Shortcut syntheses of naturally occurring 5-alkylresorcinols with DNA-cleaving properties

Article abstract of DOI:10.1021/jo962423i

Resorcinols such as 1-5 bearing long alkyl- or alkenyl substituents at the C-5 position, including bola-formed bis-resorcinol derivatives, have recently been isolated from natural sources and were shown to exhibit exceptional DNA-cleaving properties under oxidative conditions. Previous synthetic approaches to such compounds seem inappropriately lengthy with regard to their structural simplicity. Disclosed is a very flexible synthesis which assembles these targets from triflate 7 and well accessible alkenes, dienes, enynes, or dienynes, respectively, by means of a boron-mediated reaction manifold. As a typical example, hexadeca-1,15-dien-8-yne 11 is hydroborated with 9-H-9-BBN at all possible sites, the alkenyl borane entity of the resulting tris-borane 12 is selectively cleaved off to afford the desired (Z)-alkene group in a stereoselective manner, the remaining two terminal alkylboranes are treated with NaOMe, and the bis-borate complex 13 thus formed is finally used as the nucleophile for a palladium-catalyzed Suzuki cross-coupling reaction with triflate 7. This sequence is carried out in one pot and provides product 14 in 62% overall yield. Demethylation of 14 (and analogues) can be conveniently achieved by means of 9-iodo-9-BBN to afford the natural product 5. The efficiency and flexibility of this unprecedented approach which combines different features of classical and modern boron chemistry is further demonstrated by the synthesis of anacardic and ginkgolic acid derivatives.

Full text of DOI:10.1021/jo962423i

2332
J . Org. Chem. 1997, 62, 2332-2336
Articles
Sh or tcu t Syn th eses of Na tu r a lly Occu r r in g 5-Alk ylr esor cin ols w ith
DNA-Clea vin g P r op er ties
Alois Fu¨rstner* and Gu¨nter Seidel
Max-Planck-Institut fu¨r Kohlenforschung, Kaiser-Wilhelm-Platz 1, D-45470 Mu¨lheim/ Ruhr, Germany
Received December 30, 1996X
Resorcinols such as 1-5 bearing long alkyl- or alkenyl substituents at the C-5 position, including
bola-formed bis-resorcinol derivatives, have recently been isolated from natural sources and were
shown to exhibit exceptional DNA-cleaving properties under oxidative conditions. Previous synthetic
approaches to such compounds seem inappropriately lengthy with regard to their structural
simplicity. Disclosed is a very flexible synthesis which assembles these targets from triflate 7 and
well accessible alkenes, dienes, enynes, or dienynes, respectively, by means of a boron-mediated
reaction manifold. As a typical example, hexadeca-1,15-dien-8-yne 11 is hydroborated with 9-H-
9-BBN at all possible sites, the alkenyl borane entity of the resulting tris-borane 12 is selectively
cleaved off to afford the desired (Z)-alkene group in a stereoselective manner, the remaining two
terminal alkylboranes are treated with NaOMe, and the bis-borate complex 13 thus formed is finally
used as the nucleophile for a palladium-catalyzed Suzuki cross-coupling reaction with triflate 7.
This sequence is carried out in one pot and provides product 14 in 62% overall yield. Demethylation
of 14 (and analogues) can be conveniently achieved by means of 9-iodo-9-BBN to afford the natural
product 5. The efficiency and flexibility of this unprecedented approach which combines different
features of classical and modern boron chemistry is further demonstrated by the synthesis of
anacardic and ginkgolic acid derivatives.
Recent reports on the exceptional potency of the
resorcinols 1-5, isolated from the west Australian shrub
Hakea trifurcata, to cleave DNA under oxidative condi-
tions [O2, Cu(II)] denote a highlight in the vast literature
on non-isoprenoid phenol lipids.1 Elegant studies of
Hecht et al. brought some insight into the mechanism of
action of these metabolites.2 Thus, DNA cleavage is most
likely triggered by copper-assisted oxygenation of their
benzene rings and generation of diffusible oxygen radicals
which effect the scission of the nucleic acid strand.2,3
However, the way of binding of these compounds to DNA
is still obscure as they lack structural elements that
might entail intercalation, groove binding, or electrostatic
interaction. A correlation between the length of their
aliphatic chain and the biological response has been
observed which seems to indicate an essentially hydro-
phobic interaction.2
Subsequent work has demonstrated that various struc-
turally related 3-alk(en)ylcatechols found in poison oak
(Toxicadendron diversilobum) or poison ivy (Toxicaden-
dron radicans) have similar DNA-cleaving properties as
compounds 1-5.4 Moreover, several other phenolic lipids
are well known to exhibit cytotoxic activity.5 Thus, a
further pharmacological evaluation of this class of com-
pounds is promising which requires a straightforward
entry into long chain alkylphenols in order to study the
structure/activity profile in more detail. Existing meth-
ods, however, seem inappropriately lengthy with regard
X Abstract published in Advance ACS Abstracts, April 1, 1997.
(1) Review: Tyman, J . H. P. Chem. Soc. Rev. 1979, 499-537.
(2) (a) Lytollis, W.; Scannell, R. T.; An, H.; Murty, V. S.; Reddy, K.
S.; Barr, J . R.; Hecht, S. M. J . Am. Chem. Soc. 1995, 117, 12683-
12690. (b) Singh, U. S.; Scannell, R. T.; An, H.; Carter, B. J .; Hecht, S.
M. J . Am. Chem. Soc. 1995, 117, 12691-12699. (c) Scannell, R. T.;
Barr, J . R.; Murty, V. S.; Reddy, K. S.; Hecht, S. M. J . Am. Chem. Soc.
1988, 110, 3650-3651.
(3) This metal-assisted scenario is reminiscent of the mode of action
of metallobleomycins, although the elementary steps of oxygen transfer
to the DNA may be different. For reviews see i.a.: (a) Hecht, S. M.
Pure Appl. Chem. 1989, 61, 577-580. (b) Sugiyama, H.; Ehrenfeld, G.
M.; Shipley, J . B.; Kilkuskie, R. E.; Chang, L.-H.; Hecht, S. M. J . Nat.
Prod. 1985, 48, 869-877. (c) Stubbe, J .; Kozarich, J . W. Chem. Rev.
1987, 87, 1107-1136.
(4) Wasser, C.; Silva, F.; Rodriguez, E. Experientia 1990, 46, 500-
502.
(5) (a) Arisawa, M.; Ohmura, K.; Kobayashi, A.; Morita, N. Chem.
Pharm. Bull. 1989, 37, 2431-2434. (b) Itokawa, H.; Totsuka, N.;
Nakahara, K.; Takeya, K.; Lepoittevin, J .-P.; Asakawa, Y. Chem.
Pharm. Bull. 1987, 35, 3016-3020.
S0022-3263(96)02423-1 CCC: $14.00 © 1997 American Chemical Society

5-Alkylresorcinols with DNA Cleaving Properties
J . Org. Chem., Vol. 62, No. 8, 1997 2333
Sch em e 1a
Sch em e 2a
a
[a] Triflic anhydride, 2,6-lutidine, CH2Cl2, 94%; [b] NaOMe,
PdCl2(dppf) cat., THF, 88% (7 f 8), 87% (7 f 9); [c] 9-iodo-9-BBN,
hexane, 90% (8 f 1), 88% (9 f 3).
a
[a] LiCtCLi, THF/HMPA, 72%; [b] 9-H-9-BBN (3 equiv), THF;
[c] MeOH/HOAc (99:1); [d] NaOMe (2 equiv); [e] 7 (2 equiv),
PdCl2(dppf) cat., 62% (over steps [b-e]); [f] 9-iodo-9-BBN, hexane,
98%.
to the structural simplicity of such targets.1,2,6 Therefore
we were prompted to develop a new approach which
requires a minimum number of steps and clearly sur-
passes the established routes in terms of flexibility and
overall yield.
equiv), and a final cleavage of the OMe groups as
described leads to the bola-form resorcinol 3 without
incident.
Our synthesis relies on the palladium-catalyzed, base-
induced cross-coupling of 9-alkyl-9-BBN derivatives with
aryl triflate 7 which is obtained from cheap 3,5-dimeth-
oxyphenol (6) and triflic anhydride in the presence of 2,6-
lutidine (Scheme 1). In view of the performance of
Suzuki reactions in general,7,8 the 88% isolated yield of
8 on coupling of 7 with 9-tridecyl-9-BBN in the presence
of NaOMe and catalytic amounts of PdCl2(dppf)9 may not
be surprising. Subsequent cleavage of the methyl ethers
by 9-iodo-9-BBN (see below)10 affords compound 1 in
excellent overall yield. In a similar sequence, bis-
hydroboration of 1,13-tetradecadiene with 9-H-9-BBN
dimer under standard conditions, followed by a twofold
Suzuki reaction of the resulting bis-borane with 7 (2
Previous syntheses of phenolic lipids containing (Z)-
configurated double bonds in the side chain essentially
relied on Lindlar hydrogenations of the respective alkyne
precursors. However, we encountered problems in ef-
fecting such semihydrogenations in a reproducible man-
ner.11 The formation of minor, but inseparable byprod-
ucts, most likely isomers formed by a scrambling of the
double bond, could not be suppressed (cf. Supporting
Information). Therefore we explored an unambiguous
alternative route.
A very convenient solution takes advantage of the
largely different stabilities of B-C(sp3) and B-C(sp2) bonds
towards hydrolysis (Scheme 2).12 Specifically, dilithio-
acetylene13 was alkylated with 2 equiv of 7-iodo-1-heptene
(10) to afford diene-yne 11. This compound was hydro-
borated with 9-H-9-BBN dimer at both double bonds as
well as at the alkyne site to afford the tris-borane 12.
Addition of MeOH (containing 1% HOAc, w/w) then
(6) See also: (a) Baylis, C. J .; Odle, S. W. D.; Tyman, J . H. P. J .
Chem. Soc., Perkin Trans. 1 1981, 132-141. (b) Durrani, A. A.; Tyman,
J . H. P. J . Chem. Soc., Perkin Trans. 1 1980, 1658-1666. (c) Alonso,
E.; Ramon, D. J .; Yus, M. J . Org. Chem. 1997, 62, 417-421.
