Diversity-Oriented Synthesis of Morpholine-Containing Molecular Scaffolds

Article abstract of DOI:10.1002/chem.200900744

The possibility of using selected building blocks from the chiral pool to develop a diversity-oriented synthesis (DOS) strategy to access stereochemically rich and rigid morpholine-based heterocycles according to the build/couple/pair approach was reporte

Full text of DOI:10.1002/chem.200900744

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DOI: 10.1002/chem.200900744
Diversity-Oriented Synthesis of Morpholine-Containing Molecular Scaffolds
Claudia Lalli, Andrea Trabocchi,* Filippo Sladojevich, Gloria Menchi, and
Antonio Guarna[a]
Dedicated to the Centenary of the Italian Chemical Society
Since the early reports by Schreiber et al.,[1] diversity-ori-
ented synthesis (DOS) has become a new paradigm for de-
veloping large collections of structurally diverse small mole-
cules as probes to investigate biological pathways and also
to provide a larger array of the chemical space in drug dis-
covery issues.[2] The principles of DOS have evolved from
the concept of generating structurally diverse compounds
from a divergent approach consisting in a complexity-gener-
ating reaction followed by cyclization steps and appendage
diversity, to the development of different cyclic structures
through the build/couple/pair approach.[3] The building stage
of the overall DOS process involves the generation of suita-
ble building blocks for subsequent coupling reactions, and it
is generally achieved by using compounds from the chiral
pool or achiral moieties as substrates for stereoselective re-
actions. The generation of heterocycles using amino acid
and sugar derivatives as building blocks is a powerful ap-
proach to access chemical and geometrical diversity thanks
to the high number of stereocenters and the polyfunctionali-
ty of such compounds, and numerous examples in the litera-
ture report the use of such substrates to access combinatori-
al libraries of heterocyclic compounds.[4] During the past few
years we have reported the generation of bicyclic com-
pounds from the combination of sugar or tartaric acid and
amino acid derivatives through two key steps consisting of
the coupling of two components from the chiral pool fol-
lowed by an intramolecular cyclization step to achieve the
bicyclic structure.[5] Recently, we turned our attention to the
synthesis of morpholine rings,[6] as among the various struc-
tures employed by medicinal chemists, this heterocycle rep-
resents a common motif.[7] For example, the morpholine
moiety can be found in several bioactive molecules, such as
TACE (TNF-a converting enzyme),[8] MMP (matrix metal-
loproteinase), and TNF (tumor necrosis factor) inhibitors,[9]
and it has been included in the core structure of tricyclic
benzodiazepines,[10] 6-methylidene penems as b-lactamase
inhibitors,[11] and of 8,6-fused bicyclic peptidomimetic com-
pounds as interleukin-1b-converting enzyme inhibitors.[12]
Thus, we envisioned the possibility of using selected building
blocks from the chiral pool to develop a DOS strategy to
access stereochemically rich and rigid morpholine-based het-
erocycles according to the build/couple/pair approach.
The strategic approach to the generation of morpholine
scaffolds utilizes some a-amino acid derivatives as amino
acetals or as b-amino alcohols to be coupled with suitable
building blocks possessing complementary functionalities to
achieve structurally diverse heterocycles after the cyclization
step. Specifically, the four derivatives A–D (Scheme 1) were
[a] Dr. C. Lalli, Dr. A. Trabocchi, Dr. F. Sladojevich, Dr. G. Menchi,
Prof. A. Guarna
Scheme 1. Selected building blocks for the coupling step.
Department of Organic Chemistry “Ugo Schiff”
University of Florence
Polo Scientifico e Tecnologico
Via della Lastruccia 13, 50019 Sesto F.no, Florence (Italy)
Fax : (+39)055-457-3531
considered for the coupling step, whose combination result-
ed in highly functionalized acyclic precursors as substrates
for the cyclization step. Path i consisted in a SN2 coupling re-
action followed by trans-acetalization, whereas a reductive
amination was envisaged for the coupling step in path ii.
E-mail: andrea.trabocchi@unifi.it
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900744.
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According to path i, the selection of building blocks to be
assembled and the choice of the reaction conditions to give
the cyclic scaffolds allowed a first degree of skeletal diversi-
ty around the morpholine nucleus (Scheme 2).
oriented in a pseudo-equatorial position and trans with re-
spect to the lactone moiety.
The modulation of skeletal diversity through the selection
of different stereoisomeric building blocks was exemplified
with compound 1, bearing R,R configuration at a and b ste-
reocenters, respectively, which could not cyclize to the bicy-
clic lactone as above under the same reaction conditions, as
a consequence of steric bias, but resulted in the polyfunc-
tional morpholine scaffold 9 (85% yield). Compounds 4 and
5 containing the amino group protected with fluorenylme-
thoxycarbonyl (Fmoc) and benzyloxycarbonyl (Cbz) groups,
respectively, gave access to a larger modulation of the reac-
tivity upon treatment under different conditions, thus giving
the N-protected bicyclic lactones similar to 10 (not shown),
the bicyclic scaffold 6 in 46% yield upon treatment with
neat trifluoroacetic acid (TFA),[14] and oxazine 8 in 23%
