I2-mediated diversity oriented diastereoselective synthesis of amino acid derived trans-2,5-disubstituted morpholines, piperazines, and thiomorpholines

Article abstract of DOI:10.1021/co200129t

Diastereoselective trans-2,5-disubstituted amino acids derived diverse morpholines, piperazines and thiomorpholines were prepared in 30 min-1 h with high yields through iodine-mediated 6-exotrig type cyclization from a single common synthetic intermediate. The displacement of iodine with hydride ion gave a methyl substituent at the 2-position of morpholines which provides an additional opportunity for diversity oriented nucleophilic substitution on the rings as well as incorporation of substituents at the 5-position from amino acids constituents.

Full text of DOI:10.1021/co200129t

Letter
pubs.acs.org/acscombsci
I2-Mediated Diversity Oriented Diastereoselective Synthesis of
Amino Acid Derived trans-2,5-Disubstituted Morpholines,
Piperazines, and Thiomorpholines
Saurav Bera and Gautam Panda*
Medicinal and Process Chemistry Division, CSIR, Central Drug Research Institute, Lucknow-226001, UP, India
S
* Supporting Information
ABSTRACT: Diastereoselective trans-2,5-disubstituted amino
acids derived diverse morpholines, piperazines and thiomor-
pholines were prepared in 30 min-1 h with high yields through
iodine-mediated 6-exotrig type cyclization from a single
common synthetic intermediate. The displacement of iodine
with hydride ion gave a methyl substituent at the 2-position of
morpholines which provides an additional opportunity for
diversity oriented nucleophilic substitution on the rings as well
as incorporation of substituents at the 5-position from amino
acids constituents.
KEYWORDS: amino acids, morpholines, piperazines, thiomorpholines, diastereoselective reaction
so SAR studies have been dominated by changes in the N-
itrogen-, oxygen-, and sulfur-containing heterocyclic
Nframeworks are ubiquitous subunits in biologically active substituents. Many of the existing protocols for accessing these
molecules.1−3 For example, 2,5-disubstituted morpholine
types of 2,5-disubstituted heterocycles give diastereomeric
mixtures of products.11 For example, morpholines can be pre-
derivatives are used as chiral auxiliaries in asymmetric
synthesis,4 and in a variety of biologically active structures
pared by the epoxide ring-opening with amino alcohols, with
such as the antidepressant drug reboxetine5 and the antifungal
cyclization of the resulting amino diol to give the desired product.
De Kimpe and co-workers12 have shown that disubstituted
morpholines can also be prepared by ring enlargement of
2-(allyloxymethyl)aziridine via an electrophile−induced ring closure
reaction, but isolated yields are low in many cases. Although
C-functionalized disubstituted chiral morpholines have been
synthesized,13 only two enantioselective synthesis of trans-2,5-
disubstituted morpholines have been reported so far.14
Substituted piperazines have been mostly prepared by
dimerization of amino acids to afford diketopiperazines,
which were subsequently reduced.15
compound fenpropimorph.6 Similarly, the piperazine moiety is
present in various biologically active compounds including the
antimicrobial7 pefloxacin and related quinolones, dopaminergic
D3 agents,8 HIV-protease inhibitors,9 and the antidepressant
clozapine.10
We have been working on the synthesis and biology of
S-amino acid-derived chiral heterocycles and natural-product-like
molecules.16 Recently, we have published a new series of amino
acids derived benzoxazepines as antitumor agents in breast
cancer16b and a novel methodology for the synthesis of sub-
stituted piperazine.16d In continuation of our work, herein we
describe the asymmetric synthesis of trans-2,5-disubstituted
morpholines, piperazines and thiomorpholines through a
straightforward and modular pathway involving (iodine mediated
6-exotrig cyclization of precursors) bearing four different groups
at N1, C2, N4 and C5 (Scheme 1).17
Figure 1. Some bioactive disubstituted morpholines and piperazine
derivatives.
One major constraint of using morpholines, piperazines and
thiomorpholines as building blocks is the difficulty of
introducing functional groups on the carbon backbone, and
Received: August 10, 2011
Revised: November 14, 2011
Published: November 29, 2011
© 2011 American Chemical Society
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ACS Combinatorial Science
Letter
Scheme 3. Synthesis of Disubstituted Piperazines
Scheme 1. Synthesis of Amino Acid Derived trans-2,5-
Disubstituted Morpholines, Piperazines, and
Thiomorpholines
A similar pathway was adopted for the synthesis of chiral thio-
morpholines from the common carbinol precursor (Scheme 4).
RESULT AND DISCUSSION
■
Scheme 4. Synthesis of Disubstituted Thiomorpholines
The synthesis of the required substrates for iodocyclization began
with S-amino acids 1a−e which were converted to their methyl-
esters 2a−e followed by allylation to give 3a−e (Scheme 2).
Scheme 2. Synthesis of Disubstituted Morpholines
Compounds 5b,c were thioesterified with thioacetic acid under
Mitsunobu conditions and then reduced to the corresponding
thiol compounds 12b,c in good yield. Under similar iodocycliza-
tion condition, 12b,c provided thiomorpholines 13b,c with
