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Angewandte
Communications
Table 1: Phosphoramidite ligands for the cyclization of 5 to form 6.[a]
methylpiperidyl) according to the method of Bresser and
Knochel,[15] followed by transmetalation with CuCN·2LiCl
and exposure to acid chloride 2 to form dienone 4 in 70%
yield. Oxidative removal of the 3,4-dimethoxybenzyl (DMB)
protecting group was accomplished in 72% yield (Scheme 1,
step c).[16] As a result of the ease with which acid-catalyzed
Nazarov cyclization of 4 takes place, the deprotection had to
be performed under almost neutral conditions. Diketoester 5
was treated with Pd0 and TADDOL-derived phosphoramidite
7 (TADDOL = a,a,a,a-tetraaryl-1,3-dioxolane-4,5-dimetha-
nol).[17] After 40 h at RT, cyclic product 6 was isolated in
70% yield in 89:11 e.r. The stereochemistry at the C3 position
(rocaglamide numbering) controlled all subsequently intro-
duced stereocenters.
Entry
ligand
R1
R2
e.r. of ent-6[b]
1
2
3
4
5
10
ent-7
11
12
13
Me
Me
Et
nBu
Ph
2-pyridyl
85:15
89:11
85.5:14.5
75:25
72:28
2-(4-chloro)pyridyl
2-(6-phenyl)pyridyl
2-pyridyl
2-pyridyl
6
7
14
15
2-pyridyl
H
2-pyridyl
2-pyridyl
71.5:28.5
60:40
8
9
10
16
17
18
Me
2-quinolyl
71.5:28.5
27:73[c]
25:75[c]
In our earlier study of the asymmetric Pd0-catalyzed
Nazarov-type cyclizations, we had not examined substrates
bearing aryl substitution at the a-enone carbon atom, nor any
that lacked substitution at positions a to the ester.[12b] We
predicted that these unique features in 5 might alter the
stereochemical outcome of the reaction by enabling alter-
native modes of interaction of the substrate with the catalyst,
either sterically or through p stacking. Our prediction was
correct, and the conversion of 5 into 6 differed from our
earlier work in that the absolute stereochemical course of the
cyclization was reversed in the case of 5. This was revealed
when, based on precedence from our earlier work, we
initiated the synthesis using the enantiomer of 7, assuming
that the stereochemical outcome would lead to natural (À)-
rocaglamide. Instead, when we recorded the optical rotation
of the final product we found that we had prepared unnatural
(+)-rocaglamide. Thus ligand 7, derived from d-(À)-tartrate
was needed for the desired (S)-C3 stereochemistry. We then
repeated the steps from 5 (Scheme 1) using 7 as the ligand,
which led to the formation of (À)-rocaglamide, as detailed
below.
A modest number of ligands were prepared from which 7
was selected (Table 1). Our starting point was N-methyl-N-2-
pyridyl phosphoramidite (10) that we have described in
earlier work[12b] and which led to ent-6 in 85:15 e.r. but in
a slow reaction. Ligand ent-7 accelerated the cyclization and
improved the e.r. value to 89:11. Varying the size of the
aliphatic group on the phosphoramidite nitrogen atom while
maintaining the 2-pyridyl (entries 4–7, 12–15) led to inferior
results. Ligand 11 (entry 3) was comparable to 10, whereas
16–18 (entries 8–10) were inferior. Varying the phenyl groups
on the TADDOL fragment decreased the product e.r. and led
to a slower reaction. Accordingly, ligand 7 was chosen for
further reactions.[18]
(CH2)2O(CH2)2
Me (2-furyl)methyl
[a] All reactions were performed with [Pd2(dba)3] (10 mol%) and ligand
(25 mol%) in MeCN at RT. [b] e.r. values were determined by HPLC
analysis on a chiral stationary phase using Chiralpak AD-H, OD-H, or OD
columns. [c] The ligand was derived from (4S,5S)-TADDOL.
cleaved allyl ether might be small enough to permit nucleo-
philic addition at C8b. Accordingly, treatment of 6 with PIFA
in a 2:1 mixture of allyl alcohol and HFIP (Scheme 1) resulted
in the introduction of an allyloxy group at the C3a position in
a stereoselective reaction (4:1 d.r.).[19,20] Exposure of the
product to Meerweinꢀs salt (Me3O·BF4) led to formation of
the enol ether 8 in 55% overall yield for the two steps. Ester
hydrolysis followed by conversion of the carboxylate into the
dimethyl amide gave 9 in 73% yield.
The concluding steps of the synthesis are summarized in
Scheme 2. Commercially available 3,5-dimethoxyfluoro-
benzene (19) was lithiated and then transmetallated with
LaCl3·2LiCl prior to exposure to 9,[21,22] producing tertiary
alcohol 20 in 87% yield as a single isomer. The two adjacent
cis aryl groups in 9 direct the nucleophilic addition. Trans-
metallation to lanthanum is essential to the success of the
reaction. If this step is omitted, the yield of 20 is 38% and
substantial amounts of 24 are formed from competitive
deprotonation at the C3 position. Recrystallization of the
scalemic mixture from dichloromethane/hexanes led to the
recovery of highly optically enriched 20 (98.5:1.5 e.r.) in 75%
yield from the mother liquor. This material was carried
forward to the end of the synthesis.
Cleavage of the allyl protecting group in 20 was challeng-
ing. Palladium-catalyzed reductive cleavage of the allyl
protecting group[23] failed under a number of conditions,
possibly because of steric inhibition to forming the initial
complex. However, SeO2-mediated oxidative cleavage of the
allyl group in refluxing dioxane[24] took place in 78% yield
leading to the formation of diol 21.
Exposing 21 to potassium tert-butoxide in THF at RT for
a few minutes led to the formation of the dihydrobenzofuran
ring, leading to 22 in 89% yield.[25] This process likely takes
place by means of nucleophilic aromatic substitution, as these
conditions do not generate the benzyne. For the cleavage of
the methyl ether at the C1 position in 22, MgI2 was freshly
prepared in ether, the solution was diluted with toluene, 22
was added, and the solution heated to 908C for 15 min leading
The introduction of the oxygen atom at the C3a position
was challenging. In the presence of base, oxidation invariably
took place at the C2 position so a procedure for regio- and
stereospecific oxidation at C3a was developed that proceeded
under mildly acidic conditions. We combined the oxidation
with the protection of the hydroxy group at the C3a position.
The protecting group must be small enough to not suppress
later addition of the aryl nucleophile at C8b, precluding the
use of trialkylsilyl ethers. Protection as the methyl ether did
not suppress the nucleophilic addition, but its subsequent
removal could not be achieved. We postulated that the readily
2
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Angew. Chem. Int. Ed. 2015, 54, 1 – 5
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