2-tert-Butoxy-3-phenylcyclopropanone acetal, a stable precursor of lithiated 2-phenylcyclopropenone acetal

Article abstract of DOI:10.1016/j.tetlet.2007.07.133

2-tert-Butoxy-3-phenylcyclopropanone acetal 8 was found to be a stable precursor of lithiated cyclopropenone acetal. Acetal 8 was used in the practical synthesis of cysteine proteinase inhibitors; isolated yield of the key intermediate 14 was better than

Full text of DOI:10.1016/j.tetlet.2007.07.133

Tetrahedron Letters 48 (2007) 7011–7014
2-tert-Butoxy-3-phenylcyclopropanone acetal, a stable
precursor of lithiated 2-phenylcyclopropenone acetal
Toshiro Sakaki and Ryoichi Ando*
Chemistry Laboratory, Mitsubishi Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan
Received 21 June 2007; revised 19 July 2007; accepted 23 July 2007
Available online 27 July 2007
Abstract—2-tert-Butoxy-3-phenylcyclopropanone acetal 8 was found to be a stable precursor of lithiated cyclopropenone acetal.
Acetal 8 was used in the practical synthesis of cysteine proteinase inhibitors; isolated yield of the key intermediate 14 was better
than the one by the previous method.
Ó 2007 Elsevier Ltd. All rights reserved.
Lithiated cyclopropenone acetal 2 is a very useful inter-
mediate, and many reactions have been reported so far.
For example, reaction with alkyl halides or carbonyl
compounds gave the alkylated derivative 31 or adduct
4,1,2 and transmetalation to the zinc salt followed by
coupling reaction with aryl iodides in the presence of
palladium catalyst afforded the arylated derivative 5.1
Cyclopropenone acetals obtained by these reactions
were used as key intermediates for biologically active
compounds containing a cyclopropenone moiety, for
example, antimicrobial penitricin derivatives,3 cysteine
proteinase inhibitors,4,5 or factor XIIIa inhibitor alutac-
enoic acid derivatives6 (Scheme 1).
It is reported that intermediate 2 was prepared by treat-
ment of cyclopropenone acetal 1 with n-BuLi in the
presence of HMPA or TMEDA.1 However, there is a
serious problem in the synthesis of the starting material
O
O
O
H
R3
R4
n-BuLi
O
O
O
O
O
O
O
N
HMPA
THF
R3
R4
N
H
R1
R1
R1
O
OH
Li+
1
2
OH
4
1a : R1 = H
2a : R1 = H
6
1b : R1 = Ph
2b : R1 = Ph
1) ZnCl2
2) cat. Pd(PPh3)4
Ar-I
R2-I or R2-Br
O
O
O
O
R2
R1
Ar
R1
3
5
Scheme 1. Preparation and reactions of the lithiated cyclopropenone acetal 2.
*
Corresponding author. Tel.: +81 45 963 4279; fax: +81 45 963 4436; e-mail: Ando.Ryoichi@mk.m-pharma.co.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.133

