Probing chemical space with alkaloid-inspired libraries

Article abstract of DOI:10.1038/nchem.1844

Screening of small-molecule libraries is an important aspect of probe and drug discovery science. Numerous authors have suggested that bioactive natural products are attractive starting points for such libraries because of their structural complexity and sp 3 -rich character. Here, we describe the construction of a screening library based on representative members of four families of biologically active alkaloids (Stemonaceae, the structurally related cyclindricine and lepadiformine families, lupin and Amaryllidaceae). In each case, scaffolds were based on structures of the naturally occurring compounds or a close derivative. Scaffold preparation was pursued following the development of appropriate enabling chemical methods. Diversification provided 686 new compounds suitable for screening. The libraries thus prepared had structural characteristics, including sp 3 content, comparable to a basis set of representative natural products and were highly rule-of-five compliant.

Full text of DOI:10.1038/nchem.1844

ARTICLES
PUBLISHED ONLINE: 19 JANUARY 2014 | DOI: 10.1038/NCHEM.1844
Probing chemical space with alkaloid-inspired
libraries
Michael C. McLeod, Gurpreet Singh, James N. Plampin III, Digamber Rane, Jenna L. Wang,
´
Victor W. Day and Jeffrey Aube
*
Screening of small-molecule libraries is an important aspect of probe and drug discovery science. Numerous authors have
suggested that bioactive natural products are attractive starting points for such libraries because of their structural
complexity and sp3-rich character. Here, we describe the construction of a screening library based on representative
members of four families of biologically active alkaloids (Stemonaceae, the structurally related cyclindricine and
lepadiformine families, lupin and Amaryllidaceae). In each case, scaffolds were based on structures of the naturally
occurring compounds or a close derivative. Scaffold preparation was pursued following the development of appropriate
enabling chemical methods. Diversification provided 686 new compounds suitable for screening. The libraries thus
prepared had structural characteristics, including sp3 content, comparable to a basis set of representative natural products
and were highly rule-of-five compliant.
atural products have played a central role in medicine for as that such families might embody a ‘privileged structure’23–28 that
long as humans have sought to cure and ameliorate could be optimized for new biological properties following suitable
N
disease1,2. Many have been fine-tuned by evolution for pur- modification. We therefore created a nested set of synthetically
poses that bear a mechanistic relationship to a given therapeutic derived cores that represented salient structural features of the
need3. Natural products are often potent, selective and able to natural-product starting point. These were further modified to
cross biological membranes, although many do not adhere to produce ‘secondary scaffolds’ that differ more substantially from
common paradigms for oral absorption4 (it is worth recalling that the original structure but retain attractive elements of scaffold
natural products were specifically excluded from Lipinski’s guide- design. In previous work, we used these tenets to create a library
lines of drug-like properties5). For these reasons, natural products based on Stemonaceae alkaloids that ultimately led to potent
continue to inspire creativity in both medicinal chemistry and Sigma-1 ligands, an activity not known to be associated with this
chemical synthesis.
family of natural products29.
As screening of small-molecule libraries remains an important
Here, we generalize this concept to structurally diverse alkaloids
aspect of early-stage drug and probe discovery, there has been inter- of the cylindricine, Amaryllidaceae and lupin families. We sought to
est in increasing the representation of natural products and related address the synthetic challenges presented by these families by
structures in libraries6–10. Approaches include the straightforward repurposing a suite of thematically related chemical reactions to
approach of collecting natural products or natural-product extracts library construction, most of which were developed in the context
from their natural sources, which requires access to libraries of total synthesis. Additional method development ultimately
obtained from bioprospecting and, for extracts, a downstream allowed us to obtain diversifiable scaffolds unavailable directly
deconvolution step. To supplement such sources, synthetic chemists from natural-product starting materials. Overall, we synthesized a
have co-opted natural product structures for the construction of total of 686 new compounds, of which .90% were prepared in
natural product-like libraries. More often than not, these efforts .20 mg quantities and all in .90% purity.
provide purpose-built libraries for biological indications closely
Figure 1 depicts scaffolds inspired by the architecture of four bio-
logically active alkaloid families: (1) Stemonaceae alkaloids (exem-
related to known bioactivities of the natural products itself11–13
.
Diversity-oriented synthesis (DOS) has also been used to create plified by neostenine)30,31; (2) the structurally related cylindricine,
natural product-inspired libraries9,14,15
suggested that the higher sp3/sp2 content and rich stereochemistry collectively called the cylindricine series)32; (3) the Amaryllidaceae
. Some authors have lepadiformine and fascicularine families of marine alkaloids (here,
typical of natural products and, by extension, libraries derived alkaloid mesembrine33; and (4) sparteine, a lupin alkaloid34,35
.
from them is correlated with suitability as drug candidates16–20. In Structurally, each starting alkaloid contains at least one fused pair
all of these approaches, the complexity of natural products presents of rings, but one spiro and one bridged ring system are also rep-
synthetic challenges that must be surmounted to provide screening resented. Biologically, these classes represent a variety of reported
libraries that contain chemotypes that can be modified in the case of activities, ranging from those described in traditional medicine for
attractive hits21,22
.
the natural-product source to pharmacologically verified and clini-
We sought an approach to natural product-like screening cally used agents (Supplementary Table 1). According to the
libraries that would balance the likelihood of finding molecules approach outlined above, each polycyclic alkaloid was simplified
useful in the pursuit of new biology with synthetic tractability. We to the primary and secondary scaffolds indicated (Fig. 1). The sec-
chose to focus on selected families of alkaloids, preferring those ondary scaffolds contain the same number of rings as the central
with established biological activity at multiple targets, hypothesizing scaffold, but with different ring sizes and/or connectivities.
