Stereoselective synthesis of the C1-C11 tetrahydropyran core unit of (+)-zincophorin

Article abstract of DOI:10.1055/s-0030-1259967

Synthesis of the C1-C11 tetrahydropyran core unit of (+)-zincophorin using a desymmetrization strategy is reported. Horner-Wadsworth-Emmons (HWE) and Mitsunobu cyclization reactions are the key transformations. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1259967

1484
PAPER
Stereoselective Synthesis of the C1–C11 Tetrahydropyran Core Unit of
(+)-Zincophorin
T
he C1–C11 Tetra
o
hydropyran
w
Core
U
nit of (+)-
Z
r
incopho
a
r
in varam Sabitha,* Rangavajjula Srinivas, Jhillu S. Yadav1
Division of Organic Chemistry, Indian Institute of Chemical Technology (CSIR), Hyderabad 500 607, India
Fax +91(40)27160512; E-mail: gowravaramsr@yahoo.com; E-mail: sabitha@iict.res.in
Received 18 February 2011; revised 23 February 2011
The retrosynthetic analysis of zincophorin (1) is outlined
in Scheme 1. It was envisaged that the trisubstituted tet-
rahydropyran ring could be constructed by Mitsunobu cy-
clization. The two fragments – the C1–C4 unit 5 and the
C5–C11 unit 4 – could be combined by a HWE reaction.
Fragment 4, in turn, could be made from the bicyclic ole-
fin 6 by a desymmetrization strategy. Fragment 5 could be
prepared from the (R)-Roche ester.
Abstract: Synthesis of the C1–C11 tetrahydropyran core unit of
(+)-zincophorin using a desymmetrization strategy is reported.
Horner–Wadsworth–Emmons (HWE) and Mitsunobu cyclization
reactions are the key transformations.
Key words: tetrahydropyran, zincophorin, desymmetrization,
Mitsunobu cyclization, HWE reaction
As shown in Scheme 2, the synthesis of the C1–C11 seg-
(+)-Zincophorin (1; Figure 1) is a polyoxygenated iono-
phoric antibiotic that was isolated independently by two
groups from Streptomyces griseus in 1984.2,3 Its strong
ability to bind with divalent cations, especially zinc, was
the origin of its trivial name zincophorin. This compound
exhibits broad in vitro antibiotic activity against Gram-
positive bacteria as well as Clostridium welchii. In addi-
tion, the ammonium and sodium salts of zincophorin
shows significant anticoccidal activity against Eimeria
tenella in chicken embryos.2,3 Its methyl ester has also
been reported to possess antiviral activity, with reduced
host cell toxicity compared to the free acid.4 The structure
of zincophorin was first established by extensive NMR
experiments, and its three-dimensional structure, includ-
ing its absolute configuration, was ascertained by X-ray
diffraction of its zinc-magnesium salt.3 The challenging
structure of the molecule, coupled with its biological ac-
tivity, prompted us to undertake its total synthesis. Until
now, three total syntheses and several elaborated fragment
syntheses have been reported.5 In a continuation of our ef-
forts towards the synthesis of natural products using de-
symmetrization strategies,6 we herein report the
stereoselective synthesis of the C1–C11 tetrahydropyran
core unit 3 of (+)-zincophorin using a desymmetrization
strategy involving Horner–Wadsworth–Emmons (HWE)
and Mitsunobu cyclization reactions as key steps.
ment commenced with a known triol 9,6 which was pre-
5
OBn
1
11
3
7
9
TIPSO
O
OMOM
H
H
3
+
P(OEt)2
OHC
TIPSO
O
O
PMBO
OBn
OMOM
5
4
O
CO2Me
OH
7
OBn
6
Scheme 1 Retrosynthetic analysis
O
O
HO
a
ref. 6
OBn
OBn
6
8
c
b
O
O
OBn OR
OH OH OBn OH
5
OH
9
OH
11
OH
O
1
PMP
9
3
7
10 R = H
11 R = MOM
RO
O
19
15
H
H
OH
26
d
22
OHC
1 R = H: (+)-zincophorin
HOPMBO
OBn OMOM
2 R = Me: zincophorin methyl ester
PMBO
OBn OMOM
4
12
Figure 1
Scheme 2 Reagents and conditions: (a) (+)-IPC2BOMe, THF,
–20 °C, 5 d, 92%; (b) (i) 1-(MeO)2CH-4-MeOC6H3, anhyd CH2Cl2,
CSA, 0 °C to r.t., 2 h, 85%; (ii) MOM-Cl, DIPEA, anhyd CH2Cl2,
0 °C, 3 h, 75%; (c) DIBAL-H, anhyd CH2Cl2, 0 °C, 1 h, 80%; (d)
IBX, anhyd DMSO, anhyd CH2Cl2, 0 °C, 2 h, 90%.
