Cyclopentane Formation from Flexible Precursors Using Samarium(II) Reagents

Article abstract of DOI:10.1002/ejoc.201800102

Three efficient methods for five-membered ring carbocycle synthesis have been developed from simple starting materials using samarium(II) reagents. A Reformatsky aldol reaction proceeded efficiently with samarium(II) iodide using lithium bromide as an additive. A new intramolecular alkylation of a samarium enolate was realized with a pendant sulfonate ester leaving group. Pinacol cyclization of a simple diketone was also demonstrated giving a diol product in high stereoselectivity. A promising lead result has been established demonstrating enantioselectivity in a chiral ligand controlled Reformatsky aldol reaction.

Full text of DOI:10.1002/ejoc.201800102

A Journal of
Accepted Article
Title: Cyclopentane formation from flexible precursors using
samarium(II) reagents
Authors: Christopher D. Aretz, Humberto Escobedo, and Bryan James
Cowen
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800102
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800102
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10.1002/ejoc.201800102
European Journal of Organic Chemistry
COMMUNICATION
Cyclopentane formation from flexible precursors using
samarium(II) reagents
Christopher D. Aretz,[b] Humberto Escobedo, and Bryan J. Cowen*[a]
Abstract: Three efficient methods for five-membered ring carbocycle
synthesis have been developed from simple starting materials using
O
O
O
OH
samarium(II) reagents. A Reformatsky aldol reaction proceeded
efficiently with samarium(II) iodide using lithium bromide as an
additive. A new intramolecular alkylation of a samarium enolate was
realized with a pendant sulfonate ester leaving group. Pinacol
cyclization of a simple diketone was also demonstrated giving a diol
product in high stereoselectivity. A promising lead result has been
X
X
O
Reformatsky aldol
Enolate alkylation
R1
R1
O
LG
R1
R1
established demonstrating enantioselectivity in
controlled Reformatsky aldol reaction.
a chiral ligand
O
OH
R2
HO
R1
Pinacol
R1
R2
O
Introduction
Scheme 1. This work: Sm(II)-promoted cyclizations providing pentacyclic
products.
Since its discovery in 1977 by Kagan, samarium(II) iodide (SmI2)
has been employed in several types of organic transformations as
a single electron reducing agent.[1] Powerful carbon-carbon bond
forming processes like carbonyl-alkene, radical-alkene, pinacol,
Reformatsky aldol, Barbier, and Grignard reactions proceed
smoothly with SmI2 that would be difficult to accomplish with other
methods.[2] Furthermore, tandem processes are often facilitated
with this reagent through careful substrate design and judicious
choice of reaction conditions.[3] Recent work has confirmed the
sensitivity of SmI2 to exogenous ligands and has served to
develop additives that increase the reduction potential of SmI2
leading to a more facile electron transfer to the organic substrate
acceptor.[4] These studies have greatly expanded the reaction
scope and applications of newly discovered ligand-SmI2 systems.
Also, the use of the carcinogenic Lewis base additive
hexamethylphorsphoramide (HMPA) has become less common
with the identification of more benign additives for Sm(II)-
promoted reactions. Furthermore, Sm(II) reagents other than
SmI2 have proven to be successful reducing agents for a range of
organic transformations.[4c,d]
Results and Discussion
We began our studies with the synthesis of various aryl
ketone precursors for reductive cyclization reactions with Sm(II)
reagents. Starting from e-caprolactone (1), Grignard addition to
the in situ generated Weinreb amide gave alcohol product 2 in
good yield (Scheme 2).[7] After some experimentation, we found
phenyltrimethylammonium tribromide (PTT) as a convenient
reagent for the synthesis of a-bromoketone 3 without the
requirement for first protecting the primary alcohol.[8] Subsequent
oxidation of this alcohol with Dess-Martin periodinane (DMP)
provided aldehyde product 4a in good yield.[9] This three-step
sequence proved general for a set of aryl ketones providing
substrates to be studied in Sm(II)-promoted intramolecular
Reformatsky aldol reactions. Furthermore, simple substitution of
DMP for methanesulfonyl chloride (MsCl) in the sequence then
provided a method for the synthesis of primary mesylated
compounds such as phenyl ketone 5a in short order. These
substrates would be investigated in Sm(II)-promoted
intramolecular alkylation reactions. Finally, Grignard addition of 5-
bromopentene (6) to benzaldehyde (7) provided benzylic alcohol
8 which was oxidized with DMP to give aryl ketone 9. Wacker
oxidation of the pendant alkene gave diketone product 10a which
The formation of 5-membered ring carbocycles remains an
avenue for further discovery in synthetic organic chemistry. While
recent examples of Pauson-Khand[5] reactions and Lewis base
promoted [3+2]-cycloadditions[6] provide efficient methods to
access these ring systems, more numerous and robust methods
exist for the synthesis of 6-membered ring carbocycles, by
comparison. Recently, our lab became interested in synthesizing
5-membered rings through application of SmI2-promoted
intramolecular Reformatsky aldol, enolate alkylation, and pinacol
reactions (Scheme 1). Cyclization precursors were designed to be
accessed quickly from common simple starting materials. We
selected flexible, unsubstituted carbon chains containing pendant
reactive groups as desirable substrates for the synthesis of
cyclopentanes through Sm(II)-mediated cyclization reactions.
