First total synthesis of the potent anticancer natural product dideoxypetrosynol A: Preparation of the skipped (Z)-enediyne moiety by oxidative coupling of homopropargylphosphonium ylide

Article abstract of DOI:10.1002/ejoc.200800593

Dideoxypetrosynol A is a C30 polyacetylenic alcohol with C₂ symmetry. The first total synthesis of both enantiomers of the potent anti-cancer natural product (+)- and (-)-dideoxypetrosynol A is reported. The key step is an oxidative coupling of a homopropargylphosphonium ylide to prepare the skipped (Z)-enediyne moiety. The natural dideoxypetrosynol A was isolated as a racemic mixture as shown in structure 1. The absolute configurations of the chiral centers are established for the (+)- and (-)-enantiomers using Burgess' enzymatic resolution procedure with Pseudomonas AK lipase. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800593

FULL PAPER
DOI: 10.1002/ejoc.200800593
First Total Synthesis of the Potent Anticancer Natural Product
Dideoxypetrosynol A: Preparation of the “Skipped” (Z)-Enediyne Moiety by
Oxidative Coupling of Homopropargylphosphonium Ylide
Benjamin W. Gung*[a] and Ann O. Omollo[a]
Keywords: Total synthesis / Antitumor agents / Natural products / (Z)-Enediyne / Dideoxypetrosynol A
Dideoxypetrosynol A is a C30 polyacetylenic alcohol with C2
symmetry. The first total synthesis of both enantiomers of the
potent anti-cancer natural product (+)- and (–)-dideoxypetro-
synol A is reported. The key step is an oxidative coupling of a
homopropargylphosphonium ylide to prepare the “skipped”
(Z)-enediyne moiety. The natural dideoxypetrosynol A was
isolated as a racemic mixture as shown in structure 1. The
absolute configurations of the chiral centers are established
for the (+)- and (–)-enantiomers using Burgess’ enzymatic
resolution procedure with Pseudomonas AK lipase.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
Along with three similar polyacetylenic alcohols, dide-
oxypetrosynol A (1) was isolated by Jung and co-workers
off the Komun Island, Korea from the marine sponge Pe-
trosia sp. guided by a brine shrimp assay.[1] These com-
pounds (Figure 1) have structural features related to duryne
(2)[2] and petrosynol (3),[3,4] both of which have been found
to possess anticancer and other interesting biological activi-
ties.[5] Dideoxypetrosynol A (1) was also found to have po-
tent anticancer activity and exhibited an ED50 of 0.02 µg/
mL against human ovarian cancer cells and of 0.01 µg/mL
against human skin cancer cells.[1] It is noteworthy that the
cytotoxic activities of compound 1 is one order of magni-
tude higher than those found for doxorubicin, which is one
of the most commonly used chemotherapeutic drugs and
exhibits a wide spectrum of activity against solid tumors,
lymphomas, and leukemias.[6] Dideoxypetrosynol A (1) was
also found to inhibit DNA replication at the initiation
stage.[7] However, due to the minute yield (23 mg out of
14.5 kg of dry sponge) from the natural source, only limited
studies of biological activity have been performed. To the
best of our knowledge, no synthetic study of dideoxypetro-
synol A has been reported.
Figure 1. Anticancer C30 polyacetylenic alcohols, dideoxypetrosy-
nol A (1), duryne (2), and petrosynol (3). Compound 1 contains
a central (Z)-enedipropargyl moiety, also known as a “skipped”
enediyne.
“skipped” enediyne by Gleiter)[9] in 1 posed a new problem
for an efficient synthesis. Here we are pleased to report a
successful total synthesis of dideoxypetrosynol A with an
oxidative coupling strategy to prepare the “skipped”
enediyne moiety.
Recently we reported a total synthesis of duryne (2) and
assigned the geometry of the central C=C olefin and the
absolute stereochemistry of the chiral centers.[8] Although
the structures of compounds 1 and 2 are similar, the central
(Z)-enedipropargyl moiety (which was first coined the
Results and Discussion
Current literature method for constructing the “skipped”
(Z)-enediyne system such as compound 4, Scheme 1, is an
SN2 alkylation of (Z)-1,4-dichloro-2-butene with a Grig-
nard reagent made from alkyne.[9–11] The concurrent forma-
tion of the SN2Ј product 5 and the elimination product 6,
as shown in Scheme 1, are the main problems for this ap-
proach. So far only poor yields have been reported.[11,12]
[a] Department of Chemistry & Biochemistry, Miami University,
Oxford, OH 45056, USA
Fax: +1-513-529-5715
E-mail: gungbw@muohio.edu
Supporting information for this article is available on the
WWW under http://www.eurjoc.org/ or from the author.
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Eur. J. Org. Chem. 2008, 4790–4795

Total Synthesis of Dideoxypetrosynol A
to give the elimination product 10. Propargylic CHs are well
known to be acidic and amide bases have been used to re-
move propargylic protons,[16–18] though there is little data to
be found concerning the pKa of propargylic CH groups.[19]
Propargyllithium is known to have an allene-like struc-
ture,[20] suggesting that propargylic CH groups are less
acidic than allenylic CH groups, which is consistent with
gas phase acidity orders of allene and propyne.[21] Thus the
CH2 bonded to the positively charged phosphorus atom in
9a should be more acidic than the propargylic CH2. There-
fore, it should be possible to selectively remove the
Ph3P+CH2 proton in compound 9a. A survey of different
bases was performed and the results are shown in Scheme 2.
Scheme 1. Results from the existing method.
Gleiter and Merger reported an improvement of yield
from 20% to 60% by using ethynylmagnesium chloride in
stead of ethynylmagnesium bromide.[9]
Unfortunately reactions of long-chain alkynylmagnesium
chloride did not seem to give any better yields.[11,12] In our
hands, little of the desired product was obtained when using
the alkynylmagnesium chloride reagent prepared from com-
pound 12 (see Scheme 3).
We turned our attention to an alternate strategy after
failing to improve the yields with the alkynylation of cis-
1,4-dichloro-2-butene. In our recent effort in the synthesis
of duryne (2),[8] the (Z)-geometry of the central double
bond was established by an autooxidation of the Wittig rea-
gent 7 generated in situ as reported by Poulain and co-
workers, Equation (1).[13] The reaction mixture was satu-
rated with oxygen before refluxing for 16 h to produce the
cis-olefin 8.[14]
Scheme 2. Base effect on Wittig reagent formation and oxidative
coupling.
The use of n-butyllithium in place of NaHMDS led to a
much better yield of the desired product 11b than the SN2
alkynylation procedure shown in Scheme 1. Interestingly,
the less strong bases are all inferior in this reaction com-
pared to n-butyllithium. A previous report also indicated
that n-butyllithium gave smooth formation of the desired
Wittig reagent on a similar phosphonium salt.[22] On the
basis of these observations, the formation of the by prod-
ucts such as enyne 10 might be due to (1) the steric bulk of
the base used and (2) the reversibility of the deprotonation
step when the less strong bases such as NaHMDS are used.
Thus, a significant amount of the elimination product 10
could occur through a shift of the reaction equilibrium even
only a small percentage of the propargylic proton was ini-
tially removed. The following elimination and the formation
of enyne 10 are not reversible. This explains why enyne 10
was produced when KOtBu and NaHMDS were used.
When the reaction was performed in a mixed solvent sys-
tem containing methanol, the homopropargyl(diphenyl)-
phosphane oxide 11c was produced in 88% yield. The for-
mation of 11c did not require the presence of oxygen. It is
However, when the same condition was applied to the
phosphonium salt 9a in an attempt to prepare the cis-olefin
11a, the only identifiable product was the enyne 10, along
with mixtures of unidentified products, Equation (2). It ap-
peared that a proton abstraction from the propargylic posi-
tion, at least in part, had occurred in compound 9a when
sodium hexamethyldisilazide (NaHMDS) was used as the
base in the reaction.
