Towards the synthesis of (-)-callipeltoside A: Stereoselective synthesis of the C1-C14 macrolactone core

Article abstract of DOI:10.1002/ejoc.201101635

A highly stereoselective synthesis of the C1-C14 macrolactone core of the cytotoxic macrolide (-)-callipeltoside A has been achieved by utilizing an anti-selective aldol reaction and Wittig olefination to introduce an (E)-trisubstituted alkene, chemoselec

Full text of DOI:10.1002/ejoc.201101635

FULL PAPER
DOI: 10.1002/ejoc.201101635
Towards the Synthesis of (–)-Callipeltoside A: Stereoselective Synthesis of the
C1–C14 Macrolactone Core
Jhillu S. Yadav,*[a,b] Animesh Haldar,[a] and Tapas Maity[a]
Keywords: Natural products / Macrocycles / Aldol reactions / Enantioselectivity / Epoxidation / Wittig reactions / Lactones
A highly stereoselective synthesis of the C1–C14 macrolact-
one core of the cytotoxic macrolide (–)-callipeltoside A has
been achieved by utilizing an anti-selective aldol reaction
and Wittig olefination to introduce an (E)-trisubstituted alk-
ene, chemoselective diisobutylaluminum hydride (DIBAL-H)
reduction of the 2,3-epoxy tosylate to install the C13 stereo-
center, and intramolecular trapping of the acyl-ketene inter-
mediate by the C13 hydroxy group as key steps.
pects of callipeltoside A (Figure 1) were ascertained to be a
14-membered macrolactone linked glycosidically through
Introduction
In 1996, Minale and co-workers reported the isolation of C5 to a highly functionalized deoxyamino sugar, and a di-
three macrocyclic lactones, callipeltosides A–C, of the same enyne-trans-chlorocyclopropane chain appended at C13. An
aglycon skeleton appended with dissimilar sugar subunits, encapsulated six-membered hemiketal pyran ring, an (E)-
from the shallow-water lithistid sponge callipelta sp, col- trisubstituted olefin, and a dipropionate backbone con-
lected off the east coast of New Caledonia.[1] In preliminary sisting of five contiguous stereocenters with a total of seven
biological investigations of (–)-callipeltoside A (1) it was stereocenters are among the notable features of the macro-
found to inhibit in vitro proliferation of P388 cells (IC50
=
lactone core of callipeltoside A (Figure 1). The low natural
15.26 μg/mL) and NSCLC-N6 human bronchopulmunary abundance, incomplete biological evaluation, initial stereo-
non-small-cell-lung carcinoma (IC50 = 11.26 μg/mL). The chemical ambiguities, integrated with challenging molecular
results indicate that this activity is cell-cycle-dependent, architecture attracted and prompted the synthetic com-
blocking cell proliferation in the G1 phase and thereby es- munity to produce a number of successful synthetic efforts
tablishing callipeltoside A (1) as an interesting mechanism- toward callipeltoside A.[2] In a continuation of the synthesis
based lead.[1] Further biological evaluation was restricted of complex natural products, we herein disclose our stereo-
owing to the low natural abundance of callipeltoside A (ob- selective synthesis of the C1–C14 macrolactone core seg-
tained in 1.4ϫ10–4 % yield).[1] The appealing structural as- ment 2 of callipeltoside A.
Figure 1. Structures of (–)-callipelltoside A (1) and the C1–C14 macrolactone core 2 of callipeltoside A.
Retrosynthetic analysis, summarized in Figure 2, in-
volved cleavage of the hemiketal pyran portion at the C4–
C5 bond as well as the ester linkage of macrolactone 2 to
give aldehyde 3, bearing five stereogenic centers with an
(E)-trisubstituted olefin and dienyl silyl ether 4. Aldehyde 3
could be obtained from chemoselective reduction of 2,3-
epoxy tosylate 5, which, in turn, could be derived from alde-
[a] Natural Products Chemistry Division, CSIR – Indian Institute
of Chemical Technology,
Hyderabad 500007, India
E-mail: yadavpub@iict.res.in
[b] Bee Research Chair, College of Food and Agriculture Science,
King Saud University,
Riyadh, Saudi Arabia
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101635.
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Synthesis of the C1–C14 Core of (–)-Callipeltoside A
Figure 2. Retrosynthetic analysis of 2.
hyde 6 through Wittig reactions and Katsuki–Sharpless
asymmetric epoxidation to install the (E)-trisubstituted ole-
fin and the requisite stereochemistry at the C13 stereocen-
ter. As outlined in Figure 2, the C8 and C9 stereocenters in
aldehyde 6 could be established through a magnesium hal-
ide catalyzed aldol reaction, and C6 and C7 through epox-
ide opening with Me2CuLi by starting from trans-cinnamal-
dehyde.
Results and Discussion
Synthesis of Aldehyde 6
The synthesis began with an aldol reaction between chi-
ral N-acylthiazolidinethiones and trans-cinnamaldehyde (8)
[3]
in the presence of MgBr2·OEt2 as catalyst to afford the
known anti-aldol adduct 9 (Scheme 1).
Reduction of
9 with diisobutylaluminum hydride
(DIBAL-H) (2.5 equiv.) at –78 °C in tetrahydrofuran (THF)
furnished the corresponding aldehyde.[4] The following Wit-
tig olefination reaction with Ph3P=CHCO2Et in benzene
afforded α,β-unsaturated ester 10 (65% yield over two
steps). The allylic hydroxy group present in 10 was con-
verted into its methyl ether with Ag2O and MeI to obtain
11 in quantitative yield. Reduction of ester 11 with DIBAL-
H in THF furnished allyl alcohol 12 (98%), which was then
subjected to Katsuki–Sharpless asymmetric epoxidation[5]
reaction conditions to obtain α-epoxy alcohol 7 (α/β Ն
24:1) in 92% yield. Epoxide opening proceeded smoothly
with high regioselectivity after treatment of α-epoxy alcohol
7 with Me2CuLi[6] to give diol 13 in good yield; the latter
compound possesses anti-syn-anti stereochemistry concern-
Scheme 1. Reagents and conditions: (a) DIBAL-H, THF, –78 °C,
20 min; (b) Ph3P=CHCO2Et, benzene, 80 °C, 4 h, 2 steps, 65%; (c)
Ag2O, CH3I, 40 °C, 36 h, quantitative; (d) DIBAL-H, THF, 0 °C,
30 min, 98%; (e) Ti(OiPr)4, (+)-l-DIPT, TBHP, MS (4 Å), CH2Cl2,
–23 °C, 18 h, 92%; (f) Me2CuLi, Et2O, –45 °C, 90 min, 80%; (g)
TBDPSCl, imidazole, DMAP, CH2Cl2, –5 °C, 1 h, 94%; (h)
ing the four contiguous stereocenters. The assignments of TBSOTf, 2,6-lutidine, CH2Cl2, 30 min, –50 °C, 96%; (i) OsO4,
NMO, THF/acetone, pH 7 buffer, room temp., 14 h, then NaIO4,
THF, pH 7 buffer, room temp., 3 h.
the stereocenters of diol 13 were further supported by its
X-ray crystal structure (Scheme 1).[7] Diol 13 was then
transformed into aldehyde 6 by a three-step, high-yielding
reaction sequence (Scheme 1). Selective protection of the (DMAP) at –5 °C afforded compound 14 in 94% yield. The
primary alcohol functionality as its TBDPS ether with secondary alcohol functionality of 14 was then protected as
TBDPSCl, imidazole, and 4-(dimethylamino)pyridine its TBS ether with tert-butyldimethylsilyl trifluoromethane-
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J. S. Yadav, A. Haldar, T. Maity
FULL PAPER
sulfonate (TBSOTf) and 2,6-lutidine to obtain 15 (96%); Ph3P=CH2CO2Et, resulted in the formation of (2E,4E)-di-
subsequent oxidative cleavage of the double bond present enyl ester 18 [(2E)/(2Z) Ն 5:1, as an inseparable mixture] in
in 15 under standard reaction conditions [OsO4, N-methyl- 93% yield from 17. Reduction of 18 with DIBAL-H af-
morpholine N-oxide (NMO), then NaIO4] furnished alde- forded the corresponding (2E,4E)-dienyl allylic alcohol 19
hyde 6 as an unpurified mixture with coproduct benzalde- (81%), which was easily purified by silica gel column
hyde.
chromatography as a single isomer.
Dienyl allylic alcohol 19 was subjected to Katsuki–
Sharpless asymmetric epoxidation[5] [with near stoichiomet-
ric amounts of Ti(OiPr)4 and l-(+)-DIPT] reaction condi-
tions to afford β-epoxy alcohol 20 (α/βՆ1:52) in 89% yield.
Epoxy alcohol 20 was derivatized as the corresponding 2,3-
epoxy tosylate 5 with TsCl and Et3N in 94% yield. The
key reduction step of 5 with DIBAL-H (3 equiv.) occurred
chemoselectively in CH2Cl2 at –40 °C to furnish the requi-
site 1-tosyloxy-2-alkanol 21 in excellent yield and selecti-
vity.[9] Formation of the terminal epoxide 22 proceeded
smoothly after treatment of 21 with NaH in THF (97%).
