Highly stereoselective Michael addition reactions of CamTHP*- desymmetrized glycinamide for the synthesis of functionally dense amino acid derivatives

Article abstract of DOI:10.1021/ol048568q

(Chemical equation presented) The camphor-derived tetrahydropyran (camTHP*)-desymmetrized glycinamide 1 undergoes efficient and highly diastereoselective lithium enolate Michael additions to nitro olefins, α,β-unsaturated ketones, esters, and lactones. St

Full text of DOI:10.1021/ol048568q

ORGANIC
LETTERS
2004
Vol. 6, No. 24
4427-4429
Highly Stereoselective Michael Addition
Reactions of CamTHP*-Desymmetrized
Glycinamide for the Synthesis of
Functionally Dense Amino Acid
Derivatives
Darren J. Dixon,*,† Richard A. J. Horan,‡ Nathaniel J. T. Monck,§ and Paul Berg‡
Department of Chemistry, UniVersity of Manchester, Manchester, M13 9PL, U,K.,
Department of Chemistry, UniVersity of Cambridge, Lensfield Road,
Cambridge CB2 1EW, U.K., and Vernalis plc, Oakdene Court, 613 Reading Road,
Winnersh, Wokingham RG41 5UA, U.K.
darren.dixon@man.ac.uk
Received July 23, 2004 (Revised Manuscript Received October 2, 2004)
ABSTRACT
The camphor-derived tetrahydropyran (camTHP*)-desymmetrized glycinamide 1 undergoes efficient and highly diastereoselective lithium enolate
Michael additions to nitro olefins, -unsaturated ketones, esters, and lactones. Straightforward manipulation of these products affords
3-substituted pyroglutamides and -aryl- -diamino acid derivatives, highlighting the ease of synthesis of enantiomerically enriched, functionally
r,â
â
r,γ
dense molecules using this novel building block.
The biological importance of R-amino acid derivatives has
been clearly demonstrated over the past few years.1 Equally,
glutamic acid derivatives, pyroglutamic acid derivatives, and
related structures are important as both chiral building blocks2
and bioactive substances.3
In the preceding paper, we introduced the camTHP*-
desymmetrized glycinamide 1 (Figure 1) for the enantiose-
An attractive approach to such derivatives involves the
stereocontrolled Michael addition of a chiral glycine-derived
enolate to the corresponding electron-poor olefin.3a,b,4,7a This
process leads to the generation of up to three new stereogenic
centers in the product, and clearly, when high levels of
control are observed, these reactions are of considerable
importance.
Figure 1. CamTHP*-desymmetrized glycinamide 1 as a building
block for R-amino carbonyl derivatives 2.
† University of Manchester.
lective synthesis of R-amino carbonyl compounds 2 through
highly diastereoselective enolate alkylation reactions and
subsequent deprotection and manipulation of the dimethyl
amide.5 Here, we report the use of this building block in
highly diastereoselective Michael addition reactions.
‡ University of Cambridge.
§ Vernalis.
(1) Jung, M. J. In Chemistry and Biochemistry of the Amino Acids;
Barrett, G. C., Ed.; Chapman and Hall: London, 1985; p 227.
(2) For a recent review, see: Na´jera, C.; Yus, M. Tetrahedron:
Asymmetry 1999, 10, 2245.
10.1021/ol048568q CCC: $27.50
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Published on Web 10/26/2004

In all cases, the reaction yields were good (78-100%)
and the observed diastereoselectivities were uniformly excel-
lent (>95% de). Notable is entry 3, where a quantitative yield
of only one of the possible four diastereoisomers was
obtained. The structures of compounds 5, 6, 8, and 9 were
assigned by analogy to compound 7, the stereochemistry of
which was unambiguously established by single-crystal X-ray
diffraction.
Figure 2. Synthesis of camTHP*-desymmetrized glycinamide 1
from (+)-camphor 3.
Having established the utility in the addition to reactive
nitro olefin acceptors, we next turned our attention to less
reactive Michael acceptors (Table 2).
Multigram quantities of camTHP*-desymmetrized glyci-
namide 1 are readily prepared in four high-yielding steps
from commercially available (+)-camphor 3. The stereogenic
tertiary alcohol center is created in a facially selective
allylation reaction, and the stereogenic aminol center is
established via a chiral relay effect during the condensation
of glycinamide with the lactol 4 (Figure 2).
Table 2. Diastereoselective Michael Addition of 1 to
R,â-Unsaturated Esters, Lactones, and Ketones
Our preliminary studies focused on the Michael addition
of camTHP*-desymmetrized glycinamide 1 to reactive nitro
olefin Michael acceptors. The optimal reaction conditions
were established quickly and comprised treatment of a -78
°C THF solution of the building block 1 (1.0 equiv) with
2.0 equiv of lithium hexamethyldisilazide (LHMDS) for 1
h followed by the nitro olefin acceptor (1.1 equiv). After
being stirred for 1 h at this temperature and 1 h at -20 °C,
the reaction mixture was quenched by the addition of 4.0
equiv of acetic acid. On warming to room temperature,
diethyl ether was added, and the mixture was filtered through
a short (1-2 cm) plug of silica eluting with diethyl ether.
Evaporation of solvents gave the corresponding crude
products 5-9, which were purified by silica gel column
chromatography (Table 1).
Table 1. Diastereoselective Michael Addition of 1 to Nitro
Olefin Acceptors
a Yield of purified material. b Measured by analysis of the 500 MHz 1H
NMR spectra of the crude reaction product.
Using the previously described conditions, good to excel-
lent isolated yields were obtained with R,â-unsaturated tert-
butyl and ethyl esters, lactones, and ketones. Reaction
diastereoselectivities ranged from good to excellent in all
cases.
(3) (a) Wehbe, J.; Rolland, V.; Roumestant, M. L.; Martinez, J.
Tetrahedron: Asymmetry 2003, 14, 1123 and references therein. (b)
Hartzoulakis, B.; Gani, D. J. Chem. Soc., Perkin Trans. 1 1994, 2525 and
references therein. (c) Hruby, V. J.; Sharma, S. D.; Collins, N.; Matsunaga,
T. O.; Russell, K. C In Synthetic Peptides: A User’s Guide; Grant, G. A.,
Ed.; W. H. Freeman and Co.: New York, 1992; p 259. (d) Hruby, V. J.;
Qian, X. In Methods in Molecular Biology, Vol. 35, Peptide Synthesis and
Purification Protocols; Pennington, M. W., Dunn, B. M., Eds.; Humana
Press: Clifton, NJ, 1994; p 201.
a Yield of purified material. b Measured by analysis of the 500 MHz 1H
NMR spectra of the crude reaction product.
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Org. Lett., Vol. 6, No. 24, 2004

