Catalytic asymmetric aza-Darzens reaction with a vaulted biphenanthrol magnesium phosphate salt

Article abstract of DOI:10.1021/ol200407r

Chemical equations presented. Conditions for a catalytic asymmetric aza-Darzens aziridine synthesis mediated by a vaulted biphenanthrol (VAPOL) magnesium phosphate salt is described. Using simple substrates, this methodology explores the scope and reactiv

Full text of DOI:10.1021/ol200407r

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2188–2191
Catalytic Asymmetric Aza-Darzens
Reaction with a Vaulted Biphenanthrol
Magnesium Phosphate Salt
Shawn E. Larson,† Guilong Li,‡ Gerald B. Rowland,§ Denise Junge,† Rongcai Huang,†
H. Lee Woodcock,† and Jon C. Antilla*,†
†Department of Chemistry, University of South Florida, 4202 East Fowler Avenue
CHE205A, Tampa, Florida 33620, United States, ‡Department of Chemistry, Sun
Yat-Sen University, Guangzhou 510275, China, and §Department of Chemistry, Box 9573,
Mississippi State University, Mississippi State, Mississippi 39762-9573, United States
jantilla@usf.edu
Received February 14, 2011
ABSTRACT
Conditions for a catalytic asymmetric aza-Darzens aziridine synthesis mediated by a vaulted biphenanthrol (VAPOL) magnesium phosphate salt is
described. Using simple substrates, this methodology explores the scope and reactivity of a new magnesium catalyst for an aziridination reaction
capable of building chirality and complexity simultaneously.
The Darzens aziridine synthesis, first proposed by
Deyrup,1 is a pathway to prepare complex aziridines, with
considerable synthetic utility, from common synthetic
building blocks. Examples where such aziridines are used
as versatile intermediates are mainly through their ring-
opening reactions for the preparation of chiral amines.2
Clearly, new catalytic asymmetric methods of aziridine
synthesis via the aza-Darzens reaction would be interesting
due to this synthetic potential. In two reports from 1999
and 2000, a breakthrough by Wulff in the area of catalytic
asymmetric aziridination of imines was reported.3 The
catalyst for this reaction, while initially believed to be a
boron Lewis acid, was later proven to be a chiral Brønsted
acid after intense mechanistic study.4 Additionally, in
1999, independently both Sweeney5 and Davis6 reported
asymmetric versions of the aza-Darzens reaction using
stoichiometric amounts of chiral reagents. In other early
studies, Johnston and co-workers published a triflic acid-
catalyzed aza-Darzens variant.7 More recently, a number
(4) Desai, A. A.; Wulff, W. D. J. Am. Chem. Soc. 2010, 132, 13104.
(5) (a) McLaren, A. B.; Sweeney, J. B. Org. Lett. 1999, 1, 1339. For
asymmetric aziridination with chiral sulfur ylides, see: (b) Aggarwal,
V. K.; Thompson, A.; Jones, R. V. H.; Standen, M. C. H. J. Org. Chem.
1996, 61, 8368. (c) Aggarwal, V. K.; Alonso, E.; Fang, G.; Ferrara, M.;
Hynd, G.; Porcelloni, M. Angew. Chem., Int. Ed. 2001, 40, 1433.
(6) Davis, F. A.; Liu, H.; Zhou, P.; Fang, T.; Reddy, G. V.; Zhang, Y.
J. Org. Chem. 1999, 64, 7559.
(7) (a) Williams, A. L.; Johnston, J. N. J. Am. Chem. Soc. 2004, 126,
1612. For a review of acid catalysis with diazoalkanes, see: (b) Johnston,
J.; Muchalski, H.; Troyer, T. L. Angew. Chem., Int. Ed. 2010, 49, 2290.
(8) (a) Hashimoto, T.; Uchiyama, N.; Maruoka, K. J. Am. Chem.
Soc. 2008, 130, 14380. (b) Akiyama, T.; Suzuki, T.; Mori, K. Org. Lett.
2009, 11, 2445. (c) Zeng, X.; Zeng, X.; Xu, Z.; Lu, M.; Zhong, G. Org.
