Exploratory studies aimed at a synthesis of vinigrol. 3. Evaluation of a lactone bridge as a conformational lock

Article abstract of DOI:10.1021/jo0484575

(Chemical Equation Presented) Evaluated in the present investigation are possible synthetic approaches to vinigrol based on the involvement of lactone rings as tools for the conformational rigidification of functionalized cis-octalins. Emphasis was placed

Full text of DOI:10.1021/jo0484575

Exploratory Studies Aimed at a Synthesis of Vinigrol. 3.
Evaluation of a Lactone Bridge as a Conformational Lock
Leo A. Paquette* and Ivan Efremov
Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210
paquette.1@osu.edu
Received September 1, 2004
Evaluated in the present investigation are possible synthetic approaches to vinigrol based on the
involvement of lactone rings as tools for the conformational rigidification of functionalized cis-
octalins. Emphasis was placed on the structural arrangements resident in 3 and 5. The first of
these systems proved to be highly strained and inaccessible. Especially notable was the finding
that hydroxy ketenes 14 and 21 could be isolated and shown not to be amenable to cyclization
when heated. The stereocontrolled assembly of 5 was successfully accomplished through exploitation
of a related synthetic pathway. However, neither this attractive intermediate nor its close relative
33 could be processed in a manner that delivered the vinigrol framework. Nonetheless, several
features of the routes deployed offer the prospect of wider application in other contexts.
Since our attempts to advance syntheses of vinigrol (1)
either by intramolecular SN2 chemistry1 or by ring-
closure metathesis2 were not rewarded with success, the
deliberate decision was made to alter the system signifi-
cantly by imposing a suitable form of structural con-
straint. Iodolactones 3 and 5 came to be regarded as
candidates suited to our objectives. The projected use of
3 and 5 is reminiscent of a strategy employed by
Woodward in his reserpine synthesis.3
The perceived practical advantages of this approach
included the possible operation of stepwise conforma-
tional change and the availability of a large array of
lactonization protocols. In addition, the transformations
3 f 2 and 5 f 4 are to be driven by the migration of
negative charge from carbon (where it is generated by
metal-halogen exchange or oxidative addition) to oxygen,
a process that provides a thermodynamic driving force
for the reactions under consideration.
The plan of action was supported by molecular me-
chanics calculations4 involving 3 and 5. Two rather
dissimilar conformations prevail in each instance. The
differences in energy between the conformations are
compiled in Table 1. Of special note was the determina-
tion that 3a and 5b are virtually isoenergetic. This
consideration gave rise to the assumption that intercon-
version between the two conformers might well occur
freely, thereby allowing for bond-forming processes se-
lected for passage from 3 to 2 to operate without serious
impediment.
(1) Paquette, L. A.; Guevel, R.; Sakamoto, S.; Kim, I. H.; Crawford,
J. J. Org. Chem. 2003, 68, 6096.
(2) Paquette, L. A.; Efremov, I.; Liu, Z. J. Org. Chem. 2005, 70, 505.
(3) Woodward, R. B.; Bader, F. E.; Bickel, H.; Frey, A. J.; Kierstead,
R. W. Tetrahedron 1958, 2, 1.
Since iodolactone 3 offered the greatest promise on the
basis of this analysis, a synthetic route to this intermedi-
ate was developed first. As outlined in Scheme 1, the
(4) Allinger, N. L. J. Am. Chem. Soc. 1977, 99, 8127.
10.1021/jo0484575 CCC: $30.25 © 2005 American Chemical Society
Published on Web 12/09/2004
510
J. Org. Chem. 2005, 70, 510-513

