This document describes the total synthesis of the natural product (+)-anamarine and its stereoisomers from D-mannitol. It involves the convergent coupling of fragments synthesized from D-mannitol. The synthesis of (+)-anamarine is described in detail involving the stereoselective synthesis of fragments I and II and their coupling. Similarly, the total synthesis of 8-epi-(-)-anamarine and (-)-anamarine is reported. The document also reports the synthesis of β2,2-amino acids and β3-amino acid from D-ribose to understand their effect on helix formation and stability.

1. Organic and Biomolecular Chemistry Division
CSIR-Indian Institute of Chemical Technology Hyderabad-500
007, India.
“SYNTHESIS OF (+)-ANAMARINE, ITS
STEREOISOMERS; 2,2-AMINO ACIDS, 3-AMINO ACID
WITH RIBOSE SIDE CHAIN AND PEPTIDES; C3-C12
AND C13-C15 FRAGMENTS OF IRIOMOTEOLIDE-1A”
24 JANUARY 2015
RAJENDER REDDY KARNEKANTI
Research supervisor
Dr. G. V. M. Sharma, FNASc
1

2. Contents
Chapter I: Stereoselective total synthesis of (+)-anamarine and 8-epi-(-)-
anamarine from D-mannitol
Chapter II: Synthesis of 2,2-amino acids, 3-amino acid with D-ribose side
chain and peptides
Chapter III: Attempts towards the synthesis of iriomoteolide-1a: synthesis of
C3-C12 and C13-C15 fragments
2

3.  Isolated from the flowers and leaves of a pruvian hyptis.
 Shows a wide range of biological activities
 The α,β-unsaturated-δ-lactone containing natural product (+)-
anamarine
Alemany et al. Tetrahedron Lett. 1979, 20, 3583.
Stereoselective total synthesis of (+)-anamarine,
(-)-anamarine and 8-epi-(-)-anamarine from D-mannitol
CHAPTER I
OAc
OAc
OAc
OAcO
O
(+)-anamarine 1
OAc
OAc
OAc
OAcO
O
8-epi-(-)-anamarine 2
OAc
OAc
OAc
OAcO
O
(-)-anamarine 3
Figure . (+)-Anamarine 1, 8-epi-(-)-anamarine 2 and (-)-anamarine 3
1
2
3
4
5
6
7
8
9
10
11 12
3

4. Retrosynthesis of (+)-anamarine
CHAPTER I
4
OAc
OAc
OAc
OAcO
O
OAc
OAc
OAc
OAc
O
O
O
O
OH
O
O
O
O
D-mannitol
(+)-anamarine 1
+
I
II
III
IV
Retrosynthetic strategy of (+)-anamarine 1

5. Synthesis of (+)-anamarine
Synthesis of Fragment-I
OAc
OAc
OAc
OAc
I
CHAPTER I
5
O
O
O
O
O
OHO
HO
O
O
PPh3, I2, imidazole,
CH2Cl2, 0 ºC -rt, 4 h O
O
OH
OH
CuCl2. 2H2O,
0 oC, CH3CN, 15 min
O
O
OH
OBz
BzCl, n-Bu2SnO, Et3N
CH2Cl2, 0 oC-rt, 1h
O
O
OTs
OBz
p-TsCl, cat. DMAP, Et3N
CH2Cl2, rt, 5 h
O
O
O
K2CO3, MeOH,
0 oC-rt, 1 h
O
O
OH
Me3SI, n-BuLi,
THF, -20 oC, 30 min
O
O
OH
Otable 1
(-)-DIPT Ti(OiPr)4 CHP (-)-DIPT Ti(OiPr)4 TBHP
0.4 0.4 2 1.2 1.1 1.5
1.05 1.05 2 1.1 1.2 2
Table 1
78% 98%
89% 90%
82% 68%

6. Synthesis of (+)-anamarine
Synthesis of Fragment-I
OAc
OAc
OAc
OAc
I
CHAPTER I
6
O
OO
O
O
OO
O
O
OH
Me3SI, n-BuLi,
THF, -20 oC, 30 min
O
OO
O
OH
OH
OH
AD-mix-, MeSO2NH2
t-BuOH:H2O, 0 oC, 24 h
O
OO
O
OH
OH
LiAlH4, THF,
0 oC-rt, 3 h
p-TsCl, n-Bu2SnO, Et3N,
CH2Cl2, 0 oC-rt, 1 h
O
OO
O
OH
OH
OTs
O
OO
O
O
O
2,2-dimethoxypropane,
acetone, cat. PTSA, 0 oC-rt,
1 h
O
OHO
HO
O
OCuCl2. 2H2O, CH3CN,
0 oC, 15 min O
O
O
O
PPh3, imidazole, I2,
CH2Cl2, 0 ºC -rt, 4 h
OAc
OAc
OAc
OAc
CF3COOH, CH2Cl2,
0 oC-rt, 15 min
Ac2O, Pyridine, cat. DMAP,
CH2Cl2, rt, 20 h
OH
OH
OH
OH
I
65% 90%
80%
91% 98% 72%
90%