The most acidic proton in the phosphonium salt 9a presumably formed through a CH3O– attack on the phos-
should be the CH2 attached to the positively charged phos- phonium salt at the phosphorus atom followed by proton-
phorus atom (Ph3P+CH2, pKa ≈ 22).[15] However, the adja- ation of a phenyl anion and an SN2 attack on the resulting
cent propargylic CH2 in compound 9a could lose a proton Ph2RP=O+–CH3 by a CH3O group.
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Once we found the proper base to use in the preparation
Although the natural product dideoxypetrosynol A was
of the Wittig reagent, the synthesis of the target started with reported as a possible racemic mixture, it was unclear
the known terminal acetylene 12, Scheme 3.[23] Homopro- whether racemization had occurred during the isolation-
pargyl alcohol 13 was prepared following a procedure re- identification process.[1] It is important to identify the effi-
ported by Brummond.[24] This procedure employs Me3Al as cacy of each enantiomer’s action on cancer cells. Therefore,
an additive in the ethylene oxide opening reaction and gives we decided to carry out an enzymatic resolution to assign
a reproducible yield of the desired product. Compound 13 the absolute configurations to each enantiomer.
was converted into the homopropargyl bromide by a modi-
The general procedures of Burgess were followed using li-
fication of the Appel reaction.[25] The preparation of the pase AK from pseudomonas sp for the enzymatic resolution
phosphonium salt 9a [Equation (2)] follows the reported of the acetylenic alcohol 1.[27,28] The progress of the reaction
procedure by Dawson.[26] nBuLi treatment of 9a followed was followed by both thin-layer chromatography and 1H
by saturating the reaction mixture with oxygen and reflux NMR to ensure a clean kinetic resolution of the enantiomers.
in THF produced the cis-enediyne 11a in 86% yield. With The separation of the diacetate 16, the meso monoacetate 17,
the key intermediate 11a in hand, dial 15 was obtained and the diol (–)-1 was done by column chromatography.
through a two-step sequence: (1) removal of the TBS pro-
The (R,R)-diol 1 has a negative optical rotation of [α]D
tecting group with TBAF in THF and (2) PCC oxidation = –40.4. The removal of the acetate group from 16 yields
of the resulting diol, Scheme 3. The Wittig reaction of the (S,S)-diol 1, which gives a positive optical rotation of [α]D
dialdehyde with Ph3P=CHCHO yielded a α,β-unsaturated = +41.3. The assignment of the absolute configurations is
dial and the addition of acetylenic magnesium bromide to based on Burgess active site model for the lipases from
the dial produced the racemic natural product 1.
Pseudomonas sp.[27] This model predicts that alcohols re-
solved most efficiently have one small and one relatively
large group attached to the hydroxylmethine carbon. Dide-
oxypetrosynol A (1) is similar in structure to several C2-
symmetric polyacetylenic alcohols including adociacetylene,
duryne, and a C20 acetylenic alcohol, all of which we have
successfully resolved using lipase from Pseudomonas
sp.[8,23,29] For most secondary alcohols, the rate of acylation
is faster for the (R)-configuration than for the (S)-configu-
ration. However, for the acetylenic alcohol 1, the isomer
with (S,S) configuration is acylated faster because the small
acetylenic group has a higher priority in the nomenclature
system. From these considerations and the data obtained,
we assign the (3S,28S) configurations to the enantiomer
with a positive optical rotation and the (3R,28R) to the en-
antiomer with a negative optical rotation. To corroborate
this assignment, several known C2-symmetric acetylenic
alcohols isolated from marine sources[3,4,30,31] are listed in
Table 1 for comparison purpose.
Table 1. Absolute configurations of naturally occurring C2-sym-
metric acetylenic alcohols.
Name
Chain [α]D
length
Configura- Origin
tion
Adociacetylene
Petrosynol
C20 alkynol
30
30
20
+21.7
+107
+26
S,S
S,S
S,S
Adocia sp.
Petrocia sp.
Callyspongia
pseudoreticulata
Cribrochalina
dura
Duryne
30
30
+29
S,S
S,S
Dideoxy-petro-
+41.3
Petrocia sp.
synol A (1)
Conclusions
A total synthesis of the potent anticancer polyacetylenic
alcohol dideoxypetrosynol A (1) has been achieved. The key
step involves the coupling of a homopropargylphospho-
nium ylide to produce the cis-“skipped” enediyne moiety.
