Ph.d. research presentation 2008
78
a) Efforts Towards the Total Synthesis of Aigialomycin D and b) Development of Two Novel Methodologies Naval Bajwa Research Advisor: Dr. Michael P. Jennings The University of Alabama Department of Chemistry RESEARCH PRESENTATION
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Transcript of Ph.d. research presentation 2008
a)Efforts Towards the Total Synthesis of Aigialomycin D and
b)Development of Two Novel Methodologies
Naval Bajwa
Research Advisor: Dr. Michael P. Jennings
The University of Alabama
Department of Chemistry
RESEARCH PRESENTATION
Project I: Efforts towards the total synthesis of the biologically active natural product aigialomycin D.
Project II: Efficient and selective reduction protocols of the 2,2-dimethyl-1,3-benzodioxan-4-one functional group to readily provide both substituted salicylaldehydes and 2-hydroxy benzyl alcohols.
Project III: An Efficient 1,2-chelation controlled reductions of protected hydroxy ketones via Red-Al
Structure and Isolation
OH
HO
OH
O
O
OH
aigialomycin D (1)
Isaka, M.; Suyarnsestakorn, C.; Tanticharoen, M.; Kongsaeree, P.; Thebtaranonth, Y. J. Org. Chem. 2002, 67, 1561.
• Isolated from mangrove fungus Aigialus Parvus BCC 5311 by Isaka and coworkers.• 14-membered resocylic macrolide, 3 stereogenic centers, 2 trans double bonds and a cis-diol functionality.
Resorcinol natural products that inhibit HSP90: aigialomycin D and radicicol
OH
HO
OH
O
O
OH
OH
HO
O
O
O
O
H H
Cl
aigialomycin D (1) radicicol (3)
OH
MeO
OH
O
O
OHaigialomycin C (2)
O
Isaka, M.; Suyarnsestakorn, C.; Tanticharoen, M.; Kongsaeree, P.; Thebtaranonth, Y. J. Org. Chem. 2002, 67, 1561.
• Modest anti-malarial properties against Plasmodium falciparum K1 (IC50 6.6 g/mL and cytotoxic to KB and Vero cell lines (IC50 3.0 and 1.8 g/ml)• Mechanism of action is currently unknown, but it has been shown to bind to HSP90• Could be developed as a selective HSP90 inhibitor
OH O
HO
O
OH
OH
OO
TMSO
O
O
O
O
O OTMSO
+
OTMS
TMSO
OBrZn
HO
O
O
CO2
1 4
5
6
7
Geng, X.; Danishefsky, S. J. Org. Lett. 2004, 6, 413.
Danishefsky’s Total Synthesis of aigialomycin D
OH O
HO
O
OH
OH
OMOM
MOMO
COOH
O
O
OH
OMOM
MOMO
Br O
O
OHO
OHN
N N
NS
OO
TBSO
Ph
+
OMOM
MOMO
Br
O
H
+
N
N N
NS
OO
OPiv
O
O
BnOOH
O
Ph
1 8
910
11
1213
14
Lu, J.; Ma, J., Xie, X.; Chen, B.; She, X.; Pan, X. Tetrahedron: Asymmetry. 2006, 17, 1066.
