Concise Synthesis of Enantiomerically Pure (1′S,2′R)-and (1′R,2′S)-2S-Amino-3-(2′-aminomethyl-cyclopropyl)propionic Acid: Two E-Diastereoisomers of 4,5-Methano-l-lysine

Article abstract of DOI:10.1071/CH13309

A concise synthesis of both E-isomers of 2S-amino-3-(2′-aminomethyl- cyclopropyl)propionic acid, new methano-l-lysines, is described. The synthetic route includes nine steps from l-methionine, with a key step involving the cyclopropanation of an intermediate E-allylic alcohol. The resultant hydroxymethylcyclopropanes were readily separated and converted into the title α-amino acids. The stereochemistry around the cyclopropane rings was deduced by conducting the cyclopropanation in the presence of N,N,N′,N′-tetramethyl-d-tartaric acid diamide butylboronate, a chiral controller which is known to favour the production of S-hydroxymethyl cyclopropanes from allylic alcohols.

Full text of DOI:10.1071/CH13309

CSIRO PUBLISHING
Aust. J. Chem. 2013, 66, 1105–1111
Communication
http://dx.doi.org/10.1071/CH13309
Concise Synthesis of Enantiomerically Pure
(19S,29R)- and (19R,29S)-2S-Amino-3-(29-aminomethyl-
cyclopropyl)propionic Acid: Two E-Diastereoisomers
of 4,5-Methano-L-lysine
A
A
B
Timothy M. Altamore, Oanh T. K. Nguyen, Quentin I. Churches,
B
B
A
Kate Cavanagh, Xuan T. T. Nguyen, Sandhya A. M. Duggan,
Guy Y. Krippner, and Peter J. Duggan
C
B D E
, ,
A
School of Chemistry, Monash University, Clayton, Vic. 3800, Australia.
B
CSIRO Materials Science and Engineering, Bag 10, Clayton South, Vic. 3169, Australia.
C
Baker IDI Heart and Diabetes Institute, Melbourne, Vic. 8008, Australia.
D
School of Chemical and Physical Sciences, Flinders University, Adelaide,
SA 5042, Australia.
E
Corresponding author. Email: peter.duggan@csiro.au
A concise synthesis of both E-isomers of 2S-amino-3-(20-aminomethyl-cyclopropyl)propionic acid, new methano-L-
lysines, is described. The synthetic route includes nine steps from L-methionine, with a key step involving the
cyclopropanation of an intermediate E-allylic alcohol. The resultant hydroxymethylcyclopropanes were readily separated
and converted into the title a-amino acids. The stereochemistry around the cyclopropane rings was deduced by conducting
the cyclopropanation in the presence of N,N,N0,N0-tetramethyl-D-tartaric acid diamide butylboronate, a chiral controller
which is known to favour the production of S-hydroxymethyl cyclopropanes from allylic alcohols.
Manuscript received: 14 June 2013.
Manuscript accepted: 15 July 2013.
Published online: 14 August 2013.
Introduction
as potential 4,5-cyclopropanated forms of proteogenic amino
acids that remain unreported.
a-Amino acids incorporating highly strained rings are of sig-
nificant interest as mimics of natural amino acids, for incorpo-
ration into conformationally constrained peptidomimetics, and
as biologically active compounds or precursors to biologically
active compounds.[1] Amongst this class of compounds, cyclo-
propanated a-amino acids have been widely investigated[2,3]
while cyclobutyl-,[4,5] bicyclo[1.1.1]pentanyl-,[6–11] and
cubanyl-[12,13] a-amino acids have received much less attention.
Cyclopropanated versions of proteogenic amino acids are
termed methanoamino acids and are classified according to the
position of the cyclopropane ring on the amino acid side chain
(Fig. 1).[2] Examples of 2,3-methano-, 3,4-methano-, and 4,5-
methanoamino acids are known. The 2,3- and 3,4-analogues
have considerable conformational constraint at, or near, the
amino acid centre, whichispresumablywhy theyhave been much
more extensively studied. Of the possible 4,5-methanoamino
acids, 4,5-methanoisoleucine,[14] a natural plant growth regu-
lator,[15] 4,5-methanoproline,[16] and 4,5-methanoornithine[17]
have been synthesised. The latter is the central component of
belactosin A and B, biologically active compounds isolated
from Streptomyces sp. fermentation broth.[18] The N-Boc pro-
tected form of 4,5-methanoleucine has also been prepared,[19]
which leaves only 4,5-methanolysine and 4,5-methanoarginine
Cyclopropanated compounds are of interest as potential
mechanism-based inhibitors of enzymes that employ free radi-
cal intermediates, as cyclopropylmethyl radicals can undergo
rapid and irreversible ring opening reactions.[20] One fascinating
class of free radical enzyme employs S-adenosylmethione to
generate a substrate free radical within the enzyme active
site.[21,22] The most widely studied enzyme in this class is
lysine-2,3-aminomutase which catalyses the isomerisation of
a-L-lysine 4 to b-L-lysine 5 (Scheme 1). A potential mechanistic
probe for this enzyme is 4,5-methano-L-lysine (3, R¼ –CH2NH3þ),
as it would be expected to undergo ring opening when a free
radical is generated at the 3-position. Herein is described an
expedient synthesis of the two E-diastereomers of 4,5-methano-
L-lysine.
