An expedient asymmetric synthesis of N-protected (S, S)-2-aminomethyl-1- cyclopropanecarboxylic acid

Article abstract of DOI:10.1055/s-0030-1258814

An enantioselective synthesis of a N-Boc-protected trans-cyclopropane γ-amino acid is reported. The key chiral aldehyde intermediate is prepared in enantiomerically pure form using a three-step aldol-cyclopropanation-retro- aldol protocol.

Full text of DOI:10.1055/s-0030-1258814

LETTER
2729
An Expedient Asymmetric Synthesis of N-Protected (S,S)-2-Aminomethyl-1-
cyclopropanecarboxylic Acid
N
-Protected (
S
,
S
)-
a
2-Aminom
e
v
thyl-1-cyclo
i
propan
d
e
carboxylic
A
cid J. Aitken,*a Steven D. Bull,*b Iwan R. Davies,a,b Ludovic Drouin,a Jean Ollivier,a Jennifer Peedb
a
ICMMO (UMR 8182), Université Paris-Sud, 15 Rue Georges Clemenceau, 91405 Orsay Cedex, France
E-mail: david.aitken@u-psud.fr; fax +33(1)69156278
b
Department of Chemistry, University of Bath, Bath BA2 7AY, UK
E-mail: s.d.bull@bath.ac.uk; fax +44(1225)386231
Received 21 July 2010
Dedicated to Professor Henri Kagan on the occasion of his 80th birthday
auxiliary fragment to be used to generate remote stereo-
centres in very high de. In this paper we report application
of this methodology to the enantioselective synthesis of
compound 3. The strategy employed relies on the conve-
nient and stereo-controlled access to the intermediate
chiral cyclopropane aldehyde 9, using a three-step aldol–
cyclopropanation–retro-aldol protocol, which implicates
intermediate structures 6–8 (Scheme 1).
Abstract: An enantioselective synthesis of a N-Boc-protected
trans-cyclopropane g-amino acid is reported. The key chiral alde-
hyde intermediate is prepared in enantiomerically pure form using
a three-step aldol–cyclopropanation–retro-aldol protocol.
Key words: aldol reaction, amino acids, asymmetric synthesis, car-
bocycle, chiral auxiliary, enantioselectivity
g-Amino acids have been of interest to chemists for some
time, since the parent compound, GABA, plays an impor-
tant role in the central nervous system, and structural ana-
O
N3
H2N
COOH
COOH
O
2
logues are of significant therapeutic value.1 General
synthetic methods for this family of compounds have
evolved as a consequence.2 In the rapidly developing area
of foldamer science,3 oligomers containing g-amino acids
have been shown to adopt well-defined conformations.4 In
this regard, Smith recently identified the unique role
played by a trans-cyclopropyl g-amino acid 1 (Figure 1)
in peptides which adopted parallel sheet structure in the
solid state5 and in reverse turn mimetics.6 Smith’s synthet-
ic building block was the azide ester derivative 2
(Figure 1), which is obtained in four steps from the expen-
sive (S)-benzyl glycidol.
H2N
Boc
N
COOH
H
1
3
Figure 1 The two enantiomers of the parent g-amino acid 1 and two
synthetically useful derivatives 2 and 3; the latter is the target struc-
ture in this work
The requisite starting aldehyde (E)-4-(benzyloxy)but-2-
enal 5 was prepared in quantitative yield by chromi-
um(VI)-mediated oxidation–isomerisation of (Z)-4-(ben-
zyloxy)but-2-en-1-ol 4, according to literature
precedent,13 and was used without purification.
Given the increasing interest in the g-amino acid 1 and the
established interest in cyclopropane-based amino acids in
general,7–9 we thought that access to the complementary
N-Boc-derivative 3 would be a welcome addition
(Figure 1). This compound has been described in enantio-
merically enriched form only twice before, using a six-
step synthesis which involved the enantioselective cyclo-
propanation of (E)-cinnamyl alcohol (89% ee),10 or the
diastereoselective cyclopropanation of a protected allylic
alcohol derived from (R)-glyceraldehyde,11 with both pro-
tocols proceeding through azide intermediates.
