Anti-Beckwith stereoselectivity in amidyl radical cyclisations: Bu 3SnH-mediated 5-exo-trig acyl mode cyclisation of 2-substituted pent-4-enamide radicals

Article abstract of DOI:10.1016/j.tetlet.2013.05.109

2-Substituted amidyl radicals derived from 8a-d and 9a-d undergo acyl mode 5-exo-trig cyclisation to give 3,5-trans pyrrolidinones 11a-d and 14a-d as the major products in low diastereoselectivity (de = 9-36%). The steric nature of the nitrogen substituent attached to the amidyl radical does not have a significant effect on selectivity. The stereochemical outcome is opposite to that expected based upon applying the Beckwith rule.

Full text of DOI:10.1016/j.tetlet.2013.05.109

Tetrahedron Letters 54 (2013) 4094–4097
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Anti-Beckwith stereoselectivity in amidyl radical cyclisations:
Bu3SnH-mediated 5-exo-trig acyl mode cyclisation of 2-substituted
pent-4-enamide radicals
a
b
a
Andrew J. Clark a, , Robert P. Filik , Gerard H. Thomas , John Sherringham
⇑
a Chemistry Department, University of Warwick, Coventry CV4 7AL, West Midlands, UK
b Knoll Pharmaceuticals, Research and Development Department, Pennyfoot Street, Nottingham NG1 1GF, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Substituted amidyl radicals derived from 8a–d and 9a–d undergo acyl mode 5-exo-trig cyclisation to
give 3,5-trans pyrrolidinones 11a–d and 14a–d as the major products in low diastereoselectivity
(de = 9–36%). The steric nature of the nitrogen substituent attached to the amidyl radical does not have
a significant effect on selectivity. The stereochemical outcome is opposite to that expected based upon
applying the Beckwith rule.
Received 15 March 2013
Revised 13 May 2013
Accepted 24 May 2013
Available online 3 June 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Stereochemistry
Amidyl radical
Cyclisation
Pyrrolidinones
Beckwith model
The rules governing the stereochemical outcome of 5-exo carbon
radical cyclisations are well known1–4 but the analogous nitrogen-
centred radical cyclisations have been less well investigated.5–8 The
stereochemical outcome of hex-5-enyl radical 1 cyclisations can
normally be predicted by application of the Beckwith–Houk mod-
el,1–4 which predicts that cyclisation preferentially takes place via
a chair-like transition state 3 with the substituent preferring a
pseudo equatorial position. Thus, 1- and 3-substituted hex-5-enyl
radicals afford mainly cis-disubstituted products, whereas 2- or
4-substituted species give mainly trans products (Scheme 1).1–4
Investigations into the stereochemistry of 5-exo-trig aminyl and
aminium cation radical 2 cyclisations have also been reported.6
Bowman looked at the stereoselectivity of cyclisations of aminyl
radicals derived from sulfenamides7,8 while Newcomb investigated
the cyclisation of cation radical 2 produced from the corresponding
N-hydroxy pyridine-2-thione (PTOC) carbamate, which gave trans
and cis pyrrolidines in a ratio of 3:1 at 25 °C (Scheme 1).6 The
cyclisation of related amidyl radicals has received less attention
with only a few applications of their use in target synthesis.5,9
Amidyl radicals can undergo cyclisation via two possible ‘modes’:
cyclisation onto the alkyl side-chain (e.g., 4) and onto the acyl side
chain (e.g., 5) (Scheme 2).