was
a
desired precursor for studying Sm(II)-promoted
intramolecular pinacol cyclization reactions to deliver substituted
cyclopentane products.
[*]
C. D. Aretz, H. Escobedo, Prof. Dr. B. J. Cowen
Department of Chemistry & Biochemistry, University of Denver
2190 E. Iliff Ave., Denver, CO 80208 (USA)
E-mail: bryan.cowen@du.edu
https://portfolio.du.edu/bcowen
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201800102
European Journal of Organic Chemistry
COMMUNICATION
O
O
Br
O
Ph
Ph
O
O
O
SmI2 (2.2 equiv)
LiBr (8 equiv)
O
OH
DMP
97%
MsCl
81%
O
O
PhMgBr
HNMeOMe
PTT
Br
O
O
OH
Br OH
Ar
Ar
Ph
Ph
4a
Br OMs
62%
79%
THF, −15 °C
1
2
3
O
OH
O
OH
OH
5a
MgBr
O
OH
O
O
6
DMP
PdCl2
37%
Me
Ph
Ph
Ph
Ph
Me
96%
11b, 65%[a]
11d, 54%
70%
11c, 51%
7
8
9
10a
O
O
OH
O
OH
O
OH
MeO
S
Scheme 2. Synthesis of cyclization substrates from e-caprolactone. PTT =
phenyltrimethylammonium tribromide, DMP = Dess-Martin periodinane.
MeO
11f, 53%
11e, 64%
11g, 54%
[a] Isolated yield after silica gel chromatography. All products isoldated as a single
diastereomer (>20:1 dr as determined by 1H NMR spectroscopy of the crude
reaction mixture).
Investigations into the Reformatsky aldol reaction
commenced with evaluation of a-bromoketone 4a. Although there
are numerous reports of successful intramolecular Reformatsky
aldol reactions using SmI2, most cases invoke a-halo ester
substrates to provide six-membered ring products. Surprisingly,
there are no reported Sm(II)-promoted cyclization reactions of
simple a-halo ketones such as 4a. We wished to study this
reaction for the facile synthesis of disubstituted cyclopentane
products. Encouragingly, subjection of 4a to SmI2 (2.2 equiv) in
THF at -15 °C gave b-hydroxyketone product 11a with high
diastereoselectivity (>20:1) albeit in a modest 14% yield (Table 1,
entry 1). Raising the temperature to 0 °C increased isolated yield
to 53% but lowered the observed diastereomer ratio (dr) to 8:1
(entry 2). Inclusion of HMPA as an additive was detrimental to the
reaction leading to no observable product formation (entry 3).
However, when lithium bromide was included in the reaction at
-15 °C in THF, product 11a was isolated in 66% yield as a single
diastereomer (dr >20:1; entry 4). Presumably, the strong reducing
agent, samarium(II)bromide (SmBr2), is generated with this
additive allowing for smooth Reformatsky aldol cyclization.[10]
Figure 1. Substrate scope for intramolecular Reformatsky aldol cyclization
We next investigated the intramolecular alkylative cyclization
of mesylated substrate 5a. Unlike the Sm(II)-promoted
Reformatsky reaction, enolate alkylation reactions mediated by
SmI2 are rare.[12],[13] Thus we wished to establish an additional
method for cyclopentane synthesis while also expanding the
scope of Sm(II)-promoted reactions. A survey of a set of
substrates bearing different leaving groups at the e-position to the
carbonyl group were synthesized and studied in a SmI2-promoted
cyclization reaction (Scheme 3). When alkyl halide derivative 5b
was treated with a THF solution of SmI2 (2.2 equiv) at 23 °C no
cyclization to the desired product was observed.[14] Ester
substrates 5c and 5d also led only to recovery of starting material.
