Modular, gold-catalyzed approach to the synthesis of lead-like piperazine scaffolds

Article abstract of DOI:10.1021/ol402988s

Ring-opening of cyclic sulfamidates with propargylic sulfonamides yielded substrates for a gold-catalyzed cyclization to yield tetrahydropyrazines. Manipulation of the tetrahydropyrazines, by reduction or using multicomponent reactions, yielded piperazine scaffolds in which substitution of the carbon atoms was varied. Such scaffolds may have value in the synthesis of novel screening compounds with lead-like molecular properties.

Full text of DOI:10.1021/ol402988s

ORGANIC
LETTERS
2013
Vol. 15, No. 23
6094–6097
Modular, Gold-Catalyzed Approach to the
Synthesis of Lead-like Piperazine
Scaffolds†
Thomas James,§ Iain Simpson,‡ J. Andrew Grant,‡ Visuvanathar Sridharan,§ and
Adam Nelson*,§
School of Chemistry and Astbury Centre for Structural Molecular Biology, University of
Leeds, LS2 9JT Leeds, U.K., and AstraZeneca, Mereside, Alderley Park, Macclesfield,
Cheshire SK10 4TG, U.K.
a.s.nelson@leeds.ac.uk
Received October 17, 2013
ABSTRACT
Ring-opening of cyclic sulfamidates with propargylic sulfonamides yielded substrates for a gold-catalyzed cyclization to yield tetrahydropyrazines.
Manipulation of the tetrahydropyrazines, by reduction or using multicomponent reactions, yielded piperazine scaffolds in which substitution of the
carbon atoms was varied. Such scaffolds may have value in the synthesis of novel screening compounds with lead-like molecular properties.
Sourcing large numbers of diverse, lead-like small mo-
lecules is a major challenge in maintaining high-quality
screening collections.1,2 This challenge stems both from the
poor availability of lead-like compounds2 and the histori-
cally uneven exploration of chemical space by synthesis.3
As an example, many commercially available screening
compounds and bioactive molecules contain a piperaz-
ine ring (5.4% of the ZINC database and 7.7% of the
ChEMBL database respectively; Supporting Information).
Yet, in the vast majority of these compounds, the piperazine
ring is isolated and is not substituted on any of its carbon
atoms. Such piperazines are widely exploited in drug dis-
covery because they allow the medicinal chemist to design
molecules that may be grown in two directions while
retaining basicity through appropriate substitution. As a
result, many important bioactive small molecules are piper-
azines, including 13 of the 200 best-selling drugs in 2012.4
In this paper, we describe anapproach to the synthesis of
substituted piperazines from pairs of biconnective5 build-
ing blocks (Scheme 1).6 Ring-opening of a cyclic sulfami-
date 1,7,8 prepared from the corresponding amino alcohol,
with a propargylic sulfonamide 2 would yield a substrate, 3,
for a cyclization reaction. Metal-catalyzed cyclization9,10
of the N-Boc- (or N-Cbz-)protected amine onto the alkyne
would then yield a heterocyclic product 4. This synthesis
of tetrahydropyrazines 4 from the biconnective building
(5) MacLellan, P.; Nelson, A. Chem. Commun. 2013, 2383.
(6) For a recent approach to substituted piperazines, see: Ruider,
€
S. A.; Muller, S.; Carreira, E. M. Angew. Chem., Int. Ed. 2013, 52, 11908.
† Dedicated to the memory of J. Andrew Grant, a great colleague,
collaborator, and scientist.
(7) For a review of the application of cyclic sulfamidates in hetero-
cycle synthesis, see: Bower, J. F.; Rujirawanich, J.; Gallagher, T. Org.
Biomol. Chem. 2010, 8, 1505.
(8) Williams, A. J.; Chakthong, S.; Gray, D.; Lawrence, R. M.;
Gallagher, T. Org. Lett. 2003, 5, 811.
(9) For other similar cyclizations, see: (a) Nicolai, S.; Waser, J. Org.
Lett. 2011, 13, 6324. (b) Han, J.; Xu, B.; Hammond, G. B. J. Am. Chem.
Soc. 2010, 132, 916.
‡ AstraZeneca.
§ University of Leeds.
(1) Krier, M.; Bret, G.; Rognan, D. J. Chem. Inf. Model. 2006, 46,
512.
(2) Nadin, A.; Hattotuwagama, C.; Churcher, I. Angew. Chem., Int.
Ed. 2012, 51, 1114.
(3) Lipkus, A. H.; Yuan, Q.; Lucas, K. A.; Funk, S. A.; Bartelt, W. F.;
Schenck, R. J.; Trippe, A. J. J. Org. Chem. 2008, 73, 4443.
(4) The structures of the top 200 selling drugs can be downloaded
from: http://cbc.arizona.edu/njardarson/group: McGrath N. A.;
Brichacek M.; Njardarson, J. T . J. Chem. Educ. 2010, 87, 1348.
(10) For cyclizations of N-propargylamides to yield oxazoles, see: (a)
Hashmi, A. S. K.; Weyrauch, J. P.; Frey, W.; Bats, J. W. Org. Lett. 2004,
6, 4391. (b) Weyrauch, J. P.; Hashmi, A. S. K.; Schuster, A.; Hengst, T.;
Schetter, S.; Littmann, A.; Rudolph, M.; Hamzic, M.; Visus, J.;
Rominger, F.; Frey, W.; Bats, J. W. Chem.;Eur. J. 2010, 16, 956.
r
10.1021/ol402988s
Published on Web 11/12/2013
2013 American Chemical Society

