Stereoselective synthesis of δ-lactones from 5-oxoalkanals via one-pot sequential acetalization, tishchenko reaction, and lactonization by cooperative catalysis of samarium ion and mercaptan

Article abstract of DOI:10.1021/jo016058t

By the synergistic catalysis of samarium ion and mercaptan, a series of 5-oxoalkanals was converted to (substituted) δ-lactones in efficient and stereoselective manners. This one-pot procedure comprises a sequence of acetalization, Tishchenko reaction and lactonization. The deliberative use of mercaptan, by comparison with alcohol, is advantageous to facilitate the catalytic cycle. The reaction mechanism and stereochemistry are proposed and supported by some experimental evidence. Such samarium ion/mercaptan cocatalyzed reactions show the feature of remote control, which is applicable to the asymmetric synthesis of optically active δ-lactones. This study also demonstrates the synthesis of two insect pheromones, (2S,5R)-2-methylhexanolide and (R)-hexadecanolide, as examples of a new protocol for asymmetric reduction of long-chain aliphatic ketones.

Full text of DOI:10.1021/jo016058t

J . Org. Chem. 2001, 66, 8573-8584
8573
Ster eoselective Syn th esis of δ-La cton es fr om 5-Oxoa lk a n a ls via
On e-P ot Sequ en tia l Aceta liza tion , Tish ch en k o Rea ction , a n d
La cton iza tion by Coop er a tive Ca ta lysis of Sa m a r iu m Ion a n d
Mer ca p ta n
J ue-Liang Hsu and J im-Min Fang*
Department of Chemistry, National Taiwan University, Taipei, Taiwan 106, Republic of China
jmfang@ccms.ntu.edu.tw
Received August 25, 2001
By the synergistic catalysis of samarium ion and mercaptan, a series of 5-oxoalkanals was converted
to (substituted) δ-lactones in efficient and stereoselective manners. This one-pot procedure comprises
a sequence of acetalization, Tishchenko reaction and lactonization. The deliberative use of
mercaptan, by comparison with alcohol, is advantageous to facilitate the catalytic cycle. The reaction
mechanism and stereochemistry are proposed and supported by some experimental evidence. Such
samarium ion/mercaptan cocatalyzed reactions show the feature of remote control, which is
applicable to the asymmetric synthesis of optically active δ-lactones. This study also demonstrates
the synthesis of two insect pheromones, (2S,5R)-2-methylhexanolide and (R)-hexadecanolide, as
examples of a new protocol for asymmetric reduction of long-chain aliphatic ketones.
In tr od u ction
chenko oxidoreductions on treatment with stoichiometric
amounts of (t-BuO)SmI2 or aged SmI2 solution (presum-
ably containing Sm3+ ion), followed by in situ cyclizations,
to give the corresponding δ-lactones. They also indicate
that the silyloxy substituent is essential for such trans-
formation. Otherwise, an unsubstituted substrate like
5-oxohexanal affords only a low yield (∼10%) of δ-methyl-
δ-lactone on treatment with (t-BuO)SmI2, or simply the
pinacolic coupling product on treatment with freshly
prepared SmI2 solution. Iadonisi and co-workers9 have
employed (t-BuO)SmI2 (2.5 equiv) to promote the Tish-
chenko reactions of hexos-5-uloses to give the tert-butyl
esters of aldonic acids, which were subsequently con-
verted into the corresponding sugar lactones. By using
stoichiometric amounts of SmI2 as the Lewis acid pro-
moter, we have converted 5-trimethylsilyl-5-oxopentanal
to δ-trimethylsilyl-δ-lactone in the presence of MeOH
(Figure 1).3b
Lanthanoid reagents have been widely utilized in
organic synthesis.1 SmI2 can function as a one-electron
reducing agent,2 and both SmI2 and SmI3 can function
as Lewis acids to promote a variety of reactions, such as
aldol reactions,3 Diels-Alder reactions,4 Meerwein reduc-
tions,5 oxirane rearrangements,6 Tishchenko reactions,3b,7
and sequential aldol-acetalization-Tishchenko reactions.3c,7
Uenishi and co-workers8 have demonstrated that 5-oxo-
4-silyloxyhexanals can undergo the intramolecular Tish-
(1) (a) Molander, G. A. In Comprehensive Organic Synthesis; Trost,
B. M.; Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 1, pp 251-
282. (b) Molander, G. A. Chem. Rev. 1992, 92, 29. (c) Imamoto, T.
Lanthanides in Organic Synthesis; Academic Press: London, 1994.
(2) Reviews of the reactions of SmI2: (a) Kagan, H. B.; Namy, J . L.
Tetrahedron 1986, 42, 6573. (b) Inanaga, J . J . Synth. Org. Chem. 1989,
47, 200. (c) Soderquist, J . A. Aldrichim. Acta 1991, 24, 15. (d)
Brandukova, N. E.; Vygodskii, Y. S.; Vinogradova, S. V. Russ. Chem.
Rev. 1994, 63, 345. (e) Molander, G. A.; Harris, C. R. Chem. Rev. 1996,
96, 307. (f) Molander, G. A.; Harris, C. R. Tetrahedron 1998, 54, 3321.
(3) (a) Van de Weghe, P.; Collin, J . Tetrahedron Lett. 1993, 34, 3881.
(b) Chuang, T.-H.; Fang, J .-M.; J iaang, W.-T.; Tsai, Y.-M. J . Org. Chem.
1996, 61, 1794. (c) Lu, L.; Chang, H.-Y.; Fang, J .-M. J . Org. Chem.
1999, 64, 843.
(4) Van de Weghe, P.; Collin, J . Tetrahedron Lett. 1994, 35, 2545.
(5) (a) Evans, D. A.; Nelson, S. G.; Gagne, M. R.; Muci, A. R. J . Am.
Chem. Soc. 1993, 115, 9800. (b) Ding, Z.-B.; Wu, S.-H. Huaxue Xuebao
1997, 55, 351. (c) Ding, Z.-B.; Cheng, K.-J .; Wu, S.-H. Huaxue Xuebao
1997, 55, 1030.
(6) Prandi, J .; Namy, J . L.; Menoret, G.; Kagan, H. B. J . Organomet.
Chem. 1985, 285, 449.
(7) (a) Collin, J .; Namy, J . L.; Kagan, H. B. Nouv. J . Chem. 1986,
10, 229. (b) Evans, D. A.; Hoveyda, A. H. J . Am. Chem. Soc. 1990,
112, 6447. (c) Curran, D. P.; Wolin, R. L. Synlett 1991, 317. (d)
Horiuchi, Y.; Taniguchi, M.; Oshima, K.; Utimoto, K. Tetrahedron Lett.
1995, 36, 5353. Examples of sequential aldol-acetalization-Tishchenko
reactions using the promoters other than samarium ions: (e) Burkhardt,
E. R.; Bergman, R. G.; Heathcock, C. H. Organometallics 1990, 9, 30.
(f) Baramee, A.; Chaichit, N.; Intawee, P.; Thebtaranonth, C.; Thebt-
aranonth, Y. J . Chem. Soc., Chem. Commun. 1991, 1016. (g) Mahrwald,
R.; Costisella, G. Synthesis 1996, 1087. (h) Bodnar, P. M.; Shaw, J . T.;
Woerpel, K. A. J . Org. Chem. 1997, 62, 5674. (i) Mascarenhas, C. M.;
Miller, S. P.; White, P. S.; Morken, J . P. Angew. Chem., Int. Ed. 2001,
40, 601.
The above-mentioned reactions3b,8,9 are presumably
initiated by addition of ROH (or RO-) to the aldehyde
group to form a hemiacetal with the assistance of
samarium ion as depicted in Figure 1. An intramolecular
hydride transfer to the ketone group (Tishchenko reac-
tion) occurs via a rigid chelate transition state.3c,7 The
δ-oxyester intermediate can proceed with an in situ
cyclization in appropriate cases to give the observed
δ-lactone product. Along this line, we considered that
using mercaptan RSH to replace alcohol ROH would be
advantageous. RSH would be a better nucleophile than
ROH on addition to the aldehyde group of 5-oxopenta-
nals, and the resulting thioester intermediates would also
be more reactive than esters in the subsequent lacton-
izations. We thus set out a detailed study of such one-
pot sequential acetalization, Tishchenko reaction, and
lactonization by the promotion of samarium ions and
mercaptans. The effects of substrates, nucleophiles,
(8) Uenishi, J .; Masuda, S.; Wakabayashi, S. Tetrahedron Lett. 1991,
32, 5097.
(9) Adinolfi, M.; Barone, G.; De Lorenzo, F.; Iadonisi, A. Synlett 1999,
336.
10.1021/jo016058t CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/13/2001

8574 J . Org. Chem., Vol. 66, No. 25, 2001
Hsu and Fang
Sch em e 1. P r ep a r a tion of 5-Oxoa lk a n a ls 1a -m
F igu r e 1. Samarium ion promoted formation of δ-lactone
from 5-oxo-5-silylpentanal: (i) acetalization, (ii) Tishchenko
reaction, and (iii) lactonization.
catalysts, and reaction conditions would be examined. In
a preliminary report,10 we have utilized SmI2 and 2-pro-
panethiol (i-PrSH) as the combined catalysts to convert
5-oxopentanals into their corresponding δ-lactones. (eq
1). Our ultimate goal is to devise a catalytic method for
the synthesis of optically active δ-lactones, which often
occur in nature or as parts of natural products.11
Resu lts a n d Discu ssion
P r ep a r a tion s a n d Rea ction s of 5-Oxoa lk a n a ls. A
series of 5-oxoalkanals 1a -g and 1j-m were prepared
from cyclopentanone by a three-step sequence12 (Scheme
1): (i) addition of Grignard reagents, (ii) dehydration, and
(iii) ozonolysis. 6,6-Dimethyl-5-oxoheptanal (1h ) was
prepared by alkylation of the N,N-dimethylhydrazone of
3,3-dimethyl-2-butanone, followed by ozonolysis.13 Alter-
natively, the silyl enol ether of isobutyraldehyde under-
went a Michael addition with methyl vinyl ketone to give
2,2-dimethyl-5-oxohexanal (1i).14 We found that this
reaction was facilitated by using BF3.OEt2 as the pro-
moter in addition to Al2O3-ZnCl2.
(a) The overall yield of three steps. (b) The yield of 1f was low
because the dehydration step also gave a side product of ben-
zylidenecyclopentane. (c) Because the alkene precursors were
partially soluble in CH2Cl2 on ozonolysis, significant amounts of
alkenes were also recovered.
Ta ble 1. Rea ction s of 5-Oxo-5-p h en ylp en ta n a l (1a )
P r om oted by Sm I2 in th e P r esen ce of i-P r SH or i-P r OH
(THF , 25 °C, 30 m in )
Using 5-oxo-5-phenylpentanal (1a ) as a model sub-
strate, its reactions with SmI2 in the presence of i-PrOH
or i-PrSH were investigated (Table 1). In the presence
of 50 mol % of SmI2 and 50 mol % of i-PrOH, the tandem
acetalization-Tishchenko reaction gave a 36% yield of
isopropyl 5-hydroxy-5-phenylpentanoate. The subsequent
lactonization did not occur under such reaction conditions
(25 °C, 30 min). However, a dramatic increase of the
δ-lactone product 2a (53% yield) was obtained when
i-PrSH was introduced to the reaction media (entry 2,
Table 1). Moreover, a quantitative yield of lactone 2a was
procured when 1a was stirred with SmI2 (50 mol %) and
entry
mol % of SmI2
additive (mol %)
yield (%) of 2a
1
2
50
50
i-PrOH (50)
i-PrOH (50) +
i-PrSH (50)
i-PrSH (40)
i-PrSH (10)
i-PrSH (20)
i-PrSH (5)
a
53b,c
3
4
5
6
50
20
10
10
99b
100b
27b
0
a
This reaction gave 36% yield of isopropyl 5-hydroxy-5-phenyl-
pentanoate. The yield was estimated by 1H NMR analysis of the
b
crude product mixture. c This reaction also gave 3% yield of
isopropyl 5-hydroxy-5-phenylpentanoate.
(10) Hsu, J .-L.; Chen, C.-T.; Fang, J .-M. Org. Lett. 1999, 1, 1989.
(11) (a) Ohloff, G. Fortschr. Chem. Org. Naturst. 1978, 35, 431. (b)
Mulzer, J . In Compr. Org. Funct. Group Transform; Katrizky, A. R.;
Meth-Cohn, O.; Rees, C. W., Eds.; Elsevier: Oxford, 1995; Vol. 5, 121-
179. (c) Ley, S. V.; Cox, L. R.; Meek, G. Chem. Rev. 1996, 96, 423. (d)
Collins, I.; J . Chem. Soc., Perkin Trans. 1 1998, 1869. Mcrae, K. J .;
Rizzacasa, M. A. J . Org. Chem. 1997, 62, 1196. Urabe, H.; Matsuka,
T.; Sato, F. Tetrahedron Lett. 1992, 33, 4183.
(12) (a) Garbish, E. W., J r. J . Org. Chem. 1961, 26, 4165. (b) Hon,
Y.-S.; Lin, S.-W.; Lu, L.; Chen, Y.-J . Tetrahedron 1995, 51, 5019.
(13) (a) Corey, E. J .; Enders, D. Tetrahedron Lett. 1976, 17, 3. (b)
Corey, E. J .; Enders, D. Chem. Ber. 1978, 111, 1362. (c) Molander, G.
A.; Cameron, K. O. J . Am. Chem. Soc. 1993, 115, 830.
i-PrSH (40 mol %) at room temperature for 30 min (entry
3, Table 1).
A quantitative yield of lactone 2a was also obtained
by using smaller amounts of promoters, 20 mol % of SmI2,
and 10 mol % of i-PrSH (entry 4, Table 1). The repre-
sentative procedure is described in the Experimental
Section (method D). No aldol or pinacol products were
observed in such reaction conditions. However, using 10
mol % of SmI2 only provided a low yield of the desired
product (entries 5 and 6, Table 1). SmI2 or i-PrSH alone
did not promote the formation of lactone 2a .
(14) (a) Amice, P.; Blanco, L.; Conia, J . M. Synthesis 1976, 197. (b)
Ranu, B. C.; Saha, M.; Bhar, S. J . Chem. Soc., Perkin Trans. 1 1985,
2701. (c) Ranu, B. C.; Saha, M.; Bhar, S. Tetrahedron Lett. 1993, 34,
1989.

