Diastereoselective approach to an HIV protease inhibitor intermediate using a cation-exchange resin mediated Mannich-type reaction

Article abstract of DOI:10.3987/COM-07-S(U)25

Mannich-type reaction of ketene silyl acetals with a chiral imine proceeded smoothly to give β-amino esters in good yields with high diasetereoselectivity under the influence of a cation-exchange resin, and the subsequent functional group transformations gave an HIV protease inhibitor intermediate. This paper is dedicated to the memory of Professor Ivar Ugi who passed away on 27th September, 2005.

Full text of DOI:10.3987/COM-07-S(U)25

HETEROCYCLES, Vol. 73, 2007
191
HETEROCYCLES, Vol. 73, 2007, pp. 191 - 195. © The Japan Institute of Heterocyclic Chemistry
Received, 21st June, 2007, Accepted, 9th August, 2007, Published online, 10th August, 2007. COM-07-S(U)25
DIASTEREOSELECTIVE APPROACH TO AN HIV PROTEASE
INHIBITOR INTERMEDIATE USING A CATION-EXCHANGE RESIN
MEDIATED MANNICH-TYPE REACTION
Makoto Shimizu,* Yukinori Hayashi, Ryosuke Hamanaka, and Iwao
Hachiya
Department of Chemistry for Materials, Graduate School of Engineering, Mie
University, Tsu, Mie 514-8507, Japan. E-mail: mshimizu@chem.mie-u.ac.jp
Abstract –Mannich-type reaction of ketene silyl acetals with a chiral imine
proceeded smoothly to give β-amino esters in good yields with high
diasetereoselectivity under the influence of a cation-exchange resin, and the
subsequent functional group transformations gave an HIV protease inhibitor
intermediate.
Our continuous interests in the stereodivergent construction of the β-lactam rings using a chiral imine led
to a new approach to 2-isocephem intermediate in a highly stereoselective manner.1 During these
investigations cation-exchange resins have been found to be excellent activators for Mannich-type
reaction of ketene silyl acetals with imines, which after cyclization lead to the stereodivergent synthesis
PMP
PMP
NH
O
O
N
O
MeO
O
MeO
O
Amberlyst® 15DRY
OSO2Me
PMP
S
OTMS
OMe
OMe
H
O
+
N
MeO
O
CH2Cl2, -78 ˚C ~ rt
97%, syn : anti = 95 : 5
96% de (syn)
OMe
N
CO2H
MeO
OMe
MeO
OMe
2-Isocephem
PMP = 4-MeOC6H4
NH2
O
O
O
N
O
Ph
HO
OR'
N
H
N
H
OH
OH
S
KNI 764
Scheme 1
-----------------------------------
This paper is dedicated to the memory of Professor Ivar Ugi who passed away on 27th September, 2005.

