Asymmetric synthesis of diarylmethylamines: Preparation of selective opioid delta receptor ligands

Article abstract of DOI:10.1016/S0957-4166(98)00419-4

Two different methods were used for the construction of optically active diarylmethylamines. Diastereoselective alkylation on an aldimine/oxazolidine 2a/2b derived from (R)/(S)-phenylglycinol or enantioselective reduction of 4- [η⁶-chromium tri

Full text of DOI:10.1016/S0957-4166(98)00419-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 3963–3966
Asymmetric synthesis of diarylmethylamines: preparation of
selective opioid delta receptor ligands
Daniel Delorme,∗,† Carl Berthelette, Rico Lavoie and Edward Roberts
Department of Medicinal Chemistry, Astra Research Centre Montreal, 7171 Frederick-Banting, Saint-Laurent, Quebec,
Canada H4S 1Z9
Received 2 October 1998; accepted 6 October 1998
Abstract
Two different methods were used for the construction of optically active diarylmethylamines. Diastereoselective
alkylation on an aldimine/oxazolidine 2a/2b derived from (R)/(S)-phenylglycinol or enantioselective reduction of
4-[η6-chromium tricarbonylbenzoyl] bromobenzene using chiral oxazoborolidine followed by amine introduction
to furnish optically active diarylmethylamines. © 1998 Elsevier Science Ltd. All rights reserved.
Diarylmethylamine moieties are part of many pharmacologically active compounds including the
recently described (+)BW373U86 as a delta receptor agonist.1 Our recent interest in developing selective
non-peptidic delta receptor agonists prompted us to search for a simple and efficient methodology
for the preparation of chiral diarylmethylamines. Numerous methods are available for the asymme-
tric synthesis of α-arylalkylamines2 but few methods are available for the synthesis of diarylmethyl-
amines in optically pure form.3 Resolution using (+)- or (−)-tartaric acid salt has been previously
used on diarylmethylamines.4 We now report an efficient method for the asymmetric synthesis of
diarylmethylamines in optically pure form based on diastereoselective addition of phenyllithium to
aldimine/oxazolidine 2a/2b. A second approach consists of chiral reduction of benzophenone chromium
tricarbonyl complex followed by amine introduction.5
Chiral 1,2-amino alcohols have been extensively used as chiral auxiliaries in asymmetric
synthesis.6 Consequently, the aldimine/oxazolidine 2a/2b7 were prepared in quantitative yield from
4-bromobenzaldehyde 1 using either (R)- or (S)-phenylglycinol in THF in the presence of anhydrous
magnesium sulfate at room temperature (Scheme 1).
Several parameters were evaluated for the alkylation reaction in order to optimize the yield (Table 1).
Alkylation reactions were performed on aldimine/oxazolidine 2a/2b prepared using (R)-phenylglycinol.
The best addition conditions found were when phenyllithium was used as nucleophile in anhydrous
THF in the presence of HMPA (10% v/v) at 0°C for 30 min to afford, after purification by flash
∗
†
Corresponding author. E-mail: delormed@methylgene.com
Present address: MethylGene Inc., 7220 Frederick-Banting, Montreal, Quebec, Canada H4S 2A1.
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00419-4

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D. Delorme et al. / Tetrahedron: Asymmetry 9 (1998) 3963–3966
Scheme 1.
chromatography, 71% yield of the coupling product 3.8 Analysis by chiral HPLC revealed that compound
3 was generated with 95% de9 The use of lower or higher temperatures or varying the amounts of
alkylating agent led to reduced yields. For example, the same reaction performed at room temperature
without additives does not change the de (95% de) but lowers the yield (see Table 1). Other nucleophiles
were also investigated, such as phenylmagnesium bromide or phenylcerium dichloride10 which gave
lower yields.
Table 1
Addition of organolithium reagent to aldimine/oxazolidine 2a/2b in dry THF
Cleavage of the chiral auxiliary was accomplished using lead tetraacetate11 in methanol at 0°C follo-
wed by acidic treatment (HCl conc., CH2Cl2) to give diarylmethylamine 4 in 60% yield12 (Scheme 2).
Oxidative cleavage of 3 using sodium metaperiodate did not improve the yield of compound 4. The
diarylmethylamine 4 was derivatized to the Mosher amide 5 and found to have 92% de after GC–MS
analysis.13 The absolute stereochemistry (R) in 4 is obtained by using aldimine/oxazolidine 2a/2b derived
from (R)-phenylglycinol.14
The same sequence of reaction has been effected starting from aldehyde 6.15 Alkylation of 7a/7b (from
(R)-phenylglycinol) under the same conditions as for 2a/2b gave 40% yield of the amide 8 with 93% de.
Cleavage of the chiral auxiliary and derivatization to the Mosher amide gave compound 10 with 93% de
based on GC–MS analysis.16
The second approach uses chiral reduction of the 4-bromobenzophenone chromium tricarbonyl com-
plex developed by Corey,5 followed by N-benzylpiperazine introduction. Thus compound 12 (Scheme 3)
obtained with 91% ee from chiral oxazaborolidine-catalyzed reduction was treated with tetrafluoroboric

