Stereoselective synthesis of cyclic ethers via the palladium-catalyzed intramolecular addition of alcohols to phosphono allylic carbonates

Article abstract of DOI:10.1021/ol900980s

Cross metathesis of the acrolein-derived phosphono allylic carbonate and hydroxy alkenes using second generation Grubbs catalyst and copper(l) iodide gave the substituted phosphonates in good yield. Stereospecific palladium(0)-catalyzed cyclization gave t

Full text of DOI:10.1021/ol900980s

ORGANIC
LETTERS
2009
Vol. 11, No. 14
3124-3127
Stereoselective Synthesis of Cyclic
Ethers via the Palladium-Catalyzed
Intramolecular Addition of Alcohols to
Phosphono Allylic Carbonates
Anyu He, Nongnuch Sutivisedsak, and Christopher D. Spilling*
Department of Chemistry and Biochemistry, UniVersity of Missouri-St. Louis,
One UniVersity BouleVard, St. Louis, Missouri 63121
cspill@umsl.edu
Received May 4, 2009
ABSTRACT
Cross metathesis of the acrolein-derived phosphono allylic carbonate and hydroxy alkenes using second generation Grubbs catalyst and
copper(I) iodide gave the substituted phosphonates in good yield. Stereospecific palladium(0)-catalyzed cyclization gave tetrahydrofuran and
tetrahydropyran vinyl phosphonates. Regioselective Wacker oxidation of the vinyl phosphonate gave the ꢀ-keto phosphonate, which underwent
HWE reaction with benzaldehyde to yield the unsaturated ketone. The utility of the cross metathesis/cyclization protocol was further demonstrated
by a formal synthesis of centrolobine.
Tetrahydrofurans (thf) and tetrahydropyrans (thp) are struc-
tures frequently found in several important classes of
biologically active natural products, such as polyether
antibiotics, acetogenins, and C-glycosides. Specific examples
inlcude the cyctotoxic amphidinolides E and F, the aceto-
genin mucocin, and the brown algae lipids (Figure 1).1 Not
surprisingly, the importance of thf- and thp-containing
molecules has caught the attention of synthetic chemists, and
several approaches to their synthesis have been reported.2
Reactions most frequently used include oxidation of dienes
and hydroxy alkenes, intramolecular addition of alcohols to
epoxides and alkenes, cyclodehydration of diols and ap-
plication of the chiral pool (carbohydrates) via reduction or
Figure 1. Some natural products containing thf and thp.
(1) (a) Kobayashi, J.; Ishibashi, M.; Murayama, T.; Takamatsu, M.;
Iwamura, M.; Ohizumi, Y.; Sasaki, T. J. Org. Chem. 1990, 55, 3421. (b)
Tsuda, M.; Ishibashi, M.; Shigemori, H.; Yamasu, T.; Hirota, H.; Sasaki,
T. J. Antibiot. 1991, 44, 1259. (c) Shi, G.; Alfonso, D.; Fatope, M. O.;
Zeng, L.; Gu, Z.-M.; Zhao, G.-X.; He, K.; MacDougal, J. M.; McLaughlin,
J. L. J. Am. Chem. Soc. 1995, 117, 10409. (d) Warren, R. G.; Wells, R. J.;
Blount, J. F. Aust. J. Chem. 1980, 33, 891.
nucleophilic addition of carbon nucleophiles to oxacarbenium
ions.1 Each of these methods has its own advantages and
disadvantages that tend to be specific to each substrate or
target molecule. However, many of the methods leading to
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 2009 American Chemical Society