Synthesis of δ-Lactones from 5-Oxoalkanals
J . Org. Chem., Vol. 66, No. 25, 2001 8575
Sch em e 2. Con ver sion of 5-Alk yl- a n d
5-P h en yl-5-oxop en ta n a ls to δ-La cton es by Usin g
th e P r em ixin g a n d Rein jection P r oced u r e
F igu r e 2. A proposed catalytic cycle for the formation of
δ-lactones.
Ta ble 2. Tr a n sfor m a tion of 5-Oxo-5-p h en ylp en ta n a l (1a )
a n d 5-Oxotr id eca n a l (1e) in to La cton es 2a a n d 2e by
Usin g Sm I2 a n d Disu lfid e (THF , 25 °C, 1 h )
mol %
of SmI2
disulfide
(mol %)
product
(yield, %)
entry
substrate
1
2
3
4
5
6
7
1a
1a
1a
1a
1e
1e
1e
42
12
42
42
42
85
42
(PhS)2 (20)
(PhS)2 (5)
2a (100)
2a (100)
2a (67)
2a (68)
2e (100)
2e (87)
2e (56)
To our surprise, only a small portion (<10%) of 5-alkyl-
5-oxopentanals 1b-h could be converted into their cor-
responding δ-substituted-δ-lactones 2b-h by using the
above-mentioned procedure with SmI2 and i-PrSH as the
promoters. This discrepancy might be attributable to the
lower reactivity of aliphatic ketones (e.g., 1b-h ) by
comparison with aromatic ketones (e.g., 1a ). Fortunately,
we found that a slightly modified procedure, premixing
and re-injection (method E in Experimental Section),
could lead to efficient formations of lactones 2b-h
(Scheme 2). Thus, an aliquot of SmI2/i-PrSH (1-5 mol %
in 1 mL of THF) was premixed with the substrate (1b-
h ) in an oven-dried syringe. The resulting yellow solution,
an indicator of trivalent samarium ion, was then added
dropwise to the original SmI2/i-PrSH (50/40 mol %)
solution in THF (14 mL). Accordingly, the desired lac-
tones 2b -h were obtained in excellent yields (>90%).
This modified procedure was also suitable for the trans-
formation of aromatic ketone 1a into lactone 2a . Even
the sterically demanding aldehyde 1i was also success-
fully converted to lactone 2i in 80% yield.
It was noted that lactone 2i would not be prepared by
Baeyer-Villiger oxidation of 2,2,5-trimethylcyclopen-
tanone due to the incompatible regiochemistry.15 When
5-oxotridecanal (1e) was treated with stoichiometric
amounts of SmI2 and i-PrOH, both Tishchenko oxi-
doreduction and intramolecular pinacolic coupling oc-
curred to give a mixture of isopropyl 5-hydroxytride-
canoate and 1-octyl-1,2-cyclopentanediol in a ratio of 1:1.
No lactone 2e was formed in the absence of mercaptan.
Rea ction m ech a n ism . On the basis of the above
experimental results, one can propose a possible reaction
mechanism for the formation of δ-lactones (Figure 2). A
Lewis acid such as the presumed (i-PrS)SmI2 or the
related samarium species16 can promote the addition of
i-PrSH to the aldehyde group of a 5-oxopentanal sub-
strate. The samarium-bound hemithioacetal intermediate
(A) can undergo an intramolecular hydride shift to give
the intermediate of δ-oxyacid thioester (B). The reaction
would proceed further with an irreversible lactonization,
and release the catalyst (i-PrS)SmI2 (or the related
(MeS)2 (20)
(i-PrS)2 (20)
(PhS)2 (20)
(MeS)2 (40)
(i-PrS)2 (20)
samarium species) for the next cycle. The deliberative use
of mercaptan is proved to facilitate the catalytic cycle, due
to its strong nucleophilicity toward aldehyde and the high
aptitude of the thioester intermediate toward lactoniza-
tion.
It is known that SmI2 can cleave the S-S bond of
diphenyl disulfide.17 Indeed, by replacing SmI2/i-PhSH
with SmI2/(PhS)2, the reactions of oxoalkanals 1a and 1e
also proceeded smoothly to give lactones 2a and 2e in
quantitative yields (entries 1 and 5, Table 2). When
(MeS)2 or (i-PrS)2 were used instead of (PhS)2, lactones
2a and 2e were obtained in modest yields (56-87%,
entries 3, 4, 6, and 7, Table 2). This trend was consistent
with the higher reactivity of diphenyl disulfide toward
SmI2 than dialkyl disulfides. The combination of SmI3
(20 mol %) and PhSLi (20 mol %), instead of SmI2 and
mercaptan, was also utilized to promote the transforma-
tion of oxopentanal 1a into lactone 2a (99% yield) in an
expedient manner. These experiments support that the
in situ generated (RS)SmI2 or the related species actually
plays a role as a reactive catalyst to facilitate the
sequence of acetalization, Tishchenko reaction and lac-
tonization. The protocol using the solid reagent of (PhS)2
to replace the odoriferous reagent i-PrSH also makes this
method more attractive. A quantitative yield of lactone
2a was also achieved by using even less amounts of
promoters, SmI2 (12 mol %), and (PhS)2 (5 mol %) (entry
2, Table 2). By comparison, the conventional route to
δ-lactones often requires excess amounts of oxidizing and
reducing agents to convert 5-oxoalkanals into 5-hydroxy-
alkanoic acid for the subsequent lactonization. From the
point of atom economy, our method using catalytic
amounts of samarium ion and mercaptan to effect the
intramolecular oxidoreduction of 5-oxoalkanals appears
to surpass the conventional methods of δ-lactone forma-
tion.
(15) (a) Krow, G. R. Org. React. 1993, 43, 251. (b) Krow, G. R. In
Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vol. 7, p 671-688.
(16) It has been reported (ref 7a) that SmI2 reacts with alcohol ROH
to give (RO)SmI2 in the presence of a metallic salt as the electron
carrier.
(17) (a) J ia, X.; Zhang, Y.; Zhou, X. Synth. Commun. 1994, 24, 387.
(b) Chen, R.; Zhang, Y. Synth. Commun. 1999, 29, 3699. It has been
reported that disulfide RS-SR is reduced by Sm to give (RS)3Sm by
the catalysis of Ph2CO. See (c) Taniguchi, Y.; Maruo, M.; Takaki, K.;
Fujiwara, Y. Tetrahedron Lett. 1994, 35, 7789.

8576 J . Org. Chem., Vol. 66, No. 25, 2001
Hsu and Fang
Sch em e 3. Ster eoselective Sequ en tia l
Aceta liza tion , Tish ch en k o Rea ction , a n d
La cton iza tion
Ta ble 3. Com p a r ison of Differ en t Lew is Acid s in th e
Rea ction s of 5-Oxo-5-p h en ylp en ta n a l (1a ) a n d
5-Oxotr id eca n a l (1e)
mol % of products
entry substrate
Lewis acid (mol %)
i-PrSH
(yield, %)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1e
1e
1e
SmI2 (50)
SmI3 (110)
SmI3 (10)
SmI2 (25)/SmI3 (25)
SmI2 (50)/SmI3 (25)
SmF3 (20)
SmCl3 (20)
SmBr3 (20)
Sm(OAc)3 (20)
Sm(OTf)3 (20)
Sm(i-PrO)3 (20)
Al(i-PrO)3 (20)
Ti(i-PrO)3 (20)
SmI2 (50)
40
100
100
20
20
50
50
50
50
50
50
50
50
40
100
100
2a (99)
3a (85)a
3a (75)a
2a (67)
2a (99)
b
b
b
b
b
b
b
b
2e (94)
3e (87)a
3e (79)a
SmI3 (110)
SmI3 (10)
a
The product 3a (or 3e) existed as a mixture of two geometric
b
isomers (cis/trans ) 1:1). No compounds 2a or 3a were obtained.
Although evidence indicated that SmI2 was actually a
pre-catalyst to generate the corresponding trivalent
samarium species as the real Lewis acid catalyst.3-9
However, some studies (Table 3) also showed that the
direct introduction of trivalent samarium species did not
reach the same results as that using SmI2 precatalyst.
For example, treatment of 1a with stoichiometric amounts
of SmI3 and i-PrSH gave thioenol ether 3a (85% yield)
but not lactone 2a (entry 2, Table 3). When the amount
of SmI3 was decreased to 10 mol %, compound 3a was
still obtained in 75% yield in the presence of i-PrSH
(entry 3, Table 3). The yields of 3a changed as different
amounts of i-PrSH were used. By using 20 and 40 mol %
of i-PrSH along with SmI3, oxopentanal 1a was converted
to thioenol ether 3a in 18 and 38% yields, respectively.
A variety of Lewis acids were also examined (entries
6-13, Table 3). However, neither SmF3, SmCl3, SmBr3,
Sm(OAc)3, Sm(OTf)3, Sm(i-PrO)3, Al(i-PrO)3, nor Ti(i-
PrO)4 could convert oxopentanal 1a to lactone 2a or
thioenol ether 3a . We speculated that SmI3 underwent
an ligand exchange with i-PrSH to produce the strong
acid HI, which would promote the subsequent dehydra-
tion (a diverted elimination process of intermediate A in
Figure 2).18 Oxopentanal 1a remained unchanged when
an equimolar amount of Et3N or 1,8-bis(dimethylamino)-
naphthalene (Proton-Sponge) was added to the media of
SmI3/i-PrSH.
Table 3) and produced thioenol ether 3e in the presence
of SmI3/i-PrSH (entries 15 and 16, Table 3).
Ster eoch em istr y. To know the stereochemistry in
formation of substituted δ-lactones, we synthesized the
2-, 3-, and 4-methyl-5-oxoalkanals and examined their
SmI2/i-PrSH promoted reactions (Scheme 3). Compounds
4a ,b, 5a , and 7a ,b were prepared via their hydrazone
derivatives according to the procedure used for 1h
(Scheme 1).13 Thus, the hydrazones of 3-pentanone and
propiophenone were alkylated with 4-bromo-1-butene,
followed by ozonolysis, to give the 4-methyl-5-oxoalde-
hydes 4a and 4b. The hydrazone of acetophenone was
alkylated with 2-(2-iodopropyl)-1,3-dioxolane, followed by
acid-catalyzed hydrolysis, to give 3-methyl-5-oxo-5-phe-
nylpentanal (5a ). The cyclic compounds 7a and 7b were
similarly prepared from the hydrazone of cyclohexanone
and 4-tert-butylcyclohexanone via alkylation with 2-(2-
iodoethyl)-1,3-dioxolane and hydrolysis.
The SmI2/i-PrSH-catalyzed reactions of substituted
oxoalkanals occurred in a highly stereoselective manner.
Lactones 8a ,b,19,20 derived from 4-methyl-5-oxopentanals
4a ,b, had a cis configuration as indicated by a small
coupling constant (3 Hz) between H-4 and H-5. Treat-
ment of 3-methyl-5-oxo-5-phenylpentanal (5a ) with SmI2/
i-PrSH at 25 °C in THF solution gave lactone 9a as a
mixture of trans and cis isomers (77:23).21 The trans/cis
isomeric ratio was increased to 94:6 by performing the
When the reaction of 1a was conducted in the media
containing both SmI2 and SmI3, the formation of lactone
2a promoted by SmI2 dominated over the formation of
thioenol ether 3a promoted by SmI3 (entries 4 and 5,
Table 3). The reactions of 5-oxotridecanal (1e) afforded
lactone 2e by the catalysis of SmI2/i-PrSH (entry 14,
(18) Condensation of carbonyl compounds with mercaptans has been
achieved by the promotion of TiCl4/Et3N to give thioenol ethers. See
(a) Mukaiyama, T.; Saigo, K. Chem. Lett. 1973, 479. There is no
previous report on the formation of thioenol ethers by using SmI3 as
the promoter. In our preliminary report (ref 10), we wrongly assigned
the structures of 3a and 3e as isopropyl thioesters of 5-phenylpent-
4-enoic acid and tridec-4-enoic acid.
(19) (a) Kobayashi, Y.; Kitano, Y.; Takeda, Y.; Sato, F. Tetrahedron
Lett. 1986, 27, 2937. (b) Fereira, J . T. B.; Marques, J . A.; Marino, J . P.
Tetrahedron: Asymmetry 1994, 5, 641.
(20) Oshima, M.; Yamazaki, H.; Shimizu, I.; Nisar, M.; Tsuji, J . J .
Am. Chem. Soc. 1989, 111, 6280.

