Development of a tandem cyclization mediated by samarium(II) iodide: sequential intramolecular conjugate addition/nucleophilic acyl substitution

Article abstract of DOI:10.1016/j.tetlet.2006.06.146

The development of a one-pot tandem intramolecular conjugate addition/nucleophilic acyl substitution using samarium(II) iodide is reported. The reaction relies on the reagent's unique ability to mediate both radical and anionic pathways, which are likely integral to the mechanism of this transformation. The tricyclic hemiacetal product was formed in good yield, with excellent diastereoselectivity, and its structure was verified by X-ray crystallographic analysis.

Full text of DOI:10.1016/j.tetlet.2006.06.146

Tetrahedron Letters 47 (2006) 6225–6227
Development of a tandem cyclization mediated by
samarium(II) iodide: sequential intramolecular conjugate
addition/nucleophilic acyl substitution
*
David J. St. Jean, Jr., Edward P. Cheng and Eric A. Bercot
Chemistry Research and Development, Amgen, Inc., One Amgen Center Dr. Thousand Oaks, CA 91320, United States
Received 21 June 2006; revised 27 June 2006; accepted 27 June 2006
Available online 18 July 2006
Abstract—The development of a one-pot tandem intramolecular conjugate addition/nucleophilic acyl substitution using sama-
rium(II) iodide is reported. The reaction relies on the reagent’s unique ability to mediate both radical and anionic pathways, which
are likely integral to the mechanism of this transformation. The tricyclic hemiacetal product was formed in good yield, with excellent
diastereoselectivity, and its structure was verified by X-ray crystallographic analysis.
Ó 2006 Elsevier Ltd. All rights reserved.
Since the initial report by Kagan, samarium diiodide has
been shown to be a versatile reducing agent in organic
cyclic hemiacetal (2). Realization of this method could
potentially be utilized to construct a variety of tricyclic
acetals, including epimeric analogues of the carotene
1
chemistry. This one-electron reductant has been shown
to mediate a variety of transformations.2–8 Interestingly,
although there exist a number of tandem reactions med-
iated by samarium diiodide, only a few fully utilize this
reagent’s unique ability to mediate both radical and
sesquiterpene class of natural products.
15
This tandem process presents two primary challenges.
The first is deleterious side reactions, which could be
minimized by modulating the reactivity of one halide
5
,9,10
anionic processes.
(i.e. X, Fig. 1). The second challenge is protonation of
Samarium diiodide has been shown to mediate the con-
the enolate that results from conjugate addition without
quenching the intermediate organosamarium (1). Selec-
tion of an appropriate alcoholic additive and careful
temperature control may ameliorate this issue.
jugate addition of alkyl halides onto a variety of a,b-
1
1,12
unsaturated systems.
Furthermore, this reagent has
also proven to be a suitable reductant for intramolecular
1
3,14
nucleophilic acyl substitutions.
Given the unique
ability of SmI to mediate either radical or anionic path-
In order to examine the effect of the halide on the tan-
2
1
6
ways, we envisioned a tandem ring forming reaction that
would capitalize on this reactivity. This proposed novel
tandem process is shown in Figure 1. After initial disso-
ciative electron transfer, the resulting radical would
undergo a facile conjugate addition. It has been shown
previously that similar reactions proceeded stereoselec-
dem process, compounds 3, 4, and 5 were synthesized.
Our initial efforts focused on the conditions previously
1
2
reported and utilized unsaturated lactones 3 and 4.
Unfortunately, when 3 was exposed to the conditions
shown below (Table 1), no product was seen after visible
1
7–20
light irradiation.
The more reactive alkyl bromide 4
1
2
tively forming the syn isomer exclusively. After a sec-
also failed, providing only small amounts of the desired
ond reduction by SmI , the samarium enolate should
product. However, when 5 was exposed to SmI , 2 was
2
2
be protonated by an alcoholic additive present in solu-
tion to provide an intermediate halo lactone. Following
formed in 32% as a single diastereomer.
two additional reductions by SmI , the organosamarium
intermediate (1) would cyclize to yield the desired tri-
Since the selective quenching of the intermediate enolate
was crucial to the success of this reaction, a survey of
alcoholic additives was undertaken (Table 1). A variety
of different protic additives were examined. Eventually,
it was determined that 1 equiv of MeOH was optimal
2
*
Corresponding author. Tel.: +1 805 313 5153; fax: +1 805 480
337; e-mail: dst.jean@amgen.com
1
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.146