the formation of 2,5-disubstituted thf or 2,6-disubstituted thp
rings are limited to the formation of either the cis or trans
isomer, or the level of diastereoselectivity can be an issue.
We set out to design a method that allows selective access
to both cis- and trans-2,5-disubstituted tetrahydrofurans and
2,6-tetrahydropyrans. A further goal was to include func-
tionality in the molecule that would allow for additional C-C
bond formations to aid in the coupling of fragments for
complex molecule synthesis.
We have been investigating the application of allylic
R-hydroxyphosphonates as building blocks for natural prod-
uct synthesis.3 We reported the palladium-catalyzed cycliza-
tion of phosphono allylic carbonates (1a and 1b) with a
pendant amine to give pyrollidine- and piperidine-subsitituted
vinyl phosphonates (2a and 2b) (Scheme 1).3b This cycliza-
The intermolecular addition of alcohol nucleophiles to
palladium π-allyl complexes is more problematic than the
well-known addition of amine nucleophiles.9-11 However,
the corresponding intramolecular additions appear to proceed
more smoothly.12-15 Stork first demonstrated chirality
transfer in the intramolecular palladium(0)-catalyzed addition
of alcohol to an allylic benzoate.12 Trost later explored the
regioselectivity for the cyclization of a series of racemic diols.
The ring size preference is 5 > 6 > 7 and primary, secondary,
and tertiary alcohols were all viable nucleophiles.13 There
are several examples of the cyclization of more complex
substrates in natural product synthesis.14 In particular, Burke
demonstrated an elegant use of the Trost ligand in the cyclo
desymmetrization of diols and tetraols.15 The cyclization of
a C2 1,2-diol represents one of the most efficient bidirectional
approaches to the bis-furan core found in some aceto-
genins.15a
The required phosphono allylic carbonates were prepared
by the cross metathesis of alkenols (4) with the acrolein-
derived phosphono carbonate (3) (Table 1).16 Initial reactions
with Grubbs second generation catalyst alone (5-7%,
Method A) proved to be sluggish. A typical reaction usually
required 3 days to achieve good conversion and gave modest
ioslated yields. However, the addition of CuI as a cocatalyst17
resulted in a remarkable acceleration in the reaction rate and
improved isolated yields (e.g., entries 1 and 2). The reactions
were typically run with either the alkenol (4) or the
phosphonate (3) in a 2:1 excess. The choice of alkenol or
phosphonate as the reagent in excess did not seem to affect
the overall yield.
Scheme 1. Cyclization of Amino Phosphono Allylic Carbonates
tion reaction showed an unusual temperature dependence.
The Z to E ratio in the vinyl phosphonates was dependent
upon the reaction temperature, with the Z product being
dominant at lower tempertaures.
It was clear that the related cyclization of a pendant alcohol
would lead to thf and thp ring systems (Scheme 2). Since
Reaction of the phosphono allylic carbonates in the
presence of Pd(PPh3)4 or Pd2(dba)3/dppe in THF and Hunig’s
base at 40 °C gave the corresponding tetrahydrofuran and
tetrahydropyran (E)-vinyl phosphonates (6a and 6b), respec-
tively (Scheme 3). The reactions proceeded equally well with
(3) (a) Yan, B.; Spilling, C. D. J. Org. Chem. 2008, 73, 5385. (b) De la
Cruz, A.; He, A.; Thanavaro, A.; Yan, B.; Spilling, C. D.; Rath, N. P. J.
Organomet. Chem. 2005, 690, 2577. (c) Yan, B.; Spilling, C. D. J. Org.
Chem. 2004, 69, 2859. (d) Rowe, B. J.; Spilling, C. D. J. Org. Chem. 2003,
Scheme 2. Proposed Approach to Cyclic Ethers
68, 9502
(4) (a) Poss, A. J.; Smyth, M. S. Synth. Commun. 1987, 17, 1735. (b)
Stutz, G.; Pondaven-Raphalen, A. J. Chem. Res. Synop. 1980, 175
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.
Organic Molecules, 2nd ed.; University Science Books, Sausalito, CA, 1999
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(b) Stanton, S. A.; Felman, S. W.; Parkhurst, C. S.; Godleski, S. A. J. Am.
.
the addition of the alcohol to the palladiun π-allyl complex
is expected to be stereospecific, the stereochemistry of the
cyclic ether should be predetermined by the stereochemistry
of the coupling partners in the cross metathesis reaction.
Furthermore, the vinyl phosphonate can be converted into
ꢀ-keto phosphonate,4 R-and ꢀ- hydroxy phosphonates,5,6
saturated phosphonate,7 and aldehyde.8
Chem. Soc. 1983, 105, 1964
(11) Johannsen, M.; Jorgensen, K. A. Chem. ReV. 1998, 98, 1708
(12) Stork, G.; Poirier, J. M. J. Am. Chem. Soc. 1983, 105, 1073
(13) Trost, B. M.; Tenaglia, A. Tetrahedron Lett. 1988, 29, 2827
(14) (a) Trost, B. M.; Greenspan, P. D.; Geissler, H.; Kim, J. H.; Greeves,
N. Angew. Chem., Int. Ed. Engl. 1994, 33, 2182. (b) Williams, D. R.; Meyer,
K. G. Org. Lett. 1999, 1, 1303. (c) Vares, L.; Rein, T. Org. Lett. 2000, 2,
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J. E.; Englund, E. E.; Burke, S. D. Org. Lett. 2002, 4, 2273. (c) Jiang, L.;
Burke, S. Org. Lett. 2002, 4, 3411. (d) Lucas, B. S.; Burke, S. D. Org.
(2) For reviews, see: (a) Wolfe, J. P.; Hay, M. B. Tetrahedron 2007,
63, 271. (b) Clarke, P. A.; Santos, S. Eur. J. Org. Chem. 2006, 2045. (c)
Koert, U. Synthesis 1995, 115. (d) Harmange, J.-C.; Figade´re, B. Tetrahe-
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(16) He, A.; Yan, B.; Thanavaro, A.; Spilling, C. D.; Rath, N. P. J.
Org. Chem. 2004, 69, 8643.
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Org. Lett., Vol. 11, No. 14, 2009
3125

