Studies towards the total synthesis of canataxpropellane
Dissertation submitted for the degree of Doctor of Natural Science
(Dr. rer. nat.)
Presented by Konstantin Samarin
At the University of Konstanz Faculty of Science Department of Chemistry
Konstanz, 2017
Konstanzer Online-Publikations-System (KOPS) URL: http://nbn-resolving.de/urn:nbn:de:bsz:352-0-416473
Tag der mündlichen Prüfung: 21.07.2017
1. Referent/Referentin: Prof. Dr. Gaich
2. Referent/Referentin: Prof. Dr. Wittmann
3. Referent/Referentin: Prof. Dr. Kalesse
i Abstract
Following Ph.D. thesis describes the synthetic studies towards the total synthesis of canataxpropellane.
Canataxpropellane was isolated in 2007 from the canadian yew Taxus canadensis. It belongs to the taxane terpenoid family, amongst which paclitaxel is one of the most famous and commercially used compounds. Canataxpropellane is the first dipropellane-containing taxane, which comprises a very uncommon 5/5/5/4/6/6/6- membered heptacyclic ring system. Neither synthetic nor biological activity studies considering canataxpropellane have been reported up to date.
During this work, three approaches were pursued to establish a successful synthetic route towards canataxpropellane and its derivatives.
Our final retrosynthetic analysis implies a highly efficient and convergent approach towards the central core of this molecule starting from a literature-known dienone and isobenzofuran. Applying a Diels-Alder reaction between these two building blocks with subsequent intramolecular [2+2]-photocycloaddition, we were able to set up five of six quaternary carbon centers and build up the first [4.4.2]propellane scaffold. We have already shown that the synthesis of an advanced intermediate, whose structure highly resembles the structure of canataxpropellane, could be achieved in total 13 steps.
It was also possible to perform the Diels-Alder reaction with 2-ethoxy-isobenzofuran under high-pressure conditions to get to a pre-functionalized cage-like intermediate, which will lead directly to the desired canataxpropellane in the same manner as we have shown for the unsubstituted isobenzofuran.
Summarized, we promoted first synthetic studies in this field and pioneered the synthesis of complex derivatives of canataxpropellane. The final total synthesis of this challenging molecule should be achieved in the course of time.
ii
iii Zusammenfassung
Die vorliegende Doktorarbeit beschreibt synthetische Studien zur Totalsynthese von Canataxpropellane.
Canataxpropellane wurde 2007 aus der kanadischen Eibe Taxus Canadensis isoliert.
Dieses gehört zur Familie der Taxane, unter denen Paclitaxel eine der bekanntesten kommerziell verwendeten Verbindungen ist. Canataxpropellane ist das erste Dipropellan-enthaltende Taxan, das ein sehr ungewöhnliches 5/5/5/4/6/6/6-gliedriges, heptazyklisches Ringsystem aufweist. Bis heute gibt es noch keine synthetischen oder biologischen Untersuchungen hierzu.
Während dieser Arbeit wurden insgesamt drei Syntheseansätze verfolgt, um die Darstellung von Canataxpropellane und entsprechenden Derivaten zu erreichen.
Unsere finale retrosynthetische Analyse beinhaltet einen höchst effizienten und konvergenten Syntheseansatz zur Kernstruktur dieses Moleküls ausgehend von einem bekannten Dienon und einem Isobenzofuran. Eine Diels-Alder Reaktion zwischen diesen Bausteinen, gefolgt von einer intramolekularen [2+2]-Photozykloaddition haben die Ausbildung der Käfig-Struktur von Canataxpropellane ermöglicht, indem wir fünf von sechs quaternären Kohlenstoffzentren und den [4.4.2]Propellan-Teil aufbauen konnten. Wir haben des Weiteren gezeigt, dass die Synthese eines fortgeschrittenen Intermediates, das Canataxpropellane strukturell sehr ähnlich ist, in insgesamt 13 Schritten erreicht werden konnte.
Es war auch möglich, die Diels-Alder Reaktion mit 2-Ethoxy-Isobenzofuran durchzuführen, indem eine Hochdruckapparatur verwendet wurde. Auf diese Weise wurde das prefunktionalisierte Substrat mit Käfig-Struktur als Kernelement synthetisiert, das analogerweise direkt zum gewünschten Canataxpropellane führen sollte, wie wir es bereits für das unsubstituierte Isobenzofuran gezeigt haben.
Zusammenfassend haben wir erste synthetische Untersuchungen in diesem Bereich durchgeführt und die Synthese von komplexen Derivaten von Canataxpropellane erfolgreich ausgeführt. Die finale Totalsynthese von diesem anspruchsvollen, unikalen Molekül sollte im Laufe der Zeit erreicht werden.
iv Graphical Abstract
v Table of contents
1. Introduction ... 1
2. Canataxpropellane ... 3
2.1. Isolation and structural key features ... 3
2.2. Biosynthesis of canataxpropellane ... 4
3. Related taxane diterpenoids containing propellane fragment ... 5
4. Total synthesis of natural products containing propellane fragment ... 6
4.1. Total synthesis of modhephene ... 6
4.2. Total synthesis of colombiasin A ... 13
4.3. Total synthesis of salvileucalin B ... 17
5. Synthesis and chemistry of cage compounds ... 21
6. Results and Discussions ... 24
6.1. First retrosynthetic analysis of canataxpropellane ... 24
6.1.1. First synthetic approach towards canataxpropellane ... 25
6.2. Second retrosynthetic analysis of canataxpropellane ... 31
6.2.1. Second synthetic approach towards canataxpropellane ... 32
6.3. Third retrosynthetic analysis of canataxpropellane ... 38
6.3.1. Third synthetic approach towards canataxpropellane ... 39
6.3.2. Investigation on opening of the oxygen-ether-bridge ... 50
6.4. Fourth synthetic approach towards canataxpropellane ... 55
6.4.1. Application of benzo[c]thiophene in Diels-Alder reaction ... 55
6.4.2 Application of substituted isobenzofurans in Diels-Alder reaction ... 57
6.4.3. Application of high-pressure Diels-Alder reaction ... 63
7. Conclusions and outlook ... 66
8. Experimental ... 69
8.1. General information ... 69
vi
8.2. Experimental procedures ... 70
8.2.1. First approach... 70
8.2.2. Second approach ... 78
8.2.3 Third approach ... 90
8.2.4 Fourth approach ... 115
9. Appendix ... 133
9.1. Spectra ... 133
9.2. X-Ray analysis ... 197
9.3. List of Figures ... 209
9.4. List of Schemes ... 209
9.5. List of Tables ... 212
9.6. References ... 213
Danksagung ... 221
Curriculum Vitae ... 223
vii List of Abbreviations
Ac acetyl
AIBN azobisisobutyronitrile
Bn benzyl
Bu butyl
Bz benzoyl
CAN cerium ammonium nitrate
CDI 1,1′-carbonyldiimidazole
cod 1,5-cyclooctadiene
Cp cyclopentadiene
CSA camphorsulfonic acid
dba dibenzylideneacetone
DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
DCC N,N´-dicyclohexylcarbodiimide
DCM dichloromethane
DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
DIBAL diisobutylaluminum hydride
DIC N,N´-diisopropylcarbodiimide
DIPEA diisopropylethylamine
DMA dimethylacetamide
DMAP N,N-4-dimethylaminopyridine
DMDO dimethyldioxirane
DMF N,N-dimethylformamide
DMP Dess-Martin periodinane
DMSO dimethyl sulfoxide
dr diastereomeric ratio
EDC·HCl 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
ee enantiomeric excess
EE ethyl acetate
Et ethyl
hfacac hexafluoroacetylacetonate
HMDS hexamethyldisilazane
HMPA hexamethylphosphoramide
HRMS high resolution mass spectrometry
viii
hv irradiation with light
i iso
IBX 2-iodoxybenzoic acid
Im imidazole
IR infrared spectroscopy
KHMDS potassium bis(trimethylsilyl)amide
LDA lithium diisopropylamide
LHMDS lithium bis(trimethylsilyl)amide L-selectride lithium tri-sec-butylborohydride
m meta
mCPBA meta-chloroperbenzoic acid
Me methyl
MS mass spectrometry
MW microwave irradiation
n normal
NMR nuclear magnetic resonance
o ortho
p para
Ph phenyl
PIDA phenyliodonium diacetate
ppm parts per million
Pr propyl
Py pyridine
SEM [2-(Trimethylsilyl)ethoxy]methyl acetal
TBAF tetrabutylammonium fluoride
TBS tert-butyldimethylsilyl
TCBC 2,4,6-trichlorobenzoyl chloride
Tf triflate
TFA trifluoroacetic acid
THF tetrahydrofuran
TIPS triisopropylsilyl
TMS trimethylsilyl
Ts tosyl
1 1. Introduction
In the past, evergreen trees and shrubs from Taxaceae family were widely used in folk medicine against infection, skin cancer, headache, etc. The leaves and needles of these plants are highly poisonous since they contain considerable amounts of derivatives called taxanes. To the end of 2009 over 550 different taxanes were isolated from various parts of these plants1 which are all structurally related to tricyclic core of taxadiene 1 (Figure 1).
