tetrathiomolybdate

Tetrathiomolybdate and Tetraselenotungstate as Sulfur/Selenium Transfer Reagents: Applications in the Synthesis of New Thio/Seleno Sugars

Sivapriya Kirubakaran,*[a] Devarajulu Sureshkumar,*[b] and Srinivasan Chandrasekaran*[c]

Abstract: Sulfur and selenium containing sugars have gained prominence in the last two decades because of their importance in several biological applications. These type of carbohydrate scaffolds are also challenging targets for synthesis. In this personal note, we have summarised the results of our investigation over the last 20 years on the use of two reagents, benzyltriethylammo- nium tetrathiomolybdate and tetraethylammonium tetraselenotungstate, in efficient transfer of sulfur and selenium respectively to the synthesis of a number of carbohydrate derivatives.
Keywords: Tetrathiomolybdate, Tetraselenotungstate, Carbohydrate scaffold, Thiosugar, Sele- nosugar, Aziridine ring-opening, Tandem one-pot reactions

sugars are widely present in nature and, particularly in oligosaccharides where they are frequently present as the

The four major classes of macromolecules in biology are proteins, nucleic acids, carbohydrates and lipids. Proteins and nucleic acids are almost exclusively linear and they have only a single type of linkage (amide bonds for proteins and phosphodiester for nucleic acids). However, carbohydrates can have many types of linkages (O, S, and N). This complexity allows carbohydrates to provide almost unlimited variations in their structures.
Glycoproteins are carbohydrates that are attached to proteins present in the cell surface. They are found to be very important in many biological events like viral replication, cell growth, degradation of blood clots and inflammation.[1] Deoxy
terminal sugars necessary for mediation of recognition proc- esses and trafficking of molecules within biological systems.[2]
Blood group antigens such as Leaa, Lebb, Lexx and SialylLewisxx are typical examples of biologically active molecules where deoxy sugars are the main constituents.
Thiosugars[3] play an important role in carbohydrate chemistry as saccharide bioisosteres in terms of biological relevance as potential new therapeutics.[4] These thio-analogs provide interesting possibilities in probing enzyme mechanism by mimicking the conventional sugars through their conforma- tional flexibility in the field of glycobiology.[5] In addition, the major challenge of evaluating them as glycosidase inhibitors[6]
is of predominant influence. The varied importance of

[a] Dr. S. Kirubakaran Department of Chemistry
Indian Institute of Technology Gandhinagar Palaj, Gandhinagar 382355, Gujarat, India
E-mail: [email protected] [b] Dr. D. Sureshkumar Department of Chemistry
Indian Institute of Science Education and Research Kolkata Mohanpur 741246, West Bengal, India
E-mail: [email protected] [c] Prof. S. Chandrasekaran
Department of Organic Chemistry Indian Institute of Science, Bangalore 560012, India
E-mail: [email protected]
thiosugars is eventually because of the sulfur mimic of the ring oxygen atom possess unique physico-chemical properties which elaborates them as good mechanism-based glycosidase
inhibitors[7] and also in understanding post-translational modifications[8] and as potential agents against virus,[9] meta- stasis, and diabetes[10] etc.
Thioglycosides have gained prominence as reliable glycosyl donors in the preparation of oligosaccharides. The stability of thioglycosides to a broad range of reagents and conditions makes them ideal starting materials for the preparation of diversely functionalized glycosyl donors. Furthermore, sulfo- nated thio-oligosaccharides have been found to activate lymphocytes that destroy certain tumors and virally infected

