Synthesis of skeletally diverse alkaloid-like small molecules

Article abstract of DOI:10.1002/ejoc.201100116

A synthetic approach to skeletally diverse alkaloid-like compounds, involving two consecutive three-component reactions, was developed. First, reaction between a range of secondary amines, carbonyl compounds and triazines yielded cyclic imines. Crucially, the identity of the substituents in the amine and carbonyl compound components determined-through a "folding" pathway-the alkaloid-like scaffold that was prepared. The cyclic imine products were substrates for a second reaction, most usually a Joullie-Ugi reaction with an isocyanide and a carboxylic acid. Thus, the final products were, in general, ultimately derived from five separate components, and wide and independent variation of the substitution of each scaffold was possible. The 43 products were based on 28 distinct graph-node level frameworks. The high skeletal diversity of the products stemmed both from the "folding" pathway used to define the scaffolds of the cyclic imines, and from cyclic substituents used in each of the components. A synthetic approach to skeletally diverse alkaloid-like compounds, involving two consecutive three-component reactions, was developed. First, reaction between a range of secondary amines, carbonyl compounds and triazines yielded alternative complex cyclic imines. The cyclic imineswere substrates for a second reaction, most usually a Joullie-Ugi reaction. The final products were, in general, ultimately derived from five separate components. The 43 products were based on 28 distinct graph-node level frameworks. Copyright

Full text of DOI:10.1002/ejoc.201100116

FULL PAPER
DOI: 10.1002/ejoc.201100116
Synthesis of Skeletally Diverse Alkaloid-Like Small Molecules
[a]
[a]
[b]
[c]
Sarah Murrison, Sushil K. Maurya, Christian Einzinger, Ben McKeever-Abbas,
[a]
[a]
Stuart Warriner, and Adam Nelson*
Keywords: Diversity-oriented synthesis / Multi-component reactions / Molecular diversity / Alkaloids
A synthetic approach to skeletally diverse alkaloid-like com-
pounds, involving two consecutive three-component reac-
tions, was developed. First, reaction between a range of sec-
ondary amines, carbonyl compounds and triazines yielded
cyclic imines. Crucially, the identity of the substituents in the
amine and carbonyl compound components determined –
through a “folding” pathway – the alkaloid-like scaffold that
was prepared. The cyclic imine products were substrates for
a second reaction, most usually a Joullié–Ugi reaction with
an isocyanide and a carboxylic acid. Thus, the final products
were, in general, ultimately derived from five separate com-
ponents, and wide and independent variation of the substitu-
tion of each scaffold was possible. The 43 products were
based on 28 distinct graph-node level frameworks. The high
skeletal diversity of the products stemmed both from the
“folding” pathway used to define the scaffolds of the cyclic
imines, and from cyclic substituents used in each of the com-
ponents.
Introduction
The alkaloids are an extremely diverse group of natural
products that generally possess a basic nitrogen atom. In
morphine and strychnine, for example, the basic nitrogen is
found in the context of a highly complex polycyclic scaffold
Historically, chemists have explored chemical space in an
exceptionally uneven and unsystematic manner, with half of
known compounds being based on just 0.25% of the known
molecular scaffolds![1] Indeed, the development of synthetic
approaches that allow wide variation of the molecular scaf-
folds of small molecules has proved extremely challeng-
ing.[ Synthetic strategies have, however, been developed to
(Figure 1). In this paper, we describe a synthetic approach
to skeletally diverse alkaloid-like compounds which exploits
[8]
two consecutive three-component reactions (Scheme 1).
2]
allow the scaffolds of small molecules to be varied. In the
folding” pathway strategy,[ the scaffolds of products are
3]
“
determined by structural features in the starting materials
[
3]
(
“
sometimes referred to as σ elements ). In contrast, in the
branching” pathway strategy,[ complementary reactions
4]
convert common starting materials into a range of skeletally
diverse products. Molecular scaffolds may also be varied
Figure 1. Chemical structures of the alkaloid natural products,
morphine and strychnine.
