Total Synthesis of Sch 725674

Article abstract of DOI:10.1016/j.tet.2018.04.014

A concise total synthesis of the macrolactone natural product Sch 725674 is accomplished starting from commercially available 2-deoxy-d-ribose. Pivotal reactions employed in the synthesis include the addition of 4-pentenylmagnesium bromide to the lactol derived from 2-deoxy-d-ribose, olefin cross metathesis and Yamaguchi macrolactonization.

Full text of DOI:10.1016/j.tet.2018.04.014

Accepted Manuscript
Total Synthesis of Sch 725674
Kannan Vaithegi, Kavirayani R. Prasad
PII:
S0040-4020(18)30382-X
10.1016/j.tet.2018.04.014
TET 29429
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 21 February 2018
Revised Date: 4 April 2018
Accepted Date: 5 April 2018
Please cite this article as: Vaithegi K, Prasad KR, Total Synthesis of Sch 725674, Tetrahedron (2018),
doi: 10.1016/j.tet.2018.04.014.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Total Synthesis of Sch725674
Leave this area blank for abstract info.
Kannan Vaithegi and Kavirayani R. Prasad*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, INDIA

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Total Synthesis of Sch 725674
Kannan Vaithegi and Kavirayani R. Prasad*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, INDIA
FAX: +0091-80-23600529; E-mail: prasad@orgchem.iisc.ernet.in
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A concise total synthesis of the macrolactone natural product Sch 725674 is accomplished starting
from commercially available 2-deoxy-D-ribose. Pivotal reactions employed in the synthesis include
the addition of 4-pentenylmagnesium bromide to the lactol derived from 2-deoxy-D-ribose, olefin
cross metathesis and Yamaguchi macrolactonization.
Available online
2014 Elsevier Ltd. All rights reserved
.
Keywords:
Macrolactone, total synthesis, natural products, Sch
725674
1. Introduction
synthesis of 1 from tartaric acid, the pivotal RCM reaction to
afford the natural product suffered with a low yield. In
continuation of our efforts on the use of chiral pool compounds
in the total synthesis of natural products and to accomplish an
improved synthesis of 1, we undertook the total synthesis of Sch
725674 starting from commercially available 2-deoxy-D-ribose.
Sch 725674 (1) (Figure 1) is a 14-membered macrolactone
isolated by Yang and co-workers in 2005 from the culture of
Aspergillus sp.1 The structure of Sch 725674 was elucidated by
extensive 2D NMR spectroscopy. It contains three free hydroxy
groups and a E- α, β-unsaturated lactone. It was shown to exhibit
antifungal activity against Saccharomyces cerevisiae and
Candida albicans with MICs of 8ꢀg mL-1 and 32ꢀg mL-1
respectively. First total synthesis of Sch 725674 (1) and the
confirmation of the absolute configuration was disclosed by
Curran’s group using their trademark fluorous tagging strategy.2
2. Results and Discussion
We envisaged the formation of 1 from the seco acid 2 via
Yamaguchi macrolactonization and further deprotection of the
acetonide group. Formation of the seco acid 2 was anticipated
from the alcohol 3, which in turn could be obtained by olefin
cross metathesis of the alkenes 4 and the masked tetrol
containing alkene 5. Addition of 4-pentenylmagnesium bromide
to 6 obtained from 2-deoxy-D-ribose was chosen as appropriate
transformation for the synthesis of triol containing alkene 5
(Scheme 1).
Figure 1: Sch 725674
Following Curran’s synthesis our group have reported the
total synthesis of Sch 725674 starting from tartaric acid using
Ley’s dithiaketalization as the pivotal reaction to install the
trihydroxy unit.3 Later, many groups reported the total synthesis
of Sch 725674,4a-4f Kaliappan and Ramakrishna4a reported the
total synthesis of Sch 725674 starting from (S)-epichlorohydrin
using Smith’s Linchpin coupling of silyldithianes as key step.