blocks 1 and 2 may be classified as a bi/bi process5 or as an
ambiphile11 pairing reaction sequence. It was envisaged that
the eneꢀdiamine functionality might serve as a useful
handle for decoration to yield small molecules with lead-
like2 properties.
reaction time (3 h) was required (Table 1, entry 2). At room
temperature in dichloromethane, 6a (83%) was accompa-
nied by the ketone 7a (15%) (Table 1, entry 3). Additional
experiments demonstrated that the ketone 7a is a kinetic
product of this reaction and is a competent intermediate in
the formation of the thermodynamic product, 6a. Cycliza-
tion was also effective with 1 mol % of the N-heterocyclic
carbene complex14 Au(IPr)Cl and 1 mol % of AgSbF6,
yielding 6a in 97% yield (Table 1, entry 4).
Scheme 1. Overview of the Proposed Modular Synthetic
Approacha
a R = Boc or Cbz; R0 = o- or p-nitrophenylsulfonyl.
Table 1. Optimization of the Synthesis of the
Tetrahydropyrazine 6aa
entry
1
conditions
yield 6a (%)
Figure 1. Structures of building blocks. Ns = o-nitrophenylsul-
fonyl; Ns0 = p-nitrophenylsulfonyl.
5 mol % Au(PPh3)Cl, 5 mol % AgSbF6,
dioxane, 100 °C, μw, 10 min
98
2
3
4
5 mol % Au(PPh3)Cl, 5 mol % AgSbF6,
95
A range of building blocks (Figure 1) was prepared to
allow the investigation of the scope and limitations of the
cyclization reaction. The potential substrates 5 were pre-
pared by treatment of a propargylic sulfonamide 8 with
sodium hydride in DMF and reaction with a cyclic sulfa-
midate 9 (Table 2).
The cyclization substrates 5bꢀi were treated with 5 mol
% of Au(PPh3)Cl and 5 mol % of AgSbF6 in dioxane at
100 °C (Table 2 and Figure 2). Under these conditions, the
substrates 5bꢀe and 5gꢀi cyclized smoothly to give the
corresponding tetrahydropyrazines in 79ꢀ98% yield. This
study demonstrated that either a Boc- or a Cbz-protected
amine is a competent nucleophile in the cyclization. How-
ever, 5f possesses two potential nucleophiles, a Boc-pro-
tected amine and an alcohol, positioned at the same
distance from the alkyne: at 100 °C in dioxane, the two
possible products, 6f and 10,15 were obtained in 36% and
48% yield, respectively. The outcome was controlled at
room temperature, and the dihydrooxacine 10 (81%) was
the only product observed.
dioxane, 100 °C, 3 h
5 mol % Au(PPh3)Cl, 5 mol % AgSbF6,
CH2Cl2, rt, 16 hc
1 mol % Au(IPr)Cl,b 1 mol % AgSbF6,
dioxane, 100 °C, μw, 10 min
83d
97
a Ns = o-nitrophenylsulfonyl. b IPr = 1,3,-Bis(2,6-diisopropylphenyl)-
1,3-dihydro-2H-imidazol-2-ylidene. c Analysis of the crude reaction mix-
ture by 500 MHz 1H NMR spectroscopy revealed a 85:15 mixture of the
tetrahydropyrazine 6a and the ketone 7a. d The ketone 7a was also obtained
in 15% yield.
Initially, the cyclization of the substrate 5a (and subse-
quent double bond isomerization10) was investigated
(Table 1).12 With 5 mol % of Au(PPh3)Cl and 5 mol %
of AgSbF613 in dioxane at 100 °C with microwave irradia-
tion, the tetrahydropyrazine 6a was obtained in 98% yield
after 10 min (Table 1, entry 1). With heating at 100 °C in
dioxane, 6a was obtained in 95% yield, although a longer
(11) Rolfe, A.; Samarakoon, T. B.; Hanson, P. R. Org. Lett. 2010, 12,
1216.
(12) (a) Li, Z.; Brouwer, C.; He, C. Chem. Rev. 2008, 108, 3239. (b)
Ito, H.; Harada, T.; Ohmiya, H.; Sawamura, M. Beilstein J. Org. Chem.
2011, 7, 951. (c) Zhang, Y.; Donahue, J. P.; Li, C.-J. Org. Lett. 2007, 9,
627. (d) Kang, J.-E.; Kim, H.-B.; Lee, J.-W.; Shin, S. Org. Lett. 2006, 8,
ꢀ
(14) Marion, N.; Ramon, R. S.; Nolan, S. P. J. Am. Chem. Soc. 2009,
131, 448.
(15) For a base-catalyzed cyclization to give 1,4-oxazines, see: Van-
davasi, J. K.; Hu, W.-P.; Chen, H.-Y.; Senadi, G. C.; Chen, C.-Y.;
Wang, J.-J. Org. Lett. 2012, 14, 3134.
€
3537. (e) Muller, T. E.; Grosche, M.; Herdtweck, E.; Pleier, A.-K.;
Walter, E.; Yan, Y.-K Organometallics 2000, 19, 170.
(13) Teles, J. H.; Brode, S.; Chabanas, M. Angew. Chem., Int. Ed.
1998, 37, 1415.
(16) In contrast, the reactions of 5jꢀm, catalyzed by 5 mol% of
Au(PPh3)Cl and 5 mol% of AgSbF6 in dioxane at 100 °C, were not clean.
Org. Lett., Vol. 15, No. 23, 2013
6095

