In the Classroom
Percy Julian, Robert Robinson, and the Identity of Eserethole Addison Ault Department of Chemistry, Cornell College, Mount Vernon, IA 52314;
[email protected] One of the most interesting of the scientific episodes in the Nova production Percy Julian–Forgotten Genius (1) was the very public disagreement between Percy Julian and Robert Robinson as to the identity of “eserethole”, an intermediate in the synthesis of the alkaloid eserine, also known as physostigmine. H
Me
N
Me
O N O
N
Me
H
Me
l-physostigmine; l-eserine C15H21N3O2 mp 105–106 °C 17 [a]D 76p
This substance is the main alkaloid component of the fruit of the African vine Physostigma venenosum, the Calabar bean, also known as the esère bean. H Me
O N O
N
Me
H
Me
physostigmine, 1 NaOH
Me
Me EtO
HO N N
Me
N
Me
N
Me
EtOTos
N
H
Me eseroline, 2
H
Me eserethole; 3
Scheme I. Formation of eserethole from physostigmine. Me
Me HO
EtO N N Me eserethole; 3
H
Me
AlCl3 petroleum ether; boil
N
H Me
N
C
Me
N
O N
physostigmine; 1
N Me
Scheme II. Formation of physostigmine from eserethole.
H
The Disputants The parties to this dispute were Percy Julian and Robert Robinson. Percy Julian was an unknown American chemist who worked with only one assistant, Josef Pikl, at DePauw University, a small college in the American Midwest. Robert Robinson, on the other hand, was a well-known British chemist who employed a large research group as Waynflete Professor of Chemistry in the Dyson Perrins Laboratories at Oxford University, one of the most prestigious research universities in the world. Furthermore, it was Robinson who had first suggested the accepted structure for physostigmine (2). The Dispute As stated above, the dispute was over the identity of synthetic eserethole. Julian stated his position in this way.
O
O
1524
H
Me eseroline; 2
Me
Unanswered Questions For the organic chemist the Nova production leaves at least three questions unanswered: (i) How was it possible that a supposed “eserethole” could be misidentified? (ii) What was the actual identity of the “false eserethole”? and (iii) How did it happen that a “false eserethole” was formed? Physostigmine and Eserethole The relationship between physostigmine, the alkaloid, and eserethole, the molecule whose identity was in dispute, is as follows. Physostigmine, 1, can be hydrolyzed by base to eseroline, 2, and eseroline can be converted to eserethole, 3, by treatment with ethyl p-toluenesulfonate (Scheme I). Since eserethole, 3, can be reconverted to eseroline, 2, by the action of anhydrous aluminum chloride, and eseroline can be converted to physostigmine, 1, by treatment with methyl isocyanate, the synthesis of eserethole, 3, is a formal synthesis of physostigmine (Scheme II). In the latter scheme the synthesis of eserethole, 3, is an intermediate in the synthesis of physostigmine.
Me
N
Many naturally occurring alkaloids have pronounced physiological properties, with more familiar examples being caffeine, nicotine, strychnine, and curare. Physostigmine is also physiologically active, and a traditional use of the Calabar bean was in the administration of divine justice, wherein guilt or innocence was indicated by whether the accused died of respiratory failure caused by physostigmine or whether the accused was saved by the quicker action of an emetic that is present in the hull of the bean. More recently, physostigmine has been investigated for its ability to increase cognition, particularly in demented patients.
Me
In a series of ten beautiful papers Robinson and his co-workers have described syntheses of compounds which they call “d,l-eserethole” and “d,l-esermethole”. Their “d,l-eserethole” is not the compound (XII) described in this [ Julian’s] communication as d,l-eserethole, and the constitution of which can hardly be questioned. We believe that the English authors are in error, that the compound they describe as d,leserethole is not the substance, and that we are describing for the first time the real d,l-eserethole. (3)
Journal of Chemical Education • Vol. 85 No. 11 November 2008 • www.JCE.DivCHED.org • © Division of Chemical Education
In the Classroom
The First Question: How Could Synthetic Eserethole Be Misidentified?
regard the isomerism of dl-eserethole-a, m.p. 38 °C (synthesized by Julian and Pikl, loc. cit.), and our dl-eserethole-b, m.p. 80 °C, as another case of the same kind. (4)
The eserethole molecule, 3, contains two chiral stereocenters, indicated by asterisks, that are differently substituted.
