Expanding the scope of donor/acceptor carbenes to N -phthalimido donor groups: Diastereoselective synthesis of 1-cyclopropane α-amino acids

Article abstract of DOI:10.1021/ol3029127

Warming of 4-phthalimido-N-mesyl-1,2,3-triazole in the presence of alkenes followed by silica gel induced hydrolysis results in a highly diastereoselective and catalyst-free entry to N-phthalimidocyclopropanecarboxaldehydes.

Full text of DOI:10.1021/ol3029127

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Expanding the Scope of Donor/Acceptor
Carbenes to N‑Phthalimido Donor
Groups: Diastereoselective Synthesis of
1‑Cyclopropane R‑Amino Acids
Joshua S. Alford and Huw M. L. Davies*
Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia
30322, United States
hmdavie@emory.edu
Received October 22, 2012
ABSTRACT
Warming of 4-phthalimido-N-mesyl-1,2,3-triazole in the presence of alkenes followed by silica gel induced hydrolysis results in a highly
diastereoselective and catalyst-free entry to N-phthalimidocyclopropanecarboxaldehydes.
Cyclopropane R-amino acids have attracted much at-
tention over the years due to their significant biological
properties.1 They are constituents of agrochemicals2 and
therapeutic agents3 and have been applied to the design of
conformationally restricted peptides.4 Several approaches
have been developed for the synthesis of cyclopropane
R-amino acids.1 One of the most established approaches
has been the metal-catalyzed reaction of diazo compounds
with alkenes, which proceed via carbenoid intermediates.5
We have demonstrated that donor/acceptor carbenoids
routinely undergo highly diastereoselective cyclopropana-
tion reactions.6 When the reaction is conducted with
styryldiazoacetates in the presence of Rh2(S-DOSP)4 as a
chiral catalyst, the cyclopropanations are highly diaster-
eoselective and enantioselective. The resulting products
can be converted to cyclopropane R-amino acids, but this
requires a four-step process.5a Alternative strategies using
acceptor/acceptor carbenoids have been developed since
(1) For selected reviews on cyclopropane R-amino acids, see: (a)
Brackmann, F.; de Meijere, A. Chem. Rev. 2007, 107, 4538–4583. (b)
Salaun, J. Top. Curr. Chem. 2000, 207, 1–67. (c) Reichelt, A.; Martin,
S. F. Acc. Chem. Res. 2006, 39, 433–442. (d) Gnad, F.; Reiser, O. Chem.
Rev. 2003, 103, 1603–1623. (e) Burgess, H.; Kwon-Kan; Destradi, M. S.
Synlett 1994, 575–583.
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J. Chem. Soc., Chem. Commun. 1985, 21, 1496–1498. (b) Adams, D. O.;
Yang, S. F. Proc. Natl. Acad. Sci. U.S.A. 1979, 76, 170–174. (e) Ichihara,
A.; Shiraishi, K.; Sakamura, S.; Furusak, A.; Hashiba, N.; Matsumoto,
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1985, 24, 1485–1487.
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Faucher, A. M.; Ferland, J. M.; Grand-Maitre, C.; Poirier, M.; Simoneau,
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Gibbons, S. E.; Graham, S. R.; Colbry, N. L.; Guzzo, P. R.; Le, V.;
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Bonnert, R. V.; Bressel, B.; Cox, R. J.; Shepherd, J.; de Vicente, J.;
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Chem. 2009, 74, 8939–8955. (f) Lindsay, V. N. G.; Wei., L.; Charette,
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424. (c) Davies, H. M. L.; Morton, D. Chem. Soc. Rev. 2011, 40, 1857–
1869.
r
10.1021/ol3029127
XXXX American Chemical Society

then. They involve either potential hazardous R-nitrodiazo
compounds5f,g or dicarbonyl derivatives5e which require
subsequent Curtius-type rearrangement of one of the
carbonyl groups or suffer from low diastereoselectivity.
In this paper, we describe a direct approach for the diaster-
eoselective synthesis of cyclopropane R-amino acids using
donor/acceptor carbenes in which the donor group is a
protected amine functionality.
transannulation reactions with nitriles10d and asymmetric
intramolecular deoxygenation of sulfones.10e These studies
have focused on the generation of rhodium(II)-stabilized
R-aryldiazo sulfonylimines. Extension of this approach to
N-sulfonyl-4-amino-1,2,3-triazoles would lead to the forma-
tion of R-amino substituted carbenoid intermediates (eq 3).