Synthesis of δ-Lactones from 5-Oxoalkanals
J . Org. Chem., Vol. 66, No. 25, 2001 8577
reaction at 0 °C. The trans lactone showed an NOE
correlation between Me-3 and H-5, whereas the cis
isomer was devoid of this effect. The SmI2/i-PrSH-
catalyzed reactions of 2-(3-oxopropyl)cyclohexanones 7a ,b
at 25 °C afforded 1-oxa-2-decalones 11a ,b in preponder-
ance of the 9,10-trans isomers.22,23 The trans decalones
had H-9 and H-10 on axial positions as characterized by
the ddd splitting pattern (J ) 10, 10, 4 Hz) of H-9 in the
1H NMR spectra.
in obtaining long-chain aliphatic precursors with chiral
carbinyl centers. A general approach to δ-alkyl-δ-lactones
utilizes the natural source of chiral alcohols, which are
elaborated (often in a lengthy sequence) to reach the
target molecules. For example,25a (S)-lactate and (R)-â-
hydroxyisobutyrate have been used to synthesize a sex
pheromone, (2S,5R)-2-hexanolide (10), in a ten-step
sequence. Chemical resolution of alcohols, by derivati-
zation and chromatographic separation, has provided an
alternative source of optically active 5-hydroxy-6-hexa-
decynenitrile,26 which is further elaborated to a phero-
mone of Oriental hornet (Vespa orientalis), (R)-5-hexa-
decanolide (2j). Although asymmetric reduction27 of
phenones and the ketones with adjuvant groups (e.g.,
R-methoxyketones and â-ketoesters) has advanced in this
decade, the highly enantioselective reduction of unsub-
stituted long-chain aliphatic ketones remains a challeng-
ing task.28 Microbial reduction (e.g., using bakers’ yeast)29
has shown some success in this aspect, but it is still
limited by low yielding and substrate specificity.
An inseparable mixture (1:1) of (R)-3-methyl-5-oxo-
hexanal [(R)-5b] and (R)-2-methyl-5-oxohexanal [(R)-6]
was prepared from (R)-3-methylcyclopentanone by a
three-step sequence similar to that for 1b (Scheme 1).
Thus, the addition reaction with MeMgCl, followed by
acid-catalyzed dehydration afforded a mixture of 1,3-
dimethylcyclopentene and 1,4-dimethylcyclopentene, which
was subjected to ozonolysis to give (R)-5b and (R)-6.
Treatment of the mixture of (R)-5b and (R)-6 (1:1) with
SmI2 (50 mol %) and i-PrSH (40 mol %) at 0 °C gave a
mixture of lactones (3S,5S)-9b and (2R,5S)-10 (1:1)
1
according to the H NMR analysis. The analytic samples
As to the samarium ion catalyzed reactions, we syn-
thesized many optically active δ-lactones via three
routes: (i) using chiral 5-oxoalkanals such as (S)-6, (ii)
using stoichiometric amount of chiral alcohols to react
with 5-oxoalkanals, and (iii) using catalytic amount of
chiral mercaptan to promote the conversion of 5-oxoal-
kanals. All three methods showed a common feature of
remote control to establish the chirality of carbinyl center
at C-5.
of lactones (3S,5S)-9b and (2R,5S)-10 were isolated by
HPLC, and their optical rotations were in agreement with
the reported values.24,25 The enantiomer of lactone (2R,5S)-
10 is a pheromone of carpenter bee (Xylocopa hirsutis-
sima).25
The stereochemical outcomes can be interpreted by
comparisons of the transition states C versus D and E
versus F . Transition state C, giving cis-8a ,b, trans-9a ,b,
and cis-10 is energetically favored due to the equatorial
dispositions of substituents (R2, R3, and R4), whereas the
alternative transition state D exerts steric repulsions due
to the axially oriented substituents. Transition state E,
giving trans-11a ,b, having hydride attack the cyclohex-
anone moiety from the axial direction is superior to an
equatorial attack in the transition state F . Many previous
studies support that axial H- delivery to cyclohexanones
is a kinetically favored process.3d Under such circum-
stances, product development control also favors forma-
tion of the more stable equatorial alcohol (as shown in
E). The stereoselectivities are in agreement with the
previous findings3d,7c of the related intermolecular Tish-
chenko reactions.
To prepare (S)-2-methyl-5-oxohexanal (6), propional-
dehyde was condensed with (S)-1-amino-2-(methoxy-
methyl)pyrrolidine (SAMP)30 to give a chiral hydrazone
(eq 2). Alkylation of such hydrazone with 4-iodo-2-methyl-
1-butene, followed by ozonolysis, thus occurred in a highly
stereoselective fashion to give (S)-6. Treatment of (S)-6
with SmI2 (50 mol %) and i-PrSH (40 mol %) afforded
(2S,5R)-2-methylhexanolide (10) exclusively. The melting
point (40-42 °C) and optical rotation ([R]D +63.5) were
in agreement with the values reported for the natural
product.25 The stereochemistry was consistent with the
mirror image of transition state C (Figure 3), in which
R ) R2 ) Me and R3 ) R4 ) H. The preferable equatorial
Syn th esis of op tica lly Active δ-La cton es. For the
synthesis of optically active δ-lactones, many methods
rely on obtaining chiral 5-hydroxyalkanoic acids or
derivatives as the requisite starting materials. The
asymmetric synthesis of δ-alkyl-δ-lactones, as those
found in nature as sex pheromones, has extra difficulties
(21) Barbero, A.; Blakemore, D. C.; Fleming, I.; Wesley, R. N. J .
Chem. Soc., Perkin Trans. 1 1997, 1329.
(22) (a) Forzato, C.; Nitti, P.; Pitacco, G.; Valentin, E. Tetrahedron:
Asymmetry 1999, 10, 1243. (b) Griffiths, D. V.; Wilcox, G. J . Chem.
Soc., Perkin Trans. 2 1988, 431. (c) Chandrasekhar, S.; Venkatesan,
V. J . Chem. Research (M), 1995, 1137. It has been reported (ref 22c)
that 2-(3-oxopropyl)cyclohexanone (7a ) underwent an intramolecular
Cannizzaro reaction in boiling NaOH solution (3 M) to give 3-(2-
hydroxycyclohexyl)propionic acid, which was subjected to lactonization
on treatment with concentrated HCl to give exclusively the trans
isomer of 11a (59%), based on an analysis of the 1H NMR spectrum
(90 MHz). In our hand, the two-step reaction afforded a trans/cis
mixture of 11a in a ratio of 91:9 based on an analysis of the 1H NMR
spectrum (300 MHz).
(26) Pirkle, W. H.; Adams, P. E. J . Org. Chem. 1979, 44, 2169.
(27) (a) Nishizawa, M.; Noyori, R. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 8, pp 159-182. (b) Singh, V. K. Synthesis 1992, 605. (c)
Downham, R.; Edwards, P. J .; Entwistle, D. A.; Hughes, A. B.; Kim,
K. S.; Ley, S. V. Tetrahedron: Asymmetry 1995, 6, 2403.
(28) (a) Imai, T.; Tamura, T.; Yamamura, A.; Sato, T.; Wollmann,
T. A.; Kennedy, R. M.; Masamune, S. J . Am. Chem. Soc. 1986, 108,
7402. (b) Brown, H. C.; Ramachandran, P. V. J . Org. Chem. 1989, 54,
4504.
(23) Edward, J . T.; Cooke, E.; Paradellis, T. C. Can. J . Chem. 1982,
60, 2546.
(24) Carroll, F. J .; Meck, R. Synth. Commun. 1971, 169. Carroll, F.
J .; Meck, R. J . Org. Chem. 1974, 39, 3890.
(25) (a) Mori, K.; Senda, S. Tetrahedron 1985, 41, 541. (b) Katsuki,
T.; Yamaguchi, M. Tetrahedron Lett. 1987, 28, 651. (c) Schink, H. E.;
Baeckvall, J .-E. J . Org. Chem. 1992, 57, 1588.
(29) (a) Utake, M.; Watabu, H.; Takeda, A. J . Org. Chem. 1987, 52,
4363. (b) Haase, B.; Schneider, M. P. Tetrahedron: Asymmetry 1993;
4, 1017.
(30) (a) Enders, D.; Kipphardt, H.; Fey, P. Org. Synth. 1987, 65,
183. (b) Enders, D.; Bockstiegel, B. Synthesis 1989, 7, 493.

