Stereoselective synthesis of cis-2,6-disubstituted morpholines and 1,4-oxathianes by intramolecular reductive etherification of 1,5-diketones

Article abstract of DOI:10.1002/ejoc.201403294

A simple and efficient, Lewis acid catalysed reductive etherification strategy for the stereoselective synthesis of cis-2,6- disubstituted morpholines and 1,4-oxathianes starting from readily available 1,5-diketones has been developed. The strategy is used in the total synthesis of morpholine-based natural products (±)-chelonin A and formal total synthesis of (±)-chelonin C.

Full text of DOI:10.1002/ejoc.201403294

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201403294
Stereoselective Synthesis of cis-2,6-Disubstituted Morpholines and 1,4-
Oxathianes by Intramolecular Reductive Etherification of 1,5-Diketones
Santosh J. Gharpure,*[a] Dandela Anuradha,[a] Jonnalagadda V. K. Prasad,[b] and
Pidugu Srinivasa Rao[b]
Keywords: Morpholines / 1,4-Oxathianes / Diketones / Lewis acids / Reductive etherification / Natural products
A simple and efficient, Lewis acid catalysed reductive etheri-
fication strategy for the stereoselective synthesis of cis-2,6-
disubstituted morpholines and 1,4-oxathianes starting from
readily available 1,5-diketones has been developed. The
strategy is used in the total synthesis of morpholine-based
natural products (Ϯ)-chelonin A and formal total synthesis of
(Ϯ)-chelonin C.
various asymmetric transformations as chiral auxiliaries
and chiral templates.[7] Recently, oxathianes have been used
as glycosyl donors for stereoselective formation of 1,2-cis-
glycosides.[8]
Introduction
In recent years, substituted six-membered 1,4-hetero-
cycles have attracted considerable attention because of their
ubiquity in natural products and drug molecules. Morph-
oline is an important pharmacophore and it is present in
many compounds, which exhibit antimicrobial, anti-inflam-
matory and anti-Alzheimer’s activities.[1] The natural prod-
ucts chelonin A (1) and chelonin C (2) have been reported
to exhibit antimicrobial and anti-inflammatory activities
(Figure 1).[2] (Ϯ)-Reboxetine (3) is used for the treatment of
depression, whereas its (+)-(S,S)-enantiomer is utilised to
cure fibromyalgia and neuropathic pain.[3] Similarly, the
1,4-oxathiane scaffold is also often found in many biolo-
gically active molecules; for example, the drug 1-(1,4-oxath-
ian-2-yl)-5-fluorouracil (5-FUra) (4) possesses significant
antitumor activity.[4a] Substituted oxathianes are important
precursors in the synthesis of biologically significant 1,4-
oxathiins, which are useful as fungicides and pesticides.[4b]
Raphanuside (5) is an unusual oxathiane-fused thiogluco-
side isolated from the seeds of Raphanus sativus, a tradi-
tional Chinese herbal medicine used for expectorant, anti-
cough, and anti-asthmatic purposes.[5] Tagetitoxin (6) is a
phytotoxin produced by the pathogenic bacterium Pseu-
domonas synringae pv., which targets and induces chlorosis
in the apex of the host plant by specifically inhibiting chlo-
roplast RNA polymerase.[6] Apart from that 2,6-disubsti-
tuted morpholines and 1,4-oxathianes have found use in
Figure 1. Morpholines and 1,4-oxathiane ring bearing natural
products and bioactive molecules.
It is thus not surprising that the synthesis of 2,6-disubsti-
tuted morpholines and 1,4-oxathianes has attracted con-
siderable attention from synthetic chemists. Over the years,
good progress was made on the synthesis of 2,6-disubsti-
tuted morpholines and corresponding 2,6-disubstitued 1,4-
oxathianes.[9,10] However, given the importance of these 1,4-
heterocycles, a common strategy, which can give access to
both morpholines, as well as oxathianes, in a highly dia-
stereoselective manner is still desirable. In a programme di-
rected at developing methods for the stereoselective synthe-
sis of 1,4-heterocycles,[11] herein, we disclose a concise, re-
ductive-etherification-based approach for the stereoselective
synthesis of 2,6-disubstituted morpholines and 1,4-oxa-
thianes starting from readily accessible 1,5-diketones.
[a] Department of Chemistry, Indian Institute of Technology
Bombay,
Powai, Mumbai - 400076, India
E-mail: sjgharpure@iitb.ac.in
http://www.chem.iitb.ac.in/people/Faculty/prof/sjg.html
[b] Department of Chemistry, Indian Institute of Technology
Madras,
Chennai - 600036, India
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403294.
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Intramolecular Reductive Etherification of 1,5-Diketones
moderate to good yields (Scheme 3). In general, primary
(methyl as well as long chain) and tertiary alkyl groups,
phenyl and aryl groups substituted with moderately elec-
tron-releasing or moderately electron-withdrawing groups
were tolerated under the reaction conditions employed.
