Synthesis of -trans-4-Hydroxy-2-nonenal

Full text of DOI:10.1021/jo972320f

3504
J . Org. Chem. 1998, 63, 3504-3507
To facilitate studies on the reactions of HNE with
Syn th esis of
[9-3H]-tr a n s-4-Hyd r oxy-2-n on en a l
biological nucleophiles and on the chemistry of the
resulting covalent adducts, we developed a synthesis of
tritium-labeled HNE. To rule out the possibility of
radiolabel loss by exchange, tritium was appended to the
terminal methyl of an n-pentyl chain. Because HNE is
prone to decomposition, the synthesis was designed to
generate this reactive aldehyde from a stable precursor
1, which is suitable for long-term storage. Furthermore,
to minimize the necessity for manipulation of radioactive
intermediates, the introduction of tritium was delayed
until the last step of the synthesis of 1.
Yijun Deng and Robert G. Salomon*
Department of Chemistry, Case Western Reserve University,
Cleveland, Ohio 44106-7078
Received December 29, 1997
Because polyunsaturated lipids are prone to oxidative
damage, aerobic organisms wage a continual and, ulti-
mately, losing battle against oxidative injury.1 The
failure of a redoubtable array of enzymatic and chemical
antioxidant defenses has pathological consequences that
contribute to aging and a host of degenerative disease
processes. Oxidation not only damages lipids but also
generates reactive electrophilic products that chemically
modify biological nucleophiles.2,3 An especially cytotoxic
aldehyde, trans-4-hydroxy-2-nonenal (HNE), is created
by free-radical oxidative cleavage of arachidonate and
linoleate esters.3 HNE forms hemiacetal-stabilized
Michael adducts of protein-based thiol,3 imidazole, and
amino groups,4-7 as well as pyrroles that incorporate
protein amino groups.8 Such covalent modifications may
result in enzyme inhibition,4,5,7,9-12 neurodegeneration,13-15
or receptor-mediated uptake by macrophages, e. g., of
low-density lipoprotein (LDL) that occurs during the
initial stages of atherosclerosis.16-22
Resu lts a n d Discu ssion
P r eviou s Syn th eses of Tr itiu m La beled HNE.
[2-3H]-trans-4-Hydroxy-2-nonenal was prepared (Scheme
1) by hydroalumination of alkyne 2 followed by hy-
drodealumination by treatment with T2O and, finally,
hydrolysis of the acetal.23 Isotope exchange during
reactions of [2-3H]-trans-4-hydroxy-2-nonenal is antici-
pated since several tautomerization reactions are pos-
sible. Indeed, some loss (7%) of label was observed
during Michael addition of N-acetylcysteine to [2-2H]-
trans-4-hydroxy-2-nonenal in dilute aqueous NaOH.
* To whom correspondence should be addressed. Tel.: (216) 368-
2592. Fax: (216) 368-3006. E-mail: rgs@po.cwru.edu.
(1) Halliwell, B.; Gutteridge, J . M. C. Free Radicals in Biology and
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1991, 11, 81-128.
Sch em e 1a
(4) Friguet, B.; Stadtman, E. R.; Szweda, L. I. J . Biol. Chem. 1994,
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a
Key: (a) LiAlH4; (b) T2O; (c) H+, H2O.
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6693.
[4-3H]-trans-4-Hydroxy-2-nonenal is readily available
(Scheme 2) by reduction of ketone 3 with NaBT4.24,25
However, complete loss of tritium is anticipated for the
reaction of [4-3H]-trans-4-hydroxy-2-nonenal with pri-
mary amines that affords 2-pentylpyrroles, a reaction
that occurs when proteins react with HNE.8 This “pyr-
rolyzation” of proteins is especially interesting because
we found that such protein modifications are present in
(11) Schaur, R. J .; Zollner, H.; Esterbauer, H. In Membrane Lipid
Oxidation; Virgo-Pelfry, C., Ed.; CRC Press: Boca Raton, 1991; Vol.
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R. G.; Smith, M. A. J . Neurochem. 1997, 68, 2092-2097.
(14) Montaine, T. J .; Amarnath, V.; Martin, M. E.; Strittmatter, W.