7. Synthesis of (+)-anamarine
Synthesis of Fragment-II
O
O
II
CHAPTER I
7
O
O
OH
O
O
O
O
NO2
p-nitrobenzoic acid,
PPh3, DIAD, THF,
0 °C-rt, 5 h
O
O
OH
K2
CO3
, MeOH
rt, 1 h
acryloyl chloride, Et3N, cat. DMAP
CH2Cl2, 0 oC-rt, 2 h
O
O
O
O
Grubbs-I generation catalyst,
CH2Cl2 , reflux, 6 h.
O
O
O
O
HO
HO
O
O
CuCl2. 2H2O, CH3CN,
0 oC-rt, 30 min
O
O
PPh3, imidazole, I2,
CH2Cl2, 0 ºC -rt, 4 h
II
74%
86% 82%
80% 74%

8. Grubbs, R. H.; Chang, S.
Tetrahedron, 1998, 54, 4413.
Synthesis of (+)-anamarine
Synthesis of Fragment-II
CHAPTER I
8
Ru
PCy3
PCy3
Cl
Cl
Ph
Ru
PCy3
Cl
Cl
NN
MesMes
Ru
PCy3
PCy3
Cl
Cl
Ph
I: Grubbs-I generation catalyst II: Grubbs-II generation catalyst III: Furstner's catalyst
Ph

9. Synthesis of (+)-anamarine
Coupling of Fragment-I and II
The spectral data of the synthetic was in accordance with the literature
,
[]25
D = +16.8 (c 0.3, CHCl3); lit. []25
D +17.8 (c 0.3, CHCl3).
Gao, D.; Doherty, G. A. O. J. Org. Chem. 2005, 70, 9932.
CHAPTER I
9
Grubbs-II generation catalyst,
CH2Cl2, reflux, 5h.
O
O
OAc
OAc
OAc
OAcO
O
OAc
OAc
OAc
OAc
+
68%

10. OAc
OAc
OAc
OAcO
O
8-epi-(-)-anamarine 2
OH
O
O
OTPSO
O
OAc
OAc
OAc
OAc
OH
O
O
OTPS
O
O
+
D-mannitol+
O
O
OH
I II III
IVV
II III
Retrosynthesis of 8-epi-(-)-anamarine
CHAPTER I
10

11. Synthesis of 8-epi-(-)-anamarine, (-)-anamarine
Synthesis of fragment-III
CHAPTER I
11
O
OO
O
OH
O
OO
O
OH OH O
OO
O
OH
OTs
LiAlH4
, THF,
0 oC-rt, 3 h
P-TsCl, n-Bu2
SnO, Et3
N,
CH2Cl2, 0 oC-rt, 1 h
O
OO
O
OTPS
TPSCl, imidazole
CH2Cl2, rt, 1 h
CuCl2. 2H2O
CH3CN, 0 oC, 30 min
O
OHO
HO
OTPS
O
OHO
TsO
OTPS O
O
O
OTPS
K2CO3, MeOH,
0 oC-rt, 1h
p-TsCl, Et3N, n-Bu2SnO,
CH2Cl2, 0 oC-rt, 30 min
O
OHO
OTPS
Me3SI, n-BuLi, THF,
-20 oC, 30 min
III
74%
66%
98%
89% 70%

12. Synthesis of 8-epi-(-)-anamarine, (-)-anamarine
Synthesis of fragment-II
CHAPTER I
12
acryloyl chloride, Et3N,
CH2Cl2, 0 oC-rt, 2 h
O
O
OH
O
O
O
O
Grubbs-I generation catalyst,
CH2Cl2 , reflux, 6 h.
O
O
O
O
HO
HO
O
O
O
O
PPh3, imidazole, I2,
CH2Cl2, 0 ºC-rt, 4 h
CuCl2
. 2H2
O, CH3
CN,
0 oC-rt, 30 min
II
82%
acryloyl chloride, Et3N,
CH2Cl2, 0 oC-rt, 2 h
O
O
OH
O
O
O
O
Grubbs-I generation catalyst,
CH2Cl2 , reflux, 6 h.
O
O
O
O
HO
HO
O
O
O
O
PPh3, imidazole, I2,
CH2Cl2, 0 ºC-rt, 4 h
CuCl2
. 2H2
O, CH3
CN,
0 oC-rt, 30 min
II
81% 70%

13. Synthesis of 8-epi-(-)-anamarine, (-)-anamarine
Coupling of fragment-II, III & II, VII
CHAPTER I
13
O
O
OH
O
O
OTPSGrubbs-II generation catalyst,
toluene, reflux, 8 h
O
O
OH
O
O
OTPS
+
II III
I
i) CF3COOH, CH2Cl2,
0 oC-rt, 15 min
ii) Ac2O, pyridine,
CH2Cl2, rt, 20 h.
O
O
8-epi-(-)-anamarine 2
OAc
OAc
OAc
OAc
82%
86%

14. Synthesis of 8-epi-(-)-anamarine
CHAPTER I
14
O
OHO
OTPS
i) CF3COOH, CH2Cl2,
0 oC-rt, 15 min
ii) Ac2O, pyridine,
cat. DMAP, CH2Cl2, rt,
20 h
OAc
OAc
OAc
OAc
V
III
8-epi-(-)-anamarine 2
O
O
OAc
OAc
OAc
OAc
OAc
OAc
OAc
OAc
O
O
+
Grubbs-II generation catalyst,
CH2Cl2, reflux, 5 h
II V
83%
64%

15. In conclusion, general and efficient convergent synthetic strategies are develo
ped for the synthesis of (+)-anamarine and 8-epi-(-)-anamarine from D-mannitol.
Two enantiomeric vinyl lactones and two olefinic acyclic fragments were synthesi
zed and coupled to give natural and non-natural anamarine. This approach is adopt
able for the diversity oriented synthesis of such lactones efficiently.
CHAPTER I
Conclusion
15

16. Boc-(R)-3-Caa-OMe 1
O
MeO O
OMeO
O NHBoc
Figure . Structures ofβ3-amino acids
The α/β-peptides derived from β3-Caa 1 with a side chain havi
ng D-ribo configuration have shown the participation of C3-OMe grou
p in H-bonding.
O
O
O
MeO2C
BocHN
2(R)-2,2-Caa
Figure Structures of 2,2-amino acids
MeO
O
O
O
MeO2C
BocHN
3(S)-2,2-Caa
MeO
2,2-amino acids, 3-amino acid with ribose side chain an
d peptides
Sharma et al. J. Org. Chem. 2012, 77,
6834.
(a) Sharma et al J. Org. Chem. 2011,
76, 1562. (b) Sharma et al Tetrahed
ron 2012, 68, 4390.
CHAPTER II
16

17. The β2,2-peptides derived from 2 and 3 have also shown the partic
ipation of C3-OMe group in H-bonding. Based on these findings it was pr
oposed to synthesize new β2,2-Caas 4 and 5 from D-ribose , to understand t
he effect of C-3 inversion and 1,2-acetonide in β2,2-Caas on helix formatio
n and stability.
2,2-amino acids, 3-amino acid with ribose side chain
and peptides
CHAPTER II
17
OMeO2C
BocHN
O O
OMeO
BocHN
O O
OMe
Figure . Structures of 2,2-amino acids from ribose
MeO2C
4 5

18. Retrosynthesis of β2,2-Caa 4, 5 from ribose
Retrosynthetic strategy of β2,2-Caas from ribose
CHAPTER II
18
O
HO
O O
OMeOHO
TBSO
O O
OMe
OMeO2C
BocHN
O O
OMe
OMeO2C
TBSO
O O
OMe
O
BocHN
O O
OMe
O
TBSO
O O
OMe
BocHN
D-ribose
MeO2C
4
5

19. Synthesis of β2,2-Caa 4
OMeO2C
BocHN
O O
OMe
S
Synthesis of β2,2-Caa
CHAPTER II
19
O
H
O
OHO
HO
THF, H2O, 0 ºC-rt,
16 h
98%HCHO, 1N NaOH,
O O
O O
OMe
OMe
O
O O
OMe
HO
IBX, EtOAc, DMSO,
reflux, 1h
O
TBSO
HO
TBSCl, imidazole, n-Bu2SnO,
CH2Cl2, -20 ºC, 1h
O O
OMe
D-ribose
con. H2SO4, acetone:MeOH
reflux, 1h
55%
44% 73%