Exploratory Studies Aimed at a Synthesis of Vinigrol. 3
periodinane reagent.5 Also encouraging was the unevent-
ful generation of carboxylic acid 11 upon subsequent
treatment with buffered sodium chlorite.6 When 11 was
subjected to the action of sodium borohydride, a mixture
of R- and â-alcohols was produced in 82% and 12% yield,
respectively. As a consequence of chromatographic in-
separability at this stage, all lactonization protocols were
performed on this mixture.
TABLE 1. Calculated Steric Energies for 3 and 5
Recourse was initially made to the Corey method,7 to
conditions developed by Yamaguchi,8 and to reagents
such as p-toluenesulfonic acid, EDC, and dibutyltin oxide9
in addition to simple fusion. All such conditions were to
no avail, showing no tendency for product formation. In
contrast, application of the Mukaiyama cyclization10 led
to clean formation of a single product. The spectral
features of this substance, most notably its distinctive
infrared (2091, vs), mass spectral (m/z 416.1145), and
NMR features (δ CdCdO ) 204.4, 135.9), confirmed it
to be the hydroxy ketene 14. The stability of this entity
is noteworthy. Not only does 14 survive aqueous workup
and mildly acidic conditions, but it also can be recovered
efficiently from chromatography on silica gel. At this
point, thermal cyclization appeared to be an attractive
option for the generation of lactone 3. Based on this line
of reasoning, several experiments were undertaken to
effect this attractive conversion. However, under no
circumstances was cyclized material produced at a useful
level. To illustrate, heating dilute, dry solutions of 14 in
xylenes (reflux) or 1,2-dimethoxyethane (150 °C, sealed
vessel) only returned starting material. A somewhat more
gratifying result was realized upon heating in diphenyl
ether in that a very small amount of nonpolar material
with the correct molecular mass could be recovered. This
matter was not further pursued because it obviously
lacked preparative utility.
a For the calculations, the encased substituents were replaced
by methyl groups.
SCHEME 1a
To substantiate our conclusion that the inability of 14
to experience cyclization resides in the elevated ring
strain of the lactone, an alternative pathway was pursued
wherein the iodine atom would be installed at a post-
lactonization stage. This goal was realized by an inver-
sion in the synthetic sequence (Scheme 2). The expecta-
tion that 151 could be chemically transformed into
hydroxy acid 19 was realized in four efficient steps.
Submission of 19 to the Mukaiyama conditions gave rise
before to a ketene. Although 21 exhibited no tendency to
experience cyclization to form lactone 22 under a variety
of conditions, this intermediate proved to be quite
unstable to acidic conditions and consequently did not
lend itself to further modification.
The preceding observations were meaningful in con-
tributing to our improved understanding of the three-
dimensional properties of these all-cis octalin systems.
The formation of lactones 3 and 22 is dependent on the
operation of conformational changes in both six-mem-
bered rings. Were this state of affairs readily attainable,
elaboration of the vinigrol framework would presumably
a Reagents and conditions: (a) DDQ, CH2Cl2, H2O (99%); (b)
Ph3P, imid, I2, CH2Cl2 (94%); (c) 1.0 M HCl, acetone (98%); (c)
Dess-Martin periodinane, CH2Cl2 (74%); (d) NaClO2, NaH2PO4,
t-BuOH, MeCN, H2O, 2-methyl-2-butene (quant); NaBH4, EtOH
(82% of 12, 12% of 13); (g) 2-chloro-1-methylpyridinium iodide,
MeCN, reflux, slow addition of 12 and Et3N (77%); (h) heat in
various solvents.
previously described bicyclic ketone 61 was the point of
origin. Following the removal of its PMB group by means
of DDQ in an aqueous solvent system, the liberated
hydroxyl substituent proved amenable to conversion into
iodide 8 in 94%yield. The second OH group was liberated
under acidic conditions, thereby allowing for conversion
to aldehyde 10 by oxidation with the Dess-Martin
(5) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(6) Hase, T.; Wa¨ha¨la¨, K. In Encyclopedia of Reagents for Organic
Synthesis; Paquette, L. A., Ed.; Wiley: Chichester, 1995; Vol. 7, p 4533.
(7) Corey, E. J.; Nicolaou, K. C. J. Am. Chem. Soc. 1974, 96, 5614.
(8) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. Jpn. 1979, 52, 1989.
(9) Steliou, K.; Szczygielska-Nowosielska, A.; Favre, A.; Poupart, M.
A.; Hanessian, S. J. Am. Chem. Soc. 1980, 102, 7578.
(10) Mukaiyama, T.; Usui, M.; Saigo, K. Chem. Lett. 1976, 49.
J. Org. Chem, Vol. 70, No. 2, 2005 511

