Scope and limitations of samarium diiodide induced cyclizations of alkenyl-substituted γ-keto esters to benzannulated cyclooctanol derivatives

Article abstract of DOI:10.1055/s-0029-1217520

A series of γ-keto esters bearing various alkenyl substituents were synthesized and subjected to samarium diiodide mediated 8-endo-trig ketyl-alkene coupling reactions. Highly substituted benzannulated cyclooctanol derivatives were obtained in good yields

Full text of DOI:10.1055/s-0029-1217520

LETTER
2089
Scope and Limitations of Samarium Diiodide Induced Cyclizations of
Alkenyl-Substituted g-Keto Esters to Benzannulated Cyclooctanol Derivatives
S
amarium
a
D
iiodide In
k
duced Cycli
u
zations of
A
l
b
kenyl-Substitute
d
S
g
-Keto Estersaadi, Hans-Ulrich Reissig*
Institut für Chemie und Biochemie, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany
Fax +49(30)83855367; E-mail: Hans.Reissig@chemie.fu-berlin.de
Received 9 April 2009
leading to benzannulated cyclooctanol6a,b,3b and
Abstract: A series of g-keto esters bearing various alkenyl substit-
uents were synthesized and subjected to samarium diiodide mediat-
ed 8-endo-trig ketyl–alkene coupling reactions. Highly substituted
benzannulated cyclooctanol derivatives were obtained in good
cyclooctenol6c,3b derivatives, respectively (Scheme 1). In
continuation of this work we have now extended our
methodology to the cyclization of precursors with addi-
yields and with moderate to excellent stereoselectivities. The ob- tional substituents at the alkene moiety. Herein we de-
tained results demonstrate the influence of steric and electronic fac-
scribe how steric and electronic factors at the alkene
tors on the regio- and stereoselectivity of ketyl-alkene cyclizations.
moiety influence the regio- and the stereoselectivity of the
Stilbenyl-substituted derivatives can cyclize either to cyclooctanol
samarium-ketyl cyclizations.
or to cycloheptanol derivatives depending on the substitution pat-
The preparation of starting materials was performed anal-
ogously to our previously described modular approach6a,b
via siloxycyclopropanes,7 which allowed simple synthe-
ses of g-keto esters 1–4 bearing a 2-iodobenzyl moiety
(Scheme 2). These were then equipped with different al-
kenyl groups using Suzuki coupling reactions8a–8d to fur-
nish the cyclization precursors 5–13.
tern at the carbonyl group.
Key words: samarium diiodide, ketyl, cyclizations, radical reac-
tions, medium-sized rings, cyclooctanols, cycloheptanols
Medium-sized rings, in particular cyclooctane deriva-
tives, are important structural features in a variety of nat-
ural products and biologically active substances. The
development of new efficient methods for their construc-
tion is therefore highly desirable.1 Since 1977 samarium
diiodide is known as a selective electron-transfer reagent
for many synthetic transformation,2 and it often allows re-
gio- and stereoselective construction of ring systems un-
der mild reaction conditions.3 SmI2 has been reported to
successfully promote the formation of medium-sized
rings in a number of ways. Direct cyclization strategies
used SmI2 to induce, for example, intramolecular cou-
pling reactions of a-bromoesters with aldehydes,4a allyl
chlorides with aldehydes4b and ketones,4c as well as ke-
tones with alkenes.4d Indirect methods employed SmI2
in sequential reactions, generating intermediates which
then formed the desired ring either via intramolecular
SmI2-induced acyl substitution5a–5d or by fragmentation
reactions.5e
R2
R2
BXn
R3
MeO2C
R1
MeO2C
R1
R4
O
O
a or b or c
I
R4
R3
1 R1 = Me
2 R1 = Et
R2 = H
89%a
93%b
91%b
75%a
87%b
88%b
90%c
99%b
95%b
R
R
3 = Me
3 = H
R4 = H
5
6
7
8
9
10
11
12
13
R4 = Me
R
2 = H
R3 = H
R
4 = Me
3 R1 = i-Pr R2 = H
R3 = Me
R3 = Ph
R4 = H
R4 = H
R
3 = H
R4 = Me
R4 = c-Pr
R4 = Ph
R4 = Ph
R3 = H
R3 = H
R3 = H
4 R1 = R2 = -(CH2)4-
(dr = 1:1)
(dr = 1:1)
Scheme 2 Synthesis of cyclization precursors 5–13. Reagents and
conditions: a) for coupling of alkenyl trifluoroborates: Pd(OAc)2 (5
mol%), Ph3P (10 mol%), Cs2CO3 (3 equiv), THF–H2O (10:1, 4 mL/
mmol), 70 °C, 4 h; b) for coupling of alkenyl boronic acids: Pd(OAc)2
(5 mol%), Ph3P (20 mol%), K2CO3 (1.5 equiv), DMF (4 mL/mmol),
70 °C, 12–72 h; c) for coupling of alkenyl boronic esters:
Pd(Ph3P)2Cl2 (3 mol%), dppf (3 mol%), K2CO3 (3 equiv), DMF (4
mL/mmol), 80 °C, 18 h.