7012
T. Sakaki, R. Ando / Tetrahedron Letters 48 (2007) 7011–7014
1 because it is thermally unstable. According to the eval-
uation by a differential scanning calorimeter (DSC),
cyclopropenone 2,2-dimethyl-1,3-propanediyl acetal 1a
started the generation of heat below 50 °C, and the peak
temperature of that was 136 °C. The calorific value of
the exothermic peak was 752 J/g7—which suggests that
a violent explosion of 1a would occur by even mild heat-
ing. 2-Phenylcyclopropenone 2,2-dimethyl-1,3-propane-
diyl acetal 1b, which is the key intermediate for
cysteine proteinase inhibitor 6, was slightly more stable
than 1a; the starting and peak temperature of the gener-
ation of heat were 87 °C and 126 °C, respectively, and
the calorific value of the exothermic peak was 514 J/g.
These results suggest that it is necessary to conduct
experiments carefully, especially at the isolation, purifi-
cation, and drying steps in the synthesis of cycloprop-
enone acetal 1.
deprotonation at the benzylic position, cyclization to
produce the cyclopropane ring, dehydrochlorination to
produce the cyclopropenone acetal 1b, and addition of
tert-butoxide anion.8,9 Compound 8 is more stable and
much less explosive than compound 1b; the starting
and peak temperature of the generation of heat were
106 °C and 138 °C, respectively, and the calorific value
of the exothermic peak was 64.3 J/g. 2-Methoxy-3-phenyl-
cyclopropanone acetal 9 was also prepared in a simi-
lar manner in the presence of 1.1 equiv of methanol in
73% yield. 2-tert-Butoxycyclopropanone acetal 11 was
prepared from 2-bromomethyl-2-chloromethyl-5,5-di-
methyl-1,3-dioxane 10 by treatment with t-BuOK in
DMSO in 55% yield10,11 (Scheme 2).
Treatment of cyclopropanone acetal 8 with 1 equiv of
strong base such as n-BuLi would give cyclopropenone
acetal 1b via deprotonation of the benzylic position fol-
lowed by elimination of the tert-butoxy group. How-
ever, in this reaction mixture lithium tert-butoxide
exists as the side product, which would add to acetal
1b to regenerate intermediate 12 as shown in Scheme
3. Thus this reaction is reversible, and quenching by
water would give a mixture of 8 and 1b whose ratio
would depend on the reaction condition. In order to
overcome this equilibrium, addition of one more equiv-
alent of strong base such as n-BuLi would be effective
because formation of lithiated cyclopropenone acetal
2b would lead shift of this equilibrium to the right side.
During our continuous study of practical synthesis of
cysteine proteinase inhibitors, we have found that 2-
tert-butoxy-3-phenylcyclopropanone acetal 8 could be
prepared from 2-bromomethyl-2-(chlorophenylmethyl)-
5,5-dimethyl-1,3-dioxane 7 via 2-phenylcyclopropenone
acetal 1b.8 Although the tert-butoxy group is not a good
leaving group, it would be possible to generate cyclo-
propenone acetal 1b from 8 by elimination of the tert-
butoxy group by treatment with a strong base. We will
report herein a thermally stable precursor of lithiated
2-phenylcyclopropenone acetal 2b.
2-tert-Butoxy-3-phenylcyclopropanone acetal
8
was
Reaction of acetal 8 with 2 equiv of n-BuLi at À60 °C
followed by quenching by the addition of water afforded
cyclopropenone acetal 1b12 as we had expected. How-
ever, it took long time to complete the reaction because
the deprotonation or elimination step was slow. Thus we
investigated reaction conditions and found that it
needed at least 2 h to produce lithiated cyclopropenone
acetal 2b completely. This intermediate was thermally
very unstable; it decomposed at À50 °C. Isolated yield
of 1b after reacting acetal 8 with 2 equiv of n-BuLi at
À60 °C for 2 h was 78%.13 Reaction of methoxy deriva-
easily prepared even in a large scale from dihalide 7
by treatment with 2.5 equiv of t-BuOK in THF at room
temperature in excellent yield via successive reactions of
t
-BuOK
O
O
(1.1 eq MeOH)
O
O
Ph
THF
R5O
8: R5
9: R5 = Me (y. 73%)
Ph
t-Bu (y. 92%)
Br
Cl
=
7
2 eq n-BuLi
TMEDA
O
O
O
O
3 eq t-BuOK
O
O
O
O
THF
DMSO
y. 55%
O
y. 78%
Br
Cl
BuO
t-
10
11
8
1b
Scheme 2. Synthesis of 2-alkoxycyclopropanone acetals.
Scheme 4. Synthesis of the cyclopropenone acetal 1b.
1 eq n-BuLi
O
O
O
O
O
O
n-BuLi
TMEDA
THF
O
O
t-BuOLi
+
t-BuO
Ph
Li+
t-BuO
Ph
Ph
Li+
12
Ph
2b
8
1b
Scheme 3. Generation of the lithiated 2-phenylcyclopropenenone acetal 2b.