Reddy’s synthesis of 1 originated from chiral pool D-ribose and
have utilized Wacker oxidation as the key step to install the
required triol fragment.4b Hanson et al4c disclosed the synthesis of
1 based on a one pot sequential RCM/CM/hydrogenation reaction
to install the triol unit. Kumar group4d reported the total synthesis
of 1 commencing from (S)-glycidol in a multi-step sequence
while Reddy and Sabitha4e utilised D-mannitol for the synthesis
of 1. Aggarwal’s group accomplished the total synthesis of 1
using enatioselective diboration and subsequent oxidation of the
chiral boronates to install the required triol.4f In our earlier
Scheme 1. Retrosynthesis for Sch725674 (1)
Accordingly, the synthesis commenced with the addition of 4-
pentenylmagnesium bromide to the lactol 65 which resulted in a
seperable 1: 1 diastereomeric mixture of diols 7 and 8 in 42% and
40% yields, respectively.6 The diastereomer 7 was transformed to
the required α-isomer 8 using Mitsunobu inversion in 60% yield
(65% combined yield of 8 from 6). The diol 8 was converted to
the corresponding bis-silyl ether 5 under standard conditions in

2
Tetrahedron
ACCEPTED MANUSCRIPT
4. Experimental section
97% yield. Olefin cross metathesis of the alkene 5 with the allyl
acetate 47 in presence of Grubbs’ second generation catalyst8
furnished the product 9 in 70% yield. Hydrogenation of the olefin
in 9 using Pd/C rendered the acetate 10 in 97% yield (Scheme 2).
General Procedures: Column chromatography was performed
on silica gel, Acme grade 100-200 mesh. TLC plates were
visualized either with UV, in an iodine chamber, or with
phosphomolybdic acid spray, unless noted otherwise. Unless
stated otherwise, all reagents were purchased from commercial
sources and used without additional purification. THF was
freshly distilled over Na-benzophenone ketyl. Melting points
were uncorrected. Unless stated otherwise, H NMR and 13C
1
NMR spectra were recorded on 400 MHz machine in CDCl3 as
solvent with TMS or residual solvent CDCl3 or CD3OD peak as
reference. Unless stated otherwise, all the reactions were
performed under inert atmosphere. All the specific rotations were
determined at 24 °C.
Preparation
of
(S)-1-((4S,5R)-5-(hydroxymethyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)hept-6-en-2-ol (7)
In an oven dried two neck 100 mL round-bottom flask equipped
with a magnetic stir bar, rubber septum and argon inlet was
placed 4-pentenylmagnesium bromide (9.2 mmol, 18.4 mL of
0.5M solution in THF). It was cooled to −15 °C and a solution of
the lactol 6 (0.7 g, 3.6 mmol) in THF (10 mL) was added
dropwise, at the same temperature. The reaction mixture was
stirred for 30 min at the same temperature, slowly warmed to 0
°C and stirred for 5 h at the same temperature. After the reaction
was complete (TLC), it was cautiously quenched by addition of
saturated solution of aqueous NH4Cl (20 mL) and was extracted
with EtOAc (3 × 20 mL). The combined organic layers were
washed with brine (10 mL) and dried over anhydrous Na2SO4.
Removal of the solvent gave the crude residue (as 1:1 mixture of
diastereomers), which were separated by silica gel column
chromatography to afford the less polar 3,5-syn diastereomer 7
(2:3 ethylacetate/hexane) (0.38 g, 42%), and the more polar 3,5-
anti diastereomer 8 (1:1 ethylacetate/hexane) (0.36 g, 40%). Data
for diastereomer (7):[α]ꢁꢀꢂ: +9.9 (c 1.2, CHCl3). IR (neat): 3415,
2984, 2933, 2362, 1640, 1376 cm–1.1H NMR (400 MHz, CDCl3):
δ = 5.80 (ddt, J = 16.8, 10.0, 6.8 Hz, 1H), 5.05 – 4.91 (m, 2H),
4.42 – 4.33 (m, 1H), 4.23 – 4.16 (m, 1H), 3.85 – 3.75 (m, 1H),
3.62 (t, J = 5.6 Hz, 2H), 3.17 (bs, 1H), 2.13 – 2.00 (m, 3H), 1.69
– 1.61 (m, 2H), 1.57 – 1.43 (m, 7H), 1.37 (s, 3H). 13C NMR (100
MHz, CDCl3): δ = 138.6, 114.6, 108.7, 78.0, 77.0, 71.4, 61.5,
36.7, 35.7, 33.6, 28.0, 25.4, 24.7. HRMS (ESI): m/z [M+Na]+
calcd for C13H24O4Na: 267.1572; found: 267.1570.
Scheme 2. Synthesis of the key polyol unit 10
Selective deprotection of the primary TBS group in 10 with
TBAF afforded the primary alcohol 3 in 40% yield (80% based
on starting material recovery). Oxidation of the primary alcohol
in 3 with Dess Martin periodinane9 followed by Wittig
homologation of the resultant aldehyde furnished the conjugated
ester 11 in 63% yield. Hydrolysis of both ethyl ester and acetate
in 11 with 1M aqueous LiOH provided the seco acid 2 in 94%
yield, which under Yamaguchi lactonization reaction conditions
afforded the 14-membered macrolactone 12 in 76% yield.
