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Cembranoids of Marine Invertebrates!Hundreds of Natural Products, So Little Time
H3CO2C OH
OH
mandapamate
HH
O
CO2CH3H3CO
O
O
OHO
H3COO
O
OH
havellockate
1
3
4
6
8
O
O
O
OCH3O2C
Sinularia granosa
43
1
Jennifer RoizenStoltz Group Literature Presentation
Noyes 1478pm, April 17, 2006
O
O
O
O
H1
4 8
12
intricarene
6
O
O
HO H
AcOO
O
H
O
H
H3CO2C
H
providencinPseudopterogorgia kallos
O
O
rubifolideGersemia rubiformis
O
juncin NJunceella juncea
OO
OAcAcOH 3 8HO
HO2COAc
OAc
Cl
O
1
8
9
3
11
4
Pachyclavulariolide OPachyclavularia violacea
OO
O
H
HO
H
O
O
OHsinulariolone
Sinularia flexibilis
1
411
8O HO O
5
11
4
14
1
Outline
O
O
O
OCH3O2C
CH3O2C
hypotheticalO
O
OHO
H3COO
O
OH
havellockate
1
3
4
6
8
43
16
11
OO
O O
O
H
H
ineleganolideSinularia inelegans
4 8 O
OO
OH
HO
H
H HOOH
H
AcO
1
4
bielschowskysinPseudopterogorgia kallos
O
O O
O
O
O H
HO
H
H OH
1
4
verrillinPseudopterogorgia bipinnata
1. ID the cembranoid
2. Origins of cembranoids
- corals - biosynthesis - stereochemical implications
Reviews (among others):1. Wahlberg, I.; Eklund, A.-M. Prog. Chem. Org. Nat. Prod. 1992, 60, 1-141 - comprehensive review of cembranoids.2. Kamel, H. N.; Slattery, M. Pharmaceutical Biology 2005, 43(3), 253-269 - comprehensive review of terpenoids from Sinularia.3. Anything titled "Marine Natural Products" in Nat. Prod. Rep. - annual review of marine natural products (Blunt, prev. Faulkner).
3 8
O 1
11
briaran
43 8
1
11
erythranoid
4
3
81
11
4
2,6-cyclized cembranoid
O
O
3 81
11
4
asbestinincladiellin
O
sarcodictyin
3
8
1
11
4
3
8
1
11
4
gersolanoid
1 8
9
3
11
4
15
16
17
18
20
19
cembrane capnosane
38
1
11
4
1
3
811
4
basmane
11
secotrinervitane
3 8
11
415
triervitane
38
111
415
rippertane
17
17
3 8
1 11
4
15
kempane
17
38
111
415 17
longipane
3 8
1
415
1
1
8
4
dolabellane
O3
8
1
11
4
1
4 8
11
yonarane
taxanediterpene
1 8
9
3
11
4
15
16
17
20
19
norcembrane
Most skeletons: Wahlberg, I.; Eklund, A.-M. Prog. Chem. Org. Nat. Prod. 1992, 60, 1-141 (review).Yonarane skeleton: Iguchi, Kazuo Tetrahedron Lett. 1995, 36(48), 8807-8808.
Skeletal Termsditerpene?
A AA
A A
1
48
1114
14
8
11
3 8
O 1
11
43 8
1
11
4
3
81
11
4
O
O
3 81
11
4
O3
8
1
11
4
3
8
1
11
4
1 8
9
3
11
4
15
16
17
18
20
19
38
1
11
4
1
3
811
4
11
3 8
11
415
38
111
415
17
17
3 8
1 11
4
15
17
38
111
415 17
3 8
1
415
1
1
8
4
O3
8
1
11
4
1
4 8
11
14
8
11
1
48
1114
1 8
9
3
11
4
15
16
17
20
19
Most skeletons: Wahlberg, I.; Eklund, A.-M. Prog. Chem. Org. Nat. Prod. 1992, 60, 1-141 (review).Yonarane skeleton: Iguchi, Kazuo Tetrahedron Lett. 1995, 36(48), 8807-8808.
Skeletal Termsditerpene: composed of 4 isoprene subunits
A AA
A A
3 8
O 1
11
briaran
43 8
1
11
erythranoid
4
3
81
11
4
2,6-cyclized cembranoid
O
O
3 81
11
4
asbestinincladiellin
O
sarcodictyin
3
8
1
11
4
3
8
1
11
4
gersolanoid
1 8
9
3
11
4
15
16
17
18
20
19
cembrane capnosane
38
1
11
4
1
3
811
4
basmane
11
secotrinervitane
3 8
11
415
triervitane
38
111
415
rippertane
17
17
3 8
1 11
4
15
kempane
17
38
111
415 17
longipane
3 8
1
415
1
1
8
4
dolabellane
O3
8
1
11
4
1
4 8
11
yonarane
taxanediterpene
1 8
9
3
11
4
15
16
17
20
19
norcembrane
Most skeletons: Wahlberg, I.; Eklund, A.-M. Prog. Chem. Org. Nat. Prod. 1992, 60, 1-141 (review).Yonarane skeleton: Iguchi, Kazuo Tetrahedron Lett. 1995, 36(48), 8807-8808.
Skeletal Termsnorditerpene?
A AA
A A
1
48
1114
14
8
11
3 8
O 1
11
43 8
1
11
4
3
81
11
4
O
O
3 81
11
4
O3
8
1
11
4
3
8
1
11
4
1 8
9
3
11
4
15
16
17
18
20
19
38
1
11
4
1
3
811
4
11
3 8
11
415
38
111
415
17
17
3 8
1 11
4
15
17
38
111
415 17
3 8
1
415
1
1
8
4
O3
8
1
11
4
1
4 8
11
1 8
9
3
11
4
15
16
17
20
19
Most skeletons: Wahlberg, I.; Eklund, A.-M. Prog. Chem. Org. Nat. Prod. 1992, 60, 1-141 (review).Yonarane skeleton: Iguchi, Kazuo Tetrahedron Lett. 1995, 36(48), 8807-8808.
Skeletal Termsnorditerpene: composed of 4 isoprene subunits, sans one (or more) carbons
A AA
A A
1
48
1114
14
8
11
3 8
O 1
11
briaran
43 8
1
11
erythranoid
4
3
81
11
4
2,6-cyclized cembranoid
O
O
3 81
11
4
asbestinincladiellin
O
sarcodictyin
3
8
1
11
4
3
8
1
11
4
gersolanoid
1 8
9
3
11
4
15
16
17
18
20
19
cembrane capnosane
38
1
11
4
1
3
811
4
basmane
11
secotrinervitane
3 8
11
415
triervitane
38
111
415
rippertane
17
17
3 8
1 11
4
15
kempane
17
38
111
415 17
longipane
3 8
1
415
1
1
8
4
dolabellane
O3
8
1
11
4
1
4 8
11
yonarane
1 8
9
3
11
4
15
16
17
20
19
norcembrane
Most skeletons: Wahlberg, I.; Eklund, A.-M. Prog. Chem. Org. Nat. Prod. 1992, 60, 1-141 (review).Yonarane skeleton: Iguchi, Kazuo Tetrahedron Lett. 1995, 36(48), 8807-8808.
Skeletal Termscembrane?
A AA
A A
taxanediterpene
1
48
1114
14
8
11
3 8
O 1
11
43 8
1
11
4
3
81
11
4
O
O
3 81
11
4
O3
8
1
11
4
3
8
1
11
4
1 8
9
3
11
4
15
16
17
18
20
19
38
1
11
4
1
3
811
4
11
3 8
11
415
38
111
415
17
17
3 8
1 11
4
15
17
38
111
415 17
3 8
1
415
1
1
8
4
O3
8
1
11
4
1
4 8
11
1
48
1114
1 8
9
3
11
4
15
16
17
20
19
Most skeletons: Wahlberg, I.; Eklund, A.-M. Prog. Chem. Org. Nat. Prod. 1992, 60, 1-141 (review).Yonarane skeleton: Iguchi, Kazuo Tetrahedron Lett. 1995, 36(48), 8807-8808.
