Asymmetric C-H oxidation of vic-diols to α-hydroxy ketones by a fructose-derived dioxirane: Electronic effects on the enantioselectivity of oxygen transfer

Article abstract of DOI:10.1021/jo9907843

A mechanistic study on the enantioselective C-H oxidation of vic-diols with the in-situ-generated dioxirane from the fructose-derived ketone 1 is presented. The asymmetrization of meso-configured and the kinetic resolution of racemic vic-diols 2 afforded the optically active α-hydroxy ketones 3 in opposite configurations with moderate to good ee values. Significant electronic effects on the enantioselectivity of C-H insertion have been observed, which are explained in terms of the hydrogen-bonded transition- state structures for the concerted C-H oxygen insertion.

Full text of DOI:10.1021/jo9907843

7
492
J . Org. Chem. 1999, 64, 7492-7497
Asym m etr ic C-H Oxid a tion of vic-Diols to r-Hyd r oxy Keton es by a
F r u ctose-Der ived Dioxir a n e: Electr on ic Effects on th e
En a n tioselectivity of Oxygen Tr a n sfer
Waldemar Adam,* Chantu R. Saha-M o¨ ller, and Cong-Gui Zhao
Institute of Organic Chemistry, University of W u¨ rzburg, Am Hubland, D-97074 W u¨ rzburg, Germany
Received May 12, 1999
A mechanistic study on the enantioselective C-H oxidation of vic-diols with the in-situ-generated
dioxirane from the fructose-derived ketone 1 is presented. The asymmetrization of meso-configured
and the kinetic resolution of racemic vic-diols 2 afforded the optically active R-hydroxy ketones 3
in opposite configurations with moderate to good ee values. Significant electronic effects on the
enantioselectivity of C-H insertion have been observed, which are explained in terms of the
hydrogen-bonded transition-state structures for the concerted C-H oxygen insertion.
In tr od u ction
Several methods are available for the preparation of
optically active R-hydroxy ketones, which are valuable
Dioxiranes, either in isolated form1 or in-situ-gener-
10
building blocks in asymmetric synthesis. In metal-free
2
ated, have been established as very reactive yet highly
methods, silyl enol ethers and enol esters have been
3
11
selective oxidants. One of the highlights of dioxirane
oxidized to optically active R-hydroxy ketones by the
chemistry is the efficient oxyfunctionalization of unacti-
in-situ-generated dioxirane from the fructose-derived
4
12
vated as well as activated C-H bonds. Although the
ketone 1. Moreover, it is well-known that vic-diols may
possibility of a radical-chain reaction has been recently
be readily oxidized by dioxiranes to yield the correspond-
raised,5 convincing experimental evidence as well as
6
13
ing R-hydroxy ketones. When optically active vic-diols
7
theoretical work have confirmed the concerted mecha-
were used, the resulting R-hydroxy ketones were obtained
with complete retention of configuration.1 Since opti-
cally active dioxiranes have been established as efficient
3b
nism for this insertion reaction, especially under carefully
6
a
controlled experimental conditions. The concerted na-
ture of this oxidation process provides an opportunity to
oxidants for the asymmetric epoxidation of unfunction-
8
12,14
conduct enantioselective C-H oxidations, which still
alized olefins,
we envisaged that optically active
present a formidable challenge in organic chemistry.9
R-hydroxy ketones should be accessible through asym-
metrization of meso-configured vic-diols or kinetic resolu-
tion of racemic vic-diols by enantioselective C-H oxida-
tion. In a recent paper,15 we described such an oxidation
of vic-diols to enantiomerically enriched R-hydroxy ke-
tones by the in-situ-generated, fructose-derived dioxirane
in eq 1 and demonstrated the preparative convenience
of this direct and metal-free asymmetric oxidation. Pres-
ently, we report the electronic substituent effects on the
*
To whom correspondence should be addressed. Tel: +49-
31-8885340. Fax: +49-931-8884756. E-mail: adam@chemie.uni-
wuerzburg.de.
