Chiral oxime ethers in asymmetric synthesis. O-(1-Phenylbutyl)- benzyloxyacetaldoxime, a versatile reagent for the asymmetric synthesis of protected 1,2-aminoalcohols, α-amino acid derivatives, and 2-hydroxymethyl nitrogen heterocycles including iminosugars

Article abstract of DOI:10.1039/b500390c

Addition of a range of organolithium and Grignard reagents to (E)-O-(1-phenylbutyl)benzyloxyacetaldoxime 1 in the presence of boron trifluoride dietbyl etherate is highly diastereoselective. The resulting hydroxylamines 2 undergo N-O bond cleavage upon treatment with zinc-acetic acid or molybdenum hexacarbonyl to give, after N-protection, protected 1,2-aminoalcohols 3 in high enantiomeric purity. Debenzylation of 3a and 3d gave N-Boc (R)-alaninol and (S)-phenylalaninol respectively. The hydroxylamines 2 also serve as α-amino acid precursors, 2i being converted into N-formyl-(R)-alaninyl-(S)-(4-bromo)phenylalanine ester 7, the N-terminal dipeptide of a natural depsipeptide. The versatility of the 1,2-aminoalcohol derivatives was further illustrated by their conversion into 5-, 6- and 7-membered 2-hydroxymethyl nitrogen heterocycles 15-19 in high enantiomeric excess by a ring-closing metathesis reaction. Further reaction of the dihydropyrrole 15 gave the iminosugar 1,4-dideoxy-1,4-imino-D-ribitol. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b500390c

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A R T I C L E
Chiral oxime ethers in asymmetric synthesis.† O-(1-Phenylbutyl)-
benzyloxyacetaldoxime, a versatile reagent for the asymmetric
synthesis of protected 1,2-aminoalcohols, a-amino acid derivatives,
and 2-hydroxymethyl nitrogen heterocycles including iminosugars
Tracey S. Cooper,a Alexander S. Larigo,‡a Pierre Laurent,a Christopher J. Moody*a and
Andrew K. Takleb
a Department of Chemistry, University of Exeter, Stocker Road, Exeter, UK EX4 4QD
b GlaxoSmithKline, New Frontiers Science Park North, Third Avenue, Harlow, UK CM19 5AW
Received 11th January 2005, Accepted 4th February 2005
First published as an Advance Article on the web 28th February 2005
Addition of a range of organolithium and Grignard reagents to (E)-O-(1-phenylbutyl)benzyloxyacetaldoxime 1 in
the presence of boron trifluoride diethyl etherate is highly diastereoselective. The resulting hydroxylamines 2 undergo
N–O bond cleavage upon treatment with zinc–acetic acid or molybdenum hexacarbonyl to give, after N-protection,
protected 1,2-aminoalcohols 3 in high enantiomeric purity. Debenzylation of 3a and 3d gave N-Boc (R)-alaninol and
(S)-phenylalaninol respectively. The hydroxylamines 2 also serve as a-amino acid precursors, 2i being converted into
N-formyl-(R)-alaninyl-(S)-(4-bromo)phenylalanine ester 7, the N-terminal dipeptide of a natural depsipeptide. The
versatility of the 1,2-aminoalcohol derivatives was further illustrated by their conversion into 5-, 6- and 7-membered
2-hydroxymethyl nitrogen heterocycles 15–19 in high enantiomeric excess by a ring-closing metathesis reaction.
Further reaction of the dihydropyrrole 15 gave the iminosugar 1,4-dideoxy-1,4-imino-D-ribitol.
in our previous publications,1,12,13 or using molybdenum
Introduction
hexacarbonyl.14,15 The resulting amines were not usually isolated
Compounds with a chiral centre adjacent to nitrogen occur
commonly in Nature and are also widely used as synthetic inter-
mediates, ligands and chiral auxiliaries. Although many routes
but immediately protected as their t-butyl or benzyl carbamates.
The protected 1,2-aminoalcohols 3 were formed in good yield
and high enantiomeric excess as evidenced by HPLC on a
to this structural unit already exist, new stereoselective methods
chiral stationary phase (Table 2).16 In most cases, the ee of the
remain of interest. One powerful method for the construction
of such asymmetric centres is the stereoselective addition
carbamate 3 mirrors the de of the hydroxylamine 2 although in
case of 2a/3a there is a significant difference, possibly as a result
of using a different batch of starting hydroxylamine.
=
to C N bonds of imines, hydrazones, oximes, nitrones and
sulfinimines,2–7 and, in this area, we have described the addition
The benzyl protecting group can be readily removed to give
reactions of O-(1-phenylbutyl) oxime ethers in the asymmetric
N-Boc-protected 1,2-aminoalcohols. For example, the O-benzyl
synthesis of amines, a-amino acids and their b-homologues
1,2-aminoalcohols 3a and 3e were deprotected by hydrogenolysis
and a range of nitrogen heterocycles.8 We now report that one
oxime ether, O-(1-phenylbutyl)benzyloxyacetaldoxime 1, is a
to give the known compounds, N-Boc-(R)-alaninol 4a 17 and
N-Boc-(S)-phenylalaninol 4b 18 (Scheme 1), thereby confirming
particularly versatile intermediate for the asymmetric synthesis
the stereochemistry of the original addition to the chiral oxime
of a wide range of nitrogen-containing compounds.9
ether 1.
The (E)-oxime ether 1 was prepared in either enantiomeric
form by reaction of the commercially available benzyloxyacet-
aldehyde with either (R)- or (S)-O-(1-phenylbutyl)hydroxyl-
amine.10 The (E) : (Z) ratio in the oxime ether formation was 49 :
22 (isolated yields), and chromatographic separation is unfortu-
nately necessary since it is essential to use a single isomer in the
subsequent reactions. Addition of a range of organolithium or
Grignard reagents in the presence of boron trifluoride diethyl
etherate in toluene at low temperature proceeded smoothly
and gave the corresponding hydroxylamines 2 in reasonable
yield and in good diastereomeric excess (Table 1). The only
exception to this was the reaction involving the addition of
allylmagnesium bromide that showed poor diastereoselectivity
(42% de), although the major diastereomer was readily isolated
in pure form. The stereochemistry at the new asymmetric
centre was assigned on the basis of previous work, and on
the subsequent transformations of the hydroxylamines 2. The
precise origin of the stereocontrol remains unclear, although we
have proposed predictive models in earlier publications.8
Scheme 1
N-Boc-protected 1,2-aminoalcohols such as 4 are readily
oxidized to the corresponding a-amino acid derivatives using
reagents such as PDC in DMF,19 RuCl3–NaIO4,20 trichloroiso-
cyanuric acid–TEMPO,21 or the Dess–Martin periodinane fol-
lowed by sodium chlorite.22 However, we only investigated this
in one case, namely the conversion of the hydroxylamine 2i into
the N-terminal dipeptide 7 of the depsipeptide polydiscamide
A.23 Thus cleavage of the N–O bond in hydroxylamine 2i was
followed by coupling to N-formyl-(R)-alanine24 using DCC to
give N-formyl-(R)-alaninyl-(S)-(4-bromo)phenylalaninol ben-
zyl ether 5 in modest yield. Subsequent cleavage of the benzyl
ether using boron trichloride gave the alcohol 6 that was oxidized
with PDC in DMF to give the dipeptide 7 after esterification
(Scheme 2).
The N–O bond in the hydroxylamines 2 was readily cleaved
using either zinc in acetic acid with sonication,11 as described
The versatility of the 1,2-aminoalcohol derivatives obtained
by stereoselective addition to O-(1-phenylbutyl)benzyloxy-
acetaldoxime 1 was further illustrated by the synthesis of a range
† Part 7. For part 6 see ref. 1.
‡ Deceased 30 August 2002.
1 2 5 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 2 5 2 – 1 2 6 2
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

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Table 1 Addition of organometallic reagents to O-(1-phenylbutyl)benzyloxyacetaldoxime 1
Oxime configuration
Organometallic reagent
MeLi
Hydroxylamine (configuration at new centre)
Yield (%)
Dea (%)
R
S
R
R
R
S
R
R
S
2a (R)
2b (S)
2b (R)
2c (R)
2d (R)
2e (S)
2f (R)
2g (R)
2h (S)
2i (S)
2j (S)
2k (S)
75
61
69
82
79
44b
72
56
83
45
81
84
75
87
89
90
90
42
90
>95
90
90
=
H2C CHLi
=
H2C CHLi
n-PrMgCl
i-PrMgCl
=
H2C CHCH2MgBr
n-BuLi
PhLi
PhCH2MgBr
4-BrC6H4CH2MgBr
2-Lithiothiophene
2-Lithiothiazole
S
R
R
80
>95
1
a Determined from the H-NMR spectrum of crude hydroxylamine 2 (before chromatography) by integration of the CHNH signals. b Yield of the
major diastereomer after separation.
Table 2 N–O bond cleavage in hydroxylamines 2 and protection of resulting amines as carbamates 3
Hydroxylamine
Methoda
R
Rꢀ
Protected 1,2-aminoalcohol 3 configuration
Yield (%)
Eeb (%)
2a
2b
2ed
2f
2h
2i
2k
A
B
B
A
A
B
A
Me
H2C CH
H2C CHCH2
n-Bu
Bn
4-BrC6H4CH2
2-Thiazolyl
t-Bu
Bn
Bn
t-Bu
t-Bu
t-Bu
t-Bu
3a
3b
3c
3d
3e
3f
R
S
S
R
S
S
S
67
76
70
67
84
53
77
97
Ndc
91
93
83
97
98
=
=
3g
a Method A: Mo(CO)6, MeCN; Method B: Zn, AcOH, ultrasound. b Determined by HPLC on ChiralCel OD using hexane–isopropanol (85 : 15 to
95 : 5) as eluant. c Nd = not determined d The pure major diastereomer was used in this reaction.
Scheme 2
Scheme 3
of nitrogen heterocycles (Schemes 3–6). This was conveniently
achieved by the incorporation of a second unsaturated sidechain
(allyl or butenyl) into the derivatives obtained by addition of
vinyl and allyl nucleophiles, thereby setting up dienyl systems
for ring-closure by a ring-closing metathesis (RCM) reaction.25
Thus N-allylation of the benzyl carbamates 3b and 3c gave the
corresponding (S)-N-allyl derivatives 8 and 9 in good yield. At-
tempted reaction of carbamates 3b and 3c with 4-bromobutene
under similar conditions was unsatisfactory, and therefore the
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 2 5 2 – 1 2 6 2
1 2 5 3

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Scheme 4
Scheme 6
bis-(tricyclohexylphosphine)dichlororuthenium (10 mol%)
(Grubbs’ catalyst) at room temperature until complete
consumption of starting material was observed by TLC. The
2-benzyloxymethyl-5-, -6-, and -7-membered heterocycles 15–19
were formed in excellent yield as shown in Scheme 5. Thus the
dihydropyrrole 15, the isomeric tetrahydropyridines 16 and 17,
the tetrahydroazepine 18 and the tetrahydropyridine 19 were all
prepared by this method.
Some of the 2-benzyloxymethyl heterocycles formed in
the RCM reaction were elaborated further as shown in
Scheme 6. Catalytic hydrogenation of tetrahydropyridine 17
over palladium-on-carbon resulted in concomitant reduction
of the double bond and hydrogenolysis of the benzyl ether
protecting group to give (S)-piperidine-2-methanol20. Similarly,
the tetrahydropyridine 19 gave the isoleucinyl piperidine 21, a
potential precursor (by oxidation of the hydroxymethyl group)
of the isoleucinyl pipecolic acid dipeptide of the apicidins,
naturally occurring cyclic peptides.26 Finally, the dihydropyrrole
15 was used in a synthesis of 1,4-dideoxy-1,4-imino-D-ribitol
23, a naturally occurring glycosidase inhibitor isolated from
the mulberry tree Morus alba.27–31 Thus reaction of the dihy-
dropyrrole 15 with a catalytic amount of osmium tetroxide in
the presence of N-methylmorpholine-N-oxide (NMO) resulted
in dihydroxylation from the least hindered face to give, after
acetylation, the protected iminosugar 22 (84% over two steps).
Hydrogenolysis of 22 over palladium-on-carbon in methanolic
hydrochloric acid gave 1,4-dideoxy-1,4-imino-D-ribitol 23 as its
hydrochloride salt in quantitative yield (Scheme 6).
Scheme 5
In summary, we have shown that the oxime ether 1 is a
versatile reagent for the asymmetric synthesis of protected 1,2-
aminoalcohols and nitrogen heterocycles.
RCM precursors 12 and 13 were prepared differently. The N–O
bond in hydroxylamines 2b and 2e was cleaved as before, and the
resulting amines were alkylated with 4-bromobutene to give the
(S)-secondary amines 10 and 11, protection of which with benzyl
chloroformate gave the (S)-dienes 12 and 13 (Scheme 3). In a
related sequence, hydroxylamine (R,R)-2b was converted into
(R)-10, DCC-coupling of which with N-Boc isoleucine gave the
RCM precursor 14 (Scheme 4).
Experimental
For general experimental details, see ref. 12. With the exception
of compound 2e, which was isolated as a single diastereomer,
hydroxylamines 2 were characterized as diastereomeric mix-
tures; the NMR data refer to the major diastereomer.
The RCM reactions of the five dienes were carried out by stir-
ring a dichloromethane solution of the diene with benzylidene-
1 2 5 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 2 5 2 – 1 2 6 2

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(E)-(S)-(−)-O-(1-Phenylbutyl)benzyloxyacetaldoxime (E)-(S)-1
(2S,1ꢀS)-(−)-1-Benzyloxy-N-(1-phenylbutoxy)-2-but-3-enyla-
mine (S,S)-2b. Obtained from the addition of vinyllithium
(6.05 mmol) (prepared from tetravinyltin and methyllithium32)
to oxime (E)-(S)-1 (1.85 mmol). The crude product was purified
by column chromatography on silica gel, eluting with light
petroleum–dichloromethane (1 : 2) to give the pure product as
a colourless oil (61%, 87% de); (Found: C, 77.9; H, 9.0; N, 4.3.
C21H27NO2 requires C, 77.5; H, 8.4; N, 4.3%); (Found: MH+,
Obtained from the cleavage of (S)-(−)-N-(1-phenylbutoxy)-
phthalimide10 (10.17 mmol) and subsequent condensation of
the hydroxylamine with benzyloxyacetaldehyde (10.17 mmol).
The crude product was purified by column chromatography on
silica gel, eluting with light petroleum–dichloromethane (1 : 2) to
give the pure product as a colourless oil (49%); (Found: C, 77.0;
H, 8.0; N, 4.7. C19H23NO2 requires C, 76.7; H, 7.8; N, 4.7%);
(Found: MH+, 298.1806. C19H23NO2 + H requires 298.1807);
22
326.2123. C21H27NO2 + H requires 326.2120); [a]D −42.5 (c
1.20, CHCl3); mmax (film)/cm−1 3263 (NH), 3083, 3068, 3032,
2950, 2930, 2863, 1501, 1455, 1363, 1096, 1030, 994, 917, 738,
692; dH (300 MHz; CDCl3) 7.31 (10 H, m, ArH), 5.78 (2 H,
[a]D −6.7 (c 0.90, CHCl3); mmax (film)/cm−1 3063, 3032, 2960,
24
2935, 2868, 1496, 1450, 1363, 1091, 1020, 922, 738, 697; dH
=
(300 MHz; CDCl3) 7.54 (1 H, t, J = 6.8 Hz, N CH), 7.31 (10 H,
=
=
m, CH, NH), 5.24 (2 H, m, CH2), 4.57 (1 H, dd, J = 7.6,
5.8 Hz, OCH), 4.46 (2 H, AB, J 12.3, CH2Ph), 3.75 (1 H, m,
NCH), 3.48 (1 H, dd, J 9.6, 4.3, OCHH), 3.39 (1 H, dd, J 9.6,
8.1, OCHH), 1.79 (1 H, m, CHH), 1.59–1.16 (3 H, m, CHH,
CH2), 0.89 (3 H, t, J 7.2, Me); dC (75 MHz; CDCl3) 143.7 (C),
138.5 (C), 136.6 (CH), 128.8 (CH), 128.7 (CH), 128.06 (CH),
128.03 (CH), 127.7 (CH), 127.0 (CH), 118.3 (CH2), 85.8 (CH),
73.5 (CH2), 70.5 (CH2), 63.9 (CH), 39.3 (CH2), 19.6 (CH2), 14.5
(Me); m/z (CI) 326 (MH+, 10%), 194 (59), 193 (15), 162 (31),
133 (100), 119 (9), 107 (11), 91 (99).
m, ArH), 5.09 (1 H, t, J 7.0, OCH), 4.44 (2 H, AB, J 12.5,
CH2Ph), 4.07 (2 H, m, CH2CHN), 1.95 (1 H, m, CHH), 1.73
(1 H, m, CHH), 1.51–1.26 (2 H, m, CH2Me), 0.95 (3 H, t, J
7.3, Me); dC (75 MHz; CDCl3) 147.5 (CH), 142.8 (C), 137.9 (C),
128.8 (CH), 128.7 (CH), 128.4 (CH), 128.2 (CH), 127.8 (CH),
127.1 (CH), 85.6 (CH), 72.7 (CH2), 67.1 (CH2), 38.7 (CH2), 19.3
(CH2), 14.4 (Me); m/z (CI) 298 (MH+, 4%), 174 (6), 133 (100),
117 (35), 107 (35), 105 (95), 92 (88), 77 (99), 51 (81).
Also formed was (Z)-(S)-O-(1-phenylbutyl)benzyloxyacetal-
doxime (Z)-(S)-1 as a colourless oil (22%); dH (300 MHz; CDCl3)
7.30 (10 H, m, ArH), 6.89 (1 H, t, J = 3.6 Hz, N CH), 5.07 (1 H,
(2R,1ꢀR)-(+)-1-Benzyloxy-N-(1-phenylbutoxy)-2-but-3-enyla-
mine (R,R)-2b. Obtained from the addition of vinyllithium
(20.20 mmol) to oxime (E)-(R)-1 (6.73 mmol). The crude
product was purified by column chromatography on silica gel,
eluting with light petroleum–dichloromethane (1 : 2) to give the
=
t, J 6.9, OCH), 4.57 (2 H, s, CH2Ph), 4.43 (2 H, m, CH2CHN),
1.92 (1 H, m, CHH), 1.71 (1 H, m, CHH), 1.49–1.24 (2 H, m,
CH2Me), 0.94 (3 H, t, J 7.4, Me); dC (75 MHz; CDCl3) 150.7
(CH), 142.9 (C), 137.9 (C), 128.9 (CH), 128.7 (CH), 128.3 (CH),
128.2 (CH), 127.9 (CH), 126.8 (CH), 85.9 (CH), 73.6 (CH2), 65.2
(CH2), 38.7 (CH2), 19.3 (CH2), 14.4 (Me).
23
pure product as a colourless oil (69%, 89% de); [a]D +45.7
(c 1.05, CHCl3); spectroscopic properties are identical to the
enantiomer (S,S)-2b.
(E)-(R)-(+)-O-(1-Phenylbutyl)benzyloxyacetaldoxime (E)-(R)-1
(2R,1ꢀR)-1-Benzyloxy-N-(1-phenylbutoxy)-2-pentylamine 2c.
Obtained from the addition of n-propylmagnesium chloride to
Obtained from the cleavage of (R)-(+)-N-(1-phenylbutoxy)-
phthalimide10 (10.17 mmol) and subsequent condensation of
the hydroxylamine with benzyloxyacetaldehyde (10.17 mmol).
The crude product was purified by column chromatography on
silica gel, eluting with light petroleum–dichloromethane (1 : 2)
17
oxime (E)-(R)-1 as a colourless oil (82%, 90% de); [a]D +57.4 (c
0.6, CHCl3); (Found: MH+, 342.2441. C22H31NO2 + H requires
342.2433); mmax (film)/cm−1 3262 (NH), 3032, 2863, 1454; dH
(300 MHz; CDCl3) 7.45–7.08 (10 H, m, ArH), 5.56 (1 H, br s,
NH), 4.45 (1 H, t, J = 5.9 Hz, OCH), 4.39 (2 H, AB, J 14.0,
CH2Ph), 3.45 (1 H, dd, J 9.5, 3.9, OCHH), 3.28 (1 H, dd, J 9.5,
6.5, OCHH), 2.99 (1 H, m, NCH), 1.74 (1 H, m, CHH), 1.26
(7 H, m, CHH, 3 × CH2), 0.83 (6 H, m, 2 × Me); dC (75 MHz;
CDCl3) 143.9 (C), 139.1 (C), 129.7 (CH), 129.0 (2 × CH), 128.2
(CH), 127.9 (CH), 127.3 (CH), 85.8 (CH), 73.7 (CH2), 70.4
(CH2), 60.8 (NCH), 39.4 (CH2), 32.3 (CH2), 19.9 (CH2), 19.8
(CH2), 14.9 (Me), 14.7 (Me); m/z (CI) 342 (MH+, 100%), 286
(22), 210 (89), 133 (9).
26
to give the pure product as a colourless oil (60%); [a]D +11.2
(c 1.07, CH2Cl2); spectroscopic properties are identical to the
(S)-enantiomer (E)-(S)-1.
General procedure for the addition of organometallics
The oxime ether 1 (3.9 mmol, 1 equiv.) was dissolved in
toluene (10 mL) under nitrogen and cooled to −78 ◦C or
−90 ◦C. Boron trifluoride etherate (11.8 mmol, 3 equiv.) was
added and the mixture stirred for 15 min. The organometallic
reagent (11.8 mmol, 3 equiv.) was added dropwise over 30 min
at this temperature, and the mixture stirred until all starting
material was consumed. The reaction mixture was quenched at
this temperature with aqueous saturated ammonium chloride
solution (10 mL), and allowed to warm to room temperature.
The mixture was extracted with diethyl ether (3 × 15 mL),
combined, dried (K2CO3), filtered and evaporated. The residue
was purified by column chromatography on silica gel.
(2R,1ꢀR)-1-Benzyloxy-3-methyl-N-(1-phenylbutoxy)-2-butyla-
mine 2d. Obtained from the addition of isopropylmagnesium
chloride to oxime (E)-(R)-1 as a colourless oil (79%, 90% de);
[a]D +38.8 (c 1.6, CHCl3); (Found: M+, 341.2373. C22H31NO2
19
requires 341.2355); mmax (film)/cm−1 3252 (NH), 3032, 2955,
2868, 1490, 1454; dH (300 MHz; CDCl3) 7.23 (10 H, m, ArH),
6.15 (1 H, br s, NH), 4.47 (1 H, t, J = 5.9 Hz, OCH), 4.37 (2 H,
AB, J 12.0, CH2Ph), 3.47 (1 H, dd, J 9.7, 6.3, OCHH), 3.26
(1 H, dd, J 9.7, 7.3, OCHH), 2.83 (1 H, m, NCH), 1.84 (1 H, m,
CHMe2), 1.64 (1 H, m, CHH), 1.46 (1 H, m, CHH), 1.32 (2 H,
m, CH2), 0.86 (6 H, d, J 6.8, 2 × Me), 0.79 (3 H, t, J 7.2, Me);
dC (75 MHz; CDCl3) 143.8 (C), 138.8 (C), 128.7 (CH), 128.6
(CH), 127.9 (2 × CH), 127.6 (CH), 127.0 (CH), 85.3 (CH),
73.4 (CH2), 67.8 (CH2), 65.9 (CH), 39.1 (CH2), 27.7 (CH), 20.1
(Me), 19.6 (CH2), 18.8 (Me), 14.5 (Me); m/z (EI) 341 (M+, 6%),
298 (10), 278 (8), 209 (22), 178 (87), 133 (100), 107 (29), 91 (83),
77 (26).