J .; Graham, D. G. Am. J . Pathol. 1996, 148, 89-93.
(15) Yoritaka, A.; Hattori, N.; Uchida, K.; Tanaka, M.; Stadtman,
E. R.; Mizuno, Y. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 2696-2701.
(16) J urgens, G.; Lang, J .; Esterbauer, H. Biochim. Biophys. Acta
1986, 875, 103-114.
(21) Palinski, W.; Yla-Herttuala, S.; Rosenfeld, M. E.; Butler, S. W.;
Socher, S. A.; Parthasarathy, S.; Curtiss, L. K.; Witztum, J . L.
Arteriosclerosis 1990, 10, 325-335.
(22) Montaine, T. J .; Huang, D. Y.; Valentine, W. M.; Amarnath,
V.; Saunders: A.; Weisgraber, K. H.; Graham, D. G.; Strittmatter, W.
J . J . Neuropathol. Exp. Neurol. 1996, 55, 202-210.
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deur, J . N.; Vermeulen, N. P. Xenobiotica 1996, 26, 1087-100.
(24) Chandra, A.; Srivastava, S. K. Lipids 1997, 32, 779-82.
(25) Alary, J .; Bravais, F.; Cravedi, J . P.; Debrauwer, L.; Rao, D.;
Bories, G. Chem. Res. Toxicol. 1995, 8, 34-9.
(17) Hoff, H. F.; O’Neil, J .; G. M. Chisolm, I.; Cole, T. B.; Quehen-
berger, O.; Esterbauer, H.; J urgens, G. Arteriosclerosis 1989, 9, 538-
549.
(18) Hoff, H. F.; O’Neil, J . J . Lipid Res. 1993, 34, 1209-1217.
(19) Esterbauer, H.; Gebicki, J .; Puhl, H.; J urgens, G. Free Radical
Biol. Med. 1992, 13, 341-390.
(20) Palinski, W.; Rosenfeld, M. E.; Yla-Herttuala, S.; Gurtner, G.
C.; Socher, S. S.; Butler, S. W.; Parthasarathy, S.; Carew, T. E.;
Steinberg, D.; Witztum, J . L. Proc. Natl. Acad. Sci. U.S.A. 1989, 86,
1372-1376.
S0022-3263(97)02320-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/28/1998

Notes
J . Org. Chem., Vol. 63, No. 10, 1998 3505
Sch em e 2a
Sch em e 4a
a
Key: (a) NaBT4; (b) H+, H2O.
a
Key: NaI, acetone; (b) Zn(Cu), D2O; (c) An(Cu), T2O.
Sch em e 3a
Sch em e 5
Sch em e 6
a
Key: (a) Ph3PdCHCHO; (b) NaI, TBDMSCl, CaCO3, THF;
(c) 5, Mg, Et2O; (d) 4; (e) DHP, PPTS, CH2Cl2; (f) Bu4NF, THF; (g)
Ts2O, CH2Cl2; (h) NaBH4, DMSO; (i) NaBT4, DMSO.
the neurofibrillary tangles that are a hallmark of Alzhe-
imer’s disease.13
HNE and its 9-3H derivative was accomplished by an
efficient one-pot procedure that we have exploited previ-
ously to generate the chemically sensitive δ-hydroxy-â,γ-
unsaturated aldehyde array present in levuglandins.
Thus, exposure of 6h or 1 to a solution of NaIO4 in
aqueous acetic acid generated the corresponding γ-hy-
droxy-R,â-unsaturated aldehyde in excellent yield (Scheme
5).
Previously, HNE was prepared by a related synthetic
strategy involving generation of the acetal intermediate
8 by addition of a pentyl Grignard reagent to the
monoacetal 7 of fumaric dialdehyde followed by depro-
tection of the resulting hydroxy acetal 8 (Scheme 6).24
However, we abandoned this approach for preparing a
chemically stable tritiated precursor of HNE because
intermediates containing the dimethyl acetal masking
group were too susceptible to adventitious hydrolysis. The
3,3-dimethyl-2,4-dioxolanyl moiety that serves as a latent
formyl group in our intermediates is much more robust
than the dimethyl acetal.
A Sta ble Tr itia ted P r ecu r sor . Carbons 1-4 of the
target molecule were provided by a synthetic equivalent
4 of fumaric dialdehyde in which one of the formyl groups
is present in latent form as a 3,3-dimethyl-2,4-dioxolanyl
moiety (Scheme 3). Wittig olefination of 2,3-O-isopropy-
lidene-D-glyceraldehyde26 with (formylmethylene)triph-
enylphosphorane delivered 3-(3,3-dimethyl-2,4-dioxolanyl)-
prop-2-enal (4). Carbons 5-9 of the target molecule were
provided by the TBDMS ether 5 of 5-iodopentanol that
is readily available from TBDMS chloride, NaI, and
tetrahydropyran.27 Addition to aldehyde 4 of a Grignard
reagent prepared from iodide 5 provided alcohol 6a .
Protection of the secondary alcohol as a THP derivative
6b and desilylation afforded the primary alcohol 6c.
Tritium was introduced by reduction of the corresponding
tosylate 6d with NaBT4 in DMSO.
An alternative route for converting tosylate 6d into
isotopically labeled precursors of HNE was also explored
(Scheme 4). Thus, reduction of the derived iodide 6i with
zinc-copper couple in the presence of D2O afforded the
precursor 6j for [9-2H]-trans-4-hydroxy-2-nonenal. This
approach allows the tritium in the key intermediate 1 to
be derived from T2O, which is less expensive than NaBT4
and is available with high specific activity.
Exp er im en ta l Section
Gen er a l Meth od s. All proton magnetic resonance (1H NMR)
spectra were recorded on a Varian Gemini spectrometer operat-
ing at 300 MHz. Proton chemical shifts are reported in parts
per million (ppm) on the δ scale relative to tetramethylsilane (δ
0.00) or CHCl3 (δ 7.24). 1H NMR spectral data are tabulated in
terms of multiplicity of proton absorption (s, singlet; d, doublet;
dd, doublet of doublet; t triplet; m multiplet; br broad), coupling
constants (Hz), and number of protons. Carbon magnetic
resonance (13C NMR) spectra were recorded on a Varian Gemini
spectrometer operating at 75 MHz. These spectra are reported
Gen er a t ion of HNE b y Oxid a t ive Clea va ge of
3-Decen e-1,2,4-t r iol. Completion of our synthesis of
(26) Schmid, C. R.; Bryant, J . D.; Dowlatzedah, M.; Phillips, J . L.;
Prather, D. E.; Schantz, R. D.; Sear, N. L.; Vianco, C. S. J . Org. Chem.
1991, 56, 4056-4058.
(27) Sodeoka, M.; Yamada, H.; Shibasaki, M. J . Am. Chem. Soc.
1990, 112, 4906-4911.

3506 J . Org. Chem., Vol. 63, No. 10, 1998
Notes
in ppm on the δ scale relative to CDCl3 (δ 77.0). Proton and
carbon NMR samples were analyzed as solutions in CDCl3. All
high-resolution mass spectra were recorded on a Kratos AEI
MS25 RFA high-resolution mass spectrometer at 20 eV. All
solvents were distilled under a nitrogen atmosphere prior to use.
Tetrahydrofuran was distilled over potassium and benzophe-
none. Methylene chloride, diethyl ether, and N,N-dimethyl
formamide (DMF) were distilled over calcium hydride. Chloro-
form and carbon tetrachloride were distilled over P2O5.
63.17 (CH2), 37.16, 37.04 (CH2), 32.78 (CH2), 26.71 (CH3), 26.01
(CH2), 25.93, 25.77 (CH2), 25.23 (CH3), 25.17 (CH3), 18.41 (-C-
), -5.22 (CH3); HRMS m/z calcd for C18H35O4Si (M+ - CH3)
343.2305, found 343.2380.
(7E)-1-[[8-(3,3-Dim eth yl-2,4-d ioxola n yl)-6-(2-oxa n yloxy)-
oct-7-en yl]oxy)-1,1,2,2-tetr a m eth yl-1-sila p r op a n e (6b).
