Rapid access to enantiopure bupropion and its major metabolite by stereospecific nucleophilic substitution on an α-ketotriflate

Article abstract of DOI:10.1016/S0957-4166(00)00349-9

A stereospecific method for the synthesis of enantiopure α-aminoketone from its corresponding α-hydroxy-ketone via the triflate intermediate is discussed. This strategy provides a rapid and efficient route for the preparation of either enantiomer of bupro

Full text of DOI:10.1016/S0957-4166(00)00349-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 3659–3663
Rapid access to enantiopure bupropion and its major
metabolite by stereospecific nucleophilic substitution on an
a-ketotriflate
Qun K. Fang,* Zhengxu Han, Paul Grover, Donald Kessler, Chris H. Senanayake* and
Stephen A. Wald
Chemical Process Research and Development, Sepracor Inc., 111 Locke Drive, Marlborough, MA 01752, USA
Received 25 July 2000; accepted 1 August 2000
Abstract
A stereospecific method for the synthesis of enantiopure a-aminoketone from its corresponding
a-hydroxy-ketone via the triflate intermediate is discussed. This strategy provides a rapid and efficient
route for the preparation of either enantiomer of bupropion and its biologically active hydroxylated
metabolite. © 2000 Elsevier Science Ltd. All rights reserved.
Racemic bupropion 1 is the active ingredient of Wellbutrin® (Glaxo Wellcome) marketed for
the treatment of depression. Recently, it has also been approved as an aid to smoking cessation
under the brand name of Zyban® (Glaxo Wellcome). Bupropion is extensively metabolized in the
body and the major active metabolite is hydroxybupropion 2.1 Enantiopure bupropion has been
prepared by chemical synthesis and hydroxybupropion has been separated by chiral columns.2
Studies have shown that a-aminoketones readily racemize in neutral and basic media.3 It has been
reported that bupropion’s therapeutic activity may result from the active hydroxylated metabolite
(hydroxybupropion)4 and structure–activity relationship studies of 2-phenylmorpholinols led to
the discovery of 155U888 3.5 In order to explore further the biological activities of single
enantiomers of these compounds, and to develop analogs with novel biological activities, a general
and rapid synthetic method for the synthesis of this class of compounds was required.6
* Corresponding authors. E-mail: kfang@sepracor.com
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00349-9

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During the last two decades, numerous methods for the synthesis of enantiopure a-hydroxy
ketones have been developed.7 With the advancement of these technologies, a-hydroxy ketones
with high enantiopurity are readily available. At the onset of our studies, the stereoselective
replacement of the hydroxyl group in a-hydroxy ketones with an alkylamine appeared to be the
most efficient approach to generate enantiomers of a-amino-ketones, such as bupropion and
hydroxybupropion. Interestingly, conversion of chiral a-hydroxy esters to chiral a-amino esters
(or acid) with complete inversion of stereochemistry is well established and practiced exten-
sively,8 however, to the best of our knowledge, no work has been published on the stereospecific
conversion of a-hydroxy ketones to a-amino ketones, even though this transformation has been
applied to racemic substrates.9 In addition, Creary reported that a-keto mesylates, triflates, and
trifluoroacetates can undergo solvolysis in polar solvents through a cationic transition state,10
which indicates the possibility of racemization during the substitution reaction. Herein, we wish
to report the stereospecific nucleophilic substitution of a-hydroxy ketones with alkylamines
utilizing a-ketotriflate intermediates to prepare enantiomers of bupropion and hydroxy-
bupropion.
The synthesis of either enantiomer of compound 6 was accomplished by Sharpless’s asymmet-
ric dihydroxylation of silyl enol ether 511 in multi-gram quantities, as outlined in Scheme 1.
Scheme 1.
3%-Chlorophenyl propanone was treated with LDA at −78°C, followed by addition of
TBDMS-Cl to give the silyl enol ether. The Z/E ratio of the vinyl ethers was estimated to be
1
99:1 by H NMR analysis. Asymmetric dihydroxylation of the silyl ether with AD-mix-a and
AD-mix-b as catalysts in t-BuOH/H2O yielded the corresponding hydroxyketones. (R)-6 and
(S)-6 were isolated from the reaction mixture and purified by flash chromatography in 82% yield
with 98 and 99% ee, respectively. These a-hydroxyphenylketones can be stored at −10°C under
nitrogen atmosphere for one month without any racemization.
Stereospecific nucleophilic substitution on a-ketotriflate 7 readily available from a-hydroxy-
ketone 6 with t-butylamine for the synthesis of (S)-bupropion is outlined in Scheme 2.

Q. K. Fang et al. / Tetrahedron: Asymmetry 11 (2000) 3659–3663
3661
Scheme 2.
(R)-3%-Chloro-2-hydroxypropiophenone 6 (98% ee) was treated with trifluoromethyl sulfonic
anhydride at −40°C in the presence of lutidine to form the ketotriflate intermediate 7. Without
isolation, the triflate intermediate was treated with t-butylamine at −40°C to give (S)-bupropion
in 60% yield after chromatographic purification (lower yield of the product was obtained when
Et3N or pyridine was used as base). Based on chiral HPLC analysis, enantiomeric excess of the
product was 98% with complete inversion of the stereogenic center.12 (R)-Bupropion was
obtained similarly starting from (S)-6. Bupropion free base is prone to racemization and was
converted to its hydrochloride salt in ethyl ether (>95% yield). Racemization studies of the HCl
salt of the bupropion isomer in phosphate buffer (pH 7.4) at 25°C indicated that racemization
readily takes place (42% in 2 h, 62% in 4 h, and >94% in 24 h, based on chiral HPLC analysis).
Due to the rapid racemization of bupropion enantiomers, our attention was focused on the
synthesis of configurationally more stable active metabolites. Since the biologically active
hydroxylated metabolite of bupropion is a hemiketal (2-phenylmorpholinol), it would be less
subject to racemization, and the biological testing results of the enantiomers would be more
reliable and desirable.2b This newly developed mild synthetic entry for the a-aminoketone was
extended to the preparation of the hydroxybupropion isomer, as outlined in Scheme 3.
Scheme 3.
When inexpensive and readily available 2-amino-2-methyl-1-propanol is reacted with (R)-tri-
flate 7, conformationally locked (2S,3S)-hydroxybupropion is isolated in 65% yield without any
racemization (98% ee) as the only product, and (2R,3S)-isomer was not observed.13 The absolute
configuration of the product was determined unambiguously by single-crystal X-ray analysis of
its di-toluoyl-
-tartrate salt (Fig. 1).14 Racemization studies of the hydroxy metabolite at 25°C
L
and pH 7.4 phosphate buffer were conducted, and as expected, racemization takes place slowly
(0.1% in 2 h, and ca. 2% in 24 h), which makes it much more desirable as an enantiomerically
pure drug candidate. (2R,3R)-Hydroxybupropion was obtained similarly from (S)-6.

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Figure 1. Perspective view (ORTEP) showing the crystallography labels for (2S,3S)-hydroxybupropion
In summary, we have developed a mild stereospecific displacement reaction for the transfor-
mation of readily available enantiopure a-hydroxy ketone to enantiopure a-aminoketone, which
allows the production of either enantiomer of bupropion and hydroxybupropion from readily
available ethyl 3%-chlorophenyl ketone. This is the first asymmetric synthesis of bupropion and
its biologically active metabolite. The scope of this reaction utilizing other ketones to prepare
biologically active targets is under investigation.
References
1. Welch, R. F.; Lai, A. A.; Schroeder, D. H. Xenobiotica 1987, 17, 287 and references cited therein.

Q. K. Fang et al. / Tetrahedron: Asymmetry 11 (2000) 3659–3663
3663
2. (a) Kelley, J. L.; Musso, D. L.; Boswell, G. E.; Soroko, F. E.; Cooper, B. R. J. Med. Chem. 1996, 39, 347–349.
(b) Musso, D. L.; Mehth, N. B.; Soroko, F. E.; Ferris, R. M.; Hollingsworth, E. B.; Kenney, B. T. Chirality 1993,
5, 495. (c) Musso, D. L.; Mehth, N. B.; Soroko, F. E. Bioorg. Med. Chem. Lett. 1997, 1.
3. Mey, B.; Paulus, H.; Lamparter, E.; Blaschke, G. Chirality 1998, 307.
4. Suckow, R. F.; Zhang, M. F.; Cooper, T. B. Biomed. Chromatogr. 1997, 11, 174 and references cited therein.
5. Boswell, G. E.; Musso, A. O.; Davis, D. L.; Kelley, J. L.; Soroko, F. E.; Cooper, B. R. J. Heterocycl. Chem.
1997, 34, 1813.
6. Due to the presence of chlorine substitution (meta) on the phenyl ring and the t-butylamine substitution on the
side chain, common methods for the synthesis of arylketone (e.g. Friedel–Crafts reaction with enantiomerically
enriched acid chloride) are not applicable to bupropion synthesis.
7. (a) Hashiyama, T.; Morikawa, K.; Sharpless, K. B. J. Org. Chem. 1992, 57, 5067–8; (b) Adam, W.; Fell, R. T.;
Stegmann, V. R.; Saha-Moller, C. R. J. Am. Chem. Soc. 1998, 120, 708; (c) Davis, F. A.; Chen, B. C. Chem. Rev.
1992, 92, 919. (d) Davis, F. A.; Sheppard, A. C.; Chen, B. C. J. Am. Chem. Soc. 1990, 6679. (e) Duh, T. H.;
Wang, Y. F.; Wu, M. J. Tetrahedron: Asymmetry 1993, 4, 1793. (f) Bradshaw, C. W.; Fu, H.; Shen, G. J.; Wong,
C. H. J. Org. Chem. 1992, 57, 1526. (g) Zhu, Y.; Manske, K. J.; Shi, Y. J. Am. Chem. Soc. 1999, 121, 4080. (h)
Zhu, Y.; Tu, Y.; Yu, H.; Shi, Y. Tetrahedron Lett. 1998, 39, 7819.
8. (a) Coppola, G. M.; Schuster, H. F. a-Hydroxy Acids in Enantioselective Synthesis; Wiley–VCH: Weinheim, 1997.
(b) Effenberger, F.; Burkard, U. Liebigs Ann. Chem. 1986, 334. (c) Kunz, H.; Lerchen, H. G. Angew. Chem. 1984,
84, 798.
9. Giordani, A.; Carera, A.; Pinciroli, V.; Cozzi, P. Tetrahedron: Asymmetry, 1997, 8, 253. Synthesis of chiral ketone
traflate has been reported and has been used for the preparation of chiral a-fluoroketone. See Liu, A.; Carlson,
K. E.; Katzenellenbogen, J. A. J. Med. Chem. 1992, 35, 2113.
10. Creary, X. J. Am. Chem. Soc. 1984, 106, 5568 and references cited therein.
11. In order to obtain high ee’s of hydroxyketone TBS ether is crucial; when TMS was used 93% ee was obtained
in the ADH reaction. When the TBS enol ether is replaced with vinyl chloride, the ee of the hydroxy ketone was
90% (also see Ref. 7a).
12. 1H NMR data was identical to the racemate sample. Ee’s were analyzed with ChiralPAK® AD column eluted
with hexane/IPA/DEA (99/1/0.1). (R)-(−)-Isomer, 4.51 min; (S)-(+)-isomer, 5.66 min. (Absolute configuration of
(S)-bupropion is established on AD chemistry.) Also see Ref. 14, which is further confirmed by X-ray analysis.
13. Typical experimental procedure: To a solution of (R)-3%-chloro-2-hydroxylpropiophenone (0.30 g) in CH2Cl2 (6
mL) at −78°C was added trifluromethane sulfonic anhydride (0.50 g), followed by the addition of 2,6-lutidine
(0.26 g). The reaction mixture was allowed to warm to −40°C and was stirred at this temperature for 40 min.
Then 2-amino-2-methyl-1-propanol (0.40 g, 2.5 equiv.) was added and the mixture was stirred for 2 h at −40°C,
warmed to 0°C and stirred overnight. CH2Cl2 (10 mL) was added and the organic phase was washed with
aqueous sodium bicarbonate, water and brine. The organic phase was concentrated to give a residue, which was
passed through a short column of silica gel eluted with CH3CN to give the product (260 mg, free base), ee 98%.
The ee was analyzed with ChiralCel® OD column eluted with hexane/IPA/DEA (98/2/0.1). (1R,2R)-Isomer, 7.45
min; (1S,2S)-isomer, 8.70 min. 1H NMR (CDCl3): l 0.78 (d, 3H), 1.1 (s, 3H), 1.4 (s, 3H), 3.2 (q, 1H), 3.4 (d, 1H),
3.8 (d, 2H), 7.2–7.65 (m, 4H). [h]=+66 (c=1, EtOH). (1R,2R)-Hydroxybupropion was prepared from (S)-1 with
97% ee [h]=−56 (c=1, EtOH).
14. Single crystals of (1S,2S)-hydroxybupropion ditoluoyl L-tartrate suitable for X-ray analysis were obtained first by
salt formation and subsequent crystallization from ethanol. As shown in the crystal structure, the methyl group
(C11) is clearly cis to the hydroxy group (O2) in the morpholine ring.
.