Studies on the diastereo-selective reduction of 2-acetyl-2-alkyl-γ-butyrolactones with boron hydrides

Article abstract of DOI:10.1081/SCC-120002396

Reduction of 2-acetyl-2-alkyl-γ-butyrolactone derivatives with boron hydrides in the presence and absence of several chelating agents were studied. This process is influenced more by steric than chelation factors, yielding the isomeric alcohols syn (13-23

Full text of DOI:10.1081/SCC-120002396

This article was downloaded by: [Columbia University]
On: 10 December 2014, At: 09:54
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer
House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
STUDIES ON THE DIASTEREO- SELECTIVE REDUCTION
OF 2-ACETYL-2-ALKYL- γ-BUTYROLACTONES WITH
BORON HYDRIDES*
Lis H. P. Teixeira a , Maria Cecília B. V. de Souza b , Maria da Conceição K. V. Ramos a ,
Francisco R. de Aquino Neto a , Eliezer J. Barreiro a & Carlos A. M. Fraga c
a Universidade Federal do Rio de Janeiro , LASSbio, Faculdade de Farmácia, P.O. Box
68006, Rio de Janeiro, 21944-970, Brazil http://www.farmacia.ufrj.br/lassbio
b Departamento de Química Orgânica , Universidade Federal Fluminense , Instituto de
Química, Rio de Janeiro, Brazil
c Universidade Federal do Rio de Janeiro , LASSbio, Faculdade de Farmácia, P.O. Box
68006, Rio de Janeiro, 21944-970, Brazil http://www.farmacia.ufrj.br/lassbio
Published online: 16 Aug 2006.
To cite this article: Lis H. P. Teixeira , Maria Cecília B. V. de Souza , Maria da Conceição K. V. Ramos , Francisco R. de
Aquino Neto , Eliezer J. Barreiro & Carlos A. M. Fraga (2002) STUDIES ON THE DIASTEREO- SELECTIVE REDUCTION OF 2-
ACETYL-2-ALKYL- γ-BUTYROLACTONES WITH BORON HYDRIDES*, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 32:4, 505-526, DOI: 10.1081/SCC-120002396
To link to this article: http://dx.doi.org/10.1081/SCC-120002396
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of
the Content. Any opinions and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied
upon and should be independently verified with primary sources of information. Taylor and Francis shall
not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other
liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

SYNTHETIC COMMUNICATIONS, 32(4), 505–526 (2002)
STUDIES ON THE DIASTEREO-
SELECTIVE REDUCTION
OF 2-ACETYL-2-ALKYL-
c-BUTYROLACTONES WITH
BORON HYDRIDES*
Lis H. P. Teixeira,1 Maria Cecılia B. V. de Souza,2
Maria da Conceicao K. V. Ramos,3
Francisco R. de Aquino Neto,3
Eliezer J. Barreiro,1 and Carlos A. M. Fraga1,
y
1LASSBio (http://www.farmacia.ufrj.br/lassbio),
Faculdade de Farmacia, Universidade Federal
do Rio de Janeiro, P.O. Box 68006, Rio de Janeiro,
Brazil, 21944-970
2Departamento de Quımica Organica, Instituto de
Quımica, Universidade Federal Fluminense,
Rio de Janeiro, Brazil
3LADETEC, Instituto de Quımica, Universidade
Federal do Rio de Janeiro, Centro de Tecnologia,
Bloco A, sala 607, Rio de Janeiro, Brazil
ABSTRACT
Reduction of 2-acetyl-2-alkyl-g-butyrolactone derivatives with
boron hydrides in the presence and absence of several
*This paper is the contribution #53 from LASSBio.
yCorresponding author. E-mail: cmfraga@pharma.ufrj.br
505
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

ORDER
REPRINTS
506
TEIXEIRA ET AL.
chelating agents were studied. This process is influenced more
by steric than chelation factors, yielding the isomeric alcohols
syn (13–23) and anti (14–24) in good diastereomeric excess.
2-Oxabicyclo[3.3.0]octane derivatives (1) constitute attractive syn-
thons to new antithrombotic compounds, e.g., a prostacyclin (PGI2) analo-
gue1 (2) and new PAF antagonists2 (3) (Scheme 1).
Scheme 1.
Previous results described an efficient method to obtain, diastereo-
selectively, 2-allyl-2-alkoxycarbonyl-cyclopentanol derivatives (4) and (5)

