Synthesis of γ- and δ-lactones from alkynols

Article abstract of DOI:10.1055/s-2006-932477

The reaction of alkynyl phenyl selenides with p-toluene-sulfonic acid gives rise to a proton-induced ring-closure reaction affording γ- and δ-lactones. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-932477

LETTER
587
Synthesis of g- and d-Lactones from Alkynols
S
ynthesis of
g
-
and
d
-L
a
actones rcello Tiecco,* Lorenzo Testaferri, Andrea Temperini, Raffaella Terlizzi, Luana Bagnoli, Francesca Marini,
Claudio Santi
Dipartimento di Chimica e Tecnologia del Farmaco, Sezione di Chimica Organica, Università di Perugia, 06123 Perugia, Italy
Fax +39(075)5855116; E-mail: tiecco@unipg.it
Received 22 December 2005
rivatives 5 of compounds 1, with an excess of p-toluene-
sulfonic acid monohydrate (PTSA), in dichloromethane,
gave the phenyl selenocarboxylates 7 (Scheme 2).
Abstract: The reaction of alkynyl phenyl selenides with p-toluene-
sulfonic acid gives rise to a proton-induced ring-closure reaction
affording g- and d-lactones.
Key words: alkynes, lactone-cyclization reactions, organoseleni-
um reagents, regiospecificity
SePh
PTSA
O
PhSeBr
CuI
n
n
n
SePh
R
OAc
R
OAc
R
OAc
Substituted g- and d-lactones are the basic structural units
of many complex and biologically active natural products
and they are also of great interest as synthetic intermedi-
ates in organic synthesis.1 Several synthetic methods for
the synthesis of lactones have been developed2 during the
last few years and some of these involve alkynols as start-
ing products. Thus, MaGee3 has shown that g- or d-lac-
tones can be formed by intramolecular trapping of
ketenes, themselves available from the corresponding hy-
droxy alkynyl ethers by a retro-ene reaction. Schreiber
and co-workers4 developed a protocol for the conversion
of hydroxy alkynyl ethers into the corresponding d-lac-
tones by treatment with mercuric(II) chloride and p-tolu-
enesulfonic acid. g-Lactones were also obtained from 4-
trimethylsilyl-3-alkyn-1-ols via Wacker-type oxidation
reactions as reported by Compain.5 More recently,
Jacobsen6 proposed a direct method for the conversion of
terminal epoxides into g-lactones in a single step by the
formation of a cyclic keteneaminal intermediate and sub-
sequent hydrolysis and protodesilylation.
7
5
6
n = 1, 2
Scheme 2
In the present paper we now describe a simple procedure
to convert alkynols 1 into g- or d-lactones 12 or 13 by an
acid-promoted regiospecific cyclization reaction of alkyn-
yl phenyl selenide derivatives 8 (Scheme 3). The alkynyl
phenyl selenides 8 were easily prepared from the corre-
sponding alkynyl alcohols9 1 according to the method
reported in literature.10
SePh
PhSeBr
CuI
PTSA
n
n
n
SePh
R
R
OH
R
OH
R
OH
1
9
8
In a previous work7 we reported that alkynols 1 can be
transformed into the corresponding (Z)-a-(phenylsele-
no)vinyl p-toluenesulfonates 2. These latter compounds
undergo to a selenium-promoted regiospecific ring-clo-
H+
n
n
n
– PhSeH
SePh
R
SePh
OH
R
O
H2O
O
O
O
12 n = 1, 13 n = 2
11
10
sure reaction affording a-phenylseleno g- or d-lactones 3 Scheme 3
or 4, respectively (Scheme 1).
Moreover, we have also reported8 that the reaction of
alkynyl phenyl selenides 6, prepared from the acetyl de-
Thus, it can be suggested that the reaction of 8 with an ex-
cess of p-toluenesulfonic acid monohydrate, in dichloro-
methane at 60 °C, proceeds through a regiospecific proton
addition to 8 with the formation of the selenium-stabilized
vinylic cation intermediate 9. This cation is then intra-
molecularly trapped by the hydroxy group to afford the
cyclization product 10, which readily adds a molecule of
water to give 11. Under the reaction conditions employed,
11 eliminates a molecule of phenylselenol to give g-lac-
tone 12 or d-lactone 13. The yellow color of the final
reaction mixture is due to the presence of diphenyl di-
selenide, which is formed by the oxidation of the
phenylselenol. The products obtained by this procedure
and the reaction yields11 are reported in Table 1.