(7) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483.
(b) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.;
Suzuki, A. J . Am. Chem. Soc. 1989, 111, 314-321. (c) Oh-e, T.;
Miyaura, N.; Suzuki, A. J . Org. Chem. 1993, 58, 2201-2208.
(8) For recent methodological advancements in Suzuki reactions and
for applications to the synthesis of physiologically active natural
products from our laboratory see: (a) Fu¨rstner, A.; Seidel, G. Tetra-
hedron 1995, 51, 11165-11176. (b) Fu¨rstner, A.; Konetzki, I. Tetra-
hedron 1996, 52, 15071-15078. (c) Fu¨rstner, A.; Nikolakis, K. Liebigs
Ann. 1996, 2107-2113. (d) Fu¨rstner, A.; Seidel, G.; Gabor, B.; Kopiske,
C.; Kru¨ger, C.; Mynott, R. Tetrahedron 1995, 51, 8875-8888.
(9) Hayashi, T.; Konishi, M.; Kobori, Y.; Kumada, M.; Higuchi, T.;
Hirotsu, K. J . Am. Chem. Soc. 1984, 106, 158-163.
(11) Review: Marvell, E. N.; Li, T. Synthesis 1973, 457-468.
(12) (a) Brown, H. C.; Wang, K. K. J . Org. Chem. 1986, 51, 4514-
4517. (b) Brown, H. C.; Scouten, C. G.; Liotta, R. J . Am. Chem. Soc.
1979, 101, 96-99.
(13) (a) Prepared from n-BuLi and acetylene according to: Brands-
ma, L. Preparative Acetylenic Chemistry, 2nd ed.; Elsevier: Amster-
dam, 1988; pp 23-24. (b) For an alternative synthesis from n-BuLi
and trichloroethylene see: Sekiguchi, A.; Ichinohe, M.; Kabuto, C.;
Sakurai, H. Bull. Chem. Soc. J pn. 1995, 68, 2981-2988. Dilithioacetyl-
ene prepared according to this latter procedure on alkylation with 10
gave, however, a somewhat lower yield of dienyne 11.
(10) Ko¨ster, R.; Seidel, G. In Organometallic Syntheses; King, R. B.,
Eisch, J . J ., Eds.; Elsevier: Amsterdam, 1988; Vol. 4, pp 440-442.

2334 J . Org. Chem., Vol. 62, No. 8, 1997
Fu¨rstner and Seidel
Sch em e 3a
Sch em e 4a
a
[a] 1-Octynyllithium, THF, 90%; [b] 9-iodo-9-BBN, hexane,
a
96%.
[a] (i) 1-Pentadecene, 9-H-9-BBN, THF; (ii) NaOMe, PdCl2(dppf)
cat. 79%; [b] KOH, H2O/DMSO, 95%; [c] (i) 15, 9-H-9-BBN (2
equiv), THF; (ii) MeOH/HOAc (99:1); (iii) NaOMe, PdCl2(dppf) cat.,
67%.
effects a smooth and regioselective protonolysis of the
alkenylborane group without affecting the terminal alkyl-
borane entities. Subsequent treatment with NaOMe
leads to the bis-borate complex 13 as the actual nucleo-
phile for the ensuing Suzuki coupling with 2 equiv of
triflate 7. It is worth mentioning that this sequence
comprising the triple hydroboration, the selective pro-
tonoloysis, the subsequent borate formation, and two
final Pd-catalyzed C-C-bond formations is effected in one
pot and proceeds with 62% isolated yield overall. Since
the hydroboration of internal alkynes is strictly (Z)-
selective, the formation of any isomeric product is pre-
cluded. The same one-pot procedure, when applied to
enyne 15 as the substrate, leads in a single operation to
product 16 in 83% yield (Scheme 3). From these ex-
amples it is obvious that the series of homologues of the
resorcinol targets in question can be assembled from
triflate 7 and simple alkenes, dienes, enynes, or dienynes,
respectively, by highly efficient and routine steps. The
reactions can easily be up-scaled and are likely suitable
for automatization. This clearly surpasses previous
approaches in all preparative respects.
