Acidity-directed synthesis of substituted γ-Butyrolactones from aliphatic aldehydes

Article abstract of DOI:10.1021/ol0705806

The strength of the Lewis or Brensted acids controls the formation of either β,γ-disubstituted-α-methylene-γ-butyrolactones or γ-substituted-α-alkylidene-γ-butyrolactones via the lactonization or oxonia cope rearrangement-lactonization, respectively, of t

Full text of DOI:10.1021/ol0705806

ORGANIC
LETTERS
2007
Vol. 9, No. 11
2087-2090
Acidity-Directed Synthesis of
Substituted -Butyrolactones from
Aliphatic Aldehydes
γ
P. Veeraraghavan Ramachandran* and Debarshi Pratihar
Department of Chemistry, Purdue UniVersity, 560 OVal DriVe,
West Lafayette, Indiana 47907-2084
chandran@purdue.edu
Received March 8, 2007
ABSTRACT
The strength of the Lewis or Brønsted acids controls the formation of either
-alkylidene- -butyrolactones via the lactonization or oxonia cope rearrangement
from the crotylboration of aliphatic aldehydes with ester-containing crotylboronates, such as (E)-methyl 2-boramethyl-2-butenoates.
â
,
γ
-disubstituted-r-methylene-γ-butyrolactones or γ-substituted-
r
γ
−lactonization, respectively, of the borate intermediates resulting
R-Methylene-γ-butyrolactones have been shown to target the
Iκâ kinase (IKK) and the transcription factor regulator
nuclear factor-kappaB (NF-κB),1 indicating their important
role in inter- and intracellular signaling.2 The binding of a
series of suitably γ-substituted-R-alkylidene-γ-butyrolac-
tones, analogues of diacylglycerol (DAG)-lactones, to protein
kinase C (PK-C) revealed the enhanced affinity due to the
R-alkylidine group.3 Strategically substituted γ-butyrolac-
tones, particularly R-alkylidene-γ-butyrolactones, are very
important structural units in many natural products.4 Their
wide range of biological properties makes them popular
synthetic targets.5,6 Although several routes to their syntheses
have been reported,7 simple procedures are still being sought.
Preparation of diverse lactones by minor modifications in
reaction conditions enhances the ability of synthetic chem-
ists.8 The following is the description of the first controlled
one-pot synthesis of either â,γ-disubstituted-R-methylene-
or γ-substituted-R-alkylidene-γ-butyrolactones from aliphatic
aldehydes by an appropriate choice of Lewis or Bronsted
acid-catalyzed crotylboration.9
In the presence of 10% In(OTf)3, crotylboration of
cyclohexanecarboxaldehyde (ChxCHO, 2a) with (E)-methyl
(5) (a) Katsumi, I.; Kondo, H.; Yamashita, K.; Hidaka, T.; Hosoe, K.;
Yamashita, T.; Watanabe, K. Chem. Pharm. Bull. 1986, 34, 121. (b)
Shaikenov, T. E.; Adekenov, S. M.; Williams, R. M.; Baker, F. L.; Prasad,
N.; Madden, T. L.; Newman, R. Oncol. Rep. 2001, 8, 173.
(6) (a) Nattrass, G. S.; Diez, E.; McLachlan, M. M.; Dixon, D. J.; Ley.
S. V. Angew. Chem., Int. Ed. 2005, 44, 580. (b) Biel, M.; Kretsovali, A.;
Karatzali, E.; Papamatheakis, J.; Giannis, A. Angew. Chem., Int. Ed. 2004,
43, 3974. (c) Gonzalez, A. G.; Silva, M. H.; Pardon, J. I.; Leon, F.; Reyes,
E.; Alvarez-Mon, M.; Pivel, J. P.; Quintana, J.; Estevez, F.; Bermejo, J. J.
Med. Chem. 2002, 45, 2358. (d) Trost, B. M.; Corte, J. R. Angew. Chem.,
Int. Ed. 1999, 38, 3664. (e) Trost, B. M.; Corte, J. R.; Gudiksen, M. S.
Angew. Chem., Int. Ed. 1999, 38, 3662.
(7) (a) Hughes, M. A.; McFadden, J. M.; Townsend, C. A. Bioorg. Med.
Chem. Lett. 2005, 15, 3857. (b) Tong, X.; Li, D.; Zhang, Z.; Zhang, X. J.
