were separated and the aqueous was re-extracted with
dichloromethane (50 mL) the layers were separated and the combined
organics dried over Na
with sat. NH
sat. NaHCO
4
Cl (aq) (10 mL). The organic phase was then washed with
(aq) (10 mL) followed by 5% aq LiCl solution (10 mL) and
3
2 4
SO and concentrated to give the desired amine
finally brine (10 mL). The organics were dried over Na
concentrated to give an orange oil (410 mg). Purification by flash column
chromatography (1% methanol in dichloromethane with 1% NH in H O,
0.50 in 10% methanol in dichloromethane with 0.1% NH in H O) gave
2 4
SO and
1
6a as a pale orange oil (4.0 g, 14 mmol, quantitative) that required no
+
+
further purification. HRMS m/z (ESI ) Found 287.1747 [M+H] ,
C H N O requires 287.1754. max (ATR)/cm 2979, 1738, 1494, 1455,
17 23 2 2
1
-
1
3
2
R
f
3
2
1
409, 1370, 1336, 1256, 1168, 1133, 1061, 881, 848, 732. H NMR (400
MHz; CDCl )  7.38–7.30 (m, 4H), 7.26–7.23 (1m, 1H), 7.22 (dd, J 3.3,
.8, 1H), 6.15 (d, J 7.2, 1H), 6.12 (m, 1H), 3.97 (d, J 0.4, 1H), 3.80 (s,
the desired compound 12 as a colorless foamy solid (287 mg, 0.6 mmol,
3
H
+
+
79
8
4%). HRMS m/z (ESI ) Found 502.1303 [M+Na] , C22
H
3 4
30 BrN NaO
1
2
1
1
requires 502.1312. H NMR (400 MHz; CDCl
d, J 8.5, 2H), 6.27 (br s, 1H), 4.50–4.30 (m, 4H), 3.77 (br s, 1H), 3.21 (d,
J 5.0, 1H), 3.16 (s, 3H), 2.93 (s, 3H), 1.88–1.74 (m, 2H), 1.67–1.49 (m,
H), 1.43 (s, 9H). C NMR(100 MHz, CDCl )  172.3, 169.9, 154.8,
3 C
37.5, 131.7, 129.5, 129.4, 80.3, 51.7, 48.7 (2 C), 43.1, 38.6, 37.3, 35.9,
) 
3 H
7.44 (J 8.5, 2H), 7.15
13
H), 1.60 (s, 9H). C NMR (100 MHz, CDCl
28.3, 128.1, 126.7, 121.6, 113.4, 110.0, 83.7, 52.4, 46.3, 28.0
3 C
)  149.4, 140.5, 133.7,
(
13
2
1
2
(
E)-tert-Butyl
2-((N-benzyl-4-ethoxy-4-oxobut-2-enamido)methyl)-
1H-pyrrole-1-carboxylate 17a To a solution of 16a (4.0 g, 14.00 mmol),
9.6, 28.2, 24.0.
in dichloromethane (70 mL) and dimethylformamide (70 mL) was added
mono-ethyl fumarate (1.9 g, 12.17 mmol), followed by HATU (6.9 g,
2
3
3
(
[
(
1S*,2S*,3R*,4R*)-N -(4-Bromobenzyl)-N ,N -dimethyl-7-azabicyclo-
2.2.1]heptane-2,3-dicarboxamide 2,2,2-trifluoroacetate 13 Adduct 12
287 mg, 0.6 mmol) was dissolved in dichloromethane (2 mL), cooled to
18.26 mmol) and the mixture was cooled to
0
ºC. N,N-
Diisopropylethylamine (8.5 mL, 48.68 mmol) was then added and the
reaction was stirred at rt for 18 h. Following dilution with ethyl acetate
0
ºC and TFA (523 L) added dropwise over 20 sec. The reaction
(
100 mL) the reaction mixture was extracted with sat. NH
the organic phase was then washed with sat. NaHCO
followed by 5% aq LiCl solution (100 mL) and finally brine (80 mL). The
organics were dried over Na SO and concentrated to give a deep red oil
5.9 g). Purification by flash column chromatography (50–70% ether in
4
Cl (aq) (80 mL),
mixture was then stirred at rt for 20 h. The volatiles were removed under
reduced pressure to give 13 as an off-white solid (342 mg, 0.7 mmol,
quantitative), which required no further purification. MP 150–152 °C.
3
(aq) (80 mL)
2
4
+
+
79
HRMS m/z (ESI ) Found 380.0974 [M+H] , C17
H
3 2
23 BrN O requires
(
-
1
3
1
80.0968. max (CHCl
648, 1524, 1490, 1407, 1173, 1073, 1013, 835. H NMR (400 MHz; d
9.41 (br s, 1H), 8.84 (t, J 5.8, 1H), 8.29 (br s, 1H), 7.51 (d, J
3
)/cm 3440, 3012, 2931, 2717, 2542, 1778, 1673,
3 2
light petroleum with 1% NH in H O) gave the desired amide 17a as a
pale yellow oil (3.0 g, 7.15 mmol, 59%). HRMS m/z (ESI ) Found
1
6
-
+
+
-1
DMSO) 
H
413.2077 [M+H] , C23
H N O
29 2 5
requires 413.2071. max (ATR)/cm 2981,
8.3, 2H), 7.22 (J 8.3, 2H), 4.45 (t, J 4.6, 1H), 4.31 (d, J 4.6, 1H), 4.25 (t, J
5.3, 2H), 3.68 (td, J 4.1, 1.1, 1H), 3.27 (d, J 5.0, 1H), 3.06 (3 H, s, 3H),
2.88 (s, 3H), 1.93–1.80 (m, 1H), 1.80–1.68 (m, 1H), 1.68–1.49 (m, 2H).
