Increased yields and simplified purification with a second-generation cobalt catalyst for the oxidative formation of trans-THF rings

Article abstract of DOI:10.1021/ol9023375

[Chemical Equation Presented] The synthesis of a second-generation cobalt catalyst for the formation of trans-THF products via the Mukalyama aerobic oxidative cycllzation is reported. Two procedures have been developed with the new water-soluble catalyst

Full text of DOI:10.1021/ol9023375

ORGANIC
LETTERS
2009
Vol. 11, No. 24
5614-5617
Increased Yields and Simplified
Purification with a Second-Generation
Cobalt Catalyst for the Oxidative
Formation of trans-THF Rings
Cory Palmer, Nicholas A. Morra, Andrew C. Stevens, Barbora Bajtos, Ben
P. Machin, and Brian L. Pagenkopf*
The UniVersity of Western Ontario, Department of Chemistry, London, Ontario, N6A 5B7
bpagenko@uwo.ca
Received October 9, 2009
ABSTRACT
The synthesis of a second-generation cobalt catalyst for the formation of trans-THF products via the Mukaiyama aerobic oxidative cyclization
is reported. Two procedures have been developed with the new water-soluble catalyst that give superior yields and greatly simplify purification
compared to the previous catalysts.
The ubiquitous nature of tetrahydrofuran (THF) rings in a wide
variety of biologically active natural products has inspired the
development of methods for their synthesis and derivatization.1
In particular, the ability to form 2,5-trans-THF rings in an
efficient and diastereoselective manner is essential for the
synthesis of many natural products displaying this structural
motif. Many methods have been utilized to access trans-THF
rings. However, some methods have poor yields or low
diastereoselectivities.2 The Mukaiyama aerobic oxidative cy-
clization is emerging as a powerful synthetic tool that uses
molecular oxygen as the stoichiometric oxidant to convert
pentenols to trans-THF rings (Scheme 1).3 The reaction has
been the subject of mechanistic investigations4 and has also
been utilized in total synthesis (Figure 1).5 Our research group
has applied this strategy in the total synthesis of aplysiallene6
and bullatacin.7 Herein, we report our success in the develop-
ment of a second-generation cobalt catalyst for the formation
(3) Inoki, S; Mukaiyama, T. Chem. Lett. 1990, 1, 67–70.
(4) (a) Pe´rez, B. M.; Schuch, D.; Hartung, J. Org. Biomol. Chem. 2008,
6, 3532–3541. (b) Schuch, D.; Fries, P.; Donges, M.; Pe´rez, B. M.; Hartung,
J. J. Am. Chem. Soc. 2009, 131, 12918–12920.
(5) (a) Wang, Z.-M.; Tian, S.-K. ; Shi, M. Tetrahedron Lett. 1999, 40,
997–980. (b) Tian, S.-K.; Wang, Z.-M.; Jiang, J.-K.; Shi, M. Tetrahedron:
Asymmetry 1999, 10, 2551–2562. (c) Wang, Z.-M.; Tian, S.-K.; Shi, M.
Tetrahedron: Asymmetry 1999, 10, 667–670. (d) Wang, Z.-M.; Tian, S.-
K.; Shi, M. Eur. J. Org. Chem. 2000, 2, 349–356. (e) Wang, Z.-M.; Tian,
S.-K.; Shi, M. Chirality 2000, 12, 581–587. (f) Evans, P. A.; Cui, J.;
Gharpure, S. J.; Polosukhin, A.; Zhang, H.-R. J. Am. Chem. Soc. 2003,
125, 14702–14703.
(1) (a) Bermejo, A.; Figadere, B.; Zafra-Polo, M.-C.; Barrachina, I.;
Estornell, E.; Cortes, D. Nat. Prod. Rep. 2005, 22, 269–303. (b) Kobayashi,
J.; Kubota, T. J. Nat. Prod. 2007, 70, 451–460. (c) Kobayashi, J. J. Antibiot.
2008, 61, 271–284.
(2) For reviews see: (a) Cardillo, G.; Orena, M. Tetrahedron 1990, 46,
3321–3408. (b) Wolfe, J. P.; Hay, M. B. Tetrahedron 2007, 63, 261–290.
(c) Li, N.; Shi, Z.; Tang, T.; Chen, J.; Li, X. Beilstein J. Org. Chem. 2008,
4.
(6) Wang, J.; Pagenkopf, B. L. Org. Lett. 2007, 9, 3703–3706.
(7) Zhao, H.; Gorman, J. S. T.; Pagenkopf, B. L. Org. Lett. 2006, 8,
4379–4382.
10.1021/ol9023375  2009 American Chemical Society
Published on Web 11/19/2009

of trans-THF rings that gives superior yields and greatly
simplifies purification when compared to the standard catalysts.
Scheme 1
.
Representative Mukaiyama Aerobic Oxidative
Cyclization
Figure 2. Commonly used modp (1) and piper (2) ligands and
water-soluble nmp (3).
of triethylamine, which proceeded in near quantitative yield
(Scheme 2). A significant loss of product was observed (ca.
Scheme 2. Synthesis of Co(nmp)2
50%) when the subsequent Claisen condensation of 4 with
pinacolone was subjected to a standard aqueous workup.7
Fortuitously, an alternative protonation method employing acetic
acid in CH2Cl2 followed by removal of the salts by filtration
afforded ligand 3 in 95% yield. Complexation of the nmp ligand
3 with Co(ethyl-2-hexanoate)2 in dry benzene was initially low
yielding, and the resulting purple-colored solid performed poorly
in subsequent cyclization reactions. Previously, we reported the
first X-ray structures of these types of catalysts that clearly
Figure 1. Natural products containing trans-THF rings synthesized
using the Mukaiyama oxidation.8
The Mukaiyama oxidation typically proceeds in good yield
and excellent diastereoselectivity (>99:1 dr); however, in some
cases, the catalyst was extraordinarily difficult to remove from
the desired THF product when the standard ligands 1 and 2
(Figure 2) were utilized.9 Furthermore, paramagnetic cobalt
residues interfere with NMR analysis, making characterization
of the cyclized product difficult or impossible. The difficulties
associated with purification detract from the synthetic advan-
tages of the catalyst. Thus, we set out to prepare a new catalyst
that retains high efficiency but also exhibits significantly
increased polarity. This and related strategies have seen great
success with EDC, water-soluble ligands, sulfonated phosphines,
fluorous phases, and ionic liquids.10 Using the well-established
modp ligand 1 as a template, it was envisioned that replacing
the neutral morpholine subunit with a basic N-methyl piperazine
(3, 5,5-dimethyl-1-(4-methylpiperazin-1-yl)hexane-1,2,4-trione,
henceforth nmp) might facilitate removal of the cobalt species
from the reaction mixture by a straightforward acidic extraction.
The synthesis of the nmp ligand commenced with reaction
of N-methyl piperazine with ethyl oxalyl chloride in the presence
Table 1. Initial Comparison of the Catalysts
yield (%)
starting
material
nmp
buffera
nmp
MeI
entry
n
modp
piper
1
2
3
6a
6b
6c
1
2
3
65
68
79
39
75
74
92
90
92
93
90
95
a pH 4 phosphate buffer.
(8) For aplysiallene, see ref 6. For bullatacin, see ref 7. For asimilobin,
see ref 5a. For mucocin, see ref 5f.
(9) See Supporting Information for photographs showing elution of
cobalt residues.
(10) (a) Sheehan, J. C.; Cruickshank, P. A.; Boshart, G. L. J. Org. Chem.
1961, 26, 2525–2528. (b) Herrmann, W. A.; Kulpe, J. A.; Konkol, W.;
Bahrmann, H. J. Organomet. Chem 1990, 389 (1), 85–101. (c) Water-soluble
ligands: Herrmann, W. A.; Herrmann, W. A.; Kohlpaintner, C. W. Angew.
Chem., Int. Ed. Engl. 1993, 32, 1524–1544. (d) Curran, D. P. Aldrichimica
Acta 2006, 39, 3–9.
showed adventitious water in the crystal structure.11 Complex-
ation in aqueous benzene provided Co(nmp)2 (5) as a tan-
(11) Wang, J.; Morra, N. A.; Zhao, H.; Gorman, J. S. T.; Lynch, V.;
McDonald, R.; Reichwein, J. F.; Pagenkopf, B. L. Can. J. Chem. 2009, 87,
328–334. The actual molecular formula is most likely
[{Co(nmp)3}2Co(H2O)6] but is represented as Co(nmp)2 for simplicity.
Org. Lett., Vol. 11, No. 24, 2009
5615

colored solid in 89% yield over three steps, using benchtop
centrifugation as the only method of purification to collect the
catalyst. Gratifyingly, the oxidation results with the Co(nmp)2
catalyst formed under aqueous conditions proved to be excep-
tional (vide infra).
Table 2. Effect of Catalyst Loadings on the Oxidation of 6b
To compare the new Co(nmp)2 catalyst to previous ones
(Co(modp)2 and Co(piper)2), a family of TBS-protected pentenol
derivatives that have proven to be reliable substrates in these
reactions were selected (Table 1). Encouragingly, these early
results with Co(nmp)2 demonstrated a remarkable improvement
in the overall yield of the oxidative cyclization process. These
new conditions also circumvent the undesired side reactions
leading to aldehydes and protocyclization products, typically
observed with traditional catalysts.4
entry
catalyst
mol %
yield (%)
1
2
3
4
5
6
7
8
Co(modp)2
Co(modp)2
Co(modp)2
Co(nmp)2
Co(nmp)2
Co(nmp)2
Co(nmp)2
Co(nmp)2
15
10
5
15
10
5
68
65
47a
95
97
93
3
1
57 (93)b
10 (77)b
With regards to product purification, it is important to note
that when using the Co(nmp)2 catalyst system complete removal
of the cobalt residues from the trans-THF products was
achieved easily with pH 4 phosphate buffer wash of the organic
layer. Anticipating the need for a neutral workup procedure to
remove the catalyst from more acid-sensitive substrates, the
a All starting material was consumed. b Yield based on recovered starting
material.
Table 3. Cyclization Precursors and Their Respective Cyclized Products
a Typical reaction conditions: cyclization precursor (1 equiv), Co(nmp)2 (10 mol %), tBuOOH (10 mol %), iPrOH (10 mL), O2 (1 atm), 55 °C. b Racemic
material. c Enantiomerically pure. d This yield is for a mixture of THF product contaminated with cobalt species that could not be removed after repeated
chromatography. Thus, the yield is artificially elevated. e See ref 6. f See ref 7.
5616
Org. Lett., Vol. 11, No. 24, 2009

tertiary amine was quaternized by treating the reaction mixture
with MeI under an argon atmosphere. The resulting salts are
highly water soluble and can be removed using a simple neutral
water extraction. The new Co(nmp)2 catalyst system facilitates
a mild and straightforward isolation and purification process,
and when coupled with the improved yields, it greatly enhances
the synthetic potential of this methodology.
The effect of catalyst loading on cyclization efficiency was
investigated (Table 2). The typical catalyst loading reported for
Co(modp)2 cyclizations is 10 mol %. In the oxidation of 6b
(Table 2), the yield did not improve significantly at higher
loading (entry 1), while with lower catalyst loading the yield
dropped significantly (entry 3). Gratifyingly, it was observed
that reactions using Co(nmp)2 proceeded efficiently with catalyst
loadings as low as 5 mol % (entries 4-6), while lower loadings
resulted in incomplete conversion (entries 7 and 8). It is
noteworthy that with Co(modp)2 at 5 mol % catalyst loading
byproduct formation becomes seriously competitive, but these
side reactions are not observed with catalyst loading as low as
3 mol % with the new Co(nmp)2 system (compare entries 3
with 6 and 7).
found to readily cyclize under the oxidation conditions.
Furthermore, aromatic substrates including phenyl, benzyl, and
cinnamic acid derivatives all gave favorable results (entries 6-9,
respectively). Finally, the compounds in entries 10 and 11 are
intermediates that were employed in the total synthesis of
aplysiallene6 and bullatacin,7 respectively, thus further illustrat-
ing the overall superiority and utility of this new catalyst for
natural product synthesis.
In summary, a second-generation catalyst for the Mu-
kaiyama oxidative cyclization is reported. The catalyst
preparation is straightforward at gram scale with centrifuga-
tion as the only means of purification. In all cases examined,
cyclization reactions using Co(nmp)2 have shown improved
yields and fewer side products. Most importantly, Co(nmp)2
has greatly simplified postreaction purification by replacing
difficult column chromatography with an aqueous workup.
We believe this new second-generation catalyst now clearly
stands among the best methods to prepare 2,5-disubstituted
trans-THF rings, and it is sure to find applications in total
synthesis.
Encouraged by the results with Co(nmp)2 in the initial
screening of TBS-protected pentenol derivatives, its perfor-
mance was compared against the standard cobalt catalysts with
a variety of additional substrates (Table 3). In all cases
examined, reactions run with the new Co(nmp)2 catalyst resulted
in an increased yield compared to the original catalyst. The polar
hydrophilic THF (entry 1) was impossible to separate from the
Co(modp)2 and Co(piper)2 catalyst residues even after repeated
column chromatography with different eluents. In contrast, after
in situ methylation of the Co(nmp)2 species, the THF product
was obtained in pure form in 85% yield after an aqueous
extraction. The results in entries 2 and 3 were equally satisfying,
and it is noteworthy that the oxidatively labile benzyl and
p-methoxyphenyl ether protecting groups survive the reaction
conditions.12 A symmetric pentadienol (entry 4), in addition to
sterically encumbered substrates (entries 5 and 6), was also
Acknowledgment. We thank the University of Western
Ontario and the National Sciences and Engineering Research
Counsil of Canada for financial asistance. N.M. (NSERC
CGS D) and B.B. (Vanier CGS) thank NSERC for their
graduate fellowships. We also thank James Russell Mac-
donald for experimental assistance.
Supporting Information Available: Experimental pro-
cedures and characterization of all new compounds and
copies of NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL9023375
(12) Previous studies in our laboratory have shown that PMB protective
groups are destructively cleaved under the conditions of the oxidative
cyclization.
Org. Lett., Vol. 11, No. 24, 2009
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