3. Synthesis of Fragment D
3.1 Synthesis of L-hexoses
The synthesis of L-hexoses has been an interest for organic chemists for the past few dec-ades. Many organic chemists have been trying to develop methods for synthesizing hexoses.
The synthesis of L-hexoses involves the construction of four stereocenters with five similar hydroxyl groups. The hexoses are stereoisomers having a concatenation of four contiguous hydroxy-bearing carbogenic centers. Their enantio-controlled synthesis therefore requires a procedure leading to eight pairs of stereoisomers in enantio-and diastereo-controlled manner.
3.1.1 Sharpless's Reiterative Two Carbon Extension Cycle
Sharpless et al.[22] described a systematic, stereoselective synthesis of all eight L-hexoses by a synthetic methodology developed in their laboratories for the preparation of polyhy-droxylated natural products. Their strategy is based on the reiterative two-carbon extension cycle (Scheme 17). It consists of four steps, (i) conversion of an aldehyde into its corres-ponding E-allylic alcohol, (ii) asymmetric epoxidation (AE) with titanium tetraisopropoxide, t-butylhydroperoxide, and (+) or (-) diethyl tartrate, (iii) treatment of the epoxy alcohol with benzenethiolate anion in a basic medium, (iv) oxidation and Pummerer reaction of the sulf-ide followed by the net hydrolysis of the resulting gem-acetoxysulfsulf-ide with or without inver-sion of the carbon center. The synthesis of the hexoses was accomplished in 14 synthetic steps and most of the reaction proceeding in a very good regio- and stereoselectivity.
Scheme 17. Sharpless's Synthesis of Hexoses
OH
OR
92%
(20:1)
OR O
OH
71%
(8:1)
OR O
OH
O Steps
107 108 109
R=CH(Ph)2 110
CHO HO HO
OH HO
OH
Theoretical Part 27
3.1.2 Modifications to Sharpless's Strategy
Ogasawara et al.[23] reported an alternative to Sharpless route which required reiteration of two-carbon elongation and asymmetric epoxidation. They described a new strategy capable of producing all stereoisomers of L-hexoses from a single starting material employing an asymmetric chiral induction step (Scheme 18).
Scheme 18. Ogasawara's Synthesis of L-Hexoses
Their strategy involves the utilization of the levo-glucosenone-type intermediate 113. The intermediate 113 have an extra hydroxymethyl functionality to control the regioselective cleavage of the bicyclic system as well as to discriminate the two terminal functionalities of the substrate. With respect to the construction of the four contiguous hydroxy-bearing cen-ters, as the key intermediate 115 possesses fixed oxygen functionality fated to be one of the four contiguous hydroxyl functionalities which planned to install the three remaining
O HO
O
OH
OTBS
p-TsOH 69%
O O TBSO
1) NaBH4.CeCl3 2) BnBr, NaH
2 steps, 86% 116, R=H 117, R=Bn
111 112
114 115
1) OsO4, NMO 2) BnBr, NaH 2 steps, 66%
118, R=H 119, R=Bn
1) TBAF, THF 2) MsCl, Et3N 3) LiI, THF
3 steps, 93% 120, R=OH 121, R=OMs 122, R=I
1) Zn, AcOH 2) BnOH, p-TsOH 82%
O
OBn OBn
OBn
123, R=H 124, R=Bn
OR
1) O3 2) NaBH4 96%
O
HO OBn
OBn OBn
125 BnO
H2 Pd(OH)2 99%
126 CHO HO HO
OH HO
OH O O 113 O O O
OHC HO
OH
O
O O TBSO
OR
O O TBSO
OBn OBn O OBn
O TBSO
OR OR OR
hydroxyl function by modification of the enone functionality. The most salient feature of the strategy is the use of the key intermediate 115 in two ways, namely the acetal carbon and the C-2 of the glycol carbons are placed at either the C-1 formyl functionality or the C-6 hy-droxymethyl functionality of the target hexoses so as to produce the isomeric and/or the en-antiomeric hexoses from the same precursor.
3.1.3 Hetero-Diels-Alder Reaction
Tietze et al.[24] reported the synthesis of sugars using hetero Diels-Alder reactions. The hetero Diels-Alder reactions of 130 with 132 was carried out using TMSOTf or Me2AlCl which has provided in a very good yield and with high endo-selectivity 133. The dihydropyran 133 was converted into carbohydrates in five step reaction sequences in a very good yield and high stereoselectivity (Scheme 19).
