Generation of a Heteropolycyclic and sp3-Rich Scaffold for Library Synthesis from a Highly Diastereoselective Petasis/Diels–Alder and ROM–RCM Reaction Sequence

Article abstract of DOI:10.1002/ejoc.201801551

Efficient access to diverse screening compounds with desirable, lead-like properties can be a bottleneck in early drug discovery and chemical biology. Herein we present an efficient, rapid route to three structurally distinct classes of compounds (A–C) from a single precursor, which in turn is available through a one-pot Petasis 3-component reaction/Diels–Alder cascade reaction. We demonstrate the versatility of the approach through the synthesis of 35 exemplary compounds from the three classes, as well as by the production of 2188 final compounds, which have been included in the Joint European Compound Library of the European Lead Factory.

Full text of DOI:10.1002/ejoc.201801551

A Journal of
Accepted Article
Title: Generation of a Heteropolycyclic and Sp3-Rich Scaffold for
Library Synthesis from a Highly Diastereoselective Petasis/Diels-
Alder and ROM-RCM Reaction Sequence
Authors: Thomas Flagstad, Carlos Azevedo, Nikolaj Troelsen, Geanna
Min, Yohan Mace, Anthony Willaume, Rachel Guilleux,
Melanie Velay, Karine Bonnet, Remy Morgentin, Thomas
Nielsen, and Mads Hartvig Clausen
This manuscript has been accepted after peer review and appears as an
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 published
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.201801551
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801551
Supported by

10.1002/ejoc.201801551
European Journal of Organic Chemistry
FULL PAPER
Generation of a Heteropolycyclic and Sp3-Rich Scaffold for
Library Synthesis from a Highly Diastereoselective Petasis/Diels-
Alder and ROM-RCM Reaction Sequence
Thomas Flagstad, [a] Carlos M. G. Azevedo,[a] Nikolaj S. Troelsen,[a] Geanna K. Min,[a] Yohan Macé,[b]
Anthony Willaume,[b] Rachel Guilleux,[b] Mélanie Velay,[b] Karine Bonnet,[b] Remy Morgentin,[b] Thomas
E. Nielsen,*[c] Mads H. Clausen*[a]
Abstract: Efficient access to diverse screening compounds with
desirable, lead-like properties can be a bottleneck in early drug
discovery and chemical biology. Here we present an efficient, rapid
route to three structurally distinct classes of compounds (A–C) from a
single precursor, which in turn is available through a one-pot Petasis
combination with two ring opening/ring closing metathesis
(ROM/RCM) cascade reactions enabled us to access different,
diverse and sp3-rich scaffolds. Herein we present the synthesis of
a new library that has led to the production of 2188 HTS
compounds.
3-component-reaction–Diels-Alder
cascade
reaction.
We
demonstrate the versatility of the approach through the synthesis of
35 exemplary compounds from the three classes, as well as by the
production of 2188 final compounds, which have been included in the
Joint European Compound Library of the European Lead Factory.
Results and Discussion
In order to rapidly build a compact functionalized core system, we
focused on
a synthetic route which includes a highly
diastereoselective 3-component Petasis/Diels-Alder tandem
reaction from allylic amines (1a), furylboronic acids (1b), and α-
hydroxylated aldehydes (1c) (Scheme 1). This reaction manifold
was first reported by Norsikian, Beau, and co-workers and later
further explored by us.[8] We envisioned that this strategy would
allow us to access different libraries depending on the N-
substituent on the boronic acid building block 1b and the R3
substituent on the aldehyde 1c as a single diastereomer. Based
on this scaffold 1, we wish to report the generation of three
different sub-libraries (library A-C) using robust and scalable
chemistry.
Introduction
Accessing new drug candidates through high-throughput
screening (HTS) has become an increasingly difficult challenge
primarily due to the lack of investigatory efforts into compounds
inhabiting a different chemical space.[1] The libraries typically
generated for screening often bear similar chemical topology, flat
in structure possessing mostly sp2-hybridized carbon atoms
making it more challenging to discover new biological activity.[2]
Thus, it has become necessary to increase efforts towards
screening simple natural product like and sp3-rich cores through
diversity-oriented synthesis.[3] However, routine syntheses of
such sp3-rich molecules with stereochemical control for use in
screening library productions remains a significant challenge.[4]
The European Lead Factory initiative addresses this developing
issue by targeting natural product-like libraries,[5] while providing
production feasible routes from cheap and commercially available
building blocks in order to access scaffolds that are sp3-rich with
3–5 functional group handles.[6] These handles can be further
functionalized to provide a large library of compounds to be
screened for biological activity.
R2
Petasis 3-CR
Diels-Alder
Tandem reaction
H
NHR1
BocN
R2
N
R1
H
N
O
O
Boc
B(OH)2
1b
OH
HO
R3
1a
O
R3
1
1c
R2 = Me
R3 = allyl
R2 = Me
R
2 = allyl
We recently published the synthesis of a sp3-rich library based on
a 3-component Petasis/Diels–Alder strategy.[7] This sequence in
R2
R4
H
R2
H
H
N
N
R4
N
R1
N
R4
R1
O
N
R1
H
N
H
H
Et
O
O
R4
Et
O
R5
N
R3
[a]
Dr. T. Flagstad, Dr. C. M. G. Azevedo, N. S. Troelsen, Dr. G. K. Min,
Prof. Dr. M. H. Clausen, Center for Nanomedicine & Theranostics,
Department of Chemistry
O
R5
R5
O
Library A
Library B
Library C
Technical University of Denmark
Kemitorvet 207, DK-2800, Kongens Lyngby, Denmark,
mhc@kemi.dtu.dk, www.kemi.dtu.dk/mhc
Dr. Y. Macé, Dr. A. Willaume, Dr. R. Guilleux, Dr. M. Velay, Dr. K.
Bonnet, Dr. R. Morgentin, EDELRIS
115 Avenue Lacassagne, F-69003, France
Prof. Dr. T. E. Nielsen, Singapore Centre on Environmental Life
Science Engineering,
Nanyang Technological University
Singapore 637551, Singapore and
Costerton Biofilm Center, Department of Immunology and
Microbiology, University of Copenhagen
Copenhagen DK-2200, Denmark
[b]
[c]
Scheme 1: Synthetic strategy for the generation of libraries A–C from
tandem Petasis 3-CR/Diels-Alder product 1.
The Petasis 3-component reaction[9] followed by an
intramolecular Diels-Alder reaction[10] was introduced early in the
scaffold synthesis to provide the core skeleton with the
stereocenters pre-set for the library generation. The benzyl group,
used in lieu of R1 during scaffold construction, was strategically
employed to serve as an orthogonal protecting group to the Boc-
protected amine tethered to the furylboronic acid 1b. This would
allow for selective late stage deprotection and functionalization.
Boronic acids 3 and 4 were obtained through a reductive
ten@sund.ku.dk
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201801551
European Journal of Organic Chemistry
FULL PAPER
amination of commercially available 5-formyl-2-furanylboronic
acid (2) and a primary amine followed by a subsequent Boc
protection (Scheme 2). The boronic acid obtained could not easily
be purified using conventional methods, so it was directly
employed in the Petasis/Diels- Alder reaction after extraction to
afford key intermediates 5 (library A), 6 (library B), and 7 (library
C) in 75%, 31%, and 44% isolated yields, respectively - each as
a racemic mixture of a single diastereomer.
Library A was constructed from scaffold 5 through a series of
deprotection and derivatisation steps of the three available
handles as depicted in Scheme 3. The primary alcohol of 5 could
be functionalized using Mitsunobu conditions[11] to provide aryl
ether 8. N-Functionalization of the two amines was then
performed, first by Boc-deprotection of the exocyclic amine
followed by either acylation or sulfonylation, and then benzyl
deprotection of the pyrrolidine amine followed by reductive
alkylation, sulfonylation, or acylation to provide 9-14 in high yields
over four steps. Alternatively, subjecting 5 to reductive conditions
followed by reductive alkylation of the resulting amine provided 2-
fluorobenzyl amine 15 in 84% isolated yield over two steps.
Subsequently, arylation of the primary alcohol, like described
above, followed by Boc-deprotection of the exocyclic amine and
either alkylation or acylation gave 16 and 17 in excellent yields
over three steps.
1) R1NH2, MS,
MeOH, 1 h, 20 °C
then
NaBH4, 0 °C, 30 min
R1
NHBn
(HO)2
B
O
(HO)2B
O
NBoc
O
2) Boc2O, Et3N,
CH2Cl2, 20 °C, 1 h
3: R1 = Me
4: R1 = allyl
2
The synthesis of library B core scaffold 18 relied on a metathesis
cascade reaction[12] from 6 (Scheme 4). Upon subjection to
Grubbs’ 2nd generation catalyst (Grubbs II) under acidic
OH
1) glyoxylic acidH2O,
CH2Cl2, 20 °C, 16 h
2) K2CO3, MeI,
acetone, 20 °C, 16 h
3) MeCN, reflux, 16 h
O
1) R2
,
CH2Cl2, 20 °C, 16 h
conditions, the 7-oxabicyclo[2.2.1]hept-2-ene underwent
a
2) MeCN, reflux, 16 h
ROM/RCM cascade reaction with the distal monosubstituted
alkene to provide core 18 in 86% yield. Olefin reduction and
pyrrolidine amine benzyl deprotection was performed using
palladium on carbon and ammonium formate. The pyrrolidine
amine could then be selectively alkylated over the exocyclic
secondary amine using reductive alkylation conditions. Finally,
the exocyclic secondary amine was derivatised by reaction with
an acid chloride or an isocyanate to provide 19 and 20,
respectively, in high yields over three steps.
H
H
R1
N
Boc
NBoc
O
BnN
O
BnN
H
H
MeO
HO
R2
O
5: R1 = Me, R2 = H, 75% (over 4 steps)
6: R1 = Me, R2 = allyl, 31%(over 4 steps)
7: 44% (over 5 steps)
Scheme 2: Petasis 3-component reaction accessing key intermediates 5-
7.
2) c
N
Me
O
R
N
3) d
Me
4) e, f, g, or h
H
O
OMe
9: R = CyCH2-, 48%
10
H
: R = 2-carboxythiophene , 47%
11 : R = Ms, 44%
12
NMeBoc
O
BnN
: R = CyNH2C(O)-, 44%
a
1) b
H
O
OMe
O
O
8
, 60%
H
2) g
S
N
Me
O
3) d
R
N
Me
4) i or j
H
H
O
OMe
NMeBoc
O
13
BnN
: R = 3-PyrCH2-, 47%
14: R = n-C6H13NHC(O)-, 25%
H
5
OH
H
1) l
H
NR
O
F
N
2) b
1) d
2) k
NMeBoc
Me
O
F
N
3) m or n
H
H
O
OH
16
: R = n-C5H11-, 90%
17: R = i-PrNHC(O)-, 86%
15, 84%
N
Me
Scheme 3: Synthesis of library A through N-functionalization of the pyrrolidine amine, arylation of the primary alcohol using Mitsunobu conditions, and
exocyclic amine functionalisation. Reagents and conditions: (a) 2-methoxyphenol, PPh3, DEAD, THF, 0→20 °C, 18 h. (b) TFA, CH2Cl2, 20 °C, 1 h. (c)
AcCl, DIPEA, DMF, 20 °C, 18 h. (d) 5% Pd/C, HCOONH4, MeOH, reflux, 1.5 h. (e) CyCHO, NaBH3CN, HOAc, MeOH, 20 °C, 18 h. (f) thiophene-2-
carbonyl chloride, DIPEA, DMF, 20 °C, 18 h. (g) MsCl, DIPEA, DMF, 0 °C, 1 h. (h) cyclopentyl isocyanate, DMF, 20 °C, 18 h. (i) nicotinaldehyde,
NaBH3CN, HOAc, MeOH, 20 °C, 18 h. (j) n-HexNCO, DMF, 20 °C, 18 h. (k) 2-fluorobenzaldehyde, NaBH3CN, HOAc, MeOH, 20 °C, 18 h. (l) 5-
hydroxy-2-methylpyridine, PPh3, DEAD, THF, 0→20 °C, 18 h. (m) valeraldehyde, NaBH3CN, HOAc, MeOH, 20 °C, 18 h. (n) i-PrNCO, DMF, 20 °C, 18
h.
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10.1002/ejoc.201801551
European Journal of Organic Chemistry
FULL PAPER
global reduction using hydrogenation and subsequent acylation of
the pyrrolidine afforded 24 in 77% yield over four steps. Ester
hydrolysis and amidation provided morpholine amide 25 in 60%
yield over two steps. Using this procedure, an additional three
compounds, 30, 31, and 32, were likewise synthesised from 24 to
give examples of both primary, secondary, and tertiary amides in
the R1 handle (Scheme 7).
H
NMeBoc
NMeBoc
H
O
1M HCl in Et2O
BnN
BnN
H
CH2Cl2, 20 °C, 5 min
O
HO
H
then Grubbs II
reflux, 16 h
HO
6
18, 86%
Starting from 22, deprotection of the pyrrolidine ring and global
reduction was performed first followed by reductive alkylation to
provide 26 in quantitative yield. Subsequent Boc deprotection of
the piperidine with TFA followed by sulfonylation afforded 27 in
93% over two steps (Scheme 6). Using this deprotection and
derivatisation sequence, compounds 33-38 were synthesised to
provide examples of acylation and reductive alkylation on both
heterocyclic amines (Scheme 7).
The order of functionalization of the two saturated heterocycles
can also be reversed. Boc deprotection of the piperidine in 23
followed by acylation provided 28 in 85% yield over two steps.
Subsequent hydrogenation deprotected the pyrrolidine amine and
globally reduced the olefins. The pyrrolidine amine was then
functionalized by sulfonylation to afford 29 in 75% yield over two
steps (Scheme 6). Five additional compounds, 39-44, were
synthesised in this fashion using acylation or reductive alkylation
(Scheme 7).
1) Pd/C, H2, EtOH/H2O, 60 C, 28 h
2) RCHO, HOAc, NaBH(OAc)3
CH2Cl2, 20 °C, 16 h, then TFA, 1 h
3) 3-chlorophenyl isocyanate,
DIPEA, DMF, 20 °C, 18 h
3) thiophene-2-carbonyl chloride,
DIPEA, DMF, 20 °C, 18 h
S
H
O
O
N
N
NMe
Me
H
NMe
Me
H
Me
N
O
Cl
N
O
H
H
HO
HO
20, 60%
19, 61%
Scheme 4: Library B scaffold synthesis and diversification.
The developed strategy was subsequently used to produce 2,188
high-throughput screening compounds for the European Lead
Factory. The library showed a high degree of three-dimensionality
with an average Fsp3 of 0.72 and good distributions of cLogP,
molecular weight, and polar surface area (PSA) (Figure 1). Figure
2 shows a comparison of cLogP vs. molecular weight.
By switching the methyl substituent to an allyl group on the
exocyclic amine, library C core scaffold 21 was accessed after
treatment of the HCl salt of 7 with 2 mol% of Grubbs II (Scheme
5). Ring opening of the internal olefin followed by ring closing
metathesis with the tethered allyl amine provided spirocycle 21 in
83% isolated yield as a single diastereomer, the stereochemistry
being determined in the preceding tandem Petasis/Diels-Alder
reaction. Based on 21, library C scaffold diversification was
achieved through N-functionalization of both the pyrrolidine and
piperidine rings and amidations of the ester. The orthogonal
protecting groups allowed for the selective deprotection of either
the methyl ester, pyrrolidine amine, or piperidine amine and their
subsequent functionalisations.
Distribution of Fsp3
Distribution of MW
0.4
0.4
0.3
0.2
0.1
0.0
0.3
0.2
0.1
0.0
0
0
0
0
0
0
0
0
0
0
6
5
5
5
2
8
0
2
4
6
8
0
2
4
0
1
35
45
55
65
75
85
95
0.
3
4
4
4
4
4
5
5
5
5
0.
0.
0.
0.
0.
0.
0.
0.
0.
MW (Da)
Fsp3
Distribution of PSA
Distribution of cLogP
0.25
0.20
0.15
0.10
0.05
0.00
0.4
0.3
0.2
0.1
0.0
-1
0
1
2
3
4
5
0
0
0
0
0
0
0
0
0
0
0
0
5
4
5
6
7
8
9
0
1
2
3
4
1
1
1
1
1
1
cLogP
Polar Surface Area (Å2)
Scheme 5: Library C scaffold synthesis.
Figure 1: Analysis of the 2,188 synthesised high-throughput screening
compounds for the European Lead Factory. Average Fsp3 = 0.72, average
MW = 486 Da, average cLogP = 1.98, and average PSA = 83.5 Å2.
Hydrolysis of the methyl ester using LiOH followed by TBTU
mediated amidation provided 22 and 23 in high yields (Scheme
5). Based on compounds 21, 22, and 23, one of three different
derivatisation pathways were used to access final screening
compounds. Scheme 6 shows one example of each reaction
sequence. To further demonstrate functional group tolerability,
additional compounds were synthesised using these three routes
with varying N-functionalisations. An overview of these
compounds are shown in Scheme 7.
