On the rapid synthesis of highly substituted proline analogues by 5-endo-trig iodocyclisation

Article abstract of DOI:10.1016/j.tetlet.2006.02.017

Highly substituted α-alkenyl-α-amino esters undergo smooth if rather slow 5-endo-iodocyclisations both in the presence or absence of base to give good to excellent yields of substituted proline derivatives. The stereoselectivities are often only moderate,

Full text of DOI:10.1016/j.tetlet.2006.02.017

Tetrahedron Letters 47 (2006) 2825–2828
On the rapid synthesis of highly substituted proline analogues
by 5-endo-trig iodocyclisation
Muhammad Amjad and David W. Knight*
Centre for Heterocyclic Synthesis, School of Chemistry, Cardiff University, Main College, Park Place, Cardiff CF10 3AT, UK
Received 8 December 2005; revised 23 January 2006; accepted 1 February 2006
Available online 21 February 2006
Abstract—Highly substituted a-alkenyl-a-amino esters undergo smooth if rather slow 5-endo-iodocyclisations both in the presence
or absence of base to give good to excellent yields of substituted proline derivatives. The stereoselectivities are often only moderate,
except when the amino ester residue carries a substituent, which is branched at its a-position.
Ó 2006 Elsevier Ltd. All rights reserved.
The utility of 5-endo-trig cyclisations for the usually
highly stereoselective synthesis of tetrahydrofurans1 or
pyrrolidines2,3 has been demonstrated by a number of
groups. Generally, these are best induced by species such
as halonium or phenylselenenonium ions;4 the trans-
formation, overall, can also be achieved using protons5
or palladium(II) salts6 in the case of homoallylic sulfon-
amides. Despite initial appearances, this general trans-
formation (Scheme 1) of homoallylic precursors 1 into
heterocycles 2, being electrophile-driven, probably does
not represent an exception to Baldwin’s rules.7,8
more stable 2,5-cis diastereoisomers, in the presence of
protons. Thus, while exposure of the (E)-homoallylic
sulfonamides 3 to an excess of iodine in the presence
of potassium carbonate showed a distinct preference
for formation of the 2,5-trans isomers 5, omission of
the base leads to the corresponding 2,5-cis isomers 6,
often as the sole products (Scheme 2).
We have ascribed these results to an initial cyclisation
via a chair-like transition state conformation 4, which
leads to the 2,5-trans isomers 5 and which can then be
followed by proton-induced cyclo-reversion and re-clo-
sure and hence equilibration towards, eventually only,
the more stable 2,5-cis isomers 6.
Our experiments towards defining a pyrrolidine synthe-
sis based on Scheme 1 have revealed a marked tendency
for equilibration in favour of the thermodynamically
This led us to question whether such cyclisations could
be applied successfully to much more highly substituted
examples and, if so, whether these would show useful
levels of stereoselection. A prime motivation was that,
if successful, this would represent a rapid approach to
highly substituted proline analogues. As one of the 20
or so ubiquitous a-amino acids, the synthesis of such
analogues is an important aspect of drug discovery.
E
E+
R1
R2
R1
R2
X
HX
1
2
Scheme 1.
I
I
R1
TsHN
I
R1
R2
I2
R1
R2
R1
R2
N
N
HN
Ts
H+
K2CO3
R2
[no base]
Ts
Ts
4
3
5
6
Scheme 2.
*
Corresponding author. Fax: +44 02920 874 210; e-mail: knightdw@cf.ac.uk
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.017

