Catalytic asymmetric syntheses of ICI-199441 and CP-99994 using nitro-Mannich reaction

Article abstract of DOI:10.1246/cl.2002.276

Catalytic asymmetric syntheses of ICI-199441 and CP-99994 were achieved using the nitro-Mannich reaction as a key step.

Full text of DOI:10.1246/cl.2002.276

276
Chemistry Letters 2002
Catalytic Asymmetric Syntheses of ICI-199441 and CP-99994 Using Nitro-Mannich Reaction
Natsuko Tsuritani, Ken-ichi Yamada, Naoki Yoshikawa, and Masakatsu Shibasakiꢀ
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033
(Received November 27, 2001;CL-011200)
Catalytic asymmetric syntheses of ICI-199441 and CP-
99994 were achieved using the nitro-Mannich reaction as a key
step.
1,2-Diamines1 are abundantly present in biologically active
compounds. ICI-199441 (1)2 and CP-99994 (2)3 are examples of
such compounds with clinically appealing activities (Figure 1).
Compound 1 is a highly potent ꢀ-opioid agonist, which is
expected to provide useful analgesics without the serious side
effects of ꢁ-agonists like morphine, and 2 is a competent
antagonist of substance P, which is implicated in the pathogenesis
of a variety of inflammatory diseases. Moreover, 2 also inhibits
the emetic response4 and might be useful for controlling emesis
evoked by chemotherapy against cancer. Although definite
pharmacophore models of these two compounds have not yet
been clarified, the orientation of the amino groups is very
important. Thus, enantioselective synthesis is strongly desirable.
All syntheses reported to date2a,b,3a,d commence from readily
available chiral-pool organic substrates like amino acids that are
converted to 1,2-diamines by transformation of hydroxyl or
carboxyl groups to an amino group.
Figure 1.
We recently developed the catalytic asymmetric addition of
nitroalkanes to imines, referred to as the nitro-Mannich reaction.
This reaction provides chiral ꢂ-nitroamines, which are easily
converted to chiral 1,2-diamines.5;6 We, therefore, attempted to
develop more straightforward and flexible routes to 1 and 2.
Herein, we report the catalytic asymmetric syntheses of 1 and 2
utilizing the nitro-Mannich reaction.
Our plans for the syntheses are outlined in the Figure 1.
Compounds 1 and 2 can be traced to chiral ꢂ-nitroamines 3 and 4
respectively, which are produced by the catalytic asymmetric
nitro-Mannich reaction. Although 4 was expected to have an
undesirable stereochemistry (S, R) based on previously obtained
results,6b we planned to obtain the desirable isomer by
epimerization.
The synthesis of 1 is summarized in Scheme 1. The catalytic
asymmetric nitro-Mannich reaction of benzaldehyde imine 6 was
performed at ꢁ40 ꢂC in the presence of YbKH2[(R)-
binaphthoxide]3 (8) (20 mol%)7 with nitromethane (5) added
over 27 h, to give the nitroamine 3 in 79% yield with 91% ee,6a,8
which was converted to an enantiomerically pure form (>99% ee)
in 78% yield upon recrystallization from MeOH.9 After the nitro
group was reduced in 92% yield using Raney nickel, the
pyrrolidine ring was constructed in 81% yield by reductive
alkylation. The cleavage of the diphenylphosphinoyl group was
realized under mildly acidic conditions, cleanly affording
diamine 10 in 98% yield. Reductive methylation of 10 by
formamide formation and the following LiAlH4 reduction
furnished N-methylated diamine 11 in 90% yield in two steps.
Finally, acylation of the secondary amino group and treatment
with methanolic HCl gave an enantiomerically pure HCl salt of 1
Scheme 1. Reagents and conditions: a) i) 8 (20 mol%), toluene/THF
(7 : 1), ꢁ40 ꢂC, 79%, 91% ee;ii) recrystallization from MeOH, 78%, >99%
ee;b) Raney-Ni, H 2, EtOH, rt, 92%;c) OHC(CH 2)2CHO, NaBH3CN, EtOH,
pH 5, 0 ꢂC, 81%;d) 1.5 M HCl-EtOH, rt, 98%;e) i) HCO 2Ac, ꢁ20 ꢂC;
ii)LiAlH4, reflux, 90% from 10;f) ArCH 2COCl, CH2Cl2, rt, 87%, Ar ¼ 3,4-
dichlorophenyl.
25
in 87%yield (35% overall yield), ½ꢃŠ ꢁ105 ꢂ (c 1.1, CHCl3);lit.,
D
20
D
½ꢃŠ ꢁ128 ꢂ (c 1.0, CHCl3).2b
Scheme 2 shows the synthesis of 2. For the first step, the
second-generation ALB (ALB-II, 12), prepared from AlLi[(S)-
binaphthoxide]2 and KO-t-Bu,10 was used as a catalyst for the
asymmetric nitro-Mannich reaction. The ALB-II is the catalyst of
choice for nitroalkanes having a longer carbon chain, whereas the
Yb catalyst is suitable for nitromethane.6b The reaction of 6 with
nitroalkane 13 in the presence of (S)-ALB (20 mol%) and KO-t-
Bu (18 mol%) at ꢁ40 ꢂC provided nitroamine 14 as a mixture of
diastereomers (anti : syn 6 : 1) in 90% yield with 77% ee (anti)
after purification by column chromatography.9;11 Chromatogra-
phy-free purification of anti-14 was also possible. After
quenching the reaction, concentration of the crude mixture gave
a precipitate, which was filtered off and washed with diethyl ether
to afford crude crystal of almost diastereomerically pure anti-14.
Eventually, recrystallization from MeOH produced anti-14 with
97% ee in 40% yield (from 6, two crops). Removal of the TBS
group with HF/pyridine, Dess–Martin oxidation, and succeeding
Copyright Ó 2002 The Chemical Society of Japan