However, sulfonate ester 5e smoothly cyclized to cyclopentane
12 which was isolated in 56% yield. Better results were obtained
using the mesylate derivative 5a giving product 12a in 75% yield.
Notably, additives like LiBr did not improve the reaction efficiency
as seen previously for the Reformatsky aldol reaction.
Table 1. Optimization of an intramolecular Reformatsky aldol cyclization
O
O
OH
Br
SmI2 (2.2 equiv)
THF, conditions
O
Ph
Ph
O
O
SmI2 (2.2 equiv)
Br LG
Ph
Ph
4a
11a
Yield (%)[a] dr[b]
THF, 23 °C
Entry
Temperature (°C)
Additive
None
12a
1
2
−15
14
53
0
>20:1
8:1
Substrates and product yields
O
O
O
0
None
Br Cl
Br
O
Me
Br
O
CF3
Ph
Ph
Ph
HMPA[c]
LiBr[d]
−
3
4
0
O
O
−15
66
>20:1
5b
0%
5c
5d
0%
0%
[a] Isolated yield after silica gel chromatography. [b] Determined by 1
NMR spectroscopy of the crude reaction mixture. [c] 10 equiv. [d] 8 equiv.
H
O
O
O
O
Br
O
O
Br
O
Ph
S
Ph
S
Various aromatic a-bromoketones gave similarly good results.
The 1-naphthyl derivative cyclized under the optimized conditions
to give b-hydroxyketone product 11b in 65% yield (Figure 1). The
2-naphthyl substrate underwent reductive Reformatsky aldol
cyclization to provide product 11c in 51% yield. A p-tolyl
substituted ketone cyclized to give cyclopentane product 11d in
54% yield. Electron-rich substrates were competent in the
cyclization with the p-methoxy derivative providing product 11e in
64% yield and m-methoxy ketone giving b-hydroxyketone 11f in
53% yield.[11] A heteroaromatic derivative was also shown to
undergo the Sm(II)-promoted intramolecular Reformatsky aldol
reaction with a thiophene derivative cyclizing to provide product
11g in 54% yield (entry 6). While side products resulting from over
reduction of the carbonyl moieties provided the mass balance of
these reactions, it is notable that all cyclcopentanes were isolated
as the single syn diastereomer.
Me
O
Me
5e
5a
56%
75%
Scheme 3. Alkylative cyclization reactions promoted by SmI2.
Investigation of the substrate scope paralleled the types of
starting materials evaluated for the Reformatsky aldol cyclization.
For example, cyclization of the 1-naphthyl derivative gave product
12b in a moderate 39% yield (Figure 2). The 2-naphthyl derivative
was less efficient delivering product 12c in 21% yield. Treatment
of the p-tolyl substrate with SmI2 in THF resulted in cyclization to
cyclopentane 12d in 53% yield. An electron-rich p-methoxy a-
bromoketone cyclized providing product 12e in 44% isolated yield.
The m-methoxy derivative also cyclized to give product 12f in 36%
yield. We also evaluated our method using a heterocyclic
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10.1002/ejoc.201800102
European Journal of Organic Chemistry
COMMUNICATION
O
OH
Me
substrate as thiophene-substituted a-bromoketone smoothly
underwent the intramolecular cyclization to give product 12g in
58% yield.
HO
Ar
SmI2 (2.2 equiv)
Ar
Me
THF, 23 °C
O
O
O
OH
Me
OH
Me
OH
Me
OH
Me
HO
HO
HO
HO
Br OMs SmI2 (2.2 equiv)
Ar
O
Ar
THF, 23 °C
13a, 62% (64%)[a,b]
13b, 66% (52%)
13c, 26% (64%)
13d, 67%
(79%)
Me
O
O
OH
Me
OH
Me
OH
Me
13g, 22%
(83%)
X = Br
HO
HO
HO
MeO
Me
12b, 39%[a]
12d, 53%
12c, 21%
13h, 15%
(40%)
X = Cl
13f, 73% (90%)[c]
X
MeO
13e, 65% (56%)
O
O
O
MeO
S
[a] Isolated yield after silica gel chromatography. All products isolated as a single diastereomer
(>20:1 dr as determined by 1H NMR spectroscopy of the crude reaction mixture). [b] Yields in
parentheses for reactions run with LiBr (8 equiv). [c] Based on recovered starting material.
MeO
12f, 36%
12e, 44%
12g, 58%
Figure 3. Substrate scope for intramolecular pinacol cyclization.
[a] Isolated yield after silica gel chromatography.
Our lab is also interested in the identification of suitable chiral
ligands for samarium that would result in the enantioselective
formation of cyclopentane products. Sm(II)-promoted reactions in
total synthesis often result in highly diastereoselective reactions
but ligand systems for general enantioselective Sm(II)-promoted
reactions have been elusive.[17] Considering that a Sm(III)-enolate
intermediate species is likely operative in the Reformatsky aldol
cyclization reaction, we sought ligands that were able to bind the
radius of this oxidized lanthanide intermediate. Kobayashi
investigated the intermolecular Mukaiyama aldol reaction of
benzaldehyde (7) with silyl enol ether 14 using crown ether type
ligand 15 and various lanthanide (III) triflates (Scheme 4A).[18]
Sm(OTf)3 catalyzed the reaction to give syn-product 16 in 78%
yield with 53% ee. Preliminary results using this ligand in the
intramolecular Reformatsky aldol reaction gave product 11a with
a promising 30% ee (Scheme 4B). Further investigation of these
types of crown ligands for enantioselective transformations of
Sm(II)-reagents are underway in our lab.
Figure 2. Substrate scope for intramolecular alkylative cyclization.
The next reaction we sought to exploit for the synthesis of
functionalized 5-membered carbocycles was the intramolecular
pinacol cyclization. Sm(II)-promoted pinacol cyclizations are well
established in the literature, although the reaction’s utilization for
the synthesis of cyclopentanes is limited. Implementing the three-
step route to access diketone substrates (see Scheme 2), we
wondered how efficient intramolecular pinacol cyclization of such
flexible precursors to b-hydroxy ketone products would be and if
the resulting diastereomer ratio could be controlled. Notably,
these types of substrates have been cyclized under
electroreductive conditions and using in situ generated Ti(III) do
give anti and syn diastereomers of product respectively.[15] Since
the more convenient SmI2 reagent has not been reported to act
on these substrates, we investigated the pinacol cyclization of aryl
ketone substrates similar to those evaluated in the Reformatsky
aldol and alkylative cyclization reactions. This reaction would lead
to cyclopentane diols with synthetic utility.
Pleasingly, we quickly identified suitable conditions for the
intramolecular pinacol cyclization reaction of diketone 10a.
Treatment with SmI2 (2.2 equiv) in THF at 23 °C led to diol product
13a in 62% isolated yield as a single diastereomer (Figure 3).
Inclusion of LiBr in the reaction led to significant improvement in
isolated yields in several cases.[16] While the 1-naphthyl
substituted diketone cyclized efficiently to give diol product 13b in
66% yield, the corresponding 2-naphthyl derivative led to only a
modest 26% yield of diol 13c. However, this yield increased to
64% of 13c with LiBr as an additive. The p-tolyl-substituted ketone
underwent a smooth pinacol cyclization to give product 13d in
67% yield. The electron rich p-methoxy diketone underwent the
pinacol cyclization to give diol 13e in 65% yield. The m-methoxy
analog was even more efficient in the SmI2-promoted cyclization
providing product 13f in 73% isolated yield. Aryl ketones bearing
p-substituted halogens were less efficient in the process with the
bromo derivative giving diol product 13g in 22% yield and the
chloro derivative providing product 13h in 15% yield. Pleasingly,
these yields increased to 83% (13g) and 40% (13h) with inclusion
of LiBr.
A
15 (24 mol%)
Sm(OTf)3 (20 mol%)
OSiMe3
Ph
OH
O
O
+
78% yield
Ph 53% ee
Me
Ph
O
H
Ph
H2O/EtOH = 1/9, 0 °C
7
14
16
Me
B
O
SmI2 (2.2 equiv)
OH
N
N
Br
O
15 (1 equiv)
Ph
Ph
Me
Me
O
O
O
O
Me
Me
THF, 0 °C
11a
30% ee
15
Scheme 4. Enantioselective aldol reactions with chiral crown ether 15.
Conclusions
In summary, we have identified conditions for three Sm(II)-
promoted intramolecular cyclization reactions en route to
cyclopentane products. Two such reactions, an intramolecular
Reformatsky aldol and
a pinacol cyclization, are highly
diastereoselective. In regard to the former, we found LiBr as an
effective additive in terms of isolated product yields presumably
through formation of SmBr2 from SmI2. We have also established
that primary mesylates are efficient electrophilic handles for
intramolecular alkylation reactions of samarium enolates.
Alkylation of such enolates is only sporadically reported in the
literature and use of primary mesylates could allow for further
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10.1002/ejoc.201800102
European Journal of Organic Chemistry
COMMUNICATION
applications of this functional group in Sm(II)-mediated processes.
