REARRANGEMENTS IN NATURAL PRODUCT SYNTHESIS - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 248

TBSO TBSO

OBn
Cl

OBn
Cl

1. O 3 , Py, Et 3 N, EtOAc
2. MeNH 2 , NaBH 3 CN, 4 Å MS, MeOH
54%

t -BuOK, 18-crown-8

THF, 0°C
92%

TBSO

TBSO

OMe O OMe

HO

MeO OMe MeO OMe

MeO

TBSO TBSO

OH
Cl

OBn
Cl

OBn
Cl BCl 3 (1.5 equiv)

CH 2 Cl 2 , -40°C

TBSO

O

TBSO NMe

MeHN

NMe

O OMe

O OMe O OMe

OMe

MeO OMe

OMe

(-)-Acutumine

SCHEME 8.11 Synthesis of ( )-acutumine.

hexamethyldisilazide or potassium carbonate) at room temperature, the group was
able to synthesize various targets such as the sesterpenic acids bilosespenes A and
B [43],

( )-dihydronepetalactone [44], the alkaloid norsuaveoline [45],

( )-palominol [46], paclitaxel [47], ( )-precapnelladiene [48], the insect antifeedant

( )-homogynolide A [49], and the sesquiterpene lactone vulgarolide [50], all in a

simple and efficient manner [51].
(

)-Acutumine is a tetracyclic alkaloid isolated from the Asian vine
Menispermum dauricum , which possesses a selective T-cell cytotoxicity and anti-
amnesic properties and was recently prepared by Castle and coworkers
(Scheme 8.11) [52]. Extremely facile and high yielding (0 C, 1 h, 92%) Potassium
tert -butoxide promoted the anionic oxy-Cope rearrangement of the key enantiomeri-
cally pure tertiary alcohol to afford the desired ketone in a stereospecific fashion.
The latter was then converted to the corresponding secondary amine after oxidative
cleavage and reductive amination. Next, reaction with boron trichloride promoted
the critical cyclization that allowed installation of the pyrrolidine motif and therefore
the entire tetracyclic framework of ( )-acutumine. With this intermediate in hand, the

rest of the synthesis proceeded uneventfully to give ( )-acutumine.

)-Nootkatone, a sesquiterpene isolated from the heartwood of the Alaskan
yellow cedar ( Chamaecyparis nootkatensis (D. Don)) and the peel of Citrus paradisi
McFadden, is a carrier of the grapefruit essence that has foundwide applications in the
flavor and fragrance industry. Also used as a potent repellent, (

( þ

)-nootkatone has
recently been synthesized in a very simple and straightforward manner starting from
a key tertiary alcohol easily obtained from cheap b -pinene (Scheme 8.12) [53].
The potassium hydride-mediated anionic oxy-Cope rearrangement followed by an
alkylationwithmethyl iodide gave the desired ketone intermediate bearing themethyl
groups at C4 and C4a with the correct configuration in 59% overall yield. The final
steps of the synthesis involved the oxidative cleavage of the olefin with potassium
permanganate, reaction with hydrogen chloride in order to open the cyclobutane ring
and promote the aldol cyclization, and a final dehydrochlorination.
The synthesis of the nonnatural enantiomer of (

þ

þ

)-okilactomycin, isolated from
Streptomyces griseoflavus and showing significant in vitro cytotoxicity against
a number of human cancer cell lines, has been recently reported [54] and includes