8578 J . Org. Chem., Vol. 66, No. 25, 2001
Hsu and Fang
than 84%. It appeared that (-)-menthol with (R)-chirality
at the carbinyl center directed the (S)-chirality in hy-
droxyester 12a , whereas hydroxyester 12a with (S)-
chirality guided the (5′R)-chirality in diester 13a .
By the promotion of SmI2, oxopentanal 1a reacted with
(-)-8-phenylmenthol to give hydroxyester 12b (48%
yield), which was subsequently converted to lactone 2a
with 72% ee in favor of the (S)-enantiomer. The reaction
of 1a with (+)-neomenthol gave a low yield (4%) of
hydroxyester 12c with decreasing stereoselectivity as
deduced by its conversion to lactone 2a of 21% ee (entry
3, Table 4). To avoid the complication of pinacolic
coupling reactions, oxopentanal 1a was treated with SmI3
(20 mol %) and (-)-menthol (100 mol %) in refluxing THF
for 1 h (entry 4, Table 4). The crude product mixture was
subsequently treated with trifluoroacetic acid in CH2Cl2
to give lactone 2a (65% overall yield) with 78% ee in favor
of the (S)-enantiomer.
The SmI2-promoted reaction of 5-oxotridecanal (1e)
with (-)-menthol afforded hydroxyester 12e (51%), di-
ester 13e (20%), pinacol 14e (20%), and lactone 2e (9%).
The lactone 2e obtained directly from this reaction had
32% ee in favor of the (R)-enantiomer, whereas hydroxy-
ester 12e was saponified and subjected to cyclization to
give lactone 2e with 72% ee in favor of the (R)-enantio-
mer.32 When oxoalkanal 1e was heated with (-)-menthol
(100 mol %) and SmI3 in refluxing THF, lactone 2e (31%
ee) was obtained after the subsequent treatment with
CF3CO2H (entry 6, Table 4).
F igu r e 3. Transition states in the SmI2/i-PrSH promoted
reactions of substituted 5-oxoalkanals 4a -7b. Transition state
C having equatorial substituents is favored over transition
state D having axial substituents. Transition state E with
hydride transfer to the axial positions of cyclohexanones is
favored over transition state F with hydride transfer to the
equatorial positions of cyclohexanones.
orientation of R2 group at C-2 determined the newly
generated stereocenter at C-5 in a sense of remote
control.
As shown in Table 4, the reaction of oxopentanal 1a
with (-)-menthol (110 mol %) was promoted by SmI2 (100
mol %) to give the desired 5-hydroxy ester 12a (61%),
along with diester 13a (31%) and pinacol 14a (8%). The
As we have demonstrated that oxoalkanals 1a -i could
be converted directly to δ-lactones 2a -i by the synergistic
catalysis of SmI2 and mercaptan, we also wished to
investigate whether the related asymmetric reactions
could be achieved in the presence of chiral additives?
Using the SmI2/i-PrSH-promoted reaction of 5-oxotride-
canal (1e) as a model, several additives were examined.
The reaction of 1e with SmI2 (50 mol %), i-PrSH (40 mol
%), and (S)-1,1-bi-2-naphthol (50 mol %) at room tem-
perature gave lactone 2e (42% yield) with 15% ee in favor
of the (R)-enantiomer. No asymmetric induction was
found with the chiral additives of (-)-sparteine, bispho-
sphoramide 1533, or salen 16.34 In the presence of (R)-
hydroxyester 12a was saponified and treated with acid
to give lactone 2a with predominance of the (S)-enan-
tiomer (84% ee) as determined by HPLC analysis on a
Chiralcel OB column.31 The diastereomeric excess of
hydroxyester 12a was deduced to be 84% by analogy to
that of lactone 2a , although our primary examination of
12a with 300 MHz NMR or HPLC analyses could not tell
the difference of two diastereomers. Diester 13a could
be derived either by transesterification between two
molecules of hydroxyester 12a , or by the second acetal-
ization-Tishcheko reaction of oxopentanal 1a with hy-
droxyester 12a . A clue was found by the following
experiment. In the presence of SmI2, oxopentanal 1a (84%
ee) was treated with an equimolar amount of hydroxyes-
ter 12a in THF at room temperature for 30 min to give
a mixture of 12a (45%), 13a (35%), and 2a (20%). The
mixture was then treated with trifluoroacetic acid in CH2-
Cl2 to give lactone 2a (87% overall yield) with 72% ee in
favor of the (S)-enantiomer. The ee value should keep
unchanged if diester 13a were formed by transesterifi-
cation of two molecules of hydroxyester 12a . As the ee
values varied, oxopentanal 1a and hydroxyester 12a
likely underwent the tandem acetalization-Tishchenko
reaction to give 13a with a predominance of the (5S,5′R)
isomer. The subsequent lactonization would give both (S)-
and (R)-enantiomers of 2a , causing the ee value lower
methyl p-tolylsulfoxide or (S)-proline, a reductive cou-
pling reaction of 1e was effected by SmI2 to give pinacol
14e, instead of the desired lactone 2e.
As we have shown that chiral alcohols did induce the
reactions of 5-oxoalkanals to give optically enriched
5-hydroxyesters and δ-lactones, we wished to devise the
asymmetric catalytic reactions of 5-oxoalkanals by using
chiral mercaptans to facilitate the formation of chiral
δ-lactones. There are only a few chiral mercaptans
available in nature; we thus prepared a series of chiral
(32) (a) Utaka, M.; Watabu, H.; Takeda, A. Chem. Lett. 1985, 1475.
(b) Godnon, R.; Grogan, G.; Levitt, M. S.; Roberts, S. M.; Wan, P. W.
H.; Willetts, A. J . J . Chem. Soc., Perkin Trans. 1 1994, 2537.
(33) Yang, W.-B.; Fang, J .-M. J . Org. Chem. 1998, 63, 1356.
(34) (a) Pozzi, G.; Cavazzini, M.; Cinato, F.; Montanari, F.; Quici,
S. Eur. J . Org. Chem. 1999, 1947, 7.
(31) (a) Bolm, C.; Schlinggloff, G.; Weickhardt, K. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 1848. (b) Downham, R.; Edwards, P. J .;
Entwistle, D. A.; Hughes, A. B.; Kim, K. S.; Ley, S. V. Tetrahedron:
Asymmetry 1995, 6, 2403.

Synthesis of δ-Lactones from 5-Oxoalkanals
J . Org. Chem., Vol. 66, No. 25, 2001 8579
Ta ble 4. Sa m a r iu m Ion P r om oted Rea ction s of 5-Oxoa lk a n a ls w ith Ch ir a l Alcoh ols (Step i), a n d th e Su bsequ en t
La cton iza tion (Step ii)
promoter
(mol %)
step i
(yield, %)
step ii
(yield, %)
configurationa
(% ee)
entry
substrate
R*OH
1
2
3
4
5
6
1a
1a
1a
1a
1e
1e
(-)-menthol
SmI2 (100)
SmI2 (100)
SmI2 (100)
SmI3 (20)
SmI2 (100)
SmI3 (20)
12a (61)b
12b (48)c
12c (4)d
2a (65)
2a (77)
2a (70)
2a (65)
2e (69)
2e (58)
S (84)
S (72)
R (21)
S (78)
R (72)
R (31)
(-)-8-Ph-menthol
(+)-neomenthol
(-)-menthol
e
-
(-)-menthol
(-)-menthol
12e (51)f
e
-
a
b
The configuration of the major enantiomers of lactonic products. This reaction also gave diester 13a (31%) and pinacol 14a (8%).
c This reaction also gave lactone 2a (21%), diester 13b (25%) and pinacol 14a (6%). This reaction also gave lactone 2a (14%), diester 13c
(52%), and pinacol 14a (29%). e The reaction mixture was directly treated with CF3CO2H in CH2Cl2 to give lactone 2a (or 2e). f This
reaction also gave lactone 2b (9% yield, 32% ee), diester 13e (20%) and pinacol 14e (20%).
d
mercaptans 17-38 by derivatization of terpene alcohols,
sterols, R-amino acids, and â-amino alcohols (Scheme 4).
We also utilized the reaction of 5-oxotridecanal (1e) as a
model to study the effects of chiral mercaptans on the
enantioselective synthesis of δ-lactone 2e.
and thus improved the enantioselectivity in the reaction
with 1e. Indeed, the reaction occurred in higher enantio-
selectivities (38 and 44% ee) by using the camphor-type
mercaptans39 20 and 21 annexed with hydroxyl groups.
However, the reaction using the camphor-type mercap-
tans39 22-24 with neighboring alkoxy groups did not
show any improved enantioselectivity (12-22% ee). It
was noted that the isomeric mercaptans 22 and 24
showed the opposite enantiotopic preference in promoting
lactone formation, a phenomenon also observed in the
reactions promoted by menthol and neomenthol.
Derivatization of L-cysteine and (S)-proline gave the
chiral mercaptans 2540 and 26,41 of which the â-carbons
are chiral but the R-carbons are achiral. The enantiose-
lectivities in the SmI2 promoted reactions of 1e with
mercaptans 25 or 26 and SmI2 turn out to be low, giving
24 and 10% ee of lactone 2e. We found that the ephe-
drine-related mercaptans containing stereocenters at
both R- and â-carbons showed higher enantioselectivities
(up to 68% ee). The ephedrine-related mercaptans were
generally prepared via the ring-opening reactions of
aziridines with thio acids (Scheme 5).42 For example,
(1R,2S)-(-)-norephedrine underwent a Mitsunobu reac-
tion (DIAD, Ph3P, Et3N) to give an aziridine, which was
then treated with thioacetic acid to give mercaptan 30
after an in situ migration of the acetyl group. The
chirality at C-1 was unchanged due to the double SN2
reactions.42 The structure of 30 was confirmed by an
X-ray diffraction analysis. Mercaptan 3342 was similarly
prepared form (1R,2S)-(-)-ephedrinium chloride, whereas
mercaptan 36 was prepared from (1R,2R)-(-)-pseu-
doephedrine. Mercaptans 37 and 38 were prepared from
(1S,2R)-(+)-2-amino-1,2-diphenylethanol.
The tosylate ester of (-)-menthol was treated with
potassium thioacetate (AcSK), followed by reduction with
DIBAL to give neomenthanethiol 17,35 a reminiscent of
neomenthol. In the presence of SmI2 (40 mol %) and
mercaptan 17 (50 mol %), 5-oxotridecanal was converted
to lactone 2e (37% yield) in favor of the (S)-enantiomer
(18% ee). The ee value was determined by HPLC analysis
on a Chiracel OB column, and the absolute configuration
of the preferable enantiomer was determined by com-
parison with the optical rotation of the authentic sample
reported in the literature.32 Since menthol exerted a
higher asymmetric induction than neomenthol in the
reaction with 5-oxoalkanal (compared entries 1 and 3 in
Table 4), menthanethiol might be a better promoter for
the enantioselective reaction of 5-oxoalkanal. However,
attempts to prepare pure menthanethiol failed. The
tosylate ester of (-)-menthol, having the tosyloxy group
on the axial position, underwent elimination on treat-
ment with AcSK, instead of the desired SN2 reaction.
Treatment of the dithiolane derivative of (-)-menthone
with BuLi gave a mixture of menthanethiol and neomen-
thanethiol,36 which could not be separated by chroma-
tography. The reaction of 1e with this mixture and SmI2
gave 80% yield of 2e with 33% ee in favor of the
(S)-enantiomer. One might argue whether using enan-
tiomerically pure menthanethiol as the promoter would
enhance the enantioselective reaction?
When the pinane-type mercaptan 1837 and the choles-
terol-type mercaptan 1938 were used together with SmI2,
the reactions of 1e gave lactone 2e in 20 and 14% ee,
respectively, in favor of the (R)-enantiomer. We specu-
lated that an annexed group at the neighboring position
of the thiol might help in chelation with samarium ion,
By comparison of the reactions of 1e promoted by SmI2
and mercaptans 27-38, it appeared that the chirality of
the lactonic product 2e was dictated by the chirality at
(39) (a) Goodridge, R. J .; Hambley, T. W.; Haynes, R. K.; Ridley, D.
D. J . Org. Chem. 1988, 53, 2881. (b) Lee, D.-S.; Huang, S.-M.; Lai,
M.-C.; Chu, H.-Y.; Tang, T.-K. Org. Prep. Proc. Int. 1993, 25, 673. (c)
Yang, T.-K.; Chu, H.-Y.; Lee, D.-S.; J iang, Y.-Z.; Chou, T.-S. Tetrahe-
dron Lett. 1996, 37, 4537.
(40) (a) Lesk, A.; Nudelman, A. Synth. Commun. 1999, 29, 1405.
(b) Uhrig, R. K.; Picard, M. A.; Beyreuther, K.; Wiessler, M. Carbohydr.
Res. 2000, 325, 72.
(35) Taj, S. S.; Soman, R. Tetrahedron: Asymmetry 1994, 5, 1513.
Mikolajczyk, M.; Perlikowska, W.; Omelanczuk, J . Synthesis 1987,
1009.
(36) Wilson, S. R.; Georgiadis, G. M.; Khatri, H. N.; Bartmess, J . E.
J . Am. Chem. Soc. 1980, 102, 3577.
(37) Aggarwal, V. K.; Kalomiri, M.; Thomas, A. P. Tetrahedron:
Asymmetry 1994, 5, 723.
(38) (a) Volante, R. P. Tetrahedron Lett. 1981, 22, 3119. (b) Hojo,
K.; Yoshino, H.; Mukaiyama, T. Chem. Lett. 1977, 437.
(41) Gibson, C. L. Tetrahedron: Asymmetry 1999, 10, 1551.
(42) (a) Poelert, M. A.; Hof, R. P.; Peper, N. C. M. W.; Kellogg, R.
M. Heterocycles 1994, 37, 461. (b) Kang, J .; Kim, D. S.; Kim, J . I. Synlett
1994, 842.

