Stereoselective concise total synthesis of leodomycin C and D

Article abstract of DOI:10.1055/s-0031-1289640

Stereoselective concise total synthesis of leodomycin C and D from commercially available propylene oxide using Jacobsens hydrolytic kinetic resolution (HKR), base-promoted alkyne zipper reaction, TPP-promoted enyne ester (ynoate) to diene ester (dienoate

Full text of DOI:10.1055/s-0031-1289640

PAPER
311
Stereoselective Concise Total Synthesis of Leodomycin C and D
Total
Synthesis
o
.
f
Leodomyci
C
n C and
D
hinnababu, S. Purushotham Reddy, D. Kumar Reddy, D. Chandra Rao, Y. Venkateswarlu*
Organic Chemistry Division-I, Natural Products Laboratory, Indian Institute of Chemical Technology, Hyderabad, 500 007, India
Fax +91(40)27160512; E-mail: luchem@iict.res.in
Received 10 October 2011; revised 17 November 2011
Jacobsen’s hydrolytic kinetic resolution (HKR), base-pro-
moted alkyne zipper reaction, TPP-promoted enyne ester
(ynoate) to diene ester (dienoate) isomerization, and (R)-
(+)-2-methyl-CBS-oxazaborolidine reduction.5
Abstract: Stereoselective concise total synthesis of leodomycin C
and D from commercially available propylene oxide using Jacobsen’s
hydrolytic kinetic resolution (HKR), base-promoted alkyne zipper
reaction, TPP-promoted enyne ester (ynoate) to diene ester (di-
enoate) isomerization, and (R)-(+)-2-methyl-CBS-oxazaborolidine
reduction as key steps is reported.
O
OH
Key words: Bacillus sp, leodomycin C and D, antimicrobial activ-
ity, hydrolytic kinetic resolution, HKR, alkyne zipper reaction, (R)-
(+)-2-methyl-CBS-oxazaborolidine
OH
1
OH
O
OH
OH
O
OH
2
Marine fungi are attractive sources for anticancer, antifun-
gal, and antibacterial secondary metabolites.1 Marine
Bacillus species, ubiquitous and diverse in marine ecosys-
tems, are well known for producing antimicrobial and an-
ticancer compounds, bio-surfactants, and so on.2 Marine
bacteria isolated from the sediments and the surface of
marine algae and invertebrates have been shown to pro-
duce secondary metabolites that display antibacterial
properties.3 Recently, four antimicrobial compounds 1–4
(Figure 1) were isolated from marine bacterial strain Ba-
cillus sp.4 These compounds exhibited interesting antimi-
crobial activity against Bacillus subtilis and Escherichia
coli with minimum inhibitory concentrations (MICs) of
32–64 mg/mL.4a Recently, the stereoselective synthesis of
pharmaceutically active natural products have become
significant4b,c and to the best of our knowledge, there is no
report in the literature on the synthesis of these com-
pounds. Our continued interest towards the total synthesis
of biologically active natural products prompted us to un-
dertake the synthesis of demanding targets compounds 1
and 2 from commercially available propylene oxide using
O
OH
O
OH
3
OH
4
Figure 1 Leodomycin C (1), leodomycin D (2), leodomycin B (3),
leodomycin A (4)
The synthesis commenced with propylene oxide (5)
(Scheme 1), which was subjected to Jacobsen’s hydrolyt-
ic kinetic resolution (HKR) using (R,R)-salen-Co-(OAc)
catalyst to afford (R)-propylene oxide (6).6 Compound 6
was reacted with the lithiated hex-1-yne to afford alkynol
7 in 89% yield. The alkynol 7 was subjected to base-
mediated alkyne zipper reaction7 using sodium 3-amino-
propylamide in which alkyne functionality moves from
the center to the terminus of a chain to give the alkyne 8
in 80% yield. The secondary hydroxy group in compound
8 was protected as tert-butyldimethylsilyl ether 9 using
OH
OH
a
c
b
O
O
5
6
7
8
O
OTBS
OTBS
OMe
e
d
f
9
10
O
O
OTBS
OH
g
OMe
OH
11
1
Scheme 1 Reagents and conditions: (a) R,R-salen-Co-(OAc) (0.5 mol%), dist. H2O (0.55 equiv), 0 °C, 14 h, 46%; (b) hex-1-yne, n-BuLi,
HMPA, –40 to 0 to –20 °C, 16 h; (c) NaH, 1,3-diaminopropane, 60 °C to r.t., 8 h; (d) TBDMSCl, imidazole, CH2Cl2, r.t., 3 h; (e) methyl chlo-
roformate, n-BuLi, THF, –78 °C, 1 h; (f) TPP, phenol, benzene, 50 °C, 6 h; (g) KOH, EtOH–H2O (4:1), 60 °C, 6 h, 6 M HCl.
SYNTHESIS 2012, 44, 311–315
x
x
.x
x
.2
0
1
1
Advanced online publication: 08.12.2011
DOI: 10.1055/s-0031-1289640; Art ID: Z95211SS
© Georg Thieme Verlag Stuttgart · New York

312
B. Chinnababu et al.
PAPER
O
OTBS
OTBS
a
c
b
OMe
OH
O
11
13
12
14
O
OH
OTBS
OTBS
d
H
OEt
O
O
OH
OH
O
O
OTBS
OTBS
OTBS
e
g
f
OEt
OH
OEt
OH
15
16
OH
O
OH
17
2
Scheme 2 Reagents and conditions: a) DIBAL-H, –78 °C, CH2Cl2, 2 h; b) DMP, NaHCO3, CH2Cl2, 1.5 h; c) LiHMDS, EtOAc,, THF, –78 °C
to r.t., 4 h; d) DMP, NaHCO3, CH2Cl2, 1 h; e) (R)-CBS catalyst, DMS⋅BH3, THF, –40 °C, 1.5 h; f) LiOH, THF–H2O (1:1), r.t., 2.5 h; g) HF⋅Py-
ridine, THF, 0 °C to r.t., 6 h.
TBDMSCl and imidazole in dichloromethane in 96% 13C NMR) were found to be in agreement with the natural
yield. The terminal alkyne group in 9 was carboxylated by product4{[a]D +18 (c 0.1, CHCl3), Lit.4 [a]D +17.9 (c
reacting with methyl chloroformate in the presence of n- 0.35, MeOH)}.
25
25
butyllithium to afford alkyne ester 10 in 92% yield. The
In conclusion, an efficient and straightforward total syn-
alkyne ester 10 was converted to the diene ester 11 under
thesis of leodomycin C and D has been achieved by using
Rychnovsky’s modified conditions for the Trost isomer-
Jacobsen’s hydrolytic kinetic resolution (HKR), base-pro-
ization.8 Thus, the ynoate 10, exposed to Ph3P/PhOH in
moted alkyne zipper reaction, TPP-promoted enyne ester
(ynoate) to diene ester (dienoate) isomerization, and (R)-
(+)-2-methyl-CBS-oxazaborolidine reduction reactions.
benzene at 50 °C for six hours led to the clean formation
of diene ester 11 in 93% yield.
Finally the ester 11 was hydrolyzed using KOH/EtOH– The synthesis of leodomycin A and B is in progress.
THF (1:4) under reflux conditions for 6 hours and during
acidic workup the TBS ether was deprotected to give final
All solvents and reagents were purified by standard techniques.
compound 1 in 80% yield. The physical and spectral data
Crude products were purified by column chromatography on silica
gel (60–120 mesh). FTIR spectra were recorded on Thermo Nicolet
Nexus 670 spectrometer. Optical rotations were measured on Horiba
high sensitive polarimeter in 10 mm cell. 1H and 13C NMR spectra
were recorded in CDCl3 on Varian Gemini 500 and Bruker Avance
300 spectrometers. Chemical shifts were reported in parts per mil-
lion (d) with respect to internal TMS. Coupling constants (J) are
13
of synthetically prepared compound 1 (1H NMR and C
NMR) are found to be in agreement with the natural
product4{[a]D25 +15 (c 0.8, CHCl3) Lit.4 [a]D25 +14.9 (c 1,
CHCl3)}.