Deprotection of the acetonide as well as TBS group in 12 with
camphorsulphonic acid furnished the natural product Sch 725674
(1) in 50% yield. All the physical and spectral properties of 1
were in good agreement with that reported in the literature3b
(Scheme 3).
OTBS
OAc
C5H11
O
i) DMP, NaHCO3
CH2Cl2, 0 °C to rt, 2 h
ii) PPh3=CHCO2Et
toluene, , 2 h, 63%
TBAF, THF
10 °C to 0 °C, 5 h
40% (80%, brsm)
O
10
3
OH
3
O
O
O
OTBS
OAc
O
aqueous 1M LiOH
MeOH:THF (1:2)
rt, 6 h, 94%
C5H11
OTBS
3
CO2H
OH
11
Data for diastereomer (8): [α]ꢁꢀꢂ: +4.8 (c 1.35, CHCl3). IR
C5H11
O
OEt
1
(neat): 3392, 2984, 2932, 2359, 1640, 1453 cm–1. H NMR (400
2
Cl
MHz, CDCl3): δ = 5.79 (ddt, J = 16.4, 10.4, 6.8 Hz, 1H), 5.05 –
4.90 (m, 2H), 4.42 (dt, J = 8.0, 5.6 Hz, 1H), 4.19 (q, J = 5.6 Hz,
1H), 3.85 – 3.74 (m, 1H), 3.61 (m, 2H), 2.62 (brs, 1H), 2.51 (brs,
1H), 2.12 – 2.00 (m, 2H), 1.79 (ddd, J = 14.4, 8.4, 2.8 Hz, 1H),
1.65 – 1.40 (m, 8H), 1.35 (s, 3H). 13C NMR (100 MHz, CDCl3):
δ = 138.5, 114.7, 107.7, 77.8, 74.5, 69.2, 61.4, 37.4, 35.7, 33.5,
28.1, 25.4, 24.8. HRMS (ESI): m/z [M+Na]+ calcd for
C13H24O4Na: 267.1572; found: 267.1572.
O
O
O
Cl
Cl
Cl
Camphor sulphonic acid
MeOH:THF:H2O (10:5:1)
rt, 24 h, 50%
1
OTBS
Et3N, DMAP, toluene
0 °C to rt, 2 h, 76%
O
O
C5H11
12
Scheme 3. Total synthesis of Sch 725674 (1)
Preparation
of
(S)-1-((4S,5R)-5-(hydroxymethyl)-2,2-
3. Conclusions
dimethyl-1,3-dioxolan-4-yl)hept-6-en-2-ol (8) from 7: To a
pre-cooled (0 °C) solution of diol 7 (0.14 g, 0.57 mmol) in THF
(10 mL) were added triphenylphosphine (0.9 g, 3.44 mmol) and
DIAD (0.68 mL, 3.44 mmol) and was stirred for 10 min at the
same temperature. p-Nitrobenzoic acid (0.57 g, 3.44 mmol) was
added at once to the reaction mixture and stirred at room
temperature for 4 h. After completion of the reaction (monitored
by TLC), most of the solvent was evaporated under vacuum and
the residue thus obtained was purified by silica gel column
chromatography using petroleum ether: EtOAc (9:1) as eluent
furnish the corresponding p-nitro benzoate (80 mg) as colourless
In conclusion, a consise total synthesis of Sch 725674 was
accomplished starting from known lactol derived from
commeriallyl available 2-deoxy-D-ribose in ~4% overall yield in
10 steps. Key reaction in the synthesis include cross metathesis
and Yamaguchi lactonization to effect the macrolactonization.
The reaction sequence is amenable for the synthesis of number of
analogues of Sch 725674
.

3
oil, which was used in the next step without further
characterization.
was stirred for 1 h under H2 atmosphere. After the reaction was
ACCEPTED MANUSCRIPT
complete, the reaction mixture was filtered through a short pad of
celite and the celite pad was washed with EtOAc (10 mL).
Evaporation of solvent followed by column chromatography
(silica gel, PE–EtOAc, 9:1) yielded 10 (0.2 g, 97%) as a
colourless oil; [α]ꢁꢀꢂ: −19.8 (c 1.35, CHCl3). IR (neat): 2930,
To a stirred solution of the p-nitrobenzoate (obtained above) in
ethanol was added K2CO3 (0.48 g, 3.44 mmol) and was stirred for
3h at room temperature. After completion of the reaction
(monitored by TLC), the solvent was evaporated off under
vacuum and the residue thus obtained was diluted with water (10
mL) and was extracted with EtOAc (2 x 10 mL). The combined
organic layer was washed with brine (10 mL) and dried over
anhydrous Na2SO4. Evaporation of solvent gave the crude residue
which was purified by silica gel column chromatography using
petroleum ether: EtOAc (6:4) as eluent to furnish 8 (0.084 g,
60%) as a colourless oil.
2858, 2360, 1730, 1460 cm−1. H NMR (400 MHz, CDCl3): δ =
1
4.85 (quint, 1H), 4.32 (ddd, J = 10.0, 6.0, 2.4 Hz, 1H), 4.08 –
3.98 (m, 1H), 3.94 – 3.82 (m, 1H), 3.62 (dd, J = 10.0, 7.6 Hz,
1H), 3.55 (dd, J = 10.0, 4.8 Hz, 1H), 2.03 (s, 3H), 1.68 – 1.43 (m,
8H), 1.39 (s, 3H), 1.34 – 1.22 (m, 15H), 0.96 – 0.83 (m, 21H),
0.08 – 0.02 (m, 12H). 13C NMR (100 MHz, CDCl3): δ = 170.9,
107.6, 77.9, 74.4, 73.9, 69.2, 62.1, 38.4, 36.1, 34.1 (2C), 31.7,
29.8, 28.3, 25.92 (3C), 25.87 (3C), 25.6, 25.3, 24.9, 24.3, 22.5,
21.3, 18.2, 18.1, 14.0, −4.2, −4.6, −5.4, −5.5. HRMS (ESI): m/z
[M+Na]+ calcd for C33H68O6Si2Na: 639.4452; found: 639.4452.
Preparation of (6R,12R)-12-((tert-butyldimethylsilyl)oxy)-13-
((4S,5R)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-
yl)tridecan-6-yl acetate (3)
Preparation
of
tert-butyl(((4R,5S)-5-((R)-2-((tert-
butyldimethylsilyl)oxy)hept-6-en-1-yl)-2,2-dimethyl-1,3-
dioxolan-4-yl)methoxy)dimethylsilane (5)
To a pre-cooled solution of diol 8 (0.16 g, 0.66 mmol) in dry
CH2Cl2 (8 mL) at 0 °C, under argon atmosphere, diisopropylethyl
amine (0.46 mL, 2.6 mmol), TBSOTf (0.32 mL, 1.4 mmol) were
added at the same temperature. The reaction mixture was warmed
to room temperature and stirred for 1 h. After completion of the
reaction (TLC), water (15 mL) was added and was extracted with
EtOAc (3 × 10 mL). The combined organic layers were washed
with brine (10 mL) and dried over anhydrous Na2SO4. Silica gel
column chromatography of the residue obtained after evaporation
of the solvent using petroleum ether:EtOAc (20:1) as eluent gave
the bis-silylether 5 (0.3 g, 97%) as a colorless oil; [α]ꢁꢀꢂ: −26.7 (c
0.9, CHCl3). IR (neat): 2936, 2860, 2358, 1466, 1373 cm−1.
1H NMR (400 MHz, CDCl3): δ = 5.79 (ddt, J = 16.8, 10.0, 6.4
Hz, 1H), 5.03 – 4.96 (m, 1H), 4.94 (d, J = 10.0 Hz, 1H), 4.33
(ddd, J = 10.0, 6.0, 2.4 Hz, 1H), 4.07 – 3.99 (m, 1H), 3.95 – 3.85
(m, 1H), 3.62 (dd, J = 10.4, 7.6 Hz, 1H), 3.55 (dd, J = 10.4, 4.8
Hz, 1H), 2.03 (q, J = 7.2 Hz, 2H), 1.73 – 1.36 (m, 9H), 1.32 (s,
3H), 0.88 (s, 18H), 0.08 – 0.02 (m, 12H). 13C NMR (100 MHz,
CDCl3): δ 138.8, 114.4, 107.6, 77.9, 73.8, 69.0, 62.1, 37.9, 36.1,
33.9, 28.3, 25.9 (3C), 25.86 (3C), 25.6, 23.7, 18.2, 18.1, ‒4.2, ‒
4.6, ‒5.4, ‒5.5. HRMS (ESI): m/z [M+Na]+ calcd for
C25H52O4Si2Na: 495.3302; found: 495.3300.
