Optically active nitroalkenes - Synthesis, addition reactions and transformation into amino acids

Article abstract of DOI:10.1016/S0040-4020(02)01406-0

Optically active nitroalkenes 4 were synthesized via Henry reaction. Conjugate addition of vinylmagnesium bromide to 4 gave nitroalkane syn-5 while cyclopropanation with sulfur ylides or dibromocarbene afforded nitrocyclopropanes 8, 10 and 11 in a diaster

Full text of DOI:10.1016/S0040-4020(02)01406-0

Tetrahedron 58 (2002) 10485–10500
Optically active nitroalkenes—synthesis, addition reactions
and transformation into amino acids
*
¨
Jan Hu¨bner, Ju¨rgen Liebscher and Michael Patzel
¨
¨
Institut fur Chemie, Humboldt-Universitat Berlin, Brook-Taylor-Strasse 2, D-12489 Berlin, Germany
Dedicated to Professor Dr Dr h. c. Ekkehard Winterfeldt on the occasion of his 70th birthday
Received 12 June 2002; revised 19 September 2002; accepted 24 October 2002
Abstract—Optically active nitroalkenes 4 were synthesized via Henry reaction. Conjugate addition of vinylmagnesium bromide to 4 gave
nitroalkane syn-5 while cyclopropanation with sulfur ylides or dibromocarbene afforded nitrocyclopropanes 8, 10 and 11 in a
diastereoselective manner. These products were used to synthesize optically active b-amino acids 7 and 16 as well as cyclopropane g-amino
acids 19 and 20 by reduction of the nitro group and oxidative cleavage of the dioxolane substituent. q 2002 Elsevier Science Ltd. All rights
reserved.
Nitroalkenes have found wide application in organic
synthesis.1 Their character as electron deficient alkenes
allows easy 1,4-addition reactions or cycloadditions to the
C–C-double bond. Such additions can be diastereoselective
if chiral substituents are attached to the C–C-double bond.2
Recently the stereoselective 1,3-dipolar cycloaddition of
diazomethane to nitroalkenes derived from glyceraldehyde
was reported.3 Elimination of nitrogen from the resulting
pyrazolines gave access to chiral nitrocyclopropanes.
Following our strategy to use optically active nitroalkenes
as precursors for amino acids, we described first results of
the conjugate addition of organometallics and cyclopropa-
nation at nitroalkenes 4 (Rp¼dioxolanyl) derived from
glyceraldehyde, to nitroalkanes and nitrocyclopropanes,
respectively.4 We now report attempts to convert these
products into optically active b-amino and g-amino acids
mainly in the cyclopropane series. Such amino acids are
incorporated in a series of biologically active1 natural
products, e.g. bestatin, pepstatin and cryptophycin A.5a,b
Furthermore, they are of interest in the synthesis of
unnatural peptides and b-lactams. g-Amino acids have
gained considerable attention as analogues of g-amino
butyric acid, which acts a neurotransmitter in the brain.6
acid moiety by glycol cleavage. The nitroalkenes 4 appeared
as E/Z-mixtures, which could be separated by flash
chromatography (Scheme 1). Nitroalkenes 4f–4h were
prepared by protective group manipulation at the (E)-isomer
of nitroalkenes 4b and 4e.
Investigations of conjugate additions of organometallic
reagents to nitroolefines 4 by Cossio et al. and our group2e,4
revealed that the anti-adduct predominated the syn-isomer
in most cases. We chose the vinylated adduct syn-5,
obtained by Grignard addition of vinylmagnesium bromide
to nitroolefin (E)-4a, as precursor for an enantiopure
b-amino acid by reduction of the nitro group and glycol
cleavage (Scheme 2). After reduction of the nitro group and
Boc-protection the resulting homoallyl amine was hydro-
genated and O-deprotected affording the aminoalcohol 6.
The latter gave the envisaged b-amino acid 7 upon glycol
cleavage with NaIO4/RuCl3. This method is known to
maintain chirality in the synthesis of other b-amino acids.8
The optical purity and the configuration of the final
product 7 could be proved by comparison with literature
data of the corresponding methyl derivative,8 which served
as building block in the total synthesis of cryptophycin-
derivatives.8
Nitroalkenes 4 (Table 1) were obtained starting from
(R)-glyceraldehyde, (L)-serine and the Garner aldehyde
adopting known procedures, i.e. by Henry reaction and
dehydration of the resulting nitroaldols 3.7 The chiral
substituents Rp will later serve as precursors for a carboxylic
As shown in the previous short communication,4 sulphur
ylides are useful reagents for the cyclopropanation of
nitroalkenes (Z)-4 and (E)-4 to nitrocyclopropanes 8b and
10 or 11 (Table 2), respectively (Schemes 3 and 4,
respectively). Polymerisation of the nitroalkene and for-
mation of a 1,2-oxazoline-N-oxide 12 (v.i.) were occasion-
ally observed as side reactions. Further investigations
(Scheme 3) using dibromocarbene allowed cyclopropa-
nation of (Z)-4b to 8a but in comparatively low yield.
Keywords: cyclopropanation; nitroolefines; conjugate addition; amino
acids.
*
Corresponding author. Fax: þ49-3020936940;
e-mail: michael.paetzel@rz.hu-berlin.de
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01406-0

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J. Hubner et al. / Tetrahedron 58 (2002) 10485–10500
10486
Scheme 1. (a) KF (cat.), neat, room temperature, 18 h; or (b) KF (cat.), iPrOH, benzene (10:1), room temperature, 18 h; 62–95%; (c) DCC (1.2 equiv.), CuCl
(cat.), Et2O, room temperature, 24–100 h; 14–70%; (d) MsCl (1.2 equiv.), Hu¨nig’s base (2.5 equiv.), CH2Cl2, 2788C to room temperature, 2 h; 60–70%.
In contrast to the other cases 10/11 (Table 2) no
diastereoselectivity could be achieved in the cyclopropana-
tion of the nitroalkene (E)-4d to 10f/11f with sulphur ylides.
In this sterically congested case, relatively high reaction
temperature was necessary thus preventing a stereoselective
reaction. Unfortunately neither the diastereomers 10f and
11f nor diastereomeric mixtures of their derivatives, such as
the corresponding aminocyclopropanes could be separated.
In the other cases, cyclopropanation of (Z)-4 and (E)-4 gave
preferentially syn/cis 8 and syn/trans 10, respectively. This
stereochemical outcome can be explained by the anti-
periplanar effect,9 where negatively charged nucleophiles
add anti with respect to an a-heteroatom-substituted group
attached to the reactive site. This situation is shown for the
dioxolane-substituted nitroalkene 4b in Scheme 5a and b.
According to Houks, outside crowded model,10 the
transition state b leading to the syn-product is preferred
because it keeps the small hydrogen atom in the crowded
outside position. Density functional calculations of related
nitroalkenes and their transition states in 1,3-dipolar
cycloaddition with diazomethane show the same preferred
conformations and diastereofacilities.3 Since the relative
orientation of the substituents at the alkene moiety of 4 was
maintained, i.e. (Z)-4 gave cis-8 (Scheme 3) and 4 gave
trans-10/11 (Scheme 4), the second step of the cyclo-
propanation must be fast. Thus there is not enough time for a
Table 1. Nitroalkenes 4
4
Rp
R
Starting material
Method
Isolated yield (%) of 4
(E)-4/(Z)-4
a
H
1
B
60
90:10
b
c
Me
Me
Me
1
1
1
B
70
70:30
A (Et2O)
A (THF)
35
26
92:8
20:80
d
B
61
76:24
e
f
Me
Me
Me
Me
1
A (Et2O)
14a
72
95:5
4b
4f
4e
Pure E
Pure E
Pure E
g
25
h
100
a
80% starting material recovered.

¨
J. Hubner et al. / Tetrahedron 58 (2002) 10485–10500
10487
Scheme 2. (a) HCvCH–MgBr, THF, 2788C; (b) LiAlH4 (4.0 equiv.), Et2O, room temperature, 1 h; 96%; (c) Boc2O (3.2 equiv.), NaHCO3 (excess), dioxane,
H2O (1:1), room temperature, 18 h; 90%; (d) H2 (1 bar), Pd–C (cat.), MeOH, room temperature, 2 h; (e) TsOH (cat.), MeOH, room temperature 2 h, 78% (over
the two steps); (f) NaIO4 (2.5 equiv.), RuCl3£7H2O (cat.), H2O, MeCN, CCl4 (1:1:1), room temperature, 2 h; 73%.
rotation around the C–C-bond derived from the starting
C–C-double bond in the intermediate 9 (Scheme 4).11 The
formation of the 1,2-oxazoline-N-oxide 12 as by-product in
some cyclopropanations (see also footnote Table 2) can be
explained via the same intermediate 9, by nucleophilic
intramolecular displacement of the diphenylsulfide group by
the nitro oxygen atom rather than by the carbon atom
(Scheme 4). Similar 1,2-oxazoline-N-oxides were observed
before in cyclopropanation reactions of other nitroalkenes
with dimethyloxosulfoniummethylide.12
The structure of products 10–12 was elucidated by
NMR-data and X-ray crystal analyses of 10c and 8b.4
In order to synthesize 2-aminocyclopropane-1-carboxylic
acids such as 16 from nitroalkenes 10 the nitro group had to
Table 2. Nitrocyclopropanes 10 and 11
10
11
Rp
R
R1
Yield
60
10/11
a
a
H
CH3
70:30a
b
c
b
CH3
H
25b
60:40
97:3
CH3
CH3
90
d
CH3
CH3
74
95:5
e
f
CH3
CH3
CH3
CH3
37
3:97
f
54a,c
50:50
a
Not separable.
By-product 12 in 15% yield, d.v. 60:40.
84% conversion.
b
c

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J. Hubner et al. / Tetrahedron 58 (2002) 10485–10500
10488
Scheme 3. (a) CHBr3 (1.05 equiv.), NaOH (50% in H2O), benzene, room temperature, 17 h; 24%, d.r. .95:5; (b) PhSþ2CMe (1.2 equiv.), DME, 2708C to
room temperature, 18 h; 74%, d.r. 94:6.
Scheme 4.
be reduced and the glycol moiety had to be oxidized. It was
advantageous to reduce the nitro group first. Catalytic
hydrogenation at 15 or 25 atm, respectively, gave high
yields of the corresponding aminocyclopropanes 13a and
13b under optimised conditions (Scheme 6, Table 3).
Higher pressures caused unfavourable ring opening reac-
tions. In order to lower the nucleophilicity of the amino
groups and thus stabilizing the expected amino acids one or
two electron-withdrawing protective groups were intro-
duced affording N-protected aminocyclopropanes 14
(Table 3) and 15, respectively. The O-deprotected amino-
cyclopropylglycols, obtained after acid hydrolysis of 13
or 14 were submitted to glycol cleavage. However,
N-monoprotected aminocyclopropanes gave only complex
reaction mixtures under different conditions such as with
Pb(OAc)4 in dichloromethane at 2788C, with NaIO4 in
methanol or with NaIO4/RuCl3, without the possibility of
isolating definite products. Presumably, the amino cyclo-
propane carbaldehydes formed by glycol cleavage from
the amines 13 or 14 were sensitive to opening of the
cyclopropane ring. Such cleavages are well known, if donor
and acceptor substituents are attached to adjacent positions
of the cyclopropane ring. This assumption is supported by
the fact that the N,N-ditosylated aminocyclopropane 15,
which has no nucleophilicity at the nitrogen atom could
successfully converted to the anticipated 2-aminocyclopro-
pane-1-carboxylic acid 16 upon treatment with NaIO4/
RuCl3. Product 16 is the first example of an optically active
b-alkylsubstituted b-aminocyclopropane carboxylic acid.
The total yield of 16 over six steps starting from the
nitroalkene (E)-4b was 14%. Hitherto racemic b-amino-
cyclopropane carboxylic acids or derivatives have been
known with a hydrogen atom or an ester or acid moiety
attached to the b-position or in the bicyclic series. They
were synthesized via Curtius or Hoffmann rearrangement,
by cyclopropanation of N,N-disubstituted vinylamines with
Scheme 5.