To synthesize leodomycin D (2), in a separate experiment
the ester 11 was reduced with DIBAL-H in CH2Cl2 at quoted in Hz. Mass spectra were acquired on a Micro mass Quattro
–78 °C to the allylic alcohol 12 in 90% yield (Scheme 2).
The allyl alcohol 12 on oxidation with Dess–Martin peri-
microTM API (Waters) and high-resolution mass spectra were ac-
quired on QSTARXL Hybrid MS/MS system (applied Biosystems
US) mass spectrometers.
odinane (DMP) afforded aldehyde 13 in 81% yield. The
aldehyde 13 was subjected to C–H insertion reaction us-
(R)-Non-4-yn-2-ol (7)
ing LiHMDS and ethyl acetate to form the racemic alco-
hol 14 in 80% yield.9 Dess–Martin oxidation of the
secondary hydroxy group in 14 afforded the correspond-
ing ketone 15 in 89% yield.
To a cooled (–40 °C) solution of hex-1-yne (7.10 mL, 62.05 mmol)
in anhyd THF (40 mL) was added dropwise n-BuLi in hexane (1.6
M, 32.22 mL, 51.56 mmol). The reaction mixture was warmed to
0 °C over 30 min and then cooled to –20 °C. To this solution, after
the addition of anhyd HMPA (15 mL), was added (R)-(+)-propylene
oxide (2.0 g, 34.48 mmol) in HMPA (10 mL) over 15 min. The mix-
ture was stirred at –20 °C for 30 min, warmed to 20 °C over 4 h, and
Selective reduction of the carbonyl group in 15 employing
Corey–Bakshi–Shibata (CBS) reagent [(R)-(+)-2-methyl
CBS-oxazaborolidine] afforded the b-chiral allylic alco- stirred for 12 h. The mixture was then poured into ice water (100
hol 16 in 80% yield10 with an excellent enantioselectivity
mL) and extracted with Et2O (4 × 50 mL). The combined organic
extracts were washed with brine (30 mL), dried (MgSO4), and con-
centrated under reduced pressure. The crude product was purified
of 87.18%de. The ester 16 was hydrolyzed with LiOH in
H2O–THF (1:1) to form acid 17 in 86% yield. Finally, the
TBS ether in 17 is removed by using HF·Pyridine, to form
final compound 2 in 72% yield. The physical and spectral
data of synthetically prepared compound 2 (1H NMR and
by column chromatography on silica gel (EtOAc–hexane, 1:9) to
provide 4.29 g (89%) of 7 as a yellow liquid; [a]D25 –15.7 (c 0.35,
CHCl3).
IR (neat): 3445, 2924, 2855, 1461, 771 cm–1.
Synthesis 2012, 44, 311–315
© Thieme Stuttgart · New York

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Total Synthesis of Leodomycin C and D
313
1H NMR (300 MHz, CDCl3): d = 3.94–3.82 (m, 1 H), 2.40–2.31 (m,
1 H), 2.30–2.21 (m, 1 H), 2.21–2.11 (m, 2 H), 1.92 (br s, 1 H), 1.53–
1.33 (m, 4 H), 1.23(d, J = 6.2 Hz, 3 H), 0.92 (t, J = 7.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 82.6, 77.2, 66.2, 39.8, 37.1, 22.2,
21.8, 18.3, 13.5.
IR (neat): 2935, 2860, 2238, 1719, 1467, 1437, 1376, 1254, 1136,
1101, 1054, 835, 774 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.77–3.73 (m, 1 H), 3.74 (s, 3 H),
2.33 (t, J = 6.9 Hz, 2 H), 1.68–1.54 (m, 2 H), 1.47–1.24 (m, 6 H),
1.09 (d, J = 6.0 Hz, 3 H), 0.88 (s, 9 H), 0.04 (s, 3 H), 0.03 (s, 3 H).
ESI-MS: m/z = 141.7 [M + H]+.
13C NMR (75 MHz, CDCl3): d = 153.8, 89.3, 73.1, 68.3, 52.3, 39.4,
39.0, 28.9, 27.5, 25.9, 25.1, 23.9, 18.6, –4.3, –4.7.
(R)-Non-8-yn-2-ol (8)
ESI-MS: m/z = 335.1 [M + Na]+.