ORDER
REPRINTS
2-ACETYL-2-ALKYL-c-BUTYROLACTONES
507
from cyclopentanone (6) employing sodium borohydride as the reducing
agent, in the presence or absence of calcium chloride.3 The cyclopentanol
derivative (4) can be converted into the bicyclic compound (1) applying the
diastereoselective cationic oxidative cyclization process.4 The initial study
showed that the diastereoselectivity of this process was sensitive to the bulk
of the reducing species and to the size of the alkoxycarbonyl group present
in these derivatives.3 Moreover, by changing the alkyl group (R) from allyl
(6a) to propyl (6b), propargyl (6c), benzyl (6d) and butenyl (6e), we showed
that the reductive process with sodium borohydride is mainly dependent on
steric factors. In the 2-allyl derivative (6a), the reduction is particularly
influenced by carbonyl ꢀ-stack type blockage suggested by the mechanism
illustrated in Scheme 2.5,6
Scheme 2.
In this paper, we describe the chemo and diastereoselective reduction
of 2-acetyl-2-alkyl-g-butyrolactones (7–12) designed as analogues of 2-alkyl-
2-alkoxycarbonyl-cyclopentanone derivatives (6). The present study aims at
identifying the effect of a conformationally free ketone group on the dia-
stereoselectivity of the reductive process.
C-2 alkylated b-keto-esters (8–12) were prepared, in moderate yield
(13 to 93%), from commercially available 2-acetyl-g-butyrolactone7 (7)
using modified Barco’s conditions8,9 (Table 1).

ORDER
REPRINTS
508
TEIXEIRA ET AL.
Scheme 3.
Table 1. Alkylation of the 2-Acetyl-g-butyrolactone (7) with Alkyl Bromides
Entry
Product
Alkylant Agent
Reaction Time (h) Yield (%)
1
2
3
4
5
(8) R¼allyl
Allyl bromide
Propyl bromide
6
48
17
6
93
13
91
63
83
(9) R¼propyl
(10) R¼propargyl Propargyl bromide
(11) R¼benzyl
Benzyl bromide
Cinnamyl bromide
(12) R¼cinnamyl
2
Compounds (7–12) were spectroscopically fully characterized and
then submitted to several reduction conditions, to give the correspond-
ing diastereomeric alcohols (13–24) in yields ranging from 53 to 96%
(Table 2).

ORDER
REPRINTS
2-ACETYL-2-ALKYL-c-BUTYROLACTONES
509
Table 2. Reduction of the 2-Acetyl-2-alkyl-g-butyrolactone Derivatives (7–12)
T
Yield Rateb,c
MCl2 Product (%) syn : anti
Entry Compound
Conditionsa Solvent (ꢀC)
1
2
(7) R¼H
A
A
A
A
A
A
A
A
A
A
A
A
A
B
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
0ꢀC
0ꢀC
r.t.
–
13–14
CaCl2 13–14
15–16
CaCl2 15–16
15–16
CaCl2 15–16
15–16
31
44
79
66
88
96
76
87
60
81
79
77
78
68
80
94
82
62
53
79
63
99
96
1 : 1.8
1 : 8.4
1 : 1
(7) R¼H
3
(8) R¼allyl
–
4
(8) R¼allyl
r.t.
1 : 2
1.4 : 1
5
(8) R¼allyl
0ꢀC
0ꢀC
–
6
(8) R¼allyl
1 : 1.9
1 : 1
7
(8) R¼allyl
MeOH À78ꢀC
–
8
(8) R¼allyl
MeOH À78ꢀC CaCl2 15–16
1 : 1.7
1 : 1.2
1 : 1.5
1 : 2.2
9
(8) R¼allyl
MeOH
MeOH
MeOH
IprOH
IprOH
THF
0ꢀC
0ꢀC
MgCl2 15–16
MnCl2 15–16
10
11
12
13
14
15
16
17
18
19
20
21
22
23
(8) R¼allyl
(8) R¼allyl
0ꢀC
CeCl3
–
CaCl2 15–16
15–16
15–16
(8) R¼allyl
0ꢀC
1.2 : 1
1.9 : 1
1 : 7.6
1 : 5.7
1.4 : 1
(8) R¼allyl
0ꢀC
(8) R¼allyl
À78ꢀC
–
15–16
(8) R¼allyl
B
THF
À78ꢀC CaCl2 15–16
(9) R¼propyl
(9) R¼propyl
(10) R¼propargyl
(10) R¼propargyl
(11) R¼benzyl
(11) R¼benzyl
(12) R¼cinnamyl
(12) R¼cinnamyl
A
A
A
A
A
A
A
A
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
0ꢀC
0ꢀC
0ꢀC
0ꢀC
0ꢀC
0ꢀC
0ꢀC
0ꢀC
–
17–18
CaCl2 17–18
19–20
CaCl2 19–20
21–22
CaCl2 21–22
23–24
CaCl2 23–24
1 : 2
–
1 : 1.4
1 : 2.4
1 : 1
–
1 : 2.5
–
1.8 : 1
1 : 2
aConditions : A-NaBH4 (1.2 eq.), solvent, MCl2 (2 eq.), TꢀC, 30 min; B-L-Selectride
(1.5 eq.), THF, MCl2 (2 eq.), À78ꢀC (30 min) ! 0ꢀC (15 min). The relative diaster-
b
eomeric ratio was determined by HRGC in a 10% de 2,3-di-O-methyl-6-O-t-butyl-
dimethylsilyl-b-cyclodextrin in SE-54 capillary column (20 m ꢁ 0.3 mm ꢁ 0.3 mm) at
The composition of the diastereomeric alcohols mixture (13–24) was
elucidated by NMR spectroscopy (nOe investigations included) (Table 3)
and the relative diastereomeric ratio determined by HRGC (Table 2), using
a b-cyclodextrin derivative as the stationary phase. The diastereomeric

ORDER
REPRINTS
510
TEIXEIRA ET AL.