(2R,1ꢀR)-1-Benzyloxymethyl-N-(1-phenylbutoxy)-2-propyl-
amine 2a. Obtained from the addition of methyllithium to
18
oxime (E)-(R)-1 as a colourless oil (75%, 75% de); [a]D +41.6
(c 1.4, CHCl3); (Found: MH+, 314.2131. C20H27NO2 + H
requires 314.2120); mmax (film)/cm−1 3238 (NH), 3011, 2965,
2873, 1449; dH (300 MHz; CDCl3) 7.22 (10 H, m, ArH), 5.59
(1 H, br s, NH), 4.49 (1 H, t, J = 5.9 Hz, OCH), 4.38 (2 H, s,
CH2Ph), 3.35 (1 H, m, NCH), 3.23 (2 H, m, OCH2), 1.46 (1 H,
m, CHH), 1.34 (1 H, m, CHH), 1.23 (2 H, m, CH2), 1.00 (3 H,
t, J 6.2, Me), 0.86 (3 H, t, J 7.3, Me); dC (75 MHz; CDCl3) 143.6
(C), 138.7 (C), 128.72 (CH), 128.69 (CH), 127.9 (2 × CH),
127.6 (CH), 126.9 (CH), 85.8 (CH), 73.4 (CH2), 71.8 (CH2),
56.1 (CH), 39.3 (CH2), 19.6 (CH2), 15.8 (Me), 14.5 (Me); m/z
(CI) 314 (MH+, 12%), 210 (4), 192 (3), 181 (69), 164 (7), 150
(37), 133 (100), 91 (65).
(2S,1ꢀS)-(−)-1-Benzyloxy-N-(1-phenylbutoxy)-2-pent-4-enyl-
amine 2e. Obtained from the addition of allylmagnesium
bromide (3.03 mmol) to oxime (E)-(S)-1 (1.01 mmol). The
crude product was purified by column chromatography on
silica gel, eluting with light petroleum–dichloromethane (1 :
2) to give the pure product as a colourless oil (44% of major
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 2 5 2 – 1 2 6 2
1 2 5 5

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diastereoisomer, 42% de); (Found: C, 78.0; H, 8.8; N, 3.9.
C22H29NO2 requires C, 77.8; H, 8.6; N, 4.1%); (Found: M+,
7.28 (10 H, m, ArH), 7.07 (2 H, d, J 8.2, ArH), 5.62 (1 H, br s,
NH), 4.54 (1 H, dd, J 6.1, 7.7, OCH), 4.49 (2 H, dd, J 11.8, 22.5
CH2Ar), 3.48 (1 H, dd, J 5.2, 9.4, CHHOCH2Ph), 3.36 (1 H,
dd, J 5.2, 9.4, CHHOCH2Ph), 3.26 (1 H, m, HCNH), 2.87
(1 H, dd, J 7.0, 12.7, CH2OCHHPh), 2.64 (1 H, dd, J 7.0, 12.7,
CH2OCHHPh), 1.80 (1 H, m, CHH), 1.57 (1 H, m, CHH), 1.43
(1 H, m, CHH), 1.30 (1 H, m, CHH), 0.93 (3 H, t, J 7.3, Me); dC
(75 MHz; CDCl3) 142.9 (C), 138.1 (C), 137.9 (C), 131.4 (CH),
131.1 (CH), 130.9 (CH), 128.3 (CH), 127.8 (CH), 127.6 (CH),
127.4 (CH), 126.6 (CH), 120.0 (C), 85.3 (CH), 73.1 (CH2), 68.9
(CH2), 61.7 (CH), 38.6 (CH2), 35.0 (CH2), 19.2 (CH2), 14.1
(Me); m/z (CI) 468/466 (MH+, 46%), 320 (15), 166 (13), 150
(100), 133 (21), 108 (40), 91 (64), 78 (5).
24
339.2209. C22H29NO2 requires 339.2198); [a]D −44.7 (c 0.76,
CHCl3); mmax (film)/cm−1 3478 (NH), 3063, 3027, 2960, 2925,
2863, 1496, 1450, 1358, 1102, 1025, 917, 733, 692; dH (300 MHz;
=
CDCl3) 7.30 (10 H, m, ArH), 5.79 (1 H, m, CH), 5.67
=
(1 H, br s, NH), 5.05 (2 H, m, CH2), 4.55 (1 H, t, J = 6.8 Hz,
OCH), 4.46 (2 H, AB, J 12.1, CH2Ph), 3.50 (1 H, dd, J 9.6,
4.1, OCHH), 3.38 (1 H, dd, J 9.6, 7.0, OCHH), 3.17 (1 H, m,
=
=
NCH), 2.34 (1 H, m, CHHCH ), 2.19 (1 H, m, CHHCH ),
1.80 (1 H, m, CHH), 1.55 (1 H, m, CHH), 1.48–1.20 (2 H, m,
CH2), 0.91 (3 H, t, J 7.4, Me); dC (75 MHz; CDCl3) 143.5 (C),
138.7 (C), 135.6 (CH), 128.73 (CH), 128.69 (CH), 127.98 (CH),
127.96 (CH), 127.7 (CH), 127.0 (CH), 117.5 (CH2), 85.7 (CH),
73.5 (CH2), 69.8 (CH2), 60.3 (CH), 39.1 (CH2), 34.4 (CH2), 19.6
(CH2), 14.5 (Me); m/z (EI) 339 (M+, 3%), 298 (3), 207 (24), 176
(23), 166 (96), 133 (88), 107 (48), 91 (100), 77 (39).
(2S,1ꢀR)-1-Benzyloxy-N-(1-phenylbutoxy)-1-(2-thienyl)ethyla-
mine 2j. Obtained from the addition of 2-lithiothiophene to
24
oxime (E)-(R)-1 as a yellow oil (81%, 80% de); [a]D +86.9
(c 1.0, CHCl3); (Found: MH+, 382.1835. C23H27NO2S + H
requires 382.1841); mmax (film)/cm−1 3267 (NH), 3027, 2955,
2929, 1454, 1106; dH (300 MHz; CDCl3) 7.31 (11 H, m, ArH),
7.01 (2 H, m, ArH), 5.98 (1 H, br, NH), 4.63 (1 H, m, OCH),
4.53 (1 H, m, NCH), 4.50 (2 H, s, CH2Ph), 3.61 (2 H, m, OCH2),
1.66 (1 H, m, CHH), 1.44 (1 H, m, CHH), 1.31 (2 H, m, CH2),
0.78 (3 H, t, J = 7.3 Hz, Me); dC (75 MHz; CDCl3) 143.7 (C),
143.5 (C), 138.2 (C), 128.8–124.9 (9 × CH), 85.9 (CH), 73.6
(CH2), 72.0 (CH2), 61.2 (CH), 39.1 (CH2), 19.3 (CH2), 14.3
(Me); m/z (CI) 382 (MH+, 23%), 309 (4), 281 (10), 260 (17),
237 (36), 217 (58), 199 (7), 133 (32), 107 (13), 91 (100).
(2R,1ꢀR)-1-Benzyloxy-N-(1-phenylbutoxy)-2-hexylamine 2f.
Obtained from the addition of n-butyllithium to oxime (E)-
24
(R)-1 as a colourless oil (72%, 90% de); [a]D +38.6 (c 1.1,
CHCl3); (Found: M+, 355.2518. C23H33NO2 requires 355.2511);
mmax (film)/cm−1 3032, 2965, 2863, 1495, 1449; dH (300 MHz;
CDCl3) 7.21 (10 H, m, ArH), 5.22 (1 H, br s, NH), 4.67 (1 H, t,
J = 5.7 Hz, OCH), 4.38 (2 H, AB, J 12.0, CH2Ph), 3.42 (1 H, m,
OCHH), 3.28 (1 H, m, OCHH), 2.98 (1 H, m, NCH), 1.70 (1 H,
m, CHH), 1.47 (1 H, m, CHH), 1.26 (2 H, m, CH2), 1.19 (6 H,
m, 3 × CH2), 0.84 (3 H, t, J 7.3, Me), 0.79 (3 H, t, J 4.0, Me); dC
(75 MHz; CDCl3) 143.6 (C), 138.8 (C), 128.7 (CH), 128.6 (CH),
127.94 (CH), 127.91 (CH), 127.6 (CH), 126.9 (CH), 85.5 (CH),
73.5 (CH2), 70.1 (CH2), 60.8 (CH), 39.2 (CH2), 29.5 (CH2), 28.7
(CH2), 23.3 (CH2), 19.6 (CH2), 14.6 (Me), 14.4 (Me); m/z (EI)
355 (M+, 4%), 223 (24), 192 (99), 174 (7), 150 (4), 133 (83), 107
(40), 91 (100), 77 (32).
(1S,1ꢀR)-1-Benzyloxy-N -(1-phenylbutoxy)-1-(2-thiazolyl)-
ethylamine 2k. Obtained from the addition of 2-lithiothiazole
18
to oxime (E)-(R)-1 as a yellow oil (84%, >95% de); [a]D +31.7
(c 2.3, CHCl3); (Found: M+, 382.1720. C22H26N2O2S requires
382.1715); mmax (film)/cm−1 3262 (NH), 3037, 2960, 2960, 2868,
1501, 1460; dH (300 MHz; CDCl3) 7.61 (1 H, d, J = 3.3 Hz,
thiazole H-4), 7.16 (11 H, m, ArH, thiazole H-5), 5.96 (1 H,
br s, NH), 4.60 (1 H, dd, J 8.9, 4.1, NCH), 4.51 (1 H, t, J 5.8,
OCH), 4.35 (2 H, AB, J 12.0, CH2Ph), 3.65 (1 H, dd, J 9.9,
4.1, OCHH), 3.46 (1 H, dd, J 9.9, 4.0, OCHH), 1.53 (1 H, m,
CHH), 1.36 (1 H, m, CHH), 1.21 (2 H, m, CH2), 0.65 (3 H, t, J
7.3, Me); dC (75 MHz; CDCl3) 170.9 (C), 143.1 (C), 142.7 (CH),
137.9 (C), 128.8 (2 × CH), 128.2 (CH), 128.0 (CH), 127.8 (CH),
126.9 (CH), 119.5 (CH), 86.1 (CH), 73.6 (CH2), 70.6 (CH2),
63.5 (CH), 39.0 (CH2), 19.3 (CH2), 14.3 (Me); m/z (EI) 382
(M+, 5%), 295 (3), 219 (15), 250 (25), 199 (11), 150 (7), 133 (38),
107 (58), 91 (100), 85 (25), 77 (32).
(1R,1ꢀR)-1-Benzyloxy-1-phenyl-N-(1-phenylbutoxy)ethylamine
2g. Obtained from the addition of phenyllithium to oxime
21
(E)-(R)-1 as a colourless oil (56%, >95%); [a]D +45.8 (c 0.5,
CHCl3); (Found: MH+, 376.2286. C25H29NO2 + H requires
376.2277); mmax (film)/cm−1 3243 (NH), 3023, 2955, 2866, 1497,
1448; dH (300 MHz; CDCl3) 7.21 (15 H, m, ArH), 5.89 (1 H,
br s, NH), 4.37 (2 H, s, CH2Ph), 4.30 (3 H, m, OCH, OCH2),
3.39 (1 H, m, NCH), 1.47 (1 H, m, CHH), 1.24 (1 H, m, CHH),
0.85 (2 H, m, CH2), 0.56 (3 H, t, J = 7.3 Hz, Me); dC (75 MHz;
CDCl3) 144.0 (C), 140.2 (C), 138.3 (C), 128.8–126.4 (9 × CH),
85.7 (CH), 73.5 (CH2), 72.2 (CH2), 65.5 (CH), 39.3 (CH2), 19.4
(CH2), 14.4 (Me); m/z (CI) 376 (MH+, 14) 254 (19), 244 (41),
212 (57), 182 (7), 150 (8), 133 (100), 122 (23), 107 (68), 91 (99).
General procedure for the preparation of N-Boc-protected
t
amines 3 (R = Bu)
(2S,1ꢀS)-1-Benzyloxy-3-phenyl-N-(1-phenylbutoxy)-2-propyl-
amine 2h. Obtained from the addition of benzylmagnesium
bromide to oxime (E)-(S)-1 as a colourless oil (83%, 90%
Hydroxylamine 2 (0.5 mmol) was dissolved in acetonitrile (8 mL)
and water (2 mL). Molybdenum hexacarbonyl (0.5 mmol)
was added and the mixture heated under reflux overnight.
