Intramolecular rhodium-catalyzed [2+2+2] cyclizations of diynes with enones

Full text of DOI:10.1021/jo9001678

SCHEME 1
Intramolecular Rhodium-Catalyzed [2+2+2]
Cyclizations of Diynes with Enones
Amanda L. Jones and John K. Snyder*
Center for Chemical Methodology and Library DeVelopment,
and the Department of Chemistry, Boston UniVersity, 590
Commonwealth AVenue, Boston, Massachusetts 02215
jsnyder@bu.edu
ReceiVed January 26, 2009
prepare highly substituted tricyclic core structures with central
benzene rings (Scheme 1, eq 2).
Examples of the participation of R,ꢀ-unsaturated carbonyl
compounds in such chemistry, however, are quite limited, and
there are no reports of intramolecular variants utilizing
diyne-enone cyclizations to the best of our knowledge. Ikeda
employed nickel catalysts to achieve cyclizations of cycloalk-
enones with alkynes in intermolecular reactions,5 also achieving
a modest level of enantioselectivity (up to 53% ee) with a
dihydrooxazole ligand in some cyclizations (Scheme 2, eqs 1
The Rh(I)-catalyzed inter- and intramolecular [2+2+2]
cyclization of diynes with R,ꢀ-unsaturated enones proceeds
with microwave promotion in good yields. This chemistry
was applied to the synthesis of (-)-alcyopterosin I.
SCHEME 2
Transition metal-catalyzed [2+2+2] cyclizations of three
nonconjugated π-systems exemplify synthetic organic processes
that would have been considered extraordinary not all that long
ago.1 Along with other remarkable transformations mediated
by transition metals, such as cross couplings and olefin
metathesis, these ring-forming reactions have rapidly become
valuable synthetic tools, able to accomplish chemistry in a single
step that often would have required tedious and low-yielding
multistep strategies. A great variety of such transition metal-
catalyzed [2+2+2] cyclizations are now well-established using
a variety of metals, and these have proven to be particularly
effective at producing highly substituted aromatic and nonaro-
matic rings.1,2
We recently reported the application of a cobalt-catalyzed
intramolecular [2+2+2] cyclization of diynes with tethered
nitriles to produce tetrahydro-[1,6]-naphthyridines and related
analogues (Scheme 1, eq 1),3 which were later used as scaffolds
for diversification, resulting in the discovery of several antitu-
berculoid agents.4 We have now begun to look at similar
cyclizations using diynes tethered to enones as a strategy to
(1) (a) Vollhardt, K. P. C. Acc. Chem. Res. 1977, 10 (1), 1–8. (b) Vollhardt,
K. P. C. Angew. Chem., Int. Ed. 1984, 23, 539–556. (c) Kotha, S.; Brahmachery,
E.; Lahiri, K. Eur. J. Org. Chem. 2005, 22, 4741–4767. (d) Candon, V.; Aubert,
C.; Malacria, M. Chem. Commun. 2006, 2209, 2217. (e) Chopade, P. R.; Louie,
J. AdV. Synth. Catal. 2006, 348 (16-17), 2307–2327. (f) Agenet, N.; Buisine,
O.; Slowinski, F.; Gandon, V.; Aubert, C.; Malacria, M. In Organic Reactions;
Overman, L. E., Ed.; John Wiley & Sons: Hoboken, NJ, 2007; Vol. 68, pp 1-
302. (g) Shibata, T; Tsuchikama, K. Org. Biomol. Chem. 2008, 6, 1317–1323.
(2) (a) Lautens, M.; Klute, W.; Tam, W. Chem. ReV. 1996, 96, 49–92. (b)
Varela, J. A.; Saa, C. Chem. ReV. 2003, 103, 3787–3801.
and 2).6 Montgomery had also observed R,ꢀ-enones participating
in [2+2+2] cotrimerizations with alkynes using nickel catalysts,
though two enone moieties had intriguingly cyclized with a
single alkyne (Scheme 2, eq 3).7 Shortly thereafter, Cheng
reported the cyclization of methyl vinyl ketone with diynes using
a similar nickel catalyst system with yields ranging from 29%
(3) Zhou, Y.; Porco, J. A., Jr.; Snyder, J. K. Org. Lett. 2007, 9, 393–396.
(4) Zhou, Y.; Beeler, A. B.; Cho, S.; Wang, Y.; Franzblau, S. G.; Snyder,
J. K. J. Comb. Chem. 2008, 10, 534–540.
(5) Ikeda, S.; Mori, N.; Sato, Y. J. Am. Chem. Soc. 1997, 119, 4779–4780.
