An efficient protocol for the oxidative hydrolysis of ketone SAMP hydrazones employing SeO2 and H2O2 under buffered (pH 7) conditions

Article abstract of DOI:10.1055/S-0029-1218352

An effective oxidative protocol for the liberation of ketones from SAMP hydrazones employing peroxyselenous acid under aqueous buffered conditions (pH 7) has been developed. The procedure proceeds without epimerization of adjacent stereocenters or dehydration, in representative SAMP alkylation and aldol reaction adducts, respectively.

Full text of DOI:10.1055/S-0029-1218352

LETTER
3131
An Efficient Protocol for the Oxidative Hydrolysis of Ketone SAMP
Hydrazones Employing SeO2 and H2O2 under Buffered (pH 7) Conditions
O
xidative Hydroly
m
sis of
K
etone SA
M
o
P
H
ydrazone
s
s
B. Smith III,* Zhuqing Liu, Vladimir Simov
Department of Chemistry, Laboratory for Research on the Structure of Matter, and Monell Chemical Senses Center,
University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
E-mail: smithab@sas.upenn.edu
Received 19 June 2009
cols, occurred under these optimized conditions. To the
best of our knowledge, this report presents the first exam-
ples exploiting SeO2 and H2O2 under buffered conditions
for the oxidative deprotection of ketone-derived hydra-
Abstract: An effective oxidative protocol for the liberation of ke-
tones from SAMP hydrazones employing peroxyselenous acid un-
der aqueous buffered conditions (pH 7) has been developed. The
procedure proceeds without epimerization of adjacent stereocenters
or dehydration, in representative SAMP alkylation and aldol reac- zones.
tion adducts, respectively.
Table 1 Attempted Conditions to Cleave SAMP Hydrazone 2
Key words: SAMP, oxidative cleavage, aldol reactions, ketones,
SeO2
MeO
O
O
N
N
H
H
O
The (S)- and (R)-amino-2-methoxypyrrolidines (SAMP
and RAMP), effective chiral auxiliaries introduced by the
Enders group,1 have found wide use in asymmetric alky-
lation and aldol reactions.2 Consequently, a large number
of methods have been developed to liberate the resultant
aldehydes and ketones from the SAMP/RAMP hydrazone
products.3 In conjunction with an ongoing synthetic pro-
gram directed towards the total synthesis of (+)-noduli-
sporic acid A (1, Figure 1), a wide variety of known oxi-
dative, hydrolytic, or reductive methods were explored to
liberate ketone 3 from advanced SAMP intermediate 2, al-
beit with limited success (Table 1 entries 1–12). We even-
tually discovered that peroxyselenous acid, generated in
situ from SeO2 and 30% H2O2 (1:4 equiv) was a superior
oxidant for the removal of the chiral auxiliary in 2 accom-
panied by a small amount of epimerization at the a-posi-
tion of ketone 3 (entry 13).
OH
conditions
H
H
H
OSEM
H
I
OH
H
OSEM
I
N
H
O
N
O
O
2
3
O
Entry Conditions
Observations
epimerization
epimerization
1
Oxalic acid, Et2O, 23 °C, 15 h
CuCl2, THF–H2O, 23 °C, 15 h
2
3
SnCl2, Pd(OAc)2 DMF–H2O, 23 °C, 15 h no reaction
SnCl2, Pd(OAc)2 DMF–H2O, 50 °C, 15 h epimerization
4
5
SnCl2, DME–H2O, 23 °C, 15 h
SnCl2, DME–H2O, 50 °C, 15 h
O3, CH2Cl2, –78 °C, 1 min
no reaction
epimerization
21%
6
H
7
O
CO2H
8
NaBO3, AcOH, 23 °C, 2 h
decomposition
decomposition
N
H
9
NaBO3, pH 7 buffer–t-BuOH, 23 °C 5 h
OH
HO
O
10
11
MMPP, pH 7 buffer–MeOH, 23 °C, 24 h no reaction
nodulisporic acid A (1)
30% H2O2, pH 7 buffer–MeOH, 23 °C to decomposition
70 °C, 19 h
Figure 1 Structure of nodulisporic acid A
12
13
14
NaIO4, THF–H2O–pH 7 buffer, 23 °C, 15 h decomposition
Pleasingly, the epimerization problem could be alleviated
simply by the introduction of a pH buffer 7 (entry 14). Im-
portantly, no epimerization or retro-aldol fragmentation,
which was observed with several of the alternative proto-
30% H2O2/SeO2, MeOH, 23 °C, 48 h
76%
30% H2O2/SeO2, MeOH–pH 7 buffer, 23 °C, 91%
24 h
Previous reports have, however, recorded the oxidative
cleavage of aldehyde SAMP hydrazones to furnish the
corresponding nitriles, via an oxy-Cope-like elimination
SYNLETT 2009, No. 19, pp 3131–3134
Advanced online publication: 16.11.2009
DOI: 10.1055/s-0029-1218352; Art ID: S06809ST
x
x
.x
x
.2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

