Multicomponent macrocyclization reactions (MCMRs) employing highly reactive acyl ketene and nitrile oxide intermediates

Article abstract of DOI:10.1021/ol202024a

An efficient synthesis of spiro-fused macrolactams by a multicomponent macrocyclization reaction (MCMR) is reported. The use of highly reactive, transient intermediates in this MCMR permits short reaction times, even at high dilution. The methods employed

Full text of DOI:10.1021/ol202024a

ORGANIC
LETTERS
2011
Vol. 13, No. 17
4732–4735
Multicomponent Macrocyclization
Reactions (MCMRs) Employing Highly
Reactive Acyl Ketene and Nitrile Oxide
Intermediates
John M. Knapp, James C. Fettinger, and Mark J. Kurth*
Department of Chemistry, University of California, Davis, 1 Shields Avenue, Davis,
California 95616, United States
mjkurth@ucdavis.edu
Received July 27, 2011
ABSTRACT
An efficient synthesis of spiro-fused macrolactams by a multicomponent macrocyclization reaction (MCMR) is reported. The use of highly
reactive, transient intermediates in this MCMR permits short reaction times, even at high dilution. The methods employed for this MCMR were first
developed as a four-component strategy for the synthesis of β-ketoamide isoxazolines and a new macrocyclization reaction is reported.
Macrocycles occur widely in nature and have important
applications in medicine, material science, and supra-
molecular chemistry.1 Their intrinsic three-dimensional
geometry isanalogoustotertiary protein structure, lending
to site-specific recognition, and macrocycles constitute
a unique class of privileged scaffold.1a,2 Despite the pro-
mise of macrocycles, they are under-exploited in libraries
for screening;3 one possible cause is the limited availabil-
ity of macrocycle diversification chemistry. An area of
study that begins to address this issue is macrocycle-
forming reactions involving the union of multiple reactive
components, pioneered in the laboratories of Zhu,4
Wessjohann,5 Severin,6 and Luis.7 Herein, we demon-
strate a unique multicomponent macrocyclization reaction
(MCMR), which derives from a new multicomponent
reaction (MCR).
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Chem.;Eur. J. 2008, 14, 8879–8891. (b) Alfonso, I.; Bolte, M.; Bru, M.;
Burguete, M. I.; Luis, S. V.; Rubio, J. J. Am. Chem. Soc. 2008, 130, 6137–
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r
10.1021/ol202024a
Published on Web 08/09/2011
2011 American Chemical Society

While acyl ketenes provide a powerful ring closing
strategy in the synthesis of macrocycles (the Boeckman
approach),8 we are unaware of any multicomponent reac-
tions forming macrocycles with this methodology. As
depicted in Scheme 1, we envisioned macrocyclization
by exploiting dioxinone 1 (Scheme 2a) or Meldrum’s acid
analog 11 (Scheme 2b; prepared by EDC coupling of a
carboxylic acid with Meldrum’s acid) as the acyl ketene
precursor. Importantly, we have found that the acyl
ketene’s high reactivity toward the amine reactant effec-
tively out-competes potential side reactions between the
amine and chlorooxime reactants.
Scheme 1. Multicomponent Macrocyclization Plan
Scheme 2. β-Ketoamide-based 4CRs
occurring by intramolecular condensation of a primary
amine with an acyl ketenes. The resulting macrolactam is
poised to condense with a formaldehyde equivalent, yield-
ing a methylene derivative that reacts as a dipolarophile in
a KHCO3-initiated nitrile oxide (from a chlorooxime) 1,3-
dipolar cycloaddition and would yield a spiro-fused
macrolactam product. This MCMR strategy could poten-
tially access a range of macrocycles that complement those
made with previously reported strategies.4ꢀ7
Spiro-heterocycles and isoxazolines are important bio-
relavent scaffolds that have been extensively used in the
synthesis of natural products.9 However, there are few
examples of MCRs leading to spirocyclic products10 and
none, to our knowledge, including a macrocyclization step.
Our long-standing interest in 1,3-dipolar cycloadditions
prompted development, reported herein, of the novel 4CR
summarized in Scheme 2.
MCRs are attractive because they enable formation of
complex structures while minimizing synthetic effort, re-
ducing synthesis length and optimizing atom economy.3b,11
This 4CR strategy (Scheme 2) allows, in principle, for the
incorporation of four independently variable components.
Both aryl- (e-donating, e-withdrawing, and heterocyclic)
and carboalkoxy functionalized nitrile oxides are toler-
ated. Aromatic and alky (1° or 2°) amines can be used in
the amide bond-forming step. The keto R-group (R =
CH3 or C6H4OCH3) in the final product is easily modified
(8) (a) Reber, K. P.; Tilley, S. D.; Sorensen, E. J. Chem. Soc. Rev.
2009, 38, 3022–3024. (b) Boeckman, R. K., Jr.; Perni, R. B. J. Org. Chem.
1986, 51, 5486–5489. (c) Boeckman, R. K., Jr.; Pruitt, J. R. J. Am. Chem.
Soc. 1989, 111, 8286–8288. (d) Hoye, T. R.; Danielson, M. E.; May,
A. E.; Zhao, H. Angew. Chem., Int. Ed. 2008, 47, 9743–9746. (e)
Henderson, J. A.; Phillips, A. J. Angew. Chem., Int. Ed. 2008, 47,
8499–8501. (f) Chen, C.; Quinn, E. K.; Olmstead, M. M.; Kurth, M. J.
J. Org. Chem. 1993, 58, 5011–5014.
(9) (a) Ichiba, T.; Scheuer, P. J.; Kelly-Borges, M. J. Org. Chem. 1993,
58, 4149–4150. (b) Lacy, C.; Scheuer, P. J. J. Nat. Prod. 2000, 63, 119–
121. (c) Nicholas, G. M.; Newton, G. L.; Fahey, R. C.; Bewley, C. A.
Org. Lett. 2001, 3, 1543–1545. (d) Bull, J. A.; Balskus, E. P.; Horan,
R. A. J.; Langner, M.; Ley, S. V. Chem.;Eur. J. 2007, 13, 5515–5538. (e)
Kozikowski, A. P. Acc. Chem. Res. 1984, 17, 410–416. (f) Jaeger, V.;
Grund, H.; Buss, V.; Schwab, W.; Mueller, I.; Schohe, R.; Franz, R.;
Ehrler, R. Bull. Soc. Chim. Bel. 1983, 92, 1039–1054.
(10) For example see: Liang, B.; Kalidindi, S.; Porco, J. A., Jr.;
Stephenson, C. R. J. Org. Lett. 2010, 12, 572–575.
(11) (a) Trost, B. M. Angew. Chem., Int. Ed. 1995, 34, 259–281. (b)
Noyori, R. Nat. Chem. 2009, 1, 5–6. (c) Bienayme, H.; Hulme, C.;
Oddon, G.; Schmitt, P. Chem.;Eur. J. 2000, 6, 3321–3329. (d) Posner,
G. H. Chem. Rev. 1986, 86, 831–844.
We also investigated a 3CR variant of this 4CR
employing commercial β-ketoamide 18 (Scheme 3a).
The yield of this 3CR was significantly improved over
the 4CRs in Scheme 2 (85% compared to yields of
36ꢀ50%). Attempts at using benzaldehyde in place of
Eschenmoser’s salt in this 3CR gave condensation pro-
duct 22 (19:1 undefined alkene selectivity) but no cy-
cloaddition to 23 (Scheme 3b). Condensation with
Eschenmoser’s salt delivers effective MCR dipolaro-
philes (Scheme 2), whereas the dipolarophile derived
Org. Lett., Vol. 13, No. 17, 2011
4733

Scheme 3. Beta-ketoamide 3CRs
Scheme 5. 12-Membered Macrocycle-forming Reactions
proceeds more cleanly than Cbz hydrogenolysis; that said,
both strategies accommodate the Meldrum’s acid moiety.
As with 28a, zwitterion 28b cyclizes in excellent yield (28b
f 29b in 92%). We speculate that zwitterions 28a and b
form an internal ion pair taking on geometries that resem-
ble the respective macrocyclic products. This preorganiza-
tion perhaps aids ring closure, explaining in part these
high macrocyclization yields. Additionally, deprotonated
Meldrum’s acids are reported to be thermally stable13
and decomposition of 28a and 28b occurs at >180 °C
and >220 °C, respectively. However, in solution, proton
transfer presumably occurs allowing for effective cyclo-
reversion. We are unaware of any examples of 5-acyl
Meldrum’s acid-based macrolactamizations.12
from benzaldehyde (e.g., 22) fails to yield the multi-
component product.
Having thus established these 3 and 4CR, we next
investigated the corresponding MCMR. Intermediates
28aꢀc (Scheme 4) were prepared by opening anhydride
25withcarbamate-protected amino-alcohol24a (P = Cbz)
or diamines 24b/c (P = Boc) to give 26aꢀc. Meldrum’s
acid was next coupled to these carboxylic acids using
EDC. Attempts at macrocyclization from 27a gave
hydrolyzed [e.g., ∼C(dO)CH2CO2H] then decarboxy-
lated [e.g., ∼C(dO)CH3] product, even with rigorous
drying as analogously reported by Hoye.8d Removal of
the nitrogen protecting group in 27aꢀc delivers zwit-
terions 28aꢀc, which we hoped would avoid hydrolysis/
decarboxylation problems.
Our MCMR results are delineated in Scheme 6. Most
macrocyclizations must be carried out under high dilu-
tion or with slow addition of a reactant/reagent to avoid
Scheme 6. Four Related MCMRs
Scheme 4. Synthesis of Macrocycle Precursors 24aꢀc
With 28a in hand, we addressed the challenge of forming
a large ring from a 5-acyl Meldrum’s acid/amine-based
precursor12 with minimal conformational bias toward
cyclization (Scheme 5). We were pleased to find that
macrocyclization 28a f 29a proceeded in excellent yield
(94%) portraying the MCMR potential of this ring closing
strategy. We explored both Cbz and Boc protecting group
strategies and found that Boc deprotection with SnCl4
4734
Org. Lett., Vol. 13, No. 17, 2011

