A direct and versatile access to α,α-disubstituted 2-pyrrolidinylmethanols by SmI2-mediated reductive coupling

Article abstract of DOI:10.1021/ol800982n

(Chemical Equation Presented) Various α,α-disubstituted 2-pyrrolidinylmethanols are efficiently prepared in a single step from ketones using a SmI₂-mediated cross-coupling with 1-pyrroline N-oxide. The N-hydroxy-α,α-diphenylprolinol is also easily prepared and resolved.

Full text of DOI:10.1021/ol800982n

ORGANIC
LETTERS
2008
Vol. 10, No. 14
3021-3023
A Direct and Versatile Access to
r,r-Disubstituted
2-Pyrrolidinylmethanols by
SmI2-Mediated Reductive Coupling
Olga N. Burchak, Christian Philouze, Pierre Yves Chavant,* and Sandrine Py*
De´partement de Chimie Mole´culaire (SERCO) UMR-5250, ICMG FR-2607,
CNRS-UniVersite´ Joseph Fourier, BP 53, 38041 Grenoble Cedex 09, France
sandrine.py@ujf-grenoble.fr; pierre-yVes.chaVant@ujf-grenoble.fr
Received April 29, 2008
ABSTRACT
Various r,r-disubstituted 2-pyrrolidinylmethanols are efficiently prepared in a single step from ketones using a SmI2-mediated cross-coupling
with 1-pyrroline N-oxide. The N-hydroxy-r,r-diphenylprolinol is also easily prepared and resolved.
Enantiopure proline-derived molecules are widely used as
the source of chirality in enantioselective catalysis.1 Among
them, R,R-diphenyl-2-pyrrolidinylmethanol (DPP, Figure 1)
In general, these compounds have been prepared from
naturally occurring l-proline, using double Grignard addi-
tions.4 However, this pathway is limited to structures where
R1 ) R2 (Figure 1).
Alternatively, DPP has been prepared by asymmetric
deprotonation of N-Boc-pyrrolidine, followed by addition
onto benzophenone.5 A general method that would allow the
synthesis of both symmetrically (R1 ) R2) and nonsym-
Figure 1. DPP and R,R-disubstituted 2-pyrrolidinylmethanols.
(3) (a) Zhu, S.; Yu, S.; Ma, D. Angew. Chem., Int. Ed. 2008, 47, 545.
(b) Trost, B. M.; Mu¨ller, C. J. Am. Chem. Soc. 2008, 130, 2438. (c) Hayashi,
Y.; Itoh, T.; Aratake, S.; Ishikawa, H. Angew. Chem., Int. Ed. 2008, 47,
2082. (d) Chu, Q.; Yu, M. S.; Curran, D. P. Org. Lett. 2008, 10, 749. (e)
Balskus, E. P.; Jacobsen, E. N. Science 2007, 317, 1736. (f) Aleman, J.;
Cabrera, S.; Maerten, E.; Overgaard, J.; Jorgensen, K. A. Angew. Chem.,
Int. Ed. 2007, 46, 5520. (g) Canales, E.; Corey, E. J. J. Am. Chem. Soc.
2007, 129, 12686. (h) Palomo, C.; Mielgo, A. Angew. Chem., Int. Ed. 2006,
45, 7876.
was initially introduced for the preparation of oxazaboro-
lidines, as catalysts for CBS enantioselective reduction of
ketones.2 More recently, R,R-disubstituted 2-pyrrolidinyl-
methanols and their derivatives have found new and promis-
ing applications as organocatalysts for different asymmetric
transformations.1,3
(4) Mathre, D. J.; Jones, T. K.; Xavier, L. C.; Blacklock, T. J.; Reamer,
R. A.; Mohan, J. J.; Jones, E. T. T.; Hoogsteen, K.; Baum, M. W.;
Grabowski, E. J. J. J. Org. Chem. 1991, 56, 751.
(5) Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J. J. Am. Chem. Soc. 1994,
116, 3231. For other examples of synthesis of R,R-disubstituted 2-pyrro-
lidinylmethanols from reaction of 2-lithiopyrrolidines with symmetrical
ketones or aldehydes, see also: (a) Reitz, D. B.; Beak, P.; Tse, A. J. Org.
Chem. 1981, 46, 4316. (b) Gawley, R. E.; Zhang, Q. J. Org. Chem. 1995,
60, 5763. (c) Bertini Gross, K. M.; Beak, P. J. Am. Chem. Soc. 2001, 123,
315. (d) Coldham, I.; Dufour, S.; Haxell, T. F. N.; Patel, J. J.; Sanchez-
Jimenez, G. J. Am. Chem. Soc. 2006, 128, 10943.
(1) (a) Erkkila, A.; Majander, I.; Pihko, P. M. Chem. ReV. 2007, 107,
5416. (b) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. ReV.
2007, 107, 5471. (c) Fache, F.; Schulz, E.; Tommasino, M. L.; Lemaire,
M. Chem. ReV. 2000, 100, 2159.
(2) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987,
109, 5551. (b) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37,
1986.
10.1021/ol800982n CCC: $40.75
Published on Web 06/13/2008
2008 American Chemical Society

metrically (R1 * R2) R,R-disubstituted 2-pyrrolidinylmetha-
nols would be valuable.
at room temperature, workup provided directly ꢀ-amino
alcohols 2,10 3, 4,11 and 5 in moderate to good yields
(Scheme 1).12 When aliphatic ketones (cyclopentanone and
cyclohexanone) were used, the addition of 10 equiv of water
during the coupling step was necessary for obtaining products
613 and 713 in good yields.
Since its introduction by Kagan, SmI2 has become one of
the most popular and versatile reagents for single-electron
tranfers.6 A few years ago, we reported the chemoselective
cross-coupling of nitrones with carbonyl compounds in the
presence of SmI2. This reaction produces vicinal N-hy-
droxyamino alcohols in excellent yields.7 We thus thought
that the coupling of nitrone 1 with various ketones under
these reductive conditions would give access to novel R,R-
diphenyl-2-pyrrolidinylmethanols (Scheme 1).
Thus, this reaction provides a direct access to various
racemic R,R-disubstituted 2-pyrrolidinylmethanols in two
steps from pyrrolidine and aromatic or aliphatic ketones.
Convenient methods for the resolution of 2 using enantiopure
O-acetylmandelic acid10 or 1,1′-bi-2-naphthol and boric
acid14 have been previously described.
This synthetic pathway obviously allows easy access to
original structures: compounds 3 and 5 have been prepared
here for the first time.
Scheme 1. Synthesis of R,R-Disubstituted
2-Pyrrolidinylmethanols 2-7 by Reductive Coupling of Nitrone
1 with Various Ketones
Particularly noteworthy is the high degree of diastereo-
selectivity obtained in the reaction of tetralone (product 4: a
single isomer was detected by 1H and 13C NMR) and
indanone (product 5: dr 80/20). This prompted us to
determine the relative configurations of 4 and 5 (major
isomer) by X-ray crystallographic analysis of their iodhy-
drates15 (Figure 2).
Figure 2. ORTEP drawings of 4,HI and 5,HI.
A requisite to this synthesis was an efficient preparation
of the 1-pyrroline N-oxide (1) by oxidation of pyrrolidine.
This was best achieved using the UHP-MTO system.8
Nitrone 1 was found to be quite unstable, but it could be
stored for several days as a 0.5 M solution in THF at 5 °C
under an inert atmosphere.
When a mixture of nitrone 1 and an aromatic ketone
(benzophenone, fluorenone, tetralone, or indanone) in THF
was treated at -78 °C with 2.2 equiv of SmI2, the
intermediate vicinal N-hydroxyamino alcohol was obtained
within 15 min (Scheme 1).
We were surprised to find that although product 4 exhibits
a like (S*,S*)16 configuration, the major diastereoisomer of
5 was unlike. This result is difficult to rationalize at this stage;
(10) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh, V. K.
J. Am. Chem. Soc. 1987, 109, 7925.
(11) Seebach, D.; Wykypiel, W. Synthesis 1979, 6, 423.
(12) General Procedure for the Synthesis of R,R-Disubstituted 2-Pyr-
rolidinylmethanols 2-7. Method A (for aromatic ketones): To a stirred and
carefully deoxygenated solution of the nitrone 1 (60 mg, 0.7 mmol) and
aromatic ketone (0.5 mmol) in dry THF was added a 0.1 M solution of
SmI2 (11.0 mL, 1.1 mmol) at -78 °C under argon. After 15 min, degassed
water (36 µL, 2.0 mmol) and SmI2 (14.0 mL, 1.4 mmol) were added, and
the reaction mixture was allowed to reach room temperature. After 1 h, a
saturated solution of Na2S2O3 (5 mL) and 1 M NaOH solution (15 mL)
were added, and the mixture was extracted with EtOAc (20 mL). Usual
workup yielded racemic products 2-5. Method B (for aliphatic ketones):
Same procedure as for method A, but degassed water (90 µL, 5.0 mmol)
was added at the beginning of the reaction (products 6 and 7).
(13) Reiners, I.; Wilken, J.; Martens, J. Tetrahedron: Asymmetry 1995,
6, 3063.
At this stage, addition of excess SmI2 and degassed water
allowed in situ reduction of the hydroxylamine.9 After 1 h
(6) Kagan, H.; Namy, J. L.; Girard, P. Tetrahedron Suppl. 1981, 37,
175. For reviews, see: (a) Edmonds, D. J.; Johnston, D.; Procter, D. J. Chem.
ReV. 2004, 104, 3371. (b) Kagan, H. Tetrahedron 2003, 59, 10351. (c) Krief,
A.; Laval, A.-M. Chem. ReV. 1999, 99, 745. (d) Molander, G. A.; Harris,
C. R. Chem. ReV. 1996, 96, 307.
(7) Masson, G.; Py, S.; Vallee, Y. Angew. Chem., Int. Ed. 2002, 41,
1772.
(14) Periasamy, M.; Kumar, N. S.; Sivakumar, S.; Rao, V. D.;
Ramanathan, C. R.; Venkatraman, L. J. Org. Chem. 2001, 66, 3828, and
references therein.
(8) (a) Goti, A.; Cardona, F.; Soldaini, G. Org. Synth. 2005, 81, 204.
(b) Goti, A.; Nannelli, L. Tetrahedron Lett. 1996, 37, 6025. (c) Murray,
R. W.; Iyanar, K.; Chen, J.; Wearing, J. T. J. Org. Chem. 1996, 61, 8099.
(9) Kende, A. S.; Mendoza, J. S. Tetrahedron Lett. 1991, 32, 1699.
(15) Those were easily obtained by neutral (instead of basic) hydrolysis
of the SmI2 reaction mixture; see the Supporting Information.
(16) Seebach, D.; Prelog, V. Angew. Chem., Int. Ed. 1982, 21, 654.
3022
Org. Lett., Vol. 10, No. 14, 2008

