The resolution of important pharmaceutical building blocks by palladium-catalyzed aerobic oxidation of secondary alcohols

Article abstract of DOI:10.1002/adsc.200303188

The palladium-catalyzed aerobic oxidative kinetic resolution of key pharmaceutical building blocks is described. Substrates investigated are relevant to the enantioselective preparation of Prozac, Singulair, and the promising hNK-1 receptor antagonist from Merck. The latter provides the most selective aerobic oxidative kinetic resolution yet described.

Full text of DOI:10.1002/adsc.200303188

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The Resolution of Important Pharmaceutical Building Blocks by
Palladium-Catalyzed Aerobic Oxidation of Secondary Alcohols
Daniel D. Caspi, David C. Ebner, Jeffrey T. Bagdanoff, Brian M. Stoltz*
The Arnold and Mabel Beckman Laboratories of Chemical Synthesis, Division of Chemistry and Chemical Engineering,
California Institute of Technology, 1200 E. California Blvd., MC 164-30, Pasadena, CA 91125, USA
Fax: ( ‡ 1)-626-564-9297, e-mail: stoltz@caltech.edu
Received: October 27, 2003; Accepted: January 16, 2004
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de or from the author.
Abstract: The palladium-catalyzed aerobic oxidative
kinetic resolution of key pharmaceutical building
blocks is described. Substrates investigated are
relevant to the enantioselective preparation of
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Prozac , Singulair , and the promising hNK-1 re-
ceptor antagonist from Merck. The latter provides
the most selective aerobic oxidative kinetic resolu-
tion yet described.
Keywords: asymmetric catalysis; kinetic resolution;
oxidation; oxygen; palladium; pharmaceutical sub-
stance
As part of a general program initiated in the area of
asymmetric dehydrogenation chemistry, we recently
reported the oxidative kinetic resolution of secondary
alcohols using a simple palladium dichloride catalyst
precursor [Pd(nbd)Cl2] in conjunction with (À)-spar-
teine serving as both ligand and base and molecular
oxygen as the stoichiometric oxidant.[1 3] We have made
a number of conceptual improvements to this system
that allow a range of alcohols to be resolved under a
variety of experimental procedures depending on the
substrate.[1b,1c] Additionally, this catalysis has been
extended to oxidative cyclizations including both hetero-
Figure 1. Palladium-catalyzed aerobic oxidation chemistry.
cyclizations and carbocyclizations (Figure 1).[4,5] Herein, (Figure 2). The pharmaceutical substances included A)
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we report the resolution of a number of key building the antidepressants fluoxetine hydrochloride (Prozac ,
blocks for the synthesis of biologically relevant drug 1a), norfluoxetine (1b), tomoxetine (2), and nisoxetine
substances. The versatility of this resolution is further (3),[6] B) the orally active leukotriene receptor antago-
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demonstrated by the diversity associated with the nist monteleukast sodium (Singulair , 4),[7] and C)
substrates chosen for this study, and for the first time Merck×s promising human neurokinin-1 (hNK-1) re-
extends the utility of the resolution to include amino ceptor antagonist (5).[8] These compounds were specif-
alcohol derivatives, cyclic allylic alcohols, and highly ically chosen due to the inclusion of a key benzylic or
functionalized benzylic alcohols.
allylic alcohol in the known synthetic routes (i.e., 6 8).
To demonstrate the potential utility of our palladium- We believed that such intermediates would represent an
catalyzed enantioselective alcohol oxidation, we inves- ideal testing ground for our new asymmetric method-
tigated the aerobic oxidative kinetic resolution of a ology.
diverse set of small molecules representing key building
To this end, we prepared a number of key intermedi-
blocks of bioactive pharmaceutically relevant materials ates by the literature procedures and subjected them to
Adv. Synth. Catal. 2004, 346, 185 189
DOI: 10.1002/adsc.200303188
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185

Daniel D. Caspi et al.
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Figure 2. Pharmaceutical substances.
Scheme 1. Functionalization of 6a and recycling of 11.
kinetic resolution using a variety of our palladium- Importantly, these resolutions provide a guide to the
catalyzed aerobic conditions. To our delight, all of the functional group compatibility of the rate-accelerated
intermediates were resolved to high enantiomeric system, as aryl bromides and benzoate esters are
excess and with good to excellent selectivity(ies) tolerated in the oxidation. Again, the corresponding
between the R and S enantiomers (s ˆ 9 82).[9] As ketones 12a and 12b could be easily recycled via
shown in Table 1, the amino alcohol derivatives 6a and borohydride reduction. Furthermore, elaboration of
6b, relevant to the antidepressants 1 3, could be both 7a and 7b to intermediates used in the production
resolved under our original conditions, employing of monteleukast sodium proceeded by intermolecular
Pd(nbd)Cl2, (À)-sparteine, and O2.[1a] While acetamide Heckreactions to provide the quinoline derivatives 13a
6b was reasonably selective (s ˆ 9), the more syntheti- and 13b (Scheme 2).
cally versatile BOC derivative 6a could be resolved with
Toour delight, the cyclopentenol structure8responded
a selectivity factor of nearly 18. Notably, the carbamate toallofourkineticresolutionconditionswithexceptional
6a could be easily converted to the N-methyl derivative selectivity and enhanced reactivity (Table 1, entry 5).
9 by reduction with LiAlH4 (78% yield) or to the Under all three of our reaction conditions (original,[1a]
primary amine 10 by treatment with TFA (68% yield), rate-accelerated,[1b] and room temperature chloro-
and the ketone 11 could be recycled to ( Æ )-6a by form[1c]) this substrate performed exceedingly well. It is
quantitative reduction with NaBH4 (Scheme 1).[10]
noteworthy that these resolutions represent the most
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The molecules relevant to the Singulair system also selective reactions observed to date for a palladium-
resolved quite efficiently (Table 1, entries 3 and 4). In catalyzed aerobic oxidation, with relative rates greater
order to minimize the experimental time involved for than 50:1. Gratifyingly, again the ketone by-product (i.e.,
the resolution of compounds 7a and 7b, we chose to 14) couldbetrivially recycled totheracemic alcohol( Æ)-
employ our recently described base-accelerated condi- 8 (Scheme 3). We are currently investigating the general-
tions.[1b] Smooth and rapid kinetic resolution was ity of these important substrates (2-arylcycloalk-2-en-1-
observed for both substrates (4.5 h) leading to produc- ols) toward oxidative kinetic resolution and planning
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tion of the relevant enantiomer for use in Singulair . their use in the synthesis of complex natural products.
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Table 1. Oxidative kinetic resolution of pharmaceutical building blocks.
Entry
1
Unreacted alcohol, major enantiomer
Method[a]
A
Time
24 h
Conversion [%]
57.5[c]
ee ROH [%][f]
93.1
s
17.9
2
3
4
A
14.5 h
4.5 h
4.5 h
70.0[c]
62.5[d]
70.6[c]
97.0
92.9
99.9
9.0
B[b]
11.2
15.3
B[b]
5
A
B
C
4 h
1 h
9 h
55.6[e]
55.5[e]
50.8[e]
99.5
99.5
94.7
50.2
51.1
82.7
[a]
Method A: 5 mol % Pd(nbd)Cl2, 20 mol % (À)-sparteine, MS 3 ä, O2 (1 atm), 0.1 M in PhCH3, 808C. Method B: 5 mol %
Pd(nbd)Cl2, 20 mol % (À)-sparteine, 0.5 equiv. Cs2CO3, 1.5 equivs. t-BuOH, MS 3 ä, O2 (1 atm), 0.25 M in PhCH3, 608C.
Method C: 5 mol % Pd(nbd)Cl2, 12 mol % (À)-sparteine, 0.4 equiv Cs2CO3, MS 3 ä, O2 (1 atm), 0.25 M in CHCl3, 238C.
Performed at 808C.
[b]
[c]
[d]
[e]
[f]
Conversion determined by isolated yield.
1
Conversion determined by H NMR.
Conversion determined by GC using a DB-wax column.
Enantiomeric excess (ee) determined by chiral HPLC (see Supporting Information for details). Total mass recovery in all
cases is greater than 85%.
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Scheme 2. Recycling and functionalization in the Singulair series.
In conclusion, we have employed the palladium-
catalyzed aerobic oxidative kinetic resolution for the
enantioselective preparation of a variety of pharma-
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ceutical substances including Prozac (1a), Singu-
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lair (4), and Merck×s hNK-1 receptor antagonist (5). Scheme 3. Recycling in the hNK-1 series.
These examples demonstrate the power and utility of
the methods that we have developed to overcome many functionalized aromatic molecules. We have also dis-
subtleties of substrate functionality. In this regard we covered the novel resolution capacity of 2-arylcyclo-
have resolved amino alcohol derivatives and multi- pentenol derivatives (i.e., 8), which is the most selective
Adv. Synth. Catal. 2004, 346, 185 189
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Daniel D. Caspi et al.
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8 (236.3 mg, 1.0 mmol) in chloroform (2 mL). The reaction was
