The silylalkyne-prins cyclization: Stereoselective synthesis of tetra- and pentasubstituted halodihydropyrans

Article abstract of DOI:10.1021/ol060247m

A new type of Prins cyclization using silylated secondary homopropargylic alcohols and aldehydes yielding tetra- and pentasubstituted dihydropyrans is described. The presence of the trimethylsilyl group in the triple bond favors the Prins cyclization and

Full text of DOI:10.1021/ol060247m

ORGANIC
LETTERS
2006
Vol. 8, No. 8
1633-1636
The Silylalkyne-Prins Cyclization:
Stereoselective Synthesis of Tetra- and
Pentasubstituted Halodihydropyrans
Pedro O. Miranda, Miguel A. Ram´ırez, V´ıctor S. Mart´ın,* and Juan I. Padro´n*
Instituto UniVersitario de Bio-Orga´nica “Antonio Gonza´lez”, UniVersidad de La
Laguna, C/Astrof´ısico Francisco Sa´nchez 2, 38206 La Laguna, Tenerife, Spain
jipadron@ull.es; Vmartin@ull.es
Received January 27, 2006
ABSTRACT
A new type of Prins cyclization using silylated secondary homopropargylic alcohols and aldehydes yielding tetra- and pentasubstituted
dihydropyrans is described. The presence of the trimethylsilyl group in the triple bond favors the Prins cyclization and minimizes the 2-oxonia-
[3,3]-sigmatropic rearrangement as a competitive alternative pathway. Ab initio theoretical calculations of the species involved in the
rearrangements support the proposed mechanism. The process is highly stereoselective, affording cis-dihydropyran as the only isomer.
The Prins cyclization is a powerful tool to obtain substituted
tetrahydropyrans.1,2 When homoallylic alcohols or R-acetoxy
ethers are used to generate the oxocarbenium ion intermedi-
ate, an oxonia-Cope rearrangement can take place as a
competitive process with the Prins cyclization (Figure 1).
When enantiomeric chiral starting materials are used, this
rearrangement occasionally becomes deleterious to the Prins
cyclization, giving a partial or total racemization.1d,f,3 A full
study including factors to modulate these competitive
processes has been recently reported by Rychnovsky et al.2f
(1) (a) Adams, D. R.; Bhatnagar, S. P. Synthesis 1977, 661-672. (b)
Cloninger, M. J.; Overman, L. E. J. Am. Chem. Soc. 1999, 121, 1092-
1093. (c) Lo´pez, F.; Castedo, L.; Mascaren˜as, J. L. J. Am. Chem. Soc. 2002,
124, 4218-4219. (d) Rychnovsky, S. D.; Marumoto, S.; Jaber, J. J. Org.
Lett. 2001, 3, 3815-3818. (e) Marumoto, S.; Jaber, J. J.; Vitale, J. P.;
Rychnovsky, S. D. Org. Lett. 2002, 4, 3919-3922. (f) Barry, C. S. J.;
Crosby, S. R.; Harding, J. R.; Hughes, R. A.; King, C. D.; Parker, G. D.;
Willis, C. L. Org. Lett. 2003, 5, 2429-2432.
(2) For recent examples in the use of Prins reaction, see: (a) Dobbs, A.
P.; Guesne´, J. J.; Martinovic, S.; Coles, S. J.; Hursthouse, M. B. J. Org.
Chem. 2003, 68, 7880-7883. (b) Yadav, V. K.; Kumar, N. V. J. Am. Chem.
Soc. 2004, 126, 8652-8653. (c) Rychnovsky, S. D.; Dalgard, J. E. J. Am.
Chem. Soc. 2004, 126, 15662-15663. (d) Yu, C.-M.; Yoon, S. K.; Hong,
Y. T.; Kim, J. Chem. Commun. 2004, 1840-1841. (e) Overman, L. E.;
Velthuisen, E. J. Org. Lett. 2004, 6, 3853-3856. (f) Jasti, R.; Anderson,
C. D.; Rychnovsky, S. D. J. Am. Chem Soc. 2005, 127, 9939-9945 and
references therein. (g) Chan, K.-P.; Loh, T.-P. Org. Lett. 2005, 7, 4491-
4494.
Figure 1. Prins cyclization and oxonia-Cope rearrangement.
We have found a new Prins-type cyclization between
homopropargylic alcohol and aldehydes in the presence of
inexpensive, environmentally friendly, and stable iron(III)
halides to obtain 2-alkyl-4-halo-5,6-dihydro-2H-pyrans 4 (R1
) R2 ) R4 ) H).4 However, when secondary homopropar-
gyllic alcohols were used the reaction proceeded by a domino
(3) (a) Crosby, S. R.; Harding, J. R.; King, C. D.; Parker, G. D.; Willis,
C. L. Org. Lett, 2002, 4, 577-580. (b) Barry, C. S.; Bushby, N.; Harding,
J. R.; Hughes, R. A.; Parker, G. D.; Roe, R.; Willis, C. L. Chem. Commun.
2005, 3727-3729.
(4) (a) Miranda, P. O.; Diaz, D. D.; Padro´n, J. I.; Bermejo, J.; Mart´ın,
V. S. Org. Lett. 2003, 11, 1979-1982. (b) Miranda, P. O.; Diaz, D. D.;
Padro´n, J. I.; Ram´ırez, M. A.; Mart´ın, V. S. J. Org. Chem. 2005, 70, 57-
62.
10.1021/ol060247m CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/25/2006