Scheme 3. Synthesis of dideoxypetrosynol A.
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Eur. J. Org. Chem. 2008, 4790–4795

Total Synthesis of Dideoxypetrosynol A
(75 MHz, CDCl3, 23 °C): δ = 0.04, 18.4, 18.7, 23.4, 25.7, 25.9, 28.7,
28.8, 28.9, 30.3, 32.8, 63.2, 77.3, 82.7 ppm.
n-Butyllithium was found to be the most effective base in
the preparation of the Wittig reagent from the triphenyl-
phosphonium salt containing a homopropargyl substituent.
Two-directional synthesis is executed in the remaining steps
to obtain the racemic polyacetylenic natural product 1 in
an efficient 8 steps and 33.7% overall yield starting from
the known compound 12. The absolute configurations of
the (+)- and (–)-dideoxypetrosynol have been established
through the total synthesis of 1 and the subsequent enzy-
matic resolution of the racemic mixture.
1,22-Bis[tert-butyl(dimethyl)silanyloxy]docos-11-ene-8,14-diyne (11a):
A solution of 14 (2.4 g, 6.4 mmol) and Ph3P (1.65 g, 6.4 mmol) in
CH3CN (15 mL) was stirred at reflux for 16 h and then concen-
trated under reduced pressure to afford the crude product which
was triturated with hexanes several times to afford 9a (3.2 g, 88%):
IR: ν = 1110, 1254, 1437, 1471, 1587, 1824, 2176, 2855, 2928, 3055
˜
1
cm–1. H NMR (300 MHz, CDCl3, 23 °C): δ = 0.02 (s, 6 H), 0.86
(s, 9 H), 1.12–1.26 (m, 8 H), 1.57 (t, J = 2.1 Hz, 2 H), 1.67 (br., 2
H), 2.81 (br. d, 2 H), 3.57 (t, J = 6.6 Hz, 2 H), 4.12 (dt, J = 12.2,
6.3 Hz, 2 H) 7.67 (dd, J = 7.9, 3.4 Hz, 6 H), 7.85 (dt, J = 8.2,
4.2 Hz, 3 H), 7.88 (dt, J = 8.5, 7.3, 6 H5 Hz) ppm. 13C NMR
(75 MHz, CDCl3, 23 °C): δ = 0.04, 13.2, 18.3, 18.4, 22.6, 23.0, 25.7,
25.8, 25.9, 28.3, 28.8, 32.8, 63.2, 76.9, 85.4, 128.7, 130.2, 130.3,
133.9, 134.9 ppm.
Experimental Section
General: All reactions were carried out under nitrogen in oven-
dried glassware with magnetic stirring. Reagents were purchased
from commercial sources and used directly without further purifi-
cation. Purification of reaction products was carried out by flash
chromatography using silica gel 40–63 µm (230–400 mesh), unless
otherwise stated. Reactions were monitored by 1H NMR and/or
thin-layer chromatography. Visualization was accomplished with
UV light, staining with 5% KMnO4 solution followed by heating.
Chemical shifts are recorded in ppm (δ) using tetramethylsilane (H,
C) as the internal reference. Data are reported as follows: s = sing-
let, d = doublet, t = triplet, q = quartet, m = multiplet; integration,
coupling constant(s) in Hz.
A solution of 9 (2.2 g, 3.91 mmol) in THF (20 mL) under N2 was
cooled to 0 °C followed by dropwise addition of nBuLi (2.44 mL,
3.91 mmol) by a syringe. The mixture was stirred at 0 °C for 2 h
then warmed to room temperature and stirred for a further 1 h and
then oxygen was bubbled into the reaction mixture. Stirring was
continued at 60 °C for 16 h. The reaction mixture was quenched
with saturated NH4Cl and the mixture poured into H2O. Purifica-
tion was effected by column chromatography to give 11 as an oil
(1.9 g, 86%): IR: ν = 1005, 1048, 1094, 1253, 1360, 1462, 2855,
˜
1
2928 cm–1. H NMR (300 MHz, CDCl3, 23 °C): δ = 0.02 (s, 6 H),
0.86 (s, 9 H), 1.28–1.50 (m, 20 H), 2.11 (t, J = 2.3 Hz, 2 H), 2.90
(br., 4 H), 3.57 (t, J = 6.6 Hz, 2 H), 5.47 (t, J = 4.5 Hz, 2 H) ppm.
