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Back to Sugars: “Enzymatic” Synthesis
Zhensheng DingNov. 04
Northrup, A. B.; MacMillan, D. W. C. Science 2004, 305, 1752
Northrup, A. B. and MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798 - 6799
Northrup, A. B.; Mangion, I. K.; Hettche, F.; MacMillan, D. W. C. Angew. Chem. Int. Ed. Engl. 2004, 43, 2152
List, B. Tetrahedron 2002, 58, 5573
Ko, S. Y.; Lee, A. W. M.; Masamune, S.; Reed , L. A.; Sharpless, K. B. Science 1983, 220, 949
List, B. ; Lerner, R. A. and Barbas III, C. F. J. Am. Chem. Soc., 2002, 122, 2395 -2396
Introduction to Hexoses
• Play vital roles in biological process - signal transduction, cognition, immune response• Synthetically challengeable to chemistry - 4 stereocenters with 5 similar hydroxyl groups
Common Methods toward Sugars
• Sharpless’s reiterative two-carbon extension cycle - Ko, S. Y.; Lee, A. W. M.; Masamune, S.; Reed , L. A.; Sharpless, K. B. Science 1983, 220, 949
- Takeuchi, M; Taniguchi, T; Ogasawara, K. Synthesis 1999, 1999, 341
• Hetero-Diels-Alder reactions - Danishefsky, S. J.; Maring, C. J. J. Am. Chem. Soc. 1985, 107, 7761
- Boger, D. L.; Robarge, K. D. J. Org. Chem. 1988, 53, 5793
- Tietze, L. F.; Montenbruck, A.; Schneider, C. Synlett. 1994, 1994, 509
- Bataille, C. et al., J. Org. Chem. 2002, 67, 8054
• Iterative syn-Glycolate aldol strategy - Davies, S. G.; Nicholson, R. L.; Smith, A. D. Synlett. 2002, 2002, 1637
Sharpless’s Two-carbon Extension Cycle: the Idea
Ko, S. Y.; Lee, A. W. M.; Masamune, S.; Reed , L. A.; Sharpless, K. B. Science 1983, 220, 949
Key step: Sharpless asymmetric epoxidation
Completion of the 1st Cycle
R1
S R2
O
R1
S R2
O Ac2O
R1
S R2
OAc
H
AcO R1S R2 AcO
R1S R2
OAc
AcO
OH
OHPh Ph
O
SPh
BhO
OH
OH
H
HO
O
O
Ph
Ph
NaOH
OH
BhOO
OH
OBhH
OBh
O
OBh
OH
NaBH4
LAH / AlCl3 [ O ]
L - DET
Ti ( O - i - Pr )4
1) PhSH
1 : 4
83 % 56 %
92 % yield
> 90 % ee
HOMe
OMe
SPh
OBh
O
O
CH3CO2
OBh
O
O
OAc
SPhO
OCHO
OBn4
71 %
1) mCPBA
2) (CH3CO)2O
DIBAL - H
- 78 o C
84 %
O
OCHO
OBn593 %
1
2
3
Ph3P
H
O
H
HO
O
O
OBh
1)
2) NaBH4 88 %
E / Z = 20 : 1
Ph3P
H
O
H
HO
O
OBh
1)
2) NaBH491 %
E / Z = 20 : 1
O
6
7
Ko, S. Y.; Lee, A. W. M.; Masamune, S.; Reed , L. A.; Sharpless, K. B. Science 1983, 220, 949
Pummerer rearrangement
Completion of the 2nd Cycle to 8 Hexoses6 7
Ko, S. Y.; Lee, A. W. M.; Masamune, S.; Reed , L. A.; Sharpless, K. B. Science 1983, 220, 949
Modifications to Sharpless’s Strategy
Takeuchi, M; Taniguchi, T; Ogasawara, K. Synthesis 1999, 1999, 341
C
O
HCO CHO
HCO CH
ORAD-Mix reagent
HCO CH
!
!OR
OH
OH
1) oxidative ring-expansion
2) acid cyclization
O
C
H
HPO
O
Hexoses
24
25
HCO CH
!
!OTBS
OH
OH
24
mCPBA
CHO
O
CH OTBS
OH
HO
pTsOH C
O
O
C
H
HTBSO
O
25
69% from 24
The key step:
Boger’s Hetero-Diels-Alder Reactions toward Hexoses
Boger, D. L.; Robarge, K. D. J. Org. Chem. 1988, 53, 5793
Other Hetero-Diels-Alder Reactions toward Hexoses
OMe
HO O
OH
BOMO
O H
MeO OBzOTBDMS
Ce(OAc)3-BF3.OEt2
-78oC
OMe
HO O
OH
BOMOO
OBzO
HO OH
OH
HOO
OAcNHAc
OAc
N
NH
O
OO
O
OHNH
OH
OH
Ac
Tunicamycins
35 36 37
45% conversion, single isomer
29
BzlO
O
O
N O
O
Al
AcO
OEt
-35oC
DCM
OEtO
AcO
OBzl
COX
97% endo/ exo: >50:1
OEtO
HO
OH
OH
OHand
OEtO
HO
OH
OH
OH
2627 28 30
Danishefsky, S. J.; Maring, C. J. J. Am. Chem. Soc. 1985, 107, 7761
Tietze, L. F.; Montenbruck, A.; Schneider, C. Synlett. 1994, 1994, 509
Bataille, C. et al., J. Org. Chem. 2002, 67, 8054
50oC
12kbar OEtOOC
RO
OMe
40-69% endo/ exo: >99:1
OMeH
EtOOC O
(D, L)-mannose
Oxidation Deprotection Reduction
3132 33 34
OR
O OMe
OH
OH
HO
HO
Iterative syn-Glycolate Aldol Strategy
Davies, S. G.; Nicholson, R. L.; Smith, A. D. Synlett. 2002, 2002, 1637
O N
O O
ORR
O N
O O
ORR
OR
OP
H
O
OR OR
OP
O N
O O
ORR
OH
OR
OR
OP
O
HO
OH
OH
OHHO
1) Glycolate Aldol
2) Protect
DIBAL-H
Cleavage
Iterative Glycolate Aldol
Cleavage
Deprotection
38 39
40
4142
O N
O O
OBnBn
O N
O O
OBnBn
OBn
OR
Et2BOTf, iPr2NEt
BnOCH2CHO
THF, -78oC73%, 94% d.e.
R= H
R=TBDMS90%
1) DIBAL, DCM
2) K2CO3, MeOH, H2O
H
O
OBn OBn
OTBDMS
O N
O O
OBnBn
54%
Et2BOTf
iPr2NEt
THF, -78oC
O N
O O
OBnBn
OH
OBn
OBn
OTBDMS
TBAF
HOAc, THF
O
BnO
OH
OBn
OBnO
63%, >95% d.e.
1) DIBALH, DCM
2) H2, Pd/C EtOAc, EtOH
O
HO
OH
OH
OHHO
98%65%
43 44
45
464748
Disadvantages and Advantages of the Old Methods
Disadvantages:• Require protection-group manipulations• Need for iterative oxidation-state adjustment• Long synthetic pathways
Advantages:• Hexoses can be independently derivatized• Hydroxyl groups of hexoses are protected• Hydroxyl groups of hexoses are chemically discriminated• Ready to couple with other sugars to produce polysaccharides and
other derivatives
Can hexoses be synthesized more efficiently by such de novo methods?
The Idea: L-Proline Catalyzed Cross Aldol Reactions
• Both steps are not practically proved• Product of step 1 must be inert to further aldol
Northrup, A. B.; M acMillan, D. W. C. Science 2004, 305, 1752
First Proline-catalyzed Direct Asymmetric Aldol Reactions- Breakthrough
• Not require the pregeneration of enolates or enolate equivalents• Stereoselectivity is usually good• Nucleophilic partners are acetone and a-hydroxyl acetone• Stereoselectivity is substrate-sensitive with a-brached alkyl aldehydes
give better e.e.s.
O+
H R
O
R
O OH30mol%L-Proline
DMSO
22-94% yield36-77% ee
R= Ar, !"unbrached Alkyl
O+
H R
O
R
O OH30mol%L-Proline
DMSO
63-97% yield84-99% ee
R= !"brached Alkyl
O+
H R
O
R
O OH30mol%L-Proline
DMSO
OH OH
38-95% yield67-99% ee1.5:1- 20:1 dr
List, B. Tetrahedron 2002, 58, 5573List, B. ; Lerner, R. A. and Barbas III, C. F. J. Am. Chem. Soc., 2002, 122, 2395 -2396
Features of Proline as Catalyst
NH O
OH
O
N
R2
O
ON
R2
R1 H
OH
ON
R2
R2
O
H
O
H
O
H2O
R1 R1
R2
O
NH
O
OH
Lewis base
Bronst acid
rigidity back bones
H2ONucleophilicattack
Dehydration
Deprotonation
Hydrolysis
O H
N
HR1
R2
H
R3O
O
R1
HO H
N
HR1
R2
H
R3O
O
R3 H
O
OH
R3
R1
47
48
49
50
51
1) Bifunctional catalyst with increase lewis basicity and rigid back bones2) Nontoxic, inexpensive, readily available in both enantiomeric forms3) No prior modification of carbonyls4) Water soluble5) No metal required
M
N
OO
52
H
H
Open book structure
List, B. Tetrahedron 2002, 58, 5573List, B. ; Lerner, R. A. and Barbas III, C. F. J. Am. Chem. Soc., 2002, 122, 2395 -2396
Direct Enantioselective Cross-Aldol of Aldehydes— Elusive Transformations
• Nonequivalent aldehydes must selectively partition into two discretecomponents - nucleophilic donor and electrophilic acceptor
• The propensity of aldehydes to polymerize
Northrup, A. B. and M acMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798 - 6799
H
O
X
+ H
O
Y
enantioselective
catalyst
H!
