Stereoselective synthesis of fully protected (2S,4S,6S)-2-amino-6-hydroxy-4-methyl-8-oxodecanoic acid (AHMOD)

Article abstract of DOI:10.1002/psc.1433

The stereocontrolled synthesis of fully protected (2S,4S,6S)-2-amino-6-hydroxy-4-methyl-8-oxodecanoic acid was accomplished using a glutamate derivative as starting material. The key steps of this stereochemical synthetic pathway involved an Evans asymmetric alkylation, a Sharpless asymmetric epoxidation, and a Grignard reaction.

Full text of DOI:10.1002/psc.1433

Research Article
Received: 28 July 2011
Revised: 28 October 2011
Accepted: 28 October 2011
Published online in Wiley Online Library: 16 January 2012
(wileyonlinelibrary.com) DOI 10.1002/psc.1433
Stereoselective synthesis of fully protected
(2S,4S,6S)-2-amino-6-hydroxy-4-methyl-8-
oxodecanoic acid (AHMOD)
Wei Zhang, Xiangpeng Li, Ning Ding and Yingxia Li*
ABSTRACT: The stereocontrolled synthesis of fully protected (2S,4S,6S)-2-amino-6-hydroxy-4-methyl-8-oxodecanoic acid was
accomplished using a glutamate derivative as starting material. The key steps of this stereochemical synthetic pathway in-
volved an Evans asymmetric alkylation, a Sharpless asymmetric epoxidation, and a Grignard reaction. Copyright © 2012 Euro-
pean Peptide Society and John Wiley & Sons, Ltd.
Keywords: amino acids; peptaibiotics; AHMOD; synthesis; stereoselectivity
non-stereoselectivity in the construction of the C-6 chiral center.
Recently, we reported the preparation of (2S,4S)-2-amino-4-
Introduction
Over the past half century, more than 850 peptaibiotics have
been isolated from fungi. These special peptides, with high con-
tent of a-aminoisobutyric acid (Aib), have attracted considerable
attention because of their broad bioactivities and particular struc-
tural properties. A special issue on these interesting molecules
was published in the Journal of Peptide Science in 2003 [1]. Four
years later, a similar topical issue with updated studies and over-
views on peptaibiotics was published in Chemistry & Biodiversity
[2]. Generally, peptaibiotics exhibit a broad range of biological
activities such as antibacterial [3–7], antifungal [8–11], antiviral
[12–14], and antimycoplasmic [15,16]. Inhibition of mitochondrial
ATPase, immunosuppression, uncoupling of oxidative phosphor-
ylation, and inhibition of platelet aggregation have also been
reported [17–20]. Besides, peptaibiotics with sufficient chain
length can form voltage-dependent ion channels in bilayer
membranes [21–23].
Structurally, peptaibiotics can be divided into four subfamilies
[24]: peptaibols, lipopeptaibols, lipoaminopeptides (also called
aminolipopeptides), and others. Among them, the third subfam-
ily has the most conservative structure. A proline or a modified
proline (mainly trans-4-hydroxy-proline or cis-4-hydroxy-proline)
is located in position 1, with C4–C15 fatty acids at the N-terminus.
In position 2, to our present knowledge, is 2-amino-6-hydroxy-4-
methyl-8-oxodecanoic acid (AHMOD). This unique amino acid
residue has only been detected in this subfamily up till now.
Some lipoaminopeptides containing this unit are listed in
Figure 1. However, none of these compounds bearing the
AHMOD residue has been synthesized by chemical methods,
which limits further biological and structure–activity relationship
(SAR) research. Lack of practical preparing methods of this highly
modified amino acid is one of the reasons that hampered so
far the chemical synthesis of lipoaminopeptides. To the best of
our knowledge, only one chemical synthetic route for this unit
has been disclosed so far, by Hadrami et al. 20 years ago [29].
But this route has not been widely adopted until now because
of some drawbacks: (i) the use of expensive starting materials,
(ii) the use of foul sulfide and highly toxic mercuride, and (iii)
methyl decanoic and (2S,4R)-2-amino-4-methyl decanoic acids
(AMDs) [30]. Based on this previous work, here we would like to
report a novel, practical, and stereoselective synthetic route to
the fully protected (2S,4S,6S)-AHMOD.
Results and Discussion
As displayed in Scheme 1, an inexpensive and commercially avail-
able glutamate derivative [Boc-Glu(OBn)-OH] was chosen as start-
ing material, which was transformed into compound 1 smoothly
according to reported procedures [31]. The resulting intermedi-
ate 1, equipped with chiral auxiliary (R)-4-benzyl-2-oxazolidinone,
was ready for Evans asymmetric alkylation. Notably, the structure
of nucleophilic reagent 1a was crucial to the following proce-
dures. The trans-allylic alcohol was selected as it gives better
results than its cis-isomer in the subsequent Sharpless asymmet-
ric epoxidation. The tert-butyldimethylsilyl (TBS) protecting group
for the hydroxyl group of 1a was chosen as it is stable under the
base-mediated enolization conditions and the reductive environ-
ment (to remove the auxiliary) and can be easily removed.
