Total synthesis and structure confirmation of cryptocaryol A

Article abstract of DOI:10.1002/ejoc.201201309

The first enantioselective total synthesis of Pdcd4-stabilizing cryptocaryol A, a secondary metabolite obtained from a tropical tree, has been achieved through an iterative approach to the 1,3-polyol motif. The key steps are a Maruoka allylation, a Reetz chelation-controlled allylation with 1,3-induction, iterative diastereoselective iodocyclization, and ring-closing metathesis reactions. Maruoka asymmetric allylation, chelation-controlled 1,3-induced allylation, iterative iodocyclization and ring-closing metathesis reactions were used sequentially to achieve the first total synthesis and structure confirmation of cryptocaryol A. Copyright

Full text of DOI:10.1002/ejoc.201201309

FULL PAPER
DOI: 10.1002/ejoc.201201309
Total Synthesis and Structure Confirmation of Cryptocaryol A
D. Srinivas Reddy[a] and Debendra K. Mohapatra*[a]
Dedicated to Dr. Mukund K. Gurjar on the occasion of his 60th birthday
Keywords: Natural products / Asymmetric synthesis / Synthetic methods / Protecting groups
The first enantioselective total synthesis of Pdcd4-stabilizing
cryptocaryol A, a secondary metabolite obtained from a trop-
ical tree, has been achieved through an iterative approach to
the 1,3-polyol motif. The key steps are a Maruoka allylation,
a Reetz chelation-controlled allylation with 1,3-induction, it-
erative diastereoselective iodocyclization, and ring-closing
metathesis reactions.
hance the stability of Pdcd4 in response to tumor-promot-
ing conditions. The relative and absolute stereochemistry
of cryptocaryol A (1) was established by a series of elegant
spectroscopic and degradative studies. 5,6-Dihydro-2H-ones
modules having polyhydroxy or polyacetoxy groups have
been widely explored by synthetic organic and medicinal
chemists because of their broad range of biological activi-
ties. As part of our research interest in biologically potent
active natural products[14] and because of its specific ac-
tivity, we consider cryptocaryol A as an attractive synthetic
target.
Introduction
The recent isolation of cryptocaryol A (1) and B (2), a
new structural class of programmed cell death 4 (Pdcd4)
stabilizing compounds from the Papua New Guinea collec-
tion of the plant Cryptocarya sp. have been reported by Gu-
stafson et al. (Figure 1).[1] The genus Cryptocarya is dissem-
inated throughout the tropic, subtropic, and temperate re-
gions of the world, and its members produce an array of
secondary metabolites including flavonoids such as crypto-
chinones A–F,[2] pavine and proaporphine alkaloids,[3] and
a variety of 5,6-dihydro-α-pyrones exemplified by passiflor-
icin,[4] (–)-pironetin,[5] fostriecin,[6] strictofolione,[7] callysta-
tin A,[8] leptomycin,[9] kurzilactone,[10] rugulactone,[11] and
cryptocaryone[12]. The degradation and EC50 values range
from 1.3 to 4.9 μm. Pdcd4, also called apoptosis, plays a
pivotal role in life and is an indispensable event in many
biological processes such as embryogenic development, nor-
mal tissue turnover and metamorphosis.[13] The molecular
mechanisms of programmed cell death reveal the existence
of several distinct pathways. Recent observations suggest
that Pdcd4 acts as a tumor suppressor gene and might rep-
resent a promising target for future antineoplastic therapy.
In this aspect, natural products that bring out a specific
and unique biological activity in mammalian cells represent
valuable tools to target possible gene products. With ac-
tivity in the low micromolar range, the crytocaryols repre-
sent a new structural class of natural products that can en-
Figure 1. Structures of cryptocaryol A, and B.
The strategy is presented in Scheme 1. The key steps are
a Maruoka allylation reaction followed by a chelation-con-
trolled allylation with 1,3-induction to install two
stereogenic centers. The remaining chiral centers could then
be introduced by iterative iodocyclization reactions. The
lactone moiety could be achieved through a ring-closing
metathesis reaction. Herein, we describe our successful reali-
zation of this strategy for the first total synthesis of crypto-
caryol A and its structure confirmation.
[a] Natural Products Chemistry Division, CSIR – Indian Institute
of Chemical Technology Habsiguda,
Uppal Road, Hyderabad 500007, India
Fax: +91-40-27160512
E-mail: mohapatra@iict.res.in
dkm_77@yahoo.com
Homepage: www.iictindia.org
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201309.
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thought worthwhile to adopt a chelation-controlled stereo-
selective allylation reaction occurring through 1,3-induc-
tion.[16] Accordingly, oxidative cleavage of the olefin with
OsO4, NaIO4, and 2,6-lutidine in 1,4-dioxane at room tem-
perature afforded the corresponding aldehyde that was im-
mediately treated with allyltrimethylsilane in the presence
of TiCl4 as Lewis acid at –78 °C to obtain homoallyl
alcohol 10 in 89% yield with a diastereomeric excess Ͼ98%
(Scheme 1). To assign the anti geometry according to the
method reported by Rychnovsky and co-workers,[17] the
benzyl group was deprotected with Li/naphthalene to give
diol 11 in 91% yield. Diol 11 was subsequently transformed
into isopropylidene derivative 12 with dimethoxypropane
and a catalytic amount of camphorsulfonic acid in 94%
yield. In the 13C NMR spectrum of 12, the resonance aris-
ing from the acetonide methyl groups appeared at δ = 24.75
and 24.83 ppm and that of the quaternary carbon atom at
δ = 100.17 ppm, indicating a 1,3-trans relationship.