From compound 21, both N-functionalisations were performed in
the same reaction sequence (Scheme 6). First, piperidine
derivatisation was achieved by removal of the Boc-group with TFA
followed by reductive alkylation. Then, benzyl deprotection and
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10.1002/ejoc.201801551
European Journal of Organic Chemistry
FULL PAPER
1) TFA, CH2Cl2, 20 °C, 1 h
2) valeraldehyde, NaBH(OAc)3
CH2Cl2, 20 °C, 1 h
Me
Me
3) 5% Pd/C, HCOONH4
MeOH, reflux, 1.5 h
S
1) LiOH, MeOH/H2O, 80 °C
2) morpholine, TBTU, DIPEA
CH2Cl2, 20 °C, 30 min
H
H
S
N
N
4) thiophene-2-carbonylchloride
DIPEA, DMF, 20 °C, 18 h
N
N
O
H
O
O
H
O
R1 = MeO
Et
Et
MeO
N
O
O
O
24, 77%
25, 60%
Me
H
1) 5% Pd/C, HCOONH4
MeOH, reflux, 1.5 h
N
N
O
O
1) TFA, CH2Cl2, 20 °C, 1 h
2) 1-butanesulfonylchloride,
DIPEA, DMF, 20 oC, 1 h
S
H
H
2) benzaldehyde, NaBH(OAc)3
DMF, 20 °C, 16 h
NBoc
NBoc
N
BnN
H
N
N
O
H
H
O
O
R1 = (CH2)4N
Et
Et
R1
N
N
O
O
O
21: R1 = MeO
22: R1 = (CH2)4N
23: R1 = i-PrHN
26, >95%
27, 93%
1) 5% Pd/C, HCOONH4
MeOH, reflux, 1.5 h
1) TFA, CH2Cl2, 20 °C, 1 h
2) benzoyl chloride, DIPEA,
DMF, 20 °C, 18 h
O
H
O
N
H
2) cyclopropanesulfonylchloride,
DIPEA, DMF, 20 oC, 1 h
N
BnN
O
S
N
H
O
R1
= i-PrHN
H
O
O
i-PrHN
Et
O
i-PrHN
O
28, 85%
29, 75%
Scheme 6: Library C scaffold diversification through ester amidation and N-functionalization of pyrrolidine and piperidine rings. Orthogonal protecting
groups allowed for variation in the order of functionalizations which is exemplified by three different routes. All compounds in library C were synthesised
using one of these three overall derivatisation pathways.
boronic acid building block or the R3 substituent on the aldehyde,
we could access the core structures for libraries A–C. By judicious
selection of the protecting group strategy in the initial step, we
executed the synthesis of the libraries with a wide variety of
different functional groups, thus providing a method to access an
expansive set of natural product-like and sp3-rich compounds for
6
4
biological testing. 2,188 of these have been included in the ELF
Joint European Compounds Library.
2
Experimental Section
0
-2
All reagents and solvents were purchased from commercial
suppliers and used without further purification. All solvents used
were of HPLC-grade, which predominantly were used without
further drying. Unless otherwise stated, reactions were run as
open-system reactions, using only a loosely fitted plastic plug in
order to avoid contamination of the reaction mixture. Reaction
products have been purified using flash column chromatography
or preparative high-performance liquid chromatography (prep-
HPLC). Reactions were routinely monitored using thin layer
chromatography (TLC), ultra-performance liquid-chromatography
mass-spectrometry (UPLC-MS) and/or high performance liquid-
chromatography with UV detection (HPLC-UV). Analytical TLC
was performed using Merck aluminum sheets covered with silica
(C60). The plates were visualized using UV light and/or a KMnO4
staining solution (3 g in water (300 mL), K2CO3 (20 g) and 5% aq
NaOH (5 mL)) followed by heating. Analytical UPLC-MS (ESI)
350
400
450
MW (Da)
500
550
600
Figure 2: Physical chemical property analysis of the compounds reported
here (red) compared to entire library of 2,188 high-throughput screening
compounds synthesised for the European Lead Factory (blue).
Conclusions
In conclusion, we were able to construct a compact functionalized
scaffold as a single diastereomer in one step from allylic amines,
furylboronic acids, and α-hydroxylated aldehydes by employing a
highly diastereoselective 3-component Petasis/Diels-Alder
tandem reaction. By simply varying the N-substituent on the
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10.1002/ejoc.201801551
European Journal of Organic Chemistry
FULL PAPER
was performed on a S2 Waters ACQUITY RPUPLC system
equipped with a diode array detector using an ACQUITY UPLC
BEH C18 column (d 1.7 µm, 2.1 x 50mm; column temp: 65 °C;
flow: 0.6 mL/min), as well as a SQD ESI MS detector. Eluents A1
(0.1% HCOOH in H2O), A2 (0.1% NH4COOCH3), B1 (0.1%
HCOOH in MeCN) and B2 (0.1% NH4COOCH3 in MeCN) were
used in a linear gradient 5% B1/B2 to 100% B1/B2 in a total run
time of 2.6 min. Analytical LC-HRMS (ESI) analysis was
performed on an Agilent 1100 RP-LC system equipped with a
diode array detector using a Phenomenex Luna C18 column (d 3
µm, 2.1 x 50 mm; column temp: 40 °C; flow: 0.4 mL/min).
Eluents A (0.1% HCOOH in H2O) and B (0.1% HCOOH in MeCN)
were used in a linear gradient (20% B to 100% B) in a total run
time of 15 min. The LC system was coupled to a Micromass LCT
orthogonal time-of-flight mass spectrometer equipped with a Lock
Mass probe operating in positive electrospray mode. Flash
column chromatography was achieved using a glass column
packed with Merck Geduran® 60 silica gel (40- 63 μm particles)
as stationary phase, and liquid phase as specified in the individual
experimental.
H
H
NR1
NR1
R2N
BnN
H
O
H
O
Et
3R4RN
MeO
O
41-93%
21
O
Me
Me
Me
Me
Me
S
H
H
H
H
H
S
S
S
S
N
N
N
N
N
N
N
N
N
H
N
O
O
Me
H
H
O
O
H
O
O
O
O
H
O
O
Et
Et
Et
Et
Et
MeO
H2N
N
N
HN
24a
O
MeO
32b
O
O
25b
O
30b
O
31b
O
Me
Me
t-Bu
O
N
N
t-Bu
O
N
O
N
N
NH
N
N
O
O
O
O
Me
H
H
H
O
S
H
H
N
N
N
N
N
N
N
H
O
H
O
H
O
H
O
H
O
Et
Et
Et
N
Et
N
N
N
26c
34d
N
O
22a
O
O
27d
O
33d
O
Me
N
t-Bu
O
t-Bu
O
N
O
O
H
O
O
H
H
O
H
S
i-PrHN
N
H
N
i-PrHN
i-PrHN
N
i-PrHN
N
N
H
N
N
N
N
O
O
H
O
H
O
O
H
O
O
Et
H
O
O
Et
N
Et
i-PrHN
N
Et
36e
23a
N
O
O
N
O
35c
37e
O
38e
O
Me
H
O
O
O
O
O
O
S
H
H
H
H
Me
HN
O
N
N
N
N
N
N
O
S
N
N
H
N
N
H
O
H
O
O
H
O
H
O
O
Et
Et
Et
i-PrHN
i-PrHN
i-PrHN
i-PrHN
i-PrHN
29g
41f
28f
40g
39g
O
O
O
O
O
H
N
O
O
S
O
O
O
Me
N
O
S
S
Me
H
H
Me
S
H
Me
N
N
N
N
N
H
O
H
O
O
H
O
O
Et
Et
i-PrHN
i-PrHN
Et
43h
-PrHN
i
O
42h
O
44h
O
Scheme 7: Functional group tolerability in functionalization of library C. From 21, 23 screening compounds were synthesised with varying R1-R5
substituents. Compounds were synthesised using one of the three derivatisation pathways depicted in Scheme 6. Yields of final compounds were 41–
93% over 2 steps. See appendix for reagents and conditions. a synthesised from 21; b synthesised from 24; c synthesised from 22; d synthesised from 22;
e synthesised from 35; f synthesised from 23; g synthesised from 28; h synthesised from 41.
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10.1002/ejoc.201801551
European Journal of Organic Chemistry
FULL PAPER
Amine (0.53 mmol) was dissolved in MeOH (5 mL, 0.1 M).
Aldehyde (0.79 mmol), AcOH (45 µL, 0.79 mmol), and sodium
cyanoborohydride (50 mg, 0.79 mmol) were added to the solution.
The reaction was stirred for 16 hours at 20 °C. The reaction was
concentrated and partitioned between sat. aq. NaHCO3 (25 mL)
and CH2Cl2 (25 mL). The two phases were separated and the
aqueous phase extracted with CH2Cl2 (2 x 25 mL). The combined
organic phases were dried over sodium sulfate anhydrous, filtered
and concentrated. The crude was purified by flash column
chromatography to provide the alkylated amine.
1
All purified compounds have been routinely characterized by H
NMR, 13C NMR, RP-UPLC-MS, and RP-HPLC-UV. Novel
compounds were further characterized via HRMS. NMR spectra
were recorded on a Bruker Ascend spectrometer with a Prodigy
cryoprobe (operating at 400 MHz for 1H NMR and at 101 MHz for
13C NMR), and analyzed via the NMR software MestReNova
(version 6.2.1-7569) released by Mestrelab Research S.L. The
chemical shifts (δ) are reported in parts per million (ppm) and the
coupling constants (J) in Hz. The majority of the spectra have
been recorded in CDCl3, and the signals were adjusted relative to
this position (δ 7.26 ppm for 1H NMR and δ 77.2 ppm for 13C NMR).
For spectra recorded in DMSO-d6, the signals were adjusted
General Method E. Reductive amination conditions
Amine (1.39 mmol) was dissolved in CH2Cl2 (7 mL). Aldehyde
(1.74 mmol, 1.25 equiv.) was added followed by NaBH(OAc)3
(426 mg, 2.01 mmol, 1.5 equiv.). The mixture was stirred 1 h at
20 °C and then purified directly using flash column
chromatography.
1
relative to the DMSO signal (δ 2.5 ppm for H NMR and δ 39.5
ppm for 13C NMR). For spectra recorded in CD3OD, signal were
adjusted relative to this position (δ 3.31 ppm for H NMR and δ
49.00 ppm for 13C NMR).Compounds have been drawn and
named through use of the visualization software ChemDraw Ultra
14.0 released by PerkinElmer Informatics. Molecular- and exact
masses have been calculated via this program as well.
1
General Method F. Boc deprotection of amines
Boc protected amine (0.19 mmol) was dissolved in a 3:1 mixture
of DCM and TFA (0.1 M, 1.5 mL). The reaction was stirred for 1 h
at 20 °C and then concentrated under reduced pressure. The
crude was solubilized in ethyl acetate (20 mL) and washed with
sat. aq. NaHCO3 (2 x 15 mL), dried over sodium sulfate anhydrous,
filtered and concentrated. The crude was used directly in the next
step without further purification.
General Method A. Mitsunobu conditions for arylation of
alcohols
Alcohol (0.19 mmol), 5-hydroxy-2-methylpyridine (25 mg, 0.23
mmol) and triphenylphosphine (60 mg, 0.23 mmol) was dissolved
in dry THF (2 mL, 0.1 M) under nitrogen atmosphere and cooled
to 0 °C.DEAD (131 µL of a 40% toluene solution, 0.29 mmol) was
added dropwise and then warmed slowly to 20 °C where it was
stirred for 16 hours. The reaction was concentrated, and the crude
was purified by flash column chromatography.
General Method G. Acylation of amines using isocyanate
Amine (0.05 mmol) was dissolved in 1 mL of DMF. Isopropyl
isocyanate (0.06 mmol) was added and stirred 18 h at 20 °C. The
reaction mixture was diluted with 1 mL of DMF and purified by
preparative HPLC to give the desired acylated amine.
General Method H. Acylation of amines using acid chlorides
General Method B. Hydrogenation conditions for
deprotection of benzyl groups and/or for the reduction of
olefins
Amine (0.07 mmol) was dissolved in 1 mL of DMF. DIPEA (36 µL,
0.21 mmol) and acid chloride (0.077 mmol) was added, and the
reaction stirred 18 h at 20 °C. The reaction mixture was diluted
with 1 mL of DMF and purified by preparative HPLC to give the
desired compound.
Benzylamine or olefin (2.56 mmol) was dissolved in MeOH (9 mL,
0.3 M) and added Pd/C (5 wt% Pd/C (10%), 0.13 mmol) and
HCOONH4 (12.8 mmol, 5 equiv.) and the mixture was stirred 1.5
h at reflux. The reaction mixture was then filtered using celite and
the filtrate was concentrated in vacuo. The residue was added
CH2Cl2 (30 mL), H2O (20 mL) and sat. NaHCO3 (aq.) (10 mL) and
the layers were separated. The aqueous phase was extracted
with CH2Cl2 (2x 30 mL) and the combined organic layers were
dried over Na2SO4 and concentrated in vacuo to give the reduced
compound.
General Method I. Acylation of amines using acid chlorides
Methyl ester (6.96 mmol) was dissolved in MeOH:H2O (24 mL,
2:1) and added LiOH (500 mg, 20.9 mmol, 3 equiv.) and the
mixture was stirred 5 h at 80 °C. The mixture was cooled to 20 °C
and added H2O (40 mL) and ether (30 mL) and the layers were
separated. The organic layer was extracted with 1 M NaOH (20
mL) and the combined aqueous phases were combined and
acidified (pH = 6). The aqueous phase was then extracted with
CH2Cl2 (3 x 60 mL) and the combined organic layers were dried
over Na2SO4 and concentrated in vacuo. The crude extract was
used in the next step without further purification.
General Method C. Hydrogenation conditions for
deprotection of benzyl groups and/or for the reduction of
olefins
Benzyl amine or olefin (2.05 mmol) was dissolved in EtOH:H2O
(10:1, 20 mL, 0.1 M). Pd/C (109 mg of 10% Pd/C, 0.103 mmol)
was added and stirred at 60 oC under a hydrogen gas atmosphere
for 28 hours. The reaction mixture was filtered through a celite
pad and the filtrate was concentrated.
General Method J. Amide formation from carboxylic acids
Carboxylic acid (3.47 mmol) was dissolved in CH2Cl2 (11 mL, 0.3
M) and added DIPEA (0.91 mL, 5.21 mmol, 1.5 equiv.) followed
by TBTU (1.23 g, 3.82 mmol, 1.1 equiv.) and the mixture was
stirred at 20 °C. After 5 min, amine (6.96 mmol, 2 equiv) was
added and the mixture was stirred for another 30 min. The mixture
General Method D. Reductive amination conditions
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10.1002/ejoc.201801551
European Journal of Organic Chemistry
FULL PAPER
was then concentrated and purified by flash column
chromatography to provide the desired amide product.
mixture was again concentrated in vacuo. (NOTE: done to ensure
full removal of allyl amine before step 2).
The crude was dissolved in CH2Cl2 (150 mL, 0.4 M), added Et3N
(20 mL, 143 mmol, 2 equiv.) followed by Boc2O (15.6 g, 71 mmol)
dissolved in CH2Cl2 (30 mL) and the mixture was stirred 1 h at
20 °C. Then sat. aq. NaHCO3 (200 mL) was added and the layers
were separated. The aqueous phase was extracted with CH2Cl2
(2x100 mL) and the combined organic layers were dried over
sodium sulfate anhydrous, concentrated to 100 mL and used
directly in the next step without further purification.
General Method K. Sulfonylation of amines
Amine (1.49 mmol) was dissolved in CH2Cl2 (8 mL), added Et3N
(312 µL, 2.24 mmol, 1.5 equiv.) and cooled to 0 °C. The mixture
was added sulfonyl chloride (1.79 mmol, 1.2 equiv.), and the
mixture was stirred 1 h at 0 °C and then purified directly using
flash column chromatography to give the desired sulfonylated
amine.
Synthesis of aldehyde building block
2-Hydroxypent-4-enoic acid 5 (S2). To a solution of allyl bromide
(11.3 mL, 131 mmol) in THF:H2O (2:1) (300 mL) at 0 oC was
added glyoxylic acid (8 g, 87 mmol). Then, indium (11 g, 96 mmol)
was added in one portion and the suspension stirred vigorously,
and allowed to reach 20 °C, where it was stirred for more 19 h.
The reaction was quenched by the addition of HCl 1M (350 mL)
and the aqueous phase was extracted with CH2Cl2 (3 x 350
mL). The combined organic layers were dried over sodium sulfate
anhydrous, filtered and concentrated. The crude was distilled
Synthesis of building blocks for library A-C
Synthesis of N-benzylprop-2-en-1-amine
N-Benzylprop-2-en-1-amine (S1). Benzaldehyde (40 g, 38.5 mL,
0.377 mol) was dissolved in MeOH (300 mL, 1.2 M) and allyl
amine was added (43 g, 57 mL, 0.753 mol) (Warning: Exothermic
reaction). After stirring for 5 min, MgSO4 (40 g) was added and
the mixture was stirred 1 h at 20 °C. The mixture was then cooled
to 0 °C and added NaBH4 (15.7 g, 0.415 mmol) portion wise over
30 min (Warning: Very exothermic reaction) and after the last
addition the mixture was stirred for another 30 min. The ice bath
was then removed and the mixture was stirred 1 h at 20 °C. where
upon sat. aq. NaHCO3 (100 mL) was added and the mixture
stirred for more 30 min. The mixture was then filtered and the
volatiles were removed under reduced pressure. The residue was
partitioned between water (100 mL) and EtOAc (200 mL) and the
layers separated. The aqueous phase was extracted with EtOAc
(100 mL) and the combined organic layers were washed with
brine, dried over sodium sulfate, filtered and concentrated in
vacuo to give the title compound as a colorless oil (49 g, 88%)
that was used directly in the next step without further purification.
o
under reduced pressure (2.7 mbar, 120-130 C), to give the title
compound as a colorless oil (4.85 g, 48 %). 1H NMR (400 MHz,
CDCl3) δ 6.12 (broad s, 1H), 5.88 – 5.76 (m, 1H), 5.25 – 5.13 (m,
2H), 4.36 (dd, J = 6.7, 4.5 Hz, 1H), 2.70 – 2.58 (m, 1H), 2.56 –
2.43 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 178.7, 132.1, 119.6,
69.9, 38.5. The data is in accordance with the literature [ACS
Comb. Sci. 2012, 14, 253−257].
5-Allyl-2,2-dimethyl-1,3-dioxolan-4-one (S3). To a solution of 2-
hydroxypent-4-enoic acid (S4) (4.85 g, 41.8 mmol) in acetone (84
mL) was added 2,2-dimethoxypropane (41.1 mL, 334 mmol) and
pyridinium p-toluenesulfonate (5.25 g, 20.9 mmol) and the
reaction stirred at reflux for 2½ h. The reaction was allowed to
cool to 20 °C and filtered through a pad of celite, and the solid
washed with EtOAc (2 x 100 mL). The filtrate was concentrated
and the crude distilled (3-4 mbar, 80 oC), to give the title
compound as colorless oil (5.3 g/33.9 mmol). 1H NMR (400 MHz,
CDCl3) δ 5.79 (ddt, J = 17.1, 10.2, 6.9 Hz, 1H), 5.22 – 5.12 (m,
2H), 4.45 (dd, J = 6.7, 4.4 Hz, 1H), 2.62 (dddt, J = 14.8, 6.9, 4.4,
1.4 Hz, 1H), 2.46 (dtt, J = 14.9, 6.9, 1.3 Hz, 1H), 1.58 (d, J = 0.8
Hz, 3H), 1.52 (d, J = 0.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
172.6, 131.9, 119.2, 110.7, 73.8, 35.8, 27.2, 26.0. The data is in
accordance with the literature [ACS Comb. Sci. 2012, 14,
253−257].