Compound 1 was enolized at low temperature, followed by the
addition of nucleophilic reagent 1a, giving the alkylated R-adduct
2 as the major product (dr = 19 : 1), which could be easily sepa-
rated from its diastereomer by column chromatography. Reduc-
tive removal of the chiral auxiliary furnished the primary alcohol
3, which was subsequently transformed to its tosylate. The tosy-
late, without purification, was treated with LiAlH4, releasing a
methyl group after displacement of the –OTs group with hydride.
After simple washes, the new intermediate was treated with
TBAF, removing the TBS group and then giving alcohol 4. All
*
Correspondence to: Yingxia Li, School of Pharmacy, Fudan University,
Zhangheng Rd. 826, Shanghai, China. E-mail: liyx417@fudan.edu.cn
Department of Medicinal Chemistry, School of Pharmacy, Fudan University,
Shanghai 201203, China
J. Pept. Sci. 2012; 18: 163–169
Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd.

ZHANG ET AL.
Figure 1. Structures of AHMOD and some AHMOD-containing lipoaminopeptides [25–28].
intermediates formed during the conversion of compound 3 to
compound 4 were not subjected to column chromatography.
The overall yield for these three steps was 90%. Allylic alcohol 4
was subjected to standard Sharpless asymmetric epoxidation
conditions providing the epoxy alcohol 5 in 91% yield as a single
diastereomer (by 1H NMR). Direct epoxide ring opening of 5 and
its transformation to the corresponding b-hydroxyl aldehyde
(precursor of compound 9) were found inefficient. Alternatively,
epoxide 5 was converted to its iodide (Scheme 1) [32], followed
by treatment with zinc dust in methanol at reflux, giving allylic al-
cohol 6 in satisfactory yields. The secondary hydroxyl group was
masked with benzyl ether, giving compound 7, which was then
elaborated into alcohol 8 by treatment with BH3 smoothly. Note
that other hindered boranes, such as 9-borabicyclo[3.3.1]nonane,
did not work in this hydroboration–oxidation reaction. Primary al-
cohol 8 was exposed to Swern conditions, and the resultant
crude aldehyde was treated with Grignard reagent, lengthening
the carbon chain to yield compound 9. Oxidative cleavage of
the oxazolidine, oxidation of the secondary alcohol and the
newly released primary alcohol, could be smoothly achieved in
a single step using freshly prepared Jones reagent, yielding
88% of carboxylic acid 10. Finally, this acid was transformed to
its methyl ester with diazomethane, giving the fully protected
(2S,4S,6S)-AHMOD (11)1 in 79% yields.
by Sharpless asymmetric epoxidation. The approach is economic,
stereoselective, and flexible, which will be beneficial for the
chemical synthesis and SAR research of the peptaibiotics bearing
AHMOD unit.
Experimental
General Information
Solvents were purified by standard methods. TLCs were carried out
on Merck 60 F254 silica gel plates and visualized by UV irradiation or
by staining with iodine absorbed on silica gel, ninhydrin solution, or
with aqueous acidic ammonium molybdate solution as appropri-
ate. Flash column chromatography was performed on silica gel
(200–300 mesh, Qingdao, China). Petroleum ether used as eluting
solvent in this paper was the fraction of boiling range 60–90 ꢀC.
Optical rotations were measured using a JASCO P-1020 digital
polarimeter (JASCO, Tokyo, Japan). NMR spectra were recorded
on JEOL JNM-ECP 600MHz spectrometer (JEOL Ltd, Tokyo, Japan).
Chemical shifts are reported in parts per million (ppm), relative to
the signals due to the solvent. Data are described as follows: chem-
ical shift, multiplicity (s= singlet, d = doublet, t = triplet, q = quartet,
br= broad, m = multiplet), coupling constants (Hz), integration, and
assignment. High resolution electrospray ionization mass spectros-
copy (HRESIMS) were recorded on a Q-Tof Ultima Global mass
spectrometer (Waters Asia Ltd, Singapore).
Conclusion
(S)-tert-Butyl 4-(3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-3-oxopropyl)-2,2-
dimethyloxazolidine-3-carboxylate (compound 1)
In conclusion, we have achieved a novel and stereoselective syn-
thesis of fully protected (2S,4S,6S)-AHMOD in 9.2% yield over 14
steps. In this route, the chiral C-2 center originated from
L-glutamates, the stereochemistry of C-4 was controlled by Evans
asymmetric alkylation, and the C-6 chiral center was introduced
This compound was prepared as reference [31] described. Starting
from Boc-Glu(OBn)-OH, the title compound was obtained as a white
solid: mp 123–124 ꢀC; [a]D26 = ꢁ37.0 (c 1.3, MeOH); H NMR (CDCl3,
1
600 MHz) d 1.46 (s, 12H, (CH3)3COC=O +
), 1.58 and 1.64
1This unusual amino acid unit shows quite different characters to other amino
acids. It has been proved that the skeleton of this amino acid derivate can be
destroyed by treatment with TFA (50% volume in CH2Cl2, 0 ꢀC, 1 h) or aqueous
solution of LiOH (0.2 mol/l, 0 ꢀC, 1 h). But the structures of products have not
been identified yet.
