Neighboring group effect in Pd-catalyzed carbonylation terminated by lactonization: A need for a protective group and/or DMF

Article abstract of DOI:10.1021/jo049114+

Synthesis of analogues of antifungal podolactones via Pd-catalyzed processes revealed that tandem 6-exo-alkyne carbopalladation/carbonylative lactonization sequence is strongly solvent-dependent. Contrary to earlier reports, premature esterification was t

Full text of DOI:10.1021/jo049114+

Neigh bor in g Gr ou p Effect in P d -Ca ta lyzed Ca r bon yla tion
Ter m in a ted by La cton iza tion : A Need for a P r otective Gr ou p
a n d /or DMF †
Radan Schiller,‡ Milan Pour,‡,* Helena Fa´kova´,‡ J irˇ´ı Kunesˇ,‡ and Ivana C´ısarˇova´§
Laboratory of Structure and Interactions of Biologically Active Molecules, Department of Inorganic and
Organic Chemistry, Faculty of Pharmacy, Charles University, Heyrovske´ho 1203,
CZ-500 05 Hradec Kra´love´, Czech Republic, and Department of Inorganic Chemistry, Faculty of Sciences,
Charles University, Albertov 6, CZ-118 23 Prague, Czech Republic
pour@faf.cuni.cz
Received May 26, 2004
Synthesis of analogues of antifungal podolactones via Pd-catalyzed processes revealed that tandem
6-exo-alkyne carbopalladation/carbonylative lactonization sequence is strongly solvent-dependent.
Contrary to earlier reports, premature esterification was the predominant pathway when the
starting enynes derived from (Z)-2-iodohex-2-en-1,4-diol were subjected to Pd-catalyzed carbonylation
in MeOH. Apparently, irreversible complexation of Pd by the OH group prevented decarbonylation
and hence 6-exo-alkyne carbopalladation. Similarly, the influence of the chelation was also evident
when the reaction was applied to the analogous preparation of 3-hydroxymethylbutenolides. The
neighboring group effect can be efficiently overcome through using DMF as the solvent in
combination with protection of the OH function.
In tr od u ction
In the course of exploring antifungal properties of
analogues of natural butenolides, we found that the
presence of an unsaturated γ-lactone moiety in combina-
tion with a halogen-substituted phenyl ring (structure
1) attached to the R-position is essential for a compound
to display significant antifungal activity.1 Following on
from these results, we became interested in elucidating
the properties of δ-lactones bearing a similar substitu-
tion, since literature reports indicated that structurally
related pyranones would highly likely exhibit the same
biological effect. Most notably, Barrero et al. concluded2
that the presence of the 7,9(11)-dien-12,17-olide moiety
in podolactones and related compounds, exemplified by
2, is the structural feature responsible for their antifun-
gal activity, and the structure of another potent natural
antifungal,3 CR 377 (3), is based on 5-methylene-5,6-
dihydro-2H-pyran-2-one. Thus, we assumed that biologi-
cal evaluation of simple analogues of type 4 and 5 will
provide further insight into the origin of antifungal
activity of podolactone-related compounds.
F IGURE 1. Selected butenolides and pentenolides with
antifungal activity.
In choosing compounds 4 and 5 for a large-scale
synthesis and biological screening, we were guided by two
requirements. First, consistent with the natural products,
the analogues must incorporate the above structural
features, and, second, they should be preparable in
quantities, sufficient for extensive pharmacological evalu-
ation, as economically as possible. While both compounds
possess the dienolide function, lactone 5 has also a phenyl
ring attached to the R-position of the functional group,
as in butenolides of type 1. As regards the latter require-
ment, these compounds would be easily accessible via
intramolecular carbopalladation/carbonylative lactoniza-
tion of easy-to-make enyne precursors, a sequence, the
* Corresponding author.
† Dedicated to Professor Lew Mander on the occasion of his 65th
birthday.
‡ Department of Inorganic and Organic Chemistry.