using the “build-couple-pair” strategy in which building
blocks are exploited judiciously in combination:[
2a,5]
here
building blocks are prepared (built), connected (coupled),
and then reacted intramolecularly (paired), to yield alterna-
tive molecular scaffolds. We recently used the “build-cou-
ple-pair” strategy to harness metathesis cascade chemistry
in the synthesis of natural product-like small molecules with
unprecedented scaffold diversity.[
Initially, it was envisaged that a three-component reac-
tion involving a secondary amine 1, a carbonyl compound
(
e.g. 2) and a triazine 3 would be used to define an alkaloid-
[
9]
like scaffold (e.g. 6, 7 or 8). Thus, condensation between
the secondary amine 1 and the carbonyl compound 2 was
expected to yield an enamine 4 which could undergo an
inverse-electron demand Diels–Alder reaction with the tri-
azine 3 (Ǟ 5); expulsion of molecular nitrogen would then
yield a 2-aza-diene 6. In a subsequent “folding” pathway,[
the substituents in the 2-aza-diene 6 would determine the
molecular scaffold obtained. Thus, in the absence of a teth-
ered dienophile, the 2-aza-diene 6 would be the product of
the reaction. However, with an appended dienophile in
6,7]
[
a] School of Chemistry and Astbury Centre for Structural
Molecular Biology, University of Leeds,
Leeds, LS2 9JT, UK
3]
Fax: +44-113-343-6401
E-mail: a.s.nelson@leeds.ac.uk
[
[
b] Institute of Applied Synthetic Chemistry,
Getreidemarkt 9/163, 1060 Vienna, Austria
c] AstraZeneca, Hurdsfield Industrial Estate,
Macclesfield, SK10 2NA, UK
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100116.
1
3
either the R or R substituent, a subsequent intramolecu-
2354
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Synthesis of Skeletally Diverse Alkaloid-Like Small Molecules
Table 1. Three-component reactions between secondary amines 1,
aldehydes 2 and triazines 3.
Scheme 1. Overview of the proposed synthetic approach.
1
lar Diels–Alder reaction could take place [e.g. with R =
3
allyl Ǟ 7, or with R = (E)-oct-3-enyl Ǟ 8] to yield an
alternative scaffold. The cyclic imines 6, 7 and 8 are all po-
tential substrates for a second three-component reaction –
a Joullié–Ugi reaction[
9c,10]
– to yield products such as 9, 10
and 11. Finally, it was envisaged that imine intermediates
such as 7–9) might also be fragmented or cyclised: for ex-
(
3
ample, cyclisation of a pendant nucleophile in R might al-
low allow the synthesis of additional molecular scaffolds
(e.g. 7 Ǟ 12). Crucially, in this synthetic approach, each of
the final products would ultimately have been derived from
up to five separate components, allowing wide and indepen-
dent variation of the substitution of each scaffold.
Results and Discussion
The outcomes of three-component reactions between
secondary amines 1, carbonyl compounds 2 and triazines 3
are summarised in Table 1. In general, a triazine 3, a sec-
ondary amine 1 (5 equiv.) and a carbonyl compound 2
(5 equiv.) were refluxed in toluene in the presence of 4-Å
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A. Nelson et al.
FULL PAPER
Table 1. (Continued).
The 2-aza-dienes 6 were obtained in the absence of an
appended dienophile. Thus, with saturated substrates – di-
ethylamine (1a) and pentanal (2a) – the 2-aza-dienes 6a–b
were obtained with Ͼ98:Ͻ2 diastereoselectivity. Here, the
high trans selectivity was consistent with stereospecific reac-
tion between a trans-configured enamine 4 and a triazine 3.
In contrast, with an allylic secondary amine, such as 1b–
f, a polycyclic imine (7, 14 or 16) was generally obtained.
The outcome of these reactions was consistent with the de-
livery of the dienophile to the 2-aza-diene intermediate 6 to
control the diastereoisomer produced. The reaction was
high yielding with unsaturated amines with either an unsub-
stituted or a substituted (2- or 3-bromoallyl) allyl substitu-
1
ent, R . It was envisaged that it might be possible exploit
radical chemistry to induce fragmentation of the bromin-
ated scaffolds 13 and 14.