(s each, total 3H,
2.81 (m, 1H, PhCHaHb), 2.85–3.10 (brm, 2H, CH2CH2C=O), 3.30–3.33
(m, 1H, PhCHaHb), 3.75 (d, J= 9.0 Hz, 1H, ), 3.91 and 4.08–4.12
), 1.94–2.08 (brm, 2H, CH2CH2C=O), 2.74–
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SYNTHESIS OF FULLY PROTECTED (2S,4S,6S)-AHMOD
Scheme 1. Stereoselective synthesis of fully protected (2S,4S,6S)-AHMOD. Boc, tert-butoxycarbonyl; Bn, benzyl; NaHMDS, sodium bis(trimethylsilyl)am-
ide; TBS, tert-butyldimethylsilyl; TsCl, p-toluenesulfonyl chloride; DMAP, 4-dimethylaminopyridine; TBAF, tetrabutylammonium fluoride; DET, diethyl
tartrate.
J = 15.6, 4.6 Hz, 1H, CH=CH), 5.72 (dt, J = 15.5, 4.6 Hz, 1H, CH=CH);
(brm, 1H,
), 3.96 (dd, J= 9.0, 5.7 Hz, 1H,
), 4.15–4.23
13C NMR (DMSO-d6, 150 MHz) d ꢁ5.3 (Me2SiC(CH3)3), 17.9 (Me2SiC
(CH3)3), 25.8 (Me2SiC(CH3)3), 60.8 (C-4), 62.6 (C-1), 128.4 (CH=CH),
130.3 (CH=CH).
(m, 2H, oxazolidinone H-5), 4.68–4.72 (m, 1H, oxazolidinone H-4),
7.22–7.35 (m, 5H, Ar H); 13C NMR (CDCl3, 150MHz) d 24.3
To a stirred solution of the mono protected silyl ether obtained
above (9.78 g, 48.3 mmol) in DCM (250 ml) at 0 ꢀC were added im-
idazole (8.22 g, 120.7 mmol), Ph3P (16.47 g, 62.8 mmol), and
iodine (13.50 g, 53.2mmol), respectively. After being stirred at 0 ꢀC
for 1 h, the reaction was quenched with 10% Na2S2O3 (100 ml)
and concentrated at low temperature. The residue was extracted
with petroleum ether for three times. The extracts were com-
bined, washed with 10% Na2S2O3 and brine, dried over Na2SO4,
and concentrated in vacuo. The residue was purified by column
chromatography (100% petroleum ether) to give iodide 1a
(9.80 g, 65%) as a pale yellow oil [Rf 0.69 (10 : 1, petroleum
ether/EtOAc)]. This compound was unstable at room temperature
and was used immediately for the next step.
(
), 27.7 (
), 28.1 (
), 28.4 ((CH3)3COC=O),
31.9 (
), 38.1 (PhCH2), 55.3 (oxazolidinone C-4), 56.0
(
), 66.3 (oxazolidinone C-5), 67.3 (
), 80.1 ((CH3)3COC=O),
93.5 (
), 127.2 (Ar CH), 128.9 (Ar CH), 129.4 (Ar CH), 135.5 (Ar C),
152.7 (C=O), 153.7 (C=O), 172.6 (C=O); HRESIMS calcd for
C23H32N2O6Na 455.2153 [M + Na]+, found 455.2116.
(E)-1-Iodo-4-(tert-butyldimethylsilyloxy)-2-butene (1a)
Sodium hydride (60% dispersion in mineral oil, 2.88 g, 72.0 mmol)
was added in portions to a solution of (E)-2-butene-1,4-diol [33]
(5.29 g, 60.0 mmol) in 70 ml of anhydrous THF at 0 ꢀC. The mixture
was stirred at 0 ꢀC for 1 h, followed by dropwise addition of TBSCl
(9.05 g, 60.0 mmol) in 50 ml of THF. The reaction was stirred at
0 ꢀC for 1 h and then warmed to room temperature for another
2 h. The reaction was quenched carefully with crushed ice, di-
luted with 300 ml of Et2O, and washed with saturated NaHCO3
and brine, respectively. The organic phase was dried over
Na2SO4, concentrated in vacuo and purified by flash column chro-
matography, giving the monoprotected silyl ether (10.44 g, 86%)
as a colorless oil: 1H NMR (DMSO-d6, 600 MHz) d 0.039 (s, 6H, (CH3)
3CSi(CH3)2), 0.87 (s, 9H, (CH3)3CSi(CH3)2), 3.92–3.93 (m, 2H, H-1),
4.12 (d, J = 4.2 Hz, H-4), 4.69 (t, J = 5.7 Hz, 1H, OH), 5.66 (dt,
(S)-tert-Butyl 4-((R,E)-2-((R)-4-benzyl-2-oxooxazolidine-3-carbonyl)-6-(tert-butyldi-
methylsilyloxy)hex-4-enyl)-2,2-dimethyloxazolidine-3-carboxylate (compound 2)
To a solution of oxazolidinone 1 (8.65 g, 20.0 mmol) in anhydrous
THF (80 ml) at ꢁ78 ꢀC was added sodium bis(trimethylsilyl)amide
(2.0 M in THF, 10.0 ml, 20.0 mmol) via syringe. After stirring for
30 min at that temperature, iodide 1a (9.80 g, 31.4 mmol) in
20 ml of THF was added slowly via syringe. The mixture was stirred
in the dark at ꢁ78 ꢀC for 6 h, then quenched with saturated NH4Cl
and warmed to room temperature. The mixture was diluted with
Et2O (300 ml) and washed with 10% Na2S2O3 and brine. The or-
ganic phase was dried over Na2SO4 and concentrated in vacuo.
