Stereoselective total synthesis of Ieodomycin A and B

Article abstract of DOI:10.1016/j.tetasy.2013.05.002

The stereoselective total synthesis of Ieodomycin A and B, bioactive secondary metabolites from marine sources with potent anti-microbial activity was achieved starting from commercially available geranial. The key steps involved in the synthetic sequence of Ieodomycin A and B are the Sharpless asymmetric epoxidation, the formation of a β-ketoester, and the 1,3-anti reduction. The synthesis of C-3 epimer of Ieodomycin A and B was also accomplished in good yields.

Full text of DOI:10.1016/j.tetasy.2013.05.002

Tetrahedron: Asymmetry xxx (2013) xxx–xxx
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective total synthesis of Ieodomycin A and B
Emmadi Narender Reddy , Atmakur Krishnaiah , Tadikamalla Prabhakar Rao b
a
a,
⇑
a
Crop Protection Chemical Division, Indian Institute of Chemical Technology, Hyderabad 500607, India
Centre for NMR & Structural Chemistry, Indian Institute of Chemical Technology, Hyderabad 500607, India
b
a r t i c l e i n f o
a b s t r a c t
Article history:
The stereoselective total synthesis of Ieodomycin A and B, bioactive secondary metabolites from marine
sources with potent anti-microbial activity was achieved starting from commercially available geranial.
The key steps involved in the synthetic sequence of Ieodomycin A and B are the Sharpless asymmetric
epoxidation, the formation of a b-ketoester, and the 1,3-anti reduction. The synthesis of C-3 epimer of
Ieodomycin A and B was also accomplished in good yields.
Received 3 April 2013
Accepted 8 May 2013
Available online xxxx
Ó 2013 Elsevier Ltd. All rights reserved.
OH
1
. Introduction
OH
OH
Marine microorganisms have a wealth of novel secondary
COOMe
metabolites with diverse chemical structures. Marine Bacillus spe-
cies, prevalent and distinct in similar marine ecosystems, are
known to produce anticancer,1 antimicrobial compounds , and
bio-surfactants. Some of the natural products from marine micro-
organisms with anti-microbial activity are also prominent sources
O
O
2
Ieodomycin B 1
Ieodomycin A 2
OH
OH
OH
O
O
3
for antifungal, anti-inflammatory, and anti-viral agents. Since sev-
OH
OH
eral pathogens are developing a resistance to antibiotics; there is a
great need to discover new anti-microbial agents, as they are
known to combat infectious diseases effectively.
Ieodomycin C
Ieodomycin D
Figure 1. Ieodomycin A–D.
4
Recently, Shin et al. isolated four bioactive secondary metabo-
lites, Ieodomycin A–D (Fig. 1) from the marine bacterium strain
Bacillus species, which have shown potent anti microbial activity
against Bacillus subtilis and Escherichia coli with minimum inhibi-
2
3
, which in turn was obtained by 1,3-anti-reduction of b-ketoester
. Compound 3 was prepared from epoxyalcohol 4, which was de-
tory concentration (MICs) of 32–64 lg/mL. There has been much
rived from alkene 5, which was further obtained from geraniol.
significance to the synthesis of pharmaceutically active natural
products and until very recently, there was no report on the syn-
thesis of Ieodomycin A and B. However, during the preparation of
2
. Results and discussion
5
this manuscript, Koul reported on the synthesis of Ieodomycin A
The synthesis of compound 1 started with the conversion of
and B starting from D-glucose in 15 steps.
geraniol into the corresponding alkene 5 in 88% yield as reported
in the literature (Scheme 2) via Swern oxidation followed by Wit-
tig reaction of the resulting aldehyde with methyltriphenylpho-
sponium bromide in the presence of nBuLi in THF. The obtained
alkene 5 was epoxidised with mCPBA in CH
mixture of 6 in 75% yield.
However, there is still scope to find a shorter and more straight-
forward synthesis to these molecules based on their structural and
biological activities. As part of our continuous interest to synthe-
7
6
size new chemical entities of biological interest, we herein report
8
2 2
Cl to afford a racemic
a short, simple, straightforward and practical stereoselective syn-
thesis of Ieodomycin A and B starting from commercially available
In the next step, the epoxy group of compound 6 was cleaved by
3
,7-dimethyl-2,6-octadien-1-ol (geraniol). Our synthetic strategy
9
using sodium periodate/periodic acid to give the aldehyde, which
for Ieodomycin A and B is outlined in Scheme 1, where Ieodomycin
was then subjected to a Wittig reaction by treatment with ethoxy-
carbonyl methylenetriphenyl phosporane in benzene to give con-
jugated ester 7 in 80% yield. Next, compound 7 was reduced with
B 1 was obtained by intramolecular lactonization of Ieodomycin A
10
DIBAL-H in CH
2
Cl
2
at 0 °C to give allyl alcohol 8 in 85% yield.
with
⇑
Corresponding author. Tel.: +91 40 27191436; fax: +91 40 27193382.
E-mail address: srikrishnua@yahoo.com (A. Krishnaiah).
