Partial Synthesis of a trans Vitamin D [603862]

ESSAY
Angew. Chem. Int. Ed. 2001 ,40, No. 8  WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001 1433-7851/01/4008-1411 $ 17 .50+.50/0 1411Wittig and His Accomplishments: Still Relevant Beyond His 100th Birthday**
Reinhard W. Hoffmann*
To understand the developments in chemistry at the turn of
the 20th into the 21st century, one has to recognize the
guidelines laid down at the beginning and in the middle of thelast century. Georg Wittig was one of the scientists who, in themiddle of the last century, founded such guiding principles.The 100th anniversary of Wittigs birth was in 1997. By virtueof this, Wittig has become a historical person, a subject for thehistory of chemistry.
Perspectives tend to be shortened when looking at the past,
developments are seen in a compression of time and someaspects, which are considered not to be of relevance, arediscarded. To evaluate the importance of Wittigs contribu-tions in such a manner one should simply ask which of Wittigsaccomplishments are known to the young generation ofchemists today. Of course, the Wittig reaction and the Wittig
ether rearrangement would be at the top of the list. For many,
the name of Wittig is also attached to the chemistry ofdehydrobenzene (benzyne). If, however, todays youngerchemists do not know more about Wittigs accomplishments,this has to be blamed primarily on those currently in theirsixties, for not handing down more information on Wittig tothe next generation.
Is the carbonyl olefination of ketones or aldehydes by
phosphorous ylids, that is, the Wittig reaction, his mostimportant contribution? The initial investigations by Wittigand Schöllkopf
[1]revealed that this reaction allows the
conversion of cyclohexanone into methylenecyclohexane[Eq. (1)], a compound with a semicyclic double bond.Structures of this kind could previously only be obtained bycircuitous routes and with low selectivity.
From todays point of view, it is quite normal that this very
aspect of Wittigs chemistry found an immediate application[*] Prof. Dr. R. W. Hoffmann
Fachbereich Chemie
Philipps-Universität MarburgHans-Meerwein-Strasse, 35032 Marburg (Germany)Fax : (‡49) 6421-282-8917
E-mail: [anonimizat]
[**] A condensed version of a lecture given on the occasion of the
inauguration of the Georg Wittig Lectureship at the Universität
Heidelberg (27.10.1999)
Prof. Georg Wittig
1897 Born in Berlin (Germany)1916 Enrollment for chemistry at the university of Tübingen
1916 – 1919 Lieutenant and prisoner of war in World War I
1919 – 1923 Studied chemistry in Marburg1923 – 1926 Habilitation in Marburg1926 – 1932 Privatdozent in Marburg1932 – 1937 Junior Professor in Braunschweig1937 – 1944 Associate Professor in Freiburg1944 – 1956 Professor in Tübingen1956 – 1967 Professor in Heidelberg
1979 Award of the Nobel prize for chemistry
1987 Died in Heidelberg

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1412  WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001 1433-7851/01/4008-1412 $ 17 .50+.50/0 Angew. Chem. Int. Ed. 2001 ,40,N o .8in natural product synthesis. As the synthesis of vitamin D
required the construction of such a moiety, Inhoffen et al.
utilized the Wittig reaction in this context immediatelyfollowing Wittig and Schöllkopfs first publication on thesubject (Figure 1).
[2]
This fact, however, is remarkable considering the context of
natural product synthesis in those days: in the first half of the
twentieth century and even far into the sixties, the onus ofnatural product synthesis was to provide proof for theproposed structure of a natural product by synthesis.
[3]This
restricted natural product synthesis to the use of only suchreactions, the reliability of which was beyond doubt. It atteststo the uniqueness of the Wittig reaction that it was applied innatural product synthesis (Figure 1) within one year of first
being reported, despite not being an “established” reaction.
The Wittig reaction was unique in yet another aspect: it was
applied just as rapidly in industrial synthesis as in naturalproduct synthesis. Since the fifties vitamin A and othercarotenoids had been produced by Hoffmann LaRoche inBasel. Horst Pommer at BASF was studying alternative routesto this class of compounds and he immediately recognized the
potential of the Wittig reaction for the synthesis of vitamin A
[Eq. (2)].
[4]
A collaboration between Wittig and Pommer soon led to a
landmark patent.[5]It was an outstanding achievement both
scientifically and economically to bring a vitamin A synthesisfrom the first experiments in the laboratory to large-scale
commercial production within five years, an accomplishment,
of which BASF can be proud. Ever since, the Wittig reactionhas been used like no other as one of the standard reactions toassemble molecules by C ˆC bond formation.
It should be stressed that Wittig did not
conceive the Wittig reaction, he discovered it.People today tend to forget that truly innovativeresearch cannot be planned. It is foremost the
ability of the scientists to properly comprehend
unexpected observations and to recognize theirpotential. Wittig possessed this ability second tonone. In part, this was related to Wittigstendency to frown upon trendy topics of histime. The choice of his research projects restedcompletely within his own thinking. For a
scientist in an academic institution this is a risky
predisposition, that can lead to a loss in standingamongst peers, but this is also a predispositionwhich is the seedbed of truly novel insights.
Wittig was impressed by the daring concepts of
Meerweins carbocation chemistry. He was di-rectly exposed to it as a Privatdozent at theMarburg chemical institute (1929 – 1932) headed
by Meerwein. Wittig envisioned carbanion
chemistry becoming the counterpart of Meer-weins carbocation chemistry. For this reason,Wittig investigated in breadth reactions that
might lead to carbanionic species. This approach led him toylids such as the simplest nitrogen ylid formed on deproto-nation of the tetramethyl ammonium ion [Eq. (3)].
However, in truth, the experiments shown were carried out
for a different purpose: Wittig always felt challenged bydogmas. He wanted to prove them wrong or at least define thelimits of their validity. One dogma prevalent at Wittigs timewas that elements of the first period of the periodic tablecould only form tetravalent compounds. Pentavalent carbon
was considered, if at all, only as a transition state in an
S
N2 reaction. Wittig nevertheless wanted to see whether
phenyllithium might be added to the tetramethylammoniumion to form a compound with a pentavalent nitrogen atom. Hedid not succeed, because deprotonation of the ammonium ionled to a nitrogen ylid.
[6]As a control, he reacted phenyllithium
with the tetramethylphosphonium ion; this constituted theentry to phosphorus ylids and their chemistry.
[7]To obtain
compounds with pentavalent phosphorous, Wittig turned to
phosphonium salts which cannot be deprotonated. Followingthis line of thought, Wittig generated the first pentarylphos-phorane starting from the tetraphenylphosphonium ion.
[8]
This compound has not reached a similar level of importanceas the phosphorus ylids, but these studies exemplify someaspects of Wittigs thinking and work. We tend to forget how
important the determination of melting points was to the
Figure 1. Reproduction of the publication by H. H. Inhoffen on the application of the Wittig
reaction, Angew. Chem. 1955 ,67, 276 (English translation given in ref. [40]).

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Angew. Chem. Int. Ed. 2001 ,40, No. 8  WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001 1433-7851/01/4008-1413 $ 17 .50+.50/0 1413chemists of the first half of the twentieth century. Melting
points provided the only means to prove the identity or
nonidentity of two compounds. Accordingly, the process ofcrystal growing was central to the activities of chemists ofthose days. In many cases, the “boss” did it himself—at thevery least, he reproduced the crystallization process with hisown hands. Next, he had to find out whether the “meltingpoint” was a true melting point, or whether it was merely adecomposition point, or caused by a chemical transition or a
crystal modification. To clarify those matters, the melt was
resolidified in the melting point tube (after taking the meltingpoint) by scratching with a thin wire, and then the meltingpoint was determined a second time. A difference in themelting behavior was a clear indication of an unexpectedprocess. It was this “standard procedure” that brought to lightthe rearrangement of pentaarylphosphoranes to triarylphos-
phines [Eq. (4)].