Donor/acceptor carbenoids have become widely used in
organic synthesis.6 Currently, the donor group is limited to
aryl, heteroaryl, vinyl, alkynyl, or chloro.7 These groups
stabilize not only the electron-deficient carbenoid by elec-
tron donation through resonance but also the diazo com-
pound by being inductively electron accepting.8 Considering
the importance of donor/acceptor carbenoids, expanding the
nature of the donor group would be highly beneficial. All of
our attempts to prepare diazo compounds with a protected
amine donor group have been unsuccessful. Representative
examples of some of our unsuccessful efforts can be seen in
eq 1. The rapid evolution of dinitrogen during their at-
tempted synthesis suggests that the diazo compounds 2 were
decomposing as they were being formed. From these studies,
we concluded amino-substituted diazo compounds would be
best prepared in situ; however, the diazo transfer reaction is
unlikely to be useful in this type of scenario due to the
incompatibility of the transfer agent, amine base, and solvent
with the subsequent metal-catalyzed reaction.9
We envisioned that a 4-N-phthalimido-N-sulfonyl-1,2,3-
triazole 11 would be a suitable precursor to an amino-
functionalized donor/acceptor carbenoid (Scheme 2). A
reasonable synthetic approach to 11 would be the copper(I)-
catalyzed azideÀalkyne cycloaddition.11 The synthetic ap-
proaches to ynimides is relatively limited.12 A recent report of
an experimentally simple copper-catalyzed aerobic oxidative
amidation of terminal alkynes resulting in the efficient
synthesis of ynamides appeared ideal for our needs.13 Adap-
tation of this procedure to phthalimide 7 and TMS-acetylene
8 in the presence of 20 mol % of Cu(OAc)2 generated the
TMS-protected ynimide 9, which was then deprotected to
furnish the N-ethynylphthalimide 10 in 89% yield over both
steps (Scheme 1). The ynimide 10 was then transformed into
the benchtop stable 4-phthalimido-N-mesyl-1,2,3-triazole
11 through a copper-catalyzed alkyneÀazide cycloaddition
by treatment with mesyl azide in the presence of copper(I)
thiophene-2-carboxylate (CuTC).11
A potential solution to the in situ generation of R-amino-
substituted carbenoids comes from the recent studies by
Fokin,10 which showed that N-sulfonyl-4-aryl-1,2,3-triazoles
could be used as precursors to donor/acceptor carbenoids in
the presence of a dirhodium(II) catalyst (eq 2). The resulting
aza-vinyl carbenoids underwent not only a few classic donor/
acceptor reactions including enantioselective cyclopro-
panation of olefins10a,b and CÀH insertion reactions of
alkanes10c but also a few unusual transformations such as
Scheme 1. Synthesis of 4-N-Phthalimido-N-sulfonyl-1,2,
3-triazole
(7) (a) Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev.
2009, 110, 704–724. (b) Denton, J. R.; Cheng, K.; Davies, H. M. L.
Chem. Commun. 2008, 1238. (c) Denton, J. R.; Davies, H. M. L. Org.
Lett. 2009, 11, 787–790. (d) Hansen, J.; Autschbach, J.; Davies, H. M. L.
J. Org. Chem. 2009, 74, 6555–6563. (e) Briones, J. F.; Hansen, J.;
Hardcastle, K. I.; Autschbach, J.; Davies, H. M. L. J. Am. Chem. Soc.
2010, 132, 17211–17215. (f) Davies, H. M. L.; Nikolai, J. Org. Biomol.
Chem. 2005, 3, 4176–4187.
(8) (a) Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103,
2861–2903. (b) Bonge, H. T.; Hansen, T. J. Org. Chem. 2010, 75, 2309–
2320. (c) Panaro, S. A.; Davies, H. M. L. Tetrahedron 2000, 56, 4871–
4880.
The metal-catalyzed reaction of the triazole 11 in the
presence of styrene was examined as a test reaction. To our
delight, 11 reacted smoothly at 55 °C in the presence of
(9) For an example of a donor/acceptor carbene containing an R-
amino group derived from an oxirene, see: Li, H.; Antoline, J.; Yang, J.;
Al-Rashid, Z.; Hsung, R. New J. Chem. 2010, 34, 1309–1316.
(10) (a) Chuprakov, S.; Kwok, S. W.; Zhang, L.; Lercher, L.; Fokin,
V. V. J. Am. Chem. Soc. 2009, 131, 18034–18035. (b) Grimster, N.;
Zhang, L.; Fokin, V. V. J. Am. Chem. Soc. 2010, 132, 2510–2511. (c)
Chuprakov, S.; Malik, J. A.; Zibinsky, M.; Fokin, V. V. J. Am. Chem.
Soc. 2011, 133, 10352–10355. (d) Horneff, T.; Chuprakov, S.; Chernyak,
N.; Gevorgyan, V.; Fokin, V. V. J. Am. Chem. Soc. 2008, 130, 14972–
14974. (e) Selander, N.; Fokin, V. V. J. Am. Chem. Soc. 2012, 134, 2477–
2480.
