Conversion of 1,4-diketones into para -disubstituted benzenes

Article abstract of DOI:10.1021/jo101489g

Reaction of acetylides with aldehydes to form but-2-yne-1,4-diols, followed by triple bond reduction and oxidation of the hydroxyl groups, gives 1,4-diketones; these react with vinyllithium, and the resulting diols undergo ring-closing metathesis to form 2-cyclohexene-1,4-diols. Dehydration, usually by acid treatment, then gives benzenes carrying substituents in a 1,4 relationship. Use of substituted vinyllithiums provides further substitution on the final benzene rings. The method can be applied to the synthesis of C5-aryl carbohydrates.

Full text of DOI:10.1021/jo101489g

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Conversion of 1,4-Diketones into para-Disubstituted Benzenes
Vincent E. Ziffle, Ping Cheng, and Derrick L. J. Clive*
Chemistry Department, University of Alberta, Edmonton,
Alberta T6G 2G2, Canada
derrick.clive@ualberta.ca
Received July 28, 2010
Reaction of acetylides with aldehydes to form but-2-yne-1,4-diols, followed by triple bond reduction
and oxidation of the hydroxyl groups, gives 1,4-diketones; these react with vinyllithium, and the re-
sulting diols undergo ring-closing metathesis to form 2-cyclohexene-1,4-diols. Dehydration, usually
by acid treatment, then gives benzenes carrying substituents in a 1,4 relationship. Use of substituted
vinyllithiums provides further substitution on the final benzene rings. The method can be applied to
the synthesis of C5-aryl carbohydrates.
Introduction
SCHEME 1. Previous Route to Benzenes
Several years ago a need arose in this laboratory to convert
a methyl ester into a benzene ring that incorporated the ester
carbonyl carbon as part of the ring. Such a transformation
was intended to allow, for example, conjugate addition to an
R,β-unsaturated ester (or synthetic equivalent), followed by
conversion of the ester into a phenyl group. The required
transformation was solved1 along the lines summarized in
Scheme 1. While that method, which affords not only mono-
substituted benzenes but also a limited range of polysubsti-
tuted benzenes, was being developed, a related procedure
SCHEME 2. Synthetic Plan
(1) Clive, D. L. J.; Pham, M. P. J. Org. Chem. 2009, 74, 1685–1690.
(2) Reviews on the preparation of benzenes: (a) Bamfield, P.; Gordon,
P. F. Chem. Soc. Rev. 1984, 13, 441–488. (b) Snieckus, V. Chem. Rev. 1990,
90, 879–933. (c) Donohoe, T. J.; Orr, A. J.; Bingham, M. Angew. Chem., Int.
Ed. 2006, 45, 2664–2670. (d) Ballini, R.; Palmieri, A.; Barboni, L. Chem.
Commun. 2008, 2975–2985.
(3) For recent methods for the preparation of aromatic rings, see: (a) Langer,
P.; Bose, G. Angew. Chem., Int. Ed. 2003, 42, 4033–4036. (b) Park, D. Y.;
Kim, S. J.; Kim, T. H.; Kim, J. N. Tetrahedron Lett. 2006, 47, 6315–6319.
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(c) Grise, C. M.; Barriault, L. Org. Lett. 2006, 8, 5905–5908. (d) Park, D. Y.;
Gowrisankar, S.; Kim, J. N. Tetrahedron Lett. 2006, 47, 6641–6645. (e) Dai,
M.; Sarlah, D.; Yu, M.; Danishefsky, S. J.; Jones, G. O.; Houk, K. N. J. Am.
€
Chem. Soc. 2007, 129, 645–657. (f) Mamat, C.; Buttner, S.; Trabhardt, T.;
was also explored (Scheme 2). In this approach, 1,4-diketones
were converted by reaction with vinyllithium into diols,
which were then subjected to ring-closing metathesis and
dehydration, producing in the simplest case para-disubsti-
tuted benzenes. We describe here full details of this work.
Numerous methods are, of course, available for making
aromatic compounds,2,3 and a growing number of them do
Fischer, C.; Langer, P. J. Org. Chem. 2007, 72, 6273–6275. (g) Sher, M.; Ali,
A.; Reinke, H.; Langer, P. Tetrahedron Lett. 2008, 49, 5400–5402. (h) Reim,
S.; Adeel, M.; Hussain, I.; Yawer, M. A.; Ahmed, Z.; Villiger, A.; Langer, P.
Tetrahedron Lett. 2008, 49, 4901–4904. (i) Reim, S.; Langer, P. Tetrahedron
Lett. 2008, 49, 2329–2332. (j) Austin, W. F.; Zhang, Y.; Danheiser, R. L.
Tetrahedron 2008, 64, 915–925. (k) Bunescu, A.; Reimann, S.; Lubbe, M.;
Spannenberg, A.; Langer, P. J. Org. Chem. 2009, 74, 5002–5010. (l)
Takahashi, H.; Yoshida, K.; Yanagisawa, A. J. Org. Chem. 2009, 74,
3632–3640.
8024 J. Org. Chem. 2010, 75, 8024–8038
Published on Web 11/10/2010
DOI: 10.1021/jo101489g
r
2010 American Chemical Society

Ziffle et al.
JOCArticle
TABLE 1. Formation of Ketones
aYield corrected for recovered 1; methyl 2,3,4-tri-O-methyl-R-D-gluco-hexodialdo-1,5-pyranoside (1 equiv) and 1 (1.8 equiv) were used.
involve ring-closing metathesis.4 The present approach dif-
fers from the others both in the manner of constructing the
diene for the metathesis step and in the fact that the design
specifically allows an aliphatic aldehyde to be converted into
a benzene ring incorporating the original carbonyl carbon.
with K2CO3 in MeOH. Small but conventional modifications of
this route were applied to make acetylene 19 (entry 6). In this
case, the initial adduct from dihydrocinnamaldehyde and
lithium trimethylsilylacetylide was silylated with i-Pr3SiCl,
and after that step, removal of the Me3Si group gave
acetylene 19. The overall sequence of entry
7
is also different from the others as it is based on an R,
ω-dialdehyde that is converted into a 16-membered cyclic
1,4-diketone (26) by way of ring-closing metathesis under
conditions of high dilution (24 f 25), followed by double
bond hydrogenation and Jones oxidation (25 f 26). The
starting R,ω-dialdehyde was assembled as shown in eq 1.6
Results and Discussion
1,4-Diketones, the key intermediates for our approach, are
available by a number of classical routes,5 and we selected the
use of acetylenes as representing a straightforward and
versatile method that met our needs. To this end, various
acetylenic alcohols (Table 1, column 1, entries 1-6, 8) were
prepared by the standard process of acetylide addition to
an aldehyde. We generally used trimethylsilylacetylene as a
convenient acetylide synthon and then removed the silicon group
(4) (a) Kotha, S.; Mandal, K. Tetrahedron Lett. 2004, 45, 2585–2588.
(b) Yoshida, K.; Imamoto, T. J. Am. Chem. Soc. 2005, 127, 10470–10471.
(c) Yoshida, K.; Kawagoe, F.; Iwadate, N.; Takahashi, H.; Imamoto, T.
Chem. Asian J. 2006, 1, 611–613. (d) Yoshida, K.; Toyoshima, T.; Imamoto,
T. Chem. Commun. 2007, 3774–3776. (e) Yoshida, K.; Horiuchi, S.; Iwadate,
N.; Kawagoe, F.; Imamoto, T. Synlett 2007, 1561–1564. (f) Yoshida, K.;
Shishikura, Y.; Takahashi, H.; Imamoto, T. Org. Lett. 2008, 10, 2777–2780.
(g) Yoshida, K.; Takahashi, H.; Imamoto, T. Chem.;Eur. J. 2008, 14, 8246–
8261.
Each of the acetylenes listed in Table 1, column 1, entries
1-6 and 8, was deprotonated and treated with an aldehyde,
so as to generate the internal acetylenes shown in column 2.
Hydrogenation over Pt-C or Pd-C served to saturate the
triple bond, and the resulting diols for entries 1-5 were
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TABLE 2. Formation of Substituted Benzenes
aYield of less polar isomer 35%; yield of more polar isomer 62%. bYield from more polar diol. cYield from less polar diol. dYield of less polar isomer
64%; yield of more polar isomer 35%. eYield of less polar isomer 67%; yield of more polar isomer 33%. fYield of less polar isomer 64%; yield of more
polar isomer 22%. gCorrected for recovered starting material. hYield of less polar isomer 29%; yield of more polar isomer 69%. iYield from more polar
isomer of 55. jYield from the less polar isomer of 55.
oxidized to the corresponding 1,4-diketones with Jones
reagent. Generally, Pt-C was used for the hydrogenation,
but Pd-C was used for reduction of acetylenes 207 and
olefins 25. Optimization of the triple bond reduction was
made, using 2 as a test substrate, the conditions and yields
with several catalysts being as follows: 10% w/w Pd-C/
THF, 47%; 20% w/w Pd(OH)2/MeOH, 21%; 5% w/w
Rh-Al2O3/EtOAc, 62%; Wilkinson’s catalyst/PhH, 55%;
PtO2/MeOH, 23%, and 5% w/w Pt-C, MeOH, 75%.
In the series of entry 6, the second acetylide coupling
affords a monoprotected diol (21) after hyrogenation, so
that oxidation gives a monoketone (22), which was processed
as described below. The cyclic diketone 26 of entry 7 was pre-
pared by ring-closing metathesis of 24, mediated by Grubbs
II catalyst8 at high dilution; the resulting olefinic diol 25 was
a mixture of stereoisomers, but this is of no consequence as
(5) For methods to prepare 1,4-diketones, see, for example: (a) Sudweeks,
W. B.; Broadbent, H. S. J. Org. Chem. 1975, 40, 1131–1136. (b) Einhorn, J.;
Soulier, J.-L.; Bacquet, C.; Lelandais, D. Can. J. Chem. 1983, 61, 584–587.
(c) Piancatelli, G.; D’Auria, M.; D’Onofrio, F. Synthesis 1994, 867–889.
(d) Rio, G.; Lecas-Nawrocka, A. Bull. Soc. Chim. France 1976, 317–326.
(e) Nimgirawath, S.;Ritchie, E.;Taylor, W. C.Aust.J. Chem. 1976, 29, 339–356.
(f) Miyakoshi, T. Org. Prep. Proced. Int. 1989, 21, 659–704. (g) Miyashita, M.;
Yanami, T.; Yoshikoshi, A. Org. Synth. 1981, 60, 117–120.
(6) (a) Lemieux, R. U. U.S. Patent 2,725,392, 1955. (b) For a preparation
of 23a, see: Cao, X.; Yang, Y.; Wang, X. J. Chem. Soc., Perkin Trans. 1 2002,
2485–2489.
(7) For protection of a benzylic carbon;oxygen bond against hydro-
genolysis by silylation, see: Clive, D. L. J.; Wang, J. J. Org. Chem. 2004, 69,
2773–2784.
(8) [1,3-Bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(phen-
ylmethylene)(tricyclohexylphosphine)ruthenium.
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the following steps of double bond hydrogenation and
hydroxyl oxidation remove all centers of stereogenicity.
The ketones listed in Table 2 (column 1, entries 1-5, 8,
and 9) were treated with an excess (8-16 mol per mol dione)
of vinyllithium (made in situ from tetravinyltin/MeLi) to
generate the expected 1,4-diols as isomer mixtures that were
used without need for separation. Except for compound 54,
where we used the Grubbs II catalyst, ring-closing metathesis
of these diols (Table 2, column 2, entries 1-5, 8, and 9) with
the Grubbs I catalyst (loading 2-20 mol %) in CH2Cl2 at
room temperature served to generate the required cyclohex-
ene diols, again as isomer mixtures. In some cases (31, 34, 37)
the isomers could be separated easily by flash chromatogra-
phy, but this is not necessary, and the mixtures were usually
amount of incorporation must have been very small as the
1H NMR spectrum of the final product failed to reveal incor-
poration of the isotope.
Our method for making para-disubstituted benzene can be
used as a route to paracyclophanes, as illustrated by the
preparation of [12]paracyclophane (53). In this connection,
though, we noted a restriction on the size of the paracyclo-
phane ring, as an attempt to make [8]paracyclophane was
surprisingly thwarted at an early stage because ring closure
of the appropriately olefinic alcohol (tetradeca-1,13-diene-
3,12-diol) was unsuccessful, using Grubbs II catalyst (under
high dilution). Similarly, we found that the diol 57 did not
undergo ring-closing metathesis with Grubbs I, Grubbs II,
or Schrock catalysts, and we do not know if this should be
attributed to unfavorable steric or conformational factors or
the presence of multiple coordination sites. In connection
with the carbohydrate series (Table 2, entry 9), it should be
mentioned that a number of carbohydrates bearing a C5-aryl
unit have potentially important medicinal properties as
examples are known that suggest use for control of diabetes13
by inhibiting sodium-dependent glucose cotransporter 214
and thereby increasing urinary excretion of glucose. The
present route offers an approach to the preparation of C5-
aryl sugars starting from an intact sugar; conventional
methods15 usually involve early introduction of the aromatic
unit followed by assembly of the pyranose ring (often by
Diels-Alder reaction with a Danishefsky diene15a-c) or
addition of a carbanion to a dialdehydofuranose, followed
by ring expansion to the pyranose system.16,17
carried forward by heating in PhH with TsOH H2O to gen-
3
erate the benzene ring. The amount of acid used was varied
from 0.3 to 1.5 mol per mol diol to evaluate the robustness of
the protocol. The conditions for the aromatization by double
dehydration were optimized using 31 as a test substrate. The
less polar and the more polar diols of structure 31 were
individually treated with p-TsOH H2O in DMSO at 85 °C;
3
with MsCl, Et3N, in THF at 85 °C; with POCl3, pyridine at
room temperature; and with p-TsOH H2O (1 equiv) in re-
3
fluxing PhH. The last set of conditions gave nearly quan-
titative yields for both isomers, whereas the other conditions
never gave yields above 58%. Likewise the two individual
isomers of 34 gave quantitative yields of 35 with p-TsOH
3
H2O (1 equiv) in refluxing PhH. With the carbohydrate 55 our
standard conditions led to an appreciable amount of an
inseparable byproduct, but POCl3 in ice-cold pyridine9 was
satisfactory. We noticed, in the preparation of 44, that partial
aromatization occurred in the ring-closing metathesis step.
In the sequence of Table 2, entry 6, two different vinyl units
were introduced by first using 2-propenyllithium and then
removing the silyl group (Bu4NF), oxidizing the liberated
hydroxyl (Jones oxidation), and treating the resulting ketone
with vinyllithium. For the ring-closing metathesis in this series
(45 f 46) we used the Grubbs II catalyst8 (25 mol %), as prior
literature suggested10 it is more effective than the Grubbs I
catalyst for construction of trisubstituted double bonds.
The example of Table 2, entry 7, illustrates formation of a
tetrasubstituted double bond; consequently, after dehydra-
tion, a 1,2,3,4-tetrasubstituted benzene is produced. The
metathesis step required the use of the Schrock catalyst11
(two portions, each of 20 mol %) and a prolonged reaction
time (2.5 days at 80 °C in PhH). Experiments with the
Grubbs II and a Hoveda-Grubbs12 catalyst did not work.
In most of the dehydration experiments, loss of water can
in principle occur to give an endocyclic or an exocyclic
double bond, and in the latter case, isomerization would
afford the observed benzenoid. Using 34 as a test case, we
performed the acid-mediated double dehydration with
Conclusion
Many methods are available for making 1,4-diketones,
and the present route links those well-established procedures
to the construction of substituted benzene rings. In particu-
lar, aldehydes (and their synthetic equivalents) are easily
(13) Goodwin, N. C.; Mabon, R.; Harrison, B. A.; Shadoan, M. K.;
Almstead, Z. Y.; Xie, Y.; Healy, J.; Buhring, L. M.; DaCosta, C. M.;
Bardenhagen, J.; Mseeh, F.; Liu, Q.; Amr Nouraldeen, A.; Wilson,
A. G. E.; Kimball, S. D.; Powell, D. R.; Rawlins, D. B. J. Med. Chem.
2009, 52, 6201–6204.
(14) Jabbour, S. A.; Goldstein, B. J. Int. J. Clin. Pract. 2008, 62, 1279–
1284.
(15) See, for example: (a) Bednarski, M.; Danishefsky, S. J. Am. Chem.
Soc. 1986, 108, 7060–7067. (b) Berkowitz, D. B.; Danishefsky, S. J.; Schulte,
G. K. J. Am. Chem. Soc. 1992, 114, 4518–4529. (c) Helliwell, M.; Phillips,
I. M.; Pritchard, R. G.; Stoodley, R. J. Tetrahedron Lett. 1999, 40, 8651–
8655. and references therein. (d) Hauser, F. M.; Ganguly, D. J. Org. Chem.
ꢀ
2000, 65, 1842–1849. (e) Cheng, G.; Fan, R.; Hernandez-Torres, J. M.;
Boulineau, F. P.; Wei, A. Org. Lett. 2007, 9, 4849–4852.
TsOD D2O and found that the disubstituted benzene pro-
3
(16) (a) Harrison, B. A.; Kimball, S. D.; Mabon, R.; Rawlins, D. B. WO
2008/042688A2, 2008. (b) Goodwin, N.; Harrison, B. A.; Kimball, S. D.;
Mabon, R.; Rawlins, D. B. WO 2008/109591A1, 2008. (c) Mincher, D. J.;
Shaw, G. J. Chem. Soc., Perkin Trans. 1 1984, 1279–1282. (d) Inch, T. D.;
Ley, R. V.; Rich, P. J. Chem. Soc. C 1968, 1683–1692. (e) Bruns, R.;
duced contained some deuterium (mass spectrum), but the
(9) Dauben, W. G.; Boswell, G. A. J. Am. Chem. Soc. 1961, 83, 5003–
€
Wernicke, A.; Koll, P. Tetrahedron 1999, 55, 9793–9800. (f) Popsavin, V.;
ꢀ ꢀ ꢀ
Benedekovic, G.; Sreco, B.; Popsavin, M.; Francuz, J.; Kojic, V.;
5005.
(10) Cf. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953–956.
ꢀ
Bogdanovic, G. Org. Lett. 2007, 9, 4235–4238. (g) Prakash, K. R. C.; Rao,
(11) 6-Diisopropylphenylimidoneophylidene molybdenum(VI)bis(hexafl-
uoro-tert-butoxide).
(12) Grela, K.; Harutyunyan, S.; Michrowska, A Angew. Chem., Int. Ed.
2002, 41, 4038–4040. We used the nitro variant (compound 9 in this
reference).
S. P. Synlett 1993, 123–124. (h) For a route via a dialdehydofuranose and a
derived epoxide, see: Kilaas, L.; Anthonsen, T. Acta Chem. Scand. 1992, 46,
994–999.
(17) For a route via sugar-derived acetylenes, see: Kaliappan, K. P.;
Subrahmanyam, A. V. Org. Lett. 2007, 9, 1121–1124.
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converted into 1,4-diketones and so C-6 of hexoses can be
incorporated into the benzene structure. Application of this
approach to readily available carbohydrates may be useful in
preparing medically important compounds such as inhibi-
tors of sodium glucose cotransporter type 2 that are of
interest for the treatment of diabetes.13,14
observed due to overlap); exact mass m/z calcd for C20H26NaO2
(M þ Na) 321.1825, found 321.1821.
1,8-Diphenyloctane-3,6-dione (4). Jones reagent20 (7.0 M in
acetone, 0.54 mL, 3.8 mmol) was added dropwise to a stirred
and cooled (0 °C) solution of 3 (0.1620 g, 0.5428 mmol) in
acetone (15 mL). After 30 min, the orange mixture was quenched
with MeOH (15 mL), and stirring was continued for 30 min, by
which time the mixture had become dark green. The mixture was
diluted with EtOAc (30 mL), washed with water and brine, dried
(Na2SO4), and evaporated. Flash chromatography of the resi-
due over silica gel (1.4ꢀ16 cm), using EtOAc-petroleum ether
mixtures from 10% to 15% EtOAc, gave 4 (0.1448 g, 90%) as an
oil: FTIR (CH2Cl2, cast microscope) 3062, 3027, 2925, 1711,
1603, 1496 cm-1; 1H NMR (CDCl3, 500 MHz) δ 2.68 (s, 4 H),
2.81 (apparent t, J = 7.7 Hz, 4 H), 2.91 (t, J = 7.2 Hz, 4 H),
7.17-7.22 (m, 6 H), 7.27-7.31 (m, 4 H); 13C NMR (CDCl3,
125 MHz) δ 29.8 (t), 36.2 (t), 44.3 (t), 126.1 (d), 128.3 (d), 128.5
(d), 141.0 (s), 208.4 (s); exact mass m/z calcd for C20H22O2
295.1693, found 295.1696.
Experimental Section
5-Phenylpent-1-yn-3-ol (1)18. K2CO3 (1.459 g, 28.24 mmol)
was added to a stirred and cooled (0 °C) solution of 5-phenyl-
1-(trimethylsilyl)pent-1-yn-3-ol18 (1.459 g, 6.276 mmol) in dry
MeOH (60 mL). The ice bath was left in place but not recharged,
and stirring was continued for 13 h. The mixture was evapo-
rated, and the residue was partitioned between water and Et2O.
The aqueous phase was extracted with Et2O, and the combined
organic extracts were dried (MgSO4) and evaporated. Flash
chromatography of the residue over silica gel (2.8ꢀ21 cm), using
20% EtOAc-petroleum ether, gave 1 (0.9515 g, 94%) as an oil:
FTIR (CH2Cl2, microscope) 3292, 3063, 3027, 2927, 2863, 2115,
1603, 1496 cm-1; 1H NMR (CDCl3, 500 MHz) δ 1.79-1.93 (br
s, 1 H), 2.00-2.12 (m, 2 H), 2.50 (d, J=2.2 Hz, 1 H), 2.82 (t, J=
7.9 Hz, 2 H), 4.38 (td, J=12.5, 1.9 Hz, 1 H), 7.19-7.24 (m, 3 H),
7.28-7.33 (m, 2 H); 13C NMR (CDCl3, 125 MHz) δ 31.2 (t), 39.1
(t), 61.6 (d), 73.3 (s), 84.6 (d), 126.1 (d), 128.47 (d), 128.48 (d),
141.1 (s); exact mass m/z calcd for C11H12AgO (M þ Ag)
266.9934, found 266.9933.
1-Phenylundec-4-yne-3,6-diol (5). BuLi (2.5 M in hexane,
0.87 mL, 2.2 mmol) was added dropwise to a stirred and cooled
(-78 °C) solution of 1 (0.1576 g, 0.9837 mmol) in dry THF
(12 mL). After 0.5 h, freshly distilled n-hexanal (0.23 mL,
2.0 mmol) was added dropwise. The cold bath was removed,
and stirring was continued for 36 h. The mixture was cooled to
0 °C and quenched with hydrochloric acid (1.0 N, 15 mL). The
organic solvent was evaporated, and the resulting aqueous
mixture was extracted with Et2O. The combined organic ex-
tracts were dried (MgSO4) and evaporated. Flash chromatog-
raphy of the residue over silica gel (1.8ꢀ21 cm), using EtOAc-
petroleum ether mixtures from 20% to 40% EtOAc, gave 5
(0.2321 g, 90%) as an oil: FTIR (CH2Cl2, cast microscope) 3322,
3027, 2953, 2931, 2860, 1943, 1873, 1803, 1745, 1604, 1496, 1455
cm-1; 1H NMR (CDCl3, 400 MHz) δ 0.90 (t, J=7.0 Hz, 3 H),
1.29-1.38 (m, 4 H), 1.41-1.51 (m, 2 H), 1.63-1.78 (m, 2 H),
1.95-2.11 (m, 2 H), 2.12-2.22 (br s, 1 H), 2.22-2.36 (br s, 1 H),
2.79 (t, J=7.8 Hz, 2 H), 4.41 (t, J=6.1 Hz, 2 H), 7.17-7.23 (m, 3
H), 7.27-7.32 (m, 2 H); 13C NMR (CDCl3, 100 MHz) δ 14.0 (q),
22.6 (t), 24.9 (t), 31.39 (t), 31.43 (t), 37.7 (t), 39.1 (t), 61.7 (d), 62.5
(d), 85.6 (s), 86.4 (s), 126.0 (d), 128.4 (d), 128.5 (d), 141.2 (s);
exact mass m/z calcd for C17H24NaO2 (MþNa) 283.1669, found
283.1670.
1,8-Diphenyloct-4-yne-3,6-diol (2)19. BuLi (2.5 M in hexane,
2.20 mL, 5.49 mmol) was added dropwise to a stirred and cooled
(-78 °C) solution of 1 (0.4000 g, 2.497 mmol) in dry THF (20 mL).
After 1.5 h, freshly distilled hydrocinnamaldehyde (0.43 mL,
3.25 mmol) was added dropwise. The cold bath was removed,
and stirring was continued for 4 h. The mixture was cooled to
0 °C and quenched with hydrochloric acid (1.0 N, 20 mL). The
organic solvent was evaporated, and the resulting aqueous
mixture was extracted with Et2O. The combined organic ex-
tracts were dried (Na2SO4) and evaporated. Flash chromatog-
raphy of the residue over silica gel (4ꢀ25 cm), using EtOAc-
petroleum ether mixtures from 25% to 60% EtOAc, gave 2
(0.6376 g, 86%) as an oil that was a mixture of diastereoisomers
(13C NMR): FTIR (CHCl3, microscope) 3331, 3062, 3026, 2948,
2927, 2862, 1947, 1871, 1804, 1603, 1496 cm-1 1H NMR
;
1-Phenylundecane-3,6-diol (6). Pt-C (5% w/w, ca. 3 mg)
was added to a solution of 5 (0.0274 g, 0.1052 mmol) in MeOH
(5 mL), and the mixture was stirred under H2 (doubled balloon)
for 1 h and then filtered through Celite, using EtOAc as a rinse.
Evaporation of the filtrate and flash chromatography of the
residue over silica gel (0.7 ꢀ 16 cm), using EtOAc-petroleum
ether mixtures from 20% to 50% EtOAc, gave 6 (0.0182 g, 65%)
as a solid that was a mixture of diastereoisomers (13C NMR): mp
56-62 °C; FTIR (CH2Cl2, cast microscope) 3215, 3086, 3063,
3027, 2955, 2937, 2920, 2871, 2854, 1942, 1496, 1453 cm-1; 1H
NMR (CDCl3, 500 MHz) δ 0.90 (t, J=6.7 Hz, 3 H), 1.24-1.38
(m, 6 H), 1.38-1.60 (m, 4 H), 1.63-1.74 (m, 2 H), 1.77-1.83 (m,
2 H), 1.85-2.27 (br s, 2 H), 2.69 (apparent dt, J=13.9, 8.1 Hz, 1
H), 2.80 (dt, J = 14.2, 7.5 Hz, 1 H), 3.59-3.73 (m, 2 H),
7.17-7.24 (3 H), 7.27-7.32 (m, 2 H); 13C NMR (CDCl3, 125
MHz) δ 14.0 (q), 22.6 (t), 25.38 (t), 25.39 (t), 31.9 (t), 32.2 (t), 33.2
(t), 33.5 (t), 33.9 (t), 34.2 (t), 37.5 (t), 37.8 (t), 39.1 (t), 39.4 (t),
71.3 (d), 71.6 (d), 72.0 (d), 72.3 (d), 125.8 (d), 128.4 (d), 129.2 (d),
142.1 (s); exact mass m/z calcd for C17H28NaO2 287.1982, found
287.1985.
(CDCl3, 500 MHz) δ 2.07-2.13 (m, 6 H), 2.81 (t, J=7.9 Hz, 4
H), 4.42 (t, J=6.8 Hz, 2 H), 7.18-7.24 (m, 6 H), 7.28-7.32 (m, 4
H); 13C NMR (CDCl3, 125 MHz) δ 31.41 (t), 31.42 (t), 39.1 (t),
61.7 (d), 86.08 (s), 86.09 (s), 126.1 (d), 128.47 (d), 128.50 (d),
141.1 (s); exact mass m/z calcd for C20H22NaO2 (M þ Na)
317.1509, found 317.1509.
1,8-Diphenyloctane-3,6-diol (3). Pt-C (5% w/w, ca. 5 mg) was
added to a solution of 2 (0.0377 g, 0.128 mmol) in MeOH (5 mL),
and the mixture was stirred under H2 (doubled balloon) for 18 h
and then filtered through Celite, using EtOAc as a rinse.
Evaporation of the filtrate and flash chromatography of the
residue over silica gel (0.7 ꢀ 16 cm), using EtOAc-petroleum
ether mixtures from 20% to 50% EtOAc, gave 3 (0.0286 g, 75%)
as an oil that slowly solidified: mp 83-88 °C; FTIR (CH2Cl2,
microscope) 3323, 3243, 3022, 2937, 2913, 2861, 1942, 1495,
1454 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.50-1.61 (m, 2 H)
1.61-1.74 (m, 2 H), 1.75-1.84 (m, 4 H), 2.15-2.60 (br s, 2 H),
2.63-2.73 (m, 2 H), 2.74-2.84 (m, 2 H), 3.62-3.72 (m, 2 H),
7.17-7.23 (m, 6 H), 7.26-7.32 (m, 4 H); 13C NMR (CDCl3,
100 MHz) δ 31.1 (t), 33.3 (t), 34.1 (t), 39.1 (t), 71.3 (d), 71.6 (d),
125.8 (d), 128.39 (d), 128.41 (d), 142.0 (s) (two signals not
1-Phenylundecane-3,6-dione (7). Jones reagent20 (7.0 M in
acetone, 0.07 mL, 0.46 mmol) was added dropwise to a stirred
and cooled (0 °C) solution of 6 (0.0175 g, 0.0662 mmol) in
(18) Matsuda, F.; Kawatsura, M.; Hosaka, K.-i.; Shirahama, H. Chem.;
Eur. J. 1999, 5, 3252–3259.
ꢀ
(19) Adje, N.; Breuilles, P; Uguen, D. Tetrahedron Lett. 1993, 34, 4631–
4634.
(20) Bowden, K.; Heilbron, I. M.; Jones, E. R. H.; Weedon, B. C. L.
J. Chem. Soc. 1946, 39–45.
8028 J. Org. Chem. Vol. 75, No. 23, 2010