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J. Hubner et al. / Tetrahedron 58 (2002) 10485–10500
10489
Scheme 6. (a) H2 (10–15bar), Pd–C (cat.), MeOH, room temperature, 48 h; 74%; (b) N-protection yields, see Table 3; (c) NaH (1.07 equiv.), TsCl (1.0 equiv.),
DMF, room temperature, 15 h; 74%; (d) p-TsOH£1H2O (cat.) MeOH, H2O (10:1), room temperature, 18 h; 86%; (e) NaIO4 (8.0 equiv.), RuCl3£7H2O (cat.),
MeCN, CHCl3, H2O (1:1:1.5), room temperature, 5 h; 56%; (f) p-TsOH£1H2O (cat.) MeOH, H2O (10:1), room temperature, 18 h; R¼Me: PG¼Boc, 72%,
PG¼Cbz, 80%; PG¼Bz, 83%; PG¼CF3CO, 92%; PG¼Ts, 89%; PG¼N-Cbz-Gly, 67%; R¼–(CH)–: PG¼Boc, 93%, PG¼Bz, 80%; (g) Et3SiCl (3.0 equiv.),
Net3 (4.0 equiv.), CH2Cl2, DMAP (cat.), 2188C to room temperature, 18 h; PG¼Bz, 76%; PG¼N-Cbz-Gly, 85%; PG¼CF3CO, 97%; (h) Swern oxidation;
PG¼Bz, 68%; PG¼N-Cbz-Gly, 77%; PG¼CF3CO, 77%; (i) NaOCl2 (1.4 equiv.), H2O (1.05 equiv.), NaH2PO4 (cat.), MeCN, H2O (2:1), 08C to room
temperature, 1 h; PG¼Bz, 99%; PG¼N-Cbz-Gly, 82%; PG¼CF3CO, 42%; (j) Ba(OH)2£8H2O (4.8 equiv.), MeOH, room temperature/reflux, 24 and 2 h,
respectively; 96%.
diazoacetate,13,14 by addition of amines to cyclopropene
carboxylates15 or by carboxylation of lithiated cyclopropyl-
amines.16 Some of those investigations also revealed that
N-unprotected b-aminocyclopropane carboxylic acids show
a tendency towards ring opening reactions affording
derivatives of b-formyl or b-acylcarboxylic acids.13
Since the sensitivity of 2-aminocyclopropane-1-carboxylic
Table 3. Aminocyclopropanes 13, 14, 17, 18 and aminocyclopropane carboxylic acids 19, 20
PG
R0
Product (yield (%))
17
13
14
18
19
20
H
H
Boc
Z
Me
a (74)
b (47)
(CH2)3
Me2
Me2
a (80)
b (99)
c (99)
d (70)
e (57)
f (63)
g (88)
CFCO
N-Z-Gly
Ts
Boc
Bz
Me2
Me2
Me2
(CH2)5
(CH2)f
c (97)
d (85)
ca
d (77)
c (42)b
d (82)
(96)
g (76)
g (68)
g (99)
a
Used as crude product in the oxidation to 19c.
Yield over two steps starting from 17c.
b

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J. Hubner et al. / Tetrahedron 58 (2002) 10485–10500
10490
Scheme 7. (a) p-TsOH£1H2O (cat.) MeOH, H2O (10:1), room temperature, 18 h; 100%; (b) NaIO4 (1.1 equiv.), MeOH, phosphate buffer (pH 7) (4:1), room
temperature, 2 h; 77%; (c) air, CHCl3, 48 h; 90% or NaIO4 (1.0 equiv.), RuCl3£7H2O (cat.), MeCN, CCl4, H2O (1:1:1.5), room temperature, 2.5 h; 79%;
(d) CH2N2 (3.0 equiv.), Et2O, 08C, 1 h; 100%; (e) p-TsOH£1H2O (cat.) MeOH, H2O (10:1), room temperature, 18 h; 100%; (f) NaIO4 (2.2 equiv.),
RuCl3£7H2O (cat.), MeCN, CCl4, H2O (1:1:1.5), room temperature, 2.5 h; 70%.
acids against ring opening reactions is caused by the
presence of an electron-withdrawing and an electron-
donating substituent at the cyclopropane ring, higher
homologues, i.e. 2-(2-aminocyclopropyl)-2-hydroxycarb-
oxylic acids such as 20, with the electron acceptor not
directly being attached to the ring, can be expected to be
more stable.17 The synthesis of the g-amino acid 20 was
straightforward. The glycols, obtained from the N-mono-
protected amines 14 were O,O-deprotected with triethylsilyl
chloride (formation of 17) and submitted to Swern oxidation
affording aldehydes 18 (Scheme 6, Table 3). Upon further
oxidation of the aldehyde with sodium chlorite/H2O2 the
remaining TES-group was also lost and thus the correspond-
ing b-hydroxy carboxylic acids 19 were directly obtained
(Table 3). The target molecule 20 could be generated by
deprotection of the trifluoroacetyl derivative 19c and was
found to be stable, as expected. The successful synthesis of
the glycine derivative 19d further demonstrated that
nitroalkenes 4 can also serve as precursors for interesting
dipeptides of an a-amino and a g-amino acid.
first glycol cleavage of the dioxolane moiety and final
reduction of the nitro group. Thus trans-10c was depro-
tected and oxidized with NaIO4 in methanol affording the
cyclopropane carbaldehyde 21, which could be transformed
into the corresponding acid 22a in high yield by air-
oxidation or with NaIO4/RuCl3. A one-pot procedure, i.e.
direct conversion of 10c into 22a with NaIO4/RuCl3 was
less efficient. The aldehyde 21 turned out to be reluctant to
oxidation by other oxidizing reagents such as NaOCl,
KMnO4, H2O2 or pyridinium dichromate probably due to
sterical hindrance. The synthesis of the cis-2-nitro-cyclo-
propane-1-carboxylic acid 23 could be achieved in a similar
sequence starting from the cis-nitrocyclopropane 8b. The
cyclopropane carboxylic acid 22a was converted into the
corresponding methyl ester 22b with diazomethane.
Unfortunately, the final reduction of the nitro groups of 22
and 23 which would have led to the anticipated amino acids,
was unsuccessful, because the envisaged cyclopropanes
face the problem of donor and acceptor substituents at
adjacent positions again. Thus opening of the cyclopropane
ring occurred under catalytic hydrogenation or with Ni2B
leading to the oximes of the corresponding g-ketoacid or
ester. NaBH4 reduction of 22b effected the ester moiety
rather than the nitro group affording the corresponding
alcohol.
In order to synthesize 2-amino-cyclopropane-carboxylic
acids similar to 16 starting from nitrocyclopropane 10c we
approached a reversed reaction sequence (Scheme 7), i.e.
If the hydrolytic acetal cleavage of the dioxolane in
compound 10c was exerted under too strongly acid
conditions, i.e. with concentrated aqueous HCl, the cis-
tetrahydrofurane 26 was obtained in up to 38% yield. This
product could be formed via carbenium ion 24, which gave
intramolecular ether formation and final Neef reaction
(Scheme 8). 3-Acyl-4-hydroxytetrahydrofuranes are rare
compounds. Besides some sugar derivatives with hetero-
substituents in position 5, racemic 3-aroyl-4-hydroxy-
tetrahydrofuranes were reported by ring opening of
isoxazolines18 and optically active compounds were
obtained by kinetic resolution of the products or precursors
using lipase.19
In summary, it could be demonstrated that nitroalkenes are
versatile precursors for the synthesis of interesting optically
active b-amino and g-amino acids either via conjugate
addition of organometallics or via cylopropanation with
Scheme 8.

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J. Hubner et al. / Tetrahedron 58 (2002) 10485–10500
10491
sulphur ylides. The nitro group served as a precursor for the
amino functionality and a dioxolanyl side chain as precursor
for the carboxylic acid moiety. Amino acids where the
amino group and the carboxylate group are attached to
adjacent positions of a cyclopropane ring are instable and
have to be protected by two strong electron withdrawing
N-protective groups.
was washed with water, 2N HCl and sat. NH4Cl-solution.
After drying with MgSO4 the solvent was evaporated under
reduced pressure and the remaining residue was purified by
chromatography as described above.
1.1.1. (4S)-(E)-2,2-Dimethyl-4-(2-nitro-vinyl)-[1.3]dioxo-
lane [(E)-4a].2d Yellow oil. [a] ¼þ39.6 (c 1.3, CH2Cl2).
20
546
rf¼0.55 (hexane/AcOEt, 7:3). 13C NMR d 140.2 (Cq–NO2),
139.0 (CHv), 110.8 (C), 72.0 (CH), 68.3 (CH2), 26.3
1
(CH3), 25.4 (CH3). H NMR d 7.14 (s, 2H), 4.73 (t, J¼
1. Experimental
6.7 Hz, 1H), 4.21 (dd, J¼7.5, 7.9 Hz, 1H), 3.70 (dd, J¼7.1,
1H NMR spectra were recorded on Bruker AC-300
(300 MHz) spectrometer, 13C NMR spectra on Bruker
AC-300 (75 MHz) spectrometer. If not otherwise mentioned
the samples were dissolved in CDCl3 with tetramethylsilane
(TMS) as internal standard. The following abbreviations are
used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet;
br, broad singlet. Elemental analyses were performed in a
Leco CHNS-932 apparatus. Optical rotations were
measured on a Perkin–Elmer 241 polarimeter using a
2 mL cell (c¼1.0 in CHCl3). Solvents were dried and
purified according to standard procedures. Silica (0.040–
0.063 mm) was used for column chromatography.
Dimethoxyethane (DME) was distilled from LiAlH4 before
use.
8.1 Hz, 1H), 1.40 (s, 3H), 1.35 (s, 3H).
1.1.2. (4S)-(E)-2,2-Dimethyl-4-(2-nitro-propenyl)-[1.3]-
20
dioxolane [(E)-4b]. Yellow oil. [a] ¼þ6.8 (c 1.0,
546
CHCl3). rf¼0.42 (hexane/AcOEt, 8:2), 13C NMR d 149.5
(Cq–NO2), 132.4 (CHv), 110.6 (Cq), 71.8 (CH), 68.6
(CH2), 26.5 (CH3), 25.6 (CH3), 12.7 (CH). 1H NMR d 6.99
(dd, J¼0.9, 8.1 Hz, 1H), 4.75 (m, 1H), 4.17 (dd, J¼6.3,
8.4 Hz, 1H), 3.71 (dd, J¼6.7, 8.4 Hz, 1H), 2.19 (s, 3H), 1.41
(s, 3H), 1.37 (s, 3H).
1.1.3. (4S)-(Z)-2,2-Dimethyl-4-(2-nitro-propenyl)-[1.3]-
20
dioxolane [(Z)-4b]. Yellow oil. [a] ¼þ7.5 (c 1.0,
546
CHCl3). rf¼0.53 (hexane/AcOEt, 8:2). 13C NMR d 147.3
(Cq–NO2), 136.9 (CHv), 110.5 (Cq), 73.6 (CH), 69.7
(CH2), 26.8 (CH3), 25.5 (CH3), 18.8 (CH3). 1H NMR d 6.09
(d, J¼5.8 Hz, 1H), 5.12 (m, 1H), 4.37 (dd, J¼7.1, 8.5 Hz,
1H), 3.66 (dd, J¼6.4, 8.5 Hz, 1H), 2.15 (t, J¼1.1 Hz, 3H),
1.39 (s, 3H), 1.31 (s, 3H).
1.1. General procedure for the synthesis of nitroalkenes
4
Formation of nitroaldols.
1.1.4. (2S)-(E)-2-(2-Nitro-propenyl)-1,4-dioxa-spiro[4,5]-
20
To a solution of enantiomerically pure aldehyde 1
(10 mmol, 1.0 equiv.) in i-PrOH (20 mL) and benzene
(2 mL) nitroalkane 2 (50 mmol, 5.0 equiv.) and KF (cat.,
100 mg) were added. The mixture was stirred at room
temperature for 24 h. CH2Cl2 (20 mL) was added and the
solution was filtered through a pad of celite. After
evaporation of the solvents under reduced pressure the
residue was dissolved in CH2Cl2, washed with saturated
NaCl-solution and dried with MgSO4. Evaporation of the
solvent under reduced pressure gave crude nitroaldols,
as diastereomeric mixtures, which were used in the
dehydration step without further purification.
decane [(E)-4c]. Yellow oil. [a] ¼þ6.5 (c 1.01, CHCl3).
546
rf¼0.48 (hexane/AcOEt, 7:3). 13C NMR d 148.4 (Cq–NO2),
131.7 (CHv), 110.2 (Cq), 70.5 (CH), 67.3 (CH2), 35.1
(CH2), 34.1 (CH2), 24.0 (CH2), 22.8 (2£CH2), 12.0 (CH3).
1H NMR d 6.95 (dd, J¼0.7, 8.1 Hz, 1H), 4.72 (dd, J¼7.0,
14.1 Hz, 1H), 4.13 (dd, J¼6.9, 14.1 Hz, 1H), 3.66 (m,
1H), 1.55 (m, 10H), 1.38 (s, 3H). Anal. calcd for
C11H17NO4: C 58.14; H 7.54; N 6.16. Found: C 58.28; H
7.68; N 6.18.
1.1.5. (2S)-(Z)-2-(2-Nitro-propenyl)-1,4-dioxa-spiro[4,5]-
decane [(Z)-4c]. Yellowish solid (melting at room
20
546
temperature). [a] ¼214.2 (c 1.06, CHCl3). rf¼0.54
Dehydration of nitroaldols.
(hexane/AcOEt, 7:3). 13C NMR d 147.1 (Cq–NO2), 137.3
(CHv), 111.2 (Cq), 73.3 (CH), 69.3 (CH2), 36.4 (CH2), 35.0
Method A. The crude nitroaldol (10 mmol, 1.0 equiv.) was
dissolved in dry Et2O or THF (20 mL). DCC (2.48 g,
12 mmol, 1.2 equiv.) and CuCl (cat., 25 mg) were added.
The mixture was stirred at room temperature for 3–5 days
while the progress of the reaction was monitored by TLC.
After completion of the reaction pentane (20 mL) was added
and the dicyclohexylurea was filtered off. Evaporation of the
solvent and purification by chromatography (4a–4d:
hexane/AcOEt, 9:1!7:3, 4e: hexane/AcOEt, 8:2!1:1)
afforded pure nitroolefines 4.
1
(CH2), 25.4 (CH2), 24.2 (CH2), 24.1 (CH2) 18.8 (CH3). H
NMR d 6.10 (d, J¼6.0 Hz, 1H), 5.11 (m, 1H), 4.36 (dd,
J¼7.0, 8.4 Hz, 1H), 3.35 (dd, J¼6.4, 8.4 Hz, 1H), 1.58, 1.53
and 1.35 (3 broad m, 10H), 1.41(s, 3H).
1.1.6. (4R)-(E)-3-N-t-Butyloxycarbonyl-2,2-dimethyl-4-
(2-nitro-propenyl)-oxazolidine [(E)-4d]. Yellow oil.
20
546
[a] ¼242.2 (c 1.0, CHCl3). rf¼0.43 (hexane/AcOEt,
7:3). 13C NMR d 152.2 (C), 144.3 (Cq–NO2), 134.6/133.5
(CH), 133.5 (CH), 95.0/94.4 (C), 81.3/81.0 (C), 67.7/67.5
(CH), 64.0/63.5 (CH), 28.7 (CH3), 27.8/26.7 (CH3),
Method B. Methanesulfonyl chloride (0.445 g, 3.89 mmol,
1.2 equiv.) was added to a solution of crude nitroaldol
(3.25 mmol, 1.0 equiv.) in 20 mL of dry CH2Cl2 in one
portion at 2788C (2188C for 4e) within 10 min followed by
i-Pr2NEt (1.05 g, 8.12 mmol, 2.5 equiv.). The reaction
mixture was allowed to warm to room temperature and
1
25.1/24.3 (CH3), 13.1 (CH3). H NMR d 6.92 (dd, J¼0.7,
9.8 Hz, 1H), 4.57 (m, 2H), 4.46 (m, 1H), 4.09 (m, 1H),
1.58/1.53 (s, 3H), 1.48/1.45 (s, 3H), 1.40 (s, 9H), 1.34 (s,
3H). Due to the appearance of rotamers some signals are
doubled. Anal. calcd for C13H22N2O5: C,54.53; H 7.74; N