The residue was purified by flash chromatography providing
J. Pept. Sci. 2012; 18: 163–169 Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd. wileyonlinelibrary.com/journal/jpepsci

ZHANG ET AL.
9.87 g (80%) of compound 2 as a colorless oil: [a]2D0 = ꢁ6.2 (c 0.5,
(
), 25.9 (Me2SiC(CH3)3), 27.7 (
), 28.4 ((CH3)
), 37.7
1
CHCl3); H NMR (CDCl3, 600 MHz) d 0.05 (s, 6H, (CH3)2SiC(CH3)3),
0.89 (s, 9H, (CH3)2SiC(CH3)3), 1.42 (s, 9H, (CH3)3COC=O), 1.45
3COC=O), 34.3 ), 36.4
(
(
(s, 3H,
), 1.51 (s, 3H,
), 1.93–1.97 (m, 1H,
), 2.48–2.51 (m, 1H,
), 1.73–1.78 (m, 1H,
), 2.25–2.30 (m, 1H,
), 2.75 (dd, J = 13.2,
(
(
), 55.2 (
), 63.6 (CH2OTBS), 66.5 (CH2OH), 68.3
), 128.5 (CH=CH),
), 80.5 ((CH3)3COC=O), 93.3 (
131.3 (CH=CH), 153.0 (C=O); HRESIMS calcd for C23H45NO5NaSi
466.2965 [M + Na]+, found 466.2953.
10.2 Hz, 1H, PhCHaHb), 3.26 (dd, J = 13.5, 3.3 Hz, 1H, PhCHaHb),
3.59–3.63 (m, 1H,
), 3.66 (d, J = 9.0 Hz, 1H,
), 4.03–4.06 (m, 1H,
), 3.91
(S)-tert-Butyl 4-((R,E)-6-hydroxy-2-methylhex-4-enyl)-2,2-dimethyloxazoli-
dine-3-carboxylate (allylic alcohol 4)
(dd, J= 8.7, 5.7 Hz, 1H,
), 4.10–4.14
Triethylamine (TEA) (4.2 ml, 30.0 mmol) was added to a solution
of 3 (4.44 g, 10.0 mmol) in DCM (100 ml) at 0 ꢀC. TsCl (3.81 g,
20.0 mmol) and 4-dimethylaminopyridine (244 mg, 2.0 mmol)
were then added at the same temperature and stirred overnight.
The mixture was diluted with DCM (100 ml) and then washed
with 1 M HCl, water, saturated aqueous NaHCO3 and brine, dried
over Na2SO4, and concentrated in vacuo, giving the crude tosy-
late. This intermediate was used for the next step without further
purification.
(m, 3H, oxazolidinone H-5a + CH2OTBS), 4.27 (t, J = 8.4Hz, 1H,
oxazolidinone H-5b), 4.77–4.80 (m, 1H, oxazolidinone H-4), 5.62–5.67
(m, 2H,
), 7.22–7.25 (m, 2H, Ar H), 7.31–7.34 (m, 3H, Ar H);
13C NMR (CDCl3, 150 MHz) d ꢁ5.2 ((CH3)3CSi(CH3)2), 18.4 (Me2SiC
(CH3)3), 24.4 (
), 25.9 (Me2SiC(CH3)3), 28.2 (
), 28.4
((CH3)3COC=O), 35.4 (
), 35.7 (
), 38.7 (PhCH2),
LiAlH4 (1.14 g, 30.0 mmol) was added in small portions to a
solution of the crude tosylate obtained above in Et2O (100 ml)
at 0 ꢀC. The reaction mixture was stirred for 3 h at room temper-
ature. TLCs showed that the starting material was completely
consumed. Partly cleavage of the TBS ether was also observed
at the same time. The reaction was quenched by dropwise addi-
tion of water (1 ml), 15% aqueous NaOH (1 ml), and water (3 ml).