She-Pan’s Total Synthesis of aigialomycin D
Retrosynthetic analysis of aigialomycin D
HO
OH
O
O
OH
OH
BnO
O
O
O
BnO
O
OTf
O
O
HO
OO
H
O
OMOM
OTBS
RCM
esterification alkynyl addition
+
Suzuki coupling
HO
OH
OH
O
OH
116
15
17 18 19 20
1'
2'
7'8'
Completion of the aromatic portion of aigialomycin D
BnO
O
O
O
HO
O
OH
O
O
BnO
O
OH
O
O
BnO
O
OTf
O
O
a) BnOH, DIAD
b) Tf2O, pyr. 87%
c) Pd(dppf)Cl2
F3B-K+
PPh3,
88%
77%
18 21
1715
Completion of the MOM protected olefinic aldehyde coupling partner
a) Li2CuCl4
b) MOMCl, DIPEA 93%
OTBDPSO OTBDPS
OH
OTBDPS
OMOMH
OMOM
Oc) TBAF
d) TPAP-NMO
allylMgBr, 87%
OCl N
MOM-ClDIPEA
71% over two steps
22 23
2419
Completion of the C1-C11 subunit via a lithium alkynylation addition
a) nBuLi, 71%
b) Red-Al 72%
OH
OMOM
OTBSTBSO
OH
OMOM
TBSO
H
OMOM
O2:1
2:1
Red-Al: Na+H2Al-(OCH2CH2OMe)2
E:Z, 15:1
O
OMOM
TBSO E:Z, 15:1
c) TPAP-NMO
92%
20
19 25
2627
6'
OH
OMOM
TBSO
6:1
E:Z, 15:1
O
OMOM
TBSO E:Z, 15:1
27 28
# Reagent Temp. anti syn yield
1 NaBH4 0 1.4 1 882 LiBH4 -40 1 2.5 803 LiAlH4 0 2.3 1 864 Red-Al 0 6 1 84
a) Red-Al, Toluene
84%
Chelation controlled reduction of hydroxy ketone
Burke, S. D.; Deaton, D. N.; Olsen, R. J.; Armistead, D. M.; Blough, B. E. Tetrahedron Lett. 1987, 28, 3905.
c) HCl, MeOH
OH
OMOM
TBSO
6:1
d) DMP, PPTS, 62%
HO
OO
E:Z, 15:1
O
OMOM
TBSO E:Z, 15:1
a) Red-Al, Toluene
6:1
84%
27 28
16
Completion of the aliphatic portion of aigialomycin D
Completion of aigialomycin D via a chemo-and diastereoselective RCM reaction ??
a) NaH, 78%
b) Grubbs'
HO
OO
O
OO
OOH
BnO
O
OO
OOH
BnO
O
BnO
O
O
84%
6:1dr 6:1dr
16 29
30
15 31
Ru
PCy3
NN
Cl
Cl
Ph
MesMes
31
XCH2Cl2, reflux
+
32
O
BnO
O
O
15
OH
OMOM
O
BnO
O
O
OMOM
OH
Ru
PCy3
NN
Cl
Cl
Ph
MesMes
31
33
O
R+
ORu
Cl
Cl
NNMes Mes
Ru
PCy3
NN
Cl
Cl
Ph
MesMes
R
Attempted cross metathesis reaction to construct C1’-C2’ double bond
Slugovc, C.; Perner, B.; Stelzer, F.; Mereiter, K. Organometallics 2004, 23, 3622.
Grubbs'O
OO
OO
BnO
Grubbs'O
OO
OOH
BnO
Ru
NN
Ph
PCy3
Cl
Cl
O
OO
OOH
BnO
Ru
O
OO
OO
BnORu
HH
PATH A:
PATH B:
29
29
31
Possible pathways for RCM
O
R+
ORu
Cl
Cl
NNMes Mes
Ru
PCy3
NN
Cl
Cl
Ph
MesMes
R
Formation of Carbonyl-Ru chelate????
Slugovc, C.; Perner, B.; Stelzer, F.; Mereiter, K. Organometallics 2004, 23, 3622.
Grubbs'O
OO
OO
BnO
O
OO
OO
BnORu
HH
PATH A:
29
11.7ppm
Grubbs'O
OO
OO
BnO
Grubbs'O
OO
OOH
BnO
Ru
NN
Ph
PCy3
Cl
Cl
O
OO
OOH
BnO
Ru
O
OO
OO
BnORu
HH
PATH A:
PATH B:
29
29
31
Possible pathways for RCM
Electronic or steric “guidance” of Grubbs’ catalyst to provide the macrolactone
O
OOH
BnO
Grubbs'O
OO
OOH
BnO
Ru
6 membered ring formation
OO
+
Dead End !!!