Skeletal Termscembrane: natural monocyclic diterpene
A AA
A A
14
8
11
3 8
O 1
11
briaran
43 8
1
11
erythranoid
4
3
81
11
4
2,6-cyclized cembranoid
O
O
3 81
11
4
asbestinincladiellin
O
sarcodictyin
3
8
1
11
4
3
8
1
11
4
gersolanoid
1 8
9
3
11
4
15
16
17
18
20
19
cembrane capnosane
38
1
11
4
1
3
811
4
basmane
11
secotrinervitane
3 8
11
415
triervitane
38
111
415
rippertane
17
17
3 8
1 11
4
15
kempane
17
38
111
415 17
longipane
3 8
1
415
1
1
8
4
dolabellane
O3
8
1
11
4
1
4 8
11
yonarane
1 8
9
3
11
4
15
16
17
20
19
norcembrane
Most skeletons: Wahlberg, I.; Eklund, A.-M. Prog. Chem. Org. Nat. Prod. 1992, 60, 1-141 (review).Yonarane skeleton: Iguchi, Kazuo Tetrahedron Lett. 1995, 36(48), 8807-8808.
Skeletal Termscembranoid?
A AA
A A
taxanediterpene
1
48
1114
14
8
11
3 8
O 1
11
43 8
1
11
4
3
81
11
4
O
O
3 81
11
4
O3
8
1
11
4
3
8
1
11
4
1 8
9
3
11
4
15
16
17
18
20
19
38
1
11
4
1
3
811
4
11
3 8
11
415
38
111
415
17
17
3 8
1 11
4
15
17
38
111
415 17
3 8
1
415
1
1
8
4
O3
8
1
11
4
1
4 8
11
1
48
1114
1 8
9
3
11
4
15
16
17
20
19
Most skeletons: Wahlberg, I.; Eklund, A.-M. Prog. Chem. Org. Nat. Prod. 1992, 60, 1-141 (review).Yonarane skeleton: Iguchi, Kazuo Tetrahedron Lett. 1995, 36(48), 8807-8808.
Skeletal Termscembranoid: natural monocyclic diterpene derived from cembranes
A AA
A A
14
8
11
3 8
O 1
11
briaran
43 8
1
11
erythranoid
4
3
81
11
4
2,6-cyclized cembranoid
O
O
3 81
11
4
asbestinincladiellin
O
sarcodictyin
3
8
1
11
4
3
8
1
11
4
gersolanoid
1 8
9
3
11
4
15
16
17
18
20
19
cembrane capnosane(found in tobacco and marine)
38
1
11
4
1
3
811
4
basmane
11
secotrinervitane
3 8
11
415
triervitane
38
111
415
rippertane
17
17
3 8
1 11
4
15
kempane
17
38
111
415 17
longipane
3 8
1
415
1
1
8
4
dolabellane
O3
8
1
11
4
1
4 8
11
yonarane
taxane
1
48
11
diterpene
14
1 8
9
3
11
4
15
16
17
20
19
norcembrane
Most skeletons: Wahlberg, I.; Eklund, A.-M. Prog. Chem. Org. Nat. Prod. 1992, 60, 1-141 (review).Yonarane skeleton: Iguchi, Kazuo Tetrahedron Lett. 1995, 36(48), 8807-8808.
Skeletal Origincembranoids are found in marine invertebrates, insects and tobacco
A AA
A A
found in insects:
found in tobacco: 1
4
8
11
3
81
11
4
coralloidolide FAlcyonium coralloides
2,6-cyclized cembranoid
sarcophytol LSarcophyton glaucum
absolute stereochemistry
capnosane(found in tobacco and marine)
3 811
4
1
Coralloidoilide F: D'Ambrosio, M.A. et al. Helv. Chim. Acta, 1990, 73, 804-807; pinnatin A: Rodríguez, A. D. J. Org. Chem. 1998, 63(13), 4425-4432.Cembrene: Zhang, T. et al. Synthesis 2001, 3, 393; sinulochmodin C: Tseng, Y. J. et al. Org. Lett. 2005, 7(17), 3813-3816.
Sarcophytol L: Kobayashi, M.; Osabe, K. Chem. Pharm. Bull. 1989, 37, 1192-1196; Sclerophytin A: Paquette, L. A. Org. Lett. 2000, 2, 1879; Uchio, Y. Tetrahedron Lett. 1989, 30, 3331; Overmann, L. E. Org. Lett. 2001, 3, 135; Pennington, L. D. J. Am. Chem. Soc. 2001, 123, 9033; Paquette, L. A. J. Am. Chem. Soc. 2001, 123, 9021.
Erythrolide V: Andersen, R. J. et al. Eur. J. Org. Chem. 2003, 3515.Briarellin E enantioselective total synthesis: Overman, L. E. J. Am. Chem. Soc. 2003, 125, 6650 ; isolation: Rodríguez, A. D. Chem. Pharm. Bull. 1995, 43, 1853.
Minabein-4 absolute stereochemistry: (60) Molinski, J. Nat. Prod. 2004, 67, 2130; other identical isolate: Scheuer, P. J. Heterocycles 1996, 42, 325; Acetate: Higa, T. J. Nat. Prod. 2004, 67, 1368.Sarcodictyin A: Nakao, Y. et al. J. Nat. Prod. 2003, 66, 524.
Skeletal Termsexamples
A AA
AA
sclerophytin Atotal syntheses
cladiellin
O
3
8
111
4
OH
H
HOH
OH
O
O
3 81R
11
4
briarellin EBriareum aspestinum
enantioselective total synthesis
asbestinin
H
HOH
H
OCOC7H15
OHO
CO2CH3
(Z)-sarcodictyin ABellonella albiflora
absolute stereochemistry via transesterification to sarcodictyin A
sarcodictyin
3
8
1R
11
4H
H
OH
O
O
NNO
O
O
O
O
sinulochmodin CSinularia lochomodes
absolute configuration via analogy (Mosher)
yonarane
H
H
OO
OAcOAc
H3 8HO
AcO
HO
Cl
minabein-4, R=Habsolute stereochemistry (X-ray)
identical to other isolateR=OAc, Ellisella
briaran
R
1
(–)-13-hydroxy-11,12-epoxyneocembreneabsolute stereochemistry
(total synthesis)Sinularia trocheliophorum
cembrane
OH
O
O
H
AcO
OH
Cl
OH
AcO
O
O
erythrolide VErythropodium caribaeorum
erythranoid
3
1
O
OO
O
OH
HHO OH
O
H
O
HO
pinnatin Aabsolute stereochemistry
by synthesis from bipinnatin J
gersolanoid
O88
11
5
Aglantha digitale: Fautin, Daphne G. and Romano, Sandra L. 1997. Cnidaria. Sea anemones, corals, jellyfish, sea pens, hydra. Version 24 April 1997. http://tolweb.org/Cnidaria/2461/1997.04.24 in The Tree of Life Web Project, http://tolweb.org
Alcyonium variable: http://www.museums.org.za/bio/cnidaria/alcyonacea.htmAcropora: people.hws.edu/mitchell/cards01/LEI2.html
Taxonomic relationships: Coll, John C. Chem. Rev. 1992, 92(4), 613-631.Cool taxonomic tree: http://www.aims.gov.au/pages/reflib/bigbank/images/bb44a.gif
Aglantha digitalemouth, radial symmetry, gonads,
nematocysts (tentacles with singing cells), carnivorous
PHYLUMCoelenterata
(Cnidaria)
SUBPHYLUMAnthozoa
(lack medusa stage= "adult" sexual phase)
(other SUBPHYLUMMedusozoa)
CLASSAlcyontaria
(8 pinnate tentacles / polyp)
Zoantharia(6 pinnate tentacles / polyp)
ORDERAlcyonacea
Gorgonacea
Pennatulacea
Stolonifera
Telestacea
Coenothecalea
Scleractina
Actiniaria
Corallimorpharia
Zoanthiniaria(Zoanthidae)
soft corals0-75% CaCO3
per colony
hard corals95% CaCO3per colony
Alcyonium variable
Acropora(scleractina)
Taxonomic Relationships
Lobophytum compactum: http://www.reefed.edu.au/explorer/landscapes/reefs/Pseudopterolide: Fenical, W.; Clardy, J. et al. J. Am. Chem. Soc. 1982, 104, 6463-6466.
