Total synthesis of the antifungal antibiotic PF1163A

Article abstract of DOI:10.1016/j.tetasy.2012.05.013

The total synthesis of a novel antifungal antibiotic PF1163A is reported utilising Keck asymmetric allylation, Sharpless kinetic resolution, regioselective epoxide-ring opening, esterification and ring-closing metathesis as the key reactions.

Full text of DOI:10.1016/j.tetasy.2012.05.013

Tetrahedron: Asymmetry 23 (2012) 769–774
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Tetrahedron: Asymmetry
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Total synthesis of the antifungal antibiotic PF1163A
⇑
Palakodety Radha Krishna , Palabindela Srinivas
D-211, Discovery Laboratory, Organic and Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The total synthesis of a novel antifungal antibiotic PF1163A is reported utilising Keck asymmetric allyla-
tion, Sharpless kinetic resolution, regioselective epoxide-ring opening, esterification and ring-closing
metathesis as the key reactions.
Received 13 April 2012
Accepted 15 May 2012
Available online 15 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
RCM reaction between carbons C11–C12 rather than C7–C8 as re-
ported earlier, as the key reactions.
Recently two novel antifungal antibiotics, PF1163A 1 and
PF1163B 2 (Fig. 1), were isolated from the fermentation broth of
Penicillium sp.1a Both 1 and 2 exhibit potent growth inhibitory
activity against the pathogenic fungal strain Candida albicans and
have been shown to inhibit the biosynthetic pathway from lanos-
terol to ergosterol in Candida albicans, with the inhibiting activity
of 1 being equal to fluconazol and four times higher than 2
(Fig. 1). Sasaki et al.1b elucidated the structures of 1 and 2 by exten-
sive chemical and spectroscopic analysis. The absolute structure of
2 was unambiguously assigned by extensive spectroscopic analysis
of the degradation products and single crystal X-ray diffraction
analysis of its de-2-hydroxyethyl derivative. Similar attempts were
made to elucidate the absolute structure of 1, but its de-2-hydroxyl
ethyl derivative was obtained as an amorphous powder. The abso-
lute structure of 1 was eventually confirmed by its total synthesis.3a
The unique structural features of 1 include it having a 13-mem-
bered macrolide consisting of an ester and amide functional groups;
O
OH
3
O
N
4
2
1
5
O
6
O
13
12
R
11
8
7
9
10
R = OH, PF1163A 1
2
R = H, PF1163B
Figure 1.
2. Results and discussions
a 2-hydroxy ethyl derivative of N-methyl L-tyrosine, an isolated
From our retrosynthetic analysis (Scheme 1) it could be deduced
that 6, 11 and 17 were the key building blocks. Initially, a cross-
metathesis based approach between ester 4 and 17 was attempted
resulting in the corresponding product. However, this approach
was discontinued due to scale up problems. Alternatively, a ring-
closing metathesis (RCM) approach was envisioned. Accordingly,
fragment 6 identified as one of the key building blocks, could be vis-
ualised from compound 5 (vide infra Scheme 2) through a series of
reactions such as oxidative cleavage of the olefin, vinylation and
Sharpless kinetic resolution. Compound 5 could in turn be obtained
from commercially available n-butyraldehyde by Keck asymmetric
allylation4 followed by further transformations as reported in the
methyl stereocentre on the macrocyclic core and an aliphatic side
chain possessing one hydroxyl group. The structures of 1 and 2
are similar except for the presence of an additional hydroxyl group
in the side chain of 1; this may be responsible for the four times
higher biological activity compared to 2. This attractive biological
activity and our interest in the synthesis2 of biologically active mac-
rolide natural products prompted us to take up the synthesis of 1.
So far two syntheses3a,b have been reported for 1. In the first synthe-
sis,3a asymmetric allyltitanation and esterification were the key
steps; the second synthesis3b was accomplished by Prins cyclisation
and an RCM protocol. Herein we report the total synthesis of 1 using
Keck asymmetric allylation, Sharpless kinetic resolution, regiose-
lective epoxide-ring opening and ring-closing metathesis, and an
literature.5 The synthesis of
L-tyrosine derivative 11 started from
the known compound 7.6 In order to introduce the lone methyl ste-
reocentre of 17, we chose the known allylic alcohol 127 which upon
Sharpless asymmetric epoxidation and regioselective ring-opening
of the 2,3-epoxy alcohol with trimethyl aluminium in an SN2
fashion and further transformations of the ensuing product would
⇑
Corresponding author. Tel.: +91 4027193158.
E-mail address: prkgenius@iict.res.in (P. Radha Krishna).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.05.013

770
P. Radha Krishna, P. Srinivas / Tetrahedron: Asymmetry 23 (2012) 769–774
O
OH
O
O
N
OBn
O
O
O
O
NBoc
+
O
OH
OBn
OH
17
4
1
O
OH
OBn OH
NBoc
O
+
11
BnO
6
Scheme 1. Retrosynthetic analysis.
