Transformation of fused bicyclic and tricyclic β-lactones to fused γ-lactones and 3(2H)-furanones via ring expansions and O-H insertions

Article abstract of DOI:10.1021/jo7012934

(Chemical Equation Presented) A two-step strategy for conversion of β-lactones to γ-lactones and 3(2H)-furanones was developed involving initial acyl C-O cleavage leading to δ-hydroxy-α-diazo-β- ketoesters and β-ketophosphonates. Subsequent tandem Wolff r

Full text of DOI:10.1021/jo7012934

Transformation of Fused Bicyclic and Tricyclic
â-Lactones to Fused γ-Lactones and
3(2H)-Furanones via Ring Expansions and O-H
Insertions
Wei Zhang and Daniel Romo*
Department of Chemistry, Texas A&M UniVersity,
College Station, Texas 77842-3012
FIGURE 1. Intramolecular cyclizations leading to bicyclic and tricyclic
â-lactones.
romo@tamu.edu
ReceiVed July 9, 2007
philes. In addition, we previously reported a catalytic, asym-
metric, intramolecular nucleophile catalyzed aldol-lactonization
(NCAL) process of aldehyde acids that enables access to
optically active bicyclic-â-lactones employing quinidine and
quinine as nucleophilic catalysts (Figure 1 (i)).5 More recently,
we expanded this process to keto acid substrates employing
4-pyrrolidinopyridine (4-PPY) as a nucleophilic promoter al-
lowing access to a variety of functionalized bicyclic and tricyclic
carbocycle-fused â-lactones6 and heterocycle fused-â-lactones7
with good to excellent diastereoselectivity based on substrate
control (Figure 1 (ii)).
The frequent occurrence of carbocycle-fused γ-lactones and
both 3(2H)-furanones and derivable 3-hydroxy tetrahydrofurans
in natural products8 led us to consider expedient strategies for
conversion of bicyclic and tricyclic â-lactones to these moieties.
While several elegant strategies have been developed for the
synthesis of these systems,9,10 the combination of the catalytic,
asymmetric NCAL process of aldehyde acids or bis-cyclization
of keto acids in conjunction with an efficient method for
conversion of â-lactones to γ-lactones and 3(2H)-furanones
appeared to provide a particularly expedient strategy. Building
on previous work of Moody,11 we envisioned that â-lactone acyl
C-O cleavage with ethyl lithio-R-diazo acetate would provide
A two-step strategy for conversion of â-lactones to γ-lactones
and 3(2H)-furanones was developed involving initial acyl
C-O cleavage leading to δ-hydroxy-R-diazo-â-ketoesters
and â-ketophosphonates. Subsequent tandem Wolff rear-
rangement/lactonization of these R-diazo intermediates pro-
vided cis-fused γ-lactones efficiently under photolytic or
thermolytic conditions. In addition, cis-fused 3(2H)-furanones
were obtained by rhodium(II)-catalyzed O-H insertion
reactions of the δ-hydroxy-R-diazo intermediates.
Several methods for the asymmetric synthesis of â-lactones
have appeared recently1 and have stimulated the development
of new transformations of these versatile intermediates.2 As part
of our ongoing efforts to further exploit â-lactones as synthetic
intermediates, we have studied various transformations involving
both acyl C-O3 or alkyl C-O4 cleavage with diverse nucleo-
(5) (a) Cortez, G. S.; Oh, S. H.; Romo, D. Synthesis 2001, 1731. (b) Oh,
S. H.; Cortez, G. S.; Romo, D. J. Org. Chem. 2005, 70, 2835.
(6) Riyad, H.; Lee, C. S.; Purohit, V.; Romo, D. Org. Lett. 2006, 8,
4363.
(7) Ma, G.; Nguyen, H.; Romo, D. Org. Lett. 2007, 9, 2143.
(8) Selected examples: (a) Schmidt, T. J. Current Org. Chem. 1999, 3,
577. (b) Saku, F.; Ohkuma, H.; Koshiyama, H.; Naito, T.; Kawaguchi, H.
