A Stereoselective Synthesis of (±)-3-Aryl-6-phenyl-1-oxa-7- azaspiro[4.5]-decanes

Article abstract of DOI:10.1055/s-2003-42040

A novel stereoselective synthesis of the 3-aryl-6-phenyl-1-oxa-7- azaspiro[4.5]decane ring is reported. Palladium(0)-mediated cyclocarbonylation of γ-iodoallylic alcohol is a key step in the formation of the spirocyclic ring.

Full text of DOI:10.1055/s-2003-42040

LETTER
2021
A Stereoselective Synthesis of ( )-3-Aryl-6-phenyl-1-oxa-7-azaspiro[4.5]-
decanes
A
S
tereoselect
i
ive Syn
o
thesis of
(
)
t
-3-Ary
r
l-6-phenyl-1-o
R
xa-7-azaspiro[4.5
a]decanes ubo,* Janusz J. Kulagowski, Christopher J. Swain
Department of Medicinal Chemistry, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park,
Eastwick Road, Harlow, Essex, CM20 2QR, UK
Fax +44(1279)440187; E-mail: piotr_raubo@merck.com
Received 24 July 2003
native approach to racemic 1 that was developed in our
Abstract: A novel stereoselective synthesis of the 3-aryl-6-phenyl-
laboratory.
1-oxa-7-azaspiro[4.5]decane ring is reported. Palladium(0)-mediat-
ed cyclocarbonylation of g-iodoallylic alcohol is a key step in the
formation of the spirocyclic ring.
We envisaged that 1 could be accessible from the spirocy-
clic lactone 2 through stereoselective manipulation of the
Key words: spirocyclic compounds, lactones, stereoselective syn- double bond (Scheme 1). Palladium(0)-mediated cyclo-
thesis, regioselective lithiation, substance P (NK1 receptor) antago-
nist
carbonylation of the propargyl alcohol 3 would be then re-
quired to form the spirocycle in 2. A further disconnection
at C4–C5 in 3 leads to the known ketone 47 and alkyne 5.
The synthesis began with the regioselective ortho-lithia-
The demonstration of antidepressant activity by substance
tion of the hydroquinone derivative 68 (Scheme 2) fol-
P (NK1 receptor) antagonists1 has significantly accelerat-
lowed by treatment with N,N-dimethylformamide to give
the aldehyde 7 in 76% yield. The terminal acetylene at C2
was subsequently created by reaction of the aldehyde 7
ed efforts in identification of new selective NK1 receptor
ligands. Since 1991, when the first non-peptidic antago-
nist was reported,2 numerous selective and structurally
with the Ohira reagent.9
diverse NK1 modulators have been identified and subse-
quently developed.3,4
As a part of our existing programme, we were interested
in examining conformationally restricted piperidine de-
rivatives. The 6-phenyl-1-oxa-7-azaspiro[4.5]decane ring
O
O
O
c
a, b
OHC
system can operate as a structural scaffold to dispose both
aromatic rings required for binding to the NK1 receptor.4e
Recently, the synthesis of spirocyclic NK1 receptor antag-
onist (+)-1 has been disclosed.5 In addition, two different
routes to the 6-phenyl-1-oxa-7-azaspiro[4.5]decane
scaffold have been published.6 We herein report an alter-
7
OCF3
OCF3
OCF3
6
5
Scheme 2 a) t-BuLi, THF, –78 °C; b) DMF, 76%;
c) CH3COC(N2)PO(OMe)2, K2CO3, MeOH, r.t., 94%.
O
O
O
O
OH
O
O
3
6
N
Ph
N
Ph
N
Ph
OCF3
OCF3
OCF3
H
Boc
Boc
3
1
2
O
O
N
Ph
Boc
OCF3
5
4
Scheme 1
SYNLETT 2003, No. 13, pp 2021–2024
1
6
.1
0
.2
0
0
3
Advanced online publication: 08.10.2003
DOI: 10.1055/s-2003-42040; Art ID: D18803ST
© Georg Thieme Verlag Stuttgart · New York