Grubbs'O
OO
OOH
BnO
Ru
14 membered ring formation
O
OO
OOH
BnO
Ru
NN
Ph
PCy3
Cl
Cl
29a
29b30
34
31
6'
6'
b) Grubbs'O
OO
OOH
BnO
O
OO
OOH
BnO
O
OOH
BnO
+
84%
13%
O
OHOH
OOH
HO
BBr3
6:129 34
30epi-174%
Diastereo- and Chemoselective RCM reaction
Total synthesis of epi-C6’-aigialomycin D ?? The proof is in the 1H NMR
O
OOH
HO
OH
OH
--vs--
H
H
H
O
OOH
HO
OH
OHH
H
H
5.68 ppm
4.35 ppm
3.62 ppm
5.58 ppm
3.81 ppm
3.40 ppm
d6 acetone d6 acetone
O
OOH
MeO
OH
OHH
H
H
5.43 ppm
3.92 ppm
3.48 ppm
O
CDCl3
aigialomycin D (1) epi-aigialomycin D (epi-1)
aigialomycin C (2)
Isaka, M.; Suyarnsestakorn, C.; Tanticharoen, M.; Kongsaeree, P.; Thebtaranonth, Y. J. Org. Chem. 2002, 67, 1561.
Diastereoselective macrocyclization via a RCM reaction with Grubbs’ II catalyst
O
OO
OOH
BnO
O
OO
OOH
BnO
O
OOH
BnO
OO
+
O
OO
OOH
BnO
84%
13%
6:1dr
Ru
PCy3
NN
Cl
Cl
Ph
MesMes
29a
29b
34
30
31
6'
6'
Similarities between epi-C6’-aigialomycin D and aigialomycin C
--vs--O
OOH
HO
OH
OHH
H
H
5.58 ppm
3.81 ppm
3.40 ppm
epi-aigialomycin D (d6 acetone)
O
OOH
MeO
OH
OHH
H
H
5.43 ppm
3.92 ppm
3.48 ppm
O
aigialomycin C (CDCl3)
O
OO
OOH
MeO
O
OOH
MeO
OH
OH
O
a) Selective epoxidation
b) Acetonide removal
aigialomycin C
(epi-1) (2)
Isaka, M.; Suyarnsestakorn, C.; Tanticharoen, M.; Kongsaeree, P.; Thebtaranonth, Y. J. Org. Chem. 2002, 67, 1561.
Completion of aigialomycin C via a chemo- and diastereoselective RCM reaction ??
a) NaH
b) Grubbs'
HO
OO
O
OO
OOH
MeO
O
OO
OOH
MeO
O
MeO
O
O
33%
72%
c) mCPBAO
OO
OOH
MeOO
3:1 dr63%
2:116
35
36
3738
Attempted completion of aigialomycin C via aq. HCl mediated acetonide removal
Acetonide removal ??O
OO
OOH
MeOO
O
OOH
MeOO
OH
OH
aq. HClO
OO
OOH
MeOO
O
OOH
MeOO
OH
OH
X
aigialomycin C
38 2
38
(2)
Proposed synthesis of aigialomycin D
O
OOH
HO
OH
OH6'
1'
epi-C6'-aigialomycin D
inversion @ C6' O
OOH
HO
OH
OH6'
1'
aigialomycin D
O
OOH
MeO
OH
OH6'
1'
O
OOH
MeO
O
O6'
1'
NaIO4
O
OOH
MeO
OH
OH6'
1'
aigialomycin D
a) SmI2, THF/MeOH
acetone:H2O
X
39
(1)
37
b) BBr3
Attempted synthesis of aigialomycin D
Diastereoselective macrocyclization via a RCM reaction with Grubbs’ II catalyst
O
OO
O
Ru
OH
BnO
O
OO
OOH
BnO
O
OOH
BnO
OO
+
O
OO
OOH
BnO
84%
13%
6:1dr
Ru
PCy3
NN
Cl
Cl
Ph
MesMes
29a
29b
31
34
30
6'
6'
Retrosynthetic analysis of aigialomycin D
MeO
OH
O
O
OH
OH
HO
OO
H
O
OMOM
OTBS
esterification alkynyl addition
+
5040
41 20
HO
OH
O
O
OHOHRCM
esterification
1
MeO
O
O
O
HO
O
OH
O
O
3518
OH
OMOM
OTBDPS
OMOM
TBAF, THF, 73%
H
OMOM
O
TPAP/NMO
CH2Cl2
OTBDPSO
OMOM
H
OTBDPS
OMOMO3
CH2Cl2
PPh3
LHMDS, THF,77%