Srinivasan Chandrasekaran is working as INSA Distinguished Professor at the Department of Organic Chemistry, Indian Institute of Science, Bangalore, India. He obtained his MSc and PhD degrees from the University of Madras in 1967 and 1972 respectively. He has also been a Research Associate at Harvard University (with Professor E.J.Corey) and Syntex Research, USA. He served on the Faculty at the Depart- ment of Chemistry, IIT, Kanpur (1978–1989). He then moved to the Department of Organic Chemistry, Indian Institute of Science, Banga- lore as Professor (1989–2011). He served as the Chairman of the Department, Chairman, Division of Chemical Sciences and Dean, Faculty of Science at IISc, Bangalore. He held the position of Honorary Professor and SERB Distinguished Fellow at IISc. His significant contributions in four major areas of synthetic organic chemistry include: Development of New Synthetic Methodologies and Organo- metallic Chemistry; Total Synthesis of Natural Products; Homogeneous and Heterogeneous Catalysis and Organic Materials. Prof Chandra- sekaran is an elected Fellow of the Indian Academy of Sciences, Indian National Science Academy, and The World Academy of Scien- ces, Italy (TWAS). He served as an elected member of the Bureau of IUPAC and Member of the Executive Committee of IUPAC, Presi- dent of the Chemical Research Society of India (CRSI), the Chairman of the National Organic Symposium Trust (NOST) and as the Editor in Chief of the journal, Tetrahedron Letters published by Elsevier. He is a recipient of Basudev Banerji Medal and Prize (Indian Chemical Society), Shanti Swarup Bhatnagar Prize (Council of Scientific and Industrial Research), Ram Goyal Prize in Chemistry and Silver Medal of the Chemical Research Society of India.
Dr. Sivapriya Kirubakaran did her Ph.D (Organic chemistry) from Indian Institute of Science, Bangalore and Postdoctoral fellowship From Harvard Medical School and Whitehead Institute, MIT. She is an associate professor in chemistry at Indian Institute of Technology, Gandhinagar. She has co-authored about 32 publications, 1 book chapter and have 6 US

and 8 Indian patents to her credit. She is also a recipient of prestigious DST Ramanujan Fel- lowship. Her current areas on interest include targeted drug discovery and medicinal chemistry. She is studying mechanistic path- ways of DDR kinases using small molecules to develop novel therapeutics for cancer as well exploring H pylori survival pathways for developing drugs against the infection. Her long-term goal would be to make affordable medicines for cancer.
Devarajulu Sureshkumar did his B. Sc. in Chemistry and M. Sc. in Organic Chemistry at the University of Madras, Chennai, India. He obtained Ph.D. under the supervision of Prof. S. Chandrasekaran, Department of Organic Chemistry, Indian Institute of Science Banga- lore in 2007. He worked with Dr. Martin Klussman in Prof. Benjamin List group at the Max-Planck-Institut für Kohlenforschung, Ger- many as an AvH postdoctoral fellow from 2008 to 2010. After a short stay as a postdoctoral associate with Prof. Wilhelm Boland at the Max-Planck-Institut for Chemical Ecology in Jena, Germany, he moved to Japan as a JSPS fellow to work with Prof. Masakatsu Shibasaki at the Institute of Microbial Chemistry in Tokyo (2010–2015). He joined the Indian Institute of Science Education and Research Kolkata as an Assistant Professor in the Depart- ment of Chemical Sciences in February 2015. He is the recipient of the Ramanujan fellowship and Early Career Research Award. Currently, his lab is focusing on visible-light-mediated
photocatalysis for CtiC bond-forming and fluorination reactions using C(sp3)tiH func- tionalization

cells.[11] While the lack of solubility of oganoselenium compounds limited their usefulness in clinical applications, selenosugars with their intrinsic polarity do not have this problem and they can be devised as a useful alternative.[12a]
Selenium-containing glycosides have also been identified as efficient antiviral and antitumour compounds.[12b,c] In addition to the above, selenoglycosides have been efficiently used as glycosyl donors in various oligosaccharide syntheses.[13]

