Type: Object |
Advantage: None |
Novelty: New |
ConceptID: Obj1
Type: Object |
Advantage: None |
Novelty: New |
ConceptID: Obj1
2
The synthesis of the 1,6,8-trioxadispiro[4.1.5.2]tetradec-11-enes 12 present in the shellfish toxins spirolides B 1 and D 2, is reported.
Type: Object |
Advantage: None |
Novelty: None |
ConceptID: Obj1
3
The two spirocentres were constructed via iterative radical oxidative cyclization of hydroxyalkyl dihydropyran 14 and hydroxyalkyl spiroacetal 13 using iodobenzene diacetate and iodine.
Type: Object |
Advantage: None |
Novelty: None |
ConceptID: Obj1
4
This procedure initially afforded a 1 : 1 : 1 : 1 mixture of bis-spiroacetals 12a : 12b : 12c : 12d, however subsequent acid catalysed equilibration afforded a 3 : 1 : 0.9 thermodynamic mixture of 12a : 12b : 12c.
Type: Result |
Advantage: None |
Novelty: None |
ConceptID: Res1
5
The major bis-spiroacetal 12a underwent stereoselective epoxidation using dimethyldioxirane to α-epoxide 33a.
Type: Result |
Advantage: None |
Novelty: None |
ConceptID: Res2
6
Subsequent base induced rearrangement of this epoxide 33a using lithium diethylamide in pentane afforded allylic alcohol 34a, that was converted to the more thermodynamically favoured homoallylic alcohol 11a upon treatment with lithium pyrrolidinylamide in tetrahydrofuran.
Type: Result |
Advantage: None |
Novelty: None |
ConceptID: Res2
7
Homoallylic alcohol 11a possesses a hydroxyl group at C-12 as required for introduction of the tertiary alcohol group present at this position in spirolides B 1 and D 2.
Type: Result |
Advantage: None |
Novelty: None |
ConceptID: Res3
Introduction
8
Spirolides B 1 and D 2 are toxic metabolites of the marine dinoflagellate Alexandrium ostenfeldii that were isolated from the digestive glands of mussels (Mytilus edulis) and scallops (Placopecten magellanicus) during routine monitoring for diarrhetic shellfish toxins in Nova Scotia, Canada, in .19951,2
Type: Background |
Advantage: None |
Novelty: None |
ConceptID: Bac1
Type: Background |
Advantage: None |
Novelty: None |
ConceptID: Bac1
10
Spirolides A–D contain an unusual 5,5,6-bis-spiroacetal moiety, together with a rare 6,7-spirocyclic imine.
Type: Background |
Advantage: None |
Novelty: None |
ConceptID: Bac1
11
Spirolides E 6 and F 7 are keto amine hydrolysis derivatives resulting from ring opening of the cyclic imine, suggesting that this functionality is the pharmacophore responsible for toxicity.
Type: Background |
Advantage: None |
Novelty: None |
ConceptID: Bac1
12
Although the absolute stereochemistry of the spirolide family of toxins has not been established to date, a computer-generated relative assignment of 13-desmethyl spirolide C 5 showing the same relative stereochemistry as the related toxins pinnatoxin A 8 and D 95 in the region of their common structure, was later reported.6
Type: Background |
Advantage: None |
Novelty: None |
ConceptID: Bac2
13
Preliminary pharmacological research into the mode of action of the spirolides suggested that they are antagonists of the muscarinic acetylcholine receptor.7
Type: Background |
Advantage: None |
Novelty: None |
ConceptID: Bac3
14
A total synthesis of the spirolides has not been reported to date, however, an elegant total synthesis of pinnatoxin A 8 has been reported by Kishi et al.8
Type: Background |
Advantage: None |
Novelty: None |
ConceptID: Bac4
15
Partial syntheses of the bis-spiroacetal moiety of the pinnatoxins are also discussed in a recent review on the synthesis of bis-spiroacetal ring systems.9
Type: Background |
Advantage: None |
Novelty: None |
ConceptID: Bac4
16
Our continued interest in the synthesis of natural products containing bis-spiroacetal ring systems led us to pursue the synthesis of the bis-spiroacetal ring system present in the spirolides using a radical oxidative cyclization strategy that we have previously applied to the synthesis of several polyether antibiotics.10
Type: Motivation |
Advantage: None |
Novelty: None |
ConceptID: Mot1
17
In the present case, it was envisaged that radical oxidative cyclizations would provide an ideal method to construct the two five membered rings in the 5,5,6-bis-spiroacetal unit of the spirolides.
Type: Hypothesis |
Advantage: None |
Novelty: None |
ConceptID: Hyp1
18
Therefore, herein we report the full details11 of this synthetic work, addressing the stereochemical issues associated with the assembly of bis-spiroacetals 12 and the base-induced rearrangement of the derived epoxides.
Type: Conclusion |
Advantage: None |
Novelty: None |
ConceptID: Con1
Results and discussion
19
The key disconnection in our proposed retrosynthesis of spirolides B 1 and D 2 (Scheme 1) involves Ni(ii)/Cr(ii)-mediated Kishi–Nozaki coupling12 between an aldehyde and a vinyl iodide to form the C-9–C-10 bond of the macrocyclic ring in a similar fashion to that used by Kishi et al. in the synthesis of pinnatoxin A 8.
Type: Method |
Advantage: None |
Novelty: Old |
ConceptID: Met1
20
The substituted allyl group at C-22 can be introduced via Lewis acid-mediated addition of an allyl stannane to bis-spiroacetal 10 that possesses an acetate functionality at the anomeric position.
Type: Method |
Advantage: None |
Novelty: None |
ConceptID: Met1
21
Precedent for this latter step has been demonstrated by this research group13 using a simpler 6,6-spiroacetal.
Type: Method |
Advantage: None |
Novelty: None |
ConceptID: Met1
22
Acetate 10 is available via hydration and acetylation of alkene 11, that in turn can be synthesised from alkene 12 by epoxidation followed by a base-induced rearrangement.
Type: Method |
Advantage: None |
Novelty: None |
ConceptID: Met1
23
The C-19 tertiary alcohol group in spirolides B 1 and D 2 is then accessible by oxidation of the hydroxyl group introduced in the rearrangement step, followed by addition of a methyl group.
Type: Method |
Advantage: None |
Novelty: None |
ConceptID: Met1
24
Our earlier successful application of radical chemistry to the synthesis of bis-spiroacetal ring systems suggested that an iterative oxidative radical cyclization strategy might provide a valuable route to the key bis-spiroacetal intermediate 12.
Type: Background |
Advantage: None |
Novelty: None |
ConceptID: Bac5
25
This synthetic approach forms the basis of the current study.
Type: Method |
Advantage: None |
Novelty: New |
ConceptID: Met2
26
Thus, bis-spiroacetal 12 can be derived from spiroacetal alcohol 13 using a radical oxidative cyclization mediated by hypervalent iodine.
Type: Method |
Advantage: None |
Novelty: None |
ConceptID: Met2
27
The spirocentre in 13 can, in turn, be formed using a similar cyclization of dihydropyran 14, that is available from aldehyde 15, and the Grignard reagent, prepared from dihydropyranyl bromide 16.
Type: Method |
Advantage: None |
Novelty: None |
ConceptID: Met2
28
The Brown and Bhat crotyl metallation methodology can be used to prepare aldehyde 15 in a flexible approach that also allows access to varying configurations at the two stereogenic centres by the appropriate choice of (Z)- or (E)-2-butene and (−)- or (+)-diisopinocampheylborane starting materials.14
Type: Method |
Advantage: None |
Novelty: None |
ConceptID: Met2
29
The most practical preparative route to dihydropyran 16 (Scheme 2) involved addition of the lithium acetylide of 18 to aldehyde 17 (available in two steps from propane-1,3-diol).
Type: Method |
Advantage: None |
Novelty: None |
ConceptID: Met2
30
The trimethylsilyl ether in the resultant alcohol 19 was selectively cleaved to alcohol 20 using K2CO3 (catalytic) in methanol, followed by careful partial hydrogenation of the acetylene over a Lindlar catalyst to give (Z)-alkene 21 in high yield.
Type: Method |
Advantage: None |
Novelty: None |
ConceptID: Met2
31
Conversion of the primary alcohol 21 into the tosylate 22, followed by treatment with sodium hydride (1.0 equiv.) in THF afforded dihydropyran 23.
Type: Method |
Advantage: None |
Novelty: None |
ConceptID: Met2
32
After cleavage of the silyl ether, alcohol 24 was converted to bromide 16via displacement of the corresponding tosylate 25.