Lett. 2009, 11, 3036. For other recent examples, see: (d) Giubellina, N.;
(1) Deyrup, J. A. J. Org. Chem. 1969, 34, 2624.
(2) For reviews, see: (a) Yudin, A. K. Aziridines and Epoxides in
Organic Synthesis; Wiley-VCH: Weinheim, Germany, 2006. (b) Masahiko,
H.; Ono, K.; Hoshimi, H.; Oguni, N. Tetrahedron 1996, 52, 7817. (c)
Jacobsen, E. N. In Comprehensive Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 2, p 607.
(3) (a) Antilla, J. C.; Wulff, W. D. J. Am. Chem. Soc. 1999, 121, 5099.
(b) Antilla, J. C.; Wulff, W. D. Angew. Chem., Int. Ed. 2000, 39, 4518.
For the background information for catalytic asymmetric aziridination
before 1999, please see the cited references within these two papers.
€
Mangelinckx, S.; Tornroos, K. W.; De Kimpe, N. J. Org. Chem. 2006,
71, 5881. (e) Valdez, C.; Leighton, J. J. Am. Chem. Soc. 2009, 131, 14638.
(f) Hashimoto, T.; Nakatsu, H.; Watanabe, S.; Maruoka, K. Org. Lett.
2010, 12, 1668.
r
10.1021/ol200407r
Published on Web 04/05/2011
2011 American Chemical Society

of new Brønsted acid variants similar to these reactions
were subsequently published, with highly enantioselective
conditions described.8 We believed that, despite the above
efforts, the use of typical aza-Darzens-type nuceophiles9
like R-halo-1,3-dicarbonyl compounds could lead to
functionalized aziridines using chiral phosphoric acids as
potential catalysts.10
We were encouraged by recent reports that successfully
demonstrated a variety of chiral phosphate salts for cata-
lytic asymmetric induction.13 Using chiral phosphate salts
as catalysts, we wish to report an asymmetric aza-Darzens
reaction that employs R-chloro-1,3-diketones as compe-
tent nucleophiles for addition to N-benzoyl imines, allow-
ing access to trisubstituted aziridines with good
enantioselectivity.
Table 1. Optimization of Aza-Darzens Aziridination Reactiona
entry catalystb catalyst loading (mol %) yield (%)c ee (%)d
1
2
H[P1]
5
48
63
32
65
83
0
0
ꢀ7
52
80
4
H[P2]
5
3
H[P3]
5
4e
5
H[P3]
5
Figure 1. Common phosphoric acids and their phosphate salt
equivalents.
Li[P3]1
Na[P3]1
Ca[P3]2
Ba[P3]2
Mg[P3]2
Mg[P3]1
Mg[P3]4
Mg[P1]2
Mg[P2]2
5
6
5
7
2.5
2.5
2.5
5
57
49
74
63
14
57
65
44
49
80
70
75
ꢀ4
ꢀ5
After some limited initial success while focusing on
chiral phosphoric acids, we turned our attention to chiral
phosphate metal salts as viable mediators for this reaction.
We were attracted to these catalysts after a report by
Ishihara on similar Mannich reactions showed that metal
phosphate salts were superior catalysts when screening
versus the free phosphoric acids.11 These investigations
were supported by the findings of List,12 who showed that
phosphoric acids used directly after column chromatogra-
phy can be the neutralized mixtures of phosphate salt
impurities and acid, rather than just the pure acid.
8
9
10
11
12
13
1.25
2.5
2.5
a General reaction conditions: THF was removed before step 2 while
1.5 equiv of 1e, 1.0 equiv of 2, and 2.0 equiv of DMAP were added. b See
the Supporting Information for details on the preparation of the
catalysts. c Isolated yield. d Determined by chiral HPLC analysis. e Pur-
ified on silica gel without re-acidification.
As we began our screening, we found that common
phosphoric acids (Table 1, entries 1ꢀ3) were relatively
poor catalysts for this reaction. However, these catalysts
did indicate, based on enantioselectivity, that the reaction
carried a strong preference for P3 (VAPOL), a phosphoric
acid derived from (R)-2,20-diphenyl-3,30-(4-biphenanthrol)
(Figure 1). When P3 was used directly after purification on
silica gel (entry 4), the enantiomeric excess was significantly
higher than the re-acidified phosphoric acid (entry 3); this led
to the obvious pursuit of a phosphate salt catalyst with
chirality from VAPOL. To explore this new chiral phosphate
system, we matched P3 with commerically available alkali or
alkaline salts. Group 1 elements were not promising: lithium
showed excellent efficiency, leading to a high yield but low
enantioselectivity (entry 5), while sodium prevented the aza-
Darzens reaction from occurring at all (entry 6). While all
three of the group 2 alkalines promoted the reaction with
some enantioselectivity, the most selective example was the
pairing of P3 with magnesium (entries 7ꢀ9). From the
comparison of the yields and selectivities of the various salts,
it became clear that magnesium VAPOL phosphate salt
impurities originating from the silica gel were most likely
catalyzing the reaction in entry 4. To our knowledge, this is
the first example of a magnesium phosphate salt being the
(9) For select Mannich-type reactions with 1,3-dicarbonyl reagents,
see: (a) Hamashima, Y.; Sasamoto, N.; Hotta, D.; Somei, H.;
Umebayashi, N.; Sodeoka, M. Angew. Chem., Int. Ed. 2005, 44, 1525.
(b) Song, J.; Wang, Y.; Deng, L. J. Am. Chem. Soc. 2006, 128, 6048. (c)
Chen, Z.; Morimoto, H.; Matsunaga, S.; Shibasaki, M. J. Am. Chem.
Soc. 2008, 130, 2170. (d) Hatano, M.; Maki, T.; Moriyama, K.; Arinobe,
M.; Ishihara, K. J. Am. Chem. Soc. 2008, 130, 16858. (e) Han, X.;
Kwiatkowski, J.; Xue, F.; Huang, K.-W.; Lu, Y. Angew. Chem., Int. Ed.
2009, 48, 7604. (f) Hatano, M.; Horibe, T.; Ishihara, K. J. Am. Chem.
Soc. 2010, 132, 56.
(10) For pioneering chiral phosphoric-acid-catalyzed methods, see:
(a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem., Int.
Ed. 2004, 43, 1566. (b) Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004,
126, 5356. For reviews with considerable chiral phosphoric acid cover-
age, see: (c) Akiyama, T.; Itoh, J.; Fuchibe, K. Adv. Synth. Catal. 2006,
348, 999. (d) Connon, S. Angew. Chem., Int. Ed. 2006, 45, 3909. (e)
Akiyama, T. Chem. Rev. 2007, 107, 5744. (f) Terada, M. Chem. Commun.
2008, 4097. (g) Adair, G.; Mukherjee, S.; List, B. Aldrichchim. Acta.
2008, 41, 31. (h) Terada, M. Bull. Chem. Soc. Jpn. 2010, 83, 101.
(11) (a) Hatano, M.; Moriyama, K.; Maki, T.; Ishihara, K. Angew
Chem., Int. Ed. 2010, 49, 3823. (b) Hatano, M.; Ikeno, T.; Matsumura,
T.; Torii, S.; Ishihara, K. Adv. Synth. Catal. 2008, 350, 1776. (c) Shen, K.;
Liu, X.; Cai, Y.; Lin, L.; Feng, X. Chem.;Eur. J. 2009, 15, 6008.
(12) Klussmann, M.; Ratjen, L.; Hoffmann, S.; Wakchaure, V.;
Goddard, R.; List, B Synlett 2010, 2189.
(13) (a) Lv, J.; Li, X.; Zhong, L.; Luo, S.; Cheng, P. Org. Lett. 2010,
12, 1096. (b) Rueping, M.; Koenigs, R. M.; Atodiresei, I. Chem.;Eur. J.