20. 20
i) IBX, DMSO, EtOAc,
reflux, 1 h
tBuOH:H2O (7:3),
0 ºC-rt, 5 h
O
TBSO
O
OH
ii) NaClO2, 30% H2O2,
CH2N2, ether,
0 ºC-rt, 2 h
OMeO2C
TBSO
O OO O
OMe OMe
OMeO2C
HO
TBAF, THF,
0 ºC-rt, 3 h
O O
OMe
i) Tf2O, pyridine, CH2Cl2,
-20 ºC, 30 min
OMeO2C
N3
O O
OMe i) 10% Pd/C-H2,
MeOH, rt, 4 h
OMeO2C
BocHN
ii) (Boc)2O, Et3N,
CH2Cl2, 0 ºC-rt, 5 h
O O
OMe
ii) NaN3, DMF,
0 ºC-rt, 3 h
54%
83% 80% 80%
Synthesis of β2,2-Caa 4

21. Synthesis of β2,2-Caa 5
OMeO2C
BocHN
O O
OMe
R
Synthesis of β2,2-Caa 6
CHAPTER II
21
O
TBSO
N3i) Tf2
O, pyridine, CH2
Cl2
, -20 ºC, 30 min
ii) NaN3, DMF, 0 ºC-rt, 3 h
O O
OMe
O
TBSO
HO
O O
OMe
i ) 10% Pd/C-H2, MeOH, rt, 4 h
O
TBSO
O O
OMeBocHN O
HO
TBAF, THF,
0 ºC-rt, 3 h
O O
OMeBocHN
tBuOH:H2
O (7:3),
0 ºC-rt, 5 h
NaClO2, 30% H2O2,
CH2N2, ether,
0 ºC-rt, 2 h
O
HOOC
O
MeOOC
O OO O
OMe OMe
BocHN BocHN
O
OHC
O O
OMeBocHN
IBX, DMSO,
EtOAc, reflux, 1 h
ii) (Boc)2O, Et3N, CH2Cl2, 0 ºC-rt, 5 h
77%
92% 89%
53%

22. 2,2-amino acid with ribose side chain
OHO2
C
BocHN
OMeO2C
HOOCF3CH2N dipeptide
aq. 4N NaOH,
MeOH,
0 oC-rt, 1 h
CF3COOH,
CH2Cl2,
0 oC-rt, 2 h
OMe
OMe
O O
O O
BocHN O
O
O
O
OMeO
O
N
H
O
O
OMe OMe
OHO2C
BocHN
OMe
O O
Stereochemistry in β2,2-Caa
O
HO
O O
OMe
BocHN NaH, THF,
0 oC-rt, 3 h
OO
HN
O O
OMe
O S
Peptides from (R)-β2,2-Caa
CHAPTER II
22

23. 2,2-amino acid with ribose side chain
OHO2
C
BocHN
OMeO2
C
HOOCF3CH2N dipeptide
aq. 4N NaOH,
MeOH,
0 oC-rt, 1 h
CF3COOH,
CH2Cl2,
0 oC-rt, 2 h
OMe
OMe
O O
O O
BocHN O
O
O
O
OMeO
O
N
H
O
O
OMe OMe
OHO2C
BocHN
OMe
O O
Peptides from (S)-β2,2-Caa
It was evident that the D-ribo configuration at C-3 OMe has a role to
play in the peptide synthesis
CHAPTER II
23

24. 2,2-amino acid
O
O
O
O
O
O
TBSO
HO
O
O
O
MeO2C
N3
DAG
O
O
O
MeO2C
BocHN
HO
Retrosynthetic strategy of β2,2-Caa:
O
O
O
MeO2C
BocHN
CHAPTER II
24
O
O
O
MeO2C
BocHN
6
Figure . Structures of 2,2
-amino acid
S

25. 2,2-amino acid
O
O
O
MeO2C
BocHN
Synthesis of β2,2-Caa 6
Epp et al. J. Org. Chem. 1999, 64, 293
CHAPTER II
25

26. 2,2-amino acid
O
O
O
MeO2C
BocHN
Stereochemistry in β2,2-Caa
Peptides from (S)-β2,2-Caa
CHAPTER II
26

27. 2,2-amino acid
O
O
O
MeO2C
BocHN
CHAPTER II
27

28. 2,2-amino acid
The analytical studies evidently shows that the sugar side chain
has effect on the formation of peptides and their helical stability.
O
O
O
MeO2C
BocHN
CHAPTER II
28

