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TERPENOID NMR STUDIES: NMR PARAMETERSFOR BICYCLO(3.1.1)HEPTANES AND REVISED
STRUCTURES FOR ARCHANGELIN AND PEREZONE
Item Type text; Dissertation-Reproduction (electronic)
Authors Thalacker, Victor Paul, 1941-
Publisher The University of Arizona.
Rights Copyright © is held by the author. Digital access to this materialis made possible by the University Libraries, University of Arizona.Further transmission, reproduction or presentation (such aspublic display or performance) of protected items is prohibitedexcept with permission of the author.
Download date 29/05/2021 14:18:58
Link to Item http://hdl.handle.net/10150/290208
This dissertation has been
microfilmed exactly as received
THALACKER, Victor Paul, 1941-TERPENOID NMR STUDIES: NMR PARAMETERS FOR BICYCLO[3.1.1]HEPTANES AND REVISED STRUCTURES FOR ARCHANGELIN AND PEREZONE.
University of Arizona, Ph.D., 1968 Chemistry, organic
University Microfilms, Inc., Ann Arbor, Michigan
TERPENOID NMR STUDIES: NMR PARAMETERS FOR
BICYCLo[3.1.1]HEPTANES AND REVISED STRUCTURES
FOR ARCHANGELIN AND PEREZONE
by
Victor Paul Thalacker
A Dissertation Submitted to the Faculty of the
DEPARTMENT OF CHEMISTRY
In Partial Fulfillment of the Requirements For the Degree of
DOCTOR OF PHILOSOPHY
In the Graduate College
THE UNIVERSITY OF ARIZONA
1 9 6 8
THE UNIVERSITY OF ARIZONA
GRADUATE COLLEGE
I hereby recommend that this dissertation prepared under my
direction by Victor Paul Thalacker
entitled Terpenoid MR Studies': NMR Parameters for 6107010"
[jS. 1. i] heptanes and Revised Structures for Archangelin and Perezone
be accepted as fulfilling the dissertation requirement of the
degree of Doctor of Philosophy
7C
Dissertation Director Date
After inspection of the dissertation, the following members
of the Final Examination Committee concur in its approval and
recommend its acceptance:*
2 2
Aut.. 1 . I W 7
7. JU7
l ? C 7
*This approval and acceptance is contingent on the candidate's adequate performance and defense of this dissertation at the final oral examination. The inclusion of this sheet bound into the library copy of the dissertation is evidence of satisfactory performance at the final examination.
STATEMENT BY AUTHOR
This dissertation has been submitted in partial fulfillment of requirements for an advanced degree at The University of Arizona and is deposited in the University Library to be made available to borrowers under rules of the Library.
Brief quotations from this dissertation are allowable without special permlssiont provided that accurate acknowledgment of source is made. Requests for permission for extended quotation from or reproduction of this manuscript in whole or in part may be granted by the head of the major department or the Dean of the Graduate College when in his judgment the proposed use of the material is in the interests of scholarship. In all other instances, however, permission must be obtained from the author.
SlGNEDt
ACKNOWLEDGMENTS
The author wishes 4to express his gratitude to Dr. Robert B.
Bates for his counsel and aid throughout the course of this research
and to Dr. S. K. Paknikar for his contributions to the synthesis prob
lem. Thanks are also given to Mr. H. S. Craig for writing the plotter
program.
Support for this research was provided by Public Health Service
Grant No. GM-11721.
iii
TABLE OF CONTENTS
} Page
LIST OF ILLUSTRATIONS vi
LIST OF TABLES viil
ABSTRACT ix
INTRODUCTION 1
Nuclear Magnetic Resonance Spectra of Terpenoids I
Archangel in 4
PsoraLens 6
Peiezone ........ 7
DISCUSSION 9
NMR Spectral Parameters in Bicyclo^3.1.llheptanes: Ot-Pinene, Myrtenal, and Verbenone •••••• 9
Chemical Shifts 10
Coupling Constants 12
Terpenoid NMR Spectral Compilation ..... 17
Archangelin 17
Psoralens 25
Perezone 27
EXPERIMENTAL 28
General Methods ..•• 28
NMR Spectral Parameters in Bicyclo^3.1.lJheptanes 28
Terpenoid NMR Spectral Compilation 29
iv
V
TABLE OF CONTENTS--Continued
Page
Synthesis of Archangelln ......... 29
2,6-Dimethyl-5-heptene-2-ol (XVII) 29
Ot-Cyclogeraniolene (XVIII) ••••«•••• 30
Acetylcyclogeranioiene (XX) , . . . 31
Regeneration of XX From Its Semicarbazone 32
^-Cyclolavandulic Acid (XXI) . . . . 32
Methyl 0-Cyclolavandulate •••••••«••• . .. . 33
^Cyclolavandulol (XV) 34
0-Cyclolavandulyl Acetate .. 34
P-Cyclolavandulyl Bromide . 35
Sodium Salt of Umbelliferone (XXIV) 35
{9-Cyclolavandulyl Umbelliferonyl Ether (XXV) 36
Acetic Acid Cleavage 37
Cleavage of Archangel in ••.••••••••••••• 37
Reduction of Psoralen Mixture 38
Reduction of Linalool-ff)f-Dimethylallyl Alcohol ••••»• 39
APPENDIX A . 40
APPENDIX B 45
APPENDIX Cl NMR AND IR SPECTRA 53
LIST OF REFERENCES 68
LIST OF ILLUSTRATIONS
Page Figure
I. Preparation of j£»cyclolavandulyl umbelliferonyl ether . . 21
2a. Verbenone (IX) experimental spectrum (100 Mc) 54
2b. Verbenone (IX) simulated spectrum (100 Mc) 54
3a. Myrtenal (X) experimental spectrum (100 Mc) 55
3b. Myrtenal (X) simulated spectrum (100 Mc) 55
4a. 01-Pinene (XI) experimental spectrum (100 Mc) 56
4b. 0(-Pinene (XI) simulated spectrum (100 Mc), system 1 (Insert) 56
4c. 01-Pinene (XI) simulated spectrum (100 Mc), system 2.. 56
5. Myrtenal (X) experimental and simulated spectra (60 Mc; upper negative, middle J^ positive) ..... 57
6. Commercial methylheptenone (XVI) 57
7. 2,6-Dimethyl-5-heptene-2-ol (XVII) . ••• 58
8. 0t+ -Cyclogeraniolene (XVIII + XIX) 58
9. Commercial methylheptenone (XVI} neat) 59
10. 2,6-Dimethyl-5-heptene-2-ol (XVII; neat) . .. 59
11. <X + -Cyclogeraniolene (XVIII + XIX; neat) 60
12. Acetylcyclogeraniolene (XX; neat) 60
13* Acetylcyclogeraniolene (XX) ...... . « . . 61
14. ^-Cyclolavandulic acid (XXI) . . . . . 61
15. ^-Cyclolavandulic acid (XXI; KBr) . . . . . 62
16. f-Cyclolavandulol (XV; CC14) 62
vi
vil
LIST OF ILLUSTRATIONS—Continued
Page Figure
17. ^Cyclolavandulol (XV) . . . 63
18. f?-Cyclolavandulyl bromide (XXIII) ............ 63
19. Natural archangelln (XXVI; 60 Mc) ••...••••... 64
20. Natural archangelln (XXVI; 100 Mc) ...... 64
21. ^-Cyclolavandulyl umbelliferonyl ether (XXV; 60 Mc) ... 65
22. ^-Cyclolavandulyl umbelliferonyl ether (XXV; 100 Mc) . . 65
23. Natural archangelln (XXVI; CCl^) .. ... 66
24. ^-Cyclolavandulyl umbelliferonyl ether (XXV; CCl^) ... 66
25. Compound B 67
26. Perezone (VIII) 67
LIST OF TABLES
Page
Table
1. NMR ABSORPTIONS REPORTED FOR ARCHANGELIN 6
2. CHEMICAL SHIFTS (T) AT 100 Mc 11
3. COUPLING CONSTANTS IN CPS 14
4A. RESULTS OF ITERATION ON VERBENONE (IX, 60 Mc) 40
5A. ERROR VECTORS AND PROBABLE ERRORS 42
6A. TABLE OF ORDERED LINES 43
7B. LIST OF TERPENOIDS Cj-C^ 45
8B. LIST OF TERPENOIDS C15»C19 47
9B. LIST OF TERPENOIDS C.0-C.n 50 20 40
10B. TERPENOIDS OVER C^ AND STEROIDS 51
vlii
ABSTRACT
NMR spectral parameters were derived, by computer analysis, for
three bicyclo^3.1.ljheptane derivatives. As expected, the coupling
constants vary little among the three compounds. A 4-bond coupling con
stant of +5.9 to +6.5 cps was observed between bridgehead protons, and
two 5-bond couplings of 1.8 cps were found in cf-pinene.
The structure of archangelin, a natural furocoumarin, was re
vised by NMR analysis and synthesis of the alkyl portion, y?-cyclolav-
andulol. A new ether, -cyclolavandulyl umbelliferonyl ether, was
synthesized and its NMR spectrum compared with that of archangelin.
This is the first reported occurrence of the -cyclolavandulyl carbon
skeleton in nature.
A furocoumarin recently isolated from Hercleum candicans was
shown to be a mixture of the known compounds, imperatorin and 8-geran-
oxypsoralen, by stereospecific Birch reduction and NMR analysis*
The structure of perezone, a natural terpenoid, was revised by
inspection of its NMR spectrum.
ix
INTRODUCTION
Nuclear Magnetic Resonance Spectra of Terpenoids
In addition to charge and mass, which all nuclei have, some iso
topes possess spin or angular momentum. Since a spinning charge gener
ates a magnetic field, there is associated with this angular momentum
a magnetic moment (fJI). Nuclei which possess spin when placed in a mag
netic field will precess about the direction of the field. An increase
in the field strength causes the nuclei to precess faster.
By applying a second, much weaker, magnetic field at right
angles to the first magnetic field and causing this second field to ro
tate at exactly the precession frequency, the nuclei can be caused to
align themselves with the strong magnetic.field. The frequency at which
the nuclei flip can be observed by a receiver coil.
Interactions of the electrons and nuclei in a molecule modify
.the magnetic environment in which various nuclei are found and this
leads to the observation of chemical shifts and spin coupling. The
chemical shift is a result of the induced orbital motion of the elec
trons when the molecule is placed in an external field and is propor
tional to the applied field, Hq. Ramsey'1 first developed a theory for
the chemical shift.
Nuclear spin-spin coupling, which causes the fine structure, is
independent of the external field and arises from magnetic fields within
2 the molecule itself. Ramsey and Purcell developed the first successful
theory to explain these interactions.
1
2
Resolution sufficient to distinguish chemical shifts of non-
equivalent nuclei in the same molecule is referred to as "high resolu
tion" nuclear magnetic resonance (NMR) spectra. By observing such
spectra in liquids, where the direct magnetic dipole Interaction is
averaged to zero by the rapid motion of the molecules, sufficient reso
lution may be obtained to observe the fine structure due to nuclear
spin-spin interaction.
The chemical shift and spin-spin coupling parameters can com
pletely describe high resolution NMR spectra, but in most cases these
are related in such a complex manner that a lengthy analysis must be
carried out in order to obtain these parameters from the spectrum.
3 Pople, Schneider, and Bernstein have described procedures for such
analyses for certain systems. During the past several years much effort
has been directed toward extracting information regarding spin-spin
coupling from the fine structure of high resolution NMR spectra, espec
ially with regard to coupling between protons.
Theoretical calculations explaining and predicting spin coupling
A 5 constants have been developed using molecular orbital ' and valence
6*8 bond methods. Karplus' calculations show especially good agreement
with regard to vicinal coupling constants in substituted ethanes and
ethylenes.
Nuclear spin coupling decreases rapidly through saturated bonds
and coupling through as many as four saturated bonds has been reported
9-13 14 in only a few cases. Barfield has calculated proton spin coupling
across four bonds in both saturated and unsaturated systems, but his
calculations are based on exchange integrals for unstrained and
3
unsubstituted hydrocarbons and extension to strained or substituted sys
tems is risky.
Complete spectral analysis is a laborious and sometimes impos
sible undertaking, especially when many spins are involved* Computers
have reduced the time and effort necessary to analyze spectra and have
extended the scope of analysis to 7-10 spins. A number of computer pro-
15-19 grams have been written which are helpful in determining chemical
shifts and coupling constants accurately using iterative techniques.
3 20*23 A number of books ' dealing with nuclear magnetic resonance
spectroscopy, which include theory, fundamentals of instrumentation, and
some applications to organic chemistry, have appeared. Other predomin-
24 25 ately theoretical treatments ' have also been published. A monograph
explaining and illustrating the basic knowledge necessary to obtain
structural information from an NMR spectrum has been written with refer-
26 ence mainly to steroid systems.
The chemistry of the terpenoids has been discussed in a number
27-29 30 31 of books. In addition, physical constants ' and infrared spec-
30 tra have been compiled for a large number of mono- and sesquiterpen
oids. The latter (31) contains literature references to sources,
structures, and IR, UV, and NMR spectra of sesquiterpenoids.
Nuclear magnetic resonance spectroscopy has been used to great
advantage in determining the structures of natural products. Correla
tions between structure and NMR spectra have been reported for the
32 33 34 lower terpenoids and for triterpenoids. *
Varian Associates and Sadtler Research have compiled NMR
spectra of a wide range of commercially available compounds. Of use to
4
natural product chemists would be a similar undertaking involving as
many terpenoids as possible. Part of the purpose of this work was to
collect and interpret the NMR spectra of as many terpenoids as could be
obtained commercially and from chemists working in this field.
Archangelin
Furocoumarins of the type I have been isolated from a number of
37-43 different plants. Thus, 5-methoxypsoralen (I, Xj»Ht X^OMe),
X 1
1
5-hydroxypsoralen {I, X^«Hf X^OH), and 5-geranoxypsoralen (I, X^*H,
39 *2™OC10H17^ have been isolated from bergamot oil { 5,8-dimethoxypsora-
len (I, Xj-Xj^QMe) from lime oil ; 5-geranoxypsoralen (1, Xj»H, X^a
OC10H17>' 8-geranoxypsoralen (1, XJ-OCJQH^, X2>H) and byakangelicin
(I, X^»OCH2^H^(CH^)2» X2»0Me) from lemon oil^; imperatorin (I, Xj-
OC^H^, X^-H) and isoimperatorin (I, Xj-H, X2»OC^H9t where is
37 38 y,Jf-dimethylallyl) from Imperatoria ostruthium. ' The nature of the
44 aromatic portion of these terpenoids is easily established, but the X
45 part is more difficult to elucidate. A study was made on the stereo
chemistry and synthesis of some of these terpenoids.
From the root of Angelica a r change Ilea JL., an Indian medicinal
46 plant, five crystalline compounds were isolated. Three of these were
furocourmarinsjangelicin, prangolarlne, and archan
gelin, C21H2204.
Archangel in, mp 132°, crystallized from methanol in thick rods
and was shown to have no methoxyl, methylenedioxy, or active hydrogens,
but to contain at least one group. Its furocoumarin nature was
shown by its behavior towards 57. aqueous and alcoholic alkali. The
ultraviolet 222<1o8C *.38), 251(log£ 4.19), and 310 m|i( loge 4.08)],
infrared ^5.8p(conjugated lactone), 8.9|i(ether), and 9.3|i(benzofuran)J,
and NMR ^doublets (J«2.5cps) at 2.38 and 2.75Tand doublets (J»10cps) at
1.85 and 3.7*|] further confirmed its furocoumarin structure.
Hydrogenolysis, pyrolysls, or acid hydrolysis yielded a known
phenol, isobergaptol (II), plus a volatile terpenoid compound having a
OH
II
-C^q unit. This suggested that archangelin was an isobergaptol ether
of a monoterpene alcohol.
The possibility of the fragment being geranyl or its stereo
isomer was ruled out from comparison of their NMR spectra. The mass
number of archangelin also excluded the possibility of the terpenoid
fragment as dehydro or tetrahydrogeranyl but rather suggested a cyclic
structure.
46 The authors suggested from the NMR data (Table 1) that the
structure of the side chain was III.
0 —
III
TABLE 1
NMR ABSORPTIONS REPORTED FOR ARCHANGELIN
Group Resonance (r) No. of Protons
gem-dimethyl 9.08(s) 6
olefinic methyl 8.32(B) 3
coumarin 1.85(d), 3.7(d) 2
furan 2.38(d), 2.75(d) 2
benzene 2.99(a) 1
olefinic 4.35(a) 1
methylenes 7.58-8.9(m) 7
s • singlet; d • doublet; tn • multiplets
Psoralens
Two other furocoumarins were recently Isolated from Heracleum
candlcan roots.The furocoumarin nature of the two compounds (A
and B) was indicated by three strong absorption maxima in their ultra*
violet spectra. Infrared measurements on both compounds showed the
7
absence of free hydroxy 1 groups and the presence of a 6-membered
i unsaturated lactone carbonyl. Acid catalyzed degradation of both A and
B resulted in only xanthotoxol (IV) and geraniol (V) OH
OH
V
Ozonolysis of both compounds gave levulinlc aldehyde and acetone, which
were identified as 2,4-dinitrophenylhydrazone derivatives. This sug
gested that they were 8-geranoxypsoralen (I, Xj»0-geranyl, X^-H) and
S-neroxypsoralen (I, Xj«0-nerylf X^H). Comparison with an authentic
sample showed that compound A was identical with the known 8-geranoxy
psoralen, but it remained to be established whether or not B was
8-neroxypsoralen.
Perezone
Isolated over thirty years ago from the roots of Perezia cuer-
47 navucana was a compound, ci5H20°3* c®He<* perezone* It was assigned
structure VI on the basis of some poorly understood reactions of itself
and its derivatives in warm concentrated sulfuric acid. Pyrolysls of
perezone gave two products identified as 4and -pipitzol. Romo et al.*®
recently reported the structures Vila and Vllb for o( and^-pipitzol,
I
8
VI
respectively. A mechanism involving a cyclobutane intermediate and two
alkyl shifts was proposed for the perezone-pipitzol conversion.
Vllb
It seemed that a much more straightforward mechanism (see arrows
in structure VIII) could be written for this unusual reaction if the
0
OJ
VIII
structure of perezone were VIII, Examination of molecular models shows
that there should be no serious nonbonded interactions or angle deforma
tions in the transition state for the concerted process, although a
stepwise mechanism cannot be ruled out*
DISCUSSION
NMR Spectral Parameters in Bicvclo^3. 1. ljheptanesi
QC-Pinene. Myrtenal, and Verbenone
Among the bicyclo^3.1.lj heptanes are members of the pinene fam
ily of naturally occurring terpenoids. In this thesis the Laocoon II
computer program^ was used to analyze completely the spectra of three
of these compounds, verbenone (IX), myrtenal (X), and o(-pinene (XI),
the latter of which is the most abundant natural cyclobutane.
H
CH CHO H
CH CH
CH CH
IX XI
The NMR spectra of related compounds containing cyclobutane
rings, including bicyclo^2al.ljhexanes,^'^ bicyclo^l.l.ljpentanes,^
and tricyclo^l.l.l.O^'^Jpentanes,have previously been analyzed.
Bicyclo|^2,2. lj heptanes, isomeric with the ^3. l.lj heptanes, have been
studied extensively.^ In some of these compounds, long range couplings
£ (through more than 3 bonds) have been observed. Some progress has been
14 made in developing the theory of long-range coupling, but a thorough
understanding awaits the measurement of more such couplings in compounds
of known molecular geometry such as the ones discussed in this thesis.
9
10
The experimental spectra (100 Mc) of IX, X, and XI as shown in
Appendix C, Figures 2at 3a, and 4a were analyzed by computer techniques.
A set of chemical shifts and coupling constants which fits the NMR spec
trum of each of these compounds has been found and is given in Tables
2 and 3. The spectra which result from the calculated parameters are
shown in Appendix C, Figures 2b, 3b, and 4b. The excellent agreement
between the experimental and calculated spectra is evident. These re
sults are discussed below. All the chemical shift values in this thesis
are given in T units.
T
Chemical Shifts
The simplest case, that of IX, will be considered first. In the
spectrum (Fig. 2a), methyl groups a and b appear as sharp singlets at
9.00 and 8.52, respectively. The assignment of the higher field reson
ance to a is based on its position above the IT cloud of the olefinic
double bond; the contribution from If electrons to shielding of groups
20 situated above the plane of the double bond is well known. The ole
finic methyl absorbs at 8.00 and the olefinic proton at 4.27. The
doublet centered at 7.94 (one line obscured by the olefinic methyl ab
sorption) is assigned to proton because of the relationship of this
proton to the olefinic double bond. The 6-line pattern at 7.22 is
due to H^, since, of the remaining three protons, only should be
split by three protons with couplings of 5.5 cps or larger. A decision
as to which of and gives rise to which of the "triplets" at 7.60
and 7.38 is difficult, and a tenuous assignment of the lower field peaks
to was made because it was thought that this proton wocld be
11
deshielded more by the carbonyl than would be by the carbon-carbon
double bond*
The assignments of chemical shifts (Table 2) for X (Pig. 3a) and
XI (Fig. 4a) are based primarily on the ones discussed above for IX.
