Total synthesis of sulfobacin A through dynamic kinetic resolution of a racemic β-keto-α-amino ester hydrochloride

Article abstract of DOI:10.1016/j.tetasy.2004.05.004

A total synthesis of sulfobacin A, a von Willebrand factor receptor antagonist, is described. Our synthetic approach relies uniquely on catalytic asymmetric reactions for the creation of the three stereogenic centers without using chiral building blocks.

Full text of DOI:10.1016/j.tetasy.2004.05.004

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 1899–1908
Total synthesis of sulfobacin A through dynamic kinetic resolution
of a racemic b-keto-a-amino ester hydrochloride
*
^
Olivier Labeeuw, Phannarath Phansavath and Jean-Pierre Genet
Laboratoire de Synthꢀese Sꢁelective Organique et Produits Naturels, UMR CNRS 7573,
Ecole Nationale Supꢁerieure de Chimie de Paris, 11 rue Pierre et Marie Curie, 75231 Paris cedex 05, France
Received 25 March 2004; accepted 7May 2004
Available online 4 June 2004
Abstract—A total synthesis of sulfobacin A, a von Willebrand factor receptor antagonist, is described. Our synthetic approach relies
uniquely on catalytic asymmetric reactions for the creation of the three stereogenic centers without using chiral building blocks. The
key steps of this short route to sulfobacin A involve ruthenium-mediated asymmetric hydrogenation reactions of a b-keto ester and a
racemic b-keto-a-amino ester hydrochloride to afford, respectively, the corresponding enantiomerically pure b-hydroxy ester and the
enantioenriched anti b-hydroxy a-amino ester hydrochloride through dynamic kinetic resolution.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
approaches involved either a chiral building block or a
chiral auxiliary to set one or two of the three stereogenic
centers present in the natural product. We have also
recently achieved an efficient total synthesis of this
compound via sequential catalytic asymmetric hydro-
genation and diastereoselective electrophilic amination.5
We report herein an improved synthesis of sulfobacin A
1 by using uniquely catalytic asymmetric reactions for
the highly diastereo- and enantioselective construction
of the three stereogenic centers.
Sulfobacins A 1 and B (Scheme 1) are novel von
Willebrand factor (vWF) receptor antagonists produced
by Chryseobacterium sp. NR 2993. They were isolated
by Kamiyama et al.1 in 1995 from a soil sample collected
in Iriomote Island. The same year, Kobayashi et al.2
also isolated sulfobacin A 1 from Flavobacterium sp.,
separated from the marine bivalve Cristaria plicata
collected in Ishikary Bay.
It has been established in previous work6 that dynamic
kinetic resolution of b-keto a-amido ester using ruthe-
nium-catalyzed hydrogenation allows the efficient
preparation of syn-b-hydroxy-a-amino acids with
excellent diastereo- and enantioselectivities.7 We have
recently disclosed that highly stereoselective synthesis of
anti-b-hydroxy-a-amino ester hydrochlorides can be di-
rectly achieved from the racemic b-keto-a-amino ester
hydrochlorides by asymmetric hydrogenation with chi-
ral ruthenium complexes through dynamic kinetic res-
olution.8;9
SO3H
SO3H
O
OH
O
N
N
11
11
11
11
H
H
OH
OH
sulfobacin A 1
sulfobacin B
Scheme 1. Structures of sulfobacins A and B.
Sulfobacins A and B showed potent inhibitory activity
against the binding of vWF to its receptor in a com-
petitive manner with IC50 of 0.47 lM for sulfobacin A
and 2.2 lM for sulfobacin B.1 These compounds also
exhibit inhibitory activity against DNA polymerase a.2
Herein as an extension of this work, and in connection
with our ongoing program directed towards the total
synthesis of biologically relevant natural products,10 the
application of this methodology to the total synthesis of
sulfobacin A is described.
Two total syntheses of sulfobacin A 1 were reported
in 1998 by the groups of Shioiri3 and Mori.4 Their
Our retrosynthetic analysis for sulfobacin A 1 involves
disconnection of the amide bond into b-hydroxy acid 7
* Corresponding author. Tel.: +33-1-4427-6743; fax: +33-1-4407-1062;
e-mail: genet@ext.jussieu.fr
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.05.004

1900
O. Labeeuw et al. / Tetrahedron: Asymmetry 15 (2004) 1899–1908
and aminosulfonic acid 19 (Scheme 2). Thus, compound
19 would result from the anti-b-hydroxy-a-amino ester
hydrochloride 11, which could be obtained by asym-
metric hydrogenation of racemic b-keto-a-amino ester
hydrochloride 9 through dynamic kinetic resolution. b-
Keto ester 5 would serve both for the preparation of
compound 9 and for the synthesis of b-hydroxy acid 7
by ruthenium-mediated asymmetric hydrogenation fol-
lowed by simple alkaline treatment.
bonyl diimidazole to 4 followed by treatment with the
magnesium salt of monomethyl malonic acid afforded
b-keto ester 5 in 81% yield.
For the asymmetric hydrogenation of 5, we used our
recently reported simple procedure for the in situ prep-
aration of chiral ruthenium catalysts12 starting directly
from anhydrous ruthenium trichloride.
Thus, hydrogenation of 5 was carried out in methanol at
80 °C under a low pressure of hydrogen (6 bar), using
1 mol % of the RuCl3/(R)-MeO-BIPHEP system. Under
these conditions, b-hydroxy ester 6 was obtained in 96%
SO3H
OH
O
N
H
11
11
yield and with excellent enantiomeric excess (ee >99%,
OH
25
D
1
determined by chiral HPLC analysis), ½aŠ ¼ À14:3 (c
–
20
0.51, CHCl3), lit.1b ½aŠ ¼ À12:7 (c 0.52, CHCl3).
SO3
OH
D
OH
O
O
Finally, alkaline treatment of 6 furnished b-hydroxy
+
H3N
25
carboxylic acid 7, ½aŠ ¼ À11:6 (c 1.0, CHCl3), lit.13
11
OH
D
11
20
D
coupling reaction with aminosulfonic acid 19.
½aŠ ¼ À12:0 (c 1.0, CHCl3), required for the final
7
19
The synthesis of 19 also involved b-keto ester 5, which
was first converted into b-keto a-amino ester hydro-
chloride 9 via a two-step sequence (Scheme 4). Thus,
reaction of 5 with butyl nitrite in the presence of sulfuric
acid afforded the corresponding oxime 8 and subsequent
hydrogenation with Pd/C in a solution of HCl/MeOH
then provided quantitatively the b-keto a-amino ester
hydrochloride 9 required for the dynamic kinetic reso-
lution. To study the influence of the counter ion of the
ammonium salt on the reaction, we also prepared the
parent compound p-toluenesulfonic acid salt 10 by
hydrogenation of 8 with Pd/C in the presence of a
stoichiometric amount of p-toluenesulfonic acid. The
dynamic kinetic resolution of these compounds was then
studied using as a ligand either (R)-MeO-BIPHEP or
(R)-SYNPHOS,14 a new atropisomeric ligand bearing a
benzodioxane core synthesized in our group (Scheme 5,
Table 1).
OH
O
OH
OMe
OMe
11
11
NH2.HCl
6
11
asymmetric
hydrogenation
dynamic kinetic
resolution
[Ru]*/H2
[Ru]*/H2
O
O
O
O
OMe
OMe
11
11
NH2.HCl
5
9
Scheme 2. Retrosynthetic analysis for sulfobacin A 1.
The synthesis of the required b-hydroxy acid 7 began
with the commercially available 10-bromodecan-1-ol 2,
which was converted into alcohol 3 by treatment with
isoamylmagnesium bromide in the presence of dilithium
tetrachlorocuprate4b (Scheme 3). After oxidation with
Jones’ reagent to the corresponding carboxylic acid 4,
homologation to b-keto ester 5 was performed using
Masamune’s procedure.11 Thus, the addition of car-
O
O
O
O
a
b
5
OMe
OH
OMe
NH2. HX
11
11
N
8
9 : HX = HCl
10 : HX = TsOH
a
b
d
Br
OH
OH
O
Scheme 4. Reagents and conditions: (a) BuONO, conc. H2SO4, Et2O,
0 °C, 45 min then rt, 1.5 h, 98%; (b) for 9, H2 (1 atm), Pd/C 5%, HCl/
MeOH, quant.; for 10, H2 (1 atm), Pd/C 5%, MeOH, PTSA, quant.
