Cladiellin, Briarellin, Asbestinin & Sarcodictyin
Diterpenes
Baran Lab
I. Introduction
Tom Maimone
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
The Classification largely rests on the type of ether linkage, thus leading
to various ring-systems (although some possess no ether linkages)
bond-forming
event
[O]
[O]
O
O
Cembrane skeleton
O
Within each Class there is also a large variation in oxygenation patterns:
(Not all positions are simultaneously oxidized)
Cladiellins
Briarellins
Cladiellins
largest group
[O]
1,2 Shift?
Detailed biosynthetic studies
have not been performed
O
O
O
O
Sarcodictyins
Asbestinins
Sites of oxygenation in the Cladiellins
O
Some oddities worth noting:
O
O
O
O
O
O
CHO
CHO
O
Briarellin oxygenation sites
O
Asbestinin oxygenation sites
for excellent reviews see:
Bernardelli, P., Paquette, L.A. Heterocycles. 1998, 49, 531-556
Sung, P-J., Chen, M-C. Heterocycles. 2002, 57, 1705-1715
O
Sarcodictyin oxygenation
ring-opened briarellin
O
ring-opened asbestinin
1
Cladiellin, Briarellin, Asbestinin & Sarcodictyin
Diterpenes
Baran Lab
AcO
H
HO
O
H
AcO
H
HO
HO
O
H
H
O
H HO
OAc
H
Tom Maimone
OH
H H
H H
OH
OAc
OAc
O
O
H
H
H
HH
HH
H
OH
OH
solenopodin B
solenopodin A
HO
AcO
solenopodin C
OH
H
O
AcO
solenopodin D
OAc
H
Cladiell-11-ene3,6,7-triol
6-Acetoxycladiella
7(16),11-dien-3-ol
PrOCO
H H
H H
H H
OOH
H
O
AcO
H
H
O
12,13-Diacetoxycladiella2,6-dien-11-ol
No Name
Litophynin C
HO
H H
O
OAc
HO
HH
OCOPr
OH
Litophynin I
Sclerophytin B (revised)
OH
H H
O
HO
H H
O
O
OH
AcO
HH
OAc
3-Acetoxycladiell11-ene-6,7-diol
OAc
Cladiellin
HH
HH
OCOPr
Litophynin I
monoacetate
H H
O
O
AcO
HH
OH
O
HH
Sclerophytin F, A (revised)
OAcHO
H H
O
OH
OH
H H
O
OH
OCOPr
3-Acetoxycladiella6,11-diene
OH
H H
HH
OAc
OH
Litophynin B
Litophynin A
O
HH
OH
OH
OCOPr
OCOPr
OH
H H
O
HH
H H
OAc
alcyonin (revised)
H H
O
O
Cladiella-6,11dien-3-ol
HH
HH
OH
HO
HH
OH
Labiatin A
H H
H H
HH
H
O
O
O
HH
OCOPr
Litophynin J
OCOPr
Litophynin H
HH
OCOPr
Litophynin D
2
Cladiellin, Briarellin, Asbestinin & Sarcodictyin
Diterpenes
Baran Lab
AcO
H
AcO
H
AcO
OH AcO
H H
Labiatin C
labiatamide A
HO
OH
H
OAc
AcO
AcO
O
O
PrOCO
HH
HH
3,6-Diacetoxy-11,12epoxycladiellan-7-ol
AcO
H
H
AcO
H
H
OAc
O
AcO
AcO
OH
H
OMe
HH
OAc
labiatamide B
AcO
Palmonine C
AcO
H H
AcO
O
O
H H
OH
O
O
AcO
HH
O
HH
OH AcO
AcO
OH
Cladiellane-3,7,11triol
O
AcO
AcO
OH
O
HH
Me
H H
O
HH
massileunicellin-A
polyanthellin A
vigulariol
AcO
O
HH
Palmonine E
H
O
OAc
HH
H H
O
OAc
HO
OH
OH
H
O
O
11-Acetoxycladiellane-3,7-diol
Palmonine D
H
Me
HH
OH
H H
HH
OAc
HO
HH
H H
Palmonine F
NAc
(6Z)-11-Acetoxycladiellin
O
HH
OAc
O
OAc
OH
H
O
H
AcO
O
HH
H
H
HH
(6E)-11-Acetoxycladiellin
AcO
OAc
AcO
H
OAc
H
O
Palmonine B
OAc
O
HH
12-Acetoxy-3,13dibutanoyloxycladiell6-ene-4,11-diol
HH
Palmonine A
O
OH
OCOPr
OAc
OH
O
HH
OAc
AcO
H
O
HH
H H
H
OMe
Calicophirin B