MeO2C
R
CO2Me
O
SmI2
R
OH
We have then systematically investigated these starting
materials in samarium diiodide induced intramolecular
ketyl–alkene coupling reactions. The samarium diiodide
induced reactions of 2-propenyl-substituted g-keto esters
5 and 8 under standard conditions (2.2 equiv SmI2, 18
equiv HMPA, 2.0 equiv t-BuOH in THF) furnished mix-
tures of 14 and 15,9 respectively, 16 and 17 in good com-
bined yield and with low to moderate stereoselectivity in
favor of products with trans arrangement of the methoxy-
carbonyl and the hydroxyl group10 (Scheme 3). The stereo-
Scheme 1 Samarium diiodide induced cyclizations of g-styryl- and
g-phenylalkynyl-substituted ketones to benzannulated cyclooctanols
Our group has utilized SmI2 for cyclizations of a variety
of g-styryl- and g-phenylalkynyl-substituted ketones
SYNLETT 2009, No. 13, pp 2089–2092
x
x
.x
x
.2
0
0
9
Advanced online publication: 01.07.2009
DOI: 10.1055/s-0029-1217520; Art ID: G12209ST
© Georg Thieme Verlag Stuttgart · New York

2090
J. Saadi, H.-U. Reissig
LETTER
selectivity was slightly improved for substrate 8 with a terial. It should be emphasized here that the 1,2-diaryl al-
larger substituent R1 adjacent to the carbonyl group. Anal- kene unit could potentially react with samarium-ketyls at
ogous g-keto ester precursors bearing a styryl substituent both carbon atoms, affording alternative stabilized ben-
underwent this cyclization with slightly higher stereose- zylic radicals. Interestingly, the 8-endo-trig-cyclization
lectivity, also in favor of trans products.6b On the other mode was clearly preferred here over the 7-exo-trig reac-
hand, the cyclization of compound 9, equipped with a tion.
phenyl substituent at the a-styryl position, afforded two
Finally, the reactions of two epimers of the stilbenyl-sub-
epimeric g-lactones (cis products) 18a and 18b11 in a ratio
stituted cyclic g-keto ester 13 were investigated
of 1.7:1.
(Scheme 5). In our previous report cyclizations of the
analogous styryl-substituted keto esters were described.6b
MeO2C
R1
a
Interestingly, only the unlike-configured starting material
underwent the cyclization process while the like-config-
ured starting material was inert to reaction conditions due
to its impaired geometry for cyclization. To our surprise
both stilbenyl-substituted precursors 13 afforded cycliza-
tion products, and in both cases formation of cyclohep-
tanol derivatives was preferred. Remarkably, the like-
configured 13b, which was expected to be unreactive,
gave the tetracyclic product 2811 in better yield than its
epimer 13a furnishing compound 27. Studies to determine
scope and selectivity of the formation of similar cyclohep-
tanol derivatives via samarium diiodide mediated pro-
cesses are currently under way.
