A Stereoselective Synthesis of a 3,4,5-Substituted Piperidine of Interest as a Selective Muscarinic (M1) Receptor Agonist

Article abstract of DOI:10.1055/s-0035-1560753

A stereoselective synthesis of (1RS,2SR,6SR)-7-benzyl-6-cyclo-butyl-2-methoxymethyl-4,7-diaza-9-oxobicyclo[4.3.0]nonan-8-one, which is representative of a novel series of selective muscarinic (M₁) receptor agonists, is described.

Full text of DOI:10.1055/s-0035-1560753

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
©
Georg Thieme Verlag Stuttgart · New York
2016, 27, 45–50
45
letter
Synlett
K. J. Broadley et al.
Letter
A Stereoselective Synthesis of a 3,4,5-Substituted Piperidine of
Interest as a Selective Muscarinic (M ) Receptor Agonist
1
Kenneth J. Broadleya
O
O
Maxime G. P. Buffatb
Robin H. Davies † a
Eric J. Thomas*b
Me
MgBr
O
O
OHC
NHCbz
H
H
NH 4 steps
NBn
Me
MeO
TBSO
then H3O+
TBSO
TBSO
BH3•THF
a
The Welsh School of Pharmacy, Redwood Building, King
Edward VII Avenue, Cardiff, CF10 3NB, UK
The School of Chemistry, The University of Manchester,
Manchester, M13 9PL, UK
O
b
then oxid
O
O
H
O
e.j.thomas@manchester.ac.uk
Deceased October 2011
NBn
H
NBn
†
a 50% agonist of the M1
receptor with micromolar
potency
MeO
4 steps
MeO
H
Dedicated to Steve Ley on the occasion of his 70th birthday
N
H
HO
TBSO
Received: 22.09.2015
Accepted: 01.10.2015
Published online: 20.10.2015
DOI: 10.1055/s-0035-1560753; Art ID: st-2015-d0758-l
The first member of the series selected for synthesis
was 7-benzyl-6-cyclobutyl-2-methoxymethyl analogue 3
(Scheme 1). Oxazolidinone 4 was identified as a likely pre-
cursor of piperidine 3 and, in turn, alkenyloxazolidinone 5,
which was possibly accessible from aldehyde 6, was consid-
ered to be a plausible intermediate for the synthesis of ox-
azolidinone 4. Aldehyde 6 was recognised as the equivalent
of an alkylated, reduced serine derivative, but the presence
of the cyclobutyl group limited the options available for its
synthesis. In the end, it was decided to study a preparation
of aldehyde 6 from ketone 7, which would, in turn, be pre-
pared from the commercially available cyclobutane carbox-
ylic acid 8 (Scheme 1).
Abstract A stereoselective synthesis of (1RS,2SR,6SR)-7-benzyl-6-cyclo-
butyl-2-methoxymethyl-4,7-diaza-9-oxobicyclo[4.3.0]nonan-8-one,
which is representative of a novel series of selective muscarinic (M ) re-
ceptor agonists, is described.
1
Key words piperidines, oxazolidinones, hydroboration, muscarinic re-
ceptors, trifluoroacetimidates
Agonists of muscarinic M receptors have been identi-
fied as potential chemotherapeutic agents for the treatment
of Alzheimer’s disease. In particular, they would provide
alternatives to cholinesterase inhibitors that tend to lose ef-
1
1
Although this synthesis looked reasonable, at the onset
of the work it was difficult to be certain how to control the
stereoselectivities of several of the steps.
ficacy over time and, indeed, several M receptor agonists
1
have already been found to alleviate the symptoms of this
illness. It is, however, crucial to find compounds selective
2
O
O
O
O
O
O
for M receptors to avoid side-effects arising from stimula-
1
H
H
H
NBn
NBn
Me
NH
tion of other muscarinic receptor subtypes. Early computa-
tional studies using bacterial rhodopsin as a model for the
MeO
MeO
H
M receptor led to the identification of the 2-alkoxymethyl-
N
HO TBSO
TBSO
1
H
and 2-hetaryl-oxazolidinonylpiperidines 1 and 2 as possi-
3
4
5
3
ble selective M agonists (Figure 1). We now describe a ste-
1
reoselective synthesis of the first representative of this class
of novel compounds.