2826
M. Amjad, D. W. Knight / Tetrahedron Letters 47 (2006) 2825–2828
Table 1. Cyclisations of 1,2,2-trisubstituted alkenyl derivatives 9 and
13
LDA
N
CO2Me
CO2Me
N
Br
i) 1 M HCl
ii) TsCl, py
Precursor
Products
Ph
Ph
I
I
8
7
R
R
R
CO2Me
HN
CO2Me
CO2Me
N
N
CO2Me
HN
Ts
9a
Ts
9
Ts
Ts
10
11
(a) R = Me
Basic: 3I2, 2 h, 76%
Acidic: 3I2, 16 h, 82% 62%
(b) R = Ph
Basic: 3I2, 96 h, 88%
48%
52%
38%
Scheme 3.
38%
62%
0%
However, at the outset, it was far from clear if such
highly crowded substrates would indeed undergo cycli-
sation, especially as the overall 5-endo-trig process is
already disfavoured.7,8 Fortunately, a relevant sub-
strate, the C-prenyl derivative of alanine 9a was readily
prepared, in racemic form, using the excellent Stork
procedure, by C-alkylation of the carbanion derived
from Schiff’s base 7 (Scheme 3).9
Acidic: 3I2, 96 h, 91% 20%
[80% deiodo 16a]
(c) R = CH2Ph
Basic: 3I2, 2 h, 75%
Acidic: 3I2, 2 h, 76%
26%
0%
74%
25%
[75% deiodo 16b]
I
I
R1
R2
R2
R1
R2
i
CO2 Pr
HN
R1
CO2 Pr
CO2 Pr
i
i
N
N
The resulting homologated product 8 was subsequently
hydrolysed by brief exposure to 1 M hydrochloric acid
then the resulting free amine N-tosylated to give the pre-
cursor 9a in good overall yield. Gratifyingly, the desired
iodocyclisation was found to proceed smoothly using
3 equiv of iodine in acetonitrile under both sets of con-
ditions, that is, either in the presence or absence of
potassium carbonate (Table 1). However, in both cases,
there was virtually no stereocontrol. Careful column
chromatography and crystallisation separated samples
of both diastereomers 10a and 11a, the stereochemistry
of which was determined using a GOSEY experiment
at 500 MHz. The key results are shown below. All other
enhancements were below 2%, except for those of the
geminal methyls and protons.
Ts
Ts
Ts
13
14
15
(a) R1 = Prn; R2 = H
Basic: 3I2, 24 h, 87%
Acidic: 3I2, 24 h, 87% 60%
(b) R1 = Ph; R2 = H
35%
65%
40%
Basic: 3I2, 48 h, 96%
Acidic: 3I2, 24 h, 90%
22%
78%
[Mainly deiodo 16c]
(c) R1 = Ph; R2 = Me
Basic: 5I2, 48 h, 96%
42%
58%
25%
Acidic: 5I2, 48 h, 97% 75%
H2, 10% Pd-C
10a or 11a
Et3N, MeOH
20 oC, 10 h
N
CO2Me
~95%
Ts
5.6%
6.5%
12
6%
Scheme 4.
8%
I
H
H
H
H
H
I
H
4.5%
3.7%
N
N
CO2Me
CO2Me
90 h to reach completion at ambient temperature.
Again, the predominant isomer 11b was that having
the ester and iodine atom disposed cis to each other.
However, a quite different result arose in the absence
of base, when the preferred pathway was acid-catalysed
cyclisation5 to give pyrrolidine 16a, together with a min-
or amount of iodopyrrolidine 10b, in excellent overall
yield. Much the same result was obtained from the
prenylated phenylalanine derivative 9c: under basic con-
ditions, isomer 11c predominated while, under acidic
conditions, pyrrolidine 16b was the major product. In
both cases, however, the rates of cyclisation were much
higher, reflecting the lower degree of steric crowding rel-
ative to the phenylglycinate derivative 9b. In line with
the originally proposed chair-like transition state con-
formation 4 (Scheme 2), the foregoing results are consis-
tent with the predominant intermediary, albeit only
slightly, of a conformation 17 in which the ester occu-
pies an equatorial position.
Ts
Ts
10a
11a
Evidence for these two structures was also obtained by
hydrogenolytic removal of the iodine atom; as expected,
both iodopyrrolidines [10a and 11a] gave the same de-
iodinated product 12a (Scheme 4).
Subsequently, the same route9 was used to prepare all
other substrates tested in such iodocyclisations. In all
cases, similar GOSEY experiments were used to deter-
mine product stereochemistry, often using (partly sepa-
rated) mixtures.
A similar result was obtained upon cyclisation of the
prenylated derivative 9b of N-tosyl phenylglycinate,
under basic conditions. Although the overall yield was
excellent, the cyclisation was rather slow, taking over