sequence through an allenolate formation, further 1,3-O-
transposition, and enolate coupling leading to unsaturated
â-hydroxy ketones 5 as the main products. In this sequence,
an oxonia-[3,3]-sigmatropic rearrangement over the oxocar-
benium ion 2, as competitive alternative pathway to the Prins
cyclization, leads to the key allenolate 3 (Scheme 1).5 The
Table 1. Silylalkyne-Prins Cyclization of Secondary
Trimethylsilyl Homopropargylic Alcohols and Aldehydes Using
FeX3 as a Promoter
Scheme 1. Coupling of Homopropargylic Alcohols and
Aldehydes Catalyzed by Iron(III) Halides
entry
R1
Me
Me
Me
Me
Me
Et
Bn
R2
R3
X
6/7
yield (%)
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
H
i-Bu
Cl
50:50
80
65
c-C6H11
Ph
Cl >99:1c
Cl
s-Bu
s-Bu
Cl >99:1c
Br >99:1c
Cl >99:1c
Cl >99:1c
Cl >99:1c
Cl >99:1c
82
75
75
57
55
61
60
62
c-C6H11
c-C6H11
c-C6H11
Bn
c-C6H11
c-C6H11
Me
10a
11b
Me Br2CdCH(CH2)- Cl >99:1c
Me c-C6H11
Cl >99:1c
Me
a Racemic (2R*,3R*)-3-methyl-5-(trimethylsilyl)pent-4-yn-2-ol was used
as 1. b Racemic (2S*,3R*)-3-methyl-5-(trimethylsilyl)pent-4-yn-2-ol was
used as 1. c Within the NMR detection limit, 7 was not observed.
reaction works well with a wide range of aldehydes except
benzaldehyde (entry 3). However, other aldehydes containing
aromatic rings, although located on a distal position relative
to the carbonyl group, proceeded satisfactorily (entry 9).
The presence of the silyl group at the alkyne is essential
to achieve the reaction since when the acetylene is substituted
with a methyl group the process is inhibited. In addition,
the size of the substituent at the silicon atom is also a critical
factor. For instance, when the triple bond bears a triisopropyl
silyl group instead of TMS, the reaction does not take place.
The alkyne silyl-Prins reaction proceeds at room temper-
ature and with complete diastereocontrol, obtaining exclu-
sively the cis-2,6-dihydropyran product. An exception was
found for 3-methylbutanal (entry 1).
With this methodology in hand, we can access tetra- and
pentasubstituted dihydropyrans in one step using the suitable
secondary trimethylsilyl homopropargylic alcohol. The alkyne-
Prins cyclization worked in good yields, leading to the
pentasubstituted dihydropyrans, when 3-methyl-5-(trimeth-
ylsilyl)pent-4-yn-2-ol was used as starting material (entries
10 and 11).
To account for the stereochemical course of the reaction,
“ab initio” theoretical calculations at the B3LYP/6-31G(d)
level were performed for some cases of 6 and 7 (Table 2).
The calculations showed that the cis stereoisomers 6 are
always more stable than trans isomers 7. The small energetic
difference for both stereoisomers when R3 ) i-Bu accounts
for the only exception (50:50) (Table 1, entry 1) relative to
the general stereochemical course of the reaction.
As pointed out above, the presence of the trimethylsilane
is essential to generate the corresponding dihydropyran.
Surprisingly, the obtained halosilylalkene proved to be a very
unreactive system. For instance, all standard conditions
course of the reaction (rearrangement or Prins type cycliza-
tion) depends directly on the stability of the species involved
in this rearrangement.
Considering the well-documented silyl-modified Prins
cyclization,6 we decided to explore the introduction of a
trimethylsilyl group in the triple bond (R4 ) TMS), as a
way to minimize the 2-oxonia-[3,3]-sigmatropic rearrange-
ment in the above-mentioned equilibrium.7
In this paper, we describe a new, general, and stereose-
lective method to obtain tetra- and pentasubstituted dihy-
dropyrans based on an alkyne silyl-Prins cyclization cata-
lyzed by iron(III) halides. Ab initio theoretical calculations
of the species involved in the rearrangement support our
results and the proposed mechanism.
First, to test the scope of FeX3 in this coupling reaction,
we carried out the reaction between secondary trimethylsilyl
propargyllic alohols (1, R4 ) TMS, R2 * H) and several
8
aldehydes using FeCl3 and FeBr3 as promoters.9 Table 1
summarizes the results obtained in this study.
The methodology produced exclusively and in good yield
the desired six-membered rings. No traces of the products
resulting from the oxonia rearrangement were observed. The
(5) Miranda, P. O.; Ram´ırez, M. A.; Padro´n, J. I.; Mart´ın, V. S.
Tetrahedron Lett. 2006, 47, 283-286.
(6) Silyl-modified Prins cyclization: (a) Semeyn, C.; Blaauw, R. H.;
Hiemstra, H.; Speckamp, W. N. J. Org. Chem. 1997, 62, 3426-3427. (b)
Viswanathan, G.; S.; Yang, J.; Li, C.-J. Org. Lett. 1999, 1, 993-995.(c)
Dobbs, A. P.; Martinovic, S. Tetrahedron Lett. 2002, 43, 7055-7057. (d)
Dobbs, A. P.; Guesne, S. J. J.; Martinovic, S.; Coles, S. J.; Hursthouse, M.
B. J. Org. Chem. 2003, 68, 7880-7883. (c) Meilert, K.; Brimble, M. A.
Org. Lett. 2005, 7, 3497-3500.
(7) Lee, K.-C.; Lin, M.-J.; Loh, T.-P. Chem. Commun. 2004, 2456-
2457.
(8) FeCl3 and FeBr3 were purchased form the Aldrich Chemical Co.
(9) For availability or synthesis of 1, see the Supporting Information.
1634
Org. Lett., Vol. 8, No. 8, 2006

