Stereoselective, nitro-Mannich/lactamisation cascades for the direct synthesis of heavily decorated 5-nitropiperidin-2-ones and related heterocycles

Article abstract of DOI:10.3762/bjoc.8.64

A versatile nitro-Mannich/lactamisation cascade for the direct stereoselective synthesis of heavily decorated 5-nitropiperidin-2-ones and related heterocycles has been developed. A highly enantioenriched substituted 5-nitropiperidin-2-one was synthesised in a four component one-pot reaction combining an enantioselective organocatalytic Michael addition with the diastereoselective nitro- Mannich/lactamisation cascade. Protodenitration and chemoselective reductive manipulation of the heterocycles was used to install contiguous and fully substituted stereocentres in the synthesis of substituted piperidines.

Full text of DOI:10.3762/bjoc.8.64

Stereoselective, nitro-Mannich/lactamisation
cascades for the direct synthesis of
heavily decorated 5-nitropiperidin-2-ones
and related heterocycles
Pavol Jakubec1, Dane M. Cockfield2, Madeleine Helliwell2, James Raftery2
and Darren J. Dixon*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 567–578.
1The Department of Chemistry, Chemistry Research Laboratory,
University of Oxford, Mansfield Road, Oxford OX1 3TA, UK and
2School of Chemistry, The University of Manchester, Oxford Road,
Manchester, M13 9PL, UK
doi:10.3762/bjoc.8.64
Received: 23 December 2011
Accepted: 12 March 2012
Published: 16 April 2012
Email:
Darren J. Dixon* - Darren.dixon@chem.ox.ac.uk
This article is part of the Thematic Series "Organocatalysis".
Guest Editor: B. List
* Corresponding author
Keywords:
© 2012 Jakubec et al; licensee Beilstein-Institut.
License and terms: see end of document.
cascade; imine; Michael addition; nitro-Mannich; organocatalysis;
piperidine alkaloids
Abstract
A versatile nitro-Mannich/lactamisation cascade for the direct stereoselective synthesis of heavily decorated 5-nitropiperidin-2-ones
and related heterocycles has been developed. A highly enantioenriched substituted 5-nitropiperidin-2-one was synthesised in a four
component one-pot reaction combining an enantioselective organocatalytic Michael addition with the diastereoselective nitro-
Mannich/lactamisation cascade. Protodenitration and chemoselective reductive manipulation of the heterocycles was used to install
contiguous and fully substituted stereocentres in the synthesis of substituted piperidines.
Introduction
The piperidine ring is a common motif found in many bio- The abundance of this motif in desirable targets has led to
logically active natural products and drugs. The structures of considerable interest from the synthetic community [12-19].
these compounds range from the architecturally complex poly- Common synthetic approaches to incorporate this motif include
cyclic ring systems, such as those found in the alkaloids nucleophilic additions to pyridine rings and further manipula-
haliclonacyclamine F [1], manzamine A [2-6], and reserpine tion [20-25], intramolecular iminium ion cyclisation [26-29],
[7,8] (Figure 1), to relatively simple piperidines found in phar- reduction of unsaturated heterocycles [30-32], ring closure via
maceutical compounds, such as paroxetine [9,10] and intramolecular nucleophilic substitution [33-37], cascade reac-
alvimopan [11].
tions of enamines/imines and aldehydes [38-41], and ring-
567

Beilstein J. Org. Chem. 2012, 8, 567–578.
Figure 1: Biologically active natural products and drugs containing the piperidine ring.
closing metathesis followed by hydrogenation [42-48]. Argu- In pursuit of this we have successfully harnessed the power of
ably the most general route employs cycloadditions and the nitro-Mannich/lactamisation cascade in a formal synthesis
subsequent manipulation of the partially unsaturated ring of (3S,4R)-paroxetine [60], in the construction of architectur-
system [49-53]. We believed a powerful entry to piperidine ally complex polycyclic alkaloid structures [61] and more
rings and related heterocyclic structures could employ a nitro- recently as a key complexity building step in the total synthesis
Mannich/lactamisation cascade of γ-nitro ester starting ma- of nakadomarin A [62-65]. Herein we wish to report our full
terials with imines (cyclic or acyclic, preformed or formed in findings in this synthetically powerful cyclisation cascade.
situ) as a key step. Not only could this approach allow the rapid
generation of structural complexity, but the products would be The first example of a simple nitro-Mannich/lactamisation
amenable to further synthetic transformations. Furthermore, the cascade was reported independently by Mühlstädt and Jain in
γ-nitro ester starting materials are accessible in an enantioen- the mid-1970s [66,67]. The condensation of methyl
riched form by using an organocatalytic Michael addition meth- 4-nitrobutanoate 6 (Scheme 1; R2 = R3 = R4 = H) with aromatic
odology, which was developed by our group and others [54-59]. aldehydes 3 (R5 = Ar) and ammonium acetate provided access
Scheme 1: A general strategy to 5-nitropiperidin-2-ones and related heterocycles.
568

