Stereoselective synthesis of cyclic amino acids via asymmetric phase-transfer catalytic alkylation

Article abstract of DOI:10.1039/c2ob26778k

An asymmetric synthesis of cyclic amino acids having piperidine and azepane core structures was realized starting from readily available glycine and alanine esters by combination of phase-transfer catalyzed asymmetric alkylation and subsequent reductive a

Full text of DOI:10.1039/c2ob26778k

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PAPER
Stereoselective synthesis of cyclic amino acids via asymmetric phase-transfer
catalytic alkylation†
Taichi Kano, Takeshi Kumano, Ryu Sakamoto and Keiji Maruoka*
Received 10th September 2012, Accepted 4th October 2012
DOI: 10.1039/c2ob26778k
An asymmetric synthesis of cyclic amino acids having piperidine and azepane core structures was realized
starting from readily available glycine and alanine esters by combination of phase-transfer catalyzed
asymmetric alkylation and subsequent reductive amination.
Introduction
Organocatalysis is well-recognized as a powerful tool for the
preparation of optically active compounds including natural pro-
ducts and biologically active compounds.1 An important benefit
of organocatalysis is the lack of toxic metal byproducts that
often accompany metal-catalyzed reactions. In this area, chiral
quaternary ammonium salts are frequently utilized as a phase-
transfer catalyst for the asymmetric synthesis of non-proteino-
genic amino acids.2 Recently, we have developed an organocata-
lytic approach to asymmetric one-pot synthesis of proline
derivatives with a five-membered ring through the phase-transfer
catalyzed asymmetric 1,4-addition of a readily available glycine
ester 1 to α,β-unsaturated ketones and subsequent reductive
amination (Scheme 1).3 With this method, however, other cyclic
amino acid derivatives with a larger ring size could not be acces-
sible in spite of their synthetic and pharmacological importance.4
Accordingly, we have been interested in applying the powerful
phase-transfer catalyzed asymmetric alkylation as the initial C–C
bond forming reaction to prepare cyclic amino acids with several
different ring sizes (Scheme 1).5 Here we wish to report a cataly-
tic asymmetric synthesis of a wide variety of cyclic amino acid
derivatives starting from glycine ester 1 in combination with
phase-transfer catalyzed asymmetric alkylation and subsequent
diastereoselective reductive amination.
Scheme 1 Asymmetric synthesis of cyclic amino acids.
Fig. 1
Results and discussion
(Table 1).5 Attempted reaction of 1 and 3a with CsOH in the
presence of 1 mol% of catalyst (S)-2a in toluene at −20 °C gave
alkylation product 4a in 46% yield with 88% ee (entry 1).7
While use of (S)-2b improved the yield (entry 2), a sterically
more hindered catalyst (S)-2c was not as effective as (S)-2a
(entry 3). Lowering reaction temperature improved the enantio-
selectivity (entry 4). Using a decreased amount of CsOH and an
increased amount of 3a, the desired 4a was obtained in a satis-
factory yield with virtually complete enantioselectivity (entries 6
and 7).
We first examined asymmetric alkylation of N-(diphenylmethy-
lene)glycine ester 1 and alkyl bromide 3a with an acetal moiety
by using a chiral phase transfer catalyst of type (S)-26 Fig. 1
Department of Chemistry, Graduate School of Science, Kyoto
University, Sakyo, Kyoto 606-8502, Japan.
E-mail: maruoka@kuchem.kyoto-u.ac.jp; Fax: +81-75-753-4041;
Tel: +81-75-753-4041
†Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/c2ob26778k
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With the optimal reaction condition for asymmetric alkylation
at hand, we then examined the reactions of various alkyl bro-
mides 3 (n = 0–2, R = H or Me) and subsequent reductive amin-
ation (Table 2). The reaction between 1 and 3b (n = 0, R = H)
gave the corresponding alkylation product 4b (n = 0, R = H) in
good yield, and subsequent one-pot acetal hydrolysis with
CF3CO2H (3 equiv.) in aqueous EtOH at room temperature and
intramolecular reductive amination with Pd on carbon under a
H2 atmosphere at 45 °C proceeded to furnish proline ester 5b
(n = 0, R = H) in good yield and enantioselectivity (entry 1).
Unfortunately, however, the reaction using the sterically more
hindered alkyl bromide 3c (n = 0, R = Me) gave only a trace
amount of the alkylation product (entry 2). Under similar con-
ditions, the reactions of alkyl bromides 3 (n = 1–2, R = H or
Me) with a longer alkyl chain were examined. The reaction of 3
Scheme 2 Synthesis of cyclic amino ester 7.
(n = 1–2, R = H) with an acetal moiety proceeded to afford the
corresponding alkylated products in good yield, and the follow-
ing cyclization gave cyclic amino esters 5 (n = 1–2, R = H) in
excellent enantioselectivity (entries 3 and 5). The reaction of 3
(n = 1–2, R = Me) with a ketal moiety also gave the correspond-
ing cyclic amino esters 5 (n = 1–2, R = Me) in excellent dia-
stereo- and enantioselectivity (entries 4 and 6).8 In all the cases
examined, the minor diastereomers were not detected. When
N-(4-chlorophenylmethylene)alanine ester 6 was used instead of
glycine ester 1, cyclic amino ester 7 having a tetrasubstituted
carbon was obtained with excellent diastereo- and enantioselec-
tivity (Scheme 2).5
Table 1 Asymmetric alkylation of glycine ester 1 with (S)-2a–c under
phase transfer conditionsa
We then turned our attention to the stereoselective synthesis of
cyclic amino esters 10 with a different substitution pattern
(Table 3).9 Using racemic branched alkyl bromides 8 (n = 1, R1
= H, R2 = Me or Ph) with an acetal moiety, 4-substituted pipeco-
lic acid esters were obtained as an almost 1 : 1 diastereomixture
(entries 2 and 3). On the other hand, the reaction of branched
alkyl bromide 8d (n = 1, R1 = Me, R2 = Me) with a ketal moiety
gave the all-cis 4,5-dimethylpipecolic acid ester as a major dia-
stereomer, albeit with low diastereoselectivity (entry 4). In the
case of alkyl bromide 8 (n = 1, R1, R2 = (CH2)3 or (CH2)4) with
a 5 or 6-membered ring, further improvement of diastereoselec-
tivity was observed (entries 5 and 6). The reaction of alkyl
bromide 8g (n = 2, R1, R2 = (CH2)3) with a longer alkyl chain
also gave the all-cis isomer as a major diastereomer (entry 7).
In the reaction using racemic branched alkyl bromide 8d (n =
1, R1 = Me, R2 = Me), dimethylpipecolic acid ester (2R,5S,6R)-
10d was also obtained as a minor diastereomer along with the
all-cis isomer (2R,5R,6R)-10d (Table 3, entry 4 and Scheme 3).