8580 J . Org. Chem., Vol. 66, No. 25, 2001
Hsu and Fang
Ta ble 5. Rea ction s of 5-Oxoa lk a n a ls P r om oted by Sm I2
(50 m ol %) a n d Mer ca p ta n 30 (40 m ol %) a t 0 °C in THF
Solu tion
Sch em e 4 En a n tioselective F or m a tion of
δ-La cton e 2e by Tr ea tm en t of 1e w ith Sm I2 a n d
Ch ir a l Mer ca p ta n s in THF a t 0 °C
product
% ee
entry substrate
R
(yield, %) (configuration)a [R]D
1
2
3
4
5
6
7
8
9
1a
1b
1d
1e
1f
1g
1h
1j
Ph
Me
2a (83)
2b (84)
2d (80)
2e (75)
2f (73)
2g (74)
2h (73)
2j (75)
49 (S)
47 (R)
40 (R)
68 (R)
48b
-19.1
+14.8
+18.6
+22.0
+7.7
-11.3
-12.0
+27.9
+16.0
+10.2
-9.4
n-hexyl
n-octyl
benzyl
c-hexyl
t-Bu
43b
44b
n-undecyl
74 (R)
1k
1l
1m
n-tetradecyl 2k (76)
n-octadecyl 2l (84)
o-MeOC6H4 2m (74)
63b
10
11
65b
49b
a
The absolute configuration of major enantiomer. The ee value
was determined by HPLC analysis on chiral columns. The absolute
configuration of major enantiomer was determined by comparison
b
of optical rotation with that reported in the literature. The
absolute configuration of major enantiomer was not determined.
the enanatiomeric preference of lactone 2e. The reactions
using mercaptans with the neighboring acetamido group
appeared to give lactone 2a in a higher ee value (com-
pared mercaptan 30 with 29 and 33). Among the exam-
ined examples, we obtained a 75% yield of (R)-enriched
lactone 2e (68% ee) by treatment of 5-oxotridecanal with
SmI2 (50 mol %) and mercaptan 30 (40 mol %) in THF at
0 °C for 1 h.
Mercaptan 30 was also applied to the enantioselective
synthesis of other δ-lactones (Table 5). A series of
optically enriched δ-lactones 2a -m was obtained by
treatments of 5-oxoalkanals 1a -m with SmI2 (50 mol %)
and mercaptan 30 (40 mol %). All the reactions occurred
in a consistent enantiotopic preference. The observed
enantioselectivity was accounted on the intramolecular
hydride transfer to the 5-keto group, similar to the
intermediate A depicted in Figure 2. Thus, the major
5-phenyl lactones 1a and 1m have the (S)-configuration
via the si-face hydride transfer, whereas the major
lactones 1b, 1d , 1e, and 1j with primary alkyl substit-
uents have the (R)-configuration via the re-face hydride
transfer. Accordingly, a hornet pheromone (R)-5-hexa-
decanolide43 (74% ee) was synthesized in 75% yield from
5-oxohexadecanal (entry 8, Table 5). The major enantio-
mers of 2a , 2f, and 2m having phenyl substituents tended
to be less retained in Chiralcel OB and OB-H columns
than their corresponding minor enantiomers. On the
other hand, the major enantiomers of 2b, 2d , 2e, and
2g-l with alkyl substituents had longer retetion times
on the chiral columns. It was noted that lactones 2a and
2m were formed in the same enantioselectivity (entries
1 and 11, Table 5), even though the ortho methoxy group
of 1m might involve in the coordination with samarium
ion.
a
Referring to the yield and ee value of the lactonic product 2e
obtained by using the individual mercaptan promoter.
Sch em e 5. P r ep a r a tion of Ep h ed r in e-Rela ted
Mer ca p ta n s via th e Azir id in e In ter m ed ia tes
Con clu sion . We have demonstrated a general method
for conversion of various 5-oxoalkanals to substituted
δ-lactones and 1-oxa-2-decalones by the synergistic ca-
the R-carbons of mercaptans. For example, the mercap-
tans 30, 33, and 36 with (R)-chirality at the R-carbons
induced the (R)-enriched lactone 2a , whereas the mer-
captans 37 and 38 with (S)-chirality at the R-carbons
promoted the formation of (S)-enriched 2e. The chirality
at the â-carbons of mercaptans hardly had influence on
(43) (a) Taberm D. F.; Deker, P.; Gaul, M. D. J . Am. Chem. Soc.
1987, 109, 7488. (b) Paolucci, C.; Mazzini, C.; Fava, A. J . Org. Chem.
1995, 60, 169. (c) Ottolina, G.; Carrea, G.; Colonna, S.; Ruckemann,
A. Tetrahedron: Asymmetry 1996, 7, 1123. (d) Kayser, M. M.; Chen,
G.; Stewart, J . D. J . Org. Chem. 1998, 63, 7103.

Synthesis of δ-Lactones from 5-Oxoalkanals
J . Org. Chem., Vol. 66, No. 25, 2001 8581
The mixture was extracted with Et2O (3 ×). The ethereal phase
was combined, washed with brine (3×), dried (Na2SO4), and
concentrated to give a crude addition product.
The crude product was dissolved into benzene (30 mL), and
p-TsOH (20 mg) was added. The mixture was heated at reflux
for 8 h while the generated water was removed azeotropically
via Dean-Stark equipment. The mixture was concentrated
and purified on a silica gel column by elution with hexane to
give alkene (4.0 g, 93%).
talysis of samarium ion and mercaptan. This transforma-
tion involves a sequential acetalization, Tishchenko
reaction, and lactonization in a one-pot procedure. The
deliberative use of mercaptan is advantageous to facili-
tate the catalytic cycle (Figure 2). For example, 5-oxo-5-
pentanal (1a ) was converted to 5-phenylpentanolide (2a )
in a quantitative yield by using 20 mol % of SmI2 and 10
mol % of i-PrSH as the promoters (entry 4, Table 1). The
active catalyst may be considered as RS-SmI2. Thus,
SmI2/RSSR and SmI3/PhSLi can replace SmI2/i-PrSH to
promote the transformation of 5-oxoalkanals to their
corresponding δ-lactones (Table 2). This approach to
δ-lactones adapts the atom economy of intramolecular
redox process, unlike the conventional methods requiring
excess amounts of oxidizing and reducing agents to
convert 5-oxoalkanals into 5-hydroxyalkanoic acid for the
subsequent lactonization.
The SmI2/i-PrSH-promoted reactions of 2-methyl-,
3-methyl-, and 4-methyl-5-oxoalkanals occurred in a high
stereoselective manner. The stereochemistry can be
explained by the favorable transition states C and E
(Figure 3). We have also utilized the remote control of
such samarium-ion-catalyzed reactions to synthesize
optically active δ-lactones via three routes, by using
chiral substituted-5-oxoaldehydes (eq 2), stoichiometric
amount of chiral alcohols (Table 4), and catalytic amount
of chiral mercaptan (Scheme 4). Thus, enantiomerically
pure (2S,5R)-2-methylhexanolide (10), (S)-enriched 5-phe-
nylpentanolide (2a , 78% ee), and (R)-enriched hexade-
canolide (2j, 74% ee) were synthesized from their corre-
sponding 5-oxoalkanals practically in one-pot procedures.
The synthesis of insect pheromones 2j and 10 also
demonstrates a new protocol for asymmetric reduction of
long-chain aliphatic ketones.
The alkene was dissolved into CH2Cl2 (40 mL), and a stream
of ozone passed through the solution at -78 °C until the light
blue color of ozone persisted. The solution was purged with
N2, and stirred at room temperature for 10 min. The mixture
was stirred with Me2S (5 mL) for 5 h, followed by addition of
Ph3P in portions (4 × 1 g). The mixture was stirred for 5 h,
concentrated, and purified on a silica gel column by elution
with EtOAc/hexane (1:4) to give 5-oxo-5-phenylpentanal (1a ,
4.3 g, 88%).
Meth od B.13 A mixture of pinacolone (3.0 g, 30 mmol) and
1,1-dimethylhydrazine (3.6 g, 60 mmol) was heated at reflux
for 10 h. Distillation using Kugelrohr apparatus gave hydra-
zone product (3.80 g, 89%).
To a solution of the hydrazone product (1.0 g, 7.2 mmol) in
THF (10 mL) was added dropwise BuLi (6.0 mL of 1 M solution
in hexane) at 0 °C. The mixture was stirred for 30 min, and
4-bromo-1-butene (1.29 g, 9.6 mmol) was added dropwise. The
mixture was stirred at room temperature for 10 h, quenched
by addition of water (5 mL), and extracted with EtOAc (2×).
The organic phase was concentrated, after which acetone (20
mL) and acidic resin (Amberlyte IR 120, ca. 2 g) were added.
The mixture was stirred for 9 h, concentrated, and chromato-
graphed on a silica gel column by elution with EtOAc/hexane
(5:95) to give alkene product (762 mg, 69%). Ozonation by a
procedure similar to that for 1a gave 6,6-dimethyl-5-oxohep-
tanal (1h , 241 mg, 97%).
Meth od C.14 Isobutyraldehyde (2.37 g, 32.9 mmol) was
added to a mixture of Me3SiCl (5.23 g, 49.3 mmol) and Et3N
(6.6 g, 65.8 mmol) in DMF (20 mL). The mixture was heated
at reflux for 4 h, cooled, diluted with hexane (40 mL), and
washed with cold aqueous NaHCO3 solution (3 ×). The organic
phase was dried (Na2SO4) and distilled at 70 °C to give the
corresponding silyl enol ether (4.10 g, 87%).
Exp er im en ta l Section
Gen er a l. All reactions requiring anhydrous conditions were
conducted in flame-dried apparatus under an atmosphere of
argon or nitrogen. Syringes and needles for the transfer of
reagents were dried at 100 °C and allowed to cool in a
desiccator over P2O5 before use. Ethers were distilled from
sodium benzophenone ketyl; (chlorinated) hydrocarbons, and
amines from CaH2. Reactions were monitored by TLC pre-
A mixture of the silyl enol ether (1.02 g, 7.1 mmol) and
methyl vinyl ketone (840 mg, 12 mmol) was added to a
suspension of Al2O3 (5.00 g) and ZnCl2 (1.35 g) in Et2O (30
mL) at 0 °C. The mixture was stirred for 30 min, after which
BF3‚OEt2 (1.5 mL) was added. The mixture was stirred at 0
°C for 4 h, and quenched by addition of water (1 mL).
Chromatography on a short silica gel column by elution with
EtOAc/hexane (1:4) gave 2,2-dimethyl-5-oxohexanal (1i, 992
mg, 99%).
R ep r esen t a t ive P r oced u r e for Tr a n sfor m a t ion of
5-Oxoa lk a n a ls t o δ-La ct on es (Sch em es 2, 3 a n d 4).
Meth od D. Under an atmosphere of argon, i-PrSH (30 mg,
0.04 mL, 0.4 mmol) was added to a deep blue SmI2 (0.5 mmol)
solution freshly prepared from samarium (80 mg) and 1,2-
diiodoethane (140 mg) in THF (15 mL). The mixture was
stirred for 5 min at room temperature, and a THF solution (5
mL) of 5-oxo-5-phenylpentanal (1a , 176 mg, 1.0 mmol) was
added dropwise. The mixture was stirred for 1 h, and then
filtered through a short silica gel column by elution with
EtOAc/hexane (1:1). The filtrate was concentrated by rotary
evaporation to give a practically pure lactone 2a (174 mg, 99%).
Meth od E. A slightly modified procedure was conducted
by premixing an aliquot of SmI2/i-PrSH (ca. 3 mol % in 1 mL
of THF) with the THF solution (5 mL) of 5-oxohexanal (1b,
114 mg, 1.0 mmol) in an oven-dried syringe. The resulting
yellow solution, an indicator of trivalent samarium ion, was
then added dropwise to the original SmI2/i-PrSH (50/40 mol
%) solution in THF (14 mL). Accordingly, the desired product
5-hexanolide (2b, 133 mg) was also obtained in an excellent
yield (99%).
coated with
a 0.25 mm layer of silica gel containing a
fluorescent indicator (Merck Art. 5544). Column chromatog-
raphy was carried out on Kieselgel 60 (40-63 µm). HPLC was
performed on Lichrosorb Si 60 and Nucleosil 100 columns (25
cm × 1 cm i.d.) with particle size of 7 µm. Chiracel OB, OB-H,
and OD columns (25 cm × 0.46 cm i.d.) were used for analysis
of enantiomeric excesses. Refractive index or UV detectors
were used. Melting points are uncorrected. Optical rotations
were measured on a digital polarimeter with a cuvette of 10
cm length. [R]D values are given in 10-1 deg cm2 g-1. Chemical
shifts of 1H and 13C NMR spectra are reported relative to
CHCl3 [δH 7.24, δC (central line of t) 77.0]. Coupling constants
(J ) are given in hertz (Hz). Distortionless enhancement
polarization transfer (DEPT) spectra were taken to determine
the types of carbon signals. The X-ray diffraction data were
collected on a CAD-4 diffractometer. The analyses were carried
out on a microVAX III computer using NRC VAX software.
Representative Procedure for the Preparation of 5-Oxoal-
kanals (Scheme 1).
Meth od A.12 Under an atmosphere of N2, an ethereal
solution (20 mL) of Grignard reagent was prepared from
bromobenzene (6.0 g, 38 mmol) and Mg (960 mg, 40 mmol) by
the activation of I2 (small amount). A solution of cyclopen-
tanone (2.5 g, 30 mmol) in Et2O (10 mL) was added dropwise
at room temperature (25 °C). The mixture was stirred for 2 h
and then poured into an ice-cold 1 N HCl solution (60 mL).
By a similar procedure, chiral mercaptans were used to
replace i-PrSH in the enantioselective reactions (Scheme 4 and
Table 5).

