Anomalies in the asymmetric transfer hydrogenation of several polycyclic meso compounds

Article abstract of DOI:10.1016/j.tetlet.2011.12.123

Over the course of developing a multigram scale preparation of epoxy quinol 1 via asymmetric transfer hydrogenation (ATH) using the Noyori Ru(arene)(S,S-TsDPEN) catalysts, we observed several unexpected phenomena, including (i) chemoselective alkene versus ketone reduction of an enedione, (ii) a significant arene ligand effect (p-cymene vs mesitylene) on the reaction pathway, and (iii) solvent-based reversal of the sense of enantioinduction.

Full text of DOI:10.1016/j.tetlet.2011.12.123

Tetrahedron Letters 53 (2012) 1691–1694
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Anomalies in the asymmetric transfer hydrogenation of several polycyclic
meso compounds
⇑
David R. Clay, Matthias C. McIntosh
Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR 72701, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 May 2011
Revised 29 December 2011
Accepted 30 December 2011
Available online 14 January 2012
Over the course of developing a multigram scale preparation of epoxy quinol 1 via asymmetric transfer
hydrogenation (ATH) using the Noyori Ru(arene)(S,S-TsDPEN) catalysts, we observed several unexpected
phenomena, including (i) chemoselective alkene versus ketone reduction of an enedione, (ii) a significant
arene ligand effect (p-cymene vs mesitylene) on the reaction pathway, and (iii) solvent-based reversal of
the sense of enantioinduction.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Transfer hydrogenation
Noyori
Asymmetric
meso
In the course of our ongoing synthesis of antascomicin B,1–3 we
identified epoxy quinol 1 as an early intermediate in the synthesis
(Scheme 1). Since the Noyori asymmetric transfer hydrogenation
(ATH) of ketones is a widely used reaction in both industrial and
academic laboratories,4,5 ATH of meso-diketones 26 or 37 appeared
to offer a mild, scalable method for large scale synthesis of the qui-
nol (Eq. 1). Unlike aryl ketones or ynones, however, there are only a
few examples of ATH of cyclohexenones.8,9 The ATH of ketoisoph-
orone reported by a Hoffman-La Roche group seemed to augur well
for the success of the reduction, although the reported reaction
scale was only ca. 100 mg (Eq. 2).9
We initially sought to desymmetrize meso-enedione 2 via ATH.
Noyori transfer hydrogenations are typically performed using
either iPrOH as both solvent and reductant or trialkylamine/formic
acid as reductant with or without added solvent.4,5 To our surprise,
subjection of diketone 2 to typical ATH conditions using Ru(p-
cymene)(S,S-TsDPEN) as catalyst and triethylammonium formate
as the reductant resulted principally in alkene rather than ketone
reduction to give dihydro diketone 4,6b hydroquinone 5,10 and a
small amount of recovered starting material (Scheme 2).11 Use of
2-propanol as reductant and solvent gave similar results.
and a small amount of diketone 4 were detected. After 6 h, all of the
enedione had disappeared, leading principally to diketone 4. No ke-
tone reduction product was detectable. These results imply that
either direct alkene reduction occurred, or isomerization of the keto
alcohol to the diketone was very rapid. Deng et al have reported
that some electron deficient enones undergo preferential alkene
reduction using the Noyori Ru(arene)(TsDPEN) catalyst system,
and that activated alkenes lacking ketones also undergo alkene
reduction.15
The Noyori and related ATH catalysts can effect both reduction
of ketones and oxidation of alcohols. In 1997 Noyori et al reported
the oxidative desymmetrization of meso-diol 616 using Ru(mesity-
lene)(S,S-TsSPEN) to give hydroxy enone 7 in a 70% yield and 96%
ee, although the scale of the reaction was not disclosed (Scheme
3).17 This could also lead to our desired epoxy alcohol 1, although
it would require an additional undesirable reduction/oxidation se-
quence. While Noyori employed the Ru catalyst with the mesity-
lene ligand, we first examined the more widely used p-cymene
variant. On a preparative scale,18,19 the treatment of enediol 6 with
Ru(p-cymene)(S,S-TsDPEN) in acetone at rt afforded none of the
hydroxy enone 7, but rather diketones 2 and 4 in roughly equal
yield, along with recovered diol (20%) and a small amount of
hydroquinone 5. Use of the mesitylene catalyst did indeed provide
hydroxy ketone 7, albeit in our hands in only 42% isolated yield,
along with an equivalent amount of enedione 2 as well as 9% of
dihydro diketone 4 and recovered diol (10%).18,19 The er of hydroxy
enone 7 ranged from 87:13 to 96:4 over the course of the reactions.