The mixture was stirred for 1 h at room temperature, and then
MgSO4 (5 g) was added. The suspension was filtered through a
pad of celite, washed with Et2O, and concentrated in vacuo. The
residue was then dissolved in 20 ml of THF, followed by the
addition of TBAF (1.0 M in THF, 10 ml, 10.0 mmol). The reaction
was stirred at room temperature for another 2 h and quenched
with saturated NH4Cl. The mixture was diluted with EtOAc
(150 ml), washed with brine, dried over Na2SO4, and concen-
trated in vacuo. The oily residue was purified by flash silica gel
chromatography, eluting with EtOAc/petroleum ether (1 : 3) to
give allylic alcohol 4 as a colorless oil (2.82 g, 90% for three steps):
[a]2D0 = 5.1 (c 0.4, CHCl3); 1H NMR (CDCl3, 600 MHz) d 0.97 (d,
39.7 (
), 54.8 (
), 55.4 (oxazolidinone C-4), 63.6
(CH2OTBS), 66.3 (oxazolidinone C-5), 68.4 (
), 80.1 ((CH3)
3COC=O), 93.6 ( ), 126.9 (Ar CH), 127.1 (CH=CH), 128.8 (Ar CH),
129.4 (Ar CH), 132.4 (CH=CH), 135.8 (Ar C), 153.3 (C=O), 153.4 (C=O),
175.1 (C=O); HRESIMS calcd for C33H52N2O7NaSi 639.3442 [M + Na]+,
found 639.3452.
(S)-tert-Butyl 4-((R,E)-6-(tert-butyldimethylsilyloxy)-2-(hydroxymethyl)hex-
4-enyl)-2,2-dimethyloxazolidine-3-carboxylate (compound 3)
LiAlH4 (1.14 g, 30 mmol) was added in small portions to a solution
of oxazolidinone 2 (6.17 g, 10 mmol) in Et2O (100 ml) at 0 ꢀC. The
reaction mixture was stirred for 3 h at room temperature and
quenched by dropwise addition of iced water (1 ml), 15% aque-
ous NaOH (1 ml), and water (3 ml). The mixture was stirred for
1 h at room temperature, and then MgSO4 (5 g) was added. The
suspension was filtered through a pad of celite, washed with
Et2O, and concentrated in vacuo. The residue was purified by
flash silica gel chromatography, eluting with EtOAc/petroleum
J = 6.6 Hz, 3H, CH3CH), 1.31–1.36 (m, 1H,
), 1.45–1.59
(brm, overlapped, total 17H,
), 1.77–1.86 (m, 1H,
ether (1 : 3) to give alcohol 3 as a colorless oil (4.00 g, 90%): [a]
1
20 = 51.4 (c 0.2, CHCl3); H NMR (CDCl3, 600 MHz) d 0.062 (s, 6H,
D
tBuSi(CH3)2), 0.90 (s, 9H, tBuSi(CH3)2), 1.48 (brs, 12H, (CH3)
), 2.04–2.07 (m, 1H,
), 3.72–3.96 (brm, over-
3COC=O +
), 1.54 (s, 3H,
), 1.60–1.86 (brm, 3H,
), 3.39–3.57 (m, 2H,
lapped, total 3H,
), 4.08–4.10 (m, 2H, CH2OH), 5.66–5.76
(m, 2H, CH=CH); 13C NMR (CDCl3, 150 MHz) d 21.3 (CH3CH), 24.5
), 1.99–2.21 (m, 2H,
(
), 27.7 (
(
), 28.4 ((CH3)3COC=O), 30.2 (CH3CH),
CH2OH), 3.65–3.76 (m, 1H,
), 3.88–4.20 (brm, 1H,
),
38.5
(
),
38.6
(
),
56.2
),
3.94 (dd, J = 8.4, 5.4 Hz, 1H,
), 4.12 (d, J = 4.2 Hz, 2H,
), 63.9 (
), 66.6 (
CH2OTBS), 5.58–5.62 (brm, 2H, CH=CH); 13C NMR (CDCl3,
150 MHz) d –5.2 ((CH3)3CSi(CH3)2), 18.4 (Me2SiC(CH3)3), 24.5
80.2 ((CH3)3COC=O), 93.0 (
), 130.5 (CH=CH), 131.4 (CH=CH),
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SYNTHESIS OF FULLY PROTECTED (2S,4S,6S)-AHMOD
152.0 (C=O); HRESIMS calcd for C17H31NO4Na 336.2151 [M + Na]+,
found 336.2136.
The iodide (1.33 g, 3.0 mmol) obtained above was dissolved in
50 ml of methanol, followed by the addition of zinc dust (1.97 g,
30 mmol). The suspension was refluxed for 2 h and then cooled
to room temperature, filtered through a pad of celite, and
washed with EtOAc. After concentration, the residue was redis-
solved in EtOAc (80 ml), washed with 20% Na2S2O3 and brine,
dried over Na2SO4, and concentrated in vacuo. The oily residue
was purified by flash silica gel chromatography, eluting with
EtOAc/petroleum ether (1 : 3) to give alcohol 6 (765 mg, 81%) as
a colorless oil: [a]D20 = 16.5 (c 0.5, CHCl3); 1H NMR (CDCl3,
600 MHz) d 0.98 (br, 3H, CH3CH), 1.37–1.85 (brm, overlapped, total
(S)-tert-Butyl 4-((S)-3-((2S,3S)-3-(hydroxymethyl)oxiran-2-yl)-2-methylpro-
pyl)-2,2-dimethyloxazolidine-3-carboxylate (epoxy alcohol 5)
Activated 4 Å molecular sieves powder (~2 g) was added to
100 ml of dry DCM and cooled to ꢁ20 ꢀC. Fifteen minutes later,
0.6 ml (2.0 mmol) of Ti(OiPr)4 was added, followed by the addition
of L-(+)-diethyltartrate (600 mg, 2.9 mmol, in 5 ml of DCM) via
syringe. The mixture was stirred for 15 min before tert-butyl
hydroperoxide was added (7.67 M in DCM, 61.4 mmol, 8.0 ml).
Thirty minutes later, allylic alcohol 4 (7.84 g, 25.0 mmol) in 50 ml
of DCM was added dropwise via syringe. The mixture was
allowed to stir at ꢁ20 ꢀC for 30 h. When TLCs showed that all of
the allylic alcohol 4 was consumed, the mixture was treated with
10 ml of 30% NaOH and then warmed to room temperature. The
suspension was filtered through a pad of celite. The filtered liquid
was treated with citric acid–ferrous sulfate solution. After stirring
at room temperature for 30 min, the mixture was extracted with
DCM for three times. The combined organic layers were washed
with brine, dried over Na2SO4, and concentrated in vacuo. The
residue was purified by flash silica gel chromatography, eluting
with EtOAc/petroleum ether (1 : 5 ! 1 : 1) to give epoxy alcohol
5 as a colorless oil (7.50 g, 91%): [a]2D0 = 10.6 (c 0.4, CHCl3); 1H
20H,
), 3.71 (d, J = 7.8 Hz, 1H,
), 3.83 (brm,
1H,
), 3.92–3.95 (m, 1H,
), 4.18–4.24 (m, 1H, CHOH),
5.07–5.13 (m, 1H, CH=CH2), 5.23 (d, J = 17.4 Hz, 1H, CH=CH2),
5.78–5.87 (m, 1H, CH=CH2); 13C NMR (CDCl3, 150 MHz) d 21.3
(CH3CH), 23.2 (CH3CH), 26.9 (
((CH3)3COC=O), 40.3 (
), 27.8 (
), 43.2 (
), 28.4
), 56.2
(
(
), 67.6 (
), 71.8 (CHOH), 80.1 ((CH3)3COC=O), 93.1
), 114.2 (CH=CH2), 141.0 (CH=CH2), 152.3 (C=O); HRESIMS
NMR (CDCl3, 600 MHz) d 1.04 (d, J = 6.6 Hz, 3H,
1.37 (brm, 2H, ), 1.48 (brs, 12H, Boc + CH3), 1.54 and
1.42 (s, total 3H, CH3), 1.65–1.67 (m, 2H, ), 1.83
(brm, 1H, ), 2.87–2.91 (m, 1H, epoxy H), 3.00 (brm,
),
calcd for C17H32NO4 314.2331 [M + H]+, found 314.2344.
(S)-tert-Butyl 4-((2S,4S)-4-(benzyloxy)-2-methylhex-5-enyl)-2,2-dimethylox-
azolidine-3-carboxylate (compound 7)
To a stirred solution of alcohol 6 (3.77 g, 12 mmol) in 50 ml of
DMF at 0 ꢀC was added NaH (60% dispersion in mineral oil,
960 mg, 24 mmol) in portions. The mixture was stirred at 0 ꢀC
for 30 min and another 30 min at room temperature. After that,
the mixture was re-cooled to 0 ꢀC, followed by the addition of
BnBr (3.6 ml, 30 mmol). The reaction was stirred at 0 ꢀC for
30 min and then warmed to room temperature. One hour later,
the reaction was quenched by addition of crushed ice and
diluted with Et2O (400 ml). The mixture was washed with water
and brine, dried over Na2SO4, and concentrated in vacuo. The res-
idue was purified by flash chromatography, giving compound 7
1H, epoxy H), 3.64–3.96 (brm, overlapped, 5H,
);
),
13C NMR (CDCl3, 150 MHz) d 21.7 (CH3CH), 24.5 (
27.7
(
), 28.4 ((CH3)3COC=O), 29.5 (CH3CH), 38.6
), 40.3 ( ), 55.3 (epoxy C), 56.6
), 58.3 (epoxy C), 61.8 (CH2OH), 67.3 (
(
(
(4.45 g, 92%) as a colorless oil: [a]2D0 = 11.1 (c 0.4, CHCl3); H NMR
1
), 80.2
(CDCl3, 600 MHz) d 0.94 (d, J = 5.4 Hz, 3H, CH3CH), 1.46–1.78
((CH3)3COC=O), 93.1 (
), 152.3 (C=O). HRESIMS calcd for
(brm, overlapped, total 20 H,
), 3.66 (d, J = 8.4 Hz,
C17H32NO5 330.2281 [M + H]+, found 330.2288.
