2
J. Oshita et al. / Tetrahedron Letters xxx (2015) xxx–xxx
O
3
OH
3
O
O
O
O
O
O
3
7
R1R2
R1 R2
OH
HO
7'
OH
HO
OH
O
O
O
O
O
O
11
2'
7
9'
10'
10'
1'
3'
11
OH
Actinoallolide A (1) (R1 = R2 = O)
Actinoallolide B (2) (R1 = OH, R2 = H)
Actinoallolide C (3) (R1 = R2 = O)
Actinoallolide D (4) (R1 = OH, R2 = H)
Actinoallolide E (5)
Figure 1. Structure of Actinoallolides.
In previous our isolation study and structural analysis of Acti-
reagent and Lewis acid combination. We further developed a
stereo-divergent synthesis of both Center part 10 and Right part
11 using a common intermediate 12 origin.
noallolides,1 the structure of 1, together with structural informa-
tion of related compounds and observation of naturally occurring
1, indicated that the hemiacetal moiety would easily undergo
b-elimination of the hydroxy group at the C-3 position under acidic
conditions to afford enone-type Actinoallolides C (3) and D (4).1 In
addition, the acid-sensitive hemiacetal moiety could be led from
the b-ketoester precursor, which is highly reactive moiety under
acidic and basic conditions.
Synthesis of Left part
Synthesis of Left part (9) was accomplished using commercially
available mono-methylhydroquinone (13), following the known
protocol12 to provide 14. Subsequently, ortho-bromination using
N-bromosuccinimide and Hartwig’s
was carried out to furnish the homobenzaldehyde ( )-15
(Scheme 2). This was transformed into ,b-unsaturated ester ( )-
a
-arylation13 of aldehyde
Hence, we needed to develop selective preparation of the hemi-
acetal moiety from a b-ketoester at the late stage to complete the
total synthesis. From the remark mentioned above, we envisaged
that utilizing a phenolether (7) as a key precursor for construction
of a highly reactive hemiacetal moiety could overcome possible
instability toward the total synthesis of 1 (Scheme 1). The hemiac-
etal moiety would, accordingly, be constructed in the late stage of
the total synthesis as a key conversion by a Birch reduction of 7
and subsequent chemoselective oxidative cleavage of cyclohexadi-
ene (6),7 which could be accomplished by introduction of sub-
stituents on the benzene ring of 7 to heighten the electron
density of the olefins compared with others (i.e., C8–C9, C50–C60)
(Scheme 1).8 The disconnection of 7 into three distinct parts (the
Left (9), Center (10), and Right parts (11)) at the phenolether bond
and the two tri-substituted olefin sites through Mitsunobu
macroetherification, Negishi9 and Stille10 coupling could allow the
convergent synthetic route, not merely for total synthesis but also
to enable the synthesis of several derivatives. The similarity of the
stereo-chemical triad of 10 and 11 suggested use of a common inter-
mediate (12), which could be efficiently afforded by construction of
its stereocenters.11 As stated above, we envisioned the convergent
total synthetic route of 1 would also furnish a range of derivatives.
Herein, we report the synthesis of key intermediate 8 as an
essential intermediate including full carbon framework for com-
pleting the convergent total synthesis of Actinoallolide A (1). In
a
16 under the Wittig condition, followed by reduction of the ester
moiety to afford racemic allyl alcohol ( )-17. Simultaneously, we
attempted kinetic resolution of ( )-17, which was separated by
Sharpless asymmetric epoxidation to afford the optically-active
epoxy alcohol in 93% ee.14 In the next four steps, the hydroxy group
of (+)-18 was mesylated, followed by deprotection of benzyl group
to yield phenol (+)-19. Subsequently, protection of the phenolic-
OH with a TBS group, followed by Finkelstein reaction provided
iodo-epoxide (+)-20. Selective deprotonation of the methylene
proton from (+)-20 enabled opening of the epoxy ring via anti-
elimination to provide the E-vinyl iodide.15 Finally, iodine–tin
exchange using Pd(PPh3)4 and hexamethylditin produced E-vinyl
stannane (+)-9 in good yield.
Synthesis of Center part
The stereo-divergent synthesis of Center part (10) began with
common intermediate (ꢀ)-12, which was easily prepared from
commercial methyl (R)-(+)-3-hydroxy-2-methylpropionate (21)
using the known procedure16 and Krische’s catalytic asymmetric
crotylation17 (Scheme 3). With common intermediate (ꢀ)-12 in
hand, synthesis of the Center part began with acetalization of
(ꢀ)-12 to provide the PMP acetal in good yield. PMP acetal was
then converted to aldehyde (ꢀ)-23 using ozonolysis, followed by
the nucleophilic addition of allenyl zinc species,18 to afford homo-
propargyl alcohol (+)-24 and (ꢀ)-25 as a separable diastereomer
synthesis of the Left part 9, we utilized Hartwig’s a-arylation and
kinetic resolution of the racemic allyl alcohol using Sharpless
asymmetric epoxidation to achieve our goal. We also employed a
new stereoselective reduction of 3-alkoxyketone using Schwartz’s
Scheme 1. Retrosynthetic analysis of Actinoallolide A (1).
Oshita, Jun
