Stereocontrolled preparation of diversely trifunctionalized cyclobutanes

Article abstract of DOI:10.1021/acs.joc.9b01463

The expedient and stereoselective syntheses of small libraries of trifunctionalized cyclobutane scaffolds bearing an acid, an amine, and a third functional group are described. Starting from a single precursor, the readily available protected derivative of all-cis-2-amino-3-hydroxycyclobutane-1-carboxylic acid, cis-trans stereoisomers are obtained following an S_N2-type reaction, while all-trans stereoisomers are obtained using the same strategy preceded by a C1 epimerization reaction.

Full text of DOI:10.1021/acs.joc.9b01463

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Note
Stereocontrolled Preparation of Diversely Tri-Functionalized Cyclobutanes
Zong Chang, Régis Guillot, Thomas Boddaert, and David J. Aitken
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01463 • Publication Date (Web): 24 Jul 2019
Downloaded from pubs.acs.org on July 27, 2019
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Stereocontrolled Preparation of Diversely Tri-Functionalized
Cyclobutanes
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Zong Chang, Régis Guillot, Thomas Boddaert,* and David J. Aitken*
CP3A Organic Synthesis Group & Services Communs, ICMMO, CNRS UMR 8182, Université Paris Sud,
Université Paris Saclay, 15 rue Georges Clemenceau, 91405 Orsay Cedex, France.
david.aitken@u-psud.fr, thomas.boddaert@u-psud.fr
Toc graphic & Abstract
The expedient and stereoselective syntheses of small libraries of tri-functionalized cyclobutane scaffolds
bearing an acid, an amine and a third functional group are described. Starting from a single precursor, the
readily available protected derivative of all-cis-2-amino-3-hydroxycyclobutane-1-carboxylic acid, cis-trans
stereoisomers are obtained following an SN2 type reaction, while all-trans stereoisomers are obtained using
the same strategy preceded by a C1 epimerization reaction.
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Cyclobutanes are of wide-ranging interest in organic chemistry.1 These four-membered rings are present in
the structures of many natural products and in a large panel of synthetic compounds used in medicinal
chemistry,2 and they are high-value intermediates in organic synthesis, due to their inherent ring strain and
their resulting reactivity.3 While some noteworthy late-stage functionalization strategies have been
described,4 most of the currently used synthetic methodologies for the preparation of multiply-
functionalized cyclobutanes employ precursors which provide the required functional group suite before or
during the construction of the cyclobutane ring.5 In this respect, photochemical [2+2]-cycloaddition
strategies are among the most powerful synthetic tools available.6
Functionalized cyclic β-amino acids7 are valuable building blocks for the constructions of more complex
molecular architectures such as biologically active molecules,8 peptidomimetics and foldamers.9,10 We have
previously reported several syntheses of cyclobutane β-amino acid derivatives using photochemical
approaches.11,12,13 Those studies provided access to 2-aminocyclobutane-1-carboxylic acid (ACBC)
derivatives with a variety of substituents at the C1 or C2 positions,11d but so far the only C3 or C4-
substituted ACBCs which have been accessed feature a hydroxymethyl11b,c or a hydroxy11a functional group.
In order to expand the inventory of ring-substituted ACBCs, we considered that the protected derivative of
all-cis-2-amino-3-hydroxycyclobutane-1-carboxylic acid 1 was a promising intermediate. This compound can
be prepared in diastereomerically pure form on multigram scale from maleimide and t-butyl vinyl ether in
only two steps.11a In the present paper, we describe the selective transformations of 1 into small libraries of
both cis-trans and all-trans-ACBC scaffolds featuring thiol, amine, azide or halogen substituents at the 3-
position. An overview of the strategy is outlined in Scheme 1: after protecting group adjustment and
activation, cis-trans compounds would be obtained by SN2 type displacement of a leaving group at C3, while
C1 epimerization followed by SN2 displacement at C3 would lead to all-trans compounds.
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Scheme 1. Synthetic strategy for the target molecules.
We first required the preparation of all-cis and trans-cis alcohols 3 and 5. Multigram scale esterification of
starting material 1 provided compound 2 in 95 % yield. Compound 3 was obtained efficiently from 2 on a
large scale by performing double N,O-deprotection using TFA followed by selective reprotection of the
amine using di-tert-butyl dicarbonate (88 % yield for two steps on 6.2 g scale). In order to access
compounds with a trans-cis geometry, C1 epimerization of 2 was carried out. After considerable
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experimentation (see Table S1 in the Supporting Information), compound 4 was obtained in 62 % yield (4.0
g scale) by treating 2 with 30 equiv. of sodium methoxide (0.01 M in methanol) for two days, followed by
quenching using an anhydrous methanol solution of acetic acid. Following this process, 30 % of unreacted 2
was recovered and recycled. The two-step N,O-deprotection/N-reprotection sequence was then applied to
compound 4 to afford the trans-cis alcohol 5 in 87 % yield (2.1 g scale) for two steps (Scheme 2). We
examined an alternative pathway and applied the epimerization conditions to derivative 3. After two days,
no trace of the starting material 3 was observed. Unfortunately, the target epimerized product 5 was
accompanied by unidentified degradation products (see Scheme S1 in the Supporting Information). Based
on these investigations, the preferred two-step access to compound 5 from substrate 2 proceeds via
intermediate 4.
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Scheme 2. Preparation of the starting materials 3 and 5.
We then focused our attention on the central objective of introducing a new functional group at C3 in a
stereoselective manner, for which a Mitsunobu reaction appeared to be the method of choice.14 Employing
triphenylphosphine and diisopropyl azodicarboxylate (DIAD) as standard reagents, some experimentation
was required to determine the optimal conditions for each nucleophile, but we were able to establish
efficient procedures for the installation of oxygen, sulfur and nitrogen functions using para-nitrobenzoic
acid (entries 1-2, left), thiobenzoic acid (entries 3-4, left) and diphenylphosphorylazide (DPPA) (entries 5-6,
left), respectively. In this way, the transformations of alcohols 3 and 5 provided cis-trans derivatives 6a-c
and all-trans derivatives 7a-c in high yields (78-93 %), as unique diastereoisomers in every case. Treatment
of each ester 6a-b and 7a-b with potassium carbonate solution in methanol furnished the corresponding
alcohols 8a, 9a and thiols 8b, 9b in very high yields (90-95 %) (entries 1-4, right). In order to generate
derivatives bearing an amine substituent, azides 6c and 7c were hydrogenolysed for 2 h under a hydrogen
atmosphere in the presence of palladium on charcoal to provide 8c and 9c in high yields (96-98 %) (entries
5-6, right) (Table 1).
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Table 1. Two steps sequence for the synthesis of compounds 8a-c and 9a-c
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Entry
Subst.