ORDER
REPRINTS
2-ACETYL-2-ALKYL-c-BUTYROLACTONES
511

ORDER
REPRINTS
512
TEIXEIRA ET AL.

ORDER
REPRINTS
2-ACETYL-2-ALKYL-c-BUTYROLACTONES
513

ORDER
REPRINTS
514
TEIXEIRA ET AL.

ORDER
REPRINTS
2-ACETYL-2-ALKYL-c-BUTYROLACTONES
515

ORDER
REPRINTS
516
TEIXEIRA ET AL.

ORDER
REPRINTS
2-ACETYL-2-ALKYL-c-BUTYROLACTONES
517
mixture of the allyl-alcohols (15) and (16) was separated by silica gel column
chromatography. Their relative configurations were assigned by nOe-experi-
ments, which showed a positive correlation (4.9%) between the carbinolic
hydrogen and the methylenic hydrogen atom of the allyl substituent in
the compound (16) (Scheme 4). Considering that pseudo-rotation of five
Scheme 4.
membered rings can influence the results from nOe experiments, we decided
to correlate them with minimal energy conformers of (15) and (16). Then,
molecular modeling studies of the derivatives (15) and (16) were carried out
using the AM1 Hamiltonian.10 After geometry optimizations, we are able to
find the minimal energy conformation of (15) and (16), which presented a
heat formation of 124.77 and 126.12 Kcal/mol, respectively (Scheme 4). The
relative configuration was confirmed by derivation, through the formation
of less conformationally flexible six-membered ring ketal derivatives (27)
and (28), which were characterized by NMR spectroscopy, as described in
the previous work by Takeshita et al.11 (Scheme 5). These results were
extended for all structurally correlated derivatives, since they presented
the same spectroscopic pattern, as presented in Table 3.
There are striking aspects of the data displayed in Table 2. Firstly,
in comparison with the profile of the correspondent cyclopentanone deriva-
tives, e.g. (6a) (Scheme 2), the increase of the conformational freedom of the
ketone carbonyl group in butyrolactone derivative (8), resulted in a decrease
of the diastereoselectivity of the reductive process with sodium borohydride
in the absence or in the presence of calcium chloride (Entries 3 and 4).
Nevertheless, most studies showed that the reduction of compounds

ORDER
REPRINTS
518
TEIXEIRA ET AL.
Scheme 5.
(8–13) leads to preferential formation of the alcohol presenting the anti
configuration (Table 2).
The reduction of allyl derivative (8), under a variety of conditions
(Table 2), which include changing the reaction temperature from r.t.
(Entries 3 and 4) to 0ꢀC (Entries 5 and 6) and À78ꢀC (Entries 7 and 8),
did not significantly increase the diastereoselectivity.
The use of CaCl2 as complexating agent in reductions mediated by
sodium borohydride (Entries 1 vs 2, 3 vs 4, 5 vs 6, 7 vs 8) increased the
diastereoselectivity of the process, possibly due to the fixation of a pseudo-
periplanar conformation (Scheme 6), which favored the hydride attack from
the opposite carbonyl face. On the other hand, other Lewis acids selected
according to previously reported procedures,12,13 i.e. MgCl2 (Entry 9),
MnCl2 (Entry 10) and CeCl3 (Entry 11), did not lead to remarkable
variations on the diastereoselectivity.
Scheme 6.

ORDER
REPRINTS
2-ACETYL-2-ALKYL-c-BUTYROLACTONES
519
Interestingly, the change of the solvent from methanol to isopropanol
(entries 6 vs 13) led to an inversion of the diastereoselectively, with the
formation of the syn alcohol (15) in 34% diastereomeric excess. This distinct
profile may be explained by the presence of different reducing species in the
media, since sodium borohydride reacts with methanol to give sterically
demanding trimethoxyborohydride [(MeO)3BHÀ], whereas solutions of
sodium borohydride in isopropanol are very stable.14
Reducing the allyl-substituted derivative (8) using bulky lithium
tri-sec-butyl-borohydride (L-Selectride)15 led to the formation of the alcohol
presenting anti configuration (16) in a greater diastereomeric excess (77%)
(entry 14). Curiously, the use of CaCl2 in the reductive process mediated by
L-Selectride (Entry 15) decreased the diastereoselectivity, probably due to
exchanging the counter-ion reducing agent from monovalent lithium to
divalent calcium ion, resulting in the formation of a more bulky dimeric
form of Selectride.
Varying the C-2 substituent from propyl (9) (Entries 16 and 17), to
propargyl (10) (Entries 18 and 19), benzyl (11) (Entries 20 and 21) and
cinnamyl (12) (Entries 22 and 23), allowed us to conclude that the electronic
variations of these substituents did not affect substantially the diastereo-
selectivity of the reductive process. Benzyl (11) (Entries 20 and 21) and
cinnamyl derivatives (12) (Entries 22 and 23) presented a slightly higher
diastereoselectivity profile, probably because of steric effects.
In conclusion, the results obtained from this research work indicated
that, contrary to the diastereoselective reductive behavior previously
described for the 2-allyl-2-carbomethoxy-cyclopentanone derivative (6a),
the diastereoselectivity of 2-acetyl-2-alkyl-g-butyrolactones (8–12) reduction
using borohydrides is more dependent on steric interactions than on
chelation factors.
The substituted g-butyrolactone derivatives disclosed in this work are
useful for the synthesis of natural chiral compounds16 and constitute an
attractive synthon to new bioactive compounds, e.g., anticonvulsants17,18
and antitumoral19 agents, muscarinic antagonists20 and conformationally
semirigid diacylglycerol analogues.21,22
EXPERIMENTAL
1H-NMR spectra were determined in deuterated chloroform, con-
taining ca. 0.3% tetramethylsilane as an internal standard, with UNITY
plus-300 at 300 MHz, Brucker AC 200 or Varian VRX 200 at 200 MHz.
Splitting patterns are as follows: br, broad; s, singlet; d, doublet; dd, double