Ziffle et al.
JOCArticle
acetone (5 mL). After 10 min, the orange mixture was quenched
with MeOH (5 mL), and stirring was continued for 30 min, by
which time the mixture had become dark green. The mixture was
diluted with EtOAc (20 mL), washed with water and brine, dried
(Na2SO4), and evaporated. Flash chromatography of the resi-
due over silica gel (0.7ꢀ16 cm), using EtOAc-petroleum ether
mixtures from 15% to 25% EtOAc, gave 7 (0.0162 g, 94%) as an
oil: FTIR (CH2Cl2, cast microscope) 3028, 2956, 2931, 2872,
1712, 1604, 1454 cm-1; 1H NMR (CDCl3, 500 MHz) δ 0.90 (t,
J=7.0 Hz, 3 H), 1.23-1.37 (m, 4 H), 1.59 (quintet, J=7.6 Hz,
2 H), 2.45 (t, J=7.4 Hz, 2 H), 2.64-2.71 (m, 4 H), 2.80 (apparent
t, J=7.9 Hz, 2 H), 2.91 (t, J=8.0 Hz, 2 H), 7.17-7.21 (m, 3 H),
7.26-7.30 (m, 2 H); 13C NMR (CDCl3, 125 MHz) δ 13.9 (q),
22.4 (t), 23.5 (t), 23.5 (t), 29.7 (t), 31.4 (t), 36.0 (t), 36.2 (t), 42.8
(t), 44.3 (t), 126.1 (d), 128.3 (d), 128.5 (d), 141.0 (s), 208.5 (s),
209.7 (s); exact mass m/z calcd for C17H24NaO2 (M þ Na)
283.1669, found 283.1671.
1-(1-Adamantyl)-6-phenylhexane-1,4-dione (10). Jones reagent20
(7.0 M in acetone, 0.052 mL, 0.362 mmol) was added dropwise to a
stirred and cooled (0 °C) solution of 9 (0.0170 g, 0.0518 mmol) in
acetone (3 mL). After 20 min, the orange mixture was quenched
with MeOH (3 mL), and stirring was continued for 30 min, by
which time the mixture had become dark green. The mixture was
diluted with EtOAc (20 mL), washed with water and brine, dried
(MgSO4) and evaporated. Flash chromatography of the residue
over silica gel (0.7ꢀ15 cm), using 10% EtOAc-petroleum ether,
gave 10 (0.0161 g, 95%) as an oil: FTIR (CH2Cl2, cast) 3027, 2905,
2851, 1716, 1698, 1453 cm-1; 1H NMR (CDCl3, 500 MHz) δ 1.68-
1.79 (m, 6 H), 1.85 (d, J=2.7 Hz, 6 H), 2.05 (apparent s, 3 H), 2.64
(apparent t, J=6.5 Hz, 2 H), 2.75 (apparent t, J=6.1 Hz, 2 H), 2.82
(apparent t, J=7.9 Hz, 2 H), 2.91 (apparent t, J=7.1 Hz, 2 H),
7.17-7.21 (m, 3 H), 7.26-7.30 (m, 2 H); 13C NMR (CDCl3, 125
MHz) δ 28.0 (d), 29.7 (t), 30.1 (t), 36.1 (t), 36.6 (t), 38.4 (s), 44.4 (t)
46.2 (t), 126.0 (d), 128.3 (d), 128.5 (d), 141.1 (s); exact mass m/z
calcd for C22H28NaO2 (M þ Na) 347.1982, found 347.1988.
1-(1-Adamantyl)prop-2-yn-1-ol (11). (a) 1-(1-Adamantyl)-3-
(trimethylsilyl)prop-2-yn-1-ol (11a)21. BuLi (2.5 M in hexane,
0.32 mL, 0.81 mmol) was added dropwise to a stirred and cooled
(-78 °C) solution of trimethylsilylacetylene (0.12 mL, 0.81
mmol) in dry THF (8 mL). After 55 min, 1-adamantanecarbox-
aldehyde (0.1332 g, 0.8110 mmol) in THF (1.5 mL plus 1.5 mL as
a rinse) was added dropwise by cannula. The cold bath was
removed and, after 2.5 h, the mixture was recooled to 0 °C,
quenched with saturated aqueous NH4Cl (10 mL) and extracted
with EtOAc. The combined organic extracts were washed with
brine, dried (MgSO4) and evaporated. Flash chromatography of
the residue over silica gel (1.8ꢀ20 cm), using EtOAc-petroleum
ether mixtures from 5% to 15% EtOAc, gave 11a (0.1888 g,
88%) as an oil: FTIR (CH2Cl2, cast) 3390, 3309, 2906, 2849,
2676, 2658, 2170, 1718, 1452 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 0.98 (s, 9 H), 1.55-1.75 (m, 12 H), 1.76 (s, 1 H), 1.98-2.04 (br
m, 3 H), 3.83 (s, 1 H); 13C NMR (CDCl3, 100 MHz) δ -0.03 (q),
28.2 (d), 36.7 (s), 37.1 (t), 37.7 (t), 71.9 (d), 90.7 (s), 104.9 (s);
exact mass m/z calcd for C16H26NaOSi (M þ Na) 285.1645,
found 285.1648.
1-(1-Adamantyl)-6-phenylhex-2-yne-1,4-diol (8). BuLi (2.5 M
in hexane, 0.26 mL, 0.65 mmol) was added dropwise to a stirred
and cooled (-78 °C) solution of 1 (0.0472 g, 0.295 mmol) in
dry THF (10 mL). After 1.5 h, 1-adamantanecarboxaldehyde
(0.0414 g, 0.252 mmol) in THF (2 mL plus 2 mL as a rinse) was
added dropwise, producing an orange solution. The cold bath
was left in place but not recharged, and stirring was continued
for 18.5 h. The mixture was cooled to 0 °C and quenched with
hydrochloric acid (1.0 N, 6 mL). The organic solvent was evapo-
rated, water (10 mL) was added, and the mixture was extracted
with Et2O. The combined organic extracts were dried (Na2SO4)
and evaporated. Flash chromatography of the residue over silica
gel (1.4ꢀ15 cm), using EtOAc-petroleum ether mixtures from
20% to 40% EtOAc, gave 8 (0.0743 g, 91%) as a semisolid
mixture of diastereoisomers (13C NMR): FTIR (CH2Cl2, cast
microscope) 3350, 3026, 2905, 2848, 1722, 1604, 1453 cm-1
;
1H NMR (CDCl3, 500 MHz) δ 1.58-1.77 (m, 12 H), 1.99-2.11
(m, 5 H), 2.11-2.72 (br s, 2 H), 2.82 (t, J=7.8 Hz, 2 H), 3.93 (dd,
J=5.9, 1.4 Hz, 1 H), 4.42-4.47 (m, 1 H), 7.19-7.25 (m, 3 H),
7.28-7.32 (m, 2 H); 13C NMR (CDCl3, 125 MHz) δ 28.2 (d),
31.53 (s), 31.54 (s), 37.1 (t), 37.3 (t), 37.4 (t), 37.8 (t), 39.37 (t),
39.39 (t), 61.8 (d), 71.52 (d), 71.53 (d), 84.25 (s), 84.27 (s), 87.15
(s), 87.17 (s), 126.0 (d), 128.46 (d), 128.50 (d), 141.295 (s),
141.303 (s); exact mass m/z calcd for C22H28NaO2 (M þ Na)
347.1982, found 347.1981.
(b) 1-(1-Adamantyl)prop-2-yn-1-ol (11)21. K2CO3 (0.5528 g,
4.000 mmol) was added to a stirred and cooled (0 °C) solution of
11a (0.1765 g, 0.6725 mmol) in dry MeOH (8 mL). The ice bath
was left in place but not recharged, and stirring was continued
for 18 h. The mixture was evaporated, and the residue was parti-
tioned between water and Et2O. The aqueous phase was ex-
tracted with Et2O, and the combined organic extracts were dried
(MgSO4) and evaporated. Flash chromatography of the residue
over silica gel (1.6ꢀ16 cm), using 10% EtOAc-petroleum ether,
gave 11 (0.1167 g, 91%) as an oil: FTIR (CH2Cl2, cast micro-
scope) 3278, 2902, 2848, 2674, 2656, 2111, 1449 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 1.56-1.76 (m, 12 H), 1.83 (s, 1 H), 1.98-
2.04 (m, 3 H), 2.46 (d, J=2.2 Hz, 1 H), 3.87 (d, J=2.2 Hz, 1 H);
13C NMR (CDCl3, 100 MHz) δ 28.2 (d), 37.0 (t), 37.6 (t), 71.4
(d), 74.2 (d), 82.9 (s); the molecular ion could not be detected and
a satisfactory mass spectrum could not be obtained.
1,4-Bis(1-adamantyl)but-2-yne-1,4-diol (12). BuLi (2.5 M in
hexane, 0.48 mL, 1.2 mmol) was added dropwise to a stirred and
cooled (-78 °C) solution of 11 (0.1071 g, 0.5401 mmol) in dry
THF (10 mL). After 1 h, 1-adamantanecarboxaldehyde (0.0895 g,
0.5449 mmol) in THF (2 mL plus 2 mL as a rinse) was added
dropwise. The cold bath was removed, and stirring was con-
tinued for 18 h. The mixture was cooled to 0 °C and quenched
with hydrochloric acid (1.0 N, 10 mL). The organic solvent was
evaporated, and the resulting aqueous mixture was extracted
with Et2O. The combined organic extracts were dried (Na2SO4)
and evaporated. Flash chromatography of the residue over silica
1-(1-Adamantyl)-6-phenylhexane-1,4-diol (9). Rh-Al2O3
(5% w/w, ca. 8 mg) was added to a solution of 8 (0.023 g,
0.071 mmol) in MeOH (3 mL) and the mixture was stirred
under H2 (thick-walled balloon) for 24 h. At this point there
1
appeared to have been no reaction (TLC, H NMR) and so
the mixture was filtered through Celite, using EtOAc as a
rinse. The solvent was evaporated, and the residue was kept
under oil pump vacuum. Pt-C (20% w/w, ca. 6.5 mg) was
added to a solution of the recovered 8 in MeOH (3 mL) and
the mixture was stirred under H2 (balloon). After 30 min the
mixture was filtered through Celite, using EtOAc as a rinse.
Evaporation of the filtrate and flash chromatography of the
residue over silica gel (1.4ꢀ15 cm), using EtOAc-petroleum
ether mixtures from 20% to 40% EtOAc, gave 9 (0.0184 g,
79%) as an oil that was a mixture of diastereoisomers (13
C
NMR): FTIR (CH2Cl2, cast) 3351, 3026, 2905, 2849, 2677,
1743, 1603, 1452 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.25-
1.42 (m, 2 H), 1.48-1.83 (m, 16 H), 2.00 (apparent s, 3 H),
2.00-2.42 (br s, 2 H), 2.64-2.74 (m, 1 H), 2.76-2.85 (m, 1 H),
3.04 (apparent d, J=9 Hz, 1 H), 3.61-3.75 (m, 1 H), 7.16-
7.23 (m, 3 H), 7.26-7.31 (m, 2 H); 13C NMR (CDCl3, 100 MHz)
δ 25.7 (t), 26.8 (t), 28.3 (d), 32.17 (s), 32.19 (s), 35.0 (t), 35.4 (t),
37.2 (t), 37.93 (t), 37.96 (t), 39.1 (t), 39.6 (t), 71.1 (d), 71.8 (d),
80.4 (d), 80.7 (d), 125.75 (d), 125.77 (d), 128.37 (d), 128.41 (d),
142.20 (s), 142.23 (s); exact mass m/z calcd for C22H32NaO2
(M þ Na) 351.2295, found 351.2297.
(21) Cf. Bach, J.; Berenguer, R.; Garcia, J.; Loscertales, T.; Vilarrasa, J.
J. Org. Chem. 1996, 61, 9021–9025.
J. Org. Chem. Vol. 75, No. 23, 2010 8029

