Studies Towards Synthesis Of

Strasseriolide A & B
Dhulshette B. S
(CSIR-SRF)
AcSIR Enroll. No- 10CC18A18043

Supervisor
Dr. Subhash Ghosh
(Chief Scientist)
CSIR-IICT, Hyderabad
DAC Meeting - III
14-02-2025
02/25/2025 1
 Content

 Previuos Work- Short

Summary.
O
 Introduction- Antimalarial
Drugs
O O
 Previous Synthetic O OH
Approaches. Strasseria geniculata
Strasseriolide A
 Present Work.

 Acknowledgement.
02/25/2025 2
 Our previous Work (Summary)

Chapter-1 Chapter-2 Chapter-3

Brief Introduction of First Total Synthesis Studies Towards
Biologically Active Of Synthesis
Natural Products; Maltepolide F Of
Macrolides Strasserilide A & B
Intramolecular Heck Reaction

Evans syn Aldol Reaction O Browns Allylation

D-Mannitol 33 steps 21.39% Yamaguchi Esterification OH

OH O O O
Barbier Allylation

OMe
MeO
Evans syn Aldol Reaction
Noyori Reduction

Maltepolide F
(Manuscript under preparation)

02/25/2025 3
 Introduction (Antimalarial drugs)

Cl N H
OMe
O O
 Malaria - Highly infectious & O N
NH
life threatening disease- OH
N N
Plasmodium falciferum O
Artemecinin
(Anopheles mosquito). Chloroquine
IC50
11nm (3D7)
Quinine
IC50
IC50 50–150 nM (3D7)
12 nm (3D7)
 WHO - Global health challenge
OH O OH O O
OH
 Chloroquine, Doxycycline, NH2

Artemisinin, H H
OH N
OH

Hydroxynaphthoquinones.
Doxycycline
IC50
0.5-5 µm (3D7)
Distribution of malaria in the world
02/25/2025 4
 Strasseriolide (An Antimalarial Drug)

O OH
 In 2020, Reyes et al. (HTS) of a 11 11

large collection of 22000 13 13

microbial extracts from O O O O

Fundacion MEDINA, O OH O OH

Plasmodium falciparum lactate 1

Strasseriolide A
2
Strasseriolide B
dehydrogenase phenotypic (16 mg) (17.3 mg)
IC50 9.8 µM (3D7) IC50 0.162 µM (3D7)
assay OH OH

11 11

 Isolated family of four novel 13

O
13
OH

macrolides Strasseriolides A−D O O O O

(Strasseria geniculata CF- O OH O OH

247251 ). 3
Strasseriolide C
4
Strasseriolide D
(6.3 mg) (6.2 mg)

 2-D NMR, Molecular modelling. IC50 0.130 µM (3D7) IC50 0.128 µM (3D7)

02/25/2025
Fernando Reyes and co-workers, Org. Lett. 2020, 22, 6709–6713 5
 Previous Work
1. Scott D. Rychnovsky:-

O OH O
O
I
S

O O O O O O O

O OH O OH OH HO OR HO OR

1 2 5 6 10 11

Strasseriolide A Strasseriolide B
O

O
OR
P3P
O S

I O 13

OH
12
7
O
9 (S)-Citronellal
8
(R)-Citronellic acid

02/25/2025 6
Scott D. Rychnovsky and co-workers, Org. Lett. 2022, 24, 1190−1194
 Previous Work
2. Rajib Kumar Goswami:-

O O O
O P OEt O
OEt

O
O O
O O HO OMe
HO HO OMe TrO
O OH 15 16
14
1
Strasseriolide A

O
HO OTHP TBDPSO OH O S
MeO OH BnO
N S
20 19
S-Roche ester
Bn

O
18
17

02/25/2025 Rajib Kumar Goswami, J. Org. Chem. 2022, 87, 11805−11815 7

 Previous Work
3. A K. Gosh:-

O O O
I

O O O O O
O
O OH HO HO OH HO OBn
OEt

Strasseriolide A 23
e 22
21 hyd
e
ald
an
ot
cr
Strasseriolide B OH
HO
O O OH 24

N O
O
OEt OR1
Bn
OEt OH
28 OEt 27 N
I Ph
triethyl orthopropionate 4-pentynoic acid
methacroliene O
26 25

02/25/2025
A K. Ghosh, J. Org. Chem. 2024, 89, 12331−12340 8
 Retrosynthetic Analysis (This Work)

O OR O

PMBO O

O O 32
O OH OPMB OTBDPS TBSO OPMB
HO
COOH
1 30 31 OTBDPS
29
Strasseriolide A
33

N N
O N
HO OH OTBDPS
PMBO S N
O O O
38 O
36
1,5- pentanediol 35 TBDPSO O N O

Bn
34
O 94

MeO OH NC OTBDPS

(R)-Roche Ester 37

02/25/2025 9
 Synthesis of Alkyne-31
O OH O O 1. MsCl, TEA, DMAP
3 steps (94), Bu2BOTf, DIPEA, DCM DCM,0 oC -rt, 3 h
HO OEt TBDPSO O N TBDPSO OH
TBDPSO O
-78 ° C - 0 ° C, 2.5 h, 81%, (dr 94:6) 2. LiBH4, THF, 0 oC-rt,
(S)-Roche ester Bn 18 h, 83% (over two steps)
34 40
39
OH
1. (COCl)2, DMSO, TEA OPMB DMP, NaHCO3, DCM
(32), n-BuLi, THF
DCM, -78 ° C, 2.5 h Br n-BuLi, THF
TBDPSO TBDPSO TBDPSO 0 °C-rt, 30 min, 83%
2. CBr4, TPP, TEA, DCM, Br -78 ° C-rt, 64% -78 ° C, 1 h, 72%
(over three steps)
-78 ° C- rt, 2 h, (quant) 33 42
41
OH OH H2, Pd/C
O Noyori reduction NH2-NH2.H2O, H2O2 (10 wt%)
(R,R)-Ru catalyst (2 mol %) OPMB TBDPSO OPMB
OPMB EtOH, 80 °C-rt, 48 h,
TBDPSO EtOAc, rt,
TBDPSO i-PrOH, 24 h, rt, 73% 40 min, 53%
45 (over two
43 44 steps)

OTBS OH
OTBS TBSOTf, DIPEA, DCM
1. (COCl)2, DMSO, TEA Table-1 OPMB
TBDPSO OPMB TBDPSO
DCM, -78 ° C- rt, 2 h

HO OPMB 0 °C- rt, 2 h, 79%

°
DCM, -78 C, 2.5 h
Table-1
2. CBr4, TPP, TEA

46
48 47
Sr. No Conditions Yield

OTBS O O
Ts 18-Crown-6, KOH, No
3. n-BuLi, THF Ph N Cl 1 THF:H2O (100:2), Reaction
O OPMB Ru
OPMB N O 0 °C – rt, 6 h.
-78 ° C, 1 h, 64% N
(over three steps) (94) Ph H
Bn (32)
(31) 2 NH4F, MeOH, 75 °C
(96) (R,R)-Ru catalyst 24 h. 80 %

02/25/2025 10
 Synthesis Of Sulfone - 4
O
PMB-OH, Amberlyst-15 CrO3, H2SO4 (95), BuLi, Piv-Cl
HO OH PMBO OH PMBO OH
DCM, 36 °C, 6 h, Acetone, 0 °C, 1 h, 60% THF, -78 °C,
79% 9 50 3 h, 82%
1,5- pentanediol

O O O O
NaHMDS, MeI, THF, NaBH4, MeOH
PMBO N PMBO N PMBO OH
O O
-78 °C, 4 h, 70%, (90:10) 0 °C, 1 h, 80%
Bn Bn
51 53
52

N N
DEAD, PPh3, DCM N N O N
N (NH4)6Mo7.4H2O, H2O2
PMBO S N
PMBO S N
0 °C, 1 h, 90% EtOH, rt, 18 h, 76% O
O
N N (35)
54
N HN
O
HS N
Bn (95)
96
(R)-4-benzyloxazolidin-2-one

02/25/2025
Angew. Chem. Int. Ed. 2015, 54, 12618 –12621 11
Synthesis Of Ketone -5
O
2 steps CBr4, PPh3, DCM NaCN, DMSO
HO OMe TBDPSO OH TBDPSO Br
0 °C-rt, 30 min, 89% 80 °C, 30 min, 95%

(R)-Roche ester 55 56

MeMgBr, THF
Table-2
DIBAL-H, DCM O Sr. Conditions Yields
TBDPSO CN TBDPSO
-78 °C, 40 min -78 °C- 0 °C, 30 min, No
96% (63:37)
57 1 KHMDS, THF, -78 °C, overnight No Reaction
58
2 KHMDS, DMF, -78 °C, overnight No Reaction
DMP, NaHCO3, DCM TBDPSO
TBDPSO
O 3 LHMDS, DMF, -78 °C, overnight No Reaction
OH 0 °C - rt, 30 min, 82 %
(36)
59 4 NaHMDS, DMF, -55 °C, overnight No Reaction

Julia−Kocienski Olefination 5 n- BuLi (1 eq), THF, -78 °C, 4 h No Reaction

N N (36)
O N PMBO
6 n- BuLi, (1 eq) DIPA, CeCl3, THF, 0 No Reaction
OTBDPS
PMBO S N °C (30 min) -78 °C - 0 °C, 1.5 h
O Table-2 7 n- BuLi (1.3 eq), THF, -78 °C, No Reaction
60
35 overnight.

02/25/2025 Kaori Ando et. al Org. Lett. 2020, 22, 17, 6907–6910 12
Retrosynthetic Analysis of 5
O

PMBO OTBDPS TBDPSO

O 61 O
62 36
OR

5
PMBO OH
53 Table-3
Sr.No Conditions Result
1. DMP, DCM, 0 °C - rt
25 min
Synthesis of Alkene -61 PMBO OH PMBO
2. Ph3PCH3Br, n-BuLi 1 G-2, DCM, rt No Reaction
53 THF, 0 °C-rt, 90 min, 87% 61

2 G-2, DCM, 45 °C No Reaction

Ph3PCH3Br, n-BuLi
Synthesis of Alkene -62 TBDPSO TBDPSO
O THF, 0 °C-rt, 90 min, 80% 3 G-2, toluene, 80 °C No Reaction
36 62

Table-3
Synthesis Of Alkene -60 PMBO TBDPSO PMBO OTBDPS

61 62 60

02/25/2025 13
 Retrosynthetic Analysis (Revised Strategy-1)

O OR OR

OH
O O O O
O OH O OPMB HO OPMB 62a

64
1 63
Strasseriolide A

OTBDPS
O
62

PMBO OH
OTBS
53 TBSO OPMB
65
31

02/25/2025 14
 Synthesis of Aldehyde-65

TBSCl, imidazole DDQ, pH=7 phosphate buffrer

PMBO OH PMBO OTBS HO OTBS
DCM, °C-rt,, 4 h, 92% DCM, 0 °C, 1 h, 84%

53 66 67

DMP, NaHCO3, DCM

O OTBS Table-4
0 °C-rt, 30 min
65

Sr. No Conditions Result

Zinc and Titanium mediated coupling of Aldehyde 65 and Alkyne 31

1 Zn(OTf)2 (1.3 eq), (+) NME (1.3 No reaction

OTBS Table-4
eq), TEA (1.3 eq), Toluene 0 °C-rt,
TBSO O OPMB 18 h.
65 31 2 Ti(OiPr)4 (0.5 eq), Et2Zn (1 eq), (S)- No reaction
BINOL (1.1 eq), THF, 0 °C-rt, 24
OH h.
OTBS
TBSO 3 Ti(OiPr)4 (0.5eq), Et2Zn No reaction
OPMB
(1 eq), THF, 0 °C, 6 h.
68

02/25/2025 15
Coupling of Aldehyde 65 & alkyne 31 using n-BuLi

OTBS OH
Table-5 OTBS OH
TBSO O OPMB TBSO
OPMB TBSO
65 31
69 70
Sr. No Conditions Result
(69 : 70)
1 BuLi (1eq), THF, -78 °C, 2 h. No reaction
2 BuLi (1eq), HMPA, THF, -78 °C, 2 h. No reaction

Table-5 3 BuLi (excess), THF, -78 °C, 2 h. No reaction

4 BuLi (1eq), DEE, -78 °C to -10 °C, 3 h. No reaction
5 BuLi (1eq), THF, 0 °C , 1.5 h. (0:quantitative)
6 BuLi (1eq), THF, 0 ° -rt, C, 1 h. (0:quantitative)
7 BuLi (1.9), THF, -78 °-0 °C, 4 h. (0:quantitative)
8 BuLi (1.9), THF, 0 °C-rt , 4 h. (0:quantitative)

02/25/2025 16
Coupling of Aldehyde 65 and Alkyne 31 using Grignard reagents
OTBS OH
Table-6 OH OH
OTBS
TBSO O OPMB TBSO
OPMB TBSO TBSO

69
65 31 71
70
Table-6
Synthesis of Weinreb Ketone -72 Result
Sr. No Conditions (69 : 70 : 71)
1. NaH2PO4.H2O, NaClO2
2-methyl-2-butene, O
t-BuOH:H2O (2:1), 0 °C-rt, 1 h O
1 EtMgBr (0.9 eq), THF, -78 No reaction
TBSO O TBSO N
O °C, 3 h
2. N TEA, CDI, THF,
65
H
HCl 0 °C - rt, 16 h, rt, 72 2 EtMgBr (0.9 eq), THF, 0 (0:0:quantitative)
68%, (over two steps)
°C, 12 h
3 MeMgBr (0.9 eq), THF, 0 (0:quantitative:0:)
Synthesis of Ketone -73 °C, 12 h

O O
OTBS
O BuLi (1.9 eq), THF OTBS
TBSO N TBSO
OPMB
0 °C-rt, 15 h, trace OPMB

72 30
73

02/25/2025 17
 Retrosynthetic Analysis (Revised Strategy-2)

O O

O HO

O O O O

O OH O OPMB OH HO OPMB HO OPMB

1 74 76 48
75
Strasseriolide A

OPMB O
OPMB
O O BrMg
N O
HO OH isopropelyne magnesium bromide
Bn
OH OR
O 94
53

77 30

02/25/2025 18
Synthesis Acid-75
O
Ph3P O
OEt
(95) DIBAL-H, DCM
PMBO O PMBO OEt PMBO OH
Toluene, 80 °C, 2 h, 85% -78 °C, 30 min, 90% O O
(E:Z >97:3)
78 80 N
79 O
Bn (94)
TMSO O O
DMP, DCM, 0 °C-rt, MgCl2, ET3N, EtOAc PPTS, DCM
PMBO O PMBO N
30 min, 83% 0 °C-rt 18 h, 72%, (dr 94:6) O
0 °- rt, 25 min, 85%
Bn
77 81

OH O O OH
NaBH4, MeOH, Table-7
PMBO N PMBO OH
O
0 °C, 1 h, 79%
Bn
82 83
Sr. No Conditions Results
S
1 TCDI, DMAP, THF, 0 °C - rt No Reaction
O O
Table-7
PMBO
2 TCDI, DMAP, THF, 60 °C Decomposition

84

02/25/2025 19
 Synthesis of Acid (75)
O O
TPP, I2, imidazole O O
PMBO OH PMBO Table-8 PMBO
I N O
DCM, 0 °C-rt, 5 min N O
Bn
80 85 86 Bn (94)

NaBH4, Methanol TBDPSCl, TEA, DMAP

PMBO OH PMBO OTBDPS
0 °C, 30 min, 79 % DCM, 0 °C - rt, 3 h
94 %
87 50

1. DMP, NaHCO3 OH
DDQ, DCM:buffer pH=7
(5:1)
DCM, 15 min Table- 8
OTBDPS
HO OTBDPS
0 °C, 2 h, 76 %
2. MgBr Sr. Conditions Result
89
88 THF, 0 °C, 30 min, 63% No
(over two steps)
O O
DMP, NaHCO3, DCM, 3HF.TEA, Acetonitrile 1 LDA, LiCl, THF, -78 56 %
0 °C - rt, 35 min, 91 %
OTBDPS OH °C to -35 °C, 4.5 h (dr 100:25)
3 days, rt, 94 %

90 91
2 LDA, LiCl, THF, -78 50 %
O O °C (1 h) then -45 (dr >100:10)
DMP, NaHCO3, DCM, 0 °C, rt, 30 min °C, overnight
OH
NaH2PO4.2H2O, NaClO2, 2-methyl-2-butene,
t-BuOH:H2O (2:1). 0 °C, 90 min, 73 % (in two steps)
75

02/25/2025 20
Synthesis of Alcohol -76

OTBS OH
OTBS 1. (COCl)2, DMSO, DCM
-78 °C - 0 °C, 2.5 h 3HF.TEA, acetonitrile
OPMB OPMB
HO OPMB
2. Ph3PCH3Br, n- BuLi 0 °C- rt, 4 days, 81 %
THF, 0 °C, 1 h,
48 92 76
69 % (over two steps)

Sr. Conditions Result

No
Table-9
Coupling of Acid 75 & Alcohol -76 1 G-2, DCM, rt, 24 h No Reaction

2 G-2, DCM, 45 °C, No Reaction

O O 24 h
3 G-2, toluene, 110 °C, No Reaction
O 24h
DCC, DMAP, DCM Table-9
0 °C, rt, 6 h, 53 % 4 HG-2, DCM, rt, 24 h No Reaction
O O
O
OH HO OPMB O OPMB 5 HG-2, DCM, Reflux, No Reaction
O OPMB 24 h

75 76
93 6 HG-2, toluene,`110 °C, No Reaction
74 24 h

02/25/2025 21
 Conclusion

 We have successfully
synthesized bis-olefinic
Evan Aldol reaction
precursor for Strasseriolide A
Evans Alkylation
and Strasseriolide B. O

Wittig Olefination O Noyori Reduction

 Key reaction- Evans aldol O OPMB
reaction, Noyori Reduction,
Wittig olefination, Evans Evans Alkylation Steglich Esterification
alkylation, Steglich
Esterification.

02/25/2025 (Manuscript under preparation) 22

 Acknowledgement

 Supervisor - Dr. SUBHASH GHOSH (Chief Scientist)

 DAC Members- 1. Dr. P. Srihari (Chief Scientist)

2. Dr. Rajesh Chandra (Sr. Principal Scientist)
3. Dr. Y. Soujanya (Sr. Principal Scientist)
 Director (CSIR-IICT).
 HOD (OSPC).
 JRF/SRF Evaluation Committee.
 CSIR-IICT.
 CSIR.
 AcSIR Team.
 Lab mates.
02/25/2025 23
 THANK YOU

02/25/2025 24