Rapid access to the synthesis of polysubstituted δ-lactones via tandem stereoselective conjugate addition/α-alkylation of unsaturated 7,3-lactone-α-d-xylofuranose derivative

Article abstract of DOI:10.1016/j.tetlet.2013.08.036

α-d-xylo-7,3-Unsaturated lactone, a versatile chiral building block, undergoes Cu-catalyzed conjugated addition with high yield and stereoselectivity. When the conjugated reaction is quenched with a suitable alkyl halide, a tandem stereoselective conjugated/α-alkylation reaction is achieved. Further, selective hydrolysis of the 1,2-O-isopropylidene moiety followed by oxidative cleavage and reduction reaction, afforded the title compounds.

Full text of DOI:10.1016/j.tetlet.2013.08.036

Tetrahedron Letters 54 (2013) 5751–5754
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Rapid access to the synthesis of polysubstituted d-lactones via
tandem stereoselective conjugate addition/
a-alkylation of
unsaturated 7,3-lactone- -D-xylofuranose derivative
a
⇑
Elsie Ramírez, Leticia Quintero, Rosa L. Meza-León, Martha Sosa-Rivadeneyra, Silvano Cruz-Gregorio ,
Fernando Sartillo-Piscil
⇑
Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla (BUAP), 14 Sur Esq. San Claudio, San Manuel, 72570 Puebla, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 July 2013
Revised 7 August 2013
Accepted 10 August 2013
Available online 16 August 2013
a
-
D
-xylo-7,3-Unsaturated lactone, a versatile chiral building block, undergoes Cu-catalyzed conjugated
addition with high yield and stereoselectivity. When the conjugated reaction is quenched with a suitable
alkyl halide, a tandem stereoselective conjugated/ -alkylation reaction is achieved. Further, selective
a
hydrolysis of the 1,2-O-isopropylidene moiety followed by oxidative cleavage and reduction reaction,
afforded the title compounds.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Conjugate addition
Stereoselectivity
d-Lactones
Carbohydrates
Tandem
O
O
Conjugate addition (sometimes known as the Michael addition),
probably represents the best way for introducing a nucleophile in
the b-position of an unsaturated carbonyl compound.1 As this
nucleophilic introduction affords an incipient enolate intermedi-
ate, the chemical reaction can be quenched by a suitable electro-
phile and thus turns this reaction into a sequential or tandem
transformation that, not only allows the incorporation of two func-
tional groups during the same chemical transformation, but can
also be done under enantio-and diastereoselective fashion.2
Regarding the diastereoselective conjugated addition (DCA),3 the
use of chiral auxiliary4 and chiral substrates5 have proven to be
two powerful tools which provide optical purity at low cost; espe-
cially if the source of chirality comes from carbohydrates (chiral
pool).
O
O
O
N
O
O
H
O
O
N
O
H
(+)-Scholarisine A
Limonin
OH
O
OH
H2N
OH
(+)-Discodermolide
O
O
OH
O
Figure 1. Biological important compounds containing the polysubstituted d-
lactone fragment.7
During the course of a project designed to synthesize biologi-
cally important lactones, the preparation of novel optically pure
polysubstituted d-lactones was required; those by the way, are
common fragments in many biologically important compounds
(Fig. 1).6 For that reason, we report here a rapid and efficient meth-
odology for the synthesis of the required lactones based on the
of the unsaturated 7,3-d-lactone-a-D-xylofuranose derivative 1
was planned. Once the DCA methodology is set up, we will try to
trap the enolate intermediate with alkyl halides to thus developing
a tandem DCA/
Finally, by conducting a selective hydrolysis of the 1,2-O-isopro-
pyliden moiety of the DCA/ -alkylation products, followed by oxi-
a-alkylation reaction.
DCA-and the tandem DCA/a-alkylation reaction by taking advan-
a
tage of the chiral substrate approach.5,8 To this end, a DCA reaction
dative cleavage of the respective 1,2-diols; and the reduction of the
formed dicarbonyl compounds with NaBH4, the required polysub-
stituted d-lactones will be obtained (Fig. 2). This simple strategy
may result to be attractive because the preparation of the chiral
⇑
Corresponding authors. Tel.: +52 222 2295500/7391; fax: +52 222 2454972.