13C NMR (75 MHz, CDCl3, 23 °C): δ = 0.04, 17.1, 18.3, 18.8, 25.7,
25.9, 28.8, 28.9, 29.0, 32.8, 63.2, 77.6, 80.4, 126.5 ppm.
11-(tert-Butyldimethylsilanyloxy)undec-3-yn-1-ol
(13):
nBuLi
(7.2 mL, 11.5 mmol) wass added dropwise to a solution of the al-
kyne 12 (2.45 g, 9.6 mmol) in THF (10 mL) at –78 °C. After 45 min
the flask was placed in an ice bath for 15 min then Me3Al (1 mL,
1.92 mmol) was added followed by ethylene oxide (0.6 mL,
11.5 mmol). The ice bath was removed and the reaction mixture
was stirred at room temperature for 36 h after which it was
quenched by the addition of H2O and diethyl ether. The biphasic
mixture was transferred into a separatory funnel and 10% HCl was
added until it eliminated the aluminum emulsion. The aqueous
layer was extracted using EtOAc. The combined organics were
dried (MgSO4), filtered, and concentrated under reduced pressure.
Purification was effected by column chromatography to afford 13
(Z)-Docos-11-ene-8,14-diynedial (15): TBAF (9.23 mL, 9.23 mmol)
was added to a stirred solution of 11 (1.3 g, 2.3 mmol) in THF
(21 mL) at 0 °C. The mixture was stirred at this temperature for
10 min then warmed to room temperature and stirred for 2 h. The
reaction mixture was then filtered through a silica gel pad and
washed with 80% EtOAc/hexanes. The filtrate was concentrated
under high vacuum and the crude material was purified by column
chromatography to afford the diol as a yellow solid (694 mg, 87%);
m.p. 38–39 °C: IR: ν = 1057, 1096, 1255, 1462, 2855, 2929, 3339
˜
cm–1. 1H NMR (300 MHz, CDCl3, 23 °C): δ = 1.28–1.54 (m, 20
H), 2.09–2.13 (m, 4 H), 2.89 (br., 4 H), 3.60 (t, J = 6.7 Hz, 4 H),
5.45 (t, J = 4.5 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3, 23 °C):
δ = 17.2, 18.7, 25.6, 28.8, 28.9, 29.0, 32.7, 62.9, 77.7, 80.4, 126.5
ppm.
as clear oil (2.2 g, 78%): IR: ν = 1045, 1097, 1254, 1471, 2244,
˜
2856, 2929, 3380 cm–1. 1H NMR (300 MHz, CDCl3, 23 °C): δ =
0.02 (s, 6 H), 0.86 (s, 9 H), 1.27–1.49 (m, 10 H), 1.81 (br., 1 H),
2.13 (t, J = 2.3 Hz, 2 H), 2.41 (t, J = 4.1 Hz, 2 H), 3.58 (t, J =
6.7 Hz, 2 H), 3.66 (dt, J = 6.2, 4.3 Hz, 2 H) ppm. 13C NMR
(75 MHz, CDCl3, 23 °C): δ = 0.04, 18.4, 18.7, 23.4, 23.2, 25.6, 25.9,
28.8, 28.9, 32.8, 61.3, 63.2, 76.3, 82.5 ppm. HRMS: calcd. for
C17H34O2Si [M + Na] 321.2226; found 321.2204.
The diol (690 mg, 1.77 mmol) was dissolved in CH2Cl2 (2 mL).
This mixture was added to a stirred suspension consisting of PCC
(1.2 g, 5.32 mmol) and Celite (1.2 g) in CH2Cl2 (15 mL) under N2.
