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Synthesis of the Tetrahydroisoquinoline Alkaloid(±)-Renieramycin G and a (±)-Lemonomycinone
Analogue from a Common Intermediate
Philip Magnus* and Kenneth S. MatthewsDepartment of Chemistry and Biochemistry, University of Texas at Austin
J. Am Chem. Soc. 2005, ASAP.
O
Me
MeO
O
N
NMe
O
Me
OMe
O
H
HH
O
H
O
Me
MeO
(±)-Renieramycin G
O
Me
MeO
O
N
NH
H
HH
OH
H
O
OHHO
(±)-Lemonomycinone amide
Shinya Iimura @ Wipf Group 1 9/4/2005
Tetrahydroisoquinoline Antitumor Antibiotics
Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102, 1669.
■ The two core structures of this family are the quinone A and the aromatic core B. Todate, nearly 60 natural products in this family have been isolated, and hundreds ofsynthetic analogues have been reported.
A B
■ The tetrahydroquinoline family of antitumor antibioticshas been studied since naphthriydinomycin was isolated in1974 by Kluepfel et al.
Shinya Iimura @ Wipf Group 2 9/4/2005
Tetrahydroisoquinoline Antitumor Antibiotics
Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102, 1669.Shinya Iimura @ Wipf Group 3 9/4/2005
Tetrahydroisoquinoline Antitumor Antibiotics
Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102, 1669.Shinya Iimura @ Wipf Group 4 9/4/2005
Renieramycins: Isolation and Biological Activity
■ Renieramycines are isolated from various marine sponges belonging to generaReniera, Xestospongia, Haliclona, Cribrochalina, and Neopetrosia.
■ The ring systems and their relative stereochemistry are identical with those ofsaframycins which exhibit strong cytotoxicity against cultured cells and antitumor activityagainst several experimental tumors.
■ Renieramycins A–D, and H have moderate antimicrobial activities. Renieramycin Ghas cytotoxicity against human cancer cells with MIC values of 0.5 and 1.0 µg/mL againstKB and LoVo cell lines, respectively.
Shinya Iimura @ Wipf Group 5 9/4/2005
Fukuyama: First Total Synthesis of (±)-Renieramycin A
Fukuyama, T. et al. Tetrahedron Lett. 1990, 31, 5989.
Total Synthesis of Renieramycins
OR
OMOM
Me
OMe
OHCAcN
NAc
O
OOMe
Me
MeO
OBn
CHO
OMe
Me
MeO
OBn
HN
NCbz
O
O
OMe
Me
OR
OMOM
OMe
Me
MeO
OBn
HN
NR
O
OMe
Me
OR
HO
H
H
O
Me
MeO
O
N
NMeO
Me
OMe
O
H
HH
OHOMe
Me
MeO
OH
HN
NMeOMe
Me
OMe
HO
H
HH
OHO
H
O
Me
Me
29 steps from
CHO
OMe
Me
OMe
0.5% overall yield
+ +
Pictet–Spengler
Shinya Iimura @ Wipf Group 6 9/4/2005
Total Synthesis of RenieramycinsDanishefsky: First Asymmetric Total Synthesis of Cribrostatin IV (Renieramycin H)
Danishefsky, S. J. et al. J. Am. Chem. Soc. 2005, 127, 4596.