Julian’s comparisons of his synthetic racemate with the authentic natural product also suffered from the same problem. The natural material was described as an “oil”, while Julian’s material was just barely a solid with a melting point of 38 °C, recrystallization having been effected by slow cooling of an ether/ petroleum ether solution in a mixture of solid carbon dioxide in acetone. The melting points of the natural, enantiomerically pure picrate salt (135 °C) and of Julian’s synthetic, racemic picrate salt (155 °C) were different as well.
Me
EtO
N
N
Me
H
Me eserethole; 3
A particular sample of eserethole could, therefore, be any one of the four possible pure enantiomers or either one of the two possible racemates. While the material that is obtained from physostigmine would most likely be a pure enantiomer, the synthetic materials prepared by both Julian and Robinson would be a racemate, an equimolar mixture of the members of one of the pairs of enantiomers. We would therefore expect that some of the properties of the synthetic samples would be different from those of the natural product. The most obvious difference would be in the optical rotation, finite for the enantiomerically pure natural product but zero for the synthetic racemate. Other properties, however, such as the melting point, could also be different. As Robinson said,
Me
EtO N
Me
picrate
HH
N Me
Preparation of the Two “Eseretholes” Julian’s Synthesis of Eserethole For the synthesis of eserethole (Scheme III) Julian started with the acetyl derivative of p-ethoxyaniline, 4 (phenacetin; acetophenetidine; an analgesic that is still in use), converting it to the conjugate base 5 by treatment with sodium metal in boiling xylene (3). Addition of dimethyl sulfate with continued boiling gave 6 by methyl transfer to nitrogen, and removal of the solvent gave a residue that was boiled with aqueous alcoholic sodium hydroxide to produce N-methylphenetidine, 7, in an overall yield of 96%.
In our opinion [our] base is structurally identical with eserethole, and it may be a stereoisomeride of this base. ... It is relevant to note that Linstead and Meade ( J., 1934, 935) have isolated cis-cis and cis-trans isomerides of fused dicyclooctanes (two five-membered rings), and we provisionally
Br
EtO
EtO
O N
C
O
sodium metal
Me
xylene
N
C
dimethyl sulfate
EtO
O
xylene
Me
Me
ethanol
Me Br C
AlCl3
O N
O
EtO
O
Me
C
H
N
H2 /Pd
Me
Me
H N
Ph
O
Me
Me N O H N
Me
sodium metal ethanol
2. hydrolysis
Me
EtO
N
Me
EtO N
OH H N Me
Me 15
1. methyl iodide
Me 14
Me 13
EtO
Ph
N
N
N
11
O
H
O H
12
Me
10
EtO O
N
sodium ethoxide
Me
Me
N
EtO
O
Cl CH2 C N
N
base
9
8
Me
EtO
diethyl sulfate
Me
Me
7
Me
HO
Me
Me
6
5
O
H
N
Me
4
N
Br
NaOH
C
N
H
EtO
EtO
16
H
N
Me
H
Me dl-eserethole; 3
Scheme III. Julian’s synthesis of eserethole. © Division of Chemical Education • www.JCE.DivCHED.org • Vol. 85 No. 11 November 2008 • Journal of Chemical Education
1525
In the Classroom
The N-methylphenetidine, 7, was then acylated with
Me
α-bromopropionyl bromide to give the acyl derivative 8. Treat-