excellent diastereoselectivity. In this case, the starting materials
were fully consumed within 30 min as monitored by TLC even at
30 °C, representing considerably faster reactions than the other
two substrates. This is presumably because of the high
nucleophilicity of sulfur in 12b,c compared to nitrogen and oxygen
in 5a−e and 9a−e.
Tosylation to 4a−e proceeded smoothly, followed by ester
reduction to give primary alcohols 5a−e. All of these steps were
accomplished in excellent yields and are amenable to easy scale-up.
The carbinols were used as common intermediates for
diversification. Thus, direct iodine mediated cyclization of, 5a−e
furnished 6a−e in 1 h with diastereoselectivity up to >99%. The
replacement of iodine by hydride through nucleophilic displace-
ment furnished compounds 7b,c in 75% yield. Of course, other
nucleophiles than hydride can be easily introduced at this step give
diverse trans-2,5-disubstituted morpholines. In addition, the tosyl
group can be removed as shown for 7b using sodium naphtha-
lenide.16d Derivatization of the resulting secondary amine provides
additional opportunity for diversity oriented synthesis.
With intermediate carbinols 5a−e in hand, synthesis of 2,5
disubstituted piperazines was attempted (Scheme 3). The derived
tosylates 8a−e reacted smoothly with benzyl amine and KI as
catalyst to give 9a−e. As above, iodine-mediated cyclization at
55 °C gave 2,5-disubstituted piperazines 10a−e in diastereose-
lective fashion and good yield. Only one isomer each was
detected by chiral HPLC analysis of the products derived from
R- and S-leucine, showing complete retention of absolute
stereochemistry as well as completely diastereoselectivity in the
iodocyclization step.
Figure 2. Possible iodocyclization transition states.
All the final molecules were characterized by 1D NMR, mass,
IR, and elemental analysis. The stereochemistries of final mole-
cules were confirmed by NOESY spectroscopy and chiral
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ACS Combinatorial Science
Letter
HPLC analysis (see Supporting Information). The stereochemistry
at 5-position of six membered ring was also confirmed by NMR
and NOESY spectroscopic analysis (see Supporting Information).
In compound 10d, (Figure 3) the location of all protons were
AUTHOR INFORMATION
■
Corresponding Author
* Tel: 91-522-2612411-18, Ext. 4385, 4603. Fax: 91-522-
2623405. E-mail: gautam.panda@gmail.com; gautam_panda@
cdri.res.in.
ACKNOWLEDGMENTS
■
This research project was supported by Department of Science
and Technology, New Delhi, India. Saurav thanks CSIR for
providing fellowship (NET-SRF) and Mr. Purushottam for
HPLC analysis. For Instrumental facilities from SAIF, CDRI
(communication no 8167), Lucknow is acknowledged.
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Figure 3. Confirmation of stereochemistry of 10d by NOESY (400
MHz, CDCl3).
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confirmed on the basis of the DEPT, HSQC and COSY spectra.
The H-5 showed NOESY correlation with H-3, which is syn to
H-2′, whereas H-2 showed NOESY correlation with H-6, which is
syn to H-5′.
The trans-stereoselectivity of the iodocyclization reactions of
heterosubstituted amino acids derived allylamines 5a−e, 9a−e,
and 12b,c can be explained on the basis of the expected confor-
mational preferences in the proposed transition state of the
reaction (Figure 2). The reaction does not follow “path b” giving
rise to seven-membered rings, and selects the trans isomer of the
6-membered ring. A chairlike transition state exposes the iodo-
methyl group to 1,3-diaxial interactions for the cis isomer but not
for the trans isomer, giving rise to considerably more steric
crowding in the former case.
In summary, we have described a simple and powerful
synthetic route that provides access to diastereoselective 2,5-
disubstituted diverse morpholines, piperazines and thiomorpho-
line starting from commercially available S-amino acids derived
synthetic intermediates. The key step involves iodine mediated
cyclization under mild reaction condition, giving heterocycles that
can be further elaborated in several ways, such as by nucleophilic
substitution on the rings as well as incorporation of substituent at
5-position from amino acids constituents.
EXPERIMENTAL PROCEDURES
■
General Experimental Procedure for the Synthesis of
6a−e. To a stirred solution of compound 5a−e (1 equiv) in
anhydrous THF (10 mL), I2 (1 equiv) was added at 60 °C. Then
it was continuously stirred for 1 h. The reaction mixture was
quenched by addition of sodium thiosulfite and diluted with water
(10 mL). The aqueous layer was extracted with ethyl acetate (3 ×
50 mL), and the organic layer was dried over anhydrous Na2SO4.
After concentration under vacuum, the crude product was chro-
matographed on silica gel with as eluent (hexane/ethyl acetate,
9.5/0.5) to furnish the disubstituted morpholine 6a−e (75−80%
yield) as a colorless oil.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed experimental procedures and compound character-
ization data for products. This information is available free of
charge via the Internet at http://pubs.acs.org/.
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