optimization.in.organic.chemistry

optimization.in.organic.chemistry, biotransformation

[ Pobierz całość w formacie PDF ]
Optimization in
Organic Synthesis
Victor Snieckus
Department of Chemistry, Queen’s University, Kingston, Ontario, Canada K7L 3N6
t
“Art is always a bonus to synthesis....the artistic aspect of synthesis, beautiful and marvelous
as it is, should not be a justification for carrying out a total synthesis. If your problem is truly es-
sential then you don’t care about the elegance. The more essential your first E is, the less impor-
tant your last E becomes.”
1
“Will we be able to recapture the many millions of presumed ‘transient’ natural products that were
evolutionarily de-selected along the paths that eventually led to the natural products synthesized
on Earth today?
...
I cannot imagine that in a young synthetic chemist’s lifetime, it will not be ac-
complished.”
2
Organic Synthesis,
quo vadis
?
3
has been a phrase, perhaps in a more modern language, on the lips
of the practitioners of this demanding science-art, undoubtedly from the earliest times
4
but more vig-
orously in the last two decades.
5
Comparison of achievements of yesterday
6
and today
7
suggests
progress in our abilities to construct molecules of complexity, with higher stereocontrol, faster analy-
sis, and greater prediction of eventual success. However, the practical aspects, on any scale, of brevi-
ty, efficiency, safety, eco-consciousness, and energy- and resource-frugality remain, as noted by a
major synthetic craftsman,
8
crudely addressed. The Y2K symbolism is perhaps also appropriate for
urgently dedicating our efforts to making headway in the solution of these interrelated goals.
Our central science
5a
progresses on fronts of method development and total synthesis with a
great deal of cross-talk and interdependency (see Fig. 1). The burgeoning literature of new methods
suggests that 70% are not repeated, perhaps even in the original laboratories, a situation with dire
consequences for ascertaining true yield ranges and reproducibility a la the
Org. Syn.
religion. Fur-
thermore, as judged from a cursory glance of tables in recent journals, much is left to be desired in
giving confidence to the user that a method has generality (substrate diversity, FG and steric toler-
ance, catalyst or reagent minimization, and temperature and solvent optimization). Although the
beauty of judiciously modeled use of PGs is to be applauded,
9
FG protection is a continuing embar-
rassment and annoyance. Synthetic chemists are challenging the dogma by daring the multi-FG mol-
ecules to behave in the manner desired. Ugi multicomponent reactions
10
and combinatorial synthe-
sis
11
will undoubtedly soon influence the PG-expediency problem. In industry, statistical programs
12
at times drive optimization of reactions thus meeting the normal intense time constraints to produce
mulit-kg of commercial substances.
Atom-economy,
a term coined by another influential synthetic chemist,
13
has brought awareness
of an issue to academic scientists which their industrial process and development colleagues un-
Medicinal Research Reviews, 19, No. 5, 342–347, 1999
© 1999 John Wiley & Sons, Inc.
CCC 0198-6325/99/050342-06
342
343
ORGANIZATION IN ORGANIC SYNTHESIS
•
Figure 1.
Method development.
flinchingly face in their task to produce a commercial drug or agrochemical within defined cost con-
straints. Actuality is a multidimensional term which embodies efficiency, economy, of course, but as
justly demanded by society, safety, energy and resource sentience, and enviro–compassion. The
greening of synthesis is a timely subject,
14
at the basic levels of hazardous organic solvent and waste
byproduct (organic, inorganic) curtailment is receiving attention in initiatives in fluorous phase,
15
supercritical fluid,
16
and ionic liquid
17
research. Metal catalysis, both heterogeneous and homoge-
neous, advancing to a competitive position with natural enzyme rates, has exceptionally influenced
how we conceptualize C&bond;C bond formation
18
and now require increase in turnover number,
19
in addition to the continuing discovery and mechanistic understanding of new catalytic systems.
Stimulated by availability of such catalytic processes, sequential/tandem/domino/cascade reac-
tions
20
are increasingly noted
21
and may constitute new horizons in industrial practice. Although still
considered as intrusions into chemical synthesis by some, biotransformations
22
should be welcomed
into our armementarium, especially in view of exciting new developments in modular enzymes.
23
To extrapolate to industrial process operation again,
24
the trouble with scale-up synthesis in-
cludes, in addition to factors of academic or industrial drug discovery labs mentioned above, the more
often-than-not divergence from the method established in a mg-scale route, impurities, chromatog-
raphy, engineering, and clock-ticking, among other factors, play demonic roles
.