Scheme 19. Tietze's Synthesis of L-Hexoses
3.1.4 Proline Catalyzed Aldol Reaction
MacMillan et al.[25] reported a synthetic route based on aldol coupling of aldehydes in only two synthetic steps. The first step is a stereoselective dimerization of α-oxyaldehydes
cataly-BzIO
O
O
Cl HN O
O
+ n-BuLi
THF
X OBzX
O O
127
128 129
130, R=BzX 131, R=Et
AcO OEt
+ TMSOTf
CH2Cl2 90%
O
132
COX
OBzX AcO
LAH, THF 85%
O
OBzX HO
OH 1) NaOAc, Ac2O 2) BH3.SMe2 3) NaOH, H2O2 2 steps, 82%
O
OBzX AcO
OH OH
O
OH HO
OH OH 133
134 135 136
N O O X=
X OR
O O
EtO
EtO EtO EtO
Theoretical Part 29
zed by D-proline which was then followed by a tandem Mukaiyama aldol addition- cycliza-tion step catalyzed by a Lewis acid. The initial step requires that the α-oxyaldehyde 137 par-ticipate both as a nucleophile and an electrophile, whereas the product 138 must be inert for further aldol reactions. Mukaiyama aldol reaction of oxy-enolsilane 139 with TIPS- protec-ted β-oxyaldehyde 138 in the presence of a Lewis acid afforded the cyclization products, carbohydrate ring system (Scheme 20). Exposure of the β-oxyaldehyde 138 and enolsilane 139 to TiCl4 in CH2Cl2 affords high selectivity for allose 140a with a 97% yield and 19:1 se-lectivity. The use ofMgBr2.OEt2 in solvents such as Et2O, toluene or pentane shows prefer-ence for glucose 140b with 8:1-10:1 selectivity. Using optimized condition, a 79% yield and a 10:1 preference for glucose in Et2O was obtained, whereas using MgBr2.OEt2 in CH2Cl2
resulted in 87% yield and 19:1 selectivity for mannose 140c.
Scheme 20. MacMillan's Synthesis of Hexose
3.2 Synthesis of L-glucose Fragment
The synthesis of L-glucose fragment started using commercially available ethylene glycol 79, was selectively protected with TBSCl/NaH conditions to afford TBS-protected alcohol 141 in 82% yield. Compound 141 was selectively oxidized using DMP/CH2Cl2 condition to provide aldehyde 142 in 81% yield[25].
HO OH 1) TIPSCl, NaH 2) DMSO, (COCl)2 2 steps, 75%
O OTIPS D-Proline 74%
O
OTIPS OH
OTIPS
O
OTIPS OH
OTIPS + TMSO OAc TiCl4, CH2Cl2 97%
O
OTIPS AcO
HO
OTIPS
O
OTIPS OH
OTIPS + TMSO OAc
79% O
OTIPS OH
AcO HO
OTIPS
O
OTIPS OH
OTIPS + TMSO OAc
87% O
OTIPS OH
AcO HO
OTIPS
79 137
138
138
138
138
139
139
139
140a
140b
140c OH
Et2O
CH2Cl2 MgBr2.Et2O MgBr2.Et2O
The aldehyde 142, was used both as nucleophile and electrophile, underwent dimerization using D-proline/DMSO condition to afford TBS-protected β-oxyaldehyde 143 in 76%
(syn:anti, 1:3.4) yield (Scheme 21).
Scheme 21. Synthesis of Oxyaldehyde
The synthesis of oxy-enolsilane 139 started from commercially available cis-2-butenediol 144 which was acylated using Ac2O/Py condition[28] to afford the acylated alkene 145 in 86%
yield. The alkene 145 was oxidized with ozone to give the corresponding aldehyde 146 in 51% yield and subsequent selective protection of 146 with TMSCl/Et3N/CH3CN condition[29]
provided the Z-isomer oxy-enolsilane 139 in 66% yield and very good selectivity (Scheme 22).
HO OH TBSCl, NaH THF 82%
OTBS
D-Proline DMSO 76%
O
OTBS OH
OTBS
79 HO 141 DMP, CH2Cl2
81%
O OTBS
O OTBS + OTBS
O
N
O
H OH
142
142 142
143
Nucleophilic attack
H20
O OTBS
N
O O OTBS
O H
H
N
OTBS H
O O
N O
OH N OTBS
O TBSO O
TBSO O
H
Dehydration
Deprotnation
H20
Hydrolysis O
OTBS OH
OTBS 143
142
Theoretical Part 31
Scheme 22. Synthesis of Oxy-enolsilane
TBS-protected β-oxyaldehyde 143 underwent Mukaiyama aldol reaction with oxy-enolsilane 139 using MgBr2.Et2O/Et2O as a promoter to afford the intermediate oxocarbenium product 147 which rapidly cyclized to afford the hexose fragment 148 in 75% yield. The treatment of 148 with HBr/AcOH followed by Zn/AcOH furnished the TBS-protected glucal 149 in 60%
yield[30] (Scheme 23).
Scheme 23. Synthesis of L-glucose Fragment