Paquette and Efremov
SCHEME 2a
SCHEME 3a
a Reagents and conditions: (a) 1.0 M HCl, acetone (quant); (b)
Ph3P, imid, I2, CH2Cl2 (91%); (c) DDQ, CH2Cl2, H2O (quant); (d)
Swern oxidation (96%); (e) NaClO2, NaH2PO4, t-BuOH, MeCN,
H2O, 2-methyl-2-butene (quant); (f) NaBH4, EtOH (84%); (g)
2-chloro-1-methylpyridinium iodide, MeCN, reflux; slow addition
of 27 and Et3N (44%).
strong literature precedent,12 5 was also treated with zinc
powder in DME containing sodium iodide and water.
Only deiodinated material was obtained in 67% yield. If
water was scrupulously removed from the reaction
mixture and heating was applied incrementally, gradual
decomposition was uniquely observed. Barbier-type reac-
tions featuring magnesium as the active metal were
likewise examined, but without success. Various modi-
fications of Molander’s protocol13 also met with disap-
pointment.
For these reasons, we were directed to the examination
of other less obvious synthetic options. A ploy considered
interesting involved the possible conversion of aldehyde
33 to its dithioacetal 34 in preparation for the possible
olefination involving the lactone carbonyl. Titanium-
promoted reactions of this type have been developed by
Takeda.14 In this particular instance, treatment of the
intermediate enol ether with acid would give rise to the
targeted tricyclic structure 35 (Scheme 4). The avail-
ability of 33 could allow as well for examination of its
response to McMurry reaction conditions.15 Although the
intermediate enol ether would be rather strained, the
possibility exists that the chelating effect of titanium
might prove to serve as a significant driving force for
C-C bond formation.
a Reagents and conditions: (a) Swern oxidation (86%); (b)
NaClO2, NaH2PO4, t-BuOH, MeCN, H2O, 2-methyl-2-butene (quant);
(c) 1.0 M HCl, acetone; (d) NaBH4, EtOH (89%, two steps); (e) from
19, Ph3P, DEAD, THF, 0 °C; (f) 2-chloro-1-methylpyridinium
iodide, MeCN, reflux with slow addition of 20 and Et3N (73%).
ensue with relative ease. Our findings suggest this route
not to be viable. We undertook therefore to pursue the
construction of lactone 5. This intermediate could prove
to be a viable alternative since the cyclization leading to
this entity requires conformational flexing only within a
single ring. Should sufficient energy then be provided to
invert the second ring, the reactive functionalities would
be brought into proximity with each other and a second
cyclization leading to the vinigrol framework could
operate.
Ultimately, a set of conditions was devised to provide
5 (Scheme 3). With ketone 6 as the point of departure,
the “lower” hydroxyl group was chemoselectively un-
masked and converted to the iodo derivative 23. There
followed oxidative cleavage of the PMB group to give 24,
thereby setting the stage for two-step oxidation to car-
boxylic acid 26. Treatment of 26 with sodium borohydride
led predominantly to 27, which underwent conversion to
lactone 5 upon application of the Mukaiyama conditions.
The yield of 44% is not considered to be optimized.
With 5 in hand, the time had come to explore intramo-
lecular opening of its lactone ring. In a first experiment,
tert-butyllithium was added in an attempt to bring about
halogen-metal exchange, with nucleophilic attack at the
lactone carbonyl expected to follow.11 No cyclization
occurred at low temperatures. When heat was applied
incrementally, several products were obtained, each of
which had an intact lactone ring. On the strength of
The preparation of lactone aldehyde 33 began with the
previously accessed 7. Oxidation of its primary hydroxyl
to the carboxylic acid level was performed as before. The
conversion of 29 to 30 made possible arrival at lactone
31 (49%). Unexpectedly, this material proved to be an
unusually unstable compound. An underlying reason for
this phenomenon may be the presence of a space-
demanding -OTBS group in the interior of the molecule,
(12) Astudillo, L.; Gonza´lez, A. G.; Galindo, A.; Mansilla, H.
Tetrahedron Lett. 1997, 38, 6737.
(13) (a) Molander, G. A.; McKie, J. A. J. Org. Chem. 1993, 58, 7216.
(b) Molander, G. A.; Shakya, S. R. J. Org. Chem. 1994, 59, 3445.
(14) Rahim, M. A.; Sasaki, H.; Saito, J.; Fujiwara, T.; Takeda, T. J.
Chem. Soc., Chem. Commun. 2001, 625.
(11) (a) van der Does, T.; Klumpp, G. W.; Schakel, M. Tetrahedron
Lett. 1986, 27, 519. (b) Kim, D.; Kim, I. H. Tetrahedron Lett. 1997, 38,
415. (c) Kim, D.; Lee, Y. K. Tetrahedron Lett. 1991, 32, 6885.
(15) McMurry, J. E.; Miller, D. D. J. Am. Chem. Soc. 1983, 105, 1660.
512 J. Org. Chem., Vol. 70, No. 2, 2005

Exploratory Studies Aimed at a Synthesis of Vinigrol. 3
SCHEME 4a
SCHEME 5a
a Reagents and conditions: (a) 1.0 M HCl, THF (22%); (b) concd
HCl, THF (85%); (c) 2-chloro-1-methylpyridinium iodide, MeCN,
reflux; slow addition of 38 and Et3N (38%).
method,15,16 and the latter conditions were therefore
utilized. Unfortunately, extensive decomposition occurred
and none of the desired product was detected. When the
second important observation was made that 33 could
not be transformed into dithioacetal 34 in the presence
of Lewis acids,17 further studies along these lines were
shelved in favor of alternative ring contraction ap-
proaches.18
Overview. The use of a lactone bridge as a device to
merge otherwise awkwardly positioned functional side
chains has been explored. In the first instance involving
the structural elements resident in 3, high levels of ring
strain precluded assembly of the lactone ring. This state
of affairs became most clearly apparent when hydroxy
ketenes 14 and 21 failed to cyclize when thermally
activated. Lactone intermediates of type 5 did prove
amenable to synthesis as reflected in the production of
31-33 as well. Although this collective group of com-
pounds exhibited a reasonable level of hydrolytic stabil-
ity, their potential for added intramolecular C-C bond
formation could not be reduced to practice. The variety
of reductive ways deployed to achieve a desirable coupling
result validates the difficulties associated with generation
of the vinigrol framework.
a Reagents and conditions: (a) Swern oxidation (95%); (b)
NaClO2, NaH2PO4, t-BuOH, MeCN, H2O, 2-methyl-2-butene (quant);
(c) NaBH4, EtOH (91%); (d) 2-chloro-1-methylpyridinium iodide,
MeCN, reflux; slow addition of 30 and Et3N (49%); (e) HF-
pyridine, THF (89%); (f) Dess-Martin periodinane, CH2Cl2 (91%).
which translates into a rapid rate of hydrolysis of the
lactone bridge. While removal of the silyl protecting group
in 31 was consequently not a trivial task, it ultimately
proved possible to obtain 32 and to implement its
oxidation to 33 by means of the Dess-Martin periodinane
reagent.
A major byproduct of the lactonization step was
anhydride 36, isolated in 35% yield (Scheme 5). This
compound is the obvious end result of the intermolecular
capture of an activated form of the carboxylic acid,
perhaps the ketene, with a second molecule of 30.
Compound 36 becomes 37 on desilylation, thereby en-
abling recycling to 32 via 38. The recalcitrance of the
anhydride linkage in 36 and 37 to hydrolysis is notewor-
thy. For the conversion of 37 to 38 to proceed at a
reasonable rate, it was necessary to use 30% HCl in THF.
Advancement via Scheme 5 appeared to offer no advan-
tages relative to the forward progress defined in Scheme
4.
Acknowledgment. Partial financial support was
provided by Aventis and the Yamanouchi USA Founda-
tion whom we thank.
Supporting Information Available: Experimental de-
tails and high field 1H and 13C NMR spectra for all compounds
described herein. This material is available free of charge via
the Internet at http://pubs.acs.org.
The time had arrived to investigate the possibility of
converting 33 into 35 by means of the McMurry reaction.
Although keto-ester couplings have been successfully
performed with ketones only,16 the higher reactivity of
aldehydes could make matters problematic. TiCl3/LiAlH4
is recognized to be superior to the TiCl3/Zn-Cu-based
JO0484575
(17) (a) Kametani, T.; Suzuki, Y.; Honda, T. Heterocycles 1985, 23,
305. (b) Kametani, T.; Suzuki, Y.; Honda, T. Chem. Pharm. Bull. 1986,
34, 4971. (c) Tanoguchi, M.; Kashima, T.; Saika, H.; Inoue, T.; Arimoto,
M.; Yamaguchi, H. Chem. Pharm. Bull. 1989, 37, 68. (d) Kutney, J.
P.; Hewitt, G. M.; Jarvis, T. C.; Palaty, J.; Rettig, S. J. Can. J. Chem.
1992, 70, 2115.
(16) (a) McMurry, J. E. Chem. Rev. 1989, 89, 1513. (b) Lectka, T.
In Active Metals; Fu¨rstner, A., Ed.; Wiley-VCH: Weinheim, 1995; pp
85-131.
(18) Paquette, L. A.; Liu, Z.; Efremov, I. J. Org. Chem. 2005, 70,
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