Rabe rest in peace: Confirmation of the rabe-kindler conversion of d-quinotoxine into quinine: Experimental affirmation of the woodward-doering formal total synthesis of quinine

Article abstract of DOI:10.1002/anie.200705421

(Chemical Equation Presented) Put to rest: The three-step conversion of d-quinotoxine into quinine, as originally reported by Rabe and Kindler in 1918, has been experimentally verified. This conversion serves to reaffirm the formal total synthesis of quin

Full text of DOI:10.1002/anie.200705421

Communications
DOI: 10.1002/anie.200705421
Quinine: Controversy in Synthesis
Rabe Rest in Peace: Confirmation of the Rabe–Kindler Conversion of
d-Quinotoxine Into Quinine: Experimental Affirmation of the
Woodward–Doering Formal Total Synthesis of Quinine**
Aaron C. Smith and Robert M. Williams*
Dedicated to Professor William von Eggers Doering on the occasion of his 90th birthday
Robert Burns Woodward and William von Eggers Doering of
Harvard University published a communication in 1944 and a
full paper in 1945in the Journal of the American Chemical
Society both entitled “The Total Synthesis of Quinine”.[1] This
now famous full paper has been the subject of much attention
over the years, particularly recently. It is now well-under-
stood, that the Woodward–Doering “total synthesis” was
actually a “formal” total synthesis of quinine (1) that relied on
a seminal 1918 publication by Paul Rabe and Karl Kindler,
wherein d-quinotoxine (2), the final synthetic substance in the
Woodward–Doering work, was converted into quinine by a
three-step sequence (Scheme 1).[2] This sequence involved:
1) oxidation of d-quinotoxine with sodium hypobromite to
produce “N-bromoquinotoxine” (3); 2) base-mediated cycli-
zation of 3 to produce “quininone” (4); and 3) aluminum-
powder reduction of “quininone” to produce quinine (1) and
quinidine (6, as a minor product). The 1918 paper, termed a
“preliminary notice” by the authors, provided only a terse
summary of this three-step process. This paper referenced
Rabeꢀs 1911 conversion of cinchotoxine into cinchoninone
and cinchonidinone (employing the analogous reactions for
the quinotoxine to quininone and quinidinone conversion)[3]
but subsequently in 1932, complete experimental details for
the reduction protocol were published.[4]
Scheme 1. Conversion of d-quinotoxine (2) to quinine (1). a) NaOBr,
NaOH,HCl (aq),Et 2O,55% yield of crude product; b) NaOEt,EtOH,
88% yield of crude product; c) aluminum powder,NaOEt,EtOH,5%
yield (as the tartrate salt).
Despite the significant fanfare accompanying the publi-
cation of the Woodward–Doering paper during World War II,
and the ensuing rich history of quinine and the Cinchona
alkaloids in modern medicine,[5] it is surprising that appa-
rently no one has reported efforts to simply attempt to repeat
the Rabe–Kindler conversion of d-quinotoxine into quinine.
This is particularly significant since concomitant with their
relatively recent total synthesis of quinine,[6] Gilbert Stork
and co-workers raised some possible doubts about the validity
of this conversion, referring to Woodward and Doeringꢀs
“total synthesis” as a “widely believed myth.”[7] Consequently,
the Woodward–Doering claim for a “total synthesis” albeit as
a “formal” total synthesis by relay through d-quinotoxine
based on the Rabe–Kindler sequence, has been besmirched.[7]
This fascinating saga, spanning more than eighty years,
was meticulously researched very recently by Seeman whose
2007 publication entitled: “The Woodward–Doering/Rabe–
Kindler Total Synthesis of Quinine: Setting the Record
Straight”,[8] helped kindle our own interest in this story. In
his analysis of all the available data in the literature and in
archival materials, Dr. Seeman stated: “I conclude that Paul
Rabe and Karl Kindler did convert d-quinotoxine into quinine
[*] Dr. A. C. Smith,Prof. R. M. Williams
Department of Chemistry
Colorado State University
Fort Collins,CO 80523 (USA)
Fax: (+1)970-491-3944
E-mail: rmw@lamar.colostate.edu
Prof. R. M. Williams
University of Colorado Cancer Center
Aurora,CO 80045 (USA)
[**] We are grateful to the National Institutes of Health for financial
support (GM068011). Mass spectra were obtained on instruments
supported by the NIH Shared Instrument Grant GM49631. We are
particularly grateful to Prof. William von Eggers Doering of Harvard
University for insightful and provocative discussions. We are
indebted to Dr. Jeffrey I. Seeman for many thoughtful discussions
and encouragement. We thank our co-workers,Dr. Thomas J.
Greshock and Brandon English,for independently checking and
repeating our best determined experimental conditions using the
Rabe–Kindler conversion of d-quinotoxine into quinine procedure.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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as they reported in 1918.” and: “I therefore also conclude that
the Woodward–Doering/Rabe–Kindler total synthesis of qui-
nine is a valid achievement.” This insightful and perhaps even
bold conclusion, based on a painstaking and meticulous
review of a large body of published and unpublished material,
still lacked unambiguous experimental data to back up the
purported d-quinotoxine to quinine conversion originally
reported in 1918 and so significantly relied upon by Wood-
ward and Doering.[8]
In connection with our laboratoryꢀs work on a novel
approach, which relies on an intramolecular SN2’ reaction at
C3/4, to the total synthesis of quinine and the related
Cinchona alkaloids,[9] we became very interested in this
controversial, historically potent, yet from the perspective of
the 21st century, straightforward semisynthesis of quinine
from d-quinotoxine. We have carefully examined this con-
version as described by Rabe and Kindler in 1918[2] and in
associated papers by Rabe and co-workers published in
1911,[3] 1932,[4] and 1939.[10] We report herein the successful
conversion of d-quinotoxine into quinine deploying the
experimental protocols originally described by Rabe and his
co-workers. This further serves to re-affirm the (formal) total
synthesis claimed by Woodward and Doering in 1944.[1]
We prepared our d-quinotoxine (2) on a 29-gram scale
from commercially available quinine (Aldrich, 90%) as
described by Biddle in 1912 (Scheme 2).[11] Heating quinine
We were struck by the initial low yield of quinine obtained
from the aluminum-powder reduction and the trace material
which we were able to isolate mandated the use of silica gel
chromatography, a purification technique not yet discovered
at the time of the Rabe–Kindler work nor available in 1944 to
Woodward and Doering. It is of course impossible now to
determine where Rabe and Kindler had obtained their
aluminum powder or the level of purity of the reagent that
they had employed in their work. We thus set out to examine
other methods to reduce the quinidinone/quininone mixture
into quinine, to establish the robustness of this general
transformation, before returning to the issue of the quality of
the aluminum powder. This was achieved through a relay
synthesis of quinidinone (formed through oxidation of
quinine)[13,15] to provide adequate quantities of pure material
to study the reduction step.
As shown in Table 1, in 1973 Uskokovic and co-workers,
had reported that quininone could be reduced to quinine
through the agency of diisobutylaluminum hydride (entry 1,
Table 1).[12] This protocol provided a mixture of quinine and
Table 1: Conditions for reducing quinidinone/quininone to quinine.