Results and Discussion
To ensure enantiomeric purity at the a-position in the final
products, the initial starting material employed for the synthesis
of the target 4,5-methano-L-lysines was a natural a-L-amino
acid. L-Methionine 6 served this purpose and was easily con-
verted into L-homoserine 7y by a two-step process involving
yNote that L-homoserine is also commercially available but its two step preparation from L-methionine is convenient and economical.
Journal compilation Ó CSIRO 2013
www.publish.csiro.au/journals/ajc

1106
T. M. Altamore et al.
ϩ
ϩ
ϩ
NH3
NH3
NH3
R
R
Ϫ
CO2
Ϫ
CO2
Ϫ
CO2
R
1
2
3
2,3-methanoamino acids
3,4-methanoamino acids
4,5-methanoamino acids
Fig. 1. General structures of methanoamino acids.
ϩ
NH3
ϩ
H3N
Lysine 2,3-aminomutase
Ϫ
CO2
ϩ
H3N
Ϫ
CO2
NH3
ϩ
4
5
Scheme 1. Interconversion of a-L-lysine and b-L-lysine catalysed by the S-adenosyl methionine (SAM)
dependent enzyme lysine 2,3-aminomutase.
NHCbz
ϩ
NH3
ϩ
NH3
NHCbz
a
a
O
Ϫ
CO2
Ϫ
CO2
Ϫ
CO2
ϩ
Q
S
HO
HO
O
7
6
9
8
b
Scheme 3. Reagents and conditions: a: (i) 0.1 M KOHaq. 608C, (ii) HCl,
(iii) Et2O, dicyclohexylamine, 61 %. Qþ ¼ dicyclohexylammonium.
NHCbz
O
NHCbz
NHCbz
c
Ϫ
ϩ
Q
ϩ
HO
CO2Bn
HO
CO2
DMF, ensured that both amino and carboxylate groups could
later be deprotected simultaneously under hydrogenolysis con-
ditions. Chain extension was achieved by pyridinium chloro-
chromate oxidation of the alcohol to the aldehyde 11,[24]
followed by a Wittig reaction with triphenylphosphanylidene
acetaldehyde to give the a,b-unsaturated aldehyde 12. Some
experimentation was required in order to find the optimum
conditions for the reduction of the a,b-unsaturated aldehyde
12 to the allylic alcohol 13. Treatment with sodium borohydride
in THF at 08C, in the presence of cerium chloride hepta-
hydrate,[25] gave the best result, furnishing the required allylic
alcohol 13 in 84 % yield.
O
10
8
9
d
NHCbz
CO2Bn
NHCbz
e
CO2Bn
O
O
11
12
f
NHCbz
CO2Bn
Treatment of the E-allylic alcohol 13 with diethyl zinc and
diiodomethane in dichloromethane gave an almost equimolar
mixture of the two possible E-cyclopropanes 14 and 15, which
could be separated by careful column chromatography to give
one isomer in 34 % isolated yield and the other in 35 % yield.
The stereochemistry of these products was deduced by repeating
the cyclopropanation reaction in the presence of the chiral
dioxaborolane, N,N,N0,N0-tetramethyl-D-tartaric acid diamide
butylboronate (16), derived from D-tartaric acid. This latter
experiment yielded the same E-cyclopropanes in a ratio of
94 : 6. It has been demonstrated by Charette’s group that
cyclopropanation of E-allylic alcohols in the presence of 16
consistently gives the cyclopropane with the S-configuration at
the position bearing the hydroxymethyl substituent as the major
product.[26,27] The major product from the stereoselective
cyclopropanation reaction performed on 13 was therefore
assigned to have the 10R,20S configuration (14), with the minor
product assigned to have the 10S,20R configuration (15),
as indicated in Scheme 4.
HO
13
Scheme 2. Reagents and conditions: a: (i) CH3I, 45 % aq. MeOH,
(ii) NaHCO3, reflux; b: (i) PhCH2OCOCl, NaHCO3, H2O, (ii) HCl (conc.),
(iii) Et2O, dicyclohexylamine, 8, 48 %, 9, 23 % from 6; c: PhCH2Br, DMF;
˚
d: pyridinium chlorochromate (PCC), NaOAc, 4 A sieves, CH2Cl2, 73 %
from 8; e: Ph3P¼CHCHO, CH2Cl2, 81 %; f: NaBH4, CeCl3ꢀ7H2O, THF,
08C, 84 %. Qþ ¼ dicyclohexylammonium.
S-methylation and hydrolysis, following the method of
Baldwin and Flinn[23] (Scheme 2). The amine functionality of
L-homoserine was then protected as the benzylcarbamate and
precipitated from diethyl ether as the stable dicyclohexyl-
ammonium salt 8,[24] which was obtained in 48 % yield from
L-methionine. A g-lactone side product 9, which resulted from
cyclisation of the intermediate hydroxy acid, was also produced
during the course of this experiment, and was isolated in 23 %
yield. This g-lactone 9 could be converted into the ammonium
salt 8 in 61 % yield through a sequence of basic hydrolysis,
acidification, and precipitation, as shown in Scheme 3.
The hydroxymethyl cyclopropanes 14 and 15 were separately
converted into the corresponding azides 17 and 18 in a two-step
process involving initial conversion into the corresponding
bromides by treatment with carbontetrabromide and triphenyl-
phosphine, followed by displacement of the bromides with azide
(Scheme 5). Reduction of the azides under hydrogenation
Protection of the carboxylate functionality as the benzyl ester
10, by treatment of the ammonium salt 8 with benzyl bromide in

Synthesis of Two E-Diastereoisomers of 4,5-Methano-L-lysine
1107
NHCbz
CO2Bn
HO
O
O
13
O
O
Me2N
e2N
B
Bu
a or b
M
16
NHCbz
CO2Bn
NHCbz
CO2Bn
R
S
ϩ
HO
HO
S
R
14
15
Scheme 4. Reagents and conditions: a: Et2Zn, CH2I2, CH2Cl2, 14, 34 %, 15, 35 % (isolated); b: Et2Zn, CH2I2,
CH2Cl2, N,N,N0,N0-tetramethyl-D-tartaric acid diamide butylboronate (16); 14, 94 %, 15, 6 % (HPLC).
ϩ
NHCbz
CO2Bn
NH3
a
b
14
15
Ϫ
H2N
CO2
N3
17
18
19
20
ϩ
NH3
NHCbz
CO2Bn
a
b
Ϫ
H2N
N3
CO2
Scheme 5. Reagents and conditions: a: (i) CBr4, PPh3, CH2Cl2, (ii) NaN3, DMF, 17 72 %, 18, 74 %; b: H2,
10 % Pd-C, MeOH, 19 78 %, 20 86 %.
conditions simultaneously cleaved the protecting groups on the
amino acid centres to give the target 4,5-methano-L-lysines 19
and 20 in good yield and high purity.
Experimental
General Remarks
THF was dried by distillation over sodium/benzophenone,
dichloromethane was dried by distillation over calcium hydride,
methanol was dried by storage over freshly activated 3 A
Conclusion
˚
˚
molecular sieves, and DMF was dried by storage over 4 A
molecular sieves.
The non-natural amino acid, 4,5-methano-L-lysine, is one of the
few possible cyclopropanated analogues of proteogenic
a-amino acids that have yet to be reported. The four possible
diastereomers of 4,5-methano-L-lysine are of interest as possible
mechanism-based inhibitors of lysine 2,3-aminomutase.
Described here is a convenient synthesis of the two E-isomers of
4,5-methano-L-lysine starting from L-methionine. A key step in
the sequence involved the cyclopropanation with diethyl zinc
and diiodomethane of a homochiral E-allylic alcohol bearing a
protected a-amino acid functionality. Surprisingly, the pro-
tected a-amino acid did not noticeably influence the stereo-
chemical outcome of this cyclopropanation reaction, but the two
resulting hydroxymethyl E-cyclopropanes could be readily
separated and converted separately into the target a-amino
acids. The inclusion of the chiral controller N,N,N0,N0-
tetramethyl-D-tartaric acid diamide butylboronate in the
cyclopropanation reaction led to the two hydroxymethyl
E-cyclopropanes in a diastereomeric ratio of 94 : 6. The known
preference of this reagent to favour the production of cyclo-
propanes from E-allylic alcohols with the S-configuration at the
position bearing the hydroxymethyl substituent was used to
deduce the stereochemistry of each of the cyclopropanated
products.