1
1741, 1660, 1440, 1335, 1164, 1120, 1029, 973, 847, 755. H NMR (400
MHz; DMSO-d
6 H
)  7.47–7.14 (m, 7H), 6.69 (d, J 15.3, 2H), 6.16 (dt, J
6.5, 3.3, 1H), 5.97 (dd, J 3.1, 1.6, 1H), 4.80 (s, 1H), 4.75 (d, J 3.3, 2H),
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601177
COMMUNICATION
4
.62 (s, 1H), 4.16 (q, J 7.0, 2H), 1.49 (s, 9H), 1.21 (J 7.1, 3H), additional
mL) and dimethylformamide (35 mL) was added 4-bromobenzylamine
hydrochloride (852.0 mg, 3.75 mmol), followed by HATU (1.8 g, 4.70
mmol) and the mixture was cooled to 0 ºC. N,N-Diisopropylethylamine
(2.7 mL, 15.65 mmol) was then added and the mixture was stirred at rt
for 24 h. Following dilution with ethyl acetate (50 mL) the reaction mixture
13
minor signals due to the presence of rotamers. C NMR (100 MHz;
DMSO-d , 70 ºC)  164.6, 164.5, 154.9, 148.4, 137.0, 134.3, 129.9,
28.1, 127.1, 126.8, 121.7, 111.9, 110.1, 83.9, 60.3, 50.4, 45.4, 27.2,
3.6, additional minor signals due to the presence of rotamers.
6
C
1
1
was extracted with sat. NH
washed with sat. NaHCO
(60 mL) and finally brine (40 mL). The organics were dried over Na
and concentrated to give a foamy pale brown solid (1.9 g). Purification
by flash column chromatography (30–50% ethyl acetate in light
4
Cl (aq) (30 mL), the organic phase was then
(aq) (30 mL) followed by 5% aq LiCl solution
SO
(
3aR*,6S*,7S*,7aS*)-8-tert-Butyl 7-ethyl 2-benzyl-1-oxo-1,2,3,6,7,7a-
hexahydro-3a,6-epiminoisoindole-7,8-dicarboxylate 18a To amide
7a (2.9 g, 7.15 mmol) in dry ether (50 mL) was added lithium triflamide
50 g, 174.16 mmol; dried at 150 ºC under high vacuum immediately prior
3
2
4
1
(
to use) and the mixture stirred at rt for 6 days. The reaction mixture was
diluted with water (150 mL) and chloroform (100 mL). The phases were
separated and the organic layer was washed with water (2 x 70 mL), the
combined organics were washed with brine (150 mL) and dried over
3 2
petroleum with 1% NH in H O) gave the desired amide 21a as a
+
colorless oil (1.4 g, 2.54 mmol, 81%). HRMS m/z (ESI ) Found 576.1457
+
79
-1
[M+Na] , C28
H
32 BrN
3
NaO
4
requires 576.1468. max (ATR)/cm 3305,
3011, 2877, 2456, 1686, 1548, 1487, 1431, 1338, 1246, 1164, 1124,
1
Na
chromatography (40–80% ethyl acetate in light petroleum with 1% NH
O) gave the Diels-Alder adduct 18a as a colouless foamy oil (1.7 g,
2
SO
4
to give a pale yellow oil (3.3 g). Purification by flash column
1072, 1048, 1030, 1011, 925, 856, 754, 703, 667, 635. H NMR (400
3
in
3 H
MHz; CDCl )  7.44 (d, J 8.4, 2H), 7.36–7.28 (m, 3H), 7.21 (m, 2H), 7.16
(d, J 8.5, 2H), 7.06 (t, J 5.6, 1H), 4.55–4.36 (m, 4H), 4.28 (dd, J 14.9, 5.6,
H
2
+
+
4.17 mmol, 58%). HRMS m/z (ESI ) Found 413.2096 [M+H] ,
1H), 3.45 (d, J 11.8, 1H), 3.17–3.09 (m, 1H), 2.86 (d, J 6.0, 1H), 2.08–
-
1
13
C
23
H
29
N
2
O
5
requires 413.2093.max (ATR)/cm 2979, 1720, 1630, 1425,
2.00 (m, 1H), 1.89–1.81 (m, 2H), 1.74–1.66 (m, 1H), 1.36 (s, 9H).
C
1
1
369, 1331, 1159, 1117, 1062, 1028, 971, 843, 724, 698. H NMR (400
MHz; CDCl )  7.40–7.18 (m, 5H), 6.51 (d, J 4.8, 1H), 6.28 (d, J 4.8, 1H),
.05 (d, J 1.9, 1H), 4.78–4.66 (m, 1H), 4.55 (br s, 2H), 4.14 (q, J 7.1, 2H),
NMR (100 MHz, CDCl )  173.9, 170.3, 156.0, 137.4, 135.9, 131.7,
3
C
3
H
129.4, 128.7, 127.9, 127.6, 121.2, 80.7, 69.7, 61.3, 54.6, 49.0, 48.0, 46.6,
42.9, 29.5, 28.1, 24.9.
5
3
1
.77 (d, J 11.5, 1H), 3.47 (t, J 4.0, 1H), 2.87 (d, J 4.0, 1H), 1.31 (br s, 9H),
.26 (t, J 7.1, 3H), additional minor signals due to the presence of the
(3aR*,6S*,7S*,7aS*)-2-Benzyl-N-(4-bromobenzyl)-1-oxooctahydro-
3a,6-epiminoisoindole-7-carboxamide 22a Adduct 21a (688 mg, 0.91
mmol) was dissolved in dichloromethane (6 mL), cooled to 0 ºC and TFA
(1.1 mL) added dropwise over 30 sec. The reaction mixture was then
stirred at rt for 15 h. The volatiles were removed under reduced pressure
to give 22a.TFA as a pale pink foam (727 mg). Purification by ion-
13
retro Diels-Alder product (17a). C NMR (100 MHz, CDCl
3
) 
70.7, 155.8, 136.3, 133.7, 132.0, 128.6, 127.9, 127.5, 81.2, 74.2, 65.3,
1.1, 53.6, 47.4, 46.6, 43.4, 28.0, 14.1, additional minor signals due to
C
172.0,
1
6
the presence of the retro Diels-Alder product (17a).
(
3
3aR*,6S*,7S*,7aS*)-8-tert-Butyl 7-ethyl 2-benzyl-1-oxooctahydro-
a,6-epiminoisoindole-7,8-dicarboxylate 19a Adduct 18a (1.7 g, 4.17
3
exchange chromatography (SCX*, 5% NH in MeOH) gave free amine
22a as a colorless solid (516 mg, 1.14 mmol, 92%). MP 221–223 °C.
