Manganese-promoted regioselective ring-opening of 2,3-epoxy acid derivatives: a new route to α-hydroxy acid derivatives

Article abstract of DOI:10.1002/adsc.200900257

A simple and general methodology directed towards the synthesis 3-aryl-2-hydroxy amides, or esters with total regioselectivity from the easily available 2,3-epoxy amides or esters, promoted by active manganese is described. Utilizing enantiopure epoxy amides as starting materials, the corresponding 3-aryl-2-hydroxy amides in enantiopure form are also available. Some synthetic applications of selected examples of 3-aryl-2-hydroxy carboxylic acid derivatives are shown. A mechanism has been proposed to explain this novel reaction.

Full text of DOI:10.1002/adsc.200900257

FULL PAPERS
DOI: 10.1002/adsc.200900257
Manganese-Promoted Regioselective Ring-Opening of 2,3-Epoxy
Acid Derivatives: A New Route to a-Hydroxy Acid Derivatives
Josꢀ M. Concellꢁn,a,* Pablo L. Bernad,a Humberto Rodrꢂguez-Solla,a
and Pamela Dꢂaza
a
Departamento de Quꢂmica Orgꢃnica e Inorgꢃnica, Facultad de Quꢂmica, Universidad de Oviedo, 33071 Oviedo, Spain
Fax : (+34)-98-510-3446; e-mail: jmcg@uniovi.es
Received: April 14, 2009; Revised: July 9, 2009; Published online: September 10, 2009
This paper is dedicated with best wishes to Professor Benito Alcaide on the occasion of his 60th birthday.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900257.
Abstract: A simple and general methodology direct- available. Some synthetic applications of selected ex-
ed towards the synthesis 3-aryl-2-hydroxy amides, or amples of 3-aryl-2-hydroxy carboxylic acid deriva-
esters with total regioselectivity from the easily avail- tives are shown. A mechanism has been proposed to
able 2,3-epoxy amides or esters, promoted by active explain this novel reaction.
manganese is described. Utilizing enantiopure epoxy
amides as starting materials, the corresponding 3- Keywords: amides; epoxides; esters; hydroxy acids;
aryl-2-hydroxy amides in enantiopure form are also manganese
Introduction
novel and straightforward route to 2-hydroxy esters
from the corresponding 2,3-epoxy esters avoiding the
Many synthetic applications of 2-hydroxy acid deriva- use of hydrogen gas, or the synthesis of 2-hydroxy
tives have been reported,[1] amongst these 2-hydroxy amides promoted by a reagent cheaper than SmI2
acid derivatives have also used as starting materials to would be still of interest.
obtain biologically active molecules.[2] In addition, the
It has been shown that manganese is a non-toxic[11]
2-hydroxy acid moiety is present in an important and cheap[12] metal, with a reduction potential of the
number of natural products,[3] and some derivatives Mn2+/Mn(0) system of À1.03 V[13] [between the reduc-
possessing pharmacological applications.[4]
tion potentials of Zn2+/Zn(0) and Mg2+Mg(0)], ade-
Several methods have been reported for obtaining quate to reduce an important number of organic func-
2-hydroxy acid derivatives,[5] and inter alia, the most tions. However, in contrast to other metals, the appli-
direct access to these species could be considered to cations of manganese in organic synthesis have been
be the regioselective ring-opening[6] of 2,3-epoxy acid scarcely developed due to the inability of the com-
derivatives, involving the hydrogenation of the corre- mercially available manganese to react directly with
sponding 2,3-epoxy acid derivatives, which generally organic compounds as consequence of its passivity.[14]
has been applied to obtain 2-hydroxy esters.[7] To the
To overcome the lack of reactivity of manganese
best of our knowledge, only three papers reporting metal, different procedures to obtain active manga-
the transformation of epoxy amides into 2-hydroxy nese (Mn*) have been described in 1996 by Rieke[15]
amides have been published. Thus, the treatment of and Fꢄrstner[16] and in 1998 by Oshima.[17] After the
2,3-epoxy amides with samarium diiodide in the pres- appearance in the literature of the aforementioned
ence of H2O[8] (aromatic amides) or MeOH (aliphatic procedures for the preparation of Mn*, the number of
amides) afforded 2-hydroxy amides.[9] However, this contributions reporting new synthetic applications of
last method failed to obtain 2-hydroxy esters giving 3- this metal has increased.[18] Recently, we reported the
hydroxy esters rather than the desired regioisomer. first sequential processes promoted by Mn*, in which,
Recently, the catalytic hydrogenation of epoxy amides starting from aldehydes and 2,2-dichloro esters or
to obtain 2-hydroxy amides has also been de- amides, (E)-a,b-unsaturated esters[19] or amides,[20]
scribed.[10] Taking into account these precedents, a were obtained, respectively, with complete or total
2178
ꢅ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 2178 – 2184

Manganese-Promoted Regioselective Ring-Opening of 2,3-Epoxy Acid Derivatives
FULL PAPERS
diastereoselectivity. In a similar manner we have also
reported the synthesis of (Z)-a,b-unsaturated 2-halo
esters or amides with high stereoselectivity,[21] promot-
ed by Mn* from aldehydes and trihalo esters or
amides.