Department of Medicinal Chemistry, Delbert M. Shankel Structural Biology Center, University of Kansas, 2034 Becker Drive, Lawrence, Kansas 66047, USA.
e-mail: jaube@ku.edu
*
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133

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1844
ARTICLES
Natural product family
(representative members)
Representative
biological activities
Primary scaffold
Secondary scaffold
Stemonaceae alkaloids
Me
O
H
Me
H
O
N
H
H
• Antitussive
N
N
O
• Insecticidal/antifeedant/larvicidal
• Anthelmintic
Me
H
H
O
A
N
• Acetylcholinesterase inhibition
• P-glycoprotein modulation
O
O
O
A
O
H
O
Et
R
R
[ref. 29]
Et
Neotuberostemonine
Ring A excised
Neostenine
Pyrrolo- and pyridoquinoline marine alkaloids
R2
O
OH
C6H13
OH
C6H13
HO
N
C6H13
N
NCS
O
N
R2
O
N
N
N
B
• General cytotoxicity
• Cardiovascular actions
B
B
O
R1
R1
R
Cylindricine C
Lepadiformine
Fasicularin
1. Ring B excised
2. Alcohol attachment moved
Lupin alkaloids
H
O
R
D
O
• Anti-arrhythmic
C
N
H
N
H
N
H
N
H
• Acetylcholine agonism
C
N
N
NH
• Nicotinic receptor agonism/antagonism
O
O
O
Sparteine
Cytisine
1. Ring D excised
2. Ring C contracted
Amaryllidaceae alkaloids
OMe
O
R
O
R
OMe
H
H
• Serotonin reuptake inhibition
• 5-Hydroxytryptamine reuptake inhibition
• PDE4 inhibition
O
OH
O
H
H
O
O
• Acetylcholinesterase inhibition
• Antileukemic
N
O
O
N
• Cytotoxicity
Me
H
N
N
O
MeO
Me
O
Me
H
H
Me
Mesembrine
Me
Pretazettine
1. Fused bicycle retained
2. Aryl attachment moved
Figure 1 | Strategic overview of natural-product families selected for library expansion and corresponding scaffold selection. Each family of natural
products is exemplified by two to three members and the biological activities cited are representative of each family as a whole. Reviews30–35 provide
overviews of the biological landscape, with additional references provided in Supplementary Table 1. In each case, a primary scaffold embodies the minimal
structural aspects of the natural-product family that were pursued. This involved removal of some features to enhance both versatility and synthetic
accessibility. Secondary scaffolds (far right) represent more substantially modified variants of the primary scaffold, either through functional group or
substitution changes or modification of ring structures.
intermediates. Finally, the route in Fig. 2c parlays an advanced
total synthesis intermediate into the scaffold 16. To use the
Diels–Alder/Schmidt chemistry in Fig. 2a and d, we needed to
explore new variations using highly substituted dienes. Schmidt
reactions related to those shown in Fig. 2b and c were first developed
during total synthesis efforts toward sparteine, and the lepadiformine
and cylindricine alkaloids39,40. The azido alcohol-mediated Schmidt
reaction has been previously used for building a library of g-turn
mimetics41. We prepared most of the scaffolds in racemic form, as
therewasnoreason tofavoura particularenantiomerfor broadscreen-
ing, often in straightforward biochemical assays (in a few cases, we did
make scaffolds from L-configured amino-acid derivatives).
The Lewis acid-promoted reaction of unsubstituted diene 1a with
2 has been reported previously37, but dienes 1b–d, which contain an
additional element of diversity and are readily prepared in three or
fewer steps from commercially available starting material, were
unknown to engage in Diels–Alder/Schmidt chemistry before this
work. All four dienes underwent the desired conversions, which
were reproducible and scalable to provide up to 12 g of lactam
with no loss of efficiency. Mechanistically, such reactions are
believed to proceed via a Diels–Alder reaction, from which the
product stereochemistry arises, followed by an intramolecular
Results
Synthesis of scaffolds. To construct libraries containing 402320
members each, it was necessary to develop enabling chemistries
that would permit practical access to the desired chemotypes
(Fig. 2). This was pursued using the azido-Schmidt conversion of
keto azides to lactams as the primary unifying technology36. Four
variations of this reaction were used to create the desired
scaffolds: (1) the combined Diels–Alder/Schmidt reaction
between a silyloxy diene and an azide-containing dienophile37
(Stemonaceae alkaloid series and one scaffold for the mesembrine
series (Fig. 2a,d); (2) the reaction of a ketone with a hydroxyalkyl
azide38 (cylindricine series; Fig. 2b); (3) the intramolecular
Schmidt reaction of a ketone tethered to an azide39 (sparteine
series; Fig. 2c); and (4) another combined Diels–Alder/Schmidt
reaction, but this time one in which the azide is attached to the
diene (the second mesembrine scaffold; Fig. 2d).
The Diels–Alder/Schmidt sequence is particularly powerful, as it
extends the applicability of the ubiquitous Diels–Alder reaction by
tying it to the in situ conversion of the new ring into a heterocycle.
The other sequences rely in one case (Fig. 2b) on a spiroannulation
step to afford a cyclobutanone (itself pressed into service as a scaf-
fold; see below) that can be converted into the desired spirocyclic
134
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1844
ARTICLES
a
c
Intramolecular Schmidt
N3
Diels–Alder/Schmidt
O
O
O
O
N
N
N3
TiCl4
O
NH4OAc
TiCl4
O
N
+
TBSO
H
NaCNBH3
up to
4.5 g scale
O
O
O
H2N
up to
12 g scale
R
1
12
13
62%
H
H
R1 = a H, b Me,
c nPr, d Bn
R
R
2
3a–d
4a–d
44–90%, >19:1 d.r.
58–89%, 2:1-6:1 d.r.
O
b
OH
R2
R2
HO
(i) RMgCl
N
H
O
O
HO
(ii) NaCNBH3
(iii) HCl
N
TMSCl
H
O
HO
R1
N
n
n
14
70%
R1
R2
Azido alcohol Schmidt
10
65–78%
O
8
H
LiAlH4
Ph2S
O
38–87%
+
N3
R2
N
R
R
R2
OH
+
n
NaBH4
BF4
7a–d
N
H
N
H
H
HO
HO
O
BF3•OEt2
R1
n
O
OH
n
R1
5a–h
up to
6a–h
59–80%, 9:1 d.r.
N
2.2 g scale
15
16a–c
85–88%, >19:1 d.r.
R = a Me, b nPr, c Bn
85–90%, >19:1 d.r.
R1
R1
11
65%
9
0–45%
d
Diels–Alder/Schmidt
N3
R
Diels–Alder/Schmidt
O
N3
H
TMSO
H
H
R
O
O
Me
20
TBSO
BF3•OEt2
N
H
N
EtAlCl2
Me
up to
O
Me
17
4.5 g scale
up to 1.1 g scale
Me
21
60%
O
R = a Ph, b 4-MePh,
c 4-ClPh, d 4-OMePh
O
18a–d
19
53–64%, 3:1-4:1 d.r.
R
H
via:
R
R
O
PMBO
R
O
TfOH
TBSO
TBSO
HO
H
O
ZnCl2
OPMB
H
22
H
Me
O
O
H
24a–d
R = a Ph, b 4-MePh,
23a–d
55–75%
c 4-ClPh, d 4-OMePh
55–67%
Figure 2 | Construction of primary and secondary scaffolds. In each section, coloured boxes indicate enabling chemistry developed for scaffold syntheses.
a, Synthesis of Stemonaceae alkaloid scaffolds using a Diels–Alder/Schmidt reaction. b, Cylindricine scaffolds were prepared by sulfur ylide-mediated
spiroannulation followed by ring expansion using an azido alcohol variant of the Schmidt reaction. c, Azide 12 was prepared from a previously reported
C2-symmetrical diketone39 using an improved method (see Supplementary Section II) and converted to the tricyclic sparteine scaffolds using the intramolecular
Schmidt reaction. d, Two different variations of bicyclic analogues of mesembrine were prepared using a Diels–Alder/Schmidt reaction. In addition, reaction of 22
with the interesting dienophile cyclobutenone43 followed by rearrangement afforded a non-nitrogenous scaffold 24. Full synthetic schemes, including
experimental details and characterization data of representative compounds, are provided in the Supplementary Sections II and V.
Schmidt reaction37. The relative stereochemistries of lactams 3b–d whereas three-carbon homologues afforded ꢀ1:1 mixtures of con-
were confirmed by X-ray crystallography. Reductive amination stitutional isomers. Previous work has shown the selectivity of
with ammonium acetate provided amines 4a–d in good yield in such reactions to be highly substrate-dependent, and a discussion
2:1 to 6:1 d.r. The diastereomers of amines 4b–d were separated of the relevant topics has been published38. Additionally, lactams
by reverse-phase chromatography (the isomers of 4a were insepar- 8 and 9 were reduced to afford tertiary amine cores 10 and 11.
able and not used for library synthesis). The relative stereochemistry
The tricyclic lactam core of the sparteine-inspired scaffolds
of 4b and 4c was confirmed by X-ray crystallography of sulfonamide (Fig. 2c) was prepared by intramolecular Schmidt reaction of
derivatives (see Supplementary Section VI), and amine 4d was azide 12, an intermediate in the total synthesis of sparteine39.
assigned by analogy.
Scale-up to 4.5 g quantities was possible by optimizing the previous
Trost spiroannulation was used to create spirocyclic ketones route to compound 12. The multistep reduction shown in
6a–h (Fig. 2b)42. Once in hand, these ketones were used as the the scheme afforded amines 15a–c as single diastereomers, and
basis of one sublibrary, but our main objective was to convert further reduction with NaBH4 similarly led to isomerically
them to the cylindricine-inspired substructures 8 and 9. This was pure alcohols 16a–c. The stereochemistry of the endo-
accomplished by previously unexamined Schmidt reactions of selective Grignard addition and ketone reduction was confirmed
6a–h with hydroxyalkyl azides 7a–d. This led to a mixture of readily by X-ray crystallography of
separable lactam regioisomers 8 and 9, thereby affording a pair of Supplementary Section VI).
a
derived carbamate (see
useful scaffolds from ketones 6. The use of a two-carbon hydro-
The primary scaffold of the mesembrine series 18 was prepared
xyalkyl azide led predominantly to the formation of scaffolds 8, in moderate yield and 3:1 to 4:1 d.r. by reacting previously unknown
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135

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1844
ARTICLES
a
O
O
O
O
O
vii
H
N
N
N
N
N
O
i
ii
iv
v
R2
R2
N
H
N
O
iii
R2
N
H
H2N
H
H
H
H
H
H
R1
R1
R1
R1
R1
3a–d
26
4b–d
28
25
vi
ix
viii
O
N
O
O
O
O
O
O
N
N
N
N
S
R2
N
H
O
O
R1
Me
29
R2HN
O
R2
N
N
R2HN
N
H
H
H
H
R1
Me
R1
Me
R1
R1
27
32
31
30
b
S
O
X
X
X
R3HN
R3HN
xii
xiii
HO
N
O
O
N
N
n
n
n
R1
R1
R1
8 X = O
10X = H2
O
R2HN
O
35
37
O
x
xi
R2HN
R1
O
S
R1
R1
R3HN
R3HN
HO
X
6
O
O
33
n
34
n
n
xii
xiii
X
N
X
N
N
R1
R1
R1
9 X = O
11X = H2
36
38
Figure 3 | Library construction from Stemonaceae and cylindricine alkaloid-inspired scaffolds. a, Ketone scaffolds 3a–d and amines 4b–d were converted
into libraries of quinolines, amines, amides, sulfonamides, ureas and carbamates. Key scaffolds are indicated by boxes. b, Ketone scaffolds 6, lactams 8 and
9, and amines 10 and 11 were converted into a series of libraries of amines, carbamates and thiocarbamates. A total of 499 unique structures, each obtained
in .90% purity (high-performance liquid chromatography (HPLC), ultraviolet detector at 214 nm) and .20 mg quantities were obtained. Scaffold
(number of final products obtained): 3a–d (131), 4c–d (191), 6 (112), 8 (19), 9 (12), 10 (32), 11 (2). (i) 2-Nitrobenzaldehyde, Fe0, 0.1 M aq. HCl, EtOH, 85 8C;
then 3a–d, KOH, 85 8C; (ii) amine, AcOH, Na(OAc)3BH, CH2Cl2, rt; (iii) (a) L-Selectride, THF, 278 8C to rt, 90–95%, 9:1 to .19:1 d.r., (b) 4-nitrophenyl-
chloroformate, pyridine, rt, 55276%, (c) R2NH2, CH2Cl2, rt; (iv) R2CHO, AcOH, Na(OAc)3BH, CH2Cl2, rt; (v) R2CO2H, EDC, DMAP, CH2Cl2, rt; (vi) R2SO2Cl,
Et3N, CH2Cl2, rt; (vii) R2N¼C¼O, PhMe, rt; (viii) H2C¼O, HCO2H, 95 8C; (ix) H2C¼O, AcOH, Na(OAc)3BH, CH2Cl2, rt; (x) R2NH2, DCE, microwave, 150 8C;
(xi) (a) NaBH4, THF, MeOH, rt, 94297%, (b) R2N¼C¼O, Et3N, THF, rt; (xii) R2N¼C¼O, Et3N, THF, rt; (xiii) R2N¼C¼S, NaH, THF, rt.
b
H
a
O
RHN
O
ii
H
H
N
H
O
vi
N
N
H
O
NHR2
H
O
O
O
N
Me
vii
Ar
44
45
40
O
O
i
39
O
O
19
H
Me
N
H
iii
R
iv
O
N
H
N
N
N
H
13
O
NHR2
H
O
OH
Me
42
O
41
H
H
R1
R1
N
H
v
N
H
O
NHR2
OH
16a–c
43
O
Figure 4 | Library construction from sparteine and mesembrine-inspired scaffolds. a, Library construction from sparteine-inspired scaffolds led to
carbamates generated both from lactam 13 directly or by first converting it to the amine-containing scaffold 41. Similar chemistry could be used on the
additional alkyl-group-containing scaffolds 16a–c. b, Amide scaffold 19 was converted into amine and quinoline libraries. A total of 132 unique structures,
each obtained in .90% purity (HPLC, ultraviolet detector at 214 nm) and .10 mg quantities, were obtained. Scaffold (number of final products obtained):
13 (44), 16a–c (52), 19 (36). (i) (a) NaBH4, MeOH, rt, 88%, .19:1 d.r., (b) 4-nitrophenyl chloroformate, pyridine, THF, rt, 95%; (ii) R2NH2, DCE, rt;
(iii) LiAlH4, THF, reflux, 80%; (iv) R2N¼C¼O, MeCN, microwave, 110 8C; (v) R2N¼C¼O, THF, rt; (vi) RNH2, AcOH, Na(OAc)3BH, THF;
(vii) 2-nitrobenzaldehyde, Fe0, 0.1 M HCl, EtOH, 85 8C; then 19, KOH, 85 8C.
136
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1844
ARTICLES
O
O
N
O
N
O
N
O
O
O
N
N
N
Cl
O
O
O
F
Me
N
N
S
N
H
H
H
N
N
O
H
N
H
N
H
H
Me
H
Me
H
H
O
Me
F3C
Me
N
Me
O
O
H
H
S
N
O
N
N
N
O
O
O
O
O
F
O
N
N
H
N
N
H
S
N
Me
O
N
H
Br
H
H
Cl
H
O
O
N
O
H
NH
N
H
N
H
H
O
O
O
N
H
H
O
Me
O
N
H
N
O
H
N
H
H
O
N
O
O
N
N
H
Me
Me
O
N
N
NH
H
H
H
H
H
H
N
H
N
H
H
Me
F3C
CF3
N
N
O
N
H
N
H
O
H
H
H
H
N
O
N
N
O
N
N
O
N
H
H
H
O
O
Me
O
O
Me
Me
O
Me
Me
Figure 5 | Representative selection of library compounds used in cheminformatic analyses. For a full list of scaffold and library compounds used in this
analysis, see Supplementary Figs 3 and 4.
dienes 17 with methylvinylketone. These isomers proved insepar- formation of an unidentified by-product that co-eluted with the car-
able and were not subjected to additional diversification. We simi- bamate product upon purification. However, by first converting the
larly prepared secondary scaffold 21 by a modification of the alcohol to the corresponding para-nitrobenzyl carbonate, sub-
previously reported Diels–Alder/Schmidt reaction of diene 20 and sequent reaction with a wide range of amines resulted in a much
azide-tethered enone 19 (Fig. 2d)37. Attaching the azide to either cleaner and more effective preparation of library members. Amine
the diene or dienophile allows access to either the cis or trans scaffolds 4b–d were used to synthesize sublibraries of amides 28,
fused scaffold, (cf. routes to 18 versus 21). Hypothesizing that sulfonamides 29, ureas 30 and secondary amines 26, while tertiary
greater selectivity might be obtained with a more biased ring amine libraries were obtained either by reductive amination of sec-
system, we reacted 17 with the unusual dienophile cyclobutenone ondary amines 26 with formaldehyde, or by Eschweiler–Clarke
(introduced to the Diels–Alder reaction by Danishefsky43), but a reaction of primary amines 4b–d.
complex mixture of products was obtained, with no desired
Spirocyclic ketone scaffolds 6 were converted into libraries of
lactam evident. For comparison, we prepared azide-less silyloxy- amines 33 by microwave-assisted reductive amination, and libraries
diene 22 and submitted it to the Diels–Alder reaction conditions of carbamates 34 by reduction with NaBH4 followed by reaction
with cyclobutenone. In this case, the cycloaddition proceeded with isocyanates (Fig. 3b). Similarly, the alcohol moieties of
smoothly to afford bicyclic ketone 23, but, surprisingly, treatment lactams 8 and 9 and cyclic amines 10 and 11 were reacted with iso-
with trifluoromethanesulfonic acid resulted in the formation of cyanates and isothiocyanates to produce libraries of carbamates 35
the previously unknown isochromenones 24 as single diastereo- and 36 and thiocarbamates 37 and 38, respectively.
mers. This reaction is previously unknown and could proceed via
The ketone of scaffold 13 was stereoselectively reduced to afford the
a retro-Michael reaction from the intermediate shown (an alterna- corresponding endo-alcohol (Fig. 4a), the structure of which was
tive enolization/electrocyclic ring-opening sequence is also possible, determined by X-ray of the corresponding para-bromobenzoyl ester
but available evidence does not currently allow us to differentiate (see Supplementary Section VI). The alcohol was converted into a
between the possibilities).
library of carbamates 40 by carbonate formation and subsequent reac-
tion with a range of amines. The corresponding library containing a
Library construction. We took three main tacks toward diversifying basic amine in the ring system was prepared by double reduction
our scaffolds: direct conversion of ketones to additionally fused with LiAlH4 in THF, giving 41, which was further diversified into car-
heterocycles or amines, conversion of alcohols to carbamates, or bamates 42 by microwave-promoted reaction with isocyanates. Similar
decoration of amines as amides, sulfonamides or ureas. These treatment of 16a–c led to libraries exemplified by 43.
methods were chosen because they increase structural diversity,
Reductive amination of mesembrine-inspired scaffold 19 pro-
provide various degrees of hydrogen-bonding capabilities, and vided the corresponding secondary amines 44 in 2:1 to 1:1 d.r.
yield functional groups consistent with probe or drug development. (Fig. 4b). We ascribe the poor stereoselectivity to the relatively flat
For the Stemonaceae-derived library, scaffold 3a gave quinolines nature of the trans ring-fused system inherent in 19. In this case,
25 by a modified Friedla¨nder reaction and secondary amines 26 by the amine diastereomers were separable by reverse-phase chromato-
reductive amination with various benzylamines (Fig. 3a). Analogous graphy, which allowed us to incorporate a modest number of amines
reactions with scaffolds 3b–d resulted in an inseparable mixture of containing this scaffold into our library (relative stereochemistries
diastereomers, which were not pursued. Further diversification was were determined by two-dimensional NMR). The use of anilines
achieved by reducing ketones 3a–d with L-Selectride to generate the in the reductive amination resulted in inseparable mixtures of dia-
corresponding alcohols with excellent diastereoselectivity (relative stereomeric products, which were unsuitable for our screening
stereochemistry of the major product was determined by X-ray crys- requirements. A library of quinolines 45 was also synthesized by
tallography). These were used to prepare a library of carbamates 27. reacting scaffold 19 with either substituted 2-aminobenzaldehydes
Direct reaction of the alcohol with isocyanates resulted in the or 2-aminobenzophenones or acetophenones.
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a
b
4
4
3
Lib_cmps
AVG-Lib_cmpc
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AVG-Scaffolds
Alk_NPs
Lib_cmps
AVG-Lib_cmps
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Alk_NPs
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3
2
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Drugs
AVG-Alk_NPs
Drugs
2
AVG-Drugs
NPs
AVG-NPs
Comm
AVG-Drugs
NPs
AVG-NPs
Comm
1
1
Alkaloid-inspired libraries
AVG-Comm
AVG-Comm
0
0
–1
–2
–3
–4
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–2
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Alkaloid NPs
Alkaloid-inspired libraries
–4
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–1
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Alk Libraries
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Lib_cmps
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0
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I1/I3
Figure 6 | Cheminformatic analysis of alkaloid-inspired scaffolds and library members. Structural and physiochemical properties of a representative
selection of synthesized scaffolds (14 compounds, yellow diamonds) and library members (29 compounds, red diamonds) were compared with those of
alkaloid natural products (NPs, 20 compounds, green squares) and an established reference set48 of drugs (40 compounds, blue triangles), commercially
available drug-like molecules (20 compounds, purple crosses) and natural products (60 compounds, green circles) using PCA and PMI analysis. The
hypothetical average (mean) structure for each series is also plotted (AVG-). a, PCA plot of PC1 versus PC2. b, PCA plot of PC1 versus PC3. c, PCA plot of
PC2 versus PC3. d, PMI plot showing the three-dimensional shape of the lowest-energy conformer of each compound. The shaded red, green and blue areas
outline the regions of the plot where the majority of our alkaloid inspired libraries, alkaloid natural products and drugs, respectively, are located.
Cheminformatic analysis. The chemical properties of our alkaloid- parameter (defined as the number of R–S stereocentres; this may be
inspired libraries were analysed using principal component analysis viewed as a rough descriptor of stereochemical complexity), shifts
(PCA), a statistical tool to condense multidimensional chemical compounds downward in these plots. Finally, PC3 is affected to the
properties (for example, molecular weight, log P, ring complexity) greatest degree by X log P (calculated octanol/water partition
into single dimensional numerical values (principal components), coefficient), number of rings, and ALOGPs (an alternative log P
allowing greater ease of comparison with different sets of calculation), which together shift compounds in a negative
compounds44. This analysis was performed on a representative direction along the PC3 axis in plots PC1 versus PC3 and PC2
sample of scaffolds and library members, as summarized in Fig. 5 versus PC3, and ALOGpS (calculated aqueous solubility), which
(for full list see Supplementary Figs 3 and 4), which compared shifts compounds in a positive direction in these plots.
them with a selection of alkaloid natural products and a reference
In two of the three variations, the data show significant overlap
set of drugs, natural products and commercial drug-like between our alkaloid-inspired library compounds with both drug
compounds using the protocols employed by Tan45. The and natural-product regions (Fig. 6a,b). In the PC2 versus PC3
parameters that have the greatest influence on principal component plot, there is less overlap between our library compounds and com-
1 (PC1) are molecular weight, number of oxygen atoms, number of mercial drug space, but the compounds still overlap considerably
hydrogen-bond acceptors, and topological polar surface area with natural alkaloid space and abut drug space (Fig. 6c). This
(tPSA). Together, these parameters have the effect of moving might be expected to arise naturally from the combination of two
compounds to the right in plots PC1 versus PC2 and PC1 versus different modes of synthetic chemistry: the natural-product inspired
PC3. The descriptors with the largest loading on PC2 are the routes that led to the key scaffolds versus the diversity-generating
number of nitrogen atoms, number of aromatic rings and the steps that followed in the library expansion phase.
number of ring systems, which shift compounds upward in plots
PC1 versus PC2 and PC2 versus PC3. In contrast, the nStMW compare the three-dimensional shapes of the lowest-energy
Principal moment of inertia (PMI) analysis46 was also used to
138
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1844
ARTICLES
conformations of our scaffolds and library members with the above natural products have very different chemical properties from syn-
reference sets45. Our compounds were found to lie along the rod- thetically derived drug scaffolds. Overall, the PCA and PMI analyses
disc side of the triangle, with a preference for the rod vertex support the fact that the primary goal of this project was achieved
(Fig. 6d). We note that drugs and the commercial screening libraries insofar as we created libraries different enough from highly occupied
represented in the reference sets also reside in this region of the drug discovery space to be interesting (and thus addressing our
plot46.
mission of ‘probing chemical space’), but not so different as to
These analyses suggest that our scaffolds and library compounds lack potential in screens. The ultimate determination of this poten-
are similar to natural products, particularly alkaloid natural pro- tial by screening against a variety of targets (for example, by sub-
ducts, while also sharing attractive properties of drugs believed to mission into the Small Molecule Repository of the US National
be compatible with bioavailability. We note that the fraction of Institutes of Health) and the extension of the concept to other
carbon atoms with an sp3 centre (Fsp3) in our scaffolds (0.77) and libraries is currently being pursued.
library compounds (0.66) is very similar to the values obtained
Methods
for our reference natural products (0.64) and alkaloids (0.65), and
substantially higher than that for drugs (0.41) (Supplementary
Table 2). Alkaloids (average Mw of 319, rotatable bonds 2.8) are gen-
erally smaller and more rigid than non-alkaloid natural products
(629, 9.7), and more closely resemble our library compounds
(355, 4.1). Although we did not particularly set out to adhere to
any filters for drug-likeness in our design, we point out that 72%
of our library compounds satisfied each of Lipinski’s rules of five,
General procedures for the key Schmidt reactions used in the syntheses of
scaffolds 3, 8, 9, 13, 18 and 21 are described below. All reactions were performed
using flame-dried glassware under an argon atmosphere. Additional experimental
details and analytical data for scaffold synthesis and library preparation are provided
in the Supplementary Methods, together with full details of the cheminformatic
analysis. CAUTION: The authors remind all experimentalists contemplating use of
these methods to follow established safety protocols in the use of alkyl azides and
their precursors.
with 100% meeting three out of four of the criteria. Moreover, all General procedure for Diels–Alder/Schmidt reaction for preparation of scaffolds
3 (Stemonaceae alkaloid series). Titanium tetrachloride (1 M solution in
dichloromethane, 2.5 equiv.) was added dropwise to a solution of azide 2 (1 equiv.)
and silyloxydiene 1a–d (2.5 equiv.) in anhydrous dichloromethane (0.06 M w.r.t.
azide) at 0 8C under argon. The resulting red/brown solution was stirred at 0 8C for
2 h, then allowed to warm slowly to room temperature overnight. The reaction
mixture was then quenched with water and stirred at room temperature for 1 h. The
organic layer was removed, and the aqueous extracted with dichloromethane (×3).
The combined organics were dried (Na2SO4) and concentrated to afford a brown oil.
The crude product was purified by chromatography (silica gel, 95:5 ethyl acetate:
methanol) to afford lactams 3a–d.
library members fulfilled Veber’s requirements for good oral bioa-
vailability (≤10 rotatable bonds; ≤140 Å2 total polar surface area)47.
Discussion
We have described one approach to balancing two concerns that
arise in the development of libraries for biological screening: (1)
the desire to provide compound collections that are different
enough from existing libraries to inform interesting new biology,
and (2) dealing with the sheer vastness of chemical space, which
makes it hard to create useful new bioactive molecules that are strik-
ingly different from typical drug-like libraries. Using four alkaloids
as inspiration agents, we used straightforward reaction sequences
and moderately advanced synthetic intermediates to generate scaf-
fold structures that were easily converted to libraries using parallel
synthesis technology. The particular routes combine azide-mediated
methods for the incorporation of nitrogen into organic frameworks
with established ketone syntheses. Regarding the latter, we used one
very well known reaction for the generation of fused ring systems
(Diels–Alder) and a powerful but somewhat underutilized method
for generating spirocycles (Trost spiroannulation). Overall, a total
of 686 previously unknown structures were synthesized, comprising
55 separate scaffolds and 631 analogues. Of these, 266 (39%) of the
compounds contained a basic nitrogen atom (ranging from 21% for
the Stemonaceae alkaloid libraries to 68% of those derived from
mesembrine). Overall, more than 90% of the library members
were obtained in the 20 mg quantities and 90% purities that we
had initially targeted (with the remainder achieving the purity
goal but only being obtained in 10–20 mg quantities), with all of
the compounds being .90% diastereomerically pure. The synthetic
routes developed are amenable for use with both hit re-synthesis and
downstream structure–activity relationship studies, both critical for
real-world applications of small-molecule libraries.
General procedure for azido-alcohol Schmidt reaction for preparation of
scaffolds 8 and 9 (cylindricine series). Boron trifluoride diethyl etherate (5 equiv.)
was added dropwise to a solution of spiro[3.5]nonan-1-one 6a–h (1 equiv.) in
anhydrous dichloromethane (0.15 M w.r.t. spirononanone) at 278 8C under argon.
The reaction mixture was stirred for 30 min at 278 8C, then a solution of
hydroxyalkyl azide (3 equiv.) in dichloromethane (1.5 M) was added. The reaction
mixture was stirred at 278 8C for 3 h, then allowed to warm slowly to room
temperature overnight. The reaction mixture was then concentrated under reduced
pressure and the resulting oil was dissolved in 15% aqueous potassium hydroxide
solution and stirred for 30 min. The reaction mixture was then extracted with
dichloromethane (×3). The combined organics were washed with water, dried
(MgSO4) and concentrated. The crude product was purified by automated
chromatography (silica gel 02100% ethyl acetate in hexanes) to afford lactams 8
and 9.
Alkyl azide Schmidt reaction for preparation of scaffold 13 (sparteine series).
Titanium tetrachloride (20.7 ml, 188.5 mmol, 5 equiv.) was added dropwise to a
solution of azide 12 (10 g, 37.7 mmol, 1.0 equiv.) in anhydrous dichloromethane
(350 ml) at 0 8C under argon. A yellow precipitate was formed. The reaction mixture
was allowed to warm to room temperature, stirred for 24 h and then quenched with
water. The aqueous layer was extracted with dichloromethane. The organic layer was
dried (Na2SO4) and concentrated to give an oil. The crude product was purified by
chromatography (silica gel, 100% ethyl acetate) to afford lactam 13 (4.5 g, 62%) as a
colourless solid.
General procedure for Diels–Alder/Schmidt reaction for preparation of scaffolds
18 (mesembrine series). Methyl vinyl ketone (1 equiv.) was added to a solution of
silyloxydiene 20 (1.5 equiv.) in anhydrous dichloromethane (0.4 M w.r.t. diene) and
the reaction mixture cooled to 278 8C. Boron trifluoride diethyl etherate (1.5 equiv.)
was then added and the reaction mixture stirred at 278 8C for 4 h then warmed to
room temperature. A further aliquot of boron trifluoride diethyl etherate (2 equiv.)
was then added and the reaction mixture stirred at room temperature for an
The computational assessment of our libraries shows that the
new compounds have many of the attributes that some authors
have proposed to arise from using natural products in the first
place—notably high sp3 counts relative to commercial libraries additional 16 h. The reaction mixture was diluted with dichloromethane and
quenched with saturated aqueous NaHCO3. The organic layer was washed with
saturated aqueous NH4Cl, water and brine, dried (MgSO4) and concentrated. The
crude product was purified by automated column chromatography (silica gel 0
to 100% ethyl acetate in hexanes, then 90:10 dichloromethane:methanol) to afford
and comparable to those in a previously used natural-product
set48. This feature naturally arose from the selection of alkaloid-
based scaffolds and reflects the choice of targets in the first place.
In fact, the slight drop in average sp3 content in the libraries made
lactams 18.
versus the scaffolds themselves can be attributed to our selection
of common ‘medicinal chemistry’ subunits (for example, aromatics)
for our specific diversification efforts. On the other hand, the obser-
vation that the libraries were highly Lipinski- and Veber-compliant
Diels–Alder/Schmidt reaction for preparation of scaffold 21 (mesembrine
series). Ethylaluminium dichloride (1 M solution in hexane, 25 ml, 1 equiv.) was
added dropwise to a solution of trimethylsilyloxy butadiene 20 (3.5 g, 25 mmol,
2.5 equiv.) and azide 19 (1.4 g, 10 mmol, 1 equiv.) in anhydrous dichloromethane
may be viewed as a surprise, given the conventional viewpoint that (15 ml) under argon at 278 8C. After the addition was complete, the reaction
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1844
ARTICLES
mixture was stirred at 278 8C for 2 h then gradually warmed to room temperature
and stirred for a further 16 h, then quenched with water and diluted with
dichloromethane (100 ml). The combined organics were washed with saturated
aqueous NaHCO3 (50 ml) and brine (50 ml), dried (Na2SO4) and concentrated. The
crude product was purified by chromatography (silica gel 100% ethyl acetate) to
afford lactam 19 (800 mg, 45%) as a light yellow oil.
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compounds. The authors also acknowledge financial support from the US Institute of
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Author contributions
M.C.M., J.N.P., D.R., G.S. and J.A. designed the experiments and analysed the data. M.C.M.,
J.N.P., D.R. and G.S. performed the synthesis and characterization. J.L.W. and M.C.M.
performed the cheminformatic analysis and V.W.D. performed and analysed the X-ray
structures. M.C.M. and J.A. wrote the manuscript.
Additional information
24. DeSimone, R. W., Currie, K. S., Mitchell, S. A., Darrow, J. W. & Pippin, D. A.
Privileged structures: applications in drug discovery. Comb. Chem. High T. Scr. 7,
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chemistry. Curr. Med. Chem. 13, 65–85 (2006).
Supplementary information and chemical compound information are available in
the online version of the paper. Reprints and permissions information is available online at
www.nature.com/reprints. Correspondence and requests for materials should be
addressed to J.A.
26. Duarte, C. D., Barreiro, E. J. & Fraga, C. A. M. Privileged structures: a
useful concept for the rational design of new lead drug candidates. Mini-Rev.
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Competing financial interests
The authors declare no competing financial interests.
140
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