Type: Method |
Advantage: None |
Novelty: None |
ConceptID: Met2
33
Aldehyde 15 was prepared via stereocontrolled crotyl metallation of aldehyde 26 (Scheme 3) using (Z)-2-butene and (−)-β-methoxydiisopinocampheylborane to give (3R,4R)-27 in 82% yield and 90% ee.14,15
Type: Method |
Advantage: None |
Novelty: New |
ConceptID: Met3
34
The (3R,4R) configuration was selected by both analogy with pinnatoxin A 8 and the relative stereochemistry of the spirolides proposed by Falk et al.6
Type: Method |
Advantage: None |
Novelty: None |
ConceptID: Met3
35
The 1H NMR spectrum of the known Mosher ester derivative prepared by treatment of 27 with (R)-2-methoxy-2-trifluoromethyl-2-phenylacetyl chloride, exhibited a methoxy group singlet at δ 3.46 ppm and a methyl group doublet at δ 0.98 ppm (J 6.9 Hz), as reported previously.
Type: Observation |
Advantage: None |
Novelty: None |
ConceptID: Obs1
36
The 19F NMR spectrum of the Mosher ester derivative contained two resonances for the trifluoromethyl group at δ −72.47 and −72.28 ppm, in the ratio of 19.2 : 1, corresponding to an enantiomeric excess of 90%.
Type: Observation |
Advantage: None |
Novelty: None |
ConceptID: Obs2
37
The secondary hydroxyl group in alcohol 27 was subsequently protected as a triethylsilyl ether 28.
Type: Method |
Advantage: None |
Novelty: None |
ConceptID: Met3
38
Subsequent hydroboration to alcohol 29 followed by Dess–Martin oxidation afforded aldehyde 15, required for union with bromide 16.
Type: Method |
Advantage: None |
Novelty: None |
ConceptID: Met3
39
With both the required coupling partners in hand, addition of aldehyde 15 to the Grignard reagent prepared from dihydropyran bromide 16 was investigated.
Type: Goal |
Advantage: None |
Novelty: None |
ConceptID: Goa1
40
It was initially disappointing to find that the use of standard Grignard conditions in either diethyl ether or tetrahydrofuran at room temperature or reflux afforded none of the desired product 14 (Scheme 4).
Type: Observation |
Advantage: None |
Novelty: None |
ConceptID: Obs3
41
Pre-activation of the magnesium metal, the use of iodine, or prolonged dry stirring of the magnesium under an inert atmosphere, only led to the formation of the undesired Wurtz coupling of bromide 16.
Type: Observation |
Advantage: None |
Novelty: None |
ConceptID: Obs4
Type: Background |
Advantage: None |
Novelty: None |
ConceptID: Bac6
43
Thus, a Barbier mixture of aldehyde 15 and an excess of bromide 16 was slowly added to a slurry of magnesium powder in THF at 0 °C.
Type: Method |
Advantage: None |
Novelty: New |
ConceptID: Met4
44
Standard work-up and flash column chromatography afforded alcohols 14 as a 1 : 1 : 1 : 1 mixture of diastereomers in 64% yield.
Type: Method |
Advantage: None |
Novelty: None |
ConceptID: Met4
45
Prolonged vigorous dry stirring of the magnesium powder under an inert atmosphere or a high vacuum in a pear-shaped flask, addition of a crystal of iodine and entrainment with 1,2-dibromoethane were necessary to ensure consistent yields.
Type: Method |
Advantage: None |
Novelty: None |
ConceptID: Met4
46
Use of the analogous dihydropyran iodide in the Barbier reaction or the generation of an organolithium reagent via lithium–iodide exchange18 using tert-butyllithium (2.0 equiv.) did not improve the yield of 14.
Type: Observation |
Advantage: None |
Novelty: None |
ConceptID: Obs5
47
The 1 : 1 : 1 : 1 mixture of Barbier coupled products 14 could be further separated by flash chromatography into two fractions.
Type: Method |
Advantage: None |
Novelty: None |
ConceptID: Met4
48
The 13C NMR spectra of each of these fractions established the presence of two diastereomers in each fraction that were later assigned as 14a, 14b (less polar fraction) and 14c, 14d (more polar fraction).
Type: Result |
Advantage: None |
Novelty: None |
ConceptID: Res4
49
The alcohols 14a, 14b and 14c, 14d were converted to the diols 30a, 30b and 30c, 30d and then to the seven-membered acetonides 31a, 31b and 31c, 31d in order to establish the stereochemistry of these two fractions.
Type: Method |
Advantage: None |
Novelty: New |
ConceptID: Met5
50
The strong NOE observed between H-3 and H-6 in acetonides 31a, 31b (derived from less polar 14a, 14b) established that acetonides 31a, 31b possessed the (3S)-configuration.
Type: Result |
Advantage: None |
Novelty: None |
ConceptID: Res5
51
The absence of a similar correlation in acetonides 31c, 31d (derived from more polar 14c, 14d) established that 31c, 31d had the (3R)-configuration.
Type: Observation |
Advantage: None |
Novelty: None |
ConceptID: Obs6
52
Both 31a, 31b and 31c, 31d were 1 : 1 mixtures as the stereogenic centre at C-2′ was not controlled during the synthesis.
Type: Method |
Advantage: None |
Novelty: None |
ConceptID: Met5
53
This position is transformed into a quaternary spirocentre and its configuration was later determined by the outcome of the oxidative radical cyclization step and the thermodynamically controlled isomerisation of the 5,5,6-bis-spiroacetal ring system (vide infra).
Type: Result |
Advantage: None |
Novelty: None |
ConceptID: Res6
54
With the Barbier coupling products 14 in hand, attention turned to formation of the bis-spiroacetal system via iterative oxidative radical cyclization.
Type: Goal |
Advantage: None |
Novelty: None |
ConceptID: Goa2
55
Although the pairs of diastereomers 14a, 14b and 14c, 14d could be separated and cyclized independently for spectroscopic purposes, the 1 : 1 mixture resulting from the Barbier coupling was routinely used for the preparation of bis-spiroacetals 12 (Scheme 5).
Type: Method |
Advantage: None |
Novelty: New |
ConceptID: Met6
56
Towards this end, a 1 : 1 : 1 : 1 mixture of alcohols 14a, 14b, 14c, 14d was stirred with iodobenzene diacetate (2.0 equiv.) and iodine (2.0 equiv.) in cyclohexane with irradiation using a standard 40 W tungsten filament desk lamp.
Type: Method |
Advantage: None |
Novelty: None |
ConceptID: Met6
57
The iodobenzene produced as a by-product from this reaction was easily separated by flash chromatography affording spiroacetals 32 as a 1 : 1 : 1 : 1 mixture of diasteromers in 90% yield.
Type: Method |
Advantage: None |
Novelty: None |
ConceptID: Met6
58
Selective deprotection of the triethylsilyl group in 32 using HF·pyridine resulted in significant loss of the tert-butyldiphenylsilyl ether, possibly attributed to the steric influence of the C-4 methyl substituent hindering access to the secondary triethylsilyl ether.
Type: Result |
Advantage: None |
Novelty: None |
ConceptID: Res7
59
Alcohols 13 were therefore best prepared by deprotection of bis-silyl ethers 32 using hydrogen chloride in pyridine19 for 48 h.
Type: Method |
Advantage: None |
Novelty: None |
ConceptID: Met6
60
(2R,3R)-5,5,6-Bis-spiroacetals 12 were then successfully obtained as an equimolar mixture of four diastereomers in 83% yield upon further irradiation with iodobenzene diacetate and iodine.
Type: Result |
Advantage: None |
Novelty: None |
ConceptID: Res8
61
The possibility of a direct one-step formation of bis-spiroacetals 12 from diols 30 was also investigated.
Type: Goal |
Advantage: None |
Novelty: None |
ConceptID: Goa3
62
Treatment of diols 30 with iodobenzene diacetate and iodine afforded a complex mixture in line with the findings of Suarez et al20. who were unable to effect the formation of a 6,6,5-spiroacetal system in one-step from a diol precursor that contained the central ring.
Type: Result |
Advantage: None |
Novelty: None |
ConceptID: Res9
63
The four diastereomers of the 5,5,6-bis-spiroacetal system 12a, 12b, 12c, 12d result from the stereogenic spiroacetal centres at C-5 and C-7.
Type: Result |
Advantage: None |
Novelty: None |
ConceptID: Res10
64
These can be designated cis or trans based on the disposition of oxygen atoms across the central tetrahydrofuran ring.
Type: Result |
Advantage: None |
Novelty: None |
ConceptID: Res10
65
These two pairs of diastereomers can be further classified as syn or anti, defined in this case by the relationship of the central ring C-5–O-6 bond and the hydroxyalkyl substituent at C-2 (Scheme 6).
Type: Result |
Advantage: None |
Novelty: None |
ConceptID: Res11
66
Bis-spiroacetal systems exhibit a thermodynamic preference for particular configurations at the spiroacetal centres based on stereoelectronic, steric and hydrogen bonding effects.
Type: Result |
Advantage: None |
Novelty: None |
ConceptID: Res11
67
It was therefore decided to equilibrate the 1 : 1 : 1 : 1 mixture of bis-spiroacetals 12a, 12b, 12c, 12d obtained from the final radical cyclization with the idea of obtaining a simpler mixture of thermodynamically favoured diastereomers.
Type: Method |
Advantage: None |
Novelty: New |
ConceptID: Met7
68
Accordingly, the equimolar mixture of bis-spiroacetals 12a, 12b, 12c, 12d was dissolved in dichloromethane and stirred at room temperature for 24 h with a catalytic quantity of p-toluenesulfonic acid.
Type: Method |
Advantage: None |
Novelty: None |
ConceptID: Met7
69
Analysis of the crude product mixture by 1H and 13C NMR spectroscopy indicated that only three of the four possible diastereomers (Scheme 6) were now present, in a ratio of 3 : 1 : 0.9.
Type: Observation |
Advantage: None |
Novelty: None |
ConceptID: Obs7
70
This equilibrium product distribution proved largely independent of the choice of reaction solvent or acid catalyst, although the use of trifluoroacetic acid or camphorsulfonic acid resulted in substantial destruction of the bis-spiroacetal ring system.
Type: Observation |
Advantage: None |
Novelty: None |
ConceptID: Obs8
71
The mixture was partially separable by careful preparative layer chromatography on glass-backed plates using hexane–diethyl ether (9 : 1) as eluant that also contained ca. 0.1% triethylamine to prevent epimerisation.
Type: Method |
Advantage: None |
Novelty: None |
ConceptID: Met7
72
After several consecutive elutions, a less polar minor band and a more polar major band were isolated.
Type: Method |
Advantage: None |
Novelty: None |
ConceptID: Met7
73
The 1H and 13C NMR spectra of the less polar minor band indicated that a single diastereomer was present, while the 1H and 13C NMR spectra of the more polar major band indicated that two further diastereomers were present in a 3 : 0.9 ratio.
Type: Observation |
Advantage: None |
Novelty: None |
ConceptID: Obs9
74
Further separation of these latter two diastereomers proved elusive.
Type: Observation |
Advantage: None |
Novelty: None |
ConceptID: Obs10
75
In an effort to unambiguously assign the stereochemistry of the individual bis-spiroacetals using X-ray crystallography, the tert-butyldiphenylsilyl ethers 12 were deprotected with tetrabutylammonium fluoride and converted to their bromobenzoate esters.
Type: Method |
Advantage: None |
Novelty: New |
ConceptID: Met8
76
Disappointingly, none of the bromobenzoate derivatives yielded crystals suitable for X-ray analysis and the stereochemistry of bis-spiroacetals 12a, 12b, 12c was assigned using extensive two-dimensional NMR studies in conjunction with molecular modelling studies.
Type: Result |
Advantage: None |
Novelty: None |
ConceptID: Res12
77
Close examination of NOESY correlations involving H-2, H-4a, H-4b, H-12 and the methyl group provided the most useful information about the relative disposition of the rings of the bis-spiroacetal system (Fig. 1).
Type: Result |
Advantage: None |
Novelty: None |
ConceptID: Res12
78
The bis-spiroacetal ring system in the less polar minor band was assigned as trans syn12b in the following manner.
Type: Result |
Advantage: None |
Novelty: None |
ConceptID: Res13
79
The trans stereochemistry of the bis-spiroacetal rings was established from the NOE correlation observed between H-14 and both H-2 and H-12.
Type: Result |
Advantage: None |
Novelty: None |
ConceptID: Res13
80
Nicolaou et al21. reported similar correlations as evidence for the assignment of trans stereochemistry to the bis-spiroacetal moiety of azaspiracid.
Type: Background |
Advantage: None |
Novelty: None |
ConceptID: Bac7
81
The absence of a correlation between H-4 and the methylene protons H-13 and H-14 indicated that this diastereomer also possessed a syn relationship between the C-2 alkyl substituent and the central C-5–O-6 bond.
Type: Result |
Advantage: None |
Novelty: None |
ConceptID: Res13
82
The major component 12a, of the 3 : 0.9 mixture of diastereomers present in the more polar major band, was also assigned as syn due to the lack of an NOE correlation between H-14 and H-4, whereas the stereochemistry of the minor component 12c was established as having an anti relationship between the C-2 alkyl substituent and the C-5–O-6 bond due to the strong NOE correlation observed between H-4a and the unresolved methylene protons H-13 and H-14.
Type: Result |
Advantage: None |
Novelty: None |
ConceptID: Res14
83
Assignment of these latter two diasteromers as cis or trans was more difficult.
Type: Result |
Advantage: None |
Novelty: None |
ConceptID: Res14
84
For the anti diastereomer 12c, NOEs were observed between the vinylic proton H-12 and one of the geminal methylene protons H-14a, as well as between the other geminal proton H-14b and H-4, suggesting that H-12 and H-4 were on opposite faces of the central five-membered ring, thus establishing the stereochemistry of the terminal rings to be trans.
Type: Result |
Advantage: None |
Novelty: None |
ConceptID: Res14
85
The minor component of the more polar band was therefore assigned as trans anti12c.
Type: Result |
Advantage: None |
Novelty: None |
ConceptID: Res14
86
The lack of similar NOEs being observed in the case of the major component of the more polar major band suggested assignment of this bis-spiroacetal diastereomer as cis syn12a.
Type: Result |
Advantage: None |
Novelty: None |
ConceptID: Res14
87
In an effort to gain more information about the thermodynamic preferences of the 5,5,6-bis-spiroacetal ring system, each of the four diastereomers 12a, 12b, 12c, 12d were examined using computer-based molecular modelling (tert-butyldiphenylsilyl ether replaced by trimethylsilyl ether for calculations).
Type: Method |
Advantage: None |
Novelty: None |
ConceptID: Met9
88
Relative energies were calculated at the ab initio level (Hartree–Fock, 3–21 G* basis set), using semi-empirical optimized geometries (AM1) for all molecular mechanics conformers (MMFF94) within 3 kcal−1 mol−1 of the global minimum.
Type: Method |
Advantage: None |
Novelty: None |
ConceptID: Met9
89
The calculated energies followed the trend: cis syn12a < trans syn12b < trans anti12c ≪ cis anti12d (Fig. 1), thus further supporting the assignment of the major component of the more polar band as cis syn12a and the minor component as trans anti12c.
Type: Result |
Advantage: None |
Novelty: None |
ConceptID: Res15
90
The major isomer formed in the present work is the most stable cis syn diastereomer 12a and this isomer has the same configuration as the bis-spiroacetal ring system present in spirolides B 1 and D 2.
Type: Conclusion |
Advantage: None |
Novelty: None |
ConceptID: Con2
91
With bis-spiroacetals 12a, 12b, 12c in hand, epoxidation of the alkene and subsequent base-induced rearrangement of the resultant epoxides 33 to allylic alcohols 34 and homoallylic alcohols 11 was next investigated (Scheme 6).
Type: Method |
Advantage: None |
Novelty: New |
ConceptID: Met10
92
The more polar major band, containing alkenes 12a and 12c (3 : 1), was treated with a solution of dimethyldioxirane in acetone22 to afford epoxides 33a and 33c (3 : 1) in 78% yield.
Type: Method |
Advantage: None |
Novelty: None |
ConceptID: Met10
93
H-12 of the predominant component of the product mixture 33a resonated as a doublet at δ 3.02 ppm in the 1H NMR spectrum (CDCl3), while H-12 of the remaining component 33c resonated as a doublet at δ 2.87 ppm.
Type: Observation |
Advantage: None |
Novelty: None |
ConceptID: Obs11
94
Both doublets exhibited coupling constants of 3.9 Hz.
Type: Observation |
Advantage: None |
Novelty: None |
ConceptID: Obs12
95
It was interesting to note that when the NMR spectrum was recorded in deuterated benzene, these two H-12 doublets resonated at δ 3.10 and 2.69 ppm, respectively.
Type: Observation |
Advantage: None |
Novelty: None |
ConceptID: Obs13
96
Analogous treatment of the minor band 12b with dimethyldioxirane afforded a single epoxide 33, exhibiting a doublet assigned to H-12 with a coupling constant of 3.9 Hz, at δ 2.92 in CDCl3 or 3.12 ppm in C6D6 respectively.
Type: Observation |
Advantage: None |
Novelty: None |
ConceptID: Obs14
97
Due to the fact that a single alkene gave rise to a single epoxide, it appeared that the epoxidation with dimethyldioxirane proceeded with high facial selectivity, as previously observed13 in related 1,7-dioxaspiro[5,5]undec-4-ene ring systems.
Type: Result |
Advantage: None |
Novelty: None |
ConceptID: Res16
98
This can be rationalised by significant steric interactions involving the bulky tert-butyldiphenylsilyl ether which disfavour the approach of dimethyldioxirane from the β face.
Type: Result |
Advantage: None |
Novelty: None |
ConceptID: Res16
99
Dipole–dipole repulsions, which would also disfavour β approach,23 reinforce the steric influence upon facial selectivity for the syn configurations cissyn12a and transsyn12b, due to the β disposition of the central ring oxygen with respect to the C-1112 double bond.