Am. Chem. Soc. 2004, 126, 7601. (c) Lei, A.; He, M.; Zhang, X. J. Am.
Chem. Soc. 2002, 124, 8198. (d) Lee, K.; Jackson, J. A.; Wiemer, D. F. J.
Org. Chem. 1993, 58, 5967.
(1) Huang, W. C.; Chan, S. T.; Yang, T. L.; Tzeng, C. C.; Chen, C. C.
Carcinogenesis 2004, 25, 1925.
(2) Hoffmann, A.; Levchenko, A.; Scott, M. L.; Baltimore, D. Science
2002, 298, 1241.
(3) (a) Kang, J. H.; Peach, M. L.; Pu, Y.; Lewin, N. E.; Nicklaus, M.
C.; Blumberg, P. M.; Marquez, V. E. J. Med. Chem. 2005, 48, 5738. (b)
Tamamura, H.; Bruno, B.; Nacro, K.; Nancy, E. L.; Blumberg, P. M.;
Marquez, V. J. Med. Chem. 2000, 43, 3209.
(4) (a) Janecki, T.; Blaszczyk, E.; Janecka, A.; Krajewaska, U.; Rozalski,
M. J. Med. Chem. 2005, 48, 3516 and references cited therein. (b) For a
review on R-methylene-γ-butyrolactones, see: Hoffmann, H. M. R.; Rabe,
J. Angew. Chem., Int. Ed. 1985, 24, 110. (c) For a review on lactones as
generic inhibitors of enzymes, see: Konaklieva, M. I.; Plotkin, B. J. Mini-
ReV. Med. Chem. 2005, 5, 73.
(8) Ramachandran, P. V.; Pratihar, D.; Biswas, D. Org. Lett. 2006, 8,
3877.
10.1021/ol0705806 CCC: $37.00
© 2007 American Chemical Society
Published on Web 05/01/2007

2-boramethyl-2-butenoate, E-1,10,11 led to the formation of
a mixture of R-E-ethylidene-γ-cyclohexyl-γ-butyrolactone
(E-3a), along with the expected cis-R-methylene-â-methyl-
γ-cyclohexyl-γ-butyrolactone (cis-4a) in a 3:2 ratio (Scheme
1). In contrast, a similar reaction of aromatic aldehydes, in
Table 1. Optimization of Reaction Conditions for the Selective
Formation of E-3a/cis-4aa
ChxCHO time yieldb
entry catalyst (mol %)
(equiv)
(h)
(%)
E-3a:cis-4ac
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
In(OTf)3(10)
In(OTf)3(20)
In(OTf)3(10)
In(OTf)3(20)
In(OTf)3(20)
CF3SO3H(20)
In(OTf)3(20)
In(OTf)3(10)
In(OTf)3(10)
Sn(OTf)2(20)
Cu(OTf)2(20)
Sc(OTf)3(20)
Bu2OTf(20)
Zn(OTf)2(20)d
Yb(OTf)3(20)d
TFA(10)
1.0
1.0
1.2
1.2
1.5
1.5
0.8
0.8
0.5
1.1
1.1
1.1
1.1
1.1
1.1
1.1
32
24
36
30
30
10
24
36
24
30
24
24
18
24
18
24
75
78
82
80
90
75
80
75
75
80
76
85
70
80
90
80
60:40
65:35
65:35
75:25
99:1
Scheme 1. In(OTf)3-Catalyzed Crotylboration of 2a with
Crotylboronate E-1
99:1
40:60
25:75
15:85
70:30
66:34
58:42
58:42
1:99
the presence of Lewis or Bronsted acid, resulted in a general
diastereoselective synthesis of either cis- or trans-â,γ-
disubstituted-γ-butyrolactones.8,12 Unlike the aromatics, the
unexpected formation of E-3a for the aliphatic aldehydes
led us to explore the reaction and determine the conditions
for the exclusive preparation of either E-3a or cis-4a.
1:99
1:99
a Reaction conditions: E-1, 2a, and catalyst in toluene at rt. b Isolated
yield after chromatography. c Determined by 1H NMR of the crude reaction
mixture. d See ref 14.