To pre-cooled solution of 10 (80 mg, 0.13 mmol) in THF (5 mL)
at −10 °C was added TBAF (0.16 mmol, 0.16 mL of 1M in THF)
under argon atmosphere, and the resulting solution allowed to
stir at 0 °C for 5 h. After the reaction was complete (TLC), it was
diluted with cold water and extracted with EtOAc (3 × 10 mL).
The combined organic extract was washed with brine (10 mL)
and dried over anhydrous Na2SO4. Evaporation of the solvent
followed by silica gel column chromatography of the crude
residue using petroleum ether/EtOAc (3:2) as eluent furnished 3
(26 mg, 40%), (80% brsm) as pale yellow oil; [α]ꢁꢀꢂ −8.9 (c 2.5,
CHCl3). IR (neat): 3486, 2986, 2930, 1733, 1640 cm−1. H NMR
1
(400 MHz, CDCl3): δ = 4.83 (quint, J = 6.2 Hz, 1H), 4.36 – 4.25
(m, 1H), 4.11 (dd, J = 11.2, 6.2 Hz, 1H), 3.85 (d, J = 3.6 Hz, 1H),
3.64 – 3.48 (m, 2H), 2.20 (s, 1H), 2.02 (s, 3H), 1.70 – 1.59 (m,
1H), 1.58 – 1.39 (m, 10H), 1.33 (s, 3H), 1.25 (s, 12H), 0.85 (d, J
= 10.9 Hz, 12H), 0.05 (s, 6H). 13C NMR (100 MHz, CDCl3): δ =
170.9, 107.7, 77.8, 74.3, 73.6, 69.4, 61.9, 38.2, 35.6, 34.04, 34.0,
31.6, 29.7, 28.1, 25.8 (3C), 25.4, 25.2, 24.9, 24.2, 22.3, 21.2,
18.0, 14.0, −4.3, −4.6. HRMS (ESI): m/z [M+Na]+ calcd for
C27H54O6SiNa: 525.3587; found: 525.3592.
Preparation of (6R,12R,E)-12-((tert-butyldimethylsilyl)oxy)-
13-((4S,5R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)tridec-7-en-6-yl acetate (9)
Preparation of ethyl (E)-3-((4R,5S)-5-((2R,8R)-8-acetoxy-2-
((tert-butyldimethylsilyl)oxy)tridecyl)-2,2-dimethyl-1,3-
dioxolan-4-yl)acrylate (11)
To a solution of the bis-silyl ether 5 (135 mg, 0.3 mmol) in
CH2Cl2 (6 mL) was added 4 (73 mg, 0.43 mmol) followed by
Grubbs’ 2nd generation catalyst (10.0 mg, 0.011 mmol) under
argon atmosphere and the resulting solution was stirred under
reflux for 3 h. After completion of the reaction (TLC), the solvent
was evaporated off and the crude residue thus obtained was
purified through silica gel column chromatography to afford the
compound 9 (123 mg, 70%) as colourless oil; [α]ꢁꢀꢂ: −12.6 (c 1.0,
CHCl3). IR (neat): 2933, 2859, 2359, 1739, 1465 cm−1.
To a stirred solution of the alcohol 3 (24 mg, 0.05 mmol) in dry
CH2Cl2 (2 mL) under nitrogen atmosphere, were added NaHCO3
(20 mg, 0.24 mmol) and Dess-Martin periodinane (30 mg, 0.07
mmol) at 0 °C. The reaction mixture was warmed to room
temperature and stirred for 2 h. After completion of the reaction
it was quenched by addition of saturated aqueous NaHCO3 (5
mL) and Na2S2O3 (5 mL). The aqueous phase was extracted with
Et2O (2 × 10 mL). The combined organic layers were washed
with water (10 mL), brine (10 mL) and dried over anhydrous
Na2SO4 and concentrated. The crude aldehyde thus obtained was
used as such in the next step without further purification.
