Novel fragmentation reaction of 2-alkyl- and 2,4-dialkyl-3-iodo-1- oxocyclohexan-2,4-carbolactones

Article abstract of DOI:10.1021/jo0490853

2-Alkyl- and 2,4-dialkyl-3-iodo-1-oxocyclohexan-2,4-carbolactones undergo lithium hydroxide- and lithium alkoxide-induced fragmentation reactions to provide butenolides, γ-hydroxycyclohexenones, and/or γ- butyrolactones. In general, product distribution is governed by two factors: (1) the nature of nucleophiles and (2) the steric bulkiness of the substituents at C-2 and C-4 of the cyclohexanones. Lithium hydroxide-induced fragmentation provides butenolides and γ-hydroxycyclohexenones. In contrast, lithium alkoxide-promoted fragmentation results in predominantly 5-substituted γ-butyrolactones along with a small amount of butenolides in limited cases. Fragmentation products induced by lithium hydroxide are largely influenced by the steric bulkiness of the substituents at C-2 and C-4 of the cyclohexanone ring. The bulky substituents render the exclusive formation of butenolides.

Full text of DOI:10.1021/jo0490853

Novel F r a gm en ta tion Rea ction of 2-Alk yl- a n d
2,4-Dia lk yl-3-iod o-1-oxocycloh exa n -2,4-ca r bola cton es
Seock-Kyu Khim,* Mingshi Dai, Xuqing Zhang, Lei Chen, Liping Pettus,
Kshitij Thakkar, and Arthur G. Schultz†
Department of Chemistry, Rensselaer Polytechnic Institute, Troy, New York 12180
seock-kyu_khim@berlex.com
Received J une 1, 2004
2-Alkyl- and 2,4-dialkyl-3-iodo-1-oxocyclohexan-2,4-carbolactones undergo lithium hydroxide- and
lithium alkoxide-induced fragmentation reactions to provide butenolides, γ-hydroxycyclohexenones,
and/or γ-butyrolactones. In general, product distribution is governed by two factors: (1) the nature
of nucleophiles and (2) the steric bulkiness of the substituents at C-2 and C-4 of the cyclohexanones.
Lithium hydroxide-induced fragmentation provides butenolides and γ-hydroxycyclohexenones. In
contrast, lithium alkoxide-promoted fragmentation results in predominantly 5-substituted γ-but-
yrolactones along with a small amount of butenolides in limited cases. Fragmentation products
induced by lithium hydroxide are largely influenced by the steric bulkiness of the substituents at
C-2 and C-4 of the cyclohexanone ring. The bulky substituents render the exclusive formation of
butenolides.
SCHEME 1
In tr od u ction
Optically active 2-alkyl- and 2,4-dialkyl-3-iodo-1-oxo-
cyclohexan-2,4-carbolactones (1) are readily available
through an efficient asymmetric Birch reduction-alky-
lation protocol developed in our laboratories.1 Previously,
we reported that these iodolactones undergo lithium
hydroxide- and lithium alkoxide-induced fragmentation,
as shown in Scheme 1.2 This process provides syntheti-
cally versatile chiral building blocks, such as butenolides
(2), γ-butyrolactones (3), and/or γ-hydroxycyclohexenones
(4) in enantiomerically pure form. In particular, the
predominant formation of butenolide 2 from 1 induced
by lithium hydroxide offers a general method for prepar-
ing optically active 3,5-disubstituted butenolides.3 It
appears that the product distribution of the fragmenta-
tion is influenced primarily by the steric bulkiness of the
C-2 (R2 group) and C-4 (R1 group) substituents of the
carbolactones 1 and by the nature of the nucleophiles
used, such as hydroxide and alkoxide. Intrigued by this
unique transformation and its synthetic potential, we
elected to explore the scope and limitations of the process.
We examined several fragmentation substrates pos-
sessing substituents at C-2 and C-4 of 1, which differ in
steric bulkiness and functionality. Herein, we (1) describe
the full details of these studies focusing on the C-2 and
C-4 substituent effect and (2) propose a working mech-
anism for the fragmentation process promoted by both
hydroxide and alkoxide nucleophiles.
Resu lts a n d Discu ssion
P r epar ation of Fr agm en tation Su bstr ates 2-Alkyl-
a n d 2,4-Dia lk yl-3-iod o-1-oxocycloh exa n -2,4-ca r bo-
la cton es (1a -l). The requisite substrates for fragmenta-
(3) For recent syntheses of butenolides, see: (a) Rao, Y. S. Chem.
Rev. 1976, 76, 625. (b) Larock, R. C.; Riefling, B.; Fellows, C. A. J .
Org. Chem. 1978, 43, 131. (c) Herrmann, J . L.; Berger, M. H.;
Schlessinger, R. H. J . Am. Chem. Soc. 1979, 101, 1544. (d) Cowell, A.;
Stille, J . K. J . Am. Chem. Soc. 1980, 102, 4193. (e) Hanessian, S.;
Hodges, P. J .; Murray, P. J .; Sahoo, S. P. J . Chem. Soc., Chem.
Commun. 1986, 754. (f) Figureredo, M.; Font, J .; Virgili, A. Tetrahedron
1987, 43, 1881. (g) Tanabe, Y.; Ohno, N. J . Org. Chem. 1988, 53, 1560.