(S)-tert-Butyl 4-((2S,4S)-4-hydroxy-2-methylhex-5-enyl)-2,2-dimethyloxazo-
lidine-3-carboxylate (compound 6)
1H,
), 3.80–3.96 (brm, overlapped, total 3H,
+
CHOBn), 4.34 (d, J = 11.4 Hz, 1H, PhCHaHb), 4.58 (d, J = 11.4 Hz,
1H, PhCHaHb), 5.21–5.26 (m, 2H, CH=CH2), 5.64–5.71 (m, 1H,
CH=CH2), 7.28–7.38 (m, 5H, Ar H); 13C NMR (CDCl3, 150 MHz) d
Ph3P (4.04 g, 15.4 mmol) was dissolved in DCM (100 ml) and
cooled to 0 ꢀC. Imidazole (1.62 g, 23.8 mmol) and iodine (3.92 g,
15.4 mmol) were added to the mixture, respectively. Ten minutes
later, epoxy alcohol 5 (3.91 g, 11.9 mmol) in 30 ml of DCM was
added. The mixture was then allowed to be stirred in the dark
at 0 ꢀC for 2 h, diluted with Et2O, washed with 20% Na2S2O3 and
brine, and concentrated in vacuo. The oily residue was purified
by flash silica gel chromatography, eluting with EtOAc/petroleum
ether (1 : 5) to give corresponding iodide (5.15 g, 98%) as pale
yellow oil: 1H NMR (CDCl3, 600 MHz) d 1.04 (d, J = 6.6 Hz, 3H),
1.04 (brm, 2H), 1.48 (brs, 12H), 1.54 and 1.42 (s, total 3H), 1.65–1.67
(m, 2H), 1.83 (brm, 1H), 2.87–2.91 (m, 1H), 3.00 (brm, 1H), 3.64–3.96
(brm, overlapped, 5H).
21.3 (CH3CH), 23.2 (CH3CH), 27.0 (
((CH3)3COC=O), 41.0 (
), 27.2 (
), 42.0 (
), 28.6
), 55.6
(
), 67.6 (
), 69.9 (OCH2Ph), 79.5 (CHOCH2Ph), 79.7
), 117.7 (CH=CH2), 127.4 (Ar CH),
((CH3)3COC=O), 93.5 (
127.6 (Ar CH), 128.3 (Ar CH), 138.6 (Ar C), 138.8(CH=CH2), 151.7
(C=O); HRESIMS calcd for C24H37NO4Na 426.2620 [M + Na]+, found
426.2633.
J. Pept. Sci. 2012; 18: 163–169 Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd. wileyonlinelibrary.com/journal/jpepsci

ZHANG ET AL.
(S)-tert-Butyl 4-((2S,4S)-4-(benzyloxy)-6-hydroxy-2-methylhexyl)-2,2-
dimethyloxazolidine-3-carboxylate (compound 8)
(
(
), 28.4 ((CH3)3COC=O), 30.4 (CH2CH3), 38.8 (
), 42.4 ( ), 55.6 ( ), 67.2 (CHOH), 67.5 (
), 39.7
BH3-THF (1.0 M in THF, 20 ml, 20 mmol) was added dropwise to a
stirred solution of compound 7 (4.04 g, 10 mmol) in 20 ml of THF
at 0 ꢀC. After the reaction mixture had been stirred at room temper-
ature for 2 h, phosphate buffer solution (pH = 9.2) was added until
the pH was 9.0. Then 15 ml of H2O2 (30%) was added, and the
mixture was stirred at room temperature overnight. The reaction
mixture was extracted with EtOAc. The combined organic phase
was washed with saturated Na2S2O3 and brine, dried over Na2SO4,
and concentrated. Flash chromatography (EtOAc: petroleum
ether = 1 : 4 ! 1 : 2) gave primary alcohol 8 (1.87 g, 44%) as a
colorless oil: [a]2D0 = 39.1 (c 0.3, CHCl3); 1H NMR (CDCl3, 600 MHz) d
0.95 (d, J =6.6 Hz, 3H, CH3CH), 1.45–1.85 (brm, overlapped, 22H,
),
),
69.8 (CHOBn), 70.9 (PhCH2O), 79.6 ((CH3)3COC=O), 93.6 (
127.9 (Ar CH), 128.1 (Ar CH), 128.4 (Ar CH), 138.1 (Ar C), 151.6 (C=O);
HRESIMS calcd for C26H44NO5 450.3220 [M + H]+, found 450.3237.
(2S,4S,6S)-Methyl 6-(benzyloxy)-2-(tert-butoxycarbonylamino)-4-methyl-8-
oxodecanoate (compound 11)
Freshly prepared Jones reagent (~2.67 M, 3.6 ml, 9.6 mmol) was
added at 0 ꢀC to a solution of compound 9 (1.10 g, 2.4 mmol) in
25 ml of acetone. The reaction mixture was stirred at 0 ꢀC for
2 h and then stirred overnight at room temperature. A saturated
solution of NaHCO3 was added to obtain a pH value of 5–6. The
aqueous phase was then extracted with Et2O, and the combined
organic extracts were washed with brine, dried over Na2SO4, and
concentrated to give the crude carboxylic acid 10 (890 mg, 88%),
which was used for the next step directly.
), 3.66–3.89 (brm, 6H,
), 4.48 (d,
J = 11.4 Hz, 1H, PhCHaHb), 4.59 (d, J = 11.4Hz, 1H, PhCHaHb),
7.28–7.34 (m, 5H, Ar H); 13C NMR (CDCl3, 150 MHz) d 21.5 (CH3CH),
The crude acid obtained above was treated with 2 eq. of diazo-
methane in Et2O for 30 min. A few drops of HOAc were added
carefully when TLCs showed that all of the acid was consumed.
The reaction mixture was diluted with Et2O, washed with water,
saturated aqueous NaHCO3 and brine, dried over Na2SO4, and
concentrated in vacuo. The residue was purified by flash silica
gel chromatography, eluting with EtOAc/petroleum ether (1 : 10)
to give ester 11 (727 mg, 79%) as a colorless oil: [a]2D0 = 55.2
(c 0.07, CHCl3); 1H NMR (CDCl3, 600 MHz) d 0.96 (d, J = 6.6 Hz,
3H, 4-CH3), 1.05 (t, J = 7.2 Hz, 3H, H-10), 1.33–1.38 (m, 1H, H-5a),
1.44 (s, 9H, Boc), 1.49–1.58 (m, 3H, H-5b + H-3), 1.68–1.74 (m, 1H,
H-4), 2.449 (q, J = 7.2 Hz, 1H, H-9a), 2.453 (q, J = 7.2 Hz, 1H, H-9b),
2.49 (dd, J = 15.6, 5.4 Hz, 1H, H-7a), 2.75 (dd, J = 16.2, 6.6 Hz, 1H,
H-7b), 3.71 (s, 3H, CO2CH3), 3.98 (quintet, J = 6.2 Hz, 1H, H-6), 4.30
(dt, J = 9.6, 3.8 Hz, 1H, H-2), 4.45 (d, J = 11.4 Hz, 1H, PhCHaHbO),
4.50 (d, J = 11.4 Hz, 1H, PhCHaHbO), 4.74 (d, J = 9.0 Hz, 1H, NH),
7.29–7.37 (m, 5H, Ar H); 13C NMR (CDCl3, 150 MHz) d 7.6 (C-10),
19.6 (4-Me), 26.1 (C-4), 28.3 ((CH3)3COC=O), 37.3 (C-9), 39.3 (C-3),
42.6 (C-5), 47.4 (C-7), 51.5 (C-2), 52.2 (CO2CH3), 71.4 (PhCH2O),
73.2 (C-6), 79.8 ((CH3)3COC=O), 127.8 (Ar CH), 128.0 (Ar CH),
128.4 (Ar CH), 138.2 (Ar C), 155.6 ((CH3)3COC=O), 173.8 (C-1),
210.2 (C-8); HRESIMS calcd for C24H37NO6Na 458.2519 [M + Na]+,
found 458.2535.
23.2 (CH3CH), 27.0 (
), 27.5 (
), 28.4 ((CH3)3COC=O),
),
), 70.7 (OCH2Ph), 76.5 (CHOCH2Ph), 80.0
), 127.8 (Ar CH), 128.0 (Ar CH), 128.5
36.0 (CHCH2CH), 40.7 (CHCH2CH), 42.4 (CHCH2CH), 55.6 (
60.5 (CH2OH), 67.5 (
((CH3)3COC=O), 93.6 (
(Ar CH), 138.4 (Ar C), 152.1 (C=O); HRESIMS calcd for C24H39NO5Na
444.2726 [M + Na]+, found 444.2743.
(S)-tert-Butyl 4-((2S,4S)-4-(benzyloxy)-6-hydroxy-2-methyloctyl)-2,2-dimethy-
loxazolidine-3-carboxylate (compound 9)
A solution of DMSO (1.1 ml, 15.6 mmol) in DCM (10 ml) was added
dropwise to a stirred solution (COCl)2 (660 ml, 7.8 mmol) in DCM
(90 ml) at ꢁ78 ꢀC. Twenty minutes later, a solution of the primary
alcohol 8 (1.63 g, 3.9 mmol) in 15 ml of DCM was added dropwise
via syringe. The mixture was stirred for 2 h, and then TEA (3.0 ml,
21.6 mmol) was added. The reaction mixture was stirred at
ꢁ78 ꢀC for 15 min and then warmed to room temperature. The
mixture was diluted with 80 ml of 10% NaHSO4 solution and then
extracted with Et2O. The combined organic layers were washed
with water and brine and concentrated to give the crude alde-
hyde, which was used for the next steps without further
purification.
Acknowledgements
To the solution of the aldehyde obtained above in dry Et2O (20ml)
at 0 ꢀC was added ethylmagnesium bromide (3.0 M in Et2O, 2.6 ml,
7.8 mmol). The mixture was stirred at 0 ꢀC for 30min and then at
room temperature for 1 h. The reaction was quenched by the addi-
tion of saturated NH4Cl solution and diluted with Et2O. After washing
with brine and drying over Na2SO4, the ether layer was concentrated.
Flash chromatography gave compound 9 (1.22 g, 70% for two steps)
as a colorless oil: [a]D20 =12.7 (c 0.2, CHCl3); 1H NMR (CDCl3,
600 MHz) d 0.92 (t, J= 7.5 Hz, 3H, CH3CH2), 0.95 (d, J= 6.6 Hz, 3H,
This work was supported by the National Natural Science Foundation
of China (81001392), the Fundamental Research Funds for the
Central Universities (10FX070), and the School of Pharmacy, Fudan
University.
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J. Pept. Sci. 2012; 18: 163–169 Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd. wileyonlinelibrary.com/journal/jpepsci