To anhyd 1, 3-diaminopropane (15 mL) was added NaH (60 wt%,
3.42 g, 142.85 mmol). The heterogeneous mixture was stirred at r.t.
for 10 min during which, the solution changed to orange to brown
in appearance. The mixture was refluxed at 60 °C for 5 h during
which period ammonia gas was released. Then, the solution was al-
lowed to reach 0 °C, and treated with (R)-non-4-yn-2-ol (7; 4.0 g,
28.57 mmol) in one portion and stirred at 20 °C for 3 h. After com-
pletion of the reaction, the mixture was quenched cautiously by the
addition of crushed ice in portions and extracted with Et2O (3 × 30
mL). The combined organic extracts were washed with brine (15
mL), dried (MgSO4), and concentrated. The crude product was pu-
rified by column chromatography on silica gel (EtOAc–hexane,
1:9) to yield 3.2 g (80%) of 8 as a colorless liquid; [a]D25 –14.1 (c
0.35, CHCl3).
Methyl (R,2E,4E)-9-(tert-Butyldimethylsilyloxy)deca-2,4-di-
enoate (11)
To a solution of 10 (3.5 g, 11.21 mmol) in benzene (30 mL) was
added phenol (1.05 g, 11.21 mmol) and Ph3P (2.93 g, 11.21 mmol)
and stirred at 50 °C for 6 h. After completion of the reaction, the
mixture was diluted with H2O (30 mL) and extracted with Et2O
(3 × 50 mL). The combined organic layers were washed with aq 1
M NaOH (2 × 10 mL), dried (Na2SO4), and concentrated. The crude
product was purified by column chromatography on silica gel
(EtOAc–hexane, 0.1:9.9) to give pure 11 (3.25 g, 93%) as a color-
less liquid; [a]D25 –11.6 (c 0.6, CHCl3).
IR (neat): 2933, 2859, 1727, 1657, 1439, 1376, 1261, 1198, 1174,
983, 836, 774 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.24–7.16 (m, 1 H), 6.14–6.01 (m,
2 H), 5.72 (d, J = 16.0 Hz, 1 H), 3.75–3.68 (m, 1 H), 3.67 (s, 3 H),
2.13–2.06 (m, 2 H), 1.40–1.17 (m, 4 H), 1.05 (d, J = 6.00, 3 H), 0.81
(s, 9 H), 0.02 (s, 3 H), 0.03 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 167.7, 145.3, 144.7, 128.4, 118.7,
68.3, 51.5, 39.1, 33.0, 29.7, 25.9, 24.8, 23.8, –4.4, –4.7.
MS-EIMS: m/z = 335 [M + Na]+.
IR (neat): 3306, 2934, 2860, 2116, 1460, 1374, 1262, 847, 771 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.86–3.71 (m, 1 H), 2.22–2.14 (m,
2 H), 1.88 (t, J = 3 Hz, 1 H), 1.60–1.35 (m, 8 H), 1.2 (d, J = 6 Hz, 3
H).
13C NMR (75 MHz, CDCl3): d = 84.4, 68.4, 67.6, 39.0, 28.7, 28.3,
25.2, 23.4, 18.3.
ESI-MS: m/z = 141.6 [M + H]+.
(R)-tert-Butyldimethyl(non-8-yn-2-yloxy)silane (9)
(R,2E,4E)-9-Hydroxydeca-2,4-dienoic Acid (1)
To a cooled solution (0 °C) of secondary alcohol 8 (3.1 g, 22.14
mmol) and imidazole (3.16 g, 46.49 mmol) in anhyd CH2Cl2 (20
mL) was added TBDMSCl (3.67 g, 24.35 mmol) slowly and stirred
for 3 h. After completion of the reaction, the mixture was diluted
with H2O (15 mL) and extracted with CH2Cl2 (3 × 10 mL). The
combined organic extracts were washed with brine (10 mL), dried
(Na2SO4), and concentrated under vacuum. The crude residue was
purified by column chromatography on silica gel (EtOAc–hexane,
0.2:9.8) to afford pure TBS ether 9 (5.39 g, 96%) as a colorless liq-
uid; [a]D25 –10 (c 1.5, CHCl3).
