A general, enantioselective synthesis of 2-substituted thiomorpholines and thiomorpholine 1,1-dioxides

Article abstract of DOI:10.1016/j.tetlet.2019.151104

In the course of our drug discovery programs, we had need to access chiral, 2-substituted thiomorpholines and their oxidized congeners, thiomorpholine 1,1-dioxides. Here, we disclose a high-yielding, general protocol for the enantioselective synthesis of

Full text of DOI:10.1016/j.tetlet.2019.151104

Tetrahedron Letters xxx (xxxx) xxx
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A general, enantioselective synthesis of 2-substituted thiomorpholines
and thiomorpholine 1,1-dioxides
Carson W. Reed a, Craig W. Lindsley a,b,
⇑
a Department of Chemistry, Vanderbilt University, Nashville, TN 37232-6600, USA
b Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232-6600, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
In the course of our drug discovery programs, we had need to access chiral, 2-substituted thiomorpholi-
nes and their oxidized congeners, thiomorpholine 1,1-dioxides. Here, we disclose a high-yielding, general
protocol for the enantioselective synthesis of C2-functionalized thiomorpholines and thiomorpholine
1,1-dioxides.
Received 22 July 2019
Revised 30 August 2019
Accepted 1 September 2019
Available online xxxx
Ó 2019 Elsevier Ltd. All rights reserved.
Keywords:
Thiomorpholine
Thiomorpholine 1,1-dioxide
Enantioselective
Organocatalysis
Introduction
10 and 11 were first prepared according to literature 4-step proto-
cols (Scheme 1) [16].
Despite their importance and presence in biologically active and
therapeutically relevant compounds (Fig. 1), the chemistry to
access thiomorpholine and thiomorpholine 1,1,-dioxides is very
limited, and general, enantioselective protocols are lacking [1–6].
Moreover, many traditional approaches do not enable C2 substitu-
tion, rely on chiral pool substitution (typically at C3) and/or require
heavy metals, coupled with chiral chromatography/chiral SFC [7–
12]. In our discovery efforts, we required a general strategy to
readily prepare either C2-enantiomer, with the broadest range of
possible substituents.
To test this new route towards thiomorpholines, we prepared a
diverse array of b-chloro alcohol substrates (R)-15 and (S)-16
(Scheme 2) utilizing organocatalysts 10 and 11, respectively, to
enable the preparation of thiomorpholines with both (R)- and
(S)-configurations at C2, according to the stereochemical assign-
ment proposed in the seminal methodology of Jørgensen and
Having previously utilized organocatalytic, enantioselective
chlorination of diverse aldehyde substrates as a starting point to
readily access chiral C2-substituted morpholines and differentially
protected piperazines [13,14], we elected to develop a related, and
much needed, method for the enantioselective synthesis of
thiomorpholines (Fig. 2).
Based on previous work, the C2-symmetric diphenylpyrrolidine
organocatalysts (2S,5S)-10 and (2R,5R)-11 were ideal for the enan-
tioselective chlorination of aldehydes, coupled with immediate
reduction to the corresponding b-chloro alcohols in high % ee
[15]. However, they were not commercially available; thus, both
⇑
Corresponding author at: Department of Chemistry, Vanderbilt University,
Nashville, TN 37232-6600, USA.
Fig. 1. Examples of biologically active and therapeutically relevant thiomorpholi-
nes 1–3 and thiomorpholine 1,1-dioxides 4 and 5.
E-mail address: craig.lindsley@vanderbilt.edu (C.W. Lindsley).
https://doi.org/10.1016/j.tetlet.2019.151104
0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: C. W. Reed and C. W. Lindsley, A general, enantioselective synthesis of 2-substituted thiomorpholines and thiomorpholine 1,1-
dioxides, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.151104

2
C.W. Reed, C.W. Lindsley / Tetrahedron Letters xxx (xxxx) xxx
Fig. 2. Envisioned organocatalytic approach for the enantioselective synthesis of C2-functionlized thiomorpholines.
Scheme 1. Synthesis of (2S,5S)-10 and (2R,5R)-11.
Scheme 2. Organocatalytic, Enantioselective Synthesis of b-Chloro Alcohols 15a-h and 16a-h.
coworkers [15]. As expected, good overall yields (60–86%) and high
enantioselectivity for the one-pot, two-step procedure resulted
[13–15].
With b-chloro alcohol substrates (R)-15a-h and (S)-16a-h in
hand, we transformed these scaffolds into latent cyclization tem-
plates (R)-19a-h and (S)-20a-h (Scheme 3). Here, chloro alcohol
substrates (R)-15a-h and (S)-16a-h were converted into the corre-
sponding triflates, and then treated with N-benzylethanolamine to
provide the primary alcohols (R)-17a-h and (S)-18a-h in isolated
yields ranging from 60 to 78% for the two-step, one-pot procedure
[13,14]. A subsequent Mitsunobu reaction with thioacetic acid
smoothly provided the analogous acetyl-protected thiols (R)-19a-
h and (S)-20a-h in good isolated yields (62–80%). All that remained
was to develop conditions to cleave the acetate moiety and gener-
ate a reactive thiol nucleophile to displace the chloride and deliver
thiomorpholines.
Please cite this article as: C. W. Reed and C. W. Lindsley, A general, enantioselective synthesis of 2-substituted thiomorpholines and thiomorpholine 1,1-
dioxides, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.151104

C.W. Reed, C.W. Lindsley / Tetrahedron Letters xxx (xxxx) xxx
3
Scheme 3. Synthesis of Cyclization Substrates 19a-h and 20a-h.
For this key deprotection/cyclization step, we employed 19a as
a model system (Table 1). Several standard conditions (NaOMe and
KOtBu) were surveyed, and all afforded complex mixtures of prod-
ucts, with only traces of the desired thiomorpholines. Ultimately,
LiBH4 in THF, from 0 °C to rt, provided complete conversion to
the thiomorpholine 21a by LCMS. Conformation of this result on
larger scale yielded thiomorpholine 21a in 79% isolated yield and
in 95% ee, with inversion of stereochemistry as expected producing
the (S)–C2 enantiomer. Thus, these ideal deprotection/cyclization
conditions were applied to the broader collection of substrates
(R)-19a-h and (S)-20a-h (Scheme 4). Here, these conditions proved
general, affording good isolated yields (60–81%) of the desired
thiomorpholines (S)-21a-f,h and (R)-22a-f,h and in excellent enan-
tioselectivities (84–96% ee, with most >95% ee) [17]. Only one sub-
strate afforded inferior results, the hindered pyranyl analog (S)-
21 g and (R)–22 g, wherein chemical yields were modest (58–
62%) and enantioselectivity was also low (52–61% ee), showing
one limitation to this new methodology.
Table 1
Finally, we hoped to address another limitation in the field
and convert our chiral C2 thiomorpholines 21 and 22 into the
corresponding chiral sulfone congeners, the thiomorpholine
1,1,-dioxides 23. Attempts at the chemoselective oxidation of
the sulfur atom in the presence of the tertiary amine (N-benzyl
protected substrate) always led to varying degrees of N-oxide for-
mation in addition to the desired thiomorpholine 1,1,-dioxide 23.
Therefore, an excess of oxone was used to fully oxidize both the
nitrogen and the sulfur atoms of the thiomorpholine, and the
resulting N-oxide was chemoselectively reduced in the same
pot by treatment with B2pin2 [18], affording the desired N-benzyl
thiomorpholine 1,1,-dioxides 23 (Scheme 5) in good isolated
yields (56–72%) and excellent enantioselectivities (95–96% ee)
[17].
Optimization of the Deprotection/Cyclization Cascade.
Entry
Reaction Conditions
Conversion
1
2
3
4
5
NaOMe, 0 °C, THF
NaOMe, À20 °C, THF
tBuOK, 0 °C, DMF
complex mixture by LCMS
complex mixture by LCMS
complex mixture by LCMS
complex mixture by LCMS
>95%
tBuOK, À20 °C, DMF
In conclusion, we have developed and optimized
a new
LiBH4, 0 °C to rt, THF
organocatalytic, five-step protocol for the enantioselective synthe-
Please cite this article as: C. W. Reed and C. W. Lindsley, A general, enantioselective synthesis of 2-substituted thiomorpholines and thiomorpholine 1,1-
dioxides, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.151104

4
C.W. Reed, C.W. Lindsley / Tetrahedron Letters xxx (xxxx) xxx
Scheme 4. Synthesis of Chiral C2 Thiomorpholines 21a-h and 22a-h.
Scheme 5. Synthesis of Chiral C2 Thiomorpholine 1,1-Dioxides 23.
sis of N-benzyl protected thiomorpholines with diverse sub-
stituents at the C2 position. This methodology enables the rapid
preparation of functionalized, pharmaceutically relevant thiomor-
pholines in generally good yields and in excellent enantioselectiv-
ities (typically >95% ee). Of major significance, this methodology
does not rely on the chiral pool or chiral chromatography; instead,
we can employ simple, commercial aldehydes and organocatalysts,
thereby allowing access to either enantiomer of the corresponding
thiomorpholines. Moreover, chiral thiomorpholine 1,1-dioxides,
another high demand drug pharmacophore, is readily accessible
in high enantioselectivities (>95% ee) as well. This report offers
new opportunities for medicinal chemists in their drug discovery
programs, and further highlights the power of synthetic organic
chemistry to drive innovation and advance drug discovery. Addi-
tional refinements are under development and will be reported
in due course.
Author contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Please cite this article as: C. W. Reed and C. W. Lindsley, A general, enantioselective synthesis of 2-substituted thiomorpholines and thiomorpholine 1,1-
dioxides, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.151104

C.W. Reed, C.W. Lindsley / Tetrahedron Letters xxx (xxxx) xxx
5
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Appendix A. Supplementary data
Supplementary data (Experimental procedures, characteriza-
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new compounds) to this article can be found online at
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Please cite this article as: C. W. Reed and C. W. Lindsley, A general, enantioselective synthesis of 2-substituted thiomorpholines and thiomorpholine 1,1-
dioxides, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.151104