A Concise and Stereoselective Total Synthesis of Pestalotioprolide C Using Ring-Closing Metathesis

Article abstract of DOI:10.1055/s-0036-1589152

The stereoselective total synthesis of the pestalotioprolide C is disclosed in 13 linear steps in 4% overall yield. The key steps in this approach are a ring-closing-metathesis protocol for the construction of the 14-membered macrolide with E -olefinic bo

Full text of DOI:10.1055/s-0036-1589152

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
©
Georg Thieme Verlag Stuttgart · New York
2017, 49, A–G
paper
A
en
Synthesis
G. R. Kundoor et al.
Paper
A Concise and Stereoselective Total Synthesis of Pestalotioprolide C
Using Ring-Closing Metathesis
Govinda Reddy Kundoor
Suresh Kumar Battina
Keck allylation
Sharpless kinetic resolution
Palakodety Radha Krishna*
OH
OH
D-211, Discovery Laboratory, Organic and Biomolecular
Chemistry Division, CSIR-Indian Institute of Chemical
Technology, Hyderabad-500007, India
prkgenius@iict.res.in
O
O
Ring-closing metathesis
pestalotioprolide C
Received: 12.11.2017
Accepted after revision: 16.11.2017
Published online: 20.12.2017
OH
O
H
7
4
OH
OMe
O
OH
OH
3
2
DOI: 10.1055/s-0036-1589152; Art ID: ss-2017-n0598-op
14
O
H
1
O
1
3
Abstract The stereoselective total synthesis of the pestalotioprolide C
is disclosed in 13 linear steps in 4% overall yield. The key steps in this
approach are a ring-closing-metathesis protocol for the construction of
the 14-membered macrolide with E-olefinic bond, a Keck allylation, and
a Sharpless kinetic resolution for the installation of desired stereocen-
ters at C4 and C7.
O
O
O
O
pestalotioprolide C (1)
pestalotioprolide B (2)
RO
pestalotioprolide D (3)
HO
R
O
O
O
O
Key words pestalotioprolide C, 14-membered macrolide, Keck allyla-
tion, Sharpless kinetic resolution, ring-closing metathesis
O
pestalotioprolide E, R = alpha-OH (4)
pestalotioprolide F, R = beta-OH (5)
pestalotioprolide G, R = Me (6)
pestalotioprolide H, R = H (7)
Fourteen-membered macrolides have received a lot of
attention from researchers because of their prominent bio-
Figure 1 Structures of pestalotioprolides
1
2
logical activities like antibacterial, antifungal, and cyto-
3
cidal properties. Some of the 14-membered lactones are
the key step to assemble the macrolactone while Keck al-
lylation and Sharpless kinetic resolution were invoked to
acquire the required C7, C4 stereogenic centers and C13
was achieved through commercially available (S)-propylene
oxide.
The retrosynthetic analysis of macrolide 1 is depicted in
Scheme 1. RCM was envisioned to be the key macrocycliza-
tion strategy. The RCM precursor diene 8 could be realized
from 9 by silyl deprotection, followed by acryloylation.
Compound 9 could be generated from 10 by sequential
transformations such as hydroboration, oxidation, vinyla-
tion, and Sharpless kinetic resolution. Further, the homoal-
lylic alcohol 10 can be synthesized from 11 by hydrobora-
tion, and oxidation followed by Keck allylation. The alcohol
11 could be accessed from regioselective ring-opening reac-
tion of epoxide 13 with 5-bromopent-1-ene (12).
used in the treatment of bacterial infections (erythromy-
4
5
cin, clarithromycin ). Recently, new 14-membered macro-
lides, pestalotioprolide B–H (Figure 1) were isolated from
the Mangrove derived endophytic fungus Pestalotiopsis mi-
6
crospora by Liu and Prokch. Amongst these pestalospro-
lides, structurally pestalotioprolide C (1) is endowed with
three stereogenic centers at C4, C7, C13 and an E-olefinic
bond, which is in conjugation with an acid functional group
that is locked in the form of a macrolide. The absolute ste-
reochemistry at three stereocenters of pestalotioprolide C
was determined as 4S, 7S, and 13S by X-ray crystal struc-
ture analysis. The key structural features and the potential
biological activities of this group of macrolides motivated
us to take up their synthesis.
7
Recently Sabitha et al. reported the first synthesis of
pestalotioprolide C and its C7 epimer using Shinna macro-
lactonization as the key step. Our approach is strategically
different, which involved ring-closing metathesis (RCM) as
Accordingly, to begin our synthesis, the commercially
available starting material (S)-propylene oxide (13) on
regioselective ring-opening reaction with freshly prepared
pent-4-en-1-ylmagnesium bromide [generated in situ from
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

B
Synthesis
G. R. Kundoor et al.
Paper
OMOM
OMOM
OTBDPS
OMOM
OH
OH
O
OMOM
9
O
O
O
1
8
OTBDPS
OTBDPS
OH
O
+
Br
13
12
11
10
Scheme 1 Retrosynthetic analysis of pestalotioprolide C
5
-bromopent-1-ene (12) and Mg] in the presence of cata-
diastereoselectivity (dr 96:4 as determined by HPLC). The
stereochemical outcome of this reaction is consistent with
the model for Keck allylation, wherein (R)-BINOL provides
the S-enantiomer of the homoallylic alcohol, which was
confirmed by Mosher ester analysis11 (see the Supporting
Information for details).
