Multicomponent approach to the synthesis of oxidized amides through nitrile hydrozirconation

Article abstract of DOI:10.1021/ol702184n

"Oxidized" amides, as represented by acyl aminals and acyl hemiaminals, are integral subunits of several natural products that exhibit useful biological activity. In this paper a multicomponent approach to these groups from acylimine intermediates is demonstrated. The acylimines are accessed through a sequence of nitrile hydrozirconation and acylation, making this highly versatile amide synthesis useful for a range of applications in target- and diversity-oriented synthesis.

Full text of DOI:10.1021/ol702184n

ORGANIC
LETTERS
2007
Vol. 9, No. 26
5385-5388
Multicomponent Approach to the
Synthesis of Oxidized Amides through
Nitrile Hydrozirconation
Shuangyi Wan, Michael E. Green, Jung-Hyun Park, and Paul E. Floreancig*
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
florean@pitt.edu
Received September 5, 2007
ABSTRACT
“Oxidized” amides, as represented by acyl aminals and acyl hemiaminals, are integral subunits of several natural products that exhibit useful
biological activity. In this paper a multicomponent approach to these groups from acylimine intermediates is demonstrated. The acylimines
are accessed through a sequence of nitrile hydrozirconation and acylation, making this highly versatile amide synthesis useful for a range of
applications in target- and diversity-oriented synthesis.
Natural products that contain “oxidized” amides, in which
the carbon bonded to the nitrogen atom has an oxidation
state that is higher than the usual (+1) level, effect
an impressive range of biological responses. These com-
pounds are represented acyl hemiaminals such as the
cytotoxins zampanolide1 (1) and tallysomycin,2 and acyl
(1) Tanaka, J.; Higa, T. Tetrahedron Lett. 1996, 37, 5535.
(2) Konishi, M.; Saito, K.; Numata, K.; Tsuno, T.; Asama, K.; Tsukiura,
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(3) (a) Pettit, G. R.; Xu, J.; Chapuis, J.; Pettit, R. K.; Tackett, L. P.;
Doubek, D. L.; Hooper, J. N. A.; Schmidt, J. M. J. Med. Chem. 2004, 47,
Figure 1. Natural products that contain oxidized amides.
1149. (b) Cichewicz, R. H.; Valeriote, F. A.; Crews, P. Org. Lett. 2004, 6,
1951.
(4) (a) Cardani, C.; Ghiringhelli, D.; Mondelli, R.; Quilico, A. Tetra-
hedron Lett. 1965, 2537. (b) Matsumoto, T.; Yanagiya, M.; Maeno, S.;
aminals such as the protein synthesis inhibitors psymberin
Yasuda, S. Tetrahedron Lett. 1968, 6297.
(2)3 and pederin.4 These compounds have evoked substantial
synthetic efforts, and several approaches to the synthesis of
the oxidized amide groups5 and natural product total
syntheses6 have been disclosed. SAR studies have demon-
strated that oxidized amides are important for the biological
activities of these natural products.7 While these groups have
been proposed to serve as latent acyliminium ions8 only one
(5) Representative examples: (a) Bayer, A.; Maier, M. E. Tetrahedron
2004, 60, 6665. (b) Hoye, T. R.; Hu, M. J. Am. Chem. Soc. 2003, 125,
9576. (c) Troast, D. M.; Porco, J. A., Jr. Org. Lett. 2002, 4, 991. (d) Rech,
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R. W .; Schlapbach, A. Tetrahedron Lett. 1993, 34, 7903. (h) Kocienski,
P.; Jarowicki, K.; Marczak, S. Synthesis 1991, 1191.
(6) Representative examples: (a) Smith, A. B., III; Safonov, I. G.;
Corbett, R. M. J. Am. Chem. Soc. 2002, 124, 11102. (b) Jiang, X.; Garcia-
Fortanet, J.; De Brabander, J. K. J. Am. Chem. Soc. 2005, 127, 11254. (c)
Shangguan, N.; Kiren, S.; Williams, L. J. Org. Lett. 2007, 9, 1093. (d)
Jewett, J. C.; Rawal, V. H. Angew. Chem., Int. Ed. 2007, 46, 6502.
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J. Chem. Soc., Perkin Trans. I 1994, 1025. (b) Petri, A. F.; Sasse, F.; Maier,
M. E. Eur. J. Org. Chem. 2005, 1865.
10.1021/ol702184n CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/17/2007

report9 has appeared in the literature that compellingly
establishes protein alkylation through Schiff base formation
from an enamide, another important class of oxidized amide.
In addition to their roles in conferring biological activity,
acyl aminals have been used as latent electrophiles in
stereoselective carbon-carbon bond-forming reactions.10
Scheme 2. Acylimine Formation through Nitrile
Hydrometalation and Acylation
In principle oxidized amide groups can be prepared from
acylimine intermediates (Scheme 1), with acyl aminals being
workers have reported16 that treating sterically hindered
nitriles with Schwartz’ reagent (Cp2Zr(H)Cl)17 followed by
adding sterically hindered acid chlorides yields isolable
acylimines.18 In this paper we demonstrate that the sequence
of nitrile hydrozirconation, acylation, and nucleophile ad-
dition results in a versatile multicomponent approach to
oxidized amides.
Scheme 1. Oxidized Amides from Acylimines
In our initial foray into this method (Scheme 3), we
Scheme 3. Acyl Aminal Formation through Nitrile
Hydrozirconation and Stereochemical Assignment through
Chemical Correlation
accessed through alcohol addition11 and acyl hemiaminals
being accessed through water addition. Additionally, ena-
mides could be accessed through tautomerization. This
strategy is limited, however, by the dearth of methods for
preparing acylimines. Condensation reactions between al-
dehydes and amides are ineffective when the aldehyde is
enolizable. While this problem can be addressed by adding
sulfonates to form R-sulfonyl amides,12 regenerating and
isolating the acylimine is difficult (though not impossible)13
because of the sensitivity of the intermediates.
In consideration of our interests in the synthesis of 1, 2,
and related structures14 we sought to develop a universal
approach to acylimine construction from easily handled
precursors and to establish conditions for the preparation of
each class of oxidized amide. Acylating metalloimines15 is
an attractive approach to acylimine formation (Scheme 2).
This route can be executed by preparing metalloimines from
selective nitrile hydrometalation followed by acid chloride
addition. Given the abundant reactions that have been
developed for nitrile synthesis and the relatively inert nature
of nitriles (compared to other electrophilic groups) to most
reaction conditions, this strategy should be useful in the
synthesis of complex natural products. Majoral and co-
exposed cyanohydrin ether 3, prepared through a BiBr3-
mediated addition of TMSCN to the corresponding dimethyl
acetal,19 to hydrozirconation, acylation with PhOC(O)Cl, and
MeOH addition. Diastereomers 4 and 5 were isolated from
the reaction in a 55% combined isolated yield and with a
diastereomeric ratio of 2.4:1. This reaction is consistent with
the formation of linear18a metalloimine 6, which can undergo
acylation to provide an acylimine intermediate. Nucleophilic
addition of MeOH can proceed through intermediate 7, in
which chelation is enforced through hydrogen bonding with
MeOH to form major product 4 or through Felkin-type
intermediate 8 to form minor product 5. The stereochemical
(8) (a) Hong, C. Y.; Kishi, Y. J. Org. Chem. 1990, 55, 4242. (b) Gentle,
C. A.; Bugg, T. D. H. J. Chem. Soc., Perkin Trans. 1 1999, 1279.
(9) Xie, X. S.; Pardon, D.; Liao, X. B.; Wang, J.; Roth, M. G.; De
Brabander, J. K. J. Biol. Chem. 2004, 279, 19755.
(10) Sugiura, M.; Hagio, H.; Hirabayashi, R.; Kobayashi, S. J. Am. Chem.
Soc. 2001, 123, 12510.
(11) (a) Rowland, G. B.; Zhang, H.; Rowland, E. B.; Chennamadhavuni,
S.; Wang, Y.; Antilla, J. C. J. Am. Chem. Soc. 2005, 127, 15696. (b) Huang,
X.; Shao, N.; Palani, A.; Aslanian, R. Tetrahedron Lett. 2007, 48, 1967.
(12) Kanazawa, A. M.; Denis, J. N.; Greene, A. E. J. Org. Chem. 1994,
59, 1238.
(16) Maraval, A.; Igau, A.; Donnadieu, B.; Majoral, J. P. Eur. J. Org.
Chem. 2003, 385.
(17) (a) Hart, D. W.; Schwartz, J. J. Am. Chem. Soc. 1974, 96, 8115. (b)
Buchwald, S. L.; LaMaire, S. J.; Nielsen, R. B.; Watson, B. T.; King, S.
M. Tetrahedron Lett. 1987, 28, 3895. (c) Hunag, Z.; Negishi, E.-i. Org.
Lett. 2006, 8, 3675.
(13) Song, J.; Wang, Y.; Deng, L. J. Am. Chem. Soc. 2006, 128, 6048.
(14) (a) Aubele, D. L.; Wan, S.; Floreancig, P. E. Angew. Chem., Int.
Ed. 2005, 44, 3485. (b) Rech, J. C.; Floreancig, P. E. Org. Lett. 2005, 7,
4117.
(15) (a) Savarin, C. G.; Boice, G. N.; Murry, J. A.; Corley, E.; DiMichele,
L.; Hughes, D. Org. Lett. 2006, 8, 3903. (b) Fleming, F. F.; Wei, G.; Zhang,
Z.; Steward, O. W. Org. Lett. 2006, 8, 4903.
(18) For other examples of nitrile hydrozirconation, see: (a) Erker, G.;
Fro¨mberg, W.; Atwood, J. L.; Hunter, W. E. Angew. Chem., Int. Ed. 1984,
23, 68. (b) Fro¨mberg, W.; Erker, G. J. Organomet. Chem. 1985, 280, 343.
(c) Anbhaikar, N. B.; Herold, M.; Liotta, D. C. Heterocycles 2004, 62,
217.
(19) Komatsu, N.; Uda, M.; Suzuki, H.; Takahashi, T.; Domae, T.; Wada,
M. Tetrahedron Lett. 1997, 38, 7215.
5386
Org. Lett., Vol. 9, No. 26, 2007

