Enantioselective synthesis of (1E, 3S)-1-iodoundec-1-en-5-yn-3-ol, the eicosanoid synthon

Article abstract of DOI:10.1007/s11172-009-0136-x

A synthesis of the title compound, the synthon for the constanolactones and other eicosanoids, has been developed from achiral starting compounds. The synthesis is based on the S-enantiodirected dihydroxylation of the double bond to introduce a chirality and on the use of conformational restriction of the triple bond (the latent Z-double bond) surroundings.

Full text of DOI:10.1007/s11172-009-0136-x

Russian Chemical Bulletin, International Edition, Vol. 58, No. 5, pp. 1067—1071, May, 2009
1067
Enantioselective synthesis
of (1E,3S)ꢀ1ꢀiodoundecꢀ1ꢀenꢀ5ꢀynꢀ3ꢀol, the eicosanoid synthon
M. A. Lapitskaya, L. L. Vasiljeva, and K. K. Pivnitsky
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: kpiv@mail.ru
A synthesis of the title compound, the synthon for the constanolactones and other
eicosanoids, has been developed from achiral starting compounds. The synthesis is based on the
Sꢀenantiodirected dihydroxylation of the double bond to introduce a chirality and on the use of
conformational restriction of the triple bond (the latent Zꢀdouble bond) surroundings.
Key words: constanolactones, total synthesis, synthons, chiral catalysis, eicosanoids,
enantioselective dihydroxylation.
The soꢀcalled “marine” eicosanoids (ME), a vast
family of polyunsaturated fatty acid oxidized metabolites
isolated from marine aglae are of interest due to their
possible biological activity (see review 1). Constanoꢀ
lactones (CL) A and B (Scheme 1) isolated from alga
Constantinea simplex2 are typical representatives of the
ME family.
The ME samples for biological study are available virꢀ
tually only by total chemical synthesis widely developed
during the last 15 years (see review 3, for the recent synꢀ
thesis of CLA,B, see Ref. 4). In the case of constanoꢀ
lactones, a convergent strategy is the most efficient and
popular. It consists in the retrosynthetic cleavage of the
structure into the two synthons A and В, the coupling of
which by the Kishi—Nozaki5 reaction is a relatively easy
solving problem.4—7
synthons have been used in the total syntheses of not
only constanolactones, but also leukotrienes B 10 and
12ꢀhydroxyeicosaꢀ5(Z),8(Z),10(E),14(Z)ꢀtetraenoic
acids,11 i.e., they are the synthons for several types of
eicosanoids. Scalemic and homochiral synthons of the
type A are commonly obtained by a multiꢀstep synthesis
from malic acid12 or carbohydrates6 as the sources of
chirality, as well as by kinetic resolution of late racemic
intermediates.10,11 This work describes more efficient way
for the preparation of nonracemic synthon of the type A
from achiral starting compounds using an enantioselective
reaction for the introduction of chirality.
The Cꢀallylation of heptꢀ1ꢀyne with allyl bromide
under weakly basic conditions13 smoothly led to decꢀ
1ꢀenꢀ4ꢀyne (1) (Scheme 2). The Sꢀenantiodirected
dihydroxylation of the double bond in enyne 1 using the
Sharpless reagent ADꢀmixꢀα14 afforded diol 2 in high
yield, but in only 61% ee. The same low ee, not characterꢀ
istic of the enantioselective dihydroxylation reaction
of olefins (EDO),15 was also obtained earlier in EDO of
Recently, we have developed an enantiodirected
biomimetic method for the preparation of synthon of the
type B (see Refs 8 and 9). Preparation of chiral synthons
of the type A was the following problem. Note that such
Scheme 1
R = CHO, CH2OH
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 1039—1043, May, 2009.
1066ꢀ5285/09/5805ꢀ1067 © 2009 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 58, No. 5, May, 2009
Lapitskaya et al.