Scheme 1. Preparation of epoxy amides 1.
Herein we report the transformation of aromatic
a,b-epoxy esters or amides into 2-hydroxy esters or
amides, respectively, promoted by active manganese
(Mn*). The homochiral version of this method is also
Treatment of aromatic a,b-epoxy amides 1 with
reported starting from the corresponding enantiopure 3 equivalents of Mn*[23] at room temperature for 2.5 h
epoxy amides. All ring-opening reactions took place afforded the corresponding aromatic 2-hydroxy
with complete regioselectivity. To explain the ob- amides 2 in high yields and with complete regioselec-
tained results a mechanism is proposed.
tivity. When consumption of the starting epoxy amide
was not complete, the reaction was performed at
room temperature for 12 h (Table 1, entries 1–3).
This proposed methodology to obtain aromatic or
unsaturated 2-hydroxy amides 2 seems to be general.
Thus, the reaction was carried out with electron-rich
(Table 1, entries 2 and 5) or electron-deficient
Results and Discussion
Synthesis of Aromatic 2-Hydroxy Amides
Initially we tested the transformation of epoxy amides (Table 1, entries 3, 6–8 and 10) groups on the aromat-
1 into 2-hydroxy amides 2, as a cheaper alternative ic ring. This process also allowed the employment of
procedure to that previously reported with SmI2.
disubstituted (Table 1, entries 1–3), or trisubstituted
The starting epoxy amides 1 were readily prepared (Table 1, entries 4–12) oxirane rings, and amides de-
by reaction of various aldehydes or ketones 3 with rived from different amines, including bulky amines
the lithium enolates of chloro amides 4[22] for 2 h and such as diisopropylamine (Table 1, entries 2, 5, 6, 9,
further stirring overnight at room temperature and 13). The method tolerated various organic func-
(Scheme 1).
tions such as ethers, nitriles, or chlorine atoms. The
reaction could be carried out from epoxy amides de-
Table 1. Synthesis of 2-hydroxy amides 2 by regioselective ring-opening of 2,3-epoxy amides 1.
4
Entry
1
2[a]
R1
R2
R3
NR2
NEt2
Yield [%][b]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
2a[c]
2b[c]
2c[c]
2d
2e
2f
2g
2h
2i
2j
Ph
H
H
H
H
H
H
H
H
H
H
H
Me
Et
H
H
H
78 (60)
81
82
81 (64)
79 (70)
83
85 (69)
84
80
70
65
73
p-MeOC6H4
p-ClC6H4
Ph
NACHTUNREGTG(NNUN i-Pr)2
[d]
Me
Me
Me
Me
Me
Me
n-Bu
n-Bu
H
NEt2
p-MeOC6H4
p-ClC6H4
p-CNC6H4
p-CNC6H4
(E)-MeCH=CH
p-ClC6H4
(E)-PhCH=CH
Ph
N
N
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
NEt2
[d]
9
N
A
10
11
12
13
1j
1k
1l
NEt2
NEt2
NEt2
2k
2l[e]
2m[e]
1m
Ph
H
N
A
76
[a]
Unless otherwise noted, all reactions were performed at room temperature for 2.5 h.
Isolated yield after column chromatography based on compounds 1; the yield of the same reaction carried out using SmI2
[b]
instead of Mn* is shown in parentheses.
This reaction was performed at room temperature for 12 h.
From morpholine amide.
Diastereoisomeric ratios of the starting epoxides 1l,m (dr>98/2 in both cases) were the same to those observed for a-hy-
droxy amides 2l,m.
[c]
[d]
[e]
Adv. Synth. Catal. 2009, 351, 2178 – 2184
ꢅ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2179

Josꢀ M. Concellꢁn et al.