(h) Buchwald, S. L.; Fang, Q.; King, S. M. Tetrahedron Lett. 1988, 29,
3445. (i) Hoye, T. R.; Humpal, P. E.; J imenez, J . I.; Mayer, M. J .; Tan,
L.; Ye, Z. Tetrahedron Lett. 1994, 35, 7517. (j) Trost, B. M.; Muller, T.
J . J .; Martinez, J . J . Am. Chem. Soc. 1995, 117, 1888. (k) Marshall, J .
A.; Wolf, M. A. J . Org. Chem. 1996, 61, 3238. (l) Kablaoui, N. M.; Hicks,
F. A.; Buchwald, S. L. J . Am. Chem. Soc. 1996, 118, 5818. (m) Renard,
M.; Ghosez, L. Tetrahedron Lett. 1999, 40, 6237. (n) Rousset, S.;
Thibonnet, J .; Abarbri, M.; Ducheˆne, A.; Parrain, J .-L. Synlett 2000,
260. (o) Yao, M.-L.; Deng, M.-Z. J . Org. Chem. 2000, 65, 5034. (p) He,
Y.-T.; Yang, H.-N.; Yao, Z.-J . Tetrahedron 2002, 58, 8805. (q) Brown,
S. P.; Goodwin, N. C.; MacMillan, D. W. C. J . Am. Chem. Soc. 2002,
124, 2456. (r) Ma, S.; Yu, Z. J . Org. Chem. 2003, 68, 6149. (s) Yoneda,
E.; Zhang, S.-W.; Zhou, D.-Y.; Onitsuka, K.; Takahashi, S. J . Org.
Chem. 2003, 68, 8571.
* To whom correspondence should be addressed.
† Deceased J anuary 20, 2000.
(1) (a) Schultz, A. G. Acc. Chem. Res. 1990, 23, 207. (b) Schultz, A.
G. J . Chin. Chem. Soc. (Taipei) 1994, 41, 487. (c) Schultz, A. G. Chem.
Commun. 1999, 1263.
(2) For a preliminary account of this work, see: Schultz, A. G.; Dai,
M.; Khim, S.-K.; Pettus, L.; Thakkar, K. Tetrahedron Lett. 1998, 39,
4203.
10.1021/jo0490853 CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/05/2004
7728
J . Org. Chem. 2004, 69, 7728-7733

Novel Fragmentation Reaction
SCHEME 2 a
SCHEME 3
TABLE 2. F r a gm en ta tion of 1 w ith LiOH
yield (%)a
entry
1
R1
R2
11
12
1
2
3
4
5
6
7
8
9
1a
1b
1d
1e
1f
1g
1h
1i
H
H
H
H
Me
28
68
74
77
78
38
88
81
88
81
76
58
15
7
13
9
47
8
5
(CH2)3Cl
(CH2)2C6H4(o-Br)
(CH2)3OBn
CH2O(CH2)2TMS
Me
H
Me
Me
Me
Me
Bn
a
Reagents and conditions: (a) K, NH3, THF, t-BuOH (1 equiv),
Et
piperylene, R2X; (b) 6 N HCl, MeOH, rt; (c) I2, THF/H2O, rt.
(CH2)3CHdCH2
(CH2)2OPMB
Et
1j
1k
1l
10
2
b
TABLE 1. P r ep a r a tion of F r a gm en ta tion Su bstr a tes
1a -l
10
11
C6H4(o-OMe)
Me
yield (%)a
a
b
Isolated yields. Compound 13 was isolated in 8% yield.
entry
R1
R2
9
10
95
1
a
b
c
d
e
f
g
h
i
H
H
H
H
H
H
Me
Me
Me
Me
Bn
Me
95
93
89
89b
87
82
90
75
85
82
86
84
79
80
62
73
81
98
(CH2)3Cl
(CH2)4Cl
(CH2)2C6H4(o-Br)
(CH2)3OBn
CH2O(CH2)2TMS
Me
89
92
97
86
95
100
98
95
71
96
93
100
100
91
75
93
that the steric bulkiness at R1 and R2 controls the
fragmentation product distribution. For example, when
R1 is H and R2 is Me (entry 1, Table 2), γ-hydroxycyclo-
hexenone 12a was the major product (11a :12a , 1:2). As
the steric bulkiness of R2 increased (entries 2-5, Table
2), butenolides 11b,d -f became the major products
(11b,d -f:12b,d -f, 5-11:1). A similar trend was observed
for the fragmentation of the 2,4-disubstituted substrates
1g-j (entries 6-9, Table 2). Interestingly, when R1 is
bulkier than R2 (Bn vs Et for entry 10 and o-methoxy-
phenyl vs Me for entry 11), 11k (81% yield) and 11l (76%
yield) were formed almost exclusively. In the case of 1l,
the biphenyl 13 was observed as a minor side product,
possibly resulting from the sequential dehydration-
aromatization of the intermediate tertiary benzylic al-
cohol 12 or spontaneous decomposition of 1l.6
Structural assignments of butenolides 11 and γ-hy-
droxycyclohexenones 12 were established by the diag-
nostic chemical shift differences of vinyl protons in the
1H NMR. We have previously established that the vinyl
protons of butenolides 11 resonate downfield at a region
between 6.78 and 7.27 ppm compared to the vinyl protons
of γ-hydroxycyclohexenones 12, which resonate between
6.09 and 6.85 ppm (∆δ ) 0.32-0.94).
Two plausible mechanisms which would account for the
observed formation of 11 and 12 are shown in Figure 1.
