total synthesis from india

7
Total Synthesis from India Rohan Merchant Baran Group Meeting 07/11/2015 Facts: Capital: New Delhi Independence day: 15 th August 1947 7th largest country Population: 1.252 billion (2013) World's largest democracy Largest City: Mumbai (18.4 million) GDP: $2.3 trillion (7 th ) National Language: Hindi 122 major languages, 1599 other languages 3 rd largest standing army Largest flim industry in the world Prof. Goverdhan Mehta, FNA, FRS (1943–) BSc, MSc: University of Rajasthan PhD: 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 University PhD: 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 established 1927: Indian Chemical Society established in Kolkata 1927: Journal of Indian Chemical Society started to publish 1961: First Indian Institute of Technologies established 2015: Budget of Ministry of Science and Technology – $1.5 billion (2014 NIH budget: $30.1 billion)

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Page 1: 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)

Page 2: Total Synthesis from India

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

Page 3: Total Synthesis from India

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

Page 4: Total Synthesis from India

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

Page 5: Total Synthesis from India

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

Page 6: Total Synthesis from India

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

Page 7: Total Synthesis from India

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