(R = Me) gives poorer selectivity with 3-substituted systems.11
Recent calculations at the UB3LYP/6-31+G(d,p) level have
indicated that 5-exo chair-like (+5.3 kcal/mol) and 5-exo boat-
like (+5.6 kcal/mol) transition states are very similar in energy
for the cyclisation of unsubstituted pent-4-enamidyl radicals in
the acyl mode,12 and this may be partly responsible for the poor
selectivities observed. For cyclisations of 5 the nature of the nitro-
gen substituent had little effect on the stereochemical outcome of
the reaction,11 which could be predicted via the Beckwith–Houk
model, but more hindered groups (R = iPr) led to slow cyclisations,
in line with modelling predictions.12 Recently, the stereochemical
outcome of 6-exo-trig cyclisations of amidyl radicals has been
Cyclisation in the alkyl mode 4 occurs with similar stereoselec-
tivity to aminyl radical cations,10 but cyclisation in the acyl mode 5
⇑
Corresponding author. Tel.: +44 2476 523242; fax: +44 2476 524112.
E-mail address: a.j.clark@warwick.ac.uk (A.J. Clark).
Scheme 1. Stereochemistry of cyclisations.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.109

A. J. Clark et al. / Tetrahedron Letters 54 (2013) 4094–4097
4095
the resulting hydroxamic acids (Scheme 4). The yields are com-
bined yields for both of these steps. The cyclisations15 were con-
ducted by slow addition (syringe pump over 8h) of a solution of
tributyltin hydride (1.0 equiv) and AIBN (0.1 equiv) in toluene, to
a refluxing solution of the precursor in toluene or in a 1/1 v/v mix-
ture of toluene and cyclohexane. In each reaction the initial con-
centration of precursor in the solvent was between 0.08 and
0.16 mmol/ml. The tin hydride and AIBN were added in an equiv-
alent amount of solvent thereby doubling the initial volume. After
refluxing for a further 12 h, if analysis by TLC showed the reactions
to not be fully complete an additional amount of tributyltin
hydride (1.0 equiv) and AIBN (0.1 equiv) were added over another
8 h.
Purification of the crude mixtures was often difficult. The
majority of the tin residues were removed by partitioning the
crude product mixtures between, firstly, acetonitrile and hexane,
and secondly, between acetonitrile and cyclohexane. Flash chro-
matography was used to purify the mixtures further. Generally,
the diastereoisomers could not be separated fully, but in some
cases, a pure sample of the major isomer could be obtained. The
diastereomeric ratio was determined from either the 250 MHz 1H
NMR spectrum of the crude mixture directly after removal of the
toluene solvent in vacuo, or after the first partitioning between
acetonitrile and hexane. After this partition both the layers were
carefully examined by 1H NMR spectroscopy to determine whether
any compounds were being extracted selectively. Diastereomers
11–12 and reduced products 13 were only found in the acetonitrile
layer indicating that the diastereomeric ratio determined for this
layer was representative of that of the reaction (Table 1).
Scheme 2. Cyclisation modes of amidyl radicals
studied extensively both experimentally and theoretically.13 How-
ever, while the regiochemical and stereochemical outcome of
5-exo-trig cyclisation of 3-,11 4- and 5-13 substituted amidyl radi-
cals in the acyl mode has been reported, the outcome of cyclisation
of 2-substituted amidyl radicals has not. In this Letter we provide
data to complete this series of stereochemical studies. Application
of the Beckwith model would predict cis diastereomers should be
the major products, but we anticipated that the diastereoselectiv-
ity of cyclisation would be poor, as observed for 4-substituted
analogues 5 (Scheme 3).
The hydroxamic acid derivatives 8a–d and 9a–d were prepared
by one of two methods (Scheme 4). The first method was based on
the procedures of Zinner14 and involved a two-step, one-pot reac-
tion starting from the corresponding amine. The second procedure
utilised a two-step approach involving initial selective N-acylation
of commercially available hydroxylamine hydrochlorides with the
appropriate acid chlorides 10a,b, followed by O-benzoylation of
Identification of the major isomers was accomplished from nOe
difference spectra and by chemical correlation. Thus nOe could be
used to assign unambiguously the stereochemistry of the major
isomer of the cyclisation of 8b (major isomer = 11b). Analysis indi-
cated a trans relationship for the major diastereomer (Scheme 5).