8582 J . Org. Chem., Vol. 66, No. 25, 2001
Hsu and Fang
Rep r esen ta tive P r oced u r e for th e Rea ction s of 5-Oxo-
a lk a n a ls w ith Ch ir a l Alcoh ols P r om oted by Sm I2 or Sm I3
(Ta ble 4). Meth od F . A solution of 5-oxo-5-phenylpentanal
(88 mg, 0.5 mmol) and (-)-menthol (79 mg, 0.5 mmol) in THF
(10 mL) was added to the freshly prepared SmI2 (5 mL of 0.1
M solution in THF). The mixture was stirred for 1 h at room
temperature, and filtered through a short silica gel column
by elution with EtOAc/hexane (1:1). The filtrate was concen-
trated to give a mixture of lactone 2a , hydroxyester 12a , and
0.23 mmol) at room temperature to give the title compound
2g (47 mg, 96%). Solid, mp 47-49 °C; HPLC (Chiralcel OD
column) tR(minor isomer)/tR(major isomer) ) 9.1 min/10.3 min,
eluent 5% i-PrOH in hexane, flow rate 1.3 mL/min (UV 225
nm). [R]29 ) -11.3 (c ) 1.0, CHCl3, 43% ee in favor of the
D
more retained enantiomer).
6,6-Dim eth yl-5-h ep ta n olid e (2h ).48 By a procedure simi-
lar to that for 2b (Method E), 6,6-dimethyl-5-oxoheptanal (1h ,
181 mg, 1.2 mmol) was treated with SmI2/i-PrSH (0.50 mmol/
0.34 mmol) at room temperature to give the title compound
2h (165 mg, 91%). HPLC (Chiralcel OB column) tR(minor
isomer)/tR(major isomer) ) 9.9 min/11.0 min, eluent 5% i-PrOH
1
diester 13a in a ratio of 61:31:8 as indicated by the H NMR
analysis. Hydroxyester 12a was further separated by chro-
matography with elution of EtOAc/hexane (1:9). Saponification
of 12a , followed by acidification, gave lactone 2a with 84% ee
in favor of the (S)-enantiomer as determined by HPLC analysis
on a Chiralcel OB column.
in hexane, flow rate 1.5 mL/min (UV 225 nm). [R]30 ) -12.0
D
(c ) 0.3, CHCl3, 44% ee in favor of the more retained
enantiomer).
2,2-Dim eth yl-5-h exa n olid e (2i).49 By a procedure similar
to that for 2b (Method E), 2,2-dimethyl-5-oxohexanal (1i, 58
mg, 0.41 mmol) was treated with SmI2/i-PrSH (0.17 mmol/
0.15 mmol) at room temperature to give the title compound
2i (46 mg, 80%).
Meth od G. A solution of SmI3 was prepared from Sm (150
mg, 1 mmol) and I2 (390 mg, 1.5 mmol) in THF (1.5 mL). An
aliquot of SmI3 solution (0.15 mL, 0.15 mmol) was taken, and
the reaction of 5-oxo-5-phenylpentanal (100 mg, 0.57 mmol)
and (-)-menthol (95 mg, 0.61 mmol) was conducted in reflux-
ing THF (10 mL) for 1 h. The crude product was treated with
trifluoroacetic acid (0.5 mL) in CH2Cl2 (10 mL) at 0 °C for 3 h
to give lactone 2a (65 mg, 65% yield) with 78% ee in favor of
the (S)-enantiomer.
5-Hexa d eca n olid e (2j).43 By a procedure similar to that
for 2b (Method E), 5-oxo-hexadecanal (1j, 51 mg, 0.20 mmol)
was treated with SmI2/i-PrSH (0.15 mmol/0.13 mmol) at room
temperature to give the title compound 2j (43 mg, 85%). Solid,
mp 39-40 °C; HPLC (Chiralcel OB-H column) tR(S)/tR(R) )
21.9 min/23.3 min, eluent 1.25% i-PrOH in hexane, flow rate
5-P h en yl-5-p en ta n olid e (2a ).31 Solid, mp 91-93 °C; HPLC
(Chiralcel OB column) tR(S)/tR(R) ) 13.4 min/15.9 min, eluent
0.5 mL/min (RI detector). [R]26 ) +27.9 (c ) 0.5, THF, 74%
10% i-PrOH in hexane, flow rate 2 mL/min (UV 254 nm). [R]26
D
D
ee in favor of the R-enantiomer).
) -19.1 (c ) 0.9, CHCl3, 49% ee in favor of the S-enantiomer).
5-Hexa n olid e (2b).44 HPLC (Chiralcel OB column) tR(S)/
tR(R) ) 11.0 min/14.3 min, eluent 10% i-PrOH in hexane, flow
5-Non a d eca n olid e (2k ). By a procedure similar to that for
2b (Method E), 5-oxononadecanal (1k , 110 mg, 0.37 mmol) was
treated with SmI2/i-PrSH (0.40 mmol/0.30 mmol) at room
temperature to give the title compound 2k (84 mg, 76%). Solid,
mp 49-51 °C; TLC [EtOAc/hexane (20:80)] Rf ) 0.40; IR (neat)
rate 2 mL/min (UV 225 nm). [R]29 ) +14.8 (c ) 0.3, CHCl3,
D
47% ee in favor of the R-enantiomer)
5-Hep ta n olid e (2c).45 By a procedure similar to that for
2b (Method E), 5-oxoheptanal (1c, 170 mg, 1.3 mmol) was
treated with SmI2/i-PrSH (0.5 mmol/0.4 mmol) at room tem-
perature to give the title compound 2c (155 mg, 91%).
5-Un d eca n olid e (2d ).29b By a procedure similar to that for
2b (Method E), 5-oxoundecanal (1d , 184 mg, 1.0 mmol) was
treated with SmI2/i-PrSH (0.5 mmol/0.4 mmol) at room tem-
perature to give the title compound 2d (182 mg, 99%). HPLC
(Chiralcel OB-H column) tR(S)/tR(R) ) 15.5 min/16.9 min,
eluent 5% i-PrOH in hexane, flow rate 1 mL/min (RI detector).
1
1725 cm-1; H NMR (CDCl3, 200 MHz) δ 0.85 (3 H, br t, J )
6.1 Hz), 1.23 (20 H, br s), 1.51-1.71 (4 H, m), 1.75-1.93(2 H,
m), 2.41-2.56 (2 H, m), 4.18-4.28 (1 H, m); 13C NMR (CDCl3,
50 MHz) δ 14.0 (CH3), 18.5 (CH2), 22.6 (CH2), 24.9 (CH2), 27.8
(CH2), 29.3 (CH2), 29.37 (CH2), 29.4 (CH2), 29.5 (CH2), 29.6
(CH2), 31.9 (CH2), 35.8 (CH2), 80.6 (CH), 171.9 (C). HR-FAB-
MS calcd for C19H37O2 (M+ + 1): 297.2794. Found: 297.2793.
HPLC (Chiralcel OB-H column) tR(minor isomer)/tR(major
isomer) ) 18.6 min/20.1 min, eluent 1.25% i-PrOH in hexane,
flow rate 0.8 mL/min (RI detector). [R]25 ) +16.0 (c ) 1.5,
[R]24 ) +18.6 (c ) 0.9, CHCl3, 40% ee in favor of the
D
D
CHCl3, 63% ee in favor of the more retained enantiomer).
5-Tr icosa n olid e (2l).50 By a procedure similar to that for
2b (Method E), 5-oxotricosanal (1l, 170 mg, 0.48 mmol) was
treated with SmI2/i-PrSH (0.30 mmol/0.25 mmol) at room
temperature to give the title compound 2l (146 mg, 86%). Solid,
mp 56-57 °C; HPLC (Chiralcel OB-H column) tR(minor
isomer)/tR(major isomer) ) 19.9 min/22.1 min, eluent 1.25%
R-enantiomer).
5-Tr id eca n olid e (2e).32 By a procedure similar to that for
2b (Method E), 5-oxotridecanal (1e, 220 mg, 1.0 mmol) was
treated with SmI2/i-PrSH (0.5 mmol/0.4 mmol) at room tem-
perature to give the title compound 2e (207 mg, 94%). Solid,
mp 42-43 °C; HPLC (Chiralcel OB-H column) tR(S)/tR(R) )
8.7 min/11.2 min, eluent 5% i-PrOH in hexane, flow rate 1.0
i-PrOH in hexane, flow rate 0.8 mL/min (RI detector). [R]25
mL/min (UV 225 nm or RI detector). [R]27 ) +22.0 (c ) 0.7,
D
D
) +10.2 (c ) 3.0, CHCl3, 65% ee in favor of the more retained
CHCl3, 68% ee in favor of the R-enantiomer).
enantiomer).
5-P h en yl-5-h exa n olid e (2f).46 By a procedure similar to
that for 2b (Method E), 5-oxo-6-phenylhexanal (1f, 97 mg, 0.5
mmol) was treated with SmI2/i-PrSH (0.25 mmol/0.23 mmol)
at room temperature to give the title compound 2f (96 mg,
99%). HPLC (Chiralcel OB column) tR(minor isomer)/tR(major
isomer) ) 12.0 min/13.3 min, eluent 10% i-PrOH in hexane,
flow rate 1 mL/min (UV 254 nm). [R]30D ) +7.7 (c ) 0.5, CHCl3,
48% ee in favor of the less retained enantiomer).
5-(2-Meth oxyp h en yl)-5-p en ta n olid e (2m ). By a proce-
dure similar to that for 2b (Method E), 5-(2-methoxyphenyl)-
5-oxopentanal (1m , 206 mg, 1.0 mmol) was treated with SmI2/
i-PrSH (0.50 mmol/0.40 mmol) at room temperature to give
the title compound 2m (176 mg, 85%). Solid, mp 79-81 °C;
TLC [EtOAc/hexane (50:50)] Rf ) 0.33; IR (neat) 1726 cm-1
;
1H NMR (CDCl3, 200 MHz) δ 1.70-1.86 (1 H, m), 1.89-1.98
(2 H, m), 2.14-2.20 (1 H, m), 2.49-2.74 (2 H, m), 3.87 (3 H,
s), 5.67 (1 H, dd, J ) 10.1 Hz, J ) 3.5 Hz), 6.83-7.00 (3 H,
m), 7.22-7.38 (2 H, m); 13C NMR (CDCl3, 50 MHz) δ 18.5
(CH3), 28.9 (CH2), 29.7 (CH2), 55.3 (CH3), 76.9 (CH), 110.3
(CH), 120.7 (CH), 126.4 (CH), 128.1 (C), 128.9 (CH), 155.6 (C),
171.8 (C). HR-FAB-MS calcd for C12H15O3 (M+ + 1): 207.1021.
Found: 207.1017. HPLC (Chiralcel OB column) tR(major
isomer)/tR(minor isomer) ) 10.9 min/13.5 min, eluent 20%
i-PrOH in hexane, flow rate 2 mL/min (254 nm). [R]24D ) -9.4
(c ) 1.5, CHCl3, 49% ee in favor of the less retained enantio-
mer).
5-Cycloh exyl-5-p en ta n olid e (2g).47 By a procedure simi-
lar to that for 2b (Method E), 5-oxo-5-cyclohexylpentanal (1g,
49 mg, 0.27 mmol) was treated with SmI2/i-PrSH (0.25 mmol/
(44) White, J . D.; Somers, T. C.; Reddy, G. N. J . Am. Chem. Soc.
1986, 108, 5352.
(45) (a) Soai, K.; Yokoyama, S.; Hayasaka, T.; Ebihara, K. Chem.
Lett. 1988, 843. (b) Sato, M.; Sugita, Y. A.; Kaneko, C. Tetrahedron:
Asymmetry 1992, 3, 1157.
(46) J ones, J . B. J . Org. Chem. 1979, 44, 2165.
(47) Otsubo, K.; Kawamura, K.; Inanaga, J .; Yamaguchi, M. Chem.
Lett. 1987, 1487.
(48) Garner, P.; Anderson, J . T. Tetrahedron Lett. 1997, 38, 6647.
(49) Souma, Y., Iyoda, J .; Sano, H. Bull. Chem. Soc. J pn. 1976, 49,
3291.
4-Meth yl-5-h ep ta n olid e (8a ).19 By a procedure similar to
that for 2b (Method E), 4-methyl-5-oxoheptanal (4a , 160 mg,
1.23 mmol) was treated with SmI2/i-PrSH (0.50 mmol/0.43
mmol) at room temperature to give the title compound 8a (cis
(50) J etter, R.; Riederer, M. Phytochemistry 1999, 50, 1359.