2.Benzyltriethylammonium Tetrathiomolybdate and Tetraethylammonium Tetraselenotungstate, [BnEt3N]2MoS4/[Et4N]2WSe4
Benzyltriethylammonium tetrathiomolybdate ([BnEt3N]2MoS4), 1,[14] an efficient sulfur transfer reagent is
proven to be useful in a number of synthetic transformations.[15a–h] The state-of-art advances of tetrathiomo- lybdate 1 as an effective sulfur transfer reagent resulted in the synthesis of various natural and non-natural molecules of diverse importance. This involves a facile entry to well-known organo disulfides and the reductive dimerization of organic
thiocyanates to disulfides,[15i] synthesis of thioglycosides,[15j]
alcohols to disulfides[15k] sulfur containing thiolactones,[15l] and one-pot synthesis of thiourea[15m] derivatives. In spite of the wide applicability of tetrathiomolybdate 1 in sulfur organics, its utility in the synthesis of sulfur glycomimetics (thiosugars) is not well explored. In a review published recently, Falconer has nicely summarized the importance, synthesis and biological applications of glycosyl disulfides.[15n]
We have shown that glucose-derived disulfides 4 can be synthesized using tetrathiomolybdate 1 as a sulfur transfer reagent. Similarly, tetraethylammonium tetraselenotungstate,[16a–c] [Et4N]2WSe4, 2 has been found to be
an efficient reagent in selenium transfer in organic synthesis.[16d] The utility of tetraselenotungstate 2 has been demonstrated in the synthesis of alkyl and aryl diselenides, selenocystine derivatives and also glucose diselenides 5 (Scheme 1).[18,19]

3.Synthesis of Carbohydrate Derived Sulfur and Selenium Derivatives by Ring-Opening of Aziridines
In order to explore this strategy, we decided to start with simple carbohydrate scaffolds. D-glucose, D-mannose and D- mannitol derived aziridines 6, 7 and 8 were synthesized using literature procedure.[20] Ring-opening of aziridines is used as a strategy for the synthesis of biologically interesting disulfides/
diselenides and sulfur/selenium heterocycles using [BnEt3N]2MoS4 1 and [Et4N]2WSe4 2 as sulfur and selenium transfer reagents respectively. Treatment of aziridines 6, 7 and 8 with 1 (1.1 equiv, CH2Cl2, 28 °C) afforded the correspond- ing disulfides 9, 10 and 11 respectively in good yields
(1.1(Schemeequiv,2). CH2Cl2,Similarly, 28 °C)aziridinesled6, 7toandthe8 onformationreaction ofwith 2the corresponding diselenides 12, 13 and 14 respectively in moderate yields (Schemes 2).[21] These enantiopure disulfide/
diselenide derivatives have the potential to be used as chiral ligands in diethyl zinc addition to aldehydes and in peptide chemistry.

4.Synthesis of Carbohydrate Derivatives with Sulfur in the Ring
4.1.Synthesis of 1-Deoxythiosugars using Tetrathiomolybdate 1 as the Key Reagent for Sulfur Transfer
The significance of deoxythiosugars, in contrast to thiosugars is the enhanced hydrophobicity which is pivotal in many physiological processes and significantly affect the rate of glycosidic hydrolysis. Moreover, the relative scarcity of 1- deoxythiosugars in nature makes them more interesting to study for various applications.
A useful and efficient synthesis of biologically relevant thiofuranoses, 1,4-dideoxy-1,4-epithio-D-arabinitol 17 and 1,4-anhydro-4-thio-D-lyxitol 20 and the synthesis of rare thiopyranoses such as 1-deoxythiotalonojirimycin 23 and 1- deoxythioidonojirimycin 26 were developed.[22] The method- ology involves the synthesis of ditosylates, sulfur transfer reaction with tetrathiomolybdate 1 followed by reduction with borohydride exchange resin (BER). The examples developed through this approach demonstrate the generality of this methodology and wider applicability of the synthesis of 1- deoxythiosugars through a protection/ deprotection-free se- quence. The details related to this strategy are presented below.
acetone at 0 °TreatmentCof D-(yielded+28% of)-xylonolactone withxylonoditosylateTsCl/15. pyridineXylonodi-in

Scheme 1. Synthesis of carbohydrate derived anomeric disulfides/diselenides. tosylate 15 when treated with tetrathiomolybdate 1 in DMSO

Scheme 2. Synthesis of carbohydrate derived disulfides/diselenides by aziridine ring-opening reaction.