Type: Result |
Advantage: None |
Novelty: None |
ConceptID: Res16
100
Epoxides 33a, 33b, 33c were therefore all assigned as α and this assignment was later verified by the successful execution of the base-induced rearrangement reaction.
Type: Conclusion |
Advantage: None |
Novelty: None |
ConceptID: Con3
101
Due to the small amount of epoxide 33b available, the rearrangement studies were only carried out on epoxides 33a and 33c derived from the more predominant 3 : 1 mixture of bis-spiroacetal alkenes 12a and 12c.
Type: Method |
Advantage: None |
Novelty: New |
ConceptID: Met11
102
Exposure of the 3 : 1 mixture of epoxides 33a and 33c to lithium diethylamide (10 equiv.) in tetrahydrofuran at −78 °C disappointingly did not effect the desired rearrangement and returned only the unreacted starting material.
Type: Method |
Advantage: None |
Novelty: None |
ConceptID: Met11
103
The reaction also failed to proceed either at room temperature or under reflux for periods of up to 24 h.
Type: Observation |
Advantage: None |
Novelty: None |
ConceptID: Obs15
104
It was concluded that the Lewis basicity of the tetrahydrofuran solvent disrupted the required coordination of lithium diethylamide and the epoxide oxygen.
Type: Conclusion |
Advantage: None |
Novelty: None |
ConceptID: Con4
105
The 3 : 1 mixture of epoxides 33a and 33c was therefore treated with lithium diethylamide (10 equiv.) in the non-coordinating solvent pentane at −78 °C (Scheme 6).
Type: Method |
Advantage: None |
Novelty: None |
ConceptID: Met11
106
The reaction mixture was then allowed to warm slowly to room temperature and stirred for a further 16 h, to afford a 3 : 1 mixture of allylic alcohols 34a and 34c in 74% yield.
Type: Method |
Advantage: None |
Novelty: None |
ConceptID: Met11
107
The 1H NMR spectrum of the 3 : 1 mixture of alcohols 34a and 34c lacked the doublets at δ 3.02 and 2.87 ppm corresponding to H-12 of epoxides 33a and 33c, respectively.
Type: Observation |
Advantage: None |
Novelty: None |
ConceptID: Obs16
108
A new two proton multiplet was observed at δ 5.8 ppm indicating the presence of a double bond.
Type: Observation |
Advantage: None |
Novelty: None |
ConceptID: Obs16
109
In the 13C NMR spectrum, the methine resonances at δ 51.3 and 53.6 ppm corresponding to the epoxide carbons C-11 and C-10 were no longer present.
Type: Observation |
Advantage: None |
Novelty: None |
ConceptID: Obs17
110
Two new vinylic carbons assigned to C-10 and C-11 were observed at δ 126.0 and 128.0 ppm together with a methine resonance at δ 67.5 ppm assigned to C-12.
Type: Observation |
Advantage: None |
Novelty: None |
ConceptID: Obs17
111
The C-7 spiro carbon also shifted downfield from δ 103.4 ppm in the epoxide to δ 107.2 ppm.
Type: Observation |
Advantage: None |
Novelty: None |
ConceptID: Obs17
112
Alcohols 34a, 34c were also converted to their acetate derivatives 35a, 35c under standard conditions in order to aid the interpretation of the NMR spectra.
Type: Observation |
Advantage: None |
Novelty: None |
ConceptID: Obs18
113
The outcome of this base-induced rearrangement confirmed that 33a and 33c were in fact α-epoxides, as only the α-epoxides possess a pseudo-axial proton required for base-induced rearrangement to proceed successfully (Fig. 2).
Type: Result |
Advantage: None |
Novelty: None |
ConceptID: Res17
114
With allylic alcohols 34a, 34c in hand, attention focussed on their rearrangement to homoallylic alcohols 11.
Type: Goal |
Advantage: None |
Novelty: None |
ConceptID: Goa4
115
Our earlier studies on base-induced rearrangements of epoxides using bicyclic spiroacetal systems established that better yields of the homoallylic alcohols were obtained using tetrahydrofuran as solvent rather than hexane or hexane–diethyl ether mixtures.
Type: Background |
Advantage: None |
Novelty: None |
ConceptID: Bac8
116
In the present work isomerisation of allylic alcohols 34a, 34c to the more thermodynamically favoured homoallylic alcohols 11a, 11c was investigated using tetrahydrofuran as solvent.
Type: Goal |
Advantage: None |
Novelty: None |
ConceptID: Goa4
117
Thus, a 3 : 1 mixture of allylic alcohols 34a, 34c was added to a solution of lithium diethylamide (10 equiv.) in tetrahydrofuran at −78 °C and the mixture was warmed slowly to room temperature.
Type: Method |
Advantage: None |
Novelty: New |
ConceptID: Met12
118
After 16 hours, subsequent work-up and purification by flash chromatography afforded recovered starting materials 34a, 34c, together with the desired homoallylic alcohols 11a, 11c (3 : 1 mixture) in 35% yield.
Type: Method |
Advantage: None |
Novelty: None |
ConceptID: Met12
119
In the course of their investigations into the rearrangement of epoxides with lithium amide bases, Rickborn and Kissel24 found that the secondary amine used to generate the amide base also influenced the relative amounts of allylic alcohols and homoallylic alcohols formed in these reactions.
Type: Background |
Advantage: None |
Novelty: None |
ConceptID: Bac9
120
In particular, the lithium amide of pyrrolidine was found to be the most effective base to maximise the formation of the homoallylic alcohols.
Type: Background |
Advantage: None |
Novelty: None |
ConceptID: Bac9
121
Accordingly, allylic alcohols 34a, 34c (3 : 1) were treated with the lithium amide base derived from pyrrolidine and n-butyllithium (10 equiv.) at −78 °C and the mixture was allowed to warm slowly to room temperature over 16 hours.
Type: Method |
Advantage: None |
Novelty: None |
ConceptID: Met12
122
Subsequent work-up and purification by flash chromatography afforded homoallylic alcohols 11a, 11c (3 : 1) in an improved 50% yield.
Type: Method |
Advantage: None |
Novelty: None |
ConceptID: Met12
123
The 1H NMR spectrum of the mixture of homoallylic alcohols 11a, 11c (3 : 1) showed significant differences in the resonances due to the alkene protons, in comparison to the allylic alcohol starting materials.
Type: Observation |
Advantage: None |
Novelty: None |
ConceptID: Obs19
124
In the mixture of allylic alcohols 34a, 34c, H-10 and H-11 resonated as a single multiplet at δ 5.8 ppm, however the spectrum of homoallylic alcohols 11a, 11c exhibited multiplets at δ 4.64 and 6.17 ppm corresponding to H-10 and H-9 respectively.
Type: Observation |
Advantage: None |
Novelty: None |
ConceptID: Obs19
125
This large difference in chemical shifts observed for the vinylic protons reflects the fact that honoallylic alcohols 11a, 11c are in fact cyclic enol ethers.
Type: Result |
Advantage: None |
Novelty: None |
ConceptID: Res18
126
In the 13C NMR spectrum, the resonance due to C-9 appeared significantly downfield at δ 141.2 ppm.
Type: Observation |
Advantage: None |
Novelty: None |
ConceptID: Obs20
127
Alcohols 11a, 11c were also converted to their acetate derivatives 36a, 36c under standard conditions in order to aid in the interpretation of the NMR spectra.
Type: Observation |
Advantage: None |
Novelty: None |
ConceptID: Obs21
128
Acetylation of the secondary alcohol caused a large downfield shift in the resonance of H-12, from δ 3.8 ppm in homoallylic alcohols 11a, 11c, to δ 4.9 ppm in homoallylic acetates 36a, 36c.
Type: Observation |
Advantage: None |
Novelty: None |
ConceptID: Obs21
129
More importantly, separate resonances were now observed for C-10 and C-7, at δ 98.0 and 105.0 ppm respectively, which were previously coincidental at δ 98.7 ppm in the homoallylic alcohols 11a, 11c.
Type: Observation |
Advantage: None |
Novelty: None |
ConceptID: Obs21
130
In summary, the first synthesis of the 5,5,6-bis-spiroacetal ring system present in spirolides B 1 and D 2 has been achieved using a novel iterative oxidative radical cyclization strategy.
Type: Conclusion |
Advantage: None |
Novelty: None |
ConceptID: Con1
131
The mild conditions used, and the high yields obtained for the cyclization steps, suggest that this approach is a practical method for the construction of this ring system.
Type: Conclusion |
Advantage: None |
Novelty: None |
ConceptID: Con1
132
The stereogenic centres at C-2 and C-3 on the bis-spiroacetal ring were assembled using the Brown and Bhat crotyl metallation methodology.
Type: Conclusion |
Advantage: None |
Novelty: None |
ConceptID: Con5
133
Unsaturated bis-spiroacetals 12a, 12c were successfully elaborated to homoallylic alcohols 11a, 11cvia epoxidation and base-induced rearrangement, however the synthetic utility of this approach is limited by the presence of inseparable diastereomers due to the stereogenic spirocentres at C-5 and C-7.