Entry Reducing
conditions
T [oC] Yield of isolated
quinine/quinidine quinine[f]
Yield of
1[a]
DIBAL-H
20
72%
33%
benzene
2[b]
3
NaBH4,EtOH
Al powder (new)[c]
NaOEt,EtOH
Al powder (new)[d]
NaOEt,EtOH
Al powder + Al2O3
NaOEt,EtOH
Al powder (aerated)[c]
NaOEt,EtOH
Al powder
0
11%
4%
trace
reflux trace
4
5
6
7
8
9
reflux 30% (1.1:1)
reflux 26% (1.1:1)
reflux 24% (1.1:1)
reflux 8% (1.2:1)
16%
14%
13%
4%
Scheme 2. Preparation of d-quinotoxine (2) from natural quinine (1).[11]
MeOH,NaOMe
Al powder (sonication) reflux 22% (1.1:1)
NaOEt,EtOH
12%
15%
Al powder,
reflux 32% (1:1.2)
in H2O/acetic acid (13:1) at 1008C for 35h provided between
50–75% yield of pure d-quinotoxine. Thus, according to Rabe
and Kindler,[2] d-quinotoxine (2) was treated with a solution
of freshly made sodium hypobromite (Scheme 1). The
resultant product, “N-bromoquinotoxine” (3), proved to be
an unstable substance recalcitrant to purification and was
immediately treated with sodium ethoxide in ethanol under
the same conditions described by Rabe and Kindler to effect
quinuclidine cyclization and provided a mixture of quininone
(4) and quinidinone (5). As documented in the literature, the
product that Rabe and Kindler assumed to be quininone, was
in fact its less-soluble epimer, quinidinone (5).[6,8,12,13] Quini-
dinone, when dissolved, spontaneously epimerizes at the
position a to the ketone moiety at C8 immediately establish-
ing an equilibrium mixture of quininone (4) and quinidinone
(5).[12] The mixture thus obtained was treated with newly
purchased aluminum powder (Aldrich)[14] in a solution of
sodium ethoxide and ethanol at reflux temperature to effect
reduction of the carbonyl moiety but only provided quinine
(1) in trace amounts as detected by the appropriate signatures
in the 1H NMR spectrum.
Na(OiPr), iPrOH
Al(OiPr)3, iPrOH
LiAlH4,ether
10
11
12
13
14
reflux 28%
16%
trace
trace
trace
16%
À78
45%
59%
LiAlH4,ether
0
LiAlH4,ether
20
0
56%
40% (1:1.5)
LiAlH4,ether [e]
[a] Experiment from Ref. [11]. [b] General reaction conditions here.
[c] Bottle #1. [d] Bottle #2. [e] After epimerization. [f] Calculated based
on 1H NMR spectra.
quinidine in 72% yield (33% yield of quinine as calculated by
1H NMR spectroscopy). Sodium borohydride also effects this
reduction but in much lower yield (entry 2, Table 1). These
control experiments provided us with authentic mixtures of
quinine and quinidine for use as comparison standards to
evaluate the aluminum-powder reductions in more detail.
When a new bottle of aluminum powder (“bottle #1”)[14]
was employed in the Rabe–Kindler protocol, quinine was
evident in trace amounts by analysis of the 1H NMR spectrum
of the crude mixture after workup (entry 3, Table 1). When a
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different batch of fresh aluminum powder was examined
these powerful tools were not available to Rabe and Kindler
in 1918 and that most of these tools were likewise still not
available to Woodward and Doering in 1944. It then remained
for us to repeat the Rabe–Kindler work under conditions and
using techniques that would have been available in 1944 to
reasonably validate the relay conversion of their synthetic d-
quinotoxine into quinine had Woodward and Doering chosen
to do so. In our hands, the oxidation of quinotoxine with
sodium hypobromite was performed on a multigram scale and
the crude N-bromoquinotoxine product was directly used for
the subsequent steps without purification. This substance
proved to be somewhat unstable to handling and we were
unable to crystallize this material as reported.[2] This notwith-
standing, the crude N-bromoquinotoxine was successfully
converted into a mixture of quininone and quinidinone
through the action of sodium ethoxide in ethanol.[2] Rabe
and Kindler reported that: “The N-bromoquinotoxine, pre-
pared in the same way as the bromo compound obtained from
cinchotoxine, crystallizes from ether as colorless needles with
m.p. 1238. The quininone obtained from it with m.p. 1088 is in
(“bottle #2”, entry 4 in Table 1),[14] we obtained a mixture of
quinine and quinidine in 30% combined yield of which
1
quinine made up roughly half ( ꢀ 16% overall yield) by H
NMR analysis. We reasoned that it was possible that the
material used by Rabe and Kindler in 1918 may have
contained significant AlIII impurities, either as a consequence
of the manufacture of elemental aluminum in the early 1900s
or as a consequence of their bulk reagent becoming “stale”
through exposure to air. To test this speculative hypothesis,
we added Al2O3 to the aluminum-powder reduction using
bottle #1 and observed a significant improvement in the yield
(26% combined yield of quinine and quinidine; ꢀ 14%
overall yield of quinine; entry 5, Table 1).