9
(
1) Murray, R. W.; J eyaraman, R. J . Org. Chem. 1985, 50, 2847-
2
1
853. (b) Adam, W.; Bialas, J .; Hadjiarapoglou, L. P. Chem. Ber. 1991,
24, 2377.
(2) Curci, R.; Fiorentino, M.; Triosi, L.; Edwards, J . O.; Pater, R. H.
J . Org. Chem. 1980, 45, 4758-4760. (b) Adam, W.; Hadjiarapogolou,
L. P.; Smerz, A. Chem. Ber. 1991, 124, 227-232. (c) Yang, D.; Wong,
M.-K.; Yip, Y.-C. J . Org. Chem. 1995, 60, 3887-3889. (d) Denmark, S.
E.; Wu, Z. J . Org. Chem. 1997, 62, 8964-8965. (e) Denmark, S. E.;
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X.; Shi, Y. J . Org. Chem. 1998, 63, 6425-6426.
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1998, 39, 8295-8298. (b) Miyafuji, A.; Katsuki, T. Tetrahedron 1998,
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1996, 37, 7577-7580. (e) Hamada, T.; Irie, R.; Mihara, J .; Hamachi,
K.; Katsuki, T. Tetrahedron 1998, 54, 10017-10028. (f) Groves, J . T.;
Viski, P. J . Org. Chem. 1990, 55, 3628-3634.
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B. A.; Bergman, R. G.; Mobley, A.; Peterson, P. H. Acc. Chem. Res.
1992, 25, 504-512. (c) Asensio, G.; Gonz a´ lez-N u´ n˜ ez, M. E.; Bernardini,
C. B.; Mello, R.; Adam, W. J . Am. Chem. Soc. 1993, 115, 7250-7253.
(d) Reiser, O. Angew. Chem., Int. Ed. Engl. 1994, 33, 69-72.
(10) Hanessian, S. Total Synthesis of Natural Products: The Chiron
Approach, Pergamon: New York, 1983; Chapter 2. (b) Davis, F. A.;
Chen, B.-C. Chem. Rev. 1992, 92, 919-934.
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hedron: Asymmetry 1998, 9, 397-401. (b) Zhu, Y.; Tu, Y.; Yu, H.; Shi,
Y. Tetrahedron Lett. 1998, 39, 7819-7822.
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62, 2328-2329. (c) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J .-R.; Shi,
Y. J . Am. Chem. Soc. 1997, 119, 11224-11235.
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Ohga, Y.; Eaton, P.; Yip, Y.-C. Tetrahedron Lett. 1993, 34, 4559-4562.
(b) D’Accolti, L.; Detomaso, A.; Fusco, C.; Rosa, A.; Curci, R. J . Org.
Chem. 1993, 58, 3600-3601. (c) Bovicelli, P.; Lupattelli, P.; Sanetti,
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P.; Sanetti, A.; Lupattelli, P. Tetrahedron 1996, 52, 10969-10978.
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2
05-211. (b) Murray, R. W. Chem. Rev. 1989, 89, 1187-1201. (c) Curci,
R. In Advances in Oxygenated Process; Baumstark, A. L., Ed.; J AI:
Greenwich, CT, 1990; Vol. 2, Chapter I, pp 1-59. (d) Adam, W.;
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W., Ed.; Wiley: New York, 1992; Chapter 4, pp 195-219. (e) Curci,
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Adam, W.; Smerz, A. K. Bull. Soc. Chim. Belg. 1996, 105, 581-599.
(
2
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98-300.
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1
986, 108, 2470-2472. (b) Mello, R.; Fiorentino, M.; Fusco, C.; Curci,
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Chem. 1998, 63, 254-263. (b) Vanni, R.; Garden, S. J .; Banks, J . T.;
Ingold, K. U. Tetrahedron Lett. 1995, 36, 7999-8002.
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rini, F.; Kluge, R.; Paredes, R.; Schulz, M.; Smerz, A. K.; Veloza, L. A.;
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(
1
1
0.1021/jo9907843 CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/11/1999

Asymmetric C-H Oxidation of vic-Diols
J . Org. Chem., Vol. 64, No. 20, 1999 7493
enantioselectivity of this C-H insertion in an effort to
optimize its efficiency through such a mechanistic study.
Ta ble 1. En a n tioselective Oxid a tion of m eso-Diols 2 by
th e in -Situ -Gen er a ted Dioxir a n e fr om th e
F r u ctose-Der ived Keton e 1
Resu lts
Of the several recently reported optically active ke-
tones, which were employed as precursors of dioxiranes
in asymmetric epoxidation, the ones prepared from
binaphthol1
4d,e,g
and TADDOL proved to be ineffective.
14d
1
2
The fructose-derived ketone 1 was the best choice for
the enantioselective oxidation of vic-diols to optically
active R-hydroxy ketones. The results are presented
below, separately for the various substrate types.
Asym m etr iza tion of m eso-Diols. Our initial inves-
tigation started with the asymmetrization of meso-
hydrobenzoins (Table 1). Under standard conditions (pH
of 10.5 and 3.0 equiv of ketone 1), a conversion of 89%
for meso-hydrobenzoin (2a ) and an ee value of 45% for
the R-hydroxy ketone 3a were achieved (Table 1, entry
1
), with about 50% of ketone 1 recovered after the
reaction. Under these conditions, similar high conver-
sions were obtained with the electron-rich methyl- and
methoxy-substituted meso diols 2b (Table 1, entry 2) and
2
c (Table 1, entry 3), but with still lower ee values for
the products 3b and 3c. The electron-poorer fluoro-,
chloro-, or bromo-substituted meso-diols 2d -f (Table 1,
entries 4-6) are less reactive (except the fluoro deriva-
tive), but exhibit higher ee values, which are considerably
better than the previously reported ones.1 Of the
electron-poor substrates, the cyano derivative 2g (Table
6a
1
, entry 7) was barely oxidized, but the highest ee value
was achieved, while the nitro-subsituted meso-diol 2h
was unreactive under these conditions (Table 1, entry 8).
The o-chloro substitution in meso-2i is disadvantageous
since a low conversion and the worst ee value was
obtained (Table 1, entry 9).
Since the enantiomers of the racemic R-hydroxy ke-
tones 3e and 3f are not baseline-separated on chiral
OD-H or OB-H columns, these enantiomerically enriched
products were acetylated with acetic anhydride/pyridine
to their acetates and readily separated on an OD-H
column to determine their ee values. The R configura-
tions were assigned to the major enantiomers of 3a -f,
(14) Yang, D.; Yip, Y.-C.; Tang, M.-W.; Wong, M.-K.; Zheng, J .-H.;
Cheung, K.-K. J . Am. Chem. Soc. 1996, 118, 491-492. (b)Yang, D.;
Wang, X.-C.; Wong, M.-K.; Yip, Y.-C.; Tang, M.-W. J . Am. Chem. Soc.
a
Diols 2 (0.1 mmol), ketone 1 (0.3 mmol), Curox (0.15 mmol),
1
6
1
996, 118, 11311-11312. (c) Wang, Z.-X.; Shi, Y. J . Org. Chem. 1997,
2, 8622-8623. (d) Adam, W.; Zhao, C.-G. Tetrahedron: Asymmetry
997, 8, 3995-3998. (e) Song, C. E.; Kim, Y. H.; Lee, K. C.; Lee, S.-g.;
K2CO3 (0.63 mmol), and Bu4NHSO4 (4 µmol) in CH3CN (1.5 mL)
b
1
and 0.05 M Na2B4O7 (1.0 mL) at 0 °C. Determined by H NMR
analysis, error e5% of the stated values. c Determined by chiral
HPLC analysis, error e2% of the stated values. d Configuration
of the major isomer was determined by comparison of the specific
rotation with literature values, numbers in brackets are the
references. e Determined for the acetate of the R-hydroxy ketone
J in, B. W. Tetrahedron: Asymmetry 1997, 8, 2921-2926. (f) Denmark,
S. E.; Wu, Z.; Crudden, C. M.; Matsuhashi. H. J . Org. Chem. 1997,
6
Tang, M.-W.; Zheng, J .-H.; Cheung, K.-K. J . Am. Chem. Soc. 1998,
1
Am. Chem. Soc. 1998, 120, 7659-7660. (i) Armstrong, A.; Hayter, B.
R. Chem. Commun. 1998, 621-622. (j) Tu, Y.; Wang, Z.-X.; Frohn, M.;
He, M.; Yu, H.; Tang, Y.; Shi, Y. J . Org. Chem. 1998, 63, 8475-8485.
2, 8288-8289. (g) Yang, D.; Wong, M.-K.; Yip, Y.-C.; Wang, X.-C.;
20, 5943-5952. (h) Yang, D.; Yip, Y.-C.; Chen, J .; Cheung, K.-K. J .
f
by chiral HPLC analysis. Configuration tentatively assigned.
(15) Adam, W.; Saha-M o¨ ller, C. R.; Zhao, C.-G. Tetrahedron: Asym-
obtained by asymmetric oxidation of meso-diols 2a -f, on
metry 1998, 9, 4117-4122.
16
the basis of the known sign of the optical rotations. The
(16) Enders, D.; Breuer, K.; Teles, J . H. Helv. Chim. Acta 1996, 79,
major enantiomers of the products 3g and 3i were
tentatively assigned as the R-configured ones based on
1
6
217-1221. (b) Gu, J . X.; Li, Z. Y.; Lin, G. Q. Chin. Chem. Lett. 1995,
, 457-458.

7
494 J . Org. Chem., Vol. 64, No. 20, 1999
Adam et al.
Ta ble 2. En a n tioselective Oxid a tion of d ,l-Diols 2 by th e
in -Situ -Gen er a ted Dioxir a n e fr om th e F r u ctose-Der ived
Keton e 1
conversions could be increased by using Curox (potassium
monoperoxysulfate) in excess. For example, the conver-
sion of d,l-4,4′-difluorohydrobenzoin (d,l-2d ) was raised
from 10 to 31% by using 1.5 instead of 0.75 equiv of
Curox, with the same ee value (69 vs 71%) of the product
(S)-3d within the experimental error (Table 2, entries 3
and 4). The ee values of the remaining diols were not
determined since the enantiomers were inseparable on
either OD-H or OB-H columns. For this case, the ee
values of the remaining diol were determined to be 11%
at 10% conversion and 28% at 31% conversion because
the two enantiomers of the diol d,l-2d are easily sepa-
rated on an OD-H column.
Kin etic Resolu tion of Un sym m etr ic vic-Diols.
These results are summarized in Table 3. The oxidation
of the unsymmetrical threo-1-phenyl-1,2-propanediol
(
threo-2j) led to the two regioisomeric S-configured
products 2-hydroxy-1-phenyl-1-propanone (3j) and 1-hy-
1
8
droxy-1-phenyl-2-propanone (3j′) in a ratio of 84:16,
with ee values of 69% and 44% (Table 3, entry 1). The
oxidation of the erythro-2j also yielded these two regio-
1
8
isomeric R-hydroxy ketones in a ratio of 89:11 (entry 2),
with ee values of only 23% (S) and 8% (R). Although some
nonbenzylic C-H oxidation was observed with erythro-
and threo-2j, attempted oxidation of cis-1,2-cyclohex-
anediol and meso-2,3-butanediol failed completely (data
not shown). The oxidation of cis- and trans-1,2-indanediol
(2k ) and of cis- and trans-1,2,3,4-tetrahydronaphthalene-
1
,2-diol (2l) gave R-hydroxy ketones 3k and 3l in low ee
values and again in opposite configurations (Table 3,
entries 3-6).
En a n tioselective Oxid a tion of Aceta ls. Since the
acetals of vic-diols are also known to be oxidized by
(
trifluoromethyl)methyldioxirane (TFD), and even DMD,
1
9
with complete retention of configuration, the enantio-
selective oxidation of some acetals of the above-mentioned
diols was examined (Table 3). The cis-4a derived from
meso-2a (Table 3, entry 7) and cis-4b derived from meso-
2
b (entry 8) gave almost the same ee values (63 vs 65%)
for the products (S)-3a and 3b, but in very low conver-
sions (ca. 10%), even when a large excess of Curox was
used. The trans-4a is still less reactive, and no consump-
tion could be achieved (data not shown). The oxidation
of the cis- and trans-4c acetals took place regioselec-
a
Diols 2 (0.1 mmol), ketone 1 (0.3 mmol), Curox (0.075 mmol),
K2CO3 (0.32 mmol), and Bu4NHSO4 (4 µmol) in CH3CN (1.5 mL)
and 0.05 M Na2B4O7 (1.0 mL) at 0 °C, unless otherwise indicated.
Determined by H NMR analysis, error e5% of the stated values.
Determined by chiral HPLC analysis, error e2% of the stated
values, numbers in parentheses are the ee values of the remaining
diol. Configuration of the major isomer was determined by
comparison of the specific rotation with literature values; numbers
in the brackets are the references. The ee value of the remaining
b
c
1
20
tively (Table 3, entries 9 and 10) to yield exclusively
the (S)-2-hydroxy-1-phenyl-1-propanone (3j). In both
cases, the conversions were very low and the enantiose-
lectivities inferior to those observed in oxidations of the
corresponding diols erythro- and threo-2j.
d
e
f
diol was not determined. 0.15 mmol of Curox and 0.63 mmol of
K2CO3 were used. Determined for the acetate of the R-hydroxy
ketone by chiral HPLC analysis. Configuration tentatively as-
g
h
Discu ssion
signed.
Ster eoselectivity. In the asymmetrization of meso-
hydrobenzoins (Table 1) and kinetic resolution of d,l-
hydrobenzoins (Table 2), noteworthy is the finding that
R-hydroxy ketones of opposite configurations were formed
the mechanism discussed below (vide infra). Moreover,
the major enantiomer of 3i has the same elution order
and sign of optical rotation as the known R-configured
R-hydroxy ketones 3a -f.
Kin etic Resolu tion of d ,l-Diols. The results of this
asymmetric oxidation are collected in Table 2. The kinetic
resolution of the d,l diastereomers led to higher enantio-
selectivities (ee g 61%) than for the corresponding meso
substrates (Table 1), with the S rather than the R
enantiomer as the major product. Again, the highest ee
value (75%) was observed for the poorly reactive cyano-
substituted substrate d,l-2g (Table 2, entry 7). Generally,
the conversions of the d,l substrates were much lower
than that for their meso counterparts; however, the
(
17) Adam, W.; D ´ı az, M. T.; Fell, R. T.; Saha-M o¨ ller, C. R. Tetra-
hedron: Asymmetry 1996, 7, 2207-2210. (b) Davis, F. A.; Shepperd,
A. C.; Chen, B.-C.; Haque, M. S. J . Am. Chem. Soc. 1990, 112, 6679-
6690.
(
18) The oxidation of 1-phenyl-1,2-propanediol by dimethyldioxirane
DMD) gave a mixture of 2-hydroxy-1-phenyl-1-propanone, 1-hydroxy-
-phenyl-2-propanone, and 1-phenyl-1,2-propanedione in a ratio of 52:
32:16 (see ref 13d).
19) Curci, R.; D’Accolti, L.; Dinoi, A.; Fusco, C.; Rosa, A. Tetrahe-
dron Lett. 1996, 37, 115-118.
20) DMD oxidizes acetal-4c regioselectively to give the 2-hydroxy-
1-phenyl-1-propanone as the only product (see refs 13c and 19).