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HETEROCYCLES, Vol. 73, 2007
of β-lactams.2 Use of ion-exchange resins offers several advantages in organic synthesis, e.g.,
simplification of reaction procedures, easy separation of products without discharging harmful waste
water, repeated use, and so on. In our previous report, a cation-exchange resin, in particular Amberlyst®
15DRY, having a large surface area (45 m2 /g), was found to be one of the most useful resins that
promoted Mannich-type reaction, where the addition reactions proceeded with high chemoselectivity in
the presence of two kinds of imines and/or nucleophiles. This time we used a cation-exchange resin
promoted Mannich-type reaction for the synthesis of a key component for the construction of HIV
protease inhibitor (KNI 764)3 using the chiral imine (1).
The starting chiral imine (1) was prepared from (2S,3S)-1,4-dimethoxy-2,3-butanediol in 3 steps.4 The
initial Mannich-type reaction proceeded with the ketene silyl acetal (2) to give the adduct (3) in 87%
yield. Cyclization into the β-lactam (4) was readily carried out under the influence of
isopropylmagnesium bromide in 98% yield.5 However, we have encountered much difficulty to remove
the chiral ketal group. Although a variety of hydrolysis conditions were examined, we obtained either the
desilylated product (6) or the dimerized cyclic ether (7), and the desired ketone (5) was not obtained at
all.
PMP
PMP
N
NH
O
O
Ph
N
O
O
OMe
OMe
OMe
Ph
O
Ph
O
Amberlyst® 15DRY (1.0 eq)
CH2Cl2, -78 ˚C ~ rt, 19 h
TBSO
O
iPrMgCl (3.0 eq)
Et2O, 0 ˚C, 2.0 h
H
OMe
TBSO
+
O
OTBS
OTBS
OMe
2
MeO
OMe
PMP
MeO
1
(E : Z = 94 : 6, 1.2 eq)
4
3
98%, cis : trans = 90 : 10
87%, syn : anti = 90:10
PMP
O
Ph
N
MeO
O
Ph
O
O
OMe
OMe
HO
O
MeO
Ph
O
HO
O
O
N
OH
OMe
HO
O
N
6
PMP
O
PMP
O
OMe
N
Ph
5
7
PMP
Scheme 2
We therefore turned our attention to the removal of the ketal group using a multi-step procedure. First, the
TBS group was replaced with a benzyl group via hydrolysis with PPTS in refluxing acetone/water
followed by benzylation with BnBr under the phase-transfer catalysis conditions in good overall yield.6
Bis-bromination was readily carried out first by cleavage of the methyl ether with BBr3 followed by
NBS-PPh3 treatment. Reductive elimination of the ketal was conducted with Zn-Cu in the presence of
TMSCl in refluxing THF, and the desired ketone (5) was obtained in good overall yield.

HETEROCYCLES, Vol. 73, 2007
193
1) cat PPTS
acetone/H2O reflux
18 h, 97%
Ph
.
O
O
Ph
OMe
OMe
O
O
1) BBr3 SMe2 (6.0 eq)
OMe
OMe
BnO
O
TBSO
O
CH2Cl2, rt, 3.5 h, 63%
N
8
2) 50% aq NaOH
BnBr, TBAI, CH2Cl2
rt, 14 h, 92%
2) NBS (6.0 eq), PPh3 (6.8 eq)
CH2Cl2, rt, 15 h, 81%
N
4
PMP
PMP
O
Ph
O
O
Br
Br
HO
BnO
O
Ph
Zn-Cu (15 eq), TMSCl (8 eq)
THF refl, 17.5 h, 90%
N
N
O
PMP
PMP
5
9
Scheme 3
For the synthesis of the desired hydroxyaminoester (14) epimerization of the benzoyl group was needed.
This was readily carried out using DBU as a base, and the trans-β-lactam (10) was obtained. Further
functional group transformations were conducted as follows: The phenyl ketone (10) was reduced to the
alcohol (a 74:26 mixture of diastereomers), which in turn acetylayed to give the acetate (11). The PMP
group was removed with CAN in MeCN/water in quantitative yield. Hydrogenolysis of the acetate with
cat Pd/C-ammonium formate gave 4-benzyl-3-hydroxy-β-lactam (13), which upon methanolysis and
N-benzoylation gave the desired methyl ester (14)3j-m,7 in good overall yield.
1) NaBH4 (1.1 eq)
OAc
O
O
EtOH / THF
BnO
BnO
O
DBU (0.2 eq)
BnO
O
CAN (4.0 eq)
Ph
rt, 30 min, 94%
Ph
PMP
Ph
CH2Cl2, rt, 19.0 h
N
MeCN / H2O
0 ˚C, 1.0 h
2) Ac2O (excess)
4-DMAP (0.2 eq)
Py, rt, 2.0 h, 99%
N
N
PMP
O
PMP
11 (dr = 74:26)
5
10
91% (at 69%conversion)
Bz
OAc
Ph
10% Pd/C (1.0 eq)
1) TMSCl (excess)
MeOH, reflux, 1.0 h
NH
HO
O
O
NH4+.HCO2- (20.0 eq)
Ph
BnO
O
Ph
OMe
NH
MeOH, reflux
30 min
2) BzCl (1.2 eq), NEt3 (2.4 eq)
CH2Cl2, rt, 1.0 h
NH
OH
14 86%
13 73%
12 quant.
Scheme 4
In conclusion, we have found that an ion-exchange resin promoted Mannich-type reaction of the ketene
silyl acetal derived from glycolate with a chiral imine offers a useful method for β-amino ester, which
upon treatment with isopropyl Grignard reagent gives β-lactam. Appropriate functional group
transformations provide a rapid approach to an HIV protease inhibitor intermediate. Since we have
succeeded in the epimrization of the 3-TBSO group of the β-lacam (4) under the influence of t-BuOK in

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HETEROCYCLES, Vol. 73, 2007
refluxing THF,8 the enantiomer (16) of the ester (14) may also be prepared using the same procedures.
These transformations are under active investigation in our laboratories.
Bz
Ph
N
Ph
N
O
O
O
O
OMe
OMe
OMe
OMe
NH
O
TBSO
O
1) t-BuOK (0.5 eq)
HO
O
Ph
THF reflux, 15 h
OMe
2) 6 M HCl
OH
16
PMP
PMP
0 oC to rt, 4 h
4
15 79%
Scheme 5
REFERENCES AND NOTES
1. M. Shimizu, M. Tachi, and I. Hachiya, Chem. Lett., 2004, 33, 1394.
2. (a) M. Shimizu and S. Itohara, Synlett, 2000, 1829. (b) M. Shimizu, S. Itohara, and E. Hase, Chem.
Commun., 2001, 2318. (c) M. Shimizu, M. Tachi, S, Fukushima, and I. Hachiya, Heterocycles, 2005,
66, 75.
3. (a) J. Luly, J. F. Dellaria, J. J. Plattener, J. L. Soderquist, and N. Yi, J. Org. Chem., 1987, 52, 1487.
(b) R. Metternich and W. Ludi, Tetrahedron Lett., 1988, 29, 3923. (c) K. Hattori and H. Yamamoto,
Tetrahedron, 1994, 50, 2785. (d) J. V. N. Prased and D. H. Rich, Tetrahedron Lett., 1990, 31, 1803.
(e) D. J. Kyle, J. A. Martin, S. G. Farmer, and R. M. Burch, J. Med. Chem., 1991, 34, 1228. (f) D.
Askin, M. A. Wallace, J. P. Vacca, R. A. Reamer, R. P. Volante, and I. Shinkai, J. Org. Chem., 1992,
57, 2771. (g) A. M. Diderich and D. M. Ryckman, Tetrahedron Lett., 1993, 34, 6169. (h) D. P.
Potella, Tetrahedron Lett., 1995, 36, 5453. (i) A. K. Ghosh, K. A. Hussain, and S. Fidanze, J. Org.
Chem., 1997, 62, 6080. (j) H.-J. Ha, Y.-G. Ahn, and G. S. Lee,. Tetrahedron: Asymm., 1999, 10,
2327. (k) J.-M. Lee, H.-S. Lim, K.-C. Seo, and S.-K. Chung,. Tetrahedron: Asymm., 2003, 14, 3639.
(l), D. Y. Jung, S. Kang, S. Chang, and Y. H. Kim, Synlett, 2006, 86. (m) R. Nishizawa, A. Saino,
and K. Setani, Jpn. Kokai Tokkyo Koho, 1980, 55000355.
4. Cf. T. Fujisawa, Y. Ukaji, T. Noro, K. Date, and M. Shimizu, Tetrahedron, 1992, 48, 5629.
5. The following example represents a procedure for the synthesis of β-lactam (4): To a suspension of
Amberlyst® 15DRY (43.0 mg, 0.2 mmol on the sulfonic acid portion, washed EtOH and dried in
vacuo at 100 oC) and the imine (1) (74.0 mg, 0.2 mmol) in CH2Cl2 (0.5 mL) was added a solution of
ketene silyl acetal (2) (76.0 mg, 0.24 mmol) in CH2Cl2 (0.6 mL) at -78 oC under an argon atmosphere.
After being stirred at at -78 oC for 2 h, the reaction mixture was allowed to stand at rt for 12 h. Then,
triethylamine (1.1 mL) was added at -78 oC. The suspension was filtrated through a Celite pad. The
filtrate was concentrated in vacuo to afford a crude oil. Purification by silica gel column