FULL PAPERS
Scheme 2. Preparation of hydroxy ketone 5.
rived from a,b-unsaturated aldehydes (Table 1, en- unsaturated amides 6a, and 6b with the same com-
tries 9 and 11).
pounds previously reported in the literature.[25] It is
The complete regioselectivity (>98%) of the ring- noteworthy that this is first example reported in the
1
opening reaction was established by H and 13C NMR literature of a deoxygenation reaction promoted by
analysis of the crude reaction products, which re- active manganese.[26] Hence, studies concerning the
vealed the presence of only one regioisomer.
synthetic applications of this novel reaction are being
The regiochemistry of the ring-opening reaction carried out in our laboratory.
1
was established by analysis of H and 13C NMR spec-
tra and DEPT experiments of the 2-hydroxy amides 2
prepared, showing that the hydroxy group is bonded Synthesis of Aromatic 2-Hydroxy Esters 8
to a tertiary carbon atom in compounds 2d–k, and to
the secondary carbon atom in amides 2l–m. To con- The reaction conditions to carry out the ring opening
firm the structures of 2a–c, HMBC NMR experiments reaction of a,b-epoxy esters 7, in general terms,
were carried out.
depend on the substitution pattern of the starting
Interestingly, the reaction could be carried out with epoxy ester. Thus, the synthesis of 8a–c, and 8g (from
aromatic epoxy amides derived from morpholine 1c, disubstituted epoxy esters 7a–c and trisubstituted
and 1h, the corresponding 2-hydroxy amides 2c, and ester 7g) was attained by the treatment with Mn* at
2h being obtained in high yields (Scheme 2). Amides room temperature for 12 h; compounds 8d–f and 8h
derived from morpholine can be readily transformed were prepared after reaction with Mn* at reflux for
into ketones by reaction with organolithium re- 3 h.[27]
agents.[24] Thus, amide 2c, was allowed to react with
As is summarized in Table 2, 2-hydroxy esters 8
n-butyllithium at À788C for 3 h, obtaining the expect- were obtained in good to high yields and with com-
ed 1-aryl-2-hydroxyheptan-3-one 5, in 91% yield plete regioselectivity. Similarly to amides, the trans-
(Scheme 2).
formation of aromatic epoxy esters into 2-hydroxy
In addition to the low price of manganese with re- esters seems to be general and the aromatic ring can
spect to SmI2, the use of Mn* instead of SmI2 to open be substituted with electron-donor or electron-with-
the epoxide ring presents other additional advantages. drawing substituents. Moreover, esters 8 can be de-
Manganese afforded higher yields of 2-hydroxyamides rived from bulky alcohols as, for example, isopropyl
than SmI2. Thus, some yields of 2-hydroxy amides re- alcohol (Table 2, entry 5), or from heteroaromatic
ported when using SmI2 are shown in Table 1 in pa- a,b-epoxy esters such as the furan derivative (Table 2,
rentheses. In all of these cases, the yields obtained in entry 8) and from g,d-unsaturated a,b-epoxy esters
the ring-opening of epoxy amides promoted by Mn* (Table 1, entry 3).
were higher than using SmI2.
In a similar manner to what is indicated in the case
When the reaction was performed on aliphatic 2,3- of amides, the regioselectivity in the ring-opening pro-
epoxy amides under the same reaction conditions cess of compounds 7a–h was examined based on the
(2.5 h at room temperature), a mixture of the starting spectroscopic data of the crude reaction products.
material and the corresponding a,b-unsaturated These studies have shown the presence of only one
amide was obtained and no trace of 2-hydroxy amides regioisomer. The regiochemistry of the final products
was observed. Modifications to the reaction condi- was similar to that of product 2 and was established
1
tions only allowed the synthesis of a,b-unsaturated by H, 13C, DEPT and HMBC NMR experiments.
amides. Thus, after refluxing for 3 h a mixture of Mn*
and 2,3-epoxy-N,N-diethyl-2-methyldecanamide 1n or have been carried out. Thus, the hydrolysis and reduc-
3-cyclohexyl-N,N-diethyl-2-methylpropanamide 1o tion of 8a readily afforded the corresponding a-hy-
Some synthetic applications of a-hydroxy ester 8a
the corresponding (E)-N,N-diethyl-2-methyldecan-2- droxy acid 9 and 1,2-alkanediol 10 in high yields
enamide 6a (E/Z 80/20, 70% yield) or (E)-3-cyclohex- (Scheme 3).
yl-N,N-diethyl-2-methylprop-2-enamide 6b (E/Z 90/
When the reaction was performed from 7i, and 7j,
10, 75% yield) were isolated, respectively. The E-rela- under the same reaction conditions, the corresponding
tive configuration of the C=C double bond was estab- 3-hydroxy esters 11a, and 11b were obtained rather
lished by comparison with the spectroscopic data of than the desired 2-hydroxy esters in high yields
2180
asc.wiley-vch.de
ꢅ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 2178 – 2184

Manganese-Promoted Regioselective Ring-Opening of 2,3-Epoxy Acid Derivatives
FULL PAPERS
Table 2. Synthesis of 2-hydroxy esters 8 by regioselective ring-opening of 2,3-epoxy esters 7.
