Medium-sized carbocycles by samarium diiodide-lnduced carbonyl-alkene cyclizations

Article abstract of DOI:10.1021/ol901183h

Intramolecular samarium diiodide-induced carbonyl-alkene or carbonyl- alkyne coupling reactions afforded without high dilution conditions 9- and 10-membered benzannulated carbocycles of type Il and III in surprisingly good yields and stereoselectivities.

Full text of DOI:10.1021/ol901183h

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3334-3337
Medium-Sized Carbocycles by Samarium
Diiodide-Induced Carbonyl-Alkene
Cyclizations
Jakub Saadi, Dieter Lentz,† and Hans-Ulrich Reissig*
Institut fu¨r Chemie und Biochemie, Freie UniVersita¨t Berlin, Takustrasse 3, 14195
Berlin, Germany
hans.reissig@chemie.fu-berlin.de
Received May 27, 2009
ABSTRACT
Intramolecular samarium diiodide-induced carbonyl-alkene or carbonyl-alkyne coupling reactions afforded without high dilution conditions
9- and 10-membered benzannulated carbocycles of type II and III in surprisingly good yields and stereoselectivities. A novel samarium diiodide-
mediated cascade process leading to tricyclic compounds of type IV was also observed. Bisbenzannulated 10- and 11-membered carbocycles
were prepared in very good yields.
Samarium diiodide was introduced as a reagent for organic
synthesis by Kagan and his co-workers.1 Over the years this
selective electron transfer agent has gained remarkable
importance due to its unique properties. It promotes a variety
of synthetic transformations, providing products often with
high regio- and stereoselectivity and under mild reaction
conditions.2 One of the areas where SmI2 may be applied is
the construction of medium-sized rings, which are key
structural features of a wide range of biologically active
compounds or natural products.3 SmI2 has been reported to
successfully facilitate formation of medium-sized carbocycles
in a number of ways. For example, 8-, 9-, 11-membered and
even larger rings were synthesized by intramolecular Re-
formatsky-type reactions of R-bromoesters with aldehydes.4a
The related Barbier couplings of allyl chlorides with
aldehydes4b and ketones4c furnished 8- and 9-membered
carbocycles. Molander et al. constructed cyclooctanol deriva-
tives by radical couplings of ketones with alkenes.4d Indirect
methods used SmI2 in sequential reactions, generating
intermediates which either form the desired carbocycles via
† Responsible for X-ray analyses.
(1) Namy, J. L.; Girard, P.; Kagan, H. B. New J. Chem. 1977, 1, 5–7.
(2) Reviews: (a) Gopalaiah, K.; Kagan, H. B. New J. Chem. 2008, 32,
607–637. (b) Ebran, J.-P.; Jensen, C. M.; Johannesen, S. A.; Karaffa, J.;
Lindsay, K. B.; Taaning, R.; Skrydstrup, T. Org. Biomol. Chem. 2006, 4,
3553–3564. (c) Concellon, J. M.; Rodriguez-Solla, H. Eur. J. Org. Chem.
2006, 161, 3–1625. (d) Jung, D. Y.; Kim, Y. H. Synlett 2005, 3019–3032.
(e) Edmonds, D. J.; Johnston, D.; Procter, D.-J. Chem. ReV. 2004, 104,
3371–3404. (f) Berndt, M.; Gross, S.; Ho¨lemann, A.; Reissig, H.-U. Synlett
2004, 422–438. (g) Kagan, H. B. Tetrahedron 2003, 59, 10351–10372. (h)
Steel, P. G. J. Chem. Soc., Perkin Trans. I 2001, 2727–2751. (i) Krief, A.;
Laval, A.-M. Chem. ReV. 1999, 99, 745–777. (j) Kagan, H. B.; Namy, J. L.
Top. Organomet. Chem. 1999, 2, 155–198. (k) Molander, G. A.; Harris,
C. R. Tetrahedron 1998, 54, 3321–3354. (l) Molander, G. A.; Harris, C. R.
Chem. ReV. 1996, 96, 307–338.
(3) Selected reviews: (a) Shiina, I. Chem. ReV. 2007, 107, 239–273. (b)
Mehta, G.; Singh, V. Chem. ReV. 1999, 99, 881–930. (c) Petasis, N. A.;
Patane, M. A. Tetrahedron 1992, 48, 5757–5821.
(4) (a) Inanaga, J.; Yokoyama, Y.; Hanada, Y.; Yamaguchi, M.
Tetrahedron Lett. 1991, 32, 6371–6374. (b) Matsuda, F.; Sakai, T.; Okada,
N.; Miyashita, M. Tetrahedron Lett. 1998, 39, 863–864. (c) Tamiya, H.;
Goto, K.; Matsuda, F. Org. Lett. 2004, 6, 545–547. (d) Molander, G. A.;
McKie, J. A. J. Org. Chem. 1994, 59, 3186–3192.
10.1021/ol901183h CCC: $40.75
Published on Web 07/07/2009
 2009 American Chemical Society