+
+
81
mmol) was dissolved in methanol (85 mL) and palladium on activated
carbon added (44 mg, 0.42 mmol, 10 mol%). The solution was stirred
under an atmosphere of hydrogen at rt for 1.5 h. Filtration through Celite
and removal of methanol under reduced pressure gave a colorless oily
solid (1.5 g) that was purified by flash column chromatography (30–40%
ethyl acetate in light petroleum with 1% NH
product 19a as a colorless oil (1.3 g, 3.15 mmol, 76%). HRMS m/z (ESI )
Found 415.2232 [M+H] , C23
HRMS m/z (ESI ) Found 456.1118 [M+H] , C23
H
3 2
25 BrN O requires
-
1
456.1119. max (ATR)/cm 3274, 2939, 2361, 1672, 1643, 1548, 1487,
1439, 1331, 1238, 1080, 1009, 832, 723, 692, 648. H NMR (400 MHz;
1
3 H
CDCl )  7.44 (d, J 8.3, 2H), 7.38–7.28 (m,3H), 7.22 (m, 2H), 7.17 (d, J
8.2, 2H), 7.00 (br s, 1H), 4.56 (d, J 14.8, 1H), 4.48 (dd, J 14.9, 6.1, 1H),
4.35 (d, J 14.9, 1H), 4.29 (dd, J 14.9, 9.8, 1H), 3.82 (t, J 3.7, 1H), 3.51 (d,
3 2
in H O) to give the desired
+
J 11.1, 1H), 3.33 (d, J 11.0, 1H), 3.06 (t, J 4.4, 1H), 2.86 (d, J 5.4, 1H),
+
-1
13
H N O
30 2 5
requires 415.2227. max (ATR)/cm
3 C
2.02–1.92 (m, 1H), 1.74–1.59 (m, 3H). C NMR (100 MHz, CDCl ) 
2
1
7
3
1
981, 2933, 1739, 1654, 1494, 1414, 1372, 1335, 1165, 1120, 1062,
016, 958, 891, 844, 755, 699, 666. H NMR (400 MHz; CDCl )  7.30–
3 H
175.0, 170.7, 137.5, 136.0, 131.7, 129.5, 128.8, 128.0, 127.7, 121.2,
68.7, 60.1, 53.3, 52.7, 49.5, 46.9, 43.0, 30.5, 25.8.
1
.17 (m, 5H), 4.49–4.38 (m, 4H), 4.16 (q, J 7.1, 2H), 3.40 (d, J 11.5, 1H),
.26 (t, J 4.6, 1H), 3.01 (d, J 5.0, 1H), 1.88–1.72 (m, 2H), 1.71–1.61 (m,
tert-Butyl 2-((isopropylamino)methyl)-1H-pyrrole-1-carboxylate 16b
N-Boc-pyrrole-2-carboxaldehyde 15 (2.0 g, 10.25 mmol) and
isoproylamine (0.97 mL, 11.27 mmol) were dissolved in 1,2-
dichloroethane (90 mL), sodium triacetoxyborohydride (6.9 g, 30.75
mmol) was added and the solution stirred at rt for 16 h. Following dilution
with dichloromethane (90 mL), the solution was washed with sat.
13
H), 1.60–1.53 (m, 1H), 1.32 (s, 9H), 1.25 (t, J 7.1, 3H). C NMR (400
)  172.9, 170.9, 155.5, 136.1, 128.4, 127.7, 127.2, 80.5,
9.9, 61.0, 60.8, 53.7, 47.9, 47.2, 46.3, 28.4, 27.8, 25.2, 14.0.
MHz; CDCl
6
3
C
(
3aR*,6S*,7S*,7aS*)-2-Benzyl-8-(tert-butoxycarbonyl)-1-
oxooctahydro-3a,6-epiminoisoindole-7-carboxylic acid 20a To
a
NaHCO
was re-extracted with dichloromethane (50 mL) the layers were
separated and the combined organics dried over Na SO and
concentrated to give the desired amine 16b as a pale orange oil (3.0 g,
12.49 mmol, quantitative) that required no further purification. HRMS m/z
3
(aq) (60 mL). The organics were separated and the aqueous
solution of ester 19a (1.31 g, 3.15 mmol) in THF (16 mL) was added an
aqueous solution of 1 M LiOH (5.1 mL) and the mixture was stirred at 40
ºC for 28 h. 1 M HCl was added until pH 3 and the mixture extracted with
dichloromethane (3 x 20 mL). The organic phase was dried over Na SO
2 4
and concentrated to give acid 20a (1.2 g, 3.13 mmol, 99%) as a colorless
solid that required no further purification. MP 207–208 °C. HRMS m/z
2
4
+
+
(ESI ) Found 239.1777 [M+H] , C13
H
23
N
2
O
2
requires 239.1754. max
-
1
(ATR)/cm 2978, 2346, 1740, 1655, 1561, 1477, 1409, 1371, 1336, 1255,
+
+
1
(
(
9
1
1
ESI ) Found 387.1914 [M+H] , C21
27 2
H N O
5
requires 387.1914. max
1171, 1124, 1068, 1013, 882, 847, 730, 652. H NMR (400 MHz; CDCl
7.19 (dd, J 3.3, 1.8, 1H), 6.55 (br s, 1H), 6.21 (dd, J 3.1, 1.8, 1H), 6.10
(t, J 3.3, 1H), 4.04 (s, 2H), 2.94 (sep., J 6.4, 1H), 1.60 (s, 9H), 1.16 (d, J
6.4, 6H). C NMR (100 MHz, CDCl
110.2, 84.2, 47.4, 43.3, 28.0, 21.7.
3
)
-
1
ATR)/cm 2928, 1730, 1697, 1637, 1486, 1453, 1329, 1241, 1151, 1122,
34, 874, 737, 701, 654, 632. H NMR (400 MHz; CDCl
H), 7.49–7.08 (m, 5H), 4.56 (m, 4H), 3.49 (d, J 11.8, 1H), 3.36 (t, J 4.6,

H
1
3 H
)  11.64 (br s,
13
3 C
)  149.6, 131.1, 122.0, 114.6,
13
H), 3.21 (d, J 5.1, 1H), 1.93–1.74 (m, 4H), 1.40 (br s, 9H). C NMR
)  175.3, 172.5, 155.6, 135.4, 128.6, 127.8, 127.6,
0.7, 70.0, 61.1, 54.3, 48.4, 47.8, 46.8, 28.5, 28.0, 25.1.