In pathway A, the nucleophilic addition of hydroxide to
the ketone carbonyl moiety of 1 results in intermediate
14, which undergoes a ring-opening reaction through a
Grob-type fragmentation7 to give lactone enolate 15
followed by a loss of iodide to provide butenolide 11.
In contrast, the formation of 12 could be explained by
the competitive addition of hyroxide to the lactone
carbonyl moiety of 1. Thus, in pathway B, the hydroxide
Et
(CH2)3CHdCH2
(CH2)2OPMB
Et
j
k
l
C6H4(o-OMe)
Me
78
a
b
Isolated yields. LiBr was added for metal exchange.
tion reactions, 2-alkyl- and 2,4-dialkyl-3-iodo-1-oxocyclo-
hexan-2,4-carbolactones (1a-l), were prepared from chiral
benzamides 5-8, as shown in Scheme 2 and summarized
in Table 1. Birch reduction of chiral benzamides 5-8
resulted in the chiral amide enolates, which were alky-
lated in situ using alkyl halides to provide the corre-
sponding enol ether 1,4-cyclohexadienes 9 as single
diastereomers. Acid-catalyzed hydrolysis of 9 gave the
corresponding â,γ-enones 10. Subsequent iodolactoniza-
tions4 of 10 using iodine in THF/H2O afforded the
enantiomerically pure 2-alkyl- and 2,4-dialkyl-3-iodo-1-
oxocyclohexan-2,4-carbolactones 1a -l.
Lith iu m Hyd r oxid e-In d u ced F r a gm en ta tion of
1a -l. With the required substrates in hand, we first
investigated the fragmentation of 1a -l promoted by
lithium hydroxide. As shown in Scheme 3 and Table 2,
the addition of lithium hydroxide (2.0 equiv) to a solution
of 1a -l in THF/H2O (5:1, v/v) at room temperature
resulted in a mixture of the butenolides 11 and γ-hy-
droxycyclohexenones 125 in excellent yield. It is evident
(4) (a) Corey, E. J .; Shibasaki, M.; Knolle, J . Tetrahedron Lett. 1977,
19, 1625. (b) Harding, K. E.; Tiner, T. H. In Comprehensive Organic
Synthesis; Trost, B. M., Ed.; Pergamon Press: New York, 1991; Vol.
4, p 363. (c) Schultz, A. G.; Holoboski, M. A.; Smyth, M. S. J . Am. Chem.
Soc. 1993, 115, 7904.
(5) For the synthesis of γ-hydroxycyclohexenone, see: (a) Ochoa, M.
E.; Arias, M. S.; Aguilar, R.; Delgado, F.; Tamariz, J . Tetrahedron 1999,
55, 14535. (b) de March, P.; Escoda, M.; Figueredo, M.; Font, J .; Garcia-
Garcia, E.; Rodriguez, S. Tetrahedron: Asymmetry 2000, 11, 4473.
(6) 1l was found to slowly decompose to 13.
J . Org. Chem, Vol. 69, No. 22, 2004 7729

Khim et al.
TABLE 3. P r od u ct Distr ibu tion s a s a F u n ction of
Solven ts
yield (%)a
1H NMR ratiob
entry
THF:H2O
11a :12a
11a :12a
1
2
3
4
1:2
1:1
5:1
12:71
15:72
28:58
41:40
21:79
27:73
45:55
59:41
10:1
a
b
Isolated yields. On the basis of the integration of vinyl
protons of the crude mixture (7.03 ppm for 11a and 6.09 ppm for
12a ).
SCHEME 4
F IGURE 1. Proposed mechanisms for the fragmentation of
1 with LiOH.
product ratios as a function of solvents suggests that
protic polar solvent facilitates and stabilizes the forma-
tion of intermediate 17 (pathway B in Figure 1) by
promoting the enhanced solvation of lithium ions. We
hypothesized, therefore, that intermediate 17 is more
solvated in protic solvents such as THF/H2O (1:2),
thereby leading to the formation of 12a as the major
product.
ion attacks the lactone moiety of 1 resulting in interme-
diate 16, which subsequently undergoes a ring opening
to give the tert-alkoxide intermediate 17. Intramolecular
decarboxylative fragmentation of 17 would provide the
γ-hydroxycyclohexenone 12.
It is clear that the chemoselectivity of hydroxide
addition is greatly influenced by the steric bulkiness of
the R2 substituents. Substituents larger than the methyl
group significantly impede the Re-face attack of hydrox-
ide on the lactone moiety of 1, while the corresponding
Si-face attack would be sterically disfavored due to the
presence of axial C-6 hydrogen. Consequently, addition
of hydroxide to the ketone moiety of 1 exclusively
furnishes butenolide 11.
Considering the overall yield, the ease of workup, and
the reaction time for this process, we screened several
bases such as NaHCO3, Na2CO3, K2CO3, LiOH, NaOH,
KOH, CsOH, Ba(OH)2, and tetrabutylammonium hydrox-
ide. Of the bases screened, LiOH was found to be the
choice.
The effect of solvent composition on this fragmentation
process was also investigated. The results are sum-
marized in Table 3. When the ratio of THF to H2O was
e1, fragmentation of 1a provided the γ-hydroxycyclo-
hexenone 12a as the major product (entries 1 and 2,
Table 3). As the ratio of THF to H2O was increased to
5-10:1, the ratio of 11a to 12a increased to approxi-
mately 1:1 (entries 3 and 4, Table 3). The variation in
To determine the enantiomeric purities of the frag-
mentation products, 11a and 12a were structurally
modified and analyzed by chiral HPLC. Analysis showed
8
that 11a and 12a are produced in >99 and >96% ee,9
respectively, indicating that the fragmentation proceeds
with complete retention of stereochemistry.
Ster eoelectr on ic Effect of th e Lea vin g Gr ou p s of
1 in F r a gm en ta tion . To investigate the stereoelectronic
effect of the leaving groups at C-3 of 1 in these fragmen-
tation processes, we needed access to both axial and
equatorial leaving groups (Scheme 4).10 Iodide exchange
of 1 catalyzed by substrates containing 2,2,6,6-tetra-
methyl-1-piperidinyloxy free radical (TEMPO) allowed
(8) The enantiomeric purity of 11a was determined with the silyl
ether derivative i, and its racemic derivative was prepared from the
pyrrolidine amide corresponding to 5 [chiral OJ column, hexane/2-
propanol (99:1), 0.35 mL/min, λ ) 220 nm, tR ) 24.0 min (minor
enantiomer), tR ) 28.0 min (major enantiomer)].
(7) (a) Grob, C. A.; Schiess, P. W. Angew. Chem., Int. Ed. Engl. 1967,
6, 1. (b) Grob, C. A. Angew. Chem., Int. Ed. Engl. 1969, 8, 535. (c)
Becker, K. B.; Grob, C. A. In The Chemistry of Double-Bonded
Functional Groups; Patai, S., Ed.; Wiley: New York, 1977; Part 2, p
653. (d) Weyersthal, P.; Marschall, H. Fragmentation Reactions. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: New York, 1991; Vol. 6, p 1041.
(9) A racemic sample of 12a was prepared from the pyrrolidine
amide corresponding to 5 and was used as a control for the analysis
[chiral OJ column, hexane/2-propanol (25:1), 0.55 mL/min, λ ) 220
nm, tR ) 40.8 min (major enantiomer), tR ) 44.5 min (minor enanti-
omer)].
(10) Schultz, A. G.; Zhang, X. Chem. Commun. 2000, 399.
7730 J . Org. Chem., Vol. 69, No. 22, 2004

Novel Fragmentation Reaction
SCHEME 5
SCHEME 6 a
TABLE 4. F r a gm en ta tion of 1 w ith LiOR3
entry
1
R1
R2
R3
product yield (%)a
1
2
3
4
5
6
7
8
9
1a
1a
1a
1b
1b
1c
1d
H
H
H
H
H
H
H
Me
Me
Me
(CH2)3Cl
(CH2)3Cl
(CH2)4Cl
Me
Bn
PMB
Me
Bn
20
21
22
23
24
25
26
27
28
29
87
80
87
68
65
63
35b
31c
47
32
Bn
a
(CH2)2C6H4(o-Br) Me
Reagents and conditions: (a) DDQ, CH2Cl2, sealed tube for
1h Me Et
1h Me Et
1h Me Et
Me
Bn
PMB
32; (b) DDQ, CH2Cl2/H2O, rt for 33; (c) Et3N, THF, rt.
10
was found that the 2,4-disubstituted substrates (entries
8-10) gave much lower chemical yields of the fragmenta-
tion products 27-29 as well as lower chemoselectivity
(a ratio of 2:1 of 27:31, entry 8). The nature of the
alkoxide (methyl, benzyl, and p-methoxybenzyl) employed
seems to have no significant impact on either the yield
or the chemoselectivity of the process.
a
b
Isolated yields. With inseparable 30. c With inseparable 31.
Structural assignments of γ-butyrolactones 20-29
were characterized via chemical shifts of the vinyl
protons in the H NMR spectra.15 The vinyl protons of
1
such access. Utilizing the procedure described by Boger,11
1a was heated with TEMPO (5 equiv) and n-Bu3SnH (3
equiv) in benzene to give 18 and 19 in 21 and 61% yield,
respectively.12 Predominant formation of 19 over 18 is a
consequence of the preferential equatorial approach of
TEMPO to the resulting secondary radical in a way that
relieves 1,3-interaction with the axial hydrogen atom at
C-5.13 Under the standard fragmentation conditions
(LiOH, THF/H2O, room temperature), 18 provided a
mixture of 11a (18%) and 12a (51%). In contrast, 19
provided chemoselective hydrolytic fragmentation result-
ing only in 11a (78%).
Lith iu m Alk oxid e-In d u ced F r a gm en ta tion . Frag-
mentation of 1 promoted by lithium alkoxides was also
examined, as shown in Scheme 5. The results sum-
marized in Table 4 indicated that when, in general, R1
is H, fragmentation yielded γ-butyrolactones 20-2514
(entries 1-6) as single fragmentation products in 63-
87% yield. However, when R2 is a relatively bulky group
(entry 7), fragmentation provided not only γ-butyro-
lactone 26 but also butenolide 30 in a ratio of 1.7:1. It
20-29 resonate downfield between 6.67 and 6.85 ppm
as a doublet of quartets (J ) 8.1, 1.4 Hz, 20 and 21), a
doublet (J ) 8.1-8.8 Hz, 22-26), and a singlet (27-29).
