Internal Nucleophilic Catalyst Mediated Cyclisation/Ring Expansion Cascades for the Synthesis of Medium-Sized Lactones and Lactams

Article abstract of DOI:10.1002/anie.201907206

A strategy for the synthesis of medium-sized lactones and lactams from linear precursors is described in which an amine acts as an internal nucleophilic catalyst to facilitate a novel cyclisation/ring expansion cascade sequence. This method obviates the n

Full text of DOI:10.1002/anie.201907206

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Accepted Article
Title: Internal nucleophilic catalyst mediated cyclisation/ring expansion
cascades for the synthesis of medium-sized lactones and lactams
Authors: Aggie Lawer, James A Rossi-Ashton, Thomas C Stephens,
Bradley J Challis, Ryan G Epton, Jason M Lynam, and
William Paul Unsworth
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201907206
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10.1002/anie.201907206
Angewandte Chemie International Edition
RESEARCH ARTICLE
Internal nucleophilic catalyst mediated cyclisation/ring expansion
cascades for the synthesis of medium-sized lactones and lactams
Aggie Lawer, James A. Rossi-Ashton†, Thomas C. Stephens†, Bradley J. Challis, Ryan G. Epton,
Jason M. Lynam and William P. Unsworth*
Abstract: A strategy for the synthesis of medium-sized lactones and
lactams from linear precursors is described in which an amine acts as
an internal nucleophilic catalyst to facilitate a novel cyclisation/ring
expansion cascade sequence. This method obviates the need to use
high-dilution conditions usually associated with medium-ring
cyclisation protocols, as the reactions operate exclusively via
kinetically favourable ‘normal’ sized cyclic transition states. This same
feature also enables biaryl-containing medium-sized rings to be
prepared with complete atroposelectivity via point-to-axial chirality
transfer.
reactions and obviate the need to use impractical high
dilution/pseudo high dilution conditions that are common in typical
medium-sized ring and macrocycle cyclisation reactions.10
The realisation of this strategy is reported herein. Thus, a
method based on the formation (6 → 7) and spontaneous
expansion (7 → 8) of reactive acyl-ammonium ion intermediates
is described that enables nitrogen-containing medium-sized rings
to be prepared from simple linear precursors (Scheme 1d). Using
these cascade reactions, we show that a wide range of
functionalised medium-sized lactones and lactams (40 examples,
31–100% yield) can be prepared under mild, practical reaction
conditions. Furthermore, in suitably designed cases, biaryl
containing medium-sized rings can also be formed with complete
atroposelectively via a new type of point-to-axial chirality transfer
reaction.11
Introduction
Medium-sized rings have much promise in medicinal chemistry1,2
but are difficult to prepare via conventional cyclisation methods.3
Destabilising transannular interactions and loss of entropy during
cyclisation mean that medium ring cyclisation reactions of the type
1 → 2 (Scheme 1a) typically suffer from competing intermolecular
reactions or other side processes.4,5 Synthetic routes to access
medium-sized rings that avoid end-to-end cyclisation are
therefore desirable, and ring expansion reactions have proven to
be especially useful in this context.6,7
In this manuscript, a new process is described by which
medium-sized rings can be accessed directly from simple linear
precursors. The avoidance of medium-sized cyclic transitions
states is key to our design principle, in which we use a
nucleophilic catalyst built into the linear starting material to
promote a cyclisation/ring expansion cascade. For example, while
the direct synthesis of 10-membered ring 2 from a hypothetical
linear precursor 1 (Scheme 1a) is usually a slow/difficult process,4
we reasoned that similar medium-sized ring frameworks would be
more effectively synthesised from alternative linear precursors of
the form 3, in which a reactive motif ‘Z’ built into the linear starting
material mediates a cyclisation/ring expansion cascade (3 → 4
→ 5, Scheme 1b).8,9 By designing the reactions so that both
discrete cyclisation reactions proceed via ‘normal’-sized cyclic
transition states (especially if they are 5- or 6-membered), it is
reasonable to expect that a kinetically more favourable reaction
course will be followed, as illustrated in the stylised reaction
coordinate for these two scenarios depicted in Scheme 1c. By
allowing this lower energy pathway to operate, medium-sized ring
transition states can be avoided, which should help to reduce side
Scheme 1. a) Direct medium ring cyclisation; b) cyclisation/ring expansion; c)
hypothetical reaction coordinates; d) This work - Internal nucleophilic catalyst
mediated cyclisation/ring expansion cascade reactions.