ment of 8 with aluminum chloride effected ring closure and incidental loss of the ethyl group from the phenolic oxygen to form 9. An ethyl group was restored to the phenolic oxygen by the action of a basic solution of diethyl sulfate to give 10, which was then alkylated, via its conjugate base, 11, by chloroacetonitrile to form the nitrile 12. Catalytic hydrogenation of the nitrile, 12, gave the corresponding primary amine, 13, which was then converted by methylation via the benzylidene derivative, 14, to the secondary amine, 15. Intermediate conversion of the primary amine, 13, to a Schiff base, 14, with benzaldehyde, removed the possibility for “overalkylation” of 13 by the alkylating agent, methyl iodide. Hydrolysis of the immediate product of alkylation of 14 (not shown) produced 15. Reduction of the N-methyllactam, 15, by sodium metal and alcohol led, possibly by way of intermediate formation of 16, to racemic eserethole, or dl-eserethole, 3. This synthesis is summarized in Scheme III. The formation of dl-eserethole, 3, by reduction of 15 could be anticipated by seeing that the immediate product of reduction, 16, corresponds to a carbinol–amine intermediate for the addition of an amine to an aldehyde, 16a, and that continued cyclization to 3 could be expected. Me
Me
EtO
N
Me
EtO O
OH H
N
N
H
Me
Me
16
N
Me
EtO N N H dl-dinoreserethole; 18 C13H18N2O mp 35–39 °C Me
H H
N N
N
H
Me
H
H
Me dl-noreserethole; 17 C14H20N2O oil
dl-isonoreserethole; 22 C14H20N2O mp 71–72 °C Me
Me Me
EtO N N
N
EtO
Me
Me
H
H N
Me dl-eserethole; 3 C15H22N2O mp 38 °C Julian’s eserethole
Robinson’s “eserethole-b” Kobayashi’s “methyleserethol”; 19 C15H22N2O mp 80–81 °C
16a; aldehyde form of 16
Julian also prepared the substance known as dl-noresere thole, 17, by an analogous sodium and alcohol reduction of the primary amine 13.
Robinson’s Synthesis of Eserethole Robinson summarized his synthesis of “eserethole” (4) in a single sentence, On controlled methylation with methyl-p-toluenesulphonate we found that it [dl-noreserethole] yielded a crystalline dl-eserethol (IV), m.p. 79–80 °C( J., 1934, 1416), and we then surmised that this substance would prove to be identical with a base, m.p. 80–81 °C, obtained by Hoshino and Kobayashi (Proc. Imp. Acad. Japan, 1934, 10, 99).
Me
Me
EtO
N O H N
H
EtO
sodium metal
N
ethanol
Me
N
H
H
“controlled methylation”
“eserethole-b”
Me dl-noreserethole; 17
Me
EtO N N
H
H
Me dl-noreserethole; 17 C14H20N2O oil
The synthesis of dl-noreserethole, 17, was important because its identity was agreed upon by all interested parties, and dlnoreserethole was the material from which Robinson prepared his “eserethole-b”.
1526
N
H
Figure 1. Structures of several eseretholes.
The Synthesis of Noreserethole
Me EtO
EtO
H
Furthermore, eserethole itself can be seen as a nitrogen analog of an acetal of an aldehyde, and cyclic acetals are well-known to be stable relative to their open-chain analogs.
13
H
H
mp 79–80 pC The structures of several eseretholes are shown in Figure 1.
Enter the Japanese Chemists with the Answer to the Second Question: What Was the Actual Identity of the “False Eserethole”? Julian and Robinson were not alone in trying to synthesize eserethole. The Japanese chemists Hoshino and Kobayashi were also working on its preparation. Their approach was to start with dl-dinoreserethole, 18, and to transfer methyl groups to each of the two nitrogens with methyl iodide as the methyl donor (5, p 564).