After establishing the stereochemistry, protection of the
homoallylic hydroxy group in 10 as its MOM ether was ac-
complished by the treating with MOM-Cl and DIPEA in
8a
lytic amount of CuI (10 mol%) in anhydrous THF furnished
1
ing hydroxyl group of olefinic alcohol 14 with tert-butyldi-
phenylsilyl chloride (TBDPSCl) in CH Cl and imidazole af-
forded 11 in 91% yield. Subsequently, the terminal olefin in
compound 11 was transformed into primary alcohol by hy-
droboration-oxidation reaction set with 9-BBN and hydro-
gen peroxide to result in 15 (79% yield). The thus generated
primary alcohol 15 was oxidized using IBX and DMSO in
CH Cl at 0 °C to room temperature for 2 hours to provide
8b
4
in 86% yield (Scheme 2). Next, protection of the ensu-
10
2
2
9
CH Cl2 at 0 °C to room temperature to afford 16 in 87%
2
yield. Next, the terminal olefin 16 was subjected to hydrob-
oration-oxidation with 9-BBN and hydrogen peroxide to af-
ford primary alcohol 17 in 80% yield. The thus obtained pri-
mary alcohol 17 was oxidized using Dess–Martin reagent to
offer the corresponding aldehyde, which was treated with
2
2
the corresponding aldehyde. Immediately, this aldehyde
was subjected to asymmetric Keck allylation [(R)-BINOL,
Ti(Oi-Pr) and allyltributyltin in CH Cl at –20 °C, 36 h] to
10
4
2
2
afford the homoallylic alcohol 10 in 76% yield with high
OH
OTBDPS
O
a
b
13
14
11
OTBDPS
OTBDPS
OH
c
d
OH
15
10
OTBDPS
OMOM
OTBDPS
OMOM
e
f
OH
16
17
OTBDPS
OMOM
g
OH
1
8
Scheme 2 Reagents and conditions: a) pent-4-en-1-yl magnesium bromide, CuI, anhyd THF, –78 °C to r.t., 3 h, 86%; b) TBDPSCl, imidazole, CH Cl , 0 °C
2
2
to r.t., 12 h, 91%; c) 9-BBN, THF, NaOH, H O , 0 °C to r.t., 8 h,79%; d) (i) IBX, DMSO, CH Cl , 0 °C to r.t., 2 h; (ii) (R)-BINOL, allyltributyltin, Ti(Oi-Pr) ,
2
2
2
2
4
–
0
78 °C, 36 h, 76% (over two steps); e) MOM-Cl, DIPEA, CH Cl , 0 °C to r.t., 4 h, 87%; f) 9-BBN, THF, NaOH, H O , 0 °C to r.t., 8 h, 80%; g) (i) DMP, CH Cl ,
°C to r.t., 2 h, (ii) vinylmagnesium bromide, THF, –78 °C,1 h, 75% (over two steps).
2
2
2
2
2
2
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

C
Synthesis
G. R. Kundoor et al.
Paper
OTBDPS
OMOM
OTBDPS
OMOM
O
a
18
+
18a
OH
19
OH
Scheme 3 Reagents and conditions: a) Ti(Oi-Pr) , (–)-DIPT, TBHP, CH Cl , –20 °C, 16 h, 44%.
4
2
2
vinylmagnesium bromide (1 M solution in THF) at –78 °C to
furnish a mixture of diastereomers 18 (dr 48:52 as deter-
mined by HPLC).
not initiated even at longer reaction times. Next, when the
reaction mixture was run at higher temperature for 12
hours, lower yields (<30%) of the cyclized product was ob-
tained. Higher catalyst loading of G-I (up to 10 mol%) did
not improve the yield. To enhance the yield of macrocycle
product, next we conducted the RCM13 reaction of diene 8
under G-II conditions at reflux for 12 hours to furnish 21
with an E-olefinic bond (J = 15.8 Hz) in 65% yield. Finally,
the deprotection of MOM groups on exposure to 6 N HCl af-
forded the target compound 1 in 88% yield.
Interestingly, both the diastreomers were found to have
same R values and our attempts to separate them were un-
f
successful. Alternatively, allylic alcohol 18 was protected as
its MOM ether in an effort to facilitate the separation of di-
asteromers, however, their separation could not be realized.
Therefore, we resorted to the Sharpless kinetic resolution to
garner the S-configured allylic alcohol in optically pure
form. Thus, alcohol 18 (Scheme 3) was resolved under Shar-
1
13
The H and C NMR data of synthetic compound 1 were
12
pless kinetic resolution [Ti(Oi-Pr) , (–)-DIPT and TBHP in
in agreement with the natural product and the optical rota-
4
6
CH Cl at –20 °C, 16 h] conditions to afford the allylic alco-
tion has shown equal sign to that of natural product. In
2
2
hol 18a (dr 97:3 by HPLC analysis) in 44% yield, which was
separated from epoxy alcohol 19. Later, the absolute stereo-
chemistry of the thus-generated stereocenter in allylic alco-
hol 18a was established on completion of the total synthe-
summary, we have accomplished the stereoselective total
synthesis of pestalotioprolide C (1) in 13 linear steps by in-
voking Keck allylation, Sharpless kinetic resolution, and
ring-closing metathesis as key steps in an overall yield of
4%.
6,7
sis and correlating with the reported data.
Next, the allylic alcohol 18a (Scheme 4) was protected
as its MOM ether (MOM-Cl and DIPEA in CH Cl at 0 °C to
2
2
1
H NMR spectra were recorded at 300/400/ 500 MHz, as specified, 13C
r.t.) to furnish the MOM protected olefin 9 in 85% yield.
Then deprotection of the silyl group by TBAF in THF gave
the secondary alcohol 20 in 89% yield. Esterification of sec-
ondary alcohol 20 with acryloyl chloride and triethylamine
in CH Cl provided the RCM precursor diene 8 in 86% yield.
