A rapid divergent synthesis of highly substituted δ-lactones

Article abstract of DOI:10.1021/ol0617695

(Chemical Equation Presented) Nucleophilic 1,2-addition of (Z)-γ-silyloxyvinylzinc reagents to ethyl glyoxylate followed by desilylation and cyclization affords 3,6-dihydro-3-hydroxypyran-2-ones in good chemical yields. In situ formation of allylic phosph

Full text of DOI:10.1021/ol0617695

ORGANIC
LETTERS
2006
Vol. 8, No. 21
4779-4782
A Rapid Divergent Synthesis of Highly
Substituted -Lactones
δ
R. Karl Dieter* and Fenghai Guo
Howard L. Hunter Laboratory, Department of Chemistry, Clemson UniVersity,
Clemson, South Carolina 29634-0973
dieterr@clemson.edu
Received July 18, 2006
ABSTRACT
Nucleophilic 1,2-addition of (Z)-γ-silyloxyvinylzinc reagents to ethyl glyoxylate followed by desilylation and cyclization affords 3,6-dihydro-3-
hydroxypyran-2-ones in good chemical yields. In situ formation of allylic phosphates followed by reaction with RCu(CN)Li reagents affords
substituted 5,6-dihydropyran-2-ones. The parent compound, 3,6-dihydro-3-hydroxypyran-2-one, undergoes allylic phosphate formation, cuprate-
mediated allylic substitution, and 1,4-conjugate addition to afford trans-4,5-disubstituted tetrahydropyran-2-ones in a one-pot process.
The δ-lactone moiety comprises structural subunits in a
number of natural products, and substituted nonannulated
δ-lactones are important both as naturally occurring com-
pounds and in synthetic applications. Unsaturated 5,6-
dihydropyran-2-one derivatives substituted at the 6-position,
found largely in plants and bacteria, display antifungal,
antitumor, and cytotoxic activity,1 while the saturated
analogues are aroma constituents of fruit and meat products.2
Saturated tetrahydropyran-2-ones are also found in compactin
and (+)-mevinolin (cholesterol biosynthesis inhibitors),3 as
prelactones which may serve as possible shunts in macrolide
biosynthesis,4 HMG-C-CoA reductase inhibitors,5 the with-
asteroids,6 and in the antitumor macrolide rhizoxin.7 Rhizoxin
reached Phase II clinical trials for the treatment of ovarian,
colorectal, renal, breast, and melanoma cancers.7 Tetrahy-
dropyran-2-ones have been employed in the synthesis of
amino sugars,8 macrolides,9 and the C16-C35 fragment of
integramycin.10 The Prelog-Djerassi lactone is an oxidative
(4) (a) Yadav, J. S.; Reedy, M. S.; Prasad, A. R. Tetrahedron Lett. 2005,
46, 2133-2136. (b) Yamashita, Y.; Saito, S.; Ishitani, H.; Kobayashi, S. J.
Am. Chem. Soc. 2003, 125, 3793-3798. (c) Enders, D.; Haas, M. Synlett
2003, 2182-2184. (d) Chakraborty, T. K.; Tapadar, S. Tetrahedron Lett.
2003, 44, 2541-2543. (e) Chakraborty, T. K.; Tapadar, S. Tetrahedron
Lett. 2001, 42, 1375-1377. (f) Hanefeld, U.; Hooper, A. M.; Staunton, J.
Synthesis 1999, 401-403.
(5) Singer, R. A.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 12360-
12361
(6) Ray, A. B.; Gupta, M. In Progress in the Chemistry of Organic
Natural Products; Herz, W., Kirby, G. W., Moore, R. E., Steglich, W.,
Tamm, C., Eds.; Springer-Verlag: New York, 1994; Vol. 63, pp 1-106.
(7) N’Zoutani, M.-A.; Pancrazi, A.; Ardisson, J. Synlett. 2001, 769-
772.
(1) For reviews of 5,6-dihydro-2H-pyran-2-ones, see: (a) Collett, L. A.;
Davis-Coleman, M. T.; Rivett, D. E. A. In Progress in the Chemistry of
Organic Natural Products; Herz, W., Falk, H., Kirby, G. W., Moore, R.
