Synthesis and structure of hydroxyl acids of general structure 7,7-alkenyl/alkynyl-5-hydroxymethyl-6-oxabicyclo[3.2.1]octane-1-carboxylic acid

Article abstract of DOI:10.1021/jo052237p

The open-ended hollow tubular structure formed by inclusion of water molecules in the packing of the hydroxyl acid 1 (R₁ = CH ₂OH, R₂ = ethyl groups) led to the synthesis and structural study of their unsaturated analogues

Full text of DOI:10.1021/jo052237p

Synthesis and Structure of Hydroxyl Acids of General Structure
7,7-Alkenyl/alkynyl-5-hydroxymethyl-6-oxabicyclo[3.2.1]octane-
1-carboxylic Acid
Natalia Pe´rez-Herna´ndez,† Mart´ın Febles,‡ Cirilo Pe´rez,‡ Ricardo Pe´rez,†
Mat´ıas L. Rodr´ıguez,‡ Concepcio´n Foces-Foces,§ and Julio D. Mart´ın*,†
Instituto de InVestigaciones Qu´ımicas, CSIC, Americo Vespucio 49, 41092 SeVille, Spain, Instituto de
Bioorga´nica, UniVersidad de La Laguna, CSIC, Ctra Vieja de la Esperanza, 2, 38206 La Laguna,
Tenerife, Spain, and Instituto de Qu´ımica-F´ısica Rocasolano, CSIC, Serrano 119, E-28006 Madrid, Spain
jdmartin@iiq.csic.es
ReceiVed October 27, 2005
The open-ended hollow tubular structure formed by inclusion of water molecules in the packing of the
hydroxyl acid 1 (R1 ) CH2OH, R2 ) ethyl groups) led to the synthesis and structural study of their
unsaturated analogues. In this article we report on a general and practical large-scale synthesis of hydroxyl
acids that possess alkenyl and alkynyl appendages. Substitution of the ethyl groups in 1 with unsaturated
two-carbon appendages has a different effect on the molecular structure and on the hydrogen-bonding
pattern. No variation has been induced by substitution of only one ethyl group with a vinyl one, although
the substitution of both ethyl groups with vinyl or acetylene appendages has the greatest effect on the
molecular structure and results in different hydrogen-bonding motifs.
Introduction
solution, energy barriers between the different aggregations are
low or nonexistent and conversion from one to the other in either
direction is possible. At the moment of nucleation the energy
barrier grows, equilibrium is interrupted, and the process
continues irreversibly toward the building of the chosen
crystalline structure. The anhydrous/hydrated molecular ag-
gregate which crystallizes is the result of interconversions that
take place in solution, associating molecular structural factors
with the thermodynamic and kinetic principles ruling the
equilibrium.4,5 Thus, to the extent to which hydrated arrange-
ments increase their H-bonding (∆H decrease), their motions
will decrease (∆S decrease) and their relative intermolecular
distances are shortened (∆V decrease). The reverse also happens.
This means that hydration/dehydration is the cause/effect of the
An amphiphilic molecule would be found at the water/
nonpolar solvent interface forming ordered, anhydrous or
hydrated, H-bonding arrangements.1,2 In principle, all aggrega-
tion options can be present in the equilibrium. However, at any
given moment the nucleation of one of the aggregates progresses
irreversibly toward a three-dimensional crystalline packing.3 In
† Instituto de Investigaciones Qu´ımicas.
‡ Instituto de Bioorga´nica, Universidad de La Laguna.
§ Instituto de Qu´ımica-F´ısica Rocasolano.
(1) Recent studies of the ordering of amphiphilic molecules at liquid-
liquid interfaces: (a) Steel, W. H.; Warker, R. A. Nature 2003, 296-299.
(b) Tikhonov, A. N.; Schlossman, M. L. J. Phys. Chem. B 2003, 107, 3344-
3347. (c) Zhang, Z.; Mitrinovic, D. M.; Williams, S. M.; Huang, Z.;
Schlossman, M. L. J. Chem. Phys. 1999, 110, 7421-7423.
(2) Revision articles: (a) Pratt, L. R.; Pohorille, A. Chem. ReV. 2002,
102, 2671-2692. (b) Richmond, G. L. Chem. ReV. 2002, 102, 2693-2724.
(c) Kuzmenko, I.; Rapaport, A.; Kjaer, K.; Als-Nielsen, J.; Weissbuch, I.;
Lahav, M.; Leiserowitz, L. Chem. ReV. 2002, 102, 1659-1696.
(3) The central problem of nucleation, at the experimental and theoretical
levels, is the determination of the rate of nucleation as a function of the
controlling parameters: (a) Yau, S.-T.; Vekilov, P. G. J. Am. Chem. Soc.
2001, 123, 1080-1089. (b) Chin, D. N.; Palmore, G. T. R.; Whitesides, G.
M. J. Am. Chem. Soc. 1999, 121, 1, 2115-2122. (c) Talenquer, V.; Oxtoby,
D. W. J. Chem. Phys. 1998, 109, 223-227. (d) Oxtoby, D. W. Acc. Chem.
Res. 1998, 31, 91-97.
(4) (a) Williams, D. H.; O’Brien, D. P.; Bardsley, B. J. Am. Chem. Soc.
2001, 123, 737-738. (b) Searly, M. S.; Williams, D. H. J. Am. Chem. Soc.
1992, 114, 10690-10697.
(5) The hydration cost is more dependent on the number of water H
bonds than on their strength. Hence, the closer water is to an aqueous/
nonpolar solvent interface transition, the stronger the expected hydrophobic
assembly. For an experimental study that probes the weakness of water
H-bonding at H2O/CCl4 and H2O/hydrocarbon interfaces, see: Scatena, L.
F.; Brown, M. G.; Richmond, G. L. Science 2001, 292, 908-912.
10.1021/jo052237p CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/10/2006
J. Org. Chem. 2006, 71, 1139-1151
1139

Pe´rez-Herna´ndez et al.
FIGURE 1. (A) Schematic drawing for chain-folding at the water/nonpolar solvent interface of an amphiphilic molecule forming, in competence,
a hydrophilic pore or a hydrophobic pore. (B) Crystal structures obtained by crystallization at the water/carbon tetrachloride interface of hydroxy-
acid 1 (R1 ) CH2OH, R2 ) Et) (ref 8) and diacid 1 (R1 ) CO2H, R2 ) cyclopropyl) (ref 12). In the first case, the pore is refilled by water molecules
(hydrophilic). In the second case, the pore is refilled by carbon tetrachloride molecules (hydrophobic).
functional characteristics and structural specificities of each
molecule.6
crystallization from the H2O/CCl4 interface, the homologue 1
(R1 ) CO2H, R2 ) cyclopropyl) contains the appendix of
maximum volume allowed to give a hydrated structure in the
crystalline state. For this particular molecule, crystallization at
the H2O/CCl4 interface in an atmosphere of methane or ethane
showed that the displacement of water takes place with chain
folding and the creation of hydrophobic pores that are refilled,
in competition with water, by nonpolar molecules12 (Figure 1).
The model illustrates how the assembly of hydrophobic moieties
is enhanced by removal of water molecules from regions
between these groups.13
Research into the solid state of different homologues of the
family of hydroxyl acids7 of general structure 1 (R1 ) CH2-
OH, R2 ) alkyl)8 shows that all nucleation options are possible
and that there is a single member of the family 1 (R1 ) CH2-
OH, R2 ) ethyl) which is able to form, at the H2O/CCl4
interface, a cyclic two-dimensional organization which extends
in the third dimension to form channels in the solid state (Figure
1). The result is that 1 (R1 ) CH2OH, R2 ) ethyl) is the only
one observed which optimizes, among all possible options, the
packing to a channel-forming structure, where water molecules
are incorporated in the structure and inner surface of the pore.9
The study in solid state of different members of the diacid10
family 1 (R1 ) CO2H, R2 ) alkyl)11 shows that by slow
Background
The retrosynthetic analysis identified as route A in Scheme
1 has proven to be highly efficient in the synthesis of hydroxyl
acids of general structure 1a when R and R′ are alkyl
appendages. Thus, a large family of homologues of this general
structure has been prepared, and the crystal packing of each of
them has been studied in solid state.8 Each homologue was
synthesized using the carboxylic acid 5a as a common precursor
to all of them. Thus, following route A in the synthetic sense,
dialkyl compounds were synthesized by condensing the di-
lithium salt of 3-methylenecyclohexanecarboxylic acid with the
appropriate dialkyl ketone to give the hydroxyl acid 4a, which
was iodinated to the iodolactone 3a. Base treatment of 3a
produced the unstable epoxide 2a. The construction of the
desired oxolane ring was stereoselectively carried out by treating
crude epoxy alcohol 2a with TMSOTf or TIPSOTf and 2,6-
lutidine in CH3NO2 at 0 °C for 10-15 min. Brønsted acid-
catalyzed cyclizations afforded mixtures of 6-endo-tet and 5-exo-
tet compounds in some of the substrates studied.14 However,
for most of the epoxy alcohols studied with structure 2a,
(6) Revisions of general interest in the prediction and synthesis of
crystalline aggregates: (a) Gavezotti, A. Synlett 2002, 201-214. (b) Steiner,
T. Angew. Chem., Int. Ed. 2002, 41, 48-76. (c) Allen, F. H.; Motherwell,
W. D. S.; Raithby, P. R.; Shields, G.; Taylor, R. New J. Chem. 1995, 25-
34. (d) Desiraju, G. R. Angew. Chem., Int. Ed. 1995, 34, 2311-2327. (e)
Desiraju, G. R. Crystal Engineering. The Design of Organic Solids;
Elsevier: Amsterdam, The Netherlands, 1985.
(7) A revision of related models of bile acids, the most studied hydroxyl-
carboxylic acids ordering in the solid state: Miyata, M.; Sada, K. In
ComprehensiVe Supramolecular Chemistry; McNicol, D. D., Toda, F.,
Bishop, R., Eds.; Pergamon: Oxford, 1996; Vol. 6, pp 147-175.
(8) (a) Carrasco, H.; Foces-Foces, C.; Pe´rez, C.; Rodr´ıguez, M. L.; Mart´ın,
J. D. J. Am. Chem. Soc. 2001, 123, 11970-11981. (b) Pe´rez, C.; Esp´ınola,
C. G.; Foces-Foces, C.; Nu´nez-Coello, P.; Carrasco, H.; Mart´ın, J. D. Org.
Lett. 2000, 2, 1185-1188.
(9) Pe´rez-Herna´ndez, N.; Pe´rez, C.; Rodr´ıguez, M. L.; Foces-Foces, C.;
Tolstoy, P. M.; Limbach, H. H.; Morales, E. Q.; Pe´rez, R.; Mart´ın, J. D.
Bioorg. Med. Chem. 2004, 12, 1305-1314.
(10) Representative examples of dicarboxylic acid packing in solid state
are: (a) Moorthy, J. N.; Natarajan, R.; Mal, P.; Venugopalan, P. J. Am.
Chem Soc. 2002, 124, 6530-6531. (b) Thalladi, V. R.; Nusse, M.; Boese,
R. J. Am. Chem. Soc. 2002, 124, 6530-6531. (c) Kobayashi, K.; Shikahara,
T.; Horn, E.; Furukawa, N. Tetrahedron Lett. 2000, 41, 89-93. (d) Jetti,
R. K. R.; Xue, F.; Mak, T. C. W.; Nangia, A. Perkin Trans. 2 2000, 1223-
1232. (e) Holy, P.; Zavada, J.; Cisarova, I.; Podlaha, J. Angew. Chem., Int.
Ed. 1999, 38, 381-383.
(12) Febles, M.; Pe´rez, C.; Foces-Foces, C.; Rodr´ıguez, M. L.; Pe´rez-
Herna´ndez, N.; Morales, E. Q.; Mart´ın, J. D. Org. Lett. 2004, 6, 877-880.
(13) For a recent computer simulation study, see: ten Wolde, P. R.;
Chandler, D. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 6539-6543.
(11) Pe´rez, C.; Rodr´ıguez, M. L.; Foces-Foces, C., Pe´rez-Herna´ndez, N.;
Pe´rez, R.; Mart´ın, J. D. Org. Lett. 2003, 5, 641-644.
1140 J. Org. Chem., Vol. 71, No. 3, 2006

