Application of the intramolecular yamamoto vinylogous aldol reaction to the synthesis of macrolides

Article abstract of DOI:10.1021/ol0704901

An intramolecular version of the Yamamoto vinylogous aldol reaction, a method that employs the bulky Lewis acid ATPH to control the site of aldolization, is described. This macrocyclization process is effective for the construction of 10-, 12-, and 14-mem

Full text of DOI:10.1021/ol0704901

ORGANIC
LETTERS
2007
Vol. 9, No. 11
2103-2106
Application of the Intramolecular
Yamamoto Vinylogous Aldol Reaction to
the Synthesis of Macrolides
Joseph A. Abramite and Tarek Sammakia*
Department of Chemistry and Biochemistry, UniVersity of Colorado,
Boulder, Colorado 80309-0215
sammakia@colorado.edu
Received March 1, 2007
ABSTRACT
An intramolecular version of the Yamamoto vinylogous aldol reaction, a method that employs the bulky Lewis acid ATPH to control the site
of aldolization, is described. This macrocyclization process is effective for the construction of 10-, 12-, and 14-membered macrolides. The
yields are high (70−90%), and the reaction can proceed with excellent remote stereocontrol (dr g 20:1) with chiral substrates.
The construction of medium and large membered rings has
been an important and challenging problem in organic and
natural products synthesis.1 The intramolecular aldol reaction,
although studied extensively for the assembly of small (five-
to seven-membered) rings,2 has only occasionally been
employed for the synthesis of macrocycles.3 Selective
enolization, inter- vs intramolecular reactivity, and the
possibility of enolate decomposition are issues that can
complicate the macroaldolization process, and as such,
intramolecular variations of the Mukaiyama and Refor-
matsky4 reactions have constituted the majority of the
macroaldolization examples known. Recently, Yamamoto
described a method for performing vinylogous aldol reac-
tions5 with R,â-unsaturated carbonyl compounds and alde-
hydes in which both reactants are initially subjected to
precomplexation with the bulky Lewis acid, aluminum tris-
(2,6-diphenylphenoxide) (ATPH), then treated with a bulky
amide base, such as LDA or LTMP.6 A simplified depiction
of the ATPH-carbonyl complexes is provided in Scheme
1. Yamamoto has studied these structures in depth and has
shown that the binding is flexible and subject to steric
effects.6d The resulting ATPH-bound enolate then undergoes
addition to the aldehyde at the terminal carbon of the enolate
(Scheme 1). This positional selectivity is thought to be due
to the bulk of the ATPH which blocks reaction at the
proximal sites of the conjugated enolate.
The Yamamoto protocol is unusual in that both the
aldehyde and the R,â-unsaturated carbonyl compound are
(3) For selected references relating to macroaldolization processes, see:
(a) Tsuji, J.; Yamada, T.; Kaito, M.; Mandai, T. Bull. Chem. Soc. Jpn. 1980,
53, 1417. (b) Robin, J. P.; Gringore, O.; Brown, E. Tetrahedron Lett. 1980,
21, 2709. (c) Vo¨gtle, F.; Mayenfels, P.; Luppertz, F. Synthesis 1984, 7,
580. (d) Kuroda, S.; Maeda, S.; Hirooka, S.; Ogisu, M.; Yamazaki, K.;
Shimao, I.; Yasunami, M. Tetrahedron Lett. 1989, 30, 1557. (e) Hayward,
C. M.; Yohannes, D.; Danishefsky, S. J. J. Am. Chem. Soc. 1993, 115,
9345. (f) Romero, M. A.; Franco, R. P.; Cruz-Almanza, R.; Padilla, F.
Tetrahedron Lett. 1994, 35, 3255. (g) Takao, K.; Ochiai, H.; Yoshida, K.;
Hashizuka, T.; Koshimura, H.; Tadano, K.; Ogawa, S. J. Org. Chem. 1995,
60, 8179. (h) Toshima, K.; Ohta, K.; Yanagawa, K.; Kano, T.; Nakata, M.;
Kinoshita, M.; Matsumura, S. J. Am. Chem. Soc. 1995, 117, 10825. (i)
Magnus, P.; Carter, R.; Davies, M.; Elliott, J.; Pitterna, T. Tetrahedron 1996,
52, 6283. (j) Meng, D.; Bertinato, P.; Balog, A.; Su, D.-S.; Kamenecka,
T.; Sorensen, E. J.; Danishefsky, S. J. J. Am. Chem. Soc. 1997, 119, 10073.
(k) Katoh, T.; Nagata, Y.; Yoshino, T.; Nakatani, S.; Terashima, S.
Tetrahedron 1997, 53, 10253. (l) Caddick, S.; Delisser, V. M.; Doyle, V.
E.; Khan, S.; Avent, A. G.; Vile, S. Tetrahedron 1999, 55, 2737. (m) Wei,
C.-Q.; Zhao, G.; Jiang, X.-R.; Ding, Y. Chem. Soc., Perkin Trans. 1 1999,
3531. (n) Rassu, G.; Auzzas, L.; Pinna, L.; Zambrano, V.; Zanardi, F.;
Battistini, L.; Gaetani, E.; Curti, C.; Casiraghi, G. J. Org. Chem. 2003, 68,
5881.
(1) For selected reviews on the synthesis of macrocycles, see: (a)
Wessjohann, L. A.; Ruijter, E. Top. Curr. Chem. 2005, 243, 137. (b) Yet,
L. Chem. ReV. 2000, 100, 2963. (c) Roxburgh, C. J. Tetrahedron 1995, 51,
9767. (d) Rousseau, G. Tetrahedron 1995, 51, 2777. (e) Meng, Q.; Hesse,
M. Top. Curr. Chem. 1992, 161, 107. For a discussion of the role of strain
in macrocyclic ring closure, see: (f) Galli, C.; Mandolini, L. Eur. J. Org.
Chem. 2000, 18, 3117.
(2) Heathcock, C. H. In ComprehensiVe Organic Synthesis; Trost, B.
M., Fleming, I., Heathcock, C. H., Eds.; Pergamon Press: Oxford, 1991;
Vol. 2, p 133.
10.1021/ol0704901 CCC: $37.00
© 2007 American Chemical Society
Published on Web 04/25/2007

