Probing the mechanism of Prins cyclisations and application to the synthesis of 4-hydroxytetrahydropyrans

Article abstract of DOI:10.1039/b504562b

Trapping intermediates on the Prins cyclisation pathway with carbon-based nucleophiles has given further insight into factors affecting the acid-mediated reactions of homoallylic alcohols with aldehydes, enabling the design of efficient syntheses of 4-hyd

Full text of DOI:10.1039/b504562b

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Probing the mechanism of Prins cyclisations and application to the
synthesis of 4-hydroxytetrahydropyrans
Conor S. Barry,a Nick Bushby,b John R. Harding,b Rachael A. Hughes,a Gregory D. Parker,a Richard Roea
and Christine L. Willis*a
Received (in Cambridge, UK) 1st April 2005, Accepted 19th May 2005
First published as an Advance Article on the web 16th June 2005
DOI: 10.1039/b504562b
and C and homoallylic acetals were selected as simple precursors
to the charged intermediates. Rychnovsky has shown that Bu3SnH
or Et3SiH can be used as hydride sources in trapping experiments
and our studies began using analogous conditions.4a Thus,
treatment of the electron-rich methoxyethoxymethyl (MEM)
ethers 6a and 6b with BF3?OEt2 in the presence of Et3SiH gave
solely the deoxygenated species 7a and 7b in 83% and 99% yield
respectively (Scheme 1).
Trapping intermediates on the Prins cyclisation pathway with
carbon-based nucleophiles has given further insight into factors
affecting the acid-mediated reactions of homoallylic alcohols
with aldehydes, enabling the design of efficient syntheses of
4-hydroxy-2,6-disubstituted tetrahydropyrans.
Substituted tetrahydropyrans are common structural features of
an array of biologically active natural products and many
incorporate an alcohol (or sugar) at C-4. A valuable approach
to the synthesis of these heterocycles is the acid-promoted Prins-
type cyclisation of an oxycarbenium ion generated in situ, for
example, from reaction of a homoallylic alcohol with an aldehyde
or from a homoallylic acetal or a-acetoxy ether.1 Various reaction
conditions have been employed to prepare C-4 oxygenated
tetrahydropyrans.2 In many cases they are formed in high yield
and with good stereocontrol, incorporating an equatorial hetero-
atom at the C-4 position. Interestingly, the selective introduction of
an axial bromide has been achieved recently.3
The mechanism of the Prins cyclisation is not simple and there is
good evidence for the participation of oxonia-Cope rearrange-
ments.4 In addition, Alder and co-workers have proposed that
cyclisation proceeds via a delocalised cationic intermediate.5 In this
paper we report our recent investigations which have led to a
deeper understanding of Prins-type cyclisations which facilitate the
design of synthetic routes to 4-hydroxytetrahydropyrans.
Fig. 1 Proposed mechanistic pathway for the reaction of a benzylic
homoallylic alcohol with RCHO, AcOH, TMSOAc and BF3?OEt2.
We have reported that treatment of benzylic homoallylic
alcohols with aldehydes in the presence of BF3?OEt2, AcOH and
TMSOAc gave up to 4 products depending upon the electron
density of the aromatic ring.6 The isolated species include the
desired 4-acetoxytetrahydropyran 1, symmetrical tetrahydropyran
2 arising from an allyl exchange process, homoallylic acetate 3 and
the parent benzaldehyde 4 (Fig. 1). The proposed reaction
mechanism involves oxycarbenium ion A which may undergo an
oxonia-Cope rearrangement to give B; both A and B may be
intermediates to the required tetrahydropyran 1. Alternatively,
fragmentation of B leads to an allyl exchange process giving
aldehyde 4 and a new homoallylic alcohol 5 with an alkyl side-
chain. Reaction of 5 with the parent aldehyde gives symmetrical
tetrahydropyran 2. Furthermore
a benzylic carbocation is
implicated in the formation of acetate 3.