6226
D. J. St. Jean, Jr. et al. / Tetrahedron Letters 47 (2006) 6225–6227
O
O
O
SmI , conditions
2
O
O
O
Me
Conjugate Addition
radical cyclization)
X
X
X
Me
Me
(
I
OSmIII
O
SmI2
1 equiv. ROH
O
O
Me
Me
X
Enolate Protonation
X
OSmIII
O
OH
O
O
2
SmI2
Me
H2O
Me
O
Me
Nucleophilic Acyl
Substitution
anionic cyclization)
SmIII
(
1
2
2
Figure 1. Proposed tandem cyclization mediated by SmI .
Table 1. Optimization of the tandem conjugate addition/nucleophilic
acyl substitution mediated by samarium(II) iodide
O
OH
6
equiv SmI2
O
1 equiv ROH
Me
O
Me
3
mol % NiI2
THF, -78 °C to rt,
X
12 h
2
I
X = Cl, 3
X = Br, 4
X = I, 5
X
ROH
Isolated yield of 2 (%)
Cl
Br
Br
I
t-BuOH
t-BuOH
MeOH
0
Trace
8
t-BuOH
32
I
I
CF
MeOCH
3
CH
2
OH
OH
0
27
Figure 2. X-ray crystal structure of 2.
2
I
I
I
I
MeOH
3 equiv MeOH
None
43
Trace
0
2
Table 2. SmI -mediated tandem conjugate addition/nucleophilic acyl
substitution
a
MeOH
67
a
Substrate
Product
OH
Yield (%)
After warming to À20 °C, the temperature was maintained for 2.5 d.
O
H
for this system. In addition to screening protic additives,
the effect of temperature was also investigated. Main-
taining the reaction at À20 °C (rather than warming to
rt) delivered 2 in 67% yield. Under these conditions,
the competing quench of the alkyl organosamarium
intermediate (1) was avoided. The product of this tan-
dem cyclization protocol, 2, was verified by X-ray crys-
tallographic analysis (Fig. 2).
O
O
45
I
I
6
OH
O
H
O
37
O
I
This optimized method (6 equiv SmI , 3 mol % NiI ,
I
2
2
7
1
equiv of MeOH, À78 to À20 °C) appears to be appli-
2
1
cable to other unsaturated lactones (Table 2).
It is important to note that when the reaction was car-
ried out in the presence of excess MeOH (see Table 1),
only trace amounts of 2 were formed. The major prod-
uct from this reaction was 8 (44% yield, Scheme 1),

