A short entry to a-substituted 7-alkylidene pentenolides. Synthesis and preliminary biological evaluation of novel gelastatin analogues

Article abstract of DOI:10.1021/jo802082t

Biologically interesting 2-substituted 4-alkylidene pentenolides were prepared with complete control of regio-and stereoselectivity from 2-iodo allylic alcohols via an array of Pd-catalyzed processes, including alkynylation with methyl propiolate, tributy

Full text of DOI:10.1021/jo802082t

A Short Entry to r-Substituted γ-Alkylidene Pentenolides. Synthesis
and Preliminary Biological Evaluation of Novel Gelastatin
Analogues
ˇ
ˇ
Jan Pavl´ık, Ivan Snajdr, Jirˇ´ı Kunesˇ, Marcel Spula´k, and Milan Pour*
Centre for New AntiVirals and Antineoplastics, Department of Inorganic and Organic Chemistry, Charles
UniVersity, Faculty of Pharmacy, HeyroVske´ho 1203, CZ-500 05 Hradec Kra´loVe´, Czech Republic
pour@faf.cuni.cz
ReceiVed September 22, 2008
Biologically interesting 2-substituted 4-alkylidene pentenolides were prepared with complete control of
regio- and stereoselectivity from 2-iodo allylic alcohols via an array of Pd-catalyzed processes, including
alkynylation with methyl propiolate, tributyltin hydride addition, and R-functionalization. Some of the
compounds possess selective cytostatic activity against ovarian carcinoma HeLa S3 and leukemia CCRF-
CEM cell lines.
Introduction
The development of novel drugs inspired by natural products
(NP) has been particularly successful in the advancement of
new antineoplastic and antiinfective agents into the clinic.1 This
approach, i.e., the synthesis and biological evaluation of small
series of NP analogues, may prove to be a more rational
approach towards novel medicinal agents than the production
of large combinatorial libraries. Accordingly, the goal of a
synthetic medicinal chemist pursuing an NP lead should be the
development of a short synthetic route that would allow access
to a maximum number of possible analogues.
Bioactive γ-alkylidene butenolides are widely distributed
throughout the plant kingdom and have inspired many synthetic
efforts.2,3 Surprisingly though, the synthesis of pentenolide
analogues, i.e., 4-alkylidene pentenolides, has been virtually
unexplored, probably because most of the biologically active
FIGURE 1. Structures of the gelastatins and CR377.
pentenolides comprise the R,ꢀ-unsaturated δ-lactone unit with
a structurally complex substituent attached at C5.4 Our interest
in 4-alkylidene pentenolides stems from a few recent reports
on the activity of pentenolide natural products against a range
of biological targets suggesting that they may be privileged
structures for drug development. By way of example, gelastatins
A and B (Figure 1) are structurally unique inhibitors5 of matrix
metalloproteases (MMPs) responsible for tissue remodeling and
degradation of the extracellular matrix. These enzymes are
involved in malignant pathologies and constitute promising
(1) Cho, Y. S.; Wu, K.-D.; Moore, M. A. S.; Chou, T.-C.; Danishefsky, S. J.
Drugs Future 2005, 30, 737.
(2) For reviews on γ-alkylidene butenolide synthesis, see: (a) Negishi, E.;
Kotora, M. Tetrahedron 1997, 53, 6707. (b) Bru¨ckner, R. Curr. Org. Chem.
2001, 5, 679.
(3) For the most recent examples of γ-alkylidene butenolide synthesis, see:
(4) For a review on isolation and biological activity, see: (a) Collett, L. A.;
Davies-Coleman, M. T.; Rivett, D. E. A. Prog. Chem. Org. Nat. Prod. 1998,
75, 181. (b) For a recent review on synthesis, see: Boucard, V.; Broustal, G.;
Campagne, J. M. Eur. J. Org. Chem. 2007, 225.
(5) Lee, H.-J.; Chung, M.-C.; Lee, C.-H.; Yun, B.-S.; Chun, H.-K.; Kho,
Y.-H. J. Antibiot. 1997, 50, 357.
ˇ
(a) Fa´kova´, H.; Pour, M.; Kunesˇ, J.; Senel, P. Tetrahedron Lett. 2005, 46, 8137.
(b) Xu, H.-W.; Wang, J.-F.; Liu, G.-Z.; Hong, G.-F.; Liu, H.-M. Org. Biomol.
Chem. 2007, 5, 1247. (c) Boukouvalas, J.; Beltra´n, P. P.; Lachance, N.; Coˆte´,
ˇ
S.; Maltais, F.; Pouliot, M. Synlett 2007, 219. (d) Nova´k, P.; Pour, M.; Spula´k,
M.; Votruba, I.; Kotora, M. Synthesis 2008, 3465.
10.1021/jo802082t CCC: $40.75
Published on Web 12/04/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 703–709 703

Pavl´ık et al.
targets for anticancer therapy.6 CR 377 is another natural
product7 with potent antifungal activity against Candida albi-
cans.
SCHEME 2. Proposed Pathways to 2-Substituted
γ-Alkylidene Pentenolides
Given the biological effects of the above NPs and apparent
analogy to biologically active alkylidene butenolides, the
2-substituted 4-alkylidene pentenolide skeleton was believed to
be an interesting scaffold for the preparation and biological
evaluation of a small library. Since the published syntheses of
the gelastatins8 and their 4-benzylidene analogues9 involve 13
and 12 steps, respectively, that are not readily adjusted to the
preparation of analogues, we set out to develop a general
pathway to this class of compounds that would enable the
attachment of a broad array of substituents to both positions.
Results and Discussion
The easiest possible path to 2-substituted 4-alkylidene pen-
tenolides, outlined in Scheme 1, is based on the sequential
functionalization of the commercially available 5,6-dihydro-2H-
pyran-2-one (1). As is the case with the analogous butenolide
core, the γ position can be functionalized via enolate formation
and subsequent reaction with aldehydes10 (steps 1 and 2), and
Johnson R-iodination11 followed by a coupling process (steps
3 and 4) would introduce a substituent into the R position.
of each contains the 4-alkylidene unit as well as vinyl iodide
and hydroxymethyl groups that are integral for the construction
of the six-membered ring (Scheme 2). In addition, the Z1-
protected OH group should facilitate production of compound
libraries at this position. Apparently though, the Z1-protected
OH group is not crucial for the strategy and can be replaced by
other substituents.
SCHEME 1. Direct Functionalization of the Pentenolide
Core
Thus, Sonogashira coupling with an alkyne, followed by
trans-hydrometalation/iodination of the triple bond, would
deliver an iodo alcohol that would be subjected to carbonylation
in the last step (path a). Alternatively, attachment of a propiolic
acid ester via a suitable coupling would deliver the remaining
portion of the pentenolide ring. A stereoselective cis-hydro-
metalation of the conjugated triple bond would set the stage
for another coupling process in the R-position as well as the
ring closure (path b).
The preparation of 2,5-disubstituted pentenolides from ho-
mopropargylic alcohols through OH group-directed trans-
hydroalumination/iodination followed by Pd-catalyzed carbo-
nylative lactonization has been described13 recently by us.