Scheme 2
Catalyst
Reagents and conditions: i. H2C=CHCH2Br, K2CO3, CuI, NaI, Cu, MeCN (92%); ii. K2OsO2(OH)4, (DHQ)2Х (Х = AQN, PHAL,
PYR), K3Fe(CN)6, K2CO3, ButOH—H2O (92%); iii. a) BzCl, Py, PhMe; b) Et3N, MeCN; iv. Recrystallization from Et2O, –78 °C
(65%); v. a) ButMe2SiCl, Py, Et3N, C6H6; b) BzCl, Py, DMAP, C6H6; vi. AcOH—PriOH—H2O (92%); vii. PDC, AcOH, MS 3 Å,
CH2Cl2 (79%); viii. a) CHI3, CrCl2, THF (47%); b) K2CO3, MeOH (84%).
analogous 1,4ꢀenynes9 and is apparently a specific feature
of the substrates of this type.
primary monobenzoate 3b of diol 2, but enantiomers of
these benzoates were not resolved by chiral HPLC. Good
separation was observed for enantiomers of secondary
monobenzoate 3c, which is formed as a small impurity
(3—5%) during synthesis of monobenzoate 3b by partial
benzoylation. Increasing the fraction of benzoate 3c up to
20—25% by equilibrating of the mixture 3b + 3c under
basic conditions solved the problem of sensitive chiral
analysis.
It was somewhat difficult to determine enantioꢀ
meric composition of diol 2. The use of optical rotation
values is not acceptable due to their low values for
such terminal diols,16 whereas running HPLC on chiral
columns is difficult due to the high polarity and full
UV transparency of the diol. Such disadvantages are
absent in the cases of easily obtained dibenzoate 3a and

Eicosanoid synthon
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 5, May, 2009
1069
The reagent ADꢀmixꢀα contains (DHQ)2PHAL as a
chiral catalyst. According to the literature data, the next
generation analogous catalysts, (DHQ)2PYR (see Ref. 17)
and (DHQ)2AQN (see Ref. 18)*, provide higher ee in
EDO of terminal olefins. In the case of enyne 1, a reꢀ
placement of the catalyst in ADꢀmixꢀα with (DHQ)2PYR
for unexplainable reasons led to a sharp decrease in the ee
of diol 2 obtained (down to 19—28%) with retention of
the high yield and Sꢀenantiodirection. Such a dramatic
drop in enantioselectivity during EDO with (DHQ)2PYR
has not been earlier observed. Good result was obtained
when (DHQ)2AQN was used, which led to diol 2 in sigꢀ
nificantly higher ee 78%. However, the intermediate prodꢀ
uct with such ee is not yet enantiopure enough to be
efficiently used in the synthesis of the target enantiopure
compounds, CLA,B.
tertꢀbutyldimethylsilyl ether (4a) at the primary hydroxy
group under mild conditions. The benzoylation of ether
4a and desilylation of obtained compound 4b under
standard conditions and without purification of the interꢀ
mediate compounds led to the desired benzoate 3c in
92% overall yield on three steps.
By analogy with other schemes for obtaining synthons
of the type A, the creation of the iodovinylic group was
performed by the Takai reaction.19 For this, the correꢀ
sponding aldehyde 5 was obtained by oxidation of the
primary hydroxy group in benzoate 3c, the reaction of
which with CHI3 and CrCl2 led to vinylic iodide 6a in
satisfactory yield. Its mild debenzoylation smoothly gave
alcohol 6b, a desired synthon of the type A. Alcohol 6b
has also proved easy to crystallize, which at necessity can
be used for its enantiomeric purification.
Further increase in the ee of diol 2 was based on straꢀ
tegic use of the triple bond as a latent Zꢀdouble bond. In
the synthesis of enyne 1, this resulted in the easy creation
of the C—C bond, while in the synthesis of diol 2, this
provided chemoselectivity of EDO. To increase the ee of
diol 2, it turned out possible to use a well known property
of the triple bond, viz., the higher tendency of acetylene
compounds to crystallize as compared to the correspondꢀ
ing Zꢀolefin compounds. This is due to a sharp restriction
in conformational mobility in the vicinity of the triple
bond (as compared to the Zꢀdouble). Diol 2 easily crysꢀ
tallized near 0 °C and could be recrystallized from diethyl
ether at –78 °C with simultaneous increase in the ee to
90%. A further increase in enantiomeric purity is possible
by next recrystallization (with additional losses, too).