Thin-layer chromatography was performed on silica-coated
aluminium-backed sheets (silica gel 60/F254). Flash chromato-
graphy was performed with Merck silica gel 60 (0.040–
0.063 mm), and gravity chromatography was performed with
Merck silica gel 60 (0.063–0.200 mm). Optical rotations were
recorded at room temperature on a Perkin Elmer 141 Polarime-
ter. The units for concentration (c) are g per 100 mL. NMR
spectra were recorded on a Varian Mercury 300 MHz spectrom-
eter (1H, 300 MHz; 13C, 75.5 MHz) unless otherwise stated.
CDCl3 solutions were referenced to internal tetramethylsilane
(TMS) and D2O solutions were referenced to internal
d6-acetone. Infrared spectra were recorded on a Perkin Elmer
1600 Series Fourier Transform Spectrophotometer of either thin
films (neat) or Nujol mulls between sodium chloride plates. Low
resolution electrospray mass spectra were recorded on a Micro-
mass Platform Spectrometer and high resolution mass spectra
were recorded on a Bruker BioApex 47e Fourier Transform
spectrometer, both using electrospray ionisation.
High performance liquid chromatography (HPLC) analysis
of diastereomeric mixtures of 14 and 15 were carried out on an
Agilent Technologies 1260 Infinity System (1260 series pump,

1108
T. M. Altamore et al.
1260 autosampler and a Diode Array detector 1260 series) using
a reverse phase C18 column (Luna (2) 150 ꢁ 4.50 mm, 5 mm,
Phenomenex). The gradient used consisted of acetonitrile
(AcN)/water with 0.1 % trifluoroacetic acid (TFA) with the
following program: t ¼ 0–3 min, 50 % AcN; t ¼ 23 min,
100 % AcN.
2.20 (m, 2H); dC (CDCl3) 175.0, 156.1, 135.9, 128.6, 128.3
128.1, 67.4, 65.9, 50.6, 30.3; nmax (Nujol)/cmꢂ1 3329, 1779,
1695, 1543, 742; m/z 258 ([M þ Na]þ), 236 ([M þ H]þ).
Dicyclohexylammonium 2S-Benzyloxycarbonylamino-
4-hydroxy Butyrate (8) from 2S-
[(Benzyloxycarbonylamino]-4-butyrolactone (9)
Synthesis
The lactone 9 (0.25 g, 1.1 mmol) was added to aq. KOH
(0.1 M, 10 mL) and the resulting solution was heated to 608C for
24 h. The mixture was allowed to cool to room temperature and
then washed with diethyl ether (15 mL). The aqueous phase was
acidified to pH ,3 with conc. HCl and extracted with diethyl
ether (3 ꢁ 15 mL). These latter extracts were combined, dried
over sodium sulphate, and filtered. Dicyclohexylamine was
added to the filtrate to afford 8 (0.28 g, 61 %) as a white powder.
mp 138–1418C.
Dicyclohexylammonium 2S-Benzyloxycarbonylamino-
4-hydroxy Butyrate (8) and 2S-
[(Benzyloxycarbonylamino]-4-butyrolactone (9)
Iodomethane (21.1 mL, 0.34 mmol) was added dropwise to a
stirred mixture of L-methionine (25.1 g, 0.17 mol) in 45 % aq.
methanol (500 mL), and the resulting mixture was stirred at
room temperature for 20 h. Thereafter, the solution was placed
under reduced pressure for half an hour to remove excess
iodomethane before being cooled to 08C. This reaction mixture
was then used in the next step without further purification.
A small sample was removed, concentrated under vacuum and
then analysed to confirm formation of the sulfonium salt.
dH (D2O) 3.90 (t, J 6.3, 1H), 3.70–3.49 (m, 2H), 2.98 (s, 6H),
2.53–2.44 (m, 2H); dC (D2O) 172.9, 53.4, 49.6, 40.2, 25.7; nmax
(Nujol)/cmꢂ1 3444, 1614;m/z328 (2Mþ),164(Mþ);m/z(HRMS)
Calc. for C6H14NO2Sþ [Mþ]: 164.0745, found 164.0739.