Ziffle et al.
JOCArticle
gel (4 ꢀ 25 cm), using EtOAc-petroleum ether mixtures from
5% to 40% EtOAc, gave 12 (0.1258 g, 65%) as an oil that was a
mixture of diastereoisomers (13C NMR): FTIR (CH2Cl2, cast
(m, 3 H), 2.18 (s, 1 H), 4.20 (d, J = 5.5 Hz, 1 H); 13C NMR
(CDCl3, 125 MHz) δ -0.1 (q), 26.6 (t), 26.7 (t), 28.39 (t), 28.42
(t), 29.5 (t), 45.5 (d), 67.9 (d), 89.9 (s), 106.1 (s); exact mass m/z
calcd for C13H24NaOSi (M þ Na) 247.1489, found 247.1488.
(b) 1-Cycloheptylprop-2-yn-1-ol (15). K2CO3 (0.2697 g, 1.952
mmol) was added to a stirred and cooled (0 °C) solution of 15a
(0.0365 g, 0.1626 mmol) in dry MeOH (5 mL). The ice bath we
left in place but not recharged, and stirring was continued for
13 h. The mixture was evaporated, and the residue was parti-
tioned between water and Et2O. The aqueous phase was ex-
tracted with Et2O, and the combined organic extracts were dried
(Na2SO4) and evaporated. Flash chromatography of the residue
over silica gel (0.7ꢀ7 cm), using 20% EtOAc-petroleum ether,
gave 15 (0.0226 g, 91%) as an oil: FTIR (CH2Cl2, microscope)
microscope) 3285, 2899, 2846, 2679, 2657, 1742, 1451 cm-1
;
1H NMR (CDCl3, 500 MHz) δ 1.60-1.68 (m, 14 H), 1.68-1.77
(m, 12 H), 2.05 (s, 6 H), 3.93 (s, 1 H), 3.94 (s, 1 H); 13C NMR
(CDCl3, 125 MHz) δ 28.2 (d), 37.1 (t), 37.4 (s), 37.5 (s), 37.81 (t),
37.83 (t), 71.6 (d), 71.7 (d), 85.2 (s), 85.3 (s); exact mass m/z calcd
for C24H34NaO2 (M þ Na) 377.2451, found 377.2454.
1,4-Bis(1-adamantyl)butane-1,4-diol (13). Rh-Al2O3 (5% w/w,
0.0100 g) was added to a solution of 12 (0.0571 g, 0.161 mmol) in
MeOH (5 mL) and the mixture was stirred under H2 (doubled
balloon) for 19 h and then filtered through Celite, using EtOAc as a
rinse. Evaporation of the filtrate and flash chromatography of the
residue over silica gel (1.4ꢀ15 cm), using EtOAc-petroleum ether
mixtures from 5% to 20% EtOAc, gave 13 (0.0106 g, 18%) and
recovered starting material 12 (18.4 mg, 0.052 mmol). Rh-Al2O3
(5% w/w, 0.0050 g) was added to a solution of the recovered
starting material in MeOH (3 mL) and the mixture was stirred
under H2 (balloon). After 14 h, more Rh-Al2O3 (5% w/w, ca.
5 mg) was added and stirring under H2 (doubled balloon) was
continued for 7 h. The mixture was filtered through Celite using
EtOAc as a rinse. Evaporation of the filtrate and flash chroma-
tography of the residue over silica gel (1.4ꢀ16 cm), using EtOAc-
petroleum ether mixtures from 5% to 20% EtOAc, gave 13 (0.0120g,
21%), providing a combined yield of 39%. The product was a mix-
ture of diastereoisomers (13C NMR): FTIR (CH2Cl2, microscope)
3376, 2901, 2848, 2657, 1638, 1449 cm-1; 1H NMR (CDCl3, 400
MHz) δ1.36-1.48 (m, 2 H), 1.48-1.86 (m, 28 H), 2.00 (apparent s,
6 H), 3.03 (d, J=10.1 Hz, 2 H); 13C NMR (CDCl3, 125 MHz)
δ 27.5 (t), 27.6 (t), 28.3 (d), 36.7 (s), 36.8 (s), 37.3 (t), 37.99 (t),
38.03 (t), 80.4 (d), 80.6 (d); exact mass m/z calcd for C24H38NaO2
(M þ Na) 381.2764, found 381.2758.
1
3308, 2923, 2856, 2688, 2114, 1461 cm-1; H NMR (CDCl3,
300 MHz) δ 1.30-1.65 (m, 8 H), 1.65-1.95 (m, 6 H), 2.43
(apparent d, J=2.2 Hz, 1 H), 4.22 (dd, J=5.4, 2.1 Hz, 1 H); 13
C
NMR (CDCl3, 125 MHz) δ 26.66 (t), 26.71 (t), 28.24 (t), 28.29
(t), 29.4 (t), 29.8 (t), 45.4 (d), 67.4 (d), 73.3 (d), 84.2 (s); exact
mass m/z calcd for C10H16O 152.1201, found 152.1203.
1-Cycloheptyl-4-cyclohexylbut-2-yne-1,4-diol (16). BuLi (2.5 M
in hexane, 0.527 mL, 1.32 mmol) was added dropwise to a stirred
and cooled (-78 °C) solution of 15 (0.080 g, 0.527 mmol) in dry
THF (10 mL). After 1 h, cyclohexanecarboxaldehyde (0.096 mL,
0.79 mmol) in THF (2 mL plus 2 mL as a rinse) was added drop-
wise by cannula. Stirring at -78 °C was continued for 45 min. The
cold bath was left in place but not recharged, and stirring was
continued for 10.5 h. The mixture was cooled to 0 °C and quenched
with hydrochloric acid (1.0 N, 10 mL). The organic solvents were
evaporated, water (10 mL) was added, and the mixture was
extracted with Et2O. The combined organic extracts were dried
(Na2SO4) and evaporated. Flash chromatography of the residue
over silica gel (1.4 ꢀ19 cm), using EtOAc-petroleum ether mix-
tures from 5% to 40% EtOAc, gave 16 (0.1120 g, 80%) as an oil
that was a mixture of diastereoisomers (13CNMR):FTIR(CH2Cl2,
microscope) 3327, 2924, 2853, 2673, 1450 cm-1; 1H NMR (CDCl3,
500 MHz) δ 1.01-1.31 (m, 6 H), 1.31-1.64 (m, 8 H), 1.65-1.92
(m, 12 H), 4.20 (apparent t, J=5.0 Hz, 1 H), 4.27 (apparent br s,
1 H); 13C NMR (CDCl3, 125 MHz) δ 25.8 (t), 25.9 (t), 26.4 (t),
26.70 (t), 26.74 (t), 28.0 (t), 28.1 (t), 28.28 (t), 28.33 (t), 28.34 (t),
29.5 (t), 29.97 (t), 30.00 (t), 67.2 (t), 67.5 (t), 85.29 (s), 85.31 (s),
85.91 (s), 85.94 (s); exact mass m/z calcd for C17H28NaO2 (M þ
Na) 287.1982, found 287.1982.
1,4-Bis(1-adamantyl)butane-1,4-dione (14)22. Jones reagent20
(7.0 M in acetone, 0.024 mL, 0.167 mmol) was added dropwise
to a stirred and cooled (0 °C) solution of 13 (0.0200 g, 0.0558
mmol) in acetone (4 mL). After 45 min, the orange mixture was
quenched with MeOH (1 mL), and stirring was continued for
30 min, by which time the mixture had become dark green. The
mixture was diluted with EtOAc (20 mL), washed with water
and brine, dried (Na2SO4), and evaporated. Flash chromatog-
raphy of the residue over silica gel (1.4ꢀ16 cm), using EtOAc-
petroleum ether mixtures from 2% to 10% EtOAc, gave 14
(0.0142 g, 71%) as an oil: FTIR (CH2Cl2, cast microscope) 2905,
2850, 2678, 2658, 1699, 1452 cm-1; 1H NMR (CDCl3, 500 MHz)
δ 1.66-1.78 (m, 12 H), 1.85 (apparent d, J = 2.8 Hz, 12 H),
2.02-2.08 (m, 6 H), 2.71 (s, 4 H); 13C NMR (CDCl3, 100 MHz) δ
28.0 (d), 29.9 (t), 36.6 (t), 38.4 (t), 46.2 (s), 214.5 (s); exact mass
m/z calcd for C24H34NaO2 (M þ Na) 377.2451, found 377.2452.
1-Cycloheptylprop-2-yn-1-ol (15). (a) 1-Cycloheptyl-3-(trime-
thylsilyl)prop-2-yn-1-ol (15a). BuLi (2.5 M in hexane, 0.124 mL,
0.309 mmol) was added dropwise to a stirred and cooled (-78 °C)
solution of trimethylsilylacetylene (0.044 mL, 0.309 mmol) in
dry THF (3 mL). After 90 min, cycloheptanecarboxaldehyde
(0.039 g, 0.309 mmol) in THF (1 mL plus 1 mL as a rinse) was
added dropwise. The dry ice bath was replaced by an ice bath
and, after 45 min, the ice bath was removed, and stirring was
continued for 14 h. The mixture was quenched with a mixture of
water (5 mL) and saturated aqueous NH4Cl (5 mL) and ex-
tracted with Et2O. The combined organic extracts were washed
with brine, dried (Na2SO4), and evaporated. Flash chromatog-
raphy of the residue over silica gel (1.4ꢀ15 cm), using EtOAc-
petroleum ether mixtures from 5% to 15% EtOAc, gave 15a
(0.0569 g, 82%) as an oil: FTIR (CH2Cl2, microscope) 3344,
1-Cycloheptyl-4-cyclohexylbutane-1,4-diol (17). Pt-C (10%
w/w, ca. 0.020 g) was added to a solution of 16 (0.102 g, 0.384
mmol) in MeOH (6 mL), and the mixture was stirred under H2
(thick-walled balloon) for 12 h and then filtered through Celite,
using EtOAc as a rinse. Evaporation of the filtrate and flash
chromatography of the residue over silica gel (1.4ꢀ20 cm), using
EtOAc-petroleum ether mixtures from 5% to 40% EtOAc,
gave 17 (0.0761 g, 74%) as an oil that was a mixture of dia-
stereoisomers (13C NMR): FTIR (CH2Cl2, microscope) 3299,
2920, 2852, 2696, 1460, 1448 cm-1; 1H NMR (CDCl3, 500 MHz)
δ 0.96-1.40 (m, 8 H), 1.40-1.63 (m, 10 H), 1.63-1.88 (m, 10 H),
2.35 (s, 2 H), 3.43-3.14 (m, 1 H), 3.45-3.58 (m, 1 H); 13C NMR
(acetone-d6, 125 MHz) δ 26.97 (t), 26.99 (t), 27.1 (t), 27.3 (t),
27.67 (t), 27.69 (t), 27.97 (t), 28.00 (t), 28.70 (t), 28.72 (t), 29.1 (t),
29.3 (t), 29.4 (t), 29.6 (t), 29.7 (t), 29.8 (t), 29.9 (t), 30.0 (t), 30.2
(t), 31.15 (t), 31.20 (t), 31.9 (t), 32.0 (t), 44.7 (d), 44.9 (d), 46.2 (d),
46.3 (d), 76.0 (d), 76.1 (d), 76.7 (d), 76.8 (d); exact mass m/z calcd
for C17H32NaO2 (M þ Na) 291.2295, found 291.2294.
1-Cycloheptyl-4-cyclohexylbutane-1,4-dione (18). Jones re-
agent20 (7.0 M in acetone, 0.17 mL, 1.2 mmol) was added drop-
wise to a stirred and cooled (0 °C) solution of 17 (0.0346 g,
0.129 mmol) in acetone (10 mL). After 1.5 h, an additional
portion of Jones reagent (7.0 M in acetone, 0.10 mL, 0.70 mmol)
was added, and after a further 5 min, the mixture was quenched
withMeOH (15 mL). Stirring was continued for 30 min, by which
1
2924, 2855, 2172, 1460 cm-1; H NMR (CDCl3, 500 MHz) δ
0.95 (s, 9 H), 1.31-1.64 (m, 7 H), 1.68-1.79 (m, 3 H), 1.79-1.90
(22) Maas, G.; Fronda, A. J. Organomet. Chem. 1990, 398, 229–239.
8030 J. Org. Chem. Vol. 75, No. 23, 2010

Ziffle et al.
JOCArticle
time the mixture had become dark green. The mixture was
diluted with EtOAc (25 mL), washed with water and brine,
dried (Na2SO4), and evaporated. Flash chromatography of
the residue over silica gel (0.7 ꢀ 16 cm), using EtOAc-
petroleum ether mixtures from 5% to 15% EtOAc, gave 18
(0.0239 g, 70%) as an oil: FTIR (CH2Cl2, microscope) 2928,
2855, 2668, 1707, 1450 cm-1; 1H NMR (CDCl3, 300 MHz) δ
1.10-1.43 (m, 6 H), 1.43-1.65 (m, 6 H), 1.65-1.83 (m, 6 H),
1.83-1.94 (m, 4 H), 2.32-2.44 (m, 1 H), 2.52-2.62 (m, 1 H),
2.66-2.75 (m, 4 H); 13C NMR (CDCl3, 125 MHz) δ 25.7 (t),
25.9 (t), 26.7 (t), 28.3 (t), 28.5 (t), 30.0 (t), 34.1 (t), 34.2 (t), 50.8
(d), 52.4 (d), 212.8 (s), 213.1 (s); exact mass m/z calcd for
under H2 (thick-walled balloon) for 14 h and then filtered
through Celite, using EtOAc as a rinse. Evaporation of the
solvent and flash chromatography of the residue over silica gel
(1.4ꢀ17 cm), using EtOAc-petroleum ether mixtures from 5%
to 20% EtOAc, gave 21 (0.0704 g, 67%) as an oil that was a
mixture of diastereoisomers (13C NMR): FTIR (CH2Cl2, neat
film microscope) 3370, 3086, 3063, 3027, 2943, 2891, 2866, 1941,
1
1869, 1801, 1604, 1496 cm-1; H NMR (CDCl3, 500 MHz) δ
1.06-1.08 (m, 21 H), 1.47-1.98 (m, 8 H), 2.21-2.50 (br s, 1 H),
2.55-2.73 (m, 3 H), 2.77-2.84 (m, 1 H), 3.57-3.67 (m, 1 H),
3.90-3.97 (m, 1 H), 7.16-7.23 (m, 6 H), 7.26-7.31 (m, 4 H);
13C NMR (CDCl3, 125 MHz) δ 12.6 (d), 12.7 (d), 18.18 (q),
18.19 (q), 18.22 (q), 31.45 (t), 31.50 (t), 31.9 (t), 32.1 (t), 32.3 (t),
32.5 (t), 32.6 (t), 37.8 (t), 38.2 (t), 39.1 (t), 39.2 (t), 71.37 (d), 71.42
(d), 71.8 (d), 71.9 (d), 125.72 (d), 125.73 (d), 125.76 (d), 125.80
(d), 128.29 (d), 128.30 (d), 128.36 (d), 128.40 (d), 128.5 (d), 142.1
(s), 142.26 (s), 142.29 (s), 142.4 (s); exact mass m/z calcd for
C29H46NaO2Si (M þ Na) 477.3159, found 477.3161.
C
17H28O2 264.2089, found 264.2090.
Tris(1-methylethyl)[(5-phenylpent-1-yn-3-yl)oxy]silane (19). NaH
(0.4543 g, 18.93 mmol) was added quickly to a stirred and cooled
(0 °C) solution of 1a (1.466 g, 6.310 mmol) in dry THF (50 mL).
After 15 min, i-Pr3SiCl (4.05 mL, 18.9 mmol) was added dropwise.
The cold bath was left in place but not recharged, and stirring was
continued for 12 h. The mixture was cooled to 0 °C and quenched
with saturated aqueous NH4Cl (40 mL). The aqueous phase was
extracted with Et2O, and the combined organic extracts were dried
(Na2SO4) and evaporated. The residue (19a) was kept under oil
pump vacuum for several hours. Oven-dried K2CO3 (2.617 g,
18.94 mmol) was added to a stirred and cooled (0 °C) solution of
crude 19a in dry MeOH (38 mL). The cooling bath was left in place
but not recharged, and stirring was continued for 17 h. The mixture
was evaporated, and the residue was partitioned between Et2O and
water. The aqueous phase was extracted with Et2O, and the com-
bined organic extracts were washed with brine, dried (MgSO4), and
evaporated. Flash chromatography of the residue over silica gel
(5 ꢀ 22 cm), using EtOAc-petroleum mixtures from 1% to 5%
EtOAc, gave 19 (1.927 g, 96% over two steps) as an oil: FTIR
(CH2Cl2, cast microscope) 3309, 3028, 2944, 2891, 2867, 1463, 1454
6-[[Tris(1-methylethyl)silyl]oxy]-1,8-diphenyloctan-3-one (22).
Jones reagent20 (7.0 M in acetone, 0.04 mL, 0.12 mmol) was
added dropwise to a stirred and cooled (0 °C) solution of 21
(0.0532 g, 0.117 mmol) in acetone (4 mL). After 10 min, the
orange mixture was quenched with MeOH (5 mL), and stirring
was continued for 30 min, by which time the mixture had be-
come dark green. The mixture was diluted with EtOAc (15 mL),
washed with water and brine, dried (Na2SO4), and evaporated.
Flash chromatography of the residue over silica gel (1.4ꢀ17 cm),
using EtOAc-petroleum ether mixtures from 2% to 10%
EtOAc, gave 22 (0.0516 g, 97%) as an oil: FTIR (CH2Cl2, neat
film microscope) 3086, 3063, 3027, 2943, 2892, 2866, 1942, 1869,
1800, 1717, 1604, 1497 cm-1 1H NMR (CDCl3, 500 MHz)
;
δ 1.06 (apparent s, 21 H), 1.72-1.84 (m, 3 H), 1.85-1.93 (m,
1 H), 2.45-2.57 (m, 2 H), 2.58-2.69 (m, 2 H), 2.76 (t, J=7.9 Hz,
2 H), 2.92 (t, J=7.4 Hz, 2 H), 3.93 (dddd, J=5.4, 5.4, 5.4, 5.4 Hz,
1 H), 7.16-7.22 (m, 6 H), 7.27-7.31 (m, 4 H); 13C NMR
(CDCl3, 125 MHz) δ 12.7 (d), 18.2 (q), 29.8 (t), 29.9 (t), 31.5
(t), 38.1 (t), 38.5 (t), 44.4 (t), 70.9 (d), 125.8 (d), 126.1 (d), 128.3
(d), 128.4 (d), 128.5 (d), 141.1 (s), 142.3 (s), 210.0 (s) (two signals
overlap in the aromatic region); exact mass m/z calcd for
C29H44NaO2Si (M þ Na) 475.3003, found 475.3009.
cm-1 1H NMR (CDCl3, 500 MHz) δ 1.06-1.18 (m, 21 H),
;
1.97-2.09 (m, 2 H), 2.44 (d, J = 2.1 Hz, 1 H), 2.76-2.89 (m, 2
H), 4.50 (ddd, J = 6.7, 5.6, 2.1 Hz, 1 H), 7.17-7.23 (m, 3 H),
7.27-7.31 (m, 2 H); 13C NMR (CDCl3, 125 MHz) δ 12.2 (d), 18.0
(q), 31.1 (t), 40.5 (t), 62.3 (d), 72.5 (d), 85.3 (d), 125.8 (d), 128.4 (d),
128.5 (d), 141.8 (s); exact mass m/z calcd for C20H32NaOSi (M þ
Na) 339.2115, found 339.2118.
6-[[Tris(1-methylethyl)silyl]oxy]-1,8-diphenyloct-4-yn-3-ol (20).
BuLi (2.5 M in hexane, 1.67 mL, 4.17 mmol) was added drop-
wise over 3 min to a stirred and cooled (-78 °C) solution of 19
(1.0153 g, 3.207 mmol) in dry THF (50 mL). After 35 min,
freshly distilled hydrocinnamaldehyde (0.68 mL, 5.1 mmol) was
added dropwise over 3 min. The cold bath was left in place but
not recharged, and stirring was continued for 7.5 h. The mixture
was cooled to 0 °C and quenched with hydrochloric acid (1.0 N,
50 mL). The organic solvent was evaporated, and the resulting
aqueous phase was extracted with Et2O. The combined organic
extracts were dried (Na2SO4) and evaporated. Flash chroma-
tography of the residue over silica gel (4ꢀ22 cm), using EtOAc-
petroleum ether mixtures from 10% to 50% EtOAc, gave 20
(1.4457 g, 100%) as an oil that was a mixture of diastereoisomers
(13C NMR): FTIR (CH2Cl2, cast film) 3361, 3063, 3027, 2944,
Tetradecanedial (23). (a) Tetradecane-1,14-diol (23b). Pt-C
(10% w/w, ca. 10 mg) was added to a solution of 23a6 (0.1535 g,
0.6904 mmol) in MeOH (10 mL), and the mixture was stirred
under H2 (doubled balloon) for 20 h and then filtered through
Celite, using EtOAc as a rinse. Evaporation of the solvent and
flash chromatography of the residue over silica gel (1.8ꢀ19 cm),
using EtOAc-petroleum ether mixtures from 40% to 80%
EtOAc, gave 23b (0.0959 g, 60%) as a solid: mp 83.5-89 °C.
(b) Tetradecanedial (23)6a. (COCl)2 (0.36 mL, 4.1 mmol) was
added dropwise to a stirred and cooled (-78 °C) solution of
DMSO (0.5800, 8.163 mmol) in CH2Cl2 (5 mL). After 15 min, a
solution of 23b (0.122 mL, 0.529 mmol) in CH2Cl2 (3 mL)
was added dropwise. After a further 45 min, Et3N (1.474 mL,
10.57 mmol) was added dropwise, and stirring was continued for
30 min. The mixture was then stored at -20 °C (freezer) for 20 h,
transferred to an ice bath, and stirred at 0 °C for 3 h. Water
(6 mL) and CH2Cl2 (10 mL) were added, and the aqueous phase
was extracted with CH2Cl2. The combined organic extracts were
washed with saturated aqueous NaHCO3, dried (MgSO4) and
evaporated. Flash chromatography of the residue over silica gel
(1.4ꢀ16 cm), using EtOAc-petroleum ether mixtures from 5%
to 15% EtOAc, gave 23 (0.0901 g, 83%) as an oil: FTIR
1
2866, 1604, 1496, 1455 cm-1; H NMR (CDCl3, 500 MHz) δ
1.07-1.19 (m, 21 H), 1.64-1.72 (br s, 1 H), 1.98-2.11 (m, 4 H),
2.78-2.89 (m, 4 H), 4.42 (t, J=6.3 Hz, 1 H), 4.58 (td, J=5.8,
1.6 Hz, 1 H), 7.18-7.24 (m, 6 H), 7.28-7.33 (m, 4 H); 13C NMR
(CDCl3, 125 MHz) δ 12.3 (d), 18.1 (q), 31.27 (t), 31.29 (t), 31.39
(t), 31.41 (t), 39.18 (t), 39.23 (t), 40.46 (t), 40.49 (t), 61.9 (d), 62.5
(d), 85.06 (s), 85.08 (s), 86.86 (s), 86.88 (s), 125.8 (d), 126.0 (d),
128.4 (d), 128.45 (d), 128.47 (d), 128.48 (d), 141.3 (s), 141.8 (s);
exact mass m/z calcd for C29H42NaO2Si (M þ Na) 473.2846,
found 473.2846.
(CH2Cl2, cast) 2915, 2850, 2749, 1788, 1705, 1674, 1471 cm-1
;
1H NMR (CDCl3, 500 MHz) δ 1.23-1.37 (m, 16 H), 1.63
(quintet, J=7.2 Hz, 4 H), 2.42 (td, J=7.4, 1.9 Hz, 4 H), 9.77
(t, J=1.9 Hz, 2 H); 13C NMR (CDCl3, 125 MHz) δ 22.1 (t), 29.2
(t), 29.3 (t), 29.4 (t), 29.5 (t), 43.9 (t), 202.9 (d); exact mass m/z
calcd for C14H26NaO2 (M þ Na) 249.1825, found 249.1828.
6-[[Tris(1-methylethyl)silyl]oxy]-1,8-diphenyloctan-3-ol (21).
Pd-C (5% w/w, ca. 20 mg) was added to a solution of 20 (0.1035 g,
0.2296 mmol) in EtOAc (4 mL), and the mixture was stirred
J. Org. Chem. Vol. 75, No. 23, 2010 8031

Ziffle et al.
JOCArticle
Octadeca-1,17-diene-3,16-diol (24). MeLi (1.6 M in Et2O,
0.61 mL, 0.98 mmol) was added dropwise to a stirred and cooled
(0 °C) solution of tetravinyltin (0.045 mL, 0.246 mmol) in dry
Et2O (6 mL). After 1 h, the mixture was cooled to -78 °C, and a
solution of 23 (0.0139 g, 0.0614 mmol) in Et2O (2 mL plus 2 mL
as a rinse) was added by cannula. The cold bath was left in place
but not recharged, and stirring was continued for 22 h. The mix-
ture was cooled to 0 °C and quenched with water (10 mL), and
the aqueous phase was extracted with Et2O. The combined
organic extracts were washed with brine, dried (Na2SO4), and
evaporated. Flash chromatography of the residue over silica gel
(0.7ꢀ15 cm), using EtOAc-petroleum mixtures from 10% to
20% EtOAc, gave 24 (0.0141 g, 81%) as a solid: mp 49-53 °C;
FTIR (CH2Cl2, microscope) 3312, 3092, 3015, 2986, 2914, 2849,
(CDCl3, 100 MHz) δ 23.2 (t), 25.7 (t), 26.8 (t), 26.9 (t), 27.5 (t),
36.5 (t), 42.0 (t), 210.4 (s); exact mass m/z calcd for C16H28O2
252.2089, found 252.2091.
Methyl 7,8,10,11-Tetradeoxy-2,3,4-tris-O-methyl-11-phenyl-
r-D-gluco-unedec-7-ynopyranoside (27). BuLi (2.5 M in hexanes,
1 mL, 2.5 mmol) was added dropwise to a stirred and cooled
(-78 °C) solution of 1 (196.5 mg, 1.23 mmol) in THF (11 mL).
After 1 h, a solution of freshly prepared crude methyl 2,3,4-
tri-O-methyl-R-D-gluco-hexodialdo-1,5-pyranoside24 (161.2 mg,
0.69 mmol) in THF (2 mL) was added dropwise. The cooling
bath was left in place but not recharged, and stirring was
continued for 23 h. The mixture was quenched with saturated
aqueous NH4Cl (8 mL) and extracted with EtOAc. The com-
bined organic extracts were dried (MgSO4) and evaporated.
Flash chromatography of the residue over silica gel (2.5ꢀ15 cm),
using 75% EtOAc-hexanes, gave 27 (181.2 mg, 67% or 85%,
based on recovered starting material) as an oil that was a
mixture of diastereoisomers (13C NMR): FTIR (CHCl3, micros-
cope) 3423, 3085, 3062, 3026, 2934, 2836, 2248, 1604, 1496,
1454 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.94-2.12 (m, 2 H),
2.19-2.32 (m, 1 H), 2.73-2.83 (m, 3 H), 3.18-3.26 (m, 1 H),
3.31-3.73 (m, 15 H), 4.39-4.46 (m, 1 H), 4.62-4.73 (m, 1 H),
4.85 (d, J=3.2 Hz, 1 H), 7.17-7.22 (m, 3 H), 7.26-7.31 (m, 2 H);
13C NMR (CDCl3, 100 MHz) δ 31.58 (t), 31.66 (t), 31.69 (t), 39.3
(t), 39.4 (t), 55.4 (q), 55.5 (q), 59.3 (q), 60.9 (q), 61.1 (q), 61.2 (q),
61.5 (q), 61.6 (q), 61.8 (q), 61.9 (q), 62.8 (q), 72.21 (d), 72.26 (d),
72.30 (d), 79.5 (d), 81.3 (d), 81.4 (d), 81.99 (d), 82.04 (d), 82.5 (s),
82.6 (s), 83.6 (d), 83.8 (d), 84.3 (s), 86.2 (s), 88.0 (s), 97.7 (d), 97.9
(d), 126.30 (d), 126.31 (d), 128.71 (d), 128.72 (d), 141.34 (s),
141.36 (s); exact mass m/z calcd for C21H30NaO7 (M þ Na)
417.1884, found 417.1891.
Methyl 7,8,10,11-Tetradeoxy-2,3,4-tris-O-methyl-11-phenyl-
r-D-gluco-unedecanopyranoside (28). Pt-C (5% w/w, 14 mg)
was added to a solution of 27 (35.9 mg, 0.091 mmol) in MeOH
(1.5 mL), and the mixture was stirred under H2 (balloon) for 1 h
and then filtered through Celite, using EtOAc as a rinse.
Evaporation of the filtrate and flash chromatography of the
residue over silica gel (0.6ꢀ8 cm), using EtOAc-hexanes from
50% EtOAc to 100% EtOAc, gave 28 (27.3 mg, 75%) as an
oil that was a mixture of diastereoisomers (13C NMR): FTIR
(CHCl3, microscope) 3448, 3085, 3061, 3025, 2933, 2836, 1603,
1496, 1454 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.52-1.90 (m,
6 H), 2.42 (s, 1 H), 2.64-2.85 (m, 2 H), 3.14-3.20 (m, 2 H),
3.26-3.31 (m, 1 H), 3.36-3.69 (m, 15 H), 3.79 (s, 1 H), 4.78 (dd,
J=3.4, 15.4 Hz, 1 H), 7.16-7.21 (m, 3 H), 7.26-7.30 (m, 2 H);
13C NMR (CDCl3, 125 MHz) δ 28.1 (t), 28.9 (t), 30.3 (t), 31.3 (t),
32.09 (t), 32.13 (t), 32.15 (t), 32.19 (t), 33.8 (t), 34.1 (t), 34.4 (t),
34.7 (t), 39.1 (t), 39.4 (t), 55.17 (q), 55.24 (q), 55.29 (q), 55.31 (q),
58.9 (q), 59.0 (q), 60.2 (q), 60.6 (q), 60.7 (q), 60.8 (q), 69.3 (d),
69.4 (d), 70.9 (d), 71.0 (d), 71.1 (d), 71.3 (d), 71.4 (d), 72.1 (d),
72.4 (d), 73.2 (d), 73.3 (d), 79.5 (d), 81.7 (d), 82.0 (d), 82.26 (d),
82.33 (d), 83.6 (d), 83.7 (d), 97.2 (d), 97.6 (d), 125.7 (d), 125.8 (d),
128.34 (d), 128.38 (d), 128.39 (d), 128.41 (d), 142.0 (s), 142.27 (s),
142.29 (s); exact mass m/z calcd for C21H34NaO7 (M þ Na)
421.2197, found 421.2199.
1
1857, 1646, 1465 cm-1; H NMR (CDCl3, 500 MHz) δ 1.24-
1.44 (m, 22 H), 1.48-1.58 (m, 4 H), 4.10 (apparent qt, J=6.1,
1.2 Hz, 2 H), 5.11 (dt, J=10.4, 1.5 Hz, 2 H), 5.22 (dt, J=17.2,
1.5 Hz, 2 H), 5.87 (ddd, J=17.2, 10.4, 6.2 Hz, 2 H); 13C NMR
(CDCl3, 125 MHz) δ 25.3 (t), 29.5 (t), 29.55 (t), 29.59 (t), 37.1 (t),
73.3 (d), 114.5 (t), 141.3 (d); exact mass m/z calcd for C18H34-
NaO2 (M þ Na) 305.2451, found 305.2450.
Cyclohexadec-2-ene-1,4-diol (25). A solution of 24 (0.0107 g,
0.0379 mmol) in dry CH2Cl2 (10 mL) was added dropwise
over 20 h to a stirred solution of Grubbs II catalyst8 (0.0032 g,
0.0038 mmol) in CH2Cl2 (5 mL) (N2 atmosphere). After 6 days,
the mixture was evaporated and flash chromatography of the
residue over silica gel (0.7 ꢀ 15 cm), using EtOAc-petroleum
ether mixtures from 10% to 100% EtOAc, gave 25 (0.0069 g,
72%) as a semisolid that was a mixture of diastereoisomers (13C
NMR): FTIR (CH2Cl2, cast microscope) 3357, 2925, 2855,
2680, 1956, 1660, 1633, 1460 cm-1; 1H NMR (CDCl3, 500 MHz)
δ 1.15-1.42 (m, 22 H), 1.50-1.60 (m, 2 H), 1.60-1.72 (m, 2 H),
4.10-4.15 (m, 1 H), 4.23-4.28 (m, 1 H), 5.58 (dd, J=5.0, 2.5 Hz,
1 H), 5.71 (dd, J = 3.0, 1.3 Hz, 1 H); 13C NMR (CDCl3, 125
MHz) δ 23.6 (t), 24.2 (t), 25.0 (t), 25.90 (t), 25.94 (t), 27.2 (t), 27.3
(t), 27.8 (t), 28.0 (t), 36.9 (t), 37.0 (t), 72.1 (d), 73.5 (d), 133.1 (d),
135.0 (d); exact mass m/z calcd for C16H30NaO2 (M þ Na)
277.2138, found 277.2139.
Cyclohexadecane-1,4-diol. Pd-C (5% w/w, ca. 4 mg) was
added to a solution of 25 (0.0252 g, 0.0991 mmol) in MeOH
(1 mL), and the mixture was stirred under H2 (doubled balloon)
for 8 h and then filtered through Celite, using EtOAc as a rinse.
Evaporation of the solvent and flash chromatography of the
residue over silica gel (0.7ꢀ15 cm), using 2% MeOH-EtOAc,
gave cyclohexadecane-1,4-diol (0.0179 g, 70%) as an oil that was
a mixture of diastereoisomers (13C NMR): FTIR (CH2Cl2, cast)
3392, 3313, 2921, 2850, 1644, 1469 cm-1; 1H NMR (CDCl3, 400
MHz) δ 1.18-1.43 (m, 26 H), 1.44-1.70 (m, 4 H), 3.72-3.82 (m,
2 H); 13C NMR (CDCl3, 100 MHz) δ 23.1 (t), 23.6 (t), 26.47 (t),
26.51 (t), 26.56 (t), 26.64 (t), 26.7 (t), 26.8 (t), 26.9 (t), 27.0 (t),
29.7 (t), 30.9 (t), 31.3 (t), 31.4 (t), 35.18 (t), 35.24 (t), 70.2 (d), 71.0
(d); exact mass m/z calcd for C16H32NaO2 (M þ Na) 279.2295,
found 279.2296.
Cyclohexadecane-1,4-dione (26)23. Jones reagent20 (7.0 M in
acetone, 0.025 mL, 0.176 mmol) was added dropwise to a stirred
and cooled (0 °C) solution of cyclohexadecane-1,4-diol (0.0150
g, 0.0585 mmol) in acetone (4 mL). After 1.5 h, the orange
mixture was quenched with MeOH (3 mL), and stirring was
continued for 30 min, by which time the mixture had become
dark green. The mixture was diluted with EtOAc (15 mL),
washed with water and brine, dried (Na2SO4), and evaporated.
Flash chromatography of the residue over silica gel (0.4ꢀ6 cm),
using 10% EtOAc-petroleum ether, gave 26 (0.0126 g, 86%) as
an oil: FTIR (CH2Cl2, cast microscope) 2930, 2856, 1712, 1457,
1408 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.14-1.40 (m, 16 H),
1.58-1.66 (m, 4 H), 2.46-2.51 (m, 4 H), 2.69 (s, 4 H); 13C NMR
6-Phenyl-1-[(2S,3S,4S,5R,6S)-tetrahyro-3,4,5,6-tetramethox-
ypyran-2-yl]hexane-1,4-dione (29). DMSO (0.09 mL, 1.27 mmol)
in CH2Cl2 (1.5 mL) was added dropwise to a stirred and cooled
(-78 °C) solution of (COCl)2 (0.06 mL, 0.694 mmol) in CH2Cl2
(1 mL). After 15 min, a solution of 28 (101.6 mg, 0.255 mmol) in
CH2Cl2 (1.5 mL) was added dropwise, and stirring at -78 °C
was continued for 35 min. Then Et3N (0.2 mL) was added
dropwise, and stirring at -78 °C was continued for 5 min. The
cooling bath was removed, and stirring was continued for 25 min.
Water (2 mL) was added, and the organic phase was dried
(24) Collins, D. J.; Hibberd, A. I.; Skelton, B. W.; White, A. H. Aust.
J. Chem. 1998, 51, 681–694.
(23) Corey, E. J.; Helquist, P. Tetrahedron Lett. 1975, 16, 4091–4094.
8032 J. Org. Chem. Vol. 75, No. 23, 2010

Ziffle et al.
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(MgSO4) and evaporated. Flash chromatography of the residue
over silica gel (1.5ꢀ13 cm), using 50% EtOAc-hexanes, gave 29
(83.9 mg, 83%) as an colorless oil: [R]20D 79.2 (c 1.35, CHCl3);
FTIR (CHCl3, cast microscope) 3062, 3027, 2933, 2836, 1716,
water and CH2Cl2. The aqueous phase was extracted with hexane,
and the combined organic extracts were dried (Na2SO4) and
evaporated. Flash chromatography of the residue over silica
gel (0.7ꢀ18 cm), using EtOAc-petroleum ether mixtures from
0% to 2% EtOAc, gave 32 (0.0161 g, 98%) as a solid: mp 85-
90 °C; FTIR (CH2Cl2, cast microscope) 3084, 3062, 3023, 2933,
2916, 2852, 1902, 1698, 1602, 1512, 1496, 1452 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 2.90 (s, 8 H), 7.11 (s, 4 H), 7.17-7.23 (m,
6 H), 7.26-7.31 (m, 4 H); 13C NMR (CDCl3, 125 MHz) δ 37.5
(t), 38.0 (t), 125.9 (d), 128.3 (d), 128.38 (d), 128.44 (d), 139.3 (s),
141.9 (s); exact mass m/z calcd for C22H22 286.1722, found
286.1723.
1
1604, 1497, 1454 cm-1; H NMR (CDCl3, 400 MHz) δ 2.60-
2.68 (m, 1 H), 2.72-2.85 (m, 4 H), 2.89-3.03 (m, 3 H), 3.20-
3.31 (m, 2 H), 3.45-3.63 (m, 13 H), 4.06 (dd, J=1.6, 10 Hz, 1 H),
4.87 (dd, J=1.6, 3.2 Hz, 1 H), 7.17-7.21 (m, 3 H), 7.26-7.30 (m,
2 H); 13C NMR (CDCl3, 100 MHz) δ 30.0 (t), 34.7 (t), 36.0 (t),
44.5 (t), 55.9 (q), 59.4 (q), 60.8 (q), 61.2 (q), 74.0 (d), 80.9 (d), 81.5
(d), 83.7 (d), 98.1 (d), 126.3 (d), 128.5 (d), 128.7 (d), 141.2 (s),
205.8 (s), 208.2 (s); exact mass m/z calcd for C21H30NaO7
(M þ Na) 417.1884, found 417.1879.
Use of Less Polar Isomer of 31. TsOH H2O (0.0074 g, 0.039 mmol)
3
3,6-Bis(2-phenylethyl)octa-1,7-diene-3,6-diol (30). MeLi (1.6 M
in Et2O, 3.31 mL, 5.29 mmol) was added dropwise to a stirred and
cooled (0 °C) solution of tetravinyltin (0.24 mL, 1.3 mmol) in dry
Et2O (20 mL). After 35 min, the mixture was cooled to -78 °C, and
asolutionof4(0.1146 g, 0.3893 mmol) in Et2O (3.5 mL plus 3.5 mL
as a rinse) was added by cannula. The cold bath was left in place but
not recharged, and stirring was continued for 12 h. The mixture
was quenched with a mixture of water (50 mL) and saturated
aqueous NH4Cl (25 mL). The aqueous phase was extracted with
Et2O, and the combined organic extracts were washed with brine,
dried (MgSO4), and evaporated. Flash chromatography of the
residue over silica gel (1.8ꢀ19 cm), using EtOAc-hexane mixtures
from 15% to 30% EtOAc, gave 30 (0.1070 g, 78%) as an oil that
was a mixture of diastereoisomers (13C NMR): FTIR (CH2Cl2,
cast microscope) 3416, 3085, 3062, 3026, 2946, 2863, 1945, 1867,
1744, 1642, 1603, 1497 cm-1;1HNMR(CDCl3, 500 MHz) δ1.55-
1.70 (m, 3 H), 1.70-1.85 (m, 4 H), 1.85-1.97 (m, 3 H), 2.58-2.71
(m, 4 H), 5.18-5.24 (m, 2 H), 5.25-5.32 (m, 2 H), 5.79-5.89 (m,
2 H), 7.15-7.20 (m, 6 H), 7.25-7.30 (m, 4 H); 13C NMR (CDCl3,
125 MHz) δ 30.0 (t), 34.3 (t), 34.4 (t), 42.7 (t), 43.3 (t), 75.2 (s), 75.3
(s), 113.3 (t), 113.5 (t), 125.78 (d), 125.79 (d), 128.36 (d), 128.41 (d),
142.36 (s), 142.38 (s), 143.2 (d), 143.5 (d); exact mass m/z calcd for
C24H30O2 373.2138, found 373.2139.
was added to a solution of the less polar diastereoisomer of 31
(0.0126 g, 0.0391 mmol) in dry PhH (1.5 mL), and the mixture was
refluxed for 5 h, cooled to room temperature, and partitioned
between water and CH2Cl2. The aqueous phase was extracted with
hexane, and the combined organic extracts were dried (Na2SO4)
and evaporated. Flash chromatography of the residue over silica gel
(0.7ꢀ15 cm), using EtOAc-petroleum ether mixtures from 0% to
2% EtOAc, gave 32 (0.011 g, 100%).
3-Pentyl-6-(2-phenylethyl)octa-1,7-diene-3,6-diol (33). MeLi
(1.6 M in Et2O, 1.81 mL, 2.89 mmol) was added dropwise to
a stirred and cooled (0 °C) solution of tetravinyltin (0.13 mL,
0.72 mmol) in dry Et2O (10 mL). After 45 min, the mixture was
cooled to -78 °C and a solution of 7 (0.0471 g, 0.181 mmol) in
Et2O (2 mL plus 2 mL as a rinse) was added by cannula. The
cooling bath was left in place but not recharged, and stirring was
continued for 12 h. The mixture was quenched with a mixture of
water (25 mL) and saturated aqueous NH4Cl (25 mL). The
aqueous phase was extracted with Et2O, and the combined
organic extracts were washed with brine, dried (MgSO4), and
evaporated. Flash chromatography of the residue over silica gel
(1.4ꢀ16 cm), using EtOAc-hexane mixtures from 15% to 30%
EtOAc, gave 33 (0.0533 g, 93%) as an oil that was a mixture of
diastereoisomers (13C NMR): FTIR (CH2Cl2, cast microscope)
3419, 3086, 3063, 3026, 3006, 2953, 2933, 2861, 1942, 1844, 1734,
1,4-Bis(2-phenylethyl)cyclohex-2-ene-1,4-diol (31). Grubbs I
catalyst (0.0192 g, 0.0233 mmol) was added to a stirred solution
of 30 (0.1152 g, 0.3287 mmol) in dry CH2Cl2 (20 mL) (N2 atmo-
sphere). After 24 h, the mixture was evaporated and flash chro-
matography of the residue over silica gel (1.3 ꢀ 11 cm), using
EtOAc-petroleum ether mixtures from 10% to 100% EtOAc,
gave 31 [0.0376 g, 35% less polar diastereoisomer; 0.0666 g, 62%
more polar diastereoisomer (98% overall)] as semisolids: The
more polar diastereoisomer: FTIR (CH2Cl2, cast microscope)
1
1642, 1604, 1497, 1455 cm-1; H NMR (CDCl3, 400 MHz) δ
0.88 (t, J=6.7 Hz, 3 H), 1.20-1.38 (m, 6 H), 1.44-1.72 (m, 6 H),
1.72-1.98 (m, 4 H), 2.56-2.73 (m, 2 H), 5.09-5.33 (m, 4 H),
5.72-5.90 (m, 2 H), 7.15-7.20 (m, 3 H), 7.24-7.30 (2 H); 13C
NMR (CDCl3, 100 MHz) δ 14.0 (q), 22.6 (t), 23.1 (t), 30.0 (t),
32.2 (t), 34.0 (t), 34.4 (t), 34.5 (t), 41.0 (t), 41.6 (t), 42.7 (t), 43.3
(t), 75.1 (s), 75.2 (s), 112.6 (t), 112.9 (t), 113.1 (t), 113.4 (t), 125.70
(d), 125.73 (d), 128.35 (d), 128.37 (d), 142.5 (s), 143.4 (d), 143.5
(d), 143.6 (d), 143.9 (d); exact mass m/z calcd for C21H32NaO2
(M þ Na) 339.2295, found 339.2288.
3377, 3061, 3025, 2933, 2858, 1945, 1870, 1663, 1496 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 1.56-1.65 (br s, 2 H), 1.77-1.92
(m, 8 H), 2.71 (t, J=8.7 Hz, 4 H), 5.77 (s, 2 H), 7.17-7.23 (m,
6 H), 7.26-7.30 (m, 4 H); 13C NMR (CDCl3, 125 MHz) δ 29.9
(t), 32.9 (t), 42.8 (t), 70.3 (s), 125.9 (d), 128.3 (d), 128.5 (d), 134.4
(d), 142.2 (s); exact mass m/z calcd for C22H26NaO2 (M þ Na)
345.1825, found 345.1824.
1-Pentyl-4-(2-phenylethyl)cyclohex-2-ene-1,4-diol (34). Grubbs
I catalyst (0.0027 g, 0.0033 mmol) was added to a stirred solution
of 33 (0.0523 g, 0.165 mmol) in dry CH2Cl2 (7 mL) (N2 atmo-
sphere). After 12 h, the mixture was evaporated and flash chro-
matography of the residue over silica gel (1.4 ꢀ 14 cm), using
EtOAc-petroleum ether mixtures from 10% to 40% EtOAc,
gave 34 [0.0306 g, 64% less polar diastereoisomer; 0.0171 g, 35%
more polar diastereoisomer (99% overall)] as oils. The more polar
diastereoisomer: FTIR (CH2Cl2, neat film microscope) 3309, 3061,
The less polar diastereoisomer: FTIR (CH2Cl2, cast micro-
scope) 3377, 3062, 3025, 2931, 2859, 1946, 1603, 1496 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 1.55-1.65 (br s, 2 H), 1.77-1.94
(m, 8 H), 2.74 (t, J=8.6 Hz, 4 H), 5.76 (s, 2 H), 7.16-7.23 (m,
6 H), 7.26-7.32 (m, 4 H); 13C NMR (CDCl3, 125 MHz) δ 29.9
(t), 31.8 (t), 44.0 (t), 69.5 (s), 125.9 (d), 128.3 (d), 128.4 (d), 134.2
(d), 142.1 (s); exact mass m/z calcd for C22H26NaO2 (M þ Na)
345.1825, found 345.1823.
1
3026, 2954, 2929, 2861, 1940, 1864, 1740, 1603 cm-1; H NMR
(CDCl3, 500 MHz) δ 0.90 (t, J=6.8 Hz, 3 H), 1.20-1.46 (m, 6 H),
1.47-1.65 (m, 4 H), 1.63-1.85 (m, 2 H), 1.81-2.17 (m, 4 H),
2.67-2.81 (m, 2 H), 5.70-5.74 (m, 2 H), 7.16-7.23 (m, 3 H),
7.28-7.32 (m, 2 H); 13C NMR (CDCl3, 125 MHz) δ 14.1 (q), 22.6
(t), 23.2 (t), 29.9 (t), 32.3 (t), 32.7 (t), 32.9 (t), 41.1 (t), 42.8 (t), 70.3
(s), 70.4 (s), 125.8 (d), 128.3 (d), 128.4 (d), 134.0 (d), 134.7 (d), 142.3
(s); exact mass m/z calcd for C19H28NaO2 (M þ Na) 311.1982,
found 311.1982.
1,4-Bis(2-phenylethyl)benzene (32)25. Use of More Polar Iso-
mer of 31. TsOH H2O (0.0112 g, 0.0589 mmol) was added to a
3
solution of the more polar diastereoisomer of 31 (0.0185 g,
0.0574 mmol) in dry PhH (2 mL), and the mixture was refluxed
for 7 h, cooled to room temperature, and partitioned between
The less polar diastereoisomer: FTIR (CH2Cl2, neat film
microscope) 3538, 3389, 3063, 3027, 2930, 2860, 1946, 1870,
1741, 1603, 1497, 1454 cm-1; 1H NMR (CDCl3, 500 MHz) δ 0.91
(25) Agranat, I.; Avnir, D. J. Chem. Soc., Perkin Trans. 1 1974, 1155–
1161.
J. Org. Chem. Vol. 75, No. 23, 2010 8033