The lactam 21a had been reported by Armstrong16 and thus offered
a potential handle to check the stereochemistry of the products via
chemical correlation. Hence, S-2-pyrolidinone-5-carboxylic acid
was esterified using methanol to give the ester 17 in quantitative
yield. Reduction of the ester to the alcohol followed by simulta-
neous protection of the NH and OH groups with benzaldehyde
furnished the bicyclic lactam 18 in 47% yield for both steps. Depro-
tonation using LDA and methylation with methyl iodide gave a 3:1
ratio of the known diastereomers 19a,b which could be separated
by careful chromatography. Each of these diastereomers was then
Scheme 3. An amidyl radical cyclisation approach to 3,5-disubstituted c-lactams.
Table 1
Products from reactions of 8a–d with Bu3SnH
Substrate
Cyclised:reduced (11+12):13a
deb (%)
Yield (11+12) (%)
8a
8b
8c
8d
9.0:1.0
—
2.3:1.0
2.3:1.0
1116
10
64
90
40
47
d
12c
9c
a
b
c
Determined from the crude 1H NMR spectrum (250 MHz).
Major product 11.
Determined by GC.
d
No 13c detected.
Scheme 4. Synthesis of amidyl radical precursors 8 and 9.
Scheme 5. Cyclisation of precursors 8a–d.

4096
A. J. Clark et al. / Tetrahedron Letters 54 (2013) 4094–4097
two pieces of literature precedence. Firstly, Ollis and Stoddart18
published a thorough analysis of the stereochemical assignment
of related 3,5-disubstituted- -butyrolactones 22a,b in which they
were able to correlate the shift of the H-3 proton and the relative
difference of the chemical shift of the - and b-H-4 protons with
stereochemical assignment based upon authentic samples
(Fig. 1). Thus, the d between the - and b-protons at C-4 is gen-
erally larger for cis butyrolactones 22a ( d = 0.75) than trans deriv-
atives 22b ( d = 0.28) and the H-3 proton is more deshielded for
trans derivatives (3.90 ppm) relative to cis compounds
(3.85 ppm). We can now extend this analysis to -lactams because
the same phenomena were observed for all of the unambiguously
assigned 3-methyl substituted -lactams 11a–d and 12a–d (e.g.,
trans 11b d = 0.09, cis 12b d = 1.20).
c
a
D
a
D
D
c
c
D
D
Applying the same criteria to the 3-phenyl series 14a–d and
15a–d indicates that the major products are also trans.19 The sec-
ond piece of evidence for the proposed assignment is that replacing
the pendant methyl group with a phenyl group in the cyclisation of
5 and 23 (Scheme 8), did not change the sense of the major diaste-
reomer.11 Indeed moving from a methyl group to a phenyl group
5?23 increased the de by ꢀ20%. This correlates with the similar
observation made with the c-lactam series 8?9 (15–26% increase).
The results obtained indicate that the nature of the nitrogen
substituent had little or no effect on the diastereoselectivity in
the cyclisations of 8a–d, and only a minor effect in the cyclisations
of 9a–d. It was found that the larger pendant substituents (Me vs
Ph) provide higher selectivity upon cyclisation. A similar conclu-
sion was reached in the study of 5 and 23. The major isomer in
all cases arising from cyclisation of 8a–d and 9a–d was found to
be the trans isomer (determined by nOe, chemical correlation
and spectral correlation). This is contrary to that expected by appli-
cation of the Beckwith rule. trans-Isomers were also reported as
the major products in the cyclisation of 5 and 23 indicating that
substitution at either the 2- or 3-positions leads to the same sense
of diastereoselectivity.
Scheme 6. Determination of the stereochemistry of 11a,b.
Theoretical work indicates that for pent-4-enamide radicals the
competing chair-like and boat-like transition states are close in
Scheme 7. Cyclisation of precursors 9a–d.