To a solution of the crude aldehyde (obtained above), in toluene
(2 mL) were added the ylide (carbethoxymethylene)
triphenylphosphorane (25 mg, 0.07 mmol) under argon
atmosphere, and the reaction mixture was refluxed for 2 h. After
the reaction was complete (TLC), most of the solvent was
evaporated off and the residue thus obtained was purified by
column chromatography using petroleum ether/EtOAc (20:1) as
eluent to obtain the unsaturated ester 11 (17 mg, 63% over 2
steps) as yellow oil; [α]ꢁꢀꢂ −12.1 (c 0.85, CHCl3).IR (neat): 2936,
2857, 2361, 1729, 1651, 1373 cm−1. 1H NMR (400 MHz, CDCl3):
δ 6.83 (dd, J = 15.2, 6.0 Hz, 1H), 6.04 (dd, J = 15.2, 1.2 Hz, 1H),
4.90 – 4.79 (m, 1H), 4.63 (t, J = 6.0 Hz, 1H), 4.41 (ddd, J = 9.6,
1H NMR (400 MHz, CDCl3): δ = 5.67 (dt, J = 15.2, 6.4 Hz, 1H),
5.37 (dd, J = 15.2, 7.6 Hz, 1H), 5.18 (q, J = 6.8 Hz, 1H), 4.32
(ddd, J = 10.0, 6.0, 2.4 Hz, 1H), 4.08 – 3.99 (m, 1H), 3.93 – 3.85
(m, 1H), 3.62 (dd, J = 10.4, 7.6 Hz, 1H), 3.55 (dd, J = 10.4, 4.8
Hz, 1H), 2.07 – 1.97 (m, 5H), 1.72 – 1.42 (m, 8H), 1.39 (s, 3H),
1.32 (s, 3H), 1.31 – 1.24 (m, 6H), 0.91 – 0.85 (m, 21H), 0.07 –
0.03 (m, 12H). 13C NMR (100 MHz, CDCl3): δ = 170.4, 134.0,
128.6, 107.6, 77.9, 75.0, 73.8, 69.0, 62.1, 38.0, 36.1, 34.5, 32.4,
31.5, 28.3, 25.9 (3C), 25.86 (3C), 25.6, 24.8, 23.7, 22.5, 21.4,
18.2, 18.1, 14.0, −4.2, −4.6, −5.4, −5.5. HRMS (ESI): m/z
[M+Na]+ calcd for C33H66O6Si2Na: 637.4296; found: 637.4298.
Preparation of (6R,12R)-12-((tert-butyldimethylsilyl)oxy)-13-
((4S,5R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)tridecan-6-yl acetate (10)
To a solution of 9 (0.122 g, 0.2 mmol) in hexane (5 mL) was
added 10% Pd/C (20 mg) under argon atmosphere. The mixture

4
Tetrahedron
ACCEPTED MANUSCRIPT
6.4, 3.2 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 3.89 – 3.78 (m, 1H),
The reaction mixture was diluted with EtOAc (5 mL) and washed
2.03 (s, 3H), 1.55 – 1.39 (m, 11H), 1.36 (s, 3H), 1.34 – 1.16 (m,
15H), 0.91 – 0.83 (m, 12H), 0.053 (s, 3H), 0.049 (s, 3H). 13C
NMR (100 MHz, CDCl3): δ 170.9, 166.1, 144.3, 122.8, 108.7,
77.3, 74.4, 74.3, 69.0, 60.4, 38.2, 37.5, 34.1, 34.0, 31.7, 29.8,
28.0, 25.9 (3C), 25.5, 25.3, 24.9, 24.3, 22.5, 21.3, 18.0, 14.2,
14.0, −4.3, −4.6. HRMS (ESI): m/z [M+Na]+ calcd for
C31H58O7SiNa: 593.3850; found: 593.3848.
