Synthetic applications of the amino-Cope rearrangement: Enantioselective synthesis of some tetrahydropyrans

Article abstract of DOI:10.1016/S0040-4039(02)00760-8

We report a novel and enantioselective approach to 2,4-disubstituted tetrahydropyrans that utilises the asymmetric amino-Cope rearrangement as a key synthetic step.

Full text of DOI:10.1016/S0040-4039(02)00760-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4195–4197
Synthetic applications of the amino-Cope rearrangement:
enantioselective synthesis of some tetrahydropyrans
Steven M. Allin,* Robert D. Baird and Roger J. Lins
Department of Chemistry, Loughborough University, Loughborough, Leicestershire, LE11 3TU, UK
Received 8 February 2002; revised 9 April 2002; accepted 17 April 2002
Abstract—We report a novel and enantioselective approach to 2,4-disubstituted tetrahydropyrans that utilises the asymmetric
amino-Cope rearrangement as a key synthetic step. © 2002 Elsevier Science Ltd. All rights reserved.
Asymmetric synthetic routes to tetrahydropyran sub-
units are of considerable interest since these hetero-
cyclic components are found in many biologically active
molecules and natural products. In this communication
we wish to present the first demonstration of the syn-
thetic utility of the asymmetric anionic amino-Cope
rearrangement, and highlight its potential for future
application in natural product synthesis. The novel
route described in this paper delivers functionalised
2,4-disubstituted tetrahydropyrans in high enantiomeric
excesses from readily available precursors. The key step
in our synthetic protocol is the introduction of asym-
metry via our recently developed asymmetric anionic
amino-Cope rearrangement methodology.
rearrangement/enamine derivatisation reaction.2 More
recently we have established that an anionic variant of
the amino-Cope rearrangement is possible, and that
asymmetric induction can be achieved at an asymmetric
centre created during the rearrangement of
a
diastereoisomerically pure substrate.3
Although the precise mechanism of the amino-Cope
rearrangement remains a matter for debate,4 we have
demonstrated that the asymmetric amino-Cope rear-
rangement can have significant advantages over the
analogous oxy-Cope rearrangement in terms of asym-
metric induction.5 For example, the axial/equatorial
preference of an oxy-anion substituent in the proposed
chair-like transition state of the oxy-Cope rearrange-
ment can be low, leading to a rearrangement product
with a correspondingly low e.e.6
There is growing interest in asymmetric variants of
sigmatropic rearrangements,1 and we are continuing to
develop the amino-Cope rearrangement as a new syn-
thetic protocol. Scheme 1 summarises our ultimate
goal: the one-pot asymmetric synthesis of acyclic
targets containing (up to) three contiguous chiral cen-
tres via amino-Cope rearrangement (Step 1) and subse-
quent (tandem) enamine derivatization and hydrolysis
(Step 2).
The preparation of the 3-amino-1,5-diene substrate
required for the asymmetric amino-Cope rearrangement
has been detailed elsewhere.5 Substrate 1 was readily
isolated in diastereoisomerically pure form by column
chromatography on silica gel, and the relative stereo-
chemistry has been confirmed by single-crystal X-ray
analysis. Amino-Cope rearrangement of 1 was carried
out by treating the substrate with 2.5 equiv. of n-BuLi
at −78°C in THF, the reaction mixture was then
Our group has demonstrated the key steps of this
protocol, including a successful tandem amino-Cope
Scheme 1. Synthetic potential of the amino-Cope rearrangement.
* Corresponding author. E-mail: s.m.allin@lboro.ac.uk
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00760-8

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S. M. Allin et al. / Tetrahedron Letters 43 (2002) 4195–4197
allowed to reach room temperature, and heated under
reflux for 2 h before dilute acid work-up (Scheme 2).
The target aldehyde 3 was not observed in the crude
99% yield by sodium borohydride reduction. Analysis
of 5 by chiral HPLC9 showed essentially the same level
of e.e. for the alcohol product (92%) as was observed
for the aldehyde precursor by NMR determination.
1
product mixture by H NMR, but rather the oxazo-
lidine 2 resulting presumably from ring-closure of the
intermediate enamine on acidic work-up. Liberation
and purification of aldehyde 3 was effected simply by
column chromatography of the crude oxazolidine on
silica gel.
With 5 in hand we performed an iodine-induced cycli-
sation at room temperature (I2, NaHCO3, MeCN) and
achieved an almost quantitative conversion to the
target iodo-THP 6. 1H NMR analysis of the crude
reaction mixture revealed that the cyclisation had pro-
ceeded with a diastereoselectivity of 4:1 in favour of the
cis-diastereoisomer 6a.10
The enantiomeric excess and absolute configuration of
aldehyde 3 was determined by conversion to the corre-
sponding diastereoisomeric oxazolidine derived from
1R,2S-(−)-ephedrine, as described by Agami.7 The
absolute stereochemistry induced on rearrangement of
the 3-amino-1,5-diene substrates used in all of our
studies to date has been rationalised by invoking a
chair-like transition state model, 4, having the amine
component occupying a pseudo-equatorial orientation,
although a model such as this is surely an over-simplifi-
cation. Indeed, as mentioned above, there is currently
some debate over the mechanism of the rearrangement,
with certain 4-substituted 3-amino-1,5-dienes having
been shown4 to rearrange by a stepwise mechanism.
Nevertheless, model 4 provides a useful ‘rule of thumb’.
The major diastereoisomer 6a was isolated by column
chromatography in 60% yield and further analysis by
chiral HPLC11 showed this compound to have an e.e.
of 92%, confirming no loss of stereochemical integrity
during cyclisation (Scheme 3).
After our success with iodine as the electrophile we
chose to investigate a variant of this cyclisation
methodology. The phenylselenyl group is a useful han-
dle that can allow further molecular elaboration, and
by applying
a suitable selenium electrophile, N-
(phenylseleno)phthalimide (NPSP, 1.7 equiv.), in the
presence of pyridinium p-toluenesulfonate (PPTS, 0.3
equiv.) in CH2Cl2 at −78°C we were able to achieve
cyclisation to the corresponding tetrahydropyran prod-
ucts. In this case however, a 1:1 diastereoisomeric ratio
1
was observed by H NMR analysis of the crude reac-
tion mixture. We were able to separate each component
by column chromatography to yield 39% of 7a and 36%
of 7b.
One useful method for the formation of oxygen hetero-
cycles involves the electrophile-induced cyclisation of
an unsaturated alcohol precursor.8 We were able to
access the corresponding alcohol 5 from aldehyde 3 in
A
significant reduction in the level of product
diastereoselectivity is observed on moving from the I+
Scheme 2. Asymmetric amino-Cope rearrangement.
Scheme 3. Electrophile mediated cyclisations.