66%
24 42 43
4441
82%
Completion of the MOM protected olefinic aldehyde coupling partner
O OTBS
TBSO
OMOMOH
Li, DMSO 41
THF
a)
b) TBSCl, imidazole, DMF 60%20
45
TBSO
OMOM
OH
Red-Al
THF78%
46
TBSO
OMOM
O
TBSO
OMOM
OH
HO
OHOH
TPAP/NMOCH2Cl2
Red-Al
Toluene
HCl,
MeOH
53%
95%
474849
HO
OO
2,2 - DMP,
PPTS, CH2Cl2
66% overtwo steps
40
Completion of the C1-C11 subunit via a lithium alkynylation addition
O
MeO
O
O
HO
OO
+NaH
THF/DMF (1:1)
O
MeO
O
O
O
O
H
49%
504035
11.7ppm
OH
MeO
O
O
Ru
O
O
Cl
Cl
N N MesMes52
OH
MeO
O
O
O
O
Ru
PCy3
NN
Cl
Cl
Ph
MesMes
31
CH2Cl2,reflux
X
51
Slugovc, C.; Perner, B.; Stelzer, F.; Mereiter, K. Organometallics 2004, 23, 3622.
OH
MeO
O
O
O
O
Ru
PCy3
NN
Cl
Cl
Ph
MesMes
31
Ti(OiPr)4,CH2Cl2,
reflux
HO
MeO
O
O
O
O
TiO
OO
50
OH
MeO
O
O
O
O
X
51
Attempted RCM via carbonyl chelation
OH
MeO
O
O
O
O
OH
MeO
O
O
O
O
Ru
PCy3
NN
Cl
Cl
Ph
MesMes
31
Toluene, reflux
OH
HO
O
O
OH
OH
4 equiv. BBr3
CH2Cl2, -78 oC
aigialomycin D
X
50
51
Attempted RCM at higher temperature
Conclusions: The syntheses of three aigialomycin family hybrids
O
OOH
MeO
OH
OH6'
1'
O
OOH
HO
OH
OH
O
OOH
MeO6'
1'
OO
O
6'
1'
epi-C6'-aigialomycin D deoxy-aigialomycin C
C5'-C6' isopropylidene-aigialomycin C
Bajwa, N.; Jennings, M. P. Tetrahedron Lett. 2008, 49, 390.
Project II: Efficient and selective reduction protocols of the 2,2-dimethyl-1,3-benzodioxan-4-one functional group to readily provide both substituted salicylaldehydes and 2-hydroxy benzyl alcohols.
O
O
O OH
H
O
BnO BnO
OH OH
BnO
LiAlH4 DIBAL-H
-78 oC rt -78 oC
O
O
O
OH
H
O
OH OH
OH
OR
OOH
OH
O
OH
NR2
O
OH
R
R
R
R
R
R
R
-OR
HNR2NaOH
60 oC
NaOH
120 oC
Selective manipulation of 2,2-dimethyl-1,3-benzodioxan-4-one functional group
(a) Bolshakov, S.; Leighton, J. L. Org. Lett. 2005, 7, 3809. (b) Soltani, O.; De Brabander, J. K. Org. Lett. 2005, 7, 2791.
OMe OH
O
HOOH
OO
H OOH OH
OH
HO
O
MeO OH
O
OH
OHO
OH
O
O
OH
HO
OH
HO
OH
OH
O
OOHHO HO
(a) Malmstrom, J.; Christophersen, C.; Barrero, A. F.; Oltra, J. E.; Justicia, J.; Rosales, A. J. Nat. Prod. 2002, 65, 364. (b) Herath, K. B.; Jayasuriya, H.; Guan, Z.; Schulman, M.; Ruby, C.; Sharma, N.; MacNaul, K.; Menke, J. G.; Kodali, S.; Galgoci, A.; Wang, J.; Singh, S. B. J. Nat. Prod. 2005, 68, 1437. (c) Oshima, Y.; Konno, C.; Hikino, H.; Matsushita, K. Heterocycles 1980, 14, 1287. (d) Su, C.-R.; Kuo, P.-C.; Wang, M.-L.; Liou, M.-J.; Damu, A. G.; Wu, T.-S. J. Nat. Prod. 2003, 66, 990. (e) Ngameni, B.; Ngadjui, B. T.; Folefoc, G. N.; Watchueng, J.; Abegaz, B. M. Phytochemistry 2004, 65, 427.