However, this sequence is limited to substrates with a stable
aryl group on the triple bond due to the harsh hydrometalation
conditions. Thus, simple (E)-2-(2-phenylethynyl)-but-2-en-1-
ol (3) was prepared via standard Sonogashira coupling first and
subjected to sequential treatment14 with Red-Al and I2 in order
to assess the influence of the alkylidene moiety on the
hydrometalation process (Scheme 3). However, the reaction gave
an inseparable mixture of the starting material with less than
5% of the product as judged by NMR, and increasing both
temperature and time led to complete decomposition.
In practice, all attempts to introduce the alkylidene moiety
into position 4, including simple enolate generation/quenching
with an aldehyde,10a as well as treatment10b of 1 with an
aldehyde in the presence of TBDMSOTf/DIPEA followed by
DBU-induced elimination, resulted in the decomposition of the
unsaturated pyranone. NMR spectra of the crude reaction
mixtures indicated that under basic conditions, the pentenolide
ring is much more prone to opening than its butenolide congener.
It quickly became apparent that de novo construction of the
pentenolide core with the desired substitution already in place
would be preferable to repeating reactions from the butenolide
system.
(E)- and (Z)-2-iodobut-2-en-1,4-diols were considered12 as
suitable four-carbon synthons in this approach. The structure
(6) For reviews on MMPs, see: (a) Gupta, S. G. Chem. ReV. 2007, 107, 3042.
(b) Verma, R. P.; Hansch, C. Bioorg. Med. Chem. 2007, 15, 2223.
(7) Brady, S. F.; Clardy, J. J. Nat. Prod. 2000, 63, 1447.
(8) Lee, H.-Y.; Tae, H. S.; Kim, B. G.; Choi, H.-M. Tetrahedron Lett. 2003,
44, 5803.
(9) (a) Cho, J.-H.; Ko, S. Y.; Oh, E.; Park, J. C.; Yoo, J. U. HelV. Chim.
Acta 2002, 85, 3994. (b) Kim, E. J.; Ko, S. Y. Bioorg. Med. Chem. 2005, 13,
4103.
SCHEME 3. Attempted Hydroalumination of 3
(10) For recent examples, see: (a) Pohmakotr, M.; Tuchinda, P.; Premkaisorn,
P.; Reutrakul, V. Tetrahedron 1998, 54, 11297–11304. (b) Boukouvalas, J.;
Lachance, N.; Ouellet, M.; Trudeau, M. Tetrahedron Lett. 1998, 39, 7665–7668.
(c) Bellina, F.; Anselmi, Ch.; Viel, S.; Mannina, L.; Rossi, R. Tetrahedron 2001,
57, 9997–10007. (d) Boukouvalas, J.; Pouliot, M. Synlett 2005, 343. (e) Bellina,
F.; Anselmi, Ch.; Rossi, R. Tetrahedron Lett. 2002, 43, 2023–2027. (f) Bellina,
F.; Anselmi, Ch.; Martina, F.; Rossi, R. Eur. J. Org. Chem. 2003, 2290–2302.
(11) Johnson, C. R.; Adams, J. P.; Braun, M. P.; Senanayake, C. B. W.;
Wovkulich, P. M.; Uskokovic´, M. R. Tetrahedron Lett. 1992, 33, 917.
(12) For recent synthetic applications of these synthons, see: (a) Schiller,
R.; Pour, M.; Fa´kova´, H.; Kunesˇ, J.; C´ısaˇrova´, I. J. Org. Chem. 2004, 69, 6761.
(b) Reference 3a.
ˇ
(13) Snajdr, I.; Pavl´ık, J.; Schiller, R.; Kunesˇ, J.; Pour, M. Collect. Czech.
Chem. Commun. 2007, 72, 1472.
(14) (a) Marshall, J.; Shearer, B.; Crooks, S. J. Org. Chem. 1987, 52, 1236.
(b) Denmark, S. E.; Jones, T. K. J. Org. Chem. 1982, 47, 4595. (c) Crousse, B.;
Alami, M.; Linstrumelle, G. Synlett 1997, 992.
704 J. Org. Chem. Vol. 74, No. 2, 2009

R-Substituted γ-Alkylidene Pentenolide
The poor results led us to explore the alternative route
whereby the iodo alcohols 5 and 6 were prepared by protecting
the known (Z)-4-tert-butylsilyloxy-3-iodobut-2-en-1-ol15 and
(E)-3-iodobut-2-en-1,4-diol16 as THP-ethers followed by cou-
pling with methyl propiolate (path b) to afford the enyne esters
7 and 8 (Scheme 4).
FIGURE 2. Structures of O to Pd chelates.
SCHEME 4. Negishi Coupling of Iodides 5 and 6
Pd-catalyzed hydrostannation20,21 of enyne esters 7 and 8 was
explored during the next stage of the scaffold synthesis (Scheme
5). In both cases, we expected the electronic effect of the ester
group to steer the course of the addition.22 Accordingly, ester
8 underwent a smooth stereo- and regioselective addition, while
a somewhat surprising loss of regioselectivity was observed in
the hydrostannation of 7; the identity of both regioisomers 11
and 12 was established from NOE connectivities, as depicted
in Scheme 5.
SCHEME 5. Pd-Catalyzed Hydrostannation of Enyne
Esters 7 and 8
TABLE 1. Catalyst Screening for the Coupling of 5 and 6
SM
catalyst
product
yield (%)
5
5
5
5
5
6
6
6
6
6
6
5% Pd(PPh3)4
7
7
7
7
7
8
8
8
8
8
8
30
35
61
56
10
14
20
37
16
25
72
5% Pd2dba3, 20% (Biphenyl-2-yl)Cy2P
5% Pd2dba3, 20% TFP
5% (TFP)2PdCl2
10% PEPPSI-iPra
5% Pd2dba3, 20% Cy3P
5% Pd2dba3, 20% (Biphenyl-2-yl)Cy2P
5% Pd2dba3, 20% (t-Bu)2CH3P
5% Pd2dba3, 20% dppf
5% Pd2dba3, 20% TFP
10% (TFP) PdCl2/20% BuLi
2
a [1,3-Bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)-
palladium(II) dichloride.
Even though chelation of the organopalladium intermediate
might again be invoked to explain this result, Alami et al. have
recently reported23 that the regioselectivity of Pd-catalyzed
hydrostannation of (Z)-enynols analogous to 7 is controlled by
the geometry of the double bond (Z- or syn-directing effect)
rather than the nature of the substituents. Hence, the formation
of both regioisomers in the hydrostannation of 7 is more likely
the result of the competition between the electronic effect of
the ester group (favoring 11) and the syn-directing effect arising
from the geometry of the double bond (favoring 12). Because
11 and 12 formed an inseparable mixture, the last step of the
sequence was investigated with ester 13 as the starting material.
