Kinetic resolution of hydroperoxides with enantiopure phosphines: Preparation of enantioenriched tertiary hydroperoxides

Article abstract of DOI:10.1021/ja070482f

An efficient reductive kinetic resolution strategy capable of accessing optically active tertiary hydroperoxides is reported. Readily accessible tertiary hydroperoxides are resolved with commercially available (R)- or (S)-xylyl-PHANEPHOS with selectivity factors as large as 37. The resulting bis(phosphine oxide) can be recycled in high yields. The isolated mono(phosphine oxide) intermediate resolved hydroperoxides with the same selectivity as the parent bisphosphine. Copyright

Full text of DOI:10.1021/ja070482f

Published on Web 03/15/2007
Kinetic Resolution of Hydroperoxides with Enantiopure Phosphines:
Preparation of Enantioenriched Tertiary Hydroperoxides
Tom G. Driver, Jason R. Harris, and K. A. Woerpel*
Department of Chemistry, UniVersity of California, IrVine, California 92697-2025
Received January 22, 2007; E-mail: kwoerpel@uci.edu
Table 1. Kinetic Resolution of Hydroperoxide 11 with Various
Enantiopure Phosphines
Hydroperoxides can serve as both biologically active agents and
precursors to therapeutically valuable endoperoxides.1 For example,
planaxool is a cytotoxic agent representative of the complex tertiary
hydroperoxides found in nature.2 In addition, appropriately substi-
tuted tertiary hydroperoxides have been utilized as intermediates
in the syntheses of antimalarial agents such as the natural product
yingzhaosu C3 and the synthetic 1,2,4-trioxane 1.4
b
entry
phosphine
% conva
% ee of 11a
krel
1
2
3
4
5
6
7
8
9
(2S,3S)-CHIRAPHOS (2)
(R,R)-Me-DuPHOS (3)
(S,S)-i-Pr-DuPHOS (4)
CARBOPHOS (5)
47
39
50
41
28
56
55
50c
50
0
0
19
13
6
23
36
45
86
1.0
1.0
1.2
1.3
1.5
1.7
2.5
3.5
(S)-MOP (6)
(S)-xylyl-BINAP (7)
(S,S)-NORPHOS (8)
(R)-PHANEPHOS (9)
(S)-xylyl-PHANEPHOS (10)
37
Applications of these compounds and related structures in
medicinal chemistry would benefit from a method capable of
obtaining enantiopure tertiary hydroperoxides. The accessibility of
racemic hydroperoxides, often available in one step from the
corresponding alcohol, has spurred the exploration of kinetic5 and
classical6 resolution strategies to synthesize these compounds.
Although enzymatic kinetic resolutions of a few secondary benzylic7
and R-hydroxy allylic hydroperoxides8 proceed with excellent
selectivities, these systems are limited in substrate scope. To date,
all resolutions of tertiary hydroperoxides occur with selectivity
factors of less than three.9
a Conversion and ee were determined by HPLC or SFC analysis using
Chiracel OD-H columns. b See ref 11. c Conversion was determined by 1H
NMR spectroscopic analysis.
The reduction of chiral tertiary hydroperoxides by chiral phos-
phines was examined using compound 11. This substrate contains
three sterically different substituents, including a chromophore to
facilitate HPLC analysis. Although all of the phosphines screened
are effective at enantioselective transformations in metal-mediated
syntheses,10 most gave low selectivities for the reduction of
hydroperoxide 11 (Table 1, entries 1-8). The cyclophane-derived
phosphine 10, however, reduced hydroperoxide 11 with a krel of
37, providing recovered starting material with 86% ee at 50%
conversion (Table 1, entry 9).11,12
The kinetic resolution of benzylic tertiary hydroperoxides is
general using the optimized bisphosphine. xylyl-PHANEPHOS (10)
was effective in resolving hydroperoxides containing three sterically
different substituents (Table 2, entries 1-5). In all cases, (R)-10
reduced the (-)-(S)-hydroperoxide preferentially, and the enanti-
omer, (S)-10, had the opposite selectivity.13 Phosphine (R)-10 also
resolved the functionalized hydroperoxide 18, although the selectiv-
ity was lower (Table 2, entry 6).
The phosphine optimized for tertiary benzylic hydroperoxides
is less efficient for the resolution of secondary benzylic and non-
benzylic hydroperoxides. The reduction of secondary benzylic
hydroperoxides with phosphine (R)-10 proceeded with moderate
selectivity. This process, however, complements other methods of
obtaining these compounds in enantiopure form (Table 2, entries
6-9).7 Selectivities diminished with increasing length of the alkyl
linker in the resolutions of non-benzylic hydroperoxides 23 and
24 with (R)-10 (Scheme 1). Presumably, as the tether length
increases, the steric differentiation decreases at the reactive center.
The kinetic resolution of racemic tertiary hydroperoxides is
amenable to preparative scale reactions. One gram of hydroperoxide
(()-11 was subjected to resolution conditions with commercially
In this communication, we demonstrate that a reductive kinetic
resolution strategy, employing commercially available enantiopure
phosphines, can provide optically pure tertiary hydroperoxides with
high efficiency. The use of phosphines in stoichiometric quantities
is mitigated by the ease with which the resulting phosphine oxide
can be recycled (vide infra). In addition, this strategy can be applied
to secondary hydroperoxides as a complementary method to those
reported.7
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J. AM. CHEM. SOC. 2007, 129, 3836-3837
