Studies directed towards the total synthesis of (-)-Dictyostatin

Article abstract of DOI:10.1002/ejoc.200901448

The stereoselective synthesis of the three major fragments (C1-C9, C10-C17, and C19-C26) of an antimitotic marine macrolide, (-)-dictyostatin, has been achieved with a desymmetrization strategy and Oppolzer syn and anti aldol proto-cols as the key reactio

Full text of DOI:10.1002/ejoc.200901448

FULL PAPER
DOI: 10.1002/ejoc.200901448
Studies Directed Towards the Total Synthesis of (–)-Dictyostatin
Jhillu S. Yadav*[a] and Vemula Rajender[a]
Keywords: Aldol reactions / Natural products / Cross coupling / Stereoselective synthesis
The stereoselective synthesis of the three major fragments
(C1–C9, C10–C17, and C19–C26) of an antimitotic marine
macrolide, (–)-dictyostatin, has been achieved with a desym-
metrization strategy and Oppolzer syn and anti aldol proto-
cols as the key reactions. Takai olefination and Sonogashira
coupling reactions were successfully utilized to establish the
2Z,4E-dienoate portion of the C1–C9 fragment and Stille cou-
pling for the Z-diene core of C19–C26.
Interesting structural features combined with the impor-
tant biological activity of dictyostatin has attracted several
research groups to attempt its total synthesis,[6] as well as
the synthesis of its analogues[7] and crucial intermediates.[8]
Herein, we report our efforts, en route to (–)-dictyostatin
(1), at a highly stereoselective synthesis of the key interme-
diates (C1–C9, C10–C17, and C19–C26) of 1 (Scheme 1),
comprising nine of its eleven stereocentres and including a
cis-1,2-disubstituted olefin, a 2Z,4E-dienoate, and a ter-
minal Z-diene core.
Introduction
Scarce, biologically potent marine macrolides with intri-
cate structural features are always attractive synthetic tar-
gets to organic chemists. Natural products of marine origin
are generally obtained in minute quantities that are insuf-
ficient for detailed biological activity studies.[1] For instance,
dictyostatin, a polyketide antimitotic marine macrolide, was
first isolated in 1994 by Pettit et al.[2] from the marine
sponge Spongia sp. off the coast of Maldives and later by
Wright and co-workers[3] from Corralistidae sponges. Al-
though it was isolated in 1994, due to its low availability,
its complete stereochemical structure was not known for a
further decade. In 2004, Paterson and Wright and co-
workers proposed structure 1 for dictyostatin (Figure 1) on
the basis of extensive high-field NMR experiments, Murata
J-based configuration analysis, and molecular modeling,[4]
and it was finally confirmed by total synthesis.[5] The 22-
membered macrolide is an efficient inhibitor of human can-
cer cell growth at low concentrations with the same mode
of action as taxol, which promotes tubulin polymerization
and prevents mitosis from proceeding beyond the G2/M
phase of the cell cycle.[3]
Scheme 1. Retrosynthetic analysis of 1.
Results and Discussion
As depicted in Scheme 2, the construction of the C10–
C17 segment was initiated with the preparation of xanthate
6 from bicyclic alcohol 5[9] using NaH, CS2, and MeI at
0 °C (96%) followed by exposure of xanthate 6 to Barton–
McCombie[10] conditions (Bu3SnH, cat. AIBN in benzene)
to afford the deoxygenated symmetric volatile bicyclic olefin
7 (87%). The bicyclic olefin 7 was subjected to the key de-
Figure 1. Structure of (–)-dictyostatin (1).
[a] Organic Chemistry Division I, Indian Institute of Chemical
Technology (CSIR),
Hyderabad 500007, India
Fax: +91-40-27160512
E-mail: yadavpub@iict.res.in
2148
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Studies Directed towards the Total Synthesis of (–)-Dictyostatin
symmetrization reaction using the chiral hydroboration re- DIPEA (1.2 equiv.) at –78 °C followed by the addition of
action of Brown et al.[11] [(+)-Ipc2BH, THF, 0 °C, NaOH, aldehyde 18 in CH2Cl2 produced the anti product along
H2O2] to afford the required alcohol 8 with good enantio- with the syn isomer in minor quantities. These two isomers
and regioselectivity (90% yield). Alcohol 8 was oxidized were readily separated by column chromatography on silica
with PCC[12] to furnish the corresponding ketone 9 (90%). gel and yielded anti aldol compound 19 (9:1 anti/syn; 77%).
The ketone 9 was further oxidized to yield lactone 10 (92%) The hydroxy group of 19 was silylated using TBDMSOTf[18]
under Bayer–Villiger conditions[13] (m-CPBA, NaHCO3, and 2,6-lutidine to give 20 (91%). The reductive cleavage of
CH2Cl2). The so-formed bicyclic lactone was then subjected the chiral auxiliary was achieved with LiBH4 (generated in
to enolization using LDA in THF at –78 °C followed by situ) in diethyl ether to yield alcohol 21 (94%). This alcohol
treatment with MeI to furnish the methylated lactone 11 was oxidized with Dess–Martin periodinane to give alde-
as a single diastereomer (87%). The alkylation was totally hyde 22 (95%). Takai olefination[19] of aldehyde 22 provided
stereocontrolled by the substrate and occurs only from the E-vinyl iodide 23 (E/Z = 20:1, 85% yield). The E-vinyl io-
exo face. Reductive ring-opening of the lactone 11 using dide 23 was then subjected to Pd-mediated cross-coupling
excess LiAlH4 resulted in the triol 12 (89%), the key inter- under Sonogashira reaction conditions[20] using [Pd-
mediate in our desymmetrization strategy with four chiral (PPh3)4], catalytic CuI, and NEt3 followed by ethyl pro-
centers. The 1,3-diol functionality in triol 12 was protected piolate to furnish 24 in 90% yield. The oxidative removal
as the benzylidene acetal using benzaldehyde dimethyl ace- of the PMB ether with DDQ in CH2Cl2/H2O (19:1) gave
tal and catalytic CSA in CH2Cl2 at 0 °C to afford 13 (95%) alcohol 25 (95%). The dienoate precursor 25 was treated
and the free hydroxy group was silylated with TBDPS-Cl to with the Lindlar catalyst (Pd–CaCO3 poisoned with Pb) in
furnish the fully protected triol 14. Subsequent regioselec- the presence of isoquinoline in benzene to give dienoate 26
tive reductive ring-opening of the benzylidene acetal using (98%). Oxidation of the hydroxy group in the dienoate with
DIBAL-H[14] at –15 °C in CH2Cl2 led to alcohol 15 (92%). Dess–Martin periodinane led to the construction of the C1–
1
Oxidation of the alcohol with Dess–Martin periodinane[15] C9 fragment (3) in 95% yield. The H and 13C NMR data
in the presence of NaHCO3 at 0 °C produced aldehyde 16 of aldehyde 3 were identical to the reported data.[6b]
without any epimerization. The key intermediate Z-vinyl
iodide 2 was obtained from aldehyde 16 using Stork’s pro-
tocol.[16]
Scheme 3. Synthesis of the C1–C9 segment 3.
As outlined in Scheme 4, the synthesis of the C19–C26
fragment was initiated with the Oppolzer syn aldol reac-
tion[17] between N-propionylsultam 17 and methacrolein
using TiCl4 (3 equiv.) and DIPEA (2.2 equiv.) at –78 °C to
afford a diastereomeric mixture of syn and anti products.
Scheme 2. Synthesis of the C10–C17 segment 2.
These two isomers were easily separated by column
chromatography on silica gel to obtain the syn isomer 27
with good selectivity (95:5 syn/anti; 73%). Reductive re-
The construction of the C1–C9 fragment (Scheme 3) was moval of the chiral auxiliary using LiAlH4 furnished diol
initiated with the installation of anti centers in 3 by em- 28 (94%). This diol was protected as its PMB acetal with
ploying the Oppolzer anti aldol protocol.[17] Thus, treat- anisaldehyde dimethyl acetal and catalytic CSA to give 29
ment of N-propionylsultam 17 with TiCl4 (1 equiv.) and in 93% yield.
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J. S. Yadav, V. Rajender
FULL PAPER
rimeter. NMR spectra were recorded in CDCl3 with a Varian Gem-
ini 200, Bruker 300, or Varian Unity 400 NMR spectrometer. Col-
umn chromatographic separations were carried out on silica gel
(60–120 mesh). Mass spectra were obtained on
a Finnigan
MAT1020B or micromass VG 70-70H spectrometer operating at
70 eV using a direct inlet system.
O-(2,4-Dimethyl-8-oxabicyclo[3.2.1]oct-6-en-3-yl) S-Methyl Car-
bonodithioate (6): Alcohol 5[9] (8 g, 51.9 mmol) in THF (20 mL)
was added to a suspension of NaH (4.98 g, 103 mmol) in THF
(20 mL) under nitrogen at 0 °C. The reaction mixture was heated
at 60 °C for 30 min. After cooling the reaction mixture again to
0 °C, CS2 (4.7 mL, 77.9 mmol) was added and the reaction mixture
was stirred for 30 min. MeI (4.8 mL, 77.9 mmol) was added and
the reaction mixture was stirred at room temperature for 6 h. After
complete consumption of the starting material (confirmed by
TLC), the reaction mixture was cooled to 0 °C and quenched with
aqueous ammonium chloride solution, extracted with EtOAc
(3ϫ50 mL), dried with anhydrous Na2SO4, evaporated under re-
duced pressure, and purified by silica gel column chromatography
using 5% EtOAc/hexane to furnish the xanthate 6 (12.09 g, 96%)
Scheme 4. Synthesis of the C19–C26 segment 4.
