Synthesis of the unusual α-amino acid component of some novel histone deacetylase inhibiting cyclic peptides

Article abstract of DOI:10.1016/j.tet.2014.07.045

A flexible protocol for the synthesis of three lipophilic α-amino acid components of some novel cyclic peptides having important histone deacetylase inhibiting properties has been developed from a common source, which featured a cross-metathesis reaction

Full text of DOI:10.1016/j.tet.2014.07.045

Tetrahedron 70 (2014) 7185e7191
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of the unusual a-amino acid component of some novel
histone deacetylase inhibiting cyclic peptides
*
Amit K. Pahari, Jyoti Prasad Mukherjee, Shital K. Chattopadhyay
Department of Chemistry, University of Kalyani, Kalyani 741235, West Bengal, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 April 2014
Received in revised form 1 July 2014
Accepted 9 July 2014
Available online 15 July 2014
A flexible protocol for the synthesis of three lipophilic a-amino acid components of some novel cyclic
peptides having important histone deacetylase inhibiting properties has been developed from a common
source, which featured a cross-metathesis reaction between two unhindered terminal olefins as the key
step.
Ó 2014 Elsevier Ltd. All rights reserved.
This work is respectfully dedicated to fond
memories of my mentor Late Professor A.
McKillop
Keywords:
a
-Amino acid
Cyclic peptides
Cross-metathesis
Histone deacetylase inhibitor
Chiral pool
1. Introduction
a common synthetic entry into Aoe or Aoda with additional op-
portunity of incorporation of skeletal diversity remains important.
Several members of an interesting family1 of cyclic tetrapeptides
contain a lipophilic amino acid, such as 2-amino-8-oxodecanoic
acid (Aoda) or (2S,9S)-2-amino-8-oxo-9,10-epoxydecanoic acid
(Aoe) as an unusual component of their structure. Typical examples
include apicidines2 (1, 2), microsporin3 (3), trapoxin4 (4), HC-toxin5
(5) etc. (Fig. 1), which display useful levels of histone deacetylase
inhibition activity and a great deal of attention is currently being
expended on the discovery of new inhibitor (HDACi) designs.6 In
the quest for more selective HDACi, hybrid structures accommo-
dating structural features of different subclasses, e.g., CHAP 31 (6)
have also been targeted.7 It has been suggested8 that the terminal
carbonyl group in members of this family functionally mimics the
C-8 keto group of the acetylated lysine residue (7) of histones and
additional substituents, such as epoxide (as in Aoe) or an alkyl
group (as in Aoda) control the reversibility/irreversibility of in-
hibition. Because of the fascinating biological activity associated
with the molecules, many elegant reports on the synthesis of the
individual members of the family of natural products3,9 and/or the
unusual amino acid component10 have emerged. However,
Herein, we report the synthesis of Aoe, Aoda and a related
acid from a common source.
a-amino
2. Results and discussion
We argued that a successful cross-metathesis (CM) reaction11
between two suitably substituted C-6 olefins would install the 10-
carbon framework of Aoe, Aoda and related amino acids.9f Thus, we
identified the glutamic acid-derived terminal olefin 11 (Scheme 1)
as one such C-6 olefin with which cross metathesis of either of the
other C-6 olefins 14,16 or 22 would deliver the desired amino acids.
We therefore focused on the preparation of these sub-units.
Thus, the known12 glutamic acid-derived aldehyde 8 on Wittig
methylenation followed by one-pot conversion of the oxazolidine
unit in the resulting olefin 9 into an a-amino-carboxylic acid unit
involving deprotectioneoxidation sequence produced the carbox-
ylic acid 10 in good yield. Esterification of the latter with methyl
iodide under conventional conditions led quick access to the de-
sired C6 fragment 11 in an overall yield of 38.6% over three steps.
The CM partner 14 was prepared by allylation of propionaldehyde
(12) with allylzinc bromide [prepared in situ by treatment of allyl
bromide with zinc powder].
* Corresponding author. Fax: þ91 33 25828282; e-mail address: skchatto@yahoo.
com (S.K. Chattopadhyay).
http://dx.doi.org/10.1016/j.tet.2014.07.045
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

7186
A.K. Pahari et al. / Tetrahedron 70 (2014) 7185e7191
R1
R1
CH2Ph
O
N
O
O
O
N
R2
R3
O
O
N
H
N
N
H
N
H
NH
H
N
NH
O
NH
O
H
H
N
n
N
n
N
O
O
O
OMe
O
O
O
O
O
4, Trapoxin A, R1 = R2 = Bn, R3 = H
5, HC-Toxin C, R1 = R3 =Me, R2 = H
1, Apicidin B, n = 1, R1=CH(CH3)Et
2, Apicidin C, n = 2, R1=CHMe2
3, Microsporin A
O
N
O
O
N
H
N
H
N
H
H
OMe
OH
NH
O
H
8
O
N
N
H
O
O
N
7
O
6, CHAP 31
Fig. 1. Structures of some naturally occurring histone deacetylase inhibitors.