Next, we took our initial batch of aluminum powder
(bottle #1), and aerated this material for 72 h by passing a
stream of air over a beaker containing the metal. Resubject-
ing the quinidinone (5) to the “aerated” aluminum powder
yielded quinine in ꢀ 15% yield (entry 6, Table 1). Several
variations on these reductions were also employed and
provided similar results (entries 7–9, Table 1). These results
clearly establish that the “aluminum powder” reagent that is
deployed in these reductions must contain some AlIII
impurities to give significant conversion of the ketone
substrates to the secondary-alcohol products. A further
inference from these studies is that the Rabe–Kindler
aluminum-powder reduction may be viewed as an early,
“activated” progenitor of the Meerwein–Ponndorf–Verley
(MPV) reduction.[16] We also conducted a classical MPV
reduction[13,16] (entry 10, Table 1) to compare the reactivity of
that system to that of the aluminum powder. The MPV
reaction did provide quinine (16%), but the reaction took
48 h compared to just 2 h for the other conditions employed.
Finally, lithium aluminum hydride was investigated
(entries 11–13, Table 1). When pure quinidinone (5) was
utilized as the substrate, LiAlH4 provided quinidine (6) as the
major reduction product in most cases with only a trace
amount of quinine detectable by 1H NMR spectroscopy
(entries 11–13, Table 1). This shows that minimal epimeriza-
tion of quinidinone takes place under these reaction con-
ditions. When epimerization of quinidinone is effected prior
to exposure to LiAlH4, and a mixture of quininone and
quinidinone is employed as the substrate mixture, quinine was
formed in 16% yield, which comports with that obtained with
the Rabe–Kindler aluminum-powder-reduction conditions.
Therefore, we can speculate that, had Woodward and Doering
attempted to repeat the Rabe–Kindler reduction protocol and
experienced difficulties (i.e., because of the absence of
sufficient AlIII impurities in their reagent), they could have
(and in our view, would have) reasonably turned to other
reducing agents available in 1944; lithium aluminum hydride
being one such reasonable alternative and the MPV reac-
tion[13,16] as another that, as demonstrated here, provides
quinine (see below).
[2a]
all respects identical to quininone obtained from quinine.”
Unfortunately in our hands, and despite extensive efforts,
neither quininone nor its epimer, quinidinone, could be
purified from the aforementioned reaction mixture using
crystallization techniques.[17] We nevertheless continued to
carry the crude material forward as a mixture of quininone
and quinidinone which also contained several, unidentified
impurities. In the event, treatment of the crude ketone
mixture with aluminum powder[14] in the presence of sodium
ethoxide in ethanol at reflux temperature according to the
protocol described by Rabe and Kindler[2] delivered a
diastereomeric mixture of alcohols from which pure quinine
tartrate (5% yield of isolated product; see Figure 1) could be
crystallized as described below.
Thus, the entire three-step sequence originally reported
by Rabe and Kindler in 1918 was validated, from d-
The bulk of the experiments that we performed to
ascertain the molecular validity of the Rabe–Kindler con-
version of d-quinotoxine into quinine relied on the utilization
of all of the modern separation, analytical, and spectroscopic
techniques available to us today. We of course realize that
Figure 1. Crystals of quinine tartrate obtained directly from quinotoxine
according to the Rabe–Kindler protocol[2] without the use of any
modern isolation,chromatographic,or analytical techniques.
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quinotoxine to quinine, without needing to purify any
intermediates nor resorting to any modern separation,
purification, or analytical technologies. This sequence was
found to be consistently reproducible and was done under
laboratory conditions that existed in 1944.
the data for the natural alkaloid. To further corroborate this
procedure, we asked two additional co-workers (see
Acknowledgement) to repeat and check this sequence in its
entirety as just described (the optimal conditions were
employed using entry 6, Table 1; see Supporting
Information) starting with 9–15grams of quinotoxine and
culminating with the isolation of pure, crystalline quinine
tartrate. In the event, both individuals were able to success-
fully repeat and confirm the Rabe-Kindler conversion of
quinotoxine into quinine.
