Total Synthesis from India
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Transcript of Total Synthesis from India
Total Synthesis from IndiaRohan Merchant Baran Group Meeting07/11/2015
Facts:
Capital: New DelhiIndependence day: 15th August 19477th largest countryPopulation: 1.252 billion (2013)World's largest democracyLargest City: Mumbai (18.4 million)GDP: $2.3 trillion (7th)National Language: Hindi122 major languages, 1599 other languages3rd largest standing armyLargest flim industry in the world Prof. Goverdhan Mehta, FNA, FRS (1943–)
BSc, MSc: University of RajasthanPhD: University of Poona (Prof. Sukh Dev)Post–doc: Michigan State University (Prof. Don Farnum) Ohio State University (Prof. Paul Gassman)
Lecturer: Indian Institute of Technology, Kanpur (1969–1977)Professor: University of Hyderabad (1977–1998) Indian Institute of Science, Bangalore (1998–2005)
Research Interests: total synthesis, strained polylic systems
>450 publications
Prof. Adusimilli Srikrishna, FASc, FNASc, FNA (1955–2013)
MSc: Andhra UniversityPhD: University of Hyderabad (Prof. Goverdhan Mehta)Post–doc: University of Chicago (Prof. Phil Eaton) Columbia University (Prof. Gilbert Stork)
Professor: Indian Institute of Science, Bangalore (1989–2005)
Research Interests: total synthesis, radical cyclisations
>280 publications
Brief timeline:
1909: Indian Institute of Science, Bangalore established1927: Indian Chemical Society established in Kolkata1927: Journal of Indian Chemical Society started to publish1961: First Indian Institute of Technologies established2015: Budget of Ministry of Science and Technology – $1.5 billion (2014 NIH budget: $30.1 billion)
Total Synthesis from IndiaRohan Merchant Baran Group Meeting07/11/2015
A. Srikrishna, JOC, 1993, 58, 2509
OMe
Me
i) PhMgBr, Et2Oii) PCC, silica gel, CH2Cl2
85%
PhMe
Me
O NBS,CH2Cl2, MeOH
75%, dr 1:1
PhMe
Me
O
OMeBr
tBuOK,THF, tBuOH, rt
75%
O
OMeMe
MePhBBr3,
CH2Cl2, –60 °C
O
BrMe
MePh
OPh Me
BrMe
78%, 3:1
O
MePh
MeO2C
CO2Me
AIBN, nBu3SnH,C6H6, reflux
O
MePhH
85%
O
OMeMe
MeO
Me
Me
BBr3,CH2Cl2, –60 °C
O
Me
Me
Br78%
CO2Me
AIBN, nBu3SnH,C6H6, reflux
O
Me
MeO2C50%
O
Me NPNP
Me
Me
Me
20%
O
BrMe
Me
O
Me
Me
BrHH
CO2Me
+vs.
+
NC
Me
9–isocyano–pupukeanane
Me
MeMe
MeO
Me(R)–carvone
LiHMDs, –78 °C
OMeMe
O
60%
OMe
MeMe
CO2Me
1. NaOH, MeOH: H2O (1:1)2. i) (COCl)2, C6H6, rt ii) CH2N2, CH2Cl2, 0 °C O
Me
MeMe
ON2
83%(2 steps)
Rh2(OAc)4, CH2Cl2,
reflux
OMe
MeMe
89%
10% Pt–C, H2,EtOH
96%
O
OMe
Me
MeMe
O9–epineo–
pupukeanane–2,5–dione
1. (CH2OH)2, pTSA, C6H6, reflux2. LiAlH4, THF, 0 °C
79%(2 steps)
Me
Me
MeMe
OO
OH
NaH, TBAI, CS2,MeI, THF, 60 °C
Me
Me
MeMe
OO
OCS2Me
i) nBu3SnH, AIBN conditionsii) 3N HCl, rt
Me
Me
MeMe
Me
Me
MeMeOMe
conditions
O O
C6H6 (0.026 M), refluxC6H6 (0.008 M), reflux PhMe (0.026 M), reflux
91%N/A73%
yield ratio (A:B)3:24:11:0
neopupukean–4–one
+
1. NaBH4, MeOH, 0 C2. MsCl, Py, DMAP, rt
80%
Me
Me
MeMe
MsO
Me
Me
MeMe
NCS
76%(2 steps)
KSCN,acetone,
80 °C
4–thiocyanatoneo–pupukeanane
A. Srikrishna, JOC, 2001, 66, 4379
(S)–carvone
A B
Me
Total Synthesis from IndiaRohan Merchant Baran Group Meeting07/11/2015
A. Srikrishna, J. Chem. Soc. Perkin Trans. 1, 1999, 2877
Me
Me
OMe Me
i) O3/O2, MeOH, –70 °Cii) NaBH4
Me
OH
Me Me
Hg(OAc)2, 170 °C
OEt
Me Me
MeCHO
MgBr1.