The presence of 20% In(OTf)3 modestly increased the
formation of the rearranged product E-3a from the crotyl-
boration of 1 equiv of 2a with E-1. While a similar result
was also achieved by increasing the aldehyde equiv to 1.2,
a combination of both variables provided a 3:1 ratio of E-3a
and cis-4a. Further increasing the aldehyde to 1.5 equiv
resulted in the formation of E-3a almost exclusively (Table
1, entry 5).
reaction provided cis-4a essentially exclusively (Table 1,
entries 14 and 15) (Scheme 2).14
Scheme 2. Selective Synthesis of γ-Substituted-R-
E-alkylidene- or cis-â,γ-Disubstituted-R-methylene-
γ-butyrolactones
A mixture of E-3a and cis-4a in a 2:3 ratio was observed
in the presence of 20% In(OTf)3 when the aldehyde (2a)
equivalent was decreased to 0.8. With 10% In(OTf)3, a 1:3
mixture of lactones favoring cis-4a was obtained. Further
decreasing the amount of aldehyde to 0.5 equiv provided
E-3a and cis-4a in 15:85 ratio (Table 1, entry 9). Additional
reduction of aldehyde renders this procedure impractical. The
results are summarized in Table 1.
To achieve an exclusive synthesis of cis-4a, our next
option was to examine the effect of Lewis acid strength13
on the lactonization. While Sn(OTf)2, Cu(OTf)2, Sc(OTf)3,
and Bu2BOTf-catalyzed reaction provided mixtures of lac-
tones E-3a and cis-4a, the Zn(OTf)2, Yb(OTf)3-catalyzed
On the basis of our earlier experience that the triflic acid-
catalyzed reaction is faster than the Lewis acid-mediated
reactions,8 we also examined the effect of Brønsted acids,
such as trifluoroacetic acid (TFA) and triflic acid, for the
selective formation of either lactones. While a triflic acid-
catalyzed reaction of E-1 and 2a provided E-3a in 99%
selectivity (Table 1, entry 6), the weaker Brønsted acid, TFA-
catalyzed crotylboration provided cis-4a in 99% selectivity
(Table 1, entry 16).
(9) For earlier reports on Lewis or Bronsted acid-catalyzed crotylboration,
see: (a) Kennedy, J. W. J.; Hall, D. G. J. Am. Chem. Soc. 2002, 124, 11586.
(b) Ishiyama, T.; Ahiko, T.-a.; Miyaura, N. J. Am. Chem. Soc. 2002, 124,
12414. (c) Yu, S. H.; Ferguson, M. J.; McDonald, R.; Hall, D. G. J. Am.
Chem. Soc. 2005, 127, 12808.
(10) Ramachandran, P. V.; Pratihar, D.; Biswas, D.; Reddy, M. V. R.
Org. Lett. 2004, 6, 481.
(11) (a) Following the Cahn-Ingold-Prelog priority rules, the parent
Z- and E-crotylboronates become E- and Z-, respectively (E-1 and E-5,
and Z-1 and Z-5), when substituted with a COOMe group. Cahn, R. S.;
Ingold, C.; Prelog. V. Angew. Chem., Int. Ed. Engl. 1966, 5, 385. (b) It
should be remembered that the parent Z- and E-crotylboronates give cis-
and trans-R-methyl homoallyl alcohols, respectively, via a six-membered
Zimmerman-Traxler transition state. Zimmerman, H. E.; Traxler, M. D.
J. Am. Chem. Soc. 1957, 79, 1920
To expand the versatility of this crotylboration-lacton-
ization, we prepared the Z-crotylboronate11 Z-1 via the
homologation15 of the corresponding vinylaluminum16 with
(14) It is noteworthy that we obtained the cis-lactone diastereoselectively
with all of the catalysts, except in the case of Zn(OTf)2 where a cis/trans
ratio of 92:8 was obtained. The Yb(OTf)3-catalyzed reaction provided a
cis/trans lactone ratio of 99:1.
(15) Chataigner, I.; Lebreton, J.; Zammatio, F.; Villie´ras, J. Tetrahedron
Lett. 1997, 38, 3719.
(16) (a) Ramachandran, P. V.; Reddy, M. V. R.; Rudd, M. T. Chem.
Commun. 1999, 1979. (b) Ramachandran, P. V.; Rudd, M. T.; Burghardt,
T. E.; Reddy, M. V. R. J. Org. Chem. 2003, 68, 9310.
(12) Elford, T. G.; Arimura, Y.; Yu, S. H.; Hall, D. G. J. Org. Chem.
2007, 72, 1276.
(13) For a review on the relative strengths of Lewis acids, see:
Kobayashi, S.; Manabe, K. Pure Appl. Chem. 2000, 72, 1373.
2088
Org. Lett., Vol. 9, No. 11, 2007

iodomethylboronate.17 The crotylboration of 1.5 equiv of 2a
with Z-1, in the presence of 20% In(OTf)3, provided the
corresponding R-Z-alkylidene lactone, Z-3a, almost exclu-
sively (99:1) and the Yb(OTf)3-catalyzed reaction provided
trans-4a in 99% selectivity (Scheme 3).
Table 3. Selective Synthesis of cis/trans-â,γ-
Disubstituted-R-methylene-γ-butyrolactonesa
RCHO
lactone
entry rgnt no.
R
cat.b
LA cis-4a
E-1 2b Ph(CH2)2 LA cis-4b
no.
yieldc 3/6:4/7d
1
2
E-1 2a Chx
95
85
75
80
90
85
80
70
80
82
80
75
1:99
1:99
1:99
1:99
1:99
1:99
1:99
1:99
1:99
1:99
1:99
1:99
Scheme 3. Selective Synthesis of γ-Substituted-
R-Z-alkylidene- or trans-â,γ-Disubstituted-R-
methylene-γ-butyrolactones
3
4
5
6
E-1 2c i-Pr
E-1 2d t-Bu
Z-1 2a Chx
E-5 2a Chx
LA cis-4c
LA cis-4d
LA trans-4a
LA cis-7a
7
E-5 2b Ph(CH2)2 LA cis-7b
8
9
10
11
12
E-5 2d t-Bu
Z-5 2a Chx
E-1 2a Chx
E-1 2b Ph(CH2)2 BA cis-4b
E-1 2d t-Bu BA cis-4d
LA cis-7d
LA trans-7a
BA cis-4a
a Reaction conditions: aldehyde 2 (1.1 mmol) added to crotylboronate
(1 mmol) and 20% LA or BA in toluene at rt for 18-36 h. b LA: Yb(OTf)3.
BA: TFA. c Percent isolated yield after chromatography. d Determined by
1H NMR of the crude reaction mixture.
Having achieved the optimal conditions for the one-pot
exclusive preparation of either R-E- or R-Z-alkylidene-γ-
cyclohexyl-γ-butyrolactone (3a) or cis- or trans-R-methyl-
ene-â-alkyl-γ-cyclohexyl-γ-butyrolactone (4a) by changing
the reagent (E- or Z-1) or the catalyst [In(OTf)3 or Yb(OTf)3],
we further established the generality of the reaction with the
crotylboration of a series of aliphatic aldehydes (2b-d) with
1 in the presence of either Lewis acid or Bronsted acid. In
all of the cases the R-alkylidene lactone 3 or R-methylene
lactone 4 was obtained almost exclusively (>99%) (Tables
2 and 3).
with 98% selectivity. These results are also included in
Tables 2 and 3.
The formation of the unexpected R-E-alkylidene lactone
was now analyzed. In the absence of a catalyst and under
thermal condition, the crotylboration of aldehyde 2a with
E-1 provides the intermediate syn-8.11b Exclusive formation
of cis-4a in 99% de occurs upon lactonization with use of
20% pTSA, In(OTF)3, or Yb(OTf)3. However, the addition
of 0.5 equiv of 2a to syn-8 in the presence of 20% In(OTf)3
resulted in the exclusive formation of E-3a. A similar
rearrangement did not occur in the presence of excess
aldehyde and Yb(OTf)3 (Scheme 4). This rearrangement is
Table 2. Selective Synthesis of γ-Substituted-R-E/Z-
alkylidene-γ-butyrolactonesa
RCHO
R
lactone
entry rgnt no.
cat.b
no.
yieldc 3/6:4/7d
1
2
3
4
5
6
7
8
9
E-1
E-1
E-1
E-1
Z-1
E-5
E-5
E-5
Z-5
E-1
E-1
2a Chx
2b Ph(CH2)2
LA
LA
LA
LA
LA
LA
LA
LA
LA
BA
BA
E-3a
E-3b
E-3c
E-3d
Z-3a
E-6a
E-6b
E-6d
Z-6a
E-3a
E-3b
95
85
75
80
90
85
80
70
80
75
75
99:1
99:1
99:1
99:1
99:1
98:2
98:2
98:2
98:2
99:1
99:1
Scheme 4. Lactonization or Rearrangement-Lactonization
from Crotylboration Intermediate
2c
i-Pr
2d t-Bu
2a Chx
2a Chx
2b Ph(CH2)2
2d t-Bu
2a Chx
2a Chx
2b Ph(CH2)2
10
11
an irreversible process since the interconversion of cis-4a
and E-3a was not possible in the presence of 20% In(OTf)3
and excess aldehyde.