The terminal epoxide 22 was transformed into one-carbon-
homologated allylic alcohol 23 in 92% yield by treatment
with an excess of dimethylsulfonium methylide.[10] Having
all the requisite stereogenic centers in place, we employed
the remaining synthetic operations to arrive at aldehyde 3
from the terminal olefin 23. Protection of the allylic hy-
droxy group in 23 as its TBS ether to afford 24 in 95%
yield and subsequent selective deprotection of the primary
TBDPS ether present in 24 with NH4F in methanol at
50 °C furnished 25 in 89% yield. The primary alcohol 25
was smoothly converted into aldehyde 3 under Dess–Mar-
tin periodinane oxidation conditions.[11]
Synthesis of Aldehyde 3
With the C5–C10 dipropionate chain in hand, we focused
on the conversion of 6 into the C5–C14 segment 3
(Scheme 2). Freshly prepared, unpurified aldehyde 6 was
first converted into α,β-unsaturated ester 16 by a Wittig re-
action with Ph3P=C(CH3)CO2Et in toluene (91% overall
yield from 15) to install the requisite (E)-trisubstituted alk-
ene with complete control over the geometry of the double
bond. DIBAL-H mediated reduction of ester 16 in THF
furnished trisubstituted allylic alcohol 17 (98%), which,
upon Swern oxidation[8] followed by Wittig olefination with
Synthesis of the C1–C14 Segment of (–)-Callipeltoside A
With aldehyde 3 in hand, we proceeded to install the C5
stereogenic center along with the requisite carbon–oxygen
framework to construct the 14-membered macrolactone 2
embedded with the hemiketal pyran ring. As illustrated in
Scheme 3, by employing a diastereoselective aldol addition
from the C5–C14 aldehyde segment 3 and dienyl silyl ether
4 afforded Felkin–Anh-type adduct 26 as the only product
in 85% yield from 25.[12]
The resultant hydroxy group in 26 was protected as its
MOM ether by using standard conditions to obtain 27. At
this juncture, initially we decided to adopt the Hoye[2i] pro-
tocol for dual macrolactonization/pyran-hemiketal forma-
tion via acyl-ketenes. Several efforts to liberate both C7 and
C13 hydroxy groups from 27 were found to be unsuccessful
with HF·Py in MeOH, Et3N·3HF in CH3CN, and TASF in
N,N-dimethylformamide (DMF)/H2O. Use of these reac-
tion conditions liberated only the C13 hydroxy group, with
the C7 TBS ether remaining intact, giving the TBS-pro-
tected product 28 in excellent yield; as a result, the di-
hydroxy dioxinone precursor for the Hoye protocol could
not be attained. With compound 28 in hand, we designed
our synthetic operations in a stepwise fashion to implement
first Boeckman macrolactonization[13] via monohydroxy
acyl-ketene intermediate 29 and subsequent hemiketal py-
Scheme 2. Reagents and conditions: (a) Ph3P=C(CH3)CO2Et, tolu-
ene, 90 °C, 18 h, 91% from 15; (b) DIBAL-H, THF, 30 min, 98%;
(c) (1) (COCl)2, DMSO, Et3N, –78 °C, 90 min, (2)
Ph3P=CHCO2Et, benzene, 80 °C, 12 h, 2 steps, 93%; (d) DIBAL-
H, THF, 30 min, 81%; (e) Ti(OiPr)4, (+)-l-DIPT, TBHP, MS (4 Å),
CH2Cl2, –23 °C, 22 h, 89%; (f) TsCl, Et3N, DMAP, CH2Cl2, 18 h,
94%; (g) DIBAL-H (3 equiv.), CH2Cl2, –40 °C, 3 h, 91%; (h) NaH,
THF, 0 °C, 30 min, 97%; (i) Me3S+I–, nBuLi, THF, –10 °C to 0 °C
to room temp., 2 h, 92%; (j) TBSOTf, 2,6-lutidine, CH2Cl2, –50 °C,
30 min, 95%; (k) NH4F, MeOH, 50 °C, 4 h, 89%; (l) Dess–Martin
periodinane, pyridine, wet CH2Cl2, 2 h.
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Synthesis of the C1–C14 Core of (–)-Callipeltoside A
Figure 3. Tetrahydropyran/hemiketal ring stereochemistry of
macrolactone 2.
Conclusions
By utilizing high-yielding chemical transformations, we
have accomplished a highly convergent and stereoselective
linear synthesis of the macrolactone core segment of callip-
eltoside A, a potent cytotoxic macrolide. The notable
feature of the synthesis is the construction of the C5–C14
segment (aldehyde 3) consisting of five stereogenic centers
with an (E)-trisubstituted olefin in a highly concise and
stereoselective manner. The C8 and C9 stereocenters of the
dipropionate portion were introduced by employing the
Evans anti-aldol method. Katsuki–Sharpless asymmetric
epoxidation and regioselective epoxide opening with Me2-
CuLi installed the stereocenters at C6 and C7. A straight-
forward and useful access to the (E)-trisubstituted olefin
along with the C13 stereocenter has been illustrated ef-
ficiently through Wittig olefination and chemoselective DI-
BAL-H reduction of the 2,3-epoxy tosylate. The installation
of the C5 stereocenter and penultimate macrolactonization
were performed by a Mukaiyama aldol addition and intra-
molecular trapping of acyl-ketene intermediate by the pen-
dant secondary hydroxy group at C13.
Scheme 3. Reagents and conditions: (a) BF3·OEt2, CH2Cl2, –78 °C,
1 h, 85% from 25; (b) MOMCl, iPr2EtN, CH2Cl2, 0 °C, 90 min,
97%; (c) HF·Py, MeOH, 0 °C to room temp., 6 h, quantitative; (d)
toluene, 110 °C, 1 h, 84%; (e) HF·Py, MeOH, 0 °C, 2 h, 96%.
ran formation as elaborated in Trost’s[2d] synthesis of this
natural product. Thus, heating of a dilute solution of hy-
droxy dioxinone 28 in refluxing toluene induced the loss of
acetone through thermal decomposition to evolve the acyl-
ketene intermediate 29, which was then trapped intramolec-
ularly by the pendant secondary hydroxy group at C13 to
generate the 14-membered lactone 30 in an impressive yield
of 84%. The final synthetic operation was carried out by
using HF·Py in methanol to transform the macrolacone 30
into the C1–C14 segment 2 of (–)-callipeltoside A by re-
moval of the silyl protecting group through in situ partici-
pation of the free hydroxy group at C7 and the carbonyl
functionality at C3 to form the requisite tetrahydropyran/
hemiketal ring.[2b]
Experimental Section
General Methods: All reactions requiring anhydrous conditions
were conducted in flame-dried glass apparatus under nitrogen.
THF and Et2O were freshly distilled from sodium benzophenone
ketyl prior to use. CH2Cl2 was freshly distilled from CaH2; toluene
and benzene were dried azeotropically by using a Dean–Stark ap-
paratus. Anhydrous methanol was obtained by distillation from
1
Compound 2 was extensively characterized by using H
NMR spectroscopy. Analysis of the 1H NMR coupling con-
stants (Figure 3) of the tetrahydropyran/hemiketal ring pro- magnesium alkoxide and stored under nitrogen over activated 4 Å
molecular sieves. Reactions were monitored by TLC analysis using
silica plates with fluorescent indicator (254 nm). All commercially
available reagents were purchased and typically used as supplied.
1H and 13C NMR spectra were recorded in Fourier transform mode
at the field strength specified (300, 400, 500, or 600 MHz for 1H
and 75 or 150 MHz for 13C). Chemical shifts (δ) are reported in
ppm referenced to CDCl3 (δ = 7.26 ppm) or C6D6 (δ = 7.16 ppm)
tons, specifically the large coupling constants JHb/Hc
=
11.0 Hz, JHc/Hd = 10.5 Hz, JHe/Hd = 10.3 Hz, together with
the small coupling constant JHa/Hc = 4.7 Hz unambiguously
established that Hb, Hc, Hd and He are all axially disposed
in a six-membered ring. Hence, we have illustrated a
straightforward and highly stereoselective approach to com-
plete the synthesis of the C1–C14 segment 2 of (–)-callipel-
toside A through acyclic stereocontrol in 26 steps (longest
linear sequence) with 11% overall yield from the known
intermediate 9.
1
for H and CDCl3 (δ = 77.16 ppm) or C6D6 (δ = 128.06 ppm) for
13C. Data are reported as follows: chemical shift, multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br. =
broad, ABq = AB quartet), coupling constant (Hz), and integra-
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J. S. Yadav, A. Haldar, T. Maity
FULL PAPER
tion. Ratios of diastereomers (dr) were obtained from 1H NMR
(300 MHz) spectra obtained with a signal/noise ratio Ͼ 200:1. In-
frared spectra were recorded with an FTIR instrument, and the
values are reported in terms of frequency of absorption (cm–1).
Melting points were recorded with an uncorrected melting point
instrument. Optical rotations were measured with a polarimeter
fitted with a sodium lamp (589 nm, D-line) by using a 1 dm, 1 mL
quartz sample cell and are reported as [α]D (concentration in g/
100 mL solvent). For high-resolution mass spectra (HRMS), ion
mass/charge (m/z) ratios are reported as values in atomic mass
units.
15.8, 14.4 ppm. HRMS (ESI): calcd. for C17H22O3Na+ [M + Na]+
297.1466; found 297.1461.
{(2S,3S)-3-[(1R,2R,3E)-2-Methoxy-1-methyl-4-phenyl-3-butenyl]-
oxiran-2-yl}methanol (12): To a stirred solution of α,β-unsaturated
ester 11 (1.10 g, 4.0 mmol) in THF (25 mL) was added DIBAL-H
(1.5 m in toluene, 5.9 mL, 8.8 mmol) at 0 °C. After stirring for
30 min, the reaction was quenched with saturated aqueous potas-
sium sodium tartrate (20 mL). The heterogeneous mixture was
warmed to room temperature and stirred vigorously for 2 h. The
organic layer was washed with brine (10 mL), and the aqueous
layer was back-extracted with Et2O (3ϫ20 mL). The combined or-
ganic layers were dried with Na2SO4 and concentrated. The crude
product was purified by flash chromatography (SiO2; ethyl acetate/
hexane, 20%) to furnish allylic alcohol 12 (910 mg, 98%) as a col-
Ethyl (2E,4S,5R,6E)-5-Hydroxy-4-methyl-7-phenyl-2,6-heptadieno-
ate (10): To a stirred solution of aldol adduct 9 (2.2 g, 5.54 mmol)
in THF (100 mL), DIBAL-H (1.5 m in toluene, 9.23 mL,
13.85 mmol) was added dropwise at –78 °C by using a syringe. The
reaction was monitored by TLC and quenched by the dropwise
addition of MeOH (1.5 mL). After warming to room temperature,
saturated aqueous sodium potassium tartrate (25 mL) was added,
and the mixture was stirred for 30 min. The mixture was poured
into brine (20 mL) and extracted with ethyl acetate (3ϫ50 mL).
The combined organic layers were dried with Na2SO4 and concen-
trated. The crude product was purified through a short plug of
silica gel (SiO2; ethyl acetate/hexane, 20–30%) to obtain the corre-
sponding aldehyde, which was immediately used for the next reac-
tion. A 100 mL round-bottomed flask fitted with a cold-finger con-
denser was charged with the above crude aldehyde [predried by
coevaporation from benzene (2ϫ10 mL)] and benzene (50 mL).
Ethyl triphenylphosphorylideneacetate (3.8 g, 11.0 mmol) was
added in a single portion, and the resulting suspension was heated
to 80 °C for 12 h. After being cooled to room temperature, the
reaction mixture was diluted with hexane, filtered, and concen-
trated to remove Ph3PO and unreacted ethyl triphenylphosphor-
ylideneacetate. The crude product was purified by flash chromatog-
raphy (SiO2; ethyl acetae/hexane, 15%) to afford α,β-unsaturated
ester 10 (936 mg, 65% from 9) as a colorless liquid. [α]2D7 = –22.6
orless liquid. [α]2D5 = –7.1 (c = 2.14, CHCl ). IR (neat): ν = 3423,
˜
3
2971, 2930, 1690, 1453, 1087, 972 cm–1
.