29. 3-amino acid with ribose side chain and peptides
Boc-(S)-3-Caa-OMe
O
MeO O
OMeO
O NHBoc
O
O O
OMe
MeO
O NHBoc
Boc-(S)-3-Caa-OMe
Figure . 3-Caa amino acids
It was proposed to synthesize β3-Caa with D-ribo side chain to under
stand the impact of D-ribo configuration or the disubstitution, which one is re
sponsible for the observed results.
CHAPTER II
29

30. 3-amino acid with ribose side chain and peptides
Synthetic strategy of (S)-β3-Caa:
O
O O
OMe
MeO
O NHBoc
O
O O
OMe
MeO
O
O
O O
OMe
O
D-ribose
Retrosynthetic strategy of (S)-β3-Caa:
CHAPTER II
30

31. 3-amino acid with ribose side chain and peptides
CHAPTER II
31
3-amino acid with ribose side chain and peptides
H3N
OMe
O
BocHN
OH
O
HCl. NH2-L-Ala-OMe Boc-L-Ala-OH
Cl
O
O O
OMe
MeO
O NHBoc
(S)--Caa
Figure. (S)-β-Caa, L-Ala-OMe hydrochloride and Boc-L-Ala-OH
CHAPTER II
31

32. 3-amino acid with ribose side chain and peptides
CHAPTER II
32
3-amino acid with ribose side chain and peptides
CHAPTER II
32

33. 3-amino acid with ribose side chain and peptides
CHAPTER II
33

34. 3-amino acid with ribose side chain and peptides
CHAPTER II
34

35. 3-amino acid with ribose side chain and peptides
CHAPTER II
35
3-amino acid with ribose side chain and peptides
CHAPTER II
35

36. Conclusion
Conformational analysis of peptides by 1H NMR and CD (Figure s) data inferr
ed the presence of some secondary structures, which could not be unambiguously a
ssigned. The analytical studies evidently show that the ribose side chain has effect
on the formation of peptides and their helical stability. Thus study gives interesting
insights into the carbohydrate side chain in peptide design.
CHAPTER II
36

37. O
OHHO
OH
O
H
O
OH
1
2
3
45
6
7
9
11
13 14
15
16 18
19
20
21 23
Iriomoteolide-1a
Attempts towards the synthesis of iriomoteolide-1a: synthe
sis of C3-C12 and C13-C15 fragments
• Isolated from the dinoflagellate Amphidinium species
• Exhibits potent cytotoxicity against human B lymphocyte DG-7
5 cells
CHAPTER III
37
Kobayashi,et al. J. Nat. Prod. 2007, 70, 451.

38. O
OHHO
OH
O
H
O
OH
O
OHHO
OH
OH
H COOH
OH
OMOM
OPMB
O
HO
OH
H
OTBS
O
+
COOMe
OTBS
COOMe
Br
OTPS
ArO2S
HO
OPMB
+
OTBS
COOMe
PMBO
OTPS
+
OHBnOHO
OH
S
S
1
2
3
45
6
7
9
11
13 14
15
16 18
19
20
21 23
HO
OPMBHO
1
23
4
5
6
7
8
9
10
11
12
A
B
C D
Retro synthesis of iriomoteolide-1a:
Attempts towards the synthesis of iriomoteolide-1a: synt
hesis of C3-C12 and C13-C15 fragments
CHAPTER III
38

39. Synthesis of dithiane A:
Attempts towards the synthesis of iriomoteolide-1a: synt
hesis of C3-C12 and C13-C15 fragments
CHAPTER III
39

40. Synthesis of fragment C: route-I
CHAPTER-III : Attempts towards the synthesis of iriom
oteolide-1a: synthesis of C3-C12 and C13-C15 fragments
CHAPTER III
40

41. Synthesis of fragment C: route-II
Attempts towards the synthesis of iriomoteolide-1a: synt
hesis of C3-C12 and C13-C15 fragments
CHAPTER III
41

42. Synthesis of fragment D:
Attempts towards the synthesis of iriomoteolide-1a: synt
hesis of C3-C12 and C13-C15 fragments
CHAPTER III
42

43. Coupling between the fragments:
Attempts towards the synthesis of iriomoteolide-1a: synt
hesis of C3-C12 and C13-C15 fragments
CHAPTER III
43

44. In conclusion, in the attempted synthesis of iriomoteolide-1a, a syn
thetic protocol was developed for the synthesis of C3 to C12 fragment, w
hich has three chiral centres and one exo-double bond and C13 to C15 fr
agment, which has one chiral center.
44
Conclusion

45.  Dr. G. V. M. SHARMA
 CSIR-IICT
 Faculty, Dept. Of Chemistry, Osmania University
 UGC-New Delhi
ACKNOWLEDGEMENT
45
CHAPTER III

46. Thank You
46