Thus, the formation of R-E-alkylidene-γ-alkyl-γ-butyro-
lactones can be rationalized as follows (Scheme 5).19,20 The
borate intermediate, syn-8, obtained from the initial crotyl-
boration forms the acetal 9 in the presence of excess
aldehyde.21 The strong Lewis acid coordination to 9 results
in an oxonium ion intermediate 11 via the elimination of
10. This then undergoes an oxonia-Cope rearrangement and
a Reaction conditions: aldehyde 2 (1.5-1.7 mmol) added to crotylbo-
ronate (1 mmol) and 20% LA or BA in toluene at rt for 12-48 h. b LA:
In(OTf)3. BA: CF3SO3H. c Percent isolated yield after chromatography.
1
d Determined by H NMR of the crude reaction mixture.
Crotylboration of these aldehydes with the phenyl-
substituted “higher crotylboronate”18 E-5 was also examined.
In these cases, the reaction rate was slower and 1.7 equiv of
aldehyde was required to obtain the R-alkylidene lactone E-6
(17) Wallace, R. H.; Zong. K. K. Tetrahedron Lett. 1992, 33, 6941.
(18) Reagents such as E- and Z-5 have been termed “higher crotylbo-
ranes”, see: Brown, H. C.; Narla, G. Tetrahedron Lett. 1997, 38, 219.
(19) For a discussion of a related one-pot synthesis of â- and δ-substituted
homoallylic alcohols via crotylboration, see: Ramachandran, P. V.; Pratihar,
D.; Biswas, D. Chem. Commun. 2005, 1988.
Org. Lett., Vol. 9, No. 11, 2007
2089

disubstituted-γ-butyrolactones or E- or Z-R-alkylidine-γ-
substituted-γ-butyrolactones via crotylboration with either
the E- or Z-reagent, respectively, and the proper choice of
either the Lewis or Bronsted acids. Further applications of
this methodology for target synthesis are under way.
Scheme 5. Catalytic Cycle for the Formation of R-Alkylidene
Lactones
Supporting Information Available: Experimental details
and spectral data of all compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0705806
(20) For the Lewis acid-catalyzed conversion of â- to δ-substituted
homoallylic alcohols, see: (a) Nokami, J.; Yoshizane, K.; Matsuura, H.;
Sumida, S. J. Am. Chem. Soc. 1998, 120, 6609. (b) Sumida, S. I.; Ohga,
M.; Mitani, J.; Nokami, J. J. Am. Chem. Soc. 2000, 122, 1310. (c) Nokami,
J.; Nomiyama, K.; Matsuda, S.; Imai, N.; Kataoka, H. Angew. Chem., Int.
Ed. 2003, 42, 1273. (d) Loh, T. P.; Hu, Q. Y.; Ma, L. T. J. Am. Chem. Soc.
2001, 123, 2450. (e) Loh, T. P.; Tan, K. T.; Hu, Q. Y. Angew. Chem., Int.
Ed. 2001, 40, 2921. (f) Cheng, H. S.; Loh, T. P. J. Am. Chem. Soc. 2003,
125, 2958.
(21) Addition of a different aldehyde (2d) to the intermediate syn-8,
obtained from the allylboration of 2a with E-1 under refluxing conditions,
provided a mixture of lactones cis-4a and E-3d.
(22) (a) The formation of B-methoxypinacolborane 13 was confirmed
by 11B NMR spectroscopy (δ 22 ppm, see the experimental details in the
Supporting Information). (b) The PMR spectra of the progress of the reaction
for the formation of the rearranged product E-3a is also provided in the
Supporting Information.
further addition of 10 providing the rearranged borate
intermediate 12. Lactonization and elimination of borate ester
13 provides the γ-substituted-R-alkylidene-γ-butyrolactones
E-3.22 A similar mechanism holds true for the formation of
Z-3 as well from anti-8.
In conclusion, we have developed an efficient process for
the selective synthesis of cis- or trans-R-methylene-â,γ-
2090
Org. Lett., Vol. 9, No. 11, 2007