Titanium(IV)-promoted Mukaiyama aldol-Prins cyclizations

Article abstract of DOI:10.1021/ol035303n

(Matrix presented) A new version of the Mukaiyama aldol-Prins (MAP) cyclization has been developed. Unsaturated enol ethers such as 3 were found to couple with aldehydes in the presence of TiBr₄ to give 4-bromotetrahydropyran products. This cascade reaction sequence leads to the formation of two new carbon-carbon bonds, a ring, and three new stereogenic centers. We expect this reaction to be a powerful new tool in synthesis.

Full text of DOI:10.1021/ol035303n

ORGANIC
LETTERS
2003
Vol. 5, No. 17
3163-3166
Titanium(IV)-Promoted Mukaiyama
Aldol−Prins Cyclizations
Brian Patterson, Shinji Marumoto, and Scott D. Rychnovsky*
Department of Chemistry, 516 Rowland Hall, UniVersity of California,
IrVine, California 92697-2025
srychnoV@uci.edu
Received July 15, 2003
ABSTRACT
A new version of the Mukaiyama aldol−Prins (MAP) cyclization has been developed. Unsaturated enol ethers such as 3 were found to couple
with aldehydes in the presence of TiBr4 to give 4-bromotetrahydropyran products. This cascade reaction sequence leads to the formation of
two new carbon−carbon bonds, a ring, and three new stereogenic centers. We expect this reaction to be a powerful new tool in synthesis.
Cascade reactions can be very powerful transformations in
organic synthesis.1 We recently reported the first examples
of a Mukaiyama aldol-Prins (MAP) cascade cyclization
reaction (Scheme 1).2 In our initial work, a very reactive
importance of selecting the appropriate Lewis acid to
promote the reaction.
Cationic cascade reactions are well-known in organic
chemistry. Johnson’s polyene cyclizations represent an
important milestone in this area.3 In most cases, the cycliza-
tion reaction is initiated by the addition of a proton or Lewis
acid. Berrisford demonstrated that a silicon-tethered bis-
nucleophile could add to an external aldehyde electrophile
in a cascade reaction.4 More recently, Leighton has developed
a powerful strategy to prepare polyol segments using similar
silicon-tethered bis-nucleophiles.5 The Mukaiyama aldol-
Prins cyclization developed in our lab uses the reaction of a
bis-nucleophile and an aldehyde to couple two fragments
and build a ring. A formal synthesis of leucascandrolide A
demonstrated the potential of this method in synthesis.2
Synthesis of allylsilane substrates such as 1 requires several
steps, and an important advantage of the unsubstituted alkene
substrates such as 3 is that they are very simple to make.
The alkene substrate 3 was prepared in two steps from
dihydrocinnamaldehyde. Allyl Grignard addition followed
Scheme 1. Mukaiyama Aldol-Prins (MAP) Cyclization
Cascade with an Allylsilane Internal Nucleophile
allylsilane was selected as the internal nucleophile to promote
a rapid and clean Prins cyclization. The allylsilane substrate
1, however, is more difficult to prepare than a simple alkene
analogue such as 3. In this paper, we describe the use of
simple alkene substrates in MAP cyclizations and the
(3) (a) Johnson, W. S. Angew. Chem. 1976, 88, 33-41. (b) Bartlett, P.
A. in Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: New
York, 1984; Vol. 3, pp 341-409. (c) Johnson, W. S. Tetrahedron 1991,
47, R11-R50.
(4) Frost, L. M.; Smith, J. D.; Berrisford, D. J. Tetrahedron Lett. 1999,
40, 2183-2186.
(5) Wang, X.; Meng, Q.; Nation, A. J.; Leighton, J. L. J. Am. Chem.
Soc. 2002, 124, 10672-10673.
(1) (a) de Meijere, A.; von Zezschwitz, P.; Nuske, H.; Stulgies, B. J.
Organomet. Chem. 2002, 653, 129-140. (b) Malacria, M. Chem. ReV. 1996,
96, 289-306. (c) Heumann, A.; Reglier, M. Tetrahedron 1996, 52, 9289-
9346. (d) Tietze, L. F. Chem. Ind. 1995, 453-457.
(2) Kopecky, D. J.; Rychnovsky, S. D. J. Am. Chem. Soc. 2001, 123,
8420-8421.
10.1021/ol035303n CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/02/2003