An intramolecular Diels–Alder reaction was also ob-
3
served with a dienophile appended in the R . Thus with
diethylamine, (E)-deca-5-enal (2e), and the triazine 3a, the
polycyclic imine 8a was obtained. Again, the outcome of
the reaction was consistent with delivery of the dienophile
to the corresponding 2-aza-diene intermediate 6. Surpris-
ingly, with the combination of 1a, 2d and 3b, a low yield of
[
a] For the structures of the reagents, see Figure 1. [b] Reaction the 2,4-disubstituted pyridine 15 was obtained, presumably
conditions: triazine 3, secondary amine 1 (5 equiv.), aldehyde 2
5 equiv.), 4-Å molecular sieves, toluene, Δ. [c] Analysis of the crude
[11]
after elimination of the corresponding amine 6.
(
1
Remarkably, slow rotation around the single bond be-
product by 500 MHz H NMR spectroscopy revealed a Ͼ98:Ͻ2
mixture of diastereomers. [d] The reaction was performed in anhy-
drous chloroform.
tween the p-substituted phenyl ring and the polycyclic ring
1
system (Figure 3) was evident from the 500 MHz H NMR
spectrum of the imine 8a. Although we had previously ob-
served slow bond rotation in more heavily substituted deriv-
atives, slow rotation was not evident in other polycyclic
imines such as 7, 13, 14 or 16. We used variable temperature
molecular sieves. (Figure 2) Thus, a wide range of skeletally
diverse products 7–8 and 13–17 were obtained, invariably,
where relevant, with high (Ͼ98:Ͻ2) diastereoselectivity. For
each scaffold, the sense of diastereoselectivity was deter-
mined after conversion into a derivative.
[9c]
NMR experiments to measure the barrier to bond rotation
–1
for 8a in [D ]DMSO (70 kJmol ) (see Supporting Infor-
6
mation).
Figure 3. Slow bond rotation in the polycyclic imine 8a. Two pairs
A
B
C
D
of diastereotopic aryl protons (H /H and H /H ) were evident in
1
3
the 500 MHz H NMR spectrum in CDCl at 298 K.
The use of a cyclic ketone as the carbonyl component –
cyclopentanone 2f – resulted in the scaffolds 16 with an
additional ring fused to the polycyclic core. Furthermore, it
was possible to incorporate a pendant nucleophilic group
in the carbonyl component – in the Cbz-protected β-amino
aldehyde 2g – to promote cyclisation after formation of the
polycyclic imine scaffold 7. Thus with the allylic amine 1b,
the triazine 3a and 2g, the cyclised product 17 was obtained
in 97% yield.
The imines 6, 7, 8, 13, 14 and 16 were treated with appro-
4
5
priate isocyanides, R NC, and carboxylic acids, R CO H,
Figure 2. The secondary amines 1, aldehydes 2 and triazines 3 ex-
ploited in three-component reactions (see Table 1).
2
in ethanol at room temperature, and the corresponding sub-
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Synthesis of Skeletally Diverse Alkaloid-Like Small Molecules
stituted products 9, 10, 11, 18, 19 and 20 (Figure 4) were
obtained (Table 2). In most cases, the products were ob-
tained with high (Ͼ98:Ͻ2) diastereoselectivity. However,
with the 2-aza-dienes 6a and 6b, the diastereoselectivity of
the reaction was considerably lower (70:30 to 85:15, see
Table 2). The relative configuration of the products 9, 10,
1
8, 19 and 20 was assigned by correlation with related de-
[9c]
Figure 5. Assignment of the relative configuration of the products
a and 11b. Diagnostic NOESY correlations are indicated.
rivatives of known configuration. The relative configura-
tion of the major products 9a and the exclusive product 11b
was determined by the observation of diagnostic NOESY
correlations (Figure 5).
9
Figure 4. General structures of the products of Joullié–Ugi reac-
tions.
The stereochemical outcome of the Joullié–Ugi reactions
[
12]
of the imines 6, 7 and 8 is rationalised in Figure 6.
In
each case, the isocyanide can attack either face of the imine;
reaction with a carboxylic acid and cyclisation would then
yield the cyclic intermediates 21, 22 or 23. In these cyclic and 16 may be rationalised analogously to those of the imines 7.
Figure 6. Rationalisation of the stereochemical outcome of Joullié–
Ugi reactions. The outcome of the reactions of the imines 13, 14
Table 2. Outcome of Joullié–Ugi reactions.
