Oxidative cyclization of tertiary pentenol derivatives forming 2,5,5-trisubstituted THF rings and the total synthesis of cyclocapitelline

Article abstract of DOI:10.1016/j.tetlet.2015.09.064

The synthesis of 2,5,5-trisubstituted tetrahydrofuran rings was accomplished via the Mukaiyama aerobic oxidative cyclization of tertiary 5-pentenols employing the Co(nmp)₂ catalyst. A variety of THFs were formed in moderate to good yield and diastereoselectivity. The method developed herein was successfully applied to an enantioselective total synthesis of cyclocapitelline.

Full text of DOI:10.1016/j.tetlet.2015.09.064

Accepted Manuscript
Oxidative Cyclization of Tertiary Pentenol Derivatives Forming 2,5,5-trisub-
stituted THF Rings and the Total Synthesis of Cyclocapetalline
Geoffrey A. Phillips, Cory Palmer, Andrew C. Stevens, Mathew L. Piotrowski,
Daryl S.R. Dekruyf, Brian L. Pagenkopf
PII:
S0040-4039(15)30106-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.09.064
TETL 46736
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
23 July 2015
9 September 2015
16 September 2015
Please cite this article as: Phillips, G.A., Palmer, C., Stevens, A.C., Piotrowski, M.L., Dekruyf, D.S.R., Pagenkopf,
B.L., Oxidative Cyclization of Tertiary Pentenol Derivatives Forming 2,5,5-trisubstituted THF Rings and the Total
Synthesis of Cyclocapetalline, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.09.064
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1
Tetrahedron Letters
Oxidative Cyclization of Tertiary Pentenol Derivatives Forming 2,5,5-trisubstituted
THF Rings and the Total Synthesis of Cyclocapetalline
Geoffrey A. Phillips, Cory Palmer, Andrew C. Stevens, Mathew L. Piotrowski, Daryl S. R. Dekruyf, and
Brian L. Pagenkopf 
a The University of Western Ontario, Department of Chemistry, London, Ontario, N6G 5B7, Canada
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The synthesis of 2,5,5-trisubstituted tetrahydrofuran rings was accomplished via the Mukaiyama
aerobic oxidative cyclization of tertiary 5-pentenols employing the Co(nmp)2 catalyst. A variety
of THFs were formed in moderate to good yield and diastereoselectivity. The method developed
herein was successfully applied to an enantioselective total synthesis of cyclocapetalline.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Mukaiyama oxidative cyclization
Co(nmp)2
tetrahydrofuran
cyclocapitelline
cross metathesis
———
 Corresponding author. Tel.: +1-519-661-2111; fax: +1-519-661-3022; e-mail: bpagenko@uwo.ca

2
Tetrahedron Letters
1. Introduction
Previous work from our laboratory has explored the
synthesis of 2,5-trans-THF rings through the oxidative
cyclization of secondary pentenol derivatives7–10, with the best
results obtained utilizing our Co(nmp)2 catalyst.13 The expanded
substrate scope, improved yields, enhanced reactivity and
simplified workup procedure with the nmp catalyst prompted us
to explore the feasibility of extending the scope of the oxidative
cyclization to the synthesis of 2,5,5-trisubstituted THF rings.
The tetrahydrofuran (THF) ring system is a common motif
found in a wide variety of natural products with potent and varied
biological activity.1 Their prevalence has led to numerous
methods for the efficient and selective synthesis of THFs with
varying levels of substitution about the ring. Of the possible
substitution patterns, 2,5-disubstituted THFs have received the
most synthetic attention.2 The synthesis of the 2,5,5-
trisubstituted-THFs has seen considerably less attention, yet this
structure is found in a number of notable biologically active
compounds including boivinianin B, the ionophore ionomycin,
and the kalihinols, a large family of triterpenoids.3–5
2. Results and Discussion
Our initial investigations began with exploration of the
cyclization of tertiary pentenol 1 (Table 1), prepared by addition
of homoallylmagnesium bromide to acetophenone. Conditions
successfully employed for the cyclization of various secondary
pentenols proved ineffective when applied to tertiary pentenols
(entry 1).13 With elevation of the temperature only traces of
product were observed (entry 2). Previously we reported that pre-
oxidizing the catalyst prior to substrate introduction successfully
increased catalyst activity as well as reduced over oxidation by-
product.10b Mechanistic studies by Hartung have suggested that
substrates can interfere with oxidation of the Co(II) precatalyst to
the active Co(III) catalyst.14 Therefore, conditions were
established for the cyclization of tertiary pentenols using pre-
oxidized catalyst.
The Mukaiyama aerobic oxidative cyclization stands
apart as an effective synthetic tool for the synthesis of 2,5-trans-
THFs and has been successfully employed in synthetic studies
and total synthesis of natural products including asimilobin6,
bullatacin7, aplysiallene8, bovidic acid9, and amphidinolides C10
and F11. The catalytic Mukaiyama oxidative cyclization facilitates
the synthesis of THFs under mild reaction conditions, using
oxygen as the stoichiometric oxidant.12 The method produces the
desired THFs with excellent trans diastereoselectivity and
cyclization substrates can generally be accessed easily through
simple additions to aldehydes, ketones, and epoxides. The
primary alcohol formed in the cyclization also serves as a useful
handle for further synthetic transformations.
Table 1. Optimization of Cyclization Conditions
Entry
Catalyst loadinga (mol %)
Time (Temp)
Concentration
[M]
SM/pdt, % Mass Recovery
h (˚C)
1
2
10b
10b
15
16 (55)
16 (80)
16 (80)
16 (80)
16 (80)
16 (80)
16 (80)
16 (80)
16 (80)
16 (80)
24 (70)
16 (70)
16 (70)
16 (80)
16 (80)
16 (80)
16 (80)
0.13 i-PrOH
0.13 i-PrOH
0.13 i-PrOH
0.13 i-PrOH
0.25 i-PrOH
0.25 i-PrOH
2.0 i-PrOH
2.0 i-PrOH
1.0 i-PrOH
0.5 s-BuOH
0.5 s-BuOH
0.5 C6H6
Only S.M.
2.5/1.0, 72%
3
1.9/1.0, 76%
4
20
1.3/1.0, 69%
5
10
1.0/1.0, 77%
6
20
0.27/1.0, 81%
0.27/1.0, 79%
0.19/1.0, 80%
0.38/1.0, 75%
0.12/1.0, quant.
0.14/1.0, 88%
0.38/1.0, quant.
0.71/1.0, quant.
0.09/1.0, quant.
0.22/1.0, quant.
0.20/1.0, 84%
0.29/1.0, quant.
7
10
8
20
9
20
10
11
12
13
14
15
16
17
20
20
20
20
0.5 C2H4Cl2
0.5 s-BuOH
0.5 s-BuOH
0.5 s-BuOH
0.5 i-PrOH
30
15
17.5
15b
a Pre-activated catalyst was employed (see text).
b in-situ catalyst activation.

3
Pre-oxidation of the catalyst with tBuOOH under an
atmosphere of oxygen followed by solvent removal gave a green
solid. The cyclization substrate was then introduced and
subjected to the reaction conditions (entries 3-16). An increase in
the catalyst loading allowed for the isolation of product 1b
(entries 3-8) in modest yield with a high degree of mass recovery.
Lowering the concentration (entries 9-11) improved overall ratios
of product to starting material. An increase of the catalyst loading
to 30% gave excellent levels of conversion; however, we felt
such a loading to be impractical (entry 14). Overall, a catalyst
loading of 17.5% was found to provide good levels of conversion
to products along with an acceptable level of mass recovery
(entry 16). In comparison to the optimized conditions, in-situ
oxidation of the catalyst (entry 17) was less effective overall with
lower levels of conversion.
Table 2. Reaction Scopea
With optimized conditions at hand the substrate scope of the
reaction was explored (Table 2). The synthesis of the cyclization
substrates was carried out simply by Grignard additions to
ketones, aldehydes, or epoxides. The cyclization proved to be
tolerant of a wide range of tertiary pentenols providing products
in poor to moderate yields. The effect of sterics appears to be of
consequence in the cyclizations as substrates with less steric bulk
at the tertiary alcohol generally gave higher yields and better
diastereomeric ratios (entries 1-2 and 5-6). Greater steric bulk in
the proximity of the alcohol resulted in poorer levels of
conversion and lower yields, possibly due to interference in
catalyst coordination. THFs with differing electronics were also
synthesized with both electron rich and electron deficient
pentenols (entries 9-11) cyclizing with similar yields and levels
of diastereoselectivity. Elucidating the fate of unaccounted
material and the correspondingly poor mass recovery proved
elusive, and we have no supposition as to its whereabouts.
aYield in brackets based on recovered starting material
Confirmation of the relative orientation of the substituents at
the 2 and 5 positions of the THF products proved difficult, with
NOE analysis being inconclusive. We surmised that the major
diastereomeric component of the product mixtures corresponded
to a trans orientation of the substituents at the 2 and 5 positions
(vide infra).15
Having extended the use of the Co(nmp)2 catalyst to the
synthesis of 2,5,5-trisubstituted THFs we chose to apply the
method to the synthesis of cyclocapitelline (Figure 1.0) which
would affirm the predicted stereochemical assignments.16,17

4
Tetrahedron
Scheme 1. Completion of Cyclocapitelline.
Following comparison of the reported literature spectral data
for cyclocapitelline and its diastereomer, isocyclocapitelline, the
major diastereomer was found to correspond with
cyclocapitelline (24) with trans orientation at the 2 and 5
positions of the THF ring,15 whereas the minor diastereomer
corresponded to isocyclocapitelline. Confirmation of the relative
stereochemistry of the diastereomeric THFs confirmed our
previous hypothesis that the oxidative cyclization of tertiary
Figure 1. Cyclocapitelline
The synthetic effort began with the Sharpless
epoxidation of commercially available geraniol (13) providing
access to epoxide 14 (Scheme 1).18 After protection as a TBS
ether, cross metathesis reaction of 15 with ethylene gas gave
epoxy alkene 16 in 54% yield.19 An oxidative workup facilitated
easy removal of unreacted olefin 15. Epoxide opening was then
accomplished with L-Selectride providing access to oxidative
cyclization substrate 17. Oxidative cyclization was then carried
with Co(nmp)2 under the optimized conditions to yield THF
product 18 in 43% yield (52% BRSM) as a 3:1 mixture of
diastereomers, that were carried through the synthesis. Oxidation
of the primary alcohol of 18 with a TEMPO/BAIB oxidation
system followed by methylation of the resulting carboxylic acid
provided THF ester 19.20 The addition of two equivalents of
methylmagnesium bromide furnished the tertiary alcohol of the
natural product 20, a mild deprotection of the primary alcohol
with 10-CSA then afforded THF alcohol 21.
pentenols proceeds with
a preference for relative trans
stereochemistry of the larger substituents at the 2 and 5 positions.
3. Conclusion
2,5,5-Trisubstituted tetrahydrofurans were synthesized using
the modified Mukaiyama aerobic oxidative cyclization in
combination with our second generation nmp catalyst. The
method provides access to the desired trisubstituted THFs in
moderate to good yields over a broad range of substrates. The
methodology was also applied to the total synthesis of the natural
product cyclocapitelline and isocyclocapitelline.
4. Acknowledgements
Scheme 1. Synthesis of the Cyclocapitelline Core.
We thank the University of Western Ontario and the Natural
Sciences and Engineering Research Council of Canada for
financial assistance. We also thank Mr. Doug Hairsine (UWO)
for obtaining high-resolution mass spectrometry and Dr. Mathew
Willans (UWO) for NMR assistance. We thank UWO for
undergraduate research support (DSRD).
To complete the synthesis, the primary alcohol 21 was
oxidized under Parikh-Doering conditions to afford THF
aldehyde 22 (Scheme 2).21 The Pictet-Spengler reaction between
22 and tryptamine provided access to 23 as a complex mixture of
diastereomers. After careful purification, oxidation of the
tetrahydro-β-carboline 23 with Pd/C provided cyclocapitelline
(24) and isocyclocapitelline (25) in 17% yield over two steps as a
1.5:1 mixture of diastereomers.
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Graphical Abstract
Oxidative Cyclization of Tertiary Pentenol
Derivatives Forming 2,5,5-trisubstituted
THF Rings and the Total Synthesis of
Cyclocapetalline
Leave this area blank for abstract info.
Geoffrey A. Phillips, Cory Palmer, Andrew C. Stevens, Mathew L. Piotrowski, Daryl S. R. Dekruyf, and Brian
L. Pagenkopf*