A
small amount of pyridinium p-toluenesulfonate (PPTS) was
added to a solution of compound 6a (50 mg, 0.14 mmol) and
dihydropyran (18.0 mg, 0.21 mmol) in dry methylene chloride
(2 mL).30 The resulting solution was stirred overnight at room
temperature, water (2 mL) was added, and the resulting mixture
was extracted with ethyl ether. The organic solution was
washed with half-saturated brine. The solvent was removed by
rotary evaporation. The crude product was purified by flash
chromatography on silica gel (ethyl acetate-hexanes 8:92),
affording 6b (60.0 mg, 97%): Rf ) 0. 20 (ethyl acetate-hexanes
1:9); 1H NMR (CDCl3) δ 5.55-5.85 (m, 2H), 4.55-4.80 (m, 1H),
4.42-4.54 (m, 1H), 3.98-4.12 (m, 2H), 3.76-3.88 (m, 1H), 3.35-
3.60 (m, 2H), 3.56 (t, J ) 6.4 Hz, 1H), 1.20-1.80 (14H), 1.40 (s,
3H), 1.35 (s, 3H), 0.89 (s, 9H), 0.02 (s, 6H); HRMS m/z calcd for
C23H43O5Si (M+ - CH3) 427.2880, found 427.2862.
Chromatography was performed with ACS-grade solvents
(ethyl acetate, hexane). High-performance liquid chomatogra-
phy (HPLC) was performed with HPLC-grade solvents using a
Waters Associates system consisting of a Waters M6000A solvent
delivery system and a Waters U6K injector. The eluants were
monitored using a Waters R401 differential refractometer. Thin-
layer chromatography (TLC) was performed on glass plates
precoated with silica gel (Kieselgel 60 F254, E. Merck, Darmstadt,
West Germany); Rf values are quoted for plates of thickness 0.25
mm. The plates were visualized by viewing the developed plates
under short-wavelength UV light or with iodine or by heating
the plates after spraying with vanillin-sulfuric acid. Flash
column chromatography was performed on 230-400 mesh silica
gel supplied by E. Merck. All reactions performed in an inert
atmosphere were in argon unless otherwise specified. (Formyl-
methylene)triphenylphosphorane was prepared as described
previously28 or obtained from Lancaster Synthesis. Isopropy-
lidene-D-glycerladehyde26 and 1-[(tert-butyldimethylsilyl)oxy]-5-
iodopentane (5)27 were prepared as described previously.
(E)-3-(3,3-Dim eth yl-2,4-d ioxola n yl)p r op -2-en a l (4). To a
stirred suspension of (formylmethylene)triphenylphosphorane
(1.98 g, 6.5 mmol) in toluene (30 mL) at 0 °C29 was added 2,3-
O-isopropylidene-D-glyceraldehyde (845.0 mg, 6.5 mmol)26 drop-
wise. The resulting mixture was stirred for 39 h at 0-3 °C. Then
the solvent was removed on a rotary evaporator. The residue
was extracted with ethyl ether. Evaporation of the extracts gave
a crude product that was purified by flash chromatography on
silica gel (ethyl acetate-hexanes 15:85) to yield compound 4 (690
mg, 68%): Rf ) 0.19 (ethyl acetate-hexanes 15:85); 1H NMR
(CDCl3) δ 9.57 (d, J ) 7.8 Hz, 1H), 6.74 (dd, J ) 15.7, 5.4 Hz,
1H), 6.33 (ddd, J ) 15.7, 7.8, 1.2 Hz, 1H), 4.77 (m, 1H), 4.23
(dd, J ) 15.6, 6.7 Hz, 1H), 3.71 (dd, J ) 6.7, 8.2 Hz, 1H), 1.44
(s, 3H), 1.40 (s, 3H); 13C NMR (CDCl3, APT) δ 193.00 (CHO),
153.06 (CHdCH), 132.38 (CHdCH), 110.55 (-C-), 74.83 (CH),
68.70 (CH2), 26.42 (CH3), 25.62 (CH3); HRMS (EI) m/z calcd for
C7H9O3 (M+ - Me) 141.0552, found 141.0552.