Isolobophytolide: Michalek-Wagner, K. et al. Marine Biology 2001, 138, 753-760.Kallolide A: Kerr, R. G. et al. Mar. Ecol. Prog. Ser. 2005, 303, 105-111.
Coralssimple animals with endo-symbiotic algae (zooxanthellae)
Lobophytum compactumpolyp tissue (green); zooxanthellae (red)
Corals derive energy from:(1) carnivorous consumption(2) photosynthesis by internal algae
Cembranoids in corals - formed by zooxanthellae or made by corals
Evidence:
(1) Pseudopterogorgia acerosa with pseudopterolide without zooxanthellae - could be dietary in origin
(2) larvae from Lobophytum compactum reared with and without zooxanthellae with isolobophytolide
(3) 3H-labeled precursor (GGPP) converted to kallolide A by zooxanthellae
pseudopterolideabs. by X-ray of derivative
O
O
H3CO2C
O
O
isolobophytolide
1 8
9OO
O
O
O
O
HO
kallolide ASymbiodinium (zooxanthellae)
Coll, J. C. Chem. Rev. 1992, 92(4), 613-631 (review).Pukalide absolute configuration: Marshall, J. A. et al. J. Org. Chem. 2001, 66, 8037-8041.
Reasons for Being role of cembranoids in coral colonies
OO
O
HO H
Dihydroflexibilide Sinularia flexibilis
H 1 8
OO
O
HO H
FlexibilideSinularia flexibilis
killed hard coral at 5-10 ppm over 8 h
1 8
O
O
HOH
O
SinulariolideSinularia flexibilis
absolute configuration
1 4
118
O
O
AcO
O
O
Sinularia maxima
OOOH
1 8
Uchio's toxinSinularia flexibilis
O
OO
O
pukalideSinularia polydactylaabsolute configuration
by synthesis of unnatural deoxypukalide
CO2CH3
CO2CH3
(1) Toxic to fish (mosquitofish) (2) Feeding deterrence (local reef fish) (3) Allelopathy (to eliminate the competition)
(4) Antifouling (to limit / select algae) (5) spawning (expulsion of egg from polyp)
Dewick, P. M. Nat. Prod. Rep. 2002, 19, 181-222 (review).Eisenreich, W. et al. Cell. Mol. Life Sci. 2004, 61, 1401-1426 (review).
Biogenesis of CembranesLessons from terrestrial metabolism applied to marine organisms
OPPgeranylgeranyl diphosphate (GGPP)
a cembrane
OPPisopentyl
diphosphate (IPP)
OPPdimethyl
allyl diphosphate
(DMAPP)
OH
HO
H
HO
H
OHOHH H
OH
D-Glucose
+
A
A
A
A
Garson, M. J. J. Nat. Prod. Res. 1989, 6(2), 143-170 (review).Dewick, P. M. Nat. Prod. Rep. 2002, 19, 181-222 (review).
Eisenreich, W. et al. Cell. Mol. Life Sci. 2004, 61, 1401-1426 (review).
Biogenesis of CembranesLessons from terrestrial metabolism applied to marine organisms
OPPgeranylgeranyl diphosphate (GGPP)
a cembrane
OPPisopentyl
diphosphate (IPP)
OPPdimethyl
allyl diphosphate
(DMAPP)
OH
HO
H
HO
H
OHOHH H
OH
D-Glucose
+
Marine metabolism:
(1) symbiotic associations
(2) seawater pH~ 8.2-8.5 (NaHCO3/Na2CO3), 40% salt with osmotoic pressure 15-25 atm • unique cellular strucutres to cope with marine environment
(3) halogens, isocyanates rare in terrestrial metabolites
(4) product absolute stereochemistry may differ
A
A
A
A
Dewick, P. M. Nat. Prod. Rep. 2002, 19, 181-222 (review).Eisenreich, W. et al. Cell. Mol. Life Sci. 2004, 61, 1401-1426 (review).
Pathway ComparisonMevalonate (MVA) Pathway; Methylerythritol Phosphate (MEP) Pathway
OPP
OPP(DMAPP)
(IPP)
OH
HO
H
HO
H
OHOHH H
OH
D-GlucoseOPP
OPP(DMAPP)
(IPP)
MEPMVA
Dewick, P. M. Nat. Prod. Rep. 1999, 16, 97-130 (review).
Mevalonate Pathwayto geranylgeranyl diphosphate
SCoA
O
OH
HO
H
HO
H
OHOHH H
OH
D-Glucose
SEnz
O
Oacetoacetyl-CoA
thiolace
SCoA
O
3-hydroxy-3-methylglutaryl-CoA
(HMG-CoA) synthase
SCoA
OOH
HO
O
HMG-CoA reductase
NADPH OHOH
HO
O
1) mevalonate kinase, ATP
2) phosphomevalonatekinase, ATP
mevalonic acid
OOH
HO
O
mevalonate 5-diphosphate
P O P OHO
O–
O
O–
mevalonate 5-diphosphate
decarboxylase, ATP OPPOP
–O
O
PP
–CO2
-PO4H2– OPPisopentyl
diphosphate (IPP)
IPP
isomerase OPPdimethyl
allyl diphosphate
(DMAPP)
Dewick, P. M. Nat. Prod. Rep. 2002, 19, 181-222 (review).Eisenreich, W. et al. Cell. Mol. Life Sci. 2004, 61, 1401-1426 (review).
Deoxyxylulose Phosphate PathwayMethylerythritol Phosphate Pathway; Mevalonate-Independent Pathway
CO2H
OO
H
HO
H
HO
H
OHOHH H
OH
D-Glucose pyruvateSNR
OPP
thiamine diphosphate
H+
SNROPP
HOO
OH
:B
SNROPP
OH
O OP
OH
(D-glyceraldehyde 3-phosphate)
DXP synthase(rate-limiting step)
H+
(hydroxyethyl)-thiamine diphosphate
SNROPP
(hydroxyethyl)-thiamine diphosphate
OOH
OH
OPH:B
OO
OH
OPH
DXP
OO
OH
OPDXP reductoisomerase
N
CONH2
R
HH
N
CONH2
R
HHO
O
OH
OPH
H
(NADPH)
2-C-methyl-D-erythritol 4-P (MEP)
Dewick, P. M. Nat. Prod. Rep. 2002, 19, 181-222 (review).Eisenreich, W. et al. Cell. Mol. Life Sci. 2004, 61, 1401-1426 (review).
Green algae image: http://www.cryptogamicbotany.com/oa_chlorophyta_01.html
Deoxyxylulose Phosphate PathwayMethylerythritol Phosphate Pathway; Mevalonate-Independent Pathway
HOO
OH
OPH
H2-C-methyl-
D-erythritol 4-P (MEP)
N
NH2
ON
O
OHHH
PPPO
OH(CTP)
4-(CDP)-2-C-methyl-D-erythritol synthase(CDP-ME synthase)
HOO
OH
OCDPH
H2-C-methyl-
D-erythritol 4-P (MEP)
CDP-ME kinaseATP HO
PO
OH
OCDP
H2-C-methyl-
D-erythritol 4-P (MEP)
-CMP
HO
H2-C-methyl-
D-erythritol 4-P (MEP)
P
OP
OO–O O
O–
O
HO
HOOPP
1-hydroxy-2-methyl-2-(E)-butenyl 4-diphosphate
OPP
OPP(DMAPP)
(IPP)
Dewick, P. M. Nat. Prod. Rep. 2002, 19, 181-222 (review).Eisenreich, W. et al. Cell. Mol. Life Sci. 2004, 61, 1401-1426 (review).
