nineteen-step total synthesis of (+) - phorbolccc.chem.pitt.edu/wipf/current...
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Nineteen-step Total Synthesis of (+) - Phorbol Shuhei Kawamura, Hang Chu, Jakob Felding, and Phil Baran
[1] Science 2013, 341, 878. [2] Nature 2016, 0, 1.
Evan Carder Wipf Group Current Literature
April 09, 2016
HO OH
HO
O OH OH
MeMe
MeTMSO
O OTBS
Me
H
1 Cyclase Phase
2 Oxidase Phase
Advanced Intermediate [1] (+) – Phorbol [2]
Oxidase Phase
MeMe
MeHO
H
OH
OH
O
Me
OH
HO
-
Phorbol Background
04/09/16 Evan Carder @ Wipf Group 2
§ Phorbol and phorbol derivatives are members of the tigliane diterpenoid family.
§ The tigliane diterpenoid family are isolated from the Euphorbiaceae and the
Thymelaeaceae family members 1. Structural elucidation was confirmed by X-ray crystallography of a phorbol derivative in 1967 2.
Structural characteristics:
§ Tigliane diterpenoids have a 5/7/6/3- tetracyclic ring system consisting of a five-membered ring (A), a seven-membered ring (B), a six-membered ring (C), and a cyclopropane system (D).
§ Phorbol has a polyhydroxylated tigliane carbon skeleton that contains eight contiguous asymmetric centers, six of which are sited around the six-membered C ring.
§ Phorbol derivatives are isolated as mixed esters, most commonly existing as
12,13 or 13,20-diesters.
[1] Arch. Exp. Pathol. Pharmakol. 1935, 177, 212. [2] Angew. Chem. Int. Ed. Engl. 1967, 6, 809.
HO OH
HO
O OH OH
1
2 3
19
4 5 6
20
7
8 9 10
11 18
12 13
14
15 16
17
A" B"
C"D"
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04/09/16 Evan Carder @ Wipf Group 3
§ As a downstream effector of G-protein coupled receptors and receptor tyrosine kinases, PKC propagates important signaling events.
§ Deregulation of PKC has been associated with
multiple cancer-promoting pathways, which can lead to an array of adverse phenotypes.
§ Therefore, PKC has been implicated in the
development and progression of disease.
§ PKC is commonly activated by second messenger molecule 1,2-diacylglycol (DAG) at the cellular surface.
§ Phorbol esters have been shown to strongly activate PKC and potently promote tumor development - tetradocecanoyl phorbol acetate is active at 20 nM. Paradoxically, deoxygenated derivatives can inhibit tumor formation; therefore, synthesis of phorbol and phorbol derivatives may provide therapeutically active agents toward the treatment of cancer.
Protein Kinase C (PKC) Activation and Tumor Promotion Stimuli
Carcinogenesis Tumor Progression
PKC
Anti-Apoptosis Survival
DNA Synthesis Proliferation
Motility Angiogenesis
P
PLC
DAG
Phorbol
[1] Nature Review 2011, 11, 937. [2] J. Bio. Chem. 2000, 275, 12136.
Effector
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Efforts toward the synthesis of Phorbol
§ Paul Wender and co-workers:
Racemic total synthesis, 52 steps, 0.16% overall yield 1 Racemic formal synthesis, 42 steps, 0.02% overall yield 3 Asymmetric formal synthesis; 36 steps, 1.2% overall yield 4
§ Jin Kun Cha and co-workers:
Asymmetric formal synthesis, 43 steps, 0.4% overall yield 5 § Work from the labs of Shibasaki, Wilson, Rigby, Harwood, Little,
Page, Dauben, McMills, Paquette, Singh, Ovaska, West, Evans, Li, and others.
A-B-C-D, B-C-D, A-B-C skeletal components
[1] J. Am. Chem. Soc. 1989, 111, 8954. [2] J. Am. Chem. Soc. 1989, 111, 8957. [3] J. Am. Chem. Soc. 1990, 112, 4956. [4] J. Am. Chem. Soc. 1997, 119, 7897. [5] J. Am. Chem. Soc. 2001, 123, 5590.
H
HO O
Me Me
MeO
OMe
MeMe
MeO2C
8 kbar2:1 dr (exo)
60%
Z is unreactive
H
HO O
MeMe
MeO
OMe
MeMe
CO2Me
2:1 E/ZTet. Lett. 1989, 30, 5073.
Rigby Lab – [4+2] cycloaddition
J. Org. Chem. 1993, 58, 7635.
Dauben Lab – carbonyl ylide cycloaddition
O OAcH
HMeMe
H
HO
N2EtO2C
OAc
MeMe
H
O CO2Et
O
H
H
Rh2(OAc)4
toluene, 100 oC86%
(both isomers)
HH
Tet. 1994, 50, 4071.
Paquette Lab – anionic oxy-Cope
OMeMe
H
H
O
Me
HLDA
THF, -78 oC71%
MeMe
H
O
OH
H
H
H H
Me
1
2
3
19
4
5 6
20
7
8 9 10
11 18
12 13
14
15 16
17
A" B"
C"D"
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Wender’s racemic total synthesis
04/09/16 Evan Carder @ Wipf Group 5
H
O O
Me Me
Me
Me
Me
OTBS
H
O
O
MeMe
OAc
O
Me Me
Me
Me
Me
OTBS
OOAc
O OPh2SC(Me)2
THF, CH2Cl2, -78 oC85%
MeMe
MeHO
H
OH
OH
O
Me
OH
HO
14 steps 20 steps
Phorbol52 steps
0.16% Total yield
OAcMe
OHO
TBSO
OAcMe
OO
OAcOTBS
O+
O- H OAc
OTBS
OAc
H
Me
O
OTBS
O92%dr 2:1
DBUOxidopyrylium-Olefin [5+2] Cycloaddition1. MCPBA, THF2. Ac2O, DMAP, pyr
5 steps
B and C ring
A ring
D ring
[1] J. Am. Chem. Soc. 1989, 111, 8954. [2] J. Am. Chem. Soc. 1989, 111, 8957.
OAc
H
Me
OTBS
OOHCTMSO
OAc
H
Me
OTBS
OONTMSO
H1. NH2OH2. NaOCl
46%
OAc
H
Me
OTBS
O
TMSO
N+-O
1,3-dipolar cycloaddition
7 steps
-
Wender’s racemic formal synthesis
04/09/16 Evan Carder @ Wipf Group 6
6 stepsO
TBSO
O
OTBS
Me
heat
71% O+
TBSO H
OTBS
H
Me
O
OTBS
O
Oxidopyrylium-Olefin [5+2] Cycloaddition
-O
TBSO
B and C ring
A ring
26 steps
MeMe
MeHO
H
OH
OH
O
Me
OH
HO
Phorbol42 steps
0.02% Total yield
[1] J. Am. Chem. Soc. 1990, 112, 4956.
5 stepsH
Me
OTBS
O
TMSO
Me
Cp2ZrBu2, THF, -78 - rtthen, AcOH
69%
OAc
H
Me
OTBS
O
OTMS
HMe
Me
1. O3; NaBH42. 2-methoxypropene, PPTS
2. PCC, NaOAc24%, three steps
H
O O
Me Me
Me
Me
Me
OTBS
OOAc
O
16 steps, 1% total yieldoriginal: 26 steps. 11% total yield
-
N
OMe
O
O
Bn
O CHOTBSO + 7 steps O
O
HMe
OAcTBSO
OAcO+
O- H OAc
OTBS
OAc
H
Me
O
OTBS
O79%
DBUOxidopyrylium-Olefin [5+2] Cycloaddition
Wender’s asymmetric formal synthesis
04/09/16 Evan Carder @ Wipf Group 7
B and C ring
A ring
[3] J. Am. Chem. Soc. 1997, 119, 7897.
6 stepsH
Me
OTBS
O
TMSO
Ph
1. Cp2ZrCl2, nBuLi then, AcOH2. PCC, NaOAc
84%
OAc
H
Me
OTBS
O
OTMS
HPh
Ph
OAc
21 steps
MeMe
MeHO
H
OH
OH
O
Me
OH
HO
Phorbol36 steps
1.2% Total yield
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Current work: Two phase synthetic strategy
04/09/16 Evan Carder @ Wipf Group 8
[1] Science 2013, 341, 878. [2] Nature 2016, 0, 1.
Cyclase Phase 1
MeMeMe NCS, DMAP
DCM, rt MeMe
Cl
(+)-3-carene
O3, CH2Cl2/MeOH-78 oC
then, thiourea-78 oC - rt
OMeMe
Cl
Two steps, 48%
Li-napthalenide, THF, -78 oCthen, HMPA, MeI, -78 oC -rt
then, LiHMDS, -78 oC OMeMe
Me
44%Me
OHH
OMe
THF, -78 oC - 15 oC MeMe
Me
81%
MeOHHHO
BrMgTBSOTf, Et3NCH2Cl2, 0 oC
then, TMSOTf, Et3N MeMe
Me
71%
MeOTBSHTMSO
[RhCl(CO)2]2, CO
p-xylene, 140 oC
72%
MeMe
MeTMSO
O OTBS
Me
H
Advanced Intermediate>100 g, LEO Pharmaceutical
Oxidase Phase
(+) – Phorbol [2] Advanced Intermediate [1] (+) – 3-Carene
MeMeMe
(+)-3-carene
MeMe
MeTMSO
O OTBS
Me
HCyclase Phase
MeMe
MeHO
H
OH
OH
O
Me
OH
HO
Advanced Intermediate LEO Pharmaceutics
> 100 grams
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04/09/16 Evan Carder @ Wipf Group 9
Oxidase Phase 2
MeTMSO
O OTBS
Me
H
TBSO
Me
Mn(acac)2 (4.0 eq), O2PhSiH3 (3.5 eq.), PPh3 (1.5 eq.)
EtOH
2 steps, 34%SM, 62%
2.16 g scale
MeTMSO
O OTBS
Me
H
TMSO
Me
MeOH
RuCl3 (0.61 eq.)NaBrO3 (54 eq.)NaHCO3 (3.1 eq.)
EtOAc/CH3CN/H2O 0.002 M, (6/6/1)
0.103 g scale
96%
MeTMSO
O OTBS
Me
H
TMSO
Me
MeOH
OO TFAA (10 eq.)
DMAP (3.0 eq.)CH2Cl2, 0 oC
then, Zn (120 eq.)AcOH, CH2Cl2
MeTMSO
O OTBS
Me
H
TMSO
O
O
CF3
MeMe
OHHO
1.01 g scale
MeMe
MeTMSO
O OTBS
Me
H
MeMe
MeTMSO
O OTBS
Me
H
TMSO
Mn(acac)2 (4.5 eq.)PhSiH3 (7.0 eq.), O2EtOH
then, TMSOTf (28 eq.), Et3N (42 eq.), 0 oC
1.25 g scale
70%
MeMe
MeTMSO
O OTBS
Me
H
TMSO
TFDO (1 eq.)
CH2Cl20 oC
HO
1.04 g scale
then, ZnI2 (5.0 eq.)MgI2 (5.0 eq.)
Et2O
MeTMSO
O OTBS
Me
H
TBSO
Me
then, Ac2O (4.0 eq.)DMAP (2.5 eq.)
CH2Cl2, 0 oC
MeTMSO
O OTBS
Me
H
TMSO
O
O
CF3
MeMe
OO
HOMe
Et3N
DMF, 60 oC
64%
MeMe
MeTMSO
O OTBS
Me
H
TMSO
O OAc
TsNHNH2 (6.0 eq.)MeOH, reflux
then, NaBH3CN (18 eq.)AcOH, reflux
40%
0.7 g scale
MeMe
MeTMSO
OTBS
Me
H
TMSO
O OAc
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04/09/16 Evan Carder @ Wipf Group 10
Oxidase Phase 2
MeMe
MeHO
H
OTMS
O OAc
O
Me
OAc
NaBH4, MeOH, -40 oC
then, Ac2O (7.0 eq.)DMAP (5.0 eq.), CH2Cl2
93%
MeMe
MeHO
H
OH
OH
O
Me
OH
NaBH(OAc)3benzene, reflux
then, TBAF, THF, 0 oCthen, Ba(OH)2, MeOH
72%
13 mg scale
HO
(+) - Phorbol15 mg
MeMe
MeTMSO
OTBS
Me
H
TMSO
O OAc
CrO3 (100 eq.)3,5-DMP (105 eq.)
CH2Cl2, 0 oC - rt
46%
0.2 g scale
MeMe
MeTMSO
OTBS
Me
H
OTMS
O OAc
O
1. TMSN2 (218 eq.) DCE, 70 oC then, I2 (339 eq.), pyrdine
2. Me4Sn, AsPh3 PdCl2(PhCN)2 CuI, NMP, 80 oC
two steps, 64%SM, 33%
MeMe
MeTMSO
OTBS
Me
H
OTMS
O OAc
O
13 mg scale
Me
1. HF-Py, THF, 0 oC
2. Martin sulfurane (8.0 eq.) DCE, 60 oCthen, SeO2 (12 eq.)benzene, 80 oC
two steps, 51%
MeMe
MeHO
H
OTMS
O OAc
O
Me
13 mg scale 13 mg scale
HO
-
04/09/16 Evan Carder @ Wipf Group 11
Notable steps: C-H Activation
C-H Activation Considerations § Steric shielding of C6, C7,
C8, and C11.
§ Higher s-character of tertiary cyclopropane C-H bonds (C13/C14).
§ Compared to the remaining
carbon centers, C13 NMR suggests C12 is the most nucleophilic position.
§ Hyperconjugation from the pi-like cyclopropane system should facilitate oxidation.
MeMe
MeO
O OTBS
Me
H
TMSO
OHH
SiMeMeMe
12
11
13
14 8
7
6 5 3
12 Eq.
Ax.
Eq. vs Ax. Considerations
§ Activation by cyclopropane occurs through electron donation of its C-C σ bonding orbital to neighboring C-H σ antibonding orbitals.
§ Proper orbital overlap is
required in order for activation through cyclopropane hyperconjugation.
§ Hindered C-H bonds can
experience reduced rates of oxidation.
Angew. Chem. Int. Ed. 2011,50, 3362.
MeMe
MeTMSO
O OTBS
Me
H
TMSO
MeMe
MeTMSO
O OTBS
Me
H
TMSO
TFDO (1 eq.)
CH2Cl20 oC
HO
then, ZnI2 (5.0 eq.)MgI2 (5.0 eq.)
Et2O
MeTMSO
O OTBS
Me
H
TBSO
Me
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04/09/16 Evan Carder @ Wipf Group 12
MeTMSO
O OTBS
Me
H
TMSO
Me
MeOH
RuCl3 (0.61 eq.)NaBrO3 (54 eq.)NaHCO3 (3.1 eq.)
EtOAc/CH3CN/H2O 0.002 M, (6/6/1)
0.103 g scale
96%
MeTMSO
O OTBS
Me
H
TMSO
Me
MeOH
OO
Notable steps: 1,2 –Diketone
-
04/09/16 Evan Carder @ Wipf Group 13
MeTMSO
O OTBS
Me
H
TMSO
Me
MeOTFA
HOOH
acetylationthen, reduction
Sc(OTf)3
not observed
ring closure
MeMe
MeTMSO
O OTBS
Me
H
TMSO
O OH
O OTBS
MeTMSO1,2 - shift
TMSOMe
O
H
HO
62%
TFAA then, Zn
MeTMSO
O OTBS
Me
H
TMSO
Me
MeOH
OO
TFAA then, Zn, Sc(OTf)3
MeMe
MeTMSO
O OTBS
Me
H
TMSO
O OH
product not obtained
Alternative product
Notable steps: Reforming the cyclopropane ring
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04/09/16 Evan Carder @ Wipf Group 14
MeTMSO
O OTBS
Me
H
TMSO
O
O
CF3
MeMe
OO
HOMe
MeTMSO
O OTBS
Me
H
TMSO
Me
MeO
HOOH
MeTMSO
O OTBS
Me
H
TMSO
O
O
CF3
MeMe
OHHO
CF3
O
acetylationthen, reduction
TFAA then, Zn
aldol
Ac2O
acetylation
MeTMSO
O OTBS
Me
H
TMSO
Me
MeOTFA
HOOAc
ring closure
MeMe
MeTMSO
O OTBS
Me
H
TMSO
O OAc
Et3N
retro-Aldol
Desired product
MeTMSO
O OTBS
Me
H
TMSO
Me
MeOH
OO
1.TFAA (10 eq.) DMAP (3.0 eq.), CH2Cl2, 0 oC2. Zn (120 eq.) AcOH, CH2Cl2
3. Ac2O (4.0 eq.) DMAP (2.5 eq) CH2Cl2, 0 oC4. Et3N, DMF, 60 oC
MeMe
MeTMSO
O OTBS
Me
H
TMSO
O OAc
64%
Notable steps: Reforming the cyclopropane ring
-
04/09/16 Evan Carder @ Wipf Group 15
MeMe
MeHO
H
OH
OH
O
Me
OH
HO
MeMe
MeHO
H
OH
OH
O
Me
OH
HO
-
Conclusions
04/09/16 Evan Carder @ Wipf Group 16
§ Accomplished an enantiospecific total synthesis of (+) – Phorbol in 19 steps.
§ Demonstrated an effective, symbiotic relationship between an academic organic chemist and a pharmaceutical company in a collaborative pursuit toward a complex natural product synthesis.
MeMe
MeTMSO
O OTBS
Me
H
Advanced Intermediate [1] (+) – Phorbol [2]
Oxidase Phase
MeMe
MeHO
H
OH
OH
O
Me
OH
HO
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