intramolecular SmI2-induced acyl substitutions5a-d to give
7- to 9-membered rings or by fragmentation reactions leading
to 8- to 10-membered carbocycles.5e
leads to the formation of the γ-lactone bridge of 18 (Scheme
2). The analogous 8-membered product was isolated in only
41% yield, giving the trans-isomer predominantly (3.1:1).6b
A bulkier substituent adjacent to the carbonyl group was well
tolerated as demonstrated by the isopropyl-substituted com-
pound 12, which furnished cyclization products 19/20 in 67%
combined yield. Again a clear preference for the lactone-
bridged products 20 and its cis-configured precursor 19b was
observed over trans-compound 19a (Scheme 2). The δ-hy-
droxyester 19b was converted into 20 under acid catalysis.
Remarkably, the analogous 8-membered product was formed
in 84% yield with exclusive trans selectivity.6b
Our group has utilized SmI2 for cyclizations of a variety
of ketones bearing γ-(2-alkenyl)aryl or γ-(2-alkynyl)aryl
moieties which furnished benzannulated cycloheptanol,6c
cyclooctanol6a-c,2f and cyclooctenol6d,2f derivatives. In con-
tinuation of this work we have now extended our method to
the synthesis of larger rings. Herein we describe an approach
to 9-, 10-, and 11-membered carbocycles via SmI2-induced
ketyl-alkene and ketyl-alkyne cyclization reactions.
The preparation of starting materials was easy starting from
protected δ- and ε-ketoesters 1-5 which are available by
standard methods. Alkylation of compounds 1-5 with
2-iodobenzyl iodide followed by ketal cleavage under acidic
conditions furnished key intermediates 6-10 (Scheme 1).
These were then equipped with different alkenyl groups by
using Suzuki-coupling reactions7a-d to furnish cyclization
precursors 11-16.
Scheme 2. Samarium Diiodide-Induced 9-endo-trig Cyclizations
of Styryl-Substituted δ-Ketoesters 11 and 12
Scheme 1
.
Synthesis of Alkenyl-Substituted δ- and ε-Ketoesters
11-16
Models explaining the observed stereoselectivities are so
far speculative. A transition state as presented in Figure 1
for the 9-endo-trig cyclization of styryl-substituted δ-ke-
toesters such as 11 and 12 can rationalize the preferred
formation of cis-products. As a crucial feature we position
To our delight compound 11, the simplest precursor of
9-membered ring analogous to our previously described
systems, reacted with SmI2 under standard conditions (2.2
equiv of SmI2, 18 equiv of HMPA,8 2.0 equiv of t-BuOH in
THF) to furnish a 1:4.6 mixture of benzannulated cy-
clononane derivatives 17 and 18 in 73% combined yield.
The intermediate with cis-arrangement of the methoxycar-
bonyl group and the samariumoxy moiety is favored, which
(5) (a) Molander, G. A.; Alonso-Alija, C. J. Org. Chem. 1998, 63, 4366–
4373. (b) Molander, G. A.; Machrouhi, F. J. Org. Chem. 1999, 64, 4119–
4123. (c) Molander, G. A.; Koellner, C. J. Org. Chem. 2000, 65, 8333–
8339. (d) Molander, G. A.; Brown, G. A.; Storch de Gracia, I. J. Org. Chem.
2002, 67, 3459–3463. (e) Molander, G. A.; Le Huerou, Y.; Brown, G. A.
J. Org. Chem. 2001, 66, 4511–4516.
Figure 1. Suggested transition state for 9-endo-trig cyclizations of
styryl-substituted δ-ketoesters such as 11 or 12 leading to cis-
products (HMPA ligands at samarium are omitted for simplicity).
(6) (a) Khan, F. A.; Czerwonka, R.; Zimmer, R.; Reissig, H.-U. Synlett
1997, 995–997. (b) Reissig, H.-U.; Khan, F. A.; Czerwonka, R.; Dinesh,
C. U.; Shaikh, A. L.; Zimmer, R. Eur. J. Org. Chem. 2006, 4419–4428. (c)
Saadi, J.; Reissig, H.-U. Synlett 2009, in press. (d) Nandanan, E.; Dinesh,
C. U.; Reissig, H.-U. Tetrahedron 2000, 56, 4267–4277.
the methoxycarbonyl and the R substituents in extra-annular
positions. The samarium ketyl approaches the alkene in an
antiperiplanar fashion hence leading to a staggered confor-
mation. As a result cis-products are obtained in preference.
Certainly, more detailed studies are required to substantiate
these ideas.
(7) (a) Suzuki, A. J. Organomet. Chem. 1999, 576, 147–168. (b)
Molander, G. A.; Rivero, M. R. Org. Lett. 2002, 4, 107–109. (c) Molander,
G. A.; Bernardi, C. R. J. Org. Chem. 2002, 67, 8424–8429. (d) Yin, L.;
Liebscher, J. Chem. ReV. 2007, 107, 133–173. (e) Beletskaya, I. P.;
Cheprakov, A. V. Chem. ReV. 2000, 100, 3009–3066. (f) Chinchilla, R.;
Na´jera, C. Chem. ReV. 2007, 107, 874–922.
Org. Lett., Vol. 11, No. 15, 2009
3335