In previous work on aldol reactions of N-acyl-oxazolidi-
none 6, 9-BBNOTf/i-Pr2NEt-mediated efficient conden-
sation with simple a,b-unsaturated aldehydes gave the
desired syn-aldol products in good yield.12 However, reac-
tion of 6 with aldehyde 5 under these conditions gave the
desired syn-aldol 7 in only 5% yield. A modified set of
conditions employing n-Bu2BOTf/Et3N for the aldol reac-
tions of Evans N-acyl-oxazolidin-2-ones in good yield
had been reported previously by Anderson and cowork-
ers,14 and we were pleased to observe that application of
this procedure resulted in the formation of the desired al-
lylic alcohol syn-aldol adduct 7 in 81% yield and >95%
de.15 Compound 7 was subjected to Furukawa-modified
Simmons–Smith cyclopropanation16 to provide cyclopro-
pane-aldol 8 in 92% yield with complete diastereoselec-
tively (>95% de).17 The chiral auxiliary fragment was
then cleaved by treating 8 with LiHMDS in toluene at
0 °C, which resulted in a clean retro-aldol reaction to af-
ford the desired cyclopropane aldehyde 9 in 92% yield,18
as well as 6 which could be recovered and recycled. It is
Previous work in the Bath group has focused around the
use of b-hydroxy-b-vinyl-N-acyl-oxazolidin-2-one sub-
strates as novel synthons for the asymmetric synthesis of
chiral aldehydes.12 This methodology often relies on the
reversible generation of a novel ‘temporary stereocentre’
that is used to relay stereocontrol, which enables a chiral
SYNLETT 2010, No. 18, pp 2729–2732
x
x
.x
x
.2
0
1
0
Advanced online publication: 08.10.2010
DOI: 10.1055/s-0030-1258814; Art ID: D19810ST
© Georg Thieme Verlag Stuttgart · New York

2730
D. J. Aitken et al.
LETTER
O
OH
H
i
O
O
OH
OBn
OBn
N
OBn
O
ii
5
4
O
O
7
N
O
iii
6
O
O
OH
OBn
N
O
iv
O
OBn
H
8
9
Scheme 1 Reagents and conditions: i) PCC (3.0 equiv), NaOAc (3.0 equiv), Celite, CH2Cl2, r.t., 3 h, ca. 100%; ii) n-Bu2BOTf (1.2 equiv),
N-acyl-oxazolidin-2-one 6 (1.0 equiv.), Et3N (1.3 equiv), CH2Cl2, –10 °C to 0 °C, 30 min,; then aldehyde 5 (1.2 equiv), CH2Cl2, –78 °C, 45 min
then 0 °C, 3 h, 81%; iii) Et2Zn (10.0 equiv), CH2I2 (10.0 equiv), CH2Cl2, –10 °C, 5 min, then aldol 7 (1.0 equiv), 2 h, –10 °C to r.t., 92%; iv)
LiHMDS (2.2 equiv), cyclopropane-aldol 8 (1.0 equiv), toluene, 0 °C, 3 h, 92%.
noteworthy that 2.2 equivalents of LiHMDS were neces- Reductive amination of aldehyde 9 with dibenzylamine in
sary to drive the reaction to completion and ensure full re- the presence of sodium triacetoxyborohydride20 led to
producibility of this step.
amine 10 in 62% yield,21 thus establishing an entry to the
target skeleton without the need for proceeding through
azide-based intermediates. Attempts to remove the N-ben-
zyl protecting groups of amine 10 under commonly used
hydrogenolysis conditions (Pd/C, H2, MeOH) were unsat-
isfactory. Transfer hydrogenolysis conditions proved to
be more productive, and treatment of amine 7 with
HCO2H and Pd/C in methanol followed by N-Boc protec-
tion afforded the desired N-Boc-protected cyclopropane
alcohol 12 in 50% yield,22 along with the N-benzyl-N-Boc
derivative 11 in 50% yield.23 After some investigation, we
found that the N-benzyl protecting group of 11 could be
removed by treatment with Pd(OH)2/C (20%; 60% wet) in
dry tetrahydrofuran under a H2 atmosphere to afford cy-
clopropane alcohol 12 in quantitative yield.24 When amine
10 was subjected to the above-mentioned hydrogenolysis
conditions [Pd(OH)2/C (20%; 60% wet), H2], followed by
the N-Boc protection procedure, 12 was isolated as the
sole product, but in only 23% yield.