Scheme 1. Yamamoto Vinylogous Aldol Reaction
Table 1. Optimization Studies
entry
Lewis acid
LTMP equiv
temp
% yieldb
1
2
3
4
5
6
7
8
9
ATPH
none
1.1
1.1
1.1
1.1
1.1
2.0
2.0
2.0
2.0
-25
-25
-25
-78
0
-78
-25
-48
-48
25
0
0
34
6
44
50
62
70c
Me3Al
ATPH
ATPH
ATPH
ATPH
ATPH
ATPH
present prior to the addition of the base. As such, we felt
that this method could be applied to the macroaldolization
of crotonate esters (Scheme 2),7 and we describe herein our
a
LTMP was slowly added to a solution of 1 precomplexed with the
specified Lewis acid (2.2 equiv) at the specified temperature (°C). All
reactions were performed at a 0.01 M final substrate concentration in 10:1
toluene/THF. b Isolated yield after purification. c A solution of the 1-ATPH
complex was slowly added to a solution of LTMP.11
Scheme 2. Intramolecular Yamamoto Vinylogous Aldol
Reaction
of one of these wherein a solution of LTMP (1.1 equiv) in
THF was added to a solution of 1 and ATPH (2.2 equiv) in
toluene at -25 °C.6b We were pleased to find that these
conditions provide the desired macrolide (2) albeit in only
25% yield (entry 1). The stereochemistry of the alkene of 2
was assigned as Z on the basis of the coupling constant
between the alkenyl protons (11.2 Hz).8 In the absence of
ATPH, or in the presence of the precursor to ATPH, Me3-
Al,9 none of the desired product was observed (entries 2 and
3).10 A brief solvent survey was conducted wherein we
studied cyclizations in dichloromethane, toluene, and THF
and found that these solvents provided only trace amounts
of product (data not shown).10 At lower temperature (-78
°C), a slight improvement in yield was observed (34%, entry
4); however, at higher temperatures (0 °C), the yield
decreased significantly (6%, entry 5).10 The best results were
obtained when the amount of LTMP used was increased from
1.1 to 2.0 equiv (entries 6-9), and under these conditions
at -48 °C, a 62% yield was observed (entry 8). Finally, it
was found that reversing the order of addition, such that a
solution of 1 and ATPH (2.2 equiv) in toluene was slowly
added to a cooled (-48 °C) solution of LTMP (2.0 equiv)
in THF/toluene, cleanly provides 2 in 70% yield (entry 9).11
Using these optimized conditions,11 we examined the
cyclizations shown in Table 2. We wished to study the effects
of ring size and whether or not remote asymmetric induction
could be observed in these reactions.
initial results which establish this as an effective method for
macrocyclic ring synthesis. Furthermore, we show that these
cyclizations can proceed with high levels of remote asym-
metric induction.
In our initial studies, we examined the cyclization of
compound 1 (Table 1). Yamamoto has described different
reaction conditions for various substrate combinations,6 and
in our first cyclization attempts, we used a slight modification
(4) For Mukaiyama and Reformatsky macrocyclizations, see: (a) Maruo-
ka, K.; Hashimoto, S.; Kitagawa, Y.; Yamamoto, H.; Nozaki, H. J. Am.
Chem. Soc. 1977, 99, 7705. (b) Smith, A. B.; Gauciaro, M. A.; Schow, S.
R.; Wovkulich, P. M.; Toder, B. H.; Hall, T. W. J. Am. Chem. Soc. 1981,
103, 219. (c) Tabuchi, T.; Kawamura, K.; Inanaga, J.; Yamaguchi, M.
Tetrahedron Lett. 1986, 33, 3889. (d) Vedejs, E.; Ahmad, S. Tetrahedron
Lett. 1988, 29, 2291. (e) Mukaiyama, T.; Shiina, I.; Iwadare, H.; Saitoh,
M.; Nishimura, T.; Ohkawa, N.; Sakoh, H.; Nishimura, K.; Tani, Y.;
Hasegawa, M.; Yamada, K.; Saitoh, K. Chem.-Eur. J. 1999, 5, 121. (f)
Inoue, M.; Sasaki, M.; Tachibana, K. J. Org. Chem. 1999, 64, 9416. (g)
Hachiya, I.; Kobayashi, N.; Kijima, H.; Pudhom, K.; Mukaiyama, T. Chem.
Lett. 2000, 8, 932. (h) Hong, Z.; Xu, X. Tetrahedron Lett. 2003, 44, 489.
(i) Kigoshi, H.; Kita, M.; Ogawa, S.; Itoh, M.; Uemura, D. Org. Lett. 2003,
5, 957. (j) Nagamitsu, T.; Takano, D.; Fukuda, T.; Otoguro, K.; Kuwajima,
I.; Harigaya, Y.; Omura, S. Org. Lett. 2004, 6, 1865.
(5) For reviews on the vinylogous aldol reaction, see: (a) Casiraghi, G.;
Zanardi, F.; Appendino, G.; Rassu, G. Chem. ReV. 2000, 100, 1929. (b)
Denmark, S. E.; Heemstra, J. R.; Beutner, G. L. Angew. Chem., Int. Ed.
2005, 44, 4682.
(6) (a) Saito, S.; Shiozawa, M.; Ito, M.; Yamamoto, H. J. Am. Chem.
Soc. 1998, 120, 813. (b) Saito, S.; Shiozawa, M.; Yamamoto, H. Angew.
Chem., Int. Ed. 1999, 38, 1769. (c) Saito, S.; Shiozawa, M.; Nagahara, T.;
Nakadai, M.; Yamamoto, H. J. Am. Chem. Soc. 2000, 122, 7847. (d) Saito,
S.; Nagahara, T.; Shiozawa, M.; Nakadai, M.; Yamamoto, H. J. Am. Chem.
Soc. 2003, 125, 6200. (e) For an asymmetric variation, see: Takikawa, H.;
Ishihara, K.; Saito, S.; Yamamoto, H. Synlett 2004, 732.
Entries 1-3 describe cyclizations which produce 10-
membered rings, and we were pleased to find that these
reactions proceed in high yields (77-82%) and with excellent
(8) See the Supporting Information for details.
(9) ATPH is prepared by the treatment of Me3Al (1 equiv) with 2,6-
diphenylphenol (3 equiv). See Supporting Information or ref 6a for details.
(10) Varying amounts of starting material and unidentified side products
were observed in these reactions.
(11) For details, see the general cyclization procedure in the Supporting
Information.
(7) For an example of an intramolecular vinylogous aldol reaction, see:
Takao, K.-i.; Hiroshi, O.; Yoshida, K.-i.; Hashizuka, T.; Koshimura, H.;
Tadano, K.-i.; Ogawa, S. J. Org. Chem. 1995, 60, 8179.
2104
Org. Lett., Vol. 9, No. 11, 2007

