Diastereoselective syntheses of functionalized five-membered carbocycles and heterocycles by a SmI2-promoted intramolecular coupling of bromoalkynes and α,β-unsaturated esters

Article abstract of DOI:10.1021/ol101034s

An intramolecular coupling of bromoalkynes with α,β-unsaturated esters afforded functionalized five-membered carbocycles and heterocycles with high diastereoselectivities in excellent yields. The vinyl bromides newly generated as the products serve as adequate intermediates for further chemical modification.

Full text of DOI:10.1021/ol101034s

ORGANIC
LETTERS
2010
Vol. 12, No. 13
3026-3029
Diastereoselective Syntheses of
Functionalized Five-Membered
Carbocycles and Heterocycles by a
SmI2-Promoted Intramolecular Coupling of
Bromoalkynes and r,ꢀ-Unsaturated Esters
Kazunori Takahashi and Toshio Honda*
Faculty of Pharmaceutical Sciences, Hoshi UniVersity, Ebara 2-4-41, Shinagawa-ku,
Tokyo 142-8501, Japan
honda@hoshi.ac.jp
Received May 5, 2010
ABSTRACT
An intramolecular coupling of bromoalkynes with r,ꢀ-unsaturated esters afforded functionalized five-membered carbocycles and heterocycles
with high diastereoselectivities in excellent yields. The vinyl bromides newly generated as the products serve as adequate intermediates for
further chemical modification.
There has been increasing interest in the development of new
methods for selective syntheses of functionalized small- and
medium-sized carbocycles and heterocycles with control of
relative and absolute configurations due to both pharmacological
applications of many of these cores and the presence of these
skeletons in biologically relevant compounds including natural
products.1 An intramolecular coupling reaction of alkynes with
activated alkenes provides one of the most promising routes to
furnish functionalized cyclic compounds. For this purpose,
transition-metal-mediated carbon-carbon bond-forming reac-
tions of alkynes with R,ꢀ-unsaturated carbonyl compounds using
Rh, Pd, Co, Ni, and Ti complexes remain as outstanding
methods for the construction of five-membered cyclic com-
pounds,2 in which the corresponding metalacycles generated
from an intramolecular enyne coupling of the starting materials
are involved as intermediates. When this type of reaction was
applied to terminus-substituted alkynes, (E)-isomers were
always isolated as the major products as shown in Scheme 1.
Interestingly, a sequential rhodium-catalyzed silylcarbocy-
clization of enynes afforded the corresponding (Z)-silylated
isomer, exclusively, which on a palladium-catalyzed, silicon-
based cross-coupling reaction afforded highly substituted cy-
clopentanes stereoselectively.2a,b
An intramolecular samarium diiodide-promoted cou-
pling of aldehydes or ketones with R,ꢀ-unsaturated
carbonyl compounds via a conjugate addition of ketyl
radicalsgeneratedinsituisawell-establishedcarbon-carbon
bond-forming reaction to give the corresponding cycliza-
tion products.3
(2) Rh catalyst, see: (a) Denmark, S. E.; Liu, J. H.-C. J. Am. Chem.
Soc. 2007, 129, 3737–3744. (b) Denmark, S. E.; Liu, J. H.-C.; Muhuhi,
J. M. J. Am. Chem. Soc. 2009, 131, 14188–14189. Pd catalyst, see: (c)
Tsukamoto, H.; Suzuki, T.; Uchiyama, T.; Kondo, Y. Tetrahedron Lett.
2008, 49, 4174–4177. Co catalyst, see: (d) Chang, H.-T.; Jayanth, T. T.;
Wang, C.-C.; Cheng, C.-H. J. Am. Chem. Soc. 2007, 129, 12032–12041.
Ni catalyst, see: (e) Montgomery, J.; Oblinger, E.; Savchenko, A. V. J. Am.