M. Amjad, D. W. Knight / Tetrahedron Letters 47 (2006) 2825–2828
2827
Table 2. Cyclisations of 1,2-disubstituted alkenyl derivatives 18, 21
and 24
I
R1
R2
Precursor
Products
TsHN
CO2Me
N
CO2Me
Ts
I
I
a) R1 = Me; R2 = Ph
b) R1 = Me; R2 = CH2Ph
c) R1 = Ph; R2 = H
16
17
R
R
CO2Me
HN
R
CO2Me
R
CO2Me
N
N
Ts
Ts
Ts
18
19
20
Highly efficient cyclisations of the (E)-alkenyl glycinate
13a followed a similar pattern: under basic conditions,
isomer 15a predominated whereas under acidic condi-
tions, an alternative, presumably more thermodynami-
cally stable isomer 14a was the major product, in
which the larger a-substitutes (propyl and CO2Me) are
orientated cis to each other. The formation of only
two diastereoisomers is also notable indicating a highly
stereocontrolled cyclo-reversion process. More peculiar
results were obtained from the phenyl-substituted
glycinate 13b: whilst under basic conditions, the pre-
dominance of isomer 15b suggested control arising from
a chair conformation related to structure 17, under
acidic conditions, pyrrolidine 16c lacking iodine was
formed almost exclusively. However, cyclisation of the
homologous alanine derivative 13c was found to require
5 equiv of iodine to reach completion and, even then,
only after an extended reaction period of 48 h. The ste-
reochemical patterns, however, followed a now familiar
sequence, even though the molecules are now very steri-
cally crowded.
(a) R = Me
Basic: 5I2, 16 h, 80%
Acidic: 5I2, 16 h, 85% 35%
30%
70%
65%
(b) R = Ph
Basic: 5I2, 48 h, 73%
44%
56%
24%
Acidic: 5I2, 16 h, 80% 76%
I
I
Ph
i
CO2 Pr
HN
i
i
Ph
CO2 Pr Ph
CO2 Pr
N
N
Ts
21
Ts
Ts
22
23
Basic: 5I2, 16 h, 83%
Acidic: 5I2, 16 h, 76%
18%
33%
82%
67%
I
I
Ph
Ph
CO2Me Ph
Ph
Ph
CO2Me
HN
Ph
CO2Me
N
N
Ts
Ts
Ts
24
25
26
Basic: 5I2, 16 h, 51%a
Acidic: 5I2, 16 h, 95%
42%
58%
58%
42%
a 37% starting material 24 recovered.
A similar pattern of results was observed in iodocyclisa-
tions of a series of alanine derivatives 18 having mono-
substituted (E)-alkenyl substituents (Table 2). Five
equivalents of iodine were necessary to achieve a reason-
able rate of cyclisation as well as completion of the
reaction.
Table 3. Cyclisations of a-branched-cinnamyl and crotyl derivatives
27 and 30
Precursor
Products
I
I
R
Once again, while chemical yields were very good, the
levels of stereoselection were not particularly exciting,
showing only a moderate preference for those isomers
20 with a trans disposition between the ester and
5-substituent under basic conditions but the reverse
(19) under acidic conditions, at least when R = Ph. In
an effort to encourage greater stereocontrol, the methyl
ester precursor 18b was transesterified into the bulkier
isopropyl ester 21. This resulted in a marginal increase
in formation of the ‘2,5-trans’ isomer 23 together with
a pronounced reluctance to undergo acid-catalysed
isomerisation to the ‘2,5-cis’ isomer 22, presumably
because of the increase in the size of the ester. Placing
the bulk of a substituent further away from the reacting
centres, as in the phenylalanine derivative 24 resulted in
little stereocontrol under both extremes of conditions,
probably reflecting the relatively similar steric influences
of the benzyl and methoxycarbonyl groups.
Ph
R
R
CO2Me
HN
Ph
CO2Me Ph
CO2Me
N
N
Ts
27
Ts
Ts
28
29
(a) R = iPr
Basic: 5I2, 48 h, 88%
Acidic: 5I2, 16 h, 89% 82%
20%
80%
18%
(b) R = Ph
Basic: 3I2, 48 h, 95%
12%
88%
65%
Acidic: 3I2, 48 h, 98% 35%
I
I
Ph
Ph
Ph
CO2Me
CO2Me
HN
CO2Me
N
N
Ts
30
Ts
Ts
31
32
Basic: 3I2, 40 h, 88%
Acidic: 3I2, 40 h, 82%
6%
92%
94%
8%
Really high levels of stereocontrol were only observed
when the a-amino ester residue was substituted by a
group having an a-branch, in the present cases, isopro-
pyl or phenyl (Table 3).
basic conditions, but showed a contrary stereoselection
in favour of the ‘2-5-cis’ isomer 28a under acidic condi-
tions. Both the requirements for 5 equiv of iodine and
the relatively slow rate of cyclisation reflect the high
level of steric congestion. Similarly, the phenylglycine
derivative 27b gave the ‘2,5-trans’ isomer 29b as a
Thus, the valine-derived cinnamyl derivative 27a gave
largely the ‘2,5-trans’ proline homologue 29a under