assignments for 4 and 5 were established through subjecting
9, prepared as a single stereoisomer, to a Curtius rearrange-
ment20 and observing the formation of 5 as the sole product.
With the initial reactivity patterns established, we turned
our attention to studying the scope of the process (Table 1).
minutes and the MeOH addition is instantaneous. Chelation
control can be improved (dr ) 5.7:1) without sacrificing yield
by adding a stoichiometric amount of Mg(ClO4)2 following
the acylation step and conducting the MeOH addition at
-78 °C (entry 3). Notably, the MeOH addition reaction is
still instantaneous at -78 °C. Metalloimine acylation with
R-methoxy acetyl chloride provides an acyl aminal (entry
4) that is electronically similar to the acyl aminal in
psymberin. A readily cleaved carbamate can be accessed
through acylation with CbzCl (entry 5). Unfortunately
sulfonyl aminals could not be prepared in high yields, as
shown in entry 6, with substantial amounts of the aldehyde
that results from direct nitrile reduction and hydration being
isolated.
Table 1. Nucleophile and Electrophile Scope in Acyl Aminal
Synthesisa
Nucleophiles other than MeOH also proved to be suitable
for the reaction. Steric hindrance does not suppress nucleo-
philic addition, as demonstrated by the reaction with tBuOH
(entry 7), though the major product results from the Felkin-
type pathway. Phenol (entry 8) and thiophenol (entry 9) are
also suitable nucleophiles, with phenol reacting through the
chelation pathway and thiophenol reacting through the
Felkin-type pathway, consistent with their relative abilities
to engage in hydrogen bonding. In addition to the capacity
to reverse the stereochemical outcome of the addition
reaction, entry 9 represents an excellent method to prepare
latent acyliminium ions that can be revealed through oxida-
tion.22
Structural variations in the nitrile component are also
tolerated (Table 2). Benzoylated cyanohydrin 19 can be
Table 2. Nucleophile and Electrophile Scope in Acyl Aminal
Synthesisa
a Representative procedure: Cp2Zr(H)Cl (1.2 equiv) was added to a
solution of the substrate in the solvent (0.1 M). The mixture was stirred for
10 min at rt, then was cooled to 0 °C. The electrophile (1.2-1.5 equiv)
was added and the solution was stirred for 10 min. The nucleophile (20
equiv) was added and the reaction was stirred for a few additional minutes.
b Yields refer to the sum of the yields of the diastereomers. c Nucleophilic
addition was conducted at -78 °C.
Ethoxy nitrile 10 served as the substrate for the initial phases
of this study. When isobutyroyl chloride is used for the
acylation reaction, both CH2Cl2 (entry 1) and THF (entry 2)
can be employed as reaction solvents. Interestingly, a modest
change in stereoselectivity occurs when the solvent is
changed from CH2Cl2 to THF whereby the major product
in CH2Cl2 results from chelation control and the major
product in THF results from Felkin-type addition.21 The
capacity of THF to form hydrogen bonds with MeOH is
likely the souce of diminished chelation control. For reactions
that are conducted in CH2Cl2, the entire process can be
executed in approximately 30 min since the hydrozirconation
and acylation steps proceed to completion within a few
a See Table 1 for representative procedures. b Stereochemical relationships
for the major and minor product diastereomers were not determined.
converted to acyl aminal 20 in 64% yield (entry 1),
demonstrating that hydrozirconation can be selective for
nitriles in the presence of ester groups.23 In consideration of
(22) Sugawara, M.; Mori, K.; Yoshida, J.-i. Electrochim. Acta 1997, 42,
1995.
(23) For an overview of the chemoselectivity patterns of Schwartz’
reagent, see: Wipf, P.; Jahn, H. Tetrahedron 1996, 52, 12853.
(20) Ninomiya, K.; Shioiri, T.; Yamada, S. Tetrahedron 1974, 30, 2151.
(21) Stereochemical assignments were based on analogy to 5 and 6
through the remarkably consistent coupling constant patterns in H NMR.
1
Org. Lett., Vol. 9, No. 26, 2007
5387