(6) Ikeda, S.; Kondo, H.; Arii, T.; Odashima, K. J. Chem. Soc., Chem.
Commun. 2002, 2422, 2423.
10.1021/jo9001678 CCC: $40.75
Published on Web 03/12/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 2907–2910 2907

TABLE 1. Select Results of Catalyst Screening: Intermolecular
[2+2+2] Cyclizations of Diyne 1 with MV.
CHART 1. Unreactive Reaction Partners with Diyne 1
microwave-promoted experiments with use of Wilkinson’s
catalyst. Equally intriguing, the thermal reaction with Wilkin-
son’s catalyst resulted in a lower combined yield of 2 and 3
(item 2). In this case, dimer 4 was observed as the major product.
Thus, microwave irradiation seems better able to promote the
[2+2+2] cyclization of diyne 1 and MVK rather than the
unproductive dimerization pathway.13 Other R,ꢀ-unsaturated
carbonyl compounds, including amides, esters, and more
substituted enones (Chart 1), were either poorly or completely
unreactive under the screened conditions, yielding primarily
diyne dimer 4. The results from these preliminary studies
confirmed the feasibility of using enones in [2+2+2] cycliza-
tions, and led us to Wilkinson’s catalyst for application in
intramolecular variants where the entropic advantage might
allow for cyclizations with R,ꢀ-unsaturated carbonyls in higher
yields.
item
catalyst
conditionsa
2:3b
1
2
3
4
5
6
7
RhCl(PPh3)3
RhCl(PPh3)3
microwave, 150 °C, 15 min
120 °C, 5 h
3:53
0:18
20:0
5:<5
19:5
11:34
6:0
c
CpCo(CO)2
microwave, 120 °C, 15 min
microwave, 150 °C, 15 min
microwave, 150 °C, 15 min
microwave, 150 °C, 15 min
microw, 150 °C, 15 min
Cp*Ru(CH3CN)3PF6
[Rh(CO)2Cl]2
Rh(cod)2BF4
[Rh(cod)2Cl]2
a All reactions were carried out in chlorobenzene, 0.04 M in diyne.
b NMR yields for single trials. c 20 mol % catalyst used.
to 80%, though slow addition from a syringe pump was essential
to minimize diyne dimerization (Scheme 2, eq 4).8 More
recently, Shibata has shown that asymmetric cyclizations of
diynes with exocyclic enones can be achieved with a cationic
Rh(I) catalyst using the (S)-xylylBINAP ligand (Scheme 2, eq
5).9 Spirocenters were generated in up to 94% yield with ee
values as high as 99%. Bisalkynyl diones have also been used
by McDonald in intermolecular cyclizations with alkynes.10
We began catalyst screening with the Cheng reaction system:8
diyne 1, readily prepared from diethyl malonate,11 with MVK
(Table 1). We3 and others12,13 have already established the value
of microwave irradiation in promoting transition metal-catalyzed
[2+2+2] cyclizations using diynes, so this activation protocol
was again applied.
SCHEME 3
Of the catalysts screened, Co(I), Rh(I), and Ru(II) were all
successful in producing [2+2+2] cyclization products. Both the
aromatized product 2 and cyclohexadiene 3, which presumably
results from the double bond migration of the initially formed
[2+2+2] adduct to conjugate the ketone with the diene system,
were formed in varying amounts. Cyclohexadiene 3 slowly
aromatized to 2 upon standing on the benchtop over several
days. Diyne dimer 4 was also observed to a certain extent in
all trials. Commercial Wilkinson’s catalyst (item 1) and
Rh(cod)2BF4 (item 6) gave the highest combined yields of the
desired cyclization products 2 and 3 as determined by NMR
analysis of the crude reaction mixtures. In addition, isolated
yields of up to 63% of 2 were achieved in subsequent
Intramolecular cyclizations were examined in two different
subgroups. A cycloalkanone ring fused to the aromatic system
is produced when the carbonyl is part of the tether linking the
enone and diyne. When the carbonyl lies external to the tether,
a carbonyl substituent on the aryl ring results (Scheme 3). The
former system is referred to as the “endocyclic” cyclization
while the latter is termed the “exocyclic” cyclization with
reference to the location of the carbonyl group in the final
product. Preliminary examination of the endocyclic process used
vinyl ketones 6, while the exocyclic precursors were R,ꢀ-
unsaturated esters 8, both varying the linker “X” between the
two yne systems.
(7) Seo, J.; Chui, H. M. P.; Heeg, M. J.; Montgomery, J. J. Am. Chem. Soc.
1999, 121, 476–477.
(8) Sambaiah, T.; Li, L.-P.; Huang, D.-J.; Lin, C.-H.; Rayabarapu, D. N.;
Cheng, C.-H. J. Org. Chem. 1999, 64, 3663–3670.
SCHEME 4
(9) Tsuchikama, K.; Kuwata, Y.; Shibata, T. J. Am. Chem. Soc. 2006, 128,
11766–11767.
(10) McDonald, F. E.; Zhu, H. Y. H.; Holmquist, C. R. J. Am. Chem. Soc.
1995, 117, 6605–6606.
(11) Llerena, D.; Buisine, O.; Aubert, C.; Malacria, M. Tetrahedron 1998,
54 (32), 9373–9392.
(12) (a) Young, D. D.; Senaiar, R. S.; Deiters, A. Chem. Eur. J. 2006, 12,
5563–5568. (b) Shanmugasundarum, M.; Aguirre, A. L.; Leyva, M.; Quan, B.;
Maritnez, L. E. Tetrahedron Lett. 2007, 47, 7698–7701. (c) Young, D. D.;
Sripada, L.; Deiters, A. J. Comb. Chem. 2007, 9 (5), 735–738. (d) Hrdina, R.;
Valterova, I.; Hodacova, J.; Cisarova, I.; Kotora, M. AdV. Synth. Catal. 2007,
349, 822–826. (e) Hrdina, R.; Dracinsky, M.; Valterova, I.; Hodacova, J.;
Cisarova, I.; Kotora, M. AdV. Synth. Catal. 2008, 350, 1449–1456. (f) Novak,
P.; Cihalova, S.; Otmar, M.; Hocek, M.; Kotora, M. Tetrahedron 2008, 64, 5200–
5207. (g) Turek, P.; Hocek, M.; Pohl, R.; Klepetarova, B.; Kotora, M. Eur. J.
Org. Chem. 2008, 25, 3335–3343.
(13) Young, D. D.; Deiters, A. Angew. Chem., Int. Ed. 2007, 46, 5187–
5190.
2908 J. Org. Chem. Vol. 74, No. 7, 2009

SCHEME 5
CHART 2. Cyclization/Aromatization Products of
Diyne-Enones (Yields over 2 steps, Scheme 3)
the cyclizations, and analogous 5- and 6-membered rings
resulting from varying the tether length could be produced in
comparable yields (5b and 5c). Preparation of larger rings has
not as yet been examined. Amino groups in the tether which
did not have their Lewis basicity reduced with an electron
withdrawing protecting group were not tolerated (6f and 8e).
Presumably coordination of the nucleophilic nitrogen to the
rhodium catalyst prevented the cyclization. Amines protected
as sulfonamides, however, worked well (5b-d and 7d).
The preparations of the cyclization precursors were very
straightforward. O-Linked substrates 6a and 8a-c were prepared
by additions of the acetylides from the O-protected terminal
alkynyl alcohols 9a,b to formaldehyde, followed by propargy-
lations and deprotections to give primary alcohols 11a-d
(Scheme 4). Oxidations (PCC) provided aldehydes 12a-d.
Vinyl Grignard addition to 12a, then Swern oxidation of 13
gave O-linked endocyclic precursor 6a. Horner-Wadsworth-
Emmons olefinations of the aldehydes 12b-d yielded exocyclic
precursors 8a-c.
N-Linked precursors 6b-d and 8d were prepared similarly
beginning with the appropriate N-tosylpropargylamines 14a,b
(Scheme 5). Mitsunobu attachment of the terminal alkynyl
alcohols 15a,b, then deprotection, gave dipropargyl tosyla-
mides 16a-c. Conversion to the cyclization prescursors 6b-d
and 8d then followed the same strategy as applied to the
O-linked cyclization precursors. The malonate linked diyne
6e was analogously prepared beginning with propargyl
bromide 19 and commercially available dimethylpropargyl
malonate (Scheme 6).
These studies demonstrated that enones do participate with
diynes in [2+2+2] cyclizations with rhodium catalysts, and that
the intramolecular cyclizations can be relatively easy to ac-
complish. To demonstrate the applicability of these studies, a
short synthesis of the marine natural product alcyopterosin I
(23), isolated from the Antarctic soft coral Alcyonium
paessleri,14 was undertaken. Members of this family of rare
marine illudane sesquiterpenes are reported to have activity
against human larynx and colon cancer cell lines, though no
activity has been reported for 23. While the synthesis of 23 has
not been reported, other members of the alcyopterosin family
and structurally similar analogues have been synthetically
prepared.15,16 Furthermore, several of these syntheses have
employed a [2+2+2] cyclization as the key step.16 Retrosyn-
thetically, 23 was envisioned as arising from the cyclization of
diyne-enone 24, followed by reduction of the aryl ketone
(Scheme 7).
SCHEME 6
SCHEME 7
Intramolecular cyclizations employed the conditions opti-
mized with the intermolecular chemistry (RhCl(PPh3)3, 5 mol
%, microwave, 150 °C, 10 min in chlorobenzene, 0.02-0.04
M in cyclization precursor). Catalysts were not further screened
for the intramolecular systems. Subsequent to the cyclizations,
partial aromatization was observed during workup, so complete
aromatization was accomplished with DDQ. The results for the
cyclization/aromatization sequences are shown in Chart 2 with
the reported isolated yields resulting after both the cyclization
and aromatization steps.
(14) Palermo, J. A.; Brasco, M. F. R.; Spagnuolo, C.; Seldes, A. M. J. Org.
Chem. 2000, 65, 4482–4486.
(15) (a) Tanaka, R.; Nakano, Y.; Suzuki, D.; Urabe, H.; Sato, F. J. Am. Chem.
Soc. 2002, 124 (33), 9682–9683. (b) Finkelstein, L. M.; Bruno, A. M.; Renou,
S. G.; Iglesias, G. Y. M. Bioorg. Med. Chem. 2006, 14, 1863–1870.
(16) (a) Neeson, N. J.; Stevenson, P. J. Tetrahedron Lett. 1988, 29, 813–
814. (b) Neeson, S. J.; Stevenson, P. J. Tetrahedron 1989, 45, 6239–6248. (c)
Witulski, B.; Zimmermann, A.; Gowans, N. D. Chem. Commun. 2002, 2984,
2985.
From the results in Chart 2 it can be seen that both endocyclic
and exocyclic cyclizations were successful. Both internal (5a-c
and 7a,b,d) and terminal (5d,e and 7c) alkynes worked well in
J. Org. Chem. Vol. 74, No. 7, 2009 2909

SCHEME 8
have been achieved under microwave irradiation with Wilkin-
son’s catalyst. Diversity in the cyclized products was attained
by variation of the diyne linking group, tether length, and the
identity and location of the carbonyl function (“endo-” or
“exocyclic”). This methodology was applied to a synthesis of
ent-alcyopterosin I in 25% overall yield and 57% ee over 7
steps. Further work is focused on asymmetric cyclization
catalytic systems to produce the cyclohexadienes, as well as
trapping these products for use as library scaffolds.
Experimental Section
Representative Procedure for Microwave-Promoted [2+2+2]
Cyclizations/DDQ Aromatization: Synthesis of 5,8,8-Trimethyl-
3,4,8,9-tetrahydrocyclopenta[h]isochromen-7(1H)-one (28).26 To a
solution of diynyl enone 24 (15 mg, 0.06 mmol, 1.0 equiv) in
chlorobenzene (1.5 mL, 0.04 M) was added commercial RhCl(PPh)3
(3 mg, 3.2 µmol, 0.05 equiv). The tube was sealed and the reaction
mixture was subjected to microwave irradiation (300 W, 150 °C
maximum temperature as measured by a volume-independent
microwave sensor located in the microwave cavity)27 for 15 min.
After irradiation, the crude reaction mixture was filtered through a
silica gel plug to remove chlorobenzene and catalyst, washing with
hexanes:EtOAc (1:1), and the solvent was removed in vacuo. To
the crude residue was added CH2Cl2 (1.5 mL, 0.04 M), followed
by DDQ (17.6 mg, 0.08 mmol, 1.2 equiv). The reaction mixture
was stirred at rt for 1 h followed by quenching with H2O (2 mL)
and saturated aqueous NaHCO3 (1 mL). The aqueous layer was
extracted with CH2Cl2 (2 × 3 mL), and the combined organic layers
were dried over Na2SO4 and filtered, and the solvent was removed
in vacuo. The crude residue was purified via flash chromatography
on silica gel to give 28 (hexanes: EtOAc, 90:10, Rf 0.26, 10.5 mg,
Cyclization precursor 24 was easily prepared by sequential
bromide displacements on 1,4-dibromo-2-butyne,17 first with the
enolate of ethyl isobutyrate,18 then with commercially available
3-pentyn-1-ol (Scheme 8). Subsequent formation of Weinreb
amide 27, then vinyl ketone formation by the addition of vinyl
Grignard reagent gave 24 in only four steps and in 29% overall
unoptimized yield. Cyclization with DDQ workup then produced
aryl ketone 28. Borohydride reduction of 28 gave racemic 23
in 84% yield, which had spectroscopic data identical with those
of the naturally occurring compound.
Several procedures have been reported for the asymmetric
reduction of aryl ketones, including Noyori’s Ru(II)/diamine/
KOH system,19 the Rh(I)-PennPhos catalyst,20 as well as
Martens’ aminoalcohol 29 with borane,21 and Corey’s ox-
azaborolidine/catechol borane.22 We have had considerable
success with the latter two in the past in aryl ketone reductions.23
Our attempts with 29 as catalyst ligand in the reduction of 28
have produced ent-(-)-23, the enantiomer of naturally occurring
alcyopterosin I, in quantitative yield, but in only 57% ee. Other
asymmetric reduction attempts with a Ru(II) catalyst specifically
developed by Noyori for similar tert-alkyl ketones24 as well as
a chiral, tartaric acid-derived boronic ester25 resulted only in
recovery of ketone 28.
71% yield) as a white solid: mp 91-92 °C: IR (neat) 1707 cm-1
;
1H NMR (400 MHz, CDCl3) δ 1.20 (s, 6H), 2.27 (s, 3H), 2.71 (s,
2H), 2.76 (t, J ) 5.6 Hz, 2H), 4.02 (t, J ) 5.6 Hz, 2H), 4.73 (s,
2H), 7.45 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 19.0, 25.4 (2C),
27.0, 40.1, 45.5, 64.8, 65.7, 122.8, 132.1, 132.8, 136.4, 139.4, 145.8,
210.9; HRMS (ESI) m/z 231.1381 ([M + H],+100%), calcd for
C15H18O2 231.1385.
Acknowledgment. This work was supported by the National
Institutes of Health NIGMS CMLD Initiative (P50 GM067041).
We thank Professor Linda Doerrer for helpful discussions and
assistance in preparing reduction catalysts.
In conclusion, both inter- and intramolecular [2+2+2]
cyclizations of diynes with R,ꢀ-unsaturated carbonyl compounds
(17) Blond, G.; Bour, C.; Salem, B.; Suffert, G. Org. Lett. 2008, 10 (6),
1075–1078.
(18) Witham, C. A.; Mauleon, P.; Shapiro, N. D.; Sherry, B. D.; Toste, F. D.
J. Am. Chem. Soc. 2007, 129, 5838–5839.
(19) Ohkuma, T.; Ooka, H.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1995, 117, 2675–2676.
(20) Jiang, Q.; Jiang, Y.; Xiao, D.; Cao, P.; Zhang, X. Angew. Chem., Int.
Ed. 1998, 37, 1100–1103.
(21) Reiners, I.; Martens, J. Tetrahedron: Asymmetry 1997, 8, 27–28.
(22) Corey, E. J.; Bakshi, R. K. Tetrahedron Lett. 1990, 31, 611–614.
(23) (a) Sanyal, A.; Snyder, J. K. Org. Lett. 2000, 2, 2527–2530. (b) Corbett,
M. S.; Liu, X.; Sanyak, A.; Snyder, J. K. Tetrahedron Lett. 2003, 44, 931–935.
(24) Ohkuma, T.; Sandoval, C. A.; Srinivasan, R.; Lin, Q.; Wei, Y.; Mun˜iz,
K.; Noyori, R. J. Am. Chem. Soc. 2005, 127, 8288–8289.
(25) Eagon, S.; Kim, J.; Yan, K.; Haddenham, D.; Singaram, B. Tetrahedron
Lett. 2007, 48, 9025–9029.
Supporting Information Available: General experimental
information, full experimental procedures and characterization
1
data of all new compounds, and copies of H and 13C spectra
of all new products. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO9001678
(26) See the Supporting Information for specific experimental details for all
other cyclized products.
(27) All microwave reactions were run in sealed 10 mL thick-walled
microwave pressure tubes.
2910 J. Org. Chem. Vol. 74, No. 7, 2009