cladiellin, briarellin, asbestinin & sarcodictyin · aco aco litophynin d. baran lab tom...
TRANSCRIPT
Baran Lab Tom MaimoneCladiellin, Briarellin, Asbestinin & Sarcodictyin Diterpenes
for excellent reviews see:Bernardelli, P., Paquette, L.A. Heterocycles. 1998, 49, 531-556Sung, P-J., Chen, M-C. Heterocycles. 2002, 57, 1705-1715
I. Introduction Cembranes are a large class of macrocyclic diterpenes (C20) isolated from a diverse group of organisms (both plants and animals)They are especially abundant in marine environments and often possess interesting biological profiles (defense mechanisms)Gorgonian corals produce a large number of cyclized and oxidized cembranes which can grouped into four main categories:(1) Cladiellin = eunicellin (2) Briarellin (3) Asbestinin (4) Sarcodictyins
Cembrane skeleton
bond-forming event
Detailed biosynthetic studies have not been performed
[O]
O
Sarcodictyins
O
Cladiellins
The Classification largely rests on the type of ether linkage, thus leading to various ring-systems (although some possess no ether linkages)
largest groupCladiellins
O
O
[O]
Briarellins
O
O
1,2 Shift?
Asbestinins
[O]Within each Class there is also a large variation in oxygenation patterns:
O
Sites of oxygenation in the Cladiellins
O
O
Briarellin oxygenation sites
O
O
Asbestinin oxygenation sites
(Not all positions are simultaneously oxidized)
O
Sarcodictyin oxygenation
Some oddities worth noting:
OO
O
CHO
ring-opened briarellin
OO
O
CHO
ring-opened asbestinin
1
Baran Lab Tom MaimoneCladiellin, Briarellin, Asbestinin & Sarcodictyin Diterpenes
2
O
H
H
H
H
OOH
OH OAc
alcyonin (revised)
H
H
solenopodin D
HOOAc
OAc
H
H
HOAcO
AcO
12,13-Diacetoxycladiella- 2,6-dien-11-ol
H
H
HOO H
solenopodin C
H
H
HO O H
AcO
solenopodin B
H
H
HO O H
AcO
solenopodin A
AcO
O
H H
H
HO OAc
Labiatin A
O
OH
No Name
O
H
H
H
HOH
Cladiella-6,11- dien-3-ol
O
H
H
H
HOAc
3-Acetoxycladiella-6,11-diene
O
H
H
H
HOH
OAc
6-Acetoxycladiella7(16),11-dien-3-ol
O
H
H
H
HOH
OHOH
Cladiell-11-ene- 3,6,7-triol
O
H
H
H
HOAc
OHOH
3-Acetoxycladiell- 11-ene-6,7-diol
O
H
H
H
HOAc
Cladiellin
O
H
H
H
HOCOPr
Litophynin A
O
H
H
H
HOCOPr
PrOCO
Litophynin B
O
H
H
H
HOCOPr
HO
Litophynin C
O
H
H
H
HOH
OHOH
Sclerophytin F, A (revised)
O
H
H
H
HOH
OAcOH
Sclerophytin B (revised)
O
H
H
H
HOCOPr
OH
OH
HO
Litophynin I
O
H
H
H
HOCOPr
OAc
OH
HO
Litophynin I monoacetate
O
H
H
H
HOCOPr
OH
HO O
Litophynin J
O
H
H
H
HOCOPr
HO OH
Litophynin H
O
H
H
H
HOCOPr
AcO
AcO
Litophynin D
Baran Lab Tom MaimoneCladiellin, Briarellin, Asbestinin & Sarcodictyin Diterpenes
3
O
H
H
H
HOAc
AcOAcO NAc
Me
O
H
H
H
H
OH
OAc
AcOAcO
Labiatin C labiatamide A
O
H
H
H
HOCOPr
HOAcO
PrOCO
12-Acetoxy-3,13-dibutanoyloxycladiell-6-ene-4,11-diol
OH
O
H
H
H
HOAc
AcO
Calicophirin B
O
H
H
H
H
OH
OAc
AcOAcO
O
H
H
H
H
OAc
OAc
O OH
3,6-Diacetoxy-11,12-epoxycladiellan-7-ol
O
H
H
H
HOAc
AcO
(6E)-11-Acetoxy- cladiellin
O
H
H
H
HOAc
AcO