Large coupling constants (J ) 8.1-8.8 Hz) observed for
the vinyl protons of 20-26 suggest that a vinyl proton
and the adjacent methine proton have an orthogonal
stereochemical relationship. Indeed, the anticipated or-
thogonal stereochemical relationship of a vinyl proton
and the adjacent methine proton was unambiguously
confirmed by the X-ray crystal structure of 22.16 The
expected reduced acidity of the methine proton might
explain why the γ-vinylogous butyrolactones 20-26 do
not epimerize even under the relatively basic reaction
conditions.2 The (E)-geometric configuration of the trisub-
stituted alkene was also confirmed by the X-ray crystal
structure of 22. The structure of butenolide ester 30 was
assigned by comparison with the independently prepared
esterification product (MeOH, TFA, room temperature)
from butenolide carboxylic acid 11d .
We further examined the feasibility of this fragmenta-
tion process in an intramolecular fashion (Scheme 6).
Thus, the O-protecting groups in R2 of 1e and 1j were
removed17 to afford hydroxy carbolactones 32 and 33,
which existed presumably as a mixture of the hydroxy
ketone and the hemiketal tautomers. It was somewhat
surprising that even under mild basic conditions (Et3N),
32 and 33 underwent facile intramolecular fragmentation
affording bislactones 34 and 35 as sole products in 96
and 86% yield, respectively. Diagnostic downfield shifts
(11) (a) Boger, D. L.; McKie, J . A. J . Org. Chem. 1995, 60, 1271 and
references therein. (b) Schultz, A. G.; Dai, M.; Tham, F. S.; Zhang, X.
Tetrahedron Lett. 1998, 39, 6663.
(12) For a radical-promoted rearrangement of iodo carbolactones,
see: Hart, D. J .; Havas, F. C. R. Acad. Sci. 2001, 4, 591.
(13) (a) Coblens, K. E.; Muralidharan, V. B.; Ganem, B. J . Org.
Chem. 1982, 47, 5041. (b) Keck, G. E.; Yates, J . B. J . Org. Chem. 1982,
47, 3590. (c) Ramaiah, M. Tetrahedron 1987, 43, 3541. (d) Chung, C.-
P.; Gallucci, J . C.; Hart, D. J . J . Org. Chem. 1988, 53, 3210. (e) Schultz,
A. G.; Kirincich, S. J . J . Org. Chem. 1996, 61, 5626.
(14) For recent syntheses of γ-butyrolactones, see: (a) Fukuzawa,
S.-i.; Seki, K.; Tatsuzawa, M.; Mutoh, K. J . Am. Chem. Soc. 1997, 119,
1482. (b) Charani, N.; Tobisu, M.; Asaumi, T.; Fukumoto, Y.; Murai,
S. J . Am. Chem. Soc. 1999, 121, 7160. (c) Trost, B. M.; Rhee, Y. H. J .
Am. Chem. Soc. 1999, 121, 11680. (d) Gagnier, S. V.; Larock, R. C. J .
Org. Chem. 2000, 65, 1525. (e) Zhang, Q.; Lu, X. J . Am. Chem. Soc.
2000, 122, 7604. (f) Peng, Z.-H.; Woerpel, K. A. Org. Lett. 2001, 3, 675.
(g) Sibi, M. P.; Liu, P.; J i, J .; Hajra, S.; Chen, J .-x. J . Org. Chem. 2002,
67, 1738. (h) Shindo, M.; Itoh, K.; Ohtsuki, K.; Tsuchiya, C.; Shishido,
K. Synthesis 2003, 9, 1441. (i) Yoshimitsu, T.; Makino, T.; Nagaoka,
H. J . Org. Chem. 2003, 68, 7548.
(15) (a) To determine the enantiomeric purities of the fragmentation
products, 24 was chosen as a representative example and chemically
modified in order to utilize the Mosher method (see details in the
Supporting Information). (b) Dale, J . A.; Mosher, H. S. J . Am. Chem.
Soc. 1968, 90, 3732. (c) Sullivan, G. R.; Dale, J . A.; Mosher, H. S. J .
Org. Chem. 1973, 38, 2143. (d) Yamaguchi, S.; Yasuhara, F.; Kabuto,
K. T. Tetrahedron 1976, 32, 1363.
(16) See the Supporting Information for X-ray crystallographic data.
(17) Nakajima, N.; Abe, R.; Yonemitsu, O. Chem. Pharm. Bull. 1988,
36, 4244 and references therein.
J . Org. Chem, Vol. 69, No. 22, 2004 7731

Khim et al.
Con clu sion
In summary, we have demonstrated that optically pure
2-alkyl- and 2,4-dialkyl-3-iodo-1-oxocyclohexan-2,4-car-
bolactones undergo lithium hydroxide- and lithium alkox-
ide-induced fragmentation reactions to afford buteno-
lides, γ-hydroxycyclohexenones, and/or γ-butyrolactones.
The product distributions of this process are governed
by the nature of nucleophiles used and the steric bulki-
ness of substituents at C-2 and C-4 of the cyclohexanones.
Fragmentation induced by lithium hydroxide was found
to be a general method for obtaining optically active 3,5-
disubstituted butenolide, which otherwise is not readily
available.18 Lithium alkoxide-induced fragmentation ex-
clusively provides γ-butyrolactone.
Exp er im en ta l Section
For general experimental procedures, see the Supporting
Information.
The following compounds were prepared by literature
methods: 2-(2′-bromophenyl)-1-iodoethane,19 1-iodo-3-benzyl-
oxypropane,20 1-(2′-trimethylsilyl)ethyloxy-1-chloromethane,21
and 2-(p-methoxybenzyloxy)-1-iodoethane.22
Gen er a l P r oced u r e for th e F r a gm en ta tion of 1 w ith
LiOH‚H2O. To a solution of 1a (255 mg, 0.9 mmol) in THF/
H2O (12 mL, 5:1) was added LiOH‚H2O (76 mg, 1.8 mmol).
