Inexpensive multigram-scale synthesis of cyclic enamines and 3-N spirocyclopropyl systems

Article abstract of DOI:10.1039/c7ob02659e

Cyclic enamines are important synthons for many synthetic and pharmacological targets. Here, we report an inexpensive, catalyst-free, multigram-scale synthesis for cyclic enamines with exocyclic double bonds and four- to seven-membered rings. This strategy is more conducive to scale up, permissive of functionalization around the cyclic system, and less sensitive to the nature of the N-protecting group than previously-described methods for cyclic enamine synthesis. Further, we explore application of these enamines to the synthesis of highly-strained spirocyclic 3N-cyclopropyl scaffolds.

Full text of DOI:10.1039/c7ob02659e

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: P. Kumar, O.
Zainul and S. T. Laughlin, Org. Biomol. Chem., 2017, DOI: 10.1039/C7OB02659E.
This is an Accepted Manuscript, which has been through the
Volume 14 Number
1 7 January 2016 Pages 1–372
Royal Society of Chemistry peer review process and has been
accepted for publication.
Organic &
Biomolecular
Chemistry
www.rsc.org/obc
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1477-0520
COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
rsc.li/obc

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 1 of 5
View Article Online
DOI: 10.1039/C7OB02659E
Journal Name
COMMUNICATION
Inexpensive multigram-scale synthesis of cyclic enamines and 3-N
spirocyclopropyl systems†
Pratik Kumar,a Omar Zainula and S. T. Laughlina,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Cyclic enamines are important synthons for many synthetic and
pharmacological targets. Here, we report an inexpensive, catalyst-
free, multigram-scale synthesis for cyclic enamines with exocyclic
double bonds and four- to six-membered rings. This strategy is
more conducive to scale up, permissive of functionalization around
the cyclic system, and less sensitive to the nature of the N-
protecting group than previously-described methods for cyclic
enamine synthesis. Further, we explore application of these
enamines to the synthesis of highly-strained spirocyclic 3N-
cyclopropyl scaffolds.
Cyclic enamines are valuable building blocks for the preparation
of synthetic, naturally-occurring, and pharmacologically active
molecules1–6. For example, they are key components of
synthetic azacyclic hexahydroindoles7, the naturally-occurring
alkaloid Plakoridine A8, and a pharmaceutically relevant
derivative of the sugar α-D-xylofuranose9 (Fig. 1). Naturally,
chemists have devoted considerable effort to developing
strategies for the synthesis of cyclic enamines. Among the cyclic
enamines, those containing an exocyclic double bond, like
Fig 1. An array of synthetic, naturally-occurring, and pharmaceutical molecules
utilizes cyclic enamines as key motifs. Additionally, cyclic enamines containing an
exocyclic double bond can provide access to 3-N spirocyclic systems.
ROM polymerization19,20 and poly-cyclopropane-based
materials21, and reagents in the bioorthogonal tetrazine
azetidine enamine
1 and pyrrolidine enamine 2 (Fig. 1), have
garnered attention7,10–15 for their wide use as precursors in the
syntheses of biologically active molecules ranging from β-
lactams10,16 and macrolactams11 to unnatural amino acids14 and
ligation22–24
.
Traditionally, cyclic enamines like compounds
been synthesized in modest yields by cyclization of the
respective halo-imine precursors with strong bases25–27
1 and 2 have
substituted 2-pyrrolidines8. Our interest in cyclic enamines
1
.
and
2 stems from their potential use as intermediates in the
Unfortunately, these strategies are limited in their substrate
scope by their use of strong base and requirement for a
quaternary carbon adjacent to the amine to prevent elimination
of the halogen.