Entry
7
8[a]
R1
R3
R4
Yield [%][b]
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7f
7g
7h
8a
8b
8c
Ph
H
H
H
Et
77
60
65
75
73
80
76
61
p-ClC6H4
(E)-MeCH=CH
Ph
p-MeOC6H4
p-CNC6H4
p-CNC6H4
2-furyl
Me
Me
Et
i-Pr
Et
8d
Me
Me
Me
n-C5H11
Me
8e[c]
8f[c]
8g
Et
Et
8h[c]
[a]
Unless otherwise noted these reactions were performed at room temperature for 12 h.
Isolated yield after column chromatography based on compounds 1.
This reaction was performed at reflux for 3 h.
[b]
[c]
Scheme 5. Transformation of enantiopure epoxy amides into
optically active a-hydroxy amides 12.
Scheme 3. Transformation of a-hydroxy ester 8a into a-hy-
droxy acid 9 and 1,2-alkanediol 10.
were readily obtained by enantioselective epoxidation
of the corresponding (E)-a,b-unsaturated amides
being obtained with ee 95 and >98%, for 1p and 1q,
respectively.[29b] The ee were determined by HPLC
analysis.[30]
The synthesis of aromatic 2-hydroxyamides 2 and 2-
hydroxy esters 8 might be explained by assuming the
À
regioselective reduction of the C O bond promoted
Scheme 4. Transformation of 7i,j into 11a,b.
by Mn* (Scheme 6). Thus, we could initially surmise
that the reduction of the oxirane ring on amides 1 or
esters 7 could take place through two different paths:
À
(Scheme 4). The regiochemistry in the ring-opening a) the reduction of the Cb O bond to afford the 2-hy-
reaction was established by comparison of the spec- droxy acid compound; and b) the reduction of the
to yield the 3-hydroxy acid derivative
thos eof same compounds previously reported in the (Scheme 6). We could consider that the cleavage of
À
troscopic data of hydroxy esters 11a, and 11b to the Ca
O
literature.[28]
the Cb O bond in 3-aryl-2,3-epoxy amides or esters is
À
À
This methodology is also useful to obtain enantio- favoured, in comparison to the Ca O bond, due to a
merically enriched 3-aryl-2-hydroxy amides 12. Thus, benzylic anion 13 (or conjugated anion in the case of
starting from optically active (2R,3S)-2,3-epoxy- epoxy compounds 1i, 1k, and 7c) being obtained,
N,N-dimethyl-3-phenylpropanamide 1p or (2R,3S)- since this anion is stabilized by resonance. In order to
2,3-epoxy-N,N-diisopropyl-3-(4-methoxyphenyl)prop-
justify the anionic or radical pathway, we have exam-
ACHTUNGTRENNUNGanamide 1q the corresponding enantiopure (2R)-2-hy- ined the treatment of 3-(4-chlorophenyl)-N,N-diiso-
droxy-N,N-dimethyl-3-phenylpropanamide 12a[29] or propyl-2,3-epoxypropanamide 1f with Mn*: i) in the
(2R)-2-hydroxy-N,N-diisopropyl-3-(4-methoxyphenyl)- absence of light; and ii) in the presence of AIBN. In
ACHTUNGTRENNUNGpropanamide 12b could be prepared, with same ee to both cases, no differences were observed in the reac-
that shown by the starting materials (95 and >98%, tion products when compared with the data described
respectively; Scheme 5). Both chiral epoxy amides in Table 1 so, an anionic mechanism is suggested.
Adv. Synth. Catal. 2009, 351, 2178 – 2184
ꢅ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2181

Josꢀ M. Concellꢁn et al.
FULL PAPERS
Scheme 6. Mechanistic proposal for the conversion of 1 or 7 into 2, 6, 8, or 11.
Experimental Section
Another indirect probe of this mechanism is the
result obtained from aliphatic esters (Path b). In
these compounds, the absence of a stabilization of the
anionic intermediate, after the oxiraneopening, af-
forded the corresponding 3-hydroxy regioisomer in-
stead of the 2-hydroxy derivative. In this latter case,
the stabilization is due to the resonance with the car-
bonyl group in 14. Hydrolysis of enolate 14 would
afford 3-hydroxy esters 11. A similar intermediate 14
has been proposed in the previously reported synthe-
sis of (E)-a,b-unsaturated amides promoted by active
Characterization data for all new compounds are available
in the Supporting Information file.
Preparation of 2,3-Epoxy Amides 1
To a À788C stirred solution of the corresponding 2-chloro
amide (4.5 mmol) in dry THF (4 mL) was added dropwise
lithium diisopropylamide [prepared from MeLi (3.2 mL of
1.5M solution in diethyl ether, 5 mmol) and diisopropyl-
AHCTUNGTREGaNNUN mine (0.8 mL, 5 mmol) in THF 25 mL at 08C]. After stir-
manganese. Hence this intermediate 14 would also ex- ring for 10 min, a solution of the corresponding aldehyde or
ketone (3.5 mmol) in dry THF (4.5 mL) was added dropwise
at À788C and the mixture was stirred for 2 h. Then, the re-
sulting mixture was allowed to warm to room temperature
and stirred for 12 h at this temperature. Then this was
quenched with aqueous saturated solution of NH4Cl
(20 mL) and extracted with diethyl ether (3ꢆ10 mL). The
combined organic layers were dried (Na2SO4), filtered, and
concentrated under vacuuum. The crude 2,3-epoxy amides 1
were purified by flash column chromatography on silica gel
(hexane:EtOAc, 3:1) provided pure compounds.
plain the formation of compounds 6 from aliphatic
a,b-epoxy amides 1n–o.[20]
Conclusions
In conclusion, a simple and general methodology has
been developed to synthesize aromatic 3-aryl-2-hy-
droxycarboxylic derivatives, with total regioselectivity,
from the readily available 2,3-epoxy esters or amides,
promoted by active manganese. The synthesis of 3-
aryl-2-hydroxy amides in enantiopure form has been
described to demonstrate that this method can be also
used to obtain optically active 2-hydroxy derivatives.
A mechanism has been proposed to explain this reac-
tion.
Preparation of 2,3-Epoxy Esters 7
To a stirred solution of the corresponding 2-halo ester
(2.5 mmol) at À788C in dry THF (4 mL) was added drop-
wise potassium hexamethyldisilazide (6.5 mL of 0.5 M solu-
tion in toluene, 3.25 mmol). After the stirring for 10 min, a
solution of the corresponding aldehyde or ketone
(2.5 mmol) in dry THF (4 mL) was added dropwise at
À788C, and the resulting mixture was allowed to warm to
room temperature. The resulting solution was quenched
with a saturated aqueous solution of NH4Cl (20 mL). Usual
2182
asc.wiley-vch.de
ꢅ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 2178 – 2184

Manganese-Promoted Regioselective Ring-Opening of 2,3-Epoxy Acid Derivatives
FULL PAPERS
work-up provided crude 2,3-epoxy esters 7, which were puri-
fied by column flash chromatography over silica gel (hex-
on silica gel (hexane:EtOAc 10:1) provided the pure com-
pounds 8 and 11.
A
In the case of 2-hydroxy esters 8d–f and 8h, they was pre-
pared after reaction with Mn* at reflux for 3 h.
Preparation of Highly Active Manganese (Mn*)
General Procedure for the Synthesis of 2-Hydroxy-3-
phenylpropanoic Acid 9
A
mixture of lithium (26 mmol) and 2-phenylpyridine
(4 mmol) in THF (20 mL) under a nitrogen atmosphere was
stirred for 1 h. In a separate flask a solution of the Li2MnCl4
complex was prepared by stirring a suspension of anhydrous
MnCl2 (13 mmol) and LiCl (26 mmol) in THF (20 mL) for
30 min. Then, this yellow solution was added at room tem-
perature via syringe to the 2-phenylpyridine/lithium solution
previously prepared and was stirred, under a nitrogen at-
mosphere at room temperature for 1 h. The black slurry was
allowed to stir at room temperature for 3 h further.
To a solution of the corresponding a-hydroxy ester 8a
(1.0 mmol) in MeOH (2 mL) under a nitrogen atmosphere
was added KOH (3.0 mmol). After stirring the mixture for
12 h at room temperature the reaction was quenched by the
addition of HCl 1M (5 mL). The organic material was then
extracted with diethyl ether (3ꢆ10 mL) and dried over
Na2SO4. Solvents were removed under vacuum. Purification
by flash column chromatography on silica gel (hexane:
EtOAc, 1:1) afforded pure compound 9.