Figure 1. Structures of taxadiene 1 and paclitaxel 2.
The most representative member of the taxane diterpene family is paclitaxel 2, which is also one of the most prominent anti-cancer drugs with wide clinical use.2,3,4,5 Since decades both, the physiological activity and the molecular structure of this compound gained a great attention in the scientific community, especially in the field of total synthesis. Until now the highly oxidized bridged 6/8/6 tricyclic carbon framework with an additional oxetane ring remains a challenging synthetic target.
Nine total syntheses of paclitaxel6,7,8,9,10,11,12,13,14 and various synthetic approaches to the classic taxane core 315 have been published up to date. Along with the common tricyclic system of 3, there are many other related scaffolds which are derived from this parent structure (Figure 2).1 For instance, there is a subclass of taxanes which contains a degraded 6/8/6 tricyclic taxane core leading to the formation of the following bicyclic systems 8/6 4 and 6/12 5, which could be considered as less structurally complex. Another subclass of taxane derivatives consists of rearranged tricyclic systems like 5/7/6 6, 5/6/6 7 and 6/10/6 8. The last subclass are the derivatives containing the complex taxane core, where additional intramolecular C-C bonds contribute to the increase of structural complexity. Compared to the initial taxane core
2
3 structures 9 and 10 contain a single additional C-C bond, skeleton 11 two new and scaffold 12 three additional bonds which form a new annulated four-membered ring.
Figure 2.Structural diversity of naturally occurring taxanes.1
Surprisingly, to the best of our knowledge, no synthetic studies towards the total synthesis of any other taxane family member except the classic core 3 have been reported up to date.
To explore the high synthetic and biological potential of the taxane derivatives a novel synthetic access towards the most challenging taxane canataxpropellane was developed.
3 2. Canataxpropellane
2.1. Isolation and structural key features
Canataxpropellane 13 (Figure 3) was first isolated in 2007 from the needles of the Canadian yew, Taxus Canadensis.16 The Canadian yew grows in eastern North America and, as other members of the Taxus genus, is highly poisonous. Nevertheless numerous taxanes were isolated during the last twenty years from Taxus Canadensis.17 Canataxpropellane 13 is the first taxane, which contains a very uncommon 5/5/5/4/6/6/6-membered heptacyclic ring system. Neither synthetic nor biological activity studies considering canataxpropellane 13 have been reported up to date.
Figure 3. Structural key features of canataxpropellane 13.
This unique compound possesses numerous of remarkable structural key features, which are depicted in figure 3. First, the taxane skeleton is spatially folded to the highly sterically hindered framework highlighted in violet (A, Figure 3). Furthermore, it is the first known natural product harboring two propellane frameworks – a [3.3.2] and [4.4.2]propellane in one single molecule (B and C, Figure 3). It should be noticed that even individually considered, these features are rare in natural products. In addition, 13 contains a cage-like backbone, which comprises five of seven rings (D, Figure 3).
4
The pivotal fully substituted cyclobutane ring (E, Figure 3) predestinates the existence of both previously mentioned propellane fragments. Finally, canataxpropellane 13 has twelve contiguous stereocenters (F, Figure 3) and six contiguous quaternary centers (G, Figure 3), five of which are at the same time stereogenic atoms.
To the best of our knowledge, canataxpropellane 13 was the first known natural product which contains four quaternary stereogenic carbons within the cyclobutane ring. Recently, another [4.4.2]propellane terpene artesin A 14 (Figure 4) was isolated which structure contains fully substituted cyclobutane core.18
Considering the high biological activity of paclitaxel, it is of great interest to investigate physiological activity of canataxpropellane 13 for the possible pharmacological applications.
Figure 4. Structure of artesin A 14.
2.2. Biosynthesis of canataxpropellane
Scheme 1. Proposed biosynthesis of canataxpropellane 13.16
5
Along with the isolation of canataxpropellane 13 a plausible biosynthetic pathway has been discussed by the same group (Scheme 1).16 Presumably, the biosynthesis commences with 9-deacetyltaxinine A 15, which is a very common taxane found in the Taxus genus. The epoxidation of the exocyclic double bond of 15, leads to the corresponding epoxide 16. The following base-mediated epoxide opening with consecutive oxidation gives the unsaturated aldehyde 17. Next the aldol reaction could take place yielding tetracyclic compound 18. Finally, as soon as the two olefin moieties of 18 are in the spatial proximity to each other, [2+2]-photocycloaddition occurs, furnishing canataxpropellane 3.
It should be mentioned, that the tetracyclic taxane 18 was isolated in 2002.19 This finding supports the aforementioned hypothesis.
3. Related taxane diterpenoids containing propellane fragment
To date all identified naturally occurring taxanes which contain a propellane-fragment were isolated from the same plant Taxus Canadensis.20 Canataxapropellane 19 was obtained in 200221 and elucidation of it structure revealed the [3.3.3]propellane fragment (Figure 5). Two years later the same group found three new taxane-derived dipropellanes 20, 21 and 22, which beside the [3.3.3]propellane moiety contain an additional [5.4.3]propellane fragment.22 In 2008 a new taxpropellane 23 has been found.23 In comparison to 13 taxpropellane 23 contains a [6.4.2]propellane instead of a [4.4.2]propellane fragment. As it can be seen in figure 5 all these natural products are closely related to each other and it is not surprising, that all of them are assumed to originate from taxinine A.
Figure 5. Other propellane-containing taxanes.
6
4. Total synthesis of natural products containing propellane fragment
Recently two comprehensive reviews about the total synthesis of propellane- containing compounds were published.24,20 All known examples of the total synthesis of propellane-containing natural products are described there in full detail. Considering structural features of canataxpropellane 13, only the natural products with propellane fragments consisting solely of carbon atoms and without any heteroatoms will be described further.