Beilstein J. Org. Chem. 2012, 8, 567–578.
to simple 6-aryl-substituted 5-nitropiperidin-2-ones 1 (R1 = With a range of suitable test substrates in hand, formaldehyde-
R2 = R3 = R4 = H, R5 = Ar). The power of this transformation derived imines were then investigated in the nitro-Mannich/lac-
was not immediately recognised and only in the last two tamisation reaction. Aqueous formaldehyde (3a) and allylamine
decades has the cascade been successfully applied to the syn- (4a) were added to a methanol solution of lactam 6a and the
thesis of simple biologically active compounds and their mixture heated under reflux for 4 hours until judged to be
precursors, such as (±)-CP-99,994 [68,69], inhibitors of farne- complete by TLC. Pleasingly, the desired δ-lactam product 1a
syltransferase [70,71], selective dipeptidyl peptidase IV inhibi- was isolated in 90% yield as a single diasteromer (Scheme 3)
tors [72,73], and functionalised bispidines [74]. Very recently, a [84]. Under identical reaction conditions the other Michael
related cascade inspired by the original work of Jain incorpor- adducts, lactone 6b and ester 6c, provided moderate yields of
ating C–C bond formation was accomplished through a nitro- the desired δ-lactams 1b and 1c as single diastereoisomers in
Mannich reaction [75-80] of nitro carbonyl compounds with both cases. The diastereoselectivity in the latter case is notable,
imines, followed by ring-closure condensation [81-83]. Despite as the quaternary stereogenic centre is created in the lactamisa-
improvements of, and developments to, the nitro-Mannich/lac- tion step. The relative stereochemical configurations of 1a–c
tamisation cascade during the last few decades, we recognised, were established by 1H NMR spectroscopic analysis. For more
that further enhancement of the method was necessary to trans- details on the elucidation of the relative configuration see [61]
form it into a general synthetic tool of use in both medicinal and Supporting Information File 1. To incorporate substituents
chemistry and natural-product synthesis.
at the 6 position of the piperidine ring in 1, imines derived from
aldehydes other than formaldehyde were required in the reac-
tion. Thus acetaldehyde (3b), anisaldehyde (3c) and glyoxylic
Results and Discussion
To allow us to further explore the nitro-Mannich/lactamisation acid (3d) were chosen as representative aliphatic, aromatic and
cascade, a range of Michael adducts 6a–e were synthesised on a functionalised aldehydes, respectively, and reacted with
gram scale by the reaction of active methylene or methine Michael adducts 6a and 6d under the conditions described
carbon acids with nitro olefins in the presence of DABCO above with allylamine. High diastereoselectivities were
(20–30 mol %) in THF (Scheme 2). Where diastereoisomers observed in each case and the reaction products 1d–g were
were created in the Michael addition step and stereocontrol was obtained in moderate to good yields (50–74%). The relative
poor, the diastereomeric mixtures were recrystallised to afford stereochemistry of 1g was assigned unambiguously by single-
single diastereomers 6a, b, e. The relative stereochemistry of crystal X-ray analysis. Similarly, variation at position 1 required
the major diastereomer 6e was assigned unambiguously by the use of an alternative amine for in situ imine formation. Thus
single-crystal X-ray analysis.
replacement of allylamine (4a) with benzylamine (4b) in the
Scheme 2: The synthesis of Michael adduct model substrates for the nitro-Mannich/lactamisation cascade.
569

Beilstein J. Org. Chem. 2012, 8, 567–578.
Scheme 3: Nitro-Mannich/lactamisation cascade with in situ formed imines.
reaction afforded the desired product 1h in good yield and as a
single diastereoisomer (Scheme 3).
The use of substrate 6e allowed us to investigate further vari-
ations at positions 1 and 4; piperidin-2-ones 1i and 1j were
formed as single diastereoisomers in good yields (82% and
75%) when nitro-Mannich/lactamisation cascades were carried
out with formaldehyde (3a) and butylamine (4c) or hept-5-yn-1-
amine (4d), respectively. To extend the cascade methodology to
the potential construction of architecturally complex piperidine-
ring-containing polycyclic natural products, the successful
employment of preformed cyclic imines was required.
Accordingly, the imine 5a (Figure 2) was synthesised from
commercially available 2-phenylethylamine [85] and reacted
with the chromatographically inseparable mixture of diastereo-
Figure 2: Cyclic imines employed in nitro-Mannich/lactamisation
cascade.
570