SmI2-induced reactions of the two diastereomeric cyclic
δ-ketoesters 13a and 13b (Scheme 3) demonstrate that higher
substituted precursors also undergo 9-endo-trig cyclizations
affording fairly complex cyclononane derivatives 21 and 22
in low or moderate yields but with excellent stereoselectivi-
ties.9 Remarkably, the methyl group at the newly formed
stereogenic center was found to be in a trans relationship to
the hydroxyl group (similar to that in analogous cyclooctanol
derivatives6c).
6-exo-trig ketyl-alkene coupling.10c Remarkably, this ex-
periment was performed with only 2.4 equiv of SmI2. The
sequence most probably requires 6 equiv of SmI2 for
completion.11 To the best of our knowledge the transforma-
tion 23 to 24 is the first one with these steps occurring in a
sequential manner.
Scheme 3. Samarium Diiodide-Induced 9-endo-trig Cyclizations
of Isopropenyl-Substituted Cyclic δ-Ketoesters 13a and 13b
Figure 2.
Molecular structure (Diamond12) of tricyclic compound
24a.
For the investigation of related alkynyl-substituted com-
pounds we prepared δ-ketoester 25 by Sonogashira
coupling7f of 7 with 3-methoxyprop-1-yne. Its SmI2-
promoted 9-endo-dig cyclization furnished cyclononenol
derivative 26 in moderate yield (Scheme 5).6d,13 This protocol
gives access to medium-sized rings featuring an attractive
allylic alcohol function opening many possibilities for their
further functionalization.14
Stilbenyl-substituted δ-ketoester 23 was prepared by a
Heck reaction7e of 7 with styrene. To our surprise, its
cyclization gave two diastereomers (dr ) 1:1) of the
unexpected tricyclic product 24 in 30% yield together with
29% of starting material (Scheme 4). The structure and
Scheme 5. Samarium Diiodide-Induced 9-endo-dig Cyclization
of 3-Methoxypropynyl-Substituted δ-Ketoester 25
Scheme 4
.
Samarium Diiodide-Induced Cascade Reaction of
Stilbenyl-Substituted δ-Ketoester 23
Encouraged by these results we examined SmI2-promoted
cyclizations for the construction of larger rings. Upon
exposure to SmI2 the methyl ketone 14 provided the desired
cyclodecanol 27 in 54% yield as a 2:1 mixture of two
diastereomers (Scheme 6). Increase of the size of the
substituent adjacent to the carbonyl group retarded the
cyclization. The isopropyl-substituted ε-ketoester 15 fur-
nished product 28 in only 26% yield as an inseparable 1.4:1
relative configuration of 24a was unambiguously determined
by X-ray crystallography (Figure 2). We assume that these
products result from a SmI2-induced 5-exo-trig ketyl-me-
thoxycarbonyl coupling,10a followed by a SmI2-mediated
R-hydroxyketone deoxygenation10b and a SmI2-induced
(10) (a) Liu, Y.; Zhang, Y. Tetrahedron Lett. 2001, 42, 5745–5748. (b)
Kamochi, Y.; Kudo, T.; Masuda, T.; Takadate, A. Chem. Pharm. Bull. 2005,
53, 1017–1020. (c) Molander, G. A.; McKie, J. A. J. Org. Chem. 1992, 57,
(8) For the role of HMPA see: (a) Flowers, R. A., II Synlett 2008, 1427–
1439. (b) Sadasivam, D. V.; Antharjanam, P. K. S.; Prasad, E.; Flowers,
R. A., II J. Am. Chem. Soc. 2008, 130, 7228–7229. (c) Farran, H.; Hoz, S.
Org. Lett. 2008, 10, 865–867. (d) Inokuchi, T. J. Org. Chem. 2005, 70,
1497–1500. (e) Miller, R. S.; Sealy, J. M.; Shabangi, M.; Kuhlman, M. L.;
Fuchs, J. R.; Flowers, R. A., II J. Am. Chem. Soc. 2000, 122, 7718–7722.
(f) Curran, D. P.; Wolin, R. L. Synlett 1991, 317–318.
3132–3139
.
(11) A suggestion for the detailed mechanism is presented in the
Supporting Information.
(12) Crystal Impact GbR Diamond software ver. 2.1d.
(13) Molander, G. A.; Kenny, C. J. Am. Chem. Soc. 1989, 111, 8236–
(9) Many cyclizations with SmI2 provide only moderate or low yields.
In general, no additional products could be isolated. In several cases
fragmentation products could be identified. For examples see ref 6b.
8246.
(14) E.g.: (a) Dudley, G. B.; Danishefsky, S. J Org. Lett. 2001, 3, 2399–
2402. (b) Ho¨lemann, A.; Reissig, H.-U. Synlett 2004, 2732–2735.
3336
Org. Lett., Vol. 11, No. 15, 2009