10
11
2
3
O
O
c
The asymmetric hydrogenation of 9 was first conducted
in methanol at 50 °C under 20 bar of hydrogen using
2 mol % of the [Ru((R)-MeO-BIPHEP)Br2] complex,
generated in situ according to our convenient proce-
dure15 from commercially available (COD)Ru(2-methyl-
allyl)2. Under these conditions, (2R,3R)-11 was obtained
with excellent diastereoselectivity while moderate
enantioselectivity was observed for the anti product
(de ¼ 96%, ee ¼ 41%, entry 1). The de and ee were
measured by chiral HPLC after conversion of the
hydrogenated product into the corresponding carba-
mate 13, which will serve as well for the end of the
synthesis of sulfobacin A.
OH
OMe
11
11
4
5
OH
O
OH
O
e
OMe
OH
11
11
6
7
Scheme 3. Reagents and conditions: (a) Me2CH(CH2)2MgBr,
Li2CuCl4, THF, )78 °C to rt, 12 h, 95%; (b) Jones’ reagent, acetone, rt,
1 h, 88%; (c) carbonyl diimidazole, THF, rt, 6 h then
Mg(O2CCH2CO2Me)2, THF, rt, 16 h, 81%; (d) H2 (6 bar), RuCl3/(R)-
MeO-BIPHEP (1 mol %), MeOH, 80 °C, 23 h, 96%, ee >99%; (e) 1 N
NaOH, MeOH, 0 °C, 30 min, then rt, 3 h, 89%.

O. Labeeuw et al. / Tetrahedron: Asymmetry 15 (2004) 1899–1908
1901
O
O
OH
O
OH
O
H2 (bar)
Boc2O, NaHCO3
OMe
NH2. HX
OMe
NHBoc
OMe
NH2. HX
[Ru((R)-P*P)Br2] (2 mol%)
solvent, T (˚C), t (h)
100% conversion
MeOH, ultrasound, rt, 2 h
90-92% (two steps)
11
11
11
9 : HX = HCl
10 : HX = TsOH
(2R,3R)-13
(2R,3R)-11 : HX = HCl
(2R,3R)-12 : HX = TsOH
Scheme 5.
Table 1. Dynamic kinetic resolution of racemic 9 and 10 by using ruthenium-catalyzed asymmetric hydrogenationa
Entry
HX
Ligand
Solvent
P (bar)
T (°C)
t (h)
d.r. anti/synb Eeb;c (%)
1
HCl
HCl
HCl
HCl
HCl
HCl
(
(R)-MeO-BIPHEP
(R)-MeO-BIPHEP
(R)-MeO-BIPHEP
(R)-SYNPHOS
MeOH
MeOH
20
80
20
130
70
12
12
70
12
12
50
50
50
50
50
50
50
50
50
50
72
48
72
96
72
30
30
72
72
72
98/2
97/3
90/10
90/10
91/9
96/4
96/4d
92/8
93/7
93/7
41
35
85
88
88
92
92
84
82
83
2
3
CH2Cl2
CH2Cl2
4
5
(R)-MeO-BIPHEP
(R)-SYNPHOS
S)-SYNPHOS
CH2Cl2/MeOH (10/1)
CH2Cl2/MeOH (10/1)
CH2Cl2/MeOH (10/1)
CH2Cl2/MeOH (10/1)
CH2Cl2/MeOH (10/1)
CH2Cl2/MeOH (10/1)
6
7HCl
8
TsOH
TsOH
TsOH
(R)-MeO-BIPHEP
(R)-MeO-BIPHEP
(R)-SYNPHOS
9
10
a Complete conversions were observed for the asymmetric hydrogenation in all cases and were determined by 1H NMR analysis of the crude reaction
mixture.
b The diastereo- and enantiomeric excesses were determined by chiral HPLC after conversion of 11 and 12 into the corresponding carbamate 13:
Chiralcel OD-H column; eluent, hexane/propan-2-ol: 99/1; flow rate: 1.0 mL/min; UV detection: 215 nm; tR 17.93 min, (2S,3S)-13 isomer; tR
19.21 min, (2S,3R)-13 isomer; tR 20.15 min, (2R,3S)-13 isomer; tR 21.17min, (2 R,3R)-13 isomer.
c The enantiomeric excess was measured for the anti-b-hydroxy-a-amino ester 13.
d The (2S,3S)-11 isomer was the major product in this case.
Increasing the hydrogen pressure to 80 bar resulted in a
slight decrease of both diastereo- and enantioselectivities
(de ¼ 94%, ee ¼ 35%, entry 2). Interestingly, when using
dichloromethane in place of methanol, the ee raised to
85% while the de remained correct (de ¼ 80%, ee ¼ 85%,
entry 3). Similar results were obtained using (R)-SYN-
PHOS at higher pressure (130 bar) instead of (R)-MeO-
BIPHEP (de ¼ 80%, ee ¼ 88%, entry 4).
and 10). Nevertheless the de and ee with the p-toluene-
sulfonic acid salt 10 remained inferior to the best results
obtained with hydrochloride compound 9 (entry 10 vs
entry 6).
The absolute configuration of b-hydroxy a-amino ester
13 was unambiguously established by comparison with
an authentic sample of anti-(2R,3R)-13 prepared during
our former total synthesis of sulfobacin A5 by sequential
catalytic hydrogenation and diastereoselective electro-
philic amination (Scheme 6).
When the reaction was carried out in a mixture of di-
chloromethane/methanol (10/1), both de and ee were
still high (de ¼ 82%, ee ¼ 88%, entry 5). The best results
were obtained when using 2 mol % of [Ru((R)-SYN-
PHOS)Br2] in dichloromethane/methanol (10/1) at 50 °C
under 12 bar of hydrogen.
OH
O
OH
O
b, c, d
a
6
OMe
NBoc
NHBoc
OMe
NHBoc
11
11
Under these conditions, anti-(2R,3R)-11 was obtained
with a high level of diastereo- and enantioselectivity
(de ¼ 92%, ee ¼ 92%, entry 6). For analytical purposes,
the (2S,3S)-11 isomer has been prepared as well using
the other configuration of the chiral diphosphine
(de ¼ 92%, ee ¼ 92%, entry 7).
14
(2R,3R)-13
Scheme 6. Reagents and conditions: (a) MeZnBr (1 equiv), 0 °C, 1 h;
LDA (2 equiv), )78 °C, 1 h; DTBAD (2 equiv), )78 °C, 2 h, 72%,
de >95%; (b) TFA, CH2Cl2, rt, 3 h; (c) H2 (1 atm), Raney Ni, MeOH,
ultrasound, rt, 14 h; (d) Boc2O, NaHCO3, MeOH, ultrasound, rt, 3.5 h,
80% from 14.
We have then studied the dynamic kinetic resolution of
the p-toluenesulfonic acid salt 10 to investigate the effect
of the counter ion of the ammonium salt. The hydro-
genation reaction was first performed at 50 °C in di-
chloromethane/methanol (10/1) under 70 bar of hyd-
rogen with (R)-MeO-BIPHEP and afforded (2R,3R)-12
with 84% de and 84% ee, comparable to the results
obtained previously for compound 9 under the same
conditions (entry 8 vs entry 5). Decreasing the hydrogen
pressure to 12 bar resulted in similar diastereo- and
enantioselectivities (de ¼ 86%, ee ¼ 82–83%, entries 9
The anti-N,N0-Boc-a-hydrazino-b-hydroxy ester 14 was
readily obtained from enantiomerically pure b-hydroxy
ester 6 by electrophilic amination with di-tert-butyl-
azodicarboxylate (DTBAD).16 Thus, treatment of 6 with
methylzinc bromide followed by lithium diisopropyl-
amide at )78 °C furnished the resulting zinc enolate,
which was reacted with DTBAD to afford 14 in 72%
yield as a single diastereomer after separation by flash
1
chromatography (de >95%, determined by H NMR).
Deprotection of the hydrazine function followed by

1902
O. Labeeuw et al. / Tetrahedron: Asymmetry 15 (2004) 1899–1908
cleavage of the N–N bond by hydrogenolysis with Ra-
ney nickel under ultrasound,18 and subsequent protec-
tion of the resulting amine with di-tert-butyl dicarbonate
under ultrasound18 finally afforded (2R,3R)-13
(de ¼ 96%, ee ¼ 99%, chiral HPLC) in 80% overall yield
starting from 14.