When a p-anisyl group was present as the substituent in the
diketone, the oxathiane 7j was not formed, instead the
ketone Ar–CO–CH2–S–CH2–CH2–Ar (11) and Ar–CH2–
CH2–S–CH2–CH2–Ar [Ar = p-(MeO)C6H4–] 12 were ob-
tained in 45 and 36% yield, respectively. Interestingly, the
p-anisyl group was tolerated in the morpholine synthesis
and the product 7e was obtained in good yield. Formation
of the reduced ketone in the former case is perhaps the out-
come of a combination of the strong electron-releasing anis-
yl group and neighbouring group participation by sulfur.
When the electron-withdrawing nitro group was present as
a substituent in the diketone 8l, not only were higher
amounts of Lewis acid (4 equiv.) and Et3SiH (6 equiv.) re-
quired for the reaction to proceed to completion, but also
the time required was slightly longer (3.5 h) to give the
product 7l. In all cases, the formation of 1,4-heterocycles
7b–7l proceeded with excellent diastereoselectivity and only
formation of the cis-isomer was observed. The stereochem-
istry was assigned based on spectroscopic data and further
Results and Discussion
Olah and co-workers reported only one example of the
synthesis of tetrahydropyran from 1,5-diketone using re-
ductive etherification by employing TMSOTf and triethyl-
silane.[12] Interestingly, this reaction has received very little
attention subsequently. Based on this, we envisioned that
the 1,4-heterocycles 7 could be readily synthesised from the
1,5-diketones 8 by a Lewis acid catalysed intramolecular
reductive etherification reaction. The unsymmetrically sub-
stituted 1,5-diketones 8 (R ϶ R1) could be readily prepared
by the alkylation of α-amino- or α-mercapto ketones 9 with
appropriate α-bromoketones 10 (Scheme 1). On the other
hand, the symmetrically substituted 1,5-diketones 8 (R =
R1) could be assembled by dialkylation of p-toluenesulfon-
amide or sodium sulfide with α-bromoketones 10.
Scheme 1. Retrosynthesis for 2,6-disubstituted morpholine and 1,4-
oxathianes 7.
To test the feasibility of this proposed strategy, the diket-
one 8a was prepared by treating phenacyl bromide (10a)
with p-toluenesulfonamide with K2CO3 as the base. The di-
ketone 8a, when subjected to an intramolecular reductive
etherification reaction by treatment with TMSOTf
(1.1 equiv.) and Et3SiH (2 equiv.), gave meso-2,6-diphenyl
morpholine (7a) in good yield and excellent diastereoselec-
tivity (Scheme 2). The cis-stereochemistry of the product
was confirmed by comparison of the spectroscopic data
with that reported earlier.[11a,13]
Scheme 2. Stereoselective synthesis of meso-2,6-diphenyl morph-
oline (7a) by a reductive etherification reaction.
After successful synthesis of the morpholine derivative
7a, we turned our attention towards expanding the scope
of this strategy for the synthesis of differently substituted
symmetrical morpholines and oxathianes. The diketones
8b–8e required for the synthesis of morpholines were pre-
pared by alkylation of p-toluene sulfonamide with α-bromo
ketones 10 by following a slight modification of the re-
ported protocol.[14] On the other hand, the diketones 8f–
8l required for the synthesis of 1,4-oxathianes were readily
assembled by alkylation of Na2S with α-bromo ketones 10
following literature methods.[15] All the diketones 8b–8l
were then subjected to reductive etherification by using Et3-
SiH and TMSOTf to give the corresponding disubstituted
Scheme 3. Stereoselective synthesis of symmetrical meso-2,6-disub-
stituted morpholines and 1,4-oxathianes 7b–7l. [a] In all cases, the
dr was determined on the crude reaction mixtures by 1H NMR
spectroscopy. [b] TMSOTf (4 equiv.) and Et3SiH (6 equiv.) was
morpholines 7b–7e and 1,4-oxathiane derivatives 7f–7l in used and reaction time was 3.5 h.