(
1
(
(

Asymmetric C-H Oxidation of vic-Diols
J . Org. Chem., Vol. 64, No. 20, 1999 7495
Ta ble 3. En a n tioselective Oxid a tion of Un sym m etr ic vic-Diols a n d Aceta ls by th e in -situ -Gen er a ted Dioxir a n e fr om th e
F r u ctose-Der ived Keton e 1
a
In CH3CN (1.5 mL) and 0.05 M Na2B4O7 (1.0 mL) at 0 °C as described in Table 2, unless otherwise indicated. b Determined by 1
H
c
NMR analysis, error e5% of the stated values. Enantiomeric excess of R-hydroxy ketones 3 determined by chiral HPLC analysis, error
e2% of the stated values; ee values of the remaining diols or acetals were not determined. Configuration of the major isomer was
determined by comparison of the specific rotation with literature values, in brackets are given the references. Ratio of 2-hydroxy-1-
phenyl-1-propanone to 1-hydroxy-1-phenyl-2-propanone is 84:16. Ratio of 2-hydroxy-1-phenyl-1-propanone to 1-hydroxy-1-phenyl-2-
propanone is 89:11. In 3.0 mL of CH3CN-dimethoxymethane (DMM) (1:2) and 2.0 mL of 0.05 M Na2B4O7 with 1.89 mmol of K2CO3 at
°C. In 3.0 mL of CH3CN-DMM (1:2) and 2.0 mL of 0.05 M Na2B4O7 with 0.95 mmol of K2CO3 at 0 °C.
d
e
f
g
h
0
in the oxidation of the d,l-diols (S configuration) and that
of the meso-diols (R configuration). This may be explained
in terms of the transition-state structures for the con-
certed oxygen transfer6 , in which hydrogen bonding
of the remote hydroxy group is a key feature7 (Scheme
of d,l-2 (Scheme 1, right) (S)-3 is formed. Clearly, in both
cases the same sense of stereoselection applies. Also, the
oxidation of the unsymmetrical threo-1-phenyl-1,2-pro-
panediol (threo-2j) and the erythro-2j (Table 3, entries 1
and 2) may be rationalized in terms of the concerted
mechanism depicted in Scheme 1, with the exception of
the benzylic oxidation of erythro-2j to the (S)-2-hydroxy-
1-phenyl-1-propanone [(S)-3j], for which the R-configured
product [(R)-3j] would be expected according to Scheme
1. The enantioselective oxidation of the cis and trans
diastereomers of cyclic diols 2k and 2l (Table 3, entries
,7,13
,13
1
). Thus, the S-configured site is more readily oxidized
than the R-configured one since the sterically demanding
aryl group minimally interacts with the exocyclic dioxo-
lane ring of the dioxirane. Consequently, the asymmetric
oxidation of meso-2 (Scheme 1, left) gives the R-hydroxy
ketone (R)-3, while in the case of the kinetic resolution

7
496 J . Org. Chem., Vol. 64, No. 20, 1999
Adam et al.
Sch em e 1
Sch em e 2
F igu r e 1. Electronic effects in the asymmetrization of meso-
2
diols [b log (R/S) vs σpara, r ) 0.9338] and in the kinetic
2
resolution of d,l-diols [O log (S/R) vs σpara, r ) 0.9047] by
enantioselective oxidation with the fructose-derived dioxirane
from ketone 1.
2
(Table 1, entries 1-7, and Table 2) influence the
enantioselectivity of the C-H oxidation. This electronic
effect is more pronounced in the case of the asymmetri-
zation of meso-diols; that is, the enantioselectivities
drop considerably in the order CN (60%) > Br (58%) ≈
F (58%) > Cl (54%) > H (45%) > CH
3
(30%) > OCH
3
(
24%). The diminution of the enantioselectivity can
hardly be of steric origin because the para substituent is
too far away from the reaction center (Scheme 1); besides,
these groups are not sufficiently sterically demanding.
To confirm that electronic effects operate, a Hammett
correlation was constructed by plotting the logarithmic
values of the ratio of major to minor enantiomers [log
3
-6) also afforded the R-hydroxy ketones 3k and 3l in
opposite configurations. In these cyclic cases, in contrast
to the acyclic diols, it is not possible to form the
intermolecular hydrogen bonds between the dioxirane
and the diol due to the constraints imposed by the ring
structures. An alternative mechanism has been proposed
(
(
major/minor)], which provide the energy difference
q
∆∆G ) between the favored and disfavored transition
2
1
by us previously15 for the asymmetric oxidation of these
cyclic diols.
states (Scheme 1), against the Hammett σpara values of
the substituents. As is evident in Figure 1, with the
exception of the cyano-substituted meso-2g and d,l-2g
cases, reasonably good linear correlations were found for
the asymmetrization of the meso diols (r ) 0.9338) and
for the kinetic resolution of the d,l-diols (r ) 0.9047);
In the asymmetrization of the acetals cis-4a and cis-
b (Table 3, entries 7 and 8), again there is no possibility
4
2
to form intermolecular hydrogen bonds since both hy-
droxy groups are protected. As depicted in the respective
transition-state structures in Scheme 2, there is no steric
interaction between the dioxolane ring of the acetals 4
and the exocyclic dioxolane ring of the dioxirane in the
upper transition state (Scheme 2), so that the R-config-
ured center is the favored site of oxidation and, therefore,
2
clearly, the observed enantioselectivity is controlled by
electronic effects. The positive F values (0.71 for the
asymmetrization and 0.47 for the kinetic resolution)
indicate that electron-withdrawing groups yield higher
enantioselectivities.
The present dependence of the enantioselectivity on the
electronic nature of the para substituents may be un-
derstood by considering hydrogen bonding in the transi-
tion-state structures of the oxidations (Scheme 1). From
experimental evidence,13 it has been established that
intermolecular hydrogen bonding plays an important role
in the oxidation of vic-diols by dioxiranes. The transition
(
S)-3a and (S)-3b are formed as the major products. This
is to be contrasted with the meso-diols 2a and 2b (the
precusor to the cis acetals 4a and 4b), which afford the
R enantiomers (Scheme 1) due to hydrogen bonding
(
1
(
Table 1, entries 1 and 2). The formation of (S)-2-hydroxy-
-phenyl-1-propanone [(S)-3j] from the acetal cis-4c
Table 3, entry 9) may also be explained by the transition
7
,13
state for the dioxirane C-H insertion is a polar one,
structures depicted in Scheme 2, but preferential produc-
tion of the S enantiomer from the trans-4c diastereomer
(
However, as in the case of the oxidation of erythro-2j,
for which our mechanistic rationale also fails, the low ee
values of the product 3j reflect remote steric interactions
that are difficult to diagnose.
in which the carbon atom that is oxidized bears a partial
+
positive charge (δ ), while the hydrogen-bonded oxygen
Table 3, entry 10) cannot be reconciled in this manner.
-
atom of the dioxirane bears a partial negative charge (δ ).
Thus, the electron-accepting para substituent of the aryl
group will increase the positive charge at the carbon atom
through electron withdrawal, which will lower the reac-
Electr on ic Effects on th e En a n tioselectivity. It is
also evident from Tables 1 and 2 that the electronic
properties of the para substituents in the hydrobenzoins
(
21) Exner, O.; In Correlation Analysis in Chemistry; Chapman, N.
B., Shorter, J ., Eds.; Plenum Press: New York, 1978; Chapter 10. (b)
Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165-195.

Asymmetric C-H Oxidation of vic-Diols
J . Org. Chem., Vol. 64, No. 20, 1999 7497
tivity of the diol substrate toward the electrophilic C-H
insertion. At the same time, the electron withdrawal of
the para group on the adjacent phenyl ring of the vic-
diol will enhance the acidic character of the hydroxy
group and facilitate hydrogen bonding to the negatively
charged dioxirane oxygen atom. In the disfavored transi-
tion state for the asymmetrization of meso-diols (Scheme
2b (entry 8) gave almost the same ee values (63 vs 65%)
for the products 3a and 3b, which are significantly higher
than for the corresponding meso-diols. The better enan-
tioselectivity for cis-acetals 4 than for meso-diols 2 might
be due to an increased energy difference between the
favored and disfavored transition-state structures, since
the steric interaction of the exocyclic dioxolane ring of
the dioxirane with the dioxolane ring of cis-acetals 4
should be considerably larger than that with an aryl
group in the case of the meso-diols 2. This enhanced steric
interaction should be beneficial in developing more
effective asymmetric oxidations by chiral dioxiranes.
1
, lower left), there is steric interaction between the aryl
group and the exocylic dioxolane ring of the dioxirane.