Ziffle et al.
JOCArticle
(t, J = 6.9 Hz, 3 H), 1.25-1.46 (m, 6 H), 1.46-1.64 (m, 4 H),
1.66-1.81 (m, 2 H), 1.83-2.20 (m, 4 H), 2.67-2.81 (m, 2 H),
flash chromatography of the residue over silica gel (0.7ꢀ16 cm),
using EtOAc-petroleum ether mixtures from 10% to 100% EtOAc,
gave 37 [0.0091 g, 67% less polar diastereoisomer; 0.0046 g, 33%
more polar diastereoisomer (100% overall)] as semisolids. The
less polar diastereoisomer: FTIR (CH2Cl2, cast) 3352, 3085,
5.69-5.76 (m, 2 H), 7.17-7.23 (m, 3 H), 7.26-7.32 (m, 2 H); 13
C
NMR (CDCl3, 125 MHz) δ 14.1 (q), 22.6 (t), 23.2 (t), 30.0 (t),
31.7 (t), 31.9 (t), 32.3 (t), 42.2 (t), 44.0 (t), 69.5 (s), 69.6 (s), 125.8
(d), 128.3 (d), 128.4 (d), 133.8 (d), 134.7 (d), 142.2 (s); exact mass
m/z calcd for C19H28NaO2 (M þ Na) 311.1982, found 311.1977.
1-Pentyl-4-(2-phenylethyl)benzene (35)26. Use of More Polar
3025, 2984, 2928, 2901, 2847, 2675, 1742, 1603, 1451 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 1.20-1.45 (br m, 2 H), 1.54-1.82
(m, 15 H), 1.82-2.00 (m, 3 H), 2.04 (apparent s, 3 H), 2.68-2.82
(m, 2 H), 5.83 (dd, J = 10.1, 1.7 Hz, 1 H), 5.95 (dd, J = 10.3,
1.8 Hz, 1 H), 7.16-7.23 (m, 3 H), 7.26-7.31 (m, 2 H); 13C NMR
(CDCl3, 100 MHz) δ 25.3 (t), 28.5 (d), 29.9 (t), 31.1 (t), 35.8 (t),
36.4 (s), 37.1 (t), 38.4 (t), 44.3 (t), 72.7 (s), 125.8 (d), 128.32 (d),
128.37 (d), 128.39 (d), 131.3 (d), 134.9 (d), 142.3 (s); exact mass
m/z calcd for C24H32NaO2 (M þ Na) 375.2295. The molecular
ion could not be detected as the compound readily aromatized
under all conditions tried.
Isomer of 34. TsOH H2O (0.0113 g, 0.0593 mmol) was added to
3
a solution of the more polar diastereoisomer of 34 (0.0171 g,
0.0593 mmol) in dry PhH (4 mL), and the mixture was refluxed
for 1 h, cooled to room temperature, and partitioned between
water and CH2Cl2. The aqueous phase was then extracted with
hexane, and the combined organic extracts were dried (Na2SO4)
and evaporated. Flash chromatography of the residue over silica
gel (0.7ꢀ15 cm), using EtOAc-petroleum ether mixtures from
0% to 2% EtOAc, gave 35 (0.0150 g, 100%) as an oil: FTIR
(CH2Cl2, neat film microscope) 3026, 2955, 2928, 2857, 1604,
The more polar diastereoisomer: FTIR (CH2Cl2, cast) 3397,
3085, 3062, 3026, 2904, 2849, 2677, 1742, 1603, 1452 cm-1
;
1
1514, 1496 cm-1; H NMR (CDCl3, 400 MHz) δ 0.91 (t, J =
1H NMR (CDCl3, 400 MHz) δ 1.42-1.60 (br m, 2 H), 1.60-1.80
(m, 15 H), 1.80-1.98 (m, 3 H), 2.02 (apparent s, 3 H), 2.68-2.84
(m, 2 H), 5.81 (dd, J = 10.4, 1.5 Hz, 1 H), 5.85 (dd, J = 10.3,
1.8 Hz, 1 H), 7.16-7.23 (m, 3 H), 7.26-7.32 (m, 2 H); 13C NMR
(CDCl3, 100 MHz) δ 27.7 (t), 28.4 (d), 29.9 (t), 33.1 (t), 35.7 (s),
35.8 (t), 37.1 (t), 41.1 (t), 71.2 (s), 72.9 (s), 125.8 (d), 128.3 (d),
128.4 (d), 128.9 (d), 137.4 (d), 142.5 (s); exact mass m/z calcd for
C24H32NaO2 (M þ Na) 375.2295, found 375.2295.
7.0 Hz, 3 H), 1.27-1.42 (m, 4 H), 1.63 (apparent quintet, J =
7.6 Hz, 2 H), 2.58 (dd, J=7.7, 7.7 Hz, 2 H), 2.87-2.96 (m, 4 H),
7.14 (s, 4 H), 7.18-7.24 (m, 3 H), 7.27-7.33 (2 H); 13C NMR
(CDCl3, 100 MHz) δ 14.0 (q), 22.6 (t), 31.2 (t), 31.5 (t), 35.5 (t),
37.5 (t), 38.0 (t), 125.8 (d), 128.2 (d), 128.30 (d), 128.34 (d), 128.4
(d), 138.9 (s), 140.5 (s), 142.0 (s); exact mass m/z calcd for C19H24
252.1878, found 252.1877.
Use of Less Polar Isomer of 34. TsOH H2O (0.0202 g,
1-[4-(2-Phenylethyl)phenyl]adamantane (38). Use of less polar
3
0.106 mmol) was added to a solution of the less polar diaster-
eoisomer of 34 (0.0306 g, 0.106 mmol) in dry PhH (4 mL), and
the mixture was refluxed for 1 h, cooled to room temperature,
and partitioned between water and CH2Cl2. The aqueous phase
was then extracted with hexane, and the combined organic
extracts were dried (Na2SO4) and evaporated. Flash chroma-
tography of the residue over silica gel (0.7 ꢀ 16 cm), using
EtOAc-petroleum ether mixtures from 0% to 2% EtOAc, gave
35 (0.027 g, 100%) as an oil.
isomer of 37. TsOH H2O (0.0012 g, 0.0064 mmol) was added
3
to a solution of the less polar diastereoisomer of 37 (0.0075 g,
0.021 mmol) in dry PhH (4 mL), and the mixture was refluxed
for 2 h, cooled to room temperature, and partitioned between
water and CH2Cl2. The aqueous phase was extracted with
hexane, and the combined organic extracts were dried (Na2SO4)
and evaporated. Flash chromatography of the residue over silica
gel (0.7ꢀ15 cm), using EtOAc-petroleum ether mixtures from
0% to 2% EtOAc, gave 38 (0.0064 g, 95%) as a solid: mp 96-
99 °C; FTIR (CH2Cl2, cast) 3060, 3025, 2903, 2848, 2657, 1603,
3-(1-Adamantyl)-6-(2-phenylethyl)octa-1,7-diene-3,6-diol (36).
MeLi (1.6 M in Et2O, 0.41 mL, 0.66 mmol) was added dropwise
to a stirred and cooled (0 °C) solution of tetravinyltin (0.030 mL,
0.165 mmol) in dry Et2O (3 mL). After 45 min, the mixture was
cooled to -78 °C, and a solution of 10 (0.0134 g, 0.0413 mmol) in
Et2O (1 mL plus 1 mL as a rinse) was added by cannula. The cold
bath was left in place but not recharged, and stirring was con-
tinued for 5 h. The mixture was cooled to 0 °C and quenched
with a mixture of water (50 mL) and saturated aqueous NH4Cl
(25 mL). The aqueous phase was extracted with Et2O, and
the combined organic extracts were washed with brine, dried
(MgSO4), and evaporated. Flash chromatography of the residue
over silica gel (0.7ꢀ15 cm), using 15% EtOAc-hexane, gave 36
(0.0146 g, 93%) as a semisolid mixture of diastereoisomers (13C
NMR): FTIR (CH2Cl2, cast) 3433, 3085, 3025, 2905, 2849, 2679,
1
1515, 1496, 1452 cm-1; H NMR (CDCl3, 500 MHz) δ 1.75-
1.83 (m, 6 H), 1.93 (d, J=2.7 Hz, 6 H), 2.10 (apparent s, 3 H),
2.87-2.96 (m, 4 H), 7.18 (apparent d, J = 8.4 Hz, 2 H),
7.20-7.24 (m, 3 H), 7.28-7.32 (m, 4 H); 13C NMR (CDCl3,
125 MHz) δ 29.0 (d), 35.9 (s), 36.8 (t), 37.5 (t), 37.9 (t), 43.3 (t),
124.8 (d), 125.9 (d), 128.1 (d), 128.3 (d), 128.4 (d), 138.9 (s), 142.1
(s), 149.0 (s); exact mass m/z calcd for C24H28 316.2191, found
316.2192.
Use of more polar isomer of 37. TsOH H2O (0.0007 g, 0.004
3
mmol) was added to a solution of the more polar diastereoi-
somer of 37 (0.0043 g, 0.012 mmol) in dry PhH (3 mL), and the
mixture was refluxed for 2 h, cooled to room temperature, and
partitioned between water and CH2Cl2. The aqueous phase was
extracted with hexane, and the combined organic extracts were
dried (Na2SO4) and evaporated. Flash chromatography of the
residue over silica gel (0.7 ꢀ 15 cm), using EtOAc-petroleum
ether mixtures from 0% to 2% EtOAc, gave 38 (0.0035 g, 91%)
as a solid: mp 96-99 °C.
1
1742, 1667, 1497 cm-1; H NMR (CDCl3, 400 MHz) δ 1.44-
1.53 (m, 3 H), 1.57-1.72 (m, 13 H), 1.72-1.90 (m, 3 H), 1.99 (br
s, 3 H), 1.99-2.56 (br s, 1 H), 2.56-2.72 (m, 2 H), 5.12-5.32 (m,
4 H), 5.75-5.92 (m, 2 H), 7.14-7.20 (m, 3 H), 7.24-7.30 (m,
2 H); 13C NMR (CDCl3, 100 MHz) δ 25.69 (t), 25.76 (t), 28.6 (d),
30.0 (t), 34.2 (t), 34.5 (t), 36.4 (t), 37.1 (t), 39.3 (t), 42.6 (t), 43.7
(t), 75.3 (s), 75.4 (s), 79.1 (s), 79.2 (s), 112.9 (t), 113.3 (t), 113.8 (t),
114.0 (t), 125.65 (d), 125.72 (d), 128.34 (d), 128.35 (d), 128.37 (d),
140.5 (d), 140.6 (d), 142.5 (s), 142.6 (s), 143.7 (d), 143.8 (d); exact
mass m/z calcd for C26H36NaO2 (M þ Na) 403.2608, found
403.2608.
Use of a mixture of isomers of 37. Grubbs I catalyst (0.0041 g,
0.0049 mmol) was added to a stirred solution of 36 (a mixture of
isomers, 0.0188 g, 0.0494 mmol) in dry CH2Cl2 (5 mL) (N2 atmo-
sphere). After 3 h, the mixture was evaporated, and the residue
was stored for a few minutes under oil pump vacuum and then
dissolved in PhH (5 mL). TsOH H2O (0.0028 g, 0.0148 mmol)
3
was added to the solution of crude 37, and the mixture was
refluxed for 30 min, cooled to room temperature, and stirred for
an additional 36 h. The mixture was then partitioned between
water and CH2Cl2, and the aqueous phase was extracted with
hexane. The combined organic extracts were dried (Na2SO4)
and evaporated. Flash chromatography of the residue over silica
gel (0.7ꢀ15 cm), using EtOAc-petroleum ether mixtures from
1-(Adamantyl)-4-(2-phenylethyl)cyclohex-2-ene-1,4-diol (37).
Grubbs I catalyst (0.0020 g, 0.0024 mmol) was added to a stirred
solution of 36 (0.0146 g, 0.0384 mmol) in dry CH2Cl2 (2.5 mL)
(N2 atmosphere). After 3 h, the mixture was evaporated, and
(26) Sundaresan, A. K.; Ramamurthy, V. Org. Lett. 2007, 9, 3575–3578.
8034 J. Org. Chem. Vol. 75, No. 23, 2010

Ziffle et al.
JOCArticle
0% to 2% EtOAc, gave 38 (0.0149 g, 95%) as a solid, identical to
material obtained from the less polar isomer of 37.
NH4Cl (12 mL), and the aqueous phase was extracted with
Et2O. The combined organic extracts were washed with brine,
dried (Na2SO4), and evaporated. Flash chromatography of the
residue over silica gel (0.7ꢀ17 cm), using EtOAc-hexane mix-
tures from 5% to 10% EtOAc, gave 42 (0.0148 g, 81%) as a
semisolid that was a mixture of diastereoisomers (13C NMR):
FTIR (CHCl3, cast microscope) 3450, 3010, 2926, 2853, 1841,
1640, 1451 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.84-1.10 (m,
2 H), 1.10-1.32 (m, 6 H), 1.32-1.62 (m, 10 H), 1.62-1.87 (m,
10 H), 1.87-2.12 (br s, 2 H), 5.10-5.24 (m, 4 H), 5.70-5.87 (m,
2 H); 13C NMR (CDCl3, 125 MHz) δ 25.50 (t), 26.53 (t), 26.6 (t),
26.7 (t), 27.56 (t), 27.62 (t), 27.64 (t), 27.7 (t), 27.8 (t), 27.9 (t),
28.0 (t), 28.1 (t), 28.17 (t), 28.24 (t), 28.3 (t), 29.00 (t), 29.02 (t),
30.9 (t), 31.1 (t), 31.3 (t), 31.4 (t), 46.9 (d), 47.3 (d), 48.1 (d), 48.6
(d), 77.2 (s), 77.3 (s), 78.1 (s), 78.2 (s), 112.9 (t), 113.06 (t), 113.11
(t), 113.3 (t), 142.57 (d), 142.62 (d), 142.7 (d); exact mass m/z
calcd for C21H36NaO2 (M þ Na) 343.2608, found 343.2609.
4-Cycloheptyl-1-cyclohexylbenzene (44). Grubbs I catalyst
(0.0035 g, 0.0043 mmol) was added to a stirred solution of 42
(0.0138 g, 0.0431 mmol) in dry CH2Cl2 (5 mL) (N2 atmosphere).
After 18 h, the mixture was evaporated to afford a mixture of
diol 43 and aromatized product 44. The crude material was dis-
3,6-Bis(1-adamantyl)octa-1,7-diene-3,6-diol (39). MeLi (1.6 M
in Et2O, 0.50 mL, 0.80 mmol) was addeddropwise toa stirred and
cooled (0 °C) solution of tetravinyltin (0.037 mL, 0.201 mmol) in
dry Et2O (5 mL). After 1 h, the mixture was cooled to -78 °C, and
a solution of14 (0.0089g, 0.025mmol) inEt2O (1mLplus1 mL as
a rinse) was added by cannula. After 1.75 h the cold mixture was
quenched with saturated aqueous NH4Cl (6 mL), and the aque-
ous phase was extracted with Et2O. The combined organic
extracts were washed with brine, dried (Na2SO4), and eva-
porated. Flash chromatography of the residue over silica gel
(0.7ꢀ12 cm), using EtOAc-hexane mixtures from 2% to 10%
EtOAc, gave 39 as a mixture of diastereoisomers [6.6 mg, 64%
less polar diastereoisomer; 2.3 mg, 22% more polar diastereoi-
somer (86% overall)]. The less polar diastereoisomer: FTIR
(CH2Cl2, microscope) 3614, 3085, 2932, 2904, 2871, 2851, 2680,
2658, 2639, 1838, 1730, 1640, 1450, 1408 cm-1; 1H NMR (CDCl3,
400 MHz) δ 1.20-1.36 (m, 4 H), 1.36-1.50 (m, 4 H), 1.51-1.72
(m, 22 H), 1.97 (s, 6 H), 5.14 (dd, J=17.4, 1.7 Hz, 2 H), 5.21 (dd,
J=11.0, 1.7 Hz, 2 H), 5.83 (dd, J=17.3, 11.0 Hz, 2 H); 13C NMR
(CDCl3, 125 MHz) δ 25.9 (t), 28.6 (d), 36.4 (t), 37.1 (t), 39.4 (s),
79.4 (s), 113.5 (t), 141.0 (d); exact mass m/z calcd for C28H42NaO2
(M þ Na) 433.3077, found 433.3076.
solved in PhH (4 mL) and TsOH H2O (0.0112 g, 0.0589 mmol)
3
was added. The solution was refluxed for 1 h, cooled to room
temperature, and partitioned between water and CH2Cl2. The
aqueous phase was extracted with hexane, and the combined
organic extracts were dried (Na2SO4) and evaporated. Flash
chromatography of the residue over silica gel (0.7ꢀ16 cm), using
EtOAc-petroleum ether mixtures from 0% to 2% EtOAc, gave
44 (0.0105 g, 95%) as a solid: mp 75-80 °C; FTIR (CH2Cl2,
microscope) 3050, 3010, 2923, 2850, 2668, 1899, 1785, 1647,
1515, 1447 cm-1; 1H NMR (CDCl3, 500 MHz) δ 1.20-1.34 (m,
1 H), 1.34-1.50 (m, 4 H), 1.50-1.75 (m, 8 H), 1.75-1.97 (m, 9
H), 2.44-2.51 (m, 1 H), 2.61-2.68 (m, 1 H), 7.12 (apparent s,
4 H); 13C NMR (CDCl3, 100 MHz) δ 26.2 (t), 27.0 (t), 27.2 (t),
28.0 (t), 34.5 (t), 36.8 (t), 44.1 (d), 46.6 (d), 126.5 (d), 126.6 (d),
145.1 (s), 147.3 (s); exact mass m/z calcd for C19H28 256.2191,
found 256.2184.
The more polar diastereoisomer: FTIR (CH2Cl2, cast micro-
1
scope) 3476, 2905, 2849, 1718, 1451 cm-1; H NMR (CDCl3,
500 MHz) δ 1.18-1.36 (m, 8 H), 1.54-1.74 (m, 22 H), 1.97
(apparent s, 6 H), 5.18 (dd, J=17.2, 1.8 Hz, 2 H), 5.21 (dd, J=
11.0, 1.8 Hz, 2 H), 5.78 (dd, J=17.2, 11.0 Hz, 2 H); 13C NMR
(CDCl3, 125 MHz) δ 25.2 (t), 28.7 (d), 36.4 (t), 37.2 (t), 39.4 (s),
79.2 (s), 113.8 (t), 141.1 (d); exact mass m/z calcd for C28H42-
NaO2 (M þ Na) 433.3077, found 433.3079.
1,4-Bis(1-adamantyl)cyclohex-2-ene-1,4-diol (40). Grubbs I
catalyst (0.0033 g, 0.0039 mmol) was added to a stirred solution
of 39 (mixture of isomers, 0.008 g, 0.019 mmol) in dry CH2Cl2
(1 mL) (N2 atmosphere). After 24 h, the reaction mixture was
evaporated, and flash chromatography of the residue over silica
gel (0.7ꢀ18 cm), using EtOAc-petroleum ether mixtures from
2% to 10% EtOAc, gave 40 as a mixture of two impure diaster-
eoisomers (13C NMR) (ca. 5.6 mg). We were unable to obtain
satisfactory NMR data: exact mass m/z calcd for C26H38NaO2
(M þ Na) 405.2764, found 405.2768.
2-Methyl-3,6-bis(2-phenylethyl)octa-1,7-diene-3,6-diol (45). (a) 2-
Methyl-6-[[tris(1-methylethyl)silyl]oxy]-8-phenyl-3-(2-phenylethyl)-
oct-1-en-3-ol (45a). t-BuLi (1.7 M in pentane, 0.46 mL, 0.78 mmol)
was added dropwise to a stirred and cooled (-78 °C) solution of
2-bromopropene (0.035 mL, 0.390 mmol) in dry Et2O (6 mL). After
45 min, a solution of 22 (0.0222 g, 0.0490 mmol) in Et2O (2 mL plus
1 mL as a rinse) was added by cannula. After 15 min, the dry ice bath
was replaced by an ice bath, and the mixture was quenched with
saturated aqueous NH4Cl (5 mL). The aqueous phase was extracted
with CH2Cl2, and the combined organic extracts were dried
(Na2SO4) and evaporated. Flash chromatography of the residue
over silica gel (0.7ꢀ18 cm), using EtOAc-hexane mixtures from 2%
to 10% EtOAc, gave 45a (0.0243 g, 100%) as a semisolid that was a
mixture of diastereoisomers (13C NMR): FTIR (CH2Cl2, cast film
microscope) 3576, 3476, 3086, 3063, 3027, 2944, 2891, 2866, 1940,
1-[4-(1-Adamantyl)phenyl]adamantane (41)27. TsOH H2O
3
(0.0025 g, 0.013 mmol) was added to a solution of the above
sample of 40 (0.0050 g, 0.013 mmol) in dry PhH (2 mL), and
the mixture was refluxed for 4.5 h, cooled to room tempera-
ture, and partitioned between water and CH2Cl2. The aqueous
phase was extracted with hexane, and the combined organic
extracts were dried (Na2SO4) and evaporated. Flash chroma-
tography of the residue over silica gel [0.5 ꢀ 6 cm (Pasteur
pipet)], using EtOAc-petroleum ether mixtures from 0% to
2% EtOAc, gave 41 (0.0043 g, 95%) as a solid: sublimes at
215-227 °C; FTIR (CH2Cl2, microscope) 3085, 3047, 3027,
2907, 2849, 2657, 1507 cm-1; 1H NMR (CDCl3, 500 MHz) δ
1.72-1.82 (m, 12 H), 1.93 (d, J=2.3 Hz, 12 H), 2.09 (apparent
s, 6 H), 7.31 (s, 4 H); 13C NMR (CDCl3, 125 MHz) δ 29.0 (d),
35.8 (s), 36.9 (t), 43.2 (t), 124.5 (d), 148.4 (s); exact mass m/z
calcd for C26H34 346.2661, found 346.2665.
1866, 1802, 1642, 1604, 1496, 1454 cm-1 1H NMR (CDCl3,
;
400 MHz) δ 1.08 (apparent s, 21 H), 1.45-1.75 (m, 5 H), 1.77
(dd, J=3.0, 0.7 Hz, 3 H), 1.80-1.97 (m, 4 H), 2.44-2.57 (m, 1 H),
2.58-2.76 (m, 3 H), 3.91 (dddd, J=5.2, 5.2, 5.2, 5.2 Hz, 1 H), 5.01
(apparent q, J=1.5, 1 H), 5.09 (apparent dq, J=5.7, 0.7 Hz, 1 H),
7.16-7.22 (m, 6 H), 7.27-7.32 (m, 4 H); 13C NMR (CDCl3, 100
MHz) δ 12.7 (d), 18.2 (q), 19.8 (q), 29.6 (t), 29.9 (t), 31.3 (t), 31.4 (t),
34.5 (t), 34.6 (t), 38.3 (t), 38.4 (t), 41.6 (t), 41.8 (t), 71.97 (d), 72.01
(d), 111.4 (t), 111.7 (t), 125.7 (d), 128.3 (d), 128.35 (d), 128.36 (d),
128.38 (d), 142.5 (s), 142.7 (t), 147.8 (s), 147.9 (s); exact mass m/z
calcd for C32H51O2Si 495.3653, found 495.3651; exact mass m/z
calcd for C32H50NaO2Si (M þ Na) 517.3472, found 517.3471.
(b) 2-Methyl-8-phenyl-3-(2-phenylethyl)oct-1-ene-3,6-diol (45b).
Bu4NF (1.0 M in THF, 0.163 mL, 0.163 mmol) was added
dropwise to a stirred and cooled (0 °C) solution of 45a (0.0230 g,
3-Cycloheptyl-6-cyclohexylocta-1,7-diene-3,6-diol (42). MeLi
(1.6 M in Et2O, 1.16 mL, 1.86 mmol) was added dropwise to a
stirred and cooled (0 °C) solution of tetravinyltin (0.09 mL, 0.47
mmol) in dry Et2O (8 mL). After 45 min, the mixture was cooled
to -78 °C, and a solution of 18 (0.0150 g, 0.0567 mmol) in Et2O
(2 mL plus 2 mL as a rinse) was added by cannula. The cold bath
was left in place but not recharged, and stirring was continued
for 11.5 h. The mixture was quenched with saturated aqueous
€
(27) Brase, S.; Waegell, B.; de Meijere, A. Synthesis 1998, 2, 148–152.
J. Org. Chem. Vol. 75, No. 23, 2010 8035