At this juncture, the methyl center was installed by hy-
droboration of the unsymmetrical double bond in 29 with
9-BBN[21] in THF at 0 °C to afford the 1,2-anti isomer 30
with 86% de. The alcohol 30 was oxidized using Dess–Mar-
tin periodinane to give aldehyde 31 and subsequently elabo-
rated to the (Z)-vinyl iodide 32 using Stork’s protocol. The
diene precursor 32 was subjected to Stille cross-coupling[22]
with vinyltributyltin in the presence of [Pd(CH3CN)2Cl2] in
DMF at room temperature for 15 min to obtain the Z-diene
33 in 95% yield. Regioselective reductive ring-opening of
the PMB acetal with DIBAL-H in CH2Cl2 at –15 °C fur-
nished the alcohol 34 (91%). The primary alcohol of 34 was
oxidized with Dess–Martin periodinane reagent to afford
aldehyde 4[23] in 91% yield, thus, completing the synthesis
of the C19–C26 segment of (–)-dictyostatin.
as a colorless liquid. IR (KBr): ν = 2964, 2933, 2880, 1628, 1220,
˜
1
1159, 1049, 935 cm–1. H NMR (CDCl3, 300 MHz): δ = 6.4 (s, 2
H, 6-H, 7-H), 6.29 (t, J = 4.9 Hz, 1 H, 3-H), 4.48 (d, J = 3.0 Hz,
2 H, 1-H, 5-H), 2.54 (s, 3 H, SMe), 2.50–2.42 (m, 2 H, 2-H, 4-H),
0.84 (d, J = 7.3 Hz, 6 H, 2 Me) ppm. 13C NMR (CDCl3, 75 MHz):
δ = 217.0, 133.7 (2 C), 82.5, 81.5 (2 C), 37.3 (2 C), 18.7, 12.1 (2
C) ppm.
2,4-Dimethyl-8-oxabicyclo[3.2.1]oct-6-ene (7): (Bu)3SnH (14.9 mL,
56.5 mmol) followed by a catalytic amount of AIBN were added
to a stirred solution of xanthate 6 (11.5 g, 47.1 mmol) in benzene
(20 mL) and the reaction mixture was heated at reflux in the pres-
ence of the light of an incandescent lamp for 6 h. The residue was
purified on a silica gel column using 5% EtOAc in hexane as elu-
ent. The column fractions were distilled to remove the solvent and
finally the compound was distilled at atmospheric pressure by
maintaining the receiver at –78 °C to obtain the olefin 7 as a light-
yellow oil (5.85 g, 87%). IR (KBr): ν = 2955, 2924, 2853, 1660,
˜
1
1458, 1045, 940 cm–1. H NMR (CDCl3, 300 MHz): δ = 6.16 (s, 2
H, 6-H, 7-H), 4.46 (d, J = 3.3 Hz, 2 H, 1-H, 5-H), 1.91–1.79 (m, 2
H, 2-H, 4-H), 1.60–1.52 (m, 1 H, 3-H), 0.91 (m, 1 H, 3Ј-H), 0.71
(d, J = 7.1 Hz, 6 H, 2 Me) ppm. 13C NMR (CDCl3, 75 MHz): δ =
130.2 (2 C), 82.9 (2 C), 34.2, 30.3 (2 C), 17.2 (2 C) ppm.
Conclusions
We have synthesized, en route to the total synthesis, three
major segments of (–)-dictyostatin in a highly stereoselec-
tive manner. By using a desymmetrization approach and
Oppolzer syn and anti aldol protocols, the requisite ste-
reocenters were achieved. Takai olefination and Sonoga-
shira and Stille cross-coupling reactions were used in the
construction of the two diene systems. Attempts to couple
these fragments en route to the total synthesis of (–)-
dictyostatin are in progress.
(6R)-2,4-Dimethyl-8-oxabicyclo[3.2.1]octan-6-ol (8): Olefin 7 (5.5 g,
39.8 mmol) predissolved in THF (10 mL) was added to the white
crystals of (+)-Ipc2BH [generated in situ from (–)-α-pinene] in THF
(3 mL) at –20 °C. The reaction was stirred at the same temperature
for 1 h and kept in the refrigerator for 5 d at –20 °C. After this, the
trialkylborane was treated with 3  sodium hydroxide (50 mL) and
30% hydrogen peroxide (12.5 mL) and stirred at 25 °C for 5 h. The
reaction mixture was extracted with diethyl ether (3ϫ50 mL), dried
(Na2SO4), and evaporated. The residue was purified by silica gel
chromatography (hexane/ethyl acetate, 9:1, used as eluent) to re-
move the olefin and (–)-α-pinene alcohol and then eluted with hex-
ane/ethyl acetate (1:1) mixture to give the alcohol as a colorless
Experimental Section
General: Unless otherwise mentioned, all reactions were carried out
under an inert atmosphere of argon or nitrogen using standard
syringe, septa, and cannula techniques. Commercial reagents were
used without further purification. All solvents were purified by
standard techniques. Infrared (IR) spectra were recorded with a
Perkin–Elmer 683 spectrometer with NaCl optics. Spectra were cal-
ibrated against the polystyrene absorption at 1610 cm–1. Samples
were scanned neat, in KBr wafers or in chloroform as a thin film.
Optical rotations were obtained with a Jasco DIP-360 digital pola-
liquid (5.58 g, 90%). [α]2D5 = +4.3 (c = 2.0, CHCl ). IR (KBr): ν =
˜
3
3408, 2950, 2877, 1458, 1046 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 4.21 (m, 2 H, 1-H, 5-H), 3.85 (d, J = 3.39 Hz, 1 H, 6-H), 2.67
(br., 1 H, OH), 2.16 (m, 1 H, 7-H), 1.89–1.77 (m, 2 H, 2-H, 4-H),
1.71–1.63 (m, 1 H, 7Ј-H), 1.59–1.51 (m, 1 H, 3-H), 0.88 (d, J =
6.9 Hz, 3 H, 4-Me), 0.72 (d, J = 6.9 Hz, 3 H, 2-Me), 0.63–0.51 (m,
1 H, 3Ј-H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 87.3, 79.8, 71.4,
36.6, 34, 33.5, 32.7, 17.2, 17.0 ppm. MS (EI): m/z = 157.1 [M +
2150
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Studies Directed towards the Total Synthesis of (–)-Dictyostatin
H]+. HRMS: calcd. for C9H17O2 [M + H]+ 157.1228; found 16.1 ppm. MS (EI): m/z = 185.1 [M + H]+. HRMS: calcd. for
157.1224.
C10H17O3 [M + H]+ 185.1177; found 185.1180.
2,4-Dimethyl-8-oxabicyclo[3.2.1]octan-6-one (9): Pyridinium chloro-
chromate (PCC; 10.38 g, 48.0 mmol) was added to a solution of
alcohol 8 (5 g, 32.0 mmol) in dichloromethane (50 mL) at room
temperature. After stirring the reaction mixture for 3 h, 2-propanol
(10 mL) was added and the solvent was removed under reduced
pressure, the residue was filtered and washed with diethyl ether.
The organic layer was washed with 1  HCl (20 mL), water, and
brine, dried (Na2SO4) and removal of solvent afforded a gummy
material, which was purified by silica gel column chromatography
using 20% EtOAc/hexane as eluent to afford the ketone 9 (4.43 g,
90% yield) as a light-yellow liquid. [α]2D5 = –17.1 (c = 1.5, CHCl3).
(2S,3R,4S,6R)-2,4,6-Trimethylheptane-1,3,7-triol (12): A solution
of lactone 11 (0.85 g, 4.61 mmol) in THF (15 mL) was added to
an ice-cooled suspension of LiAlH4 (0.526 g, 13.8 mmol) in THF
(10 mL) under nitrogen and the reaction mixture was stirred for
5 h at room temperature. It was then cooled to 0 °C and quenched
with a saturated solution of Na2SO4 by portionwise addition and
stirred at room temperature for 4 h. The white precipitate was fil-
tered off through a pad of Celite, washed with ethyl acetate, dried
with Na2SO4, concentrated, and purified by chromatography on
silica gel (1:1 EtOAc/hexane) to afford the triol 12 (0.776 g, 89%)
as a viscous colorless liquid. [α]2D5 = +29.6 (c = 2.05, CHCl3). IR
1
IR (KBr): ν = 2955, 2860, 1756, 1155, 1040 cm 4.41 (dd, J = 7.5,
(KBr): ν = 3339, 2961, 2923, 1722, 1461, 1278, 1027, 981 cm–1. H
˜
˜
3.0 Hz, 1 H, 5-H), 3.65 (d, J = 3.7 Hz, 1 H, 1-H), 2.45 (dd, J = NMR (300 MHz, CDCl3): δ = 3.74–3.60 (m, 2 H, 1-H), 3.50 (m, 2
18.1, 8.3 Hz, 1 H, 7-H), 2.20 (m, 1 H, 4-H), 2.16 (d, J = 18.1 Hz, H, 7-H), 3.40 (dd, J = 10.1, 6.9 Hz, 1 H, 3-H), 1.88 (m, 1 H, 2-H),
1 H, 7Ј-H), 1.97 (m, 1 H, 2-H), 1.72 (m, 1 H, 3-H), 1.42 (m, 1 H, 1.75 (m, 2 H, 4-H, 6-H), 1.67–1.58 (m, 1 H, 5-H), 1.03–0.94 (m, 1
3Ј-H), 0.90 (d, J = 6.7 Hz, 3 H, 4-Me), 0.83 (d, J = 6.7 Hz, 3 H,
2-Me) ppm. 13C NMR (CDCl3, 75 MHz): δ = 215.1, 80.1, 78.2,
37.5, 34.2, 33.4, 33.1, 17, 15.4 ppm. MS (EI): m/z = 155.1 [M +
H, 5Ј-H), 0.89 (m, 6 H, 2Ј-Me, 4Ј-Me), 0.80 (d, J = 6.7 Hz, 3 H,
6Ј-Me) ppm. 13C NMR (CDCl3, 75 MHz): δ = 76.7, 68.3, 68.2,
37.1, 37, 32.3, 31.9, 16.8, 13.5, 13.4 ppm. MS (EI): m/z = 191.1 [M
H]+. HRMS: calcd. for C9H15O2 [M + H]+ 155.1047; found + H]+. HRMS: calcd. for C10H23O3 [M + H]+ 191.1647; found
155.1063.
191.1648.