Animal image: http://www.youam.de/~alphascorpii/img/animal.jpg
Pathway ComparisonMevalonate (MVA) Pathway; Methylerythritol Phosphate (MEP) Pathway
CCC
COPPC
CCC
COPPC
(DMAPP)
(IPP)
O
C
C C
H
HO
H
HO
H
OHOHH
C
HCC
OH
D-GlucoseCCC
COPPC
CCC
COPPC
(DMAPP)
(IPP)
MEP
AnimalsArchaea
Fungi
Green AlgaePlantsEubacteria
In bacteria: MVP in cytosol
(steroids, triterpenoids, sesquiterpenoids)
MEP in plastids(monoterpenes, diterpenes, sesquiterpenes, tetraterpenes)
MVA
OPP
Dewick, P. M. Nat. Prod. Rep. 2002, 19, 181-222 (review).Eisenreich, W. et al. Cell. Mol. Life Sci. 2004, 61, 1401-1426 (review).
chain length control: Nishino, T. et al. J. Biol. Chem. 1996, 27(31), 18831-18837.residues binding GPP and IPP: Koyama, T. et al. Biochemistry 1996, 35(29), 9533-9538.
Casbene examples (in review): Dewick, P. M. Nat. Prod. Rep. 1999, 16, 97-130.
Away We GoTo a Cembrane via Geranylgeranyl Diphosphate
OPP(IPP)
OPPOPP(DMAPP) (IPP)
+geranyl diphosphate
synthaseOPP
geranyl diphosphate (GPP)
+farnesyl diphosphate
synthase
catalysis viaMg2+-bound to aspartates (2)
binding vialysines (2) and aspartate (1)
OPP(IPP)farnesyl diphosphate (FPP)
geranylgeranyl
diphosphate synthase+OPP
geranylgeranyl diphosphate (GGPP)
cembrane
SN1
metal-initiated(casbene synthase)
geranylgeranyl diphosphate
PPO H
:Bcasbene
(a cembranoid)
Biosynthesis of Cembranoids v. Non-cembranoidsrevisiting skeletal terms
A AA
A A
cembrane
1
84
dolabellyl cation
verticillyl cationgeranylgeranyl diphosphate
PPO
1
84
geranylgeranyl diphosphate
OPP
1
84
vibsyl cation
1
84
dolabellane scaffold
SN1
metal-initiatedenzymatic
Dolabellane review: Hiersemann, M.; Helmboldt, H. Top. Curr. Chem. 2005, 243, 73-136.Verticilene and Casbene examples: Dewick, P. M. Nat. Prod. Rep. 1999, 16, 97-130 (review).
(1S)-verticilene
SN1
metal-initiated(casbene synthase)
geranylgeranyl diphosphate
PPO
SN1
metal-initiatedenzymatic
H
:Bcasbene
(a cembranoid)
HH
H
sarcophytol LSarcophyton glaucum
absolute stereochemistry
38
11
4
1
Aquariolide A: Andersen, R. J. Org. Lett. 2002, 4, 4085; pinnatin A: Rodríguez, A. D. J. Org. Chem. 1998, 63(13), 4425-4432.Sinulochmodin C: Tseng, Y. J. et al. Org. Lett. 2005, 7(17), 3813-3816;Sarcophytol L: Kobayashi, M.; Osabe, K. Chem. Pharm. Bull. 1989, 37, 1192-1196.
Sclerophytin A: Paquette, L. A. Org. Lett. 2000, 2, 1879; Uchio, Y. Tetrahedron Lett. 1989, 30, 3331; Overmann, L. E. Org. Lett. 2001, 3, 135; Pennington, L. D. J. Am. Chem. Soc. 2001, 123, 9033; Paquette, L. A. J. Am. Chem. Soc. 2001, 123, 9021.
Briarellin E enantioselective total synthesis: Overman, L. E. J. Am. Chem. Soc. 2003, 125, 6650 Minabein-4 absolute stereochemistry: (60) Molinski, J. Nat. Prod. 2004, 67, 2130; other identical isolate: Scheuer, P. J. Heterocycles 1996, 42, 325; Acetate:
Higa, T. J. Nat. Prod. 2004, 67, 1368; Sarcodictyin A: Nakao, Y. et al. J. Nat. Prod. 2003, 66, 524.
More Complex CembranoidsA AA
AA
O
O
3 81R
11
4
briarellin EBriareum aspestinum
enantioselective total synthesis
H
HOH
H
OCOC7H15
OHO
CO2CH3
(Z)-sarcodictyin ABellonella albiflora
absolute stereochemistry via transesterification to sarcodictyin A
3
8
1R
11
4H
H
OH
O
O
NNO
O
O
O
O
sinulochmodin CSinularia lochomodes
absolute configuration via analogy (Mosher)
H
H
OO
OAcOAc
H3 8HO
AcO
HO
Cl
minabein-4, R=Habsolute stereochemistry (X-ray)
identical to other isolateR=OAc, Ellisella
R
HHO OH
O
H
O
HO
pinnatin Aabsolute stereochemistry
by synthesis from bipinnatin J
O88
O
O
H
H
AcOH
RO
OAc
Cl
HO
Oaquariolide A, R=H
Erythropodium caribaeorumabsolute stereochemistry (ROSEY, NMR)
H
3 8
1ROH
plumarellic acid
HH
O
CH2OHHO
OH
H
EtO2C
Ineleganolide: Duh, C.-Y. et al. Tetrahedron Lett. 1999, 40, 6033-6035.Mandapamates, havellockate norcembrene and biosynthetic proposal thereof: Anjaneyulu, A. S. R. et al. Indian Journal of Chemistry 2000, 39B, 530-535.
Sinulochmodin C and sinuleptolide: Sheu, J.-H. et al. Org. Lett. 2005, 7(17), 3813-3816.Disclaimer: Retrosynthetic analysis for ineleganolide, sinuleptolide proposed by me.
Yonaranes and more!
H3CO2C OH
OH
mandapamate
HH
O
CO2CH3
H3CO2C OH
OH
isomandapamateR1=b-H, R2=CH3, R3=CH3
bishomoisomandapamateR1=a-H, R2=Et, R3=Et
R1H
O
R2O CO2R3
H3CO2C OH
OH
HO
CO2CH3OH3CO
Inverse-demandDiels-Alder
hemiketalization
O
O
O
OCH3O2C
R
furan
Sinularia granosa, R=Hhypothetical, R=CO2CH3
O
O
OHO
H3COO
O
OH
havellockate
1
3
4
6
88
34
43
1
retro-aldol-likeC(3)-C(4) break
OO
O O
O
H
H
ineleganolideSinularia inelegans
O
O
O
O
O
sinulochmodin CSinularia lochmodes
H
H Double Michael
Addition
O
O
O
O OHH
O
sinuleptolide (71)absolute stereochemistry (Mosher)
Sinularia dissecta
H
1Rreductive
condensation4
4
885
11
5
11
Biosynthetic proposal: Anjaneyulu, A. S. R. et al. Indian Journal of Chemistry 2000, 39B, 530-535.
Proposed Biogenesis of Havellockate
H3CO2C OH
OH
HO
CO2CH3O
O
O
O
OCH3O2C
R
Sinularia granosa, R=Hhypothetical, R=CO2CH3
O
O
OHO
H3COO
O
OH
havellockate
1
3
4
6
8
8
34
43
1
O
OHO
H3COO
OH
1
3
4
6
8
H3CO2CHO
rearrangementhydrolysis
lactonization
H3CO2C OH
OHR1H
O CO2R3
O4
3
1
6
bond cleavagelactonization
H
Diels-Alderepoxidation
furan opening
H3CO2C O
OHO
CO2CH3O
8
34
enolizationrearrangement
5
11
Ineleganolide: Duh, C.-Y. et al. Tetrahedron Lett. 1999, 40, 6033-6035.Mandapamates, havellockate norcembrene and biosynthetic proposal thereof: Anjaneyulu, A. S. R. et al. Indian Journal of Chemistry 2000, 39B, 530-535.
Sinulochmodin C and sinuleptolide: Sheu, J.-H. et al. Org. Lett. 2005, 7(17), 3813-3816.Disclaimer: Retrosynthetic analysis for ineleganolide, sinuleptolide proposed by me.
Yonaranes and more!