After confirming the stereocenters, compound 10 was
treated with di-tert-butyl dicarbonate in the presence of 4-
(dimethylamino)pyridine (DMAP) to form homoallylic
tert-butyl carbonate 13 in 90% yield.[18] The next stereo-
genic center of the hexanol system was achieved through a
Bartlett–Smith iodocarbonate cyclization reaction.[19] Ac-
cordingly, treatment of compound 13 with N-iodosuccin-
imide (NIS) in CH3CN at 0 °C produced the desired iodo-
carbonate derivative 14 in 91% yield as the only product.
Iodocarbonate 14 was treated with K2CO3 in MeOH that
rapidly underwent hydrolysis to give in situ epoxy alcohol
15 in 92% yield. The secondary hydroxy group was pro-
tected as its p-methoxybenzyl (PMB) ether with PMBCl in
the presence of NaH in DMF at 0 °C to afford epoxide 16
in 89% yield. Treatment of 16 with vinylmagnesium brom-
ide in the presence of a catalytic amount of CuI[20] at 0 °C
furnished homoallyl alcohol 17 in 87% yield (Scheme 3).
Scheme 1. Retrosynthetic analysis of cryptocaryol A.
Results and Discussion
The oxidation of palmityl alcohol (7) with pyridinium
chlorochromate (PCC) in CH2Cl2 at room temperature af-
forded hexadecanal, which – on treatment with allyltri-
butyltin in the presence of Ti(iPrO)4 and (S)-BINOL in
CH2Cl2 at –20 °C – furnished homoallyl alcohol 8 in 87%
yield with an enantiomeric excess Ͼ97% (Scheme 2).[15]
Compound 8 was protected as its benzyl ether with benzyl
bromide in the presence of NaH in N,N-dimethylformamide
(DMF) to give 9 in 95% yield. To establish the second
stereogenic center with the required stereochemistry, it was
Scheme 3. Synthesis of intermediate 17.
With 17 in hand, the stage was set for the introduction
of the remaining stereogenic centers of cryptocaryol A
through iterative use of the 2OH-3SOH sequence as shown
Scheme 2. Synthesis of intermediate 12.
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Total Synthesis and Structure Confirmation of Cryptocaryol A
Scheme 4. Synthesis of cryptocaryol A.
hydrofuran (THF) were freshly distilled from sodium/benzophe-
none ketyl and transferred by syringe. Dichloromethane was freshly
distilled from CaH2. Tertiary amines were freshly distilled from
KOH. Commercially available reagents were used as received. Un-
less detailed otherwise, “workup” refers to pouring the reaction
mixture into brine, followed by extraction with the solvent indi-
cated in parentheses. If the reaction medium was acidic (basic), an
additional washing with 5% aq. NaHCO3 (aq. NH4Cl) was per-
formed. Washing with brine, drying with anhydrous Na2SO4 and
elimination of the solvent under reduced pressure was followed by
in Scheme 3. Three further cycles led to diastereomerically
pure hexanol precursor 20.[21] To complete the synthesis of
cryptocaryol A, we now needed to construct the α-pyrone
ring. To this end, esterification of alcohol 20 with acryloyl
chloride afforded 21 in 90% yield, which set the stage for
a ruthenium-catalyzed ring-closing metathesis reaction.[22]
Treatment of diene 21 with second-generation Grubbs’ cat-
alyst (10 mol-%) in CH2Cl2 at reflux temperatures afforded
lactone 22 in 89% yield (Scheme 4). Global deprotection
[23]
was achieved with excess TiCl4
in CH2Cl2 to complete chromatography on a silica gel column (60–120 μm) with the indi-
cated eluent. When solutions were filtered through a Celite pad,
the pad was washed with the same solvent used, and the washings
combined with the main organic layer. NMR spectra were mea-
sured at 25 °C. The signals of the deuterated solvent (CDCl3) were
taken as the reference. Multiplicity assignments of 13C signals were
made by means of the DEPT pulse sequence. The following ab-
breviations are used to designate signal multiplicity: s = singlet, d
= doublet, t = triplet, q = quartet, m = multiplet, br. = broad.
High-resolution mass spectra were recorded in the electron impact
mode (EIMS, 70 eV) or in the fast atom bombardment (FAB)
mode (m-nitrobenzyl alcohol matrix). IR spectroscopic data were
measured with films on NaCl plates (oils) or KBr pellets (solids)
and are given only for molecules with relevant functional groups
(OH, C=O). Optical rotations were measured at 25 °C.
the first total synthesis of cryptocaryol A (1) in 76% yield.
The integrity of the synthetic cryptocaryol A (1) was as-
signed by analysis of the spectroscopic data (1H and 13C
NMR) and analytical data {[α]2D5 = +11.4 (c = 1.5, MeOH);
ref.[1] [α]D = +12 (c = 0.1, MeOH)} that are in good agree-
ment with the reported values for the natural product con-
firming the assigned structure of 1.
