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High-Yield Synthesis of Lipid Systems with Giant Rings.

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[(H,&J4'Ti+,
851, 152 [(H8C,)4'Ti+. 411, 130 [(H,,C,,)48Ti2+. 141, 77
[(H,,C,)48Ti2t, 91, 48 [4*TiZ+,
51.
d) Bis(s6-mesitylene)titanium: Procedure analogous to that described in a);
mesitylene was used as the solvent, reaction mixture treated for 16h in the
ultrasonic bath. Yield: < 5%. ' H N M R ([DJbenzene, 300K. TMS): S =1.99
(s, 9H, CH,), 4.74 (s, 3H, CH); (according to ref.[S]; S (in [D,,]SiMe,) =1.96,
4.69); MS: m/: 288 [(H,4C,,)48Ti+, loo%], 168 [(H,,C,)48Ti', 421, 166
[(H,,C,)48Ti', 381. 144[(H,,C,,)"'Ti",
211, 48[48Ti+,41.
Received: June 27, 1992
Revised: July 28, 1992 [Z5436IE]
German version: Angen.. Chem. 1992, 104. 1506
CAS Registry numbers:
2, 143746-11-6; TiHm. 11140-68-4; TiDm, 53095-13-9; ZrHm. 11105-16-1;
[(C,H,),TI]. 52462-43-8; [(C,H,Me),Ti], 55527-82-7;[(C,H,Me,),Ti], 14374612-7; [(C,H,Me,),Ti], 57347-27-0;TiC14.2THF, 3101 1-57-1; ZrCI,, 10026-116; C,H,, 71-43-2; C,H,Me, 108-88-3; C,H,Me,, 106-42-3; C,H,Me,, 108.678; K[BEt,H], 22560-21-0; K[BEt,D], 143773-88-0.
[l] H. Bonnemann, W Brijoux, T. JouOen, Angew. Chem. 1990, 102,324-326;
Angew. Chem. Int. Ed. Engl. 1990,29, 273-275.
[2] A. Chretien, W. Freundlich, M. Bichara, C. R. Hebd. Seances Acad. Sri.
1954, 238, 1423.
[3] S. S. Sidhu, L. Heaton, D. D. Zauberis. Acta Crystallogr. 1956, 9, 607.
[4] Dr. L. Aleandri, Max-Planck-Institut fur Kohlenforschung, Miilheim an
der Ruhr, 1991. The X-ray absorption spectrum was recorded on the Ti
K-edge (77K) with an EXAFS 3 spectrometer in DCI (French Synchrotron
Facility in Lure) with monochromatic X-ray radiation.
[5] H. Bonnemann, W. Brijoux, R. Brinkmann, E. Dinjus, R. Fretzen, T.
Mol. Calul., 1992. 74. 323-333.
JouRen, B. Korall, .l
[6] F. Benfield, M. L. H. Green, J. S. Ogden, D. Young, J. Chem. Soc. Chpm.
Commun. 1973, 866-867; P. N. Hawker, E. P. Kiindig, P. L. Timms, ibid.
1978, 730-731. See also D. W Blackburn, D. Britton, J. E. Ellis, Angen.
Chem. 1992, 104, 1520; Angew. Chem. Int. Ed. Engl. 1992, 31, 1495.
[7] H. Bonnemann, W Brijoux, R. Brinkmann, E. Dinjus, T. JouRen, B. Korall,
Angew. Chem. 1991,103,1344-1346; Angew. Chem. Int. Ed. Engl. 1991.30,
1312-1314.
[8] M. T. Anthony, M. L. H. Green, D. Young, 1 Chem. Soc. Dalton Trans.
1975, 1419-1422.
intriguing question required the synthesis of "giant rings" up
to 72 atoms in size.[41Any synthesis chosen to construct the
macrocyclic lipids15]had to proceed in high yields if we were
to secure sufficient amounts for subsequent physical/chemical studies.[', 31 And the route had to be flexible enough to
give, in addition to the looped diesters, the diether analogues
(interesting molecules because of their similarity to lipids of
archaebacterial thermophiles).[61Our answer to the synthetic
challenge is described in the ensuing text.