1
NMR spectra were recorded at 100 or 125 MHz, as specified. H and
13
C NMR spectra were obtained from CDCl3 or CD OD as solvent.
3
Chemical shifts are reported in parts per million (ppm) on the δ scale
and coupling constants, J, are in hertz (Hz). Reactions were carried
out under N2 in anhydrous solvents. Air-sensitive reagents were
transferred by syringe and double-ended needle. All reactions were
monitored by TLC and silica-coated plates were visualized by expo-
sure to ultraviolet light and/or α-naphthol charring. Organic solutions
were dried (Na SO ) and concentrated below 40 °C under reduced
2
2
Our next task is the construction of macrolactone by invok-
ing the ring-closing metathesis reaction. Thus, initially we
tried RCM with G-I catalyst in CH Cl at room temperature
2
2
conditions. However, under these conditions, the diene 8
remained inert and it was observed that the reaction was
2
4
pressure. All column chromatographic (CC) separations were
OTBDPS
OMOM
OH
OMOM
a
b
18a
OMOM
OMOM
9
20
OMOM
OMOM
OMOM
c
d
e
OMOM
1
Mes
N
N
Mes
Ph
O
O
Cl
Cl
O
O
Ru
8
21
PHCy3
2nd generation
Grubbs catalyst
Scheme 4 Reagents and conditions: a) MOM-Cl, DIPEA, CH Cl , 0 °C to r.t., 4 h, 85%; b) TBAF, THF, 0 °C to r.t.,12 h, 89%; c) acrolyl chloride, Et N, CH Cl ,
2
2
3
2
2
0
°C to r.t., 0.5 h, 86%; d) Grubbs-II catalyst, anhyd CH Cl , reflux, 12 h, 65%; e) 6 N HCl, THF, r.t., 2 h, 88%.
2 2
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

D
Synthesis
G. R. Kundoor et al.
Paper
performed using silica gel (SiO ; 60–120 mesh) with EtOAc and n-hexane
To a mixture of (R)-BINOL (0.43 g, 1.56 mmol), molecular sieves (4Å)
in CH Cl (25 mL) was added Ti(Oi-Pr) (0.23 mL, 0.78 mmol), and the
2
as eluents. Yields refer to chromatographically and spectroscopically
2
2
4
1
13
(
H and C NMR) homogeneous materials. IR spectra were recorded
resultant mixture was heated under reflux for 1 h. To the reaction
mixture at r.t. was added the above prepared aldehyde (3 g, 7.85
mmol) in CH Cl (6 mL), and the resultant mixture was stirred for 10
on a Bruker alpha spectrometer. Optical rotations were measured
–
1
with a JASCO P-2000 instrument and [α] values were in units of 10
D
2
2
2
–1
deg cm g at 20 °C, Elemental analysis was performed with an Ele-
mental Micro Qube CHN analyzer and High-resolution mass spectra
were recorded by using a Thermo Scientific Orbitrap.
min. The mixture was cooled to –78 °C and treated with allyltribut-
yltin (2.6 mL, 8.57 mmol). The resultant mixture was stirred at –20 °C
for 76 h. The mixture was quenched with sat. aq NaHCO3 at –78 °C.
The resultant mixture was diluted with CH Cl (25 mL), allowed to
Chromatography was carried out using a Shimadzu HPLC system
2
2
warm to r.t. over 1.5 h, and filtered through a pad of Celite. The filtrate
was extracted with CH Cl (3 × 30 mL), and the combined organic lay-
(20AD Japan), consisting of a Binary Pump and Degasser. The separa-
tion of analytes was performed on C18 (250 mm × 4.6 mm i.d, 5 μm)
2
2
ers were washed with brine (20 mL), dried (Na SO ), concentrated un-
using a mobile phase consisting of MeCN/H O (90:10, v/v), pumped at
2
4
2
der reduced pressure. The residue was purified by column chroma-
tography on silica gel (9:1, hexane/EtOAc) to afford the homoallylic
a flow rate of 1.0 mL/min. The injection volume was 20 μL and the
total analysis time per sample was 15 min.
20
alcohol 10 (2.52 g, 76%) as a pale yellow oil; [α]D –7.1 (c 0.4, CHCl3).
IR (neat): 3395, 2930, 2857, 1464, 1427, 1108, 702 cm–1
1H NMR (500 MHz, CDCl
): δ = 7.70–7.65 (m, 4 H), 7.44–7.33 (m, 6 H),
.
(S)-tert-Butyl(oct-7-en-2-yloxy)diphenylsilane (11)
To a solution of alcohol 148b (2 g, 15.62 mmol) in anhyd CH Cl (45
2
2
3
mL) was added imidazole (2.1 g, 31.17 mmol) at 0 °C and the mixture
was stirred for 15 min. Then TBDPSCl (5.1 mL, 18.69 mmol) was add-
ed and the mixture was stirred at r.t. for 12 h. After completion of the
reaction, the solvent was evaporated and the residue purified by col-
umn chromatography on silica gel (15:1, hexane/EtOAc) to afford 11
5.82 (dddd, J = 14.3, 9.3, 7.7, 6.8 Hz, 1 H), 5.13 (dd, J = 13.7, 1.4 Hz, 2
H), 3.83 (dd, J = 12.0, 6.0 Hz, 1 H), 3.61 (s, 1 H), 2.33–2.25 (m, 1 H),
2.16–2.08 (m, 1 H), 1.50–1.25 (m, 10 H), 1.06–1.03 (m, 12 H).