these conditions, highly regioselective hydration of the
alkyne was observed.16,17 With the 1,2-disubstituted al-
kynes 5j, 5k, and 5m, hydration occurred distal to the
N-sulfonyl group, which might be explained by the inter-
mediacy of a chelated intermediate (Figure 3).18,19
Table 2. Synthesis and Gold-Catalyzed Reactions of Alkyne
Substrates (See Figure 2)
building
blocks
substratea
(methodb, yield (%))
producta
(methodb, yield (%))
entry
1
8a, 9b
8a, 9c
8b, 9d
8a, 9e
8b, 9f
5b (A1, 95)
5c (A1, 72)
5d (A1, 70)
5e (A1, 94)
5f (A1, 68)
5f
6b (B1, 98)
6c (B1, 90)
6d (B1, 96)
6e (B1, 96)
6f (B1, 36)c
10 (B2, 81)
6g (B1, 79)
6h (B1, 85)
6i (B1, 92)
7b (B3, 68)
7c (B3, 85)
7d (B3, 46)
7e (B3, 61)
2
3
4
5
6
7
8b, 9f
8b, 9g
8b, 9h
8c, 9a
8d, 9b
8e, 9b
8c, 9i
5g (A2, 74)
5h (A2, 67)
5i (A1, 89)
5j (A1, >98)
5k (A1, 91)
5l (A1, 90)
5m (A1, 83)
8
Figure 3. Proposed intermediate in the highly regioselective
hydration of the 1,2-disubstituted alkynes 5j, 5k, and 5m.
9
10
11
12
13
a Ns = o-nitrophenylsulfonyl; Ns0 = p-nitrophenylsulfonyl. b Meth-
ods: (A1) 8, NaH (1.1 equiv), DMF then 9 then 5 M HCl; (A2) 8, NaH
(1.1 equiv), DMF then 9 then 1 M citric acid solution; (B1) 5 mol %
Au(PPh3)Cl, 5 mol % AgSbF6, dioxane, 100 °C; (B2) 5 mol % Au-
(PPh3)Cl, 5 mol % AgSbF6, CDCl3, rt; B3: 1 mol % Au(IPr)Cl, 1 mol %
AgSbF6, 2:1 dioxaneꢀH2O, 120 °C, sealed tube (IPr = 1,3,-Bis(2,6-
diisopropylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene). c 10 was also
obtained in 48% yield.
Figure 4. Products of the reductions of the tetrahydropyrazines
6 and the ketone 7d. Where appropriate, the major diastereo-
meric product is drawn. Method: TFA (10 equiv), Et3SiH (6 equiv),
CH2Cl2, 0 °C f rt.
The tetrahydropyrazines6cꢀd and 6i, and the ketone 7d,
were reduced to the corresponding piperazines by treat-
ment with triethylsilane and trifluoroacetic acid (Figure 4).
The sense of diastereoselectivity depended on the identity
of the carbamate protecting group. With the Cbz-pro-
tected substrate 6c, the 2,6-trans-disubstituted piperazine
11a was obtained predominantly, presumably as a result of
axial attack of the reducing agent on the conformation of
the intermediate iminium ion in which 1,3-strain20 is
minimized. The Boc-protected substrates 6d and 6i yielded
predominantly the 2,6-cis-disubstituted piperazines 11b
and 11c; here, Boc deprotection may precede reduction
via analternative reactive conformation. Finally, reductive
amination of the NHCbz-substituted ketone 7d yielded
highly selectively the 2,3-cis-disubstituted piperazine 11d.
Multicomponent reactions of the tetrahydropyrazines
6a and 6i and the NHBoc-substituted ketone 7b were also
Figure 2. Structures of the substrates 5f,g and the products of
a
gold-catalyzed reactions. Ns = o-nitrophenylsulfonyl; Ns0 =
p-nitrophenylsulfonyl.
The reactions of 5jꢀmcouldbecontrolledbyusing1mol%
of Au(IPr)Cl and 1 mol % of AgSbF6 in 2:1 dioxaneꢀH2O
at 120 °C in a sealed tube (entries 10ꢀ13, Table 2); under
(18) Tsukano, C.; Yokouchi, S.; Girard, A.-L.; Kuribayashi, T.;
Sakamoto, S.; Enomoto, T.; Takemoto, Y. Org. Biomol. Chem. 2012,
10, 6074.
(19) For a related directing effect, see: Hansmann, M. M.; Rudolph,
M.; Rominger, F.; Hashmi, S. K. A. Angew Chem. Int. Ed. 2013, 52,
2593.
(17) See also: Hashmi, A. S. K.; Molinari, L.; Rominger, F.; Oeser, T.
Eur. J. Org. Chem. 2011, 2256.
(20) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841.
6096
Org. Lett., Vol. 15, No. 23, 2013

Figure 6. Rationalization of stereochemical outcome of the
multicomponent reaction of 6i.
the Mumm rearrangement (Figure 6).22 Finally, the ketone
7b was converted into the 1,4-diazepane 13 in 71% yield.
In summary, we have developed a modular approach to
the synthesis of lead-like piperazine scaffolds. The approach
involves reaction between cyclic sulfamidate and propargylic
sulfonamide building blocks to yield substrates for a gold-
catalyzed cyclization reaction. Crucially, by variation of the
specific building blocks used, it was possible to be vary the
substitution and relative configuration of the piperazine
scaffolds obtained. It is envisaged that the approach may be
exploited in the synthesis of libraries of substitutionally
diverse piperazines with lead-like molecular properties.
Figure 5. Products of the multicomponent reactions of the
tetrahydropyrazines 6 and the ketone 7b. Where appropriate,
the major diastereomeric product is drawn. Method: (1) TFA,
CH2Cl2 then evaporate; (2) benzylisontrile or 2-morpholi-
noethylisonitrile, EtOH, 0 °C.
investigated (Figure 5). In each case, the substrate was
treated with TFA in dichloromethane, evaporated, and
treated with an isonitrile in ethanol. The tetrahydropyr-
azines 6a and 6i yielded the differentially protected piper-
azine carboxylic acid derivatives 12a,b.21 The reaction of 6i
was highly (>98:<2) diastereoselective; the sense of dia-
stereoselectivity may stem from minimization of steric
interactions in the product-determining transition state of
Acknowledgment. We thank AstraZeneca and EPSRC
for funding.
Supporting Information Available. General experimen-
tal procedures and spectra of key transformations. This
material is available free of charge via the Internet at
http://pubs.acs.org.
ꢀ
(21) Bowers, M. M.; Carroll, P.; Joullie, M. M. J. Chem. Soc., Perkin
Trans. 1 1989, 857.
(22) El Kaim, L.; Grimaud, L. Tetrahedron 2009, 65, 2153.
The authors declare no competing financial interest.
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