Synthesis of Oxetane- and Azetidine-Containing Spirocycles Related to the 2,5-Diketopiperazine Framework

Article abstract of DOI:10.1055/s-0035-1560593

A simple two-step sequence is used to efficiently make novel spirocyclic analogues of the diketopiperazine nucleus. Conjugate addition of chiral α-amino esters to nitroalkenes, generated from oxetan-3-one or N-Boc-azetidin-3-one, followed by nitro group r

Full text of DOI:10.1055/s-0035-1560593

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, 169–172
letter
169
J. D. Beadle et al.
Letter
Synlett
Synthesis of Oxetane- and Azetidine-Containing Spirocycles Relat-
ed to the 2,5-Diketopiperazine Framework
Jonathan D. Beadlea
Nicola H. Powella
Piotr Raubob
Guy J. Clarksona
Michael Shipman*a
O
H2N
CO2Me
R1
NO2
R2
O2N
H2
Raney Ni
H
HN
R1
R2
48–89%
N
CO2Me
R1
NH
61–93%
R2
X
X
X
14 examples where X = O or NBoc; R1 = H, Me or Bn;
2 = H, Me, Ph, Bn, iPr, CH2OH, CH2CO2 Bu, (CH2)4NHBoc
a Department of Chemistry, University of Warwick,
Gibbet Hill Road, Coventry, CV4 7AL, UK
m.shipman@warwick.ac.uk
b AstraZeneca, Mereside, Alderley Park, Macclesfield,
SK10 4TG, UK
t
R
This article is dedicated to Professor Steven V. Ley
CBE FRS on the occasion of his 70th birthday
Received: 13.10.2015
Accepted after revision: 03.11.2015
Published online: 24.11.2015
strated the benefits of carbonyl to oxetane substitution in
other common scaffolds used in drug discovery.10 More-
over, 2 has much potential for derivatization via selective
substitution at up to four carbon atoms and two nitrogen
atoms (three nitrogens for the azetidine series) of the rigid
framework. Thus, they should serve as excellent templates
for the precise display of various biological receptor binding
groups in three-dimensional space.
DOI: 10.1055/s-0035-1560593; Art ID: st-2015-d0812-l
Abstract A simple two-step sequence is used to efficiently make novel
spirocyclic analogues of the diketopiperazine nucleus. Conjugate addi-
tion of chiral α-amino esters to nitroalkenes, generated from oxetan-3-
one or N-Boc-azetidin-3-one, followed by nitro group reduction pro-
vides, after spontaneous cyclization, the spirocycles in good overall
yields. These rigid scaffolds can be functionalized by selective N-alkyla-
tions as well as by carbonyl reduction to the corresponding piperazines.
O
O
R1
R2
NO2
O2N
R2
H
HN
R1
N
CO2R3
Key words oxetanes, diketopiperazines, spirocycles, peptidomimet-
ics, piperazines
HN
R1
NH
NH
1R
R2
X
X
O
X
diketopiperazine
2
4
3
There is much interest in the preparation of spirocyclic
heterocycles for use in medicinal chemistry.1 Important
properties of these scaffolds include their inherent rigidity,
structural novelty, reduced lipophilicity, and greatly in-
creased potential for the precise presentation of pendant
functional groups in three-dimensional space. Considerable
progress has been made towards the development of gener-
al methods for the preparation of such spirocycles,2,3 how-
ever, efficient access to new scaffolds has the potential to
open up further regions of chemical space for drug discov-
ery.
The 2,5-diketopiperazine subunit (2,5-DKP, 1) is found
in many bioactive natural products and medicinal agents
including in the marketed drug, Tadalafil (Scheme 1).4,5 As
part of an ongoing interest in the preparation of useful oxe-
tane-containing frameworks,3h,6,7 we sought to examine the
feasibility of preparing novel spirocyclic scaffolds related to
2,5-DKP. Specifically, we targeted the synthesis of 2-hetero-
5,8-diazaspiro[3.5]nonan-7-ones 2 wherein one of the C=O
bonds is replaced by four-membered oxetane (2a) or azeti-
dine (2b) rings.8,9 This was inspired, in part, by the work of
Carreira, Rogers–Evans, and co-workers who have demon-
(2,5-DKP, 1)
where a (X = O); b (X = NBoc)
Scheme 1 Route to 2-hetero-5,8-diazaspiro[3.5]nonan-7-ones 2
Our retrosynthetic strategy to 2 is outlined in Scheme 1.