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S. J. Gharpure, D. Anuradha, J. V. K. Prasad, P. Srinivasa Rao
SHORT COMMUNICATION
confirmed by single-crystal X-ray diffraction studies on the ucts was observed with more equivalents of Et3SiH and
morpholine 7d and the 1,4-oxathianes 7k and 7l.[16]
TMSOTf. Interestingly, no such effect was observed during
We next turned our attention towards expanding the the formation of morpholine 7q. However, the diastereo-
scope of the reaction to unsymmetrically substituted selectivity in all cases was excellent and the cis-diastereomer
morpholines and oxathianes. Various unsymmetrically sub- was the only detectable isomer formed. The stereochemistry
stituted aza-1,5-diketones 8m–8s and thio-1,5-diketones 8t– of the products was assigned based on NOE experiments
8bЈ were then subjected to the optimised reductive etherifi- and it was further confirmed by single-crystal X-ray diffrac-
cation conditions with TMSOTf and Et3SiH. The reaction tion studies on the morpholine 7o.[16]
was found to be general and cis-2,6-disubstituted morph-
The stereochemical outcome of all these reactions can be
olines 7m–7s and 1,4-oxathianes 7t–7bЈ were obtained in rationalised based on the model proposed earlier, wherein
good yields and excellent diastereoselectivities (Scheme 4). the substituent on the cyclic oxonium ion intermediate oc-
As for the symmetrical cases, both alkyl and aryl substitu- cupies a pseudoequatorial orientation to reduce steric inter-
ents were tolerated. It was found that when activated aryl action and the incoming hydride nucleophile is delivered
groups were present in the diketones 8x, controlling the re- from the axial direction to result in a chair conformation
action time, the amount of Lewis acid and Et3SiH and the for the 1,4-heterocyclic product.[11a,17]
temperature was crucial for getting good yields of the 1,4-
Sulfoxides and sulfones are important functional groups
oxathianes 7x. Typically, formation of over-reduction prod- in organic synthesis. It was thought that expanding this
method to the synthesis of cyclic sulfoxides and sulfones
would be useful. To test this, the diketone 8h was converted
to sulfone 13 using m-CPBA. When sulfone 13 was sub-
jected to reductive etherification conditions, the reaction
proceeded smoothly leading to the ether 14 in excellent
yield and diastereoselectivity. In a similar manner, the sulf-
oxide 15 was prepared from the ketone 8h, by using Chand’s
sulfoxidation protocol.[18] Interestingly, when the sulfoxide
was subjected to reductive etherification conditions, the
product 16 was formed in very good yields as an approxi-
mately 1:1 mixture of diastereomers (with respect to sulfox-
ide stereocenter). However, the relative orientation of 2,6-
substituents on both the diastereomers of 16 was cis. The
structures of sulfone 14 and the sulfoxide 16 were further
confirmed by independent synthesis from the 1,4-oxathiane
7h (Scheme 5).
Scheme 5. Reductive etherification reaction for the synthesis of
sulfone 14 and sulfoxide 16.
Finally, the method was used in the stereoselective total
synthesis of (Ϯ)-chelonin A (1) and the formal synthesis of
(Ϯ)-chelonin C (2) isolated from Chelonaplysilla sp.[2] The
first total synthesis of (Ϯ)-chelonin A (1) was reported by
Somei et al. The key steps of their synthesis involved the
ring opening of the epoxide with amino alcohol, acid cata-
Scheme 4. Stereoselective synthesis of unsymmetrical (Ϯ)-2,6-di-
lysed cyclisation of the diol followed by removal of the N-
substituted morpholines and 1,4-oxathianes 7m–7bЈ. [a] In all cases,
methoxy group to obtain (Ϯ)-chelonin A.[19] For the total
synthesis of (Ϯ)-chelonin A (1), the requisite diketone 17
the dr was determined on the crude reaction mixtures by 1H NMR
spectroscopy.
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Intramolecular Reductive Etherification of 1,5-Diketones
was prepared by alkylation of amine 18 with the bromide thianes starting from diketones. Both symmetrical as well
19 (Scheme 6). The diketone 17 on subjecting to reductive as unsymmetrical derivatives could be prepared in high
etherification reaction gave the corresponding protected yields and excellent diastereoselectivities. The method could
(Ϯ)-chelonin A 20 in good yield and excellent diastereo- be used for the construction of cyclic sulfoxide- or sulfone-
selectivity. Deprotection of tosyl group in (Ϯ)-morpholine containing 1,4-heterocycles. Finally, it was used in the syn-
20 was effected by using sodium naphthanalide to give (Ϯ)- thesis of (Ϯ)-chelonin A and C.
chelonin A (1) the data of which was found to be in good
Supporting Information (see footnote on the first page of this arti-
agreement with those reported in the literature.[2]
cle): Experimental procedures and characterisation data along with
1
copies of the H and 13C NMR spectra for all new compounds.
Acknowledgments
The authors thank the Council of Scientific and Industrial Re-
search (CSIR), New Delhi and Department of Science and Tech-
nology (DST), New Delhi for financial support. Mr. Darshan
Mhatren (X-ray facility of the Department of Chemistry, IIT Bom-
bay) is thanked for collecting the crystallographic data. The au-
thors are grateful to the University Grants Commission (UGC),
New Delhi and to CSIR for the awards of research fellowship to
D. A. and J. V. K. P., respectively.
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SHORT COMMUNICATION
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Received: October 2, 2014
Published Online: November 26, 2014
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