!O
X
OH
X
H!
!O
X
OH
Y
H!
!O
Y
OH
Y
H!
!O
Y
OH
X
aldehydePolymer
Can proline be used for direct enantioselective cross-aldol reaction of aldehydes?
NH O
OH
H
O2 + 10mol% catalyst
DMF, 4oCH
O OH
80% yield, 4:1 anti: syn, 99%ee53 54
First Proline-catalyzed Direct Asymmetric Cross-AldolReactions of Aldehydes
a) Good yields with excellent eesb) Tolerate a large range of substratesc) Aldehyde donors must be added slowlyd) Lower catalyst loadings and shorter reaction time compared with ketone substratese) Scalable
Northrup, A. B. and M acMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798 - 6799
For sugar synthesis: a-oxyaldehydes as substrates:
N
O
O
H
O+
H
O
OX
OH
OX
HH
O
OX
OXOX
55 56 57
H
O
OYO OH
OX
OYXO
58
aldol 1aldol 2
OX
Step 1 toward Sugar: Direct Asymmetric Aldol Reactions ofOxyaldehydes
1) Greatly affected by electronic nature of oxyaldehydes2) Bulky aldehydes with a-silyloxy
group can work3) Products are protected forms of naturally occurring sugar erythrose4) Products are nonreactive in aldol union
Northrup, A. B.; M angion, I. K.; Hettche, F.; M acMillan, D. W. C. Angew. Chem. Int. Ed. Engl. 2004, 43, 2152
Direct Asymmetric Aldol Reactions of Oxyaldehydes withAlkyl Aldehydes
Glycoaldehydes: 1) Electrophile when a-methylene
exists 2) Nuceophile when carbonyl is next to a-methine group
Northrup, A. B.; M angion, I. K.; Hettche, F.; M acMillan, D. W. C. Angew. Chem. Int. Ed. Engl. 2004, 43, 2152
Step 2 toward Sugar: Metal Catalyzed Carbohydrate Construction
Northrup, A. B.; M acMillan, D. W. C. Science 2004, 305, 1752
Effects of solvent and LA
H
O
OX
OH
OX
59
H
O
OY
O OH
OX
OYXO
60
aldol 2
OX
TMSLA
+
Structural Variation: A Lot Sugars!
1) Quick construct polysaccharides
2) Broad diversification of subs. at C4 & C6 of sugars3) Unnatural sugar synthesis with heteroatoms
Northrup, A. B.; M acMillan, D. W. C. Science 2004, 305, 1752
H
O
OX
OH
OX
59
H
O
OY
O OH
OX
OYXO
60
aldol 2
OX
TMSLA
+
A Little Extension: Enzyme Catalyzed Aldol Reaction-Aldolase I and Aldolase II
Hoffmann, T.; Barbas III, C. F. et al J. Am Chem. Soc. 1998, 120, 2768
1) Aldolase I utilize an enamine based mechanism2) Aldolase II uses zinc cofactor3) How Aldolase I works?
A Little Extension: Proline, An Aldolase I mimics
Movassaghi, M.; Jacobsen, E. N. Science 2002, 298, 1904
NH O
OH
O
N
R2
O
ON
R2R1 H
OH
ON
R2
R2
O
H
O
H
O
H2O
R1 R1
R2
O
H2ONucleophilicattack
Dehydration
Deprotonation
Hydrolysis
O H
N
HR1
R2
H
R3O
O
R1
HO H
N
HR1
R2
H
R3O
O
R3 H
O
OH
R3
R1
47
48
49
50
51
Proline, the simplest enzyme —E. N. Jacobsen
Proline- A Universal Enzyme?
NH
O
OH
O
N
R2
O
ON
R2
R1 H
OH
ON
R2
R1
O
ON
R2R1 E*
R2
O
H
O
H
O
E+
H2O
R1 R1
!R2
O
R1
E
H2ONucleophilicattack
Dehydration
Deprotonation
Electrophilicattack
Hydrolysis
E+=R3 R4
O
R3 R4
NHR
EWGR3
PhN
O
R2
!
O
R1
OH
R4R3
R2
!
O
R1
NHR
R4R3
R2
!
O
R1
EWG
R3
R2
! O
O
R1
NH
Ph
L-Proline
Aldol reaction
Manich reaction
Michael addtion
"-Aminoxylation reaction
And More....
List, B. Tetrahedron 2002, 58, 5573Merino, P.; Tejero, T. Angew. Chem. Int. Ed. Engl. 2004, 43, 2995
Summary
The strategy for the synthesis of differentially protected hexoses provides rapid enantioselective access to key building blocks in saccharide and polysaccharide synthesis. The approach efficiently yields isotopic and functional variants of the hexoses that have not been readily accessible for pharmaceutical study. Proline is a bifunctional catalyst that is efficient for many transformations
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