O
OHC
NHCbz
HO2C
O
O
TBSO
O
O
TBSO
H
H
8
7
6
N
R
N
R
het
RO
2
Ar
2
Ar
Scheme 1 Proposed synthesis of oxazolidinonylpiperidine 3
N
N
H
H
A synthesis of the racemic modification of aldehyde 6 is
outlined in Scheme 2. tert-Butyldimethylsilyloxymethyl ke-
tone 7 was prepared in four steps from cyclobutanecarbox-
ylic acid 8 by conversion into methyl ketone 9, bromination
1
2
Figure 1 Oxazolidinonylpiperidines of interest as M receptor agonists
1
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 45–50

4
6
Synlett
K. J. Broadley et al.
Letter
4
of the ketone, and hydrolysis of the known bromide 10 to
give the corresponding alcohol, which was protected as its
silyl ether 7. A Wadsworth–Emmons–Horner reaction of
protected hydroxyketone 7 followed by reduction of the re-
sulting α,β-unsaturated esters gave a 75:25 mixture of the
geometrical isomers of the alcohols 11, with the major al-
cohol being identified as the Z-isomer on the basis of a sig-
nificant NOE signal between 2-H and 3-CH. This mixture of
alcohols was converted into the corresponding trifluoro-
acetimidates 12 by reaction with trifluoroacetonitrile, and
heating the trifluoroacetimidates initiated a [3,3]-sigma-
tropic rearrangement to give racemic tertiary trifluoroacet-
give adduct 17. The latter compound cyclised in situ on
standing, possibly via isocyanate 18 formed by loss of bro-
momagnesium benzyloxide, to give the oxazolidinone 5 af-
ter work-up (Scheme 3). The structure assigned to this ox-
azolidinone was confirmed by X-ray diffraction analysis
(Figure 2).
7
O
O
H
OHC
TBSO
– H+
NHCbz
i
NH
Me
TBSO
5
amide 13. Cleavage of the trifluoroacetamide was carried
6
5
out under mild conditions by using sodium borohydride in
ethanol, and the resulting amine 14 was converted into its
Cbz-derivative 15, which was ozonolysed to give the re-
quired aldehyde (±)-6 (Scheme 2).
H+
+
O
C
N
Br
O
O
Ph
Mg
O
BrMgO
H
BrMgO
H
NCbz
N
Me
MgBr
Me
H
MgBr
–
BnOMgBr
OH
+
O
O
TBSO
TBSO
Me
TBSO
2
3
16
17
18
ii
iv
X
TBSO
Scheme 3 Preparation of the oxazolidinone 5. Reagents and conditions:
i) MeC(MgBr)=CH , THF, toluene, –78 °C, 2 h then r.t., 48 h (66%).
X
(
2
8
9
X = OH
X = Me
10 X = Br
7 X = OTBS
11
i
iii
v
CF3
NH2
NHCO•CF3
vii
vi HN
O
TBSO
TBSO
TBSO
14
13
12
viii
OHC
NHCbz
NHCbz
ix
TBSO
TBSO
15
(± ±)6
Figure 2 The structure of oxazolidinone 5 as established by X-ray dif-
Scheme 2 Synthesis of the aldehyde (±)-6. Reagents and conditions:
fraction analysis
(
(
(
i) MeLi, Et O, 0 °C to r.t., 3 h (90%); (ii) Br , MeOH, 0 to 15 °C, 1.5 h
2
2
80%); (iii) a. KOCHO, MeOH, reflux, 12 h (71%); b. TBSCl, imid., DMAP
cat.), TBAI (cat.), CH Cl , r.t., 1 h (62%); (iv) a. (EtO) P(O)CH CO Et,
2
2
2
2
2
To convert oxazolidinone 5 into the cyclisation precur-
sor 4 it was necessary to oxidise the methyl group, ben-
zylate the oxazolidinone, and stereoselectively hydrate the
alkene. These conversions are outlined in Scheme 4. Epoxi-
dation of alkene 5 gave a mixture of epoxides 19 and 20, ra-
tio 77:23, which were reacted as a mixture with lithium
NaH, THF, r.t., 45 min, add 7, r.t., 2.5 h; b. DIBAL-H, hexanes, THF,
78 °C, 3 h, r.t., 30 min [89% from 7, Z/E = 75:25]; (v) NaH, THF, r.t., 1 h,
add to CF CN, THF, –115 to –78 °C, 1 h (88%); (vi) xylene, reflux 18 h
–
3
(
91%); (vii) NaBH , EtOH, 0 °C to r.t., 18 h (80%); (viii) CbzCl, Et N,
4
3
CH Cl , r.t., 18 h (83%); (ix) O , CH Cl , –78 °C, then Ph P, r.t. (84%).
