New reactions of 2-methylenetetrahydropyrans. A three component coupling protocol for the synthesis of tetrahydropyranyl ketides

Article abstract of DOI:10.1039/b916190b

Three component coupling of a 2-methylenetetrahydropyran, an activated aldehyde or ketone and a secondary nucleophile provides an efficient preparation of tetrahydropyranyl ketides, a unit common to many complex natural products.

Full text of DOI:10.1039/b916190b

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New reactions of 2-methylenetetrahydropyrans. A three component
coupling protocol for the synthesis of tetrahydropyranyl ketidesw
Guohua Liang, Laura J. Bateman and Nancy I. Totah*
Received (in College Park, MD, USA) 7th August 2009, Accepted 2nd September 2009
First published as an Advance Article on the web 23rd September 2009
DOI: 10.1039/b916190b
Three component coupling of a 2-methylenetetrahydropyran, an
activated aldehyde or ketone and a secondary nucleophile
provides an efficient preparation of tetrahydropyranyl ketides,
a unit common to many complex natural products.
2-Methylenetetrahydropyrans are useful intermediates for the
synthesis of complex molecules.1 These substrates have been
utilized for the preparation of C-glycosides,2 fused polyethers,3
spiroketals,4 and related compounds. Nonetheless, the chemistry
of these systems is less developed than that of the corresponding
2,3-dihydropyrans. Efforts to functionalize the exocyclic double
bond have largely focused on the introduction of heteroatoms,
while protocols for carbon–carbon bond formation, particularly
at the terminus, are more limited. Attempts to further elaborate
the enol ether include B-alkyl Suzuki coupling,5 radical
Scheme 2 Proposed synthesis of tetrahydropyranyl ketides 5.
processes,6 and cycloaddition reactions7 (Scheme 1). Less
nucleophile (Scheme 2). Such a process could be used to form
common are methods that take advantage of the nucleophilic
character of the exocyclic enol ether for direct formation of a
carbon–carbon bond (2). Such examples have been limited to
dimerization processes (3)8 and reaction with epi-sulfonium ions
(4).9 As functionalized tetrahydropyrans are integral components
of many biologically significant compounds, the development of
more general nucleophilic processes could find broad application
in complex molecule synthesis.
the C8–C9 bond of spirastrellolide A. Though this mode of
reactivity has previously been reported for 2,3-dihydropyrans,11
similar reactions for the corresponding exocyclic enol ethers have
remained largely unexplored. This omission is likely due to the
propensity of these systems to undergo rapid double bond
isomerization (7) upon heating or in the presence of trace
amounts of protic acid. Nonetheless, the requisite exocyclic enol
ethers are readily available via dehydrohalogenation of a suitably
substituted tetrahydropyran12 or by lactone methylenylation.13
In order to evaluate the feasibility of using exocyclic enol
ethers in nucleophilic addition processes, we examined the
Our interest in the synthesis of tetrahydropyran containing
polyketide natural products such as spirastrellolide A10 led us
to consider methods for the synthesis of tetrahydropyranyl
ketides like 5. We anticipated that the nucleophilic addition of
an exocyclic enol ether 1 to an aldehyde or ketone would give
the desired 2-tetrahydropyranylethanol derivative 5 upon
reaction of the intermediate oxonium species with a secondary
Table 1 Reaction of enol ether 1 with ethyl glyoxylate 8 and Et3SiH
Entry Ratio 1 : 8 Lewis acid Equiv. LA Timea
Yield (%)
1
2
3
4
5
6
7
8
1 : 1.2
1 : 1.2
1 : 1.2
1 : 1.2
1 : 1.2
1 : 1.2
1.5 : 1
1 : 1.2
1 : 1.2
1 : 1.2
1.2 : 1
1 : 1.2
1 : 1.2
1 : 1.2
BF3ÁOEt2
SnCl2
ZnCl2
EtAlCl2
Et2AlCl
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
1
1
1
1
1
1
1
1
1
1
1
0.5
0.2
0.1
1 h
1 h
1 h
1 h
1 h
1 h
1 h
—
—
—
—
—
48
56
20 min 45
10 min 59
9
Scheme 1 C–C bond forming reactions of 2-methylenetetrahydropyrans.
b
10
11
12
13
14
—
—
—
—
—
86
84
45
23
10
b
b
b
b
TiCl4
TiCl4
TiCl4
TiCl4
Department of Chemistry, Syracuse University, Syracuse, NY 13244,
USA. E-mail: ntotah@syr.edu; Fax: +1 315 443 4070;
Tel: +1 315 443 2657
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization data for all new compounds. See
DOI: 10.1039/b916190b
a
b
Time reaction mixture stirred prior to addition of Et3SiH. Et3SiH
added before the Lewis acid.
