Intramolecular Prins cyclisations for the stereoselective synthesis of bicyclic tetrahydropyrans

Article abstract of DOI:10.1039/b717078e

Methyl (4E,7R)-7-hydroxyoctanoate was prepared in 71% yield from ethyl (R)-3-hydroxybutanoate and on reaction with a series of aldehydes in the presence of TMSOTf gave bicyclic oxygen heterocycles in good yields and with the creation of three new stereogenic centres in a single pot. The Royal Society of Chemistry.

Full text of DOI:10.1039/b717078e

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Intramolecular Prins cyclisations for the stereoselective synthesis of
bicyclic tetrahydropyransw
Jon D. Elsworth and Christine L. Willis*
Received (in Cambridge, UK) 5th November 2007, Accepted 21st January 2008
First published as an Advance Article on the web 21st February 2008
DOI: 10.1039/b717078e
Methyl (4E,7R)-7-hydroxyoctanoate was prepared in 71% yield
from ethyl (R)-3-hydroxybutanoate and on reaction with a series
of aldehydes in the presence of TMSOTf gave bicyclic oxygen
heterocycles in good yields and with the creation of three new
stereogenic centres in a single pot.
Saturated oxygen containing heterocycles, of varying size, are
common structural features of many biologically active natural
products, for example the phorboxazoles1 and bryostatins;
often these compounds are isolated in only minute quantities.2
In order to confirm their structures and gain sufficient material
for full biological assessment of the natural products and
analogues, the development of efficient methods for the synth-
esis of oxygen heterocycles remains an important goal.3
Whilst Prins cyclisations4 have been used for the stereoselec-
tive assembly of functionalised tetrahydrofurans5 and larger
oxacycles,6 they are more commonly employed for the synthesis
of tetrahydropyrans.7 The reaction involves the acid mediated
in situ generation of a homoallylic oxycarbenium ion, which
cyclises in the presence of a nucleophile to give the tetrahydro-
pyran. In the majority of cases an intermolecular reaction
between oxycarbenium ions and nucleophiles has been used8
but we envisaged that by tethering a suitable nucleophilic
functional group, novel bicyclic oxygen heterocycles may be
prepared (Scheme 1). Oxygenated nucleophiles such as acetic
acid or trifluoroacetic acid have been employed for intermole-
cular variants and consequently our investigations began with a
homoallylic alcohol with a tethered carboxylic acid.
Scheme 1 Proposed intramolecular Prins cyclisation.
allyl transfer processes may occur depending on the stabilisa-
tion of the initially formed oxycarbenium ion compared with
that subsequently generated via a [3,3]-sigmatropic rearrange-
ment.9 In the case illustrated in Scheme 2 the driving force
behind the rearrangement is likely to be stabilisation of the
oxycarbenium ion by the methyl group in 5 compared with the
terminal oxycarbenium ion present in 4.
Rychnovsky and coworkers have illustrated that the reac-
tion conditions also play an important role in controlling the
participation of an oxonia-Cope rearrangement and as such
the use of a non-polar solvent can minimise the production of
any unwanted by-products.9g Therefore, acetal 1 was treated
again with BF3ÁOEt2 but instead of using CH2Cl2 the reaction
was conducted in hexane. Encouragingly, lactone 3 was no
longer detected in the mixture and only the desired tetrahy-
dropyran 2 was isolated as a single diastereomer, albeit in only
41% yield (Table 1, Entry 3).
First, acetal 1 was treated with a catalytic amount of triflic
acid in CH2Cl2 but none of the expected bicyclic product, 2,
was isolated. Indeed the only product obtained after column
chromatography was the unsaturated lactone 3 (Table 1, Entry
1). Next acetal 1 was treated with catalytic BF3ÁOEt2 in
CH2Cl2 which mainly led to degradation and again the only
product isolated was 3 in 18% yield (Table 1, Entry 2). We
propose that lactone 3 was formed via an oxonia-Cope
rearrangement of the initially formed oxycarbenium ion, 4,
to 5 followed by hydrolytic cleavage to the hydroxy acid and
in situ lactonisation (Scheme 2).
Whilst MEM acetal 1 was originally selected as a simple
model to investigate the potential of Prins cyclisations for the
Table 1 Acid mediated cyclisation of homoallylic acetal 1
It has been demonstrated that the mechanism of the Prins
cyclisation is not simple and oxonia-Cope rearrangements and
Yielda (%)
2
3
Entry
Conditions
1
2
3
TfOH(cat), DCM, RT, 1 h
BF3ÁOEt2(cat), DCM, RT, 4 h
—
—
41
37
18
—
School of Chemistry, University of Bristol, Bristol, UK BS8 1TS.
E-mail: chris.willis@bristol.ac.uk; Fax: +44 (0) 117 929 8611;
Tel: +44 (0) 117 928 7660
w Electronic supplementary information (ESI) available: Experimental
data for the tetrahydroprans. See DOI: 10.1039/b717078e
BF3ÁOEt2, TMSOAc, Hexane, RT, 1 h
a
Isolated yield.
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Table 2 Optimisation of the conversion of 9 to 10
Entry Conditionsa
Yieldd of 10 (%)
1b
2c
3
4
5
TFA, DCM, RT, 5 h
29
MeSO3H, DCM, À10 1C - RT, 2.5 h 48
BF3ÁOEt2, DCM, À78 1C - RT, 2.5 h 56
Sc(OTf)3, DCM, À10 1C - RT, 2.5 h 83
TfOH, DCM, 0 1C - RT, 1.5 h
90
93
6
TMSOTf, DCM, À45 1C - RT, 2 h
a
General procedure: acid (1.0 eq, 1.5 mmol) was added to 9 (1.5
mmol) and 4-anisaldehyde (1.1 eq, 1.65 mmol) in dry CH2Cl2
b
under N2. 5.0 eq of TFA was required. 2.0 eq of MeSO3H was
c
Scheme 2 Competing oxonia-Cope cascade.
d
required. Isolated yield.
synthesis of bicyclic targets, it is limited to the introduction of
a methylene next to the oxygen in the tetrahydropyran ring
and in the event led to poor yields of 2. Ideally we required an
approach that not only would give an improved yield but also
allow greater structural variation in the target bicyclic oxygen
heterocycles. An attractive option was to use a functionalised
homoallylic alcohol which could react with an aldehyde to
introduce a range of substituents at C-7 of the tetrahydropyr-
an. We have previously found that on treatment of unsatu-
rated a-hydroxy esters with iodine at room temperature
cyclisation occurred to give lactones in good yields.10 Hence
we envisaged that tethering an ester onto the homoallylic
alcohol would potentially facilitate the required cyclisation.
Homoallylic alcohol 9 was prepared in 71% yield from ethyl
(R)-3-hydroxybutanoate 6 as shown in Scheme 3. The key
steps were the addition of vinylmagnesium bromide to the
known aldehyde 711 to give 8, which on reaction with tri-
methylorthoacetate in the presence of catalytic propionic acid
underwent a Claisen rearrangement to give, after deprotection,
the required (E)-unsaturated ester 9.
crystalline solid but in just 29% yield (Table 2, entry 1).
Different acids were screened as summarised in Table 2 and
the optimised conditions proved to be the use of TMS triflate
in CH2Cl2 to give the required product 10 in 93% yield.
It was clear from the spectral data of 10 that a single
diastereomer had been formed with a trans ring junction and
the two substituents on the tetrahydropyran ring in an equa-
torial position (Fig. 1). Hence in a single-pot process homo-
allylic alcohol 9 had been converted to lactone 10 in 93% yield,
with the creation of 3 new stereogenic centres and the forma-
tion of two new heterocyclic rings.
Anisaldehyde was selected in these initial studies mainly
because an electron-rich aromatic ring has been shown to
stabilise an adjacent oxycarbenium ion,9b,c which removes the
potential complication of a competing oxonia-Cope rearran-
gement. However, the next stage was to explore the scope of
the reaction using a series of electrophiles. Accordingly,
Table 3 illustrates that this variant on the Prins cyclisation
may be used to prepare a wide range of bicyclic products with
different substituents at C-7. For example, alcohol 9 reacts
efficiently with either benzaldehyde or p-nitrobenzaldehyde to
give the bicyclic lactones 11 and 12, confirming that the
electronic properties of the aromatic ring have little influence
on the outcome of the reaction. Furthermore propanal, with a
simple aliphatic side-chain, gave 14 in 72% yield (Entry 4)
whilst in the case of a functionalised aldehyde such as acrolein
Treatment of homoallylic alcohol 9 with anisaldehyde in the
presence of TFA gave the novel tetrahydropyran 10 as a
Fig. 1 Diagnostic coupling constants in the 1H-NMR spectrum
(400Mz, CDCl3) of 10.
Scheme 3 Synthesis of homoallylic alcohol 9.
1588 | Chem. Commun., 2008, 1587–1589
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Table 3 Reaction of alcohol 9 with a range of electrophiles
reaction was also successful with a ketone (Entry 6) giving the
spirocyclic product 16; in this case a longer reaction time and
extra equivalents of ketone and TMS triflate were required.
Thus it is evident that this chemistry has widespread applica-
tion for the synthesis of a series of novel bicyclic heterocycles.
In summary, an efficient method for the synthesis of methyl
(4E,7R)-7-hydroxyoctanoate 9 is described from commercially
available ethyl (R)-3-hydroxybutanoate 6 using a Claisen
rearrangement to establish the E-double bond. Reaction of
hydroxy ester 9 with various aldehydes in the presence of
TMSOTf gave novel bicyclic products in good yield and with
the creation of 3 new stereogenic centres in a single pot
process. Furthermore a spirocyclic product 16 was isolated
when cyclopentanone was used as the electrophile.
Entrya Electrophile
Product
Yieldc (%)
1
81
We would like to thank the EPSRC for financial support
and Dr D. O. Rees for a preliminary investigation of the
cyclisation of 1.
Notes and references
2
71
1 (a) P. A. Searle and T. F. Molinski, J. Am. Chem. Soc., 1996, 118,
9422; (b) T. F. Molinski, Tetrahedron Lett., 1996, 37, 7879.
2 (a) Review: G. R. Pettit, The Bryostatins, in Progress in the
Chemistry of Organic Natural Products, ed. W. Herz, G. W. Kirby,
W. Steglich and C. Tamm, Springler-Verlag, New York, 1991, vol.
57, pp 153–195; (b) G. R. Pettit, F. Gao, P. M. Blumberg, C. L.
Herald, J. C. Coll, Y. Kamano, N. E. Lewin, J. M. Schmidt and J-
C. Chapuis, J. Nat. Prod., 1996, 59, 286, and references therein.
3 (a) S. Santos and P. A. Clarke, Eur. J. Org. Chem., 2006, 2045; (b)
M. C. Elliott, J. Chem. Soc., Perkin Trans. 1, 2002, 2301, and
previous articles in the series.
3
73
4 (a) E. Arundale and L. A. Mikeska, Chem. Rev., 1952, 51, 505; (b)
D. R. Adams and S. P. Bhatnagar, Synthesis, 1977, 661; (c) B. B.
Snider, in Comprehensive Organic Synthesis, ed. B. M. Trost,
Pergamon Press, New York, 1991, vol. 2, p. 527.
5 (a) P. Mohr, Tetrahedron Lett., 1993, 34, 6251; (b) F. Cohen, D. W.
C. MacMillan, L. E. Overman and A. Romero, Org. Lett., 2001, 3,
1225.
6 L. E. Overman and A. S. Thompson, J. Am. Chem. Soc., 1988, 110,
2248.
4
72
84
63
7 (a) S. D. Rychnovsky, Y. Hu and B. Ellsworth, Tetrahedron Lett.,
1998, 39, 7271; (b) M. J. Cloninger and L. E. Overman, J. Am.
Chem. Soc., 1999, 121, 1092; (c) D. J. Kopecky and S. D.
Rychnovsky, J. Org. Chem., 2000, 65, 191; (d) C. S. Barry, S. R.
Crosby, J. R. Harding, R. A. Hughes, C. D. King, G. D. Parker
and C. L. Willis, Org. Lett., 2003, 5, 2429; (e) K.-P. Chan and T.-P.
Loh, Org. Lett., 2005, 7, 4491.
8 Intramolecular variants include: (a) M. L. Bolla, B. Patterson and
S. D. Rychnovsky, J. Am. Chem. Soc., 2005, 127, 16044; (b) X.-F.
Yang, M. Wang, Y. Zhang and C.-J. Li, Synlett, 2005, 1912.
9 (a) L. D. M. Lolkema, C. Semeyn, L. Ashek, H. Hiemstra and W.
N. Speckamp, Tetrahedron, 1994, 50, 7129; (b) S. R. Crosby, J. R.
Harding, C. D. King, G. D. Parker and C. L. Willis, Org. Lett.,
2002, 4, 577; (c) S. R. Crosby, J. R. Harding, C. D. King, G. D.
Parker and C. L. Willis, Org. Lett., 2002, 4, 3407; (d) S. Marumoto,
J. J. Jaber, J. P. Vitale and S. D. Rychnovsky, Org. Lett., 2002, 4,
3919; (e) R. Jasti C. D. Anderson and S. D. Rychnovsky, J. Am.
Chem. Soc., 2005, 127, 9939; (f) R. Jasti and S. D. Rychnovsky,
Org. Lett., 2006, 8, 2175; (g) R. Jasti and S. D. Rychnovsky, J. Am.
Chem. Soc., 2006, 128, 13640; (h) C. S. Barry, N. Bushby, J. R.
Harding, R. A. Hughes, G. D. Parker, R. Roe and C. L. Willis,
Chem. Commun., 2005, 3727.
5
6b
a
General procedure: TMSOTf (1.0 eq, 1.5 mmol) was added to 9
(1.5 mmol) and electrophile (1.1 eq, 1.65 mmol) in dry CH2Cl2 at
b
À10 1C under N2 and stirred for 15 min. After 2 h at RT extra
TMSOTf (0.5 eq) and cyclopentanone (0.5 eq) were added with
c
stirring for a further 1.5 h. Isolated yield.
10 J. A. Macritchie, T. M. Peakman, A. Silcock and C. L. Willis,
Tetrahedron Lett., 1998, 39, 7415.
11 See for example: (a) M. M. Claffey and C. H. Heathcock, J. Org.
Chem., 1996, 61, 7646; (b) S. G. Nelson, W. S. Cheung, A. J.
Kassick and M. A. Hilfiker, J. Am. Chem. Soc., 2002, 124, 13654.
(Entry 5) the product 15 was formed with an alkene side-chain,
a useful handle for further manipulations. Interestingly, the
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