13
C NMR (125 MHz, CDCl ): δ = 135.9, 134.9, 134.7, 129.5, 129.4,
3
127.5, 127.4, 118.0, 70.7, 69.6, 42.0, 39.4, 36.8, 29.7, 27.1, 25.6, 25.2,
25
(5.2 g, 91%) as a colorless oil; [α]D –5.4 (c 0.9, CHCl3).
23.3, 19.3.
IR (neat): 2930, 2857, 1468, 1437, 1106 cm–1
.
HRMS: m/z [M + NH4]+ calcd for C27H44NO Si: 442.3136; found:
2
1
H NMR (400 MHz, CDCl ): δ = 7.69–7.66 (m, 4 H), 7.41–7.34 (m, 6 H),
442.3162.
3
5
1
.76 (ddt, J = 16.9, 10.2, 6.7 Hz, 1 H), 4.99–4.88 (m, 2 H), 3.85–3.81 (m,
H), 1.96 (t, J = 6.8 Hz, 2 H), 1.51–1.24 (m, 6 H), 1.06–1.03 (m, 12 H).
(4S/R,10S)-10-[(tert-Butyldiphenylsilyl)oxy]undec-1-en-4-ol14
1
3
C NMR (100 MHz, CDCl ): δ = 139.1, 135.9, 135.0, 134.6, 129.4,
Conducted Grignard allylation of aldehyde (aldehyde taken from
above, which was used for the Keck allylation) to produce homoallylic
alcohol (dr 1:1 as determined by HPLC; see Supporting Information).
3
1
29.4, 127.5, 127.4, 114.2, 69.6, 39.3, 33.7, 28.9, 27.1, 24.8, 23.2, 19.3.
Anal. Calcd for C24H34OSi: C, 78.63; H, 9.35. Found: C, 78.32; H, 9.42.
Mosher Method; General Procedure
(S)-7-[(tert-Butyldiphenylsilyl)oxy]octan-1-ol (15)
Mosher acid (S or R) (5.4 mg, 0.023 mmol), DCC (4.8 mg, 0.023 mmol),
and DMAP (cat.) were added to a solution of 10 (5 mg, 0.011 mmol) in
CH Cl (2 mL) at r.t. and the reaction mixture was stirred for 4 h. After
To a stirred solution of terminal olefin 11 (4.6 g, 12.56 mmol) in an-
hyd THF (20 mL) at 0 °C was added 9-BBN (0.5 M in THF, 37.0 mL,
18.85 mmol) dropwise over 10 min. After 6 h at r.t., a solution of aq 3
2
2
completion of the reaction (indicated by TLC), the mixture was fil-
tered through a short pad of Celite and the Celite pad was washed
with Et O (25 mL). Et O was evaporated under reduced pressure and
M NaOH (20 mL) and 35% H O (20 mL) was added portionwise at
2
2
0
°C. After 2 h at r.t., the reaction mixture was poured into brine (50
mL) and extracted with Et O (2 × 100 mL). The combined organic lay-
2
2
2
the residue was purified by column chromatography on silica gel
9.7:0.3, hexane/EtOAc) to afford compound 10a (if S-Mosher acid is
used) and 10b (if R-Mosher acid is used).
ers were dried (Na SO ), concentrated, and the residue was purified
2
4
(
by flash chromatography on silica gel (9:1, hexane/EtOAc) to afford
20
alcohol 15 (3.8 g, 79%) as a colorless oil; [α]D –40.9 (c 0.9, CHCl3).
IR (neat): 3363, 2927, 2856, 1447, 1167, 1107, 1052, 754 cm–1
.
(
4S,10S)-10-[(tert-Butyldiphenylsilyl)oxy]undec-1-en-4-yl (S)-
1
H NMR (400 MHz, CDCl ): δ = 7.71–7.64 (m, 4 H), 7.46–7.32 (m, 6 H),
3
3,3,3-Trifluoro-2-methoxy-2-phenylpropanoate (10a)
3.90–3.77 (m, 1 H ), 3.60 (t, J = 6.6 Hz, 2 H), 1.52–1.20 (m, 10 H), 1.08–
Yield: 6.6 mg (88%); pale yellow oil.
1
1.00 (m, 12 H).
H NMR (400 MHz, CDCl ): δ = 7.69–7.63 (m, 4 H), 7.56–7.51 (m, 2 H),
13
3
C NMR (100 MHz, CDCl ): δ = 135.9, 134.9, 134.7, 129.4, 129.4,
3
7
3
.43–7.34 (m, 9 H), 5.75 (ddt, J = 16.5, 10.8, 7.0 Hz, 1 H), 5.15–5.08 (m,
H), 3.81–3.78 (m, 1 H), 3.55 (s, 3 H), 2.40 (t, J = 6.5 Hz, 2 H), 1.54–
127.4, 127.4, 69.6, 63.1, 39.4, 32.7, 29.4, 27.1, 25.7, 25.2, 23.2, 19.3.
HRMS: m/z [M + Na]+ calcd for C24H36O SiNa: 407.2382; found:
2
1.28 (m, 4 H), 1.19–1.06 (m, 6 H), 1.06–1.02 (m, 12 H).
407.2390.
(
3
4S,10S)-10-[(tert-Butyldiphenylsilyl)oxy]undec-1-en-4-yl (R)-
,3,3-Trifluoro-2-methoxy-2-phenylpropanoate (10b)
(
4S,10S)-10-[(tert-Butyldiphenylsilyl)oxy]undec-1-en-4-ol (10)
To an ice-cooled solution of IBX (3.6 g, 12.85 mmol) in DMSO (2.9 mL,
8.58 mmol) and CH Cl (25 mL) was added a solution of alcohol 15
Yield: 6.8 mg (91%); pale yellow oil.