General Procedure for the Synthesis of 2-Hydroxy
Amides 2 and 12
Procedure for the Synthesis of the 1,2-Alkanediol 10
To a suspension of LiAlH4 (1.0 mmol) in THF a solution of
the corresponding a-hydroxy ester 8a (1.0 mmol) in THF
(1 mL) was added dropwise at 08C. After stirring of the
mixture for 12 h at room temperature, the reaction was
quenched by addition of a mixture of water/ice and extract-
ed with ether. The combined organic phases were dried over
Na2SO4 and the solvents were removed under reduced pres-
sure. The crude products 10 were purified by flash column
chromatography on silica gel (hexane:EtOAc, 1:1).
In the case of 2-hydroxy amides 2a–c and 12a,b, the slurry
of Mn* (1.5 mmol, 4.5 mL) in THF was added to a stirred
solution of 2,3-epoxy amides 1 (0.5 mmol) in THF (2 mL)
under an inert atmosphere. The mixture was stirred at room
temperature for 12 h before it was quenched with 3M HCl.
The organic material was extracted with diethyl ether (3ꢆ
20 mL), the combined organic extracts were washed succes-
sively with HCl 3M (2ꢆ10 mL), saturated NaHCO3 (2ꢆ
20 mL), and water (2ꢆ20 mL) and dried over Na2SO4. Sol-
vents were removed under vacuum. Purification by flash
column chromatography on silica gel (hexane:EtOAc, 3:1)
provided pure compounds. However, for the case of the syn-
thesis of compounds 2d–m instead of at room temperature
for 12 h, the reaction was carried out at room temperature
for 2.5 h.
Acknowledgements
We acknowledge MICINN (CTQ2007-61132), Principado de
Asturias (FICYT IB08-028) and European Union (Fondo
Europeo de Desarrollo Regional) for financial support.
J.M.C. thanks his wife Carmen Fernꢀndez-Flꢁrez for her
time. H.R.S. and P.D. thank MICINN for a Ramꢁn y Cajal
Contract and Principado the Asturias for a predoctoral fel-
lowship, respectively. Our thanks to Dr. Euan C. Goddard
(CRL, University of Oxford) for his revision of the English.
General Procedure for the Synthesis of Butyl [2-(4-
Chlorophenyl)-1-hydroxy-1-ethyl] Ketone 5
n-Butyllithium (3.0 mmol) was added dropwise to the corre-
sponding 2-hydroxy amide 2c (1.0 mmol) in THF (4 mL) at
À788C. After stirring for 3 h the reaction was quenched
with a saturated aqueous solution of NH4Cl (10 mL), fol-
lowed by extraction with diethyl ether (3ꢆ10 mL). Usual
work-up provided crude product 5, which were purified by
flash column chromatography on silica gel (hexane:EtOAc,
3:1)
References
[1] a-Hydroxy Acids in Enantioselective Syntheses, (Eds.:
G. M. Coppola, H. F. Schuster), VCH, Weinheim, 1997.
[2] a) L. Thijs, J. Zhu, Jie, WO Patent 2005080387A2,
2005; Chem. Abstr. 2005, 143, 248416; b) K. Tomitani,
K. Sato, H. Takahashi, Japanese Patent 2001039973,
2001; Chem. Abstr. 2001, 134, 162911; c) P. Mayer, T.
Imbert, K. Couture, V. Gouverneur, C. Mioskowski,
WO Patent 2000002836A1, 2000; Chem. Abstr. 2000,
132, 93199.
General Procedure for the Synthesis of 2-Hydroxy
Esters 8 and 3-Hydroxy Esters 11
The procedure for the synthesis of 8a–c, 8g and 11a,b con-
sists of the addition of the slurry of Mn* (2 mmol, 6.8 mL)
in THF to a stirred solution of 2-hydroxy ester 7 (0.5 mmol)
in THF (2 mL) under an inert atmosphere. The mixture was
stirred at room temperature for 12 h before it was quenched
with HCl 3M. The organic material was extracted with di-
ethyl ether (3ꢆ20 mL), the combined organic extracts were
washed sequentially with HCl 3M (2ꢆ10 mL), saturated
NaHCO3 (2ꢆ20 mL), saturated Na2S2O3 (2ꢆ20 mL), brine
(2ꢆ20 mL) and dried over Na2SO4. Solvents were removed
under vacuum. Purification by flash column chromatography
[3] Studies in Natural Products Chemistry, (Ed.: Atta-ur-
Rahman), Elsevier, 1988; Vol. 2, p 680.
[4] B. M. Markaverich, R. R. Gregory, M. A. Alejandro,
K. S. Kittrell, D. Medina, J. H. Clark, M. Varma, R.
Varma, Cancer Res. 1990, 50, 1470–1478.
