N-phosphinyl phosphoramide-A Chiral Bronsted acid motif for the direct asymmetric N,O-acetalization of aldehydes

Article abstract of DOI:10.1002/anie.201005347

Fine-tuning the sites: The readily accessible N-phosphinyl phosphoramide 1 proved to be highly efficient and enantioselective in catalyzing the title reaction. The synthetic utility of this methodology was demonstrated with the first catalytic asymmetric synthesis of the analgesic pharmaceutical (R)-chlorothenoxazine (see scheme). Copyright

Full text of DOI:10.1002/anie.201005347

Angewandte
Chemie
DOI: 10.1002/anie.201005347
Organocatalysis
N-Phosphinyl Phosphoramide—A Chiral Brønsted Acid Motif for the
Direct Asymmetric N,O-Acetalization of Aldehydes**
ˇ
´
Sreekumar Vellalath, Ilija Coric, and Benjamin List*
The advent of 1,1’-binaphthalene-2,2’-diol (BINOL) phos-
phates as powerful Brønsted acid catalysts heralded a new era
in asymmetric organocatalysis.[1] The recognition of the
bifunctional mode of activation of these catalysts in reactions
of imines with nucleophiles inspired organic chemists to
design a variety of new asymmetric transformations.[2] At the
same time, significant effort has also been devoted to the
construction of other Brønsted acid motifs such as thioureas,[3]
dicarboxylic acids,[4] and disulfonic acids.[5] A remarkable
innovation in this area occurred when Yamamoto et al.
introduced N-triflyl phosphoramides for the activation of
less reactive substrates such as ketones, silyl enol ethers, and
aldehydes.[6–8] Our recent discovery of chiral disulfonimides
and their use as Lewis acid precatalysts for the activation of
aldehydes, has revealed yet another potentially important
class of chiral acid catalysts.[9] In research on BINOL-derived
phosphoric acids little effort has been made towards the
design of new analogues with alternative functionalities,
except for certain modifications of their backbone[10] and
the above-mentioned derivatization. As theoretical studies
confirm that these catalysts simultaneously activate electro-
Figure 1. N-Phosphinyl phosphoramide as a new motif for asymmetric
Brønsted acid catalysis.
The importance of the stereochemistry of the acetal carbon in
N,O-acetal-containing drugs is illustrated by the different
bioactivities of their enantiomers.[14a,15] In 2005, Antilla et al.
reported the first catalytic asymmetric method for the syn-
thesis of chiral aminals by the addition of sulfonamides to
imines, using a VAPOL (vaulted biphenanthrol)-derived
phosphoric acid.[16] They also extended this strategy to the
preparation of chiral N,O-acetals by the BINOL phosphoric
acid catalyzed enantioselective addition of alcohols to N-
benzoyl imines.[17] However, this methodology is limited to
acyclic N,O-acetals and to the use of preformed imines as
electrophiles. As part of our long-standing interest in the
development of asymmetric acetalization reactions,[18] we
reported the direct enantioselective synthesis of cyclic
aminals from aldehydes through a sequence consisting of
imine formation and intramolecular amidation (Scheme 1).[19]
However, analogous N,O-acetalizations have been entirely
unknown, which is unsatisfying since cyclic N,O-acetals,
especially benzoxazinones, have recently gained importance
because of their pharmaceutical applications.[20] For example,
chlorothenoxazine is well appreciated for its analgesic
activity.[21] So far only achiral acids or amines have been
used in the preparation of benzoxazinones from substituted
philes by protonation and nucleophiles through interaction
[11]
=
with the basic P O group, we are interested in exploring
derivatives with alternative acidic and basic sites to further
expand the utility of this fascinating type of organocatalyst.[12]
Here we introduce N-phosphinyl phosphoramides as a new
motif for organocatalysis (Figure 1).
=
We hypothesized that the additional basic P O function-
ality of an N-phosphinyl phosphoramide could stabilize
different transition-state geometries in the bifunctional
activation of two reacting substrates. Additionally, by bring-
ing in two new substituents, these catalysts could be easily
modified and fine-tuned for a particular reaction. We now
show that this new class of Brønsted acids can indeed be used
in the first highly enantioselective direct N,O-acetalization of
aldehydes.