Dienoate 11 (100 mg, 0.32 mmol) was refluxed in a solution of
EtOH–H2O (8:2) containing KOH (300 mg) for 6 h. After comple-
tion of the reaction, the mixture was neutralized with aq 6 M HCl to
liberate the free acid, which was extracted into EtOAc (3 × 10 mL).
The combined organic layers were washed with brine (5 mL), dried
(Na2SO4), and concentrated under reduced pressure. The crude res-
idue was purified by column chromatography on silica gel (EtOAc–
hexane, 9:1) to afford pure 1 as a colorless solid (47 mg, 80%);
[a]D25 +14.8 (c 1, CHCl3).
IR (neat): 3368, 2924, 2853, 1685, 1032, 772 cm–1.
IR (neat): 2934, 2860, 2238, 1467, 1437, 1376, 1254, 1136, 1101,
1054, 835, 774 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.86–3.71 (m, 1 H), 2.23–2.13 (m,
2 H), 1.93 (t, J = 2.4 Hz, 1 H), 1.58–1.24 (m, 8 H), 1.11 (d, J = 6.0
Hz, 3 H), 0.88 (s, 9 H), 0.04 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 68.5, 68.0, 39.5, 28.8, 28.5, 25.9,
25.2, 23.8, 18.3, –4.4, –4.7.
1H NMR (300 MHz, CD3OD): d = 7.24 (dd, J = 9.8, 14.7 Hz, 1 H),
6.22 (dd, J = 9.8, 14.7 Hz, 1 H), 6.17–6.11 (m, 1 H),5.78 (d,
J = 15.7 Hz, 1 H), 3.86–3.74 (m, 1 H), 2.29–2.16 (m, 2 H), 1.67–
1.54 (m, 1 H), 1.53–1.41 (m, 3 H), 1.16 (d, J = 5.8 Hz, 3 H).
13C NMR (75 MHz, CD3OD): d = 171.1, 146.5, 145.1, 128.9, 120.8,
67.9, 39.6, 33.3, 26.2, 23.4.
HRMS-ESI: m/z calcd for C10H15O3 [M – H]–: 183.1026;
found: 183.1033.
ESI-MS: m/z = 277 [M + Na]+.
Methyl (R)-9-(tert-Butyldimethylsilyloxy)dec-2-ynoate (10)
To a cooled (–78 °C) solution of 9 (3.0 g, 11.81 mmol) in anhyd
THF (10 mL) was added n-BuLi (11.03 mL, 17.65 mmol) dropwise
and stirred for 0.5 h. To this mixture was added methyl chlorofor-
mate (1.18 mL, 15.35 mmol) at –78 °C and stirred for another 1 h.
The reaction mixture was then warmed to 0 °C and stirred for 15
min. After completion of the reaction, the mixture was quenched
with sat. aq NH4Cl (10 mL), extracted with Et2O (3 × 15 mL), the
combined organic layers were washed with brine (10 mL), and dried
(Na2SO4). The solvent was evaporated under reduced pressure and
the crude product was purified by column chromatography on silica
gel (EtOAc–hexane, 0.1:9.9) to give ester 10 (3.39 g, 92%) as a col-
orless liquid; [a]D25 –10.9 (c 1.1, CHCl3).
(R,2E,4E)-9-(tert-Butyldimethylsilyloxy)deca-2,4-dien-1-ol (12)
To a cooled (–78 °C) solution of 11 (2.0 g, 6.41 mmol) in anhyd
CH2Cl2 (40 mL) was added DIBAL-H (13.51 mL, 13.51 mmol,
20% solution in toluene) and the reaction mixture was allowed to
stir at –78 °C for 2 h. After completion of the reaction, the mixture
was quenched with sodium potassium tartarate solution (5 mL). The
organic layer was separated and washed with brine (20 mL), dried
(Na2SO4), and concentrated under reduced pressure. The crude res-
idue was purified by column chromatography on silica gel (EtOAc–
hexane, 2:8) to afford pure 12 (1.63 g, 90%) as a colorless liquid;
[a]D25 –0.8 (c 1, CHCl3).
