Communications
using the Hoveyda–Grubbs catalyst[26] provided allylic alco-
hol 22 in 70% yield. Adding p-benzoquinone to this reaction
proved to be useful in suppressing ketone formation through
alkene isomerization.[27] At this stage allylic alcohol trans-
position was required prior to macrolide formation. While 22
and the product of its transposition are both secondary allylic
alcohols, we postulated that the desired transposed product
would be formed preferentially under equilibrating condi-
tions. This assertion was based on the capacity for the
transposed hydroxy group to engage in hydrogen bonding
with the tetrahydropyranyl ether and, in consideration of
Kozmin and co-workersꢀ report[3f] of the unexpected stability
of the leucascandrolide macrolactol, for its potential to add
into the pendent C1 carbonyl group. Thus we exposed 22 to
Re2O7 in Et2O, conditions shown by Lee and Hansen[28] to
promote suprafacial migration, thereby transposing the allylic
alcohol group and forming lactol 23 directly in 69% yield.
Notably, we observed that subjecting the C19-epimer of 22,
prepared through the cross metathesis of 20 with the
enantiomer of 21, to the transposition conditions provided
23 in 49% yield. This result suggests that epimerization can
occur during the transposition and that resolving 21 prior to
metathesis is not necessary. While the reason for the
epimerization has yet to be determined, we speculate that
the transposition is rapid and reversible, and that rearrange-
ment occasionally proceeds through a boat-like rather than a
chair-like transition state. Oxidizing 23 with PCC completed
the synthesis of leucascandrolide macrolactone 24. Since 24
has been converted in one step into leucascandrolide A by the
Leighton group, this completes a formal synthesis. Cleaving
the phosphonoacetate group (Na2CO3, MeOH) provided a C5
alcohol that is spectroscopically identical to material that was
derived from cleaving the ester side chain from 1,[1] thereby
confirming the structural assignment.
We have completed a concise formal synthesis of leucas-
candrolide A through a sequence in which our ETIC method
was employed for the stereoselective formation of a key
tetrahydropyran ring from an advanced intermediate, thereby
establishing the utility of the method in the context of
complex molecule construction. Additional noteworthy
advances include the minimization of protecting group
manipulations (only two steps in the longest linear sequence
were solely devoted to functional group protection or
deprotection), the use of BiBr3 in a mild and efficient lactol
functionalization, the extensive use of substrate-derived
stereocontrol, and the utilization of macrolactol formation
as a thermodynamic driving force for allylic alcohol trans-
position. The sequence proceeds in 17 linear steps from the
known alcohol 7 (20 steps from commercially available
material) and in 4.5% yield, making this route quite
competitive with the most efficient enantioselective routes
to leucascandrolide A.
Scheme 5. Completion of the synthesis. a) l-Selectride, THF, À908C,
76%. b) (CF3CH2O)2P(O)CH2CO2H, EDC, HOBt, CH2Cl2, 92%. c) HCl,
MeOH, 98%. d) Dess-Martin periodinane, CH2Cl2, 95%. e) 21, Hov-
eyda–Grubbs catalyst, 1,4-benzoquinone, CH2Cl2, reflux, 70%.
f) Re2O7, Et2O, 69%. g) PCC, CH2Cl2, 81%. EDC=1-(3-dimethylamino-
propyl)-3-ethylcarbodiimide hydrochloride, HOBt=1-hydroxybenzotri-
azole, PCC=pyridinium trioxochlorochromate, R=OCH2CF3.
and EDC with the expectation that this group would
ultimately be used for the construction of the C5 side chain
through a Still–Gennari reaction.[22] The presence of the
electrophilic phosphonate group, however, required us to
complete the synthesis under very mild conditions. Silyl group
cleavage was achieved with hydrochloric acid in methanol,
with no phosphonate transesterification being observed.
Notably, attempts to conduct this reaction with fluoride
sources promoted the cleavage of one trifluoroethoxy group
from the phosphonate group. Oxidation of the resulting
alcohol with the Dess–Martin periodinane[23] yielded alde-
hyde 20. A cross-metathesis reaction[24] between 20 and 21[25]
Received: July 5, 2007
Revised: August 7, 2007
Published online: September 26, 2007
Keywords: leucascandrolide A · natural products · radical ions ·
.
rearrangement · stereoselectivity
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 8464 –8467