O
OBn
OBn OH
a
ref: 5
H
6
5
Scheme 2. Reagents and conditions. (a) (i) OsO4, NaIO4, 2,6-lutidine, 1,4-dioxane:H2O (3:1), rt, 4.5 h; (ii) vinyl magnesium bromide, dry THF, ꢀ20 °C, 1 h, 75%; (iii) (+)-DIPT,
Ti(OiPr)4, CHP, 4 Å MS, dry CH2Cl2, ꢀ20 °C, 12 h, 45%.
eventually lead to olefin 15. Deprotection of the TBDPS protecting
group in 15 would give the primary alcohol 16, which upon oxida-
tion under TEMPO and BIAB conditions would furnish the requisite
carboxylic acid 17.
(CH3I/Ag2O/DMF/rt/9 h) of compound 7 afforded 8 (85%). Oxidative
cleavage8 {NaIO4/OsO4/2,6 lutidine/1,4-dioxane:H2O (3:1)/ rt/4 h}
of the olefin in compound 8 afforded the aldehyde, which without
further purification was subjected to reduction (NaBH4/MeOH/
0 °C to rt/1 h) to afford 9 (80%, over two steps). The thus obtained
primary alcohol 9 was protected as its benzyl ether (BnBr/Ag2O/
DMF/rt/12 h) to furnish 10 (83%). Finally, saponification of the com-
pound 10 {LiOH/THF:MeOH:H2O (3:1:1)/0 °C to rt/6 h} gave 11
(84%). The spectroscopic data of 10 and 11 were in agreement with
the reported values.10
The synthesis of fragment 17 (Scheme 4) started from the
known allylic alcohol 12.07 Accordingly, Sharpless epoxidation11
{(+)-DIPT/Ti(OiPr)4/CHP/4 ÅA MS/dry CH2Cl2/ꢀ20 °C/6 h/90%} of 12
afforded 13 and its ee was evaluated by HPLC as 88.76%. The 2,
3-epoxy alcohol 13 upon a regioselective12 ring-opening reaction
by the methyl nucleophile generated in situ from Me3Al (Me3Al/
hexane/0 °C/1 h) in an SN2 fashion gave a mixture of 1,2- and
1,3-diols (C3:C2, in an 8:2 ratio, 86% combined yield). This mixture
Thus, our initial focus was on the synthesis of fragment 6
(Scheme 2), from commercially available n-butyraldehyde. Trans-
formation of n-butyraldehyde into benzyl protected homoallyl alco-
hol 55 (its ee was found to be 95%) was previously reported on
during the synthesis of some piperidine alkaloids. Oxidative cleav-
age8 {NaIO4/OsO4/2,6-lutidine/1,4-dioxane:H2O (3:1)/rt/4.5 h} of
the terminal double bond in 5 afforded the aldehyde, which upon
vinylation (vinyl magnesium bromide/dry THF/ꢀ20 °C/1 h) gave a
1:1 diastereomeric mixture of allylic alcohols 6 (75% combined
yield). Alternatively, diastereomerically pure compound 6 could
be obtained by Sharpless kinetic resolution9 {(+)-DIPT/Ti(OiPr)4/
0
CHP/4 ÅA MS/dry CH2Cl2/ꢀ20 °C/12 h/45%}.
The synthesis of amino acid fragment 11 (Scheme 3) started from
the known compound O-allyl N-Boc-
L
-tyrosine 7.6 N-Methylation
O
O
O
OMe
a
OMe
b
OMe
NBoc
NBoc
H
O
NBoc
O
O
7
8
9
HO
O
O
c
d
OH
OMe
NBoc
NBoc
O
O
BnO
BnO
11
10
Scheme 3. Reagents and conditions. (a) MeI, Ag2O, DMF, rt, 9 h, 85%; (b) (i) NaIO4, OsO4, 2,6-lutidine, 1,4-dioxane:H2O (3:1), rt, 4 h; (ii) NaBH4, MeOH, 0 °C to rt, 1 h, 80% (over
two steps); (c) Benzyl bromide, Ag2O, DMF, rt, 12 h, 83% (d) LiOH, THF:MeOH:H2O (3:1:1), 0 °C to rt, 6 h, 84%.

P. Radha Krishna, P. Srinivas / Tetrahedron: Asymmetry 23 (2012) 769–774
771
OH
a
OH
b
TBDPSO
TBDPSO
O
12
13
OH
OH
OH
TBDPSO
TBDPSO
d
c
14a
TBDPSO
+
15
OH
14b
O
e
HO
HO
17
16
Scheme 4. Reagents and conditions. (a) (+)-DIPT, Ti(OiPr)4, CHP, 4 Å MS, dry CH2Cl2, ꢀ20 °C, 6 h, 90%; (b) Me3Al, hexane, 0 °C, 1 h, 86%; (c) I2, TPP, imidazole, dry CH2Cl2, 0 °C
to rt, 2 h, 70%; (d) TBAF, dry THF, 0 °C to rt, 1 h, 90%; (e) TEMPO, BIAB, CH2Cl2:H2O (3:1), 0 °C to rt, 12 h, 82%.
