An introduction to total synthesis and retrosynthesis. A quick overview of retrosynthesis followed by one of the many syntheses of (–)-stenine. This is just an overview of the fascinating world of organic synthesis, it is not intended to teach retrosynthesis or organic synthesis. For that see some of my other lecture notes.

1. LECTURE THREE
total synthesis
©Michael Budde@flickr
1

2. O
O
OAc
O
O
O
O
O
OO
HO
OH
Cl
AcO
OH
OH
OH
HO
OMe
HO
(+)-spongistatin 1
altohyrtin A
©Saad.Akhtar@flickr
2

3. ?
PPh3I
O
O
OH
HO
OH
Cl OH
OH
OH
O
O
OHO
AcO
HO
O
O
O
O
O
HO
OMe
how
total synthesis
do we
design a
3

4. ©_Max-B@flickr
retrosynthesisnys
backwards
thinking
4

5. R1 R2
?
how
alkene
do we
make an
5

6. R1 R2
R1
R2
R1 R2
O
R1
IPh3P
R2
O
R1
O
R2
Wittig
alkene
metathesis
reduction
McMurry
targets
new
6

7. more
reactions
you
know...
7

8. ©spackletoe@flickr
...the easier
retrosynthesis is
8

9. RETROSYNTHESIS
123.312
REVISE
©jeffrey_bos@flickr
9

10. read
this
book
10

11. guidelines
retrosynthesis
11

12. representations
0. draw multiple
N
N
H
H
N N
N
N
H
H
H
H
N N
H
H
N N
H
H
12

13. 1. identify
functional groups
N
OO
O
O
cocaine
N
OO
O
O
ester
N
OO
O
O
ester
N
OO
O
O
tertiary amine
N
OO
O
O
N
OO
O
O
pyrrolidine piperidine
13

14. 2. identify patterns
N
OO
O
O
aldol
N
OO
O
O
Mannich
N
OO
O
O
1,3-diX
(conjugate addition)
14

15. N
OH
HO
CO2H
O
HN
F
OEtEtO
NH2
O
Ot-Bu
OR*O
F
CHO
CHO
O
HN
O
atorvastatin
(lipitor®)
3. simplification
15

16. O
O N
H
O
OH
H
N
O
O
O
OH
HH
bistramide A
peptide
coupling
O
O
O
HH
OH
H2N
OTBS
OTIPS
O
H2N
O
O
OTBS
4. convergent
16

17. N
O
O
Cl
OH
H
H
NO
H
H
OH
OH
Cl
HO
(+)-halichlorine
Angew. Chem. Int. Ed. Engl. 1999, 38, 3542
lactone
formation
C–X
C–X
5. disconnections
17

18. C–X
5. disconnections
EtO2C
O
NH3•H2PO4
NHAc
C–X
EtO2C NH3•H2PO4
NHAc
Tamiflu
Angew. Chem. Int. Ed. Engl. 2009, 38, 1070
aziridine
opening
18

19. C–C next to functional group
6. disconnections
O
O
OH
O
H
bipinnatin J
Org. Lett. 2006, 8, 345
C–C
O
O
O
O
Br
nucleophilic
addition
Nozaki-Hiyama-Kishi
19

20. C–C next to functional group
6. disconnections
O
OH
OH
H
H
O
halicholactone
J. Org. Chem. 1997, 62, 6638
C–C
nucleophilic
addition
Nozaki-Hiyama-Kishi
OH
I
O
O
H
H
CHO
20

21. C–C next to functional group
6. disconnections
N
N
N
H
N
H
OH
manzamine A
J. Am. Chem. Soc. 2012, 134, 17482
C–C
N
N
H
OH
OTf
Bu3Sn
N
N
H
Pd-cross
coupling
21

22. N
N
H
OH
OTf
N
N
H
OH
OTf
precursor manzamine A
J. Am. Chem. Soc. 2012, 134, 17482
RCM
C=C
C=C
7. disconnections
22

23. O
TIPSO
O
O
OH
MeO2C
O
TIPSO
O
OH
MeO2C
O
O
P(O)(OMe)2
C=C
precursor to palmerolide A
J. Am. Chem. Soc. 2007, 129, 6386
Horner-Wadsworth-Emmons
C=C
7. disconnections
23

24. group interconversions
8. functional
TBSO
O
ON
O
O
O
precursor to penarolide sulfate A1
Eur. J. Org. Chem. 2008, 6213
FGI
N
O
O
O
O
O
OTBS
C–C
Sonogashira
TBSO
O
ON
O
O
O
I
simplification
24

25. N
O
O
HO
O
O
O
C7H15
hapalosin
Tetrahedron Lett. 1996, 37, 6557
C7H15
OTBS
CO2H
C7H15
OH O
ON
O
Bn
O
ON
O
Bn
O
C7H15
FGI
C–C
Evans
aldol
group interconversions
8. functional
control
25

26. recognition
9. pattern
H
O
H
H H
NH
OH
OH
hirsutellone B
J. Org. Chem. 2013, 78, 9584
≡ H
O
H
H H
NH
OH
OH
O O
Diels-Alder
H
O
H
H H
NH
O
O
OP
H
O
H
NH
O
OP
O
26

27. 9. pattern
R
OH OH
R2 R
O OH
R2
R
O O
R2
FGI C–C
aldol
recognition
OHO
O
O
O
O
HO
OH
OH O
rutamycin B
≡
OHO
O
O
O
O
HO
OH
OH O
6 obvious aldol
disconnections
27

28. ©Christian Puff
Angew. Chem. Int. Ed., 1996, 35, 904
(–)-stenine
N
O
H
H
H H
O
H
28