ORDER
REPRINTS
520
TEIXEIRA ET AL.
doublet; ddd, double double doublet, dddd, double double double doublet;
td, triple doublet; t, triplet; dt, double triplet; ddt, double double triplet; q,
quartet; m, multiplet. 13C-NMR spectra were determined in the same
spectrometers described above at 75 or 50 MHz, employing the same sol-
vents. Infrared (IR) spectra were obtained with Nicolet 505 Magna
spectrophotometers by using sodium chloride cell or potassium bromide
plates. Gas chromatography (HRGC) were recorded in a Hewlett Packard
model 5890 series II using injection in the split mode. The HRGC analy-
sis were performed in 10% 2,3-di-O-methyl-6-O-t-butyldimethylsilyl-b-
cyclodextrin in SE-54 (1% vinyl; 5% phenyl; 94% methylpolysiloxane)
house made capillary column (20 m  0.3 mm  0.3 mm) at 100ꢀC/2ꢀC/min
to 130ꢀC. Microanalysis data was obtained with Perkin Elmer 240 analyzer,
using Perkin Elmer AD-4 balance.
The progress of all reactions was monitored by tlc, which was per-
formed on aluminum sheets precoated with silica gel 60 (HF-254, Merck) of
0.25 mm thickness. The eluents used for tlc were: Mixture A: AcOEt : hexane
(3 : 7), and Mixture B: isopropanol : hexane (1 : 9). The developed chromato-
grams were viewed under ultraviolet light or iodine revelation. For column
chromatography Merck silica-gel (70–230 mesh) was used. Solvents used in
the reactions were redistilled prior to use and stored over 3–4 A molecular
sieves. Reactions were generally carried out under nitrogen atmosphere and
magnetic stirring. The usual work-up means that the organic extracts prior
to concentration under reduced pressure, were treated with a saturated
aqueous sodium chloride solution, dried over anhydrous sodium sulfate
and filtered.
General Procedure for the C-Alkylation of
the 2-Acetyl-c-butyrolactone (7)
To a suspension of anhydrous potassium carbonate (3.23 g; 23.4 mmol)
in acetone (8 mL) was added 2-acetyl-g-butyrolactone (1 g; 7.8 mmol). The
reaction mixture displays a characteristic yellow color after stirring at room
temperature for 30 min. Then, the respective alkyl bromide (9.4 mmol) was
added slowly and the mixture was stirred at room temperature for 2–48 h
(monitored by tlc, mixture A as eluent). The suspension formed was filtered,
the organic solution concentrated at reduced pressure (80 mmHg) and the
residue diluted with ether (40 mL). The ‘‘usual work-up’’ gave the respective
2-acetyl-2-alkyl-g-butyrolactone (8–12).
2-Acetyl-2-allyl-c-butyrolactone (8): This compound was obtained in
93% yield as a colorless oil, from alkylation of (7) with allyl bromide (1.12 g;

ORDER
REPRINTS
2-ACETYL-2-ALKYL-c-BUTYROLACTONES
521
0.8 mL), after 6 h (for spectroscopic data see Table 3). Anal. Calcd. for
C9H12O3: C, 64.27; H, 7.19. Found: C, 64.34; H, 7.09.
2-Acetyl-2-propyl-c-butyrolactone (9): This compound was obtained in
13% yield as a colorless oil, from alkylation of (7) with propyl bromide
(1.16 g; 0.9 mL), after 48 h (for spectroscopic data see Table 3). Anal. Calcd.
for C9H14O3: C, 63.51; H, 8.29. Found: C, 63.62; H, 8.20.
2-Acetyl-2-propargyl-c-butyrolactone (10): This compound was
obtained in 91% yield as a colorless oil, from alkylation of (7) with
propargyl bromide (1.11 g; 0.7 mL), after 17 h (for spectroscopic data
see Table 3). Anal. Calcd. for C9H10O3: C, 65.05; H, 6.07. Found: C, 64.94;
H, 6.13.
2-Acetyl-2-benzyl-c-butyrolactone (11): This compound was obtained
in 63% yield as a white solid (m.p. 56–58ꢀC), from alkylation of (7) with
benzyl bromide (1.6 g; 1.1 mL), after 6 h (for spectroscopic data see Table 3).
Anal. Calcd. for C13H14O3: C, 71.54; H, 6.47. Found: C, 71.47; H, 6.59.
2-Acetyl-2-cinnamyl-c-butyrolactone (12): This compound was obtained
in 83% yield as a light yellow solid (m.p. 67–68ꢀC), from alkylation of
(7) with cinnamyl bromide (1.85 g; 1.4 mL), after 2 h (for spectroscopic
data see Table 3). Anal. Calcd. for C15H16O3: C, 71.75; H, 6.60. Found:
C, 73.71; H, 6.53.
General Procedure for Reduction of 2-Acetyl-2-alkyl-
c-butyrolactone (7–12) with Sodium Borohydride, in the
Presence or in the Absence of CaCl2 (Reduction Condition A)
A solution of the 2-acetyl-2-alkyl-g-butyrolactone derivative (7–12)
(0.89 mmol) in solvent (methanol or isopropanol) (6 mL), in the presence
or absence of the anhydrous calcium chloride (1.78 mmol), was stirred at
room temperature for 30 min. The reaction mixture was cooled at 0ꢀC
(r.t. or À78ꢀC), and 0.04 g (1.07 mmol) of sodium borohydride was slowly
added. A clear solution was obtained, which was stirred for 30 min. The
solvent was concentrated at reduced pressure (80 mmHg). The white doughy
residue was diluted with methylene chloride (30 mL). The resulting solution
was washed with saturated aqueous ammonium chloride solution (30 mL).
Usual work-up of the organic layer afforded the mixture of diastereomeric
alcohols as described in Table 2. The diastereomeric allyl alcohols mixture
(15–16) was separated by silica gel (70–230 mesh) column chromatography
using a mixture of hexane and isopropanol (99 : 1 to 90 : 10 v/v) as eluent
(for spectroscopic data see Table 3).
(6)-2-[10-(10-Hydroxyethyl)]-c-butyrolactone (13–14): This compound
was obtained in 93% yield as a colorless oil (for spectroscopic data see

ORDER
REPRINTS
522
TEIXEIRA ET AL.
Table 3). Anal. Calcd. for C6H10O3: C, 55.37; H, 7.74. Found: C, 55.48; H,
7.88.
(6)-2-Allyl-2-[10-(10-hydroxyethyl)]-c-butyrolactone (15–16): This com-
pound was obtained in 93% yield as a colorless oil (for spectroscopic data
see Table 3). Anal. Calcd. for C9H14O3: C, 63.51; H, 8.29. Found: C, 63.62;
H, 8.44.
(6)-2-Propyl-2-[10-(10-hydroxyethyl)]-c-butyrolactone (17–18): This
compound was obtained in 13% yield as a colorless oil (for spectroscopic
data see Table 3). Anal. Calcd. for C9H16O3: C, 62.77; H, 9.36. Found: C,
62.63; H, 9.51.
(6)-2-Propargyl-2-[10-(10-hydroxyethyl)]-c-butyrolactone (19–20): This
compound was obtained in 91% yield as a colorless oil (for spectroscopic
data see Table 3). Anal. Calcd. for C9H12O3: C, 64.27; H, 7.19. Found: C,
63.15; H, 7.11.
(6)-2-Benzyl-2-[10-(10-hydroxyethyl)]-c-butyrolactone (21–22): This
compound was obtained in 63% yield as a yellow oil (for spectroscopic
data see Table 3). Anal. Calcd. for C13H16O3: C, 70.89; H, 7.32. Found: C,
71.04; H, 7.19.
(6)-2-Cinnamyl-2-[10-(10-hydroxyethyl)]-c-butyrolactone (23–24): This
compound was obtained in 83% yield as a light yellow oil (for spectroscopic
data see Table 3). Anal. Calcd. for C15H18O3: C, 73,15; H, 7.37. Found: C,
73.28; H, 7.43.
Reduction of 2-Acetyl-2-allyl-c-butyrolactone (8) with
Lithium-tri-sec-butyl-borohydride, in the Presence or in
the Absence of CaCl2 (Reduction Condition B)
A solution of anhydrous 2-acetyl-2-allyl-g-butyrolactone derivative (8)
(0.89 mmol) in anhydrous THF (2 mL), under nitrogen atmosphere, in the
presence or absence of the solution of calcium chloride in anhydrous THF
(1 mL), was stirred at room temperature for 30 min. The reaction mixture
was cooled at 78ꢀC and 1.3 mL (1.3 mmoles) of 1 M solution of lithium-tri-
sec-butyl-borohydride (L-Selectride) in anhydrous THF was added to it. The
reaction mixture was stirred for 30 min, at À78ꢀC, then for 15 min at 0ꢀC,
and afterwards 5 mL of 1 M solution of H2O2 and 7 mL of 0.2 N aqueous
solution of NaOH were added. After 15 min, the system was diluted with
ether (5 mL) and the organic layer was separated, washed with a saturated
aqueous solution of sodium bisulfite (5 mL), and submitted to the ‘‘usual
work-up’’ affording the mixture of diastereomeric alcohols as described in
Table 2 (Entries 14 and 15).

ORDER
REPRINTS
2-ACETYL-2-ALKYL-c-BUTYROLACTONES
523
Reduction of (syn)-2-Allyl-2-[10-(10-hydroxy-ethyl)]-
c-butyrolactone (15) with Lithium Aluminumhydride
To a solution of lithium-aluminum-hydride (0.98 g, 25.8 mmol) in
anhydrous THF (20 mL), under nitrogen atmosphere, was added at r.t. a
solution of the syn-2-acetyl-2-allyl-g-butyrolactone derivative (15) (0.44 g,
2.58 mmol) in anhydrous THF (20 mL). The reaction mixture was stirred
for 2 h, at r.t., and 20 mL of 1 M aq. solution of H2O2 and 28 mL of 0.2 N
aq. solution of NaOH were added. After 15 min, the system was diluted with
ethyl acetate (60 mL) and the organic layer was filtered off over celite
column. The organic filtrate was evaporated under reduced pressure to
afford (25) in 98% yield, as a colorless oil; 1H NMR (300 MHz): 1.18
(d, 3H, J ¼ 6.6 Hz, -CH(OH)CH3), 1.51 (dt, 1H, J ¼ 4.6 and 15.8 Hz,
-CH2CH2OH), 2.02 (m, 3H, -CH2CH2OH and -CH2CH¼CH2), 3.72
(q, 2H, J ¼ 11.5 Hz, -CH2OH), 3.82 (m, 2H, -CH2CH2OH), 3.94 (q,
1H, J ¼ 6.3 Hz, -CH(OH)CH3), 5.08 (m, 2H, -CH2CH¼CH2), 5.78 (m,
1H, -CH2CH¼CH2); 13C NMR (75 MHz): 17.2 (-CH(OH)CH3), 33.2
(-CH2CH¼CH2), 38.8 (-CH2CH2OH), 43.2 (C-2), 58.4 (-CH2CH2OH),
68.2 (-CH2OH), 72.9 (-CH(OH)CH3), 118.0 (-CH2CH¼CH2), 133.5
(-CH2CH¼CH2). Anal. Calcd. for C9H18O3: C, 62.04; H, 10.41. Found:
C, 61.93; H, 10.49.
Reduction of (anti)-2-Allyl-2-[10-(10-hydroxy-ethyl)]-
c-butyrolactone (16) with Lithium Aluminumhydride
To a solution of lithium-aluminum-hydride (0.45 g, 11.7 mmol) in
anhydrous THF (10 mL), under nitrogen atmosphere, was added at r.t. a
solution of the anti-2-acetyl-2-allyl-g-butyrolactone derivative (16) (0.2 g,
1.17 mmol) in anhydrous THF (10 mL). The reaction mixture was stirred
for 2 h, at r.t., and afterwards 10 mL of 1 M aq. solution of H2O2 and 14 mL
of 0.2 N aq. solution of NaOH were added. After 15 min, the system was
diluted with ethyl acetate (30 mL) and the organic layer was filtered off celite
in a sintered glass filter. The organic filtrate was evaporated under reduced
pressure to afford (26) in 92% yield, as a colorless oil; 1H NMR (300 MHz):
1.24 (d, 3H, J ¼ 6.4 Hz, -CH(OH)CH3), 1.94 (m, 4H, -CH2CH2OH
and -CH2CH¼CH2), 3.59 (d, 1H, J ¼ 11.3 Hz, -CH2OH), 3.81 (m, 3H,
-CH2OH and -CH2CH2OH), 4.11 (q, 1H, J ¼ 7.1 Hz, -CH(OH)CH3), 5.08
(m, 2H, -CH2CH¼CH2), 5.77 (m, 1H, -CH2CH¼CH2); 13C NMR (75 MHz):
17.3 (-CH(OH)CH3), 34.5 (-CH2CH¼CH2), 36.6 (-CH2CH2OH), 43.4
(C-2), 58.1 (-CH2CH2OH), 66.5 (-CH2OH), 71.6 (-CH(OH)CH3), 118.1

ORDER
REPRINTS
524
TEIXEIRA ET AL.
(-CH2CH¼CH2), 133.6 (-CH2CH¼CH2). Anal. Calcd. for C9H18O3: C,
62.04; H, 10.41. Found: C, 62.12; H, 10.33.
Ketalization of (syn)-2-Allyl-2-[10-(10-hydroxy-ethyl)]-
1,4-butanediol (25) with 2,2-Dimethoxypropane
To a suspension of derivative (25) (0.1 g, 0.57 mmol) in dichloro-
methane (5 mL) containing catalytic amount of p-toluenesulfonic acid,
was added 2,2-dimethoxypropane (0.14 mL, 1.14 mmol). The reaction mix-
ture was stirred at r.t. for 2 h. Then, dichloromethane (5 mL) was added and
the resulting organic layer was washed with 5% aqueous sodium bicarbo-
nate solution and submitted to the ‘‘usual work-up,’’ affording an oily
residue, which was purified by silica gel column chromatography using a
mixture of hexane : isopropanol : pyridine (90 : 9.9 : 0.1 v/v) as eluent, to give
(27) in 62% yield, as a colorless oil; 1H NMR (300 MHz): 1.15 (d, 3H,
J ¼ 6.3 Hz, -CH(O)CH3), 1.42 (s, 3H, CH3-a), 1.46 (s, 3H, CH3-b), 1.53
(ddd, 1H, J ¼ 4.2, 7.2 and 15.3 Hz, -CH2CH2OH), 1.91 (dd, 2H, J ¼ 1.2
and 7.5 Hz, -CH2CH¼CH2), 1.96 (m, 1H, -CH2CH2OH), 3.62 (d, 1H,
J ¼ 12.0 Hz, -CH2O-), 3.83 (dd, 1H, J ¼ 1.5 and 12.3 Hz, -CH2O-), 3.89
(ddd, 2H, J ¼ 4.5, 6.9 and 15.0 Hz, -CH2CH2OH), 3.96 (q, 1H, J ¼ 6.6 Hz,
-CH(O)CH3), 5.08 (m, 2H, -CH2CH¼CH2), 5.72 (m, 1H, -CH2CH¼
CH2); 13C NMR (75 MHz): 14.8 (-CH(OH)CH3), 18.7 (-C(CH3)2), 29.2
(-CH2CH¼CH2), 36.3 (-CH2CH2OH), 41.2 (C-5), 59.4 (-CH2CH2OH),
67.4 (-CH2OC(CH3)2), 71.8 (-CH(OH)CH3), 98.4 (-C(CH3)2), 118.5
(-CH2CH¼CH2), 132.4 (-CH2CH¼CH2). Anal. Calcd. for C12H22O3: C,
67.26; H, 10.35. Found: C, 67.35; H, 10.43.
Ketalization of (anti)-2-Allyl-2-[10-(10-hydroxy-ethyl)]-
1,4-butanediol (26) with 2,2-Dimethoxypropane
To a suspension of derivative (26) (0.06 g, 0.34 mmol) in dichloro-
methane (3 mL) containing catalytic amount of p-toluenesulfonic acid,
was added 2,2-dimethoxypropane (0.08 mL, 0.68 mmol). The reaction mix-
ture was stirred at r.t. for 2 h. Then, dichloromethane (5 mL) was added and
the resulting organic layer was washed with 5% aq. sodium bicarbonate
solution and submitted to the ‘‘usual work-up,’’ affording an oily residue,
which was purified by silica gel column chromatography using a mixture of
hexane : isopropanol : pyridine (90 : 9.9 : 0.1 v/v) as eluent, to give (28) in
1
61% yield, as a colorless oil; H NMR (300 MHz): 1.10 (d, 3H, J ¼ 6.6 Hz,
-CH(O)CH3), 1.40 (s, 3H, CH3-a), 1.43 (s, 3H, CH3-b), 1.51 (m, 1H,

ORDER
REPRINTS
2-ACETYL-2-ALKYL-c-BUTYROLACTONES
525
-CH2CH2OH), 1.85 (dt, 1H, J ¼ 4.8 and 14.7 Hz, -CH2CH2OH), 2.04 (ddt,
1H, J ¼ 1.4, 7.5 and 15 Hz, -CH2CH¼CH2), 2.65 (ddt, 1H, J ¼ 1.4, 7.2 and
14.1 Hz, -CH2CH¼CH2), 3.48 (d, 1H, J ¼ 11.8 Hz, -CH2O-), 3.60 (d, 1H,
J ¼ 12 Hz, -CH2O-), 3.83 (m, 2H, -CH2CH2OH), 4.00 (q, 1H, J ¼ 6.3 Hz,
-CH(O)CH3), 5.08 (m, 2H, -CH2CH¼CH2), 5.74 (m, 1H, -CH2CH¼
CH2); 13C NMR (75 MHz): 15.0 (-CH(OH)CH3), 17.3 (-C(CH3)2), 30.8
(-CH2CH¼CH2), 34.4 (-CH2CH2OH), 36.7 (C-5), 58.4 (-CH2CH2OH),
66.7 (-CH2OC(CH3)2), 71.8 (-CH(OH)CH3), 98.5 (-C(CH3)2), 118.1
(-CH2CH¼CH2), 133.6 (-CH2CH¼CH2). Anal. Calcd. for C12H22O3: C,
67.26; H, 10.35. Found: C, 67.30; H, 10.27.
ACKNOWLEDGMENTS
We are grateful to FAPERJ (BR.) and FUJB (BR.) for financial sup-
port and also CAPES and CNPq for fellowships (to L.H.P.T., M.C.B.V.S.,
C.A.M.F. & E.J.B.). Thanks are due to Prof. Carlos R. Rodrigues
(Universidade Federal do Rio de Janeiro – BR.) for molecular modeling
data and Laboratorio de Ressonancia Magnetica Nuclear (Universidade
Federal Fluminense – BR.) for spectroscopic facilities.
REFERENCES
1. Fraga, C.A.M.; Miranda, A.L.P.; Barreiro, E.J. Chem. Pharm. Bull.
1996, 44, 2157–2161.
2. Pecanha, E.P.; Fraga, C.A.M.; Sant’Anna, C.M.R.; Miranda, A.L.P.;
Barreiro, E.J. II Farmaco 1998, 53, 327–336.
3. Fraga, C.A.M.; Barreiro, E.J. Synth. Comm. 1995, 25, 1133–1144.
4. Barreiro, E.J.; Garcia, V.L. An. Acad. Brasil. Cienc. 1985, 57, 417–425
[Chem. Abstr. 106, 1985, 138176d].
5. Sant’Anna, C.M.R.; Alencastro, R.B.; Barreiro, E.J.; Fraga, C.A.M.
J. Mol. Structure (TheoChem) 1995, 340, 193–199.
6. Teixeira, L.H.P.; Barreiro, E.J.; Fraga, C.A.M. Synth. Comm. 1997,
27, 3241–3257.
7. Purchased from Aldrich Chemical C., Milwaukee, Wis., USA.
8. Araujo, A.C.V.; Almeida, F.V.; Bieber, L.W. Quımica Nova 1996, 19,
79 [Chem. Abstr. 124, 1996, 260343q].
9. Barco, A.; Benetti, S.; Pollini, G.P. Synthesis 1973, 316.
10. Dewar, M.J.S.; Zoebisch, E.G.; Healy, E.F.; Stewart, J.J.P. J. Am.
Chem. Soc. 1985, 107, 3902–3909.