D. Delorme et al. / Tetrahedron: Asymmetry 9 (1998) 3963–3966
3965
Scheme 2.
acid followed by addition of N-benzyl piperazine to provide compound 13 in 91% ee.17 Decomplexation
using ammonium cerium(IV) nitrate18 in methanol gave 95% yield of 14 without loss of enantiomeric
purity.19 Finally, the selective opioid delta receptor ligand 15 was obtained first by transmetallation in dry
THF at −78°C with n-BuLi, followed by bubbling with carbon dioxide. The resulting acid was treated
with thionyl chloride followed by the addition of diethylamine to give in 34% overall yield, compound
15 in 91% ee.20
Scheme 3.
In vitro binding assays of 15 using cloned human delta, mu and kappa opioid receptors gave an
IC50 of 1.2 nM, 2400 nM and 5500 nM, respectively, demonstrating that optically active substituted
diarylmethylamines such as 15 are highly selective delta receptor ligands. Futhermore, the enantiomer of
15 (with (R) stereochemistry derived from (R)-diphenyl-2-pyrrolidinemethanol chiral reduction) has an
IC50 of 17 nM on human delta receptor showing a better affinity for the (S)-isomer.
In conclusion, we have demonstrated that two different approaches can allow the preparation of
optically active substituted diarylmethylamines which are part of very active and selective delta opioid
receptor ligands. Further investigations into the development of selective delta receptor agonists are
underway.
Acknowledgements
C.B. is grateful to the Natural Sciences and Engineering Research Council of Canada for an Under-
graduate Student Research Award.

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D. Delorme et al. / Tetrahedron: Asymmetry 9 (1998) 3963–3966
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in deuterated chloroform while a ratio of 20:1 is observed in THF-d8. The ratios were obtained from 1H NMR integration
of the corresponding aldimine Ha and oxazoline proton Hb.
8. Typical procedure for the alkylation of aldimine/oxazolidine using phenyllithium. To a solution of imine 2 (125 mg, 0.4
mmol) in dry THF (3 ml) was added HMPA (0.3 ml) followed at 0°C with PhLi (500 µl, 0.9 mmol) under nitrogen
over a period of 1 min. The reaction mixture was stirred at 0°C for 30 min then quenched with aqueous NH4Cl. The
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7.16–7.50 (m, 14H); 13C NMR (100 MHz, CDCl3); δ: 61.58, 62.87, 66.99, 127.30, 127.44, 127.58, 127.79, 128.77, 128.90,
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9. Compound 3: HPLC (Chiracel OD, 10% i-PrOH in hexanes, 1 ml/min, λ=215 nm) >95% de.
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25
12. Compound 4 derived from (R)-phenylglycinol gave [α]D −2.3 (c 1.0, MeOH) and compound 4 derived from (S)-
phenylglycinol gave [α]D25+2.3 (c 1.0, MeOH).
13. Compound 5: GC–MS (method 200-280, column HP-5, 1 ml/min) 92% de.
14. A similar negative optical rotation value for compound 4 was obtained using compound A5 and the following synthetic
scheme:
15. The aldehyde 6 was prepared by heating 4-carboxybenzaldehyde with one equivalent of thionyl chloride at 50°C in a
mixture of CH2Cl2:DMF 9:1 followed by the addition of diethylamine at 0°C. This procedure gave 90% yield of aldehyde
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16. Compound 10: GC–MS (method 200-280, column HP-5, 1 ml/min) 93% de.
17. Compound 13: HPLC (Chiracel AD, 20% i-PrOH in hexanes, 1 ml/min, λ=215 nm) 91% de. [α]D25 +90.8 (c 1.0, CH2Cl2).
18. Schinzer, D.; Abel, U.; Jones, P. G. Synlett 1997, 632–634.
19. Compound 14: HPLC (Chiralcel AD, 1% i-PrOH in hexanes, 1 ml/min, λ=215 nm) 91% ee. [α]D25 +6.37 (c 1.0, CH2Cl2).
25
20. Compound 15: HPLC (Chiralcel AD, 20% i-PrOH in hexanes, 1 ml/min, λ=215 nm) 91% ee. [α]D +2.52 (c 2.02,
CH2Cl2).