by Hg(TFA)2-catalyzed exchange with ethyl vinyl ether6
produced 3 reliably and in good overall yield.7 The optically
pure substrate (-)-3 was prepared using an enantioselective
Ti(BINOL)-catalyzed allylation8 (ca. 97% ee) followed by
the vinyl ether exchange. These procedures have been used
in our laboratory to prepare half a dozen substrates using
different aldehyde starting materials.
TiBr4 but not with SnBr4. The combination of a powerful
Lewis acid with a nucleophilic halide led to the best yields
in the Mukaiyama aldol-Prins cyclization with unsubstituted
alkenes.
The scope of the TiBr4-promoted MAP reaction using
optimized reaction conditions10 is presented in Table 2.
Initially, the Mukaiyama aldol addition and Prins cycliza-
tion with a simple alkene substrate 3 was evaluated using
the optimized conditions from Scheme 1. Reaction of 3 with
2.5 equiv of dihydrocinnamaldehyde in the presence of BF3‚
OEt2 and 2,6-di-tert-butylpyridine (2,6-DTBP) at -78 °C
led to the unexpected product 4 in 82% yield, Table 1, entry
Table 2. MAP Cyclization Promoted by TiBr4
Table 1. Effect of Lewis Acid on the MAP Cyclization with
an Unactivated Alkene
entry
Lewis acid
X
4 (%)
5 (%)
1
2
3
4
5
6
BF3‚OEt2
SnBr4
SnCl4
TiCl2(OiPr)2
TiCl4
TiBr 4
82
58
40
15
0
Br
Cl
Cl
Cl
Br
11
15
47
62
72
0
1. The Mukaiyama aldol reaction has taken place but the
oxocarbenium ion, rather than cyclizing onto the alkene,
added a second equivalent of the aldehyde to produce the
1,3-dioxane structure 4.9 Compound 4 was not the desired
product, but it was formed very cleanly. Other Lewis acids
were used to promote the condensation with better success.
Tin halides and titanium blend reagents led to a mixture of
the MAP product 5 and the 1,3-dioxane 4. The more
powerful Lewis acids, TiCl4 and TiBr4, did not produce 1,3-
dioxane 4 and gave the best yields of 5, entries 5 and 6. The
TiBr4 is particularly effective and gave the adduct 5 in 72%
isolated yield. In each of these experiments, compound 5
was produced as a ca. 1:1 mixture of diastereomers at the
alcohol stereogenic center. The selectivity for the equatorial
bromide was >95:5. Control experiments established that
dioxane 4 was efficiently converted to 5 on treatment with
Entries 1-4 show the outcome with several aliphatic
aldehydes. The yields clustered around 80% and the stereo-
selectivity at the bromide center favored equatorial by >95:
(10) Tetrahydropyran (7). Cyclohexanecarboxaldehyde (215 µL, 1.65
mmol, 2.0 equiv), enol ether 3 (167 mg, 0.826 mmol, 1.0 equiv), and 2,6-
di-tert-butylpyridine (278 µL, 1.24 mmol, 1.5 equiv) were dissolved in
methylene chloride and cooled to -78 °C. A solution of TiBr4 in methylene
chloride (3.2 mL, 0.52 M, 2.0 equiv) was added dropwise, and the dark
red solution was allowed to stir at -78 °C. TLC analysis showed complete
consumption of starting material in 5 min, at which point the reaction was
quenched by addition of saturated aqueous NaHCO3 (10 mL) at -78 °C.
The mixture was allowed to come to room temperature, and the layers were
separated. The aqueous layer was extracted with methylene chloride (3 ×
10 mL), and the combined organic layers were dried (Na2SO4), filtered,
and concentrated in vacuo. The crude oil was purified by flash column
chromatography (5-30% diethyl ether/hexanes) to give a 1:1 isomeric
mixture of 7 (268 mg, 0.678 mmol, 82%) as a clear, colorless oil.
Characterization is included in the Supporting Information.
(6) Watanabe, W. H.; Conlon, L. E. J. Am. Chem. Soc. 1957, 79, 2828-
2833.
(7) Details are provided in the Supporting Information.
(8) (a) Costa, A. L.; Piazza, M. G.; Tagliavini, E.; Trombini, C.; Umani-
Ronchi, A. J. Am. Chem. Soc. 1993, 115, 7001-7002. (b) Keck, G. E.;
Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993, 115, 8467-8468.
(9) (a) Hoaglin, R. I.; Hirsh, D. H. Production of Unsaturated Aldehydes,
U.S. Patent 2,628,257, Feb 10, 1953. (b) Chretien-Bessiere, Y.; Leotte, H.
Compt. Rend. 1962, 255, 723-724.
3164
Org. Lett., Vol. 5, No. 17, 2003