1H NMR (300 MHz,
CDCl3): δ = 7.40–7.15 (m, 5 H), 6.48 (d, J = 15.9 Hz, 1 H), 6.00
(dd, J = 15.9, 8.1 Hz, 1 H), 5.76–5.58 (m, 2 H), 4.09 (dd, J = 4.5,
0.9 Hz, 2 H), 3.49 (ddd, J = 8.1, 6.0, 0.9 Hz, 1 H), 3.28 (s, 3 H),
2.41 (m, 1 H), 1.47-1.33 (br. m, 1 H), 1.03 (d, J = 6.9 Hz, 3 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 136.6, 134.8, 133.5, 129.5,
128.7, 128.4, 127.9, 126.6, 86.6, 63.8, 56.7, 41.5, 16.5 ppm. HRMS
(ESI): calcd. for C15H20O2Na+ [M + Na]+ 255.1360; found
255.1356.
{(2S,3S)-3-[(1R,2R,3E)-2-Methoxy-1-methyl-4-phenyl-3-butenyl]-
oxiran-2-yl}methanol (7): To a stirred suspension of activated pow-
dered 4 Å molecular sieves (1.40 g) in CH2Cl2 (30 mL), was added
titanium(IV) isopropoxide (0.42 mL, 1.43 mmol) followed by (+)-
l-diisopropyl tartrate (0.30 mL, 1.43 mmol) at –23 °C. After stir-
ring for 10 min, a solution of allylic alcohol 12 (1.66 g, 7.15 mmol)
in CH2Cl2 (15 mL) was added to the reaction mixture. After stir-
ring for 30 min, tert-butyl hydroperoxide (TBHP; 2 m in toluene,
8.6 mL, 17.1 mmol) was added, and the mixture was stirred at
–23 °C for 18 h. The reaction was then quenched with water
(20 mL) and 30% NaOH solution saturated with aqueous NaCl
(20 mL). The mixture was stirred vigorously at room temperature
for 2 h, then the reaction mixture was filtered through a plug of
Celite, and the organic layer was separated. The aqueous layer was
extracted with CH2Cl2 (3ϫ30 mL). The combined organic layers
were washed with brine (50 mL), dried with Na2SO4, and concen-
trated. The crude product was purified by column chromatography
(SiO2; ethyl acetate/hexane, 25%) to furnish epoxy alcohol 7 (α/β
Ն 24:1, 1.63 g, 92%) as a colorless liquid. [α]2D5 = –44.5 (c = 2.24,
(c = 1.88, CHCl ). IR (neat): ν = 3447, 2974, 1709, 1651, 1369,
˜
3
1272, 1180, 1029, 970 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.42–
7.17 (m, 5 H), 6.96 (dd, J = 15.9, 7.8 Hz, 1 H), 6.58 (d, J = 15.9 Hz,
1 H), 6.15 (dd, J = 15.9, 6.9 Hz, 1 H), 5.87 (dd, J = 15.9, 1.2 Hz,
1 H), 4.18 (q, J = 7.2 Hz, 2 H), 4.17 (m, 1 H), 2.54 (m, 1 H), 1.63–
1.56 (br. s, 1 H), 1.30 (t, J = 7.2 Hz, 3 H), 1.12 (d, J = 6.9 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.7, 150.3, 136.5,
132.3, 129.8, 128.7, 128.0, 126.7, 122.4, 76.2, 60.5, 43.1, 15.7,
14.3 ppm. HRMS (ESI): calcd. for C16H20O3Na+ [M + Na]+
283.1310; found 283.1309.
CHCl ). IR (neat): ν = 3629, 2925, 2854, 1463, 1253, 1087,
˜
3
833 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.42–7.16 (m, 5 H),
6.52 (d, J = 15.9 Hz, 1 H), 5.99 (dd, J = 15.9, 8.1 Hz, 1 H), 3.84
(dt, J = 12.3, 3.9 Hz, 1 H), 3.64 (dd, J = 6.3, 3.9 Hz 1 H), 3.56
(ddd, J = 8.1, 7.5, 0.6 Hz, 1 H), 3.30 (s, 3 H), 2.98 (dt, J = 4.2,
2.4 Hz, 1 H), 2.91 (dd, J = 7.2, 2.4 Hz, 1 H), 1.73 (m, 1 H), 1.57
(m, 1 H), 1.01 (d, J = 6.9 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 136.4, 133.8, 128.8, 128.2, 128.0, 126.6, 85.2, 62.0,
59.1, 58.3, 56.7, 41.0, 13.4 ppm. HRMS (ESI): calcd. for
C15H20O3Na+ [M + Na]+ 271.1310; found 271.1299.
Ethyl (2E,4S,5R,6E)-5-Methoxy-4-methyl-7-phenyl-2,6-heptadieno-
ate (11): A 50 mL round-bottomed flask fitted with a cold-finger
condenser was charged with free hydroxy compound 10 (690 mg,
2.65 mmol) and MeI (30 mL). Ag2O (1.84 g, 7.95 mmol) was added
in a single portion, and the resulting suspension was heated to
50 °C whilst stirring in the dark for 36 h. After being cooled to
room temperature, the reaction mixture was filtered and concen-
trated. The product was purified by flash chromatography (SiO2;
ethyl acetate/hexane, 10%) to afford methyl ether 11 (726 mg,
quantitative) as a yellow liquid. [α]2D5 = –11.5 (c = 2.22, CHCl3). IR
(2R,3R,4S,5R,6E)-5-Methoxy-2,4-dimethyl-7-phenyl-6-heptene-1,3-
(neat): ν = 2979, 2933, 1719, 1652, 1452, 1368, 1266, 1180, 1090, diol (13): To a stirred solution of Me2CuLi [prepared from CuI
˜
1037, 973 cm–1. H NMR (300 MHz, CDCl3): δ = 7.40–7.17 (m, 5
H), 6.96 (dd, J = 15.9, 7.8 Hz, 1 H), 6.51 (d, J = 15.9 Hz, 1 H),
5.98 (dd, J = 15.9, 8.4 Hz, 1 H), 5.81 (dd, J = 15.9, 1.2 Hz, 1 H),
4.18 (q, J = 7.2 Hz, 2 H), 3.56 (ddd, J = 8.4, 6.6, 0.9 Hz, 1 H), 3.28
(2.66 g, 14 mmol) and MeLi (1.4 m in Et2O, 20 mL, 28 mmol) in
Et2O (30 mL) at –23 °C] was added a solution of epoxy alcohol 7
(694 mg, 2.8 mmol) in Et2O (10 mL) at –45 °C. After stirring for
90 min, the reaction mixture was quenched with a mixture of satu-
1
(s, 3 H), 2.55 (m, 1 H), 1.30 (t, J = 7.2 Hz, 3 H), 1.08 (d, J = rated NH4Cl and 28% aqueous NH3 (2:1, 25 mL). The organic
6.9 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.8, 151.0,
layer was separated, and the aqueous layers were extracted with
136.4, 134.2, 128.8, 128.0, 127.9, 126.7, 121.5, 86.0, 60.4, 56.8, 41.8,
CH2Cl2 (3ϫ15 mL). The combined organic layers were dried with
2066
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2062–2071

Synthesis of the C1–C14 Core of (–)-Callipeltoside A
Na2SO4 and concentrated. The residue was dissolved in 60% aque-
ous acetonitrile (25 mL) followed by slow addition of NaIO4 (1.2 g,
5.6 mmol) at 0 °C. After stirring at room temperature for 1 h,
acetonitrile was removed under reduced pressure, and the aqueous
layer was extracted with CH2Cl2 (3ϫ20 mL). The combined or-
ganic layers were washed with brine (40 mL), dried with Na2SO4,
and concentrated. The crude product was purified by column
chromatography (SiO2; ethyl acetate/hexane, 40%) to afford diol 13
(591 mg, 80%) as a solid, which, upon crystallization from ethyl
acetate/hexane, gave colorless crystals. M.p. 64–65 °C. [α]2D6 = –6.5
1 3 . 9 , 1 0 . 8 , – 3 . 8 , – 4 . 0 p p m . H R M S ( E S I ) : c a l c d . fo r
C38H56O3NaSi2 [M + Na]+ 639.3665; found 639.3636.
+
Ethyl (E,4R,5R,6R,7R)-6-[(tert-Butyldimethylsilyl)oxy]-8-[(tert-
butyldiphenylsilyl)oxy]-4-methoxy-2,5,7-trimethyl-2-octenoate (16):
To a stirred solution of 15 (387 mg, 0.63 mmol) in THF (3 mL),
acetone (3 mL) and pH 7 buffer (3 mL), was added NMO (105 mg,
0.9 mmol) and OsO4 (0.2 m in toluene, 96 μL, 0.019 mmol). The
mixture was stirred at room temperature for 14 h, then diluted with
ethyl acetate (30 mL). The reaction mixture was cooled to 0 °C,
and saturated aqueous NaHSO3 (6 mL) was added. The ice bath
was removed, and the mixture was stirred for an additional 30 min
and extracted with ethyl acetate (3ϫ30 mL). The combined or-
ganic layers were washed with brine (50 mL), dried with Na2SO4,
and concentrated. The crude diol was used for the next reaction
without further purification. A stirred biphasic solution of the
crude diol in THF (8 mL) and pH 7 buffer (4 mL) was treated with
NaIO4 (270 mg, 1.26 mmol) and stirred at 23 °C for 3 h. The reac-
tion mixture was diluted with Et2O (30 mL) and filtered through a
plug of Celite. The filtrate was washed with saturated aqueous
NaHCO3 (20 mL), then dried with Na2SO4 and concentrated to
(c = 1.35, CHCl ). IR (KBr): ν = 3338, 2925, 2854, 1450, 1384,
˜
3
1
1079, 975 cm–1. H NMR (300 MHz, CDCl3): δ = 7.40–7.18 (m, 5
H), 6.55 (d, J = 15.9 Hz, 1 H), 6.14 (dd, J = 15.9, 7.8 Hz, 1 H),
3.92 (dd, J = 9.6, 1.5 Hz, 1 H), 3.79 (ddd, J = 7.8, 4.8, 0.6 Hz, 1
H), 3.69-3.52 (m, 2 H), 3.49-3.37 (br. m, 2 H), 3.35 (s, 3 H), 1.93–
1.71 (m, 2 H), 1.04 (d, J = 7.1 Hz, 3 H), 0.72 (d, J = 6.9 Hz, 3 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 136.4, 133.3, 128.7, 128.5,
127.9, 126.6, 86.6, 76.6, 69.1, 57.3, 40.0, 37.4, 13.4, 10.3 ppm.
HRMS (ESI): calcd. for C16H24O3Na+ [M + Na]+ 287.1623; found
287.1616.