(
8
100 MHz, CDCl
3
C
(E)-tert-Butyl 2-((4-ethoxy-N-isopropyl-4-oxobut-2-enamido)methyl)-
H-pyrrole-1-carboxylate 17b To a solution of 16b (3.0 g, 12.49 mmol),
1
(
3aR*,6S*,7S*,7aS*)-
carbamoyl)-1-oxooctahydro-3a,6-epiminoisoindole-8-carboxylate
1a To a solution of acid 20a (1.2 g, 3.13 mmol), in dichloromethane (35
tert-Butyl
2-benzyl-7
-((4-bromobenzyl)
in dichloromethane (60 mL) and dimethylformamide (60 mL) was added
mono-ethyl fumarate (1.7 g, 10.86 mmol), followed by HATU (6.2 g,
2
16.29 mmol) and the mixture was cooled to
0
ºC. N,N-
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601177
COMMUNICATION
+
+
Diisopropylethylamine (7.6 mL, 43.44 mmol) was then added and the
mixture was stirred at rt for 18 h. Following dilution with ethyl acetate
26 2 5
HRMS m/z (ESI ) Found 361.1725 [M+Na] , C17H N NaO requires
-
1
361.1734. max (neat)/cm 2974, 2180, 1996, 1726, 1697, 1625, 1478,
(
100 mL) the reaction mixture was extracted with sat. NH
the organic phase was then washed with sat. NaHCO
followed by 5% aq LiCl solution (100 mL) and finally brine (80 mL). The
organics were dried over Na SO and concentrated to give a deep red oil
4.7 g). Purification by flash column chromatography (50–70% ether in
4
Cl (aq) (80 mL),
1369, 1332, 1224, 1166, 1126, 1034, 1004, 857, 811, 775, 653, 620, 554.
H NMR (400 MHz; CDCl )  4.70 (1 H d, J 11.7, 1H), 4.47 (t, J 4.4, 1H),
3 H
4.34 (sep., J 6.8, 1H), 3.41 (d, J 11.7, 1H), 3.20 (t, J 4.4, 1H), 3.08 (d, J
1
3
(aq) (80 mL)
2
4
5.0, 1H), 1.90–1.80 (m, 4H), 1.41 (s, 9H), 1.13 (d, J 6.7, 3H), 1.12 (d, J
13
(
6.9, 3H). C NMR (100 MHz, CDCl
3 C
)  174.5, 172.6, 155.5, 80.6, 70.1,
3 2
light petroleum with 1% NH in H O) gave the desired amide 17b as a
67.9, 61.0, 54.9, 48.4, 43.2, 28.5, 28.1, 25.5, 19.7, 19.6.
+
yellow oil (2.2 g, 6.00 mmol, 55%). HRMS m/z (ESI ) Found 365.2078
+
-1
[
1
M+H] , C19
H N O
29 2 5
requires 365.2071. max (ATR)/cm 2975, 1691,
(3aR*,6S*,7S*,7aS*)-tert-Butyl
7-((4-bromobenzyl)carbamoyl)-2-
1
422, 1367, 1327, 1244, 1159, 1120, 1076, 1030, 709. H NMR (400
isopropyl-1-oxooctahydro-3a,6-epiminoisoindole-8-carboxylate 21b
To a solution of acid 20b (820.0 mg, 2.42 mmol), in dichloromethane (27
mL) and dimethylformamide (27 mL) was added 4-bromobenzylamine
hydrochloride (661.0 mg, 2.91 mmol), followed by HATU (1.4 g, 3.63
mmol) and the mixture was cooled to 0 ºC. N,N-Diisopropylethylamine
(2.1 mL, 12.10 mmol) was then added and the reaction was stirred at rt
for 24 h. Following dilution with ethyl acetate (50 mL) the reaction mixture
MHz; CDCl
3
) 
5.2, 1H), 6.08 (t, J 3.4, 1H), 5.99 (dd, J 3.3, 1.7, 1H), 4.85 (sep., J 6.8,
H), 4.71 (s, 2H), 4.19 (q, J 7.1, 2H), 1.63 (s, 9H), 1.26 (t, J 7.2, 3H),
H
7.18 (dd, J 3.1, 1.8, 1H), 7.14 (d, J 15.2, 1H), 6.88 (d, J
1
1
1
1
2
13
3 C
.16 (d, J 6.8, 3H). C NMR (100 MHz, CDCl )  165.9, 165.1, 149.4,
34.8, 132.4, 131.6, 121.7, 112.7, 110.5, 84.3, 60.9, 46.3, 41.9, 28.1,
0.1, 14.1.