O
O
O
53a
OH
OH
O
52
TFA-TFAA
acetone, rt, 48h
O
O
O
reduction
OH
H
O OH OH
+
53a 53b 53c
Attempted reductions of 2,2-dimethyl-1,3-benzodioxan-4-one subunit
O
O
O
OH
H
O OH OH
+
53a
53b 53c
or LiAl(OtBu)3H
X
OH
H
O OH OH
+
53b 53c
TolueneX
Red-Al
NaBH4
Attempted reductions with weakly nucleophilic reagents
O
O
O
OH
H
O OH OH
+
53a
53b 53c
OH OH
53c
OH OH
53c
LAH(1eq.)
-780C,
0.5h
excessLAH
rt
excess
LiBH4
(84%)
(83%)
Attempted reductions with LAH
O
O
O
OH
H
O OH OH
+
53a
53b 53c
LAH (1eq.)
BH3.SMe2
or DIBAL-H
OH
H
O
53b
O
O
O
53a
OH
H
O
53b
OH
H
O
53b
OH
H
O
53b
OH
H
O
53b
(45%)
(45%)
(68%)
X
BH3.SMe2
1.5eq. DIBAL-H
CH2Cl2
CH2 Cl2
1.5eq. DIBAL-H
3eq. DIBAL-H
Toluene
Attempted reductions with electrophilic reagents
Reduction of 1a with various reducing reagents
# Reagent Equiv Solvent Temp. Product Yield %
1 NaBH4 2 EtOH rt 53a NR
2 Red-Al 2 toluene rt→110 oC decomposed NA
3 LiAl(OtBu)3H 2 THF rt 53a NR
4 LiAlH4 1 THF -78 oC→ rt 53b and 53c (1:1) 81
5 LiAlH4 4 THF rt 53c 84
6 LiBH4 4 THF rt 53c 83
7 BH3•SMe2 2 THF rt 53a NR
8 DIBAL-H 1.5 toluene -78 oC 53b 45
9 DIBAL-H 1.5 CH2Cl2 -78 oC 53b 45
10 DIBAL-H 3 CH2Cl2 -78 oC 53b 68
O
O
O
DIBAL-H
OH
H
O
R1
R2
R3R1
R2
R3
59-94%
-780C
R1 R2 R3
OBnCl
BrI
OHOTfOBnOMOMOTBSiPrO-allylvinylF
Reduction of orthogonally protected phenols with DIBAL-H
Starting Material Product (Yield) Starting Material Product (Yield)
O
O
O OH
H
O
OH OH
39%54a 55a
O
O
O OH
H
O
OBn91%
OBn
54b 55b
O
O
O OH
H
O
OMOM OMOM
94%54c 55c
O
O
O OH
H
O
O O
54d 55d
O
O
OOH
H
O
OTfOTf
90%54e 55e
54f
O
O
O OH
H
O
BnO BnO75%55f
71%
Starting Material Product (Yield) Starting Material Product (Yield)
O
O
O OH
H
O
F F70%54g 55g
O
O
O OH
H
O
O
O
O OH
H
O
Br
Cl
Br
Cl
75%
71%
54h
54i
55h
55i
O
O
O
OTBS62%
O
O
O
OH54l 54a
O
O
O
NR
OH
H
O
54k 55k
O
O
O OH
H
O
81%54j 55jI I
Corey, E. J.; Jones, G. B. J. Org. Chem. 1992, 57, 1028.