SePh
OTs
n
n
n
PhSeSePh
DDQ
SePh
R
O
R
OH
R
OH
O
1
2
3 n = 1, 4 n = 2
Scheme 1
SYNLETT 2006, No. 4, pp 0587–0590
0
3.
0
2.
2
0
0
6
Advanced online publication: 20.02.2006
DOI: 10.1055/s-2006-932477; Art ID: G39605ST
© Georg Thieme Verlag Stuttgart · New York

588
M. Tiecco et al.
LETTER
Table 1 Synthesis of g- and d-Lactones 12 and 13 from the Reaction of 8 with Monohydrated p-Toluenesulfonic Acid in CH2Cl2 at 60 °C
Entry
1
Substrate
Lactone
Yield (%)a
60
SePh
8a
8b
12a
12b
O
O
OH
SePh
2
3
71
BnO
O
O
BnO
OH
SePh
(Bn)2N
8c
12c
67b
O
O
(Bn)2N
OH
Bn
Bn
4
5
8d
8e
13a
13b
68
SePh
OH
O
O
75c
SePh
SePh
OH
O
O
O
6
8f
13c
65b
O
OH
O
O
7
8
9
8g
8h
8i
13d
13e
13f
58d
61b
59b
R1
R1
SePh
O
OH
O
O
O
BnO
BnO
SePh
BnO
OH
O
O
SePh
O
OH
O
BnO
a Isolated yield after column chromatography.
b Yields based on the starting alkynol. The corresponding alkynyl phenyl selenide was not isolated.
c Racemic product.
d A 1:1 mixture of the two diastereoisomers; R1 = (–)-endo-borneyl.
Substrates 8a–c gave the expected g-lactones 12a–c in 8h and 8i the optically active d-lactones 13e and 13f,
good yields. The reactions were not influenced by the respectively, were obtained. Lactone 13e is a protected
presence of the other functional groups. Optically active derivative of (S)-5-hydroxymethyl-d-valerolactone,
lactones 12b and 12c were obtained from the correspond- which is a valuable synthetic intermediate for the synthe-
ing chiral non-racemic alkynyl alcohols. Compound 12b sis of LTB514a and is potentially useful for the preparation
has been used by several authors for the synthesis of of a range of insect pheromones.14b On the other hand, the
various natural products,12 whereas g-lactone 12c is a S enantiomer of 13f was employed for the synthesis of the
valuable and versatile intermediate for the synthesis of ionophore antibiotic Routiennocin.15
hydroxymethylene dipeptide isosters, which are pharma-
In conclusion, in this paper we described a new cyclofunc-
ceutically important compounds that possess the basic
tionalization reaction, involving organoselenium inter-
structure of HIV protease13a and g-secretase inhibitors.13b
mediates, which can be conveniently employed for the
The cyclofunctionalization of alkynols mediated by orga- synthesis of g- and d-lactones. The procedure reported
noselenium intermediates proceeds easily also for sub- herein favorably compares with similar methods de-
strates 8d–i affording the expected d-lactones 13a–f in scribed in the literature particularly in the case of the
fairly good yields. Lactone 13d is constituted by 1:1 mix- synthesis of d-lactones. Very likely, our procedure can
ture of two diastereoisomers which could not be separat- also be applied to the synthesis of medium-sized lactones.
ed. From the chiral non-racemic alkynyl phenyl selenides
Synlett 2006, No. 4, 587–590 © Thieme Stuttgart · New York

LETTER
Synthesis of g- and d-Lactones from Alkynols
(3R)-1-(Benzyloxy)hept-6-yn-3-ol (1i).
589
Applications of the presently described method to the
synthesis of other biologically active compounds are
presently under way.