3
Reaction 1
6 or 7
Yield 1a
Reaction 2
8 or 9
Yield 2a
p-NO2C6H4CO2H, Ph3P,
DIAD, THF, 23 °C, 8 h
6a
80 %
K2CO3, MeOH,
23 °C, 20 min
8a
94 %
1b
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p-NO2C6H4CO2H, Ph3P,
DIAD, THF, 23 °C, 8 h
7a
83 %
K2CO3, MeOH,
23 °C, 20 min
9a
90 %
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5
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5
PhCOSH, Ph3P, DIAD,
THF, 23 °C, 6 h
6b
78 %
K2CO3, MeOH,
23 °C, 20 min
8b
95 %
PhCOSH, Ph3P, DIAD,
THF, 23 °C, 6 h
7b
82 %
K2CO3, MeOH,
23 °C, 20 min
9b
91 %
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DPPA, Ph3P, DIAD,
THF, 50 °C, 3 h
6c
90 %
H2, Pd/C, MeOH,
23 °C, 2 h
8c
96 %
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DPPA, Ph3P, DIAD,
THF, 50 °C, 3 h
7c
93 %
H2, Pd/C, MeOH,
23 °C, 2 h
9c
98 %
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a Isolated yields. b Ar : p-NO2C6H4.
Confirmation of the anticipated inversion of configuration during the Mitsunobu reaction was provided by
single crystal X-ray diffraction analysis of compounds 6a and 7a. The cis-trans geometry of the former and
the all-trans geometry of the latter are illustrated in Figure 1.
Figure 1. X-ray crystal structures of compounds 6a and 7a
With these collections of protected 3-substituted ACBCs in hand, we investigated the deprotection of the β-
amino acid suite. For each of the compounds 6c, 7c, 8a,c, and 9a,c hydrolysis of the ester function was
performed using lithium hydroxide in tetrahydrofuran then the tert-butoxycarbonyl group was removed
using TFA in dichloromethane; the resulting amino acids were isolated after passage through a column of
Dowex® cation exchange resin. This two-step protocol, which can be performed in less than 2 hours,
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successfully provided the unprotected cis-trans ACBCs 10a,c,d with 3-hydroxy, 3-amino and 3-azido
substituents, respectively, as well as the corresponding all-trans amino acids 11a,c,d. The procedure was
likewise applied to the trans-cis intermediate 4 to provide 12a (a longer reaction time was required for the
second step). For all of these examples, isolated yields of amino acids were uniformly high (83-96 %).
Surprisingly, hydrolysis in acidic or basic conditions of thiol derivatives 6b to 9b resulted in extensive
degradation. Consequently, the corresponding thio amino acids could not be obtained successfully (Scheme
3).
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Scheme 3. Synthesis of free amino acids 10 to 13
Compound 13a was also prepared from starting material 1 by acid-mediated N,O-deprotection,11a meaning
that this strategy provides satisfying access to all diastereoisomers of 2-amino-3-hydroxycyclobutane-1-
carboxylic acid (10a to 13a). Furthermore, the panel of products prepared using the above-described
protocols demonstrates that any stereoisomer of protected 2-aminocyclobutane-1-carboxylic acid bearing
an additional alcohol, thiol, amine, or azide at the C3 position can be achieved starting from the
appropriate stereoisomer of a common intermediate (3 or 5).
Halogen derivatives are ideally-adapted synthetic intermediates for the installation of other functional
groups via substitution reactions, organometallic reagents or transition metal coupling reactions. To
increase the scope of our strategy for the preparation of tri-substituted cyclobutanes, we sought to replace
the alcohol group of starting materials 3 and 5 with a bromine or an iodine atom. To provide access to
halogen derivatives 14 and 15, we considered the Appel reaction,15 and gratifyingly the desired cis-trans
and all-trans iodo-derivatives 14e and 15e were obtained in 34 % and 80 % yields respectively, employing
PPh3, imidazole and I2 (entries 1-2). The corresponding bromo-derivatives 14f and 15f were also synthesized
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in 65 % and 30 % yields, respectively, using PPh3, tetra-n-butylammonium bromide (TBAB) and CBr4 (entries
3-4, Table 2).
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Table 2. Synthesis of compounds 14e-f and 15e-f.
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Entry Subst.
Conditions
14 or 15
Yielda
Ph3P, imidazole, I2,
toluene, reflux, 2 h
14e
34 %
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5
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5
Ph3P, imidazole, I2,
toluene, reflux, 2 h
15e
80 %
Ph3P, TBAB, CBr4,
THF, 23 °C, 16 h
14f
65 %
Ph3P, TBAB, CBr4,
THF, 23 °C, 16 h
15f
30 %
a Isolated yields.
To conclude, the divergent strategy established in this study employed a single, readily-available starting
material, all-cis-2-amino-3-hydroxycyclobutane-1-carboxylic acid in a protected form, to access diversely
substituted tri-functionalized cyclobutane scaffolds in a stereoselective manner. Using either a Mitsunobu
reaction or an Appel reaction, hydroxy, thio, amine, azide and halogen functions were installed
stereoselectively and efficiently at the C3 position of a cyclobutane ring bearing protected C1 acid and C2
amine groups. The cis-trans stereoisomers were obtained by a stereospecific SN2 type reaction conducted
on the all-cis starting material, while the all-trans stereoisomers were prepared from the trans-cis
intermediate, itself obtained by C1 epimerization of the all-cis starting material. The above procedures
provide a useful expansion of the inventory of cyclic β-amino acids.
EXPERIMENTAL SECTION
General Experimental. All reagents and solvents were of commercial grade and were used without further
purification, with the exception of dichloromethane which was dried over activated alumina, THF which
was distilled from sodium/benzophenone, acetonitrile which was distilled from P2O5, triethylamine which
was distilled on potassium hydroxide. Methanol extra dry Acrosseal® was purchased from Acros. Flash
chromatography was performed on 35–70 μm columns of silica gel (Merk-Chimie SAS). Analytical thin-layer
chromatography was carried out on commercial 0.25 mm silica gel plates (EMD, Silica Gel 60F254) which
were visualized by UV fluorescence at 254 nm then revealed using a phosphomolybdic acid solution (10 %
in EtOH) or a ninhydrin solution (0.3 % in n-BuOH). Retention factors (Rf) are given for such TLC analyses.
Melting points were determined with a Büchi B-545 apparatus in open capillary tubes and are uncorrected.
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Fourier-transform Infrared (IR) spectra were recorded for neat samples on a FT-IR PerkinElmer Spectrum
Two spectrophotometer using an ATR diamond accessory; maximum absorbances (ν) are given (in cm-1).
Nuclear magnetic resonance (NMR) data were acquired on spectrometers operating at 360/300/250 MHz
1
for H and at 90/75/63 MHz for 13C{1H}. Chemical shifts () are reported in ppm with respect to
1
tetramethylsilane ( = 0 ppm). Splitting patterns for H NMR and 13C{1H} NMR signals are designated as: s
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(singlet), d (doublet), t (triplet), q (quartet), quint (quintuplet), br. s (broad singlet), app. (apparent) or m
(multiplet). Coupling constants (J) are reported in Hz. High-resolution mass spectrometry (HRMS) data were
recorded on a Bruker Daltonics MicroTOF-Q spectrometer equipped with an electrospray ionization source
either in positive or negative mode as appropriate, with a tandem Q-TOF analyzer. Details on X-ray
diffraction analysis data are given in the Supporting Information.
General procedure A for deprotection of tert-butyl and Boc group followed by Boc reprotection.
