Enantioselective 1,3-dipolar cycloadditions of diazoacetates with electron-deficient olefins

Article abstract of DOI:10.1021/ol070364x

Equation presented A general strategy for highly enantioselective 1,3-dipolar cycloaddition of diazoesters to β-substituted, α-substituted, and α,β-disubstituted α,β-unsaturated pyrazolidinone imides is described. Cycloadditions utilizing less reactive α,β-disubstituted dipolarophiles require elevated reaction temperatures, but still provide the corresponding pyrazolines with excellent enantioselectivities. Finally, an efficient synthesis of (-)-manzacidin A employing this cycloaddition methodology as a key step is illustrated.

Full text of DOI:10.1021/ol070364x

ORGANIC
LETTERS
2007
Vol. 9, No. 8
1553-1556
Enantioselective 1,3-Dipolar
Cycloadditions of Diazoacetates with
Electron-Deficient Olefins
Mukund P. Sibi,* Levi M. Stanley, and Takahiro Soeta
Department of Chemistry, North Dakota State UniVersity, Fargo, North Dakota 58105
mukund.sibi@ndsu.edu
Received February 12, 2007
ABSTRACT
A general strategy for highly enantioselective 1,3-dipolar cycloaddition of diazoesters to
-unsaturated pyrazolidinone imides is described. Cycloadditions utilizing less reactive
reaction temperatures, but still provide the corresponding pyrazolines with excellent enantioselectivities. Finally, an efficient synthesis of
)-manzacidin A employing this cycloaddition methodology as a key step is illustrated.
â
-substituted,
r-substituted, and r,â-disubstituted
r
,
â
r,â
-disubstituted dipolarophiles require elevated
(
−
Cycloadditions of nitrogen-containing dipoles with olefinic
dipolarophiles continue to be attractive for the synthesis of
a variety of heterocycles.1 Over the past decade, highly
enantioselective cycloadditions of nitrones, azomethine
ylides, azomethine imines, nitrile oxides, and nitrile imines
have been reported.2 In comparison, asymmetric 1,3-dipolar
cycloadditions of diazoalkanes and diazoesters are less
prominent. Only in the past decade have highly diastereo-
selective examples been illustrated,3 while we are aware of
only two highly enantioselective variants to date. Kanemasa
and Kanai reported the first enantioselective, chiral Lewis
acid-catalyzed cycloadditions of trimethylsilyldiazomethane
to â-alkyl-substituted, R,â-unsaturated oxazolidinone imides.4
Subsequently, Maruoka and co-workers developed a titanium
BINOLate-catalyzed cycloaddition of diazoesters with R,â-
unsaturated aldehydes, which was applied in a very efficient
synthesis of (-)-manzacidin A.5 The pyrazolines prepared
in this work were isolated in moderate to good yields with
(1) For a comprehensive review of 1,3-dipolar cycloadditions, see:
Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry toward
Heterocycles and Natural Products; Padwa, A., Pearson, W. H., Eds.; John
Wiley and Sons: Hoboken, NJ, 2003. For recent reviews of asymmetric
1,3-dipolar cycloadditions, see: (a) Pellissier, H. Tetrahedron 2007, 63, in
press. (b) Gothelf, K. V.; Jørgensen, K. A. Chem. ReV. 1998, 98, 863.
(2) For recent examples, see the following and references therein: (a)
Evans, D. A.; Song, H.-J.; Fandrick, K. R. Org. Lett. 2006, 8, 3351. (b)
Kano, T.; Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2005, 127, 11926.
(c) Yan, X.-X.; Peng, Q.; Zhang, Y.; Zhang, K.; Hong, W.; Hou, X.-L.;
Wu, Y.-D. Angew. Chem., Int. Ed. 2006, 45, 1979. (d) Cabrera, S.; Go´mez
Arraya´s, R.; Carretero, J. C. J. Am. Chem. Soc. 2005, 127, 16394. (e) Suga,
H.; Funya, A.; Kakehi, A. Org. Lett. 2007, 9, 97. (f) Chen, W.; Yuan, X.-
H.; Li, R.; Du, W.; Wu, Y.; Ding, L.-S.; Chen, Y.-C. AdV. Synth. Catal.
2006, 348, 1818. (g) Shintani, R.; Fu, G. C. J. Am. Chem. Soc. 2003, 125,
10778. (h) Sibi, M. P.; Ma, Z.; Itoh, K.; Prabagaran, N.; Jasperse, C. P.
Org. Lett. 2005, 7, 2349. (i) Sibi, M. P.; Itoh, K.; Jasperse, C. P. J. Am.