at room temperature provided the bicyclic thiosugar lactone, 1-deoxy-4-thio-D-lyxono-2,5-lactone 16 in 53% yield. Reduc- tion of lactone 16 with borohydride exchange resin in methanol yielded 1-deoxythiosugar, 1,4-dideoxy-1,4-epithio- D-arabinitol 17 in good yield (Scheme 3).[22] 1,4-Anhydro-4- thio-D-arabinitol 17 is the core of many of the natural products such as salaprinol, salacinol, ponkoranol, kotalanol,
and de-O-sulfonated kotalanol known especially for the treat- ment of diabetes mellitus.
Unlike the reported synthesis of 17 from D-glucose in 12 steps and from D-xylose which involves nine steps, our method reports a shorter synthesis of 1,4-anhydro-4-thio-D- arabinitol 17 from D-xylose. To further establish the efficacy of this method, 1,4-anhydro-4-thio-D-lyxitol 20, a pentose sugar, ubiquitous and vital in several biological processes, was synthesized as described in Scheme 4.[22]
Tosylation of D-(+)-ribonolactone with tosyl chloride/
pyridine produced ribonoditosylate 18 in 63% yield. Treat- ment of ribonoditosylate 18, with tetrathiomolybdate 1 provided 1-deoxy-4-thio-D-arabino-2,5-lactone 19 in good yield (68%). Reduction of 1-deoxy-4-thio-D-arabino-2,5- lactone 19 with borohydride exchange resin (BER) in methanol produced the thiosugar, 1,4-anhydro-4-thio-D-lyx- itol 20 in 67% yield (Scheme 4).[22] Interestingly, the synthesis of 20 is achieved in three simple steps with an overall yield of 29%, which is far superior to the only known published

Scheme 3. Synthesis of 1,4-anhydro-4-thio-D-arabinitol 17.

Scheme 4. Synthesis of 1,4-anhydro-4-thio-D-lyxitol 20.
report[23] that utilizes eleven linear steps for the synthesis of compound 20 starting from D-xylose.
Synthesis of 1-deoxythiotalonojirimycin 23 from D-allono- treated1,4-lactonewithis tosyldepicted in Scheme 5.chloride/pyridine at 0 °C to produceD-Allono-1,4-lactone 21,was which on treatment with tetrathiomolybdate 1 in DMSO furnished the bicyclic thialactone 22 in 49% yield. Compound 22 when subjected to reduction with borohydride exchange resin (BER) in methanol yielded the required 1-deoxythiotalo- nojirimycin 23 in good yield.[22]
Following the procedure as shown in Scheme 6, 1- deoxythioidonojirimycin 26 was synthesized from gulono-1,4-

Scheme 5. Synthesis of 1-deoxythiotalonojirimycin 23.

Scheme 6. Synthesis of 1-deoxythioidonojirimycin 26.

ingly, D-mannose was converted to mannono-1,4-lactone, followed by reaction with HBr/acetic acid to yield the 2,6- dibromo- 2,6-dideoxy-D-glucono-1,4-lactone 27. Reaction of dibromo lactone 27 with tetrathiomolybdate 1 (DMSO, rt, 30 min) afforded the 1-deoxy-5-thio-D-mannopyrano-3,6- lactone 28 in 59% yield. Subsequent reduction of bicyclic lactone 28 with BER furnished the 1-deoxythiomannose 29 in good yield (Scheme 8).[24a–b]
Next, the synthesis of 1-deoxythiotalonojirimycin 32 was accomplished starting from D-ribose. Accordingly, one carbon extension of D-ribose using NaCN under Kiliani-Fischer synthesis conditions produced altronolactone, which on subsequent bromination with HBr in acetic acid afforded the 2,6-dibromo-2,6-dideoxy-D-allono-1,4-lactone 30. Double displacement of dibromide in 30 with tetrathiomolybdate 1 in DMSO smoothly furnished the bicyclic lactone 31 in 63% yield. BER reduction of 1-deoxy-5-thio-D-talopyrano-3,6- lactone 31 in methanol yielded the required 1-deoxythiotalo- nojirimycin 32 in good yield (Scheme 9).[24]
The above protocol illustrates the efficiency of the synthesis of 1-deoxyglyconojirimycins involving a protective group-free strategy and the use of tetrathiomolybdate 1 as the key sulfur transfer reagent.[24]