(2R,3R,4S,5R,6E)-1-[(tert-Butyldiphenylsilyl)oxy]-5-methoxy-2,4-di- give crude aldehyde 6 as an inseparable mixture with coproduct
methyl-7-phenyl-6-hepten-3-ol (14): To a stirred solution of the diol
13 (219 mg, 0.83 mmol) in CH2Cl2 (8 mL), was added imidazole
(75 mg, 1.08 mmol), tert-butyldiphenylsilyl chloride (TBDPSCl;
0.24 mL, 0.90 mmol) and 4-(dimethylamino)pyridine (DMAP;
catalytic) at –5 °C, and stirring was continued for 1 h. The reaction
mixture was partitioned between CH2Cl2 (20 mL) and H2O
(10 mL), and the organic layer was washed with brine (10 mL),
dried with Na2SO4, and concentrated. The crude product was puri-
fied by flash chromatography (SiO2; ethyl acetate/hexane, 10%) to
obtain alcohol 14 (390 mg, 94%) as a white solid. M.p. 72–73 °C.
benzaldehyde. The crude aldehyde 6 was directly used for the Wittig
reaction. A 50 mL round-bottomed flask fitted with a cold-finger
condenser was charged with crude aldehyde 6 [predried by coevapo-
ration from benzene (2ϫ8 mL)] and toluene (25 mL). [1-(Ethoxy-
carbonyl)ethylidene]triphenylphosphorane (1.14 g, 3.15 mmol) was
added in a single portion, and the resulting suspension was heated
to vigorous reflux for 18 h. After having been cooled to room tem-
perature, the reaction mixture was diluted with hexane, filtered, and
concentrated to remove Ph3PO and unreacted [1-(ethoxycarbonyl)-
ethylidene]triphenylphosphorane. The crude product was purified
by column chromatography (SiO2; ethyl acetate/hexane, 6%) to ob-
tain α,β-unsaturated ester 16 (360 mg, 91% from 15) as a yellow
[α]2D5 = –20.2 (c = 2.17, CHCl ). IR (KBr): ν = 3505, 2959, 2929,
˜
3
2857, 1462, 1428, 1112, 1086, 969, 822 cm–1. H NMR (300 MHz,
1
CDCl3): δ = 7.73–7.64 (m, 4 H), 7.45–7.17 (m, 11 H), 6.54 (d, J =
liquid. [α]2D5 = +14.4 (c = 1.35, CHCl ). IR (neat): ν = 2929, 2857,
˜
3
15.9 Hz, 1 H), 6.04 (dd, J = 15.9, 8.1 Hz, 1 H), 3.99 (dt, J = 9.6, 1715, 1650, 1465, 1385, 1258, 1225, 1106, 1080, 1029, 832 cm–1. 1H
1.8 Hz, 1 H), 3.79–3.70 (m, 3 H), 3.38 (br. d, J = 1.8 Hz, 1 H), 3.35 NMR (400 MHz, CDCl3): δ = 7.72–7.61 (m, 4 H), 7.44–7.31 (m, 6
(s, 3 H), 1.89–1.66 (m, 2 H), 1.07 (s, 9 H), 0.89 (d, J = 7.0 Hz, 3
H), 6.42 (dd, J = 10.0, 1.2 Hz, 1 H), 4.22 (q, J = 7.2 Hz, 2 H), 4.16
H), 0.77 (d, J = 6.9 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ (dd, J = 6.8, 1.0 Hz, 1 H), 3.81 (dd, J = 10.0, 9.6 Hz, 1 H), 3.72
= 136.8, 135.8, 134.9, 133.4, 129.9, 129.8, 129.5, 128.7, 127.9, 126.6,
84.9, 73.7, 69.3, 56.9, 40.1, 38.1, 27.0, 19.3, 13.4, 9.5 ppm. HRMS
(ESI): calcd. for C32H42O3NaSi+ [M + Na]+ 525.2800; found
525.2822.
(dd, J = 9.8, 5.6 Hz, 1 H), 3.36 (dd, J = 9.8, 7.8 Hz, 1 H), 3.18 (s,
3 H), 1.90 (m, 1 H), 1.87 (d, J = 0.8 Hz, 3 H), 1.74 (m, 1 H), 1.34
(t, J = 7.2 Hz, 3 H), 1.07 (s, 9 H), 0.92 (d, J = 6.9 Hz, 3 H), 0.83
(s, 9 H), 0.69 (d, J = 6.9 Hz, 3 H), 0.04 (s, 3 H), –0.11 (s, 3 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 167.9, 141.4, 135.8, 134.1,
131.7, 129.6, 127.7, 78.1, 71.0, 66.9, 60.9, 56.0, 41.7, 40.1, 27.0,
26.2, 19.4, 18.5, 14.4, 13.8, 13.4, 9.8, –3.8, –4.0 ppm. HRMS (ESI):
tert-Butyl{[(1R,2R,3R,4E)-1-{(1R)-2-[(tert-butyldiphenylsilyl)oxy]-
1-methylethyl}-3-methoxy-2-methyl-5-phenyl-4-pentenyl]oxy}di-
methylsilane (15): A stirred solution of alcohol 14 (595 mg,
1.18 mmol) in CH2Cl2 (15 mL) at –50 °C was treated with 2,6-lut-
calcd. for C36H58O5NaSi2 [M + Na]+ 649.3720; found 649.3700.
+
idine (0.27 mL, 2.36 mmol) and TBSOTf (0.41 mL, 1.77 mmol). (E,4R,5R,6R,7R)-6-[(tert-Butyldimethylsilyl)oxy]-8-[(tert-butyldi-
After 30 min, saturated NaHCO3 (10 mL) was added. The organic
layer was separated and the aqueous layer extracted with CH2Cl2
(3ϫ15 mL). The combined organic layers were dried with Na2SO4
and concentrated. The crude product was purified by flash column
chromatography (SiO2; ethyl acetate/hexane, 5%) to afford com-
pound 15 (698 mg, 96%) as a yellow liquid. [α]2D5 = +15.0 (c = 1.08,
phenylsilyl)oxy]-4-methoxy-2,5,7-trimethyl-2-octen-1-ol (17): To a
stirred solution of α,β-unsaturated ester 16 (334 mg, 0.534 mmol)
in THF (10 mL), was added DIBAL-H (1.5 m in toluene, 0.75 mL,
1.12 mmol) at 0 °C. After stirring for 30 min, the reaction was
quenched with saturated aqueous potassium sodium tartrate
(10 mL). The heterogeneous mixture was warmed to room tem-
perature and stirred vigorously for 2 h. The organic layer was sepa-
CHCl ). IR (neat): ν = 2956, 2929, 2857, 1461, 1388, 1252, 1106,
˜
3
1086, 1029, 968, 835 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.72– rated, and the aqueous layer was extracted with Et2O (3ϫ10 mL).
7.62 (m, 4 H), 7.44–7.17 (m, 11 H), 6.44 (d, J = 15.9 Hz, 1 H), 5.90 The combined organic layers were dried with Na2SO4 and concen-
(dd, J = 15.9, 8.7 Hz, 1 H), 4.14 (br. d, J = 6.3 Hz, 1 H), 3.76 (dd,
J = 9.6, 5.7 Hz, 1 H), 3.45 (dd, J = 9.0, 8.7 Hz, 1 H), 3.39 (dd, J
= 9.6, 7.5 Hz, 1 H), 3.23 (s, 3 H), 1.92 (m, 1 H), 1.78 (m, 1 H),
trated. The crude product was purified by chromatography (SiO2;
ethyl acetate/hexane, 15%) to furnish allylic alcohol 17 (306 mg,
98%) as a colorless liquid. [α]2D6 = –5.0 (c = 0.7, CHCl3). IR (neat):
1.08 (s, 9 H), 0.94 (d, J = 6.9 Hz, 3 H), 0.84 (s, 9 H), 0.77 (d, J = ν = 3429, 3070, 2959, 2931, 2856, 1681, 1463, 1428, 1384, 1111,
˜
1
6.9 Hz, 3 H), 0.03 (s, 3 H), –0.10 (s, 3 H) ppm. 13C NMR (75 MHz,
1006, 855 cm–1. H NMR (500 MHz, CDCl3): δ = 7.69–7.71 (m, 4
CDCl3): δ = 136.8, 135.9, 134.2, 133.8, 129.8, 129.6, 128.7, 127.8,
H), 7.42–7.31 (m, 6 H), 5.17 (dq, J = 9.5, 1.5 Hz, 1 H), 4.12 (dd,
127.7, 126.6, 84.2, 71.7, 66.9, 55.9, 41.8, 40.5, 27.1, 26.3, 19.4, 18.6, J = 7.0, 1.0 Hz, 1 H), 4.05 (s, 2 H), 3.74 (dd, J = 10.0, 5.5 Hz, 1
Eur. J. Org. Chem. 2012, 2062–2071
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2067

J. S. Yadav, A. Haldar, T. Maity
1465, 1428, 1386, 1254, 1108, 832 cm–1 1H NMR (300 MHz,
FULL PAPER
H), 3.72 (dd, J = 10.0, 9.5 Hz, 1 H), 3.35 (dd, J = 10.0, 7.9 Hz, 1
H), 3.15 (s, 3 H), 1.88 (m, 1 H), 1.70 (d, J = 1.0 Hz, 3 H), 1.64 (m,
1 H), 1.07 (s, 9 H), 0.92 (d, J = 6.9 Hz, 3 H), 0.82 (s, 9 H), 0.69 (d,
J = 6.9 Hz, 3 H), 0.04 (s, 3 H), –0.12 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 139.9, 135.9, 134.2, 129.6, 127.7, 125.7, 77.6,
71.5, 68.4, 67.0, 55.3, 41.7, 40.5, 27.0, 26.2, 19.4, 18.5, 14.6, 14.0,
.
CDCl3): δ = 7.72–7.60 (m, 4 H), 7.44–7.30 (m, 6 H), 6.30 (dtd, J
= 15.6, 1.5, 0.6 Hz, 1 H), 5.80 (dt, J = 15.6, 6.0 Hz, 1 H), 5.21 (dd,
J = 9.6, 0.9 Hz, 1 H), 4.21 (br. d, J = 6.0 Hz, 2 H), 4.12 (dd, J =
6.9, 1.2 Hz, 1 H), 3.81 (dd, J = 9.6, 9.6 Hz, 1 H), 3.75 (dd, J = 9.8,
5.6 Hz, 1 H), 3.36 (dd, J = 9.8, 7.9 Hz, 1 H), 3.15 (s, 3 H), 1.89
(m, 1 H), 1.80 (d, J = 0.9 Hz, 3 H), 1.66 (m, 1 H), 1.06 (s, 9 H),
0.93 (d, J = 6.9 Hz, 3 H), 0.83 (s, 9 H), 0.68 (d, J = 6.9 Hz, 3 H),
0.04 (s, 3 H), –0.12 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 137.0, 136.0, 135.9, 134.2, 133.3, 129.6, 127.7, 127.3, 77.9, 71.5,
67.0, 63.9, 55.5, 41.7, 40.7, 27.0, 26.2, 19.4, 18.5, 14.0, 13.4, 10.0,
+
10.0, –3.8, –4.0 ppm. HRMS (ESI): calcd. for C34H56O4NaSi2 [M
+ Na]+ 607.3614; found 607.3625.