Sodium hydrogen carbonate (16.93 g, 0.20 mol) was added
to the mixture containing the sulfonium salt, described above,
and the resultingsolution was stirred atrefluxfor 24h. Thereafter,
the mixture was concentrated under vacuum to yield crude 7 as a
pale yellow oil. This crude oil was used in the next step without
purification.
dH (D2O, 400 MHz) 3.71 (t, J 8, 1H), 3.43 dd, J 12, 8, 2H),
2.58 (t, J 8, 2H); dC (D2O) 177.2, 61.7, 56.4, 35.2; nmax (Nujol)/
cmꢂ1 3424, 1631, 1058; m/z 261 ([2M þ Na]þ), 142 ([M þ
Na]þ); m/z (HRMS) Calc. for [(C4H9O3N)Na]þ: 142.0480,
found 142.0473.
The crude oil containing 7, described above, was dissolved in
water (350 mL) with sodium hydrogen carbonate (35.7 g,
0.43 mol). Benzyl chloroformate (31.5 mL, 0.22 mol) was added
dropwise, andtheresulting solutionstirredfor2.25 h. Thereafter,
the reaction mixture was washed with diethyl ether (3 ꢁ 60 mL)
and the aqueous phase acidified with concentrated HCl (to pH
,3). The butyrolactone 9 (10.1 g, 23 % from L-methionine) was
isolated from the ether wash as a white solid. The acidified
aqueous phase was extracted with diethyl ether (5 ꢁ 80 mL), the
organic layers were combined, dried over sodium sulfate, and
filtered. Dicyclohexylamine was added to the filtrate to afford 8
(25.0 g, 31 % from L-methionine) as a white precipitate.
2S-Benzyloxycarbonylamino-4-hydroxy Butyric
Acid Benzyl Ester (10)
Benzyl bromide (1.7 mL, 14 mmol) was added to a suspen-
sion of 8 (5.13 g, 12 mmol) in dry DMF (20 mL) and left to stir
for 21 h at room temperature under an atmosphere of nitrogen.
Thereafter, the mixture was poured into water (150 mL) and
subsequently extracted with diethyl ether (5 ꢁ 50 mL). The
organic layers were combined, washed with water (50 mL),
dried over sodium sulfate, and filtered. The filtrate was concen-
trated under vacuum to yield crude 10 (3.89 g, 95 % crude yield)
as a viscous, yellow oil. This crude product was used in the next
reaction without further purification.
dH (CDCl3) 7.31 (br s, 10H), 5.72 (br d, J 7.3, 1H), 5.18
(s, 2H), 5.11 (s, 2H), 4.59 (m, 1H), 3.75–3.65 (m, 2H), 2.15 (m,
1H), 1.71 (m, 1H); dC (CDCl3) 172.2, 156.6, 136.0, 135.l, 128.5
(4 carbons), 128.2, 128.1, 67.4, 67.3, 58.4, 51.6, 35.4; nmax
(neat)/cmꢂ1 3343, 1721, 1669, 1530, 1498, 1060, 738; m/z 366
([M þ Na]þ); m/z (HRMS) Calc. for [(C19H21NO5)Na]þ:
366.1317, found 366.1307.
2S-Benzyloxycarbonylamino-4-oxo-butyric
Acid Benzyl Ester (11)
Pyridinium chlorochromate (0.62 g, 2.9 mmol), anhydrous
˚
sodium acetate (0.25 g, 2.9 mmol), and powdered 4 A molecular
sieves (,0.25 g) was added to a solution of 10 (0.83 g,
2.4 mmol) in dry dichloromethane (15 mL). The reaction mix-
ture was left to stir at room temperature under nitrogen for 1.5 h.
Thereafter, the reaction mixture was filtered through a plug of
silica eluting first with dichloromethane (100 mL) followed by
ethyl acetate (100 mL). The ethyl acetate fraction was concen-
trated under vacuum to yield the crude product as a yellow oil.
The crude product was purified by flash chromatography
(n-hexane/ethyl acetate 7 : 3, Rf 0.16) to yield 11 (0.67 g, 73 %
from 8) as a white solid.
Mp 74–758C (lit. 76–788C[24]); dH (CDCl3) 9.68 (s, 1H), 7.29
(br s, 10H), 5.71 (br d, J 8.1, 1H), 5.17 (s, 2H), 5.10 (s, 2H), 4.64
(m, 1H), 3.25–2.95 (m, 2H), 3.11 (dd, J 19.1, 35.1); dC (CDCl3)
199.0, 170.5, 155.9, 136.0, 135.7, 128.4 (4 carbons), 128.2, 128.1,
67.9, 67.3, 49.3, 46.0; nmax (Nujol)/cmꢂ1 3316, 1746, 1716, 1681,
1538, 1053, 753; m/z 705 ([2M þ Na]þ), 342 ([M þ H]þ).
Characterisation of Dicyclohexylammonium
2S-Benzyloxycarbonylamino-4-hydroxy Butyrate (8)
Mp 139–1418C; dH (CDCl3) 9.27 (br s, 2H), 7.36 (br s, 5H),
5.96 (br d, J 6.1, 1H), 5.11 (s, 2H), 4.13 (m, 1H), 3.80–3.70 (m,
2H), 2.95–2.85 (m, 2H), 2.06 – 1.22 (m, 22H); dC (CDCl3)
176.4, 156.4, 136.6, 128.5, 128.1 (2 carbons), 66.8, 60.2, 54.6,
52.8, 37.2, 29.6, 25.4, 24.9; nmax (Nujol)/cmꢂ1 3358, 1712,
1628, 1552; m/z 435 ([M þ H]þ); m/z (HRMS) Calc. for
[(C24H38N2O5)H]þ: 435.2859, found 435.2851.
Characterisation of 2S-[(Benzyloxycarbonylamino]-
4-butyrolactone (9)
2S-Benzyloxycarbonylamino-6-oxo-hex-4-enoic
Acid Benzyl Ester (12)
Mp 126–1278C (lit., 129–1308C[28]); dH (CDCl3) 7.36 (br s,
5H), 5.37 (br s, 1H), 5.13 (s, 2H), 4.43 (m, 2H), 4.25 (m, 1H),
Triphenylphosphoranylideneacetaldehyde (2.15 g, 7.1 mmol)
was added to a solution of 11 (0.81 g, 2.4 mmol) in dry

Synthesis of Two E-Diastereoisomers of 4,5-Methano-L-lysine
1109
dichloromethane (30 mL). The resulting mixture was stirred at
room temperature under nitrogen for 20 h. Thereafter, the
reaction mixture was concentrated under vacuum to yield the
crude product as a sticky red solid. The crude product was
purified by flash chromatography (n-hexane/ethyl acetate 10 : 3,
Rf 0.24) to yield 12 (0.71 g, 81 %) as a yellow oil.
[a]D þ9.2 (c 0.4, CHCl3); dH (CDCl3) 9.42 (d, J 7.8, 1H),
7.35 (br s, 10H), 6.64 (dt, J 7.2, 15.6, 1H), 6.10 (dd, J 7.8, 15.6,
1H), 5.40 (m, 1H), 5.23 (d, J 12.0, 1H), 5.14 (d, J 12.0, 1H), 5.11
(s, 2H), 4.66 (m, 1H), 3.00–2.63 (m, 2H); dC (CDCl3) 193.1,
170.6, 155.6, 150.8, 135.5, 134.7 (2 carbons), 128.8, 128.7,
128.6, 128.3, 128.1, 67.7, 67.2, 52.9, 35.7; nmax (neat)/cmꢂ1
3331, 1724, 1642, 1526, 1052, 977, 739, 698; m/z 757 ([2M þ
Na]þ), 390 ([M þ Na]þ). m/z (HRMS) Calc. for [(C21H21NO5)
Na]þ: 390.1317, found 390.1299.
[a]D þ2.0 (c 0.4, CHCl3); dH (CDCl3) 7.40–7.25 (m, 10H),
5.54 (br d, J 8.0, 1H), 5.20–5.05 (m, 4H), 4.48 (m, 1H), 3.55 (m,
1H), 3.06 (dd, J 9.7, 9.9, 1H), 2.03 (m, 1H), 1.40 (m, 1H), 0.74
(m, 1H), 0.57 (m, 1H), 0.34 (m, 2H). dC (CDCl3) 172.4, 156.2,
136.2, 135.1, 128.8 (2 carbons), 128.7 (2 carbons), 128.4, 128.3,
67.3, 67.0, 66.4, 54.3, 36.0, 20.8, 14.2, 9.1; nmax (neat)/cmꢂ1
3335, 2928, 1719, 1586, 1528, 1499, 1455, 1343, 1194, 1104,
1054, 918, 751, 698; m/z 789 ([2M þ Na]þ), 406 ([M þ Na]þ);
m/z (HRMS) Calc. for [(C22H25NO5)Na]þ; 406.1630; found
406.1618.
The higher Rf (0.20 in n-hexane/ethyl acetate 7 : 3) alcohol,
15 (0.64 g, 35 %) was obtained as a colourless oil. HPLC
retention time: 7.4 min.
[a]D ꢂ12.8 (c 0.6, CHCl3); dH (CDCl3) 7.40–7.25 (m, 10H),
5.59 (br d, J 9.0, 1H), 5.20–5.05 (m, 4H), 4.58 (m, 1H), 3.83 (m,
1H), 2.98 (br d, J 5.3, 1H), 2.86 (t, J 4.6, 1H), 1.99 (m, 1H), 1.30
(m, 1H), 0.94 (m, 1H), 0.57 (m, 1H), 0.40–0.30 (m, 2H); dC
(CDCl3) 172.1, 156.5, 136.2, 135.2, 128.8, 128.7 (2 car-
bons),128.5, 128.4 (2 carbons), 67.3, 67.2, 66.7, 54.5, 37.6,
21.2, 14.6, 9.2; nmax (neat)/cmꢂ1 3335, 2928, 1719, 1586, 1528,
1499, 1455, 1343, 1194, 1104, 1054, 918, 751, 698; m/z 789
([2M þ Na]þ), 406 ([M þ Na]þ); m/z (HRMS) Calc. for
[(C22H25NO5)Naþ]; 406.1630, found 406.1622.
2S-Benzyloxycarbonylamino-6-hydroxy-hex-4-enoic
Acid Benzyl Ester (13)
Sodium borohydride (0.01, 0.3 mmol) was added in small
portions to a cooled solution of 12 (0.10 g, 0.3 mmol) and cerium
trichloride heptahydrate (0.12 g, 0.3 mmol) in dry THF (5 mL).
The resulting solution was allowed to warm to room temperature
and stirred for 1 h under nitrogen. Thereafter, the reaction
mixture was diluted with water (30 mL, dropwise at first) and
then extracted into chloroform (3 ꢁ 30 mL). The organic layers
were combined, washed with water (10 mL), brine (10 mL),
dried over sodium sulfate, and filtered. The filtrate was concen-
trated under vacuum to yield the crude product as a yellow oil.
The crude product was purified by flash chromatography
(n-hexane/ethyl acetate 4 : 1, Rf 0.14) to yield 13 (0.87 g,
84 %) as a yellow oil.
[a]D þ12.3 (c 0.4, CHCl3); dH (CDCl3) 7.40–7.25 (m, 10H),
5.64 (m, 1H), 5.49 (m, 1H), 5.20 (d, J 5.8, 1H), 5.15 (d, J 5.8,
1H), 5.10 (s, 2H), 4.49 (m, 1H), 3.99 (d, J 5.5, 2H), 2.60–2.40
(m, 2H); dC (CDCl3) 172.1, 155.9, 136.3, 135.4, 134.2, 128.6
(2 carbons), 128.7, 128.6, 128.3, 128.1, 125.3, 67.6, 67.3, 63.0,
53.8, 35.6; nmax (neat)/cmꢂ1 3343, 1783, 1715, 1609, 1588,
1530, 1053, 913, 739, 698; m/z 761 ([2M þ Na]þ), 392 ([M þ
Na]þ); m/z (HRMS) Calc. for [(C21H23NO5)Na]þ: 392.1474,
found 392.1472.
Stereoselective Synthesis of (10R,20S)-2S-
Benzyloxycarbonylamino-3,2(20-hydroxymethyl
cyclopropyl)propionic Acid Benzyl Ester (14)
To a solution of diethylzinc (0.675 mmol) in anhydrous
dichloromethane (1.4 mL) at 08C was added diiodomethane
(110 mL,1.35 mmol, 4.4 equiv.). The mixture was stirred at 08C
for 10 min while a white precipitate formed. A solution of
N,N,N0,N0-tetramethyl-D-tartaric acid diamide butylboronate
16 (93.7 mg, 0.344 mmol, 1.1 equiv.) and allylic alcohol 13
(112 mg, 0.30 mmol, 1 equiv.) in dichloromethane (2.0 mL)
was added rapidly by a cannula. The resulting mixture was
stirred at room temperature for 2 h and then cooled to 08C.
Saturated aq. ammonium chloride was added and the mixture
was extracted with three portions of ethyl acetate. The combined
organic layers were washed with brine, dried over magnesium
sulfate, and the solvent removed under reduced pressure. The
crude residue was analysed by NMR and HPLC showing .95 %
conversion and a 94 : 6 diastereomeric ratio (d.r.). The major
diastereomer was found to have identical NMR and HPLC
properties as the lower Rf compound mentioned above. Based
on consistent stereochemical outcomes observed by Charette
and co-workers,[26,27] the configuration of this major diastereo-
mer was assigned to be 10R,20S.
(10R,20S)- and (10S,20R) 2S-Benzyloxycarbonylamino-
3,2(20-hydroxymethyl cyclopropyl)propionic Acid
Benzyl Ester (14 and 15)
Diiodomethane (2.4 mL, 30.0 mmol) was added dropwise to
a solution of 1 M diethyl zinc in n-hexane (15.1 mL, 15.0 mmol)
in dry dichloromethane (10 mL), under nitrogen at 08C. This
mixture was stirred for 10 min while a white precipitate formed.
A solution of 13 (1.77 g, 4.7 mmol) in dry dichloromethane
(10 mL) was added to the mixture. The reaction mixture was
allowed to warm to room temperature and stirred for 4 h.
Thereafter, the reaction mixture was cooled to 08C and
quenched with saturated aq. ammonium chloride (10 mL) and
extracted with ethyl acetate (3 ꢁ 10 mL). The organic layers
were combined, washed with brine (10 mL), dried over magne-
sium sulfate, and filtered. The filtrate was concentrated under
vacuum to give the crude product as a yellow oil. The crude
product was purified by gravity column chromatography
(n-hexane/ethyl acetate 7 : 3) allowing separation of the two
diastereomers.
(10S,20R) 3-(20-Azidomethyl cyclopropyl)-2S-
benzyloxycarbonylamino-propionic Acid
Benzyl Ester (18)
Triphenylphosphine (0.16 g, 0.6 mmol) and carbon tetrabro-
mide (0.20 g, 0.6 mmol) was added to a solution of 15 (0.15 g,
0.4 mmol) in dichloromethane (5 mL). The resulting mixture
was stirred under nitrogen at room temperature for 2 h. There-
after, the reaction mixture was quenched with saturated aq.
NaHCO3 (5 mL). The organic layer was separated from the
aqueous layer, washed with brine, dried over sodium sulfate, and
filtered. The filtrate was then concentrated under vacuum and
redissolved in dry DMF (5 mL). Sodium azide (0.10 g 2.4 mmol)
was then added and the reaction mixture was stirred under
nitrogen for 4 h. Thereafter, the reaction mixture was treated
The lower Rf (0.19 in n-hexane/ethyl acetate 7 : 3) alcohol,
14 (0.62 g, 34 %) was obtained as a colourless oil. HPLC
retention time: 6.9 min.

1110
T. M. Altamore et al.
with water and extracted into dichloromethane. The organic
layer was separated from the aqueous layer, dried over sodium
sulfate, and filtered. The filtrate was concentrated under vacuum
to yield the crude product as a yellow oil. The crude product was
purified by flash chromatography (n-hexane/ethyl acetate 15 : 5)
to yield 18 (0.12 g, 74 %) as a colourless oil.
Rf (0.18 in n-hexane/ethyl acetate, 15 : 5); [a]D ꢂ31.9 (c 0.3,
MeOH); dH (CDCl3) 7.36 (br s, 10H), 5.64 (br d, J 8.4, 1H), 5.19
(s, 2H), 5.12 (s, 2H), 4.53 (m, 1H), 3.07 (m, 2H), 1.77 (m, 2H),
0.86 (m, 1H), 0.58 (m, 1H), 0.42 (m, 2H); dC (CDCl3) 171.2,
155.8, 136.3, 135.3, 129.3–127.9 (6 carbons), 68.3 (3 carbons),
53.4, 35.4, 23.8, 13.3, 11.1; nmax (neat)/cmꢂ1 3340, 2128, 1786,
1726, 1587, 1520, 1055, 739, 698; m/z 409 ([M þ H]þ), 381
([(M ꢂ N2) þ H]þ).
3132, 2098, 1626, 1601; m/z 159 ([M þ H])þ; m/z (HRMS)
Calc. for [(C7H14N2O2)Hþ]; 159.1134, found 159.1138.
Supplementary Material
Characterisation data for compounds 12–15, 19, and 20 as well
as HPLC traces and proton NMR spectra relevant to the ste-
reoselective cyclopropanation reaction are available on the
Journal’s website.
Acknowledgements
This work was carried out with funding from the Australian Research
Council, Monash University and CSIRO.
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[a]D ꢂ8.1 (c 0.3, H2O); mp 162–1638C; dH (D2O) 3.68 (m,
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