[9]I doubt whether present day chemists take
advantage of these simple techniques to unveil unprecedentedthermal transformations.
Another reaction named after Wittig is the anionic ether
rearrangement [Eq. (5)]. This reaction was discovered upon
attempting to generate carbanions by deprotonation of benzyl
alkyl ethers.[10]The resulting ether rearrangement forms a new
carbon – carbon bond. Such bond-forming reactions are ofinterest today, as they permit the generation of stereogenic
centers in a predefined configuration. Thus, the Wittig
rearrangement of benzyl allyl ethers
[11][Eq. (6)] has become
an important tool for the stereoselective synthesis of alco-hols.
[12]
A reaction of even broader importance is the halogen/
metal-exchange reaction, which few chemists today associatewith the name of Wittig. The bromine/lithium-exchangereaction was described simultaneously (the manuscripts werereceived within three months of each other) and independent
from one another by Wittig
[13]and by Gilman;[14]thus Wittigscontribution is clear! This reaction was so fundamentally
novel and paradoxical that Wittig characterized it as shown in
Figure 2 (a translation of the original German text is given in
Figure 2. Reproduction of the publication by Wittig on the halogen/metal-
exchange reaction, Ber. Dtsch. Chem. Ges. 1938 ,71, 1903 (English
translation given in ref. [41]).
ref. [41]). To publish these findings and concepts required
courage. If the interpretation had been found to be wrong, theprofessional career of the young assistant professor atBraunschweig would have been jeopardized. The observa-tions on the halogen/metal-exchange reaction however,
turned out to be correct. This reaction has since grown into
one of the most widely used procedures for the generation ofvinyl- and aryllithium compounds.
In this key paper by Wittig,
[13]another important observa-
tion is documented (again parallel to Gilmans paper[14]), this
is the directed metalation of aromatic compounds in theposition ortho to a methoxy group [Eqs. (7, 8)].
Today, it is common knowledge that electronegative sub-
stituents which may coordinate a lithium cation can induce adirected ortho -metalation by alkyl- or aryllithium reagents.
[15]
Following the first record of this reaction by Wittig and
Gilman, the method has since been developed into a general
tool in the chemistry of aromatic compounds.[16]Wittig could
not have foreseen that some of todays big-selling drugs suchas Losartan
[17]or Efavirenz[18]would be produced utilizing a
directed ortho -metalation. Over the whole breadth of Wittigs
research, phenyllithium was the key reagent, he himselfdescribed it as his “divining rod”. But how did Wittig come to
use phenyllithium? The preparation of phenyllithium was

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1414  WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001 1433-7851/01/4008-1414 $ 17 .50+.50/0 Angew. Chem. Int. Ed. 2001 ,40,N o .8pioneered 1930 by Karl Ziegler,[19]a close friend of Wittigs;
both started their academic career at Marburg and overlapped
there for many years.
Forortho -metalation and complexation assisted metalation
Wittig continually tested more and more reactive bases. Hewas the first to have used complex bases, such as a 1:1 mixtureof phenyllithium and phenylsodium. This complex basedeprotonated anisole more rapidly than either of its constit-uents [Eq. (9)].
[20]
With this finding, Wittig described and studied the fore-
runner of the complex bases presently in use, such as theLochmann – Schlosser base (potassium tert-butoxide‡n-butyl-
lithium
[21]) or Caube `res system (sodium tert-butoxide‡
sodium amide).[22]The chemistry of these complex bases is
still in its infancy.
Another concept of Wittig was quickly accepted by the
scientific community: neutral Lewis base plus positivelycharged electrophile forms an onium-complex. An anionicLewis base plus a neutral electrophile forms an ate complex, aterm coined by Wittig.