IR (neat): 3393, 2932, 2860, 1717, 1459, 1375, 1254, 1184, 1129,
1048, 978, 835 cm–1.
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314
B. Chinnababu et al.
PAPER
1H NMR (300 MHz, CDCl3): d = 6.27–6.12 (m, 1 H), 6.09–5.95 (m,
1 H), 5.80–5.59 (m, 2 H), 4.15 (d, J = 6 Hz, 2 H), 3.84–3.69 (m, 1
H), 2.14–2.02 (m, 2 H), 1.57–1.21 (m, 4 H), 1.11 (d, J = 6 Hz, 3 H),
0.88 (s, 9 H), 0.03 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 208.3, 191.9, 169.6, 167.3, 146.9,
145.0, 141.7, 137.5, 129.3, 128.7, 126.9, 123.2, 90.9, 68.3, 61.3,
60.0, 47.3, 39.1, 33.2, 33.0, 29.7, 25.9, 25.1, 24.8, 23.9, 14.3, 14.1,
–4.4, –4.7.
13C NMR (75 MHz, CDCl3): d = 135.4, 132.0, 129.4, 68.5, 63.5,
39.2, 32.6, 29.7, 25.9, 25.4, 23.8, –4.3, –4.7.
MS-ESI: m/z = 391 [M + Na]+.
Ethyl (3S,4E,6E,11R)-11-(tert-Butyldimethylsilyloxy)-3-hy-
droxydodeca-4,6-dienoate (16)
MS-ESI: m/z = 302.6 [M + NH4]+.
The reagent (R)-Me-CBS (1 M in toluene, 0.07 mL, 0.24 mmol) and
DMS·BH3 (1 M in THF, 0.074 mL, 0.86 mmol) were mixed under
N2 and at r.t. and stirred for 15 min. The mixture was cooled at
–40 °C and treated with a solution of 15 (300 mg, 0.81 mmol) in an-
hyd THF (5 mL). The reaction mixture was stirred for 1.5 h. After
completion of the reaction, MeOH (10 mL) was added and the so-
lution was stirred further for additional 1 h and allowed to warm up
to r.t. The solvents were then removed under vacuum and the crude
was purified by column chromatography on silica gel (EtOAc–hex-
ane, 2:8) to afford pure product 16 with excellent enantioselectivity
of 87.18% de [determined by Chiral HPLC: column: Chiral pack-
OJ-H (250 × 4.6 mm particle size 5 m); mobile phase: hexane–i-
PrOH (95:5); flow rate: 1.0 mL/min; detection: UV/visible detector]
(241 mg, 80%) as a clear liquid; [a]D25 –26.0 (c 0.25, CHCl3).
Ethyl (R,4E,6E)-11-(tert-Butyldimethylsilyloxy)-3-hydroxy-
dodeca-4,6-dienoate (14)
To solution of compound 12 (1.0 g, 3.52 mmol) and NaHCO3 (529
mg, 6.30 mmol) in CH2Cl2 (8 mL) was added DMP (3.31 g, 7.39
mmol) and stirred for 1.5 h. After completion of the reaction, the
mixture was diluted with cold H2O (10 mL) and extracted with
CH2Cl2 (3 × 15 mL). The combined organic extracts were dried
(Na2SO4) and concentrated to yield crude aldehyde 13 (0.80 g,
81%), which was directly used for the next reaction.
To a cooled (–78 °C) solution of anhyd EtOAc (2.74 mL, 27.95
mmol) in anhyd THF (5 mL) was added a 1 M solution of LiHMDS
in THF (14.16 mL, 14.16 mmol) and the solution was stirred for 0.5
h. Then, the previously prepared aldehyde 13 (0.8 g, 2.83 mmol) in
anhyd THF was added slowly by cannula and the resulting mixture
was stirred for 2 h at –78 °C and 2 h at r.t. After completion of the
reaction, the mixture was quenched with sat. aq NH4Cl (5 mL),
stirred for an additional 30 min, and extracted with EtOAc (3 × 10
mL). The combined organic layers were washed with H2O (15 mL),
dried (Na2SO4), and the solvent was evaporated under reduced pres-
sure. The crude residue was purified by column chromatography on
silica gel (EtOAc–hexane, 2:8) to afford an inseparable diastereo-
meric mixture of aldol product 14 (0.83 g, 80%) as a clear liquid;
[a]D25 –6.36 (c 1.1, CHCl3).
IR (neat): 3441, 2954, 2933, 2858, 1733, 1469, 1374, 1253, 1218,
1136, 1094, 1019, 835, 773 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.22 (dd, J = 10, 15 Hz, 1 H), 5.98
(dd, J = 11, 15 Hz, 1 H), 5.72–5.63 (m, 1 H), 5.55 (dd, J = 6, 15 Hz,
1 H), 4.58–4.47 (m, 1 H), 4.16 (q, J = 7.0 Hz, 2 H) 3.80–3.69 (m, 1
H), 2.83 (br s, 1 H), 2.57–2.46 (m, 2 H), 2.11–2 (m, 2 H), 1.48–1.30
(m, 4 H), 1.26 (t, J = 7.0 Hz, 3 H), 1.10 (d, J = 6.0 Hz, 3 H), 0.87 (s,
9 H), 0.03 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 172.2, 136.0, 131.4, 130.8, 129.3,
68.7, 68.5, 60.8, 41.5, 39.1, 32.6, 25.9, 25.3, 23.9, 18.1, 14.2, –4.4,
–4.7.
IR (neat): 3441, 2954, 2931, 2858, 1733, 1466, 1374, 1253, 1220,
1136, 1094, 1038, 835, 773 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.23 (dd, J = 10,1 Hz, 1 H), 5.99
(dd, J = 11, 15 Hz, 1 H), 5.73–5.65 (m, 1 H), 5.57 (dd, J = 6, 15 Hz,
1 H), 4.60–4.51 (m, 1 H), 4.15 (q, J = 7 Hz, 2 H), 3.80–3.71 (m, 1
H), 2.87 (br s, 1 H), 2.58–2.47 (m, 2 H), 2.10–2.01 (m, 2 H), 1.51–
1.29 (m, 4 H), 1.25 (t, J = 7.0 Hz, 3 H), 1.09 (d, J = 6.0 Hz, 3 H),
0.86 (s, 9 H), 0.02 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 172.6, 136.3, 131.7, 131.2, 129.6,
69.0, 68.8, 61.1, 41.9, 39.5, 33.0, 26.3, 25.7, 24.2, 18.5, 14.6, –4.0,
–4.3.
MS-ESI: m/z = 393.0 [M + Na]+.
Ethyl (3S,4E,6E,11R)-11-(tert-Butyldimethylsilyloxy)-3-hy-
droxydodeca-4,6-dienoic Acid (17)
To solution of 16 (150 mg, 0.40 mmol) in THF–H2O (1:1) was add-
ed LiOH (14 mg, 0.60 mmol) and stirred for 2.5 h. After completion
of the reaction, the mixture was diluted with cold H2O (5 mL) and
extracted with EtOAc (3 × 10 mL). The combined organic extracts
were dried (Na2SO4) and concentrated to yield crude acid 17. The
crude compound was purified by column chromatography on silica
gel (CH2Cl2–MeOH, 8:2) to afford pure 17 (119 mg, 86%) as a clear
liquid; [a]D25 –20.6 (c 1, CHCl3).
MS-ESI: m/z = 393.1 [M + Na]+.
Ethyl (R,4E,6E)-11-(tert-Butyldimethylsilyloxy)-3-oxododeca-
4,6-dienoate (15)
IR (neat): 3445, 2933, 2859, 1727, 1657, 1439, 1376, 1261, 1198,
1174, 1042, 836, 774 cm–1.
To solution of 14 (500 mg, 1.35 mmol) and NaHCO3 (327 mg, 3.90
mmol) in CH2Cl2 (8 mL) was added DMP (1.0 g, 2.43 mmol) and
stirred for 1 h. After completion of the reaction, the mixture was di-
luted with cold H2O (5 mL) and extracted with CH2Cl2 (3 × 15 mL).
The combined organic extracts were dried (Na2SO4) and concentrat-
ed to yield crude b-keto ester 15. The crude compound was purified
by column chromatography on silica gel (EtOAc–hexane, 0.5:9.5)
to afford pure 15 (442 mg, 89%) as a viscous liquid; [a]D25 –12.8 (c
0.35, CHCl3).
1H NMR (300 MHz, CDCl3): d = 6.14 (dd, J = 10.4, 15.6 Hz, 1 H),
5.93 (dd, J = 10.4, 15.6 Hz, 1 H), 5.72–5.34 (m, 2 H), 4.60–4.26 (m,
2 H), 3.85–3.66 (m, 1 H), 2.51–2.18 (m, 2 H), 2.13–1.92 (m, 2 H),
1.52–1.17 (m, 4 H), 1.10 (d, J = 6 Hz, 3 H), 0.87 (s, 9 H), 0.03 (s, 6
H).
13C NMR (75 MHz, CDCl3): d = 175.4, 135.2, 131.9, 130.7, 129.6,
69.9, 68.4, 39.4, 32.9, 29.7, 25.9, 25.5, 23.9, 18.1, –4.4, –4.6.
MS-ESI: m/z = 365.0 [M + Na]+.
IR (neat): 2928, 2856, 1735, 1664, 1598, 1465, 1374, 1235, 1146,
1038, 835, 806, 776 cm–1.
(3S,4E,6E,11R)-3,11-Dihydroxydodeca-4,6-dienoic Acid (2)
To an ice-cold flask containing acid 17 (60 mg, 0.175 mmol) in THF
(10 mL) was added a solution of HF·Pyridine (0.2 mL) and stirred
at 0 °C for 6 h. After completion of the reaction, the mixture was di-
luted with H2O (5 mL) and extracted with EtOAc (3 × 10 mL). The
combined organic extracts were dried (MgSO4) and concentrated to
leave a colorless amorphous solid, which was purified by column
1H NMR (300 MHz, CDCl3): d = 11.85 (s, 1 H), 7.02 (dd, J = 10.9,
15.5 Hz, 1 H), 6.24–6.08 (m, 1 H), 6.05–5.95 (m, 1 H), 5.78 (d,
J = 14.8 Hz, 1 H), 4.99 (s, 1 H), 4.21 (q, J = 7.0 Hz, 2 H), 3.80–3.73
(m, 1 H), 3.55 (s, 1 H), 2.25–2.15 (m, 2 H), 1.57–1.36 (m, 8 H),
1.35–1.23 (m, 5 H), 1.11 (d, J = 6.2 Hz, 3 H), 0.88 (s, 9 H), 0.03 (s,
6 H).
Synthesis 2012, 44, 311–315
© Thieme Stuttgart · New York

PAPER
Total Synthesis of Leodomycin C and D
315
chromatography on silica gel (CH2Cl2–MeOH, 1:1) to furnish pure
5, 1669. (d) Das, S. M. P.; Sivapathasekaran, C.; Sen, R.
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2 (28.8 mg, 72%); [a]D25 +17.9 (c 0.35, MeOH).
IR (neat): 3449, 2933, 2869, 1727, 1439, 1350, 1261, 1134, 836,
772 cm–1.
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1H NMR (300 MHz, CDCl3): d = 6.18 (dd, J = 9.8, 14.9 Hz 1 H),
6.01 (dd, J = 9.8, 14.9 Hz, 1 H), 5.65 (dt, J = 14.8, 7.05 Hz, 2 H),
4.61–4.28 (m, 1 H), 3.86–3.66 (m, 1 H), 2.41(d, J = 6 Hz, 2 H),
2.12–1.96 (m, 2 H), 1.53–1.18 (m, 4 H), 1.11 (d, J = 6 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 175.4, 136.2, 133.5, 131.9, 130.9,
70.1, 68.4, 43.7, 39.8, 33.7, 26.2, 23.9.
HRMS-ESI: m/z calcd for C12H19O4 [M – H]–: 227.1286;
found: 227.1293.
Acknowledgment
The authors are thankful to MOES and CSIR, New Delhi, India for
financial support and Dr. J. S. Yadav, Director, Indian Institute of
Chemical Technology (IICT), for his encouragement.
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© Thieme Stuttgart · New York
Synthesis 2012, 44, 311–315