Entry
Cat
Conditions (°C, h)
Yieldb (%)
eec (%)
1
2
3
4
(S)-2a
(S)-2b
(S)-2c
(S)-2a
(S)-2a
(S)-2a
(S)-2a
−20, 6
46
58
36
31
50
79
85
88
85
39
98
97
99
99
−20, 6
−20, 6
−40, 18
−40, 20
−40, 20
−40, 16
5d
6d,e
7d,e,f
a Unless otherwise specified, the reaction was carried out with glycine
derivative 1 and 5 equiv. of alkyl bromide 3a in the presence of 1 mol%
of (S)-2a–c, and 5 equiv. of CsOH under the given reaction conditions.
b Isolated yield. c Determined by HPLC analysis using a chiral column
(Chiralpak AD-H, Daicel Chemical Industries, Ltd). d 2.5 equiv. of
CsOH. e 10 equiv. of 3. f 2 mol% of (S)-2a.
Table 2 Asymmetric alkylation of glycine ester 1 with various alkyl bromides 3 under phase transfer conditions and reductive aminationa
Entry
3 (n, R)
Time (h)
Yield of 4b (%)
Yield of 5b (%)
eec (%)
1d
2
3
4
5
3b (0, H)
3c (0, Me)
3d (1, H)
3a (1, Me)
3e (2, H)
3f (2, Me)
14
12
16
16
16
20
78 (4b)
<5
87 (4d)
85 (4a)
76 (4e)
81 (4f)
71 (5b)
—
75 (5d)
88 (5a)
77 (5e)
79 (5f)
90
—
99
99
99
98
6
a Unless otherwise specified, the reaction was carried out with glycine derivative 1 and 5 equiv. of alkyl bromide 3 in the presence of 2 mol% of
(S)-2a, and 5 equiv. of CsOH under the given reaction conditions. b Isolated yield. c Determined by HPLC analysis using a chiral column.
d Hydrogenation was performed at 45 °C.
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Table 3 Asymmetric alkylation of glycine ester 1 with various alkyl bromides 8 under phase transfer conditions and reductive aminationa
Entry
8 (n, R1, R2)
Conditions (°C, h)
Yield of 9b (%)
Yield of 10b (%)
drc
eed (%)
1e
2f
3f
4
8a (0, (CH2)3)
8b (1, H, Me)
8c (1, H, Ph)
8d (1, Me, Me)
8e (1, (CH2)3)
8f (1, (CH2)4)
8g (2, (CH2)3)
0, 6
n.d.
—
—
—
−40, 28
−30, 16
−40, 16
−40, 14
−40, 30
−40, 20
73 (9b)
71 (9c)
84 (9d)
87 (9e)
71 (9f)
84 (9g)
75 (10b)
79 (10c)
82 (10d)
82 (10e)
72 (10f)
73 (10g)
1.2/1
1.0/1
2.5/1
13/1
6.0/1
5.7/1
98/96
92/89
98
99
99
5
6
7g
90
a Unless otherwise specified, the reaction was carried out with glycine derivative 1 and 5 equiv. of alkyl bromide 8 in the presence of 2 mol% of
(S)-2a, and 5 equiv. of CsOH under the given reaction conditions. b Isolated yield. c Determined by 1H-NMR analysis. d Determined by HPLC
analysis using a chiral column. e User of TBAB (20 mol%) instead of (S)-2a. f Hydrogenation was performed at 45 °C. g Hydrogenation was
performed for 35 h.
Scheme 4 Synthesis of 4-methylpipecolic acid ester 15.
Scheme 3 Postulated origins of stereocontrol in the reaction cascade.
Conclusions
Since (2R,5R,6R)-10d was obtained in more than 50% yield,
In summary, we were successfully able to develop an asymmetric
synthesis of piperidine and azepane core structures starting from
a readily available glycine ester by combination of phase-transfer
imine intermediate (2R,5S)-11 would be partially epimerized to
(2R,5R)-11 via the enamine tautomer (R)-12, giving (2R,5R,6R)-
10d after reduction of (2R,5R)-11 and/or (R)-12, as shown in
catalyzed asymmetric alkylation and subsequent diastereoselec-
Scheme 3. Based on the fact that reduction proceeded through
tive reductive amination.
imine (2R,5S)-11, 6-methylpipecolic acid ester 5a (n = 1, R =
Me) seemed to be obtained via facile reduction of the corre-
sponding sterically less hindered imine intermediate than
(2R,5S)-11.
Experimental
With the present asymmetric alkylation/reductive amination
protocol, stereoselective synthesis of 4-methylpipecolic acid
ester 1510 has also been realized by using 2-substituted allyl
bromide 13, and the stereochemistry at the 4-position of the
piperidine ring was found to be controllable (Scheme 4). Indeed,
treatment of the alkylation products with CF3CO2H in aqueous
EtOH and then the catalytic hydrogenation with Pd on carbon
under a H2 atmosphere produced 4-methylpipecolic acid ester 15
stereoselectively.5
General information
Infrared (IR) spectra were recorded on a Shimadzu IRPrestige-21
spectrometer. 1H NMR spectra were measured on a JEOL
JNM-FX400 (400 MHz) spectrometer. Chemical shifts were
reported in ppm from tetramethylsilane (in the case of CDCl3) as
an internal standard. Data were reported as follows: chemical
shift, integration, multiplicity (s = singlet, d = doublet, t =
triplet, q = quintet, m = multiplet, br = broad, and app =
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apparent), and coupling constants (Hz). 13C NMR spectra were
recorded on a JEOL JNM-FX400 (100 MHz) spectrometer with
complete proton decoupling. Chemical shifts were reported in
ppm from the residual solvent as an internal standard. High per-
formance liquid chromatography (HPLC) was performed on Shi-
madzu 10A instruments using Daicel CHIRALPAK AD-H,
AS-H and CHIRALCEL OD-H 4.6 mm × 25 cm columns. The
high-resolution mass spectra (HRMS) were performed on an
Applied Biosystems Mariner 8295 API-TOF and a Bruker micro-
TOF. Optical rotations were measured on a JASCO DIP-1000
digital polarimeter. For thin layer chromatography (TLC) analy-
sis throughout this work, Merck precoated TLC plates (silica gel
60 GF254, 0.25 mm) were used. The products were purified by
flash column chromatography on silica gel 60 (Merck
1.09386.9025, 230–400 mesh). Glycine t-butyl ester-benzophe-
noneimine Schiff base 1,11 alanine t-butyl ester-p-chlorobenzal-
dimine Schiff base 6,12 chiral phase transfer catalysts (S)-2a, (S)-
2b and (S)-2c were prepared according to the literature proce-
dure.6b Alkyl halides 3,13–15 813 and 1316 were prepared accord-
ing to the literature procedure. Cyclic amino esters 5b,17 5d,18
5a,8a 10e9 and 10f9 are known compounds. Other simple chemi-
cals were purchased and used as such.
C24H30NO4: 396.2169 ([M
([M + H]+).