The first goal was to gain further evidence for the proposed
mechanism (Fig. 1) by trapping the putative intermediates A, B
aSchool of Chemistry, University of Bristol, Cantock’s Close, Bristol,
UK BS8 1TS. E-mail: chris.willis@bristol.ac.uk
bAstraZeneca UK Ltd., Mereside, Alderley Park, Macclesfield, UK
SK10 4TG
Scheme 1 Hydride reduction of intermediates A, B and C.
Chem. Commun., 2005, 3727–3729 | 3727
This journal is ß The Royal Society of Chemistry 2005

View Article Online
In contrast, under identical conditions the more electron-
deficient analogue 6c gave allyl ether 8 in 64% yield. These results
are in accord with the mechanism shown in Fig. 1. In the case of
the 3,4-methylenedioxy and 4-methoxy species 6a and 6b, the
benzylic carbocation C is stabilised by the electron-rich aromatic
ring and reduction gives 7, whereas with the 4-chloro derivative 6c,
in which a benzylic cation is less favoured, the pathway via the
oxycarbenium ions (A and B) predominates. Reduction occurs on
the more stabilised oxycarbenium ion B (in conjugation with the
aromatic ring) giving ether 8. In neither case was there evidence for
the formation of tetrahydropyrans.7 Similar results were obtained
using BF3?OEt2-promoted reactions in the presence of carbon-
based nucleophiles. Reaction of the electron-rich substrate 6a with
allylTMS and BF3?OEt2 gave diene 9 in 81% yield via attack on
the benzylic carbocation (Scheme 2), whereas with the electron-
deficient 4-chloro derivative 6c, ether 10 was isolated in 51% yield.
Formation of 10 gives no indication as to whether or not an
oxonia-Cope rearrangement is occurring as the product from
oxycarbenium ions A or B with allylTMS would be the same. Thus
TMS cyanide was examined as an alternative carbon-based
nucleophile (Scheme 3). Homoallylic acetal 6c was treated with
TMS triflate and TMS cyanide to yield a 1:9 mixture of isomeric
cyanides 11 and 12, confirming that in this case an oxonia-Cope
rearrangement preferentially occurs prior to formation of the new
carbon–carbon bond.
Scheme 4 Reactions of aliphatic homoallylic acetals.
Scheme 5 Cyclisation of a primary and secondary homoallylic alcohol.
and theoretical calculations, it would be predicted that in the acid-
promoted reaction of homoallylic primary alcohol 17 with
propanal, an oxonia-Cope rearrangement would not be favoured
(Scheme 5).
Having probed the acid-promoted reaction of benzylic homo-
allylic acetals with carbon-based nucleophiles, next trapping of
oxycarbenium ions derived from aliphatic homoallylic acetals was
investigated (Scheme 4). Treatment of the homoallylic MEM
derivative 13 with AlMe3 gave a 1:2 mixture of ethers 14 and 15,
albeit in a disappointing 42% overall yield, whilst with BF3?OEt2
and allylTMS, ether 16 was isolated in 40% yield as approximately
a 1:1 mixture of diastereomers.
The initially formed oxycarbenium ion (A, R 5 H) is more
stable than the unsubstituted oxycarbenium ion B by 9.6 kcal mol21
(by semi-empirical energy minimisations calculated using
Spartan212) and the disubstituted tetrahydropyran should be
formed cleanly. Indeed this proved to be the case and treatment of
17 with propanal and TFA gave tetrahydropyran 18 in 94% yield
following hydrolysis of the initially formed trifluoroacetate
(Scheme 5). In contrast, in the case of the secondary alcohol 19,
the two oxycarbenium ions A and B (R 5 CH3) are of similar
energy (A was calculated to be just 0.42 kcal mol21 more stable
using Spartan212), thus an oxonia-Cope rearrangement and
subsequent allyl transfer reaction may occur leading to a mixture
of products. As expected, treatment of 19 with propanal and TFA
indeed gave, after hydrolysis, two symmetrical tetrahydropyrans
20 and 21 arising from allyl transfer processes as well as the
unsymmetrical tetrahydropyran 22.
