882 LETTERS SYNLETT

A Practical Removal Method of Camphorsultam

Tomoyuki Hasegawa and Hisashi Yamamoto*
Graduate School of Engineering, Nagoya University, Chikusa, Nagoya 464-8603, Japan
Fax +81(52)789-3331; E-mail j45988@nucc.cc.nagoya-u.ae.jp
Received 19 May 1998
Abstract: A mild and efficient removal of camphorsultam was realized
using tetrabutylammonium hydrogen peroxide as a key reagent.
Oppolzers sultam has been shown to be a versatile chiral auxiliary in
various diastereoselective carbon-carbon bond constructions.
1-7
Effective methods for removal of this chiral auxiliary
8,9
have been
reported, for example, lithium hydrogen peroxide was utilized to convert
N-acyl sultam directly into the corresponding carboxylic acids without
racemization of the newly created stereocenters.
10
This method,
however, requires a large volume of solvent and long reaction times.
Furthermore, in cases of sterically hindered substrates, these methods
gave low yields of the desired products because of competitive N-S
bond cleavage: a hydrolysis of N-acyl sultam gave the desired
carboxylic acid along with a corresponding sulfonic acid derivative in
fairly large amount (Scheme 1).
Scheme 1
We describe here a mild and efficient cleavage method of N-acyl
sultams using hydrogen peroxide-tetrabutylammonium hydroxide
(TBAH)
11,12
hydrolysis with higher regioselectivity than the technique
formerly used.
Various hydrolytic conditions of N-(2S)-hexyl-4-pentenoyl-(1S)-(-)-
2,10-camphorsultam 1 were examined and the results are summarized in
Table 1.
The use of aqueous TBAH by itself gave the corresponding sulfonic acid
(63%) as the main product (entry 6), while combination of hydrogen
peroxide and TBAH produced the desired product 2 (75%) and a small
amount of sulfonic acid (4%) (entry 7).
13
This new condition is six
times as regioselective as the previous method (entry 1).
Potassium hydrogen peroxide was also an effective base for the
hydrolysis (entry 2). Unfortunately, however, the yield of the product in
this system was low in larger-scale experiments. Lithium tert-
butylperoxide to remove camphor-derived lactam was not successful in
our system (entry 3).
14
The most successful hydrolysis was achieved with TBAH using DME as
a solvent (entry 7); other solvent systems gave lower yields (entries 8-
11). A less hindered ammonium hydroxide and tetramethylammonium
hydroxide showed low reactivity (entries 4,5), whereas bulky
alkylammonium hydroxides remarkably decreased the yields because of
the instability of these hydrophobic reagents and/or, their technically
troublesome separation from the desired products.
The hydrolysis rate was remarkably affected by the structural features of
the substrates. For example, the substrate (R=propargyl) was found to be
much more reactive than the corresponding saturated analogs. The
present method, however, was equally effective for all substrates (Table
2).
In all cases, these TBAH-reactions were very fast at normal
concentrations and gave the desired products in higher yields in a
shorter period than the alkali metal hydroxide-hydrogen peroxide
system with no racemization (for example, entry 2, from 99% d.e. to
99% e.e.).
August 1998 SYNLETT 883
It was essential for the success of the present method to use dry-TBAH
which is prepared from commercially available 40wt% reagent by
azeotropic removal of water with DME and toluene (entry 1).
As a major side reaction in our system, lactone 4 was isolated from the
residue of concentrated acidic aqueous layer after work-up. The lactone
can be derived from an intermediate 3 via intramolecular epoxidation
(Scheme 2).
Scheme 2
To suppress the side reaction, addition of excess 2-methyl-2-butene was
effective in giving carboxylic acid 2 in maximum yield (entry 2, c.f.
entry 7 in Table 1).
As another application of the new method, we attempted hydrolyses of
hindered esters and amides. Dry-TBAH was very effective for these
hydrolyses and the results are shown in Table 3.
15
These yields were
superior to those obtained by the previous technique.
Interestingly, di-(-)-menthyl bicyclo[2.2.2.]octane-2,3-di-carboxylate
was selectively converted to corresponding half ester (entry 2).
19
This
may have been caused by the electronic repulsion of the naked
carboxylate anion under our anhydrous condition.
In conclusion, the dry-TBAH with hydrogen peroxide system showed
mild and powerful removal potency for Oppolzers sultam. Dry-TBAH
was also very effective for hydrolysis of sterically hindered esters and
amides.
A typical procedure for removal of camphorsultam:
To a solution of N-(2S)-hexyl-4-pentenoyl-(1S)-(-)-2,10-
camphorsultam 1 (1.00 g, 2.62 mmol) and 2-methyl-2-butene (0.83 ml,
7.8 mmol) in DME (10 ml) was added dropwise 30% aqueous hydrogen
peroxide (0.54 ml, 5.3 mmol) at 0
o
C, followed by aqueous
tetrabutylammonium hydroxide (40% w/w, 3.4 ml, 5.3 mmol). After
stirring for 2h, the reaction was quenched with 1.5N aqueous Na
2
SO
3
(3.5 ml), then the cooling bath was removed. The mixture was further
stirred for 1h and concentrated in vacuo. The residue was acidified with
2N aqueous HCl and extracted twice with EtOAc-
i
Pr
2
O (1:3). The
combined organic layers were washed with H
2
O, brine, dried over
Na
2
SO
4
and concentrated. To the residue was added
i
Pr
2
O-Hex (1:1)
and an insoluble recovered camphorsultam was filtered off. The filtrate
was concentrated and the residue was purified by silica gel
chromatography (EtOAc:Hex, 5:95) to afford (2S)-hexyl-4-pentenoic
acid 2 (397 mg, 82%) as a colorless oil.
