Regioselective O-sulfonylation of N,N-bis(2-hydroxyalkyl)tosylamides as a synthetic key step to enantiopure morpholines

Article abstract of DOI:10.1021/acs.orglett.6b03342

The synthesis of enantiopure 2,6-disubstituted morpholines was realized through sequential ring opening of two different optically pure oxiranes by a tosylamide, under solid-liquid phase-transfer catalysis (SL-PTC) conditions, mono-O-sulfonylation of the

Full text of DOI:10.1021/acs.orglett.6b03342

Letter
pubs.acs.org/OrgLett
Regioselective O‑Sulfonylation of N,N‑Bis(2-
hydroxyalkyl)tosylamides as a Synthetic Key Step to Enantiopure
Morpholines
Francesca Foschi,† Domenico Albanese,† Ilir Pecnikaj,‡,§ Aaron Tagliabue,†,∥ and Michele Penso*,‡,†
†Department of Chemistry, Universita
̀
degli Studi di Milano, via Golgi 19, I-20133 Milano, Italy
‡Institute of Molecular Science and Technologies, via Golgi 19, I-20133 Milano, Italy
S
* Supporting Information
ABSTRACT: The synthesis of enantiopure 2,6-disubstituted morpholines was
realized through sequential ring opening of two different optically pure oxiranes by
a tosylamide, under solid−liquid phase-transfer catalysis (SL-PTC) conditions, mono-
O-sulfonylation of the resulting tosylamido-2,2′-diol, and cyclization to the
morpholine. The crucial step, the regioselective formation of the monosulfonate,
was controlled by taking advantage of the different stereo, electronic, and
coordination properties of the oxirane-derived side chains in the diol backbone. As
an application of this protocol, a new morpholine-3-carboxamide was synthesized
starting from threonine.
Scheme 1. Synthesis of 2,6-Disubstituted Morpholines 3:
Direct Regioselective Protocol (a) vs Protection/
Deprotection Protocol (b)
egiochemical control is a stimulating and challenging task
in many synthetic transformations of important com-
R
pounds and, in particular, of small molecules. As evidence of
this, several reviews have been recently published on the
regioselectivity of processes such as the manipulation of
hydroxy groups in monosaccharide derivatives,1 addition
reactions to allenes,2 alkenes,3 and alkynes,4 transglycosylation
of nucleosides,5 transformations of chiral substrates controlled
by a chiral catalyst,6 cross-coupling reactions carried out in
water,7 Fujiwara−Moritani coupling,8 Pd-catalyzed cross-
coupling of dihaloarenes,9 and functionalization of hetero-
aromatics by metal-catalyzed coupling.10 In the present paper,
we describe the regiocontrolled mono-O-sulfonylation of diols,
whose hydroxy groups have minimal steric and electronic
differences, and the application of this chemistry in an
enantiopure morpholine synthesis. Interest in the regio- and
stereoselective synthesis of optically pure C-substituted
morpholines is increasing due to their wide spectrum of
biological activity. In particular, 2,6-disubstituted morpholines
have found applications in antisense11 and foldamer chem-
istry,12 whereas morpholine 3-carboxylic acids induce β-
conformations when they replace proline units in peptide
chains.13 Furthermore, morpholine derivatives have been used
as HIV protease inhibitors,14 anti-inflammatory15 and anti-
microbial agents,16 therapeutics in the treatment of diabetes
and obesity,17 mental disorders,18 sexual dysfunction,19 and
tumors,20 and inhibitors of both tumor necrosis factor-α21 and
matrix metalloproteinases.22
the tosylamido alcohol 4 as the THP derivative 5. Then, the
reaction with a different oxirane, activation of the new formed
hydroxy function as an O-tosylate (6 → 7), and final removal of
the protective group afforded the desired intermediate 2.