Chem. Pharm. Bull. 1976, 24, 114. (c) Hata, K.; Kozowa, M.; Baba, K.;
Knonoshima, M.; Chi, H. J. Tetrahedron Lett. 1970, 11, 4379.
(9) For lead references to synthesis of cis-fused bicyclic γ-lactones,
see: (a) Corey, E. J.; Gross, A. W. Tetrahedron Lett. 1985, 26, 4291. (b)
Junji, I. Trends in Org. Chem. 1990, 1, 23. (c) Lee, G. H.; Choi, E. B.;
Lee, E.; Pak, C. S. J. Org. Chem. 1994, 59, 1428. (d) Paquette, L. A.;
Sturino, C. F.; Wang, X.; Prodger, J. C.; Koh, D. J. Am. Chem. Soc. 1996,
118, 5620. (e) Black, H. T.; Smith, D. C.; Eisenbeis, S. A.; Peterson, K.
A.; Harmon, M. S. Chem. Commun. 2001, 753. (f) Yu, M.; Pagenkopf, B.
L. Org. Lett. 2003, 5, 4639. (g) Dams, I.; Bialonska, A.; Ciunik, Z.;
Wawrzenczyk, C. Tetrahedron: Asymmetry 2005, 16, 2087.
(10) For lead references to the synthesis of cis-fused 3(2H)-furanones,
see: (a) Smith, A. B., III; Empfield, J. R.; Vaccaro, H. A. Tetrahedron
Lett. 1989, 30, 7325. (b) Linderman, R. J.; Viviani, F. G.; Kwochka, W. R.
Tetrahedron Lett. 1992, 33, 3571. (c) Cossy, J.; Bellosta, V.; Ranaivosata,
J.; Gille, B. Tetrahedron 2001, 57, 5173. (d) Sha, C.; Huang, S.; Zhan, Z.
J. Org. Chem. 2002, 67, 831. (e) Kuroda, H.; Tomita, I.; Endo, T. Org.
Lett. 2003, 5, 129. (f) Muthusamy, S.; Gnanaprakasam, B.; Suresh, E. Org.
Lett. 2005, 7, 4577.
(1) For a review, see: (a) Yang, H. W.; Romo, D. Tetrahedron 1999,
55, 6403. For more recent examples, see: (b) Evans, D. A.; Janey, J. M.
Org. Lett. 2001, 3, 2125. (c) Cortez, G. S.; Tennyson, R. L.; Romo, D. J.
Am. Chem. Soc. 2001, 123, 7945. (d) Nelson, S. G.; Zhu, C.; Shen, X. J.
Am. Chem. Soc. 2004, 126, 14. (e) Zhu, C.; Shen, X.; Nelson, S. G. J. Am.
Chem. Soc. 2004, 126, 5352. (f) Calter, M. A.; Tretyak, O. A.; Flascheriem.
C. Org. Lett. 2005, 7, 1809. (g) Wilson, J. E.; Fu, G. C. Angew. Chem.,
Int. Ed. 2004, 43, 6358. (h) Gnanadesikan, V.; Corey, E. J. Org. Lett. 2006,
8, 4943. (i) Lin, Y.; Boucau, J.; Li, Z.; Casarotto, V.; Lin, J.; Nguyen, A.
N.; Ehrmantraut, J. Org. Lett. 2007, 9, 567.
(2) For a review, see: (a) Pommier, A.; Pons, J.-M. Synthesis 1995, 729.
(b) Wang, Y.; Tennyson, R.; Romo, D. Heterocycles 2004, 64, 605. See
also ref 1a. For selected recent examples, see: (c) Donohoe, T. J.; Sintim,
H. O.; Sisangia, L.; Harling, J. D. Angew. Chem., Int. Ed. 2004, 43, 2293.
(d) Getzle, Y. D. Y. L.; Kundnani, V.; Lobkovsky, E. B.; Coates, G. W. J.
Am. Chem. Soc. 2004, 126, 6842. (e) Mitchell, T. A.; Romo, D. Heterocycles
2005, 66, 627. (f) Shen, X.; Wasmuth, A. S.; Zhao, J.; Zhu, C.; Nelson, S.