After 2 h the starting material disappeared and the mixture was
diluted with Et2O then filtered through a pad of Celite. This was
thoroughly rinsed with Et2O followed by solvent removal under
(11-Bromoundec-8-ynyloxy)-tert-butyl(dimethyl)silane (14): A reac-
tion mixture containing 13 (2.2 g, 7.34 mmol) in dry THF (18 mL)
was treated with Ph3P (3.9 g, 14.68 mmol), dry pyridine (0.6 mL,
7.34 mmol) and CBr4 (2.42 g, 7.34 mmol). After stirring for 4 h at
room temperature the reaction mixture was diluted with H2O and
the aqueous solution was extracted with EtOAc. The combined
organic solution was washed with 1  HCl, H2O and brine in that
order. This was then dried (MgSO4) filtered and concentrated in
vacuo. The resulting oil was triturated with hexanes and the com-
bined washings were concentrated in vacuo. Purification was ef-
reduced pressure to afford 15 as an oil (634 mg, 92%): IR: ν =
˜
1
1464, 1724, 2857, 2932 cm–1. H NMR (300 MHz, CDCl3, 23 °C):
δ = 1.35–1.67 (m, 16 H), 2.12 (t, J = 2.1 Hz, 4 H), 2.39 (dt, J =
7.2, 1.5 Hz, 4 H), 2.89 (br., 4 H), 5.45 (t, J = 4.5 Hz, 2 H), 9.73 (t,
J = 1.8 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3, 23 °C): δ =
17.2, 18.7, 21.7, 21.9, 28.5, 28.6, 43.8, 77.8, 80.2, 126.5, 202.8 ppm.
HRMS: calcd. for C22H32O2 [M + Na] 351.2300; found 351.2297.
fected by column chromatography to give 14 as clear oil (2.4 g,
(2E,13Z,24E)-Hexacosa-2,13,24-triene-10,16-diynedial: To a stirred
solution of the dialdehyde 15 (568 mg, 1.5 mmol) in benzene
(15 mL) was added Ph3PCHCHO (1.8 g, 6 mmol) under N2. The
reaction mixture was refluxed in an oil bath until complete con-
1
86%): IR: ν = 1005, 1097, 1253, 1471, 2856, 2928 cm–1. H NMR
˜
(300 MHz, CDCl3, 23 °C): δ = 0.02 (s, 6 H), 0.86 (s, 9 H), 1.27–
1.45 (m, 10 H), 2.12 (t, J = 2.3 Hz, 2 H), 2.69 (t, J = 5.1 Hz, 2 H),
3.38 (t, J = 7.4 Hz, 2 H), 3.57 (dt, J = 6.6 Hz, 2 H) ppm. 13C NMR sumption of the starting material (TLC/1H NMR). This was then
Eur. J. Org. Chem. 2008, 4790–4795
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B. W. Gung, A. O. Omollo
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filtered through silica gel, concentrated, then purified by column
chromatography to give the dienedialdehyde as an oil (510 mg,
4 H), 2.54 (d, J = 2.1 Hz, 2 H), 2.90 (br., 4 H), 5.45 (t, J = 4.5 Hz,
2 H), 5.51 (dd, J = 15.2, 6.4 Hz, 2 H), 5.80 (d, J = 6.0 Hz, 2 H),
5.98 (dt, J = 15.3, 6.5 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3,
23 °C): δ = 18.7, 20.9, 24.0, 28.6, 28.7, 28.9, 31.8, 34.5, 64.1, 74.7,
77.7, 79.9, 80.4, 124.4, 126.5, 137.0, 169.7 ppm. HRMS: calcd. for
79%): IR: ν = 1124, 1461, 1690, 2857, 2931 cm–1. 1H NMR
˜
(300 MHz, CDCl3, 23 °C): δ = 1.32–1.51 (m, 16 H), 2.12 (t, J =
2.1 Hz, 4 H), 2.32 (dt, J = 7.2, 1.5 Hz, 4 H), 2.89 (br., 4 H), 5.45
(t, J = 4.5 Hz, 2 H), 6.10 (dd, J = 15.6, 7.9 Hz, 2 H), 6.83 (dt, J = C34H44O4 [M + Na] 539.3137; found 539.3115.