mixture of diastereomers. These results indicate a higher
sensitivity of the 10-endo-trig process to steric hindrance. It
32a-c in 82% combined yield and in 5.7:1.5:1 ratio. The
relative configuration of the major stereoisomer 32a was
unambiguously determined by X-ray crystallography (Figure
3). The configurations of the two minor diastereomers could
not be assigned so far, but we assume that one should also
be a trans-product, however, with an alternate orientation of
the chiral axis with respect to the stereogenic centers.
The X-ray structure determination of the major undecanol
derivative 32a shows that the dihedral angle between both
aromatic rings is 67.0(1)° (Figure 3). The bond linking the
two aryl rings is slightly bent (intersection angle of the lines
C8, C11 and C12, C15 4.9°) by the strain of the 11-
membered ring.
Scheme 6. Samarium Diiodide-Induced 10-endo-trig
Cyclizations of Styryl-Substituted ε-Ketoesters 14 and 15b
a As separable diastereomers. b As inseparable mixture; dr determined
by the integration of NMR signals of the methoxy groups.
is also reasonable that in both reactions no lactone bridge
was formed since ε-lactones are kinetically and thermody-
namically much less preferred. The flexibility of the cyclo-
decane ring and the distance between the two stereocenters
so far did not allow assignment of the relative configuration
of these compounds by NMR spectroscopy.
The efficacy of the 10-endo-trig cyclization was strongly
improved by use of ketoesters bearing 2′-vinylbiphenyl
moieties.15 Starting material 29 was prepared (analogously
to 16) from the corresponding 2-iodobenzyl-substituted
γ-ketoester6b by Suzuki-coupling with commercially avail-
able 2-vinylphenylboronic acid. It afforded bisbenzannulated
cyclodecanol derivatives 30 and 31 in 65% combined yield
and with a stereoselectivity of 2.6:1 in favor of the lactone-
bridged cis-product 31 (Scheme 7). The higher homologue-
Figure 3.
Molecular structure (Diamond12) of the major undecanol
derivative 32a.
In conclusion, we have demonstrated that SmI2-induced
radical cyclizations are a surprisingly efficient tool for the
construction of medium-sized benzannulated carbocycles.
Several 9-, 10-, and 11-membered rings have been synthe-
sized in moderate to good yields and with good stereose-
lectivities. This method is especially attractive as it is
functional-group compatible, and starting materials are
readily available from simple and inexpensive building
blocks, allowing a wide range of variations. Further inves-
tigations are required to explore the scope and limitations
of this method and factors determining the stereoselectivity.
Scheme 7. Samarium Diiodide-Induced 10- and 11-endo-trig
Cyclizations of the 2′-Vinylbiphenyl-Substituted γ- and
δ-Ketoesters 29 and 16
Acknowledgment. Generous support of this work by the
Deutsche Forschungsgemeinschaft, the Fonds der Chemis-
chen Industrie, and the Bayer Schering Pharma AG is most
gratefully acknowledged. We thank R. Zimmer for help
during preparation of this manuscript.
Supporting Information Available: Experimental pro-
cedures, detailed mechanistic suggestions for the described
cascade reaction leading to compounds 24, X-ray crystal-
lographic data, and complete characterization for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
δ-ketoester 16 underwent the 11-endo-trig cyclization with
excellent efficacy affording three diastereoisomeric products
(15) For an example of a carbonyl-alkene coupling with a biphenyl
moiety leading to a dibenzocyclooctadiene system see: Molander, G. A.;
George, K. M.; Monovich, L. G. J. Org. Chem. 2003, 68, 9533–9540.
OL901183H
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