Stereoselective preparation of β,γ-methano-GABA derivatives

Article abstract of DOI:10.1039/c1ob06095c

The Kulinkovich-de Meijere reaction between an unsaturated Grignard reagent and a chiral amide takes place with a high trans stereoselectivity and provides a convenient access to non-racemic trans cyclopropylamines. These compounds are transformed in four steps into the corresponding N-protected β,γ-methano-GABA derivatives, which are obtained for the first time in enantiomerically pure form. The corresponding transformations of the cis cyclopropylamine adducts are also described.

Full text of DOI:10.1039/c1ob06095c

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PAPER
Stereoselective preparation of b,c-methano-GABA derivatives†‡
David J. Aitken,* Ludovic Drouin, Sarah Goretta, Re´gis Guillot, Jean Ollivier* and Marco Spiga
Received 6th July 2011, Accepted 5th August 2011
DOI: 10.1039/c1ob06095c
The Kulinkovich–de Meijere reaction between an unsaturated Grignard reagent and a chiral amide
takes place with a high trans stereoselectivity and provides a convenient access to non-racemic trans
cyclopropylamines. These compounds are transformed in four steps into the corresponding
N-protected b,g-methano-GABA derivatives, which are obtained for the first time in enantiomerically
pure form. The corresponding transformations of the cis cyclopropylamine adducts are also described.
diverse neurodegenerative disorders, including Parkinson’s and
Introduction
Alzheimer’s diseases.11 A wide diversity of strategies have been
developed for the stereoselective synthesis of g-amino acids.12 The
inclusion of two of the GABA backbone carbon atoms into a
cyclopropane ring provides conformationally restricted GABA
analogues, and both the cis and trans isomers a,b-methano-GABA
(CAMP, 1 and TAMP, 2, respectively) have been the focus of some
attention (Fig. 1). (+)-CAMP is a potent agonist of human r1 and
r2 GABAC receptors, while (-)-CAMP exerts weak antagonist
activity.13 Racemic TAMP is a non-inhibiting substrate for GABA
and pyruvate transaminases;14 it also differentiates r3 from other
GABAC receptors in vitro,15 while each of its enantiomers show
partial agonist activity at both GABAC and GABAA receptors.13b
Synthetic efforts have progressed in parallel with the advances in
pharmacology studies, and several preparations of racemic16 and
enantiopure17 CAMP and racemic14,16,18 and enantiopure10c,17c,17e,19
TAMP have been described to date.
There is a growing interest in oligomeric materials which can
adopt well-defined spatial conformations (foldamers), since these
self-organized non-natural structures can provide new insights
into the rules which govern macromolecular folding, and inspire
the design of functional molecular structures fulfilling specific
functions in biological systems or in materials science.1 b-Peptides
have emerged at the forefront of foldamer science in the last
decade or so, largely due to the capacity of these materials to
form intramolecular hydrogen bonds in analogy with Nature’s
a-peptides, thus inducing regular conformational preferences.2
Among the most promising building blocks for such materials
are cyclic b-amino acids: homo-oligomers and mixed peptides
incorporating these compounds have been studied, and a number
of regular folding preferences have been observed, including
helices, sheets, and other well-defined conformational features.3
Following the pioneering studies by Seebach4 and Hanessian,5
peptides containing g-amino acids have now become a centre of
focus for foldamer manifolds.6–10 Significantly, g-amino acids in
which the backbone is rigidified by a cyclic feature appear to
promote specific conformational preferences in oligopeptides.9,10
In a particular case, Smith has shown that short peptide sequences
based on a repeating cyclopropyl g-amino acid sequence adopt
parallel sheet structures in the solid state10c and in reverse turn
mimetics10a which are stabilised by unique C–H ◊ ◊ ◊ O hydrogen
bonds.
g-Amino acids have in fact been of interest to chemists
for quite some time, partly due to the importance of GABA
in the central nervous system; thus derivatives and structural
analogues of GABA are of great interest for the treatment of
Fig. 1 The four methano-analogues of GABA, differentiated by the
ring position and the relative ring stereochemistry (cis or trans); absolute
stereochemistry is not shown.
In marked contrast with their a,b- congeners, the cis and
trans isomers of b,g-methano-GABA, 3 and 4, have received
very little attention (Fig. 1). Indeed, only racemic syntheses have
been described: one of the cis compound 3,20,21 and three of the
trans compound 4.14,20,22 In this paper, we present our work on
the Kulinkovich–de Meijere reaction using a chiral non-racemic
electrophilic partner, which provides for the first time an access to
single enantiomeric forms of trans-b,g-methano-GABA 4, as well
Laboratoire de Synthe`se Organique et Me´thodologie, ICMMO (UMR 8182
CNRS), Baˆt. 420, Universite´ Paris-Sud 11, 15 rue Georges Clemenceau,
91405, Orsay, France. E-mail: jean.ollivier@u-psud.fr, david.aitken@
u-psud.fr; Fax: +33-1-69156278
† This article is part of an Organic & Biomolecular Chemistry web theme
issue on Foldamer Chemistry
‡ Electronic supplementary information (ESI) available. CCDC reference
number 809952. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c1ob06095c
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as the cis isomer 3 in racemic form. With a view to using these
materials in future peptide construction, the N-Boc derivatives
were selected as the targets in the present work.
Results and Discussion
Synthetic strategy for cyclopropylamine formation
The titanium-mediated transformation of N,N-dialkylcarboxa-
mides to cyclopropylamines using alkyl magnesium bromides
was first described by de Meijere.22 In one particular case, the
reaction of N,N-dibenzylformamide 5 with 4-benzyloxybutyl
magnesium bromide 6 gave a good yield of the cyclopropylamine
7 (Scheme 1). The reaction had a low diastereoselectivity
(E : Z ratio of 1.7 : 1) but the isomers were separable, and the
E-isomer was transformed in several steps into 8, a protected
derivative of racemic 4 (Scheme 1).
Scheme 3 Kulinkovich–de Meijere reactions using chiral formamide 9.
Reagents and conditions: a) 6 (1.5 eq.), MeTi(OiPr)3 (1.2 eq.), Et2O, THF,
0
◦C. b) CH2 CHCH2CH2MgBr (13) (1.5 eq.), MeTi(OiPr)3 (1.2 eq.),
Et2O, THF, 0 ◦C.
described procedure using 3-butenyl magnesium bromide 13. This
time, the cyclopropylamines 14 were formed in 81% overall yield
with an E : Z ratio of 9 : 1; once again, each of these geometric
isomers was present as a 1 : 1 mixture of diastereoisomers
(Scheme 3). A key point was that the minor Z component mixture
as well as each of the two major E stereoisomers were separable by
column chromatography. Thus, each trans-vinylcyclopropylamine
E-14a and E-14b was obtained in enantiomerically pure form
and in exploitable yield. The absolute configurations of these
compounds (indicated on Scheme 3) were not known at this stage,
but were deduced from a subsequent X-ray crystallography study
(vide infra).