Journal of Chemical Education • Vol. 85 No. 11 November 2008 • www.JCE.DivCHED.org • © Division of Chemical Education
In the Classroom
Me
EtO N N
H
H
methyl iodide
“methyleserethol”
sodium benzoate
H dl-dinoreserethole; 18
mp 80–81 pC
Although eserethole has a molecular formula C15H22N2O, the Japanese chemists believed that the analytical results for their product indicated the presence of 16 carbons and a molecular formula of C16H24N2O. It was for this reason that they named their product “methyl-dl-eserethol” (5, p 565). However, it was established that “methyleserethole” was the same as Robinson’s “eserethole-b” by direct comparison of the melting points: the melting points were the same and the mixture melting point showed no depression (4). The Identity of “Methyleserethol” At this time it was clear that Julian and Pikl had prepared the “real eserethole”. Robinson’s product was not the real thing, and, as Robinson pointed out, it was hard to imagine that methylation of either dl-dinoreserethole or dl-noreserethole could give a nonionic 16-carbon product. Me
Me
EtO
EtO N
N
N
H
N
H
H dl-dinoreserethole; 18 C13H18N2O
B
N
Me
H
Robinson’s “eserethole-b” Kobayashi’s “methyleserethol”; 19 C15H22N2O Kobayashi showed that dl-dinoreserethole, 18, could be conmp 80–81 °C verted to “methyleserethole”, 19, bywith three similar procedures, constitutionally isomeric eserethole
methods (a), (b), and (c).
(a), (b), or (c)
H “methyleserethol”; 19
Kobayashi also showed that, in contrast to the results of the application of method (a), (b), or (c) to dl-dinoreserethole, 18, analogous treatment of dl-noreserethol, 17, gave no “methyleserethole” but instead gave the eserethol-methin-base, 21, plus recovered starting material, or to 21 alone (6, pp 144–145). Me H
(a), (b), or (c)
H Me
Me dl-noreserethole; 17
Me
N
EtO N
EtO H N
“methyleserethol”; 19
H OH
eserethol-methin-base; 21 Kobayashi pointed out that this result is the opposite of that of the English researchers. “Die Resultate dieser Versuche unterscheiden sich völlig von Denen der englischen Forscher, die bei der Reaction von Nor-eseräthol mit p-Toluolsulfoester das Methyl-eseräthol erhalten haben” (6, p 145). Kobayashi continued by reporting that treatment of the benzoate of isonoreserethole (italics in the original) by method (c) gave a good yield of “methyleserethole” (6, p 144). Me (c)
Me
H
Me Me
N
EtO
Me N
Me
Me
H dl-isonoreserethole; 22
H Me
Me
N
N
H
N
EtO
20
Me
H dl-dinoreserethole; 17
Me Me
EtO
EtO
elimination
H Me
N
N
Me
H
N
N
N
N
Me N
N
EtO
That is, it was hard to imagine how, after both nitrogen atoms are present as tertiary amines, yet another proton can be replaced by a methyl group. Robinson never published again on this subject, but Kobayashi, in 1938, identified “methyleserethole” as a constitutional isomer of eserethole (6, p 144). Me
Me
EtO
H
H
Me dl-noreserethole; 17 C14H20N2O
EtO
where (a) is treating the free base with methyl iodide in either alcohol or ether; (b) is treating the amine benzoate with either methyl iodide or methyl-p-toluenesulfonate; and (c) is treating the amine benzoate with methyl iodide or methyl-p-toluenesulfonate in the presence of sodium benzoate or sodium acetate (7). A reasonable mechanism would be two successive “methylplus” transfers from the methyl donor to the more basic, aliphatic nitrogen to give 20, followed by elimination to form the double bond.
Me
H
Me
N
“methyleserethol”; 19 A further improvement made use of methyl iodide in ether to form the methiodide, 23, and then dilute base to convert 23, to “methyleserethol” (6, p 145).
© Division of Chemical Education • www.JCE.DivCHED.org • Vol. 85 No. 11 November 2008 • Journal of Chemical Education
1527
In the Classroom
Kobayashi’s Interpretation Kobayashi’s interpretation of these reactions was that dinoreserethole, 18, and isonoreserethole, 22, react analogously to form a methine-base, 24, but the methine-base then loses water to form “methyleserethole”, 19, a Schiff base (6, p 147).