Sharpless asymmetric epoxidation of allylic alcohol
8
0
957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.05.002
Please cite this article in press as: Reddy, . N.; et al. Tetrahedron: Asymmetry (2013), http://dx.doi.org/10.1016/j.tetasy.2013.05.002

2
Emmadi Narender Reddy et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
OH
OH
OH
COOMe
O
O
1
2
OTBS O
O
COOMe
OH
3
4
geraniol
5
Scheme 1. Retrosynthetic route to Ieodomycin A and B.
a
ref 7
geraniol
, and cumene hydroperoxide11 in dry CH
2 2
Cl
afforded epoxy alcohol 4 in 85% yield with 93% enantiomeric
excess.
(
ꢀ)-DIPT, Ti(Oi-Pr)
4
5
O
b,c
COOEt
Regioselective reduction of epoxide 4 using Red-Al yielded the
1
2
6
7
corresponding 1,3-diol 9 in 84% yield. Protection of the hydroxyl
groups of compound 9 with TBDMSCl (tert-butyldimethylsilyl
d
e
chloride), imidazole, and DMAP in CH
ylsilyl ether 10 and selective deprotection of the primary silyl ether
2 2
Cl as bis tert-butyldimeth-
OH
8
13
with CSA in CH
The oxidation of alcohol 11 by using IBX, DMSO in CH
2
Cl
2
:MeOH (1:1) afforded alcohol 11 in 78% yield.
Cl at 0 °C to
OH
O
2
2
f
OH
room temperature for 10 h afforded the corresponding aldehyde
OH
9
4
12. Compound 12 upon reaction with methyl diazoacetate and ti-
1
4
OTBS
n(II) chloride gave the b-keto ester 3 in 77% yield. Deprotection
of the tert-butylsilyl group in compound 3 with TBAF in THF affor-
ded the d-hydroxy-b-keto ester 13 in 90% yield.
g
i
OR
1
5
Hydroxyl-directed 1,3-anti reduction of the carbonyl group of
13 with Me NBH(OAc)
in acetic acid and MeOH (1:1) at ꢀ20 °C for
h furnished Ieodomycin A 2 in 90% yield in 96:4 diastereoselec-
1
1
0, R = TBS
1, R = H
h
4
3
2
OR
O
OTBS
tivity (Scheme 3). The physical and spectroscopic data of synthet-
j
COOMe
ically prepared compound 2 are in agreement with the natural
O
25
D
25
D
product. ½
a
ꢁ
¼ þ16:6 (c 0.9, CHCl
3
), lit. ½
a
ꢁ
¼ þ19 (c 0.9, CHCl
3
).
1
2
3, R = TBS
In the final step, Ieodomycin B 1 was obtained in 88% yield by
k
refluxing Ieodomycin A 2 in benzene for 1 h in the presence of
1
3, R = H
1
6
pyridinium-4-tolunesulfonate (PPTS); the structure was con-
firmed by extensive NMR studies. The Ieodomycin B obtained has
physical and spectroscopic data that were comparable with the
Scheme 2. Reagents and conditions: (a) mCPBA, dry CH
NaIO , HIO O, THF:H O (10:1), 0 °C to rt,1 h, (c) Ph
ꢂ2H
h, 80% (for two steps), (d) DIBAL-H, dry CH Cl
, 0 °C, 1 h, 85%, (e) (ꢀ)-DIPT, 4 Å MS,
Ti(Oi-Pr)
, cumene hydroperoxide, ꢀ20 °C, 3 h, 85%, (f) Red-Al, dry THF, 0 °C, 3 h,
4%, (g) TBDMSCl, imidazole, DMAP, CH Cl 0 °C to rt, 4 h, 88%, (h) CSA,
CH Cl Cl , 0 °C to rt, 10 h, 88%,
:MeOH (1:1), ꢀ20 °C, 1 h, 78%, (i) IBX, DMSO, CH
j) N CHCOOMe, SnCl O, 0 °C, 0.5 h, 77%, (k) TBAF, THF, 0 °C to rt, 3 h, 90%.
ꢂ2H
2
Cl
2
, 0 °C, 0.5 h, 75%, (b)
3
PCHCOOEt, benzene, 80 °C,
4
4
2
2
2
2
2
25
D
25
D
natural product. ½
.9, CHCl ).
The C-3 epimer of Ieodomycin A was synthesized by 1,3-syn
a
ꢁ
¼ þ23:5 (c 1.6, CHCl
3
), lit. ½
aꢁ
¼ þ21 (c
4
0
3
8
2
2
,
2
2
2
2
1
7
(
2
2
2
reduction (Scheme 3) of the carbonyl group of compound 13 with
OH
OH
OH
COOMe
b
O
O
a
Ieodomycin A 2
Ieodomycin B 1
OH
13
OH
OH
COOMe
c
b
O
O
epi-Ieodomycin A 2a
epi-Ieodomycin B 1a
Scheme 3. Reagents and conditions: (a) Me
80 °C, 3 h, 92%.