E., Tamm, C., Eds.; Springer-Verlag: New York, 1998; Vol. 75, pp 181-
210. (b) Davies-Coleman, M. T.; Rivett, D. E. A. In Progress in the
Chemistry of Organic Natural Products; Herz, W., Grisebach, H., Kirby,
G. W., Tamm, C., Eds.; Springer-Verlag: New York, 1989; Vol. 55, pp
1-35.
(2) Marion, F.; Fol, R. L.; Courillon, C.; Malacria, M. Synlett. 2001,
138-140.
(3) (a) Bouzbouz, S.; Cossy, J. Tetrahedron Lett. 2000, 41, 3363-3366.
(b) Honda, T.; Ono, S.; Mizutani, H.; Hallinan, K. O. Tetrahedron:
Asymmetry 1997, 8, 181-184.
(8) (a) Koskinen, A. M. P.; Otsomaa, L. A. Tetrahedron 1997, 53, 6473-
6484. (b) Evans, D. A.; Black, W. C. J. Am. Chem. Soc. 1993, 115, 4497-
4513.
(9) Solladie’, G.; Gressot, L.; Colobert, F. Eur. J. Org. Chem. 2000,
357-364.
10.1021/ol0617695 CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/19/2006

degradation product of several macrolide antibiotics and the
many syntheses of this compound are illustrative of synthetic
approaches to δ-lactones.11
Scheme 1. Retrosynthetic Analysis for δ-Lactones
Synthetic routes to 5,6-dihydropyran-2-ones include inverse-
electron-demand Diels-Alder reactions,12 Mukaiyama-aldol
reactions of vinyl-substituted ketene acetals,11 Pd(0)-cata-
lyzed rearrangement2 of (Z)-γ,δ-epoxy-R,â-enoates, Pd-pro-
moted three-component coupling of allenoates, aldehydes,
and aryl boronic acids13 and from salts of 5-hydroxy-2-enoic
acids.14 Tetrahydropyran-2-ones have been prepared by the
allylation of aldehydes,3a,10 sequential reduction of â,δ-di-
ketoesters,9 desymmetrization of 1,3,5-trihydroxycyclohexane,3b
aldol reactions involving dienolates,5 or N-acyl oxazolidin-
ones,4f,8b and alkylations of pyrrolidinyl hydrazones.4d They
have also been prepared from 3,4-dihydro-δ-lactol ethers,15
by Michael additions of allenyltitaniums to alkylidenma-
lonates,16 via ring-closing reactions of 5-hydroxyalkynyl
selenides,17 by oxidation of tetrahydropyrans,4a via carbonyl
alkylative transpositions of 5,6-dihydropyran-4-ones,18 by
conjugate addition reactions to 5,6-dihydropyran-2-ones,19
and from diastereomerically pure 5-hydroxy esters.20 3,4-
Dihydropyran-2-ones have been prepare by 1,4-additions of
ketene acetals to enones21 and can be converted to the
tetrahydro derivatives by hydrogenation.
ate. Additionally, cis-4,5-dialkyl-substituted tetrahydropyran-
2-ones are potentially available from 4-substituted derivatives
of 2.
The requisite vinyl iodides 4a-c were readily prepared
from 2-alkynoates via (Z)-3-iodo-2-alkenyl esters22a by
established procedures.22 Metalation of 4b with t-BuLi in
THF resulted in the formation of (E) 3-trimethylsily-2-en-
1-ol (91%) via rearrangement of the silyl group from oxygen
to carbon. This retro-Brook rearrangement23 could be pre-
vented by carrying out the halogen-metal exchange reaction
in Et2O. Conversion of the vinyllithium reagents to vinylzinc
species by addition of ZnBr2 afforded organometallic re-
agents that underwent clean 1,2-addition to commercially
available ethyl glyoxylate in good to excellent yields (Scheme
2, Table 1, entries 1, 3, and 4). These R-hydroxy esters 5a-c
While several of the methodologies noted above are quite
efficient, they all required modifications of the starting
components in order to prepare a diverse array of δ-lactones
(e.g., 1). The ability to introduce a variety of substituents
onto the 2-pyranone ring in a single pot operation would
provide a combinatorial approach to the synthesis of
substituted dihydro- and tetrahydropyran-2-ones. We envi-
sioned utilization of a core dihydropyrone framework (e.g.,
2, AG ) activating group) upon which a wide range of
substituents could be introduced in a sequential fashion and
perhaps in a single pot (Scheme 1). The strategy required
sequential copper-mediated allylic substitution of 2 followed
by conjugate addition. Conceptually, the unknown 3,6-
dihydro-3-hydroxypyran-2-one (2) is available by addition
of a γ-silyloxyvinyl organometallic reagent to ethyl glyoxyl-
Scheme 2. Synthesis of 3,6-Dihydropyran-2-ones
(10) Wang, L.; Floreancig, P. E. Org. Lett. 2004, 6, 569-572.
(11) (a) Bluet, G.; Baza’n-Tejeda, B.; Campagne, J.-M. Org. Lett. 2001,
3, 3807-3810. (b) For a review, see: Martin, S. F.; Guinn, D. E. Synthesis
1991, 245-262.
(12) Lin, L.; Fan, Q.; Qin, B.; Feng, X. J. Org. Chem. 2006, 71, 4141-
were stable both at room temperature and when stored in
the refrigerator.
4146.
(13) Hopkins, C. D.; Guan, L.; Malinakova, H. C. J. Org. Chem. 2005,
70, 6848-6862.
(14) Cateni, F.; Zilic, J.; Zacchigna, M.; Bonivento, P.; Frausin, F.;
Scarcia, V. Eur. J. Med. Chem. 2006, 41, 192-200.
(15) (a) Chevez, D. E.; Jacobsen, E. N. Org. Lett. 2003, 5, 2563-2565.
(b) Gademann, K.; Chavez, D. E.; Jacobsen, E. N. Angew. Chem., Int. Ed.
2002, 41, 3059-3061.
(16) Song, Y.; Okamoto, S.; Sato, F. Org. Lett. 2001, 3, 3543-3545.
(17) Tiecco, M.; Testaferri, L.; Temperini, A.; Terlizzi, R.; Bagnoli, L.;
Marini, F.; Santi, C. Synlett 2006, 587-590.
(18) Nangia, A.; Rao, P. B. Tetrahedron Lett. 1993, 34, 2681-2684.
(19) (a) Hanessian, S.; Gomtsyan, A.; Malek, N. J. Org. Chem. 2000,
65, 5623-5631. (b) Fleming, I.; Reddy, N. L.; Takaki, K.; Ware, A. C. J.
Chem. Soc., Chem. Commun. 1987, 1472-1474.
(20) (a) Ahmed, M. M.; O’Doherty, G. A. Tetrahedron Lett. 2005, 46,
3015-3019. (b) Samarat, A.; Amri, H.; Landaos, Y. Synth. Commun. 2004,
34, 3707-3717.
(21) Tozawa, T.; Yamane, Y.; Mukaiyama, T. Chem. Lett. 2005, 514-
515.
Initial efforts to effect silyl ether deprotection and subse-
quent cyclization in a two phase CH2Cl2/fluosilicic acid (25%
aqueous solution) gave only recovered starting material.
Utilization of a homogeneous methanol solution afforded the
previously unknown δ-lactones 6a-c in very good to
excellent yields (Table 1). Although these lactones were
relatively stable, CDCl3 NMR samples of 6b underwent
chemical changes upon standing.
(22) (a) Ma, S.; Lu, X.; Li, Z. J. Org. Chem. 1992, 57, 709-713. (b)
Piers, E.; Harrison, C. L.; Zetina-Rocha, C. Org. Lett. 2001, 3(21), 3245-
3247.
(23) For a review see: Moser, W. H. Tetrahedron 2001, 57, 2065-
2084.