4.1. Total synthesis of modhephene
Modhephene 24 is the most synthetically investigated natural product containing the characteristic [3.3.3]propellane moiety. Its polycyclic scaffold consists exclusively of carbon atoms and contains a single double bond, which is the only unsaturated part of the molecule. However, these structural features are synthetically challenging. There are nineteen total syntheses of modhephene published up to date, which cover all possible cationic, nucleophilic, radical and photochemical approaches.24
Scheme 2. Total synthesis of modhephene 24 by Dreiding.25
7
For the first time modhephene 24 was synthesized by the group of Dreiding in 1980 (Scheme 2).25 Starting from the unsaturated bicyclic ketone 25, a Michael addition of cyanide was performed, followed by a Wittig reaction and subsequent hydrogenation of the obtained olefin furnished nitrile 26 as a mixture of diastereomers in good yield.
After basic hydrolysis of 26 the obtained carboxylic acid was converted to the corresponding acid chloride and directly subjected to AlCl3 catalyzed reaction with bis(trimethylsilyl)acetylene 27. Following basic desilylation provided ynone 28 in 90%
yield. The next step enabled formation of the desired [3.3.3]propellane motif via thermic annulation of α-alkynone. By heating 28 at 620 °C, an alkylidene carbene is formed in situ which after abstraction of the tertiary hydrogen atom cyclizes to 31 along with the side products 30, 29 in a ratio 2:1:1 albeit in impressive 95% combined yield. The obtained mixture of regioisomers 29, 30 and 31 was not separated at this stage, but after two additional steps. Subsequent 1,2-addition of MeLi and Jones oxidation gave pure intermediate 32 30% yield over two steps. Following copper-mediated Michael addition furnished gem-dimethyl 33. Finally, the carbonyl moiety was olefinated giving 34 and the resulting exocyclic double bond was shifted providing modhephene 24.
Similar approaches were independently used in total synthesis of modhephene 24 by other research groups.26,27,28
Alternatively, the group of Smith III developed an effective strategy towards modhephene 24 utilizing a spectacular carbocationic rearrangement (Scheme 3).29 This synthesis commences with building block 35 which was subjected to irradiation in the presence of 1,2-dichlorethen 36 thus assembling the propellane scaffold 37 already
Scheme 3. Total synthesis of modhephene 24 by Smith III.29
8
in the first step. Next the ketone moiety was protected as an acetal and Birch conditions were used to install the cyclobutene ring. Following deprotection under acidic conditions, led to the highly strained β,γ-unsaturated ketone 38. Hereupon Cargill reaction was performed during which a 1,2-shift of the olefin occurred to 39 followed by the pinacol rearrangement which furnished the modhephene-like intermediate 40 in excellent 93% yield. The following MeLi addition and Jones oxidation enabled successful allylic transposition. Subsequent 1,4-addition using Me2CuLi provided compound 41. The final olefination/double bond shift sequence was performed in analogy with the synthesis of Dreiding et al.25 to give modhephene 24 in 43% yield over two steps.
Another impressive example of a modhephene synthesis in terms of cationic rearrangement was demonstrated by Fitjer (Scheme 4).30 The synthesis started with an olefination of acetone with cyclobutane phosphor ylide 42, followed by [2+2]-ketene cycloaddition furnishing spirocyclic ketone 43 in an efficient manner. Both chlorine atoms were removed by using zinc in acetic acid and after one more Wittig olefination with 42 tricyclic intermediate 44 was obtained. Subsequent epoxidation of the tetrasubstituted double bond with mCPBA worked in excellent 91% yield. Upon exposure to Lewis acid the obtained epoxide reacted in a semipinacol rearrangement with moderate yield, which was followed by α-methylation to give a mixture of diastereomeric ketones 45.
Scheme 4. Total synthesis of modhephene 24 by Fitjer.30
9
Additional deprotonation with LDA and quenching with aquatic sodium sulfate enriched desired diastereomer and after addition of methyl lithium intermediate 46 was isolated.
After nine steps the stage was set for the key cationic cascade rearrangement. Heating the 46 to 70 °C in benzene with pTsOH resulted in formation of the desired modhephene 24 and triquinane 47 in excellent combined yield. This is a remarkable example for the application of cationic cascade reactions in the synthesis of complex natural products containing propellane fragments.
Other total syntheses of modhephene utilizing a carbocationic rearrangement key step were reported by Mundy31 and Tobe.32
The group of Cook developed a very simple but rather practical approach towards the total synthesis of modhephene 24 (Scheme 5).33 The desired [3.3.3]propellane motif was assembled using Weiss reaction already in the first step. First double Knoevenagel condensation of 1,2-diketone 48 with dimethyl 3-oxoglutarate 49, followed by the double Michael addition of a second equivalent of 49 installed the propellane moiety, which after ester decarboxylation provided diketone 50. One ketone moiety was selectively converted to the corresponding enol phosphonate which was reduced under hydrogen atmosphere in the presence of Pt on charcoal in 75% yield over two steps. Subsequent classic Regitz diazo-transfer gave the diazo compound which, upon addition of copper sulfate and formation of corresponding copper carbenoid, was converted to cyclopropane 51. Next, the less sterically hindered α-position of ketone 51 was methylated twice with good yields and the tertiary alpha position was deprotonated with tBuLi. Trapping of the formed enolate with carbon dioxide followed
Scheme 5. Total synthesis of modhephene 24 by Cook.33
10
by esterification using diazomethane resulted in the formation of compound 52 in moderate yield.
Reaction with Me2CuLi resulted in the addition of methyl group on γ-position with accompanied opening of cyclopropane ring. Obtained derivative was further smoothly methylated yielding 53 with all methyl groups in place. Upon heating of 53 in the presence of lithium iodide and collidine, the ester moiety was efficiently removed and final reduction/alcohol elimination furnished modhephene 24.
Almost in a decade two other syntheses of modhephene followed, which featured anionic cyclization as key step for the propellane formation.34,35
In 1982 group of Wender pioneered the application of the meta-photocycoaddition in the synthesis of complex natural products, thus synthesizing modhephene 24 in a very short and concise manner (Scheme 6).36
Scheme 6. Total synthesis of modhephene 24 by Wender.36
The synthesis started with very simple building blocks - arene 54 and vinyl acetate 55 which were irradiated with UV-light for 35 hours using the Vycor filter. In this manner, tetracyclic compound 56 could be obtained in 21% yield, but with the already build up propellane skeleton and right oxidation states on carbon framework for further functionalization. With this in hand, in next steps the alcohol moiety was deprotected and oxidized with BaMnO4 in high yields. Obtained ketone 57 was extensively methylated, albeit in low yield (apart from 68% of double methylated product). Addition of copper reagent resulted in methylation with concomitant opening of the cyclopropane ring, whereupon the in situ generated enolate was trapped giving
11
phosphoramide 59 in 76% yield. After two additional selective reductions modhephene 24 was synthetized over 7 steps in 8.2% overall yield.