the ready syntheses of anacardic acid 19,14 the ginkgolic
acid derivative 20,15 as well as of the â-D-mannosylated
compound 21,8b,16 which acts as a selective inhibitor of
the GABAA/benzodiazepine chloride channel receptor
complex (Scheme 4). Future work will concentrate on
the synthesis of resorcinol derivatives bearing a DNA
sequence specific recognition pattern e.g. attached to one
of the phenolic OH functions.17
Exp er im en ta l Section
Gen er a l. For the instrumentation used and the spectral
formats see the Supporting Information. Melting points were
measured on a Gallenkamp apparatus (uncorrected) or by
differential scanning calorimetry (DSC). All hydroboration
and cross-coupling reactions have been monitored by 11B NMR
by taking aliquots of the crude reaction mixtures and taking
spectra relative to BF3‚Et2O as external standard; the char-
acteristic shifts (δ, ppm) are reported below. All reactions were
carried out under Ar using Schlenk techniques. 9-H-9-BBN18
dimer and 9-iodo-9-BBN10 have been prepared according to the
procedures cited; 1-tridecene, 1-pentadecene, 1,13-tetradeca-
diene, and all other reagents have been purchased and used
as received. The solvents were dried by distillation over the
A final issue concerns the cleavage of the methyl ether
groups. While BBr3 works fine for nonolefinic com-
pounds, this reagent is inapplicable to e.g. 14 and 16 due
to concomitant haloboration of the double bonds. In these
cases, deprotection has previously been achieved by
heating the substrates with MeMgI in the solid state at
100-165 °C!2 It is obvious that these rude conditions
are inappropriate for the preparation of analogues bear-
ing more sensitive functional groups. A very convenient
alternative consists in the use of 9-iodo-9-BBN.10 This
reagent readily cleaves the ether functions without
affecting the double bonds. Moreover, the workup of the
reaction mixtures is conveniently achieved by adding
ethanolamine and filtering off the crystalline 9-BBN
adduct thereof.
(14) (a) For an alternative approach to anacardic acid and related
salicylic acid derivatives and for a compilation of the literature see:
Zehnter, R.; Gerlach H. Liebigs Ann. 1995, 2209-2220. (b) For a report
on the prostaglandin synthetase inhibitory activity of this compound
see: Kubo, I.; Kim, M.; Naya, K.; Komatsu, S.; Yamagiwa, Y.; Ohashi,
K.; Sakamoto, Y.; Hirakawa, S.; Kamikawa, T. Chem. Lett. 1987, 1101-
1104.
(15) For a review on ginkgolic acid see ref 1; it is also the major
antitumor principle of the chloroform extracts of Ginkgo biloba, cf. ref
5b; for structure elucidation see: Morimoto, H.; Kawamatsu, Y.;
Sugihara, H. Chem. Pharm. Bull. 1968, 16, 2282-2286.
(16) Shan, R.; Anke, H.; Nielsen, M.; Sterner, O.; Witt, M. R. Nat.
Prod. Lett. 1994, 4, 171-178.
(17) For leading references on the design of artificial sequence
specific DNA binding/cleaving agents see i.a.: (a) Dervan, P. B. Science
1986, 232, 464-471. (b) Barton, J . K. Science 1986, 233, 727-734. (c)
Sigman, D. S. Acc. Chem. Res. 1986, 19, 180-186. (d) Chu, B. C. F.;
Orgel, L. E. Proc. Nat. Acad. Sci. U.S.A. 1985, 82, 963-967 and lit
cit.
In summary, the reaction manifold outlined above
combines all essential features for preparing series of
(more highly functionalized) analogues of these interest-
ing natural products. First results along these lines are
(18) For a convenient large-scale preparation see: Binger, P.; Ko¨ster,
R. Inorg. Synth. 1974, 15, 147-149.

5-Alkylresorcinols with DNA Cleaving Properties
J . Org. Chem., Vol. 62, No. 8, 1997 2335
following drying agents prior to use and were transferred
under Ar: THF (Mg-anthracene), hexane, Et2O (Na/K alloy),
CH2Cl2 (P4O10), MeOH (Mg). Flash chromatography: Merck
silica gel (230-400 mesh) with hexane/ethyl acetate as the
eluent in the proportions indicated.
δ ) 70.9, 50.8, rel intensity 2:1). After addition of NaOMe
(270 mg, 5 mmol), the reaction is stirred for another 60 min
until a clear solution of the respective borate complex 13 has
formed (11B NMR: δ ) 4.1, -2.7) to which triflate 7 (687 mg,
2.4 mmol) and PdCl2(dppf) (59 mg, 0.07 mmol) are added. The
mixture is refluxed for 1 h and worked-up as described above.
A final flash chromatography with hexane/ethyl acetate (15:
1) as the eluent affords product 14 as a colorless syrup (370
mg, 62%). 1H NMR: δ ) 6.34 (d, 4H, J ) 2.2), 6.29 (t, 2H, J
) 1.5), 5.34 (t, 2H, J ) 4.5), 3.77 (s, 12H), 2.54 (vt, 4H), 2.00
(m, 4H), 1.60 (m, 4H), 1.40-1.20 (m, 16H). 13C NMR: δ )
160.6, 145.3, 129.8, 106.4, 97.5, 55.2, 36.3, 31.2, 29.7, 29.4, 29.3,
29.2, 27.2. MS, m/ z (rel intensity): 496 (29) [M+], 400 (4),
345 (1), 233 (5), 219 (5), 194 (5), 165 (16), 152 (100).
