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this led to complete opening of the oxetane ring. These results
prompted us to slightly modify the deprotection procedure. After
TFA treatment of compound 14, the in situ generated compound
1a was immediately protected with a Cbz group to afford 15 in
84% yield by recrystallization. After the deprotection of the Cbz
group, the product was treated with one equivalent of acetic acid
to give 1a as the HOAc salt in 83% yield. Overall, this modified pro-
cedure required one purification step by chromatography and the
overall yield was improved from 4% to 18%, allowing us access to
multi-gram quantities of the material.
Based on the above results, we used the same route to synthe-
size compound 2a starting from ethyl nipecotate 16 (Scheme 2).
This time, the piperidine N was protected with a Cbz group and
the final product 2a as the HOAc salt was obtained in 13% yield
in five steps. Since the diol intermediate 18 was not a solid, one ex-
tra purification step by chromatography was required.
The synthesis of 2-oxa-6-azaspiro[3,4]octane 3a was accom-
plished in a similar manner (Scheme 3). The starting material 21
was made via the 1,3-dipolar cycloaddition in 75% yield. Treatment
with LDA and methyl chlorolformate provided the diester 22 in
75% yield. Reduction with LiAlH4 provided the diol 23 in 74% yield.
The monotosylation of 22 was successful with nBuLi/TsCl. How-
ever, the cyclization with nBuLi failed to proceed at room
temperature. Further heating led to the decomposition of the
monotosylate intermediate. This observation prompted us to try
weaker bases for the cyclization and eventually, the use of NaOMe
afforded the cyclization product 24 in 59% yield from 22. The final
debenzylation reaction smoothly afforded the desired product 2-
oxa-6-azaspiro[3,4]octane 3a as the HOAc salt in 88% yield (5
steps, 21% overall yield).
In summary, we have provided for the first time the detailed
synthesis of novel reagents 2-oxa-7-azaspiro[3,5]nonane 1a and
its analogs 2a and 3a. The improved synthetic procedure allowed
us quick access to these reagents in multi-gram quantities and
making them more accessible as morpholine surrogates or novel
building blocks in medicinal chemistry.
with saturated NH4Cl (800 mL) at 0 °C. The aqueous layer was ex-
tracted with EtOAc (500 mL Â 2). The combined organic phase was
washed with HCl (1 M, 1 L), brine (1 L Â 1), dried over Na2SO4 and
concentrated to get compound 11 (crude, 350.0 g, 0.622 mol) as an
oil. MS: 229.9 [MÀBoc+H]+.
To a solution of the above compound 11 (350.0 g, 0.622 mol,
crude) in dry toluene/THF (1:1, 4.0 L) was added LiBH4 (108.4 g,
4.98 mol) in portions at 5–10 °C. The reaction was stirred at 60 °C
overnight. The reaction was quenched by saturated NH4Cl at 0 °C
until the organic phase was clear. 500 mL of EtOAc was added
and the organic layer was separated. The aqueous layer was ex-
tracted with EtOAc (1 L Â 3). The combined organic phase was
washed with brine (1 L Â 1), dried over Na2SO4 and concentrated
to get crude product (230.0 g). The residue was purified by recrys-
tallization (PE: EtOAc = 3:1) to give compound 12 (60.0 g,
0.245 mol, 39% yield in two steps) as a white solid.
1H NMR (CDCl3): d 1.40 (s, 9H), 1.42 (m, 4H), 2.49 (br s, 2H), 3.32
(m, 4H), 3.60 (s, 4H).
MS: 146.3 [MÀBoc+H]+.
2.2. Preparation of compound 14
To a solution of compound 12 (60.0 g, 244.58 mmol) in dry THF
(1.2 L) at 0 °C was added nBuLi (97.8 mL, 0.245 mol, 2.5 M) and the
mixture was stirred at 0 °C for 0.5 h. TsCl (46.6 g, 0.245 mmol) in
dry THF (600 mL) was added dropwise and stirred at 0 °C for 1.5 h
when TLC showed that compound 12 was consumed completely.
To the reaction mixture was added n-BuLi (97.8 mL, 0.245 mmol,
2.5 M) at 0 °C and stirred at 0 °C for 0.5 h. The reaction mixture
was then stirred at 60 °C for 1 h. The reaction was quenched by sat-
urated NH4Cl (400 mL) at 0 °C. After separation, the aqueous layer
was extracted with EtOAc (300 mL Â 3). The combined organic
phase was washed with brine (800 mL Â 2), dried over Na2SO4 and
concentrated to get crude product (65 g). The residue was purified
by flash chromatography (PE: EtOAc = 30:1–10:1) to give compound
14 (37.0 g, 66% yield) as a white solid.
1H NMR (CDCl3): d 1.47 (s, 9H), 1.83 (t, 4H, J = 5.6 Hz), 3.35 (t,
4H, J = 5.6 Hz), 4.46 (s, 4H).
2. Representative experimental procedure
2.1. Preparation of compound 12
MS: 127.9 [MÀBoc+H]+.
2.3. Preparation of compound 15
To a solution of LDA (940 mL, 2 M, 1.87 mol) in dry THF (1.5 L)
at À78 °C was added N-Boc ethyl isonepicotate (160.0 g,
0.622 mol) in dry THF (1 L) at À78 °C dropwise. The mixture was
stirred at À78 °C for 2 h and at À40 °C for 3 h. The solution was
cooled to À78 °C and ethyl chloroformate (202.4 g, 1.87 mol) in
dry THF (1 L) was added slowly. The reaction was stirred at
À78 °C for 0.5 h and at rt overnight. The reaction was quenched
To a solution of compound 14 (29.0 g, 127.6 mmol) in DCM
(230 mL) at 0 °C was added TFA (58 mL) in DCM (60 mL) and the
mixture was stirred at rt for 3 h. The reaction mixture was cooled
to 0 °C and water (100 mL) was added. After separation, the organ-
ic phase was washed with water (50 mL Â 2). The combined aque-
ous layer was extracted with DCM (100 mL Â 2). The aqueous layer
was adjusted to pH to 7–8 by adding solid K2CO3. Dioxane
COOEt
EtOOC COOEt
HO
OH
d, e
c
a, b
N
NH
N
Cbz
Cbz
16
17
18
O
O
f
N
NH HOAc
Cbz
2a
19
Scheme 2. Synthesis of 2-oxa-6-azaspiro[3,5]nonane 2a. Reagents and conditions: (a) CbzCI, K2CO3, 99%; (b) LDA, CICO2Et; (c) LiBH4, Toluene/THF, 34% (2 steps); (d) nBuLi,
TsCI; (e) nBuLi, 46% (2 steps); (f) H2, Pd/C, then HOAc, 83%.