The reaction mixture was allowed to cool to room tem-
perature, di-tert-butyl dicarbonate (2 mmol) and 4-(N,N-
dimethylamino)pyridine (catalyst) were added and the mixture
was allowed to stir overnight. The solvent was removed in vacuo
and the residue purified by column chromatography on silica
gel eluting with ethyl acetate–light petroleum. The enantiomeric
purity of the product was assessed by HPLC on a ChiralCel OD
column using hexane–2-propanol (95 : 5) as eluant.
de); [a]D −37.4 (c 0.8, CHCl3); (Found: MH+, 390.2454.
21
C26H31NO2 + H requires 390.2433); mmax (film)/cm−1 3233 (NH),
3032, 2954, 2868, 1496, 1448; dH (300 MHz; CDCl3) 7.21 (15 H,
m, ArH), 5.56 (1 H, br s, NH), 4.47 (1 H, t, J = 6.0 Hz, OCH),
4.35 (2 H, AB, J 11.9, OCH2Ph), 3.40 (1 H, m, NCH), 3.31
(2 H, m, OCH2), 2.86 (1 H, dd, J 11.9, 7.5, CHHPh), 2.59 (1 H,
dd, J 11.9, 7.5, CHHPh), 1.69 (1 H, m, CHH), 1.49 (1 H, m,
CHH), 1.18 (2 H, m, CH2), 0.82 (3 H, t, J 6.2, Me); dC (75 MHz;
CDCl3) 143.5 (C), 139.3 (C), 138.7 (C), 130.2–126.6 (9 × CH),
85.8 (CH), 73.6 (CH2), 69.5 (CH2), 62.4 (CH), 39.1 (CH2), 36.1
(CH2), 19.7 (CH2), 14.5 (Me); m/z (CI) 390 (MH+, 84%), 365
(3), 298 (37), 278 (33), 258 (100), 242 (42), 210 (32), 165 (31).
General procedure for the preparation of N-Cbz-protected
amines 3 (R = Bn)
(2S,1ꢀS)-1-Benzyloxy-3-(4-bromophenyl)-N-(1-phenylbutoxy)-
2-propylamine 2i. Obtained from the addition of 4-bromo-
benzylmagnesium bromide to oxime (E)-(S)-1 as a yellow oil
(45%, 90% de); (Found: MH+, 468.1534. C26H3079BrNO2 + H
Zinc dust (15 mmol) was added to a solution of the hydrox-
ylamine 2 (0.38 mmol) in acetic acid–water (1 : 1; 6 mL).
The mixture was placed in a sonic bath at 40 ◦C until all
the starting material was consumed (TLC, typically 1.5–4 h).
The zinc was filtered off and rigorously washed with water and
diethyl ether. The filtrate was extracted with diethyl ether (5×),
the aqueous layer was basified to pH 12 with aqueous sodium
requires 468.1538); [a]D −28.9 (c 1.38, CHCl3); mmax (film)/cm−1
26
3062, 3021, 2934, 2868, 1490, 1449, 1357, 1203, 1014, 901, 691;
dH (300 MHz; CDCl3) 7.40 (2 H, d, J = 8.2 Hz, ArH), 7.39 −
1 2 5 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 2 5 2 – 1 2 6 2

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hydroxide solution (2 M) and a little saturated ammonium
chloride solution was added to disperse the emulsion. The
solution was further extracted with dichloromethane (3×). The
dichoromethane organic layers were combined and evaporated.
The residue was dissolved in THF–water (1 : 1; 20 mL)
and sodium carbonate (1.52 mmol) was added. The solution
was cooled to 0 ◦C and benzyl chloroformate (0.50 mmol)
added dropwise. The mixture was allowed to warm to room
temperature and was stirred overnight. The THF was evaporated
under reduce pressure. Diethyl ether (10 mL) was added, the
layers were separated, and the aqueous layer was extracted
with further portions of diethyl ether (3×). The organic layers
were combined, dried (MgSO4), filtered and evaporated. The
enantiomeric purity of the product was assessed by HPLC on a
ChiralCel OD column using hexane–2-propanol (85 : 15 to 95 :
5) as eluant, flow rate 1 mL min−1.
br, NCH), 3.39 (2 H, m, OCH2), 2.88 (2 H, m, CH2Ph), 1.43
(9 H, s, CMe3); dC (75 MHz; CDCl3) 155.8 (C), 138.6 (C), 138.5
(C), 129.9 (CH), 128.8 (CH), 128.7 (CH), 128.2 (2 × CH), 127.6
(CH), 79.7 (C), 73.6 (CH2), 70.5 (CH2), 52.1 (CH), 38.3 (CH2),
28.8 (Me); HPLC: hexane–2-propanol (90 : 10), tR = 8.1 and
8.7 (major) min.
(S)-1-Benzyloxy-3-(4-bromophenyl)-N-tert-butoxycarbonyl-
2-propylamine ◦3f. Obtained as a colourless solid (53%, 97%
ee), mp 72–73 C; Found: MH+, 420.1171. C21H2679BrNO3 + H
requires 420.1174); [a]D −4.0 (c 1.04, CH3Cl); mmax (KBr)/cm−1
26
3359, 2919, 2847, 1685, 1526, 1490, 1362, 1168; dH (300 MHz;
CDCl3) 7.40–7.30 (5 H, m, ArH), 7.35 (2 H, d, J = 8.2 Hz,
ArH), 7.03 (2 H, d, J 8.2, ArH), 4.93 (1 H, d, J 8.2, NH), 4.48
(2 H, dd, J 11.8, 24.4, CH2OCH2Ph), 3.90 (1 H, m, HCNH),
3.39 (1 H, dd, J 3.9, 9.3, CH2OCHHPh), 3.35 (1 H, dd, J 3.9,
9.3, CH2OCHHPh), 2.83 (2 H, m, CH2Ar), 1.45 (9 H, s, 3 ×
Me); dC (75 MHz; CDCl3) 155.3 (C), 137.9 (C), 137.2 (C), 131.4
(CH), 131.2 (CH), 127.86 (CH), 127.83 (CH), 126.4 (CH), 120.2
(C), 73.3 (CH2), 69.9 (CH2), 51.5 (CH), 37.3 (C), 27.9 (Me),
27.8 (CH2); m/z (CI), 420/418 (MH+, 3%), 386 (10), 339 (8),
322 (19), 193 (13), 161 (25), 129 (100), 97 (64), 90 (33).
(R)-1-Benzyloxy-N-tert-butoxycarbonyl-2-propylamine 3a.
Obtained as a colourless oil (67%, 97% ee) (lit.,20 no data); [a]D
19
+24.5 (c 0.5, CHCl3); dH (300 MHz; CDCl3) 7.24 (5 H, m, ArH),
4.65 (1 H, br s, NH), 4.46 (2 H, AB, J = 12.0 Hz, CH2Ph), 3.81
(1 H, br, NCH), 3.38 (2 H, m, OCH2), 1.36 (9 H, s, CMe3), 1.11
(3 H, d, J 6.7, Me); HPLC: hexane–2-propanol (95 : 5), tR = 8.8
(major) and 11.9 min.
(S)-2-Benzyloxy-N-tert-butoxycarbonyl-1-(2-thiazolyl)ethyl-
amine 3g. Obtained as a yellow oil (0.129 g, 77%, 98% ee);
(S)-(−)-1-Benzyloxy-N-benzyloxycarbonyl-2-but-3-enylamine
3b. Obtained as a colourless oil (76%) that slowly solidifies;
mp 39–40 ◦C; (Found: MH+, 312.1606. C19H21NO3 + H requires
23
[a]D −41.7 (c 1.2, CHCl3); (Found: C, 69.6; H, 7.3; N, 7.3.
C17H22N2O3S requires C, 69.1, H, 7.0; N, 7.3%); (Found: M+,
312.1600); [a]D −27.2 (c 0.92, CHCl3); mmax (film)/cm−1 3416
22
334.1354. C17H22N2O3S requires 334.1351); mmax (film)/cm−1
=
(NH), 3324, 3088, 3063, 3027, 2940, 2894, 2853, 1716 (C O),
=
3324 (NH), 2975, 2919, 2863, 1936, 1716 (C O); dH (300 MHz;
1496, 1450, 1404, 1342, 1219, 1096, 912, 733, 687; dH (300 MHz;
CDCl3) 7.34 (10 H, m, ArH), 5.89 (1 H, ddd, J = 17.2, 10.4,
CDCl3) 7.65 (1 H, d, J = 3.4 Hz, thiazole H-4), 7.19 (6 H,
m, ArH, thiazole H-5), 5.61 (1 H, br, NH), 5.15 (1 H, br t,
J 3.4, NCH), 4.39 (2 H, AB, J 12.0, CH2Ph), 3.88 (1 H, br,
OCHH), 3.75 (1 H, dd, 9.5, 4.6, OCHH), 1.38 (9 H, s, CMe3);
dC (75 MHz; CDCl3) 171.5 (C), 155.5 (C), 143.0 (CH), 138.0
(C), 128.9 (CH), 128.2 (CH), 128.0 (CH), 119.5 (CH), 80.6 (C),
73.7 (CH2), 72.2 (CH2), 53.2 (CH), 28.7 (Me); m/z (EI) 334
(M+, 4%), 278 (86), 230 (43), 157 (87), 139 (77), 108 (14), 91
(98), 85 (21); HPLC: hexane–2-propanol (90 : 10), tR = 3.8 and
8.7 (major) min.
=
=
5.5 Hz, CH), 5.33–5.07 (5 H, m, CH2Ph, CH2, NH), 4.54
(2 H, AB, J 12.2, CH2Ph), 4.41 (1 H, br, NCH), 3.56 (2 H, m,
NCHCH2); dC (75 MHz; CDCl3) 156.3 (C), 138.2 (C), 136.9
(C), 136.4 (CH), 128.94 (CH), 128.86 (CH), 128.5 (2 × CH),
128.2 (CH), 128.1 (CH), 116.5 (CH2), 73.7 (CH2), 72.3 (CH2),
67.2 (CH2), 53.5 (CH); m/z (CI) 312 (MH+, 23%), 268 (92), 204
(29), 181 (32), 91 (100).
(S)-(−)-1-Benzyloxy-N -benzyloxycarbonyl-2-pent-4-enyl-
amine 3c. Obtained as a colourless oil (70%, 91% ee); (Found:
MH+, 326.1758. C20H23NO3 + H requires 326.1756); [a]D
26
−10.8 (c 0.83, CHCl3); mmax (film)/cm−1 3416 (NH), 3329, 3068,
General procedure for the preparation of N-Boc-protected
aminoalcohols 4
=
3027, 2940, 2863, 1716 (C O), 1501, 1235, 1112, 1055, 912,
738, 697; dH (300 MHz; CDCl3) 7.32 (10 H, m, ArH), 5.76
The O-benzyl N-Boc-amine 3 (0.2 mmol) and 10% Pd/C (cat.)
were stirred vigorously in methanol (2 mL) under an atmosphere
of hydrogen until all starting material had been consumed (as
evidenced by TLC analysis). The solvent was removed in vacuo
and the residue purified by column chromatography on silica gel
eluting with dichloromethane–methanol.
=
=
(1 H, m, CH), 5.05 (5 H, m, CH2Ph, CH2, NH), 4.51
(2 H, AB, J = 12.0 Hz, CH2Ph), 3.89 (1 H, br, NCH), 3.50 (2 H,
=
m, NCHCH2), 2.37 (2 H, m, CH2CH ); dC (75 MHz; CDCl3)
156.3 (C), 138.4 (C), 137.0 (C), 134.7 (CH), 128.9 (CH), 128.8
(CH), 128.48 (CH), 128.46 (CH), 128.1 (CH), 128.0 (CH), 118.3
(CH2), 73.6 (CH2), 71.3 (CH2), 67.0 (CH2), 50.8 (CH), 36.8
(CH2); m/z (CI) 326 (MH+, 25%), 282 (100), 240 (25), 181 (39),
91 (75); HPLC: hexane–2-propanol (85 : 15), tR = 8.1 and 10.4
(major) min.
(R)-N-tert-Butoxycarbonyl-1-hydroxy-2-propylamine (N-Boc-
alaninol) 4a. Obtained by hydrogenolysis of 3a as a colourless
solid (0.0265 g, 70%, 96% ee), mp 49–50 ◦C (lit.,17 mp 52–53 C);
19
26
[a]D +8.6 (c 0.8, CHCl3) {lit.,17 [a]D +10.0 (c 1.0, MeOH)};
dH (300 MHz; MeOD) 4.65 (1 H, br s, NH), 3.76 (1 H, br, CH),
3.55 (1 H, AꢀAB, J = 10.8, 3.7 Hz, OCHH), 3.44 (1 H, AAꢀB, J
10.8, 4.6, OCHH), 2.68 (1 H, br s, OH), 1.44 (9 H, s, 3 × Me),
1.13 (3 H, d, J 6.8, Me).
(R)-1-Benzyloxy-N-tert-butoxycarbonyl-2-hexylamine
3d.
23
Obtained as a colourless oil (63%, 93% ee); [a]D +17.6 (c 0.9,
CHCl3); dH (300 MHz; CDCl3) 7.23 (5 H, m, ArH), 4.61 (1 H,
br s, NH), 4.43 (2 H, AB, J = 12.1 Hz, CH2Ph), 3.64 (1 H, br,
NCH), 3.39 (2 H, m, OCH2), 1.37 (9 H, s, 3 × Me), 1.22 (6 H,
m, 3 × CH2), 0.81 (3 H, t, J 6.7, Me); dC (75 MHz; CDCl3)
156.0 (C), 137.8 (C), 128.8 (CH), 128.0 (CH), 127.9 (CH), 79.4
(C), 73.4 (OCH2), 72.4 (OCH2), 50.8 (CH), 32.3 (CH2), 28.8
(Me), 28.6 (CH2), 23.0 (CH2), 14.4 (Me).
(S)-N -tert-Butoxycarbonyl-1-hydroxy-3-phenyl-2-propyl-
amine (N-Boc-phenylalaninol) 4b. Obtained by hydrogenolysis
of 3e as a colourless solid (0.0427 g, 83%, 88% ee), mp 89–91 ◦C
17
25
(S)-1-Benzyloxy-N-tert-butoxycarbonyl-3-phenyl-2-propyl-
(lit.,18 mp 91–92 ◦C); [a]D −32.4 (c 1.0, CHCl3) {lit.,18 [a]D
19
amine 3e. Obtained as a colourless oil (84%, 88% ee); [a]D
−25.0 (c 1.0, MeOH)}; dH (300 MHz; CDCl3) 7.26–7.13 (5 H,
m, ArH), 4.74 (1 H, d, J = 6.9 Hz, NH), 3.81 (1 H, br, CH),
3.60 (1 H, AꢀAB, J 10.1, 3.7, OCHH), 3.50 (1 H, AAꢀB, J 10.1,
5.3, OCHH), 2.78 (2 H, d, J 7.2, PhCH2), 2.23 (1 H, br s, OH),
1.34 (9 H, s, CMe3).
28
−22.0 (c 0.5, CHCl3) {lit.,33 [a]D −4.9 (c 0.45, CHCl3)}; mmax
(film)/cm−1 3375 (NH), 2929, 2852, 1685 (C O), 1527; dH
=
(300 MHz; CDCl3) 7.28 (10 H, m, ArH), 4.90 (1 H, br d, J =
8.3 Hz, NH), 4.50 (2 H, AB, J 12.0, OCH2Ph), 3.96 (1 H,
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 2 5 2 – 1 2 6 2
1 2 5 7

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(+)-N-Formyl-(R)-alaninyl-(S)-(4-bromo)phenylalaninol benzyl
850; dH (300 MHz; CDCl3) 8.05 (1 H, s, HCO), 7.37 (2 H, d, J =
8.3 Hz, ArH), 7.06 (1 H, d, J 7.9, NH), 6.98 (2 H, d, J 8.3,
ArH), 6.80 (1 H, d, J 7.2, NH), 4.78 (1 H, m, CH), 4.53 (1 H,
m, CH), 3.78 (1 H, d, J 14.0, CHHTMS), 3.76 (1 H, d, J 14.0,
CHHTMS), 3.10 (1 H, dd, J 6.6, 14.0, CHHAr), 2.94 (1 H, dd,
J 6.6, 14.0, CHHAr), 1.24 (3 H, d, J 6.9, CHMe), 0.00 (9 H, s,
3 × Me); dC (75 MHz; CDCl3) 172.2 (C), 171.7 (C), 161.4 (C),
134.9 (C), 131.6 (CH), 130.9 (CH), 121.1 (C), 59.2 (CH2), 53.2
(CH), 47.6 (CH), 37.4 (CH2), 18.6 (Me), 0.0 (TMS); m/z (ES)
431/429 (MH+, 36%), 416 (13), 415 (60), 413 (72), 395 (25), 316
(40), 198 (4), 170 (5), 91 (7), 73 (100), 72 (38), 45 (23), 44 (73).
ether 5
N-Formyl-(R)-alanine24 (0.20 g, 1.86 mmol) and (S)-1-benzyloxy-
3-(4-bromophenyl)-2-propylamine (0.60 g, 1.86 mmol) [ob-
tained from the Zn–acetic acid cleavage of (2S,1ꢀS)-1-benzyloxy-
3-(4-bromophenyl)-N-(1-phenylbutoxy)-2-propylamine 2i] were
dissolved in THF (10 mL) and stirred at 0 ◦C together with
HOBT (N-hydroxybenzotriazole; 0.25 g, 1.86 mmol) and DCC
(0.38 g, 1.86 mmol). The mixture was then allowed to warm
to room temperature and was stirred for 20 h. The product
was subjected to an acid–base extraction, dried, evaporated
and recrystallized from acetone and hexane to give the ti-
tle compound as a colourless solid (0.35 g, 45%); mp 150–
151 ◦C; (Found: MH+, 419.0967. C20H2379BrN2O3 + H requires
Preparation of ring-closing metathesis precursors
N-Allylation of Cbz-amines 3b and 3c. Sodium hydride
(0.42 mmol) was suspended in dry DMF (1 mL) and cooled
to 0 ◦C under nitrogen. A solution of the Cbz-amine 3b/3c
(0.21 mmol) in dry DMF (1 mL) was added and the reaction
mixture was allowed to warm to room temperature. After 30 min,
the reaction mixture was re-cooled to 0 ◦C. Allyl bromide
(0.04 mL, 0.42 mmol) was added and the reaction mixture
was allowed to warm to room temperature. After TLC analysis
showed that all starting material had been consumed, aqueous
saturated ammonium chloride solution (0.5 mL) was added
and the mixture was extracted with diethyl ether (3×), dried
(Na2SO4), filtered and evaporated under reduced pressure.
419.0970); [a]D + 7.8 (c 0.65, MeOH); mmax (KBr)/cm−1 3279,
21
1694, 1564, 1528, 1451, 1385, 1215, 1125; dH (300 MHz; CDCl3)
8.10 (1 H, s, HCO), 7.37 − 7.24 (5 H, m, ArH), 7.30 (2 H, d, J
8.3, ArH), 7.02 (2 H, d, J 8.3, ArH), 6.32 (1 H, m, NH), 6.25
(1 H, m, NH), 4.46 (2 H, m, CH2Ph), 4.46 (1 H, m, CHMe),
4.24 (1 H, m, CHCH2Ar), 3.40 (2 H, d, J 3.6, CH2OCH2Ph),
2.85 (1 H, dd, J 7.0, 13.0, CHHAr), 2.80 (1 H, dd, J 7.0, 13.0,
CHHAr), 1.26 (3 H, d, J 7.0, Me); dC (75 MHz; CDCl3) 171.1
(C), 160.5 (C), 137.6 (C), 136.7 (C), 131.4 (CH), 131.0 (CH),
128.5 (CH), 127.9 (CH), 127.9 (CH), 120.4 (C), 73.3 (CH2), 69.6
(CH2), 50.2 (CH), 47.5 (CH), 36.9 (CH2), 18.8 (Me); m/z (ES),
421/419 (MH+, 14%), 337 (10), 325 (4), 271 (6), 259 (11), 221
(9), 130 (28), 100 (39), 98 (100), 84 (98), 68 (58), 66 (39), 52 (15),
35 (83).
(S)-(+)-N-Allyl-1-benzyloxy-N-benzyloxycarbonyl-2-but-3-
enylamine 8. Obtained from the N-allylation of Cbz-amine 3b
(0.52 mmol) and purification by column chromatography on
silica gel eluting with diethyl ether–light petroleum (5 : 9) as a
colourless oil (93%); (Found: MH+, 352.1908. C22H25NO3 + H
(+)-N-Formyl-(R)-alaninyl-(S)-(4-bromo)phenylalaninol 6
requires 352.1912); [a]D +8.9 (c 1.23, CHCl3); mmax (film)/cm−1
22
(+)-N-Formyl-(R)-alaninyl-(S)-4-bromphenylalaninol benzyl
ether 5 (12.5 mg, 0.03 mmol) in dry dichloromethane (3 mL) was
treated with a solution of boron trichloride in dichloromethane
(1 M; 0.6 mL, 0.6 mmol) at 0 ◦C. The mixture was then
allowed to warm to room temperature and stirred for 2 h.
The reaction was cautiously quenched with water (2 mL) and
the product extracted with ethyl acetate (3 × 10 mL), dried
(MgSO4) and purified by trituration with ether to give the title
compound as a colourless solid (9.5 mg, 97%); (Found: MH+,
329.0501. C13H1779BrN2O3 + H requires 329.5000); mp 210–
=
3083, 3063, 3032, 2976, 2935, 2858, 1696 (C O), 1496, 1455,
1409, 1352, 1322, 1245, 1204, 1107, 1030, 989, 917, 769, 737,
692; dH (400 MHz; C6D6, 80 ◦C) 7.31 (2 H, t, J 6.3, ArH), 7.19
=
(8 H, m, ArH), 5.93 (2 H, m, 2 × CH), 5.21 (2 H, s, CH2Ph),
=
5.20–4.99 (4 H, m, 2 × CH2), 4.83 (1 H, br q, J 6.0, NCH),
4.39 (2 H, AB, J 12.1, CH2Ph), 4.01 (1 H, dd, J 16.0, 5.3,
NCHH), 3.90 (1 H, dd, J 16.0, 5.8, NCHH), 3.75 (1 H, t, J 9.6,
OCHH), 3.61 (1 H, dd, J 9.8, 5.8, OCHH); dC (100 MHz; C6D6,
80 ◦C) 155.8 (C), 138.7 (C), 137.4 (C), 135.9 (CH), 135.1 (CH),
128.2 (CH), 127.9 (CH), 127.7 (CH), 127.6 (CH), 127.5 (CH),
127.4 (CH), 116.7 (CH2), 115.5 (CH2), 72.9 (CH2), 70.8 (CH2),
66.9 (CH2), 59.1 (CH), 48.1 (CH2); m/z (ES) 720 (2 M + NH4,
62%), 647 (12), 369 (M + NH4, 95), 352 (MH+, 100).
211 ◦C; [a]D + 3.0 (c 0.5, MeOH); mmax (KBr)/cm−1 3412, 1632,
24
1398, 1112, 618; dH (300 MHz; CD3OD) 8.08 (1 H, s, CHO),
7.41 (2 H, d, J 8.2, ArH), 7.09 (2 H, d, J 8.2, ArH), 4.37 (1 H,
q, 6.8, CHMe), 4.07 (1 H, m, HCCH2Ar), 3.67 (1 H, dd, J 4.1,
11.4, CHHOH), 3.65 (1 H, dd, J 4.1, 11.4, CHHOH), 2.85 (1 H,
dd, J 7.5, 13.9, CHHAr), 2.77 (1 H, dd, J 7.5, 13.9, CHHAr),
1.20 (3 H, d, J 7.1, Me); 2 × NH and OH not observed; dC
(75 MHz; CD3OD) 174.7 (C), 163.8 (C), 139.7 (C), 133.6 (CH),
132.9 (CH), 121.6 (C), 64.9 (CH2), 54.5 (CH), 49.9 (CH), 37.9
(CH2), 19.2 (Me); m/z (CI), 329/327 (MH+, 7%), 313 (18), 311
(34), 299 (78), 297 (100), 295 (28), 260 (33), 258 (41), 219 (40),
197 (27), 168 (43), 139 (17), 116 (26), 115 (8).
