Efficient synthesis of 3-hydroxymethylated cis- and trans-cyclobutane β-amino acids using an intramolecular photocycloaddition strategy

Article abstract of DOI:10.1016/j.tet.2007.11.021

Uracil bearing a tethered allyl alcohol appendage at N1 undergoes a [2+2] photocycloaddition reaction to provide a single tricyclic adduct in high yield. This compound is transformed in one step into a cis-cyclobutane β-amino acid bearing a 3-hydroxymethyl group. Through appropriate functionalization and epimerization, the trans isomer is obtained therefrom in only three further steps.

Full text of DOI:10.1016/j.tet.2007.11.021

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 1088e1093
www.elsevier.com/locate/tet
Efficient synthesis of 3-hydroxymethylated cis- and trans-cyclobutane
b-amino acids using an intramolecular photocycloaddition strategy
a
Aurelie Mondiere , Runhui Peng , Roland Remuson , David J. Aitken
a
a,
a,b,
*
*
´
`
a Laboratoire SEESIB (UMR 6504dCNRS), De´partement de Chimie, Universite´ Blaise PascaldClermont-Ferrand II,
24 avenue des Landais, 63177 Aubie`re cedex, France
b Laboratoire de Synthe`se Organique et Me´thodologie, ICMMO (UMR 8182dCNRS), Baˆt. 420, Universite´ Paris-Sud 11,
15 rue Georges Clemenceau, 91405 Orsay cedex, France
Received 14 September 2007; received in revised form 22 October 2007; accepted 1 November 2007
Available online 7 November 2007
Dedicated to Professor Csaba Szantay on the occasion of his 80th birthday
Abstract
Uracil bearing a tethered allyl alcohol appendage at N1 undergoes a [2þ2] photocycloaddition reaction to provide a single tricyclic adduct in
high yield. This compound is transformed in one step into a cis-cyclobutane b-amino acid bearing a 3-hydroxymethyl group. Through appro-
priate functionalization and epimerization, the trans isomer is obtained therefrom in only three further steps.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
ring substituentsdshould clearly play a significant role in
this field, but until now very little study has been made of
these carbocycles.9,10 This can be partly explained by the pau-
city of convenient synthetic methods giving access to these
building blocks. Only a few synthetic strategies for the prepa-
ration of ACBAs have been disclosed. Kennewell et al.11
showed that meso-1,2-cyclobutanedicarboxylic acid deriva-
tives could be desymmetrized with one of the functions being
transformed into an amine, thus providing access to racemic
b-Amino acids, and the various peptide structures which in-
clude them, often possess interesting structural and biological
properties which are complementary to those of their more
abundant a-amino acid congeners.1 The controlled preparation
of b-amino acids is therefore of considerable importance for
synthetic chemists.2 Since a significant part of the interest
in these compounds derives from their ability to adopt and
impose marked conformational preferences, there has been a
particular focus on alicyclic b-amino acids and peptide deriva-
tives thereof.3,4 Thus, synthetic efforts have been devoted to
derivatives of cyclohexane,5 cyclopentane,6 and cyclopropane7
b-amino acids, although a number of more elaborate carbo-
cyclic scaffolds have also been studied.8
cis-ACBA. Two enantioselective versions of this approach
12
~
have been described, by the groups of Ortuno et al. and
Bolm et al.13 Until very recently, only racemic syntheses of
trans-ACBA had been described, via analogous desymmetri-
zation of the racemic trans-diacid.11,14
Ring-substituted ACBAs are rare, and the available syn-
thetic methods lack selectivity and/or generality. ACBAs
bearing simple hydrocarbon moieties (alkyl, phenyl, and meth-
ylene) at the C3 and/or C4 position have been described,6c,15
while a novel acyl nitrene insertion reaction has provided
an isolated entry to 3-hydroxy-ACBAs.16 In earlier work,
Brannock et al.17 prepared a series of N,N-dialkylated 3,3-
dialkyl-ACBA esters via a thermal [2þ2] cycloaddition
Cyclobutane b-amino acidsdmore formally, 2-amino-1-
cyclobutanecarboxylic acids (ACBAs) optionally bearing
* Corresponding authors.
E-mail addresses: roland.remuson@univ-bpclermont.fr (R. Remuson),
david.aitken@u-psud.fr (D.J. Aitken).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.11.021

A. Mondie`re et al. / Tetrahedron 64 (2008) 1088e1093
1089
between enamines and acrylates, although these reactions re-
quired harsh conditions and were bereft of stereoselectivity.
This approach for the construction of ACBAs has been adap-
ted to give related derivatives, usually under milder con-
ditions.18 Interestingly, fully functionalized derivatives of
4-hydroxymethylated cis- and trans-ACBA have been
prepared via photopyridones.19
We recently demonstrated the utility of a [2þ2] photocy-
cloaddition reaction between uracil and ethylene as a rapid
and simple entry to cis-ACBA.20 Use of a chiral uracil deriva-
tive provided access to enantiomerically pure materials,21 and
these were epimerized in a five-step procedure to establish the
first access to trans-ACBA in enantiomerically pure form.21a
In an extension of this photochemical approach, using a
series of 5- or 6-substituted uracils, the corresponding 1- and
2-substituted cis-ACBAs were prepared,22 including the
1-hydroxymethylated compound.
We wished to further extend this methodology to the prep-
aration of the hitherto unknown 3-hydroxymethyl-ACBA. The
particular interest of the primary alcohol substituent lies in its
wide potential for grafting of (or transformation into) other
side chain entities. In intermolecular [2þ2] photocycloaddi-
tions with unsymmetrical partners, the possibility of the for-
mation of regioisomers and stereoisomers arises, and in
many cases product mixtures are formed.23 An intramolecular
process is generally much more selective, and indeed a few ex-
amples have been described, which involve uracil dervatives.24
In consequence, we decided to investigate the reactivity of
a uracil bearing a cleavable tether at N1, which would deliver
the equivalent of allyl alcohol in an intramolecular fashion
(Fig. 1).
N1,N3-dialkylated material 2 was the only by-product, and
was easily separated by filtration.
O
O
N
O
NH
N
O
a
NH
N
O
O
89%
N
H
O
O
O
10%
1
2
+
b
89%
H
H
O
COOH
O
H
H
c
NH
H
4
N
NH2
77%
H
N
O
O
O
d
3
H
100%
COOH
NH2
HO
5
H
H
Scheme 1. Reagents and conditions: (a) CH2]CHCH2OCH2Cl, BSA, CsI,
CH2Cl2 rt, 4 h. (b) hn, acetone, Pyrex, rt, 4 h. (c) 0.5 M NaOH, rt, 18 h. (d)
1 M NaOH, 80 ꢀC, 10 h, then 1 M HCl.
Compound 1 was subjected to [2þ2] photocycloaddition
reaction conditions (Scheme 1). A solution of 1 in acetone
was irradiated with a 400 W medium-pressure Hg vapor
lamp fitted with a Pyrex filter under argon for 4 h. In these
conditions, the tricyclic cyclobutane adduct 3 was obtained
as a single product in 89% isolated yield.28 In alternative reac-
tion conditions, using a quartz reaction vessel and acetonitrile
as the solvent, 3 was produced along with several by-products
and its isolated yield was lower (66%). The structure of com-
pound 3 was determined by 1D and 2D NMR experiments.
The relative stereochemistry was attributed by comparison of
NMR spectral data with those of related compounds24a and
supported by NOE observations. An all-cis configuration
was thus assigned for 3, which had therefore been formed
with complete regio- and stereo-chemical selectivities.
O
OH
COOH
NH2
HO
[2+2]
NH
+
intermolecular reaction:
lacks selectivity
N
H
O
probable mixture
of isomers
O
N
COOH
[2+2]
NH
Next, the controlled degradation of the heterocyclic rings
was undertaken. It was hoped that subjecting 3 to acidic con-
ditions would induce oxazine ring opening via an intermediate
N-acyl iminium, which might then be hydrolyzed.29 In the
event, treatment of 3 with TFA or HCl yielded only unreacted
starting material. Other attempts to open the oxazine ring of 3
NH2
O
intramolecular reaction:
more likelihood of regio-
and stereo-control
HO
3-hydroxymethyl-ACBA
O
cleavable
tether
Figure 1. Retrosynthetic analysis.
31
using TMSI30or BBr3 also failed.
2. Results and discussion
We therefore turned our attention to the dihydrouracil ring.
Our recent work on cyclobutane dihydrouracil adducts had
shown that treatment with NaOH in mild conditions can effect
selective N3eC4 bond cleavage to provide the corresponding
cyclobutane b-urea acids.20e22 Indeed, overnight treatment of
3 with 0.5 M NaOH (6 equiv) at room temperature furnished
compound 4 in 77% yield (Scheme 1). Previously, it had
been noted that in more strongly basic conditions, dihydrour-
acils can be converted directly into b-amino acids.32 This ap-
peared a more attractive prospect, since we felt that removal of
2.1. Preparation of the cis-cyclobutane b-amino acid
We selected to study 1-(allyloxymethyl)uracil 1. This com-
pound, first described by Ozerov et al.,25 was conveniently
prepared by selective N1-alkylation of uracil using chloro-
methyl allyl ether26 in the presence of cesium iodide and
N,O-bistrimethylsilylacetamide (BSA) in an adaptation of
Pederson’s procedure27 (Scheme 1). A small amount of the

1090
A. Mondie`re et al. / Tetrahedron 64 (2008) 1088e1093
the acyl group from the nitrogen atom should make acid-
mediated oxazine ring opening easier. In the event, treatment
of 3 with a 1 M solution of NaOH at 80 ꢀC for 10 h followed
by neutralization and passage through acidic anion exchange
resin led directly to the target cyclobutane b-amino acid 5
in quantitative yield (Scheme 1). The probable sequence of
events for this last step is presented in Scheme 2.
(FmocONSu) in the presence of NaHCO3 furnished the re-
quired N-protected amino acid 7 in 59% yield. FmocONSu
was a superior reagent to FmocCl, which provided 7 in only
13% yield.
We were able to prepare the methyl ester 8 (62% yield)
from 7 in standard acidic conditions (MeOH/H2SO4) without
inducing lactonization, leaving the primary alcohol as the
only free functional group. The carboxamide 9 was also pre-
pared (52% yield) by treatment of 7 with NH4HCO3 in the
presence of Boc2O and pyridine.34
We have recently studied the base-mediated cis to trans C1
epimerization of the parent (i.e., bearing no other ring substit-
uents) cyclobutane b-amino acid, in both methyl ester21a and
carboxamide35 derivatized forms. The latter was arguably
more efficient, so we applied the appropriate epimerization
conditions to carboxamide 9. Treatment of this compound
with 25% aqueous NaOH solution in refluxing methanol pro-
vided the trans-b-amino acid 10 directly, in 94% yield
(Scheme 3). This final transformation is achieved via three
consecutive steps: Fmoc group cleavage, cis to trans epimeri-
zation of the intermediate carboxamide, and then hydrolysis of
carboxamide to carboxylic acid. The stability of the trans-
cyclobutane b-amino acid product in the vigorous reaction
conditions is noteworthy, and the absence of any products
with a cis configuration is remarkable. The three-step cis to
trans epimerization procedure (starting and finishing with
free b-amino acid functions) is the shortest such sequence of
which we are aware.
H
COO
O
H
COO
NH
OH
OH
H
3
H
N
NH2
H
H
H
CO2
NH3
O
O
H
H
H
H
COOH
NH
COOH
H2O
5
H
N
H
H
iminium
hydrolysis
OH
O
H
Scheme 2. Proposed sequence of events in the transformation of 3 into 5.
The new cis-cyclobutane b-amino acid 5 was thus obtained
in a very efficient and selective three-step process from uracil
(79% overall yield). It was of interest to note that 5 was only
moderately stable in aqueous solution, degrading over a period
of hours at room temperature. A similar phenomenon has been
observed for the parent b-amino acid and can be imputed to an
irreversible ‘push-pull’ induced ring opening process.33
2.2. Preparation of the trans-cyclobutane b-amino acid
3. Conclusion
With the cis-b-amino acid 5 in hand, we next investigated
its controlled epimerization at C1 in order to gain entry to
the trans isomer (Scheme 3). Initially, protection of the amine
function of 5 was necessary in order to suppress material loss
through the ring opening phenomenon. Treatment of 5 with
Boc2O in standard conditions gave the tert-butyl carbamate
6 in only moderate yield (45%), presumably due to the steric
congestion around the nitrogen atom of the all-cis cyclobutane
skeleton. The use of 9-fluorenylmethylsuccinimidyl carbonate
In conclusion, the intramolecular version of the uracile
olefin [2þ2] photocycloaddition methodology provides a short
and efficient entry to 3-hydroxylated cis-cyclobutane b-amino
acid, which can be transformed into the trans isomer via selec-
tive functionalization and an efficient multi-step epimerization
process. These procedures are expected to be of use for the
preparation of b-peptides bearing multiple and varied side
chain appendages, through further derivatization of the
primary alcohol moieties. Work in this respect is in progress.
H
H
H
H
H
H
COOH
NH2
COOH
CONH2
COOH
NH2
d
b
e
HO
HO
HO
HO
52%
59%
94%
NHFmoc
NHFmoc
H
H
H
H
H
H
7
5
9
a
c
10
45%
62%
H
H
H
H
COOH
NHBoc
COOMe
NHFmoc
HO
HO
H
H
8
6
Scheme 3. Reagents and conditions: (a) Boc2O, NaOH, dioxane/H2O, 0 ꢀC to rt, 2.5 h. (b) FmocONSu, NaHCO3, acetone/H2O, rt, 16 h. (c) MeOH, H2SO4 (cat),
ꢁ15 ꢀC, 16 h. (d) Boc2O, NH4HCO3, pyridine, dioxane, rt, 5 h. (e) 25% aq NaOH, MeOH, D, 3 h.

A. Mondie`re et al. / Tetrahedron 64 (2008) 1088e1093
1091
4. Experimental
1694 cmꢁ1
;
1H NMR (CDCl3) d 5.71 (d, 1H, J¼11 Hz),
4.23 (q, 1H, J¼4 Hz), 4.13 (d, 1H, J¼11 Hz), 3.56 (d, 2H,
J¼7 Hz), 3.22 (m, 2H), 2.66 (m, 1H), 2.57 (q, 1H, J¼
10 Hz), 2.44 (m, 1H); 13C NMR (CDCl3) d 173.8, 153.1,
71.2, 67.0, 51.2, 33.6, 31.6, 27.2; MS (CI) m/z 183
[MþH]þ. Anal. Calcd for C8H10N2O3: C, 52.74; H, 5.53; N,
15.38. Found: C, 52.37; H, 5.61; N, 14.97.
4.1. General methods
Melting points were obtained on a Reichert microscope
apparatus. Elemental analyses were performed on a Thermo-
finnigan EA 1112 instrument. IR spectra were recorded on
a PerkineElmer Aragon 500 spectrometer; only diagnostic ab-
sorbances (nmax) are given. NMR spectra were recorded on
a Bruker AC-400 spectrometer operating at 400 MHz (1H)
or 100 MHz (13C); chemical shifts (d) are reported in parts
per million, J values are given in hertz. MS data were obtained
in CI mode (150 eV; vector gas: CH4) on a HewlettePackard
5989B instrument, or in positive ESI mode (3000 V) on a
Waters micro Q-TOF instrument.
4.1.3. 2-Carbamoyl-2-aza-4-oxabicyclo[4.2.0]octane-8-
carboxylic acid (4)
A solution of 3 (0.65 g, 3.6 mmol) in 0.5 M aqueous NaOH
(23 mL) was stirred at rt overnight. Cation exchange resin
(Bio-Rad AG 50W-X8, Hþ, 20e50 mesh) was then added un-
til pH¼4e5. Filtration and then evaporation of the filtrate left
4 as yellow crystals (0.55 g, 77%). Mp 142e143 ꢀC; IR (KBr)
Flash chromatography was carried out on columns of silica
gel (40e63 mm); the appropriate eluent is indicated in parenthe-
ses. Isolation of amino acids was carried out on columns of
Dowex 50X8 ion exchange resin (50e100 mesh) in Hþ form.
nmax 3550, 3400, 1700, 1660 cmꢁ1 1H NMR (DMSO-d6)
;
d 12.09 (s, 1H), 6.00 (br s, 2H), 5.02 (d, 1H, J¼8 Hz), 4.53
(t, 1H, J¼9 Hz), 4.45 (d, 1H, J¼8 Hz), 3.95 (dd, 1H, J¼9
and 11 Hz), 3.68 (dd, 1H, J¼10 and 8 Hz), 3.40 (m, 1H),
2.72 (m, 1H), 1.96 (m, 2H); 13C NMR (DMSO-d6) d 174.6,
156.8, 74.0, 68.8, 47.0, 42.2, 31.0, 21.9. HRMS (ESI) Calcd
for C8H12N2O4Na [MþNa]þ: m/z 223.1817; found 223.1695.
4.1.1. 1-(Allyloxymethyl)uracil (1)
Uracil (3.13 g, 28 mmol) was added to a solution of N,O-
bistrimethylsilylacetamide (19.7 g, 97 mmol) in CH2Cl2
(280 mL) under argon. The reaction mixture was stirred for
10 min then chloromethyl allyl ether26 (4.50 g, 42 mmol)
and cesium iodide (7.20 g, 28 mmol) were added. The reaction
mixture was stirred at rt for 4 h. The mixture was washed with
saturated aqueous Na2CO3 solution (200 mL) and then
extracted with CH2Cl2 (3ꢂ150 mL). The combined organic
layers were dried over MgSO4, filtered, and then evaporated
to yield a yellow powder. This residue was triturated with
EtOAc and filtered to give compound 1 as a white powder
(4.55 g, 89%). Mp 117e118 ꢀC; IR (KBr) nmax 1732, 1681,
4.1.4. cis-2-Amino-3-hydroxymethyl-1-cyclobutane-
carboxylic acid (5)
A solution of 3 (1.00 g, 5.5 mmol) in 1 M aqueous NaOH
(40 mL) was stirred at 80 ꢀC for 10 h. After cooling, the solu-
tion was acidified with 1 M HCl (35 mL) and then loaded onto
a column of ion exchange resin. Elution with 1 M NH4OH so-
lution afforded 5 as yellow crystals (0.80 g, 100%). Mp 153e
154 ꢀC; IR (KBr) nmax 3360 (br), 1710 cmꢁ1; 1H NMR (D2O)
d 3.98 (t, 1H, J¼8 Hz), 3.69 (d, 2H, J¼7 Hz), 3.21 (q, 1H,
J¼9 Hz), 2.73 (q, 1H, J¼8 Hz), 2.28 (q, 1H, J¼8 Hz), 1.93
(q, 1H, J¼8 Hz); 13C NMR (D2O) d 180.1, 60.2, 48.9, 38.2,
35.2, 24.7. Anal. Calcd for C6H11NO3$H2O: C, 44.17; H,
8.03; N, 8.58. Found: C, 43.67; H, 7.68; N, 8.95.
1
1828 cmꢁ1; H NMR (CDCl3) d 9.28 (s, 1H), 7.32 (d, 1H,
J¼8 Hz), 5.80e5.95 (m, 1H), 5.77 (d, 1H, J¼8 Hz), 5.22 (d,
2H, J¼10 Hz), 5.17 (s, 2H), 4.09 (s, 2H); 13C NMR (CDCl3)
d 163.8, 151.2, 143.2, 133.1, 118.4, 103.2, 76.0, 70.5; MS
(CI) m/z 183 [MþH]þ. Anal. Calcd for C8H10N2O3: C,
52.74; H, 5.53; N, 15.38. Found: C, 52.76; H, 5.59; N, 15.26.
The filtrate was evaporated and the residue was purified by
flash chromatography (EtOAc) to furnish 2 as a colorless oil
4.1.5. cis-2-N-(tert-Butoxycarbonyl)amino-3-hydroxy-
methyl-1-cyclobutanecarboxylic acid (6)
To a solution of 5 (0.20 g, 1.7 mmol) in a mixture of di-
oxane (2 mL) and 1 M aqueous NaOH (1 mL) was added di-
tert-butyl dicarbonate (0.38 g, 1.7 mmol). The mixture was
stirred at rt for 2.5 h and then evaporated. Water (1.6 mL)
was added and the solution was acidified with 1 M HCl until
pH¼2e3. The mixture was extracted with EtOAc (3ꢂ7 mL)
and combined organic layers were dried over MgSO4, filtered,
and then evaporated to give 6 as a greenish oil (0.15 g, 45%).
IR (CCl4) nmax 3360 (br), 1740, 1710 cmꢁ1; 1H NMR (CDCl3)
d 6.25 (s, 1H), 4.42 (s, 1H), 4.23 (t, 1H, J¼7 Hz), 3.94 (dd,
2H), 3.43 (m, 1H), 2.92 (m, 1H), 2.56 (m, 2H), 2.15 (m,
2H), 1.45 (s, 9H); 13C NMR (CDCl3) d 175.6, 156.1, 84.2,
60.0, 48.4, 37.5, 35.5, 26.6, 22.5.
(0.70 g, 10%). IR (CCl4) nmax 1730, 1680, 1629 cmꢁ1 1H
;
NMR (CDCl3) d 7.30 (d, 1H, J¼8 Hz), 5.80e5.95 (m, 2H),
5.77 (d, 1H, J¼8 Hz), 5.22 (d, 4H, J¼10 Hz), 5.20 (s, 2H),
5.17 (s, 2H), 4.10 (s, 2H), 4.08 (s, 2H); 13C NMR (CDCl3)
d 163.8, 151.3, 143.3, 133.2, 118.4, 118.2, 103.4, 103.2,
76.0, 75.9, 70.8, 70.5; MS (CI) m/z 253 [MþH]þ.
4.1.2. 1,3-Diaza-9-oxa-2,4-dioxotricyclo[5.3.1.05,11]-
undecane (3)
A solution of 1 (1.00 g, 5.5 mmol) in acetone (510 mL) was
irradiated under argon for 4 h at rt in an annular reactor equip-
ped with a water cooling system using a 400 W medium-
pressure Hg vapor lamp fitted with a Pyrex filter. The solvent
was then evaporated and the residue was purified by flash
chromatography (cyclohexane/EtOAc 3:7) to give 3 as a white
powder (0.89 g, 89%). Mp 167e168 ꢀC; IR (KBr) nmax
4.1.6. cis-2-N-(9-Fluorenylmethyloxycarbonyl)amino-3-
hydroxymethyl-1-cyclobutanecarboxylic acid (7)
To a solution of 5 (0.10 g, 0.7 mmol) and NaHCO3 (0.12 g,
1.4 mmol) in a mixture of water (7 mL) and acetone (7 mL)

1092
A. Mondie`re et al. / Tetrahedron 64 (2008) 1088e1093
was added 9-fluorenylmethylsuccinimidyl carbonate (Fmo-
cONSu) (0.40 g, 1.2 mmol). The mixture was stirred at rt for
16 h and then acetone was evaporated carefully under reduced
pressure. Excess FmocONSu was removed by extraction with
EtOAc (3ꢂ10 mL). The residual aqueous layer was acidified
with 1 M HCl until pH¼1e2 and then extracted with
CH2Cl2 (3ꢂ10 mL). Combined organic layers were dried
over MgSO4, filtered, and then evaporated to give 7 as white
crystals (0.15 g, 59%). Mp 38e39 ꢀC; IR (KBr) nmax 3360,
141.2, 127.7, 127.0, 124.9, 119.9, 68.3, 67.0, 47.0, 46.9,
46.8, 38.3, 23.0.
4.1.9. trans-2-Amino-3-hydroxymethyl-1-cyclobutane-
carboxylic acid (10)
To a stirred solution of 9 (0.04 g, 0.09 mmol) in MeOH
(1 mL) was added 25% aqueous NaOH (5 mL, 6.3 mmol).
The mixture was stirred at reflux for 3 h, MeOH was evapo-
rated carefully under reduced pressure, and the residual aque-
ous phase was extracted with CH2Cl2 (3ꢂ5 mL). The aqueous
layer was then neutralized at ꢁ5 ꢀC with 1 M HCl and then
loaded onto a column of ion exchange resin. Elution with
1 M NH4OH solution afforded 10 as yellow crystals (0.01 g,
1740, 1710 cmꢁ1
;
1H NMR (CDCl3) d 7.75 (d, 2H, J¼
8 Hz), 7.56 (d, 2H, J¼8 Hz), 7.38 (t, 2H, J¼8 Hz), 7.29 (t,
2H, J¼8 Hz), 6.60 (d, 1H, J¼6 Hz), 4.67 (q, 1H, J¼8 Hz),
4.41 (m, 2H), 4.19 (t, 1H, J¼8 Hz), 3.70 (m, 2H), 3.48 (q,
1H, J¼8 Hz), 2.80 (m, 1H), 2.65 (s, 1H), 2.15 (m, 2H); 13C
NMR (CDCl3) d 176.6, 157.2, 143.7, 141.25, 127.7, 127.1,
125.2, 120.0, 67.3, 61.35, 49.2, 47.1, 39.9, 39.5, 22.9; MS
(ESI) m/z 390 [MþNa]þ. Anal. Calcd for C21H21NO5: C,
67.65; H, 5.76; N, 3.81. Found: C, 67.45; H, 5.95; N, 3.78.
1
94%). Mp 172e173 ꢀC; IR (KBr) nmax 3360, 1710 cmꢁ1; H
NMR (D2O) d 3.72 (m, 2H), 3.56 (m, 2H), 3.10 (q, 1H,
J¼8 Hz), 2.50 (m, 1H), 2.07 (q, 1H, J¼9 Hz), 1.96 (q, 1H,
J¼10 Hz); 13C NMR (D2O) d 173.8, 60.9, 50.6, 43.0, 35.8,
24.8.
4.1.7. Methyl cis-2-N-(9-fluorenylmethyloxycarbonyl)-
Acknowledgements
amino-3-hydroxymethyl-1-cyclobutanecarboxylate (8)
A solution of 7 (0.05 g, 0.14 mmol) in MeOH (0.33 mL)
was cooled to ꢁ15 ꢀC and 95% H2SO4 (4 ml) was added
slowly. The mixture was stirred at ꢁ15 ꢀC for 16 h, warmed
to 0 ꢀC, and neutralized by slow addition of a saturated aque-
ous NaHCO3 solution over 1 h. After removal of solids by fil-
tration, the filtrate was evaporated and the residue was purified
by flash chromatography (cyclohexane/EtOAc 6:4) to give 8 as
a white powder (0.03 g, 62%). Mp 85e86 ꢀC; IR (KBr) nmax
We thank undergraduate students M. Nevoso and N.
Rodrigues for carrying out some experiments.
References and notes
1. (a) Steer, D. L.; Lew, R. A.; Perlmutter, P.; Smith, A. I.; Aguilar, M.-I.
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1
3390, 2960, 1725, 1520 cmꢁ1; H NMR (CDCl3) d 7.77 (d,
2H, J¼8 Hz), 7.61 (d, 2H, J¼8 Hz), 7.39 (t, 2H, J¼8 Hz),
7.31 (t, 2H, J¼8 Hz), 6.55 (d, 1H, J¼6 Hz), 4.61 (q, 1H, J¼
8 Hz), 4.37 (m, 2H), 4.21 (t, 1H, J¼7 Hz), 3.70 (s, 1H), 3.60
(m, 2H), 3.47 (q, 1H, J¼8 Hz), 2.92 (m, 1H), 2.79 (s, 1H),
2.20 (m, 2H); 13C NMR (CDCl3) d 173.8, 156.9, 143.9,
141.3, 127.7, 127.1, 125.1, 120.0, 67.2, 61.5, 52.0, 49.6,
47.2, 46.8, 39.6, 23.2; MS (ESI) m/z 404 [MþNa]þ. Anal.
Calcd for C22H23NO5: C, 69.28; H, 6.08; N, 3.67. Found: C,
69.52; H, 5.60; N, 3.42.
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To a solution of 7 (0.07 g, 0.19 mmol) in dioxane (4 mL)
were added di-tert-butyl dicarbonate (0.06 g, 0.27 mmol), am-
monium hydrogen carbonate (0.05 g, 0.57 mmol), and pyri-
dine (0.03 g, 0.38 mmol). The mixture was stirred at rt for
5 h and then water (3 mL) was added. This mixture was ex-
tracted with EtOAc (3ꢂ3 mL) and combined organic layers
were dried over MgSO4, filtered, and then evaporated. The
residue was purified by flash chromatography (cyclohexane/
EtOAc 6:4) to give 9 as a yellow oil (0.04 g, 52%). IR
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(CCl4) nmax 3360, 1740, 1700 cmꢁ1
;
1H NMR (CDCl3)
´ ´
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d 7.76 (d, 2H, J¼8 Hz), 7.57 (d, 2H, J¼8 Hz), 7.40 (t, 2H,
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