MODEL STUDIES DIRECTED TOWARDS IONOMYCIN
by
KEVIN PAUL SHELLY
B.Sc, University College Galway, 1981
A THESIS SUBMITTED IN PARTIAL FULFILMENT OF
THE REQUIREMENTS FOR THE DEGREE OF
MASTER OF SCIENCE
in
THE FACULTY OF GRADUATE STUDIES
DEPARTMENT OF CHEMISTRY
We accept this thesis as conforming
to the required standard
The University of British Columbia
October, 1984
© Kevin Paul Shelly, 1984 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission.
Department of
The University of British Columbia 1956 Main Mall Vancouver, Canada V6T 1Y3
Date IS OCT ff*f-
DE-6 (3/81) - ii -
ABSTRACT
This work is concerned with model studies directed towards the synthesis of the polyether antibiotic ionoraycin (2).
HOjC
This involved the synthesis of:
(a) a model of the A portion of _2, namely 30a
(b) a precursor to the B portion of 2, namely 31
31 30a
Both of these racemic subunits were prepared from meso-2,4-diraethylglutaric anhydride (25).
25
Subsequent work comprised of investigating the coupling reaction of these two portions. Model studies using the simpler moieties 17 and - iii -
.39b
The use of the epoxide 40a proved more successful, providing 43a and 43b in a 39% yield.
40a
43b - iv -
The conditions found for oxidation of 20 to 21. proved fruitless
with 43a and 43b. However, dithiane hydrolysis followed by an oxidation
21
yielded the 6-diketones 44a and 44 b.
44a
44 b - v -
TABLE OF CONTENTS
Page
ABSTRACT ii
TABLE OF CONTENTS v
LIST OF FIGURES vi
LIST OF TABLES vii
LIST OF ABBREVIATIONS viii
ACKNOWLEDGEMENTS x
INTRODUCTION
A. Natural Product Synthesis.... 1
B. Polyether Antibiotics 2
C. Ionoraycin 3
D. Synthesis 4
DISCUSSION
1. Model Studies.. 19
2. Synthesis of a Common Intermediate Leading to
Subunits 25
3. Dithiane Subunit 30 31
4. Epoxide Subunit 3_1_ 33
5. Dithiane Metallation 36
6. Alkylation Reaction 39
7. Route to 3-Diketones 44a and 44b 44
EXPERIMENTAL 54
BIBLIOGRAPHY 78
SPECTRAL INDEX 81 - vi -
LIST OF FIGURES
Figure Title Page
1 Retrosynthetic plan leading from ionoraycin (2_) 12
2 Percent product vs. time in oxidation of alcohol 20 using PCC and PCC • AI2O3 22
3 Percent product vs. time in oxidation of alcohol 20 using PDC in DMF 24
4 Correlation of ^-nmr and gc data of various crops of anhydride crystals...... 27 - vii -
LIST OF TABLES
Table Title Page
I Alkylation of dithiane 17_ with 1,2-epoxybutane (19)... 20
II Oxidation of alcohol 20_ using PDC in DMF 23
III Elemental analysis of anhydride 25_ containing one water of hydration 29
IV Metallation studies on dithiane 30a using _t-butyl lithium 37
V Metallation studies on dithiane 30a using n-butyllithiura 39 - viii -
LIST OF ABBREVIATIONS
AC2O acetic anhydride n-BuLi n_-butyllithium j:-BuLi _t-butyllithium
°C degrees Celsius cone. concentration
DCC dicyclohexylcarbodilmide
DMF dimethylformamide
DMSO dimethylsulfoxide equiv. equivalent(s) ethyl ether diethyl ether gc • gas liquid chromatography h hour
^H-nmr proton nuclear magnetic resonance
HMPA hexamethylphosphoramide ir infra-red
LAH lithium aluminum hydride
MCPBA meta-chloroperoxybenzoic acid min minute(s)
PCC pyridinium chlorochrornate
PCC«Al203 pyridinium chlorochrornate on alumina (1:4)
PDC pyridinium dichromate rbf round bottom flask
S03*Py pyridine sulfur trioxide complex - ix -
TBDMS _t-butyldiraethylsilyl
TEA triethylamine
THF tetrahydrofuran
THP 2-tetrahydropyranyl tic thin layer chromatography
TMEDA tetraraethylethylenediaraine
abbreviations for multiplicities of ^-nrar signals s singlet bs broad singlet d doublet t triplet q quartet m multiplet dt doublet of triplets ddd doublet of doublets of doublets - x -
ACKNOWLEDGEMENTS
I wish to express my sincere thanks to Dr. Larry Weiler for his excellent guidance and invaluable suggestions throughout the course of my research and the preparation of this thesis.
Numerous discussions with members of the research group, past and present, have been most beneficial and valuable. To them I extend my thanks and best wishes.
The assistance of the elemental analysis, nmr, and mass spectroscopy staff, as well as the other staff in the department, is appreciated. - xi -
To My Parents - 1 -
INTRODUCTION
A. Natural Product Synthesis
"One should always be drunk,
thats all that matters. . . .
but what with? ..."
Following on this advice from the French poet Baudelaire (1821 -
1867), synthetic organic chemists seek out a natural product to (
synthesize and in effect get "drunk with". As organic chemistry
develops and provides more synthetic methods, more natural product
syntheses are attainable.
While organic chemists can debate the merits of various
syntheses, they can only allocate the silver and bronze medals.
Nature, while providing the target, also usually provides the best
solution. Indeed, some syntheses follow guidelines prompted by the
biosynthetic pathway used by nature, and often the building blocks used
in syntheses are supplied by nature, such as carbohydrates and amino
acids. Nevertheless, once a synthesis has been achieved, the group
involved will rightly feel a sense of achievement.
As well as direct gains possible from the synthesis of a natural
product such as an antibiotic or an insect pheromone, a real value lies
in the experience gained by all involved in the project.
Apprenticeship, the oldest of educational methods, is the basic concept
in the learning process. Techniques, methods, and the planning skills
learned in one synthesis can be ever so useful in subsequent work and - 2 -
thus are an investment, available only through direct experience.
There are a lot more ways to get drunk than by synthesizing a natural product. Baudelaire had these thoughts about the why and how;
"One should always be drunk
thats all that matters.
So as not to feel Time's horrible burden
that breaks your shoulders and bows you down,
You must get drunk without ceasing.
But what with?
With wine,
with poetry
or with virtue as you please."
B. Polyether Antibiotics
The polyether antibiotics are members of a much larger class of compounds called ionophores. Ionophores can complex an ion and
transport it through a lipophilic interface. Westley defines eight
structural groups of ionophores based on chemical structure (1). The polyether antibiotic group is distinguished by a linear carbon framework, containing tetrahydrofurans and tetrahydropyrans, numerous asymmetric centres and often a terminal carboxylic acid.
The first polyether antibiotic to be isolated was nigericin 0_) in 1951, it's structural determination was realized 17 years later (2).
These antibiotics are an ever growing class of ionophores, with more than 30 having been recognized by 1978; while only 6 years later, 40 - 3 -
more polyether antibiotics had been reported (3,4).
•Me
Ah
1
Economically, polyether antibiotics have been applied in the treatment of coccidiosis, a poultry disease. They have not gained any use in human therapy because of their high toxicity when administered parenterally. A number of laboratories are investigating other possible uses for the polyether antibiotics.
C. Iononycin
Liu et al. in 1978 (3) reported the production and isolation of the polyether antibiotic ionomycin (2). The antibiotic was isolated as its calcium salt from a broth concentrate which had been adjusted to pH
12 with aqueous sodium hydroxide. The high affinity for calcium ions illustrates an interesting property of ionomycin. This polyether antibiotic chelates dipositive ions as a dibasic acid, whereas the few other known ionophores which chelate such divalent cations do so as monobasic acids. - 4 -
2
The structural determination of _2 resulted from ir, nmr, x-ray and mass spectroscopic data as detailed by Toeplitz et al. in 1978 (5).
The molecular structure of the calcium and cadmium salts of ionoraycin contain a cisoid B-diketone anion that together with a carboxylate group
and three other oxygen atoms are octahedrally coordinated to the central divalent cation as shown by an x-ray structure (5).
D. Synthesis
Some of the difficulties involved in the synthesis of ionoraycin include setting up a 32 carbon linear skeleton containing 14 asymmetric centres and a variety of functional groups. While Evans has realized
the synthesis of four subunits of ionomycin (6), the total synthesis of ionoraycin has not been reported to date.
The synthesis planned by our group coincidentally involves a four part convergent synthesis. A convergent synthesis is inherently more efficient than a linear one (7). The linkage points chosen In such a plan are very important. We planned a strategy based on the bond disconnections shown In 3. - 5 -
A_ _B_ _C_ .D
3
This thesis is concerned with model studies towards linking the A and B portions of ionoraycin, as well as preparing the groundwork for the synthesis of the B portion.
A retrosynthetic analysis prompted us to consider dithiane chemistry to link the A and B subunits. Alkylation of the metallated dithiane with an epoxide and subsequent transformations might yield the desired B-diketone. - 6 -
Applying the methods of Corey and Seebach, developed since 1965, alkylation of dithiane anions with various electrophiles is possible
(8). Since regeneration of the carbonyl function can be achieved by a variety of methods, the thioacetal carbanions are equivalent to acyl anions and can be used effectively to reverse the characteristic electrophilicity of a carbonyl carbon. In 1972 Seebach proposed the use of the terra "urapolung" for this inversion of reactivity (9). - 7 -
The use of dithiane chemistry in natural product synthesis is well documented. Seebach in his 1977 review, cites numerous applications (9). Recent examples involve the total synthesis of aplasraomycin (10) and (+)-phyllanthocin (11).
aplasmomycin (+)-phyllanthocin - 9 -
We were specifically interested In the alkylation of dithianes
with an epoxide, one of the slower reactions of dithiane anions.
Seebach and Corey noted that epoxides "are opened very slowly" by
dithiane anions and suggested storage of the reaction vessel at sub-zero
temperatures for up to one week (7). This retardation in epoxide
opening allowed them to achieve the cheraoselectivity shown in equation
(i), using epichlorohydrin as an alkylating agent. The desired product
4_ was obtained in 64% yield.
(i)
There are examples of successful epoxide openings by dithiane
carbanions in natural product synthesis. Redlich et al., in their
synthesis of the pheromone lineatin, alkylated the dithiane _5 and
obtained the 3-hydroxy dithiane 6^ in 88% yield (12). - 10 - - 11 -
In the synthesis of jaborosalactone A, B and D, Hirayama et al., employed the dithiane 7_ to extend the side chain on the steroid nucleus
(13) . Alkylation of _7 with the epoxide 8^ followed by dithiane hydrolysis afforded the B-hydroxy ketone 9_ in 76% overall yield.
While these reactions were successful, each involved either a simple epoxide or a simple dithiane moiety. We planned to employ both a complex dithiane and a complex epoxide.
The B subunit in our synthesis, the epoxide, would consist of a seven-carbon chain with two asymmetric centres. This work involves preparing a precursor to this subunit and studying the coupling reaction between this subunit and a suitable model for subunit A. The dithiane model needed in these studies should be as structurally similar to the eventual A portion of ionomycin as possible. Studies directed towards the synthesis of the A portion, a nine-carbon chain with three asymmetric centres, are currently being carried out in our laboratory
(14) .
The retrosynthetic plan, shown in Fig. 1, illustrates that a model for A and a precursor for B can both be prepared from a common 2,4
-dimethyl substituted hexane intermediate _10_. We considered three possible routes to this intermediate.
I. Carbohydrates
II. (R)-3-hydroxyisobutyraldehyde (11)
III. 2,4-dimethylglutaric acid (12) Figure 1. Retrosynthetic plan leading from ionomycin (2) - 13 -
I. Carbohydrates
The use of carbohydrate precursors in the synthesis of natural products is well documented (15,16). The concept is simple and involves the use of one of nature's sources of chiral organic compounds to provide another natural product. Thereby, the synthetic chemist uses the inherent chirality and functionality of carbohydrates to provide target subunits or molecules. When used elegantly, these building
OMe
•> (-)-cx -multistriatin
OMe - 14 -
blocks are a superb source of such targets. Care must be taken so as not to get involved in a route to the desired molecule, Initiated from carbohydrates, which is long, circuitous and inefficient. Synthesis directed towards polyether antibiotics with carbohydrate starting materials include antibiotic A23187 (17) and lasalocid A (18).
The synthesis of (-)-ce-raultistriatin from D-glucose achieved by
Sum and Weiler could prove useful in providing a 2,4-diraethyl six-carbon chain (19).
This route would provide us with the two portions required for our proposed coupling studies, each with the correct absolute stereochemistry. The synthesis of the same natural product by Plaumann et al., would also provide the required carbon skeleton (20).
II. (R)-B-hydroxyisobutyraldehyde (11)
Another possible route to the two target subunits involves the aldehyde 1J_ available from (+)-S-hydroxyisobutric acid (13) (21).
13 11 - 15 -
Collum et al., synthesized the lactone 1_4_ from the starting aldehyde JL1_ in the synthesis of monensin (22).
THPO>. Js.
11
vs^^C02Et
T XX H" HPO COoEt
OH
XX > monensin 14
The lactone could, in a series of steps, lead to the aldehyde
10a, an intermediate which might be used to prepare the two required substrates. 10a - 17 -
III. 2,4-dimethylglutaric acid (12)
The acid-ester 1_5_ is readily available from 2,4-dimethylglutaric acid (12) with chemistry developed by Auwers and Thorpe (23) and modified by Allinger (24).
12 15
The acid-ester 1_5_ has been used in the synthesis of natural products (25) including ot-multistriatin (26) and Prelog-Djerassi lactone
(27). The ot-multistriatin synthesis achieved by Bartlett and Myerson produced the racemic natural product. The synthesis of ot-multistriatin from D-glucose by Weiler and Sum (15) provides the (-)-ot-isomer of the natural product and obviously has an advantage over the racemic synthesis. Since Chen et al., have described a microbiological method for the preparation of J5_ in >98% enantiomeric purity, the acid-ester 1_5 can be used effectively in non-racemic syntheses (28).
Conversion of _15_ to the aldehyde-ester 16 would provide us with a common intermediate from which both subunits could be derived. This latter route was favoured over the first two schemes because of the ready availability of large amounts of the diacid 12.
Once the coupling of the two units had been realized, subsequent hydrolysis and oxidation in either order would afford the desired
B-diketone.
- 19 -
DISCUSSION
1. Model Studies
1.1. The dithiane _17_ was obtained from isobutyraldehyde (18) following the general procedure of Seebach and Corey (8). Initial attempts at the alkylation of the dithiane with 1,2-epoxybutane (19) were not too successful. A gc analysis of the crude product indicated
that It contained about 60% of product alcohol 20. This resulted in a
42% isolated yield of 20. Increasing the amount of epoxide used produced no change in these results.
18 17
1. n-BuLi
19
20 - 20 -
When the raetallation time with n-butyllithium was increased, a higher yield of product was obtained. Doubling of the di thiane concentration afforded the product 20 in almost quantitative yield.
These results are summarized in Table I.
Table 1. Alkylatlon of dithiane V7_ with 1,2-epoxybutane (19)
Equlv, Cone. Equlv. Equlv. i aolated of In Temp of Hetalatlon of ,19/ .17:20 Yield J_7 THP •c n-BuLl Conditions Tenp gc Analysis 20
1 0.1 M -30 • 1.1 3 h/-30°C 1/0'C 40:60 421 20-40 h
0.1 M -30 1.1 3 h/-30'C 1.5/0*C 40:60 1 - 20 h
-20 1.1 3 h/-20°C 1/0*C 10:90 1 0.1 M - 16 h/-10*C 5 h
1 0.2 M -20 1.1 3 h/-20*C 1/0°C -:>95 91X 16 h/-10°C 5 h
We observed no change by gc in the yields of product obtained with longer reaction times. Further gc investigations showed the alkylation to be complete within minutes of adding the epoxide at 0°C.
The ease of this reaction was encouraging, though we realized it was achieved employing both a very simple dithiane and a very simple epoxide as models.
1.2. The first choice of oxidizing agents to convert the alcohol
20 into the corresponding ketone 21. was pyridinium chlorochroraate (PCC)
(29). Initial studies were deceptively promising. Using PCC with sodium acetate and sometimes with 4A molecular sieves in methylene chloride produced some of the desired ketone 21, but varying amounts of
the starting alcohol were always evident. Crude yields were not very - 21 -
high, due to the difficulties in extracting product from the black tar produced in the oxidations. The use of excess PCC with sodium acetate lead to the formation of some sulfoxide as evidenced by mass spectroscopic data.
We needed to modify the activity of the PCC and avoid the infamous black tar. PCC on alumina (1:4) was found to be a milder but effective oxidizing agent (30). Four reactions were monitored by gc analysis using the oxidation with 3 equiv. of PCC as the reference. The results are presented in Fig. 2. The reaction time with PCC on alumina
Is slower by a factor of six or more when compared to the reference PCC oxidation.
While the oxidation reaction mixture contained only ketone and no starting material, crude yields rarely reached 40%. This resulted from the logistical problem of extracting, typically 1 g of product from 25 g of a granular solid. A 74% crude yield obtained using 5 equiv. of
PCC*Al20 3 was the result of many washings of the solid residue and was not very reproducible.
We tried a few variations with the work-up including kugelrohr distillation and soxhlet extraction.. The former resulted in product - 22 -
1 * 1—t 1 e i—#
Time (h)
Figure 2 - Percent product vs. time in oxidation of alcohol 20_
using PCC and PCC«A1203.
decomposition and the latter only afforded crude yields of 50% to 55%.
Obviously PCC on alumina was not satisfactory in this oxidation.
PCC was adsorbed onto Florosil and we attempted the oxidation of
20 using 5 equivalents of this oxidant. The result was worse than before, yielding very impure product. - 23 -
1.3 We then turned our attention to pyridinium dichroraate (PDC) which Corey and Schmidt used to oxidize a secondary alcohol when a dithiane moiety was also present in the molecule as shown by equation
(ii) (31). They found that 7 equiv. of PDC, 1.2 M in DMF, proved successful in the oxidation. The results of our studies utilizing PDC
in DMF are summarized in Table II.
Table II. Oxidation of alcohol 20 using PDC in DMF
Equiv. Cone. PDC Temp/Time Crude Yield Ketone 21 Purity PDC in DMF («c)
1.1 M 25'C/l h 58Z 91Z
0.3 M 25"C/4 h 68Z 97Z
0.2 M 0*C/96 h 831 93Z
0.2 M 0"C/24 h 66Z 99Z
1.2 M 0°C/11 h 84 Z > 95X
1.2 M 0*C/7 h 74X > 98Z
The work-up involved with these oxidations was cleaner than with
PCC, resulting in reasonable crude yields varying between 66% and 84%.
At 0°C, the purity of the final product was generally higher than that obtained from reactions at room temperature. The monitoring of four reactions by gc analysis yielded a similar plot to that obtained with
PCC on alumina, Fig. 3.
The optimal conditions for the oxidation appear to be the use of
7 to 9 equivalents of PDC, 1.2 M in DMF at 0°C, stirred for 7 to 11 h,
affording crude yields in the 80% range. - 24 -
A > A . A • A . A . A // A, • * AL. 2 4 6 810 12 v 24 4 8 72 96 Time (h)
Figure 3 - Percent product vs. time in oxidation of alcohol 2Q using PDC in DMF.
1.3 The hydrolysis of the S-keto dithiane 21_ was achieved using mercuric chloride and mercuric oxide in refluxing aqueous acetonitrile
(19, 32). The desired 8-diketone 12_ was obtained in 52% purified yield.
As there are numerous techniques to hydrolyse dithianes we did not spend time improving this yield on our simple model. - 25 -
2. Synthesis of a Common Intermediate Leading to Subunits
The common intermediate we envisaged using in the synthesis of both the dithiane and epoxide subunits was the aldehyde 16. the reported route to this compound started with the diacid 12_ and
C^Me
16
following anhydride formation, methanolysis, acid chloride formation and
Rosenmund reduction afforded the aldehyde 16_ (27).
The diacid _12_ was prepared by a modification of the method used by Auwers and Thorpe in 1895 (23). Condensation of diethyl
V^/CC^Et (iii) X Et COoEt C02
23 24
1. NaOEt
2. H + ,A
HO,
12 - 26 -
methylmalonate (23) and ethyl-2-bromoisobutyrate (24), followed by subsequent hydrolysis and decarboxylation of the triacid provided
2,4-dimethylglutaric acid (12) in almost quantitative yield as shown by equation (iii).
The mixture of meso- and dl-diacids _12_ was converted to the corresponding anhydrides from which the meso-2,4-dimethylglutaric anhydride (25) could be isolated by crystallization following the procedure developed by Allinger (24).
By a correlation of nmr and gc data we found the first crop of crystals to be 99.3% meso-anhydride, Fig. 4. Subsequent crops were mixtures of meso- and dl-anhydrides, with the percentage of dl ever increasing. The nmr data for the meso-anhydride (25) and the dl anhydride 26^ were very different. The two protons on C-3 in the case of
25 26
25 are non-equivalent, both chemically and magnetically. On the other hand, with the dl-anhydride 26^, the two protons on C-3 are equivalent. - 27 -
These facts are evident in the 270 MHz H-nmr of each anhydride. One
signal is observed for the two Hc protons of 26_ while two signals are
observed for the two Ha and H^ protons of 25.
Crop No. 270 MHz Vl-nmr gc data
Jl 99.3 0.7 %
illL L U 37.5 62.5 %
1.9 98.1 %
ToIT
ppm
Figure 4 - Correlation of *H-nmr and gc data of various crops of anhydride crystals. - 28 -
Heating the anhydride to reflux in dry methanol provided only 30% to 40% of the desired mono-ester J_5_ with the diacid 12_ constituting the other product. Zamojski had reported this procedure affording yields of greater than 90% (33). When we treated succinic anhydride (27) to the same experimental conditions, we obtained the acid-ester _28 in 87% yield.
28
Why did this model work but not the real anhydride? A potential source of the problem would be the presence of water in the reaction but the only difference in the two experiments was the difference in anhydride's used. Could the anhydride 25_ contain water of hydration?
Elemental analysis of the anhydride provided affirmative evidence that one water of hydration had crystallized with the anhydride, Table III.
This problem was overcome by kugelrohr distillation of the hydrated anhydride. Subsequent raethanolysis of the distilled anhydride afforded the desired acid-ester J_5 in 91% distilled yield. - 29 -
Table III. Elemental analysis of anhydride 23 containing one water of hydration
Coopound Z C Z H
Calcd for 25_ 59.14 7.09
Calcd for 25_ • H20 52.4 9 7.55
Found 52.45 7.73
We decided not to resolve the acid ester 15. Once the pathway to
the B portion of ionomycin has been developed a subsequent synthesis using one enantioraer of compound 1_5 would be straightforward. The acid could be resolved using an enantioraerically pure, amine or as we alluded
to earlier, by using the microbiological method developed by Sih (28).
15 29
The conversion of racemic 1_5 to the acid chloride 29. was realized using the procedure of Burgstahler, et al. (34).
29 _16
Initially we hoped to use the crude acid chloride In the next step, which is the aldehyde formation. The reaction work-up of _29_ involved removal of the solvent and excess reagents under reduced pressure. The crude acid chloride obtained in this fashion failed to - 30 -
give reasonable yields of aldehyde _16_ in the subsequent Rosenmund reduction. For the reduction we employed the modification as detailed by Burgstahler et al. in 1976 (34) and recommended by Bartlett and Adams in their synthesis of Prelog-Djerassi lactone (27). Initially we associated the poor yields with the suspect stability of the acid chloride. As we had more dealings with both the acid chloride 29_ and the aldehyde _16_, we found the aldehyde to be the more unstable compound of the two. In fact, the crude acid chloride could be distilled at reduced pressure affording a colourless oil in 92% yield. Once distilled, it could be stored for up to a month before conversion to the aldehyde _16_ in 60% yield. The instability of the aldehyde lead us to consider employing the acid chloride 29_ as the common intermediate to the dithiane 30 and epoxide 31 subunits.
29 / \
We will discuss later the steps leading to the epoxide, after we describe our route to the dithiane 30. - 31 -
3. Dithiane Subunit 30
The dithiane 32_ can be obtained directly from the aldehyde _16_ by treatment of in chloroform with 1,3-dithiolpropane in the presence of boron trifluoride etherate.
16 32
The instability of the neat aldehyde invariably led to low yields of the purified dithiane 32_* As long as the aldehyde _16_ was in solution, its stability was greatly enhanced. So we attempted to overcome the problem of the decomposition of the neat aldehyde by combining two steps in one. Hydrogenation of the acid chloride for 8 h, followed by a careful work up provided the aldehyde in a chloroform solution. Without any time delay, the aldehyde was converted to the dithiane 32_ in a purified yield of over 60%. Reduction of the ester in
32 was achieved using lithium aluminum hydride, affording us the alcohol
33 in high yield.
Our choice of a protecting group for 33 was the
_t-butyldimethylsilyl moiety. It needed to survive dithiane metallation,
Involving a strong base, and dithiane hydrolysis conditions. Using t-butyldimethylsilyl chloride with imidazole in DMF, after 3 days at - 32 -
LAH
33
room temperature, only 50% of pure product 30a was obtained. Starting alcohol was also isolated. The use of _t-butyldimethylsilyl trifluoromethane sulfonate with 2,6-diraethylpyridine in methylene chloride (35) provided the subunit 30a in much shorter time and much higher yield (97%).
.33 30a - 33 -
4. Epoxide Subunit 31
Our plan for the synthesis of the epoxide subunit 31_ involved a
Wittig reaction of the aldehyde 16, followed by an epoxidation as shown in equation (iv).
(iv)
Attempted methylenation by adding the aldehyde to the ylid, from methyltriphenylphosphonium bromide and rv-butyllithiura, in a THF solution
Invariably gave the desired alkene 34_ in yields of 30% or less. The same unsatisfactory results were observed when the ylid was added to the aldehyde, using ether as solvent, or at lower reaction temperatures. We suspected two problems. One was the instability of the starting aldehyde _16_. It was felt that this factor alone could not account for the low yields. The base sensitivity of the ester raoity could also be a - 34 -
cause of the low yield. This possibility was supported by the loss of the methyl ester singlet in the ^-nrar of the crude product obtained when 3.5 equivalents of ylid were used.