+
H]+), Found: 396.2181
(R)-tert-Butyl 5-(1,3-dioxolan-2-yl)-2-(diphenylmethylene-amino)-
pentanoate (4d). Daicel Chiralpak AD-H, hexane/2-propanol =
50/1, flow rate 1.0 mL min−1, λ = 254 nm, retention time:
7.7 min (major) and 9.9 min (minor); [α]2D3 = 20.1 (c 1.0,
CHCl3, 99% ee); 1H NMR δ 7.66–7.63 (2H, m), 7.46–7.29 (6H,
m), 7.20–7.15 (2H, m), 4.81 (1H, t, J = 4.8 Hz), 3.96–3.88 (3H,
m), 3.85–3.77 (2H, m), 1.97–1.91 (2H, m), 1.63–1.58 (2H, m),
1.44 (9H, s), 1.42–1.26 (2H, m); 13C NMR δ 171.4, 170.0,
139.7, 136.7, 130.1, 128.7, 128.43, 128.36, 127.9, 127.8, 104.4,
80.8, 65.9, 64.8, 33.7, 33.5, 28.0, 20.6; IR (neat) 2949, 1732,
1622, 1368, 1146 cm−1
;
HRMS (ESI-TOF) Calcd
for C25H32NO4: 410.2326 ([M + H]+), Found: 410.2334
([M + H]+).
(R)-tert-Butyl 6-(1,3-dioxolan-2-yl)-2-(diphenylmethylene-amino)-
hexanoate (4e). Daicel Chiralpak AD-H, hexane/2-propanol =
50/1, flow rate 1.0 mL min−1, λ = 254 nm, retention time:
8.1 min (major) and 10.8 min (minor); [α]2D8 = 7.4 (c 1.0,
CHCl3, 99% ee); 1H NMR δ 7.66–7.63 (2H, m), 7.46–7.29 (6H,
m), 7.18–7.16 (2H, m), 4.80 (1H, t, J = 4.8 Hz), 3.97–3.88 (3H,
m), 3.85–3.77 (2H, m), 1.92–1.87 (2H, m), 1.65–1.60 (2H, m),
1.44 (9H, s), 1.41–1.20 (4H, m); 13C NMR δ 171.4, 169.8,
139.7, 136.7, 130.0, 128.7, 128.4, 128.3, 127.9, 127.8, 104.4,
80.7, 65.9, 64.7, 33.7, 33.5, 28.0, 25.9, 23.8; IR (neat) 2976,
1732, 1622, 1144, 1030 cm−1; HRMS (ESI-TOF) Calcd
for C26H34NO4: 424.2482 ([M + H]+), Found: 424.2488
([M + H]+).
General procedure for asymmetric alkylation under phase-
transfer conditions
To a mixture of 1 (30 mg, 0.10 mmol), 3a (209 mg, 1.0 mmol)
and (S)-2a (1.5 mg, 0.002 mmol) in toluene (1 mL) was added
CsOH (42 mg, 0.25 mmol) at −40 °C, and the reaction mixture
was vigorously stirred for 16 h. After the consumption of the
starting material, the mixture was diluted with H2O and extracted
with dichloromethane. The organic layer was dried over Na2SO4
and purified by chromatography on silica gel (hexane/ethyl
acetate = 5/1 as an eluent) to afford 4a (36 mg, 0.085 mmol,
85% yield) as an oil. The enantiomeric excess was determined
by HPLC analysis (Daicel Chiralpak AD-H, hexane/2-propanol
= 50/1, flow rate 1.0 mL min−1, λ = 254 nm, retention time:
6.3 min (major) and 10.0 min (minor)). [α]2D5 = 81.1 (c 1.0,
CHCl3, 99% ee); 1H NMR δ 7.66–7.63 (2H, m), 7.45–7.29 (6H,
m), 7.19–7.17 (2H, m), 3.93–3.84 (5H, m), 1.93–1.87 (2H, m),
1.60–1.55 (2H, m), 1.44 (9H, s), 1.40–1.30 (2H, m), 1.27 (3H,
s); 13C NMR δ 171.5, 169.9, 139.7, 136.7, 130.1, 128.8, 128.5,
128.4, 127.94, 127.88, 111.0, 80.8, 66.0, 64.6, 38.9, 33.8, 28.1,
23.8, 20.6; IR (neat) 2951, 1732, 1622, 1447, 1368, 1148,
1069 cm−1; HRMS (ESI-TOF) Calcd for C26H34NO4: 424.2482
([M + H]+), Found: 424.2491 ([M + H]+).
(R)-tert-Butyl
2-(diphenylmethyleneamino)-6-(2-methyl-1,3-
dioxolan-2-yl)hexanoate (4f). Daicel Chiralpak AD-H, hexane/
2-propanol = 50/1, flow rate 0.5 mL min−1, λ = 254 nm, reten-
tion time: 12.0 min (major) and 15.7 min (minor). [α]2D0 = 83.6
(c 0.5, CHCl3, 98% ee); 1H NMR δ 7.65–7.63 (2H, m),
7.56–7.30 (6H, m), 7.18–7.15 (2H, m), 3.94–3.85 (5H, m), 1.88
(2H, q, J = 7.6 Hz), 1.61–1.57 (2H, m), 1.44 (9H, s), 1.37–1.20
(7H, m); 13C NMR δ 171.6, 169.8, 136.8, 135.3, 130.1, 128.8,
128.42, 128.37, 128.0, 127.9, 110.0, 80.8, 66.0, 64.6, 39.1, 34.7,
33.6, 28.1, 26.3, 23.9, 23.7; IR (neat) 2978, 2359, 1732, 1622,
1368, 1152 cm−1; HRMS (ESI-TOF) Calcd for C27H36NO4:
438.2639 ([M + H]+), Found: 438.2646 ([M + H]+).
General procedure for diastereoselective reductive amination
To a mixture of 4a (67 mg, 0.16 mmol), EtOH (3 mL) and H2O
(1.5 mL) was added TFA (36 μL, 0.48 mmol). After stirring for
1 h, to the mixture was added 10% Pd/C (34 mg) and the
mixture was stirred at 40 °C for 24 h under a hydrogen atmos-
phere. After filtration through celite, the filtrate was basified with
aqueous NaHCO3 and extracted with dichloromethane. The
organic layer was dried over Na2SO4 and purified by chromato-
graphy on silica gel (dichloromethane/methanol = 50/1 as an
eluent) to afford 5a (28 mg, 0.14 mmol, 88% yield) as an oil.
(R)-tert-Butyl 4-(1,3-dioxolan-2-yl)-2-(diphenylmethylene-amino)-
butanoate (4b). Daicel Chiralpak AD-H, hexane/2-propanol =
50/1, flow rate 1.0 mL min−1, λ = 254 nm, retention time:
9.7 min (major) and 12.9 min (minor); [α]2D1 = 74.3 (c 1.0,
CHCl3, 90% ee); 1H NMR δ 7.66–7.63 (2H, m), 7.46–7.28 (6H,
m), 7.19–7.17 (2H, m), 4.82 (1H, t, J = 4.8 Hz), 3.97–3.87 (3H,
m), 3.84–3.75 (2H, m), 2.07–1.98 (2H, m), 1.76–1.67 (1H, m),
1.63–1.55 (1H, m), 1.44 (9H, s); 13C NMR δ 171.1, 170.1,
139.6, 136.6, 130.1, 128.7, 128.4, 128.3, 127.9, 127.8, 104.2,
80.8, 65.5, 64.8, 64.7, 30.4, 28.02, 27.98; IR (neat) 2976, 2355,
[α]2D1 = 7.1 (c 0.7, CHCl3, 99% ee); H NMR δ 3.22 (1H, dd,
1
J = 11.5, 2.7 Hz), 2.64 (1H, dqd, J = 11.0, 6.4, 2.7 Hz),
1.99–1.94 (1H, m), 1.89–1.83 (1H, m), 1.77 (1H, br), 1.62–1.57
(1H, m), 1.46 (9H, s), 1.44–1.25 (2H, m), 1.12 (3H, d, J =
6.4 Hz), 1.08–0.98 (1H, m); 13C NMR δ 172.6, 80.8, 59.8, 51.8,
1732, 1368, 1146 cm−1
; HRMS (ESI-TOF) Calcd for
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33.8, 29.0, 28.0, 24.6, 22.8; IR (neat) 2357, 2930, 2357, 1730,
1368, 1153 cm−1; HRMS (ESI-TOF) Calcd for C11H22NO2:
200.1645 ([M + H]+), Found: 200.1644 ([M + H]+).
0.24 mmol) at 0 °C. After stirring for 3 h at 0 °C, the mixture
was quenched with H2O and extracted with dichloromethane.
The organic layer was dried over Na2SO4 and purified by chrom-
atography on silica gel (hexane/ethylacetate = 5/1 as an eluent)
to afford the N-benzoylated derivative of the title compound
(41 mg, 0.11 mmol, 51% yield) as an oil. [α]1D9 = −12.6 (c 0.9,
CHCl3, 96% ee); 1H NMR δ 7.81–7.78 (2H, m), 7.51–7.41 (3H,
m), 3.92–3.83 (4H, m), 2.60–2.52 (1H, m), 1.86–1.78 (1H, m),
1.71 (3H, s), 1.69–1.55 (2H, m), 1.51 (9H, s), 1.48–1.38 (2H,
m), 1.26 (3H, s); 13C NMR δ 174.2, 166.0, 135.2, 131.3, 128.5,
126.8, 109.8, 82.3, 64.6, 64.5, 61.2, 38.8, 36.0, 27.9, 23.7, 23.4,
19.1; IR (neat) 3408, 2980, 1728, 1663, 1152 cm−1; HRMS
(ESI-TOF) Calcd for C21H32NO5: 378.2275 ([M + H]+), Found:
378.2271 ([M + H]+).
(R)-tert-Butyl azepane-2-carboxylate (5e). [α]2D3 = −6.3 (c 1.2,
1
CHCl3, 99% ee); H NMR δ 3.42 (1H, dd, J = 8.8, 5.2 Hz),
3.10–3.04 (1H, m), 2.75–2.68 (1H, m), 2.57 (1H, br), 2.09–2.02
(1H, m), 1.76–1.54 (7H, m), 1.46 (9H, s); 13C NMR δ 172.0,
82.1, 59.9, 45.8, 31.3, 29.5, 28.0, 27.4, 25.0; IR (neat) 2928,
1728, 1368, 1155 cm−1
;
HRMS (ESI-TOF) Calcd for
+
C11H22NO2: 200.1645 ([M
H]+), Found: 200.1648
([M + H]+).
(2R,7R)-tert-Butyl 7-methylazepane-2-carboxylate (5f). [α]D22
1
= 15.0 (c 0.5, CHCl3, 98% ee); H NMR δ 3.39 (1H, dd, J =
9.8, 5.1 Hz), 2.79–2.71 (1H, m), 2.07–1.98 (1H, m), 1.88 (1H,
br), 1.61–1.76 (5H, m), 1.46 (9H, s), 1.44–1.40 (1H, m),
1.34–1.26 (1H, m), 1.12 (3H, d, J = 6.6 Hz); 13C NMR δ 174.1,
80.9, 61.0, 54.5, 39.6, 33.6, 28.0, 25.3, 25.0, 23.9; IR (neat)
2926, 2359, 1726, 1368, 1157 cm−1; HRMS (ESI-TOF) Calcd
for C12H24NO2: 214.1802 ([M + H]+), Found: 214.1799
([M + H]+).
(R)-tert-Butyl 5-(1,3-dioxolan-2-yl)-2-(diphenylmethylene-amino)-
hexanoate (9b). [α]2D3 = 82.1 (c 1.1, CHCl3); 1H NMR
δ 7.66–7.63 (2H, m), 7.46–7.30 (6H, m), 7.19–7.16 (2H, m),
4.65 (1H, d, J = 5.0 Hz), 3.95–3.87 (3H, m), 3.86–3.78 (2H, m),
2.04–1.85 (2H, m), 1.60–1.67 (2H, m), 1.44 (9H, s), 1.22–1.13
(1H, m), 0.91 (3H, d, J = 6.8 Hz); 13C NMR δ 171.5, 170.0,
139.7, 136.8, 130.1, 128.8, 128.42, 128.35, 127.94, 127.87,
107.5, 80.8, 66.2, 64.97, 64.95, 36.8, 31.3, 28.0, 27.9, 13.7; IR
(neat) 2974, 1732, 1622, 1447, 1368, 1150 cm−1; HRMS
(ESI-TOF) Calcd for C26H34NO4: 424.2482 ([M + H]+), Found:
424.2469 ([M + H]+).
(2R,6R)-tert-Butyl 2,6-dimethylpiperidine-2-carboxylate (7).
To a mixture of 6 (161 mg, 0.60 mmol), 3a (1.25 g, 6.0 mmol)
and (S)-2a (9 mg, 0.012 mmol) in toluene (6 mL) was added
CsOH (280 mg, 1.5 mmol) at −20 °C, and the reaction mixture
was vigorously stirred for 20 h. After the consumption of the
starting material, the mixture was concentrated under reduced
pressure, and to the residue were added EtOH (3 mL), H2O
(3 mL), and TFA (245 μL, 3.3 mmol). After stirring for 1 h, to
the mixture was added 10% Pd/C (80 mg) and the mixture was
stirred at 40 °C for 36 h under a hydrogen atmosphere. After fil-
tration through celite, the result solution was basified with
aqueous NaHCO3 and extracted with dichloromethane. The
organic layer was dried over Na2SO4 and purified by chromato-
graphy on silica gel (dichloromethane/methanol = 30/1 as an
eluent) to afford 7 (79 mg, 0.37 mmol, 61% yield) as an oil.
Diastereo-mixture of (R)-tert-butyl 5-methylpiperidine-2-car-
1
boxylate (10b). (2R,5R)/(2R,5S) = 1.2/1. H NMR δ 3.45–3.42
(0.55H, m), 3.11 (0.45H, dd, J = 11.6, 2.8 Hz), 3.08–3.04
(0.45H, m), 2.80 (0.55H, dd, J = 11.6, 3.6 Hz), 2.52 (0.55H, dd,
J = 11.6, 9.2 Hz), 2.30 (1H, br), 2.22 (0.45H, app t), 2.04–1.96
(1H, m), 1.86–1.62 (3H, m), 1.48 (4.95H, s), 1.46 (4.05H, s),
1.15–1.01 (1H, m), 0.88 (1.65H, d, J = 6.4 Hz), 0.82 (1.35H, d,
J = 6.8 Hz); 13C NMR δ 173.2, 172.6, 80.7, 63.4, 59.2, 56.5,
53.5, 50.3, 33.2, 31.5, 30.1, 30.0, 29.7, 28.0, 27.9, 26.0, 19.2,
18.8; IR (neat) 2930, 1728, 1456, 1368, 1155 cm−1; HRMS
(ESI-TOF) Calcd for C11H22NO2: 200.1645 ([M + H]+), Found:
200.1654 ([M + H]+).
1
[α]2D1 = 18.3 (c 1.0, CHCl3, 96% ee); H NMR δ 2.91–2.86 (1H,
m), 1.73–1.49 (6H, m), 1.46 (9H, s), 1.35 (3H, s), 1.07 (3H, d,
J = 6.4 Hz), 1.02–0.91 (1H, m); 13C NMR δ 175.7, 80.4, 58.1,
45.5, 34.0, 32.8, 27.8, 22.9, 20.6, 20.1; IR (neat) 2932, 1724,
1454, 1368, 1284, 1145 cm−1; HRMS (ESI-TOF) Calcd
for C12H24NO2: 214.1802 ([M + H]+), Found: 214.1794
([M + H]+).
Determination of the enantiomeric excess of (R)-tert-butyl
5-methylpiperidine-2-carboxylate (10b). The enantiomeric excess
of 10b was determined by HPLC analysis after conversion to the
corresponding benzamide. (2R,5R)/(2R,5S) = 1.2 (98% ee)/1
(96% ee). Daicel Chiralpak OD-H, hexane/2-propanol = 200/1,
flow rate 0.5 mL min−1, λ = 254 nm, retention time: (2R,5R:
56.2 min (major) and 102.7 min (minor)), (2R,5S: 62.5 min
(major) and 78.9 min (minor)); 1H NMR (toluene-d8, 80 °C)
δ 7.48–7.46 (2H, m), 7.15–7.05 (3H, m), 5.07 (0.45H, br), 3.60
(0.55H, br), 3.35 (0.45H, d, J = 13.2 Hz), 2.85 (0.55H, br),
2.22–2.17 (1.55H, m), 2.01–1.98 (0.45H, m), 1.83–1.80 (0.55H,
m), 1.69–1.48 (2.45H, m), 1.43 (4.05H, s), 1.41 (4.95H, s),
1.24–1.21 (0.45H, m), 1.14–1.04 (0.55H, m), 0.87 (1.35H, d,
J = 6.8 Hz), 0.65 (1.65H, br); 13C NMR δ 174.6, 173.6, 173.2,
173.1, 140.40, 140.35, 132.3, 132.1, 131.3, 130.4, 130.3, 130.0,
84.2, 83.8, 61.2, 55.4, 55.2, 49.7, 34.5, 33.7, 33.2, 30.8, 30.3,
29.9, 24.4, 22.2, 21.8, 19.2; IR (neat) 2930, 1728, 1638, 1420,
1225, 1142 cm−1; HRMS (ESI-TOF) Calcd for C18H26NO3:
304.1907 ([M + H]+), Found: 304.1915 ([M + H]+).
Determination of the enantiomeric excess of (R)-tert-butyl
2-amino-2-methyl-5-(2-methyl-1,3-dioxolan-2-yl)pentanoate
To a mixture of 6 (54 mg, 0.20 mmol), 3a (418 mg, 2.0 mmol)
and (S)-2a (3 mg, 0.004 mmol) in toluene (2 mL) was added
CsOH (93 mg, 0.50 mmol) at −20 °C, and the reaction mixture
was vigorously stirred for 24 h. After the consumption of the
starting material, the mixture was concentrated under reduced
pressure, and to the residue were added MeOH (1 mL), H2O
(1 mL), and TFA (53 μL, 0.7 mmol). After stirring for 0.5 h, the
solution was basified with aqueous NaHCO3, extracted with
dichloromethane, dried over Na2SO4 and concentrated. To a sol-
ution of the residue and triethylamine (56 μL, 0.40 mmol) in
dichloromethane (2 mL) was added benzoyl chloride (34 μL,
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(R)-tert-Butyl 5-(1,3-dioxolan-2-yl)-2-(diphenylmethylene-
amino)-5-phenylpentanoate (9c). [α]2D4 = 41.5 (c 1.3, CHCl3);
1H NMR δ 7.64–7.61 (2H, m), 7.43–7.10 (13H, m), 4.96 (0.5H,
d, J = 4.8 Hz), 4.94 (0.5H, d, J = 4.4 Hz), 3.88–3.87 (1H, m),
3.80–3.74 (4H, m), 2.80–2.76 (1H, m), 1.89–1.70 (4H, m), 1.41
(4.5H, s), 1.39 (4.5H, s); 13C NMR δ 171.4, 171.2, 169.8, 169.7,
140.0, 139.9, 139.74, 139.69, 136.69, 136.65, 130.08, 130.06,
128.9, 128.78, 128.75, 128.44, 128.41, 128.38, 128.36, 128.3,
128.20, 128.17, 128.0, 127.93, 127.87, 127.85, 126.7, 126.6,
111.6, 106.8, 80.8, 80.7, 66.2, 65.9, 65.10, 65.07, 65.0, 49.9,
49.7, 33.9, 31.5, 28.02, 28.01, 26.3, 26.2, 20.9; IR (neat) 2976,
NMR (toluene-d8, 80 °C) δ 3.26–3.21 (1H, m), 2.85 (0.71H, dq,
J = 2.9, 6.6 Hz), 2.24 (0.29H, dq, J = 8.8, 6.4 Hz), 2.00–1.95
(0.29H, m), 1.81–1.78 (0.29H, m), 1.71–1.47 (5.42H, m), 1.46
(9H, s), 1.11 (0.86H, d, J = 6.4 Hz), 1.03 (2.14H, d, J = 6.6 Hz),
0.89 (2.14H, d, J = 7.1 Hz), 0.85 (0.86H, d, J = 6.1 Hz); 13C
NMR δ (2R,5R,6R/2R,5S,6R) 172.9/172.6, 80.7/80.6, 60.2/59.7,
57.9/53.6, 33.8/37.7, 31.5/32.0, 28.01/28.00, 23.6/29.9, 20.0/
20.3, 10.9/18.4; IR (neat) 1730, 1368, 1233, 1155 cm−1; HRMS
(ESI-TOF) Calcd for C12H24NO2: 214.1802 ([M + H]+), Found:
214.1807 ([M + H]+).