Scheme 2. Proposed Mechanism for the Addition of
Secondary TMS-Homopropargylic Alcohols and Aldehydes
Table 2. Ab Initio Calculations of Some cis- and
trans-2-Alkyl-4-chloro-6-methyl-5,6-dihydro-2H-pyran-3-yl)-
trimethylsilanes
entry
R1
R2
R3
Ecis - Etransa (kcal/mol)
1
2
3
Me
Me
Me
H
H
H
i-Bu
c-C6H11
s-Bu
-0.6
-3.8
-2.5
a 6 (cis) and 7 (trans) were fully optimized at B3LYP/6-31G(d) level
“ab initio” calculation.
assayed to cleave the C-Si bond proved fruitless.10 Fortu-
nately, the cleavage of the TMS group was satisfactorily
achieved under aqueous iodhydric acid11 refluxing for 1
week. Besides the long reaction time period, the correspond-
ing desilylated dihydropyrans were obtained in excellent
yields with complete retention of the cis or trans configu-
ration (Table 3).
the other hand, the suppression of the silyl group in the
alkynyl carbocation 13 leads to the 3.24 kcal/mol more stable
allenyl carbocation 14. This energy profile correlates very
well with our proposed mechanism.
Table 3. Desilylation of the Tetra- and Pentasubstituted
Dihydropyrans. Synthesis of
2,6-Dialkyl-4-chloro-5,6-dihydro-2H-pyrans
entry
R1
R2
R3
i-Bu
i-Bu
c-C6H11
c-C6H11
cis or trans
yield (%)
1
2
3
4
Me
Me
Me
Me
H
H
H
Me
cis
trans
cis
88
87a
86
92
cis
a The reflux period was extended to 2 weeks.
A plausible mechanism for this new alkyne silyl-Prins
cyclization is outlined in Scheme 2. The reaction of the
secondary silyl-homopropargylic alcohol and an aldehyde
promoted by ferric halide generates the oxocarbenium ion
8.4 This intermediate evolves to the corresponding-DHP, via
the silicon-stabilized â-carbocation 9.12
To provide further evidence of the proposed mechanism,
“ab initio” theoretical calculations at the B3LYP/6-31G(d)
level were performed on simplified structures. The results
of these calculations are summarized in the energy diagrams
shown in Figure 2. The rearrangement with silicon is less
favored than without silicon. Thus, the R-silane allenyl cation
12 is 5.70 kcal/mol less stable than 10, which indicates that
this rearrangement is not favored. In addition, the silyl cation
11 is 7.71 kcal/mol less stable than its open form 10, which
could be the intermediate toward the Prins cyclization.13 On
Figure 2. Energy (kcal/mol) profile of 2-oxonia-[3,3]-sigmatropic
rearrangements.
Interestingly, we were unable to locate a dihydropyranyl
cation intermediate for the alkynyl carbocation ion 13,
presumably indicating a concerted pathway to 14.
To confirm that no racemization was occurring during the
cyclizations to the tetrasubstituted dihydropyrans, (R)-1-
cyclohexyl-4-(trimethylsilyl)but-3-yn-1-ol (93% ee)14 was
treated with 2-phenylacetaldehyde and FeCl3. The corre-
sponding dihydropyran 16 (86% ee) shows a slightly reduced
but still synthetically useful enantiopurity compared to the
starting homopropargylic alcohol (R)-15 (93% ee) (Scheme
3). This small difference may be due either to a fast
equilibrium between the favored cationic species such as 11
(10) Desilylation conditions tested: TBAF/THF, HF/CH3CN, I2/H2O/
CH2Cl2 refluxing.
(11) Mayr, H.; Ba¨uml, E.; Cibura, G.; Koschinsky, R. J. Org. Chem.
1992, 57, 768-772.
(12) Siehl, H.-U. Pure Appl. Chem. 1995, 67, 769-775.
(13) A transition state A of close energy to the silyl cation intermediate
11 should exist.
(14) The (R)-1-cyclohexyl-4-(trimethylsilyl)but-3-yn-1-ol was prepared
in seven steps (32% overall yield, 93% ee) from (E)-3-cyclohexylprop-2-
en-1-ol. See the Supporting Information.
Org. Lett., Vol. 8, No. 8, 2006
1635

