Amino acid-derived enaminones: A study in ring formation providing valuable asymmetric synthons

Article abstract of DOI:10.1021/ja0609046

A new reaction for the preparation of enaminones has been discovered. This method employs β-amino acids as starting materials to allow diversification as well as incorporation of chirality. The β-amino acids, once converted to ynones, are readily cyclized

Full text of DOI:10.1021/ja0609046

Published on Web 06/15/2006
Amino Acid-Derived Enaminones: A Study in Ring Formation Providing
Valuable Asymmetric Synthons
Brandon J. Turunen and Gunda I. Georg*
Department of Medicinal Chemistry and Center for Methodology and Library DeVelopment, UniVersity of Kansas,
1251 Wescoe Hall DriVe, Lawrence, Kansas 66045
Received February 7, 2006; E-mail: georg@ku.edu
Cyclic, six-membered enaminones (vinylogous amides) represent
a class of molecules that demonstrate unique chemical and
biological properties.1 These compounds serve as multident scaf-
folds in the stereoselective preparation of alkaloid natural products.2
Indeed, those that are bicyclic in nature, resembling indolizidine,
quinolizidine, and quinolinone alkaloids, are particularly attractive.3
Since few direct methods exist for accessing bicyclic, asymmetric
intermediates of this type, our group initiated the exploration of a
new chiral pool approach.4 While intermolecular 1,4-additions of
aliphatic amines to ynones have been known for nearly 40 years,5
Figure 1. Intramolecular 1,4-addition strategy.
we have found no examples of an intramolecular (6-endo-dig)
variant. Although 6-endo-dig ring closures are classified as favorable
Table 1. Optimization of Deprotection and Cyclization
transformations6 in aliphatic systems, very few examples exist with
first periodic row elements.7,8 We disclose herein the results of our
investigation of 6-endo-dig ring closures of a nonattenuated amine
into a pendant ynone.
Executing this enaminone formation strategy, as shown in Figure
1, relied upon production of amino-ynone intermediates. Such
substrates could be accessed via â-amino acids, providing both
diversity and asymmetry. Of particular interest to us was the mode
of intramolecular addition, several of which are possible (Figure
1, inset A-C).8,9
entry
i. deprotection
ii. cyclization
time
yielda
1
2
3
4
5
6
7
8
TFA, CH2Cl2
TFA, CH2Cl2
TFA, CH2Cl2
4 N HCl/dioxane
4 N HCl/dioxane
4 N HCl/dioxane
4 N HCl/dioxane
TMS-I, CH2Cl2
standard workupb
30
0
38
0
74
75
87
95
THF or CH2Cl2, K2CO3
CH2Cl2, H2O, K2CO3
THF or CH2Cl2, K2CO3
CH2Cl2, H2O, K2CO3
THF, H2O, K2CO3
MeOH, K2CO3
20 h
5 h
20 h
1 h
1 h
15 min
30 min
MeOH, K2CO3
a Isolated yield. b CH2Cl2/sat. aqueous NaHCO3 (1:1).
Because of the operational simplicity of the HCl protocol (entry
7, Table 1), this method was employed unless the gentler conditions
offered by TMS-I (entry 8) were desired.11 With both deprotection
methods, the cyclization environment was held constant (Table 2).