was extracted with sat. NH
washed with sat. NaHCO
(60 mL) and finally brine (40 mL). The organics were dried over Na
4
Cl (aq) (30 mL), the organic phase was then
(aq) (30 mL) followed by 5% aq LiCl solution
SO
3
(
1
3aR*,6S*,7S*,7aS*)-8-tert-Butyl
,2,3,6,7,7a-hexahydro-3a,6-epiminoisoindole-7,8-dicarboxylate 18b
7-ethyl
2-isopropyl-1-oxo-
3
2
To amide 17b (2.2 g, 6.00 mmol) in dry ether (50 mL) was added lithium
triflamide (50 g, 174.16 mmol; dried at 150 ºC under high vacuum
immediately prior to use) and the mixture stirred at rt for 11 days. The
reaction mixture was diluted with water (150 mL) and chloroform (100
mL). The phases were separated and the organic layer was washed with
water (2 x 70 mL), the combined organics were washed with brine (150
and concentrated to give a foamy pale brown solid (1.3 g). Purification
by flash column chromatography (50–70% ethyl acetate in light
3 2
petroleum with 1% NH in H O) gave the desired amide 21b as a foamy
+
grey solid (1.0 g, 2.03 mmol, 84%). MP 156–157 ºC. HRMS m/z (ESI )
+
79
Found 528.1475 [M+Na] , C24
H
32 BrN NaO requires 528.1468. max
3 4
-
1
1
(ATR)/cm 3302, 2976, 1664, 1540, 1339, 1166, 1012, 755. H NMR
mL) and dried over Na
by flash column chromatography (80%–neat ether in light petroleum with
% NH in H O) gave the Diels-Alder adduct 18b as a colorless foamy
solid (1.5 g, 4.03 mmol, 67%).MP 87–89 °C. HRMS m/z (ESI ) Found
2
SO
4
to give a pale yellow oil (2.0 g). Purification
(400 MHz; CDCl )  7.43 (d, J 8.3, 2H), 7.14 (d, J 8.5, 2H), 7.03 (t, J 5.7,
1H), 4.63 (d, J 11.4, 1H), 4.46–4.41 (m, 2H), 4.32–4.22 (m, 2H), 3.43 (d,
J 11.5, 1H), 3.04 (t, J 4.7, 1H), 2.75 (d, J 6.0, 1H), 2.10–1.99 (m, 1H),
3
H
1
3
2
+
1.98–1.79 (m, 2H), 1.74–1.69 (m, 1H), 1.44 (s, 9H), 1.15 (d, J 6.7, 3H),
+
-1
13
3
3
1
87.1895 [M+Na] , C19
468, 2978, 2461, 1714, 1625, 1478, 1394, 1369, 1334, 1248, 1165,
124, 1077, 1060, 1032, 968, 871, 842, 722, 666. H NMR (400 MHz;
H
28
N
2
NaO
5
requires 387.1890. max (ATR)/cm
3 C
1.14 (d, J 6.9, 3H). C NMR (100 MHz, CDCl )  173.1, 170.5, 155.9,
137.4, 131.7, 129.4, 121.1, 80.7, 77.2, 61.0, 55.2, 48.9, 43.3, 42.9, 42.8,
29.5, 28.2, 25.1, 19.8, 19.7.
1
CDCl
3
) 
.61 (br s, 1H), 4.28 (sep., J 6.7, 1H), 4.02 (q, J 7.1, 2H), 3.65 (d, J 11.4,
H), 3.28 (t, J 4.1, 1H), 2.71 (d, J 3.9, 1H), 1.30 (s, 9H), 1.15 (t, J 7.2,
H
6.47 (d, J 5.5, 1H), 6.19 (d, J 5.5, 1H), 4.92 (dd, J 3.8, 1.6, 1H),
4
1
3
(3aR*,6S*,7S*,7aS*)-N-(4-Bromobenzyl)-2-isopropyl-1-oxooctahydro-
3a,6-epiminoisoindole-7-carboxamide 22b Adduct 21b (514.2 mg,
1.02 mmol) was dissolved in dichloromethane (5 mL), cooled to 0 ºC and
TFA (890.0 L) added dropwise over 20 sec. The reaction mixture was
then stirred at rt for 15 h. The volatiles were removed under reduced
pressure to give 22b.TFA as a purple solid (410.0 mg). Purification by
13
H), 1.07 (d, J 6.8, 3H), 1.02 (d, J 6.7, 3H). C NMR (100 MHz, CDCl
171.1, 170.5, 155.4, 136.2, 134.6, 80.8, 74.1, 64.7, 60.8, 53.8, 43.2,
2.3, 27.8, 19.7, 19.4, 13.9.
3
)

C
4
(
3
3aR*,6S*,7S*,7aS*)-8-tert-Butyl 7-ethyl 2-isopropyl-1-oxooctahydro-
a,6-epiminoisoindole-7,8-dicarboxylate 19b Adduct 18b (1.5 g, 4.03
3
ion-exchange chromatography (SCX*, 5% NH in MeOH) gave free
amine 22b as a brown solid (405 mg, 1.00 mmol, 98%). MP 200–201 ºC.
+
+
79
mmol) was dissolved in methanol (82 mL) and palladium on activated
carbon added (43.0 mg, 0.40 mmol, 10mol%). The solution was stirred
under an atmosphere of hydrogen at rt for 1.5 h. Filtration through Celite
and removal or methanol under reduced pressure desired tricycle 19b as
a turbid grey oil (1.4 g, 3.68 mmol, 91%), which crystallized on standing
HRMS m/z (ESI ) Found 406.1123 [M+H] , C19
H
3 2
25 BrN O requires
-
1
406.1120. max (ATR)/cm 3250, 2971, 1650, 1545, 1487, 1428, 1331,
1228, 1071, 1011, 907, 794, 727, 646. H NMR (400 MHz; CDCl ) 
3 H
1
7.44 (d, J 8.5, 2H), 7.16 (d, J 8.3, 2H), 6.94 (br s, 1H), 4.45 (dd, J 15.1,
6.1, 1H), 4.37–4.22 (m, 2H), 3.81 (t, J 4.2, 1H), 3.56–3.41 (m, 2H), 2.98 (t,
+
and required no further purification. MP 73–74 °C. HRMS m/z (ESI )
Found 389.2053 [M+Na] ,
J 4.5, 1H), 2.77 (d, J 5.6, 1H), 2.04–1.91 (m, 1H), 1.82–1.66 (m, 3H),
+
13
C
19
H
30
N
2
NaO
5
requires 389.2047.

max
3 C
1.14 (d, J 6.7, 6H). C NMR (100 MHz, CDCl )  174.2, 170.8, 137.5,
-
1
(ATR)/cm 2970, 1735, 1687, 1478, 1420, 1367, 1324, 1226, 1163, 1122,
131.6, 129.5, 121.1, 68.6, 60.0, 54.0, 52.9, 44.6, 43.0, 42.7, 30.5, 25.7,
19.9, 19.6. SCX* specifications: SCX-2 pre-packed column, Isolute SPE
column flash SCX-2 70 mL (Part no. 456-1000-F, Lot no. 4083405F1B).
