Efficient synthesis of 40- and 48-membered tetraether macrocyclic bisphosphocholines.

Article abstract of DOI:10.1021/ol990567o

An efficient route toward the synthesis of unsaturated (bis-diacetylenic) and saturated 40- and 48-membered macrocyclic biphosphocholines has been developed using 2-phenyl-5-hydroxy-1,3-dioxane as a common glycerol synthon. Ring closure was accomplished using either high-dilution Glaser oxidation of [(Cy3P)2RU==CHPh]Cl2-catalyzed olefin metathesis conditions. Deprotection of benzyl ethers using trimethylsilyl iodide (TMS-I) in the presence of diacetylenic moieties has also been demonstrated for the first time.

Full text of DOI:10.1021/ol990567o

ORGANIC
LETTERS
1999
Vol. 1, No. 2
241-243
Efficient Synthesis of 40- and
48-Membered Tetraether Macrocyclic
Bisphosphocholines
Aniruddha P. Patwardhan and David H. Thompson*
Department of Chemistry, Wetherill Laboratory of Chemistry, Purdue UniVersity,
West Lafayette, Indiana 47907-1393
daVethom@chem.purdue.edu
Received April 9, 1999
ABSTRACT
An efficient route toward the synthesis of unsaturated (bis-diacetylenic) and saturated 40- and 48-membered macrocyclic bisphosphocholines
has been developed using 2-phenyl-5-hydroxy-1,3-dioxane as a common glycerol synthon. Ring closure was accomplished using either high-
dilution Glaser oxidation or [(Cy3P)2RudCHPh]Cl2-catalyzed olefin metathesis conditions. Deprotection of benzyl ethers using trimethylsilyl
iodide (TMS-I) in the presence of diacetylenic moieties has also been demonstrated for the first time.
Archaeabacteria have recently been categorized as a third
domain organism.1 Their ability to survive under harsh
environmental conditions has been attributed in part to their
unique membrane structural features.2,3 Their membrane lipid
components differ from their eukaryotic counterparts in the
type of glycerolipids that are present. The most unusual
features of archaebacterial lipids are (i) alkyl chains that are
ether linked instead of ester linked to the glycerol backbone,
(ii) isoprenyl-based alkyl chains that occasionally include
cyclopentane ring modifications, and (iii) macrocyclic lipid
structures that contain two, presumably membrane-spanning,
alkyl chains that connect the two glycerol backbones. The
unique thermotropic properties of these membrane lipids have
led to the synthesis4 of structural mimics (e.g., bola-
amphiphiles) and their application in supported membrane
biosensor devices.5 Synthetic bolaamphiphiles have also been
used as design elements for coupled electron/ion charge
transfer across thin membrane vesicles.6,7 Interest in the
synthesis of these compounds has arisen from the difficulties
encountered in isolating gram quantities of naturally occur-
ring archaebacterial lipids and from the desire to study
structure-property relationships in this novel class of
membrane materials.8 Large quantities of bolaamphiphiles
are required to conduct such studies; however, the natural
product total syntheses are labor-intensive.9-14 As a result,
(5) Cornell, B. A.; Braach-Maksvytis, V. L. B.; King, L. G.; Osman, O.
D. J.; Raguse, B.; Wieczorek, L.; Pace, R. J. Science 1997, 387, 580-583.
(6) Thompson, D. H.; Kim, J. M. Mater. Res. Soc. Symp. Proc. 1992,
277, 93-98.
(7) Thompson, D. H.; Kim, J. M.; DiMeglio, C. Proc. SPIE-Int. Soc.
Opt. Eng. 1993, 1853, 142-147.
(8) Thompson, D. H.; Wong, K. F.; Humphry-Baker, R.; Wheeler, J. J.;
Kim, J. M.; Rananavare, S. B. J. Am. Chem. Soc. 1992, 114, 9035-9042.
(9) Arakawa, K.; Eguchi, T.; Kakinuma, K. J. Org. Chem. 1998, 63,
4741-4745.
(1) Winker, S.; Woese, C. R. Syst. Appl. Microbiol. 1991, 14, 305-
310.
(2) Tornabebe, T. G.; Langworthy, T. A. Science 1979, 203, 51-53.
(3) DeRosa, M.; Gambacorta, A.; Gliozzi, A. Microbiol. ReV. 1986, 50,
70-80.
(4) Fuhrhop, J. H.; Linman, U.; Koesling, V. J. Am. Chem. Soc. 1988,
110, 6840-6845.
(10) Eguchi, T.; Arakawa, K.; Terachi, T.; Kakinuma, K. J. Org. Chem.
1997, 62, 1924-1933.
(11) Eguchi, T.; Ibaragi, K.; Kakinuma, K. J. Org. Chem. 1998, 63,
2689-2698.
10.1021/ol990567o CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/06/1999