Type: Conclusion |
Advantage: None |
Novelty: None |
ConceptID: Con6
Experimental
(2′R,3S,5R,6R)- and (2′S,3S,5R,6R)-8-(tert-Butyldiphenylsilyloxy)-1-(5,6-dihydro-2H-pyran-2-yl)-5-methyl-6-(triethylsilyloxy)octan-3-ol (14a,14b) (2′R,3R,5R,6R)- and (2′S,3S,5R,6R)-8-(tert-butyldiphenylsilyloxy)-1-(5,6-dihydro-2H-pyran-2-yl)-5-methyl-6-(triethylsilyloxy)octan-3-ol (14c,14d)
134
Flame-dried magnesium powder (150 mg, 6.3 mmol) was vigorously stirred in a pear-shaped flask under a nitrogen atmosphere for 4 h, after which time diethyl ether (1.0 mL), a single crystal of iodine (5 mg) and 1,2-dibromoethane (50 μL, 0.2 mmol) were added.
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp1
135
When decolourisation had occurred the flask was cooled to 0 °C in an ice bath and a mixture of bromide 16 (0.69 g, 3.63 mmol), aldehyde 15 (1.45 g, 2.91 mmol) and diethyl ether (2.0 g) was added slowly dropwise over 60 min via syringe.
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp1
136
After stirring for a further 60 min at room temperature, saturated aqueous sodium bicarbonate (1.0 mL) was added and the reaction mixture extracted with diethyl ether (60 mL).
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp1
137
The organic layer was washed with water (15 mL) and brine (15 mL) and was dried over MgSO4.
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp1
138
Removal of the solvent under a reduced pressure, followed by flash column chromatography using hexane–ethyl acetate (19 : 1–1 : 1) gave a 1 : 1 : 1 : 1 mixture of the title compounds14a, 14b, 14c, 14d (1.12 g, 64%) as a colourless oil. 14a, 14b and 14c, 14d were separable by careful chromatography if desired, but the 1 : 1 : 1 : 1 mixture was routinely used for the preparation of spiroacetals 32.
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp1
139
Alcohols14a, 14b [Found (CI, NH3): MH+, 611.3960; C36H59O4Si2 requires Mr, 611.3952]; νmax/cm−1 (CDCl3): 3400, 3053, 2958, 2932, 2305, 1461, 1427, 1265, 1111, 1082, 895, 738, 705; δH (300 MHz, CDCl3): 0.59 (6H, q, J 8.2, SiCH2CH3), 0.84 (3H, d, JMe,5 7.0, Me), 0.93 (9H, t, J 8.2, SiCH2CH3), 1.05 (9H, s, SitBuPh2), 1.43–1.70 (8H, m, H-1, H-2, H-4 and H-7), 1.79–1.97 (2H, H-5 and H-5′a), 2.19–2.32 (1H, m, CH=CHCH2, H-5′b), 3.54–3.73 (4H, m, H-3, H-6′ax and H-8), 3.84–3.91 (1H, m, CHOSi, H-6), 3.93–4.03 (1H, m, CHaxHeqO, H-6′eq), 4.05–4.14 (1H, m, CHO, H-2′), 5.57–5.66 (1H, m, CH=CHCH2, H-3′), 5.79–5.87 (1H, m, CH=CHCH2, H-4′), 7.33–7.45 (6H, m, ArH, m and p), 7.60–7.69 (4H, m, ArH, o); δC (75 MHz, CDCl3): 5.8 (SiCH2CH3), 6.6 (SiCH2CH3), 15.8 (CH3, Me), 15.9 (CH3, Me*), 19.0 (quat., SitBuPh2), 25.18 (CH2, CH2CH=CH, C-5′), 25.21 (CH2, CH2CH=CH, C-5′*), 26.8 (CH3, SitBuPh2), 31.7 (CH2, CH2CH2O, C-7), 31.8 (CH2, CH2CH2O, C-7*), 34.2 (CH2, CH2CHO, C-1), 34.3 (CH2, CH2CHO, C-1*), 34.5 (CH2, CH2CHO, C-2), 34.6 (CH2, CH2CHO, C-2*), 36.6 (CH, CHMe, C-5), 40.9 (CH2, CH2CHMe, C-4), 41.0 (CH2, CH2CHMe, C-4*), 63.6 (CH2, CH2O, C-6′), 63.7 (CH2, CH2O, C-6′*), 63.9 (CH2, CH2OSi, C-8), 64.0 (CH2, CH2OSi, C-8*), 70.2 (CH, CHOH, C-3), 70.5 (CH, CHOH, C-3*), 74.1 (CH, CHO, C-2′), 74.2 (CH, CHO, C-2′*), 75.1 (CH, CHOSi, C-6), 75.2 (CH, CHOSi, C-6*), 124.8 (CH, CH=CHCH2, C-4′), 127.7 (CH, ArH, m), 129.8 (CH, ArH, p), 130.2 (CH, CH=CHCH2, C-3′), 133.0 (quat., ArSi), 135.6 (CH, ArH, o); m/z (CI, NH3): 611 (MH+, 4%), 501 (3), 485 (5), 479 (4), 455 (10), 291 (22), 216 (24), 199 (20), 196 (32), 132 (27), 120 (34), 78 (100).
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp1
140
Alcohols14c, 14d as a colourless oil [Found (CI, NH3): MH+, 611.3944.
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp1
141
C36H59O4Si2 requires Mr, 611.3952]; νmax/cm−1 (CDCl3): 3400, 3053, 2958, 2932, 2305, 1461, 1427, 1265, 1111, 1082, 895, 738, 705; δH (400 MHz, CDCl3): 0.57 (6H, q, J 8.2, SiCH2CH3), 0.84–0.93 (12H, m, SiCH2CH3 and Me), 1.05 (9H, s, SitBuPh2), 1.43–1.70 (8H, m, H-1, H-2, H-4 and H-7), 1.81 (1H, m, H-5), 1.88 (0.5H, br s, CH=CHCHaHb H-5′a), 1.92 (0.5H, br s, CH=CHCHaHb H-5′a*), 2.22–2.34 (1H, m, CH=CHCH2, H-5′b), 2.85 (0.5H, br s, OH), 3.05 (0.5H, br s, OH*), 3.62–3.73 (4H, m, H-3, H-6′ax and H-8), 3.84–3.89 (1H, m, CHOSi, H-6), 3.95–4.01 (1H, m, H-6′eq), 4.12 (1H, br s, CHO, H-2′), 5.61 (1H, br d, J3′,4′ 10.0, CH=CHCH2, H-3′), 5.78–5.85 (1H, m, CH=CHCH2, H-4′), 7.34–7.44 (6H, m, ArH, m and p), 7.61–7.69 (4H, m, ArH, o); δC (100 MHz, CDCl3): 5.1 (SiCH2CH3), 6.9 (SiCH2CH3), 16.5 (CH3, Me), 16.6 (CH3, Me*), 19.1 (quat., SitBuPh2), 25.2 (CH2, CH2CH=CH, C-5′), 25.3 (CH2, CH2CH=CH, C-5′*), 26.8 (CH3, SitBuPh2), 31.7 (CH2, CH2CH2O, C-7), 33.1 (CH2, CH2CHO, C-1), 33.2 (CH2, CH2CHO, C-1*), 35.37 (CH, CHMe, C-5), 35.43 (CH, CHMe, C-5*), 35.55 (CH2, CH2CHO, C-2), 35.64 (CH2, CH2CHO, C-2*), 40.0 (CH2, CH2CHMe, C-4), 61.1 (CH2, CH2OSi, C-8), 63.6 (CH2, CH2O, C-6′), 70.0 (CH, CHOH, C-3), 70.1 (CH, CHOH, C-3*), 72.65 (CH, CHOSi, C-6), 72.69 (CH, CHOSi, C-6*), 74.0 (CH, CHO, C-2′), 74.1 (CH, CHO, C-2′*), 124.8 (CH, CH=CHCH2, C-4′), 127.6 (CH, ArH, m), 129.6 (CH, ArH, p), 130.29 (CH, CH=CHCH2, C-3′), 130.34 (CH, CH=CHCH2, C-3′*), 133.9 (quat., ArSi), 135.6 (CH, ArH, o); m/z (CI, NH3): 611 (MH+, 13%), 479 (19), 461 (9), 455 (12), 401 (14), 283 (12), 216 (26), 205 (27), 199 (30), 196 (32), 132 (29), 120 (35), 91 (48), 83 (48), 78 (100).
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp1
(2S,2′R,3′R,5R)- and (2S,2′R,3′R,5S)-2-[5′-(tert-Butyldiphenylsilyloxy)-2′-methyl-3′-(triethylsilyloxy)pentyl]-1,6-dioxaspiro[4.5]dec-9-ene (32a,32b)
142
Iodine (60 mg, 0.24 mmol) and iodobenzene diacetate (70 mg, 0.22 mmol) were added to a 1 : 1 solution of alcohols 14a, 14b (60 mg, 0.10 mmol) in cyclohexane (10 mL).