analysis). Tertiary alcohols were also viable nucleophiles for
thf formation (6e). However, the cyclization to form the
larger seven- and eight-membered cyclic ethers (6c and 6d)
was unsucessful, and diene formation (7a and 7b) was the
predominant reaction pathway.
Table 1. Cross Metathesis
To further examine the stereochemical features of the
cyclization reaction, both the (S) and (R) enantiomers of
2-hydroxy-hex-5-ene were reacted with the (R) acrolein
phosphonate (3) (70% ee, 5.5:1 er) to give the diastereoi-
someric phosphono allylic carbonates (5f and 5g) (Table 1).
Palladium-catalyzed cyclization (Scheme 3) resulted in the
formation of the diastereoisomeric thf vinyl phosphonates
(cis-6f and trans-6g). The isomeric ratio, determined by 1H
NMR spectroscopy was 1:5.5 and 5.5:1, respectively, reflect-
ing the ratio of the starting carbonates (5f and 5g) and
indicating that the cyclization reaction is stereospecific.
In contrast, the intermolecular additions of alcohols to
phosphono allylic carbonates showed a marked substrate
dependency (Scheme 4). Methanol added smoothly to the
no. compd 4/5 R1 R2
n
conditionsa ratio 3:4 yield (%)b
1
2
3
4
5
6
7
8
a
a
b
b
c
d
e
f
H
H
H
H
H
H
H
H
H
H
H
H
1
1
2
2
3
4
1
1
1
1
1
A
B
A
B
B
B
B
A
B
A
B
2:1
2:1
1:2
1:2
1:2
1:2
2:1
1.5:1
2:1
2:1
51
66
62
67
65
62
85
53
69
56
62
Me Me
Me
Me
H
H
H
Me
9
10
f
g
11
g
H
Me
2:1
a (A) 5-7 mol % Grubbs II, CH2Cl2, reflux, 3 days. (B) 5-7 mol %
Scheme 4. Intermolecular Reaction of Alcohols
Grubbs II, 10-15 mol % CuI, CH2Cl2,reflux, 3 h. b Yields are isolated.
Scheme 3
.
Cyclization of Hydroxy Phosphono Allylic
Carbonates
cinnamyl carbonate (8) to give the γ-methoxy vinyl phos-
phonate (9) in good yield. However, the attempted addition
of methanol to the alkyl substituted allylic carbonate (10)
resulted in a crude mixture contianing the dienes (11) as the
major products. Not suprisingly,18 p-methoxyphenol reacted
with the alkyl substituted allylic carbonate (10) without
incident.
The transformation of the racemic vinyl phosphonate (6a)
into functional groups appropriate for C-C bond formation
was examined. Reduction of the alkene with hydrogen over
palladium on carbon gave the saturated phosphonate (14).
Wacker oxidation of thp vinyl phosphonate (6a) using the
traditional method [PdCl2/CuCl/O2/H2O/DMF] was unsuc-
cessful and resulted in recovered starting material.4b How-
ever, application of conditions designed for electron-deficient
alkenes (Na2PdCl4/t-BuOOH),4a gratifyingly yielded the
ꢀ-ketophosphonate (15) as the only product, although
extended reaction times (6 days) were required. In compari-
either Ph3P or dppe as ligand, but chromatographic separation
of the product from the ligand residues was more easily
achieved with dppe. The cyclization reaction also proceeded
at 25 °C; however, in contrast to the intramolecular addition
of nitrogen nucleophiles,3b only the (E)-vinyl phopshonate
was observed. Furthermore, a cyclization of nonracemic
phosphonate (5a) resulted in formation of the thp vinyl
phosphonate (6a) with complete chirality transfer (HPLC
(18) Goux, C.; Massacret, M.; Lhoste, P.; Sinou, D. Organometallics
1995, 14, 4585.
3126
Org. Lett., Vol. 11, No. 14, 2009