Conclusions
We have demonstrated an efficient, highly stereoselective
approach to accomplish the first total synthesis of cryptoca-
ryol A from commercially available palmityl alcohol. An
important element of our synthetic strategy is the use of
asymmetric catalysis to establish the initial asymmetry fol-
lowed by chelation-controlled 1,3-induction for the second
stereocenter in addition to the use of an efficient iterative
highly diastereo selective iodocyclization reaction to install
the remaining four chiral centers with high overall yield.
Application of the same protocol towards the synthesis of
other cryptocaryols is in progress and will be reported in
due course.
(R)-Octadec-1-en-4-ol (8): To a stirred solution of TiCl4 (5.0 mL,
0.50 mmol), in CH2Cl2 (25 mL), was added (iPrO)4Ti (4.25 mL,
1.5 mmol) at 0 °C under argon. The solution was allowed to warm
to room temperature. After 1 h, silver oxide (2.3 g, 1.0 mmol) was
added, and the reaction mixture was stirred in the dark for 5 h.
The reaction mixture was diluted with CH2Cl2 (50 mL) and treated
with (S)-binaphthol (5.73 g, 2.0 mmol) at room temperature for 2 h
to furnish chiral bis(S)-TiIV oxide. The in situ generated bis(S)-
TiIV oxide in CH2Cl2 (75 mL) was cooled to –15 °C and treated
sequentially with hexadecanal (25.0 g, 10.0 mmol) and allyltri-
butyltin (35.0 mL, 11.0 mmol). The reaction mixture was cooled to
0 °C and stirred for 48 h. The reaction mixture was quenched with
saturated NaHCO3 (150 mL) solution and extracted with ethyl
acetate (3ϫ 150 mL). The combined organic layers were dried with
Na2SO4, filtered, and concentrated under reduced pressure. Flash
Experimental Section
General Methods: Experiments that required an inert gas were car-
ried out under dry N2 in flame-dried glassware. Et2O and tetra-
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chromatography of the residue on silica gel (ethyl acetate/hexane =
22.6, 14.0 ppm. HRMS (ESI): calcd. for C28H48O2Na [M + Na]+
439.3551; found 439.3511.
1:20) afforded homoallylic alcohol 8 (25.5 g, 87% yield) as a white
solid. M.p. 44–45 °C. [α]2D5 = –2.5 (c = 2.2, CHCl ). IR (neat): ν
˜
3
max
(4R,6R)-6-(Benzyloxy)henicos-1-en-4-yl tert-Butyl Carbonate (13):
To a solution of alcohol 10 (20 g, 48.1 mmol) in CH2Cl2 (150 mL),
di-tert-butyl dicarbonate [(Boc)2O; 22.1 mL, 96.1 mmol], followed
by Et3N (13.4 mL, 96.1 mmol) and DMAP (2.9 g, 27.7 mmol) were
added at room temperature. After stirring for 5 h, the solvent was
evaporated under reduced pressure to give the crude product,
which – on purification by column chromatography on silica gel
(ethyl acetate/hexane = 1:19) – gave tert-butyloxycarbonyl (Boc)
protected 13 (22.2 g, 90%) as a colorless oil. [α]2D5 = –38.2 (c = 1.0,
= 3326, 2954, 2850, 1720, 1248, 1219 cm–1. 1H NMR (CDCl3,
500 MHz): δ = 5.80 (m, 1 H), 5.10 (m, 2 H), 3.60 (m, 1 H), 2.28
(m, 1 H), 2.13 (m, 1 H), 2.10 (br. s, 1 H), 1.50–1.40 (m, 3 H), 1.40–
1.20 (br. m, 25 H), 0.87 (t, J = 6.5 Hz, 3 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 134.9, 118.04, 70.7, 41.9, 36.8, 31.9, 29.7,
29.3, 25.6, 22.6, 14.0 ppm. MS (ESI): m/z = 305 [M + Na]+.
(R)-[(Nonadec-1-en-4-yloxy)methyl]benzene (9): Alcohol 8 (24.6 g,
87.3 mmol) in THF (150 mL) was added slowly to a suspension of
NaH [5.2 g, (60%), 131.0 mmol] in anhydrous THF (100 mL) at
0 °C. After 20 min, benzyl bromide (6.8 mL, 88.1 mmol) was added
dropwise at 0 °C. The reaction mixture was stirred at room tem-
perature for 12 h. After completion (monitored by TLC), the reac-
tion mixture was quenched with ice-cooled water and extracted
with ethyl acetate (3ϫ 150 mL). The combined organic layers were
dried with Na2SO4, concentrated under reduced pressure, and puri-
fied by silica gel column chromatography (ethyl acetate/hexane =
1:22) to afford compound 9 (30.79 g, 95%) as a colorless liquid.
CHCl ). IR (neat) ν
= 2925, 2854, 1739, 1459, 1167 cm–1. 1H
˜
3
max
NMR (CDCl3, 300 MHz): δ = 7.36–7.25 (m, 5 H), 5.76 (m, 1 H),
5.12–4.94 (m, 3 H), 4.63–4.40 (m, 2 H), 3.47 (m, 1 H), 2.37–2.30
(m, 2 H), 1.72–1.64 (m, 2 H), 1.46 (s, 9 H), 1.40–1.36 (m, 2 H),
1.29–1.20 (m, 24 H), 0.88 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 153.2, 138.6, 133.4, 128.3, 128.0, 127.5,
117.8, 81.6, 75.6, 73.5, 71.5, 39.5, 39.0, 34.1, 32.0, 29.5, 29.3, 27.7,
24.8, 22.6, 14.1 ppm. HRMS (ESI): calcd. for C33H56O4Na [M +
Na]+ 539.4071; found 539.4040.