CHZO(CHz),,C =CH
I
CH-O(CHz),,C
CH
I
CH,O(CH,)&
CUCnMEDA
02,140"c
*
CH,0CH2Ph
ZC
I
I
CH-O(CH,),&
I
E
C
(a)
CH,OCH,Ph
Our method is based on Glaser oxidation of dialkynyl
compounds [Eq. (a)]. When the reaction was carried out by
slow addition of the dialkynyl compound (syringe pump,
4-5 h), and at higher than usual temperatures (140"C),
yields were consistently and reproducibly high (Table 1). The
procedure seems preferable to those used in the only two
previously reported syntheses of cyclic lipids.[51
Table 1. Yields for high-temperature Glaser cyclization of seven giant-ring
lipids [a].
Lipid type
Ring size
Yield [YO]
Diester
Diester
Diester
Diether
Diether
Diether
Diether
32
36
40
32
36
40
44
52
64
60, 68
78, 79
83
77, 78, 85
71
[a] Reactions were conducted with 0.9 to 2.8 g diyne as described in the text.
Yields refer to the amounts of material after purification by column chromatography.
High-Yield Synthesis of Lipid Systems
with Giant Rings**
By Fredric M . Menger,* Stephen Brocchini,
and Xiangyang Chen
Phospholipids, a major constituent of biological membranes, possess two alkyl chains each made up of 14-18
carbon atoms (see e.g. I). Since the chains are connected only
at the ester ends, they have a certain amount of freedom
within the membrane bilayer to bend, reorient, and interdigitate."] We wondered how membrane behavior (e.g. thermotropic properties,[2]permeability,t31etc.) would be affected when the two distal ends are joined as in 11, thereby
restricting independent motion. Answering this simple but
- ;:I
f)
OH
I
CH-OCO(CH2)&H,
I 0
CH,O~'OCH,CH,~~(CH,),
I
0
I
I
CH-OCO(CH,),&H,
I
(CH2)"O
( ( C H 2 ) , 0 1 OP c
0
CH~O~'OCH,CH~~;(CH,),
I
13
II
[*I Prof. Dr. F. M. Menger, S. Brocchini, X. Chen
Department of Chemistry, Emory University
Atlanta, GA 30322 (USA)
[**I The authors gratefully acknowledge the support of the Dow Chemical Co.
and the National Institutes of Health.
1492
OCH,Ph
OCH,Ph
10
CH20CO(CHz)&H,
0
I
H-(CH2)n.20
H=(CH,),,O
9
8
CH,0CO(CH,),,CH3
g1
0 VCH Verlagsgesellsrhaft mbH, W-6940 Weinheim. 1992
(::~::~~~
-
OH
12
"]I
(CH2)n-zO
cZ(CH2)n.201
OCH,Ph
11
Scheme 1. a) Dihydropyran (DHP), p-TsOH, 90%; b) 1. 1-alkyne, nBuLi,
hexamethylphosphoric triamide (HMPA); 2. MeOH, p-TsOH, pH = 3-4,
75%; c) 1. nBuLi, HMPA; 2. (CH,O),, 84%; d) 1. Li, H,N(CH,),NH,;
tBuOK, (from 3), 44% (from 5), 70%; e) MesCl, Et,N, 90%; f) 1. PhCH,CI,
dimethylsulfoxide (DMSO), powdered KOH; 2. 10% HOAc, 9 0 T , 6 6 % ;
g) powdered KOH, DMSO, 7.76%; h) O,, CuCI, TMEDA, 140°C 71-85%;
i) H,, 10% Pd/C, 60-74%; j) 1. 2-chloro-2-oxo-l,3,2-dioxaphospholane,
Et,N, benzene, 2 h; 2. Me,N, MeCN, 60-65"C, 48 h, 35-66%.
0570-0833i92jllll-1492 S 3 . 5 0 i .25/0
Angew. Chem. Int. Ed. Engl. 1992, 31, No. 11
A total synthesis of the cyclic ether lipids, incorporating
our high-temperature Glaser cyclization as its key step, is
given in Scheme 1. The corresponding cyclic diester phospholipids were prepared by first esterifying (R)-3-benzyloxy1,2-propanediol with two equivalents of an o-alkynyl fatty
acid and then proceeding as outlined for 10 +13 in Scheme 1.
Reaction (bj exemplifies the surprising ease with which
giant rings are constructed under the modified Glaser condi-
-0
E
O(CHz),,.zCE
OCH,Ph
(CHd2n
-
-
CuCVTMEDA
02,140Oc
CH HCeC(CHz),.zO
O I
PhCHZO
0
E
O(CH&zC
-
(bl
(CHz)zn
eC
- C E C(CHz),.zO
OCH,Ph
tions described here. Thus, chromatographically pure
macrocycles of 64 atoms (n = 14) and 72 atoms (n = 16) were
formed in 66 and 54% yield, respectively. Reaction (b) provides an entry into new “double” phospholipids.
It is unclear why giant-ring formation is so efficient, especially since the chains are devoid of substituents that often
aid ring closures leading to macrocycles. Perhaps van der
Waals attractions promote side-by-side alignment of the
chains, although this would favor both intramolecular closures and the competing intermolecular reactions.
Differential scanning calorimetry studiesr7]show that the
cyclic ester lipids have higher transition temperatures than
their acyclic counterparts. For example, transition temperatures of 41.7, 55.6, and 66.5 “C have been recorded for the
acyclic series with 16, 38, and 20 carbon atoms per chain,
respectively. Linking the chain ends raises these values to
50.4, 70.1, and 82.6 “C, respectively. Clearly, cyclization produces a substantial barrier to chain-melting.
Experimental Procedure
In a typical cyclization reaction 0.37 g of copper([) chloride and 0.60 mL of
tetramethylethylenediamine were added to 200 mL of reagent-grade xylenes in
a 500 mL, three-necked flask fitted with a reflux condenser. Oxygen was bubbled through the mixture with a glass pipet while heating at 140°C with an oil
bath. A solution of 1.02 g of the diyne in 40 mL ofxylenes was added over 4 b
with a syringe pump. The reaction mixture was cooled and concentrated to
dryness. The residue was dissolved in 300 mL of ethyl acetate and washed with
100 mL of water and 5 % HCI. The organic layer was dried over Na,SO, and
the solvent removed to give the crude product. The material was purified by
chromatography (60 A silica gel. 200-425 mesh) eluting with ethyl acetate/hexane ( 1 :6) to obtain 0.78 g (77%) of product (pure by NMR spectroscopy).
Hydrogenation of the giant ring and cleavage of the benzyl group gave an
alcohol with thecorrect elemental analysis and ‘H NMR, I3C NMR, and FAB
mass spectra.
43-7; 11. (n = 20) 144002-44-8: 12, (n = 14), 144002-45-9; 12, (n = 16).
144002-46-0; 12, (n = 18), 144002-47-1; 12, (n = 20), 144002-48-2; 13,
(n = 14), 144002-49-3; 13, (n = 16), 144002-50-6; 13, (n = 18), 144002-51-7;
13, (n = 20), 144002-52-8: 1-pentyne, 627-19-0; 1-heptyne, 628-71-7: 1-nonyne,
3452-09-3; 13-butadecynoicacid, 82909-47-5; 15-hexadecynoic acid, 99208-909; 17-octadecynoic acid, 34450-18-5;diester lipid (n = 13), 144002-53-9;diester
lipid (n = 15), 113960-54-6; diester lipid (n = 17), 144002-54-0.
[l] M. Edidin. Annu. Rev. Biophy.9. Bioeng. 1974. 3, 179; N. 0. Petersen, S . I.
Chan, Biochemislry 1977, 16, 2657.
[2] F. M. Menger, M. G . Wood, Jr., Q. 2. Zhou, H. P. Hopkins, J. Fumero, J.
Am. Chem. Soc. 1988, 110, 6804.
[3] F. M. Menger, D. S. Davis, R. A. Persichetti, J-J. Lee, J. Am. Chem. SOC.
1990, 112, 2451.
[4] Macrocycles are commonly regarded as molecules with rings containing
twelve or more atoms. Since most synthetic work on macrocycles has focused on rings with less than twenty atoms, we refer to I1 as a “giant ring”.
For useful methods of synthesizing macrocycles, see ref. [9] in S. F. Martin,
M. Yamashita, J. Am. Chem. So(. 1991,113,5478; M. Hesse, Ring E n l u r p
men[ in Orgunic Chemistry, VCH, Weinheim, 1991 and ref. [l-31 in D. L.