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J. Hubner et al. / Tetrahedron 58 (2002) 10485–10500
10492
9.78. Found: C 54.26; H 7.70; N 9.69. HRMS: calcd for
(Mþ) C13H22N2O5: 271.1293, found 271.1294.
1.0 equiv.) was dissolved in a solution of DMAP (37 mg,
0.3 mmol, 0.1 equiv.) and NEt3 (0.84 mL, 6 mmol,
2.0 equiv.) in dry CH2Cl2 (60 mL). After cooling to
2788C TES-Cl (0.75 mL, 4.5 mmol, 1.5 equiv.) was
added dropwise over 10 min. The solution was allowed to
warm up to room temperature overnight and was quenched
with concentrated aqueous NaHCO3 (40 mL). The organic
layer was dried with MgSO4 and the solvent was removed
under reduced pressure. Chromatography (hexane/
AcOEt, 9:1!7:3) afforded pure product (E)-4h. Yellowish
oil. rf¼0.56 (hexane/AcOEt, 7:3). 13C NMR d 149.1
(Cq–NO2), 136.3 (C), 132.6 (CHv), 127.4 (C), 126.9
(C), 126.8 (C), 74.7 (CH), 70.6 (CH2), 63.9 (CH2), 12.3
1.1.7. (4R)-(Z)-3-N-t-Butyloxycarbonyl-2,2-dimethyl-4-
(2-nitro-propenyl)-oxazolidine [(Z)-4d]. Yellowish solid
20
546
(melting at room temperature). [a] ¼þ106.2 (c 1.0,
CHCl3). rf¼0.51 (hexane/AcOEt, 7:3). 13C NMR d 152.0
(C), 146.6 (Cq–NO2), 139.7/137.0 (CHv), 95.0/94.5 (Cq),
81.2/80.7 (Cq–tBu), 69.1/68.7 (CH2), 56.9/55.9 (CH), 28.7
(CH3–tBu), 27.7/26.9 (CH3), 24.9/23.9 (CH3), 18.9 (CH3).
1H NMR d 6.04 (d, J¼6.0 Hz, 1H), 5.06 (m, 1H), 4.92 (m,
1H), 4.25 (m, 1H), 2.15 (s, 3H), 1.57/1.54 (s, 3H), 1.44/1.41
(s, 3H), 1.31 (s, 9H). Due to the appearance of rotamers
some signals are doubled. Anal. calcd for C13H22N2O5: C
54.53; H 7.74; N 9.78. Found: C 54.25; H 7.82; N 9.49.
1
(CH3), 5.6 (CH3), 3.2 (CH2). H NMR d 7.24 (m, 5H),
6.91 (dd, J¼0.8, 8.8 Hz, 1H), 4.55 (d, J¼11.9 Hz, 1H),
4.39 (d, J¼11.9 Hz, 1H), 4.13 (m, 1H), 3.78 (dd, J¼5.6,
10.3 Hz, 1H), 3.58 (dd, J¼6.4, 10.2 Hz, 1H), 2.06 (d,
J¼0.8 Hz, 3H), 0.84 (t, J¼7.8 Hz, 9H), 0.50 (q, J¼7.8 Hz,
6H).
1.1.8. (2R)-(E)-2-Benzyloxy-4-nitro-pent-3-en-1-ol [(E)-
20
4e]. Yellow oil. [a] ¼257.7 (c 1.0, CHCl3). rf¼0.45
546
(hexane/AcOEt, 1:1). 13C NMR d 151.3 (Cq–NO2), 138.2
(C), 133.4 (CHv), 129.8 (CH), 129.4 (CH), 129.2 (CH),
77.0 (CH), 72.9 (CH2), 65.3 (CH2), 14.4 (CH3). 1H NMR d
7.23 (m, 5H), 6.89 (d, J¼8.8 Hz, 1H), 4.53 (d, J¼11.6 Hz,
1H), 4.35 (d, J¼11.6 Hz, 1H), 4.15 (m, 1H), 3.60 (dd, J¼
6.6, 11.7 Hz, 1H), 3.53 (dd, J¼4.3, 11.7 Hz, 1H), 2.07 (s, 3H).
1.2. Addition of vinylmagnesiumbromide to nitroolefin
(E)-4a
A solution of vinylmagnesium bromide (1 M in THF,
1.6 mL, 1.6 mmol, 1.3 equiv.) was diluted with THF (3 mL)
and cooled to 2788C. A solution of nitroolefin (E)-4a
(198 mg, 1.2 mmol, 1.0 equiv.) in THF (2 mL) was added
and the reaction mixture was kept at this temperature
for 2 h. The reaction was quenched by adding acetic
acid (10 drops) in 0.5 mL water and the mixture was
allowed to warm to room temperature. After the addition
of saturated aqueous NH4Cl (25 mL), the aqueous layer
was extracted with CH2Cl2 (3£25 mL). The combined
organic layers were washed with NaHCO3, dried with
Na2SO4 and the solvent was removed under reduced
pressure. The residue was purified by chromatography
(hexane/AcOEt, 7:3) to afford 156 mg (68%) of the
major diastereomer syn-5 and 12 mg (5%) of the minor
diastereomer anti-5.
1.1.9.
(2S)-(E)-4-Nitro-pent-3-en-1,2-diol
[(E)-4f].
Nitroalkene (E)-4b (1.0 g, 5.3 mmol, 1.0 equiv.) was
dissolved in a mixture of water (5 mL), 1 M HCl (5 mL)
and THF (20 mL). After stirring at room temperature for 4
days Na2CO3 was added until the pH was 8–9. The organic
layer was separated and the aqueous phase was extracted
with CH2Cl2 3 times. The combined organic layers were
dried and the solvent was evaporated under reduced
pressure. The residue was purified by chromatography
¼
20
546
(hexane/AcOEt, 1:1) to give diol (E)-4f. Yellow oil. [a]
225.4 (c 1.0, CHCl3). rf¼0.07 (hexane/AcOEt, 1:1). 13C
NMR (CD3OD) d 150.3 (Cq–NO2), 135.2 (CHv), 69.7
(CH), 66.0 (CH2), 13.2 (CH3). H NMR (CD3OD) d 6.96
1
(dd, J¼1.0, 8.5 Hz, 1H), 4.43 (m, 1H), 3.61 (dd, J¼5.9,
11.2 Hz, 1H), 3.54 (dd, J¼5.5, 11.2 Hz, 1H), 2.22 (d,
J¼1.0 Hz, 3H).
1.2.1. (4S)-2,2-Dimethyl-4-(1R)-1-nitromethyl-allyl-[1,3]-
dioxolane (syn-5). Major diastereomer. Colourless oil.
20
546
1.1.10. (2S)-(E)-4-Nitro-1-trityloxy-pent-3-en-2-ol [(E)-
4g]. Diol (E)-4f (204 mg, 1.64 mmol, 1.0 equiv.) was
dissolved in dry pyridine (5 mL). To the solution, trityl
chloride (503 mg, 1.80 mmol, 1.1 equiv.) was added in one
portion. After stirring at room temperature for 3 days,
MeOH (2 mL) was added. After 2 h pyridine was azeo-
tropically removed from the mixture with MeOH under
reduced pressure. The residue was dissolved in CH2Cl2 and
washed with saturated NH4Cl-solution (25 mL) and with
water (25 mL). After drying with MgSO4 the solvent was
evaporated under reduced pressure and the residue was
purified by chromatography (hexane/AcOEt, 9:1!8:2) to
rf¼0.8 (hexane/AcOEt, 7:3). [a] ¼þ41.2 (c 0.9, CH2Cl2).
13C NMR d 132.8 (CH), 121.3 (CH2), 109.8 (C), 76.8 (CH2),
75.0 (CH2), 66.3 (CH), 45.2 (C), 26.1 (CH3), 24.9 (CH3). 1H
NMR d 5.91 (ddd, J¼8.9, 10.2, 19.2 Hz, 1H), 5.47 (d, J¼
10.0 Hz, 1H), 5.40 (d, J¼17.2 Hz, 1H), 4.74 (dd, J¼5.8,
12.4 Hz, 1H), 4.61 (dd, J¼9.1, 12.4 Hz, 1H), 4.40 (dt, J¼
3.4, 6.1 Hz, 1H), 4.20 (dd, J¼6.7, 8.4 Hz, 1H), 3.87 (dd,
J¼6.5, 8.4 Hz, 1H), 2.97 (ddt, J¼3.4, 5.8, 9.0 Hz, 1H), 1.58
(s, 3H), 1.50 (s, 3H).
1.2.2. (4S)-2,2-Dimethyl-4-(1R)-1-nitromethyl-allyl-[1,3]-
dioxolane (anti-5). Minor diastereomer. Colourless oil.
afford (E)-4g. Yellow oil. rf¼0.46 (hexane/AcOEt, 7:3). 13
C
rf¼0.85 (hexane/AcOEt, 7:3). [a] ¼þ13.1 (c 0.8, CH2Cl2).
20
546
NMR d 150.0 (Cq–NO2), 143.7 (C), 133.5 (CHv), 128.9
(CH), 128.4 (CH), 127.8 (CH), 87.5 (Cq), 68.3 (CH), 66.6
13C NMR d 132.7 (CH), 120.8 (CH2), 110.1 (C), 76.2 (CH2),
75.4 (CH), 67.9 (CH), 47.7 (C), 26.7 (CH3), 25.3 (CH3). 1H
NMR d 5.61 (ddd, J¼8.9, 10.2, 19.1 Hz, 1H), 5.25 (d, J¼
17.0 Hz, 1H), 5.25 (d, J¼10.6 Hz, 1H), 4.72 (dd, J¼4.4,
12.2 Hz, 1H), 4.39 (dd, J¼9.7, 12.2 Hz, 1H), 4.03 (dd, J¼
6.1, 11.7 Hz, 1H), 3.99 (dd, J¼6.1, 9.0 Hz, 1H), 3.76 (dt, J¼
11.7, 9.2 Hz, 1H), 2.97 (qd, J¼9.2, 4.2 Hz, 1H), 1.43 (s,
3H), 1.33 (s, 3H).
1
(CH2), 13.5 (CH3). H NMR (CDCl3) d 7.35 and 7.23 (m,
15H), 6.86 (d, J¼8.0 Hz, 1H), 4.35 (m, 1H), 3.23 (s, 1H),
3.21 (s, 1H), 2.02 (s, 3H).
1.1.11. (2R)-(E)-2-Benzyloxy-1-trimethylsilyloxy-4-nitro-
pent-3-ene [(E)-4h]. Nitroalkene (E)-4e (711 mg, 3 mmol,