avoiding the reactions derived from a competitive 2-oxonia-
[3,3]-sigmatropic rearrangement. The coupling between
chiral secondary homopropargylic alcohols bearing a tri-
methylsilyl group at the triple bond and aldehydes in the
presence of iron(III) halides, provides (2,5,6-trialkyl-4-halo-
5,6-dihydro-2H-pyran-3-yl)trimethylsilane in good yields
maintaining the enantiopurity of the starting material at a
very good level. Ab initio theoretical calculations support
the proposed mechanism and show that the sigmatropic
rearrangement is not a serious competitive pathway providing
the secondary homopropargylic alcohol is silylated at the
triple bond. Synthetic applications of this new methodology
to the synthesis of other natural compounds are under study
and will be published in due course.
Scheme 3. Cyclization of Enantioenriched Homopropargylic
Alcohol
and the allenic form 12, or may even be caused by
experimental error during the measurement.
Finally, to explore the synthetic scope of this method we
decided to perform the synthesis of a tetrasubstituted
dihydropyran from the more elaborated and non commercial
aldehyde 17.15 The unprecedented dimer-type 18 was ob-
tained in 54% yield, showing that this new methodology
could be applied to the synthesis of complex molecules in a
highly efficient and convergent manner (Scheme 4).
Acknowledgment. This research was supported by the
Ministerio de Educacio´n y Ciencia of Spain, co-financed by
the European Regional Development Fund (CTQ2005-
09074-C02-01/BQU) and the Canary Islands Government.
P.O.M. thanks the Spanish M.E.C. for a F.P.I. fellowship.
J.I.P. thanks the Spanish MCYT-F.S.E. for a Ramo´n y Cajal
contract.
Scheme 4. Synthesis of a Tetrasubstituted Dihydropyran
Dimer Type
Supporting Information Available: 1H NMR and 13C
NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL060247M
(15) The noncommercial aldehyde 17 was prepared in three steps (51%
overall yield) from the alkyne Prins cyclization of but-3-yn-1-ol and 11-
bromoundecanal. See the Supporting Information.
In conclusion, we report on a new stereoselective method
to obtain tetra- or penta substituted halo-dihydropyrans,
1636
Org. Lett., Vol. 8, No. 8, 2006