Beilstein J. Org. Chem. 2012, 8, 567–578.
Scheme 4: Nitro-Mannich/lactamisation cascade of diastereomeric Michael adducts 6a, 6a’’ with cyclic imine 5a.
meric Michael adducts 6a and 6a’’, under slightly modified the retro-Michael reaction does not occur under standard reac-
conditions (water was used instead of MeOH as the solvent). tion conditions (Scheme 4) and assuming that the final step of
Pleasingly the reaction proceeded smoothly and only two, 2a the cascade (the δ-lactam ring formation) is irreversible, there
and 2a’’, of the possible eight diastereoisomeric tetracyclic are at least three possible explanations for the high diastereo-
compounds were obtained in good combined yield (70%, control in the formation of 1a–j and 2a–l:
Scheme 4). Chromatographic separation followed by single-
crystal X-ray diffraction studies of both isomers allowed unam- - The first is that the nitro-Mannich step is highly diastereose-
biguous determination of the relative stereochemical configura- lective and lactamisation occurs subsequently without any
tions in each case. For more details of the elucidation of the effect on the stereochemical outcome of the cascade.
relative configuration see Supporting Information File 1. The
products were epimeric only at the quaternary centre and there- - The second is that the nitro-Mannich reaction [78-80] is fast
fore both new stereogenic centres were created with high and reversible (but not necessarily stereoselective), and only
stereocontrol in each case.
one of the diastereomeric nitro-Mannich products preferentially
cyclises in the irreversible lactamisation step to the (likely)
Imines 5a–5i [61,86-94], chosen so as to afford common target most thermodynamically stable product (Scheme 6, Path A).
motifs in the products [95-102], were synthesised and reacted
with diastereomerically pure Michael adduct 6a and Michael - The third is similar to the second, but the two direct nitro-
adduct 6d following the conditions described above. Employing Mannich products A and B with the observed configurations at
the optimal reaction conditions, products 2a–2l, which possess the 6 position preferentially lactamise, and there is a postcyc-
4,5-trans relative stereochemistry, were formed in moderate to lisation epimerisation at the stereogenic carbon bearing the nitro
good yields and with high diastereoselectivities as described in group allowing equilibration to the (likely) most thermodynam-
our previous work (Scheme 5) [61].
ically stable product (thermodynamic control, Path B) or a
crystallisation-induced diastereoselectivity to give products 2 or
Interestingly, however, when diastereomerically pure Michael 2’ with the nitro group occupying an axial or equatorial pos-
adduct 6d was reacted with imine 5e, the nitropiperidinone 2m’, ition, respectively [104-108] (Scheme 6, Path B/B’).
possessing 4,5-cis relative stereochemistry [103], was isolated
in 70% yield as a single diastereomer (Scheme 5). This one A further scrutiny of each hypothesis was, unfortunately,
exceptional case together with the generally high diastereocon- hampered by our failure to isolate or identify in situ the direct
trol in the formation of piperidinones 1a–j and 2a–l is interest- nitro-Mannich products from the reaction mixtures or to prepare
ing and worthy of further commentary. With the knowledge that them separately using standard procedures for a nitro-Mannich
571

Beilstein J. Org. Chem. 2012, 8, 567–578.
Scheme 5: Nitro-Mannich/lactamisation cascade with cyclic imines. aDiastereomeric ratio in a crude reaction mixture, bH2O/MeOH 1:1 mixture used
as a solvent, cminor diastereomer 2m isolated in 5% yield.
reaction with imines [109]. The first hypothesis, however, was The formation of product 2m’ with its exceptional 4,5-cis
not supported by the low diastereoselectivity in the formation of relative stereochemistry, can be explained by following path B’
2j, in which presumably the relatively fast irreversible cyclisa- (Scheme 6). In this case the observed diastereoselectivity is
tion outcompetes the equilibration processes. Considering the believed to be driven by preferential crystallisation of the 4,5-
relatively broad range of imines and Michael adducts involved cis-configured diastereoisomer in the reaction flask rather than
in the stereoselective cascade, we believe that the second or thermodynamic equilibration. As such, this reaction represents
third explanations are the most plausible and that the observed an example of a crystallisation-induced diastereomeric trans-
diastereoselectivities in the formation of products 1a–j, 2a–l formation (CIDT) [104-108]. This is supported by the observa-
can be explained by following either Path A or B (Scheme 6). tion that 2m and 2m’, when exposed separately to simulated
572

Beilstein J. Org. Chem. 2012, 8, 567–578.
Scheme 6: Possible explanations for the observed high stereoselectivities in the nitro-Mannich/lactamisation cascade.
reaction conditions, epimerised at C5 to afford an identical asymmetric synthesis of a particular Michael adduct, so as to
63:37 thermodynamic mixture of 2m/2m’(Scheme 7; Figure 3) construct a one-pot enantio- and diastereoselective four-
[110].
component coupling reaction (Scheme 8).
With all of the necessary variations to the nitro-Mannich/lac- As described in our previous communication [61], the employ-
tamisation cascade having been tested, optimised and scoped, ment of bifunctional catalyst 9 [54,55] in a highly stereose-
we looked at the possibility of combining it with a catalytic lective two-stage one-pot cascade led to the formation of enan-
Scheme 7: Thermodynamically-driven epimerisation of 5-nitropiperidin-2-ones 2m and 2m’.
573

Beilstein J. Org. Chem. 2012, 8, 567–578.
Figure 3: Thermodynamically driven epimerisation of 5-nitropiperidin-2-ones 2m and 2m’; identical diastereomeric excess measured for both
diastereomers after 48 h and 72 h.
Scheme 8: One-pot three/four-component enantioselective Michael addition/nitro-Mannich/lactamisation cascade.
tiomerically highly enriched spirocycle (+)-1a (Scheme 8). In a were required. Although Nef-type oxidation followed by
repeat of the process but with the intention of targeting a exhaustive reduction of the resulting carbonyl group was
piperidin-2-one ring-containing polycyclic scaffold, cyclic considered, Ono’s radical procedure [113-116] was initially
imine 5a was added at the second stage. Tetracyclic spiro- investigated. With some modification and optimisation, this was
lactam 2a was isolated in high enantiomeric purity (90% ee) in found to be compatible with the piperidin-2-one scaffold. Thus
good chemical yield (62%, Scheme 8) [111,112].
treatment of 2a and 2c with tributyltin hydride and AIBN in
toluene under reflux smoothly afforded the protodenitrated
For the products of the nitro-Mannich/lactamisation cascade to products 10c and 10d in good yield (average 76% yield,
be of use in alkaloid natural-product synthesis (or even simple Scheme 9). Other examples of successful nitro-group removal
stereoselective piperidine synthesis), controlled, reductive were also achieved when substrates 1i and 1j, lacking addition-
manipulation of both the nitro group and the lactam carbonyl al rings but bearing sensitive moieties (triple bond and furan
574