Another remarkable example of application of photochemistry in total synthesis of modhephene belongs to the oxa-di-π-methane rearrangement. The synthesis started with Grignard 1,2-addition to bicyclic enone 60 followed by the acid mediated water elimination thus providing a complex and very sensitive mixture of olefins in a combined yield of 86% containing diene 61 as a major component. This mixture was immediately subjected to Diels-Alder reaction with α-chloroacrylonitrile leading to the formation of two products 62 and 63 in a 43% yield. After subsequent hydrolysis, the ketones 64 and 65 were obtained, which could be separated using silica gel column chromatography. Next the ketone 64 was irradiated with a 450W Hanovia medium- pressure lamp in acetone to give propellane 66 by pivotal oxa-di-π-methane rearrangement in 50% yield. The less substituted α-position of 66 was methylated twice furnishing intermediate 67 with 55% yield. The cyclopropane ring of 67 was opened under Birch conditions, and the ketone moiety was reinstalled using PCC oxidation.
Subsequent introduction of the last methyl group yielded derivative 68.
Scheme 7. Total synthesis of modhephene 24 by Mehta.37
12
Final reduction with lithium aluminium hydride and treatment with phosphoryl chloride completed the synthesis of modhephene 24.
The similar key oxa-di-π-methane rearrangement was also used by the group of Uyehara for the synthesis of modhephene in 1996.38
Another method which also proved to be very suitable for the assembly of propellane units is a radical cyclization cascade reaction. For example, such an approach was developed by the group of Lee (Scheme 8).39 The synthesis began with the ketoester 69 which was deprotonated with two equivalents of LDA in the presence of HMPA.
After addition of 4-bromobutene 70 the first alkylation product was obtained in 87%
yield. Repetition of this procedure with another electrophile 71 furnished the intermediate 72 in moderate yield. Subsequent treatment with KOH in MeOH under elevated temperature led to the saponification of the ester moiety and carbon dioxide extrusion.
Scheme 8. Total synthesis of modhephene 24 by Lee.39
The obtained ketone was condensed with N-amino aziridine 73 providing the hydrazone 74. Next, the key radical cyclization cascade was performed utilizing classic conditions and therefore allowing the smooth formation of 75 in 74% yield. The remaining exocyclic double bond from the alkyne part was ozonolyzed to the corresponding ketone, which in turn was deprotonated, reacted with PhSeBr and after following selenoxide elimination converted to enone 76. Compound 76 was already
13
used in several total syntheses of modhephene 24, thereby Lee successfully accomplished the formal synthesis.
A different approach to modhephene was developed by Pattenden and coworkers, who started the synthesis with cyclooctanone derivative 77 (Scheme 9).40 The intermolecular McMurry coupling of ketone 77 with acetone followed by TBS- deprotection and Swern oxidation provided intermediate 78. Next, Peterson olefination was used to introduce ester side chain. Subsequent basic hydrolysis yielded corresponding carboxylic acid which was transformed into the thioester 79 using Steglich coupling conditions. Heating of 79 and tributyltin hydride in the presence of azobisisobutyronitrile triggered the radical cyclization cascade thus enabling smooth formation of tricyclic propellane 80. Two step Regitz protocol was used for the synthesis of diazo-compound 81. The reflux of 81 with CuSO4 resulted in a C-H insertion of the corresponding carbenoid, leading to the literature-known tetracyclic derivative 82 and thus finishing the formal synthesis of modhephene 24.
Scheme 9. Formal total synthesis of modhephene 24 by Pattenden.40
Apart from the approaches mentioned above there are syntheses by Curran41, Sha42 and Rawal43 which used the radical cyclization as a key step.
4.2. Total synthesis of colombiasin A
Another intriguing natural product which contains a [4.4.4]propellane framework is colombiasin A 83. It is assumed that one of six-membered rings of 83 biosynthetically originates from a functionalized quinone. Currently there are three brilliant total
14
syntheses of this molecule which take advantage of high reactivity of quinone moiety in a Diels-Alder reaction to build up the sophisticated propellane skeleton.
The first total synthesis of colombiasin A 83 was reported by the group of Nicolaou (Scheme 10).44,45 Starting from diene 84 and quinone 85 enantioselective Diels-Alder reaction was performed using (S)-Binol-TiCl2 complex. Intermediate 86 was transformed to the methylated hydroquinone and the TIPS-protected enol ether was hydrolyzed using TFA thus providing bicyclic ketone 87 in 70% yield and excellent 94% ee. The ketone 87 was treated with LHMDS, to obtain the conjugated enolate which was afterwards trapped with chloroformate 88.
Scheme 10. Total synthesis of (-)-colombiasin A 83 by Nicolaou.44,45
15
The obtained ester 89 was subjected to the Pd(0)-catalyzed Tsuji-Trost like reaction which resulted in the formation of an inseparable mixture of ketones 90 and 91. Next, the ketone moiety was reduced diastereoselectively with sodium borohydride and protected with TBS to give 92 in high yields. Subsequent Lemieux–Johnson oxidation led to a mixture of aldehydes which could be separated by column chromatography to give pure 93. With the aldehyde 93 in hand the stereochemistry of methyl group was inverted to give the desired diastereomer 94 in 50% yield. Following three steps sequence of Wittig olefination, hydroboration/oxidation and PCC oxidation provided elongation of the side chain in high yields. The resulting aldehyde 95 was reacted with phosphor ylide 96 and the obtained diene mixture was protected with SO2. After treatment with silver oxide in nitric acid deprotected quinone 97 was obtained in 79%
yield. Heating of 97 in toluene at 180 °C allowed the release of the unmasked diene which subsequently underwent intramolecular Diels-Alder reaction, thus enabling elegant formation of the last two rings and furnishing propellane derivative 98. After following two step Barton-McCombie deoxygenation and deprotection of the obtained alcohol by BBr3, the first enantioselective synthesis of colombiasin A 83 was accomplished.
Scheme 11. Total synthesis of (-)-colombiasin A 83 by Rychnovsky.46
16
Another approach to colombiasin A was published by the group of Rycnovsky (Scheme 11).46 Compared to the previous synthesis, the strategy of Rychnovsky might appear to be similar, however the major difference is the application of advanced diene 99 with preinstalled stereoinformation.
Thus, the first Diels-Alder reaction was catalyzed by lithium perchlorate and provided a mixture of bicyclic derivatives 100 and 101 in satisfying 75% combined yield, which could be successfully separated. Regioselective ketone reduction in 101 with sodium borohydride was performed to prevent aromatization to hydroquinone. The acetate group in allylic position was substituted with LiCuMe2 thus securing the methyl group with desired stereochemical configuration in 89% yield. Following hydrogenation of double bond and reoxidation to semiquinone provided compound 102 in excellent yields. Treatment of 102 with DBU under ambient conditions led to aromatized quinone in 70% yield which after exposure to the zinc and acetic anhydride gave diacetylated hydroquinone. The subsequent TIPS-deprotection and Dess-Martin oxidation yielded aldehyde 103. The following Wittig reaction and acetate deprotection accompanied by air oxidation generated the diene 104, which was a direct precursor to colombiasin A.
Final Diels-Alder reaction performed in toluene under elevated temperature and AlCl3- mediated cleavage of methyl ether finished the total synthesis of 83.
Scheme 12. Total synthesis of (-)-colombiasin A 83 by Harrowven.47
17
A completely different approach towards colombiasin A was developed by the group of Harrowven (Scheme 12).47 The advanced intermediate 105 was prepared in 8 steps starting from (-)-dihydrocarvone. Then vinyl anion was generated using Shapiro reaction conditions, which was used for the 1,2-addition to squaric acid derivative 106 thus forming the alcohol 107 in 36% yield. The microwave irradiation of the intermediate 107 resulted in the 4π-electrocyclic ring opening forming the ketene 108, which immediately underwent 6π-electrocyclic ring closure to the bicyclic derivative 109. Hydroquinone 109 oxidized spontaneously under air atmosphere giving quinone 110 in impressive 80% yield over two steps. Finally, the total synthesis of colombiasin A 83 was successfully completed using familiar two step sequence.
4.3. Total synthesis of salvileucalin B
The first enantioselective synthesis of (+)-salvileucalin B 111 was reported by the group of Reisman in 2011 (Scheme 13).48 This rare natural product features [4.3.1]propellane moiety with the central cyclopropane ring composed exclusively of stereogenic quaternary centers. Additional cage-like system makes this compound an extremely challenging target molecule.
The synthesis of 111 started with Zn-mediated 1,2-addition of alkyne 112 to the 3- furaldehyde 114 in the presence of chiral mandelamide 113, which enabled the enantioselective formation of alcohol 115. The following alkylation with propargyl bromide, TBS-deprotection and Finkelstein reaction gave bromide 116 in 80% yield over three steps. In the next step Myers asymmetric alkylation was performed.
Deprotonation of pseudoephedrine derivative 117 with LHMDS followed by addition of bromide 116 furnished the desired triyne 118 in 90% yield. Next, the TMS moiety was removed using TBAF and obtained terminal alkyne was subjected to ruthenium- mediated triyne cyclization. The subsequent amide cleavage furnished tetracyclic intermediate 119 with high efficiency. Following two step Arndt-Eistert homologation provided elongated ester 120. Afterwards intermediate 120 was reacted with deprotonated acetonitrile and the corresponding β-ketonitrile was converted into diazo compound 121. The Cu(hfacac)2 mediated cyclopropanation secured pivotal norcaradiene intermediate 122 in 65% yield. Surprisingly after the ketone moiety of 122 was converted into corresponding vinyl triflate, reduction of nitrile with DIBAL did
18
not provide expected aldehyde 123, but rather triggered an additional retro-Claisen rearrangement giving cyclic ether 124. Since it was known that Claisen
Scheme 13. Enantioselective total synthesis of (+)-salvileucalin B 111.48
19
rearrangements are reversible49, the obtained product 124 was subjected to another reduction with DIBAL and indeed the desired primary alcohol 125 was obtained in 57%
yield over two steps. At this point the stage was set for the endgame where two missing lactone rings should be assembled in addition to already synthetized caged norcaradiene skeleton. The palladium-catalyzed carbonylation of vinyl triflate 125 with concomitant intramolecular alcohol trapping established the first lactone moiety. Then final oxidation of tetrahydrofuran ring generated mixture of desired 111 and side product 127. As a result, the first enantioselective synthesis of (+)-salvileucalin B 111 was achieved in total 18 steps utilizing elegant dearomative-cyclopropanation strategy.
Later several research groups applied similar cyclopropanation strategy in order to synthetize various derivatives of salvileucalin B containing the norcaradiene core.50,51 In contrast, group of Chen developed a biomimetic approach towards the salvileucalin B derivative 136 in terms of intramolecular Diels-Alder reaction (Scheme 14).52 First, the 1,3-dicarbonyl 130 was prepared in two steps starting from the enone 128 and aldehyde 129. Treatment of 130 with ZnI2 promoted Conia-ene reaction which delivered spirocyclic compound 131 in 85% yield. The regioselective reduction of ketone moiety followed by the TBS-protection allowed further functionalization of cyclohexenone ring. Subsequent γ-deprotonation and trapping of extended enolate gave the corresponding triflate which was further used for the Pd-catalyzed
Scheme 14. Approach towards salvileucalin B core from Chen. 52
carbonylation thus enabling smooth formation of diene 132 in good yields. The TBS- ether 132 proved to be unsuitable for bioinspired intramolecular Diels-Alder, therefore
20
it was first deprotected with HF and then heated to 250 °C using microwave irradiation in the presence of HMDS. In this manner, desired norcaradiene 133 was obtained in the remarkable 78% yield. After subsequent alcohol protection, the ester moiety was reduced to the corresponding alcohol 134 using DIBAL. The hydroboration/oxidation sequence followed by TBS-protection of primary alcohol and Dess-Martin oxidation of the secondary alcohol gave compound 135. Finally, two step carbonylation followed by the alcohol deprotection delivered structure 136, which is very similar to salvileucalin B 111.
21
5. Synthesis and chemistry of cage compounds
Lack of the synthetic work in the field of naturally occurring taxane propellanes makes detailed discussion of the different approaches towards these cage-like compounds essential. This discussion should serve as a guideline for the investigation of the pivotal strategy in terms of retrosynthetic disconnections further used for the total synthesis of canataxpropellane 13.
Numerous cage compounds have been synthetized over the last six decades, however a vast majority of them contain heteroatoms in their scaffold.53 Therefore further discussion will be limited to the compounds with all carbon cage tetracyclodecane framework 137 (Figure 6).
Figure 6. Tetracyclo[4.4.0.03,9.04,8]decane 137.
The first synthesis of such a system was reported in 1964.54 The endo Diels-Alder adduct 140 in ethyl acetate was irradiated for six hours and the [2+2]- photocycloaddition product 141 was obtained in 90% yield after sublimation (Scheme 15). The authors also investigated synthesis of other photocycloadducts, demonstrating the general applicability of this methodology.
Scheme 15. First reported synthesis of caged tetracyclodecane 141.54
Further investigation by Kushner in 1972 revealed an even more astonishing application of this approach (Scheme 16).55 Diels-Alder adduct 142 was irradiated with 450 W high-pressure Hanovia lamp in diluted benzene solution. These conditions enabled exclusive and smooth formation of cage compound 143 in 80% yield along
22
with 15% of recovered starting material. The unexpected feature of this transformation is the loss of aromaticity of the benzene ring thus providing stable cyclohexadiene moiety.
Scheme 16. First synthesis of intramolecular [6+2]-cycloaddition adduct 143.55
Later, Sasaki et al.56, 57 have demonstrated some interesting features of such systems.
For instance, reduction of the both ketone moieties in 144 provided the expected diol 145 which upon heating in glycol undergoes formation of oxabicyclic 146.
Scheme 17. Conversion of diketone 144 to cage compound 146.
They have also shown that in contrast to aminoketone 149, imine-alcohol 151 and iminoamine 153 which easily undergo transannular cyclisations giving 150, 152 and 154 correspondingly (Scheme 18), the ketol 147 does not cyclize to 148 even at elevated temperature.
Scheme 18. Transannular cyclisation reactivity of various cage derivatives.
23
In 1980 similar cage-like molecules were synthetized.58 However it should be noticed, that in this case photocyclization was induced by cis-decalin bicyclic system with no additional bridge which could conformationally fix the molecule (Scheme 19).58 First the substrate 155 was reduced with sodium borohydride delivering two diastereisomers 156 and 157, which were separated. Irradiation of both isomers in solution in presence of sensitizer, as well as direct crystal irradiation were investigated.
Scheme 19. Photocyclization of not-bridged systems.58
Both systems provided formation of the desired photocycloaddition products in high yields. In the case of 157 corresponding keto alcohols 158 were obtained, whereas in situ formed 159 cyclized further thus leading to the irreversible formation of lactols 160.
These examples point out some fine reactivity differences present even in such conformationally rigid scaffolds, which should be indeed considered while planning to synthesize similar systems.
Obviously, Diels-Alder reaction followed by [2+2]-photocycloaddition seems to be a very useful strategy for the synthesis of caged compounds, which could be applied also for the total synthesis of canataxpropellane. There is a great number of publications were this strategy was used for the synthesis of similar systems.59,60,61,62,63,64,65,66 With this in mind, a novel approach towards canataxpropellane 13 has been developed.
24 6. Results and Discussions
6.1. First retrosynthetic analysis of canataxpropellane
Scheme 20. First retrosynthetic analysis of canataxpropellane.
As described in Chapter 4, no synthesis of any molecule similar to canataxpropellane 13 is published up to date. Its unique [3.3.2] and [4.4.2]propellane systems as well as its high structural congestion caused by the fully-substituted cyclobutane ring make essential the development of a substantially new strategy for this synthetic issue.
Nevertheless, the synthesis of the tetracyclodecane core 137 was investigated in very great detail (Chapter 5). Although these syntheses did not find any useful application, various substrates were synthetized utilizing the two step sequence, namely a Diels- Alder reaction followed by a [2+2]-photocycloaddition. This methodology could as well be beneficial for the assembly of the tetracyclodecane core within the total synthesis of canataxpropellane 13.
After careful considerations, the following retrosynthesis of canataxpropellane 13 was proposed (Scheme 20). This strategy starts with a pinacol coupling in order to assemble the five-membered ring with vicinal trans diol. Due to the structural rigidity of 161, it should proceed with high efficacy, however the stereocontrol is questionable.
The next step is the [2+2]-photocycloaddition, which is required in order to build up the
25
desired [4.4.2]propellane moiety, four of six quaternary stereogenic carbon centers and the pivotal cage-like backbone within one step. In order to assemble tetracycle 162 the intermolecular Diels-Alder reaction would be used. The dienone 164 is a literature-known compound,67 whereas the novel building block 165 would be synthetized via another Diels-Alder reaction between diene 166 and selenobutenolide 167.
6.1.1. First synthetic approach towards canataxpropellane
Since the total synthesis of paclitaxel is a highly relevant topic, the synthesis of dienone 164 was already described in the literature.67 The synthesis started with commercially available β-ionone 168 (Scheme 21). The regioselective ozonolysis of the disubstituted double bond was performed at –78 °C in neat methanol. The obtained aldehyde was isolated and reduced with sodium borohydride and the resulting crude alcohol was directly acetylated to give 169. Riley oxidation followed by the Jones oxidation furnished desired enone 170 in a good overall yield. Introduction of the second double bond was achieved by heating 170 for two days in ethyl acetate under reflux in the presence of DDQ, which gave dienone 164 in 74% yield. Final exchange of the acetate protecting group to the more base and photochemically stable TBS-ether was achieved in an excellent yield providing 171.
Scheme 21. Synthesis of dienone 171.67
The selenobutenolide 167 was synthesized according to the procedures described in the literature (Scheme 22).68,69 Therefore, a diastereomeric mixture of 2,5-dimethoxy-
26
2,5-dihydrofuran 172 was treated with phenylselenyl chloride in DCM for 24h, which resulted in the formation of intermediate 173 in a good yield. Next, the double bond was introduced via the elimination of HCl mediated by sodium tert-butoxide. Obtained 174 was further hydrolyzed in acidic media providing selenobutenolide 167, in 38%
yield.
Scheme 22. Synthesis of selenobutenolide building block 167.68,69
Inspired by these results, a synthetic approach to the missing diene 166 was developed (Scheme 23). First, hydroxy ester 175 was protected with a SEM-group. In the next step, the ester moiety was reduced with DIBAL, providing the corresponding alcohol which was converted to aldehyde 176 via IBX oxidation in a good yield. The following Horner-Wadsworth-Emmons olefination provided α, β-unsaturated ester 177, which was converted to the corresponding unsaturated aldehyde 178 after a
Scheme 23. Attempted synthesis of diene 166.
Table 1. Conditions used for the pursued formation of diene 166.
Entry TBSOTf Et3N Solvent Result
1 1.05 equiv. 2 equiv. Et2O no reaction
2 2 equiv. 4 equiv. Et2O no reaction
3 1.05 equiv. 1.5 equiv. THF no reaction
27
reduction/oxidation sequence. Starting from 178, different conditions were tested in order to generate the desired diene 166 but without success (Table 1). However the synthesis of similar dienes was reported in low yields.70
Since the silyl enol ethers are known to be labile and the presence of a δ-alkoxy substituent could have an additional disfavorable impact on the stability of diene 166, another type of diene was designed (Scheme 24).
The TBS-protected allyl alcohol 179 was ozonolyzed and subsequent Horner- Wadsworth-Emmons olefination gave E-olefin 180 in 56% yield. The ester moiety was converted to the aldehyde 181 in a two-step procedure. Next the olefination step was performed using phosphonate 182 and thus providing the desired diene 183 in a good yield.
Scheme 24. Synthesis of diene 183 and attempts to synthetize 184.
Table 2. Investigation of the Diels-Alder reaction between the diene 183 and selenobutenolide 167.
Entry Solvent Additive Temperature Result
1 benzene - 100 °C Diene
decomposition
2 xylene Traces of
hydroxyquinone
140 °C Diene
decomposition 3 DCM Et2AlCl (1.5 equiv.) -78 °C Decomposition
28
Unfortunately, the following Diels-Alder reaction between the diene 183 and selenobutenolide building block 167, in refluxing benzene did not work, but rather the decomposition of diene 183 (Table 2, entry 1) could be observed. The possible explanation is that the diene 183 is not reactive enough under the applied conditions.
Another reason could be that as a result of prolonged heating radicals could be formed, thus promoting the decomposition of 183. However, using refluxing xylene and hydroxyquinone as radical scavenger, the same results were obtained (entry 2). Lewis acid catalyzed Diels-Alder reaction between 167 and 183 also proved to be unsuccessful in this case (entry 3).
The possible obstacle for this reaction could be the steric hindrance caused by the bulky TBS protecting group as well as its acid lability. Therefore, we decided to repeat the same reaction with a SEM-protecting group (Scheme 25).
Diene 188 was obtained in an analogous manner in six steps with good yields. Finally, the Diels-Alder reaction was attempted utilizing various Lewis acids (Table 3). Again, it was not possible to isolate the Diels-Alder product 189 but the decomposition of diene 188 was observed in all cases (entry 1 - 4). Addition of the catalytic amounts of Ledwith-Weitz salt (entry 5) in order to promote the cation radical pathway proved to be unsuccessful.
Scheme 25. Synthesis of SEM-protected diene 188 and attempts to synthetize 189.
29
Table 3. Investigation of the Diels-Alder reaction between the diene 188 and selenobutenolide 167.
Entry Solvent Additive Temperature Result
1 DCM MeAlCl2 (0.5equiv.) -78 °C decomposition
2 DCM Sc(OTf)3 (0.5 equiv.) -78 °C decomposition 3 DCM BF3·OEt2 (0.5 equiv.) -78 °C decomposition
4 DCM AlCl3 (0.5 equiv.) -78 °C decomposition
5 DCM Ledwith-Weitz salt
(10 mol%)
0 °C decomposition
Since selenobutenolide is a rather uncommon dienophile for Diels-Alder reactions, the reaction between diene 188 and very reactive dienophile diethyl acetylenedicarboxylate 189 was tested (Scheme 26, Table 4). Surprisingly, even in this case the reaction did not work. Based on these results one could conclude that the diene 188 is not reactive enough in the Diels-Alder reactions and thus is not suitable for this transformation.
Scheme 26. Attempted Diels-Alder reaction with alkyne 189.
Table 4. Conditions screened for the synthesis of 190.
Entry Solvent Additive Temperature Result
1 - - 110 °C No reaction
2 DCM Sc(OTf)3 -78 °C to RT Decomposition
We also tried the key Diels-Alder reaction on building block 171 with 2-methoxyfuran 191 and 2-trimethylsiloxyfuran 193 (Scheme 27). Remarkably, neither heating the dienophile 171 with an excess of furan dienes in toluene, nor performing the reaction in neat furans led to the formation of cycloaddition products 192 or 194.
30
Scheme 27. Attempted key Diels-Alder reaction on 2-substituted furans as model systems.
These observations can be explained by the fact, that furans can easily undergo retro Diels-Alder reactions, especially if weakly electron-deficient dienophiles are used as reaction partners.70, 71 Upon catalysis with Lewis acids, furans usually undergo 1,4- additions rather than the desired Diels-Alder cycloadditions.72 By applying high- pressure conditions, the reaction equilibrium can be shifted towards the cycloaddition product, however the undesired exo-adducts are obtained with high selectivity.71, 73 Obviously, the obtained results as well as the reported reactivity of furans put our initial approach into question, since diene 165 will exhibit high steric bulk due to the six- membered ring with a quaternary center and dienone 171 is not suitable for Diels-Alder reaction even with simple furans 191 and 193. This means that another synthetic approach should be developed, circumventing these obstacles.
31
6.2. Second retrosynthetic analysis of canataxpropellane
Scheme 28. Second retrosynthetic analysis of canataxpropellane.
In our second retrosynthetic strategy, we decided to avoid the previously planned intermolecular Diels-Alder reaction. The first retrosynthetic disconnection remained the same. Pinacol coupling is used for the construction of the five-membered ring, which is incorporated in the [3.3.2]propellane fragment. Oxidative functionalization leads to the lactone 195. Further, we considered a stepwise elaboration of the cage backbone.
First step is an aldol reaction, which gives intermediate 196. This disconnection could be very valuable, since taxpropellane 23 (Figure 5)23 does not possess the corresponding C-C bond, what paves the way to a collective total synthesis of these both propellane-containing taxanes. The next step is a samarium-mediated coupling of the enone 197, which was successfully applied in several total syntheses.74,75 In this manner the advanced intermediate 197, can be obtained from the corresponding lactone 198. Construction of the pivotal cyclobutane ring could be achieved utilizing a
32
[2+2]-photocycloaddition starting from advanced ester 199. Interestingly, similar cycloaddition performed with a comparably bulky substrate was already reported in the total synthesis of laurene.76,77 The last substrate 199 could be obtained from readily synthesized building block 200 and carboxylic acid 201.
6.2.1. Second synthetic approach towards canataxpropellane
Scheme 29. Synthesis of advanced intermediate 210.78
The group of Ding developed an efficient route to advanced intermediate 210 in their approach towards the stereocontrolled synthesis of the taxane CB-ring system (Scheme 29).78 This strategy could be also used in our second synthetic approach towards canataxpropellane 13.
The synthesis commences with the Steglich esterification between alcohol 202 (which is obtained from acrolein in two steps) and carboxylic acid 203 (which is obtained in one step from citraconic anhydride) furnishing the Diels-Alder precursor 204 in excellent yield. After refluxing of 204 in xylene for several days, bicyclic 205 was obtained in a satisfactory yield. After saponification of the ester moiety and concomitant epimerization of the α-carbon atom of the lactone, carboxylic acid 206 was formed. It
33
was further subjected to iodolactonization giving 207, followed by opening of the resulting strained lactone using methoxide with concomitant formation of epoxide 208.
After opening of the epoxide from the less hindered side mediated by HBr in dioxane, corresponding hydroxy bromide 209 was isolated. Finally, protection of the alcohol moiety and radical debromination furnished product 210, thus accurately reproducing the results reported by the group of Ding.78
With this compound in hands, the synthesis of building block 201 was continued. Since selenylation of neopentilic position (α-position) in 210 did not provide complete conversion of starting material, we decided to split this common procedure used for the introduction of the double bond in two separate steps. Therefore, selenylated product 211 and starting material 210 were separated by flash column chromatography. The latter was subjected to the reaction with a buffered solution of mCPBA providing desired unsaturated lactone 212 in good yields.
Scheme 30. Synthesis of α, β-unsaturated lactone 212.
Inspired by the successful synthesis of 212 we turned our attention to the last saponification which would gave building block 201 (Scheme 31). But to our surprise this step proved troublesome. The ester 212 could be cleaved solely by using TMSOK in benzene (Table 5, entry 6).
Scheme 31. Synthesis of building block 201.
34
Table 5. Conditions screened for the synthesis of 201.
Entry Solvent Additive Temperature Result
1 Pyridine LiI reflux decomposition
2 THF/H2O LiOH 45 °C TBS-
deprotection
3 EtOAc LiI reflux decomposition
4 DMF/H2O NaOH RT TBS-
deprotection
5 H2O/MeOH KOH 125 °C decomposition
6 benzene TMSOK reflux 23% of 201
Scheme 32. Synthesis of carboxylic acid 201.
THF in the presence of Cs2CO3, which led to formation of the benzyl ester 213 in 86%
yield. Remarkably, the use of K2CO3 was unsuccessful because of its poor solubility in comparison to Cs2CO3. Further steps were conducted analogously to the route previously used for the synthesis of methyl ester 210. Use of TBSOTf proved to give higher yields for the protected derivative 214. With lactone 214 in hands, we tried to introduce the double bond using the conditions (Table 6, entry 1) as applied for methyl ester 210, but to our surprise these caused the decomposition of starting material. No formation of selenylated intermediate could be observed. Other bases were also tried
35
(entry 2-3) but with no success. Alternative silyl triflate mediated selenylation or Saegusa-Ito oxidation (entry 4-5) gave very low yields. Finally, when LHMDS was used in the presence of HMPA (entry 6), the desired selenylated product could be isolated in 58% yield. Oxidation/elimination with mCPBA gave smoothly 215 and final hydrogenation of the benzyl group revealed carboxylic acid 201 in excellent yield.
Table 6. Conditions screened for the selenylation of 214.
Entry Reagents Temperature Result
1 LDA, PhSeCl -78 °C Decomposition
2 KHMDS, PhSeCl -78 °C Decomposition
3 NaH, PhSeCl reflux No reaction
4 TESOTf, Et3N, PhSeBr 0 °C Low yields
5 TMSOTf, Et3N; Pd(OAc)2 RT Low yields
6 LHMDS, HMPA, PhSeCl -78 °C 58%
With this compound in hands, we turned our attention to the synthesis of photocycloaddition precursor 199. The esterification reaction proved troublesome and standard conditions featuring DIC/DMAP gave 199 only in 27% yield (Table 7, entry 1). Therefore, optimization studies were performed. Elevated temperatures had no effect (entry 2), just as the use of another coupling reagent (entry 3). In entry 4-6 we tried to form the acid chloride at first and then add alcohol 200, but the best yield obtained by this method was 35%. Finally, we used Yamaguchi (entry 7) and Keck (entry 8) esterification conditions, which worked in satisfying yields. Since Keck esterification was higher yielding and easier to perform, we sticked to these conditions.