More recently, catalysts based on copper11,12 and
palladium13,15,28 have significantly improved the reaction yields
for the formation of cyclic enamines and have provided access
to new cyclic enamine scaffolds; however, they require
multistep syntheses of the precursors required for the catalytic
step. Additionally, the scalability of these reactions has not been
determined, and the combined cost of the catalyst and multiple
step synthesis of the precursor molecules can be prohibitive
creation of 3-N spirocyclopropyl (i.e., 4-azaspiro[2.n]alkane)
and 3-N spirocyclopropenyl (i.e., 4-azaspiro[2.n]alkene)
systems, which have utility in diverse subfields of chemistry as
synthons for cyclin-dependent kinase217 and tyrosine kinase
inhibitors18, monomers for both
a. Department of Chemistry, Stony Brook University, Stony Brook, New York, 11794,
United States.
b. Institute for Chemical Biology and Drug Discovery, Stony Brook University, Stony
Brook, New York, 11794, United States
Email: Scott.Laughlin@StonyBrook.edu
†Electronic Supplementary Information (ESI) available: Experimental procedures
and characterization data. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 5
COMMUNICATION
Journal Name
when multigram quantities of cyclic enamines like
required.
1
and
2
1
are workers for olefin syntehsis29. Our initial attemptVaiefwfoArrtdiceledOntlhinee
5-membered enamine 6b in 92% yield (1.0 g scale). Importantly,
and we observed consistent reaction yields upon scaling up this
DOI: 10.1039/C7OB02659E
Thus, in our initial foray into the synthesis of enamines
2
, we explored the scalability of a metal-catalysed Ullman-type reaction (37.0 g scale, 89.6% yield). Repeating this reaction
coupling, recently described by Li and co-workers11, to produce three more times with different batches of 5b on different days
protected enamine 6a in six steps from commercially available provided similar yields for 6b (88–93% yield).
3-Butyn-1-ol (Fig. 2). Our initial attempt to synthesize the
enamine 6a was successful on the 100–150 mg scale, with yields
of 90–92% for the final step, consistent with those reported by
Li and co-workers, and an overall yield of 34–39% over six steps.
However, five separate attempts to scale up the preparation of
enamine 6a to 500 mg scale quantities resulted in significant
loss of material in the final copper-mediated coupling step, with
yields of 45–53%. Our attempts to improve the yield for the
Scheme 1: Synthesis of N-tosyl protected enamines 6a–d in multigram-scale
quantities using inexpensive and commercially available reagents.
copper catalysed coupling by optimizing the reaction duration,
temperature, or amount of catalyst did not improve the yield.
An extensive survey of the literature for alternative, gram-scale
syntheses of molecules like cyclic enamines 1 and 2 did not yield
useful synthetic precedents, so we devised the strategy
described in this report for the large-scale synthesis of
Buoyed by the initial success of this strategy to prepare
gram-scale quantities of enamine 6b in high-yields, we tested its
generality in the preparation of cyclic enamines containing
varying ring sizes (Scheme 1, compounds 6a–d). We synthesized
N,O-bistosylated compounds 5a and 5c starting from the
relatively inexpensive and commercially available 2-
azetidinecarboxylic acid or piperidine-2-methanol. For 5a, we
molecules similar to protected enamine 6a
.
prepared the N-tosyl protected
3 in 95.2% yield (Scheme 1,
ESI†). Subsequent reduction of the carboxylic acid group using
NaBH4 afforded the alcohol 4a in 97% yield. Compound 4a was
then N,O-bistosylated using TsCl to obtain 5a in 92% yield. N,O-
bistosylated 5c was obtained in one step using TsCl in 99.6%
yield. Subsequent elimination of the tosylate under the above-
mentioned conditions afforded the enamines 6a and 6c in 90%
(30 g scale) and 85% (18.0 g scale) yields respectively. Further,
Fig 2. Initial attempts to synthesize the protected enamine 6a in six steps were high
yielding only at 100–150 mg scale. The reaction yields were significantly reduced upon
scale up.
we also tested this strategy for the seven-membered ring 4d
.
In our search for suitable starting materials for these
transformations, we were intrigued by the possibility of
leveraging economical, alcohol-based substrates for alkene
N,O-bis-tosylation afforded 5d in 77% yield, which, upon
subsequent elimination, afforded enamine 6d in 79% yield.
With an inexpensive two to four-step synthesis for
enamines 6a–d in hand, we challenged the scope of this
strategy by testing the effect of alternative N-protecting groups
on the stability and yields of these N-protected enamines.