Although preliminary experiments have shown a good ability
of ester 13 to cross-couple, subsequent hydrolysis/ring closure
was surprisingly difficult. For example, 13 underwent smooth
cross-coupling reactions with ethyl (Z)-3-iodoacrylate and
methyl (E)-3-iodoacrylate24 mediated by Pd(PPh3)4/CuI in
DMF25 to produce triene esters 14 (55%) and 15 (63%). The
former did not cyclize under a variety of acidic conditions, while
Using Negishi’s conditions A17 for the coupling of electron-
deficient alkynes [i.e., zincated methyl propiolate, Pd(PPh3)4]
gave a low yield (30%) of 7. Fortunately, subsequent catalyst
screening (Table 1) revealed that switching the ligand to tris(2-
furyl)phosphine18 (TFP) led to a satisfactory isolated yield of
61%. The (E)-isomer 6 coupled much more reluctantly, since a
mere 25% of 8 together with a substantial amount of methyl
(Z)-3-diisopropylaminopropenoate (68%) were obtained when
the same conditions were applied. Hence, the formation of the
aminopropenoate was avoided by in situ generation of the
coupling partner from HCCCO2Me with ZnBr2/Et3N (referred
to as Negishi′s conditions B17) in the presence of the more
reactive Pd(TFP)2 catalyst. This species is produced19 by the
in situ reduction of PdCl2TFP2 with BuLi and secured a
synthetically useful yield of 8 (72%). The higher reactivity of
5 compared to 6 is probably the result of chelation of the
organopalladium intermediate by the OTHP group (9, Figure
2), which facilitated oxidative addition step. Similar chelation
(10) has been recently shown12a to influence Pd-catalyzed
carbonylative lactonization.
(20) (a) Trost, B. M.; Chao, J.-L. Synthesis 1994, 1267. (b) Alami, M.;
Fabiola, F. Synlett 1996, 755.
(21) For recent reviews on metal-catalyzed hydrostannations, see: (a) Smith,
N. D.; Mancuso, J.; Lautens, M. Chem. ReV. 2000, 100, 3257. (b) Trost, B. M.;
Ball, Z. T. Synthesis 2005, 853.
(22) Zhang, H. X.; Guibe´, F.; Balavoine, G. J. Org. Chem. 1990, 55, 1857.
(23) Hamze, A.; Provot, O.; Brion, J.-D.; Alami, M. J. Org. Chem. 2007,
72, 3868.
(24) Cox, L. R.; DeBoos, G. A.; Fullbrook, J. J.; Percy, J. M.; Spencer, N.
Tetrahedron: Asymmetry 2005, 16, 347.
(25) Bellina, F.; Carpita, A.; De Mantis, M.; Rossi, R. Tetrahedron 1994,
50, 12029.
(15) Pour, M.; Negishi, E.-i. Tetrahedron Lett. 1996, 37, 4679.
(16) Sauer, E. L. O.; Barriault, L. J. Am. Chem. Soc. 2004, 126, 8569.
(17) Negishi, E.-i.; Qian, M.; Zeng, F.; Anastasia, L.; Babinski, D. Org. Lett.
2003, 5, 1597.
(18) (a) Farina, V.; Baker, S. R.; Sapino, C., Jr. Tetrahedron Lett. 1991, 32,
4453. (b) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585. (c) For
a review on TFP as ligand for transition metal-mediated organic synthesis, see:
Andersen, N. G.; Keay, B. A. Chem. ReV. 2001, 101, 997.
(19) Pour, M.; Negishi, E. Tetrahedron Lett. 1997, 38, 525.
J. Org. Chem. Vol. 74, No. 2, 2009 705

Pavl´ık et al.
TABLE 2. Overview of the Target 2-Substituted 4-Alkylidene
Pentenolides 17
FIGURE 3. Structures of the coupling products of 13 with iodo
acrylates.
SCHEME 6. Preparation of the Target Alkylidene
Pentenolides
the latter cyclized to the corresponding pentenolide (17a, vide
infra) on Dowex 50 in a moderate yield of 45% (Figure 3).
For this reason, compound 13 was subjected to treatment with
Dowex 50 to give 2-tributylstannyl pentenolide 16 in 74% yield
(Scheme 6). Subsequent coupling reactions again confirmed that
cycloalkenylstannanes in general, and especially those with the
trialkylstannyl group in the R-position to a carbonyl, do not
readily undergo Pd-catalyzed cross-coupling.26 Even though
Sweeney et al. were able27 to effect cross-coupling of the
analogous 2-tributylstannyl butenolides with aryl iodides using
PdCl2(PPh3)2 in boiling toluene, we had to resort28 to a system
composed of Pd2dba3/AsPh3/CuI and NMP in order to cross-
couple 5-ethyl-3-tributylstannyl-2,5-dihydrofuran-2-one with
various heteroaryl iodides. Similarly, variation of the reaction
conditions using methyl (E)-3-iodoacrylate24 revealed that
Pd(PPh3)4/CuI in DMF25 successfully employed for the coupling
of stannyl ester 13 (vide supra) led to a mere 10% yield of
lactone 17a, and replacement of the ligand on Pd with AsPh3
was necessary to achieve reasonable isolated yields29 of lactones
17 (Scheme 6, Table 2). In this context, the following observa-
tions should be mentioned. First, the conditions allowed the
couplings to proceed at room temperature, which was important
because of the sensitive nature of lactone 16. This compound
was stable at -18 °C, but suffered from limited stability at
a Isolated yields after two cycles of column chromatography. b Only
(Z)-isomers were observed in the crude reaction mixtures.
temperatures above 0 °C. Hence, the moderate to good isolated
yields (33-55%) achieved in the cross-coupling step resulted
from the limited stability of this coupling partner rather than
from the reaction conditions having not been fully optimized.
Second, since only Z-isomers were detected in the NMR spectra
of the crude reaction mixtures, the E/Z isomerization reported
for the phenyl- and thienyl-substituted final compounds 17 must
have occurred during subsequent operations. The ease of
isomerization clearly depends on the substitution in position 3
and is not unexpected, since the gelastatins were also isolated
as an inseparable mixture of E/Z isomers. 5 Unfortunately, none
of the catalysts and/or selected conditions including those
reported by Fu30 allowed coupling with methyl 3-iodoprope-
noate, and hence attachment of the saturated side chain of the
gelastatins could not be achieved.
All final compounds 17 were subjected to a preliminary
screening against a panel of antineoplastic cell lines, including
the mouse lymphocytic leukemia L1210 cells (ATCC CCL 219),
CCRF-CEM T lymphoblastoid cells (human acute lymphoblastic
leukemia, ATCC CCL 119), human promyelocytic leukemia
HL-60 cells (ATCC CCL 240), and human cervix carcinoma
HeLa S3 cells (ATCC CCL 2.2). Interestingly, compounds 17a,
(26) (a) Farina, V.; Baker, S. R.; Sapino, C., Jr. Tetrahedron Lett. 1988, 29,
6043. (b) Reference 18b. (c) Pour, M.; Negishi, E.-i. Tetrahedron Lett. 1996,
37, 4679. (d) Negishi, E.-i.; Pour, M.; Cederbaum, F. E.; Kotora, M. Tetrahedron
1998, 54, 7057.
(27) Hollingworth, G. J.; Perkins, G.; Sweeney, J. J. Chem. Soc., Perkin
Trans. 1 1996, 16, 1913.