H H
AcO
OH
H
O
OAc
OAc
H
OH
HH
HH
AcO
H
O
AcO
OAc
H
AcO
O
HH
H
AcO
NAc
O
O
H H
Me
Tom Maimone
AcO
AcO
H H
AcO
AcO
HH
OH
massileunicellin-B
massileunicellin-C
OAc
O
O
AcO
H H
massileunicellin-D
HH
OAc
unamed eunicellin
3
Cladiellin, Briarellin, Asbestinin & Sarcodictyin
Diterpenes
Baran Lab
H H
OH
H H
OH
Sclerophytin F
3-Butanoyloxycladiell11 (17)-ene-6,7-diol
H H
OAc
H H
O
AcO
OAc
astrogorgin
HO
H H
HH
OH
cladiellisin
O
O
OAc
3-Acetoxycladiella7(16), 11(17)-dien6-ol
AcO
O
AcO
HH
HH
AcO
OCOPr
Litophynin F
H
O
H H
(6Z)-3,13,18Triacetoxycladiella6,11-diene
Eunicellin
AcO
AcO
OAc
OAc
3-Acetoxycladiell11(17)-en-6-ones
Litophynin G
H
HH
OAc
OCOPr
AcO
OAc
HH
HH
H H
O
O
O
HH
O
O
Litophynol A
H H
OH
OH
O
OCOPr
cladiellaperoxide
H H
H H
H H
O
HH
OH
Litophynin E
H H
O
HH
COPr
OCOPr
OH
O
HH
Litophynol B
Patagonicol
OOH
O
HH
3-Acetoxy-6-(3methylbutanoyloxy)
cladiell-11 (17)-en7-ol
HO
H
H
OH
O
O
OAc
OEt
H H
OH
OH
O
HH
Sclerophytin F
methyl ether
H H
O
O
HH
OMe
Ophirin
OH
OH
OH
H H
O
HH
OAc
OH
OEt
O
HH
OAc
H H
H H
Sclerophytin C
Sclerophytin D
6-Acetoxycladiell-11
(17)-ene-3,7-diol
OH
OAc
OH
OMe
O
HH
OAc
H H
HH
HH
OH
Sclerophytin E
OH
O
O
HH
OAc
OCOPr
OH
OH
O
HH
HO
H H
OH
OAc
O
HH
OH
HO
H H
OH
OH
O
HH
H H
OH
OH
O
AcO
H H
OH
Tom Maimone
O
HH
OAc
OAc
Calicophirin A
HH
OAc
Labiatin B
4
Cladiellin, Briarellin, Asbestinin & Sarcodictyin
Diterpenes
Baran Lab
AcO
H H
AcO
AcO
H H
OAc AcO
AcO
O AcO
O
AcO
AcO
HH
unamed eunicellin
AcO
H H
AcO
OH AcO
OH
H
AcO
H
OAc
H
O
unamed eunicellin
C7H15CO2
H
unamed eunicellin
HO
H
H
HO
OH
H
HH
O
O
HO
H
OH
H
H
O
H
HH
C3H7O2
O
H
H
H
H
HH
O
H
O
deacetyl-Briarellin L
O
H
OH
O
OMe
HH
O
O
Briarellin M
OH
O
H
HH
O
OAc H
H
OH
OOH
O
HH
O
OAc H
H
peroxy Briarellin K
H
OH
O
HH
H
O
Briarellin L
OAc H
H
H
C3H7O2
HH
O
O
peroxy Briarellin L
H
O
Briarellin K
H
Briarellin F
OAc
O
O
seco-Briarellin I
O2CC7H15
O
O
HH
O
H
HH
Briarellin E
O
OOH
CHO
O
Briarellin I
H
O
HH
O
HH
Briarellin J
H
H
O
O
Briarellin H
H
O
O2CC7H15
O
OH
O
O
Briarellin G
C7H15CO2
H
OCOC7H15
H
O
HH
C3H7O2
O
HH
O
H
OAc H
H
O
H
HO
OH
Briarellin B
OAc H
H
O
H
H
O
Briarellin A tentative
H
Briarellin C
O2CC7H15
O
Briarellin D
O
HH
O2CC7H15
O
OAc
O
O
HH
HH
O
O
HO
OH
O
HH
H
O2CC7H15
O
H
OOH
O
HH
H
O
HH
unamed eunicellin
OH
OH
OCOPr
H
HH
H
H
O
OH
H
O
O
AcO
AcO
unamed eunicellin
H H
OH
H
OAc
OAc
unamed eunicellin
H
O
HH
OAc
OH
H H
O
AcO
OH
AcO
OAcAcO
O
HH
AcO
H H
Tom Maimone
O
Briarellin N
5
Cladiellin, Briarellin, Asbestinin & Sarcodictyin
Diterpenes
Baran Lab
C3H7OCO
H
H
OH
OH
O
H
H H
C3H7OCO
H
H
Briarellin P
PrOCO
H H
H H
O
H
HH
H
H
HH
H
H
H
HH
O
11-Acetoxy-4deoxyasbestinin E
O
HH
seco-asbestinin
H
HH
H
O
OAc
Asbestinin-12
OCOC7H15
O
H
OAc H
H
O
OH
H
O
HH
H
O
Asbestinin epoxide
PrCO2
H
Asbestinin -14
PrCO2
H
H
OH
OAc
O
H
OCOC5H11
O
HH
H
O
Asbestinin-5
OAc
Asbestinin -17
H
OH
HH
HH