CO2Me
O
O
O
+
R1
R1
OH
R2
R2
R2
5
8
9
R1 = Me R2 = Me
R1 = i-Pr R2 = Me
R
14 40%
16 54%
--
15 38%
17 28%
18 59%b
1 = i-Pr R2 = Ph
Scheme 3 Samarium diiodide induced 8-endo-trig cyclizations of
starting materials 5, 8, and 9 substituted at the a-styryl position. a)
Reagents and conditions: SmI2 (2.2 equiv, 0.1 M in THF), HMPA (18
equiv), t-BuOH (2.0 equiv), THF (40 mL/mmol), r.t., 16 h. b) Isolated
as two diastereomers with respect to the R2-substituted stereogenic
center (dr = 1.7:1).
H
CO2Me
H
Subsequently, we have studied the samarium diiodide in-
duced cyclizations of g-keto esters 6, 7, and 10–12 bearing
the substituents at the b-styryl position (Scheme 4). In this
series of substrates trans-substituted products were
formed in good yields and with excellent stereoselectivi-
ties. However, in several cases side products were formed.
Methyl ketone 6 provided the expected cyclization prod-
uct 19 but it also gave significant amounts of ketyl–aryl
coupling12 product 20. The ketyl–aryl coupling was not
observed in the cyclizations of the g-keto esters bearing
larger substituents adjacent to the carbonyl group. Sub-
strates 7 and 10 afforded trans-cyclooctanol derivatives
21 and 23 in a remarkably clean fashion. However, if the
steric hindrance at the reacting centers is too high, for ex-
ample, in the case of g-keto ester 11 bearing branched sub-
stituents both at the carbonyl and the alkene moieties, the
reaction afforded fragmentation product 25 as major com-
ponent along with only moderate quantities of the desired
cyclooctanol derivative 24. The stilbenyl-substituted
g-keto ester 12 afforded the cyclooctanol derivative 26 in
good yield, taking into account the reisolated starting ma-
MeO2C
SmI2, t-BuOH
O
HMPA, THF
r.t., 16 h
HO
Ph
Ph
13a
27 44%
H
MeO2C
H
O
O
SmI2, t-BuOH
O
HMPA, THF
r.t., 16 h
Ph
Ph
28 63%
13b
Scheme 5 Samarium diiodide induced 7-exo-trig cyclizations of
stilbenyl-substituted g-keto esters 13a and 13b
Models explaining the observed stereoselectivities are so
far fairly speculative, in particular with respect to the ste-
reogenic center formed by the final protonation step (com-
pounds 14–18 as presented in Scheme 3). A transition
state for the 8-endo-trig cyclization of g-keto esters sub-
OH
R1
CO2Me
CO2Me
MeO2C
R1
CO2Me
O
SmI2, t-BuOH
+
+
H
HMPA, THF
r.t., 16 h
R1
OH
R2
R2
R2
R2
19 54%
6
7
10
11
R1 = Me R2 = Me
R
R
R
20 20%
--
1 = Et
1 = i-Pr R2 = Me
1 = i-Pr R2 = c-Pra
R2 = Me
21 56%
23 63%
24 24%
26 47%b
--
--
--
--
22 5%
--
25 47%
--
12 R1 = i-Pr R2 = Ph
Scheme 4 Samarium diiodide induced 8-endo-trig cyclizations of precursors 6, 7, 10–12 substituted at the b-styryl position; a) c-Pr =
cyclopropyl; b) 20% of the starting material was reisolated from the reaction mixture.
Synlett 2009, No. 13, 2089–2092 © Thieme Stuttgart · New York

LETTER
Samarium Diiodide Induced Cyclizations of Alkenyl-Substituted g-Keto Esters
2091
(4) (a) Inanaga, J.; Yokoyama, Y.; Hanada, Y.; Yamaguchi, M.
Tetrahedron Lett. 1991, 32, 6371. (b) Matsuda, F.; Sakai,
T.; Okada, N.; Miyashita, M. Tetrahedron Lett. 1998, 39,
863. (c) Tamiya, H.; Goto, K.; Matsuda, F. Org. Lett. 2004,
6, 545. (d) Molander, G. A.; McKie, J. A. J. Org. Chem.