4
NBH(OAc)
3
, CH
3
CN:AcOH (1:1), ꢀ20 °C, 2 h, 90%, (b) PPTS, benzene, 80 °C, 2 h, 88%, (c) (C
2 5 2 4
H ) BOMe, NaBH ,THF:MeOH (4:1),
ꢀ
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Emmadi Narender Reddy et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
3
diethyl methoxy borane, NaBH
for 3 h to yield compound 2a in 92% yield. ½
CHCl ). Compound 2a was then refluxed in benzene in the pres-
ence of PPTS for 1 h to give the C-3 epimer of Ieodomycin B 1a in
4
in THF, and MeOH (4:1) at ꢀ80 °C
with EtOAc (3 ꢃ 50 mL). The combined organic layer was washed
with brine, dried over anhydrous sodium sulfate, and evaporated
under reduced pressure to give crude aldehyde (3.38 g). Next, to
a solution of the crude aldehyde (3.38 g, 27 mmol) in dry benzene
(50 mL) was added carboethoxymethylidene triphenylphospho-
rane (11.25 g, 32.4 mmol) at room temperature and the reaction
mixture was stirred at 80 °C for 2 h. After completion of the reac-
tion, the mixture was allowed to cool to room temperature, diluted
with petroleum ether (100 mL), the precipitate was filtered off, and
the filtrate was concentrated. The residue was purified by flash
chromatography (silica gel, hexanes:EtOAc = 96:04) to give 7
2
D
5
aꢁ
¼ ꢀ9:95 (c 0.9,
3
2
5
8
7% yield. ½
. Conclusion
In conclusion we have successfully synthesized Ieodomycins A
a
ꢁ
¼ þ36:1 (c 0.9, CHCl
3
).
D
3
and B and their C-3 epimer by a simple and short route, starting
from commercially available geraniol involving a Wittig reaction,
Sharpless asymmetric epoxidation, and intramolecular lactoniza-
tion of Ieodomycin A to furnish Ieodomycin B.
(
1
4.19 g, 80% yield for two steps). IR (KBr):
m
max 2980, 1720, 1653,
ꢀ1
1
266, 1219, 772 cm . H NMR (CDCl , 300 MHz): d 6.96 (ddd,
3
J = 15.7, 6.6, 6.8 Hz,1H), 6.56 (ddd, J = 16.8, 10.6, 10.6 Hz, 1H),
5
4
.9–5.8 (m, 2H), 5.12 (d, J = 16.8 Hz, 1H), 5.0 (d, J = 10.2 Hz, 1H),
.18 (q, J = 7.2 Hz, 2H), 2.4–2.3 (m, 2H), 2.24–2.17 (m, 2H), 1.77
4
4
. Experimental
1
3
(
s, 3H), 1.28 (t, J = 7.2 Hz, 3H). C NMR (CDCl
3
, 75 MHz): d 166.5,
1
48.3, 137.5, 133, 126.1, 121.5, 115.3, 60.1, 38.0, 30.5, 16.5, 14.2.
.1. General
+
12 2
C H18NaO
[M+Na]+
ESI-MS: 217 [M+Na] . HRMS calcd for
2
17.1199; found 217.1203.
2
Reactions were conducted under N in anhydrous solvents such
as CH
silica-coated plates and visualizing under UV light). Light petro-
leum ether (bp 60–80 °C) was used. Yields refer to chromatograph-
ically and spectroscopically ( H, C NMR) homogeneous material.
Air-sensitive reagents were transferred by a syringe or double-
2 2
Cl , THF, and benzene. All reactions were monitored by TLC
4
.1.3. (2E,6E)-6-Methylnona-2,6,8-trien-1-ol 8
To a stirred solution of ester 7 (4.0 g, 20.6 mmol) in anhydrous
Cl (50 mL), DIBAL-H (12.5 mL, 25% wt in toluene, 43.2 mmol)
(
1
13
CH
2
2
was added at 0 °C and the mixture was allowed to stir at the same
temperature for 1 h. After completion of the reaction as indicated
by TLC, the reaction was quenched with a saturated solution of so-
dium potassium tartrate (25 mL) at 0 °C and the stirring continued
ended needle. Evaporation of solvents was performed at reduced
pressure on a Buchi rotary evaporator. 1H and 13C NMR spectra
of samples in CDCl
00 MHz, and 500 MHz (Avance) spectrometers. Chemical shifts
d) are reported relative to TMS (d = 0.0) as the internal standard.
3
were recorded on Bruker UXNMR FT-
for 1 h. The aqueous phase was extracted with CH
and the combined organic extracts were dried over anhydrous
Na SO , concentrated, and purified by column chromatography
silica gel, hexanes:EtOAc = 85:15) to afford the desired allylic
alcohol 8 (2.66 g, 85%). IR (KBr): max 3415, 2924, 1670, 1219,
, 300 MHz): d 6.57 (ddd, J = 16.6,
0.6, 10.6 Hz, 1H), 5.86 (d, J = 10.6 Hz, 1H), 5.70–5.66 (m, 2H), 5.1
2
Cl
2
(3 ꢃ 50 mL)
3
(
2
4
Mass spectra were recorded in ESI spectrometers. All high resolu-
tion mass spectra were recorded on QSTAR XL hybrid ms/ms sys-
tem (Applied Bio systems/MDS sciex, foster city, USA), equipped
with an ESI source (IICT, Hyderabad). Column chromatography
was performed on silicagel (60–120 mesh) supplied by Acme
Chemical Co., India. TLC was performed on Merck 60 F-254 silica
gel plates. Optical rotations were measured with a JASCO DIP-
(
m
ꢀ1 1
9
71, 772 cm . H NMR (CDCl
3
1
(
dd, J = 16.6, 1.5 Hz, 1H), 5.0 (dd, J = 10.6, 2.2 Hz, 1H), 4.09 (br s,
1
3
2
H), 2.24–2.12 (m, 4H), 1.76 (s, 3H). C NMR (CDCl
3
, 75 MHz): d
1
38.6, 133.2, 132.4, 129.3, 125.8, 114.8, 63.6, 39.2, 30.5, 16.6.
3
70 Polarimeter at 25 °C.
+
ESI-MS: 175 [M+Na] .
4
.1.1. (E)-2,2-Dimethyl-3-(3-methylhexa-3,5-dienyl)oxirane 6
To a solution of 5 (6 g, 40 mmol) in CH
mCPBA (7.56 g, 75%, 44 mmol) in CH Cl (30 mL) over a period at
°C while stirring. After the addition, stirring was continued at
the same temperature for 0.5 h to complete the reaction as indi-
cated by TLC. The reaction mixture was then quenched by the addi-
2
Cl
2
(80 mL) was added
4.1.4. (((2R,3R)-3-(E)-3-Methylhexa-3,5-dienyl)oxiran-2-
yl)methanol 4
2
2
0
To a stirred solution of (ꢀ)-DIPT (1.84 g, 7.9 mmol) in CH Cl
2
2
(30 mL) containing 4 Å molecular sieves (0.6 g), was sequentially
added Ti(Oi-Pr)4 (1.5 g, 5.3 mmol), and cumene hydroperoxide
(6 g, 39.5 mmol) at ꢀ20 °C and the reaction mixture stirred for
20 min; to this a solution of allyl alcohol 8 (4 g, 26.3 mmol) in
CH Cl (15 mL) was added and the stirring continued for 3 h at
tion of a saturated NaHCO
CH Cl
(3 ꢃ 50 mL). The organic layer was washed with brine and
dried over anhydrous Na SO . The solvent was removed under vac-
3
solution (30 mL), and extracted with
2
2
2
4
2
2
uum, and the residue was purified by column chromatography (sil-
the same temperature to complete the reaction (monitored by
TLC). The reaction was then quenched with 10% KOH solution
(1.5 g in 15 mL brine, 3 mL), stirred for 2 h, and filtered. The organic
layer from the filtrate was dried over anhydrous Na SO and evap-
ica gel, hexanes:EtOAc = 95:05) to give 6 (4.98 g) in 75% yield. IR
ꢀ1 1
(
KBr):
m
max 2923, 1219, 772 cm
3
. H NMR (300 MHz, CDCl ): d
6
5
1
3
1
.57 (ddd, J = 17.0, 11.0, 11.0 Hz, 1H), 5.89 (d, J = 11.0 Hz, 1H),
.11 (d, J = 17.0 Hz, 1H), 5.0 (d, J = 10.9 Hz, 1H), 2.71 (t, J = 7.0 Hz,
H), 2.27–2.13 (m, 2H), 1.78 (s, 3H), 1.72–1.64 (m, 2H), 1.3 (s,
2
4
orated to dryness under reduced pressure. The residue was purified
by column chromatography (silica gel, hexanes:EtOAc = 90:10) to
furnish epoxy alcohol 4 (3.75 g, 85%, 93% ee) as a colorless syrup.
HPLC analysis (Chiral pak IC-3, Hexane/Isopropanol, 70/30, flow
1
3
3
H), 1.25 (s, 3H). C NMR (75 MHz, CDCl ): d 138.2, 133.1, 125.9,
+
15.1, 64.0, 36.4, 29.7, 27.2, 24.8, 18.7. ESI-MS: 199 [M+Na] .
2
D
5
0
.6 mL/min, t ).
R
(R) = 8.63, t
R
(S) = 9.70; ½
a
ꢁ
¼ þ15:3 (c 1.67, CHCl
3
ꢀ
1 1
4
.1.2. (2E,6E)-Ethyl 6-methylnona-2,6,8-trienoate 7
IR (KBr): mmax 3415, 2925, 2856, 1670, 1453, 1035 cm . H NMR
A solution of epoxide 6 (5 g, 28.4 mmol) in THF:H
0 mL) was treated sequentially at 0 °C with NaIO
8 mmol) and HIO
sic mixture was stirred at 0 °C for 10 min and then warmed to
room temperature. After 1 h, the reaction mixture was quenched
with a saturated aqueous sodium bicarbonate solution (20 mL), di-
luted with water (25 mL), and the aqueous layer was extracted
2
O (10:1,
(3.84 g,
(CDCl , 300 MHz): d 6.56 (ddd, J = 16.7, 10.8, 9.8 Hz, 1H), 5.88 (d,
3
3
1
4
J = 10.84 Hz, 1H), 5.11 (d, J = 16.7 Hz, 1H), 5.0 (d, J = 10.8 Hz, 1H),
4
ꢂ2H
2
O (7.52 g, 33.1 mmol). The resultant bipha-
3.90–3.86 (m, 1H), 3.64–3.59 (m, 1H), 2.96–2.90 (m, 2H), 2.26–
1
3
2.15 (m, 2H), 1.77 (s, 3H), 1.72 (q, J = 7.9 Hz, 2H). C NMR (CDCl3,
75 MHz): d 137.8, 133.0, 126.1, 115.3, 61.6, 58.5, 55.5, 35.8, 29.7,
16.5. ESI-MS: 191 [M+Na] . HRMS calcd for C10H16NaO2 [M+Na]+
191.0854; found 191.0858.