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp2
143
After stirring for 1 h under 40 W irradiation at room temperature, the reaction mixture was diluted with diethyl ether (50 mL) and shaken with saturated aqueous sodium thiosulfate–sodium bicarbonate (1 : 1, 10 mL) until colourless.
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp2
144
The organic layer was washed with brine (10 mL) and dried over anhydrous potassium carbonate.
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp2
145
Removal of the solvent under a reduced pressure, followed by flash column chromatography using hexane–diethyl ether (9 : 1) as eluant afforded a 1 : 1 mixture of the title compounds32a, 32b (54 mg, 90%) as a colourless oil [Found (CI, NH3): MH+, 609.3791.
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp2
146
C36H57O4Si2 requires Mr, 609.3795]; νmax/cm−1 (CDCl3): 3053, 2986, 2959, 2876, 2305, 1422, 1265, 1111, 1079, 1018, 895, 736; δH (300 MHz, CDCl3): 0.57 (6H, q, J 8.0, SiCH2CH3), 0.82–0.91 (12H, m, Me and SiCH2CH3), 1.05 (9H, s, SitBuPh2), 1.48–2.29 (11H, m, H-1′, H-2′, H-3, H-4, H-4′ and H-8), 3.64–3.77 (3H, m, H-5′ and H-7ax), 3.80–3.84 (1H, m, CHOSi, H-3′), 3.92–4.01 (1H, m, CHaxHeqO, H-7eq), 4.17–4.26 (1H, m, CHO, H-2), 5.60 (1H, br d, J10′,9′ 11.3, CH=CHCH2, H-10), 5.93–6.02 (1H, m, CH=CHCH2, H-9), 7.36–7.44 (6H, m, ArH, m and p), 7.64–7.70 (4H, m, ArH, o); δC (100 MHz, CDCl3): 5.2 (CH3, SiCH2CH3), 7.0 (CH3, SiCH2CH3), 14.1 (CH3, Me), 14.5 (CH3, Me*), 19.2 (quat., SitBuPh2), 24.54 (CH2, CH2CH=CH, C-8), 24.59 (CH2, CH2CH=CH, C-8*), 26.8 (CH3, SitBuPh2), 31.1 (CH2, CH2CH2O, C-4′), 31.4 (CH2, CH2CH2O, C-4′*), 35.4 (CH, CHMe, C-2′), 36.2 (CH2, CH2CHO, C-3), 36.7 (CH2, CH2CHO, C-3*), 37.3 (CH2, CH2CHO, C-4), 38.4 (CH2, CH2CHO, C-4*), 41.6 (CH2, CH2CHMe, C-1′), 58.5 (CH2, CH2O, C-7), 59.1 (CH2, CH2O, C-7*), 61.2 (CH2, CH2OSi, C-5′), 72.9 (CH, CHOSi, C-3′), 73.3 (CH, CHOSi, C-3′*), 76.4 (CH, CHO, C-2), 78.8 (CH, CHO, C-2*), 102.2 (quat., C-5), 102.5 (quat., C-5*), 127.6 (CH, ArH, m), 128.9 (CH, CH=CHCH2, C-9), 129.5 (CH, ArH, p), 130.2 (CH, CH=CHCH2, C-10), 134.0 (quat., ArSi), 135.6 (CH, ArH, o); m/z (CI, NH3): 609 (MH+, 11%), 593 (6), 579 (11), 551 (6), 477 (54), 455 (23), 397 (12), 283 (16), 221 (20), 216 (25), 199 (26), 196 (28), 139 (35), 78 (100).
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp2
(2R,2′R,3′R,5R)- and (2R,2′R,3′R,5S)-2-[5′-(tert-Butyldiphenylsilyloxy)-2′-methyl-3′-(triethylsilyloxy)pentyl]-1,6-dioxaspiro[4.5]dec-9-ene (32c,32d)
147
Iodine (60 mg, 0.24 mmol) and iodobenzene diacetate (69 mg, 0.22 mmol) were added to a 1 : 1 solution of alcohols 14c, 14d (60 mg, 0.10 mmol) in cyclohexane (10 mL).
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp3
148
After stirring for 1 h under 40 W irradiation at rt, the reaction mixture was diluted with diethyl ether (50 mL) and shaken with saturated aqueous sodium thiosulfate–sodium bicarbonate (3 : 1, 10 mL) until colourless.
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp3
149
The organic layer was washed with brine (10 mL) and dried over anhydrous potassium carbonate.
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp3
150
Removal of the solvent under a reduced pressure, followed by flash column chromatography using hexane–diethyl ether (9 : 1) as eluant afforded a 1 : 1 mixture of the title compounds32c, 32d (54 mg, 90%) as a colourless oil [Found (CI, NH3): MH+, 609.3791; C36H57O4Si2 requires Mr, 609.3795]; νmax/cm−1 (CDCl3): 3053, 2986, 2959, 2876, 2305, 1422, 1265, 1111, 1079, 1018, 895, 736; δH (300 MHz, CDCl3): 0.55 (6H, q, J 8.0, SiCH2CH3), 0.84–0.93 (12H, m, Me and SiCH2CH3), 1.04 (9H, s, SitBuPh2), 1.40–2.30 (11H, m, H-1′, H-2′, H-3, H-4, H-4′ and H-8), 3.68–3.76 (3H, m, H-7ax and H-5′), 3.78–3.83 (1H, m, CHOSi, H-3′), 3.93–4.02 (1H, m, CHaxHeqO, H-7eq), 4.12–4.20 (1H, m, CHO, H-2), 5.61 (1H, br d, J10′,9′ 11.2, CH=CHCH2, H-10), 5.95–6.01 (1H, m, CH=CHCH2, H-9), 7.36–7.44 (6H, m, ArH, m and p), 7.64–7.70 (4H, m, ArH, o); δC (100 MHz, CDCl3): 5.2 (CH3, SiCH2CH3), 7.0 (CH3, SiCH2CH3), 15.0 (CH3, Me), 15.3 (CH3, Me*), 19.2 (quat., SitBuPh2), 24.5 (CH2, CH2CH=CH, C-8), 24.6 (CH2, CH2CH=CH, C-8*), 26.9 (CH3, SitBuPh2), 30.4 (CH2, CH2CH2O, C-4′), 30.9 (CH2, CH2CH2O, C-4′*), 35.8 (CH2, CH2CHO, C-3), 36.0 (CH2, CH2CHO, C-3*), 36.49 (CH, CHMe, C-2′), 36.52 (CH, CHMe, C-2′*), 37.2 (CH2, CH2CHO, C-4), 37.4 (CH2, CH2CHO, C-4*), 38.4 (CH2, CH2CHO, C-1′), 40.3 (CH2, CH2CHO, C-1′*), 58.5 (CH2, CH2O, C-7), 59.2 (CH2, CH2O, C-7*), 61.17 (CH2, CH2OSi, C-5′), 61.21 (CH2, CH2OSi, C-5′*), 72.7 (CH, CHOSi, C-3′), 72.8 (CH, CHOSi, C-3′*), 77.5 (CH, CHO, C-2), 80.2 (CH, CHO, C-2*), 102.3 (quat., C-5), 127.6 (CH, ArH, m), 128.2 (CH, CH=CHCH2, C-9), 128.8 (CH, CH=CHCH2, C-9*), 129.0 (CH, CH=CHCH2, C-10), 129.2 (CH, CH=CHCH2, C-10*), 129.5 (CH, ArH, p), 133.98 (quat., ArSi), 134.04 (quat., ArSi*), 135.6 (CH, ArH, o); m/z (CI, NH3): 609 (MH+, 11%), 593 (6), 579 (11), 551 (6), 477 (54), 455 (23), 397 (12), 283 (16), 221 (20), 216 (25), 199 (26), 196 (28), 139 (35), 78 (100).
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp3
(2S,2′R,3′R,5R)- and (2S,2′R,3′R,5S)-2-[5′-(tert-Butyldiphenylsilyloxy)-3′-hydroxy-2′-methylpentyl]-1,6-dioxaspiro[4.5]dec-9-ene (13a,13b) (2R,2′R,3′R,5R)- and (2R,2′R,3′R,5S)-2-[5′-(tert-butyldiphenylsilyloxy)-3′-hydroxy-2′-methylpentyl]-1,6-dioxaspiro[4.5]dec-9-ene (13c,13d)
151
A solution of pyridinium hydrochloride was prepared by bubbling freshly prepared hydrogen chloride gas through pyridine (100 mL) with the formation of a crystalline precipitate.
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp4
152
Further pyridine was added portionwise until the precipitate just redissolved.
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp4
153
An equimolar mixture of bis-silyl ethers 13a, 13b, 13c, 13d (150 mg, 0.25 mmol) was dissolved in an aliquot of this HCl–pyridine solution (5.0 mL) and stirred for 48 h at 50 °C.
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp4
154
Saturated aqueous sodium bicarbonate (1.0 mL) was then added and the reaction mixture extracted with ethyl acetate (2 × 15 mL).