Chem. Soc. 1997, 119, 4911–4920. (f) Ni, Y.; Kassab, R. M.; Chevliakov,
M. V.; Montgomery, J. J. Am. Chem. Soc. 2009, 131, 17714–17718. Ti
catalyst, see: (g) Urabe, H.; Suzuki, K.; Sato, F. J. Am. Chem. Soc. 1997,
119, 10014–10027.
(1) (a) Heathcock, C. H.; Graham, S. L.; Pirrung, M. C.; Plavac, F.;
White, C. T. The Total Synthesis of Natural Products; ApSimon, J., Ed.;
John Wiley & Sons: New York, 1983; Vol. 5. (b) Rigby, J. H. Studies in
Natural Products Chemistry; Atta-ur-Rahman, Ed.; Elsevier Science
Publishers B.V.: Amsterdam, 1988; Vol. 12. (c) Chang, C. W. J.; Scheuer,
P. J. Top. Curr. Chem. 1993, 167, 33–75. (d) Fraga, B. M. Nat. Prod. Rep.
1995, 12, 303–320. (e) Fraga, B. M. Nat. Prod. Rep. 1998, 15, 73–92.
10.1021/ol101034s  2010 American Chemical Society
Published on Web 06/01/2010

We envisaged that the installation of a functional group at
the terminal alkyne moiety might enhance the coupling of
alkynes with R,ꢀ-unsaturated carbonyl compounds since sa-
marium metal would be expected to coordinate with both a
functional group on the alkyne and an ester oxygen. The
formation of such a relatively rigid structure might facilitate
the reactivity of R,ꢀ-unsaturated esters.5 Moreover, if the
installed functional group remained untouched during the
coupling, it would be a suitable precursor for further chemical
modification to highly substituted carbocycles or heterocycles
(Figure 1). On the basis of this concept, we decided to introduce
a bromine atom to the alkyne moiety, although the correspond-
ing alkynylsamarium was suspected to be formed prior to the
expected carbon-carbon bond-forming reaction.6
Scheme 1
.
Previously Reported Transition-Metal-Mediated
Enyne Coupling
A similar reaction of alkynes with R,ꢀ-unsaturated carbonyl
compounds has also been reported as a general synthetic route
to cyclic compounds by Moloney,4 in which the cyclization
occurred at the ꢀ-position of the enone system, leading to
preferential formation of five-membered compounds as the
major products. However, low chemical yields as well as poor
diastereoselectivities were observed in these carbon-carbon
bond-forming reactions, especially in the case of R,ꢀ-unsaturated
esters due to their low reactivity as shown in Scheme 2.
Scheme 2
.
Moloney’s SmI2-Mediated Cyclization of Alkynes
with Unsaturated Carbonyl Compounds
Figure 1. Basic concept for SmI2-promoted cyclization.
Thus, we investigated a samarium diiodide-promoted in-
tramolecular cyclization of bromoalkynes with R,ꢀ-unsaturated
esters, and we disclose herein an unprecedented coupling
reaction leading to the corresponding five-membered cyclization
products with high diastereoselectivities in excellent yields.
We first examined the reaction of 1-ethyl 4,4-dimethyl (1E)-
7-bromohept-1-en-6-yne-1,4,4-tricarboxylate 1a with SmI2 (3
equiv) in THF in the presence of MeOH as a proton source at
0 °C for 1 h; however, none of the cyclized product 2a was
isolated (Table 1, entry 6). When a similar reaction was carried
out in the presence of HMPA7 as an additive, the desired
product 2a was isolated in 64% yield, in which the bromine
atom remained on the exo-methylene moiety (Table 1, entry
1).
This report prompted us to investigate a general and efficient
samarium diiodide-promoted intramolecular coupling reaction
of alkynes with R,ꢀ-unsaturated esters, leading to functionalized
cyclic products, hopefully with high stereoselectivity, under mild
reaction conditions.