With ynones of undefined stereochemistry (compounds 4-8),
quinolizidine (15 and 16) and indolizidine (17-19) systems are
accessed in excellent yields. Terminally substituted ynones are well
tolerated, allowing installation of aliphatic and aromatic substituents
adjacent to the ring-fused nitrogen (15, 16, 18, 19, and 21). Using
stereodefined substrates (2, 9, 10, 13, and 14), as well as chiral but
racemic ynones (11 and 12), maintenance of asymmetry was
evaluated. The quinolizidine 3 and the pyridinones 2012 and 21 are
obtained in excellent yields with minimal, if any, loss of optical
purity.13 We next turned to ynone pairs with a built in preference
to convert to a more favorable diastereomer (11 and 12, 13 and
14). Both the racemic trans- and cis-fused quinolinones 22 and 23
can be accessed in excellent yields; however, some diastereomeric
interconversion is observed.14 The hydroxylated pyrrolidine ynones
13 and 14 formed the bicyclic indolizidine core in reasonable yields;
however, the stereogenic center adjacent to the amine is compro-
mised. As expected, the pyrrolidine ring with anti-substituents (13)
provided a diastereomeric ratio superior to that with the syn-
appendages (14). With careful addition of TMS-I (24 and 25,
method 2), this can be minimized, providing improved yields and,
more significantly, synthetically useful diastereomeric ratios.15
Two experimental observations were made which provided
insight into the reaction pathway. The first was that deprotection
reagents that incorporate a halogen counteranion (e.g., HCl or
TMS-I) improved reaction yields. Comparison of the crude amine
To test the feasibility of the reaction, we first targeted known
bicyclic enaminone 3 (eq 1).10 The requisite ynone (2) was generated
from the commercially available acid 1 via Weinreb amide
formation and subsequent addition of ethynylmagnesium bromide
(two steps, 81% yield).
A two-tier optimization of both amine deprotection and subse-
quent cyclization to convert 2 to 3 was next initiated. Early efforts
revealed that no enaminone formation occurred under the conditions
of acidic amine deprotection. However, when employing TFA to
remove Boc, followed by basic aqueous workup, the desired
enaminone (3) was formed (entry 1, Table 1), albeit in modest yield.
This indicated the desired product formed under the conditions of
basic workup. In attempts to optimize this transformation, the crude
TFA salt derived from deprotection (entry 2) was subjected to
anhydrous basic conditions, but formation of enaminone 3 was not
observed. Under these same conditions, with the addition of water,
the enaminone 3 was generated (entry 3), although the yield was
still unsatisfactory. When HCl was used in place of TFA, again,
no product was observed under anhydrous conditions (entry 4);
however, 3 was isolated in good yield and with short reaction times
with the addition of water (entries 5 and 6). Conditions found to
be optimal were employing either HCl or TMS-I to facilitate
deprotection and a solution of K2CO3 in methanol to promote
enaminone formation (entries 7 and 8, respectively).
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J. AM. CHEM. SOC. 2006, 128, 8702-8703
10.1021/ja0609046 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Ynone to Enaminone Conversion
addition-elimination pathway which is controlled by judicious
selection of deprotection reagent and reaction solvent. Further
investigations concerning the mechanism and synthetic utility of
this process are ongoing.
Acknowledgment. We thank the National Institutes of Health
for their generous support of our programs (NIH CA 90602 and
NIH GM069663). We thank Micah Niphakis for preparing 24 and
25 in Table 2 by method 2. B.J.T. was supported by the Department
of Defense breast cancer predoctoral fellowship (DAMD17-02-1-
0435).
Supporting Information Available: Representative experimental
procedures, characterization data for all new compounds, and spectra
for compounds 2, 4-19, 21-26, 29, and 30. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
(1) For recent reviews, see: (a) Negri, G.; Kascheres, C.; Kascheres, A. J. J.
Heterocycl. Chem. 2004, 41, 461-491. (b) Elassar, A.-Z. A.; El-Khair,
A. A. Tetrahedron 2003, 59, 8463-8480.
(2) (a) Michael, J. P.; De Koning, C. B.; Gravestock, D.; Hosken, G. D.;
Howard, A. S.; Jungmann, C. M.; Krause, R. W. M.; Parsons, A. S.; Pelly,
S. C.; Stanbury, T. V. Pure Appl. Chem. 1999, 71, 979-988. (b) Comins,
D. L. J. Heterocycl. Chem. 1999, 36, 1491-1500.
a Isolated yield. b All enaminones were prepared employing method 1
unless indicated by superscript b, in these cases, method 2 was used. Method
1: (a) 4 M HCl/dioxane, (b) MeOH, K2CO3. Method 2: (a) TMS-I,
CH2Cl2, -78 to 0 °C, (b) MeOH, K2CO3. c As determined by the following
method. d Chiral HPLC. e 1H NMR analysis of Mosher amide derivatives.
f 1H NMR.
(3) Cordell, G. A. The Alkaloids: Chemistry and Biology, 60; Elsevier:
Amsterdam, The Netherlands, 2003.
