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Казанский национальный исследовательский технологический университет

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Химия

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Solid Support Oligosaccharide Synthesis

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148 STEREOSELECTIVE β-MANNOSYLATION ON POLYMER SUPPORT

					OBn
					HO	O		OAc		OBn
O				OAc	HO	O				OBn
O					BnO	SEt	AcO	O
					BnO	SEt	AcO	O	O	O
O		AcO		O	PhthN		O		O	O
O					PhthN		O		BnO	SEt
O						O		AcO	BnO	SEt
OH		O				O		AcO		PhthN
		O
				AcO Br	AgOTf		NHPh
O		O			AgOTf
O		O			toluene, -40 °C
O		NHPh							94%
					1. Tf2O			O
	O				2. DMF-pyridine,			O
Ph				OBn	2. DMF-pyridine,
Ph		O		OBn	70	°C		O
	O				70	°C
	O		O	O		Ph	O			OBn
	O		O	O		Ph	O	O		OBn
	O		BnO		SEt		O	O	O	O
O		OH	BnO		SEt		O
O		OH		PhthN			O
	NHPh			PhthN					BnO	SEt
	NHPh		13							PhthN
			13					96%		PhthN
								96%

PhthN

OBn

OAc

BnO

OBn

AcO

OBn

PhthN

BnO

AcO

O BnO

NHPh

OBn

PhthN

NHPh

PhthN

OBn

Chemical Transformations

BnO

OBn

PhthN

NHAc

O HO

NHAc

OH O

OHO

N Asn

NHAc

Enzymatic Reactions

OHO

NHAc

AcHN

CO2-

OH HO

NHAc

Asn

OH O

OHO

CO2-

NHAc

AcHN

OHO

NHAc

Scheme 7.12 Intramolecular SN2 reaction by Kunz.

7.1 p-METHOXYBENZYL-ASSISTED INTRAMOLECULAR AGLYCON DELIVERY										149
							TfO	OBz
								O
						Bu	BzO
						Bu
HO	OH		Bu SnO		O	Sn Bu	BzOOMe
HO	O		2	HO	O
HO	O			HO		O O
RO				HO		O O	CsF
		OH		RO			CsF
		OH
					15
	HO		OH	OBz			15 R		solvent	yield (%)
	HO		O	OBz			15 R		solvent	yield (%)
	HO		O	O
	RO		O	O			a	H	DMSO	59
	RO		O				a	H	DMSO	59
			BzO
				BzO			b	Bn	DMF	67
				OMe

Scheme 7.13 β-Mannosylation using mannose-derived 1,2-O-stannylene acetal in combination with an aglycon-derived triflate.

delivery (IAD), which was first reported by Baressi and Hindsgaul (Scheme 7.16).62–64 This approach is highly attractive because exclusive formation of the correct stereoisomer can be expected. The aglycon is linked to the axially oriented oxygen at the 2 position, and can approach the oxocarbenium ion only from the β face. Formation of α-isomer is essentially prohibited by the stereochemical constraint. Starting with 2-O-acetylated thiomannoside, isopropenyl ether 17 was prepared and converted to the mixed isopropylidene acetal 18. The latter compound serves as the tethered intermediate for IAD. Subsequent treatment with NIS activates the thioglycosidic linkage to give β-mannoside. Shortly after this disclosure, Stork and coworkers reported the use of silylketal-like intermediate 19 for a similar purpose (Scheme 7.17).65,66 Although these important achievements convincingly demonstrated the potential of IAD for β-mannosylation, the absolute

BnO	BnO		HO			TMSOTf		BnO	BnO	OMe
BnO	O	+	HO	O	TMSOMe			BnO	O	BnO
BnO			HO	O	TMSOMe			BnO		BnO
BnO			BnO					BnO		BnO
BnO			BnO			toluene		BnO		O
BnO								BnO		O
	O			BnOOMe						O
	O			BnOOMe						O
									16	77%
										77%
			LiAlH4				BnO		OMe
			AlCl3		BnO		BnO		OMe
			AlCl3		BnO		O	BnO
			CH2Cl2-Et2O		BnO		O	BnO
			CH2Cl2-Et2O		BnO			O

98% OH

Scheme 7.14 β-Mannoside via anomeric orthoester.