Boger, R. J. Mathvink, 1 Am. Chem. Sue. 1990, 112. 4008; M u c r o c y k s
(Eds.: E. Weber, F. Vogtle), Springer, Berlin, 1992.
[S] An analogue of 11 with a 36-membered ring was synthesized in only 8 %
yield by a macrolactonization. See K. Yamauchi, I. Yamamoto, M . Kinoshitd, J. Chew SUC.Chem. Commun. 1988, 445. An analogue of I1 with a
32-membered ring was synthesized in 50-60% yield by a Glaser coupling
with 10 equivalents of Cu(OAc), ’ H,O in refluxing pyridine. N. Hebert, A.
Beck, R. B. Lennox, G. Just. J. Org. Chem. 1992,57,1777.In our hands, this
procedure gave substantial amounts of starting material and hydrolysis
product.
[6] K. Yamauchi, Y Sakamoto, A. Moriya, K. Yamada, T. Hosokawa, T.
Higuchi, M. Kinoshita, J. Am. Chem. SOC.1990, 112, 3188.
[7] The calorimetry work was carried out by Prof. Harry Hopkins, Georgia
State University. A joint report on the data is planned.
Arborols Based on Luminescent and Redox-Active
Transition Metal Complexes **
By Scolastica Serroni, Gianfranco Denti,*
Sebastiano Campagna,* Albert0 Juris, Mauro Ciano,
and Vincenzo Balzani*
The development of strategies for synthesizing supramolecular species (“nanostructures”) with specific functions
is one of the most important challenges now facing chemistry.“] “Cascade moIecules”12-‘I (also called arborols or
dendrimers) are of great interest in this regard. We have
designed a strategy to obtain arborols, based on transition
metal complexes, which exhibit interesting photophysical
and electrochemical properties. In this paper we illustrate
our synthetic strategy and report the properties of a luminescent and redox-active arborol which contains 22 metal centers.
[*I
Received: July 10, 1992
Revised: August 17, 1992 [Z 5457 IE]
German version: Angew. Chem. 1992, 104, 1542
CAS Registry numbers:
I, 1611-56-9; 2, 52056-69-6; 3, (n = 2), 144002-31-3; 3, (n = 4), 21721-01-7; 3,
(n = 6), 144002-32-4: 4, (n = lo), 26186-02-7; 4, (n = 12), 765-13-9; 5,
(n = 10). 51309-22-9; 5 , (n = 12), 2833-99-0; 6, (n = 14), 18202-12-5; 6,
(n = 16), 62914-53-8; 6, (n = lX), 87640-OX-2; 6, (n = 20), 144017-86-7; 7,
(n = 14). 144002-33-5: 7, (n = 16), 144002-34-6; 7, (n = 18), 144002-35-7: 7.
(n = 20). 144002-36-8;8,22323-82-6; 9,56522-80-8; 10, (n = 14), 144002-37-9;
10, (n = 16). 144002-38-0; 10, (n = IS), 144002-39-1; 10. (n = 20), 144002.404; 11, (n = 14). 144002-41-5; 11, (n = 16). 144002-42-6; 11, ( n = 18), 144002Angew. t h e m . In[. Ed. Engl. 1992, 31, No. 11
0 VCH Verlugsgesellschufi mhH,
[**I
Prof. Dr. G. Denti, Dr. S. Serroni
Laboratorio di Chimica lnorganica
Istituto di Chimica Agraria dell’universita
1-56 124 Pisa (Italy)
Dr. S. Campagna
Dipartimento di Chimica Inorganica e Strutturd Molecokare
dell’universiti
1-98 166 Messina (Italy)
Prof. Dr. V. Balzani, Prof. Dr. A. Juris, Dr. M. Ciano
Dipartimento di Chimica dell’Universiti
and Istituto FRAE-CNR
1-40 126 Bologna (Italy)
This work was supported by the Minister0 della Universitli e della Ricerca
Scientifica e Tecnologica and by the Consiglio Nazionale delle Ricerche
(Progetto Finalizzato Chimica Fine I1 and Research Grant 91.03 355CT03). We wish to thank V. Cacciari for technical assistance.
W-6940 Weinhrim, 1992
0570-0833i92j1111-1493$3.50+.25/0
1493
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