neatlactone.solution of tosylGulono-1,4-lactonechloridein inpyridine,acetone atwas 0 °Ctreatedfor 3 hwith toa obtain ditosylate 24. 2,6-DitiO-tosyl-gulono lactone 24 when treated with tetrathiomolybdate 1, in DMSO at room temper- ature produced the bicyclic lactone ring system 25, 1-deoxy-5- thio-D-glucopyrano-2,6-lactone in 56% yield. The formation of 25 is believed to go through the formation of lactone 24a as the intermediate. Finally, the reduction of 25 with BER in methanol provided the 1-deoxythioidonojirimycin 26 in 67% yield (Scheme 6).[22]

4.2.Alternate Approach to the Synthesis of 1-Deoxyglyconojirimycins
We anticipated that the synthesis of thio-analogues of 1- deoxy-glyconojirimycins 28 can also readily achieved starting from commercially available carbohydrates like D-mannose and D-ribose. General retrosynthesis is depicted in scheme 7.
Thus, conversion of carbohydrate into suitably positioned dibromide 27 followed by reaction with tetrathiomolybdate 1 is expected to yield the 1-deoxythioglyconojirimycins. Accord-

Scheme 7. Retrosynthesis of 1-deoxythioglyconojirimycins.

Scheme 8. Synthesis of 1-deoxythiomannojitrimycin 29.

Scheme 9. Synthesis of 1-deoxythiotalonojirimycin 32.

5.Importance of Conformational Locking in Carbohydrates and Biological Activity
α-Mannosidases remove mannose residues from the maturing oligosaccharide by hydrolyzing the mannosyl glycosidic bond. The trimming of a single mannose at this step is a targeting signal for translocation out of the ER to proteosome for degradation. Because mannosidase inhibitors block degrada- tion of misfolded glycoproteins, it has been suggested that the removal of mannose units by a-mannosidase might work as the timer for glycoprotein degradation.[11a,25]
Mannose exists in the 4C1 conformation predominantly, in solution or as a part of an oligosaccharide. However, the existing inhibitors of α-mannosidase reportedly adopt a 1C4 chair conformation at the active site of the enzyme, which is unfavourable and axial rich, with the help of stabilizing hydrogen bonding and hydrophobic interactions. Since recent reports indicate that the inhibitor adopts a single conformation in its bound state, conformational locking of the groups provides a promising scope in the development of pharmaco- phoric drug candidates.[11a,b] There are a few interesting reports on the synthesis and biological activity of thiomannosides.[26a–c]

5.1.Synthesis of Conformationally Locked Thiosugars Thiolevomannosan 35 (TLM) was synthesized readily from D-
mannose. Mannosyl bromide 33, when treated with tetrathio- molybdate 1, yielded the benzoyl protected thiosugar 34
(1 h,(93%).28 °C)Hydrolysisfurnishedof 35 (TLM)compoundin3499%withyield. Oxidation ofNaOMe/MeOH 34 using m-CPBA (CH2Cl2, 2 h, 28 °C) led to the formation of sulfoxide 36 in 96% yield and when the reaction of 34
with excess m-CPBA was carried out for a longer period (24 h),Hydrolysis ofsulfone3638andwas38 usingformed in 94% yieldNaOMe/MeOH (1 h,(Scheme28 °10).C) furnished the sulfoxide 37 (XLM) and sulfone 39 (NLM),
respectively, in high yields (99%) as shown in Scheme 10.[25]
The synthesized compounds TLM (35), XLM (37), and NLM (39) are depicted in Scheme 10, which were further studied for their inhibitory activity against α-mannosidase to show their potency.
[26d] from D-Mannose is depicted in Scheme 11. D-Mannose was converted into its per-O-acetyl-6-O-tosyl derivative 40. Compound 40 when treated with HBr/AcOH led to the formation of mannosyl bromide 41. Compound 41 on treatment with tetrathiomo- lybdate 1 (2 equiv, CH3CN, ultrasonic cleaning bath 25 kHz, 3 h) yielded two products, TLM derivative 42 and thioor- thoester 43 (55:45), respectively, in 90% yield. The thioorthoester obtained was further studied for its glycosylating properties.