(28) Kunesˇ, J.; Balsˇa´nek, V.; Pour, M.; Buchta, V. Collect. Czech. Chem.
Commun. 2001, 66, 1809.
(29) (a) Because biological screening of the target compounds was planned,
isolated yields after two rounds of column chromatography are reported. (b)
Attempts to attach halogenated aryl moieties were also successful, but the
corresponding (E/Z)-3-(halogenated aryl)-5-(2-hydroxyethylidene)-5,6-dihydro-
2H-pyran-2-ones were unstable.
(30) (a) Menzel, K.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 3718. (b) Tang,
H.; Menzel, K.; Fu, G. C. Angew. Chem., Int. Ed. Engl. 2003, 42, 5079. (c)
Frisch, A. C.; Beller, M. Angew. Chem., Int. Ed. Engl. 2005, 44, 674.
706 J. Org. Chem. Vol. 74, No. 2, 2009

R-Substituted γ-Alkylidene Pentenolide
138.6, 122.2, 98.5, 86.1, 81.9, 65.2, 64.2, 62.2, 52.7, 30.5, 25.8,
25.4, 19.4, 18.3, -5.4; IR (CDCl3) νmax 1436, 1463, 1471, 1711,
2212 2247, 2857, 2930, 2954 cm-1; LRMS m/z (relative intensity)
369.1 [M + H]+ (22), 337.4 (5), 285.2 (12), 249.2 (37), 203.4 (8),
177.0 (100), 153.4 (4); HRMS [M + H]+ calcd for C19H33O5Si,
369.2097, found 369.2089.
17b, and 17d displayed selective activity against the HeLa S3
and CCRF-CEM cells, with the most active compound 17a
having IC50 values of 3.50 ( 0.39 and 1.80 ( 0.07 µmol/L,
respectively.
Conclusion
(Z)-Methyl 6-(Tetrahydropyran-2-yloxy)-4-[(tetrahydropyran-2-
yloxy)methyl]hex-4-en-2-ynoate (8). Solution A: Zinc bromide (3.29
g, 14.6 mmol) was melted under high vacuum, then allowed to
cool down to room temperature under Ar atmosphere and dissolved
in dry THF (26 mL). Triethylamine (8.22 mL, 59.0 mmol) was
then added, with the reaction mixture having turned red after stirring
for 1-3 min at ambient temperature. Solution B: (TFP3)2PdCl2
(418.4 mg, 0.65 mol) was suspended in dry THF (5 mL) under Ar
atmosphere, and the mixture cooled down to -78 °C. A solution
of 2.5 M BuLi (0.52 mL, 1.30 mmol) was added, and the mixture
was allowed to gradually warm to -30 °C over 30 min. Iodide 6
(2.49 mg, 6.52 mmol) was then added, the reaction mixture was
warmed to 0 °C, and freshly prepared solution A (via cannula) and
methyl propiolate (1.1 mL, 12.3 mmol) were added. After 4 h of
stirring at room temperature, the reaction mixture was diluted with
ethyl acetate (50 mL), and washed with saturated aqueous NH4Cl
solution (50 mL). The organic layer was dried with anhydrous
Na2SO4 and concentrated under reduced pressure. The crude product
was purified by column chromatography (petroleum ether/ethyl
acetate 9:1). Yield 72%; yellowish oil; 1H NMR (300 MHz, CDCl3)
δ 6.49-6.43 (m, 1H, CH), 4.67-4.63 (m, 1H, OCH), 4.63-4.58
(m, 1H, OCH), 4.43-4.32 (m, 1H, OCH2), 4.29-4.09 (m, 3H,
OCH2), 3.89-3.74 (m, 2H, OCH2), 3.76 (s overlapped, 3H, OCH3),
3.55-3.45 (m, 2H, OCH2), 1.88-1.45 (m, 12H, CH2); 13C NMR
(75 MHz, CDCl3) δ 154.2, 144.1, 119.2, 98.1, 97.5, 86.4, 79.4,
63.2, 63.0, 62.1, 61.9, 52.6, 30.4, 30.2, 25.3, 25.3, 19.1, 18.9; IR
In summary, we have shown that a viable route to 2-substi-
tuted 4-alkylidene pentenolides analogous to the gelastatins and
CR 377 leads to the assembly of a few suitably substituted
building blocks, namely, a 2-iodo allylic alcohol, methyl
propiolate, and an electrophile (RX). Notably, the preparation
of R-alkenylated and arylated δ-lactones has been explored for
the first time. The presence of OH groups both in the alkylidene
moiety and the C3 substituent (17c) enables further modifica-
tions as well as attachment to the solid phase to facilitate the
production of further series of analogues and combinatorial
libraries. The preliminary screening results suggest that the
synthesis of compound libraries based on the pentenolide
scaffold should be a worthwhile endeavor.
Experimental Section
(E)-2-(2-Phenylethynyl)but-2-en-1-ol (3). Pd(PPh3)4 (58 mg, 0.05
mmol) and copper(I) iodide (19.5 mg, 0.1 mmol) were added to a
solution of phenylacetylene (0.22 mL, 2 mmol) and iodide 231 (198
mg, 1.0 mmol) in pyrrolidine (4.6 mL) under Ar atmosphere. The
mixture was stirred at ambient temperature for 10 min, then diluted
with ethyl acetate (20 mL) and washed with saturated aqueous
NH4Cl solution (20 mL). The organic layer was dried with
anhydrous Na2SO4 and concentrated under reduced pressure. The
crude product was purified by column chromatography (petroleum
(CDCl3) νmax 1436, 1454, 1709, 2215, 2248, 2853, 2874, 2948 cm-1
;
LRMS m/z (relative intensity) 339.2 [M + H]+ (2), 305.2 (14),
271.3 (7), 249.2 (63), 219.2 (4), 205.3 (8), 177.0 (100), 169.4 (7),
130.1 (6); HRMS [M + H]+ calcd for C18H27O6, 339.1808, found
339.1814.
1
ether/ethyl acetate 8:2). Yield 93%; yellowish oil; H NMR (300
MHz, CDCl3) δ 7.43-7.38 (m, 2H, H2′, H6′), 7.30-7.25 (m, 3H′,
H3′, H4′, H5′), 6.18-6.09 (m, 1H, CH), 4.26 (t, 2H, J ) 0.8 Hz,
OCH2), 1.92 (bs, 1H, OH), 1.79 (d, 3H, J ) 7.4 Hz, CH3); 13C
NMR (75 MHz, CDCl3) δ 134.9, 131.5, 128.3, 128.1, 123.4, 123.1,
88.9, 88.6, 59.8, 14.0; IR (CDCl3) νmax 1443, 1490, 1597, 1682,
2250, 2873, 2925, 2958, 3604 cm-1; LRMS m/z (relative intensity)
173.2 [M + H]+ (100), 161.0 (8), 151.3 (51), 135.3 (8), 123.4 (42),
119.5 (12), 107.4 (8), 87.3 (5); HRMS [M + H]+ calcd for C12H13O,
173.0966, found 173.0968.