RO2C
i
ii
O
O
O
NBoc
NHBoc
NBoc
10, R = H
11
iii
, R = Me
9
8
OBn
OH
v
iv
O
14
12
13
vi
CONHOBn
CO2H
15
16
OH
O
O
ix
vii
HO
viii
O
O
OBn
OH
OH
OBn
19
17
18
O
OTs
x
xi
TBDMSO
TBDMSO
OBn
OBn
OBn
21
22
20
Scheme 1. Reagents: (i) MePh3PBr, n-BuLi, THF, 0 ꢀC, 3 h, 83%; (ii) chromic acid, acetone, 2 h, 64%; (iii) Cs2CO3, CH3I, DMF, 12 h, 75%; (iv) Zn-dust, allyl bromide, NH4Cl; (v) NaH, BnBr,
45% over two steps; (vi) NH2OBn$HCl, NMM, HOBt, EDC, 94%; (vii) NaH, benzyl bromide, 91%; (viii) 6(N) HCl, THF, 79%; (ix) imidazole, DMAP, TBDMSCl, DCM, 8 h, 84%; (vi) DMAP, p-
TSCl, pyridine, 24 h, 86%; (vii) TBAF, THF, 1 h, 74%.
The resulting secondary alcohol 13 was used without purifi-
cation in the subsequent benzylation reaction. The O-benzyl
ether 14 was obtained in a yield of 45% over two steps.
Conversion of 5-hexenoic acid (15) into its hydroxamate 16 was
achieved by treatment of the former with O-benzylhydroxylamine
in the presence of DCC & HOBt using N-methylmorpholine as
a base. The remaining CM partner 22 was prepared from the
known13 homoallyl alcohol 18 derived from (R)-2,3-O-cyclo-
hexylidene-glyceraldehyde. Thus, benzylation of the secondary al-
cohol 17 leading to 18 followed by cleavage of the dioxolane moiety

A.K. Pahari et al. / Tetrahedron 70 (2014) 7185e7191
7187
in the latter resulted in the formation of the diol 19. The latter was
selectively silylated at the primary hydroxyl function leading to 20
and subsequently the secondary-OH was O-tosylated to get the
triply protected triol derivative 21. Removal of the TBDMS group
using TBAF resulted in the concomitant formation of the epoxide
ring perhaps involving intramolecular displacement of the OTs-
group by the in situ generated alkoxy anion. The five step se-
quence proceeded in an overall yield of 38%.
concomitant removal of the O-benzyl group to provide the desired
product 28 in an overall yield of 55% over two steps. Analogously,
cross metathesis of 11 with the epoxy-olefin 22 provided the CM
product 29, also as a mixture of geometric isomers. This was then
hydrogenated into the epoxy alcohol 30. The latter was used as such
in the subsequent oxidation reaction leading to the desired Aoe
derivative 31 in an overall yield of 32% over three steps.
MeO2C
MeO2C
ii
i
11 14
+
NHBoc
OH
NHBoc
OBn
24
25
MeO2C
iii
NHBoc
O
26
MeO2C
MeO2C
i
ii
11
CONHOBn
16
22
+
+
CONHOH
O
NHBoc
NHBoc
27
28
O
MeO2C
MeO2C
i
ii
11
NHBoc
OBn
NHBoc
OH
29
30
O
iii
MeO2C
NHBoc
O
31
Scheme 2. Reagents and conditions: (i) Grubbs’ catalyst 23 (5 mol %), CuI (10 mol %), CH2Cl2, reflux, 4 h, 54% (24), 62% (27), 52% (29). (ii) H2, Pd(OH)2, THF/MeOH, 2 h, 85% (25), 88%
(28), 79% (30). (iii) DesseMartin periodinane, CH2Cl2, 1 h, 78% (26), 62% (31).
Having all four CM ingredients (11, 14, 16, 22) in hand, we then
focused on their union. Cross-metathesis of terminal and un-
hindered olefins (i.e., not having a bulky functionality on the allylic
carbon) [Category ‘A’ according to Grubbs’ classification14] is
known to be statistical in nature and several methodological de-
velopments have emerged for yield improvement.15 We tried some
of these most successful conditions for the CM between the olefins
11 and 14 using Grubbs’ first and second generation catalysts.
However, the desired conversion to 24 (Scheme 2) was obtained in
<20% yield in most of the cases. Pleasingly, the yield of 24 could be
improved up to 54% when Grubbs’ second-generation catalyst16
benzylidene[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene
]dichloro-(tricyclohexylphosphine)ruthenium (23) was used in the
presence of CuI as an additive.17 However, several attempts to im-
prove the yield further were fruitless. Since the product was an
epimeric mixture, it could not be ascertained whether it also con-
sisted of geometric isomers. However, geometric isomerism was
not considered important since the isomeric identity will be lost in
the subsequent hydrogenation step. The CM-product 24 on hy-
drogenation led to saturation of the double bond with concomitant
deprotection of the OBn-group as expected. The resulting 2ꢀ-alco-
hol 25 was then oxidized with DesseMartin periodinane to obtain
the Aoda derivative 26. Similarly, CM between the olefins 11 & 16
under the developed conditions provided the product olefin 27 in
slightly better yield (62%) and as one isomer. However, the nature
of the geometric isomer formed could not be ascertained since the
two olefinic protons appeared together in the 1H NMR spectrum.