Importantly, the strength of the electron withdrawing nature of
the N-protecting group has been shown to greatly affect the
synthetic yields of enamines in previously-described methods10.
For example, when the enamine 6a was synthesized by Li and
co-workers using their Ullman-type coupling strategy (Fig. 2) the
yield for enamine formation reduced by half when Boc was used
for N-protection instead of tosyl10. Additionally, most of the
reported procedures for cyclic enamine syntheses have used
only tosyl-protection of the amine7,10–13,28, so the stability and
yields for the formation of N-protected enamines with other
production via
a straightforward elimination reaction.
Surveying the literature for N-heterocyclic rings with a
methylene alcohol on the α-position, we identified prolinol, a
commercially available inexpensive alcohol analogue of the
amino acid proline, as an ideal substrate for our initial attempts
to incorporate the alkene functionalization to form protected
enamine 6b (Scheme 1). Importantly, formation of an alkene
adjacent to a nitrogen atom can lead to an imine rearrangement
product, which can be suppressed by protecting the nitrogen
with an electron withdrawing protecting group. Thus, we chose
to begin with the electron withdrawing tosyl group for nitrogen
protection prior to establishing the applicability of the approach
to more conventional, and less electron withdrawing, nitrogen
protecting groups.
Exploration of this synthetic route began with the synthesis
of the N,O-bistosylated prolinol 5b (Scheme 1) in one step from
prolinol using TsCl in 94.4% yield (1.0 g scale with respect to
prolinol). As expected for this reaction, the yield was consistent
upon scaling up to the multigram scale (13.0 g scale with respect
to prolinol, 91.7% yield). Next, we performed the elimination to
obtain N-tosyl protected enamine 6b using in situ activation
with NaI in presence of the bulky base DBU under refluxing
conditions, a method previously developed by Maier and co-
strategies are unknown.
Scheme 2: Use of alternative N-protecting groups for synthesis of enamines 6e–h
in multigram-scale quantities.
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 5
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
Using the same reaction conditions employed for the N-
COMMUNICATION
We employed the cyclic enamines in the preparation of 4-
View Article Online
tosyl protected compound 5a–d, we attempted eliminations of azaspiro[2.n]alkanes
by insertion ofDOaI: 10d.1i0b3r9o/mC7oOcBa0r2b6e5n9eE
activated alcohol analogues of N-boc, N-trifluoroacetamide, N- generated using bromoform and NaOH (Scheme 4). Both the N-
mesyl, and N-benzoyl prolinols 5e–h (Scheme 2). N-boc, N- tosylated enamines 6a–c and N-boc enamine 6e produced the
trifluoroacetamide, and N-mesyl tosylated prolinols (Scheme 2, corresponding dibromo-4-azaspiro[2.n]alkanes 7a–d in 49%,
ESI†) afforded the Boc protected enamine 6e and the volatile 65.2%, 40% and 37.6% yields respectively, and boc deprotection
enamines 6f and 6g in 71 % (15 g scale), 45% (5 g scale), and of 7d proceeded in excellent yield (99%) to the free amine
55% (2.5 g) yields respectively, whereas the Bz-protected cyclopropane
activated alcohol 5h was not stable to the elimination report of dibromo-4-azaspiro[2.n]alkanes . Furthermore, 7a
conditions and produced no observable enamine product 6h adds another entry to the short list of 4-azaspiro[2.n]alkanes
Further, tosylation of trityl protected prolinol to obtain N-trityl with a spiro[2.3]hexane spirocyclic system.
9. To the best of our knowledge, this is the first
.
enamine was unsuccessful, possibly due to the steric hindrance
We also explored cyclic enamine conversion to a mixed
provided by the bulky trityl group. Importantly, the reaction’s bromo-fluoro-cyclopropane. As expected, the tosylated
compatibility with deprotection conditions for removal of enamine 6b formed the desired 1-bromo-1-fluoro-4-
protecting groups that are gentler than Ts provides a significant azaspiro[2.4]heptane 8b in 78% yield. However, subjecting the
advantage over strategies that require Ts protection, especially weaker electron withdrawing N-boc-protected enamine 6e to
when using these enamines as precursors for sensitive or base-mediated bromofluorocarbene insertion resulted in a
complex targets.
rearrangement-elimination to generate 10. Ultimately, having
8b, and 9)
We next explored the enamine formation’s compatibility access to the halogen-containing synthons (7a–d
,
with substitutions around the pyrrolidine ring (Scheme 3). opens the door for further functionalization with these N-
Towards this, we synthesized the tosylated alcohol analogues of heterocycles.