ꢀc
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reaction of enol ether 114 with ethyl glyoxylate 815 using
Et3SiH as the secondary nucleophile (Table 1). Though a
variety of Lewis acids were screened in this application, TiCl4
gave the best results providing the desired 2-hydroxy ester 9
in the highest yields and with the fewest side reactions
(entries 1–6). Variation in the reaction stoichiometry and time
to addition of reducing agent were evaluated in order to
optimize yields further. As shown, the relative percentage of
reactive components 1 and 8 has little impact on the yield of
the reaction (entries 6 and 7, 10 and 11). More important
to the success of this transformation is the ready availability
of the nucleophile upon generation of the intermediate oxonium
species (entries 6, 8–10). Best results are obtained when Et3SiH
is present in the reaction mixture prior to addition of the Lewis
acid. In these cases, reduction in the amount of TiCl4 utilized
results in a corresponding decrease in the product yield
(entries 10, 12–14). Based on these findings, the protocol that
unfolds is one in which (1) activation of the aldehyde with
equimolar amounts of Lewis acid to facilitate rapid addition of
the exocyclic enol ether prior to double bond isomerization,
and (2) immediate reaction of the oxonium intermediate thus
formed with an appropriate nucleophile to minimize side reactions.
The scope of this transformation was next evaluated by
varying both carbonyl and nucleophile components. As shown
in Table 2, both 2-methylenetetrahydropyrans (1 and 15) and
the corresponding chroman derivative (14) can be utilized as
the enol component in these transformations. Addition of
these substrates to activated aldehydes 8 and 17 occurs
readily at À78 1C. Both hydride and allyl functions can be
subsequently incorporated at the C2 position upon treatment
of the intermediate oxonium ion with triethylsilane or
allyltrimethylsilane, respectively. Similar reactivity is observed
with 2,3-butanedione 16 (entries 3, 9, 13). The resulting aldol
equivalents are produced in excellent yields. This reaction is
significant in that ketones are typically poor electrophiles in
intermolecular aldol reactions because the reaction equilibrium
Table 2 Three component coupling reaction of 2-methylenetetrahydropyrans
Yield
(%)
Entry Enol ether
Electrophile
Timea Nucleophile
Product
Nu
H
dr
1
5 min Et3SiH
9a
1 : 1 86
2
3
1
8
5 min CH2QCHCH2TMS
9b CH2CHQCH2 2 : 1 55
1
1
1 h
1 h
Et3SiH
18a
H
4 : 1 79
4
5
6
16
8
CH2QCHCH2TMS
18b CH2CHQCH2 2 : 1 51
1.5 :
1
5 min Et3SiH
19a
H
97
14
14
5 min CH2QCHCH2TMS
19b CH2CHQCH2 1 : 1 96
7
1 h
Et3SiH
20a
H
1 : 1 87
8
9
14
14
14
17
1 h
1 h
1 h
CH2QCHCH2TMS
Et3SiH
20b CH2CHQCH2 1 : 1 97
21a
H
5 : 1 95
10
11
16
8
CH2QCHCH2TMS
21b CH2CHQCH2 1 : 1 97
22a 5 : 1 77
5 min Et3SiH
H
12
13
15
15
5 min CH2QCHCH2TMS
22b CH2CHQCH2 1 : 1 67
23 2 : 1 56
1 h
Et3SiH
H
a
Time before secondary nucleophile addition.
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Synthesis, 1999, 783; (d) A. N. Cuzzupe, C. A. Hutton, M. J. Lilly,
R. K. Mann, K. J. McRae, S. Zammit and M. A. Rizzacasa,
J. Org. Chem., 2001, 66, 2382; (e) M. El Sous, D. Ganame,
P. A. Treggloan and M. A. Rizzacasa, Org. Lett., 2004, 6, 3001;
(f) C. C. Lindsey, K. L. Wu and T. R. R. Pettus, Org. Lett., 2006, 8,
2365; (g) G. Zhou, D. Zheng, S. Da, Z. Xie and Y. Li, Tetrahedron
Lett., 2006, 47, 3349.
5 (a) B. A. Johns, Y. T. Pan, A. D. Elbein and C. R. Johnson, J. Am.
Chem. Soc., 1997, 119, 4856; (b) M. Sasaki, H. Fuwa, M. Inoue
and K. Tachibana, Tetrahedron Lett., 1998, 39, 9027; (c) M. Sasaki
and H. Fuwa, Synlett, 2004, 1851, and references therein;
(d) S. Ciblat, J. Kim, C. A. Stewart, J. Wang, P. Forgione,
D. Clyne and L. A. Paquette, Org. Lett., 2007, 9, 719.
Fig. 1 Stereochemistry of nucleophile addition.
lies far to the left. Further, use of a ketone electrophile provides
access to compounds that contain a quaternary center b to the
tetrahydropyran ring. When allyltrimethylsilane is used as the
secondary nucleophile (entries 4, 10), two oxygenated quaternary
centers are generated in a single process.