Hydrogenation of the CM product 27 proceeded smoothly with
3. Conclusion
In brief, we have developed a general synthetic entry into three
lipophilic a-amino acids (26, 28, 31) from easily available starting
materials and using amino acid and carbohydrate derivatives as
source of chirality. The key step of the synthesis is a CM reaction
between two terminal olefins having remote functionality. Al-
though the yield of the CM reaction is somewhat modest, it allows
diversity creation. The prepared amino acids may prove to be bi-
ologically relevant for analogue design and the protocol may prove
to be adaptable for the synthesis of related amino acids. It may thus
complement to the existing procedures for the synthesis of such
type of compounds.3,9
4. Experimental
4.1. General
Optical rotations were recorded in spectroscopic grade chloro-
form on a Rudolph Autopol polarimeter, [
units of 10ꢁ1 deg cm2 ꢁ1. Infrared spectra were recorded on
PerkineElmer Spectrum-1 spectrophotometer purchased
a]D values are recorded in
g
a
through a DST-FIST grant. Proton and carbon NMR spectra were
recorded on a Bruker DRX-400 spectrometer and the chemical
shifts are recorded relative to residual solvent or TMS as standard.
Data for the rotamers are given in parentheses. Mass spectra were
recorded on a JEOL-JMS 600 instrument from I. I. C. B., Kolkata or
IACS, Kolkata. Petroleum ether refers to the fraction boiling in the

7188
A.K. Pahari et al. / Tetrahedron 70 (2014) 7185e7191
range 60e80 ꢀC. Silica gel (120e200 mesh) for column chroma-
1.76e1.67 (1H, m), 1.44 (9H, s). 13C NMR (100 MHz, CDCl3):
d 173.3,
tography was purchased from Spectrochem, India.
155.3, 136.9, 115.6, 79.8, 52.9, 52.2, 31.9, 29.4, 28.2. m/z (TOF MS
ESþ) 266 ([MþNa]þ). Elemental analyses: C, 59.13%; H, 8.50%; N,
5.89%; C12H21NO4 requires C, 59.24%; H, 8.70%; N, 5.76%.
4.1.1. (S)-tert-Butyl 4-(but-3-enyl)-2,2-dimethyloxazolidine-3-
carboxylate (9). n-BuLi (2 M in hexane, 0.5 ml) was added drop-
wise over 10 min to a stirred suspension of the Wittig salt
(MePh3PþBrꢁ) (416 mg, 1.16 mmol) in dry THF (8 ml) at 0 ꢀC under
argon atmosphere and the resulting solution was allowed to come
to room temperature over 30 min when the solution turned deep
yellow. It was cooled back to 0 ꢀC and then a solution of the alde-
hyde 8 (200 mg, 0.78 mmol) in THF (8 ml) was added dropwise over
15 min while stirring. It was stirred for 30 min and then allowed to
come to room temperature and stirring was continued for 3 h. The
reaction mixture was then quenched with aqueous NH4Cl solution
(10 ml) and extracted with ethyl acetate (2ꢂ25 ml). The combined
organic extract was washed successively with water (1ꢂ25 ml) and
brine (1ꢂ25 ml), and then dried over MgSO4. It was then filtered
and the filtrate was concentrated in vacuo to leave the crude
product, which was purified by flash chromatography over silica gel
4.1.4. 3-Benzyloxy-hex-5-ene (14). Zn-dust (1.79 g, 27.4 mmol)
followed by allyl bromide (2.2 ml, 26 mmol) were added to a cold
(w10 ꢀC) and well-stirred solution of propionaldehyde (1 ml,
13.7 mmol), in tetrahydrofuran (5 ml) and then a saturated aqueous
solution of NH4Cl (10 ml) was added dropwise over a period of
30 min. The reaction mixture was then stirred at ambient tem-
perature for 5 h until the aldehyde was totally consumed. The
mixture was then filtered and the precipitate was washed thor-
oughly with ether. The combined filtrate was then diluted with
water (10 ml) and extracted with ether (2ꢂ20 ml). The combined
organic layer was washed successively with HCl (5%, 10 ml), water
(2ꢂ10 ml) and brine (10 ml). It was then dried (MgSO4), filtered and
the filtrate was reduced to w2 ml and the resulting solution of the
crude allyl alcohol 13 was cooled to 0 ꢀC under nitrogen. NaH
(672 mg, 28 mmol) was added portionwise to it and then benzyl
bromide (1.7 ml, 14 mmol) was added dropwise over 15 min. The
reaction mixture was stirred at the same temperature for 12 h. It
was quenched with saturated NH4Cl solution (10 ml) at 0 ꢀC and
then diluted with ether (1ꢂ25 ml). The organic phase was washed
with water (20 ml) and brine (20 ml), and then dried over MgSO4. It
was then filtered and the filtrate was concentrated at reduced
pressure to leave a crude product, which on chromatography over
silica gel using ethyl acetate/hexane mixture (1:49) afforded the
benzyl ether 14 as a colourless liquid (1.2 g, 45% over two steps). IR
using a mixture of ethyl acetate/hexane (1:10) to give the product 9
25
as a colourless oil (168 mg, 83%). [
a]
þ5.6 (c 0.28 in CHCl3). IR
D
(neat): 2980, 1698, 1389, 1366, 1176, 1095 cmꢁ1. 1H NMR (400 MHz,
CDCl3):
5.83e5.79 (1H, m), 5.05 (1H, dd, J¼1.6, 17.2 Hz), 4.98 (1H,
d
d, J¼9.2 Hz), 3.93e3.90 (1H, m), 3.79e3.68 (2H, m), 2.06e2.01 (2H,
m), 1.59 (2H, d, J¼1.8 Hz), 1.47 (9H, s), 1.33 (3H, s), 1.21 (3H, s). 13
C
NMR (100 MHz, CDCl3): d 152.1, 137.8, 115.0 (114.9), 93.6 (93.1), 79.9
(79.4), 66.8 (66.6), 57.2 (56.8), 32.6 (31.9), 30.5, 28.4, 27.5 (26.7),
24.5 (23.2). m/z (TOF MS ESþ) 278 ([MþNa]þ). Elemental analyses:
C, 65.77%; H, 9.75%; N, 5.58%; C14H25NO3 requires C, 65.85%; H,
9.87%; N, 5.49%.