TABLE 2
CHEMICAL SHIFTS (T) AT 100 Mc
IX X XI
CH3-a 9.00 9.26 9.16
CH3-b 8.52 8.67 8.74
CH3-C 8.00 8.35
H1 7.94 8.96 8.84
H2 7.38 7.80 7.92
H3 7.22* 7.51 7.66
H4 7.60 7.12 8.06
VH6 7.43 7.79,7.81
H7 4.27 3.29 4.88
CHO 0.48
The most striking difference is the large upfleld shift (1 T unit) ob
served for in going from IX to X and XI, This difference should re-
2 suit from the sp hybridization of the carbonyl carbon in the former
3 compound as compared to the sp hybridization of the corresponding
carbon in the other compounds, but it is not clear how much of the extra
shielding in X and XI is due simply to the presence of the H^-C bond,
how much to the difference in the field around the IT system, and how
much to a slight change in conformation which could put closer to the
ITsystem in X and XI, Whatever the reason for this difference is, the
methyl group (CH^-a) corresponding to undergoes parallel but smaller
shifts in going from IX to X and XI,
Part of the 6-line pattern due to is easily discernable in
the spectra of X and XI at 7,51 and 7,66, respectively. The "triplet"
pattern at 7.60 in IX due to should change little among the three
compounds, except for the chemical shift, and is observed at 7,12 in X
and 8,06 in XI, These large differences in the chemical shift of can
be rationalized in terms of the anisotropic magnetic fields around the
unsaturated systems. H^, unlike H^, should show greater multiplicity in
X and XI than in IX due to the introduction of and H^. clearly
absorbs at 7.80 in X and, since it should have about the same chemical
shift and splitting pattern in X and XI, apparently gives rise to the
partially obscured absorption centered at 7.92 in the spectrum of XI,
The remaining absorption centered at 7,43 in X and 7.80 in XI
must be due to and H^« In each compound and should have very
nearly the same chemical shift because of their very similar environ
ments, and this is observed to be the case.
Coupling Constants
Coupling constants (Table 3) were estimated for IX and then im
proved using a least squares refinement program (see Appendix A for
computer results). Using the values thus obtained as starting points,
the coupling constants for X and XI were determined by trial and error.
13
Hj appears in all cases as a doublet with a separation of 8*5 to
9,1 cps. This separation also occurs in the pattern and therefore
represents It is somewhat larger than the corresponding coupling
in bicyclo^2.1.ljhexanes.^' Using a plot of gem vs. H-C-H angle
for other systems,our finding of • 8.5 to 9.1 cps predicts a bond
angle of about 113°• This geminal coupling constant is assigned as
52 53 negative by analogy with related systems. '
The signs of the coupling constants given in Table 3 are based
13 on recent work which has related C-H couplings, which are believed to
be positive, to vicinal H-C-C-H couplings. Other experiments in-
57 58 volving high resolution analysis, double resonance, and double quan-
59 turn transition spectra have shown that the sign of the geminal
proton-proton NMR coupling constant is opposite from the sign of the
vicinal proton-proton coupling constant.
The very small coupling between and the remaining protons on
the four membered ring is no doubt due to the unfavorable dihedral
8 angle. The Karplus equation for vicinal cases gives poor agreement
when applied to small strained ring systems,and so it would be
dangerous to deduce dihedral angles in this case.
From the appearance of the absorptions for H^, H^, and in IX,
it is apparent that JJJ, 4* and ^34 are a11 About 6 cps. Starting
with each of these couplings as 6 cps and iterating gave the values
shown in Table 3 for IX. The signs of the vicinal couplings 3^$ atM*
are undoubtedly positive,but the sign of the large 4-bond
coupling, 24' rema*ned t0 found. Barfield^*^ summarized the
available data on 4-bond couplings and came to the conclusion that
1
14
TABLE 3
COUPLING CONSTANTS IN CPS
IX X XI
12
13
14
23
24
25
26
27
34
37
47
56
57
67
c5
c6
c7
0.32a 0.3 0.3
-9.08a -8.9 -8.5
0.04a
5.53a 5.9 5.7
6.50a,d 5.9C,d 5.9d
3.0 2.8
3.0 2.8
1.41a,d 1.4d 1.4d
5.904 5.7 5.7
o.ua
1.32a,d 1.4C»d 1.4d
b b
3aO 2.8
3.0 2.8
1.8d
1.8d
-1.5 -1.5
a. Results from least squares refinement using Laocoon II, part II.
b. Spectrum insensitive to this constant.
c. Sign verified by spin tickling.
d. Sign based on calculations by M. Barfield and J. Reed.67
large couplings of this type are positive. That is positive in the
present case was verified in two ways. First, by calculating and then
plotting the 60 Mc spectrum for X , changing only the sign o£ J^» a
noticeable change in the spectrum is observed (Fig. 5). This change in
the spectrum is observed only at 60 Mc, presumably due to the greater
peak distortion at this field strength. For positive, the calcu
lated spectrum shows the absorption as a broad band of peaks, virtu
ally identical with that found in the observed spectrum. When J^ is
negative, however, the absorption of becomes less well resolved. In
addition, the appearance of the two peaks at about 7.55, due to H^, fits
much better with positive. A second test of the sign of Jwas
58 accomplished by spin-tickling experiments. Irradiation at the low
field line of the triplet causes distortion of the low field side of
the absorption, indicating and to have the same sign.
Long range coupling has been reported by some to require a near
planar arrangement of the protons for detectable couplings, while a re
cent article^ has observed that planarity of the system may not be dom
inant in determining the size of coupling over four bonds. In this
series, the coupling through four saturated bonds (J24) large even
though models show that the system is not planar.
Our finding of 5.9 to 6.5 cps for the bridgehead-bridgehead
coupling constant (^24) *n these bicyclo^3.l.lj heptanes compares with
values of 18 cps for £l.l.lj^ and 1.5 cps for systems.
Surprisingly, a value for the ^2.1.lj system, probably the only other
bicyclic system which has a long-range bridgehead-bridgehead coupling
constant over 1.5 cps, has not been reported. The 2.1.1 constant is
16
probably between the ^l.l.lj and ^3.1.lj value, and should be much
closer to the latter value since the number of 4-bond paths seems to be
dominant in determining the magnitude of these couplings.
J i s s m a l l e r f o r X a n d X I b y 0 . 6 c p s w h i l e i n c r e a s e s b y
0.2 to 0.4 cps. The removal of the carbonyl from the ring system and
2 3 the resulting hybridization change from sp to sp is probably responsi-
ble for these coupling changes.
J2j and are observable 4-bond couplings ranging in magnitude
from 1.3 to 1*5 cps and were calculated^ to be positive. By spin tick
ling, and were shown to have the same sign as J^. In all three
2 compounds J^ and are through at least one sp hybridised carbon,
and the atoms are rigidly arranged in the "W" shape, which seems to pro
vide maximum coupling.^®
The values of 2.8 to 3.0 cps for the vicinal couplings
J^, and in X and XI conform with expectation for dihedral angles of
60°.8
The aldehydic proton of X is a sharp singlet at 0.48. This is
9 consistent with results reported by others for aldehydes in which the
carbonyl group is able to become coplanar with an CKv/?-double bond. The
olefinic methyl appears as a doublet (J * -1.5 cps) in IX and a 1x3s3s1
quartet (J " +1.5 cps) in XI. accounts for the splitting in IX, but
two additional couplings to the vinyl methyl in XI are required. These
additional couplings are almost undoubtedly 5-bond couplings with Hj and
This coupling is confirmed by the close agreement between the H^,
H^, and vinyl methyl absorbances in the observed (Fig. 4a) and
17
calculated spectra (Fig. 4c; for this comparison, the seven spin system,
vinyl methyl, H^, H^, H^, and was used).
Some of the coupling constants found above by calculations were
confirmed by decoupling experiments. Thus, decoupling of X gave the fol
lowing results: Irradiation at causes to become a triplet (J ™
5.8 cps), H2 to become 7 peaks with average distance 3.0 cps, and
a doublet (J - 5*8 cps). Irradiation at in XI collapses the vinyl
methyl absorption to a doublet (J * 1.5 cps).
69 Earlier investigators have assigned gem coupling constants on
3 sp carbon from -12.0 to -20.0 cps. Our results show that in the case
of X, J56 can be varied over a wide range (0 to -16 cps) with no appre
ciable effect on the calculated spectrum.
Terpenoid NMR Spectral Compilation
The NMR spectra of terpenoids which were obtained will not be
reproduced here nor will a detailed analysis of individual spectra be
attempted. Rather, the complete spectra, together with the assignments
and indexing done during this research, are to be published by Varian
Associates, Palo Alto, California. An alphabetical list of the com
pounds which will appear in the compilation is given in Appendix B,
Tables 7B-10B. It is hoped that these spectra will be of use, not only
to natural product chemists, but also to organic chemists in general,
because of the diverse number of structural types included.
Archangelin
46 Natural archangelin as obtained from Chatterjee was reinvesti
gated by NMR with careful integration. The NMR spectra (60 and 100 Mc,
Figs. 19 and 20; see Appendix C for NMR and IR spectra) show a 6 proton
singlet at 9.08, a 2 proton triplet (J • 6 cps) centered at 8.56, a
broadened singlet for 3 protons at 8.30, a broadened singlet for 2 pro
tons at 8.16, a broad multiplet for 2 protons at 7.75, a sharp singlet
for 2 protons at 5.01, doublets (J " 10 cps) at 3.65 and 1.92 (each 1
proton), doublets (J - 2.5 cps) at 2.94 and 2.32 (each 1 proton), and a
sharp singlet for 1 proton at 2.80. The absorptions in the region 2.2*
3.7 are in agreement with the isobergaptol (II) portion of archangelin
which was previously found.
Analysis of the 5-10T portion of this spectrum leads to a dif
ferent conclusion than that reported. The absorption at 5.01 Integrates
46 for 2 protons and is a singlet. The structure reported, III, for the
terpenoid side chain would demand at least a broad peak and more prob
ably a triplet for this absorption. The resonance at 7.75 is broad, but
a triplet and a separation of 6 cps is suggested by careful inspection.
The same separation is observed in the triplet at 8.56 and these two
facts suggest the partial structure -CH^CH^- . The absorption at 8.30
is in the well known region for methyl groups attached to double bonds.
The absorption at 8.16 is an isolated methylene while the sharp singlet
at 9.08 is a gem dimethyl group. Putting together these observations
leads to -the partial structures Xlla and Xllb which are both consistent
with the NMR spectrum of this natural compound.