15.6, 6.8 Hz, 2 H), 9.48 (d, J = 7.9 Hz, 2 H) ppm. 13C NMR
(75 MHz, CDCl3, 23 °C): δ = 17.2, 18.7, 27.7, 28.6, 28.8, 32.6, 43.8,
77.7, 80.2, 126.5, 133.0, 158.8, 194.1 ppm.
(3S,4E,15Z,26E,28S)-Triaconta-4,15,26-triene-1,12,18,29-tetrayne-
3,28-diol (+)-1: The diacetate (60 mg, 0.11 mmol) and K2CO3
(6 mg, 0.04 mmol) were dissolved in MeOH (2 mL) with stirring
under N2. The reaction was allowed to proceed at room tempera-
ture for several hours until the complete consumption of the start-
ing material, the reaction mixture was then quenched using 1 
HCl and the organic layer was extracted with EtOAc. Purification
was effected using column chromatography to give (+)-1 as a vis-
(4E,15Z,26E)-Triaconta-4,15,26-triene-1,12,18,29-tetrayne-3,28-diol
(1): To a stirred solution of ethynylmagnesium bromide (6.2 mL,
3.06 mmol) in THF (11 mL) at 0 °C under N2, was added the dien-
edialdehyde (490 mg, 1.1 mmol). The reaction mixture was stirred
at this temperature for 2 h then quenched by the addition of satu-
rated NH4Cl solution. The aqueous layer was thoroughly extracted
using EtOAc. The organics were combined, dried (MgSO4) and
purified by column chromatography to afford 1 as a solid (480 mg,
cous oil (45 mg, 96%). [α]D = +41.3 (c = 0.03, CHCl ): IR: ν =
˜
3
736, 970, 1283, 1433, 1663, 2856, 2930, 3290, 3355 cm–1. 1H NMR
(300 MHz, CDCl3, 23 °C): δ = 1.30–1.48 (m, 16 H), 1.85 (br., 2 H)
2.06 (t, J = 6.4 Hz, 4 H) 2.12 (t, J = 2.3 Hz, 4 H), 2.54 (d, J =
2.1 Hz, 2 H), 2.90 (br., 4 H), 4.81 (t, J = 5.1 Hz, 2 H), 5.46 (t, J =
4.5 Hz, 2 H), 5.61 (dd, J = 15.2, 6.4 Hz, 2 H), 5.87 (dt, J = 15.1,
6.7 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3, 23 °C): δ = 17.2,
18.7, 28.6, 28.7, 28.8, 28.9, 31.8, 62.7, 73.9, 77.7, 80.4, 83.3, 126.5,
128.4, 134.4 ppm. HRMS: calcd. for C30H40O2 [M + Na] 455.2926;
found 455.2914.
92%); m.p. 33–42 °C: IR: ν = 736, 970, 1282, 1433, 1661, 2856,
˜
2920, 3298, 3355 cm–1. 1H NMR (300 MHz, CDCl3, 23 °C): δ =
1.28–1.45 (m, 16 H), 2.03 (br., 2 H) 2.05–2.11 (m, 8 H), 2.54 (d, J
= 2.1 Hz, 2 H), 2.90 (t, J = 2.4 Hz, 4 H), 4.80 (br., 2 H), 5.45 (t, J
= 4.4 Hz, 2 H), 5.58 (dd, J = 15.3, 6.1 Hz, 2 H), 5.88 (dt, J = 14.3,
6.6 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3, 23 °C): δ = 17.2,
18.7, 28.6, 28.7, 28.8, 28.9, 31.9, 62.8, 74.0, 77.7, 80.4, 83.4, 126.5,
128.5, 134.0 ppm. HRMS: calcd. for C30H40O2 [M + Na] 455.2926;
found 455.2914.
Supporting Information (see also the footnote on the first page of
this article): 1H and 13C NMR, and HRMS spectra for compounds
1, 9, 11, 13–17.
Enzymatic Resolution of 1: A flask was charged with lipase AK
Amano “20” (960 mg) molecular sieves (960 mg) vinyl acetate
(1.6 mL, 17 mmol) hexanes (12 mL) and the racemic diol (480 mg,
1.12 mmol). The mixture was stirred at room temperature for sev-
eral hours. Reaction progress was monitored by TLC and 1H NMR
spectroscopy. When the amount of the diacetate was about the
same as the amount of the diol and half the amount of the
monoacetate the reaction was stopped. The reaction mixture was
filtered through a pad of silica then purified by column chromatog-
raphy to give (–)-1 as a viscous oil (99 mg, 21%). [α]D = –40.4 (c =
Acknowledgments
Financial support from the National Institutes of Health (NIH)
(GM069441) is gratefully acknowledged. We thank Professors
James Marshall and Hans Reich for helpful discussions.
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0.04, CHCl ). IR: ν = 737, 970, 1283, 1433, 1663, 2856, 2930, 3290,
˜
3
1
3355 cm–1. H NMR (300 MHz, CDCl3, 23 °C): δ = 1.30–1.48 (m,
16 H), 1.85 (br., 2 H) 2.04 (t, J = 7.1 Hz, 4 H) 2.11–2.12 (m, 4 H),
2.54 (d, J = 2.4 Hz, 2 H), 2.90 (br., 4 H), 4.81 (t, J = 5.1 Hz, 2 H),
5.46 (t, J = 4.7 Hz, 2 H), 5.61 (dd, J = 15.2, 6.4 Hz, 2 H), 5.87 (dt,
J = 15.1, 6.7 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3, 23 °C): δ
= 17.2, 18.7, 28.6, 28.7, 28.8, 28.9, 31.8, 62.7, 73.9, 77.7, 80.4, 83.3,
126.5, 128.4, 134.4 ppm. HRMS: calcd. for C30H40O2 [M + Na] [6] R. B. Weiss, Semin. Oncol. 1992, 19, 670.
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The monoacetate 17 was obtained as an oil (248 mg, 46%). [α]D
=
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+12.4 (c = 0.12, CHCl ). IR: ν = 732, 911, 1015, 1228, 1370, 1739,
˜
3
1
2856, 2930, 3291, 3449 cm–1. H NMR (300 MHz, CDCl3, 23 °C):
δ = 1.27–1.48 (m, 16 H), 2.04–2.08 (m, 4 H), 2.10 (s, 3 H), 2.11–
2.12 (m, 4 H), 2.54 (d, J = 2.1 Hz, 2 H), 2.89 (br., 4 H), 4.81 (br.
d, J = 5.1 Hz, 2 H), 5.45 (t, J = 4.5 Hz, 2 H), 5.51 (dd, J = 15.3,
6.5 Hz, 1 H), 5.57 (dd, J = 15.1, 6.1 Hz, 1 H), 5.79 (d, J = 6.3 Hz,
1 H) 5.87 (dt, J = 15.3, 6.1 Hz, 2 H), 5.97 (dt, J = 15.3, 6.5 Hz, 2
H) ppm. 13C NMR (75 MHz, CDCl3, 23 °C): δ = 17.2, 18.7, 21.0,
24.8, 28.5, 28.6, 28.7, 28.9, 31.8, 31.9, 34.5, 62.7, 63.7, 64.1, 72.8,
73.9, 74.7, 77.7, 79.8, 80.4, 124.4, 126.5, 128.4, 134.4,137.0, 169.7
ppm. HRMS: calcd. for C32H42O3 [M + Na] 497.3032; found
497.3025.
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(c = 0.04, CHCl ): IR: ν = 969, 1015, 1228, 1370, 1433, 1741, 2857,
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3
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1.45 (m, 16 H), 2.04–2.07 (m, 4 H), 2.10 (s, 6 H), 2.11 (t, J = 4.6 Hz,
4794
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Total Synthesis of Dideoxypetrosynol A
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Received: June 19, 2008
Published Online: August 21, 2008
Eur. J. Org. Chem. 2008, 4790–4795
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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