.
(neat): 2933, 1093, 1067, 735 cmꢁ1 1H NMR (400 MHz, CDCl3):
d
7.36e7.25 (5H, m), 5.91e5.80 (1H, m), 5.11e5.04 (2H, m), 4.55 (1H,
4.1.2. (S)-2-(tert-Butoxycarbonylamino)hex-5-enoic acid (10). An
aqueous solution of chromic acid (3 ml, 8 equiv) was added drop-
wise to a vigorously stirred solution of 9 (200 mg, 0.76 mmol) in
acetone (8 ml) and stirring was continued for 2 h at room tem-
perature. The reaction mixture was then partitioned between water
(25 ml) and ether (25 ml). The organic layer was washed succes-
sively with water (3ꢂ20 ml), brine (20 ml) and then dried over
MgSO4. It was filtered and the filtrate was concentrated to leave the
crude product as a yellowish oil, which on chromatography over
d, J¼11.9 Hz), 4.51 (1H, d, J¼12.0 Hz), 3.38 (1H, quin., J¼6.0 Hz),
2.36e2.28 (2H, m), 1.60e1.53 (2H, m), 0.95 (3H, t, J¼7.2 Hz). 13C
NMR (100 MHz, CDCl3): d 138.9, 135.1, 128.3, 127.7, 127.4, 116.8, 79.8,
70.9, 37.9, 26.3, 9.6. m/z (TOF MS ESþ) 213 ([MþNa]þ). Elemental
analyses: C, 82.27%; H, 9.69%. C13H18O requires C, 82.06%; H, 9.53%.
4.1.5. N-(Benzyloxy)hex-5-enamide
(16). N-Methylmorpholine
(230 l, 2.0 mmol) was dropwise added to a stirred solution of O-
m
benzylhydroxylamine hydrochloride (160 mg, 1.0 mmol) in anhy-
drous CH2Cl2 (12 ml) at 0 ꢀC under N2 atmosphere. The resulting
mixture was stirred for 10 min and then hexenoic acid 15 (115 mg,
1.0 mmol) and HOBt (135 mg, 1.0 mmol) were added sequentially
and stirring was continued for another 15 min at the same tem-
perature. EDC$HCl (230 mg, 1.2 mmol) was then added in one
portion and the reaction mixture was stirred for 45 min more be-
fore being allowed to come to room temperature over 2 h. It was
then diluted with CH2Cl2 (20 ml) and the combined organic solu-
tion was washed sequentially with saturated aqueous solution of
NaHCO3 (20 ml), HCl (3%, 20 ml), H2O (25 ml) and brine (25 ml). It
was then dried over MgSO4, filtered and the filtrate was concen-
trated in vacuo to leave the crude product as a light yellow liquid,
which was purified by column chromatography over silica gel using
petroleum ether/ethyl acetate (6:4) as eluent to provide the prod-
uct 16 as a colourless viscous liquid (206 mg, 94%). IR (neat): 3199,
silica using a mixture of petroleum ether/ethyl acetate (1:1) as el-
25
uent afforded the product 10 as a colourless oil (112 mg, 64%). [a]
D
þ17.4 (c 0.57 in CHCl3). IR (neat): 3370, 2925, 1694, 1367, 1168 cmꢁ1
.
1H NMR (400 MHz, CDCl3):
d 5.85e5.77 (1H, m), 5.16e5.00 (3H, m),
4.33 (1H, br s), 4.02e4.01 (1H, m), 2.23e2.14 (2H, m), 1.97 (1H, br s),
1.79e1.73 (1H, m), 1.45 (9H, s). 13C NMR (100 MHz, CDCl3):
d
177.3
(177.0), 156.0 (155.6), 136.8, 115.8, 80.2 (54.0), 53.0, 31.6, 29.4, 28.3.
HRMS (TOF MS ESþ) calcd for C11H19NO4 ([MþNa]þ) 252.1212,
found 252.1210.
4.1.3. (S)-Methyl 2-(tert-butoxycarbonylamino)hex-5-enoate
(11). Methyl iodide (0.08 ml, 1.3 mmol) was added dropwise to
a stirred solution of 10 (100 mg, 0.43 mmol) in dry DMF (4 ml) at
0
ꢀC under nitrogen atmosphere in the presence of anhydrous
Cs2CO3 (275 mg, 0.84 mmol) and stirring continued for 12 h at room
temperature. It was then diluted with water (25 ml) and extracted
with ethyl acetate (2ꢂ25 ml). The combined organic layer was
washed successively with water (2ꢂ25 ml) and brine (25 ml). The
organic extract was then dried over anhydrous MgSO4, filtered and
the filtrate was concentrated in vacuo to leave a crude product,
which was purified by column chromatography on silica gel using
ethyl acetate in petroleum ether (1:9) solvent to provide the
3032, 2935, 1655, 1498, 1456 cmꢁ1. 1H NMR (400 MHz, CDCl3):
d 8.4
(1H, s), 7.44e7.38 (5H, m), 5.77e5.71 (1H, m), 5.00e4.96 (2H, m),
4.90 (2H, s), 2.07e2.05 (4H, m), 1.72 (2H, t, J¼7.2 Hz). 13C NMR
(100 MHz, CDCl3):
d 171.1, 137.8, 135.5, 129.1, 128.5, 128.4, 115.3,
78.0, 33.0, 32.3, 24.6. HRMS (TOF MS ESþ) calcd for C13H17NO2
([MþNa]þ) 242.1157, found 242.1157.
compound 11 as a liquid (80 mg, 75%). [
a
]
D
25 þ13.8 (c 0.98 in CHCl3).