Scheme 10. Synthesis of conformationally locked thiosugars as α-mannosi- dase inhibitors.

Scheme 11. Synthesis of conformationally locked thiosugars 42 and 43.

5.2.Conformationally Locked Thiosugars as Glycosylation Partners
The thioorthoester 43 synthesized (as shown Scheme 11) was used as glycosylating agent owing to its stability. The synthesis of compounds 44–47 (Scheme 12) is illustrative of the fact that the thioorthoester 43 is a good glycosylating agent and the glycosylated products were obtained in good yields. Furthermore, it is noteworthy that the glycosylation reactions carried out did not require any activators like CF3SO3H, since the thioorthoester 43 by itself was highly reactive. Thioor- thoesters of this type have earlier been used for the synthesis of thioglycosides.[27]

6.Synthesis of Unusual Selenosugars
Synthesis of novel selenosugars 50a and 50b from D-mannose is illustrated in Scheme 13. D-Mannose was converted into its anomeric acetate 48a which on further treatment with HBr/

Scheme 12. Synthesis of glycosylated products using thioorthoester 43.

Scheme 13. Synthesis of tetraselenides with sugar backbone.

AcOH led to the formation of bromide 49a. When compound 28 °49aC, 8was h)treated withcompound 50a was formedtetraselenotungsatein2 (2goodequiv,yield ACH3similarCN, procedure was followed to obtain compound 50b. These tetraselenides 50a and 50b are novel, and are the first cyclic tetraselenides reported with carbohydrate backbone.[28]
Synthesis of benzoyl protected tetetraselenide of D- mannose 52 is portrayed in Scheme 14. Benzoyl-protected anomeric bromide 51 was synthesized from D-mannose using the reported procedure.[19] Compound 51 on treatment with tetraselenotungstate 2 gave two products 52 and 53 (3:1) in 84% yield. While tetraselenide 52 was formed as the major product, compound 53 was also formed as a minor product (19% yield).
Apart from carbohydrate scaffolds, utility of these two reagents (1 and 2) has also been explored in the synthesis of nucleoside derivatives.[29a–b] Uridine was converted into the tosylate 54 after protecting as acetal. When compound 54 was treated with tetrathiomolybdate 1 (1.1 equiv, CH3CN, 28 °C,

Scheme 14. Synthesis of benzoyl-protected tetraselenide 52 from D-man- nose.

20 h), it gave the corresponding disulfide 55 in 77% yield. Similarly, thymidine derived tosylate 57 also gave similar disulfide 58 when treated with reagent 1. Interestingly 57 on treatment with reagent 2 gave a cyclic diselenide 59 instead of a linear diselenide (Scheme 15). The structure of 59 was confirmed by single crystal X-ray.[29b]

7.Ring-Opening of Carbohydrate-Derived Aziridines followed by Michael Reaction using 1
In the process of studying the redox chemistry associated with MotiS systems we find that tetrathiomolybdate 1 can mediate not only the aziridine ring-opening to form disulfide bond but can also cleave the disulfide bond under appropriate reaction conditions. In order to expand the scope of this methodology and to study the reactivity of other aziridines having different functionality and complexity, D-glucose and D-mannitol derived aziridines 60 and 64 were synthesised.[20,21d,30] Tetra- thiomolybdate 1 mediated tandem regio- and stereospecific ring-opening of aziridines (60 and 64), disulfide formation, in situ reduction of disulfide bond followed by Michael reaction in a one-pot operation was anticipated. Accordingly,

Scheme 15. Synthesis of uridine and thymidine based disulfides and diselenides.

when aziridines 60 and 64 were treated with 1 [2.2 equiv, CH3CN, 28 °C, 4–5 h] in the presence of 61 the correspond- ing sulfur containing sugar amino acid conjugates 63 and 65 respectively were obtained in good yields (Scheme 16). The main advantage of this methodology is that four reactions involving three components take place in a tandem one-pot operation.[21a,b,30]
Interestingly, by incorporating a suitable Michael acceptor in the same aziridine backbone, intramolecular 1,4-addition could be performed in a single pot operation to access interesting bicyclic derivatives. For example, selective aziridina- tion at the electron rich olefin of (R)-carvone using Sharpless aziridination protocol afforded the carvone derived aziridine