(4) For a scalemic example, see: (a) Slosse, P.; Hootele, C. Tetrahedron 1981,
37, 4287-4294. For examples in which an intermediate enaminone or
related structure is then converted to a bicycle, see: (b) refs 2a and 2b.
(c) Back, T. G.; Hamilton, M. D.; Lim, V. J. J.; Parvez, M. J. Org. Chem.
2005, 70, 967-972.
(5) Huisgen, R.; Herbig, K.; Siegl, A.; Huber, H. Chem. Ber. 1966, 99, 2526-
2545.
(6) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734-736.
(7) For attempts with oxygen nucleophiles, see: (a) Suzuki, K.; Nakata, T.
Org. Lett. 2002, 4, 2739-2741. (b) Dreessen, S.; Schabbert, S.; Schau-
mann, E. E. J. Org. Chem. 2001, 245-251.
(8) For a notable exception using carbon nucleophiles which inspired our
approach, see: Lavallee, J. F.; Berthiaume, G.; Deslongchamps, P.; Grein,
F. Tetrahedron Lett. 1986, 27, 5455-5458.
(9) Rudorf, W. D.; Schwarz, R. Synlett 1993, 369-374.
(10) Comins, D. L.; LaMunyon, D. H. J. Org. Chem. 1992, 57, 5807-5809.
(11) Olah, G. A.; Narang, S. C. Tetrahedron 1982, 38, 2225-2277.
(12) Comins, D. L.; Zhang, Y.; Joseph, S. P. Org. Lett. 1999, 1, 657-659.
(13) Retro-Michael and retro-Mannich-type processes have been reported
previously on â-amino ketones. For examples, see: (a) Slosse, P.; Hootele,
C. Tetrahedron 1981, 37, 4287-4294. (b) Morley, C.; Knight, D. W.;
Share, A. C. J. Chem. Soc., Perkin Trans. 1 1994, 2903-2907. (c)
Harrison, J. R.; O’Brien, P.; Porter, D. W.; Smith, N. M. J. Chem. Soc.,
Perkin Trans. 1 1999, 3623-3631.
Figure 2. Proposed enaminone formation pathway.
TFA and HCl salts revealed their marked difference in reactivity.
The TFA salt (26, Figure 2) clearly presented characteristics of
the intact ynone. The HCl salt, on the other hand, appeared as a
6:1 mixture of two compounds, the dichloroethane derivative 27
and the vinylogous acid chloride 28. The second observation was
that an oxygen nucleophile (MeOH or H2O) was necessary for
cyclization regardless of the deprotection method. Under the
prescribed reaction conditions, in an NMR tube, it was observed
that the mixture of 27 and 28 first converts to only 29 then to
enaminone 3. Although we have no direct evidence, the dependence
upon water or methanol may be explained by an addition-
(14) Diastereomeric conversion in these examples (22 and 23) may be explained
by simple enolization.
(15) Studies are underway to clearly determine how this protocol is able to
suppress the diastereomeric interconversion.
(16) Under anhydrous conditions or when a sterically demanding alcohol was
employed as solvent (e.g., s-BuOH), 29 was recovered and formation of
3 was not observed. An alternative pathway to 3, suggested by Professor
Barry M. Trost, involves addition of a carboxylate anion to 29 (eq 2).
The poor solubility of this nucleophile in s-BuOH or other anhydrous
solvents (THF or CH2Cl2) could account for these observations.
elimination sequence via intermediates i and ii (Figure 2).16
A
similar path can be envisaged from TFA ynone salt 26 via a
dimethyl acetal intermediate, bringing to light the dependency on
exogenous oxygen nucleophiles with both the TFA and HCl salts.17
In summary, we have developed a remarkably simple protocol
for preparing valuable synthetic intermediates that previously were
only obtainable in a circuitous fashion. Preliminary data in these
laboratories indicate that the proposed 6-endo-dig mode of cycliza-
tion does not occur. Instead, enaminone formation proceeds via an
(17) When ynone 2 was subjected to reaction conditions, near quantitative
conversion to 30 was observed (eq 3).
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