You are on page 1of 71

Organic Photochemistry

Introduction to Photochemistry Classifications of Photochemical Reactions Application of Photochemistry in Organic Synthesis

Energies 100 kcal/mol= 4.3 eV= 286 nm= 35000 /cm (near UV)nano= 10-9 286 kcal/mol= 12.4 eV= 100 nm= 100000 /cm (far UV) Typical Bond Energies C-H = 110 kcal/mol C-C = 80 C=C = 150 C=O = 170 Uv light 150 -40 nm wavelength, so this is sufficient energy to break bonds knock electrons out of bonding orbitals (electronic excitation).

Chemically useful light is generally in the range of 200-400 nm Often employ filters to regulate the wavelength of the radiation

T*

T*

T*

T*

T*

T T-T* (S1)

T T-T* (T1)

ground state (S0)

n-T* (S1)

n-T* (T1)

A Jablonski diagram, named after the Polish physicist AleksanderJab o ski, is a diagram that illustrates the electronic states of a molecule and the transitions between them. The states are arranged vertically by energy and grouped horizontally by spin multiplicity. Radiative transitions are indicated by straight arrows and nonradiative transitions by squiggly arrows. The vibrational ground states of each electronic state are indicated with thick lines, the higher rotational states with thinner lines.

Physical Processes Undergone by Excited Molecules


So + hv --- S1 Excitation S1v -- S1 + heat Vibrational Relaxation S1 ----- So + hv Fluorescence S1 ---- So + heat Internal Conversion S1 --- T1 Intersystem Crossing T1v -- T1 + heat Vibrational Relaxation T1v -- So + hv Phosphorescence T1 --- So + heat Intersystem Crossing S1 + A (So) --- So + A (S1) Singlet-Singlet Energy Transfer T1 + A (So) -- So + A (T1) Triplet-Triplet Energy Transfer

Why Use Photochemistry


Overcome large kinetic barriers in a short amount of time Produce immense molecular complexity in a single step Form thermodynamically disfavored products Allows reactivity that would otherwise be inaccessible by almost any other synthetic method The reagent (light) is cheap, easily accessible, and renewable

Drawback
Reactivity is often unpredictable Many substrates are not compatible Selectivity and conversion are sometimes low

Chemical Processes undergone by Excited Molecules


A-B. + E+ F
.

(A-B- ) (A-B- ) (A-B- ) (A-B- ) (A-B- ) (A-B- ) (A-B- ) A RH

imple leavage Decomposition Intramolecular Rearrangement Photoisomerization Hydrogen Atom Abstraction Photodimerization Photosensitization

A- -B A-B- ' A-B- -H + R. (AB )2 AB + A*

1) -Cleavage (Norrish type I reaction). In solution the radicals undergo further reactions to give products.

hv 0n

h hv h

h C

2) Hydrogen Abstraction followed by cleavage = Norrishtype II cleavage.The radicals can abstract a Hydrogen atom from a donor. The resulting radicals can then undergo further reactions.

hv 1 % H H

9 %

An intramolecular example:

Chang, S.-Y.; Huang, S.-L.; Villarante, N. R.; Liao, C.-C. Eur. J. Org. Chem. 2006, 4648-4657.

Chemoselective Photorearrangement of Diazinobarrelenes. Deuterium Labeling Study

Cheng, A.-C.; Chuang, G.; Villarante, N.; Liao, C.-C. J.Org. Chem. 2007, 72, 6 0- 6 7

Substituent Effects on the Bridging Modes of Photochemical Rearrangements of Pyrazino-, quinoxalino-, and benzoquinoxalinobarrelenes

Chen, A.-C.; Lin, S.-Y.; Villarante, N.R.; Chuang, G.J. Tetrahedron, 2008, 62, 8 088 21

Recent Advances in the Chemistry of Masked o-Benzoquinones

Nelson R. Villarante
Department of Chemistry National Tsing Hua University Hsinchu 300, TAIWAN

28

Generation of Masked oBenzoquinones


OMe O [Oxidant] 'O OMe O ' O

Oxidant : TTN = Thallium(III) nitrate [Tl(NO3)3] BTIB = Bis(trifluoroacetoxy)iodobenzene [PhI(OCOCF3)2] DAIB = Diacetoxyiodobenzene [PhI(OAc)2]

Self-dimerization of MOBs

The formation of a dimer occurs via Diels-Alder reaction between two molecules of MOB The reaction is highly siteselective regioselective stereoselective