2
2
3
2
2
3
8
The next step was the conversion of aldehyde 6 into ox-
azolidinone 5 (Scheme 3). This was achieved in one pot by
using an excess of isopropenylmagnesium bromide with a
2,2,6,6-tetramethylpiperidide to give allylic alcohol 21.
Alkylation of 21 using sodium hydride–benzyl bromide
gave N-benzyloxazolidinone 23 as the major product, with
bis-benzylated material 22 formed only a minor side-prod-
uct (ca. 5%). Methylation of alcohol 23 led to methyl ether
24 and hydroboration–oxidation of this alkene using bo-
rane in THF at 0 °C gave a mixture of epimeric alcohols 4
6
prolonged reaction time to facilitate cyclisation. This reac-
tion was highly stereoselective and gave the cyclised prod-
uct 5 directly. The formation of this oxazolidinone is consis-
tent with addition of the Grignard reagent onto the less
hindered face of the chelated, deprotonated aldehyde 16 to
9
and 25 in a ratio of 85:15 (Scheme 4).
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 45–50

4
7
Synlett
K. J. Broadley et al.
Letter
O
O
O
The completion of the synthesis of oxazolidinonylpiper-
idine 3 is outlined in Scheme 5. Desilylation of the mixture
of hydroboration products 4 and 25 gave a mixture of diols
27 and 28, which was converted into N-benzylpiperidines
O
O
O
H
H
H
NH
NH
NH
Me
i
Me
O
Me
+
O
3
0 and 31 (ratio ca. 85:15), by reaction of the mixture of
TBSO
TBSO
TBSO
20
10
mesylates 29 with an excess of benzylamine. Following
separation of the major component N-benzylpiperidine 30
by chromatography, a selective transfer hydrogenolysis of
the piperidine N-benzyl group gave the required oxazolidi-
nonylpiperidine 3.11
The structures of the products shown in Scheme 5 were
consistent with their spectroscopic data, although the con-
figurations of the oxazolidinonylpiperidines at C2 were dif-
5
19
ii
O
O
O
O
O
O
H
H
H
NBn
NBn iii
NH
HO
+ BnO
HO
TBSO
TBSO
TBSO
21
1
ficult to assign from their H NMR spectra. The structures of
2
3
22
these products were eventually confirmed by selective de-
methylation of the major N-benzylpiperidine 30 to give al-
cohol 32, which was crystalline and whose structure was
O
iv
O
H
NBn
7
confirmed by X-ray diffraction (Figure 4). The vicinal cou-
MeO
H
pling constants J1,2 of the oxazolidinonylpiperidines were
found to be diagnostic of their relative configuration at C2,
being less than 5 Hz for the major products 3, 30 and 32,
and greater than 8 Hz for the minor product 31, consistent
with the boat-like conformation of the piperidine ring in al-
cohol 32.
O
NBn
HO
TBSO
O
H
4
v
MeO
+
O
TBSO
O
H
NBn
2
4
MeO
H
HO
TBSO
25
Scheme 4 Synthesis of (±)-oxazolidinone 4. Reagents and conditions:
i) MCPBA, CH Cl , r.t., 18 h (75%); (ii) 2,2,6,6-tetramethylpiperidine,
(
2
2
THF, n-BuLi, 0 °C to r.t., 1 h, added to 19 and 20, THF, 0 °C to r.t., 3 h
67%); (iii) NaH, BnBr, THF, reflux, 6 h (23, 79%; 22, 5%); (iv) NaH, THF,
(
MeI, r.t., 18 h (90%); (v) BH , THF, 0 °C, 18 h, then EtOH, NaOAc, 30%
3
aq. H O , reflux, 1 h (95%, 4/25 = 85:15).