2022
P. Raubo et al.
LETTER
Addition of the Grignard reagent, derived from alkyne 5, into much closer proximity, resulting in greater steric re-
to racemic ketone 4 was diastereoselective, affording the pulsion in the case of the a-epimer. This would be expect-
adduct 3 as a single stereoisomer in 62% yield.10 Forma- ed to favour the desired b-epimer under conditions of
tion of the desired spirocyclic lactone 2 was accomplished thermodynamic equilibration. To test this hypothesis, the
by a three-step sequence beginning with regioselective Boc protecting group in 10a,b (10a:10b = 1.3:1) was re-
and stereoselective hydroalumination of the propargyl al- moved and the resulting amino lactone subjected to 1,8-
cohol 3 with Red-Al® followed by metal-halogen ex- diazabicyclo[5.4.0]undec-1-ene (DBU) promoted equili-
change using iodine. The vinyl iodide 8 was obtained as a bration. This afforded a 10:1 mixture of diastereoisomeric
single isomer in 78% yield.11 Subsequently, palladium(0)- lactones 11b and 11a, respectively from which the re-
mediated cyclocarbonylation12,13 of 8 provided the spiro- quired isomer 11b could be obtained in pure form simply
cyclic lactone 2 in 68% yield (Scheme 3).14
by crystallisation (Scheme 5).
Reduction of the double bond in the model lactone 915 us- By analogy, the Boc group in 2 was removed by treatment
ing NaBH4 in the presence of a cat. amount of nickel(II) with TFA and the double bond reduced with NaBH4 in the
chloride favoured the unwanted a isomer 10a (10a:10b = presence of cat. nickel(II) chloride to give a 3:1 mixture of
2.5:1, Scheme 4). Several attempts were made to invert diastereoisomers in favour of the a isomer 12a
the configuration at the C3 centre in 10a, but all were (Scheme 6). DBU promoted epimerisation at C3 resulted
largely unsuccessful. For example, treatment of the 2.5:1 in a 1:10 mixture of 12a and 12b in favour of the desired
mixture of 10a and 10b with cat. 1,8-diazabicyc- b isomer 12b, which crystallised from the reaction mix-
lo[5.4.0]undec-1-ene (DBU) provided a 1:1.2 mixture of ture. To complete the synthesis, reduction of 12b with
10a and 10b.
LiAlH4 and subsequent cycloetherification of the result-
ing intermediate diol under Mitsunobu conditions afford-
ed the spirocyclic ether 1 in 55% yield.16
Conformational analysis showed that in the preferred con-
formation of carbamate 10a the phenyl substituent occu-
pies a pseudo-axial position on the piperidine.5 Given the In conclusion, a new convergent synthesis of the 6-phe-
relatively unhindered environment of the C3 phenyl ring nyl-1-oxa-7-azaspiro[4.5]decane 1 has been developed al-
in this conformation, there is presumably little energetic lowing its preparation with high diastereocontrol.
preference for either epimer, resulting in an equilibrium
ratio approaching unity. However, inversion of conforma-
tion of the piperidine ring would bring the two aryl rings
O
O
I
O
OH
OH
a
b
OCF3
N
Ph
N
Ph
OCF3
Boc
Boc
OCF3
5
3
8
c
O
O
O
N
Ph
OCF3
Boc
2
Scheme 3 EtMgBr, THF, then 4, 0 °C–r.t., 62%; b) Red-Al, Et2O, r.t., then I2, –78 °C–r.t., 78%; c) CO, [Ph3P]2PdCl2, N2H4, K2CO3, THF,
50 °C, 68%.
O
O
MeO
O
MeO
MeO
O
O
O
a,b
or a,c,b
N
Ph
N
Ph
OCF3
N
Ph
R=Boc 10a
OCF3
OCF3
R
Boc
R
9
R=Boc 10b
R=H 11b
R=H 11a
Scheme 4 a) NaBH4, NiCl2·hexahydrate (cat.), MeOH; b) DBU (cat.), CH2Cl2, r.t.; c) TFA, CH2Cl2, r.t., 88%.
Synlett 2003, No. 13, 2021–2024 © Thieme Stuttgart · New York