3132
A. B. Smith III et al.
LETTER
(Scheme 1),4 with oxidants such as mCPBA,5 MMPP
(magnesium monoperoxyphthalate), SeO2, or 2-nitro-
benzeneselenic acid with H2O2,6 and H2O2.7 A similar ox-
idative fragmentation is of course not an option with
SAMP ketone hydrazones.
O
O
N
N
OH
SeO2, H2O2
OMe
pH 7 buffer
MeOH
85%
OMe
17
18
16
O
Scheme 2 Oxidative hydrolysis of the SAMP hydrazone generated
from cyclohexenone
N
hydrolytic cleavage
N
R
H
OMe
R
H
drazones (19–21) were again excellent (90–96%).
Stereochemical assignments at the a-center were based on
the Enders precedent.11 Treatment of the hydrazones with
SeO2 and H2O2, again employing an aqueous buffer (pH
7), led to clean removal of the SAMP moiety to furnish
ketones (22–24) in 88–90% yield. Importantly, no
epimerization (>20:1, 500 MHz NMR) at the a-center was
observed.
oxidation
reduction
oxy-Cope-type
elimination
NR2
O
N
RCN
R
H
Scheme 1 Nitrile formation from aldehyde-derived hydrazones
To explore the scope and viability of the pH 7 buffered
peroxyselenous acid conditions, a series of ketone SAMP
hydrazones were readily prepared from simple ketones 7–
16 (Figure 2)8 using SAMP hydrazine and a catalytic
amount of TsOH in cyclohexane at reflux; yields ranged
from 70–98%. Application of the pH 7 buffered SeO2/
H2O2 protocol, optimized during the (+)-nodulisporic acid
A synthetic program, regenerated the corresponding ke-
tones 7–15 in 68–96% yields.9 Liberation of cyclohex-
enone 16 from SAMP hydrazone 17, however, was not
successful. Instead, an epimeric mixture of 2-hydroxy-3-
methoxyclohexanone 18 was isolated in 85% yield
(Scheme 2).
N
OMe
O
N
SeO2–H2O2
pH 7 buffer/MeOH
O
90%
O
19
22
23
OMe
O
SeO2–H2O2
N
N
pH 7 buffer/MeOH
89%
20
OMe
O
OMe
SeO2–H2O2
N
N
N
N
pH 7 buffer/MeOH
88%
O
N
O
NH2
SeO2, H2O2
OMe
R1
R2
R1
R2
R1
R2
TsOH
pH 7 buffer
MeOH
70–98%
21
24
4
5
6
O
O
O
O
Scheme 3 Cleavage of SAMP hydrazones to regenerate chiral ketones
O
In addition to the SAMP alkylation products, a third series
of hydrazones was examined involving the products de-
rived from an aldol reaction with benzaldehyde (cf. 25–
27).12 As these aldol products are generally sensitive to
acid, we were not surprised initially to observe significant
elimination (i.e., dehydration) and/or retro-aldol fragmen-
tation. Pleasingly, such side reactions could be suppressed
by increasing the amount of pH 7 buffer (i.e., from 1:18 to
1:3 v/v; buffer: MeOH) to afford b-hydroxy ketones 28–
30 in 65–81% yield (Scheme 4).13
O
7
11
96%
7
68%
8
82%
9
93%
10
95%
S
O
O
N
O
O
15
90%
12
92%
13
78%
14
89%
Figure 2 Oxidative cleavage of SAMP hydrazones to simple keto-
A mechanistic picture of the pH 7 buffered oxidative hy-
drolysis using SeO2 and H2O2 is proposed in Scheme 5.
After initial formation of peroxyselenous acid, oxidation
of the pyrrolidine nitrogen in 31 is envisioned to generate
intermediate 32, thereby activating the hydrazone toward
hydrolysis. Addition of water followed by fragmentation
nes
We next turned our attention toward to SAMP hydrazones
possessing an a-stereogenic center. The requisite sub-
strates were readily prepared by alkylation of a series of
ketone SAMP hydrazones with (S)-(+)-1-iodo-2-methyl-
butane (Scheme 3);10 yields for the alkylated SAMP hy-
Synlett 2009, No. 19, 3131–3134 © Thieme Stuttgart · New York

