G Model
CCLET 5852 No. of Pages 3
2
R. Guo, H. Zhai and Y. Li / Chinese Chemical Letters xxx (2019) xxx–xxx
Our synthesis commenced from the known compound 3-
chloro-2-benzyloxymethylpropene 6 which was steadily prepared
from methallyl dichloride according to the reported procedure
(Scheme 2) [9]. S
N
2’ substitution reaction of Grignard reagent (in
situ preparation from allyl chloride 6) and 2-methyl-2-vinyloxirane
7
under the catalysis of CuBr
Á
2
MeS delivered the allyl alcohol 5 in
5
6% yield. To our delight, the subsequent Sharpless asymmetric
epoxidation of allyl alcohol 5 proceeded smoothly to deliver the
epoxide 4 in high yield and enantioselectivity (92%, 96% ee) [17–
19]. Inspired by Konno group’s report [20], we then attempted the
cyanide-opening reaction of epoxide 4. Treatment of 4 with
trimethylsilyl cyanide (TMSCN) and anhydrous tetrabutylammo-
nium fluoride (TBAF) in tetrahydrofuran could afford the β-hydroxy
cyanide 8 in 51% yield, along with a large amount of starting
material 4 remaining. We speculate that the low reactivity of
epoxide may be responsible for the low yield and conversion. After
screening a series of Lewis acid, we found that when treated with
Fig. 1. Structures of pseudolaric acid A, B, C, F and G.
2
.0 equiv. of titanium tetraisopropanolate (Ti(O-iPr)
β-hydroxy cyanide could be improved to 86%, which indicates this
reaction could be significantly accelerated by Ti(O-iPr) (see the
Supporting information for details). Protection of the dihydroxy
moiety of compound with 2,2-dimethoxypropane (DMP)
4
), the yield of
4
8
smoothly gave product 9 in 95% yield. Subsequent reduction of
the cyano group with diisobutylaluminum hydride (DIBALH)
produced aldehyde 10 in 71% yield. In the next nucleophilic
addition step, the 4-methylfuryl lithium reagent was converted
into a corresponding cerium reagent to weaken its basicity [21].
Therefore, the isomerization of C3 position in 3 could be
minimized. Compounds 3 were obtained as a mixture of two
diastereoisomers (1:1 ratio) in 96% combined yield. According to
the Magnus’ procedure [22], unstable pyranenones 12 were
obtained in 72% yield, which went through acetyl protection
immediately to give pyrylium precursors 2 in high yield. Without
further purification, compounds 2 could be used directly in the
next step.
With the pyrylium precursors 2 in hand, we turned our
attention to the key intramolecular [5 + 2] cycloaddition strategy to
construct the trans-fused [5–7]-bicyclic skeleton (Scheme 2).
However, under the activation of 1,8-diazabicyclo[5,4,0]undec-7-
ene (DBU) in acetonitrile [23–25], intramolecular [5 + 2] cycload-
dition reaction took place only to form tricyclic product 13 as a
single isomer in 87% overall yields (2 steps), which contains
opposite stereocenters at the ring junction position C4 and C10
compared with pseudolaric acids. Other reaction conditions, for
example, treatment of a dilute solution of 12 in dichloromethane
with trifluoroacetic acid [22], did not give corresponding
cycloaddition product. The stereochemistry of 13 was determined
by the X-ray crystallographic analysis.
Fig. 2. The previous synthetic strategy of pseudolaric acids.
As the transition states (TS) shown in Scheme 3, we anticipate
that the dihydroxy side chain in compound 2 as the larger group
relative to the hydrogen atom should be disposed of in the
equatorial position. Besides, the more favorable endo transition
state of the pyrylium ylide and double bond would produce trans-
fused [5–7]-bicyclic skeleton. According to the experiment results,
TS-2 is presumably more favorable than TS-1, which affords 13 as
the major product. It might be because that TS-2 has a less steric
repulsion between the substituents compared with TS-1.
In summary, the C4,C10-di-epi-trans-fused [5–7]-bicyclic core
of pseudolaric acid B, has been accomplished in 10 steps from the
commercially available material methallyl dichloride. The key
transformations of our strategy include the Sharpless asymmetric
Scheme 1. Retrosynthetic analysis.
acids. Pyrylium precursors 2 could be assembled by oxidation of
furan intermediates 3, which was envisioned to be constructed
from epoxide 4 through a selective cyanide-opening reaction of
epoxide and subsequent nucleophilic addition. Finally, epoxide 4
could be obtained from allyl alcohol 5 by Sharpless asymmetric
epoxidation to introduce the initial stereocenter.
epoxidation, Ti(O-iPr) -promoted cyanide-opening reaction of the
4
epoxide, and intramolecular [5 + 2] cycloaddition. Further attempts
of adjusting cycloaddition reaction to construct correct stereo-
centers and investigations to complete the total synthesis of
pseudolaric acid B are underway.