150 STEREOSELECTIVE β-MANNOSYLATION ON POLYMER SUPPORT

	OH
HO	O
HO	OpNP
HO	NHAc	N-Acetylhexosaminidase			OH		OH
	NHAc	N-Acetylhexosaminidase			O		O
				HO	O	O
	OH			HO		O
	OH			HO		HO	OH
HO	O				NHAc		NHAc
HO	OH
HO	OH
	NHAc
β-Mannosidase		HO	OH	OH		OH
		HO	O	O		O	(Ref. 62)
		HO	O	O		O	(Ref. 62)
		HO	HO	HO		OH
				NHAc		NHAc
HO	OH			26%
HO	O
HO	O
HO	OpNP
HO

	OH		OH					β-1,4-Mannosyl
	OH		OH						transferase
HO	O	O	O O O						transferase
	O

HO	AcNH	HO	AcNHO P O P			H
	AcNH		AcNHO P O P	O		H
			O-	O-		4		HO		OH
										OH
										O
							HO			O
							HO
								HO
										O-GDP
	hydrolysis			OH		OH				(Ref. 63)
	hydrolysis		HO	OH		OH				OH
			HO	O		O				OH
			HO	O	O	O	O			O
			HO		O		O			O
			HO		HO	AcNH	HO		AcNH OH
						AcNH			AcNH OH
						80%

Scheme 7.15 Enzymatic synthesis of βMan1→4βGlcNAc1→4GlcNAc.

yield of β-mannoside was comparable only with that obtained by conventional approaches.

In order to enhance the efficiency and practical utility of IAD, we started our investigation using mannosyl donor 20 equipped with 2-O-p-methoxybenzyl (PMB or MPM) group (Scheme 7.18).14 PMB has been widely used as a versatile protecting group that can be removed quickly under specific and mild conditions, by the action of DDQ67 or CAN.68 Since the deprotection with DDQ presumably proceeds via hydrolytic quenching of quinonemethide like intermediate 21, it was expected that, when the reaction is performed in the presence of aglycon with exclusion of moisture, mixed acetal 22 could be formed. Subsequent activation of the anomeric position should trigger IAD to selectively afford β-mannoside. This scenario is highly attractive, because (1) various methods for the introduction of the PMB group have been established and (2) the conditions required for the formation of the mixed acetal

7.1 p-METHOXYBENZYL-ASSISTED INTRAMOLECULAR AGLYCON DELIVERY				151
OH
O
	O	O	O
	O	O	OH
+	X	O	O	O
+		O	O	O
O			O
O			IAD
HO		X
		X

			HO
	O			BnO	O	O
BnO	O		p-TsOH	BnO	O	O
BnO	O		p-TsOH	BnO	O
BnO				BnO	O
BnO				BnO
BnO				BnO
BnO			CH2Cl2
	SEt		CH2Cl2		SEt
					SEt

17					18
	NIS			OH
	4-Me-DTBP		BnO	OH	O
			BnO	O	O
			BnO	O
			BnO
	CH2Cl2
			OH		OBn		OBn
O	:	BnO	O	HO	O	HO	O
HO	:	BnO		BnO		BnO	OC8H17
		BnO		BnO		BnO	OC8H17
			BnO OMe		BnO OMe		PhthN
(yield of β-glycoside)			(45%)	(44%)			(28%)

Scheme 7.16 Intramolecular aglycon delivery for β-mannosylation.

are mild and near neutral, and may well be comparable to the presence of various types of protecting groups. More importantly, compared to other IAD systems developed previously, more efficient charge delocalization and therefore clean IAD via a mesomerically stabilized transition state was expected, due to the assistance of an electron donating p-methoxy group.

In practice, DDQ-mediated mixed acetal formation proved to be quite efficient and was complete within a few hours at room temperature. As expected, subsequent IAD proceeded stereoselectively to give β-glycoside. Methyl trifluoromethanesulfonate (MeOTf) proved to be the most suitable for this purpose. For instance, thiomannoside 23 afforded 60% yield of β-glycoside 27 and 28, via mixed acetal 26 (Scheme 7.19).69 One of the most distinct features of this type of transformation is its applicability to oligosaccharide fragment condensation. For instance, disaccharide donor 29 was reacted with 24 and 25 to give corresponding products with reasonable efficiency (Scheme 7.19). Even a 3+2 coupling using trimannoside donor 30 and disaccharide-derived acceptor 25 was successful. Resultant 31 was transformed to 32, thereby completing the

152 STEREOSELECTIVE β-MANNOSYLATION ON POLYMER SUPPORT

Me2SiCl2 imidazole

DMAP

BnO

THF

BnO

Tf2O

BnO

2,6-di-tert-butylpyridine

BnO

ether-CH2Cl2

OBn

BnO

OMe BnO

BnO

OC8H17

BnO

OMe

BnO OMe

PhthN

(yield of β-glycoside)

(82%)

(55%)

(72%)

(42%)

Scheme 7.17 β-Mannoside synthesis using a silylketal-like intermediate.

	OMe				O+Me
	OMe
O			DDQ	O	HO		O
			DDQ	O	HO
				O
	O			O
	O
	SMe		O		SMe
20	SMe	HO	O	21
		HO		21

	OMe
				IAD	OH
			O		OH
O	O		O		O	O	O
							O

MeS

Scheme 7.18 p-Methoxybenzyl-assisted intramolecular aglycon delivery.