Ethyl (2E,4E,6R,7R,8R,9R)-8-[(tert-Butyldimethylsilyl)oxy]-10-
[(tert-butyldiphenylsilyl)oxy]-6-methoxy-4,7,9-trimethyl-2,4-decadi-
enoate (18): A solution of anhydrous DMSO (0.12 mL, 1.64 mmol)
in CH2Cl2 (10 mL) was treated with oxalyl chloride (0.11 mL,
1.23 mmol) and stirred at –78 °C for 15 min. A solution of allylic
alcohol 17 (480 mg, 0.822 mmol) in CH2Cl2 (5 mL) was added
dropwise to the reaction mixture. The solution was stirred at –78 °C
for 30 min, Et3N (0.34 mL, 2.47 mmol) was added, and the cloudy
reaction mixture was warmed to 0 °C over 30 min and stirred at
0 °C for an additional 10 min. The white suspension was diluted
with pentane (100 mL), and the reaction mixture was filtered to
remove the majority of the Et3N salt. The filtrate was washed with
H2O (2ϫ15 mL), and the combined organic layers were washed
with saturated aqueous NaHCO3 (15 mL), dried with Na2SO4, and
concentrated. The crude aldehyde was directly used in the next re-
action without further purification. A 50 mL round-bottomed flask
fitted with a cold-finger condenser was charged with unpurified
aldehyde obtained from Swern oxidation [predried by coevapora-
tion from benzene (2ϫ10 mL)] and benzene (25 mL). Ethyl tri-
phenylphosphorylideneacetate (860 mg, 2.47 mmol) was added in a
single portion, and the resulting suspension was heated to 80 °C for
12 h. After having been cooled to room temperature, the reaction
mixture was diluted with hexane, filtered and concentrated to re-
move Ph3PO and unreacted ethyl triphenylphosphorylideneacetate.
The crude product was purified by column chromatography (SiO2;
ethyl acetate/hexane, 7%) to afford (2E,4E)-dienyl ester 18 [(2E)/
(2Z) Ն 5:1, 500 mg, 93%] as a yellow liquid. [α]2D5 = +19.9 (c =
+
–3.8, –4.0 ppm. HRMS (ESI): calcd. for C36H58O4NaSi2 [M +
Na]+ 633.3771; found 633.3766.
[(2S,3S)-3-{(E,3R,4R,5R,6R)-5-[(tert-Butyldimethylsilyl)oxy]-7-
[(tert-butyldiphenylsilyl)oxy]-3-methoxy-1,4,6-trimethyl-1-heptenyl}-
oxiran-2-yl]methanol (20): To a stirred suspension of powdered acti-
vated 4 Å molecular sieves (125 mg) in CH2Cl2 (10 mL), was added
titanium(IV) isopropoxide (0.11 mL, 0.35 mmol) followed by (+)-
l-diisopropyl tartrate (85 μL, 0.40 mmol) at –23 °C. After stirring
for 10 min, a solution of dienyl allylic alcohol 19 (385 mg,
0.625 mmol) in CH2Cl2 (5 mL) was added to the mixture. After
stirring for 30 min, tert-butyl hydroperoxide (2 m in toluene,
0.75 mL, 1.5 mmol) was added, and the mixture was stirred at
–23 °C for 22 h. The reaction was then quenched with water (5 mL)
and 30% NaOH solution saturated with aqueous NaCl (5 mL) and
stirred vigorously at room temperature for another 2 h. The reac-
tion mixture was filtered through a plug of Celite, and the organic
layer was separated. The aqueous layer was extracted with CH2Cl2
(3ϫ15 mL), and the combined organic layers were washed with
brine (25 mL), dried with Na2SO4, and concentrated. The crude
product was purified by column chromatography (SiO2; ethyl acet-
ate/hexane, 20 %) to furnish β-epoxy alcohol 20 (α/β Ն 1:52,
350 mg, 89%) as a colorless liquid. [α]2D5 = +1.1 (c = 2.98, CHCl3).
IR (neat): ν = 3428, 3070, 2931, 2857, 2891, 1655, 1465, 1428, 1386,
˜
1252, 1082, 1027, 834 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.71–
1.54, CHCl ). IR (neat): ν = 3069, 2931, 2857, 2893, 1715, 1624, 7.60 (m, 4 H), 7.44–7.29 (m, 6 H), 5.35 (d, J = 9.6 Hz, 1 H), 4.11
˜
3
1466, 1429, 1388, 1299, 1256, 1170, 1106, 1082, 1031, 836 cm–1. 1H
NMR (300 MHz, CDCl3): δ = 7.70–7.58 (m, 4 H), 7.43–7.28 (m, 7
H), 5.84 (d, J = 15.6 Hz, 1 H), 5.61 (d, J = 9.6 Hz, 1 H), 4.21 (q,
J = 7.0 Hz, 2 H), 4.14 (d, J = 6.8 Hz, 1 H), 3.84 (dd, J = 9.6,
9.6 Hz, 1 H), 3.72 (dd, J = 9.9, 5.7 Hz, 1 H), 3.36 (dd, J = 9.9,
7.8 Hz, 1 H), 3.15 (s, 3 H), 1.89 (m, 1 H), 1.83 (d, J = 0.9 Hz, 3
H), 1.69 (m, 1 H), 1.32 (t, J = 7.0 Hz, 3 H), 1.06 (s, 9 H), 0.91 (d,
(dd, J = 6.9, 0.9 Hz, 1 H), 3.96 (ddd, J = 13.2, 4.8, 2.7 Hz 1 H),
3.74 (dd, J = 9.6, 9.6 Hz, 1 H), 3.73 (dd, J = 9.9, 5.4 Hz, 1 H), 3.65
(dd, J = 7.5, 4.2 Hz, 1 H), 3.39 (br. d, J = 2.4 Hz, 1 H), 3.35 (dd,
J = 9.9, 7.8 Hz, 1 H), 3.15 (s, 3 H), 3.10 (dt, J = 3.9, 2.4 Hz, 1 H),
1.86 (m, 1 H), 1.66 (m, 1 H), 1.58 (d, J = 1.3 Hz, 3 H), 1.06 (s, 9
H), 0.92 (d, J = 6.9 Hz, 3 H), 0.82 (s, 9 H), 0.70 (d, J = 6.9 Hz, 3
H), 0.03 (s, 3 H), –0.12 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
J = 6.9 Hz, 3 H), 0.83 (s, 9 H), 0.68 (d, J = 6.9 Hz, 3 H), 0.04 (s, δ = 135.8, 135.6, 134.2, 130.2, 129.6, 127.7, 77.5, 71.4, 67.0, 61.6,
3 H), –0.11 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 167.4,
148.7, 141.3, 136.4, 135.8, 134.2, 129.6, 127.7, 117.7, 77.9, 71.2,
66.9, 60.5, 55.8, 41.7, 40.4, 27.0, 26.2, 19.4, 18.5, 14.5, 13.8, 13.2,
58.9, 57.8, 55.5, 41.7, 40.4, 27.0, 26.2, 19.4, 18.5, 13.9, 12.0, 10.0,
+
–3.8, –4.0 ppm. HRMS (ESI): calcd. for C36H58O5NaSi2 [M +
Na]+ 649.3720; found 649.3691.
+
9.9, –3.8, –4.0 ppm. HRMS (ESI): calcd. for C38H60O5NaSi2 [M
[(2S,3S)-3-{(E,3R,4R,5R,6R)-5-[(tert-Butyldimethylsilyl)oxy]-7-
[(tert-butyldiphenylsilyl)oxy]-3-methoxy-1,4,6-trimethyl-1-heptenyl}-
+ Na]+ 675.3877; found 675.3853.
(2E,4E,6R,7R,8R,9R)-8-[(tert-Butyldimethylsilyl)oxy]-10-[(tert-but- oxiran-2-yl]methyl 4-Methyl-1-benzenesulfonate (5): To a stirred
yldiphenylsilyl)oxy]-6-methoxy-4,7,9-trimethyl-2,4-decadien-1-ol
(19): To a stirred solution of dienyl ester 18 (208 mg, 0.318 mmol)
in THF (5 mL) was added DIBAL-H (1.5 m in toluene, 0.48 mL,
0.70 mmol) at 0 °C. After stirring for 30 min, the reaction was
quenched with saturated potassium sodium tartrate solution
(4 mL). The heterogeneous mixture was warmed to room tempera-
ture and stirred vigorously for 2 h. The organic layer was separated,
and the aqueous layer was extracted with Et2O (3ϫ6 mL). The
combined organic layers were dried with Na2SO4 and concentrated.
The crude product was purified by column chromatography (SiO2;
solution of epoxy alcohol 20 (192 mg, 0.306 mmol) in CH2Cl2
(12 mL) were added triethylamine (0.14 mL, 1.02 mmol), 4-(di-
methylamino)pyridine (catalytic), and toluenesulfonyl chloride
(100 mg, 0.51 mmol), and the reaction mixture was stirred at 0 °C
for 18 h. The reaction was quenched with saturated aqueous
NH4Cl (10 mL), the organic layer was separated, and the aqueous
layer was extracted with CH2Cl2 (3ϫ10 mL). The combined or-
ganic layers were dried with Na2SO4 and concentrated. The crude
product was purified by column chromatography (SiO2; ethyl acet-
ate/hexane, 10%) to afford 2,3-epoxy tosylate 5 (225 mg, 94%) as
ethyl acetate/hexane, 15 %) to obtain pure (2E,4E)-dienyl allylic a colorless liquid. [α]2D5 = –8.2 (c = 0.745, CHCl ). IR (neat): ν =
˜
3
alcohol 19 (157 mg, 81%) as a colorless liquid. [α]2D5 = +8.6 (c =
1.95, CHCl ). IR (neat): ν = 3422, 3068, 2932, 2858, 2891, 1717, 825 cm–1. H NMR (300 MHz, CDCl3): δ = 7.81 (d, J = 8.4 Hz, 2
2925, 2855, 1638, 1463, 1367, 1253, 1180, 1085, 1026, 966,
1
˜
3
2068
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2062–2071

Synthesis of the C1–C14 Core of (–)-Callipeltoside A
H), 7.69–7.59 (m, 4 H), 7.42–7.29 (m, 8 H), 5.30 (d, J = 9.6 Hz, 1 129.6, 127.9, 127.7, 77.8, 71.6, 67.0, 55.2, 51.6, 47.0, 42.9, 41.7,
H), 4.22 (dd, J = 11.4, 3.9 Hz, 1 H), 4.10 (dd, J = 6.9, 0.9 Hz, 1
H), 4.03 (dd, J = 11.4, 5.7 Hz, 1 H), 3.71 (dd, J = 9.6, 9.6 Hz, 1
H), 3.70 (dd, J = 9.9, 3.3 Hz, 1 H), 3.35 (dd, J = 9.9, 7.8 Hz, 1 H),
3.19 (br. d, J = 1.5 Hz, 1 H), 3.15 (dd, J = 3.6, 1.8 Hz, 1 H), 3.13
(s, 3 H), 2.47 (s, 3 H), 1.86 (m, 1 H), 1.64 (m, 1 H), 1.52 (d, J =
0.9 Hz 3 H), 1.06 (s, 9 H), 0.91 (d, J = 6.9 Hz, 3 H), 0.81 (s, 9 H),
0.66 (d, J = 6.9 Hz, 3 H), 0.01 (s, 3 H), –0.12 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 145.1, 135.6, 134.3, 133.9, 132.5,
130.9, 129.9, 129.4, 127.9, 127.4, 76.5, 71.0, 69.7, 66.7, 59.4, 55.3,
53.9, 41.4, 40.1, 26.8, 26.0, 21.6, 19.2, 18.2, 13.6, 11.6, 9.7, –4.1,
–4.3 ppm. HRMS (ESI): calcd. for C43H64O7NaSi2S+ [M + Na]+
803.3809; found 803.3794.