successively with saturated aqueous NaHCO3 (5 mL) and brine
(5 mL). The combined organic layers were dried over Na2SO4
and concentrated in vacuo to get the crude product, which on
purification using silica gel column chromatography with 50%
EtOAc in petroleum ether as an eluent afforded Sch 725674 (1)
(3 mg) as an amorphous white solid in 50% yield. Rf = 0.10 (50%
EtOAc in petroleum ether), M.P.: 181-184 °C, [Lit.3b M.P.: 180-
184 °C]; [α]ꢁꢀꢂ: +4.7 (c 0.15, CH3OH), [Lit.3b [α]ꢁꢀꢂ : +5.0 (c 0.1,
CH3OH)]. IR (KBr): 3441, 3268, 2926, 2855, 2363, 1705, 1590
Preparation
of
(E)-3-((4R,5S)-5-((2R,8R)-2-((tert-
butyldimethylsilyl)oxy)-8-hydroxytridecyl)-2,2-dimethyl-1,3-
dioxolan-4-yl)acrylic acid (2): To a stirred solution of 11 (17
mg, 0.02 mmol) in MeOH:THF (1:1, 1.0 mL) was added 1 M
aqueous LiOH (0.5 mL, 0.5 mmol) and was stirred at room
temperature for 7 h. After completion of the reaction (TLC), the
solvent was evaporated off to give the residue, which was diluted
with water (5 mL), neutralized with a saturated solution of citric
acid (pH 4), and extracted with EtOAc (2 × 10 mL). The
combined organic layers were washed with brine (5 mL) and
dried (anhydrous Na2SO4). The solvent was removed under
reduced pressure and the resulting seco-acid 2 (14 mg, 94%),
which was subjected to the next reaction without further
purification; [α]ꢁꢀꢂ −15.7 (c 1.1, CHCl3). IR (neat): 3401, 2929,
2857, 2685, 2359, 1704, 1653 cm−1. 1H NMR (400 MHz, CDCl3):
δ = 6.94 (dd, J = 15.6, 6.0 Hz, 1H), 6.07 (dd, J = 15.6, 1.6 Hz,
1H), 5.10 (bs, 2H), 4.75 – 4.59 (m, 1H), 4.51 – 4.38 (m, 1H),
3.96 – 3.77 (m, 1H), 3.68 – 3.52 (m, 1H), 1.54 – 1.20 (m, 26H),
0.96 – 0.81 (m, 12H), 0.063 (s, 3H), 0.060 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ = 170.3, 147.0, 122.0, 108.8, 77.2, 74.9,
72.1, 69.1, 38.2, 37.5, 37.3, 31.9, 29.9, 29.7, 27.9, 25.9 (3C),
25.5, 25.5, 25.3, 24.3, 22.6, 18.1, 14.0, −4.2, −4.6. HRMS (ESI):
m/z [M+Na]+ calcd for C27H52O6SiNa: 523.3431; found:
523.3431.
cm−1. H NMR (400 MHz, CD3OD): δ = 6.88 (dd, J = 15.6, 5.6
1
Hz, 1H), 6.09 (dd, J = 15.6, 1.6 Hz, 1H), 4.99-4.92 (m, 1H), 4.53
– 4.45 (m, 1H), 3.99 (quint, J = 6.4 Hz, 1H), 3.89 – 3.80 (m, 1H),
1.84 (dt, J = 14.8, 6.0 Hz, 1H), 1.76 – 1.52 (m, 5H), 1.49 – 1.28
(m, 11H), 1.24 – 1.11 (m, 3H), 0.91 (t, J = 6.4 Hz, 3H). 13C
NMR (100 MHz, CD3OD): δ = 168.3, 149.4, 123.1, 77.7, 76.1,
72.9, 69.5, 38.3, 36.8, 36.5, 34.1, 33.0, 29.5, 27.0, 26.4, 25.8,
23.8, 14.5. HRMS (ESI): m/z [M+Na]+ calcd for C18H32O5Na:
351.2147; found: 351.2147.
Acknowledgments
K.V. thanks University Grants commission (UGC) for
fellowship. K.R.P thanks Science and Engineering Research
Board (SERB), New Delhi for funding. We thank Mr. Yougant
Arian for his help in preparation of compounds 13-15 and Dr. L.
N. Nanda for his help in preparation of the manuscript.
Supplementary Material
Copies of H NMR and 13C NMR spectra for all the new
compounds synthesized are provided.
1
Preparation
of
(3aR,8R,14R,15aS,E)-14-((tert-
butyldimethylsilyl)oxy)-2,2-dimethyl-8-pentyl-
References and notes
3a,8,9,10,11,12,13,14,15,15a-decahydro-6H-[1,3]dioxolo[4,5-
e][1]oxacyclotetradecin-6-one (12): To a solution of the acid 2
(14 mg, 0.028 mmol) and Et3N (0.02 mL, 0.17 mmol) in
anhydrous toluene (2.0 mL) was added 2,4,6-trichlorobenzoyl
chloride (24 µL, 0.17 mmol) dropwise under argon atmosphere at
0 °C. The mixture was stirred at room temperature for 1 h and
diluted with anhydrous toluene (6 mL). It was added dropwise to
a solution of DMAP (51 mg, 0.42 mmol) in anhydrous toluene (3
mL) at room temperature. On completion of the addition, the
mixture was stirred for 1 h at room temperature. After completion
of the reaction (TLC), it was quenched by addition of NaHCO3
and extracted with EtOAc (3 × 10 mL). The combined organic
extracts were washed with brine (10 mL) and dried over
anhydrous Na2SO4. Evaporation of the solvent followed by silica
gel column chromatography of the crude residue using petroleum
ether/EtOAc (1:9) as eluent furnished the macrolactone 12 (10
mg, 76%) as yellow oil; [α]ꢁꢀꢂ: −9.1 (c 0.5, CHCl3). IR (neat):
(1) Yang, S, -W.; Chan, T. -M.; Terracciano, J.; Loebenberg, D.; Patel, M.;
Chu, M. J. Antibiot. 2005, 58, 535.