Scheme 1a
a (i) NaH/ toluene, 12a or 12b, reflux; (ii) CuCl, TMEDA, p-xylene, air, 140 °C; (iii) DIBAL-H, CH2Cl2, -78 °C; (iv) NaH/ THF, 11a
or 11b, reflux; (v) TMS-I, MeOH; (vi) Cl(O)P(OCH2)2, benzene, Et3N; (vii) CH3CN, Me3N, 3 days, 65 °C; (viii) NaH/toluene, 15a or 15b,
reflux; (ix) [(PCy3)2RudCHPh]Cl2 (Grubbs catalyst), CH2Cl2, reflux; (x) NaH/ THF, 14a or 14b, reflux; (xi) H2/ 10% Pd-C, EtOAc.
many model compounds that retain some of the essential
structural features of archea membrane lipids, such as ether
linkages and membrane-spanning hydrophobic chains, have
been reported.8,15-20 Previous synthetic studies of model
tetraether-linked bolaamphiphiles have been mostly limited
to acyclic bisphosphocholines15,17,18 and macrocyclic phos-
phocholines.19,21 Menger and co-workers22 have synthesized
72-membered saturated macrocyclic bisphosphocholines;
however, their synthesis required multiple protection-
deprotection steps. Routes to the synthesis of bolaamphiphiles
have typically exploited glycidol,17 epichlorohydrin,18 or
solketal15,18-20 as glycerol synthons. In our previous re-
port,17,18 acid-catalyzed ring opening of glycidyl m-nitroben-
zenesulfonate or epichlorohydrin using 1,16-hexandecanediol
gave good yields of diethers bearing free hydroxyls at the
sn2 and sn2′ positions of the glycerol backbones. A similar
strategy has been employed to synthesize macrocyclic
bisphosphocholines by alkylating the sn2 and sn2′ hydroxyls
with 1,ω-bromoalkynes which then allows intramolecular
ring closure via high-temperature copper-mediated Glaser
oxidation.22-24 Since this intramolecular cyclization did not
(12) Eguchi, T.; Kano, H, Arakawa, K.; Kakinuma, K. Bull. Chem. Soc.
Jpn. 1997, 70, 2545-2554.
(13) Eguchi, T.; Terachi, T.; Kakinuma, K. Tetrahedron Lett. 1993, 34,
2175-2178.
(14) Heathcock, C. H.; Finkelstein, B. L.; Jarvi, B. L.; Radel, P. A.;
Hadley, C. R. J. Org. Chem. 1988, 53, 1922-1942.
(15) Kim, J. M.; Thompson, D. H. Langmuir 1992, 8, 637-644.
(16) Yamauchi, K.; Moriya, A.; Kinoshita, M. Biochim. Biophys. Acta
1989, 1003, 151-160.
(17) Thompson, D. H.; Svendsen, C. B.; DiMeglio, C.; Anderson, V. C.
J. Org. Chem. 1994, 59, 2945-2955.
(18) Svenson, S.; Thompson, D. H. J. Org. Chem. 1998, 63, 7180-
7182.
(19) Menger, F. M.; Chen, X. Y.; Brocchini, S.; Hopkins, H. P.; Hamilton,
D. J. Am. Chem. Soc. 1993, 115, 6600-6608.
(20) Auzely-Velty, R.; Benvegnu, T.; Plusquellec, D.; Mackenzie, G.;
Haley, J. A.; Goodby, J. W. Angew. Chem., Int. Ed. Engl. 1998, 37, 2511-
2515.
(21) Bhattacharya, S.; Ghosh, S.; Easwaran, K. R. K. J. Org. Chem. 1998,
63, 9232-9242.
(22) Menger, F. M.; Chen, X. Y. Tetrahedron Lett. 1996, 37, 323-326.
(23) Menger, F. M.; Brocchini, S. Angew. Chem., Int. Ed. Engl. 1992,
31, 1492-1493.
242
Org. Lett., Vol. 1, No. 2, 1999

Scheme 2a
a (i) Li, 1,3-diaminopropane, t-BuOK, 70 °C;29 (ii) MsCl, Et3N, CH2Cl2; (iii) LiBr, THF, reflux.
yield the desired intramolecular macrocyclic product, we
sought to develop a more direct synthetic pathway involving
inexpensive starting materials that could expand the diversity
of bolaamphiphiles available. In this Letter, we report the
synthesis of a diastereomeric mixture of macrocyclic bola-
amphiphiles bearing two phosphocholines headgroups using
2-phenyl-5-hydroxy-1,3-dioxane as precursor. Two different
coupling conditions were employed: (i) the Glaser oxidation
method to synthesize 1,ω-bolaamphiphiles 5a,b and (ii)
olefin metathesis using [(Cy3P)2RudCHPh]Cl2 (Grubbs
catalyst) to synthesize the corresponding saturated bola-
amphiphile analogues 9a,b. The synthesis of 2-phenyl-5-
hydroxy-1,3-dioxane 1 (Scheme 1) as the glycerol precursor
utilized glycerol and benzaldehyde.25 Alkylation at the
secondary hydroxyl position with either 1,ω-bromoalkynes
12a,b or 1,ω-bromoalkenes 15a,b (Scheme 2) gave the
corresponding ethers 2a,b and 6a,b in 67% yield, respec-
tively. The alkylated 1,3-dioxanes were then dimerized to
yield bis-dioxane products. Glaser oxidation of compounds
2a,b produced the corresponding diacetylenic bis-dioxane
in 70% yield; dimerization of 6a,b via olefin metathesis
yielded the corresponding olefinic bis-dioxanes in 78% yield.
DIBAL-H26 was then used to open the acetal ring, giving
the bis-benzyl-protected glyceryl tetraether diols 3a,b and
7a,b. Subsequent alkylations of diols 3a,b with 1,ω-alkyne
mesylate 11a or 11b, and diols 7a,b with 1,ω-alkene
mesylate 14a or 14b, yielded products with alkyl chains
activated for coupling between the sn1 and sn1′ positions.
High-dilution Glaser oxidation23 and olefin metathesis9
reactions were again carried out to effect intramolecular
macrocyclization in high yields, (i.e., 4a,b and 8a,b in 65%
and 80% yields, respectively). It should be noted that the
yields of macrocyclic compounds 8a,b were drastically
improved by very slow addition of the triolefin precursor to
the ruthenium catalyst.27 Debenzylation of 4a,b without
polymerization was crucial for the successful synthesis of
the target tetraacetylenic lipids. Application of the most
commonly used debenzylating methods such as catalytic
hydrogenation, dissolving metals in ammonia, or Lewis acid
mediated benzyl ether cleavage would destroy the diacetyl-
enic moiety. Closer examination of the debenzylation
literature revealed that Berk and co-workers28,29 had previ-
ously reported the removal of benzyl protecting groups from
other lipid precursors bearing saturated alkyl chains in 45%
yield using trimethylsilyl iodide (TMS-I); however, there
were no indications that this transformation could be effected
in the presence of an electron rich diacetylenic moiety.
Application of TMS-I for debenzylation of 4a and 4b to the
corresponding diols was found to be reasonably efficient
(68% isolated yield). Debenzylation of 8a and 8b was
achieved using standard hydrogenolysis conditions with 10%
Pd-C catalyst. The corresponding macrocyclic diols were
then phosphorylated17,18 using 2-chloro-2-oxo-1,3,2-dioxa-
phospholane, followed by trimethylamine ring opening in
acetonitrile at 65 °C for 3 days, to give the tetrayne 5a,b
(70%) and saturated 9a,b (46%) macrocyclic bisphospho-
cholines with overall yields of 9% and 11%, respectively.
In conclusion, we have developed a novel and versatile
synthetic route using 2-phenyl-5-hydroxy-1,3-dioxane as
precursor. Two different high-dilution coupling conditions
were employed for the synthesis of macrocyclic bisphos-
phocholines in high yields. To the best of our knowledge,
this route also demonstrates for the first time the debenzyl-
ation of benzyl ethers using TMS-I in the presence of
diacetylenic moieties in good yields.
Acknowledgment. The authors gratefully acknowledge
the support of the National Science Foundation (MCB-
9319099) and the assistance of Tony Jacobs.
Supporting Information Available: 1H, 13C, and 31P
NMR spectra for compounds 1-15b. Elemental analysis for
the diols (bisphosphocholine precursor) and mass spectral
data for 5a,b and 9a,b. This material is available free of
charge via the Internet at http://pubs.acs.org.
(24) Taguchi, K.; Arakawa, K.; Eguchi, T.; Kakinuma, K.; Nakatani,
Y.; Ourisson, G. New. J. Chem. 1998, 22, 63-69.
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Longmore, R. W.; Anaya de Parrodi, C.; Quintero-Cortes, L.; Sandoval-
Ramirez, J. J. Am. Chem. Soc. 1995, 117, 8757-8768.
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4085-4088.
OL990567O
(27) Arakawa and co-workers9 have reported the total synthesis of 72-
membered macrocyclic phosphocholine precursors in lower yield (45%)
using the Grubbs catalyst.
(28) Berk, H. C.; Zwickelmaier, K. E.; Franz, J. E. Synth. Commun. 1985,
15, 57-60.
(29) Abrams, S. R. Can. J. Chem. 1984, 62, 1333-1334.
Org. Lett., Vol. 1, No. 2, 1999
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