1-P en ta d ecen -8-yn e (15). A suspension of 1-octynyl-
lithium (0.70 g, 6 mmol) and iodide 10 (1.20 g, 4.9 mmol) in
THF (40 mL) is refluxed for 7.5 h. For workup the solvent is
removed in vacuo, the residue is suspended in hexane (40 mL),
the suspension is stirred for 30 min, insoluble LiI is filtered
off through a short pad of silica, and the filtrate is concentrated
affording 15 as a colorless liquid (912 mg, 90%). 1H NMR: δ
) 5.81 (m, 1H), 4.95-5.05 (m, 2H), 2.14 (m, 2H), 2.04 (m, 2H),
1.60-1.20 (m, 14H), 0.88 (t, 3H, J ) 7). 13C NMR: δ ) 138.9
(d), 114.2 (t), 80.3 (s), 80.0 (s), 31.4 (t), 29.1 (t), 29.0 (t), 28.5
(t), 28.4 (t), 28.3 (t), 22.6 (t), 18.8 (t), 18.7 (t), 14.0 (q). MS,
m/ z (rel intensity): 206 (2) [M+], 191 (3), 177 (11), 163 (24),
149 (17), 136 (55), 121 (100), 107 (66), 95 (63), 93 (79), 81 (87),
79 (69), 67 (86), 55 (39), 41 (38). Anal. C15H26 (206.4) Calcd:
C 87.31, H 12.69. Found: C 87.64, H 12.36.
1,3-Dim eth oxy-5-[8′(Z)-p en ta d ecen -1-yl]ben zen e (16).
A solution of substrate 15 (336 mg, 1.6 mmol) and 9-BBN (415
mg, 3.4 mmol) in THF (60 mL) is stirred for 7 h at ambient
temperature. To the resulting bis-borane (11B NMR: δ ) 79.1)
is added MeOH (containing 1% HOAc, w/w, 200 mg, 6.3 mmol),
and the mixture is stirred for 2.5 h at that temperature until
selective cleavage of the alkenyl borane entity has occurred
(11B NMR: δ ) 71.1, 55.9; rel intensity 1:1). NaOMe (224 mg,
4.1 mmol) is then introduced, and the mixture is stirred for 1
h until borate formation is complete (11B NMR: δ ) 4.2, -2.6).
Subsequent addition of triflate 7 (425 mg, 1.5 mmol) and PdCl2-
(dppf) (41 mg, 0.05 mmol), refluxing of the mixture for 1 h,
evaporation of the solvent, partition of the residue between
Et2O and water (30 mL each), drying of the organic layer
(Na2SO4), evaporation of the solvent, and final flash chroma-
tography of the crude product with hexane/ethyl acetate (20:
1) affords compound 16 as a colorless syrup (431 mg, 83%).
1H NMR: δ ) 6.34 (d, 2H, J ) 2.3), 6.29 (t, 1H, J ) 2.3), 5.35
(t, 2H, J ) 4.5), 3.77 (s, 6H), 2.54 (vt, 2H), 2.01 (m, 4H), 1.60
(m, 2H), 1.40-1.20 (m, 16H), 0.88 (t, 3H, J ) 7). 13C NMR: δ
) 160.7, 145.3, 129.9, 129.8, 106.4, 97.5, 55.2, 36.3, 31.8, 31.2,
29.7(2C), 29.4, 29.3, 29.2, 29.0, 27.2, 27.1, 22.6, 14.1. MS, m/ z
(rel intensity): 346 (20) [M+], 250 (5), 233 (4), 219 (3), 194 (5),
165 (13), 152 (100).
Gen er a l P r oced u r e for th e Clea va ge of th e Meth yl
Eth er Gr ou p s by 9-Iod o-9-BBN. A mixture of the respective
1-alkyl-3,5-dimethoxybenzene derivative (1 mmol) and 9-iodo-
9-BBN (2.1 mmol) in hexane (20 mL) is stirred for 1-4 h at
ambient temperature. The volatiles are removed in vacuo, the
residue is dissolved in Et2O (10 mL), and a solution of
ethanolamine (2.2 mmol) in THF (1 mL) is added causing
spontaneous precipitation of the 9-BBN.ethanolamine adduct.
After stirring for 3 h, this precipitate is filtered off (mp ) 217-
218 °C), the filtrate is evaporated, and the crude resorcinols
are chromatographed using hexane/ethyl acetate (2:1, 1:1) as
eluent. This affords analytically pure compounds, the analyti-
cal data of which are compiled below.
3,5-Dim eth oxyp h en ol Tr iflu or om eth a n esu lfon a te (7).
A solution of triflic anhydride (11.4 g, 40 mmol) in CH2Cl2 (30
mL) is added over
a period of 45 min to a solution of
3,5-dimethoxyphenol (6) (5.04 g, 33 mmol) and 2,6-lutidine (4.9
g, 46 mmol) in CH2Cl2 (160 mL) at -10 °C. After stirring for
2 h at 0 °C the reaction is quenched with water, the organic
layer is separated and dried (Na2SO4), the solvent is removed
in vacuo, and the crude product is purified by distillation (bp
) 75-81 °C, 10-3 torr) to afford 7 as a colorless syrup (8.79 g,
94%). 1H NMR: δ ) 6.45 (t, 1H, J ) 1.5), 6.42 (d, 2H), 3.79
(s, 6H). 13C NMR: δ ) 161.5, 150.6, 118.5 (q, J CF ) 320 Hz),
100.3, 100.0, 55.7. MS, m/ z (rel intensity): 286 (88) [M+], 257
(2), 153 (8), 125 (100), 110 (8), 79 (8), 69 (22).