+
Please cite this article in press as: Reddy, . N.; et al. Tetrahedron: Asymmetry (2013), http://dx.doi.org/10.1016/j.tetasy.2013.05.002

4
Emmadi Narender Reddy et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
4
.1.5. (R,E)-6-Methylnona-6,8-diene-1,3-diol 9
To a solution of epoxy alcohol 4 (3.5 g, 20.8 mmol) in anhydrous
THF (30 mL) was added Red-Al (9.75 mL, 3.2 M solution in toluene,
1.2 mmol) over 15 min at 0 °C under a nitrogen atmosphere. The
4.1.8. (R,E)-Methyl 5-(tert-butyldimethylsilyloxy)-8-methyl-3-
oxoundeca-8,10-dienoate 3
To an ice cold solution of 2-iodoxybenzoic acid (2.4 g, 8.5 mmol)
in anhydrous DMSO (4 mL) was added a solution of alcohol 11
3
mixture was then stirred at the same temperature for 3 h. The
reaction was quenched by the addition of saturated aqueous so-
dium potassium tartrate (20 mL). The mixture was warmed to
room temperature and diluted with EtOAc (50 mL). The resulting
mixture was stirred until two clear layers were seen. The organic
layer was separated and the aqueous layer extracted with EtOAc
(1.5 g, 5.7 mmol) in anhydrous CH
stirred at rt for 10 h, then filtered through a Celite pad and washed
with CH Cl
(2 ꢃ 30 mL). The combined organic filtrates were
washed with H O and a brine solution, dried over anhydrous
Na SO , concentrated in vacuo, and the resulting crude product
2 2
Cl (25 mL). The mixture was
2
2
2
2
4
purified by flash chromatography on silica gel to give 12 (1.3 g,
88%). The unstable aldehyde 12 was used for the next reaction.
(
2 ꢃ 50 mL). The combined organic layers were dried over Na
2 4
SO
and concentrated. The resulting crude was purified by flash chro-
matography on silica gel (silica gel, hexanes:EtOAc = 70:30) to give
A solution of 12 (1.3 g, 4.6 mmol) in dry CH
suspension of methyl diazoacetate (0.56 g, 5.6 mmol) and
SnCl O (0.1 g, 0.46 mmol) in CH C1 (10 mL) at room temper-
2 2
Cl was added to a
2
D
5
diol 9 (2.97 g, 84%) as a colorless oil. ½
aꢁ
¼ þ7:5 (c 1, CHCl
3
). IR
H NMR
, 300 MHz): d 6.58 (ddd, J = 17.0, 10.6, 10.6 Hz, 1H), 5.90
d, J = 10.9 Hz, 1H), 5.10 (d, J = 16.9 Hz, 1H), 5.0 (d, J = 10.2 Hz,
H), 3.94–3.80 (m, 3H), 2.26–2.08 (m, 2H), 1.78 (s, 3H), 1.76–1.60
2
ꢂ2H
2
2
2
ꢀ
1
1
(
(
(
KBr):
m
max 3403, 2928, 1717, 1375, 1057, 756 cm
.
ature under a nitrogen atmosphere. The mixture was stirred for
0.5 h and then concentrated. The residue was chromatographed
on silica gel (silica gel, hexanes:EtOAc = 90:10) to give (R,E)-methyl
CDCl
3
1
5-(tert-butyldimethylsilyloxy)-8-methyl-3-oxoundeca-8,10-dieno-
1
3
25
D
(
7
m, 4H). C NMR (CDCl
3
, 75 MHz): d 139.0, 133.1, 125.7, 115.0,
ate 3 (1.25 g, 77%). ½
a
ꢁ
¼ ꢀ15:4 (c 0.9, CHCl
3
). IR (KBr):
, 300 MHz):
d 6.56 (ddd, J = 17.3, 10.6, 10.6 Hz, 1H), 5.84 (d, J = 10.6 Hz, 1H),
.09 (d, J = 16.6 Hz, 1H), 4.98 (d, J = 10.6 Hz, 1H), 4.20–4.12 (m,
mmax 2929,
+
ꢀ1 1
1.7, 61.5, 38.2, 35.8, 35.5, 16.5. ESI-MS: 193 [M+Na] . HRMS calcd
2856, 1751, 1720, 1253, 836, 774 cm . H NMR (CDCl
3
+
2
for C10H18NaO [M+Na] 193.1199; found 193.1203.
5
4
4
.1.6. (R,E)-2,2,3,3,9,9,10,10-Octamethyl-5-(3-methyl-3,5-dienyl)-
,8-dioxa-3,9-disilaundecane 10
1H), 3.73 (s, 3H), 3.48 (s, 2H), 2.76–2.58 (m, 2H), 2.10–2.02 (m,
2H), 1.74 (s, 3H), 1.64–1.55 (m, 2H), 0.87 (s, 9H), 0.07 (s, 3H),
1
3
To a solution of diol 9 (2.0 g, 11.7 mmol) in dry CH
2
Cl
2
was
0.03 (s, 3H). C NMR (CDCl
3
, 75 MHz): d 201.7, 175.8, 138.8,
added imidazole (2.4 g, 35.2 mmol) in CH
amount of DMAP, followed by TBDMSCl (3.88 g, 25.8 mmol) in
CH Cl after which the reaction mixture was stirred at rt for 4 h.
2 2
Cl at 0 °C and a catalytic
133.2, 125.6, 114.9, 68.5, 50.0, 35.6, 35.1, 29.7, 25.8, 18.0, 16.7,
+
ꢀ4.6, ꢀ4.8. ESI-MS: 377 [M+Na] . HRMS calcd for C19
4
H34NaO Si
+
2
2
[M+Na] 377.2118; found 377.2123.
After completion of the reaction (monitored by TLC), it was
quenched with water, after which the aqueous phase was ex-
4.1.9. (R,E)-Methyl 5-hydroxy-8-methyl-3-oxoundeca-8,10-
tracted with CH
over anhydrous Na
chromatography (silica gel, hexanes:EtOAc = 90:10) on silica gel
2
Cl
2
, and the combined organic extracts were dried
dienoate 13
2
SO , concentrated, and purified by column
4
A solution of 3 (1 g, 2.8 mmol) in dry THF (15 mL) was cooled to
0 °C. To this TBAF (3.36 mL, 1.0 M in THF, 3.36 mmol) was added
dropwise and stirred for 30 min at the same temperature. The
resulting mixture was allowed to return to room temperature
and stirring continued for 3 h. Next, water (5 mL) was added and
the aqueous layer was extracted with ethyl acetate. The combined
25
to afford the desired product 10 (4.12 g, 88%). ½
CHCl ). IR (KBr): max 2954, 2930, 2857, 1467, 1253, 1095, 835,
H NMR (CDCl , 300 MHz): d 6.57 (ddd, J = 16.6, 10.6,
a
ꢁ
¼ ꢀ3:0 (c 0.7,
D
3
m
ꢀ
1 1
7
1
1
74 cm
.
3
0.6 Hz, 1H), 5.85 (d, J = 10.6 Hz, 1H), 5.08 (dd, J = 17.4, 2.2 Hz,
H), 4.97 (dd, J = 10.6, 2.2 Hz, 1H), 3.85–3.77 (m, 1H), 3.66 (t,
2 4
organic layer was washed with brine, dried over Na SO concen-
J = 7.9 Hz, 2H), 2.14–2.0 (m, 2H), 1.75 (s, 3H), 1.70–1.52 (m, 4H),
trated under reduced pressure, and the resulting crude product
purified by column chromatography (silica gel, hex-
13
0
7
2
.91–0.85 (m, 18H), 0.06–0.03 (m, 12H).
5 MHz): d 139.6, 133.3, 125.2, 114.5, 69.0, 59.8, 40.0, 35.6, 35.3,
3
C NMR (CDCl ,
anes:EtOAc = 90:10) on silica gel to give hydroxyl ester 13
+
25
D
5.8, 16.7, ꢀ4.6, ꢀ4.5, ꢀ5.4. ESI-MS: 421 [M+Na] . HRMS calcd
(0.61 g, 90%). ½
a
ꢁ
¼ ꢀ26:1 (c 1.5, CHCl
3
). IR (KBr):
m
max 3448,
NMR (CDCl
00 MHz): d 6.56 (ddd, J = 16.8, 10.6, 10.6 Hz, 1H), 5.88 (d,
+
ꢀ1
1
for C22
H46NaO
2
Si
2
[M+Na] 421.2934; found 421.2938.
2923, 1745, 1713, 1437, 1219, 772 cm
.
H
3
,
3
4
1
.1.7. (R,E)-3-(tert-Butyldimethyloxy)-6-methylnona-6,8-dien-
-ol 11
To a solution of 10 (6.0 g, 15.0 mmol) in 150 mL of CH
J = 10.9 Hz, 1H), 5.10 (d, J = 17.0 Hz, 1H), 5.0 (d, J = 10.0 Hz, 1H),
4.11–4.01 (m, 1H), 3.75 (s, 3H), 3.5 (s, 2H), 2.78–2.68 (m, 2H),
1
3
2
Cl
2
/
2.30–2.07 (m, 2H), 1.77 (s, 3H), 1.68–1.58 (m, 2H). C NMR (CDCl
3
,
MeOH 1:1 at ꢀ20 °C were added 0.32 g (1.38 mmol) of CSA portion
wise over 5 min after which stirring was continued at the same
temperature for 1 h. After the addition of saturated aqueous NaH-
75 MHz): d 203.3, 167.3, 138.5, 133.1, 125.9, 115.1, 67.2, 52.4, 49.6,
+
35.5, 34.4, 16.5. ESI-MS: 263 [M+Na] . HRMS calcd for C13
H20NaO
4
+
[M+Na] 263.1253; found 263.1258.