(2E,4E)-Methyl 2-(Tributylstannyl)-4-(tert-butyldimethylsilyloxym-
ethyl)-6-(tetrahydropyran-2-yloxy)hexa-2,4-dienoate (11) and (2E,4E)-
Methyl 3-(Tributylstannyl)-4-(tert-butyldimethylsilyloxymethyl)-6-
(tetrahydropyran-2-yloxy)hexa-2,4-dienoate (12). To a solution of 7
(228 mg, 0.62 mmol) and Pd(PPh3)4 (35 mg, 0.03 mmol) in dry
THF (3.5 mL) under Ar atmosphere was slowly added tributylt-
inhydride (0.165 mL, 0.62 mmol). After 5 min of stirring, the
reaction mixture was diluted with ethyl acetate (10 mL) and washed
with brine (10 mL). The organic layer was dried with anhydrous
Na2SO4 and concentrated under reduced pressure. The crude product
was purified by column chromatography (petroleum ether/ethyl
acetate 95:5). Yield 45% (mixture of 11 + 12, 1:1); yellowish oil;
1H NMR (300 MHz, CDCl3) δ 6.41 (s, 1H, CH, A), 5.98 (s, 1H,
CH, B), 5.81-5.73 (m, 1H, CH, A), 5.49-5.39 (m, 1H, CH, B),
4.61-4.53 (m, 1H, OCH, A+B), 4.26-4.01 (m, 2H, OCH2, A+B),
4.18 (s overlapped, 2H, OCH2, A+B), 3.88-3.73 (m, 1H, OCH2,
A+B), 3.62 (s, 3H, OCH3, A+B), 3.50-3.37 (m, 1H, OCH2, A+B),
1.86-1.40 (m, 12H, CH2, A+B), 1.38-1.21 (m, 6H, CH2, A+B),
1.03-0.93 (m, 6H, CH2, A+B), 0.92-0.81 (m, 12H, CH3, A+B),
0.05 (s, 6H, CH3, A), 0.04 (s, 6H, CH3, B); 13C NMR (75 MHz,
CDCl3) δ 172.2, 167.1, 163.8, 145.0, 141.1, 140.9, 140.4, 129.3,
123.8, 114.3, 97.9, 97.8, 64.6, 64.6, 64.3, 63.6, 62.1, 61.9, 51.3,
51.0, 30.6, 28.9, 28.8, 28.8, 28.7, 27.3, 27.2, 26.0, 25.9, 25.5, 25.5,
19.5, 18.5, 18.3, 13.6, 13.6, 10.5, 10.4, -5.4 (A+B); IR (CDCl3)
(E)-Methyl 4-(tert-Butyldimethylsilyloxymethyl)-6-(tetrahydropy-
ran-2-yloxy)hex-4-en-2-ynoate (7). Solution A: Zinc bromide (2.79
g, 12.38 mmol) was melted under high vacuum, then allowed to
cool down to room temperature under Ar atmosphere and dissolved
in dry THF (9.1 mL). Solution B: A solution of 1.5 M LDA (7.88
mL, 11.38 mmol) was added to a stirred solution of methyl
propiolate (1.067 mL, 11.90 mmol) in dry THF (9.1 mL) under Ar
atmosphere at -78 °C. The resultant mixture was stirred for 30
min, solution A was added via cannula at -78 °C, and the mixture
was gradually warmed to room temperature over 1 h. Pd2(dba)3
(124.2 mg, 0.12 mmol), tris(2-furyl)phosphine (111.5 mg, 0.48
mmol), and iodide 5 (1.0 g, 2.42 mmol) were subsequently added,
and the reaction mixture was stirred for another 12 h. The mixture
was diluted with ethyl acetate (50 mL) and washed with a saturated
aqueous NH4Cl solution (50 mL). The organic layer was dried with
anhydrous Na2SO4 and concentrated under reduced pressure. The
crude product was purified by column chromatography (petroleum
1
ether/ethyl acetate 9:1). Yield 61%; yellowish oil; H NMR (300
ν
max 1434, 1464, 1588, 1701, 1719, 2246, 2258, 2855, 2872, 2930,
2956 cm-1; LRMS m/z (relative intensity) 659.3 [M + H]+ (1),
599.3 (100), 581.3 (9), 551.3 (1), 427.3 (1), 415.3 (4), 291.2 (3),
235.1 (1), 177.1 (15), 89.3 (6). Anal. Calcd for C31H60O5SiSn: C,
56.45; H, 9.17. Found: C, 56.50; H, 9.26
MHz, CDCl3) δ 6.48-6.39 (m, 1H, CH), 4.68-4.61 (m, 1H, OCH),
4.52-4.41 (m, 1H, OCH2), 4.38-4.28 (m, 1H, OCH2), 4.22-4.16
(m, 2H, OCH2), 3.92-3.82 (m, 1H, OCH2), 3.78 (s, 3H, OCH3),
3.57-3.47 (m, 1H, OCH2), 1.89-1.45 (m, 6H, CH2), 0.9 (s, 9H,
CH3), 0.07 (s, 6H, CH3); 13C NMR (75 MHz, CDCl3) δ 154.1,
(2E,4Z)-Methyl 2-(Tributylstannyl)-6-(tetrahydropyran-2-yloxy)-
4-[(tetrahydropyran-2-yloxy)methyl]hexa-2,4-dienoate (13). Tribu-
tyltinhydride (1.27 mL, 4.72 mmol) was slowly added under Ar
(31) Ensley, H. E.; Buescher, R. R.; Lee, K. J. Org. Chem. 1982, 47, 404.
J. Org. Chem. Vol. 74, No. 2, 2009 707

Pavl´ık et al.
atmosphere to a solution of 8 (1.59 g, 4.72 mmol) and Pd(PPh3)4
(58 mg, 0.05 mmol) in dry THF (24.1 mL). After 5 min of stirring
at room temperature, the reaction mixture was diluted with ethyl
acetate (30 mL) and washed with brine (30 mL). The organic layer
was dried with anhydrous Na2SO4 and concentrated under reduced
pressure. The crude product was purified by column chromatog-
raphy (petroleum ether/ethyl acetate 92:8). Yield 84%; yellowish
1H, CH), 6.00 (d, 1H, J ) 12.6 Hz, CH), 5.14 (d, 2H, J ) 1.8 Hz,
OCH2), 4.36-4.28 (m, 2H, OCH2), 4.15 (q, 2H, J ) 7.2 Hz, OCH2),
1.26 (t, 3H, J ) 7.2 Hz, CH3); 13C NMR (75 MHz, CDCl3) δ 163.8,
163.1, 144.5, 136.8, 136.3, 128.9, 123.4, 122.8, 66.1, 60.1, 58.9,
14.1; IR (CDCl3) νmax 1177, 1369, 1389, 1450, 1459, 1655, 1710,
1719, 2875, 2925, 3401 cm-1; LRMS m/z (relative intensity) 239.3
[M + H]+ (7), 221.2 (10), 211.2 (23), 193.2 (8), 165.2 (100), 147.3
(3), 135.3 (2), 119.3 (1); HRMS [M + H]+ calcd for C12H15O5,
239.0919, found 239.0916.
