Seven oxygens allow effective complexation of monovalent cation
Total asymmetric synthesis of complex antibiotic achieved A. Maureen Rouhi, C&EN Washington
which are compounds that help ions move across lipid rganic chemists often look to nature barriers such as the cell mem for synthetic targets. In the absence brane. By "wrapping" cations of the right synthetic tools, however, the in a highly hydrophobic shell, kinds of molecules that can be built from these ionophores enable the cations to move more freely simple precursors are limited. For lonomycin A, a particularly com through such barriers. plex natural product, the synthetic According to Evans, the tools were in place. Using them, Har ability of ionophores to modi vard University chemistry professor fy membrane transport induc David A. Evans, graduate student An es a wide range of biological drew M. Ratz, and postdoctoral fellows effects, including growth pro Bret E. Huff and George S. Sheppard motion in ruminants and anti recently completed the total asymmet bacterial, antiviral, and antiproric synthesis of lonomycin A [/. Am. tozoic activities. Chem. Soc, 117, 3448 (1995)]. Chemists, however, are drawn to these Lonomycins are polyether antibiotics compounds not so much by their biolog produced by Streptomyces ribosidificus ical activity but because of the challeng (lonomycin A) or Streptomyces hygrospi- es their complicated structures present. cus (lonomycins Β and C). Their unique "The interest is purely academic in how structures, which incorporate a carboxyl structures of such complexity are han group and two to five other oxygen dled," Evans says. Yet he acknowledges groups, allow them to complex cations that the methodology his team developed could be relevant to other compounds of effectively. Polyether antibiotics are members of a medicinal interest, like erythromycin or class of compounds called ionophores, the enzyme inhibitor calyculin.
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From 1979 to 1991, Evans' research yielded the total synthesis of four other ionophores—calcimycin, X-206, ionomycin, and ferensimycin B. With lono mycin A, which is also known as emericid, the Harvard team has synthesized what Evans considers the most struc turally complex of the polyether antibi otics that have been isolated. Lonomycin A's structure is "comparable [to] brevetoxin," says chemistry professor James
Two fragments are joined by highly stereoselective aldol reaction H3C
OCHo
H3Q
>0CH3 xOCHo
OCH3
Aldol union
Fragment B
1. Deprotection 2. Spiroketalization at C-13 H3CO^ 5 ^ Ξ OCH 3 CH 3
— ^
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Η CH 3
Ο
H CH, 3
CH 3 Fragment A
1
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t
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CH, HO
Et = CH2CH3
Lonomycin A sodium salt
CH 3
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oOCH 3
= ^ γ " 1 "ONa Ε ΟΗ [ CH 3 CH3
OCH,
OCH3
H 3 C„
H3CO^ 5 X
3. Hydrolysis of lactol methyl ethers at C-3 and C-29
J
1. Methylation of C-11 hydroxyl «*" 2. Removal of chiral auxiliary at C-1
H3C, HO H c o
^
5 \ / ζ γ ι ζ ÔH CH 3 CH 3
CH 3
-Ν
O'
Ph = C6H5
MAY 1,1995 C&EN 5 1
SCIENCE/TECHNOLOGY
Nearly half the backbone comes from the same building block . . . Ο
Ο
HO 1 Τ
OCH3 OH
3
]
OH3
V
5
V/H3
^Y
OH
OCHo Ο
OCH3
25vv^VvY^29^CH3
7
V/H3
ν
OCH3 Ο
V/H3
CH3
>-Ή3
CH3
CH3
'
CH3
—
Dipropionyl synthon
Dipropionyl synthon
.. .but through different enolate-based bond constructions
Η
PhCH2
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CH,
Sn(ll) enolate A
*
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Ο
Ο
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7
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CH 3 CH 3
CH 3
Ο C-5 through C-11
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H3C
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CH3 CH3 CH2Ph Dipropionyl synthon
PhÇH2 ο
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C-1 through C-11
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C-25 through C-30
D. White of Oregon State University, synthesis. The overall yield for the total Corvallis, "or rutamycin Β and cytovari- synthesis, 6%, is considered very good for cin/' The latter two compounds also a molecule as compex as lonomycin A. have been synthesized in Evans' lab. Says White: "I was very impressed. The Like brevetoxin Β (C&EN, Jan. 30, target is a very complex molecule, and the page 32), lonomycin A has 23 stereo- synthesis is elegant and economical." genie centers. And its highly oxygenat Like other complex syntheses, this one ed backbone complicates the problem: required the appropriate technological "The more oxygen, the higher the level base. As part of the groundwork for the of reactivity," says Evans. synthesis, Evans and his coworkers had By itself, the total synthesis is an out to elaborate on concepts already in place. standing achievement. It was the culmi For example, they used "allylic strain nation of eight man-years of painstaking concepts" developed by chemistry pro efforts, says Evans, especially by Ratz, fessor Yoshito Kishi, also at Harvard, to who got involved in the project in his build the polypropionate sections of the first year in graduate school and execut molecule: C-1 through C-8 of fragment ed all the difficult terminal stages of the A (which consists of C-1 through C-11) 52
MAY 1,1995 C&EN
