Journal of the American Chemical Society
Communication
2
9,30
catalyst
furnished the quantitative formation of the D cycle
in 19 in less than 4 h at RT on a gram scale. Thus, at this point,
we achieved a robust, efficient, and scalable construction of the
unique tetracyclic 5/6/3/6 backbone of the peyssonnosides in
only 8 steps in 38% overall yield, which enables routes to
structural derivatives that can be used for biological
investigations.
With the tetracyclic skeleton of the target diterpenoid
prepared, the next steps included the functional group
modification in order to install all required functionalities in
peyssonnosol (3). First, the alcohol 19 was quantitatively
converted to the corresponding ketone (20) via Ley−Griffith
3
1
oxidation with TPAP/NMO. It is noteworthy that ketone 20
provides an interesting example of the anisotropic magnetic
effect of the carbonyl group: the methylene protons at C(5)
display a 1.55 ppm difference in chemical shifts. With the
32
ketone 20 in hand, the Mukaiyama hydration protocol was
attempted; however, no conversion was observed. At the time
of these failed attempts, an anaerobic Mukaiyama hydration
protocol with a large scope of terpenoids was published by
33
Studer and co-workers. This method involved the use of
nitroarylsulfonate B and Fe catalysis, which led to the tertiary
alcohol 21 in good yield (71%). The hydration afforded only
one diastereoisomer 21, which was assigned to be the desired
one based on 2D NMR experiments and computation of DP4+
34
probability (>99.9%). The high facial selectivity could be
explained with structural rigidity of the ketone 20, with the
C(12) methylene group effectively blocking one side of the
double bond from the attack, which gives an interesting
example of exclusive diastereoselectivity governed by molecule
oxophilicity, and in our case, more nitrophilic activators are
needed. For that role, three candidates were evaluated
3
5
4
5
46
47
topology.
The obtained ketoalcohol 21 was further
(
Cu(OTf)2, AgOTf, and (PhCN) Pd(OTf) ), and
2 2
submitted to Wittig methylenation under standard condi-
AgOTf led to the best performance. After some optimization
runs, 3 equiv of the glucoside donor 23 and 1 equiv of AgOTf
in DCM at RT after 5 h provided 98% yield of the 1:1
diastereomeric mixture of glucosides of both peyssonnosol (3)
enantiomers (24 and 25). This mixture can be separated by
3
6
tions (Ph PMeBr/KOt-Bu) affording the corresponding
3
unsaturated alcohol 22 in 98% yield. The diastereoselectivity
of the hydrogenation of compound 22 proved to be highly
dependent on both the catalyst and solvent ranging from 1:6.8
for (Ph P) RhCl in toluene to 4.7:1 for Rh/Al O in EA/
3
3
2
3
flash column chromatography on silica gel with CHCl . The
3
MeOH (1:1); however, the conversion was almost always
quantitative. Fortunately, the diastereisomeric mixture can be
easily separated by standard flash column chromatography.
Thus, with the installation of the C(7) hydrogen atom, our
synthesis of racemic peyssonnosol (3), the tetracyclic 5/6/3/6
diterpenoid core of peyssonnosides A−B (1−2), was
accomplished. It was achieved in only 12 steps from a
compound known from the literature and in 21% overall yield
with high diastereoselectivity. The developed route is scalable,
and more than 0.5 g of 3 was prepared in a single run.
less polar component was identified to be the desired one
based on the comparison between the relative positions of
1
proton signals at C(18) and C(1) in H NMR spectra and the
9
corresponding data from the isolation study, assuming that
further peripheral modification would not change the core
geometry. Isolated yields were 88% and 78%, respectively,
based on both enantiomers of 3. Based on J-coupling constant
analysis of protons at C(1′) and C(2′) (7.9 Hz for 24 and 7.8
Hz for 25), both glucosides were assigned as pure β-isomers.
The diastereoisomer 24 was further hydrolyzed with KOH/
MeOH and sulfated on the hydroxy group without
intermediate purification affording the sulfate 26 in 93%
yield. Hydrogenolysis of the benzyl groups over Pearlman’s
catalyst afforded peyssonnoside A (1) in 99% yield. All
With 3 in hand, we moved to the glucosylation stage of
synthesis (Scheme 3). As a glucosyl donor, we favored the
37
trichloroacetimidates introduced by Schmidt and co-workers
due to the mild activation conditions needed for the
3
8,39
1
13
reaction.
In order to be able to install sulfate functionality
characterization data ( H and C NMR, HRMS, [α]D)
matched those reported for the isolated natural product.
Therefore, we achieved the first total synthesis of enantiopure
peyssonnoside A in only 15 steps.
at C(2′), this position should be orthogonally protected from
the other hydroxy groups of the glucosyl donor. The best
match for our purposes was the compound 23, easily accessible
40
from D-glucose in 7 steps. With the glucoside donor in hand,
we attempted the glucosylation. However, it turned out that
The synthesis can be optimized further by an enantiose-
lective approach to peyssonnosol (3, Scheme 4) with the
asymmetric 1,4-addition step to 11 as a key challenge. In
4
1
39
typical conditions (TMSOTf, BF ·Et O ) led to the
3
2
48
complete decomposition of peyssonnosol (3) (most probably,
through dehydration), which was associated with high acid
sensitivity of the peyssonnosol (3). As a consequence, it was
hypothesized that other frequently used activators (Ln-
general, this chemistry is well-developed, yet 2-methyl-2-
cyclopenten-1-one (11) turned out to be a quite challenging
substrate, for which it is difficult to achieve high
49−51
52
enantioselectivity.
Quinkert and co-workers reported
4
2,43
44
(
OTf)3,
Tf O, etc.) would not work due to their high
in 1992 that isopropenyl lithium can be asymmetrically added
2
C
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX