1. ARE WE THERE YET?
OUR JOURNEY FROM SIMPLE CLASSICAL CHEMISTRY
TO TRANSFER-HYDROGENATION OF ALKENES,
TO NEW CYCLOHEXYL β-AMINO ACIDS
AND TO CYCLODIMERIZATION OF STYRENE OXIDES
Ishmael B. Masesane
Chemistry Department
University of Botswana

3. POST-GRADUATE SYMPOSIUM IN 1998

5. PALLADIUM-CATALYSED TRANSFER HYDROGENATION OF ALKENES IN
THE PRESENCE OF ZINC POWDER AND VARIOUS ORGANIC ACIDS
Classic hydrogenation
O O
CO2Et H2, Pd/C, Solvent CO2Et
NHBoc NHBoc
Avoiding hydrogen gas for safety reasons

6. PALLADIUM-CATALYSED TRANSFER HYDROGENATION
OF ALKENES IN THE PRESENCE OF ZINC POWDER AND
VARIOUS ORGANIC ACIDS
O cat. PdCl2, Zn, acid, O
CO2Et CO2Et
acetonitrile, 25 oC, 16 h
NHBoc NHBoc
Entry Organic acid Isolated yield (%)
1 HCO2H 96
2 CH3CO2H 94
3 CH3CO2NH4 97
4 PhCO2H 93
10% PdCl2, Zn, CH3CO2H
CO2H CO2H
acetonitrile, 25 oC
84%
10% PdCl2, Zn, CH3CO2H,
acetonitrile, 25 oC
HO 98% HO
OMe OMe

7. CATALYTIC CYCLE OF THE REDUCTION REACTION
O
CO2Et
RCOO
Pd (II) NHBoc
RCOOH H
Pd (0) RCOO O
Pd CO2Et
H
Zn (II)
NHBoc
Zn (0)
Pd(O2CR)2
O
CO2Et
O
NHBoc (RCO2)Pd CO2Et
H
NHBoc
RCOOH
Masesane I. B.; Steel P. G. Bulletin of the Chemical Society of Ethiopia, 2005, vol. 19 (1): 149-152.

8. ENATIOSELECTIVE VERSION
PdCl2, Zn,
CO2H Chiral organic acid CO2H CO2H
Solvent, 25oC, 16 h +
Entry Solvent Acid Conversion Yield (%) [α]D ee
(%) (C,1; CHCl3) (%)
1 CH3CN L(+)-Mandelic acid 79 42 +28.5 98
CH3CN/ L (+)-Mandelic acid 75 32 +18.3 63
2 H2O (9:1)
3 EtOH L (+)-Mandelic acid 80 94 +11.0 37
4 MeOH L (+)-Mandelic acid 46 88 +16.0 55
5 Toluene L (+)-Mandelic acid 76 86 +20.0 69
6 CH3CN CH3CO2H 24 83 0.0 0
7 CH3CN L(+)Tartaric acid 100 71 +29.0 >99
CH3CN/
8 H2O (9:1) L(+)Tartaric acid 100 47 +2.0 0
9 MeOH L(+)Tartaric acid 45 80 +10.7 37
11 CH3CN Proline 70 96 +2.0 9
12 EtOH Proline 38 72 +2.0 9
Bwire R. N.; Majinda R. R. T.; Masesane I. B. 2007; Bull. Chem. Soc. Ethiop. 21(3), 457-460.

9. BEST SYNTHESIS DISCUSSION FORUM
http://totallysynthetic.com/blog/
………..An intriguing paper has been published
in JACS by Xinbo Wang, Bo Zhang and David Zhigang Wang.
In this, they suggest it is possible to oxidise benzylic alcohols to the corresponding
ketones using sodium hydride (amongst other chemistry).
Given that sodium hydride is, well, a hydride – this is quite something. Does it work?
Hard to say without giving it a go, so I am.
We had this gear in the lab, so I’m giving it a go.10.30 – Too
the dried flask out from the oven, flushed it with nitrogen and
vacuum. Added (dry) THF, and cooled with ice water.
Also, found the big ice scoop I’ve been looking for ages on the
biology floor. Thieving bastards…

10. SYNTHETIC APPROACHES TO CYCLIC
β-AMINO
ACID DERIVATIVES
CO2Et 1. Amine/H+ CO2Et
2. Reduction
1. REDUCTIVE AMINATION
O NHR
CO2Et R R' CO2Et
N
Li
2. MICHAEL ADDITION
NRR'
1. NaN3
CO 2Et 2. Curtis CO 2Et
3. CURTIS REARRANGEMENT Rearrangement
CO 2H NHR
Park, K.-H.; Kurth, M. J. Tetrahedron 2002, 58, 8629-8659.
Fülöp, F. Chem. Rev. 2001, 101, 2181-2204.
Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991-8035.

11. OUR OXANORBORNYL APPROACHES TO CYCLIC β-AMINO ACID
DERIVATIVES
1. Diels-Alder reaction of furan and (E)-ethyl 3-nitroacrylate
O
O
CO2Et AcO CO2Et
O2N
CO2Et
NO2 AcO NHBoc
OAc
2. Diels-Alder reaction of furan and maleic anhydride
OAc
O O O
O AcO CO2Me
O O
AcO NHCO2Me
O
O OAc

12. D-A REACTION OF ETHYL (E)-3-NITROACRYLATE AND FURAN
I
i
I2, N2O4, Et2O, 91% O2N Pr2NEt, Et2O, 84% O2N
CO 2Et CO 2Et CO 2Et
I I
O2N H H NO 2
H CO 2Et H CO 2Et
H H O 1. Zn, HCl, EtOH O
Favoured 2. iPr2NEt, (Boc)2O
NO2 77% NHBoc
CO2Et CO2Et
Furan, solvent
CO2Et O
O2N Temp. O
CO2Et CO2Et
NO2 NHBoc
Solvent/Temp.(oC) CHCl3/25 CHCl3/-20 Neat/25 MeOH/25 Toluene/80 CH3CN/25
Endo/Exo ratio 2:1 4:1 3:1 2:1 2:1 2:1
McMurry, J., E.; Musser, J., H. Organic syntheses 1977, 56, 65-68.

13. COMPOUNDS WE PREPARED FROM THE OXANORBORNYL β-AMINO ACID
OH
NH2 CO2Et
O
NHBoc
O CO2H OH
O
CO2Et
NHBoc
CO2Et
AcO CO2Et
AcO NHBoc
AcO NHBoc OAc
OAc

14. BASE-MEDIATED ELIMINATION OF THE OXYGEN BRIDGE
O EtO2C CO 2Et
CO2Et KHMDS, THF,
-50oC, 71%
H BocHN
NHBoc OH OH
Elimination of the carbamate give
(H3C)3Si
N Side product.
Si(CH3)3
O
CO2Et
NHBoc

15. TOWARDS TRIHYDROXYCYCLOHEXYL β-AMINO ACIDS
CO2Et MCPBA, NaHCO3, CH2Cl2 CO2Et CO2Et
77%
O +O
NHBoc NHBoc NHBoc
OH OH OH
Selectivity 9 : 1
1. HClO4, H2O/Acetone
2. Ac2O, pyridine
AcO CO2Et AcO CO2Et
Pd/C, EtOH
98%
H H
AcO NHAc AcO NHAc H
AcO
CO 2Et
OAc OAc AcO
NHA c
OAc
H H
Selected NOESY interactions

16. TOWARDS TRIHYDROXYCYCLOHEXYL β-AMINO ACIDS
CO2Et MCPBA, NaHCO3, CH3CN CO2Et CO2Et
63%
O + O
NHBoc NHBoc NHBoc
OH OH OH
1. HClO4, H2O/Acetone Selectivity 6:4
2. Ac2O, pyridine, 73%
AcO CO2Et AcO CO2Et
Pd/C, EtOH
98%
AcO NHAc AcO NHAc
OAc H
OAc H
OAc
CO 2Et
H
NHA c
O Ph OAc
O OAc
O Selected NOESY interaction
H3C NH

17. TYPICAL NMR SPECTRA
CO2Et
AcO
AcO
AcO CO 2Et
NHB oc
AcO NHAc AcO
OAc
CO2Et OAc
AcO
CO 2Et
AcO NHAc NHB oc
AcO
OAc
OAc

18. DIELS-ALDER REACTION OF FURAN AND MALEIC ANHYDRIDE
O O O
O
CO2Me
o O
25 C, 98% MeOH, 25oC
O + O CO2H
87%
O
O
CURTIS REARRANGEMENT
O
O ClCO2Me, O
CO2Me
CO2Me NEt3, THF CO2Me Toluene, 50 oC
CO2H then NaN3, CON3 then CH3OH, NHCO2CH3
H2O, 0 oC, 25 oC, 63%
from the acid
Chola J.; Masesane I. B. Tetrahedron Letter 2008, vol. 49, 5680-5682