The most difficult step of the Rabe–Kindler protocol in
our hands proved to be the isolation of pure quinine from the
reaction mixture obtained from the aluminum-powder reduc-
tion. We were able to readily isolate a mixture of quinine and
quinidine from the aluminum-powder reductions by silica gel
chromatography as the crude reaction mixture, which con-
sisted of at least four products: quinine, quinidine, 9-epi-
quinine, and 9-epi-quinidine, was complex as evidenced in the
crude 1H NMR spectrum. Identification of quinine in the
reaction mixture served to validate the Rabe–Kindler con-
version, and our isolation of this material by silica gel
chromatography provided further corroboration. Rabe and
Kindler state in their 1918 paper: “16.3 g synthetic quininone
when treated with the aforementioned reducing mixture
yielded, besides 0.9 g quinidine, 2 g of analytically pure
quinine. Quinine melted as required at 1778 and had an optical
rotation in absolute alcohol of [a]1D4 = À158.78 (c = 2.1432 at
In conclusion, we have demonstrated that the originally
reported conversion of quinotoxine to quinine as described by
Rabe and Kindler in 1918[2] is readily reproducible and can be
conducted under laboratory conditions and with literature
available to Woodward and Doering in the early 1940s[2,3,4,10]
without the use of any modern separation, purification,
analytical or spectroscopic methods or techniques. The
entire sequence can be conducted on crude material and
analytically pure quinine can be isolated from the final
reaction mixture by selective crystallization of the corre-
sponding tartrate salt; this isolation protocol was disclosed by
Rabe and Kindler in 1939[10] and readily available to Wood-
ward and Doering in 1944. We have discovered that the
aluminum-powder reduction, when fresh, non-aerated
reagent is employed, typically gives only trace amounts of
quinine and that “synthetically meaningful” yields are
apparently only obtainable when “aged” aluminum powder
is utilized that contains AlIII surface impurities. We note that
the quality of commercial-grade aluminum powder varies in
substantial ways with respect to the Rabe–Kindler protocol
from batch to batch and in some instances, freshly opened
bottles of aluminum powder work satisfactorily while others
do not provide sufficient quinine for selective isolation based
on crystallization. Further, we have provided solid experi-
mental support for the notion that had Woodward and
Doering chosen to follow the Rabe and Kindler protocol and
had they had difficulty reproducing the reported 12.3% yield
of quinine isolated from this last step, then other reducing
agents known at the time (1944), such as lithium aluminum
hydride or the MPV reduction, could have been alternatively
deployed to reach quinine. Indeed, Woodward and co-work-
ers actually published the reduction of quininone under MPV
conditions to provide quinine (30% yield) along with
quinidine (60%) in a full paper in 1945.[13] Woodward states
in this paper: “The only previous successful reduction of the
carbonyl group of quininone was that of Rabe3 [ref. [2] here]
who obtained 12% of quinine and 6% of quinidine by
reducing the ketone with aluminum and ethanol in the presence
of sodium ethoxide. It is worthy of note that this reaction
constitutes the last step in the total synthesis of the cinchona
alkaloid [ref. to the 1945paper, ref. [1b] here], which has thus
been noticeably improved.”
208C), while Rabe for the natural alkaloid had found [a]1D5 =
[2b, 8]
À158.28 (c = 2.1362 at 158C).”
Based on these exper-
imental disclosures, Rabe and Kindler reported obtaining a
12.3% yield of analytically pure quinine from the aluminum-
powder reduction of quininone (now known to be quinidi-
none[6,8,12,13]). Owing to the low and variable yields of the final
reduction step in our hands, which we conclude is a function
of the quality of the aluminum powder used, Rabe and
Kindler may have found it difficult to isolate pure quinine
from the reduction reaction mixture in a reproducible
manner. This would be particularly true if a new batch of
aluminum powder were used that contained less AlIII
impurities. The reduction conditions used in our studies
deployed aluminum powder that had been left open to the air
as well as newly opened bottles that were not exposed to the
air; the quality of the reagent apparently varied significantly
from batch to batch.