(6Z)-11-Acetoxy- cladiellin
O
H
H
H
HOAc
AcO
NAcMe
labiatamide B
O
H
H
H
H
OMe
OAc
OHHO
Palmonine C
O
H
H
H
H
OMe
OAc
OHAcO
Palmonine A
O
H
H
H
H
OH
OAc
AcO
Palmonine F
O
H
H
H
H
OAc
OAc
AcO
Palmonine B
O
H
H
H
HOAc
AcO
O
Palmonine D
O
H
H
H
HOAc
AcO
O
Palmonine E
O
H
H
H
HOH
OHHO
Cladiellane-3,7,11- triol
O
H
H
H
HOH
OHAcO
11-Acetoxy-cladiellane-3,7-diol
O
H
H
H
H
O
OH
vigulariol
O
H
H
H
H
O
polyanthellin A
AcO
O
H
H
H
HAcO
AcOAcO
massileunicellin-A
O
OH
O
H
H
H
HOH
AcO
massileunicellin-D
AcOAcO
O
H
H
H
HAcO
AcOAcO
O
OH
massileunicellin-B
O
H
H
H
HAcO
AcOAcO
O
OH
Me
massileunicellin-C
O
H
H
H
HOAc
AcOAcO
AcO
OAc
unamed eunicellin
Baran Lab Tom MaimoneCladiellin, Briarellin, Asbestinin & Sarcodictyin Diterpenes
4
O
H
H
H
H
OH
OH
OH
Sclerophytin F
O
H
H
H
H
OH
OCOPr
OH
3-Butanoyloxycladiell-11 (17)-ene-6,7-diol
O
H
H
H
H
OH
OAc
OH
Sclerophytin E
O
H
H
H
HOAc
OAc
AcO
OAc
astrogorgin
O
H
H
H
HOAc
AcO
OAc
Ophirin
O
H
H
H
H
OAc
OH
OH
6-Acetoxycladiell-11 (17)-ene-3,7-diol
O
H
H
H
H
OMe
OMe
OH
Sclerophytin Fmethyl ether
O
H
H
H
H
OEt
OEt
OH
Patagonicol
O
H
H
H
H
O
OAc
OH
3-Acetoxy-6-(3-methylbutanoyloxy)cladiell-11 (17)-en-7-ol
O
H
H
H
H
OH
OCOPr
OH
O
Litophynin E
O
H
H
H
H
OH
OH
OH
Sclerophytin D
HO
O
H
H
H
H
OH
OAc
OHHO
Sclerophytin C
O
H
H
H
H
OH
COPr
OHHO
Litophynol B
O
H
H
H
H
OH
OH
cladiellisin
O
H
H
H
H
OH
OAc3-Acetoxycladiella-7(16), 11(17)-dien-6-ol
O
H
H
H
H
OH
OCOPr
Litophynin F
O
H
H
H
H
OOH
OH
cladiellaperoxide
O
H
H
H
H
OH
OCOPr
HO
Litophynol A
O
H
H
H
H
O
OCOPr
Litophynin G
O
H
H
H
H
O
OAc
3-Acetoxycladiell-11(17)-en-6-ones
O
H
H
H
HOAc
AcO
(6Z)-3,13,18-Triacetoxycladiella-6,11-diene
O
H
H
H
H
OAc
OAc
Eunicellin
AcOAcO
O
H
H
H
HOAc
AcO
O
OAc
Calicophirin A
O
H
H
H
HOAc
AcOAcO O
Labiatin B
Baran Lab Tom MaimoneCladiellin, Briarellin, Asbestinin & Sarcodictyin Diterpenes
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O
H
H
H
HOH
AcOAcO
AcO
OAcO
H
H
H
HOAc
AcOAcO
AcO
OO
H
H
H
HOAc
AcO
AcOAcO
OAcO
H
H
H
HOH
AcO
AcOAcO
OAc
O
H
H
H
HOAc
AcO
AcOAcO
OHO
H
H
H
HOAc
AcO
AcOAcO
O
unamed eunicellin unamed eunicellin unamed eunicellin unamed eunicellin
unamed eunicellin unamed eunicellin
O
H
H
H
H
OH
OH
O2CC7H15
O
OOH
Briarellin A tentative
O
H
H
H
H
OH
OH
O2CC7H15
O
OH
Briarellin B
O
H
H
H
H
OH
OH
O2CC7H15
O
OCOPr
Briarellin C
O
H
H
H
H
OH
OH
O
OH
Briarellin D
O
H
H
H
H
HO
OH
OH
O2CC7H15
Briarellin E
O
H
H
H
H
HO
OH
O
O2CC7H15
Briarellin F
O
H
H
H
H
C7H15CO2
OH
OH
O
Briarellin G
O
H
H
H
H
HO
OH
O
HO
OCOC7H15
Briarellin H
O
H
H
H
H
HO
OH
C7H15CO2
Briarellin I
O
H
H
O
H
H
OH
OH
O
CHO
seco-Briarellin I
O
H
H
H
H
OAc
OH
OBriarellin J
O
H
H
H
H
OAc
OH
O
OH
Briarellin K
O
H
H
H
H
C3H7O2
OH
O
OAc
Briarellin L
O
H
H
H
H
C3H7O2
OH
O
OH
deacetyl-Briarellin L
O
H
H
H
H
C3H7O2
OH
O
OOH
peroxy Briarellin L
O
H
H
H
H
OAc
OH
O
OOH
peroxy Briarellin K
O
H
H
H
H
OAc
OH
OBriarellin M
OHOH O
H
H
H
H
OAc
OH
O
OHOMe
Briarellin N