40.6, 27.1, 26.2, 19.4, 18.5, 17.8, 14.0, 10.1, –3.8, –4.0 ppm. HRMS
(ESI): calcd. for C36H58O4NaSi2 [M + Na]+ 633.3771; found
+
633.3766.
(3R,5E,7R,8R,9R,10R)-9-[(tert-Butyldimethylsilyl)oxy]-11-[(tert-
butyldiphenylsilyl)oxy]-7-methoxy-5,8,10-trimethyl-1,5-undecadien-
3-ol (23): A stirred suspension of trimethylsulfonium iodide (70 mg,
0.35 mmol) in THF (2 mL) at –10 °C was treated with nBuLi (1.6 m
in hexane, 0.2 mL, 0.33 mmol). After 30 min, terminal epoxide 22
(35 mg, 0.057 mmol) in THF (1 mL) was added, generating a milky
suspension. The reaction mixture was warmed to 0 °C over 30 min
and then stirred at room temperature for 2 h. The reaction was
quenched with water at 0 °C, the mixture extracted with Et2O
(3 ϫ 10 mL), and the combined organic layers were dried with
Na2SO4 and concentrated. The crude product was purified by col-
umn chromatography (SiO2; ethyl acetate/hexane, 15%) to furnish
terminal olefin 23 (33 mg, 92%) as a colorless liquid. [α]2D5 = +9.0
(2R,4E,6R,7R,8R,9R)-8-[(tert-Butyldimethylsilyl)oxy]-10-[(tert-but-
yldiphenylsilyl)oxy]-2-hydroxy-6-methoxy-4,7,9-trimethyl-4-decenyl
4-Methyl-1-benzenesulfonate (21): A stirred solution of 2,3-epoxy
tosylate 5 (132 mg, 0.168 mmol) in CH2Cl2 (2 mL) at –78 °C was
treated with DIBAL-H (1.5 m in toluene, 0.34 mL, 0.51 mmol). The
reaction mixture was stirred at –78 °C for 5 min, then warmed to
–40 °C and stirred at that temperature for 3 h. The reaction mixture
was diluted with CH2Cl2 (10 mL), then quenched with a saturated
solution of potassium sodium tartrate (5 mL) and warmed to room
temperature. The organic layer was separated, and the aqueous
layer was extracted with CH2Cl2 (3ϫ10 mL). The combined or-
ganic layers were dried with Na2SO4 and concentrated. The crude
product was purified by column chromatography (SiO2; ethyl acet-
ate/hexane, 15%) to furnish 1-tosyloxy-2-alkanol 21 (120 mg, 91%)
(c = 1.2, CHCl ). IR (neat): ν = 3478, 2925, 2854, 1463, 1428, 1384,
˜
3
1255, 1111, 1083, 1028, 834 cm–1. H NMR (300 MHz, CDCl3): δ
1
= 7.69–7.59 (m, 4 H), 7.43–7.28 (m, 6 H), 5.86 (ddd, J = 15.9, 10.5,
5.7 Hz, 1 H), 5.25 (dt, J = 17.1, 1.5 Hz, 1 H), 5.10 (dt, J = 10.5,
1.5 Hz, 1 H), 4.99 (d, J = 9.6 Hz, 1 H), 4.23 (m, 1 H), 4.10 (d, J =
6.6 Hz, 1 H), 3.76 (dd, J = 9.6, 5.7 Hz, 1 H), 3.68 (dd, J = 9.6,
9.3 Hz, 1 H), 3.34 (dd, J = 9.6, 8.1 Hz, 1 H), 3.14 (s, 3 H), 2.36–
2.14 (m, 2 H), 1.87 (m, 1 H), 1.71 (d, J = 0.9 Hz, 3 H), 1.61 (m, 1
H), 1.06 (s, 9 H), 0.92 (d, J = 6.9 Hz, 3 H), 0.81 (s, 9 H), 0.70 (d,
J = 6.9 Hz, 3 H), 0.02 (s, 3 H), –0.13 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 140.7, 136.7, 135.9, 134.3, 129.6, 129.4,
127.7, 114.9, 77.8, 71.6, 70.8, 67.0, 55.2, 48.2, 41.7, 40.5, 27.1, 26.2,
19.4, 18.5, 17.4, 14.1, 10.3, –3.8, –4.0 ppm. HRMS (ESI): calcd. for
as a colorless liquid. [α]2D9 = +4.74 (c = 1.18, CHCl ). IR (neat): ν
˜
3
= 3480, 2924, 2854, 1464, 1362, 1180, 1085, 1026, 975, 832 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.80 (d, J = 8.5 Hz, 2 H), 7.70–
7.63 (m, 4 H), 7.44–7.31 (m, 8 H), 4.95 (d, J = 9.5 Hz, 1 H), 4.06
(dd, J = 6.5, 0.5 Hz, 1 H 1 H), 4.06 (dd, J = 10.0, 3.5 Hz, 1 H),
4.00 (m, 1 H), 3.92 (dd, J = 10.0, 6.5 Hz 1 H), 3.76 (dd, J = 10.0,
5.5 Hz, 1 H), 3.68 (dd, J = 9.5, 9.5 Hz, 1 H), 3.36 (dd, J = 10.0,
8.0, Hz, 1 H), 3.11 (s, 3 H), 2.44 (s, 3 H), 2.27-2.18 (m, 2 H), 2.02
(d, J = 3.5 Hz, 1 H), 1.88 (m, 1 H), 1.67 (d, J = 1.3 Hz, 3 H), 1.60
(m, 1 H), 1.06 (s, 9 H), 0.91 (d, J = 6.9 Hz, 3 H), 0.81 (s, 9 H),
0.65 (d, J = 6.9 Hz, 3 H), 0.02 (s, 3 H), –0.13 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 145.2, 135.8, 135.7, 134.2, 132.8,
130.1, 129.8, 129.6, 128.1, 127.7, 77.7, 73.6, 71.4, 67.5, 67.0, 55.3,
43.5, 41.6, 40.4, 27.0, 26.2, 21.8, 19.4, 18.5, 17.2, 14.0, 10.1, –3.8,
–4.0 ppm. HRMS (ESI): calcd. for C43H66O7NaSi2S+ [M + Na]+
805.3965; found 805.3945.
C37H60O4NaSi2 [M + Na]+ 647.3927; found 647.3912.
+
tert-Butyl{[(1R,2R,3R,4E,7R)-7-[(tert-butyldimethylsilyl)oxy]-1-
{(1R)-2-[(tert-butyldiphenylsilyl)oxy]-1-methylethyl}-3-methoxy-2,5-
dimethyl-4,8-nonadienyl]oxy}dimethylsilane (24): To a stirred solu-
tion of allylic alcohol 23 (56 mg, 0.09 mmol) in CH2Cl2 (2 mL) was
added 2,6-lutidine (22 μL, 0.18 mmol) and TBSOTf (32 μL,
0.136 mmol) at –50 °C. After 30 min, saturated aqueous NaHCO3
(2 mL) was added. The organic layer was separated, and the aque-
ous layer was extracted with CH2Cl2 (3ϫ10 mL). The combined
organic layers were dried with Na2SO4 and concentrated. The
crude product was purified by column chromatography (SiO2; ethyl
acetate/hexane, 5%) to afford 24 (64 mg, 95%) as a yellow liquid.
[α]2D7 = +8.37 (c = 0.95, CHCl ). IR (neat): ν = 2930, 2857, 1639,
˜
3
tert-Butyl({(2R,3R,4R,5R,6E)-3-[(tert-butyldimethylsilyl)oxy]-5-
methoxy-2,4,7-trimethyl-8-[(2R)-oxiran-2-yl]-6-octenyl}oxy)diphen-
ylsilane (22): A stirred solution of 1-tosyloxy-2-alkanol 21 (108 mg,
0.138 mmol) in THF (2 mL) at 0 °C was treated with NaH (4 mg,
0152 mmol). After 30 min, the reaction was quenched with water
(2 mL), and the aqueous layer was extracted with Et2O
(3ϫ10 mL). The combined organic layers were dried with Na2SO4
and concentrated. The crude product was purified by column
chromatography (SiO2; ethyl acetate/hexane, 7 %) to obtain ter-
minal epoxide 22 (82 mg, 97%) as a colorless liquid. [α]2D5 = +0.55
1464, 1383, 1253, 1081, 1023, 834 cm–1 1H NMR (300 MHz,
.
CDCl3): δ = 7.69–7.61 (m, 4 H), 7.42–7.29 (m, 6 H), 5.79 (ddd, J
= 16.8, 10.3, 6.2 Hz, 1 H), 5.12 (ddd, J = 17.1, 1.8, 1.2 Hz, 1 H),
5.02 (ddd, J = 10.5, 1.8, 1.2 Hz, 1 H), 4.90 (d, J = 9.7 Hz, 1 H),
4.25 (m, 1 H), 4.08 (dd, J = 6.9, 1.2 Hz, 1 H), 3.74 (dd, J = 9.9,
5.4 Hz, 1 H), 3.64 (dd, J = 9.6, 9.3 Hz, 1 H), 3.33 (dd, J = 9.9,
8.1 Hz, 1 H), 3.11 (s, 3 H), 2.34 (dd, J = 13.3, 5.3 Hz, 1 H), 2.22
(dd, J = 13.3, 7.4 Hz, 1 H), 1.86 (m, 1 H), 1.68 (d, J = 0.9 Hz, 3
H), 1.58 (m, 1 H), 1.06 (s, 9 H), 0.92 (d, J = 6.9 Hz, 3 H), 0.90 (s,
9 H), 0.81 (s, 9 H), 0.68 (d, J = 6.9 Hz, 3 H), 0.06 (s, 3 H), 0.04 (s,
3 H), 0.01 (s, 3 H), –0.14 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 141.3, 137.0, 135.9, 134.3, 129.6, 128.5, 127.7, 114.1,
77.7, 73.3, 71.6, 67.1, 55.2, 49.1, 41.6, 40.7, 27.0, 26.2, 26.0, 19.4,
18.5, 18.4, 18.0, 14.1, 10.1, –3.8, –4.0, –4.2, –4.7 ppm. HRMS
(c = 3.5, CHCl ). IR (neat): ν = 2930, 2857, 1630, 1466, 1385, 1253,
˜
3
1082, 1026, 833 cm–1. H NMR (300 MHz, CDCl3): δ = 7.70–7.60
1
(m, 4 H), 7.44–7.28 (m, 6 H), 5.01 (d, J = 9.6 Hz, 1 H), 4.10 (dd,
J = 6.9, 0.9 Hz, 1 H), 3.74 (dd, J = 9.9, 5.1 Hz, 1 H), 3.69 (dd, J
= 9.9, 9.6 Hz, 1 H), 3.34 (dd, J = 9.9, 7.8 Hz, 1 H), 3.15 (s, 3 H),
2.96 (m, 1 H), 2.74 (dd, J = 5.1, 3.9 Hz, 1 H), 2.45 (dd, J = 5.1,
2.7 Hz, 1 H), 2.26 (br. d, J = 6.0 Hz, 2 H), 1.88 (m, 1 H), 1.74 (d,
(ESI): calcd. for C43H74O4NaSi3 [M + Na]+ 761.4792; found
+
761.4793.