However, this is not reasonable in the convergent scheme
used for the synthesis of the final compounds, constanoꢀ
lactones. In fact, in such a scheme a coupling of the
Sꢀsynthon of the type A with ee 90% with the Sꢀsynthon
of the type B, which can be obtained with ee 98.4%,
theoretically will lead to diastereomer SSꢀAB with ee
99.9% and with ~5% admixture of diastereomer RSꢀAB
with ee 73%, which can be separated by chromatography.
In principle, now the triple bond in diol 2 can be
converted to the Zꢀdouble by the Lindlar hydrogenation.
However, because of the favorable influence of the triple
bond on the properties of products indicated above (as
well as an increase in stability), we decided to keep the
triple bond almost until the end the synthesis. This addiꢀ
tionally creates a possibility to obtain 14,15ꢀdehydroꢀ
constanolactones as well.
The scheme developed for the preparation of synthon
6b has relatively low number of steps, viz., six starting
from heptꢀ1ꢀyne. Based on this synthon, it is possible to
synthesize not only natural eicosanoids, but also their
monoacetylenic and isotopically labeled (with deuterium,
tritium) analogs. The same scheme without considerable
changes can be applied for the synthesis of the correꢀ
sponding synthon with Rꢀconfiguration, only by replaceꢀ
ment of reagent ADꢀmixꢀα with ADꢀmixꢀβ.
Experimental
1H NMR spectra were recorded on a Bruker VMꢀ250
(250.13 MHz) and Bruker AMꢀ300 (300.13 MHz) spectrometers
at 303 K using SiMe4 as an internal standard. Mass spectra
were recorded on a Kratos MSꢀ30 instrument using direct
injection of compounds into the ions source at 200 °C, EI, 60 eV.
Optical rotation was measured on a PUꢀ07 universal polarimeter
(GNIITs NP, Russia). Analytical TLC was performed on Sorbfil
silica gel plates (Sorbpolimer, Russia), visualization was performed
by spraying with aqueous phosphomolybdic acid with subsequent
heating. Column chromatography was performed on Kieselgel 60
silica gel (Merck), 230—400 mesh activated at 150 °C (30 min).
Unless otherwise stated, the extracts were dried with anhydrous
MgSO4, concentrated to dryness first on a rotary evaporator
in vacuo of a waterꢀjet pump, then under pressure <1 Torr until
the weight was constant.
Reagents ADꢀmixꢀα, (DHQ)2AQN, CHI3, CrCl2 (Aldrich),
(DHQ)2PHAL, PDC, heptꢀ1ꢀyne (Fluka), (DHQ)2PYR (Chemika),
ButMe2SiCl (Sigma) were used as purchased; K2OsO2(OH)4
was obtained according to the procedure described earlier.20
Other reagents were produced in Russia.
Decꢀ1ꢀenꢀ4ꢀyne (1). Heptꢀ1ꢀyne (15.0 g, 156 mmol) was
added in one portion to a stirred suspension of K2CO3 (38.8 g,
280 mmol), CuI (29.7 g, 150 mmol), and copper powder
(1.98 g, 31 mmol) in solution of NaI (42 g, 280 mmol) in MeCN
(75 mL) at 20 °C, followed by a dropwise addition of
CH2=CHCH2Br (22.64 g, 187 mmol). After 12 h of stirring, the
mixture was poured into saturated aq. NH4Cl (700 mL) and
hexane (300 mL), the layers were separated, the aqueous layer
was extracted with hexane (2×100 mL). Combined organic layers
To continue the synthesis, the secondary hydroxy
group in diol 2 should be protected, for example, in the
form of benzoate 3c. Preparative synthesis of this benꢀ
zoate is based on the use of very selective formation of
* (DHQ)2PHAL, (DHQ)2PYR, and (DHQ)2AQN are 1,4ꢀphthalꢀ
azinediyl, 2,5ꢀdiphenylpyrimidineꢀ4,6ꢀdiyl, and 9,10ꢀanthraꢀ
quinoneꢀ1,4ꢀdiyl ethers of dihydroquinine, respectively.

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Lapitskaya et al.
were stirred with 10% aq. NH4OH (50 mL) for 15 min, the
organic layer was separated, dried, and concentrated by distilꢀ
lation of volatile components using a distillation column under
atmospheric pressure. The residue was distilled in vacuo to obtain
enyne 1 (19.51 g, 92%) as a colorless mobile liquid, b.p. 72—78 °C
(30 Torr), Rf 0.69 (hexane—EtOAc, 9 : 1). 1H NMR (250 MHz,
CDCl3), δ: 0.90 (t, 3 H, Me, J = 7.0 Hz); 1.25—1.43 (m, 4 H,
C(8)H2 + C(9)H2); 1.51 (m, 2 H, C(7)H2); 2.18 (tt, 2 H, C(6)H2,
J = 2.3 Hz, 7.0 Hz); 2.94 (m, 2 H, C(3)H2); 5.09 (dq, 1 H,
H(1A), J = 10.0 Hz, 1.7 Hz); 5.31 (dq, 1 H, H(1В), J = 16.9 Hz,
1.7 Hz); 5.83 (ddt, 1 H, H(2), J = 16.9 Hz, 10.0 Hz, 5.2 Hz).
(S)ꢀDecꢀ4ꢀyneꢀ1,2ꢀdiol (2). A solution of enyne 1 (1.00 g,
7.35 mmol), K3Fe(CN)6 (7.25 g, 22 mmol), K2CO3 (3.04 g,
22 mmol), (DHQ)2AQN (31.5 mg, 36.7 μmol), and K2OsO2(OH)4
(5.5 mg, 15 μmol) in ButOH (35 mL) and water (35 mL) (a twoꢀ
layer mixture) was stirred at 0 °C until complete transformation
of the starting reactant (TLC control). The mixture was filtered,
a precipitate was washed with EtOAc on the filter. In the filtrate,
the organic layer was separated, the aqueous layer was extracted
with EtOAc (3×25 mL). Combined organic layers were washed
with 20% aq. H2SO4 (20 mL) and then with water to neutrality,
dried, and concentrated to dryness. The residual yellow oil was
the diol 2 (1.17 g, 92%), ee 78%, m.p. (–1)—(–0.5) °C, Rf 0.49
(EtOAc; the starting 1: Rf 0.78). Repeated recrystallizations
from Et2O at –78 °C gave diol 2 in 65% yield with ee 90%,
5.20 (the full spectrum see below). The ratios of 3b : 3c, measured
using NMR and HPLC, agreed within the experimental error.
(S)ꢀ2ꢀBenzoyloxydecꢀ4ꢀynꢀ1ꢀol (3c). a.
A
solution
of diol 2 (1.00 g, 5.88 mmol, ee 90%), ButMe2SiCl (1.31 g,
8.82 mmol), pyridine (475 μL, 5.9 mmol), and Et3N (1.52 mL,
11.0 mmol) in anhydrous benzene (7 mL) was stirred for 48 h
at ~20 °C with TLC monitoring, then, another portions of
ButMe2SiCl (442 mg, 2.9 mmol) and Et3N (510 μL, 3.7 mmol)
were added, and after 24 h the starting compound disappeared.
The mixture was diluted with benzene (20 mL) and water
(10 mL), the aqueous layer was extracted with benzene (3×5 mL),
combined organic layers were washed with water, dried, and
concentrated to dryness to obtain crude silyl ether 4a (1.85 g,
110%) as a light brown oil, Rf 0.60 (hexane—EtOAc, 7 : 3; the
starting 2: Rf 0.09), which was further used without additional
purification.
b. A solution of obtained ether 4a (5.88 mmol), BzCl
(1.02 mL, 8.83 mmol), DMAP (108 mg, 0.88 mmol), and pyriꢀ
dine (1.42 mL, 17.7 mmol) in anhydrous benzene (15 mL) was
stirred for 72 h at ~20 °C with TLC monitoring. Then, another
portions of BzCl (339 μL, 2.93 mmol) and pyridine (469 μL,
5.9 mmol) were added, and after 24 h the starting compound
was consumed. Methanol (0.5 mL) was added to the mixture,
which was stirred for 30 min, diluted with benzene (20 mL) and
water (10 mL), the aqueous layer was extracted with benzene
(3×5 mL). The combined organic layers were sequentially washed
with 10% aq. HCl (10 mL), saturated aq. NaHCO3 (10 mL),
water until neutrality, dried, and concentrated to dryness
to obtain crude product 4b (2.81 g, 123%) as a light brown oil,
Rf 0.48 (hexane—EtOAc, 95 : 5; the starting 4a: Rf 0.19), which
was further used without additional purification. The sample for
spectroscopic analysis was purified by chromatography. 1H NMR
(250 MHz, CDCl3), δ: 0.05, 0.06 (both s, 3 H each, Me2Si);
0.86 (t, 3 H, C(10)H3, J = 6.9 Hz); 0.88 (s, 9 H, ButSi); 1.31 (m,
4 H, C(8)H2 + C(9)H2); 1.45 (m, 2 H, C(7)H2); 2.12 (tt, C(6)H2,
J = 2.3 Hz, 6.9 Hz); 2.62 (ddt, 1 H, H(3A), J = 16.5 Hz, 5.9 Hz,
2.3 Hz); 2.65 (ddt, 1 H, H(3В), J = 16.5 Hz, 6.2 Hz, 2.3 Hz);
3.89 (d, 2 H, C(1)H2, J = 4.9 Hz); 5.17 (tt, 1 H, H(2), J = 4.9 Hz,
6.0 Hz); 7.43 (tt, 2 H, 2 mꢀHBz, J = 1.3 Hz, 7.2 Hz); 7.55 (tt,
1 H, pꢀHBz, J = 1.3 Hz, 7.2 Hz); 8.04 (m, 2 H, 2 oꢀHBz).
c. A solution of compound 4b (5.88 mmol) in 10% aq. AcOH
and PriOH (1 mL) was kept at ~20 °C until the starting comꢀ
pound disappeared (72 h, TLC monitoring). The solution was
concentrated to dryness and from the oil obtained (2.09 g) pure
benzoate 3c was isolated (1.78 g, 92%) by column chromatography
on silica gel (benzene—EtOAc, 95 : 5 and 90 : 10) as a light
m.p. 3—7 °C, [α] °
18 +8.4 (c 1.6, EtOH). 1H NMR (250 MHz,
D
CDCl3), δ: 0.90 (t, 3 H, Me, J = 7.0 Hz); 1.23—1.40 (m, 4 H,
C(8)H2 + C(9)H2); 1.49 (m, 2 H, C(7)H2); 2.15 (tt, 2 H, C(6)H2,
J = 2.3 Hz, 6.9 Hz); 2.39 (m, 2 H, C(3)H2); 2.98 (br.s, 2 H,
2 OH); 3.57 (dd, 1 H, H(1A), J = 6.6 Hz, 11.3 Hz); 3.75 (dd,
1 H, H(1В), J = 3.3 Hz, 11.3 Hz); 3.82 (m, 1 H, H(2)). 13C NMR
(50.32 MHz, CDCl3), δ: 14.03, 18.74, 22.25, 23.83, 28.67, 31.15,
65.67, 70.65, 75.35, 83.43.