2010, 16, 9350. (c) Rueping, M.; Nachtsheim, B. J.; Koenigs, R. M.;
Ieawsuwan, W. Chem.;Eur. J. 2010, 16, 13116. (d) Drouet, F.; Lalli, C.;
Liu, H.; Masson, G.; Zhu, J. Org. Lett. 2011, 13, 94. (e) Zhang, Z.;
Zheng, W.; Antilla, J. C. Angew. Chem., Int. Ed. 2011, 50, 1135.
Org. Lett., Vol. 13, No. 9, 2011
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Scheme 1. Substrate Scopea
a General reaction conditions: 2.5 mol % catalyst loading, THF was
removed before step 2, while 1.5 equiv of 1, 1.0 equiv of 2, and 2.0 equiv
of DMAP were added. All yields are isolated, and enantiomeric excess
was determined by chiral HPLC analysis.
optimal catalyst for an enantioselective Mannich-type
reaction.
Figure 2. Calculated structures of VAPOL magnesium
phosphate.
Initially, we assumed that a ratio of two P3 to one
magnesium would be optimal; to confirm, a screening of
other ratios of VAPOL phosphate and magnesium was
performed. A significant drop in yield and enantioselec-
tivity was observed compared with the initial ratio (entries
10 and 11). Lastly, we wanted to determine if other
common phosphoric acids could be as effective as the P3
catalyst. After conversion to the corresponding magne-
sium phosphate salt, both catalysts derived from P1 and
P2 showed little enantioselectivity for the aza-Darzens
reaction (entries 12 and 13). These results confirm that
VAPOL magnesium phosphate is ideal for promoting the
aza-Darzens reaction efficiently and with selectivity.
With the optimal conditions identified, we proceeded to
examine various substituted imines derived from their
corresponding benzaldehydes (Scheme 1). These aza-
Darzens aziridine products were formed with moderate
yields and high enantioselectivities.
around the center of chirality, the enantioselectivity de-
creased, clearly the resultofthe substituent onthe arylring.
This is evident when observing the enantioselectivities of 3c
and 3f compared to3band 3e, respectively. The presence of
electron-withdrawing halogens in the para position
(3gꢀ3i) gave comparable results with the electron-donat-
ing para-substituted substrates.
While the active catalytic species involved in these phos-
phate salt-catalyzed reactions is not yet definitively proven,
we moved forward with a theoretical study using two
biphenanthrol phosphate ions coordinated to one magne-
sium cation. Catalyst structures were geometry-optimized
using the Q-Chem ab initio package14 and employing the
B3LYP15 functional and 6-31þG* basis set.16 Figure 2
represents the lowest energy structure found.17 Interestingly,
(14) Shao, Y.; et al. Phys. Chem. Chem. Phys. 2006, 8, 3172. For the
full reference, see Supporting Information.
(15) (a) Becke, A. D. Phys. Rev. A 1988, 38, 3098. (b) Lee, C.; Yang,
W.; Parr, R. G. Phys. Rev. B 1988, 37, 785.
(16) (a) Gill, P. M. W.; Johnson, B. G.; Pople, J. A.; Frisch, M. J.
Chem. Phys. Lett. 1992, 197, 499–505. (b) Krishnan, R.; Binkley, J. S.;
Seeger, R.; Pople, J. A. J. Chem. Phys. 1980, 72, 650.
(17) These structures were calculated for the R enantiomer of VA-
POL, and negligible energy differences were noticed when the opposite
enantiomer was calculated in similar work: Simon, L.; Goodman, J.
J. Am. Chem. Soc. 2008, 130, 8741.
In example 3a when the starting material is fully con-
sumed, the mass balance of the reaction can be accounted
for by incomplete conversion in the second ring-closing
step. Various substituents at the aryl ring were evaluated in
the exploration of the substrate scope. Both methoxy and
methyl groups showed analogous tolerance and enantio-
selectivities regardless of their position on the arene ring sys-
tem (3bꢀ3f). However, as the steric environment increased
2190
Org. Lett., Vol. 13, No. 9, 2011

the dihedral angle of the phenanthrene rings was found to be
approximately 60°; the axial C2-symmetry undoubtedly
controls enantioselectivity of the products formed.
