Functionalizing the γ-position of α-diazo-β-ketoesters

Article abstract of DOI:10.1016/j.tetlet.2016.06.065

Although α-diazo-β-ketoesters are synthetically versatile intermediates, methodology for introducing this functionality into complex molecules is still limited, most frequently involving a carboxylic acid precursor, which is then activated and transformed

Full text of DOI:10.1016/j.tetlet.2016.06.065

Tetrahedron Letters 57 (2016) 3330–3333
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Tetrahedron Letters
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Functionalizing the c-position of a-diazo-b-ketoesters
Thu Q. Nguyen a, Maha Alqurafi a, Cash Edwards a, Pauline Nguyen a, Jean Kim a, Samuel Casco a,
Maricka Bennet a, Christopher Chiang a, Maureen Lohry a, Melina Cox a, Byron Meshram a, Duyen Le a,
Eugene Kim a, Snigdha Smriti a, Peter Oelschlaeger b, John D. Buynak a,
⇑
a Department of Chemistry, Southern Methodist University, Dallas, TX 75275-0314, USA
b Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, 309 East Second St., Pomona, CA 91768, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Although
a-diazo-b-ketoesters are synthetically versatile intermediates, methodology for introducing
Received 3 May 2016
Revised 13 June 2016
Accepted 14 June 2016
Available online 16 June 2016
this functionality into complex molecules is still limited, most frequently involving a carboxylic acid pre-
cursor, which is then activated and transformed into a b-ketoester, with the diazo group being subse-
quently added with a diazo transfer reagent. While introducing this highly functional moiety in a
convergent one step process would be ideal, such an objective is limited by the relatively few studies
which address functionalization of the
we evaluate strategies, both new and established, for functionalizing
with regard to generating compounds prospectively useful in the synthesis of C1-substituted carbapen-
ems. We report the first d-aldehydo- -diazo-b-ketoester as well as a method for its oxidation to the cor-
a
-diazo-b-ketoester at the
c
-position. In the present investigation,
Keywords:
Diazo
b-Ketoester
Carbapenem
Pyrazole
a
-diazo-b-ketoesters, particularly
a
responding methyl ester, and the formation of a new substituted pyrazole under basic conditions.
Ó 2016 Elsevier Ltd. All rights reserved.
Introduction
OH
OH
N2
We would like to report our recent research involving the syn-
cat. Rh2(OAc)4
EtOAc, 70 o
O
CO2PNB
thesis and reactivity of
pounds. Long recognized for their ability to undergo synthetically
useful insertion reactions, -diazo-b-dicarbonyl compounds are
c-substituted-a-diazo-b-carbonyl com-
N
C
NH
O
O
O
CO2PNB
a
1
2
of ever increasing utility. These compounds are prepared from b-
ketoesters via diazo transfer reactions1 and are valuable intermedi-
ates in the synthesis of heterocyclic systems, notably including the
synthesis of carbapenems as shown in Scheme 1.2 The stabilized
diazo group is capable of selective, and directed, activation with
transition metals, including RhII, especially Rh2(OAc)4 and Rh2(-
esp)2,3 CuI,4 CuII,5 RuII,6 as well as RhIII,7 IrIII,8 and CoIII,9 to affect
a wide array of intramolecular and intermolecular insertion reac-
tions (N–H,10 O–H,11 and C–H12) and addition of the carbenoid to
alkenes.13 The diazo functionality is also susceptible to strongly
electrophilic reagents under non-catalytic, conditions, including
reactions with bromine and dimethyldioxirane, as shown in
Scheme 2.14,15
Scheme 1. Merck carbapenem synthesis.2
O
O
Br2
OR
O
O
Br
Br
4
OR
N2
O
O
O
O
3
In complex molecules, the
a-diazo-b-ketoester functionality is
OR
often introduced in a stepwise fashion, from a functionalized car-
boxylic acid, which is then activated and converted to a b-ketoester,
and subsequent introduction of the diazo functionality by diazo
O
5
Scheme 2. Non-catalytic reactions of
a-diazo-b-dicarbonyl compounds with elec-
trophilic reagents.
⇑
Corresponding author.
E-mail address: jbuynak@smu.edu (J.D. Buynak).
http://dx.doi.org/10.1016/j.tetlet.2016.06.065
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

T. Q. Nguyen et al. / Tetrahedron Letters 57 (2016) 3330–3333
3331
O
O
O
O
O
R
TsN3
Et3N
1) CDI, ACN
OMe
R
R
OMe
OH
2) MeO2CCH2CO2K, MgCl2
N2
6
7
8
Scheme 3. Stepwise introduction of a-diazo-b-ketoester moiety.
O
O
combination of methanesulfonyl chloride and sodium azide, in
the presence of NaHCO3, as shown below to generate methanesul-
OM
O
RX
R
OMe
fonyl azide in situ. After completion, p-nitrobenzyl
a-diazo-b-
OR
N2
10
ketoester 12 cleanly precipitates from the acetone/water solvent
when cooling to 0 °C, thus enabling the rapid formation of this
N2
9
highly stabilized
a-diazo-b-ketoester. We chose to explore the
allylation of the terminal methyl, first through the corresponding
enolate. However, after examining several bases (e.g., LDA, NaH,
or KH) and allyl iodide, we were unable to achieve an acceptable
Scheme 4. Proposed single-step introduction of a-diazo-b-ketoester moiety.
transfer, as shown in Scheme 3. It may be more synthetically effi-
cient, however, to introduce the 4-carbon functionality in one piece,
as shown in Scheme 4, but synthetic methodology for selectively
yield of the corresponding allylated
in Scheme 5.
a-diazoketoester 13 as shown
We thus chose to explore reactions of the corresponding TBS
enol ether 14 as shown below. Silyl enol ethers of -diazo-b-ketoe-
attaching substituents to the
recently enhanced synthetic versatility of
the efficient utilization of methodology for
c
position is limited. In view of the
-diazo-b-ketoesters,
-position transforma-
a
a
c
tions is essential. It is also possible that efficient methodology may
have broader synthetic utility. For example, it may be possible to uti-
lize the diazo group to block reactivity at the normally more reactive
O
O
CF3CO2
17
AgOCOCF3
tol 80 o
OPNB
a
position of b-ketoesters, allowing selective reaction at the termi-
N2
C
nus of the system, subsequently utilizing the now numerous reac-
tions of the diazo functionality to introduce new bonds at the
carbon between the two carbonyl groups.
(31% yield)
O
O
O
O
I
AgF
OPNB
F
OPNB
OPNB
N2
15
CH3CN
(30% yield)
N2
18
Results
With the objective of utilizing this approach in our ongoing
studies involving the preparation of C1-substituted carbapen-
ems,16 we would now like to report our assessment of available
and new methodology for the synthetic manipulation of these
valuable intermediates. To effect the diazo transfer reaction on p-
nitrobenzyl acetoacetate, we were able to employ an inexpensive
O
O
CH3COSK
AcS
CH3CN/H2O
(78% yield)
N2
19
Scheme 7. Synthetic utility of
c
-iodo-
a
-diazo-b-ketoester 15.
1) LDA
O
O
O
O
MeSO2Cl, NaN3
O
O
OPNB
OPNB
NaHCO3, acetone/H2O = 1:1
(87% yield)
OPNB
N2
13
2) CH2CHCH2I
N2
12
11
Scheme 5. Initial efforts to functionalize
a-diazo-b-ketoesters.
O
O
ICl
I
OPNB
CH2Cl2, rt
(100% yield)
N2
15
TBSO
O
O
O
TBSOTf
OMe
O
O
HC(OMe)3
OPNB
OPNB
Et3N, CH2Cl2, 0 o
(96% yield)
C
MeO
OPNB
OPNB
ZnCl2, CH2Cl2, rt to 50 o
(53% yield)
C
N2
N2
12
N2
14
16
I
O
O
AgOCOCF3, CH2Cl2, rt
(74% yield)
N2
13
Scheme 6. Successful efforts to functionalize a C4 a-diazo-b-ketoester synthon.

