Bronsted acid activation of α-diazo imide: A syn-selective glycolate Mannich reaction

Article abstract of DOI:10.1039/b913785h

A novel α-diazo imide reagent and its activation by strong Bronsted acid is shown to produce the product of a syn-glycolate Mannich transform with high diastereoselection.

Full text of DOI:10.1039/b913785h

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Brønsted acid activation of a-diazo imide: a syn-selective glycolate
Mannich reactionw
Timothy L. Troyer, Hubert Muchalski and Jeffrey N. Johnston*
Received (in College Park, MD, USA) 10th July 2009, Accepted 28th August 2009
First published as an Advance Article on the web 14th September 2009
DOI: 10.1039/b913785h
A novel a-diazo imide reagent and its activation by strong
Brønsted acid is shown to produce the product of a syn-glycolate
Mannich transform with high diastereoselection.
The novel a-diazo imide 2 was prepared in a manner
analogous to the method of Doyle et al. (ESIw).17 Its behavior
was monitored across a range of conditions to evaluate
protonative decomposition to 4 versus productive carbon–
carbon bond formation. Diazo 2 is indefinitely stable in
purified form when stored at À20 1C, and does not react with
weak acids under the reaction conditions outlined in Table 1
(entry 1). When exposed to Brønsted acids of intermediate
acidity, carbamate 2 is readily consumed at low temperature
by protonation–cyclization to oxazolidine dione 4 (Table 1,
entries 4–6). It is significant to note that no evidence could be
identified in the crude reaction mixture for homocoupling of
the diazo to form the corresponding fumaric acid derivative.
However, a new product identified as oxazolidine dione 3 was
isolated in the reaction using 85% aqueous phosphoric acid.
Formation of this product was significant in the cases of
entries 4 and 5, where 3 and 4 were formed in nearly equal
amounts. In the case of trifluoroacetic acid (entry 6), selectivity
for 3 was much greater (3 : 4 = 6 : 1), but only 65% conversion
was observed. Brønsted acids with substantially greater
acidity further enhanced production of addition product 3
(Table 1, entries 7–9). Triflic acid provided the optimal
combination of reactivity, availability, convenience (readily
dried, distilled, and measured as a liquid), and isolated
product yield (Table 1, entry 8).
The syn-a-oxy-b-amino acid motif is a common element of
therapeutically important small molecules, including recent
isolates like the microsclerodermins1 and pedeins,2 as well as
historically and clinically important antitumor agents such as
Taxol.3 This functional group array is commonly approached
synthetically using either olefin functionalization from an
unsaturated ester4 or carbon–carbon bond formation to
establish the vic-amino alcohol subunit.5,6 The latter is
commonly referred to as the glycolate Mannich when the
nucleophile is a glycolic acid derivative. This approach must
be diastereoselective, and the variation using an ester enolate
donor (or more commonly, a functional equivalent)7 has
provided a range of useful methods.8–10 Enantioselective
variants of these reactions are limited by comparison and
often require preparation of the geometrically enriched silyl
ketene acetal.10–12
This report describes a conceptually new approach to this
motif through a carbon–carbon bond forming pathway that
involves Brønsted acid activation of an azomethine and
a-diazo imide. Following the first demonstration that
diazoalkanes can be guided selectively to carbon–carbon bond
formation using Brønsted acids,13 Maruoka et al. developed
several diastereoselective acid-catalyzed addition reactions
involving a-aryl diazo acetates.14 Terada et al.15 (and recently
Akiyama et al.)16 established that these reactions are amenable
to enantioselective catalysis through their development of
the first chiral phosphoric acid-catalyzed additions of
ethyl diazoacetate, leading to a-diazo b-amino esters. In
these transformations the intermediate diazonium ion avoids
rearrangement and elimination, but suffers from proton loss.
Together, these contributions highlight the growing potential
of a nonmetal, nonredox activation approach to diazoalkane
chemistry. This report describes the synthesis and deployment
of a novel a-diazo imide bearing a nucleophilic oxygen that
terminates the addition reaction by cyclization to the diazo
carbon. The net result is a highly diastereoselective and
efficient equivalent to a glycolate Mannich reaction.
Across the range of acids employed in Table 1 a single
Mannich addition product was observed in the crude reaction
mixtures, indicating
a high level of diastereoselectivity.
The syn relative configuration depicted was assigned to this
crystalline solid by X-ray diffraction (ESIw).
In addition to the synthesis of b-hydroxy asparagine
derivative 3a,18 we examined a variety of imines 1 toward
diazo imide 2 (Table 2). Similar to ester-substituted imine 1a,