Hydroxyl Acids with Alkenyl and Alkynyl Appendages
SCHEME 1. Retrosynthetic Pathways: Routes A and B Planned for the Synthesis of Compounds Possessing Alkyl (Route A)
and Alkenyl or Alkynyl (Route B) Appendages
cyclizations to give 1a occur in a straightforward manner during
acidification with 3% HCl of the basic aqueous solution
containing crude 2a. This method allows direct isolation of 1a
by shaking with an organic solvent, dispensing with the isolation
of the epoxy alcohol intermediate. Following this methodology,
more than 20 homologues of general structure 1a were
synthesized, starting from 5a in three steps in a 60-80% overall
yield.
Our aim in this work is to synthesize molecules that have
functionalized R and R′ in different oxidation states. Our purpose
is to study solid-state porous structures that can be formed by
the incorporation of water molecules in the crystalline structures.
From the synthetic point of view, the preparation of these
molecules is a complex problem, particularly those that are the
smallest in size, in which oxygen atoms are located at R and R′
appendages of two or three carbon atoms. The molecules would
be highly oxidized rendering it difficult for each of the
oxygenated functions existing therein to be performed inde-
pendently. Moreover, the protection/deprotection would be
difficult to control in each of the functions since their close
proximity could lead to intramolecular participation. Our
objective is to synthesize compounds that possess alkenyl and
alkynyl appendages, leaving the interconversion of these
unsaturated carbon functions into oxygenated functions as the
final stage of the synthesis.
it in a retrosynthetic expression as route B and analyze it jointly
with route A in Scheme 1.
First, the condensation between carboxylic acid and the
corresponding ketone is no longer a good synthetic reaction
when the carbonylic function of the ketone becomes conju-
gated to double and triple bonds. The disconnection cannot
be made between the C1 that sustains the carboxylic function
and the carbinolic C1′. The structural simplification would have
to be carried out between the carbinolic C1′ and the R and R′
appendages, as shown in structure 4b. This approach leads
to esters of diacid 3-methylenecyclohexanedicarboxylic acid
5b as the common starting material of the synthesis. It is to
be expected that the carbonyl group resulting from mono-
alkenylation or monoalkynylation of one of the ester groups is
more electrophilic than the carbonyl of the carboxylate not
undergoing attack in this first reaction, to give hydroxyl-esters
of the 4b type. The R and R′ groups could thus be introduced
sequentially.
Second, hydrolysis of the ester 4b to lead the synthesis
through the iodolactone, in homology with route A, must not
be an efficient reaction. Hydrolysis of 4b, independently of the
acid or medium base in which it is performed, should bring
about favorable fragmentation C1-C1′ giving place to the
dialkenyl or dialkynyl-ketone and 3-methylenecyclohexanecar-
boxylic acid. The synthetic route, in this case, cannot be led
through the iodolactone. The solution to this problem may be
the generation of intermediate oxolane compounds by means
of iodination-induced cyclizations (3b) or epoxidation (3′b)
followed by cyclization of the epoxide to give 2b. The functional
interconversion -CH2I/-CH2OH (3b f 2b) would be the
common nexus of both strategies and lead by hydrolysis of the
ester to the required hydroxyl acid 1b.
Introduction of oxygenation at the ketone or hydroxyl
oxidation state from alkenes and alkynes is a useful way to
introduce complex functionality to end the synthesis. The use
of C-C unsaturation for the installation of oxygenation can
reduce the reliance on protecting-group manipulation, thereby
improving synthetic efficiency.
Synthetic Rationale. The synthesis of structures when R and
R′ are alkenyl or alkynyl appendages requires a profound
revision of the general strategy utilized until now. We describe
A third and very important consideration is that compounds
1b where R′ and R′′ are alkenyl or alkynyl radicals are not the
final products of the synthesis. These functions have to be
interconverted into diverse oxygenated functions and therefore
have to be prepared on a gram scale. That is, the synthetic route
has to be operative on a macroscale in order to afford a final
(14) As an example where a mixture of 6-endo-tet and 5-exo-tet
cyclyzation compounds was achieved, see: Rodr´ıguez, M. L.; Febles, M.;
Pe´rez, C.; Pe´rez-Herna´ndez, N.; Mart´ın, J. D.; Foces-Foces, C. Acta.
Crystallogr., Sect. C 2005, 61, 138-142.
J. Org. Chem, Vol. 71, No. 3, 2006 1141

Pe´rez-Herna´ndez et al.
SCHEME 4. Synthesis of Compound 6 from 13ba
SCHEME 2. Chemical Structures of Compounds Prepared
in This Studya
a Details of the chemical synthesis are described in the text.
SCHEME 3. Synthesis of Compounds 10a-13a and
10b-13ba
a Conditions: (a) CH3P+ Ph3Br- (1.4 equiv), t-BuOK (1.4 equiv), toluene,
0 °C, 2 h (78%); (b) Me3SiCtCH (2.0 equiv), n-BuLi (2.0 equiv), -78 °C
to -15 °C, 30 min, 0 °C, 3 h, THF (86.3%); (c) MCPBA (1.2 equiv),
CH2Cl2, 25 °C, 1 h, (96%); (d) PTSA (cat.), CH2Cl2, -78 °C, 30 min, -15
°C, 30 min f 16 (35.8%) + 17 (7.1%) + 18 (52.9%); (e) saturated aqueous
Ba(OH)2, 50 °C, 24 h (100%); (f) MsCl (3.0 equiv), Et3N (10.0 equiv),
CH2Cl2, -40 °C, 2 h; (g) K2CO3 (4.0 equiv), MeOH, 25 °C, 30 min (99%,
two steps); (h) H2, Lindlar catalyst, EtOAc, 2 h (98%).
Although several strategies have been successfully employed
for the cyclization of active methine compounds bearing a
4-alkynyl group to functionalized methylenecyclopentanes
(Conia-ene reaction16), the high temperature needed severely
limits its synthetic utility.17 Transition metal-catalyzed versions
of this reaction18 operate at lower temperatures, although they
require enolate generation,19 strong acid,20 or photochemical
activation.21 A catalytic version of the Conia-ene reaction that
proceeds at 30 °C in the presence of copper (I) iodide19c was
the one selected for our synthetic purposes. We investigate the
gram-scale copper-catalyzed cyclization of compounds 10a and
10b. These compounds were stirred in THF under Ar at 48-
50 °C (external oil-bath temperature) in the presence of t-BuOK
(0.3 equiv) and CuI (0.2 equiv) for 12 h. Under these conditions,
methylenecyclopentanes 11a and 11b were produced in 63.2%
and 80% yields, respectively. Epoxides 12a, as a 1:1 mixture
a Conditions: (a) NaH (0.9 equiv), KI (0.4 equiv), THF/DMF (1:1),
reflux, 24 h, 10a, (84.2%), 10b (97%); (b) CuI (0.2 equiv), tert-BuOK (0.3
equiv), THF, 48-50 °C, 12 h, 11a (63.2%), 11b (80%); (c) MCPBA (1.2
equiv), CH2Cl2, 25 °C, 3 h, 12a (97.4%), 12b (93.4%); (d) LiI (0.2 equiv),
CH2Cl2, 25 °C, 4 h, 13a (78%), 13b (79.4%).
amount sufficient to prepare an extensive family of oxygenated
homologues for their study in the solid state.
Results and Discussion
To exemplify the initial concepts involved in these syntheses,
we detail here the construction of two homologues , one that
possesses two identical acetylene substituents (6), and another
that includes ethyl/vinyl appendages (7) (Scheme 2). Our initial
target became the independent synthesis of precursors 8 and 9,
respectively, in gram quantities.
I. Synthesis of Intermediates 13a and 13b. The function-
alized cyclohexanones 13a and 13b were synthesized following
the same protocol (Scheme 3). The synthesis of active methine
compounds bearing a 4-alkynyl group used in our study,
compounds 10a and 10b, were easily prepared in good yields
by alkylations of enolates of methyl propionyl acetate and
diethylmalonate, respectively, with 5-chloro-1-pentyne15 (Scheme
3). The enolates were formed by addition of NaH (0.9 equiv),
and the reaction was conducted under Ar by addition of KI (0.4
equiv) and refluxing for 24 h. A 1/1 mixture of dry THF/DMF
was used as solvent.
(16) For a review see: Conia, J. M.; Le Perchec, P. Synthesis 1975, 1-19.
(17) For recent publications, see: (a) Kennedy-Smith, J. J.; Staben, S.
T.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 4526-4527. (b) Pei, T.;
Widenhoefer, R. A. J. Am. Chem. Soc. 2001, 123, 11290-11291. (c) Qian,
H.; Widenhoefer, R. A. J. Am. Chem. Soc. 2003, 125, 2056-2057. (d) Gao,
Q.; Zheng, B.-F.; Li, J.-H.; Yang, D. Org. Lett. 2005, 7, 2185-2188.
(18) For a review of transition metal-catalyzed cycloisommerizations,
see: (a) Lloyd-Jones, G. C. Org. Biomol. Chem. 2003, 1, 215-236. (b)
Trost, B. M.; Krische, M. J. Synlett 1998, 1-16.
(19) Pd-catalyzed: (a) Balme, G.; Bouyssi, D.; Faure, R.; Gore, J.; van
Hemelryck, B. Tetrahedron 1992, 48, 3891-3902. Mo-catalyzed: (b)
McDonald, F. E.: Olson, T. C. Tetrahedron Lett. 1997, 38, 7691-7692.
Cu-catalyzed: (c) Bouyssi, D.; Monteiro, N.; Balme, G. Tetrahedron Lett.
1999, 40, 1297-1300. Ti-catalyzed: (d) Kitagawa, O.; Suzuki, T.; Inoue,
T.; Watanabe, Y.; Taguchi, T. J. Org. Chem. 1998, 63, 9470-9475.
(20) Hg/H+-catalyzed: Boaventura, M. A.; Drouin, J.; Conia, J. M.
Synthesis 1983, 801-804.
(21) Co/hν-catalyzed: (a) Cruciani, P.; Stammler, R.; Aubert, C.;
Malacria, M. J. Org. Chem. 1996, 61, 2699-2708. (b) Cruciani, P.; Aubert,
C.; Malacria, M. Tetrahedron Lett. 1994, 35, 6677-6680. (c) Renaud, J.-
L.; Aubert, C.; Malacria, M. Tetrahedron 1999, 55, 5113-5128.
(15) Fournet, G.; Balme, G.; Gore, J. Tetrahedron 1991, 47, 6293-6304.
1142 J. Org. Chem., Vol. 71, No. 3, 2006

