Tandem intramolecular Nicholas and Pauson - Khand reactions for the synthesis of tricyclic oxygen-containing heterocycles

Article abstract of DOI:10.1021/ol0479141

(Chemical Equation Presented) Simple acyclic enynes can be easily converted into tricyclic ethers upon treatment with Co₂(CO)₈ followed by Nicholas and Pauson - Khand reactions. Tricyclic [5,8,5]- and [5,7,5]-systems can be prepared in high overall yields in only seven synthetic steps.

Full text of DOI:10.1021/ol0479141

ORGANIC
LETTERS
2004
Vol. 6, No. 26
4949-4952
Tandem Intramolecular Nicholas and
Pauson Khand Reactions for the
−
Synthesis of Tricyclic
Oxygen-Containing Heterocycles
Miriam M. Quintal, Kristina D. Closser, and Kevin M. Shea*
Department of Chemistry, Smith College, Northampton, Massachusetts 01063
kshea@smith.edu
Received October 8, 2004
ABSTRACT
Simple acyclic enynes can be easily converted into tricyclic ethers upon treatment with Co2(CO)8 followed by Nicholas and Pauson
−Khand
reactions. Tricyclic [5,8,5]- and [5,7,5]-systems can be prepared in high overall yields in only seven synthetic steps.
The Nicholas and Pauson-Khand reactions are among the
most important transformations that incorporate cobalt-
complexed alkynes.1 The Nicholas reaction enables nucleo-
philic substitution of propargyl alcohols, ethers, and esters,
usually with carbon nucleophiles.2 The Pauson-Khand
reaction furnishes cyclopentenones upon combination of
alkenes and cobalt-complexed alkynes either inter- or intra-
molecularly.3
Although both transformations incorporate dicobalt hexa-
carbonyl complexed alkynes, surprisingly little is known
about sequential combinations of these two reactions. Several
groups have studied intermolecular Nicholas reactions fol-
lowed by intramolecular Pauson-Khand reactions to yield
bicyclic products;4 however, only Schreiber has investigated
a transformation that involves both intramolecular Nicholas
and Pauson-Khand reactions to furnish a tricyclic ring
system.5 This was the first report of a successful endocyclic
intramolecular Nicholas cyclization to yield a cobalt-com-
plexed cyclic alkyne.6 Using knowledge gained from this
pioneering model study, Schreiber then applied the strategy
in a total synthesis of epoxydictymene.7 It is important to
note that the Nicholas reactions in these studies involved
use of allylsilane nucleophiles to furnish carbocyclic rings.
The goal of our research is to expand the scope of the
tandem intramolecular Nicholas/Pauson-Khand strategy to
include the synthesis of a variety of tricyclic heterocycles.
We plan to study the use of heteroatom nucleophiles in the
endocyclic Nicholas reaction, and we envision producing
several differently sized tricyclic ring systems. Our current
investigation demonstrates that this strategy is a powerful
method for quickly accessing complex [5,8,5]- and [5,7,5]-
tricyclic ethers that are otherwise not easily available.
(4) (a) Jeong, N.; Yoo, S.; Lee, S. J.; Lee, S. H.; Chung, Y. K.
Tetrahedron Lett. 1991, 32, 2137. (b) Smit, W. A.; Buhanjuk, S. M.;
Simonyan, S. O.; Shashkov, A. S.; Struchkov, Y. T.; Yanovsky, A. I.; Caple,
R.; Gybin, A. S.; Anderson, L. G.; Whiteford, J. A. Tetrahedron Lett. 1991,
32, 2105.
(5) Schreiber, S. L.; Sammakia, T.; Crowe, W. E. J. Am. Chem. Soc.
1986, 108, 3128.
(6) For a review of recent syntheses of cyclic cobalt-complexed alkynes,
see: Green, J. R. Curr. Org. Chem. 2001, 5, 809.
(7) (a) Jamison, T. F.; Shambayati, S.; Crowe, W. E.; Schreiber, S. L. J.
Am. Chem. Soc. 1997, 119, 4353. (b) Jamison, T. F.; Shambayati, S.; Crowe,
W. E.; Schreiber, S. L. J. Am. Chem. Soc. 1994, 116, 5505.
(1) For a review of cobalt mediated cyclizations, see: Fletcher, A. J.;
Christie, D. R. J. Chem. Soc., Perkin Trans. 1 2000, 1657.
(2) For reviews, see: (a) Teobald, B. J. Tetrahedron 2002, 58, 4133.
(b) Caffyn, A. J. M.; Nicholas, K. M. In ComprehensiVe Organometallic
Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.;
Pergamon: Kidlington, 1995; Vol. 12, p 685.
(3) For reviews, see: (a) Brummond, K. M.; Kent, J. L. Tetrahedron
2000, 56, 3263. (b) Schore, N. E. In ComprehensiVe Organometallic
Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.;
Pergamon: Kidlington, 1995; Vol. 12, p 703.
10.1021/ol0479141 CCC: $27.50
© 2004 American Chemical Society
Published on Web 11/18/2004

Our general synthetic outline for this study is presented
in Scheme 1. We plan to convert enyne 1 into tricyclic
heterocycle 4 by way of a three-step sequence involving a
cobalt complexation (to provide 2), a Nicholas reaction (to
furnish 3), and a Pauson-Khand reaction. This route should
enable the conversion of a relatively simple starting material
(1) into a complex tricyclic heterocycle containing two
stereogenic centers (4). One key advantage of this strategy
is that it should provide Pauson-Khand products such as 4
without the formation of a true cyclic alkyne. Most standard
syntheses of 4 via the Pauson-Khand reaction would require
a cyclic alkyne synthetic intermediate that would be chal-
lenging or impossible to synthesize. Cobalt-complexed cyclic
alkynes such as 3 are much easier to prepare8 and should
perform well in the key Pauson-Khand step.
hydride, the THP protecting group was removed upon
exposure to pyridinium p-toluenesulfonate,11 and the alkyne
reacted with dicobalt octacarbonyl to afford the Nicholas
reaction precursor 8. Treatment of this cobalt-complexed
alkyne with boron trifluoride diethyl etherate induced ioniza-
tion of the methyl ether12 to yield a cobalt-stabilized cation
that reacted with the internal alcohol nucleophile to furnish
cyclic ether 9 in 89-93% yield.
Scheme 2
Scheme 1
Pauson-Khand reactions on cobalt-alkyne complex 9
successfully yielded the desired tricyclic ethers (10 and 11);
the results for these reactions are summarized in Table 1.
Table 1. Pauson-Khand Reactions To Form [5,8,5]-Tricycles
To begin our investigation, we decided to focus on the
synthesis of cyclic ethers (Y ) O in Scheme 1), keeping the
distance between the alkyne and alkene constant (m ) 1)
and varying the length of the connecting chain between the
nucleophile and the alkyne (n ) 1-3). Use of alcohol
nucleophiles in intramolecular endocyclic Nicholas reactions
is well-precedented from Isobe’s studies toward the synthesis
of ciguatoxin.9 Furthermore, intramolecular Pauson-Khand
reactions proceed most efficiently when synthesizing bicyclic
5,5-systems.3
entry
conditions
yield of 10 + 11 (%)
ratio of 10:11
1
2
3
4
5
CH3CN, ∆
NMO
CyNH2, ∆
iPrSMe, ∆
PhSMe, ∆
86
60
55
50
25
55:45
88:12
74:26
86:14
89:11
For our initial target, we focused on the synthesis of the
[5,8,5]-tricyclic ether (4, Y ) O, m ) 1, n ) 3). Synthesis
of the key cobalt-complexed cyclic alkyne 9 proceeded
uneventfully as outlined in Scheme 2. The requisite alkyne
starting material 510 was deprotonated with ethylmagnesium
bromide and then combined with 4-pentenal (6) to furnish
the desired addition product 7. This alcohol was subsequently
converted into a methyl ether using methyl iodide and sodium
Compounds 10 and 11 are available in good to excellent
yields under a variety of conditions. Refluxing acetonitrile
in air7 provided the target molecules in 86% yield but with
little selectivity. Treatment of 9 with N-methylmorpholine-
N-oxide (NMO) in dichloromethane13 proved selective (88:
12 ratio of 10:11) and furnished the products in good overall
(8) For a review of cyclic alkynes, see: Gleiter, R.; Merger, R. In Modern
Acetylene Chemistry; Stang, P. J., Diederich, F., Eds.; VCH: New York,
1995; p 285.
(9) Takai, S.; Sawada, N.; Isobe, M. J. Org. Chem. 2003, 68, 3225 and
references therein.
(11) Lee, Y. B.; Folk, J. E. Bioorg. Med. Chem. 1998, 6, 253.
(12) An alcohol and a benzyl ether were also investigated for use as the
ionizable propargyl groups; however, the methyl ether was the easiest to
handle and could be made most efficiently.
(10) Synthesized in one step from the commercially available alcohol
according to Marino, J. P.; Nguyen, H. N. J. Org. Chem. 2002, 67, 6291.
(13) Shambayati, S.; Crowe, W. E.; Schreiber, S. L. Tetrahedron Lett.
1990, 31, 5289.
4950
Org. Lett., Vol. 6, No. 26, 2004

yield. Use of promoters such as cyclohexylamine in refluxing
dimethoxyethane14 and isopropyl methyl sulfide or thioani-
sole in refluxing dichloroethylene15 afforded the target
tricycles in varying yields and selectivities.
The major isomer of the Pauson-Khand reaction was
unambiguously identified as trans isomer 10 by difference
NOE experiments (see Figure 1). Although we were unable
to chromatographically separate diastereomers 10 and 11,
the product mixture from the NMO reaction was sufficiently
enriched in the major isomer that NMR analysis proved
straightforward.
In this case, promotion of the reaction with cyclohexylamine
provided the best yield (91%) of the desired products. Use
of NMO again afforded the best ratio of trans:cis products;
however, it was much less selective than in the [5,8,5]-
system. Interestingly, in entries 1 and 2 the cis diastereomer
was the major product. Similarly to Figure 1, we were able
to use difference NOE experiments to determine the struc-
tures of the two isomers formed in this reaction.
Table 2. Pauson-Khand Reactions To Form [5,7,5]-Tricycles
entry
conditions
yield of 16 + 17 (%)
ratio of 16:17
1
2
3
4
CyNH2, ∆
CH3CN, ∆
NMO
91
63
30
29
42:58
37:63
72:28
67:33
Figure 1. Difference NOE results for tricycle 10 (only most
relevant enhancements shown for clarity).
i-PrSMe, ∆
Our initial case proved the validity of our synthetic
strategy. We prepared complex oxygen-containing tricycles
in seven steps from commercially available starting materials
in 39-46% overall yield. Our next goal was to investigate
the synthesis of a differently sized ring system, and we chose
to pursue the synthesis of the [5,7,5]-tricyclic ether target.
The synthesis is analogous to the [5,8,5]-tricycle and is
outlined in Scheme 3. Using the same steps already described
in Scheme 2 we were able to prepare cyclic ether 15 in five
steps from alkyne 12 in 22-31% overall yield.
The diastereoselectivities of Pauson-Khand reactions
often vary with the use of different promoters; however, it
is unusual to see a complete reversal in selectivity between
the major and minor isomers (e.g., entries 2 and 3 in Table
2).3 We are intrigued by these results and hope that further
study of compound 15 and related systems will help us
develop a more sophisticated mechanistic understanding of
the role the promoter plays in these intramolecular reactions.
Having proven that we could efficiently produce both the
[5,8,5]- and [5,7,5]-tricyclic ethers, we next turned our
attention to production of the [5,6,5]-system. Following the
general strategy already described, we were able to obtain
the target tricyclic cyclopentenone 2316 albeit in disappointing
overall yield. Production of the key cobalt-complexed alkyne
21 proceeded smoothly; however, both the Nicholas reaction
to yield cyclic ether 22 and the Pauson-Khand reaction to
furnish tricycle 23 were very inefficient transformations.
Intramolecular Nicholas reactions to form cyclic ethers are
thermodynamically controlled processes;17 however, exposure
of 21 to temperatures greater than 0 °C caused decomposition
of both the starting material and the desired product.
Furthermore, an efficient synthesis of cobalt-complexed
cyclic alkynes in rings smaller than seven members is an
ongoing synthetic challenge.6 The disappointing yield in the
Pauson-Khand step is presumably due to the strain inherent
in this tricyclic system.
Scheme 3
Pauson-Khand reactions of 15 provided easy access to
the target [5,7,5]-tricycles 16 and 17 as outlined in Table 2.
(14) Sugihara, T.; Yamada, M.; Ban, H.; Yamaguchi, M.; Kaneko, C.
Angew. Chem., Int. Ed. Engl. 1997, 36, 2801.
(15) Sugihara, T.; Yamada, M.; Yamaguchi, M.; Nishizawa, M. Synlett
1999, 771.
(16) Both diastereomers were obtained; cis was the major product in a
64:36 ratio.
(17) (a) Liu, T.-Z.; Li, J.-M.; Isobe, M. Tetrahedron 2000, 56, 10209.
(b) Yenjai, C.; Isobe, M. Tetrahedron 1998, 54, 2509.
Org. Lett., Vol. 6, No. 26, 2004
4951

complex mixture of uncharacterizable products either by
decomposition or polymerization. We hope to confirm this
hypothesis by incorporating a substituent on the alkene that
will stabilize the resulting carbocation.
Scheme 4
Scheme 5
In summary, we have developed a strategy for the rapid
construction of tricyclic oxygen-containing heterocycles
using a sequential combination of the Nicholas and Pauson-
Khand reactions. Thus, we can transform simple acyclic
enynes into complex tricyclic enones in a rapid and efficient
manner. Studies are currently underway in our group to
extend this method to the production of tricyclic amines and
lactones via use of amines and carboxylic acids as nucleo-
philes in the Nicholas reaction.
We obtained an interesting result when we attempted to
prepare an eight-membered ring cyclic ether that would lead
to formation of the [6,8,5]-tricyclic system. The starting
material synthesis was identical to that described in Scheme
2 except that 5-hexenal18 was used in place of 4-pentenal
(6), thus inserting an extra methylene group between the
alkene and alkyne. Attempted Nicholas reaction of cobalt-
alkyne complex 24 yielded only a trace of the desired eight-
membered ring cyclic ether product. Instead, we believe the
cobalt-stabilized cation preferentially undergoes an exocyclic
Nicholas reaction with the alkene acting as a nucleophile to
generate carbocation 25 (or the corresponding 5-exo cycliza-
tion product).19 This unstabilized carbocation leads to a
Acknowledgment. This research was supported by an
award from the Research Corporation. M.M.Q. would like
to thank Pfizer for a summer undergraduate research fel-
lowship. We thank Dr. Charles Amass, Dr. L. Charles
Dickinson, Dr. A. Chandrasekaran, and Dr. Stephen J. Eyles
for assistance with NMR, X-ray, and MS experiments. We
thank Prof. Greg Dudley for helpful discussions.
Supporting Information Available: Experimental pro-
cedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0479141
(19) In an unrelated system containing two alcohol nucleophiles, Isobe
observed a similar result in which 5-exo is favored over 7-endo cyclization;
see: Hosokawa, S.; Isobe, M. J. Org. Chem. 1999, 64, 37.
(18) Meyer, C.; Marek, I.; Courtemanche, G.; Normant, J.-F. Tetrahedron
1994, 50, 11665.
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Org. Lett., Vol. 6, No. 26, 2004