imines derived from aryl a-keto aldehydes provided the
syn-glycolate Mannich products 3b–j with high diastereo-
selection and good to excellent isolated yield. Although
electron rich substituted benzenes such as 3c and 3f performed
well, the thiophenyl ketone 1k provided the syn-adduct 3k
with noticeably lower diastereoselection at the 6 : 1 level.
a-Keto imines bearing aliphatic substituents were similarly
efficient, but provided the addition products with only modest
diastereoselection (Table 2, entries 12–14). In these cases,
however, the characteristic crystallinity of the oxazolidine diones
provided an opportunity to couple a recrystallization protocol to
the preparation, resulting in the syn-adduct 3m in 62% isolated
yield without recourse to chromatography (Scheme 1).19 In the
case of the cyclohexyl ketone, however, the nonselective addition
was mitigated only by a very efficient conversion (97% isolated
yield) to oxazolidine dione 3n (Table 2, entry 14).
Department of Chemistry & Vanderbilt Institute of Chemical Biology,
Vanderbilt University, Nashville, TN 37235-1822, USA.
E-mail: jeffrey.n.johnston@vanderbilt.edu;
Web: http://www.vanderbilt.edu/proton/; Tel: +1 615322 7376
w Electronic supplementary information (ESI) available: Preparations
and analytical data for all new compounds, NMR spectra, and X-ray
crystallographic data. CCDC 734742. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/b913785h
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Table 1 Catalyzed additions of a-diazo imide to azomethine: identi-
fication of the syn-glycolate Mannich reaction pathwaya
Table 2 syn-Selective glycolate Mannich additions to a-keto iminesa
Entry
R
drb
Yield (%)
Entry
X–H
T/1C
drb
Yield (%)
1
2
3
4
5
6
7
8
CH3O2C
C6H5C(O)
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
420 : 1
420 : 1
420 : 1
420 : 1
420 : 1
420 : 1
420 : 1
420 : 1
420 : 1
420 : 1
6 : 1
4 : 1
4 : 1
1 : 1
10 : 1
10 : 1
10 : 1
10 : 1
10 : 1
76
77
79
69
81
70
81
64
66
72
80
88
98
97
53
69
55
48
51
53
68
59
37
43
36
1
2
3
4
5
6
7
8
9
PPTS
–20
–20
–20
–78
–78
–78
–78
À78
–78
—
—
—
495 : 5
495 : 5
495 : 5
495 : 5
495 : 5
495 : 5
0
o5
o5
31
43
42
71
76
83
pCH3C6H4C(O)
pBrC6H4C(O)
pFC6H4C(O)
pH3COC6H4C(O)
pPhC6H4C(O)
pF3CC6H4C(O)
pAcOC6H4C(O)
pF3CC6H4C(O)
2C4H3SC(O)
tBuC(O)
CH3CO2H
PhCO2H
H3PO4
pTsOH
CF3CO2H
Tf2NH
TfOH
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
HBF4
a
All reactions were 0.15 M in imine and used 120 mol% diazo imide,
b
100 mol% acid. Conversion approximated by H NMR: entry 1: 0;
1
cyc-C3H5C(O)
cyc-C6H11C(O)
pF3CC6H4
2 and 3: o5%; 4: 63%; 5: 100%; 6: 65%; 7–9: 100%. Diastereomer
1
ratios were measured by H NMR. Ratios in excess of 95 : 5 indicate
pO2NC6H4
that the minor diastereomer could not be observed or identified. See
ESIw for complete details.
3,4F2C6H3
pFC6H4
pF3COC6H4
3,4Cl2C6H3
s
t
10 : 1
10 : 1
10 : 1
10 : 1
10 : 1
10 : 1
pBrC6H4
u
v
w
x
y
pClC6H4
mPhOC6H4
pAcOC6H4
pNCC6H4
a
All reactions are 0.15 M in imine and use 120 mol% of diazo imide
b
2. Diastereomer ratios were approximated by 1H NMR analysis of
the crude reaction mixture. Yields correspond to isolated, analytically
pure product.
In conclusion, a highly syn-selective glycolate Mannich
reaction has been developed using the novel a-diazo imide 2.
These additions provide a-oxy b-amino acid derivatives with
generally high diastereoselection and excellent isolated yield,
indicating high selectivity for the carbon–carbon bond
forming pathway over protonative decomposition. This
reaction provides a new platform for the development of novel
stereoselective addition reactions using a-diazo imides.
We are grateful to the NSF (CHE-0848856) for financial
support and to Dr Maren Pink (Indiana University) for X-ray
structure determination of syn-3a.
Scheme 1
The substrate scope was extended to aryl aldimines of
varying electronic character (Table 2, entries 15–25). In
contrast to a standard reaction time of one hour for a-keto
imines (3a–n), the aryl aldimines were allowed 18 hours under
otherwise identical conditions to establish the general behavior
shown. In general, reactivity was lower for these substrates,
but diastereoselection remained high in all cases at the
10 : 1 level.
Separate reports indicate the possible intermediacy of
aziridine13 and/or a-diazonium intermediates.15 Therefore, a
rationale for high syn-selectivity must await a study of
mechanism for Brønsted acid-catalyzed diazo additions to
imines. The polyfunctional products that result from these
additions can be readily manipulated using standard
approaches (Scheme 2). For example, hydrogenolysis of 3a
provides monosubstituted amine 5 in 71% yield. By simply
extending the reaction time, a subsequent regioselective
methanolysis of the oxazolidine dione, and O–N acyl transfer
provides methyl carbamate 6 in good overall yield.
Scheme 2
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Chem. Commun., 2009, 6195–6197 | 6197