Table 2
Products from reactions of 9a–d with Bu3SnH
Substrate
Cyclised:reduced (14+15):16a
deb (%)
Yield (14+15) (%)
9a
9b
9c
9d
9.0:1.0
16.0:1.0
7.3:1.0
9.0:1.0
2518
25
36
86
73
68
52
36
a
Determined from the crude 1H NMR spectrum (250 MHz).
Major product 14.
b
separately subjected to toluenesulfonic acid deprotection, mesyla-
tion, iodide formation and reduction to give both the cis and trans
21a derivatives. During the manipulation it was possible to crystal-
lise and obtain an X-ray structure for the trans mesylate 20a con-
firming the literature assignment of the stereochemistry.
Methylation of both diastereomers of 21 using NaH and MeI fur-
nished authentic samples of 11a and 12a which unambigously
assigned the major products from cyclisation as being trans
(Scheme 6).17
Using the same cyclisation protocol as before, we next turned
our attention to the cyclisation of the 2-phenyl 9a–d substituted
precursors (Scheme 7). Determining the stereochemistry of the
major isomer of the 3-phenyl substituted series 14 was more prob-
lematic (Table 2). NOe experiments were not conclusive, (due to
overlap of signals) and no authentic samples had been reported
in the literature at the time of publication. However, we have
assigned tentatively the major isomers as trans 14 based upon
Figure 1. Stereochemical assignments of 3-phenyl-c-lactams.

A. J. Clark et al. / Tetrahedron Letters 54 (2013) 4094–4097
4097
Acknowledgements
We acknowledge funding from the Knoll Pharmaceuticals
(R.P.F.) and the Home Grown Cereal Authority, HGCA, (J.S.).
References and notes
Scheme 8. Cyclisations of 5 and 23.
1. Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron 1985, 45, 3925–3941.
2. Beckwith, A. L. J.; Easton, C. J.; Lawrence, T.; Serelis, A. K. Aust. J. Chem. 1983,
545–556.
3. Beckwith, A. L. J.; Phillipou, G.; Serelis, A. K. Tetrahedron Lett. 1981, 22, 2811–
2814.
4. Spellmeyer, D. C.; Houk, K. N. J. Org. Chem. 1987, 52, 959–974.
5. Zard, S. Z. Chem. Soc. Rev. 2008, 37, 1603–1618.
6. Newcomb, M.; Marquardt, D. J.; Deeb, T. M. Tetrahedron 1990, 46, 2329–2344.
7. Bowman, W. R.; Coghlan, D. R.; Shah, H. C.R. Acad. Sci. Paris Chimie 2001, 625–
640.
8. Bowman, W. R.; Clark, D. N.; Marmon, R. J. Tetrahedron 1994, 50, 1275–1294.
9. Callier-Dublanchet, A.-C.; Cassayre, J.; Gagosz, F.; Quiclet-Sire, B.; Sharp, L. A.;
Zard, S. Z. Tetrahedron 2008, 64, 4803–4816.
10. Clark, A. J.; Deeth, R. J.; Samuel, C. J.; Wongtap, H. Synlett 1999, 444–446.
11. Clark, A. J.; Peacock, J. L. Tetrahedron Lett. 1998, 39, 6029–6032.
12. Yu, Y.-Y.; Xie, M.; Liu, L.; Guo, Q.-X. J. Org. Chem. 2007, 72, 8025–8032.
13. Zhuang, S.; Liu, K.; Li, C. J. Org. Chem. 2011, 76, 8100–8106.
14. Psiorz, M.; Zinner, G. Synthesis 1984, 217.
15. Boivin, J.; Callier-Dublanchet, A.-C.; Quiclet-Sire, B.; Schiano, A. M.; Zard, S. Z.
Tetrahedron 1995, 51, 6517–6528.
Figure 2. Possible transition states in the formation of the products.
16. Ogawa, A. K.; DeMattei, J. A.; Scarlato, G. R.; Tellew, J. E.; Chong, L. S.;
Armstrong, R. W. J. Org. Chem. 1996, 61, 6153–6161.