Starting material
Ar
R1
R2
R3
Product[a,b] (% yield) R4
R5
b,c]
6
6
6
7
7
7
7
7
7
7
7
7
7
7
1
1
8
8
1
1
1
1
1
a
p-NCC
p-NCC
6
6
H
H
4
Et
Et
Et
Et
Et
Et
–
–
–
–
–
–
–
–
–
–
–
–
–
Et
Et
–
Pr
Pr
Pr
iPr
iPr
iPr
iPr
Bn
Bn
Bn
Bn
Pr
Pr
Pr
Pr
Pr
–
9a (42)[
Bn
Bn
Bu
Bn
CH
Bn
CH
Bn
CH
Bn
CH
cHex
cHex
cHex
cHex
cHex
Bn
3-furanyl
4-tetrahydropyranyl
Ph
3-furanyl
3-furanyl
4-tetrahydropyranyl
4-tetrahydropyranyl
3-furanyl
3-furanyl
4-tetrahydropyranyl
4-tetrahydropyranyl
iPr
tBu
Me
Me
Me
3-furanyl
3-furanyl
Ph
Me
CF
3
FmocHNCH
Ph
[b,d]
a
4
9b (47)[
b,c]
b
m-O
2
NC
6
H
4
9c (36)
b,e]
b,e]
a
p-NCC
p-NCC
p-NCC
p-NCC
p-NCC
p-NCC
p-NCC
p-NCC
6
6
6
6
6
6
6
6
H
H
H
H
H
H
H
H
4
4
4
4
4
4
4
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Bn
10a (48)[
[
a
10b (23)
2
2
2
2
CO
CO
CO
CO
2
2
2
2
Et
Et
Et
Et
b,e]
a
10c (64)[
10d (62)[
10e (78)
[b,e]
a
b,e]
b
[
b,e]
b
10f (23)
b,e]
b
10g (39)[
[b,e]
b
4
10h (28)
[
b,e]
e
p-O
p-O
p-O
p-O
p-O
2
2
2
2
2
NC
NC
NC
NC
NC
6
6
6
6
6
H
4
10i (86)
b,e]
f
f
H
H
H
H
4
4
4
4
10j (82)[
[b,e]
10k (63)[
18a (79)
19a (26)[
b,e,f]
b,e]
3
Bn
Bn
Et
Et
4
[b,e]
a
p-NCC
p-NCC
6
H
H
4
11a (91)
b,e]
a
6
4
–
–
–
–
–
–
11b (46)[
CH
2
CO
2
Et
b,e]
6a
6b
6b
6b
6c
m-O
m-O
m-O
m-O
2
2
2
2
NC
NC
NC
NC
6
6
6
6
H
H
H
H
4
4
4
4
Bn
20a (80)[
cHex
cHex
cHex
cHex
cHex
[
b,e,g]
b,e,g]
b,e,g]
b,e,g]
allyl
allyl
allyl
allyl
–
–
–
–
20b (90)
20c (97)[
[
20d (46)[
2
p-NCC
6
H
4
20e (66)
[
a] Reaction conditions: imine, carboxylic acid (2 equiv.), isocyanide (2 equiv.), EtOH, room temp. For the imines 6, 9 equiv. of the acid
1
and the isocyanide were used. [b] The diastereomeric ratio of the purified products (Figure 4) was determined by 500 MHz H NMR
spectroscopy. [c] 70:30 mixture of diastereomers. [d] 85:15 mixture of diastereomers. [e] Ͼ98:Ͻ2 mixture of diastereoisomers. [f] In
addition, 60% of the corresponding unacetylated product was obtained. [g] Obtained as a mixture of rotamers.
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A. Nelson et al.
FULL PAPER
intermediates, steric interactions involving the new five- bonyl compounds 2 and triazines 3 may, therefore, be useful
membered ring are minimised: in 21 and 23, interaction in other diversity-oriented synthetic approaches.