2828
M. Amjad, D. W. Knight / Tetrahedron Letters 47 (2006) 2825–2828
not usually observed except when an a-branched substi-
I
tuent is included adjacent to the central ring.
3.I2, 3.K2CO3
CO2Me
HN
Ts
CO2Me
N
MeCN, 16 h
95%
Ts
A further demonstration of the utility of this chemistry,
perhaps not surprising in view of the results shown in
Table 1, was the finding that spiro-pyrrolidine 34 is
obtained highly selectively and efficiently from the cyclo-
hexylidene derivative 33 (Scheme 5). We would therefore
anticipate that, at the very least, this chemistry should
be useful for the rapid synthesis of a great diversity of
proline analogues.
33
34
Scheme 5.
predominant product in the presence of potassium
carbonate. Oddly, this was also the major product
under acidic conditions, perhaps suggesting a contri-
bution from a favourable interaction between the two
phenyl rings (p–p-stacking?). Enhanced levels of stereo-
selection were observed in the phenylglycine-derived
crotyl derivative 30, the ‘2,5-trans’ product 32 being
formed nearly exclusively under basic conditions at the
expense of the ‘2,5-cis’ isomer 31, favoured under acidic
conditions.
Acknowledgements
We are grateful to Robert Jenkins for assistance with
spectroscopic analysis and to the EPSRC and the
National Mass Spectrometry Service, Swansea, for the
provision of high resolution NMR and mass spectro-
scopic data, respectively.
A curiosity associated with the use of 5 equiv of iodine
was that it was found essential to add this quantity at
the outset of a reaction. Adding two further equivalents
to a cyclisation, which already contained 3 equiv of
iodine but which appeared to be progressing extremely
slowly had almost no effect. We have no explanation
for this phenomenon. Indeed, beyond a supposition of
the necessity for formation of a suitable reactive iodo-
nium species such as IþI5ꢀ, we have no certain rationale
of the need for 3 equiv2 in most iodocyclisations, includ-
ing lactonisations, etherifications and aminations,
whether of an exo- or endo-type.
References and notes
1. Bartlett, P. A.; Myerson, J. J. Am. Chem. Soc. 1978, 100,
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Soc. 1992, 114, 1084; Mihelich, E. D.; Hite, G. A. J. Am.
Chem. Soc. 1992, 114, 7318; Barks, J. M.; Knight, D. W.;
Seaman, C. J.; Weingarten, G. G. Tetrahedron Lett. 1994,
35, 7259; Bedford, S. B.; Bell, K. E.; Bennett, F.; Hayes, C.
J.; Knight, D. W.; Shaw, D. E. J. Chem. Soc., Perkin Trans.
1 1999, 2143.
2. Jones, A. D.; Knight, D. W.; Hibbs, D. E. J. Chem. Soc.,
Perkin Trans. 1 2001, 1182, and references cited therein.
3. Jones, A. D.; Knight, D. W.; Redfern, A. L.; Gilmore, J.
Tetrahedron Lett. 1999, 40, 3267; For selenocyclisations
onto indoles, see: Marsden, S. P.; Depew, K. M.; Dani-
shefsky, S. J. J. Am. Chem. Soc. 1994, 116, 11143; Crich,
D.; Huang, X. J. Org. Chem. 1999, 64, 7218.
4. French, A. N.; Bissmire, S.; Wirth, T. Chem. Soc. Rev.
2004, 33, 354; Knight, D. W. Prog. Heterocycl. Chem. 2002,
14, 19.
5. Schlummer, B.; Hartwig, J. F. Org. Lett. 2002, 4, 1471;
Haskins, C. M.; Knight, D. W. Chem. Commun. 2002, 249.
6. Koh, J. H.; Mascarenhas, C.; Gange, M. R. Tetrahedron
2004, 60, 7405, and references cited therein.
7. Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734;
Baldwin, J. E.; Cutting, J.; Dupont, W.; Kruse, L.;
Silberman, L.; Thomas, R. C. J. Chem. Soc., Chem.
Commun. 1976, 736.
The stereochemical outcomes appear to follow largely
the chair-like conformation 4 (Scheme 2), wherein the
ester group adopts an equatorial position during the
initial cyclisation (which predominates under basic
conditions), hence leading to the kinetic product.
Acid-catalysed cyclo-reversion and equilibration to the
thermodynamic isomers then follows in the absence of
base (Scheme 2). However, the highly crowded nature
of some of the precursors, together with the often low
levels of stereoselection could be concealing a more
complicated picture involving alternative transition state
conformations, making clear stereochemical predictions
rather difficult. Further, none of this takes into account
the possible influence of the relatively large N-tosyl sub-
stituent. In any event, the foregoing results clearly show
that this route, overall, represents a very rapid, flexible
and efficient approach to highly substituted proline
derivatives and no doubt many other pyrrolidines in
general. High levels of stereoselection are, however,
8. Knight, D. W.; Redfern, A. L.; Gilmore, J. Tetrahedron
Lett. 1998, 39, 8909.
9. Stork, G.; Leong, A. Y.; Touzin, A. M. J. Org. Chem. 1976,
41, 3491.