Chemistry Letters 2002
277
2856 (1994).
3
a) M. C. Desai, S. L. Lefkowitz, P. F. Thadeio, K. P. Longo, and R. M.
Snider, J. Med. Chem., 35, 4911 (1992). b) T. Rosen, T. F. Seeger, S.
McLean, M. C. Desai, K. J. Guarino, D. Bryce, K. Pratt, and J. Heym, J.
Med. Chem., 36, 3197 (1993). c) M. C. Desai, P. F. Thadeio, and S. L.
Lefkowitz, Tetrahedron Lett., 34, 5831 (1993). d) S. Chandrasekhar and
P. K. Mohanty, Tetrahedron Lett., 40, 5071 (1999).
4
5
C. Bountra, K. Bunce, T. Dale, C. Gardner, C. Jordan, D. Twissell, and
P. Ward, Eur. J. Pharm., 249, R3 (1993).
Non-enantioselective diastereoselective nitro-Mannich reaction: a) H.
Adams, J. C. Anderson, S. Peace, and A. M. K. Pennell, J. Org. Chem.,
63, 9932 (1998). b) J. C. Anderson, S. Peace, and S. Pih, Synlett, 2000,
850.
6
Enantioselective catalytic nitro-Mannich reaction: a) K. Yamada, S. J.
Harwood, H. Groger, and M. Shibasaki, Angew. Chem., Int. Ed., 38,
¨
3504 (1999). b) K. Yamada, G. Moll, and M. Shibasaki, Synlett, 2001,
980. c) K. R. Knudsen, T. Risgaard, N. Nishiwaki, K. V. Gothelf, and
K. A. Jꢀrgensen, J. Am. Chem. Soc., 123, 5843 (2001). d) N. Nishiwaki,
K. R. Knudsen, K. V. Gothelf, and K. A. Jꢀrgensen, Angew. Chem. Int.
Ed., 40, 2992 (2001).
7
8
Yb(OiPr)3 was purchased from Kojundo Chemical Co., Ltd. (Fax:
(+81)492-84-1351).
Procedure: The freshly prepared catalyst solution of 8 (0.025 M in
toluene/THF 7/1, 2.0 mL, 0.20 mol equiv) (1 M ¼ 1 mol dmꢁ3) was
added to a test tube containing imine 6 (76 mg, 0.25 mmol), and the
mixture was stirred for 10 min at room temperature. The mixture was
cooled to ꢁ40 ꢂC and stirred for 10 min before nitromethane (0.068 mL,
5.0 mol equiv) was added slowly over 27 h at the same temperature.
After the addition of nitromethane was completed, the mixture was
stirred for an additional 33 h at the same temperature, and then quenched
by the addition of water (ca. 5 drops) and diluted with CH2Cl2 (ca.
5 mL). The mixture was allowed to warm up to room temperature, and
after further dilution with CH2Cl2 (ca. 15 mL) the mixture was dried
(Na2SO4) and concentrated under reduced pressure. Purification by
flash column chromatography (SiO2, acetone/hexane 40/60 to 50/50)
gave nitroamine 3 (72 mg, 79%) with 91% ee as an off-white solid.
The ee of 3 and syn-14 was determined by HPLC analysis on a chiral
stationary phase: for 3, DAICEL Chiralcel OD; iPrOH/hexane 10/90;
flow rate 1.0 mL minꢁ1;retention time 15 and 27 min, for the syn-14,
Scheme 2. Reagents and conditions: a) 12 (20 mol%), CH2Cl2, ꢁ40 ꢂC,
90%, dr 6 : 1, 77% ee (anti), [chromatography-free purification (see text):
97% ee, 40% from 6];b) HF-pyridine, THF, 0 ꢂC to rt, quant;c) Dess-Martin
periodinane, CH2Cl2, rt, 14 h, 86%;d) i) TMSCl, DBU, CH 2Cl2, 0 ꢂC, 1 h;ii)
AcOH, ꢁ78 ꢂC, 15 min, 83% from 15;e) Zn, NH 4Cl, MeOH/H2O, rt, 85%;f)
o-anisaldehyde, NaBH3CN, MS3A, MeOH, rt, 3 h, 81%;g)LiAlH4, THF, rt,
30%.
spontaneous cyclization furnished nitropiperideine 15 in 86%
yield in three steps.12 Desired epimerization of this cyclized
product occurred via silyl nitronate to reverse the diastereomeric
ratio to 1 : 5 in favor of the desired syn-form (16) in 83% yield.
Epimerization on acyclic nitroamine 14 under the same condi-
tions also reversed the diastereomeric ratio in 90% yield, albeit in
a less satisfactory ratio (1 : 2). The nitro group of 16 was reduced
to an amino group using Zn dust in 85% yield with negligible loss
of stereochemical integrity.13 The o-anisyl group was introduced
by reductive alkylation to afford 17 in 81% yield. Treatment with
LiAlH4 induced cleavage of the diphenylphosphinoyl group and
simultaneous reduction of the enamine moiety to yield 2 in 30%
yield.14 The optical purity of 2 was determined after transforma-
9
DAICEL Chiralpak AD; iPrOH/hexane 10/90;flow rate 1.0 mL min ꢁ1
;
retention time 9 and 26 min. The ee of anti-14 was determined after
transformation of the TBS group to Bn group as follows: i) HF-pyridine,
THF, 0 ꢂC to rt, ii) benzyl trichloroacetimidate, TFA, CH2Cl2, rt. HPLC
analysis: DAICEL Chiralpak AD; iPrOH/hexane 10/90;flow rate
1.0 mL minꢁ1;retention time 35 and 52 min.
10 T. Arai, Y. M. A. Yamada, N. Yamamoto, H. Sasai, and M. Shibasaki,
Chem. Eur. J., 2, 1368 (1996).
24
tion to its HCl salt bytreating with methanolic HCl, ½ꢃŠ þ72 ꢂ (c
11 Procedure: The 0.1 M solution of catalyst 12 (0.40 mL, 0.20 mol equiv)
was added to a test tube containing imine 6 (61 mg, 0.20 mmol), and the
mixture was stirred for 10 min at rt. The mixture was cooled to ꢁ40 ꢂC
and stirred for 10 min before a 1.0 M solution of KO-t-Bu in THF
(0.036 mL, 0.18 mol equiv) and then nitroalkane 13 (0.25 ml, 5.0 mol
equiv) were added at ꢁ40 ꢂC. The mixture was stirred for 48 h at the
same temperature, diluted with cold CH2Cl2 (ꢁ78 ꢂC, ca. 5 mL) and
then quenched by the addition of HOAc (ca. 6 drops). The mixture was
transferred to a separatory funnel and diluted with additional CH2Cl2
(ca. 15 mL). The mixture was washed with H2O, sat. aq NaHCO3 and
brine, dried (Na2SO4), and concentrated in vacuo. Purification of the
resulting residue by column chromatography (SiO2, CH2Cl2/acetone
19/1 to 9/1) gave nitroamine 14 (97 mg, 90%) as an off-white solid in a
diastereomeric ratio of 6 : 1 (anti : syn) with 77% ee (anti) and 5% ee
(syn).
D
0.4, CH3OH);lit., ½ꢃŠD þ77 ꢂ (c 1.0, CH3OH).3a
In conclusion, we succeeded in synthesizing 1 and 2 using the
catalytic asymmetric nitro-Mannich reactions as a key step,
which enabled direct and stereoselective access to 1,2-diamines.
Furthermore, selective acquisition of each diastereomer of a
cyclic nitroamine was possible through epimerization, as
demonstrated in the synthesis of 2. To obtain the syn-isomer
directly, syn-selective reaction is currently under investigation in
this laboratory.
Dedicated to Prof. Teruaki Mukaiyama on the occasion of his
75th birthday.
12 When the alcohol moiety was converted to a leaving group such as
iodide, methanesulfonate, or triflate in an attemptto construct piperidine
ring by SN2 type reaction, nucleophilic attack by the nitro group
occurred exclusively, probably due to a reduced nucleophilicity of the
amino group with an electron withdrawing substituent.
References and Notes
1
D. Lucet, T. Le Gall, and C. Mioskowski, Angew. Chem., Int. Ed. Engl.,
37, 2580 (1998).
2
a) G. F. Costello, R. James, J. S. Shaw, A. M. Slater, and N. C. J.
Stutchbury, J. Med. Chem., 34, 181 (1991). b) J. J. Barlow, T. P.
Blackburn, G. F. Costello, R. James, D. J. Le Count, B. G. Main, R. J.
Pearce, K. Russell, and J. S. Shaw, J. Med. Chem., 34, 3147 (1991). c)
S. A. Weerawarna, R. D. Davis, and W. L. Nelson, J. Med. Chem., 37,
13 Other conditions such as SmI2, Pd-C/H2, Pd(OH)2/H2, Raney nickel/
H2, and HCOONH4/Pd-C all gave rise to less satisfactory results
because of epimerization, side reactions, and so on.
14 Spectroscopic data of the product obtained were identical with those
reported in Ref. 3a.