son, vinyl phosphonates with carbon substituents in the
γ-position could be oxidized using the traditional Wacker
oxidation conditions in 3 days in >80% yield.3a Presumably,
the inductive effect of the oxygen substituent is responsible
for the reduced the reactivity of the vinyl phosphonate.
Wadsworth-Emmons reaction of the ꢀ-ketophosphonate
with benzaldehyde using barium hydroxide as base19 gave
the unsaturated ketone (16) in good yield.
bearing pendant hydroxyl groups. The palladium-catalyzed
cyclization leads to thf and thp cyclic ethers with predictable
stereochemistry. The vinyl phosphonate can be further
manipulated into additional useful functional groups.
Scheme 6. Formal Synthesis of (+)-Centrolobine
Scheme 5. Further Reactions of Vinyl Phosphonates
Acknowledgment. The project described was supported
by grant number R01-GM076192 from the National Institute
of General Medical Studies. We thank National Science
Foundation (CHE-0313736) for funding the preliminary
studies on the reactions of allylic hydroxy phosphonates
employed in this project, and for grants to purchase the NMR
spectrometer (CHE-9974801), and the mass spectrometer
(CHE-9708640). We thank Mr. Joe Kramer and Prof. REK
Winter of the Department of Chemistry and Biochemistry,
University of Missouri St. Louis for mass spectra.
Finally, as an illustration of the utility of the cross metathesis/
cyclization protocol for cyclic ether formation, a formal
synthesis of (+)-centrolobine was undertaken (21). Both (+)-
and (-)-centrolobline have been isolated from the heartwood
of various Centrolobium species,20 and it was recently shown
that the (-)-centrolobine possesses anti-leishmananial activity.21
The unique structure and biological activity has made cen-
trolobine a popular demonstration target for new methods for
the synthesis of 2,6-disubstituted tetrahydropyrans.22
Synthesis of the cis thp ring of centrolobine requires the
(R)-phosphonate (3) and (R)-alkenol (17). A known alkenol23
(17) was resolved via kinetic resolution using Birman’s
method.24 A cross-metathesis reaction of the alkenol (17)
(97% ee) and the (R)-phosphono carbonate (3) (97% ee) gave
the substituted phosphono carbonate (18). The stereospecific
palladium-catalyzed cyclization proceeded uneventfully to
give the cis-thp-substituted vinyl phosphonate (19) in good
yield. Ozonolysis of the vinyl phosphonate (19) yielded the
aldehyde (+)-20. The (-)-enantiomer of 20 is a known
intermediate20 on route to (-)-centrolobine (21), and thus
using published procudures from (+)-20 would lead to the
synthesis of (+)-centrolobine (21).
Supporting Information Available: Typical experimental
procedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL900980S
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