allowed to proceed under O2 atmosphere (1 atm) at 238C.
Aliquots were filtered through a small plug of silica gel (Et2O
eluent), evaporated, and analyzed. Purification of ketone 14
and enantioenriched alcohol 8 was accomplished by direct
chromatography of the crude reaction mixture.
substrate yet investigated for aerobic oxidative kinetic
resolution. Efforts to develop new catalyst systems and
expand the utility and generality of asymmetric aerobic
dehydrogenations continue.
Experimental Section
Acknowledgements
The authors wish to thank the NIH-NIGMS (R01 GM65961
01), The NDSEG (predoctoral fellowship to DCE), the
University of California TRDRP (predoctoral fellowship to
JTB), the Dreyfus Foundation, Merck Research Laboratories,
Research Corporation, Amgen, Abbott Laboratories, Eli Lilly
(fellowship to DDC), GlaxoSmithKline, Johnson and Johnson,
Pfizer, and the A. P. Sloan Foundation for generous financial
support.
Kinetic Resolution Conditions A[1a]
To an oven-dried reaction tube with stir bar was added oven-
dried powdered 3 ä molecular sieves (250 mg). After cooling,
Pd(nbd)Cl2 (6.7 mg, 0.025 mmol) followed by toluene (2.5 mL)
and then (À)-sparteine (23.4 mg, 23 mL, 0.10 mmol) were
added. The reaction mixture was vacuum evacuated, purged
with O2 (3 Â ), and heated to 808C with vigorous stirring under
an O2 atmosphere (1 atm) for 20 min. A solution of allylic
alcohol 8 (118.1 mg, 0.50 mmol) in toluene (2.5 mL) was
added, and the reaction was allowed to proceed under O2
atmosphere (1 atm) at 808C. Aliquots were filtered through a
small plug of silica gel (Et2O eluent), evaporated, and analyzed
for conversion and ee. Purification of ketone 14 and enan-
tioenriched alcohol 8 was accomplished by direct chromatog-
raphy of the crude reaction mixture.
References and Notes
[1] a) E. M. Ferreira, B. M. Stoltz, J. Am. Chem. Soc. 2001,
123, 7725; b) J. T. Bagdanoff, E. M. Ferreira, B. M. Stoltz,
Org. Lett. 2003, 5, 835; c) J. T. Bagdanoff, B. M. Stoltz,
Angew. Chem. Int. Ed. 2004, 43, 353.
[2] Simultaneous to our publication, a related system was
reported; see: D. R. Jensen, J. S. Pugsley, M. S. Sigman, J.
Am. Chem. Soc. 2001, 123, 7475.
Kinetic Resolution Conditions B[1b]
[3] The kinetic resolutions in Refs.[1,2] were based on a non-
asymmetric alcohol oxidation employing Pd(OAc)2,
pyridine, and O2, see: T. Nishimura, T. Onoue, K. Ohe,
S. Uemura, J. Org. Chem. 1999, 64, 6750.
To an oven-dried reaction tube with stir bar was added oven-
dried powdered 3 ä molecular sieves (500 mg). After cooling,
Pd(nbd)Cl2 (13.5 mg, 0.05 mmol), followed by toluene (2 mL)
and then (À)-sparteine (46.9 mg, 46 mL, 0.20 mmol) were
added. The reaction vessel was then vacuum evacuated, purged
with O2 (3 Â ), and was heated (608C) with vigorous stirring
under an O2 atmosphere (1 atm) for 20 min. Finely powdered
anhydrous Cs2CO3 (162.9 mg, 0.50 mmol) was added, followed
bya solution of allylic alcohol 8 (236.3 mg, 1.0 mmol), t-butanol
(111.2 mg, 143 mL, 1.5 mmol) and toluene (2 mL). The reaction
was allowed to proceed under O2 atmosphere (1 atm) at 608C.
Aliquots were filtered through a small plug of silica gel (Et2O
eluent), evaporated, and analyzed. Purification of ketone 14
and enantioenriched alcohol 8 was accomplished by direct
chromatography of the crude reaction mixture.
[4] a) R. M. Trend, Y. K. Ramtohul, E. M. Ferreira, B. M.
Stoltz, Angew. Chem. Int. Ed. 2003, 42, 2892 2895;
b) R. M. Trend, Y. K. Ramtohul, E. M. Ferreira, B. M.
Stoltz, Angew. Chem. 2003, 115, 2998 3001.
[5] E. M. Ferreira, B. M. Stoltz, J. Am. Chem. Soc. 2003, 125,
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[7] a) R. D. Larsen, E. G. Corley, A. O. King, J. D. Carroll, P.
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Kinetic Resolution Conditions C[1c]
To an oven-dried reaction tube with stir bar was added oven-
dried powdered 3 ä molecular sieves (500 mg). After cooling,
Pd(nbd)Cl2 (13.5 mg, 0.05 mmol), followed by chloroform
(2 mL, stabilized with amylenes) and then (À)-sparteine
(28.1 mg, 27.6 mL, 0.12 mmol) were added. The reaction
mixture was then vacuum evacuated, purged with O2 (3 Â ),
and stirred vigorously at 238C under an O2 atmosphere (1 atm)
for 15 min. Finely powdered anhydrous Cs2CO3 (130.3 mg,
0.40 mmol) was added, followed by a solution of allylic alcohol
188
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Palladium-Catalyzed Aerobic Oxidation of Secondary Alcohols
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[8] a) J. T. Kuethe, A. Wong, J. Wu, I. W. Davies, P. G.
Dormer, C. J. Welch, M. C. Hillier, D. L. Hughes, P. J.
Reider, J. Org. Chem. 2002, 67, 5993 6000; b) R. C.
Desai, P. Cicala, L. C. Meurer, P. E. Finke, Tetrahedron
Lett. 2002, 43, 4569 4570; and references therein.
[9] The selectivity factor s was determined using the
equation: s ˆ krel(fast/slow) ˆ ln[(1 C)(1 ee)]/ln[(1 C)
(1 ‡ ee)], where C ˆ conversion.
[10] See Supporting Information for details.
Adv. Synth. Catal. 2004, 346, 185 189
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