1994, 59, 3186.
(5) (a) Molander, G. A.; Alonso-Alija, C. J. Org. Chem. 1998,
63, 4366. (b) Molander, G. A.; Machrouhi, F. J. Org. Chem.
1999, 64, 4119. (c) Molander, G. A.; Koellner, C. J. Org.
Chem. 2000, 65, 8333. (d) Molander, G. A.; Brown, G. A.;
Storch de Gracia, I. J. Org. Chem. 2002, 67, 3459.
(e) Molander, G. A.; Le Huerou, Y.; Brown, G. A. J. Org.
Chem. 2001, 66, 4511.
(6) (a) Khan, F. A.; Czerwonka, R.; Zimmer, R.; Reissig, H.-U.
Synlett 1997, 995. (b) Reissig, H.-U.; Khan, F. A.;
Czerwonka, R.; Dinesh, C. U.; Shaikh, A. L.; Zimmer, R.
Eur. J. Org. Chem. 2006, 4419. (c) Nandanan, E.; Dinesh,
C. U.; Reissig, H.-U. Tetrahedron 2000, 56, 4267.
(7) (a) Kunkel, E.; Reichelt, I.; Reissig, H.-U. Liebigs Ann.
Chem. 1984, 512. (b) For a general review, see: Reissig,
H.-U.; Zimmer, R. Chem. Rev. 2003, 103, 1151.
(8) (a) Suzuki, A. J. Organomet. Chem. 1999, 576, 147.
(b) Molander, G. A.; Rivero, M. R. Org. Lett. 2002, 4, 107.
(c) Molander, G. A.; Bernardi, C. R. J. Org. Chem. 2002, 67,
8424. (d) Yin, L.; Liebscher, J. Chem. Rev. 2007, 107, 133.
(9) Typical Procedure for SmI2-Induced Cyclizations –
Conversion of 5 into 14 and 15
stituted at the b-styryl position is suggested in Figure 1
which may rationalize our results depicted in Scheme 4.
The methoxycarbonyl group and the substituent R1 occu-
py pseudoequatorial positions, while the bulky samari-
um(III)oxy substituent is forced into a pseudoaxial
position. The olefin approaches in an antiperiplanar fash-
ion to the samarium(III)oxy group13 leading to a staggered
conformation. As a consequence trans products are ob-
tained selectively, in which the R2 group is situated at the
same face of the eight-membered ring as the methoxycar-
bonyl and the R1 substituent. More detailed studies are re-
quired to substantiate these ideas.
R2
R1
R1
MeO2C
MeO2C
H
OSmI2
H
H
R2
OSmI2
Figure 1 Suggested transition state for 8-endo-trig cyclizations of
g-keto esters substituted at the b-styryl position leading to trans pro-
ducts with high selectivity (HMPA ligands at samarium are omitted
for simplicity).
Samarium metal (278 mg, 1.85 mmol) and 1,2-diiodoethane
(477 mg, 1.69 mmol) were placed under a flow of argon in a
flame-dried, two-necked round-bottomed flask containing a
magnetic stirring bar and a septum inlet. THF (20 mL) was
added, and the mixture was vigorously stirred at r.t. for 2 h.
HMPA (2.40 mL, 13.8 mmol) was added to this solution of
SmI2, and after 10 min of stirring a solution of substrate 5
(200 mg, 0.77 mmol) and t-BuOH (146 mL, 1.54 mmol) in
THF (31 mL) was added over 2 h. The mixture was stirred at
r.t. for 16 h and quenched with sat. aq NaHCO3 solution (20
mL). The phases were separated and the aqueous layer was
extracted with Et2O (3 × 25 mL). The combined organic
layers were washed with H2O (10 mL) and brine (10 mL)
and dried (Na2SO4). The products were purified by column
chromatography (silica gel, hexane–EtOAc = 10:1) to
furnish 80 mg (40%) 14 as colorless oil and 67 mg (38%) 15
as colorless crystals (mp 130–132 °C).