Since a stronger hydrogen bond will generate a more
tightly bound transition-state structure, this steric in-
teraction will be increased in such a more rigid structure
and thereby disfavor this transition state even more.
Consequently, the stronger hydrogen bonding promoted
by the electron-accepting aryl groups leads to a higher
enantioselectivity in the asymmetrization of meso-diols.
The fact that the cyano group falls off the line (Figure 1)
suggests that the stabilizing effect of stronger hydrogen
bonding has leveled off for the cyano group, but other
factors, e.g., competitive intermolecular hydrogen bond-
ing by the water in the aqueous medium in which the
optically active dioxiranes are generated in situ, may be
responsible for the observed deviation by altering the
transition-state structure.
This same mechanistic argument also applies to the
kinetic resolution of the d,l-diols (Scheme 1, right), but
in this case the electronic effects are smaller than for the
asymmetrization of the meso-diols. The better enantio-
selectivity observed in the kinetic resolution (Table 2) of
the d,l-diols versus the asymmetrization (Table 1) of the
meso-diols is presumably due to the lower steric repul-
sions between the adjacent aryl groups for the d,l
diastereomers, which allows better alignment for inter-
molecular hydrogen bonding, and electronic effects are
less pronounced.
Con clu sion
The oxidation of vic-diols by the in-situ-generated
fructose-derived dioxirane yields the corresponding opti-
cally active R-hydroxy ketones in moderate to good
enantioselectivities. By choosing the appropriate diaster-
eomeric substrates, i.e., meso or d,l, both enantiomers
of the R-hydroxy ketones may be obtained with the same
chiral dioxirane. Electronic effects of the para substitu-
ents display a pronounced influence on the enantiose-
lectivity of the oxidation of meso and d,l hydrobenzoins
and good linear correlations between the log(major/minor)
and σpara were found for both processes. Electron-
withdrawing substituents decrease the reactivity of the
diol, but with increased enantioselectivity of the oxygen
transfer. The results are explained in terms of the
counteracting electronic effects of the electron-accepting
para substituent: On one hand, the reactivity of the C-H
bond is reduced through the inductive electron with-
drawal, and on the other hand, the intermolecular
hydrogen bonding is strengthened in the transition state
for these electrophilic C-H insertions.
Ack n ow led gm en t. This work was supported by the
Deutsche Forschungsgemeinschaft (Schwerpunktpro-
gramm “Peroxidchemie: Mechanistische und pr a¨ para-
tive Aspekte des Sauerstofftransfers”) and the Fonds der
Chemischen Industrie. The generous gift of Curox
In the oxidation of the acetals 4 of the vic-diols (Table
), hydrogen bonding cannot operate in this enantiose-
lective C-H oxidation. Hence, only the electronic effect
on the C-H bond polarity of the acetals is manifested.
It has been reported that acetals are significantly less
reactive toward electrophilic oxygen insertion than the
3
(
potassium monoperoxysulfate) from Peroxid-Chemie
GmbH (H o¨ llriegelskreuth, Germany) is gratefully ap-
preciated. C.-G.Z. thanks the DAAD (Deutscher Aka-
demischer Austauschdienst) for a doctoral fellowship.
corresponding diols due to the lack of intermolecular
hydrogen bonding.19 As experimentally confirmed, the cis-
acetals 4 are less reactive than the meso-diols 2; the
conversions of the acetals were very low (ca. 10%) even
when a large excess of Curox was used.22 The cis-4a and
cis-4b derived from meso-2a (Table 3, entry 7) and meso-
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails; characterization data for new compounds 3g and cis-4b;
1
13
H NMR and C NMR data, as well as HPLC conditions for
the separation of the enantiomers of 3g and all other known
R-hydroxy ketones 3. This material is available free of charge
from the Internet at http://pubs.acs.org.
(22) Steric factors should not be responsible for the low reactivity
of the acetals toward the fructose-derived dioxirane since these
substrates are also much less reactive towards dimethyldioxirane
(DMD) than the corresponding diols (see ref 19).
J O9907843