This is consistent with a modest intrinsic enantioselectivity in the
oxidation enhanced by kinetic resolution of the minor enantiomer
(vide infra).3c,17
There are at least two possible mechanisms for the formation of
diketone 4: direct alkene reduction, or ketone reduction followed
by isomerization.12 In order to distinguish the two pathways, the
progress of the reduction of 2 in 2-propanol was followed directly
by no-D 1H NMR analysis13 of the reaction mixture (see Supplemen-
tary data). 14 Within 3 min of mixing the reactants, only enedione 2
⇑
Corresponding author.
E-mail address: mcintosh@uark.edu (M.C. McIntosh).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.123

1692
D. R. Clay, M. C. McIntosh / Tetrahedron Letters 53 (2012) 1691–1694
Scheme 1. Asymmetric transfer hydrogenation substrates.
Scheme 2. Chemoselective alkene reduction of enedione 2.
In order to better understand the relative rates of formation of
the various products, we again followed the course of the reactions
directly by no-D 1H NMR analysis using acetone as the solvent (see
Supplementary data). 20 Using the p-cymene catalyst, within 3 min
of mixing of the reactants, a small amount of hydroxy enone 7 was
detectable, but by 60 min an equal amount of enedione 2 was also
present. At 20 h the reaction had proceeded to roughly 75% conver-
sion, with enedione 2 predominating and hydroquinone 5 also
present in minor amounts. Use of the mesitylene catalyst was more
selective for the formation of enone 7, although after 24 h it had
proceeded only to ca. 20% conversion. Interestingly, dihydro dike-
tone 4 was not detected either in the NMR experiment, although
it was always present in the preparative scale reactions in signifi-
cant amounts.21
In order to circumvent these problems, we examined the reduc-
tion of meso-epoxy diketone 3 to epoxy keto alcohol 8 using both
iPrOH and NEt3/HCO2H as reductants (Scheme 4).3c,22 We found
that the sense of enantioinduction reversed when changing the
hydrogen source/solvent from neat iPrOH to 1:1 NEt3/HCO2H
(0.2 M) in acetonitrile: 19:81 versus 82:18 8:ent-8, respectively
(see Supplementary data).23 To our knowledge, a reversal in
enantioselectivity as a function of solvent has not been previously
noted, although solvents are known to affect the enantioselectivity
of the reduction.4c
Scheme 4. Solvent dependent reversal in sense of absolute asymmetric induction.
sense of enantioinduction relies principally on the absolute config-
uration of the chelating ligand,31 although Andersson reported that
acetophenone and its perfluorophenyl analog gave opposite senses
of asymmetric induction using the same S,S-TsDPEN ligand (95% ee
S vs 12% ee R, respectively).26b
Recently, computational analysis of ATH including explicit sol-
vent (methanol32 or water33) has shown that hydrogen bonding
of the ketone oxygen to solvent lowers the transition state energies
relative to the unsolvated transition states (Scheme 6).34 In the
case of methanol, hydrogen bonding between solvent, ligand, and
ketone (transition state i), and between solvent and ketone in the
case of water (transition state ii), served to lower the transition
state energies.
We speculate that the differing dielectric constants (iPrOH =
19.9; CH3CN = 37.5)35 and hydrogen bonding abilities of the sol-
vents contributed to the reversal in enantioselectivity. The concen-
tration of hydrogen bond donors also differs significantly in the
two sets of conditions: neat iPrOH is 13.3 M, while the concentra-
tion of HNEt3CO2H was 0.2 M in acetonitrile. The epoxide oxygen
may also serve as a hydrogen bond acceptor,36 which might further
differentiate the two transition states. The latter proposal is sup-
ported by the observation that transfer hydrogenation of meso-
diketone 4 reproducibly provided the known keto alcohol 937 with
the same sense of asymmetric induction under both sets of condi-
tions: 63:33 (iPrOH) and 81:19 (HCO2H/NEt3) (Scheme 7).38,39
The mechanism of the Noyori ATH is generally agreed to involve
a concerted outer sphere transfer of hydrogen from the catalyst to
a ketone that is hydrogen-bonded to the catalyst via an N–H bond
(Scheme 5).24–27 Details regarding the origin of enantioselectivity
are a subject of dispute, but include steric, solvent, and electro-
static effects as well as dispersion forces. In the case of aryl
ketones, a favorable CH–
p interaction has been identified compu-
tationally as contributing to the asymmetric induction.28–30 The
Scheme 3. Results of attempted asymmetric oxidation of meso-diol 6 using Ru(Ar)(S,S)-TsDPEN catalysts.

D. R. Clay, M. C. McIntosh / Tetrahedron Letters 53 (2012) 1691–1694
1693
Scheme 5. Schematic mechanism of transfer hydrogenation.
3. (a) Qi, W.; McIntosh, M. C. Tetrahedron 2008, 64, 7021–7025; (b) Hutchison, J.
M.; Gibson, A. S.; Williams, D. T.; McIntosh, M. C. Tetrahedron Lett. 2011, 52,
6349–6351; (c) Clay, D. R.; Rosenberg, A. G.; McIntosh, M. C. Tetrahedron:
Asymmetry 2011, 22, 713–716.
4. See, for example: (a) Miyagi, M.; Takehara, J.; Collet, S.; Okano, K. Org. Process
Res. Dev. 2000, 4, 346–348; (b) Hansen, K. B.; Chilenski, J. R.; Desmond, R.;
Devine, P. N.; Grabowski, E. J. J.; Heid, R.; Kubryk, M.; Mathrea, D. J.; Varsolonab,
R. Tetrahedron: Asymmetry 2003, 14, 3581–3587; (c) Tanis, S. P.; Evans, B. R.;
Nieman, J. A.; Parke, T. T.; Taylor, W. D.; Heasley, S. E.; Herrinton, P. M.;
Perrault, W. R.; Hohler, R. A.; Dolak, L. A.; Hesterf, M. R.; Seestg, E. P.
Tetrahedron: Asymmetry 2006, 17, 2154–2182; (d) Zhang, J.; Blazecka, P. G.;
Bruendl, M. M.; Huang, Y. J. Org. Chem. 2009, 74, 1411–1414.
5. For reviews, see: (a) Ohkuma, T.; Noyori, R. Enantioselective Ketone and b-Keto
Ester Hydrogenations Including Mechanisms In Handbook of Homogeneous
Hydrogenation; De Vries, J. G., Elsevier, C. J., Eds.; WILEY-VCH: Weinheim, 2007;
Vol. 3, pp 1105–1163; (b) Blacker, A. J., Enantioselective Transfer
Hydrogenation, ibid, pp 1215–1244.; (c) Ikariya, T.; Blacker, A. J. Acc. Chem.
Res. 2007, 40, 1300–1308; (d) Gladiali, S.; Alberico, E. Chem. Soc. Rev. 2006, 35,
226–236; (e) Ikariya, T.; Murataa, K.; Noyori, R. Org. Biomol. Chem. 2006, 4, 393–
406; (f) Noyori, R.; Ohkuma, T. Angew. Chem. Int. Ed. 2001, 40, 40–73.
6. (a) Albrecht, W. Just. Liebig. Ann. Chem. 1906, 343, 31–49; (b) Oda, M.; Kawase,
T.; Okada, T.; Enomoto, T. Org. Syn. 1996, 73, 253–257.
Scheme 6. Transfer hydrogenation transition states with explicit methanol or
water molecule.
7. O’Brien, D. F.; Gates, J. W., Jr. J. Org. Chem. 1965, 30, 2593–2601.
8. Hannedouche, J.; Kenny, J. A.; Walsgrove, T.; Wills, M. Synlett 2002, 263–266;
(a) Peach, P.; Cross, D. J.; Kenny, J. A.; Mann, I.; Houson, I.; Campbell, L.;
Walsgrove, T.; Wills, M. Tetrahedron 2006, 62, 1864–1876; (b) Kosjek, B.;
Tellers, D. M.; Biba, M.; Farr, R.; Moore, J. C. Tetrahedron: Asymmetry 2006, 17,
2798–2803.
9. Hennig, M.; Püntener, K.; Scalone, M. Tetrahedron: Asymmetry 2000, 11, 1849–
1858.
10. Porter, R. F.; Rees, W. W.; Frauenglass, E.; Wilgus, H. S., III; Nawn, G. H.; Chiesa,
P. P.; Gates, J. W., Jr. J. Org. Chem. 1964, 29, 588–594.
11. Experimental procedure: Formic acid (0.6 mL, 16 mmol) was added dropwise
to triethylamine (1.18 mL, 16 mmol) at À10 °C. The mixture was diluted with
acetonitrile (100 mL) and Ru(p-cymene)(S,S-TsDPEN) (0.04 g, 0.067 mmol,
0.67 mol %) was added, followed by enedione 2 (1.74 g, 10 mmol, 0.1 M). The
reaction mixture was allowed to slowly warm to rt and stirred for ca. 6 h. The
mixture was concentrated in vacuo and then stirred for ca. 16 h in 30:70 ethyl
acetate/hexanes (50 mL) with activated charcoal (2 g), then filtered through a
plug of Celite with 30:70 ethyl acetate/hexanes, and concentrated in vacuo.
Flash chromatography (20:80 ethyl acetate/hexanes) of the residue gave
diketone 4 (0.88 g, 50% yield) and hydroxy phenol 5 (0.22 g, 13% yield). All 1H
NMR spectra matched reported data.
12. Hiroya, K.; Kurihara, Y.; Ogasawara, K. Angew. Chem. Int. Ed. 1995, 34, 2287–
2289.
13. Hoye, T. R.; Eklov, B. M.; Ryba, T. D.; Vologshin, M.; Yao, L. J. Org. Lett. 2004, 6,
953–956.
14. Experimental procedure: Enedione 2 (87 mg, 0.5 mmol, 0.1 M) was added to a
solution of Ru(p-cymene)(S,S-TsDPEN) (4 mg, 0.0067 mmol, 1.3 mol %) in i-
PrOH (5 mL). An aliquot was removed from the reaction mixture and placed
directly into an NMR tube. The progress of the reaction in the NMR tube was
monitored by 1H NMR spectrometry.
Scheme 7. Solvent effect on asymmetric reduction of diketone 4.
In summary, we have identified unexpected substrate, ligand,
and solvent effects in the ATH of polycyclic meso-diketones and a
meso-diol. Given the importance of the Noyori and related ATH
methods in industrial and academic syntheses, these results sug-
gest that a careful exploration of reaction parameters may be
necessary in some substrate classes to optimize chemo- and
enantioselectivities.
Acknowledgments
15. Xue, D.; Chen, Y.-C.; Cui, X.; Wang, Q.-W.; Zhu, J.; Deng, J.-G. J. Org. Chem. 2005,
70, 3584–3591.
16. Marchand, A. P.; LaRoe, W. D.; Sharma, G. V. M.; Suri, S. C.; Reddy, D. S. J. Org.
Chem. 1986, 51, 1622–1625.
We thank NSF (CHE0911638), NIH (P30RR031154) and the
Arkansas Biosciences Institute for support of this work.
17. Hashiguchi, S.; Fujii, A.; Haack, K.-J.; Matsumura, K.; Ikariya, T.; Noyori, R.
Angew. Chem. Int. Ed. 1997, 36, 288–291.
Supplementary data
18. Each reduction was performed at least 3 times. Product yields shown are
representative.
19. Experimental procedures: (a) p-Cymene catalyst: Diol 6 (0.45 g, 2.5 mmol,
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.12.123.
0.1 M) was added to
a solution of Ru(p-cymene)(S,S-TsDPEN) (0.075 g,
0.125 mmol, 5 mol %) in acetone (25 mL). The reaction mixture was allowed
to stir for ca. 24 h, then concentrated in vacuo. Activated charcoal (2 g) was
added, and the mixture stirred for ca. 16 h in 30:70 ethyl acetate/hexanes
(25 mL). After filtration through a plug of Celite with 30:70 ethyl acetate/
hexanes and concentration in vacuo, the residue was purified by flash
chromatography (20:80 ethyl acetate/hexanes) to give enedione 2 (0.13 g,
30%), diketone 4 (0.11 g, 25%), hydroquinone 5 (0.013 g, 3%), and recovered diol
(20%). (b) Mesitylene catalyst: diol 6 (65 mg, 0.36 mmol, 0.1 M) was added to a
solution of Ru(mesitylene)(S,S-TsDPEN) (3 mg, 0.0049 mmol, 1.3 mol %) in
References and notes
1. Isolation: Fehr, T.; Sanglier, J. J.; Schuler, W.; Gschwind, L.; Ponelle, M.;
Schilling, W.; Wioland, C. J. Antibiot. 1996, 49, 230–233.
2. Total synthesis: Brittain, D. E. A.; Griffiths-Jones, C. M.; Linder, M. R.; Smith, M.
D.; McCusker, C.; Barlow, J. S.; Akiyama, R.; Yasuda, K.; Ley, S. V. Angew. Chem.
Int. Ed. 2005, 44, 2732–2737.

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D. R. Clay, M. C. McIntosh / Tetrahedron Letters 53 (2012) 1691–1694
acetone (3.6 ml). The reaction mixture was allowed to stir for ca. 16 h, then
25. (a) Yamakawa, M.; Ito, H.; Noyori, R. J. Am. Chem. Soc. 2000, 122, 1466–1478; (b)
Noyori, R.; Yamakawa, Masashi; Hashiguchi, S. J. Org. Chem. 2001, 66, 7932–7944.
26. (a) Alonso, D. A.; Brandt, P.; Nordin, S. J. M.; Andersson, P. G. J. Am. Chem. Soc.
1999, 121, 9580–9588; (b) Brandt, P.; Roth, P.; Andersson, P. G. J. Org. Chem.
2004, 69, 4885–4890.
concentrated in vacuo. Activated charcoal (0.5 g) was added and the mixture
stirred for ca. 16 h in 30:70 ethyl acetate/hexanes (5 mL), then was filtered
through a plug of Celite with 30:70 ethyl acetate/hexanes and concentrated in
vacuo. Flash chromatography (20:80 ethyl acetate/hexanes) of the residue gave
enedione
2
(24 mg, 38% yield), dihydro diketone
4
(5.8 mg, 9% yield),
27. Clapham, S. E.; Hadzovic, A.; Morris, R. H. Coord. Chem. Rev. 2004, 248, 2201–
2237.
28. Casey, C. P.; Johnson, J. B. J. Org. Chem. 1998, 68, 1998–2001.
29. Yamakawa, M.; Yamada, I.; Noyori, R. Angew. Chem. Int. Ed. 2001, 40, 2818–
2821.
30. No model has been explicitly proposed for enones, ynones, or dialkyl ketones.
31. (a) Takehara, J.; Hashiguchi, S.; Fujii, A.; Inoue, S.-i.; Ikariya, T.; Noyori, R. J.
Chem. Soc., Chem. Commun. 1996, 233–234.
32. Handgraaf, J.-W.; Meijer, E. J. J. Am. Chem. Soc. 2007, 129, 3099–3103.
33. Wu, X.; Liu, J.; Tommaso, D. D.; Iggo, J. A.; Catlow, C. R. A.; Bacsa, J.; Xiao, J.
Chem. Eur. J. 2008, 14, 7699–7715.
hydroquinone 5 (0.317 mg, 0.5% yield), hydroxyl ketone 7 (27 mg, 42% yield),
and recovered starting material (6.8 mg, 10%)
20. Experimental procedure: Diol 6 (0.087 g, 0.5 mmol, 0.1 M) was added to a
solution of Ru(p-cymene)(S,S-TsDPEN) (4 mg, 0.0067 mmol, 1.34 mol %) in
acetone (5 mL). An aliquot was removed from the reaction mixture and added
directly to an NMR tube. The progress of the reaction in the NMR tube was
monitored by 1H NMR spectrometry. The oxidation with the mesitylene
catalyst was performed similarly.
21. These results collectively suggest that ATH with these catalysts is not a feasible
approach to hydroxy enone 7 on a preparative scale. While the Noyori report
(Ref. 17) of this transformation has been cited multiple times in reviews of
ATH,5 we can find no reports of its use in synthesis.
34. Transition state structures i and ii were adapted from Refs. 32,33, respectively.
35. Przybytek, J. T.; Krieger, P. A. High Purity Solvent Guide, 2nd ed.; Burdick &
Jackson Laboratories, Inc., 1984.
22. Experimental procedure: Epoxy diketone
3 (190 mg, 1 mmol, 0.1 M) was
added to solution of Ru(p-cymene)(S,S-TsDPEN) (0.04 g, 0.067 mmol,
a
36. Pihko, P. M. Hydrogen Bonding in Organic Synthesis; Wiley-VCH: Weinheim,
2009.
0.67 mol %) in i-PrOH (10 mL) and allowed to stir until no starting material
remained by TLC analysis (ca. 16 h). The mixture was concentrated in vacuo,
then stirred for ca. 16 h in 30:70 ethyl acetate/hexanes (5 mL) with activated
charcoal (1 g). The mixture was filtered through a plug of Celite with 30:70
ethyl acetate/hexanes, concentrated in vacuo, and the residue purified by
flash chromatography (30:70 ethyl acetate/hexanes) to give keto alcohol 8
(154 mg, 80% yield). Alternatively, formic acid (3.62 mL, 96 mmol) was added
dropwise to triethylamine (13.5 mL, 96 mmol) at À10 °C. The mixture was
diluted with acetonitrile (500 mL) and Ru(p-cymene)(S,S-TsDPEN) (0.24 g,
37. (a) Salles, R. C.; Lacerda, V., Jr.; Beatriz, A.; Ito, F. M.; dos Santos, R. B.; Greco, S.
J.; de Castro, E. V. R.; de Lima, D. P. Magn. Reson. Chem. 2010, 48, 409–415.
38. Experimental procedure: Diketone 4 (100 mg, 0.57 mmol, 0.1 M) was added to
a solution of Ru(p-cymene)(S,S-TsDPEN) (4.8 mg, 0.0067 mmol, 1.34 mol %) in
i-PrOH (5.7 mL) and allowed to stir until TLC analysis showed no further
consumption of diketone (ca. 48 h). The mixture was concentrated in vacuo
and was then passed through a plug of silica gel (30:70 ethyl acetate/hexanes).
The filtrate was analyzed by chiral stationary phase gas chromatography.
Alternatively, formic acid (0.036 mL, 0.97 mmol) was added dropwise to
triethylamine (0.14 mL, 0.97 mmol) at À10 °C. The mixture was diluted with
acetonitrile (5.7 mL) and Ru(p-cymene)(S,S-TsDPEN) (2.4 mg, 0.0038 mmol,
0.67 mol %) was added, followed by diketone 4 (100 mg, 0.57 mmol). The
reaction mixture was allowed to slowly warm to rt and allowed to stir until
TLC analysis showed no further consumption of diketone (ca. 24 h). The
mixture was concentrated in vacuo and then passed through a plug of silica gel
(30:70 ethyl acetate/hexanes). The filtrate was analyzed by chiral stationary
phase gas chromatography.
0.4 mmol, 0.67 mol %) was added, followed by epoxy diketone
3 (11.4 g,
60 mmol). The reaction mixture was allowed to slowly warm to rt and stirred
for ca. 16 h. The mixture was concentrated in vacuo and then stirred for ca.
16 h in 30:70 ethyl acetate/hexanes (200 mL) with activated charcoal (10 g).
The mixture was filtered through a plug of Celite with 30:70 ethyl acetate/
hexanes, concentrated in vacuo, and the residue purified by flash
chromatography (30:70 ethyl acetate/hexanes) to give keto alcohol 8 (9.8 g,
85% yield, 82:18 er).
23. Er’s were determined at low (5–10%) conversion to minimize effects of kinetic
resolution, and are an average of at least 3 runs.
24. (a) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc.
1996, 118, 2521–2522; (b) Hamada, T.; Torii, T.; Izawa, K.; Noyori, R.; Ikariya, T.
Org. Lett. 2002, 4, 4373–4376.
39. The absolute configurations of the alcohols were not determined, although it
seems likely that the major enantiomer is 9 by analogy to the reduction of
epoxy diketone 3. The reductions were repeated at least 3 times each; the er’s
are an average of the runs.