H3CO2C OH
OH
mandapamate
HH
O
CO2CH3
H3CO2C OH
OH
isomandapamateR1=b-H, R2=CH3, R3=CH3
bishomoisomandapamateR1=a-H, R2=Et, R3=Et
R1H
O
R2O CO2R3
H3CO2C OH
OH
HO
CO2CH3OH3CO
Inverse-demandDiels-Alder
hemiketalization
O
O
O
OCH3O2C
R
furan
Sinularia granosa, R=Hhypothetical, R=CO2CH3
O
O
OHO
H3COO
O
OH
havellockate
1
3
4
6
88
34
43
1
retro-aldol-likeC(3)-C(4) break
OO
O O
O
H
H
ineleganolideSinularia inelegans
O
O
O
O
O
sinulochmodin CSinularia lochmodes
H
H Double Michael
Addition
O
O
O
O OHH
O
sinuleptolide (71)absolute stereochemistry (Mosher)
Sinularia dissecta
H
1Rreductive
condensation4
4
885
11
5
11
Mandapamates, havellockate norcembrene and biosynthetic proposal thereof: Anjaneyulu, A. S. R. et al. Indian Journal of Chemistry 2000, 39B, 530-535.Plumarellide and plumarellic acid: Stonik, V. A. Tetrahedron Lett. 2002, 43, 315-317.
C(1)–C(8) StereochemistryNot Enough Data
H3CO2C OH
OH
mandapamate
HH
O
CO2CH3
H3CO2C OH
OH
isomandapamateR1=b-H, R2=CH3, R3=CH3
bishomoisomandapamateR1=a-H, R2=Et, R3=Et
R1H
O
R2O CO2R3H3CO
O
O
OHO
H3COO
O
OH
havellockatex-ray
1
3
4
6
8
OH
plumarellideNOE with CH3-19 and H-5,7,9β
HH
O
CH2OHHO
OO
H OH
plumarellic acidNOE with CH3-19 and H-5,7,9α,β
HH
O
CH2OHHO
OH
H
EtO2C
O
O
O
OCH3O2C
R
Sinularia granosa, R=Hx-ray
hypothetical, R=CO2CH3
43
188
97
5 5
11
Ineleganolide: Duh, C.-Y. et al. Tetrahedron Lett. 1999, 40, 6033-6035.Mandapamates, havellockate norcembrene and biosynthetic proposal thereof: Anjaneyulu, A. S. R. et al. Indian Journal of Chemistry 2000, 39B, 530-535.
Sinulochmodin C and sinuleptolide: Sheu, J.-H. et al. Org. Lett. 2005, 7(17), 3813-3816.Disclaimer: Retrosynthetic analysis for ineleganolide, sinuleptolide proposed by me.
Yonaranes and more!
H3CO2C OH
OH
mandapamate
HH
O
CO2CH3
H3CO2C OH
OH
isomandapamateR1=b-H, R2=CH3, R3=CH3
bishomoisomandapamateR1=a-H, R2=Et, R3=Et
R1H
O
R2O CO2R3
H3CO2C OH
OH
HO
CO2CH3OH3CO
Inverse-demandDiels-Alder
hemiketalization
O
O
O
OCH3O2C
R
furan
Sinularia granosa, R=Hhypothetical, R=CO2CH3
O
O
OHO
H3COO
O
OH
havellockate
1
3
4
6
88
34
43
1
retro-aldol-likeC(3)-C(4) break
OO
O O
O
H
H
ineleganolideSinularia inelegans
O
O
O
O
O
sinulochmodin CSinularia lochmodes
H
H Double Michael
Addition
O
O
O
O OHH
O
sinuleptolide (71)absolute stereochemistry (Mosher)
Sinularia dissecta
H
1Rreductive
condensation4
4
885
11
5
11
Ineleganolide: Duh, C.-Y. et al. Tetrahedron Lett. 1999, 40, 6033-6035.Sinulochmodin C, sinuleptolide and scabrolides: Sheu, J.-H. et al. Org. Lett. 2005, 7(17), 3813-3816.
Rameswaralide: Ramesh, P. Tetrahedron Lett. 1998, 38, 8271-8220.Dissectolide: Iguchi, K. J. Org. Chem. 1996, 61, 5998-6000.Horolide: Radhika, P. et al. J. Nat. Prod. 2002, 65, 737-739.
The depicted yonaronlide: Iguchi, K. Tetrahedron Lett. 1995, 36, 8807-8808.Disclaimer: Biosynthetic relationships of all but sinulochmodin C postulated by me.
O
O
O
O
O
sinulochmodin CSinularia lochmodes
H
H4
8
O
OHH
OH
O
OH
O
H
dissectolide
O
O
O
O
scabrolide B
HOH
horiolide
10OO
O OH
1
8
4
13 O
H H
H
O
O
O
O
(yonaronlide)
C(1)–C(8) Stereochemistryof Compounds Derived from Sinuleptolide-Like Intermediates
O
O
O
OCH3O2C
R
Sinularia granosa, R=Hhypothetical, R=CO2CH3
43
1
OO
O O
O
H
H
ineleganolideSinularia inelegans
O
O
O
O OHH
O
sinuleptolideabsolute stereochemistry (Mosher)
H
1R4 8
rameswaralide
OO
OOH
CO2CH3
OH
10
8
O
O
O
O
HOH
scabrolide A
5
11 11
Absolute Stereochemistry of SinuleptolideForays into Mosher's Ester Analysis
O
O
O
O OR H
O
H5
1R
+0.05
+0.09+0.02+0.03
+0.01
+0.02
-0.11-0.01-0.03
-0.01
-0.01
1H-NMR shifts (ppm):∆δ= δs-δR
magnetic anisotropy(ring current drawn)
externalmagneticfield
SHIELDINGregion
(above and below ring)
DESHIELDINGregion
(in plane of ring)
Explanation of magnetic anisotropy: Ege, Seyhan Organic Chemistry: Structure and Reactivity (1994 3rd edition, USA), p. 409.Mosher's method: Kakisawa, H. et al. J. Am. Chem. Soc. 1991, 113(11), 4092-4096.
Sinuleptolide: Sheu, J.-H. et al. Org. Lett. 2005, 7(17), 3813-3816.
O
H OCF3
Ph OCH3L1
L2 O
H OCF3
H3CO PhL1
L2
(S)-MTPA ester (R)-MTPA ester
shieldedshielded
so for L1, ∆δ= δs-δR > 0and for L2, ∆δ= δs-δR < 0
L1 L2
Ineleganolide: Duh, C.-Y. et al. Tetrahedron Lett. 1999, 40, 6033-6035.Mandapamates, havellockate norcembrene and biosynthetic proposal thereof: Anjaneyulu, A. S. R. et al. Indian Journal of Chemistry 2000, 39B, 530-535.
Sinulochmodin C and sinuleptolide: Sheu, J.-H. et al. Org. Lett. 2005, 7(17), 3813-3816.Disclaimer: Retrosynthetic analysis for ineleganolide, sinuleptolide proposed by me.
Yonaranes and more!
H3CO2C OH
OH
mandapamate
HH
O
CO2CH3
H3CO2C OH
OH
isomandapamateR1=b-H, R2=CH3, R3=CH3
bishomoisomandapamateR1=a-H, R2=Et, R3=Et
R1H
O
R2O CO2R3
H3CO2C OH
OH
HO
CO2CH3OH3CO
Inverse-demandDiels-Alder
hemiketalization
O
O
O
OCH3O2C
R
furan
Sinularia granosa, R=Hhypothetical, R=CO2CH3
O
O
OHO
H3COO
O
OH
havellockate
1
3
4
6
88
34
43
1
retro-aldol-likeC(3)-C(4) break
OO
O O
O
H
H
ineleganolideSinularia inelegans
O
O
O
O
O
sinulochmodin CSinularia lochmodes
H
H Double Michael
Addition
O
O
O
O OHH
O
sinuleptolide (71)absolute stereochemistry (Mosher)
Sinularia dissecta
H
1Rreductive
condensation4
4
885
11
5
11
sarcophytol LSarcophyton glaucum
absolute stereochemistry
38
11
4
1
Aquariolide A: Andersen, R. J. Org. Lett. 2002, 4, 4085; pinnatin A: Rodríguez, A. D. J. Org. Chem. 1998, 63(13), 4425-4432.Sinulochmodin C: Tseng, Y. J. et al. Org. Lett. 2005, 7(17), 3813-3816;Sarcophytol L: Kobayashi, M.; Osabe, K. Chem. Pharm. Bull. 1989, 37, 1192-1196.
Sclerophytin A: Paquette, L. A. Org. Lett. 2000, 2, 1879; Uchio, Y. Tetrahedron Lett. 1989, 30, 3331; Overmann, L. E. Org. Lett. 2001, 3, 135; Pennington, L. D. J. Am. Chem. Soc. 2001, 123, 9033; Paquette, L. A. J. Am. Chem. Soc. 2001, 123, 9021.
Briarellin E enantioselective total synthesis: Overman, L. E. J. Am. Chem. Soc. 2003, 125, 6650 Minabein-4 absolute stereochemistry: (60) Molinski, J. Nat. Prod. 2004, 67, 2130; other identical isolate: Scheuer, P. J. Heterocycles 1996, 42, 325; Acetate:
Higa, T. J. Nat. Prod. 2004, 67, 1368; Sarcodictyin A: Nakao, Y. et al. J. Nat. Prod. 2003, 66, 524.
More Complex CembranoidsA AA
AA
O
O
3 81R
11
4
briarellin EBriareum aspestinum
enantioselective total synthesis
H
HOH
H
OCOC7H15
OHO
CO2CH3
(Z)-sarcodictyin ABellonella albiflora
absolute stereochemistry via transesterification to sarcodictyin A
3
8
1R
11
4H
H
OH
O
O
NNO
O
O
O
O
sinulochmodin CSinularia lochomodes
absolute configuration via analogy (Mosher)
H
H
OO
OAcOAc
H3 8HO
AcO
HO
Cl
minabein-4, R=Habsolute stereochemistry (X-ray)
identical to other isolateR=OAc, Ellisella
R
HHO OH
O
H
O
HO
pinnatin Aabsolute stereochemistry
by synthesis from bipinnatin J
O88
O
O
H
H
AcOH
RO
OAc
Cl
HO
Oaquariolide A, R=H
Erythropodium caribaeorumabsolute stereochemistry (ROSEY, NMR)
H
3 8
1ROH
plumarellic acid
HH
O
CH2OHHO
OH
H
EtO2C
Bipinnatin J–kallolide A cycloisomerization: Rodríguez, A. D. et al. J. Org. Chem. 1998, 63(3), 420-421.Bipinnatin J–pinnatin C cycloisomerization: Rodriguez, A. D. et al. J. Org. Chem. 1998, 63(13), 4425-4432.
Hypothesized biosynthetic relationship between intricarene, BSK, rubifolide and bipinnatin J: Trauner, D. et al. Org. Lett. 2006, 8(2), 345-347.Enantioselective total synthesis of rubifolide: Marshall, J. A. et al. J. Org. Chem. 1997, 62(13),4313-4320.
Rubifolide isolation: Williams, D. et al. J. Org. Chem. 1987, 52, 332.Verrillin isolation: Cichewicz, R. H. J. Am. Chem. Soc. 2004, 126, 14910; Williams, D. E. J. Nat. Prod. 2004, 67, 2127.
Gersolanoids, Pseudopteranes, and more!
O
OO
OH
HO
H
H HOOH
H
AcO
1
4
bielschowskysinPseudopterogorgia kallos
O
O
bipinnatin Jabsolute stereochemistryby synthesis of kallolide A
O
HO
[2+2] oxidation
O
O
O
O
H1
4 8
12
intricarene
formaloxidative
[5+2]
12
6
6
O
O
O
HO
kallolide Aabsolute stereochemistry
hν, 2 hCH3CN, 25 °C, 40%1,3-allylic shift
10
7
7
10
O
H
O
HO
pinnatin Cabsolute stereochemistry
by synthesis from bipinnatin J
OO
hν (minor)1,2-migration(antarafacial)
O
O
rubifolideenantioselective total syntheses
Gersemia rubiformis
O
O
O
HO H
AcOO
O
H
O
H
H3CO2C
H
providencinPseudopterogorgia kallos
O
O O
O
O
O H
HO
H
H OH
1
4
verrillinPseudopterogorgia bipinnata
[3+2]1 8 1 8
1
4
1
48
Enantioselective total synthesis of unnatural rubifolide: Marshall, J. A. et al. J. Org. Chem. 1997, 62(13),4313-4320.
Enantioselective Total Synthesis of unnatural Rubifolide O
O
O
HO
8 steps TBSO
O
O
O
OCO2CH3
MOMO
O
OPMBMOMO
OTBS
•
SnBu3
O
OR
•
O
OR
OMOM
5 steps
(66% yield)+
8 diastereomers
1. BF3•OEt22. Dess-Martin, NEt3
(74% yield)
1. AgNO3, silica gel2. p-TsOH
(61% yield)
R=H, 2 diastereomers, undisplayedconverted to desired over 2 steps
in 96% yieldR=COCF3 (reaction intermediate)
R=CO2CH3
R=H
3
8
11
8
11
1
8
11
13
55
81
3
1
3
81
K2CO3, MeOH(96% yield)
Pd(PPh3)4, CO, THF2,6-lutidine, Tf2O
then H2O(49% yield)
Enantioselective total synthesis of kallolide A: Marshall, J. A. et al. J. Org. Chem. 1998, 63(17), 5962-5970.
Enantioselective Total Synthesis of Kallolide A
8
O
O
O
HO 7
10
O7
O
SEMOO
R2
R3
R1
O
EtO2C
O
Bu3Sn ODPS
CO2HCO2H
2,6-(OMe)2C6H3CO2
OHBH3•THF (1 eq), EtCN, Tf2O (2 eq)
(24% yield, 90% ee)2
2
2
R1=OH, R2=ODPS, R3=CO2EtR1=OSEM, R2=Cl, R3=OH
7
111
11
3-steps
NaH, Bu4NI
PhCH3(66% yield)
8
O
OH
SEMO 7
102
BuLi
THF–pentane(73% yield)
Pd2dba3, Ph3P, COTMSCH2CH2OH
THF(73% yield)
8
OSEMO 7
102
•
CO2CH2CH2TMS
4 steps
Bipinnatin J–kallolide A cycloisomerization: Rodríguez, A. D. et al. J. Org. Chem. 1998, 63(3), 420-421.Bipinnatin J–pinnatins cycloisomerization: Rodriguez, A. D. et al. J. Org. Chem. 1998, 63(13), 4425-4432.Enantioselective total synthesis of kallolide A: Marshall, J. A. et al. J. Org. Chem. 1998, 63(17), 5962-5970.Enantioselective total synthesis of rubifolide: Marshall, J. A. et al. J. Org. Chem. 1997, 62(13),4313-4320.Synthesis of deoxypukalide from pukalide and other: Marshall, J. A. J. Org. Chem. 2001, 66, 8037-8041.
Absolute Stereochemistries of 3-Furanocembranoids
1 8O
O
bipinnatin Jabsolute stereochemistryby synthesis of kallolide A
O
HO
12
6
O
O
O
HO
kallolide Aabsolute stereochemistry
hν, 2 hCH3CN, 25 °C, 40%1,3-allylic shift
8
10
7
7
10
O
H
O
HO
pinnatin Cabsolute stereochemistry
by synthesis from bipinnatin J
OO
hν (minor)1,2-migration(antarafacial)
1 8O
O
rubifolideenantioselective total syntheses
Gersemia rubiformis
O
O
O
H
O
pinnatin Aabsolute stereochemistry
by synthesis from kallolide A
+
O
OO
O
pukalideSinularia polydactyla
absolute configuration by synthesis of unnatural enantiomer of deoxypukalide
H3CO2C
sarcophytol LSarcophyton glaucum
absolute stereochemistry
38
11
4
1
Aquariolide A: Andersen, R. J. Org. Lett. 2002, 4, 4085; pinnatin A: Rodríguez, A. D. J. Org. Chem. 1998, 63(13), 4425-4432.Sinulochmodin C: Tseng, Y. J. et al. Org. Lett. 2005, 7(17), 3813-3816;Sarcophytol L: Kobayashi, M.; Osabe, K. Chem. Pharm. Bull. 1989, 37, 1192-1196.