J = 0.9 Hz, 3 H), 1.62 (m, 1 H), 1.06 (s, 9 H), 0.92 (d, J = 6.9 Hz, (2R,3R,4R,5R,6E,9R)-3,9-Bis[(tert-butyldimethylsilyl)oxy]-5-meth-
3 H), 0.81 (s, 9 H), 0.70 (d, J = 6.9 Hz, 3 H), 0.03 (s, 3 H), –0.13
oxy-2,4,7-trimethyl-6,10-undecadien-1-ol (25): To a stirred solution
of 24 (28.2 mg, 0.038 mmol) in MeOH (1.5 mL) was added NH4F
(s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 136.7, 135.9, 134.3,
Eur. J. Org. Chem. 2012, 2062–2071
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2069

J. S. Yadav, A. Haldar, T. Maity
FULL PAPER
(9 mg, 0.24 mmol). The mixture was warmed to 50 °C and stirred
for 4 h before quenching with saturated aqueous NaHCO3 (1 mL).
The aqueous layer was extracted with CH2Cl2 (3ϫ5 mL), and the
combined organic layers were dried with Na2SO4 and concentrated.
The crude product was purified by column chromatography (SiO2;
6-{(2S,3R,4S,5R,6R,7E,10R)-4,10-Bis[(tert-butyldimethylsilyl)oxy]-
6-methoxy-2-(methoxymethoxy)-3,5,8-trimethyl-7,11-dodecadienyl}-
2,2-dimethyl-4H-1,3-dioxin-4-one (27): To a stirred solution of aldol
adduct 26 (27 mg, 0.042 mmol) and iPr2NEt (44 μL, 0.252 mmol)
in CH2 Cl2 (1 mL) at 0 °C, was added MOMCl (20 μL,
ethyl acetate/hexane, 15%) to obtain alcohol 25 (18 mg, 89%) as a 0.244 mmol). After 90 min at 0 °C, the reaction mixture was diluted
colorless liquid: [α]2D7 = –11.67 (c = 0.75, CHCl ). IR (neat): ν =
with saturated aqueous NaCl (1 mL), and the aqueous layer was
extracted with CH2Cl2 (3ϫ5 mL). The combined organic layers
were dried with Na2SO4 and concentrated. The crude product was
purified by column chromatography (SiO2; ethyl acetate/hexane,
˜
3
3449, 2932, 2859, 1646, 1463, 1253, 1079, 1028, 836 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 5.79 (ddd, J = 16.9, 10.3, 6.3 Hz, 1 H),
5.12 (ddd, J = 17.1, 1.8, 1.2 Hz, 1 H), 5.02 (ddd, J = 10.2, 1.8,
1.2 Hz, 1 H), 4.91 (dq, J = 9.9, 1.2 Hz, 1 H), 4.26 (m, 1 H), 4.15 30%) to furnish MOM ether 27 (28 mg, 97%) as a light-yellow
(dd, J = 5.4, 1.3 Hz, 1 H), 3.65 (dd, J = 9.9, 9.6 Hz, 1 H), 3.56–
3.43 (m, 2 H), 3.19 (s, 3 H), 2.35 (ddd, J = 13.5, 5.7, 0.9 Hz, 1 H),
2.23 (ddd, J = 13.5, 7.2, 0.6 Hz, 1 H), 1.87 (m, 1 H), 1.70 (d, J =
liquid. [α]2D5 = –17.4 (c = 0.39, CHCl ). IR (neat): ν = 2926, 2854,
˜
3
1738, 1635, 1463, 1389, 1252, 1081, 1036, 835 cm–1
.
1H NMR
(300 MHz, CDCl3): δ = 5.79 (ddd, J = 16.9, 10.3, 6.3 Hz, 1 H),
1.5 Hz, 3 H), 1.60 (m, 1 H), 0.93 (s, 9 H), 0.90 (s, 9 H), 0.83 (d, J 5.28 (s, 1 H), 5.13 (ddd, J = 16.8, 1.8, 1.2 Hz, 1 H), 5.02 (ddd, J =
= 6.9 Hz, 3 H), 0.74 (d, J = 6.9 Hz, 3 H), 0.12 (s, 3 H), 0.11 (s, 3 10.5, 1.8, 1.2 Hz, 1 H), 4.86 (d, J = 9.6 Hz 1 H), 4.64, 4.63 (ABq,
H), 0.06 (s, 3 H), 0.05 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): J = 7.2 Hz, 2 H), 4.26 (m, 1 H), 4.22 (dd, J = 6.9, 0.6 Hz, 1 H),
δ = 141.2, 137.7, 127.7, 114.2, 79.6, 73.2, 72.7, 66.0, 55.6, 49.0,
3.88 (td, J = 6.3, 4.2 Hz, 1 H), 3.66 (dd, J = 9.9, 9.6 Hz, 1 H), 3.35
(s, 3 H), 3.15 (s, 3 H), 2.64 (dd, J = 14.4, 6.4 Hz, 1 H), 2.45 (dd, J
= 14.4, 6.3 Hz, 1 H), 2.35 (dd, J = 13.2, 5.4 Hz, 1 H), 2.22 (dd, J
= 13.2, 6.9 Hz, 1 H), 1.68 (m, 1 H), 1.70 (d, J = 0.6 Hz, 3 H), 1.69
(s, 6 H), 1.54 (m, 1 H), 0.92 (d, J = 6.9 Hz, 3 H), 0.92 (s, 9 H),
0.90 (s, 9 H), 0.70 (d, J = 6.9 Hz, 3 H), 0.11 (s, 3 H), 0.10 (s, 3 H),
0.06 (s, 3 H), 0.04 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
169.6, 161.3, 141.2, 137.5, 128.3, 114.2, 106.6, 96.9, 95.2, 78.0, 76.9,
73.2, 71.0, 55.9, 55.3, 49.1, 43.3, 40.2, 38.3, 26.4, 26.0, 25.4, 25.1,
18.7, 18.4, 18.0, 10.6, 10.1, –3.5, –4.1, –4.2, –4.7 ppm. HRMS
41.5, 39.8, 26.2, 26.0, 18.5, 18.4, 18.0, 12.7, 11.3, –4.0, –4.2, –4.2,
+
–4.7 ppm. HRMS (ESI): calcd. for C27H56O4NaSi2 [M + Na]+
523.3614; found 523.3635.
6-{(2S,3R,4R,5R,6R,7E,10R)-4,10-Bis[(tert-butyldimethylsilyl)oxy]-
2-hydroxy-6-methoxy-3,5,8-trimethyl-7,11-dodecadienyl}-2,2-di-
methyl-4H-1,3-dioxin-4-one (26): To a stirred solution of alcohol
25 (44.1 mg, 0.09 mmol) in CH2Cl2 (2 mL) and pyridine (36 μL,
0.45 mmol) at 23 °C was added Dess–Martin periodinane reagent
(51 mg, 0.12 mmol). A solution of wet CH2Cl2 (1 mL, prepared by
vigorously mixing 10 mL CH2Cl2 and 10 μL of water) was then
added dropwise over 30 min. The resulting solution was diluted
with Et2O (20 mL) and washed successively with saturated aqueous
Na2S2O3 (5 mL), saturated aqueous NaHCO3 (5 mL), and water
(5 mL). The combined aqueous layers were extracted with Et2O
(2ϫ15 mL), and the combined organic layers were washed with
saturated NaCl (20 mL), dried with Na2SO4, and concentrated.
The crude oil was dissolved in pentane and filtered through a plug
of Celite. The solvent was removed under reduced pressure to give
aldehyde 3 as a yellow liquid, which was used in the next step with-
out further purification. The crude aldehyde 3 was dissolved in
CH2Cl2 (3 mL) and cooled to –78 °C. Sequentially, dienyl silyl ether
4 (96 mg, 0.45 mmol), and BF3·OEt2 (36 μL, 0.27 mmol) were
added whilst stirring. The reaction was continued at –78 °C for 1 h
and quenched with pH 7.0 phosphate buffer (3 mL). The aqueous
layer was extracted with CH2Cl2 (3ϫ5 mL), and the combined or-
ganic layers were dried with Na2SO4 and concentrated. The crude
product was purified by column chromatography (SiO2; ethyl acet-
ate/hexane, 40%) to obtain aldol adduct 26 (48 mg, 85% 2 steps)
(ESI): calcd. for C36H68O8NaSi2 [M + Na]+ 707.4350; found
+
707.4367.