Synthesis of boronic acid building blocks
(5-(((Tert-butoxycarbonyl)(methyl)amino)methyl)furan-2-
yl)boronic acid (3). (5-Formylfuran-2-yl)boronic acid (2) (2.04 g,
14.6 mmol) and methyl amine (33% in ethanol) (3.6 mL, 29.0
mmol) were dissolved in MeOH (36 mL, 0.4 M) and 3 Å molecular
sieves (3 g) were added. The mixture was stirred 1.5 h at 20 °C,
where after the mixture was cooled to 0 °C in an ice bath and
added NaBH4 (0.607 g, 16 mmol) portion wise. After the addition,
the mixture was stirred for 10 min at 0 °C followed by 1 h at 20 °C.
The reaction mixture was concentrated in vacuo and the crude
mixture used directly in the next step.
The crude was dissolved in CH2Cl2 (36 mL, 0.4 M), added Et3N (6
mL, 43.7 mmol, 3 equiv.) followed by Boc2O (3.2 g, 14.6 mmol)
dissolved in CH2Cl2 (8 mL) and the mixture was stirred 30 min at
20 °C. Then sat. aq. NaHCO3 (50 mL) was added and the layers
separated. The aqueous phase was extracted with CH2Cl2 (2x50
mL) and the combined organic layers were dried over sodium
sulfate anhydrous, filtered and concentrated. The crude was used
directly in without further purification.
5-Allyl-2,2-dimethyl-1,3-dioxolan-4-ol (S4). To a solution of 5-allyl-
2,2-dimethyl-1,3-dioxolan-4-one (2.55 g, 16.3 mmol) (S3) in dry
toluene (25 mL) at -78 oC was added dropwise DIBAL-H (24.4 mL
of a 1M DIBAL-H toluene solution, 24.4 mmoL) and after 30 min,
the reaction was quenched with aqueous 1M HCl (30 mL). The
reaction was allowed to warm to 20 °C and stirred for another 30
min, whereupon the reaction mixture was diluted with H2O (100
mL) and extracted with CH2Cl2 (3x 100 mL). The combined
organic layers were dried over sodium sulfate anhydrous and
concentrated to give the title compound as colorless oil which was
used directly in the next step without any purification.
(5-((Allyl(tert-butoxycarbonyl)amino)methyl)furan-2-yl)boronic
acid (4). (5-Formylfuran-2-yl)boronic acid (10 g, 71 mmol) and
allyl amine (16 mL, 214 mmol) were dissolved in MeOH (180 mL,
0.4 M) and 3 Å molecular sieves were added, and the mixture
stirred 1 h at 20 °C. Then, the mixture was cooled to 0 °C in an
ice bath and added NaBH4 (3.0 g, 79 mmol) portion wise. The
mixture was dissolved in CH2Cl2 (50 mL) and Et3N (5 mL) and the
Petasis/Diels-Alder Tandem Reaction in the Synthesis of
Library A-C Scaffold and Library Production
Tert-butyl
2,3,7,7a-tetrahydro-3a,6-epoxyisoindol-6(1H)-
(((3S*,3aR*,6R*,7aR*)-2-benzyl-3-(hydroxymethyl)
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10.1002/ejoc.201801551
European Journal of Organic Chemistry
FULL PAPER
yl)methyl)(methyl)carbamate (5). To
a
solution containing
added, and the mixture was stirred 18 h at 20 °C. (NOTE: the
reaction usually takes around 1 h). Water (200 mL) was added
and the layers were separated. The aqueous phase was extracted
with CH2Cl2 (2 x 100 mL), and the combined organic layers were
dried over Na2SO4 and concentrated in vacuo. The crude was
dissolved in acetone (180 mL, 0.4 M), and K2CO3 (11.9 g, 86
mmol) was added followed by MeI (4.45 mL, 71 mmol). The
mixture was stirred for 4 h at 20 °C. Additional K2CO3 (5.5 g, 40
mmol) and MeI (2.3 mL, 37 mmol) were added, and the mixture
was stirred 16 h at 20 °C. Then EtOAc (200 mL) was added and
was washed with water. The aqueous phase was extracted with
CH2Cl2 (2 x 100 mL), and the combined organic layers were dried
over Na2SO4 and concentrated in vacuo. The residue was purified
by silica plug (EtOAc:heptane 1 : 4) to give the methyl ester as a
yellow oil. (NOTE: It is a lot easier to purify the final compound if
some of the impurities are removed using the silica plug before
the Diels-Alder reaction. Step 5: The compound from step 4 was
taken in MeCN (180 mL) and the mixture was stirred at reflux for
24 h. The mixture was then concentrated in vacuo and purified by
flash column chromatography (EtOAc:heptane 3:7, Rf = 0.2) to
give the title compound as a yellow oil (11.5 g, 44% over 5 steps,
based on allylbenzylamine). 1H NMR (400 MHz, CDCl3) δ 7.36 –
7.10 (m, 5H), 6.27 – 6.02 (m, 2H), 5.79 – 5.58 (m, 1H), 5.11 –
glycolaldehyde dimer (700 mg, 5.85 mmol) and N-
allylbenzylamine (S1) (2.15 mL, 14.6 mmol) dissolved in CH2Cl2
(36 mL, 0.4 M) was added the crude (5-(((tert-
butoxycarbonyl)(methyl)amino)methyl)furan-2-yl)boronic acid (3)
(dissolved in 10 mL CH2Cl2) and the mixture was stirred 1 h at
20 °C. Then, sat. aq. NaHCO3 (50 mL) was added and the layers
were separated. The aqueous phase was extracted with CH2Cl2
(2x 50 mL) and the combined organic layers were dried over
sodium sulfate anhydrous, filtered and concentrated. The crude
was taken in MeCN (36 mL, 0.4 M) and the mixture was stirred at
reflux for 24 h. The mixture was then concentrated and purified by
flash column chromatography (EtOAc:heptane 1:1, Rf = 0.2) to
1
give the title compound as a yellow oil (3.502 g, 75%). H NMR
(400 MHz, CDCl3) δ 7.31 – 7.12 (m, 5H), 6.49 (d, J = 5.8 Hz, 1H),
6.18 (d, J = 5.8 Hz, 1H), 3.93 (d, J = 13.7 Hz, 2H, major rotamer),
3.74 (d, J = 11.4 Hz, 1H), 3.70 – 3.54 (m, 3H), 3.48 (d, J = 13.7
Hz, 2H, minor rotamer), 3.17 (t, J = 7.7 Hz, 1H), 2.96 (s, 1H), 2.86
(s, 3H), 2.17 (dd, J = 10.6, 8.7 Hz, 1H), 1.91 (dtd, J = 10.3, 6.9,
6.5, 2.9 Hz, 1H), 1.41 (s, 9H), 1.40 – 1.22 (m, 2H). 13C NMR (101
MHz, CDCl3) δ 156.4 (major rotamer), 155.7 (minor rotamer),
138.4 (major rotamer), 138.4 (minor rotamer), 136.9 (major
rotamer), 136.6 (minor rotamer), 136.4 (major rotamer), 136.1
(minor rotamer), 129.0, 128.6 (2 carbons), 127.5 (2 carbons), 98.9, 4.94 (m, 2H), 3.95 – 3.80 (m, 2H), 3.81 – 3.61 (m, 4H), 3.56 (s,
92.4 (major rotamer), 91.8 (minor rotamer), 79.9 (minor rotamer),
79.6 (major rotamer), 65.8 (major rotamer), 65.7 (minor rotamer),
59.7, 58.7, 58.5, 50.6 (minor rotamer), 49.8 (major rotamer), 45.2,
36.0 (major rotamer), 35.9 (minor rotamer), 32.6 (major rotamer),
32.5 (minor rotamer), 28.5 (3C). HRMS (ESI) calcd for
C23H33N2O4 [M+H+] 401.2435, found 401.2468.
3H), 3.49 (s, 1H), 3.51 – 3.42 (m, 1H), 3.26 (t, J = 7.0 Hz, 1H),
2.24 – 2.08 (m, 2H), 1.38 (s, 9H), 1.35 – 1.27 (m, 1H); 13C NMR
(101 MHz, CDCl3) δ 172.3, 156.2, 138.0, 137.3, 135.3, 134.0,
129.5, 128.3 (2C), 127.4 (2C), 116.0, 98.3, 92.8, 79.8, 67.7, 59.5,
58.6, 52.1, 50.5, 47.4, 45.3, 32.2, 28.5 (major rotamer, 3C).
HRMS (ESI) calcd for C26H35N2O5 [M+H+] 455.2540, found
455.2575.
Tert-butyl (((3S*,3aR*,6R*,7aR*)-2-benzyl-3-((S*)-1-hydroxybut-
3-en-1-yl)-2,3,7,7a-tetrahydro-3a,6-epoxyisoindol-6(1H)-
Tert-butyl
(((3S*,3aR*,6R*,7aR*)-2-benzyl-3-((2-
yl)methyl)(methyl)carbamate (6). To a solution of 5-allyl-2,2-
dimethyl-1,3-dioxolan-4-ol (S4) (1.1g, 7.0 mmol) and N-
allylbenzylamine (S1) (0.93 g, 6.3 mmol) in CH2Cl2 (36 mL, 0.4 M)
was added (5-(((tert-butoxycarbonyl)(methyl)amino)methyl)furan-
2-yl)boronic acid (3) (1.86 g, 7.3 mmol), dissolved in 10 mL
CH2Cl2) and the mixture was stirred 1 h at 20 °C. Sat. aq. NaHCO3
(50 mL) was then added and the layers were separated. The
aqueous phase was extracted with CH2Cl2 (2x 50 mL) and the
combined organic layers were dried over sodium sulfate
anhydrous, filtered and concentrated. The crude was taken in
acetonitrile (18 mL, 0.4 M) and the mixture was stirred at reflux for
24 h. The mixture was then concentrated and purified by flash
column chromatography (EtOAc/heptane, 1:3, Rf = 0.25) to give
the desired compound as a clear yellow oil (0.68 g, 31%). 1H NMR
(400 MHz, CDCl3) δ 7.37 – 7.25 (m, 5H), 6.76 (dd, J = 10.2, 5.7
Hz, 1H), 6.13 (dd, J = 11.8, 5.7 Hz, 1H), 5.97 – 5.79 (m, 1H), 5.19
– 5.06 (m, 2H), 4.07 – 3.38 (m, 5H), 3.16 (br. s, 1H), 3.07 – 2.77
(m, 5H, two rotamers), 2.68 – 2.52 (m, 1H), 2.51 – 2.32 (m, 1H),
2.11 (t, J = 9.6 Hz, 1H), 1.92 (br. s, 1H), 1.47 (s, 9H), 1.41 – 1.30
(m, 2H). 13C NMR (101 MHz, CDCl3) δ 156.4 (major rotamer),
155.8 (minor rotamer), 138.9, 137.4 (minor rotamer), 137.2 (major
methoxyphenoxy)methyl)-2,3,7,7a-tetrahydro-3a,6-
epoxyisoindol-6(1H)-yl)methyl)(methyl)carbamate (8). General
Method A was applied to tert-butyl (((3S*,3aR*,6R*,7aR*)-2-
benzyl-3-(hydroxymethyl)-2,3,7,7a-tetrahydro-3a,6-
epoxyisoindol-6(1H)-yl)methyl)(methyl)carbamate (5) (1.00 g,
2.49 mmol) and 2-methoxyphenol (335 µL, 3mmol). The reaction
was concentrated and the crude was purified by flash column
chromatography (EtOAc/heptane 4:1, Rf = 0.2) to give the desired
compound as a colorless oil (762 mg, 60 %). 1H NMR (400 MHz,
CDCl3) δ 7.43 – 7.36 (m, 2H), 7.36 – 7.29 (m, 2H), 7.29 – 7.23 (m,
1H), 7.00 – 6.88 (m, 4H), 6.61 (dd, J = 10.0, 5.7 Hz, 1H), 6.26 (dd,
J = 18.8, 5.8 Hz, 1H), 4.20 – 4.06 (m, 3H), 3.83 (s, 3H), 3.81 –
3.70 (m, 2H), 3.36 (dd, J = 6.6, 4.9 Hz, 1H), 3.25 (dd, J = 7.8, 6.2
Hz, 1H), 2.99 (d, J = 7.7 Hz, 3H), 2.32 – 2.13 (m, 2H), 1.58 – 1.28
(m, 12H). 13C NMR (101 MHz, CDCl3) δ 156.3 (major rotamer),
155.7 (minor rotamer), 150.2, 148.6, 139.6 (major rotamer), 139.4
(minor rotamer), 136.4 (major rotamer), 136.1 (minor rotamer),
136.0 (major rotamer), 135.7 (minor rotamer), 129.0 (minor
rotamer), 128.9 (major rotamer), 128.3 (2C), 127.0 (2C), 121.8,
121.0, 115.1 (major rotamer), 115.0 (minor rotamer), 112.64
(major rotamer), 112.59 (minor rotamer), 98.4, 92.0 (major
rotamer), 135.0, 134.8, 128.9, 128.6 (2C), 127.4 (2C), 117.6, 97.6, rotamer), 91.5 (minor rotamer), 79.7 (major rotamer), 79.4 (minor
91.6 (major rotamer), 91.1 (minor rotamer), 79.8 (major rotamer),
79.6 (minor rotamer), 69.7, 69.3, 58.7, 58.3, 50.5 (minor rotamer),
49.6 (major rotamer), 45.7, 37.0, 35.9, 32.5, 28.6 (3C). HRMS
(ESI) calcd for C26H37N2O4 [M+H+] 441.2748, found 441.2770.
rotamer), 70.4 (major rotamer), 70.2 (minor rotamer), 63.7 (major
rotamer), 63.6 (minor rotamer), 59.9 (major rotamer), 59.1 (minor
rotamer), 56.1, 50.5, 49.7, 44.2, 35.9 (major rotamer), 35.8 (minor
rotamer), 32.4, 28.53 (minor rotamer, 3C), 28.48 (major rotamer,
3C). HRMS (ESI) calcd for C30H39N2O5 [M+H+] 507.2853, found
507.2858.
Methyl
butoxycarbonyl)amino)methyl)-2-benzyl-1,2,3,6,7,7a-hexahydro-
3a,6-epoxyisoindole-3-carboxylate (7). Glyoxylic acid
(3R*,3aR*,6R*,7aR*)-6-((allyl(tert-
1-((3S*,3aR*,6S*,7aR*)-2-benzyl-3-((2-
monohydrate (6.6 g, 71 mmol) and N-allylbenzylamine (8.42 mL,
57 mmol) was dissolved in CH2Cl2 (100 mL). (5-((allyl(tert-
butoxycarbonyl)amino)methyl)furan-2-yl)boronic acid (4) was
Methoxyphenoxy)methyl)hexahydro-3a,6-epoxyisoindol-6(1H)-
yl)-N-methylmethanamine (S5). General Method F was applied
to
tert-butyl
(((3S*,3aR*,6R*,7aR*)-2-benzyl-3-((2-
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10.1002/ejoc.201801551
European Journal of Organic Chemistry
FULL PAPER
methoxyphenoxy)methyl)-2,3,7,7a-tetrahydro-3a,6-
reaction mixture was purified by preparative HPLC to give the
desired compound as an amorphous white solid (24 mg, 65 %
over three steps). H NMR (400 MHz, CDCl3) δ 7.61 – 7.51 (m,
epoxyisoindol-6(1H)-yl)methyl)(methyl)carbamate (8) (418 mg,
0.825 mmol). The crude mixture was purified by flash column
chromatography (CH2Cl2/MeOH with 5 % of NH4OH (25 % aq.)
95:5, Rf = 0.25) to give the desired compound as a white solid
(241 mg, 72 %). 1H NMR (400 MHz, CDCl3) δ 7.40 – 7.36 (m, 2H),
7.34 – 7.20 (m, 3H), 7.02 – 6.86 (m, 4H), 6.60 (d, J = 5.8 Hz, 1H),
6.30 (d, J = 5.8 Hz, 1H), 4.16 (d, J = 13.0 Hz, 1H), 4.13 – 4.05 (m,
2H), 3.82 (s, 3H), 3.73 (d, J = 12.9 Hz, 1H), 3.36 (dd, J = 6.5, 4.8
Hz, 1H), 3.24 (dd, J = 7.7, 6.1 Hz, 1H), 3.15 (d, J = 12.6 Hz, 1H),
3.06 (d, J = 12.5 Hz, 1H), 2.53 (s, 3H), 2.34 – 2.18 (m, 2H), 1.69
– 1.63 (br. s, 1H), 1.59 (dd, J = 11.3, 2.6 Hz, 1H), 1.40 (dd, J =
11.3, 7.1 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 150.2, 148.6,
139.7, 136.7, 135.5, 129.0, 128.3 (2C), 127.0 (2C), 121.7, 121.0,
114.9, 112.6, 98.4, 90.7, 70.3, 63.7, 60.0, 59.0, 56.1, 54.4, 44.4,
37.2, 32.8. HRMS (ESI) calcd for C25H31N2O3 [M+H+] 407.2329,
found 407.2328.
1
1H), 7.48 (d, J = 5.0 Hz, 1H), 7.12 – 7.01 (m, 1H), 6.96 – 6.78 (m,
4H), 4.88 (s, 1H), 4.64 (td, J = 10.2, 9.7, 3.2 Hz, 1H), 4.31 (t, J =
9.5 Hz, 1H), 4.09 (dd, J = 10.0, 2.0 Hz, 1H), 3.86 – 3.63 (m, 5H),
3.37 (q, J = 8.9 Hz, 1H), 3.27 – 3.11 (m, 1H), 3.07 (s, 2.3H, major
rotamer), 2.98 (s, 0.7H, minor rotamer), 2.11 (s, 2.3H, major
rotamer), 2.10 (s, 0.7H, minor rotamer), 2.06 – 1.86 (m, 3H), 1.74
– 1.46 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 171.30 (major
rotamer), 171.28 (minor rotamer), 161.9, 149.6, 148.3, 139.5,
130.3, 130.2, 127.4, 121.5, 121.1, 113.5, 112.1, 93.4 (minor
rotamer), 93.3 (major rotamer), 88.3 (major rotamer), 87.9 (minor
rotamer), 66.9, 61.3 (major rotamer), 61.1 (minor rotamer), 56.9
(major rotamer), 56.7 (minor rotamer), 56.0 (major rotamer), 53.4
(minor rotamer), 49.3, 46.9 (minor rotamer), 46.8 (major rotamer),
42.1 (major rotamer), 41.6 (minor rotamer), 37.9 (major rotamer),
35.5 (minor rotamer), 32.3 (minor rotamer), 31.9 (major rotamer),
28.6, 21.9 (minor rotamer) 21.8 (major rotamer). HRMS (ESI)
calcd for C25H31N2O5S [M+H+] 471.1948, found 471.1948.
N-(((3S*,3aR*,6S*,7aR*)-2-(Cyclohexylmethyl)-3-((2-
methoxyphenoxy)methyl)hexahydro-3a,6-epoxyisoindol-6(1H)-
yl)methyl)-N-methylacetamide (9). General Method
H was
applied to 1-((3S*,3aR*,6S*,7aR*)-2-benzyl-3-((2-
N-(((3S*,3aR*,6S*,7aR*)-3-((2-Methoxyphenoxy)methyl)-2-
(methylsulfonyl)hexahydro-3a,6-epoxyisoindol-6(1H)-yl)methyl)-
N-methylacetamide (11). General Method H was applied to 1-
((3S*,3aR*,6S*,7aR*)-2-benzyl-3-((2-
methoxyphenoxy)methyl)hexahydro-3a,6-epoxyisoindol-6(1H)-
yl)-N-methylmethanamine (S5) (131 mg, 0.32 mmol) and acetyl
chloride (28 µL, 0.39 mmol) then the crude (145 mg, 0.32 mmol)
was subjected to conditions in General Method B. General
Method D was then applied to the crude (38 mg, 0.09 mmol) and
cyclohexanecarbaldehyde (14 µL, 0.11 mmol). The reaction
mixture was purified directly by preparative HPLC to give the
desired compound as a colorless oil (28.2 mg, 66% over three
steps). 1H NMR (400 MHz, CDCl3) δ 6.94 – 6.85 (m, 4H), 4.02 –
3.84 (m, 3H), 3.83 (s, 3H), 3.62 – 3.49 (m, 1H), 3.23 – 3.14 (m,
2H), 3.13 (s, 2H, major rotamer), 3.03 (s, 1H, minor rotamer), 2.59
(td, J = 11.8, 9.3 Hz, 1H), 2.45 – 2.31 (m, 2H), 2.12 (s, 2H, major
rotamer), 2.11 (s, 1H, minor rotamer), 2.02 – 1.34 (m, 13H), 1.30
– 1.04 (m, 3H), 0.95 – 0.67 (m, 2H). 13C NMR (101 MHz, CDCl3)
δ 171.4 (minor rotamer), 171.2 (major rotamer), 149.8, 148.7
(major rotamer), 148.6 (minor rotamer), 121.34 (minor rotamer),
121.31 (major rotamer), 120.97 (major rotamer), 120.95 (minor
rotamer), 113.83 (major rotamer), 113.77 (minor rotamer), 112.3,
96.0 (minor rotamer), 95.8 (major rotamer), 88.1 (major rotamer),
87.6 (minor rotamer), 70.0 (major rotamer), 69.8 (minor rotamer),
65.7 (major rotamer), 65.5 (minor rotamer), 63.3 (major rotamer),
63.1 (minor rotamer), 59.9 (major rotamer), 59.7 (minor rotamer),
56.1 (major rotamer), 53.6 (minor rotamer), 49.3, 47.01 (major
rotamer), 46.96 (minor rotamer), 37.7 (major rotamer), 37.62
(major rotamer), 37.59 (minor rotamer), 36.98 (major rotamer),
methoxyphenoxy)methyl)hexahydro-3a,6-epoxyisoindol-6(1H)-
yl)-N-methylmethanamine (S5) (131 mg, 0.32 mmol) and acetyl
chloride (28 µL, 0.39 mmol) then the crude (145 mg, 0.32 mmol)
was subjected to conditions in General Method B. General
Method K was then applied to the crude (32.3 mg, 0.09 mmol)
and methanesulfonyl chloride (8 µL, 0.11 mol). The reaction
mixture was purified by preparative HPLC to give the desired
compound as an amorphous white solid (24 mg, 61 % over three
steps). 1H NMR (400 MHz, CDCl3) δ 6.97 – 6.83 (m, 4H), 4.26 –
4.08 (m, 3H), 3.89 – 3.63 (m, 6H), 3.09 (s, 2.2H, major rotamer),
3.00 (s, 0.8H, minor rotamer), 2.99 – 2.88 (m, 1H), 2.84 (d, J =
8.4 Hz, 4H), 2.12 (s, 2.2H, major rotamer), 2.10 (s, 0.8H, minor
rotamer), 1.93 (tdd, J = 15.3, 10.2, 6.5 Hz, 3H), 1.73 – 1.45 (m,
3H). 13C NMR (101 MHz, CDCl3) δ 171.2, 149.64 (major rotamer),
149.60 (minor rotamer), 148.05 (major rotamer), 148.03 (minor
rotamer), 121.7, 121.11 (minor rotamer), 121.05 (major rotamer),
113.5, 112.22 (minor rotamer), 112.19 (major rotamer), 95.3
(minor rotamer), 95.1 (major rotamer), 88.7 (major rotamer), 88.2
(minor rotamer), 69.7 (minor rotamer), 69.5 (major rotamer), 62.0
(major rotamer), 61.9 (minor rotamer), 56.07 (major rotamer),
56.05 (minor rotamer), 55.98 (major rotamer), 55.8 (minor
rotamer), 53.4 (minor rotamer), 49.4 (major rotamer), 46.40
36.95 (minor rotamer), 35.5 (minor rotamer), 32.9 (major rotamer), (minor rotamer), 46.35 (major rotamer ), 40.9 (major rotamer),
32.7 (minor rotamer), 32.22 (major rotamer), 32.17 (minor
rotamer), 31.60 (minor rotamer), 31.58 (major rotamer), 28.80
(minor rotamer), 28.78 (major rotamer), 26.95 (major rotamer),
26.94 (minor rotamer), 26.28 (major rotamer), 26.25 (minor
rotamer), 26.1, 21.84 (minor rotamer), 21.82 (major rotamer).
HRMS (ESI) calcd for C27H41N2O4 [M+H+] 457.3061, found
457.3071.
40.7 (minor rotamer), 37.8 (major rotamer), 35.8 (minor rotamer),
34.5 (major rotamer), 33.9 (minor rotamer), 32.5 (minor rotamer),
32.4 (major rotamer), 28.2, 21.8. HRMS (ESI) calcd for
C21H31N2O6S [M+H+] 439.1897, found 439.1899.
(3S*,3aR*,6S*,7aR*)-N-Cyclopentyl-3-((2-
methoxyphenoxy)methyl)-6-((N-
methylacetamido)methyl)hexahydro-3a,6-epoxyisoindole-2(3H)-
carboxamide (12). General Method H was applied to 1-
((3S*,3aR*,6S*,7aR*)-2-benzyl-3-((2-
N-(((3S*,3aR*,6S*,7aR*)-3-((2-Methoxyphenoxy)methyl)-2-
(thiophene-2-carbonyl)hexahydro-3a,6-epoxyisoindol-6(1H)-
yl)methyl)-N-methylacetamide (10). General Method H was
methoxyphenoxy)methyl)hexahydro-3a,6-epoxyisoindol-6(1H)-
yl)-N-methylmethanamine (S5) (131 mg, 0.32 mmol) and acetyl
chloride (28 µL, 0.39 mmol) then the crude (145 mg, 0.32 mmol)
was subjected to conditions in General Method B. General
Method G was then applied to the crude (40.6 mg, 0.11 mmol)
and cyclopentyl isocyanate (15 μL, 0.135 mmol). The reaction
mixture was purified by preparative HPLC to give the desired
compound as an amorphous white solid (32 mg, 60 % over three
applied
to
1-((3S*,3aR*,6S*,7aR*)-2-benzyl-3-((2-
methoxyphenoxy)methyl)hexahydro-3a,6-epoxyisoindol-6(1H)-
yl)-N-methylmethanamine (S5) (131 mg, 0.32 mmol) and acetyl
chloride (28 µL, 0.39 mmol) then the crude (145 mg, 0.32 mmol)
was subjected to conditions in General Method B. General
Method H was then applied to the crude (28.3 mg, 0.08 mmol)
and thiophene-2-carbonyl chloride (10 µL, 0.09 mmol). The
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10.1002/ejoc.201801551
European Journal of Organic Chemistry
FULL PAPER
steps). 1H NMR (400 MHz, CDCl3) δ 6.96 – 6.79 (m, 4H), 4.78 –
4.19 (m, 3H), 4.12 – 4.01 (m, 1H), 3.98 (ddd, J = 9.7, 5.3, 3.6 Hz,
1H), 3.81 (s, 3H), 3.79 – 3.55 (m, 3H), 3.07 (s, 2.2H, major
rotamer), 2.98 (s, 0.8H, minor rotamer), 2.96 – 2.68 (m, 2H), 2.10
(s, 2.2H, major rotamer), 2.08 (s, 0.8H, minor rotamer), 2.02 –
1.78 (m, 5H), 1.69 – 1.51 (m, 6H), 1.46 (dt, J = 12.0, 3.1 Hz, 1H),
1.40 – 1.25 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 171.24 (minor
rotamer), 171.17 (major rotamer), 157.1 (major rotamer), 156.8
(minor rotamer), 149.5 (major rotamer), 149.4 (minor rotamer),
148.23 (minor rotamer), 148.19 (major rotamer), 121.5 (major
rotamer), 121.4 (minor rotamer), 121.1 (minor rotamer), 121.1
(major rotamer), 113.6 (major rotamer), 113.4 (minor rotamer),
112.0, 94.3 (minor rotamer), 94.1 (major rotamer), 88.3 (major
rotamer), 87.8 (minor rotamer), 60.0 (major rotamer), 59.8 (minor
rotamer), 56.0 (minor rotamer), 55.9 (major rotamer), 53.7 (major
rotamer), 53.4 (minor rotamer), 53.3, 52.4 (major rotamer), 52.3
(minor rotamer), 49.2, 46.0 (minor rotamer), 45.7 (major rotamer),
41.0 (major rotamer), 40.7 (minor rotamer), 37.8, 35.5, 33.7
(minor rotamer), 33.6 (major rotamer), 32.3 (minor rotamer), 32.0
(major rotamer), 28.7 (major rotamer), 28.6 (minor rotamer), 23.8
(major rotamer), 23.71 (minor rotamer), 23.69, 21.83 (minor
rotamer), 21.79 (major rotamer). HRMS (ESI) calcd for
C26H38N3O5 [M+H+] 472.2806, found 472.2809.
(m, 2H), 3.03 – 2.96 (m, 1H), 2.98 (s, 3H), 2.90 – 2.79 (m, 4H),
1.98 – 1.82 (m, 3H), 1.85 – 1.71 (m, 2H), 1.70 – 1.58 (m, 1H),
1.55 – 1.40 (m, 2H), 1.36 – 1.17 (m, 6H), 0.90 – 0.81 (m, 3H); 13
C
NMR (101 MHz, CDCl3) δ 157.5, 149.4, 148.2, 121.5, 121.1,
113.1, 111.9, 94.5, 87.7, 68.8, 60.0, 56.0, 53.6, 52.3, 45.8, 40.9,
40.7, 36.9, 35.3, 32.3, 31.7, 30.4, 28.7, 26.8, 22.7, 14.2. HRMS
(ESI) calcd for C26H42N3O5S [M+H+] 524.2789, found 524.2792.
Tert-butyl
(((3S*,3aR*,6S*,7aR*)-2-(2-fluorobenzyl)-3-
(hydroxymethyl)hexahydro-3a,6-epoxyisoindol-6(1H)-
yl)methyl)(methyl)carbamate (15). General Method
B was
applied
to
tert-butyl
(((3S*,3aR*,6R*,7aR*)-2-benzyl-3-
(hydroxymethyl)-2,3,7,7a-tetrahydro-3a,6-epoxyisoindol-6(1H)-
yl)methyl)(methyl)carbamate (5) (1.03g, 2.56 mmol) and then the
crude (165 mg, 0.53 mmol) and 2-fluorobenzaldehyde (83 µL,
0.79 mmol) were subjected to General Method D. The
benzylated compound was purified by flash column
chromatography (CH2Cl2/MeOH with 5 % of NH4OH (25 % aq)
98:2, Rf = 0.25) to give the title compound as a colorless oil (196
mg, 88 %). 1H NMR (400 MHz, CDCl3) δ 7.33 – 7.21 (m, 2H), 7.10
(t, J = 7.4 Hz, 1H), 7.07 – 7.00 (m, 1H), 3.98 (d, J = 13.0 Hz, 1H),
3.67 (td, J = 11.7, 9.9, 6.0 Hz, 3H), 3.59 – 3.54 (m, 1H), 3.44 (dd,
J = 24.0, 15.1 Hz, 1H), 3.04 (dd, J = 13.7, 5.4 Hz, 2H), 2.95 (s,
3H), 2.28 – 2.13 (m, 2H), 1.89 (dt, J = 12.8, 6.3 Hz, 1H), 1.80 (dt,
J = 11.9, 8.9 Hz, 1H), 1.71 – 1.55 (m, 3H), 1.46-1.37 (m, 10H).
13C NMR (101 MHz, CDCl3) δ 161.4 (d, J = 246.6 Hz), 156.3
(minor rotamer), 155.8 (major rotamer), 131.3 (d, J = 6.9 Hz),
129.2 (d, J = 8.2 Hz), 125.6 (d, J = 14.4 Hz), 124.0 (d, J = 3.6 Hz),
115.6 (d, J = 22.0 Hz), 95.9, 88.6 (minor rotamer), 88.4 (major
rotamer), 79.6 (major rotamer), 79.4 (minor rotamer), 66.4 (minor
rotamer), 66.3 (major rotamer), 59.5, 58.8 (minor rotamer), 58.7
(major rotamer), 51.6 (major rotamer), 51.5 (d, J = 1.7 Hz), 50.7
(minor rotamer), 47.3, 37.5, 35.8 (minor rotamer), 35.7 (major
rotamer), 32.7 (major rotamer), 32.4 (minor rotamer), 29.9, 28.5
(3C). HRMS (ESI) calcd for C23H34FN2O4 [M+H+] 421.2497, found
421.2498.
N-(((3S*,3aR*,6S*,7aR*)-3-((2-Methoxyphenoxy)methyl)-2-
(pyridin-3-ylmethyl)hexahydro-3a,6-epoxyisoindol-6(1H)-
yl)methyl)-N-methylmethanesulfonamide (13). General Method
K
was applied to 1-((3S*,3aR*,6S*,7aR*)-2-benzyl-3-((2-
methoxyphenoxy)methyl)hexahydro-3a,6-epoxyisoindol-6(1H)-
yl)-N-methylmethanamine (S5) (105 mg, 0.258 mmol) and
methanesulfonyl chloride (24 µL, 0.310 mmol) then the crude (125
mg, 0.25832 mmol) was subjected to conditions in General
Method B. General Method D was then applied to the crude (26
mg, 0.066 mmol) and nicotinaldehyde (6 μL, 0.066 mmol). The
reaction mixture was purified by preparative HPLC to give the
desired compound as a colorless oil solid (21 mg, 65 % over three
steps). 1H NMR (400 MHz, CDCl3) δ 8.54 (d, J = 2.0 Hz, 1H), 8.47
(dd, J = 4.8, 1.6 Hz, 1H), 7.65 (dt, J = 7.8, 2.0 Hz, 1H), 7.21 (dd,
J = 7.8, 4.8 Hz, 1H), 6.98 – 6.84 (m, 4H), 4.22 (d, J = 13.4 Hz,
1H), 4.04 (dd, J = 9.7, 6.1 Hz, 1H), 3.96 (dd, J = 9.6, 5.5 Hz, 1H),
3.80 (s, 3H), 3.66 (d, J = 13.4 Hz, 1H), 3.51 (d, J = 14.6 Hz, 1H),
3.42 (t, J = 5.8 Hz, 1H), 3.36 (d, J = 14.6 Hz, 1H), 3.04 – 2.95 (m,
4H), 2.81 (s, 3H), 2.40 (dtd, J = 11.0, 7.2, 4.0 Hz, 1H), 2.17 – 1.96
(m, 2H), 1.84 – 1.68 (m, 2H), 1.71 – 1.62 (m, 2H), 1.65 – 1.55 (m,
1H); 13C NMR (101 MHz, CDCl3) δ 150.3, 149.9, 148.5, 148.4,
136.8, 134.8, 123.4, 121.6, 121.0, 113.9, 112.2, 96.1, 87.6, 70.5,
64.3, 59.1, 56.9, 56.0, 52.4, 46.8, 37.6, 36.8, 35.4, 32.6, 29.0.
HRMS (ESI) calcd for C25H34N3O5S [M+H+] 488.2214, found
488.2217.
Tert-butyl
(((3S*,3aR*,6S*,7aR*)-2-(2-fluorobenzyl)-3-(((6-
methylpyridin-3-yl)oxy)methyl)hexahydro-3a,6-epoxyisoindol-
6(1H)-yl)methyl)(methyl)carbamate (S6). General Method A was
applied to tert-butyl (((3S*,3aR*,6S*,7aR*)-2-(2-fluorobenzyl)-3-
(hydroxymethyl)hexahydro-3a,6-epoxyisoindol-6(1H)-
yl)methyl)(methyl)carbamate (9) (80 mg, 0.19 mmol) and 5-
hydroxy-2-methylpyridine (25 mg, 0.23 mmol). The crude was
purified by flash column chromatography (CH2Cl2/MeOH with 5 %
of NH4OH (25 % aq.) 98:2, Rf = 0.2) to give an impure compound
which was used in the next step without further purification.