5. The alcohol stereogenic center was formed with essentially
no preference in each case. For compounds 5 and 8, the
epimeric mixture of alcohols was oxidized to a single ketone
to confirm the structure of the two diastereomeric products.
Entry 5 demonstrates that a silyl-protected alcohol was
tolerated in the reaction. Benzaldehyde led to a lower yield
(53%) than any of the aliphatic aldehydes. The product was
stable to the reaction conditions, and the origin of this
reduced yield was not obvious. The reaction is successful
with each of the aldehydes in Table 2, but the best yields
were observed with aliphatic aldehydes.
3, five of the six entries lead to significant amounts of the
axial bromide.12 The exception is entry 4, where the TBS
ether produces the expected equatorial bromide. The increase
in axial bromide correlates with the presence of a benzyl
ether in the aldehyde.
These MAP reactions are subject to the expected stereo-
chemical influences of a chiral aldehyde. In three cases,
optically pure enol ether (-)-3 was coupled with optically
pure aldehydes, Scheme 2 (and Table 3, entries 4-6). The
Aldehydes with protected alcohols lead to interesting
stereochemical consequences in the reaction, Table 3. The
Scheme 2. MAP Cyclizations with Optically Pure Components
Table 3. MAP Cyclization of Aldehydes with Protected
Alcohols
TBS ether aldehyde 17 derived from (S)-lactic acid coupled
with (-)-3 to give a 68:32 mixture of isomers in 75% yield.
Oxidation with Dess-Martin’s reagent produced ketone 18
as a single diastereomer, confirming that the alcohol center
in 14 was epimeric. The benzyloxy aldehyde 19 coupled with
(-)-3 under standard conditions to produce a 2:1 mixture
of diastereomers. Radical debromination of this mixture gave
the alcohol 20 as a single diastereomer, confirming that the
a Optically pure (-)-(S)-3 was used in these experiments.
(11) The axial and equatorial bromides were assigned by 1H NMR
analysis. The equatorial isomer of compound 5 (X ) Br) showed the
expected NOE enhancements between the 2, 4, and 6 protons on the THP
ring. For the other compounds, the distinctive chemical shift and coupling
constants (ax-Br: ca. 4.7 ppm, (quint, J ) 2.9, Hz); eq-Br: ca. 4.1 (tt, J )
4.4, 12.0 Hz)) were used to assign the axial and equatorial bromide isomers.
(12) Hart recently observed modest amounts of axial bromide in a TiBr4-
promoted Prins cyclization: Hart, D. J.; Bennet, C. E. Org. Lett. 2003, 5,
1499-1502.
TBDPS-protected aldehyde in Table 2, entry 5, reacted just
like any other aliphatic aldehyde. However, the correspond-
ing substrate with a benzyl protecting group (Table 3, entry
2) produced a THP product with 32% of the axial bromide.11
Previous cases strongly favored equatorial bromides. In Table
Org. Lett., Vol. 5, No. 17, 2003
3165

bromide carbon in 15 was epimeric. The configuration of
the major alcohol epimers for 14 and 15 were determined
by advanced Mosher’s analysis,13 confirming the expected
Felkin-Ahn and chelation-controlled selectivity, respec-
tively. These experiments establish the stereochemical
outcome of the coupling reactions but also demonstrate the
utility of the MAP reaction to coupling optically pure and
potentially complex components.
aldehydes that would be expected to chelate the Lewis acid
(e.g., aldehyde 19-TiBr4 complex in Scheme 2) and the
formation of the axial bromide. This chelation would place
the Lewis acid adjacent to the carbon chain of the aldehyde
rather than in the normally preferred geometry adjacent to
the aldehyde hydrogen (e.g., aldehyde 17-TiBr4 complex
in Scheme 2). The correlation is good but the details of the
mechanism are not. The axial bromide ends up on the face
of the THP ring opposite to the TiBr4-coordinated alkoxide,
and thus, a direct transfer of the bromide appears unlikely.
The axial selectivity is independent of the secondary alcohol
configuration, an observation that further undermines any
intramolecular bromide transfer mechanism. For example,
compounds 15 and 16 are generated with nearly identical
equatorial to axial bromide ratios, but the relative configu-
ration of the THP ring and the secondary alcohol are
opposite. The geometries of the two diastereotopic Ti-
chelates will be different, and an intramolecular bromide
transfer would be affected by the change in geometry. We
conclude that an intramolecular bromide transfer is not
important in formation of the axial bromide products. We
will continue to investigate the origin of the axial bromide
in these cyclizations.
The formation of axial bromide in the benzyl ether
substrates in Table 3 is puzzling. Entries 1-3 and 5-6 all
lead to significant amounts of axial bromides. Scheme 3
Scheme 3. MAP Cyclizations with O-Benzyl Enol Ether
Components
The TiBr4-promoted Mukaiyama aldol-Prins cyclization
is a valuable reaction for rapidly building complexity in
organic structures. The products of these MAP reactions are
structurally related to segments of common oxygenated
natural products. The reaction is suitable for coupling
fragments and thus lends itself to convergent synthetic
strategies. It is worth emphasizing that many of the MAP
cyclization products described in this paper were formed in
only three steps from commercially available precursors.
Applications of the new MAP reaction in natural product
synthesis are in progress.
shows a control experiment for the formation of axial
bromide in the cyclization. Placing a benzyl ether on the
other side of the tetrahydropyranyl ring, separated by either
two or three carbon atoms, leads to 92:8 selectivity for the
equatorial bromide. These substrates are less selective than
the examples in Table 2, but they are better than the O-benzyl
examples in Table 3. A stronger correlation is found between
Acknowledgment. The National Institutes of Health (CA-
81635) provided financial support.
Supporting Information Available: Preparation and
characterization of the compounds described in the paper.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(13) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092-4096.
OL035303N
3166
Org. Lett., Vol. 5, No. 17, 2003