Chem. Soc. 2004, 126, 5366. (j) Sibi, M. P.; Stanley, L. M.; Jasperse, C. P.
J. Am. Chem. Soc. 2005, 127, 8276.
(3) For selected diastereoselective examples, see: (a) Mish, M. R.;
Guerra, F. M.; Carreira, E. M. J. Am. Chem. Soc. 1997, 119, 8379. (b)
Whitlock, G. A.; Carreira, E. M. J. Org. Chem. 1997, 62, 7916. (c) Muray,
E.; Alvarez-Larena, A.; Piniella, J. F.; Branchadell, V.; Ortun˜o, R. M. J.
Org. Chem. 2000, 65, 388. (d) Garc´ıa Ruano, J. L.; Fraile, A.; Gonzalez,
G.; Mart´ın, M. R.; Clemente, F. R.; Gordillo, R. J. Org. Chem. 2003, 68,
6522. (e) Garc´ıa Ruano, J. L.; Peromingo, T. M.; Alonso, M.; Fraile, A.;
Mart´ın, M. R.; Titio, A. J. Org. Chem. 2005, 70, 8942.
(4) Kanemasa, S.; Kanai, T. J. Am. Chem. Soc. 2000, 122, 10710.
(5) Kano, T.; Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2006, 128,
2174.
10.1021/ol070364x CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/17/2007

generally high enantioselectivity, but it is important to note
the substrate scope is limited to R-substituted acroleins.
Given the limited substrate scope demonstrated in previous
enantioselective diazoalkane and diazoacetate 1,3-dipolar
cycloadditions as well as the potential for enhanced chemical
efficiency in enantioselective cycloadditions of diazoacetates,
we became interested in evaluating R,â-unsaturated pyr-
azolidinone imides as dipolarophiles that might serve to
address these issues (Scheme 1).6 Although the use of R,â-
Table 1. Optimization of Enantioseletive Diazoacetate
1,3-Dipolar Cycloadditionsa
Scheme 1. Enantioselective 1,3-Dipolar Cycloaddition of
Diazoacetates with R,â-Unsaturated Pyrazolidinone Imides
mol %
CLA*
temp
(°C)
yield
(%)b
ee
(%)c
entry
R
MgX2
1d
2d
3d
4
5
6
7
8
9
Et
Et
Et
Et
Et
Et
Et
Et
t-Bu
Bn
Ph
Ph
Mg(ClO4)2
Mg(ClO4)2
Mg(ClO4)2
Mg(ClO4)2
MgI2
Mg(NTf2)2
Mg(NTf2)2
Mg(NTf2)2
Mg(NTf2)2
Mg(NTf2)2
Mg(NTf2)2
Mg(NTf2)2
30
30
30
30
30
30
20
10
10
10
10
10
rt
0
93
76
38
49
53
72
81
72
79
86
25
82
54
84
86
93
97
98
99
99
99
98
46
86
-20
-20
-20
-20
-20
-20
-20
-20
-20
rt
unsaturated pyrazolidinone imides could be regarded as less
atom-economical than application of the corresponding R,â-
unsaturated aldehydes or esters, R,â-unsaturated pyrazoli-
dinone imides offer a number of noteworthy advantages,
especially for less reactive substrates such as cinnamates and
tiglates. Advantages include (1) the potential for bidentate
coordination of a chiral Lewis acid leading to a well-
organized chiral Lewis acid/substrate complex,7 (2) the ability
to provide high enantioselectivities at elevated reaction
temperatures (relative to temperatures commonly employed
in enantioselective 1,3-dipolar cycloadditions),2i,6b and (3)
the ability to control rotamer geometry in R-substituted and
R,â-disubstituted substrates, for which common auxiliaries
such as oxazolidinone perform poorly.6c
Initial reaction optimization focused on evaluation
of Mg(ClO4)2 in combination with ligand 4 as the chiral
Lewis acid. Room temperature cycloaddition of crotonate
1a with ethyl diazoacetate 2a in the presence of 30 mol %
Mg(ClO4)2/4 gave cycloadduct 3a in excellent yield and
moderate enantioselectivity (Table 1, entry 1). Lowering the
reaction temperature provided 3a with increased selectivity
(entries 2 and 3); however, a corresponding decrease in
reactivity was also observed, most notably at -20 °C. In an
attempt to increase reactivity of the chiral Lewis acid, we
employed 4 Å MS as a water scavenger. This led to a
moderate increase in yield for 3a (entry 4). Although the
increase in reactivity was less than desired, the use of 4 Å
MS led to a significiant improvement with regard to the
enantioselectivity of the cycloaddition.
