Stereoselective Aldol-Type Cyclization Reaction Mediated by Dibutylboron Triflate/Diisopropylethylamine

Article abstract of DOI:10.1021/ol036229b

(Equation presented) Dibutylboron triflate/diisopropylethylamine mediated aldol-type cyclization provides an expedient route for the stereoselective synthesis of cyclic ethers in a single step. The method is highly efficient for the stereoselective synthe

Full text of DOI:10.1021/ol036229b

ORGANIC
LETTERS
2004
Vol. 6, No. 1
123-126
Stereoselective Aldol-Type Cyclization
Reaction Mediated by Dibutylboron
Triflate/Diisopropylethylamine
Sanjib Das, Lian-Sheng Li, and Subhash C. Sinha*
The Skaggs Institute for Chemical Biology and the Department of Molecular Biology,
The Scripps Research Institute, 10550 North Torrey Pines Road,
La Jolla, California 92037
subhash@scripps.edu
Received November 13, 2003
ABSTRACT
Dibutylboron triflate/diisopropylethylamine mediated aldol-type cyclization provides an expedient route for the stereoselective synthesis of
cyclic ethers in a single step. The method is highly efficient for the stereoselective synthesis of 4-cis-tetrahydropyranones. The reaction is
proposed to proceed via an SN1-type mechanism through a chair-like transition state, in which both substituents occupy equatorial positions.
The aldol addition reaction is undoubtedly among the most
powerful methods for the formation of carbon-carbon
bonds.1 A number of new methods, including enantioselective
and catalytic processes, have been developed.1a,b Despite
these developments, however, the aldol-type reaction between
a carbonyl compound and an acetal has remained less
explored. In 1974, Mukaiyama discovered the Ti(IV)-
catalyzed reaction of silyl enol ethers with acetals to produce
â-alkoxy carbonyl compounds (eq 1).2 The process,3,4 which
requires preformation of the silyl enol ethers, can also be
accomplished in a single step by in situ generation of
corresponding enol ethers (eq 2).5,6 Nonetheless, the im-
(4) For intermolecular reactions, see: (a) Murata, S.; Suzuki, M.; Noyori,
R. Tetrahedron 1988, 44, 4259-4275. (b) Noyori, R.; Murata, S.; Suzuki,
M. Tetrahedron 1981, 37, 3899-3910. (c) Murata, S.; Suzuki, M.; Noyori,
R. J. Am. Chem. Soc. 1980, 102, 3248-3249. For reactions catalyzed by a
catalyst other than Ti(IV), see: (d) Ishitani, H.; Iwamoto, M. Tetrahedron
Lett. 2003, 44, 299-301. (e) Le Roux, C.; Ciliberti, L.; Laurent-Robert,
H.; Laporterie, A.; Dubac, J. Synlett 1998, 11, 1249-1251 and references
therein.
(5) For one-step intramolecular reactions to provide carbocyclic com-
pounds, see: (a) Nicolaou, K. C.; Jennings, M. P.; Dagneau, P. Chem.
Commun. 2002, 2480-2481. (b) Rubinger, M. M. M.; Mann, J. J. Chem.
Res., Synop. 1999, 454-455. (c) Tokunaga, Y.; Yagihashi, M.; Ihara, M.;
Fukumoto, K. J. Chem. Soc., Perkin Trans. 1 1997, 189-190. (d) Duhamel,
P.; Deyine, A.; Dujardin, G.; Ple, G.; Poirier, J. M. J. Chem. Soc., Perkin
Trans. 1 1995, 2104-2114. (e) Funk, R. L.; Fitzgerald, J. F.; Olmstead, T.
A.; Para, K. S.; Wos, J. A. J. Am. Chem. Soc. 1993, 115, 8849-8850 and
references therein.
(6) For the one-step intermolecular reactions, see: (a) Cosp, A.; Romea,
P.; Talavera, P.; Urpi, F.; Vilarrasa, J.; Font-Bardia, M.; Solans, X. Org.
Lett. 2001, 3, 615-617. (b) Cosp, A.; Romea, P.; Urpi, F.; Vilarrasa, J.
Tetrahedron Lett. 2001, 42, 4629-4631. (c) Keck, G. E.; Wager, C. A.;
Wager, T. T.; Savin K. A.; Covel, J. A.; Mclaws, M. D.; Krishnamurthy,
D.; Cee, V. J. Angew. Chem., Int. Ed. 2001, 40, 231-234. (d) Kobayashi,
S.; Nishio K. J. Org. Chem. 1993, 58, 2647-2649. (e) Evans, D. A.; Urpi,
F.; Somers, T. C.; Clark, J. S.; Bilodeau, M. T. J. Am. Chem. Soc. 1990,
112, 8215-8216. (f) Hashigaki, K.; Yoshioka, S.; Yamato. M. Synthesis
1986, 1004-1007.
(1) For reviews on aldol reactions, see: (a) Alcaide, B.; Almendros, P.
Eur. J. Org. Chem. 2002, 1595-1601 and references therein. (b) Palomo,
C.; Oiarbide, M.; Garcˆıa, J. M. Chem. Eur. J. 2002, 8, 36-44. (c) Mahrwald,
R. Chem. Rev. 1999, 99, 1095-1120. (d) Heathcock, C. H. In Asymmetric
Synthesis; Morrison, J. D., Ed.; Academic Press: New York, 1984; Vol. 3,
Chapter 2, part B, pp 111-212. (e) Evans, D. A.; Nelson, J. V.; Taber, T.
R. Top. Stereochem. 1982, 13, 1-115.
(2) (a) Mukaiyama, T.; Hayashi, M. Chem. Lett. 1974, 15-16. For
reviews, see: (b) Mukaiyama, T.; Murakami, M. Synthesis 1987, 1043-
1054. (c) Mukaiyama, T. Org. React. 1982, 28, 238-248.
(3) For the intramolecular reactions, see: (a) Villanueva, O.; Prieto. J.
A. J. Org. Chem. 1993, 58, 2718-2724. (b) Willson, T. M.; Kocienski, P.;
Jarowicki, K.; Isaac, K.; Hitchcock, P. M.; Faller, A.; Campbell, S. F.
Tetrahedron 1990, 46, 1767-1782. (c) Linderman, R. J.; Godfrey, A. J.
Am. Chem. Soc. 1988, 110, 6249-6251. (d) Cockerill, G. S.; Kocienski, P.
J. Chem. Soc., Perkin Trans. 1 1985, 2093-2100 and references therein.
(e) For the condensation of silyl enol ethers with thio ketals, see: Trost, B.
M.; Murayama, E. Tetrahedron Lett. 1982, 23, 1047-1050.
10.1021/ol036229b CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/11/2003

proved processes are still limited in scope, particularly for
the intramolecular aldol-type reactions. Here, we report that
an intramolecular aldol-type reaction of carbonyl compounds
with a resident acetal or ketal can be accomplished in a single
step using dibutylboron triflate and diisopropylethylamine
(Bu2BOTf/i-Pr2NEt).7 The usefulness of this approach is
demonstrated by the stereoselective syntheses of five- to
seven-membered 4-keto-cyclic ethers, in general, and 4-cis-
tetrahydropyranone derivatives, in particular.
tion of the cyclic ethers as byproducts could explain why
the aldol products were obtained in reduced yields. The
observation by Panek et al. that the yield of product 3b is
lower on a larger scale also supports this assumption.9
Moreover, syntheses of cyclic ethers using silyl enol ether
derivatives of carbonyl compounds possessing a resident
acetal group as in 1b or 1h have been previously reported.3d
These facts encouraged us to reinvestigate the Bu2BOTf/i-
Pr2NEt-mediated aldol-type reaction of 1b.
We found that under Evans’ conditions, the reaction
constantly produced a minor byproduct (<5% yield), which
was identified as a 4-cis-tetrahydropyrone derivative, 4b (eq
5). A slight modification in Evans’ procedure, however,
completely changed the course of reaction, and compound
4b was formed as the major product. Thus, for the aldol
reaction of 1b and 2c, the boron enolate of 1b was produced
by slow addition of Bu2BOTf (condition A) to a mixture of
1b and i-Pr2NEt in CH2Cl2 at -78 °C,11 whereas for the
production of 4b, Bu2BOTf was added at a considerably
faster rate (condition B).11 Addition of aldehyde 2c to the
latter reaction mixture barely gave any aldol product (<5%),
and the major product 4b was obtained in >50% yield. These
findings guided us to further explore the Bu2BOTf/i-Pr2NEt-
mediated intramolecular reaction of various keto-acetals (1a-
l). The results are summarized in Tables 1 and 2.
Under the conditions developed by Evans,8 the aldol
reaction of compound 1b (PMP ) p-methoxyphenyl) with
aldehyde 2a is mediated by Bu2BOTf/i-Pr2NEt to afford the
corresponding aldol product 3a in moderate yield (eq 3). The
keto-acetal compounds, such as 1b or 1h, have often been
used as donors in aldol reactions, because the acetal can
coordinate electron-deficient elements to increase the ste-
reoselectivity of the process. For example, using Evans’
conditions, Panek et al. reported the aldol reaction of 1h with
aldehyde 2b to afford the aldol product, 3b, (eq 4) in 76%
yield.9 We also prepared the aldol product 3c in 50% yield
from a Bu2BOTf/i-Pr2NEt-mediated aldol reaction of 1b with
aldehyde 2c (eq 5) enroute to the synthesis of a natural
product.10
Under the optimized conditions, Bu2BOTf (1.2 equiv) was
added rapidly to the mixture of a substrate (1 equiv) and
i-Pr2NEt (1.2 equiv) in CH2Cl2 at -78 °C (Method C).12 In
general, a higher molar ratio of Bu2BOTf (1.5 equiv, Method
D) was required for aliphatic acetals. As shown in Table 1,
the reaction was quite efficient, and the cyclized products
were obtained in up to 94% yield and high stereoselectivity
1
(>98%) as observed by H NMR spectroscopy. In fact, in
all cases, only 4-cis-tetrahydropyranone derivatives13 were
detected. The cis configuration of the 4-tetrahydropyranone
was not influenced by the substitution pattern. Thus,
compounds 1c and 1g, which possess an anti and a syn
stereochemistry, respectively, afforded cis-products 4c and
4g (entries 3 and 7, Table 1). Similarly, compounds 1h and
1l (entries 8 and 12, Table 1), which possess an alkyl group
at C-5 of the dioxane ring, do not affect the cis configuration
of the products irrespective of the relative configuration of
C-4 and C-5 substituents.
The reaction was also applicable to ketal substrates, such
as 5a and 5b, which provided the corresponding spiro-
(7) Bu2BOTf/i-Pr2NEt also mediates intermolecular aldol-type coupling
of ketones with acetals and ketals; see: Li, L.-S.; Das, S.; Sinha, S. C.
Org. Lett. 2004, 6, 127-130.
(8) (a) Evans, D. A.; Coˆte´, B.; Coleman, P. J.; Connell, B. T. J. Am.
Chem. Soc. 2003, 125, 10893-10898. (b) Evans, D. A.; Coleman, P. J.;
Coˆte´, B. J. Org. Chem. 1997, 62, 788-789.
(9) Arefolov, A.; Panek, J. S. Org. Lett. 2002, 4, 2397-2400.
(10) Das, S.; Sinha, S. C. Unpublished results.
(11) Under condition A, Bu2BOTf (1.05 mL, 1 M solution in CH2Cl2)
was added over a period of 10 min to a solution of the ketone (1 mmol)
and i-Pr2NEt (1.1 mmol) in 5 mL of CH2Cl2 at -78 °C. Under condition
B, Bu2BOTf was added within 1 min, which might increase the local
concentration of Bu2BOTf.
(12) Various other known reaction conditions, which mediate the
intramolecular aldol-type reaction in a single step, as well as replacing Bu2-
BOTf with TiCl4, Et2AlCl, and BF3Et2O, did not produce the desired
products in our case.
On the other hand, compounds 1b, 1h, and analogous
molecules are also poised to form cyclic ethers by Bu2BOTf/
i-Pr2NEt-mediated intramolecular aldol-type reaction. Forma-
124
Org. Lett., Vol. 6, No. 1, 2004