Synthesis of δ-Lactones from 5-Oxoalkanals
J . Org. Chem., Vol. 66, No. 25, 2001 8583
isomer, 155 mg, 91%). 1H NMR (CDCl3, 200 MHz) δ 0.91 (3
H, t, J ) 6.7 Hz), δ 0.96 (3 H, d, J ) 7.4 Hz), 1.44-1.72 (3 H,
m), 1.90-2.05 (2 H, m), 2.47 (2 H, t, J ) 7.6 Hz), 4.14 (1 H,
ddd, J ) 11.5 Hz, J ) 5.5 Hz, J ) 2.8 Hz).
) 6.9 Hz), 0.87 (3 H, d, J ) 6.6 Hz), 0.93-1.10 (1 H, m), 1.25-
1.52 (2 H, m), 1.60-1.81 (8 H, m), 1.89-2.01 (2 H, m), 2.27-
2.31 (2 H, m), 4.60-4.69 (2 H, m), 7.20-7.45 (5 H, m); 13C NMR
(CDCl3, 75 MHz): δ 16.1, 20.6, 21.1, 21.9, 23.3, 26.1, 31.1, 34.1,
34.2, 38.2, 40.8, 46.9, 73.8, 73.9, 125.7 (2×), 127.3, 128.3 (2×),
144.5, 173.1; HRMS calcd for C21H32O3: 332.2351. Found:
332.2341.
4-Meth yl-5-p h en yl-5-p en ta n olid e (8b).20 By a procedure
similar to that for 2b (Method E), 4-methyl-5-oxo-5-phenyl-
pentanal (4b, 61 mg, 0.32 mmol) was treated with SmI2/i-PrSH
(0.25 mmol/0.17 mmol) at room temperature to give the title
(1′R,2′S,5′R,5SR)-5-Hyd r oxy-5-tr id eca n oic a cid 2-iso-
p r op yl-5-m eth ylcycloh exyl ester (12e). TLC [EtOAc/hex-
1
compound 8b (cis isomer, 57 mg, 94%). H NMR (CDCl3, 200
ane (20:80)] Rf ) 0.55; IR (neat) 3449, 1734 cm-1 1H NMR
;
MHz) δ 0.76 (3 H, d, J ) 6.1 Hz), 1.68-1.81 (1 H, m), 2.10-
2.31 (2 H, m), 2.67 (2 H, dd, J ) 7.2 Hz, J ) 6.7 Hz), 5.48 (1
H, d, J ) 3.0 Hz), 7.13-7.36 (5 H, m).
(CDCl3, 400 MHz) δ 0.73 (3 H, d, J ) 6.9 Hz), 0.83-1.11 (12
H, m), 1.24-2.11 (25 H, m), 2.29 (2 H, dt, J ) 7.4, 1.9 Hz),
3-Meth yl-5-p h en yl-5-p en ta n olid e (9a ).21 By a procedure
similar to that for 2b (Method E), 3-methyl-5-oxo-5-phenyl-
pentanal (5a , 94 mg, 0.48 mmol) was treated with SmI2/i-PrSH
(0.50 mmol/0.43 mmol) at room temperature to give the title
compound 9a (91 mg, 97%) as a mixture of trans and cis
isomers (77:23). The isomeric ratio changed to trans/cis ) 94:6
when the reaction was conducted at 0 °C. trans-9a : 1H NMR
(CDCl3, 200 MHz) δ 1.09 (3 H, d, J ) 6.2 Hz), 1.82-1.88 (1 H,
m), 2.02-2.31 (3 H, m), 2.68 (1 H, dd, J ) 16.3 Hz, J ) 5.3
Hz), 5.50 (1 H, dd, J ) 7.3 Hz, J ) 4.6 Hz), 7.27-7.36 (5 H,
m). cis-9a : 1H NMR (CDCl3, 400 MHz) δ 1.07 (3 H, d, J ) 6.4
Hz), 1.49-1.56 (1 H, m), 2.12-2.19 (3 H, m), 2.79 (1 H, dd, J
) 11.9, 1.9 Hz), 5.29 (1 H, dd, J ) 12.0, 3.1 Hz), 7.30-7.38 (5
H, m).
3.52-3.59 (1 H, m), 4.66 (1 H, ddd, J ) 10.8, 10.8, 4.3 Hz); 13
C
NMR (CDCl3, 100 MHz): δ 14.1 (CH3), 16.3 (CH3), 20.7 (CH3),
21.1 (CH2), 22.0 (CH3), 22.6 (CH2), 23.4 (CH2), 25.6 (CH2), 26.3
(CH), 29.3 (CH2), 29.6 (CH2), 29.7 (CH2), 31.7 (CH), 31.9 (CH2),
34.3 (CH2), 34.5 (CH2), 36.7 (CH2), 37.5 (CH2), 40.9 (CH2), 47.0
(CH2), 71.4 (CH), 74.1 (CH), 173.3 (C); HR-FAB-MS calcd for
C23H45O3 (M+ + 1): 369.3369. Found: 369.3362.
(2S,2′S,4S,4′S,5R,5′R)-N,N′-Bis(3,4-d im et h yl-2-oxo-5-
p h e n y l-1,3,2-o x a za p h o s p h o la n -2-y l)-e t h a n e -1,2-d i-
a m in e (15).33 According to the known procedure, the chiral
phosphorus(V) reagent 15 was prepared from (1R,2S)-(-)-
ephedrine hydrochloric salt by subsequent treatments with
POCl3/Et3N and ethylenediamine.
Sa len 16. By a procedure similar to that for the related
salen compounds,34 the chiral salen reagent 16 was prepared
by condensation of (1R,2R)-(-)-1,2-cyclohexanediamine with
4-azidomethyl-2-hydroxybenzaldehyde.
(3S,5S)-3-Met h yl-5-h exa n olid e (9b )24 a n d (2R,5S)-2-
Meth yl-5-h exa n olid e (10)25. By a procedure similar to that
for 2b (Method E), a mixture of 3-methyl-5-oxohexanal (5b)
and 2-methyl-5-oxohexanal (6) (1:1, 128 mg, 1.0 mmol) was
treated with SmI2/i-PrSH (0.5 mmol/0.4 mmol) at 0 °C to give
a mixture of (3S,5S)-9b and (2R,5S)-10 (1:1). The analytic
samples were isolated by HPLC with elution of EtOAc/hexane
(1S,2S,5R)-2-Isopr opyl-5-m eth yl-cycloh exan eth iol (17).35
Treatment of (-)-menthol (3.12 g, 20 mmol) with p-toluene-
sulfonyl chloride (7.70 g, 40 mmol) in pyridine (30 mL) at room
temperature for 16 h gave the corresponding tosylate (6.05 g,
97%). The tosylate (2.60 g, 8.4 mmol) was heated (50-60 °C)
with potassium thioacetate (AcSK, 2.80 g, 25 mmol) in Me2-
SO (17 mL) for 36 h. The mixture was cooled and extracted
with CHCl3 (5 × 15 mL). The organic phase was dried (Na2-
SO4), concentrated, and distilled (80 °C, 0.05 mmHg) to give
(1S)-neomenthyl acetate (1.31 g, 73%). Diisobutylaluminum
hydride (DIBAL, 6 mmol, 1 M solution in CH2Cl2) was added
dropwise to a CH2Cl2 solution (20 mL) of (1S)-neomenthyl
acetate (420 mg, 1.96 mmol) at 0 °C. The mixture was stirred
for 5 h and quenched by addition of saturated NH4Cl. Water
(40 mL) and 1 M HCl (20 mL) were added, and the mixture
was extracted with Et2O (4 × 30 mL). The organic phase was
washed with brine, dried (Na2SO4), concentrated, and distilled
(90 °C, 9 mmHg) to give the title compound 17 (330 mg, 98%).
(3:7). (3S,5S)-9b: [R]25 ) -57.7 (c ) 0.1, MeOH); 13C NMR
D
(CDCl3, 125 MHz) δ 21.3, 21.4, 23.7, 36.6, 37.3, 73.6, 172.4.
(2R,5S)-10: [R]25 ) -82.5 (c ) 0.6, CHCl3); 1H NMR (CDCl3,
D
500 MHz) δ 1.20 (3 H, d, J ) 6.8 Hz), 1.34 (3 H, d, J ) 6.2
Hz), 1.49-1.64 (2 H, m), 1.87-1.93 (1 H, m), 2.02-2.10 (1 H,
m), 2.52-2.60 (1 H, m), 4.42-4.47 (1 H, m); 13C NMR (CDCl3,
125 MHz) δ 16.2, 21.1, 25.6, 28.4, 33.0, 74.4, 176.3.
(2S,5R)-2-Meth yl-5-h exa n olid e (10).25 By a procedure
similar to that for 1h (Method B), propanal was condensed
with (S)-1-amino-2-(methoxymethyl)pyrrolidine to give the
corresponding hydrazone. The hydrazone was alkylated with
4-iodo-2-methyl-1-butene, followed by ozonolysis, to give (S)-
2-methyl-5-oxohexanal, [R]26 ) -6.7 (c ) 0.6, CHCl3). By a
D
procedure similar to that for 2b (Method E), (S)-2-methyl-5-
oxohexanal (71 mg, 0.6 mmol) was treated with SmI2/i-PrSH
(0.3 mmol/0.25 mmol) at room temperature to give (2S,5R)-
[R]25 +53.6 (c ) 3.1, CHCl3).
D
(1S,2S,3R,5R)-3-P in a n eth iol (18).37 By a procedure simi-
lar to that for 17, (+)-isopinocampheol was activated as the
mesylate, which was subsequently treated with AcSK and
10 (54 mg, 76%). Solid, mp 40-42 °C; [R]21 ) +63.5 (c ) 0.2,
D
CHCl3).
1-Oxa -2-d eca lon e (11a ).22 By a procedure similar to that
for 2b (Method E), 3-(2-oxocyclohexyl)propanal (7a , 79 mg, 0.51
mmol) was treated with SmI2/i-PrSH (0.25 mmol/0.17 mmol)
at room temperature to give the title compound 11a (trans/
cis ) 96:4, 55 mg, 70%). trans-11a : 1H NMR (CDCl3, 200 MHz)
δ 0.95-2.03 (11 H, m), 2.47-2.61 (2 H, m), 3.82 (1 H, ddd, J
) 10.2 Hz, J ) 10.2 Hz, J ) 4.2 Hz)/4.44 (br dd, J ) 6.7, 3.3
Hz for cis isomer).
DIBAL to give the title compound 18. [R]25 ) -5.7 (c ) 3.7,
D
CHCl3).
(3R)-Ch olesta n eth iol (19).38 A THF solution (5 mL) of 3â-
chloesterol (772 mg, 2.0 mmol) was treated with a mixture of
Ph3P (630 mmol, 2.4 mmol) and diisopropyl diazocarbodiimide
(DIAD, 485 mg, 2.4 mmol) in THF (15 mL) at 0 °C for 2 h to
give the corresponding thioacetate (590 mg, 78%). Reduction
of the thioacetate (138 mg, 0.3 mmol) with LiAlH4 (120 mg,
3.0 mmol) in Et2O (10 mL) for 30 min gave the title compound
19 (122 mg, 99%). Solid, 80-82 °C.
1-Oxa -6-ter t-bu tyl-2-d eca lon e (11b).23 By a procedure
similar to that for 2b (Method E), 3-(2-oxo-5-tert-butylcyclo-
hexyl)propanal (7b, 160 mg, 1.2 mmol) was treated with SmI2/
i-PrSH (0.50 mmol/0.43 mmol) at room temperature to give
the title compound 11b (141 mg, 88%) as a mixture of trans
and cis isomers (81:19). trans-11b: 1H NMR (CDCl3, 300 MHz)
δ 0.84 (9 H, s), 0.82-1.17 (3 H, m), 1.40-1.60 (3 H, m), 1.80-
1.87 (3 H, m), 2.09-2.16 (1 H, m), 2.51-2.69 (2 H, m), 3.80 (1
H, ddd, J ) 10.5 Hz, J ) 10.4 Hz, J ) 4.5 Hz). cis-11b: 1H
NMR (CDCl3, 300 MHz) δ 0.83 (9 H, s), 1.06-1.33 (3 H, m),
1.46-1.61 (4 H, m), 1.81-1.87 (1 H, m), 2.07-2.14 (2 H, m),
2.48 (2 H, t, J ) 7.4 Hz), 4.42 (1 H, d, J ) 2.6 Hz).
(1′R,2′S,5′R,5SR)-5-Hyd r oxy-5-p h en ylp en t a n oic a cid
2-isop r op yl-5-m eth ylcycloh exyl ester (12a ). TLC [EtOAc/
hexane (20:80)] Rf ) 0.26; IR (neat) 3443, 1725 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 0.71 (3 H, d, J ) 6.9 Hz), 0.86 (3 H, d, J
(1S,2R,4R)-(-)-10-Mer ca p toisobon eol (20).39 Treatment
of (1S)-(+)-camphorsulfonic acid (1.16 g, 5 mmol) with SOCl2
gave the corresponding sulfonyl chloride, which was reduced
with LiAlH4 to give the title compound 20 (37% overall yield)
and its endo isomer (7%). 20: Solid, mp 70-72 °C; [R]27
-56.1 (c ) 1.1, CHCl3).
)
D
(S)-(+)-2-(r-Mer ca p t o-r-p h en ylb en zyl)-1-m et h ylp yr -
r olid in e (26).41 According to the known procedure,41 (S)-
proline-N-benzyl carbamate was subjected to a sequence of
esterification, addition with PhMgBr, reduction with LiAlH4
and substitution with Lawesson reagent to give the title
compound 26 in 32% overall yield. [R]25 ) +249.5 (c ) 1.0,
D
CHCl3).