§ Department of Inorganic Chemistry
(1) (a) Pour, M.; Sˇpula´k, M.; Balsˇa´nek, V.; Kunesˇ, J .; Buchta, V.;
Waisser, K. Bioorg. Med. Chem. Lett. 2000, 10, 1893. (b) Pour, M.;
Sˇpula´k, M.; Buchta, V.; Kubanova´, P.; Voprsˇalova´, M.; Wso´l, V.;
Fa´kova´, H.; Koudelka, P.; Pourova´, H.; Schiller, R. J . Med. Chem. 2001,
44, 2701. (c) Pour, M.; Sˇpula´k, M.; Balsˇa´nek, V.; Kunesˇ, J .; Buchta, V.
Bioorg. Med. Chem. 2003, 11, 2843. (d) Buchta, V.; Pour, M.; Kubanova´,
P.; Silva, L.; Votruba, I.; Voprsˇalova´, M.; Schiller, R.; Fa´kova´, H.;
Sˇpula´k, M. Antimicrob. Agents Chemother. 2004, 48, 873.
(2) Barrero, A. F.; Arseniyadis, S.; Qu´ılez del Moral, J . F.; Mar
Herrador, M.; Valdivia, M.; J ime´nez, D. J . Org. Chem. 2002, 67, 2501.
(3) Brady, S. F.; Clardy, J . J . Nat. Prod. 2000, 63, 1447.
10.1021/jo049114+ CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/04/2004
J . Org. Chem. 2004, 69, 6761-6765
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Schiller et al.
development of which is connected with the contributions
of E. Negishi and his group as well as some others.4
obtaining polymeric material. Surprisingly, cyclization of
enyne 14 turned out to be an extremely sluggish reaction
(ca. 50% conversion after 24 h), affording one major
product. Contrary to previous reports,4b the material was
identified as a 4:1 mixture of the product of premature
esterification 15 and the desired lactone 5, extremely
difficult to separate by column chromatography. The
structure of the major triester 15 was evident from one-
dimensional NMR spectra: the carbons of the triple bond
at 84.1 and 83.9 ppm were clearly apparent in the 13C
spectrum, while a new singlet of a methyl ester group
appeared at 3.72 ppm in the 1H spectrum. Since our
experience hinted at a possible negative role of the
hydroxy function in the vicinity of the reaction center,
the reaction was run in DMF9 as the solvent. In this case,
the desired bicyclic compound was obtained in 72% yield
in a mere 3 h.
Resu lts a n d Discu ssion
The preparation of enynes 13 and 14 is outlined in
Scheme 1. Hydroalumination of THP-protected but-2-yn-
SCHEME 1. P r ep a r a tion of Ca r bop a lla d a tion /
Ca r bon yla tive La cton iza tion P r ecu r sor s
The structure of unsaturated lactone 5 was unequivo-
cally corroborated by X-ray (Figure 2). The cyclization of
1,4-diol 6 with Red-Al terminated by iodination5 afforded
alkenyl iodide 7. The hydroxy group in compound 7 was
converted, instead of the somewhat unstable mesylate,6
into the bromo substituent with NBS/Me2S.7 The result-
ant derivative 8 was again formed in high yield8 and was
stable enough to be purified by conventional column
chromatography. Finally, compound 8 readily furnished
enynes 11 and 12 on treatment with carbanions 9 and
10, respectively (anion 10 was generated from dimethyl-
(3-phenylprop-2-yn-1-yl)malonate, prepared via standard
Sonogashira coupling from dimethyl-propargylmalonate,
see Supporting Information), and the hydroxy group was
liberated by hydrolysis.
Following the finding4b that in similar reactions,
methanol proved to be a highly satisfactory solvent,
superior to, e.g., DMF, THF, and others, enynes 13 and
14 were subjected to standard carbonylation at 1 atm CO
in MeOH (Scheme 2). In our hands, however, several
F IGURE 2. X-ray structure of dienolide 5.