OAc
O
OAc
O
O
H
HH
O
Asbestinin-2
H
Asbestinin -13
H
O
HH
O
H
4-Deoxyasbestinin G
HH
O
O
O
O
PrCO2
H
OH
CHO
OAc H
H
HH
OH
OAc H
H
O
H
O
H
OCOC7H15
OAc H
H
O
Asbestinin-8
H
O
Asbestinin-11
OAc H
H
H H
PrCO2
O
11-Acetoxy-4deoxyasbestinin F
H
Asbestinin-3
HH
O
OCOC7H15
O
O
O
O
H
HH
O
Asbestinin-1
PrOCO
H
HH
OCOC7H15
OAc H
H
O
HH
H
HH
OH
H
OAc
OH
Asbestinin-6
OAc H
H
HH
O
O
OAc
H
OCOPr
O
4-deoxyasbestinin C
OAc H
H
AcO
OAc
H
H
O
O
4-Deoxyasbestinin A
O
11-Acetoxy-4deoxyasbestinin D
H
HH
O
H
H
O
11-Acetoxy-4deoxyasbestinin B
O
O
H
H
O
O
Briarellin O
O
H
H
O
HH
O
O
OAc
O
HH
O
OCOPr
OCOPr H
H
H
H
OMe
O
HH
OAc
OH
Tom Maimone
OAc
HH
O
OAc
Asbestinin-5
acetate
6
Cladiellin, Briarellin, Asbestinin & Sarcodictyin
Diterpenes
Baran Lab
OAc H
H
OAc H
H
OAc H
H
OH
H
OCOC7H15
O
Asbestinin-7
PrOCO
H
HH
H
O
O
HH
H
OAc
O
H
HH
Asbestinin-20
Asbestinin-4
O
O
OH
CO2Me
Me
H
Me
N
N
O
Me
OH
CO2Me
Sarcodictyin F
HO
O
O
H
Valdivone B
H
O
OH
O
H
OMe
Valdivone A
methoxyketal
O
H
O
OH
O
H
O
H
O
O
H
O
O
Asbestinin-23
Valdivone A
O
O
Sarcodictyin E
OH
CO2Me
O
O
O
Sarcodictyin D
H
OH
CO2Et
imid
H
HH
O
H
N
H
O
O
O
AcO
O
O
O
OH
CO2Me
OAc H
H
Asbestinin-22
Asbestinin-21
Sarcodictyin C
O
H
O
O
Asbestinin-10
HH
O
O
O
OH
H H
O
O
H
N
H
HH
imid
H
O
O
O
PrOCO
HH
O
O
N
HO
Me
O
H
H
OH
CO2Et
Sarcodictyin B
O
H
H
N
H
O
Asbestinin-9
OH
O
O
N
Sarcodictyin A
HO
O
H
N
H
H
Asbestinin-18
O
O
OCOC7H15
O
O
HH
O
HH
OH
O
H
OCOC7H15
OAc H
H
OH
O
O
HH
Asbestinin-16
OAc H
H
OAc H
H
H
O
O
Asbestinin-19
OAc H
H
H H
H
OAc
O
Asbestinin-15
H
O
HH
OAc
O
O
O
O
HH
PrOCO
O
OH
O
H
OAc H
H
Tom Maimone
H
Valdivone B
methoxyketal
O
OH
O
H
OH
Dihydrovaldivone A
7
Baran Lab
Cladiellin, Briarellin, Asbestinin & Sarcodictyin
Diterpenes
O
O
N
O
H
O
O
H
O
O
N
H
N
O
O
H
O
OAc
OAc
O
OH
eleuthoside A
Me
OH
N
H
O
N
Me
OH
Tom Maimone
H
N
Me
OMe
O
OAc
OH
O
OAc
O
OH
OAc
eleuthoside B
OH
Eleutherobin
8
Cladiellins
Baran Lab
H H
OH
OH
OAc
Me
H H
Me Me OH
acid
R2
OH
1) H2, PtO2
I
R
Prins
78%
favored
R2
R1
R2
3-formyl THF
TMS
OTIPS
BF3 OEt2, CH2Cl2
-55°C
2
TMS
CHO
O
F3BO
O
O
R2
OH
-20°C
79%
(9:1 dr)
O
H
OTIPS
3
Single Isomer!
1) AcOH, H2O
2) hν, hexanes
71%
H CHO
R2
F3BO
R1
Pinacol
(via chair TS)
OH
1
R
O
TMS
2) PPTS, MeOH
64%
prepared in 4 steps from
(S)-glycidyl pivalate
OHC
R1
O
(-H2O)
O
OMOP
3) Pd(PPh3)4, NIS
(Me3Sn)2
O
R1
prepared
in 2 steps
1) i. t-BuLi, THF, -78°C
ii.
2) LDA, PhN(Tf)2
R2
OH
R
The Prins-Pinacol Reaction
Overman
(S)-carvone
H
R2
(−)-7-deacetoxyalcyonin
acetate (1995)
O
O
R1
O
R
Tom Maimone
O
TMS
H
R1
R1
H
O
H
R2
BF3O
R1
O
R2
BF3O
X
R1
O
R2
CHO
OH
4
O
H
R1
Stereochemical Model for the Prins-Pinacol Rearrangement
MacMillan, D.W.C., Overman, L.E. J. Am. Chem. Soc. 1995, 117, 10391-10392
9
Cladiellins
Baran Lab
TMS
H
H H
OAc
O
2) RedAl, H2O
H
H H
79%
OH
OH
H H
1
(−)-7-deacetoxyalcyonin
acetate (1995)
1) PvCl, pyr.