Scheme 1 de Meijere’s approach to a derivative of racemic 4.
We felt that it should be possible to adapt this synthetic
approach to incorporate a chiral non-racemic moiety as part
of the formamide component, thus providing an entry to single
enantiomers of 4. We decided to investigate the reactivity profile
of a chiral version of the formamide reagent, and for this
purpose we selected (R)-N-benzyl-N-(a-methylbenzyl)formamide
9. Somewhat surprisingly, this compound has not been described
previously in enantiomerically pure form.23 We prepared it in 91%
yield by treatment of (R)-N-benzyl-N-(a-methylbenzyl)amine 10
with mixed acetic formic anhydride (Scheme 2).
Access to enantiomerically pure trans-b,c-methano-GABA
derivatives
With the enantiomerically pure trans-vinylcyclopropylamines in
hand, we embarked on a functional group transformation se-
quence leading to the g-amino acid moiety. The first step was
the oxidation of the vinyl side chain to provide a primary alcohol.
Our initial efforts, conducted on E-14a using borane–THF, were
hampered by the formation of a by-product. Indeed, after work-
up with hydrogen peroxide in basic medium, a 5 : 1 mixture of the
required alcohol 15a and the double bond reduction product 16
was obtained (Scheme 4).
Scheme 2 Preparation of the chiral formamide 9. Reagents and conditions:
a) HCOOH/Ac2O, CH2Cl2, 20 ◦C.
We began our investigations by treating the chiral formamide
9 with methyltitanium triisopropoxide and 4-benzyloxybutyl
magnesium bromide 6. The requisite cyclopropylamines 12 were
obtained in 50% overall yield as a 1 : 1 mixture of E and
Z geometrical isomers; each of these was a 1 : 1 mixture of
diastereoisomers (Scheme 3). While the E and Z components
could be separated fairly easily by chromatography, efforts to
separate the diastereomeric forms proved fruitless.
Scheme 4 Reaction of borane with the vinylcyclopropylamine E-14a.
Reagents and conditions: a) (i) BH3·THF (0.7 eq.), 20 ◦C; (ii) 3 M NaOH,
35% H2O2, 20 ◦C.
This problem was resolved by replacing borane with 9-
borabicyclo[3.3.1]nonane (9-BBN). Using this latter reagent,
E-14a was transformed into 15a as a single product and in excellent
yield (Scheme 5).
We therefore decided to modify the Grignard component in
the Kulinkovich–de Meijere reaction, and repeated the above-
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Scheme 5 Preparation of enantiomerically pure trans-b,g-methano-GABA derivatives. Reagents and conditions: a) (i) 9-BBN (2.5 eq.), THF, 0 ◦C; (ii)
3 M NaOH, 35% H2O2, 20 ◦C. b) (i) HCOOH, 10% Pd–C, MeOH, reflux; (ii) Boc2O (1.8 eq.), MeOH, NaOH to pH 11, 0 ◦C to 20 ◦C. c) H2, 20%
Pd(OH)2-C, THF, 20 ◦C. d) KMnO4, t-BuOH, 20 ◦C.
As indicated in the introduction, we aimed to prepare the target
g-amino acids as their N-Boc protected derivatives. The next step,
therefore, was the removal of the benzylic groups from the amine
of 15a and protection of this latter as its t-butyl carbamate.
We attempted this operation without isolation of the interme-
diate primary amine. A solution of compound 15a in methanol
was treated with formic acid in the presence of Pd–C as a
transfer hydrogenation catalyst. After filtration through Celite,
the crude debenzylated product solution was treated with Boc2O
to afford a mixture of the desired N-Boc-cyclopropylamine
derivative 18a and the partially deprotected product 17a
(Scheme 5). Evidently, the removal of the second benzylic sub-
stituent (the a-methylbenzyl moiety) was sluggish, but studies
of other hydrogenolysis conditions did not provide a remedy;
for example, when a solution compound 15a was treated for 3
days under hydrogen (4 atm) in the presence of 20% Pd(OH)2–
C, followed by the Boc2O treatment, only 17a was obtained.
Fortunately, we had previously observed that N-benzyl-N-Boc-
GABA derivatives may be debenzylated in dry THF solution
using hydrogen and Pd(OH)2–C as the catalyst.19a Gratifyingly,
this operation allowed the smooth transformation of 17a into 18a
thus improving the overall yield of 18a from 15a. Finally, KMnO4
was used to convert 18a into 19a, the N-protected derivative of a
single enantiomer of trans-b,g-methano-GABA 4 (Scheme 5).
With the complete synthetic scheme thus established, we
performed the same sequence of operations on the second
trans-vinylcyclopropylamine, E-14b ostensibly with comparable
reaction profiles and yields in each step, to provide 19b, the oppo-
site enantiomer of the N-protected trans-b,g-methano-GABA 4
(Scheme 5). Optical rotation values for these two new compounds
were of equal magnitude and opposite sign: [a]2D5 = +32.4
(c 1.18, CHCl3) for 19a; [a]2D1 -32.3 (c 1.17, CHCl3) for 19b.
However, the absolute configuration of each still had to be
determined. The salt formed from an equimolar mixture of 19a
and (1S,2R)-(-)-ephedrine provided crystals which were amenable
to X-ray diffraction analysis. The crystal structure of the salt
(shown in Fig. 2) revealed the 1S,2R configuration for 19a
Fig. 2 ORTEP drawing of the salt from 19a and (1S,2R)-ephedrine.
Ellipsoids are drawn at the 30% probability level.
(where the numbering system refers to the 2-amino-cyclopropane
moiety).
Access to a racemic cis-b,c-methano-GABA derivative
The principle application of the Kulinkovich–de Meijere aminocy-
clopropanation reaction was the establishment of a route to
enantiomerically pure derivatives of trans-b,g-methano-GABA.
While the cis structures Z-14ab were only obtained as minor (and
inseparable) products in the reaction of chiral formamide 9 with
3-butenyl magnesium bromide 13 (Scheme 3), we confirmed the
utility of the above sequence of transformations to prepare the
N-Boc derivative of cis-b,g-methano-GABA 3. In the event, the
cis vinylcyclopropylamine mixture Z-14ab was transformed using
9-BBN into the inseparable mixture of diastereomeric alcohols
20ab in high yield (Scheme 6). The debenzylation/Boc protocol
furnished a mixture of 21ab and 22, with the former being deben-
zylated to the latter in an analogous fashion to the trans series.
Subsequent oxidation of 22 provided the target N-Boc-protected
cis-cyclopropane GABA analogue 23 in racemic form (Scheme 6).
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on a Finnigan MAT 95S instrument operation in electrospray
ionisation mode (ESI).
N-Benzyl-N-[(1R)-1-phenylethyl]formamide 9. At room tem-
perature, acetic formic anhydride (8.60 g, 98 mmol, 2.5
equiv.) was added dropwise to a solution of (R)-N-benzyl-1-
phenylethanamine (8.30 g, 39 mmol) in CH2Cl2 (50 mL). After
stirring for 1 h, the reaction was quenched with a saturated
aqueous solution of NaHCO3 (25 mL). The organic layer was
separated and the aqueous phase extracted with CH2Cl2 (2 ¥
25 mL). The combined extracts were washed with brine, dried over
MgSO4 and concentrated under reduced pressure, then the residue
was purified by FC (petroleum ether/EtOAc, 3 : 1) to give 9 as a
colourless oil (8.60 g, 91%). The compound exists as a mixture
of rotamers (7 : 3 ratio). Rf 0.15. [a]2D3 +50.0 (c 1.03, CH2Cl2).
dH (360 MHz, CDCl3) 8.57 (s, 1 H, HCOmaj), 8.35 (s, 1 H,
Scheme 6 Preparation of a racemic cis-b,g-methano-GABA derivative.
Reagents and conditions: a) (i) 9-BBN (2.5 eq.), THF, 0 ◦C; (ii) 3 M NaOH,
35% H2O2, 20 ◦C. b) (i) HCOOH, 10% Pd–C, MeOH, reflux, (ii) Boc2O
(1.8 eq.), MeOH, NaOH to pH 11, 0 ◦C to 20 ◦C. c) H2, 20% Pd(OH)2–C,
THF, 20 ◦C. d) KMnO4, t-BuOH, 20 ◦C.
3
HCOmin), 7.07–7.40 (m, 20 H, ArHmaj+min), 5.79 (q, JH,H
=
7.0 Hz, 1 H, CHmin), 4.65 (q, 3JH,H = 7.0 Hz, 1 H, CHmaj), 4.51
2
2
(d, JH,H = 14.0 Hz, 1 H, CHHmaj), 4.32 (d, JH,H = 14.0 Hz, 1
2
H, CHHmaj), 4.30 (d, JH,H = 16.5 Hz, 1 H, CHHmin), 4.09 (d,
2JH,H = 16.5 Hz, 1 H, CHHmin), 1.55 (d, JH,H = 7.0 Hz, 3 H,
3
3
Conclusions
CH3maj), 1.39 (d, JH,H = 7.0 Hz, 3 H, CH3min). dC (90 MHz,
CDCl3) 163.7 (HCOmin), 162.6 (HCOmaj), 140.5 (ArCqmaj),
139.8 (ArCqmin), 137.7 (ArCqmin), 137.5 (ArCqmaj), 128.9,
128.7, 128.6, 128.6, 128.1, 128.0, 127.9, 127.8, 127.7, 127.4, 126.9
(ArCHmaj+min), 57.8 (CHmaj), 50.8 (CHmin), 48.5 (CH2maj),
45.5 (CH2min), 20.3 (CH3maj), 17.1 (CH3min). This compound
has previously been described in racemic form.23
In summary, the Kulinkovich–de Meijere protocol has been
applied using a chiral N,N-dialkylcarboxamide, allowing easy
access to vinylcyclopropylamines in a diastereoselective manner.
While the minor cis diastereomers were not separable, the major
trans diastereomers were isolated in enantiomerically pure form,
and were transformed into the corresponding N-Boc-b-g-methano
GABA derivatives. This methodology permits a first synthetic
entry to these conformationally restricted g-amino acids, which ex-
pand the inventory of available building blocks for peptidomimetic
foldamer construction.
Preparation of Aminocyclopropanes 14
An oven-dried 250-mL three-necked round-bottomed flask was
charged with a solution of 9.50 g (39.8 mmol) of formamide 9 in
15 mL of anhydrous THF. MeTi(OiPr)3 (11.5 mL, 47.7 mmol, 1.2
equiv.) was added in one portion by syringe and then 3-butenyl
magnesium bromide (1.38 M in THF, 43.2 mL, 59.6 mmol, 1.5
equiv.) was added dropwise over 30 min. The resulting black
suspension was stirred further at ambient temperature for an 1 h,
then quenched by slow addition of Et2O (75 mL) followed by
water (16 mL). The mixture was stirred vigorously for 1 h, filtered,
and the colourless precipitate was washed with Et2O (2 ¥ 25 mL).
The combined organic phases were washed with brine (30 mL),
dried over anhydrous MgSO4, filtered, and concentrated under
reduced pressure to afford a mixture of aminocyclopropanes E-
14a, Z-14b, E-14a and Z-14b (9 : 1 ratio E : Z-isomers) as a deep
yellow oil (9.6 g). This mixture was separated by FC (petroleum
ether/Et2O, 49 : 1) to yield the following three components, which
represent a combined reaction yield of 81%.
Experimental
General
All reactions were carried out under argon using solvents which
were purified using standard procedures. Reagent grade solvents
were used without purification for all extractions and work-
up procedures. Flash chromatography (FC) was performed on
columns of silica gel 60 (0.040–0.063 mm); mobile phases are
indicated in parentheses. Rf values were obtained by TLC on
0.25 mm silica gel plates (60-F254) using the same eluent as the
FC procedure, unless otherwise stated. Optical rotations were
measured on a Jasco P-1010 polarimeter, using a 10 cm quartz
cell. Values for [a] were obtained with the D-line of sodium at the
indicated temperature T, using solutions of concentration (c) in
units of g·100 mL-1. IR spectra were acquired on a Perkin Elmer
Spectrum One spectrophotometer; only significant absorbances
(1R,2S)-{N -benzyl-N -[(1R)-1-phenylethyl]}-2-vinylcyclopro-
panamine E-14a. Yellowish oil (3.99 g, 36%). Rf 0.45 (petroleum
ether/Et2O, 19 : 1). [a]D25 +36.0 (c 1.35, CHCl3). nmax (film) 3000
(CH), 1650 (C C), 1450 (CN) cm-1. dH (360 MHz, CDCl3) 7.20–
7.40 (m, 10 H, ArH), 5.33 (ddd, 3JH,H = 18.0 Hz, 3JH,H = 11.0 Hz,
◦
1
(nmax) are reported. H NMR spectra were recorded at 25 C on
a Bruker AM250 (250 MHz) or Bruker AC360 (360 MHz) or
Bruker AC300 (300 MHz) spectrometer. Chemical shifts (d) are
recorded in parts per million from the residual protonated solvent
resonance (CHCl3 at 7.26 ppm). 13C NMR spectra were recorded
at 25 ◦C on a Bruker AM250 (63 MHz) or Bruker AC300 (75 MHz)
or Bruker AC360 (90 MHz) spectrometer. Chemical shifts (d) are
reported in parts per million from the solvent resonance (CDCl3 at
77.0 ppm). High-resolution mass spectra (HRMS) were recorded
3JH,H = 8.5 Hz, 1 H, H2C CH), 4.83 (dd, 3JH,H = 18.0 Hz, 2JH,H
=
3
2
2.0 Hz, 1 H, H2C CH), 4.81 (dd, JH,H = 11.0 Hz, JH,H = 2.0
Hz, 1 H, H2C CH), 3.91 (q, 3JH,H = 7.0 Hz, 1 H, CHCH3), 3.69
2
3
(d, JH,H = 14.0 Hz, 1 H, CH2Bn), 3.50 (d, JH,H = 14.0 Hz, 1 H,
CH2Bn), 1.80 (ddd, JH,H = 7.0 Hz, JH,H = 4.5 Hz, JH,H = 3.0 Hz, 1 H,
cPr-H), 1,42 (d, JH,H = 7.0 Hz, 3H, CH3),1.25 (ddd, JH,H = 9.0 Hz,
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JH,H = 6.0 Hz, JH,H = 3.0 Hz, 1 H, cPr-H), 0.78 (ddd, JH,H = 9.0 Hz,
JH,H = 9.0 Hz, JH,H = 4.5 Hz, 1 H, cPr-H), 0.64 (dd, JH,H = 12.0 Hz,
JH,H = 5.5 Hz, 1 H, cPr-H). dC (90 MHz, CDCl3) 143.5 (ArC), 139.8
(CH2 CH), 139.7 (ArC), 129.3, 128.0, 127.9, 127.8, 126.7, 126.6,
126.5 (ArCH), 112.3 (CH2 CH), 60.5 (CH), 55.9 (CH2Bn), 43.0
(CH), 26.2 (CH), 17.6 (CH3), 15.6 (CH2). HRMS (ESI): m/z for
C20H24N [M+H]+ requires 278.1903; found 278.1902.
THF solution of 9-BBN (0.5 M, 4.9 mL, 2.5 equiv.). The reaction
was stirred at room temperature and progress was monitored by
TLC (petroleum ether/Et2O, 95 : 5). When no starting material
remained (~3 h), the reaction mixture was treated with NaOH (3
M, 1.0 mL), followed by H2O2 (35% aqueous solution, 1.0 mL)
and stirred for 2 h. Brine (15 mL) was then added and the mixture
was extracted with Et2O (3 ¥ 15 mL). The combined organic layers
were dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by FC (petroleum ether/Et2O,
3 : 1).
(1S,2R)-{N -benzyl-N -[(1R)-1-phenylethyl]}-2-vinylcyclopro-
panamine E-14b. Yellowish oil (3.92 g, 36%). Rf 0.4 (petroleum
ether/Et2O, 19 : 1). [a]D25 +15.0 (c 1.16, CHCl3). nmax (film) 3000
(CH), 1650 (C C), 1450 (CN) cm-1. dH (360 MHz, CDCl3) 7.20–
7.40 (m, 10 H, ArH), 5.36 (ddd, 3JH,H = 16.5 Hz, 3JH,H = 11.0 Hz,
2-{(1S,2R)-2-(N -benzyl-N -[(1R)-1-phenylethyl]amino)cyclo-
propyl}ethanol 15a. Following the general procedure, this com-
pound was obtained from E-14a as a colourless oil (95%). Rf
3JH,H = 9.5 Hz, 1 H, H2C CH), 4.88 (dd, 3JH,H = 16.5 Hz, 2JH,H
=
2.0 Hz, 1 H, H2C CH), 4.83 (dd, 3JH,H = 11.0 Hz, 2JH,H = 2.0 Hz,
H2C CH), 3.91 (q, 3JH,H = 7.0 Hz, 1 H, CHCH3), 3.79 (d, 2JH,H
0.2. [a]2D1 -3.0 (c 0.96, CHCl3). nmax (film) 3400 (OH) cm-1. dH
3
=
(360 MHz, CDCl3) 7.21–7.39 (m, 10 H, ArH), 3.98 (q, JH,H
=
14.0 Hz, 1 H, CH2Bn), 3.42 (d, 3JH,H = 14.0 Hz, 1 H, CH2Bn), 1.77
(ddd, JH,H = 7.0 Hz, JH,H = 4.5 Hz, JH,H = 3.0 Hz, 1 H, cPr-H), 1,47
(d, JH,H = 7.0 Hz, 3H, CH3), 1.33–1.44 (m, 1 H, cPr-H), 0.73 (ddd,
JH,H = 9.5 Hz, JH,H = 9.5 Hz, JH,H = 4.5 Hz, 1 H, cPr-H), 0.61 (dd,
JH,H = 12.0 Hz, JH,H = 5.0 Hz,1 H, cPr-H). dC (90 MHz, CDCl3)
142.1 (ArC), 140.0 (ArC), 139.8 (CH2 CH), 129.1, 128.2, 127.9,
126.8, 126.6 (ArCH), 112.3 (CH2 CH), 60.4 (CH), 56.1 (CH2Bn),
42.6 (CH), 25.7 (CH), 18.6 (CH3), 16.0 (CH2). HRMS (ESI): m/z
for C20H24N [M+H]+ requires 278.1903; found 278.1906.
2
7.0 Hz, 1 H, CHCH3), 3.66 (d, JH,H = 14.0 Hz, 1 H, CH2Bn),
3.59 (d, JH,H = 14.0 Hz, 1H, CH2Bn), 3.46 (t, JH,H = 6.0 Hz, 2
H, CH2OH), 1.68 (ddd, JH,H = 7.0 Hz, JH,H = 3.5 Hz, JH,H = 3.5
2
3
3
Hz, 1 H, cPr-H), 1.46 (d, JH,H = 7.0 Hz, 4 H, CH3, CH2OH),
1.15–1.25(m, 2 H, CH2CH2OH), 0.63 (dd, JH,H = 11.5 Hz, JH,H
=
3.5 Hz, 1 H, cPr-H), 0.59 (dd, JH,H = 9.5 Hz, JH,H = 4.0 Hz, 1H,
cPr-H), 0.33 (m, 1 H, cPr-H). dC (90 MHz, CDCl3) 143.4 (ArCq),
140.4 (ArCq), 128.9, 128.1, 128.0, 127.9, 126.7, 126.6 (ArCH),
62.4 (CH2), 59.9 (CH), 55.8 (CH2Bn), 40.7 (CH), 35.7 (CH2), 18.9
(CH), 15.7 (CH3), 13.6 (CH2). HRMS (ESI): m/z for C20H26NO
[M+H]+ requires 296.2009; found 296.2000.