the acyl hemiaminal in zampanolide, we simply subjected
the acylimine from the hydrozirconation of 19 to a direct
aqueous workup and isolated acyl hemiaminal 21 in 54%
yield (entry 2). The stereochemical outcomes of the products
from 19 were not determined. Nitriles that are not branched
at the R-position can serve as substrates for the sequence,
though THF is a superior solvent for inhibiting acylimine
tautomerization and subsequent oligomerization. Octyl cya-
nide can be converted to acyl aminal 23 and acyl hemiaminal
24 in yields that are only modestly lower than those that are
observed for branched substrates (entries 3 and 4). Aromatic
nitriles, while undergoing hydrozirconation substantially
more slowly than aliphatic nitriles, are excellent substrates,
with acyl aminal 26 being formed in 73% yield.
and MeOH addition in the presence of Mg(ClO4)2 provided
acyl aminal 30 in 54% yield, diastereomer 31 in 23% yield,
and a small amount (∼10%) of the amide that arises from
reduction of the intermediate acylimine with the slight excess
of Schwartz’ reagent that is used in these reactions. Stere-
1
ochemical assignments were based on H NMR splitting
pattern and chemical shift analogies to known compounds25
in the pederin/psymberin family. While chelation-controlled
addition could not be promoted to the same extent as was
observed for 10, the high overall chemical yield and
reasonable stereocontrol provide the desired acyl aminal with
the desired stereochemical orientation efficiently and with
the potential for extensive structural variation. Also notable
in this transformation was the absence of epimerization at
the carbon that bears the cyano group, indicating that these
conditions do not erode the stereochemical purity of cyano-
hydrin ethers.
To apply this process in a more complex setting that is
relevant to the synthesis of psymberin, pederin, and ana-
logues, we prepared (Scheme 4) nitrile 29 from the known14b
We have described a one-pot multicomponent approach
to the synthesis of oxidized amides from nitriles. In
consideration of the numerous methods that are available
for nitrile preparation, the capacity for variation of the
nucleophile, electrophile, and nitrile components, the inherent
utility of the products as subunits of numerous biologically
active compounds, and the ability to employ the products as
starting materials in stereoselective transformations, this
process is well-suited for applications in target- and diversity-
oriented26 synthesis.
Scheme 4. Synthesis of a Tetrahydropyranyl Acyl Aminal
Acknowledgment. We thank the National Institutes of
Health (GM-62924 and P50-GM067082) and the National
Science Foundation (CHE-0139851) for generous financial
support of this work. M.E.G. was supported through a
Novartis Graduate Fellowship. We thank Ms. Sarah Russick
and Ms. Liz Dotzel (University of Pittsburgh) for assisance
with the early stages of this project.
ketone 27 through a sequence that employs a Lewis acid-
promoted reduction with Bu3SnH24 to establish relative
stereocontrol to provide 28. Interestingly, the stereochemical
outcome of this reaction does not follow from the chelation-
control that is generally observed24 in this procedure.
Tetrahydropyran formation through a sequence of ozonolytic
alkene cleavage, acylation, and cyanide introduction yielded
29. Hydrozirconation, acylation with isobutyroyl chloride,
Supporting Information Available: Experimental pro-
cedures for all reactions and characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL702184N
(25) Jiang, X.; Williams, N.; De Brabander, J. K. Org. Lett. 2007, 9,
(24) Evans, D. A.; Allison, B. D.; Yang, M. G.; Masse, C. E. J. Am.
Chem. Soc. 2001, 123, 10840.
227.
(26) Schreiber, S. L. Science 2000, 287, 1964.
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Org. Lett., Vol. 9, No. 26, 2007