A tentative choice between Xlla and Xllb was made on biogenetic
grounds. It is not possible to derive the carbon skeleton which these
structures contain by cyclization of geraniol without carbonium ion
19
0—
Xlla Xllb
rearrangements, but this skeleton can be put together from two y,y-
dimethylallyl units via lavandulol XIV as shown below.
XIII XIV XV
This biogenetic route clearly favors structure Xlla over Xllb for the
terpenoid side chain in archangelin, and we proceeded under the tenta
tive assumption that Xlla was correct. Although this carbon skeleton
has apparently not been found previously in nature, the alcohol XVt
termed ^-cyclolavandulol, had been prepared in the laboratory several
70-72 73 times, once by the acid-catalyzed cyclization of lavandulol.
In order to test this proposal, the synthesis of ^-cyclolavan*
dulol (XV) was undertaken. Since the methyl ether of isobergaptol was
20
commercially available in limited quantities, a complete synthesis of
archangelin could also be attempted, using a procedure analogous to that
used to prepare umbelliprenin, the farnesyl ether of umbelliferone.^
^-Cyclolavandulol (XV) was prepared according to Fig, 1. Methyl
heptenone (XVI) (Fritzsche Brothers) was reacted with methylmagnesium
iodide to give 2,6-dimethyl-5-hepten-2-ol (XVII). The alcohol showed NMR
(Fig, 7) singlets at 8,76(6 protons), 8,35(3 protons), 8,29(3 protons),
and 5.90(1 proton). A broad multiplet centered at 7.95(4 protons) and
a triplet at 4.80(1 proton) were all consistent for the expected struc
ture. The IR (Fig. 10) showed the free -OH at 2.9||,
Dehydrative cyclization of XVII was accomplished by heating with
oxalic acid. The optimum yield (57%) of a mixture of cyclogeraniolene
isomers (0L+XVIII and XIX) was obtained when the molar ratio of al
cohol to acid was 111. The remaining portion of the reaction was an
acyclic dehydration product, 2,6-dimethyl-2,5-heptadiene. The cyclo-
geraniolenes were separated from the acyclic product by spinning band
distillation. The NMR spectra of the geranlolene mixture (Fig. 8) shows
absorptions for the gem dimethyl at 9.03(9.00 for ft isomer), methylene
absorptions at 7.8-8.8, olefinic methyl at 8.32 and the olefinic proton
at 4.58(4.75 for isomer). The approximate ratio of Of to ft isomers is
3:2 based on the integration of the olefinic protons in the NMR. The IR
(Fig, 11) spectrum (identical with that reported) shows a weak OC
stretch at 6,0p and a strong bending mode at 12,45||, confirming the
cyclohexene nature of the hydrocarbon.
21
CH3MgI
XVI
• >
W H2C2O4
XVII
n!'
COCH.
V
Br2,NaOH
COOH
XXI
^ CH3C0C1
^ SnCl.
XX
2) LiAlH,
PBr
CH2Br
XXIII
CH2OH
XV
DMF
XVIII XIX
XXV
Na.EtOH
"*Na "0
XXII XXIV
Figure I. Preparation of |9-cyclolavandulyl wnbelllferonyl ether*
22
Ho attempt was made to separate the isomers because the OCisomer
should react preferentially in the succeeding reactions.
Acylation of the cyclogeraniolene mixture was accomplished under
Friedel-Crafts conditions* Treatment of XVIII with acetyl chloride in
the presence of stannic chloride yielded acetylcyclogeraniolene (XX), in
moderate yield (447.). The NMR (Fig. 13) shows a gem dimethyl singlet at
9.10, a methylene triplet at 8.60, a broadened singlet for the olefinic
methyl at 8.2, the keto-methyl singlet at 7,90, and a broadened methyl*
ene at 7.73. The remaining methylene is obscured by the other absorp
tions. The IR (Fig, 12) shows conjugated 00 stretch at 5.95^ and OC
stretch at 6.12|1. After recrystallization, the semicarbazone of XX,
71 prepared in the usual way, had mp 196-8° (lit. 201-3°).
p-Cyclolavandulic acid (XXI) was prepared from the ketone by us
ing the bromine modification of the iodoform reaction. Treatment of XX
with bromine in sodium hydroxide yielded XXI, mp 111.5-113° (lit#^
110-111°) in 38% yield as white needle-like crystals. The NMR (Fig. 14)
has a singlet for gem dimethyl at 9.05, a methylene triplet (J » 6 cps)
centered at 8.58, one allylic methylene at 8.00, the olefinic methyl at
7.85, a broad allylic methylene absorption at 7.58, and the acid proton
at -1.33. The olefinic methyl is shifted downfield by 0.5 ppm from that
usually observed., This is presumably because of its close proximity to
the carboxyl group. The IR (Fig. 15) shows the broad -OH at 3-3.6)1,
the 00 at 5.95p, C-C at 6.2)1, and C-0 at 7.8ft.
Reduction of the acid to the alcohol with lithium aluminum hy
dride was found to proceed in poor yield unless the methyl ether was
first prepared. Methyl p-cyclolavandulate (from the acid plus
23
diazomethane) was reduced with lithium aluminum hydride in ether to
^•cyclolavandulol (XV) in 94% yield. The alcohol, bp^ 105-106*, gave
an NMR spectrum (Fig* 17) showing gem dimethyl at 9.16, a triplet (J -
6 cps) at 8.72 for 2 protons, a broadened absorption at 8.35 with a
shoulder at 8*3 (total number of protons, 5), a broad multiplet at 7.98
for 2 protons, a -OH peak at 6.10 (shift changes on change in concentra
tion), and a 2 proton singlet at 6.05. The IR (Fig. 16), identical with
that reported, shows -OH stretch at 2.95)1, a very weak OC at 6.0|i, and
the C-0 at 8.25p.
Comparison of the NMR spectrum of /?-cyclolavandulol (XV) with
the portion of the NMR spectrum of archangelln above 5.Or (see Figs. 17
and 19) shows the very close similarity both in chemical shifts and gen
eral appearance. The methylene attached to oxygen is at 5.01 in arch
angel in and 6.05 in the alcohol. This difference would be expected
because of the deshielding effect of the aromatic system in archangelln.
The deshielding power of the aromatic ring decreases as the alkyl por
tion becomes farther removed so the other alkyl resonances are not as
deshielded. The broad multiplet at 7.75 in archangelln is reproduced
at 7.88 in the alcohol. The olefinic methyl at 8.30 in archangelin is
at 8.35 in ^-cyclolavandulol. The methylene absorption at 8.16 in arch
angelin corresponds to the shoulder seen in the alcohol at 8.3. The
triplet (J • 6 cps) at 8.56 in archangelin is found at 8.72 in the alco
hol. The gem dimethyl appears as a sharp singlet at 9.08 in archangelin
and 9.16 in the alcohol.
The aromatic portion of archangelin, isobergaptol (II), was
available commercially as its methyl ether. Methyl ethers have been
24
cleaved by a number of reagents, but because of the variety of function
al groups present in isobergapten (II, -OH - (Me), it was necessary to
use a mild, selective reagent. The cleavage of methyl ethers In steroid
74 systems was accomplished by Johnson et al. using pyridine hydrochlor
ide. The procedure failed, however, with isobergapten) the IR showed
that the product was not isobergaptol.
Because of the limited supply of isobergapten it was decided to
prepare an ether between cyclolavandulol and a more readily available
hydroxycoumarln and compare the NMR spectrum of the ether with that of
archangelin. ttnbelliferone (XXII) was available and its sodium salt was
prepared by treatment with sodium metal in ethanol. Reaction of the
sodium salt with cyclolavandulyl bromide (XXIII) (from the alcohol and
phosphorous tribromide) yielded a white crystalline solid of mp 92-4°.
The microanalysis was correct for C^H^O^ an<* comparison of its NMR
spectrum, at 100 Mc (Fig. 22), with that of archangelin (Fig, 20) re
veals the close similarity. The ether (XXV) shows a gem dimethyl at
9.06 (9.08 in archangelin), an olefinic methyl at 8.25 (8.30 in arch
angelin), a 2 proton triplet (J • 6 cps) at 8.60 (impurity at 8.68)
(8.56 in archangelin), a broadened singlet for 2 protons centered at
8.18 (8.16 in archangelin), a broad multiplet at 7.88 for 2 protons
(7.75 in archangelin), and a singlet for 2 protons at 5.45 (5.01 in
archangelin). The aromatic portion of XXV shows a pair of doublets
(J « 10 cps) at 3.75 and 2.35 (coumarin protons), a singlet at 3.18,
a doublet (J - 10 cps) at 3.13 (6ne peak partially obscured by the sing
let at 3.18), and a doublet (J «* 10 cps) centered at 2.65. The latter
25
absorptions correspond to the three aromatic protons. The IR (Fig. 24)
shows the Q(fp-unsaturated lactone carbonyl at 5.75y. This data all fits
the proposed structure XXV for the -cyclolavandulyl umbel1iferonyl
ether.
Acid catalyzed degradation of archangelin yielded a terpene ace-
tate in very small yield, but it corresponded to a known sample of
p-cyclolavandulyl acetate prepared from the alcohol. The known acetate
had an of 0.55 and the acetate from archangelin had an R^ of 0.56, on
thin layer chromatography with silica gel. The infrared spectra were
nearly identical.
Even though archangelin itself was not synthesized, the evidence
presented points to this furocoumarin as the^cyclolavandulyl ether of
isobergaptol (II + Xlla • XXVI), This being the case, it is the first
reported natural occurrence of this cyclic monoterpene skeleton*
XXVI
Psoralens
A method developed for investigating the side chain in mycelia-
45 amide was applied to help resolve the structure of compound B (see In
troduction, page 6). Birch reduction of compound B and VPC analysis of
26
the product showed peaks attributed to 2-methyl-2-butene (XXVII) and
trans-2.6-dlmethvl-2.6-octadiene (XXVIII; methylgeraniolene). Birch
XXVII XXVIII XXIX
reduction of a linalool-¥,)f-dimethylallyl alcohol mixture, under the
same conditions as those used with the unknown, gave peaks with reten
tion times identical with known XXVII (2 minutes), cis-2,6-dimethyl-2.6-
octadiene (methylnerolene, XXIX, 38 minutes), and XXVIII (40 minutes).
It is noteworthy that no XXIX was observed in the reaction product
from B.