(Z)-{N -benzyl-N -[(1R)-1-phenylethyl]}-2-vinylcyclopropan-
amine Z-14ab. Yellowish oil (1.00 g, 9%). Rf 0.65 (petroleum
ether/Et2O, 19 : 1). nmax (film) 3000 (CH), 1636 (C C), 1602, 1493
(C CAr) cm-1. dH (300 MHz, CDCl3) 7.25–7.35 (m, 20 H, ArH),
2-{(1R,2S)-2-(N -benzyl-N -[(1R)-1-phenylethyl]amino)cyclo-
propyl}ethanol 15b. Following the general procedure, this com-
pound was obtained from E-14b as a colourless oil (96%). Rf
0.2. [a]2D3 = +54.7 (c 1.06, CHCl3). nmax (film) 3351 (OH) cm-1.
dH (360 MHz, CDCl3, 25 ◦C) 7.24–7.37 (m, 10 H, ArH), 3.97
3
3
3
5.87 (ddd, JH,H = 17.5 Hz, JH,H = 10.0 Hz, JH,H = 1.5 Hz, 1 H,
3
3
3
H2C CH), 5.83 (ddd, JH,H = 17.5 Hz, JH,H = 10.0 Hz, JH,H
1.5 Hz, 1 H, H2C CH), 5.16 (dd, JH,H = 17.5 Hz, JH,H = 2.0
Hz, 1 H, CH2 CH), 5.08 (dd, JH,H = 17.5 Hz, JH,H = 2.0 Hz,
1 H, CH2 CH), 4.97 (dd, JH,H = 10.0 Hz, JH,H = 2.0 Hz, 1
=
3
2
3
2
3
2
(q, JH,H = 7.0 Hz, 1H, CHCH3), 3.87 (d, JH,H = 14.0 Hz, 1 H,
3
2
3
2
CH2Bn), 3.47 (t, JH,H = 6.5 Hz, 2 H, CH2OH), 3.39 (d, JH,H
=
3
2
H, CH2 CH), 4.93 (dd, JH,H = 10.0 Hz, JH,H = 2.0 Hz, 1 H,
14.0 Hz, 1H, CH2Bn), 1.56 (ddd, JH,H = 10.0 Hz, JH,H = 3.5 Hz,
CH2 CH), 3.98 (q, 3JH,H = 7.0 Hz, 1 H, CH), 3.87 (q, 3JH,H = 7.0
3
JH,H = 3.5 Hz, 1 H, cPr-H), 1.48 (d, JH,H = 7.0 Hz, 3 H, CH3),
Hz, 1 H, CH), 3.83 (d, 2JH,H = 14.0 Hz, 1 H, CH2Bn), 3.63 (d, 2JH,H
=
1.38 (dd, JH,H = 13.5 Hz, JH,H = 6.0 Hz, 1 H, cPr-H), 1.10–1.25
13.5 Hz, 1 H, CH2Bn), 3.59 (d, 2JH,H = 13.5 Hz, 1H, CH2Bn), 3.32
(m, 2H, CH2CH2OH), 0.60–0.72 (m, 1H, cPr-H), 0.49 (dat, JH,H
8.5 Hz, JH,H = 4.0 Hz, JH,H = 4.0 Hz, 1 H, cPr-H), 0.25 (dd, JH,H
=
=
(d, 2JH,H = 14.0 Hz, 1 H, CH2Bn), 2.20 (ddd, JH,H = 7.0 Hz, JH,H
=
=
7.0 Hz, JH,H = 5.0 Hz, 1 H, cPr-H), 1.99 (ddd, JH,H = 7.0 Hz, JH,H
5.0 Hz, JH,H = 12.0 Hz, 1 H, cPr-H). dC (90 MHz, CDCl3) 142.4
(ArCq), 140.7 (ArCq), 128.8, 128.1, 127.9, 126.8, 126.6 (ArCH),
62.4 (CH2), 60.9 (CH), 55.8 (CH2Bn), 41.4 (CH), 35.6 (CH2), 18.5
(CH), 17.9 (CH3), 13.9 (CH2). HRMS (ESI): m/z for C20H26NO
[M+H]+ requires 296.2009; found 296.2003.
3
7.0 Hz, JH,H = 5.0 Hz, 1 H, cPr-H),1.44 (d, JH,H = 7.0 Hz, 3 H,
CH3), 1.41 (d, 3JH,H = 7.0 Hz, 3 H, CH3), 0.97 (dd, JH,H = 9.0 Hz,
JH,H = 5.0 Hz, 1 H, cPr-H), 0.94 (dd, JH,H = 9.0 Hz, JH,H = 5.0 Hz, 1
H, cPr-H), 0.80 (dd, JH,H = 9.0 Hz, JH,H = 5.0 Hz, 1 H, cPr-H), 0.78
(dd, JH,H = 9.0 Hz, JH,H = 5.0 Hz, 1 H, cPr-H), 0.57 (dd, JH,H = 10.5
Hz, JH,H = 5.0 Hz, 1 H, cPr-H), 0.22 (dd, JH,H = 11.0 Hz, JH,H = 5.0
Hz, 1 H, cPr-H). dC (75 MHz, CDCl3) 144.1 (ArC), 141.9 (ArC),
140.1 (ArC), 139.8 (ArC), 139.2 (CH2 CH), 139.1 (CH2 CH),
129.5, 129.1, 128.4, 128.2, 128.1, 128.0, 127.9, 126.9, 126.8, 126.7
(ArCH), 113.3 (CH2 CH), 113.1 (CH2 CH), 60.7 (CH), 58.6
(CH), 56.1 (CH2Bn), 55.7 (CH2Bn), 40.9 (CH), 39.7 (CH), 23.3
(CH), 22.2 (CH), 20.2 (CH3), 16.5 (CH2), 15.9 (CH2), 14.1 (CH3).
HRMS (ESI): m/z for C20H24N [M+H]+ requires 278.1903; found
278.1900.
2 - {(Z) - 2 - (N - benzyl - N - [(1R) - 1 - phenylethyl]amino)cyclo-
propyl}ethanol Z-20ab. Following the general procedure, this
compound was obtained from Z-14ab as a colourless oil (93%).
Rf 0.5. nmax (film) 3369 (OH) cm-1. dH (360 MHz, CDCl3) 7.19–
7.40 (m, 20 H, ArH), 3.96 (q, 3JH,H = 9.0 Hz, 1 H, CHCH3), 3.83
2
2
(d, JH,H = 16.5 Hz, 1H, CHCH3), 3.66 (d, JH,H = 16.5 Hz, 2 H,
CH2Bn), 3.55 (d, 2JH,H = 16.5 Hz, 2 H, CH2Bn), 3.37–3.47 (m, 4 H,
CH2OH), 1.50–1.60 (m, 4 H, cPr-H), 1.47 (d, 3JH,H = 9.0 Hz, 3 H,
CHCH3), 1.45 (d, 3JH,H = 9.0 Hz, 3 H, CHCH3), 1.35–1.45 (m, 4
H, CH2CH2OH), 1.10–1.23 (m, 2 H, CH2OH), 0.57–0.70 (m, 1 H,
cPr-H), 0.46 (ddd, JH,H = 16.0 Hz, JH,H = 10.5 Hz, JH,H = 5.5 Hz, 1
H, cPr-H), 0.32 (ddd, JH,H = 8.0 Hz, JH,H = 5.0 Hz, JH,H = 5.0 Hz, 1
H, cPr-H), 0.23 (dd, JH,H = 14.5 Hz, JH,H = 6.5 Hz, 1 H, cPr-H). dC
(90 MHz, CDCl3) 143.3 (ArC), 142.5 (ArC), 140.6 (ArC), 140.2
General procedure for hydroboration/oxidation using 9-BBN
To a stirred solution of the alkene (E-14a, E-14b or Z-14ab) (0.98
mmol) in anhydrous THF (15 mL) at 0 ◦C was slowly added a
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(ArC), 129.7, 129.3, 129.0, 129.0, 128.8, 128.4, 128.2, 128.1, 128.0,
127.9, 127.9, 126.8, 126.7, 126.6, 126.6 (ArCH), 62.3 (CH2), 62.2
(CH2), 60.8 (CH), 59.9 (CH), 55.8 (CH2), 5.8 (CH2), 41.4 (CH),
40.6 (CH), 35.6 (2CH2), 18.8 (CH), 18.5 (CH), 17.8 (CH3), 16.0
(CH3), 14.1 (CH2), 13.7 (CH2). HRMS (ESI): m/z for C20H26NO
[M+H]+ requires 296.2009; found 296.2004.