N-(((3S*,3aR*,6S*,7aR*)-2-(2-Fluorobenzyl)-3-(((6-
methylpyridin-3-yl)oxy)methyl)hexahydro-3a,6-epoxyisoindol-
6(1H)-yl)methyl)-N-methylpentan-1-amine (16). General Method
F was applied to (((3S*,3aR*,6S*,7aR*)-2-(2-fluorobenzyl)-3-(((6-
methylpyridin-3-yl)oxy)methyl)hexahydro-3a,6-epoxyisoindol-
6(1H)-yl)methyl)(methyl)carbamate (S6) (95 mg, 0.19 mmol). The
crude (20 mg, 0.05 mmol) was then directly subjected to General
Method D and valeraldehyde (6 µL, 0.058 mmol) and purified
directly by preparative HPLC to give the desired compound as a
colorless oil (21 mg, 90% over three steps). 1H NMR (400 MHz,
CDCl3) δ 8,18 (d, J = 2.9 Hz, 1H), 7.33 (td, J = 7.5, 1.8 Hz, 1H),
7.21 (tdd, J = 7.5, 5.2, 1.8 Hz, 1H), 7.09 (dd, J = 8.5, 2.9 Hz, 1H),
7.07 – 6.97 (m, 3H), 4.06 (dd, J = 13.4, 1.4 Hz, 1H), 4.01 – 3.89
(m, 2H), 3.79 (dd, J = 13.3, 1.2 Hz, 1H), 3.35 (dd, J = 6.1, 4.5 Hz,
1H), 3.06 (dd, J = 8.3, 6.9 Hz, 1H), 2.69 (d, J = 13.9 Hz, 1H), 2.62
(d, J = 13.9 Hz, 1H), 2.52 – 2.43 (m, 4H), 2.41 – 2.31 (m, 2H),
2.29 (s, 3H), 2.27 – 2.19 (m, 1H), 1.92 (td, J = 12.3, 11.6, 4.8 Hz,
1H), 1.76 – 1.53 (m, 5H), 1.52 – 1.39 (m, 2H), 1.39 – 1.19 (m, 4H),
(3S*,3aR*,6S*,7aR*)-N-Hexyl-3-((2-methoxyphenoxy)methyl)-6-
((N-methylmethylsulfonamido)methyl)hexahydro-3a,6-
epoxyisoindole-2(3H)-carboxamide (14). General Method K was
applied
to
1-((3S*,3aR*,6S*,7aR*)-2-benzyl-3-((2-
methoxyphenoxy)methyl)hexahydro-3a,6-epoxyisoindol-6(1H)-
yl)-N-methylmethanamine (S5) (105 mg, 0.258 mmol) and
methanesulfonyl chloride (24 µL, 0.310 mmol) then the crude (125
mg, 0.25832 mmol) was subjected to conditions in General
Method B. General Method G was then applied to the crude (32
mg, 0.081 mmol) and hexyl isocyanate (14 μL, 0.098 mmol). The
reaction mixture was purified by preparative HPLC to give the
desired compound as a colorless oil solid (15 mg, 35 % over three
steps). 1H NMR (400 MHz, CDCl3) δ 6.96 – 6.83 (m, 4H), 4.76 (br.
s, 1H), 4.46 (t, J = 3.9 Hz, 1H), 4.36 (dd, J = 9.9, 3.5 Hz, 1H), 3.99
(dd, J = 9.8, 4.2 Hz, 1H), 3.82 (s, 3H), 3.65 (t, J = 8.9 Hz, 1H),
3.48 (d, J = 14.6 Hz, 1H), 3.41 (d, J = 14.6 Hz, 1H), 3.30 – 3.10
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801551
European Journal of Organic Chemistry
FULL PAPER
0.90 (t, J = 7.0 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 161.3 (d, J
= 246.2 Hz), 153.2, 150.6, 136.9, 131.5 (d, J = 4.6 Hz), 128.9 (d,
J = 8.2 Hz), 125.8 (d, J = 14.7 Hz), 124.0 (d, J = 3.6 Hz), 123.4,
122.2, 115.5 (d, J = 22.1 Hz), 95.5, 88.4, 69.1, 64.7, 60.5, 59.2,
59.1, 52.1 (d, J = 2.2 Hz), 47.1, 44.0, 38.1, 33.9, 29.8, 29.3, 27.1,
23.5, 22.8, 14.3. HRMS (ESI) calcd for C29H41FN3O2 [M+H+]
482.3177, found 482.3176.
(3C). HRMS (ESI) calcd for C26H37N2O4 [M+H+] 441.2748, found
441.2783.
Tert-butyl
(((2S*,3aR*,5aS*,6S*,9aR*)-2-ethyl-6-
hydroxydecahydrofuro[3,2-c]indol-2-
yl)methyl)(methyl)carbamate (S7). General Method
C was
applied to tert-butyl (((2R*,3aR*,5aS*,6S*,9aR*)-5-benzyl-6-
hydroxy-2-vinyl-2,3,3a,4,5,5a,6,7-octahydrofuro[3,2-c]indol-2-
yl)methyl)(methyl)carbamate (18) (905 mg, 2.05 mmol). The
crude was purified by flash column chromatography on silica gel
(CH2Cl2/MeOH with 5 % of NH4OH (25 % aq) 9:1, Rf = 0.1) and
the desired compound S7 was isolated a colorless oil (340 mg,
78%) which was not completely pure but used in the next step
without further purification.
1-(((3S*,3aR*,6S*,7aR*)-2-(2-Fluorobenzyl)-3-(((6-methylpyridin-
3-yl)oxy)methyl)hexahydro-3a,6-epoxyisoindol-6(1H)-yl)methyl)-
3-isopropyl-1-methylurea (17). General Method F was applied to
(((3S*,3aR*,6S*,7aR*)-2-(2-fluorobenzyl)-3-(((6-methylpyridin-3-
yl)oxy)methyl)hexahydro-3a,6-epoxyisoindol-6(1H)-
yl)methyl)(methyl)carbamate (S6) (95 mg, 0.19 mmol). The crude
(20 mg, 0.05 mmol) and isopropyl isocyanate (5.7 µL, 0.06 mmol)
was then subjected to General Method G to give the desired
compound as an amorphous white solid (79 mg, 86% over three
steps). 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 2.8 Hz, 1H), 7.30
(td, J = 7.5, 1.8 Hz, 1H), 7.22 (tdd, J = 7.3, 5.2, 1.8 Hz, 1H), 7.12
– 6.98 (m, 4H), 5.43 (broad s, 1H), 4.04 (dd, J = 13.3, 1.4 Hz, 1H),
3.97 – 3.86 (m, 3H), 3.73 (d, J = 13.3 Hz, 1H), 3.49 (d, J = 16.1
Hz, 1H), 3.44 (d, J = 17.0 Hz, 1H), 3.28 (t, J = 5.3 Hz, 1H), 3.06
(d, J = 7.6 Hz, 1H), 2.92 (s, 3H), 2.48 (s, 3H), 2.44 – 2.35 (m, 1H),
2.23 – 2.12 (m, 1H), 2.02 – 1.82 (m, 1H), 1.74 (ddd, J = 12.0, 8.8,
4.1 Hz, 1H), 1.69 – 1.46 (m, 4H), 1.15 (d, J = 6.2 Hz, 3H), 1.13 (d,
J = 6.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 161.3 (d, J = 246.2
Hz), 159.2, 153.1, 150.6, 136.5, 131.6 (d, J = 4.4 Hz), 129.2 (d, J
= 8.1 Hz), 125.3 (d, J = 14.8 Hz), 124.1 (d, J = 3.6 Hz), 123.6,
122.5, 115.6 (d, J = 22.1 Hz), 96.5, 89.0, 68.7, 64.7, 59.0, 52.2,
52.1 (d, J = 1.9 Hz), 47.0, 42.7, 37.0, 36.8, 32.1, 29.3, 23.8, 23.7,
23.3. HRMS (ESI) calcd for C28H38FN4O3 [M+H+] 497.2922, found
497.2922.
(2S*,3aR*,5aS*,6S*,9aR*)-2-ethyl-2-((methylamino)methyl)-5-
(pyridin-3-ylmethyl)decahydrofuro[3,2-c]indol-6-ol (S8). General
Method D was applied to tert-butyl (((2S*,3aR*,5aS*,6S*,9aR*)-
2-ethyl-6-hydroxydecahydrofuro[3,2-c]indol-2-
yl)methyl)(methyl)carbamate (S7) (143 mg, 0.4 mmol) and
nicotinaldehyde (45 µL, 0.48 mmol). The crude was then
solubilized in a 3:1 mixture of CH2Cl2 and TFA (0.1 M) and stirred
for 1h at 20 °C. Then, it was concentrated under reduced pressure
and used directly in the next step without further purification.
3-(3-Chlorophenyl)-1-(((2S*,3aR*,5aS*,6S*,9aR*)-2-ethyl-6-
hydroxy-5-(pyridin-3-ylmethyl)decahydrofuro[3,2-c]indol-2-
yl)methyl)-1-methylurea (19) General Method G was applied to
(2S*,3aR*,5aS*,6S*,9aR*)-2-ethyl-2-((methylamino)methyl)-5-
(pyridin-3-ylmethyl)decahydrofuro[3,2-c]indol-6-ol (S8) (22.6 mg,
0.06 mmol) and 3-chlorophenyl isocyanate (10 µL, 0.065 mmol)
to give the desired compound as an amorphous white solid (19.8
mg, 61 % over three steps). 1H NMR (400 MHz, CDCl3) δ 8.70 –
8.25 (m, 3H), 7.79 – 7.55 (m, 1H), 7.50 (t, J = 2.1 Hz, 1H), 7.30 –
7.13 (m, 3H), 7.01 – 6.89 (m, 1H), 5.23 – 4.50 (m, 2H), 4.46 –
4.11 (m, 1H), 4.11 – 3.78 (m, 1H), 3.75 – 3.30 (m, 2H), 3.30 –
3.09 (m, 1H), 3.05 (s, 3H), 2.88 – 2.69 (m, 1H), 2.50 (br. s, 1H),
2.32 (br. s, 1H), 2.08 – 1.86 (m, 3H), 1.86 – 1.43 (m, 7H), 0.95 (t,
J = 7.5 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 165.1, 157.7, 149.5,
141.1, 137.4, 134.7, 130.1, 123.8, 122.6, 122.8, 119.2, 117.0,
93.5, 90.6, 77.4, 70.5, 63.9, 58.1, 46.6, 46.4, 38.8, 38.6, 33.7,
32.7, 27.0, 18.5, 8.9. HRMS (ESI) calcd for C27H36ClN4O3 [M+H+]
499.2476, found 499.2485.
Tert-butyl
(((2R*,3aR*,5aS*,6S*,9aR*)-5-benzyl-6-hydroxy-2-
vinyl-2,3,3a,4,5,5a,6,7-octahydrofuro[3,2-c]indol-2-
yl)methyl)(methyl)carbamate (18). A stirred solution of tert-butyl
(((3S*,3aR*,6R*,7aR*)-2-benzyl-3-((S)-1-hydroxybut-3-en-1-yl)-
2,3,7,7a-tetrahydro-3a,6-epoxyisoindol-6(1H)-
yl)methyl)(methyl)carbamate (6) (180 mg, 0.41 mmol) in CH2Cl2
(25 mL) was added 1M HCl in Et2O (450 µL, 1.1 equiv) followed
by the Grubbs II catalyst (18 mg, 0.021 mmol). The reaction
mixture was heated to reflux for 16 h, whereupon it was cooled to
20 °C and saturated aqueous NaHCO3 (20 mL) was added under
stirring. The organic layer was separated and the aqueous phase
was extracted with CH2Cl2 (3 x 10 mL). The combined organic
layers were dried over sodium sulfate and the volatiles were
removed in vacuo. The residue was purified by flash column
chromatography on silica gel (EtOAc/heptane, 1:4 and 3:4, Rf =
0.15 in EtOAc/heptane, 1:4) to give compound 18 as a clear
yellow oil (155 mg, 86%). 1H NMR (400 MHz, CDCl3) δ 7.41 – 7.23
(m, 5H), 5.88 (td, J = 17.3, 10.7 Hz, 1H), 5.75 – 5.60 (m, 2H), 5.23
(dd, J = 17.3, 1.4 Hz, 1H), 5.07 (dd, J = 10.9, 3.0 Hz, 1H), 4.17
(dd, J = 13.3, 6.2 Hz, 1H), 3.99 (q, J = 3.9 Hz, 1H), 3.68 – 3.20
(m, 4H), 3.19 – 3.00 (m, 2H), 2.94 (s, 3H), 2.52 – 2.29 (m, 3H),
2.28 – 1.92 (m, 3H), 1.47 – 1.42 (m, 9H, two rotamers). 13C NMR
(101 MHz, CDCl3) δ 156.8 (major rotamer), 155.9 (minor rotamer),
144.0 (major rotamer), 143.5 (minor rotamer), 138.7, 129.5 (major
rotamer), 129.3 (minor rotamer), 128.9 (2C), 128.5 (2C), 127.4,
124.6 (minor rotamer), 124.4 (major rotamer), 113.8 (minor
rotamer), 113.6 (major rotamer), 91.3 (major rotamer), 91.2
(minor rotamer), 88.6 (major rotamer), 88.1 (minor rotamer), 79.8
(minor rotamer), 79.5 (major rotamer), 70.7 (major rotamer), 70.6
(minor rotamer), 65.9 (minor rotamer), 65.6 (major rotamer), 59.2,
57.7 (minor rotamer), 57.2, 56.9 (major rotamer), 47.3 (major
rotamer), 47.2 (minor rotamer), 37.8 (minor rotamer), 37.4 (major
rotamer), 37.3 (major rotamer), 36.9 (minor rotamer), 28.7, 28.5
(2S*,3aR*,5aS*,6S*,9aR*)-2-Ethyl-2-((methylamino)methyl)-5-
pentyldecahydrofuro[3,2-c]indol-6-ol (S9). General Method E
was applied to tert-butyl (((2S*,3aR*,5aS*,6S*,9aR*)-2-ethyl-6-
hydroxydecahydrofuro[3,2-c]indol-2-
yl)methyl)(methyl)carbamate (S7) (134 mg, 0.38 mmol) and
valeraldehyde (48 µL, 0.45 mmol). After the reaction, the crude
mixture was dissolved in a 3:1 mixture of CH2Cl2 and TFA (0.1 M)
and stirred for 1h at 20 °C. The reaction mixture was concentrated
under reduced pressure and used directly in the next step without
further purification.
N-(((2S*,3aR*,5aS*,6S*,9aR*)-2-Ethyl-6-hydroxy-5-
pentyldecahydrofuro[3,2-c]indol-2-yl)methyl)-N-methylthiophene-
2-carboxamide (20). General Method H was applied to
(2S*,3aR*,5aS*,6S*,9aR*)-2-Ethyl-2-((methylamino)methyl)-5-
pentyldecahydrofuro[3,2-c]indol-6-ol (S9) (22.6 mg, 0.07 mmol)
and thiophene-2-carbonyl chloride (8 µL, 0.077 mmol) to give the
desired compound as an amorphous white solid (18.1 mg, 60f %
over three steps). 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 7.52
(d, J = 5.0 Hz, 1H), 7.46 (d, J = 3.7 Hz, 1H), 7.09 (dd, J = 5.1, 3.8
Hz, 1H), 6.92 (br. s, 1H), 4.25 (br. s, 1H), 4.13 – 3.51 (m, 2H),
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801551
European Journal of Organic Chemistry
FULL PAPER
3.51 – 3.31 (m, 4H), 3.30 – 2.58 (m, 4H), 2.13 (dd, J = 13.8, 7.3
Hz, 1H), 2.08 – 1.11 (m, 15H), 0.97 (t, J = 7.5 Hz, 3H), 0.93 – 0.84
(m, 3H); 13C NMR (101 MHz, CDCl3) δ 167.8, 166.0, 137.7, 130.5,
127.3, 92.2, 88.2, 77.4, 64.9, 59.0, 54.2, 45.4, 41.2, 39.8, 33.4,
33.1, 29.6, 29.0, 25.6, 22.3, 17.3, 14.0, 9.2, 1.1. HRMS (ESI)
calcd for C24H39N2O3S [M+H+] 435.2676, found 435.2702.
dicarboxylate (21) (3.166 g, 6.96 mmol). General Method J was
applied to the crude carboxylic acid (1.53 g, 3.47 mmol) and i-
PrNH2 (0.60 mL, 6.96 mmol). The crude mixture was purified via
flash column chromatography (EtOAc:heptane 2:3, Rf = 0.2) and
the title compound was afforded as a white solid (1.515 g, 91%).
1H NMR (400 MHz, CDCl3) δ 7.39 – 7.16 (m, 5H), 6.68 – 6.49 (m,
1H), 6.03 – 5.87 (m, 1H), 5.84 – 5.68 (m, 1H), 5.68 – 5.49 (m, 1H),
5.37 – 5.17 (m, 1H), 5.08 (d, J = 10.9 Hz, 1H), 4.24 – 3.80 (m,
4H), 3.80 – 3.47 (m, 1H), 3.43 – 3.31 (m, 2H), 3.25 (t, J = 8.4 Hz,
1H), 3.16 (d, J = 12.8 Hz, 1H), 2.81 (q, J = 8.2 Hz, 1H), 2.63 (t, J
= 9.1 Hz, 1H), 2.07 – 1.90 (m, 1H), 1.90 – 1.76 (m, 1H), 1.46 (s,
9H), 1.14 – 1.06 (m, 6H). 13C NMR (101 MHz, CDCl3) δ 169.0,
154.4, 138.6, 138.1, 133.4, 128.8, 128.6 (2C), 127.5 (2C), 124.1,
114.0, 96.3, 82.5, 80.0, 79.0, 58.5, 57.9, 51.3, 47.1, 42.5, 40.6,
37.5, 28.6 (2C), 22.9 (major rotamer, 3C). HRMS (ESI) calcd for
C28H40N3O4 [M+H+] 482.3013, found 482.3044.
1'-(Tert-butyl) 6-methyl (2R*,3aR*,6R*,6aR*)-5-benzyl-6a-vinyl-
3,3a,4,5,6,6a-hexahydro-2'H-spiro[furo[2,3-c]pyrrole-2,3'-
pyridine]-1',6(6'H)-dicarboxylate
(21).
Methyl
(3R*,3aR*,6R*,7aR*)-6-((allyl(tert-
butoxycarbonyl)amino)methyl)-2-benzyl-1,2,3,6,7,7a-hexahydro-
3a,6-epoxyisoindole-3-carboxylate (7) (5.0 g, 11 mmol) was
dissolved in CH2Cl2 (40 mL) and added 4 M HCl in dioxane (3.3
mL, 13.2 mmol) whereupon the mixture was concentrated in
vacuo followed by 30 min under vacuum using an oil pump which
gave a white HCl-salt. The salt was then added dry CH2Cl2 (55
mL) followed by Grubbs II (93 mg, 1%) and the atmosphere was
exchanged to ethylene and the mixture was stirred at 20 °C. After
16 h Grubbs II (93 mg, 1%) was added and the mixture was stirred
5 h at reflux under an ethylene atmosphere. The reaction was
allowed to cool to 20 °C, added sat. NaHCO3 (aq.) (100 mL, pH >
7) and CH2Cl2 (50 mL) and the layers were separated. The
aqueous phase was extracted with CH2Cl2 (2 x 50 mL) and the
combined organic layers were dried over Na2SO4 and
concentrated in vacuo. The residue was purified by flash column
chromatography (EtOAc:heptane 1:4, Rf = 0.2) to give the title
compound as a white solid (4.14 g, 83%). 1H NMR (400 MHz,
CDCl3) δ 7.42 – 7.13 (m, 5H), 5.88 (dd, J = 16.9, 10.6 Hz, 1H),
5.71 (s, 2H), 5.44 (d, J = 16.9 Hz, 1H), 5.11 (d, J = 10.6 Hz, 1H),
4.37 (d, J = 13.1 Hz, 1H), 4.18 (d, J = 18.5 Hz, 1H), 3.81 (d, J =
13.1 Hz, 1H), 3.72 – 3.49 (m, 6H), 3.44 (t, J = 9.9 Hz, 1H), 3.28 –
3.05 (m, 1H), 3.05 – 2.79 (m, 2H), 2.01 (d, J = 13.4 Hz, 1H), 1.88
(dd, J = 13.4, 8.0 Hz, 1H), 1.52 – 1.36 (m, 9H); 13C NMR (101
MHz, CDCl3) δ 171.6, 154.6, 138.4, 133.1, 128.9 (2C), 128.5 (2C),
127.4, 127.2, 125.1, 114.9, 96.3, 83.0, 80.1, 76.1, 58.6, 56.2,
51.4, 50.6, 47.9, 42.7, 39.3, 28.6 (major rotamer, 3C). HRMS
(ESI) calcd for C26H35N2O5 [M+H+] 455.2540, found 455.2572.
Methyl (2S*,3aR*,6R*,6aR*)-6a-ethyl-1'-pentyl-5-(thiophene-2-
carbonyl)hexahydrospiro[furo[2,3-c]pyrrole-2,3'-piperidine]-6-
carboxylate (24). General Method F was applied to 1'-(tert-butyl)
6-methyl (2R*,3aR*,6R*,6aR*)-5-benzyl-6a-vinyl-3,3a,4,5,6,6a-
hexahydro-2'H-spiro[furo[2,3-c]pyrrole-2,3'-pyridine]-1',6(6'H)-
dicarboxylate (21) (207 mg, 0.445 mmol) followed by General
Method E with valeraldehyde (63 µL, 0.592 mmol), General
Method B, and General Method H with thiophene-2-carbonyl
chloride (58 µL, 0.456 mmol), respectively. The crude mixture
was purified directly using flash column chromatography
(EtOAc:heptane 9:1 + 1% Et3N, Rf = 0.2 ) to give the title
1
compound as a yellow oil (158 mg, 77%). H NMR (400 MHz,
CDCl3) δ 7.48 (d, J = 3.4 Hz, 1H), 7.43 (d, J = 4.8 Hz, 1H), 7.04 –
6.98 (m, 1H), 4.85 (s, 1H), 4.22 – 3.85 (m, 2H), 3.67 (s, 3H), 2.80
(d, J = 4.6 Hz, 1H), 2.43 (t, J = 11.4 Hz, 2H), 2.32 – 2.04 (m, 3H),
2.04 – 1.96 (m, 2H), 1.69 – 1.59 (m, 1H), 1.60 – 1.31 (m, 5H),
1.32 – 1.07 (m, 6H), 0.95 (t, J = 7.3 Hz, 3H), 0.85 – 0.72 (m, 4H)
(two rotamers). 13C NMR (101 MHz, CDCl3) δ 170.9, 162.2, 137.8,
130.5, 130.3, 127.1, 92.7, 83.5, 71.0, 64.0, 58.6, 54.4, 53.7, 52.0,
46.0, 41.2, 37.6, 29.7, 27.2, 26.3, 23.4, 22.4, 14.1, 8.3 (major
rotamer). HRMS (ESI) calcd for C24H37N2O4S [M+H+] 449.2469,
found 449.2525.
Tert-butyl
(2R*,3aR*,6R*,6aR*)-5-benzyl-6-(pyrrolidine-1-
carbonyl)-6a-vinyl-3,3a,4,5,6,6a-hexahydro-2'H-spiro[furo[2,3-
c]pyrrole-2,3'-pyridine]-1'(6'H)-carboxylate (22). General Method
I was applied to 1'-(tert-butyl) 6-methyl (2R*,3aR*,6R*,6aR*)-5-
benzyl-6a-vinyl-3,3a,4,5,6,6a-hexahydro-2'H-spiro[furo[2,3-
c]pyrrole-2,3'-pyridine]-1',6(6'H)-dicarboxylate (21) (3.17 g, 6.96
mmol). General Method J was applied to the crude carboxylic
acid (1.53 g, 3.47 mmol) and pyrrolidine (0.57 mL, 6.96 mmol).
The crude mixture was purified by flash column chromatography
(EtOAc:heptane 1:1, Rf = 0.2) to give the title compound as a
((2S*,3aR*,6R*,6aR*)-6a-Ethyl-1'-pentyl-5-(thiophene-2-
carbonyl)hexahydrospiro[furo[2,3-c]pyrrole-2,3'-piperidin]-6-
yl)(morpholino)methanone (25). General Method I was applied to
methyl (2S*,3aR*,6R*,6aR*)-6a-ethyl-1'-pentyl-5-(thiophene-2-
carbonyl)hexahydrospiro[furo[2,3-c]pyrrole-2,3'-piperidine]-6-
carboxylate (24) (158 mg, 0.352 mmol). The carboxylic acid (20
mg, 0.046 mmol) and morpholine (8 µL, 0.092) was used following
General Method J. The mixture was purified directly using
preparative HPLC to give the title compound as a white solid (14
mg, 60%). 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 3.8 Hz, 1H),
7.49 (dd, J = 5.0, 0.8 Hz, 1H), 7.08 (dd, J = 5.0, 3.9 Hz, 1H), 5.33
(s, 1H), 4.37 (dd, J = 10.5, 8.9 Hz, 1H), 3.95 (dd, J = 10.7, 3.0 Hz,
2H), 3.87 – 3.76 (m, 1H), 3.77 – 3.65 (m, 5H), 3.50 (ddd, J = 13.0,
6.7, 3.5 Hz, 1H), 3.10 – 2.99 (m, 1H), 2.85 – 2.76 (m, 1H), 2.64
(d, J = 11.3 Hz, 1H), 2.51 – 2.32 (m, 4H), 2.26 (d, J = 11.9 Hz,
1H), 2.05 (dd, J = 13.6, 8.1 Hz, 1H), 1.92 – 1.81 (m, 1H), 1.78 –
1.67 (m, 1H), 1.67 – 1.56 (m, 4H), 1.33 (dt, J = 14.1, 7.1 Hz, 2H),
1.22 – 1.10 (m, 4H), 0.97 (t, J = 7.4 Hz, 3H), 0.82 (t, J = 6.9 Hz,
3H); 13C NMR (101 MHz, CDCl3) δ 168.9, 167.3, 138.0, 130.8,
130.5, 127.5, 94.7, 82.4, 67.1, 67.0, 66.7, 61.7, 58.0, 55.7, 53.1,
47.3, 47.1, 42.5, 41.8, 37.5, 29.5, 27.5, 25.0, 22.3, 22.1, 14.1, 9.0.
HRMS (ESI) calcd for C27H42N3O4S [M+H+] 504.2891, found
504.2955.
1
white solid (1.476 g, 86%). H NMR (400 MHz, CDCl3) δ 7.41 –
7.16 (m, 5H), 5.93 (dd, J = 16.9, 10.6 Hz, 1H), 5.80 – 5.66 (m,
2H), 5.47 (d, J = 16.7 Hz, 1H), 5.05 (d, J = 10.5 Hz, 1H), 4.70 –
3.69 (m, 4H), 3.69 – 3.30 (m, 5H), 3.21 – 2.86 (m, 4H), 2.47 –
2.20 (m, 1H), 2.11 – 1.97 (m, 1H), 1.88 (dd, J = 13.3, 8.4 Hz, 1H),
1.76 – 1.54 (m, 4H), 1.47 (s, 9H); 13C NMR (101 MHz, CDCl3) δ
169.5, 154.8, 139.3, 139.1, 133.2, 129.0, 128.4 (2C), 127.2 (2C),
125.1, 114.4, 96.8, 82.5, 80.1, 72.3, 60.3, 55.1, 50.2, 48.7, 46.4,
45.4, 42.7, 39.8, 28.7 (3C), 26.1, 24.2. HRMS (ESI) calcd for
C29H40N3O4 [M+H+] 494.3013, found 494.3051.
Tert-butyl
(2R*,3aR*,6R*,6aR*)-5-benzyl-6-
(isopropylcarbamoyl)-6a-vinyl-3,3a,4,5,6,6a-hexahydro-2'H-
spiro[furo[2,3-c]pyrrole-2,3'-pyridine]-1'(6'H)-carboxylate
(23).
General Method
(2R*,3aR*,6R*,6aR*)-5-benzyl-6a-vinyl-3,3a,4,5,6,6a-
hexahydro-2'H-spiro[furo[2,3-c]pyrrole-2,3'-pyridine]-1',6(6'H)-
I was applied to 1'-(tert-butyl) 6-methyl
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801551
European Journal of Organic Chemistry
FULL PAPER
Tert-butyl (2S*,3aR*,6R*,6aR*)-6a-ethyl-5-(pyridin-2-ylmethyl)-6-
(pyrrolidine-1-carbonyl)hexahydrospiro[furo[2,3-c]pyrrole-2,3'-
piperidine]-1'-carboxylate (26). General Method B was applied to
40.6, 38.1, 22.9, 14.3 (major rotamer). HRMS (ESI) calcd for
C30H36N3O3 [M+H+] 486.2751, found 486.2754.
tert-butyl
(2R*,3aR*,6R*,6aR*)-5-benzyl-6-(pyrrolidine-1-
(2S*,3aR*,6R*,6aR*)-1'-Benzoyl-6a-ethyl-N-
carbonyl)-6a-vinyl-3,3a,4,5,6,6a-hexahydro-2'H-spiro[furo[2,3-
c]pyrrole-2,3'-pyridine]-1'(6'H)-carboxylate (22) (1.32g, 2.65
mmol). Following this reaction, General Method E was applied to
the amine (567 mg, 1.39 mmol) and 2-pyridinecarboxaldehyde
(164 µL, 1.74 mmol). The crude mixture was purified directly
using flash column chromatography (EtOAc:MeOH 9:2, Rf = 0.2)
to give the title compound as a yellow solid (697 mg, 95%).1H
NMR (400 MHz, CDCl3) δ 8.46 (d, J = 4.9 Hz, 1H), 7.75 – 7.53 (m,
2H), 7.16 – 7.09 (m, 1H), 4.48 – 3.90 (m, 2H), 3.85 – 3.56 (m, 3H),
3.56 – 3.23 (m, 4H), 3.10 – 2.82 (m, 2H), 2.81 – 2.59 (m, 2H),
2.04 – 1.89 (m, 1H), 1.81 – 1.50 (m, 11H), 1.43 (s, 10H), 0.84 (t,
J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 174.4, 169.3, 159.6,
154.9, 148.6, 136.8, 122.1, 97.8, 83.7, 79.9, 73.4, 61.2, 57.8,
53.5, 46.5, 45.6, 43.2, 40.2, 39.1, 29.3 (3C), 28.7, 26.4, 24.1,
23.7, 21.6, 8.7. HRMS (ESI) calcd for C28H43N4O4 [M+H+]
499.3279, found 499.3376.
isopropylhexahydrospiro[furo[2,3-c]pyrrole-2,3'-piperidine]-6-
carboxamide (S10). (2R*,3aR*,6R*,6aR*)-1'-benzoyl-5-benzyl-N-
isopropyl-6a-vinyl-1',3,3a,4,5,6,6a,6'-octahydro-2'H-
spiro[furo[2,3-c]pyrrole-2,3'-pyridine]-6-carboxamide (28) (318
mg, 0.65 mmol) was hydrogenated following General Method B
to give the title compound as a white solid (245 mg, 95%). The
amine was used directly without further purification.
(2S*,3aR*,6R*,6aR*)-1'-Benzoyl-5-(cyclopropylsulfonyl)-6a-
ethyl-N-isopropylhexahydrospiro[furo[2,3-c]pyrrole-2,3'-
piperidine]-6-carboxamide (29). General Method K was applied
to
isopropylhexahydrospiro[furo[2,3-c]pyrrole-2,3'-piperidine]-6-
carboxamide (S10) (18 mg, 0.045 mmol)
(2S*,3aR*,6R*,6aR*)-1'-benzoyl-6a-ethyl-N-
and
cyclopropanesulfonyl chloride (7.6 mg, 0.054 mmol) gave after
preparative HPLC the title compound as a white foam (17 mg,
75%). 1H NMR (400 MHz, CDCl3) δ 7.43 – 7.39 (m, 3H), 7.36 (d,
J = 4.6 Hz, 2H), 6.94 (d, J = 7.2 Hz, 1H), 4.44 (s, 1H), 4.41 (s,
1H), 4.07 (dq, J = 13.3, 6.6 Hz, 1H), 3.75 (d, J = 10.3 Hz, 1H),
3.58 (dd, J = 10.4, 6.3 Hz, 1H), 3.52 (d, J = 13.5 Hz, 1H), 3.22 (d,
J = 13.1 Hz, 1H), 3.14 (t, J = 11.9 Hz, 1H), 2.91 – 2.83 (m, 1H),
2.76 (dd, J = 14.7, 6.8 Hz, 1H), 2.19 – 1.94 (m, 2H), 1.93 – 1.73
(m, 3H), 1.67 (q, J = 7.2 Hz, 2H), 1.57 (t, J = 11.8 Hz, 1H), 1.49 –
1.38 (m, 1H), 1.13 (d, J = 6.5 Hz, 3H), 1.08 (d, J = 6.5 Hz, 3H),
0.94 (t, J = 7.3 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 171.3,
168.3, 136.6, 129.6, 128.6 (2C), 126.5 (2C), 95.2, 82.1, 70.5,
52.9, 50.5, 47.9, 43.6, 41.5, 40.0, 37.5, 29.8, 25.0, 23.1, 22.8,
22.5, 8.3, 5.4, 5.3. HRMS (ESI) calcd for C26H38N3O5S [M+H+]
504.2527, found 504.2539.
((2S*,3aR*,6R*,6aR*)-1'-(Butylsulfonyl)-6a-ethyl-5-(pyridin-2-
ylmethyl)hexahydrospiro[furo[2,3-c]pyrrole-2,3'-piperidin]-6-
yl)(pyrrolidin-1-yl)methanone (27). General Method
F was
applied to tert-butyl (2S*,3aR*,6R*,6aR*)-6a-ethyl-5-(pyridin-2-
ylmethyl)-6-(pyrrolidine-1-carbonyl)hexahydrospiro[furo[2,3-
c]pyrrole-2,3'-piperidine]-1'-carboxylate (26) (85 mg, 0.17 mmol).
Following this reaction, General Method K was applied to TFA
amine salt (32 mg, 0.051 mmol) and 1-butanesulfonyl chloride (6
mg, 0.038 mmol) to give after preparative HPLC, the title
1
compound as a white foam (25 mg, 93%). H NMR (400 MHz,
CDCl3) δ 8.49 (dd, J = 4.9, 0.9 Hz, 1H), 7.64 (td, J = 7.6, 1.8 Hz,
1H), 7.52 (d, J = 7.8 Hz, 1H), 7.13 (ddd, J = 7.3, 4.9, 1.0 Hz, 1H),
3.97 (d, J = 13.8 Hz, 1H), 3.82 (d, J = 11.0 Hz, 1H), 3.81 (s, 1H),
3.73 (d, J = 13.8 Hz, 1H), 3.62 – 3.51 (m, 2H), 3.46 – 3.36 (m,
3H), 3.14 – 3.04 (m, 2H), 3.03 – 2.94 (m, 1H), 2.93 – 2.86 (m,
2H), 2.83 (dd, J = 9.0, 4.7 Hz, 1H), 2.79 – 2.72 (m, 1H), 2.12 (d, J
= 13.4 Hz, 1H), 1.88 – 1.73 (m, 8H), 1.68 – 1.54 (m, 5H), 1.49 –
(2S*,3aR*,6R*,6aR*)-6a-Ethyl-1'-pentyl-5-(thiophene-2-
carbonyl)hexahydrospiro[furo[2,3-c]pyrrole-2,3'-piperidine]-6-
carboxamide (30). General Method I was applied to methyl
(2S*,3aR*,6R*,6aR*)-6a-ethyl-1'-pentyl-5-(thiophene-2-
1.38 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H), 0.87 (t, J = 7.3 Hz, 3H); 13
C
carbonyl)hexahydrospiro[furo[2,3-c]pyrrole-2,3'-piperidine]-6-
carboxylate (24) (158 mg, 0.352 mmol). The carboxylic acid (20
mg, 0.046 mmol) and NH4Cl (7.4 mg, 0.14 mmol) were used
following General Method J. The mixture was purified using
preparative HPLC to provide the title compound as a white solid
(12 mg, 59%). 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 3.4 Hz,
1H), 7.49 (d, J = 4.9 Hz, 1H), 7.12 – 7.03 (m, 1H), 6.97 (s, 1H),
5.78 (s, 1H), 4.98 (s, 1H), 4.42 – 4.21 (m, 1H), 3.87 (dd, J = 10.7,
2.9 Hz, 1H), 2.97 (s, 1H), 2.59 – 2.27 (m, 6H), 2.17 – 1.99 (m,
2H), 1.99 – 1.76 (m, 2H), 1.73 – 1.49 (m, 4H), 1.40 – 1.07 (m, 6H),
1.01 (t, J = 7.3 Hz, 3H), 0.82 (t, J = 6.9 Hz, 3H); 13C NMR (101
MHz, CDCl3) δ 171.7, 162.40, 138.1, 130.7, 130.6, 127.5, 93.7,
82.5, 70.6, 63.0, 58.6, 55.44, 53.3, 46.5, 41.8, 37.4, 29.7, 27.0,
25.5, 22.6, 22.5, 14.2, 9.0. HRMS (ESI) calcd for C23H36N3O3S
[M+H+] 434.2472, found 434.2485.