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J. Hubner et al. / Tetrahedron 58 (2002) 10485–10500
10493
1
1.2.3. (2S,3R)-3-(t-Butyloxycarbonyl-aminomethyl)-pen-
tane-1,2-diol (6). Reduction of the nitro group. LiAlH4
(228 mg, 6 mmol, 4.0 equiv.) was added to a solution of
syn-5 (322 mg, 1.6 mmol, 1.0 equiv.) in Et2O (10 mL) at
08C. After stirring at room temperature for 1 h, water (5
drops) was added, followed by 15% aq. NaOH (5 drops).
After 15 min of stirring the mixture was filtrated through
a pad of celite and MgSO4. After removal of the
solvent under reduced pressure 263 mg (96%) of the crude
(2R)-2-((4S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-but-3-enyl-
11.9. H NMR d 3.60–3.72 (m, 1H), 3.51–3.56 (m, 2H),
3.11–3.18 (m, 2H), 1.40–1.45 (m, 3H), 1.39 (s, 9H), 0.89 (t,
J¼7.3 Hz, 3H).
1.2.5. (2R)-2-(tert-Butyloxycarbonyl-aminomethyl)-
butyric acid (7). A solution of NaIO4 (190 mg, 0.88 mol,
2.5 equiv.) in water (1.5 mL) and RuCl3 (cat., 8 mg) were
added to the diol 6 (82 mg, 0.35 mol, 1.0 equiv.) in
MeCN/CCl4 (3 mL, 1:1). After stirring at room temperature
for 2 h, the mixture was diluted with Et2O (15 mL). After
5 min of stirring, MgSO4 was added at 08C. The mixture
was filtered through celite and the celite was washed with
Et2O. The combined organic layers were evaporated under
reduced pressure. Purification of the residue by chroma-
tography (hexane/AcOEt, 1:1) afforded the protected amino
acid 7 (55 mg, 73%). HPLC analysis (0.5N HClO4 in
NaClO-solution/MeCN¼60:40), column Chiralcel ODR.
amine were obtained, which was used in the next step
20
without further purification. Colourless liquid. [a]
¼
546
þ28.0 (c 1.1, CH2Cl2). rf¼0.2 (CHCl3/MeOH, 8:2). 13C
NMR d 135.8, 118.7, 108.7, 76.4, 67.0 (CH2), 50.4 (C), 43.0
(C), 26.3 (CH3), 25.4 (CH3). 1H NMR d 5.48–5.61 (m, 1H),
5.07 (dd, J¼10.4, 1.4 Hz, 1H), 4.98 (dd, J¼16.6, 0.6 Hz,
1H), 3.98 (qd, J¼6.2, 1.5 Hz, 1H), 3.82 (tt, J¼7.9, 1.5 Hz,
1H), 3.49 (tt, J¼7.9, 1.5 Hz, 1H), 2.61 (ddt, J¼12.6, 4.9,
1.4 Hz, 1H), 2.52 (tdd, J¼12.4, 7.2, 1.4 Hz, 1H), 1.97–2.06
(m, 1H), 1.75 (br, 2H), 1.22 (s, 3H, CH3).
rate 0.8 mL/min. detection: UV (220 nm) and polarimeter
20
546
(Chiralyser): tR¼4.73 min. e.e. .95%. Colourless oil. [a]
¼
222.2, [a]2D0¼218.2 (c 1.0, CH2Cl2). rf¼0.25 (hexane/
AcOEt, 1:1). 13C NMR d 179.5 (C), 156.0 (C), 79.3 (C),
1
Introduction of N-Boc. Boc2O (960 mg, 4.8 mmol,
3.2 equiv.) and a suspension of NaHCO3 (2.65 g) in water
(10 mL) were added to a solution of the unprotected amine
(256 mg, 1.5 mmol, 1.0 equiv.) in dioxane (10 mL). The
mixture was stirred overnight and the solvents were
removed under reduced pressure. The residue was dissolved
in Et2O (20 mL) and washed with brine. After re-extraction
of the aqueous layer with Et2O, the combined organic layers
were dried with Na2SO4. Removal of the solvent under
reduced pressure afforded crude (2R)-N-t-butyloxycarbo-
nyl-2-((4S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-but-3-enyl-
amine (366 mg, 90%), which was used in the next step
without further purification. Colourless liquid. rf¼0.7
(hexane/AcOEt, 7:3). 13C NMR d 156.0 (C), 135.5 (C),
119.5 (C), 109.4 (C), 79.0 (C), 76.6 (CH), 67.4 (CH2), 47.1
(C), 42.4 (C), 28.8 (CH3), 26.7 (CH3), 25.7 (CH3). 1H NMR
d 5.67–5.79 (m, 1H), 5.24 (dd, J¼10.3, 1.6 Hz, 1H), 5.15
(dd, J¼17.3, 0.9 Hz, 1H), 4.12–4.18 (m, 1H), 4.01 (dd,
J¼6.5, 8.0 Hz, 1H), 3.69 (t, J¼7.5 Hz, 2H), 3.28–3.30 (m,
1H), 3.12 (ddd, J¼13.6, 5.3, 2.9 Hz, 1H), 2.36–2.40 (m,
1H), 1.44 (s, 9H), 1.40 (s, 3H), 1.35 (s, 3H).
47.0 (C), 41.1 (CH2), 28.3 (CH3), 22.7 (C), 11.5 (C). H
NMR d 8.40 (b, 1H), 3.18–3.30 (m, 2H), 2.30–2.45 (m,
1H), 1.43–1.65 (m, 2H), 1.38 (s, 9H), 0.92 (t, J¼7.5 Hz,
3H). Anal. calcd for C10H19NO4£H2O: C 51.04; H 8.99; N
5.95. Found: C 51.29; H 8.94; N 5.97.
1.2.6. (4S,1R,3R)-cis-4-(2,2-Dibromo-3-methyl-3-nitro-
cyclopropyl)-2,2-dimethyl-[1,3]-dioxo-lane (8a). A mix-
ture of 50%-aqueous NaOH (5 mL), benzene (5 mL)
and triethylbenzylammonium chloride (cat., 10 mg) was
cooled to 08C. A solution of CHBr3 (0.2 mL, 2.1 mmol,
1.05 equiv.) and nitroolefin (Z)-4b (375 mg, 2.0 mmol,
1.0 equiv.) in benzene (5 mL) was added dropwise. The
colour of the reaction mixture turned brown. After stirring at
room temperature for 17 h, the reaction was quenched with
water (10 mL) and extracted three times with benzene. After
drying of the combined organic layers (Na2SO4) the solvent
was removed under reduced pressure. Chromatography
afforded 172 mg (24%) of the dibromocyclopropane 8a.
Colourless crystals. Mp 60–658C. [a] ¼298.0 (c 1.0,
20
546
CHCl3). rf¼0.33 (hexane/AcOEt, 8:2). 13C NMR d 110.5
(C), 74.5 (CH), 73.6 (C), 68.1 (CH2), 40.8 (CH), 28.0 (C),
26.9 (CH3) 25.4 (CH3), 16.0 (CH3). H NMR d 4.17 (dd,
1
Hydrogenation of C–C double bond to 6. 10% Pd–C (cat.,
30 mg) was added to a solution of the preceding N-Boc-
protected amine (325 mg, 1.2 mmol, 1.0 equiv.) in MeOH
(4 mL). The mixture was hydrogenated at 1 bar H2 for 2 h.
The reaction mixture is filtered through celite to remove
the catalyst. p-TosOH (20 mg) was added and the mixture
was stirred at room temperature for 2 h. After removing
the solvent under reduced pressure, the residue was
dissolved in CH2Cl2. The organic phase was washed with
saturated aqueous NaHCO3 and dried over MgSO4.
Removal of the solvent and column chromatography
(hexane/AcOEt, 1:1) afforded 218 mg (78%) of 6, which
was used in the subsequent step (transformation into 7)
without further purification and full analytical
characterisation.
J¼5.7, 8.7 Hz, 1H), 4.00 (dd, J¼3.9, 8.7 Hz, 1H), 3.79 (m,
1H), 2.99 (d, J¼9.1 Hz, 1H), 1.92 (s, 3H), 1.41 (s, 3H), 1.28
(s, 3H). HRMS: calcd for (Mþ2Me) C8H10Br2NO4:
341.8976, found 341.8981.
1.3. General procedure for cyclopropanation with
diphenylsulfoniumisopropylylide—synthesis of 8, 10, 11
(except 10b/11b; see Table 2 and Scheme 3, respectively)
Diphenylsulfoniumisopropylylide. A freshly prepared solu-
tion of LDA [18 mmol, prepared from 1.6 M BuLi solution
in hexane (11.25 mL) and diisopropylamine (2.6 mL) in
dry DME (20 mL) at 2708C] was added to a solution of
diphenylethylsulfonium tetrafluoroborate20 (5.5 g, 18.3 mmol)
in dry DME (200 mL) under argon at-708C. The resulting
yellow-green solution became turbid after 10–15 min. After
stirring at 2708C for further 30 min, methyl iodide
(1.13 mL, 18 mmol) was added dropwise. The solution
was stirred at this temperature for 3 h. Further LDA
1.2.4. (2S,3R)-3-(t-Butyloxycarbonyl-aminomethyl)-pen-
tan-1,2-diol (6). Colourless oil. [a] ¼þ11.2 (c 1.0,
20
546
CH2Cl2). rf¼0.2 (hexane/AcOEt, 1:1). 13C NMR d 156.9
(C), 79.4 (C), 72.6, 64.4, 43.0, 40.8 (CH2), 28.3 (CH3), 12.7,

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J. Hubner et al. / Tetrahedron 58 (2002) 10485–10500
10494
(18 mmol) was added at 2708C while the mixture turned
deeply orange fast. After 1 h stirring the resulting solution
contained about 18 mmol of diphenylsulfoniumisopropyl-
ylide.
separated by column chromatography (gradient eluation
with hexane/AcOEt, 9:1!1:2).
First diastereomer (faster on TLC). Yellow oil.
20
[a] ¼2111.7 (c 1.0, CHCl3). rf¼0.23 (hexane/AcOEt,
546
Cyclopropanation. A solution of the nitroalkene 4
(15 mmol) in dry DME (20 mL) was added to a solution
of diphenylsulfoniumisopropylylide (v.s.) at 2708C during
30 min (in case of (E)-4d 1 h) while the reaction mixture
became colourless. The resulting turbid solution was
allowed to warm up to room temperature under stirring
overnight. After the addition of half saturated aqueous
NH4Cl (100 mL) and extraction with Et2O/pentane (3:1, 3
times 100 mL) the combined organic layers were washed
with saturated brine (200 mL) and dried with MgSO4. After
evaporation of the solvent nitrocyclopropanes were purified
by column chromatography (gradient eluation with hexane/
AcOEt, 9:1!7:3 for 8b, 10 and 11 but hexane/Et2O,
9.9:0.1!9:1 for 11e). For yields and diastereomeric ratios,
see Table 2.
8:2). 13C NMR d 110.1 (C), 73.8 (CH), 69.7 (CH2), 63.4 (C),
32.2 (CH3), 26.8 (CH3), 26.1 (CH2), 21.7 (CH3), 15.3 (CH).
1H NMR d 4.09 (dd, J¼6.1, 8.1 Hz, 1H), 3.90 (m, 1H), 3.67
(dd!t, J¼7.5 Hz, 1H), 2.15 (m, 1H), 1.97 (dd, J¼5.5,
10.6 Hz, 1H), 1.70 (s, 3H), 1.35 (s, 3H), 1.28 (s, 3H), 1.19
(dd, J¼5.5, 7.5 Hz, 1H). Anal. calcd for C9H15NO4: C
53.72; H 7.51; N 6.96. Found C, 54.22; H 7.52; N 6.78.
Second diastereomer (slower on TLC). Yellow oil.
20
[a] ¼þ66.3 (c 1.0, CHCl3). rf¼0.13 (hexane/AcOEt,
546
8:2). 13C NMR d 110.3 (C), 76.3 (CH), 69.2 (CH2), 64.1 (C),
32.5 (CH), 27.1 (CH3), 26.2 (CH3), 22.2 (CH3), 15.5 (CH3).
1H NMR d 4.06 (dd, J¼6.1, 8.1 Hz, 1H), 3.76 (dd, J¼6.5,
8.1 Hz, 1H), 3.57 (m, 1H), 2.19 (m, 1H), 1.92 (dd, J¼5.7,
10.5 Hz, 1H), 1.76 (s, 3H), 1.35 (s, 3H), 1.26 (s, 3H), 0.87
(dd, J¼5.8, 7.5 Hz, 1H). Anal. calcd for C9H15NO4: C
53.72; H 7.51; N 6.96. Found C, 53.93; H 7.74; N 6.91.
1.3.1. (4S,1R,3S)-cis-2,2-Dimethyl-4-(2,3,3-trimethyl-2-
nitro-cyclopropyl)-[1,3]dioxolane (8b). Colourless crys-
20
546
tals. Mp 66–678C (pentane). [a] ¼250.8 (c 1.0, CHCl3).
1.3.4. 2,2-Dimethyl-4-(2,3,3-trimethyl-2-nitro-cyclopro-
pyl)-[1,3]dioxolane(10c/11c). Major diastereomer: (4S,
1R, 3R)-trans-2,2-dimethyl-4-(2,3,3-trimethyl-2-nitro-cyclo-
rf¼0.25 (hexane/AcOEt, 8:2). 13C NMR d 109.1 (C), 73.4
(C), 73.2 (CH), 69.4 (CH2), 40.3 (CH), 27.2 (C), 27.0 (CH3),
25.3 (CH3), 22.5 (CH3), 19.8 (CH3), 16.2 (CH3). 1H NMR d
4.24 (m, 2H), 3.73 (m, 1H), 1.68 (s, 3H), 1.38 (s, 3H),
1.29(s, 3H), 1.20 (s, 3H), 1.13 (s, 3H), 1.00 (d, J¼9.0 Hz,
1H). Anal. calcd for C11H19NO4: C 57.62; H 8.35; N 6.11.
Found C, 57.41; H 8.31; N 6.08.
propyl)-[1,3]dioxolane (10c). Colourless crystals. Mp
85–878C (pentane). [a] ¼þ50.3 (c 1.0 CHCl3). rf¼0.28
20
546
(hexane/AcOEt, 8:2). 13C NMR (DMSO-d6) d 108.5 (Cq),
72.7 (C), 71.8 (CH), 68.2 (CH2), 35.8 (CH), 29.1 (C), 26.8
(CH3), 25.6 (CH3), 21.1 (CH3), 16.0 (CH3), 13.3 (CH3). 13
C
NMR (CDCl3) d 109.4 (C), 72.5 (CH), 68.8 (CH2), 35.5
(CH), 29.3 (C), 26.7 (CH3) 25.7 (CH3), 21.4 (CH3), 16.2
(CH3), 13.7 (CH3). 1H NMR (DMSO-d6) d 3.99 (dd, J¼6.2,
7.4 Hz, 1H), 3.92 (m, 1H), 3.62 (dd, J¼5.9, 7.5 Hz, 1H),
2.05 (d, J¼9.3 Hz, 1H), 1.61 (s, 3H), 1.36 (s, CH3), 1.26 (s,
3H), 1.15 (s, 3H), 1.06 (s, 3H). Anal. calcd for C11H19NO4:
C 57.62; H 8.35; N 6.11. Found C, 57.65; H 8.12; N 6.14.
1.3.2. (4S)-trans-4-(2,2-Dimethyl-3-nitro-cyclopropyl)-
2,2-dimethyl-[1,3]dioxolane (10a/11a). Diastereomers not
separated by column chromatography.
Major diastereomer. 13C NMR d 109.9 (C), 73.4 (CH), 69.6
(CH), 69.3 (CH2), 37.0 (CH), 30.4 (C), 27.0 (CH3) 26.0
(CH3), 20.7 (CH3), 20.0 (CH3).
Minor diastereomer. Colourless oil. rf¼0.20 (hexane/
AcOEt, 8:2). 13C NMR d 109.1 (C), 73.2 (CH), 69.4
(CH2), 35.9 (CH), 28.9 (C), 26.8(CH3), 25.3 (CH3), 21.1
(CH3), 16.6 (CH3), 13.4 (CH3).
Minor diastereomer. 13C NMR d 110.1 (C), 74.1 (CH), 69.5
(CH), 69.1 (CH2), 37.0 (CH), 31.0 (C), 27.2 (CH3), 25.9
(CH3), 20.6 (CH3), 20.0 (CH3).
1.3.3. (4S)-2,2-Dimethyl-4-(2-methyl-2-nitro-cyclopropyl)-
[1,3]dioxolane (10b/11b). A solution of diphenylmethyl-
sulfonium tetrafluoroborate20 (3.1 g, 10.0 mmol) and dry
CH2Cl2 (0.64 mL, 10.0 mmol) in freshly distilled absolute
DME (100 mL) under argon was cooled to 2708C and
combined with a cold solution of LDA [10 mmol, freshly
prepared from 1.6 M BuLi in hexane (6.25 mL) and
diisopropylamine (1.4 mL) in 10 mL of dry DME (10 mL)
at 2708C]. The resulting yellow-greenish solution turned
brown. After 10 min of intensive stirring nitroalkene (E)-4b
(1.3 g, 7 mmol) dissolved in dry DME (5 mL) was added
fast, while the colour of the mixture turned to greenish
brown and a solid precipitated. The mixture was allowed to
warm up to room temperature overnight. It was combined
with half-saturated aqueous NH4Cl and extracted with
Et2O/pentane (3:1, 4 times 40 mL). The combined organic
layers were washed with brine (100 mL) and dried with
MgSO4. After stripping off the solvent the nitrocyclopro-
pane 10b/11b and isoxazoline-N-oxide 12 (R¼Me) were
1.3.5. 2-(2,3,3-Trimethyl-2-nitro-cyclopropyl)-1,4-dioxa-
spiro[4,5]decane
(2S,1R,2R)-trans-2-(2,3,3-trimethyl-2-nitro-cyclopropyl)-
(10d/11d).
Major
diastereomer:
1,4-di-oxa-spiro[4,5]decane (10d). Colourless waxy solid.
20
[a] ¼þ47.0 (c 1.0, CHCl3). rf¼0.56 (hexane/AcOEt,
546
7:3). 13C NMR d 108.9 (C), 71.8 (C), 71.1 (CH), 67.6 (CH2),
35.4 (CH2), 34.7 (CH), 34.3 (CH2), 28.3 (C), 24.0 (CH2),
22.9 (CH2), 22.8 (CH2), 20.4 (CH3), 15.3 (CH3), 12.7 (CH3).
1H NMR d 3.97 (dd, J¼5.4, 7.6 Hz, 1H), 3.70 (m, 2H), 2.15
(d, J¼9.2 Hz, 1H), 1.58 and 1.49 (br, 13H), 1.16 (s, 3H),
1.11 (s, 3H). Anal. calcd for C14H23NO4: C 62.43; H 8.60; N
5.20. Found C, 62.51; H 8.61; N 5.34. MS (FAB) m/z 270.2
(Mþ1)þ.
Minor diastereomer. Light yellow oil. rf¼0.47 (hexane/
AcOEt, 7:3). 13C NMR d 108.8 (C), 71.8 (C), 71.7 (CH),
68.1 (CH2), 35.7 (CH2), 34.9 (CH), 33.8 (CH2), 28.3 (C),
24.0, 22.9 (CH2), 22.8 (CH2), 22.7 (CH3), 15.3 (CH3) 12.7
(CH3).