THF, 0 °C2. PCC, NaOAc, CH2Cl2, rt
Me Me
Me O
Me Me
Me O BF3
Me Me
Me O BF3Me
MeMe O BF3
Me
Me OO
MeMe
Me
MeMe
Me
myltaylene
β–ionone
64%
42%(2 Steps)
BF3•Et2O, CH2Cl2, 0 °C
60%
Ph3PMeBr, tAmOK,
C6H6, 0 °C71%
O
MeCO2Et
11 Steps
OMe
MeO N2
OMe
MeO
HClO4,CHCl3, "cold"
88%
10% Pd–C, H2EtOH95%
OMe
MeO
HEtO3BF4,CH2Cl2, rt
80%
OMe
Me
U. Ghatak, JACS, 1976, 3721 JOC, 1978, 43, 4598
H
T. Kasturi, JOC, 1988, 53 3178
OMe
MeO
OH
OMe O
OMe
+Triton B
xylene, reflux76%
OMe
MeO OMe
EtO
O
HCl,MeOH, rt
38%27%
OMe
OEt
ArO
OEt
ArHO
O
EtHO
10% Pd/C, H2, MeOH
97%Ar
O
EtHOAr
MeMgI,THF, 0 °C
EtHOAr
MeOH
96%pTSA,
C6H6, reflux or
BF3•Et2O, CH2Cl2, rt
MeEt O
Ar97%
RuCl3,NaIO4,CCl4/MeCN/H2O
MeEt O
CO2H
1. CH2N22. MeMgI, THF, 0 °C
MeEt O
OH
90%
MeEt O
Me
MeEt O
Me
Me7 : 3
+
MeEt O
Me
Me
MeEt O
Me
Me3 : 2
PtO2/NaBH4EtOAc/AcOH
copacamphor ylangocamphor
SOCl2, pyridine, 0 °C
92%
60% 40%
+
88%(2 Steps)
61%
Hagemann's ester
O
Total Synthesis from IndiaRohan Merchant Baran Group Meeting07/11/2015
G. Mehta, J. Chem. Soc. Perkin Trans. 1 , 1991, 395
O
MeMgI, Et2O52% Me
Cl
CNPhMe, 80 °C
43%
ClCN
Me MeClCN
Na2S•10H2O, EtOH, 60 °C58%
+
Me Me+
O
O4 : 1
hν,acetone, 45 min
50%Me
i) Li, NH3 (l), THF, NH4Clii) PCC, CH2Cl2, 4A MS
75%, 1:1 dr
OtBuOK, MeI,
THF65%
Me
O
Me Me
Me
O
Me Me LiHMDs, MeI,THF, 0 °C
60%Me
Me Me
MeMe
Me Me
Me
O
1. LiAlH4, Et2O2. POCl3, Py, DBU, CH2Cl2
26%(2 Steps)
modhephene
i) EtAlCl2, CH2Cl2 –78 °C, 45 minii) NaBH4, aq. NaOH
36%O Me
Me
Me N3 N
Me
HO MeMeH
EtAlCl2
NMe
Me
Me N2
LAO NMe
Me
N2
LAO
MeN
Me
HO MeMeH
N
Me
HO MeMeH
NaBH4
S. Baskaran, Org. Lett., 2003, 5, 583
1,2–acyl shift
O O
Me Me
Me
OHC
1. Mg,THF,2. PDC, CH2Cl2
Br
74%(2 Steps)
O O
Me Me
Me
O1. NaH, MeI, THF2. HClO4, MeOH/H2O
75%(2 Steps)
OH OH
Me
O
MeMe
NaIO4,MeCN/H2O71%
O
Me
O
MeMe
OZn, NH4Cl,MeOH/H2O
78%
MeO
O
O
Me Me
MeO
O
Me Me
HOH
MeO
O
Me Me
1. Jones [O]2. THF/H2O, Δ
1. (CH2OH)2, pTSA, C6H6, reflux2. NaBH4, THF/H2O3. HCl, acetone/H2O
73%
MeO
HO
Me MeO
OH
HH
Me
MeMe
hν, C6H6,30 min
55%
hν,acetone, 1 h
78%
O
H H
OHMe
MeMe
Bu3SnH, AIBN,C6H6, Δ
70% O
H H
OH
MeMe
coriolin
64%
O
H
OHMe
MeMe
OHO
O
V. Singh, Chem. Commun., 1999, 2519
Van Hijfite et al.J. Org. Chem., 1987, 52, 4647
1,3–acyl shift
1,2–acyl shift
HMe
Total Synthesis from IndiaRohan Merchant Baran Group Meeting07/11/2015
G. Mehta, JACS, 1986, 108 , 3443O
OMe
Me+
C6H6, reflux, 2 h
90%
MeO
O
Me hυ,EtOAc, 30 min
85%
Me
OO
Me
500 °C
O O
H H
MeMeH
quant.
PhCO2Bn,317 °C, 12 min
O O
H H
MeMeH
37%O O
H H
MeMeH
10% Pd/C,H2, EtOAc
95%
NaH, MeI,THF, reflux 65%
O O
H H
MeH MeMe
1. MeMgI, Et2O, rt2. POCl3, Py, rt
68%(2 steps) O
H H
MeH MeMe
Me
Li, NH3 (l),MeOH
63%OH
H H
MeH MeMe
Me
i) mCPBA, CH2Cl2, rtii) BF3•Et2O, CH2Cl2, 0 C
80%
OH
H H
MeH MeMe
MeO
i) LDA, TMSCl, THFii) Pd(OAc)2, MeCN, rt
90%OH
H
MeH MeMe
MeO
i) LDA, PhSeBr, THF, –78 °Cii) H2O2, AcOH, THF
35%
OH
H
MeH MeMe
Ikegami et al. Tetrahedron,
1981, 37, 4411coriolin
OH
H
MeH MeMe
OO
OOH
4 stepsFor more info on
triquinanes;Karin Weidner's GM on 'Triquinanes: Hirsutene,
Isocomene, Modhephene'O
Me
Me 1. i) 9–BBN, THF, rt ii) H2O2, NaOH2. PCC, CH2Cl2, 4A MS
63%(2 Steps)
Me
OMe
LiHMDs,THF, –78 °C
Br
MeO
Me
75%
PdCl2, CuCl, O2,
DMF/H2O, rt80%
Me
OMe
Me
O
1. KOH, MeOH, reflux2. NaH, THF, 70 °C
57%(2 Steps)
Me
Me
O
H
85% HCO2H/BF3•Et2O,
90 °C55%
H
HMe
O Me
1. Ph3PCH2OMe, tAmONa, Et2O, rt2. HClO4, Et2O, rt3. KH, MeI, THF, –5 °C
50%(3 Steps)
H
HMe
Me
i) N2H4, (CH2OH)2, (CH2CH2OH)2O, 180 °Cii) Na, 70 °C
33%MeOHC
H
HMe
MeMeMe pentalenene
G. Mehta, JACS, 1986, 108 , 8015
longipenol
G. Mehta, JOC, 1990, 55, 3568
O OH
HRuO2, NaIO4,
CCl4, MeCN, H2O70%
OH
HO
HH
H
H
OMeMeO OMe
MeO
62%(2 Steps)
H
HO
H
OHC
H
HO
H
OMe
O OH
HMe
HO
Me
HMe
1. MeOH, PPTS, (MeO)3CH2. i) LiHMDs, TMSCl, THF ii) TiCl4, CH2Cl2
1.3 : 1
+A B
CD
photo–thermal olefin metathesis
5 Steps
Total Synthesis from IndiaRohan Merchant Baran Group Meeting07/11/2015
G. Mehta, Org. Lett., 2004, 6, 3985
O
O
MeOH, 0 °C98%
O
OH
H O
OH
H
O
H2O2, Na2CO3,acetone, 0 °C
92%
1. formalin, DBU2. TBS protection3. formalin, DBU4. NaBH4, MeOH
OH
OOTBSO
HO
Ph2O, 220 °C
OH
O
HOTBSO O 96%
50%(4 Steps)
O
O
HO OC5H11
DMP,CH2Cl2
O
O
O OC5H11 CO2tBu
Me
O
O
O OC5H11
CO2tBu
Me
O
O
O
O
C5H11
CO2tBu
Mesilicagel75%
O OHO
C5H11H
C5H11
O OO Me
CO2tBu
OMe
CO2tBuO
TFA, CH2Cl2
quant.
Me
CO2tBu
O OHO
C5H11H
C5H11
O OO Me
CO2H
OMe
CO2HO
torreyanic acid
G. Mehta, Angew. Chem. Int. Ed. 2006, 45, 953
OMe
MeO
OMe
MeOO
Me
HO
Me Me
1. PDC, CH2Cl22. Ph3PCH3Br, tBuOK, Et2O
58%(2 Steps)
OMe
MeOO
Me
Me Me
Grubbs' 1st Gen,CH2Cl2, reflux76%
Cl
Cl
hυ65%
OMe
OO
Me Me
OMe
Me
Me
OO
Me Me
Me
Me
Cl
Cl2 : 1
OMe
OO
Me Me
Me
Me
Cl
Cl
NaC10H8,–60 °C
OMe
OO
Me Me
Me
Me
OTBSMe
Me
Me
OH
MeOHClO4,
CH2Cl2/THF(10:1)
OTBSMe Me
MeOMeO
OTBSMe Me
MeOO
PCC, CH2Cl2
62%(2 Steps)
OTBSMe Me
OO
OMe
OH i) O3, MeOH, –78 °Cii) NaBH4, MeOH, –78 °C
45%
OHMe Me
OO
OMe
OOH
Me
OO
OMe
OOMe Me
OO
OMe
OOMeHO
+
70%
1. PCC, CH2Cl22. TBAF, AcOH, THF
68%(2 Steps)
DMDO95%
pTSA, CH2Cl2
80%
merrilactone A
6 Steps
4 Steps
9 Steps
NSO2Ph
OH
NSO2Ph
OTBS
Me
MeOH
MsCl, Et3N,THF, 0 °C
81%N
SO2Ph
OTBS
Me
NH
OTBS
Me
MeOH
Na/Hg, Na2HPO4,MeOH, rt
BF3•Et2O, CH2Cl2, rt
78% dr 4:1 (α:β)N
SO2Ph
OH
N
Me Me
OH
Me
N
R
N SO2Ph
RMe
Me
Me
N-
R
Me
Me
MeN
R
97%
+
*
Cu(OTf)2, CH2Cl2, rt 78%, dr >19:1 (α:β)
1. IBX, EtOAc, reflux2. NHMe2, NaCNBH3, AcOH, MeOH, rt3. Na/Hg, Na2HPO4, MeOH, rt
Flinderole B (α–Me)+
Flinderole C (β–Me)
59% (3 Steps)
D. Dethe, JACS, 2011, 133 , 2864
NH
OH
Me
MeOH
BF3•Et2O,CH2Cl2, 15 min
82% NH
D. Dethe, JOC, 2013, 78, 10106
N
Me
HH
H
OHMe
Me
44%dr 5:1 (α:β)
38%dr 4:1 (α:β)
A
+ A
OH
Total Synthesis from IndiaRohan Merchant Baran Group Meeting07/11/2015
tryptophol
4 Steps