1,3-Dim et h oxy-5-t r id ecylb en zen e (8). A solution of
1-tridecene (474 mg, 2.6 mmol) and 9-BBN (317 mg, 2.6 mmol)
in THF (60 mL) is stirred for 2 h at ambient temperature (11B
NMR: δ ) 82.6). NaOMe (162 mg, 3 mmol) is then added
(11B NMR: δ ) -2.5), followed by triflate 7 (645 mg, 2.3 mmol)
and PdCl2(dppf) (56 mg, 0.07 mmol). The mixture is refluxed
for 1 h, the solvent is removed in vacuo, the crude product is
suspended in CH2Cl2, and the insoluble residues are filtered
off through a short pad of silica. Evaporation of the solvent
and flash chromatography using hexane/EtOAc (15:1) as eluent
affords product 8 as colorless crystals (647 mg, 88%). mp )
41-42 °C (lit.2a 41-42 °C); 1H NMR: δ ) 6.34 (d, 2H, J ) 2),
6.29 (t, 1H), 3.77 (s, 6H), 2.54 (vt, 2H), 1.60 (m, 2H), 1.40-
1.20 (m, 20H), 0.88 (t, 3H, J ) 7).- 13C NMR: δ ) 160.7, 145.4,
106.5, 97.6, 55.5, 36.3, 31.9, 31.3, 29.7 (3C), 29.65, 29.60, 29.5,
29.4, 22.7, 14.1. MS, m/ z (rel intensity): 320 (17) [M+], 194
(6), 165 (13), 152 (100).
1,3-Dim et h oxy-5-[14′-(3′′,5′′-d im et h oxyp h en yl)t et r a -
d ecyl]ben zen e (9). A solution of 1,13-tetradecadiene (694
mg, 3.6 mmol) and 9-BBN (878 mg, 7.2 mmol) in THF (80 mL)
is stirred for 2 h at ambient temperature (11B NMR: δ ) 79.4).
NaOMe (507 mg, 9.4 mmol) is added and the solution stirred
for another 30 min (11B NMR: δ ) -2.1) prior to the addition
of triflate 7 (1.79 g, 6.3 mmol) and PdCl2(dppf) (152 mg, 0.19
mmol). Complete conversion of the substrates is reached (11B
NMR: δ ) 55.9) after refluxing the mixture for 1 h. Workup
as described above followed by crystallization of the crude
product by slowly cooling a solution in hexane to -80 °C
affords the title compound as colorless crystals (1.285 g, 87%).
mp ) 61-62 °C (lit.2a 62.5-63 °C); 1H NMR: δ ) 6.34 (d, 4H,
J ) 2), 6.29 (t, 2H), 3.77 (s, 12H), 2.54 (vt, 4H), 1.59 (m, 4H),
1.40-1.20 (m, 20H). 13C NMR: δ ) 160.7, 145.4, 106.5, 97.5,
55.2, 36.3, 31.3, 29.7 (2C), 29.6, 29.5, 29.3.- MS, m/ z (rel
intensity): 470 (31) [M+], 194 (5), 165 (15), 152 (100).
1,15-Hexa d eca d ien -8-yn e (11). A suspension of dilithium
acetylide (104 mg, 2.75 mmol)13 and iodide 10 (1.12 g, 5 mmol)
in THF (20 mL) and HMPA (2 mL) is stirred for 16 h at
ambient temperature and 2 h at reflux. The solvent is
removed in vacuo, the residue is suspended in hexane, and
insoluble LiI is filtered off through a short pad of silica which
is subsequently washed with hexane/ethyl acetate (20:1) in
several portions. The combined filtrates are evaporated af-
fording pure 11 as colorless liquid (393 mg, 72%). 1H NMR:
δ ) 5.81 (m, 2H), 4.92-5.05 (m, 4H), 2.1 (m, 8H), 1.4 (m, 12H).
13C NMR: δ ) 138.9, 114.2, 80.1, 33.7, 29.0, 28.4, 28.3, 18.7.
MS, m/ z (rel intensity): 218 (1) [M+], 203 (4), 189 (7), 175
(11), 161 (15), 147 (28), 135 (26), 121 (77), 107 (55), 95 (66), 93
(86), 81 (89), 79 (98), 67 (100), 55 (53), 41 (65), 29 (14). Anal.
C16H26 (218.4) Calcd: C 88.00, H 12.00. Found: C 87.85, H
12.04.
1,3-Dih ydr oxy-5-tr idecylben zen e (1): 90%, colorless solid,
mp ) 83-84 °C (lit.2a 83.5-85.4 °C). 1H NMR: δ ) 6.23 (d,
2H, J ) 2.3), 6.16 (t, 1H), 5.25 (s, 2H, OH), 2.48 (t, 2H, J ) 7),
1.56 (m, 2H), 1.30-1.15 (m, 20H), 0.88 (t, 3H, J ) 7.5). 13C
NMR: δ ) 156.7, 146.1, 107.9, 100.1, 35.8, 31.9, 31.0, 29.7
(3C), 29.64, 29.58, 29.50, 29.33, 29.29, 22.7, 14.1. MS, m/ z
(rel intensity): 292 (24) [M+], 250 (2), 208 (2), 166 (6), 137 (10),
124 (100).