E-mail address: fernando.sartillo@correo.buap.mx (F. Sartillo-Piscil).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.08.036

5752
E. Ramírez et al. / Tetrahedron Letters 54 (2013) 5751–5754
Table 2
Stereoselective
A
n
a
-
optically pure
C
hydrolysis
dehomologation
/reduction
m
e
k
d
l
a-alkylation of enolate 3
a
n
o
i
t
polysubstituted δ -lactones
r
/
t
o
A
a
l
y
α
O
C
O
HO
R1
O
R1
O
O
R
HO
O
O
R2
O
O
2 equiv of R2X
-40 °C to rt
O
1
Nu
O
O
O
O
O
3
O
4
BrMgO
Figure 2. Strategy for the synthesis of polysubstituted lactones.
Entry
R1
R2X
Yielda (%)
1
2
3
4
p-F-Ph
p-F-Ph
p-F-Ph
Bn
CH3I
BnBr
Allyliodide
Allyliodide
65
63
68
63
synton 1 is rapidly achieved (in multi gram-scale) from diacetone-
D
-glucose in a sequential hydrolysis–oxidation–Wittig olefination
(SHOWO protocol9) featuring a highly diastereoselective Wittig
olefination reaction in aqueous media.9c
a
Yields after chromatographic purification.
Because the high efficiency of the Cu-catalyzed DCA of Grignard
reagents to a,b-unsaturated esters (and related compounds) is well
recognized;3a the present work begins with the treatment of lac-
tone 1 with of p-F-PhMgBr and CuBrSMe2. The use of higher
amounts of Cu catalyst or Grignard reagent (e.g., 10 equiv of RMgBr
and 5 equiv of CuBrSMe2),10 as well as additional additives (TMSCl,
LiBr, HMPA)11 was not necessary, since only 0.5 equiv of CuBrSMe2
and 2 equiv of the Grignard reagent at À40 °C was more than en-
ough to obtain high yield and high anti-stereoselectivity (see en-
tries 1 and 2).12
The use of CuI as catalyst was less effective than CuBrSMe2 (en-
try 3); therefore the CuBrSMe2 catalyst was used for the other
experiments. With ethyl, methyl and benzyl Grignard reagents (en-
tries 4–6) the DCA products were obtained with high yields (75–
85%) and stereoselectivity (96%); however, only 8% yield of the
DCA product was obtained for the case of allylMgCl (entry 7), or
only a trace was observed when CuI was used (entry 8). In these
two latter cases, the 1,2-addition compound (not shown) was ob-
tained as the major product (Table 1).
O
O
R1
H
4 O
O
H5
O
R2
H4
R
2O
H6
O
H4
H5
R2
R1
O
H3
O H3
H6
H3
R1
O
O
4
4T
4C
NOE
(R1 = p-F-Ph; R2 = allyl)
3JH5-H6 = 12.0 Hz
3JH4-H5 = 3.9 Hz
Figure 3. Stereochemistry and conformational preference of d-lactone 4.