1
1
4
7
3 H
091, 1032, 1005, 858, 831, 684, 620. H NMR (400 MHz; CDCl ) 
.61 (d, J 11.8, 1H), 4.46 (t, J 4.7, 1H), 4.33 (sep., J 6.7, 1H), 4.17 (q, J
.1, 2H), 3.40 (d, J 11.4, 1H), 3.21 (t, J 4.7, 1H), 2.97 (d, J 4.8, 1H), 1.91
(
td, J 11.4, 4.0, 1H), 1.86–1.76 (m, 1H), 1.76–1.67 (m, 1H), 1.63–1.55 (m,
Methyl 3-bromopropiolate 24 Methyl propiolate (29.4 g, 0.35 mol) was
added to a solution of recrystallized N-bromosuccinimide (70 g, 0.40 mol)
in acetone (1.1 L). Silver nitrate (6.0 g, 0.04 mol) was added and the
reaction mixture was stirred under nitrogen at room temperature for 4 h.
Volatiles were removed under reduced pressure to give a grey slurry.
This was washed with hexane (2 × 1 L). Half the volume of hexane was
removed under reduced pressure and the remainder removed by short
path distillation at atmospheric pressure with heating at 90–93 ºC.
Distillation under reduced pressure (33 mbar, 70–80 ºC external
1
3
6
H), 1.43 (s, 9H), 1.27 (t, J 7.2, 3H), 1.12 (d, J 6.9, 6H), 1.11 (d, J 6.7,
13
H). C NMR (400 MHz; CDCl
3 C
)  172.4, 171.2, 155.5, 80.6, 70.2, 61.2,
0.8, 54.4, 47.9, 42.6, 42.5, 28.4, 28.2, 25.6, 19.9, 19.7, 14.2.
(
3aR*,6S*,7S*,7aS*)-8-(tert-Butoxycarbonyl)-2-isopropyl-1-
oxooctahydro-3a,6-epiminoisoindole-7-carboxylic acid 20b To
a
solution of ester 19b (1.3 g, 3.48 mmol) in THF (18 mL) was added an
aqueous solution of 1 M LiOH (6.0 mL) and the reaction was stirred at 40
ºC for 28 h. 1 M HCl was added until pH 3 and the mixture extracted with
dichloromethane (3 x 20 mL). The organic phase was dried over Na
and concentrated to give acid 20b (820.0 mg, 2.43 mmol, 70%), as a
colorless solid which required no further purification. MP 220–221 °C.
temperature, 60 ºC internal temperature) gave the desired product 24 as
1
2
SO
4
a colorless oil (41.9 g, 0.26 mol, 74%). H NMR (400 MHz; CDCl
3
) 
H
13
3.80 (s, 3H). C NMR (100 MHz, CDCl
3
) 
C
152.8, 72.5, 53.0, 52.8. The
[
19]
data were in agreement with the literature.
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601177
COMMUNICATION
mmol, as a mixture of diastereomers 28a/28b) was dissolved in DMF (30
mL) and cooled to 0 °C. N,N-Diisopropylethylamine (1.18 mL, 6.75 mmol)
and morpholine (291 L, 3.38 mmol) were added, and after 10 min HATU
(1.28 g, 3.38 mmol) was also added. The mixture was allowed to warm to
rt and stirred for 16 h. EtOAc (30 mL) was added and the mixture was
(
1S*,4R*)-7-tert-Butyl 2-methyl 3-bromo-7-azabicyclo[2.2.1]hepta-2,5-
diene-2,7-dicarboxylate 25 Methyl 3-bromopropiolate 24 (41.9 g, 0.26
mol) and N-Boc pyrrole 4 (204 g, 1.22 mol) were dissolved in dry toluene
(50 mL), the flask was well insulated with cotton and foil then heated at
8
0 ºC for 5 days. The mixture was reduced to a dark brown oil (183.11 g).
washed with aqueous LiCl solution (10%, 50 mL), aqueous NaHCO
solution (saturated, 50 mL), water (50 mL) and brine (50 mL). The
organic layer was dried with MgSO and solvent was removed in vacuo to
3
Purification by flash column chromatography (10–30% ether in light
petroleum) gave the desired Diels-Alder product 25 (37.6 g, 0.114 mmol,
4
+
+
45%) as a bright orange oil. HRMS m/z (ESI ) Found 352.0140 [M+Na] ,
give the mixture of diastereomers (830 mg, 89%). Diastereomers could
be separated by chromatography (5  30% Acetone in light petroleum).
On 250 mg of mixed diastereomers this gave 86 mg of less polar
diastereomer 29b and 96 mg of more polar diastereomer 29a, with the
remainder being mixed fractions which could be resubjected to
79
-1
C
13
H
16 BrNNaO
4
requires 352.0115. max (ATR) / cm 2977, 1707, 1603,
1
1312,. 1254, 1207, 1158, 1032. H NMR (400 MHz; CDCl
) 
3 H
7.13 (2 H,
13
br s), 5.48 (s, 1 H), 5.13 (br s, 1H), 3.79 (s, 3H), 1.41 (s, 9H). C NMR
100 MHz, CDCl )  162.7, 154.0, 147.6, 143.2, 141.3, 140.4, 81.5, 74.7,
8.8, 51.8, 28.1. The data were in agreement with the literature.