(1E)-1-(3,3-Dim eth yl-(2,4-d ioxola n yl)-8-(1,1,2,2-tetr a m e-
th yl-1-sila p r op oxy)oct-1-en -3-ol (6a ). Magnesium turnings
(296.5 mg, 12.2 mmol) and 2.0 mL of dry ethyl ether were placed
in a 125 mL, flame-dried, three-necked flask with mechanical
stirrer and reflux condenser under an argon atmosphere at room
temperature. A few drops of a solution of iodide 5 (2.0 g, 6.1
mmol) in dry diethyl ether (1 mL) were added. After formation
of the Grignard reagent began, another 30 mL of dry ethyl ether
were added and the remaining iodide solution was added
dropwise. After complete addition, the resulting mixture was
stirred for another 1 h and then chilled to 0 °C, followed by slow
addition of sufficient 3-(3,3-dimethyl-2,4-dioxolanyl)prop-2-enal
(4) (350 mg, 2.24 mmol) to consume all of the Grignard reagent
as determined with Michler’s ketone. After the mixture was
stirred for another 30 min, saturated aqueous NH4Cl was added,
the product was then extracted into Et2O and dried with
anhydrous MgSO4, and solvent was removed by rotary evapora-
tion. The crude product was purified by flash chromatography
on silica gel (ethyl acetate-hexanes 2:8), affording 6a (667 mg,
83% yield based on 4): Rf ) 0.23 (ethyl acetate-hexanes 2:8);
1HNMR (6a R + 6a S, CDCl3) δ 5.81 (dd, J ) 15.2, 6.0 Hz, 1H),
5.64 (ddd, J ) 1 5.3, 7.1, 2.6 Hz, 1H), 4.49 (dd, J ) 14.0, 7.4 Hz,
1H), 4.05-4.13 (m, 2H), 3.57 and 3.55 (2t, J ) 3.5 Hz, J ) 4.1
Hz, 1H, from two diasteromers), 1.25-1.60 (8H), 1.40 (s, 3H),
1.37 (s, 3H), 0.87 (s, 9H), 0.02 (s, 6H); 13C NMR (6a R + 6a S,
CDCl3, APT) δ 137.43, 137.36 (CH, two diasteromers) 127.88,
127.79 (CH), 109.40 (-C-), 76.63 (CH), 72.04 (CH), 69.48 (CH2),
(7E)-8-(3,3-Dim eth yl-2,4-d ioxola n yl)-6-(2-oxa n yloxy)oct-
7-en -1-ol (6c). n-Bu4NF (135 µL, 1 M in THF, 0.135 mmol) was
added dropwise to a stirred solution of the silyl ether 6b (20.0
mg, 0.045 mmol) and THF (0.5 mL).31 The resulting mixture
was stirred at room temperature overnight. Water (1 mL) was
then added. The resulting mixture was extracted with ethyl
ether, washed with brine, dried (Na2SO4), and concentrated. The
residue was purified by flash chromatography on silica gel (ethyl
acetate-hexanes 3:7) to afford 6c (14.5 mg, 99%): Rf ) 0.19
1
(ethyl acetate-hexanes 3:7); H NMR (CDCl3) δ 5.55-5.86 (m,
2H), 4.44-4.68 (m, 2H), 4.02-4.16 (m, 2H), 3.76-3.88 (m, 1H),
3.52-3.68 (m, 2H), 3.36-3.54 (m, 1H), 1.20-1.80 (14H), 1.39
(s, 3H), 1.36 (s, 3H); HRMS calcd for C17H29O5 (M+ - CH3)
313.2015, found 313.2019.
[(7E)-8-3,3-Dim eth yl-2,4-d ioxola n yl)-6-(2-oxa n yloxy)oct-
7-en yl]oxy Tosyla te (6d ). A solution of the alcohol 6c (70.0
mg, 0.21 mmol) and 4-(N,N-dimethylamino)pyridine (51.0 mg,
0.42 mmol) in dry CH2Cl2 (3 mL) was stirred 10 min at 0 °C.
Then, p-toluenesulfonic anhydride (138.0 mg, 0.42 mmol) was
added.32 The resulting mixture was stirred for 18 h at 0-5 °C.
The solvent was removed on a rotary evaporator. The residue
was triturated with ethyl ether (3 × 10 mL). After rotary
evaporation of the solvent, the residue was purified by flash
chromatography on silica gel (ethyl acetate-hexanes 3:7) to give
6d (91.8 mg, 91%): Rf ) 0.36 (ethyl acetate-hexanes 4:6); 1H
NMR (CDCl3) δ 7.76 (d, J ) 8.4 Hz, 2H), 7.32 (d, J ) 8.4 Hz,
2H), 5.52-5.84 (m, 2H), 4.44-4.10 (m, 2H), 4.00-4.10 (m, 2H),
3.98 (t, J ) 6.3 Hz, 2H), 3.80 (m, 1H), 3.55 (m, 1H), 2.43 (s, 3H),
1.20-1.90 (14H), 1.40 (s, 3H), 1.36 (s, 3H); HRMS calcd for
C24H35O7S (M+ - Me) 467.2103, found 467.2121.
(2E)-2-[[3-(3,3-Dim eth yl-2,4-d ioxola n yl)-1-p en tylp r op -2-
en yl]oxy]oxa n e (6h ). Meth od A. Sodium borohydride (1.8
mg, 0.048 mmol) in dimethyl sulfoxide (0.5 mL) was added to
6d (8.0 mg, 0.016 mmol).33 The reaction mixture was heated at
85 °C for 2 h and diluted with water (2 mL). The resulting
solution was extracted with diethyl ether (3 × 5 mL). The
combined ether extracts were dried with anhydrous magnesium
sulfate, and solvent was removed by rotary evaporation. The
crude product was purified by flash chromatography on silica
gel (ethyl acetate-hexanes 8:9) to yield compound 6h (4.0 mg,
80%): Rf ) 0.4 (ethyl acetate-hexanes 4:6); 1H NMR (CDCl3) δ
5.54-5.88 (m, 2H), 4.56-4.70 (m, 1H), 4.50 (m, 1H), 4.05 (m,
2H), 3.84 (m, 1H), 3.42 (m, 1H), 1.40-1.90 (14H), 1.39 (s, 3H),
1.36 (s, 3H), 0.85 (t, J ) 6.4 Hz, 3H); HRMS calcd for C18H32O4
(M+) 312.2300, found 312.2290, calcd for C17H29O4 297.2067 (M+
- Me), found 297.2057.
(30) Miyashita, N.; Yoshikoshi, A.; Grieco, P. A. J . Org. Chem. 1977,
42, 3772-3774.
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(28) Trippett, S.; Walker, D. M. J . Chem. Soc. 1961, 1266-1272.
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Notes
Meth od B. Magnesium turnings (1.0 g, 41.4 mmol) and dry
J . Org. Chem., Vol. 63, No. 10, 1998 3507
temperature, diluted by adding water (1 mL), and extracted with
diethyl ether (2 × 3 mL). The ether extracts were dried with
anhydrous magnesium sulfate, and solvent was evaporated by
rotary evaporation. The crude product was purified by flash
chromatography on silica gel (ethyl acetate-hexanes 1:9) to yield
tritiated precursor 1 (322.7 µCi): Rf ) 0.20 (ethyl acetate-
hexanes 12:88). TLC showed an Rf identical to that of the
unlabeled analogue 6h .
[9-3H]-(2E)-4-Hyd r oxyn on -2-en a l. The hot tritiated precur-
sor 1 was mixed with 6h (cold analogue), and then the mixture
was purified again by flash chromatography on silica gel (ethyl
acetate-hexanes 1:9) to give a mixture (1 + 6h ) (32.0 mg) that
exhibited a specific activity of 3.35 mCi/mmol. Sodium periodate
(3.0 mg, 0.014 mmol) was dissovled in acetic acid/water (2:1, v/v,
300 µL). The solution was added to the mixture of 1 + 6h (3
mg, 0.0096 mmol). The reaction mixture was heated at 40 °C
for 4 h and then neutralized to pH ) 7 by the portionwise
addition of saturated aqueous sodium bicarbonate, extracted
with diethyl ether, and dried with anhydrous magnesium
sulfate. The solvent was removed on a rotary evaporater, and
the crude product was purified by flash chromatography on silica
gel (ethyl acetate-hexanes 3:7) to afford [9-3H]-HNE (1.4 mg,
93.3%, 3.35 mCi/mmol): Rf ) 0.23 (ethyl acetate-hexanes 3:7).