25
In all of our trials
and tribulations, the definition of a perfect chemical reaction is still far from our grasp.
In the realm of multistep (total
26
) synthesis, the oft-cited definition of an ideal synthesis attrib-
uted to a cutting-edge synthetic chemist
27
will also remain a challenge in Y2K. In initiating a syn-
thesis, the economic and “ready” availability of starting materials and reagents requires more than
lip service; at the end, the number of steps and overall % yield demands cold-daylight realism and a
thought on future credibility.
28
In setting out on the expedition for a challenging multistep synthe-
sis, the retrosynthetic analysis paradigm (disconnection approach, synthetic “trees”) all of us learned
from Corey
29
and the pointers of convergent/linear, relay (also in the new dimension of to/from bio-
transformation-derived material), and the arithmetic demon vividly taught to some of us by Ireland
30
are our constant guideposts (see Figs. 2 and 3). To this conceptual tool box, Corey added computer-
assisted design (CAD)
31
which spawned great activity that continues today.
5b
The scribbling of ret-
rosynthetic arrows are prevalent wherever synthetikers gather but it would appear that the impact of
the actual mechanics of CAD on research and teaching on our art has been modest. Nevertheless,
these contributions have more recently spawned attempts to devise semiquantative graphical repre-
sentations of topology, connectivity,
33
and molecular complexity
34
and relate them to the discon-
nection approach and chemical intuition “measures.” And at the conclusion of a multistep synthesis
344
SNIECKUS
•
Figure 2.
Multistep synthesis.
of a complex target? Aside from the well-deserved euphoria, shared by university and industrial
chemists alike, the cost, engaged personpower,
35
and environment and energy impact should receive
close scrutiny. This is (or is becoming) a
sine qua non
for an industrial process which must go
on stream (the ultimate reproducible
Org. Syn.
prep); it is incompletely practiced in small-scale
synthesis whether it be in university or industrial labs but this is destined to change. Of course, the
academic researcher must answer to the ultimate question: what have we learned?
36
and thereby con-
tribute in some way to advances in our discipline.
Quo vadis?
Chemical synthesis, being only a recent component of human evolution, will con-
tinue to respond to the solution of societal problems in health, food, environment, and material
requirements. Furthermore, the logic and technologic of our science assures that it will impact sur-
rounding disciplines.
37
Since prognosis is always dangerous,
38
only certain progressive elements on the horizon may
be mentioned. In asymmetric synthesis, enantioenrichment and amplification
39
constitute some of
the new conceptual elements in evolutionary stages. Biotransformations, practiced since the advent
of penicillin drugs, are increasingly applied in industry where prejudice and inhibition are over-
ridden by business considerations.
40
Aside from development of new effective and ecofriendly re-
action media,15 –17 solid support, microencapsulated, and aqua-stable reagents are being devised.
41
As part of the combinatorial chemistry surge, ancillary areas of analytical chemistry, robotics,
and informatics are forcing a closer chemist–engineer interface.
42
Indubitably, combichem is be-
coming part of the common practice of a synthetic lab for optimization of new methods,
43
and screen-
Figure 3.
Evolving concepts and technology.
345
ORGANIZATION IN ORGANIC SYNTHESIS
•
ing of new ligands and catalysts.
44
No combinatorial magic bullets as yet exist and the field is chang-
ing from the numbers game to focused biological relevant diversity with, as always, chemistry be-
ing the limiting factor. Such an approach essentially admits that we cannot make all the molecules
and therefore should focus on simplest ones.
45
In industry, the Discovery Chemist is now leaning over the shoulder of the process chemist.
46
Together, with ingenuity, practical savy, and with the help of the blossoming custom synthesis cot-
tage industry,
47
the high-pressure time lines to the go/kill phase of the potential drug are being met
more rapidly.
Optimization in Organic Synthesis,
the title of the symposium held during the 3rd Winter Con-
ference on Medicinal and Bioroganic Chemistry in Steamboat Springs, CL, January 22–28, 1998,
encompasses the content of this Introduction and defines some of the components addressed by the
invited speakers. Carsten Bolm illustrates how design of new enantioselective catalytic systems ad-
vances our utility of the classical (Baeyer–Villiger) reaction; Gilbert Stork instructs all of us on the
origin and the significance of selectivity in organic synthesis with illustrations, now textbook, of
work from his laboratories; Paul Wender shows how complex biological activity of natural products
drives the invention of new synthetic reactions; and Matthias Beller demonstrates the importance to
focus on the need for simple building blocks and to develop new regioselective catalytic reactions.
The many facets of
Optimization in Organic Synthesis
and our responsibility to its achievement
justifies continuing meetings under this or similar titles
48
to bring home the message which, by the
nature of the vitality of the field, is a moving target.
REFERENCES
1. Eschenmoser A. In: Chatgilialoglu C, Snieckus V. editors. Chemical synthesis. Gnosis to prognosis. NATO
ASI Series E: Applied Sciences—Vol 320, Kluwer; 1996. p 293.
2. Schreiber SL. Bioorg Med Chem 1998;1127.
3. Snieckus V. Acct Chem Res 1983;16:186.
4. We have travelled far since 1828 and the interest attached to “total tynthesis” has disappeared.” Robinson
R. Pedler Lecture, J Chem Soc 1936;1079; This statement was not really true in 1936. It will still not be
true in a hundred years. Stork G, Prix Roussel Lecture Paris, June 8, 1978.
5. (a) Seebach D. Angew Chem Int Ed Engl 1990;90:1320; (b) Hudlicky T. Chem Rev 1996;96:3; (c) Hanes-
sian S. In: Chatgilialoglu C, Snieckus V. editors. Chemical synthesis. Gnosis to prognosis. NATO ASI Se-
ries E: Applied sciences—Vol 320, Kluwer; 1996. p 61; (d) Heathcock CH. In: Chatgilialoglu C, Snieckus
V. editors. Chemical synthesis. Gnosis to prognosis. NATO ASI Series E: Applied Sciences—Vol 320,
Kluwer; 1996. p 223 (Panel Discussion); (e) for a delightful view on “The trouble with synthesis,” see Corn-
forth J. Aldrichim Acta 1994;27:71. and Austr J Chem 1993;46:157.
6. Anand N, Bindra JS, Ranganathan S. Art in organic synthesis. San Francisco: Holden-Day, Inc; 1970; Flem-
ing I. Selected organic syntheses. New York: Wiley; 1973; Turner S. The design of organic syntheses. Am-
sterdam: Elsevier; 1976.
7. Fuhrhop J, Penzlin G. Organic synthesis, 2nd ed. Weinheim: VCH; 1994; Nicolaou, KC, Sorensen EJ. Clas-
sics in total synthesis. Weinheim: VCH; 1996.
8. Noyori R. J Syn Org Chem Jpn 1998;56:883.
9. Armstrong RW, Beau J-M, Cheon SH, Christ WJ, Fujioka H, Ham W-H, Hawkins LD, Jin H, Kang SH,
Kishi Y, Martinelli MJ, McWhorter Jr WW, Mizuno M, Nakata M, Stutz AE, Talamas FX, Tanaguchi M,
Tino JA, Ueda K, Uenishi J-i, White JB, Yonaga M. J Am Chem Soc 1989;111:7530. See Greene TW, Wuts
PGM. Protective groups in organic synthesis, 2nd ed. New York: Wiley; 1995. p 5.
10. Ugi I, Domling A, Gruber B, Almstetter M. Croatica Chem Acta 1997;70. Balkenhohl F, Busche-Hunnefeld
Cvd, Lansky A, Zechel C. Angew Chem Int Ed Engl 1996;34:2288; Ugi I, Domling A, Horl W. Endeavour
1994;18:115; Armstrong RW, Combs AP, Tempest PA, Brown SD. Acc Chem Res 1996;29:123. For recent
studies, see Paulvannan K. Tetrahedron Lett 1999; 40:1851 and refs cited therein.
11. Wilson SR, Czarnik, Combinatorial chemistry: Synthesis and applications
,
New York: Wiley; 1997; Bunin,
 346
SNIECKUS
•
BA. The combinatorial index. San Diego: Academic Press; 1998. J Comb Chem has just been launched,
12. Carlson R. Design and optimization in organic synthesis. Amsterdam: Elsevier; 1992.
13. Trost BM. Science 1991;254:1471. For a recent view, see C & EN, June 19, 1995. p 32.
14. Anastas P, Williamson T. editors. Green chemistry: Frontiers in benign chemical synthesis and processing.
New York: Oxford University Press; 1998. A new journal, Green Chem has been born, visit www.rsc.org/
greenchem.
15. Curran DP, Hoshino M. J Org Chem 1996;61:6480; Juliette JJ, Horvath IT, Gladysz JA. Angew Chem Int
Ed Engl 1997;36:1610 and refs cited therein.
16. Jeong N, Hwang SH, Lee YW, Lim JS. J Am Chem Soc 997;119:10549 and refs cited therein.
17. Freemantle M. C & EN 1999, January 4, p 23; Earle MJ, McCormac PB, Seddon KR, J Chem Soc Chem
Commun 1998;2245.
18. Selective cross-coupling reactions between C(sp3) and C(sp2) centers had been one of the most difficult
tasks in carbon–carbon bond synthesis until the early 1970s. . . Now, . . .(it) has become the reaction of first
choice for this purpose. Tamao K. Comprehensive organic synthesis. London: Pergamon Press; Vol 3, 1991.
p 435.
19. Togni A, Breutel C, Schnyder A, Spindler F, Landert H, Tijani A. J Am Chem Soc 1994;116:4062. For a
phenomenal TON effect in the commercial synthesis of biotin, see Spindler F, Pugin B, Jalett H-P, Buser
HP, Pittelkow U. Blaser H-U. Proceedings, Catalysis of organic reactions. Altanta: 1996; Chem. Ind.
(Dekker); 1996:63.
20. Tietze LF. Chem Rev 1996;96:115; Ho T-L. Tandem organic reactions; New York: Wiley; 1992. For a new
concept of parallel recognition in which multifold reactions occur at individual reaction sites, see C J-x,
Otera J. Angew Chem Int Ed Engl 1998;37:91.
21. For example, Formation of 4 C&bond;C bonds in sequence. Chatani N, Kataoaka K, Murai S. J Am Chem
Soc 1998;120:9104 .
22. Faber K. Biotransformations in organic chemistry. 2nd ed., Berlin: Springer; 1995; Kelly DR. In: Rehm H-
J, Reed G. editors. Biotechnology. 2nd ed., Vol 8a, 1998.
23. Rawls RL. C & EN 1998, March 9, p 29.
24. “Anyone who has helped to plan an industrial synthesis tends to pity the poverty of the criteria that acade-
mic synthesis must meet. Work of this sort ought to be held in greater respect and published more often
than, alas, it is.” See ref 5e.
25. “The more innocuous the process change appears, the further its influence will extend.” I am grateful to
Trevor Laird, Scientific Update, for this Process Chemist’s credo.
26. Avoided common usage by persuasion from Sir John Cornforth, see Ref 5(e).
27. The ideal synthesis produces the target molecule in one step and 100% yield from readily available mate-
rials through a process that is safe, efficient, and environmentally sound. Wender PA. cited in Zurer PS. C
& EN, May 5, 1997, p 47.
28. For a comment on this issue, see Ref 5(b), footnote 11.
29. Corey EJ, Cheng X-M. The logic of chemical synthesis. New York: Wiley; 1989.
30. Ireland RE. Organic synthesis. Englewood Cliffs, NJ: Prentice-Hall; 1969.
31. Corey EJ, Long AK, Rubenstein SD. Science 228:408; Corey EJ, Long AK, Lotto I, Rubenstein SD. Recl
Trav Chim Pays Bas 1992;111:304.
32. Hendrickson JB. Angew Chem Int Ed Engl 1990;29:1286; Hendrickson JB. J Am Chem Soc 1991;113:902
and refs cited therein; Gasteiger J, Gillespie PD, Marquarding D, Hanessian S, Franco J, Larouche B. Pure
Appl Chem 1990;62:1887; Hanessian S, Franco J, Gagnon G, Laramee D, Larouche BJ
.
Chem Inf Com-
put Sci 1990;30:413; Helson HE, Jorgensen WL. J Org Chem 1994;59:3841; Ugi I. Top Curr Chem 1974;
48:1.
33. Bertz SH, Sommer TJ. In: Hudlicky T, editor. Organic synthesis: Theory and applications. Greenwich, CT:
JAI Press; 1993. Vol. 2, p. 67; Wender PA, Miller BL. ibid 1993. Vol. 2, p 27.
34. Whitlock HW. J Org Chem 1998;63:7982; Chanon M, Barone R, Baralotto C, Julliard M, Hendrickson JB.
Synthesis 1998;1559. In the latter review, a fascinating mountain metaphor for synthetic strategy is de-
scribed and illustrated.
35. An efficiency factor of step:person may be an interesting analysis.
36. Stated in various ways by many synthetic chemists, most recently by Gilbert Stork: The important question
  [ Pobierz całość w formacie PDF ]

zanotowane.pl

doc.pisz.pl

pdf.pisz.pl

anio102.xlx.pl