the anti-relationship between H5 and H6 and the pseudo diequato-
rial relationship between H4 and H5, respectively. Because all of
the d-lactones possess very similar coupling constants, it can be as-
sumed that all of them enjoy the same major conformation 4T. The
a-alkylation of the enolates is consis-
tent with models previously proposed either in cyclic or acyclic
Having set up an efficient protocol for the DCA of lactone 1, we
then focused on the tandem protocol. Thus, the reaction mixture of
DCA (with p-F-PhMgBr and BnMgCl as Grignard reagents, and CuB-
rSMe as catalyst) at À40 °C was treated with selected alkyl halides
(CH3I, BnBr, and allyliodide) and stirred at room temperature for
stereochemical outcome of
systems.2,14
We finally proceeded to transform the d-lactones 4a–c into the
desired polysubstituted d-lactones 7a–c. Selective hydrolysis of the
1,2-O-isopropyliden moiety with a mixture of acetic acid/sulfuric
acid at room temperature afforded the respective 1,2-diols 5 which
were treated with an aqueous solution of NaIO4 at 0 °C to obtain
the dicarbonyl compounds 6, and finally, with the reduction of 6
with NaBH4, the polysubstituted d-lactones 7 were prepared in
modest overall yields (Scheme 1).15
3 h.13 The expected
a-alkylation proceeded with moderated yields
(63–70%); however, only one stereoisomer was isolated after chro-
matographic purification (Table 2). The analysis of representative
coupling constants and selected 2D-NOESY interactions of lactone
4 (R1 = p-F-Phenyl, R2 = allyl) indicates that both substituents are
trans-oriented with a boat-twisted conformation 4T for the d-lac-
tone ring (Fig. 3). The large value of vicinal coupling constant
3
(3JH5-H6 = 12.0 Hz), and the smaller JH4-H5 value (3.9 Hz) confirms
F
F
Table 1
Diastereoselective conjugated addition (DCA) to lactone 1
O
O
R
OH
R
O
O
O
R
CH3CO2H
H2SO4
O
O
Conditions
OH
O
O
O
O
2 equiv of RMgBr
0.5 equiv of Cu
5
O
O
O
O
O
2
4a (R = Me)
O
1
O
F
4b
(R = Bn)
NaIO4
4c (R = allyl)
Entry
RMgX
Yield (%)
de (%)
O
O
O
O
1
2
3
4
p-F-PhMgBr
p-F-PhMgBr
p-F-PhMgBr
EtMgBr
CH3MgBr
BnMgCl
CuBrSMe2, THF at 0 °C
78
88
52
85
75
82
8
80
97
90
96
96
96
—
HO
HO
NaBH4
R
CuBrSMe2, THF at À40 °C
R
CuI, THF at 0 °C
O
O
CuBrSMe2, THF at À40 °C
CuBrSMe2, THF at À40 °C
CuBrSMe2, THF at À40 °C
CuBrSMe2, THF at À40 °C
CuI, THF at À40 °C
O
7a (R = Me): 32%
7b (R = Bn): 45%
7c (R = allyl): 32%
5
6
6
7a
8a
AllylMgCl
AllylMgCl
F
Trace
—
a
1,2-Addition compared as major product.
Scheme 1. Preparation of polysubstituted d-lactones.

E. Ramírez et al. / Tetrahedron Letters 54 (2013) 5751–5754
5753
2H), 7.21 (m, 2H). 13C NMR (100 MHz, CDCl3) d: 26.1, 26.5, 31.3, 39.1, 78.4,
81.8, 83.5, 104.9, 112.3, 116.2 (d, J = 20.6 Hz), 128.5 (d, J = 8.0 Hz), 135.1 (d,
J = 3.4 Hz), 162.1 (d, J = 246 Hz), 169.3. HRMS-EI (m/z): [M]+ calcd for
In conclusion, a fast and accessible stereoselective protocol was
developed for the preparation of optically pure polysubstituted d-
lactones16 featuring a tandem diastereoselective conjugated addi-
tion/a-alkylation reaction. Applications of this methodology to
the synthesis of biologically active lactones are in progress.
C
16H17FO5 308.1060; found 308.1075.
2 (R = Bn): as a yellow syrup, 117.3 mg (82%). [a]
25 +2.6 (CHCl3, c 1.0). 1H NMR
(400 MHz, CDCl3) d: 1.33 (s, 3H), 1.47 (s, 3H), 2.26 (dd, J = 16.8, 5.2 Hz, 1H),
2.54–2.69 (m, 3H), 2.89 (dd, J = 12.8, 5.6 Hz, 1H), 4.35, (dd, J = 3.2, 3.2 Hz, 1H),
4.34 (d, J = 3.6 Hz, 1H), 4.75 (d, J = 3.2 Hz, 1H), 5.95 (d, J = 3.6 Hz, 1H), 7.15–7.34
(m, 5H). 13C NMR (100 MHz, CDCl3) d: 26.2, 26.6, 30.6, 35.9, 38.7, 76.2, 82.0,
83.8, 104.6, 112.3, 126.9, 128.8, 137.4, 169.3. HRMS-EI (m/z): [M]+ calcd for
Acknowledgments
C
17H20O5 304.1311; found 304.1341.
We gratefully acknowledge financial support from CONACyT
(CB-2012/179074) and Benemérita Universidad Autónoma de Pue-
bla (BUAP-VIEP).
25
2 (R-allyl): as a yellow syrup, 9.5 mg (8%). [
a
]
+3.0 (CHCl3, c 0.7). 1H NMR
(400 MHz, CDCl3) d: 1.34 (s, 3H), 1.51 (s, 3H), 2.15–2.35 (m, 4H), 2.71 (dd,
J = 15.9, 4.8 Hz, 1H), 4.32 (dd, J = 3.3, 3.3 Hz, 1H), 4.67 (d, J = 3.0 Hz, 1H), 4.73 (d,
J = 3.9 Hz, 1H), 5.12 (dm, J = 8.1 Hz, 1H), 5.17 (br s, 1H), 5.75 (m, 1H), 5.94 (d,
J = 3.6 Hz). 13C NMR (100 MHz, CDCl3) d: 26.2, 26.6, 29.7, 31.1, 33.7, 36.9, 76.4,
81.9, 83.7, 104.6, 112.3, 118.6, 133.8, 169.4.
References and notes
13. General procedure for the tandem conjugate addition/a-alkylation. A mixture of
Grignard reagent solution (0.94 mmol) and copper (I) bromide–dimethyl
sulfide complex (0.24 mmol) was stirred at room temperature for 1 h. Then,
a solution of lactone 1 (100.0 mg, 0.47 mmol) in dried THF (3 mL) at À40 °C
was added to the reaction mixture. The resulting mixture was stirred for 3 h
before adding the respective alkyl halide (1.41 mmol). The reaction mixture
was warmed to room temperature and stirred for 2.5 hours. The reaction
mixture was quenched with a saturated solution of ammonium chloride, and
1. Permutter, P. Conjugate Addition Reactions in Organic in Organic Synthesis;
Pergamon: Oxford, 1992.
2. (a) Guo, H.-C.; Ma, J.-A. Angew. Chem., Int. Ed. 2006, 45, 354; (b) Reyes, E.;
Vicario, J. L.; Carrillo, L.; Badía, D.; Iza, A.; Uria, U. Org. Lett. 2006, 8, 2535.
3. (a) Harutyunyan, S. R.; Hartog, T.; Geurts, K.; Minnaard, A. J.; Feringa, B. L. Chem.
Rev. 2008, 108, 2824; (b) Rossiter, B. E.; Swingle, N. M. Chem. Rev. 1992, 92, 771.
4. (a) Seebach, D.; Beck, A. K.; Heckel, A. Angew. Chem., Int. Ed. 2001, 40, 92; (b)
Helmchen, G.; Wegner, G. Tetrahedron Lett. 1985, 26, 6047; (c) Mukaiyama, T.;
Iwasawa, N. Chem. Lett. 1981, 913; (d) Oppolzer, W.; Mills, R. J.; Pachinger, W.;
Stevenson, T. Helv. Chim. Acta 1986, 69, 1542.
5. (a) Cluzeau, J.; Lubell, W. D. J. Org. Chem. 2004, 69, 1504; (b) Nadein, O. N.;
Kornienko, A. Org. Lett. 2004, 6, 831; (c) Manpadi, M.; Kornienko, A. Tetrahedron
Lett. 2005, 46, 4433; (d) Kireev, A. S.; Manpadi, M.; Kornienko, A. J. Org. Chem.
2006, 71, 2630; (e) Rastogi, S. K.; Kornienko, A. Tetrahedron: Asymmetry 2006,
17, 3170; (f) Pearson, A. J.; Protasiewicz, J. D.; Updegraff, J.; Zhang, M.
Tetrahedron Lett. 2007, 48, 5569.
6. (a) Gesson, J. P.; Jacquesy, J. C.; Mondon, M. Tetrahedron Lett. 1987, 28, 3945; (b)
Gesson, J. P.; Jacquesy, J. C.; Mondon, M. Tetrahedron 1989, 45, 2627; (c)
Bessodes, M.; Benamghar, R.; Antonakis, K. Carbohydr. Res. 1990, 200, 493; (d)
Dongsoo, K. Agric. Chem. Biotechnol. 2005, 49, 62–64; (e) Baskaran, S.; Vasu, J.;
Kodukulla, R. P. K.; Trivedi, G. K. Tetrahedron 1996, 52, 4515; (f) Subramanian,
B.; Griski, K. T. J. Chem. Res. 1995, 308; (g) Tadano, K.-I.; Shimada, K.-I.; Miyake,
A.; Ishihara, J.; Ogawa, S. Bull. Chem. Soc. Jpn. 1989, 62, 3978.
7. (a) Cai, X. H.; Tan, Q. G.; Liu, Y. P.; Feng, T.; Du, Z. Z.; Li, W. Q.; Luo, X. D. Org. Lett.
2008, 10, 577; (b) Rosenfeld, R.; Hofmann, K. J. Am. Chem. Soc. 1951, 73, 2491;
(c) Gunasekera, S. P.; Cranick, S.; Longley, R. E. J. Nat. Prod. 1989, 52, 757.
8. Hanessian, S. Total Synthesis of Natural Products: The ‘Chiron’ Approach;
Pergamon Press: Oxford, 1985.
extracted with EtOAc (3 Â 20 mL).
25
4 (R1 = p-F-Ph, R2 = Me): as a white solid, 90.9 mg (60%). Mp = 145 °C. [a]
+41.9 (CHCl3, c 1.0). 1H NMR (400 MHz, CDCl3) d: 1.0 (d, J = 6.6 Hz, 1H), 1.32 (s,
3H), 1.43 (s, 3H), 2.60 (m, 1H), 2.85 (dd, J = 12.9, 4.5 Hz, 1H), 4.56 (dd, J = 3.9,
3.3 Hz, 1H), 4.78 (d, J = 3.0 Hz, 1H), 4.82 (d, J = 3.9 Hz, 1H), 5.97 (d, J = 3.6 Hz,
1H), 7.08 (m, 2H), 7.18 (m, 2H). 13C NMR (100 MHz, CDCl3) d: 13.55, 26.06,
26.5, 38.7, 48.5, 80.7, 82.3, 83.0, 104.6, 112.2, 116.1 (d, J = 21.7 Hz), 129.2 (d,
J = 9.1 Hz), 136.4 (d, J = 3.4 Hz), 162.1 (d, J = 244.8 Hz), 173.2. HRMS-EI (m/z):
[M]+ calcd for C17H19FO5 322.1217; found 322.1179.
4 (R1 = p-F-Ph, R2 = Bn): as a yellow syrup, 112.3 mg, (60%). [a]
25 +55.8 (CHCl3, c
1.1). 1H NMR (400 MHz, CDCl3) d: 1.31 (s, 3H), 1.42 (s, 3H), 2.63 (dd, J = 14.0,
4.0 Hz, 1H), 2.86 (m, 1H), 3.08 (m, 2H), 4.50 (t, J = 3.6 Hz, 1H), 4.74 (d, J = 2.8 Hz,
1H), 4.79 (d, J = 4.0 Hz, 1H), 5.97 (d, J = 3.6 Hz, 1H), 7.06 (m, 4H), 7.14 (m, 5H).
13C NMR (100 MHz, CDCl3) d: 26.0, 26.5, 34.3, 46.0, 80.7, 81.5, 83.0, 104.6,
112.2, 116.2 (d, J = 21.3 Hz), 126.4, 128.3, 129.2, 129.4 (d, J = 7.5 Hz), 136.3 (d,
J = 3.4 Hz), 139.1, 162.1 (d, J = 244.9 Hz), 172.1. HRMS-EI (m/z): [M]+ calcd for
C
23H23FO5 398.1530; found 398.1492.
4-(R1 = p-F-Ph, R2 = allyl): as a yellow syrup, 106.4 mg (65%). [a]
25 +38.2 (CHCl3,
c 1.1). 1H NMR (400 MHz, CDCl3) d: 1.32 (s, 3H), 1.42 (s, 3H), 2.18 (m, 1H), 2.30
(m, 1H), 2.67 (m, 1H), 3.07 (dd, J = 12.0, 3.9 Hz, 1H), 4.50 (t, J = 3.6 Hz, 1H), 4.77
(d, J = 2.7 Hz, 1H), 4.80 (d, J = 3.9 Hz, 1H), 4.85 (dm, J = 17.4 Hz, 1H), 5.01 (dm,
J = 10.2 Hz, 1H), 5.80 (m, 1H), 5.96 (d, J = 3.6 Hz, 1H), 7.07 (m, 2H), 7.17 (m, 2H).
13C NMR (100 MHz, CDCl3) d: 26.0, 26.4, 31.9, 43.1, 45.2, 80.6, 82.0, 83.0, 104.5,
112.2, 116.0 (d, J = 21.6 Hz), 118.2, 129.3 (d, J = 7.9 Hz) 134.0, 136.1 (d,
J = 3.4 Hz), 162.1 (d, J = 246.0 Hz), 172.0. HRMS-FAB (m/z): [M]+ calcd for
9. (a) Sartillo-Piscil, F.; Vargas, M.; Anaya de Parrodi, C.; Quintero, L. Tetrahedron
Lett. 2003, 44, 3919; (b) Reddy, L. V. R.; Reddy, P. V.; Shaw, A. K. Tetrahedron:
Asymmetry 2007, 18, 542; (c) Ramirez, E.; Meza-Leon, R.; Quintero, L.; Sartillo-
Piscil, F. Tetrahedron Lett. 2010, 51, 2178; (d) Sidnei, M.; Ligeour, T. C.; Caroline,
L.; Christine, G.; Delphine, J.; Emanuelle, D.; Francoise, D. Green Chem. 2011, 13,
1812; (e) Venkat, R. P.; Vikas, B.; Brijesh, K.; Shaw, A. K. Eur. J. Org. Chem. 2011,
1575.
10. (a) Totani, K.; Nagatsuka, T.; Takao, K.-I.; Ohba, S.; Tadano, K.-I. Org. Lett. 1999,
1, 1447; (b) Totani, K.; Nagatsuka, T.; Yamaguchi, S.; Takao, K.-I.; Ohba, S.;
Tadano, K.-I. J. Org. Chem. 2001, 66, 5965.
C
19H21FO5 348.1373; found 348.1402.
4 (R1 = Bn, R2 = allyl): as a yellow syrup, 97 mg (60%). [a]
25 +14.5 (CHCl3, c 1.0).
1H NMR (400 MHz, CDCl3) d: 1.29 (s, 3H), 1.39 (s, 3H), 2.34 (dd, J = 13.2, 6.0 Hz,
1H), 2.50 (m, 2H), 2.64 (dd, J = 13.8, 8.7 Hz, 1H), 2.90 (dd, J = 13.5, 6.3 Hz, 1H),
4.32 (t, J = 2.4 Hz, 1H), 4.62 (d, J = 2.4 Hz, 1H), 4.69 (d, J = 3.9 Hz, 1H), 5.09 (br s,
1H), 5.14 (dm, J = 5.7 Hz, 1H), 5.72 (m, 1H), 5.83 (d, J = 3.9 Hz, 1H), 7.17 (m, 2H),
7.29 (m, 3H). 13C NMR (100 MHz, CDCl3) d: 26.3, 26.4, 34.4, 37.7, 38.6, 41.6,
76.3, 80.5, 83.2, 104.2, 112.3, 118.1, 127.0, 128.7, 129.2, 134.6, 137.4, 172.0.
14. Shintani, R.; Tokunaga, N.; Doi, H.; Hayashi, T. J. Am. Chem. Soc. 2004, 126, 6240.
15. To a solution (3 mL) made of a mixture of acetic acid (46%), sulfuric acid (16%),
and water (38%) was added therespective lactone 4 (0.31 mmol) and allowed
to react for 2.5 h (monitored by tlc) at room temperature. Then, the reaction
mixture was neutralized with a saturated solution of sodium carbonate and
extracted with EtOAc (3 Â 20 mL). The organic phase was concentrated under
the reduced pressure and dissolved in THF (2 mL), and sodium periodate
(0.4 mmol) was added. The reaction mixture was stirred for 40 min, and the
formed solids were filtered and the organic phase was concentrated under
reduced pressure giving the respective aldehyde 6 as a yellow oil. Compound 6
was dissolved in THF (2 ml) and H2O (0.5 mL) and sodium borohydride
(0.46 mmol) was added. The reaction mixture was stirred at 0 °C for 1 h before
adding water (1 mL), and the THF was evaporated under reduced pressure and
the residue was extracted with ethyl acetate (3 Â 20 ml). The organic phase
was evaporated and the residue was purified by chromatography on silica gel
11. (a) Hanessian, S.; Gai, Y.; Wang, W. Tetrahedron Lett. 1996, 37, 7473; (b)
Hanessian, S.; Wang, W.; Gai, Y. Tetrahedron Lett. 1996, 37, 7477; (c) Raczko, J.
Tetrahedron: Asymmetry 1997, 8, 3821; (d) Han, G.; Hruby, V. J. Tetrahedron Lett.
2001, 42, 4281.
12. General procedure for the conjugate addition. A mixture of Grignard reagent
solution (0.94 mmol) and copper (I) bromide–dimethyl sulfide complex
(48.3 mg, 0.24 mmol) was stirred at room temperature for 1 h. Then, lactone
1 (100.0 mg, 0.47 mmol) dissolved in dried THF (3 mL) was added to the
reaction mixture at À40 °C. The resulting mixture was stirred for 3 h. After the
reaction was completed, the reaction mixture was quenched with a saturated
solution of ammonium chloride, and extracted with EtOAc (3 Â 20 mL). The
residue was purified through column chromatography (silica, eluent: mixture
of hexane and ethyl acetate).
2 (R = Me): as a yellow syrup, 80.5 mg (75%). [a]
25 +16.0 (CHCl3, c 1.0). 1H NMR
(400 MHz, CDCl3) d: 1.16 (d, J = 7.6 Hz, 1H), 1.34 (s, 3H), 1.52 (s, 3H), 2.25 (dd,
J = 16.8, 5.2 Hz, 1H), 2.41 (m, 1H), 2.77 (dd, J = 16.8, 5.2 Hz, 1H), 4.25 (t,
J = 3.3 Hz, 1H), 4.72 (m, 2H), 5.95 (d, J = 3.6 Hz, 1H). 13C NMR (100 MHz, CDCl3)
d: 17.9, 26.2, 26.6, 28.7, 32.9, 77.5, 81.9, 83.8, 104.8, 112.2, 169.2. HRMS-EI (m/
(hexane/ethyl acetate).
Compound 7a: as a colorless liquid, 32%, [
25
À84.5 (CHCl3, c 0.9). 1H NMR
z): [M]+ calcd for C11H16O5 228.0998; found 228.1027.
a
]
25
2 (R = Et): as a yellow syrup, 96.8 mg (85%). [
a
]
+17.2 (CHCl3, c 1.0). 1H NMR
(400 MHz, CDCl3) d: 1.22 (d, J = 6.9 Hz, 3H), 3.40 (m, 2H), 3.55 (m, 2H), 3.69 (dd,
J = 11.1, 7.5 Hz, 1H), 4.53 (dd, J = 8.4, 1.2 Hz, 1H), 7.08 (m, 2H), 7.35 (m, 2H). 13
C
(400 MHz, CDCl3) d: 1.03 (t, J = 7.6 Hz, 3H), 1.34 (s, 3H), 1.52 (m, 3H), 1.25–1.60
(m, 2H), 2.14 (m, 1H), 2.26 (dd, J = 16.8, 6.8 Hz, 1H), 2.71 (dd, J = 16.8, 5.6 Hz,
1H), 4.31 (t, J = 3.6 Hz, 1H), 4.66 (d, J = 3.2 Hz, 1H), 4.73 (d, J = 4.0 Hz, 1H), 5.95
(d, J = 3.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) d: 11.4, 25.8, 26.2, 26.6, 26.7,
31.4, 35.9, 76.6, 82.0, 83.6, 104.7, 112.1, 169.8. HRMS-EI (m/z): [M]+ calcd for
NMR (100 MHz, CDCl3) d: 14.2, 38.1, 51.8, 63.9, 69.6, 80.4, 115.9 (d, J = 20.5 Hz),
129.9 (d, J = 7.9 Hz), 130 (d, J = 3.37 Hz), 162.2 (d, J = 246.0 Hz), 179.7.
