A diversity-oriented-synthesis protocol for scaffold discovery based on a general synthetic route to spirocycles

Article abstract of DOI:10.1016/j.tetlet.2011.06.020

A diversity-oriented synthesis (DOS) protocol for scaffold discovery is described. A general synthetic route is developed from a single lactam for the access to various multi-functionalized spirocyclic keto-lactams and their derived spirocyclic keto-amines. This work provides the foundation for a sequential DOS strategy from scaffold discovery to drug discovery.

Full text of DOI:10.1016/j.tetlet.2011.06.020

Tetrahedron Letters 52 (2011) 4204–4206
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A diversity-oriented-synthesis protocol for scaffold discovery
based on a general synthetic route to spirocycles
⇑
Fu-An Kang , Zhihua Sui
Johnson & Johnson Pharmaceutical Research and Development, LLC, Welsh and McKean Roads, Spring House, PA 19477, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A diversity-oriented synthesis (DOS) protocol for scaffold discovery is described. A general synthetic
route is developed from a single lactam for the access to various multi-functionalized spirocyclic keto-
lactams and their derived spirocyclic keto-amines. This work provides the foundation for a sequential
DOS strategy from scaffold discovery to drug discovery.
Received 12 April 2011
Revised 29 May 2011
Accepted 4 June 2011
Available online 13 June 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Dedicated to Professor Yoshito Kishi on the
occasion of his 75th birthday
Keywords:
Diversity-oriented synthesis
Scaffold discovery
Drug discovery
Library design
Spirocycle
In modern drug discovery research, new molecular scaffold
discovery plays a central role in lead generation and lead optimi-
zation.1 A molecular ‘scaffold’ is also termed as ‘core’, ‘template’,
‘chemotype’, ‘framework’ and ‘skeleton’. An ideal drug-like molec-
ular scaffold should be small in size, rigid in shape and multi-
functionalized for further chemical modifications. This type of
new scaffolds is becoming extremely important for the discovery
of novel therapeutic molecules as new molecular entities. In
practice, they are the major driving force that supports the cur-
rent two leading approaches in lead generation, fragment-based
drug design (FBDD) and diversity-oriented synthesis (DOS).2
DOS is a practical concept and an effective approach for the gen-
eration of many structurally diversified compounds based on un-
ique molecular scaffolds for structure–activity relationship
studies in drug discovery.3 Current major strategies in DOS in-
clude: (1) generation of a common scaffold based on a certain
chemical technology and its subsequent derivatization, using such
reactions as multi-component reactions and macrocycle forma-
tions; (2) generation of several different scaffolds based on a
few different chemical technologies from a common precursor
and their subsequent derivatization, using the ‘functional group
pairing strategy’.4
on either heterocycles5 (Biginelli-type pyrimidines) or natural
products6 (steroid hormones). These target-oriented synthesis
and diversity-oriented synthesis have led to new synthetic meth-
odology development5,7 and identification of novel bioactive mol-
ecules8 for certain therapeutic targets.
Spirocyclic compounds have recently attracted considerable
attention from the synthetic and medicinal communities due to
their unique structural features and associated properties.9 Many
bioactive natural products also contain the spirocycle units, such
as Fredericamycin, Acorenone B, Spriofornabuxine, and Vetivone
(Fig. 1). Besides pharmaceutical interests, spirocyclic compounds
are also widely utilized in material science.9 The synthesis of spiro-
cycles is generally considered to be challenging due to the creation
of a quaternary carbon center, whose formation is usually more
difficult than other chemical bond formations. Spirocyclic keto-lac-
tams 1 and 2 (Fig. 2) are interesting small multi-functionalized
molecular scaffolds that are potentially useful for drug discovery
research. Therefore, a number of synthetic methods have been
developed for the preparation of these types of compounds.10
While effective in many occasions, these methods generally re-
quire multi-step synthesis using either expensive reagents or ad-
vanced intermediates. Herein, we report
a general synthetic
In recent years, we have been interested in new molecular scaf-
fold discovery for a number of our drug discovery programs, based
route to the synthesis of the spirocyclic keto-lactams 1 and 2 and
their derivatives using inexpensive starting materials by way of a
DOS protocol for scaffold discovery. These spirocyclic scaffolds
have been effectively incorporated into lead compounds in several
of our drug discovery programs.
⇑
Corresponding author. Tel.: +1 (0)215 628 7895; fax: +1 (0)215 540 4627.
