Role of ortho -substituents on rhodium-catalyzed asymmetric synthesis of β-lactones by intramolecular C-H insertions of aryldiazoacetates

Article abstract of DOI:10.1021/ol5011505

A rhodium-catalyzed asymmetric synthesis of β-lactones via intramolecular C-H insertion into the ester group of aryldiazoacetates has been developed. The β-lactones were synthesized in high yields and with high levels of diastereo- and enantioselectivity.

Full text of DOI:10.1021/ol5011505

Letter
pubs.acs.org/OrgLett
Role of Ortho-Substituents on Rhodium-Catalyzed Asymmetric
Synthesis of β‑Lactones by Intramolecular C−H Insertions of
Aryldiazoacetates
Liangbing Fu, Hengbin Wang, and Huw M. L. Davies*
Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States
S
* Supporting Information
ABSTRACT: A rhodium-catalyzed asymmetric synthesis of β-
lactones via intramolecular C−H insertion into the ester group
of aryldiazoacetates has been developed. The β-lactones were
synthesized in high yields and with high levels of diastereo- and
enantioselectivity. Halo and trifluoromethyl substituents at the
ortho position of the aryldiazoacetates enhance intramolecular
C−H insertions over intermolecular reactions, allowing C−H
insertion of even methyl C−H bonds.
Scheme 1. Discovery of β-Lactone Formation from Methyl
Aryldiazoacetates
irect functionalization of C−H bonds represents an area
Dof great interest in organic chemistry and provides new
strategies for streamlining the synthesis of natural products and
pharmaceuticals.1 One important type of C−H functionaliza-
tion is the insertion of a metal-bound carbene into a C−H
bond.2 By exploiting the rhodium-catalyzed decomposition of
diazo compounds, the Davies group has developed a number of
synthetically useful methods via C−H functionalization with
donor/acceptor-substituted metal carbenes.3 Herein, we report
an asymmetric synthesis of β-lactones via intramolecular
insertion of rhodium carbenes into C−H bonds.
β-Lactones are important organic intermediates and
structural motifs in natural products and pharmaceuticals.4
Thus, developing new methods for the asymmetric synthesis of
β-lactones is desirable.5 Intramolecular C−H insertion is an
attractive strategy for generating lactones and lactams.6 For the
synthesis of lactones, the formation of γ-lactones is generally
preferred over β-lactones. Aryldiazoacetates have been broadly
used in various intermolecular reactions, and Doyle and Che
showed that these systems are capable of undergoing
intramolecular C−H insertion into methylene or methine C−
H bonds to form β-lactones with modest levels of
enantiocontrol (typically <80% ee).7 In this study we
demonstrate that β-lactone formation can be greatly enhanced
by introduction of an ortho-substituent on the aryl group of the
aryldiazoacetate, enabling C−H functionalization of even
relatively unreactive methyl C−H bonds.
The unexpected role of the ortho-substituent was discovered
during studies on the Rh2(S-PTTL)4-catalyzed intermolecular
C−H insertion reaction between the ortho-bromoaryldiazo-
acetate 1 and the benzyl silyl ether 2 (Scheme 1).1e None of the
expected intermolecular C−H insertion product 4 was
observed. Instead, the β-lactone product 3 was isolated in
54% yield with 78% ee. Even though we have extensively used
methyl aryldiazoacetates in synthesis,1−3 this was the first time
we observed the formation of a β-lactone, which would require
an intramolecular C−H insertion into a methyl C−H bond.
The absolute configuration of 3 was unambiguously assigned by
X-ray crystallography.8 Encouraged by this initial discovery, we
decided to carry out systematic studies to explore the scope of
the β-lactone synthesis.
Optimization studies were conducted using aryldiazoacetate
1 as the test substrate with dichloromethane as the solvent
(Table 1). Though Rh2(S-DOSP)4 (Figure 1) is a very effective
catalyst in a range of intermolecular C−H insertion
reactions,1−3 it performed relatively poorly in this case,
generating the β-lactone 3 in 31% yield with 51% ee (entry
1). The phthalimido catalysts9 Rh2(S-PTTL)4 and Rh2(S-
PTAD)4 gave slightly better results (entries 2 and 3), but the
best catalysts were the tetrachlorophthalimido catalysts10
Rh2(S-TCPTTL)4 and Rh2(S-TCPTAD)4 (entries 4 and 5).