O
O
a
b
CO Me
(2R,3R)-13
2
OH
NBoc
11
11
NBoc
17
16
O
OH
c
d
–
Authentic samples of both enantiomers of syn-b-hy-
droxy-a-amino ester (2S,3R)-13 and (2R,3S)-13 were
also readily obtained through dynamic kinetic resolu-
tion of racemic b-keto-a-amino ester 15 using either (R)-
or (S)-MeO-BIPHEP as a ligand (Scheme 7).
SCOMe
SO
3
11
11
+
NH
NBoc
3
19
18
Scheme 8. Reagents and conditions: (a) Me2C(OMe)2, BF3ꢀEt2O,
CH2Cl2, rt, 1 h, 93%; (b) Ca(BH4)2, THF/EtOH, )15 °C to rt, 22 h,
94%; (c) CH3COSH, iPrOCON@NCO2iPr, PPh3, THF, 0 °C, 1 h, then
rt, 16 h, 95%; (d) H2O2, TFA, rt, 1 h.
O
O
OH O
a
b
8
OMe
NHBoc
(2S,3R)-13
OMe
NHBoc
15
11
11
the sodium salt of 19 in a mixture of dioxane and water
at room temperature (Scheme 9).20 After treatment with
Amberlite IR-120B (Hþ form), sulfobacin A 1 was ob-
tained in 20% yield from 18 and spectral data of 1 were
found to be in agreement with reported literature
data.1b;3b;4a
Scheme 7. Reagents and conditions: (a) Zn, AcOH, Boc2O, D, 3 h then
rt, 1.5 h, 82%; (b) for (2S,3R)-13, H2 (120 bar), [Ru((R)-MeO-BIP-
HEP)Br2] (1 mol %), CH2Cl2, 50 °C, 96 h, 94%, ee ¼ 94%, de ¼ 90%; for
(2R,3S)-13, H2 (120 bar), [Ru((S)-MeO-BIPHEP)Br2] (1 mol %),
CH2Cl2, 50 °C, 96 h, 90%, ee ¼ 94%, de ¼ 90%.
SO3H
OH
O
OH
O
a
Compound 15 was first prepared by reduction of oxime
8 with zinc in acetic acid in the presence of di-tert-butyl
dicarbonate. Subsequent hydrogenation of 15 using
1 mol % of [Ru((R)-MeO-BIPHEP)Br2] in CH2Cl2 at
50 °C under 120 bar of hydrogen delivered syn-(2S,3R)-
13 with high diastereo- and enantiomeric excesses
(de ¼ 90%, ee ¼ 94%). The (2R,3S)-13 isomer was also
prepared under similar conditions using (S)-MeO-BIP-
HEP as a ligand (de ¼ 90%, ee ¼ 94%).
OH
N
H
11
11
11
OH
7
1
Scheme 9. Reagents and conditions: (a) HONB, DCC, THF/dioxane,
0 °C, 40 min, rt, 24 h then 19, NaHCO3, dioxane/H2O, rt, 20 h, 20%
from 18.
In summary, in spite of the moderate yield obtained in
the final coupling reaction between compounds 7 and
19, our route to sulfobacin A is a very short one (14
steps) and compares favorably with the other reported
syntheses (Shiori:3 21 steps, Mori:4 24 steps). The
ruthenium-catalyzed asymmetric hydrogenation of b-
keto ester 5 and the dynamic kinetic resolution of b-
keto-a-amino ester hydrochloride 9 allowed the highly
stereocontrolled construction of the three stereogenic
centers only through catalytic asymmetric reactions
without using either chiral auxiliaries or chiral building
blocks. Moreover, by choosing either the (R) or (S)
configuration of the chiral ligand for the asymmetric
hydrogenation of compounds 5, 9 or 15, this flexible
approach should allow the easy preparation of all eight
isomers of sulfobacin A for structure–activity relation-
ship studies.
It should be pointed out that our approach should allow
an easy access to all eight stereoisomers of sulfobacin A
since both b-hydroxy acids (R)-7 and (S)-7 can be
readily obtained using the appropriate configuration of
the chiral ligand during the asymmetric hydrogenation
step of compound 5, and both enantiomers of syn- and
anti-b-hydroxy-a-amino ester 13 can be prepared via
dynamic kinetic resolution of either b-keto-a-amino
ester hydrochloride 9 or b-keto a-Boc-amino ester 15
using (R) or (S) chiral diphosphine.
Completion of the synthesis of sulfobacin A then re-
quired protection of compound (2R,3R)-13 (Scheme 8).
Thus, treatment of (2R,3R)-13 with 2,2-dimethoxypro-
pane with a catalytic amount of BF3ÆEt2O afforded the
corresponding oxazolidine 16, which was subsequently
reduced to the primary alcohol 17 by using calcium
borohydride. After conversion of 17 into the corre-
sponding mesylate, all attempts to perform nucleophilic
substitution with sodium sulfite failed to afford the ex-
pected sulfonic acid. Finally, Mitsunobu19 reaction of 17
with thioacetic acid furnished thioester 18 in 95% yield
and subsequent oxidation with hydrogen peroxide in
trifluoroacetic acid led to the target compound 19.
2. Experimental
All solvents were reagent grade and distilled under ar-
gon prior to use. Amines were distilled from potassium
hydroxide and CH2Cl2 from calcium hydride. THF and
Et2O were distilled from sodium benzophenone. Unless
special mention, all reactions were carried out under an
argon atmosphere. All commercially available reagents
were used without further purification unless otherwise
indicated. Nuclear magnetic resonance: 1H and 13C
NMR spectra were recorded either at 200 and 50 MHz,
The final coupling reaction of 19 with carboxylic acid 7
was carried out using HONB and DCC to form the
corresponding active ester of 7, which was reacted with

O. Labeeuw et al. / Tetrahedron: Asymmetry 15 (2004) 1899–1908
1903
1
respectively, on an AC200 Bruker spectrometer, or at
300 and 75 MHz, respectively, on an Avance 300 Bruker
spectrometer, or at 400 and 100 MHz, respectively, on
an Avance 400 Bruker spectrometer. Chemical shifts are
given in ppm referenced to the residual proton reso-
nance of the solvent (7.26 ppm for CDCl3) for 1H NMR.
For 13C NMR, chemical shifts are referenced to the
central peak of the solvent (77.1 ppm for CDCl3).
Coupling constants (J) are given in hertz (Hz). Infrared
spectra (IR) were recorded on either a Perkin–Elmer
783G spectrometer or an IRFT Nicolet 210 spectrome-
ter. Mass spectra (MS) were measured on a Nermag
R10-10C mass spectrometer (DCI/NH3) and on a PE
Sciex API 3000 mass spectrometer (ESI). Flash column
chromatography was performed on Merck silica gel
(0.040–0.063 mesh). Thin layer chromatography (TLC)
analysis was performed on Merck silica gel 60 PF 254
and revealed with either an ultra-violet lamp
(k ¼ 254 nm) or a potassium permanganate solution.
Specific rotation values were recorded on a Perkin–
Elmer 241 polarimeter. HPLC analyses were performed
on a Waters 600 system with a Chiralcel OD-H column.
1701 cmÀ1. H NMR (200 MHz, CDCl3) d 0.86 (d, 6H,
J ¼ 6:6 Hz), 1.17(m, 2H), 1.25 (br s, 16H), 1.45–1.69
(m, 3H), 2.35 (t, 2H, J ¼ 7:4 Hz). 13C NMR (50 MHz,
CDCl3) d 22.6, 24.6, 26.8, 27.3, 27.9, 29.0, 29.1, 29.3,
29.5, 29.8, 34.0, 39.0, 180.3. MS (DCI/NH3): m=z ¼ 260
[M+NH4]þ. Anal. Calcd for C15H30O2: C, 74.32; H,
12.47. Found: C, 74.33; H, 12.56.
2.3. Methyl 15-methyl-3-oxo-hexadecanoate 5
To a solution of methyl hydrogen malonate (21.6 g,
183 mmol) in THF (140 mL) was added magnesium
ethoxide (10.5 g, 91.5 mmol). The mixture was stirred at
room temperature for 1 h and concentrated to afford the
magnesium salt of methyl malonic acid as a yellow solid,
which was used for the next reaction without purifica-
tion. To a solution of carboxylic acid 4 (11.4 g,
47.1 mmol) in THF (250 mL) was added carbonyl di-
imidazole (9.2 g, 57.0 mmol) and the mixture was stirred
at room temperature for 6 h. This solution was then
added to the previously prepared magnesium salt
(14.9 g, 57.7 mmol). The reaction mixture was stirred for
20 h at 25 °C and concentrated. The residue was dis-
solved in Et2O (300 mL) and acidified with HCl 1 M.