Results and Discussion
[a]
Dr. A. Lawer, J. A. Rossi-Ashton, T. C. Stephens, B. J. Challis, R. G.
Epton, Dr Jason M. Lynam, Dr. W. P. Unsworth*
University of York, York, YO10 5DD (UK)
We started by examining pyridine-containing linear precursor 9a
[see Supporting Information (SI) for its synthesis]. The plan was
that activation of carboxylic acid 9a would initiate a cyclisation (9a
→ 10a) and ring expansion (10a → 11a) cascade. Thus,
carboxylic acid 9a was treated with T3P (propanephosphonic acid
E-mail: william.unsworth@york.ac.uk
†These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/anie.201907206
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RESEARCH ARTICLE
anhydride) and NEt(i-Pr)2 in chloroform12 and, after stirring for just
30 min at RT, the desired 10-membered lactone 11a was formed
and isolated in 90% yield. Of further interest, 11a was formed
exclusively as the single atropisomer shown, with the structural
and stereochemical assignment supported by X-ray
crystallographic data13 (Scheme 2; the atroposelectivity aspects
of this reaction, including data that confirms that
atropoisomerisation by free rotation is not an energetically
feasible process for this system, are discussed later in the
manuscript).
Scheme 3. a) Formation of 20-membered head-to-tail dimer 12b; b)
cyclisation/ring expansion cascade synthesis of 14a and failed synthesis of 15b.
The scope of the reaction is broad and is summarised in Scheme
4. 10-Membered lactone 11b was formed without problem using
the standard method, whilst the homologous 11-membered
lactone 11c was also prepared, albeit in lower yield, which is likely
to be a result of this example proceeding via a less favourable 7-
membered transition state. Conversely, the synthesis of the
smaller 9-membered product 11d failed, presumably due to there
being too much strain in the sp2 rich scaffold. Next, a range of
secondary alcohol-based systems were then tested, and the
reactions worked well in all cases; functionality at various
positions of the starting material, protected amine handles,
diazine and DMAP-like tethers and tertiary alcohols all being well-
tolerated, with lactones 11e–p isolated in consistently high yields.
The same strategy can also be used to make medium-sized
lactams using unprotected amine-based nucleophiles. Using the
standard protocol, lactam 11q was formed in 50% yield;
competing intermolecular amide bond-formation likely accounts
for the decreased yield, which is supported by the observation that
a significantly higher yield was obtained when the same reaction
was performed at increased dilution (78%). Other secondary
amine-based systems performed similarly under the standard
undiluted conditions (11r–v). Pleasingly, aniline-based lactam
11u was formed in quantitative yield; presumably, this system did
not suffer from competing intermolecular reaction in view of the
lower nucleophilicity of the aniline nucleophile relative to aliphatic
amines. Finally, we found that primary amine-derived lactam 11v
could be formed in 52% yield using the standard conditions.14
Medium-sized lactones 14a–m were also prepared from
aliphatic tertiary amine-containing hydroxy acids 13a–m. The
yields were generally good across this series, with broad scope
demonstrated; it is especially noteworthy that the cascade
reactions can be used to prepare lactones right across the
‘medium-sized’ ring range, with 8–11-membered lactones all
being prepared using the standard protocol. The utility of the
cyclisation/ring expansion cascade has therefore been well
demonstrated by the synthesis of 34 medium-sized lactones or
lactams using a simple and mild synthetic method, without
requiring high dilution conditions.
Scheme 2. Cyclisation/ring expansion cascade synthesis of 11a.
Given the known challenges of forming 10-membered ring
lactones,3a,4 the efficiency of this reaction was highly encouraging,
especially as it was performed under mild conditions at standard
dilution. Nonetheless, to discount the possibility that this is simply
an unusually efficient 10-membered ring lactonisation, hydroxy
acid 12a (analogous to 9a but lacking the pyridine nitrogen) was
reacted under the same conditions used to make 11a (with a 5 h
reaction time, Scheme 3a). As expected, none of the analogous
10-membered lactone was formed, with dimeric 20-membered
lactone 12b the only tractable product isolated from this reaction,
corroborating the importance of the pyridine nitrogen in mediating
the synthesis of 11a. Furthermore, our novel cyclisation/ring
expansion cascade also works well using an aliphatic tertiary
amine as the internal nucleophilic catalyst in place of the pyridine;
thus, linear hydroxy acid 13a was converted into 9-membered
lactone 14a in 76% yield (T3P, 30 min, RT), whilst an intractable
mixture of products resulted when the analogous nitrogen-free
hydroxy acid 15a was reacted under the same conditions
(Scheme 3b).
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10.1002/anie.201907206
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Scheme 4. Cyclisation/ring expansion cascade reactions of pyridine and tertiary amine containing hydroxy acids and amino acids.
An important feature of these reactions is the observation that in
all examples containing two stereochemical units, the products
were exclusively formed as single diastereoisomers (11a, 11e–o
and 11q–v; all contain a point stereogenic center and an
unsymmetrical biaryl unit with axial chirality). Thus, the point
chirality of the secondary nucleophile is able to fully control the
formed atropisomer in the medium-sized cyclic biaryl product in
all of these cases, via what is to the best of our knowledge, an
unprecedented type of point-to-axial chirality transfer.11
Atropisomerism can play a vital role in mediating ligand-target
interactions in biology,15 but while synthetic methods able to
impart exquisite levels of control over stereogenic centres on a
single atom (usually referred to as point chirality) are very well
established, methods designed to control other chirality elements
(e.g. planar, axial and helical chirality)16 are less well developed.17
Atroposelective methods capable of delivering medium-sized
rings or macrocycles are particularly rare,18 which encouraged us
to examine the atroposelectivity of our cascade reactions in more
detail.
macrocyclic scaffolds containing similar biaryl motifs have also
been shown to exist as stable atropisomers at room
temperature,19,20 nonetheless, for additional support, we modelled
the energy required to rotate about this bond using DFT (Scheme
5). Starting from the crystal structure of 11a, this was optimised at
the BP86/SV(P) level and scans were performed whilst rotating
the biaryl dihedral angle in both directions, reoptimising the
structure at each step. No minima were found from these
calculations and the energies calculated increased steeply to give
values that can be considered chemically inaccessible, strongly
suggesting that the biaryl unit is indeed unable to rotate freely
(see SI for tabulated data).
First, we confirmed that the biaryl unit in the medium-sized
ring products is unable to undergo free rotation. Based on its
geometry and ring size, we predicted that the sp2-rich medium-
ring scaffold 11a would be relatively rigid and that rotation about
the biaryl C–C single bond is unlikely to be kinetically accessible;
indeed, to the best of our knowledge, compound 11a is the
smallest ring system based on an unbridged 1,2-disubsituted and
1,3-disubstituted biaryl framework in the literature. Related larger
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10.1002/anie.201907206
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RESEARCH ARTICLE
supported by DFT calculations of the ground state energies of 11a
and 11a’; thus, the Gibbs free energy of the observed and
unobserved atropisomers 11a and 11a’ were calculated at the
M06-2X/6-311G* level of theory (see SI for full details)22 and the
observed isomer 11a was calculated to be 22 kJ/mol lower in free
energy than the unobserved isomer 11a’. Such a large energy
difference would provide a clear driving force for the selective
formation of 11a if the reactions are reversable.
The atroposelectivity was also probed experimentally
(Scheme 7). Thus, substrates with the methyl substituent
transposed α- to both the phenyl and pyridyl rings were prepared
and tested in the cyclisation/ring expansion cascade (11w and
11x). Both reactions worked very well in terms of conversion and
yield, but the atroposelectivity was low compared with 11a. This
suggests that the position α- to the nucleophile is special in terms
of its ability to control the biaryl stereochemistry. Therefore, we
next examined the steric influence of this position using
unsymmetrical
tertiary
alcohol
nucleophiles
(11y–zb).
Scheme 5. Calculated BP86/SV(P) electronic energies for 11a with a SCRF
solvent correction in CHCl3. Energies given are for geometry optimised
structures at fixed biaryl dihedral angles.
Interestingly, a clear trend of increasing atroposelectivity was
observed as the alcohol substituents become more different in
size; low atroposelectivity was observed for 11y (methyl vs. allyl),
modest atroposelectivity for 11z (methyl vs. phenyl) and complete
atroposelectivity was restored for 11za and 11zb (methyl vs. tert-
butyl).