The route involves: conjugate addition of an α-amino ester
to highly strained nitroolefin 3 followed by reduction of the
resulting nitroalkane 4 and cyclization to the target spiro-
cycle. In this Letter, we report the development of an effi-
cient and general strategy to these new spirocycles and
show how they can serve as useful intermediates en route
to spirocyclic piperazines which are themselves of current
interest.3e
We began by examining the conjugate addition of α-amino
esters to nitroalkene 3. This element of the work builds on
recent communications by us7 and by Carreira11 that out-
line the use of this reaction for the synthesis of oxetane-
based peptidomimetics. Here, 14 new examples of this con-
jugate addition chemistry are reported providing 9a–n in
moderate to good yields (Scheme 2). For derivatives 9a–i, 3-
(nitromethylene)oxetane 6 (R1 = H) was made in situ from
oxetan-3-one (5) and nitromethane prior to addition of the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 169–172

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J. D. Beadle et al.
Letter
Synlett
amino ester. Using nucleophiles derived from a variety of
proteinogenic amino acids, we are able to make products
containing nonpolar (Gly, Ala, Val), polar (Ser), aromatic
(Phe), acidic (Asp), and basic (Lys) amino acid residues. The
use of L-proline methyl ester allowed entry to tertiary
amine 9d, whilst access to aryl substitution as in 9h was ex-
emplified using (R)-phenyl glycine methyl ester. The chem-
istry was further extended to the synthesis of azetidines 9j
and 9k through use of 3-(nitromethylene)azetidine 8
(R1 = H), made in situ from commercially available N-Boc
azetidin-3-one (7). Variation in R1 was established through
the preparation of 9l–n derived from 6 (R1 = Me12 or Bn13)
made from nitroethane and 2-phenylnitroethane, respec-
tively.
the same backbone substitution pattern were selected as a
test substrates.14 Controlled reduction of the nitro group of
methyl ester 10 was explored under a variety of conditions
(Table 1, entries 1–6). In each case, 12a was isolated as a re-
sult of spontaneous cyclization of the resulting primary
amine with loss of methanol. The use of Raney Ni under an
atmosphere of hydrogen proved most effective (Table 1 en-
try 6). Under these conditions, the DKP analogue 12a was
produced in 81% over the two steps. Much lower yields
were observed using the corresponding benzyl and tert-bu-
tyl esters under these optimized conditions (Table 1, entries
7 and 8).
Table 1 Optimization of Cyclization Conditions to 12a
i. O2NCH2R1, Et3N
ii. MsCl, Et3N
O
H2N
CO2R3
NO2
O2N
R1
O
H
H
N
CO2R
CO2R3
HN
R2
conditions
N
CH2Cl2, –78 °C
O2N
R1
NH
X
R2
O
X
X
O
10 (R = Me)
11 (R = Bn)
9c (R = t-Bu)
9a–na
5 (X = O)
7 (X = NBoc)
6 (X = O)
8 (X = NBoc)
12a
Conditionsa
Yield (%)b
NO2
NO2
NO2
H
Entry
Substrate
R
H
N
H
CO2tBu
N
CO2Me
N
CO2Me
1
2
3
4
5
6
7
8
10
10
10
10
10
10
11
Me
Me
Me
Me
Me
Me
Bn
Zn, AcOH, THF
22
26
25
50
23
81
17
0d
Me
O
Zn, aq NH4Cl, EtOHc
O
O
9b, 55%
9c, 57%
9a, 55%
In, HCl, THF–H2O (1:3)
10% Pd/C, H2, MeOH
10% Pt/C, H2, MeOH
Raney Ni, H2, MeOH
Raney Ni, H2, MeOH
Raney Ni, H2, MeOH
NO2
NO2
NO2
H
H
N
CO2Me
Ph
N
CO2Me
N
CO2Me
9d, 55%
NHBoc
O
O
O
9f, 54%
9e, 53%
9c
t-Bu
NO2
NO2
NO2
H
H
H
N
CO2Me
OH
N
CO2Me
a Conducted at r.t. unless otherwise stated.
b Isolated yield after chromatography.