1732, 1368, 1146 cm−1
;
HRMS (ESI-TOF) Calcd
for C31H36NO4: 486.2639 ([M + H]+), Found: 486.1632
([M + H]+).
Determination of the enantiomeric excess of 10d
The enantiomeric excess of 10d was determined by HPLC
analysis after conversion to the corresponding benzamide.
(2R,5R,6R)/(2R,5S,6R) = 2.5 (99% ee)/1(99% ee). Daicel Chiral-
pak AS-H, hexane/2-propanol = 10/1, flow rate 1.0 mL min−1, λ
= 254 nm, retention time: (2R,5S,6R: 9.8 min (minor), 10.9 min
(2R,5S)-tert-Butyl 5-phenylpiperidine-2-carboxylate ((2R,5S)-
10c). Daicel Chiralpak AD-H, hexane/2-propanol = 50/1, flow
rate 0.5 mL min−1, λ = 254 nm, retention time: 25.1 min (major)
1
and 28.9 min (minor); [α]2D5 = 1.0 (c 0.4, CHCl3, 92% ee); H
1
(major)), (2R,5R,6R: 12.1 min (major), 20.7 min (minor)). H
NMR δ 7.31–7.27 (2H, m), 7.21–7.18 (3H, m), 3.58 (1H, dd,
J = 5.2, 3.2 Hz), 3.01–2.92 (2H, m), 2.80–2.73 (1H, m),
2.28–2.23 (1H, m), 1.93–1.81 (3H, m), 1.52 (9H, m), 1.48–1.41
(1H, m); 13C NMR δ 173.4, 144.6, 128.4, 127.2, 126.3, 81.0,
55.9, 49.6, 42.5, 28.8, 28.2, 26.8; IR (neat) 2932, 1724, 1368,
1150 cm−1; HRMS (ESI-TOF) Calcd for C16H24NO2: 262.1802
([M + H]+), Found: 262.1794 ([M + H]+).
NMR (toluene-d8, 80 °C) δ 7.19–7.13 (2H, m), 6.90–6.82 (3H,
m), 4.69–3.76 (2H, m), 1.96 (0.71H, d, J = 13.2 Hz), 1.88–1.85
(0.71H, m), 1.80–1.74 (0.29H, m), 0.81 (2.14H, d, J = 7.1 Hz),
1.64–1.55 (0.29H, m), 1.49–1.09 (11H, m), 0.95 (0.86H, d, J =
7.6 Hz), 0.93 (0.71H, m), 0.79–0.77 (0.29H, m), 0.61 (0.86H, d,
J = 7.1 Hz), 0.38 (2.14H, d, J = 6.6 Hz); 13C NMR δ (2R,5R,6R/
2R,5S,6R) 174.8/175.5, 174.1/174.4, 141.4/141.5, 140.4/140.7,
131.2/131.9, 130.0/129.9, 84.0/83.8, 56.9/55.4, 56.1/55.1, 37.8/
37.7, 36.17/36.15, 30.9/29.3, 27.3/26.1, 21.5/21.4, 15.6/23.1; IR
(neat) 2976, 2361, 1726, 1641, 1412, 1155 cm−1; HRMS
(ESI-TOF) Calcd for C19H28NO3: 318.2064 ([M + H]+), Found:
318.2048 ([M + H]+).
(2R,5R)-tert-Butyl 5-phenylpiperidine-2-carboxylate ((2R,5R)-
10c). Daicel Chiralpak AS-H, hexane/2-propanol = 50/1, flow
rate 0.5 mL min−1, λ = 254 nm, retention time: 18.2 min (major)
1
and 20.2 min (minor); [α]2D2 = −6.3 (c 0.8, CHCl3, 89% ee); H
NMR δ 7.32–7.28 (2H, m), 7.22–7.19 (3H, m), 3.30–3.25 (2H,
m), 2.74–2.63 (2H, m), 2.17–2.06 (3H, m), 1.75–1.54 (2H, m),
1.48 (9H, s); 13C NMR δ 172.4, 144.1, 128.4, 127.0, 126.4,
81.0, 59.2, 53.0, 43.4, 31.6, 29.9, 28.0; IR (neat) 2932, 1730,
1368, 1153 cm−1; HRMS (ESI-TOF) Calcd for C16H24NO2:
262.1802 ([M + H]+), Found: 262.1799 ([M + H]+).
6-(2-Bromoethyl)-1,4-dioxaspiro[4.4]nonane (8e). The title
compound was prepared by a similar method described in the lit-
erature.4 1H NMR δ 3.95–3.87 (4H, m), 3.52–3.42 (1H, m),
3.40–3.35 (1H, m), 2.12–2.05 (2H, m), 1.95–1.91 (1H, m),
1.84–1.63 (5H, m), 1.36–1.31 (1H, m); 13C NMR δ 117.8, 64.5,
64.4, 44.6, 35.5, 32.8, 32.6, 28.9, 20.6; IR (neat) 2876, 2957,
Diastereo-mixture of (2R)-tert-butyl 2-(diphenylmethylene-
amino)-5-(2-methyl-1,3-dioxolan-2-yl)hexanoate (9d). (2R,5R)/
(2R,5S) = 1/1. 1H NMR δ 7.16–7.19 (2H, m) 7.65–7.63 (2H, m),
7.46–7.30 (6H, m), 3.93–3.79 (5H, m), 2.10–1.97 (1H, m),
1.88–1.69 (1H, m), 1.65–1.51 (2H, m), 1.45 (4.5H, s), 1.44
(4.5H, s), 1.19 (3H, s), 1.11–0.99 (1H, m), 0.93 (1.5H, d, J = 7.1
Hz), 0.91 (1.5H, d, J = 6.8 Hz); 13C NMR δ 14.5, 14.6, 20.2,
20.3, 28.06, 28.12, 31.4, 31.8, 32.0, 32.1, 41.3, 41.4, 47.5, 47.6,
48.8, 48.9, 64.49, 65.54, 66.3, 66.6, 80.76, 80.81, 112.29,
112.34, 127.89, 127.90, 127.94, 128.35, 128.37, 128.43, 128.77,
128.82, 129.9, 130.1, 136.78, 136.82, 139.80, 139.83, 169.7,
169.9, 171.5, 171.6, 171.5, 169.9, 169.7, 139.83, 139.80,
136.82, 136.78, 130.1, 129.9, 128.82, 128.77, 128.43, 128.37,
128.35, 127.94, 127.90, 127.89, 112.34, 112.29, 80.81, 80.76,
66.6, 66.3, 65.54, 64.49, 48.9, 48.8, 47.6, 47.5, 41.4, 41.3, 32.1,
32.0, 31.8, 31.4, 28.12, 28.06, 20.3, 20.2, 14.6, 14.5; IR (neat)
2976, 1732, 1368, 1150 cm−1; HRMS (ESI-TOF) Calcd
for C27H36NO4: 438.2639 ([M + H]+), Found: 438.2622
([M + H]+).