(S)-(+)-N-Allyl-1-benzyloxy-N-benzyloxycarbonyl-2-pent-4-
enylamine 9. Obtained from the N-allylation of Cbz-amine 3c
(0.28 mmol) and purification by column chromatography on
silica gel eluting with ether-light petroleum (1:2) as a colourless
oil (93%); (Found: MH+, 366.2061. C23H27NO3 + H requires
366.2069); [a]D + 8.2 (c 0.97, CHCl3); mmax (film)/cm−1 3068,
23
=
3032, 2976, 2935, 2858, 1696 (C O), 1455, 1404, 1358, 1245;
dH (300 MHz; CDCl3) two rotamers 7.32 (10 H, m, ArH), 5.77
=
=
(2 H, m, 2 × CH), 5.21–4.96 (6 H, m, 2 × CH2, CH2Ph),
(+)-N-Formyl-(R)-alaninyl-(S)-4-bromphenylalanine
4.42 (2 H, m, CH2), 4.22 (1 H, m, NCH), 3.89 (2 H, m, CH2),
=
trimethylsilylmethyl ester 7
3.55 (2 H, m, CH2), 2.35 (2 H, m, CH2CH ); dC (75 MHz;
CDCl3) two rotamers 156.8 (C), 156.7 (C), 138.6 (C), 138.5
(C), 137.3 (C), 137.2 (C), 136.1 (CH), 135.8 (CH), 135.3 (CH),
135.1 (CH), 128.8–128.0 (several overlapping CH), 117.8 (CH2),
117.7 (CH2), 116.6 (CH2), 116.3 (CH2), 73.3 (CH2), 71.4 (CH2),
71.1 (CH2), 67.5 (CH2), 67.3 (CH2), 56.7 (CH), 56.6 (CH), 48.1
(CH2), 47.8 (CH2), 35.1 (CH2), 34.5 (CH2); m/z (CI) 366 (MH+,
35%), 322 (78), 280 (30), 258 (43), 200 (25), 181 (20), 168 (18),
119 (14), 91 (100).
To a solution of (+)-N-formyl-(R)-alanine-(S)-4-bromphenyl-
alaninol 6 (100 mg, 0.3 mmol) in anhydrous DMF (10 mL),
pyridinium dichromate (323 mg, 1.5 mmol) was added and
stirred at room temperature for 5 h. The mixture was diluted
with water (10 mL), the aqueous layer acidified with citric acid
and the product extracted with ethyl acetate, dried (MgSO4)
and concentrated. The residue was dissolved in anhydrous
DMF and treated with excess TMS diazomethane and stirred
overnight. The product was concentrated and purified by flash
chromatography to give the title compound as a colourless oil
(62 mg, 50%); (Found: MH+, 429.0843. C17H2579BrN2O4Si + H
General procedure for the N-alkylation of primary amines
Zinc dust (18.88 mmol) was added to a solution of the
hydroxylamine 2 (0.47 mmol) in acetic acid-water (8 mL, 1:1).
The mixture was placed in a sonic bath at 40 ◦C until all the
24
requires 429.0845); [a]D +13.9 (c 1.15, MeOH); mmax (film)/cm−1
3405, 3298, 3052, 2955, 1731, 1654, 1521, 1383, 1250, 1203, 1009,
1 2 5 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 2 5 2 – 1 2 6 2

View Article Online
starting material was consumed (TLC; typically 1.5–4 h). The
zinc was filtered and rigorously washed with water and ether.
The filtrate was extracted with ether (5x), the aqueous layer was
basified to pH 12 with aqueous sodium hydroxide solution (4 M)
and a little saturated ammonium chloride solution was added
to disperse the emulsion. The solution was further extracted
with dichloromethane (3x). The dichloromethane organic layers
were combined and evaporated. The crude amine (0.47 mmol)
was dissolved in acetonitrile (5 mL) and potassium carbonate
(0.50 mmol) and 4-bromobut-1-ene (0.80 mmol) were added
to the mixture. The reaction mixture was heated under reflux
for 24 h. The mixture was cooled to room temperature and
the solvent removed under reduced pressure. Water (5 mL)
and ether (5 mL) were added to the mixture and the layers
separated. The aqueous layer was further extracted with ether
(3 × 5 mL). The organic extracts were combined, dried
(Na2SO4), and evaporated. The residue was purified by column
chromatography on silica gel to give the bis-alkene.
(S)-(+)-1-Benzyloxy-N-benzyloxycarbonyl-N-but-3-enyl-2-
but-3-enylamine 12. Obtained from the Cbz-protection of
amine (S)-10 (0.16 mmol) and purification by column chromato-
graphy on silica gel eluting with ether-light petroleum (1:2) as
a yellow oil (80%); (Found: MH+, 366.2068. C23H27NO3 + H
requires 366.2069); [a]D + 8.9 (c 1.02, CHCl3); mmax (film)/cm−1
25
=
3063, 3027, 2976, 2935, 2858, 1696 (C O), 1634, 1501, 1455,
1409, 1286, 1255, 1102, 989, 912, 738, 687; dH (400 MHz; C6D6,
◦
=
80 C) 7.36 − 7.11 (10 H, m, ArH), 5.96 (1 H, m, CH), 5.78
=
(1 H, m, CH), 5.21 (2 H, s, CH2Ph), 5.19 − 4.98 (4 H, m,
=
2 × CH2), 4.71 (1 H, q, J 6.0, NCH), 4.39 (2 H, AB, J 12.1,
CH2Ph), 3.75 (1 H, t, J 8.1, OCHH), 3.61 (1 H, dd, J 9.8, 5.7,
OCHH), 3.40 (2 H, m, NCH2), 2.45 (2 H, m, NCH2CH2); dC
(100 MHz; C6D6, 80 ◦C) 155.8 (C), 138.6 (C), 137.5 (C), 135.7
(CH), 135.3 (CH), 128.3 − 127.4 (6 × CH), 116.6 (CH2), 115.8
(CH2), 73.0 (CH2), 70.9 (CH2), 66.8 (CH2), 59.6 (CH), 46.0
(CH2), 34.1 (CH2); m/z (ES) 748 (2 M + NH4, 30%), 383 (M +
NH4, 66), 366 (MH+, 100).
(S)-(+)-1-Benzyloxy-N-but-3-enyl-2-but-3-enylamine (S)-10.
Obtained from N–O bond cleavage and subsequent N-alkylation
of hydroxylamine (S,S)-2b (0.47 mmol) and purification by col-
umn chromatography on silica gel eluting with light petroleum-
ether (1:4) as a colourless oil (45%); (Found: MH+, 232.1706.
(S)-(+)-1-Benzyloxy-N-benzyloxycarbonyl-N-but-3-enyl-2-
pent-4-enylamine 13. Obtained from the Cbz-protection of
amine 11 (0.22 mmol) and purification by column chromato-
graphy on silica gel eluting with ether-light petroleum (1:4) as
a yellow oil (81%); (Found: MH+, 380.2236. C24H29NO3 + H
requires 380.2226); [a]D +5.9 (c 1.02, CHCl3); mmax (film)/cm−1
25
22
C15H21NO + H requires 232.1701); [a]D + 20.5 (c 0.88, CHCl3);
mmax (film)/cm−1 3329 (NH), 3073, 3027, 2976, 2909, 2853, 1639,
1450, 1352, 1091, 994, 907, 738, 697; dH (300 MHz; CDCl3) 7.31
3068, 3032, 2971, 2935, 2858, 1696 (C O), 1450, 1419, 1286,
=
1219, 1107, 994, 912, 738; dH (400 MHz; C6D6, 80 ◦C) 7.26
=
=
(5 H, m, ArH), 5.86 − 5.57 (2 H, m, 2 × CH), 5.29–4.94 (4 H,
(10 H, m, ArH), 5.76 (2 H, m, 2 × CH), 5.17 (2 H, s, CH2Ph),
=
=
m, 2 × CH2), 4.52 (2 H, s, CH2Ph), 3.51 − 3.29 (3 H, m, OCH2,
5.07 (2 H, d, J = 17.2 Hz, 2 × CHH), 5.01 (2 H, d, J 10.2, 2 ×
=
NCH), 2.72 (1 H, dt, J 11.3, 7.2, NCHH), 2.54 (1 H, dt, J 11.3,
7.0, NCHH), 2.26 (2 H, m, CH2CH ), 1.86 (1 H, br s, NH);
dC (75 MHz; CDCl3) 138.6 (C), 138.3 (CH), 136.9 (CH), 128.8
(CH), 128.09 (CH), 128.07 (CH), 118.0 (CH2), 116.7 (CH2), 73.8
(CH2), 73.6 (CH2), 61.9 (CH), 46.8 (CH2), 34.8 (CH2); m/z (CI)
232 (MH+, 41%), 164 (49), 152 (100), 149 (42).
CHH), 4.37 (2 H, AB, J 12.0, CH2Ph), 4.16 (1 H, m, NCH),
3.65 (1 H, br, OCHH), 3.49 (1 H, br, OCHH), 3.37 (2 H, t, J
=
=
7.6, NCH2), 2.41 (4 H, m, 2 × CH2CH ); dC (100 MHz; C6D6,
80 ◦C) 155.8 (C), 138.7 (C), 137.6 (C), 135.9 (CH), 135.3 (CH),
128.22 (CH), 128.20 (CH), 127.9 (CH), 127.7 (CH), 127.5 (CH),
127.4 (CH), 116.6 (CH2), 115.7 (CH2), 73.0 (CH2), 71.3 (CH2),
66.7 (CH2), 57.8 (CH), 46.0 (CH2), 34.6 (CH2), 34.1 (CH2); m/z
(CI) 380 (MH+, 19%), 336 (35), 294 (35), 272 (31), 258 (21), 214
(17), 202 (15), 181 (34), 91 (100).
(R)-(−)-1-Benzyloxy-N-but-3-enyl-2-but-3-enylamine (R)-10.
Obtained from N–O bond cleavage and subsequent N-alkylation
of hydroxylamine (R,R)-2b (4.62 mmol) and purification by col-
umn chromatography on silica gel eluting with light petroleum-
(2R,2ꢀS)-(−)-1-Benzyloxy-N-(but-3-enyl)-N-(2-tert-butyloxy-
carbonylamino-3-methylpentanoyl)-2-but-3-enylamine 14. (S)-
N-Boc-isoleucine (109 mg, 0.47 mmol), 1-hydroxybenzotriazole
(64 mg, 0.47 mmol) and (R)-(−)-1-benzyloxy-N-but-3-enyl-
2-but-3-enylamine (R)-10 (100 mg, 0.43 mmol) were added
successively to dichloromethane (8 mL) at 0 ◦C. The reaction
mixture was allowed to warm to room temperature for 15 min
25
ether (1:3) as a colourless oil (50%); [a]D − 21.1 (c 0.95, CHCl3);
Spectroscopic properties identical to the (S)-enantiomer (S)-10.
(S)-(+)-1-Benzyloxy-N-but-3-enyl-2-pent-4-enylamine 11.