25
Compound 7b: As a yellow liquid (45%). [
a
]
À76.2 (CHCl3, c 1.0). 1H NMR
(400 MHz, CDCl3) d: 2.94 (dd, J = 14.0, 5.2 Hz, 1H), 3.01 (dd, J = 14.0, 5.2 Hz, 1H),
3.35 (dd, J = 7.2, 4.4 Hz, 1H), 3.54 (m, 2H), 3.68 (m, 2H), 4.37 (dd, J = 8.4, 0.8 Hz,
1H), 7.02 (m, 4H), 7.20 (m, 5H). 13C NMR (100 MHz, CDCl3) d: 14.2, 34.1, 44.5,
47.6, 63.9, 69.7, 80.4, 115.6 (d, J = 20.5 Hz), 126.7, 128.4, 129.7, 130.1 (d,
J = 7.9 Hz), 130.6, 137.0, 162.1 (d, J = 245.8 Hz), 178.2. HRMS-EI (m/z): [M]+
calcd for C19H19FO4 330.1267; found 330.1245.
C
12H18O5 242.1154; found 242.1119.
25
2-(R = p-F-phenyl): as a yellow syrup, 127.5 mg (88%). [
a
]
À4.7 (CHCl3, c 1.0).
1H NMR (400 MHz, CDCl3) d: 1.32 (s, 3H), 1.47 (s, 3H), 2.70 (dd, J = 16.8, 6.6 Hz),
2.99 (dd, J = 16.8, 6 Hz, 1H), 3.52 (q, J = 6.0, 4.2 Hz, 1H), 4.46 (t, J = 3.6 Hz, 1H),
4.61 (d, J = 3.0 Hz, 1H), 4.75 (d, J = 3.9 Hz, 1H), 6.01 (d, J = 3.6 Hz, 1H), 7.06 (m,

5754
Compound 7c: As a yellow liquid (40%). [
E. Ramírez et al. / Tetrahedron Letters 54 (2013) 5751–5754
À76.7 (CHCl3, c 1.0). 1H NMR 16. (a) Vu, C. S.; Guisot, N.; Guillarme, S.; Martel, A.; Dujardin, G.; Pipelier, M.;
25
a
]
(400 MHz, CDCl3) d: 2.39 (m, 1H), 2.49 (m, 1H), 3.40 (m, 1H), 3.46 (m, 1H), 3.58
(m, 1H), 3.69 (m, 1H), 4.50 (d, J = 8.4 Hz, 1H), 4.99 (d, J = 8.4 Hz, 1H), 5.03 (br s,
1H), 5.55 (m, 1H), 7.06 (t, J = 8.6 Hz, 2H), 7.35 (m, 2H). 13C NMR (100 MHz,
CDCl3) d: 32.9, 43.0, 48.2, 63.9, 69.7, 80.5, 115.81 (d, J = 21.2 Hz), 118.6, 130.1
(d, J = 7.6 Hz), 130.80 (d, J = 3.1 Hz), 133.5, 162.2 (d, J = 244.4 Hz), 178.2. HRMS-
EI (m/z): [M]+ calcd for C19H17FO4 280.1111; found 380.1144.
Dubreil, D.; Saluzzo, C. Eur. J. Org. Chem. 2012, 3727; (b) Wilkinson, A. L.;
Hanefeld, U.; Wilkinson, B.; Leadlay, P. F.; Ataunton, J. Tetrahedron Lett. 1998,
39, 9827; (c) Clissold, C.; Kelly, C. L.; Lawrie, K. W. M.; Willis, C. L. Tetrahedron
Lett. 1997, 38, 8105.