4.1.6. (R)-2-((S)-1-(Benzyloxy)but-3-enyl)-1,4-dioxaspiro[4.5]decane
(18). NaH (60%, 306 mg, 7.7 mmol) was added portionwise to
a solution of the compound 17 (810 mg, 3.8 mmol) in DMF (6 ml) at
0 ꢀC during 10 min. Benzyl bromide (0.81 ml, 6.8 mmol) was then
IR (neat): 3370, 2979, 1744, 1716, 1367, 1164 cmꢁ1
.
1H NMR
(400 MHz, CDCl3):
d 5.82e5.75 (1H, m), 5.07e4.99 (3H, m), 4.33
(1H, d, J¼4.8 Hz), 3.74 (3H, s), 2.14e2.09 (2H, m), 1.93e1.88 (1H, m),

A.K. Pahari et al. / Tetrahedron 70 (2014) 7185e7191
7189
added dropwise and the resulting mixture was stirred for 12 h. It
was then slowly quenched with saturated aqueous NH4Cl solution
(10 ml) at 0 ꢀC and then diluted with ether (2ꢂ50 ml). The com-
bined organic phase was washed with water (2ꢂ25 ml) and brine
(2ꢂ25 ml), dried over MgSO4 and concentrated at reduced pressure
to leave a residue, which was purified by chromatography over
(1ꢂ20 ml), water (1ꢂ25 ml) and brine (1ꢂ25 ml) and then dried
over anhydrous MgSO4. It was filtered and the filtrate was con-
centrated in vacuo to get a residue, which was purified by silica gel
chromatography using a mixture of ethyl acetate/hexane (3:97) to
yield the corresponding tosylate 21 as a colourless viscous liquid
25
(325 mg, 86%). [
a]
ꢁ4.8 (c 3.57 in CHCl3). IR (neat): 2857, 2929,
D
silica gel using ethyl acetate/hexane mixture (2:98) to afford 18 as
1363, 1189, 1177, 1097 cmꢁ1. 1H NMR (400 MHz, CDCl3):
d 7.79e7.77
25
colourless liquid (1.04 g, 91%). [
a]
þ26.2 (c 0.92 in CHCl3). IR
(2H, d, J¼8.4 Hz), 7.33e7.25 (7H, m), 5.80e5.69 (1H, m), 5.08e5.03
(2H, m), 4.59e4.46 (3H, m) 3.90e3.76 (3H, m), 2.40 (3H, s),
2.33e2.22 (2H, m), 0.84 (9H, s), ꢁ0.001 (6H, s). 13C NMR (100 MHz,
D
(neat): 2935, 2862, 1449, 1164, 1101 cmꢁ1
.
1H NMR (400 MHz,
CDCl3): 7.33e7.25 (5H, m), 5.95e5.84 (1H, m), 5.16e5.08 (2H, m),
d
4.66 (1H, d, J¼11.2 Hz), 4.58 (1H, d, J¼11.2 Hz), 4.08 (1H, q, J¼6 Hz),
4.03e4.01 (1H, m), 3.89 (1H, dd, J¼6, 8 Hz), 3.59 (1H, q, J¼5.2 Hz),
2.47e2.32 (2H, m), 1.62e1.55 (8H, m), 1.39 (2H, br s). 13C NMR
CDCl3): d 144.6, 138.0, 134.2, 134.1, 129.7, 128.3, 128.0, 127.8, 127.7,
117.7, 83.2, 77.5, 72.7, 61.2,35.2, 25.9, 21.6, 18.3, ꢁ5.4, ꢁ5.5. HRMS
(TOF MS ESþ) calcd for C26H38O5SSi ([MþNa]þ) 513.2107, found
513.2106.
(100 MHz, CDCl3):
d 138.4, 134.3, 128.3, 127.8, 127.6, 117.5, 109.6,
79.0, 77.3, 72.5, 66.1, 36.3, 35.7, 34.9, 25.2, 24.0, 23.8. m/z (TOF MS
ESþ) 325 ([MþNa]þ). Elemental analyses: C, 75.59%; H, 8.50%.
4.1.10. (S)-2-((S)-1-(Benzyloxy)but-3-enyl)oxirane (22). A solution
of n-tetrabutylammonium fluoride (346 mg, 1.32 mmol) in anhy-
drous THF (2 ml) was added in one portion to a cooled stirred so-
lution of the silyl ether 21 (325 mg, 0.66 mmol) in anhydrous THF
(8 ml) and stirring was continued for 1 h at room temperature. The
reaction was quenched by adding a solution of NH4Cl (200 mg in
20 ml water) with continuous stirring and then diluted with ether
(25 ml). The combined organic extract was washed with brine
(25 ml) and then dried over anhydrous MgSO4. It was filtered and
the filtrate was concentrated in vacuo to leave a crude mass, which
was purified by silica gel chromatography using a mixture ethyl
acetate/hexane mixture (2:98) to yield the corresponding epoxide
C
19H26O3 requires C, 75.46%; H, 8.67%.
4.1.7. (2R,3S)-3-(Benzyloxy)hex-5-ene-1,2-diol (19). HCl (6 N, 10 ml)
was added dropwise to a solution of the acetal 18 (1.0 g, 3.31 mmol)
in THF (10 ml) at 0 ꢀC while stirring and the resulting mixture was
stirred for 3 h before being diluted with water (50 ml) and then
carefully neutralized with NaHCO3. It was then extracted with
CH2Cl2 (2ꢂ50 ml) and the combined organic extract was washed
successively with water (2ꢂ50 ml), brine (1ꢂ50 ml), and dried over
MgSO4. It was then filtered and the filtrate was concentrated in
vacuo to leave a pale yellow mass, which was purified by chro-
matography over silica gel using ethyl acetate/hexane mixture
22 as a colourless liquid (100 mg, 74%). [
a]
25 ꢁ26.4 (c 0.47 in CHCl3).
D
25
(60:40) to provide 19 (583 mg, 79%) as a colourless liquid. [
a
]
IR (neat): 2926, 1641, 1454, 1094, 1071 cmꢁ1
.
1H NMR (400 MHz,
D
þ31.9 (c 0.66 in CHCl3). IR (neat): 3401, 2928, 1641, 1454, 1089,
CDCl3): d 7.35e7.25 (5H, m), 5.96e5.85(1H, m), 5.17e5.09 (2H, m),
1073 cmꢁ1 1H NMR (400 MHz, CDCl3):
.
d
7.37e7.25 (5H, m),
4.64 (1H, d, J¼12.0 Hz), 4.54 (1H, d, J¼12.0 Hz), 3.36e3.31(1H, m),
5.92e5.82 (1H, m), 5.18e5.09 (2H, m), 4.68 (1H, d, J¼11.2 Hz), 4.51
(1H, d, J¼11.2 Hz), 3.79e3.70 (3H, m), 3.65 (1H, q, J¼5.6 Hz), 2.50
(1H, br s), 2.47e2.43 (2H, m), 2.20 (1H, br s). 13C NMR (100 MHz,
2.98e2.95 (1H, m), 2.78 (1H, dd, J¼4.0, 5.2 Hz), 2.72 (1H, dd, J¼2.8,
5.2 Hz), 2.50e2.37 (2H, m). 13C NMR (100 MHz, CDCl3):
d 137.9,
133.4, 127.8, 127.1, 127.1, 116.9, 77.2, 71.6, 52.6, 45.1, 36.7. HRMS (TOF
CDCl3):
d
137.9, 134.2, 128.5, 127.9, 127.8, 117.8, 80.4, 72.5, 72.3, 63.3,
MS ESþ) calcd for C13H16O2 ([MþNa]þ) 227.1048, found 227.1047.
35.0. m/z (TOF MS ESþ) 245 ([MþNa]þ). Elemental analyses: C,
70.36%; H, 8.01%. C13H18O3 requires C, 70.24%; H, 8.16%.
4.1.11. General procedure for cross metathesis. Grubbs’ second-
generation catalyst 23 (14 mg, 0.016 mmol) was added to a stir-
red suspension of CuI (6 mg, 0.032 mmol) in a solution of the olefin
11 (80 mg, 0.328 mmol) and appropriate second olefin 14/16/22
(0.328 mmol) in dry DCM (6.0 ml) under argon atmosphere and the
resulting mixture was stirred at room temperature for 15 min be-
fore being heated to reflux for 4 h. The reaction mixture was
allowed to cool to room temperature, a few drops of DMSO was
added and stirred for overnight. It was then concentrated in vacuo
and the residue was purified by column chromatography over silica
gel using appropriate mixture of ethyl acetate in petroleum ether
(15:85) to provide the coupled product.
4.1.8. (2R,3S)-3-(Benzyloxy)-1-(tert-butyldimethylsilyloxy)hex-5-en-
2-ol
(20). Imidazole
(244
mg,
3.58
mmol),
4-
dimethylaminopyridine (29 mg, 0.23 mmol) and tert-butyldime-
thylsilyl chloride (197 mg, 1.30 mmol) were sequentially added to
a stirred solution of the diol 19 (265 mg, 1.19 mmol) in anhydrous
CH2Cl2 (5 ml) under nitrogen at room temperature. Stirring was
continued for 8 h, and then the solution was diluted with ether
(25 ml). The combined organic extract was washed with 1(N) HCl
(1ꢂ20 ml), water (1ꢂ20 ml), brine (1ꢂ20 ml), and then dried over
anhydrous MgSO4. It was then filtered and the filtrate was con-
centrated in vacuo. The residue was purified by silica gel chroma-
tography using a mixture of ethyl acetate/hexane (4:96) to yield the
4.1.12. (S)-Methyl 8-(benzyloxy)-2-(tert-butoxycarbonylamino)dec-
25
silyl ether 20 as a colourless liquid (342 mg, 84%). [
a
]
D
þ25.0
5-enoate (24). Eluent: ethyl acetate in petroleum ether (15:85).
25
(c 2.33 in CHCl3). IR (neat): 3470, 2929, 2858, 1254, 1096, 836 cmꢁ1
.
Yield: 72 mg, 54%. [
a
]
D
þ14.8 (c 0.88 in CHCl3). IR (neat): 3369,
1H NMR (400 MHz, CDCl3):
d
7.27e7.18 (5H, m), 5.89e5.80 (1H, m),
2931, 1745, 1717, 1366, 1168 cmꢁ1
.
1H NMR (400 MHz, CDCl3):
5.11e5.01 (2H, m), 4.57 (1H, d, J¼11.6 Hz), 4.45 (1H, d, J¼11.2 Hz)
3.70e3.66 (1H, m), 3.63e3.57 (2H, m), 3.44 (1H, dd, J¼10.4, 6.0 Hz),
2.46e2.31 (3H, m), 0.83 (9H, s), ꢁ0.001 (6H, s). 13C NMR (100 MHz,
d
7.34e7.24 (5.13H, m), 7.28e7.24 (2.63H, m), 5.51e5.37 (1.54H, m),
4.99 (1H, m), 4.55e4.47 (2.59H, m), 4.35e4.29 (1.18H, m), 3.74e3.71
(3.78H, m), 3.36e3.30 (1.18H, m), 2.28e2.24 (2.76H, m), 2.13e2.03
(1.84H, m), 1.88e1.83 (1H, m), 1.70e1.64 (1.03H, m), 1.56e1.51
(5.3H, m), 1.44e1.41 (12.2H, overlapping singlets), 0.94e0.87 (4H, t,
CDCl3): d 138.4, 134.8, 128.4, 127.9, 127.7, 117.3, 78.8, 72.5, 72.1, 63.8,
34.7, 25.9, 18.3, ꢁ5.3. HRMS (TOF MS ESþ) calcd for C19H32O3Si
([MþNa]þ) 359.2018, found 359.2016.
J¼7.6 Hz). 13C NMR (100 MHz, CDCl3):
d 173.3, 155.3, 139.0, 130.7,
128.3, 127.8, 127.7, 127.4, 80.0, 79.8, 70.8, 53.1, 52.2, 36.5, 35.7, 32.5,
32.4, 31.3, 28.5, 28.3, 26.5, 26.3, 23.3, 9.9, 9.7. HRMS (TOF MS ESþ)
calcd for C23H35NO5 ([MþNa]þ) 428.2413, found 428.2386.
4.1.9. (2R,3S)-3-(Benzyloxy)-1-(tert-butyldimethylsilyloxy)hex-5-en-
2-yl 4-methylbenzenesulfonate (21). DMAP (ca. 19 mg) followed by
tosyl chloride (295 mg, 1.54 mmol) was added to a stirred solution
of the alcohol 20 (260 mg, 0.77 mmol) in pyridine (5 ml) and the
resulting solution was stirred for 24 h at room temperature. It was
then diluted with ether (25 ml), washed successively with 6(N) HCl
4.1.13. (S)-Methyl
yamino)-10-oxodec-5-enoate (27). Eluent: ethyl acetate/petroleum
ether (4:6). Yield: 88 mg (62%). [
2-(tert-butoxycarbonylamino)-10-(benzylox-
25
a
]
þ10.1 (c 1.85 in CHCl3). IR
D

7190
A.K. Pahari et al. / Tetrahedron 70 (2014) 7185e7191
(neat): 3262, 2977, 2931, 1742, 1691, 1517, 1454, 1367 cmꢁ1. 1H NMR
(400 MHz, DMSO-d6): 10.94 (1H, s), 7.42e7.32 (5H, m), 7.26 (1H, d,
chromatography over silica gel using appropriate mixture of ethyl
acetate in petroleum ether solvent to give the desired -amino acid.
d
a
J¼8.0 Hz), 5.36e5.34 (2H, m), 4.77 (2H, s), 4.27 (1H, s), 3.61e3.60
(1H, m), 3.49 (3H, s), 1.98e1.88 (6H, m), 1.64e1.62 (2H, m), 1.52 (2H,
4.1.19. (S)-Methyl 2-(tert-butoxycarbonylamino)-8-oxodecanoate
t, J¼7.2 Hz), 1.37 (9H, s). 13C NMR (100 MHz, CDCl3):
d
173.5, 170.8,
(26). Eluent: ethyl acetate in petroleum ether (2:8). Yield: 30 mg
155.5, 135.5, 131.5, 129.4, 129.1, 128.5, 80.2, 78.0, 52.3, 52.1, 32.2,
31.6, 31.3, 28.3, 28.1, 24.6. HRMS (TOF MS ESþ) calcd for C23H34N2O6
([MþNa]þ) 457.2315, found 457.2311.
(78%). [
a]
25 þ8.5 (c 0.56 in CHCl3). IR (neat): 3374, 2977, 1744, 1717,
D
1366, 1165 cmꢁ1. 1H NMR (400 MHz, CDCl3):
d
5.01 (1H, s), 4.29 (1H,
d, J¼5.2 Hz), 3.75 (3H, s), 2.43e2.37 (4H, m), 1.78 (1H, br s),
1.59e1.55 (3H, m), 1.44 (9H, s), 1.36e1.25 (4H, m), 1.06 (3H, t,
4.1.14. (2S,8S)-Methyl 8-(benzyloxy)-2-(tert-butoxycarbonylamino)-
J¼7.6 Hz). 13C NMR (100 MHz, CDCl3):
d 211.6, 173.4, 155.3, 79.8,
53.3, 52.2, 42.1, 35.9, 32.6, 28.7, 28.3, 25.0, 23.5, 7.8. HRMS (TOF MS
8-((S)-oxiran-2-yl)oct-5-enoate (29). Eluent: ethyl acetate/petro-
leum ether (15:85). Yield: 71 mg (52%). [
a
]
25 ꢁ7.4 (c 1.01 in CHCl3).
ESþ) calcd for C16H29NO5 ([MþNa]þ) 338.1943, found 338.1951.
D
IR (neat): 3362, 2929, 1745, 1716, 1366, 1166 cmꢁ1
.
1H NMR
(400 MHz, CDCl3):
d
7.35e7.26 (7.4H, m, including peak for CHCl3),
4.1.20. (S)-Methyl 2-(tert-butoxycarbonylamino)-8-((S)-oxiran-2-
25
5.60e5.39 (2.43H, m), 5.0 (1H, br s), 4.82e4.79 (0.85H, m),
4.65e4.52 (1.85H, m), 4.30 (1H, br s), 3.73e3.72 (3.8H, overlapping
singlets), 3.30e3.26 (0.34H, m), 3.10e2.94 (2H, m), 2.78e2.70
(1.64H, m), 2.52e2.49 (1.2H, m), 2.45e2.27 (2.73H, m), 2.18e2.06
(2H, m), 1.87e1.84 (1H, m), 1.44e1.43 (12H, overlapping singlets).
yl)-8-oxooctanoate (31). Yield: 28 mg (62% over two steps). [a]
D
þ36.2 (c 0.71 in CHCl3). IR (neat): 3434, 2929, 1741, 1713, 1367,
1164 cmꢁ1. 1H NMR (400 MHz, CDCl3):
5.01 (1H, br s), 4.29 (1H, s),
d
3.73 (3H, s), 3.43 (1H, dd, J¼2.4, 4.4 Hz), 3.01 (1H, t, J¼5.2 Hz), 2.87
(1H, dd, J¼2.4, 5.6 Hz), 2.46e2.41 (1H, m), 2.32e2.29 (1H, m),
1.79e1.77 (2H, m), 1.66e1.53 (4H, m), 1.44 (9H, s), 1.39e1.25 (2H,
13C NMR (100 MHz, CDCl3):
d 173.3, 155.3, 138.5, 131.4, 128.3, 128.3,
127.7, 127.6, 127.5, 126.7, 80.2, 79.9, 77.9, 72.1, 71.6, 54.6, 53.1, 53.0,
52.2, 45.6, 43.4, 38.4, 36.0, 35.8, 32.5, 30.4, 28.5, 28.3, 23.4. HRMS
(TOF MS ESþ) calcd for C23H33NO6 ([MþNa]þ) 442.2206, found
442.2207.
m). 13C NMR (100 MHz, CDCl3):
d 207.7, 173.4, 155.4, 79.9, 53.4, 53.3,
52.3, 46.1, 36.3, 32.5, 28.6, 28.3, 25.0, 22.5. HRMS (TOF MS ESþ)
calcd for C16H27NO6 ([MþNa]þ) 352.1736, found 352.1738.
Acknowledgements
4.1.15. General procedure for hydrogenation. Appropriate CM
product (0.14 mmol) was taken in a mixture of THF and MeOH (1:1,
4 ml) containing 1 drop of TFA. Then Pd(OH)2 (10 mg) was added
and the solution was degassed several times. Hydrogen gas was let
in and the resulting heterogeneous mixture was vigorously stirred
at atmospheric pressure for 2 h. It was filtered through CeliteÒ, the
filter cake was washed with methanol (5 ml) and the combined
filtrate was concentrated in vacuo. The crude product thus obtained
was purified by chromatography over silica gel using appropriate
mixture of ethyl acetate and petroleum ether as eluent.
We are thankful to Department of Science and Technology, New
Delhi, for funds (Grant No. SR/S1/OC-92/2012) and Council of Sci-
entific and Industrial Research (Grant No. 02/0164/13/EMR-II), New
Delhi, for fellowships. Partial financial supports from DST-PURSE
programme, and University of Kalyani is also gratefully
acknowledged.
Supplementary data
1H NMR and 13C NMR spectra of all new compounds are pro-
vided. Supplementary data related to this article can be found at
http://dx.doi.org/10.1016/j.tet.2014.07.045.
4 .1.16 . ( S ) - M e t hyl 2 - ( t e r t - b u t o x y c a r b o nyl a m i n o ) - 8 -
hydroxydecanoate (25). Eluent: ethyl acetate and petroleum ether
(1:3). Yield: 38 mg (85%). IR (neat): 3371, 2854, 2925, 1740, 1718,
1366, 1164 cmꢁ1. 1H NMR (400 MHz, CDCl3):
d 5.01 (1H, s), 4.30 (1H,
References and notes
s), 3.73 (3.7H, s), 3.51 (1.3H, s), 1.79 (1H, br s), 1.44e1.25 (27H, m),
0.94 (3.64H, t, J¼7.6 Hz). 13C NMR (100 MHz, CDCl3):
d 173.5, 155.4,
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ether (1:1). Yield: 42 mg (88%). [
a
]
D
25 þ5.4 (c 0.7 in CHCl3). IR (neat):
3339, 2927, 2856, 1741, 1712, 1667, 1519 cmꢁ1. 1H NMR (400 MHz,
CDCl3):
(2H, br s), 1.68 (2H, br s), 1.56e1.49 (7H, m), 1.36 (9H, s), 1.29e1.15
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173.6, 171.6, 155.6, 80.0, 53.3,
d
4.98 (1H, d, J¼6.8 Hz), 4.22 (1H, br s), 3.66 (3H, s), 2.07
d
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