Me
EtO
MeI
N N
ether
Me
H Me
H dl-isonoreserethole; 22
EtO N
Me I
Me
H Me
N
B
Me
N
EtO
H
dl-isonoreseretholemethiodide; 23
N dilute base cold
Me
N
H2O
H OH
H methine-base; 24
Me Me
N
EtO
Me EtO
Me
Me
H
Me
N “methyleserethol”; 19
H N “methyleserethol”; 19
Kobayashi’s Summary It had been determined earlier that both eserethole, 3, and noreserethole, 17, could be methylated by methyl iodide on the more basic, aliphatic nitrogen, to give a methiodide that would form eserethol-methin, 24, upon treatment with base. Me
Me
Me
EtO
EtO N N
N
Me N
H
Me eserethole; 3
Me
N
EtO N
N
H OH
eserethol-methin; 24
It now appears that the bases unsubstituted on the indoline nitrogen, dinoreserethole, 18, and isonoreserethole, 22, will give, “methyleserethole”, 19, upon methylation under neutral or slightly acidic conditions (6, p 147). Me
Me
EtO N N
N
H N
H
H
H isonoreserethole; 22
H dinoreserethole; 18
Me Me
N
EtO H N “methyleserethol”; 19
Me
“methyleserethol” and “eserethole-b” “III”; 19
The Third Question: How Did It Happen That a “False Eserethole” Was Formed?
Me
Me
EtO
Me
H
H
Me Me
N
EtO
H
Me noreserethole; 17
1528
Kobayashi’s Conclusion Kobayashi concludes that “methyleserethole” and “eserethole-b” are molecules without a methyl group on the indole nitrogen. “Auf Grund dieser Ergebnisse kommen wir zu dem Schluß, daß dem Methyl-eseräthol Formel III, die am Indolstickstoff keine Methylgruppe besitz, zukommt” (6, p 148).
Me
Kobayashi says, in the sentence following the one quoted just above, that “eserethole-b” is unlikely to have been formed from noreserethole, 17, in which the indoline nitrogen bears a methyl group, although the English researchers, as mentioned above, did observe its formation. “Deshalbe erscheint die Bildung dieser Base aus dem am Indolstickstoff methylierten Nor-eseräthol sehr unwahrscheinlich, obwohl, wie schon oben erwähnt, von den englischen Forschern in diesem Falle die Bildun der Base beobachtet wurde” (6, p 148). Could “Eserethole-b” Have Been Formed from the “Wrong” Starting Material? Could Robinson have used either dinoreserethole, 18, or isonoreserethole, 22, instead of noreserethole, 17, (see Figure 1) in his preparation of “eserethole-b”? This seems unlikely because, as Robinson says, The important intermediate dl-noreserethole ... is a rallying point, because the description of its derivatives shows that the same substance has been obtained both in the course of this series of investigations and by the Japanese and American chemists. (4)
Journal of Chemical Education • Vol. 85 No. 11 November 2008 • www.JCE.DivCHED.org • © Division of Chemical Education
In the Classroom
Could “Eserethole-b” Have Been Formed from dl-Noreserethole? Let us assume for the moment a mechanism such as this. First, a “methyl-plus” transfer from methyl p-toluenesulfonate to the more basic nitrogen of noreserethole, 17, to form the tertiary amine, which is dl-eserethole, 3, the desired product. Me
Me
EtO N
EtO
“ Meá ”
N
N
H N
H
Me
Me
H
Me dl-eserethole; 3
dl-noreserethole; 17
Since the experiment was done by combining equimolar quantities of noreserethole, 17, and methyl p-toluenesulfonate (7), there had to have been a period of time during which both product, eserethole, 3, and unreacted methyl p-toluenesulfonate were present. Thus, during this time, there was the possibility of methyl transfer to eserethole; that is, there was the possibility of “overalkylation” of eserethole to form 25. Me
Julian’s Final Proof At this point we will pause to admire the indisputable evidence presented by Percy Julian in support of his claim to have prepared the “real eserethole”. He first promises the proof: “Final proof that we have completed the synthesis of physostigmine will be forthcoming when resolution experiments now in progress are completed” (3, p 565). He then delivers the proof: “This is now proved conclusively by synthesis of l-eserethole, identical with the product of natural origin” (8, p 756). Synthesis of l-Eserethol, the “Real Eserethole” Percy Julian’s description cannot be improved upon: After some attempts to resolve d,l-eserethole into its optical antipodes with d-camphorsulfonic and d-tartaric acids, the only reagents at our disposal, had failed to yield satisfactory results, resolution of the amine (VI) was attempted.