2
2
The mixture of hydroboration products was not sepa-
rated, and the structure of the major product, which turned
out to be the required epimer 4, was only confirmed later in
the synthesis. The stereoselectivity can be explained by the
preferred participation of transition structure 26 in the hy-
droboration step (Figure 3), but this rationalisation is only
speculative because molecular modelling studies of the hy-
droboration were not carried out.
Figure 4 The structure of (±)-oxazolidinonylpiperidine 32 as estab-
lished by X-ray crystallography data
This work has resulted in the synthesis of the first mem-
ber of a novel series of compounds, oxazolidinonylpiperi-
dines, which are of interest as potential selective ligands for
muscarinic receptors. Indeed, methyl ether 3 was found to
B
H
H
H
OMe
O
H
O
O
OMe
O
HO
be a 50% partial agonist of the muscarinic M receptors with
1
N
then H2O2
N
micromolar potency, as measured by the relaxation re-
sponses of rat duodenum compared with the full agonist
McN-A-343. Of interest in the synthetic work was the stere-
oselectivities of the Grignard addition and hydroboration
steps, together with the overall strategy. This chemistry has
been applied to the synthesis of oxazolidinonylpiperidines
Bn
Bn
OTBS
OTBS
26
4
Figure 3 Facial selectivity of the hydroboration of alkene 24
1
and 2, with both alkoxymethyl and hetaryl substituents at
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 45–50

4
8
Synlett
K. J. Broadley et al.
Letter
O
O
O
O
H
H
NBn
NBn
i
MeO
+
MeO
4
+ 25
H
H
HO HO
HO HO
27
28
ii
O
O
H
NBn
MeO
MsO MsO
29
iii
O
O
O
O
H
O
H
O
H
NBn
NBn
NBn
iv
1
2
MeO
1
MeO
MeO
+
2
N
N
N
H
Bn
Bn
3
30
31
v
O
O
H
NBn
HO
N
Bn
32
Scheme 5 Completion of a synthesis of (±)-oxazolidinonylpiperidine 3. Reagents and conditions: (i) TBAF, THF, 0 °C to r.t., 30 min (67%, 27/28 = 85:15);
ii) MsCl, Et N, CH Cl , 0 °C to r.t., 1 h; (iii) BnNH , 80 °C, 18 h (30, 36%; mixture of 30 and 31, 26%, 30/31 ratio 55:45); (iv) 10% Pd/C, HCO H, MeOH,
(
3
2
2
2
2
r.t., 20 min (71%); (v) BBr , CH Cl , THF, 0 °C, 4 h (61%).
3
2
2
C2. This work will be described in full elsewhere together
with the preliminary results of an alternative synthetic
strategy.
References and Notes
(
1) (a) Fisher, A.; Pittel, Z.; Haring, R.; Bar-Ner, N.; Kliger-Spatz, M.;
Natan, N.; Egozi, I.; Sonego, H.; Marcovitch, I.; Brandeis, R. J. Mol.
Neurosci. 2003, 20, 349. (b) Dunbar, P. G.; Durant, G. J.; Fang, Z.;
Abuh, Y. F.; El-Assadi, A. A.; Ngur, D. O.; Periyasamy, S.; Hoss, W.
P.; Messer, W. S. Jr. J. Med. Chem. 1993, 36, 842.
Acknowledgment
(
2) (a) Caccamo, A.; Fisher, A.; LaFerla, F. M. Curr. Alzheimer Res.
We thank Dr. J. Raftery for help with X-ray data and Muscagen Ltd. for
a studentship (to M.G.P.B.).