was subjected to iodination (I2/TPP/imidazole/dry CH2Cl2/0 °C to
rt/2 h), wherein only the 1,2-diol was consumed to afford terminal
olefin 15 (70%). The isomeric diols were thus purified. Olefin 15
was characterised from its spectroscopic data. Next, desilylation
(TBAF/dry THF/0 °C to rt/1 h) of 15 furnished the corresponding
primary alcohol 16 (90%). The thus obtained primary alcohol 16
was subjected to oxidation {TEMPO/BIAB/CH2Cl2:H20 (3:1)/0 °C to
rt/12 h} to afford carboxylic acid 17 (82%) whose formation was
and the carbonyl signal in 13C NMR appearing at d 180.1 ppm in
addition to other spectroscopic evidence.
Next, esterification of 11 with alcohol 6 (Scheme 5) under DCC
conditions (DCC/DMAP/dry CH2Cl2/0 °C to rt/12 h) afforded ester 4
(85%). The deprotection of the Boc group (TFA/dry CH2Cl2/0 °C to
rt/2 h) in ester 4 resulted in the corresponding sec-amine, which
without further purification was acylated with carboxylic acid 17
(EDCI/HOBT/DIPEA/dry CH2Cl2/0 °C to rt/12 h) to provide diene 3
b
confirmed by the appearance of
a
-methylene protons in the 1H
(78% over two steps). Ring-closing metathesis13a,
of diene 3
NMR spectrum resonating at d 2.35 ppm (J = 7.5 Hz) as a triplet
(10 mol % G-II/dry CH2Cl2/12 h/reflux) afforded 18 (83%) as ‘E’
O
O
OBn
O
OBn OH
OH
a
NBoc
+
NBoc
O
O
O
OBn
6
BnO
11
4
O
OBn
OBn
O
O
N
N
O
O
O
b
c
d
O
OBn
OBn
3
18
O
OH
O
N
O
O
OH
1
Scheme 5. Reagents and conditions. (a) DCC, DMAP, dry CH2Cl2, 0 °C to rt, 12 h, 85%; (b) (i) TFA, dry CH2Cl2, 0 °C to rt, 2 h; (ii) 17, EDCI, HOBT, DIPEA, dry CH2Cl2, 0 °C to rt,
12 h, 78% (over two steps); (c) 10 mol % G-II, dry CH2Cl2, 12 h, reflux, 83%; (d) H2, Pd-C, EtOAc, rt, 12 h, 80%.

772
P. Radha Krishna, P. Srinivas / Tetrahedron: Asymmetry 23 (2012) 769–774
and ‘Z’ diastereomers (in a 2:1 ratio, respectively). No attempts
were made to separate the E- and Z-isomers since the isomeric sta-
tus was irrelevant because of the ensuing olefinic reduction step.
Accordingly, the saturation of the double bond and hydrogenolysis
of the benzyl groups (H2/Pd-C/EtOAc/rt/12 h) occurred in a single
step providing the target compound 1 (80%) as a colourless oil with
at ꢀ20 °C for 12 h, then warmed up to 0 °C and quenched with
an aq basic solution (3 M NaOH: brine 3:7, 5.0 mL). After stirring
for 1 h, the reaction mixture was filtered through a pad of celite
using EtOAc. The filtrate was concentrated and purified by column
chromatography (silica gel 60–120 mesh, EtOAc:n-hexane 1:19) to
afford allylic alcohol 6 (0.114 g, 45%) as a yellow oily liquid.
½
a 2D5
ꢁ
¼ ꢀ89:3 (c 0.5, MeOH) {lit.3a
½
a 2D5
ꢁ
¼ ꢀ91:0 (c 0.73, MeOH),
½
a 2D5
ꢁ
¼ þ62:2 (c 0.5, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.45–
lit.3b
½
a 2D5
ꢁ
¼ ꢀ88:5 (c 1.0, MeOH)}. The spectroscopic data of 1 were
7.24 (m, 5H), 5.96–5.80 (m, 1H), 5.27 (d, J = 18.6 Hz, 1H), 5.09 (d,
J = 10.4 Hz, 1H), 4.59 (d, AB pattern, J = 11.3 Hz, 1H), 4.50 (d, AB
pattern, J = 11.3 Hz, 1H), 4.41 (q, J = 4.5 Hz, 1H), 3.74 (p,
J = 6.2 Hz, 1H), 2.93–2.84 (br s, 1H), 1.82–1.46 (m, 6H), 0.93 (t,
J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 141.9, 128.4, 127.8,
127.7, 113.8, 76.7, 71.0, 69.8, 39.8, 35.6, 18.4, 14.3; HRMS (m/z)
[M+Na]+ Calcd 257.1512. Found 257.1510 for C15H22O2Na.
identical to the reported values.3a, b
3. Conclusion
In conclusion, the total synthesis of a novel antifungal antibiotic
1 has been accomplished wherein Keck asymmetric allylation,
Sharpless kinetic resolution, regioselective epoxide-ring opening,
esterification and ring-closing metathesis were the key reactions.
4.1.2. (S)-Methyl 3-[4-(allyloxy)phenyl]-2-[tert-butoxycarbonyl
(methyl)amino]propanoate 8
4. Experimental
4.1. General
To a stirred solution of 7 (0.5 g, 1.49 mmol) in dry DMF (6.0 mL)
was added Ag2O (0.689 g, 2.98 mmol). After 5 min, MeI (0.55 mL,
8.95 mmol) was added and allowed to stir at room temperature
for 9 h. The reaction mixture was quenched with a saturated aq
NH4Cl solution (10.0 mL) and extracted with EtOAc (2 ꢂ 50.0 mL).
The combined organic layers were washed with water (30.0 mL),
brine (30.0 mL), dried (Na2SO4) and concentrated under reduced
pressure. The residue was purified by column chromatography (sil-
ica gel 60–120 mesh, EtOAc:n-hexane 1:9) to afford 8 (0.44 g, 85%)
Column chromatography was performed on silica gel, Acme
grade 60–120 mesh. Unless stated otherwise, all reagents were
purchased from commercial sources and used without additional
purification. THF was freshly distilled over Na-benzophenoneketyl.
Unless stated otherwise, optical rotations were measured with a
JASCO P-1020 instrument at 25 °C. 1H NMR and 13C NMR spectra
were recorded either on a Bruker 300 or Varian VXR 400 or Varian
VXR 500 in CDCl3 as the solvent with TMS as the reference unless
otherwise indicated. Unless stated otherwise, HRMS spectra were
recorded on a QTOF analyser (QSTAR XL, Applied Biosystems/
MDS Sciex) at NCMS-IICT, Hyderabad. Unless stated otherwise, ele-
mental analysis was carried on a Vario Micro Cube Elementar at
Analytical Chemistry Division IICT, Hyderabad. The software
ACD/Name Version 1.0, developed by M/s Advanced Chemistry
Development Inc., Toronto, Canada, assisted nomenclature was
used in the experimental section. Unless stated otherwise, all reac-
tions were performed under an inert atmosphere.
as a yellow oil. ½a D25
ꢁ
¼ ꢀ173:9 (c 0.4, CHCl3); 1H NMR (500 MHz,
CDCl3): d 7.15–7.05 (m, 2H), 6.84 (d, J = 8.3 Hz, 2H), 6.11–5.98 (m,
1H), 5.46–5.35 (m,1H), 5.32–5.24 (m, 1H), 4.94–4.85 (m, 0.5H),
4.51 (d, J = 5.2 Hz, 2H), 4.49–4.43 (m, 0.5H), 3.74 (s, 3H), 3.31–
3.17 (m, 1H), 3.00–2.89 (m, 1H), 2.71 (s, 3H), 1.43–1.31 (m, 9H);
13C NMR (75 MHz, CDCl3): d 171.6, 157.4, 133.4, 130.0, 129.5,
117.6, 114.8, 114.6, 68.7, 61.8, 59.4, 52.1, 32.6, 31.7, 28.1; HRMS
(m/z) [M+Na]+ calcd. 372.1781. Found 372.1780 for C19H27NO5Na.
4.1.3. (S)-Methyl 2-[tert-butoxycarbonyl(methyl)amino]-3-[4-
(2-hydroxyethoxy)phenyl]propanoate 9
To a stirred solution of 8 (0.44 g, 1.26 mmol) in 1,4-dioxane:H2O
(3:1, 5.0 mL), was added OsO4 (0.4 mL, 0.5 M in toluene) dropwise.
After 5 min., 2,6-lutidine (0.3 mL, 2.52 mmol) and NaIO4 (0.54 g,
2.52 mmol) were added and stirred for 4 h at room temperature.
After completion of the reaction, the reaction mixture was
quenched with Na2SO3 (1.5 g) and extracted with EtOAc
(2 ꢂ 50.0 mL). The combined organic layers were washed with
water (30.0 mL), brine (30.0 mL), dried (Na2SO4) and evaporated.
The crude aldehyde obtained was used directly for the next reaction.
To a stirred solution of the aldehyde (0.4 g, 1.13 mmol) in MeOH
(5.0 mL) was added NaBH4 (0.043 g, 1.13 mmol) at 0 °C and al-
lowed to stir at room temperature for 1 h. Methanol was evapo-
rated and extracted with EtOAc (2 ꢂ 50.0 mL). The combined
organic layers were washed with water (30.0 mL), brine
(30.0 mL), dried (Na2SO4) and evaporated. The residue was purified
by column chromatography (silica gel 60–120 mesh, EtOAc:n-hex-
ane 2:8) to afford alcohol 9 (0.35 g, 80%, over two steps) as a yellow
4.1.1. (3R,5S)-5-(Benzyloxy)oct-1-en-3-ol 6
To a stirred solution of 5 (0.4 g, 1.96 mmol) in 1,4-dioxane:H2O
(3:1, 5.0 mL) was added OsO4 (0.4 mL, 0.5 M in toluene) dropwise.
After 5 min., 2,6-lutidine (0.45 mL, 3.92 mmol) and NaIO4 (0.83 g,
3.92 mmol) were added and stirred for 4.5 h at room temperature.
The reaction mixture was quenched with Na2SO3 (1.5 g) and ex-
tracted with EtOAc (2 ꢂ 50.0 mL). The combined organic layers
were washed with water (30.0 mL), brine (30.0 mL), dried (Na2SO4)
and concentrated under reduced pressure. The crude aldehyde ob-
tained was used directly for the next reaction.
To a solution of the aldehyde (0.33 g, 1.6 mmol) in dry THF
(5.0 mL) was added a 1.0 M solution of vinyl magnesium bromide
(3.2 mL, 3.2 mmol) at ꢀ20 °C and stirred for 1 h. After completion
of the reaction, the reaction mixture was quenched with a saturated
aq NH4Cl (10.0 mL) solution and extracted with EtOAc (2 ꢂ 50.0 mL).
The combined organic layers were washed with water (30.0 mL),
brine (30.0 mL), dried (Na2SO4) and concentrated under reduced
pressure. The residue was purified by column chromatography (Sil-
ica gel, 60–120 mesh, EtOAc:n-hexane, 1:19) to afford 1:1 diastereo-
meric mixture of allylic alcohols (0.28 g, 75%) as a yellow oily liquid.
To a suspension of activated molecular sieves 4 Å (1.0 g) in dry
CH2Cl2 (3.0 mL) was added (+)-DIPT (0.15 g, 0.64 mmol) in dry
CH2Cl2 (1.0 mL) followed by the slow addition of Ti(OiPr)4
(0.16 mL, 0.53 mmol) at ꢀ20 °C. After stirring for 20 min cumene
hydroperoxide (0.1 mL, 0.64 mmol) was added at ꢀ20 °C, and stir-
red for a further 20 min. Allylic alcohol (0.25 g, 1.06 mmol) in dry
CH2Cl2 (1.0 mL) was added and the reaction mixture was stirred
oil. ½a 2D5
ꢁ
¼ ꢀ93:6 (c 0.4, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.16–
7.04 (m, 2H), 6.85 (d, J = 7.9 Hz, 2H), 4.94–4.84 (m, 0.5H), 4.51–4.41
(m, 0.5H), 4.08–4.02 (m, 2H), 4.00–3.91 (m, 2H), 3.77–3.70 (m, 3H),
3.29–3.17 (m, 1H), 3.02–2.91 (m, 1H), 2.71 (s, 3H), 2.07–1.97 (br s,
1H), 1.56 (s, 9H); 13C NMR (75 MHz, CDCl3): d 171.5, 157.5, 130.0,
114.6, 114.5, 69.1, 61.8, 61.4, 59.5, 52.1, 34.5, 34.2, 28.2; HRMS (m/z)
[M+Na]+ Calcd 376.1730. Found 376.1728 for C18H27NO6Na.
4.1.4. {(2S,3S)-3-[5-(tert-Butyldiphenylsilyloxy)pentyl]oxiran-2-
yl}methanol 13
To a suspension of activated molecular sieves 4 Å (3.0 g) in dry
CH2Cl2 (5.0 mL) was added (+)-DIPT (0.26 g, 1.09 mmol) in dry

P. Radha Krishna, P. Srinivas / Tetrahedron: Asymmetry 23 (2012) 769–774
773
CH2Cl2 (2.0 mL) followed by the slow addition of Ti(OiPr)4 (0.27 mL,
0.91 mmol) at ꢀ20 °C. After stirring for 20 min cumene hydroper-
oxide (0.33 mL, 2.2 mmol) was added at ꢀ20 °C and stirred for a
further 20 min. Allylic alcohol 12 (0.7 g, 1.83 mmol) in dry CH2Cl2
(3.0 mL) was added and the reaction mixture was stirred at
ꢀ20 °C for 6 h, then warmed up to 0 °C and quenched with an aq
basic solution (3 M NaOH: brine 3:7, 15.0 mL). After stirring for
1 h, the reaction mixture was filtered through a pad of Celite using
EtOAc. The filtrate was concentrated and purified by column chro-
matography (silica gel 60–120 mesh, EtOAc:n-hexane 1:9) to af-
ford 13 (0.65, 90%) as a colourless oily liquid. The ee was found
to be 88.76% as determined by chiral HPLC analysis {(Chiral cel-IC:
250 ꢂ 4.6 mm, 5u, 3% iPrOH/hexane, flow rate 1 mL/min, 210 nm)}:
24.6, 20.3; LCMS: 179 [M+Na]+. Anal. Calcd for C9H16O2: C, 68.90;
H, 10.22. Found: C, 69.11; H, 10.55.