We were able to obtain pure quinine from the crude
aluminum powder reduction reaction mixture through the use
of the selective crystallization protocol first described by
Rabe in 1939[10] and successfully employed by Doering in
1947.[18] The crude aluminum reduction mixture, constituted
of quinine and the corresponding C9 and quinidine diaste-
reomers, was purified by selective formation of the di-quinine
l-tartaric acid monohydrate salt from 95% ethanol in 5%
yield (923 milligrams of white needles were isolated from 13.7
grams of the crude quininone:quinidinone mixture). The
quinine tartrate thus obtained, had a melting point of 212–
2148C (recryst. 95% ethanol; lit.[6,12] m.p. 211–212.58C; see
Figure 1) and had an optical rotation of [a]2D5 = À160 (c = 0.90,
MeOH) (lit.[12] [a]D25 = À156.4, c = 0.97, MeOH).
Finally, the conclusions reached by Seeman[8] on the
validity of the Rabe–Kindler work now have firm exper-
imental support which vanquishes any resilient doubts
initially raised by Stork in a letter to Woodward in 1944[8]
(apparently unanswered),[8] in which he queried whether the
Rabe–Kindler procedure had been repeated at Harvard;
these concerns were then made more visible in his series of
Pure quinine could then be prepared from these crystals
of the tartrate salt by simple aqueous base extraction. The
quinine thus obtained, had a melting point of 1788C (recryst.
benzene; lit.[2] m.p. = 1778C) and an optical rotation of [a]2D5 =
À1558 (c = 0.95, ethanol; lit.[19] [a]D25 = À160.4, c = 1.05, etha-
nol; lit.[6] [a]2D5 = À150.1, c = 0.995, ethanol) and thus matches
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Communications
publications in 2000 and 2001[6,7] questioning the 1918 Rabe–
[4] P. Rabe, Justus Liebigs Ann. Chem. 1932, 492, 242 – 266.
[5] a) “The Chemistry of the Cinchona Alkaloids”: R. B. Turner,
R. B. Woodward in The Alkaloids, Vol. 3 (Ed.: R. H. F. Manske),
Academic Press, New York, 1953, chap. 16; b) “The Cinchona
Kindler publication[2] and the ensuing Woodward–Doering
(formal) total synthesis.[1] The Woodward and Doering paper
concludes unambiguously: “In view of the established con-
version of quinotoxine to quinine, with the synthesis of
quinotoxine (emphasis ours) the total synthesis of quinine
was complete.”[1] The experimental facts reported herein
reaffirm that assertion. Our validation of the formal total
synthesis of quinine as originally reported by Woodward and
Doering in 1944[1] should serve to remove the blemish
asserted[6,7] on the reputations of Rabe and Kindler as well
as those of Woodward and Doering. The Supporting
Information to the present work provides the complete
experimental details to the chemical literature of the Rabe–
Kindler d-quinotoxine into quinine conversion in both a
modern experimental setting as well as a pre-1944 setting;
may Paul Rabe and Karl Kindler requiescant in pace.
´
Alkaloids”: M. R. Uskokovic, G. Grethe in The Alkaloids,
Vol. 14 (Ed.: R. H. F. Manske), Academic Press, New York,
1973, p. 181; c) T. S. Kaufman, E. A. Rfflveda, Angew. Chem.
2005, 117, 876 – 907; Angew. Chem. Int. Ed. 2005, 44, 854 – 885.
[6] G. Stork, D. Niu, A. Fujimoto, E. R. Koft, J. M. Balkovec, J. R.
Tata, G. R. Duke, J. Am. Chem. Soc. 2001, 123, 3239 – 3242.
[7] As reported in a C&E News article (M. Rouhi, Chem. Eng. News
2001, 79(May 7) 54 – 56): “The literature shows that these
accolades [to Woodward and Doering] were ꢁin part based on
wishful thinking,ꢀ Stork says… The final steps that Woodward
and Doering assumed would take that intermediate to quinine
likely would not have worked had they tried them.”; see also
letters by G. Stork, Chem. Eng. News 2001, 79, 8 and G. Stork,
Chem. Eng. News 2000, 78, 8.
[8] J. I. Seeman, Angew. Chem. 2007, 119, 1400 – 1435; Angew.
Chem. Int. Ed. 2007, 46, 1378 – 1413.
[9] D. M. Johns, M. Mori, R. M. Williams, Org. Lett. 2006, 8, 4051 –
4054.
[10] P. Rabe, K. Kindler, Ber. Dtsch. Chem. Ges. B 1939, 72, 263 – 264.
[11] a) H. C. Biddle, J. Am. Chem. Soc. 1912, 34, 500 – 515; b) C. R. L.
Pasteur, Hebd. Seances Acad. Sci. 1853, 37, 162.
[12] J. Gutzwiller, M. R. Uskokovic, Helv. Chim. Acta 1973, 56,
1494 – 1503.
[13] R. B. Woodward, N. L. Wendler, F. J. Brutschy, J. Am. Chem.
Soc. 1945, 67, 1425– 1429.
[14] The aluminum powder used in our studies was purchased from
Aldrich (catalog #21,4752, > 75micron, 99%) in both the 25-g
bottle and 500-g bottle.
[15] D. R. Hutchison, V. V. Khau, M. J. Martinelli, N. K. Nayyar,
B. C. Peterson, K. A. Sullivan, Org. Synth. 1998, 75, 223 – 234.
[16] a) H. Meerwein, R. Schmidt, Justus Liebigs Ann. Chem.. 1925,
444, 221; b) W. Ponndorf, Angew. Chem. 1926, 39, 138; c) A.
Verley, Bull. Soc. Chim. Fr. 1925, 37, 537, A. Verley, Bull. Soc.
Chim. Fr. 1925, 37, 871.
[17] We must despair that the mastery of crystallization techniques in
the early part of the 20th century certainly surpasses that
routinely practiced today.
[18] W. E. Doering, G. Cortes, L. H. Knox, J. Am. Chem. Soc. 1947,
69, 1700 – 1710.
Received: November 26, 2007
Published online: January 31, 2008
Keywords: aluminum · natural products · quinine · reduction
.
[1] a) R. B. Woodward, W. E. Doering, J. Am. Chem. Soc. 1944, 66,
849; b) R. B. Woodward, W. E. Doering, J. Am. Chem. Soc. 1945,
67, 860 – 874.
[2] P. Rabe, K. Kindler, Ber. Dtsch. Chem. Ges. 1918, 51, 466 – 467.
The original German text of the quotes taken from this paper are
as follows: a) Das N-Brom-chinicin, in analoger Weise wie der
Bromkörper au dem Cinchonicin bereitet, kommt aus Ather in
Farblosen Nadelin vom Schmp. 1238. Das aus ihm hervorgegan-
gene Chininon vom Schmp. 1088 war in allen seinen Eigen-
schaften identisch mit dem Chininon aus Chinin. b) 16.3 g
synthetisiertes Chininon gaben bei der Behandlung mit dem
genannten Reduktionsgemisch neben 0.9 g Chinidin das Chinin
in einer Aushcute von 2 g analysenreiner Substanz. Es schmolz
wie verlangt bei 177o und besaß in absolut-alkoholischer Lösung
das optische Drehugsvermögen [a]1D4 = À158.78 (c = 2.1432 bei
208C), während Rabe für das natürliche Alkaloid [a]D15
À158.28 (c = 2.1362 bei 15oC) gefunden hat.
=
[19] J. Gutzwiller, M. R. Uskokovic, J. Am. Chem. Soc. 1978, 100,
576 – 581.
[3] P. Rabe, Ber. Dtsch. Chem. Ges. 1911, 44, 2088 – 2091.
1740
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