One hypothesis for the excellent stereoselectivity, which is
depicted in Scheme 6 for prototypical substrate 11a, is a kinetic
argument that hinges on the stereochemistry-determining step
operating via a 6-membered transition state. The observed
stereochemical outcome is consistent with the alcohol attacking
the prochiral intermediate N-acyl ammonium ion with the methyl
group in a pseudo-equatorial orientation in a chair/boat-like
conformation (c.f. A → B, Scheme 6a). Conversely, to generate
the unobserved isomer 11a’, attack on the opposite face of the N-
acyl ammonium ion is required, which necessitates that the
methyl group be oriented in a pseudo-axial conformation, the
transition state for which (C → D) is likely to be higher in energy.21
Scheme 7. Cyclisation/ring expansion cascade reactions of pyridine containing
point stereogenic centers and the calculated free energy difference between the
two atropoisomeric forms.
This atroposelectivity trend is consistent with the kinetic argument
outlined in Scheme 6a (with the large substituent presumably
adopting the pseudo-equatorial conformation). However, the
thermodynamic model cannot be ruled out either, especially as
DFT calculations of the relative free energy of the two possible
atropisomers in each case correlate well with the observed
atroposelectivity; a large difference in free energy was calculated
for the atroposelective examples (11a, 11za, 11zb, ΔG = 22–26
kJ/mol) whereas the least selective examples can be considered
Scheme 6. Proposed atroposelectivity model: a) A kinetic model based on
diastereoselective attack into prochiral N-acyliminium ion (A → B); b) a
thermodynamic model based on reversible ring expansion/ring contraction.
An alternative explanation is that the reactions are reversible and
under thermodynamic control (Scheme 6b). This model is
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4-Methyl-4,5-dihydro-6,10-(azeno)benzo[d][1]oxacyclododecin-
2(1H)-one (11a) To a stirring solution of 2-(2-(6-(2-hydroxypropyl)pyridin-
2-yl)phenyl)acetic acid 9a (44.0 mg, 0.163 mmol) in chloroform (3 mL),
was added diisopropylethylamine (50.0 μL, 0.302 mmol), followed by the
addition of T3P (78.0 mg, 0.284 mmol, 156 mg of a 50% solution in ethyl
acetate). Upon the addition of T3P, the solution rapidly changed from a
colourless to an orange solution. After stirring for 30 mins at r.t., the
solution was concentrated and purified via flash column chromatography
(SiO2, 1:1 ethyl acetate:hexane) to afford the title compound 11a as a pale
yellow solid (37 mg, 90%); Rf 0.45 (3:7 ethyl acetate:hexane); m.p.
110−114 °C; νmax/cm-1 (thin film) 3063, 2973, 2928, 1720, 1586, 1575,
1450, 1422; δH (400 MHz, CDCl3) 7.80–7.78 (1H, m, ArH), 7.69 (1H, t, J =
7.6 Hz, ArH), 7.54 (1H, d, J = 7.6 Hz, ArH), 7.43–7.40 (3H, m, ArH), 7.04
(1H, dd, J = 7.6, 0.5 Hz, ArH), 5.64–5.55 (1H, m, OCH), 3.65 (1H, d, J =
14.5 Hz, CHHCO), 3.54 (1H, d, J = 14.5 Hz, CHHCO), 3.12–3.00 (2H, m,
NCCH2), 1.50 (3H, d, J = 6.4 Hz, CH3); δC (100 MHz, CDCl3) 174.3 (CO),
155.6 (ArC), 154.9 (ArC), 137.2 (ArC), 137.0 (ArC), 135.1 (ArC), 133.9
(ArC), 129.2 (ArC), 127.9 (ArC), 127.7 (ArC), 121.0 (ArC), 118.4 (ArC),
70.4 (OCH), 44.4 (CO-CH2), 40.4 (NCCH2), 21.4 (CH3); HRMS (ESI): calcd.
for C16H16NO2 254.1176. Found: [MH]+, 254.1173 (1.0 ppm error).
isoenergetic at this level of theory (11x, 11y, ΔG = 2 kJ/mol). This
arguably favours the thermodynamic model, but caution should
be exercised when interpreting these results, as the calculated
difference in free energies of the products may simply serve as
an approximation for the difference in free energy of the
analogous transition states that lead to their formation (especially
given that the products and transitions states might be expected
to have reasonably similar geometries). Indeed, it may be that
either/both models operate in different examples. Ascertaining
which operates in any given reaction system is therefore difficult,
however, what is clear is that for high atroposelectivity to be
achieved synthetically, the key is having either a secondary
nucleophile, or an unsymmetrical tertiary nucleophile with a
significant size difference between its substituents.
Finally, since the point-to-axial chirality transfer is
diastereoselective process, it is straightforward to prepare
enantioenriched biaryl-products simply by using an
a
enantioenriched nucleophile. Thus, as a simple proof-of-concept,
enantioenriched (≈71% ee) lactam 11v was formed in 51% overall
yield from 16 (72% de) following acidic cleavage of the Ellman’s
auxiliary, ester hydrolysis and cyclisation/expansion in the usual
way (Scheme 8).23
Acknowledgements
The authors thank the EPSRC (EP/P029795/1, A.L.), the
Leverhulme Trust (for an Early Career Fellowship, ECF-2015-013,
for W.P.U.) and the University of York (T.C.S., J.A.R., R.G.E.,
W.P.U.) for financial support. We also grateful for the provision of
an Eleanor Dodson Fellowship (to W.P.U.) by the Department of
Chemistry, University of York, and the EPSRC for a contribution
to the DTA studentships of T.C.S. (1792616). Finally, thanks to
Dr. Adrian. C. Whitwood (University of York) for X-ray
crystallography.
Scheme 8. Synthesis of enantioenriched planar chiral lactam 11v.
Keywords: medium-sized rings • ring expansion • atropisomers•
Conclusion
pyridines • axial chirality
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In summary, a cyclisation/ring expansion cascade reaction
protocol has been developed for the synthesis of 10-membered
cyclic biaryl systems from simple pyridyl-based linear carboxylic
acids. The novel strategy simultaneously addresses two
important synthetic challenges: 1) achieving efficient and reliable
end-to-end cyclisations of medium-sized rings from linear
precursors; 2) effectively controlling atroposelectivity in the
resulting cyclic products in biayrl-based systems. The
cyclisation/ring expansion cascade strategy is also applicable to
simple tertiary amine containing hydroxy acids to make 8–11-
membered lactones, which greatly extends its scope and potential
utility. Thus, the synthetic methods reported should facilitate the
practical and selective synthesis of biologically important
medium-sized rings, whilst a new strategy for generating planar
chiral medium rigs via point-to-axial chirality transfer is also
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Experimental Section
Full experimental details can characterisation data are included in the SI.
An exemplar synthetic procedure for the cyclisation/ring expansion
cascade is provided for the synthesis of 10-membered lactone 11a.
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RESEARCH ARTICLE
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Unsworth, Synlett 2019, DOI: 10.1055/s-0037-1611500
For rare examples of conceptually related ring expansion cascade
processes, see: (a) H. Wu, W. Zi, G. Li, H. Lu, F. D. Toste, Angew. Chem.
Int. Ed., 2015, 54, 8529; (b) B. Zhou, L. Li, X.-Q. Zhu, J.-Z. Yan, Y.-L.
Guo, L.-W. Ye, Angew. Chem. Int. Ed., 2017, 56, 4015. For ring
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[19] See reference 18b and: P. S. Baran, N. Z. Burns, J. Am. Chem. Soc.
2006, 128, 3908.
For important studies on acyl transfer processes that operate via
transient covalent catalysis and bear analogy with the new reactions
described in this manuscript, see: (a) D. S. Kemp, Biopolymers 1981, 20,
1793; (b) D. S. Kemp, D. J. Kerkman, S.-L. Leung, G. Hanson, J. Org.
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(d) J. P. Tam, C. T. T. Wong, J. Biol. Chem. 2012, 287, 27020.
[20] For the rotation of 1,3-disubstittued pyridines, see: I. R. Lahoz, A.
Navarro-Vázquez, A. L. Llamas-Saiz, J. L. Alonso-Gómez, M. M. Cid,
Chem. Eur. J. 2012, 18, 13836.
[21] We attempted to corroborate this model using DFT calculations (see SI
for full details), but unfortunately were unable to convincingly find
[10] See reference 2 and: (a) Y. H. Lau, P. de Andrade, Y. Wu, D. R. Spring,
Chem. Soc. Rev. 2015, 44, 91; (b) A. P. Treder, J. L. Hickey, M.-C. J.
Tremblay, S. Zaretsky, C. C. G. Scully, J. Mancuso, A. Doucet, A. K.