D. J. St. Jean, Jr. et al. / Tetrahedron Letters 47 (2006) 6225–6227
6227
O
O
OH
O
O
6
equiv SmI2
3
equiv MeOH
O
Me
O
Me
O
Me
3
mol % NiI2
THF
Me
CH3
-
78 °C to -20 °C,
I
trace
4
4%
8%
24 h
I
5
8
2
Scheme 1.
which is derived from conjugate addition followed by
reduction, rather than nucleophilic acyl substitution.
The formation of 6 in the presence of excess protic addi-
tive, along with other observations reported in the liter-
7. Edmonds, D. J.; Johnston, D.; Procter, D. J. Chem. Rev.
004, 104, 3371–3403.
2
8
9
. Jung, D. Y.; Kim, Y. H. Synlett 2005, 3019–3032.
. Molander, G. A.; Harris, C. R. J. Am. Chem. Soc. 1996,
118, 4059–4071.
1
1,12
ature,
supports the notion of sequential radical and
1
0. Molander, G. A.; Harring, L. S. J. Org. Chem. 1990, 55,
171–6176.
1. Molander, G. A.; Harris, C. R. J. Org. Chem. 1997, 62,
418–7429.
anionic cyclizations.
6
1
We have reported the first example of a one-pot tandem
conjugate addition/nucleophilic acyl substitution medi-
7
12. Molander, G. A.; St. Jean, D. J., Jr. J. Org. Chem. 2002,
67, 3861–3865.
13. Molander, G. A.; Brown, G. A.; Storch de Gracia, I. J.
Org. Chem. 2002, 67, 3459–3463.
2
2
ated by samarium diiodide. The reaction is unique
since it proceeds through both radical and anionic cycli-
zation. Furthermore, the process provides rapid entry to
complex tricyclic hemiacetals from relatively simple pre-
cursors in sequential steps.
1
4. Molander, G. A.; Machrouhi, F. J. Org. Chem. 1999, 64,
119–4123.
4
1
5. Fraga, B. M.; Hernandez, M. G.; Diaz, J. G.; Gonzalez,
A. G.; Gonzalez, P. Phytochemistry 1986, 25, 2883–2886.
6. See Supplementary data.
1
1
Acknowledgments
7. Ogawa, A.; Ohya, S.; Hirao, T. Chem. Lett. 1997, 275–
2
76.
The authors would like to thank Professor Gary A. Mo-
lander for his insights regarding this work. We would
also like to thank Professor Michael Leonard and Dr.
Barbara Czak o´ for their help in preparing this
manuscript.
18. Ogawa, A.; Sumino, Y.; Nanke, T.; Ohya, S.; Sonoda, N.;
Hirao, T. J. Am. Chem. Soc. 1997, 119, 2745–2746.
19. Molander, G. A.; Koellner, C. J. Org. Chem. 2000, 65,
8
333–8339.
2
0. The reaction was followed by TLC. Once the conjugate
addition was complete, the mixture was irradiated with
visible light for 12 h. This resulted in a complex mixture of
nonpolar products.
21. These substrates were synthesized from 1,7-dichlorohep-
tan-4-one based on procedures that were reported previ-
ously (see Ref. 12).
Supplementary data
The supplementary data include synthetic procedures
1
13
2
2. Optimized procedure for 2: To a 250 mL Schlenk flask was
added 0.950 g (6.0 mmol) of samarium metal. This metal
was flame-dried under vacuum and allowed to cool to rt
under nitrogen. Dry THF (60 mL) was added, and the
suspension was cooled to 0 °C. CH I (1.57 g, 0.475 mL,
for the synthesis of 3, 4, and 5 (including H and
C
NMR data), analytical data for 6 and 7, and the X-
ray data for 2. Supplementary data associated with this
article can be found, in the online version, at
doi:10.1016/j.tetlet.2006.06.146.
2
2
6
.0 mmol) was added, and the mixture was warmed to rt.
After stirring in the dark for 3 h, a dark blue solution was
obtained. This solution was then cooled to À78 °C where
References and notes
NiI (0.050 g, 0.16 mmol) was added under a stream of
2
nitrogen. A solution of 5 (0.434 g, 1.0 mmol) and MeOH
(0.041 mL, 1.0 mmol) in 10 mL of THF was then added
dropwise. The solution was slowly allowed to warm to
À20 °C (over 5 h) and was then maintained at that
temperature for 2.5 d. After that time, the blue solution
was quenched with 25 mL of a saturated aqueous solution
of Rochelle’s salt. After stirring for 3 h at rt, the mixture
was extracted with EtOAc. The combined extracts were
dried and concentrated to provide an oil, which was
purified by column chromatography (12.5–40% EA/Hex)
to yield 0.122 g of 2 (67%) as oil that slowly crystallized.
1
. Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc.
980, 102, 2693–2698.
1
2. Soderquist, J. A. Aldrichim. Acta 1991, 24, 15–23.
3. Molander, G. A. Org. React. (N.Y.) 1994, 46, 211–367.
4. Molander, G. A.; Harris, C. R. Chem. Rev. 1996, 96, 307–
3
38.
. Molander, G. A.; Harris, C. R. J. Org. Chem. 1997, 62,
944–2956.
. Molander, G. A.; Harris, C. R. Tetrahedron 1998, 54,
321–3354.
5
6
2
3