N-boc benzylether pyrrolidine 5i and N-boc difluoropyrrolidine
5j from the corresponding alcohols in 40% and 78.3% yields
respectively. Subsequent elimination produced the enamines
6i–j in 75% and 87.5 % yields. Compatibility of this NaI/DBU-
mediated elimination with heteroatom substitutions at
different ring position should be straightforward to extend to
other ring sizes and substitutions for generating a diverse array
of enamines.
Scheme 4: Cyclic enamines 6a-d provide access to 4-azaspiro[2.n]alkane synthons.
In addition to the dibromocyclopropanes 7a–d
, the
corresponding monobromocyclopropanes present useful
substrates for additional functionalization of the scaffold.
Accordingly, we explored the conversion of dibromo precursors
to the corresponding monobromo cyclopropanes. We
evaluated several strategies for the reduction of
dibromocyclopropane 7b to 11b (Table S1, ESI†). Importantly,
this reaction required complete consumption of the dibromo
starting material for purification of the monobromo product as
they have the same retention factor on silica gel in all solvent
systems tested. The best strategy employed lithium-halogen
exchange using n-BuLi at -85 °C and subsequent quenching with
a proton source like ammonium chloride to produce 11b in 60%
yield (Scheme 5). These conditions applied to compound 7a
produced the azetidine analogue bromo-4-azaspiro[2,3]hexane
11a in 49% yield.
Scheme 3: Tolerance towards ring substitutions on the synthesis of cyclic
enamines 6i–j
.
With access to multigram-scale quantities of desired
enamines, we were interested in exploring the conversion of
cyclic enamines to 3-N spirocyclopropanes (i.e., 4-
azaspiro[2.n]alkanes) via dibromocarbene addition, and then,
potentially,
to
3-N
spirocyclopropenes
(i.e.,
4-
azaspiro[2.n]alkenes). As described above, 4-azaspiro[2.n]alkyl
systems have utility as enzyme inhibitors17,18, interesting
monomers for poly-cyclopropane-based materials19–21, and
reagents in the biorthogonal cyclopropene-tetrazine22–24
ligation. To the best of our knowledge, there are only a handful
of reports describing the synthesis of 4-azaspiro[2.n]alkanes.
Most of these strategies utilized carbenoid insertion on lactams
or cyanoesters using a combination of Grignard reagents and
titanium catalysts30–33. Others utilized the cyclization reaction
between an amine and nitrile present on a cyclopropane ring
using a strong base17, carbenoid insertion on enamines flanked
by aromatic rings using zinc catalyst34, or palladium-catalysed
alkene and isocyanate reaction35.
Scheme 5: Spirocyclic 3-N dibromocyclopropanes can be converted to
corresponding monobromo versions with added functionalization.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 5
COMMUNICATION
Journal Name
Finally, we were interested in determining the ability of Spectrometry resources and analyses, and Francis Picart for
View Article Online
DOI: 10.1039/C7OB02659E
these monobromo spirocyclopropanes to produce the NMR analyses. We also thank John Mannone and Frank
corresponding, highly-strained 4-azaspiro[2,n]alkene. We Camarda for preparation of synthetic intermediates. This work
subjected 11b to potassium tert-butoxide in an effort to achieve was supported by a grant to S.T.L. from the National Science
the elimination, but instead produced a complex mixture of Foundation CHE1451366.
products that could not be identified. Subjecting the spirocyclic
dibromo-4-azaspiro[2,4]heptane 7b to the similar elimination
resulted in the alkyne rearrangement product, dihydropyrrole
Notes and references
derivative S2 (Scheme 9, ESI†). This ring opening rearrangement
is thought to proceed via an electro deficient intermediate36, so
we attempted the elimination with electron withdrawing fluoro
substitution on the cyclopropene ring 8b only to produce the
alkyne rearrangement product S2 again. We further increased
the electron withdrawing nature of the substitution by creating
the difluoro substituted spirocyclopropane using enamine 6j
(Scheme 3). However, subjecting the enamine 6j to carbene
addition produced the fluoro-eliminated pyrrole S1 (Scheme 5,
ESI†) as the major product. Previous reports have observed that
addition of alkyl groups can impart stability37 to cyclopropenes
1
V. G. Granik, V. A. Makarov and C. Párkányi, in Advances in
Heterocyclic Chemistry, Academic Press, 1998, vol. 72, pp.
283–359.
F. Guo, M. D. Clift and R. J. Thomson, European J. Org.
Chem., 2012, 2012, 4881–4896.
S. Mukherjee, J. W. Yang, S. Hoffmann and B. List, Chem.
Rev., 2007, 107, 5471–5569.
G. Stork, A. Brizzolara, H. Landesman, J. Szmuszkovicz and
R. Terrell, J. Am. Chem. Soc., 1963, 85, 207–222.
J.-H. Xie, S.-F. Zhu and Q.-L. Zhou, Chem. Rev., 2011, 111,
1713–1760.
2
3
4
5
6
7
8
in solution, so we attempted the elimination with
a
R. Borrmann, R. M. Koenigs, J. Zoller and M. Rueping,
Synthesis (Stuttg)., 2017, 49, 310–318.
monobromocyclopropane bearing a bulky tertiary alcohol
group 12, which resulted in the formation of the allene
rearrangement product, tetrahydropyrrole derivative S3
(Scheme 9, ESI†). Finally, we explored elimination with N-
trifluoroacetate 6f, a substrate bearing more heavily electron
withdrawing N-protecting group. In this case, the reaction
produced a crude reaction mixture with a characteristic
cyclopropene peak in the 1H NMR spectrum at 6.4 ppm.
However, attempts at purification via Flash chromatography
resulted in isolation of only the alkyne rearrangement product.
These results suggest that forming a 4-azaspiro[2.n]alkene
system requires the addition of stronger electron withdrawing
components to promote long-term stability, which may be
accomplished by appending electron withdrawing groups to
positions closer to the quaternary carbon that is expected to
form the offending electron deficient intermediate.
V. Chintalapudi, E. A. Galvin, R. L. Greenaway and E. A.
Anderson, Chem. Commun., 2016, 52, 693–696.
T.-Y. Lin, C.-Z. Zhu, P. Zhang, Y. Wang, H.-H. Wu, J.-J. Feng
and J. Zhang, Angew. Chemie Int. Ed., 2016, 55, 10844–
10848.
A. Cordeiro, E. Quesada, M.-C. Bonache, S. Velázquez, M.-J.
Camarasa and A. San-Félix, J. Org. Chem., 2006, 71, 7224–
7235.
9
10
11
H. Lu and C. Li, Org. Lett., 2006, 8, 5365–5367.
H. Lu, X. Yuan, S. Zhu, C. Sun and C. Li, J. Org. Chem., 2008,
73, 8665–8668.
12
C. D. Campbell, R. L. Greenaway, O. T. Holton, P. R. Walker,
H. A. Chapman, C. A. Russell, G. Carr, A. L. Thomson and E.
A. Anderson, Chem. - A Eur. J., 2015, 21, 12627–12639.
I. R. Hazelden, X. Ma, T. Langer and J. F. Bower, Angew.
Chemie - Int. Ed., 2016, 55, 11198–11202.
L. B. Wolf, K. C. M. F. Tjen, H. T. Ten Brink, R. H. Blaauw, H.
Hiemstra, H. E. Schoemaker and F. P. J. T. Rutjes, Adv.
Synth. Catal., 2002, 344, 70–83.