Oil, 73% yield. [a]D23 +24.6 (c 1.75, CHCl3). 1H NMR (200
MHz, CDCl3): d = 7.45–7.20 (m, 5 H), 4.51 (s, 2 H), 3.94
(quint, 1 H, J = 5.7 Hz), 3.79–3.57 (m, 2 H), 3.07 (br s, 1 H),
2.32 (dt, 2 H, J = 5.0, 2.6 Hz), 1.95 (t, 1 H, J = 2.6 Hz), 1.82–
1.58 (m, 4 H). 13C NMR (50 MHz, CDCl3): d = 137.7, 128.4
(2 C), 127.7 (2 C), 127.6, 84.2, 73.2 (2 C), 69.8, 68.9, 68.4,
36.2, 35.7. MS: m/z (relative intensity) = 218 (18), 159 (11),
109 (64), 91 (100), 83 (10), 65 (12). Anal. Calcd for
C14H18O2: C, 77.03; H, 8.31. Found: C, 77.29; H, 8.65.
(10) (a) Braga, A. L.; Silveira, C. C.; Reckziegel, A.; Menezes, P.
H. Tetrahedron Lett. 1993, 34, 8041. (b) Tingoli, M.;
Tiecco, M.; Testaferri, L.; Balducci, R. Synlett 1993, 211.
(11) Ring-Closure Reaction. General Procedure.
To a solution of the alkynyl phenyl selenide 8 (1 mmol) in
CH2Cl2 (15 mL) powdered p-toluenesulfonic acid
monohydrate (4 mmol) was added at r.t. and the reaction
mixture was stirred at 60 °C. The progress of the reaction
was monitored by TLC. Reaction times ranged from 1–9 h.
Solid K2CO3 and CH2Cl2 were added and the mixture was
filtered. The filtrate was dried and evaporated. After
chromatography on silica gel column, compounds 12 and 13
were obtained in a pure form. Compounds 12a and 13c are
commercial products whereas lactones 12c,20 13a21 and
13b22 have physical and spectral data identical to those
reported in the literature. Physical and spectral data of 12b,
13e and 13f are reported below.
Acknowledgment
Financial support from MIUR, National Project ‘Stereoselezione in
Sintesi Organica. Metodologie ed Applicazioni’, FIRB Project
‘Progettazione, Preparazione e Valutazione Biologica e Farmacolo-
gica di Nuove Molecole Organiche Quali Potenziali Farmaci Inno-
vativi’, Consorzio CINMPIS and the University of Perugia, Progetti
di Ateneo, are gratefully acknowledged.
References and Notes
(1) (a) Ohloff, G. Progress in the Chemistry of Organic Natural
Products, Vol. 35; Zechmeister, L., Ed.; Springer Verlag:
Wien, 1978, 431. (b) Schmidt, R. R.; Betz, R. Angew.
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Biochem. Syst. Ecol. 1986, 14, 225. (d) Mori, K.
Tetrahedron 1989, 45, 3233.
(2) (a) Kano, S.; Shibuya, S.; Ebata, T. Heterocycles 1980, 14,
661. (b) Mulzer, J. In Comprehensive Organic Synthesis,
Vol. 6; Trost, B. M.; Fleming, I., Eds.; Pergamon: New
York, 1991, 323. (c) Ogliarusco, M. A.; Wolfe, J. F.
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(d) Collins, I. J. Chem. Soc., Perkin. Trans. 1 1999, 1377.
(3) Liang, L.; Ramaseshan, M.; MaGee, D. I. Tetrahedron 1993,
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(5S)-5-[(Benzyloxy)methyl]dihydrofuran-2(3H)-one
(12b).23,
Oil, 71% yield. [a]D24 +21.0 (c 1.45, EtOH) {Lit.23 [a]D
15
+18.1 (c 2.7, EtOH)}. 13C NMR (50 MHz, CDCl3):
d = 177.2, 137.6, 128.4 (2 C), 127.7, 127.5 (2 C), 78.9, 73.4,
71.5, 28.3, 24.0. MS: m/z (%) = 206 (2), 105 (22), 91 (100),
85 (78), 65 (19).
(6S)-6-[(Benzyloxy)methyl]tetrahydro-2H-pyran-2-
one24 (13e).
Oil, 61% yield. [a]D22 +9.1 (c 2.88, CHCl3). 13C NMR (50
MHz, CDCl3): d = 171.1, 137.7, 128.4 (2 C), 127.7, 127.6 (2
C), 79.0, 73.5, 71.8, 29.6, 24.5, 18.2. MS: m/z (%) = 129 (1)
[M – 91], 114 (58), 99 (35), 91 (100), 71 (45), 55 (23).
(6R)-6-[2-(Benzyloxy)ethyl]tetrahydro-2H-pyran-2-
one25 (13f).