In conclusion, we have extended our approach to cyclooc-
tanol derivatives to substrates bearing substituents at the
alkene moiety. We have successfully determined how the
newly introduced substituents influence regio- and stere-
oselectivity of an intramolecular 8-endo-trig ketyl–alkene
coupling reaction. Furthermore, the formation of interest-
ing tricyclic and tetracyclic products by 7-exo-trig cy-
clization was observed.
Acknowledgment
Generous support of this work by the Deutsche Forschungsgemein-
schaft, the Fonds der Chemischen Industrie, and the Bayer Schering
Pharma AG is most gratefully acknowledged.
Analytical Data for Methyl (6RS,8RS,10RS)-8-Hydroxy-
8,10-dimethyl-5,6,7,8,9,10-hexahydrobenzo[8]-
annulene-6-carboxylate (14)
References and Notes
Compound 14 shows temperature-dependent NMR spectra.
At r.t. some signals appear broad, measurement at 55 °C
allowed to see the signals more clearly. 1H NMR (500 MHz,
CDCl3, 55 °C): d = 1.20 (s, 3 H, 8-Me), 1.33 (dd, J = 11.5,
14.7 Hz, 1 H, 7-H), 1.33 (d, J = 7.1 Hz, 3 H, 10-Me), 1.62
(dd, J = 11.4, 14.3 Hz, 1 H, 9-H), 1.67 (dd, J = 3.8, 14.7 Hz,
1 H, 7-H), 1.79–1.83 (m, 1 H, 9-H), 3.10 (dddd, J = 2.9, 3.8,
7.5, 11.5 Hz, 1 H, 6-H), 3.16 (dd, J = 2.9, 13.9 Hz, 1 H, 5-
H), 3.36–3.43 (m, 1 H, 10-H), 3.43 (dd, J = 7.5, 13.9 Hz, 1
H, 5-H), 3.68 (s, 3 H, CO2Me), 6.97–6.99, 7.06–7.10, 7.17–
7.25 (3 m, 1 H, 1 H, 2 H, Ar) ppm. The signal for the OH
group could not be assigned unambiguously. 13C NMR (125
MHz, CDCl3, 55 °C): d = 23.2 (q, 10-Me), 30.2 (d, C-10),
32.3 (t, C-5), 36.0 (q, 8-Me), 36.5 (t, C-7), 42.2 (d, C-6), 55.1
(t, C-9), 71.5 (s, C-8), 125.1, 125.9, 127.1, 129.6, 136.5,
146.3 (4 d, 2 s, Ar), 51.7, 176.1 (q, s, CO2Me) ppm. IR
(neat): n = 3500 (br, OH), 3100-2840 (=CH, CH), 1715
(C=O) cm–1. ESI-TOF: m/z calcd for: 217.1255 [M + H]+,
239.1074 [M + Na]+, 255.0813 [M + K]+; found: 217.1267,
239.1095, 255.0844.
(1) Selected reviews: (a) Petasis, N. A.; Patane, M. A.
Tetrahedron 1992, 48, 5757. (b) Mehta, G.; Singh, V.
Chem. Rev. 1999, 99, 881.
(2) Namy, J. L.; Girard, P.; Kagan, H. B. New J. Chem. 1977, 1,
5.
(3) Reviews: (a) Gopalaiah, K.; Kagan, H. B. New J. Chem.
2008, 32, 607. (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. (c) Concellon, J. M.;
Rodriguez-Solla, H. Eur. J. Org. Chem. 2006, 1613.
(d) Jung, D. Y.; Kim, Y. H. Synlett 2005, 3019.
(e) Edmonds, D. J.; Johnston, D.; Procter, D.-J. Chem. Rev.
2004, 104, 3371. (f) Berndt, M.; Gross, S.; Hölemann, A.;
Reissig, H.-U. Synlett 2004, 422. (g) Kagan, H. B.
Tetrahedron 2003, 59, 10351. (h) Steel, P. G. J. Chem. Soc.,
Perkin Trans. 1 2001, 2727. (i) Krief, A.; Laval, A.-M.
Chem. Rev. 1999, 99, 745. (j) Kagan, H. B.; Namy, J. L.