4.1.8. (S)-[(3R,5S)-5-(Benzyloxy)oct-1-en-3-yl] 3-[4-(2-(benzyl-
oxy)ethoxy)phenyl]-2-[tert-butoxycarbonyl(methyl)
amino]propanoate 4
To a stirred solution of 6 (0.1 g, 0.43 mmol) in dry CH2Cl2
(2.0 mL) were added DCC (0.1 g, 0.51 mmol) and DMAP (cat) fol-
lowed by 11 (0.2 g, 0.46 mmol) in dry CH2Cl2 (2.0 mL) at 0 °C and
allowed to stir at room temperature for 12 h. The solvent was
evaporated off and the residue adsorbed on to the silica and puri-
fied by column chromatography (silica gel 60–120 mesh, EtOAc:n-
hexane 1:9) to give 4 (0.23 g, 85%) as a yellow oil. ½a D25
¼ ꢀ50:2 (c
ꢁ
tR (minor) 17.115 min, tR (major) 19.727 min. ½a D25
ꢁ
¼ ꢀ32:4 (c 1.2,
0.1, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.45–7.30 (m, 10H), 7.14–
7.02 (m, 2H), 6.87–6.79 (m, 2H), 5.85–5.73 (m, 1H), 5.58–5.47 (m,
1H), 5.33–5.11 (m, 2H), 4.87–4.78 (m, 1H), 4.63 (s, 2H), 4.55–4.27
(m, 2H), 4.16–4.05 (m, 2H), 3.84–3.77 (m, 2H), 3.45–3.33 (m, 1H),
3.28–3.12 (m, 1H), 2.97–2.80 (m, 1H), 2.74–2.64 (m, 3H), 1.58 (s,
9H), 1.41–1.30 (m, 6H), 0.91 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d 136.7, 129.8, 128.4, 128.1, 128.0, 127.7, 127.6, 127.5,
114.6, 114.5, 73.3, 72.8, 72.5, 71.4, 71.1, 68.4, 67.4, 29.7, 29.3,
18.1, 14.1; HRMS (m/z) [M+Na]+ Calcd 668.3557. Found 668.3558
for C39H51NO7Na.
CHCl3); 1H NMR (300 MHz, CDCl3): d 7.72–7.62 (m, 4H), 7.46–
7.34 (m, 6H), 3.90 (d, J = 12.0 Hz, 1H), 3.66 (t, J = 6.0 Hz, 2H),
3.67–3.57 (m, 1H), 2.96–2.88 (m, 2H), 1.67–1.51 (m, 8H), 1.05 (s,
9H); 13C NMR (75 MHz, CDCl3): d 135.4 (6C), 134.0, 129.4, 127.4
(4C), 63.7, 61.6, 58.4, 55.8, 32.5, 31.4, 26.5 (3C), 25.5 (2C), 19.0;
HRMS (m/z) [M+Na]+ Calcd 421.2169. Found 421.2163 for
C24H34O3NaSi.
4.1.5. (R)-tert-Butyl(6-methyloct-7-enyloxy)diphenylsilane 15
To stirred solution of 14a and 14b (0.44 g, 1.06 mmol) in dry
CH2Cl2 (7.0 mL) were added I2 (0.54 g, 2.12 mmol), TPP (0.55 g,
2.12 mmol) and imidazole (0.21 g, 3.18 mmol) successively at
0 °C and allowed to stir at room temperature for 2 h. After the reac-
tion was complete, the solvent was evaporated and adsorbed onto
silica and purified by column chromatography (silica gel 60–120
mesh, EtOAc:n-hexane 0.5:9.5) to give 15 (70%, 0.28 g) as a colour-
4.1.9. (S)-[(3R,5S)-5-(Benzyloxy)oct-1-en-3-yl] 3-[4-(2-(benzyl-
oxy)ethoxy)phenyl]-2-[(R)-N,6-dimethyloct-7-enamido]
propanoate 3
To a stirred solution of 4 (0.21 g, 0.32 mmol) in dry CH2Cl2
(2.0 mL) was added TFA (0.1 mL) at 0 °C and allowed to stir at room
temperature for 2 h. After the reaction was completed, TFA was re-
moved under vacuum. Later DIPEA (0.17 mL, 0.97 mmol) was
added to the reaction mixture. After 5 min, a solution of carboxylic
acid 17 (0.05 g, 0.32 mmol) in dry CH2Cl2 (1.0 mL) was added to the
amine followed by EDCI (0.074 g, 0.48 mmol) and HOBT (0.064 g,
0.48 mmol) at 0 °C and allowed to stir at room temperature for
12 h. The reaction mixture was quenched with saturated aq NH4Cl
(10.0 mL) solution and extracted with CHCl3 (2 ꢂ 15.0 mL). The
combined organic layers were washed with 1 M HCl (15.0 mL),
water (15.0 mL), saturated aq NaHCO3 (15.0 mL) solution and brine
(15.0 mL), dried (Na2SO4) and evaporated. The crude residue was
purified by column chromatography (silica gel 60–120 mesh,
EtOAc:n-hexane 1:9) to give 3 (0. 16 g, 78%, over two steps) as a
less oil. ½a 2D5
ꢁ
¼ ꢀ9:7 (c 1.1, CHCl3); 1H NMR (500 MHz, CDCl3): d
7.67–7.62 (m, 4H), 7.41–7.32 (m, 6H), 5.69–5.59 (m, 1H), 4.95–
4.85 (m, 2H), 3.63 (t, J = 6.6 Hz, 2H), 2.14–2.01 (m, 1H), 1.40–1.22
(m, 8H), 1.05 (s, 9H), 0.98 (d, J = 6.6 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d 145.0, 135.5, 134.2, 129.5, 127.6, 112.4, 64.0, 37.6, 36.5,
32.6, 26.8, 25.8, 20.2, 19.2; HRMS (m/z) [M+Na]+ Calcd 403.1168.