Cyclic N,O-acetals are a frequently encountered struc-
tural motif in natural products and in pharmaceuticals.[13–14]
ˇ
´
[*] Dr. S. Vellalath, I. Coric, Prof. Dr. B. List
Max-Planck-Institut fꢀr Kohlenforschung
Kaiser Wilhelm-Platz 1, 45470 Mꢀlheim an der Ruhr (Germany)
Fax: (+49)208-306-2982
E-mail: list@mpi-muelheim.mpg.de
[**] We thank the Alexander von Humboldt Foundation (fellowship for
S.V.), the Max-Planck-Society, the DFG (Priority Program Organo-
catalysis SPP1179), and the Fonds der Chemischen Industrie for
support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201005347.
Scheme 1. Catalytic asymmetric N,N- and N,O-acetalizations.
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salicylamides and aldehydes.[22,23] Indeed, we found this
base.[26,27] Use of catalyst 6 provided product 3a with an
improved enantioselectivity of 85:15 e.r. (Table 1, entry 3). To
further rigidify the chiral pocket provided by the catalyst, we
explored the possiblity of replacing the phenoxide moiety in 6
with other groups. In the event, several chiral N-phosphinyl
phosphoramides (7a–f) were synthesized from the corre-
sponding diaryl phosphinamide and TRIP-Cl and were tested
in the model reaction. Gratifyingly, catalyst 7a considerably
improved the enantioselectivity but at the expense of the
reaction rate (Table 1, entry 4). Interestingly, the arene
substituents present in the phosphinyl moiety exerted a
striking influence on the reaction outcome.
transformation to be extremely challenging when we tested
a variety of established chiral Brønsted acid catalysts.
Consequently, we embarked on the development of a new
chiral catalyst for the asymmetric synthesis of benzoxazinones
from aldehydes.
In our initial studies we exposed a mixture of 2-hydroxy-4-
methylbenzamide (1a) and isovaleraldehyde (2a) to a
catalytic amount of (S)-TRIP[24] (4) (10 mol%) at 508C
(Figure 2). A slow but efficient reaction occurred and the
benzoxazinone[25] derivative 3a was obtained with a promis-
While catalysts 7a (Ar= Ph) and 7b (Ar= 4-tBuC6H4)
gave similar results, aryl groups containing electron-with-
drawing substituents at the meta positions provided higher
reaction rates but gave significantly lower enantioselectivities
(Table 1, entries 6 and 7). Gratifyingly, we found that catalyst
7e with a para-fluorophenyl group, significantly improved the
enantioselectivity, although the yield was only moderate
(Table 1, entry 8). A further improvement in both the
reaction rate and the enantioselectivity was observed with
catalyst 7 f (Ar= 4-CF3C6H4; Table 1, entry 9), which pro-
vided the product 3a with an e.r. of 95:5 and was selected for
exploration of the substrate scope. The yield of the reaction
could be further improved to 90% by using an excess of
aldehyde (Table 1, entry 10).
With the optimized conditions in hand, we tested a variety
of aldehydes in the reaction with amide 1a (Table 2). The
N,O-acetalization catalyzed by N-phosphinyl phosphoramide
7 f proved to be quite general. Aliphatic a-unbranched and a-
branched aldehydes were converted into benzoxazinones 3
with high yields and enantioselectivities (Table 2, entries 1–5).
The linear aliphatic aldehyde 2g afforded still good but
slightly lower enantioselectivity (Table 2, entries 6 and 7),
while benzaldehyde gave rather moderate enantioselectivity
(entry 8). We further investigated the applicability of this
Figure 2. Catalysts tested.
ing e.r. of 78:22 (Table 1, entry 1). The more acidic N-triflyl
phosphoramide catalyst 5 resulted in reduced enantioselec-
tivity (Table 1, entry 2). As various other phosphoric acids
also failed to give an improvement,[26] we began focusing on
the development of the novel bisphosphorylimide catalyst 6,
which was easily accessible from (S)-TRIP chloride (TRIP-
Cl) and diphenyl phosphoramidate using NaH as the
Table 2: Aldehyde scope.
Table 1: Optimization of reaction conditions.
Entry[a] RCHO
Product
Yield [%][b] e.r.[c]
1
2
3
4
5
6
7
8
iBuCHO (2a)
3a
90
94
90
81
95
83
97
50
95.0:5.0
Entry[a]
Catalyst
Yield [%][b]
e.r.[c]
tBuCH2CHO (2b) 3b
iPrCHO (2c) 3c
(Et)2CHCHO (2d) 3d
94.5:5.5
96.0:4.0
98.0:2.0
96.0:4.0
91.5:8.5
92.0:8.0
75.5:24.5
syn:
1
2
3
4
5
6
7
8
4
5
6
7a
7b
7c
7d
7e
7 f
7 f
66
74
80
52
50
75
73
64
73
90
78.0:22.0
57.0:43.0
85.0:15.0
93.5:6.5
94.0:6.0
60.0:40.0
87.5:12.5
94.5:5.5
95.0:5.0
95.0:5.0
CyCHO (2e)
3e
3 f
3g
3h
PhCH2CHO (2 f)
nPrCHO (2g)
PhCHO (2h)
98.5:1.5
anti:
86.5:13.5
9[d]
69
9
10[d]
[a] Unless otherwise specified, reactions were performed on 0.1 mmol
scale (0.05m solution), 5 ꢁ M.S. (50 mg). [b] Yield of isolated product.
[c] Enantiomeric ratios were determined by HPLC analysis on a chiral
stationary phase. [d] Reaction carried out with 8 equivalents of 2a.
[a] The reactions were performed with 0.1 mmol of 1a and 0.8 mmol of 2,
5 ꢁ M.S. (50 mg). [b] Yield of isolated product. [c] Enantiomeric ratios
were determined by HPLC analysis on a chiral stationary phase. [d] 2-
Hydroxybenzamide (1b) was used. Cy=cyclohexyl.
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catalyst system to the diastereoselective N,O-acetalization of
2-phenyl propionaldehyde. The reaction delivered product 3i
in good yield with 1:1 d.r. (Table 2, entry 9). The syn product
was obtained with an excellent e.r. of 98.5:1.5 and the anti
isomer with 86.5:13.5 e.r.[28]
The generality of the reaction was also investigated with
several substituted 2-hydroxybenzamides (Table 3). The elec-
tronic properties of the arene substituents showed little
influence on the enantioselectivity and all, electron-rich,
Scheme 2. Synthesis of chlorothenoxazine
tantly, highly enantiomerically enriched product 9 could be
obtained after a single recrystallization from methanol.
Mechanistically, we believe the reaction to proceed via an
N-benzoylimine, generated from the aldehyde and 2-hydroxy-
benzamide. Protonation of the imine with catalyst 7 f delivers
a chiral ion pair, in which the chiral counteranion dictates the
approach of the phenol nucleophile towards the re enantio-
face of the imine as shown in Figure 3. In accordance with our
Table 3: 2-Hydroxybenzamide scope.
Entry[a]
X
Product
Yield [%][c] e.r.[d]
design, we propose that the Brønsted basic phosphinyl oxygen
2
1
H (1b)
3j
3k
3l
3m
3n
3o
89
96
97
97
98
95
95.0:5.0
=
( P O) activates the nucleophile in the transition state.
2[b]
3
3-Me (1c)
5-Me (1d)
6-Me (1e)
4-OMe (1 f)
5-OMe (1g)
96.0:4.0
96.0:4.0
94.0:6.0
95.5:4.5
94.5:5.5
4
5
6
7
4-Me, 5-Br (1h)
5-Me, 3-Br(1i)
4-Me, 3,5-Cl (1j) 3r
5-Cl (1k)
5-F (1l)
91
96.0:4.0
8[b]
9
10
11
3q
84
78
88
89
95.0:5.0
95.5:4.5
95.0:5.0
95.0:5.0
3s
3t
12
95
93.5:6.5
Figure 3. Stereochemical model.
[a] The reactions were performed with 0.1 mmol of 1 and 0.8 mmol of 2b,
5 ꢁ M.S. (50 mg). [b] The reaction was carried out at 608C. [c] Yield of
isolated product. [d] Enantiomeric ratios were determined by HPLC
analysis on a chiral stationary phase.
To obtain further evidence for the intermediacy of a
benzoylimine, we prepared enamide 10 as a latent imine
surrogate by means of Cu-catalyzed N-alkenylation and
subjected it to the acetalization reaction conditions
(Scheme 3). This reaction afforded the corresponding product
with the same enantioselectivity as in the two-component
reaction suggesting the imine as a common intermediate.
electron-neutral, and electron-poor benzamides furnished the
corresponding products in similarly high yields and enantio-
selectivites. While substrate 1j, substituted with two chlorine
atoms, gave slightly lower yield, the enantioselectivity
remained excellent (Table 3, entry 9). Furthermore, 3-
hydroxynaphthamide (1m) gave the corresponding product
3u with similarly high enantioselectivity (Table 3, entry 12).