2) TBSOTf,
lutidine
H H
1) SAE
O
O
Tom Maimone
OH
OH
H H
I
O
3) B-I-9-BBN,
ACOH
4) i-Bu2AlH
2
O
H H
5) TPAP,
NMO
OTBS
1) Ph3P=CHOMe
THF, -30°C
2) TfOH, i-PrOH
3
78%
77%
Overman
H H
A streamlined route
was also developed
(see JACS full
paper)
OAc
1) Ac2O
O
Me
H H
OH
O
2) n-Bu4NF
88%
H H
Me Me OH
Me
H H
I
NiCl2-CrCl2
O
DMSO
65%
(>20:1 dr)
H H
Me Me OTBS
H H
5
H
H
OH
O
O
3
H
H
Sclerophytin A
(Proposed)
?
Sclerophytin A
(Revised)
Paquette and Overman groups (2000-2001)
H
H
S
O
H
H
H
R
O
O
OH
H H
O
O
H H
H
Sclerophytin A as drawn
in the isolation paper
(R and S not denoted)
R
H H
OH
B
R
C
presumably the structure
they meant to depict in
the isolation paper
B's actual conformation,
however would corrrespond
to C (Paquette's depiction)
R
O
O
R
H
A
OTBS
4
OH
R
O
Me
H H
Me
OH
O
R
D
Overmans depiction
of C (same structure)
"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
Overman, L.E., Pennington, L.D. Org. Lett. 2000, 2, 2683-2686
Gallou, F., MacMillan, D.W.C., Overman, L.E., Paquette, L.A., Pennington, L.D., Yang, J. Org. Lett. 2001, 3, 135-137
Paquette 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 10
Cladiellins
Baran Lab
OH
O
H
Thus Both the Overman and
Paquette Groups Target C
In addition:
H
H
Tom Maimone
O
H
?
H
H
H H
BF3 OEt2
O
H H
Sclerophytin A
(Revised)
O
Et2O
0 °C
An intramolecular
etherification
produces this
sterochemistry
O
Me
H H
R
O
H H
OH
H H
Cladiellin
This is known to be R-config
in all the Natural products
Reported by Faulkner in 1980
Paquette and Overman groups (2000-2001)
OH
O
R
C
Paquette's route to C:
OMen
OTMS
1) PhMe, Δ
O
O
H
O
2) TBDPSCl, imid
O
2) TMSOTf,
lutidine
OMe
OMen 1) NaBH4, CeCl3
H
O
1
TBDPSO
3) Py CSA, H2O
4) allylbromide, In
TBAB
(dr = 13:1)
(38% 6 steps)
H
1) Dibal-H
O
H
TBDPSO
O
2) Ac2O, Et3N
3) TMSCN, BF3 OEt2
4) KOtBu, tBuOH
O
H
78%
2
H
CN
3
1) O2, PdCl2, CuCl, H2O
2) CeCl3
MgBr
O
OTBDPS
H H
O
1) LHMDS, TMSCl;
HCHO, Yb(OTf)3 O
H H
O
2) TBDPSCl
H H
7
OBz
3) i-PrMgCl,
CuBr DMS
HMPA
TBDPSO
1) MeLi
2) KH, BzCl
H H
OBz
6
3)TBAF
4)TPAP, NMO
3) NaOMe, MeOH
4) Cl3C6H2COCl, Et3N,
DMAP
54%
H H
1)
O
H H
O
5
Cl
Cp2Ti
TBDPSO
H H
AlMe2
2) NaBF4, PhMe,
Δ
O
O
H H
4
O
11
Cladiellins
Baran Lab
H
H
OH
O
H
O
H
?
OTBDPS
H H
O
H H
Sclerophytin A
(Revised)
Sclerophytin A
(Proposed)
OTBDPS
H H
1) NaBH4, CeCl3
2) (Im)2C=S
O
7
H H
Paquette and Overman groups (2000-2001)
H H
O
O
OH
O
54%
H H
(+ 18% THF ring)
OH
8
9
H H
OH 1) TPAP, NMO
O
OTBDPS
H H
Hg(OCOCF3)2, DMF;
O2, NaBH4
O
3) Bu3SnH, AIBN,
toluene, 100°C
4) DIBAL
68%
OBz
Tom Maimone
OH
O
2) DIBAL
H H
1) Ac2O
2) TBAF
3)o-NitroPhenylselenocyanide,
Bu3P; H2O2
4) DIBAL
O
H H
C
Not Sclerophytin
epi-C
Not Sclerophytin
OH
O
OH
TMS
CHO
TIPSO
O
p-TsOH H2O
OTIPS
MgSO4, CH2Cl2
-20*C
76%
-50°C
88%
H
TMS
OH
O
H H
O
O
H H
epi-C
Not Sclerophytin
OH
11
O
H H
C
Not Sclerophytin
hν, AcOH
p-xylene
2-propanol
rt
80%
ratio of C:14 = 4:1
H H
OH
O
H H
14
O
TMS
CHO
2) TBAF
O
10
H H
TMS 1) hν, dioxane
CHO
SnCl4 (10%)
1:1 CH2Cl2/MeNO2
Hg(OAc)2, THF;
NaBH4, NaOH
O
3) (t-BuO)3Al
OTIPS t-BuO2H
PhMe
-20°C
(6.6:1 dr)
41%
H H
OTIPS
O
12
H H
OH
steps
O
66% bsm
H H
13
OH
12
Cladiellins
Baran Lab
H
H
OH
O
H
O
H
Sclerophytin A
(Proposed)
?