The presence of both and C^Q side chain fragments in the
psoralen mixture and their relative amounts was confirmed by analysis
of the NMk spectrum. The spectrum (Fig. 25) shows a doublet at 4.82 due
to -OCHjOC- which occurs in both and C^Q compounds while the absorp
tion at 7.91 comes from -OCCH^Cl^OC-, which occurs only in the
compound. The integrated intensities show a 2 to 1 ratio in favor of
the -OCH^OC- protons. Thus the mixture must consist of 3 times as much
imperatorin (I, X^ • OC^Hg, X^ • H) as 8-geranoxypsoralen (I, X^ -
OC10H17- *2 ' H)-
27
Perezone
A high resolution NMR spectrum of perezone (Fig, 26) clearly
shows coupling (J « + 1.7 cps) between the quinone methyl (doublet at
7.90) and quinone hydrogen (quartet at 3,38). Previous NMR studies of
75 76 quinones have shown ' that a coupling constant of this magnitude is
observed only when a methyl and proton are attached to the same quinone
double bond, thus excluding structure VI for perezone, which must be
VIII. This structure fits much better the pyrolysis to pipitzols, which
can proceed in a concerted fashion as envisioned previously (see Intro
duction, page 8). The validity of structure VIII for perezone has been
confirmed by others on the basis of further degradative and synthetic
77 work.
EXPERIMENTAL
General Methods
The experimental NMR spectra were run on 10% solutions in DCCl^
with Varian A-60 and HA-100 instruments using tetramethylsilane (TMS) as
an internal standard. Chemical shifts are reported in T units*
IR spectra were obtained with a Perkin-Elmer Model 137 spectrom
eter, either neat, on carbon tetrachloride solutions, or with KBr discs.
Melting points were taken using a Thomas-Kofler micro hot stage
instrument, model 6886-A, and are uncorrected.
VPC analyses were obtained with F and M instruments, models 609
and 770, The columns were constructed as follows and will be referred
to by code number: VPT-002, 0.25" o.d. x 5', packed with 20% Carbowax
20M on 30/60 mesh firebrick} VPT-004, 0.5" o.d. x 8*, packed with 20%
Carbowax 20M on 60/80 mesh acid washed Chromosorb W.
Spinning band distillations were carried out with a Nester-
Faust, 6ram x 18", vacuum jacketed column.
NMR Spectral Parameters in Blcvclo|^3.1 *lj heptanes
The theoretical spectra were calculated using the Laocoon II
program of Castellano and Bothner-By, modified for use on an IBM 7072
computer equipped with an XY plotter. The calculated parameters for
compound IX were obtained by least squares refinement using part II of
Laocoon II. The results of the iteration are listed in Appendix A,
Tables 4A, 5Ay and 6A. Table 4A gives the input parameters, the
28
29
parameter sets which were varied independently (the computer could
handle only 10 sets at a time so various combinations of 10 were used to
cover all 15 of the parameters; the set given in this table is a repre
sentative one), the root mean square error after each iteration, and the
best values obtained for each of the parameters* Table 5A gives the
error vectors and the probable errors (see Castellano and Bothner-By^
for a full explanation of how these are calculated and their meaning).
Table 6A tabulates the observed spectral lines, the calculated lines,
and the error in fitting,
oc-Pinene (XI) was used as obtained from the Aldrich Chemical
Co., myrtenal (X) was obtained from the Glidden Co., and verbenone (IX)
78 was prepared according to the procedure of Dupont et al.
Terpenoid NMR Spectral Compilation
The experimental spectra were determined as 10% solutions in
DCC13, primarily with a Varian A-60 spectrophotometer. Those compounds
which'were not available in sufficient quantity for an A-60 spectrum
were run on a Varian HA-100 instrument as solutions of less than 10X
concentration. Dimethyl sulfoxide-dg was used as solvent for those com
pounds insoluble in DCCl^. The spectra were run at room temperature
with sweep times of 250 sec. (60 Mc) and 500 sec. (100 Mc).
Synthesis of Archangelin
2.6-Dimethvl-5-heptene-2-ol (XVII)
79 The procedure of Callen, Dorafeld, and Coleman was followed
for the preparation of methylmagneslum iodide. Into a 1 liter round-
bottom flask fitted with a nitrogen inlet, stirrer, water condenser, and
30
dropping funnel, magnesium turnings (36 g., 1.5 mole) were added and
covered with 100 ml. anhydrous ether. While stirring the mixture,
methyl iodide (198.8 g., 1.4 mole) in 100 ml. anhydrous ether was added
dropwise (addition time 2 hours). Anhydrous ether (400 ml.) was added, .
in 100 ml. portions, to the reaction flask during the 2-hour addition
period. *
Methylheptenone (XVI; Fritzsche Brothers; 63 g«, 0.5 mole) in
100 ml. ether was added dropwise to the Grignard reagent over a 2-hour .
period so that the ether was continually refluxing. After the addition
was complete, the mixture was heated at reflux over a steam bath for 1
hour. Hydrolysis of the reaction was accomplished by pouring it slowly
into 2 liters of ice water. The hydrolyzed mixture was transferred to a
separatory funnel and allowed to stand. The water (the bottom layer)
was periodically withdrawn and then the white foamy ether layer was dis
tilled at atmospheric pressure to remove the ether and finally, with re
duced pressure (30 mm), the desired alcohol was steam distilled. The
water drawn off in the separatory funnel was used to replenish the water
supply during steam distillation. The alcohol separated from the water
in the receiving flask and was easily collected. Distillation gave 50
g. (711)of alcohol, bp8 71-3°.80 Infrared (Fig. 10) and NMR (Fig. 7)
spectra were consistent with the desired product (XVII).
Ot-Cyclogeranlolene (XVIII)8*
2,6-Dimethyl-5-heptene-2-ol (XVII; 10 g., 0.07 mole) and oxalic
acid (6.5 g., 0.07 mole) were introduced into a 100 ml« round-bottom
flask equipped with a nitrogen inlet and water condenser. The mixture
was heated at 130-140° for 5 hours, cooled, and extracted three times
with ether (100 ml.). The combined extracts were distilled first at
atmospheric pressure to remove the solvent and then under reduced pres
sure (37 nni) with a spinning band column* Using a reflux ratio of 30tl,
three fractions were collected! Fraction 1 (5.0 g., bp 51-3*), fraction
2 (1.0 g., bp 54-8°), and fraction 3 (1.0 g".', bp 58-62#). VPC (130#,
column VPT-004), NMR, and IR analysis showed that fraction 1 was cyclo-
geraniolene (mixture of isomers), fraction 2 contained cyclogeraniolene
and 2,6-dimethyl-2,5-heptadiene (1:1), and fraction 3 consisted of
cyclogeraniolene and 2,6-dimethyl-2,5-heptadiene (1:6).
The cyclogeraniolene isomers were identified as XVIII and XIX
by NMR analysis (Fig. 8) and comparison of IR spectra with those re-
81 ported. No attempt was made to separate the isomers. The yield of
cyclogeraniolenes was 57%.
Acetylcyclogeraniolene (XX) *
Into a 50 ml. round-bottom flask, equipped with a nitrogen in
let, dropping funnel, water condenser, and magnetic stirrer, acetyl
chloride (3.9 g., 0.05 mole) and stannic chloride (0.3 g., 0.001 mole)
were introduced. After cooling to 0°, 5.0 g. (0.04 mole) of the cyclo
geraniolene mixture described above was added slowly. The solution
darkened during the addition. Stirring was continued for 1 hour at 0°.
Workup of the reaction was accomplished by pouring it into 50 ml. of 10%
hydrochloric acid and extracting three times with ether. The combined
extracts were evaporated and the organic residue treated with saturated
sodium bicarbonate and extracted with ether. The ether layer was then
washed with water, dried over sodium sulfate, and evaporated. Distilla
tion of the oil through the spinning band column gave a fraction (2.8 g.
44%) bpj 53°) which was acetylcyclogeraniolene. NMR (Fig. 13) and 1R
(Fig. 12) spectra were consistent with the expected structure. The
semicarbazone, prepared in the usual way and crystallized once from
methanol-water and once from methanol-benzene, had mp 196-8° (lit.^
201-3°).
82 Regeneration of XX From Its Semicarbazone
The semicarbazone (571 mg., 2.56 mnole) was dissolved in 100 ml.
of acetone containing 3 ml. of concentrated hydrochloric acid and re-
fluxed for 1 hour. The yellow solution was cooled and treated with
stannous chloride (2.5 g», 0.013 mole) dissolved in 10 ml. of concen
trated hydrochloric acid. Water (15 ml.) was added and the mixture re-
fluxed in a nitrogen atmosphere for 1 hour. The acetone was stripped
off with a rotary evaporator at room temperature, the residue extracted
three times with 20 ml. of benzene, and the organic layer washed with
IN hydrochloric acid until it was clear. The benzene solution was
washed with a saturated sodium bicarbonate solution and water and was
then evaporated with a rotary evaporator. The crude material was dis
solved in ether, dried over sodium sulfate, and the ether evaporated to
give 207 mg. (521) of the ketone (XX).
|f?-Cyclolavandulic Acid (XXI
In a round-bottom flask equipped with dropping funnel, cone-
driven stirrer, and water condenser was placed a solution of sodium
hydroxide (7.0 g., 0.18 mole) in water (25 ml.). After cooling to 0°,
bromine (3 ml., 0,06 mole) was added. Acetylcyclogeraniolene (XX; 1.7
g., 0.01 mole) in dioxane (16 ml.) was added dropwise. The ice bath was
removed and stirring continued for 4 more hours. The reaction mixture
was then heated at 60° for % hour, cooled, and the excess sodium hypo-
bromite decomposed with saturated sodium bicarbonate. After acidifica
tion with IN hydrochloric acid and extraction three times with ether,
the combined extracts were shaken three times with 0.1N sodium hydrox
ide. The alkaline solution was then acidified and extracted with ether.
Evaporation of the ether solution gave f?-cyclolavandulic acid (XXI),
which, after one recrystallization from methanol-water, yielded 1 g.
(58%) of white needle-like crystals, mp 111.5-113° (lit.^ 110-111°).
Methyl ft-Cyclolavandulate
83 Following the Organic Synthesis procedure, to 50 ml. of ether
in a 250 ml. Erlenmeyer flask, 15 ml. of 40% potassium hydroxide was
added. While magnetically stirring the solution, it was cooled in an
ice bath and 2.5 g. of nitrosomethylurea was added in small portions.
The ether layer became yellow indicating the presence of diazomethane.
The ethereal solution of diazomethane was added in small quanti
ties to -cyclolavandulic acid (XXI{ 500 mg., 2.8 mmole) dissolved in
25 ml* of ether. When the yellow color persisted for several minutes
the addition was stopped. The excess diazomethane was decomposed with
acetic acid, the ether layer was washed with a saturated sodium bicar
bonate solution and water, and was dried over sodium sulfate and then
evapbrated to give 490 mg. (97%) of sweet smelling oil identified as the
ester from its IR and NMR spectra.