LETTER
A Stereoselective Synthesis of (±)-3-Aryl-6-phenyl-1-oxa-7-azaspiro[4.5]decanes
2023
MeO
H
F3CO
MeO
OCF3
H
O
HN
b
HN
a
O
O
H
OMe
N
O
Boc
O
O
10a
OCF3
11a
11b
Scheme 5 a) TFA, CH2Cl2, r.t.; b) DBU (cat.), CH2Cl2, r.t.
O
O
O
O
O
O
O
O
O
a, b, c
N
Ph
N
Ph
N
Ph
OCF3
OCF3
OCF3
H
Boc
H
2
d,e
12b
12a
O
O
N
Ph
OCF3
H
1
Scheme 6 a) TFA, CH2Cl2, r.t.; b) NaBH4, NiCl2·hexahydrate (cat.), MeOH, 12a:12b = 3:1; c) DBU(cat.), CH2Cl2, 12a:12b = 1:10, 82%;
d) LiAlH4, THF; e) DEAD, Ph3P, THF, 55%.
J.; Tattersall, D. F.; Williams, A.; Swain, C. J. Bioorg. Med.
Chem. Lett. 2002, 12, 2719. (f) Gale, J. D.; O’Neill, B. T.;
References
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(10) Experimental Procedure for the Preparation of 3: A solution
of EtMgBr in THF (1 M, 4.1 mL, 4.1 mmol) was added
dropwise to a stirred solution of 5 (1.0 g, 4.1 mmol) in THF
(10 mL) at r.t. After 30 min, the mixture was cooled to 0 °C
and a solution of 4 (1.07 g, 3.9 mmol) in THF (10 ml) was
added dropwise over 5 min. The mixture was stirred at 0 °C
for 2 h and at r.t. overnight. After quenching with sat. aq
NH4Cl, the mixture was extracted into 2-methylpentane. The
combined organic extracts were dried (Na2SO4) and
concentrated. The residue was purified on silica gel (2-
methylpentane–Et2O) to give the alcohol 3 (1.17 g, 62%). 1H
NMR (360 MHz, CDCl3): d = 0.78–0.90 (m, 4 H), 1.32 (s, 9
H), 1.80 (m, 1 H), 2.00–2.15 (m, 2 H), 2.14 (s, 1 H), 2.22 (m,
1 H), 3.11 (m, 1 H), 3.78 (m, 1 H), 4.15 (dd, J = 5.6, 13.4 Hz,
1 H), 5.48 (s, 1 H), 7.15 (dd, J = 2.0, 9.2 Hz, 1 H), 7.17–7.40
(m, 6 H), 7.55 (d, J = 7.2 Hz, 2 H). Relative stereochemistry
was assigned by 1H NMR experiments.6a
Synlett 2003, No. 13, 2021–2024 © Thieme Stuttgart · New York

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P. Raubo et al.
LETTER
(11) Experimental Procedure for the Preparation of 8: A solution
of Red-Al® in toluene (0.9 mL, 3.1 mmol) was added
dropwise to a stirred solution of 3 (1.17 g, 2.25 mmol) in
anhyd Et2O (15 mL) at 0 °C. The ice bath was removed and
the reaction mixture was stirred at r.t. for 2.5 h. The mixture
was cooled to –78 °C and a solution of I2 (1 g, 4 mmol) in
anhyd Et2O (10 mL) was added over 5 min. The reaction
mixture was allowed to warm to r.t. over 2 h and quenched
with sat. aq Na2SO3. The mixture was extracted into Et2O.
The combined organic extracts were dried (Na2SO4) and
concentrated. The residue was purified on silica gel (2-
methylpentane–Et2O) to give the iodide 8 (1.14 g, 78%). 1H
NMR (360 MHz, CDCl3): d = 0.80–0.90 (m, 4 H), 1.34 (s, 9
H), 1.74–1.90 (m, 2 H), 2.05 (m, 1 H), 2.31 (dt, J = 5.2, 13.2
Hz, 1 H), 2.63 (s, 1 H), 3.18 (ddd, J = 5.8, 11.3, 13.6 Hz, 1
H), 3.78 (m, 1 H), 4.10 (m, 1 H), 5.39 (s, 1 H), 6.35 (s, 1 H),
7.06 (d, J = 2.8 Hz, 1 H), 7.20 (dd, J = 2.3, 8.5 Hz, 1 H), 7.22
(d, J = 8.9 Hz, 1 H), 7.25–7.40 (m, 4 H), 7.52 (d, J = 7.2 Hz,
2 H).
(14) Experimental Procedure for the Preparation of 2: A solution
of hydrazine in THF (0.07 mL, 0.07 mmol) was added, under
an atmosphere of CO, to a stirred mixture of 8 (320 mg, 0.5
mmol), (Ph3P)2PdCl2 (50 mg, 0.07 mmol), K2CO3 (138 mg,
1 mmol) and THF (5 mL). The mixture was stirred at 50 °C
for 5 d. After cooling to r.t., the mixture was diluted with
Et2O and filtered through a pad of Celite. The filtrate was
concentrated and the residue purified on silica gel (2-
methylpentane–EtOAc) to give the lactone 2 (184 mg, 68%).
1H NMR (360 MHz, CDCl3): d = 0.76–0.94 (m, 4 H), 1.39
(s, 9 H), 1.82–2.04 (m, 3 H), 2.30 (m, 1 H), 3.20 (dt, J = 4.8,
13.7 Hz, 1 H), 3.82 (m, 1 H), 4.22 (dd, J = 5.6, 13.4 Hz, 1 H),
5.25 (s, 1 H), 7.19 (dd, J = 1.4, 9.2 Hz, 1 H), 7.22–7.33 (m,
4 H), 7.39 (d, J = 7.3 Hz, 1 H), 7.98 (d, J = 2.9 Hz, 1 H), 8.08
(s, 1 H).
(15) Baker, R.; Curtis, N. R.; Elliott, J. M.; Harrison, T.;
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(13) Cowell, A.; Stille, J. K. J. Am. Chem. Soc. 1980, 102, 4193.
(16) The spectral data exhibited by 1 was identical to reported.15
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