G. J. Am. Chem. Soc. 2006, 128, 7438. (g) Reddy, L. R.; Corey, E. J. Org.
Lett. 2006, 8, 1717.
(11) (a) Moody, C. J.; Taylor, R. J. Tetrahedron Lett. 1987, 28, 5351.
(b) Moody, C. J.; Taylor, R. J. J. Chem. Soc., Perkin Trans. 1 1989, 721.
(c) Davies, M. J.; Moody, C. J.; Taylor, R. J. J. Chem., Soc. Perkin Trans.
1 1991, 1. (d) Davies, M. J.; Moody, C. J. J. Chem. Soc., Perkin Trans. 1
1991, 9.
(3) Yang, H. W.; Romo, D. J. Org. Chem. 1999, 64, 7657.
(4) (a) Zhao, C.; Romo, D. Tetrahedron Lett. 1997, 38, 6537. (b) Yokota,
Y.; Cortez, G. S.; Romo, D. Tetrahedron 2002, 58, 7075. (c) Zhang, W.;
Matla, A.; Romo, D. Org. Lett. 2007, 9, 2111.
10.1021/jo7012934 CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/12/2007
J. Org. Chem. 2007, 72, 8939-8942
8939

TABLE 1. Acyl C-O Ring Cleavage of Bicyclic and Tricyclic
â-Lactones 1a-c to δ-Hydroxy-r-diazo-â-ketoesters 2a-c
FIGURE 2. General strategy for conversion of bi-/tricyclic â-lactones
to bi-/tricyclic γ-lactones and 3(2H)-furanones.
versatile R-diazo intermediates12 2 which could undergo a
tandem Wolff rearrangement/lactonization13 to generate cis-
carbocycle-fused γ-lactones 3 (Figure 2). Alternatively, an O-H
insertion would furnish cis-carbocycle-fused 3(2H)-furanones
4 utilizing the rhodium(II)-catalyzed process originally devel-
oped by Teyssie´,14 subsequently demonstrated in an intramo-
lecular setting by Rapoport15 and further developed by Moody,
Padwa, Calter, and others for 3(2H)-furanone synthesis.16
Previous studies of lactone cleavage reactions with lithiated
diazo carbonyl compounds have been limited to five- to eight-
membered lactones.17 Building on these previous studies, we
recognized that R-dimethyl phosphonate γ-lactones 3 and
R-dimethyl phosphonate 3(2H)-furanones 4 would be accessible
from R-diazo phosphonates 2 (E ) P(O)(OMe)2) if â-lactones
1 could be transformed to diazo compounds 2.11c The imple-
mentation of this strategy is described herein.
a 2.2 equiv of LDA and EDA, 2 h, syringe pump addition of LDA. b 4.0
equiv of LDA and EDA, 2 h, syringe pump addition of LDA. c Yields refer
to isolated, purified (silica gel) product.
TABLE 2. Acyl C-O Ring Cleavage of Bicyclic and Tricyclic
â-Lactones 1a-c Leading to δ-Hydroxy-r-diazo â-Phosphonates
2d-f
We initiated these studies by exploring the addition of ethyl
lithio-R-diazoacetate to bicyclic â-lactone (+)-1a.1c Following
several failed attempts to metalate ethyl diazoacetate (EDA)
followed by addition of â-lactone (+)-1a which led to complex
reaction mixtures, we confirmed earlier observations of Moody11c
that inverse addition of lithium diisopropylamide (LDA) into a
THF solution of substrate lactone and EDA at -78 °C was
optimal. When applied to â-lactone (+)-1a, this provided the
desired δ-hydroxyl-R-diazo-â-ketoester (-)-2a in 67% yield
(Table 1, entry 1). The exclusive chemoselectivity observed with
the lithiated diazo ester toward the â-lactone over the geminal
methyl esters is noteworthy but not unexpected due to the
inherent ring strain of the â-lactone. Compared to the cyclo-
hexyl-fused â-lactone (+)-1a, the cyclopentyl-fused bicyclic and
tricyclic â-lactones (+)-1b1c and (()-1c,6 respectively, required
additional equivalents of lithiated EDA (4.0 equiv) for complete
conversion (Table 1, entries 2 and 3). Interestingly, reaction
a Yields refer to overall yield for three steps of isolated (silica gel),
purified product.
(12) For a seminal review of preparations and applications of R-diazo
carbonyl compounds, see: Ye, T.; McKervey, A. M. Chem. ReV. 1994, 94,
1091.
(13) (a) Chantegrel, B.; Deshayes, C.; Faure, R. Tetrahedron Lett. 1995,
36, 7859. (b) Ronan, B.; Bacque´, E.; Barrie`re, J. Tetrahedron 2004, 60,
3819. (c) Liao, M.; Dong, S.; Deng, G.; Wang, J. Tetrahedron Lett. 2005,
47, 4537.
(14) Paulissen, R.; Reimlinger, H.; Hayez, E.; Hubert, A. J.; Teyssie´, P.
Tetrahedron 1973, 24, 2233.
(15) Rapoport, H.; Feldman, P. L.; Moyer, M. P. J. Org. Chem. 1985,
50, 5223.
(16) For lead references to the synthesis of 3(2H)-furanones via O-H
insertion, see: (a) Moody, C. J.; Miller, D. J. Tetrahedron 1995, 51, 10811.
(b) Karady, S.; Amato, J. S.; Reamer, R. A.; Weinstock, L. M. Tetrahedron
Lett. 1996, 37, 8277. (c) Albert, P.; Marcus, S. Tetrahedron Lett. 1997, 38,
5087. (d) Padwa, A.; Sa´, M. J. Braz. Chem. Soc. 1999, 10, 231. (e) Calter,
A. M.; Zhu, C. J. Org. Chem. 1999, 64, 1415. (f) Xu, C.; Zhang, Y.; Yuan,
C. Eur. J. Org. Chem. 2004, 2253.
(17) Previous attempts to access a R-diazo-â-keto ester from 4-methyl
â-lactone (â-butyrolactone) by with lithiated EDA were unsuccessful, see
ref 11b.
with â-lactone (+)-1b provided a separable mixture of the
expected diazo adduct (-)-2b and a R-diazo lactone (+)-2b′
resulting from subsequent trans-esterification in a 2:1 ratio
(Table 1, entry 2).
δ-Hydroxy-R-diazo-â-ketophosphonates 2d-f could be syn-
thesized using a simple three-step protocol11c involving initial
chemoselective â-lactone cleavage with lithiated dimethyl
methylphosphonate followed by in situ TMS protection of the
resulting alkoxide to provide TMS â-keto phosphonate 5 (Table
2).18 Subsequent diazo transfer with 4-acetamidobenzenesulfonyl
azide (p-ABSA) and facile desilylation gave δ-hydroxy-R-diazo-
â-ketophosphonates 2d-f in good yield over three steps.
The tandem Wolff rearrangement/lactonization of δ-hydroxy-
R-diazo-â-ketoesters and phosphonates 2 was initiated by
(18) Ditrich, K.; Hoffmann, R. W. Tetrahedron Lett. 1985, 26, 6325.
8940 J. Org. Chem., Vol. 72, No. 23, 2007

TABLE 3. Preparation of Bicyclic and Tricyclic r-Carboethoxy or
r-Dimethyl Phosphonate γ-Lactones via the Tandem Wolff
Rearrangement/Lactonization Process
SCHEME 1. Trans-Esterification of r-Diazo Ester (-)-2b
to r-Diazo-δ-lactone (+)-2b′ and Tandem Wolff Rearrange-
ment/Decarboxylation to Fused Bicyclic γ-Lactone (+)-7
conditions (Table 3, entries 4 and 5). However, an exception
was R-diazo phosphonate (()-2f, which provided the desired
product in excellent yield without evidence of O-H insertion
product under both photolytic and thermal conditions. Again,
minor diastereoisomers of phosphonate esters 3d-f were readily
converted to the major diastereomers under mild acidic condi-
tions during silica gel chromatography or treatment with TFA
in chloroform.20 These results indicate that kinetic ratios of
diastereomeric adducts are not readily ascertained but that the
major diastereomers of 3a-f initially formed are indeed the
thermodynamically more stable â-epimers which place the
phosphonate or ester moiety in the convex face of the bicycle
or tricycle as expected, which is, of course, inconsequential for
subsequent transformations, e.g., olefination.
We also determined that decarboxylated bicyclic γ-lactone
(+)-7 could be synthesized directly from R-diazo-δ-lactone (+)-
2b′, obtained as a minor product during addition of lithiated
EDA to â-lactone (+)-1b (see Table 1, entry 2). Furthermore,
conversion of R-diazo ester (-)-2b to the R-diazo-δ-lactone (+)-
2b′ was accomplished with sodium hydride (Scheme 1).
Thermolysis of R-diazo-δ-lactone (+)-2b′ in wet, boiling toluene
provided cis-fused bicyclic γ-lactone (+)-7 in nearly quantitative
yield via a tandem Wolff rearrangement/decarboxylation se-
quence.
Finally, heating δ-hydroxy-R-diazo-â-ketoesters and â-keto
phosphonates 2a-f in the presence of a catalytic amount of
rhodium(II) acetate in toluene proceeded efficiently to furnish
diastereomeric 3(2H)-furanones 4 via a rhodium carbenoid-
mediated intramolecular O-H insertion.15,16 Insertion of δ-hy-
droxy-R-diazo-â-ketoesters 2a-c proceeded to completion
within 10-30 min (Table 4, entries 1-3), while phosphonates
(-)-2d and (-)-2e required 1-2 h for complete conversion
(Table 4, entries 4-5). Interestingly, diazo ester (()-2f gave
the tandem Wolff rearrangement/lactonization product (()-3f
as the predominant product (>60%) under typical O-H
insertion conditions. This may be due to steric issues associated
with this more congested R-diazo-â-ketophosphonate (()-2f,
which retards the rate of metallocarbenoid formation. However,
use of the more reactive, electrophilic rhodium catalyst, Rh2-
(OCOCF3)4, promoted the O-H insertion providing the desired
3(2H)-furanone (()-4f in excellent yield (Table 4, entry 6).
3(2H)-Furanones 4a-f exist as rapidly equilibrating mixtures
of trans and cis diastereomers (∼1:1 dr).16e,f
a Major diastereomers are shown. The relative stereochemistry of
diastereomeric adducts 3a-f was assigned based on nOe measurements
and coupling constant analysis (JH2,H3; see the Supporting Information for
details). b Conditions: 254 nm, PhMe, 0.01 M. c Yields refer to isolated
(silica gel), purified, mixture of diastereomers 3a-f. d Diastereomeric ratios
determined (1H NMR, 500 MHz) following purification which in all cases
led to epimerization. e Conditions: 110 °C, PhMe, 0.01 M. f Yield of O-H
insertion product (i.e., furanone) obtained during thermolysis. g Not studied.
h This reaction was performed with TMS-R-diazo ester 6f which underwent
in situ desilylation (see the Supporting Information for details).
photolysis19 or thermolysis13a to give intermediate ketenes that
were efficiently trapped by the pendant alcohol to furnish
R-carboethoxy or R-dimethyl phosphonate γ-lactones 3 in good
to moderate yields (Table 3). In general, a range of diastereo-
selectivities was obtained under both photolytic and thermolytic
conditions as judged by analysis of crude reaction mixtures;
however, this was of no consequence as facile epimerization to
the thermodynamically preferred â-epimers occurred upon
purification. As indicated, O-H insertion products (5-18%)
presumably generated by direct capture of the carbene inter-
mediate with the pendant alcohol during the thermolytic process
account for the decreased yields.