1,3-Dim et h oxy-5-[16′-(3′′,5′′-d im et h oxyp h en yl)-8′(Z)-
h exa d ecen -1-yl]ben zen e (14). A solution of dienyne 11 (295
mg, 1.35 mmol) and 9-BBN (537 mg, 4.4 mmol) in THF (60
mL) is stirred at ambient temperature for 8 h. To the resulting
triorganoborane 12 (11B NMR: δ ) 79.1) is added MeOH
(containing 1% HOAc, w/w, 166 mg, 5.2 mmol), and the
mixture is stirred for 2.5 h until 11B NMR inspection indicates
quantitative cleavage of the alkenylborane group (11B NMR:
1,3-Dih ydr oxy-5-[8′(Z)-pen tadecen -1-yl]ben zen e (2): 96%,
waxy solid, mp ) 32 °C (DSC) (lit.2a 31-33 °C). 1H NMR: δ

2336 J . Org. Chem., Vol. 62, No. 8, 1997
Fu¨rstner and Seidel
) 6.25 (d, 2H, J ) 2.3), 6.17 (t, 1H), 5.61 (s, 2H, OH), 5.35 (t,
2H, J ) 4.5), 2.45 (vt, 2H), 2.01 (m, 4H), 1.53 (m, 2H), 1.40-
1.20 (m, 16H), 0.88 (t, 3H, J ) 7). 13C NMR: δ ) 156.4, 146.2,
130.0, 129.8, 108.1, 100.3, 35.8, 31.8, 31.0, 29.74, 29.71, 29.4,
29.3, 29.2, 29.0, 27.21, 27.18, 22.6, 14.1. MS, m/ z (rel
intensity): 318 (16) [M+], 222 (7), 205 (3), 191 (4), 163 (6), 137
(11), 124 (100).
1,3-Dih yd r oxy-5-[14′-(3′′,5′′-d ih yd r oxyp h e n yl)t e t r a -
d ecyl]ben zen e (3): 88%, colorless solid, mp ) 138 °C dec
(DSC) (lit.2a 118-120 °C). 1H NMR (THF-d8): δ ) 7.79 (s, 4H,
OH), 6.04 (d, 4H, J ) 2.3), 5.97 (t, 2H), 2.41 (vt, 4H), 1.55 (m,
4H), 1.28 (m, 20H). 13C NMR (THF-d8): δ ) 159.9, 145.3,
107.3, 100.8, 36.8, 32.2, 30.63 (4C), 30.57, 30.50, 30.2. MS,
m/ z (rel intensity): 414 (25) [M+], 396 (2), 291 (2), 231 (3),
166 (4), 137 (12), 124 (100).
1,3-Dih yd r oxy-5-[16′-(3′′,5′′-d ih yd r oxyp h en yl)h exa d ec-
8′(Z)-en -1-yl]ben zen e (5): 98%, colorless solid, mp ) 53 °C
dec (DSC) (lit.2a 129-132 °C). There is no obvious explanation
for this discrepancy in the melting points. 1H NMR (THF-
d8): δ ) 7.78 (bs, 4H, OH), 6.03 (d, 4H, J ) 2.3), 5.97 (t, 2H),
5.32 (t, 2H, J ) 4.5), 2.41 (vt, 4H), 2.02 (m, 4H), 1.55 (m, 4H),
1.31 (m, 18H). 13C NMR (THF-d8): δ ) 159.5, 145.3, 130.5,
107.3, 100.8, 36.8, 32.2, 30.7, 30.4, 30.2, 28.0. MS, m/ z (rel
intensity): 440 (22) [M+], 422 (1), 344 (4), 317 (2), 205 (4), 191
(4), 163 (17), 137 (14), 124 (100).
5-P en ta d ecyl-2,2-d im eth ylben zo[1,3]d ioxin -4-on e (18).
A solution of 1-pentadecene (884 mg, 4.2 mmol) and 9-H-9-
BBN (510 mg, 4.2 mmol) in THF is stirred at ambient
temperature for 1 h. The resulting borane (11B NMR: δ )
79.9) is reacted with NaOMe (227 mg, 4.2 mmol) for 30 min
(11B NMR: δ ) -2.7) prior to the addition of triflate 17 (1.24
g, 3.8 mmol)8b and PdCl2(dppf) (93 mg, 0.11 mmol). The
reaction mixture is refluxed for 1 h (11B NMR: δ ) 55.8), the
solvent is evaporated, the residue is partitioned between Et2O
and water (30 mL each), the organic layer is separated and
dried (Na2SO4), the solvent is removed in vacuo, and the crude
product is purified by flash chromatography with hexane/ethyl
acetate (20/1) as the eluent, thus affording product 18 as
colorless crystals (1.17 g, 79%): mp ) 60-61 °C. 1H NMR: δ
) 7.38 (t, 1H, J ) 8), 6.92 (d, 1H, J ) 8), 6.79 (d, 1H, J ) 8),
3.09 (vt, 2H), 1.69 (s, 6H), 1.58 (m, 2H), 1.40-1.20 (m, 24H),
0.88 (t, 3H, J ) 7). 13C NMR: δ ) 160.2, 157.1, 148.5, 135.0,
125.0, 115.0, 112.1, 104.9, 34.4, 31.9, 31.2, 29.7 (8C), 29.5, 29.3,
25.6 (2C), 22.7, 14.1. MS, m/ z (rel intensity): 388 (27) [M+],
330 (100), 312 (20), 287 (12), 273 (12), 185 (10), 161 (34), 147
(29), 55 (11), 43 (10).