Finally, we have demonstrated modest enantiocontrol in an
intramolecular Reformatsky cyclization reaction using a crown
ether type ligand. Further investigation into asymmetric reactions
using Sm(II)-species is ongoing in our laboratory.
2003, 68, 4871-4875. g) A. Dahlén, G. Hilmersson, Tetrahedron Lett.
2003, 44, 2661-2664.
T. Shibata, Adv. Synth. Catal. 2006, 348, 2328-2336.
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[6]
[7]
[8]
[9]
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Acknowledgements
We thank the University of Denver for generous funds to support
this research project. We also thank Dr. Thomas Lee and Dr.
Danijel Djukovic of the University of Colorado Boulder for the
acquisition of HRMS data.
[11] Notably, product 11f was isolated in 45% yield when LiBr was substituted
with a combination of trimethylamine and water in a 6:3 molar ratio. This
additive combination has been found to increase the reduction potential
of SmI2. For details, see: Y. Tu, L. Zhou, R. Yin, X. Lv, R. A. Flowers II,
K. A. Choquette, H. Liu, Q. Niu, X. Wang, Chem. Commun. 2012, 48,
11026-11028.
[12] For an intramolecular example, see: L. A. McAllister, R. A. McCormick,
K. M. James, S. Brand, N. Willetts, D. J. Procter, Chem. Eur. J. 2007, 13,
1032-1046.
Keywords: samarium(II) iodide • cyclopentane • alkylation •
pinacol • reductive cyclization
[13] For an intermolecular example, see: G. A. Molander, P. J. Stengel,
Tetrahedron 1997, 53, 8887-8912.
[1]
[2]
a) P. Girard, J. L. Namy, H. B. Kagan, J. Am. Chem. Soc. 1980, 102,
2693-2698. b) J. L. Namy, P. Girard, H. B. Kagan, Nouv. J. Chim. 1977,
1, 5-7.
a) M. Szostak, N. J. Fazakerley, D. Parmar, D. J. Procter, Chem. Rev.
2014, 114, 5959-6039. b) D. J. Procter, R. A. Flowers II, T. Skrydstrup,
Organic Synthesis Using Samarium Diiodide: A Practical Guide, Royal
Society of Chemistry Publishing, Cambridge, 2010. c) H. B. Kagan,
Tetrahedron 2003, 59, 10351-10372.
G. A. Molander, C. R. Harris, Chem. Rev. 1996, 96, 307-338.
a) T. V. Chciuk, R. A. Flowers II, In Science of Synthesis Knowledge
Updates, Georg Thieme Verlag Stuttgart, New York, 2016, vol. 2, 2.12.17,
p. 177. b) R. A. Flowers II, Synlett 2008, 10, 1427-1439. c) R. S.
Kumaran, I. Brüdgam, H.-U. Reissig, Synlett 2008, 7, 991-995. d) U. K.
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[14] Notably, an analogous p-tolyl substituted substrate with a pendant alkyl
iodide cyclizes inefficiently to provide 18% isolated yield of product.
[15] N. Kise, Y. Shiozawa, N. Ueda, Tetrahedron 2007, 63, 5415-5426.
[16] A. Lebrun, J.-L. Namy, H. B. Kagan, Tetrahedron Lett. 1993, 34,
2311-2314.
[17] During the preparation of this manuscript, Procter and coworkers
disclosed impressive examples of enantioselective SmI2-promoted
carbonyl-alkene coupling reactions using chiral amino alcohol ligands:
N. Kern, M. P. Plesniak, J. J. W. McDouall, D. J. Procter, Nature
Chemistry 2017, 9, 1198-1204.
[3]
[4]
[18] T. Hamada, K. Manabe, S. Ishikawa, S. Nagayama, M. Shiro, S.
Kobayashi, J. Am. Chem. Soc. 2003, 125, 2989-2996.
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10.1002/ejoc.201800102
European Journal of Organic Chemistry
COMMUNICATION
COMMUNICATION
Sm(II)-Mediated Cyclizations
Christopher D. Aretz, Humberto
Escobedo, and Bryan J. Cowen*
Cyclopentane formation from flexible
precursors using samarium(II)
reagents
This study presents three efficient methods for five-membered ring carbocycle synthesis using samarium(II) reagents. Simple organic
starting materials engage in intramolecular Reformatsky aldol, enolate alkylation, and pinacol cyclizations. A promising lead result has
also been established demonstrating enantioselectivity in a chiral ligand controlled Reformatsky aldol reaction.
This article is protected by copyright. All rights reserved.