1
2
with the R R N substituent is avoided; and in 22, interac-
The cyclic imine products were substrates for a second
3
tion with R group is avoided. After acyl transfer, therefore, reaction. Most usually, a Joullié–Ugi reaction involving an
the observed products 9, 10 and 11 were obtained. The re- isocyanide and a carboxylic acid was used to yield final
actions of the imines 13, 14 and 16 (to give 18, 19 and 20) products derived from five separate components, this al-
may be rationalised analogously to those of the imines 7 lowing wide and independent variation of substitution. In
(Scheme 2).
addition, cyclisation of a pendant nucleophile onto the cy-
clic imine enabled the synthesis of an additional distinct
molecular scaffold.
To assess of the overall synthetic approach, the scaffold
diversity of the products 7–11, 13–20 and 24 was analysed.
The 43 products were based on 28 distinct frameworks at
[
1]
the graph-node level (see Figure 7). The high skeletal di-
versity of the products stemmed both from the power of
the “folding” pathway strategy used (which defined the
scaffolds of the cyclic imines, see Table 1), and from ability
to vary substitution widely and independently. The power
of the overall synthetic approach stemmed from the exploi-
tation of consecutive multi-component reactions, a strategy
which is likely to be applied more widely in synthesis.
Scheme 2. Reduction of the p-nitrophenyl group in the polycyclic
compounds 8i and 8j.
Two alternative approaches to induce the fragmentation
of the products of Joullié–Ugi reactions were briefly investi-
gated. Initially, the reduction of the nitro groups[13] in the
polycyclic compounds 10i, 10j, 10k and 18a and acetyl-
ation, gave the corresponding N-acetylated derivatives 24a–
d. Unfortunately, exposure of 10j, 24a and 24b to alterna-
tive acid conditions did not result in cleavage of the benzylic
C–N bond: instead, the only reaction observed was the
5
cleavage of the R CO acyl group (see Supporting Infor-
mation). Secondly, the potential for fragmentation of the
radical generated from 24d was also investigated. Unfortu-
nately, treatment of 24d with tributyltin hydride and 1,1Ј-
azabis(cyclohexylcarbonitrile) in benzene at reflux did not
result in fragmentation: instead, the corresponding reduced
product 24c was obtained in 88% yield.
Conclusions
Figure 7. Analysis of the frameworks of the products at the graph-
node level. The 28 distinct scaffolds are shown as black dots at the
outside of the diagram, together with the number of compounds
prepared in each case. The diagram is divided into 10 segments that
A synthetic approach to skeletally diverse alkaloid-like
compounds, involving two consecutive three-component re-
actions, was developed. First, reaction between a range of
secondary amines, carbonyl compounds and triazines correspond to the skeletal diversity that results directly from the
“
folding” pathway approach; within each segment, the alternative
yielded cyclic imine intermediates. Crucially, the identity of
the substituents in the amine and carbonyl compound com-
ponents determined – through a “folding” pathway – the
alkaloid-like scaffold that was prepared. Remarkably, there-
fore, the reaction enabled both the condensation of three
1
3
4
5
scaffolds stem from cyclic substituents R , R , R and R in the
reactants used.
reagents – to give the 2-aza-diene intermediate 6 – and the Experimental Section
subsequent “folding” to yield alternative alkaloid-like scaf-
folds. Multi-component reactions are extremely valuable in
diversity-oriented synthesis, and the field is currently
General Procedure for Three-Component Reactions Between a Sec-
ondary Amine, a Triazine and a Carbonyl Compound: The second-
ary amine (5 equiv.), the carbonyl component (5 equiv.) and 4-Å
strongly reliant on the power of variants of the Ugi reac- molecular sieves (three times the mass of triazine) were added to a
[
2]
tion: this three-component reaction between amines, car- solution of the triazine (1 equiv.) in toluene (ca. 0.15 m) at room
358
2
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Synthesis of Skeletally Diverse Alkaloid-Like Small Molecules
temperature. The reaction mixture was heated at reflux until com-
pletion was indicated by TLC (24–72 h) and concentrated under
reduced pressure to give a crude product.
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stirred at room temperature until completion was indicated by TLC
5674.
(
24–48 h) and diluted with CH
organic layer was washed with 2 m aqueous sodium carbonate solu-
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reduced pressure to give a crude product.
2 2
Cl (20ϫ reaction volume). The
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Received: January 26, 2011
Published Online: March 8, 2011
Eur. J. Org. Chem. 2011, 2354–2359
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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