29. N
O
H
H
H H
O
H
N
O
H
H
H H
O
H
6-membered ring
6 contiguous stereocentres
29

30. R1
R2
R3
R4
R1
R2
R3
R4
Diels-Alder reaction
30

31. normally poor choice
early C–C disconnection
2 x
C–C
N
O
H
H
H H
O
H
N
O
H
H
H H
O
H
enolate
alkylation
alkylation
31

32. N
O
H
H
H H
O
H 2 x
C–N
NH2
CHO
O
H
H
H H
O
H
I
reductive
amination
alkylation
C–X disconnection
simple
32

33. NH2
CHO
O
H
H
H H
O
H
I
C–O
NH2
CHO
HO
H
H H
O
H
I
≡
(CH2)4I
NH2
CHO
CO2H
Diels-Alder
4 of the 7
stereocentres of stenine
iodolactonisation
C–X disconnection
simple
33

34. (CH2)4I
NH2
CHO
CO2H
(CH2)4I
CO2H
CHO
NH2
Diels-Alder
Diels-Alder reaction
34

35. (CH2)4I
CO2H
CHO
NH2
regiochemistry
of Diels-Alder
reactivity
enantioselectivity
issues?
35

36. N
O
H
H
H H
O
H
O
I(CH2)4
O
N
O
Ph
O
intramolecular DA
solution
+ auxiliary
36

37. S S
THPO
Cl
(CH2)4OPMB
i. BuLi,
then R–Cl
ii. H+
68%
OH
(CH2)4OPMB
SS
synthesis
umpolung
37

38. OH
(CH2)4OPMB
SS
ON
OO
(EtO)2(O)P
i. Parikh-Doering
oxidation
ii. LiCl, Et3N,
imide
77%
PMBO(CH2)4
SS
N
O
O
O
Ph
synthesis
activated DMSO (Swern)
38

39. synthesis
intramolecular Diels-Alder (IMDA)
PMBO(CH2)4
SS
N
O
O
O
Ph
S S
PMBO(CH2)4
H
H
O
O
N
O
Ph
Me2AlCl
85%
39

40. H
H
R
N
O
Al
O
O
H
H
S
S
Ph
H
H
PMBO(CH2)4
H
H S
S
aux
O
diastereoselectivity
40

41. S S
PMBO(CH2)4
H
H
O
O
N
O
Ph
H
H
R
N
O
Al
O
O
H
H
S
S
Ph
H H
determining stereochemistry
41

42. S S
PMBO(CH2)4
H
H
O
O
N
O
Ph
i. AgNO3, NCS
ii. LiSEt
iii. Et3SiH, Pd/C
iv. NaClO2,
NaH2PO4
53%
PMBO(CH2)4
H
H
O
OH
O
synthesis
removal
auxiliary
42

43. PMBO(CH2)4
H
H
C
O
OH
O
O
P
N3
PhO
PhO
DPPA, Et3N,
60°C
then MeOH
82%
PMBO(CH2)4
H
H
N
H
C
O
OMe
O
synthesis
rearrangement
Curtius
43

44. synthesis
PMBO(CH2)4
H
H
N
H
C
O
OMe
O
i. TMSCl, Et3N,
50°C
ii. mCPBA
iii. H5IO6
then I2, NaHCO3
50%
N
CO2Me
O
H
I
H
H
O
H
(CH2)4OPMB
OH
44

45. PMBO(CH2)4
H
H
NHCO2Me
O
TMSCl,
Et3N 50°C
PMBO(CH2)4
H
H
NHCO2Me
OTMS
mCPBA
PMBO(CH2)4
H
H
NHCO2Me
OTMS
O
PMBO(CH2)4
H
H
NHCO2Me
O
OH
oxidation
45

46. cleavage
PMBO(CH2)4
H
H
NHCO2Me
O
OH
H5IO4
PMBO(CH2)4
H
H
NHCO2Me
O
IO
HO
OH
OHO
OH
PMBO(CH2)4
H
H
NHCO2Me
O
HO
O
N
CO2Me
HO
H
H
O
H
(CH2)4OPMB
OH
oxidative
46

47. N
CO2Me
HO
H
H
O
H
(CH2)4OPMB
OH
I2
N
CO2Me
HO
H
H
O
H
(CH2)4OPMB
OHI
N
CO2Me
O
H
H
O
H
(CH2)4OPMB
OH
I
H
O
O
I H
(CH2)4OPMB
H
synthesis
iodolactonisation
47

48. N
CO2Me
O
H
H
O
H
(CH2)4OPMB
OH
I
i. H+, CH(OMe)3, MeOH
ii. CH2=CHCH2SnBu3, AIBN
iii. LDA, MeI
53%
N
CO2Me
O
H
H
O
H
(CH2)4OPMB
OMe
synthesis
alkylation (twice)
48

49. stereoselectivity
H
R
N
O
O
H
H
H
H
H
I
HMeO2C
H
O
H
I
O R
H
N
H
CO2Me
OMe
MeO
or
49

50. N
CO2Me
O
H
H
O
H
(CH2)4OPMB
OMe
i. Et3SiH, BF3•OEt2
ii. OsO4, NaIO4
iii. HSCH2CH2SH
50% N
O
H
H
O
H
S
S
OH
CO2Me
synthesis
50

51. synthesis
N
O
H
H
O
H
S
S
OH
CO2Me
i. Raney Ni
ii. MsCl, Et3N
iii. NaI
73% N
O
H
H
O
H
I
CO2Me
51

52. synthesis
N
O
H
H
O
H
I
CO2Me
i. TMSI
ii. heat
70%
N
O
H
H
H H
O
H
52