Sclerophytin A: Paquette, L. A. Org. Lett. 2000, 2, 1879; Uchio, Y. Tetrahedron Lett. 1989, 30, 3331; Overmann, L. E. Org. Lett. 2001, 3, 135; Pennington, L. D. J. Am. Chem. Soc. 2001, 123, 9033; Paquette, L. A. J. Am. Chem. Soc. 2001, 123, 9021.
Briarellin E enantioselective total synthesis: Overman, L. E. J. Am. Chem. Soc. 2003, 125, 6650 Minabein-4 absolute stereochemistry: (60) Molinski, J. Nat. Prod. 2004, 67, 2130; other identical isolate: Scheuer, P. J. Heterocycles 1996, 42, 325; Acetate:
Higa, T. J. Nat. Prod. 2004, 67, 1368; Sarcodictyin A: Nakao, Y. et al. J. Nat. Prod. 2003, 66, 524.
More Complex CembranoidsA AA
AA
O
O
3 81R
11
4
briarellin EBriareum aspestinum
enantioselective total synthesis
H
HOH
H
OCOC7H15
OHO
CO2CH3
(Z)-sarcodictyin ABellonella albiflora
absolute stereochemistry via transesterification to sarcodictyin A
3
8
1R
11
4H
H
OH
O
O
NNO
O
O
O
O
sinulochmodin CSinularia lochomodes
absolute configuration via analogy (Mosher)
H
H
OO
OAcOAc
H3 8HO
AcO
HO
Cl
minabein-4, R=Habsolute stereochemistry (X-ray)
identical to other isolateR=OAc, Ellisella
R
HHO OH
O
H
O
HO
pinnatin Aabsolute stereochemistry
by synthesis from bipinnatin J
O88
O
O
H
H
AcOH
RO
OAc
Cl
HO
Oaquariolide A, R=H
Erythropodium caribaeorumabsolute stereochemistry (ROSEY, NMR)
H
3 8
1ROH
plumarellic acid
HH
O
CH2OHHO
OH
H
EtO2C
Hypothetical biosynthetic pathway extrapolated from: Wahlberg, I.; Eklund, A.-M. Prog. Chem. Org. Nat. Prod. 1992, 60, 1-141.Sclerophytins: Paquette, L. A. J. Nat. Prod. 2002, 65, 126; Paquette, L. A. The Chemical Record, 2001, 1, 311.
Alcyonin misassigned: Kakisawa, H. Chem. Lett. 1988, 1077; reassigned: Overman, L. E. J. Am. Chem. Soc. 2003, 125, 6650.Polyanthellin A: Rodríguez, A. D. J. Nat. Prod. 2003, 66, 357; enantiomer: Rodríguez, A. D. et al. Tetrahedron 1995, 51, 6869.
Disclaimer: Pathway from second structure purely my own guess based on very little evidence.
CladiellinsA AA
AA
a hypotheticalcladiellin
O3
8
1
11
4
3
8
1
11
4OH
OH
OH
OH
a hypotheticalcembranoid
3
8
1
11
4
OH
OH
OHHO
HO OH
OH
HO:-
structures reassigned-sclerophytin A, R=H
sclerophytin B, R=Ac
O
H
H
HH
OH
OR
OH
3
8
1
11
4
O3
8
1
11
4
O
H
HAcO
polyanthellin ABriareum polyanthes
[also isolated ent-polyanthellin A]
(alcyonin)structure misassigned - R=H
Sinularia flexibilisstructure reassigned - R=OH
due to enantioselective synthesis
O
H
H
HH
OR
OAc
OH
3
8
1
11
4
a hypotheticalcembranoid
(enzyme catalyzed, stepwise)
[o]
a hypotheticalcembranoid
(enzyme catalyzed, stepwise)
3
8
1
11
4
OH
OH
OHHO
O
-H3
8
1
11
4
OH
OH
OHHO
HOH
:B
-OH
then
a hypotheticalcembranoid
(enzyme catalyzed, stepwise)
Briarellin E, F enantioselective syntheses: Overman, L. E. J. Am. Chem. Soc. 2003, 125, 6650 ; isolation: Rodríguez, A. D. Chem. Pharm. Bull. 1995, 43, 1853; briarellin A original: Rodríguez, A. D. Tetrahedron 1995, 51, 6869; reassigned: Coll, J. C. Aust. J. Chem. 1989, 42, 1705; briarellin M-P: Rodríguez, A.
D. J. Nat. Prod. 2003, 66, 357.Disclaimer: Pathway from second structure purely my own guess based on very little evidence.
Cladiellins and AsbestininsA AA
AA
O
O
3 81
11
4
a hypotheticalasbestinin
a hypotheticalcladiellin
O3
8
1
11
4
a hypotheticalcembranoid
(enzyme catalyzed, stepwise)
3
8
1
11
4OH
OH
OH
OH
a hypotheticalcembranoid
3
8
1
11
4
OH
OH
OH
H+
HO HO OH
OH
HO:-
O
O
3 81R 11
4
briarellin FBriareum aspestinum
enantioselective total synthesis
H
HOH
H
OCOC7H15
O
O
O
3 81R 11
4
briarellin EBriareum aspestinum
enantioselective total synthesis
H
HOH
H
OCOC7H15
OH
O
O
3 81 11
4
structure reassigned - briarellin A, R1=H, R2=OOH
structure misassigned - briarellin A, R1=OH, R2=H
Briareum polyanthes
H
HR2O
H
O
R2
OCOC7H15R1
O
O
3 81 11
4
briarellin M, R1=H, R2=Acbriarellin N, R1=CH3, R2=Ac
briarellin O, R1=H, R2=COn-Prbriarellin P, R1=CH3, R2=COn-Pr
Briareum polyanthes
H
HR2O
H
OOR1
OH
H+
Sarcodictyin A: Nakao, Y. et al. J. Nat. Prod. 2003, 66, 524.Hypothetical biosynthetic pathway extrapolated from: Wahlberg, I.; Eklund, A.-M. Prog. Chem. Org. Nat. Prod. 1992, 60, 1-141 (review).
Disclaimer: Pathway from second structure purely my own guess based on very little evidence.
Cladiellins, Asbestinins and Sarcodictyins, Oh my!A AA
AA
O
CO2CH3
(Z)-sarcodictyin ABellonella albiflora
absolute stereochemistry via transesterification to sarcodictyin A
3
8
1R
11
4H
H
OH
O
O
NN
O
a hypotheticalsarcodictyin
3
8
1
11
4
a hypotheticalcembranoid
(enzyme catalyzed, stepwise)
3
8
1
11
4OH
OH
OH
OH
a hypotheticalcembranoid
3
8
1
11
4
OH
OH
OHHO
O
CO2CH3
sarcodictyin A
3
8
1R
11
4H
H
OH
O
O
N
N
HO:-
OH
HOHO
[o]
a hypotheticalcembranoid
(enzyme catalyzed, stepwise)
3
8
1
11
4
OH
OH
OHHO
O
-H3
8
1
11
4
OH
OH
OHHO
HOH
:B
-OH
then
a hypotheticalcembranoid
(enzyme catalyzed, stepwise)
sarcophytol LSarcophyton glaucum
absolute stereochemistry
38
11
4
1
Aquariolide A: Andersen, R. J. Org. Lett. 2002, 4, 4085; pinnatin A: Rodríguez, A. D. J. Org. Chem. 1998, 63(13), 4425-4432.Sinulochmodin C: Tseng, Y. J. et al. Org. Lett. 2005, 7(17), 3813-3816;Sarcophytol L: Kobayashi, M.; Osabe, K. Chem. Pharm. Bull. 1989, 37, 1192-1196.
Sclerophytin A: Paquette, L. A. Org. Lett. 2000, 2, 1879; Uchio, Y. Tetrahedron Lett. 1989, 30, 3331; Overmann, L. E. Org. Lett. 2001, 3, 135; Pennington, L. D. J. Am. Chem. Soc. 2001, 123, 9033; Paquette, L. A. J. Am. Chem. Soc. 2001, 123, 9021.