Ziffle et al.
JOCArticle
0.0465 mmol) in dry THF (6 mL). The cooling bath was left in
place but not recharged, and stirring was continued for 19 h. The
mixture was then quenched with water (5 mL) and extracted
with EtOAc. The combined organic extracts were dried (Na2SO4)
and evaporated. Flash chromatography of the residue over silica
gel (1.4ꢀ15 cm), using EtOAc-petroleum ether mixtures from
20% to 100%, gave 45b (0.0154 g, 98%) as an oil that was a
mixture of diastereoisomers (13C NMR): FTIR (CH2Cl2,
microscope) 3381, 3085, 3062, 3026, 3001, 2943, 2861, 1946,
1870, 1805, 1707, 1643, 1604, 1584, 1496, 1454 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 1.35-1.74 (m, 2 H), 1.74 (dd, J = 1.5,
0.7 Hz, 1.8 H), 1.76 (dd, J=1.5, 0.7 Hz, 1.2 H), 1.77-1.95 (m,
6 H), 2.15-2.40 (br s, 2 H), 2.46-2.56 (m, 1 H), 2.61-2.73 (m,
2 H), 2.74-2.84 (m, 1 H), 3.57-3.65 (m, 0.6 H), 3.65-3.72 (m,
0.4 H), 4.99-5.02 (m, 0.4 H), 5.02-5.04 (m, 0.6 H), 5.07-5.08
(m, 0.4 H), 5.10-5.12 (m, 0.6 H), 7.16-7.23 (m, 6 H), 7.25-7.32
(m, 4 H); 13C NMR (CDCl3, 125 MHz) δ 19.80 (q), 19.82 (q),
29.8 (t), 29.9 (t), 31.1 (t), 31.3 (t), 32.1 (t), 32.2 (t), 35.0 (t), 36.4
(t), 38.9 (t), 39.5 (t), 41.7 (t), 41.9 (t), 71.07 (d), 72.14 (d), 77.7 (s),
77.8 (s), 111.7 (t), 112.1 (t), 125.76 (d), 125.78 (d), 125.8 (d), 125.9
(d), 128.3 (d), 128.37 (d), 128.41 (d), 141.97 (s), 142.02 (s), 142.4
(s), 142.5 (s), 147.7 (s), 147.8 (s); exact mass m/z calcd for
C23H30NaO2 (M þ Na) 361.2138, found 361.2136.
2-Methyl-1,4-bis(2-phenylethyl)benzene (47). Grubbs II catal-
yst8 (0.0012 g, 0.0014 mmol) was added to a stirred solution of 45
(0.0020 g, 0.0055 mmol) in dry CH2Cl2 (2.5 mL) (N2 atmo-
sphere). After 15 h, the mixture was evaporated, and the residue
(46) was dissolved in dry PhH (2 mL). TsOH H2O (0.0010 g,
3
0.0053 mmol) was added, and the mixture was refluxed for 30 min.
Evaporation of the solvent and preparative thin layer chromatog-
raphy of the residue over silica gel (plate 5ꢀ5ꢀ0.025 cm; 2%
EtOAc-petroleum ether), gave 47 (0.0015 g, ca. 91%) contain-
ing minor impurities: FTIR (CH2Cl2, cast film) 3085, 3062,
3026, 2926, 2856, 1943, 1869, 1734, 1603, 1497, 1453 cm-1; 1H
NMR (CDCl3, 400 MHz) δ 2.28 (s, 3 H), 2.84-2.94 (m, 8 H),
6.96-7.01 (m, 2 H), 7.06-7.11 (m, 1 H), 7.17-7.24 (6 H),
7.27-7.33 (m, 4 H); 13C NMR (CDCl3, 100 MHz) δ 19.2 (q),
35.1 (t), 36.8 (t), 37.5 (t), 38.0 (t), 125.8 (d), 125.88 (d), 125.92 (d),
128.29 (d), 128.33 (d), 128.38 (d), 128.40 (d), 128.8 (d), 130.3 (d),
135.8 (s), 137.5 (s), 139.5 (s), 142.0 (s), 142.1 (s); exact mass m/z
calcd for C23H24 300.1878, found 300.1876.
2,7-Dimethyl-3,6-bis(2-phenylethyl)octa-1,7-diene-3,6-diol
(48). Use of 2-Propenylmagnesium Bromide. Isopropenylmag-
nesium bromide (0.5 M in THF, 0.51 mL, 0.25 mmol) was added
dropwise to a stirred and cooled (-78 °C) solution of 4 (0.0299 g,
0.102 mmol) in dry THF (5 mL). After 1 h, the dry ice bath was
replaced by an ice bath, and another portion of isopropenyl-
magnesium bromide (0.5 M in THF, 0.51 mL, 0.25 mmol) was
added dropwise. The ice bath was left in place but not recharged,
and after 5 days, the mixture was cooled (0 °C) and quenched
with water (10 mL). The aqueous phase was extracted with
CH2Cl2, and the combined organic extracts were washed with
brine, dried (Na2SO4), and evaporated. Flash chromatography
of the residue over silica gel (1.4ꢀ18 cm), using EtOAc-hexane
mixtures from 5% to 40% EtOAc, gave 48 (0.0235 g, 61%) as an
oil that was a mixture of diastereoisomers (13C NMR): FTIR
(CH2Cl2, microscope) 3435, 3085, 3062, 3026, 2929, 2855, 1942,
(c) 6-Hydroxy-7-methyl-1-phenyl-6-(2-phenylethyl)oct-7-en-
3-one (45c). (COCl)2 (0.025 mL, 0.28 mmol) was added dropwise
to a stirred and cooled (-78 °C) solution of DMSO (0.0399,
0.562 mmol) in CH2Cl2 (3 mL). After 10 min, a solution of 45a
(0.0123 g, 0.0363 mmol) in CH2Cl2 (1 mL) was added dropwise.
After a further 40 min, Et3N (0.10 mL, 0.73 mmol) was added
dropwise, and stirring was continued for 10 min. The mixture
was then stored at -20 °C (freezer) for 12 h and then warmed to
0 °C. Water (10 mL) was added, and the aqueous phase was ex-
tractedwithCH2Cl2. The combined organic extracts werewashed
with saturated aqueous NaHCO3, dried (Na2SO4), and evapo-
rated. Flash chromatography of the residue over silica gel (0.7ꢀ
16 cm), using EtOAc-petroleum ether mixtures from 2% to
10% EtOAc, gave 45c (0.0105 g, ca. 86%) as an impure oil that
was used in the next step: FTIR (CH2Cl2, microscope) 3464,
3085, 3062, 3026, 2949, 2867, 1944, 1871, 1804, 1709, 1644, 1604,
1496, 1454 cm-1; exact mass m/z calcd for C23H28NaO2
(M þ Na) 359.1982, found 359.1976.
1
1870, 1804, 1727, 1643, 1604, 1496 cm-1; H NMR (CDCl3,
500 MHz) δ 1.52-1.58 (m, 1.5 H), 1.67-1.73 (m, 2.5 H), 1.75 (s,
2.5 H), 1.78 (s, 3.5 H), 1.81-1.97 (m, 6 H), 2.45-2.56 (m, 2 H),
2.62-2.72 (m, 2 H), 4.99-5.02 (m, 1.2 H), 5.03-5.06 (m, 0.8 H),
5.06-5.09 (m, 1.3 H), 5.12-5.14 (m, 0.7 H), 7.16-7.23 (m, 6 H),
7.26-7.32 (m, 4 H); 13C NMR (CDCl3, 125 MHz) δ 19.8 (q),
29.8 (t), 29.9 (t), 32.9 (t), 33.0 (t), 41.5 (t), 42.1 (t), 111.5 (s), 112.2
(s), 125.7 (d), 125.8 (d), 128.38 (d), 128.40 (d), 128.42 (d), 142.48
(s), 142.51 (s), 147.5 (t), 148.0 (t) (one signal not observed due
to overlap); exact mass m/z calcd for C26H34NaO2 (M þ Na)
401.2451, found 401.2448.
Use of 2-propenyl-lithium. t-BuLi (1.7 M in pentane, 0.28 mL,
0.47 mmol) was added dropwise to a stirred and cooled (-78 °C)
solution of 2-bromopropene (0.021 mL, 0.237 mmol) in dry
Et2O (3 mL). After 30 min, a solution of 4 (0.0105 g, 0.0296 mmol)
in Et2O (0.5 mL plus 0.5 mL as a rinse) was added dropwise by
cannula. After 3.5 h the dry ice bath was replaced by an ice bath
that was left in place but not recharged, and stirring was
continued for 17.5 h. The reaction mixture was cooled to 0 °C
and quenched with saturated aqueous NH4Cl (3 mL), and
the aqueous phase was extracted with CH2Cl2. The combined
organic extracts were washed with brine, dried (Na2SO4), and
evaporated. Flash chromatography of the residue over silica gel
(1.6ꢀ17 cm), using EtOAc-hexane mixtures from 2% to 10%
EtOAc, gave 48 (0.0094 g, 72%) as an oil that was a mixture of
diastereoisomers (13C NMR).
(d) 2-Methyl-3,6-bis(2-phenylethyl)octa-1,7-diene-3,6-diol (45).
MeLi (1.6 M in Et2O, 0.24 mL, 0.39 mmol) was added dropwise
to a stirred and cooled (0 °C) solution of tetravinyltin (0.018 mL,
0.096 mmol) in dry Et2O (4 mL). After 30 min, the mixture was
cooled to -78 °C, and a solution of 45c (0.0081 g, 0.024 mmol) in
Et2O (1 mL plus 0.5 mL as a rinse) was added by cannula. The
cold bath was left in place but not recharged, and stirring
was continued for 12 h. The mixture was cooled to 0 °C and
quenched with saturated aqueous NH4Cl (5 mL), and the aque-
ous phase was extracted with Et2O. The combined organic ex-
tracts were dried (Na2SO4) and evaporated. Flash chromatog-
raphy of the residue over silica gel (1.4ꢀ18 cm), using EtOAc-
hexane mixtures from 2% to 20% EtOAc, gave 45 (0.0066 g,
75%) as an oil that was a mixture of diastereoisomers (13C NMR):
FTIR (CH2Cl2, cast microscope) 3427, 3085, 3062, 3026, 3003,
2949, 2863, 1945, 1869, 1805, 1709, 1643, 1604, 1496, 1454 cm-1
;
1H NMR (CDCl3, 500 MHz) δ 1.48-1.72 (m, 4 H), 1.73 (dd, J=
1.5, 0.7 Hz, 1.1 H), 1.75 (dd, J=1.6, 0.6 Hz, 1.9 H), 1.76-1.94
(m, 6 H), 2.45-2.53 (m, 1 H), 2.57-2.71 (m, 3 H), 4.98-5.10 (m,
2 H), 5.18-5.32 (m, 2 H), 5.78-5.90 (m, 1 H), 7.15-7.20 (m, 6
H), 7.25-7.29 (m, 4 H); 13C NMR (CDCl3, 125 MHz) δ 14.0 (q),
17.1 (q), 19.8 (t), 22.3 (t), 29.8 (t), 30.0 (t), 33.0 (t), 33.1 (t), 34.1
(t), 34.25 (t), 34.31 (t), 41.5 (t), 41.9 (t), 42.6 (t), 75.2 (s), 77.5 (s),
111.7 (t), 112.1 (t), 113.2 (t), 113.6 (t), 125.75 (d), 125.78 (d),
128.40 (d), 128.35 (d), 142.3 (s), 142.4 (s), 143.2 (s), 143.6 (s),
147.8 (s); exact mass m/z calcd for C25H32NaO2 (M þ Na)
387.2295, found 387.2293.
2,3-Dimethyl-1,4-bis(2-phenylethyl)benzene (50). Schrock cat-
alyst11 (0.0053 g, 0.0069 mmol) and then PhH (3 mL) were added
to 48 (0.0131 g, 0.0346 mmol) in a Pyrex bomb (10 mL) in a
glovebox (N2). The bomb was sealed, removed from the glove-
box, and heated (ca. 80 °C) for 2.5 days. The mixture was cooled
to room temperature and reintroduced into the glovebox, and a
sample for TLC was removed. Little conversion to 49 had
occurred. The contents of the bomb were transferred to a flask
8036 J. Org. Chem. Vol. 75, No. 23, 2010

Ziffle et al.
JOCArticle
with a reflux condenser sealed onto it, and additional Schrock
catalyst (0.0053 g, 0.0069 mmol) was added. The reaction vessel
was removed from the glovebox, and the mixture was refluxed
(80 °C) under N2 with frequent purging, resulting in a color
change from yellow to amber after 1 h. After a further 18 h, the
solution was cooled and evaporated. Flash chromatography of
the residue over silica gel (1.3ꢀ11 cm), using EtOAc-petroleum
ether mixtures from 5% to 100% EtOAc, gave an unidentifiable
mixture (presumably containing 49) that was dissolved in dry
Methyl 7,8,10,11-Tetradeoxy-6,9-bis(ethenyl)-2,3,4-tris-O-methyl-
11-phenyl-r-D-gluco-undecanopyranoside (54). Vinylmagnesium
bromide (1.0 M in THF, 1.89 mL, 1.89 mmol) was added drop-
wise to a stirred and cooled (-78 °C) solution of 29 (74.3 mg,
0.189 mmol) in THF (3 mL). The cooling bath was left in place
but not recharged, and stirring was continued for 7 h. The mix-
ture was quenched with saturated aqueous NH4Cl (3 mL) and
extracted with Et2O. The combined organic extracts were dried
(MgSO4) and evaporated. Flash chromatography of the residue
over silica gel (1.5ꢀ13 cm), using 40% EtOAc-hexanes, gave 54
(62.7 mg, 84%) as a mixture of two diastereoisomers (13C NMR):
FTIR (CHCl3, microscope) 3453, 3086, 3061, 3025, 2931,
2837,1717, 1640, 1604, 1559, 1540, 1497, 1453 cm-1; 1H NMR
(CDCl3, 500 MHz) δ 1.56-1.92 (m, 6 H), 2.56 (s, 1 H), 2.60-
2.77 (m, 2 H), 3.11-3.15 (m, 1 H), 3.25-3.29 (m, 1 H), 3.46 (s,
3 H), 3.51-3.59 (m, 8 H), 3.61 (s, 3 H), 4.47-4.63 (m, 1 H), 4.78
(d, J=3.5 Hz, 1 H), 5.16-5.20 (m, 1 H), 5.28-5.36 (m, 2 H),
5.47-5.53 (m, 1 H), 5.78-5.95 (m, 2 H), 7.16-7.20 (m, 3 H),
7.26-7.29 (m, 2 H); 13C NMR (CDCl3, 125 MHz) δ 30.07 (t),
30.09 (t), 31.3 (t), 33.4 (t), 33.5 (t), 43.2 (t), 43.7 (t), 55.7 (q), 55.8
(q), 59.0 (q), 60.03 (q), 60.05 (q), 60.7 (q), 72.0 (d), 72.6 (d), 74.6
(s), 74.8 (s), 76.9 (s), 77.0 (s), 81.7 (d), 81.8 (d), 82.1 (d), 84.0 (d),
97.37 (d), 97.44 (d), 113.0 (t), 113.2 (t), 115.0 (t), 115.5 (t), 125.55
(d), 125.63 (d), 128.29 (d), 128.34 (d), 128.39 (d), 140.0 (d), 140.4
(d), 142.8 (s), 143.0 (s), 143.8 (d), 143.9 (d); exact mass m/z calcd
for C25H38NaO7 (M þ Na) 473.2510, found 473.2503.
PhH (3 mL). TsOH H2O (0.0066 g, 0.035 mmol) was added, and
3
the mixture was refluxed for 3 h and then evaporated. Flash
chromatography of the residue over silica gel (1.4ꢀ18 cm), using
EtOAc-hexane mixtures from 0% to 5% EtOAc, gave several
fractions containing mostly impure 50. The material was puri-
fied by preparative TLC (silica, 5ꢀ4.5ꢀ0.025 cm, 3 plates; 2%
EtOAc-hexane) providing pure 50 (0.0072 g, 66%) as an oil:
FTIR (CH2Cl2, microscope) 3085, 3061, 3025, 2961, 2928, 2868,
1943, 1869, 1801, 1735, 1704, 1678, 1603, 1582, 1540, 1496, 1453
cm-1 1H NMR (CDCl3, 400 MHz) δ 2.24 (s, 6 H), 2.91
;
(apparent s, 8 H), 7.11 (s, 2 H), 7.18-7.23 (m, 6 H), 7.27-7.34
(m, 4 H); 13C NMR (CDCl3, 100 MHz) δ 16.6 (q), 37.3 (t), 37.8
(t), 125.7 (d), 128.09 (d), 128.13 (d), 128.17 (d), 128.24 (d), 131.8
(s), 139.1 (d), 141.7 (d); exact mass m/z calcd for C24H26
314.2035, found 314.2031.
1,4-Diethenylcyclohexadecane-1,4-diol (51). MeLi (1.6 M in
Et2O, 0.97 mL, 1.6 mmol) was added dropwise to a stirred and
cooled (0 °C) solution of tetravinyltin (0.070 mL, 1.32 mmol) in
dry Et2O (6 mL). After 1.5 h, the mixture was cooled to -78 °C
and a solution of 26 (0.0122 g, 0.0483 mmol) in Et2O (1.5 mL
plus 1.5 mL as a rinse) was added by cannula. The cold bath was
left in place but not recharged, and stirring was continued for
5 h. The mixture was quenched with saturated aqueous NH4Cl
(25 mL), and the aqueous phase was extracted with Et2O. The
combined organic extracts were washed with brine, dried (Na2SO4),
and evaporated. Flash chromatography of the residue over silica
gel (0.7ꢀ12 cm), using EtOAc-hexane mixtures from 20% to
30% EtOAc, gave 51 [0.0112 g, 75%; 87% corrected for re-
covered 26 (0.0017 g)] as an oil that was a mixture of diaster-
eoisomers (13C NMR): FTIR (CH2Cl2, microscope) 3339, 3089,
3010, 2981, 2928, 2856, 1846, 1641, 1457 cm-1; 1H NMR (CDCl3,
400 MHz) δ1.28 (s, 2 H), 1.29-1.42 (m, 20 H), 1.48-1.59(m, 8H),
5.08 (dd, J = 10.8, 1.2 Hz, 2 H), 5.23 (dd, J = 17.4, 1.2 Hz,
2 H), 5.95 (dd, J = 17.4, 10.8 Hz, 2 H); 13C NMR (CDCl3,
100 MHz) δ 22.4 (t), 22.5 (t), 26.16 (t), 26.23 (t), 26.5 (t), 26.6 (t),
26.8 (t), 26.9 (t), 27.75 (t), 27.83 (t), 32.38 (t), 32.44 (t), 38.8 (t), 39.0
(t), 74.8 (s), 74.9 (s), 112.1 (t), 144.7 (d), 144.8 (d); exact mass m/z
calcd for C20H36NaO2 (M þ Na) 331.2608, found 331.2610.
[12]Paracyclophane (53)28. Grubbs I catalyst (0.0027 g,
0.0032 mmol) was added to a stirred solution of 51 (0.0100 g,
0.0324 mmol) in dry CH2Cl2 (3 mL) (N2 atmosphere). After
24 h, the reaction mixture was evaporated, and dry PhH (3 mL)
1-(2-Phenethyl)-4-[(2S,3S,4S,5R,6S)-tetrahydro-3,4,5,6-tet-
ramethoxypyran-2-yl]cyclohex-2-ene-1,4-diol (55). A solution of
54 (92.7 mg, 0.206 mmol) in CH2Cl2 (6 mL) was degassed for 30
min with a stream of Ar. Grubbs II catalyst8 (26.2 mg, 0.03
mmol) was added, and the Ar stream was continued for
15 min. The mixture was stirred and refluxed for 24 h under a
static pressure of Ar and then cooled and evaporated. Flash
chromatography of the residue over silica gel (1.5ꢀ13 cm), using
first Et2O and then EtOAc, gave 55 as a mixture of diastereoi-
somers [25.1 mg, 29% less polar diastereoisomer; 60.0 mg, 69%
more polar diastereoisomer (98% overall)]. The less polar dia-
1
stereoisomer (small impurity signals in the H and 13C NMR
spectra): FTIR (CHCl3, microscope) 3458, 3061, 3026, 2933,
2835, 2247, 1603, 1497, 1454 cm-1; 1H NMR (CDCl3, 500 MHz)
δ 1.52 (d, J=1.0 Hz, 1 H), 1.62 (s, 1 H), 1.71-2.01 (m, 4 H), 2.15
(t, J=13.0 Hz, 1 H), 2.28 (t, J=13.0 Hz, 1 H), 2.78-2.90 (m,
2 H), 3.25-3.28 (m, 1 H), 3.42 (t, J=9.2 Hz, 1 H), 3.51-3.53 (m,
4 H), 3.60-3.71 (m, 10 H), 4.90 (d, J=2.0 Hz, 1 H), 5.93 (s, 2 H),
7.25-7.30 (m, 3 H), 7.35-7.38 (m, 2 H); 13C NMR (CDCl3,
100 MHz) δ 29.2 (t), 30.1 (t), 31.4 (t), 44.3 (t), 55.8 (q), 59.2 (q),
60.3 (q), 61.1 (q), 69.5 (s), 70.5 (s), 73.7 (d), 80.6 (d), 82.1 (d), 84.5
(d), 97.6 (d), 126.0 (d), 128.6 (d), 128.7 (d), 131.0 (d), 135.2 (d),
142.6 (s); exact mass m/z calcd for C23H34NaO7 (M þ Na)
445.2197, found 445.2192.
The more polar diastereoisomer: FTIR (CHCl3, microscope)
3441, 3061, 3026, 2934, 2835, 2248, 1603, 1497, 1453 cm-1; 1H
NMR (CDCl3, 300 MHz) δ 1.74-2.07 (m, 7 H), 2.71-2.77 (m,
2 H), 3.16 (dd, J=3.6, 9.6 Hz, 1 H), 3.28-3.34 (m, 2 H), 3.40 (s,
3 H), 3.50-3.56 (m, 5 H), 3.59 (s, 3 H), 3.62 (s, 3 H), 4.78 (d, J=
3.6 Hz, 1 H), 5.81 (AB q, J = 10.3, ΔνAB = 7.4 Hz, 2 H),
7.15-7.20 (m, 3 H), 7.25-7.30 (m, 2 H); 13C NMR (CDCl3, 100
MHz) δ 30.1 (t), 30.4 (t), 32.7 (t), 42.6 (t), 55.6 (q), 59.2 (q), 60.3
(q), 61.1 (q), 70.5 (s), 71.1 (s), 73.9 (d), 80.5 (d), 82.0 (d), 84.7 (d),
97.5 (d), 126.0 (d), 128.6 (d), 128.7 (d), 131.1 (d), 135.9 (d), 142.7
(s); exact mass m/z calcd for C23H34NaO7 (M þ Na) 445.2197,
found 445.2195.
was added. TsOH H2O (0.0019 g, 0.0097 mmol) was added, and
3
the mixture was refluxed for 1 h, cooled, and partitioned be-
tween water and CH2Cl2. The aqueous phase was extracted with
CH2Cl2 and hexane, and the combined organic extracts were
dried (Na2SO4) and evaporated. Flash chromatography of the
residue over silica gel (1.4 ꢀ 6 cm), using EtOAc-petroleum
ether mixtures from 0% to 2% EtOAc, gave 53 (0.0066 g, 83%)
as an oil: FTIR (CH2Cl2, neat film microscope) 3006, 2926,
2855, 1898, 1510, 1460, 1444 cm-1; 1H NMR (CDCl3, 500 MHz)
δ 0.75-0.82 (m, 4 H), 0.93-1.00 (m, 4 H), 1.02-1.12 (m, 8 H),
1.55-1.62 (m, 4 H), 2.60-2.63 (m, 4 H), 7.08 (s, 4 H); 13C NMR
(CDCl3, 125 MHz) δ 25.4 (t), 26.6 (t), 27.4 (t), 27.5 (t), 29.8 (t),
35.2 (t), 128.8 (d), 140.0 (s); exact mass m/z calcd for C18H28
244.2191, found 244.2188.
Methyl (5R)-2,3,4-Tri-O-methyl-5-C-[4-(2-phenethyl)phenyl]-
r-D-gluco-pyranoside (56). (a) POCl3 (0.22 mL, 2.34 mmol) was
added dropwise to a stirred and cooled (0 °C) solution of the less
polar diastereoisomer of 55 (19.3 mg, 0.0457 mmol) in pyridine
(0.86 mL), and stirring was continued for 4 h. The ice bath was
left in place but not recharged, and stirring was continued for 7.5 h.
(28) Cram, D. J.; Allinger, N. L.; Steinberg, H. J. Am. Chem. Soc. 1954,
76, 6132–6141.
J. Org. Chem. Vol. 75, No. 23, 2010 8037

Ziffle et al.
JOCArticle
Water (0.5 mL) was added, and the mixture was extracted
with Et2O. The combined organic extracts were washed with
10% hydrochloric acid, saturated aqueous NaHCO3, water and
brine, dried (MgSO4), and evaporated. Flash chromatography
of the residue over silica gel (0.6 ꢀ8 cm), using 23% EtOAc-
hexanes, gave 56 (15 mg, 85%) as a thick oil: [R]20D 92.06 (c 1.22,
CHCl3); FTIR (CHCl3, microscope) 3060, 3027, 2980, 2931,
3.28-3.46 (m, 8 H), 3.47-3.74 (m, 22 H), 4.59-4.69 (m, 2 H),
4.79-4.83 (m, 2 H); 13C NMR (CDCl3, 125 MHz) δ 55.2 (q),
55.3 (q), 59.1 (q), 60.60 (q), 60.63 (q), 60.72 (q), 60.78 (q), 60.82
(q), 60.85 (q), 61.4 (q), 61.7 (q), 62.5 (q), 62.6 (q), 70.6 (d), 71.7
(d), 71.9 (d), 72.0 (d), 72.3 (d), 79.3 (d), 79.4 (d), 79.6 (d), 81.0 (d),
81.1 (d), 81.6 (d), 81.7 (d), 81.8 (d), 82.2 (s), 83.4 (d), 83.6 (d), 83.9
(s), 85.5 (s), 97.5 (d), 97.6 (d); exact mass m/z calcd for
C22H38NaO12 (M þ Na) 517.2255, found 517.2259.
1
2858, 2832, 1604, 1516, 1496, 1454 cm-1; H NMR (CDCl3,
(c) 1,4-Bis[(2R,3S,4S,5R,6S)-tetrahydro-3,4,5,6-tetramethox-
ypyran-2-yl]butane-1,4-diol (57c). Pd(OH)2-C (20% w/w, 23 mg)
was added to a solution of 57b (58.4 mg, 0.118 mmol) in MeOH
(1.5 mL), and the mixture was stirred under H2 (balloon) for 2 h and
then filtered through Celite, using EtOAc as a rinse. Evaporation of
the filtrate and flash chromatography of the residue over silica gel
(1.2ꢀ15 cm), using EtOAc and then MeOH-EtOAc (3:50), gave
57c (35.2 mg, 60%) as a white solid that was a mixture of dia-
stereoisomers (13C NMR): FTIR (CHCl3, microscope) 3472, 2935,
2835, 2248, 1445, 1379 cm-1; 1H NMR (CDCl3, 500 MHz) δ 1.50-
1.94 (m, 4 H), 2.38 (s, 1 H), 3.12-3.17 (m, 3 H), 3.26-3.31 (m, 2 H),
3.35-3.40 (m, 7 H), 3.46-3.53 (m, 9 H), 3.56-3.63 (m, 12 H), 3.80
(d, J=3 Hz, 2 H), 4.72-4.80 (m, 2 H); 13C NMR (CDCl3, 125
MHz) δ 29.1 (t), 30.5 (t), 32.0 (t), 55.2 (q), 55.3 (q), 58.9 (q), 59.0 (q),
60.2 (q), 60.7 (q), 60.8 (q), 69.2 (d), 69.4 (d), 71.1 (d), 71.6 (d), 72.2
(d), 72.5 (d), 73.2 (d), 79.5 (d), 81.7 (d), 82.0 (d), 82.6 (d), 83.6 (d),
83.8 (d), 97.3 (d), 97.6 (d); exact mass m/z calcd for C22H42NaO12
(M þ Na) 521.2568, found 521.2568.
400 MHz) δ 2.95 (s, 4 H), 3.06 (s, 3 H), 3.12 (dd, J=9.0, 9.8 Hz,
1 H), 3.37 (dd, J=3.8, 9.4 Hz, 1 H), 3.45 (s, 3 H), 3.60 (s, 3 H),
3.63 (t, J=9.2 Hz, 1 H), 3.67 (s, 3 H), 4.44 (d, J=9.6 Hz, 1 H),
4.92 (d, J=3.6 Hz, 1 H), 7.18-7.23 (m, 5 H), 7.26-7.31 (m, 2 H),
7.34-7.36 (m, 2 H); 13C NMR (CDCl3, 100 MHz) δ 37.9 (t), 38.1
(t), 55.6 (q), 59.4 (q), 60.6 (q), 61.3 (q), 72.9 (d), 82.1 (d), 83.5 (d),
86.0 (d), 98.1 (d), 126.2 (d), 127.9 (d), 128.6 (d), 128.7 (d), 128.8
(d), 136.7 (s), 141.9 (s), 142.1 (s); exact mass m/z calcd for C23-
H30NaO5 (M þ Na) 409.1985, found 409.1984.
(b) POCl3 (0.53 mL, 5.69 mmol) was added dropwise to a stirred
and cooled (0 °C) solution of the more polar diastereoisomer of 55
(47 mg, 0.11 mmol) in pyridine (2 mL), and stirring was continued
for 4 h. The ice bath was left in place but not recharged, and stirring
was continued for 7.5 h. Water (1 mL) was added, and the mixture
was extracted with Et2O. The combined organic extracts were
washed with 10% hydrochloric acid, saturated aqueous NaHCO3,
water, and brine, dried (MgSO4), and evaporated. Flash chroma-
tography of the residue over silica gel (1 ꢀ 8 cm), using 23%
EtOAc-hexanes, gave 56 (36.1 mg, 84%) as a thick oil.
(d) 1,4-Bis[(2S,3S,4S,5R,6S)tetrahydro-3,4,5,6-tetramethoxy-
pyran-2-yl]butane-1,4-dione (57d). DMSO (0.04 mL, 0.564 mmol)
in CH2Cl2 (0.5 mL) was added dropwise to a stirred and cooled
(-78 °C) solution of (COCl)2 (0.023 mL, 0.266 mmol) in CH2Cl2
(0.5 mL). After 15 min, a solution of 57c (50.0 mg, 0.10 mmol) in
CH2Cl2 (1.0 mL) was added dropwise and stirring at -78 °C was
continued for 35 min. Then Et3N (0.08 mL) was added dropwise,
and stirring was continued at -78 °C for 5 min. The cooling bath
was removed, stirringwas continued for 25min, andwater (2 mL)
was added. The organic layer was separated, dried (MgSO4), and
evaporated. Flash chromatography of the residue over silica gel
(1.2 ꢀ 15 cm), using 75% EtOAc-hexanes, gave 57d (47.6 mg,
96%) as a colorless oil: [R]D20 132.8 (c 1.32, CHCl3); FTIR (CHCl3,
3,6-Bis[(2S,3S,4S,5R,6S)-tetrahydro-3,4,5,6-tetramethoxypyran-
2-yl]octa-1,7-diene-3,6-diol (57). (a) Methyl 7,8-Dideoxy-2,3,4-
tri-O-methyl-r-D-gluco-oct-7-ynopyranoside (57a). A solution of
ethynylmagnesium bromide (0.5 M in THF, 15 mL, 7.5 mmol)
was added dropwise to a stirred and cooled (-78 °C) solution of
crude 2,3,4-tri-O-methyl-R-D-gluco-hexodialdo-1,5-pyranoside24
(540 mg, 2.31 mmol) in THF (20 mL) (Ar atmosphere). The cold
bath was left in place but not recharged, and stirring was continued
for 18 h. The yellow solution was then quenched with saturated
aqueous NH4Cl. The organic layer was separated, and the aqueous
layer was extracted with Et2O. The combined organic extracts were
dried (MgSO4) and evaporated. Flash chromatography of the
residue over silica gel (2.5ꢀ15 cm), using 50% EtOAc-hexanes,
gave 57a (304.8 mg, 51%) as an light yellow oil that was a mixture
of two diastereoisomers (13C NMR): FTIR (CHCl3, microscope)
3418, 3252, 2982, 2934, 2837, 2249, 2114, 1740, 1670, 1466, 1466
cm-1; 1H NMR (CDCl3, 500 MHz) δ 2.46-2.54 (m, 1 H), 2.65 (d,
J=10.5 Hz, 1 H), 3.17-3.26 (m, 1 H), 3.33 (dd, J=9.2, 9.7 Hz,
1 H), 3.42-3.44 (m, 3 H), 3.51-3.72 (m, 11 H), 4.56-4.67 (m,
1 H), 4.86-4.88 (m, 1 H); 13C NMR (CDCl3, 125 MHz) δ 55.1 (q),
55.3 (q), 59.1 (q), 60.6 (q), 60.8 (q), 60.9 (q), 61.3 (q), 62.4 (q), 71.8
(d), 71.9 (d), 73.1 (d), 74.8 (d), 79.3 (d), 81.0 (d), 81.8 (d), 82.7 (s),
83.4 (d), 83.6 (d), 97.55 (d), 97.59 (d); exact mass m/z calcd for
C12H20NaO6 (M þ Na) 283.1152, found 283.1152.
1
cast microscope) 2935, 2836, 1726, 1466, 1446 cm-1; H NMR
(CDCl3, 500 MHz) δ 2.79-2.87 (m, 2 H), 2.97-3.05 (m, 2 H),
3.21(dd, J=3.5, 9.5 Hz, 2 H), 3.28 (dd, J=8.5, 10.0 Hz, 2 H), 3.44
(s, 6 H), 3.51-3.56 (m, 14 H), 3.62 (s, 6 H), 4.06 (d, J=10.0 Hz, 2
H), 4.85 (d, J=4.0 Hz, 2 H); 13C NMR (CDCl3, 100 MHz) δ 34.2
(t), 55.9 (q), 59.4 (q), 60.8 (q), 61.2 (q), 74.1 (d), 81.0 (d), 81.5 (d),
83.8 (d), 98.2 (d), 205.4(s); exact mass m/z calcd for C22H38NaO12
(M þ Na) 517.2255, found 517.2265.
3,6-Bis[(2S,3S,4S,5R,6S)-tetrahydro-3,4,5,6-tetramethoxypyran-
2-yl]octa-1,7-diene-3,6-diol (57). Vinylmagnesium bromide (1.0 M in
THF, 1.1 mL, 1.10 mmol) was added dropwise to a stirred and
cooled (-78 °C) solution of 57d (55.7 mg, 0.11 mmol) in THF
(1 mL). The cooling bath was left in place but not recharged, and
stirring was continued for 16 h. The mixture was then quenched with
saturated aqueous NH4Cl (1 mL) and extracted with Et2O. The
combined organic extracts were dried (MgSO4) and evaporated.
Flash chromatography of the residue over silica gel (1.2ꢀ15 cm),
using 67% EtOAc-hexanes, gave 57 (63.0 mg, ca. 100%) as a
mixture of diastereoisomers (13C NMR) that contained some
impurities (1H NMR). The NMR spectra were too complicated to
be of diagnostic value: exact mass m/z calcd for C26H46NaO12
(M þ Na) 573.2881, found 573.2880.
(b) 1,4-Bis[(2R,3S,4S,5R,6S)-tetrahydro-3,4,5,6-tetramethoxy-
pyran-2-yl]but-2-yne-1,4-diol (57b). BuLi (2.5 M in hexanes,
0.7 mL, 1.75 mmol) was added dropwise to a stirred and cooled
(-78 °C) solution of 57a (228 mg, 0.877 mmol) in THF (8 mL).
After 1.5 h, freshly prepared crude methyl 2,3,4-tri-O-methyl-
R-D-glucohexodialdo-1,5-pyranoside24 (133.4 mg, 0.57 mmol)
in THF (1 mL) was added dropwise. The cooling bath was left in
place but not recharged, and stirring was continued for 40 h. The
mixture was quenched with saturated aqueous NH4Cl (8 mL)
and extracted with EtOAc. The combined organic extracts were
dried (MgSO4) and evaporated. Flash chromatography of the
residue over silica gel (2.5ꢀ15 cm), using 50% EtOAc-hexanes
and then MeOH-EtOAc (3:100), gave 57b (174 mg, 61% or
72%, based on recovered starting material) as a white solid that
was a mixture of diastereoisomers (13C NMR): FTIR (CHCl3,
microscope) 3433, 2934, 2836, 2249, 1466, 1446 cm-1; 1H NMR
(CDCl3, 500 MHz) δ 2.63-2.75 (m, 2 H), 3.13-3.26 (m, 2 H),
Acknowledgment. We thank the Natural Sciences and En-
gineering Research Council of Canada for financial support.
Supporting Information Available: General experimental
techniques and copies of NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
8038 J. Org. Chem. Vol. 75, No. 23, 2010