These problems were solved by the utilization of a different methylenating agent. In 1978, Takai et al. developed two methods for terminal olefin synthesis (36). They found that reaction of
or a CH2I2-Zn-Me3Al CH2Br2-Zn-TiCLit mixture with a ketone or aldehyde could provide the desired methylene product in good yield. Lombardo, in his work on giberellin syntheses 4 years later, reacted the highly electrophilic CH2Br2-Zn-TiCli+ reagent with the ketone 35_ and found it destroyed the substrate before reacting (37). He prepared a more
active reagent by using neat titanium tetrachloride instead of a 1.0 M solution and changing the temperature and time of the procedure. The desired transformation was achieved in 90% isolated yield using the more active reagent with no evidence of epimerization of the adjacent chiral centre. Upon applying this reagent to cyclododecanone (36), we obtained the terminal olefin 37 in quantitative yields. - 35 -
36 37
Reaction of this reagent with the aldehyde 1_6 afforded the olefin
34 in purified yields varying between 50% and 60%, a doubling of the yield obtained with the Wittig reaction. The overall yield from the acid chloride 29_ to the oldefin 34, with isolation of the aldehyde was now in the range of 30% to 36%. By not isolating the aldehyde, but
rather treating a methylene chloride solution of same with the methylene
reagent, we obtained the olefin 34 in a 40% purified yield from the acid chloride 29. Thus the problem of aldehyde decomposition was eliminated.
2. CH2'complex 29 34
Epoxidation of 34_ was realized by treatment of the alkene in methylene chloride with 2 equivalents of meta-chloroperoxybenzoic acid
(MCPBA) providing a 75% yield of epoxide 31.
31 - 36 -
Now we were ready to initiate a study of the metallation of the dithiane 30a and subsequent coupling with the epoxide 41.
5. Dithiane Metallation
The dithiane 30a was metallated and reacted with epoxide 3J_ under the same conditions as were successful in the case of our model dithiane
17 and the epoxide 19. Unfortunately no product was obtained.
30a
1. n-BuLi 2 31
no product
The problem was traced to the lack of formation of the metallated dithiane of 30a as shown by a deuterium oxide quench of an aliquot of the solution containing 30a and n-butyllithiura. The percentage deuterium incorporated into the substrate was determined from the ^-nrar spectrum by integration of the dithioacetal hydrogen. - 37 -
Our attention was then directed to generation of the dithiane anion using different bases, solvent, reaction times and temperatures.
Using the stronger base _t-butylli thiura with THF as solvent failed to show any deuterium incorporation, over both short and long metallation times. When we changed the solvent to _n-heptane, we found no improvement. However, with the addition of tetraraethylethylenedfamine
(TMEDA), up to 58% anion formation was shown to occur. Varying the solvent, amount of TMEDA, metallation time and temperature gave the results shown in Table IV.
Table TV. Metallation studies on dithiane 30a using _c-butylll thium
Equlv. Temp Time Solvent TMEDA •c h X D rr- heptane - -70 2 0
ir- heptane 1.1 -70 2 50
tt-heptane 3 -70 2 50
tj- heptane 5 -70 2- 49
n-heptane 1.5 -35 2 45
ether 2 -70 1 42
vr heptane 2 -30 1.5 -20 21 0
From the percentage deuterium incorporated into 30a, we seem able to obtain only about 50% anion formation with _t-butylli thiura. Longer metallation times, more TMEDA and a solvent change failed to produce increased amounts of raetallated dithiane. These results did show the very beneficial effect of TMEDA in anion formation though.
Next we turned our attention to employing ri-butyllithiura and
TMEDA in either THF or n-heptane to metallate 30a. A double-check on - 38 -
anion formation was determined by reaction with 1,2 epoxy butane (19) to
give 3_8, as well as deuterium incorporation of an aliquot. Some results
are given in Table V and they show an improvement in anion formation
over previous methods.
Longer metallation times, as in the cases using _t-butyllithium
showed no improvement over these results. Similarly using more TMEDA
proved fruitless. While anion formation could be achieved in about 70%,
the yields of alkylated dithiane 38_ were In the 35% to 45% range.
Hexamethylphosphoramide (HMPA) might increase the nucleophilicity of the
anion or result In Improved anion formation and hence higher yield in
the reaction with the epoxide. Indeed, we found this to be so,
resulting in 75% yields by gc of 3_8. Only 20% of the starting dithiane
30a remained under the conditions. This result was achieved by
treatment of 30a in THF with n-butyllithium and TMEDA at -35°C for 0.5
h, followed by addition of HMPA and the epoxide 19_ at -20°C for 48 h.
We were now prepared to attempt the alkylation using epoxide 31.
30a
1. n-BuLi
19
•Si'
38 - 39 -
Table V. Metallation studies on dithiane 30a using rr-bu tylll thlum
Solvent Equiv. Equivalent Temp Time X D Z Product TMEDA ii •c h Aliquot 38
-30 1 50» THF 1.2 3 -30 0.5
-20 40 30-40*
- -30 2 75' - THF 1.1 1.2 -20 24 - 37b
-30 0.5 55a n-heptane 1.1 3 -30 0.5
-20 72 30-408 a -30 1.25 70 tj-heptane 1.2 3 -30 0.5
-20 72 40°
* H-msr analysis bisolated yield cgc analysis
6. Alkylatlon Reaction
Reaction of epoxide 3_1_ with the anion from 30a under similar
conditions which had proved successful with 1,2-epoxybutane (19) only
yielded 13% of isolated products 39a and 39b.
The reaction was repeated. Before addition of the epoxide 31_, an
aliquot of the solution was quenched with deuterium oxide. Analysis of
the ^-nrar spectrum revealed almost 100% deuterium incorporation.
Subsequent reaction with 31_ at -20°C for 4 days showed no improvement in
the yield of 39a and 39b.
- 41 -
The deuteration results indicated that the alkyllithiura base was abstracting the dithioacetal proton providing the raetalated dithiane in high yield. Once the epoxide-ester 31_ was added, the lithiodithiane moiety might abstract a proton from the carbon alpha to the ester and thus compete with the reaction of the epoxide. This would result in a poor yield of products 39a and 39b, as shown in equation (v). This
31
39a 39b 30a
+ - 42 -
hypothesis could be tested by H-nrar or gc analysis of recovered epoxide
31 showing racemization of the methyl group alpha to the ester. As the epoxide 3_1_ was volatile at reduced pressure and had a very similar Rf
value to the products 39a and 39bt we could never recover 3_1_ to test this postulate.
As a result of this possible deprotonation we considered alkylation of the dithiane with the epoxide 40_ in which the ester was reduced and protected. A route to this substrate was developed from the
40
alkene-ester 34. Reduction of the ester with lithium aluminum hydride, followed by treatment with _t-butyldimethylsilyl trifluoromethane sulfonate afforded the alkene 42_ in just under 55% overall yield.
Epoxidation of kl^ using 3 equivalents of raeta-chloroperoxybenzoic acid (MCPBA) gave the epoxide 40a in 86% yield. The ratio of epoxide - 43 -
30a
1, n-BuU,TMEDA
2. HMPA
40a
43b
diastereoraers was 65:35 as determined by gc analysis. This asymmetric centre present in 40a was not a concern, as it would be destroyed subsequently.
Generation of the dithiane anion of 30a was achieved using - 44 -
n-butyllithium, TMEDA and HMPA in THF. The epoxide 40a was added and after 40 h the reaction was worked up. The long reaction time did not
improve product formation as shown by tic analysis after 3 h and 43 h.
The desired (3-hydroxy dithianes 43a and 43b were obtained in 39%
purified yield. We recovered 43% of the starting dithiane 30a, which
could be recycled. The yield while three times that obtained with the epoxide-ester 3J_ was not as high as we had hoped.
Our attention was then directed to the two final steps which would provide the 3-diketones 44a and 44b.
7. Route to B-Diketones 44a and 44b
7
44b
The model studies on the B-hydroxy dithiane 20_ provided the
ketone 2jL_ in crude yields of about 80% using PDC in DMF. Treatment of
the S-hydroxy dithiane 38_ to the same conditions gave the ketone 4_5 in a
crude yield of only 26%. - 45 -
PDC,DMF
V
Because of this poor yield we decided to hydrolyse the dithiane, and unmask a B-hydroxy ketone and then oxidize this substrate to a
B-dike tone.
The alkylative hydrolysis of dithianes developed by Fetizon and
Jurion (38) involving methyl iodide, and used by Markezich et al. (39), appealed to us because It was neither strongly acidic nor basic. The dithiane 3_8_ was treated with methyl iodide in refluxing aqueous acetonitrile with calcium carbonate present, and provided a good yield of the B-hydroxy ketone 46_. We were pleased to observe that the TBDMS group was not cleaved. The B-hydroxy dithianes 43a and 43b were - 46 -
Mel
hydrolysed under the same conditions to provide the desired products 47a and 47b in 54% purified yield.
Evans et al., had used the sulfur trioxide pyridine complex
(S0 3*Py) to oxidize a B-hydroxy Imide 48_ as shown by Equation (vi)
(40). The desired product 49_ was obtained in 90% yield.
(vi)
This oxidation method was a modification of that developed by Parikh and
Doering (41).
- 48 -
47b
S03-Py, TEA
?
The 8-hydroxy ketones 47a and 47b were treated with triethylamine
(TEA) and sulfur trioxide pyridine complex while being stirred in a methylene chloride:diraethylsulfoxide solution. After 20 h no change was evident by tic analysis. However, the crude product obtained exhibited spectroscopic data consistent with formation of the desired 6-diketone.
Purification by flash chromatography on silica gel provided a quantitative yield of the starting B-hydroxy ketones 47a and 47b, as shown by ^H-nmr, ir and mass spectroscopy. The use of the 3-hydroxy ketone 50 gave a similar result. - 49 -
'(CH2)12CH3
50
We speculate that a cyclic sulfite _51_ or sulfate 5_2_ may be the crude product obtained which hydrolyses on silica gel to regenerate the
B-hydroxy ketones 47a and 47b.
51 52
With the failure of this oxidation, we carried out a Moffat oxidation on the 3-hydroxy ketone 5_0_ (42), using dicyclohexylcarbodiimide (DCC), dimethylsulfoxide and dichloroacetic acid for 1.5 h at room temperature. Although some dehydration of 50, affording a,B-unsaturated ketone, was apparent the major reaction product which was isolated was the desired S-diketone 53_ in over 50% purified yield. - 50 -
DCC.H*
(CH ) CH (CH2)12CH3 2 12 3 DMSO
The substrates 47a and 47b were subjected to the same oxidative method, and the desired B-diketones 44a and 44b were isolated in 25% purified yield. About 50% of the unreacted 3-hydroxy ketones 47a and
47b were recovered. Longer reaction times did not increase the amount of product formed, nor did the addition of more reagents. The use of methylene chloride and diraethylsulfoxide as solvent was also futile in improving the yield.
- 52 -
The structural proof of the S-diketones 44a and 44 b came from 400
MHz ^-nmr, ir, high and low resolution mass spectroscopy. The ratio of diastereoraers could not be determined and their separation was not possible. However, with the use of one enantiomer of the acid-ester 1_5_ with the correct absolute stereochemistry, the B portion of ionomycin can be produced with the correct absolute stereochemistry. The A
15 B portion
portion of ionomycin which our group is deriving from carbohydrate precursors will also have the correct absolute stereochemistry (14).
Subsequent coupling of these two units would provide one half of ionomycin (2), with the correct absolute stereochemistry. The model studies reported in this thesis have provided a viable pathway for the coupling of these two units in the synthesis of ionomycin. - 53 - - 54 -
EXPERIMENTAL
General
Unless otherwise stated the following are implied.
Melting points were determined on a Kofler micro heating stage and are uncorrected. Kugelrohr distillations were performed by means of a Buchi Kugelrohr thermostat. Infrared spectra were recorded on a
Perkin-Elmer model 710B spectrophotometer. Solution spectra were performed using a sodium chloride solution cell of 0.2 mm thickness.
Absorption positions are given in cm-1 and are calibrated by means of the 1601 cm-1 band of polystyrene. The proton nuclear magnetic resonance spectra were taken in deuterochloroform solution and recorded on a Bruker WP-80 (80 MHz) instrument unless otherwise specified. The
400 MHz spectra were recorded on a Bruker WH-400 instrument, and the 270
MHz spectra were recorded on a home-built unit consisting of an Oxford instrument 63.4 KG superconducting magnet and a Nicolet 32K computer.
Signal positions are given in parts per million downfield from tetramethylsilane using the 6 scale. The signal positions were determined relative to chloroform. Signal multiplicity, coupling constants, and integrated areas are indicated in parentheses. Low resolution mass spectra were determined on either a Varian MAT CH4B or
Kratos MS50 mass spectrometer. Spectra quoted as m/z values. The major ion fragmentations are reported as percentages of the base peak. High resolution mass measurements were determined using a Kratos MS50 mass spectrometer. Gas-liquid chromatography was performed on a Hewlett - 55 -
Packard model 5880A gas chromatograph using a 12 m x 0.2 mm column of
OV-101 or Carbowax 20M. The flow rate for the 5880A model was
1.0 mL/min or 2.4 mL/min and helium was used as the carrier gas. In all cases a flame ionisation detector was used. Microanalyses were performed by Mr. P. Borda, Microanalytical Laboratory, University of
British Columbia, Vancouver.
Silica gel PF254+366 supplied by E. Merck Co. was used for preparative tic. The plates were ca. 1 mm in thickness. Analytical tic was performed on commercial, pre-coated silica gel plates (silica gel 60
F25O supplied by E. Merck Co. Visualisation was effected by a combination of UV fluorescence, iodine vapour, or a 2 M sulphuric acid spray. Flash chromatography (43) was performed using silica gel 60,
230-400 mesh ASTM, supplied by E. Merck Co.
All reactions involving air or moisture sensitive reagents were performed under an atmosphere of dry nitrogen using either oven of flame-dried glassware. All reaction products were dried by allowing the solutions to stand over anhydrous magnesium sulphate. The petroleum ether used was of boiling range ca. 30°-60°C. Dry solvents and reagents were prepared as follows:
acetonitrile and methylene chloride by distillation from phosphorus pentoxide;
benzene, boron trifluoride etherate, dimethylsulfoxide,
2,6-dimethylpyridine, diethyl methylmalonate (23), 1,2-epoxybutane (19), ethyl 2-bromoisobutyrate (24), n-heptane and hexamethylphosphoramide by distillation from calcium hydride;
dichloroacetic acid by storage over anhydrous magnesium sulfate - 56 -
followed by a filtration and distillation;
diraethylforraaraide by distillation from barium oxide followed by storage over 4A molecular sieves;
dicyclohexylcarbodiiraide and oxalyl chloride were distilled before use;
ethanol by refluxing over magnesium ethoxide followed by distillation;
ethyl ether and tetrahydrofuran by refluxing over lithium aluminum hydride followed by distillation;
methanol by refluxing over magnesium raethoxide followed by distillation;
tetramethylethylenediamine by distillation from potassium hydroxide. n-Butyllithium and _t-butyllithium were obtained from Aldrich Chemical
Company, Inc. The alkyllithium solutions were standardised by titration against 1,3-diphenyl-2-propanone tosylhydrazone in THF (44). - 57 -
1,1 (Propane-1',3' dlthlo)-2-methyl propane (17)
17
A 1-L flask was charged with 36 mL isobutyraldehyde (18)
(0.4 mole), 800 mL chloroform and 40 ml 1,3-dithiolpropane (0.4 mole).
The solution was stirred for 1 h under an atmosphere of nitrogen, then cooled to -20°C. Boron trifluoride etherate (24*6 mL, 0.2 mole) was added, and the reaction was allowed to warm to room temperature overnight. The organic layer was washed three times each with water, potassium hydroxide solution and water and was dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure yielded a yellow oil. Distillation at reduced pressure (90°C/3 Torr) gave 51 g of compound 1_7_ (71% yield) as a pale yellow oil;
ir (CHCI3): 1460, 1415, 1280, 1190, and 910 cm-1;
^-nmr (CDCI3) 6: 1.03 (d, J_ - 7 Hz, 6H), 1.67-2.23 (m, 3H),
2.70-2.93 (m, 4H), 3.98 (d, = 6 Hz, IH);
mass spectrum: a) high resolution calcd for C7H11+S2: 162.0537 amu; found: 162.0535.
b) low resolution m/z (rel Intensity): 162(M+,
41), 121(12), 119(100), 55(14), 45(18), and 41(22). - 58 -
5,5 (Propane-1',3' dithio)-6-methyl heptan-3-ol (20)
20
A 50-mL rbf was charged with 0.81 g of the dithiane _17_ (5.0 mmole) and 25 mL THF. The stirred solution was cooled to -20°C under a nitrogen atmosphere and 4.0 mL jv-butyllithiura (1.4 M in hexane, 5.6 mmole) were added dropwise. After stirring for 2.5 h at -20°C, the reaction flask was stored at -10°C for 16 h. The solution was then warmed to 0°C, and 0.43 mL of 1,2-epoxybutane (19) (5.0 mmole) was added. After 5 h, the mixture was concentrated under reduced pressure.
Water was added and the aqueous phase was extracted three times with ethyl ether. The combined organic extracts were washed with water, brine solution and water, dried over anhydrous magnesium sulfate and filtered. Removal of the solvent under reduced pressure afforded 1.06 g of the alcohol 20_ (90% yield) as a white crystalline solid. Preparative tic of a small amount of this material using petroleum ether: ethyl acetate (6:1) gave 20_ as white powdery crystals;
mp: 65-66°C;
ir (CHC13): 3425, 1460, 1420, 1385, 1130, 1060 and 990 cm-1;
^-nmr (CDC13) 6: 1.03 (t, J = 7 Hz, 3H), 1.06 (d, J = 7 Hz, 3H),
1.24 (d, J_= 7 Hz, 3H), 1.35-2.55 (m, 7H), 2.75-3.00 (ra, 4H), 3.75 (bs,
IH, exchangeable with D20), 3.75-4.10 (m, IH); - 59 -
mass spectrum: a) high resolution calcd for CHH22OS2'. 234 .1112
amu; found: 234.1108;
b) low resolution m/z (rel intensity): 234 (M+,
24), 191(79), 161(18), 135(12), 133(100), 107(13), 73(13), 69(20),
59(25), 57(29) and 41(40).