tert-butyl
[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl][(1R)-1-
phenylethyl] carbamate 17a. Colourless oil. Rf 0.6 (petroleum
ether/EtOAc, 1 : 1). [a]D26 +53.1 (c 1.25, CHCl3). nmax (film) 3422
(OH), 1676 (C O) cm-1. dH (360 MHz, CDCl3) 7.15–7.32 (m, 5
H, ArH), 4.81 (q, JH,H = 7.0 Hz, 1 H, CHCH3), 3.71–3.80 (m,
2 H, CH2OH), 2.33 (ddd, JH,H = 7.0 Hz, JH,H = 3.0 Hz, JH,H
3
3
3
3
=
3.0 Hz, 1 H, cPr-H), 1.94–2.04 (m, 1 H, OH), 1.63 (d, 3JH,H = 7.0
Hz, 3 H, CHCH3), 1.25 (s, 9 H), 0.96–1.21 (m, 3 H, CH2CH2OH,
cPr-H), 0.79 (ddd, JH,H = 9.5 Hz, JH,H = 5.5 Hz, JH,H = 4.0 Hz, 1
H, cPr-H), 0.42 (dd, JH,H = 13.0 Hz, JH,H = 6.0 Hz, 1 H, cPr-H).
dC (90 MHz, CDCl3) 157.2 (C O), 142.7 (ArC), 127.9 (2ArCH),
126.4 (ArCH), 126.1 (2ArCH), 80.4 (C(CH3)3), 62.1 (CH2), 57.4
(CH), 35.9 (CH2), 35.7 (CH), 28.1 (C(CH3)3), 20.2 (CH), 17.7
(CH), 13.1 (CH2). HRMS (ESI): m/z for C18H27NNaO3 [M+Na]+
requires 328.1883; found 328.1893.
Hydroboration/oxidation of compound E-14a using borane
To a solution of aminocyclopropane E-14a (0.50 g, 1.81 mmol)
in THF (28 mL) at 0 ◦C was added a 1 M solution of borane–
THF complex (1.26 mL, 0.7 equiv.). After stirring for 2 h at
room temperature, the reaction mixture was treated with 3 M
NaOH (0.7 mL) and H2O2 (35% solution in water, 0.7 mL)
and stirred for a further 2 h. The mixture was then partitioned
between brine (25 mL) and Et2O (25 mL), the phases were
separated, and the aqueous layer was re-extracted with Et2O (2 ¥
25 mL). The combined organic layers were dried over Na2SO4
and concentrated under reduced pressure. Purification by FC
(petroleum ether/Et2O, 3 : 1) afforded, in addition to the alcohol
E-15a (0.39 g, 74%), the following compound:
tert - butyl [(1S,2R) - 2 - (2 - hydroxyethyl)cyclopropyl][(1R) - 1-
phenylethyl] carbamate 17b. Colorless oil. Rf 0.3 (petroleum
ether/EtOAc, 3 : 1). [a]D24 +17.8 (c 1.28, CHCl3). nmax (film) 3419
(OH), 1683 (C O) cm-1. dH (360 MHz, CDCl3) 7.15–7.35 (m, 5
H, ArH), 4.97 (q, 3JH,H = 7.0 Hz, 1 H, CHCH3), 3.73–3.86 (m, 2
H, CH2OH), 2.45–2.53 (m, 1 H, cPr-H), 1.64 (d, 3JH,H = 7.0 Hz, 3
H, CHCH3), 1.46–1.55 (m, 3 H, CH2CH2OH, CH2OH), 1.31 (s, 9
H, C(CH3)3), 0.96–1.00 (m, 1 H, cPr-H), 0.54 (ddd, JH,H = 9.5 Hz,
JH,H = 5.5 Hz, JH,H = 4.0 Hz, 1 H, cPr-H), 0.32 (dd, JH,H = 13.0 Hz,
JH,H = 7.0 Hz, 1 H, cPr-H). dC (90 MHz, CDCl3) 157.4 (C O),
143.5 (ArC), 128.0 (2ArCH), 126.5 (ArCH), 126.0 (2ArCH), 80.5
(C(CH3)3), 72.0 (CH), 62.1 (CH2), 35.8 (CH2), 35.5 (CH), 28.1
(C(CH3)3), 20.1 (CH), 17.9 (CH3), 11.5 (CH2). HRMS (ESI): m/z
for C18H27NNaO3 [M+Na]+ requires 328.1883; found 328.1888.
(1R,2R)-{N -benzyl-N-[(1R)-1-phenylethyl]}-2-ethylcyclopro-
panamine 16. Colourless oil (0.08 g, 15%). Rf 0.9. dH (360 MHz,
3
CDCl3) 7.20–7.40 (m, 10 H, ArH), 3.92 (q, JH,H = 7.0 Hz, 1 H,
CHCH3), 3.70 (d, 2JH,H = 14.0 Hz, 1 H, CH2Bn), 3.53 (d, 2JH,H
=
14.0 Hz, 1 H, CH2Bn), 1.59 (ddd, JH,H = 7.0 Hz, JH,H = 7.0 Hz,
3
JH,H = 3.5 Hz, 1 H, cPr-H), 1.45 (d, JH,H = 7.0 Hz, 3 H, CH3),
1.25–1.36 (m, 2 H, CH2CH3), 0.96–1.04 (m, 1 H, cPr-H), 0.81 (t,
3JH,H = 7.0 Hz, 3 H, CH3–CH2), 0.37–0.44 (m, 1 H, cPr-H), 0.27
(dddd, JH,H = 8.0 Hz, JH,H = 7.0 Hz, JH,H = 4.5 Hz, JH,H = 4.0 Hz,
1 H, cPr-H). HRMS (ESI): m/z for C20H26N [M+H]+ requires
280.2060; found 280.2059.
tert-butyl [(Z)-2-(2-hydroxyethyl)cyclopropyl][(1R)-1-phenyl-
ethyl] carbamate 21ab. Mixture of diastereomers (1 : 1) as a
colourless oil. Rf 0.6 (petroleum ether/EtOAc, 1 : 1). nmax (film)
3419 (OH), 1673 (C O) cm-1. dH (300 MHz, CDCl3) 7.16–7.32
General procedure for N-debenzylation/Boc protection
3
(m, 10 H, ArH), 4.96 (q, JH,H = 8.5 Hz, 1 H, CHCH3), 4.79 (q,
3JH,H = 8.5 Hz, 1 H, CHCH3), 3.70–3.84 (m, 4 H, CH2OH), 2.48
(ddd, 3JH,H = 5.5 Hz, 3JH,H = 3.0 Hz, 3JH,H = 3.0 Hz, 1 H, cPr-H),
2.30 (dd, 3JH,H = 6.0 Hz, 3JH,H = 3.0 Hz, 1 H, cPr-H), 1.77–1.86 (m,
The substrate (15a, 15b or 20ab) was suspended in a mixture of
MeOH (7 mL mmol-1) and formic acid (5 mL mmol-1). Pd–C
(10%, Pd; 0.2 equiv.) was added and the reaction mixture was
refluxed. After the completion of the reaction (~4 h), as evaluated
by TLC analysis (petroleum ether/Et2O, 1 : 1), the mixture was
2 H, CH2OH), 1.63 (d, 3JH,H = 8.5 Hz, 3 H, CH3), 1.61 (d, 3JH,H
=
8.5 Hz, 3 H, CH3), 1.40–1.60 (m, 4 H, CH2CH2OH), 1.30 (s, 9 H,
C(CH3)3), 1.24 (s, 9 H, C(CH3)3), 0.90–1.05 (m, 2 H, cPr-H), 0.78
(ddd, JH,H = 8.0 Hz, JH,H = 4.5 Hz, JH,H = 3.5 Hz, 1 H, cPr-H),
0.51 (ddd, JH,H = 8.0 Hz, JH,H = 4.5 Hz, JH,H = 4.5 Hz, 1 H, cPr-H),
0.40 (dd, JH,H = 10.5 Hz, JH,H = 5.0 Hz, 1 H, cPr-H), 0.30 (dd,
JH,H = 10.5 Hz, JH,H = 5.0 Hz, 1 H, cPr-H). dC (75 MHz, CDCl3)
153.7 (C O), 143.6 (ArC), 143.0 (ArC), 128.1, 128.0, 126.6, 126.5,
126.1 (ArCH), 80.7 (Cq), 80.5 (C(CH3)3), 62.3 (CH2), 62.3 (CH2),
57.5 (CH), 56.4 (CH), 36.0 (CH2), 35.9 (CH2), 35.7 (CH), 35.7
(CH), 28.2 (C(CH3)3), 28.2 (C(CH3)3), 20.4 (CH), 20.4 (CH), 18.0
(CH3), 17.8 (CH3), 13.1 (CH2), 11.5 (CH2). HRMS (ESI): m/z for
C18H27NNaO3 [M+Na]+ requires 328.1883; found 328.1874.
R
cooled to room temperature and filtered through a sand/Celiteꢀ
pad, which was washed through with MeOH. The combined
filtrate and washings were concentrated under reduced pressure
to remove methanol. The acidic residual solution was treated with
MeOH (2.0 mL mmol-1) and aqueous NaOH (1 M) was added
until pH 11 was obtained. The stirred reaction mixture was cooled
to 0 ◦C and Boc2O (1.8 equiv.) was added; after 5 min the mixture
was allowed to return to room temperature and left for 9 h. After
this time, TLC analysis (petroleum ether/EtOAc, 3 : 1) indicated
complete disappearance of the starting material. The mixture was
concentrated under reduced pressure and the remaining aqueous
phase was washed with EtOAc (50 mL mmol-1 then 2 ¥ 20 mL
mmol-1). Combined organic extracts were washed with brine
(10 mL mmol-1), dried over MgSO4, filtered and concentrated
under reduced pressure to afford mixtures of partly and fully
deprotected products. FC (petroleum ether/EtOAc, 3 : 1) allowed
separation of each pair of components. From 15a : 17a (37%) and
18a (23%); from 15b : 17b (30%) and 18b (33%); from 20ab : 21ab
(45%) and 22 (21%).
General procedure for N-demethylbenzylation
The a-methylbenzyl carbamate (17a, 17b or 21ab) was sus-
pended in anhydrous THF (70 mL mmol-1) at room temperature.
Pd(OH)2–C (60% wet, 20%, Pd: 1.0 equiv.) was added, then
hydrogen was bubbled through the solution for 3 min. The
reaction mixture was stirred vigorously under hydrogen (1 atm)
7522 | Org. Biomol. Chem., 2011, 9, 7517–7524
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for 2 h, by which time TLC analysis (petroleum ether/EtOAc,
1 : 1) showed the disappearance of starting material and the
formation of a single new product. The mixture was carefully
CDCl3) 9.00–10.00 (br s, 1 H,COOH), 5.09 (br s, 1 H, NH), 2.70–
2.83 (m, 1 H, CH2COOH), 2.33 (m, 1 H, cPr-H), 2.03–2.17 (m, 1
H, CH2COOH), 1.45 (s, 9 H, C(CH3)), 1.10–1.22 (m, 1 H, cPr-H),
0.80–0.90 (m, 1 H, cPr-H), 0.66 (dd, JH,H = 12.5 Hz, JH,H = 5.5 Hz, 1
H, cPr-H). dC (90 MHz, CDCl3) 173.2 (CO2H), 157.8 (C O), 81.0
(C(CH3)3), 37.8 (CH2), 29.3 (CH), 28.3 (C(CH3)3), 15.8 (CH), 13.3
(CH2). HRMS (ESI): m/z for C10H17NNaO3 [M+Na]+ requires
238.1050; found 238.1052.
R
filtered through a sand/Celiteꢀ pad which was washed through
with EtOAc. Combined filtrate and washings were concentrated
under reduced pressure and the residue was subjected to FC
(petroleum ether/EtOAc, 1 : 1).
tert-butyl
[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl]carbamate
18a. Following the general procedure, this compound was
obtained from 17a as a colourless oil (81%). Rf 0.5. [a]2D6 +73.6
(c 0.80, CHCl3). nmax (film) 3343 (OH), 1686 (C O), 1171 cm-1.
dH (360 MHz, CDCl3) 5.08 (br s, 1 H, NH), 3.72–3.80 (m, 2 H,
CH2OH), 2.29 (dd, JH,H = 7.0 Hz, JH,H = 4.0 Hz, 1 H, cPr-H),
1.95–2.05 (m, 1 H, OH), 1.40 (s, 9 H, C(CH3)3), 1.24 (m, 1 H,
cPr-H), 0.76–0.95 (m, 2 H, CH2CH2OH), 0.59 (ddd, JH,H = 13.0
2-{(1R,2S)-[(tert-butoxycarbonyl)amino]cyclopropyl}acetic acid
19b. Following the general procedure, this compound was ob-
tained from 18b as a colourless oil (55%). Rf 0.5. [a]2D1 -32.3 (c
1.17, CHCl3). IR and NMR data identical to those for 19a above.
HRMS (ESI): m/z for C10H17NNaO3 [M+Na]+ requires 238.1050;
found 238.1050.
3
3
Hz, JH,H = 9.5 Hz, JH,H = 5.5 Hz, 1 H, cPr-H), 0.40 (dd, JH,H
=
2-{(Z)-[(tert-butoxycarbonyl)amino]cyclopropyl}acetic acid 23.
Following the general procedure, this compound was obtained
from 22 as a pale yellow oil (64%). Rf 0.6. nmax (film) 3329 (OH),
1710 (C O) cm-1. dH (360 MHz, CDCl3) 10.60 (br s, 1H, COOH),
5.10 (br s, 1 H, NH), 2.64–2.44 (m, 1 H, CH2COOH), 2.32 (m, 1
H, cPr-H), 2.10–2.26 (m, 1 H, CH2COOH), 1.42 (s, 9 H), 1.10–
13.0 Hz, JH,H = 5.5 Hz, 1 H, cPr-H). dC (90 MHz, CDCl3) 157.7
(C O), 80.0 (C(CH3)3), 62.3 (CH2), 35.0 (CH2), 28.6 (CH),
28.2 (C(CH3)3), 19.3 (CH), 11.3 (CH2). HRMS (ESI): m/z for
C10H19NNaO3 [M+Na]+ requires 224.1257; found 224.1271.
tert-butyl
[(1S,2R)-2-(2-hydroxyethyl)cyclopropyl]carbamate
1.20 (m, 1 H, cPr-H), 0.75–0.84 (m, 1 H, cPr-H), 0.63 (dd, JH,H
=
18b. Following the general procedure, this compound was
obtained from 17b as a colourless oil (90%). [a]2D5 -75.5 (c 0.85,
CHCl3). IR and NMR data identical to those for 18a above.
HRMS (ESI): m/z for C10H19NNaO3 [M+Na]+ requires 224.1257;
found 224.1258.
12.8 Hz, JH,H = 5.8 Hz, 1 H, cPr-H). dC (75 MHz, CDCl3) 181.0
(CO2H), 169.4 (C O), 80.6 (C(CH3)3), 37.6 (CH2), 29.3 (CH),
28.3 (C(CH3)3), 24.2 (CH2), 13.5 (CH2). HRMS (ESI): m/z for
C10H17NNaO4 [M+Na]+ requires 238.1050, found 238.1049.
tert-butyl
[(Z)-(2-hydroxyethyl)cyclopropyl]carbamate
22.
X-Ray crystallographic study on compound 19a
Following the general procedure, this compound was obtained
from 21ab as colourless oil (60%). Rf 0.4. nmax (film) 3342 (OH),
1686 (C O) cm-1. dH (250 MHz, CDCl3) 5.05 (br s, 1 H, NH),
3.69–3.78 (m, 2 H, CH2OH), 2.29 (dd, JH,H = 7.0 Hz, JH,H = 3.5
Hz, 1 H, cPr-H), 1.91–1.96 (m, 1 H, OH), 1.40 (s, 9 H, C(CH3)3),
1.10–1.35 (m, 1 H, cPr-H), 0.78–0.94 (m, 2 H, CH2CH2OH),
0.50–0.65 (m, 1 H, cPr-H), 0.43 (dd, JH,H = 12.5 Hz, JH,H = 6.5 Hz,
1 H, cPr-H). dC (75 MHz, CDCl3) 157.6 (C O), 79.8 (C(CH3)3),
62.3 (CH2), 34.5 (CH2), 28.5 (CH), 28.1 (C(CH3)3), 19.1 (CH),
11.2 (CH2). HRMS (ESI): m/z for C10H19NNaO3 [M+Na]+
requires 224.1257, found 224.1261.
N-Boc cyclopropane g-amino acid 19a (24 mg) was suspended
in EtOAc (300 mL) and (1S,2R)-(-)-ephedrine (18.8 mg, 1.0
equiv.) was added. The mixture was heated at 60 C for 15 min.
Upon cooling a white precipitate appeared, and was recovered
by filtration. This solid was recrystallised by being suspended in
acetonitrile, then warmed up to 70 ◦C. EtOAc was then added
dropwise until the solution became slightly turbid. Slow cooling
of the mixture gave crystals which were suitable for analysis.
X-ray diffraction data were collected by using a Kappa X8
APPEX II Bruker diffractometer with graphite-monochromated
◦
˚
MoK radiation (l = 0.71073 A). The temperature of the crystal
General procedure for primary alcohol oxidation
was maintained at 100 K by means of a 700-Series Cryostream
cooling device, with an accuracy of 1 K. The data were corrected
for Lorentz polarization and absorption effects. The structure was
solved by direct methods using SHELXS-9724 and refined against
F2 by full-matrix least-squares techniques using SHELXL-9725
with anisotropic displacement parameters for all non-hydrogen
atoms. Hydrogen atoms were located on a difference Fourier
map and introduced into the calculations as a riding model with
isotropic thermal parameters. All calculations were performed by
using the software package WINGX.26
A solution of the alcohol (18a, 18b or 22) in t-BuOH (10 mL
mmol-1) was treated with aqueous NaOH (0.5 M, 4.0 equiv.)
followed by aqueous KMnO4 (0.7 M, 4.0 equiv.) and the mixture
was stirred in the dark for 16 h. The reaction mixture was
quenched by addition of a saturated aqueous solution of sodium
thiosulphate (3 mL mmol-1) and then washed with Et2O (120 mL
mmol-1). The aqueous layer was then cooled to 0 ◦C and acidified
to pH 1 by addition of HCl (1 M). The resulting mixture was
extracted with EtOAc (3 ¥ 90 mL mmol-1). The combined EtOAc
extracts were dried over Na2SO4, filtered and concentrated under
reduced pressure. The residue was purified by FC (EtOAc) to
afford the target N-Boc cyclopropane g-amino acid.
X-ray crystal data of C20H32NO5, M = 380.48, orthorhombic,
˚
space group P 212121, Z = 4, T = 100 K, a = 8.1131(17) A, b =
3
˚
˚
˚
10.109(2) A, c = 25.357(6) A, V = 2079.6(8) A , d = 1.215 g
cm-3, R1 = 0.0532, wR2 = 0.1137, 3359 independent reflections
were collected (Rint = 0.0900). CCDC 809952† contains the supple-
mentary crystallographic data for this compound. These data can
be obtained free of charge from the Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
2-{(1S,2R)-[(tert-butoxycarbonyl)amino]cyclopropyl}acetic acid
19a. Following the general procedure, this compound was ob-
tained from 18a as a colourless oil (52%). Rf 0.5. [a]2D5 +32.4 (c 1.19,
CHCl3). nmax (film) 3323 (OH), 1712 (C O) cm-1. dH (360 MHz,
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Acknowledgements
M. S. is grateful for financial support from the Regione Autonoma
of Sardinia (Programma Master and Back – bando 2007–08).
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7524 | Org. Biomol. Chem., 2011, 9, 7517–7524
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©