The absolute configuration of N,O-acetal 3p was determined
to be R by single-crystal X-ray analysis.[28] The absolute
configuration of all other products was assigned by analogy.
We were also able to demonstrate the utility of our
methodology in the synthesis of the analgesic pharmaceutical
chlorothenoxazine (9, Scheme 2). The enantiomers of this
drug have been separated before by chromatography on a
chiral stationary phase, but the biological properties of the
individual enantiomers have not yet been determined.[29]
Using standard conditions, we obtained the product in good
yield with reasonable enantioselectivity (e.r. 86:14).[30] Impor-
Scheme 3. Synthesis and cyclization of enamide 10. DMEDA=N,N’-
dimethylethylenediamine.
In conclusion, we have designed chiral N-phosphinyl
phosphoramides as a new motif for asymmetric Brønsted acid
catalysis. The N-phosphinyl phosphoramide 7 f was identified
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Communications
[14] For a Lewis acid catalyzed enantioselective synthesis of oxazo-
lopyrazinone, see a) F. Saitoh, H. Nishida, T. Mukaihira, K.
Aikawa, K. Mikami, Eur. J. Org. Chem. 2006, 2269 – 2272; b) for
as the first highly effective and enantioselective catalyst for
the direct synthesis of cyclic N,O-acetals from aldehydes and
hydroxy amides. The additional functional group and sub-
stituents of the N-phosphinyl phosphoramide allow expedi-
tious fine-tuning of the chiral Brønsted acid catalyst. The
potentially broad utility of this motif will be further explored
in our laboratories.
´
3,4-benzo-5-oxacephams, see: A. Kozioł, J. Frelek, M. Woznica,
B. Furman, M. Chmielewski, Eur. J. Org. Chem. 2009, 338 – 341.
[15] D. P. Uzunov, I. Zivkovich, W. H. Pirkle, E. Costa, A. Guidotti, J.
Pharm. Sci. 1995, 84, 937 – 942.
[16] a) G. B. Rowland, H. Zhang, E. B. Rowland, S. Chennamadha-
vuni, Y. Wang, J. C. Antilla, J. Am. Chem. Soc. 2005, 127, 15696 –
15697; b) Y. Liang, E. B. Rowland, G. B. Rowland, J. A. Perman,
J. C. Antilla, Chem. Commun. 2007, 4477 – 4479.
Received: August 26, 2010
Published online: November 9, 2010
[17] G. Li, F. R. Fronczek, J. C. Antilla, J. Am. Chem. Soc. 2008, 130,
12216 – 12217.
Keywords: Brønsted acid catalysis · cyclic N,O-acetals ·
organocatalysis · N-phosphinyl phosphoramides
ˇ
.
´
[18] Also see: I. Coric, S. Vellalath, B. List, J. Am. Chem. Soc. 2010,
132, 8536 – 8537.
[19] a) X. Cheng, S. Vellalath, R. Goddard, B. List, J. Am. Chem. Soc.
2008, 130, 15786 – 15787; b) For an independent report, see: M.
Rueping, A. P. Antonchick, E. Sugiono, K. Grenader, Angew.
Chem. 2009, 121, 925 – 927; Angew. Chem. Int. Ed. 2009, 48, 908 –
910.
[20] a) E. Chiang, J. Finkelstein, J. Med. Chem. 1968, 11, 1038 – 1040;
b) G. R. Madhavan, R. Chakrabarti, K. A. Reddy, B. M. Rajesh,
V. Balraju, P. B. Rao, R. Rajagopalan, J. Iqbal, Bioorg. Med.
Chem. 2006, 14, 584 – 591.
[1] a) T. Akiyama, J. Itoh, K. Yokota, K. Fuchibe, Angew. Chem.
2004, 116, 1592 – 1594; Angew. Chem. Int. Ed. 2004, 43, 1566 –
1568; b) T. Akiyama, Chem. Rev. 2007, 107, 5744 – 5758.
[2] M. Terada, Synthesis 2010, 1929 – 1982.
[3] A. G. Doyle, E. N. Jacobsen, Chem. Rev. 2007, 107, 5713 – 5743.
[4] T. Hashimoto, K. Maruoka, J. Am. Chem. Soc. 2007, 129, 10054 –
10055.
[5] a) S. C. Pan, B. List, Chem. Asian J. 2008, 3, 430 – 437; b) D.
Kampen. A. LadꢀpÞche, G. Claßen, B. List, Adv. Synth. Catal.
2008, 350, 962 – 966; c) M. Hatano, T. Maki, K. Moriyama, M.
Arinobe, K. Ishihara, J. Am. Chem. Soc. 2008, 130, 16858 –
16860.
[6] D. Nakashima, H. Yamamoto, J. Am. Chem. Soc. 2006, 128,
9626 – 9627.
[7] C. H. Cheon, H. Yamamoto, J. Am. Chem. Soc. 2008, 130, 9246 –
9247.
[8] C. H. Cheon, H. Yamamoto, Org. Lett. 2010, 12, 2476 – 2479.
[9] P. Garcꢁa-Garcꢁa, F. Lay, P. Garcꢁa-Garcꢁa, C. Rabalakos, B. List,
Angew. Chem. 2009, 121, 4427 – 4430; Angew. Chem. Int. Ed.
2009, 48, 4363 – 4366. Also see: a) M. Treskow, J. Neudꢂrfl, R.
Giernoth, Eur. J. Org. Chem. 2009, 3693 – 3697; b) H. He, L.-Y.
Chen, W.-Y. Wong, W.-H. Chan, A. W. M. Lee, Eur. J. Org.
Chem. 2010, 4181 – 4184.
[10] a) X. Cheng, R. Goddard, G. Buth, B. List, Angew. Chem. 2008,
120, 5157 – 5159; Angew. Chem. Int. Ed. 2008, 47, 5079 – 5081;
b) X.-H. Chen, W.-Q. Zhang, L.-Z. Gong, J. Am. Chem. Soc.
2008, 130, 5652 – 5653.
[11] a) M. Yamanaka, J. Itoh, K. Fuchibe, T. Akiyama, J. Am. Chem.
Soc. 2007, 129, 6756 – 6764; b) L. Simon, J. L. Goodman, J. Am.
Chem. Soc. 2009, 131, 4070 – 4077.
[12] V. N. Wakchaure, B. List, Angew. Chem. 2010, 122, 4230 – 4243;
Angew. Chem. Int. Ed. 2010, 49, 4136 – 4139.
[21] R. Kadatz, Arzneim.-Forsch. 1957, 7, 651.
[22] a) C. A. Keane, W. W. S. Nicholls, J. Chem. Soc. 1907, 91, 266;
b) A. W. Tilherley, J. Chem. Soc. 1907, 91, 1425; c) W. L. Hicks, J.
Chem. Soc. 1910, 97, 1368; d) B. W. Horrom, H. E. Zaugg, J. Am.
Chem. Soc. 1950, 72, 721.
[23] R. B. Gammill, J. Org. Chem. 1981, 46, 3340 – 3342.
[24] G. Adair, S. Mukherjee, B. List, Aldrichimica Acta 2008, 41, 31 –
39.
[25] Benzoxazinone derivatives are configurationally stable under
the reaction conditions but undergo racemization in the
presence of strong acids such as pTSA (see the Supporting
Information).
[26] See the Supporting Information for details.
[27] For the use of [(PhO)2PO]2NH as a catalyst, see: C. A. Bruynes,
T. K. Jurriens, J. Org. Chem. 1982, 47, 3966 – 3969.
[28] CCDC 783003 (racemic syn-3i) and CCDC 782129 (3p) contain
the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
[29] J. Dꢂnnecke, W. A. Kꢂnig, O. Gyllenhaal, J. Vessman, C.
Schulze, J. High Resolut. Chromatogr. 1994, 17, 779 – 783.
[30] The low e.r. in the reaction may be a consequence of the
generation of trace amount of HCl from the decomposition of b-
chloropropionaldehyde.
[13] a) L. Heys, C. G. Moore, P. J. Murphy, Chem. Soc. Rev. 2000, 29,
57 – 67; b) P. Langer, J. Frackenpohl, H. M. R. Hoffmann, J.
Chem. Soc. Perkin Trans. 1 1998, 801 – 806.
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