The structure was confirmed by its 1H NMR spectrum, which
was indistinguishable from that of unlabeled HNE.
ethyl ether (2.0 mL) were placed in a flame-dried three-necked
125 mL flask with a mechanical stirrer and reflux condenser
under an argon atmosphere at room temperature. A few drops
of a solution of 1-bromopentane (2.5 g, 16.5 mmol, freshly
distilled) in dry diethyl ether (1 mL) were added. After the
formation of Grignard reagent began, another 30 mL of dry ether
were added. The remaining bromide solution was then added
dropwise. After completion of the addition, the reaction mixture
was stirred overnight and then chilled to 0 °C, followed by
dropwise addition of aldehyde 4 (300.0 mg, 1.92 mmol) until all
of the organometallic was consumed as determined with Michler’s
ketone. After the mixture was stirred for 30 min, saturated
aqueous NH4Cl was added, and the resulting mixture was
extracted with diethyl ether. The extract was dried with
anhydrous MgSO4. The solvent was removed on
a rotary
evaporator. The crude product was purified by flash chroma-
tography on silica gel (ethyl acetate-hexanes 35:65) to give (1E)-
1-(3,3-d im eth yl-2,4-d ioxola n yl)oct-1-en -3-ol (400.0 mg, 91.3%
1
yield based on 4): Rf ) 0.28 (ethyl acetate-hexanes 35:65); H
NMR (CDCl3) δ 5.78 (ddd, J ) 16.0, 6.3, 1.8 Hz, 1H), 5.64(ddd,
J ) 16.6, 6.5, 2.8 Hz, 1H), 4.48 (dd, J ) 13.8, 7.3 Hz, 1H), 4.05
(m, 2H), 3.56 (td, J ) 8.0, 1.8 Hz, 1H), 1.70 (m, 2H), 1.20-1.60
(14H), 1.39 (s, 3H), 1.36 (s, 3H), 0.85 (t, J ) 6.6 Hz, 3H); 13C
NMR (CDCl3, APT, two diasteromers) δ 137.48, 137.42 (CH),
127.81, 127.74 (CH), 90.39 (-C-), 76.65, 76.58 (CH), 72.10, 71.98
(CH), 69.49, 69.47 (CH2), 31.12, 31.02 (CH2), 31.73 (CH2), 26.70
(CH3), 26.01 (CH3), 25.08, 25.04 (CH2), 22.60 (CH2), 14.05 (CH3);
HRMS calcd for C13H24O3 (M+) 228.1725, found 228.1729.
A small amount of pyridinium p-toluenesulfonate (PPTS) was
added to a solution of the above alcohol (52.0 mg, 0.23 mmol)
and dihydropyran (29.0 mg, 0.35 mmol) in dry methylene
chloride (1 mL). The resulting solution was stirred overnight
at room temperature, diluted and extracted with ethyl ether,
and washed with half-saturated brine. The solvent was removed
on a rotary evaporator. The crude product was purified by flash
chromatography on silica gel (ethyl acetate-hexanes 1:90) to
afford 6h (60 mg, 97%): Rf ) 0.20 (ethyl acetate-hexanes 12:
88).
Ack n ow led gm en t. We thank the National Institute
of General Medical Sciences of the National Institutes
of the Health for support of this research by Grant No.
HL53315.
Su p p or tin g In for m a tion Ava ila ble: Details of the syn-
theses of 6i from 6d , 6j from 6i, and HNE from 6h , as well as
NMR spectra of all new compounds (14 pages). This material
is contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
[93H ]-(2E)-2-[[3-(3,3-Dim et h yl-2,4-d ioxola n yl)-1-p en t yl-
p r op -2-en yl]oxy]oxa n e (1). Tosylate 6d (8.0 mg, 1.67 µmol)
was dissolved in dimethyl sulfoxide (200 µL) and added to
sodium borotritide (0.63 mg, 1.67 µmol, 25 mCi) in a vial under
an argon atmosphere.34 The reaction mixture was stirred
magnetically and heated at 85 °C for 2 h and then cooled to room
J O972320F
(34) Tamvakopolos, C. S.; Anderson, V. E. J . Labelled Compd.
Radiopharm. 1990, 28, 187-191.