Me
EtO N N
“ Meá ”
EtO N
Me
Me
Me 25
Me EtO
EtO N
Me
N
N
H Me
Me
Me
H Me
Me
26 Transfer of “methyl plus” from the indoline nitrogen of 26 to the more basic nitrogen of another molecule of eserethole would give “eserethole-b” and another ammonium ion 25.
Me
EtO N
N
Me
H Me
N
+
N
Me
Me
Me “VI”; 15
By successive action of d-camphorsulfonic and d-tartaric acid, this amine was resolved into its optical isomers in excellent yield. The d-amine-d-camphorsulfonate first separated and the mother liquors yielded with d-tartaric acid the l-amine-d-hydrogen tartrate. The free l-base (VI) recovered from the latter, yielded on reduction with sodium and alcohol l-eserethole in excellent quantity. No trace of racemization could be detected. Its picrate and tartrate were identical with those of eserethole of natural origin (8, p 756).
The Experimental Section The Amine (VI) The l-amine (VI) was recovered from the tartrate, yield 7.6 g, 83% of the theoretical based on original quantity of racemic amine employed. Determination of rotation gave the results:
H
Me eserethole; 3
26
Me
The experimental section is also well worth reading:
Me
EtO
N N
Me
N
EtO
O H
This ammonium ion, 25, could then isomerize by a unimolecular bond cleavage to form the carbocation 26,
Me
Me
H Me
N
H
dl-eserethole; 3
would be isomerization of the “real eserethole” to “eserethole-b” by way of formation of the ammonium ion 25 and its isomer the carbocation 26.
For l-amine: [α]D28 = ‒30.1 ± 0.5 °C (in alcohol) For d-amine: [α]D28 = +30.2 ± 0.5 °C (in alcohol)
Me Me
N
EtO H
Me
Me
+
EtO N
N
N
Me
H Me
Me
“eserethole-b”; 19
25
Isomerization of the ammonium ion 25 could then give another carbocation 26, and the cycle could continue. The overall effect
The picrates of both d- and l-amine melted at 175 °C and mixed melting point of equal quantities was 192 °C, the value recorded from the racemic amine picrate (8, p 757).
The Reduction of the l-Amine (VI) to l-Eserethole This reduction was carried out in exactly the same manner as described for d,l-eserethole. ... The picrate melted at 135 °C and showed with the picrate of eserethole of natural origin no depression.
© Division of Chemical Education • www.JCE.DivCHED.org • Vol. 85 No. 11 November 2008 • Journal of Chemical Education
1529
In the Classroom
Final Comments
The d-hydrogen tartrate of our synthetic eserethole melted at 168 °C and gave with the same salt from natural eserethole no depression of melting point. Determination of rotation of l-eserethole gave [α]D28= ‒81.6 ± 0.5 °C. d-Eserethole was likewise prepared in similar manner. Mixtures of equal quantities of the picrates of d- and l-eserethole melted at 155 °C, [the] value recorded for the racemic picrate” (8, p 757).