6-{(2S,3R,4S,5R,6R,7E,10R)-4-[1tert-Butyldimethylsilyl)oxy]-10-hy-
droxy-6-methoxy-2-(methoxymethoxy)-3,5,8-trimethyl-7,11-
dodecadienyl}-2,2-dimethyl-4H-1,3-dioxin-4-one (28): In a 5 mL
round-bottom plastic tube, a stirred solution of 27 (12 mg,
0.018 mmol) in MeOH (1 mL) was cooled to 0 °C, and a solution
of HF·Py (0.3 mL in 0.7 mL of MeOH) was added. The reaction
mixture was stirred at room temperature for 6 h, then quenched at
0 °C by pouring into a solution of saturated aqueous NaHCO3
(10 mL). The product was extracted with ethyl acetate (3ϫ15 mL),
and the combined organic extracts were washed with saturated
aqueous CuSO4 (10 mL) and water (10 mL), and dried with
MgSO4. After concentration of the organic extracts, the crude
product was purified by column chromatography (SiO2; ethyl acet-
ate/hexane, 40%) to afford hydroxy dioxinone 28 (10 mg, quantita-
tive) as a colorless liquid. [α]2D7 = +5.6 (c = 0.45, CHCl3). IR (neat):
1
ν = 3316, 2928, 2851, 1714, 1385, 1256, 1199, 1083, 1035 cm–1. H
˜
NMR (500 MHz, CDCl3): δ = 5.89 (ddd, J = 17, 10.5, 6.0 Hz, 1
H), 5.32 (s, 1 H), 5.27 (dt, J = 17, 1.5 Hz, 1 H), 5.12 (dt, J = 10.5,
1.5 Hz, 1 H), 4.97 (dq, J = 9.5, 1.0 Hz, 1 H), 4.67, 4.65 (ABq, J =
7.0 Hz, 2 H), 4.26 (m, 1 H), 4.24 (dd, J = 6.5, 0.7 Hz, 1 H), 3.92
(td, J = 6.5, 4.5 Hz, 1 H), 3.72 (dd, J = 10.0, 9.5 Hz, 1 H), 3.36 (s,
3 H), 3.19 (s, 3 H), 2.65 (dd, J = 14.5, 6.5 Hz, 1 H), 2.49 (dd, J =
14.5, 6.1 Hz, 1 H), 2.32 (dd, J = 13.2, 5.3 Hz, 1 H), 2.28 (dd, J =
13.2, 8.2 Hz, 1 H), 1.72 (d, J = 1.5 Hz, 3 H), 1.70 (m, 1 H), 1.69
(s, 3 H), 1.68 (s, 3 H), 1.59 (m, 1 H), 0.93 (d, J = 7.0 Hz, 3 H),
0.92 (s, 9 H), 0.73 (d, J = 7.0 Hz, 3 H), 0.12 (s, 3 H), 0.10 (s, 3 H)
ppm. 13C NMR (150 MHz, CDCl3): δ = 169.5, 161.4, 140.5, 137.1,
129.1, 115.1, 106.6, 96.9, 95.1, 77.9, 76.7, 70.9, 70.8, 55.9, 55.4,
48.1, 43.1, 40.0, 38.3, 26.4, 25.4, 25.1, 18.7, 17.3, 10.5, 10.1, –3.5,
–4.1 ppm. HRMS (ESI): calcd. for C30H54O8NaSi+ [M + Na]+
593.3485; found 593.3477.
as a yellow liquid. [α]2D8 = –2.93 (c = 0.57, CHCl ). IR (neat): ν =
˜
3
3484, 2930, 2857, 1730, 1634, 1462, 1390, 1274, 1253, 1205, 1081,
1
1016, 835 cm–1. H NMR (600 MHz, CDCl3): δ = 5.79 (ddd, J =
16.8, 10.3, 6.4 Hz, 1 H), 5.35 (s, 1 H), 5.13 (ddd, J = 16.8, 1.8,
1.2 Hz, 1 H), 5.03 (ddd, J = 10.2, 1.8, 0.9 Hz, 1 H), 4.89 (dd, J =
9.6, 0.9 Hz, 1 H), 4.31 (m, 1 H), 4.27 (m, 1 H), 4.11 (dd, J = 4.2,
2.4 Hz, 1 H), 3.67 (dd, J = 9.6, 9.3 Hz, 1 H), 3.18 (s, 3 H), 2.45
(dd, J = 14.4, 9.0 Hz, 1 H), 2.36 (dd, J = 14.4, 5.4 Hz, 1 H), 2.24
(dd, J = 13.2, 7.2 Hz, 1 H), 2.22 (dd, J = 13.2, 4.8 Hz, 1 H), 1.72
(m, 1 H), 1.70 (d, J = 0.6 Hz, 3 H), 1.69 (s, 6 H), 1.51 (m, 1 H),
0.97 (d, J = 7 Hz, 3 H), 0.92 (s, 9 H), 0.89 (s, 9 H), 0.80 (d, J =
7 Hz, 3 H), 0.12 (s, 6 H), 0.06 (s, 3 H), 0.05 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 169.8, 161.4, 141.2, 137.9, 127.6, 114.2,
106.6, 95.0, 79.3, 75.7, 73.2, 68.4, 55.6, 49.0, 43.5, 41.9, 39.8, 26.3,
26.0, 25.5, 24.9, 18.5, 18.4, 18.1, 11.5, 10.4, –3.6, –4.0, –4.2,
(6S,7R,8S,9R,10R,14R)-8-[(tert-Butyldimethylsilyl)oxy]-10-meth-
oxy-6-(methoxymethoxy)-7,9,12-trimethyl-14-vinyl-1-oxa-11-cyclo-
tetradecene-2,4-dione (30): A solution of hydroxy dioxinone 28
+
–4.7 ppm. HRMS (ESI): calcd. for C34H64O7NaSi2 [M + Na]+
663.4088; found 663.4080.
2070
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2062–2071

Synthesis of the C1–C14 Core of (–)-Callipeltoside A
(8 mg, 0.014 mmol) in freshly azeotropically dried toluene (20 mL)
was added by using a cannula to stirred azeotropically dried tolu-
ene (60 mL) at reflux over 45 min. The reaction mixture was stirred
at 110 °C for 1 h and then concentrated. The crude product was
purified by column chromatography (SiO2; ethyl acetate/hexane,
15%) to obtain macrolactone 30 (6 mg, 84%) as a colorless liquid.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H and 13C NMR spectra for all new compounds.
Acknowledgments
A. H. and T. M. thank the Council of Scientific and Industrial
Research (CSIR), New Delhi, India, for financial assistance. The
authors acknowledge partial support from the King Saud Univer-
sity for Global Research Network for Organic Synthesis (GRNOS).
[α]2D6 = –24.3 (c = 0.3, CHCl ). IR (neat): ν = 2927, 2857, 1716,
˜
3
1629, 1463, 1251, 1096, 1038, 834 cm–1. 1H NMR (600 MHz,
C6D6): δ = 5.60 (ddd, J = 16.8, 10.8, 6.0 Hz, 1 H), 5.56 (m, 1 H),
5.41 (br. d, J = 9.0 Hz, 1 H), 5.15 (dd, J = 16.8, 1.2 Hz, 1 H), 4.96
(dd, J = 10.2, 1.2 Hz, 1 H), 4.68 (d, J = 6.5 Hz, 1 H), 4.59 (d, J =
6.5 Hz, 1 H), 4.29 (m, 1 H), 4.06–3.97 (br. m, 1 H), 3.74 (dd, J =
9.0, 1.0 Hz, 1 H), 3.21 (d, J = 15.6 Hz, 1 H), 3.15 (s, 3 H), 3.13 (d,
J = 15.6 Hz, 1 H), 3.07 (s, 3 H), 2.84 (dd, J = 15.6, 8.4 Hz, 1 H),
2.57 (dd, J = 15.6, 4.8 Hz, 1 H), 2.26 (dd, J = 14.4, 11.7 Hz, 1 H),
2.05 (d, J = 14.4 Hz, 1 H), 2.02 (m, 1 H), 1.69 (m. 1 H), 1.55 (s, 3
H), 1.23 (d, J = 7.2 Hz, 3 H), 1.07 (s, 9 H), 1.03 (d, J = 7.2 Hz, 3
H), 0.27 (s, 3 H), 0.20 (s, 3 H) ppm. 13C NMR (150 MHz, C6D6):
δ = 200.4, 166.1, 136.7, 135.1, 129.5, 116.5, 97.5, 82.4, 77.0, 72.2,
69.9, 56.0, 55.6, 50.3, 46.1, 45.8, 45.6, 40.8, 26.4, 18.8, 15.5, 15.2,
12.2, –4.1 ppm. HRMS (ESI): calcd. for C27H48O7NaSi+ [M +
Na]+ 535.3067; found 535.3063.
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C1–C14 Macrolactone Core 2 of (–)-Callipeltoside A: In a 5 mL
round-bottom plastic tube a stirred solution of macrolactone 30
(5.4 mg, 0.011 mmol) in MeOH (0.7 mL) was cooled to 0 °C, and
a solution of HF·Py (0.2 mL in 0.5 mL of MeOH) was added drop-
wise. The reaction mixture was stirred for 2 h and quenched at 0 °C
by slow dropwise addition of saturated aqueous sodium hydrogen
carbonate solution (1 mL) to the reaction vessel by using a syringe.
After transferring the mixture to a larger vessel, another 7 mL of
saturated aqueous NaHCO3 solution was added. The product was
extracted with ethyl acetate (3ϫ15 mL), and the combined organic
extracts were washed with aqueous CuSO4 solution (10 mL) and
water (10 mL) and dried with Na2SO4. After concentration of the
organic extracts, the crude product was purified by column
chromatography (SiO2; ethyl acetate/hexane, 20%) to furnish 2
(4 mg, 96%) as a colorless liquid. [α]2D4 = –17.0 (c = 0.18, CHCl3).
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[7] CCDC-852984 contains the supplementary crystallographic
data for compound 13. This data can be obtained free of
charge from The Cambrigde Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
IR (neat): ν = 3457, 2925, 2854, 1704, 1464, 1228, 1177, 1154, 1086,
˜
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1
1034, 897 cm–1. H NMR (500 MHz, CDCl3): δ = 5.88 (ddd, J =
17.0, 10.5, 6.0 Hz, 1 H), 5.78 (m, 1 H), 5.31 (d, J = 10.0 Hz, 1 H),
5.30 (dt, J = 17.0, 1.3 Hz, 1 H), 5.19 (dt, J = 10.5, 1.0 Hz, 1 H),
5.03 (d, J = 2.5 Hz, 1 H), 4.73 (d, J = 6.8 Hz, 1 H), 4.63 (d, J =
6.8 Hz, 1 H), 3.81 (dd, J = 9.5, 2.5 Hz, 1 H), 3.67 (ddd, J = 11.0,
10.5, 4.7 Hz, 1 H), 3.65 (dd, J = 10.3, 2.5 Hz,1 H), 3.38 (s, 3 H),
3.24 (s, 3 H), 2.55 (d, J = 12.9 Hz, 1 H), 2.44 (d, J = 12.9 Hz, 1
H), 2.32–2.27 (m, 2 H), 2.22 (m, 1 H), 2.22 (dd, J = 12.0, 4.7 Hz,
1 H), 1.75 (d, J = 1.3 Hz, 3 H), 1.50 (m, 1 H), 1.30 (ddd, J = 12.0,
11.0, 2.5 Hz, 1 H), 0.99 (d, J = 7.0 Hz, 3 H), 0.96 (d, J = 6.5 Hz,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 172.1, 136.3, 132.7,
127.7, 116.7, 96.1, 95.4, 80.0, 76.2, 75.2, 72.3, 55.7, 55.4, 46.9, 44.9,
41.6, 38.3, 37.1, 16.3, 12.4, 6.6 ppm. HRMS (ESI): calcd. for
C21H34O7Na+ [M + Na]+ 421.2202; found 421.2203.
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Received: November 11, 2011
Published Online: February 10, 2012
Eur. J. Org. Chem. 2012, 2062–2071
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2071