14 was also attempted in i-PrOH as a solvent and under
the conditions described by Stille10 (THF, K2CO3,
NH2NH2). The use of i-PrOH11 led to a complex mixture
of products, while no reaction was observed in the latter
case.
SCHEME 2. Ta n d em Ca r bop a lla d a tion /
Ca r bon yla tive La cton iza tion of 14 in MeOH a n d
DMF
(4) (a) For a review, see: Negishi, E.-i.; Cope´ret, C.; Ma, S.; Liou,
S.-Y.; Liu, F. Chem. Rev. 1996, 96, 365. (b) Sugihara, T.; Cope´ret, C.;
Owczarczyk, Z.; Harring, L. S.; Negishi, E.-i. J . Am. Chem. Soc. 1994,
116, 7923. (c) Grigg, R.; Sridharan, V. J . Organomet. Chem. 1999, 576,
65.
(5) (a) Denis, R. C.; Gravel, D. Tetrahedron Lett. 1994, 35, 4531. (b)
Denmark, S. E.; J ones, T. K. J . Org. Chem. 1982, 47, 4595.
(6) Treatment of (Z)-3-iodo-4-triphenylmethoxybut-2-en-1-ol with
MsCl afforded the corresponding mesylate in 40% isolated yield; see:
Cope´ret, C.; Ma, S.; Sugihara, T.; Negishi, E.-i. Tetrahedron 1996, 52,
11529.
(7) Corey, E. J .; Kim, C. U.; Takeda, M. Tetrahedron Lett. 1972, 13,
4339.
(8) Piers et al. obtained nearly the same results on treatment of
(Z)-3-iodo-4-benzyloxybut-2-en-1-ol, prepared via a different route, with
Ph3P‚Br2/imidazole; see: Piers, E.; Harrison, C. L.; Zetina-Rocha, C.
Org. Lett. 2001, 3, 3245.
(9) DMF has been shown to be one of the most desirable solvents
for Pd-catalyzed cross-coupling reactions (Negishi, E.-i.; Owczarczyk,
Z.; Swanson, D. R. Tetrahedron Lett. 1991, 32, 4456) and has been
frequently used in carbonylation reactions as well.
attempts to reproduce the cyclization4b of the known
enyne 13 with a terminal triple bond resulted only in
(10) Cowell, A.; Stille, J . K. J . Am. Chem. Soc. 1980, 102, 4193.
6762 J . Org. Chem., Vol. 69, No. 20, 2004

Neighboring Group Effect in Pd-Catalyzed Carbonylation
Encouraged by these results, we subjected the THP-
protected enyne 12 to the same cyclization conditions.
This time, lactone 5 w a s th e sole p r od u ct r ega r d less
of th e solven t u sed ; time and yield was the only
difference12 (Scheme 3). When DMF was employed as the
renders this assumption very unlikely. A plausible mech-
anism (Scheme 5) probably involves a direct nucleophilic
SCHEME 5. P ossible Mech a n ism of THP
Dep r otection
SCHEME 3. Ta n d em Ca r bop a lla d a tion /
Ca r bon yla tive La cton iza tion of P r otected
Com p ou n d 12 in MeOH a n d DMF
displacement of Pd, enabled by the lability of the C(O)-
Pd bond, which results in the regeneration of Pd0. The
protective group is then cleaved, with this process being
boosted by the assistance of the oxygen in the tetra-
hydropyranyl ring, and, finally, the resultant cation is
quenched by the reaction with Et3N. Similarly, Larock
has shown13 by converting 2-iodoanisole into 3,4-dipro-
pylcoumarin in the presence of oct-4-yne that even a
methoxy group can be deprotected under carbonylative
lactonization conditions. In that case, the need of a direct
nucleophilic attack for the methyl group to be sequestered
was probably the only difference from the cleavage of the
THP moiety described herein. Thus, it is more than likely
that a similar mechanism would also operate for all those
protective groups, which do not substantially reduce the
nucleophilicity of the protected oxygen atom (acetals, silyl
groups, etc.). For this reason, the cleavage of acyl groups
(see Scheme 8) in these reactions is improbable.
solvent, the yield was significantly higher (by 17%) as
compared to the cyclization of enyne 14 with the OH
function free.
Thus, the preparation of 5 was cut by one step, and
the smooth cyclization of the protected compound brought
further evidence of the unfavorable influence of the OH
group.
The results obtained with DMF as the solvent and/or
with the OH group protected can be interpreted in terms
of the well-documented reversibility of CO insertion. With
an equilibrium between 16 and 17 being established, the
major reaction pathway is dictated by the relative rates
of the subsequent conversions of the vinyl- and acylpal-
ladium species4b,13 (Scheme 4). Consequently, the fast
SCHEME 4. Equ ilibr iu m betw een
Alk en ylp a lla d iu m Sp ecies 16 a n d Acylp a lla d iu m
In ter m ed ia te 17
On the other hand, when the OH function is free and
a less coordinating solvent is employed in the carbony-
lative lactonization process, it is highly likely that there
is no equilibrium between alkenylpalladium 20 and
acylpalladium species 21 due to the formation of a
relatively stable five-membered cyclic complex, arising
from the coordination of the OH group to Pd (Scheme 6).
6-exo-alkyne carbopalladation opens up the channel
leading to 5, while trapping acylpalladium species 17
with a solvent nucleophile proceeds at a negligible rate.
Importantly, the reversibility of the CO insertion step
also indicates that a possible stabilization of 17 arising
from O to Pd coordination (vide infra), if any occurs at
all, is very weak.
SCHEME 6. P r even tion of Deca r bon yla tion by th e
F or m a tion of Ch ela te 21
It was interesting but not totally surprising that the
acetal protective group constituted no obstacle to lacton-
ization and was deprotected under the reaction conditions
that were essentially basic, with the yield of lactone 5
having been higher than in the cyclization of 14. While
it is tempting to speculate that the cleavage of the THP
group in the acylpalladium species 18 is assisted by PdII,
the above conclusion that the chelation ability of THP-
protected oxygen is very low even if a relatively stable
5-membered complex (see Scheme 6) could be formed
Given the fact that 6-exo intramolecular carbopalladation
is a fast process, the isolation of 15 as the major product
of the reaction of 14 in MeOH indicates that (1) the
complexation is an irreversible process and (2) CO
insertion must be faster than intramolecular carbopal-
ladation, even at 1 atm CO. With CO being “locked” as a
(11) See the literature in ref 6.
(12) In MeOH as the solvent (53% yield), the rest was recovered
starting material.
(13) For the most recent results supporting this view, see also:
Kadnikov, D. V.; Larock, R. C. J . Org. Chem. 2003, 68, 9423.
J . Org. Chem, Vol. 69, No. 20, 2004 6763

Schiller et al.
consequence of complex formation, 21 has no choice but
to undergo a slow decomposition by an external nucleo-
phile (carbonylation of 14 in MeOH, vide supra) or
remain unchanged in the reaction mixture (carbonylation
of 14 in THF, vide supra). The picture outlined in Scheme
6 complements the conclusions (Scheme 4), valid in those
cases4b,13 where the equilibrium between vinyl- or aryl-
and acylpalladium intermediates exists. In this instance,
decarbonylation is prevented and the rate of CO insertion
versus that of intramolecular carbopalladation governs
the composition of the reaction mixture.
On the other hand, the bis-protected compound 28
offered very low, if any, chance of O to Pd chelation as
well as participation by the ether oxygen as an internal
SCHEME 8. Ca r bon yla tion of Bis-P r otected
Com p ou n d 26
With a view to obtaining further experimental support
for chelate formation, we turned our attention to more
simple vinyl iodides 22, 23, and 28, because they possess
the same structural features giving rise to chelate
formation as 11-14, and subjected them to carbonylation
in both DMF and MeOH under otherwise identical
conditions. Apart from having different protective group
patterns that offer interesting possibilities of complex
formation, the carbonylation of compounds 22 and 23
would furnish 3-hydroxymethylbutenolides, potentially
useful as synthetic intermediates. Compound 23 was
prepared via hydroalumination/iodination of 2-methyl-
6-(tetrahydropyran-2-yloxy)hex-4-yn-3-ol14 (see Scheme
1) and converted into its derivatives 22 and 28 by
standard deprotection and acetylation, respectively. As
expected, carbonylation of iodo alcohols 22 and 23
(Scheme 7) brought further evidence of O to Pd chelation
nucleophile. Accordingly, a slow external trapping of the
acylpalladium intermediate16 with MeOH in a sterically
demanding environment leading to ester 29 was the
predominant pathway both in MeOH and DMF with 10
equiv of MeOH, as shown in Scheme 8.
Some literature results provide further support for the
assumption on the formation of five-membered σ-acylpal-
ladium complexes as intermediates in the Pd-catalyzed
carbonylative lactonizations (Figure 3). Thus, Hegedus
SCHEME 7. Ca r bon yla tion of Bu ten olid e
P r ecu r sor s 22 a n d 23
F IGURE 3. Examples of the formation of five-membered Pd
chelates.
and others17 explored aminocarbonylation of olefins and
showed that Pd forms analogous â-aminoacylpalladium-
(II) chelates (30) through the coordination of N to Pd.
Having been much more stable than the oxygen ana-
logues described herein, the complexes could be isolated
and characterized by X-ray. Closely related σ-alkyl-
palladium complexes were also isolated and character-
ized, if they were part of a five-membered chelate ring.18
In a similar case, Kocˇovsky´ and co-workers19 reported a
convincing example of steering the attack on a double
bond by the precoordination of the metal to a neighboring
OH group (31).
Con clu sion
In summary, we have described the influence of the
free hydroxy function, arising from the complexation of
in Pd-catalyzed reactions: while the formation of complex
26 may occur in both cases, CO insertion is apparently
facilitated through another complex formation (27) only
when the second OH group remains free. Consequently,
carbonylations of diol 22 gave significantly higher yields
of the butenolide product15 than those of 23, and the
reaction of monoprotected compound 23 in MeOH was
synthetically useless, since most of the starting material
underwent decomposition.
(16) In this case, the initially formed alkenylpalladium intermediate
could have been stabilized by the chelation of the carbonyl oxygen to
Pd, even though it should be noted that a seven-membered chelate
ring would thus be formed. This kind of stabilizing effect has been
proposed by Maleczka et al. to explain the regioselectivity of Pd-
mediated hydrostannations of terminal alkynes; see: Rice, B. M.;
Whitehead, S. L.; Horvath, C. M.; Muchnij, J . A.; Maleczka, R. E., J r.
Synthesis 2001, 1495.
(17) (a) Hemmer, H.; Rambaud, J .; Tkatchenko, I. J . Organomet.
Chem. 1975, 97, C57. (b) Hegedus, L. S.; Anderson, O. P.; Zetterberg,
K.; Allen, G.; Siirala-Hansen, K.; Olsen, D. J .; Packard, A. B. Inorg.
Chem. 1977, 16, 1887.
(18) (a) See ref 17a. (b) Hines, L. F.; Stille, J . K. J . Am. Chem. Soc.
1972, 94, 485. (c) Cope, A. C.; Kliegman, M.; Friedrich, E. C. J . Am.
Chem. Soc. 1967, 89, 287. (d) Holton, R. A.; Kjonaas, R. A. J . Am. Chem.
Soc. 1977, 99, 4177. (e) Holton, R. A.; Kjonaas, R. A. J . Organomet.
Chem. 1977, 142, C15.
(19) Kocˇovsky´, P.; Dunn, V.; Gogoll, A.; Langer, V. J . Org. Chem.
1999, 64, 101.
(14) Kimura, M.; Tanaka, S.; Tamaru, I. Bull. Chem. Soc. J pn. 1995,
68, 1689.
(15) Similar â-hydroxyalkylbutenolides were prepared by Hoye et
al. under the Stille carbonylation conditions, see: Hoye, T. R.; Humpal,
P. E.; J ime´nez, J . I.; Mayer, M. J .; Tan, L.; Ye, Z. Tetrahedron Lett.
1994, 35, 7517.
6764 J . Org. Chem., Vol. 69, No. 20, 2004

Neighboring Group Effect in Pd-Catalyzed Carbonylation
extracted with Et2O. Organic layers were dried over anhydrous
Na2SO4 and the solvent removed. The residue was chromato-
graphed on silica gel (hexanes/Et2O 7:3) to afford 87 mg (89%)
of white crystals of lactone 5. Mp 126-128 °C. 1H NMR: (300
MHz, CDCl3) δ 7.46-7.33 (3H, m, Ar), 7.29-7.25 (2H, m, Ar),
6.08-6.03 (1H, m, H8), 4.96-4.93 (2H, m, H1), 3.68 (6H, s,
COOCH3), 2.90 (2H, s, H5), 2.88-2.84 (2H, m, H7). 13C NMR:
(75 MHz, CDCl3) δ 170.3, 163.9, 143.2, 133.6, 129.9, 128.2,
127.9, 127.3, 126.95, 126.90, 68.6, 53.7, 53.1, 32.4, 31.0. IR:
(CHCl3) νmax 3027 (s), 2956 (s), 2845 (w), 2359 (w), 1732 (s),
1712 (s), 1647 (m), 1437 (s), 1264 (s) cm-1. MS: 343 (M+, 1),
329 (2), 325 (50), 311 (5), 297 (8), 283 (32), 281 (10), 279 (1),
265 (100), 255 (10), 251 (8), 237 (14), 233 (1), 223 (42), 221 (4),
205 (4), 193 (6), 189 (4), 167 (1), 149 (2), 121 (1), 115 (1), 104
(2). Identity and purity of the crystals was confirmed by X-ray
analysis (see Supporting Information for details).
the OH group to Pd, in Pd-mediated carbonylations. Even
though the resultant chelates are mere intermediates in
these reactions, they are stable enough to influence the
rate and even prevent the reversibility of the CO inser-
tion step. Hence, this phenomenon can play an important
role in the synthesis of biologically interesting butenolide
and pentenolide analogues via catalytic reactions involv-
ing Pd. The effect can be overcome by a judicious choice
of the protective group and/or solvent; interestingly, the
lactonization step does not require a free hydroxy func-
tion and proceeds with a THP-protected internal OH
group as well. On the basis of this observation, we have
established access to the desired bicyclic lactones via a
high-yielding, short, and reproducible path. Further
utilization of these results both in synthesis of natural
products and their analogues as well as biological evalu-
ation is in progress, and the results will be reported in
due course.
Ack n ow led gm en t. This work was supported by the
Grant Agency of the Czech Republic (Project 203/04/
2134).
Exp er im en ta l Section
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectral data for new compounds, copies of 13C
NMR spectra, and crystallographic information on dienolide
5. This material is available free of charge via the Internet at
http://pubs.acs.org.
Dim e t h yl-4-p h e n yl-3-oxo-3,5,6,7-t e t r a h yd r o-1H -iso-
ch r om en e-6,6-d ica r boxyla te (5). A solution of iodide 14 (150
mg, 0.28 mmol), Et3N (0.16 mL, 1.12 mmol), and Cl2Pd(PPh3)2
(10 mg, 5 mol %) in dry DMF (3 mL) was stirred at 60 °C under
1 atm CO for 3 h. The mixture was poured into H2O and
J O049114+
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