20
Acknowledgments: Financial support from the Ministry of Education,
Science and Culture of the Japanese Government is gratefully
acknowledged. We thank the analytical group of the Process Research
Laboratory of Ono Pharmaceutical Co. for measurements of the
analytical data.
References and Notes
1) Oppolzer, W.; Moretti, R. Tetrahedron Lett. 1989, 30, 5603.
2) Hanessian, S.; Yang, R. ibid. 1996, 37, 5273.
3) Oppolzer, W.; De Brabander, J. ibid. 1997, 38, 1539.
4) Csuk, R.; Schrder, C. Tetrahedron: Asymmetry 1997, 8, 1411.
5) Jurczak, J.; Jezewski, A. ibid. 1997, 8, 1741.
6) Perlmutter, P.; Bond, S. J. Org. Chem. 1997, 62, 6397.
7) Leahy, J. W.; Brzezinski, L. J. J. Am. Chem. Soc. 1997, 117, 4317.
8) Oppolzer, W. Tetrahedron 1987, 43, 1969.
9) See for another recently approach: Naito, T.; Miyata, O. Synlett
1994, 637.
10) Oppolzer, W.; Kingna, A, J. Helv. Chim. Acta 1989, 72, 1337.
11) Harlow, G. A. Analytical Chem. 1956, 28, 787.
12) Cluett, M. L. ibid. 1959, 31, 610.
13) This result agrees with Evans explanation for the regio-selectivity
of lithium hydrogen peroxide hydrolysis: Evans, D. A.; Britton, T.
C. Tetrahedron Lett. 1987, 28, 6141.
14) Boeckman, R. K. Jr.; Connell, B. T. J. Am .Chem. Soc. 1995, 117,
12368.
15) See for hydrolysis using aqueous TBAH:
a) Schuda, P .F.; Phillips, J. L. J. Org. Chem. 1986, 51, 2742.
b) Manchand, P. S.; Micheli, R. A. Tetrahedron. 1992, 48, 9391.
c) Myers, A. G.; Yang, B. H. J. Am. Chem. Soc. 1997, 119, 6496.
16) Gassman, P. G.; Schenk, W. N. J. Org. Chem. 1977, 42, 918.
17) Gassman, P. G.; Hodgson, P K. G. J. Am. Chem. Soc. 1976, 98,
1275.
18 Robbins, M. D.; Vaughn, H. L. J. Org. Chem. 1975, 40, 1187
19 A typical procedure for hydrolysis with dry-TBAH: Aqueous
tetrabutylammonium hydroxide (40% w/w, 0.28 ml, 0.42 mmol)
was azeotropically concentrated four times with DME- toluene (4
ml, 1:1). To the residue was added a solution of di-(-)-
menthylbicyclo[2.2.2.]octane-2,3-dicarboxylate (100 mg, 0.21
mmol) in THF (0.4 ml) at room temperature. The resulting
mixture was stirred for 1h, diluted with H
2
O and reverse extracted
with
i
Pr
2
O. The aqueous layer was acidified with 2N aqueous HCl
and extracted with
i
Pr
2
O. The organic layer was washed with
H
2
O, brine, dried over Na
2
SO
4
and concentrated. The residue was
purified by silica gel chromatography (EtOAc:Hex, 1:9) to afford
the half ester (66 mg, 93%) as a colorless amorphous solid.
1
H
NMR (300MHz, CDCl
3
) 4.69 (dt, 1 H, J = 10.9, 4.3 Hz), 3.19 (d,
1 H, J = 6.9 Hz), 3.02 (dd, 1 H, J = 7.0, 2.0 Hz), 2.13 (d, 2 H, J =
15.0 Hz), 2.03 (d, 1 H, J = 10.5 Hz), 1.86 (m, 1 H), 1.70-1.40 (m,
13 H), 1.00 (m, 3 H), 0.90 (d, 3 H, J = 7.5 Hz), 0.89 (d, 3 H, J =
7.5 Hz), 0.74 (d, 3 H, J = 7.5 Hz); MS (FAB) m/z 337 (M+1), 319,
199, 181, 153, 139; IR (KBr) 2950, 2870, 1727, 1701, 1458, 1422,
1387, 1372, 1339, 1304, 1271, 1240, 1192, 1103, 1080, 1040,
884 LETTERS SYNLETT
1022, 986 cm
-1
; Anal. Calcd for C
20
H
32
O
4
: C, 71.39; H, 9.59.
Found: C, 71.10; H, 9.39.
20) (2S)-Hexyl-4-pentenoic acid 2:
1
H NMR (300MHz, CDCl
3
) 5.78
(ddt, 1 H, J = 17.0, 10.1, 6.9 Hz), 5.10 (dd, 1 H, J = 17.0, 1.9 Hz),
5.05 (dd, 1 H, J = 10.1, 1.9 Hz), 2.44 (m, 2 H), 2.30 (m, 1 H), 1.64
(m, 1 H), 1.55 (m, 1 H), 1.30 (br s, 8 H), 0.90 (t, 3 H, J = 6.8 Hz);
MS (EI) m/z 184 (M+), 143, 113; IR (neat) 2930, 2859, 1709,
1644, 1460, 1420, 1289, 1250, 1210, 992, 916 cm
-1
; Anal. Calcd
for C
11
H
20
O
2
: C, 71.70; H, 10.94. Found: C, 71.56; H, 11.14.