There Is One More Detail... At this point we know that Percy Julian prepared a sample of eserethole that was identical to the eserethole that could be derived from naturally occurring physostigmine. We know that this eserethole is one member of one pair of enantiomers, but we do not yet know which one. That is, we do not yet know the stereochemical configuration of l-eserethole. Configuration of l-Eserethole More recently the relative stereochemistry of the ring junction, which had always been assumed to be cis, was confirmed to be cis through the observation of a nuclear Overhauser effect between the methyl group and the proton at the ring junction (9). Finally, the absolute configuration was determined by degradation of l-eserethole to a substance of known configuration at the chiral stereocenter adjacent to the aromatic ring (9). We can now assign the following representation to l-eserethole. Me
EtO N
N
Me
H
Me l-eserethole
The Stereoisomeric Forms of Eserethole We mentioned earlier that eserethole, with two chiral stereocenters on carbon, can exist in four stereoisomeric forms; as two pairs of enantiomers. We represent here the four possible stereoisomeric forms. Me
Me OEt
EtO N N
Me
Me
N N
H
H
Me
Me OEt
N
1530
Me
H
Me
Note 1. A note about spelling: eserethol is spelled wthout a final “e” in quotes where the original spelling is used. “Methyleserethol” refers to Kobayashi’s material. This word is now known to be a misnomer, hence the quotation marks, but it is his word and we need to be consistent.
Literature Cited 1. Percy Julian—Forgotten Genius; NOVA 492. http://www.pbs.org/ wgbh/nova/julian/ (accessed Jun 2008). 2. Stedman, E.; Barger, G. J. Chem. Soc. 1925, 247–258. 3. Julian, P. L.; Pikl, J. J. Am. Chem. Soc. 1935, 57, 563–566. 4. King, F. E.; Robinson, R. J. Chem. Soc. 1935, 755–759. 5. Hoshino, T.; Kobayashi, T. Proc. Tokyo 1934, 10, 564–567. 6. Kobayashi, T. Ann.1938, 536, 143–163. 7. King, F. E.; Robinson, R.; Suginome, H. J. Chem. Soc. 1933, 1472–1475. 8. Julian, P. L.; Pikl, J. J. Am. Chem. Soc. 1935, 57, 755–757. 9. Robinson, B. The Alkaloids 1971, 13, 213–226 10. Coxworth, E. The Alkaloids 1965, 8, 27–45; Coxworth then refers us to ref 11. 11. Jackson, A. H. Ph.D. Thesis, Cambridge University, Cambridge UK, 1954. 12. Robinson, B. Heterocycles 2002, 57, 1327–1352.
Abstract and keywords
EtO Me
I thank Mary Iber, Cornell College, for her unrelenting efforts to obtain materials through interlibrary loan and for her discovery of ref 12; Kenji Nanba, Fukushima University, Japan, for sending me copies of key references; and David Lemal, Dartmouth College, for helpful correspondence.
http://www.jce.divched.org/Journal/Issues/2008/Nov/abs1524.html
the cis pair of enantiomers
N
Acknowledgments
Supporting JCE Online Material
Me d-eserethole
Me l-eserethole
Some time ago, in 1965, a review by Coxworth stated that “Several proposals have been advanced to account for the conversion of [dl-noreserethole, 17] into [eserethol-b; 19]” (10), making reference to work reported in the Ph.D. thesis of A. H. Jackson (11). More recently, in 2002, Brian Robinson (no relation to Robert Robinson), after reading the thesis of A. H. Jackson, reported that Jackson had been unsuccessful in his efforts to convert dl-eserethole to “methyleserethole” and wrote that its formation “on methylation of noreserethole thus still remains something of a mystery...” (12).
N N
H
Me
the trans pair of enantiomers
Full text (PDF) with links to cited URL JCE Featured Molecules for November 2008 (see p 1584 for details) Structures of some of the molecules discussed in this article are available in fully manipulable Jmol format in the JCE Digital Library at http://www.JCE.DivCHED.org/JCEWWW/Features/ MonthlyMolecules/2008/Nov/.
Journal of Chemical Education • Vol. 85 No. 11 November 2008 • www.JCE.DivCHED.org • © Division of Chemical Education