34
fl-Cvclolavandulol (XV)
Anhydrous ether (20 ml.) and lithium aluminum hydride (140 mg.,
3,7 mmole) were added to a 100 ml. flask fitted with a paddle stirrer,
condenser, and dropping funnel. The ester described above (490 mg.t 2.7
mmole), dissolved in ether (20 ml.), was added dropwise over a % hour
period. Stirring was continued for 2 hours, then 2 ml. water, 2 ml. of
15% sodium hydroxide, and 10 ml. of water were added in that order. The
ether was decanted, the precipitate washed twice with fresh ether, and
the combined extracts dried over sodium sulfate. Careful evaporation of
the ether yielded the alcohol (XV; 390 mg«, 94%), identified by IR and
NMR.
5-Cyclolavandulyl Acetate^
Into a 50 ml. round-bottom flask equipped with a dry-ice conden
ser, nitrogen inlet, dropping funnel, and magnetic stirrer, ^-cyclo-
lavandulol (XV; 154 mg., 1.0 mmole) and pyridine (110 mg., 1.4 mmole)
in 10 ml. of ether were introduced. While cooling with a dry-ice ace
tone bath, acetyl chloride (118 mg., 1.5 naaole) in 10 ml. of ether was
added dropwise (addition time hour). After the addition was complete,
the dry-ice bath was removed and the reaction mixture allowed to come to
room temperature. Stirring was continued for 4 hours, after which 10 ml.
of water was added and all of the solid matter dissolved. The ether and
water layers were separated and the latter washed once with 10 ml. of
ether. The combined extracts were washed twice with 10% sulfuric acid,
twice with saturated sodium bicarbonate, dried over sodium sulfate, and
evaporated to give 140 rag. (71%) of acetate* The IR of the acetate was
72 identical with that reported.
0-Cyclolavandulvl Bromide
Following the general procedure of Schauble,^ a 50 ml. round-
bottom flask fitted with a dropping funnel, nitrogen inlet, magnetic
stirrer, and dry-ice condenser was placed in a dry-ice acetone bath.
Cyclolavandulol (XV; 154 mg.v 1 mnole) in 5 ml. ether was added to the
flask. Phosphorous tribromide (2.71 g., 10 mmole, 1 ml.) in 10 ml. of
ether was added dropwise over a ^ hour period. After the addition was
complete, the dry-ice bath was removed and the reaction flask stirred
at room temperature for 5 hours. The reaction was diluted with ether
and the excess phosphorous tribromide and phosphoric acid decomposed
by slowly adding 50 ml. of 2% potassium hydroxide. The ether layer was
separated, washed twice with 50 ml. portions of water, and dried over
sodium sulfate. Evaporation under nitrogen gave 168.mg. (781) of the
bromide (identified by the loss of -OH absorption in the IR).
Sodium Salt of Umbelllferone (XXIV)^
Crude umbelliferone (XXII; K and K Laboratories, Inc., mp 210°,
lit.^ 225-8°) was purified by sublimation at 190° (1 mm). The light
yellow product recovered after a single sublimation melted at 225-233*.
Sodium metal (49 mg., 2.1 tnmole) was dissolved in 10 ml. of
anhydrous ethanol in a 50 ml. round-bottom flask fitted with a water
condenser. Purified umbelliferone (XXII; 162 mg., 1.0 mnole) was added
to the reaction flask and the mixture refluxed until all of the
36
umbelliferone dissolved (less than 1 hour). Ether (20 ml,) was added
and a yellow precipitate immediately formed. The precipitate was col
lected by suction filtration through a fritted glass funnel using a
rubber dam to prevent undue exposure to the air. The sodium salt (XXIV}
150 Dig., 82%) was yellow and when dissolved in deuterium oxide gave an
45 NMR spectrum identical with that reported.
A second preparation of the sodium salt (XXIV) was made and im
mediately dissolved in 10 ml. of DMF for use in the following reaction
(a bluish-yellow solution was observed when the salt was dissolved in
DMF).
ft-Cvclolavandulyl Umbelliferonyl Ether (XXV)
^-Cyclolavandulyl bromide (XXIII; 100 nig., 0.45 mmole) in 10 ml.
of DMF was introduced into a 50 ml. round-bottom flask fitted with a
dropping funnel, water condenser and nitrogen inlet, and the solution
cooled to -78®. The sodium salt (XXIV) in DMF was added and the solu
tion allowed to warm to room temperature. While still under the nitro
gen atmosphere, the mixture was refluxed at 90° for 12 hours. After
cooling, ether was added, followed by ice cold 2% potassium hydroxide,
and the ether layer immediately collected. The aqueous layer was washed
four times with fresh ether and the combined extracts washed once with
ice cold 7X potassium hydroxide. The ether was dried over anhydrous
sodium sulfate and evaporated under nitrogen and then vacuum to give 69
eng. (51%) of an oily residue. Recrystallization from methanol-bensene
was unsuccessful. Sublimation of the oily residue at 100* (0.4 mu)
yielded 40 mg. of white crystals, mp 92-4°•
37
Anal. Calcd. for C19H22°3I C» 76,48f H» 7*43» Found! C,
76.88; H( 7.64.
The NMR (Fig. 21) and 1R (Fig. 24) spectra revealed that the de
sired ether (XXV) was formed.
84 Acetic Acid Cleavage " -
The ether (XXV) described above (40 mg«, 0.13 nmole) was heated
with glacial acetic acid (1 ml.) at 115° for l*j hours. After standing
overnight, the mixture was diluted with water, extracted three times
with hexane, and the extracts washed with saturated sodium bicarbonate
and water. The hexane was dried and evaporated to give a product (trace
amount) which had an R^ value (0.56) identical with a known sample of
cyclolavandulyl acetate. |jhin layer chromatography was carried out on
silica gel plates (0.25 mm), the elutant was 60% light petroleum ether-
407. chloroform (v/v), and the developer was 1% potassium permanganate .J
The phenol (umbelliferone, XXII) was recovered by acidification of the
aqueous layer, extraction with ether, and evaporation. The product (5
mg.) had mp 215°.
Cleavage of Archangelin
Archangelin (25 mg., 0.07 nmole) and glacial acetic acid (1 ml.)
were heated in a 10 ml. pear-shaped flask fitted with a water condenser
and calcium chloride drying tube for 6 hours at 110°. The solution was
then allowed to cool and stand overnight. After diluting with water (5
ml.), the solution was extracted three times with hexane. The combined
extracts were washed with a sodium bicarbonate solution and water and
then dried over sodium sulfate. Slow evaporation of the solvent yielded
38
6.7 mg. (46Z) of a residue whose IR spectrum resembled that of authentic
cyclolavandulyl acetate and whose R^ value (0.55) on TLC (same condi
tions as previously) was nearly the same as the authentic acetate.
The aqueous solutions were combined and extracted with ether.
The ether was dried and evaporated to give 5 mg. of recovered archange
lin, mp 115°. The resulting aqueous solution was acidified, extracted
twice with ether, the ether dried over sodium sulfate, and evaporated to
give a residue (5.2 mg.) whose IR was not identifical with that pub-
85 lished for the desired phenol (isobergaptol, 11), but was different
from that of archangelin.
On the assumption that this was isobergaptol, a regeneration of
archangelin was attempted. The bromide (XXIII) was prepared from
0-cyclolavandulol (XV) as described above and the sodium salt of the
residue (5.2 mg.) was likewise prepared as previously described. These
were combined under the conditions used for preparing ^-cyclolavandulyl
umbelliferonyl ether and worked up in the same way. An oily residue
(6 mg.) was obtained which failed to crystallize before or after evapor
ative distillation. The IR spectrum of the oil did not closely resemble
that of archangelin.
Reduction of Psoralen Mixture
86 After the procedure of Greenlee and Wiley, ammonia (75 ml.,
3.5 mole) was condensed in a 500 ml. round-bottom flask equipped with a
dry-ice condenser, cone-driven stirrer, dropping funnel, and nitrogen
atmosphere. Sodium metal (3 g., 0.13 mole) was added in small pieces,
producing a blue solution. To the sodium-ammonia solution, with
vigorous stirring, 500 mg. of the psoralen mixture (compound B), in 20
ml. methanol (large excess of methanol due to the low solubility of the
mixture) was added dropwise over hour. The blue color of sodium-
anmonia disappeared during the addition so more sodium was added in
small pieces to maintain the blue color. Stirring was continued for 1
hour, then heptane (25 ml.), granulated ammonium chloride (10 g.)v and
water (50 ml.) were added to the refluxing reaction mixture. The hep
tane layer was collected. The aqueous layer was washed three times with
25 ml. portions of heptane and the combined extracts were washed with
water until the washings were neutral. The heptane was dried over an
hydrous magnesium sulfate and subjected to VPC analysis.
Using column VPT-002 on an F and M 609 flame ionization chroma-
tograph at 80°, the heptane extract showed peaks attributed to 2-methyl-
2-butene (XXVII) and trans-2.6-dimethyl-2.6-octadiene (XXVIII) by
comparing retention times with known standards. The former had a re
tention time of 2 minutes while the latter had a 40-minute retention
time under the same conditions.
Reduction of Llnalool-y.y-Dimethvlallyl Alcohol
Linalool (36 mg., 0.23 mmole) and ]T,^-dimethylallyl alcohol (72
mg.f 0.84 mmole) in 5 ml. methanol were added dropwise to a solution of
sodium (46 mg., 2 nmole) in 25 ml. liquid anmonia according to the above
procedure. After stirring for 1 hour at -78°, a red color appeared at
the top of the solution. Workup as described above and VPC analysis
under Identical conditions gave peaks for XXVII (retention time 2 min
utes), cls-2.6-dlmethyl-2.6-octadiene (XXIX, retention time 38 minutes),
and XXVIII (retention time 40 minutes).
APPENDIX A
TABLE 4A
RESULTS OF ITERATION ON VERBENONE (IX, 60 Mc).