Beilstein J. Org. Chem. 2012, 8, 567–578.
chemoselective reduction would offer more options in any syn-
thesis, and thus several commercially available reducing agents
were screened in order to achieve selective reduction of only
one lactam carbonyl. A notable find was that, by short exposure
of denitrated heterocycle 10a–c to LiAlH4 in THF followed by
quenching and treatment with HCOOH, spirocycles 11a–c were
obtained in good yields. The chemoselectivity of the reduction
was unambiguously confirmed by single-crystal X-ray diffrac-
tion studies of 11c. Furthermore, the use of an excess of DIBAL
at room temperature smoothly afforded the diamines 12a and
12b (Scheme 10).
Conclusion
In summary, a versatile nitro-Mannich/lactamisation cascade
for the direct synthesis of heavily decorated 5-nitropiperidin-2-
ones and related heterocycles has been developed. A highly
enantioenriched substituted 5-nitropiperidin-2-one was synthe-
sised in a four-component one-pot cascade combining an
enantioselective Michael addition with the diastereoselective
nitro-Mannich/lactamisation cascade. Protodenitration and
chemoselective reductive manipulation of the heterocycles
could be used to install contiguous and fully substituted stereo-
centres in the synthesis of architecturally complex multicyclic
Scheme 9: Protodenitration of 5-nitropiperidin-2-ones.
moiety), were exposed to identical reaction conditions. The alkaloid structures. The first applications of the developed
piperidin-2-ones 10a and 10b were obtained in 53% and 84%, methodology were disclosed recently as the total syntheses of
respectively. The reduction of both piperidin-2-one and paroxetine [60] and nakadomarin A [61-65] were successfully
pyrrolidin-2-one heterocycles to piperidine or pyrrolidine rings finished by employing the strategy as a fundamental synthetic
by using a range of reagents is well-documented in the litera- tool. Further development is ongoing in our laboratory and the
ture [117,118]. However, we believed that a controlled, results will be disclosed in due course.
Scheme 10: Various reductions of denitrated heterocycles.
575