[23]In studying ate complexes, Wittig hit
upon the fascinating combination of triphenylmethylsodiumand triphenylboron. In this system the equilibrium for
forming an ate complex is not completely on the side of the
complex because of steric hindrance in the latter. As aconsequence, the Lewis base triphenylmethylsodium and theLewis acid triphenylboron coexist in substantial concentra-tions in solution [Eq. (10)].
This allowed, for the first time, a Lewis acid catalysis of
Lewis base induced reactions,[24]as shown in the following
example: triphenylmethylsodium by itself is stable in THF
solution, so is triphenylboron. In combination they induce a
rapid polymerization of THF [Eq. (11)] the first step beingring opening of the THF.
Wittig had no doubts about the mechanism of these
“triphenylmethylsodium-initiated and triphenylboron-assist-ed reactions” as he termed them. Subsequent to Wittigs
seminal studies, numerous examples of this type of Lewis acidcatalyzed reaction of organometallic compounds have been
described
[25]and the principle rediscovered many times!
The directed ortho -metalation was the godfather to another
completely unexpected finding by Wittig: 2-biphenyllithiumwas formed on reaction of fluorobenzene with phenyllithium[Eq. (12)].
Wittigs interpretation of this transformation envisioned an
ortho -lithiation of fluorobenzene as the first step. The
resulting ortho -fluorophenyllithium was then postulated to
loose lithium fluoride forming dehydrobenzene (benzyne; 1)
as a reactive intermediate which was then trapped by phenyl-lithium forming the 2-biphenyllithium end product.
[26]
This may seem reasonable for a chemist of today but, to a
chemist before 1950, this was a dare-devil proposition. Weshould recognize that during the forties there was noperception of reactive intermediates in the mind of mostGerman chemists. The only thing that mattered in a reaction
was the starting material and the product. In line with this, the
carbocation concept of Meerwein had not yet found generalacceptance. To postulate such a novel reactive intermediateback in those days could easily have put an academic career atrisk. This may explain why Wittig hesitated for years beforepublishing his hypothesis. He always was (and remained)skeptical about hypotheses, especially his own. Hence, he
referred for decades to “dehydrobenzene” as being a “chem-
istry as if”.
[27]To Wittig, all the results obtained were
consistent with the dehydrobenzene hypothesis, neverthelessthey failed to prove the existence and structure of this reactiveintermediate. This skepticism remained even after J. D.Roberts proved the symmetrical nature of this intermediateby brilliant isotope labeling experiments,
[28]and after Wittig
himself provided the most convincing evidence in trapping
dehydrobenzene in Diels – Alder reactions.[29]
It was finally in 1964 that Wittig accepted dehydrobenzene
as a reality, after Huisgen showed through his elegantdetermination of competition constants
[30](cf. Scheme 1) that
a common intermediate is generated from the differentprecursors 2–5, an intermediate that selects between furan
and cyclohexadiene in an identical manner.
It follows that the same intermediate is generated in all
these reactions. Simple comparison of the structures of the
precursor compounds on the one side and of the trappingproducts 6and7on the other leaves no doubt that the reactive
intermediate has to be dehydrobenzene 1with the shown
connectivity of atoms.
Wittig was the first to note that lithium dialkylamides may
transfer hydride to acceptor molecules, a reaction which
Wittig had neither planned nor sought. It was again seren-

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Angew. Chem. Int. Ed. 2001 ,40, No. 8  WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001 1433-7851/01/4008-1415 $ 17 .50+.50/0 1415
Scheme 1. Huisgens confirmation, by using various precursors, of the
identity of the intermediate dehydrobenzene.
dipity, but Wittig recognized right away the importance of this
finding. The plan had been to generate dehydrobenzene fromfluorobenzene using lithium diethylamide as base. Wittig
noted that the dehydrorobenzene generated was transformed
under these conditions into phenyllithium in a process inwhich lithium diethylamide served as a hydride source(Scheme 2),
[31]much akin to the Meerwein – Verley – Ponn-
dorf reduction.