Table 1. Synthesis of Cyclic Ethers by Bu2BOTf/
i-Pr2NEt-Mediated Aldol-Type Reactiona
Table 2. Synthesis of Cyclic Ethers by Bu2BOTf/
i-Pr2NEt-Mediated Aldol-Type Reaction (Cont’d)
a Method C was used; see Table 1.
and five-membered cyclic ethers, 8a and 9a (entry 5, Table
2). This ratio is in agreement with the preferential deproto-
nation of the methyl hydrogen in comparison to the internal
methylene hydrogens.14 Similar regioselectivity was also
obtained when the intermolecular aldol-type reaction was
carried out using butanone and an acetal.7 The regioselectivity
of the reaction could be controlled when a substituent was
installed at the R′-position of the carbonyl function. Thus,
the substrate 7b produced exclusively the seven-membered
cyclic ether, 8b (entry 6, Table 2).
Interestingly, the reaction is highly selective for the methyl
ketones. In our preliminary investigation, we found that the
corresponding ethyl ketones (1m, n) also undergo the
intramolecular coupling reaction, albeit less efficiently in
comparison to the analogous methyl ketones. Nevertheless,
the only isolatable products (4m, n) were proven to be highly
substituted stereochemically pure 4-cis-tetrahydropyranone
derivatives (entries 1 and 2, Table 2).
a Method C: substrate (1 equiv), Bu2BOTf (1.2 equiv), and i-Pr2NEt
(1.2 equiv) in CH2Cl2 at -78 °C. Method D: substrate (1 equiv), Bu2BOTf
(1.5 equiv), and i-Pr2NEt (1.2 equiv) in CH2Cl2 at -78 °C.
pyranone derivatives, 6a and 6b, respectively (entries 3 and
4, Table 2). The higher homolog, 7a, of the methyl ketone
also reacted smoothly to produce a 3:2 mixture of seven-
Analogous to the Ti(IV)-catalyzed reaction,3d,15 both SN1
and SN2 mechanisms can be considered for the Bu2BOTf-
(13) The relative configurations of all compounds were determined by
(14) Inoue, T.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1980, 53, 174-
178.
1
the analysis of their H-1H COSY, NOE, or NOESY spectra.
Org. Lett., Vol. 6, No. 1, 2004
125