6,8-Dimethyl-2,9-dioxabicyclo[3.3.1]nonan-3-one (10): Ketone
(3.5 g, 22.7 mmol) in CH2Cl2 (15 mL) was added to a suspension
9
(2R,4S)-2-Methyl-4-[(5S)-5-methyl-2-phenyl-1,3-dioxan-4-yl]pen-
tan-1-ol (13): Benzaldehyde dimethyl acetal (0.148 mL, 0.98 mmol)
of NaHCO3 (3.8 g, 45.4 mmol) in CH2Cl2 (20 mL) followed by m- and a catalytic amount of azeotropically dried CSA were added to
CPBA (7.8 g, 45.4 mmol) and the mixture was stirred at ambient
temperature for 10 h. The reaction mixture was diluted with dichlo-
romethane (25 mL) and the CH2Cl2 layer was washed with a solu-
tion of sodium metabisulfite followed by a 5% NaHCO3 solution
and water, extracted with CH2Cl2 (2ϫ30 mL), dried with Na2SO4,
concentrated under reduced pressure, and the residue purified by
silica gel column chromatography using hexane/ethyl acetate (8:2)
a stirred solution of triol 12 (125 mg, 0.65 mmol) in CH2Cl2 (5 mL)
at 0 °C. The reactionmixture was stirred at room temperature for
5 h. After the starting material was completely consumed (moni-
tored by TLC), the reaction was quenched with aqueous NaHCO3
and extracted with CH2Cl2 (3ϫ 10 mL). The organic layer was
dried with anhydrous Na2SO4, evaporated, and purified on silica
gel (5% EtOAc/hexane) to furnish the protected diol 13 (172 mg,
95%) as a colorless liquid. [α]2D5 = +8.2 (c = 0.65, CHCl3). IR
as eluent to afford the lactone 10 (3.55 g, 92%) as an oil. [α]2D5
=
+49.8 (c = 1.1, CHCl ). IR (KBr): ν = 2962, 1743, 1226, 1190, (KBr): ν = 3419, 3035, 2961, 2927, 2874, 1718, 1458, 1157, 1070,
˜
˜
3
1121, 968 cm–1. 1H NMR (300 MHz, CDCl3): δ = 5.48 (d, J =
752, 699 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.48 (m, 2 H, Ph-
2.2 Hz, 1 H, 1-H), 4.11 (dd, J = 7.7, 4.3 Hz, 1 H, 5-H), 2.83 (dd, H), 7.35 (m, 3 H, Ph-H), 5.47 (s, 1 H, Ph-CH), 4.11 (dd, J = 11.1,
J = 18.3, 7.8 Hz, 1 H, 4-H), 2.54 (d, J = 18.3 Hz, 1 H, 4Ј-H), 2.15 4.7 Hz, 1 H, 3-H), 3.53 (m, 2 H, 1-H), 3.42 (m, 2 H, 7-H), 2.13–
(m, 1 H, 8-H), 1.98 (m, 1 H, 6-H), 1.63 (m, 1 H, 7-H), 1.14 (m, 1 2.02 (m, 1 H, 2-H), 1.96–1.86 (m, 1 H, 4-H), 1.81–1.70 (m, 1 H, 6-
H, 7Ј-H), 0.98 (d, J = 6.9 Hz, 3 H, 8-Me), 0.90 (d, J = 6.9 Hz, 3 H), 1.68–1.59 (m, 1 H, 5-H), 1.55 (br., 1 H, OH), 1.17–1.07 (m, 1
H, 6-Me) ppm. 13C NMR (CDCl3, 75 MHz): δ = 167.0, 100.5, 70.7, H, 5Ј-H), 1.00 (d, J = 6.7 Hz, 3 H, 2Ј-Me), 0.97 (d, J = 6.7 Hz, 3 H,
35.3, 32.6, 29.4, 28.5, 16.6, 5.7 ppm. MS (EI): m/z = 171.1 [M +
4Ј-Me), 0.77 (d, J = 6.7 Hz, 3 H, 6Ј-Me) ppm. 13C NMR (CDCl3,
H]+. HRMS: calcd. for C9H15O3 [M + H]+ 171.1021; found 75 MHz): δ = 138.9, 128.5, 128, 126.1, 101.1, 84.2, 73.2, 68.4, 37,
171.1016.
32.9, 30.7, 30.6, 17.2, 14.2, 12.1 ppm. MS (EI): m/z = 301.0 [M +
Na]+. HRMS: calcd. for C17H26O3Na [M + Na]+ 301.1774; found
301.1762.
(4R)-4,6,8-Trimethyl-2,9-dioxabicyclo[3.3.1]nonan-3-one (11): LDA
[905 mg, 8.3 mmol, generated in situ from nBuLi (5.2 mL) and di-
isopropylamine (1.75 mL)] was added to a solution of lactone 10
(0.95 g, 5.5 mmol) in THF (15 mL) at –78 °C. The lithium enolate
thus generated was alkylated with methyl iodide (0.53 mL,
8.37 mmol) whilst stirring the reaction mixture for 2 h at the same
temperature. Then the reaction mixture was quenched with a satu-
rated ammonium chloride solution. The mixture was extracted with
diethyl ether (3ϫ15 mL) and removal of the solvent gave the meth-
ylated lactone. Purification by silica gel column chromatography
using 15% EtOAc/hexane as eluent afforded compound 11 (0.9 g,
tert-Butyl{(2R,4S)-2-methyl-4-[(5S)-5-methyl-2-phenyl-1,3-dioxan-
4-yl]pentyloxy}diphenylsilane (14): Imidazole (88 mg, 1.2 mmol) fol-
lowed by TBDPS-Cl (0.168 mL, 0.64 mmol) were added to a stirred
solution of alcohol 13 (120 mg, 0.4 mmol) in CH2Cl2 at 0 °C. The
reaction mixture was stirred at room temperature for 30 min. The
reaction was quenched with aqueous NaHCO3 and extracted with
CH2Cl2 (3ϫ15 mL), dried with Na2SO4, evaporated, and purified
on silica gel (5 % EtOAc/hexane) to furnish the silyl ether 14
(214 mg, 97%) as an oily colorless liquid. [α]2D5 = +20.7 (c = 1.0,
87%) as a colorless oil. [α]2D5 = +35.5 (c = 2.6, CHCl3). IR (KBr):
CHCl ). IR (KBr): ν = 2927, 2856, 2359, 1648, 1546, 1398, 1108,
˜
3
ν = 2963, 2928, 1736, 1459, 1227, 1180, 1138, 965 cm–1. H NMR
1024, 755 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.65 (m, 4 H,
1
˜
(300 MHz, CDCl3): δ = 5.43 (d, J = 2.3 Hz, 1 H, 1-H), 3.69 (d, J Ph-H), 7.46–7.30 (m, 11 H, Ph-H), 5.41 (s, 1 H, Ph-CH), 4.10 (dd,
= 4.68 Hz, 1 H, 5-H), 2.54 (q, J = 7.03 Hz, 1 H, 4-H), 2.11 (m, 1
H, 8-H), 1.97 (m, 1 H, 6-H), 1.64 (m, 1 H, 7-H), 1.47 (d, J =
7.8 Hz, 3 H, 4Ј-Me), 1.10 (m, 1 H, 7Ј-H), 1.0 (d, J = 7.03 Hz, 3 H,
J = 11.1, 4.7 Hz, 1 H, 3-H), 3.48 (m, 3 H, 1-H, 7-H), 3.32 (dd, J
= 1.8, 10.0 Hz, 1 H, 7-H), 2.08 (m, 1 H, 2-H), 1.81 (m, 2 H, 4-H,
6-H), 1.64 (m, 1 H, 5-H), 1.10 (m, 1 H, 5Ј-H), 1.03 (s, 9 H, SiMe3),
8-Me), 0.90 (d, J = 7.03 Hz, 3 H, 6-Me) ppm. 13C NMR (CDCl3, 0.94 (m, 6 H, 2Ј-Me, 4Ј-Me), 0.71 (d, J = 6.6 Hz, 3 H, 6Ј-Me) ppm.
75 MHz): δ = 171.6, 101.1, 77.8, 35.7, 33.9, 33, 30.1, 19.6, 16.7, 13C NMR (CDCl3, 75 MHz): δ = 139.0, 135.5, 134.0, 129.4, 128.4,
Eur. J. Org. Chem. 2010, 2148–2156
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2151

J. S. Yadav, V. Rajender
FULL PAPER
128.0, 127.5, 126.0, 100.9, 84.6, 73.2, 69.0, 37.1, 33.0, 30.6, 30.6,
(c = 0.6, CHCl ). IR (KBr): ν = 3067, 2926, 1645, 1259, 1107, 1075,
˜
3
26.8, 19.2, 17.4, 13.8, 12.0 ppm. MS (EI): m/z = 539.0 [M + Na]+.
700 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.67–7.64 (m, 5 H, Ph-
HRMS: calcd. for C33H45O3Si [M + H]+ 517.3132; found 517.3136. H), 7.41–7.35 (m, 5 H, Ph-H), 7.30–7.23 (m, 5 H, Ph-H), 6.25 (dd,
J = 8.8, 7.3 Hz, 1 H, 7-H), 6.06 (d, J = 7.3 Hz, 1 H, 8-H), 4.52 (s,
(2S,4S,6R)-3-(Benzyloxy)-7-(tert-butyldiphenylsilyloxy)-2,4,6-tri-
2 H, Ph-CH2), 3.53 (dd, J = 9.8, 4.9 Hz, 1 H, 1-H), 3.35 (dd, J =
methylheptan-1-ol (15): DIBAL-H (0.866 mL, 1.22 mmol, 20% of
9.8, 7.3 Hz, 1 H, 1Ј-H), 3.12 (t, J = 4.7 Hz, 1 H, 5-H), 2.84–2.72
DIBAL-H in toluene) was slowly added to a solution of compound
(m, 1 H, 6-H), 1.81–1.62 (m, 2 H, 2-H, 4-H), 1.48–1.39 (ddd, J =
13.2, 7.5, 5.0 Hz, 1 H, 3-H), 1.28 (m, 1 H, 3Ј-H), 1.04 (s, 9 H,
14 (210 mg, 0.407 mmol) in CH2Cl2 at –15 °C and the reaction mix-
ture was stirred at the same temperature while monitoring the pro-
gress of reaction by TLC. After consumption of all the starting
material, the reaction mixture was quenched with a saturated aque-
SiMe3), 1.01 (d, J = 6.7 Hz, 3 H, 6Ј-Me), 0.98 (d, J = 6.6 Hz, 3 H,
4Ј-Me), 0.92 (d, J = 6.7 Hz, 3 H, 2Ј-Me) ppm. 13C NMR (CDCl3,
75 MHz): δ = 143.7, 135.6, 129.4, 128.1, 127.5, 127.4, 127.2, 86.4,
ous potassium sodium tartrate solution and stirred at room tem-
81.5, 74.4, 68.8, 42.5, 37.8, 33.9, 33.3, 29.6, 26.8, 18.3, 17.3,
perature for 1 h. The reaction mixture was extracted with CH2Cl2
15.8 ppm. MS (EI): m/z = 663.0 [M + Na]+. HRMS: calcd. for
(3ϫ15 mL), concentrated under reduced pressure, and purified by
C34H49INO2Si [M + NH4]+ 658.2572; found 658.2578.
silica gel column chromatography to afford alcohol 15 (194 mg,
92%) as a colorless liquid. [α]2D5 = –6.5 (c = 2.5, CHCl3). IR (KBr):
N-[(2S,3S)-3-Hydroxy-5-(4-methoxybenzyloxy)-2-methylpentanoyl]-
bornane-10,2-sultam (19): Titanium tetrachloride (1.5 mL,
13.8 mmol) was added dropwise to a 0.2  solution of (R)-N-propi-
onylbornane-10,2-sultam[18] (17; 1.25 g, 4.6 mmol) in CH2Cl2 at
–78 °C under nitrogen. Diisopropylethylamine (1.75 mL,
10.1 mmol) was added very slowly to the resulting yellow slurry to
give a deep-red solution, which was stirred at –78 °C. After 1.5 h,
aldehyde 18 (2.6 g, 13.8 mmol) was added slowly over a period of
15 min and the mixture was stirred at –78 °C for an additional
1.5 h. The reaction was quenched with aqueous NH4Cl and the
mixture was warmed to ambient temperature. The reaction mixture
was diluted with water and extracted with CH2Cl2 (3ϫ50 mL),
dried with anhydrous Na2SO4, evaporated under reduced pressure,
and purified on silica gel using 20% EtOAc/hexane as eluent to
furnish the anti aldol product 19 (2.94 g, 77%) as a colorless oil.
1
ν = 3443, 2917, 2849, 1215, 1110, 757 cm–1. H NMR (300 MHz,
˜
CDCl3): δ = 7.65 (m, 4 H, Ph-H), 7.38 (m, 6 H, Ph-H), 7.29 (m, 5
H, Ph-H), 4.59 (d, J = 10.9 Hz, 1 H, Ph-CH), 4.53 (d, J = 10.9 Hz,
1 H, Ph-CH), 3.61 (d, J = 5.0 Hz, 2 H, 1-H), 3.47 (m, 2 H, 7-H),
3.23 (dd, J = 8.1, 2.8 Hz, 1 H, 3-H), 1.90 (m, 1 H, 2-H), 1.80 (m,
2 H, 4-H, 6-H), 1.62 (m, 1 H, 5-H), 1.02–1.06 (m, 10 H, SiMe3, 5Ј-
H), 0.97 (d, J = 6.6 Hz, 3 H, 2Ј-Me), 0.95 (d, J = 6.7 Hz, 3 H, 4Ј-
Me), 0.89 (d, J = 6.9 Hz, 3 H, 6Ј-Me) ppm. 13C NMR (CDCl3,
75 MHz): δ = 138.2, 135.58, 135.55, 133.8, 129.5, 128.3, 127.6,
127.5, 87.7, 75.1, 68.7, 66.7, 38.4, 37.8, 33.3, 33.2, 26.8, 19.2, 17.8,
15.3, 14.8 ppm. MS (EI): m/z = 541.0 [M + Na]+. HRMS: calcd.
for C33H46O3SiNa [M + Na]+ 541.3108; found 541.3110.
(2R,4S,6R)-3-(Benzyloxy)-7-(tert-butyldiphenylsilyloxy)-2,4,6-tri-
methylheptanal (16): A solution of alcohol 15 (100 mg, 0.19 mmol)
in CH2Cl2 (3 mL) was added to a suspension of Dess–Martin
periodinane (122 mg, 0.28 mmol) and NaHCO3 (32 mg,
0.38 mmol) in CH2Cl2 (3 mL) at 0 °C. The reaction mixture was
stirred at 0 °C for 1 h. Afterwards, the reaction mixture was diluted
with CH2Cl2 (10 mL) and washed with a saturated aqueous
NaHCO3 solution (3ϫ10 mL). The combined organic layers were
dried with Na2SO4, evaporated in vacuo, and purified by column
chromatography over silica gel (10% EtOAc/hexane) to afford alde-
hyde 16 (91 mg, 92%) as a slightly yellow oil. [α]2D5 = –14.8 (c =
[α]2D5 = –20.9 (c = 2.3, CHCl ). IR (KBr): ν = 3485, 2929, 2362,
˜
3
1692, 1513, 1459, 1329, 1245, 1129 cm–1 1H NMR (300 MHz,
.
CDCl3): δ = 7.26 (d, J = 8.7 Hz, 2 H, Ph-H), 6.87 (d, J = 8.7 Hz,
2 H, Ph-H), 4.44 (dd, J = 16.3, 11.3 Hz, 2 H, Ph-CH2), 3.90 (m, 2
H, 2-H, HC-N), 3.80 (s, 3 H, Ph-OMe), 3.72–3.58 (m, 2 H, 5-H),
3.50 (ABq, J = 13.7 Hz, 2 H, CH2-SO2), 3.22 (m, 1 H, 3-H), 3.09
(d, J = 7.1 Hz, 1 H, OH), 2.17–2.02 (m, 2 H, 4-H), 1.97–1.84 (m,
4 H), 1.43–1.25 (m, 3 H), 1.17 (m, 6 H, 2 Me), 0.96 (s, 3 H,
Me) ppm. 13C NMR (CDCl3, 75 MHz): δ = 175.1, 159.1, 130.0,
129.3, 113.7, 74.1, 72.9, 67.6, 65.3, 55.2, 53.1, 48.2, 47.6, 45.3, 44.6,
38.4, 34.0, 32.8, 26.4, 20.7, 19.8, 13.7 ppm. MS (EI): m/z = 488.0
[M + Na]+. HRMS: calcd. for C24H35O6NSNa [M + Na]+
488.2082; found 488.2079.
0.55, CHCl ). IR (KBr): ν = 2927, 2856, 2364, 1708, 1462, 1108,
˜
3
701 cm–1. H NMR (300 MHz, CDCl3): δ = 9.77 (d, J = 2.2 Hz, 1
1
H, CHO), 7.66–7.63 (m, 5 H, Ph-H), 7.42–7.35 (m, 5 H, Ph-H),
7.29–7.22 (m, 5 H, Ph-H), 4.55–4.43 (ABq, J = 11.3 Hz, 2 H, Ph-
CH2), 3.52–3.41 (m, 3 H, 3-H, 7-H), 2.68 (ddq, J = 6.7, 2.2, 1.8 Hz,
1 H, 2-H), 1.84–1.72 (m, 1 H, 4-H), 1.63–1.54 (m, 2 H, 5-H, 6-H),
1.30 (m, 1 H, 5Ј-H), 1.04–1.0 (m, 12 H, SiMe3, 2Ј-Me), 0.96–0.92
(m, 6 H, 4Ј-Me, 6Ј-Me) ppm. 13C NMR (CDCl3, 100 MHz): δ =
204.7, 135.5, 135.4, 133.7, 129.4, 128.2, 127.52, 127.5, 127.4, 83.8,
74.2, 68.5, 49.2, 37.8, 33.3, 33.0, 26.9, 19.3, 18.0, 14.8, 11.8 ppm.
MS (EI): m/z = 539.1 [M + Na]+. HRMS: calcd. for C33H48O3NSi
[M + NH4]+ 534.3398; found 534.3398.
N-[(2S,3S)-3-(tert-Butyldimethylsilyloxy)-5-(4-methoxybenzyloxy)-
2-methylpentanoyl]bornane-10,2-sultam (20): 2,6-Lutidine (0.878
mL, 7.5 mmol) followed by TBS-OTf (1.3 mL, 5.6 mmol) were
added to a solution of alcohol 19 (1.75 g, 8.7 mmol) in CH2Cl2
(30 mL) at –78 °C and the reaction mixture was stirred at –78 °C
for 30 min. The reaction mixture was quenched with saturated
NH4Cl and extracted with CH2Cl2 (3ϫ30 mL), dried with anhy-
drous Na2SO4, and evaporated under reduced pressure to yield a
white solid, which on purification over silica gel (10% EtOAc/hex-
(2R,4S,5R,6S,Z)-5-(Benzyloxy)-8-iodo-2,4,6-trimethyloct-7-enyl- ane) afforded the TBS-substituted product 20 (1.97 g, 91%) as a
oxy)tert-butyldiphenylsilane (2): A suspension of (iodomethyl)tri-
phenylphosphonium iodide (205 mg, 0.38 mmol) in THF (10 mL)
was treated with NaHMDS (1  in THF, 0.310 mL, 0.31 mmol)
and the resulting solution was stirred for 20 min at room tempera-
ture. The resulting dark-red solution was cooled to –78 °C and
HMPA (0.04 mL, 0.23 mmol) was added followed by aldehyde 16
(80 mg, 0.15 mmol) in THF (10 mL) at –78 °C. The reaction mix-
ture was stirred for an additional 1 h at the same temperature. Then
it was diluted with hexane (10 mL), filtered through Celite, concen-
trated in vacuo, and purified on silica gel (5% EtOAc/hexane) to
afford vinyl iodide 2 (75 mg, 76%) as a colorless liquid. [α]2D5 = +5.4
white crystalline solid. [α]2D5 = –15.2 (c = 1.0, CHCl ). IR (KBr): ν
˜
3
= 2956, 2929, 1694, 1513, 1331, 1248, 1212, 1134, 1060 cm–1. 1H
NMR (300 MHz, CDCl3): δ = 7.22 (d, J = 8.6 Hz, 2 H, Ph-H),
6.85 (d, J = 8.6 Hz, 2 H, Ph-H), 4.35 (s, 2 H, Ph-CH2), 4.30 (m, 1
H, 3-H), 3.86 (t, J = 5.5 Hz, 1 H, HC-N), 3.78 (s, 3 H, Ph-OMe),
3.48 (m, 2 H, H2C-SO2), 3.43 (d, J = 6.2 Hz, 2 H, 5-H), 3.34 (m,
1 H, 2-H), 1.96–1.76 (m, 4 H), 1.63 (m, 2 H, 4-H), 1.41–1.24 (m, 3
H), 1.13 (d, J = 6.9 Hz, 3 H, 2Ј-Me), 1.01 (s, 3 H, Me) 0.89 (s, 3
H, Me), 0.86 (s, 9 H, SiMe3), 0.11 (s, 3 H, SiMe), 0.05 (s, 3 H,
SiMe) ppm. 13C NMR (CDCl3, 75 MHz): δ = 173.5, 158.9, 130.7,
129.1, 113.5, 72.4, 69.3, 66.1, 65.1, 55.1, 53, 47.9, 47.5, 46.4, 44.5,
2152
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 2148–2156

Studies Directed towards the Total Synthesis of (–)-Dictyostatin
38.4, 32.7, 32.2, 26.3, 25.8, 20.5, 19.7, 17.9, 9.3, –4.4, –5.4 ppm.
