Asymmetric Synthesis of 2-Substituted Azetidin-3-ones via Metalated SAMP/RAMP Hydrazones

Article abstract of DOI:10.1021/acs.joc.6b01284

2-Substituted azetidin-3-ones can be prepared in good yields and enantioselectivities (up to 85% ee) by a one-pot procedure involving the metalation of the SAMP/RAMP hydrazones of N-Boc-azetidin-3-one, reaction with a wide range of electrophiles, including alkyl, allyl, and benzyl halides and carbonyl compounds, followed by hydrolysis using oxalic acid.

Full text of DOI:10.1021/acs.joc.6b01284

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Note
Asymmetric Synthesis of 2-Substituted Azetidin-3-
ones via Metalated SAMP/RAMP Hydrazones
Alpa K. Pancholi, Joanna V. Geden, Guy J. Clarkson, and Michael Shipman
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01284 • Publication Date (Web): 22 Jul 2016
Downloaded from http://pubs.acs.org on July 24, 2016
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Asymmetric Synthesis of 2-Substituted Azetidin-3-ones via Metalated SAMP/RAMP Hydrazones
Alpa K. Pancholi, Joanna V. Geden, Guy J. Clarkson, and Michael Shipman*
Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, United
Kingdom.
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*E-mail: m.shipman@warwick.ac.uk
TABLE OF CONTENTS/ABSTRACT:
2-Substituted azetidin-3-ones can be prepared in good yields and enantioselectivities (up to 85% ee) by
a one-pot procedure involving the metalation of the SAMP/RAMP hydrazones of N-Boc-azetidin-3-one,
reaction with a wide range of electrophiles, including alkyl, allyl and benzyl halides and carbonyl
compounds, followed by hydrolysis using oxalic acid.
Azetidines are an important class of azaheterocyle which has attracted considerable interest in recent
years as a structural motif within drug discovery. They possess a broad range of biological activities,1
and provide a means of introducing molecular rigidity, novelty and improved pharmacological profiles
in lead optimization programmes.2 Substituted azetidines are present in several natural products and
compounds patented for pharmaceutical applications, including the marketed drug Azelnidipine,3
Penaresidin A,1b,4 antithrombotics5 and GLPG1690 (Figure 1).6 Whilst a number of methods have been
developed for the preparation of azetidines,7 only limited methods exist for the stereocontrolled
synthesis of chiral derivatives. These include rhodium or copper catalyzed N-H insertion reactions of
diazoketones derived from α-amino acids,8 gold-catalyzed oxidative cyclization of chiral N-
propagylsulfonamides,9 nickel-catalyzed cross coupling of organozinc reagents with chiral aziridines,10
lithiation-electrophilic substitution of tert-butoxythiocarbonyl (Botc) protected azetidine in the presence
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of a chiral ligand,11 through imino-aldol reactions of ester enolates with chiral aldimines,12 and via the
organocatalyzed synthesis of α-chloro aldehydes.13 These approaches either have limited scope,
involve multiple steps with low overall yield, or introduce the azetidine substituent early on in the
synthesis thereby reducing the efficiency by which structure activity (SAR) relationships can be
explored. In particular, the asymmetric routes do not provide sufficiently general methods to 2-
substituted azetidin-3-ones.
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Figure 1. Examples of biologically active 3-oxygenated azetidines
NO2
Ph
O
O
OH
Ph
N
HO
( )
7
O
O
HO
NH
H2N
N
H
Azelnidipine3
Penaresidin A1b,4
F
HO
N
O
MeO
N
N
N
H
N
H
N
N
CN
S
N
N
O
O
N
N
Br
Et
Antithrombotic5
GLPG16906
To provide both a general and short asymmetric synthesis of 2-substituted azetidin-3-ones, and thus
increase the diversity of chiral azetidine building blocks available, we decided to explore the
SAMP/RAMP hydrazone methodology developed by Enders,14 which we recently applied to the
asymmetric synthesis of 2-substituted oxetan-3-ones.15 This could allow a rather direct and efficient
access to a broad range of 2,3-disubstituted azetidines,16 and other pharmaceutically relevant nitrogen
heterocycles.17
Our proposed strategy from commercial N-Boc-azetidin-3-one is depicted in Scheme 1. The α-
lithiation and alkylation of selected N-protected azetidines is well documented, providing further
encouragement for this study.18 In this Note, we demonstrate how a variety of chiral 2-substituted
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azetidin-3-ones can be prepared in high ee in one-pot by the metalation/alkylation of the SAMP/RAMP
hydrazones derived from N-Boc-azetidin-3-one, offering a procedurally straightforward route to these
pharmaceutically relevant building blocks.
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Scheme 1. Proposed route to chiral 2-substituted azetidin-3-ones
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OMe
MeO
N
NH2
N
O
O
N
1. stereocontrolled
alkylation
N
N
M
N
metalation
∗
N
N
OMe
R
2. hydrazone
cleavage
N
Boc
Boc
Boc
Boc
The SAMP hydrazone (S)-1 was prepared in quantitative yield by treatment of SAMP with an excess of
commercially available N-Boc-azetidin-3-one at 55 °C without solvent (Table 1). The corresponding
(R)-enantiomer was made using RAMP in an identical fashion. In order to optimize the metalation of
(S)-1, a screen of different lithium bases, metalation times, solvents and concentrations was performed,
where the lithiated intermediate was quenched with deuterated methanol. The conversion of 1 to 2 was
estimated by mass spectrometry, and deuterated product 2 isolated by chromatography (Table 1).
Initial reactions using 1.1 equivalents of either tBuLi or LDA in THF indicated a higher yield of 2 using
tBuLi (entries 1 and 2, Table 1). A decrease in the metalation time to 1 h led to an increase to 73% yield
(entry 4). This finding perhaps suggests that the lithiated heterocycle has moderate stability under these
reaction conditions. By reducing the reaction concentration to 0.1 mM, and reverting to a 2 h metalation
time, a further improvement in yield to 77% was achieved (entry 6). No improvement in yield was
observed when a mixture of THF and pentane was used as solvent (entry 7). With a highest yield of
t
77% for 2 using BuLi as the base (THF, metalation time 2 h, concentration 0.1 mM, entry 6), we
n
decided to explore use of easier to handle BuLi under the same reaction conditions. Satisfyingly, this
led to a further small improvement in yield (entry 8).
Table 1. Optimization of conditions for lithiation of SAMP hydrazone (S)-1
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i. base (1.1 eq), solvent
_78 oC, time
O
N
N
55 oC, 16 h
100%
ii. D4-methanol
N
N
N
N
OMe
+
N
OMe
OMe
N
D
NH2
6
Boc
7
Boc
Boc
(S)-1
2
8
9
entry
base
tBuLi
LDA
tBuLi
tBuLi
tBuLi
tBuLi
tBuLi
solvent
time (h) conc. (mM) yield 2 (%)a conversion (%)b
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1
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8
THF
THF
THF
THF
THF
THF
2
2
3
1
1
2
2
2
0.3
0.3
0.3
0.3
0.1
0.1
0.1
0.1
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81
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84
1:1 THF: pentane
THF
nBuLi
a isolated yield after chromatography. b determined by mass spectrometry.
Having identified practical conditions for the lithiation of 1, we turned our attention to the optimization
of the yield and stereoselectivity for the subsequent alkylation step with allyl bromide An initial
.
reaction using the best lithiation conditions and 1.2 equivalents of allyl bromide gave hydrazone 3 in
66% yield after chromatography (Scheme 2). Hydrolysis of 3 using aqueous oxalic acid provided
ketone (S)-4 in 75% yield (50% over 2 steps) and 81% ee (as determined by chiral GC). The racemic
ketone 4 was prepared from achiral hydrazone 5 using the same general approach.19,20
Scheme 2. Synthesis of enantiomerically enriched and racemic N-Boc-2-allyl-azetidin-3-one (4)
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i. nBuLi (1.1 eq)
–78 oC, 2h
(CO2H)2
Et2O, H2O
RT, 16 h
N
N
O
N
N
ii. allyl bromide (1.2 eq)
–78 oC to RT
N
N
OMe
OMe
N
75%
(50%, 2 steps)
66%
Boc
Boc
Boc
7
1
3
(S)-4, 81% ee
8
9
i) nBuLi, THF, –78 °C
ii) allyl bromide
iii) (CO2H)2
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NMe2
N
N
O
47%
N
Boc
Boc
5
4, racemic
We briefly examined the use of alternative nitrogen protecting groups in this chemistry. The alternative
SAMP hydrazone 6 derived from N-benzhydrylazetidin-3-one produced 7 in low 20% yield after
hydrolysis, indicating that the Boc group is a better N-protecting group for this chemistry (Scheme 3).
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Scheme 3. Synthesis of (S)-N-benzhydryl-2-allyl-azetidin-3-one (7)
i. nBuLi (1.1 eq), –78 o
C
N
O
N
ii. allyl bromide (1.2 eq)
iii. (CO2H)2, H2O, RT
N
N
OMe
20%
Ph
Ph
Ph
Ph
(S)-7, 7%ee
6
By performing the two-step sequence from 1 to (S)-4 in one-pot, omitting isolation of the hydrazone
intermediate 3, ketone (S)-4 was prepared in comparable overall yield (48%) with no erosion of
stereoselectivity (81% ee) (entry 1, Table 2). For convenience, all subsequent reactions to optimize the
yield and enantioselectivity were performed using this one-pot method. A switch to diethyl ether as
solvent proved detrimental to the yield (entry 2), and introduction of the additive TMEDA led to a drop in ee
o
(entry 3). Performing the lithiation at a higher temperature of −40 C gave no product (entry 4), and a
change in solvent to 1:1 THF:pentane led to an improvement in selectivity but a slight decrease in yield
(entry 5). Finally, a much improved 67% yield and high ee was achieved by maintaining the reaction
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temperature at −78 °C for two hours after addition of the electrophile prior to warming to room
temperature (entry 6). Using RAMP derived (R)-1, the opposite enantiomer (R)-4 was produced in an
identical 81% ee (see Experimental).
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Table 2. Optimization of yield and ee for the formation of (S)-4
i. nBuLi (1.1 eq), solvent, temp., 2 h
ii. allyl bromide (1.2 eq), conditions, 18 h
O
ii. (CO2H)2, H2O, 20 h
N
N
N
OMe
one-pot
N
Boc
Boc
(S)-1
(S)-4
entry
solvent
THF
temp. (oC)
−78
conditions
yield (%)
ee (%)a
81
1
2
3
4
5
6
EA, −78 oC to RT
EA, −78 oC to RT
EA, −78 oC to RT
−78 oC, EA, to RT
EA, −78 oC to RT
EA, −78 oC, 2h, to RT
48
26
44
0
Et2O
−78
79
THF, TMEDAb
THF
−78
74
−78 to −40
−78
-
1:1 THF: pentane
THF
42
67
85
−78
80
aee determined by chiral GC analysis (see Supporting Information). b1.1 eq TMEDA was used. EA = electrophile added.
Having established conditions for the one-pot preparation of (S)-4 from (S)-1 in good yield and high ee,
we sought to establish the scope of the alkylation step (Table 3). A representative range of electrophiles
including alkyl, allyl and benzyl halides, benzaldehyde and acetone were screened. Satisfyingly,
additional allyl bromides were found to react in good yield and high selectivity (entries 3 and 4), as did
both primary and secondary alkyl iodides (entries 5 and 6). The stereoselectivity for each iodide was
found to reflect its steric demand, with the most hindered, (CH3)2CHI, giving the highest ee of 85%
(entry 6). A much lower ee was observed with benzyl bromide, which suggests a different mechanism
is operating with this electrophile, possibly involving electron transfer (entry 7). Reaction of the
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lithiated intermediate with acetone gave alcohol 14 in good yield and high enantioselectivity (entry 9)
although low selectivity was seen with benzaldehyde (entry 8). Preliminary attempts to make 2,2-
disubstituted derivatives by repetition of the deprotonation/alkylation sequence have not been fruitful.
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Table 3. Stereoselective synthesis of 2-substituted N-Boc-azetidin-3-ones 4, 8-13
i. nBuLi (1.1 eq), THF, _78 oC
ii. Electrophile (1.2 eq)
O
iii. (CO2H)2, H2O
N
N
N
R
OMe
N
one-pot
Boc
Boc
(S)-4, 8-14
1
entry
1
electrophile
product
yield (%)
ee (%)
CH2=CHCH2Br
CH2=CHCH2Brc
67
55
81a
2
3
81a
O
(CH3)2C=CHCH2Br
53
81a
N
Boc
8
4
5
PhCH=CHCH2Br
74
50
77b
CH3CH2CH2I
79a
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(CH3)2CHI
PhCH2Br
PhCHO
52
57
85a
33b
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OH
H
O
Ph
71%
31, 17b,d
N
Boc
13
O
OH
9
(CH3)2CO
59
78b
N
Boc
14
aee determined by chiral GC analysis. ee determined by chiral HPLC analysis. In all cases, racemic samples were prepared
b
from achiral hydrazone 5 for comparison purposes.c(R)-1 was reacted. See Supporting Information for GC and HPLC
d
conditions and chromatograms. obtained as an inseparable 3:2 mixture of diastereomers.
The absolute configuration of the major enantiomer of 14 was established by performing a Pictet-
Spengler reaction on ketone 14 with -tryptophan methyl ester, using reaction conditions developed
L
previously.21 The major ester 15 was separated from the reaction mixture in 81% yield, and was
converted to amide 16. X-ray crystal structure analysis of 16 unambiguously determined the (S)-
configuration of the azetidine C2 stereocenter of 14 (Scheme 4, Supporting Information).
Scheme 4. Determination of absolute configuration of major enantiomer of 14
CO2Me
I2, MeCN
NH2 81 oC, 18 h
CO2Me
CONHMe
O
MeNH2
EtOH, rt
NH
NH
+
S
N
OH
OH
NBoc
OH
NBoc
81%
73%
N
H
N
H
N
H
Boc
H
H
14
15
16
The stereochemical outcome of the alkylation of SAMP hydrazone (S)-1 is in accordance with previous
studies by Enders et al, and can be explained by preferential attack of a conformationally rigid and
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chelated EC=CZC-N azaenolate by the electrophile from the less sterically hindered Si face (Scheme 5).22
4
5
The sense of asymmetric induction in the other alkylations reported herein was made by analogy.
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7
8
9
Scheme 5. Proposed mechanism of formation of the major enantiomer of 14
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MeO
N
N
N
N
(S)-14
Li
N
MeO
OH
N
Boc
Boc
O
major azaenolate
EC=CZC-N
less hindered
Si face attack
In conclusion, we have developed a practical and efficient asymmetric synthesis of 2-substituted-
azetidin-3-ones in high enantiomeric excesses via a one-pot procedure involving the alkylation of the
lithiated SAMP hydrazone of N-Boc-azetidin-3-one. Reactions with allyl bromides, alkyl iodides and
carbonyl compounds were found to be high yielding (50-74% over 2 steps) and stereoselective (up to
85% ee). These products are expected to be useful in the preparation of novel 2,3-disubstituted
azetidine containing scaffolds and other heterocycles used in drug discovery programs.
EXPERIMENTAL SECTION
NMR assignments were deduced using 2D experiments (COSY, HMBC and HMQC).
(S)-3-(2-(Methoxymethyl)-N-(azetidine-3-ylidene)pyrrolidin-1-amine)-1-tert-butylcarboxylate (1)
(S)-(-)-1-Amino-2-(methoxymethyl)pyrrolidine (537 µl, 4.00 mmol) was added dropwise to N-Boc-
azetidin-3-one (822 mg, 4.80 mmol). The mixture was heated to 55 °C for 16 h, and concentrated under
reduced pressure. The residue was purified by flash column chromatography (SiO2, 3:1, hexane:ethyl
acetate) to give (S)-1 (1.13 g, 100%) as a pale yellow oil, Rf (3:1, hexane:ethyl acetate) 0.31; [α]ꢀꢁꢂ
+23.4 (c 0.12, CHCl3); υmax (film)/cm-1 2929, 2867, 1703, 1457, 1365, 1087, 940, 859, 767; δH (400
MHz, CDCl3) 4.76−4.68 (1H, m, NCHH), 4.64−4.52 (3H, m, NCHH, NCH2), 3.50 (1H, dd, J = 8.0, 4.0
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Hz, CHHOCH3), 3.44−3.39 (2H, m, CHHOCH3, NCH), 3.38 (3H, s, CH2OCH3), 3.33−3.26 (1H, m,
NCHH), 2.79 (1H, q, J = 8.0 Hz, NCHH), 1.98−1.84 (3H, m, CHH, CH2), 1.78−1.69 (1H, m, CHH),
1.46 (9H, s, C(CH3)3); δC (100 MHz, CDCl3) 156.2 (C=O), 135.9 (C=N), 80.1 (C(CH3)3), 74.9
(CH2OCH3), 65.2 (NCH), 61.4 (NCH2), 60.4 (NCH2), 59.3 (CH2OCH3), 52.5 (NCH2), 28.4 (C(CH3)3),
25.9 (CH2), 22.7 (CH2); MS (ES+) m/z 284 (MH+); HRMS (ESI/TOF-Q) m/z: [M + H]+ Calcd for
C14H26N3O3 284.1969; Found 284.1972.
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(R)-3-(2-(Methoxymethyl)-N-(azetidine-3-ylidene)pyrrolidin-1-amine)-1-tert-butylcarboxylate (1)
(R)-(+)-1-Amino-2-(methoxymethyl)pyrrolidine (269 µl, 2.00 mmol) was added dropwise to N-Boc-
azetidin-3-one (411 mg, 2.40 mmol). The mixture was heated to 55 °C for 16 h, and and concentrated
under reduced pressure. The residue was purified by flash column chromatography (SiO2, 3:1,
hexane:ethyl acetate) to give (R)-1 (540 mg, 95%) as a pale yellow oil, Rf (3:1, hexane:ethyl acetate)
0.24; [α]ꢁꢀꢃ −21.2 (c 0.11, CHCl3); υmax (film)/cm-1 2979, 2930, 2888, 2835, 1687, 1460, 1364, 1146,
1105, 941, 858, 767; δH (400 MHz, CDCl3) 4.77−4.68 (1H, m, NCHH), 4.65−4.53 (3H, m, NCHH,
NCH2), 3.54-3.46 (1H, m, CHHOCH3), 3.45−3.35 (2H, m, CHHOCH3, NCHCH2OCH3), 3.38 (3H, s,
CH2OCH3), 3.34−3.26 (1H, m, NCHHCH2), 2.79 (1H, q, J = 8.1 Hz, NCHHCH2), 1.98−1.83 (3H, m,
CHH, CH2), 1.79−1.69 (1H, m, CHH), 1.46 (9H, s, C(CH3)3); δC (125 MHz, CDCl3) 156.2 (C=O), 135.9
(C=N), 80.1 (C(CH3)3), 74.9 (CH2OCH3), 65.1 (NCH), 61.4 (NCH2), 59.3 (CH2OCH3), 52.5
(NCH2CH2), 28.3 (C(CH3)3), 25.9 (CH2), 22.7 (CH2); MS (ES+) m/z 284 (MH+); HRMS (ESI/TOF-Q)
m/z: [M + H]+ Calcd for C14H26N3O3 284.1969: Found 284.1964.
N,N-Dimethyl-N’-azetidine-3-ylidinehydrazine-1-tert-butylcarboxylate (5)
N,N-Dimethyl hydrazine (304 µl, 4.00 mmol) was added dropwise to N-Boc-azetidin-3-one (822 mg,
4.80 mmol). The mixture was heated to 65 °C for 16 h, and concentrated under reduced pressure. The
residue was purified by flash column chromatography (SiO2, 1:1, hexane:ethyl acetate) to give 5 (784
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mg, 92%) as a pale yellow oil, Rf (1:1, hexane:ethyl acetate) 0.53; υmax (film)/cm-1 2974, 2864, 1700,
1452, 1388, 1365, 1124, 1016, 940, 859, 765; δH (400 MHz, CDCl3) 4.71 (2H, t, J = 2.7 Hz, NCH2),
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4.57 (2H, t, J = 2.7 Hz, NCH2), 2.70 (6H, s, N(CH3)2), 1.46 (9H, s, C(CH3)3); δC (125 MHz, CDCl3)
156.1 (C=O), 138.4 (C=N), 80.2 (C(CH3)3), 61.6 (NCH2), 61.0 (NCH2), 45.8 (N(CH3)2), 28.3
(C(CH3)3); MS (ES+) m/z 236 (MNa+); HRMS (ESI/TOF-Q) m/z: [M + Na]+ Calcd for C10H19N3O2Na
236.1369; Found 236.1365.
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(S)-3-(2-(Methoxymethyl)-N-(azetidine-3-ylidene)pyrrolidin-1-amine)-1-benzhydryl (6)
(S)-(-)-1-Amino-2-(methoxymethyl)pyrrolidine (671 µl, 5.00 mmol) was added dropwise to 1-
benzhydrylazetidin-3-one (1.42 g, 6.00 mmol). The mixture was heated to 90 °C for 16 h, and
concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2,
3:1, hexane:ethyl acetate) to give 6 (1.76 g, 100%) as an orange oil, Rf (3:1, hexane:ethyl acetate) 0.37;
[α]ꢁꢀꢄ +33.5 (c 0.106, CHCl3); υmax (film)/cm-1 2926, 2875, 2825, 1686, 1599, 1451, 1115, 1091, 950,
742, 700; δH (400 MHz, CDCl3) 7.44 (4H, d, J = 7.6 Hz, ArH), 7.31-7.24 (4H, m, ArH), 7.23-7.16 (2H,
m, ArH), 4.53 (1H, s, NCH), 4.00 (2H, s, NCH2), 3.92 (2H, s, NCH2), 3.54-3.48 (1H, m, CHHOCH3),
3.41−3.28 (2H, m, CHHOCH3, NCHCH2), 3.36 (3H, s, CH2OCH3), 3.23−3.15 (1H, m, NCHHCH2),
2.68 (1H, q, J = 8.3 Hz, NCHHCH2), 1.96−1.85 (1H, m, CHH), 1.85−1.75 (2H, m, CH2), 1.73-1.62 (1H,
m, NCHH); δC (125 MHz, CDCl3) 142.53 (C=N), 142.51 (C, Ar), 128.6 (CH, Ar), 127.4 (CH, Ar),
127.32 (CH, Ar), 127.28 (CH, Ar), 127.25 (CH, Ar), 77.4 (NCH), 75.1 (CH2OCH3), 65.3 (NCHCH2),
64.9 (NCH2), 64.5 (NCH2), 59.3 (CH2OCH3), 53.0 (NCH2CH2), 26.0 (CH2), 22.6 (CH2); MS (ES+) m/z
350 (MH+); HRMS (ESI/TOF-Q) m/z: [M + H]+ Calcd for C22H28N3O 350.2227; Found 350.2221.
(S)-2-Allyl-1-benzyhydrylazetidin-3-one (7)
n-Butyllithium (2.35 M solution in hexanes, 187 µl, 0.44 mmol) was added dropwise to a stirred
solution of 6 (140 mg, 0.40 mmol) in anhydrous THF (4 ml) at –78 °C under nitrogen. After 2 h at –78
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°C, allyl bromide (42 µl, 0.48 mmol) was added by syringe, and the solution maintained at this
temperature for 2 h before warming slowly to RT over 18 h. Saturated aqueous oxalic acid solution (4
ml) was added and the solution stirred vigorously at RT for 20 h. The reaction mixture was diluted with
diethyl ether (50 ml) and the layers were separated. The organic layer was washed with brine (25 ml),
saturated aqueous sodium bicarbonate (25 ml), dried (MgSO4), filtered and the solvent removed in
vacuo. Purification by flash column chromatography (SiO2, 7:1, hexane: ethyl acetate) gave 7 (22 mg,
20%) as a pale yellow oil, Rf (7:1, hexane: ethyl acetate) 0.53; [α]ꢁꢀꢅ +6.50 (c 0.100, CHCl3); υmax
(film)/cm-1 3063, 2932, 2819, 1804, 1599, 1453, 1429, 920, 743, 698; δH (400 MHz, CDCl3) 7.90-6.95
(10H, m, ArH), 5.74-5.52 (1H, m, CH2CH=CH2), 5.01-4.75 (2H, m, CH2CH=CH2), 4.53 (1H, s, NCH),
4.18-3.90 (2H, m, NCHH, NCHCH2), 3.61 (1H, d, J = 16.2 Hz, NCHH), 1.96-1.80 (2H, m, NCHCH2);
δC (125 MHz, CDCl3) 204.4 (C=O), 142.5 (C, Ar), 142.3 (C, Ar), 133.3 (CH2CH=CH2), 128.7 (CH, Ar),
128.5 (CH, Ar), 128.3 (CH, Ar), 127.8 (CH, Ar), 127.4 (CH, Ar), 127.3 (CH, Ar), 117.5 (CH2CH=CH2),
84.7 (NCHCH2), 77.3 (NCH), 72.9 (NCH2), 35.0 (NCHCH2); MS (ES+) m/z 278 (MH+); HRMS
(ESI/TOF-Q) m/z: [M + H]+ Calcd for C19H20NO 278.1539; Found 278.1541; 7% ee (determined by
chiral HPLC on a Chiralpak AD-H column (0.46cm ø x 25 cm), 99:1 hexane:propan-2-ol, 0.5 ml/min, T
= 25°C, detection wavelength = 224 nm, see Supporting Information).
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Two-Step Synthesis of (S)-4:
(2S)-2-(Methoxymethyl)-N-[2-(S)-allylazetidine-3-ylidine-1-tert-butylcarboxylate]-1-pyrrolidinamine
(3)
n-Butyllithium (2.45 M solution in hexanes, 180 ꢀl, 0.44 mmol) was added dropwise to a stirred
solution of (S)-1 (113 mg, 0.40 mmol) in anhydrous THF (4 ml) at –78 °C under nitrogen. After 2 h at –
78 °C, allyl bromide (42 ꢀl, 0.48 mmol) was added by syringe, and the solution allowed to warm slowly
to room temperature over 16 h. The reaction mixture was diluted with ether (40 ml), and washed with
water (10 ml) and brine (10 ml). The organic layer was dried (MgSO4), filtered, and concentrated under
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reduced pressure. The residue was purified by flash column chromatography (SiO2, 3:1, hexane:ethyl
4
5
acetate) to give 3 (85 mg, 66%) as a pale yellow oil, Rf (3:1, hexane:ethyl acetate) 0.34; υmax (film)/cm-1
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2925, 2870, 1703, 1477, 1457, 1390, 1365, 1129, 1030, 913, 768; δH (400 MHz, CDCl3) major isomer,
5.73-5.86 (1H, m, CH2CH=CH2), 5.19-5.07 (2H, m, CH2CH=CH2), 5.01-4.91 (1H, m,
NCHCH2CH=CH2), 4.48-4.40 (1H, m, NCHH), 4.37 (1H, dd, J = 13.6, 3.4 Hz, NCHH), 3.52 (1H, dd, J
= 9.1, 4.1 Hz, CHHOCH3), 3.46-3.25 (3H, m, CHHOCH3, NCHCH2, NCHHCH2), 3.37 (3H, s,
CH2OCH3), 2.81-2.60 (1H, m, NCHHCH2), 2.66 (1H, q, J = 8.3 Hz, CHHCH=CH2), 2.55-2.46 (1H, m,
CHHCH=CH2), 2.06-1.83 (3H, m, NCHH, NCH2), 1.71-1.63 (1H, m, NCHH), 1.47 (9H, s, C(CH3)3); δC
(176 MHz, CDCl3) 155.2 (C=O), 141.8 (C=N), 132.2 (CH2CH=CH2), 118.0 (CH2CH=CH2), 79.2
(C(CH3)3), 75.1 (CH2OCH3), 72.4 (NCHCH2CH=CH2), 65.3 (NCHCH2OCH3), 58.5 (CH2OCH3), 53.0
(NCH2CH2), 33.0 (CH2CH=CH2), 27.7 (C(CH3)3), 26.0 (CH2), 22.3 (CH2), azetidine CH2 not observed;
MS (ES+) m/z 346 (MNa+); HRMS (ESI/TOF-Q) m/z: [M + Na]+ Calcd for C17H29N3O3Na 346.2101;
Found 346.2101.
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(S)-2-(Allyl-3-oxoazetidine)-1-tert-butyl carboxylate (4)
To (S)-3 (61 mg, 0.19 mmol) was added saturated aqueous oxalic acid (1.5 ml) and diethyl ether (2.5
ml), and the reaction stirred vigorously at room temperature for 18 h. The reaction mixture was diluted
with diethyl ether (50 ml), and the layers separated. The organic layer was washed with brine (25 ml),
saturated aqueous sodium bicarbonate (25 ml), dried (MgSO4), filtered and the solvent removed in
vacuo. Purification by flash column chromatography (SiO2, 7:1, hexane: ethyl acetate) gave (S)-4 (30
mg, 75%) as a pale yellow oil; Rf (7:1, hexane: ethyl acetate) 0.32; [α]ꢁꢀꢄ +55.4 (c 0.106, CHCl3); ʋmax
(film)/cm-1 3082, 2979, 2928, 1822, 1704, 1479, 1458, 1392, 1365, 1177, 1124, 923, 772; δH (400 MHz,
CDCl3) 5.91-5.73 (1H, m, CH2CH=CH2), 5.24-5.12 (2H, m, CH2CH=CH2), 5.01-4.87 (1H, m,
NCHCH2), 4.67 (1H, d, J = 16.6 Hz, NCHH), 4.47 (1H, dd, J = 16.6, 2.2 Hz, NCHH), 2.72-2.61 (1H, m,
NCHCHH), 2.61-2.51 (1H, m, NCHCHH), 1.49 (9H, s, C(CH3)3); δC (125 MHz, CDCl3) 199.9 (C=O),
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155.9 (C=O), 131.6 (CH2CH=CH2), 119.3 (CH2CH=CH2), 82.2 (NCHCH2), 80.8 (C(CH3)3), 69.1
(NCH2), 34.1 (NCHCH2), 28.3 (C(CH3)3); MS (ES+) m/z 234 (MNa+); HRMS (ESI/TOF-Q) [M + Na]+
Calcd for C11H17NO3Na 234.1101; Found 234.1093; 81% ee (determined by chiral GC analysis on a
Chrompac cyclodextrin-β-236M-19 50m x 0.25mm x 0.25µm column, T = 110°C, P = 15 psi, H2 carrier
gas, see Supporting Information).
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One-Pot Synthesis of (S)-4, 8-13: General Procedure.
n-Butyllithium (2.5 M solution in hexanes, 1.1 eq) was added dropwise to a stirred solution of (S)-1 or
(R)-1 (0.40 mmol) in anhydrous THF (4 ml) at –78 °C under nitrogen. After 2 h at –78 °C, the
electrophile (1.2 eq) was added by syringe, and the solution was stirred at –78 °C for 2 h before
warming slowly to room temperature over 18 h. Saturated aqueous oxalic acid solution (4 ml) was
added and the solution stirred vigorously at room temperature for 20 h. The reaction mixture was
diluted with diethyl ether (50 ml) and the layers separated. The organic layer was washed with brine
(25 ml), saturated aqueous sodium bicarbonate (25 ml), dried (MgSO4), filtered and the solvent removed
in vacuo. Purification by flash column chromatography gave the 2-substituted azetidin-3-ones as
detailed below.
(S)-2-(Allyl-3-oxoazetidine)-1-tert-butyl carboxylate (4)
(S)-1 (113 mg, 0.40 mmol), n-butyllithium (2.45 M solution in hexanes, 180 µl, 0.44 mmol), anhydrous
THF (4 ml) and allyl bromide (42 µl, 0.48 mmol) were reacted according to the general procedure.
Purification by flash column chromatography (SiO2, 7:1, hexane: ethyl acetate) gave (S)-4 (57 mg, 67%)
as a pale yellow oil; Rf (7:1, hexane: ethyl acetate) 0.32; [α]ꢁꢀꢄ +52.7 (c 0.112, CHCl3); ʋmax (film)/cm-1
3082, 2979, 2928, 1822, 1704, 1479, 1458, 1392, 1365, 1177, 1124, 923, 772; δH (400 MHz, CDCl3)
5.91-5.73 (1H, m, CH2CH=CH2), 5.24-5.12 (2H, m, CH2CH=CH2), 5.01-4.87 (1H, m, NCHCH2), 4.67
(1H, d, J = 16.6 Hz, NCHH), 4.47 (1H, dd, J = 16.6, 2.2 Hz, NCHH), 2.72-2.61 (1H, m, NCHCHH),
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2.61-2.51 (1H, m, NCHCHH), 1.49 (9H, s, C(CH3)3); δC (125 MHz, CDCl3) 199.9 (C=O), 155.9 (C=O),
131.6 (CH2CH=CH2), 119.3 (CH2CH=CH2), 82.2 (NCHCH2), 80.8 (C(CH3)3), 69.1 (NCH2), 34.1
(NCHCH2), 28.3 (C(CH3)3); MS (ES+) m/z 234 (MNa+); HRMS (ESI/TOF-Q) m/z: [M + Na]+ Calcd for
C11H17NO3Na 234.1101; Found 234.1093; 81% ee (determined by chiral GC analysis on a Chrompac
cyclodextrin-β-236M-19 50m x 0.25mm x 0.25µm column, T = 110°C, P = 15 psi, H2 carrier gas, see
Supporting Information).
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(R)-2-(Allyl-3-oxoazetidine)-1-tert-butyl carboxylate (4)
(R)-1 (113 mg, 0.40 mmol), n-butyllithium (2.35 M solution in hexanes, 187 µl, 0.44 mmol), anhydrous
THF (4 ml) and allyl bromide (42 µl, 0.48 mmol) were reacted according to the general procedure.
Purification by flash column chromatography (SiO2, 7:1, hexane: ethyl acetate) gave (R)-4 (46 mg,
55%) as a pale yellow oil; [α]ꢆꢀꢇ –47.4 (c 0.116, CHCl3); 81% ee (determined by chiral GC analysis on a
Chrompac cyclodextrin-β-236M-19 50m x 0.25mm x 0.25µm column, T = 110°C, P = 15 psi, H2 carrier
gas, see Supporting Information).
(S)-2-((3-Methylbut-2-en-1-yl)-3-oxoazetidine)-1-tert-butyl carboxylate (8)
(S)-1 (113 mg, 0.40 mmol), n-butyllithium (2.35 M solution in hexanes, 187 µl, 0.44 mmol), anhydrous
THF (4 ml) and 3,3-dimethylallyl bromide (56 µl, 0.48 mmol) were reacted according to the general
procedure. Purification by flash column chromatography (SiO2, 7:1, hexane: ethyl acetate) gave (S)-8
(51 mg, 53%) as a pale yellow oil, Rf (7:1, hexane: ethyl acetate) 0.39; [α]ꢁꢀꢄ +30.3 (c 0.125, CHCl3);
υ
max (film)/cm-1 2977, 2927, 1821, 1701, 1365, 1176, 1129, 856, 772; δH (400 MHz, CDCl3) 5.18 (1H, t,
J = 7.2 Hz, CH2CH=C(CH3)2), 4.94-4.86 (1H, m, NCHCH2), 4.64 (1H, d, J = 16.5 Hz, NCHH), 4.45
(1H, dd, J = 16.6, 4.1 Hz, NCHH), 2.61-2.51 (2H, m, NCHCH2), 1.72 (3H, s, CH2CH=C(CH3)(CH3)),
1.63 (3H, s, CH2CH=C(CH3)(CH3)), 1.49 (9H, s, C(CH3)3); δC (125 MHz, CDCl3) 200.6 (C=O), 155.9
(C=O), 136.3 (CH=C(CH3)2), 116.9 (CH=C(CH3)2), 82.8 (NCHCH2), 80.6 (C(CH3)3), 68.9 (NCH2),
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28.6 (NCHCH2), 28.3 (C(CH3)3), 25.9 (CH=C(CH3)(CH3)), 17.9 (CH=C(CH3)(CH3)); MS (ES+) m/z
262 (MNa+); HRMS (ESI/TOF-Q) m/z: [M + Na]+ Calcd for C13H21NO3Na 262.1414; Found 262.1415;
81% ee (determined by chiral GC analysis on a Chrompac cyclodextrin-β-236M-19 50m x 0.25mm x
0.25µm column, T = 140°C, P = 15 psi, He carrier gas, see Supporting Information).
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(S)-2-(Phenylallyl-3-oxoazetidine)-1-tert-butyl carboxylate (9)
(S)-1 (113 mg, 0.40 mmol), n-butyllithium (2.45 M solution in hexanes, 180 µl, 0.44 mmol), anhydrous
THF (4 ml) and 3-bromo-1-phenyl-1-propene (95 mg, 0.48 mmol) were reacted according to the general
procedure. Purification by flash column chromatography (SiO2, 7:1, hexane: ethyl acetate) gave (S)-9
(85 mg, 74%) as a pale yellow oil, Rf (7:1, hexane: ethyl acetate) 0.36; [α]ꢈꢀꢃ +71.3 (c 0.122, CHCl3);
ʋ
max (film)/cm-1 2976, 2929, 1822, 1699, 1494, 1391, 1365, 1129, 966, 743, 693; δH (400 MHz, CDCl3)
7.40-7.19 (5H, m, ArH), 6.51 (1H, d, J = 15.8 Hz, CH2CH=CHAr), 6.24-6.13 (1H, m, CH2CH=CH),
5.04-4.97 (1H, m, NCHCH2), 4.67 (1H, d, J = 16.6 Hz, NCHH), 4.48 (1H, dd, J = 16.6, 4.3 Hz, NCHH),
2.88-2.77 (1H, m, NCHCHH), 2.76-2.64 (1H, m, NCHCHH), 1.48 (9H, s, C(CH3)3); δC (125 MHz,
CDCl3) 199.9 (C=O), 155.9 (C=O), 136.9 (C, Ar), 134.4 (CH2CH=CH), 128.6 (CH, Ar), 127.5 (CH,
Ar), 126.3 (CH, Ar), 122.8 (CH2CH=CH), 82.4 (NCHCH2), 80.9 (C(CH3)3), 69.2 (NCH2), 33.4
(NCHCH2), 28.3 (C(CH3)3); MS (ES+) m/z 310 (MNa+); HRMS (ESI/TOF-Q) m/z: [M + Na]+ Calcd for
C17H21NO3Na 310.1414; Found 310.1412; 77% ee (determined by chiral HPLC on a Chiralcel OJ
column (0.46cm ø x 25 cm), 97:3 hexane:propan-2-ol, 0.5 ml/min, T = 25°C, detection wavelength =
254 nm, see Supporting Information).
(S)-2-(Propyl-3-oxoazetidine)-1-tert-butyl carboxylate (10)
(S)-1 (113 mg, 0.40 mmol), n-butyllithium (2.45 M solution in hexanes, 180 µl, 0.44 mmol), anhydrous
THF (4 ml) and 1-iodopropane (47 µl, 0.48 mmol) were reacted according to the general procedure.
Purification by flash column chromatography (SiO2, 7:1, hexane: ethyl acetate) gave (S)-10 (43 mg,
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50%) as a pale yellow oil, Rf (7:1, hexane: ethyl acetate) 0.41; [α]ꢈꢀꢃ +54.8 (c 0.104, CHCl3); ʋmax
(film)/cm-1 2964, 2934, 2875, 1819, 1701, 1478, 1458, 1389, 1365, 1138, 1119, 774; δH (400 MHz,
CDCl3) 4.93-4.86 (1H, m, NCHCH2), 4.68 (1H, d, J = 16.7 Hz, NCHH), 4.51 (1H, dd, J = 16.7, 4.3 Hz,
NCHH), 1.87-1.77 (2H, m, NCHCH2), 1.60-1.37 (2H, m, CH2CH2CH3), 1.49 (9H, s, C(CH3)3), 0.95
(3H, t, J = 7.3 Hz, CH2CH2CH3); δC (125 MHz, CDCl3) 201.1 (C=O), 156.3 (C=O), 82.9 (NCHCH2),
80.7 (C(CH3)3), 68.9 (NCH2), 32.4 (NCHCH2), 28.3 (C(CH3)3), 18.1 (CH2CH2CH3), 13.9
(CH2CH2CH3); MS (ES+) m/z 236 (MNa+); HRMS (ESI/TOF-Q) m/z: [M + Na]+ Calcd for
C11H19NO3Na 236.1257; Found 236.1254; 79% ee (determined by chiral GC analysis on a CP-ChiraSil-
DEX CB 25m x 0.25mm x 0.25µm column, T = 130°C, P = 18 psi, He carrier gas, see Supporting
Information).
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(S)-2-(Isopropyl-3-oxoazetidine)-1-tert-butyl carboxylate (11)
(S)-1 (113 mg, 0.40 mmol), n-butyllithium (2.45 M solution in hexanes, 180 µl, 0.44 mmol), anhydrous
THF (4 ml) and 2-iodopropane (48 µl, 0.48 mmol) were reacted according to the general procedure.
Purification by flash column chromatography (SiO2, 7:1, hexane: ethyl acetate) gave (S)-11 (44 mg,
52%) as a colourless yellow oil, Rf (7:1, hexane: ethyl acetate) 0.40; [α]ꢁꢀꢉ +85.2 (c 0.260, CHCl3); ʋmax
(film)/cm-1 2966, 2931, 2875, 1818, 1704, 1460, 1387, 1366, 1174, 1120, 776; δH (500 MHz, CDCl3)
4.76-4.71 (1H, m, NCHCH(CH3)2), 4.65 (1H, d, J = 16.7 Hz, NCHH), 4.44 (1H, dd, J = 16.7, 4.3 Hz,
NCHH), 2.17 (1H, octet, J = 6.7 Hz, NCHCH(CH3)2), 1.49 (9H, s, NCHCH(CH3)3), 1.04 (3H, d, J = 6.9
Hz, NCHCH(CH3CH3)), 1.03 (3H, d, J = 6.9 Hz, NCHCH(CH3CH3)); δC (125 MHz, CDCl3) 201.0
(C=O), 156.7 (C=O), 88.4 (NCHCH(CH3)2), 80.8 (C(CH3)3), 69.4 (NCH2), 30.0 (NCHCH(CH3)2), 28.3
(C(CH3)3), 18.2 (CH(CH3)CH3)), 17.7 (CH(CH3)CH3)); MS (ES+) m/z 236 (MNa+); HRMS (ESI/TOF-
Q) m/z: [M + Na]+ Calcd for C11H19NO3Na 236.1257; Found 236.1255; 85% ee (determined by chiral
GC analysis on a CP-ChiraSil-DEX CB 25m x 0.25mm x 0.25µm column, T = 130°C, P = 18 psi, He
carrier gas, see Supporting Information).
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(S)-1 (113 mg, 0.40 mmol), n-butyllithium (2.45 M solution in hexanes, 180 µl, 0.44 mmol), anhydrous
THF (4 ml) and benzyl bromide (57 µl, 0.48 mmol) were reacted according to the general procedure.
Purification by flash column chromatography (SiO2, 7:1, hexane: ethyl acetate) gave (S)-12 (60 mg,
57%) as a pale yellow oil, Rf (7:1, hexane: ethyl acetate) 0.31; [α]ꢈꢀꢃ +65.5 (c 0.103, CHCl3); ʋmax
(film)/cm-1 2955, 2915, 2850, 1820, 1695, 1498, 1392, 1367, 1176, 1125, 776, 717, 703; δH (400 MHz,
CDCl3) 7.33-7.17 (5H, m, ArH), 5.15-5.09 (1H, m, NCHCH2), 4.54 (1H, d, J = 16.6 Hz, NCHH), 4.05
(1H, dd, J = 16.6, 4.3 Hz, NCHH), 3.20 (1H, dd, J = 14.2, 6.4 Hz, NCHCHH), 3.11 (1H, dd, J = 14.2,
4.1 Hz, NCHCHH), 1.48 (9H, s, C(CH3)3); δC (125 MHz, CDCl3) 199.8 (C=O), 155.6 (C=O), 135.5 (C,
Ar), 129.8 (CH, Ar), 128.5 (CH, Ar), 127.0 (CH, Ar), 83.2 (NCHCH2), 80.8 (C(CH3)3), 69.0 (NCH2),
35.8 (NCHCH2), 28.3 (C(CH3)3); MS (ES+) m/z 284 (MNa+); HRMS (ESI/TOF-Q) m/z: [M + Na]+
Calcd for C15H19NO3Na 284.1257; Found 284.1266; 33% ee (determined by chiral HPLC on a
Chiralcel OD column (0.46cm ø x 25 cm), 99:1 hexane:propan-2-ol, 0.5 ml/min, T = 23°C, detection
wavelength = 254 nm, see Supporting Information).
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(S,R)- and (S,S)-2-(-Hydroxy(phenyl)methyl-3-oxoazetidine)-1-tert-butyl carboxylate (13)
(S)-1 (113 mg, 0.4 mmol), n-butyllithium (2.45 M solution in hexanes, 180 µL, 0.44 mmol), anhydrous
THF (4 mL) and benzaldehyde (49 µL, 0.48 mmol) were reacted according to the general procedure.
Purification by flash column chromatography (SiO2, 4:1, hexane: ethyl acetate) gave (S)-13 (79 mg,
71%) as a yellow oil and inseparable 1.5:1 mixture of diastereomers; Rf (4:1, hexane: ethyl acetate)
0.29; ʋmax (film)/cm-1 3414, 2978, 2927, 1824, 1678, 1455, 1393, 1367, 1171, 1145, 1119, 768, 733; δH
(500 MHz, CDCl3) 7.38-7.29 (12.5H, m, ArH,), 5.27-5.18 (1H, m, NCHCH), 5.17-5.12 (1.5H, m,
NCHCH), 5.10-5.03 (2.5H, m, NCHCH, NCHCH), 4.65 (2H, d, J = 16.5 Hz, NCHH, NCHH), 4.52 (1H,
br s, COH), 4.47 (3H, dd, J = 16.5, 3.5 Hz, NCHH, NCHH), 1.50 (9H, s, C(CH3)3), 1.44 (13.5H, s,
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C(CH3)3); δC (125 MHz, CDCl3) 195.8 (CO), 195.6 (CO), 156.9 (COO), 156.3 (COO), 138.8 (C, Ar),
138.6 (C, Ar), 128.5 (CH, Ar), 128.42 (CH, Ar), 128.40 (CH, Ar), 128.1 (CH, Ar), 126.8 (CH, Ar),
126.5 (CH, Ar), 87.8 (NCHCH), 87.7 (NCHCH), 82.0 (C(CH3)3), 81.8 (C(CH3)3), 73.4 (NCHCH), 72.6
(NCHCH), 70.0 (NCH2), 69.8 (NCH2), 28.3 (C(CH3)3), 28.1 (C(CH3)3); MS (ES+) m/z 300 (MNa+);
HRMS (ESI/TOF-Q) m/z: [M + Na]+ Calcd. for C15H19NO4Na 300.1206; Found 300.1204; 31% (major
diastereomer), 17% (minor diastereomer) ee (determined by chiral HPLC on a Chiralpak IA column
(0.46cm ø x 25 cm), 95:5 hexane:propan-2-ol, 0.5 ml/min, T = 25°C, detection wavelength = 254nm,
see Supporting Information).
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(S)-2-((2-Hydroxypropan-2-yl)-3-oxoazetidine)-1-tert-butyl carboxylate (14)
(S)-1 (113 mg, 0.40 mmol), n-butyllithium (2.35 M solution in hexanes, 187 µl, 0.44 mmol), anhydrous
THF (4 ml) and acetone (36 µl, 0.48 mmol) were reacted according to the general procedure.
Purification by flash column chromatography (SiO2, 3:1, hexane: ethyl acetate) gave (S)-14 (54 mg,
59%) as a colourless oil, Rf (3:1, hexane: ethyl acetate) 0.34; [α]ꢁꢀꢊ +38.2 (c 0.114, CHCl3); ʋmax
(film)/cm-1 3459, 2955, 2912, 2872, 2850, 1826, 1472, 1391, 1371, 1114, 1095, 717; δH (400 MHz,
CDCl3) 4.90-4.84 (1H, m, NCHCOH), 4.70 (1H, d, J = 16.6 Hz, NCHH), 4.56-4.47 (1H, m, NCHH),
1.51 (9H, s, C(CH3)3), 1.33 (3H, s, C(CH3)(CH3)OH), 1.30 (3H, s, C(CH3)(CH3)OH); δC (125 MHz,
CDCl3) 197.2 (C=O), 156.9 (C=O), 91.2 (NCHCOH), 82.0 (C(CH3)3), 71.2 (C(CH3)2OH), 70.0 (NCH2),
28.2 (C(CH3)3), 26.1 C(CH3)(CH3)OH), 24.3 (C(CH3)(CH3)OH); MS (ES+) m/z 252 (MNa+); HRMS
(ESI/TOF-Q) m/z: [M + Na]+ Calcd for C11H19NO4Na 252.1206; Found 252.1204; 78% ee (determined
by chiral HPLC on a Chiralcel OJ column (0.46cm ø x 25 cm), 9:1 hexane:propan-2-ol, 0.5 ml/min, T =
25°C, detection wavelength = 254 nm, see Supporting Information).
(2R,3S,3’S)-2-(2-Hydroxypropan-2-yl)-2’,3’,4’,9’-tetrahydrospiro[azetidine-3,1’-pyrido[3,4-
b]indole]-1-tert-butyl-3’-methyl-dicarboxylate (15)
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To a stirred solution of 14 (123 mg, 0.54 mmol) in dry CH3CN (6 ml) was added -tryptophan methyl
L
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ester (142 mg, 0.65 mmol) and I2 (6.8 mg, 0.027 mmol), and the mixture stirred at reflux for 18 h. The
reaction mixture was cooled to room temperature and the solvent removed under reduced pressure. The
residue was dissolved in EtOAc (20 ml), and washed with saturated Na2S2O3 solution (10 ml), saturated
sodium bicarbonate solution (10 ml) and brine (10 ml). The organic layer was dried (Na2SO4), filtered
and concentrated in vacuo. Purification by flash column chromatography (SiO2, 7:3, petroleum ether:
ethyl acetate) gave 15 (188 mg, 81%) as a cream solid; m.p. 118-120 °C; Rf (7:3, petroleum ether: ethyl
acetate) 0.46; [α]ꢁꢀꢂ −44.0 (c 0.100, CHCl3); ʋmax (film)/cm-1 3347, 2975, 2939, 2848, 1734, 1677, 1500,
1456, 1380, 1366, 1144, 1133, 747, 736; δH (300 MHz, CDCl3) 8.40-8.25 (1H, br s, NH), 7.49 (1H, d, J
= 7.7 Hz, ArH), 7.36 (1H, d, J = 8.0 Hz, ArH), 7.21 (1H, td, J = 7.6, 1.2 Hz, ArH), 7.15-7.10 (1H, m,
ArH), 4.56 (1H, s, NCHC(CH3)2OH), 4.09 (1H, d, J = 8.6, NCHH), 3.98 (1H, d, J = 8.7, NCHH), 3.84
(3H, s, CO2CH3), 3.70 (1H, dd, J = 11.2, 4.1 Hz, NHCHCH2), 3.11 (1H, dd, J = 15.2, 4.1 Hz,
NHCHCHH), 2.82 (1H, dd, J = 15.2, 11.2 Hz, NHCHCHH), 1.52 (9H, s, C(CH3)3), 1.49 (3H, s,
C(CH3)(CH3)OH), 1.25 (3H, s, C(CH3)(CH3)OH), piperidine NH and OH not observed; δC (125 MHz,
CDCl3) 172.9 (C=O), 158.0 (C=O), 136.4 (C, Ar), 134.2 (C, Ar), 126.7 (C, Ar), 122.6 (CH, Ar), 120.1
(CH, Ar), 118.4 (CH, Ar), 111.2 (CH, Ar), 109.3 (C, Ar), 81.2 (C(CH3)3), 77.6 (NCHC(CH3)2OH), 72.1
(NC(CH3)2OH), 63.9 (NCH2), 56.4 (NHC), 53.6 (CO2CH3), 52.4 (NHCHCH2), 28.4 (C(CH3)3), 26.4
(C(CH3)(CH3)OH), 26.3 (C(CH3)(CH3)OH), 25.2 (NHCHCH2); MS (ES+) m/z 430 (MH+); HRMS
(ESI/TOF-Q) m/z: [M + H]+ Calcd for C23H32N3O5 430.2336; Found 430.2333.
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(2R,3S,3’S)-2-(2-Hydroxypropan-2-yl)-2’,3’,4’,9’-tetrahydrospiro[azetidine-3,1’-pyrido[3,4-b]indole]-
1-tert-butyl carboxylate-3’-N-methyl carboxamide (16)
A solution of 15 (40 mg, 0.0931 mmol) and 33% methylamine in ethanol (10 ml) were stirred at room
temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the residue
purified by flash column chromatography (SiO2, ethyl acetate) to give 16 (29 mg, 73%) as a cream
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solid; m.p. 247-248 °C; Rf (ethyl acetate) 0.30; [α]ꢁꢀꢁ −91.3 (c 0.260, CHCl3); ʋmax (film)/cm-1 3291,
2972, 1657, 1393, 1366, 1133, 741; δH (500 MHz, CDCl3) 8.14 (1H, br s, NH), 7.49 (1H, d, J = 7.9 Hz,
ArH), 7.35 (1H, d, J = 8.1 Hz, ArH), 7.22 (1H, t, J = 7.5 Hz, ArH), 7.14 (1H, t, J = 7.4 Hz, ArH), 6.63-
6.58 (1H, br m, NH), 4.53 (1H, s, CHC(CH3)2OH), 4.02 (1H, d, J = 8.7 Hz, CHHN), 3.97 (1H, d, J =
8.7 Hz, CHHN), 3.55-3.50 (1H, m, NCHCO), 3.21 (1H, dd, J = 15.6, 4.4 Hz, CHHCHCO), 2.92 (3H, d,
J = 4.9 Hz, NCH3), 2.74 (1H, dd, J = 15.6, 11.3 Hz, CHHCHCO), 2.69-2.50 (1H, br s, OH), 1.51 (12H,
br s, C(CH3)3 and C(CH3)(CH3)OH), 1.26 (3H, s, C(CH3)(CH3)OH), piperidine NH not observed; δC
(125 MHz, CDCl3) 173.1 (C=O), 158.0 (C=O), 136.4 (C, Ar), 134.1 (C, Ar), 126.8 (C, Ar), 122.8 (CH,
Ar), 120.2 (CH, Ar), 118.6 (CH, Ar), 111.2 (CH, Ar), 109.6 (C, Ar), 81.4 (C(CH3)3), 77.0
(CHCMe2OH), 72.0 (CMe2OH), 63.2 (CH2N), 56.4 (CH2CNH), 55.1 (CHCO), 28.3 (C(CH3)3), 26.8
(CH3), 26.6 (CH3), 26.2 (CH3), 25.6 (CH2CHCO); MS (ES+) m/z 252 (MNa+); HRMS (ESI/TOF-Q)
m/z: [M + Na]+ Calcd for C23H32N4O4Na 451.2316; Found 451.2315.
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ASSOCIATED CONTENT
Supporting Information
1
13
Copies of H and C NMR spectra of compounds 1 and 3-16, the X-ray crystal structure of compound
16, and copies of chiral GC and HPLC chromatograms of racemic and enantiomerically enriched 4 and
7-14. This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: m.shipman@warwick.ac.uk
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGEMENTS
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We thank the EPSRC and the University of Warwick for financial support. We are grateful to Professor
Martin Wills and Dr. Roy Hodgkinson for providing advice and access to chiral GC and HPLC
instruments. The Oxford Diffraction Gemini XRD system for X-ray structure determination was
obtained, through the Science City Advanced Materials project: Creating and Characterizing Next
Generation Advanced Materials, with support from Advantage West Midlands.
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(14) For a review on SAMP/RAMP-hydrazones see: Job, A.; Janeck, C. F.; Bettray, W.; Peters, R.;
Enders, D. Tetrahedron 2002, 58, 2253.
(15) Geden, J. V.; Beasley, B. O.; Clarkson, G. J.; Shipman, M. J. Org. Chem. 2013, 78, 12243.
(16) For examples see: (a) Barré, B.; Gonnard, L.; Campagne, R.; Reymond, S.; Marin, J.; Ciapetti, P.;
Brellier, M.; Guérinot, A.; Cossy, J. Org. Lett. 2014, 16, 6160. (b) Parmar, D.; Henkel, L.; Dib, J.;
Rueping, M. Chem. Commun. 2015, 51, 2111. (c) Dobi, Z.; Holczbauer, T.; Soós, T. Org. Lett. 2015,
17, 2634.
(17) For examples see: (a) Ishida, N.; Yuhki, T.; Murakami, M. Org. Lett. 2012, 14, 3898. (b) Ho, K. Y.
T.; Aïssa, C. Chem. Eur. J. 2012, 18, 3486. (c) Kumar, P.; Louie, J. Org. Lett. 2012, 14, 2026. (d)
Ishida, N.; Shimamoto, Y.; Yano, T.; Murakami, M. J. Am Chem. Soc. 2013, 135, 19103. (e) Thakur,
A.; Facer, M. E.; Louie, J. Angew. Chem. Int. Ed. 2013, 52, 12161.
(18) (a) Hodgson, D. M.; Kloesges, J. Angew. Chem. Int. Ed. 2010, 49, 2900. (b) Parisi, G.; Capitanelli,
E.; Pierro, A.; Romanazzi, G.; Clarkson, G. J.; Degennaro, L.; Luisi, R. Chem. Comm. 2015, 51, 15588.
(c) Jackson, K. E.; Mortimer, C. L.; Odell, B.; McKenna, J. M.; Claridge, T. D. W.; Paton, R. S.;
Hodgson, D. M. J. Org. Chem. 2015, 80, 9838. (d) Rayner, P. J.; Smith, J. C.; Denneval, C.; O’Brien,
P.; Clarke, P. A.; Horan, R. A. J. Chem. Comm. 2016, 52, 1354.
(19) The overall yield of racemic ketone 4 prepared by the two-step alkylation/hydrolysis sequence from
achiral hydrazone 5 was found to be lower (47%). We speculate that the methoxy group of SAMP
hydrazone 1 aids metalation via a complex-induced proximity effect (CIPE).
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(20) Attempts to form racemic 4 by direct formation of the enolate of N-Boc-azetidin-3-one with BuLi
at ˗78 oC, with subsequent trapping with allyl bromide, gave the carbinol as a result of direct addition of
the organolithium to the ketone.
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(21) Beasley, B. O.; Alli-Balogun, A.; Clarkson, G. J.; Shipman, M. Tetrahedron Lett. 2014, 55, 541.
(22) (a) Hazelard, D.; Fadel, A. Tetrahedron: Asymmetry 2005, 16, 2067. (b) Koch, R. Org. Biomol.
Chem. 2011, 9, 2885.
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