NMR (101 MHz, CDCl3) δ 169.4, 159.1, 148.8, 136.7, 123.9,
122.1, 98.2, 83.0, 73.6, 60.5, 57.7, 54.8, 49.6, 46.9, 46.3, 45.9,
45.7, 41.2, 38.1, 29.1, 26.4, 25.3, 24.2, 23.8, 22.0, 13.8, 8.8.
HRMS (ESI) calcd for C27H43N4O4S [M+H+] 519.3000, found
519.3035.
(2R*,3aR*,6R*,6aR*)-1'-Benzoyl-5-benzyl-N-isopropyl-6a-vinyl-
1',3,3a,4,5,6,6a,6'-octahydro-2'H-spiro[furo[2,3-c]pyrrole-2,3'-
pyridine]-6-carboxamide (28). General Method F was applied to
tert-butyl (2R*,3aR*,6R*,6aR*)-5-benzyl-6-(isopropylcarbamoyl)-
6a-vinyl-3,3a,4,5,6,6a-hexahydro-2'H-spiro[furo[2,3-c]pyrrole-
2,3'-pyridine]-1'(6'H)-carboxylate (23) (1.439 g, 2.99 mmol).
General Method H was applied to amine (570 mg, 1.49 mmol)
and benzoyl chloride (208 µL, 1.79 mmol). The mixture was
purified using flash column chromatography (gradient from
EtOAc:heptane 3:2 to 100% EtOAc, Rf = 0.3 in 100% EtOAc) to
give the title compound as a white solid (616 mg, 85%). 1H NMR
(400 MHz, CDCl3) δ 7.64 – 7.35 (m, 5H), 7.37 – 7.20 (m, 4H), 7.18
– 6.99 (m, 1H), 6.72 (s, 0.5H), 6.42 (d, J = 6.5 Hz, 0.5H), 6.07 –
5.46 (m, 3H), 5.25 (d, J = 16.9 Hz, 1H), 5.08 (d, J = 10.9 Hz, 1H),
4.65 (d, J = 11.0 Hz, 0.5H), 4.32 – 3.76 (m, 4H), 3.80 – 3.59 (m,
2H), 3.55 – 3.07 (m, 2H), 3.12 – 2.62 (m, 2.5H) , 1.95 – 1.77 (m,
(2S*,3aR*,6R*,6aR*)-6a-Ethyl-N,N-dimethyl-1'-pentyl-5-
(thiophene-2-carbonyl)hexahydrospiro[furo[2,3-c]pyrrole-2,3'-
piperidine]-6-carboxamide (31). General Method I was applied to
methyl (2S*,3aR*,6R*,6aR*)-6a-ethyl-1'-pentyl-5-(thiophene-2-
carbonyl)hexahydrospiro[furo[2,3-c]pyrrole-2,3'-piperidine]-6-
carboxylate (24) (158 mg, 0.352 mmol). The carboxylic acid (20
mg, 0.046 mmol) and dimethylamine hydrochloride (11 mg, 0.14
mmol) were used following General Method J. The mixture was
purified using preparative HPLC to provide the title compound as
a white solid (12 mg, 56%). 1H NMR (400 MHz, CDCl3) δ 7.50 (dd,
J = 3.7, 0.7 Hz, 1H), 7.43 (d, J = 5.0 Hz, 1H), 7.02 (dd, J = 4.9,
3.9 Hz, 1H), 5.30 (s, 1H), 4.34 (dd, J = 10.4, 9.1 Hz, 1H), 3.90 (dd,
1H), 1.79 – 1.54 (m, 1H), 1.19 – 0.96 (m, 6H) (two rotamers). 13
C
NMR (101 MHz, CDCl3) δ 171.1, 168.9, 138.6, 138.1, 136.2,
134.3, 132.6, 129.7, 128.7 (2C), 128.6 (2C), 127.8 (2C), 127.5
(2C), 124.6, 114.1, 96.4, 79.0, 60.5, 58.8, 58.2, 54.9, 46.7, 41.5,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801551
European Journal of Organic Chemistry
FULL PAPER
J = 10.7, 3.2 Hz, 1H), 3.26 (s, 3H), 2.99 (dd, J = 9.9, 6.9 Hz, 1H),
2.90 (s, 3H), 2.87 – 2.82 (m, 1H), 2.77 – 2.61 (m, 1H), 2.53 – 2.40
(m, 2H), 2.37 – 2.22 (m, 2H), 1.98 (dd, J = 13.6, 8.0 Hz, 1H), 1.85
– 1.74 (m, 1H), 1.69 – 1.50 (m, 6H), 1.33 – 1.24 (m, 2H), 1.16 –
1.02 (m, 4H), 0.90 (t, J = 7.4 Hz, 3H), 0.75 (t, Jz = 6.8 Hz, 3H);
13C NMR (101 MHz, CDCl3) δ 170.3, 162.0, 138.2, 130.8, 130.6,
127.6, 94.9, 82.2, 67.3, 61.3, 57.9, 55.7, 53.0, 47.4, 41.8, 38.1,
37.5, 35.9, 29.4, 27.5, 24.8, 22.3, 21.9, 14.1, 8.9. HRMS (ESI)
calcd for C25H40N3O3S [M+H+] 462.2785, found 462.2837.
3.26 (m, 3H), 2.85 (dd, J = 9.6, 7.8 Hz, 1H), 2.78 – 2.65 (m, 1H),
2.12 (s, 2.4H, major rotamer), 1.99 – 1.68 (m, 8.6H), 1.70 – 1.55
(m, 2H), 1.55 – 1.45 (m, 1H), 0.98 – 0.81 (m, 3H); 13C NMR (101
MHz, CD3OD) δ 171.5, 170.0, 159.0, 149.3, 138.9, 126.0, 125.4,
98.2, 85.6, 77.1, 61.4, 59.6, 51.9, 47.5, 47.1, 47.0, 40.9, 38.6,
30.3, 27.1, 27.0, 25.0, 24.6, 21.3, 8.4 (major rotamers). HRMS
(ESI) calcd for C25H37N4O3 [M+H+] 441.2860, found 441.2895.
Tert-butyl (2S*,3aR*,6R*,6aR*)-6a-Ethyl-5-(isopropylcarbamoyl)-
6-(pyrrolidine-1-carbonyl)hexahydrospiro[furo[2,3-c]pyrrole-2,3'-
piperidine]-1'-carboxylate (35). General Method B was applied to
(2S*,3aR*,6R*,6aR*)-6a-Ethyl-N-(2-methoxyethyl)-1'-pentyl-5-
(thiophene-2-carbonyl)hexahydrospiro[furo[2,3-c]pyrrole-2,3'-
piperidine]-6-carboxamide (32). General Method I was applied to
methyl (2S*,3aR*,6R*,6aR*)-6a-ethyl-1'-pentyl-5-(thiophene-2-
carbonyl)hexahydrospiro[furo[2,3-c]pyrrole-2,3'-piperidine]-6-
carboxylate (24) (158 mg, 0.352 mmol). The carboxylic acid (20
mg, 0.046 mmol) and 2-methoxyethylamine (8 µL, 0.092) was
used following General Method J. The mixture was purified
using preparative HPLC to provide the title compound as a white
solid (9 mg, 41%). 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 7.54
(d, J = 3.3 Hz, 1H), 7.49 (d, J = 4.8 Hz, 1H), 7.12 – 7.01 (m, 1H),
4.91 (s, 1H), 4.32 (t, J = 9.6 Hz, 1H), 4.15 – 3.83 (m, 1H), 3.59 –
3.33 (m, 4H), 3.30 (s, 3H), 2.98 (s, 1H), 2.83 – 2.35 (m, 6H), 2.25
– 1.78 (m, 4H), 1.77 – 1.30 (m, 6H), 1.28 – 1.09 (m, 4H), 1.00 (t,
J = 7.2 Hz, 3H), 0.83 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 169.6, 168.2, 138.2, 130.7, 130.5, 127.5, 94.3, 82.0,
71.1, 71.0, 61.7, 58.8, 58.1, 55.5, 52.9, 46.7, 42.0, 39.3, 37.2,
29.5, 27.1, 24.8, 22.4, 21.9, 14.2, 8.9. HRMS (ESI) calcd for
C26H42N3O4S [M+H+] 492.2891, found 492.2944.
tert-butyl
(2R*,3aR*,6R*,6aR*)-5-benzyl-6-(pyrrolidine-1-
carbonyl)-6a-vinyl-3,3a,4,5,6,6a-hexahydro-2'H-spiro[furo[2,3-
c]pyrrole-2,3'-pyridine]-1'(6'H)-carboxylate (22) (1.32g, 2.68
mmol). Following this reaction, General Method G was applied
to amine (567 mg, 1.39 mmol) and isopropyl isocyanate (145 µL,
1.47 mmol). The crude mixture was purified directly using flash
column chromatography (EtOAc:MeOH 9:1, Rf = 0.2) to give the
1
title compound as a white solid (685 mg, >95%). H NMR (400
MHz, CDCl3) δ 4.93 (s, 1H), 4.75 (s, 1H), 4.18 – 3.72 (m, 5H),
3.72 – 3.45 (m, 3H), 3.41 – 3.26 (m, 1H), 3.11 – 2.43 (m, 3H),
2.13 – 1.52 (m, 12H), 1.44 (s, 9H), 1.20 – 1.03 (m, 6H), 0.90 (t, J
= 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 170.7, 156.6, 154.5,
96.5, 82.6, 79.5, 68.4, 53.8, 51.8, 47.2, 46.5, 45.7, 44.3, 42.5,
40.7, 38.9, 28.9, 28.5, 28.1, 26.3 (3C), 24.5, 24.4, 23.5, 8.9.
HRMS (ESI) calcd for C26H45N4O5 [M+H+] 493.3384, found
493.3409.
(2S*,3aR*,6R*,6aR*)-1'-Benzyl-6a-ethyl-N-isopropyl-6-
(pyrrolidine-1-carbonyl)tetrahydrospiro[furo[2,3-c]pyrrole-2,3'-
piperidine]-5(3H)-carboxamide (36). General Method F was
(2S*,3aR*,6R*,6aR*)-N-Cyclopentyl-6a-ethyl-5-(pyridin-2-
ylmethyl)-6-(pyrrolidine-1-carbonyl)hexahydrospiro[furo[2,3-
c]pyrrole-2,3'-piperidine]-1'-carboxamide (33). General Method F
was applied to tert-butyl (2S*,3aR*,6R*,6aR*)-6a-ethyl-5-(pyridin-
2-ylmethyl)-6-(pyrrolidine-1-carbonyl)hexahydrospiro[furo[2,3-
c]pyrrole-2,3'-piperidine]-1'-carboxylate (26) (85 mg, 0.17 mmol).
Following this reaction, General Method G was applied to TFA
amine salt (37 mg, 0.059 mmol) and cyclopentyl isocyanate (8 µL,
0.071 mmol) to provide the desired product as a white solid (19
mg, 61%) from purification using the preparative HPLC. 1H NMR
(400 MHz, CDCl3) δ 8.56 (dd, J = 5.3, 1.7 Hz, 1H), 7.64 (td, J =
7.7, 1.7 Hz, 1H), 7.21 (d, J = 3.9 Hz, 1H), 7.20 (d, J = 3.8 Hz, 1H),
6.39 (br. s, 1H), 4.26 – 4.07 (m, 2H), 4.05 – 3.89 (m, 2H), 3.83 –
3.72 (m, 3H), 3.58 – 3.47 (m, 1H), 3.48 – 3.38 (m, 1H), 3.38 –
3.30 (m, 1H), 3.18 (d, J = 12.9 Hz, 1H), 3.12 – 3.00 (m, 1H), 2.97
– 2.85 (m, 2H), 2.70 (dd, J = 9.8, 8.0 Hz, 1H), 2.00 – 1.88 (m, 3H),
1.87 – 1.75 (m, 5H), 1.76 – 1.67 (m, 1H), 1.66 – 1.57 (m, 3H),
1.55 – 1.38 (m, 6H), 1.37 – 1.25 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H);
13C NMR (101 MHz, CDCl3) δ 169.6, 163.3, 157.9, 149.3, 136.9,
123.4, 122.8, 97.9, 83.8, 73.2, 61.3, 56.3, 53.1, 52.9, 47.0, 46.0,
45.6, 43.2, 38.5, 33.4, 33.2, 28.4, 26.3, 24.2, 23.9, 23.8, 23.7
(2C), 8.7. HRMS (ESI) calcd for C29H44N5O3 [M+H+] 510.3439,
found 510.3493.
applied
to
tert-butyl
(2S*,3aR*,6R*,6aR*)-6a-ethyl-5-
(isopropylcarbamoyl)-6-(pyrrolidine-1-
carbonyl)hexahydrospiro[furo[2,3-c]pyrrole-2,3'-piperidine]-1'-
carboxylate (35) (87 mg, 0.18 mmol). General Method E was
applied to resulting amine (23 mg, 0.045 mmol) and
benzaldehyde (8.8 µL, 0.086 mmol). Mixture was purified by
1
preparative HPLC to give a white solid (14 mg, 63%). H NMR
(400 MHz, CDCl3) δ 7.41 – 7.37 (m, 3H), 7.35 – 7.30 (m, 2H), 4.87
(s, 1H), 4.06 – 3.83 (m, 5H), 3.65 – 3.44 (m, 2H), 3.44 – 3.30 (m,
1H), 3.27 (d, J = 8.7 Hz, 1H), 2.95 – 2.74 (m, 3H), 2.45 – 2.19 (m,
2H), 2.07 – 1.76 (m, 6H), 1.77 – 1.49 (m, 6H), 1.13 (t, J = 6.4 Hz,
6H), 0.89 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 170.1,
156.7, 131.0, 129.3 (2C), 129.1 (2C), 97.5, 81.9, 68.0, 61.3, 60.1,
53.8, 51.0, 47.3, 46.6, 45.8, 42.6, 42.4, 36.9, 28.0, 26.3, 24.3,
23.6, 23.2 (2C), 21.6, 8.9. HRMS (ESI) calcd for C28H43N4O3
[M+H+] 483.3330, found 483.3384.
(2S*,3aR*,6R*,6aR*)-6a-Ethyl-N-isopropyl-6-(pyrrolidine-1-
carbonyl)-1'-tosyltetrahydrospiro[furo[2,3-c]pyrrole-2,3'-
piperidine]-5(3H)-carboxamide (37). General Method F was
applied
to
tert-butyl
(2S*,3aR*,6R*,6aR*)-6a-ethyl-5-
(isopropylcarbamoyl)-6-(pyrrolidine-1-
carbonyl)hexahydrospiro[furo[2,3-c]pyrrole-2,3'-piperidine]-1'-
carboxylate (35) (87 mg, 0.18 mmol). General Method K was
applied to the resulting amine (20 mg, 0.040 mmol) and 4-
toluenesulfonyl chloride (12 mg, 0.062 mmol). Mixture was
purified directly by preparative HPLC to give a white solid (13 mg,
57%). 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.2 Hz, 2H), 7.29
(d, J = 8.2 Hz, 2H), 4.71 (s, 1H), 4.51 (d, J = 7.6 Hz, 1H), 4.11 (t,
J = 9.4 Hz, 1H), 4.07 – 3.89 (m, 2H), 3.73 (d, J = 11.5 Hz, 1H),
3.63 (d, J = 11.0 Hz, 1H), 3.59 – 3.42 (m, 3H), 3.43 – 3.29 (m,
1H), 3.03 – 2.85 (m, 1H), 2.52 (d, J = 13.3 Hz, 1H), 2.41 (s, 3H),
2.15 – 1.96 (m, 3H), 1.94 – 1.53 (m, 9H), 1.54 – 1.38 (m, 1H),
1.22 (d, J = 6.4 Hz, 3H), 1.15 (d, J = 6.6 Hz, 3H), 0.89 (t, J = 7.3
Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 170.8, 156.6, 143.7, 133.6,
1-((2S*,3aR*,6R*,6aR*)-6a-Ethyl-5-(pyridin-2-ylmethyl)-6-
(pyrrolidine-1-carbonyl)hexahydrospiro[furo[2,3-c]pyrrole-2,3'-
piperidin]-1'-yl)ethan-1-one (34). General Method F was applied
to tert-butyl (2S*,3aR*,6R*,6aR*)-6a-ethyl-5-(pyridin-2-ylmethyl)-
6-(pyrrolidine-1-carbonyl)hexahydrospiro[furo[2,3-c]pyrrole-2,3'-
piperidine]-1'-carboxylate (26) (85 mg, 0.17 mmol). Following this
reaction, General Method J was applied to TFA amine salt (24
mg, 0.060 mmol) and acetic acid (4.5 μL, 0.078 mmol) to give after
preparative HPLC the title compound as a white foam (14 mg,
54%). 1H NMR (400 MHz, CD3OD) δ 8.51 – 8.44 (m, 1H), 7.89 –
7.81 (m, 1H), 7.75 – 7.66 (m, 1H), 7.36 – 7.32 (m, 1H), 4.13 –
3.99 (m, 2H), 3.80 – 3.69 (m, 1H), 3.64 – 3.34 (m, 7H), 3.33 –
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801551
European Journal of Organic Chemistry
FULL PAPER
129.9 (2C), 127.4 (2C), 96.6, 82.7, 68.8, 54.6, 54.5, 47.2, 46.7,
46.0, 45.7, 42.7, 40.9, 38.0, 28.2, 26.3, 24.4, 23.6 (2C), 23.4,
21.6, 8.9. HRMS (ESI) calcd for C28H43N4O5S [M+H+] 547.2949,
found 547.2947.
22.9, 8.2 (major rotamers). HRMS (ESI) calcd for C30H46N3O3
[M+H+] 496.3534, found 496.3594.
(2R*,3aR*,6R*,6aR*)-5-Benzyl-N-isopropyl-1'-(methylsulfonyl)-
6a-vinyl-1',3,3a,4,5,6,6a,6'-octahydro-2'H-spiro[furo[2,3-
(2S*,3aR*,6R*,6aR*)-6a-Ethyl-1'-isonicotinoyl-N-isopropyl-6-
(pyrrolidine-1-carbonyl)tetrahydrospiro[furo[2,3-c]pyrrole-2,3'-
piperidine]-5(3H)-carboxamide (38). General Method F was
c]pyrrole-2,3'-pyridine]-6-carboxamide (41). General Method F
was applied to tert-butyl (2R*,3aR*,6R*,6aR*)-5-benzyl-6-
(isopropylcarbamoyl)-6a-vinyl-3,3a,4,5,6,6a-hexahydro-2'H-
applied
to
tert-butyl
(2S*,3aR*,6R*,6aR*)-6a-ethyl-5-
spiro[furo[2,3-c]pyrrole-2,3'-pyridine]-1'(6'H)-carboxylate
(23)
(isopropylcarbamoyl)-6-(pyrrolidine-1-
(1.439 g, 2.99 mmol). General Method K was applied to amine
(570 mg, 1.49 mmol) and methanesulfonyl chloride (210 µL, 1.79
carbonyl)hexahydrospiro[furo[2,3-c]pyrrole-2,3'-piperidine]-1'-
carboxylate (35) (87 mg, 0.18 mmol). General Method I was then
applied to resulting amine (22 mg, 0.043 mmol) and isonicotinic
acid (7 mg, 0.056 mmol). The crude mixture was purified using
preparative HPLC to give the title compound as a white solid (15
mg, 69%). 1H NMR (400 MHz, CDCl3) δ 8.69 (dd, J = 4.5, 1.5 Hz,
2H), 7.31 (d, J = 5.1 Hz, 1H), 7.24 (dd, J = 4.5, 1.5 Hz, 2H), 4.83
(s, 1H), 4.68 (d, J = 7.8 Hz, 1H), 4.45 (d, J = 12.9 Hz, 1H), 4.11 –
4.00 (m, 2H), 3.98 – 3.83 (m, 1H), 3.71 (dd, J = 9.4, 3.1 Hz, 1H),
3.57 – 3.48 (m, 2H), 3.45 (d, J = 13.5 Hz, 1H), 3.40 – 3.32 (m,
1H), 3.07 – 2.93 (m, 2H), 2.81 (d, J = 13.1 Hz, 1H), 2.12 (d, J =
13.1 Hz, 1H), 2.05 – 1.77 (m, 7H), 1.74 – 1.58 (m, 2H), 1.44 –
1.34 (m, 1H), 1.12 (d, J = 3.6 Hz, 3H), 1.11 (d, J = 3.8 Hz, 3H),
0.93 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 170.5,
163.0, 156.5, 150.4 (2C), 144.0, 121.0 (2C), 96.8, 82.5, 68.3,
53.5, 50.8, 47.6, 47.2, 46.8, 45.8, 42.6, 40.7, 39.0, 28.2, 26.3,
24.9, 24.4, 23.6, 23.4, 8.9. HRMS (ESI) calcd for C27H40N5O4
[M+H+] 498.3075, found 498.3072.
mmol)
purified
using
flash
column
chromatography
(EtOAc:heptane 3:2, Rf = 0.1) to give the title compound as a
1
white solid (485 mg, 71%). H NMR (400 MHz, CDCl3) δ 7.37 –
7.30 (m, 2H), 7.28 (d, J = 7.1 Hz, 3H), 6.57 (d, J = 8.2 Hz, 1H),
5.96 (dd, J = 17.3, 10.7 Hz, 1H), 5.79 (dt, J = 10.2, 2.0 Hz, 1H),
5.69 (dt, J = 10.2, 3.1 Hz, 1H), 5.26 (dd, J = 17.3, 1.3 Hz, 1H),
5.10 (dd, J = 10.7, 1.3 Hz, 1H), 4.15 – 3.98 (m, 1H), 3.89 (d, J =
13.0 Hz, 1H), 3.87 – 3.79 (m, 1H), 3.66 (dt, J = 17.4, 2.5 Hz, 1H),
3.55 (d, J = 12.5 Hz, 1H), 3.46 (d, J = 2.0 Hz, 1H), 3.43 (d, J =
2.7 Hz, 1H), 3.35 (s, 1H), 3.29 (t, J = 8.6 Hz, 1H), 2.92 (s, 3H),
2.88 – 2.79 (m, 1H), 2.50 (t, J = 9.0 Hz, 1H), 2.05 – 1.90 (m, 2H),
1.13 (d, J = 4.0 Hz, 3H), 1.11 (d, J = 3.9 Hz, 3H); 13C NMR (101
MHz, CDCl3) δ 168.9, 138.6, 137.8, 133.4, 129.0, 128.7 (2C),
127.6 (2C), 123.1, 114.0, 96.6, 81.9, 78.7, 58.5, 58.0, 53.2, 46.9,
44.2, 40.7, 38.8, 36.8, 23.1, 22.9. HRMS (ESI) calcd for
C24H34N3O4S [M+H+] 460.2265, found 460.2298.
(2S*,3aR*,6R*,6aR*)-6a-Ethyl-N-isopropyl-1'-
(2S*,3aR*,6R*,6aR*)-1'-Benzoyl-6a-ethyl-N5-hexyl-N6-
(methylsulfonyl)hexahydrospiro[furo[2,3-c]pyrrole-2,3'-
piperidine]-6-carboxamide (S11). (2R*,3aR*,6R*,6aR*)-5-benzyl-
N-isopropyl-1'-(methylsulfonyl)-6a-vinyl-1',3,3a,4,5,6,6a,6'-
octahydro-2'H-spiro[furo[2,3-c]pyrrole-2,3'-pyridine]-6-
carboxamide (41) (365 mg, 0.79 mmol) was hydrogenated
following General Method B to give the title compound as a white
solid (298 mg, 95%). The amine was used directly without further
purification.
isopropyltetrahydrospiro[furo[2,3-c]pyrrole-2,3'-piperidine]-
5,6(3H)-dicarboxamide (39). General Method G was applied to
(2S*,3aR*,6R*,6aR*)-1'-benzoyl-6a-ethyl-N-
isopropylhexahydrospiro[furo[2,3-c]pyrrole-2,3'-piperidine]-6-
carboxamide (S10) (20 mg, 0.050 mmol) and hexyl isocyanate
(8.8 μL, 0.060 mmol) to give after preparative HPLC the title
compound as a white foam (18 mg, 69%). 1H NMR (400 MHz,
CDCl3) δ 7.46 – 7.38 (m, 3H), 7.38 – 7.32 (m, 2H), 6.49 (d, J = 7.4
Hz, 1H), 4.82 (t, J = 5.1 Hz, 1H), 4.38 (s, 1H), 4.09 – 3.94 (m, 2H),
3.89 – 3.72 (m, 1H), 3.52 – 3.38 (m, 1H), 3.38 – 3.06 (m, 4H),
2.97 – 2.74 (m, 1H), 2.10 (dd, J = 13.0, 3.0 Hz, 1H), 2.01 – 1.56
(m, 6H), 1.56 – 1.37 (m, 3H), 1.31 – 1.20 (m, 6H), 1.13 (d, J = 6.6
Hz, 3H), 1.10 (d, J = 6.5 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H), 0.90 –
0.80 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 170.6, 169.9, 157.5,
136.3, 129.7, 128.7 (2C), 126.6 (2C), 95.7, 82.3, 70.0, 51.7, 47.9,
45.4, 41.4, 41.2, s41.0, 40.4, 38.8, 31.7 (2C), 30.3, 27.2, 26.6,
24.4, 22.7, 22.5, 14.2, 8.8. HRMS (ESI) calcd for C30H47N4O4
[M+H+] 527.3592, found 527.3612.
(2S*,3aR*,6R*,6aR*)-6a-Ethyl-N6-isopropyl-1'-(methylsulfonyl)-
N5-(o-tolyl)tetrahydrospiro[furo[2,3-c]pyrrole-2,3'-piperidine]-
5,6(3H)-dicarboxamide (42). General Method G was applied to
(2S*,3aR*,6R*,6aR*)-6a-ethyl-N-isopropyl-1'-
(methylsulfonyl)hexahydrospiro[furo[2,3-c]pyrrole-2,3'-
piperidine]-6-carboxamide (S11) (20 mg, 0.054 mmol) and o-tolyl
isocyanate (6.8 μL, 0.064 mmol) and provide after preparative
HPLC, the title compound as a white foam (19 mg, 72%). 1H
NMR (400 MHz, CDCl3) δ 7.71 (d, J = 7.9 Hz, 1H), 7.13 (dd, J =
9.8, 3.3 Hz, 2H), 6.98 (td, J = 7.5, 1.1 Hz, 1H), 6.33 (s, 1H), 6.23
(d, J = 7.7 Hz, 1H), 4.42 (s, 1H), 4.10 (t, J = 9.5 Hz, 1H), 4.02 (dq,
J = 13.2, 6.6 Hz, 1H), 3.63 (dd, J = 9.6, 3.3 Hz, 1H), 3.59 – 3.49
(m, 2H), 2.98 (t, J = 8.2 Hz, 1H), 2.87 – 2.76 (m, 2H), 2.73 (s, 3H),
2.38 (d, J = 13.6 Hz, 1H), 2.25 (s, 3H), 1.93 – 1.54 (m, 7H), 1.13
(d, J = 6.6 Hz, 3H), 1.11 (d, J = 6.6 Hz, 3H), 0.98 (t, J = 7.4 Hz,
3H); 13C NMR (101 MHz, CDCl3) δ 169.7, 154.6, 137.0, 130.5,
129.3, 126.6, 124.0, 122.4, 95.9, 82.0, 70.6, 54.5, 53.3, 46.4,
45.6, 41.7, 40.5, 38.3, 36.3, 28.0, 23.6, 22.5, 22.5, 17.9, 9.0.
HRMS (ESI) calcd for C25H39N4O5S [M+H+] 507.2636, found
507.2645.
(2S*,3aR*,6R*,6aR*)-1'-Benzoyl-5-(cyclohexylmethyl)-6a-ethyl-
N-isopropylhexahydrospiro[furo[2,3-c]pyrrole-2,3'-piperidine]-6-
carboxamide (40). General Method
E
was applied to
(2S*,3aR*,6R*,6aR*)-1'-benzoyl-6a-ethyl-N-
isopropylhexahydrospiro[furo[2,3-c]pyrrole-2,3'-piperidine]-6-
carboxamide (S10) (17 mg, 0.043 mmol) and cyclohexane
carbaldehyde (7.7 μL, 0.064 mmol) gave after preparative HPLC
the title compound as a white foam (15 mg, 72%). 1H NMR (400
MHz, CDCl3) δ 7.47 – 7.31 (m, 5H), 6.76 (s, 0.5H), 6.49 (d, J =
7.8 Hz, 0.5H), 4.34 (d, J = 12.4 Hz, 1H), 4.18 – 3.98 (m, 1H), 3.80
(d, J = 13.0 Hz, 0.5H), 3.53 – 3.42 (m, 1H), 3.41 – 3.20 (m, 1.5H),
3.20 – 2.86 (m, 2H), 2.74 – 2.56 (m, 1H), 2.45 – 2.22 (m, 1.5H),
2.08 – 1.95 (m, 1.5H), 1.88 – 1.60 (m, 10H), 1.55 – 1.42 (m, 2H),
1.34 – 1.05 (m, 11H), 0.99 – 0.58 (m, 5H) (two rotamers).13C NMR
(101 MHz, CDCl3) δ 170.5, 169.7, 136.3, 129.8, 128.7, 128.6,
127.8, 126.8, 96.2, 84.7, 81.4, 62.5, 58.3, 57.3, 51.9, 47.8, 46.1
42.3, 40.6, 38.5, 38.2, 36.1, 32.0, 31.6, 31.2, 28.5, 26.8, 26.2,
(2S*,3aR*,6R*,6aR*)-6a-Ethyl-N-isopropyl-1'-(methylsulfonyl)-5-
(thiophen-3-ylmethyl)hexahydrospiro[furo[2,3-c]pyrrole-2,3'-
piperidine]-6-carboxamide (43). General Method E was applied
to
(2S*,3aR*,6R*,6aR*)-6a-ethyl-N-isopropyl-1'-
(methylsulfonyl)hexahydrospiro[furo[2,3-c]pyrrole-2,3'-
piperidine]-6-carboxamide (S11) (20 mg, 0.053 mmol) and 3-
thiophenecarboxaldehyde (7.5 µL, 0.080 mmol) gave after
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10.1002/ejoc.201801551
European Journal of Organic Chemistry
FULL PAPER
preparative HPLC the title compound as a white foam (17 mg,
68%). 1H NMR (400 MHz, CDCl3) δ 7.28 (dd, J = 4.9, 3.0 Hz, 1H),
7.13 (d, J = 2.6 Hz, 1H), 6.99 (dd, J = 4.9, 1.2 Hz, 1H), 6.54 (d, J
= 8.1 Hz, 1H), 4.25 – 4.01 (m, 1H), 3.85 (d, J = 13.4 Hz, 1H), 3.53
– 3.42 (m, 2H), 3.43 – 3.35 (m, 1H), 3.35 – 3.28 (m, 1H), 3.31 (s,
1H), 3.20 (d, J = 12.3 Hz, 1H), 3.10 – 2.98 (m, 1H), 2.93 (s, 3H),
2.58 (td, J = 10.0, 1.9 Hz, 1H), 2.52 – 2.45 (m, 1H), 1.95 (dd, J =
13.5, 2.0 Hz, 1H), 1.84 (dddd, J = 13.9, 10.5, 6.9, 3.7 Hz, 1H),
1.80 – 1.62 (m, 4H), 1.62 – 1.43 (m, 2H), 1.17 (d, J = 6.3 Hz, 3H),
1.15 (d, J = 6.4 Hz, 3H), 0.89 (t, J = 7.3 Hz, 3H); 13C NMR (101
MHz, CDCl3) δ 169.6, 138.6, 128.2, 126.0, 123.1, 96.9, 83.6, 79.1,
59.1, 55.2, 53.2, 45.7, 45.5, 40.8, 39.9, 37.4, 37.0, 28.5, 23.0,
22.94, 22.91, 8.3. HRMS (ESI) calcd for C22H36N3O4S2 [M+H+]
470.2142, found 470.2181.
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(2S*,3aR*,6R*,6aR*)-6a-Ethyl-5-(1H-indole-5-carbonyl)-N-
isopropyl-1'-(methylsulfonyl)hexahydrospiro[furo[2,3-c]pyrrole-
2,3'-piperidine]-6-carboxamide (44). Following General Method J
using
(2S*,3aR*,6R*,6aR*)-6a-ethyl-N-isopropyl-1'-
(methylsulfonyl)hexahydrospiro[furo[2,3-c]pyrrole-2,3'-
piperidine]-6-carboxamide (S11v) (24 mg, 0.064 mmol), indole-5-
carboxylic acid (14 mg, 0.084 mmol) gave after preparative HPLC
the title compound as a white foam (25 mg, 74%). 1H NMR (400
MHz, CDCl3) δ 9.07 (s, 1H), 7.90 (s, 1H), 7.46 – 7.16 (m, 3H),
6.56 (dd, J = 29.2, 11.9 Hz, 2H), 4.87 (s, 1H), 4.31 – 4.01 (m, 2H),
3.53 (dd, J = 11.4, 2.6 Hz, 1H), 3.18 (dt, J = 48.2, 9.0 Hz, 4H),
2.93 – 2.87 (m, 1H), 2.83 (s, 3H), 1.99 – 1.82 (m, 4H), 1.71 – 1.51
(m, 4H), 1.17-1.15 (m, 6H), 1.03 (t, J = 7.3 Hz, 3H) (major
rotamer); 13C NMR (101 MHz, CDCl3) δ 171.9, 168.7, 137.1,
127.3, 126.9, 125.7, 121.7, 120.9, 111.2, 103.1, 94.9, 81.2, 69.3,
55.7, 55.4, 46.2, 45.2, 41.6, 40.5, 37.8, 37.7, 26.9, 22.7, 22.6,
22.5, 8.9 (major rotamer). HRMS (ESI) calcd for C26H37N4O5S
[M+H+] 517.2479, found 517.2476.
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Acknowledgments
The research leading to these results 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
Framework Programme (FP7/2007–2013) and EFPIA companies’
in-kind contribution. We are grateful to DTU Chemistry for an
academic excellence PhD scholarship to NST. We thank Agathe
Gueret, Guillaume Ranty, and Laure Carrier for skillful technical
assistance.
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Keywords: Drug discovery; Heterocycles; Cycloaddition
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10.1002/ejoc.201801551
European Journal of Organic Chemistry
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Entry for the Table of Contents (Please choose one layout)
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An efficient and rapid route to three
structurally distinct scaffolds (A–C)
from a single precursor which in turn
is available through a one-pot Petasis
3-component-reaction–Diels-Alder
cascade reaction. We demonstrate
the versatility of the approach through
the synthesis of 35 exemplary
Library synthesis*
Thomas Flagstad, Carlos M. G.
Azevedo, Nikolaj S. Troelsen, Geanna
K. Min, Yohan Macé, Anthony
Willaume, Rachel Guilleux, Mélanie
Velay, Karine Bonnet, Remy Morgentin,
Thomas E. Nielsen,* Mads H. Clausen*
compounds from the three scaffolds,
as well as by the production of 2188
final compounds, which have been
included in the Joint European
Compound Library of the European
Lead Factory.
Page No. – Page No.
Generation of a Heteropolycyclic and
Sp3-Rich Scaffold for Library
Synthesis from a Highly
Diastereoselective Petasis/Diels-
Alder and ROM-RCM Reaction
Sequence
* Petasis/Diels-Alder
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