This oxazolidinone-based ‘temporary stereocentre’ strate-
gy therefore provided a convenient access to the key cy-
clopropane aldehyde intermediate 9. There is only one
literature precedent which provides characterisation data
for this compound (as the enantiomer),19 and in our hands
it had a limited shelf life and required a cold environment
for storage. With this intermediate in hand, we embarked
on functional-group manipulation to afford the target N-
Boc-g-amino acid 3, as summarised in Scheme 2.
9
Boc
OH
N
i
Bn
11
iii
ii
OBn
Bn2N
+
OH
10
Boc
N
H
12
Finally, treatment of 12 with Jones reagent gave the target
N-Boc-protected trans-cyclopropane g-amino acid deriv-
ative 3 in 63% yield.25 Spectroscopic characterisation of
this compound was in agreement with previously reported
data.10,11
Boc
OH
N
v
H
O
3
Scheme 2 Reagents and conditions: i) NaBH(OAc)3 (1.6 equiv),
Bn2NH (1.0 equiv), aldehyde 9 (1.0 equiv), DCE, 4 Å MS, 20 °C, 4 h,
62%; ii) Pd/C (10%), amine 10 (1.0 equiv), HCO2H, MeOH, 16 h,
20 °C; then Boc2O (1.0 equiv), NaOH, MeOH, 16 h, 20 °C: N-Boc-N-
Bn-amine 11, 50% + N-Boc-amine 12, 50%; iii) Pd(OH)2/C (20%,
60% wet), THF, H2, 20 °C, 2.5 h, ca. 100%; iv) Jones reagent, ace-
tone, 0 °C, 2 h, then 20 °C, 2 h, 63%.
In conclusion, the three-step aldol–cyclopropanation–
retro-aldol protocol allowed access to the key chiral alde-
hyde intermediate 9, which was easily transformed via a
straightforward, azide-free sequence into the N-Boc-pro-
tected trans-cyclopropane g-amino acid derivative 3 in
enantiomerically pure form. These procedures should fa-
Synlett 2010, No. 18, 2729–2732 © Thieme Stuttgart · New York

LETTER
N-Protected (S,S)-2-Aminomethyl-1-cyclopropanecarboxylic Acid
2731
2006, 1119. (e) Green, R.; Cheeseman, M.; Duffill, S.;
cilitate future access to peptides and other materials which
incorporate this rigid building block.
Merritt, A.; Bull, S. D. Tetrahedron Lett. 2005, 46, 7931.
(f) Cheeseman, M.; Feuillet, F. J. P.; Johnson, A. L.; Bull,
S. D. Chem. Commun. 2005, 2372.
(13) Danishefsky, S.; Berman, E. M.; Ciufolini, M.; Etheredge,
S. J.; Segmuller, B. E. J. Am. Chem. Soc. 1985, 107, 3891.
(14) Anderson, J. C.; McDermott, B. P.; Griffin, E. J.
Tetrahedron 2000, 56, 8747.
Acknowledgment
We acknowledge support from COST (Action CM 0803) for an
STSM grant (to I. R. D).