17. N-Methyl-3,5-dimethylpyrrolidin-2-one (11a/12a). (Initial concentration of
substrate 0.12 M); 2:1 hexane:EtOAc, 64% as an inseparable mixture of
diastereoisomers (ratio 54.5:45.5, trans:cis); IR (CDCl3)/cmÀ1 (mixture) 2966,
1674, 1456; 1H NMR (400 MHz; CDCl3) discernible data for the trans isomer:
1.15 (3H, d, J = 7.3 Hz), 1.17 (3H, d, J = 6.3 Hz), 1.75 (2H, m), 2.49 (1H, m), 2.78
(3H, s), 3.48 (1H, m); discernible data for the cis isomer: 1.18 (3H, d, J = 7.0 Hz),
1.20 (3H, d, J = 6.3 Hz), 1.18–1.20 (1H, m), 2.32–2.43 (2H, m), 2.77 (3H, s), 3.39
(1H, m); 13C NMR (100 MHz; CDCl3) (mixture) 16.5, 16.7, 19.1, 20.3, 27.3, 27.5,
35.2, 35.3, 36.5, 36.6, 53.4, 53.6, 177.1, 177.5; m/z (EI) 127 (M+, 43%), 112 (100),
105 (87). HRMS calculated for C7H14NO: 128.1075, found 128.1063.
18. Hussain, T. S. A. M.; Ollis, D. W.; Smith, C.; Stoddart, J. F. J. Chem. Soc., Perkin
Trans. 1 1975, 1480–1492.
19. N-Methyl-5-methyl-3-phenylpyrrolidin-2-one (14a/15a). (Initial concentration
of substrate 0.1 M); 2:1 hexane:EtOAc, 86% as a partially separable mixture of
diastereoisomers (ratio 62.5:37.5, trans:cis); IR (mixture) (CDCl3)/cmÀ1 2967,
1686, 1451; 1H NMR (250 MHz; CDCl3) discernible data for the trans isomer: d
1.26 (3H, d, J = 6.1 Hz), 2.03 (1H, m), 2.28 (1H, m), 2.88 (3H, s), 3.65 (2H, m)
7.19 (5H, m); discernible data for the cis isomer: d 1.30 (3H, t, J = 6.1 Hz), 1.58
(1H, m), 2.61 (1H, m), 3.53 (1H, m), 3.60 (1H, t, J = 10.1 Hz), 7.20 (5H, m); 13C
NMR (90 MHz; CDCl3) discernible data for the trans isomer: 19.2, 27.7, 36.2,
47.0, 54.0, 126.9, 128.0 (Â2), 128.7 (Â2), 140.0, 174.7; discernible data for the
cis isomer: 20.3, 27.7, 37.5, 48.3, 53.5, 126.9, 128.4 (Â2), 128.7 (Â2), 139.8,
175.1; m/z (EI) (mixture) 189 (M+, 91%), 117 (100), 174 (93). HRMS calculated
for C12H15NO: 189.1154, found 189.1150.
energy, indicating that both should be considered in any analysis.11
Examination of the Newman projections (Fig. 2), for the possible
cyclisation of 8a–d via chair-like TSs indicates a significant eclipsed
interaction between the pendant methyl substituent and the car-
bonyl group in transition state B which is absent in transition state
A where the methyl group adopts a pseudo axial position, thus
favouring the observed trans isomers. Analysis of the boat-like
TSs suggests that both have significant steric interactions indicat-
ing that these will be less important in stereochemical determina-
tion than the chair-like TS A, although modelling would have to be
undertaken to confirm this.
In conclusion we have provided data that complete the set of
stereochemical investigations for substituents attached to pent-
4-enamide radicals. We have shown that the major trans isomers
are not those predicted by application of the Beckwith–Houk rule.
We have also extended the work of Ollis and Stoddart18 on corre-
lating 1H NMR chemical shifts of cis and trans 3-phenyl-5-methyl
c-lactone diastereomers to 3-phenyl-5-methyl c-lactams.