proceed in high yields (81-84%) and produce the E-isomers
exclusively. We were pleased to again observe excellent
levels of remote asymmetric induction (g25:1 dr) and were
unable to detect any isomeric products in these reactions by
1H NMR. Interestingly, these products display fluxional
behavior at the intermediate exchange rate on the NMR time
scale with broad nondescript signals at room temperature.
When heated to 59 °C, the spectra sharpen as described in
the Supporting Information.
Table 2. Scope of the Intramolecular Vinylogous Aldol
Reaction
Entries 7-9 in Table 2 describe cyclizations which form
14-membered rings, and these reactions proceed in the
highest yields of all those that we studied (88-90%). Again,
E-alkenes are produced exclusively, and the reactions proceed
with high levels of remote asymmetric induction (entry 8, R
) Me, 20:1, entry 9, R ) i-Pr, 23:1). The diastereomeric
ratio was determined by 1H NMR integration of the alkenyl
protons. Furthermore, hydrogenation of the alkene of com-
pounds 10 and 11 provides products in which the isomeric
ratio is maintained, thereby indicating that 10 and 11 are
isomeric at the tetrahedral stereocenters and not at the alkene.
The relative stereochemistry for lactone 3 was determined
by X-ray crystallography to be syn as drawn in Table 2,
whereas that of lactones 4 and 7 was determined to be anti
as drawn in Table 2 and as shown in Figure 1.12,13
a
b
Isolated yield after purification. Ratio of alkene stereoisomers
produced. c Diastereomeric ratios determined by 1H NMR. d The macrodi-
olide was also isolated in 7% yield. e A single isomer was observed by 1H
NMR.
levels of asymmetric induction (>25:1 dr). In the case of
entry 1, the Z-alkene was produced and no diastereomeric
1
products were detected by H NMR. Entries 2 and 3 show
an interesting trend wherein an increase in the steric bulk of
the substituent on the ring provides increasing amounts of
the E-alkene8 (compare Table 1, R ) H, exclusively Z, with
Table 2, entry 2, R ) Me, 3:1 Z/E, and Table 2, entry 3, R
) i-Pr, 1:13 Z/E). In the case of entries 2 and 3, hydrogena-
tion of the isomeric products provides the same compound,
thereby indicating that the compounds have the same relative
stereochemistry between the two tetrahedral stereocenters and
differ only by the alkene geometry (Scheme 3).
Scheme 3
Figure 1. X-ray crystal structures of the 3,5-dinitrobenzoate
derivatives of lactones 3, 4, and 7.
The relative stereochemistry of lactone 10 was determined
to be anti by chemical correlation as shown in Scheme 4.14
Compound 10 was synthesized with control of the absolute
(12) Crystallographic data for the 3,5-dinitrobenzoates 14 and 15 can
be found in the Supporting Information. The stereochemistry of compound
5 was assigned by analogy.
Entries 4-6 in Table 2 describe cyclizations which
produce 12-membered macrolides, and these reactions also
Org. Lett., Vol. 9, No. 11, 2007
2105

provide 17b (5R,11R). Alcohol 17 derived from compound
10 has spectral properties identical to those of 17a (5S,11R)
and different spectral data from those of 17b (5R,11R),
thereby establishing that lactone 10 has the S configuration
at C5 and an anti relationship between the two tetrahedral
stereocenters in the macrolide, as drawn in Table 2 and
Scheme 4.
Scheme 4
In conclusion, we have described an intramolecular
variation of the Yamamoto vinylogous aldol reaction for the
construction of 10- to 14-membered macrolides in good
yields (up to 90%) and excellent remote diastereoselection
(g20:1 dr). Studies aimed at understanding the stereocontrol
element in these cyclizations, expanding the scope of this
method, and applying it to the synthesis of natural products
are in progress.
Acknowledgment. We thank the NIH (GM48498) for
financial support, Dr. Mike McNevin, Andrew Schwerin,
and Professor Cortlandt Pierpont (University of Colorado,
Boulder) for acquiring the X-ray crystal structures of 14-
16, and Dr. Mark Mitton-Fry (Pfizer) for helpful discussions.
stereochemistry at C-11 (R), then hydrogenated (Pd/C) to
provide 17. Oxidation of 17 (Dess-Martin periodinane)15
to ketone 18 was followed by asymmetric reduction with
(-)-DIP-Cl16 to provide 17a (5S,11R) and (+)-DIP-Cl to
Supporting Information Available: Spectral character-
ization and experimental procedures for the synthesis of
compounds 1-18 and a general cyclization procedure. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(13) Crystallographic data for the 3,5-dinitrobenzoate 16 can be found
in the Supporting Information. The stereochemistry of compound 8 was
assigned by analogy.
(14) The stereochemistry of compound 11 was assigned by analogy.
(15) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(16) Chandrasekharan, J.; Ramachandran, P. V.; Brown, H. C. J. Org.
Chem. 1985, 50, 5446.
OL0704901
2106
Org. Lett., Vol. 9, No. 11, 2007