MS (EI): m/z = 602.0 [M + Na]+. HRMS: calcd. for C30H49NO6N-
aSiS [M + Na]+ 602.2947; found 602.2959.
iodide, which was purified by silica gel column chromatography
(hexane/EtOAc = 95:5) to give trans-vinyl iodide 23 (352 mg, 85%)
as a colorless oil. [α]2D5 = +15.1 (c = 1.0, CHCl ). IR (KBr): ν =
˜
3
2954, 2929, 1612, 1249, 1096, 835 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 7.20 (d, J = 8.6 Hz, 2 H, Ph-H), 6.84 (d, J = 8.6 Hz,
2 H, Ph-H), 6.44 (dd, J = 14.5, 8.1 Hz, 1 H, 5-H), 5.95 (dd, J =
14.5, 0.75 Hz, 1 H, 6-H), 4.37 (dd, J = 19.0, 11.5 Hz, 2 H, Ph-
CH2), 3.80 (s, 3 H, Ph-OMe), 3.72 (td, J = 6.0, 4.1 Hz, 1 H, 3-H),
3.42 (t, J = 6.4 Hz, 2 H, 1-H), 2.30 (m, 1 H, 4-H), 1.65 (q, J =
6.4 Hz, 2 H, 2-H), 1.00 (d, J = 6.9 Hz, 3 H, 4Ј-Me), 0.88 (s, 9 H,
SiMe3), 0.04 (s, 3 H, SiMe), 0.03 (s, 3 H, SiMe) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 159.2, 148.3, 130.4, 129.2, 113.7, 75.3, 72.6,
72.0, 66.3, 55.1, 46.1, 34.0, 26.0, 18.2, 15.2, –4.24, –4.29 ppm. MS
(EI): m/z = 513.0 [M + Na]+. HRMS: calcd. for C21H35O3NaSi [M
+ Na]+ 513.1292; found 513.1294.
(2R,3S)-3-(tert-Butyldimethylsilyloxy)-5-(4-methoxybenzyloxy)-2-
methylpentan-1-ol (21): LiCl (660 mg, 15.5 mmol) and NaBH4
(590 mg, 15.5 mmol) at 0 °C were placed in a 100 mL round-bot-
tomed flask equipped with a magnetic bar. Ethanol (30 mL) was
added and the suspension was stirred at room temperature for 1 h
to generate LiBH4 as a white suspension The suspension was co-
oled to 0 °C and aldol compound 20 (1.8 g, 3.1 mmol) was added
in diethyl ether (20 mL). The reaction mixture was stirred for 2 h.
Afterwards the volatiles were removed in vacuo, the residue was
quenched with aqueous NH4Cl solution, extracted with EtOAc
(3ϫ30 mL), dried with anhydrous Na2SO4, evaporated, and puri-
fied on silica gel (20% EtOAc/hexane) to furnish 21 (1.06 g, 94%)
as an oily liquid. [α]2D5 = –2.6 (c = 0.5, CHCl ). IR (KBr): ν = 3443,
Ethyl (6R,7S,E)-7-(tert-Butyldimethylsilyloxy)-9-(4-methoxybenz-
yloxy)-6-methylnon-4-en-2-ynoate (24): CuI (26.4 mg, 0.13 mmol)
and tetrakis(triphenylphosphane)palladium (80 mg, 0.069 mmol)
˜
3
3015, 2955, 2927, 1250, 1216, 1082, 758 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 7.25 (d, J = 8.6 Hz, 2 H, Ph-H), 6.89 (d, J = 8.6 Hz,
2 H, Ph-H), 4.46–4.37 (ABq, J = 11.5 Hz, 2 H, Ph-CH2), 3.88 (dd, were added to a solution of vinyl iodide 23 (340 mg, 0.69 mmol) in
J = 10.1, 5.8 Hz, 1 H, 1-H), 3.80 (s, 3 H, Ph-OMe), 3.75–3.70 (dd, NEt3 (2 mL). The reaction mixture was stirred for 30 min at room
J = 10.9, 3.9 Hz, 1 H, 1Ј-H), 3.54–3.47 (m, 3 H, 3-H, 5-H), 1.88– temperature, after which a solution of ethyl propionate (0.141 mL,
1.81 (q, J = 6.4 Hz, 2 H, 4-H), 1.79–1.72 (m, 1 H, 2-H), 0.99 (d, J
= 7.1 Hz, 3 H, 2Ј-Me), 0.88 (s, 9 H, SiMe3), 0.08 (s, 3 H, SiMe),
0.07 (s, 3 H, SiMe) ppm. 13C NMR (CDCl3, 75 MHz): δ = 159.1,
130.3, 129.2, 113.7, 74, 72.6, 66.4, 65.2, 55.2, 38.9, 34.4, 25.8, 17.9,
1.3 mmol, 2 equiv.) in THF was added dropwise over 10 min. After
2 h, the volatiles were removed in vacuo and purified by silica gel
column chromatography (10% EtOAc/hexane) to obtain the enyno-
ate compound 24 (287 mg, 90%) as a colorless oil. [α]2D5 = +40.5 (c
13.9, –4.5, –4.6 ppm. MS (EI): m/z = 391.0 [M + Na]+. HRMS: = 0.5, CHCl ). IR (KBr): ν = 2954, 2930, 2210, 1708, 1614, 1252,
˜
3
calcd. for C20H36O4NaSi [M + Na]+ 391.2280; found 391.2295.
1097 cm–1. H NMR (300 MHz, CDCl3): δ = 7.26 (d, J = 8.6 Hz,
2 H, Ph-H), 6.89 (d, J = 8.6 Hz, 2 H, Ph-H), 6.49 (dd, J = 16.0,
8.1 Hz, 1 H, 5-H), 5.54 (dd, J = 16.0, 0.94 Hz, 1 H, 4-H), 4.41 (dd,
J = 21.1, 11.5 Hz, 2 H, Ph-CH2), 4.25 (q, J = 7.0 Hz, 2 H, CH3-
CH2-CO2), 3.80 (s, 3 H, Ph-OMe), 3.76 (m, 1 H, 7-H), 3.44 (t, J =
6.4 Hz, 2 H, 9-H), 2.38 (m, 1 H, 6-H), 1.65 (m, 2 H, 8-H), 1.31 (t,
J = 7.1 Hz, 3 H, CH3-CH2-CO2), 1.03 (d, J = 6.9 Hz, 3 H, 6Ј-Me),
0.88 (s, 9 H, SiMe3), 0.04 (s, 3 H, SiMe), 0.03 (s, 3 H, SiMe) ppm.
13C NMR (CDCl3, 100 MHz): δ = 159.1, 154.1, 153.8, 130.4, 129.2,
113.7, 107.2, 85.4, 79.7, 72.5, 72.2, 66.3, 61.8, 55.2, 43.3, 34.3, 25.8,
18, 15.2, 14, –4.4 ppm. MS (EI): m/z = 483.0 [M + Na]+. HRMS:
calcd. for C26H40NaO5Si [M + Na]+ 483.2537; found 483.2538.
1
(2S,3S)-3-(tert-Butyldimethylsilyloxy)-5-(4-methoxybenzyloxy)-2-
methylpentanal (22): A solution of alcohol 21 (500 mg, 1.35 mmol)
in CH2Cl2 (10 mL) was added to a suspension of Dess–Martin
periodinane (690 mg, 1.63 mmol) and NaHCO3 (230 mg,
2.7 mmol) in CH2Cl2 (10 mL) at 0 °C and the reaction mixture was
stirred at 0 °C for 1 h. The reaction mixture was then diluted with
CH2Cl2 (15 mL) and washed with saturated aqueous NaHCO3
(3ϫ15 mL). The combined organic layers were dried with Na2SO4,
evaporated in vacuo, and purification by silica gel column
chromatography (10 % EtOAc/hexane) afforded aldehyde 22
(472 mg, 95%) as a yellow oil. [α]2D5 = +21.1 (c = 1.6, CHCl3). IR
(KBr): ν = 2930, 2856, 1710, 1250, 1102, 770 cm–1
.