(8) Tiecco, M.; Testaferri, L.; Temperini, A.; Bagnoli, L.;
Marini, F.; Santi, C.; Terlizzi, R. Eur. J. Org. Chem. 2004,
3447.
Oil, 59% yield. [a]D28 +55.0 (c 2.01, CHCl3). 13C NMR (50
MHz, CDCl3): d = 171.8, 138.1, 128.3 (2 C), 127.9 (2 C),
127.6, 77.5, 73.1, 65.7, 36.0, 29.6, 27.9, 18.3. MS:
m/z (%) = 234 (16), 206 (8), 107 (44), 91 (100), 79 (14), 68
(30), 55 (12).
(9) All new compounds were fully characterized by MS, 1H
NMR and 13C NMR spectroscopy and by combustion
analysis. Compounds 1b,c,8 1e16 and 1h,i8 were prepared as
described in the literature from the corresponding epoxides
whereas compound 1f was obtained by reduction of the
corresponding aldehyde with NaBH4. Alkynol 1a was
obtained by reaction of a propargyl organometallic reagent
with the proper carbonyl compound.5 Compound 1d was
prepared by reduction of the corresponding ketone17 with
NaBH4. Hydroxy ester 1g was obtained by reduction of the
corresponding oxoester, which was synthesized by
alkylation of the dianion18 of (–)-endo-borneyl 3-oxo-
butanoate.19 Physical, spectral and analytical data of selected
compounds are reported below.
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2005, 7, 1813. (b) Elworthy, T. R.; Brill, E. L.; Chou, S.;
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Med. Chem. 2004, 47, 6124. (c) Yao, Z.; Wu, Y.
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Org. Chem. 1998, 63, 3560. (b) Nadin, A.; Sanchez Lopez,
J. M.; Neduvelil, J. G.; Thomas, S. R. Tetrahedron 2001, 57,
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24, 4883. (b) Taylor, R. J. K.; Wiggins, K.; Robinson, D. H.
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(15) Diez-Martin, D.; Koteka, N. R.; Ley, S. V.; Mantegani, S.;
Menendez, J. C.; Organ, H. M.; White, A. D. Tetrahedron
1992, 48, 7899.
(2S,3R)-2-(Dibenzylamino)-1-phenylhex-5-yn-3-ol (1c).
Oil, 72% yield. 1H NMR (200 MHz, CDCl3): d = 7.38–7.06
(m, 15 H), 4.05–3.90 (m, 1 H), 3.80–3.50 (m, 4 H), 3.16–
2.58 (m, 3 H), 2.58 (ddd, 1 H, J = 16.7, 3.7, 2.7 Hz), 2.23
(ddd, 1 H, J = 16.7, 8.3, 2.7 Hz), 2.08 (d, 1 H, J = 4.7 Hz),
1.94 (t, 1 H, J = 2.7 Hz). 13C NMR (50 MHz, CDCl3):
d = 140.9, 139.5 (2 C), 129.5 (2 C), 128.8 (3 C), 128.3 (4 C),
128.2 (3 C), 126.9 (2 C), 125.9, 81.3, 70.9, 70.6, 62.8, 54.7,
54.2, 32.1, 25.7. Anal. Calcd for C26H27NO: C, 84.51; H,
7.37; N, 3.79. Found: C, 84.18; H, 7.67; N, 3.62.
(16) Pale, P.; Chuche, J. Eur. J. Org. Chem. 2000, 1019.
(17) Thommen, M.; Veretenov, A. L.; Guidetti-Grept, R.; Keese,
R. Helv. Chim. Acta 1996, 461.
(18) Huckin, S. N.; Weiler, L. J. Am. Chem. Soc. 1974, 96, 1082.
Synlett 2006, No. 4, 587–590 © Thieme Stuttgart · New York

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LETTER
(19) Christoffers, J.; Onal, N. Eur. J. Org. Chem. 2000, 1633.
(20) Fukuzawa, S.; Miura, M.; Saitoh, T. J. Org. Chem. 2003, 68,
2042.
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1988, 431.
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3547.
(24) Barua, N. C.; Schmidt, R. R. Synthesis 1986, 1067.
(25) The possible use of the presently described method for the
synthesis of medium-sized lactones was suggested by a
referee.
Synlett 2006, No. 4, 587–590 © Thieme Stuttgart · New York