Diastereoselective synthesis of novel heterocyclic scaffolds through tandem Petasis 3-component/intramolecular Diels-Alder and ROM-RCM reactions

Article abstract of DOI:10.1039/c7cc02948a

A high-yielding, stereoselective and extraordinarily complexity-generating Petasis 3-component/intramolecular Diels-Alder reaction has been developed. In combination with ROM-RCM, rapid access to complex sp³-rich heterocyclic scaffolds amenable

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
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Diastereoselective Synthesis of Novel Heterocyclic Scaffolds
through Tandem Petasis 3-Component/Intramolecular Diels-Alder
and ROM-RCM Reactions
Received 00th January 20xx,
Accepted 00th January 20xx
Mette Ishoey,a,† Rico G. Petersen,a,† Michael A. Petersen,a Peng Wu,a Mads H. Clausen,a,b* and
Thomas E. Nielsena,c,d*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A high-yielding, stereoselective and extraordinarily complexity- Petasis 3-component reaction (Petasis 3-CR) with Ru-
generating Petasis 3-component/intramolecular Diels-Alder alkylidene catalyzed ring-closing metathesis (RCM).5b To
reaction has been developed. In combination with ROM-RCM, further develop this strategy, we employed 2-furylboronic acid
rapid access to complex sp3-rich heterocyclic scaffolds amenable in the Petasis 3-CR of masked
α-hydroxy aldehyde 1 (racemic)
to subsequent functionalization and library synthesis is provided.
and diallylamine, and we were delighted to observe that a
consecutive intramolecular Diels-Alder (IMDA) reaction
High-throughput screening (HTS) remains a preferred
provided
2
in 68% yield as a single diastereomer (Figure 1A).
approach for the identification of novel starting points for
chemical biology probe and drug discovery.1 Hence,
parameters such as size, design and quality of molecular
screening collections are of crucial importance for the
successful outcome of HTS campaigns. In recent years, it has
become apparent that traditional screening collections, which
are largely dominated by ‘flat’ (sp2-rich), small molecules lack
the structural complexity and diversity required to target more
challenging biological targets such as protein-protein
interactions, transcription factors and nucleic acid
macromolecules.2 Aiming for a better coverage of biologically
relevant chemical space,3 strategies relying on concise and
efficient synthetic pathways for the generation of structurally
diverse molecular libraries, featuring a higher content of sp3-
hybridization, scaffold complexity and functional group
diversity have been developed.4 Importantly, while providing
access to molecular frameworks that mimic the structural
complexity of natural products, these strategies focus on
enabling the synthesis of structural analogs to allow for a
smoother downstream optimization and advancement of
screening hits.
A)
OH
N
H
CH2Cl2:
HFIP (3:1)
+
O
O
O
reflux
(HO)2B
1
Petasis
3-CR/
ROM-RCM
H
O
H
N
N
Grubbs II,
HCl
IMDA
H
H
HO
CH2Cl2, rt
O
OH
2, 68%
4, 66%
Grubbs II
PhMe, reflux
RCM
H
O
N
H
OH
3
B)
Petasis 3-CR/
IMDA
ROM-RCM
Building
blocks
I
II
R1= allyl
R2
In our continuing efforts to develop strategies for the
generation of structurally diverse compound libraries,5 we
recently reported a build/couple/pair strategy4e combining the
R2
N
H
H
N
H
H
R1
HO
R3
O
R3
O
OR4
I
R5
II
Figure 1: Tandem Petasis 3-CR/IMDA reaction combined with
a
ROM-RCM
sequence: A) Reaction discovery and X-ray confirmation of structure; B) Strategy
for utilization of the reaction sequence in the synthesis of libraries based on
densely functionalized heterocyclic scaffolds.
In an attempt to promote RCM,
2
was subjected to Grubbs 2nd
generation catalyst (Grubbs II), however, one equivalent of
hydrochloric acid was required to promote full conversion.