(11) (a) Raushel, J.; Fokin, V. V. Org. Lett. 2010, 12, 4952–4955. (b)
Zibinsky, M.; Fokin, V. V. Org. Lett. 2011, 13, 4870–4872. (c) Raushel,
J.; Pitram, S. M.; Fokin, V. V. Org. Lett. 2008, 10, 3385–3388. Mesyl
azide was used for better atom economy; other sulfonyl azides such as
tosyl azide can be used. Fokin (ref 9) has also shown this to be the best
sulfonyl azide for the generation of rhodium(II)-stablized carbenoids.
Caution should be taken when using this reagent.
(12) Sueda, T.; Oshima, A.; Teno, N. Org. Lett. 2011, 13, 3996–3999.
(13) Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130,
833–835.
B
Org. Lett., Vol. XX, No. XX, XXXX

either Rh2(S-DOSP)4 or Rh2(S-PTAD)4 to provide cyclo-
propane imine 12 (Table 1). Hydrolysis of 12 was achieved
by simply adding wet silica to the reaction flask to furnish
the aldehyde 13a in excellent yield (92À93%) and high
diastereoselectivity (>20:1). Even though Rh2(S-DOSP)4
or Rh2(S-PTAD)4 are exceptional chiral catalysts for
donor/acceptor carbenoids,6 13 was formed as a racemate.
A control experiment without a rhodium catalyst revealed
that 13a is still formed in high yield (89%) and diastereo-
selectivity (>20:1). Therefore, the formation of 13a is
unlikely to be a rhodium-catalyzed process even though
the reaction is highly diastereoselective. Earlier studies
have shown that the metal-free thermal cyclopropana-
tion with aryldiazoacetates can also be highly diastereo-
selective.14
buildup of diazo compounds using the triazole starting
materials (eq 3).
Scheme 2. Scope with Respect to Olefina
Table 1. Representative Reaction Screena
temp
% yield
13ab
entry
catalyst
(°C)
drc
% ee
1
2
3
Rh2(S-PTAD)4
Rh2(S-DOSP)4
none
55
55
55
93
92
89
>20:1
>20:1
>20:1
<2
<2
À
a Conditions: triazole 11 (0.26 mmol), styrene (1.28 mmol), Rh(II)
catalyst (0.0026 mmol), 1,2-DCE (2 mL), 12 h. b Isolated yield; See
Supporting Information for more details. c Determined by 1H NMR
analysis of the crude reaction mixture.
a Conditions: triazole 11 (0.26 mmol), styrene (1.28 mmol), 1,2-DCE
(2 mL), 12 h, then hydrolysis with wet silica. Reported yields are isolated.
b Determined by 1H NMR analysis of the crude reaction mixture. c Yield:
86% with 1.5 equiv of styrene.
Having discovered that the cyclopropanation was not
metal catalyzed, the scope of the catalyst-free, thermal
reaction was examined (Scheme 2). A broad range of
terminal and internal alkenes were transformed into the
corresponding cyclopropanecarboxaldehydes 13aÀ13l in
good to excellent yields (75À92%) with excellent diastereo-
selectivity (>20:1). Styrenes possessing either an electron-rich
or -deficient aryl group reacted smoothly to produce cyclo-
propanes 13aÀf. 1,3-Butadiene and 1-phenyl-1,3-butadiene
readily gave monocyclopropanecarboxaldehydes 13g and
13h, respectively. The influence of the alkene geometry is not
as profound in the thermal reactions as compared to
dirhodium-catalyzed reactions,15 as both trans-β-methyl-
styrene and cis-β-methylstyrene were readily transformed
into the corresponding cyclopropanecarboxaldehydes 13j
and 13k, respectively. Cyclic substrates also furnished cy-
clopropanes 13i and 13l in excellent yield and diastereos-
electivity. It is important to note that unlike typical
rhodium-catalyzed reactions,5 there is no need to add the
carbenoid precursor slowly because there is unlikely to be a
The synthesis of the R-amino cyclopropanecarboxalde-
hydes starting from N-ethynylphthalimide 10 can be con-
ducted in a one-pot, two-step synthesis as illustrated in
Table 3. N-Ethynylphthalimide 10 was treated with mesyl
azide (1.1 equiv) in the presence of CuTC (10 mol %) in
chloroform to generate the intermediate 4-phthalimido-N-
mesyl-1,2,3-triazole 11. After 12 h, the styrene derivative
(1.5 equiv) was added to the reaction mixture and the
reaction media were warmed to 55 °C for 12 h. Once
the allotted time had passed, wet silica gel was added to
the reaction to furnish the cyclopropanecarboxaldehydes
13aÀf in good yields (74À85%) with excellent diastereo-
selectivity (>20:1). The yields of the one-pot, two-step
reaction (Table 2) are comparable tothe yields presented in
Scheme 2. Key features to this one-pot reaction are the
requirement of only a slight excess of the olefin and the
formation of only dinitrogen and methanesulfonamide as
byproducts.
