Angewandte
Communications
Chemie
Scheme 5. Synthesis of 12-desmethylherboxidiene. Reagents and con-
ditions: a) 1-Trimethylsilyl-1-propyne, THF, À788C, then K2CO3,
MeOH, 95%; b) Cp2Zr(H)Cl, CH2Cl2, then Me2Zn, then 26, then
NaOMe, 64%; c) Re2O7·SiO2, CH2Cl2, 67%; d) tBuOOH, VO(acac)2,
CH2Cl2, À158C, 38%, 48% brsm; e) K2CO3, H2O, MeOH, reflux, 69%.
These compounds were evaluated against HeLa (cervical
cancer) and 4T-1 (breast cancer) cells in an MTTassay.[34] The
IC50 values for 22 were 30 nm and 40 nm, respectively.
Minimal cytotoxicity, however, was observed for desmethyl
analogue 36 at concentrations of up to 500 nm, indicating that
the absence of the C12 methyl group causes at least a 40-fold
drop in potency. This result is remarkable in consideration of
the distance of this methyl group from the polar functionality
on the molecule.
A conformational analysis of 22 and 36 provided insight
into the origin of the potency difference. The methyl group at
C12 in 22 promotes the formation of a turn conformation,
consistent with the crystal structure[17] and modeling studies.
This is illustrated by structure 37 in Figure 1. Rotation of the
Scheme 4. Total synthesis of herboxidiene. Reagents and conditions:
a) AcCl, iPr2NEt, trimethylsilylquinidine, LiClO4, CH2Cl2, Et2O, 73%,
d.r.=9:1; b) methacrolein, Hoveyda–Grubbs metathesis catalyst, 31%,
59% based on recovered starting material (brsm); c) TiCl4, CH2Cl2,
À788C, 71%; d) Me3OBF4, Proton Spongeꢀ, CH2Cl2, 87%; e) LiBH4,
MeOH, Et2O, 08C, 95%; f) I2, Ph3P, CH3CN, Et2O; g) (R)-4-benzyl-3-
propionyloxazolidin-2-one, NaHMDS, THF, À788C, 61% (2 steps);
h) LiBH4, MeOH, Et2O, 08C, 88%; i) Dess–Martin periodinane,
NaHCO3, CH2Cl2, 76%; j) Ohira–Bestmann reagent, NaOMe, THF,
À78 to À408C, 96%; k) Cp2Zr(H)Cl, CH2Cl2, then Me2Zn, then 26,
then NaOEt, 72%; l) Re2O7·SiO2, CH2Cl2, 82%; m) tBuOOH, VO-
(acac)2, CH2Cl2, À158C, 64%; n) K2CO3, H2O, MeOH, reflux, 85%.
TBS=tert-butyldimethylsilyl, TIPS=triisopropylsilyl.
is uniquely effective for allylic alcohol ionizations. Vanadium-
mediated epoxidation and ester cleavage, in accord with
established methods,[22b,c] provided herboxidiene in 14 steps
from commercially available materials for the longest linear
sequence. This sequence matches the shortest reported linear
sequence[22j] and sets a new standard for the lowest overall
step count.
Figure 1. Preference for the turn conformation at C12.
À
C12 C13 bond by 1208 in either direction generates a highly
destabilizing syn-pentane interaction with the methyl group at
1
C14, as illustrated by conformer 38. H NMR data support
The capacity to form the tetrahydropyranyl group rapidly
creates ample opportunities for analogue synthesis. The
structure–activity relationships for 22 have been explor-
ed,[22h,31] though the influence of the methyl group at C12 on
potency has yet to be established. The considerable effort that
is dedicated to introducing this group led us to investigate
whether this group is necessary for biological activity. The
synthesis of the 12-desmethyl analogue (Scheme 5) began
with allylic chloride 34, which is available through a sequence
that follows the preparation of 30. The addition of lithiated
1-trimethylsilyl-1-propyne[32] followed by in situ silyl cleav-
age[33] yielded alkyne 35. 12-Desmethylherboxidiene (36) was
accessed by following the route that was developed for the
natural product synthesis. This route is three steps shorter
than the natural product synthesis and eliminates the need for
a chiral auxiliary.
this analysis. The C13 hydrogen atoms of 22 have coupling
constants of 4.8 and 10.8 Hz to the C12 hydrogen atom,
indicating a dominant conformation. Moreover the turn
conformation enhances the energetic penalty for rotation
À
around the C11 C12 bond as rotation would lead to enhanced
steric clashes with the C10 alkenyl hydrogen atom, as
illustrated by 39 (note the perspective change). Removal of
the C12 methyl group eliminates the energetic penalty for the
syn-pentane interaction, thereby making several additional
À
conformations available through rotation around the C12
C13 and C11 C12 bonds.[35] 1H NMR analysis again supports
À
this hypothesis, with the coupling constants of the C12 and
C13 hydrogen atoms in 36 being 5.6 and 8.1 Hz, which
correlates with a time-averaged conformational ensemble.
We postulate that 37 represents the binding conformation and
removing the methyl group leads to a significant reduction in
the population of conformers that interact with the spliceo-
some.
Access to herboxidiene and its desmethyl analogue
allowed for a comparison of their potencies as cytotoxins.
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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