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Interestingly, instead of the RCM product
3, the tricyclic
4).Furthermore, the use of masked
α-hydroxy aldehyde 1 in
scaffold
(ROM-RCM) reaction was isolated in 66% yield. The structure
of was verified by X-ray crystallography, which indirectly
4 resulting from a ring-opening ring-closing metathesis
combination with furylboronic acid 7b was well-tolerated for
various allylamines (entries 5-8), although the yield of 8g was
slightly lower. The use of salicylaldehyde in the Petasis 3-
CR/IMDA reaction with benzyl allylamine and 2-furylboronic
acid gave the corresponding product in 84% yield (see ESI), and
the X-ray structure unambiguously confirmed the
diastereoselectivity of the transformation.
4
confirmed the diastereoselectivity assigned to the IMDA
reaction.
Intrigued by the molecular complexity accessible in only two
synthetic operations, we envisaged the synthesis of screening-
relevant molecular libraries based on scaffolds I and II (Figure
To allow for
a more modular introduction of amine
1B). The multicomponent nature of the Petasis 3-CR would
allow for variation of appendage diversity around the core
scaffolds, and through appropriate incorporation of functional
groups, additional downstream diversifications would be
possible. We decided to probe the scope of the tandem Petasis
3-CR/IMDA reaction using glycolaldehyde (R1 = H), as this
would allow for the construction of a sub-library based on I,
where diversification of the resulting primary alcohol would
invoke no stereochemical consequences.
appendages, R2, we investigated the possibility of deallylating
8c, and then, through reductive amination, re-introduce amine
substituents.
Table 2: Deallylation, reductive amination, O-arylation and primary amine
functionalization for the synthesis of densely functionalized compounds 12.a
The Petasis 3-CR was conducted in methanol at room
temperature (Table 1). Under these reaction conditions,
subsequent IMDA reactions remained incomplete, and it
proved more efficient to conduct this step in refluxing
acetonitrile following removal of methanol in vacuo. Thus, the
use of glycolaldehyde and 2-furylboronic acid in combination
with diallylamine (entry 1) or benzyl allylamine (entry 2)
afforded the products as single diastereomers in good yields.
The stereochemistry of the products, resulting from an exo
transition state with the dienophile approaching from the Si
Ph
H
N
H
N
O
O
H
NH
H
O
NH
Ph
O
face, was determined by 2D NOESY correlations of 8b §
.
O
O
Table 1: Scope of the one-pot tandem Petasis 3-CR/IMDA reaction.
OMe
Br
12a
12b
63%b, 57%c, 71%d
72%b, 60%c, 66%d
H
N
H
N
Ph
O
O
H
O
H
O
NH
NH
NH
O
O
Product; yield
(%)a
Entry
R1
R2
R3
NH
Hb
allyl
Bn
H
H
8a, 65c
8b, 77c
8c, 97
Ph
4
1
2
3
4
5
6
7
8
F
Me
12c
12d
Hb
65%b, 34%c, 79%d
72%b, 64%c, 86%d
Hb
allyl
allyl
allyl
Bn
CH2NHBoc
H
CH2NHBoc
CH2NHBoc
CH2NHBoc
CH2NHBoc
H
N
allyld
allyld
allyld
allyld
allyld
2, 91
H
N
8d, 88
8e, 84
8f, 72
O
H
F
DMBe
Me
NH
O
OPh
O
H
O
S
8g, 47
NH
Me
O
O
S
a Isolated yield after flash column chromatography. b Glycolaldehyde dimer was
used as the aldehyde component. c Overall yield over two steps with isolation of
the Petasis product (see ESI). d Masked α-hydroxy aldehyde 1 was used as the
aldehyde component. e DMB = 2,4-dimethoxybenzyl.
O
F3C
12e
12f
56%b, 71%c, 78%d
57%b, 56%c, 78%d
Me
a
Reagents and conditions: a) Pd(PPh3)4, isopropylidene 2-methylmalonate,
CHCl3, reflux; b) R1CHO, NaBH(OAc)3, CH2Cl2, rt, 4 Å M.S; c) (i) ArOH, DEAD,
PPh3, THF, 0 oC to rt; (ii) TFA, CH2Cl2, 0 oC to rt; d) Carboxylic acid, PyBOP,
iPr2EtN, CH2Cl2, rt; e) Isocyanate, iPr2EtN, CH2Cl2, rt; f) Sulfonyl chloride,
iPr2EtN, CH2Cl2, rt. b Yield of 10. c Yield of 11. d Yield of 12.