8584 J . Org. Chem., Vol. 66, No. 25, 2001
Hsu and Fang
(1R,2S)-(-)-1-P h en yl-2-piper idyl-1-pr opan eth iol (27).42b
(1R,2S)-(-)-Norephedrine (2.3 g, 10 mmol) was alkylated with
1,5-dibromopentane, followed by activation to the correspond-
ing mesylate. The mesylate was treated with AcSK, followed
by reduction with DIBAL, to give the title compound 27 in
was converted to the title compounds 32 in 69% yield, via
substitution of the mesylate with AcSK and saponification.
Solid, mp 89-90 °C; [R]24 -35.0 (c ) 1.0, CHCl3).
D
(1R,2S)-2-(N-Ben zyla cet a m id o)-1-p h en yl-1-p r op a n e-
th iol (34). (1R,2S)-(-)-Norephedrine was subjected to reduc-
tive alkylation with PhCHO/NaBH3CN to give (1R,2S)-2-
benzylamino-1-phenylpropanol (70% yield), which was con-
verted to the corresponding aziridine (64% yield) by treatment
with Ph3P/CCl4 in CH3CN solution at room temperature for
18 h. The aziridine (228 mg, 1.0 mmol) was treated with
thioacetic acid, by a procedure similar to that for 30, to give
the title compound 34 (262 mg, 88%). Solid, mp 92-94 °C;
42% overall yield. [R]27 -64.2 (c ) 1.2, CHCl3).
D
(1R,2S)-2-Diben zylam in o-1-ph en yl-1-pr opan eth iol (28).
(1R,2S)-(-)-Norephedrine (2.3 g, 10 mmol) was subjected to
reductive alkylation with PhCHO/NaBH3CN (two repeated
processes) to give (1R,2S)-N,N-dibenzylamino-1-phenylpro-
panol, which was activated as a mesylate. The mesylate was
treated with AcSK, followed by saponification (KOH in aque-
ous MeOH), to give the title compound 28 in 39% overall yield.
[R]25 -25.3 (c ) 2.1, CHCl3).
D
[R]28 -101.1 (c ) 1.4, CHCl3).
D
(1R,2S)-2-(N-Met h ylb en za m id o)-1-p h en yl-1-p r op a n e-
th iol (35). By a procedure similar to that for 31, (2S,3S)-1,2-
dimethyl-3-phenylaziridine (626 mg, 4.2 mmol) was treated
with thiobenzoic acid acid (740 mg, 5.3 mmol) to give the title
(1R,2S)-1-P h en yl-2-(N-m eth yleth yla m in o)-1-p r op a n e-
th iol (29) a n d (1R,2S)-1-P h en yl-2-(N-m eth yla ceta m id o)-
1-p r op a n eth iol (33).42a (1R,2S)-(-)-Ephedrine (4.02 g, 20
mmol) was treated with Ph3P (1.1 g, 4 mmol), Et3N (8 mL)
and diethyl azodicarbodiimide (DEAD, 6.9 g, 40 mmol) in THF
(60 mL) at room temperature for 10 h. After the solids were
filtered, the filtrate was concentrated and distilled (70 °C, 0.5
mmHg) to give (2S,3S)-1,2-dimethyl-3-phenylaziridine (2.53
g, 89%). The aziridine (1.41 g, 9.9 mmol) was treated with
AcSK (1.51 g, 19.9 mmol) in CH2Cl2 (20 mL) at 0 °C for 2 h to
give compound 33 (2.09, 95%), via the ring opening reaction
and transesterification. Reduction of 33 (299 mg, 1.3 mmol)
with LiAlH4 (120 mg, 3.0 mmol) in refluxing THF (20 mL) for
compound 35 (1.19 g, 99%). [R]25 -22.5 (c ) 1.25, CH2Cl2).
D
(1R,2R)-2-(N-Met h yla cet a m id o)-1-p h en yl-1-p r op a n e-
t h iol (36). By a procedure similar to that for 30, (1R,2R)-
(-)-pseudoephedrine (1.65 g, 10 mmol) was treated with Ph3P
and DIAD to give the corresponding aziridine (1.24 g, 84%).
The aziridine (139 mg, 0.94 mmol) was treated with thioacetic
acid to give the title compound 36 (169 mg, 80%). Solid, mp
95-97 °C; [R]27 -195.0 (c ) 1.0, CHCl3).
D
(1S,2R)-2-Acet a m id o-1,2-d ip h en yl-1-et h a n et h iol (37).
By a procedure similar to that for 30, (1S,2R)-(+)-2-amino-
1,2-diphenylethanol (587 mg, 2.8 mmol) was treated with Ph3P
and DIAD to give the corresponding aziridine (496 mg, 93%).
The aziridine (333 mg, 1.7 mmol) was treated with thioacetic
acid to give the title compound 37 (519 mg, 66%). Solid, mp
5 h gave compound 29 (178 mg, 64%). 29: [R]29 ) -224.7 (c
D
) 2.5, CHCl3). 33: [R]25 -93.4 (c ) 1.96, CH2Cl2).
D
(1R,2S)-2-Acetam ido-1-ph en yl-1-pr opan eth iol (30). (1R,-
2S)-(-)-Norephedrine (1.51 g, 10 mmol) was treated with Ph3P
(3.2 g, 12 mmol) and DIAD (2.2 g, 11 mmol), by procedure
similar to that for 33, to give (2S,3S)-2-methyl-3-phenylaziri-
dine (1.15 g, 86%). The aziridine (259 mg, 1.9 mmol) was
treated with thioacetic acid (500 mg, 6.5 mmol) in CH2Cl2 at
0 °C for 2 h to give the title compound 30 (350 mg, 86%). Solid,
189-190 °C; [R]27 ) -70.2 (c ) 1.0, DMSO-d6).
D
(1S,2R)-2-(N-Ben zyla ceta m id o)-1,2-d ip h en yl-1-eth a n e-
th iol (38). By a procedure similar to that for 34, (1S,2R)-(+)-
2-amino-1,2-diphenylethanol was sequentially treated with
PhCHO/NaBH3CN, Ph3P/DIAD, and thioacetic acid to give the
mp 78-80 °C; TLC [EtOAc/hexane (1:1)] Rf ) 0.26; [R]29
)
D
1
title compound 38 in 48% overall yield. [R]27 ) -82.3 (c )
D
-67.3 (c ) 0.9, CHCl3); IR (neat) 3285, 1650, 1554 cm-1; H
NMR (CDCl3, 300 MHz) δ 1.04 (3 H, d, J ) 6.6 Hz), 1.85 (1 H,
d, J ) 7.3 Hz, SH), 1.92 (3 H, s), 4.29 (1 H, dd, J ) 7.3, 5.0
Hz), 4.34-4.45 (1 H, m), 5.71 (1 H, br s), 7.20-7.39 (5 H, m);
13C NMR (CDCl3, 75 MHz) δ 15.9 (CH3), 23.4 (CH3), 49.1 (CH),
50.2 (CH), 127.4 (CH), 127.8 (CH × 2), 128.4 (CH × 2), 140.5
(C), 169.3 (CdO). HR-FAB-MS calcd for C11H16NOS (M+ + 1):
210.0953. Found: 210.0960.
1.2, CHCl3).
Ack n ow led gm en t. We thank the National Science
Council for financial support, Professor T. -K. Yang
(National Chung-Hsing University) for providing us the
samples of compounds 20-24, and Professor C.-T. Chen
(National Taiwan University) for helpful discussion.
(1R,2S)-2-Ben za m id o-1-p h en yl-1-p r op a n eth iol (31). By
a procedure similar to that for 30, the aziridine derived from
(1R,2S)-(-)-norephedrine (164 mg, 1.2 mmol) was treated with
thiobenzoic acid (255 mg, 6.5 mmol) to give the title compound
Su p p or tin g In for m a tion Ava ila ble: Additional experi-
mental procedures, spectral data, and 1H and 13C spectra of
some selected compounds, as well as the crystal data, bond
distances, bond angles, and ORTEP drawing of compound 30.
This material is available free of charge via the Internet at
http://pubs.acs.org.
31 (331 mg, 99%). Solid, mp 145-146 °C; [R]29 -51.1 (c )
D
1.90, CHCl3).
(1R ,2S )-1-P h e n y l-2-(4-t o lu e n e s u lfo n a m id o )-1-p r o -
p a n eth iol (32). (1R,2S)-(-)-Norephedrine was treated with
p-toluenesulfonyl chloride to give the corresponding sulfona-
mide. By a procedure similar to that for 28, the sulfonamide
J O016058T