4780
Org. Lett., Vol. 8, No. 21, 2006

Table 1. 1,2-Additions of Vinyl Zinc Reagents to Ethyl
Glyoxylate and Cyclization to δ-Lactones (Scheme 2)
Table 2. Cuprate Mediated SN2′-Substitutions on
R-Phosphonoyl-â,γ-unsaturated-δ-lactones 6a-c
%
entry vinyl iodide rxn conda alcohol % yieldb lactone yieldb
1
2
3
4
4a
4b
4b
4c
A
B
A
A
5a
5b
5b
5c
78-91
34
71-91
88-86
6a
6b
6b
6c
80-90
95
72-91
76-90
a A ) Et2O. B ) THF/Et2O (1:1). b Yields are based upon isolated
products purified by column chromatography.
Application of cuprate substitution chemistry required
conversion of the hydroxy substituent into a good leaving
group. Attempted conversion to mesylates proved unsuc-
cessful and initial efforts to prepare [(PhO)2P(O)Cl, pyridine,
0 °C, 6 h] and isolate the allylic phosphates proved
unsatisfactory. Product isolation generally gave a mixture
of phosphate and starting alcohol and complex mixtures were
obtained when the mixtures of allylic phosphates and starting
alcohols were resubmitted to the phosphorylation reaction.
In situ generation of the allylic phosphates [(i) i-Pr2NLi, THF,
-78 °C; (ii) (PhO)2P(O)Cl, -78 to -20 or 0 °C.] followed
by treatment of the reaction mixture with alkyl(cyano)cuprate
reagents [i.e., R1Cu(CN)Li] failed to give allylic substitution
products. However, utilization of lithium hexamethyldisi-
lazide (LiHMDS) in place of LDA afforded δ-lactone 8a
(57%) from 6b and MeCu(CN)Li in modest yield. This
protocol was successful with lactones 6b,c which were
deprotonated at -78 °C, quenched with (PhO)2P(O)Cl at -78
°C, and warmed to -20 to 0 °C before cannulation of the
cuprate reagent into the reaction mixture. Deprotonation of
lactone 6a gave a precipitate and the solution was warmed
to -20 °C to effect dissolution of the solid (2-6 h) before
being cooled to -78 °C for addition of the chlorophosphate.
Lactones 6a-c could be converted into R,â-unsaturated-
δ-lactones 7-9 by utilization of LiHMDS for in situ
phosphate formation followed by treatment of the allylic
phosphate with specific cuprate reagents (Table 2). Although
the lithium dialkycuprate (i.e., R2CuLi) reagents failed to
give the desired products in all instances, lithium alkyl-
(cyano)cuprate reagents gave good yields of di-substituted
lactones 8 and 9 from allylic alcohols 6b,c. The lactones
8a-d and 9a-d proved difficult to purify by column
chromatography, since a phosphorus byproduct [i.e., n-
BuOP(O)(OPh)2] had nearly identical Rf values as the
lactone.24 Utilization of diethyl chlorophosphate [(EtO)2P-
(O)Cl] resolved the purification problem. The optimized
protocol readily generated lactones 8a-d and 9a-d in
modest to good chemical yields from alcohols 6b,c in a one-
pot operation.
a Ligand delivered from R1Cu(CN)Li unless otherwise noted. b Yields
based upon isolated products purified by column chromatography and are
given for the range of yields obtained for several reactions over the course
of development. c Ligand delivered from R1Cu(CN)ZnBr
reagents with ZnBr2 and CuCN generated zinc alkyl(cyano)-
cuprates [i.e., RCu(CN)ZnBr] that gave good chemical yields
of 4-substituted-δ-lactones 7a,b upon reaction with allylic
phosphate 10 (Table 2, entries 2 and 4). The dialkylzinc
cuprate, n-Bu2CuZnBr, gave none of the desired product 7b.
Zinc cuprates prepared from t-BuLi or PhLi, however, gave
a number of side reactions (eqs 1 and 2). Reaction of allylic
phosphate 10 with t-BuCu(CN)ZnBr gave R,â-enoic acid 11
which was converted to ester 12. The vicinal vinylic coupling
constants for 11 (J ) 15.6 Hz) and 12 (J ) 15.6 Hz) are
consistent with the (E)-isomer.25 Thus, enoic acid 11
plausibly arises via intial cuprate mediated lactone cleavage
followed by allylic substitution.