[α]2D5 = +8.3 (c = 1.6, CHCl ). IR (neat): ν
= 3067, 2956, 1641,
(4S,6S)-4-[(R)-2-(Benzyloxy)heptadecyl]-6-(iodomethyl)-1,3-di-
˜
3
max
1094 cm–1. H NMR (CDCl3, 300 MHz): δ = 7.26–7.34 (m, 5 H), oxan-2-one (14): To a stirred solution of Boc-protected 13 (18.0 g,
1
5.80 (m, 1 H), 5.10–5.01 (m, 2 H), 4.57–4.43 (m, 2 H), 3.2–3.4 (m,
2 H), 2.34–2.26 (m 2 H), 1.55–1.44 (m, 3 H), 1.33–122 (m, 25 H),
0.89 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ =
138.9, 135.1, 128.3, 128.2, 127.7, 127.5, 127.3, 116.7, 78.5, 70.8,
38.3, 33.8, 31.9, 29.6, 29.3, 25.3, 22.6, 14.1 ppm. MS (ESI): m/z =
395 [M + Na]+.
34.8 mmol) in acetonitrile (270 mL), N-iodosuccinimide (11.7 g,
52.2 mmol) was added at –40 °C. The resulting mixture was then
warmed up and stirred at 0 °C for 4 h. After completion of the
reaction (monitored by TLC), it was quenched with aqueous
Na2S2O3 solution (100 mL). Acetonitrile was removed under re-
duced pressure. The reaction mixture was then diluted with CH2Cl2
(100 mL), and the two layers were separated. The aqueous phase
was extracted with CH2Cl2 (2ϫ 100 mL). The combined organic
phases were washed with brine (2ϫ 100 mL) dried with Na2SO4,
and the solvent was evaporated under reduced pressure. The crude
product was purified by column chromatography on silica gel (ethyl
acetate/hexane = 1:9) to obtain iodocarbonate 14 (19.0 g) as a col-
orless liquid, which was not very stable and used immediately.
(4R,6R)-6-(Benzyloxy)henicos-1-en-4-ol (10): To a solution of 9
(26.2 g, 70.1 mmol) in 1,4-dioxane/water (3:1; 160 mL), 2,6-lutidine
(140.2 mL, 140.2 mmol), OsO4 (345 mg, 1.4 mmol) followed by
NaIO4 (59.6 g, 280.3 mmol) were sequentially added at room tem-
perature, and the mixture was stirred for 1 h. After completion of
the reaction (monitored by TLC), 1,4-dioxane was removed under
reduced pressure, and the residue was diluted with CH2Cl2
(100 mL). The organic layer was separated and the aqueous layer
extracted with CH2Cl2 (2ϫ 100 mL). The combined organic layers
were quickly washed with 1 n HCl (2ϫ 150 mL) to remove excess
2,6-lutidine followed by brine (2ϫ 150 mL), dried with anhydrous
Na2SO4, and concentrated under reduced pressure to give the crude
aldehyde that – on purification by a short flash column chromatog-
raphy on silica gel (ethyl acetate/hexane = 1:3) – afforded the corre-
sponding aldehyde (23.0 g, 87%) as a colorless liquid, which was
used immediately. To a solution of the above aldehyde (23.0 g,
61.4 mmol) in anhydrous CH2Cl2 (460 mL), TiCl4 (61.4 mL,
61.4 mmol; 1 m in CH2Cl2) was added at –78 °C. After 10 min, all-
yltrimethylsilane (11.8 mL, 73.6 mmol) was added and the reaction
mixture stirred under nitrogen at same temperature for 2 h. The
reaction mixture was poured into water (200 mL), and the organic
phase was separated. The aqueous phase was extracted with diethyl
ether (2ϫ 150 mL). The combined organic layers were washed with
10% NaHCO3 (2ϫ 100 mL) and brine (2ϫ 100 mL). The organic
layers were dried with Na2SO4, concentrated under reduced pres-
sure, and purified by silica gel column chromatography (ethyl acet-
ate/hexane = 1:14) to afford 10 (22.8 g, 89%) as a colorless liquid.
(2S,4R)-4-(Benzyloxy)-1-[(S)-oxiran-2-yl]nonadecan-2-ol (15): To a
solution of iodocarbonate 14 (19.0 g, 32.3 mmol) in MeOH
(200 mL), K2CO3 (11.1 g, 80.7 mmol) was added, and the resulting
mixture was stirred at 25 °C for 1 h. After completion of the reac-
tion (monitored by TLC), methanol was evaporated under reduced
pressure. The residue was diluted with H2O (100 mL) and extracted
with diethyl ether (3ϫ 100 mL). The combined organic layers were
washed with brine (2ϫ 100 mL), dried with anhydrous Na2SO4,
and concentrated under reduced pressure to afford the crude prod-
uct, which – on purification by column chromatography on silica
gel (ethyl acetate/hexane = 1:5) – furnished desired epoxy alcohol
15 (12.9 g, 84% over two steps) as a colorless liquid. [α]2D5 = –11.0
(c = 1.5, CHCl ). IR (neat): ν
= 3461, 2924, 1717, 1456, 1220,
˜
3
max
1080 cm–1. H NMR (CDCl3, 500 MHz): δ = 7.26–7.38 (m, 5 H),
4.58–4.48 (m, 2 H), 3.67 (m, 1 H), 3.03 (m, 1 H), 2.87 (br. s, 1 H),
2.71 (m, 1 H), 2.45 (m, 1 H), 1.83–1.63 (m, 3 H), 1.62–1.82 (m, 3
H), 1.32–1.22 (m, 26 H), 0.89 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 129.7, 128.4, 128.0, 127.7, 77.0, 71.2, 66.7,
50.0, 46.6, 40.0, 39.7, 33.3, 31.9, 29.3, 25.4, 22.6, 14.1 ppm. HRMS
(ESI): calcd. for C28H49O3 [M + H]+ 433.3676; found 433.3650.