The resulting solution was stirred overnight at room temper-
ature. The reaction mixture was neutralized with 10% aqueous
HCl solution and extracted with diethyl ether. The combined
organic layers were dried over Na2SO4 and concentrated under
reduced pressure. Flash column chromatography (hexanes/
EtOAc, 3:1) of the crude residue gave 11a (34 mg, 27%) and
12a (53 mg, 58%). (5R)-[3-Methyl-5-(2′-hydroxycarbonyl)ethyl]-
furan-2(5H)-1-one (11a ): white solid; mp 82-84 °C; [R]25
D
-35.8 (c 0.67); 1H NMR δ 7.03 (d, J ) 1.4 Hz, 3H), 5.00-4.97
(m, 1H), 2.58-2.49 (m, 2H), 2.22-2.15 (m, 1H), 1.93-1.91 (m,
3H), 1.87-1.79 (m, 1H); 13C NMR δ 177.9, 173.9, 147.9, 130.7,
79.6, 29.0, 28.2, 10.6; IR ν 3467, 2931, 1736 cm-1; CIMS 171
(M+ + 1, 100); HRMS calcd for C8H11O4 (M+ + 1) 171.0657,
F IGURE 2. Proposed mechanisms for the LiOR3-promoted
fragmentation of 1.
found 171.0657. (4R)-4-Hydroxy-2-methyl-2-cyclohexen-1-one
of the vinyl protons (6.98 ppm for 34 and 6.66 ppm for
35) and the large coupling constant (J ) 7.8 Hz for 34)
in 1H NMR spectra indicated the formation of the
γ-butyrolactones. The absolute structure of 35 was
determined by X-ray crystallography.16
1
(12a ): colorless liquid; [R]28 +48.0 (c 0.98); H NMR δ 6.09
D
(m, 1H), 4.52 (m, 1H), 2.60-2.54 (m, 2H), 2.36-2.26 (m, 2H),
1.97-1.89 (m, 1H), 1.75 (m, 3H); 13C NMR δ 199.3, 147.9,
135.6, 66.4, 35.3, 32.7, 15.6; IR ν 3411, 1669 cm-1; CIMS 127
(M+ + 1, 100); HRMS calcd for C7H10O2 (M+ + 1) 127.0759,
found 127.0759.
We postulate that there are two fragmentation path-
ways for 1. As depicted in Figure 2, lithium alkoxide
attacks either the lactone carbonyl moiety to give γ-
butyrolactones 20-29 (pathway A) or the ketone carbonyl
moiety to give butenolides 30 and 31 (pathway B). In
pathway A, when an alkoxide anion attacks the lactone
carbonyl moiety of 1, it affords 4-alkoxy cyclohexanone
intermediate 36. The fact that the â,γ-epoxycyclohex-
anone 37 was not observed strongly implies that 36
undergoes a rather rapid conformational change from a
chair conformation to a boat conformational 38 in order
to relieve the 1,3-diaxial interaction between alkoxide
anion and the ester group of 36. The boat conformation
of 38 facilitates transannular cyclization to give the
transannular lactol anion 39, and subsequent fragmenta-
tion leads to the formation of γ-butyrolactones 20-29.
In the case of pathway B, 1 undergoes alkoxide anion
addition to the ketone carbonyl moiety to afford inter-
mediate 40, which then undergoes a ring-opening reac-
tion to give the stabilized lactone enolate 41. Subsequent
elimination would yield butenolides 30 and 31.
P r ep a r a tion of 18 a n d 19. A solution of 1a (1.44 g, 5.14
mmol) and TEMPO (4.01 g, 25.7 mmol) in benzene (100 mL)
was deoxygenated by bubbling N2 into the solution for 10 min.
n-Bu3SnH (1.38 mL, 5.14 mmol) was added, and the solution
was warmed to 70 °C. Two additional solutions of n-Bu3SnH
(1.38 mL each) in benzene were added during the next 30 min.
The reaction mixture was heated for an additional 30 min.
The reaction mixture was cooled and then washed with 10%
HCl solution, brine, and water. The organic layers were
separated and dried over anhydrous Na2SO4 and concentrated
under reduced pressure. The crude residue was purified by
flash column chromatography (hexanes/EtOAc, 4:1) to give 18
(335 mg, 21%) and 19 (972 mg, 61%). (2R,3R,4R)-1-Oxo-2-
methyl-3-(2′,2′,6′,6′-tetramethyl-1′-piperidinyloxy)cyclohexan-
(18) (a) The synthetic applications of butenolide will be published
in due course. (b) Khim, S.-K.; Schultz, A. G. J . Org. Chem. 2004, 69,
7734.
(19) (a) Wender, P. A.; White, A. W. J . Am. Chem. Soc. 1988, 110,
2218. (b) Ripa, L.; Hallberg, A. J . Org. Chem. 1998, 63, 84.
(20) Singerman, G. M.; Kimura, R.; Riebsomer, J . L.; Castle, R. N.
J . Heterocycl. Chem. 1966, 3, 74.
(21) Lipschutz, B. H.; Pegram, J . J . Tetrahedron Lett. 1980, 21, 3343.
(22) Grobelny, D.; Maslak, P.; Witek, S. Tetrahedron Lett. 1979, 20,
2639.