Scheme 33. Attempts to synthetize precursor 199 for the [2+2]-cycloaddition.
36
Table 7. Conditions screened for the synthesis of photocycloaddition precursor 199.
Entry Reagents Solvent T
(°C)
Time (h)
Yield (%)
1 DIC, DMAP DCM 25 18 27
2 DIC, DMAP DCM 50 4 22
3 EDC·HCl, DMAP DCM 25 27 13
4 PPh3, CCl3CN; then alcohol 200 DMAP, Et3N
DCM 0 to 25
1 10
5 PPh3, CCl3CN; then alcohol 200, DMAP, pyridine
DCM 0 to 25
1 20
6 PPh3, CCl3CN; then alcohol 200, DMAP
DCM 0 to 25
1 35
7 TCBC, Et3N, DMAP Toluene 60 20 53
8 DIC, DMAP, CSA Toluene 25 24 57
Various conditions were tested for the key photocyclization step. As can be seen in Table 8 (entry 1-3), the standard laboratory UV-lamp used for the TLC visualization obviously does not have enough power, since only pure staring material 198 was recovered. As we changed to a 150W medium pressure Hg-lamp (Heraeus) slow decomposition of 198 was observed during prolonged irradiation time. We thought that the bulky TBS-group could probably interfere with this reaction and therefore we repeated the reaction using the unprotected alcohol. Unfortunately, no formation of product could be observed (entry 3-7, 9-11). Even harsh conditions (entry 8 and 12) previously reported for hindered substrates were completely unfruitful.76, 77
At this point, the strategy was reconsidered as it became clear that this approach had no chance for success.
Scheme 34. Attempts to synthetize lactones 198/217.
37
Table 8. Conditions screened for the key [2+2]-photocycloaddition.
Entry R Solvent Light source Temperature Result
1 OTBS MeCN 365 nm 25 °C No reaction
2 OTBS MeCN 254 + 365 nm 25 °C No reaction
OH MeCN 254 + 365 nm 25 °C No reaction
3 OTBS MeCN 150 W medium
pressure Hg-lamp
25 °C Decomposition
4 OH MeCN 150 W medium
pressure Hg-lamp
25 °C Decomposition
5 OTBS pentane 150 W medium
pressure Hg-lamp
25 °C Decomposition
6 OTBS MeCN/Me2CO (9:1)
150 W medium pressure Hg-lamp
25 °C Decomposition
7 OH MeCN/Me2CO (9:1)
150 W medium pressure Hg-lamp
25 °C Decomposition
8 OH PhCl 150 W medium
pressure Hg-lamp
100 °C Decomposition
9 OH pentane 150 W medium
pressure Hg-lamp
25 °C Decomposition
10 OH acetone 150 W medium
pressure Hg-lamp
25 °C Decomposition
11 OTBS MeCN +
benzophenone
150 W medium pressure Hg-lamp
25 °C Decomposition
12 OTBS PhCl2 150 W medium
pressure Hg-lamp
120 °C Decomposition
38
6.3. Third retrosynthetic analysis of canataxpropellane
It has been shown that system 199 does not undergo photocycloaddition to a fully substituted cyclobutane scaffold 198, presumably because of its high flexibility and significant steric hindrance. For this reason, the system we introduced in the first approach is more advantageous as it is structurally rigid and should be reactive in key [2+2]-cycloaddition. Therefore, we decided to modify the first approach.
The third approach should start with a pinacol coupling already mentioned before, which leads to intermediate 218 (Scheme 35). Now, instead of direct [2+2]- photocycloaddition we would like to obtain compound 218 from quinone 219 with an additional oxygen bridge. Pivotal [2+2]-cycloaddition will be performed between the enone moiety and the double bond of the quinone, which should be obtained from aromatic compound 220. The Diels-Alder reaction will be achieved using isobenzofuran derivative 221, as these compounds are highly reactive and have been successfully used in the total synthesis of several natural products.79
Scheme 35. Third retrosynthetic analysis of canataxpropellane.
39
6.3.1. Third synthetic approach towards canataxpropellane
We decided to took advantage of isobenzofuran 221,80 as an highly reactive diene for the Diels-Alder reaction which could be easily synthetized using a procedure developed by Warrener.81 The compound 221 was assembled from relatively simple building blocks. Tetrazine 223 was synthetized in two steps by refluxing 2- cyanopyridine 222 in aqueous hydrazine followed by oxidation with sodium nitrite (Scheme 36).82
Scheme 36. Synthesis of tetrazine 223.82
Arene 225 was accessed in one step from commercially available 1-bromo-2,5- dimethoxybenzene 224. Addition of LDA led to in situ formation of aryne, which was trapped by the excess of furan thus giving 225 in 72% yield (Scheme 37).83
Scheme 37. Synthesis of oxabyciclo-arene 225.83
Next the oxabyciclo-arene 225, enone 171 and tetrazine 223 were refluxed in toluene for 24h (Scheme 38). First, the Diels-Alder reaction with inverse electron demand between tetrazine 223 and arene 225 occurs already at room temperature. The following retro Diels-Alder reaction driven by the nitrogen elimination requires slightly elevated temperature (40-50 °C) thus giving pyrazine 227 and desired highly reactive unsubstituted isobenzofuran 221, which reacted further with dienone 171. Gratifyingly,
40
we could obtain a separable mixture of endo and exo Diels-Alder products 220 and 228 in excellent yield.
Scheme 38. Synthesis of Diels-Alder adduct 220.
Next, we tried to oxidize endo-dimethoxyhydroquinone 220 to the corresponding quinone 229 using CAN (Scheme 39). Surprisingly, after multiple tries we were not able to obtain the desired product 229, instead, the decomposition of was observed, although, the exo isomer 228 smoothly undergoes this transformation.
Scheme 39. Oxidation of Diels-Alde adducts with CAN.
41
As it was not possible to obtain quinone 229, direct ortho- photocycloaddition with endo 220 was attempted (Schem 40, Table 9). After testing several conditions and solvents, which failed to deliver product 231 (entries 1-6) benzene was used as solvent, since it was reported to be successful on the very similar system (entry 7).55 To our great delight, the solvent occurred to be the crucial issue for this reaction, therefore the desired cycloadduct 231 was isolated by flash column chromatography in 32% yield along with recovered starting material. Interestingly, this transformation proved to be a reversible process, which resulted in almost same yields after prolonged irradiation times.
Scheme 40. Synthesis of intermediate 231 by [2+2]-cycloaddition.
Table 9. Conditions screened for the synthesis of 231.
Entry Solvent Additive Result
1 EtOAc - No reaction
2 DCM - Decomposition
3 Et2O + acetone 4 : 1
- Slow decomposition
4 Acetone - Decomposition
5 MeCN Benzophenone No reaction
6 MeCN H2SO4 (cat.) Decomposition
7 Benzene - 32%, 80% brsm
To prove the structure of the pivotal cycloaddition intermediate 231 unambiguously, a series of 2D-NMR experiments was conducted. Based on to the HMBC spectrum, we could assign all quaternary carbon atoms of the cyclobutane ring in 231. The cross- peaks with the corresponding hydrogen atoms can be seen in Figure 7.
