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racemic synthesis of the O-silylated menisdaurilide 19c can be
performed in a single day, requires only one final chromato-
graphic purification, and can deliver about 2.5 g in one single
batch with an overall yield of 28% over 5 steps.
tected bubbialine and epibubbialine. This mixture was finally
desilylated using HF·pyridine to furnish (+)-bubbialine (11 b) in
about 40% over three steps from 22a, as well as trace
amounts of (+)-epibubbialine (9b) (Scheme 4), which ap-
peared quite unstable under the reaction (or purification) con-
ditions used.
With such large amounts of the racemic menisdaurilide de-
rivative 19c in hand, we decided to separate both enantiomers
by chiral chromatography (see the Supporting Information).
Typically, 1 g of (Æ)-19c could be separated to provide 400 mg
of each enantiomer (Scheme 3). Determination of their respec-
tive absolute configuration was first accomplished by desilylat-
ing (À)-19c to afford (À)-menisdaurilide (19a). Comparison of
We then turned our attention toward the synthesis of the
two neonorsecurinanes bubbialidine (5) and niruroidine (7),
which could both be prepared from the trans-azidoketone
27b. The Staudinger/aza-Wittig reaction gave the correspond-
ing cyclic imine 22b, which was engaged in the same reduc-
tion, aza-Michael addition, and desilylation to furnish (À)-bub-
bialidine (5a) and (À)-niruroidine (7a) in 15 and 37% yields,
respectively, from 22b. These two 2-azabicyclo[2.2.2]octanes
feature an antiperiplanar relation between the nitrogen atom
and secondary alcohol positionings (Scheme 4). These two al-
kaloids were thus submitted to a dehydrative ring expansion
using Magnus-Jiang’s[16,21d,e] Mitsunobu reaction conditions
(Ph3P, DIAD (diisopropyl azodicarboxylate) in THF), which medi-
ated their rearrangement into the 6-azabicyclo[3.2.1]octanic
norsecurinanes (À)-allonorsecurinine (3a) and (À)-norsecuri-
nine (1a) in 55 and 99% yields, respectively.
Encouraged by such accomplishments on the synthesis of
(neo)norsecurinane alkaloids, we continued our work by using
5-azidopentanal with the aim of constructing 6-membered A-
ring-containing (neo)securinanes (Scheme 4-II). A similar diaste-
reoselectivity trend was obtained in this series depending on
the type of aldolisation conditions used. Under classical basic
conditions (Method A), the trans-azidoketones were the major
products (cis/trans 13:87), whereas a cis/trans ratio of 93:7 was
obtained under Mukaiyama-type conditions using the O-silylat-
ed ketene acetal rac-26 (Method B). Treatment of the cis-azi-
doketone 28a with PPh3 in CH3CN for 12 h at room tempera-
ture promoted the Staudinger/aza-Wittig formation of the ex-
pected 6-membered cyclic imine 22c, together with enamine
Scheme 3. Chiral separation of the O-silylated rac-menisdaurilide 19c and
determination of the absolute configuration of each enantiomer.
the optical rotation of this synthetic sample with those of nat-
ural[20a,c–d] and previously synthesised[18b] 19a confirmed its
structure. Moreover, crystallisation attempts gave plate crystals
of the other enantiomer of 19c. Its analysis by X-ray diffraction
confirmed its (+)-19c structure. Our synthesis work was then
accomplished using each enantiomer or their racemic mixture.
The second objective of our synthesis plan was to couple
19c with nitrogen-terminated aliphatic aldehydes of type 20
(see Scheme 1). Aldol-type reactions were thus performed
using either 4-azidobutanal for the elaboration of 5-membered
A-ring-containing (neo)norsecurinanes or 5-azidopentanal for
the elaboration of (neo)securinanes (Scheme 4). To our delight,
a simple modification of the aldolisation conditions afforded
the desired products with either a 1,3-cis- or a 1,3-trans-config-
uration, thereby validating the bio-inspired strategic key of our
divergent synthesis plan.
1
29a in a 3:2 ratio, as analysed by H NMR. This 1,6-aza-Michael
product was reversed back to the imine 22c under the acidic
conditions of the following reduction reaction, which rapidly
gave rise to the desired piperidine mixture 17c. As for the syn-
thesis of neonorsecurinanes, this mixture was submitted to the
same aza-Michael annulation and desilylation conditions to fur-
nish, after a final chromatographic separation, (À)-securinol A
(12a) and (À)-episecurinol A (10a) in 6 and 27% yields, respec-
tively, over 4 steps from 28a (Scheme 4). The trans-azidoke-
tone 28b behaved similarly upon treatment with PPh3, al-
though a total, yet slow (75 h), conversion into the correspond-
Indeed, a base-promoted aldolisation between 19c and 4-
azidobutanal using LiHMDS (lithium bis(trimethylsilyl)amide) in
THF (Method A) generates mainly the trans-products (cis/trans
14:86), whereas a Mukaiyama-type aldolisation using the O-si-
lylated ketene acetal derivative of 19c (i.e., 26a) and BF3·OEt2
in CH2Cl2 (Method B) almost exclusively leads to the cis-prod-
ucts (cis/trans 95:5), albeit in much lower yields. The cis/trans
ratios were determined after oxidation of the aldol products
into the corresponding azidoketones 27a and 27b (Scheme 4-
I). The cis-azidoketone 27a was engaged in a Staudinger/aza-
Wittig reaction to yield the purifiable imine 22a in good yields.
This cyclic imine was reduced using sodium cyanoborohydride
(NaBH3CN, AcOH in THF) and the resulting pyrrolidine mixture
17a was treated with Et3N in MeOH to promote an intramolec-
ular 1,6-aza-Michael cyclisation and forge the neonorsecuri-
nane core. This sequence afforded a 9:1 mixture of TBS-pro-
1
ing enamine 29b was observed by H NMR analysis (see the
Supporting Information). Unfortunately, 29b was found too
unstable to be purified by silica gel chromatography. The
crude reaction mixture was then directly treated using
NaBH3CN to give the expected TBS-protected alkaloids, which
were desilylated using again HF·pyridine to furnish (+)-virosi-
ne A (6b) and (+)-virosine B (8b) in 17 and 27% yields, respec-
tively, over 4 steps from 28b (Scheme 4). Since these two neo-
securinanes also display the requisite N/O antiperiplanar orien-
tation for rearrangement into their 6-azabicyclo[3.2.1]octane
counterparts, they were submitted to the Mitsunobu reaction
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Chem. Eur. J. 2019, 25, 1 – 8
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