Compound 2 or 4 (1.0 equiv.) was dissolved in neat TFA (2 mL/mmol) at 0 °C. The mixture was stirred for 2
h, during this period the temperature was raised to room temperature slowly. After a completely
evaporation of TFA, the residue was diluted with THF (10 mL/mmol), then Et3N (2.15 equiv.) and Boc2O (1.1
equiv.) in THF (2 mL/mmol) were added successively at 0 °C. The mixture was stirred at room temperature
overnight. The mixture was diluted with H2O and extracted with Et2O. The combined organic phrases were
washed with HCl (1 M), saturated NaHCO3 solution, brine successively and dried over MgSO4. The solvents
were evaporated under reduced pressure, and the residue was purified by flash chromatography to afford
the desired product 3 or 5.
General procedure B for Mitsunobu reaction. To a solution of ester 3 or 5 in anhydrous THF (20 mL/mmol),
PPh3 (2.0 or 3.0 equiv.), DIAD (2.0 or 3.0 equiv.) and the nucleophile (2.0 or 3.0 equiv.) were added
successively at 0 °C and the temperature was raised to room temperature slowly. The reaction was
followed by TLC analyses and stirred at the appropriate temperature (using an oil bath) and time as
indicated in Table 1. The solvent was evaporated under reduced pressure, and the residue was purified by
flash chromatography to afford the desired product 6a,b,c or 7a,b,c.
General procedure C for methanolysis reaction. To a methanol solution (10 mL/mmol) of compound 6a,b
or 7a,b (1.0 equiv.), K2CO3 (1.5 equiv.) was added in one portion at 0 °C, then the mixture was stirred at
room temperature for 20 minutes. The reaction was quenched with HCl (1 M) and after a careful
evaporation of methanol, the residue was diluted with ethyl acetate, and then washed with H2O, brine
successively and dried over MgSO4. The solvent was evaporated under reduced pressure and the residue
was purified by flash chromatography to afford the desired product 8a,b or 9a,b.
General procedure D for hydrogenolysis reaction. To a methanol solution of compound 6c or 7c, Pd/C (10
%) was added. The mixture was stirred under hydrogen atmosphere at room temperature for 2 h, after a
filtration on a pad of Celite®, the filtrate was concentrated by evaporation to afford the product 8c or 9c.
General procedure E for saponification and Boc deprotection process. To a THF/H2O (1:1) solution (30
mL/mmol) of compound 1, 4, 6c, 7c, 8a,c or 9a,c (1.0 equiv.), LiOH monohydrate (1.0 equiv.) was added in
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one portion at room temperature and stirred for 1 h. After a careful removal of THF, the reaction mixture
was acidified with HCl (1 M) (pH ~ 4) and extracted with ethyl acetate. The combined organic extracts were
washed with H2O, brine successively and dried over MgSO4 and the solvent was evaporated under reduced
pressure. The resulting residue was dissolved in dichloromethane (5 mL/mmol), TFA (30 equiv.) was added
at 0 °C and the reaction mixture was stirred for 30 minutes at room temperature (or for the appropriate
time). Then solvents were evaporated under reduced pressure and the residue was applied to a column of
Dowex® 50W-X8 cation exchange resin (200-400 mesh) activated with HCl (3 M) and eluted using 1 M
NH4OH to afford the free amino acid 10a,c,d, 11a,c,d, 12a or 13a.
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General procedure F for iodination reaction. To a solution of methyl ester 3 or 5 (1.0 eq) in toluene, I2 (1.5
equiv.), imidazole (3.0 equiv.) and PPh3 (2.0 equiv.) were added successively. The mixture was stirred for 2
h under reflux in an oil bath. The solvent was evaporated under reduced pressure and the residue was
purified by flash chromatography to afford the methyl ester 14e or 15e.
General procedure G for bromination reaction. To a solution of methyl ester 3 or 5 (1.0 equiv.) in
anhydrous THF (16 mL/mmol), CBr4 (2.0 equiv.), PPh3 (2.0 equiv.), and TBAB (10 %) were added
successively. The mixture was stirred for 16 h at room temperature. The solvent was evaporated under
reduced pressure and the residue was purified by flash chromatography to afford the methyl ester 14f or
15f.
(±)-cis-cis-Methyl 3-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylate 2. To
a
solution of protected cis-ACBC 111a (1.44 g, 5.0 mmol) and MeOH (0.61 mL, 15 mmol) in dichloromethane,
DMAP (61 mg, 0.50 mmol) and DCC (1.24 g, 6.0 mmol) were added at 0 °C and the mixture was stirred for 1
h at this temperature. After warming up to room temperature, the reaction mixture was stirred for 20 h.
After filtration, the solvent was removed under reduced pressure, EtOAc was added and washed with 1 M
HCl solution, brine, 5 % NaHCO3 solution, brine successively. The solvent was evaporated under reduced
pressure and the residue was purified by flash chromatography (Et2O/petroleum ether, 40/60) to afford the
desired ester 2 (1.43 g, 95 %) as a white solid. Rf (Et2O/petroleum ether, 50/50): 0.53; Mp: 80-81 °C; IR ν
1
3446, 2973, 1717, 1485, 1362, 1154; H NMR (360 MHz, CDCl3) δ 5.36 (d, J = 6.5 Hz, 1H), 4.43-4.31 (m, 1H),
4.20 (app. dd, J = 15.2, 7.3 Hz, 1H), 3.57 (s, 3H), 2.89 (dt, J = 10.4, 7.3 Hz, 1H), 2.38 (td, J = 11.2, 8.8 Hz, 1H),
2.25 (dtd, J = 11.5, 7.5, 3.6 Hz, 1H), 1.36 (s, 9H), 1.10 (s, 9H); 13C{1H} NMR (90 MHz, CDCl3) δ 171.7, 155.6,
79.3, 74.6, 63.0, 55.6, 51.7, 37.1, 32.4, 28.3 (3C), 28.0 (3C); HRMS (ESI-TOF) m/z: [M+Na]+ calcd for
+
C15H27NNaO5 : 324.1781; Found: 324.1786.
(±)-cis-cis-Methyl 2-((tert-butoxycarbonyl)amino)-3-hydroxycyclobutane-1-carboxylate 3. Followed the
general procedure A, using methyl ester 2 (6.16 g, 20.5 mmol), TFA (35 mL), Et3N (6.2 mL, 44.1 mmol) and
Boc2O (4.91g, 22.5 mmol). Flash chromatography (EtOAc/petroleum ether, 60/40) afforded the desired
product 3 (4.42 g, 88 %) as a white solid. Rf (EtOAc/petroleum ether, 50/50): 0.43; Mp: 81-82 °C; IR ν 3468,
1
3353, 2956, 1735, 1161, 1530, 1337, 1276, 1248, 1150; H NMR (360 MHz, CDCl3) δ 5.70-5.34 (m, 1H), 4.40-
4.18 (m, 2H), 4.07-4.86 (m, 1H), 3.58 (s, 3H), 3.11 (app. dd, J = 14.6, 7.4 Hz, 1H), 2.36-2.25 (m, 1H), 2.19-2.05
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(m, 1H), 1.30 (s, 9H); 13C{1H} NMR (90 MHz, CDCl3) δ 174.2, 155.6, 79.6, 66.9, 52.0 (2C), 39.8, 30.9, 28.1 (3C);
+
HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C11H19NNaO5 : 268.1155; Found: 268.1156.