Tandem Wolff rearrangement/lactonization with R-diazo-â-
phosphonate substrates were less efficient in general (Table 3,
entries 4-6). Compromised yields were obtained with R-dia-
zophosphonates (-)-2d and (-)-2e due to significant intervening
O-H insertion observed under both photolytic and thermolytic
In summary, we developed a strategy for transformation of
bicyclic and tricyclic â-lactones to δ-hydroxy-R-diazo-â-ke-
toesters and δ-hydroxy-R-diazo-â-ketophosphonates. These
intermediates were then converted to fused γ-lactones or 3(2H)-
furanones via a tandem Wolff rearrangement/ lactonization
process or a rhodium(II)-catalyzed O-H insertion process,
respectively. The reactions reported herein expand the repertoire
(20) After silica chromatography, only the major isomer could be isolated.
This selective conversion was also confirmed by adding 2 µL of TFA into
NMR samples (CDCl3) of crude mixtures of 3e and 3f and analyzing by
1H NMR (500 MHz).
(19) (a) Georgian, V.; Boyer, S. K.; Edwards, B. J. Org. Chem. 1980,
45, 1686. (b) Cossy, J.; Belotti, D.; Leblanc, C. J. Org. Chem. 1993, 58,
2351.
J. Org. Chem, Vol. 72, No. 23, 2007 8941

TABLE 4. Preparation of r-Carbethoxy or r-Dimethyl
Phosphonate 3(2H)-furanones via Rhodium(II)-Catalyzed O-H
Insertion Reaction
EtOAc/hexanes (20:80) to give R-diazo ester (-)-2a (126 mg, 0.36
mmol, 67%) as a yellowish oil: [R]23D -23.3 (c 0.60, CHCl3); IR
(thin film) 3512 (br), 2956, 2140, 1709, 1650, 1434, 1378, 1280
1
cm-1; H NMR (500 MHz, CDCl3) δ 4.31 (dq, J ) 1.0, 7.0 Hz,
2H), 4.17-4.20 (m, 1H), 3.81 (s, 3H), 3.73 (s, 3H), 3.68 (dt, J )
1.5, 13.0 Hz, 1H), 3.43 (s, 1H), 2.40 (t, J ) 13.0 Hz, 1H), 2.11-
2.23 (m, 3H), 1.86-1.96 (m, 1H), 1.78-1.84 (m, 1H), 1.34 (dt, J
) 1.0, 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 196.4, 172.3,
171.4, 160.6, 65.2, 61.9, 54.1, 53.0, 52.9, 45.6, 29.0, 27.2, 24.6,
14.6; HRMS (ESI+) calcd for C15H20N2O8Li (M + Li) 363.1380,
found 363.1424.
Representative Procedure for Tandem Wolff Rearrangement/
Lactonization As Described for Conversion of R-Diazo Ester
(-)-2a to γ-Lactone (+)-3a. A solution of (-)-2a (15 mg, 0.04
mmol) in PhMe (5.3 mL) was irradiated for 16 h at 254 nm. After
evaporation, the crude material was purified by flash chromatog-
raphy, eluting with EtOAc/hexanes (20:80), to give (+)-3a (12 mg,
0.036 mmol, 85%) as a colorless oil: [R]23D +17.0 (c 0.47, CHCl3);
IR (thin film) 2954, 1785, 1729, 1439, 1258, 1172 cm-1; 1H NMR
(500 MHz, CDCl3) δ 4.80 (q, J ) 3.5 Hz, 1H), 4.25 (q, J ) 7.5
Hz, 2H), 3.80 (s, 3H), 3.75 (s, 3H), 3.27 (d, J ) 1.5 Hz, 1H), 2.95-
2.99 (m, 1H), 2.44 (ddd, J ) 2.0, 6.0, 14.0 Hz, 1H), 2.17-2.24
(m, 2H), 1.97 (dt, J ) 4.5, 9.0 Hz, 1H), 1.72-1.82 (m, 1H), 1.58
(dd, J ) 6.5, 14.0 Hz, 1H), 1.33 (t, J ) 7.5 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 171.7, 171.6, 170.8, 166.9, 77.1, 62.6, 55.9,
53.5, 53.3, 53.1, 37.0, 31.2, 24.6, 23.9, 14.3; HRMS (ESI+) calcd
for C15H20O8Li (M + Li) 335.1318, found 335.1391.