ORDER
REPRINTS
526
TEIXEIRA ET AL.
11. Takeshita, M.; Yanaglhara, H.; Yoshida, S. Heterocycles 1992, 33,
489–492.
12. Taniguchi, M.; Fujii, H.; Oshima, K. Tetrahedron 1993, 49,
11169–11182.
13. Taniguchi, M.; Fujii, H.; Oshima, K.; Utimoto, K. Tetrahedron 1995,
51, 679–686.
14. Brown, H.C.; Ichikawa, K. J. Am. Chem. Soc. 1961, 83, 4372–4374.
15. Brown, H.C.; Krishnamurthy, S. J. Amer. Chem. Soc. 1972, 94,
7159–7161.
16. Warmerdam, E.; Tranoy, I.; Renoux, B.; Gesson, J. Tetrahedron Lett.,
1988, 39, 8077–8080.
17. Canney, D.J.; Holland, K.D.; Levine, J.A.; McKeon, A.C.;
Ferrendelli, J.A.; Covey, D.F. J. Med. Chem. 1991, 34, 1460–1467.
18. Peterson, E.M.; Xu, K.; Holland, K.D.; McKeon, A.C.; Rothman,
S.M.; Ferrendelli, J.A.; Covey, D.F. J. Med. Chem. 1994, 37, 275–286.
19. Stang, P.J.; Treptow, W.L. J. Med. Chem. 1981, 24, 468–472.
20. Nilsson, B.M.; Vargas, H.M.; Ringdahl, B.; Hacksell, U. J. Med.
Chem. 1992, 35, 285–294.
21. Lee, L.; Lewin, N.E.; Acs, P.; Blumberg, P.M.; Marquez, V.E. J. Med.
Chem. 1996, 39, 4912–4919.
22. Tamamura, H.; Bienfait, B.; Nacro, K.; Lewin, N.E.; Blumberg, P.M.;
Marquez, V.E. J. Med. Chem. 2000, 43, 3209–3217.
Received in the USA March 19, 2001

Request Permission or Order Reprints Instantly!
Interested in copying and sharing this article? In most cases, U.S. Copyright
Law requires that you get permission from the article’s rightsholder before
using copyrighted content.
All information and materials found in this article, including but not limited
to text, trademarks, patents, logos, graphics and images (the "Materials"), are
the copyrighted works and other forms of intellectual property of Marcel
Dekker, Inc., or its licensors. All rights not expressly granted are reserved.
Get permission to lawfully reproduce and distribute the Materials or order
reprints quickly and painlessly. Simply click on the "Request
Permission/Reprints Here" link below and follow the instructions. Visit the
U.S. Copyright Office for information on Fair Use limitations of U.S.
copyright law. Please refer to The Association of American Publishers’
(AAP) website for guidelines on Fair Use in the Classroom.
The Materials are for your personal use only and cannot be reformatted,
reposted, resold or distributed by electronic means or otherwise without
permission from Marcel Dekker, Inc. Marcel Dekker, Inc. grants you the
limited right to display the Materials only on your personal computer or
personal wireless device, and to copy and download single copies of such
Materials provided that any copyright, trademark or other notice appearing
on such Materials is also retained by, displayed, copied or downloaded as
part of the Materials and is not removed or obscured, and provided you do
not edit, modify, alter or enhance the Materials. Please refer to our Website
User Agreement for more details.
Order now!
Reprints of this article can also be ordered at
http://www.dekker.com/servlet/product/DOI/101081SCC120002396