3
CO solution (5 mL), the organic solvents were evaporated, and the
residue was partitioned between
H
2
O
(50 mL) and CH
2
Cl
Cl
2
4.1.10. Ieodomycin A 2
(
(
Na
100 mL). The aqueous phase was further extracted with CH
2
2
To a stirred suspension of tetramethylammonium triacetoxy-
borohydride (1.1 g, 4.1 mmol) in acetonitrile (3 mL) was added gla-
cial acetic acid (3 mL). The mixture was stirred at rt for 30 min.
After cooling to ꢀ20 °C, the hydroxy ketoester 13 (0.2 g,
0.83 mmol) in a mixture of acetic acid and acetonitrile (v/v 1:1,
2 mL) was added dropwise and stirring continued at ꢀ20 °C for
over 2 h. A saturated solution of sodium potassium tartrate
(20 mL) and EtOAc (20 mL) were then added, followed by vigorous
stirring at rt for 30 min. The mixture was extracted with EtOAc
(3 ꢃ 15 mL). The combined organic layers were washed with water
2 ꢃ 30 mL), and the combined organic phase was dried over
SO and evaporated. The crude product was purified by column
chromatography (silica gel, hexanes:EtOAc = 90:10) to give 11
2
4
2
D
5
(
2
3
3.33 g, 78%). ½
a
ꢁ
¼ ꢀ13:4 (c 0.9, CHCl
3
). IR (KBr):
m
max 3371,
NMR (CDCl
00 MHz): d 6.57 (ddd, J = 16.6, 11.3, 10.6 Hz, 1H), 5.85 (d,
ꢀ1
1
928, 2855, 1465, 1254, 836, 775 cm
.
H
3
,
J = 11.3 Hz, 1H), 5.10 (dd, J = 16.6, 1.5 Hz, 1H), 4.99 (dd, J = 10.6,
2
2
9
1
.2 Hz, 1H), 3.97–3.80 (m, 2H), 3.77–3.67 (m, 1H), 2.09–2.03 (m,
H), 1.89–1.76 (m, 2H), 1.77 (s, 3H), 1.72–1.63 (m, 2H), 0.9 (s,
H), 0.10 (s, 3H), 0.09 (s, 3H). 13C NMR (CDCl
, 75 MHz): d 139.0,
33.2, 124.5, 114.8, 71.4, 60.1, 37.7, 35.5, 34.9, 25.8, 17.9, 16.7,
(20 mL), NaHCO
(2 ꢃ 10 mL), and brine, dried over Na
3
3
2 4
SO , fil-
tered, and concentrated under reduced pressure. The residue was
purified by flash column chromatography (silica gel, hex-
anes:EtOAc = 80:20) to afford Ieodomycin A 2 as an amorphous so-
+
ꢀ
4.4, ꢀ4.7. ESI-MS: 307 [M+Na] . HRMS calcd for C16
33 2
H O Si
+
[
M+H] 285.2241; found 285.2244.
Please cite this article in press as: Reddy, . N.; et al. Tetrahedron: Asymmetry (2013), http://dx.doi.org/10.1016/j.tetasy.2013.05.002

Emmadi Narender Reddy et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
5
2
D
5
ESI-MS: 265 [M+Na]+. HRMS calcd for
243.1590; found 243.1595.
[M+H]+
lid (0.18 g, 90%, dr 96:4). ½
a
ꢁ
¼ þ16:6 (c 0.9, CHCl
3
). IR (KBr):
H NMR (CD
00 MHz): d 6.58 (ddd, J = 16.8, 10.1, 10.1 Hz, 1H), 5.87 (d,
m
3
OD,
max
13 23 4
C H O
ꢀ
1
1
3
400, 2935, 1733, 1441, 1242, 1070 cm
.
5
J = 10.1 Hz, 1H), 5.04 (dd, J = 16.8, 2.2 Hz, 1H), 4.94 (dd, J = 10.1,
4.1.13. (4R,6R)-4-Hydroxy-6-(E)-3-methylhexa-3,5-dienyl)tetra-
hydro-2H-pyran-2-one 1a
2
2
1
1
.2 Hz, 1H), 4.29–4.23 (m, 1H), 3.80–3.75 (m, 1H), 3.68 (s, 3H),
.48 (dd, J = 10.0, 4.6 Hz, 2H), 2.23–2.08 (m, 2H), 1.76 (s, 3H),
The experimental procedure for 1a is the same as for 1. Yield
.60–1.52 (m, 4H). 1 C NMR (CD
3
87%; ½
a
ꢁ
25
D
¼ þ36:1 (c 0.9, CHCl
). IR (KBr): m
max 3424, 2924, 1713,
3
OD, 125 MHz): d 173.8, 140.0,
3
ꢀ
1
1
34.6, 126.9, 115.0, 68.7, 66.5, 52.1, 45.3, 43.8, 37.4, 36.9, 16.7.