(2) Moretti, J. D.; Wang, X.; Curran, D. P. J. Am. Chem. Soc. 2012, 134, 7963.
(3) (a) Sunnam, S. K.; Prasad, K. R. Tetrahedron, 2014, 70, 2096. (b) Bali, A.
K.; Sunnam, S. K.; Prasad, K. R. Org. Lett. 2014, 16, 4001.
(4) (a) Ramakrishna, K.; Kaliappan, K. P. Org. Biomol. Chem., 2015, 13, 234.
(b) Seetharamsingh, B.; Khairnar, P.V.; Reddy, D. S. J. Org. Chem. 2016,
81, 290. (c) Bodugam, M.; Javed, S.; Ganguly, A.; Torres, J.; Hanson, P. R.
Org. Lett. 2016, 18, 516. (d) Sharma, B. M.; Gontala, A.; Kumar, P. Eur.
J. Org. Chem. 2016, 1215. (e) Reddy, Y.; Sabitha, G. ChemistrySelect
2016, 1, 2156. (f) Fawcett, A.; Nitsch, D.; Ali, M.; Bateman, J. M..;
Myers, E. L.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2016, 55, 14663.
(5) Corey, E. J.; Marfat, A.; Goto, G.; Brion, F. J. Am. Chem. Soc. 1980, 102,
7984.
(6) Streochemistry of the major diastereomer 7 was assigned based on a
reported analogous addition of heptylmagnesium bromide to the lactol 6
see: Thakur, P.; Kumaraswamy, B.; Reddy, G. R.; Bandichhor, R.;
Mukantii, K. Tetrahedron: Asymmetry 2012, 23, 547. Stereochemistry of
the syn and anti alcohols 7 and 8 was further confirmed by Rychnovsky’s
method of estimation of the 13C NMR resonances of the acetal carbon and
gem-dimethyl carbons of the 1,3-acetonides 13 and 14 obtained by reaction
of 7 and 8 with 2,2-dimethoxypropane (see supporting information for
procedure and spectra)
1
2931, 2859, 2363, 1720, 1640, 1461 cm−1. H NMR (400 MHz,
CDCl3): δ = 6.77 (dd, J = 15.6, 8.4 Hz, 1H), 5.97 (d, J = 15.6 Hz,
1H), 5.00–4.88 (m, 1H), 4.69–4.61 (m, 1H), 4.48 (q, J = 6.0 Hz,
1H), 3.91–3.81 (m, 1H), 1.76–1.53 (m, 5H), 1.52-1.48 (m, 4H),
1.46–1.39 (m, 3H), 1.38–1.24 (m, 14H), 0.91–0.85 (m, 12H),
0.06 (s, 3H), 0.04 (s, 3H). 13C NMR (100 MHz, CDCl3) δ =
165.8, 144.2, 124.3, 108.7, 77.5, 76.0, 75.1, 69.1, 37.24, 37.17,
34.6, 31.7, 31.6, 29.7, 27.9, 25.9 (3C), 25.3, 25.2, 25.1, 23.7,
22.5, 18.1, 14.0, −4.6, −4.7. HRMS (ESI): m/z [M+Na]+ calcd for
C27H50O5SiNa: : 507.3325; found: : 507.3325.
Preparation
pentyloxacyclotetradec-3-en-2-one (1): To
of
(5R,6S,8R,14R,E)-5,6,8-trihydroxy-14-
solution of
a
macrolactone 12 (9 mg, 0.02 mmol) in 2.2 mL of MeOH-THF-
H2O (10:5:1) was added camphorsulphonic acid (15 mg, 0.06
mmol) in one portion at room temperature and stirred for 24 h.

5
ACCEPTED MANUSCRIPT
(7) The allyl acetate 4 was prepared from rac-4 using enzymatic procedure as
described in literature. Ferreira, H. V.; Rocha, L. C.; Severino, R. P.; Porto,
A. L. M. Molecules, 2012, 17, 8955.
(8) For a review on olefin cross metathesis see: (a) Chatterjee, A. K.; Choi, T. -
L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360. (b)
Vougioukalakis, G. C.; Grubbs, R. H. Chem. Rev. 2010, 110, 1746.
(9) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.