Scheme 2. Lithium diethylamide as a hydride donor.
As a corollary lithium diethylamide was also dehydrogen-
ated by benzophenone to a Schiff base which underwentdeprotonation to furnish an azaenolate. This very experimentprovided the first access route to azaenolates, which are nowstandard reagents in organic synthesis. Wittig himself dem-onstrated the potential of azaenolates to effect directed aldoladditions [Eq. (13)].
[32]
However, let us rather focus on the first step of the above
reaction sequence of Equation (13) the ability of lithiumdiethylamide to serve as a hydride donor. Wittig demonstrat-ed the possibility to reduce non-enolizeable ketones by
lithium diethylamide (see Scheme 2). Thus, it should bepossible to reduce prochiral ketones by application of a chiral
“lithium diethylamide”. This can indeed be accomplished as
Wittig showed in 1969 [Eq. (14)].
[33]
Wittig reached an asymmetric induction of 60 % ee, a value,
which was surely a highlight at the end of the sixties. Withmore elaborate chiral derivatives of lithium diethylamide,enantioselectivities of >95 % eewere recorded in 1999.
[34]
Wittig was therefore one of the forerunners in the develop-
ment of chiral reducing agents for prochiral ketones.
When Wittig received the Nobel price in 1979, he was at an
age which permitted only a retrospective. In his Nobel lecture
“From diyls to ylides to my idyll”, he reviewed the leading
themes of his oeuvre (Figure 3).[35]The chemistry of free
radicals marked the outset. He tried to generate kineticallypersistent diradicals ˆdiyls; he modeled his target com-
pounds on the persistent triphenylmethyl radical of M.Gomberg.
[36]
Figure 3. Reproduction of Wittigs retrospective on the chemistry of diyls
(Nobel Lecture), Angew. Chem .1980 ,92, 671 (English translation given in
ref. [42]).
Wittig hoped to arrive at persistent diradicals by stabiliza-
tion of the radical centers by pdelocalization and by
destabilization of the dimerization products by ring strain.Out of this context the experiment shown in Scheme 3 wasperformed.
The reduction of the dibromo compound 9furnished a
C
32H20hydrocarbon, a stable diradical? Careful determina-
tion of the molecular weight indicated the hydrocarbon 10to
be a “tetramer” C128H80;[37]its constitution was revealed years

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Scheme 3. Tetramerization of a stabilized diyl to the hydrocarbon
(C32H40)4.
later by X-ray crystal structure analysis.[38]This compound
held an additional fascination for Wittig, it was piezochromicand thermochromic. We should remember that Wittig is arepresentative of a generation of chemists, for whom theelucidation of the relationship between color and constitutionwas a life task. Every graduate student in Wittigs group knewhow much Wittig insisted on finding explanations for eachcolor phenomenon observed. As we know today, the color
generated on heating 10is caused by the appearance of the
desired diradical in conjunction with the dissociation of the“tetramer” into the monomer 8.
These studies rested unnoticed for decades. Today, they
have become important in quite a different context: ontetramerization of the diradical 8, four readily accessible
building blocks are joined in a single operation to give a
spherical molecular object. Thus, in 1999 a 32-armed den-
drimer with a compact core was assembled in one strokebased on Wittigs studies.
[39]
The many examples provided in this essay show that
Wittigs accomplishments become and remain important tochemists in changing contexts far beyond his hundredthbirthday. The next generation of chemists has only to realizethat Wittigs oeuvre is still a gold mine of facts and concepts to
be exploited.
[1] G. Wittig, U. Schöllkopf, Chem. Ber. 1954 ,87, 1318 – 1330.
[2] H. H. Inhoffen, J. F. Kath, K. Brückner, Angew. Chem. 1955 ,67, 276 –
278.
[3] A. Eschenmoser, Naturwissenschaften 1974 ,61, 513 – 525.
[4] H. Pommer, Angew. Chem. 1977 ,89, 437 – 443; Angew. Chem. Int. Ed.
Engl. 1977 ,16, 423 – 429.
[5] G. Wittig, H. Pommer (Badische Anilin & Soda-Fabrik AG, Ludwig-
shafen), DE Patent 950 552, 1956 [Chem. Abstr. 1959 ,53, 436].
[6] G. Wittig, M. H. Wetterling, Justus Liebigs Ann. Chem. 1944 ,557,
193 – 201.
[7] G. Wittig, M. Rieber, Justus Liebigs Ann. Chem. 1949 ,562, 177 – 187 .
[8] G. Wittig, M. Rieber, Justus Liebigs Ann. Chem. 1949 ,562, 187 – 192.
[9] G. Wittig, A. Maercker, Chem. Ber. 1964 ,97, 747 – 768.
[10] G. Wittig, L. Löhmann, Justus Liebigs Ann. Chem. 1942 ,550, 260 –
268.
[11] G. Wittig, H. Döser, I. Lorenz, Justus Liebigs Ann. Chem. 1949 ,562,
192 – 205.
[12] T. Nakai, K. Mikami, Org. React. 1994 ,46, 105 – 209.
[13] G. Wittig, U. Pockels, H. Dröge, Ber. Dtsch. Chem. Ges. 1938 ,71,
1903 – 1912.[14] H. Gilman, W. Langham, A. L. Jacoby, J. Am. Chem. Soc. 1939 ,61,
106 – 109.
[15] S. T. Chadwick, R. A. Rennels, J. L. Rutherford, D. B. Collum, J. Am.
Chem. Soc. 2000 ,122, 8640 – 8647.
[16] V. Snieckus, Chem. Rev. 1990 ,90, 879 – 933.
[17] R. D. Larsen, A. O. King, C. Y. Chen, E. G. Corley, B. S. Foster, F. E.
Roberts, C. Yang, D. R. Lieberman, R. A. Reamer, D. M. Tschaen,
T. R. Verhoeven, P . J. Reider, Y. S. Lo, L. T. Rossano, A. S. Brookes,
D. Meloni, J. R. Moore, J. F. Arnett, J. Org. Chem. 1994 ,59, 6391 –
6394.
[18] M. E. Pierce, R. L. Parsons, Jr., L. A. Radesca, Y. S. Lo, S. Silverman,
J. R. Moore, Q. Islam, A. Choudhury, J. M. D. Fortunak, D. Nguyen,
C. Luo, S. J. Morgan, W. P . Davis, P . N. Confalone, C.-y. Chen, R. D.Tillyer, L. Frey, L. Tan, F. Xu, D. Zhao, A. S. Thompson, E. G. Corley,E. J. J. Grabowski, R. Reamer, P . J. Reider, J. Org. Chem. 1998 ,63,
8536 – 8543.
[19] K. Ziegler, H. Colonius, Justus Liebigs Ann. Chem. 1930 ,479, 135 –
149.
[20] a) G. Wittig, R. Ludwig, R. Polster, Chem. Ber. 1955 ,88, 294 – 301;
b) G. Wittig, F. Bickelhaupt, Chem. Ber. 1958 ,91, 865 – 872; c) G.
Wittig, E. Benz, Chem. Ber. 1958 ,91, 873 – 882.
[21] a) L. Lochmann, Eur. J. Inorg. Chem. 2000 , 1115 – 1126; b) M.
Schlosser, Pure Appl. Chem. 1968 ,60, 1627 – 1634.
[22] P . Caube `re,Top. Curr. Chem. 1978 ,73, 49 – 124.
[23] G. Wittig, Angew. Chem. 1958 ,70, 65 – 71.
[24] a) G. Wittig, A. Rückert, Justus Liebigs Ann. Chem. 1950 ,566, 101 –
113; b) G. Wittig, H. Schloeder, Justus Liebigs Ann. Chem. 1955 ,592,
38 – 53; c) G. Wittig, D. Wittenberg, Justus Liebigs Ann. Chem. 1957 ,
606, 1 – 23; d) G. Wittig, H. G. Reppe, T. Eicher, Justus Liebigs Ann.
Chem. 1961 ,643, 47 – 67.
[25] a) B. Achmatowicz, E. Baranowska, A. R. Daniewski, J. Pankowski, J.
Wicha, Tetrahedron Lett. 1985 ,26, 5597 – 5600; b) M. J. Eis, J. E.
Wrobel, B. Ganem, J. Am. Chem. Soc. 1984 ,106, 3693 – 3694.
[26] G. Wittig, Naturwissenschaften 1942 ,30, 696 – 703.
[27] G. Wittig, Pure Appl. Chem. 1963 ,7, 173 – 191.
[28] J. D. Roberts, H. E. Simmons, Jr., L. A. Carlsmith, C. W. Vaughan, J.
Am. Chem. Soc. 1953 ,75, 3290 – 3291.
[29] G. Wittig, L. Pohmer, Chem. Ber. 1956 ,89, 1334 – 1351.
[30] R. Huisgen, R. Knorr, Tetrahedron Lett. 1963 , 1017 – 1021.
[31] G. Wittig, H.-J. Schmidt, H. Renner, Chem. Ber. 1962 ,95, 2377 – 2383.
[32] a) G. Wittig, H. D. Frommeld, P . Suchanek, Angew. Chem. 1963 ,75,
978 – 979; Angew. Chem. Int. Ed. Engl. 1963 ,2, 683 – 684; b) G. Wittig,
H. Reiff, Angew. Chem. 1968 ,80,8–1 5 ; Angew. Chem. Int. Ed. Engl.
1968 ,7, 7 – 14; see also: G. Stork, S. R. Dowd, J. Am. Chem. Soc. 1963 ,
85, 2178 – 2180.
[33] G. Wittig, U. Thiele, Justus Liebigs Ann. Chem. 1969 ,762, 1 – 12.
[34] K. Takeda, Y, Ohnishi, T. Koizumi, Org. Lett. 1999 ,1, 237 – 239.
[35] G. Wittig, Angew. Chem. 1980 ,92, 671 – 675.
[36] M. Gomberg, Ber. Dtsch. Chem. Ges. 1900 ,33, 3150 – 3163.
[37] G. Wittig, E. Dreher, W. Reuther, H. Weidinger, Justus Liebigs Ann.
Chem. 1969 ,726, 188 – 200.
[38] J. Ipaktschi, R. Hosseinzadeh, P . Schlaf, E. Dreiseidler, R. Goddard,
Helv. Chim. Acta 1998 ,81, 1821 – 1834.
[39] J. Ipaktschi, R. Hosseinzadeh, P . Schlaf, Angew. Chem. 1999 ,111,
1765 – 1768; Angew. Chem. Int. Ed. 1999 ,38, 1658 – 1660.
[40] Title: “Partial Synthesis of a “ trans ” Vitamin D
2Compound by means
of the Wittig Reaction”, Wittig and Schöllkopf have described areaction in which a ring ketone is converted into the corresponding
methylene compound with triphenylphosphine-methylid. With the
consent of Professor Wittig we have transferred this reaction to ourC
27ketone to generate the methylene group characteristic of the
antirachitic vitamin.
[41] Title: “On the Exchange of Aromatic-Bound Hydrogen for Lithium
by Phenyllithium”. The following reaction that runs contrary to allchemical intuition has been observed: that bromine and alkali metalatoms exchange between molecules rather than unite was not been
observed before; however, the result is fully secured, the reaction has
been tested repeatedly and occurs rapidly and without the formationof any significant by-products.
[42] …The conclusion of the investigations of radical formation and ring
strain seems to be that the ring closure tends to cause a stabilization,
rather than a weakening of the ethane bond.