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1.3.6. 2-Benzyloxy-1-triethylsilyloxy-(2,3,3-trimethyl-2-
nitro-cyclopropyl)-ethane (10e/11e). Major diastereomer:
(2R,1S,2S)-trans-2-benzyloxy-1-triethylsilyloxy-(2,3,3-tri-
methyl-2-nitro-cyclopropyl)-ethane (11e). Colourless oil.
rf¼0.26 (hexane/Et2O, 95:5). 13C NMR d 137.3 (C), 127.3
(CH), 126.7 (CH), 126.6 (CH), 75.5 (CH), 72.0 (C), 70.9
(CH2), 64.6 (CH2), 34.3 (CH), 28.0 (C), 20.3 (CH3), 16.0
was filtered through celite and the solvent was removed
carefully at reduced pressure. The remainder was purified
by column chromatography (CHCl3/MeOH, 90:10) to give
13a (74%) or 13b (47%).
1.4.1. (4S,1R,3R)-trans-3-(2,2-Dimethyl-[1,3]dioxolane-
4-yl)-1,2,2-trimethyl-cyclopropylamine (13a). Colourless
1
20
546
(CH3), 13.3 (CH3), 5.7 (CH3), 3.2 (CH2). H NMR d 7.25
wax. [a] ¼26.6 (c 0.5, CHCl3). rf¼0.33 (CHCl3/MeOH,
(m, 5H), 4.60 (d, J¼11.5 Hz, 1H), 4.48 (d, J¼11.5 Hz, 1H),
3.75 (dd, J¼6.2, 10.5 Hz, 1H), 3.60 (dd, J¼4.5, 10.5 Hz,
1H), 3.20 (m, 1H), 2.21 (d, J¼10.0 Hz, 1H), 1.56 (s, 3H),
1.07 (s, 3H), 1.01 (s, 3H), 0.87 (t, J¼8.0 Hz, 9H), 0.51 (q,
J¼8.0 Hz, 6H). Anal. calcd for C21H35NO4Si: C 64.08; H
8.96; N 3.56. Found C, 63.55; H 9.60; N 3.59.
8:2). 13C NMR d 108.3 (C), 74.6 (CH), 69.2 (CH2), 39.5 (C),
36.5 (CH), 26.8 (CH3), 25.9 (CH3), 24.1 (C), 22.1 (CH3),
19.1 (CH3), 16.8 (CH3). 1H NMR d 3.79 (dd, J¼5.6, 7.6 Hz,
1H), 3.53 (m, 1H), 3.41 (dd!t, J¼7.7 Hz, 1H), 1.92 (s, 2H),
1.20 (s, 3H), 1.12 (s, 3H). 1.02 (s, 3H), 0.98 (s, 3H), 0.88 (s,
3H), 0.37 (d, J¼9.6 Hz, 1H).
Minor diastereomer (10e). Colourless oil. rf¼0.23 (hexane/
AcOEt, 95:5). 13C NMR d 137.3 (C), 126.8 (CH), 126.7
(CH), 126.6 (CH), 75.5 (CH), 72.0 (C), 70.6 (CH2), 64.4
(CH2), 34.6 (CH), 28.2 (C), 20.3 (CH3), 16.3 (CH3), 12.9
(CH3), 5.5 (CH3), 3.2 (CH2).
1.4.2. (2S,1R,3R)-trans-3-(1,4-Dioxa-spiro-[4,5]dec-2-yl)-
1,2,2-trimethyl-cyclopropylamine (13b). Colourless wax.
rf¼0.17 (CHCl3/MeOH, 9:1). 13C NMR d 109.2 (C), 74.7
(CH), 69.5 (CH2), 40.0 (C), 37.4 (CH), 36.9 (CH2), 35.9
(CH2), 25.5 (CH2), 24.7 (C), 24.3 (CH2), 24.2 (CH2), 22.7
(CH3), 19.9 (CH3), 17.4 (CH3). 1H NMR d 3.97 (dd, J¼5.6,
7.9 Hz, 1H), 3.70 (m, 1H), 3.55 (dd!t, J¼7.5 Hz, 1H), 1.92
(s, 2H), 1.62–1.54 (broad, 10H), 1.19 (s, 3H), 1.14 (s, 3H),
1.08 (s, 3H), 0.50 (d, J¼9.4 Hz, 1H).
1.3.7. (4R)-3-N-tert-Butyloxycarbonyl-2,2-dimethyl-4-
(2,3,3-trimethyl-2-nitro-cyclopropyl)-oxazolidine (10f/
11f). First diastereomer (faster on TLC). Light yellow oil.
rf¼0.27 (hexane/AcOEt, 9:1). 13C NMR d 152.2 (C), 94.5
(C), 80.6 (C), 72.5 (C), 68.3 (CH2), 58.2 (CH), 54.1 (CH),
38.6 (CH3), 32.0 (Cq), 28.7 (CH3), 27.7 (CH3), 21.8 (CH3),
1.5. Introduction of protecting groups into amino-
cyclopropanes 13—synthesis of 14
1
17.4(CH3), 14.3 (CH3). H NMR d 3.95 (m, 1H), 3.65 (m,
2H), 2.25 (d, J¼9.7 Hz, 1H) 1.55 (s, 3H), 1.54 (s, 3H), 1.42
1.5.1. Boc-protection—general procedure (Table 3). The
corresponding amine 13 (0.42 mmol, 1.0 equiv.) was
dissolved in water/dioxane (1:1, 5 mL) and cooled to 08C
under stirring. NaHCO3 (352 mg, 4.2 mmol, 10 equiv.) and
Boc2O (0.45 mL, 2.09 mmol, 5.0 equiv.) were added. After
stirring overnight the solvent was evaporated under reduced
pressure. The residue was diluted with aqueous NH4Cl
(10 mL) and extracted three times with CH2Cl2 (20 mL).
The combined organic layers were dried (MgSO4) and the
solvent was stripped off under reduced pressure. Chroma-
tography on silica gel (hexane/AcOEt, 8:2) afforded the
N-Boc-aminocyclopropanes 14a and 14f.
(s, 3H), 1.42 (s, 9H), 1.20 (s, 3H) 1.08 (s, 3H).
Second diastereomer (slower on TLC). Light yellow oil.
rf¼0.24 (hexane/AcOEt, 9:1). 13C NMR d 152.2 (C), 94.7
(C), 80.7 (C), 74.8 (C), 68.4 (CH2), 54.3 (CH), 37.9 (CH),
28.6 (CH3), 28.4 (CH3), 27.9 (C), 25.8 (CH3), 21.9 (CH3),
17.0 (CH3), 14.7 (CH3). 1H NMR d 3.94 (m, 1H), 3.66 (m,
2H), 2.30 (d, J¼11.7 Hz, 1H), 1.75 (s, 3H), 1.56 (s, 3H),
1.43 (s, 3H), 1.38 (s, 9H), 1.06 (s, 3H), 1.00 (s, 3H).
1.3.8. (4S)-4-(2,2-Dimethyl-[1,3]dioxolane-4-yl)-3-
methyl-4,5-dihydro-isoxazole-2-oxide (12) (R5Me).
First diastereomer (faster on TLC). Yellow oil. rf¼0.15
(hexane/AcOEt, 1:1). 13C NMR d 111.8 (C), 108.9 (C), 73.2
(CH), 66.0 (CH2), 64.1 (CH2), 48.5 (CH), 25.5 (CH3), 24.1
1.5.1.1. (4S,1R,3R)-trans-N-t-Butoxycarbonyl-3-(2,2-
dimethyl-[1,3]dioxolan-4-yl)-1,2,2-trimethyl-cyclopro-
pylamine (14a). Colourless wax. rf¼0.27 (hexane/AcOEt,
8:2). 13C NMR d 155.4 (C), 108.4 (C), 78.8 (C), 74.2 (CH),
69.2 (CH2), 38.3 (C), 36.4 (CH), 28.3 (CH3), 26.9 (CH3),
25.8 (CH3), 24.5 (C), 22.6 (CH3), 16.4 (CH3), 15.6 (CH3).
1H NMR d 4.83 (s, 1H), 4.02 (m, 1H), 3.82 (m, 1H), 3.67 (m,
1H), 1.42 (s, 3H), 1.35 (s, 9H), 1.28 (s, 3H), 1.16 (s, 3H),
1.14 (s, 3H), 1.06 (s, 3H), 0.69 (d, J¼9.6 Hz, 1H).
1
(CH3), 10.5 (CH3). H NMR d 4.38 (m, 3H), 4.13 (dd,
J¼6.5, 8.4 Hz, 1H), 3.64 (dd, J¼6.4, 8.5 Hz, 1H), 3.48 (m,
1H), 2.00 (d, J¼1.5 Hz, 3H), 1.43 (s, 3H), 1.35 (s, 3H).
Second diastereomer (slower on TLC). Yellow oil. rf¼0.08
(hexane/AcOEt, 1:1). 13C NMR d 113.6 (C), 110.2 (C), 75.4
(CH), 66.6 (CH2), 64.7 (CH2), 49.7 (CH), 26.6 (CH3), 24.8
(CH3), 11.9 (CH3). 1H NMR d 4.42 (dd, J¼8.1, 9.4 Hz 1H),
4.30 (m, 1H), 4.16 (dd, J¼5.1, 8.1 Hz, 1H), 4.08 (dd, J¼6.4,
8.7 Hz, 1H), 3.74 (dd, J¼5.4, 8.7 Hz, 1H), 3.43 (m, 1H),
2.05 (d, J¼1.4 Hz, 3H), 1.45 (s, CH3), 1.34 (s, 3H).
1.5.1.2. (2S,1R,3R)-trans-N-t-Butoxycarbonyl-3-(1,4-
dioxa-spiro-[4,5]dec-2-yl)-1,2,2-trimethyl-cyclopropyl-
amine (14f). Colourless wax. rf¼0.63 (hexane/AcOEt, 1:1).
13C NMR d 156.0 (C), 109.3 (C), 79.0 (C), 74.1 (CH), 69.4
(CH2), 39.2 (C), 36.9 (CH), 36.9 (CH2), 35.8 (CH2), 38.7
(CH3), 25.5 (CH2), 25.0 (C), 24.3 (CH2), 24.2 (CH2), 23.0
(CH3), 16.9 (CH3), 15.9 (CH3). 1H NMR d 4.78 (s, 1H), 3.98
(m, 1H), 3.75 (m, 1H), 3.67 (m, 1H), 1.50–1.34 (m, 19H),
1.15 (s, 3H), 1.13 (s, 3H), 1.06 (s, 3H), 0.67 (d, J¼9.4 Hz, 1H).
1.4. Reduction of nitrocyclopropanes 10c,d—synthesis of
aminocyclopropanes 13a,b
Nitrocyclopropane 10c or 10d (600 mg) was dissolved in
15 mL of dry MeOH and 10% Pd/C (20 mg) was added. The
reaction mixture was hydrogenated at 15 bar (for 10c) or 25
bar (for 10d) under vigorous stirring for 48 h. The catalyst
1.5.2. Benzoylation
1.5.2.1. (2S,1R,3R)-trans-N-Benzoyl-3-(1,4-dioxa-spiro-
[4,5]dec-2-yl)-1,2,2-trimethyl-cyclopropyl-amine (14g).
A solution of benzoyl cyanide (120 mg, 0.92 mmol,

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10496
1.1 equiv.) in dry CH2Cl2 (1 mL) was dropped into a
solution of amine 13b (0.84 mmol, 1.0 equiv.) in dry
CH2Cl2 (5 mL) at 2188C during 10 min, while the evolving
HCN was stripped off by a gentle stream of argon and
absorbed in 10% aqueous NaOH. The mixture was allowed
to warm up to room temperature overnight. After stripping
off the solvent, the remainder was purified by column
chromatography (hexane/AcOEt, 8:2) affording 14g.
Colourless wax. rf¼0.45 (hexane/AcOEt 1:1). 13C NMR d
168.0 (N–CvO), 135.2 (C), 131.8 (CH), 128.9 (CH), 127.1
(CH), 109.4 (C), 74.2 (CH), 69.4 (CH2), 39.0 (C), 37.1
(CH), 36.8 (CH2), 36.0 (CH2), 25.5 (CH2), 24.8 (C), 24.3
(CH2), 24.2 (CH2), 23.2 (CH3), 16.8 (CH3), 15.7 (CH3). 1H
NMR d 7.61 (d, J¼6.9 Hz, 2H), 7.36 (m, 3H), 6.51 (s, 1H),
4.08 (dd, J¼5.9, 8.2 Hz, 1H), 3.95 (dd!t, J¼8.0 Hz, 1H),
3.75 (m, 1H), 1.53 (b, 10H), 1.25 (s, 3H), 1.20 (s, 3H), 1.13
(s, 3H), 0.84 (d, J¼9.7 Hz, 1H). MS (CI) m/z: 344 (Mþþ1,
40), 246 (95), 228 (90), 202 (100), 160 (8), 141 (10).
(CH3). 1H NMR d 6.82 (s, 1H), 4.05 (dd, J¼5.9 Hz, 8.3 Hz,
1H), 3.88 (dd!t, J¼7.7 Hz), 3.71 (m, 1H), 1.35 (s, 3H),
1.28 (s, 3H), 1.22 (s, 3H), 1.15 (s, 3H), 1.12 (s, 3H), 0.82 (d,
J¼9.7 Hz, 1H). Anal. calcd for C13H20F3NO3: C 52.88; H
6.83; N 4.74. Found: C 51.13; H 6.73; N 4.75. HRMS: calcd
for C13H20F3NO3: 295.1395, found 295.1392.
1.5.5. Introduction of N-Z-glycyl
1.5.5.1. (4S,1R,3R)-trans-N-(N0-Benzyloxycarbonyl-
glycinyl)-3-(2,2-dimethyl-[1,3]dioxolan-4-yl)-1,2,2-tri-
methyl-cyclo-propylamin (14d). Hydroxybenzotriazole
(590 mg, 4.36 mmol, 2.0 equiv.) was added to a solution
of N-Z-glycine (457 mg, 2.18 mmol, 1.0 equiv.) in dry THF
(20 mL). After cooling to 08C a solution of DCC (495 mg,
2.4 mmol, 1.1 equiv.) in dry THF (10 mL) was added under
stirring. The mixture was stirred at 08C for 1 h and at
ambient temperature for 20 min while a turbidity appeared.
After cooling to 08C a solution of the aminocyclopropane
13a (433 mg, 2.18 mmol, 1.0 equiv.) in dry THF (10 mL)
was added dropwise under stirring over 5 min. Stirring at
08C was continued for 15 min. Dicyclohexylurea was
filtered off and the filtrate was concentrated with a rotatory
evaporator. The remaining oil was mixed with AcOEt
causing precipitation of hydroxybenzotriazole, which was
filtered off and washed with AcOEt. The combined organic
layers were washed with saturated aqueous NaHCO3, 2 M
aqueous citric acid and again with saturated aqueous
NaHCO3. Each of the aqueous phases was extracted with
CH2Cl2. All combined organic layers (AcOEt and CH2Cl2)
were dried (MgSO4) and the solvents were evaporated.
The remainder was purified by column chromatography
(hexane/AcOEt, 1:1) affording 14d. Colourless wax.
rf¼0.15 (hexane/AcOEt, 1:1). 13C NMR d 170.0 (C),
157.0 (C), 136.9 (C), 128.9 (C), 128.7 (C), 128.6 (C), 128.4
(C), 128.1 (C), 108.9 (C), 74.5 (CH), 69.5 (CH2), 67.5
(CH2), 45.0 (CH2), 38.5 (C), 36.6 (CH), 27.3 (CH3), 26.3
1.5.3. Introduction of Z-group
1.5.3.1. (4S,1R,3R)-trans-N-Benzyloxycarbonyl-3-(2,2-
dimethyl-[1,3]dioxolan-4-yl)-1,2,2-trimethyl-cyclopro-
pyl-amine (14b). Na2CO3 (660 mg, 6.23 mmol, 5.0 equiv.)
and Z-Cl (0.2 mL, 1.38 mmol, 1.1 equiv.) were added to a
solution of aminocyclopropane 13a (248 mg, 1.25 mmol,
1.0 equiv.) in 1:1 water/dioxane (20 mL) at 08C under
vigorous stirring. After stirring at 08 for 1 h the temperature
was increased to room temperature over a period of another
1 h. Water (10 mL) was added and the mixture was
extracted with CH2Cl2 (4 times 25 mL). After drying of
the combined organic layers (MgSO4) the solvent was
removed by rotatory evaporator and the remainder was
purified by chromatography (silica, hexane/AcOEt, 9:1) to
20
give 14b. Waxy solid. [a] ¼þ134 (c 1.0, CHCl3). rf¼0.60
546
(hexane/AcOEt, 1:1). 13C NMR d 156.4 (C), 136.8 (C),
128.9 (CH), 128.5 (CH), 127.3 (CH), 108.9 (C), 74.5 (CH),
69.5 (CH2), 66.8 (CH2), 38.8 (C), 36.9 (CH), 27.3 (CH3),
26.4 (CH3), 24.8 (C), 23.0 (CH3), 16.7 (CH3), 16.0 (CH3).
1H NMR d 7.24 (m, 5H), 5.12 (s, 1H), 5.00 (d, J¼12.1 Hz,
1H), 4.93 (d, J¼12.1 Hz, 1H), 4.02 (m, 1H), 3.89 (dd!t,
J¼7.7 Hz, 1H), 3.67 (m, 1H), 1.34 (s, 3H), 1.27 (s, 3H), 1.15
(s, 3H), 1.11 (s, 3H), 1.05 (s, 3H), 0.77 (d, J¼9.8 Hz, 1H).
Anal. calcd for C19H27NO4: C 68.44; H 8.16; N 4.20.
Found: C 68.12; H 8.16; N 4.14.
1
(CH3), 24.4 (C), 23.0 (CH3), 16.6 (CH3), 15.5 (CH3). H
NMR d 7.24 (m, 5H), 6.62 (s, 1H), 5.82 (s, 1H), 5.02 (s, 2H),
4.01 (m, 1H), 3.88 (m, 1H), 3.67 (m, 1H), 1.33 (s, 3H), 1.27
(s, 3H), 1.11 (s, 3H), 1.05 (s, 6H), 0.70 (d, J¼9.7 Hz, 1H).
CI-MS: m/z: 390 (Mþ, 10), 375 (10), 333 (100), 315 (49),
289 (80), 232 (16), 170 (8), 142 (87), 124 (43).
1.5.6. Introduction of tosyl group
1.5.6.1. (4S,1R,3R)-trans-N-(4-Tolylsulfonyl)-3-(2,2-
dimethyl-[1,3]dioxolan-4-yl)-1,2,2-trimethyl-cyclopro-
pylamine (14e). Ts-Cl (360 mg, 1.87 mmol, 1.1 equiv.)
was added to a solution of aminocyclopropane 13a
(340 mg, 1.7 mmol, 1.0 equiv.), DMAP (22 mg,
0.18 mmol, 0.1 equiv.), and NEt3 (0.46 mL, 3.74 mmol,
2.2 equiv.) in dry CH2Cl2 (30 mL) at room temperature.
After stirring overnight saturated aqueous NH4Cl (20 mL)
was added and the mixture was extracted with CH2Cl2 (3
times 30 mL). The combined organic layers were dried
(Na2SO4) and concentrated with a rotatory evaporator.
Column chromatography (hexane/AcOEt, 7:3) of the
remainder afforded the product 14e. Colourless wax. rf¼
0.19 (hexane/AcOEt, 7:3). 13C NMR d 143.6 (C), 139.9 (C),
130.0 (CH). 127.3 (CH), 109.0 (C), 74.3 (CH), 69.2 (CH2),
41.1 (C), 34.2 (CH), 27.2 (CH3), 26.3 (CH3), 24.6 (C), 23.0
(CH3), 21.8 (CH3), 18.0 (CH3), 16.4 (CH3). 1H NMR d 7.66
(d, J¼8.2 Hz, 2H), 7.21 (d, J¼8.2 Hz, 2H), 5.27 (s, 1H),
3.94 (dd, J¼5.9, 8.2 Hz, 1H), 3.84 (dd!t, J¼7.7 Hz, 1H),
1.5.4. Introduction of trifluoroacetyl group
1.5.4.1. (4S,1R,3R)-trans-N-(Trifluoroacetyl)-3-(2,2-
dimethyl-[1,3]dioxolan-4-yl)-1,2,2-tri-methyl-cyclopro-
pylamin (14c). Trifluoroacetic anhydride (0.52 mL,
3.76 mmol, 3.0 equiv.) was added to a solution of
aminocyclopropane 13a (250 mg, 1.25 mmol, 1.0 equiv.)
and NEt3 (1.05 mL, 7.54 mmol, 6.0 equiv.) in dry Et2O
(20 mL) at 2188C under stirring over a period of 10 min.
After 1 h stirring at 2188C, the reaction mixture was
washed with saturated aqueous NaHCO3 (3 times 5 mL) and
with brine (once, 5 mL). The organic layer was dried
(Na2SO4) and the solvent was stripped off by a rotatory
evaporator. The residue was purified by column chroma-
tography (hexane/AcOEt, 7:3) affording the product 14c.
Light yellowish oil. rf¼0.48 (hexane/AcOEt, 1:1). 13C
NMR d 157.9 (C, JCF¼36.4 Hz), 116.1 (C, JCF¼288.6 Hz),
109.1 (C), 74.0 (CH), 69.4 (CH2), 38.9 (C), 36.5 (CH), 27.2
(CH3), 26.2 (CH3), 24.8 (C), 22.8 (CH3), 16.4 (CH3), 14.9