E-mail address: fkang@its.jnj.com (F.-A. Kang).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.020

F.-A. Kang, Z. Sui / Tetrahedron Letters 52 (2011) 4204–4206
4205
synthetic pathway of compounds 3–5; (3) hydroboration of the
cyclopentene ring followed by oxidation to construct the spirocyclic
b-keto-lactam system, which is used for the branch synthetic path-
way of compounds 5–1; (4) reduction of the spirocyclic b-keto-lac-
tam system to produce the spirocyclic b-keto-amine system, which
is used for the branch synthetic pathway of compounds 5–11; and
(5) allylic oxidation of the cyclopentene ring followed by hydroge-
H
N
O
HO
O
O
OH
OH
O
O
MeO
O
nation to build the spirocyclic a-keto-lactam system, which is used
for the branch synthetic pathway of compounds 5–12.
Acorenone B
Fredericamycin
Double allylation11 of the lithium enolate of lactam 3 in THF at
À78 °C using LiHMDS (2.2 equiv) and allyl bromide (2.4 equiv) fol-
lowed by warming to room temperature gave compound 4 in 60%
yield. Ring-closing metathesis of compound 4 in DCM at room tem-
perature using the first generation Grubbs catalyst12 (2 mol %)
afforded compound 5 in 95% yield. Hydroboration of compound 5
using BH3–THF (1 equiv) in THF at 0 °C followed by oxidative
workup furnished compound 6 in 93% yield. Oxidation of com-
pound 6 in DCM–MeCN using TPAP–NMO13 produced compound
7 in 95% yield. Removal of the Boc group using TFA in DCM pro-
vided compound 1 in nearly quantitative yield. Allylic oxidation
of compound 5 in DCM using Pd/C-t-BuOOH14 resulted in com-
pound 8 in 80% yield. Hydrogenation of compound 8 in EtOAc–
EtOH using Pd/C led to compound 9 in nearly quantitative yield.
A one-pot hydroboration–reduction of compound 5 in DCM using
BH3–Me2S (5 equiv) at 40 °C generated compound 10 in 90% yield.
Similar transformations of compounds 9 and 10 yielded com-
pounds 11 and 12. The straightforward chemistry using inexpen-
sive materials allowed the practical synthesis of these
compounds in gram scales.15
H
O
N
O
O
Cl
MeHN
HO
Spirofornabuxine
Vetivone
Figure 1. Natural products with spirocycles.
O
O
O
NH
( )n
NH
( )n
n = 1-3
O
1
2
Figure 2. Spirocyclic keto-lactams as new molecular scaffolds.
It is interesting to note that the chemoselectivity between hyd-
roboration of the olefin group and the reduction of the amide
group of compound 5 could be controlled by the choice of the
borane reagents and the reaction conditions (Scheme 2). The selec-
tive hydroboration of the olefin group using BH3-THF (1 equiv) at
0 °C gave compound 6 exclusively. The non-selective simultaneous
olefin-hydroboration and amide-reduction of compound 5 using
BH3–Me2S (5 equiv) at 20 °C led to a mixture of compounds 6
Our DOS protocol for scaffold discovery of spirocycles is based on
an efficient and practical route to the spirocyclic keto-lactams 1, 2
and their derivatives (Scheme 1). The key reactions of the synthesis
include: (1) double allylation of the
a-carbon of the lactam to
generate the quaternary center, and (2) ring-closing metathesis of
the allyl groups to form the spirocycle, which are used for the main
O
O
O
Boc
Boc
HO
O
O
NH
N
N
e
d
6
7
1
c
O
O
5
O
Boc
Boc
Boc
Boc
O
HO
O
f
N
d
a
N
N
N
b
Boc
N
10
3
4
11
g
O
Boc
Boc
Boc
N
N
N
h
f, d
O
O
O
12
9
8
Scheme 1. A general synthetic route to the spirocyclic keto-lactams and keto-amines. Reagents and conditions: (a) LiHMDS (2.2 equiv), ally bromide (2.4 equiv), THF, À78 °C
to rt, 60%; (b) Grubbs I (2 mol %), DCM (0.4 M), rt, 95%; (c) (1) BH3–THF (1.1 equiv), THF, 0 °C, (2) H2O2, NaHCO3, H2O, rt, 93%; (d) TPAP (5 mol %), NMO (3 equiv), MS 4 Å, DCM–
MeCN, 0 °C to rt, 95%; (e) TFA, DCM, rt, 99%; (f) (1) BH3–DMS (5 equiv), THF, 40 °C; (2) H2O2, NaHCO3, H2O, 90%; (g) 10% Pd/C (10 mol %), ButOOH (25 equiv), K2CO3 (1 equiv),
DCM, 0 °C to rt, 70%; (h) H2, 10% Pd/C, EtOAc–EtOH, 99%.

4206
F.-A. Kang, Z. Sui / Tetrahedron Letters 52 (2011) 4204–4206
O
O
Boc
Boc
Boc
1. BH3-L
2. H2O2
HO
HO
N
N
N
+
5
6
10
NMR Yield
1
NMR Yield1
BH3-L (amt, temp, time)
0%
35%
100%
100%
65%
0%
BH3-THF (1 eq, 0'C, 18h)
BH3-Me2S (5 eq, 20'C, 18h)
BH3-Me2S (5 eq, 40'C, 18h)
Scheme 2. Control of chemoselectivity.
scaffold library
compound library
O
O
O
X
O
X
Y
Y
O
Y
N
N
NH
NH
N
NH
NH
O
2nd DOS
Future
1st DOS
NH
O
This Work
Y
N
Application
X
X
O
O
diversity-oriented synthesis
for drug discovery
diversity-oriented synthesis
for scaffold discovery
Scheme 3. A sequential DOS strategy from scaffold discovery to drug discovery.
5. Kang, F.-A.; Kodah, J.; Guan, Q.; Li, X.; Murray, W. V. J. Org. Chem. 2005, 70, 1957.
6. (a) Kang, F.-A.; Jain, N.; Sui, Z. Tetrahedron Lett. 2006, 47, 9021; (b) Kang, F.-A.;
Jain, N.; Sui, Z. Tetrahedron Lett. 2007, 48, 193.
and 10, while the same reaction at 40 °C resulted in compound 10
exclusively.
This DOS protocol generated a scaffold library of the multi-func-
tionalized small spirocycles 7, 9, 11, and 12. Besides the 5,5-spiro-
7. (a) Kang, F.-A.; Sui, Z.; Murray, W. V. J. Am. Chem. Soc. 2008, 130, 11300; (b)
Kang, F.-A.; Sui, Z.; Murray, W. V. Eur. J. Org. Chem. 2009, 461; (c) Kang, F.-A.;
Lanter, J. C.; Cai, C.; Sui, Z.; Murray, W. V. Chem. Commun. 2010, 46, 1347.
8. (a) Kang, F.-A.; Allan, G.; Guan, J.; Jain, N.; Linton, O.; Tannenbaum, P.; Xu, J.;
Zhu, P.; Gunnet, J.; Chen, X.; Demarest, K.; Lundeen, S.; Sui, Z. Bioorg. Med. Chem.
Lett. 2007, 17, 907; (b) Kang, F.-A.; Guan, J.; Jain, N.; Allan, G.; Linton, O.;
Tannenbaum, P.; Chen, X.; Xu, J.; Zhu, P.; Gunnet, J.; Demarest, K.; Lundeen, S.;
Sui, Z. Bioorg. Med. Chem. Lett. 2007, 17, 2531; (c) Kang, F.-A.; Chen, X.; Jain, N.;
Allan, G.; Tannenbaum, P.; Lundeen, S.; Sui, Z. Bioorg. Med. Chem. Lett. 2008, 18,
3687.
cyclic system starting from the
c-lactam described herein, this
general synthetic route can also be adapted to the 5,6- and 5,7-spi-
rocyclic systems (compounds 1 and 2, where n = 2 and 3, respec-
tively) by starting from the corresponding d- and
e-lactams.
More importantly, this work provides the foundation for a sequen-
tial DOS strategy from scaffold discovery to drug discovery
(Scheme 3). The scaffold library generated by the first DOS protocol
will be useful in the second DOS protocol which is a process of two
successive parallel syntheses involving the conversion of the scaf-
fold library to the intermediate library and the conversion of the
intermediate library to the target compound library. Consequently,
this sequential DOS strategy will enable the generation of a large
compound library of multi-functionalized structurally diversified
spirocycles for drug discovery.
In summary, a DOS protocol for scaffold discovery of spirocycles
is described. It is based on a general synthetic route to various spi-
rocyclic keto-lactams and keto-amines involving one main syn-
thetic pathway and three branch synthetic pathways. The
practical synthesis of spirocycles in the scaffold discovery from a
single lactam includes double allylation, ring-closing metathesis,
olefin hydroboration and allylic oxidation. This work provides the
foundation for a sequential DOS strategy from scaffold discovery
to drug discovery.
9. (a) Sannigrahi, M. Tetrahedron 1999, 55, 9007; (b) Kotha, S.; Deb, A. C.; Lahiri,
K.; Manivannan, E. Synthesis 2009, 165.
10. (a) Cossy, J.; Thellend, A. Tetrahedron Lett. 1990, 31, 1427; (b) Cossy, J.; Bouzide,
A.; Pfau, M. Tetrahedron Lett. 1992, 33, 4883; (c) Hollauf, G.; Urban, E.
Heterocycles 1994, 38, 2295; (d) Bouaucheau, C.; Parlier, A.; Rudler, H. J. Org.
Chem. 1997, 62, 7247; (e) Cossy, J.; Bouzide, A. Tetrahedron 1997, 53, 5775; (f)
Cossy, J.; Bouzide, A.; Leblanc, C. J. Org. Chem. 2000, 65, 7257; (g) Bendl, M.;
Eder, M.; Langhammer, I.; Urban, E. Heterocycles 2000, 53, 115; (h) Planas, L.;
Perard-Viret, J.; Royer, J.; Selkti, M.; Thomas, A. Synlett 2002, 1629; (i) Yang, D.;
Yan, Y.; Law, K.; Zhu, N. Tetrahedron 2003, 59, 10465; (j) Hilmey, D. G.;
Paquette, L. A. Org. Lett. 2005, 7, 2067; (k) Pilling, A. W.; Boehmer, J.; Dixon, D. J.
Angew. Chem., Int. Ed. 2007, 46, 5428; (l) Zhou, C.-Y.; Che, C.-M. J. Am. Chem. Soc.
2007, 129, 5828; (m) Pasternak, A.; Goble, S. D.; Doss, G. A.; Tsou, N. N.; Butora,
G.; Vicario, P. P.; Ayala, J. M.; Struthers, M.; DeMartino, J. A.; Mills, S. G.; Yang, L.
Bioorg. Med. Chem. Lett. 2008, 18, 1374; (n) Boddaert, T.; Coquerel, Y.;
Rodriguez, J. Adv. Synth. Catal. 2009, 351, 1744; (o) Li, M.; Dixon, D. J. Org.
Lett. 2010, 12, 3784.
11. Ezquerra, J.; Pedregal, C.; Rubio, A. J. Org. Chem. 1994, 59, 4327.
12. Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 100.
13. Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994, 639.
14. Yu, J.-Q.; Corey, E. J. Org. Lett. 2002, 4, 2727.
15. Characterization data for selected compounds in Scheme 1. Compound 4: 1H
NMR (CDCl3, 400 MHz) d 5.75 (m, 2H), 5.15 (s, 2H), 5.11 (m, 2H), 3.61 (t,
J = 8 Hz, 2H), 2.36 (m, 2H), 2.26 (m, 2H), 1.90 (t, J = 8 Hz, 2H), 1.54 (s, 9H).
Compound 5: 1H NMR (CDCl3, 400 MHz) d 5.56 (s, 2H), 3.70 (t, J = 8 Hz, 2H), 2.88
(d, J = 16 Hz, 2H), 2.33 (d, J = 12 Hz), 1.98 (t, J = 8 Hz, 2H), 1.56 (s, 9H).
Compound 7: 1H NMR (CDCl3, 400 MHz) d 3.77 (t, J = 6.9 Hz, 2H), 2.73 (d,
J = 18.2 Hz, 1H), 2.57 (m, 1H), 2.34 (m, 2H), 2.21 (d, J = 18.2 Hz, 1H), 2.03 (m,
3H), 1.57 (s, 9H). Compound 11: 1H NMR (CDCl3, 400 MHz) d 3.44 (m, 2 H), 3.32
(s, 1H), 3.26 (s, 1H), 2.35 (m, 2 H), 2.22 (m, 2 H), 1.99 (m, 2 H), 1.86 (m, 2 H),
1.47 (s, 9H).
References and notes
1. Zhao, H.; Akritopoulou-Zanze, I. Expert Opin. Drug Disc. 2010, 5, 123.
2. (a) Hajduk, P. J. Nature 2011, 470, 42; (b) Galloway, W. R. J. D.; Spring, D. R.
Nature 2011, 470, 43.
3. Schreiber, S. Science 2000, 287, 1964.
4. Dandapani, S.; Marcaurelle, L. A. Curr. Opin. Chem. Biol. 2010, 14, 362.