(15) (S)-4-Benzyl-3-[(2S,3R,E)-6-(benzyloxy)-3-hydroxy-2-
methylhex-4-enoyl]-5,5-dimethyloxazolidin-2-one (7)
Colorless oil. [a]D25 –4.7 (c 0.87, CHCl3). IR (film):
n = 3461 (OH), 1774 (C=O) cm–1. 1H NMR (360 MHz,
CDCl3): d = 7.45–7.21 (10 H, m, Ph), 5.93 (1 H, dtd,
J = 15.5, 5.5, 1.0 Hz, C=CHCH2), 5.78 (1 H, ddt, J = 15.5,
5.0, 1.0 Hz, C=CHCHOH), 4.62–4.41 (4 H, m, CHN,
CH2Ph, CHOH), 4.08 (2 H, br d, J = 5.5 Hz, CH2OBn), 3.94
(1 H, qd, J = 7.0, 4.0 Hz, CHCH3), 3.10 (1 H, dd, J = 14.5,
4.5 Hz, CHAHBPh), 2.94 (1 H, dd, J = 14.5, 9.0 Hz,
CHAHBPh), 1.43 [3 H, s, (CHA )C(CHB )], 1.40 [3 H, s,
References and Notes
(1) (a) Froelund, B.; Madsen, U. In Textbook of Drug Design
and Discovery, 4th ed.; Krogsgaard-Larsen, P.; Stromgaard,
K.; Madsen, U., Eds.; CRC Press: Boca Raton, 2010, 239–
262. (b) Johnston, G. A. R. In GABA in the Nervous System;
Martin, D. L.; Olsen, R. W., Eds.; Lippincott, Williams and
Wilkins: Philadelphia, 2000, 65–80.
(2) (a) Ordóñez, M.; Cativiela, C. Tetrahedron: Asymmetry
2007, 18, 3. (b) Hanrahan, J. R.; Johnston, G. A. R. In
Amino Acids, Peptides and Proteins in Organic Chemistry,
Vol. 1; Hughes, A. E., Ed.; Wiley-VCH: Weinheim, 2009,
573–689.
3
3
(CHA )C(CHB )], 1.20 (3 H, d, J = 7.0 Hz, CH3CH2). 13
C
3
3
NMR (90 MHz, CDCl3): d = 176.6, 152.4, 138.3, 136.6,
131.8, 129.1, 128.9, 128.7, 128.4, 127.7, 127.6, 126.9, 82.4,
72.2, 70.0, 63.4, 42.7, 35.5, 28.4, 22.2, 11.5. ESI-HRMS:
m/z calcd for C26H31NNaO5: 460.2094 [M + Na]+; found:
460.2086.
(3) Hecht, S.; Huc, I. Foldamers: Structure, Properties, and
Applications; Wiley-VCH: Weinheim, 2007.
(4) Recent examples with leading references: (a) Chatterjee, S.;
Vasudev, P. G.; Raghothama, S.; Ramakrishnan, C.;
Shamala, N.; Balaram, P. J. Am. Chem. Soc. 2009, 131,
5956. (b) Sharma, G. V. M.; Jadhav, V. B.; Ramakrishna,
K. V. S.; Jayaprakash, P.; Narsimulu, K.; Subash, V.;
Kunwar, A. C. J. Am. Chem. Soc. 2006, 128, 14657.
(c) Guo, L.; Almeida, A. A.; Zhang, W.; Reidenbach, A. G.;
Choi, S. H.; Guzei, I. A.; Gellman, S. H. J. Am. Chem. Soc.
2010, 132, 7868.
(5) Qureshi, M. K. N.; Smith, M. D. Chem. Commun. 2006,
5006.
(6) Jones, C. R.; Qureshi, M. K. N.; Truscott, F. R.; Hsu, S.-T.
D.; Morrison, A. J.; Smith, M. D. Angew. Chem. Int. Ed.
2008, 47, 7099.
(7) (a) Gnad, F.; Reiser, O. Chem. Rev. 2003, 103, 1603.
(b) Salaun, J. Top. Curr. Chem. 2000, 207, 1. (c) Cativiela,
C.; Diaz-de-Viellgas, M. D. Tetrahedron: Asymmetry 2000,
11, 645. (d) Salaun, J.; Baird, M. S. Curr. Med. Chem. 1995,
2, 511. (e) Burgess, K.; Ho, K. K. Synlett 1994, 575.