Hydroxyl Acids with Alkenyl and Alkynyl Appendages
SCHEME 5. Pathway for the Epoxide Inversion to Give Compound 6
of diastereomers, and 12b required for the next reaction were
readily prepared in excellent yields by epoxidation (MCPBA,
CH2Cl2, 25 °C, 3 h) of methylenecyclopentanes 11a and 11b,
respectively.
be attacked preferentially at the ester group by the second
equivalent of acetylide.24 Thus, compound 14 was obtained in
86% yield by treatment of compound 8 with 2.0 equiv of Me3-
SiCtCH/n-BuLi in THF. The requisite epoxide 15a with
favorable stereochemistry for intramolecular attack of the
hydroxyl group could not be obtained in pure form. Epoxidation
with MCPBA gave in 96% yield an inseparable mixture of
epoxides 15a/15b in a 2:3 ratio, the less desirable isomer 15b
being the major component of the mixture. Even though the
intramolecular hydroxyl/epoxide cyclization of the epoxide
mixture was carried out at -78 °C in CH2Cl2 as solvent and a
catalytic amount of hydrated p-toluenesulfonic acid was used,
this reaction gave the required cyclized compound 16 (35.7%),
a small amount of the allylic alcohol derivative 17 (7.7%), and
triol 18 (52.9%). Longer reaction times, higher temperatures,
larger amounts of catalyst, or an anhydrous catalyst, or the use
of other acids reduced the yields of 16 and 18 in favor of 17.
Triol 18 was in turn converted to the required epoxide 15a by
selective mesylation of the primary hydroxyl group, which was
performed at -40 °C. Crude 15a was exposed to hydrochloric
acid during the extraction procedure to yield cyclized 20 as a
mixture of methyl/ethyl esters (99% yield over two steps). A
detailed study of the hydroxyl-epoxide intramolecular cyclization
is outlined in Scheme 5, where the entire process including the
interconversion of epoxides 15a/15b is outlined in more detail.
Since in cycloalkene 14 the bulkier dialkynyl substituent
preferentially adopted an equatorial position, the mixture of
epoxides 15a and 15b was thus enriched in the less interesting
epimer 15b, which was hydrated in the acid catalysis to give
the triol 18. However, inversion of configuration at C3 in
epoxide 15b to give 15a via the triol 18 not only supported the
stereochemical assignment for the C3 carbinol in 18, but also
provided a facile preparative route to overcome the unfavorable
epoxidation diastereoselectivity. Although the synthetic sequence
increased by two steps, the yield and stereoselectivity of epoxide
inversion were practically quantitative. Thus, this hydroxyla-
tion-inversion protocol represented a reliable and useful method
for the synthesis of compound 6. Esters 16 and 20 were treated
with saturated aqueous Ba(OH)2 to give the target hydroxyl acid
6 in pure form. Chromatographic purification was not required
Recently, it has been published22 that a variety of oxaspiro-
heptanes of general structure 12 can easily be transformed in
good to excellent yields into cyclohexanones 13 by treatment
with lithium iodide in dichloromethane. We decided to research
the macroscale synthetic application of this reaction. We found
that gram quantities of epoxides 12a and 12b can rearrange into
the enlarged cyclohexanones 13a and 13b in isolated compound
yields of 78% and 79.4%, respectively. The reaction conditions
used were the following: addition of 0.2 equiv of LiI to the
corresponding solution of 12a or 12b, in dichloromethane, at
25 °C. After 3 h under Ar, the reaction was completed in both
cases. These mild conditions allow the preparation of 13a and
13b as the only isolable compounds. No decarboxylative
reactions were observed in any case. In summary, compounds
13a and 13b were synthesized, using low-cost materials, in four
steps and in multigram amounts, in 40% and 57% overall yields,
respectively.
II. Synthesis of Compound 6. II.a. Epoxide-Induced
Intramolecular Cyclization Approach. We have accomplished
the synthesis of the target molecule 6 by intramolecular attack
of hydroxyl groups on epoxides to construct the oxolane ring
stereoselectively. The synthetic sequence is outlined in Scheme
4.
To carry out the synthesis starting from ketone 13b, this
compound was methylenated using either Lombardo-Takai23
or Wittig conditions to give 8. Whereas the Lombardo-Takai
olefination proceeded cleanly and without detectable unwanted
reactions, although requiring a large excess of reagent, which
made workup and isolation of 8 difficult, Wittig olefination was
trouble-free especially when large amounts of compound 8 were
required. It was expected that double alkynylation of diester 8
would proceed smoothly to the formation of the dialkynyl
derivative 14. The keto/ester intermediate in the reaction
contains a highly electrophilic ketone and, in competition, should
(22) Bouyssi, D.; Cavicchioli, M.; Large, S.; Monteiro, N.; Balme, G.
Synlett 2000, 749-751.
(23) (a) Lombardo, L. Tetrahedron Lett. 1982, 23, 4293-4296. (b)
Oshima, K.; Takai, K.; Nazaki, H. Tetrahedron Lett. 1978, 35, 2417-2420.
(24) For a recent reference, see: Jiang, B.; Chen, Z.; Tang, X. Org. Lett.
2002, 4, 3451-3453.
J. Org. Chem, Vol. 71, No. 3, 2006 1143

Pe´rez-Herna´ndez et al.
TABLE 1. Base Hydrolysis of Compounds 8, 14, and 25
SCHEME 6. Alternative Synthesis of 6a
a Conditions: saturated aqueous Ba(OH)2, 50 °C, 24 h.
SCHEME 7. Alternative Sequence for 6a
a Conditions: (a) DIPA, I2, CH2Cl2; (b) THF; KOH.
since the compound is highly crystalline and was directly
purified by crystallization from CCl4/Et2O or MeOH. Partial
hydrogenation of 6 using Lindlar catalyst gave the divinyl
derivative 21.
In summary, the compound 6 was synthesized from ketone
13b on a gram scale, following the epoxide sequence described
in Scheme 4. The overall yield was 64% in eight steps, including
epoxide interconversion.
II.b. Iodine-Induced Cyclization Approach. An alternative
synthesis of compound 6 is described in the Scheme 6. An
attempt was made to prepare the hydroxyl acid 22 by base
hydrolysis of the hydroxyl ester 14. It was expected that,
following the synthetic sequence outlined in the Scheme 6 and,
in consonance with previous results,8 treatment of the diiso-
propylamine salt of 22 with iodine in CH2Cl2 should give
iodolactone 23. Compound 23 by further reaction with aqueous
KOH would produce, via epoxide 24, the required target
molecule 6. This sequence reduces the number of synthetic steps.
However, all attempts to isolate 22 by base hydrolysis of 14
proved unsuccessful. Table 1 includes base hydrolysis results,
in mild conditions, of some intermediates prepared in this work.
No decarboxylative reactions were observed; however, com-
pound 14 is fragmented to give the corresponding dialkynyl
ketone and 3-methylenecyclohexanecarboxylic acid (28) in
almost quantitative yield. Although these results preclude
application of Scheme 6 as a valid approach to the synthesis of
compound 6, they provides an explanation for the unfavorable
preparation of 22 via the reverse reaction, that is, the direct
condensation of the dilithium salt of 28 with a disilylated 1,4-
pentadiyne-3-ketone derivative. In fact, in our hands, this
reaction failed for any related coupling using R,â-unsaturated
ketones.
a Conditions: (a) I2 (1.5 equiv), NaHCO3, CH2Cl2, 25 ° C, 3 h, 29 (72%),
30 (0.6%); (b) saturated aqueous Ba(OH)2, 50 °C, 48 h, 31 (41.5%), 32
(55%); (c) KO2 (4.5 equiv), 18-crown-6-ether (0.5 equiv), DMSO, 25 °C,
2 h, (10%); (d) saturated aqueous Ba(OH)2, 50 °C, 12 h (100%).
of the reaction was increased to 80-90 °C. Under these latter
conditions acid 32 was the only compound isolated.
With the available large amount of 29, we attempted to find
mild processes to replace the iodine atom by oxygen, using
several of the methods developed over the years as nucleophilic
sources of oxygen functionalities.25 Unexpectedly, when 29 was
treated with peracids,25c-e or utilizing combinations of phase-
transfer reagents, using polar aprotic solvents and water to
dissolve and enhance the nucleophilicity of oxygenated anions,25b
no I/OX exchange products were observed. Instead, no reaction
took place or, after long treatments, nonstudied mixtures of
compounds that retain the iodine atom were obtained. In
contrast, effective exchange was achieved to give 20, by using
a large excess of powdered potassium superoxide and 18-crown-
6-ether in dry DMSO under argon at room temperature, followed
(25) Halogen/hydroxyl interchange induced by hydroxide: (a) March,
J. AdVanced Organic Chemistry, 4th ed.; John Wiley & Sons: New York,
1992; p 370. (b) Hutchins, R. D.; Taffer, I. M. J. Org. Chem. 1983, 48,
1360-1362. Peracids: (c) Reich, H. J.; Peake, S. L. J. Am. Chem. Soc.
1978, 100, 4888-4889. (d) McDonald, T. L.; Narasimhan, N.; Burka, L.
T. J. Am. Chem. Soc. 1980, 102, 7760-7765. (e) Davidson, R. L.; Kropp,
P. J. J. Org. Chem. 1982, 47, 1904-1909. Superoxide: (f) Corey, E. J.;
Nicolaou, K. C.; Shibasaki, M.; Machida, Y.; Shiner, C. S. Tetrahedron
Lett. 1975, 3183-3186. (g) San Filippo, J., Jr.; Chern, C.-L.; Valentine, J.
S. J. Org. Chem. 1975, 40, 1679-1680. (h) Johnson, R. A.; Nidy, E. G. J.
Org. Chem. 1975, 40, 1680-1681. (i) Corey, E. J.; Nicolaou, K. C.;
Shibasaki, M. J. Chem. Soc., Chem. Commun. 1975, 658-659.
An alternative reaction sequence is outlined in Scheme 7.
Treatment of compound 14 with iodine in CH2Cl2 in the
presence of NaHCO3 yielded the iodo-ether 29. Reaction of 29
with aqueous saturated solution of Ba(OH)2 gave, after 48 h at
50 °C, a clean mixture of compounds 31 and 32. No I/OH
exchange was observed, even when the reaction was allowed
to stand at 50 °C for a week or more, or when the temperature
1144 J. Org. Chem., Vol. 71, No. 3, 2006