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(±)-trans-cis-Methyl 3-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylate 4. To a
freshly prepared NaOMe solution in methanol (0.4 M, 1 L), a solution of methyl ester 2 (4.0 g, 13.3 mmol) in
methanol (100 mL) was added at 0 °C. The mixture was stirred at room temperature for 48 h. The reaction
mixture was then poured into cold (0 °C) mixture of acetic acid (114 mL) and dry methanol (114 mL). After
evaporation of the solvents under reduced pressure, the residue was diluted with H2O and extracted with
Et2O. The combined organic phases was washed with H2O, brine and was dried over MgSO4 and
evaporated. The residue was purified by flash chromatography (EtOAc/petroleum ether, 30/70) to afford
the methyl ester 4 (2.46 g, 62 %) as a white solid and recovered substrate 2 (1.20 g, 30 %). Rf
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(Et2O/petroleum ether, 50/50): 0.66; Mp: 46-47 °C; IR ν 3435, 2974, 1711, 1487, 1364, 1245; H NMR (250
MHz, CDCl3) δ 5.36-5.18 (m, 1H), 4.36-4.22 (m, 1H), 4.22-3.96 (m, 1H) 3.56 (s, 3H), 2.84 (dt, J = 10.3, 5.2 Hz,
1H), 2.32-2.13 (m, 1H), 1.99 (ddd, J = 12.3, 10.3, 5.2 Hz, 1H), 1.31 (s, 9H), 1.04 (s, 9H); 13C{1H} NMR (63 MHz,
CDCl3) δ 174.3, 155.0, 79.2, 74.6, 65.7, 53.5, 51.7, 42.9, 31.8, 28.2 (3C), 28.0 (3C); HRMS (ESI-TOF) m/z:
+
[M+Na]+ calcd for C15H27NNaO5 : 324.1781; Found: 324.1779.
(±)-trans-cis-Methyl 2-((tert-butoxycarbonyl)amino)-3-hydroxycyclobutane-1-carboxylate 5. Followed the
general procedure A, using methyl ester 4 (1.95 g, 6.48 mmol), TFA (13.0 mL), Et3N (1.93 mL, 13.9 mmol)
and Boc2O (1.58 g, 6.48 mmol). Flash chromatography (MeOH/CH2Cl2, 10/90) afforded the methyl ester 5
(2.89 g, 87 %) as a white solid. Rf (EtOAc/petroleum ether, 50/50): 0.45; Mp: 81-82 °C; IR ν 3314, 3248,
1
2955, 1731, 1670, 1539, 1285, 1158; H NMR (360 MHz, CDCl3) δ 5.57 (br. d, J = 6.9 Hz, 1H), 4.39 (br. t, J =
5.2 Hz, 1H), 4.30-4.05 (m, 1H), 4.02-3.76 (m, 1H), 3.62 (s, 3H), 3.25-3.06 (m, 1H), 2.27-2.15 (m, 1H), 1.99-
1.90 (m, 1H), 1.35 (s, 9H); 13C{1H} NMR (90 MHz, CDCl3) δ 174.2, 155.5, 79.9, 68.1, 51.9 (2C), 44.1, 29.8, 28.3
+
(3C); HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C11H19NNaO5 : 268.1155; Found: 268.1148.
(±)-cis-trans-2-((tert-Butoxycarbonyl)amino)-3-(methoxycarbonyl)cyclobutyl
4-nitrobenzoate
6a.
Followed the general procedure B, using methyl ester 3 (0.98 g, 4.0 mmol), PPh3 (3.14 g, 12 mmol), DIAD
(2.41 mL, 12 mmol) and p-nitrobenzoic acid (2.0 g, 12 mmol). The reaction was stirred for 8 h. Flash
chromatography (EtOAc/petroleum ether, 30/70) afforded the desired product 6a (1.26 g, 80 %) as a white
solid. Rf (Et2O/petroleum ether, 40/60): 0.25; Mp: 122-124 °C; IR ν 3348, 2984, 1713, 1680, 1515, 1331,
1
1264, 1250, 1161, 1118, 1104, 1066, 1014, 721; H NMR (360 MHz, CDCl3) δ 8.23-8.17 (m, 2H), 8.16-8.10
(m, 2H), 5.65 (br. d, J = 8.8 Hz, 1H), 5.45 (app. q, J = 8.2 Hz, 1H), 4.56 (dd, J = 16.8, 8.2 Hz, 1H), 3.68 (s, 3H),
3.36 (app. br. t, J = 8.8 Hz, 1H), 2.51 (app. br. t, J = 9.6 Hz, 1H), 2.10 (dt, J = 12.0, 9.6 Hz, 1H), 1.35 (s, 9H);
13C{1H} NMR (90 MHz, CDCl3) δ 173.9, 163.8, 154.7, 150.6, 134.9, 130.9 (2C), 123.5 (2C), 79.9, 73.7, 52.8,
+
52.2, 38.5, 28.2 (3C), 27.0; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C18H22N2NaO8 : 417.1268; Found:
417.1254.
(±)-trans-trans-2-((tert-Butoxycarbonyl)amino)-3-(methoxycarbonyl)cyclobutyl
4-nitrobenzoate
7a.
Followed the general procedure B, using methyl ester 5 (245 mg, 1.0 mmol), PPh3 (786 mg, 3.0 mmol), DIAD
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(0.59 mL, 3.0 mmol) and p-nitrobenzoic acid (501 mg, 3.0 mmol). The reaction was stirred for 8 h. Flash
chromatography (EtOAc/petroleum ether, 30/70) afforded the desired product 7a (329 mg, 83 %) as a
white solid. Rf (EtOAc/petroleum ether, 30/70): 0.40; Mp: 116-118 °C; IR ν 3346, 2982, 1722, 1683, 1522,
1262, 1154, 1098; 1H NMR (360 MHz, CDCl3) δ 8.25-8.19 (m, 2H), 8.18-8.12 (m, 2H), 5.75-5.40 (m, 1H), 5.33-
5.06 (m, 1H), 4.27 (app. q, J = 7.7 Hz, 1H), 3.68 (s, 3H), 3.00-2.65 (m, 1H), 2.57 (dt, J = 11.2, 8.2 Hz, 1H), 2.09
(td, J = 10.2, 8.2 Hz, 1H), 1.36 (s, 9H); 13C{1H} NMR (90 MHz, CDCl3) δ 172.9, 164.1, 154.8, 150.6, 134.9,
130.9 (2C), 123.6 (2C), 79.9, 70.9, 56.1, 52.2, 37.7, 28.3 (3C), 26.8; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for
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+
C18H22N2NaO8 : 417.1268; Found: 417.1248.
(±)-cis-trans-Methyl
3-(benzoylthio)-2-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylate
6b.
Followed the general procedure B, using methyl ester 3 (0.98 g, 4.0 mmol), PPh3 (2.1 g, 8.0 mmol), DIAD
(1.61 mL, 8.0 mmol) and thiobenzoic acid (0.94 mL, 8.0 mmol). The reaction was stirred for 6 h. Flash
chromatography (EtOAc/petroleum ether, 20/80) afforded the desired product 6b (1.15 g, 78 %) as a white
solid. Rf (Et2O/petroleum ether, 50/50): 0.50; Mp: 133-134 °C; IR ν 3368, 2952, 1741, 1697, 1656, 1517,
1
1207, 1166, 1158, 909; H NMR (360 MHz, CDCl3) δ 7.88-7.80 (m, 2H), 7.53-7.46 (m, 1H), 7.42-7.33 (m, 2H),
5.76-5.50 (m, 0.9H), 5.45-5.22 (m, 0.1H), 4.60-4.25(m, 2H), 3.70 (s, 3H), 3.55-3.36 (m, 1H), 2.56-2.47 (m,
1H), 2.15-1.95 (m, 1H), 1.37 (s, 9H); 13C{1H} NMR (90 MHz, CDCl3) δ 191.1, 173.6, 154.7, 136.5, 133.6, 128.6
(2C), 127.3 (2C), 79.7, 52.7, 52.0, 43.4, 42.1, 28.2 (3C), 26.5; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for
C18H23NNaO5S+: 388.1189; Found: 388.1177.
(±)-trans-trans-Methyl 3-(benzoylthio)-2-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylate 7b.
Followed the general procedure B, using methyl ester 5 (245 mg, 1.0 mmol), PPh3 (524 mg, 2.0 mmol), DIAD
(0.40 mL, 2.0 mmol) and thiobenzoic acid (0.24 mL, 2.0 mmol). The reaction was stirred for 6 h. Flash
chromatography (EtOAc/petroleum ether, 20/80) afforded the desired compound 7b (298 mg, 82 %) as a
white solid. Rf (EtOAc/petroleum ether, 30/70): 0.65; Mp: 117-119 °C; IR ν 3346, 2986, 1722, 1687, 1669,
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1522, 1284, 1206, 1145; H NMR (360 MHz, CDCl3) δ 7.92-7.82 (m, 2H), 7.56-7.47 (m, 1H), 7.42-7.33 (m,
2H), 5.53 (d, J = 7.2 Hz, 1H), 4.40-4.05 (m, 2H), 3.67 (s, 3H), 3.22-2.95 (m, 1H), 2.51 (dt, J = 10.5, 8.4 Hz, 1H),
2.03 (app. q, J = 10.5 Hz, 1H), 1.38 (s, 9H); 13C{1H} NMR (90 MHz, CDCl3) δ 191.7, 172.6, 154.7, 136.4, 133.6,
128.6 (2C), 127.3 (2C), 79.7, 55.9, 52.0, 44.2, 39.4, 28.3 (3C), 26.3; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for
C18H23NNaO5S+: 388.1189; Found: 388.1169.
(±)-cis-trans-Methyl 3-azido-2-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylate 6c. Followed the
general procedure B, using methyl ester 3 (0.49 g, 2.0 mmol), PPh3 (1.57 g, 6.0 mmol), DIAD (1.2 mL, 6.0
mmol) and DPPA (1.3 mL, 6.0 mmol). The reaction was stirred at 50 °C for 3 h (using an oil bath). Flash
chromatography (EtOAc/petroleum ether, 20/80) afforded the desired product 6c (0.49 g, 90 %) as a white
solid. Rf (Et2O/petroleum ether, 30/70): 0.40; Mp: 133-134 °C; IR ν 3310, 2984, 2091, 1728, 1685, 1529,
1
1335, 1161; H NMR (300 MHz, CDCl3) δ 5.60-5.21 (m, 1H), 4.42-4.16 (m, 1H), 4.06 (app. q, J = 8.8 Hz, 1H),
3.68 (s, 3H), 3.26 (app. br. t, J = 8.8 Hz, 1H), 2.33-2.22 (m, 1H), 2.06-1.82 (m, 1H), 1.39 (s, 9H); 13C{1H} NMR
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(75 MHz, CDCl3) δ 174.1, 154.5, 80.1, 60.9, 52.4, 52.2, 39.5, 28.3 (3C), 25.9; HRMS (ESI-TOF) m/z: [M+Na]+
+
calcd for C11H18N4NaO4 : 293.1220; Found: 293.1212.
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(±)-trans-trans-Methyl 3-azido-2-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylate 7c. Followed
the general procedure B, using methyl ester 5 (245 mg, 1.0 mmol), PPh3 (0.79 g, 3.0 mmol), DIAD (0.60 mL,
3.0 mmol) and DPPA (0.65 mL, 3.0 mmol). The reaction was performed at 50 °C for 3 h (using an oil bath).
Flash chromatography (EtOAc/petroleum ether, 20/80) afforded the desired product 7c (0.25 g, 93 %) as a
white solid. Rf (EtOAc/petroleum ether, 25/75): 0.40; Mp: 94-95 °C; IR ν 3362, 2983, 2082, 1728, 1681,
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1526, 1254, 1228, 1155; H NMR (360 MHz, CDCl3) δ 5.95-5.68 (m, 0.3H), 5.56-5.14 (m, 0.7H), 4.12-3.82 (m,
1.7H), 3.72-3.50 (m, 0.3H), 3.66 (s, 3H), 3.05-2.83 (m, 0.7H), 2.73-2.50 (m, 0.3H), 2.33 (dt, J = 11.2, 8.1 Hz,
1H), 1.86 (app. q, J = 10.2 Hz, 1H), 1.39 (s, 9H); 13C{1H} NMR (90 MHz, CDCl3) δ 172.7, 154.9, 80.1, 57.4, 55.8,
52.2, 38.4, 28.3 (3C), 25.6; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C11H18N4NaO4 : 293.1220; Found:
+
293.1211.
(±)-cis-trans-Methyl 2-((tert-butoxycarbonyl)amino)-3-hydroxycyclobutane-1-carboxylate 8a. Followed
the general procedure C, using racemic methyl ester 6a (976 mg, 2.48 mmol), K2CO3 (171 mg, 1.24 mmol).
Flash chromatography (EtOAc/petroleum ether, 50/50) afforded the desired product 8a (571 mg, 94 %) as a
white solid. Rf (EtOAc/petroleum ether, 50/50): 0.30; Mp: 85-86 °C; IR ν 3368, 2979, 1692, 1511, 1364,
1250, 1160, 1046; 1H NMR (300 MHz, CDCl3) δ 5.85-5.20 (m, 1H), 4.32 (app. q, J = 8.2 Hz, 1H), 4.23-4.07 (m,
1H), 4.06-3.90 (m, 1H), 3.65 (s, 3H), 3.16 (app. br. t, J = 8.7 Hz, 1H), 2.28 (app. br. t, J = 10.1 Hz, 1H), 1.84
(app. q, J = 10.1 Hz, 1H), 1.38 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 174.7, 155.4, 79.9, 72.0, 55.8, 51.9,
+
36.9, 29.4, 28.3 (3C); HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C11H19NNaO5 : 268.1155; Found: 268.1151.
(±)-trans-trans-Methyl 2-((tert-butoxycarbonyl)amino)-3-hydroxycyclobutane-1-carboxylate 9a. Followed
the general procedure C, using methyl ester 7a (58 mg, 0.15 mmol), K2CO3 (10 mg, 0.07 mmol). Flash
chromatography (EtOAc/petroleum ether, 60/40) afforded the alcohol 9a (33 mg, 90 %) as a white solid. Rf
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(EtOAc/petroleum ether, 60/40): 0.35; Mp: 114-115 °C; IR ν 3360, 1729, 1681, 1521, 1369, 1153, 1015; H
NMR (250 MHz, CDCl3) δ 5.62-5.42 (m, 0.2H), 5.26-4.95 (m, 0.8H), 4.05 (app. q, J = 7.5 Hz, 1H); 3.96-3.78 (m,
1H), 3.69 (s, 3H), 3.49-2.95 (m, 1H), 2.61-2.29 (m, 2H), 1.88 (dd, J = 19.2, 9.9 Hz, 1H), 1.42 (s, 9H); 13C{1H}
NMR (63 MHz, CDCl3) δ 173.4, 155.7, 80.2, 69.4, 59.0, 52.2, 36.2, 29.3, 28.5 (3C); HRMS (ESI-TOF) m/z:
+
[M+Na]+ calcd for C11H19NNaO5 : 268.1155; Found: 268.1150.
(±)-cis-trans-Methyl 2-((tert-butoxycarbonyl)amino)-3-mercaptocyclobutane-1-carboxylate 8b. Followed
the general procedure C, using methyl ester 6b (73 mg, 0.20 mmol), K2CO3 (41 mg, 0.30 mmol). Flash
chromatography (EtOAc/petroleum ether, 20/80) afforded the desired product 8b (49 mg, 95 %) as a white
solid. Rf (EtOAc/petroleum ether, 20/80): 0.40; Mp: 114-115 °C; IR ν 3316, 2979, 1725, 1687, 1526, 1345,
1
1198, 1155, 1060; H NMR (250 MHz, CDCl3) δ 5.57-4.97 (m, 1H), 4.35-3.99 (m, 1H), 3.70 (s, 3H), 3.64-3.48
(m, 1H), 3.41 (app. t, J = 8.7 Hz, 1H), 2.44 (app. td, J = 10.5, 1.6 Hz, 1H), 1.97-1.74 (m, 2H), 1.42 (s, 9H);
13C{1H} NMR (90 MHz, CDCl3) δ 174.2, 154.8, 79.9, 56.8, 52.1, 42.9, 39.9, 31.0, 28.3 (3C); HRMS (ESI-TOF)
m/z: [M+Na]+ calcd for C11H19NNaO4S+: 284.0927; Found: 284.0921.
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(±)-trans-trans-Methyl
2-((tert-butoxycarbonyl)amino)-3-mercaptocyclobutane-1-carboxylate
9b.
Followed the general procedure C, using methyl ester 7b (100 mg, 0.27 mmol), K2CO3 (57 mg, 0.41 mmol).
Flash chromatography (EtOAc/petroleum ether, 20/80) afforded the title compound 9b (65 mg, 91 %) as a
white solid. Rf (EtOAc/petroleum ether, 25/75): 0.40; Mp: 99-101 °C; IR ν 3349, 2983, 1724, 1681, 1526,
1
1371, 1228, 1155; H NMR (360 MHz, CDCl3) δ 5.60-4.97 (m, 1H), 4.00-3.75 (m, 1H), 3.65 (s, 3H), 3.47-3.23
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(m, 0.8H), 3.20-2.95 (m, 1H), 3.92-2.69 (m, 0.2H), 2.46 (dd, J = 19.5, 8.8 Hz, 1H), 1.85 (d, J = 9.3 Hz, 1H), 1.79
(app. q, J = 10.6 Hz, 1H), 1.39 (s, 9H); 13C{1H} NMR (90 MHz, CDCl3) δ 172.7, 154.9, 79.9, 60.4, 52.0, 42.7,
36.6, 30.5, 28.3 (3C); HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C11H19NNaO4S+: 284.0927; Found: 284.0913.
(±)-cis-trans-Methyl 3-amino-2-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylate 8c. Followed the
general procedure D, using methyl ester 6c (195 mg, 0.72 mmol), Pd/C (10 %) (77 mg, 0.072 mmol).
Compound 8c (168 mg, 96 %) was obtained as a colorless sticky oil. Rf (EtOAc): 0.12; IR ν 3372, 2979, 1704,
1
1501, 1364, 1246, 1161; H NMR (360 MHz, CDCl3) δ 5.56-5.35 (m, 1H), 3.94 (app. q, J = 8.6 Hz, 1H), 3.64 (s,
3H), 3.52 (app. q, J = 8.9 Hz, 1H), 3.15 (br. t, J = 8.6 Hz, 1H), 2.25 (br. t, J = 9.7 Hz, 1H), 1.73 (br. s, 2H), 1.59
(app. q, J = 9.7 Hz, 1H), 1.37 (s, 9H); 13C{1H} NMR (90 MHz, CDCl3) δ 174.8, 155.2, 79.6, 56.6, 55.1, 51.9, 38.5,
+
30.0, 28.4 (3C); HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C11H20N2NaO4 : 267.1315; Found: 267.1309.
(±)-trans-trans-Methyl 3-amino-2-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylate 9c. Followed
the general procedure D, using methyl ester 7c (100 mg, 0.37 mmol), Pd/C (10 %) (39 mg, 0.037 mmol).
Methyl ester 9c (89 mg, 98 %) was obtained as a colorless sticky oil. Rf (EtOAc): 0.08; IR ν 3355, 2979, 1694,
1
1521, 1365, 1253, 1162, 1023; H NMR (360 MHz, CDCl3) δ 6.45-6.25 (m, 0.3H), 6.08-5.82 (m, 0.7H), 5.27
(br. s, 2H), 4.05-3.75 (m, 1H), 3.58 (s, 3H), 3.67-3.30 (m, 1H), 2.90-2.45 (m, 1H), 2.43-2.16 (m, 1H), 1.95-1.60
(m, 1H), 1.31 (s, 9H); 13C{1H} NMR (90 MHz, CDCl3) δ 173.3, 155.4, 79.6, 56.6, 51.9, 50.1, 39.1, 28.3 (3C),
+
27.1; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C11H20N2NaO4 : 267.1315; Found: 267.1303.
(±)-cis-trans-2-Amino-3-hydroxycyclobutane-1-carboxylic acid 10a. Followed the general procedure E
using methyl ester 8a (380 mg, 1.55 mmol), LiOH monohydrate (65 mg, 1.55 mmol), TFA (3.7 mL, 48.2
mmol). Free amino acid 10a (180 mg, 88 %) was obtained as a white solid. Mp: 102-103 °C (degradation); IR
ν 2951, 1520, 1387, 1113; 1H NMR (360 MHz, D2O) δ 4.43-4.34 (m, 1H), 3.59 (t, J = 8.1 Hz, 1H), 2.94-2.85 (m,
1H), 2.25 (ddd, J = 11.1, 9.0, 1.9 Hz, 1H), 2.01 (td, J = 11.1, 9.0 Hz, 1H), COOH, OH and NH2 are not observed;
13C{1H} NMR (90 MHz, D2O (with one drop of dioxane)) δ 180.5, 68.0, 53.3, 33.6, 31.1; HRMS (ESI-TOF) m/z:
+
[M+H]+ calcd for C5H10NO3 : 132.0655; Found: 132.0658.
(±)-trans-trans-2-Amino-3-hydroxycyclobutane-1-carboxylic acid 11a. Followed the general procedure E,
using methyl ester 9a (153 mg, 0.62 mmol), LiOH monohydrate (26 mg, 0.62 mmol), TFA (1.59 mL, 20.8
mmol). Free amino acid 11a (74 mg, 91 %) was obtained as a white solid. Mp: 116-118 °C degradation; IR ν
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3373, 3035, 2490, 2235, 1560, 1400; H NMR (360 MHz, D2O) δ 4.10-3.95 (m, 1H), 3.58-3.45 (m, 1H), 2.55-
2.40 (m, 2H), 1.76-7.63 (m, 1H), COOH, OH and NH2 are not observed; 13C{1H} NMR (90 MHz, D2O (with one
+
drop of dioxane)) δ 179.5, 65.2, 56.2, 36.6, 30.8; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C5H10NO3 :
132.0655; Found: 132.0657.
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(±)-cis-trans-2,3-Diaminocyclobutane-1-carboxylic acid 10c. Followed the general procedure E, using
methyl ester 8c (46 mg, 0.19 mmol), LiOH monohydrate (8.0 mg, 0.19 mmol), TFA (0.5 mL, 6.5 mmol). After
the saponification step, solvent was removed and the residue was used for the deprotection step directly.
Free amino acid 10c (23 mg, 95 %) was obtained as a pale yellow solid. Mp: 119-120 °C (degradation); IR ν
2947, 1534, 1383, 1113; 1H NMR (300 MHz, D2O) δ 3.86 (app. q, J = 8.6 Hz, 1H), 3.73 (t, J = 8.4 Hz, 1H), 3.11
(app. br. t, J = 8.6 Hz, 1H), 2.33 (app. br. t, J = 10.3 Hz, 1H), 2.06 (app. q, J = 9.7 Hz, 1H), COOH and both NH2
are not observed; 13C{1H} NMR (75 MHz, D2O (with one drop of dioxane)) δ 180.1, 52.0, 51.1, 39.2, 26.7;
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HRMS (ESI-TOF) m/z: [M+H]+ calcd for C5H11N2O2 : 131.0815; Found: 131.0817.
(±)-trans-trans-2,3-Diaminocyclobutane-1-carboxylic acid 11c. Followed the general procedure E, using
methyl ester 9c (100 mg, 0.41 mmol), LiOH monohydrate (17.2 mg, 0.41 mmol), TFA (1.05 mL, 13.7 mmol).
After the saponification step, the solvent was removed and the residue was used for the deprotection step
directly. Free amino acid 11c (50 mg, 94 %) was obtained as a white solid. Mp: 133-135 °C degradation; IR ν
1
2914, 2170, 1543, 1391; H NMR (360 MHz, D2O) δ 3.45 (t, J = 8.2 Hz, 1H), 3.34 (dd, J = 17.1, 8.2 Hz, 1H),
2.56 (dt, J = 9.9, 8.6 Hz, 1H), 2.41 (dt, J = 10.7, 8.6 Hz, 1H), 1.71 (ddd, J = 11.1, 10.1, 9.3 Hz, 1H), COOH and
both NH2 are not observed; 13C{1H} NMR (90 MHz, D2O (with one drop of dioxane)) δ 180.4, 55.8, 48.9, 42.7,
+
26.4; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C5H11N2O2 : 131.0815; Found: 131.0818.
(±)-cis-trans-2-Amino-3-azidocyclobutane-1-carboxylic acid 10d. Followed the general procedure E, using
methyl ester 6c (200 mg, 0.74 mmol), LiOH monohydrate (31 mg, 0.74 mmol), TFA (1.9 mL, 24.8 mmol).
Free amino acid 10d (96 mg, 83 %) was obtained as a white solid. Mp: 101-102 °C (degradation); IR ν 2705,
2105, 1558, 1406, 1255; 1H NMR (300 MHz, D2O) δ 4.33 (app. q, J = 8.7 Hz, 1H), 3.83 (t, J = 8.4 Hz, 1H), 3.13-
3.01 (m, 1H), 2.42 (ddd, J = 11.7, 9.0, 2.6 Hz, 1H), 2.29 (dt, J = 11.7, 9.7 Hz, 1H), COOH and NH2 are not
observed; 13C{1H} NMR (75 MHz, D2O (with one drop of dioxane)) δ 179.8, 57.3, 50.4, 35.8, 28.0; HRMS (ESI-
+
TOF) m/z: [M+H]+ calcd for C5H9N4O2 : 157.0720; Found: 157.0720.
(±)-trans-trans-2-Amino-3-azidocyclobutane-1-carboxylic acid 11d. Followed the general procedure E,
using methyl ester 7c (54 mg, 0.20 mmol), LiOH monohydrate (8.4 mg, 0.20 mmol), TFA (0.82 mL, 10.8
mmol). Free amino acid 11d (28 mg, 92 %) was obtained as a white solid. Mp: 178-179 °C (degradation); IR
1
ν 2594, 2096, 1556, 1413, 1244; H NMR (360 MHz, D2O) δ 3.94 (dd, J = 16.8, 8.4 Hz, 1H), 3.74 (t, J = 8.6 Hz,
1H), 2.77 (dd, J = 19.1, 9.0 Hz, 1H), 2.67-2.56 (m, 1H), 1.93 (ddd, J = 11.1, 10.2, 9.0 Hz, 1H), COOH and NH2
are not observed; 13C{1H} NMR (90 MHz, D2O and CD3OD (with one drop of dioxane)) δ 178.7, 54.2, 53.6,
+
38.8, 27.4; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C5H8N4NaO2 : 179.0539; Found: 179.0537.
(±)-trans-cis-2-amino-3-hydroxycyclobutane-1-carboxylic acid 12a. Followed the general procedure E,
using methyl ester 4 (150 mg, 0.50 mmol), LiOH monohydrate (21 mg, 0.5 mmol), TFA (1.25 mL, 16.5
mmol), 15 hours was needed instead of 30 min after addition of TFA. Free amino acid 12a (62 mg, 95 %)
1
was obtained as a white solid. Mp: 126-128 °C (degradation); IR ν 3099, 2853, 2325, 1536, 1400; H NMR
(300 MHz, D2O) δ 4.49-3.37 (m, 1H), 3.87 (t, J = 6.3 Hz, 1H), 3.19 (dd, J = 17.7, 8.5 Hz, 1H), 2.38-2.12 (m, 2H),
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COOH, OH and NH2 are not observed; 13C{1H} NMR (90 MHz, D2O (with one drop of dioxane)) δ 180.5, 64.2,
-
51.2, 43.0, 31.0; HRMS (ESI-TOF) m/z: [M-H]- calcd for C5H8NO3 : 130.0510; Found: 130.0507.
5
6
7
8
(±)-cis-trans-Methyl 2-((tert-butoxycarbonyl)amino)-3-iodocyclobutane-1-carboxylate 14e. Followed the
general procedure F, using methyl ester 3 (0.98 g, 4.0 mmol), I2 (1.52 g, 6.0 mmol), imidazole (0.82 g, 12
mmol) and PPh3 (2.1 g, 8.0 mmol). Flash chromatography (Et2O/petroleum ether, 25/75) afforded the
desired product 14e (0.49 g, 34 %) as a white solid. Rf (Et2O/petroleum ether, 25/75): 0.35; Mp: 141-143 °C;
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IR ν 3311, 2984, 1730, 1682, 1526, 1340, 1283, 1198, 1169; H NMR (360 MHz, CDCl3) δ 5.56-5.15 (m, 1H),
4.74-4.58 (m, 1H), 4.51 (app. q, J = 9.2 Hz, 1H), 3.69 (s, 3H), 3.52-3.38 (m, 1H), 2.64-2.43 (m, 1H), 2.36 (app.
dd, J = 21.6, 9.8 Hz, 1H), 1.41 (s, 9H); 13C{1H} NMR (90 MHz, CDCl3) δ 173.9, 154.4, 80.2, 56.7, 52.3, 47.6,
31.2, 28.3 (3C), 17.0; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C11H18INNaO4 : 378.0173; Found: 378.0159.
+
(±)-trans-trans-Methyl 2-((tert-butoxycarbonyl)amino)-3-iodocyclobutane-1-carboxylate 15e. Followed
the general procedure F, using methyl ester 5 (245 mg, 1.0 mmol), I2 (381 mg, 1.5 mmol), imidazole (204
mg, 3.0 mmol) and PPh3 (524 mg, 2.0 mmol). Flash chromatography (EtOAc/petroleum ether, 10/90)
afforded the desired product 15e (285 mg, 80 %) as a white solid. Rf (Et2O/petroleum ether, 50/50): 0.4;
1
Mp: 120-121 °C; IR ν 3346, 2986, 1726, 1678, 1527, 1370, 1280, 1254, 1154, 1137; H NMR (360 MHz,
CDCl3) δ 5.55-5.35 (m, 0.3H), 5.32-5.15 (m, 0.7H), 4.47-4.35 (m, 0.7H), 4.35-4.13 (m, 1H), 4.12-3.95 (m,
0.3H), 3.68 (s, 3H), 3.50-3.30 (m, 0.7H), 3.12-2.85 (m, 0.3H), 2.63 (app. dd, J = 18.9, 8.8 Hz, 1H), 2.31 (dd, J =
21.4, 10.0 Hz, 1H), 1.42 (s, 9H); 13C{1H} NMR (90 MHz, CDCl3) δ 171.3, 154.7, 80.3, 60.4, 52.3, 46.4, 30.9,
28.4 (3C), 13.7; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C11H18INNaO4 : 378.0173; Found: 378.0166.
+
(±)-cis-trans-Methyl 3-bromo-2-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylate 14f. Followed the
general procedure G, using methyl ester 3 (122 mg, 0.50 mmol), CBr4 (332 mg, 1.0 mmol), PPh3 (262 g, 1.0
mmol), and TBAB (10 mg). Flash chromatography (Et2O/petroleum ether, 25/75) afforded the product 14f
(100 mg, 65 %) as a white solid. Rf (Et2O/petroleum ether, 25/75): 0.35; Mp: 134-135 °C; IR ν 3310, 2984,
1
1732, 1690, 1529, 1340, 1288, 1198, 1170; H NMR (250 MHz, CDCl3) δ 5.55-5.30 (m, 0.8H), δ 5.25-5.05 (m,
0.2H), 4.75-4.57 (m, 1H), 4.52 (app. q, J = 8.8 Hz, 1H), 3.71 (s, 3H), 3.53 (td, J = 9.5, 2.4 Hz, 1H), 2.57 (ddd, J =
11.0, 8.4, 2.4 Hz, 1H), 2.30 (dt, J = 12.1, 9.5 Hz, 1H), 1.43 (s, 9H); 13C{1H} NMR (63 MHz, CDCl3) δ 173.8,
154.5, 80.4, 56.2, 52.3, 44.8, 44.2, 30.8, 28.4 (3C); HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C11H18N79BrNaO4 :
+
330.0311; Found: 330.0298.
(±)-trans-trans-Methyl 3-bromo-2-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylate 15f. Followed
the general procedure G, using methyl ester 5 (122 mg, 0.50 mmol), CBr4 (332 mg, 1.0 mmol), PPh3 (262 g,
1.0 mmol), and TBAB (10 mg). Flash chromatography (Et2O/petroleum ether, 25/75) afforded the product
15f (47 mg, 30 %) as a white solid. Rf (Et2O/petroleum ether, 50/50): 0.45; Mp: 116-117 °C; IR ν 3346, 2984,
1
1727, 1684, 1529, 1374, 1284, 1258, 1146; H NMR (360 MHz, CDCl3) δ 5.18 (br. s, 1H), 4.67-4.22 (m, 1H),
4.20-4.01 (m, 1H), 3.70 (s, 3H), 3.44-3.15 (m, 0.8H), 3.05-2.75 (m, 0.2H), 2.64 (dd, J = 19.6, 8.6 Hz, 1H), 2.23
(dd, J = 21.1, 9.9 Hz, 1H), 1.43 (s, 9H); 13C{1H} NMR (90 MHz, CDCl3) δ 172.0, 154.8, 80.4, 59.9, 52.3, 42.6,
41.3, 30.4, 28.4 (3C); HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C11H18N79BrNaO4 : 330.0311; Found: 330.0300.
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ASSOCIATED COMMENT
Supporting Information
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Copies of 1H and 13C{1H} NMR spectra, and crystallographic data for 6a and 7a (CCDC 1898946 and 1898947,
respectively) are presented in the Electronic Supporting Information. The ESI and crystallographic data in
CIF are available free of charge on the ACS Publications website at http://pubs.acs.org/.
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AUTHOR INFORMATION
Corresponding Author
* E-mail: david.aitken@u-psud.fr, thomas.boddaert@u-psud.fr
ORCID
David J. Aitken: 0000-0002-5164-6042
Thomas Boddaert: 0000-0002-3939-4700
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Z.C. is grateful to the China Scholarship Council for the award of a PhD grant. The authors thank Mr J.-P.
Baltaze (ICMMO) for assistance with NMR studies.
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(a) Kiss, L.; Mándity, I. M.; Fülöp, F. Highly Functionalized Cyclic β-Amino Acid Moieties as Promising
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(a) Vasudev, P. G.; Chatterjee, S.; Shamala, N.; Balaram, P. Structural Chemistry of Peptides Containing
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10 For cyclobutane-based β-peptide foldamers studied in our group, see: Declerck, V.; Aitken, D. J. Strategic
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12 For photochemical approaches for the parent cyclobutane β-amino acid, see: (a) Declerck, V.; Aitken, D. J.
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For 3- or 4-substituted ACBCs prepared using other approaches but with limited scope, see: (a) de
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(a) Kumara Swamy, K. C.; Bhuvan Kumar, N. N.; Balaraman, E.; Pavan Kumar, K. V. P. Mitsunobu and
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