In situ formation of the allylic phosphate (i.e., 10, vide
infra) from lactone 6a and subsequent reaction with lithium
alkyl(cyano)cuprates gave low yields of lactones 7a,b (Table
2, entries 1 and 3). Sequential treatment of the alkyllithium
We next turned our attention to carrying out a one-pot
tandem phosphorylation, cuprate-mediated allylic substitu-
(25) Jackman, L. M.; Sternhell, S. Applications of Nuclear Magnetic
Resonance Spectroscopy in Organic Chemistry, 2nd ed.; Pergamon Press:
London, 1969; pp 301-302.
(24) Julia, B. B.; Rolando, C. Synthesis 1982, 291-294.
Org. Lett., Vol. 8, No. 21, 2006
4781

tion, and susbsequent cuprate-mediated 1,4-conjugate addi-
tion with allylic alcohol 6a. In situ generation of 10 followed
by subsequent treatment with two equivalents of n-BuCu-
(CN)ZnBr gave a mixture of 7b (23%) and 13a (40%). To
deliver two different ligands to the 2-pyrone core, the second
cuprate reagent must either be prepared separately and added
to the reaction mixture or generated in situ in the presence
of the dihyro-2-pyranone intermediate. After 10 was allowed
to react with n-BuCu(CN)ZnBr (-78 to +25 °C), the
reaction mixture was cooled to -78 °C and chlorotrimeth-
ylsilane was added followed by n-BuCu(CN)Li to afford 13a
(61%, Table 3, entry 1) in good yield after workup. Utilizing
when Me3SiCl was added immediately after the addition of
the RCu(CN)Li reagent. Attempted introduction of a phenyl
substituent in the conjugate addition reaction gave none of
the desired product (entry 5), and only small amounts of 7a
(20%) were isolated.
Tetrahydropyran-2-one 13a was formed as a single dias-
tereomer, while 14b was formed as a 92:8 trans/cis mixture
of diastereomers as evidenced by comparison with reported
1H and 13C NMR data for these known diastereomers.26
In summary, both 4-substituted and 4-unsubstituted 3,6-
dihydro-3-hydroxypyran-2-ones 6a-c are readily available
by the 1,2-addition of 3-silyloxyvinylzinc reagents to ethyl
glyoxylate. Activation of the hydroxyl substituent as the
diethyl phosphate derivative permits cuprate mediated allylic
substitution. The resulting 5-substituted or 4,5-disubstituted
5,6-dihydropyran-2-ones can be isolated and the 5-substituted
derivatives used in subsequent conjugate addition reactions.
The latter process can be carried out in a one-pot operation
permitting the rapid construction of a wide range of 4,5-
dialkyl-substituted tetrahydropyran-2-ones. Ongoing studies
are aimed at the preparation of 4,5,6-trisubstituted tetrahy-
dropyrones and extension of the methodology to asymmetric
variations for the preparation of enantiomerically enriched
δ-lactones.
Table 3. Tandem Phosphorylation, Allylic Substitution, and
Conjugate Addition from 6a
Acknowledgment. This work was generously supported
by the American Chemical Society Petroleum Research Fund
(42853-AC1). Support of the NSF Chemical Instrumentation
Program for purchase of a JEOL 500 MHz NMR instrument
is gratefully acknowledged (CHE-9700278).
Supporting Information Available: General experimen-
tal information, general procedures A-E, experimental
procedures for 4b, 5a,b, 6a-c, and 12, data reduction for
7a,b, 8a-d, 9a-d, 13a,b, 14a,b, references, and 1H and 13
C
NMR spectra for 4b, 5a,b, 6a-c, 7a,b, 8a-d, 9a-d, 12,
13a,b, 14a,b. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL0617695
this protocol, two different alkyl substituents could be
introduced onto the 2-pyrone framework in a one-pot
operation (entries 2-4). Higher yields were not achieved
(26) (a) Fleming, I.; Reddy, N. L.; Takaki, K.; Ware, A. C. J. Chem.
Soc., Chem. Commun. 1987, 1472-1474. (b) Matsunaga, P. T.; Mavropou-
los, J. C.; Hillhouse, G. L. Polyhedron 1995, 14, 175-185.
4782
Org. Lett., Vol. 8, No. 21, 2006