Baran Lab Tom MaimoneCladiellin, Briarellin, Asbestinin & Sarcodictyin Diterpenes
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O
H
H
H
H
C3H7OCO
OH
O
OHOH
Briarellin O
O
H
H
H
H
C3H7OCO
OH
O
OHOMe
Briarellin P
O
H
H
H
HO
H
OAc
11-Acetoxy-4-deoxyasbestinin B
O
H
H
H
HO
H
OCOPr
4-Deoxyasbestinin A
O
H
H
H
HO
H
OAc
11-Acetoxy-4-deoxyasbestinin D 4-deoxyasbestinin C
O
H
H
H
HO
H
PrOCO
O
H
H
H
HO
H
OAc
OCOC7H15
Asbestinin-6
O
H
H
H
HO
H
OCOPr
OH
Asbestinin-3
O
H
H
H
HO
H
OCOPr
OAc
Asbestinin-1
O
H
H
H
HO
HOCOC7H15
O
Asbestinin-8
O
H
H
H
HO
H
OAc
OAc
11-Acetoxy-4-deoxyasbestinin E
O
H
H
H
HO
H
OAc
11-Acetoxy-4-deoxyasbestinin F
OH
O
H
H
H
HO
H
PrOCO
OH
4-Deoxyasbestinin G
O
H
H
H
HO
H
OAc
O
H
O
H
H
H
HO
H
AcO
OCHO
O
H
H
H
HO
H
OAc
OAc
Asbestinin-12seco-asbestinin
O
H
H
H
HO
H
OAc
OCOC7H15
Asbestinin-11
O
H
H
H
HO
H
PrCO2
OAc
Asbestinin-2
O
H
H
H
HO
H
PrCO2
OAc
O
Asbestinin epoxide
O
H
H
H
HO
H
OAc
OAc
OH
Asbestinin -17
O
H
H
H
HO
H
OAc
OCOC7H15
OH
Asbestinin -13
O
H
H
H
HO
H
OAc
OCOC5H11
OH
Asbestinin -14
O
H
H
H
HO
H
PrCO2
OAc
OH
Asbestinin-5
O
H
H
H
HO
H
PrCO2
OAc
OAc
Asbestinin-5 acetate
Baran Lab Tom MaimoneCladiellin, Briarellin, Asbestinin & Sarcodictyin Diterpenes
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O
H
H
H
HO
H
OAc
OCOC7H15
Asbestinin-7
OHO
H
H
H
HO
H
OAc
OAc
OH
Asbestinin-15
O
H
H
H
HO
H
OAc
OAc
O
Asbestinin-19
O
H
H
H
HO
H
OAc
OCOC7H15
O
Asbestinin-16
O
H
H
H
HO
H
PrOCO
OAc
O
Asbestinin-4
O
H
H
H
HO
H
OAc
OH
Asbestinin-20
O
H
H
H
HO
H
OAc
OCOC7H15
Asbestinin-18
OH
O
H
H
H
HO
H
OAc
Asbestinin-21
O
OH
O
H
H
H
HO
H
PrOCO
O
OH
Asbestinin-22
O
H
H
H
HO
H
OAc
O
Asbestinin-23
O
H
H
H
HO
H
PrOCO
O
Asbestinin-9
O
H
H
H
HO
H
OAc
O
Asbestinin-10
O
O
OH
O
N
N
CO2Me
H
HMe
Sarcodictyin A
O
O
OH
O
N
N
CO2Et
H
HMe
Sarcodictyin B
O
O
OH
O
N
N
CO2Me
H
HMe
O
O
OH
O
CO2Et
H
H
HO
Sarcodictyin F
HO
N
MeN
Sarcodictyin E
O
O
OHCO2Me
H
HHO
O
imid
Sarcodictyin C
O
O
OHCO2Me
H
HAcO
O
imid
Sarcodictyin D
O
O
OH
H
HO
O
O
O
OMe
H
HO
O
Valdivone A Valdivone Amethoxyketal
O
O
OH
H
HO
O
Valdivone B
O
O
OH
H
HO
O
Valdivone Bmethoxyketal
O
O
OH
H
HO
O
Dihydrovaldivone A
Baran Lab Tom MaimoneCladiellin, Briarellin, Asbestinin & Sarcodictyin Diterpenes
8
O
O
OH
O
N
N
O
OOAc
OH
OAc
H
HMe
eleuthoside A
O
O
OH
O
N
N
O
OOH
OAc
OAc
H
HMe
eleuthoside B
O
O
OMe
O
N
N
O
OOH
OH
OAc
H
HMe
Eleutherobin
CladiellinsBaran Lab Tom Maimone
(−)-7-deacetoxyalcyonin acetate (1995)
MacMillan, D.W.C., Overman, L.E. J. Am. Chem. Soc. 1995, 117, 10391-10392
Me Me
O
H
H
H
MeH
OH
OAc
The Prins-Pinacol Reaction
OH
OH
R1 O
R2
acid
O
OH
R1
R2
(-H2O)
HPrins
O
OH
R1
R2
PinacolO
R2
R1
R
R ROHC
O 1) H2, PtO2
2) LDA, PhN(Tf)2
3) Pd(PPh3)4, NIS (Me3Sn)2
I
(S)-carvone
OOMOP TMS
prepared in 4 steps from (S)-glycidyl pivalate
1) i. t-BuLi, THF, -78°Cii.
2) PPTS, MeOH
OH
OH TMS
OOTIPS
BF3 OEt2, CH2Cl2-55°C -20°C
O
CHO
R
3-formyl THF
HOTIPS
TMS
(9:1 dr)1 2 379%64%
78%
prepared in 2 steps
OR1
R2F3BO
Single Isomer!