1
[α]2D5 = –13.2 (c = 1.1, CHCl ). IR (neat) νmax = 33450, 2926, 2853,
(S)-2-{(2S,4R)-4-(Benzyloxy)-2-[(4-methoxybenzyl)oxy]nonadecyl}-
˜
3
1612 cm–1. H NMR (CDCl3, 300 MHz): δ = 7.34–7.26 (m, 5 H), oxirane (16): To a suspension of NaH (2.1 g, 55.4 mmol) in anhy-
1
5.80 (m, 1 H), 5.11–5.02 (m, 2 H), 4.63–4.40 (m, 2 H), 3.92 (m, 1 drous DMF (75 mL), compound 15 (12.0 g, 27.7 mmol) in THF
H), 3.65 (m 1 H), 2.53 (br. s, 1 H), 2.19–2.17 (m, 2 H), 1.51–1.57
(m, 4 H), 1.34–1.22 (m, 24 H), 0.89 (t, J = 6.8 Hz, 3 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 138.3, 134.9, 128.3, 127.8, 127.6,
(50 mL) was added slowly at 0 °C. After 20 min, p-methoxybenzyl
chloride (4.1 mL, 30.5 mmol) was added at 0 °C. The reaction mix-
ture was stirred at room temperature for 12 h. After completion of
117.4, 76.9, 71.1, 67.6, 42.1, 39.3, 33.3, 31.8, 29.6, 29.5, 29.3, 25.3, the reaction (monitored by TLC), it was quenched with ice-cooled
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Total Synthesis and Structure Confirmation of Cryptocaryol A
water and extracted with diethyl ether (3ϫ 100 mL). The combined
organic extracts were dried with Na2SO4, concentrated under re-
duced pressure, and purified by silica gel column chromatography
(ethyl acetate/hexane = 1:6) to afford 16 (13.65 g, 89%) as a color-
2.21–2.14 (m, 2 H), 1.71–1.44 (m, 8 H), 1.32–1.22 (m, 26 H), 0.88
(t, J = 6.9 Hz, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 159.1,
138.9, 134.8, 130.6, 129.6, 128.2, 127.8, 127.4, 117.6, 113.7, 95.4,
75.8, 75.0, 72.5, 70.7, 70.3, 70.0, 55.8, 55.2, 42.1, 41.4, 40.3, 40.0,
33.9, 31.9, 30.0, 29.7, 29.3, 24.9, 22.7, 14.1 ppm. HRMS (ESI):
calcd. for C42H68O6Na [M + Na]+ 691.5016; found 691.4893.
less liquid. [α]2D5 = –17.2 (c = 1.0, CHCl ). IR (neat): ν
= 3444,
˜
3
max
2925, 2854, 1612, 1513 cm–1. 1H NMR (CDCl3, 300 MHz): δ =
7.28–7.32 (m, 5 H), 7.21 (d, J = 8.3 Hz, 2 H), 6.84 (d, J = 8.3 Hz,
2 H), 4.50–4.43 (m, 2 H), 4.32–4.26 (m, 2 H), 3.77 (m, 1 H), 3.64
(m, 1 H), 3.04 (m, 1 H), 2.76 (m, 1 H), 2.47 (m, 1 H), 1.80–1.71
(m, 2 H), 1.82–1.59 (m, 4 H), 1.32–1.22 (m 26 H), 0.88 (t, J =
6.8 Hz, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 159.8, 138.9,
129.4, 128.3, 127.7, 127.4, 113.7, 75.6, 73.5, 70.8, 70.7, 55.2, 49.2,
46.8, 40.4, 37.1, 34.0, 32.0, 30.0, 29.7, 29.3, 24.8, 22.6, 14.1 ppm.
HRMS (ESI): calcd. for C36H56O4Na [M + Na]+ 575.4072; found
575.4096.