Analysis of enantiomeric composition of diol 2. Pyridine
(19 μL, 0.24 mmol) and BzCl (14 μL, 0.12 mmol) were
sequentially added to a solution of diol 2 (10 mg, 0.06 mmol) in
toluene (600 μL) at 0 °C. The mixture was kept for 15 h at 4 °C,
followed by addition of MeOH (20 μL) and concentration to
dryness after 15 min. The residue was dissolved in benzene, the
solution was filtered and concentrated to dryness. The residue
was dissolved in a mixture of MeCN (60 μL) and Et3N (60 μL)
and kept for 48 h at 20 °C, concentrated to dryness, the residue
was analyzed by HPLC without additional workꢀup to obtain a
mixture of products containing monobenzoates 3b and 3c in the
ratio 3b : 3c = (75—80) : (20—25) and small variable quantities
of dibenzoate 3a; the retention times were: 1.83 (3a), 7.60 (3b),
9.75 (Rꢀ3c) and 10.82 (Sꢀ3c) min (HPLC: a 250×4.6 mm
Kromasil 100ꢀ5ꢀTBB column (Eka Chemicals, Sweden) with
the copolymer of LꢀO,O´ꢀbis(pꢀtertꢀbutylbenzoyl)tartaric acid
N,N´ꢀdiallyldiamide with hydrosilane immobilized on silica gel
as a chiral phase, 0.5% PriOH in nꢀhexane as a mobile phase,
2 mL min–1, UV detector at λ = 280 nm). For spectroscopic
analysis, a mixture of monobenzoates 3b + 3c was isolated by
column chromatography on silica gel. 1H NMR (300 MHz,
CDCl3), δ for component 3b: 0.89 (t, 3 H, Me, J = 6.9 Hz);
1.25—1.40 (m, 4 H, C(8)H2 + C(9)H2); 1.50 (m, 2 H, C(7)H2);
2.16 (m, 2 H, C(6)H2); 2.54 (m, 2 H, C(3)H2); 4.10 (m, 1 H,
H(2)); 4.40 (dd, 1 H, H(1A), J = 6.1 Hz, 11.4 Hz); 4.44 (dd,
1 H, H(1В), J = 4.4 Hz, 11.4 Hz); 7.44 (t, 2 H, 2 mꢀHBz, J = 7.4 Hz);
7.57 (t, 1 H, pꢀHBz, J = 7.3 Hz); 8.06 (d, 2 H, 2 oꢀHBz, J = 7.4 Hz);
component 3c exhibits characteristic signals at δ 3.94, 3.97, and
yellow oil, Rf 0.28 (hexane—EtOAc, 80 : 20; the starting 4b: Rf
18
0.72),
[
α
]
–5.43° (c 1.1, EtOH).
1H NMR (300 MHz,
CDCl3), δD: 0.87 (t, 3 H, Me, J = 7.0 Hz); 1.20—1.40 (m, 4 H,
C(8)H2 + C(9)H2); 1.45 (quint, 2 H, C(7)H2, J = 6.9 Hz); 2.13
(tt, 2 H, C(6)H2, J = 2.4 Hz, 7.0 Hz); 2.65 (dt, 2 H, C(3)H2,
J = 6.4 Hz, 2.4 Hz); 3.94 (dd, 1 H, H(1A), J = 5.4 Hz, 12.1 Hz);
3.97 (dd, 1 H, H(1В), J = 3.9 Hz, 12.1 Hz); 5.20 (tdd, 1 H, H(2),
J = 6.4 Hz, 5.4 Hz, 3.9 Hz); 7.45 (t, 2 H, 2 mꢀHBz, J = 7.6 Hz); 7.58
(t, 1 H, pꢀHBz, J = 7.4 Hz); 8.06 (d, 2 H, 2 oꢀHBz, J = 7.8 Hz).
(S)ꢀ2ꢀBenzoyloxydecꢀ4ꢀynꢀ1ꢀal (5). A suspension of PDC
(790 mg, 2.11 mmol) and freshly calcined finely ground molecular
sieves 3 Å (1.07 g) in the solution of benzoate 3c (579 mg,
2.11 mmol) and AcOH (60 μL, 1.05 mmol) in CH2Cl2 (22 mL)
was intensively stirred for 1 h. Then, activated charcoal was
added (~100 mg), after 30 min the mixture was filtered through

Eicosanoid synthon
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 5, May, 2009
1071
silica gel (20 g) with subsequent washing with CH2Cl2 (150 mL).
