Symmetrie macrocycles by a prins dimerization and macrocyclization strategy

Article abstract of DOI:10.1021/ol9022062

A tandem dimerization/macrocyclization reaction utilizing the Prins cyclization has been developed. This reaction develops molecular complexity through the formation of highly substituted dimeric tetrahydropyran macrocycles. Mild conditions utilizing rhen

Full text of DOI:10.1021/ol9022062

ORGANIC
LETTERS
2009
Vol. 11, No. 22
5342-5345
Symmetric Macrocycles by a Prins
Dimerization and Macrocyclization
Strategy
Michael R. Gesinski, Kwanruthai Tadpetch, and Scott D. Rychnovsky*
Department of Chemistry, 1102 Natural Sciences II, UniVersity of California,
IrVine, California 92697-2025
srychnoV@uci.edu
Received September 23, 2009
ABSTRACT
A tandem dimerization/macrocyclization reaction utilizing the Prins cyclization has been developed. This reaction develops molecular complexity
through the formation of highly substituted dimeric tetrahydropyran macrocycles. Mild conditions utilizing rhenium(VII) catalysts were explored
for aromatic substrates, while harsher Lewis acidic conditions were used for aliphatic substrates. Both aldehydes and acetals are shown to
be viable substrates for this reaction.
Oxacyclic macrodimers are an important class of natural
products offering a wide array of structural complexity and
bioactivity.1 These macrolides have become popular targets for
synthetic chemists.2 The most direct way to construct these
molecules is through the union of two monomeric species in a
tandem dimerization and macrocyclization reaction. The most
common version of this strategy utilizes two esterification
reactions between an activated acid and an alcohol, first an initial
dimerization followed by a macrolactonization.3 While often
successful, this approach does not greatly enhance the complex-
ity of the intermediate through the formation of carbon-carbon
bonds. Alternative bond-forming reactions, such as Suzuki
coupling and olefin metathesis, have been used with occasional
success in dimerization and macrocyclization strategies.4,5
Herein we describe a new dimerization and macrocyclization
strategy based on the Prins cyclization reaction.
The Prins cyclization is a powerful reaction that forms
cis-2,6-disubstituted tetrahydropyrans (THPs) through the
addition of an olefin to an oxocarbenium ion generated from
the condensation of an aldehyde with a homoallylic alcohol.6
Recently, intramolecular Prins cyclizations have been utilized
as key macrocyclization steps in the synthesis of several THP
containing natural products (Figure 1A).7 We report the
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Adams, C. M.; Kozmin, S. A.; Paone, D. V. J. Am. Chem. Soc. 2001, 123,
5925–5937. (c) Condensations: Hoye, T. R.; Ye, Z.; Yao, L. J.; North, J. T.
J. Am. Chem. Soc. 1996, 118, 12074–12081.
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Curr. Org. Chem. 2007, 11, 925–957. (b) Snider, B. B. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Heathcock, C. H., Eds.;
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Bhatnagar, S. P. Synthesis 1977, 661–672. (d) Overman, L. E.; Pennington,
L. D. J. Org. Chem. 2003, 68, 7143–7157.
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10.1021/ol9022062 CCC: $40.75
Published on Web 10/29/2009
 2009 American Chemical Society

Scheme 1. Synthesis of the Aldehyde Monomers
extension of this methodology to the formation of oxacyclic
macrodimers through sequential Prins dimerization and
macrocyclization reactions (Figure 1B). This synthetic
strategy has been applied to a model for the marine
macrodiolide clavosolide A.
yield.8 Nokami’s menthone derived allyl-transfer reagent was
utilized to yield optically pure E-homoallylic alcohol 3.9 The
ethyl ester was reduced with LiAlH4 to provide the benzylic
alcohol, which was selectively oxidized with MnO2 to afford
aldehyde 4 in 61% overall yield. The meta- and ortho-
substituted substrates (8 and 12, respectively) were synthesized
in a similar manner.
With appropriate starting materials in hand, the dimerization/
macrocyclization reaction of aldehyde 4 was explored (Table
1). Previously, O3ReOSiPh3 has been shown to effectively
catalyze Prins reactions of aromatic aldehydes.10 When aldehyde
4 was exposed to O3ReOSiPh3 at room temperature for 22 h,
33% of cyclophane 13 was isolated (entry 1). The remainder
of the mass was attributed to rhenium(VII)-mediated polym-
erization. To diminish this byproduct, the reaction was run at
lower concentration, which increased the yield of the dimer
(entry 2). Gratifyingly, decreasing the catalyst loading to 25%
had little effect on the yield (entry 3), but decreasing the loading
further resulted in diminished yields (entry 4). Other rhenium-
(VII) catalysts proved less effective than O3ReOSiPh3 (entries
5 and 6). Heating the reaction in CH2Cl2 decreased the reaction
time but had minimal effect on the overall yield (entries 7 and
8). Finally, alternative Prins promoters were investigated. Both
TESOTf11 and trifluoroacetic acid12 produced acylated varia-
tions of cyclophane 13 (entries 9 and 10) but ultimately proved
inferior to the rhenium(VII) conditions.
Figure 1. Comparison of Prins macrocyclization reactions.
Having developed optimized conditions for the dimerization/
macrocyclization reaction of the para-substituted aldehyde, the
The [n,n]-cyclophanes were chosen as targets for the initial
study of this reaction since the aromatic ring of these substrates
provides rigidity that precludes the undesired macrocyclization
reaction, and the starting materials were accessible from simple
precursors. The Prins cyclization substrates 4, 8, and 12 were
synthesized from the corresponding commercially available
para-, meta-, or ortho-substituted ethyl iodobenzoate, respec-
tively (Scheme 1). Palladium-mediated coupling of allyl alcohol
and ethyl 4-iodobenzoate (1) yielded known aldehyde 2 in 85%
(8) (a) Taylor, E. C.; Gillespie, P.; Patel, M. J. Org. Chem. 1992, 57,
3218–3225. (b) Watson, S. E.; Taylor, E. C.; Patel, H. Synth. Commun.
1998, 28, 1897–1905.
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Angew. Chem., Int. Ed. 2003, 42, 1273–1276. (b) Nokami, J.; Ohga, M.;
Nakamoto, H.; Matsubara, T.; Hussain, H.; Kataoka, K. J. Am. Chem. Soc.
2001, 123, 9168–9169.
(10) Tadpetch, K.; Rychnovsky, S. D. Org. Lett. 2008, 10, 4839–4842.
(11) Ko, H. M.; Lee, D. G.; Kim, M. A.; Kim, H. J.; Park, J.; Lah,
M. S.; Lee, E. Tetrahedron 2007, 63, 5797–5805.
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C. D.; Parker, G. D.; Willis, C. L. Org. Lett. 2003, 5, 2429–2432.
Org. Lett., Vol. 11, No. 22, 2009
5343

Table 1. Screening Prins Dimerization/Macrocyclization
Conditions
entry
catalyst
conc
time temp yield
1
2
O3ReOSiPh3 (40 mol %)
O3ReOSiPh3 (50 mol %)
0.10 M
22 h 23 °C
33%
53%
51%
26%
29%
38%
51%
42%
0.050 M 24 h 23 °C
3
O3ReOSiPh3 (25 mol %) 0.050 M 24 h 23 °C
4
O3ReOSiPh3 (5 mol %)
aq O3ReOH (50 mol %)
Re2O7 (50 mol %)
O3ReOSiPh3 (25 mol %)
O3ReOSiPh3 (5 mol %)
TESOTfa (20 equiv)
TFA (20 equiv)
0.050 M 24 h 23 °C
0.050 M 24 h 23 °C
0.045 M 25 h 23 °C
5
6
7
0.050 M
0.050 M
0.030 M
0.30 M
5 h 40 °C
5 h 40 °C
Figure 2. Two alternative strategies for the dimerization and
cyclization of (-)-clavosolide A.
8
9
3 h 23 °C 27%b
10
3 h 23 °C 11%b
a Run in AcOH with 30 equiv of TMSOAc. b Yield after hydrolysis of
the crude acyl trapped product by MeOH/K2CO3.
gathered off the coast of the Philippines.13 The unique archi-
tecture of this THP-containing macrodimer inspired several total
syntheses14 and a structural revision.15 All reported approaches
utilized Yamaguchi’s macrolactonization conditions to form the
dimer from a complex, THP-containing monomer.16 The
interesting architecture of clavosolide A appeared to be well
suited to a Prins dimerization and macrocyclization strategy.
Due to concern over the lability of the cyclopropylcarbinyl
moiety of clavosolide A,17 a model system was designed that
replaced the problematic cyclopropyl side chain with a cyclo-
hexane ring. The cyclohexyl monomer was synthesized from
two simple fragments, 20 and 24 (Schemes 3 and 4). Enzymatic
resolution of known ꢀ-lactone 17 with Lipase PS Amano in
the presence of benzyl alcohol afforded the resolved (S)-lactone
(18) and ꢀ-hydroxy ester 19.18 Both substrates were then
reduced with LiAlH4, and the resultant enantiomeric diols were
monoprotected as TBS-ethers 20 and 21.
ortho- and meta-substituted aldehydes were employed to further
expand the scope of the reaction (Scheme 2). The ortho-
Scheme 2
.
Optimized Prins Macrocylization/Dimerization
Reactions
The synthesis of the acid fragment 24 began with DDQ-
mediated deprotection of the p-methoxybenzyl ether of known
silyl ether 22 to provide an inseparable mixture of alcohol 23
and p-anisaldehyde.19 The p-anisaldehyde was then removed
by reduction and chromatography. Surprisingly, oxidation to
substituted aldehyde 12 afforded cyclized monomer 14 via an
intramolecular Prins reaction in 90% yield. Prins macrocycliza-
tions can be very effective, when not precluded by the geometry
of the substrate.7 In contrast, when aldehyde 8 was exposed to
the Prins conditions, dimeric cyclophane 15 was obtained in
28% yield. Surprisingly, the trimeric macrocycle 16 was also
isolated in 13% yield. The remainder of the mass was associated
with a small amount of starting material and a complex mixture
of other products. The Prins reaction led to significant yields
of dimer in two of the three cases examined, and in each case
a single enantiomer and diastereomer of the product was
obtained.
(13) (a) Erickson, K. L.; Gustafson, K. R.; Pannell, L. K.; Beutler, J. A.;
Boyd, M. R. J. Nat. Prod. 2002, 65, 1303–1306. (b) Rao, M. R.; Faulkner,
D. J. J. Nat. Prod. 2002, 65, 386–388.
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Lett. 2006, 47, 7435–7438. (c) Barry, C. S.; Elsworth, J. D.; Seden, P. T.;
Bushby, N.; Harding, J. R.; Alder, R. W.; Willis, C. L. Org. Lett. 2006, 8,
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2099–2102. (b) Barry, C. S.; Bushby, N.; Charmant, J. P. H.; Elsworth,
J. D.; Harding, J. R.; Willis, C. L. Chem. Commun. 2005, 5097–5099.
(16) Yamaguchi, M. A.; Katsuki, T.; Sacki, H.; Hirata, K.; Inanaga, J.
Bull. Chem. Soc. Jpn. 1979, 52, 1989–1993.
(17) Poulter, D. C.; Winstein, S. J. J. Am. Chem. Soc. 1969, 91, 3650–
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Lett. 1999, 6535–6539.
The C2-symmetric macrodiolide (-)-clavosolide A (Figure
2) was isolated from the marine sponge Myriastra claVosa
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Org. Lett., Vol. 11, No. 22, 2009

Scheme 3
.
Synthesis of the Cyclohexyl Alcohols 20 and 21
Scheme 5. Prins Dimerization and Macrocyclization
was needed to avoid this side reaction, and the diol 26 (not
shown) was formed in 88% yield. Finally, TEMPO-catalyzed
selective oxidation successfully produced the requisite aldehyde
27. Aldehyde 27 was labile and decomposed upon silica gel
chromatography. Attempts to perform a Prins dimerization and
macrocyclization reaction on the crude aldehyde under various
conditions led to decomposition of the starting material,
presumably through acid-promoted elimination of the ꢀ-acyl
aldehyde.
To circumvent this decomposition, aldehyde 27 was protected
as dimethyl acetal 28. This substrate proved much more
manageable and was easily purified by column chromatography.
It has been shown that Lewis acid-promoted Prins cyclizations
of acetals are particularly effective with TESOTf in acetic
acid.11,22 Gratifyingly, when acetal 28 was subjected to these
conditions, dimeric macrolide 29 was produced in 43% yield.
Using acetal 28 avoids the decomposition of the sensitive
aldehyde 27.
the carboxylic acid proved challenging. Oxidation of alcohol
23 to the aldehyde followed by Lindgren-Pinnick oxidation
afforded very poor yields of acid 24. Additionally, TEMPO-
mediated bleach oxidations20 resulted in chlorination of the
substrate. Instead, a large excess of pyridinium dichromate was
employed over three days to produce acid 24 in 66% yield.21
The acid was then coupled to both alcohol enantiomers 20 and
21, either through esterification to maintain the alcohol stere-
ochemistry or Mitsunobu reaction to invert the stereochemistry,
to afford bis-TBS ether 25.
Scheme 4. Synthesis of the Ester Monomer 25
The first example of a Prins dimerization and macrocycliza-
tion reaction has been developed. This powerful methodology
affords macrocyclic dimers while simultaneously enhancing
molecular complexity. Several complex [n,n]-paraphanes were
prepared in only five steps from commercially available
material. A model for the synthesis of clavosolide A was
successfully demonstrated, and studies will continue to apply
this strategy to natural product synthesis.
Acknowledgment. This work was supported by the
National Institute of General Medicine (GM-43854) and by
a generous gift from the Schering-Plough Research Institute.
K.T. was supported by a fellowship from the Royal Thai
Government, and M.R.G. was supported by a Lilly Graduate
Research Fellowship.
With the completion of the monomer framework, a few
simple manipulations were needed to test the key Prins
dimerization/macrocyclization reaction (Scheme 5). Removal
of the two silyl groups proved to be surprisingly difficult. Under
standard deprotection conditions, only the primary silyl group
was cleaved. Unfortunately, unmasking the primary alcohol
under more forcing basic or acidic conditions led to a deleterious
acyl migration. Ultimately, a large excess of HF·pyridine in THF
Supporting Information Available: Characterization data
and experimental procedures for all compounds described
are included. This material is available free of charge via
the Internet at http://pubs.acs.org.
(19) Eggen, M.; Mossman, C. J.; Buck, S. B.; Nair, S. K.; Bhat, L.;
Ali, S. M.; Reiff, E. A.; Boge, T. C.; Georg, G. I. J. Org. Chem. 2000, 65,
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OL9022062
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Synth. 2005, 81, 195–203.
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