1H NMR Ethyl (6R,7S,E)-7-(tert-Butyldimethylsilyloxy)-9-hydroxy-6-meth-
(300 MHz, CDCl3): δ = 9.72 (d, J = 2.0 Hz, 1 H, CHO), 7.25 (d, ylnon-4-en-2-ynoate (25): DDQ (153 mg, 0.67 mmol) was added
J = 8.6 Hz, 2 H, Ph-H), 6.88 (d, J = 8.6 Hz, 2 H, Ph-H), 4.41 (dd, portionwise to a solution of PMB ether 24 (260 mg, 0.56 mmol) in
˜
J = 15.1, 11.5 Hz, 2 H, Ph-CH2), 4.15 (td, J = 6.4, 5.09 Hz, 1 H,
3-H), 3.81 (s, 3 H, Ph-OMe), 3.52 (t, J = 6.4 Hz, 2 H, 5-H), 2.52
(m, 1 H, 2-H), 1.79 (m, 2 H, 4-H), 1.10, (d, J = 6.9 Hz, 3 H, 2Ј-
a mixture of CH2Cl2 and water (5:1, 15 mL) at 0 °C under vigorous
stirring. After completion (confirmed by TLC), the reaction mix-
ture was quenched with a saturated NaHCO3 solution and ex-
Me), 0.87 (s, 9 H, SiMe3), 0.06 (s, 6 H, SiMe2) ppm. 13C NMR tracted with CH2Cl2 (3ϫ15 mL), dried with anhydrous Na2SO4,
(CDCl3, 75 MHz): δ = 204.6, 159.1, 130.3, 129.2, 113.7, 72.6, 70.4,
65.9, 55.2, 51.6, 34.6, 25.7, 18.0, 10.0, –4.6, –4.4 ppm. MS (EI): m/z
= 389.0 [M + Na]+. HRMS: calcd. for C20H34O4NaSi [M + Na]+
389.2119; found 389.2121.
and concentrated under reduced pressure to yield a viscous oil,
which was purified by silica gel column chromatography (15%
EtOAc/hexane) to afford the alcohol 25 (182 mg, 95%) as a color-
less oil. [α]2D5 = +15.5 (c = 0.8, CHCl ). IR (KBr): ν = 3019, 2925,
˜
3
1
2212, 1702, 1465, 1215, 758 cm–1. H NMR (300 MHz, CDCl3): δ
tert-Butyl[(3S,4R,E)-6-Iodo-1-(4-methoxybenzyloxy)-4-methylhex-
5-en-3-yloxy]dimethylsilane (23): Anhydrous (flame-dried under ar-
gon) CrCl2 (1.1 g, 8.4 mmol, 10 equiv.) in THF (10 mL) was stirred
for 30 min at room temperature, generating a creamy gray-green
suspension. CHI3 (667 mg, 1.69 mmol, 2 equiv.) in THF at 0 °C
was then added to this mixture followed by aldehyde 22 (310 mg,
0.84 mmol, 1 equiv.) in THF at 0 °C. The resulting dark-red mix-
ture was stirred for 3 h at the same temperature. After completion
of the reaction (confirmed by TLC) the reaction mixture was fil-
tered through Celite and the residue washed with diethyl ether. The
filtrate was then washed with saturated aqueous solution of sodium
thiosulfate and brine solution. The organic layer was dried with
Na2SO4 and concentrated in vacuo to afford the crude trans-vinyl
= 6.47 (dd, J = 16.0, 8.1 Hz, 1 H, 5-H), 5.60 (dd, J = 16.0, 1.3 Hz,
1 H, 4-H), 4.25 (q, J = 7.1 Hz, 2 H, CH3-CH2-CO2), 3.81 (td, J =
4.7, 2.2 Hz, 1 H, 7-H), 3.71 (m, 2 H, 9-H), 2.50 (m, 1 H, 6-H), 1.83
(br., 1 H, OH), 1.67 (m, 2 H, 8-H), 1.32 (t, J = 7.1 Hz, 3 H, CH3-
CH2-CO2), 1.05 (d, J = 6.7 Hz, 3 H, 6Ј-Me), 0.90 (s, 9 H, SiMe3),
0.09 (s, 3 H, SiMe), 0.07 (s, 3 H, SiMe) ppm. 13C NMR (CDCl3,
75 MHz): δ = 154.05, 153.6, 107.4, 85.1, 79.9, 73.2, 61.8, 59.7, 43.2,
35.7, 25.8, 17.9, 14.6, 14.03, –4.5, –4.4 ppm. MS (EI): m/z = 341.1
[M + H]+. HRMS: calcd. for C18H33O4Si [M + H]+ 341.2143;
found 341.2152.
Ethyl
(2Z,4E,6R,7S)-7-(tert-Butyldimethylsilyloxy)-9-hydroxy-6-
methylnona-2,4-dienoate (26): Isoquinoline (0.2 mL) followed by
Eur. J. Org. Chem. 2010, 2148–2156
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2153

J. S. Yadav, V. Rajender
FULL PAPER
the Pd/CaCO3 catalyst poisoned with Pb (30 mg) were added to a
solution of alcohol 25 (125 mg, 0.36 mmol) in benzene (10 mL) un-
der hydrogen. The reaction mixture was stirred at room tempera-
OH), 3.27 (dq, J = 7.1, 2.4 Hz, 1 H, 2-H), 2.07 (m, 2 H), 1.91 (m,
3 H), 1.72 (s, 3 H, 4-Me), 1.45–1.29 (m, 2 H), 1.20 (d, J = 7.1 Hz,
3 H, 2Ј-Me), 1.15 (s, 3 H, Me), 0.98 (s, 3 H, Me) ppm. 13C NMR
ture for 15 min, washed with a 0.8  HCl solution (2ϫ5 mL) to (CDCl3, 75 MHz): δ = 177, 142.9, 111.9, 72.8, 64.9, 52.9, 48.3, 47.7,
remove isoquinoline from the reaction mixture, extracted with di-
ethyl ether (3ϫ10 mL), dried with Na2SO4, and the solvents evapo-
rated in vacuo. The crude product was purified by silica gel column
chromatography (20% EtOAc/hexane) to furnish the dienoate 26
(122 mg, 98%) as yellow oil. [α]2D5 = –5.1 (c = 0.5, CHCl3). IR
44.5, 41.4, 38.2, 32.7, 26.3, 20.7, 19.8, 19.4, 10.9 ppm. MS (EI): m/z
= 364.1 [M + Na]+. HRMS: calcd. for C17H27NO4NaS [M +
Na]+ 364.1558; found 364.1556.
(2S,3R)-2,4-Dimethylpent-4-ene-1,3-diol (28): The syn aldol 27
(3.37gr, 9.87 mmol) in THF (15 mL) was added to a suspension of
LiAlH4 (570 mg, 14.8 mmol) in THF (15 mL) under nitrogen at
0 °C and the mixture was stirred for 3 h at room temperature. Then
it was quenched with saturated aqueous Na2SO4 at 0 °C. The solids
were filtered, washed with diethyl ether, the filtrate dried with
Na2SO4, evaporated under reduced pressure, and purified by silica
gel column chromatography (20% EtOAc/hexane) to afford diol 28
(1.19 g, 94%) as a colorless oil. [α]2D5 = +12.6 (c = 0.8, CHCl3). IR
(KBr): ν = 3020, 2928, 2361, 1710, 1640, 1463, 1253, 1215,
˜
763 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.39 (dd, J = 15.4,
11.3 Hz, 1 H, 3-H), 6.54 (t, J = 11.3 Hz, 1 H, 4-H), 5.99 (dd, J =
15.4, 7.7 Hz, 1 H, 2-H), 5.59 (d, J = 11.3 Hz, 1 H, 5-H), 4.18 (q, J
= 7.1 Hz, 2 H, CH3-CH2-CO2), 3.86 (m, 1 H, 7-H), 3.72 (m, 2 H,
9-H), 2.54 (m, 1 H, 6-H),1.83 (s, 1 H, OH), 1.68 (m, 2 H, 8-H),
1.30 (t, J = 7.1 Hz, 3 H, CH3-CH2-CO2), 1.07 (d, J = 6.9 Hz, 3 H,
6Ј-Me), 0.90 (s, 9 H, SiMe3), 0.09 (s, 3 H, SiMe), 0.07 (s, 3 H,
SiMe) ppm. 13C NMR (CDCl3, 75 MHz): δ = 166.5, 146.7, 145.04,
126.9, 116.2, 73.8, 59.8, 60.1, 42.6, 35.3, 25.8, 18.01, 14.6, 14.2,
–4.5, –4.3 ppm. MS (EI): m/z = 343.1 [M + H]+. HRMS: calcd. for
C18H35O4Si [M + H]+ 343.2299; found 343.2289.
(KBr): ν = 3416, 2918, 1650, 1216, 1021 cm–1. 1H NMR (300 MHz,
˜
CDCl3): δ = 5.01 (s, 1 H, 5-H), 4.93 (s, 1 H, 5Ј-H), 4.25 (d, J =
1.8 Hz, 1 H, 3-H), 3.71 (m, 2 H, 1-H), 2.62 (br., 2 H, OH), 1.90
(m, 1 H, 2-H), 1.72 (s, 3 H, 4-Me), 0.90 (d, J = 7.0 Hz, 3 H, 2Ј-
Me) ppm. 13C NMR (CDCl3, 75 MHz): δ = 146.1, 110.4, 76.8,
66.6, 37.1, 19.2, 9.7 ppm. MS (EI): m/z = 131.1 [M + H]+. HRMS:
calcd. for C7H14O2Na [M + Na]+ 153.1894; found 153.1991.
Ethyl
(2Z,4E,6R,7S)-7-(tert-Butyldimethylsilyloxy)-6-methyl-9-
oxonona-2,4-dienoate (3): A solution of alcohol 26 (100 mg,
0.29 mmol) in CH2Cl2 (3 mL) was added to a suspension of Dess–
Martin periodinane (148 mg, 0.35 mmol) and NaHCO3 (49 mg,
0.58 mmol) in CH2Cl2 (5 mL) at 0 °C and the reaction mixture was
stirred at 0 °C for 1 h. The reaction mixture was diluted with
CH2Cl2 (10 mL) and washed with aqueous NaHCO3 solution
(2ϫ10 mL). The organic layer was dried with Na2SO4, evaporated
under reduced pressure, and the crude product was purified by sil-
ica gel column chromatography (10% EtOAc/hexane) to yield alde-
hyde 3 (94.4 mg, 95%) as slightly yellow oil. [α]2D5 = +4.7 (c = 0.45,
(4R,5S)-2-(4-Methoxyphenyl)-5-methyl-4-(prop-1-en-2-yl)-1,3-diox-
ane (29): Anisaldehyde dimethyl acetal (2.15 mL, 12.6 mmol) and
a catalytic amount of azeotropically dried CSA were added to a
stirred solution of diol 28 (1.1 g, 8.4 mmol) in CH2Cl2 at 0 °C. The
reaction mixture was stirred at room temperature for 5 h. It was
then quenched with aqueous NaHCO3, extracted with CH2Cl2
(3ϫ20 mL), dried with anhydrous Na2SO4, evaporated, and puri-
fied on silica gel using 5% EtOAc/hexane as eluent to furnish the
protected diol 29 (1.93 g, 93%) as an oily liquid. [α]2D5 = +17.5 (c =
CHCl ). IR (KBr): ν = 2957, 2932, 2857, 1715, 1638, 1465, 1254,
˜
3
3.1, CHCl ). IR (KBr): ν = 2963, 2924, 1650, 1616, 1516, 1247,
˜
3
1
1184, 1090, 1028 cm–1. H NMR (300 MHz, CDCl3): δ = 9.77 (s,
1 H, CHO), 7.39 (dd, J = 15.4, 11.3 Hz, 1 H, 3-H), 6.54 (t, J =
11.3 Hz, 1 H, 4-H), 5.96 (dd, J = 15.4, 7.9 Hz, 1 H, 2-H), 5.62 (d,
J = 11.3 Hz, 1 H, 5-H), 4.19 (m, 3 H, CH3-CH2-CO2, 7-H), 2.50
(m, 3 H, 6-H, 8-H), 1.30 (t, J = 7.1 Hz, 3 H, CH3-CH2-CO2), 1.09
(d, J = 6.9 Hz, 3 H, 6Ј-Me), 0.87 (s, 9 H, SiMe3), 0.08 (s, 3 H,
SiMe), 0.04 (s, 3 H, SiMe) ppm. 13C NMR (CDCl3, 75 MHz): δ =
201.6, 166.4, 144.6, 145.2, 127.6, 116.7, 70.9, 59.9, 48.2, 43.3, 25.7,
18.0, 14.9, 14.2, –4.6, –4.5 ppm. MS (EI): m/z = 341.0 [M +
H]+. HRMS: calcd. for C18H36NO4Si [M + NH4]+ 358.2408; found
358.2410.
1117, 826 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.44 (d, J =
8.6 Hz, 2 H, Ph-H), 6.90 (d, J = 8.6 Hz, 2 H, Ph-H), 5.52 (s, 1 H,
Ph-CH), 5.10 (d, J = 1.5 Hz, 1 H, 5-H), 4.92 (d, J = 1.5 Hz, 1 H,
5Ј-H), 4.32 (d, J = 1.7 Hz, 1 H, 3-H), 4.14–4.02 (m, 2 H, 1-H), 3.80
(s, 3 H, Ph-OMe), 1.78 (m, 1 H, 2-H), 1.70 (s, 3 H, 4-Me), 1.07 (d,
J = 6.9 Hz, 3 H, 2Ј-Me) ppm. 13C NMR (CDCl3, 75 MHz): δ =
159.8, 142.2, 131.5, 127.4, 113.5, 110.4, 101.4, 81.3, 73.2, 55.2, 30.4,
19, 11.0 ppm. MS (EI): m/z = 249.1 [M + H]+. HRMS: calcd. for
C15H20O3Na [M + Na]+ 271.1312; found 271.1316.
(S)-2-[(4S,5S)-2-(4-Methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]prop-
an-1-ol (30): A solution of olefin 29 (1.73 g, 6.9 mmol) in THF
N-[(2R,3R)-3-Hydroxy-2,4-dimethylpent-4-enoyl]bornane-10,2-sul- (15 mL) at 0 °C was treated with 9-BBN (1.7 g, 13.9 mmol) in THF.
tam (27): Titanium tetrachloride (2 mL, 18.4 mmol) was added
dropwise to a 0.2  solution of (R)-N-propionylbornane-10,2-sul-
The reaction mixture was stirred at room temperature for 12 h. It
was then quenched with 3  NaOH (1.4 g) and 30% aqueous H2O2
tam[18] (17; 5 g, 18.4 mmol) in CH2Cl2 at –78 °C under nitrogen. (2.2 mL) and stirred for 6 h at room temperature. The reaction mix-
To the resulting yellow slurry, diisopropylethylamine (3.82 mL,
22.1 mmol) was added slowly and the resulting deep-red solution
was stirred at –78 °C. After 1.5 h, methacrolein (4.5 mL,
55.3 mmol) was added slowly and the mixture was stirred at –78 °C
for an additional 1.5 h. The reaction was quenched with aqueous
ture was extracted with diethyl ether (3ϫ25 mL). The combined
organic layers were washed with brine, dried with anhydrous
Na2SO4, concentrated in vacuo, and purified by silica gel column
chromatography (20% EtOAc/hexane) to afford alcohol 30 (1.66 g,
90%) as a colorless oil. [α]2D5 = –8.8 (c = 0.35, CHCl3). IR (KBr):
1
NH4Cl and the mixture was warmed to ambient temperature. The ν = 3445, 3018, 2961, 1615, 1518, 1250, 1215, 1033, 758 cm–1. H
˜
reaction mixture was then diluted with water and extracted with
CH2Cl2 (3ϫ50 mL), dried with Na2SO4, and evaporated under re-
duced pressure to yield the crude syn aldol product, which on puri-
fication by silica gel column chromatography (15% EtOAc/hexane)
NMR (300 MHz, CDCl3): δ = 7.39 (d, J = 8.6 Hz, 2 H, Ph-H),
6.87 (d, J = 8.6 Hz, 2 H, Ph-H), 5.48 (s, 1 H, Ph-CH), 4.05 (m, 2
H, 5-H), 3.79 (s, 4 H, Ph-OMe, 3-H), 3.7–3.58 (m, 2 H, 1-H), 1.99
(m, 1 H, 2-H), 1.67 (m, 1 H, 4-H), 1.21 (d, J = 6.9 Hz, 3 H, 4Ј-
Me), 0.83 (d, J = 6.9 Hz, 3 H, 2Ј-Me) ppm. 13C NMR (CDCl3,
75 MHz): δ = 160.0, 131.0, 127.3, 113.7, 101.7, 85.2, 73.9, 67.9,
gave the syn aldol product 27 (6.4 g, 73%) as a white solid. [α]2D5
=
–81.3 (c = 1.0, CHCl ). IR (KBr): ν = 3505, 2961, 2885, 2360, 1676,
˜
3
1455, 1331, 1270, 1214, 1132, 1062 cm–1
CDCl3): δ = 5.15 (s, 1 H, 5-H), 4.97 (s, 1 H, 5Ј-H), 4.42 (s, 1 H, 3- HRMS: calcd. for C15H22O4Na [M + Na]+ 289.1415; found
H), 3.91 (t, J = 6.4 Hz, 1 H, HC-N), 3.56–3.44 (m, 3 H, H2C-SO2, 289.1407.
.
1H NMR (300 MHz, 55.2, 36.6, 29.9, 11.9, 10.9 ppm. MS (EI): m/z = 289.2 [M + Na]+.
2154
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 2148–2156

Studies Directed towards the Total Synthesis of (–)-Dictyostatin
(R)-2-[(4R,5S)-2-(4-Methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]prop-
anal (31): A solution of alcohol 30 (510 mg, 1.9 mmol) in CH2Cl2
(10 mL) was added to a suspension of Dess–Martin periodinane
(1.05 g, 2.5 mmol) and NaHCO3 (322 mg, 3.84 mmol) in CH2Cl2
(15 mL) at 0 °C and the reaction mixture was stirred at 0 °C for
1 h. The suspension was diluted with hexane and the solvents were
evaporated under reduced pressure. The crude product was purified
by silica gel column chromatography (10% EtOAc/hexane) to yield
aldehyde 31 (408 mg, 95%) as a slightly yellow oil. [α]2D5 = –30.2 (c
J = 6.9 Hz, 3 H, 4Ј-Me) ppm. 13C NMR (CDCl3, 75 MHz): δ =
159.5, 135.7, 132.9, 131.4, 129.5, 127.1, 117.0, 113.3, 101.2, 83.2,
73.8, 55.2, 34.0, 29.9, 15.9, 11.0 ppm. MS (EI): m/z = 289.0 [M +
H]+. HRMS: calcd. for C18H24O3Na [M + Na]+ 311.1617; found
311.1624.
(2S,3S,4S,Z)-3-(4-Methoxybenzyloxy)-2,4-dimethylocta-5,7-dien-1-
ol (34): DIBAL-H (1.1 mL, 1.56 mmol, 20% of DIBAL-H in tolu-
ene) was added slowly to a solution of diene 33 (150 mg,
0.52 mmol) in CH2Cl2 at –15 °C and the reaction mixture was
stirred at the same temperature while monitoring the progress of
reaction by TLC. After consumption of all the starting material,
the reaction mixture was quenched with a saturated aqueous potas-
sium sodium tartrate solution and stirred vigorously at room tem-
perature for 1 h. The reaction mixture was extracted with CH2Cl2
(3ϫ15 mL), concentrated under reduced pressure, and purified by
silica gel column chromatography to afford alcohol 34 (137 mg,
91%) as a colorless liquid. [α]2D5 = +42.7 (c = 0.55, CHCl3). IR
= 1.2, CHCl ). IR (KBr): ν = 2918, 2849, 1725, 1615, 1516, 1248,
˜
3
1165, 1030, 756 cm–1. H NMR (300 MHz, CDCl3): δ = 9.84 (d, J
1
= 2.2 Hz, 1 H, CHO), 7.39 (d, J = 8.8 Hz, 2 H, Ph-H), 6.88 (d, J
= 8.8 Hz, 2 H, Ph-H), 5.48 (s, 1 H, Ph-CH), 4.11 (m, 3 H, 3-H, 5-
H), 3.79 (s, 3 H, Ph-OMe), 2.63 (m, 1 H, 2-H), 1.66 (m, 1 H, 4-H),
1.22 (d, J = 6.9 Hz, 3 H, 4Ј-Me), 1.01 (d, J = 7.1 Hz, 3 H, 2Ј-
Me) ppm. 13C NMR (CDCl3, 75 MHz): δ = 204.1, 159.8, 130.6,
127.2, 113.4, 100.8, 81.5, 72.7, 55.2, 47.3, 30.2, 11.9, 7.0 ppm. MS
(EI): m/z = 265.1 [M + H]+. HRMS: calcd. for C15H21O4 [M +
H]+ 265.1434; found 265.1436.