Armed with further evidence for the proposed intermediates
A–C (Fig. 1), further factors which may influence the utility of
Prins cyclisations for the synthesis of 4-hydroxytetrahydropyrans
were considered. Based on our understanding of the mechanism
Whilst oxycarbenium ion stability is important, the outcome of
the reaction of a homoallylic alcohol and aldehyde under acidic
conditions may be influenced by further factors including the
nature of the acid and nucleophile. For example, Rychnovsky
has shown that reaction of 3-phenyl-3-hydroxybut-1-ene and
3-phenylpropanal with BF3?Et2O and AcOH gave a mixture of 4
products, whereas with SnBr4 a cleaner reaction occurred, giving
the 4-bromotetrahydropyran as the major product in 77% yield.1f
We have reported8 the use of a Prins cyclisation (pathway A,
where P 5 Ac, Scheme 6) to construct the tetrahydropyran core of
catechols 23 and 24 isolated from extracts of the woody plant,
Plectranthus sylvestris (Labiatae).9 Treatment of (S)-homoallylic
alcohol 25 (90% ee) with hexanal in the presence of BF3?OEt2,
AcOH and TMSOAc gave the required tetrahydropyran 26 in
72% yield as a single diastereomer but with some loss of
enantiopurity (80% ee) (Scheme 7).
Scheme 2 Allyl trapping of intermediates A, B and C.
Scheme 3 Cyanide trapping of oxycarbenium ion intermediates A and B.
3728 | Chem. Commun., 2005, 3727–3729
This journal is ß The Royal Society of Chemistry 2005

View Article Online
choice of the components for the Prins cyclisation, the synthesis of
the catechols was achieved with excellent stereocontrol and with no
loss of enantiopurity of the starting homoallylic alcohol.
In conclusion, we have shown that oxycarbenium ion
intermediates A and B (Fig. 1) in Prins cyclisations may be
trapped with carbon-based nucleophiles (allylTMS, TMSCN and
AlMe3). In addition, in the case of electron-rich benzylic
homoallylic alcohols the proposed benzylic carbocation C may
be trapped with either a hydride source or allylTMS. A deeper
understanding of the mechanism of the Prins cyclisation has
enabled a more effective route to the enantioselective synthesis of
catechols 23 and 24 to be achieved. Armed with this further
knowledge of factors affecting the outcome of Prins-type
cyclisations, the design of efficient strategies to the synthesis of
complex tetrahydropyrans will be possible.
Scheme 6 Retrosynthetic analysis of catechols 23 and 24.
We are grateful to AstraZeneca UK Ltd, the University of
Bristol and EPSRC for funding to CSB, RAH and GDP and to
Professor R. W. Alder for valuable assistance with molecular
modelling and calculations.
Notes and references
1 Examples of Prins cyclisations include: (a) M. J. Cloninger and
L. E. Overman, J. Am. Chem. Soc., 1999, 121, 1092; (b) S. D.
Rychnovsky, Y. Hu and B. Ellsworth, Tetrahedron Lett., 1998, 39, 7271;
(c) E. H. Al-Mutairi, S. R. Crosby, J. Darzi, J. R. Harding,
R. A. Hughes, C. D. King, T. J. Simpson, R. W. Smith and
C. L. Willis, Chem. Commun., 2001, 835; (d) D. J. Dixon, S. V. Ley and
E. W. Tate, J. Chem. Soc., Perkin Trans. 1, 2000, 1829; (e) D. J. Hart
and C. E. Bennett, Org. Lett., 2003, 5, 1499; (f) J. E. Dalgard and
S. D. Rychnovsky, J. Am. Chem. Soc., 2004, 126, 15662.
2 For examples of the introduction of an oxygen-containing nucleophile
at C-4 see: (a) W.-C. Zhang and C.-J. Li, Tetrahedron, 2000, 56, 2403;
(b) S. D. Rychnovsky and C. R. Thomas, Org. Lett., 2000, 2, 1217; (c)
C. St. J. 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; (d)
S. A. Kozmin, Org. Lett., 2001, 3, 755; (e) M. Nishizawa,
T. Shigaraki, H. Takao and H. T. Imagawa, Tetrahedron Lett., 1999,
40, 1153.
Scheme 7 Construction of framework of catechols 23 and 24.
Based on the further insight into the mechanism of Prins
reactions gained in the investigations described herein, we returned
to the synthesis of catechols 23 and 24. It was apparent that if the
tetrahydropyran core was to be constructed via pathway A
(Scheme 6), then the aromatic ring of the benzylic homoallylic
alcohol would need to be more deactivated than in diacetate 25.
Thus the ditosylate 27 was investigated. Treatment of 27 with
hexanal under the BF3?OEt2-promoted cyclisation conditions gave
4-acetoxytetrahydropyran 28 as a single diastereomer in 44% yield
along with the corresponding 4-fluoro derivative 29 (8%) and
recovered starting material 25 (41%) (Scheme 7). All attempts to
convert ditosylate 28 to the required catechols 23 and 24 were
unsuccessful, leading to decomposition.10
3 R. Jasti, J. Vitale and S. D. Rychnovsky, J. Am. Chem. Soc., 2004, 126,
9904.
4 Examples of oxonia-Cope rearrangements include: (a) S. D.
Rychnovsky, S. Marumoto and J. J. Jaber, Org. Lett., 2001, 3, 3815;
(b) W. R. Roush and G. J. Dilley, Synlett, 2001, 955; (c) C. M. Gasparki,
P. M. Herrinton, L. E. Overman and J. P. Wolfe, Tetrahedron Lett.,
2000, 41, 9431; (d) T.-P. Loh, Q.-Y. Hu and L.-T. Ma, J. Am. Chem.
Soc., 2001, 123, 2450; (e) C. Semeyn, R. H. Blaauw, H. Hiemstra and
W. N. Speckamp, J. Org. Chem., 1997, 62, 3426; (f) H. B. Huang and
J. S. Panek, J. Am. Chem. Soc., 2000, 122, 9836.
5 R. W. Alder, J. N. Harvey and M. T. Oakley, J. Am. Chem. Soc., 2002,
124, 4960.
6 S. R. Crosby, J. R. Harding, C. D. King, G. D. Parker and C. L. Willis,
Org. Lett., 2002, 4, 577.
7 Interestingly, using a-acetoxy ethers, Rychnovsky and co-workers
observed the formation of tetrahydropyrans when using Et3SiH/
BF3?Et2O conditions,4a albeit in low yields.
8 S. R. Crosby, J. R. Harding, C. D. King, G. D. Parker and C. L. Willis,
Org. Lett., 2002, 4, 3407.
9 M. Juch and P. Ruedi, Helv. Chim. Acta, 1997, 80, 436.
10 An aromatic tosylate has been used in Prins cyclisations in the synthesis
of centrolobine: S. Marumoto, J. J. Jaber, J. P. Vitale and S. D.
Rychnovsky, Org. Lett., 2002, 4, 3919.
11 H. C. Brown, K. S. Bhat and R. S. Randad, J. Org. Chem., 1987, 52,
319.
12 Spartan, Wavefunction, Inc., Irvine, CA.
Thus the retrosynthetic analysis of catechols 23 and 24 was
reconsidered (Scheme 6). In pathway B, the homoallylic alcohol 31
now has a simple alkyl side-chain which is less able to stabilise a
carbocation than the benzylic analogue and hence it was predicted
that tetrahydropyran 26 should be formed with no loss of
stereochemical integrity. In addition, the initially formed oxycar-
benium ion would be stabilised by conjugation with the aromatic
ring and thus an oxonia-Cope rearrangement would be dis-
favoured. Using 3,4-diacetoxybenzaldehyde 30 and racemic
alcohol under the standard BF3?OEt2-mediated conditions gave
tetrahydropyran 26 in 68% yield (Scheme 7). (S)-Homoallylic
alcohol 31, was prepared in 91% yield by treatment of hexanal
with allylmagnesium chloride and (+)-DIPC1.11 Reaction of 31
(88% ee as determined by chiral GC) with hexanal under the
standard conditions gave the required tetrahydropyran 26 (88% ee)
with no loss of stereochemical purity. Hydrolysis of the acetates in
26 as previously reported gave a short and efficient route for the
syntheses of the natural products 23 and 24.8 Thus by judicious
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 3727–3729 | 3729