Aldehyde 5 (454 mg, 79%) was isolated by concentration of the
filtrate as a light yellow oil, which contained (NMR data) up to
20% nonaldehyde impurity, presumably “dimeric” ester21 (a
formal product of the Cannizzaro reaction), Rf 0.46 (CH2Cl2,
two developments; impurity: Rf 0.56, the starting 3c: Rf 0.22).
This sample of aldehyde 5 was used in the subsequent step without
additional purification. The sample for spectroscopic analysis
was isolated by chromatography. 1H NMR (300 MHz, CDCl3),
δ: 0.85 (t, 3 H, Me, J = 7.1 Hz); 1.20—1.40 (m, 4 H, C(8)H2 +
C(9)H2); 1.44 (m, 2 H, C(7)H2); 2.12 (tt, 2 H, C(6)H2, J = 2.4
Hz, 7.0 Hz); 2.83 (dt, 2 H, C(3)H2, J = 6.2 Hz, 2.4 Hz); 5.31
(t, 1 H, H(2), J = 6.2 Hz); 7.47 (tt, 2 H, 2 mꢀHBz, J = 1.5 Hz,
7.5 Hz); 7.60 (tt, 1 H, pꢀHBz, J = 1.5 Hz, 7.4 Hz); 8.12 (dt, 2 H,
2 oꢀHBz, J = 7.0 Hz, 1.5 Hz); 9.72 (s, 1 H, CHO).
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J. Hartung, K.ꢀS. Jeong, H.ꢀL. Kwong, K. Morikawa,
Z.ꢀM. Wang, D. Xu, X.ꢀL. Zhang, J. Org. Chem., 1992, 57,
2768.
(1E,3S)ꢀ3ꢀBenzoyloxyꢀ1ꢀiodoundecꢀ1ꢀenꢀ5ꢀyne (6a).
Chromium(II) chloride (1.22 g, 9.9 mmol) was quickly added in
one portion to a solution of aldehyde 5 (448 mg, 1.65 mmol) and
CHI3 (571 mg, 1.45 mmol) in anhydrous THF (45 mL) at 0 °C
and with stirring. After 15 min, an initially yellowish green
suspension turned dark brown, the cooling was removed, and
the reaction mixture was stirred at ~20 °C until the starting
compound disappeared (1.5 h, TLC data). The mixture was
diluted with water (30 mL) and extracted with diethyl ether
(3×15 mL), the extract was washed with 10% aq. Na2S2O3
(10 mL), dried, and concentrated to dryness. Vinylic iodide 6a
(308 mg, 47%) was isolated as a light yellow oil from the residue
by chromatography on silica gel eluting with toluene, Rf 0.52
(toluene; the starting 5: Rf 0.18), [α] ° (c 1.2, EtOH).
17 +15.6
1H NMR (300 MHz, CDCl3), δ: 0.8D8 (t, 3 H, Me, J = 6.8 Hz);
1.25—1.36 (m, 4 H, C(9)H2 + C(10)H2); 1.46 (m, 2 H, C(8)H2);
2.14 (tt, 2 H, C(7)H2, J = 2.4 Hz, 7.0 Hz); 2.62 (m, 2 H,
C(4)H2); 5.10 (q, 1 H, H(3), J = 6.3 Hz); 6.60 (d, 1 H, H(1),
J = 14.6 Hz); 6.73 (dd, 1 H, H(2), J = 6.3 Hz, 14.6 Hz); 7.45
(t, 2 H, 2 mꢀHBz, J = 7.6 Hz); 7.60 (t, 1 H, pꢀHBz, J = 7.4 Hz);
8.12 (d, 2 H, 2 oꢀHBz, J = 7.1 Hz). MS, m/z, Irel (%): 287
[M – (C(4)—C(11))] (11), 274 [M – BzOH] (2), 218 (4), 147
[M – BzOH—I] (45), 105 [PhCO] (100), 91 (64), 77 (70).
15. H. C. Kolb, M. S. VanNieuwenhze, K. B. Sharpless, Chem.
Rev., 1994, 94, 2483.