We previously reported a method for the synthesis of 2,6-
disubstituted morpholines 3 (Scheme 1, path b)23 by
intramolecular cyclization of the tosylamidodiol monosulfonate
2. The latter was prepared through ring-opening reaction of an
oxirane under solid−liquid phase-transfer catalysis (SL-PTC)
conditions,24 followed by protection of the hydroxy function of
Received: November 8, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03342
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Regioselective O-Sulfonylation: SN1 vs SN2
Mechanism
Table 2. Regioselective O-Sulfonylation: (+I) vs (−I) Effect
a
in Glycidyl Derivatives 1e,f
entry
substrate
X
R3SO2Cl
yield (%)
1
2
3
4
5
6
1e
1f
H
TsCl
TsCl
TsCl
TsCl
TsCl
TrisCl
2e (73)
2f (78)
2f (79)
2f (37)
2f (41)
2g (90)
reg-2e (20)
reg-2f (17)
reg-2f (17)
reg-2f (34)
reg-2f (38)
OMe
OMe
OMe
OMe
OMe
b
1f
c
1f
d
1f
1f
a
Reaction conditions: 1 (1 mmol), R3SO2Cl (1.1 mmol), NaH (2.1
b
c
a
mmol), THF (2.5 mL), at −80 °C, 1 h. In 20 mL of THF. In the
presence of LiClO4 (8 mmol), at 0 °C, 8 h. In DMF (2.5 mL).
Table 1. Regioselective Sulfonylation of Tosylamidodiol 1a
d
c
temp
(°C)
time
(h)
ee
b
entry R3SO2Cl
yield (%)
(%)
Scheme 5. Stereoselective Cyclization of Monotosylated
Compounds to Morpholines under Solid−Liquid PTC
Conditions
1
2
3
4
5
TrisCl
TsCl
TsCl
TsCl
MsCl
−80
−80
−65
25
1.25
2.5
72
2a-Tris (72) 3a (19)
98
80
65
25
65
2a-Ts (57)
2a-Ts (42)
3a (25)
3a (52)
6
ent-3a (80)
−80
4.5
2a-Ms (49) 3a (31)
a
Reaction conditions: 1a (1 mmol), R3SO2Cl (1.1 mmol), NaH (2.1
mmol), THF (2.5 mL). The dianion was generated by reaction of 1a
b
c
with NaH at 0 °C for 30 min. Isolated yields. Morpholine 3a or ent-
3a ee’s, determined by chiral HPLC analysis.
through the direct and regioselective mono-O-sulfonylation of
tosylamidodiols 1 (Scheme 1, path a).25 This reaction was
realized on diol 1 via the oxydianion formed in situ. The
approach takes advantage of different features such as (i) the
steric hindrance difference between the carbon atoms bearing
OH’s, (ii) the formation of a more stable sulfonate, and (iii) the
stabilization of the intermediate sodium alcoholate through
extra-coordination by the side arm. The tosylamidodiol 1a was
chosen as a model compound to investigate the influence on
the regioselectivity of both the steric hindrance and the
intramolecular nucleophilic ring-closing mechanism (Scheme
2). The O-sulfonylation of the 1a oxydianion with various
sulfonylating agents (TrisCl, TsCl, and MsCl) at −80 °C
produced mixtures of the monosulfonate 2a and (2R,6S)-2-
ethyl-6-phenyl-4-tosylmorpholine (3a), deriving from the
sulfonylation of the benzylic oxyanion, followed by rapid
cyclization (Table 1). The product ratio depends upon the
difference in steric hindrance around the hydroxy groups and
on the size of the R3SO2Cl. TrisCl, the largest reagent,
preferentially reacted with the less hindered hydroxyl on the
carbon atom bearing the ethyl group, giving good yields of 2a-
Tris and minor amounts of enantiopure morpholine 3a.
Scheme 3. Regioselective O-Sulfonylation: Coordination
Effect
Scheme 4. Regioselective O-Sulfonylation: (+I) vs (−I)
Effect in the Glycidyl Derivative 1d
The enantiospecific cyclization to 3a most probably proceeds
through a pseudobimolecular mechanism with inversion of the
stereogenic benzylic center (Scheme 2). The smaller TsCl and
MsCl gave different product distributions: the less the steric
hindrance of the sulfonylating agent the lower the ratio of 2a/
3a (entries 1, 2, and 5). The reaction temperature was a crucial
parameter too. Thus, the tosylation of 1a at −65 °C was less
regioselective (entry 3), and besides, the ee value of the
morpholine 3a dropped to 65% due to the parallel in situ
Although this multistep protocol gives access to a variety of
unsymmetric morpholines, it suffers from the need of additional
protection/deprotection steps, which negatively influences
yields and purification operations. Here we report that the
same approach to 2,6-disubstituted morpholines can be greatly
improved by avoiding the protection/deprotection steps
B
DOI: 10.1021/acs.orglett.6b03342
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 6. Example of Regioselective O-Tosylation Applied to the Synthesis of 2,6-Disubstitued Morpholine-3-carboxylic Acid
Derivative 12
cyclization of the thermodynamic favored 2a-Ts to the
enantiomeric morpholine ent-3a. This ring-closing side
reaction became the main process at 25 °C (entry 4), and
the morpholines were the sole products isolated, ent-3a being
the more abundant enantiomer (er 62:38).
advantage of the opposite effect exerted by the lithium cation.