O
O
O OH OH
R1
R2
R3 R1
R2
R3
53-93%
LiAlH4
-780C rt
R1 R2 R3
OBnCl
BrI
OHOTfOBnOMOMOTBSiPrO-allylvinylF
Reduction of orthogonally protected phenols with LAH
Starting Material Product (Yield) Starting Material Product (Yield)
O
O
O OH OH
O
O
OOH OH
OH
OBn
OH
OBn
68%
61%
54a
54b
56a
56b
O
O
O OH OH
OMOM OMOM93%54c 56c
O
O
OOH OH
OTBSOTBS
53%54e 56e
O
O
OOH OH
62%54f56f
O
O
O OH OH
O O68%54d 56d
Starting Material Product (Yield) Starting Material Product (Yield)
O
O
O OH OH
O
O
O OH OH
F
BnO BnO
F
71%
88%
54g
54h
56g
56h
O
O
O OH OH
Br Br 72%54i 56i
O
O
O OH OH
Cl Cl65%54j 56j
O
O
O OH OH
83%54k 56kI
O
O
O OH OH
OTf OTf-----54l
We have developed two complementary procedures that selectively allow for the synthesis of either substituted salicylaldehydes or corresponding 2-hydroxy benzyl alcohols upon treatment of 2,2-dimethyl-1,3-benzodioxan-4-one functional group with DIBAL-H or LAH respectively.
O
O
OOH
H
O
R1 R3
OH OH
LiAlH4 DIBAL-H
-78 oC rt -78 oC
R1
R2
R3R1
R2
R3R2
Bajwa, N.; Jennings, M. P. J. Org. Chem. 2006, 71, 3646.
Project III: An Efficient 1,2-chelation controlled reductions of protected hydroxy ketones via
Red-Al
RR'
O
MOMO
RR'
OH
MOMO
RR'
OH
MOMO
+Red-Al
R = alkyl, alkenyl, alkynyl, arylR' = alkyl, alkenyl, alkynyl, aryl
dr = 5-20:1 / anti:syn
Red-Al: Na+H2Al-(OCH2CH2OMe)2
RR'
O
PGO
RR'
OH
PGO
RR'
OH
PGO
+
1,2-chelationcontrolled reduction
PG = Protecting Groupanti- syn-
R R'
PGO O
R R'
PGO OM+
M +
H-
Mechanism of 1,2-chelation controlled reductions
RR'
O
OH
RR'
OH
OH
Zn(BH4)2
Limitations:
1. Lengthy preparation time2. Limited availability3. Lack of stability in ethereal solvents
RR'
O
OH
RR'
OH
OH
LiAlH4
LiBH4
?
Nakata, T.; Tanaka, T.; Oishi, T. Tetrahedron Lett. 1983, 24, 2653.
OH
OMOM
TBSO
6:1
E:Z, 15:1
O
OMOM
TBSO E:Z, 15:1
27 28
# Reagent Temp. anti syn yield
1 NaBH4 0 1.4 1 882 LiBH4 -40 1 2.5 803 LiAlH4 0 2.3 1 864 Red-Al 0 6 1 84
a) Red-Al, Toluene
84%
Chelation controlled reduction of hydroxy ketone
Burke, S. D.; Deaton, D. N.; Olsen, R. J.; Armistead, D. M.; Blough, B. E. Tetrahedron Lett. 1987, 28, 3905.
O
MOMO
OH
MOMO
+Red-Al
57a 57b
Solvent
0oC -78oC
OH
MOMO57c
Solvent: toluene diethylether THF DME MTBE CH2Cl2
hexane
Reductions of MOM-protected benzoins with Red-Al
# Solvent Temp., oC anti syn Yield %
1 toluene 0 >20 1 96
2 toluene -25 >20 1 96
3 toluene -50 >20 1 96
4 toluene -78 >20 1 91
5 Et2O 0 >20 1 94
6 THF 0 17 1 82
7 DME 0 8 1 37
8 MTBE 0 >20 1 92
9 CH2Cl2 0 >20 1 95
10 hexanes 0 18 1 91
Anti/Syn ratios were determined on the crude product. Yields are of the isolated and purified compounds.