Briarellin E enantioselective total synthesis: Overman, L. E. J. Am. Chem. Soc. 2003, 125, 6650 Minabein-4 absolute stereochemistry: (60) Molinski, J. Nat. Prod. 2004, 67, 2130; other identical isolate: Scheuer, P. J. Heterocycles 1996, 42, 325; Acetate:
Higa, T. J. Nat. Prod. 2004, 67, 1368; Sarcodictyin A: Nakao, Y. et al. J. Nat. Prod. 2003, 66, 524.
More Complex CembranoidsA AA
AA
O
O
3 81R
11
4
briarellin EBriareum aspestinum
enantioselective total synthesis
H
HOH
H
OCOC7H15
OHO
CO2CH3
(Z)-sarcodictyin ABellonella albiflora
absolute stereochemistry via transesterification to sarcodictyin A
3
8
1R
11
4H
H
OH
O
O
NNO
O
O
O
O
sinulochmodin CSinularia lochomodes
absolute configuration via analogy (Mosher)
H
H
OO
OAcOAc
H3 8HO
AcO
HO
Cl
minabein-4, R=Habsolute stereochemistry (X-ray)
identical to other isolateR=OAc, Ellisella
R
HHO OH
O
H
O
HO
pinnatin Aabsolute stereochemistry
by synthesis from bipinnatin J
O88
O
O
H
H
AcOH
RO
OAc
Cl
HO
Oaquariolide A, R=H
Erythropodium caribaeorumabsolute stereochemistry (ROSEY, NMR)
H
3 8
1ROH
plumarellic acid
HH
O
CH2OHHO
OH
H
EtO2C
Hypothetical biosynthetic pathway extrapolated from: Wahlberg, I.; Eklund, A.-M. Prog. Chem. Org. Nat. Prod. 1992, 60, 1-141.Cyclobutenebriarein A: González, N. J. Org. Chem. 2002, 67 (15), 5117-5123.
Brianthein A - Mosher: Kobayashi, M. Tetrahedron, 2001, 57, 8951.Juncenolide A - X-ray: Shen, Y. C. J. Nat. Prod. 2002, 65, 54.
Erythrolide S - Mosher: Andersen, R. J. Org. Lett. 2002, 4, 3515.Disclaimer: Second ring closure hypothesis without evidence or source other than my own brief consideration.
BriaranesA AA
AA
3 8
O 1
11
hypotheticalbriaran
4
18
9
OAc
1 8
9
3 8
1 11
4H
B:
OH
OH OH
OH
hypotheticalcembrane
OH
OH
3 8
1 11
4
OH
OH
3 8
1 11
4
OH
O
OH
H
OOH OAc
H
O
O n-Pr
O
OH
cyclobutenebriarein A absolute configuration by
analogy and proposed biogenesis
1S 38
erythrolide Sabsolute stereochemistry
by Mosher method
OO OAc
H
CO2CH3
38
AcO
HO
O
OAc
OAcO
OH
O OH
O
OAc
O
AcO
juncenolide Aabsolute stereochemistry
HO
O
Cl
OO
OAcH
3 8
brianthein A absolute stereochemistry
OAc
OAc
Hypothetical biosynthetic pathway proposed in: Wahlberg, I.; Eklund, A.-M. Prog. Chem. Org. Nat. Prod. 1992, 60, 1-141.Erythrolide L, aquarolides B, C, absolute stereochemistry of A: Andersen, R. J. Eur. J. Org. Chem. 2003, 3515.
Erythrolide A, B, V, aquariolide A: Andersen, R. J. Org. Lett. 2002, 4, 4085.
Erythranoids, AquarianesA AA
AA
O
H
AcO
OH
Cl
OAc
AcO
O
O
erythrolide A
3
1
erythrolide B(a briaran)
OO
AcOH
38
O
OH
AcO
OAc
Cl
8
6
7di-π-methane
rearrangement
O
H
AcO
OH
Cl
OAc
O
O
O
OAcO
erythrolide L
O
H
AcO
OH
Cl
OH
AcO
O
O
erythrolide V
3
1
3
1
O
O
H
H
AcOH
RO
OAc
Cl
HO
Oaquariolide A, R=H
absolute stereochemistry (ROSEY, NMR)aquariolide B, R=CH3aquariolide C, R=Ac
H
3 8
1R
vinyl cyclopropane
rearrangement
Hypothetical biosynthetic pathway proposed in: Wahlberg, I.; Eklund, A.-M. Prog. Chem. Org. Nat. Prod. 1992, 60, 1-141.
CapnosanesA AA
AA
OO
OO11
7
O
OO
OO11
7
O OH
OO
OHO11
7
O OH
3O
OO
OHO7
11O
OO
O7
11OH
3
OH
coralloidolide C
coralloidolide E
3
81
11
4
coralloidolide FAlcyonium coralloides
sarcophytol LSarcophyton glaucum
absolute stereochemistry
3 811
4
1
Coralloidoilide F: D'Ambrosio, M.A. et al. Helv. Chim. Acta, 1990, 73, 804-807; pinnatin A: Rodríguez, A. D. J. Org. Chem. 1998, 63(13), 4425-4432.Cembrene: Zhang, T. et al. Synthesis 2001, 3, 393; sinulochmodin C: Tseng, Y. J. et al. Org. Lett. 2005, 7(17), 3813-3816.
Sarcophytol L: Kobayashi, M.; Osabe, K. Chem. Pharm. Bull. 1989, 37, 1192-1196; Sclerophytin A: Paquette, L. A. Org. Lett. 2000, 2, 1879; Uchio, Y. Tetrahedron Lett. 1989, 30, 3331; Overmann, L. E. Org. Lett. 2001, 3, 135; Pennington, L. D. J. Am. Chem. Soc. 2001, 123, 9033; Paquette, L. A. J. Am. Chem. Soc. 2001, 123, 9021.
Erythrolide V: Andersen, R. J. et al. Eur. J. Org. Chem. 2003, 3515.Briarellin E enantioselective total synthesis: Overman, L. E. J. Am. Chem. Soc. 2003, 125, 6650 ; isolation: Rodríguez, A. D. Chem. Pharm. Bull. 1995, 43, 1853.
Minabein-4 absolute stereochemistry: (60) Molinski, J. Nat. Prod. 2004, 67, 2130; other identical isolate: Scheuer, P. J. Heterocycles 1996, 42, 325; Acetate: Higa, T. J. Nat. Prod. 2004, 67, 1368.Sarcodictyin A: Nakao, Y. et al. J. Nat. Prod. 2003, 66, 524.
Skeletal Termsexamples
A AA
AA
sclerophytin Atotal syntheses
O
3
8
111
4
OH
H
HOH
OH
O
O
3 81R
11
4
briarellin EBriareum aspestinum
enantioselective total synthesis
H
HOH
H
OCOC7H15
OHO
CO2CH3
(Z)-sarcodictyin ABellonella albiflora
absolute stereochemistry via transesterification to sarcodictyin A
3
8
1R
11
4H
H
OH
O
O
NNO
O
O
O
O
sinulochmodin CSinularia lochomodes
absolute configuration via analogy (Mosher)
H
H
OO
OAcOAc
H3 8HO
AcO
HO
Cl
minabein-4, R=Habsolute stereochemistry (X-ray)
identical to other isolateR=OAc, Ellisella
R
1
(–)-13-hydroxy-11,12-epoxyneocembreneabsolute stereochemistry
(total synthesis)Sinularia trocheliophorum
OH
O
O
H
AcO
OH
Cl
OH
AcO
O
O
erythrolide VErythropodium caribaeorum
3
1
O
OO
O
OH
HHO OH
O
H
O
HO
pinnatin Aabsolute stereochemistry
by synthesis from bipinnatin J
O88
11
5
Acknowledgements
OO
O O
O
H
H
ineleganolideSinularia inelegans
4 8
Sinularia elegans: http://www.upstatereef.com/gallery/albums/Inhabitant-Pictures/redlobo.thumb.jpg
Y'all
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