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp4
155
The organic extracts were washed with brine (5 mL) and dried over magnesium sulfate.
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp4
156
Removal of the solvent under a reduced pressure afforded an oil which was purified by flash column chromatography using hexane–diethyl ether (9 : 1–0 : 1) as eluant to afford a 1 : 1 : 1 : 1 mixture of the title compounds13a, 13b, 13c, 13d (105 mg, 87%) as a colourless oil.
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp4
157
Alcohols13a, 13b [Found (CI, NH3): MH+, 495.2910; C30H43O4Si requires Mr, 495.2931]; νmax/cm−1 (CDCl3): 3460, 2958, 2930, 2857, 1471, 1462, 1427, 1213, 1111, 1078, 1027, 997, 702; δH (400 MHz, CDCl3): 0.92 (1.5H, d, JMe,2′ 6.8, Me), 0.94 (1.5H, d, JMe,2′ 6.8, Me*), 1.05 (9H, s, SitBuPh2), 1.40–2.08 (10H, m, H-1′a, H-2′, H-3, H-4, H-4′ and H-8), 2.12–228 (1H, m, CHaHbCHO, H-1′b), 3.12 (0.5H, br s, OH), 3.17 (0.5H, br s, OH*), 3.73 (1H, m, CHaxHeqO, H-7ax), 3.80–3.96 (4H, m, H-3′, H-5′ and H-7eq), 4.19–4.28 (1H, m, CHO, H-2), 5.57–5.63 (1H, m, CH=CHCH2, H-10), 5.95–6.01 (1H, m, CH=CHCH2, H-9), 7.37–7.44 (6H, m, SiArH, m and p), 7.65–7.69 (4H, m, SiArH, o); δC (100 MHz, CDCl3): 14.2 (CH3, Me), 19.1 (quat., SitBuPh2), 24.4 (CH2, CH2CH=CH, C-8), 24.5 (CH2, CH2CH=CH, C-8*), 26.8 (CH3, SitBuPh2), 31.3 (CH2, CH2CHO, C-4′), 31.4 (CH2, CH2CHOSi, C-4′*), 35.7 (CH2, CH2CH2, C-4), 36.6 (CH, CHMe, C-2′), 37.3 (CH2, CH2CH2, C-3), 38.4 (CH2, CH2CH2, C-3*), 39.5 (CH2, CH2CH2, C-1′), 41.9 (CH2, CH2CHMe, C-1′*), 58.8 (CH2, CH2O, C-7), 59.2 (CH2, CH2O, C-7*), 63.3 (CH2, CH2OSi, C-5′), 73.6 (CH, CHOH, C-3′), 74.2 (CH, CHOH, C-3′*), 76.9 (CH, CHO, C-2), 79.1 (CH, CHO, C-2*), 102.6 (quat., C-5), 127.7 (CH, ArH, m), 128.8 (CH, CH=CHCH2, C-9), 128.9 (CH, CH=CHCH2, C-10), 129.7 (CH, ArH, p), 133.4 (quat., ArSi), 135.6 (CH, ArH, o); m/z (CI, NH3): 495 (MH+, 2%), 479 (14), 477 (MH+ − H2O, 28), 274 (35), 216 (41), 199 (24), 196 (72), 98 (44), 94 (38), 78 (100).
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp4
158
Alcohols13c, 13d [Found (CI, NH3): MH+, 495.2903; C30H43O4Si requires Mr, 495.2931]; νmax/cm−1 (CDCl3): 3460, 2958, 2930, 2857, 1471, 1462, 1427, 1213, 1111, 1078, 1027, 997, 702; δH (400 MHz, CDCl3): 0.94 (1.5H, d, JMe,2′ 6.7, Me), 0.95 (1.5H, d, JMe,2′ 6.7, Me*), 1.04 (9H, s, SitBuPh2), 1.48–2.30 (10.5H, m, H-1′, H-2′, H-3, H-4, H-4′ and H-8), 2.40 (0.5H, dd, J1′,2 = J1′,2′ 7.4, CHaHbCHO, H-1′b*), 3.41 (0.5H, d, JOH,3′ 2.1, OH), 3.43 (0.5H, d, JOH,3′ 2.1, OH*), 3.74 (1H, ddd, J7ax,7eq = J7ax,8ax 10.3 and J7ax,8eq 5.7, CHaxHeqO, H-7ax), 3.80–3.98 (4H, m, H-3′, H-5′ and H-7eq), 4.24–4.30 (1H, m, CHO, H-2), 5.57–5.63 (1H, m, CH=CHCH2, H-10), 5.95–6.02 (1H, m, CH=CHCH2, H-9), 7.36–7.43 (6H, m, SiArH, m and p), 7.66–7.69 (4H, m, SiArH, o); δC (100 MHz, CDCl3): 13.9 (CH3, Me), 14.2 (CH3, Me*), 19.1 (quat., SitBuPh2), 24.4 (CH2, CH2CH=CH, C-8), 24.5 (CH2, CH2CH=CH, C-8*), 26.8 (CH3, SitBuPh2), 30.6 (CH2, CH2CHO, C-4′), 31.1 (CH2, CH2CHOSi, C-4′*), 35.5 (CH2, CH2CH2, C-4), 35.9 (CH2, CH2CH2, C-4*), 36.1 (CH, CHMe, C-2′), 36.3 (CH, CHMe, C-2′*), 37.3 (CH2, CH2CH2, C-3), 38.4 (CH2, CH2CH2, C-3*), 38.9 (CH2, CH2CHO, C-1′), 41.8 (CH2, CH2CHO, C-1′*), 58.7 (CH2, CH2O, C-7), 59.3 (CH2, CH2O, C-7*), 63.5 (CH2, CH2OSi, C-5′), 63.6 (CH2, CH2OSi, C-5′*), 73.8 (CH, CHOH, C-3′), 74.0 (CH, CHOH, C-3′*), 76.4 (CH, CHO, C-2), 79.7 (CH, CHO, C-2*), 102.5 (quat., C-5), 127.7 (CH, ArH, m), 128.4 (CH, CH=CHCH2, C-9), 128.7 (CH, CH=CHCH2, C-9*), 128.9 (CH, CH=CHCH2, C-10), 129.0 (CH, CH=CHCH2, C-10*), 129.7 (CH, ArH, p), 133.2 (quat., ArSi), 133.3 (quat., ArSi*), 135.6 (CH, ArH, o); m/z (CI, NH3): 495 (MH+, 1%), 477 (2), 447 (1), 399 (1), 274 (2), 216 (4), 199 (5), 139 (2), 102 (100), 86 (47).
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp4
(2R,3R,5S,7R)-, (2R,3R,5R,7S)-, (2R,3R,5S,7S)- and (2R,3R,5R,7R)-2-[2′-(tert-Butyldiphenylsilyloxy)ethyl]-3-methyl-1,6,8-trioxadispiro[4.1.5.2]tetradec-11-ene (12a,12b,12c,12d)
159
Iodine (230 mg, 0.91 mmol) and iodobenzene diacetate (280 mg, 0.87 mmol) were added to a 1 : 1 : 1 : 1 mixture of spiroacetal alcohols 13a, 13b, 13c, 13d (205 mg, 0.41 mmol) in cyclohexane (10 mL).
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp5
160
After stirring for 1 h under 40 W irradiation at room temperature, the reaction mixture was diluted with diethyl ether (50 mL) and shaken with saturated aqueous sodium thiosulfate–sodium bicarbonate (3 : 1, 10 mL) until colourless.
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp5
161
The organic layer was washed with brine (10 mL) and dried over anhydrous potassium carbonate.
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp5
162
Removal of the solvent under a reduced pressure, followed by flash column chromatography using hexane–diethyl ether (9 : 1) as eluant afforded a 1 : 1 : 1 : 1 mixture of four diastereomers 12a, 12b, 12c, 12d (165 mg, 83%) as a colourless oil [Found (CI, NH3): MH+, 493.2782.