After the layers were separated, the aqueous phase was
extracted with Et2O and the combined organic layers
were washed with water and saturated aqueous
NaHCO3, dried with MgSO4, filtered, and concentrated.
Purification of the residue by flash chromatography
(cyclohexane/ethyl acetate: 95/5) afforded 5 (11.5 g, 81%)
as a white solid, mp 44–45 °C. Rf 0.32 (cyclohexane/ethyl
acetate: 9/1). IR (KBr): 2950, 2914, 2842, 1747,
2.1. 13-Methyl-tetradecan-1-ol 34b
To a stirred solution of 10-bromo-decan-1-ol 2 (5.0 g,
21.1 mmol) in THF (50 mL) at )78 °C was added
dropwise a solution of (Me)2CH(CH2)2MgBr in THF
(80.7mL, 0.98 M, 78.1 mmol) followed by a solution of
Li2CuCl4 in THF (2.5 mL, 0.1 M, 0.25 mmol). The
reaction mixture was allowed to warm to room tem-
perature with stirring overnight, then quenched with
saturated aqueous NH4Cl and extracted with ethyl
acetate. The combined organic layers were washed with
water, saturated aqueous NaHCO3, and brine, then
dried over MgSO4 and concentrated. Purification of the
residue by flash chromatography afforded pure 13-me-
thyl-tetradecan-1-ol 3 (4.56 g, 95%) as a colorless oil. Rf
0.21 (cyclohexane/ethyl acetate: 8/2). IR (film): 3392,
2926, 2854 cmÀ1. 1H NMR (200 MHz, CDCl3) d 0.86 (d,
6H, J ¼ 6:6 Hz), 1.16 (m, 2H), 1.26 (br s, 18H), 1.44–
1.60 (m, 4H), 3.63 (t, 2H, J ¼ 6:6 Hz). 13C NMR
(50 MHz, CDCl3) d 22.5, 25.6, 27.3, 27.9, 29.3, 29.5,
29.6, 29.8, 32.7, 39.0, 62.9. MS (DCI/NH3): m=z ¼ 246
[M+NH4]þ.
1
1711 cmÀ1. H NMR (200 MHz, CDCl3) d 0.86 (d, 6H,
J ¼ 6:6 Hz), 1.16 (m, 2H), 1.25 (br s, 16H), 1.30–1.70
(m, 3H), 2.52 (t, 2H, J ¼ 7:3 Hz), 3.44 (s, 2H), 3.74 (s,
3H). 13C NMR (50 MHz, CDCl3) d 22.3, 23.1, 27.1, 27.6,
28.7, 29.0, 29.1, 29.3, 29.6, 38.7, 42.7, 50.7, 52.0, 167.4,
202.5. MS (DCI/NH3): m=z ¼ 299 [M+H]þ, 316
[M+NH4]þ. Anal. Calcd for C18H34O3: C, 72.44; H,
11.48. Found: C, 72.30; H, 11.53.
2.4. Methyl (R)-3-hydroxy-15-methyl-hexadecanoate 6
(R)-MeO-BIPHEP (93.8 mg, 0.16 mmol) and anhydrous
RuCl3 (33.3 mg, 0.16 mmol, purchased from Aldrich
Chemicals) were placed in a round-bottomed tube and
degassed by three vacuum/argon cycles at room tem-
perature. b-Keto ester 5 (4.79 g, 16.1 mmol) was added
followed by degassed methanol (15 mL). The reaction
vessel was placed in a stainless steel autoclave, which
was purged with hydrogen and pressurized under 6 bar.
The autoclave was heated to 80 °C by circulating
thermostated water in the double wall and magnetic
stirring was started as soon as the required temperature
was reached. After stirring for 23 h, the autoclave was
cooled to room temperature, hydrogen was vented and
the reaction mixture was concentrated in vacuo. Flash
chromatography on silica gel (cyclohexane/ethyl acetate:
8/2) afforded b-hydroxy ester 6 (4.66 g, 96%) as a white
2.2. 13-Methyl-tetradecanoic acid 4
To a solution of 13-methyl-tetradecan-1-ol 3 (42.2 g,
184.8 mmol) in acetone (750 mL) was added dropwise at
0 °C Jones’ reagent [prepared by adding at 0 °C conc.
H2SO4 (21 mL) to
a solution of CrO3 (33.9 g,
339.0 mmol) in water (145 mL)]. After stirring at room
temperature for 1 h, the reaction mixture was extracted
with Et2O. The combined organic layers were washed
with brine, dried over MgSO4, and concentrated. Puri-
fication of the residue by flash chromatography (cyclo-
hexane/ethyl acetate: 8/2) afforded pure 13-methyl-
tetradecanoic acid 4 (39.4 g, 88%) as a white solid, mp
47–49 °C, lit.21 46.5–47 °C. Rf 0.28 (cyclohexane/ethyl
acetate: 8/2). IR (KBr): 3416, 2950, 2919, 2850,
solid, mp 32–34 °C (lit.,1b colorless oil). Rf 0.41 (cyclo-
hexane/ethyl acetate: 7/3). ½aŠ ¼ À14:3 (c 0.51, CHCl3),
25
D

1904
O. Labeeuw et al. / Tetrahedron: Asymmetry 15 (2004) 1899–1908
20
D
lit.1b ½aŠ ¼ À12:7 (c 0.518, CHCl3). IR (KBr): 3570,
29.2, 29.4, 29.5, 29.7, 29.8, 30.0, 37.9, 39.1, 52.9, 150.7,
162.2, 196.3. MS (DCI/NH3): m=z ¼ 345 [M+NH4]þ.
Anal. Calcd for C18H33NO4: C, 66.02; H, 10.16; N, 4.28.
Found: C, 65.87; H, 10.24; N, 4.29.
3416, 2960, 2925, 2847, 1726 cmÀ1. 1H NMR (200 MHz,
CDCl3) d 0.86 (d, 6H, J ¼ 6:6 Hz), 1.16 (m, 2H), 1.25 (br
s, 18H), 1.30–1.65 (m, 3H), 2.42 (dd, 1H, J ¼ 16:5 and
8.6 Hz), 2.54 (dd, 1H, J ¼ 16:5 and 3.5 Hz), 2.89 (d, 1H,
J ¼ 4:0 Hz, OH), 3.71 (s, 3H), 3.99 (m, 1H). 13C NMR
(50 MHz, CDCl3) d 22.5, 25.4, 27.3, 27.9, 29.5, 29.6,
29.8, 36.4, 38.9, 41.0, 51.6, 67.9, 173.4. MS (DCI/NH3):
m=z ¼ 301 [M+H]þ, 318 [M+NH4]þ. Anal. Calcd for
C18H36O3: C, 71.95; H, 12.08. Found: C, 71.76; H, 12.15.
HPLC analysis: column, Chiralcel OD-H; eluent, hex-
ane/propan-2-ol: 99/1; flow rate, 1.0 mL/min; UV
detection, 215 nm; tR: 8.52 min, (R)-6 isomer; tR:
10.99 min, (S)-6 isomer; ee >99%.
2.7. Methyl 2-amino-15-methyl-3-oxo-hexadecanoate,
hydrochloride 9
To a solution of oxime 8 (3.0 g, 9.16 mmol) in degassed
methanol (45 mL) was added Pd/C 5% (317mg,
0.15 mmol) and a degassed solution of HCl/MeOH (3 N,
10 mL). The resulting mixture was purged three times
with hydrogen and stirred at room temperature for 24 h
under atmospheric pressure of hydrogen. The reaction
mixture was then filtered on Celite, rinsed with MeOH,
and concentrated. The crude gum was dissolved in
CH2Cl2 and concentrated to afford 9 (3.2 g, 100%) as a
white solid, mp 86–89 °C. IR (KBr): 2919, 2853, 1752,
1721 cmÀ1. 1H NMR (300 MHz, CD3OD) d 0.86 (d, 6H,
J ¼ 6:6 Hz), 1.17(m, 2H), 1.30 (br s, 18H), 1.51 (hept,
1H, J ¼ 6:6 Hz), 1.62 (m, 2H), 2.77 (dt, 1H, J ¼ 18:3
and 7.1 Hz), 2.90 (dt, 1H, J ¼ 18:3 and 7.3 Hz), 3.89 (s,
3H). 13C NMR (75 MHz, CD3OD) d 23.1, 24.2, 28.6,
29.2, 30.0, 30.5, 30.6, 30.7, 30.8, 30.9, 31.1, 40.3, 41.4,
54.6, 165.3, 199.5. ESI MS: m=z ¼ 314 [M)HCl+H]þ,
336 [M)HCl+Na]þ.
2.5. (R)-3-Hydroxy-15-methyl-hexadecanoic acid 7
To a solution of methyl (R)-3-hydroxy-15-methyl-hexa-
decanoate 6 (454 mg, 1.5 mmol) in methanol (2 mL) at
0 °C was added dropwise a 1 N aqueous solution of
NaOH (4 mL). The reaction mixture was stirred at 0 °C
for 0.5 h, then 3 h at room temperature, and concen-
trated in vacuo. The residue was acidified with 0.1 M
aqueous HCl and extracted with Et2O. The combined
organic layers were dried over MgSO4, concentrated,
and recrystallization in cyclohexane afforded pure (R)-3-
hydroxy-15-methyl-hexadecanoic acid 7 (385 mg, 89%)
as colorless crystals, mp 55–56 °C, lit.4b 55–57 °C. Rf
25
0.27(cyclohexane/ethyl acetate: 8/2). ½aŠ ¼ À11:6 (c
20
2.8. Methyl 2-amino-15-methyl-3-oxo-hexadecanoate,
PTSA salt 10
D
23
D
1.00, CHCl3), lit.4b ½aŠ ¼ À12:7 (c 1.02, CHCl3), lit.13
½aŠ ¼ À12:0 (c 1.0, CHCl3). IR (KBr): 3232, 2919,
D
2845, 1711 cmÀ1. 1H NMR (200 MHz, CDCl3) d 0.86 (d,
6H, J ¼ 6:6 Hz), 1.16 (m, 2H), 1.25 (br s, 18H), 1.30–
1.65 (m, 3H), 2.45 (dd, 1H, J ¼ 16:6 and 8.5 Hz), 2.58
(dd, 1H, J ¼ 16:6 and 3.6 Hz), 4.03 (m, 1H). 13C NMR
(50 MHz, CDCl3) d 22.5, 25.4, 27.3, 27.9, 29.5, 29.6,
29.8, 36.4, 39.0, 41.0, 68.0. MS (DCI/NH3): m=z ¼ 304
[M+NH4]þ.
To a solution of oxime 8 (1.50 g, 4.58 mmol) in degassed
methanol (20 mL) was added Pd/C 5% (159 mg,
0.075 mmol) and p-toluenesulfonic acid (0.87g,
4.58 mmol). The resulting mixture was purged three
times with hydrogen, pressurized under 1 bar and stirred
for 20 h at room temperature. The reaction mixture was
then filtered on Celite, rinsed with MeOH, and con-
centrated to afford 10 (2.22 g, 100%) as a white solid, mp
1
127–130 °C. IR (KBr): 2924, 2848, 1757, 1721 cmÀ1. H
2.6. Methyl 2-hydroxyimino-15-methyl-3-oxo-hexadecano-
ate 8
NMR (300 MHz, CD3OD) d 0.88 (d, 6H, J ¼ 6:6 Hz),
1.19 (m, 2H), 1.30 (br s, 18H), 1.53 (hept, 1H,
J ¼ 6:6 Hz), 1.60 (m, 2H), 2.37(s, 3H), 2.74 (dt, 1H,
J ¼ 18:3 and 7.2 Hz), 2.89 (dt, 1H, J ¼ 18:3 and 7.3 Hz),
3.89 (s, 3H), 7.24 (d, 2H, J ¼ 8:3 Hz), 7.70 (d, 2H,
J ¼ 8:3 Hz). 13C NMR (75 MHz, CD3OD) d 21.4, 23.1,
24.2, 28.6, 29.2, 30.0, 30.5, 30.6, 30.7, 30.8, 30.9,
31.1, 40.3, 41.4, 54.5, 127.0, 129.8, 141.7, 143.4, 165.3,
199.5. ESI MS: m=z ¼ 314 [M)TsOH+H]þ, 336
[M)TsOH+Na]þ.
Butyl nitrite (8.8 mL, 75.2 mmol,) was added at room
temperature to a solution of b-keto ester 5 (11.2 g,
37.6 mmol) in Et2O (200 mL). After cooling to 0 °C,
conc. H2SO4 (4 mL, 75.2 mmol) was added dropwise and
the mixture was stirred 45 min at 0 °C and 1.5 h at room
temperature. The reaction mixture was diluted with
water and extracted with Et2O. The combined organic
layers were dried over MgSO4 and concentrated. Flash
chromatography on silica gel (cyclohexane/ethyl acetate:
85/15 to 8/2) afforded oxime 8 (12.0 g, 98%) as a pale
yellow solid, mp 38–39 °C. Rf 0.24 and 0.36 for oximes Z
and E (cyclohexane/ethyl acetate: 8/2). IR (KBr): 2919,
2.9. General procedure for the preparation of compounds
(2R,3R)-11 and (2R,3R)-12 by asymmetric hydrogenation
of compounds 9 and 10, respectively
2854, 1746, 1714, 1691 cmÀ1
.
1H NMR (300 MHz,
CDCl3) d 0.85 (d, 6H, J ¼ 6:6 Hz), 1.15 (m, 2H), 1.24 (br
s, 18H), 1.58 (hept, 1H, J ¼ 6:6 Hz), 1.62 (m, 2H), 2.73
(t, 2H, J ¼ 7:5 Hz, minor isomer), 2.78 (t, 2H,
J ¼ 7:5 Hz, major isomer), 3.88 (s, 3H, minor isomer),
3.90 (s, 3H, major isomer), 9.38 (br s, 1H, OH). 13C
NMR (75 MHz, CDCl3) d 22.7, 23.8, 27.5, 28.0, 29.0,
Either (R)-MeO-BIPHEP (7.0 mg, 0.012 mmol) or (R)-
SYNPHOS (7.7 mg, 0.012 mmol) and (COD)Ru(2-
methylallyl)2 (3.2 mg, 0.01 mmol, commercially available
from Acros) were placed in a round-bottomed tube,
degassed by three vacuum/argon cycles at room tem-
perature, and dissolved in degassed acetone (1.5 mL). To

O. Labeeuw et al. / Tetrahedron: Asymmetry 15 (2004) 1899–1908
1905
this suspension was added at room temperature a 0.15 N
methanolic hydrobromic acid solution (147 lL,
0.022 mmol) and the mixture was stirred at 25 °C for
30 min. After evaporation of the solvent under vacuum,
b-keto-a-amino esters 9 (175.0 mg, 0.5 mmol) or 10
(242.8 mg, 0.5 mmol) was added to the ruthenium com-
plex followed by degassed CH2Cl2 (2 mL) and MeOH
(0.2 mL). The reaction vessel was placed in a stainless
steel autoclave, which was purged with hydrogen and
pressurized to 12 bar. The autoclave was heated to 50 °C
by circulating thermostated water in the double wall and
magnetic stirring was started as soon as the required
temperature was reached. After stirring for 30 h, the
autoclave was cooled to room temperature, hydrogen
was vented, and the reaction mixture was concentrated
in vacuo to afford quantitatively b-keto a-amino esters
(2R,3R)-11 or (2R,3R)-12, which were used in the next
step without further purification.
the solvent, purification of the residue by flash chro-
matography on silica gel (cyclohexane/ethyl acetate: 9/1
to 85/15) afforded (2R,3R)-13 (189 mg, 91% from 9) as a
25
pale yellow solid. ½aŠ ¼ À14:4 (c 1.0, CHCl3). HPLC
D
analysis: Chiralcel OD-H column; eluent, hexane/pro-
pan-2-ol: 99/1; flow rate: 1.0 mL/min; UV detection:
215 nm; tR 21.17min, (2 R,3R)-13.
2.12. Methyl (2S,3S)-2-(N-tert-butoxycarbonyl)amino-3-
hydroxy-15-methyl-hexadecanoate (2S,3S)-13from
(2S,3S)-11
Obtained as a pale yellow solid (192 mg, 92%) from
crude (2S,3S)-11 (0.5 mmol) according to the procedure
described above for the preparation of (2R,3R)-13.
25
D
½aŠ ¼ þ14:6 (c 1.0, CHCl3). HPLC analysis: Chiralcel
OD-H column; eluent, hexane/propan-2-ol: 99/1; flow
rate: 1.0 mL/min; UV detection: 215 nm; tR 17.93 min,
(2S,3S)-13.
2.10. Methyl (2R,3R)-2-(N,N0-di-tert-butoxycarbonyl-
hydrazino)-3-hydroxy-15-methyl-hexadecanoate (2R,3R)-
14
2.13. Methyl (2R,3R)-2-(N-tert-butoxycarbonyl)amino-3-
hydroxy-15-methyl-hexadecanoate (2R,3R)-13from 14
To a cooled (0 °C) solution of MeZnBr (11.0 mmol) in
THF (13 mL) prepared at room temperature from
ZnBr2 (2.47g, 11.0 mmol) and MeLi (7.42 mL, 1.48 M in
Et2O, 11.0 mmol), was added a solution of b-hydroxy
ester 6 (3.0 g, 10.0 mmol) in THF (12 mL). The reaction
mixture was stirred at 0 °C for 1 h then cooled to )78 °C
and a solution of lithium diisopropylamide (22.0 mmol)
in THF (24 mL) was added dropwise. After a further 1 h
at )78 °C, a solution of DTBAD (4.6 g, 20.0 mmol) in
THF (12 mL) was added dropwise, the reaction mixture
was stirred for 2 h then quenched at )78 °C with satu-
rated aqueous NH4Cl (15 mL). After extraction with
Et2O, the combined organic layers were washed with
brine, dried over MgSO4, filtered, and concentrated in
vacuo. Purification of the residue by flash chromato-
graphy (cyclohexane/ethyl acetate: 8/2) afforded anti-
N,N0-Boc-a-hydrazino-b-hydroxy ester 14 (3.83 g, 72%)
To a solution of 14 (1.18 g, 2.22 mmol) in CH2Cl2
(20 mL) was added trifluoroacetic acid (14 mL) at room
temperature. After stirring at room temperature for 3 h,
the reaction mixture was concentrated and the residue
was dried under vacuum to afford the deprotected
hydrazine. The crude product was dissolved in absolute
MeOH (12 mL) and a small spatula of activated W-2
Raney nickel (washed with water then MeOH) was
added. The flask was flushed with hydrogen (1 atm),
immersed in an ultrasound cleaner filled with water and
sonicated for 14 h. The reaction mixture was then fil-
tered on Celite under nitrogen and the Raney nickel
washed with MeOH. After removal of the solvent, the
crude product was purified by flash chromatography
(cyclohexane/ethyl acetate/Et3N: 95/5/2). The purified
amine was dissolved in absolute MeOH (10 mL) and
NaHCO3 (500 mg, 6.0 mmol) and di-tert-butyl dicar-
bonate (480 mg, 2.32 mmol) were added. The mixture
was sonicated in a cleaning bath until the end of CO2
evolution (3.5 h), filtered, and concentrated. Purification
of the residue by flash chromatography (cyclohexane/
ethyl acetate: 8/2) afforded (2R,3R)-13 (738 mg, 80%
as a pale yellow solid, mp 88–89 °C. Rf 0.21 (cyclohex-
25
ane/ethyl acetate: 8/2). ½aŠ ¼ À8:0 (c 1.01, CHCl3). IR
D
(KBr): 3560, 3478, 3416, 3232, 2925, 1752, 1716, 1634,
1
1619 cmÀ1. H NMR (400 MHz, CDCl3, 50 °C) d 0.88
(d, 6H, J ¼ 6:6 Hz), 1.19 (m, 2H), 1.28 (br s, 18H), 1.38–
1.60 (m, 3H), 1.47(s, 9H), 1.49 (s, 9H), 3.11 (s, 1H, OH),
3.76 (s, 3H), 4.08 (m, 1H), 4.83 (m, 1H), 6.50 (s, 1H,
NH). 13C NMR (100 MHz, CDCl3, 50 °C) d 22.6, 26.3,
27.4, 28.0, 28.2, 29.5, 29.6, 30.0, 33.8, 39.1, 52.0, 71.0,
81.9, 82.5, 155.1, 156.0, 170.7. MS (DCI/NH3):
m=z ¼ 531 [M+H]þ, 548 [M+NH4]þ.
from 14) as a white solid, mp 38–40 °C. Rf 0.38
25
(cyclohexane/ethyl acetate 7/3). ½aŠ ¼ À18:9 (c 0.99,
D
CHCl3). IR (KBr): 3560, 3467, 3416, 3370, 2919, 2852,
1752, 1687, 1685 cmÀ1 1H NMR (300 MHz, CDCl3)
.
d 0.84 (d, 6H, J ¼ 6:6 Hz), 1.14 (m, 2H), 1.24 (br s,
18H), 1.38–1.60 (m, 3H), 1.44 (s, 9H), 2.65 (br s, 1H,
OH), 3.76 (s, 3H), 3.87(m, 1H), 4.37(m, 1H), 5.48 (br d,
1H, J ¼ 7:4 Hz, NH). 13C NMR (75 MHz, CDCl3) d
22.7, 25.8, 27.5, 28.0, 28.3, 29.5, 29.6, 29.7 (2C), 29.8,
30.0, 30.2, 33.4, 39.1, 52.5, 58.4, 73.2, 80.5, 156.0, 171.4.
MS (DCI/NH3): m=z ¼ 416 [M+H]þ, 433 [M+NH4]þ.
Anal. Calcd for C23H45NO5: C, 66.47; H, 10.91; N, 3.37.
Found: C, 66.70; H, 11.24; N, 3.03. HPLC analysis:
Chiralcel OD-H column; eluent, hexane/propan-2-ol:
99/1; flow rate: 1.0 mL/min; UV detection: 215 nm; tR
21.17min, (2 R, 3R)-13.
2.11. Methyl (2R,3R)-2-(N-tert-butoxycarbonyl)amino-3-
hydroxy-15-methyl-hexadecanoate (2R,3R)-13from
(2R,3R)-11 or (2R,3R)-12
To a solution of crude (2R,R)-11 (0.5 mmol) in methanol
(4 mL) was added NaHCO3 (160 mg, 1.9 mmol) and di-
tert-butyl dicarbonate (120 mg, 0.55 mmol). The reac-
tion vessel was immersed in an ultrasound cleaner filled
with water and sonicated for 2 h. After evaporation of

1906
O. Labeeuw et al. / Tetrahedron: Asymmetry 15 (2004) 1899–1908
2.14. Methyl 2-(N-tert-butoxycarbonyl)amino-15-methyl-
3-oxo-hexadecanoate 15
m=z ¼ 416 [M+H]þ, 433 [M+NH4]þ. Anal. Calcd for
C23H45NO5: C, 66.47; H, 10.91; N, 3.37. Found: C,
66.70; H, 11.24; N, 3.03. HPLC analysis: Chiralcel OD-
H column; eluent, hexane/propan-2-ol: 99/1; flow rate:
1.0 mL/min; UV detection: 215 nm; tR 19.21 min,
(2S,3R)-13.