O
Me
MeO
O
N
NMeOH
Me
OMe
HO
H
H
O
O
H
O
Me
Me
32 steps from
CHO
OH
1.7% overall yield
HO
Me
CHO
OH
HO
Me
OH
HO Me
NH
OH
H
PGO
R
OHC
RHN
CO2H
R
N
OH
H
PGO
R
O
RHN
O
H
R
N
NR
Me
OR
RO
H
HOH
OH
PGO
R
Lynchpin MannichCyclization
+
O
Pomeranz–FritschCyclization
Shinya Iimura @ Wipf Group 7 9/4/2005
Total Synthesis of RenieramycinsWilliams: First Asymmetric Total Synthesis of (–)-Renieramycin G
23 steps from
CH2OH
OMe
7.9% overall yield
Me
MeO
CH2I
OMe
Me
MeO
+
OBn
O
Me
MeO
O
N
NMeO
Me
OMe
O
H
HH
O
H
O
Me
MeO
BocN
O
O
Ph
PhOMe
Me
MeO
OBn
OBocN
O
Ph Ph
Pictet–Spengler
NH
OR
MeO
Me
OMe
H
H
OR
OR
OMe
Me
MeO
OR
OHRHN
O
+
N
OR
MeO
Me
OMe
H
H
OOR
NHR
MeO
Me
OMe
ORCHO
IntramolecularPictet–Spengler OMe
Me
MeO
OR
N
NMeOMe
Me
OMe
HO
H
HH
OR
H
O
OBn
Williams, R. M. et al. J. Am. Chem. Soc. 2005, ASAP.Shinya Iimura @ Wipf Group 8 9/4/2005
Lemonomycin: Isolation and Biological Activity
■ Lemonomycin was isolated in 1964 from Streptomyces candidus. However, thestructure was not elucidated until 2000.
■ Lemonomycin contains the unusual aldehyde hydrate and the sugar moiety, and is theonly member in this family of tetrahydroisoquinoline antibiotics.
■ Lemonomycin has interesting antibiotic activity against methicillin-resistantStaphylococcus aureus and vancomycin-resistant Enterococcus faecium, as well ascytotoxicity against a human colon tumor cell line.
Shinya Iimura @ Wipf Group 9 9/4/2005
Total Synthesis of Lemonomycin
15 steps from
3.1% overall yield
O
Me
MeO
O
N
NH
H
HH
O
H
O
O
OHHO
Me
OH
NMe2Me
OMe
Me
MeO
OH
HN
NR
H
HH
O
OTIPS
O
O
Me
OH
NMe2Me
OHC
+
Pictet–Spengler
HN
NR
H
H
O
OTIPS
OMe
Me
MeO
OPG
B O
O
I+
N N
HN
N
O
Bn
Br
Bn
O
Xc
O
+
Stoltz: First Asymmetric Total Synthesis of (–)-Lemonomycin
Stoltz, B. M. et al. J. Am. Chem. Soc. 2003, 125, 15000.Shinya Iimura @ Wipf Group 10 9/4/2005
New Strategy for the 1,3-cis-SubstitutedTetrahydroisoquinolines
C1 Nucleophilic Addition ApproachPictet–Spengler Approach
β α
Magnus, P. et al. Org. Lett. 2003, 5, 2181.
Shinya Iimura @ Wipf Group 11 9/4/2005
Synthesis of Common Intermediate
Magnus, P. et al. J. Am. Chem. Soc. 2005, ASAP.Shinya Iimura @ Wipf Group 12 9/4/2005
(±)-Renieramycin G
Magnus, P. et al. J. Am. Chem. Soc. 2005, ASAP.Shinya Iimura @ Wipf Group 13 9/4/2005
(±)-Lemonomycinone Amide
Magnus, P. et al. J. Am. Chem. Soc. 2005, ASAP.Shinya Iimura @ Wipf Group 14 9/4/2005
Summary
O
Me
MeO
O
N
NH
H
HH
OH
H
O
OHHO
(±)-Lemonomycinone amide
O
Me
MeO
O
N
NMeO
Me
OMe
O
H
HH
O
H
O
Me
MeO
(±)-Renieramycin G
N
NBoc
O
SPhH
H
OBnOBn
MeO
Me
OMe
18% yield (8 steps)
16% yield (9 steps)
I
OMe
Me
MeO
OBn
NtBu 32% yield (10 steps)
N
OTIPS
OBn
MeO
Me
OMe
NH
OH
OBn
MeO
Me
OMe
OBn
H
H
■ A general approach to both mono- andbistetrahydroisoquinoline alkaloids from a commonadvanced intermediate has been developed.
Shinya Iimura @ Wipf Group 15 9/4/2005