Top. Organomet. Chem. 1999, 2, 155. (k) Molander, G. A.;
Harris, C. R. Tetrahedron 1998, 54, 3321. (l) Molander,
G. A.; Harris, C. R. Chem. Rev. 1996, 96, 307.
Synlett 2009, No. 13, 2089–2092 © Thieme Stuttgart · New York

2092
J. Saadi, H.-U. Reissig
LETTER
(Brüdgam, I.; Lentz, D. unpublished results, Freie
Universität Berlin). For all other cyclization products the
suggested relative configuratations are strongly supported
by NOESY correlations.
Analytical Data for (2RS,5SR,7SR)-5,7-Dimethyl-1,5,6,7-
tetrahydro-2,5-methano-4-benzoxonin-3 (2H)-one (15)
1H NMR (500 MHz, CDCl3): d = 1.34 (d, J = 6.9 Hz, 3 H, 7-
Me), 1.36 (s, 3 H, 5-Me), 1.43 (dd, J = 1.1, 13.9 Hz,1 H, 12-
H), 1.55 (dd, J = 11.3, 14.6 Hz, 1 H, 6-H), 1.74–1.79 (m, 1
H, 12-H), 2.05–2.09 (m, 1 H, 6-H), 2.76 (dqd, J = 1.3, 6.9,
11.3 Hz, 1 H, 7-H), 3.15 (dddd, J = 1.1, 2.5, 10.3, 12.8 Hz, 1
H, 2-H), 3.20 (dd, J = 12.8, 14.5 Hz, 1 H, 1-H), 3.31 (dd,
J = 2.5, 14.5 Hz, 1 H, 1-H), 7.00–7.02, 7.15–7.18, 7.28–7.36
(3 m, 1 H, 1 H, 2 H, Ar) ppm. 13C NMR (125 MHz, CDCl3):
d = 22.5 (q, 7-Me), 29.6 (q, 5-Me), 30.0 (d, C-7), 34.2 (t, C-
12), 34.5 (t, C-1), 39.3 (d, C-2), 51.4 (t, C-6), 86.3 (s, C-5),
125.4, 126.7, 127.9, 130.4, 136.8, 146.2 (4 d, 2 s, Ar), 181.5
(s, C-3) ppm. IR (KBr): n = 3065–2825 (=CH, CH), 1755
(C=O) cm–1. Anal. Calcd for C15H18O2 (230.3): C, 78.23; H,
7.88. Found: C, 78.49; H, 7.93.
(12) (a) Dinesh, C. U.; Reissig, H.-U. Angew. Chem. Int. Ed.
1999, 38, 789; Angew. Chem. 1999, 111, 874. (b) Berndt,
M.; Reissig, H.-U. Synlett 2001, 1290. (c) Gross, S.;
Reissig, H.-U. Synlett 2002, 2027. (d) Berndt, M.;
Hlobilová, I.; Reissig, H.-U. Org. Lett. 2004, 6, 957.
(e) Aulenta, F.; Berndt, M.; Brüdgam, I.; Hartl, H.; Sörgel,
S.; Reissig, H.-U. Chem. Eur. J. 2007, 13, 6047.
(f) Wefelscheid, U. K.; Reissig, H.-U. Adv. Synth. Catal.
2008, 350, 65. (g) Wefelscheid, U. K.; Berndt, M.; Reissig,
H.-U. Eur. J. Org. Chem. 2008, 3635. (h) Kumaran, R. S.;
Reissig, H.-U. Synlett 2008, 991.
(13) For a recent study on the influence of HMPA on ketyl-alkene
cyclizations, see: (a) Sadasivam, D. V.; Antharjanam, P. K.
S.; Prasad, E.; Flowers, R. A. II. J. Am. Chem Soc. 2008, 130,
7228. (b) Flowers, R. A. Synlett 2008, 1427.
(10) In cis products the lactone bridge is formed under the
reaction conditions due to the proximity of the hydroxy and
methoxycarbonyl groups.
(11) The relative configurations of the 18b and 28 were
unambiguously determined by the X-ray crystallography
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