(
6
3
C
[
20]
+
chromatography. Data for 29b (exo) HRMS m/z (ESI ) Found 416.2549
+
-1
[
M+H] , C22
H
33
1
N
3
O
4
requires 416.2544. max (CHCl
1647, 1056. H NMR (400 MHz, CDCl )  7.43 – 7.08 (m, 5H), 4.56 –
3.91 (m, 2H), 3.84 – 3.24 (m, 10H), 3.12 – 3.00 (m, 1H), 2.86 – 2.64 (m,
3
) / cm 2977, 1688,
8-(tert-Butyl)
6-methyl
(1R*,5S*)
-3-benzyl-3,8-diazabicyclo
3
H
[3.2.1]octane-6,8-dicarboxylate 27a/27b Carbamate 25 (3.03 g, 9.18
1
3
mmol) was dissolved in dry acetonitrile (100 mL) and cooled to -15 °C
using a salt/ice bath. Sodium borohydride (870 mg, 23 mmol) was added
portionwise over 15 min, and the suspension was stirred for 1.5 h. The
reaction mixture was quenched using a saturated solution of ammonium
chloride (20 mL) and CH
washed with water to remove acetonitrile (4
dichloromethane solution of 26 was dried with MgSO
3 C
3H), 2.52 – 2.06 (m, 3H), 1.47 (s, 9H). C NMR (101 MHz, CDCl ) 
177.6, 150.4, 138.4, 129.1, 128.1, 127.0, 80.0, 67.0, 66.7, 62.1, 53.0,
+
46.1, 42.8, 31.0, 28.5, 24.0. Data for 29a (endo) HRMS m/z (ESI ) Found
+
-1
416.2555 [M+H] , C22
H
33
1
N O
3 4
requires 416.2544. max (CHCl
3
) / cm
2
Cl
2
(100 mL) was added. The organic layer was
150 mL) and the
, filtered, and used
3006, 1687, 1644, 1115. H NMR (400 MHz, CDCl
3
)  (rotamers) 7.41 –
H
x
7.20 (m, 5H), 4.54 – 4.14 (m, 2H), 3.89 – 3.38 (m, 10H), 3.33 – 3.18 (m,
13
4
1H), 2.76 – 2.59 (m, 1H), 2.60 – 1.88 (m, 4H), 1.47 (s, 9H). C NMR
(100 MHz, CDCl )  (two rotamers) 172.5, 172.3, 153.5, 153.4, 138.3,
in the next step immediately. The dichloromethane solution of 26 was
3
C
subjected to ozonolysis at -78 °C, until a blue colour was observed from
remaining O . The solution was then warmed to 0 °C and dimethyl sulfide
3
was added (3.37 mL, 45.9 mmol) and the mixture was allowed to warm to
rt and stirred for 16 h. Volatiles were then removed in vacuo and the
mixture was re-dissolved in dry 1,2-dichloroethane (50 mL) and cooled to
128.7, 128.7, 128.4, 127.2, 79.7, 67.0, 66.6, 66.5, 61.9, 57.5, 57.4, 57.4,
57.0, 56.8, 55.1, 54.0, 46.0, 44.4, 43.3, 42.5, 42.4, 38.7, 38.6, 32.9, 32.3,
28.5, 28.5.
tert-Butyl (1S*,5R*,6S*)-3-Benzyl-6-(hydroxymethyl)-3,8-diazabicyclo
[3.2.1]octane-8-carboxylate 32 Methyl ester 27a (192 mg, 0.53 mmol)
was dissolved in dry THF (10 mL), and cooled to 0 °C. Lithium
borohydride (116 mg, 5.33 mmol) was added as a solid portionwise over
5 min, and the mixture was allowed to warm to rt and stirred for 40 h.
0
°C. Benzylamine (990 L, 9 mmol) was added followed by sodium
triacetoxyborohydride (9.54 g, 45 mmol) and the mixture was warmed to
rt and stirred for 3 h. The reaction was slowly quenched with aqueous
NaHCO
3
solution (saturated, 30 mL) and after gas evolution had ceased,
Cl (2 x 50 mL), dried with MgSO
the organics were extracted with CH
2
2
4
,
Saturated NH
extracted with EtOAc (3 x 10 mL). The combined organic layers were
dried with MgSO and concentrated in vacuo to give 32 as a colorless oil
(169 mg, >95%) which could be used without further purification. HRMS
4
Cl solution (5 mL) was added and the organics were
and solvent was removed in vacuo. Purification by column
chromatography (5  15% EtOAc in light petroleum) gave two separable
diastereomers of 27, the major being less polar and isolated as a
colorless powder (823 mg, 25%). Recrystallization of the major
4
+
+
29 2 3
m/z (ESI ) Found 333.2177 [M+H] ,C19H N O requires 333.2178. max
1
-
1
diastereomer from CH
2
Cl
2
/hexane yielded crystals suitable for X-ray
(ATR) /cm 3427, 2976, 1689, 1476, 1173, 1108. H NMR (400 MHz,
CDCl )  7.52 – 6.97 (m, 5H), 5.80 (br s, 1H), 4.27 – 3.97 (m, 2H), 3.93
diffraction that confirmed the identity of the major diastereomer as endo.
The minor diastereomer could not be isolated in sufficient purity to allow
full characterization. Alternatively, both diastereomers taken together
gave a total yield of 30%.Data for 27a (endo): MP 119–120 ºC. HRMS
3
H
– 3.74 (m, 2H), 3.67 (d, J 12.6, 1H), 3.28 (d, J 12.6, 1H), 2.97 (d, J 11.3,
1H), 2.62 (d, J 11.3, 1H), 2.57 – 2.36 (m, 2H), 2.36 – 2.12 (m, 1H), 2.12 –
13
3 c
1.77 (m, 2H), 1.45 (s, 9H). C NMR (100 MHz, CDCl )  153.5, 136.2,
+
+
m/z (ESI ) Found 361.2121 [M+H] , C20
H
29
N
2
O
4
requires 361.2122. max
)/cm 3011, 1735, 1687. H NMR (400 MHz, CDCl )  7.44 –
.10 (m, 5H), 4.50 – 4.15 (m, 2H), 3.60 (s, 3H), 3.49 (d, J 13.0 Hz, 1H),
.37 (d, J 13.0 Hz, 1H), 3.10 (ddd, J 12.0, 6.9, 5.2 Hz, 1H), 2.99 – 2.87
129.6, 128.7, 127.8, 79.9, 62.3, 60.8, 57.1, 56.6, 54.1, 53.1, 42.5, 29.8,
28.6.
-
1
1
(CHCl
3
3
H
7
3
(
2
m, 1H), 2.69 (ddd, J 10.7, 2.8, 1.1 Hz, 1H), 2.44 (dd, J 12.3, 5.2 Hz, 1H),
Experimental procedures for library compounds, X-Ray diffraction data
and copies of H and C NMR spectra are given in the Supporting
Information.
13
.16 (apparent td, J 12.0, 6.9 Hz, 1H), 1.50 (s, 9H). C NMR (100 MHz,
)  172.6, 153.5, 138.5, 129.0, 128.3, 127.2, 79.9, 62.12, 60.5,
6.3, 54.6, 51.6, 46.0, 43.6, 30.3, 28.6.