10
11
12
a For experimental details see the Supporting Information. b Isolated
yields. c Determined by chiral HPLC. d Reaction run in the absence of 4 Å
MS.
Unsatisfied with the reactivity provided by Mg(ClO4)2/4
in cycloadditions at -20 °C, we chose to evaluate additional
Mg(II) salts. Interestingly, when MgI2/4 was employed as
the chiral Lewis acid, an increase in enantioselectivity was
observed, but the isolated yield was only marginally better
(entry 5). The best combination of reactivity and enantio-
selectivity was observed when Mg(NTf2)2/4 was employed
as the chiral Lewis acid (entries 6-8). In reactions conducted
with 30 mol % Mg(NTf2)2/4, 3a was isolated in 72% yield
and 98% ee (entry 6). We were pleased to observe no
decrease in reaction efficiency or selectivity upon lowering
the catalyst loading to 10 mol % (entry 8).
With optimized conditions in hand, we set out to evaluate
diazoacetates bearing additional ester substituents (entries
9-12). Reactions utilizing tert-butyl diazoaceate 2b and
benzyl diazoacetate 2c gave pyrazolines 3b and 3c in high
yields and excellent enantioselectivities (entries 9 and 10,
respectively). Unfortunately, when phenyl diazoacetate was
employed as the dipole in reactions at -20 °C, the yield
and selectivity were both poor (entry 11). The isolated yield
of 3d could be improved by performing the reaction at room
temperature. Interestingly, the enantioselectivity was in-
creased to 86% ee upon raising the reaction temperature. At
the present time a clear rationale for the increased selectivity
at increased temperature is not apparent; it is, nonetheless,
noteworthy.
(6) For enantioselective dipolar cycloadditions utilizing R,â-unsaturated
pyrazolidinone imides, see: (a) Reference 2i. (b) Sibi, M. P.; Ma, Z.;
Jasperse, C. P. J. Am. Chem. Soc. 2004, 126, 718. (c) Sibi, M. P.; Stanley,
L. M.; Soeta, T. AdV. Synth. Catal. 2006, 348, 2371.
(7) For additional enantioselective transformations utilizing R,â-unsatu-
rated pyrazolidinone imides as substrates, see: (a) Sibi, M. P.; Venkatraman,
L.; Liu, M.; Jasperse, C. P. J. Am. Chem. Soc. 2001, 123, 8444. (b) Sibi,
M. P.; Liu, M. Org. Lett. 2001, 3, 4181. (c) Sibi, M. P.; Prabagaran, N.
Synlett 2004, 2421. (d) Nakano, H.; Tsugawa, N.; Fujita, R. Tetrahedron
Lett. 2005, 46, 5677. (e) Nakano, H.; Tsugawa, N.; Takahashi, K.; Okuyama,
Y.; Fujita, R. Tetrahedron 2006, 62, 10879. (f) Sibi, M. P.; Chen, J.; Stanley,
L. M. Synlett 2007, 298. (g) Sibi, M. P.; Stanley, L. M.; Nie, X.;
Venkatraman, L.; Liu, M.; Jasperse, C. P. J. Am. Chem. Soc. 2007, 129,
395.
Attempts to expand the scope of â-substituted dipolaro-
philes applicable in enantioselective 1,3-dipolar cycloaddition
1554
Org. Lett., Vol. 9, No. 8, 2007

enantioselectivity (entry 9). Furthermore, the yield of 3k
could be increased with only minimal erosion of enantio-
selectivity by conducting the reaction at 40 °C (entry 10).
Encouraged by the good enantioselectivity observed at 40
°C in the cycloaddition of ethyl diazoacetate to cinnamate
1h, we became interested in determining whether elevated
reaction temperatures might allow us to access pyrazoline
cycloadducts derived from R,â-disubstituted, R,â-unsaturated
pyrazolidinone imides, which had proven completely unre-
active in room temperature reactions utilizing 100 mol %
chiral Lewis acid. Cycloaddition of 2a to tiglate 5a did,
however, proceed at 40 °C in the presence of 100 mol %
Mg(NTf2)2/4 (Table 3, entry 1). Although the isolated yield
Table 2. Enantioselective Dipolar Cycloaddition with
â-Substituted, R,â-Unsaturated Pyrazolidinone Imidesa
temp
(°C)
yield
(%)b
ee
entry substrate
R
product
(%)c
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1d
1e
1f
1g
1h
1h
Me
H
CO2t-Bu
Et
Et
i-Pr
CH2Ph
CH2C6H11
Ph
-20
-20
-20
-20
rt
rt
rt
rt
rt
3a
3e
3f
3g
3g
3h
3i
3j
3k
3k
72
75
91
32
85
79
58
59
54
76
99
97
99
97
99
98
95
90
90
88
Table 3. Enantioselective Dipolar Cycloaddition with
R,â-Disubstituted, R,â-Unsaturated Pyrazolidinone Imidesa
10d
Ph
40
a For experimental details see the Supporting Information. b Isolated
yields. c Determined by chiral HPLC. d Reactions performed at 40 °C were
run in sealed, heavy wall pressure vessels with threaded Teflon bushing.
mol % temp yield
CLA*
ee
of ethyl diazoacetate are illustrated in Table 2. In addition
to crotonate 1a (entry 1), cycloadditions utilizing highly
reactive dipolarophiles, such as acrylate 1b and fumarate 1c,
proceed in high yields with excellent enantioselectitivies at
-20 °C (entries 2 and 3, respectively). We were quite
intrigued by the lack of reactivity when 1d (R ) Et) was
employed as the dipolarophile given the minimal increase
in steric bulk relative to crotonate 1a (compare entry 4 with
entry 1). This apparent lack of reactivity was easily overcome
by performing the reaction at room temperature (entry 5).
Surprisingly, the enantioselectivity was once again higher
for the reaction conducted at room temperature (compare
entry 4 with entry 5). Room temperature cycloadditions also
proved optimal for additional dipolarophiles 1e-g bearing
aliphatic â-substituents (entries 6-8).
Prior to this work, no examples of enantioselective 1,3-
dipolar cycloaddition of diazoalkanes or diazoacetates to
â-aryl-subsitituted dipolarophiles have been reported. The
lack of successful examples with such substrates likely stems
from the increased energy of the LUMO relative to that of
â-alkyl-subsitituted dipolarophiles.8 Given the low temper-
atures necessary in previous work to obtain high enantio-
selectivities and minimize byproduct formation, increasing
reaction temperature was not a practical option for additional
activation of such substrates.4,5 The high enantioselectivities
observed in previous room temperature cycloadditions
(entries 5-8) led us to evaluate whether reactions utilizing
cinnamate 1h as the dipolarophile could provide access to
4-phenyl-substituted pyrazoline 3k. We were quite pleased
to isolate pyrazoline 3k in moderate yield with good
entry substrate
R1
R2
(°C)b
(%)c
(%)d
1
2
3
4
5
5a
5a
5a
5a
5b
Me
Me
Me
Me
Me
Me
Me
Me
100
50
50
30
30
40
40
50
50
50
37
42
61
52
62
95
95
99
98
99
-(CH2)3-
a For experimental details see the Supporting Information. b Reactions
performed at 40 °C or higher were run in sealed, heavy wall pressure vessels
with threaded Teflon bushing. c Isolated yields. d Determined by chiral
HPLC.
of this cycloaddition was moderate at best, it should be noted
that the enantioselectivity was high. Attempts at lowering
the loading of chiral Lewis acid had little effect on the
outcome of this reaction (entry 2). Interestingly, significant
increases in both reaction efficiency and selectivity were
observed when the cycloaddition was performed at 50 °C
(entry 3). Under optimized conditions pyrazoline 6a could
be isolated in moderate yield with excellent enantioselectivity
at 30 mol % chiral Lewis acid loading (entry 4). Bicyclic
pyrazoline 6b was also prepared with excellent enantio-
selecitivity at elevated temperature (entry 5).
Unfortunately, we were not able to isolate pyrazolines
derived from less reactive R,â-disubstituted dipolarophiles
(R1 ) Me; R2 ) Et or Ph) at 50 °C.9 Nevertheless, the
selectivities obtained for pyrazolines 6a and 6b clearly offer
additional evidence of the high levels of rotamer control
provided by R,â-disubstituted, R,â-unsaturated pyrazolidi-
(9) Cycloaddition of ethyl diazoacetate to the pyrazolidinone imide
derived from trans-2-methyl-2-pentenoic acid (R1 ) Me; R2 ) Et) at 60
°C gave the corresponding pyrazoline in low yield and reduced enantio-
selectivity. Additional increases in reaction temperature led only to increased
formation of unidentified byproducts.
(8) (a) Houk, K. N.; Sims, J.; Duke, R. E., Jr.; Strozier, R. W.; George,
J. K. J. Am. Chem. Soc. 1973, 95, 7287. (b) Houk, K. N.; Sims, J.; Watts,
C. R.; Luskus, L. J. J. Am. Chem. Soc. 1973, 95, 7301.
Org. Lett., Vol. 9, No. 8, 2007
1555

none imides, and suggest pyrazolidinone auxiliaries may have
significant potential in enantioselective transformations
requiring elevated temperatures for enhanced reactivity.