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10497
3.56 (m, 1H), 2.34 (s, 3H), 1.26 (s, 3H), 1.24 (s, 3H), 1.11
(s, 3H), 1.00 (s, 3H), 0.97 (s, 3H), 0.82 (d, J¼9.8 Hz, 1H).
1.5.6.2. (4S,1R,3R)-trans-N-Bis-(4-tolylsulfonyl)-3-
(2,2-dimethyl-[1,3]dioxolan-4-yl)-1,2,2-trimethyl-cyclo-
propylamine (15). A solution of monotosylate 14e
(200 mg, 0.56 mmol, 1.0 equiv.) in dry DMF (2 mL) was
added to a solution of 95% NaH (20 mg, 0.6 mmol,
1.07 equiv.) in dry DMF (1 mL) dropwise under stirring in
an argon atmosphere while the colour of the mixture turned
from colourless to orange and the mixture became turbid.
After stirring at room temperature for 30 min Ts-Cl
(115 mg, 0.6 mmol, 1.07 equiv.) was added. The reaction
mixture turned yellow and precipitation started. After
stirring at room temperature for 14.5 h EtOH (3 mL) was
added. The mixture was concentrated and the remainder was
dissolved in CH2Cl2 (20 mL). After washing with water
(15 mL)/1 M HCl (2 drops), water (15 mL), saturated
aqueous NH4Cl (15 mL), and brine (15 mL) the organic
phase was dried (Na2SO4) and evaporated. The remainder
was purified by column chromatography (silica, hexane/
AcOEt, 9:1!7:3) affording the ditosylated product 15
(210 mg, 74%). Colourless crystals. Mp 110–1128C. rf¼
0.32 (hexane/AcOEt, 7:3). 13C NMR d 145.1 (C), 144.8 (C),
139.7 (C), 138.5 (C), 130.0 (CH), 129.6 (CH), 129.5 (CH),
128.4 (CH), 108.9 (C), 74.4 (CH), 68.4 (CH2), 50.1 (C), 32.6
(CH), 28.0 (C), 27.5 (CH3), 26.2 (CH3), 24.9 (CH3), 22.0
with CH2Cl2. The combined organic layers were evaporated
and the remaining product was purified by twofold column
chromatography (CHCl3/MeOH, 90:10 and hexane/AcOEt,
7:3). The product was formed in 56% yield (65 mg) and was
recrystallized from hexane/AcOEt, 7:3. (1R,2R)-trans-
2,3,3-Trimethyl-2-(bis-4-tolylsulfonyl-amino)-cyclopro-
pancarboxylic acid 16. Colourless crystals. Mp 83–858C.
20
[a] ¼210.1 (c 1.0, CHCl). rf¼0.48 (CHCl3/MeOH, 9:1).
546
13C NMR d 175.9 (C), 145.6 (C), 145.2 (C), 139.0 (C),
137.6 (C), 130.2 (CH), 129.9 (CH), 129.6 (CH), 128.7 (CH),
54.7 (C), 34.3 (C), 32.9 (CH), 25.3 (CH3), 22.0 (CH3), 16.8
1
(CH3), 15.9 (CH3). H NMR d 10.63 (b, 1H), 7.96 (d, J¼
8.3 Hz, 2H), 7.85 (d, 2H, J¼8.3 Hz, 2H), 7.26 (m, 4H), 2.38
(s, 3H), 2.35 (s, 3H), 1.61 (s, 3H), 1.22 (s, 3H), 1.11 (s, 3H),
0.80 (s, 1H). EI-MS: m/z: 452 (Mþþ1, 7), 434 (100), 416
(15), 406 (28), 308 (15), 278 (18), 155 (96), 91 (100), 65
(27). HRMS: calcd for (Mþ2OH) C21H24NO5S2: 434.1096,
found 434.1099.
1.6. Conversion of dioxolane into the carboxylate
moiety—synthesis of b-aminocyclopropane carboxylate
derivatives 17–20
General procedure for hydrolytic removal of acetal
protective group from 14 to the corresponding diols.
Water (0.5 mL) and p-TsOH (cat., 25 mg) were added to a
solution of 13 (100 mg) in MeOH (10 mL). After stirring
overnight the progress of the reaction was checked (TLC)
and eventually further water (0.5 mL) and p-TsOH (cat.,
25 mg) were added. After the reaction had gone to
completeness the mixture was concentrated and saturated
aqueous NaHCO3 (10 mL) was added. The solution was
saturated with NaCl and extracted with CH2Cl2 (5–10 times
15 mL, TLC check). After drying the combined organic
layers (MgSO4) the solvent was evaporated. The remaining
crude product was further used without prior purification.
Column chromatography was possible (hexane/AcOEt,
1:1!3:7 or CHCl3/MeOH, 90:10) but caused loss of
product.
1
(CH3), 18.7 (CH3), 16.3 (CH3). H NMR d 7.93 (d, J¼
8.4 Hz, 2H), 7.88 (d, J¼8.4 Hz, 2H), 7.25 (d, J¼6.0 Hz,
2H), 7.22 (d, J¼6.0 Hz), 4.16 (dd, J¼5.8, 8.5 Hz, 1H), 3.96
(dd, J¼5.7, 8.5 Hz, 1H), 3.71 (m, 1H), 2.36 (s, 3H), 2.34 (s,
3H), 1.47 (s, 3H), 1.24 (s, 6H), 1.06 (s, 3H), 0.96 (s, 3H),
0.88 (d, J¼9.5 Hz, 1H). Anal. calcd for C25H33NS2O6 C,
59.14; H 6.55; N 2.76. S: 12.63. Found: C 59.03; H 7.01; N
2.74; S: 12.62.
1.5.6.3. Transformation of 15 into (1R,2R)-trans-2,3,3-
trimethyl-2-(bis-4-tolylsulfonyl-amino)-cyclopropancar-
boxylic acid 16. For hydrolytic cleavage the acetonide 15
(170 mg, 0.34 mmol, 1.0 equiv.) was dissolved in MeOH
(5 mL) and combined with water (0.5 mL) and p-TsOH
(cat., 40 mg). After stirring at room temperature overnight
the solvent was evaporated and the remainder was
purified by column chromatography (CHCl3/MeOH,
90:10) affording 136 mg (86%) of (1R,2R,1S)-trans-N-bis-
4-tolylsulfonyl-1-(2-amino-2,3,3-trimethyl-cyclopropyl)-
ethan-1,2-diol. Colourless foam. rf¼0.11 (hexane/AcOEt,
1:1). 13C NMR d 145.3 (C), 145.0 (C), 139.5 (C), 138.2 (C),
130.2 (CH), 129.7 (CH), 129.6 CH), 128.1 (CH), 70.7 (CH),
66.4 (CH2), 50.8 (C), 33.2 (CH), 27.6 (C), 25.2 (CH3), 22.0
General procedure for the synthesis of 17 (Table 3). NEt3
(0.412 mL, 2.96 mmol, 4.0 equiv.) and DMAP (10 mg,
0.074 mmol, 0.1 equiv.) were added to a solution of the diol
(v.s. 0.74 mmol, 1.0 equiv.) in dry CH2Cl2 (20 mL). After
cooling to 2188C TES-Cl (0.373 mL, 2.22 mmol,
3.0 equiv.) was added dropwise under stirring over a period
of 10 min. The mixture was allowed to warm up to room
temperature under stirring overnight. It was quenched
with half-concentrated aqueous NaHCO3. The organic
layer was separated, dried (Na2SO4) and concentrated.
Column chromatography (hexane/AcOEt, 9:1!7:3)
afforded products 17.
1
(CH3), 18.9 (CH3), 16.4 (CH3). H NMR d 7.93 (d, J¼
8.4 Hz, 2H), 7.85 (d, J¼8.4 Hz, 2H), 7.23 (t, J¼8.4 Hz, 4H),
3.77 (dd, J¼3.6, 11.5 Hz, 1H), 3.58 (dd, J¼6.7, 11.5 Hz,
1H), 3.39 (m, 1H), 2.35 (s, 3H), 2.32 (s, 3H), 1.50 (s, 3H),
1.05 (s, 3H), 0.95 (s, 3H), 0.79 (d, J¼9.8 Hz, 1H). HRMS:
calcd for (Mþ2CHOH–CH2OH) C20H24O4NS2: 406.1146,
found 406.1148. The diol (125 mg, 0.267 mmol, 1.0 equiv.)
was dissolved in a mixture of CHCl3 (2 mL), MeCN (2 mL),
and water (3 mL). NaIO4 (228 mg, 1.07 mmol, 4.0 equiv.)
and RuCl3£H2O (10 mg) were added under ice cooling.
After stirring at room temperature for 2 h NaIO4 (228 mg,
1.07 mmol, 4.0 equiv.) was added again. Stirring at room
temperature was continued for 3 h while the dark solution
turned temporarily light. After drying the reaction mixture
with Na2SO4 it was filtered and the Na2SO4 was washed
1.6.1. (1S,1R,3R)-trans-N-Trifluoroacetyl-3-(1,2-bis-
triethylsilyloxy-ethyl)-1,2,2-trimethyl-cyclopropylamine
(17c). Colourless oil. rf¼0.69 (hexane/AcOEt, 1:1).13C
NMR d 157.6 (C, JCF¼36.3 Hz), 116.2 (C, JCF¼288.7 Hz),
72.1 (CH), 68.2 (CH2), 39.5 (C), 37.7 (CH), 24.6 (C), 23.1
(CH3), 16.9 (CH3), 15.1 (CH3), 7.2 (CH3), 7.0 (CH3), 5.7
(CH2), 4.6 (CH2). 1H NMR d 6.44 (s, 1H), 3.62 (dd, J¼6.4,
10.3 Hz, 1H), 3.54 (dd, J¼7.0, 10.3 Hz, 1H), 3.41 (m, 1H),
1.23 (s, 3H), 1.09 (s, 6H), 0.89 (t, J¼7.9 Hz, 18H), 0.68 (d,
J¼9.8 Hz, 1H), 0.54 (q, J¼7.9 Hz, 12H). Anal. calcd for

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J. Hubner et al. / Tetrahedron 58 (2002) 10485–10500
10498
C22H44F5NSi2O3: C 54.62; H 9.17; N 2.90. Found: C 54.26;
H 8.90; N 2.92. EI-MS m/z: 484.4 (Mþþ1, 60), 454.3 (50),
352.4 (30), 338.3 (51), 322.3 (23), 261.3 (19), 220.3 (100),
206.2 (8), 145.3 (8), 115.5 (19), 107.3 (19), 87.2 (11).
1.6.5. (1S,1R,3R)-trans-N-Benzoyl-3-(2-oxo-1-triethyl-
silyloxy-ethyl)-1,2,2-trimethyl-cyclopropylamine (18g).
Light yellow oil. rf¼0.25 (hexane/AcOEt, 7:3); 13C NMR
d 200.0 (CH), 166.7 (C), 133.8 (C), 130.5 (CH), 127.6 (CH),
125.9 (CH), 74.9 (CH), 38.1 (C), 34.7 (CH), 23.9 (C), 22.0
1.6.2. (1S,1R,3R)-trans-N-(N0-Benzyloxycarbonyl-glyci-
nyl)-3-(1,2-bis-triethylsilyloxy-ethyl)-1,2,2-trimethyl-
cyclopropylamine (17d). Colourless foam. rf¼0.18 (hex-
ane/AcOEt, 7:3); 13C NMR d 169.4 (C), 157.0 (C), 136.5
(C), 128.9 (CH), 128.6 (CH), 128.4 (CH), 72.8 (CH), 68.4
(CH2), 67.4 (CH2), 45.0 (CH2), 39.1 (C), 37.5 (CH), 24.2
(C), 23.3 (CH3), 17.0 (CH3), 15.6 (CH3), 7.3 (CH3), 7.0
(CH3), 5.8 (CH3), 4.6 (CH3). 1H NMR d 7.10 (b, 5H), 6.10
(s, 1H), 5.48 (s, 1H), 4.86 (s, 2H), 3.52 (m, 3H), 3.33 (m,
1H), 3.22 (m, 1H), 1.01 (s, 3H), 0.89 (s, 3H), 0.85 (s, 3H),
0.72 (t, 18H, J¼7.9 Hz, 18H), 0.40 (m, 13H). EI-MS m/z:
578.5 (Mþ, 38), 549 (100), 447 (4), 404 (5), 289 (57), 242
(18), 189 (18), 124 (52), 91 (100), 83 (32), 75 (23), 47 (7).
Anal. calcd for C30H54N2Si2O5: C 62.24; H 9.40; N 4.84.
Found: C 61.57; H 9.28; N 4.82.
(CH3), 15.7 (CH3), 15.0 (CH3), 5.8 (CH3), 4.1 (CH2). H
1
NMR d 9.66 (d, J¼2.1 Hz, 1H), 7.61 (d, J¼7.0 Hz, 2H),
7.31 (m, 3H), 6.60 (s, 1H), 3.71 (dd, J¼2.1 Hz, 1H), 1.32 (s,
3H), 1.20 (s, 3H), 1.14 (s, 3H), 0.88 (m, J¼7.9 Hz,10H),
0.53 (q, J¼7.9 Hz, 6H).
Oxidation with NaClO2—general procedure for the syn-
thesis of carboxylic acids 19 (Table 3). A solution of the
aldehyde 18 (0.293 mmol, 1.0 equiv.) in MeCN (3 mL) was
combined with a solution of NaH2PO4 (cat., 10 mg) in water
(0.5 mL). After cooling to 08C 30% H2O2 (32 mL,
0.308 mmol, 1.05 equiv.) was added under stirring followed
by the addition of a solution of NaClO2 (47 mg,
0.410 mmol, 1.4 equiv.) in water (1 mL) over a period of
10 min while the mixture turned light yellow greenish.
Stirring was continued at 08C for 30 min and at room
temperature for 30 min. After the reaction had gone to
completion (TLC), Na2SO3 (5 mg) was added and the
solvent was evaporated under vacuum. 1 M aqueous HCl
(1 mL) and water (5 mL) were added to the remainder. After
extraction with CH2Cl2 (3 times 10 mL) the combined
organic layers were dried (Na2SO4) and concentrated. The
remainder was purified by column chromatography (CHCl3/
MeOH, 9:1).
1.6.3. (1S,1R,3R)-trans-N-Benzoyl-3-(1,2-bis-triethylsilyl-
oxy-ethyl)-1,2,2-trimethyl-cyclopropylamine
(17g).
Colourless wax. rf¼0.50 (hexane/AcOEt, 7:3). 13C NMR
d 167.9 (C), 135.4 (C), 131.6 (CH), 128.8 (CH), 127.0 (CH),
72.6 (CH), 68.4 (CH2), 39.8 (C), 37.8 (CH), 24.9 (C), 23.5
(CH3), 17.2 (CH3), 15.8 (CH3), 7.3 (CH3), 7.1 (CH3), 6.1
(CH2), 5.8 (CH2). 1H NMR d 7.61 (d, J¼6.8 Hz, 2H), 7.33
(m, 3H), 6.28 (s, 1H), 3.70 (m, 1H), 3.55 (m, 1H), 3.45 (m,
1H), 1.30 (s, 3H), 1.14 (s, 3H), 1.13 (s, 3H), 0.88 (t, J¼
7.8 Hz, 18H), 0.69 (d, J¼9.8 Hz), 0.55 (q, J¼7.9 Hz, 12 H).
Anal. calcd for C27H49NSi2O3: C 65.93; H 10.04; N 2.85.
Found: C 65.07; H 10.96; N 2.86.
1.6.6. (1R,2R,2S)-trans-(2-N-Trifluoroacetyl-amino-2,3,
3-trimethyl-cyclopropyl)-hydroxy-acetic acid (19c).
Compound 17c was oxidized according to the general
procedure. The resulting aldehyde 18c was oxidized without
prior purification and analytical characterisation affording
19c. Colourless foam. rf¼0.20 (CHCl3/MeOH, 9:1). 13C
NMR (CD3OD) d 176.2 (C), 158.4 (C, JCF¼36.3 Hz), 116.4
(C, JCF¼287.8 Hz), 68.3 (CH), 40.5 (C), 36.0 (CH), 25.1
(C), 22.1 (CH3), 15.6 (CH3), 14.1 (CH3). 1H NMR d 3.88 (d,
J¼10.5 Hz, 1H), 1.45 (s, 3H), 1.23 (s, 3H), 1.15 (s, 3H),
1.08 (d, J¼10.5 Hz, 1H).
Swern oxidation: general procedure for the synthesis of
aldehydes 18 (Table 3). A solution of DMSO (0.243 mL,
3.41 mmol, 2.5 equiv.) in dry CH2Cl2 (4 mL) was added to a
solution of oxalyl chloride (0.153 mL, 1.77 mmol,
1.3 equiv.) in dry CH2Cl2 (4 mL) dropwise under stirring
at 2788C. After 5 min of stirring a solution of 17
(1.36 mmol, 1.0 equiv.) in dry CH2Cl2 was added. The
mixture was allowed to warm up under stirring to 2458C
during 1 h. NEt3 (1.02 mL, 7.34 mmol) was added and the
mixture was allowed to warm up to room temperature over
30 min. Water (20 mL) was added and the mixture was
extracted with CH2Cl2 (3 times 15 mL). The combined
organic layers were washed with brine, were dried (MgSO4)
and concentrated. Pure aldehydes 18 were obtained after
column chromatography (hexane/AcOEt, 9:1!1:1).
1.6.7. (1R,2R,2S)-trans-2-[N-(N0-Benzyloxycarbonyl-gly-
cinyl)-amino]-2,3,3-trimethyl-cyclopropyl)-hydroxy-
20
acetic acid (19d). Colourless foam. Mp 65–688C. [a]
¼
546
226.0 (c 1.0, CHCl3). rf¼0.29 (CHCl3/MeOH, 9:1); 13C
NMR d 176.7 (C), 172.5 (C), 157.4 (C), 136.4 (C), 128.9
(CH), 128.7 (CH), 128.4 (CH), 69.3 (CH), 67.6 (CH2), 44.7
(CH2), 39.9 (C), 35.7 (CH), 24.7 (C), 23.0 (CH3), 16.9
1
(CH3), 15.5 (CH3). H NMR d 7.43 (s, 1H), 7.21 (b, 5H),
1.6.4. (1S,1R,3R)-trans-N-(N0-Benzyloxycarbonyl-glycinyl)-
3-(2-oxo-1-triethylsilyloxy-ethyl)-1,2,2-trimethyl-cyclo-
propylamine (18d). Light yellow oil. rf¼0.15 (hexane/
AcOEt, 1:1); 13C NMR d 201.1 (CH), 169.6 (C), 157.0 (C),
136.5 (C), 128.9(CH), 128.5 (CH), 128.3 (CH), 76.0 (CH),
67.4 (CH2), 45.0 (CH2), 38.8 (C), 35.7 (CH), 24.7 (C), 23.0
6.12 (s, 1H), 4.98 (s, 2H), 3.71 (m, 3H), 1.22 (s, 3H), 1.05 (b,
6H), 0.86 (d, J¼10.8 Hz, 1H). EI-MS: m/z: 365 (Mþþ1, 2),
289 (100), 188 (16), 98 (69), 91 (100), 65 (25). HR-MS:
calcd Mþþ1, {C18H25N2O6}¼365.1713. Found: 365.1717.
1.6.8. (1R,2R,2S)-trans-(2-N-Benzoyl-amino-2,3,3-tri-
methyl-cyclopropyl)-hydroxyacetic acid (19g). Colour-
1
(CH3), 16.8 (CH3), 16.1 (CH3), 7.0 (CH3), 5.3 (CH2). H
20
546
NMR d 9.57 (d, J¼2.2 Hz, 1H), 7.25 (b, 5H), 6.55 (s, 1H),
5.68 (t, J¼5.6 Hz, 1H), 5.01 (s, 2H), 3.65 (m, 3H), 1.20 (s,
3H), 1.17 (s, 3H), 1.06 (s, 3H), 0.87 (t, J¼7.9 Hz, 9H), 0.78
(d, J¼10.1 Hz, 1H), 0.53 (q, J¼7.9 Hz, 6H). Anal. calcd for
C24H38NSi2O5: C 62.31; H 8.28; N 6.05. Found: C 58.97; H
8.14; N 6.08.
less foam. Mp 110–1128C; [a] ¼215.0 (c 1.0, CHCl3).
rf¼0.17 (CHCl3/MeOH, 9:1); 13C NMR d 176.6 (C), 170.1
(C), 133.0 (C), 132.8 (CH), 129.1(CH), 127.5 (CH), 69.5
(CH), 40.2 (C), 35.5 (CH), 24.8 (C), 23.3 (CH3), 17.1 (CH3),
1
15.6 (CH3). H NMR d 11.62 (b, 1H), 7.70 (d, J¼7.1 Hz,
2H), 7.40 (m, 4H), 3.83 (d, J¼11.0 Hz, 1H), 1.40 (s, 3H),