similar inversion of stereoselectivities in SmI2-mediated
reactions have been previously observed by other groups.17
Although the in situ reduction of the hydroxylamine
intermediate was expeditious, SmI2-mediated cross-
coupling of nitrones and carbonyl compounds is also an
excellent pathway to the N-hydroxypyrrolidinylcarbinols.
To illustrate this point, we undertook the synthesis and
resolution of N-hydroxy-R,R-diphenyl-2-pyrrolidinylmeth-
anol 8 (Scheme 2).
quenched at this temperature, the expected racemic 8 was
isolated in 63% yield. We took advantage of the reactivity
of the hydroxylamine group to use it as a handle for an
original resolution of the racemate. The relatively unhindered
hydroxylamine group was easily O-acylated with (S)-N-Boc-
l-phenylalanine in high yield (Scheme 2). The resulting
diastereomers 9 and 10 could be separated by either
chromatography or crystallization. At this stage, the relative
configuration of 10 was determined by X-ray analysis,18 and
its absolute configuration was deduced to be (S,R). The
saponification of 9 and 10 was also easy, leading, respec-
tively, to (+)-(S)-11 (90% yield, 97% ee) and (-)-(R)-12
(88% yield, 96% ee).19
Scheme 2. Synthesis and Resolution of Optically Pure (S)- and
(R)-N-Hydroxy-R,R-diphenyl-2-pyrrolidinylmethanol
For confirmation, a sample of (+)-(S)-11 was reduced by
SmI2, yielding a levorotatory product identical to authentic
(-)-(S)-DPP.
In conclusion, the SmI2-mediated cross-coupling of
1-pyrroline N-oxide and diaryl, monoaryl, or dialkyl
ketones provides a very short and versatile route to R,R-
disubstituted 2-pyrrolidinylmethanols. When prochiral
ketones are used, high diastereoselectivities can be at-
tained. Thus, unsual chiral prolinol derivatives are now
readily accessible, which should find interesting applica-
tions as rigid organocatalysts or, more generally, in
enantioselective catalysis.
Acknowledgment. This work was supported by the
CNRS, the Universite´ Joseph Fourier, and the Agence
Nationale pour la Recherche (Grant No. ANR-05-JCJC-0130-
01).
Supporting Information Available: Detailed experimen-
tal procedures and complete characterization of all com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
When a mixture of nitrone 1 and benzophenone in THF
was treated at -78 °C with 2.2 equiv of SmI2 and then
OL800982N
(18) See the Supporting Information.
(19) Determined by chiral HPLC on a Daicel Chiralpak AD-RH column,
acetonitrile/water; see the Supporting Information.
(17) See for examples: (a) Aspinall, H. C.; Greeves, N.; Valla, C. Org.
Lett. 2005, 7, 1919. (b) Chiara, J. L.; Garcia, A. Synlett 2005, 2607.
Org. Lett., Vol. 10, No. 14, 2008
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