Sclerophytin A
(Revised)
Paquette and Overman groups (2000-2001)
After thoroughly re-evaluating NMR and MS
data, the Paquette lab proposes
the following:
OH
H H
OH
Tom Maimone
In a joint publication, using mostly chemistry we have discussed,
both the Overman and Paquette labs verify the new proposal. The
following compounds are prepared
O
H H
OH
sclerophytin A
OH
H H
OH
H H
OH
OAc
O
O
H H
OH
OH
OH
sclerophytin B
sclerophytin A
OH
O
H H
H H
OH
H H
Cladiell-11-ene3,6,7-triol
identical to previously
reported sclerophytin F
The Overman lab also revises
the structure of alcyonin
H H
H H
OOH
OH
O
O
H H
H H
OH
proposed
OH
revised
Friedrich, D., Doskotch, R. W., Paquette, L.A. Org. Lett. 2000, 2, 1879-1882
Corminboeuf, O., Overman, L.E., Pennington, L.D. Org. Lett. 2003, 1543-1546
13
Briarellins
Baran Lab
HO
HO
H H
O
H H
O
1) i. 9-BBN (2.2 equiv), THF, 0 °C
ii. NaOH, H2O2, rt -> reflux
OH
O
O
H
HH
H
O
O
HH
O
O
O
Tom Maimone
2) TEMPO, NCS, n-BuNCl,
CHCl3:NaHCO3:K2CO3 (2:1:1)
O
2) LiAlH4
78%
O
58%
(S)-Carvone
H
H
1) LDA, THF, -78°C;
TMSCl, -78°C −> 0°C;
AcOH, 0°C −> rt
1
O
Briarellin E
Briarellin F
Overman et al.
H
H
H
1) TFA, PhMe, 0°C;
H2O, rt
O
H
OAc 2) Ac2O
H H
H
OH OAc
steps
O
H
1) TIPSCl, imid
H
O
86%
OTIPS
OTIPS
5
4
H
OH
2) PCC
O
OAc
H H
(20:1 dr)
HO
87%
TIPSO
2
3
1) m-CPBA, 0°C
2) TBAF
3) Tf2O, 2,6-lutidine
45%
O
H
1) H2SO4, H2O
2) MsCl, Et3N;
HO
LiAlH4
3) Bu8Sn4Cl4O2,
isopropenyl
acetate
H
O
H
H
H
O
6
OAc
OAc
4) C7H15COCl,
pyr.
5) Bu3SnAlEt2,
CuCN
6) I2
35%
H
H
H
1) (t-Bu)2(OH)SnCl,
MeOH
2) DMP
I
O
H
H
O
OAc
OCOC7H15
3) CrCl2-NiCl2
DMSO-DMS
59%
HO
HO
H H
O
H
O
O
O
1) DMP
79%
HH
H H
OH
O
Briarellin E O
H
HH
O
Briarellin F
O
O
Corminboeuf, O., Overman, L.E., Pennington, L.D. J. Am. Chem. Soc. 2003, 123, 6650-6652
14
Cladiellins
Baran Lab
O
H H
OAc
AcOH, hν
Et3N
25%
OH
1
α-phellandrene
deacetoxyalcyonin
acetate
H
H
O
H
1) CrCl2, NiCl2
DMF
2) DEAD, BzOH
OAc
PPH3
1)
O
3) MeONa, MeOH
4) Ac2O, pyr. DMAP
H H
O
8
1) WCl6, n-BuLi
2) TBSOTf, KHMDS
MeO
Br
, t-BuLi
O
OAc
O
H H
TBSO
1) KH, TBSCl
O
H
2) THF/1N HCl
O
2) PhSeCl; then
m-CPBA
H
4
5
1) Ph3PCH2Br,
t-BuOK;
1N HCl
57%
O
71%
71%
6
H H
O
then Comins reag.
H
H
H
then CuBr DMS
OTf
CHO
O
OAc
3
2
H
62%
O
H
2) LiCl, H2O,
DMSO, 130°C
50%
7
H H
OH
1) n-BuLi (2.2 eq.),
LiCl; MeI
43%
O
O
TiCl4
-80 °C
43-80%
OAc
Molander et al.
1) m-CPBA
2) O3, DMS
CO2Me
H
OTES
O
86%
O
H
OTES OMe
OMe
H
OMe
OMe
Cl
O
H H
H
Tom Maimone
H H
H H
OAc
O
H H
OAc
MeLi
Yb(OTf)3
O
O
66% BRSM
H H
OH
Molander, G.A., St. Jean, D.J.Jr., Haas, J. J. Am. Chem. Soc. 2004, 126, 1642-1643
15
Cladiellins
Baran Lab
H H
OAc
AcO
The Crimmins lab has significant experience in the
construction of medium-sized ether ring natural products
H H
O
O
AcO
H H
AcO
OAc
astrogorgin
O
H H
AcO
OAc
Br
2) NaH, PMBCl
O
3) Hg(OAc)2, H2O;
PdCl2, LiCl, CuCl
H2O, O2
(S)-benzyl
glycidyl
H
Me
H
1)
MgBr
BnO
Br
C
O
H
79%
H
O
H Br
obtusenyne
(completed)
1) MeOH, HCl
2) NaH, BrCH2CO2H
BnO
2) NaH, BnBr
87%
(single isomer)
O
Thus we will see a unique approach to
the eunicellin natural products wherein
the 9-membered ether is the key synthetic
fragment.