(4R,6R,8R,10S,12R)-12-(Benzyloxy)-6,8,10-tris(methoxymethoxy)-
heptacos-1-en-4-ol (19): To a solution of terminal epoxide 18d[21]
(4.5 g, 6.1 mmol) in anhydrous THF (140 mL) under nitrogen, CuI
(0.11 g, 0.61 mmol) was added and the resulting mixture stirred at
25 °C for 30 min. It was cooled to –20 °C and C3H5MgBr
(18.5 mL, 1.0 m in THF) slowly added to it. The reaction mixture
was stirred at the same temperature for 30 min. It was then slowly
warmed to room temperature. After 1.5 h (monitored by TLC), it
was quenched with saturated NH4Cl solution (30 mL) and diluted
with ethyl acetate (50 mL). The organic phase was separated and
the aqueous phase extracted with ethyl acetate (3ϫ 50 mL). The
combined organic layers were washed with brine (2ϫ 50 mL), dried
with anhydrous Na2SO4 and concentrated under reduced pressure
to afford the crude product that – on purification by column
chromatography on silica gel (ethyl acetate/hexane = 1:3) – fur-
(4R,6R,8R)-8-(Benzyloxy)-6-[(4-methoxybenzyl)oxy]tricos-1-en-4-ol
(17): To a solution of 16 (12.0 g, 21.7 mmol) in anhydrous THF
(140 mL) under nitrogen, CuI (0.41 g, 2.17 mmol) was added, and
the resulting mixture was stirred at 25 °C for 30 min. It was cooled
to –20 °C, C3H5MgBr (65 mL, 1.0 m in THF) slowly added, and
the mixture stirred at the same temperature for 30 min. It was then
slowly warmed to room temperature. After 2 h (monitored by
TLC), it was quenched with saturated NH4Cl solution (75 mL) and
diluted with ethyl acetate (100 mL). The organic phase was sepa-
rated and the aqueous phase extracted with ethyl acetate (3 ϫ
75 mL). The combined organic layers were washed with brine (2ϫ
150 mL), dried with anhydrous Na2SO4, and concentrated under
reduced pressure to afford the crude product that – after purifica-
tion by column chromatography on silica gel (ethyl acetate/hexane
= 1:4) – gave 17 (10.99 g, 87%) as a colorless liquid. [α]2D5 = –13.6
nished 19 (4.05 g, 88%) as a colorless liquid. [α]2D5 = –10.6 (c = 2.0,
1
CHCl ). IR (neat): ν
= 3472, 2926, 1613, 1247, 1095 cm–1. H
˜
3
max
NMR (CDCl3, 300 MHz): δ = 7.36–7.27 (m, 5 H), 7.21 (d, J =
8.3 Hz, 2 H), 6.84 (d, J = 8.3 Hz, 2 H), 5.82 (m, 1 H), 5.15–5.05
(m, 1 H), 4.72–4.40 (m, 6 H), 4.34–4.23 (m, 2 H), 3.80 (m, 1 H),
3.77 (s, 3 H), 3.75–3.66 (m, 2 H), 3.60 (m, 1 H), 3.39 (s, 3 H), 3.35
(m, 1 H), 3.31 (s, 3 H), 3.05 (br. s, 1 H), 2.26–2.16 (m, 2 H), 2.03–
1.81 (m, 2 H), 1.80–1.59 (m, 8 H), 1.30–1.22 (m, 26 H), 0.88 (t, J
= 6.8 Hz, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 159.1, 139.0,
(c = 0.8, CHCl ). IR (neat): ν
= 3450, 2925, 1612, 1461, 1248, 134.7, 130.8, 129.3, 128.2, 127.6, 127.3, 117.5, 113.7, 95.6, 95.1,
˜
3
max
1066 cm–1. H NMR (CDCl3, 300 MHz): δ = 7.32–7.21 (m, 5 H), 75.8, 74.7, 72.8, 72.3, 70.7, 70.3, 69.7, 55.8, 55.1, 42.1, 41.0, 40.4,
1
7.15 (d, J = 8.5 Hz, 2 H), 6.78 (d, J = 8.5 Hz, 2 H), 5.75 (m, 1 H),
40.2, 40.1, 34.0, 31.8, 29.8, 29.6, 29.3, 24.9, 22.6, 14.1 ppm. HRMS
5.02–4.92 (m, 2 H), 4.55–4.49 (m, 4 H), 3.79 (m, 1 H), 3.70 (m, 1 (ESI): calcd. for C46H76O8Na [M + Na]+ 779.5432; found 779.5428.
H), 3.75 (s, 3 H), 3.50 (m,1 H), 2.96 (br. s, 1 H), 2.19–2.12 (m, 2
(4R,6R,8R,10S,12S,14R)-14-(Benzyloxy)-12-[(4-methoxybenzyl)-
oxy]-6,8,10-tris(methoxymethoxy)nonacos-1-en-4-ol (20): To a solu-
H), 1.74–1.65 (m, 2 H), 1.63–1.45 (m, 4 H), 1.33–1.22 (m, 26 H),
0.88 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ =
tion of MOM ether 19d[21] (0.5 g, 0.6 mmol) in anhydrous THF
159.2, 138.6, 134.8, 130.2, 129.5, 128.3, 127.8, 127.5, 117.4, 76.3,
(10 mL) under nitrogen, CuI (0.01 g, 0.06 mmol) was added, and
76.0, 70.6, 69.8, 55.2, 42.5, 41.3, 39.8, 33.9, 31.9, 29.8, 29.6, 29.3,
the resulting mixture was stirred at 25 °C for 30 min. It was cooled
24.8, 22.6, 14.1 ppm. HRMS (ESI): calcd. for C38H60O4Na [M +
to –20 °C and C3H5MgBr (2.4 mL, 1.0 m in THF) slowly added to
it; the reaction mixture was stirred at the same temperature for
Na]+ 603.4388; found 603.4380.
(4R,6R,8S,10R)-10-(Benzyloxy)-8-[(4-methoxybenzyl)oxy]-6-
(methoxymethoxy)pentacos-1-en-4-ol (18): To a solution of the ter-
minal epoxide 17d[21] (6.0 g, 9.4 mmol) in anhydrous THF (60 mL)
under nitrogen was added CuI (0.178 g, 0.9 mmol) and the re-
20 min. It was then slowly warmed to room temperature. After 1 h
(monitored by TLC), it was quenched with saturated NH4Cl solu-
tion (10 mL) and diluted with ethyl acetate (20 mL). The organic
layers were separated, and the aqueous layer was extracted with
sulting mixture stirred at ambient temperature for 30 min. ethyl acetate (3 ϫ 20 mL). The combined organic layers were
C3H5MgBr (28.1 mL, 1.0 m in THF) was slowly added at –20 °C
and stirring continued at the same temperature for 30 min. It was
slowly warmed to room temperature. After 2 h (monitored by
TLC), the reaction was quenched with saturated NH4Cl solution
(60 mL) and diluted with ethyl acetate (60 mL). The organic phase
was separated and the aqueous phase extracted with ethyl acetate
(3ϫ 60 mL). The combined organic layers were washed with brine
(2ϫ 75 mL), dried with anhydrous Na2SO4, and concentrated un-
der reduced pressure to afford the crude product, which – after
purification by column chromatography on silica gel (ethyl acetate/
hexane, 1:4) – furnished homoallyl alcohol 18 (5.71 g, 92%) as a
washed with brine (2ϫ 10 mL), dried with anhydrous Na2SO4, and
concentrated under reduced pressure to afford the crude product
that – on purification by column chromatography on silica gel
(ethyl acetate/hexane = 1:3) – furnished homoallyl alcohol 20
(0.42 g, 82%) as a colorless liquid. [α]2D5 = –8.3 (c = 1.25, CHCl3):
IR (neat): ν
= 3470, 2926, 1718, 1248, 1035 cm–1. 1H NMR
˜
max
(CDCl3, 300 MHz): δ = 7.37–7.27 (m, 5 H), 7.21 (d, J = 8.3 Hz, 2
H), 6.84 (d, J = 8.3 Hz, 2 H), 5.78 (m, 1 H), 5.15–5.05 (m, 2 H),
4.72–4.55 (m, 6 H), 4.55–4.41 (m, 2 H), 4.31–4.21 (m, 2 H), 3.83–
3.78 (m, 3 H), 3.76 (m, 1 H), 3.75–3.69 (m, 2 H), 3.61 (m, 1 H),
3.37 (s, 3 H), 3.36 (m, 1 H), 3.34 (s, 2 H), 3.77 (s, 3 H), 3.74–3.66
(m, 2 H), 3.60 (m, 1 H), 3.38 (s, 3 H), 3.35 (s, 3 H), 3.30 (s, 3 H),
colorless liquid. [α]2D5 = –9.3 (c = 1.1, CHCl ). IR (neat): ν
=
˜
3
max
3469, 2925, 2854, 1719, 1248, 1036 cm–1
300 MHz): δ = 7.33–7.26 (m, 5 H), 7.19 (d, J = 8.7 Hz, 2 H), 6.82
(d, J = 8.7 Hz, 2 H), 5.76 (m, 1 H), 5.13–5.04 (m, 2 H), 4.68–4.48 139.1, 135.0, 129.3, 128.1, 127.6, 127.3, 117.4, 113.7, 95.7, 95.2,
.
1H NMR (CDCl3, 2.28–2.18 (m, 2 H), 2.02–1.43 (m, 12 H) 1.29–1.20 (m, 26 H), 0.88
(t, J = 6.8 Hz, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 159.0,
(m, 3 H), 4.42–4.22 (m, 3 H), 3.84 (m, 1 H), 3.77 (s, 3 H), 3.67 (m,
1 H), 3.56 (m, 1 H), 3.33 (s, 3 H), 3.31 (m, 1 H), 2.97 (br. s, 1 H),
95.0, 75.7, 74.5 72.7, 72.4, 72.1, 70.8, 70.2, 69.6, 55.8, 55.7, 55.1,
42.1, 40.8, 40.4, 40.2, 39.8, 34.0, 31.8, 29.9, 29.6, 29.3, 24.9, 22.6,
Eur. J. Org. Chem. 2013, 1051–1057
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1055

D. S. Reddy, D. K. Mohapatra
FULL PAPER
14.1 ppm. HRMS (ESI): calcd. for C50H84O10Na [M + Na]+
867.5957; found 867.5958.
chromatography on silica gel (methanol/chloroform = 1:19) – fur-
nished 1 (37 mg, 76%) as a colorless liquid. [α]2D5 = +11.4 (c = 1.5,
MeOH). IR (neat): ν
= 3367, 2920, 2851, 1715, 1425, 1335,
˜
max
(4R,6S,8S,10S,12S,14R)-14-(Benzyloxy)-12-[(4-methoxybenzyl)-
oxy]-6,8,10-tris(methoxymethoxy)heptacos-1-en-4-yl Acrylate (21):
To a solution of 20 (0.3 g, 0.35 mmol) in CH2Cl2 (8 mL), DMAP
(12.8 mg, 0.10 mmol) and iPr2NEt (0.18 mL, 1.0 mmol, 3 equiv.)
were added. The reaction mixture was cooled to –78 °C, and acryl-
oyl chloride (0.04 mL, 0.5 mmol, 1.5 equiv.) was added. After 1 h
at –78 °C, the reaction mixture was poured into brine. The layers
were separated, and the aqueous phase was extracted with Et2O.