T. Sakaki, R. Ando / Tetrahedron Letters 48 (2007) 7011–7014
7013
H
BocHN
2 eq
TMEDA
n
-BuLi
O
O
13
CeCl3
THF
O
8
BocHN
THF
THF
OH
y. 79%
14
1 eq
TMEDA
n
-BuLi
CeCl3
THF
13
1b
14
THF
THF
y. 7 2%
Scheme 5. Synthesis of the key intermediate 14.
5. The falcipain inhibitor as an anti-malarial agent: Li, X.;
Chen, H.; Jeong, J.; Chishti, A. H. Mol. Biochem.
Parasitol. 2007, 155, 26.
6. Kogen, H.; Kiho, T.; Tago, K.; Miyamoto, S.; Fujioka,
T.; Otsuka, N.; Suzuki-Konagai, K.; Ogita, T. J. Am.
Chem. Soc. 2000, 122, 1842.
tive 9 with 2 equiv of n-BuLi also afforded cycloprope-
none acetal 1b in 80% yield. However, all attempts to
generate lithiated cyclopropenone acetal 2a from acetal
11 were unsuccessful (Scheme 4).
We applied this reaction to the practical synthesis of cys-
teine proteinase inhibitors. After generating lithiated
cyclopropenone acetal 2b, a THF suspension of anhydr-
ous cerium chloride, which was prepared by dehydration
of CeCl3Æ7H2O,14 was added at À78 °C. (S)-Boc-Valinal
13 was then added, and the resulting mixture was stirred
for 3.5 h at that temperature. Work-up and purification
by column chromatography afforded the key intermedi-
ate 14 whose isolated yield was 79%.15 This yield was
better than the one by the previous method (72%) in
which thermally unstable cyclopropenone acetal 1b
was used as the starting compound4b (Scheme 5).
7. Thermal stability of compounds was evaluated by a Seiko
DSC-20 instrument. For each compound, a 1 mg of
sample was placed in a sealed Ag pressure-resistant cell
under nitrogen. The sample was then heated from room
temperature to 450 °C at a rate of 10 °C/min.
8. Ando, R.; Sakaki, T.; Jikihara, T. J. Org. Chem. 2001, 66,
3617.
9. 2-tert-Butoxy-3-phenylcyclopropanone
2,2-dimethyl-1,3-
propanediyl acetal 8. To a solution of 2-bromomethyl-2-
(chlorophenylmethyl)-5,5-dimethyl-1,3-dioxane 78 (185.1 g)
in THF (750 mL), t-BuOK (155.4 g) was added slowly
at 0 °C. The resulting solution was then stirred overnight
at room temperature, and THF (about 350 mL) was
removed in vacuo. After addition of water to the residue,
the water layer was extracted with n-heptane three times.
Combined extracts were washed with saturated NaCl
solution and dried over anhydrous sodium sulfate. After
filtration of the drying agent, the filtrate was evaporated
to give crude solids (164.1 g), which was dissolved in
2-propanol (300 mL) by heating. After this resulting
solution was cooled to 0 °C, water (350 mL) was added
slowly. The precipitates formed were filtered and washed
with 2-propanol–water mixture (1:1) to afford the desired
compound (147.8 g, 92%). Spectroscopic properties were
identical with reported ones.8
In conclusion, 2-tert-butoxy-3-phenylcyclopropanone
acetal 8 was found to be a stable precursor of lithiated
cyclopropenone acetal 2b. Acetal 8 was used in the prac-
tical synthesis of cysteine proteinase inhibitors; isolated
yield of the key intermediate 14 was better than the one
by the previous method.
Acknowledgment
10. No reactions proceeded in THF.
11. Baucom, K. B.; Butler, G. B. J. Org. Chem. 1972, 37,
1730.
The authors wish to thank Professor Eiichi Nakamura,
The University of Tokyo, for helpful discussions.
12. No reaction proceeded by treatment with triethylamine or
DBU.
References and notes
13. 2-Phenylcyclopropenone 2,2-dimethyl-1,3-propanediyl acet-
al 1b. To a solution of acetal 8 (1.00 g) in THF (10 mL),
TMEDA (1.03 mL) was added at À60 °C. n-BuLi
(1.61 mol/L solution in n-hexane, 4.29 mL) was then
added at À60 °C in 5 min, and the resulting solution was
stirred at that temperature for 2 h. After 4:1 mixture of
THF–water (3 mL) was added at À60 °C, the reaction
mixture was warmed to room temperature, and anhydrous
Na2SO4 was added. Subsequently, solids in this solution
were filtered by Celite, and the filtrate was evaporated to
give the crude mixture (894 mg). Purification by column
chromatography (n-hexane/AcOEt = 20/1) afforded the
desired compound (579 mg, 78%). Spectroscopic proper-
ties were identical with reported ones.8
1. (a) Isaka, M.; Matsuzawa, S.; Yamago, S.; Ejiri, S.;
Miyachi, Y.; Nakamura, E. J. Org. Chem. 1989, 54, 4727;
(b) Isaka, M.; Ejiri, S.; Nakamura, E. Tetrahedron 1992,
48, 2045.
2. Tokuyama, H.; Isaka, M.; Nakamura, E. Synth. Commun.
1995, 25, 2005.
3. Tokuyama, H.; Isaka, M.; Nakamura, E.; Ando, R.;
Morinaka, Y. J. Antibiot. 1992, 45, 1148.
4. (a) Ando, R.; Morinaka, Y.; Tokuyama, H.; Isaka, M.;
Nakamura, E. J. Am. Chem. Soc. 1993, 115, 1515; (b)
Ando, R.; Sakaki, T.; Morinaka, Y.; Takahashi, C.;
Tamao, Y.; Yoshii, N.; Katayama, S.; Saito, K.; Toku-
yama, H.; Isaka, M.; Nakamura, E. Bioorg. Med. Chem.
1999, 7, 571.
14. Imamoto, T.; Sugiura, Y.; Takiyama, N. Tetrahedron Lett.
1984, 25, 4233.

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T. Sakaki, R. Ando / Tetrahedron Letters 48 (2007) 7011–7014
15. 2-((2S)-2-tert-Butoxycarbonylamino-1-hydroxy-3-methyl-
butyl)-3-phenylcyclopropenone 2,2-dimethyl-1,3-propane-
diyl acetal 14. Acetal 8 (996 mg) was dissolved in THF
(10 mL), and TMEDA (0.97 mL) was added. The resulting
solution was then cooled to À78 °C, and n-BuLi
(1.63 mol/L solution in n-hexane, 3.98 mL) was added in
5 min. After stirring for 1.5 h at that temperature, a cooled
suspension of anhydrous CeCl3, which was prepared from
CeCl3Æ7H2O (1.92 g) by drying in vacuo at 140 °C for
3.5 h, in THF (20 mL) was slowly added, and the resulting
suspension was stirred for 50 min at À78 °C. Subse-
quently, (S)-N-tert-butoxycarbonylvalinal 13 (293 mg) in
THF (5 mL) was added in 10 min, and the resulting
mixture was stirred at À78 °C for 3.5 h. The reaction
mixture was then quenched by addition of 4:1 mixture of
THF–water (3 mL) at À78 °C, and it was warmed to room
temperature. Subsequently, anhydrous Na2SO4 was added
to the resulting suspension; solids were filtered by Celite
and were washed well with ethyl acetate. Evaporation of
the filtrate afforded the crude mixture (1.44 g), which was
purified by column chromatography (n-hexane/ethyl
acetate = 4/1) to give the desired compound (484 mg,
79% yield base on aldehyde 13). Spectroscopic properties
were identical with reported ones.4b