[5] For other alternative methods to obtain 2-hydroxy acid
derivatives without starting from 2,3-epoxy acid deriva-
tives, see: a) A. Hoffman-Rçder, N. Krause, Synthesis
Adv. Synth. Catal. 2009, 351, 2178 – 2184
ꢅ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2183

Josꢀ M. Concellꢁn et al.
FULL PAPERS
2006, 2143–2146; b) S. G. Davies, S. W. Epstein, A. C.
Garner, O. Ichihara, A. D. Smith, Tetrahedron: Asym-
metry 2002, 13, 1555–1565; c) F. A. Davis, A. Shep-
pard, Tetrahedron 1989, 45, 5703–5742; d) R. Gamboni,
P. Mohr, N. Waespe-Sarcevic, C. Tamm, Tetrahedron
Lett. 1985, 26, 203–206; e) E. Vedejs, D. A. Engler,
J. E. Telschow, J. Org. Chem. 1978, 43, 188–196;
f) H. E. Johnson, D. Grosby, J. Org. Chem. 1963, 28,
3255–3325; g) T. Araki, Y. Yamazaki, K. Shibuya, WO
Patent 2007023906 A1, 2007; Chem. Abstr. 2007, 146,
295516.
[14] K. Takai, T. Ueda, T. Hayashi, T. Moriwake, Tetrahe-
dron Lett. 1996, 37, 7049–7052.
[15] S. H. Kim, M. V. Hanson, R. D. Rieke, Tetrahedron
Lett. 1996, 37, 2197–2200.
[16] A. Fꢄrstner, H. Brunner, Tetrahedron Lett. 1996, 37,
7009–7012.
[17] J. Tang, H. Shinokubo, K. Oshima, Synlett 1998, 1075–
1076.
[18] For some recent synthetic applications of manganese in
organic synthesis, see: J. M. Concellꢁn, H. Rodrꢂguez-
Solla, V. del Amo, Chem. Eur. J. 2008, 14, 10184–
10191.
[19] J. M. Concellꢁn, H. Rodrꢂguez-Solla, P. Dꢂaz, R. Llavo-
na, J. Org. Chem. 2007, 72, 4396–4400.
[20] J. M. Concellꢁn, H. Rodrꢂguez-Solla, P. Dꢂaz, J. Org.
[6] Several methods have been reported regarding epoxide
opening in other substrates different to 2,3-epoxyacid
derivatives: a) A. Gansꢇuer, A. Barchuk, F. Keller, M.
Schmitt, S. Grimme, M. Gerenkamp, C. Mꢄck-Lichten-
feld, K. Daasbjerg, H. Svith, J. Am. Chem. Soc. 2007,
129, 1359–1371; b) A. Gansꢇuer, C.-A. Fan, F. Keller,
J. Keil, J. Am. Chem. Soc. 2007, 129, 3484–3485; c) K.
Daasbjerg, H. Svith, S. Grimme, M. Gerenkamp, C.
Mꢄck-Lichtenfeld, A. Gansꢇuer, A. Barchuk, F. Keller,
Angew. Chem. Int. Ed. 2006, 45, 2041–2044; d) M. Na-
kajima, M. Saito, M. Uemura, S. Hashimoto, Tetrahe-
dron Lett. 2002, 43, 8827–8829; e) E. R. Jacobsen, Acc.
Chem. Res. 2000, 33, 421–431; f) A. Gansꢇuer, H.
Bluhm, Chem. Rev. 2000, 100, 2771–2788; g) M. Toku-
naga, J. F. Larrow, F. Kakiuchi, E. N. Jacobsen, Science
1997, 277, 936–938; h) L. E. Martꢂnez, J. L. Leighton,
D. H. Carsten, E. N. Jacobsen, J. Am. Chem. Soc. 1995,
117, 5897–5898; i) T. V. RajanBabu, W. A. Nugent, J.
Am. Chem. Soc. 1994, 116, 986–997; j) W. A. Nugent,
J. Am. Chem. Soc. 1992, 114, 2768–2769.
[7] a) M. S. Kwon, I. S. Park, J. S. Jang, J. S. Lee, J. Park,
Org. Lett. 2007, 9, 3417–3419; b) S. V. Ley, C. Mitchell,
D. Pears, C. Ramarao, J.-Q. Yu, W. Zhou, Org. Lett.
2003, 5, 4665–4668; c) E. J. Corey, F.-Y. Zhang, Org.
Lett. 1999, 1, 1287–1299; d) C. Grison, F. Coutrot, C.
Comoy, C. Lemilbeau, P. Coutrot, Tetrahedron Lett.
2000, 41, 6571–6574; e) J. R. Rizzo, T. Y. Zhang,
Chimia 2006, 60, 580–583; f) C. Bonini, R. Di Fabio, G.
Sotgiu, S. Cavagnero, Tetrahedron 1989, 45, 2895–2904;
g) K. Otsubo, J. Inanaga, M. Yamaguchi, Tetrahedron
Lett. 1987, 28, 4435–4436; h) M. R. Siripragada, P. Che-
biyyam, R. K. Potlapally, K. Rajendra, C. S. Batchu,
R. S. Mamillapally, O. R. Gaddam, WO Patent
2000026200 A1, 2000; Chem. Abstr. 2000, 132, 334417.
[8] J. M. Concellꢁn, E. Bardales, C. Gꢁmez, Tetrahedron
Lett. 2003, 44, 5323–5326.
Chem. 2007, 72, 7974–7979.
[21] a) J. M. Concellꢁn, H. Rodrꢂguez-Solla, P. Dꢂaz, Org.
Biomol. Chem. 2008, 6, 451–453; b) J. M. Concellꢁn,
H. Rodrꢂguez-Solla, P. Dꢂaz, Org. Biomol. Chem.
2008,6, 2934–2940.
[22] The enolate was generated by treatment of the corre-
sponding 2-chloro amide with LDA at À788C.
[23] Active manganese was readily prepared by using the
method described by Cahiez: G. Cahiez, A. Martin, T.
Delacroix, Tetrahedron Lett. 1999, 40, 6407–6410.
[24] R. Martꢂn, P. Romea, C. Tey, F. Urpꢂ, J. Vilarrasa, Syn-
lett 1997, 1414–1416.
[25] J. M. Concellꢁn, J. A. Pꢀrez-Andrꢀs, H. Rodrꢂguez-
Solla, Chem. Eur. J. 2001, 7, 3062–3068.
[26] Similar deoxygenation reactions promoted by samari-
um diiodide have been previously reported in the liter-
ature: a) J. M. Concellꢁn, E. Bardales, M. Huerta Tetra-
hedron 2004, 60, 10059–10065; b) J. M. Concellꢁn, E.
Bardales, J. Org. Chem. 2004, 1523–1526; c) J. M. Con-
cellꢁn, E. Bardales, J. Org. Chem. 2003, 68, 9492–9495;
d) J. M. Concellꢁn, E. Bardales, Org. Lett. 2002, 4,
189–191.
[27] The starting epoxy esters were prepared, similarly to
epoxy amides, by reaction of the potassium enolate
(generated by treatment of the corresponding chloro
ester with potassium hexamethyldisilazide) with
1.0 equiv. of the corresponding aldehyde at À788C for
2 h. After this time, the reaction mixture was allowed
to warm up to room temperature.
[28] S. E. Denmark, G. L. Beutner, T. Wynn, M. D. East-
gate, J. Am. Chem. Soc. 2005, 127, 3774–3789.
[29] Compound 12a displayed analytical data in accordance
with the published values: a) V. Schurig, K. Hintzer, U.
Leyrer, C. Mark, P. Pitchen, H. B. Kagan, J. Organo-
met. Chem. 1989, 370, 81–96; b) T. Nemoto, H. Kakei,
V. Gnanadesikan, S. Tosaki, T. Ohshima, M. Shibasaki,
J. Am. Chem. Soc. 2002, 124, 14544–14545.
[30] Chiral HPLC analysis for 12a and 12b show the same
ee values as those shown by the starting materials (95
and >98%): Chiracel-OJ-H, UV detector 210 nm,
0.8 mLminÀ1, 90/10 hexane/i-PrOH: 12a: tR 18.38 min;
racemic mixture: tR 15.23, and 18.38 min; 12b: tR
9.42 min; racemic mixture: tR 9.42, and 12.22 min.
[9] J. M. Concellꢁn, E. Bardales, Org. Lett. 2003, 5, 4783–
4785.
[10] T. Nemoto, H. Kakei, V. Gnanadesikan, S. Tosaki, T.
Ohshima, M. Shibasaki, J. Am. Chem. Soc. 2002, 124,
14544–14545.
[11] No special precaution is required due to the low toxici-
ty of manganese and manganese salts obtained after
the aqueous work-up of organomanganese reactions;
see: G. Cahiez, Anales de Quꢂmica, 1995, 91, 561–578.
[12] Aldrich catalogue (2009–2010): powder manganese
(325 mesh): 250 g=44 E.
[13] Handbook of Chemistry and Physics, 62nd edn., CRC
Press, Boca Raton, FL, 1982.
2184
asc.wiley-vch.de
ꢅ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 2178 – 2184