The stereochemistry of the products was assigned by
analogy to 7 and 13 in which the relative stereochemistry
was determined by chemical correlation (vide infra).
The product stereochemistry is consistent with the Michael
acceptor attacking the Re face of the lithium enolate and is
in agreement with the stereochemical outcome of the enolate
alkylation reactions of 1.5 Moreover, the configurational
assignment of the products is compatible with a synclinal
approach model6 (Figure 3).7
standard hydrogenolysis conditions afforded the open form
glutamide which cyclized on heating to the pyroglutamic acid
derivative 19 (Scheme 1).8
Scheme 1. Manipulation of 13 to Pyroglutamide 19
Reductive N-Boc protection of the nitro group following
our previous conditions9 allowed access to the differentially
protected â-aryl-R,γ-diamino acid derivatives 20-22 (Scheme
2).
Scheme 2. Reductive Manipulation of Michael Adducts 5-7
Figure 3. Stereochemical model to rationalize the outcome in the
Michael addition reactions and single-crystal X-ray structure of 7.
In summary, camTHP*-desymmetrized glycinamide build-
ing block 1 undergoes efficient and highly diastereoselective
lithium enolate Michael additions to nitro olefins, R,â-
unsaturated ketones, esters, and lactones. Subsequent ma-
nipulation of these Michael adducts gives stereochemically
defined polyfunctional R-amino acid derivatives in high
yields. Further utility and synthetic applications of this
chemistry will be reported in due course.
To confirm the relative stereochemistry of the adducts 10-
17 it was necessary to convert a representative example to a
cyclic product for NMR analysis. Hence, removal of the
camTHP* protecting group was achieved by dissolution of
the Michael adduct 13 in aqueous TFA for 6 h to give the
corresponding Cbz-protected â-substituted glutamic acid
derivative 18 in 61% yield. Subjection of this product to
Acknowledgment. We thank Vernalis plc for a student-
ship (to R.A.J.H.), Pfizer Global Research and Development
(UK) for a summer scholarship (to P.B.), the National Mass
Spectrometry Service at Swansea for HRMS, Dr. John E.
Davies for the X-ray structure determination, and Prof.
Steven V. Ley for continued and valued support.
(4) (a) For a highly diastereoselective but racemic synthesis, see:
Soloshonok, V. A.; Cai, C.; Hruby, V. J.; Van Meervelt, L.; Yamazaki, T.
J. Org. Chem. 2000, 65, 6688. For asymmetric examples, see: (b) Busch,
K.; Groth, U. M.; Ku¨hnle, W.; Scho¨llkopf, U. Tetrahedron 1992, 48, 5607.
(c) Scho¨llkopf, U.; Ku¨hnle, W.; Egert, E.; Dyrbusch, M. Angew. Chem.,
Int. Ed. Engl. 1987, 26, 480. (d) Pettig, D.; Scho¨llkopf, U.; Synthesis 1988,
173. For an example using an achiral glycine anion and chiral electrophiles,
see: (e) Soloshonok, V. A.; Ueki, H.; Tiwari, R.; Cai, C.; Hruby, V. J. J.
Org. Chem. 2004, 69, 4984 and references therein.
(5) Dixon, D. J.; Horan, R. A. J.; Monck, N. J. T. Org. Lett. 2004, 6,
4423.
(6) Although an open transition-state model cannot be ruled out:
Smitrovich, J. H.; DiMichele, L.; Qu, C.; Boice, G. N.; Nelson, T. D.;
Huffman, M. A.; Murry, J. J. Org. Chem. 2004, 69, 1903.
Supporting Information Available: Experimental pro-
cedures, 1H and 13C NMR spectra, and high-resolution mass
spectra for compounds 5-22. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL048568Q
(7) For some excellent works on the steric course of enolate Michael
addition reactions, see: (a) Suzuki, K.; Seebach, D. Liebigs Ann. Chem.
1992, 51. (b) Oare, D. A.; Henderson, M. A.; Sanner, M. A.; Heathcock,
C. H. J. Org. Chem. 1990, 55, 132. (c) Oare, D. A.; Heathcock, C. H. J.
Org. Chem. 1990, 55, 157.
(8) The relative stereochemistry of 19 is supported by NOE (see the
Supporting Information).
(9) Adderley, N. J.; Buchanan, D. J.; Dixon, D. J.; Laine´, D. I. Angew.
Chem., Int. Ed. 2003, 42, 4241.
Org. Lett., Vol. 6, No. 24, 2004
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