HETEROCYCLES, Vol. 73, 2007
195
chromatography (n-hexane / Et2O = 1/1, as an eluent) gave the adduct (3) (101.2 mg, 87%) as a pale
yellow oil. Examination by HPLC indicated the formation of diastereomers in a 90:10 (syn:anti)
ratio. Cyclization into β-lactam (4): To a solution of the adduct (3) (623.0 mg, 1.08 mmol) in Et2O
i
o
(28.5 mL) was added a THF solution of PrMgBr (4.20 mL, 3.25 mmol, 0.733 M in THF) at 0 C,
and the mixture was stirred at 0 oC for 2 hr. Sat. aqueous NaCl (20 mL) was added to the mixture.
After extracting with Et2O followed by a usual work-up, a crude oil was purified by silica gel
column chromatography (n-hexane / AcOEt = 5/1, as an eluent) gave the β-lactam (4) (572.2 mg,
98%) as a colorless oil. Examination by HPLC indicated the formation of diastereomers in a 90:10
1
cis:trans) ratio. Rf = 0.40 (n-hexane : Et2O = 1 : 1); H-NMR (500 MHz, CDCl3) δ : 0.14 (s, 3H),
0.15 (s, 3H), 1.07 (s, 9H), 3.28 (dd, J = 4.9, 10.4 Hz, 1H), 3.33-3.35 (m, 4H), 3.58 (s, 3H), 3.60 (dd,
J = 4.9, 10.7 Hz, 1H), 3.69 (dd, J = 5.8, 10.7 Hz, 1H), 3.77 (ddd, J = 4.9, 6.7, 11.9 Hz, 1H), 3.98 (s,
3H), 4.13 (ddd, J = 4.9, 5.8, 11.9 Hz, 1H), 4.91 (d, J = 5.5 Hz, 1H), 5.02 (d, J = 5.5 Hz, 1H),
13
7.03-7.06 (m, 2H), 7.47-7.50 (m, 3H), 7.72-7.74 (m, 2H), 7.81-7.83 (m, 2H); C-NMR (126 MHz,
CDCl3) δ : -5.5, -5.0, 18.4, 25.8, 55.4, 59.0, 59.5, 63.9, 72.7, 73.4, 75.0, 77.5, 79.5, 110.2, 113.8,
119.4, 126.7, 127.7, 128.2, 131.4, 140.2, 156.0, 167.3.
6. Although the ketene t-butyldimethylsilyl acetal derived from methyl benzyloxyacetate could be used
for the initial Mannich type reaction with the imine (1), the subsequent cyclization into β-lactam was
not facile as in the case with the TBS derivative (2), and therefore, replacement of the TBS group
was conducted in the present synthesis (Scheme 3).
o
7. Methyl (2S,3S)-3-(benzamido)-2-hydroxy-4-phenylbutanoate (14): White crystals; Mp 183-184 C;
Rf = 0.45 (CH2Cl2 : MeOH = 20 : 1) 1H-NMR (500 MHz, CDCl3) δ : 2.92 (dd, J = 6.7, 14.0 Hz, 1H),
2.98 (dd, J = 7.9, 14.0 Hz, 1H), 3.58 (d, J = 5.2 Hz, 1H), 3.60 (s, 3H), 4.44 (dd, J = 3.1, 5.2 Hz, 1H),
4.85 (dddd, J = 3.1, 6.7, 7.9, 8.5 Hz, 1H), 6.45 (d, J = 8.5 Hz, 1H), 7.20-7.23 (m, 1H), 7.25-7.31 (m,
4H), 7.39-7.42 (m, 2H), 7.47-7.50 (m, 1H), 7.66-7.68 (m, 2H). 13C-NMR (126 MHz, CDCl3) δ : 35.4,
52.7, 53.3, 72.0, 126.8, 126.9, 128.5, 128.6, 129.4, 131.7, 134.0, 136.8, 167.4, 173.0.
8. M. Shimizu, T. Ishida, and T. Fujisawa, Chem. Lett., 1994, 1403.