1
3
2
2
H NMR (400 MHz, CDCl ): δ = 7.69–7.65 (m, 4 H), 7.56–7.51 (m, 2 H),
3
(
3.3 g, 8.59 mmol) in CH Cl (5 mL). The mixture was stirred at r.t. for
2 2
7
1
.42–7.33 (m, 9 H), 5.63 (ddt, J = 19.9, 9.6, 7.1 Hz, 1 H), 5.13–5.07 (m,
H), 5.04–4.97 (m, 2 H), 3.84–3.80 (m, 1 H), 3.57–3.54 (m, 3 H), 2.33
2
×
h and then filtered through a Celite pad and washed with CH Cl (3
2 2
25 mL). The organic filtrate was sequentially washed with H O (25
2
(t, J = 6.2 Hz, 2 H), 1.55–1.30 (m, 4 H), 1.24–1.12 (m, 6 H), 1.07–1.02
mL) and brine (25 mL), later dried (Na SO ), and concentrated in vac-
uo. The crude aldehyde (3 g, 90%, viscous liquid) was immediately
subjected to the next reaction without further purification.
2
4
(m, 12 H).
©
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E
Synthesis
G. R. Kundoor et al.
Paper
(5S,11S)-5-Allyl-11,14,14-trimethyl-13,13-diphenyl-2,4,12-trioxa-
resulting mixture was stirred at –78 °C for 1 h, quenched by the addi-
13-silapentadecane (16)
tion of aq NH Cl, and then warmed to r.t. The mixture was extracted
4
with EtOAc (3 × 15 mL), and the combined organic layers were
To a solution of homoallylic alcohol 10 (2.3 g, 5.47 mmol) in anhyd
washed with brine (15 mL), dried (Na SO , and concentrated under
CH Cl (15 mL) at 0 °C were successively added DIPEA (2.80 mL, 16.35
2
4)
2
2
reduced pressure. The residue was purified by column chromatogra-
phy on silica gel (9:1, hexane/EtOAc) to afford allylic alcohol 18 (1.4 g,
mmol), a catalytic amount of DMAP, and MOMCl (0.62 mL, 8.20
mmol). The mixture was stirred for 4 h at r.t., then the reaction was
75% over two steps) as a pale yellow oil.
quenched by adding H O (8 mL), and the mixture was extracted with
2
IR (neat): 3434, 2929, 2856, 1427, 1464, 1105, 1034, 701 cm–1
.
CH Cl (30 mL). The organic layer was washed with brine (15 mL),
2
2
dried (Na SO ), and the solvent was evaporated under reduced pres-
sure. The residue was purified by column chromatography on silica
1
2
4
H NMR (400 MHz, CDCl ): δ = 7.69–7.66 (m, 4 H), 7.42–7.34 (m, 6 H),
3
5
.87 (ddd, J = 17.1, 10.4, 6.0 Hz, 1 H), 5.24 (ddd, J = 17.2, 2.6, 1.3 Hz, 1
H), 5.11 (ddd, J = 10.4, 3.4, 1.4 Hz, 1 H), 4.65–4.63 (m, 2 H), 4.11 (s, 1
H), 3.84–3.79 (m, 1 H), 3.59–3.52 (m, 1 H), 3.37 (dd, J = 1.7, 0.6 Hz, 3
H), 1.54–1.14 (m, 14 H), 1.07–1.03 (m, 12 H).
gel (15:1, hexane/EtOAc) to afford 16 (2.2 g, 87%); pale yellow oil;
20
[
α]D –6.6 (c 0.6, CHCl3).
IR (neat): 2931, 2857, 1467, 1428, 1107, 1047, 703 cm–1
.
1
13
H NMR (400 MHz, CDCl ): δ = 7.70–7.66 (m, 4 H), 7.42–7.34 (m, 6 H),
C NMR (100 MHz, CDCl ): δ = 141.2, 141.1, 135.9, 135.0, 134.6,
3
3
5
1
2
.81 (ddt, J = 17.2, 10.2, 7.1 Hz, 1 H), 5.12–5.03 (m, 2 H), 4.65 (dd, J =
8.0, 6.9 Hz, 2 H), 3.84–3.78 (m, 1 H), 3.59–3.55 (m, 1 H), 3.36 (s, 3 H),
.27 (td, J = 5.9, 1.1 Hz, 2 H), 1.46–1.16 (m, 10 H), 1.06–1.03 (m, 12 H).
129.4, 129.4, 127.4, 127.4, 114.7, 114.6, 95.4, 95.3, 77.4, 76.7, 73.3,
73.0, 69.6, 55.6, 39.4, 34.2, 34.1, 32.6, 32.4, 30.1, 29.84, 3.63, 27.1,
25.3, 25.2, 23.2, 19.3.
13
HRMS: m/z [M + Na]+ calcd for C31H48O SiNa: 535.3214; found:
C NMR (125 MHz, CDCl ): δ = 135.9, 135.0, 134.9, 134.6, 129.4,
3
4
1
2
29.4, 127.4, 127.4, 117.0, 95.4, 69.6, 55.5, 39.4, 38.9, 34.1, 29.7, 27.1,
5.3, 25.2, 23.2, 19.3.
535.3213.
HRMS: m/z [M + Na]+ calcd for C29H44O SiNa: 491.2951; found:
(3S,6S,12S)-12-[(tert-Butyldiphenylsilyl)oxy]-6-(methoxyme-
3
491.2948.
thoxy)tridec-1-en-3-ol (18a)
To a suspension of powdered molecular sieves (4Å) in anhyd CH Cl2
2
(4S,10S)-10-[(tert-Butyldiphenylsilyl)oxy]-4-(methoxyme-
(15 mL) were added sequentially Ti(Oi-Pr)4 (0.3 mL, 2.53 mmol) and
thoxy)undecan-1-ol (17)
(–)-DIPT (0.6 mL, 3.034 mmol) at –20 °C. After stirring for 0.5 h, allyl
alcohol 18 (1.3 g, 2.53 mmol) in anhyd CH Cl (6 mL) was added and
To a stirred solution of olefin 16 (2.1 g, 4.47 mmol) in anhyd THF (10
mL) at 0 °C was added 9-BBN (0.5 M in THF, 13.42 mL, 6.71 mmol)
dropwise over 10 min. After 6 h at r.t., a solution of aq 3 M NaOH (9
mL) and 35% H O (9 mL) were added portionwise at 0 °C. After 2 h at
2
2
stirring was continued for another 30 min at the same temperature.
Then TBHP (5 M, 1.0 mL, 5.06 mmol) was added and after stirring for
another 16 h at the same temperature, the reaction mixture was
2
2
quenched by the addition of H O (5 mL). It was then kept at r.t. and
r.t., the mixture was poured into brine (40 mL) and extracted with
Et O (3 × 50 mL). The combined organic layers were dried (Na SO ),
2
stirred for 30 min. After re-cooling to 0 °C, aq NaOH (30% w/v, 5 mL
saturated with brine) was added and the mixture was stirred at 0 °C
2
2
4
concentrated, and the residue was purified by flash chromatography
for 1 h. The mixture was extracted with CH Cl (2 × 20 mL). The com-
on silica gel (9:1, hexane/EtOAc) to afford alcohol 17 (1.73 g, 80%) as a
2
2
20
bined organic extracts were washed with brine (15 mL), dried (Na2-
colorless oil; [α]D +18.9 (c 0.3, CHCl3).
SO ), and concentrated in vacuo. The residue was purified by column
IR (neat): 3419, 2930, 2856, 1466, 1427, 1106, 1032, 700 cm–1
.
4
chromatography on silica gel (9:1, hexane/EtOAc) to give the allylic
1
H NMR (300 MHz, CDCl ): δ = 7.73–7.62 (m, 4 H), 7.45–7.33 (m, 6 H),
20
3
alcohol 18a (0.57 g, 44%) as a pale yellow oil; [α]D –15.3 (c 0.8,
4.65 (s, 2 H), 3.84–3.79 (m, 1 H), 3.70–3.61 (m, 2 H), 3.60–3.50 (m, 1
CHCl3).
H), 3.38 (s, 3 H), 1.65–1.18 (m, 14 H), 1.08–1.03 (m, 12 H).
IR (neat): 3434, 2929, 2856, 1427, 1464, 1105, 1034, 701 cm–1
.
13
C NMR (125 MHz, CDCl ): δ = 135.9, 134.9, 134.6, 129.4, 129.4,
3
1
H NMR (500 MHz, CDCl ): δ = 7.69–7.66 (m, 4 H), 7.42–7.34 (m, 6 H),
3
1
2
27.4, 127.4, 95.4, 77.4, 69.6, 63.1, 55.6, 39.4, 34.1, 30.6, 29.8, 28.4,
7.1, 25.3, 25.2, 23.2, 19.3.
5
.92–5.82 (m, 1 H), 5.24 (dt, J = 17.2, 1.4 Hz, 1 H), 5.11 (dt, J = 10.4, 1.3
Hz, 1 H), 4.65 (s, 2 H), 4.14–4.08 (m, 1 H), 3.84–3.78 (m, 1 H), 3.59–
3.52 (m, 1 H), 3.37 (s, 3 H), 1.56–1.21 (m, 14 H), 1.07–1.01 (m, 12 H).
HRMS: m/z [M + Na]+ calcd for C29H46O SiNa: 509.3057; found:
4
509.3057.
13
C NMR (125 MHz, CDCl ): δ = 141.2, 135.9, 135.0, 134.6, 129.4,
3
1
3
29.4, 127.4, 127.4, 114.6, 95.4, 77.4, 73.2, 69.6, 55.6, 39.4, 34.2, 32.6,
0.1, 29.8, 27.1, 25.3, 25.2, 23.2, 19.3.
(
6S,12S)-12-[(tert-Butyldiphenylsilyl)oxy]-6-(methoxyme-
thoxy)tridec-1-en-3-ol (18)
HRMS: m/z [M + Na]+ calcd for C31H48O SiNa: 535.3214; found:
4
To a solution of alcohol 17 (1.7 g, 3.49 mmol) in anhyd CH Cl (15 mL)
2
2
535.3213.
cooled to 0 °C was added Dess–Martin periodinane reagent (1.8 g, 4.2
mmol) was added, and the mixture was stirred at r.t. for 2 h. The reac-
tion was then quenched with sat. aq Na S O and NaHCO3 (12 mL).
The mixture was diluted with CH Cl (20 mL) and extracted with CH -
Cl2 (40 mL). The extract was washed sequentially with H O (25 mL)
(5S,8S,14S)-8-(Methoxymethoxy)-14,17,17-trimethyl-16,16-diphe-
2
2
3
nyl-5-vinyl-2,4,15-trioxa-16-silaoctadecane (9)
2
2
2
2
To a solution of allylic alcohol 19 (0.41 g, 0.79 mmol) in anhyd CH Cl2
2
(4 mL) at 0 °C were successively added DIPEA (0.4 mL, 2.33 mmol), a
and brine (25 mL), dried (Na SO ), and concentrated in vacuo to give
2
4
catalytic amount of DMAP, and MOMCl (0.08 mL, 1.18 mmol). The
mixture was stirred for 4 h at r.t., then the reaction was quenched by
adding H O (3 mL), and the mixture was extracted with CH Cl (3 × 8
the corresponding aldehyde, which was used in the next step without
further characterization.
2
2
2
To a stirred solution of the above prepared aldehyde (1.6 g, 3.29
mmol) in anhyd THF (15 mL) was added a solution of vinylmagne-
sium bromide (1 M solution in THF, 4.9 mL, 4.93 mmol) at –78 °C. The
mL). The combined organic layers were washed with brine (5 mL),
dried (Na SO ), and the solvent was evaporated under reduced pres-
2
4
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

F
Synthesis
G. R. Kundoor et al.
Paper
13
sure. The residue was purified by column chromatography on silica
C NMR (100 MHz, CDCl ): δ = 165.9, 138.3, 130.1, 129.1, 117.3, 95.4,
3
gel (15:1, hexane/EtOAc) to afford compound 9 (0.37 g 85%) as a pale
yellow oil; [α]D –31.8 (c 0.3, CHCl3).
93.8, 77.6, 71.2, 55.5, 55.4, 35.9, 34.2, 31.1, 30.0, 29.6, 25.4, 25.2, 19.9.
20
HRMS: m/z [M + Na]+ calcd for C20H36O Na: 395.2404; found:
6
IR (neat): 2930, 2856, 1465, 1147, 1101, 1030 cm–1
.
395.2395.
1
H NMR (500 MHz, CDCl ): δ = 7.69–7.66 (m, 4 H), 7.42–7.34 (m, 6 H),
3
5.67 (ddd, J = 17.9, 10.4, 7.7 Hz, 1 H), 5.23–5.17 (m, 2 H), 4.70 (d, J =
(5S,8S,14S,E)-5,8-Bis(methoxymethoxy)-14-methyloxacyclotetra-
6.7 Hz, 1 H), 4.64 (s, 2 H), 4.54 (d, J = 6.7 Hz, 1 H), 3.98 (dd, J = 13.3, 6.5
dec-3-en-2-one (21)
Hz, 1 H), 3.84–3.78 (m, 1 H), 3.54–3.49 (m, 1 H), 3.37 (s, 3 H), 3.36 (s, 3
H), 1.56–1.14 (m, 14 H), 1.06–1.03 (m, 12 H).
To a solution of diene 8 (0.1 g, 0.26 mmol) in anhyd CH Cl (150 mL)
was added second-generation Grubbs catalyst (0.02 g, 0.026 mmol)
2
2
13
and the mixture was degassed thoroughly under N . The mixture was
C NMR (125 MHz, CDCl ): δ = 138.3, 135.9, 135.0, 134.6, 129.4,
2
3
refluxed for 12 h, and the solvent was removed under reduced pres-
sure. The crude residue was purified by column chromatography on
silica gel (8:2, hexane/EtOAc) to afford 21 (0.06 g, 65%) as a colorless
1
3
29.4, 127.4, 127.4, 117.3, 95.4, 93.8, 77.6, 69.6, 55.5, 55.5, 39.4, 34.3,
1.1, 30.0, 29.9, 27.1, 25.3, 25.2, 23.2, 19.3.
HRMS: m/z [M + Na]+ calcd for C33H52O SiNa: 579.3476; found:
5
20
liquid; [α]D +1.2 (c 0.2, CHCl3).
579.3464.
IR (neat): 2926, 2855, 1716, 1656, 1149, 1096, 1037 cm–1
1H NMR (500 MHz, CDCl
): δ = 6.79 (dd, J = 15.8, 5.8 Hz, 1 H), 6.07 (dd,
J = 15.8, 1.4 Hz, 1 H), 5.08 (ddd, J = 10.1, 6.3, 3.3 Hz, 1 H), 4.68 (d, J =
.0 Hz, 1 H), 4.63 (s, 2 H), 4.59 (d, J = 7.0 Hz, 1 H), 4.41 (dt, J = 10.2, 4.4
Hz, 1 H), 3.55 (dq, J = 12.5, 4.2 Hz, 1 H), 3.40 (s, 3 H), 3.37 (s, 3 H),
.
(2S,8S,11S)-8,11-Bis(methoxymethoxy)tridec-12-en-2-ol (20)
3
To compound 9 (0.28 g, 0.50 mmol) was taken in anhyd THF (3 mL)
THF was added TBAF (1 M in THF, 0.74 mL, 0.74 mmol) and the reac-
tion mixture was then stirred for 12 h at r.t. THF was then evaporated,
and H O (2 mL) was added, and the reaction mixture was extracted
with EtOAc (20 mL). The organic layer was washed with sat. aq NaH-
CO3 (4 mL) and brine (4 mL), and dried (Na SO ), and concentrated
7
1.95–1.87 (m, 1 H), 1.78 (ddd, J = 14.1, 8.4, 4.2 Hz, 1 H), 1.75–1.68 (m,
2
1
H), 1.65–1.60 (m, 1 H), 1.52–1.39 (m, 6 H), 1.35–1.28 (m, 2 H), 1.26
(d, J = 6.3 Hz, 3 H), 1.18–1.15 (m, 2 H).
2
4
13
under reduced pressure. The residue was purified by column chroma-
C NMR (100 MHz, CDCl ): δ = 165.7, 147.0, 123.5, 94.9, 94.5, 75.3,
3
tography on silica gel (7:3, hexane/EtOAc) to afford alcohol 20 (0.14 g,
74.1, 72.7, 55.5, 55.5, 34.3, 33.0, 29.4, 29.0, 27.2, 26.1, 24.8, 20.6.
20
8
9% yield) as a colorless oil; [α]D
–26.3 (c 0.3, CHCl3).
HRMS: m/z [M + Na]+ calcd for C18H32O Na: 367.2091; found:
6
IR (neat): 3468, 2927, 2854, 1461, 1147, 1059 cm–1
.
367.2081.
1
H NMR (500 MHz, CDCl ): δ = 5.67 (ddd, J = 17.3, 10.4, 7.7 Hz, 1 H),
3
5
.23–5.17 (m, 2 H), 4.70 (d, J = 6.7 Hz, 1 H), 4.65 (s, 2 H), 4.54 (d, J = 6.7
(5S,8S,14S,E)-5,8-Dihydroxy-14-methyloxacyclotetradec-3-en-2-
one (Pestalotioprolide C, 1)
6,7
Hz, 1 H), 3.98 (dd, J = 13.5, 6.4 Hz, 1 H), 3.83–3.75 (m, 1 H), 3.58–3.51
(
m, 1 H), 3.38 (s, 3 H), 3.38 (s, 3 H), 1.63–1.32 (m, 14 H), 1.19 (d, J = 6.2
To a stirred solution of 21 (52 mg, 0.15 mmol) in THF (1.5 mL) was
added aq 6 N HCl (0.1 mL) and stirred for 2 h. After completion of re-
action, the mixture was quenched with solid NaHCO3 (0.1 g) at 0 °C
and filtered. The solvent was removed under reduced pressure and
the residue was purified by column chromatography on silica gel (3:7,
hexane/EtOAc) to give the desired compound 1 (34 mg, 88%) as a col-
Hz, 3 H).
1
3
C NMR (100 MHz, CDCl ): δ = 138.3, 117.3, 95.4, 93.8, 77.5, 77.2,
3
6
8.1, 55.6, 55.5, 39.3, 34.3, 31.1, 30.1, 29.8, 25.7, 25.2, 23.5.
HRMS: m/z [M + Na]+ calcd for C17H34O Na: 341.2298; found:
3
5
41.2276.
20
orless solid; mp 122–124 °C; [α] +36.8 (c 0.2, MeOH); [α]D for natu-
D
6
20
ral product: [α]D +40 (c 1.4, MeOH).
(
(
2S,8S,11S)-8,11-Bis(methoxymethoxy)tridec-12-en-2-yl Acrylate
8)
IR (neat): 3432, 2925, 2854, 1714, 1458, 1266, 1108 cm–1
.
1
H NMR (500 MHz, CD OD): δ = 6.98 (dd, J = 15.7, 4.2 Hz, 1 H), 6.02
To a cooled (0 °C) solution of alcohol 20 (0.13 mg, 0.40 mmol) in an-
hyd CH Cl (4 mL) were added Et N (0.11 mL, 0.80 mmol) and acryloyl
chloride (0.04 mL, 0.48 mmol) and stirred at the same temperature
for 0.5 h. After completion of the reaction, the reaction mixture was
quenched with sat. aq NaHCO (4 mL) and extracted with CH Cl (3 ×
3
(dd, J = 15.7, 1.8 Hz, 1 H), 5.05–5.00 (m, 1 H), 4.52–4.47 (m, 1 H), 3.63–
2
2
3
3.55 (m, 1 H), 1.98–1.90 (m, 1 H), 1.80–1.71 (m, 2 H), 1.62–1.32 (m, 9
H), 1.29 (d, J = 6.3 Hz, 3 H), 1.28–1.18 (m, 2 H).
13
C NMR (100 MHz, CD OD): δ = 167.8, 152.0, 121.8, 73.7, 70.7, 70.7,
3
2
2
3
15 mL). The combined organic phases were washed with brine (6 mL)
36.2, 35.8, 32.6, 30.4, 29.6, 26.2, 25.0, 21.0.
and dried (Na SO ). The solvent was removed under reduced pres-
sure, and the residue was purified by column chromatography on sili-
+
2
4
HRMS: m/z [M + H] calcd for C14H25O : 257.1747; found: 257.1748.
4
ca gel (9:1, hexane/EtOAc) to afford 8 (0.12 g, 86%) as a pale yellow
20
liquid; [α]D –45.5 (c 0.4, CHCl3).
IR (neat): 2931, 2859, 1720, 1638, 1198, 1096, 1029 cm–1
Acknowledgment
.
1
Two of the authors (G.R.K and S.K.B) thank the UGC, New Delhi for the
financial support in the form of a fellowship.
H NMR (400 MHz, CDCl ): δ = 6.38 (dd, J = 17.3, 1.2 Hz, 1 H), 6.10 (dd,
3
J = 17.3, 10.4 Hz, 1 H), 5.79 (dd, J = 10.4, 1.2 Hz, 1 H), 5.67 (ddd, J =
17.8, 10.4, 7.7 Hz, 1 H), 5.24–5.16 (m, 2 H), 5.03–4.93 (m, 1 H), 4.70 (d,
J = 6.7 Hz, 1 H), 4.64 (s, 2 H), 4.54 (d, J = 6.7 Hz, 1 H), 3.97 (dd, J = 13.1,
Supporting Information
6.5 Hz, 1 H), 3.58–3.49 (m, 1 H), 3.37 (s, 6 H), 1.68–1.58 (m, 4 H),
1.53–1.44 (m, 4 H), 1.42–1.27 (m, 6 H), 1.24 (d, J = 6.3 Hz, 3 H).
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1589152.
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©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

G
Synthesis
G. R. Kundoor et al.
Paper
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©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G