To a solution of oxime 8 (5.6 g, 17.1 mmol) in acetic acid
(64 mL) was added di-tert-butyl dicarbonate (45 mL,
196.0 mmol) and zinc (11.3 g, 172 mmol). After stirring
at reflux for 3 h and at room temperature for 1.5 h, the
solution was diluted with water, filtered on Celite, and
rinsed with Et2O. The layers were separated and the
aqueous phase was extracted with Et2O. The combined
organic layers were washed with saturated aqueous
NaHCO3, dried (MgSO4), and concentrated. Purifica-
tion of the residue by flash chromatography on silica gel
(cyclohexane/ethyl acetate: 9/1) afforded 15 (5.8 g, 82%)
as a pale yellow oil. Rf 0.78 (cyclohexane/ethyl acetate:
2.16. Methyl (2R,3S)-2-(N-tert-butoxycarbonyl)amino-3-
hydroxy-15-methyl-hexadecanoate (2R,3S)-13
Obtained as a pale yellow oil (374.0 mg, 90%) from 15
(413.6 mg, 1.0 mmol) according to the procedure de-
scribed above for the preparation of (2S,3R)-13 using
(S)-MeO-BIPHEP. Rf 0.34 (cyclohexane/ethyl acetate:
25
D
1
7/3). IR (film): 2924, 2852, 1757, 1711 cmÀ1. H NMR
7/3). ½aŠ ¼ À2:5 (c 1.0, CHCl3). IR (film): 3431, 2925,
(300 MHz, CDCl3) d 0.85 (d, 6H, J ¼ 6:6 Hz), 1.14 (m,
2H), 1.24 (br s, 16H), 1.43 (s, 9H), 1.51 (m, 1H), 1.58 (m,
2H),2.60 (dt, 1H, J ¼ 17:5 and 7.2 Hz), 2.70 (dt, 1H,
J ¼ 17:5 and 7.2 Hz), 3.79 (s, 3H), 5.02 (d, 1H,
J ¼ 7:1 Hz), 5.71 (d, 1H, J ¼ 7:1 Hz, NH). 13C NMR
(75 MHz, CDCl3) d 22.7, 23.5, 27.5, 28.2, 28.3, 29.0,
29.4, 29.5, 29.6, 29.7, 29.8, 30,0, 39.1, 40.6, 53.2, 63.6,
80.6, 155.0, 167.3, 201.5. MS (DCI/NH3): m=z ¼ 358
[M)C4H8+H]þ, 37 5 [M)C4H8+NH4]þ, 414 [M+H]þ,
431 [M+NH4]þ.
2853, 1752, 1716, 1696 cmÀ1
.
1H NMR (300 MHz,
CDCl3) d 0.85 (d, 6H, J ¼ 6:6 Hz), 1.15 (m, 2H), 1.25 (br
s, 18H), 1.38–1.56 (m, 3H), 1.45 (s, 9H), 3.77 (s, 3H),
4.07(m, 1H), 4.31 (br d, 1H, J ¼ 9:1 Hz), 5.28 (br d, 1H,
J ¼ 9:1 Hz, NH). 13C NMR (75 MHz, CDCl3) d 22.7,
25.6, 27.5, 28.0, 28.4, 29.5, 29.6, 29.7 (2C), 29.8, 30.0,
30.2, 33.8, 39.1, 52.6, 57.5, 72.2, 80.1, 156.1, 172.4. MS
(DCI/NH3): m=z ¼ 416 [M+H]þ, 433 [M+NH4]þ. Anal.
Calcd for C23H45NO5: C, 66.47; H, 10.91; N, 3.37.
Found: C, 66.70; H, 11.24; N, 3.03. HPLC analysis:
Chiralcel OD-H column; eluent, hexane/propan-2-ol:
99/1; flow rate: 1.0 mL/min; UV detection: 215 nm; tR
20.15 min, (2R,3S)-13.
2.15. Methyl (2S,3R)-2-(N-tert-butoxycarbonyl)amino-3-
hydroxy-15-methyl-hexadecanoate (2S,3R)-13
(R)-MeO-BIPHEP (7.0 mg, 0.012 mmol) and (COD)-
Ru(2-methylallyl)2 (3.2 mg, 0.01 mmol, commercially
available from Acros) were placed in a round-bottomed
tube, degassed by three vacuum/argon cycles at room
temperature and dissolved in degassed acetone (1.5 mL).
To this suspension was added at room temperature a
0.15 N methanolic hydrobromic acid solution (147 lL,
0.022 mmol) and the mixture was stirred at 25 °C for
30 min. After evaporation of the solvent under vacuum,
a degassed solution of b-keto a-amino ester 15
(413.6 mg, 1.0 mmol) in CH2Cl2 (2 mL) was added via
cannula to the ruthenium complex. The reaction vessel
was placed in a stainless steel autoclave, which was
purged with hydrogen and pressurized to 120 bar. The
autoclave was heated to 50 °C by circulating thermo-
stated water in the double wall and magnetic stirring
was started as soon as the required temperature was
reached. After stirring for 96 h, the autoclave was cooled
to room temperature, hydrogen was vented, and the
reaction mixture was concentrated in vacuo. Purification
of the residue by flash chromatography (cyclohexane/
ethyl acetate: 85/15) afforded b-keto-a-amino ester
2.17. 3-tert-Butyl 4-methyl (4R,5R)-2,2-dimethyl-5-(12-
methyl-tridecyl)-1,3-oxazolidine-3,4-dicarboxylate 16
To a solution of methyl (2R,3R)-2-(N-tert-butoxy-
carbonyl)amino-3-hydroxy-15-methyl-hexadecanoate
(2R,3R)-13 (642 mg, 1.55 mmol) in CH2Cl2 (5 mL) were
added 2,2-dimethoxypropane (0.57mL, 4.64 mmol) and
BF3.Et2O (10 lL, 0.077 mmol). After stirring at room
temperature for 1 h, the mixture was washed with brine,
dried over MgSO4, filtered, and concentrated. Flash
chromatography on silica gel (cyclohexane/ethyl acetate:
8/2) afforded oxazolidine 16 (653 mg, 93%) as a pale
yellow oil. Rf 0.64 (cyclohexane/ethyl acetate: 8/2).
25
D
½aŠ ¼ À14:0 (c 0.83, CHCl3). IR (film): 2921, 2852,
1
1750, 1710 cmÀ1. H NMR (400 MHz, CDCl3, 50 °C) d
0.88 (d, 6H, J ¼ 6:6 Hz), 1.18 (m, 2H), 1.28 (br s, 18H),
1.38–1.60 (m, 3H), 1.41 (s, 9H), 1.69 (s, 3H), 1.73 (s,
3H), 3.74 (s, 3H), 4.17 (dt, 1H, J ¼ 6:9 and 4.9 Hz), 4.29
and 4.38 (2d, 1H, J ¼ 6:3 Hz). 13C NMR (50 MHz,
CDCl3), two conformers: d 22.5, 24.2, 25.0, 25.3, 26.0,
26.4, 27.3, 27.8, 28.2, 29.4, 29.8, 30.1, 38.9, 51.6, 62.7,
62.9, 75.5, 75.7, 80.0, 80.6, 93.8, 94.1, 151.0, 152.0,
170.5, 170.7. MS (DCI/NH3): m=z ¼ 456 [M+H]þ, 47 3
[M+NH4]þ. Anal. Calcd for C26H49NO5: C, 68.53; H,
10.84; N, 3.07. Found: C, 68.76; H, 11.02; N, 2.84.
(2S,3R)-13 (390.6 mg, 94%) as a pale yellow oil. Rf 0.34
25
(cyclohexane/ethyl acetate: 7/3). ½aŠ ¼ þ2:7 (c 1.0,
D
CHCl3). IR (film): 3431, 2925, 2853, 1752, 1716,
1
1696 cmÀ1. H NMR (300 MHz, CDCl3) d 0.85 (d, 6H,
J ¼ 6:6 Hz), 1.15 (m, 2H), 1.25 (br s, 18H), 1.38–1.56
(m, 3H), 1.45 (s, 9H), 3.77(s, 3H), 4.07(m, 1H), 4.31 (br
d, 1H, J ¼ 9:1 Hz), 5.28 (br d, 1H, J ¼ 9:1 Hz, NH). 13C
NMR (75 MHz, CDCl3) d 22.7, 25.6, 27.5, 28.0, 28.4,
29.5, 29.6, 29.7(2C), 29.8, 30.0, 30.2, 33.8, 39.1, 52.6,
57.5, 72.2, 80.1, 156.1, 172.4. MS (DCI/NH3):
2.18. tert-Butyl (4R,5R)-4-hydroxymethyl-2,2-dimethyl-
5-(12-methyl-tridecyl)-1,3-oxazolidine-3-carboxylate 17
To a dispersion of CaCl2 (1.0 g, 9.2 mmol) in THF
(5.5 mL) was added a solution of ester 16 (600 mg,

O. Labeeuw et al. / Tetrahedron: Asymmetry 15 (2004) 1899–1908
1907
1.32 mmol) in MeOH (9 mL). After cooling to )15 °C,
NaBH4 (598 mg, 15.8 mmol) was added and the mixture
was stirred for 15 min at )15 °C and for 22 h at room
temperature. Saturated aqueous Na2SO4 was added and
the mixture was filtered on Celite, dried over MgSO4,
filtered, and concentrated. Purification of the residue by
flash chromatography on silica gel (cyclohexane/ethyl
acetate: 8/2) afforded pure alcohol 17 (529 mg, 94%) as a
temperature hydrogen peroxide (30% solution in water,
0.2 mL). After stirring at room temperature for 1 h, the
reaction mixture was concentrated in vacuo. The crude
yellow mixture was then crystallized by adding ethanol/
water (1:2), filtered, and dried in vacuo to afford
(2R,3R)-2-amino-3-hydroxy-15-methyl-hexadecan-1-sulf-
onic acid 19 as a white solid, which was used in the next
step without further purification. To an ice cooled
solution of (3R)-3-hydroxy-15-methyl-hexadecanoic
acid 7 (51.6 mg, 0.18 mmol) and HONB (35.2 mg,
0.19 mmol) in THF/dioxane (1/1, 1.4 mL) was added
DCC (39.4 mg, 0.19 mmol) and the mixture was stirred
at 0 °C for 40 min, then at room temperature for 24 h.
The resulting N,N0-dicyclohexylurea was filtered off, and
the filtrate was concentrated in vacuo. The residue was
dissolved in dioxane (1 mL), and a solution of the so-
dium salt of 19 [prepared by adding a solution of
NaHCO3 (16.6 mg, 0.20 mmol) in water (0.5 mL) to a
solution of 19 (0.19 mmol) in dioxane (1 mL)] was added
at room temperature. After stirring for 20 h, dioxane
was evaporated in vacuo, the remaining aqueous solu-
tion was eluted through a column packed with Amber-
lite IR-120B (Hþ form) and eluted with MeOH/CHCl3
(1/1) to afford a yellow solid after evaporation of the
eluent. Purification of the solid by flash chromatography
on silica gel (CHCl3/MeOH: 10/0 to 6/4) yielded sul-
fobacin A 1 (23.6 mg, 20% from 18) as a white solid,
mp 230–231 °C, lit3 220–222 °C, lit.4 233–235 °C. Rf
0.22 (low layer of CHCl3/MeOH/H2O: 65/25/10).
pale yellow oil. Rf 0.29 (cyclohexane/ethyl acetate: 8/2).
25
½aŠ ¼ À6:5 (c 0.79, CHCl3). IR (film): 3459, 2927, 2852,
D
1680 cmÀ1. 1H NMR (400 MHz, CDCl3, 50 °C) d 0.88 (d,
6H, J ¼ 6:6 Hz), 1.19 (m, 2H), 1.29 (br s, 18H), 1.38–1.60
(m, 3H), 1.50 (s, 9H), 1.57(s, 3H), 1.58 (s, 3H), 3.65 (ddd,
1H, J ¼ 11:0, 6.6, and 4.3 Hz), 3.82 (ddd, 1H, J ¼ 11:0,
6.6, and 4.3 Hz), 3.99 (m, 1H), 4.05 (dt, 1H, J ¼ 7:4 and
5.5 Hz). 13C NMR (50 MHz, CDCl3) d 22.5, 24.4, 26.3,
26.8, 27.3, 28.8, 29.5, 29.8, 27.8, 28.3, 38.9, 61.1, 63.2,
75.6, 81.0, 92.5, 155.0. MS (DCI, NH3): m=z ¼ 428
[M+H]þ. Anal. Calcd for C25H49NO4: C, 70.21; H, 11.55;
N, 3.28. Found: C, 70.30; H, 11.57; N, 3.18.
2.19. tert-Butyl (4R,5R)-4-acetylthiomethyl-2,2-dimethyl-
5-(12-methyl-tridecyl)-1,3-oxazolidine-3-carboxylate 18
To a solution of PPh3 (1.89 g, 7.21 mmol) in THF
(22 mL) at 0 °C was added diisopropyl azodicarboxylate
(1.48 mL, 7.04 mmol). After stirring at 0 °C for 4 h, a
solution of alcohol 17 (1.49 g, 3.48 mmol) and thioacetic
acid (0.55 mL, 7.66 mmol) in THF (15 mL) was added.
The yellow mixture was then stirred 1 h at 0 °C and 15 h
at room temperature. The reaction mixture was diluted
with ethyl acetate (500 mL), washed with saturated
aqueous NaHCO3 and brine, dried over MgSO4, fil-
tered, and concentrated. Solid impurities were then re-
moved by filtration after addition of pentane. Flash
chromatography on silica gel (cyclohexane/ethyl acetate:
95/5) afforded pure thioester 18 (1.61 g, 95%) as a pale
25
24
½aŠ ¼ À15:5 (c 0.14, MeOH), lit.1a ½aŠ ¼ À35 (c 0.14,
D
D
20
D
MeOH), lit.2 ½aŠ ¼ À7:9 (c 0.18, MeOH), lit.4a
25
D
½aŠ ¼ À15 (c 0.14, MeOH).22 IR (KBr): 3356, 2950,
2850, 1642, 1554, 1467, 1198, 1054 cmÀ1
.
1H NMR
(400 MHz, DMSO-d6) d 0.83 (d, 12H, J ¼ 6:6 Hz), 1.13
(m, 4H), 1.23 (m, 38H), 1.35 (m, 2H), 1.45 (m, 2H), 2.09
(dd, 1H, J ¼ 13:5 and 5.5 Hz), 2.13 (dd, 1H, J ¼ 13:5
and 6.7Hz), 2.69 (dd, 1H, J ¼ 14:1 and 4.3 Hz), 2.74
(dd, 1H, J ¼ 14:1 and 6.7Hz), 3.47 (m, 1H), 3.75 (m,
1H), 3.91 (m, 1H), 4.68 (d, 1H, J ¼ 4:4 Hz), 4.79 (d, 1H,
J ¼ 5:6 Hz), 7.66 (d, 1H, J ¼ 8:8 Hz). 13C NMR
(100 MHz, DMSO-d6) d 22.7, 25.4, 25.7, 27.0, 27.6, 29.3,
29.4, 29.5, 29.6, 33.5, 36.8, 38.7, 45.0, 51.3, 52.0, 67.8,
72.1, 170.4.
yellow oil. Rf 0.66 (cyclohexane/ethyl acetate: 8/2).
25
D
½aŠ ¼ þ3:0 (c 1.11, CHCl3). IR (film): 2925, 2854, 1702,
1
1455, 1379 cmÀ1. H NMR (400 MHz, CDCl3), major
conformer, d 0.86 (d, 6H, J ¼ 6:6 Hz), 1.15 (m, 2H), 1.26
(br s, 18H), 1.35-1.60 (m, 3H), 1.48 (s, 9H), 1.58 (s, 3H),
1.60 (s, 3H), 2.33 (s, 3H), 3.06 (dd, 1H, J ¼ 13:7and
4.1 Hz), 3.19 (dd, 1H, J ¼ 13:7and 6.6 Hz), 4.00 (m,
1H), 4.12 (m, 1H), minor conformer, d 0.85 (d, 6H,
J ¼ 6:6 Hz), 1.15 (m, 2H), 1.26 (br s, 18H), 1.35–1.60
(m, 3H), 1.48 (s, 9H), 1.55 (s, 3H), 1.58 (s, 3H), 2.31 (s,
3H), 3.02 (dd, 1H, J ¼ 13:5 and 5.5 Hz), 3.25 (dd, 1H,
J ¼ 13:5 and 6.3 Hz), 3.94 (m, 1H), 4.12 (m, 1H). 13C
NMR (50 MHz, CDCl3), two conformers: d 22.6, 23.3,
24.6, 26.4, 26.8, 26.9, 27.4, 27.6, 27.9, 28.3, 28.7, 28.9,
29.2, 29.4, 29.5, 29.6, 29.7, 29.9, 30.1, 30.5, 39.0, (58.5,
57.8), (80.2, 80.0), (92.9, 92.5), (152.3, 151.6), (195.0,
194.6). MS (DCI/NH3): m=z ¼ 486 [M+H]þ.
Acknowledgements
We thank Dr. R. Schmid and Dr. M. Scalone (Hoff-
mann La Roche) for a generous gift of (R)- and (S)-
MeO-BIPHEP: (R)-(+)- and (S)-())-6,60-dimethoxy-
2,20-bis(diphenyl-phosphinoyl)-1,10-biphenyl. O.L. is
ꢀ
grateful to the Ministere de l’Education Nationale et de
la Recherche for a grant (2001–2004).
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1908
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