Beilstein J. Org. Chem. 2012, 8, 567–578.
8. Woodward, R. B.; Bader, F. E.; Bickel, H.; Frey, A. J.;
Supporting Information
Kierstead, R. W. Tetrahedron 1958, 2, 1–57.
doi:10.1016/0040-4020(58)88022-9
Supporting Information File 1
9. Barnes, R. D.; Wodd-Kaczmar, M. W.; Curzons, A. D.; Lynch, I.;
Richardson, J. E.; Buxton, P. C. Anti-depressant crystalline paroxetine
hydrochloride hemihydrate. U.S. Patent 4,721,723, Oct 23, 1986.
10. Yu, M. S.; Lantos, I.; Peng, Z.-Q.; Yu, J.; Cacchio, T.
Tetrahedron Lett. 2000, 41, 5647–5651.
General experimental, copies of 1H and 13C NMR spectra
for all new compounds (1a–j, 2a, 2a’’, 2m, 2m’, 6b–e,
10a–d, 11a–c, 12a,b).
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-64-S1.pdf]
doi:10.1016/S0040-4039(00)00942-4
11. Furkert, D. P.; Husbands, S. M. Org. Lett. 2007, 9, 3769–3771.
doi:10.1021/ol0713988
Supporting Information File 2
12. Bates, R. W.; Sa-Ei, K. Tetrahedron 2002, 58, 5957–5978.
doi:10.1016/S0040-4020(02)00584-7
X-ray crystal structure of compound 2m’.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-64-S2.cif]
13. Felpin, F.-X.; Lebreton, J. Eur. J. Org. Chem. 2003, 3693–3712.
doi:10.1002/ejoc.200300193
14. Bailey, P. D.; Millwood, P. A.; Smith, P. D. Chem. Commun. 1998,
633–640. doi:10.1039/a709071d
Supporting Information File 3
X-ray crystal structures of compounds 1g, 2, 2a’’, 6e and
11c.
15. O'Hagan, D. Nat. Prod. Rep. 2000, 17, 435–446.
doi:10.1039/a707613d
16. Buffat, M. G. P. Tetrahedron 2004, 60, 1701–1729.
doi:10.1016/j.tet.2003.11.043
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-64-S3.cif]
17. Weintraub, P. M.; Sabol, J. S.; Kane, J. M.; Borcherding, D. R.
Tetrahedron 2003, 59, 2953–2989.
doi:10.1016/S0040-4020(03)00295-3
18. Husson, H.-P.; Royer, J. Chem. Soc. Rev. 1999, 28, 383–394.
doi:10.1039/a900153k
Acknowledgements
19. Escolano, C.; Amat, M.; Bosch, J. Chem.–Eur. J. 2006, 12,
8198–8207. doi:10.1002/chem.200600813
We gratefully acknowledge Merck, Sharp and Dohme
(Hoddesdon, U.K.) for a studentship (to D.M.C.); the EPSRC
for a studentship (to D.M.C), a postdoctoral fellowship (to P.J.),
and a Leadership Fellowship (to D.J.D.). We thank Dr Edward
Cleator of MSD for useful discussion, Andrew Kyle and
Katherine Bogle for X-ray structure determination and the
Oxford Chemical Crystallography Service for use of the instru-
mentation.
20. Comins, D. L.; Fulp, A. B. Tetrahedron Lett. 2001, 42, 6839–6841.
doi:10.1016/S0040-4039(01)01432-0
21. Comins, D. L.; Brooks, C. A.; Ingalls, C. L. J. Org. Chem. 2001, 66,
2181–2182. doi:10.1021/jo001609l
22. Comins, D. L.; Libby, A. H.; Al-awar, R. S.; Foti, C. J. J. Org. Chem.
1999, 64, 2184–2185. doi:10.1021/jo990192k
23. Comins, D. L.; Kuethe, J. T.; Miller, T. M.; Février, F. C.; Brooks, C. A.
J. Org. Chem. 2005, 70, 5221–5234. doi:10.1021/jo050559n
24. Kuethe, J. T.; Comins, D. L. Org. Lett. 2000, 2, 855–857.
doi:10.1021/ol0056271
References
1. de Oliveira, J. H. H. L.; Nascimento, A. M.; Kossuga, M. H.;
Cavalcanti, B. C.; Pessoa, C. O.; Moraes, M. O.; Macedo, M. L.;
Ferreira, A. G.; Hajdu, E.; Pinheiro, U. S.; Berlinck, R. G. S.
J. Nat. Prod. 2007, 70, 538–543. doi:10.1021/np060450q
2. Magnier, E.; Langlois, Y. Tetrahedron 1998, 54, 6201–6258.
doi:10.1016/S0040-4020(98)00357-3
25. Comins, D. L.; Zhang, Y.-m.; Joseph, S. P. Org. Lett. 1999, 1,
657–659. doi:10.1021/ol990738p
26. Dounay, A. B.; Overman, L. E.; Wrobleski, A. D. J. Am. Chem. Soc.
2005, 127, 10186–10187. doi:10.1021/ja0533895
27. Lin, N.-H.; Overman, L. E.; Rabinowitz, M. H.; Robinson, L. A.;
Sharp, M. J.; Zablocki, J. J. Am. Chem. Soc. 1996, 118, 9062–9072.
doi:10.1021/ja961641q
See for a review on the isolation and the biological properties of
manzamine A.
28. Castro, P.; Overman, L. E.; Zhang, X.; Mariano, P. S.
Tetrahedron Lett. 1993, 34, 5243–5246.
3. Winkler, J. D.; Axten, J. M. J. Am. Chem. Soc. 1998, 120, 6425–6426.
doi:10.1021/ja981303k
doi:10.1016/S0040-4039(00)73963-3
4. Humphrey, J. M.; Liao, Y.; Ali, A.; Rein, T.; Wong, Y.-L.; Chen, H.-J.;
Courtney, A. K.; Martin, S. F. J. Am. Chem. Soc. 2002, 124,
8584–8592. doi:10.1021/ja0202964
29. Hong, C. Y.; Kado, N.; Overman, L. E. J. Am. Chem. Soc. 1993, 115,
11028–11029. doi:10.1021/ja00076a086
30. Gedig, T.; Dettner, K.; Seifert, K. Tetrahedron 2007, 63, 2670–2674.
doi:10.1016/j.tet.2007.01.024
5. Toma, T.; Kita, Y.; Fukuyama, T. J. Am. Chem. Soc. 2010, 132,
10233–10235. doi:10.1021/ja103721s
31. Trost, B. M.; Cramer, N.; Bernsmann, H. J. Am. Chem. Soc. 2007,
129, 3086–3087. doi:10.1021/ja070142u
6. Yamada, M.; Takahashi, Y.; Kubota, T.; Fromont, J.; Ishiyama, A.;
Otoguro, K.; Yamada, H.; Ōmura, S.; Kobayashi, J.-i. Tetrahedron
2009, 65, 2313–2317. doi:10.1016/j.tet.2009.01.032
7. Chen, F.-E.; Huang, J. Chem. Rev. 2005, 105, 4671–4706.
doi:10.1021/cr050521a
32. Islam, I.; Bryant, J.; May, K.; Mohan, R.; Yuan, S.; Kent, L.; Morser, J.;
Zhao, L.; Vergona, R.; White, K.; Adler, M.; Whitlow, M.;
Buckman, B. O. Bioorg. Med. Chem. Lett. 2007, 17, 1349–1354.
doi:10.1016/j.bmcl.2006.11.078
33. Pandey, S. K.; Kumar, P. Tetrahedron Lett. 2005, 46, 4091–4093.
doi:10.1016/j.tetlet.2005.04.013
576

Beilstein J. Org. Chem. 2012, 8, 567–578.
34. Takahata, H.; Saito, Y.; Ichinose, M. Org. Biomol. Chem. 2006, 4,
1587–1595. doi:10.1039/B601489E
63. Kyle, A. F.; Jakubec, P.; Cockfield, D. M.; Cleator, E.; Skidmore, J.;
Dixon, D. J. Chem. Commun. 2011, 47, 10037–10039.
doi:10.1039/c1cc13665h
35. Kim, S.-G.; Lee, S. H.; Park, T.-H. Tetrahedron Lett. 2007, 48,
5023–5026. doi:10.1016/j.tetlet.2007.05.100
64. Jakubec, P.; Kyle, A. F.; Calleja, J.; Dixon, D. J. Tetrahedron Lett.
2011, 52, 6094–6097. doi:10.1016/j.tetlet.2011.09.016
65. Yu, M.; Wang, C.; Kyle, A. F.; Jakubec, P.; Dixon, D. J.;
Schrock, R. R.; Hoveyda, A. H. Nature 2011, 479, 88–93.
doi:10.1038/nature10563
36. Breuning, M.; Steiner, M. Synthesis 2006, 1386–1389.
doi:10.1055/s-2006-926419
37. Itoh, T.; Nishimura, K.; Nagata, K.; Yokoya, M. Synlett 2006,
2207–2210. doi:10.1055/s-2006-948203
38. Gebauer, J.; Blechert, S. Synlett 2005, 2826–2828.
doi:10.1055/s-2005-918942
66. Mühlstädt, M.; Schulze, B. J. Prakt. Chem. 1975, 317, 919–925.
doi:10.1002/prac.19753170606
39. Enders, D.; Thiebes, C. Pure Appl. Chem. 2001, 73, 573–578.
doi:10.1351/pac200173030573
67. Bhagwatheeswaran, H.; Gaur, S. P.; Jain, P. C. Synthesis 1976,
615–616. doi:10.1055/s-1976-24142
40. Davis, F. A.; Santhanaraman, M. J. Org. Chem. 2006, 71, 4222–4226.
doi:10.1021/jo060371j
68. Desai, M. C.; Thadeio, P. F.; Lefkowitz, S. L. Tetrahedron Lett. 1993,
34, 5831–5834. doi:10.1016/S0040-4039(00)73791-9
69. Desai, M. C.; Lefkowitz, S. L. Bioorg. Med. Chem. Lett. 1993, 3,
2083–2086. doi:10.1016/S0960-894X(01)81021-0
41. Ciblat, S.; Besse, P.; Papastergiou, V.; Veschambre, H.; Canet, J.-L.;
Troin, Y. Tetrahedron: Asymmetry 2000, 11, 2221–2229.
doi:10.1016/S0957-4166(00)00162-2
70. Nara, S.; Tanaka, R.; Eishima, J.; Hara, M.; Takahashi, Y.; Otaki, S.;
Foglesong, R. J.; Hughes, P. F.; Turkington, S.; Kanda, Y.
J. Med. Chem. 2003, 46, 2467–2473. doi:10.1021/jm020522k
71. Tanaka, R.; Rubio, A.; Harn, N. K.; Gernert, D.; Grese, T. A.;
Eishima, J.; Hara, M.; Yoda, N.; Ohashi, R.; Kuwabara, T.; Soga, S.;
Akinaga, S.; Nara, S.; Kanda, Y. Bioorg. Med. Chem. 2007, 15,
1363–1382. doi:10.1016/j.bmc.2006.11.007
42. Jo, E.; Na, Y.; Chang, S. Tetrahedron Lett. 1999, 40, 5581–5582.
doi:10.1016/S0040-4039(99)01081-3
43. Schaudt, M.; Blechert, S. J. Org. Chem. 2003, 68, 2913–2920.
doi:10.1021/jo026803h
44. Nicolau, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005,
44, 4490–4527. doi:10.1002/anie.200500369
45. Takahata, H.; Banba, Y.; Ouchi, H.; Nemoto, H.; Kato, A.; Adachi, I.
J. Org. Chem. 2003, 68, 3603–3607. doi:10.1021/jo034137u
46. Kim, I. S.; Oh, J. S.; Zee, O. P.; Jung, Y. H. Tetrahedron 2007, 63,
2622–2633. doi:10.1016/j.tet.2007.01.028
72. Pei, Z.; Li, X.; von Geldern, T. W.; Longenecker, K.; Pireh, D.;
Stewart, K. D.; Backes, B. J.; Lai, C.; Lubben, T. H.; Ballaron, S. J.;
Beno, D. W. A.; Kempf-Grote, A. J.; Sham, H. L.; Trevillyan, J. M.
J. Med. Chem. 2007, 50, 1983–1987. doi:10.1021/jm061436d
73. Xu, F.; Corley, E.; Zacuto, M.; Conlon, D. A.; Pipik, B.; Humphrey, G.;
Murry, J.; Tschaen, D. J. Org. Chem. 2010, 75, 1343–1353.
doi:10.1021/jo902573q
47. Felpin, F.-X.; Girard, S.; Vo-Thanh, G.; Robins, R. J.; Villiéras, J.;
Lebreton, J. J. Org. Chem. 2001, 66, 6305–6312.
doi:10.1021/jo010386b
48. Mulzer, J.; Öhler, E. Top. Organomet. Chem. 2004, 13, 269–366.
doi:10.1007/b98768
74. Xu, F.; Corley, E.; Murry, J. A.; Tschaen, D. M. Org. Lett. 2007, 9,
2669–2672. doi:10.1021/ol070909n
49. Kim, S.; Lee, Y. M.; Lee, J.; Lee, T.; Fu, Y.; Song, Y.; Cho, J.; Kim, D.
J. Org. Chem. 2007, 72, 4886–4891. doi:10.1021/jo070668x
50. Goodenough, K. M.; Moran, W. J.; Raubo, P.; Harrity, J. P. A.
J. Org. Chem. 2005, 70, 207–213. doi:10.1021/jo048455k
51. Gerasyuto, A. I.; Hsung, R. P. Org. Lett. 2006, 8, 4899–4902.
doi:10.1021/ol0619359
75. Pelletier, S. M.-C.; Ray, P. C.; Dixon, D. J. Org. Lett. 2009, 11,
4512–4515. doi:10.1021/ol901640v
76. Pelletier, S. M.-C.; Ray, P. C.; Dixon, D. J. Org. Lett. 2011, 13,
6406–6409. doi:10.1021/ol202710g
77. Barber, D. M.; Sanganee, H.; Dixon, D. J. Chem. Commun. 2011, 47,
4379–4381. doi:10.1039/c1cc10751h
52. Harrity, J. P. A.; Provoost, O. Org. Biomol. Chem. 2005, 3,
1349–1358. doi:10.1039/b502349c
78. Rychnovsky, S. D.; Beauchamp, T.; Vaidyanathan, R.; Kwan, T.
J. Org. Chem. 1998, 63, 6363–6374. doi:10.1021/jo9808831
79. Westermann, B. Angew. Chem., Int. Ed. 2003, 42, 151–153.
doi:10.1002/anie.200390071
53. Itoh, J.; Fuchibe, K.; Akiyama, T. Angew. Chem., Int. Ed. 2006, 45,
4796–4798. doi:10.1002/anie.200601345
54. Hynes, P. S.; Stranges, D.; Stupple, P. A.; Guarna, A.; Dixon, D. J.
Org. Lett. 2007, 9, 2107–2110. doi:10.1021/ol070532l
55. Ye, J.; Dixon, D. J.; Hynes, P. S. Chem. Commun. 2005, 4481–4483.
doi:10.1039/b508833j
80. Kobayashi, S.; Mori, Y.; Fossey, J. S.; Salter, M. M. Chem. Rev. 2011,
111, 2626–2704. doi:10.1021/cr100204f
81. Humphrey, J. M.; Arnold, E. P.; Chappie, T. A.; Feltenberger, J. B.;
Nagel, A.; Simon, W.; Suarez-Contreras, M.; Tom, N. J.; O’Neill, B. T.
J. Org. Chem. 2009, 74, 4525–4536. doi:10.1021/jo9003184
82. Imashiro, R.; Uehara, H.; Barbas, C. F., III. Org. Lett. 2010, 12,
5250–5253. doi:10.1021/ol102292a
56. Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125,
12672–12673. doi:10.1021/ja036972z
57. Li, H.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2004, 126,
9906–9907. doi:10.1021/ja047281l
83. Wang, Y.; Yu, D.-F.; Liu, Y.-Z.; Wei, H.; Luo, Y.-C.; Dixon, D. J.;
Xu, P.-F. Chem.–Eur. J. 2010, 16, 3922–3925.
58. McCooey, S. H.; Connon, S. J. Angew. Chem., Int. Ed. 2005, 44,
6367–6370. doi:10.1002/anie.200501721
doi:10.1002/chem.201000059
59. Connon, S. J. Chem. Commun. 2008, 2499–2510.
doi:10.1039/b719249e
84. Only one diastereomer was observed by 1H NMR.
85. Elliot, M. C.; Williams, E. Org. Biomol. Chem. 2003, 1, 3038–3047.
doi:10.1039/b306159k
60. Hynes, P. S.; Stupple, P. A.; Dixon, D. J. Org. Lett. 2008, 10,
1389–1391. doi:10.1021/ol800108u
86. Struve, C.; Christophersen, C. Heterocycles 2003, 60, 1907–1914.
doi:10.3987/COM-03-9802
61. Jakubec, P.; Helliwell, M.; Dixon, D. J. Org. Lett. 2008, 10,
4267–4270. doi:10.1021/ol801666w
87. Scully, F. E., Jr. J. Org. Chem. 1980, 45, 1515–1517.
doi:10.1021/jo01296a036
62. Jakubec, P.; Cockfield, D. M.; Dixon, D. J. J. Am. Chem. Soc. 2009,
131, 16632–16633. doi:10.1021/ja908399s
577

Beilstein J. Org. Chem. 2012, 8, 567–578.
88. Davis, B. G.; Maughan, M. A. T.; Chapman, T. M.; Villard, R.;
Courtney, S. Org. Lett. 2002, 4, 103–106. doi:10.1021/ol016970o
89. Bertrand, M.; Poissonnet, G.; Théret-Bettiol, M.-H.; Gaspard, C.;
Werner, G. H.; Pfeiffer, B.; Renard, P.; Léonce, S.; Dodd, R. H.
Bioorg. Med. Chem. 2001, 9, 2155–2164.
113.Ono, N.; Miyake, H.; Tamura, R.; Kaji, A. Tetrahedron Lett. 1981, 22,
1705–1708. doi:10.1016/S0040-4039(01)90417-4
See for seminal work.
114.Ono, N.; Kaji, A. Synthesis 1986, 693–704. doi:10.1055/s-1986-31754
115.Tormo, J.; Hays, D. S.; Fu, G. C. J. Org. Chem. 1998, 63, 5296–5297.
doi:10.1021/jo980789k
doi:10.1016/S0968-0896(01)00119-5
90. Warrener, R. N.; Liu, L.; Russell, R. A. Tetrahedron 1998, 54,
7485–7496. doi:10.1016/S0040-4020(98)00378-0
91. Caroon, J. M.; Clark, R. D.; Kluge, A. F.; Lee, C. H.; Strosberg, A. M.
J. Med. Chem. 1983, 26, 1426–1433. doi:10.1021/jm00364a013
92. Venkov, A. P.; Statkova-Abeghe, S. Synth. Commun. 1996, 26,
127–134. doi:10.1080/00397919608003871
116.Shen, B.; Johnston, J. N. Org. Lett. 2008, 10, 4397–4400.
doi:10.1021/ol801797h
117.Meyers, A. I.; Downing, S. V.; Weiser, M. J. J. Org. Chem. 2001, 66,
1413–1419. doi:10.1021/jo001548r
118.Hirosawa, C.; Wakasa, N.; Fuchikami, T. Tetrahedron Lett. 1996, 37,
6749–6752. doi:10.1016/S0040-4039(96)01458-X
93. Grunewald, G. L.; Dahanukar, V. H.; Ching, P.; Criscione, K. R.
J. Med. Chem. 1996, 39, 3539–3546. doi:10.1021/jm9508292
94. Meyers, A. I.; Hutchings, R. H. Tetrahedron 1993, 49, 1807–1820.
doi:10.1016/S0040-4020(01)80537-8
License and Terms
95. García, E.; Lete, E.; Sotomayor, N. J. Org. Chem. 2006, 71,
6776–6784. doi:10.1021/jo060903w
This is an Open Access article under the terms of the
Creative Commons Attribution License
96. Itoh, T.; Miyazaki, M.; Fukuoka, H.; Nagata, K.; Ohsawa, A. Org. Lett.
2006, 8, 1295–1297. doi:10.1021/ol0530326
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
97. Ma, J.; Yin, W.; Zhou, H.; Cook, J. M. Org. Lett. 2007, 9, 3491–3494.
doi:10.1021/ol071220l
98. Sheludko, Y.; Gerasimenko, I.; Kolshorn, H.; Stöckigt, J. J. Nat. Prod.
2002, 65, 1006–1010. doi:10.1021/np0200919
99. Bailey, P. D.; Morgan, K. M. J. Chem. Soc., Perkin Trans. 1 2000,
3578–3583. doi:10.1039/B005695M
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
100.Batista, C. V. F.; Schripsema, J.; Verpoorte, R.; Rech, S. B.;
Henriques, A. T. Phytochemistry 1996, 41, 969–973.
doi:10.1016/0031-9422(95)00666-4
(http://www.beilstein-journals.org/bjoc)
The definitive version of this article is the electronic one
which can be found at:
101.Kuehne, M. E.; Muth, R. S. J. Org. Chem. 1991, 56, 2701–2712.
doi:10.1021/jo00008a025
102.Martin, S. F.; Benage, B.; Hunter, J. E. J. Am. Chem. Soc. 1988, 110,
5925–5927. doi:10.1021/ja00225a068
doi:10.3762/bjoc.8.64
103.The relative stereochemistry was confirmed by the measurement of
J-coupling constants and unambiguously determined by single-crystal
X-ray analysis.
104.Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic
Compounds; John Wiley & Sons: New York, 1994.
See for the definition of crystallisation-induced transformations.
105.Yoshioka, R. Top. Curr. Chem. 2007, 269, 83–132.
doi:10.1007/128_2006_094
106.Brands, K. M. J.; Davies, A. J. Chem. Rev. 2006, 106, 2711–2733.
doi:10.1021/cr0406864
107.Anderson, N. G. Org. Process Res. Dev. 2005, 9, 800–813.
doi:10.1021/op050119y
108.Ďuriš, A.; Wiesenganger, T.; Moravčíková, D.; Baran, P.; Kožíšek, J.;
Daïch, A.; Berkeš, D. Org. Lett. 2011, 13, 1642–1645.
doi:10.1021/ol2001057
109.Adams, H.; Anderson, J. C.; Peace, S.; Pennell, A. M. K.
J. Org. Chem. 1998, 63, 9932–9934. doi:10.1021/jo981700d
110.The epimerisation studies were performed in MeOH (c 0.015 M) to
ensure the full solubility of all reagents and products.
111.Absolute stereochemistry assigned by analogy with previous results of
Michael addition to nitroolefin electrophiles catalyzed by 9; see
reference [55]
112.Dixon, D. J.; Ley, S. V.; Rodríguez, F. Angew. Chem., Int. Ed. 2001,
40, 4763–4765.
doi:10.1002/1521-3773(20011217)40:24<4763::AID-ANIE4763>3.0.C
O;2-D
See for a related multicomponent reaction.
578