Obtained from N–O bond cleavage and subsequent N-alkylation
of hydroxylamine 2e (0.47 mmol) and purification by column
chromatography on silica gel eluting with light petroleum-ether
(1:2) as a colourless oil (47%); (Found: M+, 245.1770. C16H23NO
◦
and then re-cooled to 0 C. N,Nꢀ-Dicyclohexylcarbodiimide
(97 mg, 0.47 mmol) was added at this temperature and the
solution was allowed to warm to room temperature and stirred
overnight. The solution was filtered and evaporated. The crude
product was directly purified by column chromatography on
silica gel eluting with diethyl ether–light petroleum (1 : 3)
to give the title compound (86 mg, 45%) as a colourless oil;
(Found: MH+, 445.3076. C26H40N2O4 + H requires 445.3066);
22
requires 245.1780); [a]D + 3.2 (c 1.24, CHCl3); mmax (film)/cm−1
3329 (NH), 3073, 3027, 2914, 2848, 1634, 1475, 1358, 1204, 1096,
994, 907, 738, 702; dH (300 MHz; CDCl3) 7.32 (5 H, m, ArH),
=
=
5.78 (2 H, m, 2 × CH), 5.07 (4 H, m, 2 × CH2), 4.52 (2 H, s,
CH2Ph), 3.43 (2 H, m, OCH2), 2.82 (1 H, m, NCH), 2.69 (2 H, m,
=
NCH2), 2.23 (4 H, m, 2 × CH2CH ), NH signal not observed;
dC (75 MHz; CDCl3) 138.8 (C), 136.8 (CH), 135.7 (CH), 128.8
(CH), 128.04 (CH), 127.99 (CH), 117.7 (CH2), 116.8 (CH2),
73.6 (CH2), 72.7 (CH2), 57.3 (CH), 46.8 (CH2), 36.6 (CH2), 34.9
(CH2); m/z (EI) 245 (M+, 4%), 219 (5), 204 (79), 124 (100),
98 (5), 91 (44), 82 (12), 65 (13), 55 (26).
23
[a]D −20.0 (c 0.60, CHCl3); mmax (film)/cm−1 3426, 3310 (NH),
=
=
3079, 2968, 2933, 2876, 1712 (C O), 1636 (C O), 1497, 1456,
1420, 1366, 1248, 1172, 1114, 1017, 919, 735; dH (400 MHz;
d6-DMSO, 120 ◦C) 7.31 (5 H, m, ArH), 6.11–5.72 (3 H, m, 2 ×
=
=
=
CH, NH), 5.20 (2 H, m, CH2), 5.03 (2 H, m, CH2), 4.75
(1 H, br m, NCH), 4.53 (2 H, AB, J = 12.0 Hz, CH2Ph),
4.29 (1 H, t, J 8.0, NCHCH), 3.73 (2 H, m, OCH2), 3.37
(2 H, m, NCH2), 2.43–2.19 (2 H, br m, CH2), 1.81 (1 H, br,
NCHCH), 1.50 (1 H, br m, CHH), 1.40 (9 H, s, CMe3), 1.11
(1 H, m, CHH), 0.82 (6 H, m, 2 × Me); dC (75 MHz; CDCl3)
two rotamers 173.0 (C), 172.7 (C), 155.6 (C), 138.0 (C), 137.5
(C), 135.7 (CH), 134.5 (CH), 134.3 (CH), 133.7 (CH), 128.42
(CH), 128.35 (CH), 127.84 (CH), 127.79 (CH), 127.6 (CH),
118.2 (CH2), 117.5 (CH2), 116.1 (CH2), 79.29 (C), 79.25 (C),
73.3 (CH2), 73.1 (CH2), 70.3 (CH2), 69.6 (CH2), 59.3 (CH), 58.5
(CH), 55.1 (CH), 54.6 (CH), 47.0 (CH2), 42.6 (CH2), 38.9 (CH),
37.8 (CH), 34.5 (CH2), 32.9 (CH2), 28.3 (Me), 24.1 (CH2),
General procedure for the preparation of Cbz-protected
secondary amines 12/13
The pure secondary amine 10/11 was dissolved in THF-water
(20 mL, 1:1) and sodium carbonate (1.52 mmol) was added.
The solution was cooled to 0 ◦C and benzyl chloroformate
(0.50 mmol) added dropwise. The mixture was allowed to warm
to room temperature and stirred overnight. The THF was
evaporated under reduce pressure. Ether (10 mL) was added, the
layers were separated, and the aqueous layer was extracted with
further portions of ether (3x). The organic layers were combined,
dried (MgSO4), filtered and evaporated.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 2 5 2 – 1 2 6 2
1 2 5 9

View Article Online
23.8 (CH2), 15.9 (Me), 15.7 (Me), 11.34 (Me), 11.25 (Me), the
spectrum shows two signals for every C, with the exception of
73.1 (CH2), 71.6 (CH2), 66.9 (CH2), 52.2 (CH), 38.2 (CH2), 24.8
(CH2); m/z (CI) 355 (M + NH4, 3%), 338 (MH+, 85), 294 (6),
246 (5), 216 (15), 204 (100), 172 (20), 157 (13), 140 (12), 108
(38), 91 (69), 82 (79).
=
=
one C O, ArCH, CH2 and Me for which only one peak is
observed; m/z (CI) 445 (MH+, 27%), 389 (89), 371 (24), 345
(100), 303 (17), 259 (13), 232 (42), 190 (13), 130 (12).
(S)-(−)-N-Benzyloxycarbonyl-2-benzyloxymethyl-2,3,6,7-tetra-
hydro-1H-azepine 18. Obtained from the ring-closing
metathesis of bis-alkene 13 (0.17 mmol) after purification by
column chromatography on silica gel eluting diethyl ether–light
petroleum (1 : 1) as a colourless oil (85%); (Found: MH+,
General procedure for ring-closing metathesis
The diene (0.470 mmol) was dissolved in dry dichloromethane
(4 mL) under nitrogen. To the solution was added benzylidene-
bis-(tricyclohexylphosphine)dichlororuthenium (38.7 mg,
0.047 mmol, 10 mol%) (Grubbs’ catalyst) and the mixture
stirred until complete consumption of starting material was
observed by TLC. The solvent was removed under reduced
pressure and the residue purified by column chromatography
on silica gel eluting with diethyl ether–light petroleum to give
the corresponding heterocycle.
25
352.1910. C22H25NO3 + H requires 352.1912); [a]D −93.1 (c
1.02, CHCl3); mmax (film)/cm−1 3083, 3058, 3022, 2935, 2889,
=
2853, 1696 (C O), 1450, 1419, 1363, 1327, 1260, 1199, 1020,
733, 692; dH (400 MHz; C6D6, 80 ◦C) 7.37–7.12 (10 H, m, ArH),
=
=
5.55 (1 H, m, CH), 5.46 (1 H, m, CH), 5.21 (2 H, AB, J =
12.5 Hz, CH2Ph), 4.58 (1 H, br, NCH), 4.40 (2 H, s, CH2Ph),
3.85 (1 H, br, CHH), 3.53 (2 H, br, CH2), 3.42 (1 H, m, CHH),
2.67–2.43 (2 H, br, CHH, CHH), 2.16 (1 H, m, CHH), 2.01
(S)-(−)-N-Benzyloxycarbonyl-2-benzyloxymethyl-2,5-dihydro-
pyrrole 15. Obtained from the ring-closing metathesis
of bis-alkene 8 (0.38 mmol) after purification by column
chromatography on silica gel eluting diethyl ether–light
petroleum (1 : 2) as a colourless oil (96%); (Found: MH+,
◦
(1 H, m, CHH); dC (100 MHz; C6D6, 80 C) 155.9 (C), 138.9
(C), 137.7 (C), 129.6 (CH), 128.3–127.1 (6 × CH), 124.9 (CH),
73.1 (CH2), 72.0 (CH2), 66.8 (CH2), 55.5 (CH), 40.7 (CH2),
31.0 (CH2), 28.1 (CH2); m/z (CI) 352 (MH+, 45%), 330 (8), 218
(100), 186 (13), 171 (20), 154 (19), 106 (60), 96 (83), 91 (66), 52
(19).
25
324.1598. C20H21NO3 + H requires 324.1599); [a]D −158.3 (c
0.84, CHCl3); mmax (film)/cm−1 3088, 3058, 3027, 2945, 2899,
=
2858, 1706 (C O), 1624, 1496, 1455, 1414, 1358, 1317, 1199,
1102, 1004, 733, 697; dH (400 MHz; C6D6, 80 ◦C) 7.42–7.13
(2R,2ꢀS)-(+)-2-Benzyloxymethyl-1-(2-tert-butyloxycarbonyl-
amino-3-methylpentanoyl)-1,2,5,6-tetrahydropyridine 19. Ob-
tained from the ring-closing metathesis of bis-alkene 14
(0.59 mmol) after purification by column chromatography on
silica gel eluting diethyl ether–light petroleum (1 : 2 to 1 : 1)
as a yellow oil (97%); (Found: MH+, 416.2680. C24H35N2O4 +
=
=
(10 H, m, ArH), 5.72 (1 H, m, CH), 5.45 (1 H, m, CH), 5.21
(2 H, AB, J = 12.5 Hz, CH2Ph), 4.77 (1 H, br, NCH), 4.41
(2 H, s, CH2Ph), 4.17 (1 H, br, CHH), 4.06 (1 H, br, CHH),
3.84 (1 H, br, CHH), 3.67 (1 H, br, CHH); dC (100 MHz; C6D6,
80 ◦C) 154.2 (C), 139.0 (C), 137.5 (C), 128.8 (CH), 128.4 (CH),
128.3 (CH), 128.1 (CH), 127.9 (CH), 127.4 (CH), 127.3 (CH),
125.6 (CH), 73.3 (CH2), 71.4 (CH2), 66.6 (CH2), 64.5 (CH), 53.9
(CH2); m/z (CI) 324 (MH+, 100%), 202 (10), 190 (85), 158 (16),
143 (10), 126 (10), 108 (48), 91 (72), 82 (52), 68 (44).
23
H requires 416.2675); [a]D +160.0 (c 0.70, CHCl3); mmax
(film)/cm−1 3416, 3291 (NH), 3032, 2967, 2931, 2863, 1701
=
=
(C O), 1635 (C O), 1497, 1455, 1391, 1365, 1304, 1244, 1171,
1116, 1043, 737, 699; dH (400 MHz; DMSO, 120 ◦C) 7.31
(5 H, m, ArH), 6.08 (1 H, br d, J = 7.3 Hz, NH), 5.91 (1 H,
(S)-(+)-N-Benzyloxycarbonyl-2-benzyloxymethyl-1,2,3,6-tetra-
hydropyridine 16. Obtained from the ring-closing metathesis
of bis-alkene 9 (0.21 mmol) after purification by column
chromatography on silica gel eluting diethyl ether–light
petroleum (1 : 2) as a colourless oil (84%); (Found: MH+,
=
=
=
m, CH), 5.75 (1 H, m, CH), 4.85 (1 H, br, NCHCH ),
4.53 (2 H, AB, J 12.4, CH2Ph), 4.31 (1 H, t, J 8.6, NCH), 4.19
(1 H, br, NCHH), 3.60 (2 H, m, OCH2), 2.87 (1 H, br, NCHH),
=
2.22–2.00 (1 H, m, NCH2CH ), 1.82 (1 H, br, CHMe), 1.52
(1 H, m, CHH), 1.40 (9 H, s, CMe3), 1.12 (1 H, m, CHH), 0.84
(6 H, m, 2 × Me); dC (75 MHz; CDCl3) two rotamers 172.1 (C),
170.8 (C), 155.9 (C), 155.5 (C), 138.2 (C), 137.8 (C), 128.39
(CH), 128.35 (CH), 127.8 (CH), 127.7 (CH), 127.52 (CH),
127.49 (CH), 126.4 (CH), 125.7 (CH), 124.9 (CH), 79.4 (C),
79.3 (C), 73.2 (CH2), 73.1 (CH2), 70.8 (CH2), 70.4 (CH2), 54.8
(CH), 58.7 (CH), 53.7 (CH), 50.7 (CH), 40.8 (CH2), 38.1 (CH),
37.3 (CH), 35.5 (CH2), 28.34 (Me), 28.27 (Me), 25.7 (CH2), 24.7
(CH2), 24.1 (CH2), 23.6 (CH2), 16.1 (Me), 15.7 (Me), 11.6 (Me),
23
338.1756. C21H23NO3 + H requires 338.1756); [a]D +7.5 (c 0.53,
CHCl3); mmax (film)/cm−1 3068, 3037, 2899, 2853, 1696 (C O),
=
1450, 1414, 1347, 1219, 1102, 1015, 743; dH (400 MHz; C6D6,
80 ◦C) 7.25 (10 H, m, ArH), 5.50 (1 H, m, CH), 5.38
=
=
(1 H, m, CH), 5.25 (2 H, s, CH2Ph), 4.86 (1 H, br, NCH), 4.39
(3 H, m, CH2Ph, OCHH), 3.53 (2 H, m, OCHH, NCHH), 3.33
(1 H, dd, J = 7.3 Hz, NCHH), 2.23 (1 H, m, NCHCHH), 1.92
(1 H, m, NCHCHH); dC (100 MHz; C6D6, 80 ◦C) 155.6 (C),
138.9 (C), 137.6 (C), 128.25 (CH), 128.17 (CH), 127.9 (CH),
127.7 (CH), 127.4 (CH), 127.3 (CH), 123.4 (CH), 122.6 (CH),
72.8 (CH2), 69.2 (CH2), 66.9 (CH2), 48.0 (CH), 40.7 (CH2), 25.4
(CH2); m/z (CI) 355 (M + NH4, 3%), 338 (MH+, 50), 294 (5),
216 (10), 204 (100), 157 (15), 140 (12), 108 (40), 91 (56), 82 (57).
=
11.0 (Me); only three peaks for the two CH of both rotamers;
m/z (EI) 416 (M+, 3%), 360 (4), 343 (7), 295 (8), 221 (84), 195
(15), 130 (26), 91 (90), 82 (100).
Reduction and deprotection of tetrahydropyridines
(S)-(−)-N-Benzyloxycarbonyl-2-benzyloxymethyl-1,2,5,6-tetra-
hydropyridine 17. Obtained from the ring-closing metathesis
of bis-alkene 12 (0.12 mmol) after purification by column
chromatography on silica gel eluting diethyl ether–light
petroleum (1 : 2) as a colourless oil (93%); (Found: MH+,
(S)-(+)-Piperidine-2-methanol hydrochloride 20. Tetrahy-
dropyridine 17 (32 mg, 0.095 mmol) was dissolved in methanol
(1 mL) and hydrochloric acid (1 M; 1 mL) and hydrogenated
over palladium on charcoal (10% w/w; 20 mg) overnight. The
catalyst was filtered through Celite and the solvent was removed
in vacuo to give the piperidine ◦20 as a yellow solid (15 mg,
quantitat◦ive yield); mp 126–128 C (lit.,34 for the racemate, mp
130–132 C); (Found: MH+, 116.1069. C6H13NO + H requires
23
338.1755. C21H23NO3 + H requires 338.1756); [a]D −173.2
(c 0.71, CHCl3); mmax (film)/cm−1 3088, 3058, 3027, 2925,
=
2894, 2848, 1701 (C O), 1496, 1450, 1424, 1363, 1327, 1276,
1250, 1194, 1107, 1025, 738, 697; dH (400 MHz; C6D6, 80 C)
◦
24
=
7.36–7.10 (10 H, m, ArH), 5.69 (2 H, m, HC CH), 5.23 (2 H,
116.1075); [a]D +5.8 (c 1.2, MeOH); mmax (KBr)/cm−1 3380,
AB, J = 12.4 Hz, CH2Ph), 4.83 (1 H, br, NCH), 4.41 (2 H, AB,
J 12.1, CH2Ph), 4.29 (1 H, br, NCHH), 3.54 (2 H, d, J 5.3,
OCH2), 2.99 (1 H, m, NCHH), 2.07 (1 H, m, NCH2CHH),
3191, 2997, 2948, 2879, 2781, 2752, 2558, 2530, 2448, 2413,
1598, 1452, 1428, 1401, 1324, 1051, 1023, 912; dH (300 MHz;
MeOD) 3.78 (1 H, dd, J = 11.8, 3.8 Hz, OCHH), 3.59 (1 H, dd,
J 11.8, 7.0, OCHH), 3.37 (1 H, br m, NCHH), 3.20 (1 H, br,
NCH), 3.02 (1 H, br m, NCHH), 2.00–1.48 (6 H, m, 3 × CH2);
OH and NH not observed; dC (75 MHz; MeOD) 64.0 (CH2),
◦
1.63 (1 H, m, NCH2CHH); dC (100 MHz; C6D6, 80 C) 155.0
(C), 138.8 (C), 137.6 (C), 128.2 (CH), 127.9 (CH), 127.7 (CH),
127.42 (CH), 127.37 (CH), 127.3 (CH), 126.3 (CH), 126.2 (CH),
1 2 6 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 2 5 2 – 1 2 6 2

View Article Online
25
60.5 (CH), 46.5 (CH2), 27.0 (CH2), 24.3 (CH2), 23.7 (CH2); m/z
C24H27NO7 + H requires 442.1866); [a]D −24.1 (c 0.83,
(CI) 116 (MH+, 100%), 114 (17), 98 (28), 84 (11).
CHCl3); mmax (film)/cm−1 3063, 3032, 2950, 2894, 2858, 1750
=
=
(C O), 1707 (C O), 1455, 1418, 1356, 1244, 1093, 1027, 740,
699; dH (400 MHz; DMSO, 120 ◦C) 7.32 (10 H, m, ArH), 5.42
(2 H, m, 2 × OCH), 5.12 (2 H, AB, J = 13.2 Hz, CH2Ph),
4.50 (2 H, AB, J 12.3, CH2Ph), 3.96 (1 H, m, NCH), 3.75
(2 H, m, OCHH, NCHH), 3.66 (1 H, dd, J 10.0, 2.3, OCHH),
3.50 (1 H, m, NCHH), 2.03 (3 H, s, Me), 2.01 (3 H, s, Me); dC
(100 MHz; DMSO, 120 ◦C) 169.8 (C), 169.7 (C), 154.4 (C),
138.6 (C), 137.2 (C), 128.8 (CH), 128.6 (CH), 128.2 (CH),
127.9 (CH), 127.8 (CH), 127.7 (CH), 73.8 (CH), 73.2 (CH2),
70.2 (CH), 68.7 (CH2), 66.9 (CH2), 61.8 (CH), 49.2 (CH2), 20.7
(Me), 20.6 (Me); m/z (CI) 442 (MH+, 100%), 398 (69), 244 (21),
181 (38), 91 (62).
(2R,2ꢀS)-(+)-1-(2-tert-Butyloxycarbonylamino-3-methylpenta-
noyl)piperidine-2-methanol 21. Tetrahydropyridine 19 (220 mg,
0.53 mmol) was dissolved in methanol (8 mL) and hydrogenated
over palladium on charcoal (10% w/w; 70 mg) overnight.
The catalyst was filtered through Celite and the solvent was
removed in vacuo to give the piperidine 21 after purification by
column chromatography on silica gel eluting with diethyl ether
as a colourless sticky oil (quantitative yield); (Found: MH+,
26
329.2446. C17H32N2O4 + H requires 329.2440); [a]D +43.9 (c
0.41, CHCl3); mmax (film)/cm−1 3416, 3327, 2965, 2936, 2875,
=
=
1701 (C O), 1625 (C O), 1521, 1446, 1391, 1366, 1248, 1172,
1046, 1020; dH (400 MHz; DMSO, 120 ◦C) 6.04 (1 H, br, NH),
4.45–4.18 (2 H, m, 2 × NCH), 4.00 (1 H, br, NCHH), 3.58
(2 H, m, OCH2), 1.78 (2 H, m, NCHCH, CHH), 1.70–1.23
(15 H, m, CHH, 2 × CH2, CHH, CMe3), 1.10 (1 H, m, CHH),
0.84 (6 H, m, 2 × Me); OH and NCHH not observed; dC
(100 MHz; DMSO, 120 ◦C) 171.2 (C), 155.7 (C), 78.7 (C), 60.0
(CH2), 55.0 (CH), 37.0 (CH), 28.7 (Me), 25.6 (2 × CH2), 24.5
(CH2), 19.4 (CH2), 16.2 (Me), 11.3 (Me); NCH and NCH2
signals not observed, probably due to extreme broadening by
J-coupling to N; m/z (CI) 329 (MH+, 8%), 311 (5), 273 (52),
255 (19), 229 (100), 116 (14).
1,4-Dideoxy-1,4-imino-D-ribitol hydrochloride 23. Pyrroli-
dine 22 (101 mg, 0.23 mmol) was dissolved in methanol (3 mL)
and hydrochloric acid (1 M; 2 mL) and hydrogenated over
palladium on charcoal (10% w/w; 20 mg) overnight. The catalyst
was filtered through Celite and the solvent was removed in
vacuo to give the title compound 23 as a yellow solid (36 mg,
quantitative yield); mp 124–125 C (lit.,28 mp 128–132 ◦C);
◦
(Found: MH+, 134.0817. C5H11NO3 + H requires 134.0817);
[a]D +53.3 (c 0.75, H2O) {lit.,28 [a]D +57.6 (c 0.59, H2O)}
25
20
{lit.,30 [a]D +53.9 (c 1, H2O)}; dH (400 MHz; D2O) 4.36 (1 H,
20
m, NCH2CHOH), 4.19 (1 H, dd, J = 8.5, 4.0 Hz, NCHCHOH),
3.94 (1 H, dd, J 12.6, 2.6, CHHOH), 3.80 (1 H, dd, J 12.6, 6.0,
CHHOH), 3.59 (1 H, m, NCH), 3.48 (1 H, dd, J 13.0, 4.0,
NCHH), 3.34 (1 H, m, NCHH); dC (75 MHz; D2O) 72.2 (CH),
70.4 (CH), 62.8 (CH), 59.0 (CH2), 50.7 (CH2); m/z (CI) 134
(MH+, 100%), 116 (20), 98 (18).
4-Bromobenzoate derivative: (2R,2ꢀS)-(−)-2-(4-bromobenzo-
yloxymethyl)-1-(2-tert-butoxycarbonylamino-3-methylpentano-
yl)piperidine. To a solution of alcohol 21 (45 mg, 0.14 mmol),
triethylamine (0.02 mL, 0.14 mmol) and DMAP (cat.) in
dichloromethane (2 mL), 4-bromobenzoyl chloride (31 mg,
0.14 mmol) was added and the reaction mixture was stirred
overnight. The solvent was evaporated and after purification
by column chromatography on silica gel eluting with diethyl
ether–light petroleum (1 : 1) the title compound was obtained
(59 mg, 84%) as a colourless sticky oil; (Found: MH+, 511.1806.
Acknowledgements
We thank the EPSRC for support of this work (studentships to
T. S. C. and A. S. L.), GlaxoSmithKline for a CASE award (to
T. S. C.), and the EPSRC Mass Spectrometry Centre at Swansea
for mass spectra, and the EPSRC Chemical Database Service at
Daresbury.35
24
C24H3579BrN2O5 + H requires 511.1808); [a]D +4.0 (c 0.99,
CHCl3); mmax (film)/cm−1 3432, 3314, 2966, 2930, 2868, 1718
=
=
(C O), 1636 (C O), 1588 1496, 1437, 1368, 1267, 1173, 1107,
1012; dH (400 MHz; DMSO, 120 ◦C) 7.83 (2 H, m, ArH), 7.67
(2 H, m, ArH), 6.07 (1 H, br, NH), 4.86 (1 H, br, NCH), 4.56
(1 H, br, OCHH), 4.40 (1 H, dd, J = 11.2, 6.1 Hz, OCHH),
4.28 (1 H, t, J 8.2, NCH), 4.02 (1 H, br, NCHH), 1.85–1.27
(17 H, m, NCHCH, CHH, 3 × CH2, CMe3), 1.10 (1 H, m,
CHH), 0.80 (6 H, m, 2 × Me); the NCHH signal is missing
and is probably under the solvent signal; dC (100 MHz; DMSO,
120 ◦C) 171.4 (C), 165.4 (C), 155.6 (C), 132.2 (CH), 131.5 (CH),
129.6 (C), 127.6 (C), 78.7 (C), 63.2 (CH2), 55.0 (CH), 37.1 (CH),
28.6 (Me), 26.0 (CH2), 25.6 (CH2), 24.4 (CH2), 19.5 (CH2), 16.2
(Me), 11.2 (Me); the NCH and NCH2 signals are not observed,
probably due to extreme broadening by J-coupling to N; m/z
(CI) 513/511 (MH+, 30%), 457/455 (22), 413/411 (100), 311
(14), 300/298 (14), 211 (24), 203/201 (24).
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1 2 6 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 2 5 2 – 1 2 6 2