Hydroxyl Acids with Alkenyl and Alkynyl Appendages
SCHEME 8. Addition of 2.2 Equiv of Vinylmagnesium
Bromide to Diester 8
required diastereomers 39-(1R*,5R*,7S*) and 7-(1R*,5R*,7S*)
were isolated by column chromatography and purified by
fractional crystallization. The structure and stereochemistry of
both compounds were determined by spectroscopic data in
combination with X-ray analysis. Our interest in the synthesis
of the diastereomer 7-(1R*,5R*,7S*) is motivated by the
expectation that the exchange of the vinyl appendage to give
oxygenated functions should occur without interference of the
carboxylic acid. The vinyl/hydroxyl or carbonyl conversion of
the non depicted diastereomer 7-(1R*,5R*,7R*) should produce
a highly stabilized lactone or hemilactal, respectively, which
precludes the formation of the hydroxyl acid H-bonding pattern
in crystalline state, one of the main purposes of this synthesis.
by a cautious addition of saturated aqueous sodium chloride.25f-i
Compound 20 was quantitatively hydrolyzed to the hydroxyl
acid 6 by further treatment with saturated aqueous Ba(OH)2
solution. Unfortunately, conversion of 29 or 31 to compound
20 is a slow reaction, and polymerization of the alkynyl moieties
occurs, which is a resource-wasteful competitive reaction and
has a deleterious effect on the overall yield. Caution: Potassium
superoxide reacts rapidly with water, producing peroxide,
hydroxide, and oxygen.26 In our experiments, excessive contact
with atmospheric moisture was avoided by quickly covering
the KO2 powder with dry solvent. More rigorous anhydrous
conditions could be attained in a drybox. In any case, special
care should be taken to avoid reaction of large amounts of KO2
with water in the presence of organic materials,27 this being a
strong limitation of this reaction for our large-scale synthetic
purposes.28
III. Synthesis of Compound 7 and Related Compounds.
III.a. Iodine-Induced Cyclization Approach. Double addition
of vinylmagnesium bromide to diester 8 gave the γ,δ-unsatur-
ated ketone 33 as the major component of the mixture.
Unavoidable Michael addition occurs in preference to carbonyl
addition over the first formed R,â-unsaturated ketone (Scheme
8).
However, synthesis of compound 7 possessing a vinyl
appendage was successfully achieved starting from diketone 13a
(Scheme 9). Protection of the C3-keto group in 13a (98%),
followed by addition of vinylmagnesium bromide and subse-
quent hydrolysis of the ketal, gave the vinyl carbinol 36 (58%,
two steps) as a 1:1 mixture of diastereomers. All attempts to
prepare the methylene derivative 37 by Wittig or related
olefination methods from 36 were unsuccessful. Instead, frag-
mentation occurred to give the methyl ester of 3-methylenecy-
clohexanecarboxylic acid as the only isolable compound.
Attempts to prepare 37 from 36 met with complete failure under
a wide variety of conditions, clearly because of the great ease
of retroaldol cleavage of the same carbon-carbon bond that
was involved in the conversion of 14 to the undesired product
28. However, compound 37 could be easily prepared by direct
Wittig olefination of diketone 13a to give 9 (44%), followed
by vinylation of the remaining ketone to yield 37 (74%) as an
inseparable 1:1 mixture of diastereomers.
In summary, in this preliminary study compound 7 was
prepared from diketone 13a in four steps. Further application
of this methodology to an improved synthesis of 7 and other
homologues for studies in solid state is currently underway in
our laboratory.
III.b. Bis-epoxide Cyclization Approach. We outline here
our studies on the synthesis of bis-epoxides 41 starting from
diene 40 and their possible application in the synthesis of our
target molecule 7 including, instead of a vinyl, a hydroxymethyl
appendage (42) (Scheme 10). Diene 40 was prepared from the
corresponding diketone 13a by Wittig reaction. Compound 40
is highly volatile, which is an added problem to its isolation
(see the Experimental Section) and the main reason for the low
yield, 46% in the best case. Treatment of diene 40 with a CH2-
Cl2 solution of MCPBA (2.5 equiv, 25 °C, 3 h) resulted in a
smooth sequential epoxidation of the more electrophilic C3-
methylene (first) and the C1′-methylene (second) in 40, leading
to a 1:9 mixture of the diastereomeric bis-epoxides 41a-
(1R*,3S*,1′S*)/41b-(1S*,3S*,1′S*), 41c-(1S*,3R*,1′S*), 41d-
(1R*,3R*,1′S*), and the already cyclized benzoate 43, in a
combined yield of 58.2% (Scheme 11). Diastereomer 41a could
be separated from the mixture 41b-d by chromatography and,
kept in a refrigerator, was stable for long periods. Benzoate 43
was isolated as the more polar component of the epoxidation
mixture.
The stereochemical structure of the benzoate 43 was estab-
lished by spectroscopic data in combination with an X-ray
analysis and is assumed to result from a SN2 cyclization of the
bis-epoxide 41a during the epoxidation process.29 Thus, a longer
epoxidation time of diene 40 (20h) under the conditions above-
described gave the inseparable mixture of bis-epoxides 41b-d
and benzoate 43 in a 4:3 molar ratio. Only a trace amount of
diastereomer 41a was isolated under these conditions. Further-
more, base hydrolysis of ester functions in 43, saturated aqueous
Ba(OH)2, 50 °C, 12 h, gave the lactone 44, which was shown
to be identical in all respects to the cyclization product achieved
by treatment of bis-epoxide 41a in 20% aqueous THF with TFA
(cat.) (0 °C, 30 min) in 52% yield. A hydroxylated homologue
(45) of lactone 44 was prepared by condensation of the dilithium
salt of 3-methylenecyclohexanecarboxylic acid with 2,2-dimeth-
yl-1,3-dioxan-5-ene following the iodolactone sequence depicted
in Scheme 1 as route A.14 In contrast, treatment of the mixture
of bis-epoxides 41b-d with TFA under the same conditions as
described above (0 °C, 15 min) was less selective, no identifiable
cyclization products being formed. Acetylation of the reaction
Iodine-induced cyclization of the mixture 37 gave the iodo-
ethers 38a and 38b (72%). Treatment of the 38a,b mixture with
potassium superoxide (6.0 equiv), 18-crown-6-ether (0.5 equiv)
in DMSO (25 °C, 8 h) gave a mixture of acids from which the
(26) Dietz, R.; Forno, A. E. J.; Larcombe, B. E.; Peover, M. E. J. Chem.
Soc. B 1970, 816-820.
(27) Precautions similar to those used with hydrogen peroxide are
recommended: Kirk-Othmer Encyclopedia of Chemical Technology, 2nd
ed.; Wiley: New York, 1967; Vol. 14, pp 748-749, 762-764.
(28) Peroxides and hydroperoxides can be visualized on silica gel TLC
plates by spraying with a freshly prepared (remains effective for about 1
day) solution of ammonium thiocyanate (0.625 g), concentrated sulphuric
acid (0.125 mL), and ferrous ammonium sulfate (0.875 g) in water (12.5
mL). With this spray, peroxidic materials give a rust-red-colored spot: Mair,
R. D.; Hall, R. T. In Organic Peroxides; Swern, D., Ed.; Wiley-
Interscience: New York, 1971; Vol. II, pp 553-560.
(29) Chlorobenzoic acid byproducts cause acid cyclization specifically
on the bis-epoxide 41a. Buffering the oxidation with NaHCO3 clearly
eliminates this cyclization with concomitant increase in the yield of
compound 41a (see the Experimental Section).
J. Org. Chem, Vol. 71, No. 3, 2006 1145

Pe´rez-Herna´ndez et al.
SCHEME 9. Synthesis of Compound 7 from 13aa
a Conditions: (a) (CH2OH)2 (1.5 equiv), CSA cat., benzene, reflux, 4 h (90%); (b) vinylmagnesium bromide (1.5 equiv), Et2O, 0 °C, 1 h (74%); (c) 5%
HCl (aqueous solution), THF, 25 ° C, 24 h (78.3%); (d) CH3P+ Ph3Br- (1.4 equiv), tert-BuOK (1.4 equiv), toluene, 0 °C, 2 h (43%); (e) I2 (1.5 equiv),
NaHCO3, CH2Cl2, 25 °C, 12 h (72%); (f) KO2 (6.0 equiv), 18-crown-6-ether (0.6 equiv), DMSO, 25 ° C, 8 h, column chromatography, 39 (24%), 7 (13%).
SCHEME 10. Retrosynthetic Pathway Planned for the
Synthesis of Compounds Possessing Hydroxymethyl
Appendages via Bis-epoxide Cyclization
SCHEME 11. Bis-epoxide Cyclization Productsa
mixture gave the hydrated monoepoxide 47 (43% yield, two
steps). The structure and stereochemistry of 47 were established
by an X-ray analysis and are assumed to result from SN2
hydration of the C3-methylene epoxide in 41d to give diol 46,
followed by acetylation of the primary hydroxymethyl alcohol
to yield 47. Base treatment of 47 with a saturated aqueous Ba-
(OH2) solution (50 °C, 48 h) gave lactone 48 in 38% yield. For
some reason, cyclization of 41b to give 42, similarly to 41a f
43 conversion, was not observed, nor can we be sure that 41b
is a true component of the bis-epoxide mixture. However, this
mixture contains at least three components that we assume are
diastereomers 41b-d.
In view of these results, we conclude here our attempts to
achieve hydroxyl acid homologues possessing oxygenated
appendages via cyclization of bis-epoxide intermediates. Al-
though some of the cyclization products proved promising,
highly stable γ-lactones is always formed, which constitutes a
considerable handicap for a rapid synthesis of the required
compounds.
IV. X-ray Crystallography. A common feature of the crystal
analysis is that all compounds crystallize as anhydrous, and the
O-H‚‚‚O hydrogen bonds are responsible for the supramolecu-
lar assembly of the molecules. The molecular structure and
supramolecular arrangement of compounds 6, 7, and 21 are
represented in Figures 2-4. The main distinguishing structural
features between compounds 6, 7, and 21 lie in the conformation
of the hydroxyl group and in the hydrogen-bonding network
(Figures 2-4). At the supramolecular level, the hydroxyl group
a Conditions: (a) Chlorobenzoic acid (byproduct in the epoxidation
reaction), CH2Cl2, 20 h; (b) (i) 20% aqueous THF, TFA cat., 0 °C, 15-30
min, (ii) Ac2O (5.3 mmol), DMAP cat., Et3N (4.0 mmol), CH2Cl2, 25 °C,
2 h, 44 (acetate) (52%, two steps), 47 (43%); (c) (i) aqueous saturated
Ba(OH)2, 50 °C, 24 h, (ii) Ac2O (5.3 mmol) DMAP cat., Et3N (4.0 equiv),
CH2Cl2, 25 ° C, 2 h, 44 (acetate) (70%, two steps); (d) aqueous saturated
Ba(OH)2, 50 °C, 48 h, 48 (38%).
acts only as donor in 6 while in 7 and 21 it acts as both donor
and acceptor of hydrogen bonds, resulting in two types of one-
dimensional heterochiral ribbons (1D) in 6 and 7 and in sheets
in 21 (2D). In the crystal structure of 6, gauche conformation,
the chain is formed by centrosymmetric carboxylic dimers
connected by pairs of hydroxyl-to-ether contacts in an alternative
tail-to-tail and head-to-head manner (Figure 2). It is noteworthy
1146 J. Org. Chem., Vol. 71, No. 3, 2006

Hydroxyl Acids with Alkenyl and Alkynyl Appendages
FIGURE 2. Molecular and secondary structure of 6 showing the
carboxylic dimeric association and the linkage of the dimers into a
chain. O1-C1-C8-O2 ) 65.3(1)°, O4-H‚‚‚O3(1 - x, -y, -z):
2.629(1), 1.79 Å, 176°. O2-H‚‚‚O1(1 - x, 1 - y, 1 - z): 2.846(2),
2.02 Å, 169°.
FIGURE 4. Molecular structure and a view of the two-dimesional
supramolecular network of 21. O1-C1-C8-O2 ) 69.2(2)°, O4-
H‚‚‚O2(-x, y + 1/2, -z + 1/2): 2.611(2), 1.77 Å, 173°. O2-H‚‚‚O3(x,
1
1
-y + /2, z + /2): 2.767(3), 1.95 Å, 162°.
chains generated by translation. These hydrogen bonds are
shorter than those between carboxylic acids as in 6. Centrosym-
metricaly related chains, connected through hydroxyl-to-carbo-
nyl hydrogen bonds, form stepladders30 (Figure 3). In 21, gauche
conformation, the 2D network can be first described as chains
of molecules connected by carboxyl-to-hydroxyl bonds, as in
7, but they are related by 2-fold screw axis instead of by
translation with significantly longer bonds. Second, the hy-
droxyl-to-carbonyl hydrogen bonds are utilized in the assembly
of centrosymmetricaly related chains to complete the sheet
(Figure 4).
The type of chains in 7 and of the sheets in 21 have been
previously observed in two analogous derivatives with one
methyl and one ethyl appendages and with two methyl groups,
respectively.31
The difference in the hydrogen bond patterns seems to be
closely related to the conformation of the hydroxyl group with
respect to the ether atom. Conformation anti should give a 1D
network, as in 6, while 1D or 2D should be observed with
gauche conformations, 7 and 21, as pointed out in ref 8a.
FIGURE 3. Molecular and secondary structure of 7 illustrating the
hydrogen-bonding ladder. O1-C1-C8-O2 ) -174.2(2)°, O4-H‚‚‚
O2(1 + x, 1 + y, z): 2.578(3), 1.76 Å, 164°. O2-H‚‚‚O3(-x, -y,
-z): 2.721(3), 1.89 Å, 168°.
that no variation has been induced by substitution of one ethyl
group for a vinyl one and the structure of 7 is isomorphous
with that of the anhydrous analogue 1-(R1 ) CH2OH, R2 )
ethyl).8a The hydroxyl group, in anti conformation, acts as the
acceptor of one hydrogen bond from the carboxylic acid forming
(30) Nguyen, V. T.; Ahn, P. D.; Bishop, R.; Scudder, M. L.; Craig, D.
C. Eur. J. Org. Chem. 2001, 4489-4499.
(31) Compounds 1o and 1q in ref 8a, respectively.
J. Org. Chem, Vol. 71, No. 3, 2006 1147