(8) Previous contributions in this area from the authors:
(a) Aitken, D. J.; Royer, J.; Husson, H.-P. J. Org. Chem.
1990, 55, 2814. (b) Aitken, D. J.; Guillaume, D.; Husson,
H.-P. Tetrahedron 1993, 49, 6375. (c) Godier-Marc, E.;
Aitken, D. J.; Husson, H.-P. Tetrahedron Lett. 1997, 38,
4065. (d) Godier-Marc, E.; Aitken, D. J.; Husson, H.-P. Nat.
Prod. Lett. 1999, 13, 263. (e) Bunuel, E.; Bull, S. D.;
Davies, S. G.; Garner, A. C.; Savory, E. D.; Smith, A. D.;
Vickers, R. J.; Watkin, J. D. Org. Biomol. Chem. 2003, 1,
2531.
(9) Both enantiomers of the parent trans-cyclopropane g-amino
acid 1, as well as the cis congeners, have been obtained by
resolution procedures: Duke, R. K.; Allan, R. D.; Chebib,
M.; Greenwood, J. R.; Johnston, G. A. R. Tetrahedron:
Asymmetry 1998, 9, 2533.
(10) Mohapatra, D. K. Synth. Commun. 1999, 29, 4261.
(11) Morikawa, T.; Sasaki, H.; Hanai, R.; Shibuya, A.; Taguchi,
T. J. Org. Chem. 1994, 59, 97.
(16) (a) Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron
Lett. 1966, 7, 3353. (b) Furukawa, J.; Kawabata, N.;
Nishimura, J. Tetrahedron 1968, 24, 53.
(17) (S)-4-Benzyl-3-{(2S,3R)-3-[(1S,2S)-2-(benzyloxymethyl)-
cyclopropyl]-3-hydroxy-2-methyl propanoyl}-5,5-
dimethyloxazolidin-2-one (8)
Colorless oil. IR (film): n = 3454 (OH), 1774 (C=O) cm–1;
[a]D25 +5.6 (c 0.75, CHCl3). 1H NMR (300 MHz, CDCl3):
d = 7.49–7.18 (10 H, m, Ph and CH2Ph), 4.61–4.46 (3 H, m,
CH2Ph, CHN), 4.02 (1 H, qd, J = 7.0, 3.5 Hz, CHCH3),
3.49–3.30 (3 H, m, CH2OBn, CHOH), 3.11 (1 H, dd,
J = 14.5, 4.0 Hz, CHCHAHBPh), 2.91 (1 H, dd, J = 14.5, 9.0
Hz, CHCHAHBPh), 2.65 (1 H, br s, OH), 1.40 [3 H, s,
(CHA )C(CHB )], 1.36 [3 H, s, (CHA )C(CHB )], 1.29 (3 H,
3
3
3
3
d, J = 7.0 Hz, CHCH3), 1.20–1.09 (1 H, m, CH-cyclopropyl),
1.01–0.90 (1 H, m, CH-cyclopropyl), 0.71 (1 H, dt, J = 5.0,
8.5 Hz, CHAHB-cyclopropyl), 0.56 (1 H, dt, J = 5.0, 8.5 Hz,
CHAHB-cyclopropyl). 13C NMR (90 MHz, CDCl3): d =
176.8, 152.6, 138.6, 136.7, 129.1, 128.7, 128.3, 127.7,
127.6, 127.5, 126.9, 82.2, 74.7, 73.2, 72.5, 63.5, 43.1, 35.4,
28.4, 22.2, 20.3, 15.9, 11.5, 8.9. ESI-HRMS): m/z calcd for
C27H33NNaO5: 474.2251 [M + Na]+; found: 474.2241.