5,5(Propane-l',3' dithio)-6-methyl heptan-3-one (21)
21
A 100-mL rbf was charged with 11.3 2 g pyridinium dichromate (30.0
mmole) and 25 mL DMF. The resulting solution was cooled to 0°C and the
alcohol _20 (1.0 g, 4.3 mmole) was added to this solution. After 11 h at
0°C, the reaction mixture was poured into 150 mL water. The aqueous
phase was extracted several times with ethyl ether. The combined
organic phases were washed four times with water, dried over anhydrous
magnesium sulfate and the solvent was removed under reduced pressure
giving 0.84 g of the crude ketone (85% yield). Preparative tic of a
small amount of this material using petroleum ether: ethyl acetate
(8:1) gave 21_ as a colourless oil;
ir (CHCI3): 1710, 1460, 1355, 1230, 1140 and 1110 cm-1;
hl-nmr (CDCI3) 270 MHz 6: 1.04 (t, J_ = 7 Hz, 3H), 1.22 (d, J_ =
6.5 Hz, 6H), 1.79-2.12 (ra, 2H), 2.41 - 2.56 (m, 1H), 2.59 (q, 2H), 2.73
- 3.01 (m, 4H), 3.16 (s, 2H); - 60 -
mass spectrum: a) high resolution calcd for Ci ^nC^J 232.0955 amu; found: 232.0942;
b) low resolution m/z (rel intensity: 232(M+,
22), 189(72), 175(13), 133(29), 107(18), 69(16), 57(100), 41(37) and
29(66).
2,4-Dimethylglutaric acid (12)
12
The diacid 1_2_ was prepared by a modified method of that employed by Auwers and Thorpe (23). A 3-necked 1-L rbf fitted with an addition funnel, condenser and nitrogen inlet, was charged with 200 mL ethanol.
Sodium (11.5 g, 0.5 mole) was added, portionwise, followed by an additional 50 mL ethanol. The mixture was heated until the solution was homogeneous. After the solution was cooled, a mixture of 100 mL diethyl methylmalonate (23) (0.58 mole) and 71.1 mL ethyl 2-bromoisobutyrate
(24) (0.485 mole) were added In two portions. The reaction was heated to reflux gently and then stirred overnight at room temperature. Most of the ethanol was removed by distillation. Then 200 mL glacial acetic acid: water (1:3) were added to the cooled flask. The organic layer was separated and the aqueous phase was washed four times with ethyl ether. The combined organic extracts were dried over anhydrous magnesium sulfate and solvent removed under reduced pressure to yield - 61 -
163 g of a pale yellow oil. This material was heated to reflux for 10 h with 270 mL concentrated hydrochloric acid and 200 mL water. The small organic layer which was still present was separated from the aqueous phase and recycled. The water in the aqueous phase was removed under reduced pressure and the resulting liquid was heated under nitrogen,
first to 120°C, then to 160°C. After 30 min, the flask was cooled and
the oil obtained was dissolved in water and extracted five times with ethyl ether. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to give 53.3 g of the diacid \2_ as a white solid. A further 20.2 g was obtained from recycling the organic layer isolated earlier to give a total crude yield
of 95%. This material was converted, without further purification, to
the anhydride 25. A small amount of the diacid _12 was recrystallized from benzene;
mp: 103-105°C (lit. (23)rap 105-107°C);
1 ir (CHC13): 2980, 1720 and 1460 cm" ;
'H-nmr (CDC13) 6: 1.20 (d, _J = 7 Hz, 3H), 1.23 (d, J = 7 Hz,
3H), 1.78-2.93 (m, 4H), 8.85 (bs, 2H, exchangeable with D20);
+ mass spectrum: a) high resolution calcd for C7H1g0 3 (M -H20):
142.0630 amu; found: 142.0624;
b) low resolution _m/_z (rel intensity):
+ 142(M -H20, 11), 118(11), 114(56), 100(17), 87(17), 74(54), 69(100),
56(79), 45(54), 44(76) and 41(68). - 62 -
Meso-2,4-dlaethylglutaric anhydride (25)
The diacid _12 (8.14 g, 0.05 mmole) was heated to 100°C with 10.8 mL acetic anhydride for 2 h. Removal of the volatile materials under reduced pressure, followed by kugelrohr distillation of the resulting
011 (80°C-140°C/0.1 Torr) afforded 7 g (97% yield) of a mixture of meso- and dl-anhydrides. This material was dissolved in 10 mL warm ethyl acetate and filtered. The filtrate was washed six times with 10 mL portions of ethyl acetate. The combined ethyl acetate washings were reduced to a volume of 50 mL. Crystallization by allowing the solution to stand afforded 2.76 g meso-anhydride 25 (38% yield from diacid 12) as a white crystalline solid;
mp: 93.5-94°C (lit.(23) mp 94-95°C);
-1 ir (CHC13): 1818, 1770, 1080 and 1020 cm ;
JH-nmr (CDC 13) 270 MHz 6: 1.37 (d, J = 8 Hz, 6H), 1.59 (q, =
12 Hz, J = 12 Hz, J_ = 12 Hz, 1H), 2.04 (dt, J = 6 Hz, J = 6 Hz, J = 12
Hz, 1H), 2.65-2.81 (m, 2H);
mass spectrum: a) high resolution calcd for C7H10O3: 142.0630 amu; found: 142.0636;
b) low resolution m/z (rel intensity):
98(M+-COO, 11) 70(10), 56(100), 55(17), 41(13), 39(13) and 28(28). - 63 -
Mono-methyl 2S*, 4R*-2,4-dimethyl glutarate (15)
15
A 50 mL rbf, fitted with a reflux condenser, was charged with
3.07 g (21.6 mmole) 25_ and 15 mL dry methanol. The resulting solution was heated to reflux and stirred overnight, after which the methanol was removed under reduced pressure. Vacuum distillation (102°C/0.2 Torr) yielded 3.41 g of the monoacid _15_ (91% yield), as a colourless oil;
-1 ir (CHC13): 2990, 1735, 1715, 1460, 1280 and 1175 cm ;
^-nmr (CDC13) 6: 1.18 (d, J - 6 Hz, 3H), 1.20 (d, J - 6 Hz,
3H), 1.53 (q, IH), 2.10 (q, IH), 2.38-2.78 (m, 2H), 3.67 (s, 3H), 11.33
(bs, IH);
+ mass spectrum: a) high resolution calcd for CgHi20 3 (M -H20):
156.0787 amu; found: 156.0784.
b) low resolution m/z (rel intensity):
+ 156(M -H20, 7) 143(32), 142(21), 128(47), 115(33), 114(45), 101(39),
88(49), 69(100), 59(50), 57(36), 56(71), 45(62) and 41(67).
Methyl 2R*, 4j5*-4-chloromethanoyl-2-me thyl pen tanoate (29)
29
The monoacid _15 (3.21 g, 18.5 mmole) was stirred in 15 mL of dry - 64 -
benzene in a 3-necked 100-mL rbf fitted with an equal pressure addition funnel and a nitrogen inlet. A catalytic amount of DMF was added (5
ML), followed by 2.42 mL oxalyl chloride (27.7 mmole) in 5 mL benzene over 30 min. After 3 h, the benzene was removed by distillation.
Vacuum distillation (52°C/0.2 Torr) afforded 3.26 g of the acid chloride
29 (92% yield) as a colourless oil;
ir (CCli,): 1800, 1745, 1460, 1200, 1180 cm-1;
J H-nmr (CDC13) 6: 1.21 (d, J = 6 Hz, 3H), 1.32 (d, J = 6 Hz,
3H), 1.58 (q, IH), 2.21 (q, IH), 2.48 (q, IH), 2.94 (q, IH), 3.70 (s,
3H);
mass spectrum: a) high resolution calcd for C7HJQ02C1 (M+-0CH3):
161.0370 amu; found: 161.0361;
b) low resolution _m/z_ (rel intensity):
16KM+-OCH3, 10), 157(35), 129(31), 128(32), 73(25), 69(100), 59(41),
56(48) and 41(56).
Methyl 2S*, 4R*-2,4-dimethy1-5,5 (propane-1',3'dithio) hexanoate (32)
A 50-mL 2-necked rbf was charged with 80 mg 9% Pd/C catalyst (15 mg per mmole acid chloride), 18 mL THF, 0.6 mL 2,6 dimethylpyridine (5 mmole). The acid chloride 29_, 0.985 g (5.1 mmole), in 7 mL THF was added and the system was hydrogenated for 8 h at atmospheric pressure. - 65 -
The reaction was filtered through Celite, and the solid was washed with ethyl ether. The filtrate was reduced to a volume of 10 to 15 mL. Then
50 mL ethyl ether was added and the organic layer was washed three times with cold 0.2 N hydrochloric acid, three times with sodium bicarbonate
solution, ammonium chloride solution twice, brine and water. The
organic phase was dried over anhydrous magnesium sulfate, filtered and
the solvent removed under reduced pressure to a volume of 5 to 10 mL.
This solution was transferred to a 50-mL rbf fitted with a nitrogen inlet. Chloroform (15 mL) was added, followed by 0.51 mL
1,3-dithiolpropane (5.1 mmole). After 1 h stirring at room temperature the solution was cooled to -20°C. Boron trifluoride etherate (0.315 mL,
2.56 mmole) was added and the reaction was allowed to warm to room temperature overnight, after which chloroform was added. The organic
layer was washed with water, three times each with potassium hydroxide
solution and water. The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure to give a yellow oil. Flash chromatography (3:1, petroleum ether: ethyl acetate) provided 787 mg of the dithiane _32_ (62% yield) as a pale yellow oil;
ir (CHC13): 1735, 1460, 1390, 1280, 1180 and 1150 cm-1;
^-nmr (CDC13) 6: 1.15 (t, 6H), 1.33-1.60 (m, 1H), 1.68-2.23 (m,
4H), 2.34-2.70 (m, 1H), 2.78-3.03 (m, 4H), 3.68 (s, 3H), 4.13 (d, J = 3
Hz, 1H);
mass spectrum: a) high resolution calcd for C11H20O2S2:
248.0905 amu; found: 248.0905; - 66 -
b) low resolution jn/jz (rel intensity): 248(M+,
26), 121(17), 119(100), 106(10), 73(15), 59(15), 45(21) and 41(32).
2S*f 4R*-2,4-dimethyl-5,5 (propane-1' ,3' dithio) hexan-l-ol (33_)
33
A 50-mL 2-neck.ed rbf was charged with 191 mg lithium aluminum hydride (5 mmole) and 8 mL ethyl ether, under a nitrogen atmosphere.
The suspension was cooled to 0°C, and then 635 mg of the ester 32 (2.56 mmole) in%7 mL ethyl ether was added. After 30 min at 0°C and 90 rain at room temperature, the reaction was carefully quenched with dilute hydrochloric acid. Ethyl ether was added and the organic layer was separated. The aqueous phase was washed three times with ethyl ether.
The combined ether extracts were dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure to give a yellow oil. Flash chromatography (1:1, petroleum ether: ethyl acetate) provided 492 mg of the alcohol 33_ (87% yield) as a pale yellow oil;
-1 ir (CHC13): 3475, 1460, 1420, 1380, 1275 and 1015 cm ;
'H-nmr (CDC13) 6: 1.00 (d, J = 9 Hz, 3H), 1.05 (d, J_ = 9 Hz, 3H),
1.58-2.33 (m, 6H), 2.15 (bs, 1H, exchangeable with D20), 2.73-3.05 (m,
4H), 3.28-3.68 (ra, 2H), 4.15 (d, J_ = 3 Hz, 1H);
mass spectrum: a) high resolution calcd for C11H20OS2: 220.0956 - 67 -
arau; found: 220.0957;
b) low resolution m/,z (rel intensity): 220(M+,
23), 121(15), 120(10), 119(100), 73(14), 55(13), 45(22) and 41(35).
2$*, 4R*-2,4-dimethyl-5,5 (propane-1',3* dithio)-l-[(t-butyldiraethyl- silyl)oxy]-hexane (30a)
-2°a
To a solution of the alcohol 33_ (0.48 g, 2.2 ramole) in 3 mL methylene chloride was added 2,6-diraethylpyridine (0.51 mL, 4.4 mmole) at 0°C under nitrogen. After 5 min, _t-butyldimethylsilyl
trifluororae thane sulfonate (0.75 mL, 3.3 mmole) was added and the reaction was stirred for 30 min at 0°C and 2.5 h at room temperature.
The reaction was diluted with ethyl ether, washed with 0.2 N hydrochloric acid twice, sodium bicarbonate solution twice, ammonium chloride solution and water. The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure giving a yellow oil. Kugelrohr distillation (140°C/0.2 Torr) afforded 0.708 g 30a as a colourless oil (97% yield);
-1 ir (CHC13): 1465, 1455, 1240, 920 and 825 cm ;
L H-nmr (CDC13) 270 MHz 6: 0.07 (s, 6H), 0.95 (s, d, 12H), 1.13
(d, J - 6 Hz, 3H), 1.63-2.22 (m, 6H), 2.84-3.05 (m, 4H), 3.35-3.59 (ddd, - 68 -
2H), 4.20 (d, J = 4 Hz, 1H);
mass spectrum: a) high resolution calcd for C 16H34OS2Si:
334.1820 amu; found: 334.1825;
b) low resolution m/z_ (rel intensity): 334(M+,
2), 319(2), 279(12), 278(19), 277(91), 171(22), 165(25), 149(11),
129(10), 119(77), 113(37), 95(23), 91(11), 75(100), 73(46) and 41(20).
Methylenation reagent
The active methlene complex was prepared by a slight modification of Lombardo's method (37). A 500-mL 2-necked rbf, fitted with an equal pressure addition funnel, was charged with 11.5 g zinc dust, 100 mL THF and 4.04 mL methylene bromide under nitrogen. The slurry was cooled to
-40°C. Titanium tetrachloride (4.6 mL) was poured into the addition funnel and dropwlse, over 30 min, was added to the slurry. As the addition of the titanium tetrachloride is very vigorous, it is recommended to leave the addition funnel stopperless. After 2 h stirring at -40°C, the grey slurry was warmed to 0°C, and stirred for
24 h. The active methylene complex can be stored between 0°C and 5°C for up to 2 weeks.
Methyl-2R*, 4j5*-2,4-dime thyl-5-hexenoate (34)
34
A 100-mL 3-necked rbf was charged with 0.18 g 9% Pd/C catalyst - 69 -
(15 mg per mmole acid chloride), 40 mL THF, 1.35 mL 2,6-dimethylpyridine
(11.6 mmole). The acid chloride 29, 2.25 g (11.7 mmole), in 15 mL THF was added and the system was hydrogenated for 8 h at atmospheric pressure. The reaction was filtered through Celite and the solid was washed with methylene chloride. The filtrate was reduced to a volume of
10 to 15 mL. Then 50 mL methylene chloride was added and the organic layer was washed three times with cold 0.2 N hydrochloric acid, three times with sodium bicarbonate solution, ammonium chloride solution twice, brine and water. The organic phase was dried over anhydrous magnesium sulfate, filtered and the solvent removed under reduced pressure to a volume of 50 mL. The methylene complex (37) stirred at
0°C was added portionwise, using a pipette, to this methylene chloride solution of the aldehyde 16. Conversion to the alkene 34_ is instantaneous and can be monitored by gc or tic analysis. After complete conversion, the black solution was poured into 150 mL super-saturated solution of sodium bicarbonate and 300 mL ethyl ether.
The mixture was stirred for 2 h until the solution was white with a black solid evident. The organic layer was separated and the aqueous layer was washed a few times with ethyl ether. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure to give a yellow oil. Flash chromatography (methylene chloride) provided 729 mg of the alkene 34_ as a pale yellow oil (40% yield);
ir (CHC13): 1735, 1650, 1460, 1170 and 920 cm-1;
^-nmr (CDC13) 6: 1.03 (d, J = 7 Hz, 3H), 1.11 (d, J - 7 Hz, - 70 -
3H), 1.28-2.65 (m, 4H), 3.65 (s, 3H), 4.83-5.13 (ra, 2H), 5.38-5.88 (m,
IH);
mass spectrum: a) high resolution calcd for C9H16O2 (M+-0CH3):
125.0966 amu; found: 125.0974;
b) low resolution m/z (rel intensity): 156(M+,
5), 125(10), 124(8), 101(12), 97(20), 96(13), 88(100), 81(12), 69(26),
57(27), 55(63), 41(36) and 29(24).
2R*. 4j>*-2,4-dime thy 1-5-hexen-l-ol (41)
41
Lithium aluminum hydride (0.185 g, 4.9 mmole) was stirred in 8 mL ethyl ether at 0°C. The alkene 34_ (0.38 g, 2.4 mmole) in 7 mL ethyl ether was added. After 30 min at 0°C and 90 min at room temperature,
the reaction was carefully quenched with dilute hydrochloric acid.
Ethyl ether was added and the organic layer was separated. The aqueous phase was washed three times with ethyl ether. The combined ether extracts were dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure to give a yellow oil. Flash chromatography (methylene chloride) afforded 0.174 g of the alcohol 41_
(56% yield) as a yellow oil;
-1 ir (CHCI3): 3480, 1650, 1460, 1380, 1020 and 920 cm 1 H-nmr (CDCI3) 6: 0.90 (d, J_ = 6 Hz, 3H), 0.98 (d, J_ =• 6 Hz, - 71 -
3H), 1.13-1.88 (in, 2H), 2.03-2.49 (m, 2H), 2.45 (bs, 1H, exchangeable
with D20), 3.30-3.63 (ra, 2H), 4.80-5.15 (ra, 2H), 5.40-5.90 (ra, 1H);
+ mass spectrum: a) high resolution calcd for C7H 13(M -CH2OH):
97.1017 amu; found: 97.1021;
b) low resolution m/_z (rel intensity): 128(M+,
1), 97(18), 95(41), 71(47), 70(29), 69(22), 68(42), 58(43), 57(21),
56(35), 55(100), 43(33), 41(54), 39(22), 31(30) and 29(36).
2R*, 4S^*-2,4-Dimethyl-l-[(t-butyldimethylsilyl)oxy]-hex-5-ene (42)
To a solution of the alcohol 41 (159 mg, 1.24 mmole) in 1.5 mL
methylene chloride was added 2,6-dimethylpyridine (0.29 mL, 2.5 mmole)
at 0°C under nitrogen. After 5 min _t-butyldimethylsilyl
trifluororaethane sulfonate (0.43 mL, 1.9 mmole) was added and the
reaction was stirred for 30 min at 0°C and 2.5 h at room temperature.
The reaction was diluted with ethyl ether, washed with 0.2 N
hydrochloric acid twice, sodium bicarbonate solution twice, ammonium
chloride solution and water. The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced
pressure giving a yellow oil. Flash chromatography (10:1, petroleum
ether: ethyl acetate) afforded 270 mg of the ether 4_2_ (90% yield) as a
colourless oil; - 72 -
ir (CHCI3): 1650, 1480, 1260, 950 and 840 cm-1;
1H-nmr (CDCI3) 400 MHz 6: 0.09 (s, 6H), 0.92 (d, J = 6 Hz, 3H),
0.95 (s, 9H), 1.02-1.11 (m, IH), 1.05 (d, J_ = 6 Hz, 3H), 1.39-1.48 (m,
IH), 1.63-1.75 (m, IH), 2.23-2.34 (m, IH), 3.37-3.51 (ddd, 2H),
4.92-5.05 (m, 2H), 5.61-5.72 (m, IH);
mass spectrum: a) high resolution calcd for CioH2lOSi
(M^-tBu): 185.1376 amu; found: 185.1369;
b) low resolution m/z (rel intensity):
lSSCM+^Bu, 57), 115(14), 76(12), 75(100), 73(27), 55(11) and 41(11).
2R*, 4S*-2t4-Dimethyl-l-[(t-butyldimethyl8ilyl)oxy]-5,6-epoxy hexane
(40a)
40a
To a stirred solution of the alkene kl_ (253 mg, 1.04 mmole) in 6
mL methylene chloride at 0°C, was added 543 mg (3.14 mmole) meta-
chloroperbenzoic acid (MCPBA). The reaction was allowed to warm to room
temperature slowly and was left stirring overnight. The reaction was
diluted with methylene chloride and washed once with sodium bicarbonate
solution, sodium thiosulfate solution, three times with sodium
bicarbnate solution and finally water. The organic layer was dried over
anhydrous magnesium sulfate, filtered and the solvent was removed under - 73 -
reduced pressure, giving a yellow oil. Flash chromatography (3:1, petroleum ether: ethyl ether) provided 231 mg of the epoxide 40a (86% yield) as a pale yellow oil;
1 ir (CHC13): 1460, 1255, 1090, 830 and 770 cm" ;
^-nmr (CDC13) 6: 0.05 (s, 6H), 0.83-1.13 (m, 8H), 0.93 (s, 9H),
1.38-1.93 (m, 2H), 2.40-2.85 (m, 3H), 3.33-3.48 (m, 2H);
mass spectrum: a) high resolution calcd for CiQH2i02Si
(M+-tBu): 201.1335 amu; found: 201.1323;
b) low resolution m/z (rel intensity):
201(M+-tBu, 16), 171(30), 145(22), 129(13), 115(28), 109(22), 105(12),
89(20), 75(100) and 73(26).
2S*, 4R*, 8S*, lORjfc-Z^.S.lO-Tetramethyl-l.ll-IdiCt^butyldlmethylsilyl) oxy]-7,7 (propane—1',3' dithio) undec-5-ol (43a) and its diastereomer
(43b)
43b
The dithiane 30a (114 mg, 0.34 mmole) was stirred in 1 mL THF at
-40°C. n-Butyllithium (0.17 mL, 2.2 M in hexane, 0.37 mmole) was added,
followed by tetramethylethylenediamine (TMEDA, 0.06 mL, 0.41 mmole), - 74 -
producing a faint yellow coloured solution. After 1 h, hexamethylphosphoramide (HMPA, 0.09 mL, 0.51 mmole) was added and a deep yellow coloured solution was observed. After 15 min, the reaction was cooled to -78°C. The epoxide 40a (96 mg, 0.37 mmole) in 1 mL THF was added dropwise. The reaction was stirred for 30 min at -78°C, 30 min at
-40°C, 2 h at -10°C and was stored at -2°C for 40 h. The reaction was diluted with water and ethyl ether. The organic layer was washed with sodium chloride solution, ammonium chloride solution, dried over anhydrous magnesium sulfate and filtered. Removal of the solvent under reduced pressure afforded on orange oil. Flash chromatography
(methylene chloride) gave the following compounds in order of elution:
(a) dithiane 30a (49 mg, 43%);
(b) B-hydroxy dithianes 43a and 43b as a pale yellow oil (79 mg, 39% yield, 69% based on recovered starting dithiane 30a);
-1 ir (CHC13): 3450, 1470, 1260, 1050, 910, 820 cm ;
^-nmr (CDC13) 6: 0.05 (s, 12H), 0.80-1.27 (m, 16H), 0.93 (s,
18H), 1.30-2.33 (m, 8H), 2.60-2.95 (m, 4H), 3.20-3.65 (m, 5H), 3.73-4.05
(m, IH);
mass spectrum: a) high resolution calcd for C3oHg^03S2Si2'•
592.3834 amu; found: 592.3834;
b) low resolution m/z_ (rel intensity): 592(M+,
3), 535(10), 377(20), 359(15), 246(19), 245(100), 187(29), 185(26),
165(16), 145(11), 133(19), 115(15), 113(99), 109(22), 107(13), 95(27),
75(58), 73(41) and 55(15). - 75 -
2R*, 4S*, 8R*, lO^-Z^.S.lO-tetraaethyl-l^U-tdl-Ct-butyldlmethylstlyl) oxy]-7 hydroxy-undec—5-one (47a) and its diastereomer (47b)
47a
+
47b
The 0-hydroxy dithianes 39a and 39b (39 mg, 0.07 mmole) and 18 mg calcium carbonate (0.4 mmole) were stirred in 5 mL acetonitrile and 2 mL water. Methyl iodide (1 mL) was added and the reaction was heated to reflux"for 17 h. The solvents were removed under reduced pressure and water was added to the residual material. The aqueous phase was washed three times with ethyl ether. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure to give a yellow oil. Flash chromatography (4:1, petroleum ether: ethyl ether) provided 18 mg of the 3-hydroxy ketones
47a and 47b (54% yield);
-1 ir (CHC13): 1710, 1460, 1390, 1260, 1110 and 840 cm ;
^-nmr (CDC13) 6: 0.05 (s, 12H), 0.80-2.15 (m, 20H), 0.93 (s,
18H), 2.48-2.70 (m, 2H), 3.33-3.53 (m, 5H), 3.80-4.05 (m, 1H);
+ t mass spectrum: a) high resolution calcd for 023^0,0^512 (M - Bu)
445.3170 amu; found: 445.3170; - 76 -
b) low resolution m/z_ (rel intensity):
445(M+-tBu, 11), 427(9), 313(5), 295(6), 287(7), 246(10), 245(57),
243(12), 221(15), 203(17), 201(24), 188(12), 187(94), 185(30), 113(100),
109(37), 95(49), 85(43), 83(31), 75(86), 73(59) and 57(47).
2R*, 4S*, 8R*, 10S*-2,4,8,10-tetramethyl-l,ll-ldi(_t-butyldimethylsilyl) oxy]-undec-5,7-dione (44a) and its diastereomer (44b)
44b
The B-hydroxy ketones 47a and 47b (10 mg, 0.02 mmole) were stirred in 0.2 mL dimethylsulfoxide and 0.2 mL methylene chloride.
Dicyclohexylcarbodiimide (DCC, 25 mg, 0.12 mmole) was added and after it dissolved, 0.8 uL (0.01 mmole) dichloroacetic acid was added. Petroleum ether was added, and the organic layer was washed with water and aqueous oxalic acid. The combined aqueous layers were washed once with petroleum ether. All the organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated affording a pasty solid.
Flash chromatography (40:1, petroleum ether: ethyl ether) provided in order of elution: -Il•
ia) product B-diketones 44 a and 44b (2.5 rag, 25% yield, 75% based on recovered starting material);
(b) starting B-hydroxy ketone 47a and 47b (5 mg, 50%).
The B-diketones 44a and 44b were characterized by the following spectral data;
1 ir (CHC13): 1600, 1460, 1260, 1060 and 1020 cm" ;
1 H-nrar(CDCl3) 400 MHz 6: 0.03 (s, 12H), 0.90 (d, s, 24H),
1.08-1.18 (ra, 2H), 1.14 (d, J = 8 Hz, 6H), 1.56-1.66 (m, 2H), 1.72-1.81
(m, 2H), 2.40-2.50 (m, 2H), 3.34-3.46 (m, 4H), 5.47 (s, 1H);
mass spectrum: a) high resolution calcd for C27H560i*Si2:
500.3719 amu; found: 500.3718;
b) low resolution m/_z_ (rel intensity): 500(M+,
2), 485(4), 445(12), 444(33), 443(100), 311(40), 244(14), 243(71),
185(49), 115(11), 109(11), 95(11), 83(30), 75(74), 73(57), 69(21) and
55(16). - 78 -
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SPECTRAL INDEX
- 88 - - 89 -
- 91 -