O
PGO
OH
PGO
+Red-Al
Toluene, 0 oC
OH
PGO
# Protecting Group anti syn Yield %
1 MOM (57a) >20 (57b) 1 96
2 BOM (58a) >20 (58b) 1 93
3 THP (59a) 7 (59b) 1 91
4 MEM (60a) >20 (60b) 1 89
5 SEM (61a) >20 (61b) 1 94
6 Me (62a) >20 (62b) 1 89
7 TBS (63a) 2 (63b) 1 92a
All reductions ran at 0 oC in toluene. Anti/Syn ratios were determined on the crude product. Yields are of the isolated and purified compounds. a Concomitant desilylation was observed under the reaction conditions.
R
O
MOMO
OH
MOMO
R
OH
MOMO
RRed-Al
+CH2Cl2, -78oC
R = SpR = Sp2
R = Sp3
O
MOMO
65a
O
MOMO
66a
O
MOMO 67a
O
MOMO
68a
O
MOMO
OH
MOMO
O
MOMO
OH
MOMO
O
MOMO MOMO
OH
O
MOMO
OH
MOMO
starting material
product anti/synentry
1
2
3
4
12:1
9:1
5:1
9:1
88%
88%
84%
93%
65a
66a
67a
68a
65b
66b
67b
68b
Anti/Syn ratios were determined on the crude product. Yields are of the isolated and purified compounds. All reductions ran at –78 oC in DCM.
R
OMOM
O
OMOM
HO
R
OMOM
HO
RRed-Al
+CH2Cl2, -78oC
R = SpR = Sp2
R = Sp3
OMOM
O
69a
OMOM
O
70a
OPG
O71a
OMOM
O
72a
OMOM
O
OMOM
HO
OMOM
O
OMOM
HO
OR
O HO
OR
OMOM
O
OMOM
HO
starting material
product anti/synentry
1
2
3
4
19:1
12:1
8:1
11:1
71%
85%
88%
80%
R=MOM
69a
70a
71a
72a
69b
70b
71b
72b
Anti/Syn ratios were determined on the crude product. Yields are of the isolated and purified compounds. All reductions ran at –78 oC in DCM.
starting material
product anti/synentry
1
2
3
5
OMOM
TBSO
OOMOM
TBSO
OH
10:1
O
OMOM
OH
OMOM
OMOMO OHMOMO
11:1
91%
1:2
O
OSEM
OH
OSEM
12:1
4
O
OBOM
OH
OBOM
12:1
82%
89%
27a
73a
74a
75a
76a
27b
73b
88%74b
84%75b
76b
Anti/Syn ratios were determined on the crude product. Yields are of the isolated and purified compounds. All reductions ran at –78 oC in DCM.
• We have shown that Red-Al is an efficient chelation controlled reducing reagent for acyclic acetal (i.e. MOM, MEM, SEM, and BOM) protected α-hydroxy ketones.
RR'
O
MOMO
RR'
OH
MOMO
RR'
OH
MOMO
+Red-Al
R = alkyl, alkenyl, alkynyl, arylR' = alkyl, alkenyl, alkynyl, aryl
dr = 5-20:1 / anti:syn
Bajwa, N.; Jennings, M. P. J. Org. Chem. 2008, 73, 3638.
Conclusions:
• We have accomplished the synthesis of epi-aigialomycin D and deoxy-aigialomycin C via
a diastereoselective RCM macrocyclization protocol.Bajwa, N.; Jennings, M. P. Tetrahedron Lett. 2008, 49, 390.
Bajwa, N.; Jennings, M. P. J. Org. Chem. “Manuscript in Progress”.
•Two complementary procedures have been developed that selectively allow for the synthesis
of both substituted salicylaldehydes as well as 2-hydroxy benzyl alcohol subunits.
Bajwa, N.; Jennings, M. P. J. Org. Chem. 2006, 71, 3646.
•Red-Al is an efficient chelation controlled reducing reagent for acyclic acetal (i.e. MOM,
MEM, SEM, and BOM) protected α-hydroxy ketones.Bajwa, N.; Jennings, M. P. J. Org. Chem. 2008, 73, 3638.