7.1 p-METHOXYBENZYL-ASSISTED INTRAMOLECULAR AGLYCON DELIVERY 153

OBn

OMP

OMe

BnO

OMe

24 NPhth

OBn

DDQ/CH2Cl2

BnO

TBDPSO

SMe

TBDPSO

SMe

NPhth

OBn

NPhth

O BnO

OMP

BnO

NPhth

OBn

NPhth

BnO

OMP

TBDPSO

MeOTf-DBMP

OBn

(CH2Cl)2

60%

NPhth

OBn

BnO

OMP

TBDPSO

BnO

OBn

NPhth

60%

OBn

OMe

OMP

BnO

NPhth

SMe

DDQ/CH2Cl2

BnO

OAc

OBn

NPhth

O BnO

OMP

BnO

NPhth

OBn

BnO

NPhth

OMP

BnO

OBn

BnO

MeOTf-DBMP

BnO

OAc

53%

(CH2Cl)2

BnO

NPhth

OBn

OMP

O BnO

BnO

OBn

NPhth

BnO

OAc

49%

Scheme 7.19 Synthesis of core structures of Asn-linked oligosaccharides.

154 STEREOSELECTIVE β-MANNOSYLATION ON POLYMER SUPPORT

OBn OMe

BnO

		O	OO
	BnO					OBn
		O			BnO	OBn
BnO				SMe	BnO	O
BnO				SMe	BnO	O
BnO				1) DDQ	BnO
BnO		O	30	2) MeOTf	BnO
BnO		O			BnO
		OBn				O	OH	NPhth		OBn
		OBn								OBn

		+				BnO	O BnO		O	O
		+		41%		BnO	O		O	OMP
						O	O	O	BnO	OMP
						O		O	BnO	NPhth
	OBn				BnO			OBn		NPhth
	OBn			NPhth	BnO	O	31
	O	BnO		NPhth	BnO	O
HO	O	BnO		OMP	BnO	OBn
HO		O		OMP
BnO		O		O
BnO				O

NPhth OBn

αMan1→6

βMan1→4βGlcNAc1→4GlcNAc

αMan1→3

(Core Pentasaccharide)

HO	OH				HO
HO	O					OH		OH
HO						O		OH
HO					Me


	O	OH	HO	NHAc			O
	HO	O	HO		O			O H
	HO		O	O	O			N	COOH
	O		O	O		HO		N	COOH
HO				OH				NHAc
HO				OH				O	NH2
HO	O							O	NH2
HO	OH				33
	HO	OH
	HO	O
	HO
HO	NHAc O		OH	HO		NHAc		OH
HO	O	O	O	HO		O		O
HO		O		O				OR
		O		O				OR
HO		O				O HO		NHAc
HO					OH			NHAc
	HO				OH
HO		O

HO OH

Scheme 7.20 Convergent synthesis of core pentasaccharide.

convergent and fully stereocontrolled synthesis of the core pentasaccharide structure of Asn-linked glycans (Scheme 7.20).70

Since all hydroxyl groups of the β-linked mannose residue can be distinguished, stereoand regiocontrolled synthetic routes to essentially all types of Asn-linked glycans can be conceived. This aspect was demonstrated by the synthesis of

7.1 p-METHOXYBENZYL-ASSISTED INTRAMOLECULAR AGLYCON DELIVERY 155

fucose-containing hexasaccharide 3371 and bisecting GlcNAc carrying structure 34,72 and subsequently by completion of the chemical synthesis of the full structure of complex type undecasaccharide.

The stereochemical issue of the acetalic carbon was subsequently addressed. Specifically, two diastereomers are possible at the stage of mixed acetal formation. Quite remarkably, the formation of mixed acetal proved to be highly selective to give almost exclusively the S-diastereomer. Mixed acetals with various substitution patterns were synthesized and uniformly stereoseletive formation of S-isomers was observed in each case (Scheme 7.21).73

The efficiency of PMB was further enhanced by modifying the protecting group pattern. As summarized in Table 7.1, highly efficient β-mannosylation was achieved with 4,6-O-disiloxane-protected 38 or 4,6-O-cyclohexylidene-protected 35. The latter afforded diand trisaccharide products 36 and 37a in ~80% yield (Scheme 7.22).74 Since 4,6-O-isopropylidene carrying 39 was less efficient compared to 35, the rigidity of the pyranose ring seems to be important. Trisaccharide product 37b obtainable from 35 was successfully used as the key intermediate in the first purely chemical synthesis of prototypical complex-type glycan chain 40.75 In this case, trisaccharide product 37b was transformed to 41 and glycosylated with sialic acid containing trisaccharide donor 42 to give 43. Subsequent deprotection and regioselective glycosylation at the 6 position afforded undecasaccharide that was transformed into target 40. The same oligosaccharide structure was synthesized previously by Unverzagt using a chemoenzymatic approach.57

		OMe		O+Me
				O+Me
RO	O
RO	O		RO O
RO	O		RO O			O
RO			O			O
RO		X	RO		O
		X	RO	H
				X
		OMe		re-face attack
RO O		H	O	RO	OH	O
RO O		O		RO	OH	O
RO	O			RO	O	O
RO				RO
RO				RO
		X
S-Diastereomer					β−Glycoside

Scheme 7.21 Stereochemical assignment of mixed acetal.

156 STEREOSELECTIVE β-MANNOSYLATION ON POLYMER SUPPORT

TABLE 7.1 Summary of β-Mannosylation Reactions

Acceptor

Donor

Yield

Promotera

Ref.

BnO OBn

BnO BnO

OBn

HO OBn

BnO BnO

	OBn
HO	O	OMP

BnO	NPhth

	OBn	BnO	NPhth
	O		NPhth
HO	O		OMP
HO		O	OMP
BnO	NPhth		O
	NPhth		OBn
			OBn

OMe

BnO OO

BnO

A		74	1				72
A		52	2				14
A		40	2				14
B		60	3				73
C		53	3				73
E		83		3			73
F		60		3			73
G		75			3		73
B		53	3				73
C		49	3				73
D		41	3				73
E		85				3	73
	BnO	OBn	OMe
	BnO	O
	BnO	O
	BnO
	BnO

O OO

BnOO

BnO

SMe

BnO O

BnO OBn

	A	OMe
		OMe		D (30)
				D (30)		OMe
Ph	O	OO
	O	OO
	O				O
TBDPSO		SMe		O	O
				O	O
				O	O
				O
				TBDPSO
	B (23)					SMe
	B (23)
		OMe		OMe	E (35)
				OMe	E (35)
Ph	O	O
	O	O
	O	O	O	O					OMe
	O			O					OMe
BnO	O	SMe		O			iPr i
BnO		SMe	O	O			iPr i	Pr
BnO	O		TBDPSO				Si	Pr
BnO OAc				SMe		O	Si
BnO OAc					iPr		O		O
					iPr		O		O
		C (29)			iPr	Si	O		O
		C (29)		F (39)		Me3SiO

SMe

G (38)

a(1) AgClO4–SnCl2/Et2O; (2) AgClO4–SnCl2/CH2Cl2; (3) MeOTf/ClCH2CH2Cl.

7.1 p-METHOXYBENZYL-ASSISTED INTRAMOLECULAR AGLYCON DELIVERY 157

OBn

OMP

BnO

NPhth

O BnO

OMe

OMP

TBDPSO

OBn

MeOTf

DDQ

DBMP

(1.5 equiv.)

83%

O BnO

NPhth

ClCH2CH2Cl

CH2Cl2, r.t., 2.5 h

TBDPSO

C, 18 h

SMe

OR1

(1.3 equiv.)

NPhth

O BnO

O OR2

TBDPSO

BnO

NPhth

OBn

NPhth

Yield (%)

BnO

NPhth

OR1

OAc

OMP

H+

O BnO

37b

OBn

O BnO

OBn

OAc

OAc CO2H

OAc

OBn

AcO

OC(NH)CCl3

AcNH

OAc

O BnO

PhthN

AcO

OBn

OMP

BnO

O BnO

OBn

OAc

OAc CO2H

AcO

OAc

OBn

AcNH

OAc

O BnO

OBn

AcO

CO2H

OH O

O O

AcNH

O HO

AcNH

OBn

NHAc

O HO

NHAc

CO2H

OH O

AcNH

O HO

AcNH

Scheme 7.22 Cyclohexylidene-protected mannosyl donor.

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A		74	1				72
A		52	2				14
A		40	2				14
B		60	3				73
C		53	3				73
E		83		3			73
F		60		3			73
G		75			3		73
B		53	3				73
C		49	3				73
D		41	3				73
E		85				3	73
	BnO	OBn	OMe
	BnO	O
	BnO	O
	BnO
	BnO

A		74	1				72
A		52	2				14
A		40	2				14
B		60	3				73
C		53	3				73
E		83		3			73
F		60		3			73
G		75			3		73
B		53	3				73
C		49	3				73
D		41	3				73
E		85				3	73
	BnO	OBn	OMe
	BnO	O
	BnO	O
	BnO
	BnO

A		74	1				72
A		52	2				14
A		40	2				14
B		60	3				73
C		53	3				73
E		83		3			73
F		60		3			73
G		75			3		73
B		53	3				73
C		49	3				73
D		41	3				73
E		85				3	73
	BnO	OBn	OMe
	BnO	O
	BnO	O
	BnO
	BnO