Organocatalytic asymmetric formal [3 + 2] cycloaddition with in situ-generated N-carbamoyl nitrones

Article abstract of DOI:10.1021/ja902458m

(Chemical Equation Presented) A novel organocatalytic formal [3 + 2] cycloaddition reaction with in situ generation of N-carbamoyl nitrones is presented. For the first time, N-Boc- and N-Cbz-protected isoxazolidines have been directly obtained as single diastereoisomers in generally high yields and enantiomeric excesses using mild reaction conditions and inexpensive, readily available Cinchona alkaloid quaternary ammonium salts as catalysts. Synthetic manipulations of the products provided highly valuable building blocks such as free isoxazolidines, a N-Boc-1,3-aminoalcohol, and a free δ-lactam. This report represents a pioneering work in the use of N-carbamoyl nitrones as electron-poor 1,3-dipoles and glutaconates as new dipolarophiles in asymmetric catalysis.

Full text of DOI:10.1021/ja902458m

Published on Web 06/24/2009
Organocatalytic Asymmetric Formal [3 + 2] Cycloaddition with in
Situ-Generated N-Carbamoyl Nitrones
Claudio Gioia, Francesco Fini,* Andrea Mazzanti, Luca Bernardi,* and Alfredo Ricci
Department of Organic Chemistry “A. Mangini”, UniVersity of Bologna, Viale Risorgimento 4, 40136 Bologna, Italy
Received March 27, 2009; E-mail: fini_f@libero.it; nacca@ms.fci.unibo.it
Table 1. Optimization of Reaction Conditions: Representative
The [3 + 2] cycloaddition of nitrones and alkenes is one of the
Resultsa
most versatile reactions in organic synthesis.1 It offers the possibility
of generating isoxazolidines with up to three new contiguous
stereocenters, which are precursors of broadly useful compounds
such as 1,3-aminoalcohols, amino acids, azasugars, and alkaloids.2
Although several catalytic asymmetric versions of this powerful
cycloaddition reaction have been developed,3 all of them invariably
involve N-benzyl- and N-aryl-substituted nitrones and thus yield
isoxazolidines bearing nitrogen protecting groups that are very
difficult to remove without concomitant cleavage of the N-O
bond.4 The unfeasibility of the preparation of unprotected isox-
azolidines for further elaborations is a significant limitation of these
otherwise exceptional methods, given the biological interest in these
heterocycles.5 On the other hand, a few contributions in the literature
have reported nitrones bearing easily removable electron-withdraw-
ing groups at nitrogen that can be generated in situ for use in
nonasymmetric 1,3-cycloadditions,6 overcoming the troublesome
isolation of these unstable dipoles.
On the basis of the recently reported in situ generation of
N-carbamoyl imines by means of phase-transfer catalysis (PTC),7 we
envisioned a novel asymmetric formal [3 + 2] nitrone cycloaddition
reaction8 using N-Boc- and N-Cbz-protected N-hydroxy-R-amido
sulfones6c (1 and 2, respectively) as nitrone precursors (Scheme 1).
Glutaconates 3 were selected as suitable reaction partners for the
formation of formal anionic dipolarophiles. We expected that highly
reactive N-carbamoyl nitrones A could be formed in situ and undergo
an enantioselective Mannich addition by the chiral quaternary am-
monium enolate B. The resulting anionic adducts C should then directly
cyclize intramolecularly to the cycloadducts D, possibly diastereose-
lectively, affording isoxazolidines 4 and 5.
entry
cat.
solvent
T (°C)
conv. (%)b
ee (%)c
1
2
3
4
6a
10:1 Tol/CH2Cl2
-30
-30
-30
-30
-30
-30
-42
90
90
90
90
65
>95
>95
70
75
76
70
82
83
91
6b 10:1 Tol/CH2Cl2
6c 10:1 Tol/CH2Cl2
6d 10:1 Tol/CH2Cl2
6c
6c
6c
5
7:3 Tol/CH2Cl2
3.5:3.5:3 Tol/TBME/CH2Cl2
3.5:3.5:3 Tol/TBME/CH2Cl2
6
7d
a Reactions were performed on a 0.10 mmol scale using 2 equiv of
3a, 10 mol % 6, and 5 equiv of 50% (w/w) K2CO3(aq) in 1.0 mL of the
solvent for 21-24 h. b Determined by 1H NMR analysis. c Determined
by chiral HPLC analysis after Boc deprotection and Cbz derivatization.
d Using 2 mL of the solvent.
best one, giving the cycloadduct 4a with modest enantioselectivity
(entries 1-4). A beneficial effect on the asymmetric induction was
obtained by increasing the amount of CH2Cl2 and adding TBME
(entries 5 and 6). Whereas the larger amount of CH2Cl2 markedly
increased the solubility of catalyst 6c, TBME facilitated solubilization
of sulfone 1a in the mixture. Finally, lowering the temperature to -42
°C and diluting the reaction led to a further improvement in the
enantioselectivity (entry 7).
With these conditions in hand, we evaluated the scope of the
formal [3 + 2] cycloaddition (Table 2).12 Several N-Boc sulfones
1a-j derived from aliphatic aldehydes reacted well with glutaconate
3a to give the cycloadducts 4a-j with good results (entries 1-10),
even on a preparative scale (entries 1 and 9). Because of the low
efficiency of the available preparations of N-hydroxy-R-amido
sulfones from aromatic aldehydes,6c,13 only the two sulfones 1k
and 1l were tested, giving the corresponding products 4k and 4l
with moderate enantioselectivities (entries 11 and 12). Variation
of the dipolarophile using glutaconates 3b-f in combination with
sulfone 1a showed a considerable sensitivity of the reaction to the
sterics of the diester used. In particular, while a simple increase in
reaction time was sufficient for obtaining the cycloadducts 4m-o
with good results (entries 13-15), the more hindered di-tert-butyl
derivative 3e did not react with sulfone 1a, even at 0 °C (entry
16). To differentiate the two ester groups in the cycloadducts
through a regioselective, sterically controlled Mannich reaction
(Scheme 1), tert-butyl methyl glutaconate 3f was reacted with 1a,
but this gave 4q in poor yield, only at 0 °C, and with a surprising
lack of regioselectivity (entry 17).14
Scheme 1. Reaction Pathway
Preliminary experiments on the reaction between sulfone 1a and
dimethyl glutaconate 3a using Cinchona alkaloid-derived ammonium
salts revealed that alkylation or acylation at the alcoholic moiety of
the catalyst had a very positive effect on the observed asymmetric
induction.9 In particular, useful enantioselectivities could be obtained
by using quinine-derived catalysts such as 6a-d (Table 1), which bear
an ortho-substituted benzyl group at the quinuclidinic nitrogen10 and
the hindered pivaloyl ester at C9.11 Remarkably, the cycloadduct 4a
was always obtained as a single diastereoisomer. As shown in Table
1, when the reaction was performed in 10:1 toluene/CH2Cl2 at -30
°C with aqueous K2CO3 as the base, catalyst 6c was identified as the
Finally this methodology was tested with Cbz as the protecting
group, affording 5a-d with good results (entries 18-21). The
9
9614 J. AM. CHEM. SOC. 2009, 131, 9614–9615
10.1021/ja902458m CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope of the Catalytic Reactiona
theoretical calculations of the ECD spectra and [R]D values using time-
dependent density functional theory performed on the tosyl derivative
8.17 X-ray analysis of the ferrocenoyl derivative 9 confirmed the
correctness of this assignment (see the Supporting Information).
In summary, we have developed a novel organocatalytic process
that uses simple reaction conditions and an inexpensive, readily
available catalyst and gives access to N-Boc- and N-Cbz-protected
isoxazolidines in generally good yields and enatioselectivities.
entry
1/2
R
3
4/5
yield (%)b
ee (%)c
1d
2f
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
PhCH2CH2
CH3
CH3CH2
CH3(CH2)3
CH3(CH2)5
(CH3)2CH
(CH3)2CHCH2
c-C5H9
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
3d
3e
3f
4a
4b
4c
4d
4e
4f
4g
4h
4i
86 (86)
53
80
70
72
93 (87)
97 (83)
97
>99 (98)
81
>99
63
60
76
73
91 (60)e
60e
88e
Acknowledgment. We acknowledge financial support from
“Stereoselezione in Sintesi Organica Metodologie e Applicazioni”
2007. Financial support by the Merck-ADP Grant 2007 is also
recognized. We thank M. Mancinelli for recording the ECD spectra.
92e
94e
99 (80)e
98 (57)e
99e
Supporting Information Available: Assignment of the relative and
absolute configurations of 4, X-ray data for 9, optimization results,
experimental procedures, spectral data, and copies of 1H and 13C NMR
spectra for compounds 4, 5, 6c, QD-6c, and 7-11. This material is
available free of charge via the Internet at http://pubs.acs.org.
9g
10
11h
12
13i
14i
15i
16i,j
17i,j
18
19
20
21
c-C6H11
PhCH2
Ph
>99 (83)e
1j
1k
1l
4j
4k
4l
95e
67
60
91
94
4-BrC6H4
PhCH2CH2
PhCH2CH2
PhCH2CH2
PhCH2CH2
PhCH2CH2
(CH3)2CHCH2
(CH3)2CH
c-C6H11
1a
1a
1a
1a
1a
2a
2b
2c
2d
4m
4n
4o
4p
4q
5a
5b
5c
5d
95
References
<10
-
25k
73l
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(2) Fredrickson, M. Tetrahedron 1997, 53, 403.
3a
3a
3a
3a
60
72
>99
68
75
80
94
85
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(4) For an oxidatively removable N-diphenylmethyl group, see: (a) Hashimoto,
T.; Omote, M.; Kano, T.; Maruoka, K. Org. Lett. 2007, 9, 4805. For
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(b) Vasella, A. HelV. Chim. Acta 1977, 60, 1273.
c-C5H9
a Reactions were performed with 0.10 mmol of 1a-l or 2a-d, 0.20
mmol of 3a-f, 0.01 mmol of 6c, and 0.50 mmol of 50% (w/w) K2CO3(aq)
in 3.5:3.5:3 Tol/TBME/CH2Cl2 (0.05 M) for 24 h. Results in parentheses
refer to the opposite enantiomer, obtained using QD-6c as the catalyst.
b Isolated yield. c Determined by chiral HPLC analysis. d On a 1.0 mmol
scale. e Determined after Boc deprotection and Cbz derivatization. f Using
4.5:4.5:1 Tol/TBME/CH2Cl2 (0.10 M) for 48 h. g On a 5.0 mmol scale.
h Using 10:1 Tol/CH2Cl2. i For 96 h. j At 0 °C. k Regioisomeric ratio: 60:40
(1H NMR analysis). l For the major regioisomer.
(5) (a) Chiacchio, U.; Balestrieri, E.; Macchi, B.; Iannazzo, D.; Piperno, A.;
Rescifina, A.; Romeo, R.; Saglimbeni, M.; Sciortino, M. T.; Valveri, V.;
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(6) (a) Hussain, S. A.; Sharma, A. H.; Perkins, M. J.; Griller, D. J. Chem.
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Y.; Denis, J.-N. Org. Lett. 2005, 7, 5147.
Scheme 2. Elaboration of the Cycloadducts
(7) (a) Fini, F.; Sgarzani, V.; Pettersen, D.; Herrera, R. P.; Bernardi, L.; Ricci,
A. Angew. Chem., Int. Ed. 2005, 44, 7975. (b) Palomo, C.; Oiarbide, M.;
Laso, A.; Lo´pez, R. J. Am. Chem. Soc. 2005, 127, 17622.
(8) For organocatalytic cycloadditions of nitrones, see: (a) [3 + 3]: Phillips,
E. M.; Reynolds, T. E.; Scheidt, K. A. J. Am. Chem. Soc. 2008, 130, 2416.
(b) [3 + 2]: Jen, W. S.; Wiener, J. J. M.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2000, 122, 9874.
(9) For example, a catalyst related to 6d (Table 1) but bearing the free OH
gave the product with 15% ee (see the Supporting Information).
(10) Yoo, M.-S.; Jeong, B.-S.; Lee, J.-H.; Park, H.-g.; Jew, S.-S. Org. Lett. 2005,
7, 1129.
(11) Poulsen, T. B.; Bernardi, L.; Bell, M.; Jørgensen, K. A. Angew. Chem.,
Int. Ed. 2006, 45, 6551.
(12) In every case, a single diastereoisomer was observed by 1H NMR analysis
of the crude mixture.
(13) 1k and 1l were prepared in low (<20%) yield according to ref 6c. Use of
this method (PhSO2Na, HCOOH, H2O/MeOH or THF) or other procedures
effective for R-amido sulfones (CH2Cl2, PhSO2H; PhSO2Na, HCOOH,
MeOH/H2O, 70 °C), other aromatic aldehydes (2-bromobenzaldehyde,
anisaldehyde), or a tertiary aliphatic aldehyde (pivalaldehyde) failed to give
the expected N-hydroxy-R-amido sulfones.
quasi-enantiomeric quinidine catalyst QD-6c gave access to the
opposite enantiomer of the products, though with lower selectivities
(values in parentheses in entries 1, 6, 7, and 9).15
The synthetic utility of the obtained isoxazolidines was first
demonstrated by chemoselectively performing Boc deprotection and
N-O cleavage. In fact, we were able to isolate the non-N-protected
isoxazolidines 7a, 7f, and 7i in good yields by treatment with
trifluoroacetic acid (TFA) in CH2Cl2 (Scheme 2, top) and the N-Boc-
protected 1,3-aminoalcohol 10 using Mo(CO)6 as the reducing
agent16 (Scheme 2, middle). The highly substituted δ-lactam 11
could instead be obtained by hydrogenolysis of 5c, giving simul-
taneous N-Cbz deprotection and N-O cleavage, followed by a
spontaneous lactamization (Scheme 2, bottom).
(14) This result seems to suggest that the two ester groups are not as independent
as assumed in the simplified two-step pathway depicted in Scheme 1,
although 1H NMR analysis of the crude products 4b-e revealed the
presence of small amounts (<7 mol %) of the linear non-cyclized products
(adduct C in Scheme 1).
(15) Other catalysts related to QD-6c gave similar or worse results (see the
Supporting Information). For a recent example of a PTC reaction where
quasi-enantiomeric Cinchona catalysts display very different behavior, see:
Mizuta, S.; Shibata, N.; Goto, Y.; Furukawa, T.; Nakamura, S.; Toru, T.
J. Am. Chem. Soc. 2007, 129, 6394.
(16) Kudoh, T.; Ishikawa, T.; Shimizu, Y.; Saito, S. Org. Lett. 2003, 5, 3875.
(17) For a review of the use of this method to assign the absolute configurations
of organic molecules, see: Bringmann, G.; Bruhn, T.; Maksimenka, K.;
Hemberger, Y. Eur. J. Org. Chem. 2009, 2717. For leading references, see
the Supporting Information.
The relative and absolute configurations of the cycloadducts were
determined by nuclear Overhauser effect NMR experiments and by
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