(5Z)-3-[(E)-3-(tert-Butyldimethylsilyloxy)prop-1-enyl]-5-(2-hydroxy-
ethylidene)-5,6-dihydro-2H-pyran-2-one (17c). Reaction details: ha-
logenide ) (E)-3-(tert-butyldimethylsilyloxy)-1-iodoprop-1-ene,
time ) 8 h, mobile phase ) petroleum ether/ethyl acetate 1:1. Yield
51%; yellowish oil; 1H NMR (300 MHz, CDCl3) δ 6.48-6.29 (m,
2H, CH), 6.19 (t, 1H, J ) 6.3 Hz, CH), 5.97 (s, 1H, CH), 4.99 (s,
2H, OCH2), 4.42-4.26 (m, 4H, OCH2), 0.93 (s, 9H, CH3), 0.098
(s, 6H, CH3); 13C NMR (75 MHz, CDCl3) δ 164.6, 150.9, 139.1,
132.6, 129.2, 122.4, 113.5, 65.9, 62.9, 58.8, 25.9, 18.4, -5.3; IR
(KBr pellet) νmax 1126, 1253, 1378, 1406, 1462, 1701, 2855, 2928,
2953, 3400 cm-1; LRMS m/z (relative intensity) 311.4 [M + H]+
(15), 247.4 (1), 211.4 (2), 179.4 (17), 161.4 (3), 133.4 (4), 102.6
(100), 74.6 (4); HRMS [M + H]+ calcd for C16H27O4Si, 311.1679,
found 311.1691.
1
oil; H NMR (300 MHz, CDCl3) δ 6.26 (t, 1H, JH,Sn ) 30.2 Hz,
CH), 5.87 (t, 1H, J ) 6.5 Hz, CH), 4.63 (s, 1H, OCH), 4.55 (s,
1H, OCH), 4.43-4.13 (m, 4H, OCH2), 3.91-3.77 (m, 2H, OCH2),
3.67 (s, 3H, OCH3), 3.55-3.44 (m, 2H, OCH2), 1.88-1.44 (m,
18H, CH2) 1.37-1.23 (m, 6H, CH2), 1.02-0.94 (m, 6H, CH2),
0.88(t, 9H, J ) 7.3 Hz, CH3); 13C NMR (75 MHz, CDCl3) δ 172.9,
143.4, 138.4, 137.1, 133.2, 98.0, 97.0, 63.3, 62.5, 62.0, 51.2, 30.6,
30.3, 28.7, 28.6, 27.2, 25.4, 25.4, 19.4, 19.3, 13.6, 10.5; IR (KBr
pellet) νmax 1261, 1341, 1456, 1582, 1706, 2851, 2870, 2924 cm-1
;
LRMS m/z (relative intensity) 629.3 [M + H]+ (6), 540.7 (7), 458.5
(16), 431.2 (31), 373.3 (100), 307.4 (24), 177.1 (8), 89.4 (16). Anal.
Calcd for C30H54O6Sn: C, 57.24; H, 8.65. Found: C, 57.31; H, 8.66.
(5Z)-3-(Tributylstannyl)-5-(2-hydroxyethylidene)-5,6-dihydro-2H-
pyran-2-one (16). Compound 13 (630 mg, 1.0 mmol) was dissolved
in methanol (5 mL), and Dowex 50 (0.6 g) was added to the
solution. The resultant mixture was stirred for 2 h at room
temperature, and the acidic resin filtered off. The solvent was
removed under reduced pressure, the residue was diluted with ethyl
acetate (20 mL), and the solution washed with brine (20 mL). The
organic layer was dried with anhydrous Na2SO4 and concentrated
under reduced pressure. The crude product was purified by column
5-(2-Hydroxyethylidene)-3-phenyl-5,6-dihydro-2H-pyran-2-one (17d).
Reaction details: halogenide ) iodobenzene, time ) 12 h, mobile
phase ) petroleum ether/ethyl acetate 1:1. Yield 55%; yellowish
oil; 1H NMR (300 MHz, CDCl3) δ 7.55-7.45 (m, 2H, H2′,
H6′A+B), 7.45-7.30 (m, 4H, H3′, H4′, H5′, A+B, CH, A), 7.07
(s, 1H, CH, B), 6.04-5.88 (m, 1H, CH, A+B), 5.18-5.09 (m, 2H,
OCH2, A), 4.93-4.90 (m, 2H, OCH2, B), 4.40-4.23 (m, 2H, OCH2,
A), 4.28 (d, 2H, J ) 6.3 Hz, OCH2, B), 2.94 (bs, 1H, OH, A+B);
13C NMR (75 MHz, CDCl3) δ 164.8, 163.6, 156.0,141.3, 136.8,
135.1, 134.9, 134.5, 132.2, 130.0, 129.2, 128.8, 128.7, 128.7, 128.5,
128.5, 128.3, 128.2, 70.8, 66.4, 58.5, 58.2 (A+B); IR (CDCl3) νmax
1152, 1401, 1446, 1693, 2885, 2924, 3025, 3401 cm-1; LRMS m/z
(relative intensity) 217.2 [M + H]+ (19), 199.2 (42), 181.2 (9),
171.2 (100), 155.2 (15), 128.3 (10), 115.3 (2), 105.4 (1). Anal.
Calcd for C13H12O3: C, 72.21; H, 5.59. Found: C, 72.36; H, 5.67.
5-(2-Hydroxyethylidene)-3-(4-methylphenyl)-5,6-dihydro-2H-pyran-
2-one (17e). Reaction details: halogenide ) 4-iodotoluene, time )
12 h, mobile phase ) petroleum ether/ethyl acetate 1:1. Yield 43%;
chromatography (petroleum ether/ethyl acetate 8:2). Yield 74%;
1
yellowish oil; H NMR (300 MHz, CDCl3) δ 7.07 (t, 1H, JH,Sn
)
22.0 and 19.5 Hz, CH), 5.89-5.80 (m, 1H, CH), 5.07 (s, 2H,
OCH2), 4.27 (t, 2H, J ) 5.8 Hz, OCH2), 1.56-1.43 (m, 6H, CH2),
1.39-1.22 (m, 6H, CH2), 1.14-0.97 (m, 6H, CH2), 0.88 (t, 9H, J
) 7.3 Hz, CH3); 13C NMR (75 MHz, CDCl3) δ 166.8, 153.7, 136.9,
132.0, 129.6, 66.5, 58.9, 29.2, 27.5, 13.9, 10.2; IR (CDCl3) νmax
1456, 1464, 1569, 1682, 1698, 2252, 2854, 2872, 2826, 2958 cm-1
;
LRMS m/z (relative intensity) 429.5 [M + H]+ (32), 332.7 (53),
304.7 (100), 262.6 (7), 238.5 (8), 216.6 (4), 186.6 (8), 118.5 (25),
102.6 (43). Anal. Calcd for C19H34O3Sn: C, 53.17; H, 7.98. Found:
C, 53.18; H, 8.01.
General Procedure for Preparation of Compounds 17a-17j.