yield under p-toluenesulfonic acid (pTSA) catalysis in re-
fluxing toluene.
Bicyclic lactones having diverse functional groups at the
nitrogen atom were more conveniently achieved from scaf-
fold 10, as a consequence of less steric bias with respect to
the corresponding acyclic compound 2, thus resulting in sig-
nificantly higher yields. Accordingly, compound 10 could be
treated with several alkylating and acylating agents to give a
set of bicyclic morpholine-containing scaffolds as outlined in
Table 1.
Scheme 2. Skeletal diversity resulting from the cyclization step.
Compounds 2 and 3 having S,R configuration at a and b
stereocenters gave, upon treatment with a methanolic SOCl2
solution, bicyclic lactone derivatives 10 and 7 in 98% and
93% yields, respectively, and with moderate stereoselectivity
ranging from 4:1 to 7:1, respectively. These compounds were
of special interest because subsequent decoration of the
morpholine nucleus takes advantage of an orthogonal pro-
tection of both the hydroxymethyl and the carboxylic func-
tions embedded in the lactone moiety. The X-ray crystallo-
graphic analysis of 7 (Figure 1),[13] showed a rigid structure
containing the morpholine ring arranged in a twist–boat
conformation, and possessing the anomeric methoxy group
Table 1. Functionalization of the amino group of scaffold 10.
Compound
R
Conditions[a]
Yield [%]
11
12
13
14
15
16
17
benzoyl
Cbz
Fmoc
2-I-benzoyl
benzyl
bromoacetyl
Bz-Cl, DIPEA
86
95
78
61
Cbz-Cl, NaHCO3
Fmoc-Cl, 2,6-lutidine
2-I-Bz-Cl, Et3N
PhCHO, NaBH
BrCH2COBr, Et3N
ACHTUNGRTEN(NUNG OAc)3 75
78
87
4-Cl-benzenesulfonyl 4-Cl-PhSO2Cl, Et3N
[a] DIPEA=N,N-diisopropylethylamine.
Crystallographic analysis of the N-benzylated bicyclic lac-
tone 15[13] (Figure 2) confirmed the preferential orientation
of the anomeric methoxy group trans with respect to the lac-
tone moiety, in analogy with compound 7, and revealed the
morpholine ring arranged in the preferred chair conforma-
tion.
Subsequent manipulation of the bicyclic lactone involved
the use of the lactone moiety for amidation with selected
amines. This step generated a new set of scaffolds bearing
two new appendages in a stereocontrolled fashion. Also, the
resulting hydroxymethyl function could serve as an addition-
al diversification point for final scaffold decoration
(Table 2).
Figure 1. Molecular structure of compound 7.
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Diversity-Oriented Synthesis of Morpholine-Containing Molecular Scaffolds
COMMUNICATION
Figure 2. Molecular structure of compound 15.
Table 2. Aminolysis of the lactone moiety of 11.
Scheme 3. Scaffold diversity around bicyclic lactones 10, 11, 12, and 16.
Compound
R1
R2
Yield [%]
18
19
20
21
22
H
H
H
H
benzyl
cyclopropyl
allyl
93
86
97
93
85
AHCTUNGTREGaNNNU zodicarboxylate) allowed the transformation of compound
19 into the corresponding bicyclic lactam 27.
The combination of building blocks C and D (Scheme 1),
as dimethoxyacetaldehyde and b-hydroxy-a-amino acid de-
rivatives, such as serine and threonine, allowed the forma-
tion of morpholine and dihydro-oxazine scaffolds bearing a
different substitution pattern. The synthesis consisted in the
coupling of the two building blocks followed by cyclization
to achieve the morpholine ring.[6] Subsequent N-acylation
and acid-catalyzed elimination of the methoxy group result-
ed in the dihydro-oxazine scaffold (Scheme 4). Notably,
these compounds could be achieved in significantly higher
yields with respect to compound 8.
propargyl
À
AHCTUNGTERG(NNUN CH2)5
À
The generation of skeletal diversity around the morpho-
line ring starting from selected bicyclic lactones was ach-
ieved by applying cyclization reactions to morpholine scaf-
folds bearing strategic functionality at the nitrogen atom
and at the C-3 carbonyl group (Scheme 3). Lactone 10 was
coupled with Fmoc-d-Val-Cl and successively treated in situ
with diethylamine to remove the Fmoc protective group,
giving the corresponding bicyclic diketopiperazine 23 in
60% overall yield by virtue of concomitant intramolecular
aminolysis of the lactone moiety. Subsequent treatment with
catalytic H2SO4/SiO2 in refluxing toluene produced the tricy-
clic scaffold 24 by intramolecular trans-acetalization of the
hydroxymethyl group. Cbz-protected bicyclic lactone 12 was
treated with benzylamine and heated under microwave irra-
diation to access the bicyclic hydantoin 25 in 52% yield as a
consequence of tandem lactone aminolysis and cyclization
of the developing amide to the Cbz carbonyl group. Com-
pound 16, obtained from the acylation of 10 with 2-bromo-
Scheme 4. Synthetic route to dihydro-oxazines from threonine-derived
hydroxy-amino acetals.
ACHTUNGTRENNUNGacetyl bromide, was treated with benzylamine to give the
corresponding lactone ring opening and concomitant ring
closure of the intermediate amido group to the electrophilic
center, ultimately resulting in the formation of the morpho-
line-containing bicyclic diketopiperazine 26. The intramolec-
ular cyclization of the amido group over the hydroxymethyl
function under Mitsunobu conditions (DIAD=diisopropyl-
Thus, taking advantage of the double bond between car-
bons C-5 and C-6 of the dihydro-oxazine nucleus, additional
skeletal diversity was explored in the threonine-derived di-
hydro-oxazines having strategic functional groups at the ni-
trogen atom. Compound 28 was functionalized at the nitro-
gen atom with a Cbz group, ortho-substituted benzoyl chlo-
Chem. Eur. J. 2009, 15, 7871 – 7875
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7873