Pe´rez-Herna´ndez et al.
(dd, J ) 7.3, 7.3 Hz, 1H), 2.58 (dq, J ) 18.2, 7.3 Hz, 1H), 2.50
(dq, J ) 18.2, 7.3 Hz, 1H), 2.20 (ddd, J ) 6.9, 6.9, 2.4 Hz, 2H),
1.98-1.91 (m, 3H), 1.52-1.48 (m, 2H), 1.04 (t, J ) 7.3 Hz, 3H);
13C NMR (CDCl3, 75 MHz) δ 205.9, 170.6, 83.8, 69.4, 58.5, 52.8,
35.6, 27.6, 26.6, 18.6, 8.0; HRMS calcd for C11H15O3 [M - H]+
195.1021, found 195.1015. Anal. Calcd for C11H16O3: C, 67.32;
H, 8.22. Found: C, 67.56; H, 7.99.
Conclusions
The present work provides the synthesis of compounds 6 and
7 in 8-10 linear steps, as valuable intermediates for the
preparation of a family of highly oxygenated compounds of
general structure 1. The direct alkenyl and alkynyl couplings
illustrated here may allow for the facile synthesis of analogues
varying in substitution and functionalization. The selective
oxygenation of alkenes in processes, such as dihydroxylation,
hydration (typically as hydroboration-oxidation), and Wacker-
type oxidation,32 is a successful and pervasive method. Similarly,
terminal alkynes have been used to afford carbonyl products
available by direct hydration33 or through the intermediacy of
vinylmetal species.
Opportunities to improve upon this route include the en-
hancement of the CH2I/CH2OH interconversion and the devel-
opment of a more stereoselective annulation process. Nonethe-
less, the current synthesis provides relative succinct access to
compounds of general structure 1, which include alkenyl and
alkynyl appendages. In the crystalline state, the assembly of
molecules via O-H‚‚‚O hydrogen bonds resulted in two types
of one-dimensional networks in 6 and 7 and a two-dimensional
network in 21. The absence of the hydroxyl group in the iodide
derivatives 32 and 39 led to carboxylic acid dimer formation
as the main hydrogen-bonding motif (see the Supporting
Information).
Methyl 2-Methylene-1-propionylcyclopentane-1-carboxylate
(11a). To a solution of 10a (16.42 g, 83.6 mmol, 1.0 equiv) in dry
THF (100 mL) at room temperature and under Ar were added
cooper (I) iodide (3.18 g, 16.7 mmol, 0.2 equiv) and potassium
t-butoxide (25.1 mmol, 25.1 mL of a 1.0 M solution in THF, 0.3
equiv). The resulting mixture was heated at 48 °C by an external
oil bath for 12 h, at which point TLC showed no remaining 10a.
The solution was cooled to room temperature, diluted with
dichloromethane (100 mL), and washed with aqueous 3% HCl (50
mL), H2O (50 mL), and saturated aqueous NaCl (50 mL). The
aqueous phases were extracted with dichloromethane (3 × 25 mL),
and the combined organic phases dried over MgSO4, filtered, and
concentrated to give crude 11a (10.54 g) as a deep yellow oil. Silica
gel column chromatography of the residue (hexanes-ethyl acetate,
10:1, v/v) gave pure 11a (10.36 g, 52.8 mmol, 63.2%) as a colorless
oil: Rf 0.59 (hexanes-ethyl acetate, 10:1, v/v); IR (neat) 3100,
1
1744, 1716, 1649, 1435, 1343, 1232, 1121, 897 cm-1; H NMR
(CDCl3, 500 MHz) δ 5.22 (dd, J ) 2.0, 2.0 Hz, 1H), 5.15 (dd, J )
2.2, 2.2 Hz, 1H), 3.68 (s, 3H), 2.55 (dq, J ) 18.0, 7.3 Hz, 1H),
2.44 (dq, J ) 18.0, 7.3 Hz, 1H), 2.39-2.35 (m, 2H), 2.34 (ddd, J
) 13.5, 6.7, 6.7 Hz, 1H), 2.13 (ddd, J ) 13.5, 6.7, 6.7 Hz, 1H),
1.72-1.58 (m, 2H), 1.00 (t, J ) 7.3 Hz, 3H); 13C NMR (CDCl3,
125 MHz) δ 206.5, 171.8, 148.7, 112.0, 70.2, 52.5, 35.1, 33.9, 32.2,
24.1, 8.5; HRMS calcd for C11H15O3 [M - H]+ 195.1021, found
195.1025. Anal. Calcd for C11H16O3: C, 67.32; H, 8.22. Found:
C, 67.47; H, 8.06.
Further synthetic and structural studies based on compounds
6 and 7 will be reported in due course.
Experimental Section
(3R*/3S*,4R*)-Methyl 4-Propionyl-1-oxaspiro[2.4]heptane-4-
carboxylate (12a). To a solution of 11a (10.36 g, 52.8 mmol, 1.0
equiv) in CH2Cl2 (50 mL) magnetically stirred in a 300 mL conical
two-necked flask was added dropwise over 30 min a solution of
3-chloroperoxybenzoic acid (15.7 g, 63.5 mmol, 1.2 equiv) in CH2-
Cl2 (120 mL). After the reaction was stirred for 3 h, it was diluted
with CH2Cl2 (50 mL), washed with saturated aqueous Na2SO3,
saturated aqueous NaHCO3, and saturated aqueous NaCl (200 mL
each). The organic phase was dried over MgSO4, filtered, and
concentrated. The residue was purified by silica gel column
chromatography (hexanes-ethyl acetate, 10:1, v/v) to give 12a
(10.91 g, 51.5 mmol, 97.4%) as a 1:1 mixture of epoxides on the
basis of integration of the 500 MHz 1H NMR resonances at δ 1.03
and 0.99, respectively: Rf 0.25 (hexanes-ethyl acetate, 9:1, v/v);
IR (neat) 2850, 1744, 1714, 1435, 1347, 1270, 1128, 1009, 946,
General Methods. Unless otherwise noted, all reactions were
carried out under argon atmosphere in oven-dried glassware using
standard syringe, cannula, and septa techniques. Toluene, diethyl
ether, and tetrahydrofuran were distilled from sodium/benzophenone
ketyl under nitrogen immediately prior to use; dichloromethane,
triethylamine, acetonitrile, dimethyl sulfoxide, and pyridine were
distilled from CaH2. LiBr, LiCl, and LiI were dried by heating at
120 °C for 20 h at ∼0.4 torr. Analytical TLC was performed with
0.25 mm EM silica gel 60 F254 plates. NMR spectra are referenced
to residual CHCl3 at 7.25 (1H) and 77.0 ppm (13C). The mass
spectrometers used show deviations of less than 5 ppm. Melting
points are uncorrected.
Typical synthetic sequences are described:
Methyl 2-Propionyl-6-heptynoate (10a). To a stirred suspension
under Ar of sodium hydride, 60% dispersion in mineral oil (3.65
g, 90.8 mmol, 0.9 equiv) in dried THF/DMF (1/1) (100 mL), was
added anhydrous potassium iodide (6.91 g, 41.1 mmol, 0.4 equiv).
This mixture was stirred at 25 °C for 30 min before methyl
propionyl acetate (12.5 mL, 99.3 mmol, 1.0 equiv) was slowly
added via cannula. The resultant solution was stirred for an
additional 15 min, at which time 5-chloro-1-pentyne (8.7 mL, 82.5
mmol, 0.8 equiv) was added over 5 min. The mixture was heated
at reflux under Ar for 24 h. The solution was cooled to room
temperature, diluted with diethyl ether (100 mL), and washed with
aqueous 3% HCl, H2O, and saturated aqueous NaCl (100 mL each).
The organic phase was dried over MgSO4, filtered, and concen-
trated. The residue was purified by silica gel column chromatog-
raphy (hexanes-ethyl acetate, 5:1, v/v) to give 10a (16.42 g, 83.6
mmol, 84.2%) as a clear, colorless oil: Rf 0.70 (hexanes-ethyl
acetate, 5:1, v/v); IR (neat) 3289, 1743, 1715, 1458, 1351, 1205,
1113, 967 cm-1; 1H NMR (CDCl3, 300 MHz) δ 3.71 (s, 3H), 3.47
1
903, 780 cm-1; H NMR (CDCl3, 500 MHz) δ 3.68 (s, 3H), 3.67
(s, 3H), 2.99-2.96 (m, 4H), 2.75-2.67 (m, 1H), 2.66-2.59 (m,
1H), 2.54-2.29 (m, 4H), 2.20-2.11 (m, 3H), 1.97-1.87 (m, 3H),
1.74-1.62 (m, 4H), 1.03 (t, J ) 7.0 Hz, 3H), 0.99 (t, J ) 7.0 Hz,
3H); 13C NMR (CDCl3, 125 MHz) δ 206.1, 204.3, 172.0, 168.6,
68.9, 67.3, 65.9, 65.8, 52.5 (2 × C), 50.3, 50.2, 34.1, 33.9, 33.3,
33.2, 33.0, 32.3, 22.9, 22.5, 8.2, 7.5; HRMS calcd for C11H16O4
M+ 212.1048, found 212.1036; calcd for C11H15O4 [M - H]+
211.0970, found 211.0966. Anal. Calcd for C11H16O4: C, 62.25;
H, 7.60. Found: C, 61.95; H, 7.73.
Methyl 3-Oxo-1-propionylcyclohexane-1-carboxylate (13a).
To a stirred room-temperature solution of 12a (10.93 g, 51.5 mmol,
1.0 equiv) in CH2Cl2 (120 mL) was added, in five portions,
anhydrous lithium iodide (1.38 g, 10.3 mmol, 0.2 equiv). This
mixture was stirred for 4 h, at which time TLC showed no
remaining 12a. The resultant pale yellow solution was quenched
with saturated aqueous NaCl (100 mL). The separated organic phase
was washed with H2O (2 × 50 mL) and saturated aqueous NaCl
(2 × 50 mL). The aqueous phases were extracted with CH2Cl2 (2
× 50 mL), and the combined organic phases were dried over
MgSO4, the residue was filtered through silica gel with hexanes-
(32) March, J. AdVanced Organic Chemistry, 4th ed.; John Wiley &
Sons: New York, 1992; pp 1196-1198.
(33) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. ReV. 2004, 104, 3079-
3159.
1148 J. Org. Chem., Vol. 71, No. 3, 2006