Triphenylarsine (7.4 mg, 0.025 mmol), Pd2(dba)3 (12.9 mg, 0.0125
mmol) and copper(I) iodide (72.4 mg, 0.38 mmol) were added to
a solution of 16 (214.6 mg, 0.50 mmol) and appropriate halogenide
(0.75 mmol) in dry DMF (2 mL) under Ar atmosphere. The reaction
mixture was stirred for 8-12 h at room temperature, then diluted
with ethyl acetate (20 mL), and washed with brine (20 mL). The
organic layer was dried with anhydrous Na2SO4 and concentrated
under reduced pressure. The crude product was purified by column
chromatography.
(2E)-Methyl 3-[(Z)-5-(2-Hydroxyethylidene)-2-oxo-5,6-dihydro-2H-
pyran-3-yl]acrylate (17a). Reaction details: halogenide ) (E)-methyl
3-iodoacrylate, time ) 8 h, mobile phase ) petroleum ether/ethyl
acetate 1:1. Yield 42%; white crystals, mp 84.7 °C; 1H NMR (300
MHz, CDCl3) δ 7.38 (d, 1H, J ) 15.9 Hz, CH), 7.17 (s, 1H, CH),
6.79 (d, 1H, J ) 15.9 Hz, CH), 6.17-6.08 (m, 1H, CH), 5.17-5.11
(m, 2H, OCH2), 4.44-4.31 (m, 2H, OCH2), 3.77 (s, 3H, OCH3);
13C NMR (75 MHz, CDCl3) δ 162.3, 161.9, 144.4, 138.2, 137.2,
129.3, 123.8, 122.7, 66.0, 59.1, 51.8; IR (KBr pellet) νmax 1201,
1363, 1436, 1457, 1653, 1718, 1733, 2341, 2359 cm-1; LRMS m/z
(relative intensity) 225.1 [M + H]+ (16), 207.2 (12), 197.1 (3),
181.3 (4), 175.2 (2), 165.2 (100), 147.3 (4), 135.2 (2), 119.4 (1).
Anal. Calcd for C11H12O5: C, 58.93; H, 5.39. Found: C, 58.84; H,
5.31.
1
yellowish oil; H NMR (300 MHz, CDCl3) δ 7.48-7.43 (m, 2H,
AA′BB′, H2′, H6′,A), 7.43-7.37 (m, 2H, AA′BB′, H2′, H6′, B),
7.27-7.21 (m.2H, AA′BB′, H3′, H5′, A), 7.23 (s, 1H, CH, A),
7.21-7.14 (m.2H, AA′BB′, H3′, H5′, B), 7.04 (s, 1H, CH, B), 6.06
-5.85 (m, 1H, CH, A+B), 5.18-5.05 (m, 2H, OCH2, A),
4.94-4.90 (m, 2H, OCH2, B), 4.42-4.31 (m, 2H, OCH2, A),
4.31-4.23 (m, 2H, OCH2, B), 2.61 (bs, 1H, OH, A), 2.49 (bs, 1H,
OH, B), 2.39 (s, 3H, CH3, B), 2.36 (s, 3H, CH3, A); 13C NMR (75
MHz, CDCl3) δ 163.9, 163.6, 156.0, 140.6, 138.8, 138.6, 136.7,
134.3, 134.0, 132.0, 131.7, 129.4, 129.3, 128.9, 128.9, 128.4, 128.3,
115.0, 70.8, 66.4, 58.6, 58.2, 21.3, 21.2 (A+B); IR (CDCl3) νmax
1160, 1215, 1400, 1456, 1512, 1702, 2875, 2929, 3020, 3400 cm-1
;
LRMS m/z (relative intensity) 231.2 [M + H]+ (14), 213.2 (44),
203.2 (17), 195.2 (8), 185.2 (100), 167.2 (6), 157.3 (40), 142.3
(9), 129.3 (3), 119.3 (1). Anal. Calcd for C14H14O3: C, 73.03; H,
6.13. Found: C, 73.12; H, 6.15.
5-(2-Hydroxyethylidene)-3-(4-methoxyphenyl)-5,6-dihydro-2H-py-
ran-2-one (17f). Reaction details: halogenide ) 4-iodoanisole, time
) 12 h, mobile phase ) petroleum ether/ethyl acetate 1:1. Yield
38%; yellowish oil; 1H NMR (300 MHz, CDCl3) δ 7.51-7.43 (m,
3H, AA′BB′, H2′, H6′, A, CH, A), 7.33-7.25 (m, 2H, AA′BB′,
H2′, H6′, B), 7.01 (s, 1H, CH, B), 6.94-6.85 (m, 2H, AA′BB′,
H3′, H5′, A+B), 6.09-5.84 (m, 1H, CH, A+B), 5.14 (s, 2H, OCH2,
A), 4.90 (s, 2H, OCH2, B), 4.41-4.21 (m, 2H, OCH2, A+B), 3.82
(s, 3H, OCH3, B), 3.80 (s, 3H, OCH3, A); 13C NMR (75 MHz,
CDCl3) δ 165.4, 163.9, 161.5, 160.2, 155.8, 140.0, 136.8, 133.7,
133.6, 131.4, 130.7, 130.2, 130.1, 129.9, 114.7, 114.5, 114.0, 113.9,
71.1, 66.7, 66.4, 58.9, 58.5, 55.7 (A+B); IR (CDCl3) νmax 1150,
(2Z)-Ethyl 3-[(Z)-5-(2-Hydroxyethylidene)-2-oxo-5,6-dihydro-2H-
pyran-3-yl]acrylate (17b). Reaction details: halogenide ) (Z)-ethyl
3-iodoacrylate, time ) 8 h, mobile phase ) petroleum ether/ethyl
acetate 1:1. Yield 45%; yellowish oil; 1H NMR (300 MHz, CDCl3)
δ 7.55 (s, 1H, CH), 6.83 (d, 1H, J ) 12.6 Hz, CH), 6.11-6.04 (m,
708 J. Org. Chem. Vol. 74, No. 2, 2009

R-Substituted γ-Alkylidene Pentenolide
1178, 1246, 1289, 1401, 1457, 1510, 1604, 1697, 2928, 2955, 3401
cm-1; LRMS m/z (relative intensity) 247.3 [M + H]+ (15), 229.2
(29), 219.2 (31), 201.3 (100), 189.2 (4), 173.3 (16), 158.3 (8), 147.3
(1), 123.3 (29). Anal. Calcd for C14H14O4: C, 68.28; H, 5.73. Found:
C, 68.09; H, 5.67.
OCH2), 4.18 (d, 2H, J ) 6.3 Hz, OCH2); 13C NMR (75 MHz,
CDCl3) δ 164.1, 144.6, 135.3, 133.5, 133.0, 131.9, 129.4, 129.3,
128.7, 128.3, 127.8, 127.4, 126.6, 126.4, 125.4, 67.1, 58.8; IR (KBr
pellet) νmax 1154, 1189, 1247, 1402, 1453, 1508, 1693, 2855, 2923,
2954, 3055, 3400 cm-1; LRMS m/z (relative intensity) 267.2 [M
+ H]+ (2), 249.2 (100), 239.2 (24), 231.2 (14), 221.2 (74), 205.2
(17), 193.3 (23), 181.3 (11), 165.2 (2), 139.3 (2), 121.4 (1); HRMS
[M + H]+ calcd for C17H15O3, 267.1021, found 267.1029.