2009, 6, 112. (b) Heinrich, J. N.; Butera, J. A.; Carrick, T.; Kramer,
A.; Kowal, D.; Lock, T.; Marquis, K. L.; Pausch, M. H.; Popiolek,
M.; Sun, S.-C.; Tseng, E.; Uveges, A. J.; Mayer, S. C. Eur. J. Pharma-
col. 2009, 605, 53. (c) Ragozzino, M. E.; Artis, S.; Singh, A.;
Twose, T. M.; Beck, J. E.; Messer, W. S. Jr. J. Pharmacol. Exp. Ther.
2012, 340, 588. (d) Digby, G. J.; Noetzel, M. J.; Bubser, M.; Utley,
T. J.; Walker, A. G.; Byun, N. E.; Labois, E. P.; Xiang, Z.; Sheffler, D.
J.; Cho, H. P.; Davis, A. A.; Nemirovsky, N. E.; Mennenga, S. E.;
Camp, B. W.; Bimonte-Nelson, H. A.; Bode, J.; Italiano, K.;
Morrison, R.; Daniels, J. S.; Niswender, C. M.; Olive, M. F.;
Lindsley, C. W.; Jones, C. K.; Conn, P. J. J. Neurosci. 2012, 32,
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560753.
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
8532.
(3) Davies, R. H. unpublished observations.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 45–50

4
9
Synlett
K. J. Broadley et al.
Letter
(
(
(
4) (a) Gaudry, M.; Marquet, A. Org. Synth. 1976, 55, 24. (b) Ramig,
K.; Dong, Y.; Van Arnum, S. D. Tetrahedron Lett. 1996, 37, 443.
c) Maehr, H.; Yang, R. Tetrahedron Lett. 1996, 37, 5445.
5) (a) Savage, I.; Thomas, E. J.; Wilson, P. D. J. Chem. Soc., Perkin
Trans. 1 1999, 3291. (b) Chen, A.; Thomas, E. J.; Wilson, P. D.
J. Chem. Soc., Perkin Trans. 1 1999, 3304.
6) (4SR,5RS)-4-(tert-Butyldimethylsilyloxymethyl)-4-cyclobu-
tyl-5-propen-2-yl-1,3-oxazolidin-2-one (5): Propen-2-ylmag-
nesium bromide (0.5 M in toluene, 297 mL, 148.5 mmol, 3.75
equiv) was added over 1 h to aldehyde 6 (15.5 g, 39.6 mmol) in
THF (800 mL) at –78 °C, and the reaction mixture was stirred at
5.5 Hz, 1 H, OH), 3.36 (s, 3 H, OCH ), 3.72 (dd, J = 9.5, 3.5 Hz, 1 H,
3
3′-H), 3.79 (dd, J = 9.5, 5.5 Hz, 1 H, 3′-H′), 4.55 (d, J = 7.8 Hz, 1 H,
13
(
5-H), 4.70 (d, J = 15.7 Hz, 1 H, PhHCH). C (100 MHz, CDCl ): δ
3
(major epimer 4) = –5.9, –5.8, 17.2, 17.9, 23.1, 23.3, 25.7, 38.7,
40.8, 45.8, 59.1, 61.2, 62.3, 68.5, 73.3, 77.4, 127.3, 127.6, 128.5,
138.4, 159.1; δ (minor epimer 25) = –5.8, 17.1, 17.9, 23.1, 23.4,
25.6, 38.7, 40.3, 45.8, 59.3, 60.8, 64.4, 68.8, 73.6, 75.4, 127.2,
+
127.6, 128.4, 138.5, 159.5. MS (CI+): m/z (%) = 464 (1) [M + 1],
90 (100).
(10) (1RS,6SR)-4,7-Bis-benzyl-6-cyclobutyl-2-methoxymethyl-
4,7-diaza-9-oxabicyclo[4.3.0]nonan-8-ones (30) and (31):
Freshly distilled methane sulfonyl chloride (0.112 mL, 1.42
–78 °C for 2 h, then allowed to warm to r.t. overnight. The reac-
tion mixture was stirred for another 36 h at r.t. before sat. aq
mmol, 3 equiv) and Et N (0.20 mL, 1.42 mmol, 3 equiv) were
3
NH Cl (500 mL) was added. The aqueous phase was extracted
added successively to a mixture of diols 27 and 28 (166 mg,
4
with Et O (3 × 500 mL) and the organic extracts were dried
0.475 mmol) in CH Cl (5 mL) at 0 °C. The reaction mixture was
2
2
2
(
MgSO ) and concentrated under reduced pressure. Chromato-
allowed to warm to r.t. and stirred for 1 h before the addition of
Et O (5 mL) and sat. aq NH Cl (10 mL). The aqueous phase was
4
graphy (EtOAc–light petroleum, 1:10) of the residue gave the
2
4
title compound 5 (8.5 g, 66%) as a single diastereoisomer as a
extracted with Et O (3 × 10 mL) and the organic extracts were
2
white solid; mp 110–112 °C; R = 0.30 (EtOAc–light petroleum,
dried (MgSO ) and concentrated under reduced pressure to give
f
4
1
:4). IR: 3240, 3137, 2952, 2935, 2892, 2859, 1756, 1465, 1384,
a mixture of bis-mesylates 29 (228 mg), which was used
without purification. Bis-mesylates 29 (228 mg) were dissolved
in benzylamine (15 mL) and the solution was heated at 80 °C for
18 h. After cooling to r.t., the benzylamine was removed by dis-
tillation under reduced pressure. Chromatography (EtOAc–light
petroleum, 1:20 to 1:10) of the residue achieved partial separa-
tion of piperidines 30 and 31 to give the title compound 30 (72
–1
1
1344, 1254, 1106, 903, 840, 777 cm
. H NMR (400 MHz,
CDCl ): δ = 0.02 (s, 6 H, 2 × SiCH ), 0.87 [s, 9 H, SiC(CH ) ], 1.69–
3
3
3 3
2.18 (m, 6 H, 3 × CH ), 1.80 (s, 3 H, 3′-H ), 2.70 (pent, J = 8.2 Hz,
2
3
1
H, 4-CH), 3.43 (s, 2 H, 4-CH ), 4.50 (s, 1 H, 5-H), 5.04 (s, 1 H, 1′-
2
13
H), 5.13 (s, 1 H, 1′-H), 5.86 (s, 1 H, NH). C (100 MHz, CDCl ): δ
3
=
8
3
3
6
–5.9, –5.8, 17.4, 18.1, 19.9, 22.4, 24.3, 25.7, 39.4, 63.9, 65.0,
+
2.2, 113.9, 138.0, 158.9. MS (CI+): m/z (%) = 343 (75) [M + 18],
26 (100) [M + 1]. HRMS: m/z [M + H] calcd for C17H32NO Si:
26.2152; found: 326.2150. Anal. Calcd for C17H31NO Si: C,
2.73; H, 9.60; N, 4.30; found: C, 62.76; H, 9.62; N, 4.20.
mg, 36%); R = 0.28 (EtOAc–light petroleum, 1:2). HRMS: m/z
f
+
+
+
[M] calcd for C26H32N O : 420.2413; found: 420.2410. IR: 3083,
3
2
3
3060, 3029, 2924, 2872, 2811, 1744, 1494, 1453, 1405, 1349,
3
–
1
1294, 1201, 1168, 1117, 1090, 1060, 1028, 978, 818, 746 cm
.
1
(
7) X-ray crystal data for oxazolidinone 5: CCDC 1413285;
H (400 MHz, CDCl ): δ = 1.40–1.78 (m, 5 H, cyclobutyl H), 2.00
3
C17H31NO Si; unit cell parameters: a = 12.250(3), b = 13.606(3),
(m, 1 H, cyclobutyl H), 2.10 (d, J = 12.5 Hz, 1 H, 5-H), 2.22 (m,
1 H, 2-H), 2.36 (t, J = 10.5 Hz, 1 H, 3-H), 2.41 (d, J = 12.5 Hz, 1 H,
5-H′), 2.49 (pent, J = 8.7 Hz, 1 H, 6-CH), 2.58 (dd, J = 7.25,
10.5 Hz, 1 H, 3-H′), 3.32–3.37 (m, 6 H, 2-CH, OCH , PhCH ), 3.57
3
c = 12.818(3); P21/c. Alcohol 32: CCDC 1413286; C25H30N O ;
2
3
unit cell parameters: a = 22.546(14), b = 9.314(10), c =
0.283(9); P21/c.
1
3
2
(
8) (a) Yasuda, A.; Tanaka, S.; Oshima, K.; Yamamoto, H.; Nozaki, H.
J. Am. Chem. Soc. 1974, 96, 6513. (b) Tanaka, S.; Yasuda, A.;
Yamamoto, H.; Nozaki, H. J. Am. Chem. Soc. 1975, 97, 3252.
9) (4SR,5RS)-3-Benzyl-4-(tert-butyldimethylsilyloxymethyl)-4-
cyclobutyl-5-[(SR)- and -(RS)-1-hydroxy-3-methoxyprop-2-
yl]-1,3-oxazolidin-2-ones (4) and (25): Borane (1 M in THF, 8.2
mL, 8.22 mmol, 5 equiv) was added dropwise to alkene 24 (660
mg, 1.48 mmol) in THF (5 mL) at 0 °C and the reaction mixture
was stirred at this temperature for 18 h before EtOH (7.1 mL),
sat. aq NaOAc (23 mL) and H O (30% in H O, 8 mL) were added.
(t, J = 8.5 Hz, 1 H, 2-CH′), 3.91 (d, J = 16.0 Hz, 1 H, PhHCH), 4.28
(d, J = 16.0 Hz, 1 H, PhHCH), 4.51 (d, J = 2.5 Hz, 1 H, 1-H), 7.21–
13
7.34 (m, 10 H, ArH). C (100 MHz, CDCl ): δ = 17.6, 22.9, 23.3,
3
(
36.7, 39.2, 44.7, 50.6, 53.0, 59.1, 61.9, 64.4, 72.0, 74.3, 127.2,
127.3, 127.9, 128.3(2), 128.9, 138.0, 138.3, 159.1; MS (EI): m/z
+
(%) = 420 (1) [M ], 91 (100). The second fraction was a mixture
of the title compounds 30 and 31 (53 mg, 26%); 30/31 ratio
55:45; R = 0.28–0.22 (EtOAc–light petroleum, 1:2). HRMS: m/z
f
+
[M] calcd for C26H32N O : 420.2413; found: 420.2412. IR: 3083,
2
3
3061, 3029, 2927, 2869, 2823, 1746, 1495, 1453, 1436, 1403,
1355, 1334, 1193, 1170, 1106, 1053, 1027, 996, 923, 809,
2
2
2
The reaction mixture was heated to reflux for 1 h then cooled.
–1 1
The aqueous phase was extracted with Et O (3 × 35 mL) and the
743 cm . H (400 MHz, CDCl ): δ (minor epimer 31) = 2.75–
2
3
organic extracts were dried (MgSO ) and concentrated under
reduced pressure. Chromatography (EtOAc–light petroleum,
2.85 (m, 2 H, 3-H, 5-H), 3.24 (d, J = 12.8 Hz, 1 H, PhHCH), 3.47
(dd, J = 3.0, 9.5 Hz, 1 H, 2-CH), 3.53 (dd, J = 5.25, 9.5 Hz, 1 H, 2-
CH′), 4.02 (d, J = 15.5 Hz, 1 H, PhHCH), 4.40 (d, J = 8.7 Hz, 1 H, 1-
4
1
9
0
:4) of the residue gave the title compounds 4 and 25 (648 mg,
13
5%), as a mixture of diastereoisomers (4/25 ratio 85:15); R =
H), 4.45 (d, J = 15.5 Hz, 1 H, PhHCH). C (100 MHz, CDCl ): δ
f
3
+
.21 (EtOAc–light petroleum, 1:2). HRMS: m/z [M + H] calcd for
(minor epimer 31) = 16.9, 23.3, 23.7, 41.2, 41.6, 44.4, 53.3(2),
C25H42NO Si: 464.2833; found: 464.2835. IR: 3443, 2930, 2892,
59.1, 62.4, 63.6, 71.8, 73.8, 127.4(2), 128.0, 128.3, 128.4, 129.3,
137.9, 138.1, 158.4. MS (CI+): m/z (%) = 421 (100) [M + 1].
(11) (1RS,2SR,6SR)-7-Benzyl-6-cyclobutyl-2-methoxymethyl-4,7-
diaza-9-oxabicyclo[4.3.0]nonan-8-one (3) A solution of formic
acid (93 μL, 0.025 mmol, 0.4 equiv) in MeOH (1 mL) was added
to N-benzylpiperidine 30 (26 mg, 0.062 mmol) and 10% Pd/C
5
+
2
859, 1732, 1468, 1409, 1357, 1297, 1255, 1169, 1104, 1036,
–1 1
840, 777 cm . H (400 MHz, CDCl ): δ (major epimer 4) = 0.04
3
(
s, 3 H, SiCH ), 0.05 (s, 3 H, SiCH ), 0.88 [s, 9 H, SiC(CH ) ], 1.50–
3
3
3
3
2
2
1
.05 (m, 6 H, 3 × CH ), 2.22 (br. s, 1 H, OH), 2.37 (m, 1 H, 2′-H),
2
.57 (m, 1 H, 4-CH), 3.36 (s, 3 H, OCH ), 3.57 (dd, J = 6.0, 9.5 Hz,
3
H, 3′-H), 3.63 (dd, J = 6.0, 9.5 Hz, 1 H, 3′-H), 3.66 (s, 2 H, 4-
(41 mg) under N , and the reaction mixture was stirred at r.t. for
2
CH ), 3.85–3.94 (m, 2 H, 1′-H ), 4.17 (d, J = 15.8 Hz, 1 H, PhHCH),
20 min. K CO (50 mg) was added, the reaction mixture was fil-
2
2
2
3
4
7
.48 (d, J = 6.0 Hz, 1 H, 5-H), 4.66 (d, J = 15.8 Hz, 1 H, PhHCH),
.24–7.40 (m, 5 H, ArH); δ (minor epimer 25) = 0.03 (s, 3 H,
tered through Celite, and the residue was washed with Et O.
After concentration under reduced pressure, chromatography
2
SiCH ), 0.05 (s, 3 H, SiCH ), 0.87 [s, 9 H, SiC(CH ) ], 2.83 (br. t, J =
(MeOH–Et O, 1:50, saturated in ammonia) of the residue gave
3
3
3
3
2
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 45–50

5
0
Synlett
K. J. Broadley et al.
Letter
the title compound 3 (14 mg, 71%); R = 0.38 (MeOH–Et O, 1:10
2.61 (d, J = 14.2 Hz, 1 H, 5-H′), 2.91 (dd, J = 6.5, 12.0 Hz, 1 H, 3-
f
2
+
saturated in ammonia). HRMS: m/z [M] calcd for C19H26N O :
H′), 3.31 (dd, J = 6.0, 9.0 Hz, 1 H, 2-CH), 3.36 (s, 3 H, CH ), 3.52 (t,
2
3
3
3
2
1
30.1943; found: 330.1941. IR: 3343, 3086, 3062, 3029, 2935,
J = 9.0 Hz, 1 H, 2-CH′), 4.22 (d, J = 15.7 Hz, 1 H, PhHCH), 4.43 (d,
871, 2832, 2815, 1742, 1672, 1496, 1454, 1432, 1409, 1345,
J = 15.7 Hz, 1 H, PhHCH), 4.71 (d, 1 H, J = 2.7 Hz, 1-H), 7.24–7.39
199, 1167, 1146, 1112, 1090, 1071, 984, 759, 707 cm– . H (400
1
1
(m, 5 H, ArH). C (100 MHz, CDCl ): δ = 17.5, 22.2, 22.8, 35.8,
13
3
MHz, CDCl ): δ = 1.54–2.00 (m, 7 H, 3 × CH , 6-CH), 2.12 (m, 1 H,
38.5, 40.7, 44.6, 45.0, 59.0, 63.4, 71.4, 73.6, 127.8(2), 128.7,
138.1, 158.7. MS (CI+): m/z (%) = 331 (60) [M + 1], 91 (100).
3
2
+
2-H), 2.37 (d, J = 14.2 Hz, 1 H, 5-H), 2.57 (t, J = 12.0 Hz, 1 H, 3-H),
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 45–50