mediated cyclization reaction. However, the intramolecular
SN2 mechanism, which could account for the exclusive
formation of cis product, is ruled out on the following
grounds. First, it would require a sterically very congested
conformer in that the two substituents would occupy the 1,3-
diaxial positions. Second, the Bu2BOTf-mediated reaction
of the enantiomerically pure substrates 10 provided two
diastereomeric products, 11 and 12, which is only possible
by an SN1 pathway (eq 6).
Scheme 1
The high selectivity in the formation of the cis product
by an SN1 mechanism, on the other hand, can be explained
as shown in Scheme 1. Presumably, the reaction proceeds
via the chair-like transition structure II, which is derived
from intermediate I. It should be noted that the Bu2BOTf/
i-Pr2NEt-mediated reaction involves the same array of
reacting sp2-hybridized centers as in the enolate Claisen
rearrangement. Thus, the structure II is analogous to the
proposed transition states for this reaction.16 A selective
production of compounds 4m and 4n from the corresponding
substrates also provide evidence for the chairlike transition
state II, assuming that the Z-enolate is formed in the
enolization step. The transition state II then collapses to
afford the cis product. Formation of the corresponding trans
product, in contrast, would require a high-energy transition
state III possessing the hydroxyethyl substituent and dibu-
tylboryloxy group in 1,3-diaxial positions.
In conclusion, the Bu2BOTf/i-Pr2NEt-mediated aldol-type
cyclization provides a novel process for the syntheses of
cyclic ethers in a single step. The process is particularly
useful for the stereoselective formation of 4-cis-tetrahydro-
pyranones. Evidently, the reaction involves an SN1-type
mechanism via a chairlike transition state, in that both
substituents occupy equatorial positions. Investigations of the
scope and limitations of the new reaction are currently
underway.
(15) (a) Sammakia, T.; Smith, R. S. J. Am. Chem. Soc. 1994, 116, 7915-
7916 and references therein. (b) Denmark, S. E.; Willson, T. M.; Almstead,
N. G. J. Am. Chem. Soc. 1989, 111, 9258-9260. (c) Tanabe, Y.; Ohno, N.
J. Org. Chem. 1988, 53, 1560-1563. (d) Mohler, D. L.; Thompson, D. W.
Tetrahedron Lett. 1987, 28, 2567-2570. (e) Bartlett, P. A. J. Am. Chem.
Soc. 1983, 105, 2088-2089.
(16) For a review, see: (a) Chai, Y.; Hong, S.-P.; Lindsay, H. A.;
McFarland, C. M.; McIntosh, M. C. Tetrahedron 2002, 58, 2905-2928.
Also see: (b) Smith, A. B., III; Minbiole, K. P.; Verhoest, P. R.; Schelhaas,
M. J. Am. Chem. Soc. 2001, 123, 10942-10953. (c) Petasis, N. A.; Lu,
S.-P. Tetrahedron Lett. 1996, 37, 141-144.
Acknowledgment. We thank the Skaggs Institute for
Chemical Biology for the financial support.
Supporting Information Available: Typical experimen-
tal procedure and analytical data for all products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL036229B
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Org. Lett., Vol. 6, No. 1, 2004