With Rh2(S-TCPTAD)4 as the catalyst, the reaction of
aryldiazoacetate 1 afforded β-lactone 3 in 72% yield with 86%
ee.
The scope of the intramolecular methyl C−H insertion
reaction was then studied using Rh2(S-TCPTAD)4 as the
standard catalyst (Scheme 2). The influence of substituents on
Received: April 21, 2014
Published: May 20, 2014
© 2014 American Chemical Society
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Letter
a
examined. With ortho-chloro and iodo groups, lactones 6c and
6d were synthesized in good yields and with high levels of
enantioselectivity. With an additional iodo group at the para-
position, compound 6e was obtained in decreased yield and
enantioselectivity. Substrates with ortho alkoxy,3i carboxylate
ester, or nitro groups are not compatible with this chemistry
because these groups react with the rhodium carbene. The
absolute configurations of β-lactones 6a−e were tentatively
assigned to be the same as 3 by analogy.
The study was then extended to insertions into methylene
C−H bonds. The added stabilization of positive charge built up
during the C−H insertion step renders these substrates more
reactive. In the presence of Rh2(S-TCPTAD)4, the reaction of
benzyl ester 7a produced cis-8a in good yield with 96% ee and
10:1 dr (Table 2, entry 1). Further studies revealed that the
Table 1. Optimization Studies
b
c
entry
Rh2L4
yield (%)
ee (%)
1
2
3
4
5
Rh2(S-DOSP)4
31
45
23
73
72
51
77
57
84
86
Rh2 (S-PTTL)4
Rh2 (S-PTAD)4
Rh2 (S-TCPTTL)4
Rh2 (S-TCPTAD)4
a
Standard reaction conditions: 1 (0.5 mmol, 1.0 equiv) in degassed
dichloromethane (5 mL) was added to 5 mL of a dichloromethane
solution of Rh2L4 catalyst (0.005 mmol, 1 mol %) at reflux over 3 h.
Isolated yield. Determined by chiral HPLC analysis.
b
c
Table 2. Optimization of Methylene C−H Insertion
b
c
cis/
trans
yield
ee
a
entry
R2
Rh2L4
solvent
DCM
(%)
(%)
1
2
3
4
5
Ph
Rh2(S-TCPTAD)4
Rh2(S-TCPTTL)4
Rh2(S-TCPTAD)4
Rh2(S-TCPTTL)4
10:1
73
96
97
82
90
94
Figure 1. Chiral rhodium catalysts used in this study.
Ph
Me
Me
Me
DCM
>19:1
1:4.0
1:8.3
1:8.3
72
d
DCM
78
Scheme 2. Exploration of the Substrate Scope: Methyl C−H
d
a
DCM
78
Insertions
d
Rh2(S-TCPTTL)4
n-pentane
83
a
b
1
Determined by H NMR analysis of the crude mixture. Isolated
c
d
yield. Refers to the ee for the major diastereomer. Combined
isolated yield.
diastereoselectivity can be improved by using Rh2(S-
TCPTTL)4 as the catalyst. With this catalyst, cis-8a was
obtained in similar yield and enantioselectivity but with >19:1
dr (entry 2). Similar improvement of the diastereoselectivity
was observed for the reaction of ethyl aryldiazoacetate 7b. The
diastereoselectivity of lactone trans-8b was improved from 4:1
to 8.3:1 when the catalyst was changed from Rh2(S-TCPTAD)4
to Rh2(S-TCPTTL)4 (entries 3 and 4). Interestingly, the
reaction of the benzyl aryldiazoacetate 7a preferentially formed
the cis-β-lactone 8a, whereas the reaction of the ethyl
aryldiazoacetate 7b preferentially formed the trans-β-lactone
8b. The absolute configurations for the major diastereomers cis-
8a and trans-8b were unambiguously assigned by X-ray
crystallography.11 Because the methylene C−H bond is more
reactive than the methyl C−H bond, hydrocarbon solvents can
be used without competing intermolecular insertions into the
solvent. Slightly higher enantioselectivity for trans-8b was
observed when the reaction of 7b was performed in refluxing
pentane (entry 5), compared to dichloromethane (entry 4).12
The scope of the methylene C−H insertions was then
explored (Scheme 3). It was quickly found that the influence of
the ortho-substituent is less pronounced in these reactions. The
reactions generally proceeded in higher yields and levels of
enantioselectivity compared to the methyl C−H insertion
reactions. Most notable is the observation that the
unsubstituted phenyldiazoacetate 9b is capable of forming the
a
Standard reaction conditions: 5a−e (0.5 mmol, 1.0 equiv) in
degassed dichloromethane (5 mL) was added to 5 mL of a
dichloromethane solution of the dirhodium catalyst (0.005 mmol, 1
mol %) at reflux over 3 h.
the phenyl ring was first examined. Compared to compound 1,
the reaction of diazo compound 5a with only an ortho-bromo
group gave the lactone 6a in decreased yield and
enantioselectivity. The reaction of phenyldiazoacetate 5b,
lacking an ortho-substituent, was very informative. None of
the β-lactone 6b was formed, demonstrating the importance of
ortho substitution to enhance intramolecular C−H insertions.
Consequently, the influence of other ortho substituents was
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Scheme 3. Exploration of the Substrate Scope: Methylene
C−H Insertions
Scheme 4. C−H Insertions of Electron-Rich Benzyl Esters
a
a
Scheme 5. Methine C−H Insertions
a
a
Standard reaction conditions: 14 (0.5 mmol, 1.0 equiv) in degassed
Standard reaction conditions: 9a−i (0.5 mmol, 1.0 equiv) in degassed
n-pentane (5 mL) was added to a 5 mL n-pentane solution of the
dirhodium catalyst (0.005 mmol, 1 mol %) at reflux over 3 h.
dichloromethane (5 mL) was added to a 5 mL dichloromethane
solution of the dirhodium catalyst (0.005 mmol, 1 mol %) under reflux
over 3 h. n-Pentane as the solvent at 36 °C.
b
β-lactone 10b in moderate yield with 64% ee. Benzyl
aryldiazoacetates with an ortho-substituent are exceptional
substrates, generating the β-lactones 10c, 10f−i with >19:1
dr and 97−99% ee. For the reaction of ethyl aryldiazoacetaes,
an ortho-trifluoromethyl substituent was also highly favorable
and the β-lactone 10e was formed in 83% yield and in 95% ee.
Interestingly, when an electron-donating methyl group was
placed at the para-position of the benzyl ester (11a), the
desired C−H insertion product 12a was isolated in low yield
(60% NMR yield). This is because lactone 12a readily
underwent CO2 extrusion to form the olefin 13a upon column
chromatography (Scheme 4). A similar reaction of β-silylethyl
aryldiazoacetates has been reported previously by our group.3a
higher enantioselectivity (43% ee) was observed when Rh2(S-
TCPTTL)4 was used as the catalyst. Further increasing the
steric environment around the phenyl group by adding a meta-
methoxy group (14b) improved the yield and enantioselectiv-
ity, and lactone 15b was produced in 95% yield and 93% ee.
In conclusion, the introduction of an ortho-substituent on
aryldiazoacetates interferes with intermolecular reactions and
enhances intramolecular C−H insertions to form β-lactones.13
Even methyl aryldiazoacetates are capable substrates in the
formation of β-lactones, suggesting that less reactive esters need
to be designed to maximize the potential of aryldiazoacetates in
intermolecular C−H insertion. In the case of methylene C−H
insertions, Rh2(S-TCPTTL)4 is an exceptional catalyst,
resulting in β-lactone formation with very high levels of
enantio- and diastereoselectivity.
1
Analysis of the H NMR of the crude reaction mixture and
HPLC analysis indicated that the diastereoselectivity (>19:1
favoring the cis isomer) and enantioselectivity (97% ee) of
lactone 12a were still very high. When the para-position of the
benzyl ester bears an even stronger electron-donating group,
such as the methoxy derivative 11b, the β-lactone 12b was not
observed in the 1H NMR of the crude reaction mixture.
Instead, the olefin 13b was isolated in 50% yield.
The intramolecular insertion into methine C−H bonds of
unsubstituted isopropyl phenyldiazoacetate has been previously
reported.6a The β-lactone was obtained in 78% yield with 41%
ee when the reaction was performed in refluxing pentane with
Rh2(S-DOSP)4 as the catalyst. Interestingly, the Rh2(S-
DOSP)4-catalyzed reaction of ortho-bromo derivative 14a
provided the lactone 15a with only 13% ee (Scheme 5).
Consistent with the methyl and methylene C−H insertions,
ASSOCIATED CONTENT
■
S
* Supporting Information
Synthetic details and spectral data. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hmdavie@emory.edu.
Notes
The authors declare no competing financial interest.
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Letter
(9) Selected examples using Rh2(PTAD)4 and Rh2(PTTL)4:
(a) Spangler, J. E.; Davies, H. M. L. J. Am. Chem. Soc. 2013, 135,
6802. (b) Smith, A. G.; Davies, H. M. L. J. Am. Chem. Soc. 2012, 134,
18241. (c) Saito, H.; Oishi, H.; Kitagaki, S.; Nakamura, S.; Anada, M.;
Hashimoto, S. Org. Lett. 2002, 4, 3887. (d) Watanabe, N.; Ogawa, T.;
Ohtake, Y.; Ikegami, S.; Hashimoto, S. Synlett 1996, 85. (e) Takahashi,
T.; Tsutsui, H.; Tamura, M.; Kitagaki, S.; Nakajima, M.; Hashimoto, S.
Chem. Commun. 2001, 1604. (f) DeAngelis, A.; Dmitrenko, O.; Yap,
G. P. A.; Fox, J. M. J. Am. Chem. Soc. 2009, 131, 7230.
(10) Selected examples using Rh2(TCPTAD)4 and Rh2(TCPTTL)4:
(a) Wang, H.; Guptill, D. M.; Varela-Alvarez, A.; Musaev, D. G.;
Davies, H. M. L. Chem. Sci. 2013, 4, 2844. (b) Reddy, R. P.; Davies, H.
M. L. Org. Lett. 2006, 8, 5013. (c) Shibuta, T.; Sato, S.; Shibuya, M.;
Kanoh, N.; Taniguchi, T.; Monde, K.; Iwabuchi, Y. Heterocycles 2014,
89, 631. (d) Shimada, N.; Hanari, T.; Kurosaki, Y.; Takeda, K.; Anada,
M.; Nambu, H.; Shiro, M.; Hashimoto, S. J. Org. Chem. 2010, 75, 6039.
(e) Shimada, N.; Oohara, T.; Krishnamurthi, J.; Nambu, H.;
Hashimoto, S. Org. Lett. 2011, 13, 6284. (f) Lindsay, V. N. G.; Lin,
W.; Charette, A. B. J. Am. Chem. Soc. 2009, 131, 16383. (g) Lindsay, V.
N. G.; Nicolas, C.; Charette, A. B. J. Am. Chem. Soc. 2011, 133, 8972.
(11) The crystal structures have been deposited at the Cambridge
Crystallographic Data Centre, and the deposition numbers CCDC
993050 and 993051 have been allocated.
(12) The use of hydrocarbon solvents often results in enhanced
enantioselectivity in the rhodium-catalyzed reactions of donor/
acceptor carbenes: (a) Davies, H. M. L.; Hutcheson, D. K. Tetrahedron
Lett. 1993, 34, 7243. (b) Davies, H. M. L.; Rusiniak, L. Tetrahedron
Lett. 1998, 39, 8811.
(13) During the course of preparation of this manuscript, we became
aware of a new paper describing enhanced intramolecular C−H
insertions of ortho-bromophenyldiazoacetates into methylene and
methine bonds using an achiral rhodium acetate catalyst: Wamser, M.;
Bach, T. Synlett 2014, 1081.
ACKNOWLEDGMENTS
■
This work was supported by NSF under the CCI Center for
Selective C−H Functionalization, CHE-1205646.
REFERENCES
■
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(8) The crystal structure has been deposited at the Cambridge
Crystallographic Data Centre, and the deposition number CCDC
988764 has been allocated.
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