10.1021/ja070482f CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Generality of Kinetic Resolution
Scheme 3
b
entry
substrate
R1
R2
% conva
% eea
krel
1
2
3
4
5
6
7
8
9
13
14
15
16
17
18
19
20
21
22
Me
Me
Me
Me
Me
Me
H
H
H
H
Et
43
46c
57
39
56
49c
84
75
50
43
63
71
90
58
95
42
77
76
62
42
21
23
16
37
25
3.8
2.6
3.4
6.9
5.2
n-Pr
n-Bu
i-Bu
c-C6H11
CH2OSiMe2t-Bu
Me
Et
i-Pr
c-C6H11
In addition, the resulting bis(phosphine oxide) can be converted
back to the phosphine in high yield.16
10
a Conversion and ee were determined by HPLC or SFC analysis using
Chiracel OD-H columns. b See ref 11. c Conversion was determined by 1H
NMR spectroscopic analysis.
Acknowledgment. This research was supported by the National
Science Foundation (CHE-0315572). J.R.H. thanks Lilly for a
predoctoral fellowship. K.A.W. thanks Amgen, Johnson & Johnson,
Lilly, and Merck Research Laboratories for awards to support
research. We thank Dr. Philip Pye and Dr. Jacqueline Smitrovich
of Merck Research Laboratories for a generous donation of pseudo-
ortho-dibromoparacyclophane, and Professor Elizabeth Jarvo (UCI)
for helpful discussions. We thank Dr. Phil Dennison (UCI) for
assistance with NMR spectrometry, and Dr. John Greaves and Shirin
Sorooshian (UCI) for assistance with mass spectrometry.
Scheme 1
Supporting Information Available: Complete experimental pro-
cedures, product characterization, and HPLC/SFC traces (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
Scheme 2
References
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of Peroxides; Wiley: Chichester, UK, 2006; pp 915-1000.
(2) Alam, M.; Martin, G. E.; Zektzer, A. S.; Weinheimer, A. J.; Sanduja, R.;
Ghuman, M. A. J. Nat. Prod. 1993, 56, 774-779.
available phosphine (R)-10 (71% conversion, Scheme 2). The
resulting enantiopure hydroperoxide (+)-(R)-11 and enriched
alcohol (-)-(S)-12 could not be separated by physical means, but
a strategy was developed to facilitate purification. When the mixture
of hydroperoxide (+)-(R)-11 and alcohol (-)-(S)-12 was treated
with Et3SiCl, the hydroperoxide was protected selectively,14 and
the resulting silylperoxy ether could be separated from the alcohol
by column chromatography. Subsequent desilylation provided
enantiopure (>99% ee) hydroperoxide (+)-(R)-11 in 24% overall
yield. This route also allows access to enantiopure tertiary alcohol
(+)-(R)-12 by reduction with triphenyl phosphine (Scheme 2).
Preliminary mechanistic studies reveal that the two phosphines
of xylyl-PHANEPHOS (10) operate independently.15 The supposed
intermediate, mono(phosphine oxide) (R)-25, was isolated from the
reaction of phosphine (R)-10 and 1 equiv of hydroperoxide 17.
Utilizing this compound in the resolution of hydroperoxide 11
(3) (a) Xu, X. X.; Dong, H. Q. Tetrahedron Lett. 1994, 35, 9429-9432. (b)
Boukouvalas, J.; Pouliot, R.; Frechette, Y. Tetrahedron Lett. 1995, 36,
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(4) O’Neill, P. M.; Pugh, M.; Davies, J.; Ward, S. A.; Park, B. K. Tetrahedron
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(5) For reviews of hydroperoxide kinetic resolutions, see: (a) Hamann, H.-
J.; Ho¨ft, E.; Liebscher, J. Peroxide Chemistry; Wiley: Weinheim,
Germany, 2000; pp 381-405. (b) Reference 1c; pp 329-348.
(6) Dussault, P.; Porter, N. A. J. Am. Chem. Soc. 1988, 110, 6276-6277.
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(8) For a representative example, see: Adam, W.; Lazarus, M.; Hoch, U.;
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(10) Valentine, D. H.; Hillhouse, J. H. Synthesis 2003, 2437-2460.
(11) Theoretically, starting material with >99% ee can be recovered in ∼43%
yield utilizing a kinetic resolution method that proceeds with a krel of 37.
Selectivity values (krel) were calculated using the equation krel ) ln[(1 -
C)(1 - ee)]/ln[(1 - C)(1 + ee)]. See: Kagan, H. B.; Fiaud, J. C. Topics
in Stereochemistry; Wiley: New York, 1988; pp 249-330.
(12) The selectivities observed using solvents such as CH2Cl2, Et2O, and THF
were approximately 10-30% lower.
afforded starting material with 84% ee at 51% conversion (krel
)
(13) The absolute configurations of previously unknown hydroperoxides have
been extrapolated from analogues. Details are provided as Supporting
Information.
25, Scheme 3). This experiment demonstrates that the monophos-
phine intermediate (R)-25 reduces hydroperoxides with a similar
selectivity to that of xylyl-PHANEPHOS. It also suggests that less
complex monophosphines may also be useful for this type of
resolution.
In conclusion, we have described a method for the stoichiometric
kinetic resolution of hydroperoxides employing commercially
available phosphines. The reaction provides access to enantiopure
hydroperoxides and, therefore, the corresponding alcohols as well.
(14) Dai, P.; Trullinger, T. K.; Liu, X.; Dussault, P. H. J. Org. Chem. 2006,
71, 2283-2292.
(15) The mechanism of reduction of hydroperoxides by phosphines involves
addition to the terminal oxygen atom: Lowe, J. R.; Porter, N. A. J. Am.
Chem. Soc. 1997, 119, 11534-11535.
(16) The bis(phosphine oxide) isolated from the resolution reaction can be
reduced with HSiCl3 in >90% yield. Details are provided as Supporting
Information.
JA070482F
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J. AM. CHEM. SOC. VOL. 129, NO. 13, 2007 3837