Cl
OPMB
OPMB
1
H
Me
isolaurallene
(completed)
Crimmins et al.
BnO
O
ophirin B
1) TMSI, n-BuLi
Tom Maimone
3) Me3CCOCl, Et3N,
then
O
OBn
2
N
H
O
OBn
O
BnO
O
N
O
O
3
1)NaHMDS,
I
3:1 E : Z
2) LiBH4, MeOH
BnO
H
O
H
MeO2C
TESO
7
4) PPTS, MeOH
5) DMP
6) Ph3PCH2OBnCl,
t-BuOK
OH
OH
1) DMP
OTHP
2) Ph3P=CHCO2Me
3) TESOTf
H
1) DMP
2) Ph3P=C(Me)2CO2Et
O
H
HO
HO
3) DIBAL
4) DHP, PPTS
5) Na/NH3
6
Crimmins, M.T., Brown, B.H. J. Am. Chem. Soc. 2004, 126, 10264-10266
Crimmins, M.T., Brown, B.H., Plake, H.R. J. Am. Chem. Soc. 2006, 128, 1371-1378
H
O
H
BnO
BnO
Grubb's II
PhH
80 °C
89%
> 15:1 ether/dimer
H
O
BnO
H
OBn
4
5
Studies Showed that the Dimer is the kinetic product,
but is converted (irreversibly) to the ether at higher
temperatures
Crimmins, M.T., Ellis, M.J. J. Am. Chem. Soc. 2005, 127, 17200-17201
16
Cladiellins, Asbestinins
Baran Lab
Tom Maimone
BnO
H H
H H
OBn
H
O
O
H
Z-7
1:3
MeO2C
80%
with
recycling
step
TESO
MeO2C
7
1) MeMgCl
2) TBAF
O
BnO
2h
exo
H
TESO
MeO2C
standing
at rt
H
O
3) Na,
naphthalene
H H
TESO
OH
H H
1) KHMDS, Ac2O
2) Bi(OTf)3, Ac2O
O
BnO
OH
O
BnO
OH
1) NaHMDS
I
N
O
H H
HO
OTIPS
H
BnO
AcO
H
MeOC
TBSO
H H
AcO
OAc
Me
OMe H
H
110 °C
BnO
MeOC
OAc
O
O
O
H H
TESO
H
HH
O
11-acetoxy-4-deoxyasbestinin D
Crimmins, M.T., Brown, B.H. J. Am. Chem. Soc. 2004, 126, 10264-10266
Crimmins, M.T., Brown, B.H., Plake, H.R. J. Am. Chem. Soc. 2006, 128, 1371-1378
H H
H H
OAc H
H
Me
H H
AcO
OAc
1) TBAF
2) o-NO2PhSeCN
3) H2O2
O
steps
O
2) LiBH4
O
AcO
OTIPS
H H
OTIPS
To access the asbestinin family:
H
H H
HO
Ophirin B
OBn
H
OMe O
H H
HO
3) H2, Pd/C
4) Ac2O, DMAP
To access astrogorgin the following modifications were made:
O
O
H H
PhSSPh (cat)
(1:1)
O
HO
O Me H
H
1) MeMgCl
2) TBAF
hν
OBn
many
acetylation
conditions
AcO
H H
AcO
OAc
OH
O
AcO
H H
AcO
OAc
1) TPAP, NMO
2) NaBH4, CeCl3
3) Ac2O, DMAP
4) TBAF
5) Bi(OTf)3, Ac2O
Astrogorgin
17
Cladiellins
Baran Lab
H
H
AcO
O
H H
As with Crimmins approach, the 9-membered ether is the key piece
Me
H H
O
H H
Cladiella-6,11dien-3-ol
H H
Polyanthellin
OH
OH
H H
OAc
O
O
H H
OH
Tom Maimone
Bn
O
O
Deacetoxy-alcyonin
acetate
OPMB
O
O
H H
OH
Bn
N
OH
n-BuOTf, Et3N
OPMB
O
N
75%
O
O
Cladiell-11-ene3,6,7-triol
Kim et al
Cl
Me2N H
H
O
1) DIBAL, n-BuLi
O
N
OTr
OTr
H
1) BHT, xylenes
reflux, 1h
MeO2C
85%
OTr
Me
OH
O
H H
CO2Me
7
OTr
OH
O
H H
H
3) K, 18-C-6
t-BuNH2
55%
H H
Cladiella-6,11dien-3-ol
2) Ac2O,
DMAP
69%
H H
OAc
O
H H
AcO
OH
1) Ac2O, DMAP
2) Burgess, 70°C
OTES
1) Hg(OAc)2,
H2O; Et3B,
NaBH4
O
OTr
2
3) TBAF
H
1) MeLi, CeCl3
2) Ac2O, DMAP
Et3N
TBDPSO
62%
OTr
OH
1
1) NaBH4
2) TBDPSCl, imid
3) trityl bromide,
DMAP
4) DDQ
69%
OH
3) PPh3, CCl4
H H
H
O
O
3
1) TESOTf
2) OsO4, NMO
H
2) SeO2; NaBH4
TBDPSO H
45 °C
92%
4
1) NaH, ClCH2CONMe2
O
then oxalic
acid
68%
1) Ph3P=CH2
2) TBAF
90%
6
O
SiMe3
5
H
LHMDS, THF
TBDPSO H
2) n-BuLi
TBDPSO H
O
Me2N
O
OH
Deacetoxy-alcyonin
acetate
H H
O
O
H H
Polyanthellin
Kim, H., Lee, H., Kim, J., Kim, S., Kim, D. J. Am. Chem. Soc. 2006, 128, 15851-15855
