Poster Modena 2011 - Giornata della Chimica dell'Emilia Romagna
1
Free-Radical Hydrothiolation of Glycals: A Thiol-Ene-Based Synthesis of S-Disaccharides Samuele Staderini 1 , Angela Chambery 2 , Alberto Marra 1 and Alessandro Dondoni 1 1 Dipartimento di Chimica, Laboratorio di Chimica Organica, Università di Ferrara, Via L. Borsari 46, 44100 Ferrara, Italy, 2 Dipartimento di Scienze della Vita, II Università di Napoli, Via Vivaldi 43, 81100 Caserta, Italy References: 1. Pachamuthu, K.; Schmidt, R. R. Chem. Rev. 2006, 106, 160-187. 2. Fiore, M.; Marra, A.; Dondoni, A. J. Org. Chem. 2009, 74, 4422-4425. 3. Dondoni, A; Marra, A. Chem. Soc. Rev. DOI: 10.1039/c1cs15157f The natural oxygen-linked oligosaccharides are not easy to isolate in a pure form due to the presence of mixtures of glycosylated species in the natural sources. Moreover, these compounds can undergo chemical and enzymatic degradation because they display an exocyclic acetal bond. On the other hand, their sulphur or carbon isosteres are hydrolytically stable compounds that can be used to study recognition phenomena for biological or pharmacological purposes. For these reasons several syntheses of S-oligosaccharides have been developed in the past decades 1 , the free-radical thiol-ene coupling (TEC) between sugar alkenes and sugar thiols was reported for the first time by our group in 2009 2 . In fact under optimized conditions (irradiation time, reagent ratio, solvent) TEC afforded S-linked disaccharides in elevated yields. 3 . O O O OH OH OH (OH) 3 (HO) 3 O-G lycoside (natural) O S O OH OH OH (O H) 3 (HO) 3 S -Glycoside(non natural) O H 2 C O OH OH OH (OH) 3 (HO ) 3 C -Glycoside (non natural) O OAc A cO AcO SH O A cO AcO OAc AcO Glycal Products Yield(% ) 5:6 ratio O OAc AcO AcO 2b 1a 1a 100 82 100 100 54:46 74:26 38:62 50:50 Thiol O OAc AcO AcO O OAc AcO A cO 1b 1b SH O A cO A cHN OAc AcO 2c SH O A cO AcH N OAc A cO 2c SH O AcO AcO OAc A cO 2b S O A cO S O A cO 5a 6a A cO O OAc A cO OAc AcO O O Ac A cO OAc AcO A cO AcO AcO S O A cO S O A cO 5b 6b OAc O O Ac AcH N OAc OAc O OAc AcH N OAc AcO A cO AcO AcO S O OAc S O AcO 5c 6c A cO O O Ac A cO OAc AcO O OAc A cO OAc AcO AcO AcO AcO S O OAc S O AcO 5d 6d OAc O OAc AcH N OAc OAc O OAc AcH N OAc AcO AcO AcO AcO SR O A cO SR O A cO (AcO ) 2 (AcO ) 2 AGR ax AGR eq We first investigated the model reaction between 3,4,6-tri-O- acetyl-D-glucal 1a and peracetylated 1-thio-β-D- glucopyranose 2a, after some experimentation optimized reaction conditions were established. (6 equiv of 2a, 1 h irradiation, DPAP as radical initiator and EtOH as the solvent). Others glycals, (1b-d) were allowed to react with the same thiol 2a, to give the products shown in Table 1. These products formed in about 1:1 ratio, hence, the reaction was essentially lacking in stereoselectivity while it appeared to be totally regioselective with the thiyl radical generated from thiol 2a attacking exclusively the C2 carbon of the glucal 1a. In agreement to that suggested for the addition of thiolacetic acid to 1a, these results are consistent with the initial formation of two anomeric glycosyl radical (AGR) intermediates stabilized by the adjacent oxygen atom, namely AGR ax in which the RS group is axial and AGR eq in which the same group is equatorial (Figure 1). In the present case these intermediates must have comparable energies with the consequence that the axial and equatorial products are formed in essentially equal amounts. It was soon realized that the relative amounts of AGR ax and AGR eq depended considerably on the stereochemistry of the OAc groups at C3 and C4 in the starting glycal. Next, the scope of the reaction was investigated by considering the addition of two more thiols 2b and 2c to glucal 1a and galactal 1b (Table 2). All reactions, however, were scarcely stereoselective as the two S-disaccharides 5 and 6 were formed in comparable or even equal amounts. Thus, it appears that the substitution pattern in the thiol exerts scarce or no the of O OAc O OAc AcO A cO (AcO ) 2 SH O AcO AcO OAc AcO S O AcO S O AcO (AcO ) 2 (AcO) 2 + Ph MeO OMe O Ph h (365 nm) DPAP + G lycal Conversion (% ) Product(s) Yield (%) 3:4 ratio O OAc A cO AcO O OAc AcO AcO O OAc A cO AcO 100 100 40 35 1 2a 3 4 1a 1b 1c 1d 80 59 38 20 57:43 37:63 100:0 100:0 OAc O OAc AcO OAc OAc O OAc A cO OAc S O AcO S O A cO 3a 4a OAc O O Ac A cO OAc OAc O OAc A cO OAc A cO A cO A cO AcO S O O Ac S O A cO 3b 4b OAc O OAc A cO OAc OAc O OAc AcO OAc AcO A cO A cO A cO S O A cO 3c OAc O OAc A cO OAc AcO AcO S O A cO 3d OAc O OAc A cO OAc AcO AcO In conclusion, it has been demonstrated for the first time that glycals can undergo a photoinduced addition of glycosylthiyl radicals with total regioselectivity to give 1-deoxy S-disaccharides in good to excellent yields. RS R ' R ' RS R ' RS R SH Table 1 Table 2
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Organic chemistry work presented in Modena in 2011
Transcript of Poster Modena 2011 - Giornata della Chimica dell'Emilia Romagna
Free-Radical Hydrothiolation of Glycals: A Thiol-Ene-Based Synthesis of S-Disaccharides
Samuele Staderini1, Angela Chambery2, Alberto Marra1 and Alessandro Dondoni1
1Dipartimento di Chimica, Laboratorio di Chimica Organica, Università di Ferrara, Via L. Borsari 46, 44100 Ferrara, Italy,2 Dipartimento di Scienze della Vita, II Università di Napoli, Via Vivaldi 43, 81100 Caserta, Italy
References:1. Pachamuthu, K.; Schmidt, R. R. Chem. Rev. 2006, 106, 160-187.2. Fiore, M.; Marra, A.; Dondoni, A. J. Org. Chem. 2009, 74, 4422-4425.3. Dondoni, A; Marra, A. Chem. Soc. Rev. DOI: 10.1039/c1cs15157f
The natural oxygen-linked oligosaccharides are not easy to isolate in a pure form due to the presence of mixtures of glycosylated species in the natural sources. Moreover, these compounds can undergo chemical and enzymatic degradation because they display an exocyclic acetal bond. On the other hand, their sulphur or carbon isosteres are hydrolytically stable compounds that can be used to study recognition phenomena for biological or pharmacological purposes. For these reasons several syntheses of S-oligosaccharides have been developed in the past decades1, the free-radical thiol-ene coupling (TEC) between sugar alkenes and sugar thiols was reported for the first time by our group in 20092. In fact under optimized conditions (irradiation time, reagent ratio, solvent) TEC afforded S-linked disaccharides in elevated yields.3
.