N
CO2Me
CO2tBu
Ph
c Reduction at 30 °C, then heated at reflux for 24 h.
O
O
O
d Major product was the primary amine from reduction of nitro group with-
out concomitant cyclization.
9g, 55%
9h, 52%
9i, 54%
NO2
NO2
NO2
H
With conditions for the reduction–ring closure opti-
mized, the substrate scope of the chemistry was explored
(Scheme 3).15 A wide variety of 2,5-DKP analogues 12a–n
were produced in good yields, and the reaction tolerates a
wide variety of substitution patterns. The structures of (S)-
12a and 12j were verified by X-ray crystallography.16 Unlike
2,5-DKP which typically adopt flat or puckered boat confor-
mations,4 12a adopts a envelope-type structure with the
spiro-ring atom projecting out of the plane with the adja-
cent nitrogen sp3-hybridized (Figure 1). Similar behavior
was seen for 12j in which the carbon substituent is located
on the opposite side of the six-membered ring (see Sup-
porting Information). Both enantiomers of 12a were made,
and we were able to confirm that no detectable racemiza-
tion occurs during the reduction–cyclization sequence (see
Supporting Information). Disubstituted derivatives such as
12l can be produced in high yield as a diastereomeric mix-
ture.
H
H
N
CO2Me
N
CO2Me
N
CO2Me
Me
N
O
N
Boc
Boc
9l, 84%b
9j, 48%
9k, 78%
NO2
NO2
H
H
N
CO2Me
Ph
N
CO2Me
Me
O
O
9n, 89%b,d
9m, 88%c
Scheme 2 Scope of the conjugate addition reaction. a Isolated yield af-
ter column chromatography. b Made from isolated 6 (R1 = Me). c Made
from isolated 6 (R1 = Bn). d Formed as a 1:1 mixture of diastereomers.
With access to a variety of oxetane- and azetidine-mod-
ified DKP precursors, we sought to identify suitable condi-
tions for the reduction–cyclization. To explore the impact of
the nature of the ester group on this chemistry, methyl es-
ter 10, benzyl ester 11, and tert-butyl ester 9c possessing
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J. D. Beadle et al.
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To explore the utility of these novel building blocks, fur-
ther manipulations of a representative compound, namely
12h, have been undertaken (Scheme 4). For example, selec-
tive benzylation of the amide and amine nitrogens of this
spirocycle can be achieved by exploiting differences in the
nucleophilicity/basicity of these centers. Thus, 13 and 14
could be separately produced in good yields. Reduction of
the amide carbonyl to afford the corresponding spirocyclic
piperazine 15 was also established. This was best achieved
in two steps via the corresponding thioamide as direct hy-
dride reduction using reagents such as LiAlH4 led to partial
opening of the oxetane ring.
O
X
NO2
R2
H2, Raney Ni
MeOH, r.t., 16 h
H
N
CO2Me
HN
1R
NH
X = O or NBoc
R2
9a–n
1R
X
12a–na
O
O
O
O
HN
HN
CO2tBu
HN
OH
NH
NH
NH
O
O
(S)-12a, 81%b
(R)-12a, 78%
12c, 69%
12b, 71%
O
O
O
H
N
O
O
HN
HN
HN
Na2CO3, BnBr, NaI
MeCN, 82 °C, 3 h
Me
Me
NBn
HN
HN
NHBoc
NH
NH
NH
76%
O
O
O
O
12d, 61%
12e, 87%
12f, 68%
O
O
12h
14
O
O
1. Lawesson's reagent
THF, r.t. to 76 °C, 79%
2. Raney Ni, MeOH
65 °C, 3 h, 68%
NaH, BnBr, DMF
0 °C to r.t.