Representative Procedure for the O-H Insertion Process As
Described for Conversion of R-Diazo Ester (-)-2a to 3(2H)-
Furanone (()-4a. To a solution of Rh2(OAc)4 (∼0.75 mg, 1.7
µmol) in PhMe (1.7 mL) at 80 °C was added a solution of (-)-2a
(12 mg, 0.034 mmol) in PhMe (1.7 mL) dropwise. After 5 min,
the reaction was cooled to 25 °C and filtered through a plug of
Celite. Concentration by rotary evaporation gave 3(2H)-furanone
(()-4a as an inseparable mixture of R-diastereomers (11 mg, 0.033
mmol, 99%) as a clear, colorless oil that did not require further
purification: IR (thin film) 2972, 1744, 1225, 1104, 1019 cm-1
;
a Obtained as rapidly equilibrating mixtures of trans and cis diastereomers
(∼1:1 dr). b Yields refer to crude products which did not require further
purification with the exception of 4f which was purified by chromatography
(silica gel). c Rh2(OCOCF3)4 was used as catalyst.
1H NMR (500 MHz, CDCl3) δ 4.71 (s, 0.5H), 4.61 (q, J ) 3.5 Hz,
0.5H), 4.45 (s, 0.5H), 4,24-4,32 (m, 2.5H), 3.77 (s, 3H), 3.74 (s,
1.5H), 3.73 (s, 1.5H), 2.68-2.77 (m, 1H), 2.42 (ddd, J ) 1.0, 7.0,
14.0 Hz, 0.5H), 2.30 (ddd, J ) 1.0, 7.0, 14.0 Hz, 0.5H), 2.15-
2.27 (m, 2.5H), 2.05 (dt, J ) 5.0, 14.0 Hz, 0.5H), 1.85 (dd, J )
12.5, 17.5 Hz, 0.5H), 1.77-1.84 (m, 1H), 1.71 (dd, J ) 12.5, 17.5
Hz, 0.5H), 1.33 (t, J ) 7.0 Hz, 1.5 H), 1.27 (t, J ) 1.5H); 13C
NMR (125 MHz, CDCl3) δ 208.8, 208.5, 171.8, 171.6, 170.8, 170.7,
166.7, 165.7, 80.9, 79.4, 74.9, 73.8, 62.5, 62.4, 53.21, 53.18, 53.15,
53.07, 53.03, 53.01, 43.5, 43.2, 27.2, 26.4, 25.0, 24.9, 24.0, 23.9,
14.4, 14.3; HRMS (ESI+) calcd. for C15H21O8 (M + H) 329.1236,
found 329.1288.
of accessible functional arrays from bicyclic and tricyclic
â-lactones to include fused bicyclic and tricyclic γ-lactones and
3(2H)-furanones which are common motifs in natural products.
Experimental Section
Representative Procedure for Addition of Lithiated Ethyl
Diazoacetate to â-Lactones As Described for Conversion of
â-Lactone (+)-1a to R-Diazo Ester (-)-2a. To a solution of ethyl
diazoacetate (132 mg, 0.12 mL, 1.16 mmol) and bicyclic â-lactone
(+)-1a (128 mg, 0.53 mmol) in THF (3.0 mL) at -78 °C was
slowly added freshly prepared LDA (3.8 mL, 1.16 mmol, 0.3 M in
THF) over 2 h via syringe pump. After 30 min, the reaction was
quenched with satd aq NH4Cl (10.0 mL). The mixture was extracted
with Et2O (3 × 20 mL). The dried (MgSO4) extract was concen-
trated in vacuo and purified by flash chromatography, eluting with
Acknowledgment. We thank the Welch Foundation (A-
1280) and the NSF (CHE-0416260) for support of this work.
Supporting Information Available: Experimental details and
full characterization of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO7012934
8942 J. Org. Chem., Vol. 72, No. 23, 2007