Pleasingly, the use of the Boc-protected 5-aminomethyl-
substituted 2-furylboronic acid 7b gave the corresponding
product 8c in quantitative yield, thereby providing an
additional handle for downstream diversification (entry 3).
Importantly, these conditions minimized the formation of a by-
The use of Pd(PPh3)4 and N,N-dimethylbarbituric acid in
refluxing chloroform6 gave full conversion of 8c to
9, but it
product resulting from the reaction of masked α-hydroxy
aldehyde with the furyl boronic acid 7b (see ESI), in
1
proved challenging to remove the barbituric acid by-products
during purification. However, the use of methyl Meldrum’s
acid (isopropylidene 2-methylmalonate)7 effectively solved this
contrast to when the reaction was carried out in a mixture of
refluxing CH2Cl2 and HFIP (Figure 1). Consequently, the yield
of 2 was improved from the original 68% to 91% (entry
2 | J. Name., 2012, 00, 1-3
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9
could be isolated in 51% yield (Table 2). We yield (entries 4 and 5, respectively), while 13d was isolated in
noted that the use of aqueous ammonium hydroxide as co- slightly lower yield (56%) (entry 5). Attempts to bring about
solvent for flash-column chromatography8 was crucial, as the ROM-RCM reaction of 8d in the absence of hydrochloric
triethylamine proved impossible to remove.
acid were unsuccessful. Altogether these findings suggested
Reductive amination of the secondary amine with NaBH(OAc)3 that the nucleophilicity as well as steric hindrance of the amine
proceeded smoothly with both aromatic and aliphatic were determining factors for the ROM-RCM reaction.
aldehydes to give 10 in good yields (Table 2). The primary Implementing the same modular approach for installation of
hydroxyl group was then arylated with a set of phenols using amine appendages as before,
4 and 13a were deallylated
the Mitsunobu reaction. Both electron-rich and electon-poor (Table 4). Pleasingly, only the most accessible allylic olefin
phenols, as well as more sterically demanding entities, were reacted to provide secondary amines 14a and 14b in good
well-tolerated, and following Boc-deprotection, primary yields of 65% and 70%, respectively (Table 4). The versatility of
amines 11 were isolated in good yields over two steps. The this approach was further demonstrated through both
concomitant Boc-deprotection was necessary in order to reductive amination and PyBOP-mediated acylation with
effectively remove by-products from the Mitsunobu reaction. carboxylic acids, to afford tertiary amines and amides 15. For
A
final diversification step consisting of acylation, example, amide 15c would otherwise be inaccessible through
carbamoylation and sulfonylation of the primary amines 11 the Petasis 3-CR. Functionalizations of the primary amine were
afforded the densely functionalized 12 Hence, library subsequently realized through Boc-deprotection followed by
members ( ) were obtained in just five synthetic operations acylation, carbamoylation or sulfonylation to afford final
,
.
I
from commercially available starting materials, thereby library members 16
.
validating the proposed library strategy.
Table 4: Deallylation, reductive amination and acylation, followed by primary amine
Encouraged by these results, we investigated the scope of the
ROM-RCM reaction (Table 3), with the goal of exploring a
broader library design by utilizing the reaction to introduce
scaffold diversity.
functionalization for the synthesis of novel scaffolds 16.a
Table 3: Scope of the ROM-RCM reaction.
Entry
Substrate
R1
R2
Product, yield (%)a
13a, 62
1
2
3
4
5
8d
2
allyl
allyl
Bn
CH2NHBoc
H
4, 76
8e
8f
8g
CH2NHBoc
CH2NHBoc
CH2NHBoc
13b, 72, (80)b
13c, N.D.,d (76)b
13d, 65, (56)b
DMBc
Me
a Isolated yield after flash column chromatography. b Reaction conditions:
Grubbs II (10 mol%), toluene, reflux. c DMB = 2,4-dimethoxybenzyl. d N.D. = not
determined.
Compared to the initial reaction conditions used for R2 = H
(Figure 1A), substrates with R2 = CH2NHBoc (Table 3), required
elevated temperatures to bring about full conversion of
starting materials. Pleasingly, 13a was obtained from 8d in a
good yield of 62% (entry 1). By employing these conditions to
the original substrate (2) the yield of 4 was improved from 66%
to 76% (entry 2). Satisfyingly, also the benzyl- and methyl-
substituted amines (8e and 8g, respectively) readily underwent
ROM-RCM to give the corresponding products 13b and 13d in
72% and 65% yield (entries 3 and 5), respectively. Interestingly,
the ROM-RCM reaction of benzyl-, 2,4-dimethoxybenzyl
(DMB)- and methyl-substituted amines took place in the
absence of hydrochloric acid when the reaction was conducted
in refluxing toluene (entries 3-5). Under these conditions the
yield of 13b was improved to 80%, 13c was isolated in 76%
a
Reagents and conditions: a) Pd(PPh3)4, isopropylidene 2-methylmalonate,
CHCl3, reflux; b) R1CHO, NaBH(OAc)3, CH2Cl2, rt, 4 Å mol sieves; c) Carboxylic
acid, PyBOP, Et3N, CH2Cl2, rt; d) (i) TFA, CH2Cl2, rt; (ii) Carboxylic acid, PyBOP,
o
Et3N, CH2Cl2, rt; e) (i) TFA, CH2Cl2, rt; (ii) Acid chloride, Et3N, CH2Cl2, 0 C to rt;
f) (i) TFA, CH2Cl2, rt; (ii) Isocyanate, Et3N, CH2Cl2, rt; g) (i) TFA, CH2Cl2, rt; (ii)
Sulfonyl chloride, Et3N, CH2Cl2, 0 oC to rt. Yield of 15. Yield of 16. DMB =
b
c
d
2,4-dimethoxybenzyl.
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2003, 302, 613; (d) M. D. Burke and S. L. Schreiber, Angew.
The introduction of the acryl amide moiety in 16b provided the
opportunity for further diversification through RCM of the
terminal olefin, and the spirocyclic product 17 was isolated in
78% yield (Scheme 1). Cross-metathesis (CM) reactions were
also investigated as a means of olefin functionalization, and
while substrates with R3 = CH2NHBoc only resulted in traces of
product, Hoveyda-Grubbs 2nd generation catalyst (H-G II) in
combination with copper(I)iodide9 efficiently promoted the
CM of 16e with ethyl acrylate to afford 18 in 74% yield.
Chem. Int. Ed., 2004, 43, 46; (e) T. E. Nielsen and S. L. Schreiber,
Angew. Chem. Int. Ed., 2008, 47, 48; (f) W. R. J. D. Galloway, A.
Isidro-Llobet and D. R. Spring, Nat. Commun., 2010, 1, 80; (g) S.
L. Schreiber, Proc. Natl. Acad. Sci. USA, 2011, 108, 6699; (h) A.
Nadin, C. Hattotuwagama and I. Churcher, Angew. Chem. Int.
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Daugaard and T. E. Nielsen, ACS Comb. Sci., 2012, 14, 253; (c) S.
T. Le Quement, T. Flagstad, R. J. T. Mikkelsen, M. R. Hansen, M.
C. Givskov and T. E. Nielsen, Org. Lett., 2012, 14, 640; (d) R.
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R1
H
H-G II, CuI
N
H
ethyl acrylate
CH2Cl2, reflux
Grubbs II
HO
R2
CH2Cl2, reflux
O
R2 = CH2NHCOCHCH2
R2 = H
16b or 15c
O
H
Ph
N
H
H
Ph
N
H
HO
HO
NH
O
O
O
18, 74%
17, 78%
CO2Et
Scheme 1: Functionalizaton of the terminal olefin via RCM and CM.
In summary, we have developed a concise strategy for the
synthesis of complex heterocyclic scaffolds utilizing a highly
diastereoselective tandem Petasis 3-CR/IMDA reaction in
combination with
incorporation of strategically positioned functional groups, we
have synthesized library of densely diversified small
a ROM-RCM sequence. Through the
a
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molecules that mimic the structural complexity of natural
products.
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. The Technical University of
Denmark is gratefully acknowledged for financial support and
we thank Associate Professor Pernille Harris for assistance with
X-ray crystallography
.
Notes and references
§ See NOESY assignments for 8b in ESI
.
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