OO
O
OH OH
OH
(OH)3(HO)3
O-Glycoside (natural)
OS
O
OH OH
OH
(OH)3(HO)3
S-Glycoside (non natural)
O H2C
O
OH OH
OH
(OH)3(HO)3
C-Glycoside (non natural)
O
OAc
AcOAcO SH
O
AcOAcO
OAcAcO
Glycal Products Yield (%) 5:6 ratio
O
OAc
AcOAcO
2b1a
1a
100
82
100
100
54:46
74:26
38:62
50:50
Thiol
O
OAcAcO
AcO
O
OAc
AcO
AcO
1b
1b
SHO
AcOAcHN
OAc
AcO
2c
SHO
AcOAcHN
OAc
AcO
2c
SHO
AcOAcO
OAcAcO
2b
S
OAcO
SO
AcO
5a 6a
AcO
O
OAcAcO
OAc
AcO
O
OAcAcO
OAcAcOAcO
AcOAcO
S
OAcO
SO
AcO
5b 6b
OAc
O OAcAcHN
OAc
OAc
O OAcAcHN
OAcAcOAcO
AcOAcO
S
OOAc
SO
AcO
5c 6c
AcO
O
OAcAcO
OAc
AcO
O
OAcAcO
OAcAcO
AcO
AcO
AcO
S
OOAc
SO
AcO
5d 6d
OAc
O OAcAcHN
OAc
OAc
O OAcAcHN
OAcAcO
AcO
AcO
AcO
SR
OAcOSR
OAcO
(AcO)2 (AcO)2
AGRax AGReq
We first investigated the model reaction between 3,4,6-tri-O-acetyl-D-glucal 1a and peracetylated 1-thio-β-D-glucopyranose 2a, after some experimentation optimized reaction conditions were established. (6 equiv of 2a, 1 h irradiation, DPAP as radical initiator and EtOH as the solvent). Others glycals, (1b-d) were allowed to react with the same thiol 2a, to give the products shown in Table 1.These products formed in about 1:1 ratio, hence, the reaction was essentially lacking in stereoselectivity while it appeared to be totally regioselective with the thiyl radical generated from thiol 2a attacking exclusively the C2 carbon of the glucal 1a. In agreement to that suggested for the addition of thiolacetic acid to 1a, these results are consistent with the initial formation of two anomeric glycosyl radical (AGR) intermediates stabilized by the adjacent oxygen atom, namely AGRax in which the RS group is axial and AGReq in which the same group is equatorial (Figure 1). In the present case these intermediates must have comparable energies with the consequence that the axial and equatorial products are formed in essentially equal amounts.It was soon realized that the relative amounts of AGRax and AGReq depended considerably on the stereochemistry of the OAc groups at C3 and C4 in the starting glycal.
Next, the scope of the reaction was investigated by considering the addition of two more thiols 2b and 2c to glucal 1a and galactal 1b (Table 2).All reactions, however, were scarcely stereoselective as the two S-disaccharides 5 and 6 were formed in comparable or even equal amounts. Thus, it appears that the substitution pattern in the thiol exerts scarce or no effect on the stereochemical course of the reaction.
O
OAc
O
OAc
AcOAcO
(AcO)2 SHO
AcOAcO
OAc
AcOS
OAcO
SO
AcO
(AcO)2
(AcO)2+Ph
MeO OMe
O
Ph
h (365 nm)
DPAP
+
Glycal Conversion (%) Product(s) Yield (%) 3:4 ratio
O
OAc
AcO
AcO
O
OAc
AcO
AcO
O
OAcAcO
AcO
100
100
40
35
1 2a 3 4
1a
1b
1c
1d
80
59
38
20
57:43
37:63
100:0
100:0
OAc
O OAcAcO
OAc
OAc
O OAcAcO
OAc
S
OAcO
SO
AcO
3a 4a
OAc
O OAcAcO
OAc
OAc
O OAcAcO
OAcAcOAcO
AcOAcO
S
O
OAc
SO
AcO
3b 4b
OAc
O OAcAcO
OAc
OAc
O OAcAcO
OAcAcO
AcO
AcO
AcO
SO
AcO
3c
OAc
O OAcAcO
OAcAcO
AcO
SO
AcO
3d
OAc
O OAcAcO
OAc
AcO
AcO
In conclusion, it has been demonstrated for the first time that glycals can undergo a photoinduced addition of glycosylthiyl radicals with total regioselectivity to give 1-deoxy S-disaccharides in good to excellent yields.
RSR'
R'
RSR'
R S
R SH
Table 1
Table 2