Yudin, E. Marsault, Chem. Eur. J. 2015, 21, 9249.
transition state structures for either scenario, which may be a
consequence of these fast reactions operating via very shallow
transitions states. We are therefore unable to comment in a quantitative
fashion about kinetic control in these reactions.
[11] The terminology ‘point-to-axial’ chirality transfer refers to the fact that the
point chirality of linear starting material controls the axial chirality of the
biaryl unit. As the medium-sized ring products overall exhibit planar
chirality we arguably could have used the terminology ‘point-to-planar’
chirality transfer but chose the former as we believe it is more intuitive to
consider the individual stereogenic units. For recent examples of point-
to-axial chiralitytransfer in synthesis, see: (a) T. Qin, S. L. Skraba-Joiner,
Z. G. Khalil, R. P. Johnson, R. J. Capon, J. A. Porco Jr, Nat. Chem. 2015,
7, 234; (b) R. J. Armstrong, M. Nandakumar, R. M. P. Dias, A. Noble, E.
L. Myers, V. K. Aggarwal, Angew. Chem. Int. Ed. 2018, 57, 8203; (c) A.
Link, C. Sparr, Angew. Chem., Int. Ed., 2018, 57, 7136; (d) H. Li, W. Fan,
X. Hong, Org. Biomol. Chem. 2019, 17, 1916.
[22] To compare the energies of the possible diastereoisomers, the structures
were optimised at the M06-2X/6-311G* level, followed by frequency
calculations at the same level. These structures were confirmed as
minima by the absence of imaginary frequencies. The M06-2X/6-311G*
SCF energies were corrected for their zero-point energies, thermal
energies and entropies obtained from the frequency calculations.
Optimisations were performed with tight convergence criteria and no
symmetry constraints were applied. An ultrafine integral grid was used
for all calculations. Solvent corrections were applied with the Polarisable
Continuum Model (PCM) using the integral equation formalism variant
(IEFPCMO). Energies in Hartrees and xyz coordinates are reported in
the SI.
[12] T3P was chosen as the activating agent in view of precedent for its use
for the N-acylation of cyclic imines, see: (a) W. P. Unsworth, C. Kitsiou,
R. J. K. Taylor, Org. Lett. 2013, 15, 258; (b) W. P. Unsworth, G. Coulthard,
C. Kitsiou, R. J. K. Taylor, J. Org. Chem., 2014, 79, 1368; (c) W. P.
Unsworth, R. J. K. Taylor, Synlett 2016, 27, 2051.
[23] Enantiomer ratios were determined using chiral HPLC (see SI). Partial
overlap of signals means that there may be a small amount of error in
the absolute ee value assigned, but what is clear that qualitatively, the
chirality transfer was successful. Further studies will be needed to build
on these preliminary data in the future.
[13] CCDC 1913413 contains the crystallographic data for 11a, see:
www.ccdc.cam.ac.uk/data_request/cif
[14] Compounds 11q, 11u and 11v exist as concentration dependant
mixtures of rotamers about the newly formed amide bond in CDCl3
solution.
[15] For the importance of atropoisomerism in drug discovery, see: (a) J.
Clayden, W. J. Moran, P. J. Edwards, S. R. L. LaPlante, Angew. Chem.
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Nat. Prod. Rep., 2015, 32, 1562; (d) P. W. Glunz, L. Mueller, D. L.
Cheney, V. Ladziata, Y. Zou, N. R. Wurtz, A. Wei, P. C. Wong, R. R.
Wexler, E. S. Priestley, J. Med. Chem. 2016, 59, 4007; (e) P. W. Glunz,
Bioorg. Med. Chem. Lett. 2018, 28, 53.
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10.1002/anie.201907206
Angewandte Chemie International Edition
RESEARCH ARTICLE
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Aggie Lawer, James A. Rossi-Ashton†,
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Internal nucleophilic catalyst
mediated cyclisation/ring expansion
cascades for the synthesis of
A strategy for the synthesis of medium-sized lactones and lactams from linear
precursors is described in which an amine acts as an internal nucleophilic catalyst
to facilitate a cyclisation/ring expansion cascade sequence. This method obviates
the need to use high-dilution-type conditions and enables medium-sized ring biaryl
scaffolds to be prepared with full control of atroposelectivity via point-to-axial
chirality transfer.
medium-sized lactones and lactams
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