1255, 1064, 900 cm
.
3
H NMR (CDCl , 300 MHz): d 6.56 (ddd,
+
+
ESI-MS: 265 [M+Na] . HRMS calcd for
C
13
H
22NaO
4
[M+Na]
J = 17.0, 11.0, 10.0 Hz, 1H), 5.89 (d, J = 11.0 Hz, 1H), 5.11 (d,
J = 17.0 Hz, 1H), 5.01 (d, J = 10.0 Hz, 1H), 4.68 (m, 1H), 4.40 (m,
2
65.1410; found 265.1412.
1
H), 2.74 (dd, J = 17.0, 5.0 Hz, 1H), 2.62 (dd, J = 17.0, 4.0 Hz, 1H),
4
.1.11. Ieodomycin B 1
2.30 (m, 1H), 2.18 (m, 1H), 1.97 (m, 2H), 1.88–1.75 (m, 2H), 1.77
(s, 3H). C NMR (CDCl , 75 MHz): d 170.8, 137.9, 133.0, 126.1,
3
1
3
To a solution of 2 (100 mg, 0.41 mmol) in benzene (15 mL), PPTS
20 mg, 0.08 mmol) was added and heated at reflux for 1 h. The
(
115.3, 75.5, 62.5, 38.5, 35.8, 34.8, 33.6, 16.6. ESI-MS: 233
+
+
reaction mixture was cooled to room temperature, the solvent
was removed under reduced pressure, and the residue was purified
by flash chromatography (silica gel, hexanes:EtOAc = 50:50) to
[M+Na] . HRMS calcd for C12
H18NaO
3
[M+Na] 233.1148; found
233.1150.
yield the d-lactone
1
(76 mg, 88%) as
¼ þ23:5 (c 1.6, CHCl ). IR (KBr): max 3423, 2926, 1725,
H NMR (CD OD, 500 MHz): d 6.58 (ddd,
a
light yellow oil.
Acknowledgements
25
½
a
ꢁ
3
m
D
ꢀ
1
1
1
252, 1071, 761 cm
;
3
We are thankful to Director IICT and Head CPC Division for
encouragement. E.N.R. is thankful to the Council of Scientific and
Industrial Research (CSIR), New Delhi for a Senior Research
Fellowship.
J = 17.0, 10.8, 10.8 Hz, 1H), 5.89 (d, J = 10.8 Hz, 1H), 5.07 (dd,
J = 17.0, 1.5 Hz, 1H), 4.97 (dd, J = 10.8, 1.5 Hz, 1H), 4.28–4.22 (m,
1
H), 4.22–4.16 (m, 1H), 2.86 (dd, J = 17.0, 5.9 Hz, 1H), 2.36 (dd,
J = 17.0, 7.0 Hz, 1H), 2.30–2.24 (m, 2H), 2.21–2.15 (m, 1H), 1.83–
1
1
3
C
.79 (m, 2H), 1.78 (s, 3H), 1.56–1.49 (m, 1H). 13C NMR (CD
3
OD,
References
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+
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, 1669–1674.
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H18NaO
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3 2 4
washed with satd aq NaHCO and brine, then dried over Na SO ,
and concentrated under reduced pressure to give a crude syn-diol,
which was purified by flash column chromatography (silica gel,
hexanes:EtOAc = 80:20) to give 2a (0.18 g, 92%, dr >97%) as a color-
less oil (confirmed by NMR spectroscopic analysis. ½
1
2
D
5
aꢁ
¼ ꢀ9:95 (c
0
8
1
5
3
3
1
.9, CHCl
98 cm
3
). IR (KBr):
m
max 3417, 2924, 2855, 1733, 1440, 992,
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ꢀ1
1
.
H NMR (CDCl , 300 MHz): d 6.57 (ddd, J = 16.8, 10.6,
3
0.4 Hz, 1H), 5.88 (d, J = 10.9 Hz, 1H), 5.10 (d, J = 17.0 Hz, 1H),
.00 (d, J = 10.4 Hz, 1H), 4.33–4.24 (m, 1H), 3.93–3.84 (m, 1H),
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4513.
.72 (s, 3H), 2.5 (d, J = 5.8 Hz, 2H), 2.22–2.06 (m, 2H), 1.77 (s,
H), 1.62–1.58 (m, 4H). 1 C NMR (CDCl
3
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Hardtman, G. E.; Prasad, K.; Repic, O.; Shapiro, M. J. Tetrahedron Lett. 1987, 28,
155–158.
3
, 75 MHz): d 172.8, 138.9,
33.1, 125.6, 114.9, 71.7, 68.9, 51.7, 42.1, 41.5, 35.7, 35.5, 16.5.
Please cite this article in press as: Reddy, . N.; et al. Tetrahedron: Asymmetry (2013), http://dx.doi.org/10.1016/j.tetasy.2013.05.002