Suharti1, Suminar S Achmadi1, Luthfan Irfana1, Purwantiningsih. Sugita1, Tuti Wukirsari1, Auliya Ilmiawati1, Budi Arifin1*. 1Department of Chemistry, Faculty of ...
Synthesis of Benzyl-Protected Robtein (2’,3,4,4’,5Pentahydroxychalcone) as An Intermediate to (–)-Robidanol
Suharti1, Suminar S Achmadi1, Luthfan Irfana1, Purwantiningsih Sugita1, Tuti Wukirsari1, Auliya Ilmiawati1, Budi Arifin1* 1Department
of Chemistry, Faculty of Mathematics and Science Bogor Agriculture University INDONESIA
Bioactivities of Merbau (Intsia palembanica) Hardwood Extract OH 3'
skin whitening agent
R1
(Batubara et al. 2011)
4'
HO
7
O
2
3
5'
OH
R2
Tyrosinase inhibitor • IC50 monophenolase 8.7 µM, • IC50 diphenolase 26.6 µM, • inhibit 46% melanine
Antiacne
R1 = OH R2 = (-)-robidanol R1 = OH R2 = (+)-epirobidanol Intsia palembanica (Fabaceae) 4'-dehidroksirobidanol R1 = H R2 =
(Batubara et al. 2013)
OH OH
• Antibactery • lipase inhibitor against P acnes (IC50 4.1 µg/mL)
OH
Antioxydant
• Superior quality: Massive illegal logging • Survival 48% • Slow growth rate
Introduction
Methods
Results
(Batubara et al. 2013)
(‒)-Robidanol synthesis research
Conclusion
References
Fitur Struktur (‒)-Robidanol
8 7
A
B
1 2
C
Cis
3
6 5
3,4,5-trihydroxyphenyl group
Hydroxy group
4
(‒)-Robidanol
A 2
C
B
3
Introduction
Methods
Results
Conclusion
References
Retrosynthetic Analysis of (‒)-Robidanol
Introduction
Methods
Results
Conclusion
References
Synthetic Pathway of Benzyl Ether Protected Robtein
Reagents and conditions: (a) BnBr, KI, K2CO3, acetone, reflux, 3 h, 85%; (b) BnBr, K2CO3, acetone, reflux, 3 h, 98%; (c) (i) LiAlH4, THF, rt, 6 h, (ii) NaOH, H2O, 98%; (d) PCC, DCM, rt, 6 h, 85%; (e) NaH, DMF, rt, 24 h, 60%.
Introduction
Method
Result
Conclusion
Refrences
Synthesis of 4'-Benzyloxy-2'-hydroxyacetophenone
HO
OH
BnO
OH
BnBr K 2 CO 3 O
O
Phenolic –OH test
N2
a) FeCl3 (negative cont.) b) FeCl3 + Rf ~0.81 c) FeCl3 + Rf ~0.60
a
b
c Rf ~0.81 Rf ~0.60
5 BnBr K2CO3 KI acetone p.a
Crude Product Solvent Removal 3h
Introduction
Method Method
Result Results
Conclusion Conclusion
Purification by preparative TLC; eluent: n-hexane:MTC (2:3)
Refrences References
Synthesis of 4'-Benzyloxy-2'-hydroxyacetophenone a) FeCl3 (negative cont.) b) FeCl3 + Rf ~0.81 c) FeCl3 + Rf ~0.60
HO
O
O
b
c Rf ~0.81 Rf ~0.60
Purification by preparative TLC; eluent: n-hexane:MTC (2:3)
Pure Product MP 100‒102 °C.
Result Results
OH
Phenolic –OH test
Recrystalized from n-hexane
Method Method
BnO
BnBr K 2 CO 3
a
Introduction
OH
Conclusion Conclusion
Refrences References
HO
O
BnO
OBn
BnO
O
H
H
BnBr, K2CO3, KI
FTIR Analysis
O
+ O
aseton, ref luks, 3 h
A
O
B
C
C
% Transmitance
ῡ = 3839 cm-1 ῡ = 1607 cm-1 ‒OH intramolecularly C=O H-bonded B
A ῡ = 3294 cm-1 ῡ = 1607 cm-1 ‒OH [free] Wave number (cm-1)
Introduction
Method
Results
Conclusion
References
1H
NMR Analysis 7.35-7.43 ppm Ph
6.50
O
O
12.73 ppm H
5.09 ppm
O
6.52 7.63
2.55 1H
NMR (500 MHz, CDCl3) 2.55 (s, 3 H) 5.09 (s, 2 H) 6.50–6.53 (m, 2 H) 7.33–7.42 (m, 5 H) 7.63 (d, J=8.45 Hz, 1 H) 12.73 (s, 1 H)
Introduction
Method
Results
Conclusion
References
13C Ph
O
NMR Analysis
O H
70.30
O
202.71 26.3
Introduction
13C
NMR (125 MHz, CDCl3): 26.3 (CH3), 70.3 (OCH2Ph), 102.0 (C-3'), 108.2 (C-5'), 114.2 (C-1'), 127.6, 128.4, 128.8, 136.0 (C-Ar), 132.5 (C-6'), 165.3 (C-2',4'), 202.7 (C=O).
Method
Results
Conclusion
References
Reaction Optimization 73 65
Yield (%)
52
14
1.1
16
15
2.2 BnBr Equivalent
3.3
4'-Benzyloxy-2'-hydroxyacetophenone
2',4'-Dibenzyloxy-acetophenone
Introduction
Method
Results
Conclusion
References
Synthesis of Methyl 3,4,5-tribenzyloxybenzoate N2
Dist. water
Recrystallized from ethanol
Extraction by ethyl acetate 6 BnBr K2CO3 acetone p.a
Organic phase solvent removal
3 jam
Rf ~ 0.68
98% yield Introduction
a
b
c
a) FeCl3 (negative control) b) FeCl3 + phenol (positive control) c) FeCl3 + methyl 3,4,5-tribenzyloxybenzoate
Method Method
Result Results
n-hexane:EA (8:2)
Conclusion Conclusion
mp. 92-95 °C.
Refrences References
OBn
Synthesis of 3,4,5-Tribenzyloxybenzyl alcohol
OBn OBn
MeO OBn
OBn
1. LiAlH4, eter 2. OH-, H2O
HO
OBn
O
LiAlH4 THF
8 in warm THF
N2
Dist. water NaOH 15%
N2
Dist. water MTC
Water and organic phase separated RT, 15 min
RT, 6 h
Organic phase dried by Na2SO4
95% Yield Rf ~ 0.26 mp. 94-97 °C.
Introduction
n-hexane : EtOAc (8:2)
Method Method
Result Results
Conclusion Conclusion
Refrences References
Synthesis of 3,4,5-Tribenzyloxybenzaldehyde N2 9 PCC Celite CH2Cl2
Organic phase dried by Na2SO4 anhydrate
RT, 6 h
Filtrate washed by 10% CuSO4 then dist. water
Filtered & washed by 10% NaHSO3 then dist. water
79% Yield
Purification by silica gel column chromatography; by n-hexane:MTC (1:2)
Rf ~0.72
n-hexane:MTC (1:2)
Introduction
Method Method
Result Results
mp. 98-101 °C.
Conclusion Conclusion
Refrences References
OH
Ph Ph
OH MeO
OH O
1. LiAlH4, THF, rt, 6 h
O
ref luk s, 3 h
3,4,5-tribenziloksibenzildehida
MeO
O
A
O
FTIR Analysis
OBn
OBn
O BnBr, K2CO3, aseton
OBn
OBn
2. NaOH, H2O
PCC, Celite 5 45
HO
OBn
Ph
CH2Cl2, rt, 6 h
OBn O
C
B
H
D 3,4,5-tribenziloksibenzildehida 3,4,5-tribenziloksibenzilalkohol
ῡ = 1692 cm-1 C=O
%T
C 3,4,5-tribenziloksibenzildehida 3,4,5-tribenziloksibenzilalkohol 3311 cm-1 m etil galat
ῡ= ‒OH %T
ῡetil=tribenzil 2948galat cm-1 3,4,5-tribenziloksibenzilalkohol m m etil galat 3 C‒H sp %T
B
ῡ = 1716 cm-1 4 00 0.0
3 00 0
2 00 0 m etil tribenzil galat m etil galat 3323 cm-1
ῡ= ‒OH 4 00 0.0
Introduction
3 00 0
1 50 0
1 00 0
4 50 .0
CM-1
A
ῡ = 1679 cm-1 2 00 0 m etil tribenzil galat
Method
1 50 0 CM-1
Results
1 00 0
Conclusion
4 50 .0
References
D
1H
NMR Analysis 7.32-7.45 Ph
5.16 O
7.32-7.45 Ph
O
7.18
5.16
9.80 H O
7.18
5.16
O
Ph
7.32-7.45
1H
NMR (500 MHz, CDCl3) 5.16 (s, 6H) 7.18 (s, 2H) 7.32-7.45 (m, 15H) 9.80 (s, 1 H)
Introduction
Method
Results
Conclusion
References
13C
NMR Analysis
Ph
71.5 O Ph
O
76.9 H O
71.5
13C
NMR (125 MHz, CDCl3) 71.5, 76.9(OCH2Ph), 109.0 (C-2',6'), 127.6, 128.2, 128.6, 136.5 (C-Ar), 131.9 (C-1'), 143.9 (C-4'), 153.3 (C-3',5'), 191.0 (C=O).
191 O
Ph
Introduction
Method
Results
Conclusion
References
Synthesis of Protected Robtein
BnO
OH
OBn
+ H
(3,4,4',5-Tetrabenzyloxy-2'-hydroxychalcone)
0 °C, 10 min
0 °C, 30 min
0 °C, 10 min RT, 24 h
Vacuum filtration; washed by dist. water; air dried
Flash column chromatography with n-hexane:MTC (3:2)
(3:2)
OBn
Ice and HCl until pH ~4
N2
N2
n-heksana:MTC
OH
O
O
10 in DMF
7 in DMF
N2
BnO
NaH 60% DMF
OBn O
NaH 60% DMF
OBn
OBn
Rf ~0.17 n-hexane:MTC (3:2)
Introduction
Method Method
Result Results
Conclusion Conclusion
Refrences References
1H
NMR Analysis
7.27-7.44
Ph 7.27-7.44
1H
5.12-5.16
Ph 5.12-5.16
O
6.55
O 13.43 OH 7.39
H
B
7.27-7.44
O 6.91
Ph
5.12-5.16
A
6.57
6.91
7.76
O
H
7.70
NMR (500 MHz, CDCl3) 5.12 (s, 4H) 5.16 (s, 4H) 6.55 (d, 1H) 6.57 (dd, 2.6, 10.4, 1H) 6.91 (s, 2H) 7.27-7.44 (m, 20H) 7.39 (d, 14.95, 1H) 7.70 (d, 14.95, 1H) 7.76 (d, 9.1, 1H) 13.43 (s, 1 H)
O
5.12-5.16
Ph
7.27-7.44
Introduction
Method
Results
Conclusion
References
Ph Ph
70.4 O
Introduction
13C
13C
NMR (125 MHz, CDCl3) 71.6 70.4, 71.6, 75.5 (OCH2Ph), O 102.2 (C-5'), OH O Ph 108.4, 108.6 (C-3',2,6), 114.4 (C-1'), H 75.5 119.7 (C-α), 119.7 127.7 (C-1), O 191.8 144.6 127.6, 128.4, 128.8, 128.9, 136.9 (C-Ar), 136.0 (C-6'), O H 71.6 141.1 (C-4), Ph 144.6 (C-β), 153.3 (C-3,5), 165.4 (C-2'), 166.8 (C-4'), 191.8 (C=O).
Method
Results
Conclusion
NMR Analysis
References
Reaction Optimization
Introduction
Method
Results
Conclusion
References
Conclusion 3,4,4,5-Tetrabenzyloxy-2-hydroxychalcone as an intermediate of (–)robidanol has been synthesized with overall yield of 49% in 4 steps from methyl gallate.
Acknowledgement We are grateful to Hibah Penelitian Unggulan Perguruan Tinggi from the Ministry of Research, Technology, and Higher Education for the financial support of this research. We thank Mr. Akhmad Darmawan of LIPI Chemistry Research Centre for the determination of NMR studies. Introduction
Method
Results
Conclusion
References
Daftar Pustaka Ahmed I. 2007. Study of enantioselective epoxidation, asymmetric reduction, and synthesis of bioactive oligomeric flavonoids [disertasi]. Paderborn (PK): Universitat Paderborn. Batubara I, Darusman LK, Mitsunaga T, Aoki H, Rahminiwati M, Djauhari E, Yamauchi K. 2011. Flavonoid from Intsia palembanica as skin whitening agent. J Biol Sci. 11(8): 475-480. doi: 10.3923/jbs.2011.475.480. Batubara I, Kuspradini H, Muddathir AM, Mitsunaga T. 2013. Intsia palembanica wood extracts and its isolated compounds as Propionicbacterium acnes lipase inhibitor. J Wood Sci. 60(2): 169-174. doi: 10.1007/s10086-013-1388-5. Irfana L. 2015. Sintesis flav-3-ena dari 2,4-dihidroksiasetofenon dan 3,4,5-trihidroksibenzaldehida [tesis]. Bogor (ID): Institut Pertanian Bogor. Manners GD dan Jurd L. 1978. Additional flavonoids in Gliricidia sepium. Phytochemistry. 18(6): 1037-1042. doi: 10.1016/S0031-9422(00)91473-0. Watanabe M, Awen BZ, Kato M. 1993. Efficient synthesis of (1S,5S)-4-alkyl-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-ones from (1R,5S)-(+)-nopinone and preparation of some chiral building blocks suitable for the asymmetric aynthesis. J Org Chem. 58(15): 3923-3927. doi: 10.1021/jo00067a026. Zaveri N, Chao W-R, Bensari A, penemu; SRI International. 2006 Okt 17. Analogs of green tea polyphenols as chemotherapeutic and chemopreventive agents. US Patent US 7 122 573 B2. Zhang M, Jagdmann GE, Zandt MV, Beckett P, Schroeter H. 2013. Enantioselective synthesis of orthogonally protected (2R,3R)-(‒)-epicatechin derivatives, key intermediates in the de novo chemical of synthesis of (‒)epicatechinglucoronides and sulfates. Tetrahedron: Asymmetry. 24(7): 362-373. doi: 10.1016/j.tetasy.2013.02.012.
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