18
Cladiellins
Baran Lab
Tom Maimone
HO
H H
O
O
O
CO2Et
O
H H
OH
SmI2, MeOH
THF, rt
76%
H
1
prepared in 4 steps
from Br(CH2)3OTBS
(+)-vigulariol
O
OTBS
O
1. TBSCl, imid.
2. LiOH, MeOH
CO2Et
H
3. i-BuO2CCl, Et3N,
then CH2N2
60%
2
H
O
H
Cu(CF3COCHCOCF3)2
5 mol%
DCM
Δ
96%
N2
3
single diastereomer!
J. Stephen Clark et al.
OEt
OEt
H
1. MVK, PhH, Δ
O
H
H
O OTBS
1. NaHMDS,
PhNTf2
H
O
2. K2CO3, MeOH
58% (4 steps)
O
OEt
O
H
8
H
OTBS
75%
O
SnBu3
(Z)-5
[2,3]
H
O
H
H
TBSO
O
TBSO
(5:1)
(E)-5
4
AIBN, EtSH, PhH,
Δ
56%
1. Ph3PCH2Br, t-BuOK
2. HCl (5% aq.), THF, rt
3. H2, PtO2
4. Ph3PCH2
58%
1. n-Bu4NF
2. DMP
3. MeMgCl
OTBS
O
6
HH
H
O
2. Pd(PPH3)4, LiCl
H
TBSO
7
H
H H
HH
m-CPBA, 0°C
O
H
69%
H
OH
HO
OO
H H
(+)-vigulariol
Clark, J. S., Hayes, S. T., Wilson, C., Gobbi, L. Angew. Chem. Int. Ed. 2007. 46, 437-440
19
Sarcodictyins
Baran Lab
Tom Maimone
O
Me
O
Me
H
Me
N
1. H2O2, NaOH, MeOH
2. H2, PtO2
O
O
H
Me
N
OMe
CO2R
Me
Me
3. LDA, CH2O
4. TBSCl, Et3N
Me
sarcodictyin A (R=Me)
sarcodictyin B (R=Et)
Me
Me
O
1. L-Selectride
2. MsCl, Et3N
OTBS
Me
Me
HO
1. CH3C(OEt)3
n-PrCO2H
OTBS
3. Na-naphthalenide
79%
H
46%
carvone
O
2. DIBAL
72%
H
Me
Me
2
1
Nicolaou et al.
Me
H
Me
OH
O
H
Me
Me
OPMB
OPMB
H
1. HC
CMgBr
2. TBAF
O
OTBS
H
3. DMP
Me
Me
Me
6
Me
H
OH
1. PMBOC(=NH)CCl3
2. Hg(OAc)2
3. Li2PdCl4, CuCl2
H
Me
58%
OTBS
Me
4. MsCl, Et3N
5. Na-naphthalenide
H
H
Me
71%
4
5
Me
1. (EtO)2P(O)CH2CO2Et
2. DIBAL
3. Ti(Oi-Pr)4, DET,
t-BuOOH
CHO
OTBS
Me
3
1. NCCH2CO2Et
β-alanine
2. TMSOTf
49%
Me
Me
OPMB
Me
OTMS 1. DIBAL
H
CN
H
Me
OPMB
Me
7
CO2Et
OPMB
Me
OTMS
H
CHO
2. TIPSOTf
67%
H
Me
OTIPS
Me
8
Me
H
Me
OH
H
Me
OH
H2, Lindlar
1. LHMDS
2. DMP
3. PPTS,
MeOH
80%
PMBO
Me
75%
H
Me
O
Me
9
OTIPS
Nicolaou, K. C., Xu, J.-Y., Kim, S., Ohshima, T., Hosokawa, S., Pfefferkorn, J. J. Am. Chem. Soc. 1997, 119, 11353-11354
Nicolaou, K. C. et al. Angew. Chem. Int. Ed. Engl. 1997, 36, 2520-2524.
Nicolaou, K. C. et al. J. Am. Chem. Soc. 1998. 120, 8661-8673
Nicolaou, K. C. et al. J. Am. Chem. Soc. 1998. 120, 8674-8680
H
Me
Me
10
O
OTIPS
20
Sarcodictyins
Baran Lab
Me
OPMB
Me
H
Me
H
1. CSA, MeOH
O
O
2. Na, liq. NH3
H
Me
OH
Me
H
72%
Me
OTIPS
Me
11
1.
OH
Me
Tom Maimone
O
O
O
N
O
t-Bu
Me
NMe
O
N
O
Me
Me
H
N
Me
O
2. TBAF
3. DMP
OMe
4. NaClO2
OTIPS 5. CH N
2 2
6. CSA, H2O
H
Me
H
Me
OTES
CHO
H
Me
NH
Cl3C
OPMB
Me
O
H
Me
N
N
H
OH
Me
O
Me
OAc
Me
N
H
OH
Me
O
Me
H
Me
OAc
OAc
Me
OH
CO2Me
O
Me
O
Me
Me
H
N
O
H
Me
Me
S
Me
Me
N
O
H
OAc
Me
N
Me
OMe OAc
O
OH
O
OH
O
OAc
eleuthoside B
Me
OMe
O
O
H
OH
O
OH
OH
O
OH
O
eleuthoside A
eleutherobin
N
Me
O
OAc
OH
Me
H
N
O
O
N
O
Me
OMe
OTBS
O
Me
N
N
Me
OTBS
O
Me
Me
OPMB
O
O
H
Me
O
O
O
Me
O
Me
OTBS
Me
OH
CO2Et
O
H
H
OTBS
Also prepared: O
Me
steps
H
O
1
Me
Me
OTES
CHO
O
OH
Me
OTES
H
TMSOTf
Me
OTES
Me
O
Me
H
N
Me
sarcodictyin B
a similar approach was used
to prepare eleutherobin
Me
H
sarcodictyin A
12
Me
O
OH
CO2Me
Me
N
O
OH
dihydro-sarcodictyin A
thiazole-eleutherobin
epi-eleutherobin
21
Sarcodictyins
Baran Lab
Tom Maimone
O
O
H
N
H
O
H
Zn, Et2O, 0 °C
sonication
65%
Me
OMe
O
Cl
ClCOCCl3
N
H
2)
N
N
OH
H
1) p-TsOH H2O, MeOH
60 °C
O
H
2) p-TsOH H2O, Me2CO
65%
1.
OH
(1.3:1 dr)
Li
H
MeLi
O
O
H
O
H
OPiv
OPiv
7
6
HO
H
Ac2O, DMAP
8
-78 °C
73%
OH
OPiv
H
9
Danishefsky et al. Angew. Chem. Int. Ed. 1998, 37, 185-186
Danishefsky et al. Angew. Chem. Int. Ed. 1998, 37, 789-792
Danishefsky et al. J. Am. Chem. Soc. 1999, 121, 6563-6579
H
CHO
Br
H
O
2) DIBAL
73%
O
H
OMe
5
2. KCN, EtOH
reflux
3. TBSOTf,
2,6-lutidine
71%
OTBS
H
1) DIBAL
O
10
H
O
2) TPAP, NMO
OMe
OPiv
H
Br
4
OTBS
1. Ag2O, MeI
MeCN
O
O
2. PivCl, DMAP
3) TBAF
64%
(15:1 dr)
OAc
H
OPiv
Br
OTBDPS
1) i. DIBAL
ii. MsCl, pyr.
iii. KCN, 18-C-6
H
1. CrCl2, NiCl2
DMF
94%
OH
H
OTBDPS
OH
1) DMDO, Me2CO
CH2Cl2
42%
H
O
2. TBDPSCl
55%
H
OH
CO2Me
3
Danishefsky et al.
O
CHO
H
60%
2
60 °C
O
eleutherobin
O
1) Zn, MeOH,
NH4Cl
t-BuO
1
α-phellandrene
OAc
Cl
NMe2
H
77%
OMe
H
O
12
22
Sarcodictyins
Baran Lab
H
H
H
OH
H
O
O
O
ii. Comins
12
O
OH
OTf
H
80%
1. TBAF
2. esterify
Pd(PPh3)4, LiCl
i. LDA
O
O
OTBS
Me
OTBS
OTBS
Tom Maimone
H
O
Bu3Sn
13
O
OAc
N
3. PPTS, MeOH
O
38%
OMe
O
O
O
H
H
O
O
O
50%
Me
OMe
OAc
14
N
OAc
OH
O
O
eleutherobin
H
H
OPMP
O
H
CHO
s-BuLi
H
Ti
OMe
H
OMe
O
OPMP
OMe
OH
H
H
OPiv
OMe
Cl
O
eleutherobin
formal synthesis
1
1. MOMCl, TBAI
DIPEA
2. LiBF4, H2O
OH
O
s-BuLi
OPMP
CHO
H
Cl
Ti
O
3
2
Ph
Ph
C. Gennari et al.
Ph
Ph
3. NaBH4
4. MsCl
5. KCN
6. DIBAL
OPMP
OMOM
H
OH
O
Ph
Ph
O
O
Ph
Ph
O
O
BF3 OEt2
H
OMOM
OH
H2O
O
H
8
OH
OPIV
H
H
O
CDCl3
O
O
1. CAN
H
OPiv
OPiv
6
O
OMOM
H
H
OPMP
2. DMP
H
7
OMOM
OMOM
OTBS
1. PivCl
2. Grubbs II
H
OPiv
H
OPMP
5
kinetically controlled
RCM (less stable product)
Castoldi, D., Caggiano, L., Panigada, L., Sharon. O., Costa, A. M., Gennari, C. Angew. Chem. Int. Ed. 2005, 44, 588-591
PMPO
OH
4
OPMP