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NATURAL PRODUCT SYNTHESIS
Polycyclic Polyprenylated Acylphloroglucinols
(PPAPS)
SYNAPS
University of Crete
25th July 2011
Nigel S. Simpkins
School of Chemistry
University of Birmingham, U.K.
O
OH
OH
O
OHO
O
Me
O
HYPERFORIN: AN IMPORTANT PPAP ANTIDEPRESSANT
Hyperforin: a type A PPAP
The major bioactive constituent of St John’s Wort (hypericum perforatum).
Antidepressant activity due to broad-spectrum inhibition of neurotransmitter
reuptake through elevation of intracellular [Na+].
Interferes with cytochrome P450 expression.
Inhibits growth of several tumor cell lines in dose-dependent fashion with
An IC50 value of 3-15 mM.Giannis and Sleeman and co-workers, ChemBioChem, 2005, 6, 171.
Inhibitor of angiogenesis through interaction with multiple targets.Medina and co-workers, Int. J. Cancer, 2005, 117, 775.
Antimalarial activity.Verotta and co-workers, Bioorg. & Med. Chem Lett., 2007, 17, 1544.
Human histone deacylaase inhibition.Giannis and co-workers, Angew. Chem. Int. Ed., 2007, 46, 5219.
AC
B
Garsubellin A
A type A PPAP with a THF type ring.
Isolated from the wood of Garcinia subelliptica. A potential Alzheimer therapeutic?
(induces choline acetyltransferase activity).
Y. Fukuyama, A. Kuwayama, and H. Minami
Chem. and Pharm. Bull., 1997, 45, 947.
Anti-inflammatory activity
Lin and co-workers, Chem. Eur. J., 2003, 9, 1958. Polycyclic Polyprenylated
Acylphloroglucinols (PPAPS)
Review: Ciochina and Grossman, Chem. Rev., 2006, 106, 3963.
GARSUBELLIN A: A POTENTIAL ALZHEIMER THERAPEUTIC?
O
O
OH
O
OH
H O
O O
OHHO
A
Clusianone - a type B PPAP from Clusia
(Full data and anti-HIV activity) Rastrelli and co-workers, Tetrahedron, 2005, 61, 8206.
Nemorosone (from resins and latex of Clusia)Cardenas and co-workers, Phytochem., 2001, 57, 279.
Shows IC50 value of 3.3 mM (HELA)
3.1 mM (HeP-2); 7.2 mM (PC-3); 3.9 mM (U251)
O-methylated derivative much less active. Cardenas and co-workers, Z. Naturforsch, 2002, 57, 372.
CLUSIANONE AND NEMOROSONE: POTENTIAL ANTITUMOUR LEADS
O
OH
OH O
Ph
OHO
OMe
Me
OPh
O
HO
OPh
O
H
B
Antitumour activity
Diaz-Carballo and co-workers, J. Clin. Pharm. & Ther., 2003, 41, 622.
Leishmanicidal activity (7-epi-clusianone)Pereira and co-workers, Phytomedicine, 2010, 17, 339.
A
BIOSYNTHESIS OF POLYCYCLIC POLYPRENYLATED PHLOROGLUCINOLS
A
B
Grossman review lists all examples
up to the end of 2005:
Type A - 80
Type B - 35
Type C - 3
R. Ciochina and R. B. Grossman
Chem. Rev. 2006, 106, 3963.
ANALYSIS OF PPAP BICYCLONONANE STRUCTURES
Clusianone[3.3.1] system
Tetraketone - 1,3 -diketone bridge in conjugation with C(O)Ph.
Prenyl substituents - note 7-exo.
Almost symmetrical.
Unknown absolute configuration.........
Hyperforin
Additional (quaternary) stereogenic centre.
Bridgehead C(O)iPr substituent.
Known absolute configuration.
Garsubellin
THF ring - additional stereocentre.
Tertiary alcohol - protection?
Unknown absolute configuration.
O
OH
OH
O
O
O
OH
O
OH
H
O
OH
OH O
Ph
Generic issues include - [3.3.1] triketone construction, diketone protection (NB enol
regioisomers), stability (retro-Dieckmann, oxidation, acid.....), prenyl installation
(including stereocontrol), contiguous quaternary carbon centres.
Review – R. Ciochina and R. B. Grossman, Chem. Rev. 2006, 106, 3963.
Clusianone
Biomimetic route via electrophilic cyclisation of prenylated acylphloroglucinolO
OH
OH O
Ph
O
OH
O
X
H O
Ph
O
OH
OO
Ph
O
COPh
O
O
=
O
OH
OH O
Ph
O
OH
OH
O
H
O
O
X
X
O
=
Annulation of 1,3-diketone part (α,α' acylative bridge formation)
RETROSYNTHETIC ANALYSIS OF PPAP STRUCTURES
Nemorosone
Adding substituents to a core structure (bridgehead substitution?)
O
OH
OH
OPh
O
OR
OH
H
H
H
Garsubellin
Disconnect side THF and consider options, including those above.
RETROSYNTHETIC ANALYSIS OF PPAP STRUCTURES
O
O
OH
O
OH
H
O
OH
OH
O
Build THF early and annulate hydrocarbon bridge
O
O
OH
O
OH
H
O
O
O
X
H
O
OH
H
O
O
O
O
OH
H
Carry oxidised side chain and annulate (masked) diketone part
O
O
OH
O
OH
H
O
H
O
H
RO
O
O
O
O
H
O
H
RO
O
O
O
INITIAL APPROACHES TO PPAP [3.3.1] SYSTEMS
Early approaches
(i) Intramolecular aldol - Nicolaou,1999 (also Shibasaki).
(ii) Effenberger annulation - Stoltz, 2002.
O
OMe
Me
O
Me
Me
O
TfOH, 63%CHO
Me
O
Me
(i)
(ii) Dess-Martin 81%
O
OH
OH
OTBS
Cl Cl
O O
(i) (2 equiv.)
CH2Cl2, -10 oC, 11h
(ii) KOH, BnEt3NCl, H2O
-10 oC to RT
(35% + rec. ketone)
INITIAL APPROACHES TO PPAP [3.3.1] SYSTEMS
Early approaches
(iii) Intramolecular nitrile oxide cycloaddition - Young (2002)
(iv) Radical cyclisation - Kraus (2003)
OTMS
C
TiCl4
MeO NO2
OMe O
C
NO2
OMeO
OMeN
OPhNCO
Et3N
44% 40%
OCOPh
O
OPh
O
OPh
Br
O
O
OPh
Br
Br
Br
O
OPh
O
O
O
OPh
OH
O
Mn(OAc)3 3.3 NBS
+
HOAc (aq)
ONa170
oC
76%
AIBN
52%overall
