Rhodium-catalyzed 1.4-additions to enantiopure acceptors: Asymmetric synthesis of functionalized pyrrolizidinones

Article abstract of DOI:10.1021/ol900843a

The rhodium-catalyzed 1,4-addition of arylboronic acids to an enantiopure heterocyclic acceptor proceeds under ligand control to effect an asymmetric synthesis of functionalized pyrrolizidinones. The protocol allows convenient access to all four stereoiso

Full text of DOI:10.1021/ol900843a

ORGANIC
LETTERS
2009
Vol. 11, No. 12
2491-2494
Rhodium-Catalyzed 1,4-Additions to
Enantiopure Acceptors: Asymmetric
Synthesis of Functionalized
Pyrrolizidinones
Ludivine Zoute, Gabriele Kociok-Ko¨hn, and Christopher G. Frost*
Department of Chemistry, UniVersity of Bath, Bath BA2 7AY, U.K.
c.g.frost@bath.ac.uk
Received April 17, 2009
ABSTRACT
The rhodium-catalyzed 1,4-addition of arylboronic acids to an enantiopure heterocyclic acceptor proceeds under ligand control to effect an
asymmetric synthesis of functionalized pyrrolizidinones. The protocol allows convenient access to all four stereoisomers of pyrrolizidinone
3a (Ar ) Ph) by appropriate selection of substrate and catalyst.
The stereoselective construction of C-C bonds using the
rhodium-catalyzed 1,4-addition of organometallics is
widely regarded as important methodology for organic
synthesis.1 For the addition of aryl and alkenylboronic
acids, the reaction is routinely carried out in aqueous
solvents and can afford excellent enantioselectivities
across a wide range of alkene acceptors. In the majority
of reported additions to prochiral acceptors, a single
stereocenter is established by an asymmetric carbometa-
lation under control of an enantiopure rhodium complex.
The sense of asymmetric induction can be reliably
predicted by means of simple stereochemical models when
using enantiopure BINAP (or related ligands).2 Interest-
ingly, despite the tremendous synthetic potential there are
relatively few examples of rhodium-catalyzed 1,4-addi-
tions to enantiopure acceptors.3 In this context we report
a convenient stereoselective route to functionalized pyr-
rolizidinones utilizing the rhodium-catalyzed 1,4-addition
(2) For a discussion of the mechanism, see: Hayashi, T.; Takahashi,
M.; Takaya, Y.; Ogasawara, M. J. Am. Chem. Soc. 2002, 124, 5052–5058.
(3) (a) Ramnauth, J.; Poulin, O.; Bratovanov, S. S.; Rakhit, S.;
Maddaford, S. P. Org. Lett. 2001, 3, 2571–2573. (b) Chen, Q.; Kuriyama,
M.; Soeta, T.; Hao, X.; Yamada, K.; Tomioka, K. Org. Lett. 2005, 7, 4439–
4441. (c) de la Herran, G.; Mba, M.; Murcia, M. C.; Plumet, J.; Csaky,
A. G. Org. Lett. 2005, 7, 1669–1671. (d) Hargrave, J. D.; Bish, G.; Frost,
C. G. Chem. Commun. 2006, 4389–4391. (e) Segura, A.; Csaky, A. G. Org.
Lett. 2007, 9, 3667–3670. (f) Chapman, C. J.; Matsuno, A.; Frost, C. G.;
Willis, M. C. Chem. Commun. 2007, 3903–3905. (g) Burgey, C. S.; Paone,
D. V.; Shaw, A. W.; Deng, J. Z.; Nguyen, D. N.; Potteiger, C. M.; Graham,
S. L.; Vacca, J. P.; Williams, T. M. Org. Lett. 2008, 10, 3235–3238. (h)
Chapman, C. J.; Hargrave, J. D.; Bish, G.; Frost, C. G. Tetrahedron 2008,
64, 9528–9539.
(1) For reviews, see: (a) Hayashi, T. Synlett 2001, 879–887. (b) Hayashi,
T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829–2844. (c) Fagnou, K.;
Lautens, M. Chem. ReV. 2003, 103, 169–196. (d) Darses, S.; Geneˆt, J.-P.
Eur. J. Org. Chem. 2003, 4313–4327. (e) Hayashi, T. Bull. Chem. Soc.
Jpn. 2004, 77, 13–21. (f) Yoshida, K.; Hayashi, T. In Modern Rhodium-
Catalyzed Organic Reactions; Evans, P. A., Ed.; Wiley-VCH: Weinheim,
Germany, 2005; Chapter 3. First report: (g) Takaya, Y.; Ogasawara, M.;
Hayashi, T.; Sakai, M.; Miyaura, N. J. Am. Chem. Soc. 1998, 120, 5579.
10.1021/ol900843a CCC: $40.75
Published on Web 05/22/2009
 2009 American Chemical Society