SYNTHESIS 2011, No. 9, pp 1484–1488
Advanced online publication: 24.03.2011
DOI: 10.1055/s-0030-1259967; Art ID: Z20811SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
1
1

PAPER
The C1–C11 Tetrahydropyran Core Unit of (+)-Zincophorin
1485
pared by desymmetrization of bicyclic olefin 6 using Cl) and imidazole, and the ester group in 13 was convert-
Brown’s chiral hydroboration.
ed into b-ketophosphonate 5 by treatment with diethyl
methylphosphonate in the presence of n-butyllithium.7
Triol 9 was converted into acetal 10 in 85% yield using p-
methoxybenzaldehyde (PMB) dimethyl acetal and a cata- The coupling reaction between two pairs (i.e., 4a/5 and
lytic amount of 10-camphorsulfonic acid (CSA) in dichlo- 4b/5) failed to give the required products 14a and 14b, re-
romethane, followed by protection of the primary spectively (Scheme 4). However, by protecting group ma-
hydroxyl group as its methoxymethyl (MOM) ether 11 us- nipulation, the reaction between b-ketophosphonate 5 and
ing chloromethyl methyl ether (MOMCl) and N,N-diiso- the unpurified aldehyde 4c in the presence of
propylethylamine (DIPEA). Further elaboration to the Ba(OH)2·8H2O8 in wet tetrahydrofuran (THF–H2O, 40:1)
aldehyde 4 was then effected by regioselective reductive was successful and gave the desired enone 14c E-selec-
ring opening of the PMP acetal 11 with diisobutylalumi- tively in good yield (83%). Thus, the selection of protect-
num hydride (DIBAL-H) and oxidation of the resulting al- ing groups in fragments 4 and 5 played a crucial role in
cohol 12 using 2-(iodoxy)benzoic acid (IBX), which further transformation; repetition of protecting groups in
completed the synthesis of fragment 4.
both the fragments failed to give HWE products 14a and
14b. The silyl protecting group in compound 5 was also
found to be a superior group for the HWE reaction.
The synthesis of the segment 5 (Scheme 3), began with
the (R)-Roche ester 7. The hydroxyl group was protected
as its silyl ether 13 using triisopropylsilyl chloride (TIPS- A reagent-controlled reduction of enone 14c was then re-
quired. The (R)-Me-CBS reagent9 was found to give ex-
cellent selectivity in setting the desired configuration at
a
CO2Me
CO2Me
C3, leading to the allylic alcohol 15 (66%, dr 19:1). Re-
duction of the double bond was achieved by using PtO2 in
ethyl acetate at room temperature, to afford the saturated
compound 16.
OH
OTIPS
7
13
b
P(OEt)2
To achieve the tetrahydropyran ring formation, the free
hydroxyl group was converted into the corresponding
mesyl group, generating compound 17; oxidative depro-
tection of the PMB group gave compound 18, which
failed to give the THP ring by SN2 reaction. Therefore, the
PMB group of compound 16 was removed and the result-
TIPSO
O
O
5
Scheme 3 Reagents and conditions: (a) TIPS-Cl, imidazole, anhyd
CH2Cl2, 0 °C, 4 h, 90%; (b) MeP(O)(OC2H5Et)2, n-BuLi, anhyd THF,
–78 °C, 1 h, 55%.
a
+
P(OEt)2
OHC
OR1 OBn OR2
TIPSO
O
O
5
4a R1 = PMB, R2 = Bn
4b R1 = TBS, R2 = MOM
4c R1 = PMB, R2 = MOM
b
OR1 OBn
PMBO
OBn
OMOM
O
OR2
OH
TIPSO
TIPSO
14a R1 = PMB, R2 = Bn
14b R1 = TBS, R2 = MOM
14c R1 = PMB, R2 = MOM
15
c
OR1
OR2
OBn OMOM
TIPSO
16 R1 = H, R2 = PMB
17 R1 = Ms, R2 = PMB
18 R1 = Ms, R2 = H
19 R1 = R2 = H
d
OBn
TIPSO
OMOM
O
H
H
3
Scheme 4 Reagents and conditions: (a) Ba(OH)2, THF–H2O (9:1), 1 h, 83%; (b) (R)-CBS, BH3·SMe2, anhyd toluene, 0 °C, 1 h, 66%;
(c) (i) PtO2, EtOAc, 3 h, r.t., 90%; (ii) DDQ, CH2Cl2–H2O (9:1), 1 h, 0 °C to r.t., 50%; (d) DEAD, Ph3P, toluene, 0 °C to r.t., 12 h, 37%.
Synthesis 2011, No. 9, 1484–1488 © Thieme Stuttgart · New York

1486
G. Sabitha et al.
PAPER
ing diol 19 was subjected to Mitsunobu cyclization10 to
give the desired C1–C11 tetrahydropyran core unit 3 in
37% yield. This cyclization is known to occur in zincoph-
orin on the side of the chain with less chiral centers. In the
present study, a similar cyclization was applied to the
fragment with more chiral centers. The bulky phosphoni-
um group was attached to the less hindered C-3 alcohol
function and the more hindered C-7 hydroxyl group acted
as the nucleophile; this assumption was based on an earli-
er report.11
drous CH2Cl2 (50 mL) at 0 °C under an N2 atmosphere, DIPEA (5.0
mL, 28.9 mmol) was added, followed by dropwise addition of
MOMCl (1.7 mL, 21.7 mmol). After stirring for 4 h at r.t., the reac-
tion mixture was diluted with H2O (25 mL) and extracted with
CH2Cl2 (2 × 20 mL). The organic extracts were washed with brine
(25 mL) and dried over anhydrous Na2SO4. The filtrate was concen-
trated under vacuum and purified by silica gel column chromato-
graphy (EtOAc–hexane, 20%) to afford the pure compound 11.