NN » 5 Preq. Range 0.00 500.0 Min. Intensity 0.050
Input Parameters
W(I) - 124.5 A(l,2) - 0.0 A( 2,4) - 5.9
W(2) - 159.0 A(l,3) - -8.7 A(2,5) - 1.5
W(3) - 169.0 A(l,4) - 0.0 A(3,4) - 5.9
W(4) - 145.5 A(l,5) - 0.0 A(3#5) - 0.0
W(5) - 347.0 A(2,3) - 5.9 A(4,5) " i'5
Parameter Sets
1 A(l,2) 5 A(2,3) 8 A(3f4)
2 A(Ir3) 6 A(2,4) 9 A(3,5)
3 A(I,4) 7 A(2,5) 10 A(4,5)
4 A(I,5)
Iteration 0 RMS Error m 1.861
Iteration 1 RMS Error - 0.584
Iteration 2 RMS Error - 0.278
Iteration 3 RMS Error - 0.273
Iteration 4 RMS Error • 0.273
40
TABLE 4A—Continued
W(l) - 124.500
W(2) - 159.000
W(3) - 169.000
W<4) - 145.500
W(5) - 347.000
Best Values
A(l,2) - 0.484
A(l,3) - -9.281
A(l,4) - 0.024
A(l,5) - 0.029
A(2,3) - 5.899
A(2,4) - 6.487
A(2,5) - 1.570
A(3,4) - 5.572
A(3,5) - -0.081
A(4,5) - 1.267
TABLE 5A
ERROR VECTORS AND PROBABLE
0. 7557 0.3443 Probable
0.3049 Error •
0.1121 0.136
-0. 1527 0.3571
-0. 5387 0.4385 Probable
0.2020 Error •
0.0025 0.111
-0. 3136 0.5436
-0. 1928 -0.5215 Probable
0.7037 Error -
0.1950 0.098
-0. 2044 -0.0057
0. 0448 -0.1474 Probable
-0.3538 Error •
0.8299 0.095
-0. 1894 0.0781
-0. 1591 0.4928 Probable
0.3224 Error »
0.2567 0.103
0. 4493 -0.3598
-0. 1190 -0.1934 Probable
-0.1998 Error •
-0.0229 0.107
0. 5133 0.6389
0. 1432 -0.0320 Probable
0.0169 Error •
-0.2008 0.124
-0. 2437 0.0234
0. 1519 -0.2186 Probable
0.3128 Error «•
0.1730 0.129
0. 4295 0.1684
-0. 1264 0.2202 Probable
-0.0532 Error •
0.3463 0.103
-0. 0877 -0.0651
-0. 0231 -0.1340 Probable
-0.0329 Error •
-0.0639 0.113
-0. 2895 -0.0003
-0.1547
0.1536
0.0837
0.2921
0.1981
-0.0870
0.6969
0.1633
-0.4823
-0.2617
-0.1568
0.2095
-0.3130
-0.0434
-0.2878
-0.4281
-0.1571
0.7264
0.0763
0.0861
-0.0523
-0.1084
-0.0477
-0.1074
0.1680
0.2129
0.5490
0.1851
0.5175
0.S429
0.0527
0.0602
-0.0927
0.1472
0.2834
0.0147
-0.2574
-0.0005
-0.5428
0.7224
TABLE 6A
TABLE OF ORDERED LINES
Line Exp. Freq. Calc. Freq. Inten. •
Error
130 119.500 119.625 0.768 -0.125 52 119.500 119.670 0.800 -0.170 1 119.500 119.698 0.800 -0.198
153 119.500 119.740 0.811 -0.240 39 119.500 119.787 0.810 -0.287 16 119.500 119.833 0.751 -0.333 198 119.500 119.934 0.778 -0.434 97 119.500 120.201 0.765 -0.701 108 128.300 127.799 1.065 0.501 204 128.300 127.999 1.103 0.301 27 128.300 128.126 1.119 0.174 141 128.300 128.295 1.172 0.005 210 128.300 128.308 1.133 -0.008 171 128.300 128.336 1.140 -0.036 187 128.300 128.365 1.206 -0.065 76 128.300 128.383 1.203 -0.083 17 134.100 134.238 0.118 -0.138 131 135.200 135.570 0.076 -0.370 98 136.100 136.189 0.117 -0.089 199 137.100 137.410 0.078 -0.310 207 138.100 137.925 0.523 0.175 190 138.100 137.983 0.412 0.117 156 139.200 139.199 0.524 0.001 79 139.200 139.246 0.412 -0.046 134 143.000 142.735 0.635 0.265 178 143.000 143.043 0.593 -0.043 20 144.000 143.919 0.638 0.081 57 144.000 144.287 0.604 -0.287 184 145.000 144.575 1.265 0.425 145 145.000 144.871 1.007 0.129 68 146.000 145.870 1.240 0.130 31 146.000 146.196 0.998 -0.196 55 149.800 149.636 1.899 0.164 123 149.800 149.706 1.685 0.094 4 151.000 150.883 1.918 0.117 9 151.000 150.972 1.687 0.028
205 151.700 151.549 0.334 0.151 209 151.700 151.857 1.021 -0.157 109 152.800 152.806 0.214 -0.006 166 153.800 153.343 0.964 0.457 154 157.800 157.704 2.609 0.096 193 157.800 157.897 1.922 -0.097 142 157.800 158.437 0.152 -0.637
44
TABLE 6A--Continued
Line Exp. Freq. Calc. Freq. Inten. Error
182 158.900 158.507 0.431 0.393 40 158.900 158.977 2.761 -0.077 87 158.900 159.391 1.956 -0.491 28 158.900 159.757 0.089 -0.857 66 160.300 160.014 0.419 0.286 200 160.300 160.960 2.385 -0.660 99 161.100 161.196 2.514 -0.096 120 164.200 164.560 0.685 -0.360 53 164.200 164.605 0.947 -0.405 132 166.000 165.712 1.464 0.288 18 166.000 165.869 1.524 0.131 2 166.000 165.942 1.033 0.058 6 166.000 166.076 0.709 -0.076
155 167.500 167.115 0.455 0.385 41 167.500 167.367 0.324 0.133 161 169.200 169.331 1.371 -0.131 208 169.200 169.334 1.323 -0.134 54 172.200 171.880 0.354 0.320 3 172.200 172.054 0.249 0.146 56 174.000 174.419 0.896 -0.419 177 174.000 174.452 0.881 -0.452 194 175.000 175.374 0.574 -0.374 88 175.000 175.379 0.542 -0.379 7 180.300 180.482 0.403 -0.182
121 180.300 180.505 0.430 -0.205 163 345.600 345.605 1.000 -0.005 206 345.600 345.608 1.000 -0.008 175 345.600 345.636 1.000 -0.036 104 345.600 345.872 0.995 -0.272 60 347.000 346.848 1.000 0.152 157 3<»7.000 346.881 1.000 0.119 115 347.000 346.893 0.995 0.107 82 347.000 346.899 1.000 0.101 23 347.000 347.055 0.993 -0.055 169 347.000 347.093 1.000 -0.093 93 347.000 347.098 1.000 -0.098 45 347.000 347.145 1.000 ' -0.145 34 348.500 348.219 0.993 0.281 12 348.500 348.364 1.000 0.136 71 348.500 348.388 1.000 0.112 5 348.500 348.392 1.000 0.108
APPENDIX B
TABLE 7B
LIST OF TERPENOIDS C.-C,, 5 14
Agglomerone
Ascaridole
C13HU°4
°10H16°2
Dimethyl-p~ tolylcarbinol
Elaholtzia Ketone
°10M14°
C10H14°2
Borneol C10MU° Eucarvone C10H14°
Calythrone C12HU°3 Fenchone C10HU°
Camphene C10H16 9(-Fenchyl Alcohol C10H18°
Camphor
^-Carene
C10H16°
C10H16
Geranial
Geraniol
°10H16°
C10HW°
Carquejol °IOhK° ctf-Ionone C13H20°
Carvomenthone C10H18° P-Ionone C13H20°
Carvone °10H14° neo-Of-Irone CHH22°
1,8-Cineole C10H1S° neo-Iso-of-irone C14H22°
Citronellal C10H18° Isomenthone CI0H18°
j?-Citronellol C10H20° Isophorone C9 H14°
p-Cymene C10HU Isopulegol °10H18°
Dehyd roangus 11one CUH14°3 Lavandulol C10H18°
trans-Dihydro-a(-terpineol
C10H20° Linalool
Linalyl Acetate
C10H18°
C12H20°2 Dimethyl
Acrylic Acid
y, y-Dime thy la 1 ly 1 Alcohol
C5K8°2
C5H10°
trana-p-Menthan-8-ol
Menthol
45
C10H20°
C10H20°
46
TABLE 7B—Continued
Menthone C10H18° Sabinene CL0H16
Methyl-trans-chrysanthemum Monocarboxyl< ate
_CllH18°2 Tasmanone
Q(-Terpinene
C14H20°4
C10HU
Myrtenal cIOhR° $-Terpinene C10H16
Neral C10H16° of-Terpineol C10H18°
Nerol C10H18° Terpinen-4-ol C10HU°
trans-P-Ocimene C10H16 ^-Thujaplicin ClOH12°2
o(-Phe 11 and rene C10H16 o(-ThuJene C10H16
o(-Plnene C10H16
Thujone C10H16°
^-Plnene C10HU Thymol
w
Pinocampheol C10H18° Thymoquinone C10H12°2
Pinocamphone Verbenol C10H16°
Piperitenone cxo"u° Verbenone C10HU°
Pulegone C10H16°
Rose Oxide C10H18°
TABLE SB
LIST OF TERPENOIDS C-.-C,,
Acoric Acid C15H24°4 oC-Cyperone C15H22°
Agarofuran cisV
Dams in C15H20°3
Ambrosiol °15H22°4 Dime thylisoshelloate C17H24°6
Arborescin C15H20°3 Dimethylshelloate C17H24°6
AriatoLone C1JH24° Drimenoi C15H26°
Balchanolide C15H22°3 Dunnione C15H14°3
Balduilin C17H20°5 Elemol C15H26°
P-Bergamotene C15H24 Eremophilone C15H22°
P-Bisabolene °15K24 /?-Eudesmol °15H2t°
^-Bourbonene C15H24 Flexuosine A C17H24°6
Bulnesol C15H26° Germacrone C15H22°
S-Cadinene °15H24 Gibberellic Acid CWH20#6
f-Cadinene C15H24 Globicin C17H22°5
oi-Gadinol C15H26° Globulol C15H26°
Carissone C15H24°2 Guaiol C15H26°
Carotol C15H26° ^•Himach&lene C15H24
Caryophyllene C15H24 o(«Humulene
C15H24
Caryophyllene Oxide C15H24° Humulene Diepoxide C15H24°2
oC-Cedrene
P'Cedrene
Cedcol
C15H24
C15H24
C15H26°
Hyd roxyd ihyd ro-eremophilenolide
6-Hydroxyeremo-philone
C15H22°2
C15H22°3
Confertifolin C15H22°2 Hyd roxyperezone C15H20°4
Cryptoacorone C15H24°2 Hydroxyvaleranone C15H26°2
Cyperene C15H24 Imperatorin C16HL4°4
48
TABLE 8B—Continued
IresIn C15H22°» Patchouli Alcohol C15H26°
Isoacorone C15H24°2 Perezone C15H20°3
Isoalantolactone C15H20°2 Petashione C15H18°2
Ivalin C15H20°3 Picrotin C15HU°7
Jatamanshic Acid C15H22°2 Q(-Picrotoxinic Acid
Vie0*
Juniper Camphor C15H2«° &>Ficrotoxinic C15H18°6
<X*Kessyl Alcohol C15H26°2 Acid C15H18°6
2-Ketotnanoyl Oxide C19H32° Picrotoxinin C15H16°6
Khusinol C15H24° Plumericin C15H14°6
Lactaroviolin C15H14° Podocarpic Acid C17H20°3
Lactucin C15H16°5 Psilostachyin A C15H2045
Ledol C15H26° Psilostachyin B Ct5H18°4
Linderalactone C15HU°3 Psilostachyin C C15H20°4
Linderane C15H16°4 Pulchellin C15H22°4
Longicyclene C15H24 V-Santalene C15H24
cls-Nerolldol C15H26° /9-Santalene C15H24
trans-Nero1idol C15H26° 0<- Santonin C1SH18°3
Nootkatin C15H20°2 Santonin °15H18°3
Occidentalol C15H24° Saussurea Lactone C15H22°2
Parthenolide C1SH20°3 ^-Selinene C15H24
^-Patchoulene C15H24 Taumerisin C15H20°4
CX+y-Pa tchou lene C15H24
Telekin C15H20°3
TABLE 8B—Continued
Tricyc1ocyperene C15H24
Tutin °15H18°6
Valerenal C15H22°
Valeranone C15H26°0
Vlridiflorol C15H26°
o(-Ylangene C15H2*
Zierone C15H22°
50
TABLE 9B
LIST OF TERPENOIDS C2Q-C40
Abietic Acid
9-Acetoxyroyie-anone
Ambrein
^-Amryin
Araucarenolone
Araucarolone
Archangelin
^-Carotene
Columbia
Dehydroabietic Acid
Eremolactone
Euphol
H«xaacetyl Aucubia
Humulone
Isopimaric Acid
Levopimaric Acid
Lycopene
Manool
Marrubiin
Mexicanolide
C20H30°2
C22H30°5
C30H52°
C30H50°
C20H28°4
C20H30°3
C21H22°4
C40H56
C20H22°5
C20H28°2
C20H26°2
C30H50°
C27H34°15
C21H30°5
C20H30°2
C20H30°2
C40H56
C20H34°
C20H28°4
C27H32°7
Mongynol A
Paeniflorin Pentaacetate
Paeniflorin Tetraacetate
Palustric Acid
Pentaacetyl Monotropeln Methyl Ester
Pimaric Acid
Quassin
Rimuene
Royleanone
Salaninn
Sand racop imar ic Acid
Sclareol
Swietenine
Swietenolide
Tetraacetyl Aaper-uloside
Tinophyllone
Uabellipenin
C20H32°0
C33H38°16
C31H36°15
C20H28°
C26H32°16
C20H30°2
C22H30°6
C20H32
C20H28°3
C34H44°9
C20H30°2
C21H30°
C31H40°9
C27H34°8
C26H32°16
C21H24°6
C24H30°3
TABLE 10B
TERPENOIDS OVER C, n AND STEROIDS 40
Androstadledlone C1?H24^2
5o(-Androstan-3°(-oi-17-one ^19^30^2
5o(.-Androstan-3^-ol- 17-one C19**30^2
5^-Androstan-3o(-ol-17-one ^19H30^2
Androstenedlone **19^26® 2
4-Androstene-3,11,17-trione C19H24°3
/^'^'^-Androstatriene-3,17-dione ^19H22®2
Calciferol (Vitamin D2> C28^44
Cevadine C32H49N09
Cholestanol C^H^O
Cholesterol C--H.,0 27 46
Conessine C,.H.-N, 24 40 2
Cortexolone ^21^30^4
Corticosterone C21H30^4
Cortisone Acetate C23**30^6
Cucurbitacin I (Elatericin B) C^qH^Oj
Desoxycortlcosterone Acetate C23H32^4
Digoxigenin C23H34°5
Diosgenin C27H«°3
Dolichol C100H164°
Estriol C18H2*°3
Fucosterol C^H^O
TABLE 10B—Continued
Gitoxigenin G23H32°5
Hecogenin Acetate ^29^44^5
Hydroxycortisone Acetate
IsofucosteroL C^H^gO
24-Ketocholesterol co-»H/, °-i 27 44 2
Lanosterol C30H50°
Lumisterol-3 C-.H..0 28 44
Lupeol Acetate ^32^52^
Prednisolone ^21^28^5
Predisone C21H26°5
5^-Pregnane-I7o(l21-dihydroxy-3,ll, 20- C..H..0. trione-2l*acetate
5^-Pregnane-3o(, 17o(-diol-ll, 20-dione C21H32°4
Pregnenolone Acetate C23H34°3
Progesterone C21H30°2
Shottenol C^H^gO
Smilagenin Acetate C^gH^gO^
Solanesol C^H^O
Stigmasterol C29H48®
Testosterone C19H28^2
(^•Tocopherol C29H50°2
Ubiquinone (Q1(J)
Vitamin D3 C27H44
APPENDIX C
NMR AND IR SPECTRA
53
A ff -X
- w aJuilIILMA 5.0 70 mtir) mn(T) "
Figure 2b. Verbenone (IX) simulated spectrum (100 Mc),
+
I 290 I
MO
I SO
A ' • • • i . . . . y . i
4.0 5.0 «.0 KT) 7.0 1.0 9.0
Figure 2a. Verbenone (IX) experimental spectrum (100 Mc).
Figure 3b. Myrtenal (X) simulated spectrum (100 Mc).
«.o 7.0 ( T ) 9.0 9.0 4.0
Figure 3a. Myrtenal (X) experimental spectrum (100 Mc).
A4 i
h J V >
li
4.0 i 5.0 7.0 FPM(T) (.0 9.0
Figure 4c. flf-Pitiene (XI) simulated spectrum (100 Mc), system 2.
+ + 1 uo i JL
A. 5.0 6.0 ffM(r)
CPS
Figure 4b. 0(-Pinene (XI) simulated spectrum (100 Mc), system 1 (Insert).
Figure 4a. 0(-Pinene (XI) experimental spectrum (100 Mc).
Ut
Jlui
lit' 1 'Hdffl'-TI
Figure 5* Myrtenal (X) experimental and simulated spectra (60 Mc} upper 3^ negative, middle J^ positive).
JJ
Figure 6. Commercial methylheptenone (XVI)*
Figure 7. 2,6-Dimethyl-5-heptene-2-ol (XVII).
7.0 • 0
Figure 8. Ct+f -Cyclogeraniolene (XVIII + XIX).
59
(MICRONS] WAVELENGTH
0.0 0.0
S.20
£•30
§.40 CO <.50
.60
.70
1.0
.40
.50
.60
.70
1.0 1.5
1000 900 800 700 4000 3000 2000 1200 1500 CM
Figure 9. Commercial methylheptenone (XVI; neat).
WAVELENGTH MICRONS 3 4 5 6 7 8 9 10 11 12 13 14 15 J : 1 1 » I I I ' . I I • . A . ! . I ). . 1 I I . I. . I I ( . 11
-1
1000 900 4000 3000
Figure 10. 2,6-Dimethyl-5-heptene-2-ol (XVII; neat).
60
WAVELENGTH (MICRONS) 3 4 5 6 7 8 9 10 11 12 13 14 15 -I H i ! 1 1 . 1 . 1 ' . I . . , I 1 I .1. I L-
1000 900 4000 3000
Figure 11. Ct+fi -Cyclogeraniolene (XVIII + XIX; neat).
! WAVELENGTH (MICRONS) 3 1 4 5 6 7 8 9 10 11 12 13 14 15 J _l I I—,—i, I ,1 1,1 I rJ L I ' 111 I I I
1000 900 4000 3000
Figure 12. Acetylcyclogeraniolene (XX; neat).
61
Figure 13. Acetylcyclogeraniolene (XX).
1.0 7T
Figure 14. ^-Cyclolavandulic acid (XXI).
(MICRONS) WAVELENGTH
0.0 0.0
.40
.60
.70
1.0 1.5
1.0
700 1000 900 800 1200 4000 3000 1500 2000 CM
Figure 15. ^-Cyclolavandulic acid (XXI; KBr).
WAVELENGTH (MICRONS)
0.0 0.0
U.20
</>.40 CO <.50
40
.60
.70
1.0
.70
1.0
1500 2000 1200 4000 3000 1000 900 800 700 CM
Figure 16. ^•Cyclolavandulol (XV; CCl^).
1
m i
» m I m e 9*
ft - . X
j» 1 >!> ' A —i" 1 'J»
. i j i -1 U 16 ii • 1 1
Figure 17. p-Cyclolavandulol (XV).
3.0 4.0 1.0 to
TT
Figure 18. £-Cyclolavandulyl bromide (XX11I).
Figure 19* Natural archangelln (XXVI; 60 Mc).
Figure 20• Natural archangelln (XXVI; 100 Mc).
65
.JiUJVJjL
1.4' ' 'MClV '4»
Figure 21. ^-Cyclolavandulyl umbelllferonyl ether (XXV; 60 Mc).
T ' | 1 , T 1 | ' T 11 m no
i i
f *• M
, .TJirt.,y, . , J ,
M NO
I"; • ;:T:7-| >*• • at
rWA-jA ic. "" T . 1 ' - i • A ii •»" »
Jl ( 1.... 1... jg 1 1 .1... 11 A " '
, - vsJ Lj Cj
11 'w\»v '—«!i" ' ' —i!r • ' • i 1
Figure 22 , ^-Cyclolavandulyl umbelllferonyl ether (XXVj 100 Mc).
66
WAVELENGTH (MICRONS) 6 7 8 9 10 11
I I r 1 .
1000 900 4000 3000
Figure 23. Natural archangelin (XXVIj CCl^).
WAVELENGTH
100 100
80
1U 60 Z 60
20
700 1000 900 800 1200 1500 2000 4000 3000 CM'
Figure 24. fl-Cyclolavandulyl umbelliferonyl ether (XXV; CCl^).
<
I I
rir—
Figure 25. Compound B.
«jo mtlfl Ji- JE£_
A,, i* i u
'••WiV»r I
-i!r •A11 'mini'—ir -j!r tr~
Figure 26, Perezone (VIII).
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