S. M. Allin et al. / Tetrahedron Letters 43 (2002) 4195–4197
4197
to the PhSe+ electrophile, and this has been noted
References
previously by Greeves for similar substrates.8c It is
likely that this results from a reduced preference by the
PhSe+ electrophile to adopt the same equatorial orien-
tation during cyclisation via a chair-like transition state
that is clearly favoured by I+. Indeed, the work of
Greeves shows that PhSe+ favours an axial orientation
during cyclisation.8c
1. Allin, S. M.; Baird, R. D. Curr. Org. Chem. 2001, 5,
395–415 and references cited therein.
2. Allin, S. M.; Button, M. A. C.; Shuttleworth, S. J. Synlett
1997, 725–727.
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39, 3345–3348; (b) Allin, S. M.; Button, M. A. C.; Baird,
R. D. Synlett 1998, 1117–1119.
4. (a) Allin, S. M.; Button, M. A. C. Tetrahedron Lett. 1999,
40, 3801–3802; (b) Dobson, H. K.; LeBlanc, R.; Perrier,
H.; Stephenson, C.; Welch, T. R.; Macdonald, D. Tetra-
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1117–1119.
Analysis of the separated diastereoisomers by chiral
HPLC11 showed that THP 7a had an e.e. of 92%, again
in good agreement with the e.e. of the starting alcohol
5. The chromatogram of THP 7b was not fully
resolved, although the HPLC trace clearly showed that
the compound was highly enantiomerically enriched.
One final class of tetrahydropyran was prepared
through epoxidation of the double bond followed by
treatment with catalytic CSA. The intermediate epox-
ides (a 2:1 mixture of diastereoisomers) were not sepa-
rated, but directly treated with CSA in CH2Cl2 at 0°C
to yield the target THP 8 as a 2:1 mixture of
diastereoisomers. We were able to separate the
diastereoisomers to yield 28% of the major diastereoiso-
mer 8a and 12% of 8b, and confirm the relative stereo-
chemistries by comparison with the 1H NMR spectra of
the iodotetrahydropyrans.10 In this case we were unable
to determine the e.e. of either diastereoisomer by NMR
or HPLC techniques.
6. Lee, E.; Lee, Y. R.; Moon, B.; Kwon, O.; Shim, M. S.; Yun,
J. S. J. Org. Chem. 1994, 59, 1444–1456.
7. Agami, C.; Meynier, F.; Berlan, J.; Besace, Y.; Brochard,
L. J. Org. Chem. 1986, 51, 73–75.
8. (a) Ting, T. C.; Bartlett, P. A. J. Am. Chem. Soc. 1984, 106,
2668–2671; (b) Bennett, F.; Knight, D. W.; Fenton, G. J.
Chem. Soc., Perkin Trans. 1 1991, 133–140; (c) Greeves, N.;
Lee, W.-M. Tetrahedron Lett. 1997, 38, 6449–6452.
9. Chiral HPLC study carried out using a Chiralcel-OD
column eluting with a 95 hexanes–5% propan-2-ol solvent
mixture at 0.6 ml/min. A racemic sample of the target
under study was prepared and investigated prior to the
enantiomerically enriched product. Retention times: major
enantiomer=18.9 min, minor=22.2 min.
10. In all cases, the major (cis-) diastereoisomers display a
large diaxial coupling of ca. 12 Hz between the C-2 proton
at the chiral centre created on electrophile-induced cyclisa-
tion and the axial C-3 proton. For the minor (trans-)
diastereoisomers, the now equatorial C-2 proton displays
a much weaker axial–equatorial coupling (ca. 4 Hz) to the
same C-3 proton.
In summary we have demonstrated the preparation of
various substituted tetrahydropyran targets in high
enantiomeric excess, representing the first synthetic
application of the asymmetric amino-Cope rearrange-
ment. Further applications are underway in our group,
and these will be reported in due course.
Acknowledgements
11. Chiral HPLC study carried out using a Chiralcel-OD
column eluting with a 99.5 hexanes–0.5% propan-2-ol
solvent mixture at 0.25 ml/min. A racemic sample of the
target under study was prepared and investigated prior to
the enantiomerically enriched product. Retention times:
6a: major enantiomer=46.9 min, minor=42.5 min; 7a:
major enantiomer=51.2 min, minor=60.1 min.
We thank the EPSRC (Quota studentship to R.D.B.;
also postdoctoral fellowship to R.J.L., GR/M41490)
and the University of Loughborough for facilities and
financial support.