5-(2-Hydroxyethylidene)-3-(thiophen-2-yl)-5,6-dihydro-2H-pyran-
2-one (17j). Reaction details: halogenide ) 2-iodothiophene, time
) 8 h, mobile phase ) petroleum ether/ethyl acetate 1:1. Yield
55%; yellowish oil; 1H NMR (300 MHz, CDCl3) δ 7.67-7.63 (m,
1H, CH, A), 7.60-7.52 (m, 1H, CH, A+B), 7.40-7.33 (m, 1H,
CH, A+B), 7.24 (s, 1H, CH, B), 7.07-7.02 (m, 1H, CH, A+B),
6.10-5.99 (m, 1H, CH, A), 5.96-5.88 (m, 1H, CH, B), 5.17-5.13
(m, 2H, OCH2, A), 4.93-4.89 (m, 2H, OCH2, B), 4.44 (bs, 2H,
OCH2, B), 4.32 (bs, 2H, OCH2, A), 2.16 (bs, 1H, OH, A), 2.11
(bs, 1H, OH, B); 13C NMR (75 MHz, CDCl3) δ 163.0, 162.7, 136.9,
136.7, 134.0, 131.8, 130.6, 129.7, 129.2, 128.4, 128.3, 127.8, 127.3,
127.3, 126.9, 124.3, 122.8, 122.2, 66.2, 66.2, 58.8, 58.5 (A+B);
IR (KBr pellet) νmax 1223, 1250, 1337, 1360, 1422, 1458, 1653,
1708, 2854, 2926, 2952 cm-1; LRMS m/z (relative intensity) 223.3
[M + H]+ (4), 205.2 (85), 191.2 (8), 177.3 (100), 163.2 (4), 149.3
(19), 135.3 (1), 111.4 (3), 97.6 (1); HRMS [M + H]+ calcd for
C11H11O3S, 223.0429, found 223.0426.
Methyl 2-[5-(2-Hydroxyethylidene)-2-oxo-5,6-dihydro-2H-pyran-
3-yl]benzoate (17g). Reaction details: halogenide ) methyl-2-
iodobenzoate, time ) 8 h, mobile phase ) petroleum ether/ethyl
acetate 1:1. Yield 33%; yellowish oil; 1H NMR (300 MHz, CDCl3)
δ 8.03-7.96 (m, 1H, CH, A+B), 7.60-7.40 (m, 2H, CH, A+B),
7.34-7.27 (m, 2H, CH, A+B, CH, A), 6.91 (s, 1H, CH, B),
6.00-5.84 (m, 1H, CH, A+B), 5.21 (s, 2H, OCH2, A), 5.00 (s,
2H, OCH2, B), 4.36 (d, 2H, J ) 6.4 Hz, OCH2, B), 4.28 (d, 2H, J
) 6.4 Hz, OCH2, A), 3.83 (s, 3H, OCH3, A+B), 2.37 (bs, 1H,
OH, A+B); 13C NMR (75 MHz, CDCl3) δ 167.3, 167.2, 164.1,
163.7, 138.9, 137.2, 136.7, 134.0, 133.7, 132.5, 132.4, 132.1, 131.4,
130.7, 130.3, 130.4, 130.1, 130.0, 129.9, 129.4, 129.1, 128.7, 128.6,
128.3,66.5, 66.4, 58.6, 58.3, 52.3, 52.2 (A+B); IR (KBr pellet)
ν
max 1263, 1284, 1401, 1434, 1450, 1596, 1702, 1708, 2853, 2923,
2952, 3401 cm-1; LRMS m/z (relative intensity) 275.2 [M + H]+
(16), 257.2 (36), 247.1 (100), 231.1 (66), 219.2 (29), 211.2 (21),
203.2 (23), 197.2 (9), 183.2 (13), 175.3 (8), 173.2 (2), 157.4 (1).
Anal. Calcd for C15H14O5: C, 65.69; H, 5.14. Found: C, 65.81; H,
5.21.
(5Z)-3-Benzyl-5-(2-hydroxyethylidene)-5,6-dihydro-2H-pyran-2-
one (17h). Reaction details: halogenide ) benzylbromide, time )
8 h, mobile phase ) petroleum ether/ethyl acetate 1:1. Yield 52%;
Acknowledgment. This work was supported by the Centre
for New Antivirals and Antineoplastics funded by the Ministry
of Education, Youth and Sports of the Czech Republic (1M0508)
and by the Czech Science Foundation (project No. 203/07/1302).
It is also a part of the research project MSM0021620822 of the
Ministry of Education, Youth and Sports of the Czech Republic.
Dr. I. Votruba of the Institute of Organic Chemistry and
Biochemistry of the Czech Academy of Science, Prague, is
gratefully acknowledged for cytostatic activity assays.
1
yellowish oil; H NMR (300 MHz, CDCl3) δ 7.36-7.16 (m, 5H,
CH), 6.55 (s, 1H, CH), 5.76 (t, 1H, J ) 6.3 Hz, CH), 5.05 (s, 2H,
OCH2), 4.20 (d, 2H, J ) 6.3 Hz, OCH2), 3.65 (s, 2H, CH2), 2.34
(bs,1H, OH); 13C NMR (75 MHz, CDCl3) δ 164.5, 140.8, 137.9,
132.6, 130.0, 129.2, 129.1, 128.6, 126.7, 66.4, 58.4, 36.5; IR (KBr
pellet) νmax 1196, 1249, 1405, 1453, 1494, 1691, 2872, 2920, 3027,
3401 cm-1; LRMS m/z (relative intensity) 231.2 [M + H]+ (9),
216.3 (100), 203.4 (30), 171.2 (6), 162.3 (24), 153.3 (32), 109.5
(4). Anal. Calcd for C14H14O3: C, 73.03; H, 6.13. Found: C, 73.22;
H, 6.19.
Supporting Information Available: General experimental
1
(5Z)-5-(2-Hydroxyethylidene)-3-(naphthalen-1-yl)-5,6-dihydro-2H-
pyran-2-one (17i). Reaction details: halogenide ) 1-iodonaphthalene,
time ) 12 h, mobile phase ) petroleum ether/ethyl acetate 1:1.
Yield 47%; yellowish oil; 1H NMR (300 MHz, CDCl3) δ 7.88-7.80
(m, 2H, CH), 7.78-7.71 (m, 1H, CH), 7.50-7.34 (m, 4H, CH),
7.00 (s, 1H, CH), 5.93-5.84 (m, 1H, CH), 5.26-5.23 (m, 2H,
section, copies of H NMR spectra for compounds 3, 7, 8, 13,
16, 17a-j and copies of 13C NMR spectra for compounds
17a-j. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO802082T
J. Org. Chem. Vol. 74, No. 2, 2009 709