7732 J . Org. Chem., Vol. 69, No. 22, 2004

Novel Fragmentation Reaction
2,4-carbolactone (18): mp 102-104 °C; [R]26 -95 (c 0.79); 1H
under reduced pressure to give a yellow oil. The crude product
was purified by flash column chromatography (hexanes/EtOAc,
1:1) to afford 32 (501 mg, 76%) as a colorless oil, which was
used without further purification for the next reaction (hy-
droxyketone/hemiketal, 10:1): [R]26D -125.2 (c 0.76); 1H NMR
δ 4.94 (s, 1H), 4.77 (d, J ) 5.4 Hz, 1H), 3.63 (m, 2H), 2.69-
2.60 (m, 2H), 2.58-2.53 (m, 1H), 2.44-2.37 (m, 1H), 1.99 (m,
1H), 1.81 (m, 1H), 1.58 (br s, 1H), 1.41 (m, 2H); 13C NMR δ
198.2, 170.1, 77.6, 62.7, 33.2, 27.6, 26.2, 23.7, 21.5; IR ν 3522,
1780, 1723 cm-1; CIMS 325 (M+ + 1).
(3E)-Tet r a h yd r o-3-[[(2R)-t et r a h yd r o-5-oxofu r a n yl]-
m eth ylen e]-2H-p yr a n -2-on e (34). To a solution of crude 32
(45 mg, 0.14 mmol) in CH2Cl2 (1 mL) was added 2 drops of
Et3N at room temperature. The reaction mixture was stirred
overnight. Water and CH2Cl2 were added, and the aqueous
phase was extracted with CH2Cl2. The combined organic layers
were dried over anhydrous Na2SO4, filtered, and concentrated
to give 34 (26 mg, 96%) as a white solid: [R]24D -41.4 (c 0.58);
1H NMR δ 6.93 (d, J ) 7.8 Hz, 1H), 5.16 (q, J ) 7.3 Hz, 1H),
4.32 (t, J ) 5.6 Hz, 2H), 2.70 (m, 1H), 2.56 (m, 4H), 2.46 (m,
1H), 2.05 (m, 1H), 1.94 (m, 1H); 13C NMR δ 176.3, 165.3, 140.3,
129.9, 128.6, 75.7, 69.0, 28.3, 28.2, 24.3, 22.6; IR ν 1763, 1719
cm-1; CIMS 197 (M+ + 1, 100). Anal. Calcd for C10H12O4: C,
61.22; H, 6.16. Found: C, 60.93; H, 6.17.
(2R,3R,4R)-2-(2′-Hyd r oxy)eth yl-3-iod o-4-m eth yl-1-oxo-
cycloh exa n -2,4-ca r bola cton e (33). To a solution of 1j (100
mg, 0.23 mmol) in CH2Cl2/H2O (21 mL, 20:1) was added DDQ
(61 mg, 0.27 mmol) at room temperature. The reaction mixture
was stirred for 3 h and quenched with water and extracted
with CH2Cl2. The combined organic layers were dried over
anhydrous Na2SO4 and concentrated to give 33. The crude
residue was directly used for the next reaction without further
purification: 1H NMR δ 4.66 (s, 1H), 3.48 (m, 1H), 3.33 (m,
1H), 2.27-1.53 (m, 6H), 1.00 (s, 3H); 13C NMR δ 198.4, 171.2,
84.5, 65.3, 58.6, 50.5, 33.6, 33.5, 33.3, 33.2, 28.1, 22.5, 22.4.
(5R)-5-[(E)-(Dih yd r o-2-oxo-3(2H)-fu r a n ylid en e)m eth yl]-
d ih yd r o-5-m eth yl-2(3H)-fu r a n on e (35). Crude 33, contami-
nated with 4-methoxybenzaldehyde, was dissolved in THF (10
mL), and Et3N (0.20 mL, 1.4 mmol) was added. The reaction
mixture was stirred for 3 h and extracted with CH2Cl2. The
combined organic layers were dried over anhydrous Na2SO4
and concentrated under reduced pressure. Flash column
chromatography (hexanes/EtOAc, 1:1) of the crude residue
D
NMR δ 5.02 (t, J ) 4.6 Hz, 1H), 4.82 (d, J ) 5.1 Hz, 1H), 2.62
(dd, J ) 8.8, 1.8 Hz, 1H), 2.54 (m, 2H), 2.42 (m, 1H), 1.62 (m,
1H), 1.53 (s, 3H), 1.51 (s, 3H), 1.49 (s, 3H), 1.40 (m, 5H), 1.15
(br s, 6H); 13C NMR δ 199.3, 172.2, 90.7, 75.3, 61.5, 40.5, 39.2,
34.3, 28.7, 26.2, 24.4, 16.8, 16.3, 16.0, 13.9, 13.2; IR ν 1790,
1725 cm-1; CIMS 310 (M+ + 1, 100). (2R,3S,4R)-1-Oxo-2-
methyl-3-(2′,2′,6′,6′-tetramethyl-1′-piperidinyloxy)cyclohexan-
2,4-carbolactone (19): mp 128-130 °C; [R]26 -126 (c 0.82);
D
1H NMR δ 5.40 (d, J ) 4.4 Hz, 1H), 4.25 (s, 1H), 2.56 (dd, J )
6.9, 2.2 Hz, 2H), 2.42 (m, 1H), 1.88 (m, 1H), 1.62-1.35 (m,
6H), 1.40 (s, 3H), 1.20 (s, 3H), 1.16 (s, 3H), 1.11 (s, 3H), 1.07
(s, 3H); 13C NMR δ 199.5, 174.7, 86.8, 76.9, 76.6, 62.5, 61.9,
60.0, 50.0, 40.4, 34.7, 34.0, 33.6, 5.0, 20.8, 20.6, 17.0, 8.80; IR
ν 1775, 1718 cm-1; CIMS 310 (M+ + 1, 100). Anal. Calcd for
C
17H27NO4: C, 65.99; H, 8.80. Found: C, 65.17; H, 8.59. The
foregoing combustion analysis of this sample indicates that
the sample was probably wet. A sample of compound 19,
sufficient for re-analysis, is no longer available.
F r a gm en ta tion of 18 w ith LiOH‚H2O. To a solution of
18 (175 mg, 0.57 mmol) in THF/H2O (4 mL, 5:1) was added
LiOH‚H2O (470 mg, 1.14 mmol). The resulting solution was
stirred overnight at room temperature. The reaction mixture
was neutralized with 10% HCl solution and extracted with
diethyl ether. The combined organic solution was dried over
anhydrous Na2SO4 and concentrated under reduced pressure
to give a colorless oil. Flash column chromatography (hexanes/
EtOAc, 3:1 to 2:1) of the crude residue gave 11a as a single
product (75 mg, 78%).
F r a gm en ta tion of 19 w ith LiOH‚H2O. To a solution of
19 (101 mg, 0.33 mmol) in THF/H2O (2.5 mL, 5:1) was added
LiOH‚H2O (140 mg, 0.65 mmol). The resulting solution was
stirred overnight at room temperature. The reaction mixture
was neutralized with 10% HCl solution and extracted with
diethyl ether. The combined organic solution was dried over
anhydrous Na2SO4 and concentrated under reduced pressure
to give a colorless oil. Flash column chromatography (hexanes/
EtOAc, 3:1 to 2:1) of the crude residue gave 11a (10 mg, 18%)
and 12a (21 mg, 51%).
Gen er a l P r oced u r e for th e F r a gm en ta tion of 1 w ith
Lith iu m Meth oxid e. Meth yl (2E)-2-Meth yl-3-[(2R)-3-tet-
r a h yd r o-5-oxofu r a n yl]-2-p r op en oa te (20). To a solution of
MeOH (30 µL, 0.8 mmol) in THF (5 mL) was added n-BuLi
(180 µL, 0.5 mmol, 2.5 M solution in hexanes) at -78 °C. The
resulting solution was stirred for 0.5 h. To this solution was
added dropwise a solution of 1a (106 mg, 0.4 mmol) in THF (5
mL) at -78 °C. The resulting solution was stirred overnight
at room temperature. The reaction mixture was diluted with
water and extracted with diethyl ether. The combined organic
layers were dried over Na2SO4 and concentrated under reduced
pressure. Flash column chromatography (hexanes/EtOAc, 3:1)
gave 35 (38 mg, 86%) as a white solid: mp 132-134 °C; [R]25
D
+30.0 (c 1.0); 1H NMR δ 6.66 (m, 1H), 4.34 (m, 2H), 3.15-
3.01 (m, 2H), 2.59 (m, 2H), 2.32-2.19 (m, 2H), 1.56 (s, 3H);
13C NMR δ 176.0, 171.6, 139.7, 126.0, 85.0, 66.1, 34.8, 28.7,
26.1, 25.7; IR ν 1766, 1744 cm-1; CIMS 197 (M+ + 1, 100).
Anal. Calcd for C10H12O4: C, 61.22; H, 6.16. Found: C, 60.95;
H, 6.24.
of the crude residue gave the desired product 20 (61 mg, 87%)
1
as a colorless oil: [R]27 -46.5 (c 0.71); H NMR δ 6.67 (dq, J
Ack n ow led gm en t. This work was supported by the
National Institutes of Health (GM 26568). We thank Dr.
Fook S. Tham for the X-ray structure determination.
D
) 8.1, 1.4 Hz, 1H), 5.25 (dd, J ) 15.1, 8.1 Hz, 1H), 3.75 (s,
3H), 2.60-2.53 (m, 2H), 2.50-2.44 (m, 1H), 2.04-1.96 (m, 1H),
1.91 (d, J ) 1.4 Hz, 3H); 13C NMR δ 176.4, 167.4, 137.6, 131.2,
76.3, 52.1, 28.3, 28.2, 13.0; IR ν 1780, 1718 cm-1; CIMS 185
(M+ + 1, 100), 153 (30). Anal. Calcd for C9H12O4: C, 58.69; H,
6.57. Found: C, 58.59; H, 6.61.
(2R,3R,4R)-2-(3′-Hydr oxy)p r opyl-3-iod o-1-oxocycloh ex-
a n -2,4-ca r bola cton e (32). 1e (840 mg, 2.03 mmol) and DDQ
(1.38 g, 6.09 mmol) were dissolved in CH2Cl2 (15 mL) at a
sealed tube. The reaction mixture was heated at 60 °C for 8 h
and then cooled to room temperature. The solid was removed
through a thin pad of Celite. The filtrate was concentrated
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for compounds discussed
in the text (but not described in the Experimental Section),
1H NMR spectra for 11e, 13, and 19, and ORTEP drawings
and crystal data and structure refinement for 23 and 35. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O0490853
J . Org. Chem, Vol. 69, No. 22, 2004 7733