Hydroxyl Acids with Alkenyl and Alkynyl Appendages
ethyl acetate (5:1, v/v), and the filtrate concentrated to yield diketone
13a (8.52 g, 40.0 mmol, 78%) as colorless foam. Rf 0.2 (hexanes-
ethyl acetate, 5:1, v/v); IR (neat) 1717, 1451, 1352, 1225, 1033,
ylsilyl)ethynyl]-3-cyclohexen-1-carboxylate (17), and (3S*,5R*)-
Ethyl 3-Hydroxy-3-hydroxymethyl-1-[1′-hydroxy-1′-bis[(trimeth-
ylsilyl)-ethynyl]-cyclohexane-1-carboxylate (18). To a solution
of 14 (8.60 g, 22.1 mmol, 1.0 equiv) in CH2Cl2 (100 mL)
magnetically stirred in a 250 mL two-necked flask was added,
dropwise over 25 min, a solution of MCPBA (6.55 g, 26.5 mmol,
1.2 equiv) in CH2Cl2 (100 mL). After the reaction was stirred for
1 h, it was washed with saturated aqueous Na2SO3, saturated
aqueous NaHCO3, and saturated aqueous NaCl (100 mL each). The
organic phase was dried over MgSO4, filtered, and concentrated in
vacuo. The residue was purified by silica gel column chromatog-
raphy (hexanes-ethyl acetate, 9:1, v/v) to give the unstable mixture
of epoxides 15a,b (8.61 g, 21.2 mmol, 96%) as a 2:3 mixture of
15a-(3S*,5R*)/15b-(3R*,5R*) on the basis of integration of the
300 MHz 1H NMR resonance signals at δ 2.72 and 2.60,
respectively. The mixture of epoxides: Rf 0.2 (hexanes-ethyl
acetate, 9:1, v/v) was dissolved in 50 mL of CH2Cl2, cooled under
Ar at -78 °C, and used in the next experiment without further
structural study.
To a stirred -98 °C solution of the mixture of epoxides 15a
and 15b (8.61 g, 21.2 mmol, 1.0 equiv) in CH2Cl2 (50 mL) under
Ar was added a catalytic amount of p-toluenesulfonic acid (6.0 mg)
in CH2Cl2 (4.0 mL) via syringe over 5 min. After 30 min at -78
°C and stirring for an additional 30 min, saturated aqueous NH4Cl
(50 mL) was added, and the mixture was allowed to reach room
temperature. The mixture was diluted with CH2Cl2 (25 mL), washed
with saturated aqueous NaHCO3 and saturated aqueous NaCl (100
mL each). The organic phase was dried over MgSO4, filtered, and
concentrated in vacuo. The residue was purified by silica gel column
chromatography (hexanes-ethyl acetate, 9:1, v/v) to give, according
to the elution from the chromatographic column, compounds 16
(3.11 g, 7.59 mmol, 35.8%), 17 (611 mg, 1.50 mmol, 7.1%), and
18 (4.75 g, 11.21 mmol, 52.9%).
1
918 cm-1; H NMR (CDCl3, 500 MHz) δ 3.72 (s, 3H), 2.66 (d, J
) 15.0 Hz, 1H), 2.60 (d, J ) 15.0 Hz, 1H), 2.46 (dq, J ) 18.1, 7.2
Hz, 1H), 2.41 (dq, J ) 18.1, 7.2 Hz, 1H), 2.29-2.22 (m, 3H),
2.11 (ddd, J ) 13.8, 6.9, 6.9 Hz, 1H), 1.80-1.74 (m, 2H), 1.02 (t,
J ) 7.2 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 206.9, 206.0,
171.8, 62.9, 52.9, 44.9, 39.9, 31.5, 29.4, 21.4, 7.9; HRMS calcd
for C11H17O4 [M + H]+ 213.1127, found 213.1126. Anal. Calcd
for C11H16O4: C, 62.25; H, 7.60. Found: 61.95; H, 7.55.
Diethyl-3-methylene-1,1-cyclohexanedicarboxylate (8). To a
room-temperature solution of methyltriphenylphosphonium bromide
(10.0 g, 28.6 mmol, 1.4 equiv) in dry toluene (100 mL) was added
in one portion potassium tert-butoxide (3.14 g, 28.6 mmol, 1.4
equiv). The resulting deep yellow mixture was heated to 90 °C for
2 h and then cooled to 0 °C before a solution of ketone 13b (4.84
g, 20.0 mmol, 1.0 equiv) in toluene (30 mL) was slowly added via
cannula. The resultant solution was further stirred a 0 °C for 2 h,
and then an aqueous saturated solution of NH4Cl (200 mL) was
added. The biphasic mixture was extracted with diethyl ether (2 ×
100 mL), and the combined organic extracts were dried (MgSO4).
Diethyl ether was removed by distillation before n-hexane (100
mL) was added, and the solution was left overnight at -20 °C,
allowing crystallization of most triphenylphosphine oxide, which
was removed by filtration. The solution was washed with H2O and
saturated aqueous NaCl (100 mL each) and then concentrated by
rotary evaporation. The residue was purified by silica gel column
chromatography (hexanes-ethyl acetate, 10:1, v/v) to give 8 (3.74
g, 15.6 mmol, 78%) as a clear colorless oil: Rf 0.49 (hexanes-
ethyl acetate, 9:1, v/v). A small fraction was purified by bulb-to-
bulb distillation under reduced pressure (0.7 torr) at 75 °C; IR (neat)
1
3075, 1732, 1655, 1448, 1310, 1244, 1101, 896 cm-1; H NMR
(CDCl3, 300 MHz) δ 4.70 (s, 2H), 4.15 (q, J ) 7.0 Hz, 4H), 2.64
(s, 2H), 2.11-2.07 (m, 2H), 2.03-1.99 (m, 2H), 1.66-1.61 (m,
2H), 1.20 (t, J ) 7.0 Hz, 6H); 13C NMR (CDCl3, 75 MHz) δ 171.2
(2 × C), 144.2, 110.5, 61.2 (2 × C), 56.6, 39.6, 33.9, 31.1, 24.1,
14.0 (2 × C); HRMS calcd for C13H21O4 [M + H]+ 241.1439,
found 241.1438. Anal. Calcd for C13H20O4: C, 64.98; H, 8.39.
Found: C, 64.95; 8.41.
Compound 16, white solid: mp 64-65 °C; Rf 0.49 (hexanes-
ethyl acetate, 3:2, v/v); IR (neat) 3561, 2171, 1722, 1248, 1067,
843, 760 cm-1; 1H NMR (CDCl3, 500 MHz) δ 4.08 (dq, J ) 10.7,
7.2 Hz, 1H), 4.03 (dq, J ) 10.7, 7.2 Hz, 1H), 3.47 (dd, J ) 11.9,
2.5 Hz, 1H), 3.37 (dd, J ) 11.9, 11.5 Hz, 1H), 2.86 (ddd, J )
12.0, 2.2, 2.2 Hz, 1H), 2.31 (brddd, J ) 13.2, 12.5, 2.5 Hz, 1H),
2.13 (ddddd, J ) 13.2, 13.2, 12.5, 6.5, 6.5 Hz, 1H), 1.98 (dd, J )
11.5, 2.5 Hz, 1H), 1.68-1.58 (m, 2H), 1.53 (d, J ) 12.0 Hz, 1H),
1.50 (brdd, J ) 13.2, 6.5 Hz, 1H), 1.24 (ddd, J ) 13.2, 11.0, 6.5
Hz, 1H), 1.19 (t, J ) 7.2 Hz, 3H), 0.12 (s, 9H), 0.05 (s, 9H); 13C
NMR (CDCl3, 125 MHz) δ 171.2, 103.2, 99.8, 90.6, 90.0, 86.0,
74.4, 65.2, 60.8, 60.5, 38.1, 31.7, 31.6, 19.1, 13.9, -0.4 (3 × C),
-0.5 (3 × C); HRMS calcd for C21H34O4Si2 M+ 406.1996, found
406.1981. Anal. Calcd for C21H34O4Si2: C, 62.02; H, 8.43. Found:
C, 61.77; H, 8.35.
Compound 17, colorless foam: Rf 0.31 (hexanes-ethyl acetate,
3:2, v/v); IR (neat) 3437, 3050, 2168, 1729, 1693, 1442, 1250, 1054,
844, 760 cm-1; 1H NMR (CDCl3, 500 MHz) δ 5.63 (brs, 1H), 4.16
(q, J ) 7.1 Hz, 2H), 4.06 (brd, J ) 14.2 Hz, 1H), 4.00 (brd, J )
14.2 Hz, 1H), 2.60 (d, J ) 17.0 Hz, 1H), 2.43 (d, J ) 17.0 Hz,
1H), 2.31 (dd, J ) 13.0, 5.5 Hz, 1H), 2.19 (brd, J ) 17.9 Hz, 1H),
2.10-2.00 (m, 1H), 1.82 (ddd, J ) 13.0, 12.5, 6.5 Hz, 1H), 1.24
(t, J ) 7.1 Hz, 3H), 0.15 (s, 9H), 0.14 (s, 9H); 13C NMR (CDCl3,
125 MHz) δ 174.7, 135.9, 121.3, 102.5, 101.7, 89.8, 89.7, 69.3,
67.0, 61.5, 54.8, 30.0, 25.7, 23.0, 14.1, -0.3 (3 × C), -0.6 (3 ×
C); HRMS calcd for C21H34O4Si2 M+ 406.1995, found 406.1974.
Anal. Calcd for C21H34O4Si2: C, 62.02; H, 8.43. Found: C, 62.04;
H, 8.47.
Ethyl 1-[1′-Hydroxy-1′-bis(trimethylsilyl)ethynyl]-3-methyl-
enecyclohexane-1-carboxylate (14). To a stirred -78 °C solution
of trimethylsilylacetylene (4.44 g, 45.2 mmol, 6.52 mL, 2.0 equiv)
in THF (10 mL) under Ar was added dropwise n-butyllithium (28.25
mL, 1.6 M solution in hexanes, 2.0 equiv). The solution was stirred
at -40 °C for 30 min. The solution was then cooled to -78 °C,
and a solution of diester 8 (5.43 g, 22.6 mmol, 1.0 equiv) in THF
(10 mL) was added via cannula. After 15 min at -78 °C, the
reaction mixture was allowed to reach -15 °C, and after 30 min
allowed to warm to 0 °C. The mixture was further stirred for 3 h
at 0 °C, allowed to reach room temperature, diluted with diethyl
ether (100 mL), washed with 5% aqueous HCl and saturated
aqueous NaCl (50 mL each). The organic phase was dried over
MgSO4, filtered, and concentrated. The residue was purified by
silica gel column chromatography (hexanes-ethyl acetate, 9:1, v/v)
to give 14 (7.62 g, 19.51 mmol, 86.3%) as a crystalline solid: mp
56-57 °C; Rf 0.56 (hexanes-ethyl acetate, 9:1, v/v); IR (KBr) 3380,
1
3070, 2168, 1714, 1653, 1452, 1300, 1030, 760 cm-1; H NMR
(CDCl3, 300 MHz) δ 4.70 (brs, 2H), 4.41 (s, 1H), 4.17 (q, J ) 7.0
Hz, 2H), 2.84 (d, J ) 13.5 Hz, 1H), 2.42 (d, J ) 13.5 Hz, 1H),
2.33-2.25 (m, 2H), 2.03-1.75 (m, 3H), 1.49-1.44 (m, 1H), 1.25
(t, J ) 7.0 Hz, 3H), 0.20 (s, 9H), 0.18 (s, 9H); 13C NMR (CDCl3,
75 MHz) δ 175.3, 145.7, 110.3, 102.6, 102.4, 90.2, 90.0, 70.1, 61.8,
58.0, 38.7, 34.7, 29.7, 25.0, 14.5, 0.1 (6 × C); HRMS calcd for
C21H34O3Si2 M+ 390.2047, found 390.2029. Anal. Calcd for
C21H34O3Si2: C, 64.56; H, 8.77. Found: C, 64.40; H, 8.69.
Preparation of (1R*,5R*)-Ethyl 5-Hydroxymethyl-7,7-bis-
[(trimethylsilyl)-ethynyl]-6-oxabicyclo[3.2.1]octane-1-carboxy-
late (16), Ethyl 3-Hydroxymethyl-1-[1′hydroxy-1′-bis[(trimeth-
Compound 18, colorless foam: Rf 0.14 (hexanes-ethyl acetate,
3:2, v/v); IR (neat) 3428, 2170, 1693, 1250, 1054, 844, 760 cm-1
;
1H NMR (CDCl3, 500 MHz) δ 4.46 (s, 1H), 4.26 (dq, J ) 10.6,
7.1 Hz, 1H), 4.14 (dq, J ) 10.6, 6.1 Hz, 1H), 3.37 (dd, J ) 10.8,
3.0 Hz, 1H), 3.33 (dd, J ) 10.8, 4.2 Hz, 1H), 2.60 (s, 1H), 2.52
(dd, J ) 4.2, 3.0 Hz, 1H), 2.38 (d, J ) 14.2 Hz, 1H), 2.28 (brd, J
) 14.0 Hz, 1H), 1.92 (ddddd, J ) 14.0, 14.0, 14.0, 3.5, 3.5 Hz,
1H), 1.69 (d, J ) 14.2 Hz, 1H), 1.66-1.56 (m, 3H), 1.29 (t, J )
J. Org. Chem, Vol. 71, No. 3, 2006 1149

Pe´rez-Herna´ndez et al.
7.1 Hz, 3H), 1.07 (ddd, J ) 13.8, 13.8, 4.0 Hz, 1H), 0.14 (s, 9H),
0.12 (s, 9H); 13C NMR (CDCl3, 125 MHz) δ 176.4, 102.4, 101.7,
90.4, 89.3, 71.5 (2 × C), 70.1, 61.8, 53.9, 36.8, 33.0, 29.0, 18.2,
14.0, -0.1 (3 × C), -0.3 (3 × C); HRMS calcd for C21H36O5Si2
M+ 424.2101, found 424.2079. Anal. Calcd for C21H36O5Si2: C,
59.39; H, 8.54. Found: C, 59.34; H, 8.63.
mL), dried (MgSO4), filtered, and concentrated in vacuo. After short
column chromatography of the residue on silica gel with hexanes-
ethyl acetate (1:3, v/v) gave an inseparable mixture of methyl and
ethyl esters (20) in a 9:1 ratio (707 mg, 2.69 mmol, 99%). After
two crystallizations from n-hexane/acetone the methyl ester deriva-
tive of 20 (RdMe) was purified: mp 107-109 °C; Rf 0.38
(hexanes-ethyl acetate, 2:3, v/v); IR (neat) 3483, 3288, 3188, 2111,
1729, 1435, 1376, 1362, 1281, 1156, 1030, 880, 745 cm-1; 1H NMR
(CDCl3, 500 MHz) δ 3.74 (s, 3H), 3.59 (dd, J ) 12.1, 3.4 Hz,
1H), 3.48 (dd, J ) 12.1, 10.2 Hz, 1H), 2.68 (ddd, J ) 12.0, 2.4,
2.4 Hz, 1H), 2.72 (s, 1H), 2.62 (s, 1H), 2.42 (ddd, J ) 12.6, 6.8,
2.4 Hz, 1H), 2.21 (ddddd, J ) 13.2, 13.2, 13.2, 6.8, 6.8 Hz, 1H),
1.89 (dd, J ) 10.2, 3.4 Hz, 1H), 1.81-1.69 (m, 2H), 1.67 (d, J )
12.0 Hz, 1H), 1.65-1.60 (m, 1H), 1.32 (ddd, J ) 12.2, 12.2, 5.8
Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 171.7, 86.6, 81.9, 78.7,
74.4, 74.3, 73.7, 65.4, 60.5, 52.3, 39.2, 31.7, 31.6, 19.1; HRMS
calcd for C14H16O4 M+ 248.1049, found 248.1042. Anal. Calcd for
C14H16O4: C, 67.73; H, 6.50. Found: C, 67.55; H, 6.62.
(1R*,5R*)-7,7-Diethynyl-5-hydroxymethyl-6-oxabicyclo[3.2.1]-
octane-1-carboxylic Acid (6). A suspension of compound 16 (244
mg, 0.60 mmol, 1.0 equiv) in a saturated aqueous solution of barium
hydroxide (50 mL) was allowed to stand at 50 °C for 24 h. A 5%
aqueous solution of HCl was added until the aqueous suspension
was acid to pH paper, and then it was extracted with CH2Cl2 (5 ×
20 mL). The combined organic extracts were washed with saturated
aqueous NaCl (2 × 50 mL), dried over MgSO4, filtered, and
concentrated in vacuo to give pure 6 (140.4 mg, 0.60 mmol, 100%)
as a crystalline solid: mp 138-140 °C; Rf 0.55 (ethyl acetate); IR
(KBr) 3502, 3292, 3180, 2588, 2110, 1704, 1340, 1112, 1055, 746
1
cm-1; H NMR (CDCl3, 500 MHz) δ 3.50 (d, J ) 11.8 Hz, 1H),
The mixture of 20 (RdMe, Et) was treated with a saturated water
solution of barium hydroxide, under similar conditions as above
indicated for the base hydrolysis of 16, to give quantitatively pure
hydroxyl/acid 6.
3.45 (d, J ) 11.8 Hz, 1H), 3.09 (s, 1H), 3.00 (s, 1H), 2.68 (ddd, J
) 11.8, 2.0, 2.0 Hz, 1H), 2.39 (ddd, J ) 11.8, 6.0, 2.0 Hz, 1H),
2.20 (ddddd, J ) 15.4, 12.8, 11.6, 7.6, 6.0 Hz, 1H), 1.76-1.68 (m,
2H), 1.72 (d, J ) 11.8, 1H), 1.60 (brdd, J ) 12.5, 6.0 Hz, 1H),
1.41 (ddd, J ) 12.8, 12.5, 6.0 Hz, 1H); 13C NMR (CDCl3, 125
MHz) δ 173.7, 85.7, 82.2, 79.1, 74.1, 73.5, 73.2, 66.2, 60.1, 39.2,
31.4, 31.2, 18.9 ; HRMS calcd for C13H14O4 M+ 234.0892, found
234.0893. Anal. Calcd for C13H14O4: C, 66.66; H, 6.02. Found:
C, 66.72; H, 5.95.
(1R*,5R*)-Ethyl 5-Iodomethyl-7,7-bis[(trimethylsilyl)ethynyl]-
6-oxabicyclo-[3.2.1]octane-1-carboxylate (29) and (1R*,4S*,5S*)-
Ethyl 4-Iodo-5-methyl-7,7-bis[(trimethylsilyl)ethynyl]-6-oxabicyclo-
[3.2.1]octane-1-carboxylate (30). Iodine (3.46 g, 13.61 mmol, 1.5
equiv) was added in one portion to a stirred under Ar solution of
compound 14 (3.54 g, 9.07 mmol, 1.0 equiv) in CH2Cl2 (150 mL).
Sodium bicarbonate (50 mg) was added, and the reaction was
allowed to stand at room temperature. When monitoring of the
reaction by TLC indicated that all starting material has been
consumed (ca. 3 h). The reaction mixture was poured into water
(200 mL) and extracted with CH2Cl2 (2 × 50 mL). The combined
organic extracts were shaken with 10% aqueous solution Na2S2O3,
saturated aqueous NaCl (2 × 50 mL each), dried (MgSO4), filtered,
and the organic solvent evaporated in vacuo. The residue was
purified by chromatography on silica gel (hexanes-ethyl acetate,
9:1, v/v) to give, according to elution from the chromatographic
column, compounds 30 (42 mg, 0.08 mmol, 0.6%) and 29 (5.06 g,
9.79 mmol, 72%).
(1R*,5R*)-7,7-Divinyl-5-hydroxymethyl-6-oxabicyclo[3.2.1]-
octane-1-carboxylic Acid (21). The hydroxyl acid 6 (234 mg, 1.0
mmol) was dissolved in ethyl acetate (20 mL), and Lindlar catalyst
(32 mg) was added. The reaction was then allowed to stir under an
excess of H2 (balloon pressure). After 3 h the reaction was filtered
through a short plug of silica gel, and the silica gel was washed
with ethyl acetate (50 mL). The filtrate was concentrated to afford
pure 21 (233 mg, 0.98 mmol, 98%) as a crystalline solid: mp 139-
140 °C; Rf 0.45 (ethyl acetate); IR (KBr) 3734, 2360, 2342, 1703,
1
1457, 1402, 1257, 1040, 1004, 928 cm-1; H NMR (CDCl3, 500
MHz) δ 6.28 (dd, J ) 17.3, 11.0 Hz, 1H), 5.91 (dd, J ) 17.0, 10.6
Hz, 1H), 5.52 (dd, J ) 17.3, 1.9 Hz, 1H), 5.33 (dd, J ) 17.0, 1.5
Hz, 1H), 5.27 (dd, J ) 11.0, 1.9 Hz, 1H), 5.14 (dd, J ) 10.6, 1.5
Hz, 1H), 3.66 (d, J ) 11.7 Hz, 1H), 3.61 (d, J ) 11.7 Hz, 1H),
2.55 (ddd, J ) 11.7, 2.2, 2.2 Hz, 1H), 2.15 (brddd, J ) 15.2, 6.8,
2.1 Hz, 1H), 2.15-2.05 (m, 1H), 1.80 (brddd, J ) 12.9, 7.2, 1.7
Hz, 1H), 1.71-1.64 (m, 1H), 1.58 (ddd, J ) 13.9, 7.2, 7.2 Hz,
1H), 1.50 (d, J ) 11.7 Hz, 1H), 1.32 (ddd, J ) 12.2, 12.2, 6.8 Hz,
1H); 13C NMR (CDCl3, 125 MHz) δ 178.1, 139.8, 135.5, 115.8,
115.3, 87.0, 83.3, 67.3, 56.3, 38.7, 31.8, 31.2, 17.8; HRMS calcd
for C13H18O4, found 238.1200, 238.1205. Anal. Calcd for C13H18O4:
C, 65.53; H, 7.61. Found: C, 65.54; H, 7.75.
Preparation of Compound 6 from Triol 18. Methanesulfonyl
chloride (928 mg, 8.1 mmol, 0.63 mL, 3.0 equiv) was added to a
solution of compound 18 (1.15 g, 2.70 mmol, 1.0 equiv) in CH2-
Cl2 (20.0 mL) and triethylamine (2.73 g, 27.0 mmol, 3.8 mL, 10.0
equiv) at -40 °C. The mixture was stirred at -40 °C for 2 h, and
then methanol (2.0 mL) was added to decompose excess MsCl.
The mixture was allowed to warm to room temperature, and then
it was poured in water (50 mL) and was extracted with CH2Cl2 (3
× 50 mL). The combined organic extracts were washed with
saturated aqueous NaCl (3 × 50 mL), dried (MgSO4), filtered, and
concentrated under reduced pressure to provide crude mesylate 19.
The crude product was dissolved in methanol (20.0 mL), and
potassium carbonate (1.5 g, 4.0 equiv) was added at room
temperature. The mixture was stirred at room temperature for 30
min, and then the resulting suspension was poured into water (100
mL) and was extracted with CH2Cl2 (3 × 30 mL). Combined
extracts containing crude epoxide were added to 0.5 M aqueous
HCl (20 mL), and the resulting heterogeneous solution was stirred
vigorously at room temperature for 10 min. The organic layer was
separated, then was washed with saturated aqueous NaCl (2 × 20
Compound 29 was isolated as a noncrystalline solid: Rf 0.50
(hexanes-ethyl acetate, 19:1, v/v); IR (neat) 2172, 1736, 1300,
1
1052, 937, 844, 760 cm-1; H NMR (CDCl3, 300 MHz) δ 4.16
(dq, J ) 10.0, 7.5 Hz, 1H), 4.08 (dq, J ) 10.0, 7.5 Hz, 1H), 3.28
(s, 2H), 2.69 (d, J ) 12.0 Hz, 1H), 2.30 (brdd, J ) 11.4, 5.0 Hz,
1H), 2.29-2.18 (m, 1H), 1.82 (d, J ) 12.0 Hz, 1H), 1.71-1.67
(m, 3H), 1.51 (ddd, J ) 13.0, 12.5, 6.0 Hz, 1H), 1.26 (t, J ) 7.5
Hz, 3H), 0.18 (s, 9H), 0.12 (s, 9H); 13C NMR (CDCl3, 75 MHz) δ
171.2, 102.8, 100.3, 90.6, 90.0, 83.3, 74.8, 61.0, 60.9, 43.1, 34.4,
31.1, 19.8, 14.0, 13.2, -0.3 (3 × C), -0.4 (3 × C); HRMS calcd
for C21H33IO3Si2 M+ 516.1013, found 516.1026. Anal. Calcd for
C21H33IO3Si2: C, 48.83; H, 6.44. Found: C, 48.83; H, 6.29.
Compound 30, colorless foam: Rf 0.70 (hexanes-ethyl acetate,
19:1, v/v); IR (neat) 2173, 1738, 1447, 1304, 1251, 845, 760 cm-1
;
1H NMR (CDCl3, 500 MHz) δ 4.19 (brd, J ) 4.8 Hz, 1H), 4.09
(q, J ) 7.2 Hz, 2H), 3.00-2.90 (m, 1H), 2.79 (d, J ) 12.6 Hz,
1H), 2.50 (d, J ) 12.6 Hz, 1H), 2.02 (brdd, J ) 14.0, 7.5 Hz, 1H),
2.04-1.94 (m, 2H), 1.50 (s, 3H), 1.24 (t, J ) 7.2 Hz, 3H), 0.17 (s,
9H), 0.12 (s, 9H); 13C NMR (CDCl3, 125 MHz) δ 170.7, 102.8,
99.7, 91.1, 89.8, 85.2, 75.1, 61.1, 60.4, 40.6, 35.6, 32.2, 27.2, 25.8,
14.0, -0.4 (3 × C), -0.5 (3 × C); HRMS calcd for C21H33IO3Si2
M+ 516.1013, found 516.1003. Anal. Calcd for C21H33IO3Si2: C,
48.83; H, 6.44. Found: C, 48.69; H, 6.49.
(1R*,5R*)-Ethyl 7,7-Diethynyl-5-iodomethyl-6-oxabicyclo-
[3.2.1]octane-1-carboxylate (31) and (1R*,5R*)-7,7-Diethynyl-
5-iodomethyl-6-oxabicyclo[3.2.1]-octane-1-carboxylic Acid (32).
A suspension of compound 29 (1.80 g, 3.49 mmol, 1.0 equiv) in a
saturated aqueous solution of Ba(OH)2 (100 mL) was stirred at 25
°C for 48 h. A 5% aqueous solution of HCl was added until the
1150 J. Org. Chem., Vol. 71, No. 3, 2006

Hydroxyl Acids with Alkenyl and Alkynyl Appendages
aqueous suspension was acid to pH paper. The reaction was
extracted with CH2Cl2 (10 × 10 mL). The combined organic
extracts were washed with saturated aqueous NaCl (2 × mL), dried
(MgSO4), filtered, and concentrated. The residue was purified by
silica gel column chromatography to yield compounds 31 (539 mg,
1.45 mmol, 41.5%) and 32 (661 mg, 1.92 mmol, 55%).
Compound 31 was isolated as a crystalline solid: mp 129-130
°C (n-hexane/CH2Cl2); Rf 0.30 (hexanes-ethyl acetate, 9:1, v/v);
IR (KBr) 3292, 3267, 2117, 1717, 1300, 1048, 923, 701 cm-1; 1H
NMR (CDCl3, 500 MHz) δ 4.21 (dq, J ) 9.7, 7.5 Hz, 1H), 4.17
(dq, J ) 9.7, 7.2 Hz, 1H), 3.31 (d, J ) 10.5 Hz, 1H), 3.29 (d, J )
10.5 Hz, 1H), 2.72 (ddd, J ) 12.2, 2.2, 2.2 Hz, 1H), 2.69 (s, 1H),
2.60 (s, 1H), 2.37 (ddd, J ) 13.3, 7.0, 2.3 Hz, 1H), 2.29-2.17 (m,
1H), 1.94 (d, J ) 12.0 Hz, 1H), 1.78-1.67 (m, 3H), 1.65 (ddd, J
) 13.3, 11.0, 6.0 Hz, 1H), 1.26 (t, J ) 7.5 Hz, 3H); 13C NMR
(CDCl3, 125 MHz) δ 171.0, 83.9, 81.7, 79.0, 74.4, 74.1, 73.8, 61.3,
60.0, 43.1, 34.3, 31.0, 19.7, 14.0, 12.6; HRMS calcd for C15H17-
IO3 M+ 372.0222, found 372.0218. Anal. Calcd for C15H17IO3: C,
48.40; H, 4.60. Found: C, 48.42; H, 4.71.
J ) 10.2, 3.4 Hz, 1H), 1.80-1.69 (m, 2H), 1.66 (d, J ) 12.1 Hz,
1H), 1.64-1.59 (m, 1H), 1.32 (ddd, J ) 12.0, 12.0, 5.8 Hz, 1H),
1.26 (t, J ) 7.1 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 171.2,
86.6, 81.9, 78.8, 74.2, 73.8, 73.7, 65.4, 61.2, 60.2, 38.2, 31.7, 31.6,
19.1, 14.0; HRMS calcd for C15H18O4 M+ 262.1205, found
262.1191. Anal. Calcd for C15H18O4: C, 68.68; H, 6.92. Found:
C, 68.50; H, 7.03.
X-ray Crystallography. Crystals of all compounds were grown
under identical conditions using a previously water-saturated
mixture of carbon tetrachloride/n-hexane as solvent. Crystal data
were collected using a Nonius Kappa CCD diffractometer (λ(Mo
KR) ) 0.7107 Å ). Data for compounds 6, 7, and 21 were collected
at 170 K while for the remaining compounds (32, 39, 43, 47, and
48) were collected at room temperature. Data reduction and cell
refinement was carried out with the programs DENZO34 and
COLLECT.35 Crystals of 7 and the anhydrous form of 1(R1dCH2-
OH, R2dC2H5) are isomorphous. The unit cell volume in 7 is
slightly greater than that in 1(R1dCH2OH, R2dC2H5), and the ethyl
and vinyl substituents are disordered. Semiempirical absorption
corrections in 32 and 39 were performed.36 The structures were
solved by direct methods,37 and the refinement process has been
carried on F2 against all data using SHELX97.38 All hydrogen atoms
were located on difference Fourier maps and were allowed to ride
during the last cycles of refinement. Details crystal data and
geometrical parameters are deposited in the Supporting Information
(CIF files).
Compound 32 was isolated as a crystalline solid: mp 130.8-
131.5 °C (n-hexane/CH2Cl2); Rf 0.25 (hexanes-ethyl acetate, 1:1,
v/v); IR (KBr) 3281, 2115, 1726, 1367, 1262, 1188, 1038, 921
1
cm-1; H NMR (MeOD, 300 MHz) δ 3.38 (d, J ) 10.8 Hz, 1H),
3.29 (d, J ) 10.8 Hz, 1H), 3.17 (s, 1H), 3.10 (s, 1H), 2.70 (d, J )
12.0 Hz, 1H), 2.39-2.33 (m, 1H), 2.28-2.23 (m, 1H), 1.91 (d, J
) 12.0 Hz, 1H), 1.86-1.66 (m, 4H). Anal. Calcd for C13H13IO3:
C, 45.37; H, 3.81. Found: C, 45.35; H, 4.17.
Acknowledgment. Financial support from the DGICYT of
Spain through the CTQ2004-01674 project is gratefully ac-
knowledged. N.P.H. and M.F. thank the Spanish Ministry of
Education and Science for a Predoctoral Fellowship.
(1R*,5R*)-Ethyl 7,7-Diethynyl-5-hydroxymethyl-6-oxabicyclo-
[3.2.1]octane-1-carboxylate (20). A solution of compound 29 (100
mg, 0.19 mmol, 1.0 equiv) in dry DMSO (0.5 mL) was cannulated
under Ar to a vigorously stirred mixture of powdered potassium
superoxide (62 mg, 0.87 mmol, 4.5 equiv) and 18-crown-6-ether
(23 mg, 0.087 mmol, 0.45 equiv) in dry DMSO (0.5 mL). The
resulting mixture was stirred for 2.5 h at room temperature, at which
time TLC showed no remaining 29. The resultant orange solution
was cautiously treated with a saturated aqueous solution of NaCl
(1.0 mL). The solution was then diluted with ethyl acetate (3.0
mL) and washed with 3% aqueous HCl, H2O, and saturated aqueous
NaCl (2.0 mL each). The aqueous phases were further extracted
with ethyl acetate (6 × 1.5 mL), and the combined organic phases
dried over MgSO4, filtered, and concentrated to give a yellow
residue (38 mg), which was purified by silica gel column chroma-
tography (hexanes-ethyl acetate, 1:1, v/v). Compound 20-(RdEt)
(5.0 mg, 0.02 mmol, 10%) was isolated as a crystalline solid: mp
113-114 °C (hexanes/CH2Cl2); Rf 0.38 (hexanes-ethyl acetate,
1:1; v/v); IR (KBr) 3230, 1710, 1460, 1366, 1317, 1267, 1052,
Supporting Information Available: Experimental procedures
1
and spectroscopic data for all other compounds and H and 13C
NMR spectra for all new compounds; CIF files containing detailed
crystal data of compounds 6, 7, 21, 32, 39, 43, 47, and 48. This
material is available free of charge via the Internet at http://
pubs.acs.org.
JO052237P
(34) Otwinowsky, Z.; Minor, W. Methods in Enzymology, Macromo-
lecular Crystallography. Part A; Carter, C. E., Sweet, R. M., Eds.; Academic
Press: New York; University of Texas, Southwestern Medical Centre at
Dallas, HKL DENZO and Scalepack, USA; 1997; Vol. 276; pp 307-326.
(35) COLLECT; Kappa CCD Server Software; Nonius B. V.: Delft, The
Netherlands, 1998.
(36) Blessing, B. Acta Crystallogr., Sect. A 1995, 51, 33-38.
(37) Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G.; Giacovazzo,
C.; Guagliardi, A.; Moliterni, A. G. G.; Polidori, G.; Spagna, R. SIR97. J.
Appl. Crystallogr. 1999, 32, 115-119.
(38) Sheldrick, G. M. SHELXL97; University of Gottingen: Germany,
1997.
1
970 cm-1; H NMR (CDCl3, 500 MHz) δ 4.19 (q, J ) 7.1 Hz,
1H), 4.18 (q, J ) 7.1 Hz, 1H), 3.59 (dd, J ) 12.1, 3.4 Hz, 1H),
3.48 (dd, J ) 12.1, 10.2 Hz, 1H), 2.95 (ddd, J ) 12.1, 2.4, 2.4 Hz,
1H), 2.71 (s, 1H), 2.62 (s, 1H), 2.42 (ddd, J ) 12.3, 7.0, 2.7 Hz,
1H), 2.21 (ddddd, J ) 12.4, 12.4, 12.4, 6.6, 6.6 Hz, 1H), 1.90 (dd,
J. Org. Chem, Vol. 71, No. 3, 2006 1151