4CRs depicted in Scheme 2 (36ꢀ50%) and comparable
to the 3CR yield reported in Scheme 3 (85%).
With the potential for two regioisomers in the 1,3-
dipolar cycloaddition, the selectivity of these nitrile oxide
cycloadditions were confirmed by X-ray crystallographic
analysis (Figure 1). The products depicted in Schemes 2, 3,
and 6 are the only regioisomers observed.
The presumed MCMR sequence of events from
Meldrum’s acid analog 28a (Scheme 7) begins with a
proton transfer step to 28a0 as the literature suggests that
deprotonated 5-acyl Meldrum’s acids will not form an acyl
ketene.13 Thermal cycloreversion of 28a0 forms the acyl
ketene, whichsubsequently condenses with the ω-1°-amine.
The amide-enol form of the β-ketoamide then condenses
with Eschenmoser’s salt to give the unsaturated ketoamide,
allowing for a sequence-ending 1,3-dipolar cycloaddition.
Figure 1. Crystal structures of (a) 3CR 20 and (b) MCMR 30.
Scheme 7. Proposed MCMR Sequence to a Spiro-fused
Macrocycle
bimolecular or oligomerization reactions.14 In contrast,
MCRs are often carried out at high concentration to
overcome entropic barriers.11c,d,15 This portends a fun-
damental dichotomy when incorporating a macrocycli-
zation within an MCR. In fact, our MCMR addresses
this issue by employing highly reactive intermediates, for
example, transient acyl ketene and nitrile oxide species ꢀ
at concentrations of 0.012 M. The reactive acyl ketene
intermediate enables the MCMR to proceed effectively
at this concentration, while still proceeding within a
short reaction time. This methodology further benefits
from microwave-assisted conditions.16 Collectively, the
MCMRs depicted in Scheme 6 show the facile formation
of spiro-fused macrolactam products with 12- and 14-
membered ring macrocycles and considerable structural
diversity. We also note that the yields are very good
(70ꢀ74%);indeed, much better than the yields of the
These results constitute a new MCMR protocol result-
ing in a facile route to spiro-fused macrolactams wherein
macrolactamization and a new multicomponent reaction
have been successfully cojoined in a single transformation.
Entropic barriers are overcome at dilutions of 0.012 M and
reaction times are reduced by using highly reactive, tran-
sient intermediates.
(12) Macrolactamization reactions from dioxolinone-derived acyl-
ketenes have been well documented by Boeckman and others.8 In
contrast, macrolactamization reactions of 5-acyl Meldrum’s acids are,
to our knowledge, absent in the literature and there are no examples of
zwitterionic species like 28a/b forming large rings
(13) Raillard, S. P.; Chen, W.; Sullivan, E.; Bajjalieh, W.; Bhandari,
A.; Baer, T. A. J. Comb. Chem. 2002, 4, 470–474.
Acknowledgment. We thank the National Science
Foundation (CHE-0910870) and the National Institutes
of Health (GM089153) for generous financial support.
(14) (a) Roxburgh, C. J. Tetrahedron. 1995, 51, 9767–9822. (b)
Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446–
452. (c) Furstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012–3043.
(15) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.;
Keating, T. A. Acc. Chem. Res. 1996, 29, 123–131.
(16) (a) Kappe, C. O. Chem. Soc. Rev. 2008, 37, 1127–1139. (b)
Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250–6284.
Supporting Information Available. Full experimental
details and characterization data (1H NMR, 13C NMR,
IR, ESI-MS and m.p.) for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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