Out of eight-possible isomers, only a single isomer is observed

Ref: 1) Anderson, G.; Berntsson, P. Acta Chem. Scand. B 1975, 29, 48. 2) Liao, C.-C.; Chu, C.-S.; Lee, T.-H.; Rao, P. D.; Ko, S.; Song. L.-D.; Shiao, H.-C. J. Org. Chem. 1999, 64, 4102.
30

Dimerization (DI) vs Diels-Alder Reaction (DA)


RateDI RateDA RateDI RateDA
DI

DA

Dieno

ile

DI DA

Dieno

ile

as ed - enzo

inone

31

Intermolecular Diels-Alder Reactions of MOBs


X OMe Rn O X R OMe OMe O
R1 = R2
1 2

OMe X OMe X
1 2

R = R = CH3 C60
=C H

X = CH2, O, NBz,

Rn O

OMe

R = R = CH3 X = O, NH OR
1

OMe R OH X OMe

DAIB R MeOH, 0 C

OR2 O

O
R1 = R2

OMe

=C H

OMe

3 CH

O X R

=C H2 C

HX =C H HC

R1 = R2 = CH3 CH2=CHX X OMe R OMe O

O OMe

Rn O

OMe

O H MeO OMe

X = CHO, COMe, CO2CH3 h, OBn, h, ePh

32 Ref: Liao, C.-C.; Peddinti, R. K. Acc. Chem. Res. 2002, 35, 856.

Intramolecular Diels-Alder Reactions of MOBs


( )n ( )n X OX O OMe OMe R1 = R2 = CH3 ( )n R3 = n=1-3 X = H or TBS R4 = H R1 = CH3 R2 = CH2CH=CH2 R4 OR1 OR2 O R3 R1 = R2 = CH3 R3 = H R4 = X = TBS H OX O 4 eq. SmI2/-78 oC THF/MeOH MeO MeO O OX + O MeO MeO OX OX H OBz O OX BzO H OX R1 = CH3 R2 = CH2CH=CHCH=CHX + OX O OMe OMe
+

O OMe O X

H O OMe O

O R O OMe

OX

33

Ref: Liao, C.-C.; Peddinti, R. K. Acc. Chem. Res. 2002, 35, 856

Diastereoselective Intermolecular Diels-Alder Reactions of MOBs


O R1 R
2

O Xc R2 R1 O OMe R
3

O R1
+

O O OMe OMe CH2Cl2, r

Xc R2

O MeO

R3 R4

R4

OMe

R4 3 R OMe

1a-k R1 1a 1b 1c 1d 1e 1f 1g 1h 1i 1j 1k 34 H H H H H H H Me H H R2 H H H H H H Ketal Br Me Me H R3 COMe CO2Me Ketal TMS Br H Br Ketal Br TMS Br R4 H H H H H OMe H H H H H

2a-k ( ajor) t/h 1 1 48 48 36 72 24 48 48 48 48 Ketal =


O O

2a-k' ( inor) de/%* 71 71 67 73 62 81 83 82 78 74 1 Yield/% 53 57 66 65 83 68 98 95 77 95 98

Products 2a2a' 2b/2b' 2c/2c' 2d/2d' 2e/2e' 2f/2f' 2g/2g' 2h/2h' 2i/2i' 2j/2j' 2k/2k'

* eter ined by 1H NMR (400 MHz) analysis.

Diastereoselective Diels-Alder Reactions of MOBs with Homochiral Furans: Enantioselective Synthesis of Highly Substituted Tricyclic K-Lactones
OH MeO HO R1 R
3

OH O R3

OH MeO R3 R2 R
1

O R'
'

O R' MeO MeO O R3

O R1 R2 OMe + 3 R3 OMe R O R2 R1

R2

DAIB MeOH

MeO O

R R
1

R R R'

OMe OMe OMe OMe O

+
R
2

(R)-3, R = iPr, R = H (R)-4, R' = Ph, R = H

(+)-5a-c (+)-6a major (+)-5, 6

(+)-5a'-c' (+)-6a' minor

7 7 Yield/ %[b]

Entry 1 2 3 4

2-Methoxyphenol (1) R1 = R2 = H R3 = COMe R1 = R2 = H R3 = CO2Me R1 = OMe, R2 = H, R3 = CO2Me R1 = R2 = H, R3 = COMe

Furan T/[oC][a] Products (R)-3 (R)-3 (R)-3 (R)-4 rt rt 80 rt (+)-5a/5a' (+)-5b/5b' (+)-5c/5c' (+)-6a/6a'

Yield/%[b] de/%[c] 77 74 60 76 98 96 99 97

[E]D[d] +56[e] +30[f] +65[g] +22[h]

----7c/14 ---

[a] Reaction temperature; [b] Yields of isolated products; [c] Determined by HPLC (Si60 column); [d] 20 oC, CHCl3; [e] c = 1.75; [f] c = 2.20; [g] c = 3.00; [h] c = 2.50.

Ref: Chou, Y.-Y.; Peddinti, R. K.; Liao, C.-C. Org. Lett. 2003, 5, 1637-1640. 35

Syntheses of Natural Products


H O H O MeO N H H H MeO2C N H

CO2H Clerodane diterpenic acid Synlett 1998, 912 H CO2Me O MeO2C H R' (+)-Forsythide aglucone dimethyl ester Tetrahedron Lett. 1989, 30, 2255 HO2C

CO2H Clerodane diterpenic acid Tetrahedron Lett. 1996, 37, 6869

OAr

(+)-Reserpine OMe Chem. Commun. 1996, 1537

OR1 R OR2 O O

(+)-Pallescensin B Chem. Commun. 1999, 117

HO O

O H

H (+)-Bilosespenes A and B H Org. Lett. 2003, 24, 4741 HH

(+)-Eremopetasidone Org. Lett. 2001, 3, 263 H H O HH O H N O O O H (+)-3F-Angeloyloxyfuranoeremophilane

(+)-Capnellene

36

Pure Appl. Chem. 2005, 7, 1221

(+)-Magellaninone Angew. Chem. Int. Ed. 2002, 41, 4090

Pure Appl. Chem. 2005, 7, 1221

Current Synthetic Targets


H O O
(+)-Eudesmadieneolide

O OR1 HO H R OR2 O O OH
(+)-Conidiogenone (+)-Drechslerine D

CO 2CH 3 O OH O O O

OH

H 3COCO H 3CO 2C

OH O

37

Azadirachtin

38

Production of 1O2 by Photochemical Method


hR Sen
1

ISC Sen*
3

O2

Sen*

O2

Photosensitizers
ye: ose engal (
Cl Cl Cl I NaO I O I Cl ONa O I O N N N N

), Tetraphenylporphyrin (TPP)

Electronic Configuration of Ground State and Excited State O2


(3Wu) (1 2p (3Wu) (1 Ground State ( 37g- )
u) g)

Excited State (1(g- ) (0.9772 eV) 94 KJmol-1

Excited State (17g+) (1.6266 eV) 157 KJmol-1

Reference: http://www.rsbs.anu.edu.au/ResearchGroups/PBE/Oxygen/O2_1_%20ElectronicConfig.htm

40

[4+2] O

t-Bu

N2

O 3

O 26
t-Bu

h , O2 MB, CH 2Cl2 - 8 oC t-Bu

O t-Bu O O N2

8 %

Ene Ene Ene OO OO 2.1 2. OO + 14


95%

h , O2 O t-Bu O O t-Bu 6% Ryang, H-S.; Foote, C. S. J. Am. Chem. Soc. 1981, 103, 495 O

OO + 1.5

OO

O O O 2, CH2Cl2 O O O O

3 atusch, .; Sch idt, G. Angew. 1988, 27, 717

hem. Int. Ed.

Wood, J. L.; Graeber, J. K.; Njardarson, J. T. Tetrahedron, 2003, 59, 8855

41

TPP / CHCl3, O2, hR Me O OMe OMe 0 oC, 3 h

O Me O O OMe OMe

S H2N NH2

HO

Me O OMe

rt, CDCl3 OH O

OMe

3a 87%)
RB / MeOH, O2, hR -25 oC, 4h O Me OMe O OOH PPh3 Me

5a 80%)
O

2a

OH

OMe

4a
O O TPP / CHCl3, O2, hR O OMe OMe 0 oC, 2 h RB / MeOH-drop of AcOH, O2, hR -10 oC, 5 h Me O

6a 69%)

OMe OMe

3b 82%)
O O OMe OH

Me

2b

6b 72%)
42

O O

O O

O OM OOH

l3

OM OM

3c (35%)
O OM OM

4c (Yield is not yet determined)

2c

O i RB / M OH O

hR

O OM OH

C 4h

ii PPh3

6c (69%)

43

/ CHCl , O , R O O O O C,

O O O

O O

R /

OH, O , R C,

2f

3f (98%)

/ CHCl , O , R O O O O

C,

O r O O O

(i) R /

OH, O , R C,

O O

3g (98%)

2g
O

2h

44

.
O

7
O O O

(60%)

O O

O R
i

O O O

8 (41%)
O


O O

(ii) R

OH

45

(i) RB / OH, O , R - 5 C, 4

O O O

t l O O

(68%)

O R t O

O O

8i (46%)

Condition 1

eOH, 0 oC
O O O e OOH

O O

OR Condition 2: R / eOH, O2, hR


O

O e O e

Recovery of starting

aterial

46

Plausible Mechanisms for the Observed Products


O R1 O O 4 + 2] O R1 OMe OMe R4 R3 R1 O R1
3 1

R3 R4

OMe OMe

O2

O O O O O R4 PPh3 R3 O R1 R4 OMe O OOH + H 2O -MeOH R1 R3 R3 R1 O O

O R4

R 4 OMe O OH

O R4 OMe OMe O O

O R
1

AcOH OMe R4 = H O O

R3

ISOLATED

R3

47

O O OMe OH C 16H33

MeO2C C16H33

H C16H33 CO2Me

O CO2Me O OH O C16H33

HO2C

H O

Untenone A

Manzamenone A Inhibitory activity against protein kinase C

Plakevulin

Inhibits cell proliferation of L1210 leukemia

Inhibitory activity against N polymerases E and K including the Cytotoxicity against murine Leukemia L1210 and carcinoma KB cells

ll the above 3 natural products were isolated from an Okinawan sponge, Plakortis sp.
References 1. Ishibashi, M.; Takeuchi, S.; Kobayashi, J. Tetrahedron Lett. 1993, 34, 3749. 2. Tsukamoto, S.; Takeuchi, S.; Ishibashi, M.; Kobayashi, J. J. Org. Chem. 1992, 57, 5255. 3. Tsuda, M.; Endo, T.; Perpelescu, M.; Yoshida, S.; Watanabe, K.; romont, J.; Mikami, Y.; Kobayashi, J. Tetrahedron 2003, 59, 1137. Few earlier synthetic works 1. Saito, .; Takeuchi, R.; Kamino, T.; Kuramochi, K.; Sugawara, .; Sakaguchi, K.; Kobayashi, S. Bioorg. Med. Chem. Lett. 2004, 14, 1975. 2. Saleh, -B.; Jermy, R. .; Michael, G. B. .; ndrew, C. R.; Roger, C. W. J. Chem. Soc. Perkin Trans I 2002, 476. 2. Saito, .; Takeuchi, R.; Kamino, T.; Kuramochi, K.; Sugawara, .; Sakaguchi, K.; Kobayashi, S.; Tsuda, M.; Kobayashi, J. Tetrahedron Lett. 2004, 45, 8069.

48

A Short Synthesis of (+/-)-Untenone A


OH OMe i C15H31MgBr ii CHO H4Cl s t. 80% HO OH OMe Pt/H2 99% C15H31 O O OMe ii PPh3 C16H33 78% C16H33 OH HO2C H O C16H33 OH OMe DAIB MeOH, 0 C 95% MeO2C ref. 1 C16H33 H C16H33 CO2Me


1
O OMe OMe i 4

2
PP / CHCl3, O2, R ,

5 (+/-)-U tenone A
ref. 1 O O O CO2Me OH C16H33

(+/-)-Manzamenone A

(+/-)-Plakev lin
References 1. Saito, .; Takeuchi, R.; Kamino, T.; Kuramochi, K.; Sugawara, .; Sakaguchi, K.; Kobayashi, S. Bioorg. Med. Chem. Lett. 2004, 14, 1975.

Diels-Alder Reactions of Nitroso Compounds


CO2Et O N O NO O NH2+Cl> % ee MeO2C Cl O N O N OH O N Ph R
1

Ph O N Ph

O O O Ph R1 R2 O N O Ph

-CO2Et H

Ph -CH2OH H O N N R1 R2 R
2 1
1

R 2 R
O N O
2

H MS OT
O N H OH O + O N HO H Ph Ph 3. : 1

OH Ph H

[Cu(MeCN)4]PF6-(S)- egphos (10 ol%) O N N up t % ee

H H, Me, OTBS

O R2

References 1.50 Yamamoto, Y.; Yamamoto, . Eur. J. Org. Chem. 2006, ASAP. 2. Wang, Y.-C.; Lu, T.-M.; Elango, S.; Lin, C.-K.; Tsai, C.-T.; Yan, T.- . Tetrahedron: Asymmetry 2002, 13, 691.

Diels-Alder Reactions of Nitroso Compounds


O O O NH2+ClMeO2C R=H Cl O NO R O PhH2CO NHOH O O Br O N R = Br O Cbz Hudlicky, T.; Olivi, H. . J. Am. Chem. Soc. 1994, 116, 5108.

Elango, S.; Yan, T.-H. J. Org. Chem. 2002, 67, 6954 O OMOM OMOM Martin, S. .; Tso, H.-H. Heterocycles 1993, 35, 85.
R1 = R4 =H R2 = R3 =Me R R
2 1

MOMO NHOH MOMO Br O N Cbz


O O N Ph O Me O N Me Ph O

PhH2CO

OH

O N

H Ph

O O N Ph

Yamamoto, Y.; Yamamoto, H. Eur. J. Org. Chem. 2006, ASAP.

Me Me

O N

Ph R1 = R2 = R3 = R4 =Me Me Me

R3 R4

Me Me

Me N Ph O

1 : 1 Me

51

Hart, H.; Ramaswami, S. K.; Willer, R. J. Org. Chem. 1979, 44, 1.

Ami

lit l

Pa

ati tati

Tet

52

  
-

t xi

Hetero-Diels-Alder Reactions of Masked o-Benzoquinones with Nitroso Compounds


R3 R2 R R3 R2 R1
1

OMe OH

PhI(OAc)2/Bu4NIO 4 MeOH-CH2Cl2, 0 oC

RNHOH (4a,b) MeOH-CH2Cl2, 0 oC or 50 oC R


3

1a-i
OMe OMe O

N O O

R=Boc or Cb for 3a, 4a, 5a-i: R = Boc for 3b, 4b, 6a-i: R = Cb

R N O

OMe OMe

3a,b

R2 R1

2a-i MOB R1 2a 2b 2c 2d H H H R2 H Me
O O

5a-i 6a-i Adduct (Yield/ )c with 3a with 3b 5a (90) 6a (96) 5e (69) 6e (81) 5c (93) 6c (95) 5d (92) 6d (96)

R3 Te p/oCa Ti e/hb H H H H 0 0 0 0 1 1 1 1

Me H

53

a) Reaction te perature. b) Reaction ti e after the addition of RNHOH. c) Yields of pure and isolated adducts.

R3 R


OMe OH R
1

PhI(OAc)2/Bu4NIO4 MeOH-CH2Cl2, 0 oC

RNHOH (4a,b) MeOH-CH2Cl2, 0 oC or 50 oC R N R3 O

1a-i
OMe OMe O

R3 R


R=Boc or Cbz for 3a, 4a, 5a-i: R = Boc for 3b, 4b, 6a-i: R = Cbz

N O R2 R1 O

OMe OMe

R1

3a,b

2a-i MOB R R 2e 2f 2g 2h 2i
1 2

5a-i 6a-i
o a

Temp/ C 0 0 50 50 50

Time/h 1 1 3 12 12

Adduct (Yield/ )c with 3a with 3b 5e (71) 6e (81) 5f (70) 6f (74) 5g (84) 6g (90) 5h (91) 6h (90) 5i (71) 6i (92)

H CO2Me H CO2Me H H H H H H H H Me Br
O O

a) Reaction temperature. b) Reaction time after the addition of RNHOH. c) Yields of pure and isolated adducts.

54

Simplified Transition State Structures of the Possible Diels-Alder Adduct Isomers


s-cis s-trans 1 57

MNC Ea = 24.0

MNT Ea = 21.0

MXC Ea = 47.2

MXT Ea = 48.5

ONC Ea = 36.5

ONT Ea = 38.0 O N O OMe OMe O meta M ortho O

OXC Ea = 45.4

OXT Ea = 48.2

ButO endo N
HF/6-31G

OO N OBut OMe OMe O

exo X

55

Diastereoselective Hetero-Diels-Alder Reactions of Masked o-Benzoquinones with Nitroso Compounds


O O OMe OH PhI(OAc)2 / u4NIO4 MeOH-CH2Cl2, -10 oC Ar NHOH

4c-g

1a

MeOH-CH2Cl2, -10 oC O N MeO O OMe MeO OMe + O O Ar

O OMe OMe O O O O Ar O N O

N O

Ar

2a
Entry 1 2 3 4 5
56

3c-g
Ar Ph 4-t-BuC6H4 4-TMSC6H4 4-OMeC6H4 2-nathathyl Temp/oC -10 -10 -10 -10 -10 Time/h 24 24 24 24 24

5c-g (major)
Products Yield/ 6 83 91 82 96

5c'-g' (mi or)


de (%)a 78 63 65 83 90

5c/5c' 5d/5d' 5e/5e' 5f/5f' 5g/5g'

a. Determined y HPLC(Shim-peak CLC-SIL column)

Diastereoselective Hetero-Diels-Alder Reaction of Masked o-Benzoquinones with Nitroso Compounds


O R3 R2 R1 O OMe OH PhI(OAc)2/Bu4NIO4 MeOH-CH2Cl2, -10oC Ph NHOH

4c

MeOH-CH2Cl2, -10oC

1a-f
R3 R
2

OMe OMe O R1

O O

O N OMe OMe O

O Ph R3 R2 O R1

O Ph

N O

+ MeO O
MeO O R1

O R3 R2 Ph

2a-f ntry 1 3 4 5 6
1

3c R H H Me H H R3 H H H H Me Br emp/o -10 -10 -10 -10 6 6 ime/h 24 24 24 24 24 24

5c-10c (major) Products 5c/5c' 6c/6c' 7c/7c' 8c/8c' 9c/9c' 10c/10c' ield/ 6 85 2 6 86 75

5c'-10c' (minor) de ( )a 78 8 8 87 46 52

H Me H H H H

O O

57

a. Determined by HPL ( him-peak

L - IL column)

Diastereoselective Hetero-Diels-Alder Reactions of Masked o-Benzoquinones with Nitroso Compounds


O O R3 R2 R
1

HOH

OMe PhI(OAc)2 /Bu4 IO4 OH MeOH CH2Cl2, 10 oC

4g
MeOH CH2Cl2, 10 oC

1a d
R3 R2 R
1

OMe OMe O

O O O R2 O R3 O R1 MeO MeO O O R1

O O R3 R2

OMe OMe O

2a d 3g Entry 1 2 3 4
1 2 3

5g-8g (major) Temp/o -10 -10 -10 -10 Time/h 24 24 24 24 Products 5g/5g' g/6g' 7g/7g' 8g/8g' Yield/% 96 92 92 96 de (%)a 90 80 88 90

5g'-8g' (minor)

Me Me
O O

58 a. etermined y PL (Shim-peak L -SIL column)

Towards the Total Synthesis of (+/-)-Valienamine

OMe CbzNHOH DAIB, Bu4NIO 4 O O OH MeOH 85% H N O O O

Cbz N O O OMe OMe DIBALH, THF 97% O O


2

Boc N O OMe OMe H OH

hydrolysis

H OH

(+/-)-Valienamine

Attempted Hydrolysis of Dimethyoxy Ketal Functionality


bz O O O bz O O O or O O bz O O O OMe OMe O O OMe OMe

Entry 1 2 3 4 5 6

ondition F3(OEt)2, u4 I, 2 l2 , reflux MSI, 2 l2, F, 1 l, 2O, F, 1 l, reflux 2O, 0.1 l : Acetone 1 : 1 0.1 l : Acetone 1 : 1 70 o

roduct messy messy recovery of SM messy 52% 5 98% 5

3
bz O OMe OMe

5 ntry 1 2 3 4 5 6 7 ondition AcO , 2 l2 , 0.1eq Oxalic Acid, F, 2 O, 50% FA : 2 l2, 1 : 5, 50% FA : 1: 5, 60 o 2 l2 O2 , entane, 0.1 l : MeO 1 : 1, 0.1 l : MeO 1 : 1, 70 o

6
bz O O O O

recovery of SM

60

OMOM 1. IBD, MeOH,0 C OH 2. Bu4NIO4, CbzNHOH CH 2Cl2, 0 oC 81% Cbz N O OMe OMOM

Cbz O

OMOM OMe

DIBALH, Cbz THF -78 oC N O 96%

OMOM OMe

O Cbz N O O

10

OH

10OH Entry 1 2 3 4 5 6 7 8 9
61

11 OH Product (11) 37% Trace Recovery of SM Recovery of SM Recovery of SM Trace Messy Messy Messy 60%

Reagent 6N HCl, THF 6N HCl, CH2Cl2 5% Oxalic acid, THF 70% AcOH, THF (CH3)2S : MeOH= 1 : 5 PTSA, Acetone BF3.OEt2, Bu4NI, CH2Cl2 MeSiCl3, NaI, CH3CN TMSI, CH2Cl2 50% TFA : CH2Cl2 = 1 : 2

10

A Short Total Synthesis of Conduramine A-1


Cbz Cbz N O L-Selectride, THF -78 oC O 76% Cbz N O OH OH H SmI2, THF 74% NH OH OH

11 OH
Cbz Acetone pTSA HC(OMe)3 NH O O

12

13

OH

14 OH
Cbz NH OH OH OH NaOMe, MeOH quant. OH NH2 OH OH

13

Conduramine A-1

62

Tetrodotoxin
OH HO HO O O O H NH N H OH NH2 OH

isolated from the ovaries and liver of the Japanese puffer fish the tora fugu (tiger puffer)

()-tetrodotoxin (TTX)

total syntheses
( )-TTX: (a) Kishi, Y.; Aratani, M.; Fukuyama, F.; Nakatsubo, F.; Goto, T.; Inoue, S.; Tanino, H.; Sugiura, S.; Kakoi, H. J. Am. Chem. Soc. 1972, 94, 217. (b) Kishi, Y.; Fukuyama, F.; Aratani, M.; Nakatsubo, F.; Goto, T.; Inoue, S.; Tanino, H.; Sugiura, S.; Kakoi, H. J. Am. Chem. Soc. 1972, 94, 21 . ()-TTX: Ohyabu, N.; Nishikawa, T.; Isobe, M. J. Am. Chem. Soc. 2003, 125, 87 8. ()-TTX: Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510. ( )-TTX: Sato, K.; Akai, S.; Sugita, N.; Ohsawa, T.; Kogure, T.; Shoji, H.; Yoshimura, J. J. Org. Chem. 2005, 70, 74 6.
63

Retrosynthetic Analysis
O OH OMe H N MeO O O O O

OH HO HO O O O

H NH N H OH NH2 OH TBSO

OAc

H H N

O O NAc

TBSO

AcO O O OAc

OAc NHAc

OH O-t-Bu

tetrodotoxin

O t-Bu-O O O TBSO N O OH OR O OMe OMe O O TBSO

OMe OMe O OR O OH

TBSO

OTBS OMe O OR O O OH

OH OMe

CHO

vanillin

64

Hetero Diels-Alder Reaction of MOBs with BocNO


OH RO
1

O OMe

DAIB
R2 O O

RO

OMe OMe R2

n-Bu4NIO4, BocNHOH solvent, temp, 5 h

t- u-O

O N

MeOH, rt
O O

O O

OR1 O OMe

R2 OMe

1a-d Entry 1 2 3 4 5 Phenol 1a 1a 1b 1c 1d R1 TBS TBS H H H R2 Me Me CH2OMe CH2OBn CHO

2a-d Product (Yield/%) 2a (95) Solvents MeOHCH2Cl2 ClCH2CH2Cl 2b (96) 2c (95) 2d (94) MeOHCH2Cl2 MeOHCH2Cl2 MeOHCH2Cl2 Temp./oC 55 85 55 55 55

3a-d Product (Yield/%) 3a (46) / 2a (48) 3a (0) / 2a (95) 3b (0) / 2b (70) 3c (0) / 2c (91) 3d (0) / 2d (75)

65

Conclusions

The iels- lder adducts obtained from MOB chemistry were realized as powerful intermediates for the preparation of various molecular skeleta. New synthetic methodologies were successfully applied for the syntheses of biologically intriguing and pharmacologically important natural products. The potentiality of MOB chemistry was further validated by the reactions with hetero dienophiles in an effort to provide methodologies in the domain of heterocyclic chemistry. The substituent effect and solvent effect on the reaction between singlet oxygen and MOBs will be studied in detail. Nitroso compounds have emerged as important hetero dienophiles for MOBs; which delivered iels- lder adducts with excellent selectivities and yields. The applicability of the methodology is exemplified by the synthesis of conduramine- 1; studies towards the synthesis of related conduramines are underway.
66

Acknowledgements
National Tsing Hua University National Science Council Ministry of Education, Taiwan

67

68

70

71

You might also like