Yield: 4.9 g (75%); colorless liquid; TLC: Rf 0.6 (EtOAc–hexane,
20%); [a]D25 +58 (c = 0.05, CHCl3).
IR (neat): 2929, 2878, 2839, 1693, 1516, 1459, 1387, 1249, 1105,
1039, 829, 738, 698 cm–1.
In summary, we have described the synthesis of the C1–
C11 tetrahydropyran core unit of (+)-zincophorin. Further
efforts towards the completion of the total synthesis of the
zincophorin are ongoing.
1H NMR (300 MHz, CDCl3): d = 7.37–7.22 (m, 7 H), 6.86 (d, J =
8.7 Hz, 2 H), 5.26 (s, 1 H), 4.63 (d, J = 4.7 Hz, 1 H), 4.60 (d, J =
6.4 Hz, 1 H), 4.57 (d, J = 6.4 Hz, 1 H), 4.52 (d, J = 11.7 Hz, 1 H),
4.06 (dd, J = 4.5, 11.1 Hz, 1 H), 3.80 (s, 3 H), 3.77–3.71 (m, 2 H),
3.49–3.43 (m, 1 H), 3.41–3.35 (m, 2 H), 3.33 (s, 3 H), 2.14–1.98
(m, 3 H), 1.11 (d, J = 6.9 Hz, 3 H), 0.97 (d, J = 6.9 Hz, 3 H), 0.72
(d, J = 6.7 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 159.8, 139.1, 131.5, 128.2, 127.3,
127.2, 113.5, 100.8, 96.5, 83.2, 81.6, 75.3, 73.3, 69.0, 55.2, 55.1,
36.7, 35.8, 30.3, 16.6, 12.0, 10.0.
Reactions were conducted under N2 in anhydrous solvents such as
CH2Cl2, THF, and EtOAc. All reactions were monitored by TLC
(silica-coated plates and visualizing under UV light). Petroleum
ether (PE; bp 60–80 °C) was used. Yields refer to chromaographi-
cally and spectroscopically (1H and 13C NMR) homogeneous mate-
rial. Air-sensitive reagents were transferred by either syringe or
double-ended needle. Evaporation of solvents was performed at re-
duced pressure on a Büchi rotary evaporator. 1H and 13C NMR spec-
tra of samples in CDCl3 were recorded with Varian FT-200 MHz
(Gemini) or Bruker UXNMR FT-300 MHz (Avance) spectrome-
ters. Chemical shifts (d) are reported relative to TMS (d = 0.0 ppm)
as an internal standard. Mass spectra were recorded under EI condi-
tions at 70 eV with an LC-MSD (Agilent technologies) spectrome-
ter. Column chromatography was performed on silica gel (60–120
mesh) supplied by Acme Chemical Co., India. TLC was performed
on Merck 60 F-254 silica gel plates. Optical rotations were mea-
sured with a JASCO DIP-370 polarimeter.
ESIMS: m/z = 459 [M]+, 481 [M + Na]+.
(2S,3S,4S,5S,6S)-5-(Benzyloxy)-3-[(4-methoxybenzyl)oxy]-7-
(methoxymethoxy)-2,4,6-trimethylheptan-1-ol (12)
A cooled (–20 °C) solution of PMB acetal 11 (4.9 g, 10.7 mmol) in
anhydrous CH2Cl2 (75 mL) was treated with DIBAL-H (26.8 mL,
26.82 mmol), and the reaction mixture was allowed to warm to 0 °C
over 1 h. After completion of reaction, excess hydride was
quenched by the dropwise addition of saturated sodium potassium
tartarate (CAUTION: vigorous evolution of H2 may result) and the
mixture was allowed to warm to r.t. After vigorous stirring for 1 h,
the two layers were separated, the aqueous layer was extracted with
Et2O (25 mL) and the combined organic phases were washed with
brine (25 mL) and dried over anhydrous Na2SO4. Solvent was re-
moved under vacuum and the residue was purified by column chro-
matography (EtOAc–hexane, 25%) to afford alcohol 7.
(2S,3S,4S)-3-(Benzyloxy)-4-[(4S,5S)-2-(4-methoxyphenyl)-5-
methyl-1,3-dioxan-4-yl]-2-methylpentan-1-ol (10)
A solution of triol 9 (5.0 g, 16.8 mmol) in anhydrous CH2Cl2 (50
mL) was cooled to 0 °C, and a catalytic amount of CSA was added,
followed by PMB acetal (3.1 mL, 18.5 mmol) over a period of
10 min. Upon completion, the reaction was quenched with NaHCO3
(2 M, 5 mL) and the product was extracted with CH2Cl2 (2 × 25
mL). The organic layer was washed with brine (20 mL) and dried
over Na2SO4. Solvent was removed under vacuum and the residue
was purified by column chromatography (EtOAc–hexane, 25%) to
give the required alcohol 10.
