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Total Synthesis of Sandresolide B and
Amphilectolide
Ingrid T. Chen, Irina Baitinger, Lucas Schreyer, and Dirk Trauner*
University of Munich, Germany
Org Lett 2014, 16, 166–169. dx.doi.org/10.1021/ol403156r
2 • Since the 1980’s more than 40 marine metabolites have been isolated from Pseudopterogorgia elisabethae, a caribbean octocoral
• 1 – 6 isolated from coral from deep-sea expedition
near Sand Andrés island, Columbia, by Rodríguez and coworker.
• Biological activity against inflammation, tuberculosis, cancer, and antiplasmodial activity
Yang et al. JACS 2010, 132, 13608.
Asymmetric Total Synthesis of Caribenol A
3
Liu, L.-Z.; Han, J.-C.; Yue, G.-Z.; Li, C.-C.; Yang, Z. J. Am. Chem. Soc. 2010, 132, 13608–13609.
Retrosynthetic Analysis
4
OO
OHMe
HMe
HOMe
Sandresolide B, 3
O
MeH
MeHO
7
O
MeH
Me8
OHOO
MeH
Me
Amphilectolide, 1
OMe
HMe
OH
O
9
Preparation of Key Furan Building Block 7
5
1 Crisp, G. T.; Meyer, A. G. J. Org. Chem. 1992, 57, 6972–6975. 2 Brancour, C.; Fukuyama, T.; Mukai, Y.; Skrydstrup, T.; Ryu, I. Org Lett 2013, 15, 2794–2797.
O
MeH
MeHO
7
O Me
(–)-β-citronellal
8 steps
O
H
MeTBSO
10
MeMeO
O
CNLDA, HMPA
–78 °C83%
O
H
MeTBSO
11
Me
O
OMe
1.) LDA, Tf2O– 78 °C (86%)2.) DIBAL–H
– 78 °C (83%)
H
MeTBSO
12
Me
OTf
OH
Pd(PPh3)4NBu3, LiCl, 85°C
with CO (3 atm) (98%)or with H2SO4, HCO2H
98%O
MeH
MeTBSO
13 O
DIBAL–H, – 78 °Cthen SIO2, CHCl3
88% O
MeH
MeTBSO
14
TBAF99%
[Ref 1]
[Ref 2]
Synthesis of Compound 102
6
O Me
(–)-β-citronellal
1.) ZnBr2 (70%)
2.) Ac2OH
Me
OAc[Ref 1]
O3, MeOHthen SMe2
89%H
Me
O OAc
(EtO)2P(=O)CH2CO2EtNaH, Δ
separation of E : Z (9:1)64% (mixture)
HMe
OAcEtO2C
semicorrin ANaBH4, CoCl2
H
Me
OAcCO2Et
90%DIBAL–H
75%
H
Me
OH
OH
1.) TBSCl, imid.2.) Swern ox.
H
Me
O
OTBS10
N N
CN
HOTBS OTBS
A
1 Nakatani, Y.; Kawashima, K. Synthesis 1978, 1978, 147–148. 2 Kocienski, P. J.; Pontiroli, A.; Qun, L.. J. Chem. Soc., Perkin Trans. 1 2001, 2356–2366. 3 Pfaltz, A. Acc. Chem. Res. 1993, 26, 339–345.
[Ref 3]
Preparation of Key Furan Building Block 7
7
1 Crisp, G. T.; Meyer, A. G. J. Org. Chem. 1992, 57, 6972–6975. 2 Brancour, C.; Fukuyama, T.; Mukai, Y.; Skrydstrup, T.; Ryu, I. Org Lett 2013, 15, 2794–2797.
O
MeH
MeHO
7
O Me
(–)-β-citronellal
8 steps
O
H
MeTBSO
10
MeMeO
O
CNLDA, HMPA
–78 °C83%
O
H
MeTBSO
11
Me
O
OMe
1.) LDA, Tf2O– 78 °C (86%)2.) DIBAL–H
– 78 °C (83%)
H
MeTBSO
12
Me
OTf
OH
Pd(PPh3)4NBu3, LiCl, 85°C
with CO (3 atm) (98%)or with H2SO4, HCO2H
98%O
MeH
MeTBSO
13 O
DIBAL–H, – 78 °Cthen SIO2, CHCl3
88% O
MeH
MeTBSO
14
TBAF99%
[Ref 1]
[Ref 2]
Total Synthesis of Amphilectolide, 1
8
Rose bengal
1 Noji, M.; Ohno, T.; Fuji, K.; Futaba, N.; Tajima, H.; Ishii, K. J. Org. Chem. 2003, 68, 9340–9347. 2 Kernan, M. R.; Faulkner, D. J. J. Org. Chem. 1988, 53, 2773–2776.
O
MeH
MeHO
7
1.) MsCl, DMAPPyr (97%)2.) KCN, 90 °C(89%) O
MeH
Me15
NO
MeH
Me16
KOH, 130 °C90%
O
HO
O
MeH
Me17
O
1.) CDI,
2.) , 0 °C to rt
81% (over 2 steps)
NH
OMeMeHCl.
MgBr O
MeH
Me8
OH
NaBH4, CeCl3– 20 °C, (95%)
La(OTf)3
MeNO270%
MeH
MeO18
OO
MeH
Me
Amphilectolide, 1
1.) hυ, O2rose bengal, – 78 °C
Hünig's base[Ref. 2]
2.) NaBH411% (over 2 steps)
[Ref 1](1:1.5 ratio)
MgBr20%
Myers Alkylation to Access Ring-Closure Precursor 9
9
O
OH19
OH
Me
NMe
H
PivCl, TEA0 °C76%
OH
Me
NMe
O
20
1.) MsCl, DMAPPyr (97%)
O
MeH
MeHO
7
2.) NaI, 85 °C(84%) O
MeH
MeI
21
LDA, LiCl– 78 °C to rt
OMe
HMe
N
O
MeMe
OH22
n-Bu4NOH90 °C99%
OMe
HMe
OH
O
9
[Ref. 2]
[Ref. 1]
1 Myers, A. G.; Yang, B. H.; Chen, H.; Gleason, J. L. J. Am. Chem. Soc. 1994, 116, 9361–9362. 2 Myers, A. G. et al. J. Am. Chem. Soc. 1997, 119, 6496–6511.
Myers Alkylation
10
OLi(solvent)nH
NR1
H
MeH OLi(solvent)n
Primary Alkyl HalidesR2 – I
OHNMe
Me OR1
OHNMe
Me OR1
R2Me
1,4–syn
α−face
OHNMe
Me O LDA, LiCl-78 °C to rt
OLiNMe
Me OLi+ I
Me
OMeH
OHNMe
Me O
Me
O
Me
OMe
HMe
N
O
MeMe
OH22
1,3-syn
Myers, A. G. et al. J. Am. Chem. Soc. 1997, 119, 6496–6511.
Myers Alkylation to Access Ring-Closure Precursor 9
11
O
OH19
OH
Me
NMe
H
PivCl, TEA0 °C76%
OH
Me
NMe
O
20
1.) MsCl, DMAPPyr (97%)
O
MeH
MeHO
7
2.) NaI, 85 °C(84%) O
MeH
MeI
21
LDA, LiCl– 78 °C to rt
OMe
HMe
N
O
MeMe
OH22
n-Bu4NOH90 °C99%
OMe
HMe
OH
O
9
[Ref. 2]
[Ref. 1]
1 Myers, A. G.; Yang, B. H.; Chen, H.; Gleason, J. L. J. Am. Chem. Soc. 1994, 116, 9361–9362. 2 Myers, A. G. et al. J. Am. Chem. Soc. 1997, 119, 6496–6511.
Ring Closure and NOE Correlation to Characterize 24
12
OMe
HMe
OH
O
9
O
HMe
Me
O
HMe
Me
H
O
O
TFAA, ZnCl2 (2.5 equiv.)40 °C, 1 hour
71%
23 (1 diastereomer)
TFAA, ZnCl2 (0.2 equiv.)40 °C, 4.5 hours
46%
24 (23%)
+ 23 (23%)
DBU99%
observed NOE
à 24 thermodynamic product, 6.7 kcal/mol more stable than 23 (kinetic product) (10’000 step Monte Carlo search, solvent-free OPLS algorithm)
Completion of Sandresolide B, 3
13
Tetraphenyl- porphyrine
O
HMe
MeO
23
1.) MeMgBr, – 78 °C
2.) hυ, O2, TPP– 78 °C then DBU51% (over 2 steps) O
OOHMe
HMe
HOMe
Sandresolide B, 3
OHOMe
HMe
Me
OO H
B
via
O
HMe
MeO
BrMgMe"top" attack
"down" attackSandresolide B, 3
OO
MeHO
HMe
HOMe
Sandresolide C,4
Conclusion ¡ Scalable route to furan building block 7
¡ First total synthesis of amphilectolide, 1, and sandresolide B, 3
¡ Intramolecular Friedel-Craft alkylation for 1 and acylation for 3 to build third ring
¡ Use of two different sensitizer for photooxygenations (rose bengal and tetraphenylporphyrine)
¡ The use of building block 7 for the synthesis of other alkaloids of same source (Pseudopterogorgia elisabethae) is under active investigation
14