Two alternative catalyst conformations were located;
these were higher in energy, relative to Figure 2 (top) by 10
and 24 kcal/mol. Different coordination patterns of mag-
nesium can partially account for these energy differences
(vide infra). In the lowest energy structure (Figure 2, top),
the magnesium is coordinated to the four terminal phos-
phoryl oxygens. In contrast the higher energy conformers,
respectively, had magnesium bound to either one or two
phosphoryl ethers in conjunction with three or two term-
inal oxygens. From the NBO18 analysis, energetics of these
interactions indicate that an approximate 5 kcal/mol pen-
alty exists when binding phosphoryl ether compared to
terminal oxygen. However, this energetic penalty is com-
pensated for by increased stabilization via interactions
with the adjacent terminal oxygen. Measuring the magne-
siumꢀoxygen distances highlights this as the magne-
Figure 3. Proposed transition state.
minimize the steric interactions with the phenanthrenes.
The validity of the proposed mechanism can be sup-
ported by its ability to predict the absolute configuration
of the major enantiomer (see below and Supporting
Information for details). The absolute configuration
was determined by HPLC comparison of the dechlori-
nated β-amino carbonyl compound to the literature.20
The absolute configuration corresponds with that of the
S enantiomer for 3a, validating the chirality predicted by
the transition state.21
In conclusion, we have demonstrated the utility of a
chiral VAPOL magnesium phosphate salt catalyst and
described its first use in the enantioselective aza-Darzens
reaction. This was accomplished while simultaneously
showing a new approach to the aza-Darzens reaction
through the addition of R-chloro-1,3-dicarbonyl com-
pounds. These chiral phosphate salts represent a powerful
step forward in our ability to tailor optimized catalytic
systems to specific reactions. Further experiments to eval-
uate the utility of VAPOL-derived phosphate salts are
currently underway in our laboratory.
˚
˚
siumꢀether oxygen distance is 2.1 A compared to 1.9 A
for the magnesiumꢀterminal oxygen (Figure 2, middle).
In contrast, the lowest energy structure (Figure 2, top)
˚
has magnesiumꢀoxygen distances of approximately 2.1 A
for all interactions. Clearly, the orbital interactions cannot
explain the energetic differences observed; however, large
structural changes are evident based on the interaction
patterns. Therefore, a combination of steric repulsion,
strain, and hydrophobic/hydrophilic effects likely dictate
the final structure.
Using this structural information, we propose a possible
transition state and mechanism to explain the high enan-
tioselectivity observed. Figure 3 shows coordination of the
magnesium to the carbonyls of the imine and diketone’s
enol form. Additionally, the enol can hydrogen bond tothe
oxygens on the catalyst. The catalyst can simultaneously
stabilize the nucleophile and electrophile, while providing
the chiral environment for asymmetric induction.19
We surmised, therefore, that the enantioselectivity is a
consequence of steric interactions between the phenan-
threne rings and the aromatic substituents of the imine,
allowing for facial selectivity. As the imine coordinates
with the catalyst, its aryl rings align perpendicular to the
plane of the catalyst while crossing the center to
Acknowledgment. We thank the National Institutes of
Health (NIH GM-082935) and the National Science
Foundation CAREER Program (NSF-0847108) for finan-
cial support. H.L.W. would like to acknowledge NIH/
NHLBI (1K22HL088341-01A1) and the University of
South Florida (start-up) for funding.
Supporting Information Available. Experimental pro-
cedures and characterization of all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(18) NBO, version 5.0; Glendening, E. D.; Badenhoop, J, K.; Reed, A. E.;
Carpenter, J. E.; Bohmann, J. A.; Morales, C. M.; Weinhold, F. Theoretical
Chemistry Institute, University of Wisconsin, Madison, WI, 2001.
(19) Simon, L.; Goodman, J. J. Am. Chem. Soc. 2009, 131, 4070.
(20) Terada, M.; Sorimachi, K.; Uraguchi, D. Synlett 2006, 133.
(21) Additional details are in the Supporting Information.
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