13
14
Conclusions
We have devised an inexpensive, catalyst-free, multigram-scale
and high yielding synthesis of protected cyclic enamines with 15
varying ring sizes. Additionally, we described a route for the
H. Jiang, J. He, T. Liu and J.-Q. Yu, J. Am. Chem. Soc., 2016,
138, 2055–2059.
preparation
of
pharmacologically
relevant
4- 16
N. De Kimpe and M. Boeykens, J. Org. Chem., 1994, 59,
5189–5191.
azaspiro[2.n]alkanes with an azetidine ring. This route produced
novel dihalo and mono-halo 4-azaspiro[2.n]alkanes, which 17
provide possibilities for further functionalization using
established halide chemistry.
M. G. Brasca, C. Albanese, R. Amici, D. Ballinari, L. Corti, V.
Croci, D. Fancelli, F. Fiorentini, M. Nesi, P. Orsini, F. Orzi, W.
Pastori, E. Perrone, E. Pesenti, P. Pevarello, F. Riccardi-
Sirtori, F. Roletto, P. Roussel, M. Varasi, A. Vulpetti and C.
Mercurio, ChemMedChem, 2007, 2, 841–852.
US 20100093727, 2009.
Conflicts of interest
18
19
20
21
22
B. R. Elling, J. K. Su and Y. Xia, Chem. Commun., 2016, 52,
9097–9100.
R. Singh, C. Czekelius and R. R. Schrock, Macromolecules,
2006, 39, 1316–1317.
C. D. DeBoer, J. Polym. Sci. Polym. Lett. Ed., 1973, 11, 25–
27.
J. M. J. M. Ravasco, C. Monteiro and A. Trindade, Org.
There are no conflicts to declare.
Acknowledgements
We thank Dr. Bela Ruzsicska and the Stony Brook University
Institute for Chemical Biology and Drug Discovery for Mass
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 5
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
COMMUNICATION
Chem. Front., , DOI:10.1039/C7QO00054E.
View Article Online
DOI: 10.1039/C7OB02659E
23
D. N. Kamber, L. A. Nazarova, Y. Liang, S. A. Lopez, D. M.
Patterson, H.-W. Shih, K. N. Houk and J. A. Prescher, J. Am.
Chem. Soc., 2013, 135, 13680–13683.
24
25
26
27
28
29
30
31
32
J. Yang, Y. Liang, J. Šečkutė, K. N. Houk and N. K. Devaraj,
Chemistry, 2014, 20, 3365–3375.
K. Abbaspour Tehrani and N. De Kimpe, Tetrahedron Lett.,
2000, 41, 1975–1978.
S. Mangelinckx, M. Boeykens and N. De Kimpe, Synlett,
2008, 2008, 1394–1398.
P. Sulmon, N. De Kimpe and N. Schamp, J. Org. Chem.,
1988, 53, 4462–4465.
R. L. Greenaway, C. D. Campbell, H. A. Chapman and E. A.
Anderson, Adv. Synth. Catal., 2012, 354, 3187–3194.
P. Phukan, M. Bauer and M. E. Maier, Synthesis (Stuttg).,
2003, 2003, 1324–1328.
K.-W. Lin, S. Yan, I.-L. Hsieh and T.-H. Yan, Org. Lett., 2006,
8, 2265–2267.
C. Madelaine, Y. Six and O. Buriez, Angew. Chemie Int. Ed.,
2007, 46, 8046–8049.
C. Laroche, D. Harakat, P. Bertus and J. Szymoniak, Org.
Biomol. Chem., 2005, 3, 3482.
33
34
P. Bertus and J. Szymoniak, Synlett, 2003, 0265–0267.
M. Fardis, H. Jin, S. Jabri, R. Z. Cai, M. Mish, M. Tsiang and
C. U. Kim, Bioorg. Med. Chem. Lett., 2006, 16, 4031–4035.
R. Shintani, T. Tsuji, S. Park and T. Hayashi, J. Am. Chem.
Soc., 2010, 132, 7508–7513.
35
36
37
R. Walsh, Chem. Soc. Rev., 2005, 34, 714.
J. Yang, J. Šečkutė, C. M. Cole and N. K. Devaraj, Angew.
Chemie Int. Ed., 2012, 51, 7476–7479.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins