Synthesis of pyroglutamic acid derivatives via double michael reactions of alkynones

Article abstract of DOI:10.1021/ol070674f

In the presence of substoichiometric quantities of potassium tert-butoxide and an additional metal salt, amide-tethered diacids undergo double Michael reactions with alkynones to provide highly functionalized pyroglutamic acid derivatives. The metal salt was found to play an important role in improving the diastereoselectivities of the reactions.

Full text of DOI:10.1021/ol070674f

ORGANIC
LETTERS
2007
Vol. 9, No. 11
2159-2162
Synthesis of Pyroglutamic Acid
Derivatives via Double Michael
Reactions of Alkynones
Myriam Scansetti,† Xiangping Hu,† Benjamin P. McDermott,‡ and Hon Wai Lam*,†
School of Chemistry, UniVersity of Edinburgh, Joseph Black Building, The King’s
Buildings, West Mains Road, Edinburgh EH9 3JJ, United Kingdom, and AstraZeneca
R&D Alderley Park, Macclesfield, Cheshire SK10 4TF, United Kingdom
h.lam@ed.ac.uk
Received March 19, 2007
ABSTRACT
In the presence of substoichiometric quantities of potassium tert-butoxide and an additional metal salt, amide-tethered diacids undergo double
Michael reactions with alkynones to provide highly functionalized pyroglutamic acid derivatives. The metal salt was found to play an important
role in improving the diastereoselectivities of the reactions.
Pyroglutamic acid (1) and its derivatives are structural units
of widespread chemical significance, having been heavily
utilized as building blocks for the synthesis of numerous
biologically active compounds.1
with electron-deficient alkynes (mostly 3-butyn-2-one) to
provide highly functionalized cyclic products.4,5 Generating
two new carbon-carbon bonds and up to three new stereo-
genic centers with often high levels of diastereoselectivity,
this reaction has been effectively utilized in the preparation
of a range of five- and six-membered carbocycles.4 In
(1) For a recent review, see: Na´jera, C.; Yus, M. Tetrahedron:
Asymmetry 1999, 10, 2245-2303.
(2) For recent, representative examples, see: (a) Soloshonok, V. A.; Cai,
C.; Yamada, T.; Ueki, H.; Ohfune, Y.; Hruby, V. J. J. Am. Chem. Soc.
2005, 127, 15296-15303. (b) Chang, M.-Y.; Sun, P.-P.; Chen, S.-T.; Chang,
N.-C. Tetrahedron Lett. 2003, 44, 5271-5273. (c) Alvarez-Ibarra, C.; Csa´ky¨,
A. G.; Go´mez de la Olivia, C. Eur. J. Org. Chem. 2002, 4190-4194. (d)
Merino, P.; Revuelta, J.; Tejero, T.; Chiacchio, U.; Rescifina, A.; Piperno,
A.; Romeo, G. Tetrahedron: Asymmetry 2002, 13, 167-172.
(3) Little, R. D.; Masjedizadeh, M. R.; Wallquist, O.; McLoughlin, J. I.
Org. React. 1995, 47, 315-512.
Considering the multitude of synthetic applications for
pyroglutamic acids, much research effort has been devoted
to the development of new methods for the synthesis of
functionalized derivatives.1,2 In this Letter, we present a novel
route to highly functionalized pyroglutamic acids using
double Michael reactions3 of amide-tethered diacids with
alkynones.
Over the past few years, Grossman and co-workers have
described a range of reactions where compounds containing
two acidic carbon atoms undergo double Michael reactions
(4) (a) Grossman, R. B.; Varner, M. A.; Skaggs, A. J. J. Org. Chem.
1999, 64, 340-341. (b) Grossman, R. B.; Rasne, R. M.; Patrick, B. O. J.
Org. Chem. 1999, 64, 7173-7177. (c) Grossman, R. B.; Pendharker, D.
S.; Patrick, B. O. J. Org. Chem. 1999, 64, 7178-7183. (d) Grossman, R.
B.; Skaggs, A. J.; Kray, A. E.; Patrick, B. O. Org. Lett. 1999, 1, 1583-
1586. (e) Grossman, R. B.; Pendharker, D. S.; Rasne, R. M.; Varner, M.
A. J. Org. Chem. 2000, 65, 3255-3258. (f) Grossman, R. B.; Rasne, R.
M. Org. Lett. 2001, 3, 4027-4030. (g) Holeman, D. S.; Rasne, R. M.;
Grossman, R. B. J. Org. Chem. 2002, 67, 3149-3151. (h) Hattori, K.;
Grossman, R. B. J. Org. Chem. 2003, 68, 1409-1417. For a review, see:
(i) Grossman, R. B. Synlett 2001, 13-21.
† University of Edinburgh.
‡ AstraZeneca.
(5) Hughes, F., Jr.; Grossman, R. B. Org. Lett. 2001, 3, 2911-2914.
10.1021/ol070674f CCC: $37.00
© 2007 American Chemical Society
Published on Web 04/25/2007