of arylboronic acids to an enantiopure acceptor 1 derived
from (S)-prolinol (Scheme 1).
ligand, the optimal reaction conditions employed 1 equiv of
Cs2CO3 and 4 equiv of boronic acid to afford a good yield of
product 3a with a preference for the (S,R)-diastereomer (entry
3). The inclusion of certain achiral bidentate phosphine ligands
led to enhanced diastereoselectivity via an amplification of the
inherent substrate control (entries 4 and 5).
Scheme 1. Asymmetric Synthesis of Pyrrolizidinones
The use of enantiopure ligands (Figure 1) in the catalytic
addition to enantiopure 1 presents a situation where
Moreover, we show that the reaction proceeds under ligand
control and the diastereoselectivity of the process can be
switched to afford (S,R)-3 or (S,S)-3 by changing the enantiomer
of ligand employed in the rhodium-catalyzed 1,4-addition.
The enantiopure acceptor 1 was prepared in one step from
N-Boc-L-prolinol using 2-iodoxybenzoic acid (IBX) as an in
situ oxidant in the presence of a stabilized Wittig reagent.4 An
initial investigation of the rhodium-catalyzed 1,4-addition of
phenylboronic acid to 1 employing a variety of reaction
conditions followed by deprotection of the Boc group and
lactamization revealed a high-yielding and stereoselective route
to the desired pyrrolizidinones (Table 1). In the absence of added
Figure 1. Enantiopure ligands used.
internal or external diastereocontrol may predominate
(double stereodifferentiation).5 The application of (S)-
BINAP as (matched) ligand afforded results comparable
to those using dppf, demonstrating a preference for the
(S,R)-diastereomer (entry 6). Interestingly, with (mis-
matched) (R)-tol-BINAP the stereoselectivity switched to
afford the (S,S)-diastereomer albeit with a lower diastero-
meric ratio (entry 7). Superior catalyst control was
observed with the commercially available chiral bicyclo-
[2.2.2]octadiene (DOLEFIN) ligands described by Carreira
and co-workers.6 Thus, the matched (S,S,S)-ligand gave
the (S,R)-diastereomer in high yield and with excellent
diastereoselectivity (entry 8). The mismatched (R,R,R)-
ligand also provided product with useful selectivity for
the (S,S)-diastereomer (entry 10).
Table 1. Ligand Control in the Synthesis Of Pyrrolizidinonesa
The synthesis of the enantiomeric substrate ent-1 (from
(R)-prolinol) allowed the efficient preparation of all four
% conversionb
(% yield)c
dr
entry
ligand
base
((S,R)-3:(S,S)-3)d
1e none
KOH
36
80:20
85:15
80:20
94:6
2e none
LiOH
66
3e none
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
93 (77)
98
Scheme 2. Matching Substrate and Catalyst for High Selectivity
4
5
6f
7
8
dppp
dppf
91
96:4
(S)-BINAP
98
95:5
13:87
99:1
97:3
10:90
(R)-tol-BINAP
58
(S,S,S)-DOLEFIN Cs2CO3
97 (89)
98
9g (S,S,S)-DOLEFIN Cs2CO3
10 (R,R,R)-DOLEFIN Cs2CO3
99 (94)
a Reaction conditions for 1,4-addition: 1 (1.0 equiv), PhB(OH)2 (4.0
equiv), [Rh(C2H4)2Cl]2 (3 mol %), ligand (7 mol %), base (1.0 equiv),
dioxane/H2O (10:1), 100 °C, 16 h. b Determined by 1H NMR of the crude
mixture of 4a. c Isolated yield of 3a. d Determined by 1H NMR of the crude
mixture after cyclization. e [Rh(cod)Cl]2 used as catalyst. f [Rh(C2H4)2(acac)]
used as catalyst. g Using 2 equiv of PhB(OH)2.
2492
Org. Lett., Vol. 11, No. 12, 2009

stereoisomers of pyrrolizidinone 3a as illustrated in
Scheme 2. The rational matching of substrate and catalyst
enabled access to the two enantiomeric pyrrolizidinones
(S,R)-3a and (R,S)-3a with very high stereoselectivity.
With the optimized set of reaction conditions, we next
explored the scope of the process with respect to the
boronic acid; in all cases the enantiopure acceptor 1 was
employed as substrate. The diastereoselectivity was con-
sistently high for a range of boronic acids (Scheme 3).
Scheme 3
.
Asymmetric Synthesis of Pyrrolizidinones; Scope of
Boronic Acid
Figure 2. ORTEP drawing of pyrrolizidinone (S,R)-3c.
the conjugate addition. This reflects the lower reactivity
of these particular boronic acids in rhodium-catalyzed
addition reactions.8
To broaden the synthetic scope of the reaction, the
asymmetric addition of phenylboronic acid to 4-hydroxypro-
line derivative 5 was carried out (Scheme 4).9 Pleasingly,
Scheme 4. Addition to 4-Hydroxyproline Derivative
deprotection of the Boc group and lactamization furnished
the hydroxy-functionalized pyrrolizidinone 6 in good yield
and high diastereoselectivity.
In conclusion, we have developed a versatile ligand-
controlled synthesis of functionalized pyrrolizidinones utiliz-
ing the rhodium-catalyzed 1,4-addition of arylboronic acids
to enantiopure acceptors generated from commercially avail-
able amino acids. Although access to all possible stereoiso-
mers is possible, rational matching of substrate and catalyst
results in very high diasteroselectivity. This is observed in
The stereochemistry of the major diastereomer was
assigned by analysis of 1H NMR and NOE spectra as (S,R)
and confirmed for the crystalline product 3b by X-ray
crystallography (Figure 2).7 It is useful to note that both
electron-donating and electron-withdrawing substituents
are tolerated alongside a range of substitution patterns.
Lower yields were obtained in the case of 3-nitrophenyl-
boronic acid and 3-thiopheneboronic acid with protode-
boronated (hetero)arene observed as a side product from
(6) For a review of chiral diene ligands in asymmetric catalysis, see:
(a) Defieber, C.; Grutzmacher, H.; Carreira, E. M. Angew. Chem., Int. Ed.
2008, 47, 4482–4502. First report: (b) Fischer, C.; Defieber, C.; Suzuki,
T.; Carreira, E. M. J. Am. Chem. Soc. 2004, 126, 1628–1629.
(7) The relative configuration within 3c was determined using single
crystal X-ray analysis, with the absolute configuration (S,R) assigned from
the known configuration of the (S)-stereocenter of the pyrrolidine ring
derived from (S)-prolinol.
(8) (a) Batey, R. A.; Thadani, A.; Avinash, N.; Smil, D. V. Org. Lett.
1999, 1, 1683–1686. (b) Yoshida, K.; Hayashi, T. Heterocycles 2003, 59,
605–611. (c) Duursma, A.; Boiteau, J. G.; Lefort, L.; Boogers, J. A. F.; De
Vries, A. H. M.; De Vries, J. G.; Minnaard, A. J.; Feringa, B. L. J. Org.
Chem. 2004, 69, 8045–8052. (d) Tokunaga, N.; Hayashi, T. AdV. Synth.
Catal. 2007, 349, 513–516.
(4) (a) Crich, D.; Mo, X.-S. Synlett 1999, 67–68. (b) Maiti, A.; Yadav,
J. S. Synth. Commun. 2001, 31, 1499–1506. (c) Taylor, R. J. K.; Reid, M.;
Foot, J.; Raw, S. A. Acc. Chem. Res. 2005, 38, 851–869.
(9) Sato, H.; Sakoh, H.; Hashihayata, T.; Imamura, H.; Ohtake, N.;
Shimizu, A.; Sugimoto, Y.; Sakuraba, S.; Bamba-Nagano, R.; Yamada, K.;
Hashizume, T.; Morishima, H. Biorg. Med. Chem. 2002, 10, 1595–1610.
(5) Walsh, P. J.; Kozlowski, M. C. Fundamentals of Asymmetric
Catalysis; University Science Books: New York, 2009.
Org. Lett., Vol. 11, No. 12, 2009
2493

the case of (S,S,S)-DOLEFIN ligand with (S)-1 and (R,R,R)-
DOLEFIN ligand with (R)-1.
Supporting Information Available: Experimental pro-
cedures, CIF file, and full characterization for all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. This work was supported by the
EPSRC. Dr Anneke Lubben (Mass Spectrometry Service
at the University of Bath) is also thanked for valuable
assistance.
OL900843A
2494
Org. Lett., Vol. 11, No. 12, 2009