Previous work from our lab,6c in combination with the
results with R,â-disubstituted dipolarophiles presented above,
suggested high levels of enantioselectivity could be achieved
for cycloaddition of ethyl diazoacetate to R-methyl acrylate
7 (Scheme 2). We were particularly interested in cyclo-
pound 8 was reduced to the corresponding amino alcohol,
which was subsequently treated with trimethyl orthoformate
to give bicycle 9 in 60% yield over two steps. It should be
noted that the difficult separation of the intermediate amino
alcohol and the cleaved pyrazolidinone need not be per-
formed, as the auxiliary is readily removed after formation
of 9. Treatment of 9 with Raney-nickel/H2 resulted in the
formation of the desired tetrahydropyrimidine core, which
was used directly. After esterification with 4-bromo-2-
trichloroacetylpyrrole an 85:15 diastereomeric mixture of
(-)-mancacidin A (10) and (ent)-manzacidin C (11) was
obtained. An analytical sample of mancacidin A was isolated
according to the literature procedure, which matched the
spectral data for previously reported syntheses11 and isola-
tion12 of (-)-manzacidin A. Based on the absolute stereo-
chemistry of (-)-manzacidin A, the absolute configuration
of pyrazoline 8 has been assigned as (5R).13
Scheme 2. Enantioselective Synthesis of (-)-Manzacidin A
In conclusion, we have illustrated a method for enantio-
selective synthesis of 2-pyrazolines via magnesium(II)-
catalyzed cycloaddition of diazoesters to R,â-unsaturated
pyrazolidinone imides. The methodology allows facile access
to enantioenriched pyrazolines derived from â-subsituted,
R-substituted, and R,â-disubstituted dipolarophiles, the latter
two resulting in pyrazolines bearing quaternary tert-alkyl
amino stereocenters at the 5-position of the pyrazoline.14 One
such pyrazoline has been elaborated to (-)-manzacidin A
in 4 additional steps via a previously reported procedure.
Work toward additional applications of chiral pyrazolines
in asymmetric synthesis and R,â-unsaturated pyrazolidinone
imides in high-temperature enantioselective transformations
is ongoing in our laboratory.
Acknowledgment. We thank the NSF (NSF-CHE-
0316203) for financial support and Ms. Jamie Jensen
(NDSU) for experimental assistance.
addition to 7 as the resulting pyrazoline core has been
elegantly elaborated to (-)-manzacidin A by Maruoka and
co-workers.5 Furthermore, we believed our catalyst/di-
polarophile system offered the potential to increase the
moderate yields previously obtained for this key cycloadduct.
Cycloaddition of 3a to 7 gave 2-pyrazoline 8 in 99% yield
with 97% ee in the presence of 30 mol % Mg(NTf2)2.10
Enantioselectivity remains high and yields are also good at
lower loadings of the chiral Lewis acid. Even with the lower
yields observed in reactions run at lower catalyst loadings,
these results represent a more efficient means to access this
key pyrazoline core.
Supporting Information Available: Experimental pro-
cedures and characterication data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL070364X
(11) For additional syntheses of (-)-manzacidin A, see: (a) Wang, Y.;
Liu, X.; Deng, L. J. Am. Chem. Soc. 2006, 128, 3928. (b) Wehn, P. M.;
DuBois, J. J. Am. Chem. Soc. 2002, 124, 12950. (c) Namba, K.; Shinada,
T.; Teramoto, T.; Ohfune, Y. J. Am. Chem. Soc. 2000, 122, 10708.
(12) Kobayashi, J.; Kanda, F.; Ishibashi, M.; Shigemori, H. J. Org. Chem.
1991, 56, 4574.
(13) Absolute stereochemistry has been tentatively assigned as (4S,5R)
for pyrazolines derived from â-substituted and R,â-disubstituted dipolaro-
philes based on related stereochemical models, see refs 2i and 2j.
(14) For a review on the total synthesis of natural products containing
tert-alkylamino stereocenters, see: Kang, S. H.; Kang, S. Y.; Lee, H.-S.;
Buglass, A. J. Chem. ReV. 2005, 105, 4537.
Pyrazoline 8 is readily elaborated to a diastereomeric
mixture of (-)-manzacidin A and (ent)-manzacidin C using
Maruoka’s previously reported approach (Scheme 2). Com-
(10) Reaction of ethyldiazoacetate with oxazolidinone methacrylate under
identical conditions gave <5% yield of the adduct.
1556
Org. Lett., Vol. 9, No. 8, 2007