66 as a model substrate in diastereomeric mixture (dr = 1:1). Treatment of diastereomeric mixture of (R)-carvone derived

28 °C,aziridine10 66h) withyielded twotetrathiomolybdatediastereomers1 of(2.2 equiv;thia-bicycloCH3[3.3.1]CN, nonane derivatives 67a and 67b (1:1), respectively in 88%
yield (Scheme 17).[21a,b] These diastereomers were easily sepa- rated using column chromatography [using ethyl acetate and hexanes (2:8) as an eluent]. After purification by chromatog- raphy,crystals with acompoundmelting67a waspoint of 174isolated°C,in verywhereasgood qualitycompound

67bpoint ofwas223 °C.isolated as fluffy, colourless solid with the melting

To demonstrate the utility of this reaction in the presence of different functionalities, the 3,4-aziridino-γ-ribonolactone- 5-tosylate 68 was synthesized from γ-ribonolactone.[21c] The aziridino-γ-ribonolactone-5-tosylate 68 underwent smooth
1 andring-opening followed bytetraselenotungstate 2 [2.1cyclizationequiv,withCH3CN, 28 °C,tetrathiomolybdate3– 5 h] to furnish thia-bicyclo-lactone 69 and seleno-bicyclo- lactone 70 respectively in good yield. Here the regio- and stereospecific ring-opening took place at C2 carbon followed by intramolecular displacement tosyl group at C5 to provide thia/seleno-bicyclo-lactone derivatives 69/70 respectively (Scheme 18).[20,21a]

8.Synthesis of Enantiopure Thiosugars via
Ring-Opening of bis-Epoxides and bis-Aziridines
The inhibitory action of compounds containing seven-mem- bered rings such as tetrahydroxy thiepanes has been tentatively

Scheme 16. One-pot tandem aziridine ring-opening, disulfide formation, reduction and Michael reaction mediated by tetrathiomolybdate 1.
ascribed to the flexibility of the seven-membered ring, which mimics the hypothetical transition state of enzymatic glycosidic cleavage. The potent HIV-1 protease inhibition reported for some orally bioavailable thiepane derivatives is particularly important.[31]
Enantiomerically pure thiosugars could be synthesized by ring-opening of various bis-aziridines, bis-epoxides and azir- idino-epoxides using tetrathiomolybdate, 1 as an efficient sulfur transfer reagent. This could be seen in the synthesis of sulfur heterocycles ranging from three membered to eight

Scheme 17. Tandem intramolecular multi-step reaction in the synthesis of thiabicyclo[3.3.1]nonane derivatives 67.

Scheme 18. Ring-opening of 2,3-aziridino-γ-ribonolactone-5-tosylate 68 with 1 and 2.

membered ring systems and especially in the synthesis of bioactive seven membered ring compounds (thiepane derivatives).[20,32]
A simple C2-symmetric enantiopure N-Boc/tosyl protected 1,3-bis-aziridines 71 have been synthesized from D-tartaric 28 °acid.C, 4 h],Reaction of bisfurnished the C2-aziridine 71 with-symmetric1 [1.2cyclicequiv,sulfideCH3CN,deriva- tive 72 and cyclic disulfide derivative 73 (1:1) in good yields (Scheme 19).[21a]
Another C2-symmetric enantiopure N-tosyl protected 3,5- bis74 with 1-aziridine 74[1.2 wasequiv, CH3synthesizedCN, 28 °fromC, 5 h],D-mannitol.failed toReactionfurnishof neither the C2-symmetric cyclic sulfide derivative nor cyclic
disulfide derivative but formation of unsymmetrical four membered thietane derivative 75 was isolated as single product in good yield (Scheme 20).[20]
The enantiomerically pure C2-symmetric N-tosyl protected 1,5-bis-aziridines 76 and 78 were synthesized from D- mannitol according to the literature procedure.[33] Reaction of N-tosyl 1,5-bis-aziridines 76 and 78 with 1 [2.2 equiv, CH3CN, 28 °C, 1 h], led to smooth regiospecific ring-opening

followed by thio-cyclisation to furnish the C2-symmetric thiepane derivatives 77 and 79 respectively in good yield with complete regio- and stereocontrol (Scheme 21).[20,21a]
Next, enantiopure unsymmetrical N-tosyl protected 1,5- bis-aziridine 80 was synthesized from D-sorbitol.[20] The unsymmetrical N-tosyl 1,5-bis-aziridine 80 on reaction with tetrathiomolybdate 1 [2.2 equiv, CH3CN, 28 °C, 1 h], under- went smooth regiospecific ring-opening followed by thiocycli- sation to furnish the unsymmetrical thiepane derivative 81 in 86% yield (Scheme 22).[20]
Even C2-symmetric 1,3 and 1,5-bis-epoxides (82 and 84) underwent smooth regiospecific ring-opening reaction with 1 in presence of acetonitrile and ethanol (1: 1) solvent system to furnish the C2-symmetric tetrahydro thiophene 83 and thiepane derivative 85 respectively in very good yield. Also, unsymmetrical 1,5-bis-epoxide 84c can used as substrate for regiospecific ring-opening with 1 to synthesize the unsym- metrical hydroxy thiepane derivative 85c in 80% yield (Scheme 23).[20]

Scheme 19. Reaction of 1,3-bis-aziridine derivatives 71 with 1.

Scheme 22. Reaction of unsymmetrical 1,5-bis-N-tosyl aziridine 80 with 1.

Scheme 20. Reaction of N-tosyl 3,4-bis-aziridine 74 with 1.

Scheme 21. Reaction of C2 symmetric 1,5-bis-N-tosyl aziridines 76 and 78 with 1.

Scheme 23. Reaction of different bis-epoxide derivatives with 1.

9.Summary and Outlook
Thiosugars and selenosugars are important compounds because of their structural complexity and crucial biological activities. In this short personal account, we have tried to highlight the utility of two reagents, benzyltriethylammonium tetrathiomo- lybdate and tetraethylammonium tetraselenotungstate, devel- oped in our laboratory, as efficient sulfur and selenium transfer reagents as applied to the synthesis of sulfur and selenium containing carbohydrate scaffolds.
Unlike, oxygen sugars, thiosugars and selenosugars are more stable and therefore much scope exists to alter their structures by chemical manipulations. Notably, thiosugars/
selenosugars can act as glycosyl donors as well as acceptors. Many functionalized thiosugars occur naturally and are potential targets for therapeutics. Greener and convergent synthesis of thio- and selenosugars is still a major challenge. Many facets of exploration of their biological activity remain to be studied. Further studies on heteroatom substituted sugar derivatives would be significant and timely since it would pave way toward new carbohydrate-based drugs in the future.

Acknowledgements
SCN thanks the Indian National Science Academy, New Delhi for financial support in the form of award of INSA Distinguished Professorship. DS thanks IISERK for start-up grant, DST-SERB for Ramanujan Fellowship and Early Career Research (ECR) Grant. SK thanks DRDO for the ERIP grant.

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Manuscript received: March 27, 2021 Revised manuscript received: May 1, 2021 Version of record online: ■■ ■■, ■■■■

PERSONAL ACCOUNT

Dr. S. Kirubakaran*, Dr. D. Sureshku- mar*, Prof. S. Chandrasekaran*
1 – 12
Tetrathiomolybdate and Tetraseleno- tungstate as Sulfur/Selenium
Transfer Reagents: Applications in the Synthesis of New Thio/Seleno Sugars

In this personal note we have delineated the importance and versatility of the use of benzyltriethylammonium tetrathiomo- lybdate and tetraethylammonium tetrase- lenotungstate as useful Sulfur and Selenium transfer reagents especially in
the synthesis of novel carbohydrate scaffolds. The reported carbohydrate scaffolds otherwise necessitate complex multistep synthetic routes. The efficacy of the reagents has been also explored in tandem one -pot reactions.