Although the mechanistic rationale for this coupling reaction
remains unclear, the presence of a bromine atom seems to play
an important role based on the consideration of the previous
works,4 and the desired carbon-carbon bond-forming reaction
takes place prior to an alternatively feasible formation of the
corresponding alkynylsamarium.
(3) For recent reviews of SmI2-mediated reaction, see: (a) Soderquist,
J. A. Aldrichimica Acta 1991, 24, 15–23. (b) Molander, G. A. Chem. ReV.
1992, 92, 29–68. (c) Molander, G. A. Org. React. 1994, 46, 211–367. (d)
Molander, G. A.; Harris, C. R. Chem. ReV. 1996, 96, 307–338. (e)
Skrydstrup, T. Angew. Chem., Int. Ed. 1997, 36, 345–347. (f) Molander,
G. A.; Harris, C. R. Tetrahedron 1998, 54, 3321–3354. (g) Nomura, R.;
Endo, T. Chem.sEur. J. 1998, 4, 1605–1610. (h) Krief, A.; Laval, A.-M.
Chem. ReV. 1999, 99, 745–777. (i) Steel, P. G. J. Chem. Soc., Perkin Trans.
1 2001, 2727–2751. (j) Agarwal, S.; Greiner, A. J. Chem. Soc., Perkin Trans.
1 2002, 2033–2042. (k) Kagan, H. B. Tetrahedron 2003, 59, 10351–10372.
(l) Berndt, M.; Gross, S.; Ho¨lemann, A.; Reissig, H.-U. Synlett 2004, 422–
438. (m) Edmonds, D. J.; Johnston, D.; Procter, D. J. Chem. ReV. 2004,
104, 3371–3403. (n) Jung, D. Y.; Kim, Y. H. Synlett 2005, 3019–3032. (o)
Gopalaiah, K.; Kagan, H. B. New J. Chem. 2008, 32, 607–637. (p) Rudkin,
I. M.; Miller, L. C.; Procter, D. J. Organomet. Chem. 2008, 34, 19–45. (q)
Nicolaou, K. C.; Ellery, S. P.; Chen, J. S. Angew. Chem., Int. Ed. 2009, 48,
7140–7165. (r) Procter, D. J.; Flowers, R. A., II; Skrydstrup, T. Organic
Synthesis Using Samarium Diiodide: A Practical Guide; Royal Society of
Chemistry Publishing: UK, 2010; p 204.
(5) Medium-sized chelation structure was proposed, see: Helm, M. D.;
Silva, M. D.; Sucunza, D.; Findley, T. J. K.; Procter, D. J. Angew. Chem.,
Int. Ed. 2009, 48, 9315–9317.
(6) It has been reported that the reaction of iodoalkyne with samarium
diiodide afforded the corresponding alkynylsamarium. See: Kunishima, M.;
Nakata, D.; Tanaka, S.; Hioki, K.; Tani, S. Tetrahedron 2000, 56, 9927–
9935.
(7) (a) Otsubo, K.; Inanaga, J.; Yamaguchi, M. Tetrahedron Lett. 1986,
27, 5763–5764. (b) Shabangi, M.; Robert, A.; Flowers, R. A., II Tetrahedron
Lett. 1997, 38, 1137–1140. (c) Prasad, E.; Flowers, R. A., II J. Am. Chem.
Soc. 2002, 124, 6895–6899. (d) Flowers, R. A., II Synlett 2008, 1427–
1439. (e) Sadasivam, D. V.; Antharjanam, P. K. S.; Prasad, E.; Flowers,
R. A., II J. Am. Chem. Soc. 2008, 130, 7228–7229.
(4) (a) Baldwin, J. E.; Turner, S. C.; Moloney, M. G. Tetrahedron 1994,
50, 9411–9424. (b) Baldwin, J. E.; Turner, S. C.; Moloney, M. G.
Tetrahedron 1994, 50, 9425–9438.
Org. Lett., Vol. 12, No. 13, 2010
3027

Table 1. SmI2-Promoted Coupling in the Presence of a Proton
Table 2. Synthesis of Five-Membered Heterocycles
Source
entry
H+ source (equiv)
yield (%)
1
2
3
4
5
6
7
8
s
64
59
67
74
76
0
77
77
79
78
77
H2O (40)
tert-BuOH (5)
MeOH (1)
MeOH (5)
MeOH (5)a
MeOH (10)
HFIP (1)
HFIP (5)
HFIP (10)
HFIP (40)
9
10
11
a Starting material (73%) and debrominated compound (18%) were
isolated in the absence of HMPA.
Since the expected cyclization was perceived to proceed in
moderate yield with the bromine atom remaining, a study was
carried out to investigate the best reaction conditions for this
conversion, and it was found that the presence of a proton source
gave the cyclopentanes in good yields. As can be seen in Table
1, almost all of the proton sources are effective for this coupling.
Among them, the use of HFIP (hexafluoroisopropanol)8 gave
the desired product 2a in 79% yield as the sole product.
It should be noted that a samarium diiodide-promoted
carbon-carbon bond formation of 1a proceeded via 5-exo-dig
mode exclusively to provide the cyclopentane 2a, and no six-
membered compound arising from 6-endo-dig cyclization was
isolated.
To extend the scope of this carbon-carbon bond formation,
syntheses of oxygen and nitrogen heterocycles, often observed
in various types of natural products as core fragments,9 were
extensively investigated. The results obtained are summarized
in Table 2.
Treatment of 1b (X ) NTs, Y ) CH2) with SmI2 (3 equiv)
in THF-HMPA (20:1, v/v) in the presence of HFIP (5 equiv)
at 0 °C for 1 h afforded 3,4-disubstituted pyrrolidine 2b in 90%
yield as the sole product with (E)-configuration (entry 1). The
stereochemistry of the alkene moiety was determined unam-
biguously by analysis of its NOE spectrum. The same reaction
for ether 1c (X ) O, Y ) CH2) also gave 3,4-disubstituted
tetrahydrofuran 2c in 69% yield with (E)-configuration (entry
2). The coupling could be applied to enol ether 1d (X ) CH2,
Y ) O), furnishing 2,3-disubstituted tetrahydrofuran 2d in 66%
a The relative stereochemistry between 2- and 4-positions is mentioned.
b (Z)-Unsaturated ester is employed as a starting material.
yield (entry 3). When this reaction was carried out with the
starting material 1e possessing a substituent at the propargylic
position, the corresponding pyrrolidine 2e was obtained as a
diastereoisomeric mixture, in a ratio of trans:cis ) 88:12, in
60% yield. In this product, the geometry of the alkene moiety
again was confirmed to be (E) (entry 4). Further application of
the strategy to amine 1f bearing an (S)-isopropyl group at the
allylic position gave the 2,3-trans-pyrrolidine 2f diastereose-
lectively, as a single product, in 81% yield (entry 5).
(8) Edmonds, D. J.; Muir, K. W.; Procter, D. J. J. Org. Chem. 2003,
68, 3190–3198.
(9) (a) Faulkner, D. J. J. Nat. Prod. Rep. 1984, 1, 251–280. (b) Faulkner,
D. J. Nat. Prod. Rep. 1984, 1, 551–598. (c) Faulkner, D. J. Nat. Prod. Rep.
1986, 3, 1–33. (d) Faulkner, D. J. Nat. Prod. Rep. 1987, 4, 539–576. (e)
Faulkner, D. J. Nat. Prod. Rep. 1988, 5, 613–663.
It can be rationalized on the basis of results shown in Table
2 that the bulkiness of a substituent at the allylic position seems
3028
Org. Lett., Vol. 12, No. 13, 2010

to play an important role in control of the stereochemistry at
the 3-position of 2,3-substituted pyrrolidines (entries 5-9). By
investigation of the ester group, it was found that chemical yields
were not influenced by the steric bulk of the ester alkyl group;
however, higher diastereoselectivities were observed for methyl
and ethyl esters than for the tert-butyl group, probably due to
the absence of steric hindrance between the substituent at the
2-position and the ester (entry 6). Surprisingly, trans:cis ratios
of the products were greatly improved when the coupling was
carried out with the use of the corresponding (Z)-unsaturated
esters as starting materials (entries 7 and 9).
less-hindered side after carbon-carbon bond-forming reaction
to furnish the corresponding (E)-alkene isomers as major
products.11
Interestingly, the coupling reaction of N-allyl-N-(3-bro-
moprop-2-yn-1-yl)-4-methylbenzenesulfonamide (de-ethoxy-
carbonyl, 1b) with samarium diiodide did not take place under
the same reaction conditions even in the presence of HMPA.
This result might support the hypothesis that the first electron
transfer occurred at the R,ꢀ-unsaturated ester rather than at the
triple bond.
Scheme 3. Chemical Modification of the Alkenyl Bromide
An advantage of this reaction is being able to control
stereochemistry at the allylic position and to modify the alkenyl
bromide newly elaborated in the products leading to highly
functionalized five-membered compounds. To prove the po-
tential utility of the bromine atom, a functionalization of alkenyl
bromide was attempted by palladium-catalyzed coupling reac-
tions as shown in Scheme 3.
In summary, we were able to establish a general and efficient
samarium diiodide-promoted intramolecular coupling reaction
of bromoalkynes with R,ꢀ-unsaturated esters leading to highly
functionalized five-membered carbocycles and heterocycles,
where the carbon-carbon bond-forming reaction occurred with
high diastereoselectivity under mild reaction conditions. We
believe that the synthetic strategy developed here has great potential
for the synthesis of a wide range of bioactive compounds, including
natural products, bearing such a cyclic system.
Figure 2. Plausible SmI2-mediated coupling of (E)-R,ꢀ-unsaturated esters.
Preferential formation of 2,3-trans-pyrrolidines from (E)-R,ꢀ-
unsaturated esters would be realized based on examination of
molecular models of the transition states as depicted in Figure
2, where the transition state (A) was preferred to the transition
state (B) in terms of energetic and steric reasons.
Acknowledgment. This research was supported financially
in part by a grant for The Open Research Center Project and a
Grant-in-Aid from the Ministry of Education, Culture, Sports,
Science and Technology of Japan.
Figure 3. SmI2-mediated coupling of (Z)-R,ꢀ-unsaturated esters.
The improved trans:cis ratio for (Z)-R,ꢀ-unsaturated esters
is consistent with the mechanistic proposal shown in Figure
3,10 where severe steric repulsion was observed in the transition
state (D) leading to the 2,3-cis-isomer. Thus, the 2,3-trans-
isomer from the transition state (C) would be a preferential
product. In both cases, protonation occurred from the sterically
Supporting Information Available: Experimental details
and compound characterization. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL101034S
(11) When the phenylacetylene derivative was subjected to the same
reaction, the (Z)-benzylidene derivative (Z-3b) was obtained as a major
compound (58%, Z:E ) 88:12). On the other hand, a similar reaction of alkyl-
substituted alkynes did not give any coupling products. Thus, it is assumed
that the substituents on alkynes contributing to stabilization of radicals generated
as intermediates is important for this type of cyclization.
(10) (a) Prasad, E.; Flowers, R. A., II J. Am. Chem. Soc. 2002, 124,
6357–6361. (b) Honda, T.; Naito, K.; Yamane, S.; Suzuki, Y. J. Chem.
Soc., Chem. Commun. 1992, 1218–1219. (c) Hansen, A. M.; Lindsay, K. B.;
Antharjanam, P. K. S.; Karaffa, J.; Daasbjerg, K.; Robert, A.; Flowers, R. A.,
II; Skrydstrup, T. J. Am. Chem. Soc. 2006, 128, 9616–9617.
Org. Lett., Vol. 12, No. 13, 2010
3029