16. S. E. Schaus, B. D. Brandes, J. F. Larrow, M. Tokunaga,
K. B. Hansen, A. E. Gould, M. E. Furrow, E. N. Jacobsen,
J. Am. Chem. Soc., 2002, 124, 1307 (Supplementary materials).
17. A. Crispino, K.ꢀS. Jeong, H. C. Kolb, Z.ꢀM. Wang, D. Xu,
K. B. Sharpless, J. Org. Chem., 1993, 58, 3785; H. Becker,
S. B. King, M. Taniguchi, K. P. M. Vanhessche, K. B.
Sharpless, J. Org. Chem., 1995, 60, 3940.
18. H. Becker, K. B. Sharpless, Angew. Chem., Int. Ed. Engl.,
1996, 35, 448.
19. K. Takai, K. Nitta, K. Utimoto, J. Am. Chem. Soc., 1986,
108, 7408.
20. G. Brauer, W. P. Fehlhammer, O. Glemser, H.ꢀJ. Grube,
K. Gustav, W. A. Herrmann, S. Herzog, H. Lux, II. Muller,
K. Ofele, E. Schill, R. Scholder, H. Schwarz, E. Schwarzmann,
K. Schwochau, A. Simon, J. Strahle, Handbuch der präparativen
anorganischen Chemie, 3te Aufl., Ferdinand Enke Verlag,
Stuttgart, 1981.
21. N. Cohen, B. L. Banner, R. J. Lopresti, F. Wong,
M. Rosenberger, Y.ꢀY. Liu, E. Thom, A. A. Liebman,
J. Am. Chem. Soc., 1983, 105, 3661; L. L. Vasiljeva, T. A.
Manukina, P. M. Demin, M. A. Lapitskaja, K. K. Pivnitsky,
Tetrahedron, 1993, 49, 4099.
(1E,3S)ꢀ1ꢀIodoundecꢀ1ꢀenꢀ5ꢀynꢀ3ꢀol (6b).
A solution
of benzoate 6a (292 mg, 0.735 mmol) and K2CO3 (60 mg,
0.44 mmol) in MeOH (5 mL) was kept for 1 h at ~20 °C, diluted
with water (5 mL), neutralized with 5% aq. H3PO4, and MeOH
was evaporated. The aqueous residue was extracted with EtOAc
(3×3 mL), the extract was washed with water, dried, and
concentrated to dryness. Alcohol 6b (180 mg, 84%) was isolated
as a light yellow oil from the residue by chromatography
on silica gel (eluent, hexane—EtOAc, 9 : 1), crystallizing at
–18 °C, Rf 0.35 (hexane—EtOAc, 8 : 2; the starting 6a: Rf 0.46),
[α] ° (c 1.56, EtOH), [α] ° (c 1.68, CHCl3).
18 +35.2 17 –22.6
1H D NMR (250 MHz, CDCl3)D, δ: 0.91 (t,
3 H, Me,
J = 7.1 Hz); 1.25—1.36 (m, 4 H, C(9)H2 + C(10)H2); 1.50 (m,
2 H, C(8)H2); 2.17 (tt, 2 H, C(7)H2, J = 2.5 Hz, 6.9 Hz); 2.40
(ddt, 1 H, H(4A), J = 16.4 Hz, 6.2 Hz, 2.3 Hz); 2.46 (ddt, 1 H,
H(4В), J = 16.4 Hz, 5.3 Hz, 2.7 Hz); 2.70 (br.d, 1 H, OH); 4.21
(dddd, 1 H, H(3), J = 1.2 Hz, 5.3 Hz, 5.6 Hz, 6.2 Hz); 6.45 (dd,
1 H, H(1), J = 1.2 Hz, 14.4 Hz); 6.62 (dd, 1 H, H(2), J = 5.6 Hz,
14.4 Hz). 13C NMR (75 MHz, CDCl3), δ: 14.05, 18.78, 22.27,
27.43, 28.62, 31.11, 72.61, 74.69, 78.23, 84.34, 146.59.
This work was partially financially supported by the
Presidium of the Russian Academy of Sciences (Program
for Basic Research, Grant for 2008).
Received November 6, 2008