R.N. Yadav et al.
Journal of the Indian Chemical Society 98 (2021) 100010
Scheme 4. Scope of intramolecular β-lactam tethered oxy-Michael reaction in synthesis of 1,4-Dioxepane derivative.
(90%) with excellent diastereoselectivity (dr ¼ 9:1)
isomer as an impurity. As we mentioned earlier, that silyl protection of
hydroxy methyl functionality leads to efficient separation of major iso-
mer 14c-d in 95–85% following the earlier procedure. In a similar
manner, Ethyl 4-bromocrotonoate 11b has been transformed into vic-diol
12b under DDQ mediated de-ketilization followed by the base assisted
annulation en route to 1,4-dioxepane-β-lactam 13b in excellent yield.
The major diastereomer in its pure form has been obtained by trans-
forming 13b in its corresponding silyl ether 14b a good yield (Scheme 4).
It envisioned that chemoselective 10 vs 20 hydroxy functionalities in
oxa-nucleophilic Michael reaction had been controlled by the resulting
product’s ring size and the acidic nature of alcohol functionality. In our
investigation, we exclusively demonstrated the formation of a seven-
membered saturated oxa-cycle over an 8-membered ring. Under basic
conditions, the secondary alcohol groups react faster than the primary
alcohol due to its more significant acidic character over primary alcohol.
The resulting potassium salt generated in situ is enough to bring the
annulation via 7-exo-trig mode of cyclization to give exclusive 1,4-dioxe-
pane-2,3-fused β-lactam.
Analyzing the crude reaction mixture via 1H NMR analysis, it was
realized that compound 13 a has been obtained in an inseparable mixture
of 9:1 diastereomeric ratio. It is important to note that this mixture ap-
pears as a single spot on TLC plate and cannot be distinguishable even
running the TLC thrice to make sure the separation of spot over a thin
layer chromatography (TLC) mixture of many solvents of different con-
centration. Therefore, to get rid of the contaminated major isomer, we
have decided to derivatized the 10 hydroxy functionalities with various
protecting groups. In this context, the compound 13a has been protected
with tert-Butyldimethylsilyl chloride (TBDMSCl) in dichloromethane in a
catalytic amount of imidazole at room temperature for 1 h. The silyl
protected compound 14a, was separated as a single diastereoisomer in a
95% yield. The 1H NMR spectrum has also been recorded of the pure
sample to make sure its purity. Furthermore, after realization of the
successfully partial synthesis of target compounds 13a, we turn our
attention to find out the optimal reaction condition for the de-ketilization
reaction towards the exclusive synthesis of the vic-diol 12a, which could
serve as Michael donor of this projected study on intramolecular oxy-
Michael addition reaction.
In summary, a base assisted high diastereoselective and chemo-
selective strategy for rapid cyclization for intramolecular 7-exo-trig oxy-
As we have mentioned earlier that FeCl3⋅6H2O mediated de-
ketilization of isopropylidene group of the compounds 11a was not ul-
timately offered the full conversion in route to the synthesis of 12a. In
our revised synthetic course, the free hydroxy functionality in compound
9a-b has been alkylated with Methyl 4-bromocrotonate 10b likely, the
ester 10a to get the β-lactam tethered crotonoate methyl ester 11c-d in
good yield. The next step of the reaction is de-ketilization and could be
easily achieved using DDQ (1.5 equiv.) (2,3-Dichloro-5,6-dicyano-1,4-
benzoquinone) in dichloromethane solution under reflux condition for
2–3 h afford the vic diol 12c-d in excellent yield. The resulting diol has
been treated under our optimized condition with 1.0 M KOH solution in
mixture of THF: H2O at 00C-RT to form an annulated 2,3 fused 1,4-diox-
epane β-lactam 13c-d in good to excellent yield with high degree of
diastereoselectivity. It is worthy to note that all the reaction gives an
exclusive single diastereoisomer along with trace amount of minor
Michael reaction of α β-unsaturated ester tethered with β-lactam ring
has been successfully established. The enantiomerically pure 2,3-fused
1,4-dioxepane were synthesized in exceptionally high yield and excel-
lent diastereoselective under mild reaction conditions. All the products
were formed are very easily purified. Notably, the designed protocol is
highly versatile and easily executable. As the ever-growing interest and
demands of highly functionalized chiral 1,4-dioxepane, the detailed ac-
count of the diverse substrate scope of the present methodology is under
investigation and will be disclosed within the due date.
Declaration of competing interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
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