3332
T. Q. Nguyen et al. / Tetrahedron Letters 57 (2016) 3330–3333
OTBS
CHO N2
O
OPNB
OTBS
OAc
NH
22
O
O
(not observed)
NH
21
O
O
OMe
O
O
O
TFA
NO2
OPNB
O
MeO
OPNB
H2O/CH2Cl2
(90% yield)
N2
2 eq DBU, THF, rt
N2
20
H
N
16
O
O
TBS
O
H
O
N
O
NH
O
23
(50% yield)
Scheme 8. Attempted utilization of 20 in the synthesis of C1 substituted carbapenems.
the first example of a d-aldehydo-a-diazo-b-ketoester, and exists
in equilibrium with its enol tautomers 24. We subsequently
reacted aldehyde 20 with 3-(tert-butyldimethylsilyloxy)ethyl-4-
acetoxyazetidinone 21 as shown in Scheme 8. However, instead
of producing a C1-substituted carbapenem precursor, 22, the pro-
duct was pyrazole 23, the structure of which was crystallographi-
cally verified as shown in Figure 1.
As we again envisioned the formation and use of a stabilized
c-carbanion, we attempted oxidation of b-ketoaldehyde 20, ini-
tially using the Pinnick oxidation. This reaction produced only
the chloride 25, the structure of which was verified by prepara-
tion directly from iodide 15 as shown in Scheme 9. This com-
pound was presumably formed by the trapping of the enol
tautomer 24 by adventitious HOCl, followed by oxidation and
decarboxylation. Thus to achieve the desired oxidation, and
bypass the easily decarboxylated b-ketoacid, we were able to oxi-
dize 20 using 1 equiv of oxone in methanol,21 to directly produce
methyl ester 26 as shown in Scheme 10. This material could like-
wise be utilized in reaction with the acetate to produce pyrazole
28.
Figure 1. Crystal structure of 23.
sters have proven to be useful synthetic intermediates in reaction
with selected electrophiles,17 and, with loss of the reactive diazo
functionality, in rhodium-catalyzed enantioselective additions to
enol ethers,18 in rhodium-catalyzed cycloadditions with 1,3-
dienes,19 and other rhodium-catalyzed cycloadditions involving
enol carbenoid intermediates.20
Two recent publications have also observed the formation of
pyrazoles from substituted
a-diazo-b-dicarbonyl compounds,
made using other methodology.22 Mechanistically, the reaction
likely follows an electrocyclic process, similar to the more highly
studied vinyldiazomethane system,23 with the initially formed
enolate rearranging to the crystallographically observed more
thermodynamically stable nitrogen anion before reacting with
the acyl imine as shown in Scheme 11.
Our objective, however, was to effect simple chain extension
and/or functionalization of the
a-diazo-b-ketoester while main-
taining the reactive diazo functionality in the product, and we
found that reaction of 14 with more potent electrophiles, including
ICl, HC(OMe)3 in the presence of ZnCl2,17c and allyl iodide in the
presence of silver trifluoroacetate allowed the production of
In summary, we have demonstrated that the
c-position of a-
diazo-b-ketoesters can be efficiently functionalized through their
corresponding silyl enol ethers, and we have developed a viable
method for the selective oxidation of d-aldehydo-
ster 20, and methodology for preparation of substituted pyrazoles.
We have not only demonstrated that the -diazo-b-ketoester moi-
ety is stable to a wide array of reaction conditions, but also shown
a-diazo-b-ketoe-
functional and chain-extended
Scheme 6.
a-diazo-b-ketoesters as shown in
a
The iodide could be further converted into numerous other sub-
stituted -diazo-b-ketoesters, as shown in Scheme 7. Acetal 16 was
deprotected to the corresponding aldehyde 20 in good yield. This is
a
that selected functionality, particularly including
a
-diazo-b-ketoe-
O
O
O
O
NaClO2,
O
O
O
O
20 eq LiCl
2-methyl-2-butene
I
Cl
OPNB
OPNB
HO
OPNB
OPNB
O
DMF
(yield 82%)
NaH2PO4,
H2O, t-BuOH
(yield 40%)
N2
15
N2
25
N2
24
N2
20
Scheme 9. Attempted Pinnick oxidation of 20.

T. Q. Nguyen et al. / Tetrahedron Letters 57 (2016) 3330–3333
3333
CO2Me
N2
OTBS
OPNB
OTBS
OAc
NH
O
O
O
27
(not observed)
NO2
NH
O
O
O
O
O
O
1 eq Oxone
21
OPNB
MeO
OPNB
O
MeOH, 50 oC, 18 h
(yield 60%)
N2
N2
2 eq DBU, THF, rt
20
26
H
O
O
TBS
O
O
CO2Me
N
N
NH
O
28
(yield 92%)
Scheme 10. Successful oxidation of 20 and attempt to utilize
a
-diazo-b-ketodiester 26 in the synthesis of C1 substituted carbapenems.
OTBS
OTBS
N
N
N
N
OAc
N
DBU
N
CO2PNB
CO2PNB
CO2PNB
NH
21
N
O
O
OH
O
O
O
O
O
23
29
30
31
Scheme 11. Mechanistic rationale for observed product 23.
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Acknowledgments
JDB acknowledges support from the National Institutes of
Health (1R15AI109624), the SMU Chemistry Department, and the
SMU Undergraduate Research Assistantship (URA) Program. TQN
acknowledges support from an Ed Biehl predoctoral fellowship.
We thank Dr. Doug Powell, University of Oklahoma, Department
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