6 (a) W. B. Motherwell, B. C. Ross and M. J. Tozer, Synlett, 1989,
68; (b) A. G. Myers, D. Y. Gin and K. L. Widdowson, J. Am.
Chem. Soc., 1991, 113, 9661; (c) L. Cipolla, L. Liguori, F. Nicotra,
G. Torri and E. Vismara, Chem. Commun., 1996, 1253;
(d) H.-S. Dang, M. R. J. Elsegood, K.-M. Kim and
B. P. Roberts, J. Chem. Soc., Perkin Trans. 1, 1999, 2061;
(e) B. Vauzeilles and P. Sinay, Tetrahedron Lett., 2001, 42, 7269.
7 Hetero Diels–Alder: (a) R. E. Ireland and D. Haebich, Chem. Ber.,
1981, 114, 1418; (b) P. Hayes and C. Maignan, Synlett, 1994, 409;
(c) L. F. Tietze, G. Schneider, J. Wolfling, T. Nobel, C. Wulff,
I. Christian and A. Rubeling, Angew. Chem., Int. Ed., 1998, 37,
2469; (d) J. K. Gallos, V. C. Sarli, C. I. Stathakis, T. V. Koftis,
V. R. Nachmia and E. Coutouli-Argyropoulou, Tetrahedron, 2002,
58, 9351; (e) G. Zhou, D. Zheng, S. Da, Z. Xie and Y. Li,
Tetrahedron Lett., 2006, 47, 3349. Intramolecular Diels–Alder;
(f) P. A. Wender, R. M. Keenan and H. Y. Lee, J. Am. Chem.
Soc., 1987, 109, 4390. 1,3-Dipolar cycloaddition; (g) J. K. Gallos
and T. Koftis, J. Chem. Soc., Perkin Trans. 1, 2001, 415;
(h) P. A. Colinas, V. Jager, A. Lieberknecht and R. D. Bravo,
Tetrahedron Lett., 2003, 44, 1071; (i) X. Li, H. Takahashi,
O. Hideyo and S. Ikegami, Tetrahedron Lett., 2004, 45, 4123;
(j) G. Enderlin, C. Taillefumier, C. Didierjean and Y. Chapleur,
Tetrahedron: Asymmetry, 2005, 16, 2459; (k) P.-Z. Zhang, X.-L. Li,
H. Chen, Y.-N. Li and R. Wang, Tetrahedron Lett., 2007, 48, 7813.
8 (a) L. Lay, F. Nicotra, L. Panza, G. Russo and E. Caneva, J. Org.
In cases where a pre-existing stereocenter is present at C6 of
the tetrahydropyran, the three component coupling proceeds to
give the corresponding 2,6-cis-tetrahydropyrans as the only
isolated products (entries 11–13). The stereochemistry of these
compounds 22 and 23 was determined by nOe. The observed
stereoselectivity can be rationalized as shown in Fig. 1. The
observed stereoselectivity is consistent with addition of the
secondary nucleophile to an oxonium ion intermediate that exists
in a half-chair conformation in which the C6 substituent is
pseudo-equatorial (24B).16 Subsequent axial attack of the
nucleophile is then anticipated on both steric and stereoelectronic
grounds.17 Similar selectivity is observed in the addition of
nucleophiles to related tetrahydropyranyl oxonium species.18
In conclusion, we have demonstrated a facile synthesis of
tetrahydropyranyl ketide derivatives using a three component
coupling protocol. These studies demonstrate that 2-methylene-
tetrahydropyrans are suitable nucleophiles for addition to
activated aldehydes and ketones. Competing double bond iso-
merization is not a factor. The resulting 2-(tetrahydropyran-2-yl)-
alcohols will be useful intermediates for complex molecule
synthesis. Current efforts are aimed at the synthesis of
spirastrellolide A and related polyketide natural products.
These studies will be reported in due course.
Chem., 1992, 57, 1304; (b) G. Fra
Chem., 2007, 72, 1112.
´
ter and F. Schroder, J. Org.
¨
9 H. Liu, I. P. Smoliakova and L. N. Koikov, Org. Lett., 2002, 4, 3895.
10 (a) D. E. Williams, M. Roberge, R. Van Soest and R. J. Andersen,
J. Am. Chem. Soc., 2003, 125, 5296; (b) D. E. Williams,
M. Lapawa, X. Feng, T. Tarling, M. Roberge and
R. J. Andersen, Org. Lett., 2004, 6, 2607; (c) K. Warabi,
D. E. Williams, B. O. Patrick, M. Roberge and R. J. Andersen,
J. Am. Chem. Soc., 2007, 129, 508.
Financial support from the National Institutes of Health
(R01 GM064357) is gratefully acknowledged. We thank
Mr. Alex Augatis for assistance with nOe studies.
11 (a) T. Mukaiyama, K. Wariishi and Y. Sato, Chem. Lett., 1988,
1101; (b) H. Sugimura and K. Osumi, Tetrahedron Lett., 1989, 30,
1571; (c) A. K. Ghosh and R. Kawahama, Tetrahedron Lett., 1999,
40, 1083; (d) A. K. Ghosh and R. Kawahama, Tetrahedron Lett.,
1999, 40, 4751; (e) A. K. Ghosh, R. Kawahama and D. Wink,
Tetrahedron Lett., 1999, 40, 1083; (f) A. K. Ghosh, C.-X. Xu,
S. S. Sarang and D. Wink, Org. Lett., 2005, 7, 7.
Notes and references
1 For general reviews on the synthesis and use of exo-glycals, see:
(a) C. Taillefumier and Y. Chapleur, Chem. Rev., 2004, 104, 263;
(b) C.-H. Lin, H.-C. Lin and W.-B. Yang, Curr. Top. Med. Chem.,
2005, 5, 1431.
12 For example, see: (a) J. D. Prugh, C. S. Stanley, A. A. Deana and
H. G. Ramjit, Tetrahedron Lett., 1985, 26, 2947; (b) J. Prandi and
J. M. Beau, Tetrahedron Lett., 1989, 30, 4517; (c) C. Taillefumier
and Y. Chapleur, Can. J. Chem., 2000, 78, 708.
2 (a) T. V. RajanBabu and G. S. Reddy, J. Org. Chem., 1986, 51,
5458; (b) C. R. Johnson and B. A. Johns, Synlett, 1997,
1406; (c) T. F. Herpin, W. B. Motherwell and M. J. Tozer,
Tetrahedron: Asymmetry, 1994, 5, 2269; (d) A. D. Campbell,
D. E. Paterson, R. J. K. Taylor and T. M. Raynham,
Chem. Commun., 1999, 1599; (e) J. T. Link and B. K. Sorensen,
Tetrahedron Lett., 2000, 41, 9213; (f) J. R. Walker, G. Alshafie,
N. Nieves, J. Ahrens, M. Clagett-Dame, H. Abou-Issa and
R. W. Curley, Jr., Bioorg. Med. Chem., 2006, 14, 3038, see also ref. 1.
3 (a) H. Fuwa, N. Kainuma, K. Tachibana and M. Sasaki,
Tetrahedron Lett., 2004, 45, 4795; (b) K. C. Nicolaou,
K. P. Cole, M. O. Frederick, R. J. Aversa and R. M. Denton,
Angew. Chem., Int. Ed., 2007, 46, 8875; (c) M. Sasaki and H. Fuwa,
Nat. Prod. Rep., 2008, 25, 401, and references therein.
13 (a) N. A. Petasis and E. I. Bzowej, J. Am. Chem. Soc., 1990, 112, 6392;
(b) N. A. Petasis and S.-P. Lu, Tetrahedron Lett., 1995, 36, 2393.
14 A. Neokosmidi, V. Ragoussis and G. Evangelatos, J. Agric. Food
Chem., 2004, 52, 4368, see also ref. 4d and 7a.
15 Ethyl glyoxylate was freshly distilled before use according to the
procedure of Evans: D. A. Evans, D. W. C. MacMillan and
K. R. Campos, J. Am. Chem. Soc., 1997, 119, 10859.
16 R. J. Woods, C. W. Andrews and J. P. Bowen, J. Am. Chem. Soc.,
1992, 114, 859.
17 (a) P. Deslongchamps, Stereoelectronic Effects in Organic
Chemistry, Pergamon, New York, 1983, p. 211; (b) R. V. Stevens
and A. W. M. Lee, J. Am. Chem. Soc., 1979, 101, 7032;
(c) R. V. Stevens, Acc. Chem. Res., 1984, 17, 289.
18 (a) D. S. Brown, S. V. Ley and M. Bruno, Heterocycles, 1989, 28,
773; (b) C. G. Lucero and K. A. Woerpel, J. Org. Chem., 2006, 71,
2641; (c) C. Crawford, A. Nelson and I. Patel, Org. Lett., 2006, 8,
4231.
4 (a) R. E. Ireland, S. Thaisrivongs and P. H. Dussault, J. Am.
Chem. Soc., 1988, 110, 5768; (b) A. Haudrechy and P. Sinay,
Carbohydr. Res., 1991, 256, 375; (c) P. Hayes and C. Maignan,
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Chem. Commun., 2009, 6457–6459 | 6459