Found 403.1166 for C25H36ONaSi.
4.1.6. (R)-6-Methyloct-7-en-1-ol 16
To a stirred solution of 15 (0.2 g, 0.52 mmol) in dry THF (3.0 mL)
was added a 1.0 M solution of TBAF (0.6 mL, 0.6 mmol) at 0 °C and
allowed to stir at room temperature for 1 h. Next, the THF solvent
was evaporated and adsorbed onto silica and purified by column
chromatography (silica gel 60–120 mesh, EtOAc:n-hexane 1:9) to
colourless oil. ½a D25
ꢁ
¼ ꢀ32:4 (c 0.2, CHCl3); 1H NMR (300 MHz,
CDCl3): d 7.45–7.28 (m, 10H), 7.08 (d, J = 8.4 Hz, 2H), 6.87–6.76
(m, 2H), 5.85–5.59 (m, 2H), 5.57–5.46 (m, 1H), 5.35–5.10 (m,
2H), 5.25–5.19 (m, 1H), 5.00–4.84 (m, 2H), 4.62 (s, 2H), 4.54–4.42
(m, 1H), 4.37–4.28 (m, 1H), 4.15–4.04 (m, 2H), 3.85–3.77 (m,
2H), 3.46–3.33 (m, 1H), 3.30–3.17 (m, 1H), 2.94–2.73 (m, 4H),
2.22–2.11 (m, 1H), 1.76 (t, J = 6.6 Hz, 2H), 1.70–1.42 (m, 6H),
1.41–1.11 (m, 6H), 0.98 (d, J = 7.9 Hz, 3H), 0.94 (t, J = 7.3 Hz, 3H);
13C NMR (75 MHz, CDCl3): d 173.6, 170.4, 157.5, 144.6, 136.4,
135.9, 129.9, 129.7, 129.2, 128.4, 128.3, 128.0, 127.7, 127.6,
127.5, 116.6, 114.8, 114.5, 112.3, 74.9, 73.3, 72.7, 71.2, 68.4, 67.2,
57.8, 39.4, 37.5, 36.3, 36.0, 33.4, 33.8, 29.6, 26.9, 24.9, 20.1, 18.1,
14.2; HRMS (m/z) [M+Na]+ Calcd 706.4078. Found 706.4076 for
give 16 (0.07 g, 90%) as a yellow oil. ½a D25
¼ ꢀ17:3 (c 1.3, CHCl3);
ꢁ
1H NMR (300 MHz, CDCl3): d 5.70–5.58 (m, 1H), 4.96–4.85 (m,
2H), 3.61 (t, J = 6.7 Hz, 2H), 2.15–2.04 (m, 1H), 1.60–1.48 (m, 2H),
1.39–1.23 (m, 6H), 0.98 (d, J = 6.8 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d 144.8, 112.4, 62.9, 37.6, 36.5, 32.6, 26.8, 25.7, 20.2; LCMS:
165 [M+Na]+. Anal. Calcd for C9H18O: C, 75.66; H, 12.40. Found: C,
75.42; H, 12.33.
4.1.7. (R)-6-Methyloct-7-enoic acid 17
To stirred solution of 16 (0.07 g, 0.5 mmol) in CH2Cl2:H2O (3:1,
2.0 mL) were added TEMPO (cat) and BIAB (0.24 g, 0.73 mmol) suc-
cessively at 0 °C and allowed to stir at room temperature for 12 h.
Later, the reaction mixture was quenched with saturated aq
Na2S2O3 (10.0 mL) and extracted with CH2Cl2 (2 ꢂ 15.0 mL). The
combined organic layers were washed with water (10.0 mL), brine
(10.0 mL), dried (Na2SO4) and evaporated. The residue was purified
by column chromatography (silica gel 60–120 mesh, EtOAc:n-hex-
C43H57NO6Na.