A. Trabocchi et al.
ride derivatives, and N-protected valine, and successively
processed to give the corresponding dihydro-oxazines 29–32
(Table 3).
lar framework in terms of appendage diversity can be ach-
ieved from two divergent synthetic pathways. The reactivity
of the double bond was taken into account to generate a
new ring junction at positions 4 and 5 of the oxazine ring by
pairing the C-5 with the functional group at N-4. Specifical-
ly, the tricyclic scaffold 35 was obtained by intramolecular
Heck reaction of the corresponding N-2-iodobenzoyl-oxa-
zine derivative 31. A significant improvement in the yield
was achieved by using microwave irradiation, which, as well
as accelerating the process, gave the title tricyclic scaffold in
84% yield compared to the low yield of 18% obtained
under conventional heating.
Table 3. Functionalization of scaffold 28.
Compound
R
Conditions
Yield [%]
Investigations by X-ray crystallography of compound 34[13]
revealed an interesting propensity of the substituents at the
dihydro-oxazine nucleus to retain a diaxial orientation
(Figure 3). This behavior is consistent with previous NMR
analysis on the cyclopropane-containing molecule 33,[6b] in-
dicating a strong preference for the axial orientation of both
the methyl and the carbonyl groups of the six-membered
ring.
29
30
31
32
Cbz
Cbz-Cl, DIPEA
2-NO2-Bz-Cl, DIPEA
2-I-Bz-Cl, DIPEA
95[a]
53
91
2-NO2-Ph-CO
2-I-Ph-CO
Fmoc-d-Val
Fmoc-d-Val-Cl, 2,6-lutidine
81
[a] See ref. [6b].
The introduction of the cyclopropane on the double bond
was achieved on the Cbz-morpholine derivative 29 by ste-
reoselective CuI-catalyzed cyclopropanation in the presence
of a BOX ligand, as reported,[6b] to give compound 33 as the
main stereoisomer, with a d.r. of 10:1 (Scheme 5). The pair-
ing strategy using the carbomethoxy group at C-3 and the
functional group at N-4 was applied for compounds 30 and
32. Catalytic hydrogenation of compound 30 over Pd/C gave
the corresponding benzodiazepine-2,5-dione 34, and treat-
ment of 32 with excess diethylamine removed the Fmoc
group and promoted the intramolecular amidation, thus
leading to the clean formation of the bicyclic diketopipera-
zine 36. Compound 36 showed structural similarities with 23
and 26, although differing in the degree of substitution
around the scaffold; thus a modulation of the same molecu-
Figure 3. Molecular structure of compound 34.
In conclusion, the selection of building blocks from the
chiral pool bearing complementary functional groups al-
lowed the exploration of new rigid scaffolds according to
the principles of diversity-oriented synthesis. Specifically,
sugar and amino acid derivatives having functional groups
for the generation of morpholine-based scaffolds were se-
lected, with the aim of achieving a first set of molecules
after a two-step coupling and cyclization procedure. Subse-
quent decoration of the scaffolds with suitable functional
groups allowed a second generation of cyclic compounds ac-
cording to the functional group pairing strategy. The herein
described chemical method for generating scaffolds accord-
ing to DOS principles is an excellent starting point for the
subsequent generation of libraries of small molecules as
probes to investigate biological mechanisms and for drug
discovery.
Acknowledgements
Financial support from Istituto Superiore di Sanitꢁ and University of
Florence is acknowledged. Dr. Cristina Faggi is gratefully acknowledged
for carrying out X-ray crystallographic analyses.
Scheme 5. Skeletal diversity from dihydro-oxazines 29–32.
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Diversity-Oriented Synthesis of Morpholine-Containing Molecular Scaffolds
COMMUNICATION
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Received: March 23, 2009
Published online: June 5, 2009
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