OR1
R2F3BO
(via chair TS)
OR1
BF3O
R2
favored
Overman
O
CHO
H
HR2
R1
XO
R1
BF3OR2
O
CHO
H R1
R2
Stereochemical Model for the Prins-Pinacol Rearrangement
1) AcOH, H2O2) hν, hexanes
O
H
HOH
TMS
4
9
71%
CladiellinsBaran Lab Tom Maimone
(−)-7-deacetoxyalcyonin acetate (1995)
O
H
H
H
HOH
OAcO
H
HOH
TMS
1
1) SAE
2) RedAl, H2O79%
O
H
HOHOH
H
H
2
Overman
1) PvCl, pyr.2) TBSOTf, lutidine
3) B-I-9-BBN, ACOH
O
H
HOTBS
H
H
O
I
4) i-Bu2AlH5) TPAP, NMO
78%
O
H
HOTBS
H
H
IO
1) Ph3P=CHOMe THF, -30°C2) TfOH, i-PrOH
3
4
77%
Me Me
O
H
H
H
MeH
OTBS
OH NiCl2-CrCl2DMSO
65%(>20:1 dr)
1) Ac2O
2) n-Bu4NF88%
Me Me
O
H
H
H
MeH
OH
OAc
5
Sclerophytin A (Revised)
Sclerophytin A (Proposed)
"Particularly enigmatic to us was the manner in which the isolation group depicted the configuration at C-3 in their formulation. Unfortunately, the intentions behind the use of an "inverted carbon" symbolism here will never be known." L. A. Paquette
?
Paquette, L.A., Moradei, O.M., Bernardelli, P., Lange, T. Org. Lett. 2000, 2, 1875-1878
Paquette and Overman groups (2000-2001)
Overman, L.E., Pennington, L.D. Org. Lett. 2000, 2, 2683-2686Gallou, F., MacMillan, D.W.C., Overman, L.E., Paquette, L.A., Pennington, L.D., Yang, J. Org. Lett. 2001, 3, 135-137Paquette et. al. J. Am. Chem. Soc. 2001, 123, 9021-9032 MacMillan, D.W.C., Overman, L. E., Pennington, L.D. J. Am. Chem. Soc. 2001, 123, 9033-9044
A streamlined route was also developed(see JACS fullpaper)
O
OH
O
H
H
H
H3
Sclerophytin A as drawnin the isolation paper(R and S not denoted)
O
OH
O
H
H
H
H
presumably the structurethey meant to depict inthe isolation paper
R
S
O
HH
H
O
OH
A B
R
R
B's actual conformation,however would corrrespondto C (Paquette's depiction)
O
H
H
H
H
O
OHR
RMe Me
O
H
H
H
H
O
OH
D
Overmans depictionof C (same structure)
C
R
R
10
CladiellinsBaran Lab Tom Maimone
11
Sclerophytin A (Revised)
?Paquette and Overman groups (2000-2001)
O
OH
O
H
H
H
H
Paquette's route to C:
O
O
OMen
OMe
OTMS1) PhMe, Δ
2) TMSOTf, lutidine
O
O
OH
H
OMen 1) NaBH4, CeCl32) TBDPSCl, imid
3) Py CSA, H2O4) allylbromide, In TBAB
O
O
H
H
(38% 6 steps)
TBDPSO
O
H
H
H
H
O
MeO
H
H
H
R
R
OHH
Reported by Faulkner in 1980
O
H
H
H
H
OBF3 OEt2
0 °CEt2O
CladiellinThis is known to be R-configin all the Natural products
An intramolecular etherification produces this sterochemistry OH
In addition: Thus Both the Overman andPaquette Groups Target C
C
(dr = 13:1)
1) Dibal-H
2) Ac2O, Et3N3) TMSCN, BF3 OEt2
78%
O
H
H
TBDPSO
CN4) KOtBu, tBuOH1 2 3
1) O2, PdCl2, CuCl, H2O2) CeCl3
MgBr3) NaOMe, MeOH4) Cl3C6H2COCl, Et3N, DMAP
O
H
HO
H
H
TBDPSO
O4
1) ClCp2Ti AlMe2
2) NaBF4, PhMe, Δ
O
H
H
H
HO
TBDPSO
5
1) MeLi2) KH, BzCl
3)TBAF4)TPAP, NMO
O
H
H
H
H
O
OBz6
1) LHMDS, TMSCl; HCHO, Yb(OTf)3
2) TBDPSCl3) i-PrMgCl, CuBr DMS HMPA
O
H
H
H
H
O
OBz
OTBDPS
7
54%
CladiellinsBaran Lab Tom Maimone
12
Sclerophytin A (Revised)
Sclerophytin A (Proposed)
?Paquette and Overman groups (2000-2001)
1) hν, dioxane2) TBAF
3) (t-BuO)3Al t-BuO2H
PhMe-20°C
O
CHO
H
TMS
OTIPS
(6.6:1 dr)41%
OH
O
OH
O
H
H
H
H
OH
OH
TMS
CHO
TIPSO
p-TsOH H2OMgSO4, CH2Cl2
-20*C76%
O
CHO
H
TMS
OTIPS
SnCl4 (10%) 1:1 CH2Cl2/MeNO2
-50°C88%
OO
TMS
OTIPS
O
H
H
H
H
O
OBz
OTBDPS
7
1) NaBH4, CeCl32) (Im)2C=S
3) Bu3SnH, AIBN, toluene, 100°C4) DIBAL
O
H
H
H
HOH
OTBDPS
68%
Hg(OCOCF3)2, DMF;O2, NaBH4 O
H
H
H
H
O
OTBDPS
OH
54%
8 9
(+ 18% THF ring)
1) Ac2O2) TBAF3)o-NitroPhenyl-
selenocyanide,Bu3P; H2O2
4) DIBALO
H
H
H
H
O
OH1) TPAP, NMO
2) DIBALO
H
H
H
H
O
OH
Cepi-CNot SclerophytinNot Sclerophytin
O
H
H
H
H
OH
OH
Hg(OAc)2, THF;NaBH4, NaOH
hν, AcOHp-xylene
66% bsm2-propanol rt
80%
ratio of C:14 = 4:1
O
H
H
H
H
O
OHstepsO
H
H
H
H
O
OH
10 11 12
1314CNot Sclerophytin
O
H
H
H
H
O
OH
epi-CNot Sclerophytin
CladiellinsBaran Lab Tom Maimone
13
Sclerophytin A (Revised)
Sclerophytin A (Proposed)
?Paquette and Overman groups (2000-2001)
O
OH
O
H
H
H
H
After thoroughly re-evaluating NMR and MSdata, the Paquette lab proposesthe following:
Friedrich, D., Doskotch, R. W., Paquette, L.A. Org. Lett. 2000, 2, 1879-1882
O
H
H
H
HOH
OHOH
sclerophytin A
In a joint publication, using mostly chemistry we have discussed,both the Overman and Paquette labs verify the new proposal. Thefollowing compounds are prepared
O
H
H
H
HOH
OHOH
sclerophytin A
O
H
H
H
HOH
OAcOH
sclerophytin B
identical to previouslyreported sclerophytin F
O
H
H
H
HOH
OHOH
Cladiell-11-ene-3,6,7-triol
The Overman lab also revises the structure of alcyonin
O
H
H
H
HOH
OH
proposed revised
O
H
H
H
HOH
OOH
Corminboeuf, O., Overman, L.E., Pennington, L.D. Org. Lett. 2003, 1543-1546
BriarellinsBaran Lab Tom Maimone
14
O
H
H
H
HO
H
HO
O
O
O
Briarellin F
O
H
H
H
HO
H
HO
O
O
OH
Briarellin E
Overman et al.
Corminboeuf, O., Overman, L.E., Pennington, L.D. J. Am. Chem. Soc. 2003, 123, 6650-6652
O
1) i. 9-BBN (2.2 equiv), THF, 0 °C ii. NaOH, H2O2, rt -> reflux
2) TEMPO, NCS, n-BuNCl, CHCl3:NaHCO3:K2CO3 (2:1:1)
O
O
H H
1) LDA, THF, -78°C; TMSCl, -78°C −> 0°C; AcOH, 0°C −> rt
78%2) LiAlH4
(S)-Carvone
H
HO
OH
(20:1 dr)1) TIPSCl, imid
2) PCC
58%
87%
H
TIPSO
O
1
23
steps
H
OTIPS
O
H
H
H
H OAcO
1) TFA, PhMe, 0°C; H2O, rt
2) Ac2OH
OTIPS
O
H
H
H
H OAcOH OAc
45
1) m-CPBA, 0°C2) TBAF3) Tf2O, 2,6-lutidine
45%
86%
H
O
H
H
H
H OAcOAc
O
O
6
1) H2SO4, H2O2) MsCl, Et3N; LiAlH43) Bu8Sn4Cl4O2, isopropenyl acetate
4) C7H15COCl, pyr.5) Bu3SnAlEt2, CuCN6) I2
H
O
H
H
H
H OAcOCOC7H15O
HO
I 1) (t-Bu)2(OH)SnCl, MeOH2) DMP
3) CrCl2-NiCl2 DMSO-DMS
35%
O
H
H
H
HO
H
HO
O
O
OH
59%
O
H
H
H
HO
H
HO
O
O
O
1) DMP79%
Briarellin E Briarellin F
CladiellinsBaran Lab Tom Maimone
Molander, G.A., St. Jean, D.J.Jr., Haas, J. J. Am. Chem. Soc. 2004, 126, 1642-1643
α-phellandrene
O
H
H
H
HOH
OAc
deacetoxyalcyonin acetate
Molander et al.
O
ClOMe
Et3N25%
H
H
OMe
O
AcOH, hν86%
H
H
O
OMe
OAc
OTES
OTES OMe
TiCl4-80 °C43-80%
H
H
O OH
CO2Me
1 2 31) n-BuLi (2.2 eq.), LiCl; MeI2) LiCl, H2O, DMSO, 130°C
H
H
O O1) KH, TBSCl
2) PhSeCl; then m-CPBA
H
H
O O
1)BrMeO, t-BuLi
then CuBr DMSthen Comins reag.
