E3: Synthesis of Manzamine A and Related Alkaloids [1,3]

Manzamine A and related alkaloids

NH 2 a.) PPh 3CBrCO2Me, have been isolated from marine
a.) Boc 2O, aq. Na 2CO 3 CH2Cl2 sponges of the genera Haliclona and
b.) TBDPSCl b.) TMSOTf, 2,6-lutidine Pellina found in the Okinawa Sea in
c.) CH 2CHCHO, CSA then p-TsOH
1986, which exhibit a broad biological
HO
activity (anti-bacterial, antimalarial,
anti-tumor, anti-inflammatory and
anti-HIV).[2] The combination of the
complex and unusual structure of
Manazamine A (pentacyclic core, two
A
tertiary amides, two Z-olefins and five
stereocenters) and its promising
biological activity have inspired
a.) SOCl2, EtOH numerous synthetic investigations.[1,2]
a.) TBDPSCl, imid., DMF
H 2N CO2H b.) 150°C, 15 mmHg, 15 h b.) Boc 2O, DMAP, Et 3N Four total syntheses by Winkler
c.) NaBH 4, EtOH (1999), Martin (1998), Fukuyama
c.) LHMDS, THF, CO2, -78°C (2010) and Dixon (2012) have been
then NaBH 4, EtOH reported.[2]
CO2H then Na 2CO 3


commercially available [3] B

one step CO2Me

O H
MeO 2C
(COCl) 2
N H
then A, NEt 3 Br N Boc N
B
toluene, ∆ O N Boc
OTBDPS
OTBDPS
OTBDPS OTBDPS

Name?

[1] J. M. Humphrey, Y. Liao, A. Ali, T. Rein, Y.-L. Wong, H.-L. Chen, A. K.

Countrey, S. F. Martin, J. Am. Chem. Soc. 2002, 124, 8584-8592. Sparr Group Seminar
[2] P. Jakubec, A. Hawkins, W. Felzmann, D. J. Dixon, J. Am. Chem. Soc.
2012, 134, 17482-17485.
01.10.2015
[3] Y. Hamada, O. Hara, A. Kawai. Y. Kohno, T. Shioiri, Tetrahedron 1991, 47, Vincent Fäseke
8635-8652.
 CHO
CO2Me H
H
H
H CrO 3, 3,5-dimethylpyrazole, N
N CH2Cl2, –18°C O
N Boc
O N Boc

OTBDPS
OTBDPS 5 steps

a.) HC(OMe) 3 MeOH, HCl

a.) KOH, MeOH, ∆ b.) CH2CHCH2CH2Li,
b.) CH2CH(CH2)3COCl, –78 °C to – 20°C then H 2O
cat (+ formation of a carbamate)
Et 3N, CH2Cl2

N
N N
H NH
a.) tryptamine, H H
CF 3CO2H H OH
cat DIBAL-H DMP b.) DDQ, Et 3N N H OH
N
then 1N HCl
N
Name? N

Ircinol A Ircinal A Manzamine A

Sparr Group Seminar

01.10.2015
Vincent Fäseke