Acknowledgements• Research Advisor: Dr. Michael P. Jennings
• Committee Members Dr. Silas C. Blackstock Dr. Kevin H. Shaughnessy Dr. Timothy S. Snowden Dr. Kevin W. Hunt
• NMR Lab Manager Dr. Ken Belmore
• Mass Spec Lab Manager Dr. Qiali Liang
• Group Members: Dr. Fei Ding Dr. Kailas B. Sawant Mr. James A. Reed Dr. Ryan T. Clemens Dr. Jesse D. Carrick Mr. Dionicio Martinez-Solorio Ms. Amanda Joy Mueller-Hendrix Ms. Aymara Albury Ms. Dripta De Joarder
• The University of Alabama $$
• Friends and Family
Additional Slides
O
O
O
R1
R2
R3
OH
OH
O
R1
R2
R3
TFA-TFAA
acetone, rt, 48h
Xa-Xj
R1 R2 R3
OBnCl
BrI
OHOTfOBnOMOMOTBSiPrO-allylvinylF
Synthesis of starting substrates
O
O
O
OH
OH
OH
O
OH
TFA-TFAA
acetone, rt, 48h
XX
Synthesis of 5-hydroxy-2,2-dimethyl-1,3-benzodioxin-4-one
O
O
O
OH
O
O
O
OTf
O
O
O
OBn
O
O
O
OMOM
O
O
O
OTBS
XX
O
O
O
O
a
bc
d
e
a)MOMCl, Hunig's base, CH2Cl2, 0oC rt, b)TBSCl, imidazole,DMF,0oC rt, c)BnBr, NaH,
THF:DMF (1:1) d)Tf2O, pyridine, 0oC, e)allylbromide, NaH, THF:DMF (1:1).
O
O
O
OH
OH
O
R1
R2
R3
R4
O
O
O
F
O
O
O
Br
O
O
O
I
O
O
O
Cl
TFA-TFAAacetone, rt, 48h
O
O
O
OHHO
O
O
O
OHBnO
O
O
O
OTfBnO
O
O
O
BnO
R
O
MOMO
OH
MOMO
R
OH
MOMO
RRed-Al
+CH2Cl2, -78oC
R = SpR = Sp2
R = Sp3
O
MOMO
65a
O
MOMO
66a
O
MOMO 67a
O
MOMO
68a
H
O
MOMO
OH
MOMOnBuLi
a) HPh
53%AA BB
O
MOMO
b) Swern
82%
65a
OH
MOMO44%
OH
MOMO
BB
a) Red-Al
CC
b) Dess-MartinO
MOMO88%
66a
Synthesis of ketones 65a & 66a
O
MOMO
b) Dess-Martin
80%
67a
OH
MOMO
a) Lindlar, H2
50%
OH
MOMO
BB DD
O
MOMO
b) Dess-Martin
67%
68a
OH
MOMO
a) Pd-C
H2, 78%
OH
MOMO
BB EE
Synthesis of ketones 67a & 68a
R
OMOM
O
OMOM
HO
R
OMOM
HO
RRed-Al
+CH2Cl2, -78oC
R = SpR = Sp2
R = Sp3
OMOM
O
69a
OMOM
O70a
OPG
O 71a
OMOM
O72a
OMOM
TBSO
MOMCl, DIPEA
HH
TBAF
H
O
TBSO
FF
O
HMgBr
b) TBSCl, imidazole
a)
c) O3, DCM
OMOM
OH
II
Synthesis of intermediate II
OH
TBSOnBuLi
HPh
GG
OMOM
O
OMOM
OH
Dess-Martin
II69a
OMOM
OH
a) Pd/C,OMOM
OH
LLII
H2
OMOM
O
d) Dess-Martin
72a
Synthesis of ketones 69a & 72a
OMOM
OH
a) Red-AlOMOM
OH
JJII
OMOM
O
b) Dess-Martin
70a
OPG
OH
a) Lindlar OPG
O
H2
OMOM
OH
b) Dess-Martin
KK 71a
PG = MOM
II
Synthesis of ketones 70a & 71a