Yield: 3.9 g (80%); colorless liquid; TLC: Rf 0.3 (EtOAc–hexane,
20%); [a]D25 +24 (c = 0.05, CHCl3).
IR (neat): 3450, 2931, 2880, 1612, 1513, 1459, 1247, 1040, 958,
821 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.32–7.26 (m, 5 H), 7.14 (d, J =
8.7 Hz, 2 H), 6.81 (d, J = 8.7 Hz, 2 H), 4.66 (d, J = 11.3 Hz, 1 H),
4.61 (d, J = 6.6 Hz, 1 H), 4.59 (d, J = 6.6 Hz, 1 H), 4.51 (d,
J = 10.7 Hz, 1 H), 4.46 (d, J = 11.3 Hz, 1 H), 4.39 (d, J = 10.7 Hz,
1 H), 3.81–3.79 (m, 1 H), 3.78 (s, 3 H), 3.71–3.62 (m, 2 H), 3.59–
3.52 (m, 2 H), 3.49 (dd, J = 7.4, 9.3 Hz, 1 H), 3.35 (s, 3 H), 2.73–
2.65 (m, 1 H), 1.99–1.84 (m, 2 H), 1.10 (d, J = 7.0 Hz, 3 H), 1.04 (d,
J = 7.0 Hz, 3 H), 0.89 (d, J = 7.0 Hz, 3 H).
Yield: 6.0 g (85%); colorless liquid; TLC: Rf 0.7 (EtOAc–hexane,
30%); [a]D25 +56 (c = 0.05, CHCl3).
IR (neat): 3449, 2961, 2926, 1614, 1516, 1458, 1387, 1248, 1075,
1030, 828, 737, 698 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.38–7.25 (m, 7 H), 6.87 (d,
J = 8.5 Hz, 2 H), 5.30 (s, 1 H), 4.66 (d, J = 11.1 Hz, 1 H), 4.54 (d,
J = 11.1 Hz, 1 H), 4.13–4.06 (m, 1 H), 3.91–3.87 (m, 1 H), 3.81 (s,
3 H), 3.80–3.76 (m, 1 H), 3.62–3.52 (m, 2 H), 3.43 (t, J = 11.1 Hz,
1 H), 2.14–2.01 (m, 2 H), 1.98–1.87 (m, 1 H), 1.22 (d, J = 7.2 Hz,
3 H), 0.95 (d, J = 7.0 Hz, 3 H), 0.75 (d, J = 6.6 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 159.1, 138.6, 130.7, 129.2, 128.3,
127.5, 127.4, 113.7, 96.6, 84.8, 83.0, 74.3, 73.8, 69.7, 66.5, 55.2,
39.0, 38.6, 36.2, 15.7, 14.7, 12.0.
ESIMS: m/z = 461 [M]+, 483 [M + Na]+.
13C NMR (75 MHz, CDCl3): d = 159.8, 138.3, 131.4, 128.5, 127.7,
27.4, 127.3, 113.5, 100.9, 85.7, 81.5, 76.0, 73.3, 64.1, 55.2, 37.2,
35.8, 30.3, 16.3, 12.0, 10.3.
Methyl (2R)-2-Methyl-3-[(1,1,1-triisopropylsilyl)oxy]pro-
panoate (13)
To a solution of alcohol 7 (3.0 g, 25.3 mmol) in anhydrous CH2Cl2
(30 mL) was added imidazole (2.0 g, 30.4 mmol), followed by
dropwise addition of TIPS-Cl (5.3 mL, 25.3 mmol) at 0 °C and the
reaction was stirred for 2 h at the same temperature. Upon comple-
tion, the reaction was quenched by addition of sat. NH4Cl (20 mL)
and extracted with CH2Cl2 (2 × 25 mL). The organic phase was
ESIMS: m/z = 415 [M]+, 437 [M + Na]+.
(4S,5S)-4-[(1S,2S,3S)-2-(Benzyloxy)-4-(methoxymethoxy)-1,3-
dimethylbutyl]-2-(4-methoxyphenyl)-5-methyl-1,3-dioxane (11)
To a stirred solution of compound 10 (6.0 g, 14.4 mmol) in anhy-
Synthesis 2011, No. 9, 1484–1488 © Thieme Stuttgart · New York

PAPER
The C1–C11 Tetrahydropyran Core Unit of (+)-Zincophorin
1487
washed with H2O (20 mL) and brine (20 mL), dried over Na2SO4,
concentrated under vacuum, and the residue was purified by silica
gel column chromatography (EtOAc–hexane, 5%) to afford 13.
Yield: 4.4 g (83%); colorless liquid; TLC: Rf 0.7 (EtOAc–hexane,
10%); [a]D25 –10 (c = 0.025, CHCl3).
IR (neat): 2937, 2867, 1669, 1619, 1619, 1513, 1460, 1247, 1103,
1044, 686 cm–1.
Yield: 6.2 g (90%); colorless liquid; TLC: Rf 0.8 (EtOAc–hexane,
10%); [a]D25 –23 (c = 0.05, CHCl3).
IR (neat): 2944, 2866, 1742, 1463, 1106, 882, 680 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.85 (dd, J = 6.6, 9.3 Hz, 1 H),
3.74 (dd, J = 6.0, 9.3 Hz, 1 H), 3.66 (s, 3 H), 2.68–2.57 (m, 1 H),
1.15 (d, J = 7.0 Hz, 3 H), 1.08–1.02 (m, 21 H).
13C NMR (75 MHz, CDCl3): d = 175.5, 65.6, 51.4, 42.6, 17.8, 13.4,
11.9.
ESIMS: m/z = 297 [M + Na]+.
1H NMR (300 MHz, CDCl3): d = 7.34–7.22 (m, 5 H), 7.10 (d,
J = 8.3 Hz, 2 H), 6.91 (dd, J = 8.3, 15.8 Hz, 1 H), 6.76 (d,
J = 8.3 Hz, 2 H), 6.18 (d, J = 15.8 Hz, 1 H), 4.63–4.53 (m, 3 H),
4.46–4.32 (m, 3 H), 3.85 (dd, J = 6.8, 9.1 Hz, 1 H), 3.77 (s, 3 H),
3.70–3.59 (m, 2 H), 3.56 (dd, J = 1.5, 6.8 Hz, 1 H), 3.45 (dd, J =
7.6, 9.1 Hz, 1 H), 3.32 (s, 3 H), 3.31–3.27 (m, 1 H), 2.96–2.85 (m,
1 H), 2.64–2.52 (m, 1 H), 2.29 (t, J = 7.6 Hz, 1 H), 1.98–1.90 (m,
1 H), 1.10–1.94 (m, 33 H).
13C NMR (75 MHz, CDCl3): d = 202.7, 158.9, 149.7, 138.8, 131.0,
129.2, 128.8, 128.2, 127.3, 113.5, 96.6, 84.4, 81.8, 74.2, 73.3, 69.6,
65.8, 55.1, 46.6, 41.3, 38.7, 36.1, 17.9, 16.6, 15.9, 13.5, 11.8, 11.7.
Diethyl (3R)-3-Methyl-2-oxo-4-[(1,1,1-triisopropylsilyl)oxy]bu-
tylphosphonate (5)
ESIMS: m/z = 699 [M]+, 722 [M + Na]+.
Diethyl methylphosphonate (3.9 g, 26.2 mmol) was dissolved in an-
hydrous THF (30 mL) under an N2 atmosphere, and n-BuLi (1.6 M
in n-hexane, 15 mL, 24.06 mmol) was added dropwise at –78 °C
over 10 min and the reaction was stirred at the same temperature for
1 h. Compound 13 in THF (10 mL) was introduced into the reaction
mixture slowly over a period of 10 min under an N2 atmosphere.
The resulting mixture was stirred for 1 h at the same temperature
and then warmed to ambient temperature before quenching with sat.
aq NH4Cl (15 mL) at 0 °C. The product was extracted with EtOAc
(2 × 50 mL), washed with H2O (20 mL), brine (20 mL), dried over
Na2SO4, the solvent was removed under vacuum and the residue
was purified by column chromatography (EtOAc–hexane, 50%) to
afford 5.
(2R,3R,4E,6S,7S,8S,9S,10S)-9-(Benzyloxy)-7-[(4-methoxyben-
zyl)oxy]-11-(methoxymethoxy)-2,6,8,10-tetramethyl-1-[(1,1,1-
triisopropylsilyl)oxy]-4-undecen-3-ol (15)
A flame-dried 100 mL round-bottomed flask was charged with ke-
tone 14c (2.5 g, 6.0 mmol) and toluene (25 mL). The vessel was
cooled to –20 °C and (R)-methyl-CBS-oxazaborolidine (1.00 M in
toluene, 1.2 mL, 1.2 mmol) was added. Borane–methyl sulfide
complex (2 M, 4.5 mL, 9.01 mmol) was slowly added over 10 min
and the reaction was stirred for 50 min at this temperature before be-
ing slowly quenched with MeOH (10 mL) over a period of about 15
min. The reaction was warmed to r.t. and, after the majority of gas
evolution had subsided, the solvent was removed under vacuum.
The crude oil was purified by column chromatography (EtOAc–
hexane, 10%) to afford alcohol 15.
Yield: 4.7 g (55%); yellow liquid; TLC: Rf 0.4 (EtOAc–hexane,
50%); [a]D25 –73 (c = 0.05, CHCl3).
IR (neat): 2941, 2867, 1714, 1463, 1390, 1256, 1099, 1025, 965,
882, 790, 683 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.21–4.07 (m, 4 H), 3.80 (d,
J = 9.6 Hz, 1 H), 3.74 (d, J = 9.6 Hz, 1 H), 3.33 (dd, J = 13.6,
22.9 Hz, 1 H), 3.12–2.97 (m, 2 H), 1.34 (t, J = 7.0 Hz, 6 H), 1.10–
1.00 (m, 24 H).
13C NMR (75 MHz, CDCl3): d = 205, 62.3, 49, 43.4, 41.7, 17.8,
16.15, 12.6, 11.7.
ESIMS: m/z = 395 [M]+, 417 [M + Na]+.
Yield: 2.77 g (66%); colorless liquid; dr = 19:1; TLC: Rf 0.5
(EtOAc–hexane, 10%); [a]D25 +12 (c = 0.025, CHCl3).
IR (neat): 3477, 2938, 2867, 1512, 1459, 1247, 1100, 1043, 686
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.30–7.21 (m, 5 H), 7.15 (d,
J = 8.7 Hz, 2 H), 6.77 (d, J = 8.7 Hz, 2 H), 5.71 (dd, J = 8.3,
15.7 Hz, 1 H), 5.50 (dd, J = 6.6, 15.7 Hz, 1 H), 4.60–4.52 (m, 3 H),
4.49 (d, J = 11.0 Hz, 1 H), 4.44 (d, J = 11.5 Hz, 1 H), 4.36 (d,
J = 11.0 Hz, 1 H), 4.22–4.14 (m, 1 H), 3.77 (s, 3 H), 3.73–3.68 (m,
2 H), 3.67–3.61 (m, 1 H), 3.51–3.41 (m, 2 H), 3.32 (s, 3 H), 3.31–
3.26 (m, 1 H), 2.79–2.74 (m, 1 H), 2.52–2.43 (m, 1 H), 2.01–1.92
(m, 1 H), 1.87–1.75 (m, 1 H), 1.14–0.96 (m, 30 H), 0.84 (d,
J = 6.9 Hz, 3 H).
(2R,4E,6S,7S,8S,9S,10S)-9-(Benzyloxy)-7-[(4-methoxyben-
zyl)oxy]-11-(methoxymethoxy)-2,6,8,10-tetramethyl-1-[(1,1,1-
triisopropylsilyl)oxy]-4-undecen-3-one (14c)
13C NMR (75 MHz, CDCl3): d = 139.0, 134.6, 131.5, 130.4, 128.7,
128.6, 128.2, 127.2, 113.7, 96.6, 84.5, 82.1, 75.8, 74.1, 73.0, 69.8,
67.6, 55.2, 40.8, 40.1, 38.5, 36.1, 17.9, 16.0, 12.0, 11.7, 11.3.
To an ice-cold solution of 2-(iodoxy)benzoic acid (IBX; 3.5 g, 12.7
mmol) in anhydrous DMSO (3.6 mL, 50.8 mmol) was added a so-
lution of alcohol 12 (3.9 g, 8.4 mmol) in anhydrous CH2Cl2 (20
mL). The mixture was stirred at r.t. for 2 h and then filtered through
a Celite pad. The filtrate was concentrated under reduced pressure,
extracted with Et2O (20 mL) and H2O (20 mL), and the organic lay-
er was concentrated under vacuum to give crude aldehyde 4 (3.4 g,
90%), which was used directly for the next reaction.
ESIMS: m/z = 723 [M + Na]+.
(2R,3R,6S,7S,8S,9S,10S)-9-(Benzyloxy)-7-[(4-methoxyben-
zyl)oxy]-11-(methoxymethoxy)-2,6,8,10-tetramethyl-1-[(1,1,1-
triisopropylsilyl)oxy]undecan-3-ol (16)
To a solution of b-ketophosphonate 5 (3.2 g, 8.1 mmol, 1.1 equiv)
in THF (50 mL) was added Ba(OH)2·8H2O (2.3 g, 7.4 mmol, 1.0
equiv), which was preactivated by heating at 110 °C for 1 h and
then dried under vacuum. The reaction mixture was stirred for
30 min, then crude aldehyde 8 (3.4 g, 7.4 mmol) in THF–H2O (9:1;
20 mL) was added. Upon completion, the reaction mixture was di-
luted with sat. aq NH4Cl (25 mL) and EtOAc (50 mL). The layers
were separated and the aqueous phase was extracted with EtOAc
(2 × 50 mL). The combined organic layers were washed with brine
(2 × 15 mL), dried over Na2SO4 and concentrated under reduced
pressure. The crude residue was purified by column chromatogra-
phy (EtOAc–hexane, 8%) to furnish keto compound 14c.
To a stirred solution of 15 (2.5 g, 3.5 mmol), PtO2 (0.08 g, 0.35
mmol) in EtOAc (50 mL) was added, and the reaction was stirred
under an H2 atmosphere for 4 h. The contents were then filtered
over Celite and the crude reaction mixture was concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy (EtOAc–hexane, 10%) to give pure 16.
Yield: 2.25 g (90%); colorless liquid; Rf 0.5 (EtOAc–hexane, 10%);
[a]D25 –16 (c = 0.05, CHCl3).
IR (neat): 3507, 2936, 2867, 1612, 1513, 1461, 1247, 1101, 1045,
688 cm–1.
Synthesis 2011, No. 9, 1484–1488 © Thieme Stuttgart · New York

1488
G. Sabitha et al.
PAPER
1H NMR (300 MHz, CDCl3): d = 7.30–7.22 (m, 5 H), 7.14 (d,
J = 8.6 Hz, 2 H), 6.77 (d, J = 8.6 Hz, 2 H), 4.60–4.53 (m, 3 H),
4.48–4.33 (m, 3 H), 3.81–3.62 (m, 4 H), 3.77 (s, 3 H), 3.49–3.41
(m, 2 H), 3.22 (s, 3 H), 3.30–3.24 (m, 1 H), 2.13–1.90 (m, 2 H),
1.83–1.56 (m, 2 H), 1.14–0.96 (m, 27 H), 0.92 (d, J = 7.0 Hz, 3 H),
0.88 (d, J = 7.0 Hz, 3 H).
Acknowledgment
R.S. thanks CSIR, New Delhi for the award of a fellowship.
References
13C NMR (75 MHz, CDCl3): d = 158.7, 139.4, 131.7, 128.7, 128.2,
127.2, 113.5, 96.6, 84.9, 82.2, 75.0, 74.1, 72.8, 69.8, 68.9, 55.2,
55.1, 38.5, 37.8, 36.7, 36.0, 31.9, 29.0, 17.9, 16.4, 16.0, 12.1, 11.8,
1.0.
(1) Currently a Visiting Professor at King Saud University, P.O.
Box 2455, Riyadh 11451, Saudi Arabia.
(2) (a) Gräfe, U.; Schade, W.; Roth, M.; Radics, L.; Incze, M.;
Ujszaszy, K. J. Antibiot. 1984, 37, 836. (b) Radics, L.
J. Chem. Soc., Chem. Commun. 1984, 599.
ESIMS: m/z = 703 [M]+, 725 [M + Na]+.
(3) Brooks, H. A.; Gardner, D.; Poyser, J. P.; King, T. J.
J. Antibiot. 1984, 37, 1501.
(2R,3R,6S,7S,8R,9S,10S)-9-(Benzyloxy)-11-(methoxymethoxy)-
2,6,8,10-tetramethyl-1-[(1,1,1-triisopropylsilyl)oxy]undecane-
3,7-diol (19)
(4) (a) Gräfe, U.; Tonew, E.; Schade, W.; Reinhardt, G.; Härtl,
A. East German Patent DD 231793, 1986. (b) Tonew, E.;
Tonew, M.; Gräfe, U.; Zopel, P. Pharmazie 1988, 43, 717.
(5) (a) Danishefsky, S. J.; Selnick, H. G.; DeNinno, M. P.; Zelle,
R. E. J. Am. Chem. Soc. 1987, 109, 1572. (b) Danishefsky,
S. J.; Selnick, H. G.; Zelle, R. E.; DeNinno, M. P. J. Am.
Chem. Soc. 1988, 110, 4368. (c) Cossy, J.; Meyer, C.;
Defosseux, M.; Blanchard, N. Pure Appl. Chem. 2005, 77,
1131. (d) Defosseux, M.; Blanchard, N.; Meyer, C.; Cossy,
J. J. Org. Chem. 2004, 69, 4626. (e) Defosseux, M.;
Blanchard, N.; Meyer, C.; Cossy, J. Org. Lett. 2003, 5,
4037. (f) Komatsu, K.; Tanino, K.; Miyashita, M. Angew.
Chem. Int. Ed. 2004, 43, 4341. (g) Song, Z.; Hsung, R. Org.
Lett. 2007, 9, 2199. (h) Cossy, J.; Blanchard, N.; Defosseux,
M.; Meyer, C. Angew. Chem. Int. Ed. 2002, 41, 2144.
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G.; Bencheqroun, M.; Faucher, A.-M.; Guerin, B. J. Org.
Chem. 2001, 66, 5427. (j) Burke, S. D.; Ng, R. A.; Morrison,
J. A.; Alberti, M. J. J. Org. Chem. 1998, 63, 3160.
(k) Marshall, J. A.; Palovich, M. R. J. Org. Chem. 1998, 63,
3701. (l) Chemler, S. R.; Roush, W. R. J. Org. Chem. 1998,
63, 3800. (m) Booysen, J. F.; Holzapfel, C. W. Synth.
Commun. 1995, 25, 1473. (n) Cywin, C. L.; Kallmerten, J.
Tetrahedron Lett. 1993, 34, 1103. (o) Balestra, M.;
Wittman, M. D.; Kallmerten, J. Tetrahedron Lett. 1988, 29,
6905. (p) Zelle, R. E.; DeNinno, M. P.; Selnick, H. G.;
Danishefsky, S. J. J. Org. Chem. 1986, 51, 5032.
(6) (a) Yadav, J. S.; Abraham, S.; Reddy, M. M.; Sabitha, G.;
Sankar, A. R.; Kunwar, A. C. Tetrahedron Lett. 2001, 42,
4713. (b) Yadav, J. S.; Reddy, K. B.; Sabitha, G.
Tetrahedron Lett. 2004, 45, 6475. (c) Yadav, J. S.; Reddy,
K. B.; Sabitha, G. Tetrahedron 2008, 64, 1971. (d) Sabitha,
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Yadav, J. S. Tetrahedron: Asymmetry 2010, 21, 2524.
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S. Synthesis 2010, 4307.
To a solution of 16 (2.1 g, 2.9 mmol) in CH2Cl2–H2O (10:1, 20 mL)
was added dichlorodicynoquinone (DDQ; 1.0 g, 4.4 mmol) at 0 °C
and the reaction was stirred for 1 h. When the reaction was com-
plete, the solution was filtered through a pad of Celite and washed
with CH2Cl2 (2 × 25 mL). The combined filtrate was concentrated
and purified by column chromatography (EtOAc–hexane, 12%) to
provide diol 19.
Yield: 0.87 (50%); yellow liquid; Rf 0.3 (EtOAc–hexane, 10%);
[a]D25 –22 (c = 0.025, CHCl3).
IR (neat): 3450, 2934, 2867, 1460, 1101, 1047, 683 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.33–7.24 (m, 5 H), 4.66–4.55 (m,
4 H), 3.82–3.72 (m, 2 H), 3.69–3.61 (m, 1 H), 3.61–3.44 (m, 4 H),
3.33 (s, 3 H), 1.97–1.64 (m, 2 H), 1.62–1.38 (m, 2 H), 1.11–1.02
(m, 24 H), 0.98 (d, J = 6.8 Hz, 3 H), 0.92 (d, J = 7.0 Hz, 3 H), 0.79
(d, J = 6.6 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 137.9, 128.5, 127.8, 127.6, 96.7,
87.2, 76.0, 75.2, 74.0, 69.9, 69.1, 55.3, 38.2, 36.6, 35.8, 34.5, 30.6,
29.1, 17.9, 15.4, 14.8, 11.8, 11.4, 9.8.
ESIMS: m/z = 583 [M]+.
({(2R)-2-(2S,5S,6R)-6-[(1S,2S,3S)-2-(benzyloxy)-4-(methoxy-
methoxy)-1,3-dimethylbutyl]-5-methyltetrahydro-2H-2-pyr-
anylpropyl}oxy)(triisopropyl)silane (3)
To a solution of diol 19 (0.8 g, 1.3 mmol) in anhydrous toluene (10
mL) was added Ph3P (1.8 g, 6.8 mmol), followed by dropwise addi-
tion of diethyl azodicarboxylate (DEAD; 1.0 mL, 6.8 mmol) at 0 °C
and the reaction was stirred at r.t. for 12 h. After completion of the
reaction, H2O (20 mL) was added and the two layers were separat-
ed. The aqueous layer was extracted with EtOAc (2 × 20 mL) and
the combined organic layers were washed with brine (2 × 5 mL),
dried over Na2SO4, concentrated under vacuum, and the residue was
purified by column chromatography (EtOAc–hexane, 8%) to fur-
nish the cyclized product 3.
(7) (a) Heathcock, C. H.; Hadley, C. R.; Rosen, T.; Theisen, P.
D.; Hecker, S. J. J. Med. Chem. 1987, 30, 1858.
Yield: 0.271 g (37%); colorless liquid; TLC: Rf 0.6 (EtOAc–hexane,
10%); [a]D25 –20 (c = 0.025, CHCl3).
IR (neat): 2925, 2858, 1742, 1460, 1379, 1047, 968, 761 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.35–7.17 (m, 5 H), 4.64–4.53 (m,
4 H), 3.77–3.39 (m, 7 H), 3.34 (s, 3 H), 2.50–2.04 (m, 2 H), 2.01–
1.65 (m, 3 H), 1.63–1.45 (m, 2 H), 1.44–1.34 (m, 1 H), 1.11–0.92
(m, 30 H), 0.79 (d, J = 6.8 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 137.9, 128.5, 127.8, 127.7, 96.8,
87.3, 76.1, 74.3, 73.9, 70.0, 68.7, 55.3, 36.7, 31.9, 31.6, 31.4, 30.2,
29.4, 18.0, 14.9, 14.1, 12.1, 12.0, 11.4.
(b) Yasuda, N.; Hsiao, Y.; Jensen, M. S.; Rivera, N. R.;
Yang, C.; Wells, K. M.; Yau, J.; Palucki, M.; Tan, L.;
Dormer, P. G.; Volante, R. P.; Hughes, D. L.; Reider, P. J.
J. Org. Chem. 2004, 69, 1959.
(8) (a) Alvarez-Ibarra, C.; Arias, S.; Banon, G.; Fernandez, M.;
Rodriguez, V.; Sinisterra, V. J. Chem. Soc., Chem. Commun.
1987, 1509. (b) Paterson, I.; Yeung, K. S.; Smail, J. B.
Synlett 1993, 774.
(9) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh,
V. K. J. Am. Chem. Soc. 1987, 109, 7925.
(10) Mitsunobu, O. Synthesis 1981, 1.
(11) Mulzer, J.; Sieg, A.; Brucher, C.; Müller, D.; Martin, H. J.
Synlett 2005, 685.
ESIMS: m/z = 565 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C33H61O5Si: 565.4283; found:
565.4284.
Synthesis 2011, No. 9, 1484–1488 © Thieme Stuttgart · New York