The combined organic extracts were dried with Na2SO4, filtered,
and concentrated under reduced pressure. The crude material was
purified by flash chromatography on silica gel (ethyl acetate/hexane
= 1:3) to obtain acrylate 21 (0.28 g, 90%) as a colorless liquid.
1094 cm–1. H NMR (CD3OD, 500 MHz): δ = 7.04 (m, 1 H), 5.97
(dd, J = 9.8, 2.1 Hz, 1 H), 4.69 (m, 1 H), 4.07–3.97 (m, 4 H), 3.80
(m, 1 H), 2.52 (m, 1 H), 2.39 (m, 1 H), 1.98 (m, 1 H), 1.87 (m, 1
H), 1.72–1.57 (m, 7 H), 1.54–1.50 (m, 2 H), 1.46–1.42 (m, 2 H),
1.32–1.24 (br. m, 26 H), 0.89 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR
(CD3OD, 75 MHz): δ = 167.0, 148.4, 121.3, 77.3, 69.9, 69.8, 69.0,
68.1, 67.3, 46.0, 45.7, 45.3, 45.0, 43.0, 39.2, 33.1, 30.8, 30.5, 30.2,
26.8, 23.8, 14.5 ppm. HRMS (ESI): calcd. for C30H56O7Na [M +
Na]+ 551.3918; found 551.3915.
1
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra of all key intermedi-
[α]2D5 = –11.4 (c = 1.0, CHCl ). IR (neat): ν
= 2925, 2853, 1723,
ates and final products.
˜
3
max
1613, 1218, 1035 cm–1. 1H NMR (CDCl3, 300 MHz): δ = 7.34–7.27
(m, 5 H), 7.22 (d, J = 8.4 Hz, 2 H), 6.84 (d, J = 8.4 Hz, 2 H), 6.38
(dd, J = 16.1, 1.3 Hz, 2 H), 6.09 (m, 1 H), 5.84–5.69 (m, 2 H),
5.13–5.04 (m, 2 H), 4.64–4.54 (m, 6 H), 4.53–4.43 (m, 2 H), 4.30–
4.21 (m, 2 H), 3.79 (m, 1 H), 3.77 (s, 3 H), 3.74–3.66 (m, 3 H), 3.61
(m, 1 H), 3.37 (s, 3 H), 3.36 (m, 1 H), 3.35 (s, 3 H), 3.28 (s, 3 H),
2.50–2.28 (m, 2 H), 1.98–1.77 (m, 5 H), 1.75–1.61 (m, 5 H), 1.57–
1.43 (m, 2 H), 1.33–1.20 (m, 26 H), 0.88 (t, J = 6.8 Hz, 3 H) ppm.
13C NMR (CDCl3, 75 MHz): δ = 165.5, 159.0, 139.1, 133.3, 130.9,
130.5, 129.4, 128.7, 128.2, 127.6, 127.2, 118.0, 113.7, 95.6, 95.5,
95.4, 75.7, 72.7, 72.4, 72.3, 72.2, 70.8, 70.7, 70.2, 55.8, 55.7, 55.2,
40.6, 40.3, 40.0, 39.9, 38.6, 38.5, 34.5, 34.1, 31.9, 29.7, 29.6, 29.3,
24.9, 22.6, 14.1 ppm. HRMS (ESI): calcd. for C53H86O11Na [M +
Na]+ 921.6060; found 921.6062.
Acknowledgments
We are grateful to the Director, CSIR – Indian Institute of Chemi-
cal Technology, Hyderabad, for his constant support and encour-
agement. D. S. R. thanks the Council of Scientific and Industrial
Research (CSIR), New Delhi, India, for financial assistance in the
form of a research fellowship. D. K. M. also thanks the Council of
Scientific and Industrial Research (CSIR), New Delhi, India, for a
research grant (INSA Young Scientist Award Scheme).
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3
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1
1219 cm–1. H NMR (CDCl3, 300 MHz): δ = 7.34–7.27 (m, 5 H),
7.22 (d, J = 8.3 Hz, 2 H), 6.87 (m, 1 H), 6.84 (d, J = 8.3 Hz, 2 H),
6.02 (d, J = 9.8 Hz, 1 H), 4.70–4.39 (m, 8 H), 4.31–4.20 (m, 2 H),
4.12 (dd, J = 7.6, 6.8 Hz, 2 H), 3.86 (m, 1 H), 3.81–3.66 (m, 5 H),
3.60 (m, 1 H), 3.40–3.25 (m, 10 H), 2.48–2.21 (m, 2 H), 2.04–1.43
(m, 10 H), 1.36–1.15 (m, 26 H), 0.88 (t, J = 6.8 Hz, 3 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 164.2, 159.0, 144.8, 139.0, 130.8,
129.4, 129.4, 129.3, 128.2, 127.6, 127.3, 121.4, 113.7, 95.7, 95.6,
95.5, 77.2, 75.7, 75.2, 72.7, 72.3, 71.6, 70.8, 70.2, 55.7, 55.2, 40.6,
40.3, 40.0, 39.6, 39.5, 34.0, 31.9, 29.9, 29.7, 29.6, 29.3, 29.2, 22.6,
14.1 ppm. HRMS (ESI): calcd. for C51H82O11Na [M + Na]+
893.5749; found 893.5757.
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Received: October 4, 2012
Published Online: December 19, 2012
Eur. J. Org. Chem. 2013, 1051–1057
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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