19. LEWIS ACID MEDIATED OPENING OF BICYCLIC β-AMINO ACID AND SYN-DIHYDROXYLATION
OAc
O BF3.Et2O, Ac2O, CO2Me
CO2Me 0 oC, 61%,
NHCO2CH3
NHCO2Me
OAc
i. OsO4, Me3NO.H2O,
H H
H
R acetone
R ii. Ac2O, py,
CO2Me
H 76% from the
H
R
R
NHCO2Me
alkene
R = OAc OAc
Selected NOESY interactions AcO CO2Me
AcO NHCO2Me
OAc
Chola J.; Masesane I. B. Tetrahedron Letter 2008, vol. 49, 5680-5682

20. ANTI-DIHYDROXYLATION THROUGH EPOXIDATION
OAc OAc OAc
MCPBA, CO2Me
CO2Me CO2Me
CH2Cl2,
O + O
25 oC
NHCO2Me NHCO2Me NHCO2Me
OAc OAc OAc
90:10
OAc OAc
CO2Me AcO CO2Me
HClO4,
O H2O/acetone
NHCO2Me Ac2O, pyridine, AcO NHAc
OAc
64% from epoxide OAc
H H
R
H
R
R CO2Me
H
R
H NHAc
R = OAc
Selected NOESY interactions
Chola J.; Masesane I. B. Tetrahedron Letter 2008, vol. 49, 5680-5682.

21. http://www.scirus.com/
is the most comprehensive scientific research tool on the web. With over 370
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Some of the Information Sources

22. BACKGROUND TO CYCLODIMERIZATION OF STYRENE OXIDES
O
O O
CHO OH
H3PO4
+
OH O
R
R
H3PO4
R
R O
O
O
O OR
R
R

23. CYLODIMERIZATION OF STYRENE OXIDES

24. CYCLODIMERIZATION OF STYRENE OXIDE
mCPBA, CH2Cl2, O
NaHCO3, 25 oC,
88%
H3PO4, 25 oC
61%
O O
+
O O
75:25
Mazimba, O.; Majinda, R. R.; Masesane, I. B. Tetrahedron Letters 2009, vol. 50, 5927-5929

25. CYCLODIMERIZATION OF CHLOROSTYRENE OXIDES
O
Cl Cl
H3PO4,
25 oC O O
72% +
Cl
O O
Cl Cl
75:25
O
Cl Cl
H3PO4,
25 oC O O
62% +
Cl O Cl O
Cl
75:25
Cl
O
H3PO4, O
25 oC, 65%
Cl
O
Cl
Mazimba, O.; Majinda, R. R.; Masesane, I. B. Tetrahedron Letters 2009, vol. 50, 5927-5929

26. POSSIBLE MECHANISM OF THE CYCLODIMERIZATION REACTION
H
Ph Ph
O H O O O
Ph OH Ph O
Ph OH Ph
Ph
1,2-hydride
shift
Ph
Ph
Ph O
O cyclisation O
O OH
OH Ph
Ph Ph
Mazimba, O.; Majinda, R. R.; Masesane, I. B. Tetrahedron Letters 2009, vol. 50, 5927-5929

27. CYCLODIMERIZATION OF METHYLSTYRENE OXIDE
Me
O O
o
H3PO4, 25 C
81% O
Me
Me
O O
o Me
H3PO4, 25 C
Me
82% O
Me

28. CYCLODIMERIZATION OF METHOXYSTYRENES
MeO
mCPBA, CH2Cl2, O
NaHCO3, 25 oC,
85% O
MeO
OMe
MeO
mCPBA, CH2Cl2,
O
NaHCO3, 25 oC, MeO
96% OMe
MeO O
OMe
OMe

29. ARE WE THERE YET?
SUMMARY
O cat. PdCl2, Zn, acid, O
CO2Et CO2Et
acetonitrile, 25 oC, 16 h
NHBoc NHBoc
R
O AcO CO2R
O CO2R
AcO NHR'
NHR' OAc
O
H3PO4 O
O

30. ACKNOWLEDGEMENTS
Research associates Financial assistance
 Dr P. G. Steel  University of Botswana
Dr Thota Ganesh University of Durham
 Dr Darren Orton Royal Society of Chemistry
 Prof. N. Torto  Academy of Science for the
 Dr R. Mapitse Developing world (TWAS)
 Prof. R. Majinda
 Dr Mothanka
Students
 Reginah Bwire
 Jushua Chola
 Dr Musa Chacha
Ofentse Mazimba
 Nayang Kgakatsi
And thank you for your attention!