(18) (S,S)-2-(Benzyloxymethyl)cyclopropane
Carboxaldehyde (9)
Colorless oil. IR (film): n = 2859, 2731 (CHO), 1708 (C=O)
cm–1. [a]D25 +80 (c 0.45, CHCl3). 1H NMR (360 MHz,
CDCl3): d = 9.17 (1 H, d, J = 5.0 Hz, CHO), 7.40–7.21 (5 H,
m, Ph), 4.53 (2 H, s, CH2Ph), 3.50 (1 H, dd, J = 10.5, 5.5 Hz,
CHAHBOBn), 3.42 (1 H, dd, J = 10.5, 5.0 Hz, CHAHBOBn),
1.89–1.77 (2 H, m, CH-cyclopropyl), 1.33 (1 H, dt, J = 8.5,
5.0 Hz, CHAHB-cyclopropyl), 1.12–1.04 (1 H, m, CHAHB-
cyclopropyl). 13C NMR (90 MHz, CDCl3): d = 200.2, 138.0,
128.4, 127.7, 127.6, 72.8, 70.9, 28.1, 12.4. ESI-HRMS: m/z
calcd for C12H14NaO2: 213.0886 [M + Na]+; found:
213.0886.
(19) Our synthesis of aldehyde (S,S)-9 provided material whose
specific rotation of +80 (c 0.45, CHCl3) did not match that
described in the literature for the R,R-enantiomer [+43.37
(c 0.52, CHCl3)]: Kazuta, Y.; Abe, H.; Yamamoto, T.;
Matsuda, A.; Shuto, S. J. Org. Chem. 2003, 68, 3511; we are
grateful to Prof. Shuto and his group for cooperative
(12) (a) Davies, I. R.; Cheeseman, M.; Green, R.; Mahon, M. F.;
Merritt, A.; Bull, S. D. Org. Lett. 2009, 11, 2896. (b) Bull,
S. D.; Cheeseman, M.; Davies, I. R.; Axe, P.; Johnson, A. L.
Org. Biomol. Chem. 2009, 7, 3537. (c) Niyadurupola, D.
G.; Davies, I. R.; Wisedale, R.; Bull, S. D. Eur. J. Org.
Chem. 2007, 5487. (d) Cheeseman, M.; Bull, S. D. Synlett
Synlett 2010, No. 18, 2729–2732 © Thieme Stuttgart · New York

2732
D. J. Aitken et al.
LETTER
(60 MHz, CDCl3): d = 156.1 (C=O), 79.2 [(CH3)C], 66.0
(CH2), 44.5 (CH2), 28.3 [(CH3)C], 19.9 (CH), 17.1 (CH), 8.2
(CH2). ESI-HRMS: m/z calcd for C10H19NNaO3: 224.1257
[M + Na]+; found: 224.1254.
discussions, and for disclosing a revision of their [a]D value
for (R,R)-9: –78.8 (c 0.51, CHCl3).
(20) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.;
Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849.
(21) [(1S,2S)-2-(Dibenzylaminomethyl)cyclopropyl]-
methanol (10)
(23) N-Benzyl N-tert-Butoxycarbonyl [(1S,2S)-2-
(Aminomethyl)cyclopropyl]methanol (11)
Yellow oil which solidified to give an amorphous solid on
standing. [a]D15 +18 (c 2.1, CHCl3). 1H NMR (400 MHz,
CDCl3): d = 0.30 (1 H, ddd, J = 5.0, 5.0, 10.5 Hz, CHAHB-
cyclopropyl), 0.39 (1 H, ddd, J = 5.0, 5.0, 10.5 Hz, CHAHB-
cyclopropyl), 0.80–0.86 (2 H, m, CH-cyclopropyl), 2.27 (1
H, dd, 7.0, 13.0 Hz, CHAHBOBn), 2.41 (1 H, dd, J = 6.0,
13.0 Hz, CHAHBOBn), 3.26–3.32 (2 H, m, CH2NBn2), 3.59
(2 H, d, J = 13.5 Hz, CH2NBn), 3.65 (2 H, d, J = 13.5 Hz,
CH2NBn), 4.47 (2 H, s, CH2Ph), 7.16–7.40 (15 H, m, ArH).
13C NMR (100 MHz, CDCl3): d = 140.0 (2 × Cq), 138.6
(Cq), 128.7 (4 × ArCH), 128.3 (2 × ArCH), 128.1 (4 ×
ArCH), 127.5 (2 × ArCH), 127.4 (ArCH), 126.7 (2 × ArCH),
73.9 (CH2), 72.4 (CH2), 58.1 (2 × CH2), 57.2 (CH2), 17.9
(CH), 14.8 (CH), 9.5 (CH2). ESI-HRMS: m/z calcd for
C26H30NO: 372.2322 [M + H]+; found: 372.2349.
Colorless oil. IR (film): n = 3354 (OH), 1698 (C=O), 1172
cm–1. [a]D27 +16 (c 1.77, CHCl3). 1H NMR (250 MHz,
CDCl3): d = 0.42–0.50 (2 H, m, CHAHB-cyclopropyl), 0.86–
0.93 (1 H, m), 0.95–1.04 (1 H, m), 1.45 [9 H, s, C(CH3)3],
2.95–3.10 (2 H, m), 3.29 (1 H, dd, J = 6.5, 10.0 Hz), 3.37 (1
H, dd, J = 6.5, 10.0 Hz), 4.53 (2 H, s, CH2Bn), 7.27–7.39 (5
H, m, ArCH). 13C NMR (86 MHz, CDCl3): d = 156.0 (C=O),
138.6 (ArC), 128.5 (2 × ArCH), 127.7 (2 × ArCH), 127.6
(ArCH), 100.1 (CH2Bn), 73.5 (CH2), 72.6 (CH2), 71.0 (Cq),
28.5 [C(CH3)3], 17.4 (CH), 17.2 (CH), 8.8 (CH2). ESI-
HRMS: m/z calcd for C13H17NNaO3: 314.1732 [M + Na]+;
found: 314.1716.
(24) Evans, D. A.; Adams, D. J. J. Am. Chem. Soc. 2007, 129,
1048.
(25) (1S,2S)-2-(tert-Butoxycarbonyl)aminomethyl
Cyclopropanecarboxylic Acid (3)
(22) N-tert-Butoxycarbonyl [(1S,2S)-2-(Aminomethyl)-
cyclopropyl]methanol (12)
Colorless oil. [a]D27 +51 (c 0.30, CHCl3) {lit. for (S,S)-3:
[a]D +52.4 (c 2, CHCl3);10 lit. for (R,R)-3: [a]D25 –53.3 (c
1.87, CHCl3)11}. 1H NMR (360 MHz, CDCl3): d = 0.93 (1 H,
dd, J = 7.0, 11.0 Hz), 1.23 (1 H, ddd, J = 13.0, 4.5, 4.5 Hz),
1.48 (9 H, s), 1.57 (1 H, ddd, J = 13.0, 4.5, 4.5 Hz), 1.60–
1.74 (1 H, m), 2.95–3.15 (1 H, m), 3.16–3.30 (1 H, m), 4.72
(1 H, br s), 5.62 (1 H, br s). ESI-HRMS: m/z calcd for
C10H17NNaO4: 238.1050 [M + Na]+; found: 238.1049.
Colorless oil. IR (film): n = 3344 (OH), 1691 (C=O) cm–1.
[a]D20 +7.1 (c 0.50, CHCl3). 1H NMR (250 MHz, CDCl3):
d = 0.42 (2 H, dd, J = 5.0, 5.0 Hz, CHAHB-cyclopropyl),
0.83–0.91 (1 H, m, CH-cyclopropyl), 0.93–1.10 (1 H, m,
CH-cyclopropyl), 1.42 [9 H, s, (CH3)3C], 2.90 (1 H, dd,
J = 5.0, 9.5 Hz), 3.09 (1 H, dd, J = 4.5, 9.5 Hz), 3.28 (1 H,
dd, J = 5.0, 8.0 Hz), 3.57 (1 H, dd, J = 4.5, 8.0 Hz). 13C NMR
Synlett 2010, No. 18, 2729–2732 © Thieme Stuttgart · New York

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