the title compound as a colorless solid (924 mg, 95%): mp )
87-88 °C (lit.14b 89-89.5 °C). 1H NMR: δ ) 9.80 (br. s, 1H),
7.30 (t, 1H, J ) 8), 6.82 (d, 1H, J ) 8), 6.74 (d, 1H, J ) 8),
2.94 (vt, 2H), 1.56 (m, 2H), 1.25 (br. s, 24H), 0.88 (t, 3H, J )
7). 13C NMR: δ ) 175.8, 162.9, 147.3, 134.8, 122.6, 115.6,
111.3, 36.2, 32.0, 31.9, 29.8, 29.7, 29.6, 29.5, 29.4, 25.6, 22.7,
14.1. MS, m/ z (rel intensity): 348 (100) [M+], 330 (60), 312
(23), 304 (15), 301 (13), 287 (16), 273 (14), 259 (10), 175 (13),
161 (41), 152 (28), 147 (32), 134 (25), 108 (43), 55 (16), 43 (26).
5-[8′(Z)-P en ta d ecen yl]-2,2-d im eth ylben zo[1,3]d ioxin -
4-on e (20). A solution of compound 15 (454 mg, 2.2 mmol)
and 9-H-9-BBN (552 mg, 4.52 mmol) in THF (60 mL) is stirred
at ambient temperature for 14 h. The resulting bis-borane
(11B NMR: δ ) 79.4) is treated with MeOH (containing 1%
HOAc, w/w, 158 mg, 4.9 mmol) for 5 h causing selective
cleavage of the alkenylborane group (11B NMR: δ ) 72.9, 55.9,
rel intensity ) 1:1). Addition of NaOMe (250 mg, 4.6 mmol)
and stirring of the mixture for 30 min leads to the correspond-
ing borate complex (11B NMR: δ ) 7.6, -2.4) which is cross
coupled with triflate 17 (1.403 g, 4.3 mmol) at reflux temper-
ature for 1 h in the presence of PdCl2(dppf) (106 mg, 0.13
mmol). Workup as described above followed by flash chroma-
tography with hexane/ethyl acetate (15:1) as the solvent
affords product 20 as a colorless syrup (574 mg, 67%). 1H
NMR: δ ) 7.38 (t, 1H, J ) 8), 6.92 (d, 1H, J ) 8), 6.79 (d, 1H,
J ) 8), 5.34-5.38 (m, 2H), 3.09 (vt, 2H), 1.99 (m, 4H), 1.69 (s,
6H), 1.60 (m, 4H), 1.40-1.20 (m, 14H), 0.88 (t, 3H, J ) 7). 13
C
NMR: δ ) 160.2, 157.1, 148.5, 135.0, 130.3, 129.8, 125.0, 115.0,
104.9, 34.3, 32.6, 31.2, 29.7, 29.6, 29.4, 29.3, 29.2, 29.1, 29.0,
27.2, 25.6 (2C), 22.6, 14.1. MS, m/ z (rel intensity): 386 (46)
[M+], 328 (100), 310 (52), 285 (11), 271 (16), 257 (19), 243 (10),
225 (11), 211 (18), 197 (16), 185 (11), 161 (27), 146 (56), 133
(15), 107 (13), 95 (12), 81 (15), 67 (19), 55 (23), 41 (21).
Ack n ow led gm en t. Generous financial support by
the Fonds der Chemischen Industrie, Frankfurt, is
gratefully acknowledged. We would like to thank Mr.
W. Ko¨nen for the large scale fractional distillation of
some starting materials.
Su p p or tin g In for m a tion Ava ila ble: Copies of the 1H and
13C NMR spectra of products 1, 2, 3, 5, 8, 9, 14, 16 and of the
DSC curves of products 2, 3, and 5; large scale preparation of
7-iodo-1-heptene (10); a scheme depicting an alternative
approach to product 14 based on Lindlar semihydrogenation
as the key-step; description of the instrumentation used and
of the spectra formats (30 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.
An a ca r d ic Acid (19). A solution of substrate 18 (1.09 g,
2.8 mmol) in aqueous KOH (50%, 8 mL) and DMSO (20 mL)
is heated at 80 °C for 1 h. The reaction mixture is cooled to
ambient temperature and diluted with water (20 mL) and ethyl
acetate (50 mL), the organic layer is separated and dried (Na2-
SO4), the solvent is removed in vacuo, and the crude product
is purified by passing through a short silica gel column with
hexane/ethyl acetate/HOAc (66:33:1) as the eluent. This gives
J O962423I