Finally, the reaction of 1f with TrisCl (entry 6) gave exclusively
2g. The mono-O-sulfonylated derivatives 2 and reg-2 were
cyclized under SL-PTC conditions to the corresponding
enantiopure morpholines 3 and ent-3, respectively, in yields
up to 95% (Scheme 5).25 The overall process was successfully
applied to the synthesis of the new morpholine-3-carboxylic
acid derivative 12 starting from L-threonine. Regioselective
tosylation of the diol 9 as previously described gave the sole
regioisomer 10 (Scheme 6) which, in turn, was SL-PTC
cyclized. The resulting N-tosylmorpholine 11 was detosylated
to 12 by treatment with 40% HBr−AcOH in the presence of
phenol.
In summary, we have described a rapid and efficient
regioselective mono-O-sulfonylation of oxa-dianions derived
from nonsymmetric 3-tosylamido-1,5-diols. This selective
reactivity, which to the best of our knowledge is unexplored,
depends on both the stability and the nucleophilicity of the oxa-
dianion ion pairs: the combination of steric hindrance and
electron-donating effects generate a reactive “loose ion pair”
that is preferentially tosylated. The 5-hydroxy sulfonates
prepared through the reported procedure are key intermediates
for the direct synthesis of enantiopure polysubstituted morpho-
lines, such as 12, that can be used for the preparation of anti-
HBV agents.27
All of the intermediates 2a were cyclized to enantiopure
morpholine 3a in good yields (90−93%) under SL-PTC in
acetonitrile by using anhydrous Cs2CO3 as base in the presence
of a catalytic amount of benzyltriethylammonium chloride
(TEBA) as phase-transfer agent (see Scheme 5 and the
Supporting Information). The effect of coordination on
regioselectivity has been proven by direct O-tosylation26 of
the phenylglycidyl ether derived tosylamidodiols 1b,c (Scheme
3), which gave only the regioisomers 2b and 2c in 89% and
91% yield, respectively. These results can be explained by
assuming that two different types of ion pairs are present in the
intermediate dianions: a poorly nucleophilic “tight ion pair”
near the alkyl (or aryl) group and a more reactive “loose ion
pair”, formed through coordination of the sodium cation by the
glycidyl oxygen atom on the other side arm.
The tosylation regioselectivity of diol 1d (Scheme 4), which
contains the glycidyl-derived phenoxy and benzyloxy groups on
the side chains, is clearly influenced by the inductive effects of
these groups. Whereas both of the sodium cations are
coordinated by the ether oxygen atoms, the aliphatic benzyl
group, through its (+I) effect along the σ bonds, increases the
charge of the near oxyanion, which forms a more tight and then
less nucleophilic ion pair with the sodium cation. As a result,
even though the regioselectivity was not complete, the tosylate
derivative 2d was the major product.
Sulfonylation of the N-tosylamidodiols 1e,f (Table 2)
provided further confirmation that the higher the difference
in the inductive effect between the side chains in diols the
higher the regioselectivity. Thus, the hydroxy group in the C-2
position, adjacent to an aryloxymethyl group bearing the
strongly electron-withdrawing nitro function, was readily
tosylated under the optimized reaction conditions to give
compounds 2e,f, which were isolated in good yield together
with minor amounts of the regioisomers reg-2e,f (entries 1−3).
Loss of regioselectivity was found by performing the
tosylation of 1f in the presence of LiClO4 (entry 4), which
formed “tight ion pairs” with both the oxyanions, smoothing
their relative reactivity. The same result was reached in the
aprotic dipolar DMF as solvent (entry 5), which solvated both
of the sodium alcoholates to generate two “solvent-separated
ion pairs” that had similar enhanced reactivity, i.e., by taking
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03342.
Full experimental details; 1H and 13C NMR spectra
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: michele.penso@istm.cnr.it.
ORCID
Michele Penso: 0000-0003-2992-3100
Present Addresses
§(I.P.) Faculty of Pharmacy, Catholic University Our Lady of
Good Counsel, Tirana, Albania.
C
DOI: 10.1021/acs.orglett.6b03342
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
∥(A.T.) Chemical Roadmaster Italia, via Liberazione 2, I-20098
S. Giuliano, Milanese, Italy.
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This research was supported by MIUR (Rome) and CNR
(Italy).
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