4.1.10. (3S,10R,13S)-3-[4-(2-Hydroxyethoxy)benzyl]-13-[(S)-2-
hydroxypentyl]-4,10-dimethyl-1-oxa-4-azacyclotridecane-2,5-
dione 1 (PF1163A)
To a solution of compound 18 (0.022 g 0.044 mmol) in EtOAc
(1.0 mL) was added Pd/C (0.005 g, 10 mol%) and stirred under
H2 atmosphere for 12 h. After completion of the reaction, the
mixture was filtered through a Celite pad, and concentrated un-
der reduced pressure. The residue was purified by column chro-
matography (silica gel 60–120 mesh, EtOAc:n-hexane 4:6) to
ane 1:9) to give 17 (0.06 g, 82%) as a yellow oil. ½a D25
¼ ꢀ35:9 (c 0.2,
ꢁ
CHCl3); 1H NMR (300 MHz, CDCl3): d 5–74–5.59 (m, 1H), 4.98–4.88
(m, 2H), 2.35 (t, J = 7.5 Hz, 2H), 2.16–2.05 (m, 1H), 1.70–1.57 (m,
2H), 1.38–1.24 (m, 4H), 0.98 (d, J = 6.8 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d 180.1, 144.7, 112.7, 37.6, 36.1, 34.0, 26.7,

774
P. Radha Krishna, P. Srinivas / Tetrahedron: Asymmetry 23 (2012) 769–774
give 1 (0.011 g, 80%) as a colourless oil. ½a D25
¼ ꢀ89:3 (c 0.5,
ꢁ
2. (a) Radha Krishna, P.; Srinivas, P. Tetrahedron Lett. 2010, 51, 2295–2296; (b)
Radha Krishna, P.; Anitha, K. Tetrahedron Lett. 2011, 52, 4546–4549; (c) Radha
Krishna, P.; Jagannadha Rao, T. Org. Biomol. Chem. 2010, 8, 3130–3132; (d)
Radha Krishna, P.; Srinivas, R. Tetrahedron: Asymmetry 2008, 19, 1153–1160; (e)
Radha Krishna, P.; Ramana, D. V. J. Org. Chem. 2012, 77, 674–679.
3. (a) Tatsuta, K.; Takano, S.; Ikeda, Y.; Nakano, S.; Miyajzaki, S. J. Antibiot. 1999,
52, 1146–1151; (b) Yadav, J. S.; Venkatesh, M.; Thrimurthulu, N.; Prasad, A. R.
Synlett 2010, 1255–1259.
4. Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993, 115, 8467–8468.
5. (a) Radha Krishna, P.; Karunakar Reddy, B.; Srinivas, P. Tetrahedron 2012, 68,
841–845; (b) Sabitha, G.; Yadagiri, K.; Swapna, R.; Yadav, J. S. Tetrahedron Lett.
2009, 50, 5417–5419.
MeOH); 1H NMR (300 MHz, CDCl3): d 7.19–7.02 (m, 2H), 6.81
(d, J = 8.3 Hz, 2H), 5.83–5.69 (m, 1H), 5.11–4.93 (m, 1H), 4.02 (s,
2H), 3.91 (s, 2H), 3.52–3.27 (m, 1H), 3.26–3.10 (m, 1H), 3.04–
2.86 (m, 3H), 2.85–2.54 (m, 1H), 2.38–2.26 (m, 1H), 1.75–1.04
(m, 19H), 0.88 (t, J = 7.2 Hz, 3H), 0.83 (d, J = 7.2 Hz, 3H); 13C
NMR (75 MHz, CDCl3): d 173.4, 171.6, 157.6, 130.4, 128.9, 114.3,
73.1, 69.0, 66.5, 61.4, 55.8, 49.2, 42.0, 39.2, 33.8, 33.3, 29.7,
24.2, 20.6, 18.9, 14.2; HRMS (m/z) [M+Na]+ Calcd 500.29826.
Found 500.29825 for C27H43NO6Na.
6. Boyle, T. P.; Bremner, J. B.; Coates, J.; Deadman, J.; Keller, P. A.; Pyne, S. G.;
Rhodes, D. I. Tetrahedron 2008, 64, 11270–11290.
7. Murphy, J. A.; Rasheed, F.; Roome, S. J.; Scott, K. A.; Lewis, N. J. Chem. Soc., Perkin
Trans. 1 1998, 2331–2339.
Acknowledgments
8. Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6, 3217–3219.
9. Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda, M.; Sharpless, K. B. J.
Am. Chem. Soc. 1981, 103, 6237–6240.
10. Bouazza, F.; Renoux, B.; Bachmann, C.; Gesson, J. P. Org. Lett. 2003, 5, 4049–
4052.
One of the authors (P.S.) thanks the CSIR, New Delhi, for finan-
cial support in the form of a fellowship.
11. Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974–5976.
12. Suzuki, T.; Saimoto, H.; Tomioka, H.; Oshima, K.; Nozaki, H. Tetrahedron Lett.
1982, 23, 3597–3600.
13. (a) Scholl, M.; Ding, S.; Lee, C.; Grubbs, R. H. Org. Lett. 1999, 1, 953–956; (b)
Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am. Chem. Soc. 2000,
122, 3783–3784.
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