comparison, application of this methodology to heterocycle
construction has been limited, with just one report of a [5 +
1] annulation route to piperidines having been described.5
In view of the convergent and modular nature of these
transformations, we were drawn to the prospect of utilizing
double Michael reactions of alkynones in a concise synthesis
of highly functionalized pyroglutamic derivatives, according
to the strategy outlined in Scheme 1. It was hoped that under
Scheme 1. Proposed Double Michael Addition Route to
Pyroglutamic Acid Derivatives
Figure 1. X-ray crystal structure of double Michael product 8.
that the small size of the nitrile group reduces the magnitude
of unfavorable 1,3-diaxial interactions between acidifying
groups in the transition state for cyclization, which would
otherwise inhibit ring closure.4i At the outset of this work, it
was therefore uncertain whether diacid 7a, which does not
possess a nitrile substituent, would undergo successful double
Michael reaction. Although treatment of a mixture of 7a and
3a with PPh3 in acetonitrile4c gave no reaction (entry 1), we
4a
found that KOtBu in CH2Cl2 led to the formation of the
suitable conditions, an amide-tethered diacid 2 would react
with an alkynone 3 to first give mono-Michael adduct 4 and/
or 5, which would then cyclize to the pyroglutamic acid
derivative 6.
Our preliminary investigations began with the double
Michael reaction of amide-tethered diacid 7a with aromatic
alkynone 3a (Table 1). In all previous examples of double
Michael reactions reported by Grossman and co-workers,4,5
a mandatory requirement for success is the presence of at
least one nitrile substituent in the tethered diacid, which ends
up in a pseudoaxial position in the product.4i It is proposed
desired pyroglutamic acid derivative 8, albeit as a 1:1 mixture
of diastereomers (entry 2).
We next investigated the effect of Lewis acidic additives
7
on the reaction.6 Substoichiometric quantities of Fe(acac)3
8
and Zn(OTf)2 were found to inhibit the reaction (entries 3
and 4), though Zn(OTf)2 had a beneficial effect on di-
9
astereoselectivity (entry 4). Finally, we identified Mg(OTf)2
10
(entry 5) and Ni(acac)2 (entry 6) as promising additives,
allowing double Michael product 8 to be isolated in 68-
76% yield and with up to 18:1 diastereomeric ratio.
Recrystallization of 8 from a mixture of diethyl ether and
hexane afforded crystals that were suitable for X-ray crystal-
lography, which allowed us to confirm that the major
diastereomer obtained in these reactions possesses trans
stereochemistry (Figure 1).
Table 1. Reaction Condition Optimization
With optimized conditions in hand, the scope of the
reaction was explored (Figure 2). Using 7a as the tethered
(6) For a review of transition-metal-catalyzed Michael reactions of 1,3-
dicarbonyl compounds, see: Christoffers, J. Eur. J. Org. Chem. 1998, 1259-
1266.
yield
(7) For examples of iron-catalyzed Michael reactions of 1,3-dicarbonyl
compounds, see: (a) Fei, C. P.; Chan, T. H. Synthesis 1982, 467-468. (b)
Kocˇovksy´, P.; Dvorˇa´k, D. Tetrahedron. Lett. 1986, 27, 5015-5108. (c)
Christoffers, J. Chem. Commun. 1997, 943-944. (d) Christoffers, J. J. Chem.
Soc., Perkin Trans. 1 1997, 3141-3149. (e) Christoffers, J. Synlett 2001,
723-732.
(8) For examples of zinc-catalyzed Michael reactions of 1,3-dicarbonyl
compounds, see: Brunner, H.; Krumey, C. J. Mol. Catal. A 1999, 142,
7-15.
entry
reagents
dra
n/a
1:1
1:1
>19:1
11:1
18:1
(%)b
1c
2
3
4
5
6
PPh3 (20 mol %)
0
68
31
27
68
76
KOtBu (20 mol %)
KOtBu (20 mol %), Fe(acac)3 (20 mol %)
KOtBu (20 mol %), Zn(OTf)2 (20 mol %)
KOtBu (20 mol %), Mg(OTf)2 (20 mol %)
KOtBu (20 mol %), Ni(acac)2 (20 mol %)
(9) For examples of magnesium-catalyzed Michael reactions of 1,3-
dicarbonyl compounds, see: (a) Ji, J.; Barnes, D. M.; Zhang, J.; King, S.
A.; Wittenberger, S. J.; Morton, H. E. J. Am. Chem. Soc. 1999, 121, 10215-
10216. (b) Barnes, D. M.; Ji, J.; Fickes, M. G.; Fitzgerald, M. A.; King, S.
A.; Morton, H. E.; Plagge, F. A.; Preskill, M.; Wagaw, S. H.; Wittenberger,
S. J.; Zhang, J. J. Am. Chem. Soc. 2002, 124, 13097-13105. (c)
MacCulloch, A. C.; Yolka, S.; Jackson, R. F. W. Synlett 2002, 1700-1702.
a As determined by 1H NMR analysis of the isolated product. Due to
overlapping signals from other compounds, diastereomeric ratios could not
be determined from 1H NMR analysis of the unpurified reaction mixtures.
b Isolated yields of mixtures of diastereoisomers that were inseparable by
column chromatography. c MeCN used as solvent in place of CH2Cl2.
2160
Org. Lett., Vol. 9, No. 11, 2007

Scheme 2. Experiments Probing the Role of Mg(OTf)2 and
Ni(acac)2
the only observable Michael product in 52% yield, with the
remainder of material being unreacted 7a. This experiment
indicates that under these conditions, the methylene carbon
adjacent to the amide carbonyl of 7a is the more reactive of
the two acidic positions. However, the analogous experiment
using Ni(acac)2 provided a mixture of 19 and the alternative
Michael product 20, among other side-products.
Exposure of a 1:1 diastereomeric mixture of double
Michael product 8 obtained using KOtBu alone (Table 1,
entry 2) to standard reaction conditions including additional
Mg(OTf)2 or Ni(acac)2 led to recovery of 8 in high yield
with no discernible change in diastereomeric composition
(eq 2). These experiments suggest that under these conditions,
post-cyclization epimerization (which could occur via a
deprotonation-reprotonation sequence or a retro-Michael-
Michael sequence) does not occur, and therefore diastereo-
selection observed in the presence of additional metal salt
is the result of a kinetically controlled process. However,
the manner in which the metal salt imparts diastereoselec-
tivity is not clear at this time.
Figure 2. Double Michael reactions of amide-tethered diacids 7a
and 7b with assorted aromatic alkynones. Cited yields are of isolated
inseparable mixtures of diastereoisomers. Diastereomeric ratios were
1
determined by H NMR analysis of the isolated products. Due to
overlapping signals from other compounds, diastereomeric ratios
could not be determined by 1H NMR analysis of unpurified reaction
mixtures.
diacid, a range of different aromatic alkynones 3 possessing
substituents of varying electronic character underwent double
Michael reactions to provide pyroglutamic acid derivatives
9-13 in 61-77% yield. Tethered diacid 7b, containing
methyl esters in place of the ethyl esters in 7a, also
underwent reaction uneventfully, affording double Michael
products 14-17.
Conversion of double Michael product 8 into other
potentially useful compounds is shown in Scheme 3. Treat-
ment of 8 with NaH and BnBr provided alkylated product
Additional experiments provided some insight into the
reaction pathway and the role played by the metal salts
(Scheme 2). Equation 1 highlights differences in the effect
of Mg(OTf)2 and Ni(acac)2. Reaction of methyl vinyl ketone
(18) with diacid 7a using Mg(OTf)2 as additive led to 19 as
Scheme 3. Elaboration of Double Michael Product 9
(10) For examples of nickel-catalyzed Michael reactions of 1,3-dicarbonyl
compounds, see: (a) Nelson, J. H.; Howells, P. N.; DeLullo, G. C.; Landen,
G. L.; Henry, R. A. J. Org. Chem. 1980, 45, 1246-1249. (b) Clariana, J.;
Ga´lvez, N.; Marchi, C.; Moreno-Man˜as, M.; Vallribera, A.; Molins, E. Tetra-
hedron 1999, 55, 7331-7344. (c) Christoffers, J.; Ro¨âler, U.; Werner, T.
Eur. J. Org. Chem. 2000, 701-705. (d) Evans, D. A.; Seidel, D. J. Am.
Chem. Soc. 2005, 127, 9958-9959. (e) Evans, D. A.; Thomson, R. J.;
Franco, F. J. Am. Chem. Soc. 2005, 127, 10816-10817. (f) Itoh, K.;
Hasegawa, M.; Tanaka, J.; Kanemasa, S. Org. Lett. 2005, 7, 979-981. (g)
Yanagita, H.; Kodama, K.; Kanemasa, S. Tetrahedron Lett. 2006, 47, 9353-
9357.
Org. Lett., Vol. 9, No. 11, 2007
2161

21,11 and monodecarboxylation to 22 was accomplished by
heating a DMF solution of 8 to 110 °C.
Acknowledgment. This work was supported by the
University of Edinburgh, AstraZeneca, the Royal Society,
and the EPSRC. We thank Peter A. Wood at the University
of Edinburgh for assistance with X-ray crystallography. The
EPSRC National Mass Spectrometry Service Centre at the
University of Wales, Swansea is thanked for their assistance.
In summary, we have developed a double Michael addition
route to highly functionalized pyroglutamic acid deriva-
tives that utilizes amide-tethered carbon diacids and aro-
matic alkynones as substrates. The reactions proceed with
good levels of trans-diastereoselectivity, provided that
substoichiometric quantities of Mg(OTf)2 or Ni(acac)2 are
employed as additives. Further work will address the
development of enantioselective variants of these reactions.
Supporting Information Available: Experimental pro-
cedures, full spectroscopic data for all new compounds, and
crystallographic data in CIF format. This material is available
free of charge via the Internet at http://pubs.acs.org.
(11) Tentative relative stereochemical assignment. NOESY spectra proved
inconclusive in establishing the relative stereochemistry of 21.
OL070674F
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Org. Lett., Vol. 9, No. 11, 2007