2876, 1738, 1315, 1260, 1206, 1139, 1026 cm−1
.
Diastereo-mixture of (2R)-tert-butyl 2-(diphenylmethylene-
amino)-4-(1,4-dioxaspiro[4.4]nonan-6-yl) butanoate (9e). [α]D24
=
1
91.6 (c 1.0, CHCl3); H NMR δ 7.65–7.63 (2H, m), 7.44–7.29
(6H, m), 7.19–7.17 (2H, m), 3.91–3.81 (5H, m), 1.94–1.81 (4H,
m), 1.74–1.57 (4H, m), 1.44 (9H, s), 1.42–1.21 (3H, m); 13C
NMR δ 171.6, 169.8, 139.8, 136.8, 130.1, 128.8, 128.4, 128.3,
127.9, 118.2, 80.7, 66.3, 64.6, 64.4, 46.0, 35.8, 32.5, 31.6, 29.4,
28.1, 25.4, 20.6; IR (neat) 2953, 1732, 1148, 1030 cm−1; HRMS
(ESI-TOF) Calcd for C28H36NO4: 450.2639 ([M + H]+), Found:
450.2619 ([M + H]+).
Determination of the enantiomeric excess of 10e
The enantiomeric excess of 10e was determined by HPLC analy-
sis after conversion to the corresponding benzamide. Daicel
Chiralpak AS-H, hexane/2-propanol = 10/1, flow rate 1.0 mL
min−1, λ = 254 nm, retention time: 16.4 min (major) and
22.3 min (minor). [α]D20 = 41.6 (c 0.7, CHCl3, 99% ee); 1H NMR
(toluene-d8, 80 °C) δ 7.15–7.13 (2H, m), 6.89–6.86 (3H, m),
Diastereo-mixture of (2R,6R)-tert-butyl 5,6-dimethyl-piperi-
dine-2-carboxylate (10d). (2R,5R,6R)/(2R,5S,6R) = 2.5/1. 1H
Org. Biomol. Chem.
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4.68 (1H, br), 4.04 (1H, br), 1.88–1.84 (1H, m), 1.73–1.65 (2H,
m), 1.57–1.51 (1H, m), 1.27 (3H, br), 1.12 (9H, s), 1.06–0.92
(4H, m); 13C NMR δ 174.6, 174.4, 141.6, 140.4, 131.2, 129.9,
83.8, 60.2, 57.2, 39.6, 33.1, 31.8, 30.9, 28.1, 27.7, 24.4; IR
(neat) 1726, 2972, 1726, 1603, 1414, 1368, 1153 cm−1; HRMS
(ESI-TOF) Calcd for C20H28NO3: 330.2064 ([M + H]+), Found:
330.2069 ([M + H]+).
(2H, m), 3.92–3.79 (5H, m), 1.94–1.80 (4H, m), 1.74–1.58 (4H,
m), 1.44 (9H, s), 1.42–1.40 (1H, m), 1.30–1.15 (4H, m); 13C
NMR δ 171.57, 171.56, 169.68, 169.66, 139.73, 139.71, 136.78,
136.75, 130.1, 130.0, 128.7, 128.37, 128.35, 128.32, 127.90,
127.85, 127.83, 127.82, 118.17, 118.15, 80.8, 66.1, 66.0, 64.52,
64.47, 64.4, 46.04, 45.96, 35.7, 34.0, 33.9, 29.4, 29.3, 28.7,
28.5, 28.0, 24.71, 24.67, 20.6; IR (neat) 2947, 1732, 1622,
1368, 1287, 1150 cm−1
;
HRMS (ESI-TOF) Calcd
for C29H38NO4: 464.2795 ([M + H]+), Found: 464.2796
([M + H]+).
6-(2-Bromoethyl)-1,4-dioxaspiro[4.5]decane (8f). The title
compound was prepared by a similar method described in the lit-
erature.4 1H NMR δ 3.99–3.91 (4H, m), 3.55–3.49 (1H, m),
3.45–3.38 (1H, m), 2.28–2.15 (1H, m), 1.81–1.76 (3H, m),
1.72–1.59 (3H, m), 1.49–1.43 (1H, m), 1.39–1.25 (3H, m); 13C
NMR δ 110.4, 64.7, 64.5, 43.2, 34.5, 32.9, 32.3, 29.1, 24.5,
(2R,5aR,8aR)-tert-Butyl decahydrocyclopenta[b]azepine-2-car-
1
boxylate (10g). [α]2D3 = −6.7 (c 1.2, CHCl3); H NMR δ 3.59
(1H, app t), 2.75–2.70 (1H, m), 2.44–2.42 (1H, m), 2.04–1.51
(11H, m), 1.45 (9H, s), 1.26–1.15 (1H, m), 1.12–1.02 (1H, m);
13C NMR δ 174.3, 80.9, 63.2, 60.5, 50.2, 34.3, 33.2, 32.6, 32.4,
23.6; IR (neat) 2978, 3335, 2978, 1713, 1524, 1221, 1117 cm−1
.
Diastereo-mixture of (2R)-tert-butyl 2-(diphenylmethylene-
28.0, 23.7, 21.6; IR (neat) 2930, 1724, 1368, 1225, 1155 cm−1
;
amino)-4-(1,4-dioxaspiro[4.5]decan-6-yl) butanoate (9f).
1
HRMS (ESI-TOF) Calcd for C14H26NO2: 240.1952 ([M + H]+),
Found: 240.1958 ([M + H]+).
(2R,4R)/(2R,4S) = 1/1. [α]2D2 = 87.9 (c 1.0, CHCl3); H NMR
δ 7.66–7.63 (2H, m), 7.44–7.29 (6H, m), 7.20–7.16 (2H, m),
3.93–3.81 (5H, m), 2.00–1.97 (1H, m), 1.81–1.65 (3H, m),
1.62–1.59 (2H, m), 1.50–1.47 (1H, m), 1.45 (4.5H, s), 1.44
(4.5H, s), 1.44–1.41 (2H, m), 1.34–1.18 (4H, m); 13C NMR
δ 171.7, 171.6, 169.8, 169.5, 139.9, 139.8, 136.9, 136.8, 130.03,
130.01, 128.77, 128.75, 128.42, 128.36, 128.28, 128.26, 128.0,
127.93, 127.91, 127.98, 110.83, 110.80, 82.0, 80.7, 66.7, 66.3,
64.8, 64.7, 64.64, 64.61, 44.43, 44.39, 34.9, 34.8, 31.9, 31.8,
29.2, 29.0, 28.1, 24.7, 24.6, 24.52, 24.49, 23.9, 23.8, 21.8; IR
(neat) 2932, 1732, 1368, 1150 cm−1; HRMS (ESI-TOF)
Calcd for C29H38NO4: 464.2795 ([M + H]+), Found: 464.2785
([M + H]+).
Determination of the enantiomeric excess of (2R,5aR,8aR)-
tert-butyl decahydrocyclopenta[b]azepine-2-carboxylate (10g).
The enantiomeric excess of 10g was determined by HPLC analy-
sis after conversion to the corresponding benzamide. Daicel
Chiralpak OD-H, hexane/2-propanol = 50/1, flow rate 0.5 mL
min−1, λ = 254 nm, retention time: 13.8 min (minor) and
16.8 min (major); [α]D23 = −5.6 (c 1.1, CHCl3, 90% ee); 1H
NMR (toluene-d8, 80 °C) δ 7.51–7.48 (2H, m), 7.19–7.12 (2H,
m), 7.08–7.06 (1H, m), 5.04 (1H, br), 4.06–3.99 (1H, m), 2.79
(1H, br), 2.30–1.92 (3H, m), 1.85–1.81 (1H, m), 1.76–1.42 (6H,
m), 1.42 (9H, s), 1.29–1.09 (2H, m); 13C NMR δ 175.0, 174.1,
142.1, 140.4, 132.1, 130.0, 84.0, 69.2, 64.1, 46.3, 36.6, 35.5,
35.3, 35.2, 31.0, 27.5, 24.4; IR (neat) 2930, 1728, 1639, 1404,
1327, 1155 cm−1; HRMS (ESI-TOF) Calcd for C21H30NO3:
344.2220 ([M + H]+), Found: 344.2211 ([M + H]+).
Determination of the enantiomeric excess of 10f
The enantiomeric excess of 10f was determined by HPLC analy-
sis after conversion to the corresponding benzamide. Daicel
Chiralpak AS-H, hexane/2-propanol = 10/1, flow rate 1.0 mL
min−1, λ = 254 nm, retention time: 13.6 min (major) and
16.5 min (minor). [α]D19 = 67.1 (c 1.0, CHCl3, 99% ee); 1H NMR
(toluene-d8, 80 °C) δ 7.59–7.57 (1H, m), 7.30–7.23 (3H, m),
7.17–7.15 (1H, m), 5.05 (1H, br), 4.45 (1H, br), 2.46 (1H, d, J =
12.4 Hz), 2.28–2.27 (1H, m), 2.12–2.01 (2H, m), 1.88–1.73
(3H, m), 1.67–1.54 (2H, m), 1.51 (9H, s), 1.33–1.23 (4H, m);
13C NMR δ 174.2, 174.1, 141.4, 140.4, 131.2, 129.9, 83.9, 58.0,
55.9, 39.3, 38.0, 35.8, 34.9, 30.9, 30.1, 29.3, 24.7; IR (neat)
2930, 1724, 1638, 1411, 1368, 1325, 1153 cm−1; HRMS
(ESI-TOF) Calcd for C21H29NNaO3: 366.2040 ([M + H]+),
Found: 366.2033 ([M + H]+).
(R,Z)-tert-Butyl 2-(diphenylmethyleneamino)-6,6-dimethoxy-4-
methylhex-4-enoate (14). Daicel Chiralpak OD-H, hexane/2-pro-
panol = 50/1, flow rate 0.5 mL min−1, λ = 254 nm, retention
time: 17.2 min (minor) and 23.4 min (major). [α]1D9 = 82.2
(c 0.9, CHCl3; 92% ee); 1H NMR δ 7.65–7.62 (2H, m),
7.46–7.28 (6H, m), 7.18–7.14 (2H, m), 5.30 (1H, dd, J = 6.4,
0.8 Hz), 4.95 (1H, d, J = 6.4 Hz), 4.07 (1H, dd, J = 8.3, 5.1 Hz),
3.26 (3H, s), 3.15 (3H, s), 2.68–2.56 (2H, m), 1.52 (3H, d, J =
1.2 Hz), 1.45 (9H, s); 13C NMR δ 171.0, 170.0, 139.6, 138.1,
136.4, 130.1, 128.8, 128.5, 128.3, 127.94, 127.91, 124.9, 100.1,
81.2, 64.7, 52.6, 51.5, 43.4, 28.0, 17.1; IR (neat) 2367, 1734,
1150, 1053 cm−1; HRMS (ESI-TOF) Calcd for C26H34NO4:
424.2482 ([M + H]+), Found: 424.2465 ([M + H]+).
6-(3-Bromopropyl)-1,4-dioxaspiro[4.4]nonane (8g). The title
compound was prepared by a similar method described in the lit-
erature.1 1H NMR δ 3.94–3.86 (4H, m), 3.45–3.36 (2H, m),
1.95–1.82 (4H, m), 1.80–1.54 (5H, m), 1.40–1.30 (2H, m); 13C
NMR δ 118.0, 64.5, 64.4, 45.4, 35.7, 34.1, 31.6, 29.5, 27.7,
20.6; IR (neat) 2876, 2953, 2876, 1450, 1209, 1142, 1110,
(2R,4S)-tert-Butyl 4-methylpiperidine-2-carboxylate (15). [α]D21
1
= 8.8 (c 0.4, CHCl3; 92% ee); H NMR δ 3.18 (1H, dd, J =
11.7, 2.7 Hz), 3.16–3.11 (1H, m), 2.60 (1H, td, J = 12.5,
2.7 Hz), 1.99–1.93 (1H, m), 1.63–1.48 (2H, m), 1.46 (9H, s),
1.05–0.95 (2H, m), 0.94 (3H, d, J = 6.4 Hz); 13C NMR δ 172.6,
80.8, 59.6, 45.8, 38.1, 34.7, 31.3, 28.0, 22.4; IR (neat) 2949,
2924, 1732, 1368, 1269, 1161 cm−1; HRMS (ESI-TOF)
Calcd for C11H22NO2: 200.1645 ([M + H]+), Found: 200.1641
([M + H]+).
1028 cm−1
.
(R)-tert-Butyl 2-(diphenylmethyleneamino)-5-(1,4-dioxaspiro
[4.4]nonan-6-yl)pentanoate (9g). [α]2D3 = 70.2 (c 0.7, CHCl3);
1H NMR δ 7.65–7.63 (2H, m), 7.46–7.29 (6H, m), 7.18–7.16
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This work was supported by a Grant-in-Aid for Scientific
Research from MEXT, Japan. R.S. thanks the Japan Society for
the Promotion of Science for Young Scientists for Research
Fellowships.
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