H
H
O OTf
2) THF/1N HClCHO
H
H
O
1) CrCl2, NiCl2 DMF2) DEAD, BzOH PPH3
3) MeONa, MeOH
OAc
4) Ac2O, pyr. DMAP
4567
50%
71%71%62%
1) m-CPBA2) O3, DMS
O
H
H
H
H
O
OAcO
O
43%
8
1) WCl6, n-BuLi2) TBSOTf, KHMDS O
H
H
H
H
O
OAc
TBSO
1) Ph3PCH2Br, t-BuOK; 1N HCl O
H
H
H
H
OAc
O
MeLiYb(OTf)3
O
H
H
H
HOH
OAc
66% BRSM57%
15
CladiellinsBaran Lab Tom Maimone
OBr
Me
O
HH
H
C
BrHisolaurallene(completed)
OBr
Me
Cl
HH
obtusenyne(completed)
Crimmins, M.T., Brown, B.H. J. Am. Chem. Soc. 2004, 126, 10264-10266Crimmins, M.T., Brown, B.H., Plake, H.R. J. Am. Chem. Soc. 2006, 128, 1371-1378
O
H
H
H
HAcO
OOAc
AcO
OAc
astrogorgin ophirin B
O
H
H
H
HAcO
OAc
AcO
Crimmins et al.
The Crimmins lab has significant experience in the construction of medium-sized ether ring natural products
Thus we will see a unique approach tothe eunicellin natural products whereinthe 9-membered ether is the key syntheticfragment.
BnOO
1) TMSI, n-BuLi2) NaH, PMBCl
3) Hg(OAc)2, H2O; PdCl2, LiCl, CuCl H2O, O2
O
OPMB
BnO1) MgBr
2) NaH, BnBr
OPMB
BnO
(S)-benzyl glycidyl
OBn
(single isomer)79%
87%1 2
1) MeOH, HCl2) NaH, BrCH2CO2H
3) Me3CCOCl, Et3N, then
NH
O
O
O
OBn
BnO
O
N
OO3
1)NaHMDS,
I
2) LiBH4, MeOH
BnOOBn
OH
H
OH
4
Studies Showed that the Dimer is the kinetic product, but is converted (irreversibly) to the ether at highertemperatures
O
OH
H
HBnO
BnO
5
> 15:1 ether/dimer89%
1) DMP2) Ph3P=C(Me)2CO2Et
3) DIBAL4) DHP, PPTS
OH
HHO
HO
OTHP
5) Na/NH3
1) DMP2) Ph3P=CHCO2Me3) TESOTf
4) PPTS, MeOH5) DMP6) Ph3PCH2OBnCl, t-BuOK
OH
H
TESO
BnO
MeO2C
67
Grubb's IIPhH80 °C
3:1 E : Z
Crimmins, M.T., Ellis, M.J. J. Am. Chem. Soc. 2005, 127, 17200-17201
16
Cladiellins, AsbestininsBaran Lab Tom Maimone
Crimmins, M.T., Brown, B.H. J. Am. Chem. Soc. 2004, 126, 10264-10266Crimmins, M.T., Brown, B.H., Plake, H.R. J. Am. Chem. Soc. 2006, 128, 1371-1378
OH
H
TESO
BnO
MeO2CZ-7
OH
H
TESOMeO2C
OBn
71:3
standing at rt
2 hO
H
H
H
HMeO2CTESO
BnO
80%
hνPhSSPh (cat)
(1:1)
withrecycling step
1) MeMgCl2) TBAF O
H
H
H
HHO
HO3) Na, naphthalene
OH
O
H
H
H
HHO
MeO manyacetylationconditions
1) MeMgCl2) TBAF
O
H
H
H
HHO
BnO
OH
1) KHMDS, Ac2O2) Bi(OTf)3, Ac2O
3) H2, Pd/C4) Ac2O, DMAP
O
H
H
H
HAcO
AcO
OAc
To access astrogorgin the following modifications were made:
O
OBn
BnO
O
N
OOBnO
OBn
OH
H
OH OTIPS1) NaHMDS
I OTIPS
2) LiBH4
steps O
H
H
H
HAcO
OAc
AcO
exo
OTIPS
O
H
H
H
HAcO
OAc
AcO
1) TBAF2) o-NO2PhSeCN3) H2O2
OH
1) TPAP, NMO2) NaBH4, CeCl33) Ac2O, DMAP4) TBAF5) Bi(OTf)3, Ac2O
Ophirin B
O
H
H
H
HAcO
OAc
AcO
OAc
Astrogorgin
To access the asbestinin family:
OH
H
TBSOMeOC
OMe
Me
110 °C O
H
H
H
H
OMe
MeOCTESO
BnO
Me O
H
H
H
HO
H
OAc
11-acetoxy-4-deoxy- asbestinin D
17
CladiellinsBaran Lab Tom Maimone
O
H
H
H
OHH
O
H
H
H
H
O
MeAcO
O
H
H
H
HOH
OAc
O
H
H
H
HOH
OHOH
Cladiell-11-ene- 3,6,7-triol
PolyanthellinCladiella-6,11- dien-3-ol
Deacetoxy-alcyonin acetate
Kim et al
Kim, H., Lee, H., Kim, J., Kim, S., Kim, D. J. Am. Chem. Soc. 2006, 128, 15851-15855