Me
Ph
HN
Ph
HN
HN
68%
NH
O
NH
NH
O
O
Me
O
O
O
O
O
Me
NH
12g, 80%
12h, 80%
12i, 85%
HN
BnN
NBn
O
HN
HN
HN
13
15
NH
NH
NH
Me
Me
Scheme 4 Illustrative manipulations of oxetane-containing spirocycle
Ph
12h
O
O
O
12l, 77%c
12j, 74%
12k, 81%
O
N
O
N
In conclusion, we have developed a general and efficient
route to new spirocycles related to the medicinally import-
ant 2,5-DKP nucleus. Future work will focus on the applica-
tion of these new scaffolds in drug discovery programmes.
HN
HN
NH
NH
Boc
Boc
12m, 93%
12n, 69%
Scheme 3 Scope of reductive cyclization for the synthesis of spirocy-
cles 12a–n. a Isolated yield after column chromatography. b >95% ee as
determined by 1H NMR analysis in the presence of Pirkle’s reagent (see
Supporting Information). c Obtained as a 1:1 mixture of diastereomers.
Acknowledgment
We thank AstraZeneca, the EPSRC, and the University of Warwick for
financial support. The Oxford Diffraction Gemini XRD system for X-
ray structure determination was obtained, through the Science City
Advanced Materials project: Creating and Characterizing Next Gener-
ation Advanced Materials, with support from Advantage West Mid-
lands.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560593. Experimental procedures
and characterization data for all new compounds, copies of 1H and 13
C
NMR spectra of compounds 9a–n, 12a–n, 13–15 and chiral Pirkle
analysis of 12a are included.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
Figure 1 X-ray crystal structure of 12a with thermal ellipsoids drawn
at 50% probability level
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References and Notes
(8) We have previously reported the isolation of 12g as an
unwanted byproduct in the synthesis of oxetane-based peptid-
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(14) The synthesis of 10 and 11 was realized as previously reported,
see ref. 7.
(15) General Procedure for Nitro Reduction and Cyclization to 12
The substrate (1 equiv) and Raney Ni (1.0 mL, slurry in H2O) in
MeOH (10 mL/mmol) were stirred at r.t. under an atmosphere
of H2 (balloon) for 16 h. The reaction mixture was filtered
through a plug of Celite®, eluting with EtOAc. The eluent was
concentrated under reduced pressure, and the crude product
was purified by column chromatography. Using this method,
(S)-10 (325 mg, 1.32 mmol) gave, after column chromatography
(0–10% MeOH in EtOAc), (S)-12a (197 mg, 81%) as white solid.
Rf = 0.31 (10% MeOH in EtOAc); mp 153–158 °C; [α]D25 –118.1 (c
0.10, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 6.36 (1H, br s,
NHCO), 4.62 (2H, s, OCH2), 4.50 (1H, d, J = 7.1 Hz, OCHH), 4.45
(1H, d, J = 7.1 Hz, OCHH), 3.65 (1H, dd, J = 11.5, 4.6 Hz, NHCHH),
3.51–3.40 (2H, m, NHCHH, CHi-Pr), 2.50–2.34 (1H, m, CHMe2),
1.80 (1H, br s, NH), 0.99 (3H, d, J = 7.3 Hz, CH3), 0.91 (3H, d,
J = 6.8 Hz, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 170.4 (C),
81.5 (CH2), 79.3 (CH2), 59.3 (CH), 54.7 (C), 48.4 (CH2), 29.5 (CH),
18.5 (CH3), 15.6 (CH3) ppm. IR (film): 3253, 2965, 2869, 1649,
1321, 980 cm–1. MS (ES+): m/z = 185 [M + H]+, 207 [M + Na]+.
HRMS (ES+): m/z calcd for C9H17N2O2 [M + H]+: 185.1285; found:
185.1284.
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(16) CCDC 1430502 (12j) and 1430503 (12a) contain the supple-
mentary crystallographic data. These data can be obtained free
of charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 169–172