The initial product of the thermal cyclopropanation, the
sulfonyl imines, is a synthetically versatile intermediate.
This is illustrated with examples of in situ manipulations of
the sulfonyl imine 12 (Scheme 3). Reduction of 12 with
sodium borohydrideprovided easyaccesstothe sulfonated
(14) Ovalles, S. R.; Hansen, J. H.; Davies, H. M. L. Org. Lett. 2011,
13, 4284–4287.
(15) Thompson, J. L.; Davies, H. M. L. J. Am. Chem. Soc. 2007, 129,
6090–6091.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 2. Development of a One-Pot, Two-Step Reactiona
Scheme 4. Unmasking of the Cyclopropyl R-Amino Acid
entry
Ar
product
% yieldb
drc
1
2
3
4
5
6
Ph
13a
13b
13c
13d
13e
13f
85
77
74
80
79
82
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
4-CF3Ph
4-BrPh
4-ClPh
4-MePh
2-MePh
a Conditions: 10 (0.58 mmol), mesyl azide (0.64 mmol), CuTC
˚
(0.058 mmol), 4 A MS, and CHCl3 (3 mL) were stirred for 12 h at rt, then
styrene (0.88 mmol) was added, and the reaction was stirred for 12 h at
55 °C. Hydrolysis of 11 with wet silica added to the reaction mixture.
b Isolated yield. c Determined by 1H NMR analysis of the crude reaction.
a Deprotection A: reflux in acetic acid with
4 h. Deprotection B: NaBH4 (6 equiv) in 6:1:0.5 iPrOH/H2O/aq
NaHCO3 for 8 h and then dry HCl in ether.
3 M HCl for
b
undergo a direct cyclopropanation. Although it is not
possible to distinguish unequivocally between the two me-
chanisms at this time, the carbene mechanism is more
consistent with the observed results. The initial results
directed toward the synthesis of R-amino diazo compounds
revealed such compounds were very prone to thermal
decomposition. The inability to influence the reaction with
the highly active dirhodium catalysts suggests that the diazo
compounds are very short-lived species. Unless the 1,3-
dipolar cycloaddition is extremely facile with R-amino diazo
compounds, then the intermediacy of the amino-stabilized
carbene is the more likely scenario.
Scheme 3. Representative Synthetic Variation from the Imine
monoamine 14 in good yield.10c The addition of sodium
chlorite under Pinnick oxidation conditions gave the cor-
responding sulfonyl amide 15 in high yield.16
Inconclusion, 4-phthalimido-N-mesyl-1,2,3-triazoleun-
dergoes a facile thermal reaction to generate a donor/
acceptor carbene, in which the donor group is the phthali-
mido group. This carbene undergoes highly diastereoselec-
tive cyclopropanation with a range of alkenes and dienes,
leading to a ready access to cyclopropane R-amino acids in
an experimentally simple way. Current studies are directed
toward a better understanding of the thermal dinitrogena-
tion mechanism, developing an enantioselective metal-cata-
lyzed reaction of aminotriazoles and expanding the scope of
the chemistry to other classes of substituted triazoles.
The most attractive feature of this thermal cyclopropa-
nation is the opportunity for ready access of cyclopropane
R-amino acids as illustrated in Scheme 4. The N-cyclopro-
panecarbaldehyde phthalimide derivatives 13 were con-
verted to the free R-amino acid by first conducting a mild
Pinnick oxidation of the aldehyde to provide the corre-
sponding acids. Then the N-phthaloyl acid was depro-
tected by either direct acid hydrolysis or a modified sodium
borohydride reduction17 of the phthaloyl group to give the
R-amino acid derivatives 16aÀf in 73À88% yields over
both steps.
There are two plausible mechanisms possible for this
thermal cyclopropanation. The first would be the classic
1,3-dipolar cycloaddition to form a pyrazoline intermedi-
ately followed by a thermal dinitrogen extrusion event to
form the cyclopropane.5c The second would be a thermal
decomposition of the diazo compound, which would then
Acknowledgment. This research was supported by the
National Science Foundation (CHE 1213246). Additional
financial support was obtained from Boehringer-Ingelheim.
Supporting Information Available. Full experimental
data. This material is available free of charge via the
Internet at http://pubs.acs.org.
(16) Mohamed, M. A.; Yamada, K.; Tomioka, K. Tetrahedron Lett.
2009, 50, 3436–3438.
(17) Osby, J. O.; Martin, M. G.; Ganem, B. Tetrahedron Lett. 1984,
25, 2093–2096.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX