Sandy Ma is one of the more unusual (in a good way) characters I've come across. DOGGIE!) Always makes me laugh and has the most quotable quotes. I will always treasure our many memories in some of the most beautiful places in the world.
A BSTRACT
P ROLOGUE
Some important drugs that are natural products or derivatives include the antibiotics penicillin and vancomycin, contraceptives (+)-norgestrel and 17α-ethynyl estradiol, the anti-inflammatory drug indomethacin, and the ovarian, breast, and small lung cancer drug paclitaxel (taxol) . This difference suggests the possibility of a different mechanism of action than estrogen therapy, making the zoantamines an important family of natural products to target for synthesis.
L IST OF S CHEMES
195 Scheme 3.7.1 Synthesis of an acid-derived A-C ring system ..196 Scheme 3.7.2 Cyclization of carboxylic acid-derived bonded A-C ring. 371 Scheme 4.4.2 Attempts at cyclization of ester-derived A-C ring system ..372 Scheme 4.5.1 Synthesis of 7-membered acetal-derived radical cyclization.
L IST OF T ABLES
371 Table B.3 Distances and angles of full bonds ..372 Table B.4 Anisotropic displacement parameters ..373 Table B.5 Hydrogen atomic coordinates ..374 Table B.6 Distances and angles of hydrogen bonds ..375 Table B.7 Crystal data ..377 Table B.8 Atomic coordinates..379 Table B.9 Distances and full bond angles..381 Table B.10 Anisotropic displacement parameters.
L IST OF A BBREVIATIONS
C HAPTER O NE
Hypothetical polyketide precursor
The conversion of 22 to 1 begins with tautomerization, electrocyclization, and Diels-Alder steps to form intermediate 23. Tautomerization and carbonyl activation of 23 yields 24, which undergoes 6-exo alcohol attack and protonation to form intermediate 25.
Potential mechanism for cyclization of polyketide precursor 22
Proposed biosynthesis of norzoanthamine
Structure of zooxanthellamine
Norzoanthamine forms iminium 30 under acidic conditions and returns after neutralization.19 Under neutral to basic conditions, elimination occurs to form enamine 31. Treatment of norzoanthamine with sodium borohydride produces two abnormal products, enone 34 and allylic alcohol 35 (Scheme The formation of these products is can be explained by the opening of the hemiaminal to form iminium 36.
Equilibria between lactone and enamine isomers of norzoanthamine
Anomalous reduction of norzoanthamine
The intriguing diversity of biological activities and the densely functionalized structures of the zoantamine alkaloids have inspired a host of synthetic chemistry groups to publish strategies for the total synthesis of these molecules. Their Diels-Alder strategy for the construction of the ABC ring system of norsoantamine was published in 2002 (Scheme 1.4.1).36.
Miyashita’s Diels-Alder construction of the ABC core
After treatment with lithium tert-butoxide and methyl iodide in DMPU, lactone 63 underwent C-alkylation to form quaternized δ-lactone 64.
Functionalization of the ABC core
Attaching the southern side chain
The completion of norzoanthamine
Removal of the silyl group and subsequent treatment with lead tetraacetate led to the desired methyl ketone 74. Closure of the kinetic enolate with PhSeBr and oxidation of the peroxide allowed installation of the enone, and subsequent reduction of LAH led to the allylic alcohol 75 as a single diastereomer.
Tanner’s approach to a model ABC ring system
With DBU in the reaction mixture, the thermodynamically favored product was irreversibly trapped by HI elimination. Oxidation of manganese dioxide provided the Diels-Alder precursor 79, and heating this intermediate in d8-toluene provided quantitative conversion of 79 to the tricycle 80. It was found that the additional electron density in the diene made the desired inverse electron demand for the Diels-Alder cycloaddition inefficient .
However, homologation of the one-carbon chain at C(22) (86) was sufficient to avoid side product formation, providing 87 in 66% yield with the correct stereochemistry for the synthesis of zoanthamine.
Model cyclizations of compounds derived from (–)-carvone
A 6π electrocyclization afforded pyran 90 , which then underwent intramolecular Diels–Alder reaction to form the byproduct 85 .
Mechanism for formation of undesired products
Tanner’s approach to the functionalized ABC ring system
Mechanism for formation of by-product 95
At this point, the side chain of 102 was treated with t -butyl lithium, the aldehyde 101 was added, and the resulting alcohol was oxidized to give the advanced intermediate 103 .
Diels-Alder cyclization and cycloadduct advancement
Recently, Uemura and co-workers have reported a synthetic strategy based on their biosynthetic hypothesis, which posits that zoanthamine alkaloids arise from a linear polyketide skeleton, which then undergoes multiple pericyclic cyclizations.43 To support this hypothesis , they attempted to synthesize and cyclize. on the way to the natural product (Figure 1.4.3). Vinyl iodide 105 and alkyne 106 were efficiently assembled and then coupled by Sonogashira coupling.44 Conversion to enyne 107 was completed by oxidation and methylation (Scheme 1.4.11). To date, no reports have appeared of the selective reduction of enyne 107 to the linear polyene 104 or of attempts to cyclize 104 or 107 .
Uemura’s approach to norzoanthamine
Their Diels–Alder strategy constructs the AB rings, which will be followed by addition of the C ring (Figure 1.4.4).45 The EFG ring system is formed by conjugate addition of an enamine to a functionalized linear enone and then cyclization to form the stereochemistry and connectivity observed in the natural products. In the key Diels–Alder reaction, nitro-alkene 108 reacted in benzene at reflux via an endo transition state to give decalin 109 in good yield and 10:1 dr (Scheme 1.4.12).
Williams’s early efforts toward the norzoanthamine AB rings
Williams’s recent efforts toward the norzoanthamine AB rings
Williams’s synthesis of a model EFG ring system
Theodorakis’s approach to the ABC ring system
Additionally, the alkylation provided complete selectivity for the desired C(9) epimer of acetal 128 as confirmed by X-ray structure determination. Taken in conjunction with Theodorakis' other work, this strategy solves the difficult problem of generating all three C-ring quaternary centers and produces a norzoanthamine ABC ring system well equipped for the completion of the total synthesis.
Theodorakis’s installation of the C(9) quaternary center
Kobayashi’s sulfone approach to the CDEFG ring system
After considerable optimization, conditions were established to produce the desired enol ether 147 in modest yield.61 Although the reaction proceeded with excellent diastereoselectivity, it had several drawbacks, including high palladium loading, long reaction times, and byproducts side by simple reduction of the triflate substrate.
Hirama’s Heck strategy for the zoanthenol ABC ring system
Hirama’s alternative assembly of the B ring
Hirama’s installation of the C(9) methyl group
An alternate approach by Hirama
Hirama’s synthesis of the fully functionalized ABC core of zoanthenol
Construction of the carbocyclic ABC rings is hindered by the stereochemical density of this region of the molecule. This architecture has inspired a number of creative annulation strategies that use Diels–Alder, Heck, Friedel–Crafts, and Robinson annulation reactions. Pioneering syntheses of the heterocyclic region of these molecules have determined the feasibility of various cyclization strategies.
For more than two decades, the novel bioactivities and synthetic challenges of zoanthamine natural products have generated much research. Due to the many unanswered questions, interest in zoanthamine alkaloids is likely to increase in the near future. Fattorusso, E.; Romano, A.; Taglialatela–Scafati, O.; Achmad, M. Symposium Papers, 38th Symposium on Natural Product Chemistry.
C HAPTER T WO
Retrosynthetic analysis of zoanthenol
The reduction of the aldehydes was achieved by treatment with 10% Pd/C under a balloon of hydrogen, giving benzyl alcohol 175 in a yield of 96%.6 Treatment of this benzyl alcohol (175) with phosphorus tribromide and pyridine led to benzyl bromide 168 with a yield of 92%. after distillation. This approach to the A-ring synthon was efficient and highly scalable, allowing the production of 20-25 g of benzyl bromide 168 per batch.
Synthesis of the A ring synthon
Ortho -lithiation was directed through the C(17) methoxy group, and quenching with N,N -dimethylformamide afforded a mixture of aldehyde 174 and the corresponding desilylated aldehyde 173 . After considerable optimization to accommodate the steric challenges of the substrate, an efficient one-step reductive carbonylation of triflate 178 was developed. Treatment of triflate 178 under an atmosphere of CO with Pd(OAc)2, 1,4-bis-(dicyclohexylphosphino)butane as a ligand, and TES-H as a reducing agent afforded the desired enal 169 in good yield.