O N
O
Bn
O
OPMB
O
n-BuOTf, Et3N O N
O
Bn
O
OPMB
OH
1) NaBH42) TBDPSCl, imid3) trityl bromide, DMAP
TBDPSO
OH
OTr
1
2
75%
69%4) DDQ
1) NaH, ClCH2CONMe2
2) SeO2; NaBH4
3) PPh3, CCl4TBDPSO
OTr
O
Me2N
OH
Cl
LHMDS, THF
45 °C92%
62%
TBDPSO
OTr
O
Me2N
OH
H
1) DIBAL, n-BuLi
2)SiMe3
N
n-BuLiTBDPSO
OTr
OH
HO
then oxalic acid
68%
345
1) Ph3P=CH22) TBAF
OTr
O
H
H
MeO2C
90%
1) BHT, xylenes reflux, 1h
85%
O
H
H
H
OTrH
6 7
CO2Me
1) MeLi, CeCl32) Ac2O, DMAP Et3N
3) K, 18-C-6 t-BuNH2
55%
O
H
H
H
OHH
Cladiella-6,11- dien-3-ol
O
H
H
H
H
O
AcO
Polyanthellin
1) Hg(OAc)2, H2O; Et3B, NaBH4
2) Ac2O, DMAP
69%
O
H
H
H
HOTES
MeOH
OH1) Ac2O, DMAP2) Burgess, 70°C
3) TBAFO
H
H
H
HOH
OAc
Deacetoxy-alcyonin acetate
1) TESOTf2) OsO4, NMO
18
As with Crimmins approach, the 9-membered ether is the key piece
CladiellinsBaran Lab Tom Maimone
O
H
H
H
O
HO
H
(+)-vigulariol
O
O
CO2Et
prepared in 4 stepsfrom Br(CH2)3OTBS
1
OCO2Et
H H
OH
single diastereomer!
SmI2, MeOH
THF, rt76%
2
1. TBSCl, imid.2. LiOH, MeOH
3. i-BuO2CCl, Et3N, then CH2N2
60%
OH H
OTBSO
N2
OH
OTBS
O
Cu(CF3COCHCOCF3)25 mol%
DCM Δ
96%
[2,3]O
OH
HTBSO
O
OH
HTBSO
3
4(Z)-5
AIBN, EtSH, PhH, Δ 56%
(E)-5
1. NaHMDS, PhNTf2
2. Pd(PPH3)4, LiCl
SnBu3
OEt
(5:1)
O
H
HTBSO
OEt
1. MVK, PhH, Δ
2. K2CO3, MeOH58% (4 steps)
O
H
HOTBS
67
OEt
HO
1. Ph3PCH2Br, t-BuOK2. HCl (5% aq.), THF, rt3. H2, PtO24. Ph3PCH2
O
H
HOTBS
H
H
8
58%
1. n-Bu4NF2. DMP3. MeMgCl
75%O
H
HH
H
OH
O
H
H
H
O
HO
H
m-CPBA, 0°C
69%
(+)-vigulariol
J. Stephen Clark et al.
Clark, J. S., Hayes, S. T., Wilson, C., Gobbi, L. Angew. Chem. Int. Ed. 2007. 46, 437-44019
SarcodictyinsBaran Lab Tom Maimone
Me
Me
O 1. H2O2, NaOH, MeOH2. H2, PtO2
3. LDA, CH2O4. TBSCl, Et3N
O
MeO
OMe
O
N
N
CO2R
Me
Me Me
H
HMe
sarcodictyin A (R=Me)sarcodictyin B (R=Et)
Nicolaou et al.
MeMe
OO
OTBS
Me
H
146%
1. L-Selectride2. MsCl, Et3N
3. Na-naphthalenide79%
MeMe
OTBS
H
Me
HO
carvone 2
1. CH3C(OEt)3 n-PrCO2H
2. DIBAL
MeMe
H
MeH
CHO
OTBS
3
1. (EtO)2P(O)CH2CO2Et2. DIBAL3. Ti(Oi-Pr)4, DET, t-BuOOH
4. MsCl, Et3N5. Na-naphthalenide
72%
71%MeMe
H
MeH
OTBS
OH
4
1. PMBOC(=NH)CCl32. Hg(OAc)2
3. Li2PdCl4, CuCl2MeMe
H
MeH
OTBS
O
OPMB
5
1. HC CMgBr2. TBAF
3. DMP
58%MeMe
H
MeH
O
OPMBMeOH
MeMe
H
MeH
OPMB
OTMSMe
CN
CO2Et
1. NCCH2CO2Et β-alanine2. TMSOTf
6
49%
1. DIBAL
2. TIPSOTf67%
MeMe
H
MeH
OPMB
OTMSMe
CHO
OTIPS
7 8
1. LHMDS
2. DMP
MeMe
H
MeH
OPMB
OOTIPS
MeOH
3. PPTS, MeOH
80% 9MeMe
H
MeH
PMBO MeOH
OOTIPS
H2, Lindlar
75%
10Nicolaou, K. C., Xu, J.-Y., Kim, S., Ohshima, T., Hosokawa, S., Pfefferkorn, J. J. Am. Chem. Soc. 1997, 119, 11353-11354Nicolaou, K. C. et al. Angew. Chem. Int. Ed. Engl. 1997, 36, 2520-2524.Nicolaou, K. C. et al. J. Am. Chem. Soc. 1998. 120, 8661-8673Nicolaou, K. C. et al. J. Am. Chem. Soc. 1998. 120, 8674-8680 20
SarcodictyinsBaran Lab Tom Maimone
O
MeOPMB
OH
Me
Me Me
H
H
OTIPS
1. CSA, MeOH
2. Na, liq. NH3
72%
O
MeOH
OMe
Me
Me Me
H
H
OTIPS
11 12
NMe
NO
O
O
t-Bu
1.