LETTER
Oxidative Hydrolysis of Ketone SAMP Hydrazones
3133
would then deliver the ketone 34 and diazene 35 as a
byproduct.
Acknowledgment
Support was provided by the National Institutes of Health (Institute
of General Medical Sciences) through grant GM-29028 and the
University of Pennsylvania. We thank Drs. G. Furst, J. Gu, and
R. Kohli (University of Pennsylvania) for assistance in obtaining
NMR spectra and high-resolution mass spectra, respectively.
OMe
O
OH
N
SeO2–H2O2
N
OH
Ph
MeOH, pH 7 buffer
(3:1)
Ph
28
References and Notes
78%
25
(1) Enders, D.; Eichenauer, H. Angew. Chem., Int. Ed. Engl.
1976, 15, 549.
OMe
(2) Job, A.; Janeck, C. F.; Bettray, W.; Peter, R.; Enders, D.
Tetrahedron 2002, 58, 2253; and references therein.
(3) Enders, D.; Wortmann, L.; Peters, R. Acc. Chem. Res. 2000,
33, 157.
(4) Enders, D.; Plant, A. Synlett 1994, 1054.
(5) Said, S. B.; Skarzewski, J.; Mlochowski, J. Synthesis 1989,
223.
O
OH
N
N
OH
SeO2–H2O2
Ph
Ph
MeOH, pH 7 buffer
(3:1)
81%
29
26
(6) Stupp, S. I.; Son, S.; Li, L. S.; Lin, H. C.; Keser, M. J. Am.
OMe
Chem. Soc. 1995, 117, 5212.
(7) Eichenauer, H.; Friedrich, E.; Lutz, W.; Enders, D. Angew.
Chem., Int. Ed. Engl. 1978, 17, 206.
O
OH
N
N
O
OH
SeO2–H2O2
Ph
MeOH, pH 7 buffer
(3:1)
(8) General Procedure for the Synthesis of Hydrazones
A mixture of SAMP (0.04 mmol), ketone (0.04 mmol), and
PTSA (0.004 mmol) was heated at reflux in cyclohexane
(1 mL) overnight. The mixture was then cooled to r.t.,
neutralized with sat. NaHCO3 (3 mL) and the aqueous layer
was extracted with EtOAc (3 × 5 mL). The combined
organic layers were dried over Na2SO4 and concentrated.
The residue was purified by flash chromatography to
provide the desired hydrazone (70–98%).
Ph
O
65%
30
27
Scheme 4 Oxidative hydrolysis of SAMP aldol products to regene-
rate b-hydroxy ketones
O
+
H2O2
SeO2
(9) General Procedure for the Synthesis of Ketones 7–15 and
22–24
HOO Se OH
To a r.t. solution of hydrazone (0.18 mmol) and SeO2 (0.14
mmol) in MeOH (2.3 mL) was added pH 7 phosphate buffer
(0.066 mL) followed by 30% H2O2 (0.066 mL). After
completion of the hydrolysis reaction, sat. NaHCO3 (3 mL)
was added, and the aqueous layers were extracted with
pentane (3 × 3 mL). The combined organic layers were
combined, dried over Na2SO4, and concentrated. The residue
was purified via flash chromatography to provide the
corresponding ketone in 68–96% yield.
O
N
MeO
N+
HOO Se OH
OH
MeO
N
H2O
N
R
R
H2SeO3
31
32
(10) General Procedure for the Synthesis of Alkylated SAMP
Hydrazones 19–21
+
H2O
SeO2
O
To a solution of the corresponding hydrazone (0.26 mmol) in
THF (2 mL) at –78 °C was added t-BuLi (1.6 M in pentane,
0.39 mmol). The mixture was kept at this temperature for 2
h before cooling to –100 °C. (S)-(+)-1-Iodo-2-methylbutane
(0.52 mmol) was then added via syringe, the solution stirred
at –100 °C for 0.5 h, and then at –78 °C for 2 h. The reaction
was quenched with sat. NH4Cl (3 mL). The aqueous layers
were extracted with Et2O (3 × 5 mL), and the combined
organic layers were dried over Na2SO4, concentrated, and
the residue was purified by flash chromatography to furnish
the alkylated hydrazone in 90–96% yield.
N+
R
MeO
N
OH
R
MeO
34
N+
N–
diazene
35
33
Scheme 5 Proposed mechanism for the oxidative hydrolysis of
SAMP hydrazones using peroxyselenous acid
(11) Enders, D.; Bockstiegel, B. Synthesis 1989, 493.
(12) General Procedure for the Synthesis of SAMP Aldol
Products 25–27
In summary, an efficient method to regenerate ketones
from SAMP ketone hydrazones employing SeO2 and
H2O2 under buffered conditions has been developed. Al-
dol hydrazone adducts derived from the SAMP hydrazone
require additional buffer to suppress side reactions. Given
the scope of this protocol, this method holds promise as an
effective and mild alternative to the more conventional
methods to regenerate ketones from SAMP hydrazones.
To a solution of hydrazone (0.18 mmol) in THF (1.2 mL) at
–78 °C was added t-BuLi (1.6 M in pentane, 0.18 mmol).
The mixture was maintained at this temperature for 2 h
before cooling to –100 °C. Benzaldehyde (0.36 mmol) was
then added via syringe, the solution stirred at –100 °C for 0.5
h, and then at –78 °C for 2 h. The reaction was quenched
with sat. NH4Cl (3 mL), the aqueous layer extracted with
Et2O (3 × 5 mL), and the combined organic layers were
Synlett 2009, No. 19, 3131–3134 © Thieme Stuttgart · New York

3134
A. B. Smith III et al.
LETTER
dried over Na2SO4 and concentrated. The residue was
purified by flash chromatography to furnish aldol products
in 68–96% yield
H2O2 (0.015 mL). After completion, sat. NaHCO3 (2 mL)
was added to the mixture, and the aqueous layers were
extracted with EtOAc (2 × 3 mL). The combined organic
layers were dried over Na2SO4 and concentrated. The
residue was purified by flash chromatography (SiO2
deactivated with 18% H2O) to provide b-hydroxy ketones
(65–81%).
(13) General Procedure for the Synthesis of b-Hydroxy
Ketones 28–30
To a r.t. solution of the corresponding hydrazone (0.03
mmol) and SeO2 (0.045 mmol) in MeOH (0.45 mL) was
added pH 7 phosphate buffer (0.15 mL) followed by 30%
Synlett 2009, No. 19, 3131–3134 © Thieme Stuttgart · New York