To our knowledge, this is the first time that such a hindered vinyl triflate is directly carbonylated to the enal oxidation state.8.
Racemic synthesis of the C ring synthon
Addition of Grignard reagent 181, derived from A-ring synthon 168, to enal 169 produced allylic alcohol 183 in high yield and diastereoselectivity (Scheme 2.2.4). We hypothesize that the addition of this noncoordinating solvent promotes the chelation of Mg between the aldehyde and the t -butyl ester, resulting in selective attack of the surface of the aldehyde by the incoming Grignard reagent (182).
Diastereoselective Grignard addition
With the A and C rings together, we could begin to probe the 6-exo cyclization by subjecting allyl alcohol 183 to TFA at reflux (Scheme 2.2.5). To our delight, the major product contained a single aromatic CH peak by 1H NMR as well as two isolated aliphatic CH3. Interestingly, cyclization of allylic alcohol 183 had occurred, but via 6-endo SN′ cyclization to give acid 187.9,10 In addition, the solid-state structure confirmed the antidisposition of the methyl groups at C(12) and C(22) in 187 .
Discovery of an unusual acid-mediated cyclization
Even dilution of pure TFA with methylene chloride, benzene, or acetic acid caused cyclization to fail. Interestingly, both lactone 184 and allyl acetate 188 underwent cyclization in TFA, yielding acid 187 in similar yields and diastereoselectivities (Scheme 2.2.6).11 Furthermore, C(16) des-oxy arene 189 failed to generate cyclized products , indicating the importance of the nucleophilicity conferred by C(16) oxygenation.
Other substrates for cyclization
With an efficient route in hand to construct a zoanthenol carbocyclic ring system containing two of the three quaternary stereocenters, we turned our attention to completing our proposed intermediate 165. Following diazomethane-mediated esterification, deoxygenation of the phenol C(16 ) from the formation of the aryl triflate 191 and subsequent treatment with PdCl2(PPh3)2 and formic acid to form 192 in 92% yield (Scheme 2.2.8).13.
Deoxygenation of the A ring
Refunctionalization of the C(20)-C(21) olefin
Plan for elaboration of the tricyclic core
Interestingly, when tricycle 192 was treated with kinetic enolization conditions, a ratio of 4:1 silylenol ethers (199:200) was observed. The major product of the inseparable mixture of enol ethers was identified via 1D nOe experiments as 199. Given our uncertainty about the cause of the selectivity in this system, we also tested tricycle 196.
This improvement was promising, although certainly not feasible at this stage of the synthesis.16 Despite efforts to improve the selectivity of these alkylations, we were unable to improve the ratio beyond a 1:1 mixture.
Attempts to enolize at C(9)
We envisioned that enone 166 could be accessed from caprolactam 203 , which we decoupled across the amide C–N bond to reveal amine 204 .
Retrosynthetic analysis of the DEFG synthon
Jacobsen hetero-Diels-Alder cycloaddition
Conjugate addition and Mitsunobu reaction provide key intermediate
Conversion of the δ-lactone to the ε-lactam synthon
After stirring for an additional 30 min at 0 °C, the reaction mixture was allowed to warm to ambient temperature and stirred for an additional 2.5 h. The reaction mixture was quenched with saturated aqueous NaHCO3 (10 mL), extracted with CH2Cl2 (6 x 30 mL), dried (MgSO4), and concentrated to an oil, which was purified by gradient flash chromatography. After a further hour at -12 °C, the reaction mixture was allowed to warm to 0 °C, stirred for 1 h and quenched with sat.
The reaction mixture was cooled to ambient temperature, poured into brine (50 mL) and H 2 O (10 mL), acidified with 3 M HCl to pH 0, extracted with EtOAc (6 x 20 mL), dried (Na 2 SO 4 ), concentrated and used in the next step without further purification. The reaction mixture was cooled to ambient temperature, diluted with H 2 O (20 mL), brine (20 mL) and CH 2 Cl 2 . After cooling to ambient temperature, the reaction mixture was filtered and the filter cake was washed with toluene (2 x 25 mL).
The mixture was allowed to warm to room temperature and then diluted with H2O (10 mL) and Et2O (20 mL).
S YNTHETIC S UMMARY
A PPENDIX A