¨
J. Hubner et al. / Tetrahedron 58 (2002) 10485–10500
10499
1.25 (s, 3H), 1.17 (s, 3H), 1.02 (d, J¼11.0 Hz, 1H). EI-MS:
m/z: 278 (Mþþ1, 2), 202 (36), 112 (6), 105 (100), 85 (2), 77
(39), 55 (3), 42 (8), 31 (12).
5.41 mmol, 1.0 equiv.) and RuCl3£nH2O (41% Ru, cat.,
120 mg) were added and the resulting brownish-black
solution was vigorously stirred at room temperature for
2.5 h. After the addition of brine (50 mL) and CH2Cl2
(100 mL) the organic layer was separated and the aqueous
phase was extracted with CH2Cl2 (twice 50 mL). After
drying of the combined organic layers (MgSO4), removal of
solvent and chromatography (hexane/AcOEt, 1:1) the
product 22 (739 mg, 79%) was obtained. Colourless
crystals. Mp 1148C. rf¼0.21 (hexane/AcOEt, 1:1). 13C
NMR (CD3OD) d 170.9 (C), 77.2 (C), 35.2 (CH), 32.3 (C),
21.9 (CH3), 15.9 (CH3) 13.3. 13C NMR (CDCl3) d 174.4
(C), 33.9 (CH), 32.5 (C), 21.7 (CH), 15.7 (CH), 12.9 (CH).
1H NMR (CDCl3) d 11.00 (b, 1H), 2.86 (s, 1H), 1.87 (s, 3H),
1.27 (s, 3H), 1.18 (s, 3H). Anal. calcd for C7H11NO4: C,
48.55. H, 6.40; N 8.09. Found: C 48.88. H, 5.71; N 7.95.
1.6.9. (1R,2R,2S)-trans-2-Amino-2,3,3-trimethyl-cyclo-
propyl-2-hydroxyacetic acid (20). Ba(OH)2£8H2O (4
portions, 183 mg, 0.58 mmol each, 4.8 equiv.) were added
to a solution of the trifluoroacetyl protected amino acid 19c
(130 mg, 0.483 mmol, 1.0 equiv.) in MeOH (10 mL) at
room temperature over a period of 24 h. After refluxing for
2 h the solvent was removed under vacuum and the
remainder was dissolved in 1 M H3PO4 (6 mL). This
solution was transferred to a Dowex 50WX8 column
(swelled in half concentrated HCl and washed chloride
free with water). Eluation with 1 M H3PO4 (20 mL), water
(200 mL) and 2% aqueous NH3 (150 mL) afforded the
amino acid 20 in the last 130 mL of eluent. Further
purification by column chromatography was possible
(CHCl3/MeOH, 6:4). Colourless foam. rf¼0.14 (CHCl3/
MeOH, 6:4). 13C NMR (CD3OD) d 180.5 (C), 71.0 (CH),
42.3 (C), 37.4 (CH), 23.6 (Cq), 22.4 (CH3), 17.4 (CH3), 15.5
1.6.12. Methyl (1R,2R)-trans-2,3,3-trimethyl-2-nitro-
cyclopropanecarboxylate (22b). A cold 0.7 M solution of
diazomethane in ether (3.8 mL, 2.68 mmol, 3.0 equiv.) was
added to a solution of the acid 22a (155 mg, 0.895 mmol,
1.0 equiv.) in Et2O (5 mL) dropwise under stirring at 08C.
After stirring at 08C for 1 h, the solvent was evaporated
leaving back pure methyl ester 22b. Light yellow oil.
rf¼0.60 (hexane/AcOEt): 13C NMR (d 168.8 (C), 76.5 (C),
52.2 (CH3), 34.4 (CH), 32.1 (C), 22.0 (CH3), 16.0 (CH3),
1
(CH3). H NMR d 3.49 (d, J¼10.5 Hz, 1H), 1.40 (s, 3H),
1.18 (s, 3H), 1.08 (s, 3H), 1.98 (d, J¼10.5 Hz, 1H).
1.6.10. (1R,2R)-trans-2,3,3-Trimethyl-2-nitro-cyclopro-
pancarbaldehyde (21). Water (5 drops) and p-TsOH
(cat., 25 mg) were added to a solution of the acetonide
10c (100 mg, 0.44 mmol, 1.0 equiv.) in MeOH (5 mL).
After stirring at room temperature for 12 h, solvents
were removed and the deprotected diol was obtained in
quantitative yield as colourless wax after column chroma-
tography (hexane/AcOEt, 1:1. rf¼0.21). The diol (720 mg,
3.81 mmol, 1.0 equiv.) was dissolved in MeOH (30 mL) and
was combined with a suspension of NaIO4 (902 mg,
4.19 mmol, 1.1 equiv.) in buffer solution (pH¼7,7 mL)
under ice cooling. After 2 h stirring at room temperature the
colourless precipitate was filtered off under suction and was
washed with Et2O. The combined filtrates were concen-
trated under vacuum and the remainder was dissolved in
brine. The solution was extracted with Et2O four times,
the combined organic layers were dried (Na2SO4) and
evaporated. After column chromatography hexane/AcOEt,
7:3) the product 21 (459 mg, 77%) was obtained. Light
yellow oil. rf¼0.53 (hexane/AcOEt, 1:1). 13C NMR d 196.9
(CH), 78.5 (C), 41.3 (CH), 35.3 (C), 22.1 (CH3), 16.2 (CH3),
1
13.2 (CH3). H NMR d 3.64 (s, 3H), 2.84 (s, 1H), 1.85 (s,
3H), 1.25 (s, 3H), 1.15 (s, 3H). Anal. calcd for C8H13NO4 C,
51.33; H 7.00; N 7.48. Found: C 51.47; H 6.61; N 8.07.
1.6.13. (1R,2S)-cis-2,3,3-Trimethyl-2-nitro-cyclopropane-
carboxylic acid (23). The cis-nitrocyclopropane 8b
(100 mg, 0.44 mmol, 1.0 equiv.) was hydrolysed (formation
of the corresponding diol) and oxidized with NaIO4 and
RuCl3£nH2O as reported for 22 affording the corresponding
(1R,2S)-cis-2,3,3-trimethyl-2-nitro-cyclopropanecarbalde-
hyde (45 mg, 45%) after column chromatography (hexane/
AcOEt, 8:2). Light yellow oil. rf¼0.48 (hexane/AcOEt,
1:1). 13C NMR d 196.1 (CH), 79.0 (C), 45.3 (CH), 32.8 (C),
1
22.9 (CH3), 19.6 (CH3), 16.6 (CH3). H NMR d 9.48 (d,
J¼5.2 Hz, 1H), 1.77 (s, 3H), 1.69 (d, J¼5.2 Hz, 1H), 1.40
(s, 3H), 1.25 (s, 3H). This aldehyde (342 mg, 2.18 mmol)
was oxidized to the corresponding carboxylic acid 23 by the
procedure applied for the synthesis of 22 (vide supra) using
CCl4 (3 mL), MeCN (3 mL), water (3.5 mL), NaIO4
(930 mg, 4.35 mmol, 2.2 equiv.), RuCl3£nH2O (41% Ru,
cat., 92 mg) affording 24 (263 mg, 70%). Colourless wax.
rf¼0.16 (hexane/AcOEt, 1:1). 13C NMR (CD3OD) d 168.2
(C), 74.3 (C), 35.8 (CH), 28.9 (C), 20.5 (CH3), 16.9 (CH3),
14.3 (CH3). 1H NMR (CD3OD) d 1.82 (s, 1H), 1.70 (s, 3H),
1.26 (s, 3H), 1.16 (s, 3H). Anal. calcd for C7H11NO4: C
48.55; H 6.40; N 8.09. Found: C 50.06; H 6.57; N 7.60.
1
13.5 (CH3). H NMR d 9.77 (d, J¼3.3 Hz, 1H), 3.16 (d,
J¼3.3 Hz, 1H), 1.97, 1.37 (s, 3H), 1.28 (s, 3H). Anal. calcd
for C7H11NO3: C 53.49; H 7.05; N 8.91. Found: C 53.28; H
7.05; N 8.98.
1.6.11. (1R,2R)-trans-2,3,3-Trimethyl-2-nitro-cyclopro-
panecarboxylic acid (22a). By oxidation with air.
A solution of the aldehyde 21 (242 mg, 1.54 mmol,
1.0 equiv.) in CHCl3 (10 mL) was stirred at room
temperature in an open flask. Eventually some CHCl3 has
to be added. After the reaction had gone to completion
(TLC check, maximum 48 h), the solvent was evaporated
and the remainder was purified by column chromatography
(hexane/AcOEt, 1:1) affording product 22 (239 mg, 90%).
1.6.14. (3R,4S)-1-(Hydroxy-2,2-dimethyl-tetrahydro-
furan-3-yl)-ethanone 26. Compound 10c (420 mg,
1.7 mmol, 1.0 equiv.) was dissolved in MeOH (15 mL).
Aqueous concentrated HCl (5 drops) was added. The
solution was stirred at room temperature for 8 h and then
at 408C for 30 min. The volatiles were evaporated under
reduced pressure and the residue was diluted with CH2Cl2
(20 mL). The organic solution was washed with brine, dried
with MgSO4. After removal of the solvent the residue was
purified by chromatography (hexane/AcOEt, 1:1) to afford
By oxidation with RuCl3/NaIO4. MeCN (6 mL) and water
(9 mL) were added to a solution of the aldehyde 21 (850 mg,
5.41 mmol, 1.0 equiv.) in CCl4 (6 mL). NaIO4 (1.153 g,

¨
J. Hubner et al. / Tetrahedron 58 (2002) 10485–10500
10500
Andruszkiewicz, R.; Yuen, P. -W.; Sobieray, D. M.; Franklin,
L. C.; Schwindt, M. A. US Patent 5,710,304, January 20, 1998;
CAN 121, 158191.
(109 mg, 41%) tetrahydrofurane 26. Yellow liquid. rf¼0.11
(hexane/AcOEt, 1:1). 13C NMR d 206.7 (C), 81.6 (C), 73.9
(CH), 71.6 (CH2), 69.8 (CH), 31.4 (CH3), 29.6 (CH3), 23.8
(CH3). 1H NMR d 4.79 (dd, J¼6.2, 12.2 Hz, 1H), 4.01 (dd,
J¼6.2, 9.3 Hz, 1H), 3.62 (dd, J¼5.4, 9.3 Hz, 1H), 2.96 (d,
J¼6.2 Hz, 1H), 2.19 (s, 3H), 1.50 (s, 3H), 1.02 (s, 3H). Anal.
calcd for C8H14O3: C 60.73; H 8.92. Found: C 60.13; H
8.90.
7. Compound 4a was recently described by Cossio.2d
8. Barrow, R. A.; Hemscheidt, T.; Liang, J.; Paik, S.; Moore,
R. E.; Tius, M. J. Am. Chem Soc. 1995, 117, 2479.
9. Caramella, P.; Rondan, N. G.; Paddon-Row, M. N.; Houk,
K. N. J. Am. Chem. Soc. 1981, 103, 2438.
10. (a) Houk, K. N.; Paddon-Row, M. N.; Rondan, N. G.; Wu,
Y. D.; Brown, F. K.; Spellmeyer, D. C.; Metz, J. T.; Li, Y.;
Loncharich, R. J. Science 1986, 231, 1108. (b) Houk, K. N.;
Wu, Y. D.; Duh, H.-Y.; Moses, S. R. J. Am. Chem. Soc. 1986,
108, 2754.
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