1
13
CDCl
5
3
C
(
1S*,5R*)-3-Benzyl-8-(tert-butoxycarbonyl)-3,8-diazabicyclo
octane-6-carboxylic acid 28a/b Methyl ester 27 (900 mg, 2.5 mmol)
was dissolved in THF (24 mL), MeOH (6 mL) and H O (6 mL) and cooled
[3.2.1]
Acknowledgements
2
to 0 °C. Lithium hydroxide monohydrate (1.05 g, 25 mmol) was added
and the mixture was warmed to r.t. and stirred for 20 h. The reaction was
quenched with 1 M HCl, and acidified to a pH of ~2. Extraction with
The research leading to these results was done within the
European Lead Factory and has received support from the
Innovative Medicines Initiative Joint Undertaking under grant
agreement no. 115489, resources of which are composed of
financial contribution from the European Union’s Seventh
4
EtOAc (3 x 20 mL) followed by drying with MgSO and removal of solvent
in vacuo gave the carboxylic acid 28 (780 mg, 90%) as a 1:1 mixture of
diastereomers 28a/b that were used directly in the subsequent step
without characterization.
Framework
Programme
(FP7/2007–2013)
and
EFPIA
companies’ in-kind contribution.
tert-Butyl (1S*,5R*,6R*/S*) -3-benzyl-6-(morpholine-4-carbonyl)-3,8-
diazabicyclo [3.2.1]octane-8-carboxylate 29a/b Acid 28 (780 mg, 2.25
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601177
COMMUNICATION
Keywords: Nitrogen heterocycles • Diels-Alder reaction • Drug
discovery • Medicinal chemistry • Library synthesis
[9]
B. Badio, H. M. Garraffo, C. V. Plummer, W. L. Padgett, J. W.
Daly, Eur. J. Pharmacol. 1997, 321, 189-194.
R. W. Fitch, X.-F. Pei, Y. Kaneko, T. Gupta, D. Shi, I.
Federova, J. W. Daly, Biorg. Med. Chem. 2004, 12, 179-190.
A. Kamimura, T. Nakano, J. Org. Chem. 2010, 75, 3133-3136.
a) C. C. Nawrat, C. J. Moody, Org. Lett. 2012, 14, 1484-1487;
b) C. E. Blunt, C. Torcuk, Y. Liu, W. Lewis, D. Siegel, D. Ross,
C. J. Moody, Angew. Chem. Int. Ed. 2015, 54, 8740-8745.
A. Nortcliffe, C. J. Moody, Bioorg. Med. Chem. 2015, 23,
2730-2735.
[
10]
[
[
[
1]
2]
3]
J. W. Daly, G. B. Brown, M. Mensah-Dwumah, C. W. Myers,
Toxicon 1978, 16, 163-168.
[11]
[12]
T. F. Spande, H. M. Garraffo, M. W. Edwards, H. J. C. Yeh, L.
Pannell, J. W. Daly, J. Am. Chem. Soc. 1992, 114, 3475-3478.
a) C. A. Broka, Tetrahedron Lett. 1993, 34, 3251-3254; b) D. F.
Huang, T. Y. Shen, Tetrahedron Lett. 1993, 34, 4477-4480; c)
S. R. Fletcher, R. Baker, M. S. Chambers, S. C. Hobbs, P. J.
Mitchell, J. Chem. Soc., Chem. Commun. 1993, 1216-1218; d)
S. C. Clayton, A. C. Regan, Tetrahedron Lett. 1993, 34, 7493-
[13]
[14]
[15]
A. Basso, L. Banfi, G. Guanti, R. Riva, Org. Biomol. Chem.
2009, 7, 253-258.
7496; eE. J. Corey, T. P. Loh, S. AchyuthaRao, D. C. Daley, S.
4-Bromophenyl substituted compounds were used as library
molecule examples as they will not appear in the Joint
European Compound Library
Sarshar, J. Org. Chem. 1993, 58, 5600-5602.
[
4]
a) D. A. Evans, K. A. Scheidt, C. W. Downey, Org. Lett. 2001,
3
, 3009-3012; b) V. K. Aggarwal, B. Olofsson, Angew. Chem.
[16]
[17]
[18]
S. T. Handy, P. A. Grieco, C. Mineur, L. Ghosez, Synlett 1995,
1995, 565-567.
Int. Ed. 2005, 44, 5516-5519; c) A. Armstrong, Y. Bhonoah, S.
E. Shanahan, J. Org. Chem. 2007, 72, 8019-8024.
R. D. MacArthur, R. M. Novak, Clin. Infect. Dis. 2008, 47, 236-
241.
[
[
5]
6]
B. Badio, J. W. Daly, Mol. Pharmacol. 1994, 45, 563-569.
N. M. Rupniak, S. Patel, R. Marwood, J. Webb, J. R. Traynor,
J. Elliott, S. B. Freedman, S. R. Fletcher, R. G. Hill, Br. J.
Pharmacol. 1994, 113, 1487-1493.
C. Traversa, K. Fégy, G. Balme, J. Goré, Synth. Commun.
1997, 27, 1087-1096.
[19]
[20]
J. Leroy, Synth. Commun. 1992, 22, 567-572.
C. Zhang, M. L. Trudell, J. Org. Chem. 1996, 61, 7189-7191.
[
[
7]
8]
H. M. Garaffo, T. F. Spande, M. Williams, Heterocycles 2009,
79, 207-217.
M. I. Damaj, K. R. Creasy, A. D. Grove, J. A. Rosecrans, B. R.
Martin, Brain Res. 1994, 664, 34-40.
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601177
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
Library synthesis
A. T. Murray, E. Packard, A. Nortcliffe,
W. Lewis, D. Hamza, G. Jones, and C.
J. Moody*
Page No. – Page No.
Synthesis of epibatidine analogues
by pyrrole Diels-Alder reactions:
rapid access to azabicyclo[2.2.1]-
heptane and 3,8-diazabicyclo[3.2.1]-
octane scaffolds for library synthesis
Text for Table of Contents
3
Efficient access to sp -rich bicyclic amines using pyrrole Diels-Alder reactions: novel scaffolds for library synthesis in the European
Lead Factory.
This article is protected by copyright. All rights reserved