(KBr): ν = 3421, 2926, 1612, 1513, 1247, 1033 cm–1 1H NMR
.
˜
(300 MHz, CDCl3): δ = 7.26 (d, J = 8.6 Hz, 2 H, Ph-H), 6.87 (d,
J = 8.6 Hz, 2 H, Ph-H), 6.69 (dt, J = 16.9, 10.7 Hz, 1 H, 7-H), 6.03
(t, J = 10.7 Hz, 1 H, 6-H), 5.54 (t, J = 10.3 Hz, 1 H, 5-H), 5.22 (d,
J = 16.9 Hz, 1 H, 8-H), 5.12 (d, J = 10.2 Hz, 1 H, 8Ј-H), 4.55 (d,
J = 10.7 Hz, 1 H, Ph-CH), 4.47 (d, J = 10.7 Hz, 1 H, Ph-CH), 3.79
(s, 3 H, Ph-OMe), 3.63–3.50 (m, 2 H, 1-H), 3.40 (dd, J = 5.8,
4.3 Hz, 1 H, 3-H), 2.93–3.05 (ddq, J = 9.8, 6.7, 6.6 Hz, 1 H, 4-H),
1.90–2.02 (m, 1 H, 2-H), 1.63 (br. s, 1 H, OH), 1.03 (d, J = 6.7 Hz, 3
H, 4-Me), 0.96 (d, J = 6.9 Hz, 3 H, 2-Me) ppm. 13C NMR (CDCl3,
75 MHz): δ = 159.1, 135.3, 132.4, 130.9, 129.5, 129.0, 117.4, 113.6,
84.2, 73.8, 66.1, 55.2, 37.6, 35.0, 18.5, 11.5 ppm. MS (EI): m/z =
313.1 [M + Na]+. HRMS: calcd. for C18H26O3Na [M + Na]+
313.1779; found 313.1770.
(4S,5S)-4-[(S,Z)-4-Iodobut-3-en-2-yl]-2-(4-methoxyphenyl)-5-
methyl-1,3-dioxane (32): A suspension of (iodomethyl)triphenyl-
phosphonium iodide (1.03 g, 1.98 mmol) in THF (10 mL) was
treated with NaHMDS (1  in THF, 1.98 mL, 1.98 mmol) and the
resulting solution was stirred for 20 min at room temperature. The
resulting dark-red solution was cooled to –78 °C and to it was
added HMPA (0.276 mL, 1.59 mmol) followed by aldehyde 31
(350 mg, 1.32 mmol) in THF (10 mL). After stirring for 30 min at
–78 °C the reaction mixture was warmed to room temperature and
stirred for an additional 1 h. The reaction mixture was diluted with
hexane (10 mL), filtered through Celite, concentrated in vacuo, and
purified by silica gel column chromatography (5% EtOAc/hexane)
to afford vinyl iodide 32 (405 mg, 79%). [α]2D5 = +84.6 (c = 0.9,
CHCl ). IR (KBr): ν = 2960, 2362, 1646, 1615, 1395, 1248, 1078,
˜
3
(2R,3S,4S,Z)-3-(4-Methoxybenzyloxy)-2,4-dimethylocta-5,7-dienal
(4): A solution of alcohol 34 (100 mg, 0.34 mmol) in CH2Cl2
(5 mL) was added to a suspension of Dess–Martin periodinane
(219 mg, 0.51 mmol) and NaHCO3 (86 mg, 1.03 mmol) in CH2Cl2
(10 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. It
was then diluted with CH2Cl2 (10 mL) and washed with saturated
aqueous NaHCO3 (3ϫ10 mL). The combined organic layers were
dried with Na2SO4, evaporated in vacuo, and purified by silica gel
column chromatography (10% EtOAc/hexane) to afford aldehyde
4 as a slightly yellow oil (90 mg, 91%). [α]2D5 = +31.5 (c = 0.65,
1024 cm–1. H NMR (300 MHz, CDCl3): δ = 7.42 (d, J = 8.7 Hz,
1
2 H, Ph-H), 6.88 (d, J = 8.8 Hz, 2 H, Ph-H), 6.22 (d, J = 7.4 Hz,
1 H, 6-H), 6.15 (dd, J = 7.9, 7.4 Hz, 1 H, 5-H), 5.42 (s, 1 H, Ph-
CH), 4.09–4.04 (dd, J = 11.2, 2.4 Hz, 1 H, 1-H), 4.03–3.99 (dd, J
= 11.2, 1.5 Hz, 1 H, 1Ј-H), 3.80–3.75 (m, 4 H, Ph-OMe, 3-H), 2.83–
2.70 (m, 1 H, 4-H), 1.73–1.65 (m, 1 H, 2-H), 1.22 (d, J = 6.9 Hz,
3 H, 2Ј-Me), 0.99 (d, J = 6.9 Hz, 3 H, 4Ј-Me) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 159.7, 144.0, 131.3, 127.2, 113.4, 101.4, 82.6,
82.1, 73.8, 55.2, 41.4, 30.1, 14.5, 11.2 ppm. MS (EI): m/z = 389.0
[M + H]+. HRMS: calcd. for C16H21IO3 [M + Na]+ 411.1535;
found 411.1546.
CHCl ). IR (KBr): ν = 2925, 2854, 1709, 1610, 1512, 1252, 1032,
˜
3
758 cm–1. H NMR (CDCl3, 300 MHz): δ = 9.69 (d, J = 1.13 Hz,
1
(4S,5S)-4-[(S,Z)-Hexa-3,5-dien-2-yl]-2-(4-methoxyphenyl)-5-methyl-
1,3-dioxane (33): Bis(acetonitrile)palladium(II) chloride (33 mg,
0.12 mmol) followed by vinyltributyltin (0.282 mL, 0.96 mmol)
were added to a degassed and stirred solution of vinyl iodide 32
(250 mg, 0.64 mmol) in dry DMF (4 mL) and the reaction mixture
was stirred at room temperature for 3 h. The reaction mixture was
quenched with water (15 mL) and extracted with diethyl ether
(3ϫ15 mL). The combined organic layers were dried with Na2SO4,
evaporated under reduced pressure, and purified by silica gel col-
umn chromatography (l5 % EtOAc/hexane) to afford the diene
(175 mg, 95%) as an oily colorless liquid. [α]2D5 = –26.8 (c = 0.55,
1 H, CHO), 7.23 (d, J = 8.7 Hz, 2 H, Ph-H), 6.87 (d, J = 8.7 Hz,
2 H, Ph-H), 6.55 (ddd, J = 16.8, 10.9, 0.9 Hz, 1 H, 7-H), 6.04 (t, J
= 10.9 Hz, 1 H, 6-H), 5.44 (t, J = 10.5 Hz, 1 H, 5-H), 5.23 (dd, J
= 16.8, 1.8 Hz, 1 H, 8-H), 5.12 (d, J = 10.2 Hz, 1 H, 8Ј-H), 4.50
(d, J = 10.7 Hz, 1 H, Ph-CH), 4.44 (d, J = 10.7 Hz, 1 H, Ph-CH),
3.79 (s, 3 H, Ph-OMe), 3.70 (t, J = 5.0 Hz, 1 H, 3-H), 3.02–2.90
(m, 1 H, 4-H), 2.63–2.54 (ddq, J = 6.9, 5.0, 1.1 Hz, 1 H, 2-H), 1.17
(d, J = 6.9 Hz, 3 H, 4Ј-Me), 1.07 (d, J = 6.9 Hz, 3 H, 2Ј-Me) ppm.
13C NMR (CDCl3, 75 MHz): δ = 204.1, 159.2, 133.7, 132.1, 130.3,
130.1, 129.4, 118.0, 113.7, 81.9, 73.5, 55.2, 49.4, 35.5, 18.2,
9.1 ppm. MS (EI): m/z = 311.0 [M + Na]+. HRMS: calcd. for
C18H24O3Na [M + Na]+ 311.1623; found 311.1631.
CHCl ). IR (KBr): ν = 2963, 2933, 2876, 1690, 1614, 1517, 1250,
˜
3
1031 cm–1. H NMR (300 MHz, CDCl3): δ = 7.38 (d, J = 8.8 Hz,
1
2 H, Ph-H), 6.85 (d, J = 8.8 Hz, 2 H, Ph-H), 6.70 (dt, J = 16.9,
10.7 Hz, 1 H, 7-H), 6.07 (t, J = 10.7 Hz, 1 H, 6-H), 5.42 (s, 1 H,
Ph-CH), 5.39 (t, J = 10.1 Hz, 1 H, 5-H), 5.20 (d, J = 16.9 Hz, 1 H,
8-H), 5.10 (d, J = 10.2 Hz, 1 H, 8Ј-H), 4.08 (m, 2 H, 1-H), 3.78 (s,
3 H, Ph-OMe), 3.60 (dd, J = 9.4, 1.8 Hz, 1 H, 3-H), 2.90 (m, 1 H,
Acknowledgments
We thank the University Grants Commission (UGC), New Delhi,
4-H), 1.71 (m, 1 H, 2-H), 1.20 (d, J = 6.7 Hz, 3 H, 2Ј-Me), 0.97 (d, India, for the award of a fellowship to V. R.
Eur. J. Org. Chem. 2010, 2148–2156
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2155

J. S. Yadav, V. Rajender
FULL PAPER
J. Jagel, M. E. Maier, Synlett 2006, 693–696; f) C. Monti, O.
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Received: December 12, 2009
Published Online: February 22, 2010
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