and C-25 through C-28 of fragment Β (which consists of C-12 through C-30). Kishi proposed that the preferred con formation of an allylic carbon relative to a carbon-carbon double bond is special. "Depending on the functional group attached to an allylic carbon, one can predict the stereochemical outcome for the reactions on the double bond," says Kishi. The concept originally came out of hydroboration studies, he adds, but it has proven to be "quite a general and powerful concept." And the Evans team used "macrocyclic stereocontrol" to create the polyether subunit in fragment B. This strategy al lows "formation of new chiral centers
based on the conformational preference of a maoOcycle," says chemistry professor William G Still of Columbia University, who first advanced this approach. According to Stuart L. Schreiber, an other Harvard chemistry professor, the lonomycin A synthesis is "the first demonstration that [macrocyclic stereocontrol] can be used to synthesize this family of natural products." Schreiber previously had used the same strategy on model compounds. The chiral enolate bond construc tions are the most noteworthy of the new synthetic tools resulting from the research, Evans says. For these reac tions to work, his team had to develop and skillfully exploit various chiral auxiliaries—groups attached to sub strates to direct the stereochemical out come of a reaction and later removed. The successful use of a simple building block—a dipropionyl synthon—is the work's most notable accomplishment, in Evans' view. "We used this pivotal building block to build the propionaterich regions of lonomycin," he says. And from mat building block, the team de rived 12 of lonomycin A's 30 skeleton carbons, proving its value for synthesis of polypropionate natural products. Although the starting materials for these sections are similar, the resulting carbon skeletons arise from quite dif ferent enolate-based bond construc tions. In fragment A, the polypropi onate section arises from two aldol bond constructions using a tin(II) eno late derivative of the dipropionyl building block. In fragment B, the sec tion is produced through ortho ester acylation of the titanium enolate deriv ative of the building block. Fragment A results solely from the dipropionyl synthon. But fragment Β re quires assembly from two smaller units: a macrolactone (C-13 through C-24) and the polypropionate subunit (C-25 through C-30) in the form of a phosphoniumsalt. "The method is extremely powerful for the rapid construction of polypropi onate substructures," says William R. Roush, professor of chemistry at Indi ana University, Bloomington. "It is pat terned after the way nature [is thought to assemble] them. Prior to Evans' pio neering studies in this area, no one be lieved it could be done." The chemists used a convergent ap proach in the final assembly of the mol ecule, building lonomycin's backbone
from two fragments. The spiroketal at C-13 told them the molecule could be put together by a reaction to form the bond between C-ll and C-12. To join the two fragments, Evans and his team used an aldol reaction with very high diastereoselectivity (>95:5) to form this bond. Π
Dual-natured molecules self-organize into films When Samuel I. Stupp talks about nee dles and threads, he's not talking about his grandma's embroidery. He's talk ing about long, thin molecules that, on one end, are stiff like needles, and on the other are loose and pliable like threads. When these molecular units are allowed to associate with their own kind, they organize themselves into two-dimensional assemblies of orient ed molecules that stack to give a multi layer, macroscopic film or tape. What's special about this film or tape is that the top and bottom surfaces can have strikingly different properties. One surface can be sticky, for example, while the other is nonadhesive. Thus, one can make an ultrathin adhesive tape in a single step, says Stupp, a pro fessor of chemistry and of materials sci
ence and engineering at the University of Illinois, Urbana-Champaign. Bent into a tube, the tape could serve as an artificial blood vessel whose out er surface binds to tissue while its inner surface allows blood to flow unimped ed. And if the film were made adhesive on both sides, it could be wrapped around carbon fibers, bonding the fi bers tightly to a matrix to create stron ger carbon composites for airplane, boat, and car bodies. These are just some of the potential uses that Stupp envisions for his selforganized films, which he unveiled be fore the Division of Polymer Chemistry at the recent American Chemical Soci ety meeting in Anaheim, Calif. The building blocks for these films are what Stupp calls "rodcoil" molecules. They consist of a "needle" or "rod" covalently attached to a "thread" or "coil." The needle, for example, is a sequence of biphenyl esters tipped with a phenolic or carboxyl functional group that makes that end hydrophilic (wettable). The thread is a co-oUgomer of styrene and isoprene units that terminates in an alkyl chain, making this end hydrophobic (water-resistant). A film can be prepared simply by dis pensing a few drops of a solution of one of these rodcoil compounds on a sub strate. As the solvent evaporates, the
Multilayer film has two different self-organized surfaces
Multilayer film
Monolayer
Multilayer film (left) consists of about 100 stacked monolayers (one of which is shown onright).The top surface of the film, formed by the methyl group (green) at one end of the monolayer's rodcoil molecules, is hydrophobic. The bottom surface of the film, formed by the phenolic group (OH shown in red) at the other end of the molecules, is hydrophilic.
MAY 1,1995 C&EN 53