2. TBAF3. DMP4. NaClO25. CH2N26. CSA, H2O
O
MeO
OHCO2Me
Me
Me Me
H
H
sarcodictyin A
O
NMe
N
MeMe
H
MeH
OTES
OTESMe
CHO
OH
a similar approach was usedto prepare eleutherobin
O
OTBS
OTBSOPMB
O
NH
Cl3C
TMSOTf
1
MeMe
H
MeH
OTES
OTESMe
CHO
O
OTBS
OTBSOPMB
O
steps
O
MeO
OHCO2Et
Me
Me Me
H
H
O
NMe
N
sarcodictyin B
O
MeO
OMe
O
N
N
O
OOH
OH
OAc
Me
Me Me
H
HMe
eleutherobin
O
MeO
OH
O
N
N
O
OOAc
OH
OAc
Me
Me Me
H
HMe
eleuthoside A
O
MeO
OH
O
N
N
O
OOH
OAc
OAc
Me
Me Me
H
HMe
eleuthoside B
O
MeO
OHCO2Me
Me
Me Me
H
H
O
NMe
N
dihydro-sarcodictyin A
O
MeO
OMe
O
S
N
O
OOH
OH
OAc
Me
Me Me
H
H
Me
thiazole-eleutherobin
O
MeO
OMe
O
N
N
OOH
OH
OAc
Me
Me Me
H
HMe
O
epi-eleutherobin
Also prepared:
21
SarcodictyinsBaran Lab Tom Maimone
O
OTBSH
HO
OMe
12
O
O
OMe
O
N
N
O
OOH
OH
OAc
H
HMe
eleutherobin
Danishefsky et al.
α-phellandrene
ClCOCCl3Zn, Et2O, 0 °C sonication
H
H O
ClCl
1) Zn, MeOH, NH4Cl
65%N
N
t-BuO
2)
60 °C
65%
1
H
H O
NMe2
2
p-TsOH H2O, MeOH60 °C
1)
2)60%
p-TsOH H2O, Me2CO
H
HCO2Me
CHO
3
O BrLi
55%
1.
2. TBDPSCl
(1.3:1 dr)
OTBDPSH
H
O
BrO
OMe
4
1. CrCl2, NiCl2 DMF
(15:1 dr)
2. PivCl, DMAPO
OHH
HOPiv
5
1) i. DIBAL ii. MsCl, pyr. iii. KCN, 18-C-6
73%2) DIBAL
OTBDPSH
H
O
BrCHO3) TBAF
64%6
1) DMDO, Me2CO CH2Cl2
94%
H
HOPiv
O
HO
OH
H
HOPiv
O
OH
HO
MeLi
7
8
42%
Ac2O, DMAP
-78 °C73%
O
OAcH
H OHOPiv
O
OTBSH
H OMeOPiv
1) DIBAL
2) TPAP, NMO77%
1. Ag2O, MeI MeCN
2. KCN, EtOH reflux3. TBSOTf, 2,6-lutidine
71%9 10
22Danishefsky et al. J. Am. Chem. Soc. 1999, 121, 6563-6579
Danishefsky et al. Angew. Chem. Int. Ed. 1998, 37, 185-186Danishefsky et al. Angew. Chem. Int. Ed. 1998, 37, 789-792
SarcodictyinsBaran Lab Tom Maimone
O
OTBSH
HO
OH O O
O
OAcOBu3Sn
i. LDA
ii. Comins
O
OTBSH
H OHOTf
O
MeOTBS
OMe
O
OO
O
OAc
H
H80%
Pd(PPh3)4, LiCl1. TBAF2. esterify
3. PPTS, MeOH
50%
O
O
OMe
O
N
N
O
OOH
OH
OAc
H
HMe38%
eleutherobin
eleutherobin formal synthesis
H
HOPiv
O
HO
OH
H CHO
OMe
OMe
H
OPMP
s-BuLi
OO
Ph
PhPh
Ph
O
O
TiCl
C. Gennari et al.
H
OMeOMeH
OH
OPMP
1. MOMCl, TBAI DIPEA2. LiBF4, H2O
3. NaBH44. MsCl5. KCN6. DIBAL
H
H
OMOM
OPMPCHO
OO
Ph
PhPh
Ph
O
O
TiCl
OPMP
s-BuLi
H
H
OMOM
OPMPPMPO
OH
12 13 14
1 2 3
4
1. PivCl
2. Grubbs II
H
HOPiv
OMOM
OPMP
OPMP
kinetically controlledRCM (less stable product)
5
H
HOPiv
OMOM
O
O 1. CAN
2. DMP
CDCl3
OTBSH
H
OO
OPiv
H2OO
OMOMH
H
OH
OHOPIV
678
Castoldi, D., Caggiano, L., Panigada, L., Sharon. O., Costa, A. M., Gennari, C. Angew. Chem. Int. Ed. 2005, 44, 588-591
BF3 OEt2