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp5
163
C30H41O4Si requires Mr, 493.2774]; νmax/cm−1 (CDCl3): 2958, 2931, 2877, 2857, 1472, 1462, 1427, 1111, 1078, 994, 975, 702; δH (400 MHz, CDCl3): 0.85–0.91 (3H, m, Me), 1.60–2.61 (11H, m, H-1′, H-3, H-4, H-10, H-13 and H-14), 3.58–4.29 (5H, m, H-2, H-2′ and H-9), 5.53–5.66 (1H, m, CH=CHCH2, H-12), 5.85–5.99 (1H, m, CH=CHCH2, H-11), 7.33–7.44 (6H, m, SiArH, m and p), 7.62–7.70 (4H, m, SiArH, o); δC (100 MHz, CDCl3): 14.1 (CH3, Me), 14.3 (CH3, Me*), 14.5 (CH3, Me**), 14.6 (CH3, Me***), 19.17 (quat., SitBuPh2), 19.22 (quat., SitBuPh2*), 24.3 (CH2, CH2CH=CH, C-10), 24.4 (CH2, CH2CH=CH, C-10*), 24.5 (CH2, CH2CH=CH, C-10**), 26.9 (CH3, SitBuPh2), 33.3 (CH2, CH2CH2O, C-1′), 33.49 (CH2, CH2CH2O, C-1′*), 33.56 (CH2, CH2CH2O, C-1′**), 33.64 (CH2, CH2CH2O, C-1′***), 34.5 (CH, CHMe, C-3), 34.6 (CH, CHMe, C-3*), 35.3 (CH, CHMe, C-3**), 35.7 (CH2, CH2CHO, C-13 or C-14), 36.2 (CH2, CH2CHO, C-13* or C-14*), 36.4 (CH2, CH2CHO, C-13** or C-14**), 36.6 (CH2, CH2CHO, C-13*** or C-14***), 37.0 (CH2, CH2CHO, C-14 or C-13), 37.2 (CH2, CH2CHO, C-14* or C-13*), 37.4 (CH2, CH2CHO, C-14** or C-13**), 37.5 (CH2, CH2CHO, C-14*** or C-13***), 44.97 (CH2, CH2CHO, C-4), 45.01 (CH2, CH2CHO, C-4*), 45.2 (CH2, CH2CHO, C-4**), 45.9 (CH2, CH2CHO, C-4***), 59.20 (CH2, CH2O, C-9), 59.26 (CH2, CH2O, C-9*), 59.31 (CH2, CH2O, C-9**), 59.3 (CH2, CH2O, C-9***), 61.5 (CH2, CH2O, C-2′), 61.6 (CH2, CH2O, C-2′*), 61.69 (CH2, CH2O, C-2′**), 61.71 (CH2, CH2O, C-2′***), 78.0 (CH, CHO, C-2), 78.8 (CH, CHO, C-2*), 79.3 (CH, CHO, C-2**), 102.6 (quat., C-7), 102.9 (quat., C-7*), 114.3 (quat, C-5), 114.8 (quat, C-5*), 115.3 (quat, C-5**), 127.6 (CH, ArH, m), 127.8 (CH, CH=CHCH2, C-11), 128.2 (CH, CH=CHCH2, C-11*), 128.4 (CH, CH=CHCH2, C-11**), 128.98 (CH, CH=CHCH2, C-11***), 129.03 (CH, CH=CHCH2, C-12), 129.4 (CH, CH=CHCH2, C-12*), 129.5 (CH, ArH, p), 129.8 (CH, CH=CHCH2, C-12**), 130.1 (CH, CH=CHCH2, C-12***), 133.9 (quat., ArSi), 134.1 (quat., ArSi*), 135.6 (CH, ArH, o); m/z (EI): 492 (M+, 1%), 474 (M+ − H2O, 83), 447 (1), 435 (M+ − tBu, 55), 417 (13), 337 (6), 219 (14), 199 (69), 136 (56), 109 (100).
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp5
(2R,3R,5S,7R)-, (2R,3R,5S,7S)- and (2R,3R,5R,7R)-2-[2′-(tert-Butyldiphenylsilyloxy)ethyl]-3-methyl-1,6,8-trioxadispiro[4.1.5.2]tetradec-11-ene 12a,12b,12c
164
A 1 : 1 : 1 : 1 mixture of the four diastereomers 12a, 12b, 12c, 12d (165 mg, 0.33 mmol) was dissolved in dichloromethane (10 mL) and stirred with p-toluenesulfonic acid (5 mg, 0.03 mmol) at room temperature.
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp6
165
After 24 h, triethylamine (50 μL) was added and the solution filtered through a plug of silica.
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp6
166
Removal of the solvent under a reduced pressure afforded a colourless oil which was purified by preparative layer chromatography (8 sweeps, hexane–diethyl ether (9 : 1) containing 0.1% triethylamine) to give band A containing the less polar trans syn bis-spiroacetal 12b (30 mg, 18%) and band BC containing an inseparable 3 : 1 mixture of the more polar bis-spiroacetals cis syn12a and trans anti12c (113 mg, 68%).
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp6
167
trans syn Bis-spiroacetal12b (minor band A), colourless oil [Found (CI, NH3): MH+, 493.2782; C30H41O4Si requires Mr, 493.2774]; [α]20D = +10.0 10−1 deg cm2 g−1 (c = 1.8, CDCl3); νmax/cm−1 (CDCl3): 2958, 2931, 2877, 2857, 1472, 1462, 1427, 1111, 1078, 994, 975, 702; δH (400 MHz, CDCl3): 1.01 (3H, d, JMe,3′ 6.8, Me), 1.04 (9H, s, SitBuPh2), 1.67–1.75 (1H, m, H-1′a), 1.82–2.06 (6H, m, H-1′b, H-4a, H-10a, H-13a, H-14), 2.13–2.26 (4H, m, H-3, H-4b, H-10b and H-13b), 3.74 (1H, dddd, Jgem 11.2, J9eq,10ax 5.6 and J9eq,10eq = J9eq,11 1.2, CHeqHaxO, H-9eq), 3.77–3.82 (2H, m, CH2OSi, H-2′), 3.91 (1H, ddd, Jgem = J9ax,10ax 11.2 and J9ax,10eq 3.8, CHeqHaxO, H-9ax), 4.09 (1H, m, CHO, H-2), 5.57 (1H, ddd, J12,11 10.0, J12,10a 2.6 and J12,10b 1.4, CH=CHCH2, H-12), 5.89 (1H, dddd, J11,12 10.0, J11,10a 5.4, J11,10b 2.2 and J11,9a 1.2, CH=CHCH2, H-11), 7.36–7.42 (6H, m, SiArH, m and p), 7.65–7.70 (4H, m, SiArH, o); δC (100 MHz, CDCl3): 14.3 (CH3, Me), 19.2 (quat., SitBuPh2), 24.4 (CH2, CH2CH=CH, C-10), 26.9 (CH3, SitBuPh2), 33.7 (CH2, CH2CH2O, C-1′), 35.3 (CH, CHMe, C-3), 36.5 (CH2, CH2CH2, C-13 or C-14), 36.6 (CH2, CH2CH2, C-14 or C-13), 45.0 (CH2, CH2CHO, C-4), 59.4 (CH2, CH2O, C-9), 61.5 (CH2, CH2OSi, C-2′), 78.8 (CH, CHO, C-2), 102.9 (quat., C-7), 114.8 (quat., C-5), 127.6 (CH, ArH, m), 127.8 (CH, CH=CHCH2, C-11), 129.5 (CH, ArH, p), 130.1 (CH, CH=CHCH2, C-12), 134.1 (quat., ArSi), 135.6 (CH, ArH, o); m/z (EI): 492 (M+, 1%), 474 (M+ − H2O, 83), 447 (1), 435 (M+ − tBu, 55), 417 (13), 337 (6), 219 (14), 199 (69), 136 (56), 109 (100).
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp6
168
cis syn Bis-spiroacetal12aand trans anti bis-spiroacetal12c (major band BC), colourless oil [Found (CI, NH3): MH+, 493.2782.
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp6
169
C30H41O4Si requires Mr, 493.2774]; [α]20D = +17.2 10−1 deg cm2 g−1 (c = 1.8, CDCl3); νmax/cm−1 (CDCl3): 2958, 2931, 2877, 2857, 1472, 1462, 1427, 1111, 1078, 994, 975, 702; δH (400 MHz, CDCl3): 0.87 (0.75H, d, JMe,3′ 6.8, Me*), 0.89 (2.25H, d, JMe,3′ 6.8, Me), 1.04 (9H, s, SitBuPh2), 1.54–1.73 (3H, m, H-1′ and H-4a), 1.82–2.31 (7H, m, H-4b, H-10, H-13 and H-14), 2.38–2.52 (1H, m, CHMe, H-3), 3.7 (3H, m, H-2′ and H-9eq), 3.87–3.98 (1H, m, CHaxHeqOSi, H-9ax), 4.19–4.28 (1H, m, CHO, H-2), 5.57 (0.25H, br d, J12,11 10, CH=CHCH2, H-12*), 5.64 (0.75H, br d, J12,1110, CH=CHCH2, H-12), 5.96 (1H, m, CH=CHCH2, H-11), 7.34–7.42 (6H, m, SiArH, m and p), 7.65–7.71 (4H, m, SiArH, o); δC (100 MHz, CDCl3): 14.5 (CH3, Me), 14.6 (CH3, Me*), 19.2 (quat., SitBuPh2), 24.3 (CH2, CH2CH=CH, C-10*), 24.4 (CH2, CH2CH=CH, C-10), 26.9 (CH3, SitBuPh2), 33.56 (CH2, CH2CH2O, C-1′), 35.4 (CH, CHMe, C-3), 35.6 (CH, CHMe, C-3*), 35.7 (CH2, CH2CH2, C-13 or C-14), 36.2 (CH2, CH2CH2, C-13* or C-14*), 37.0 (CH2, CH2CH2, C-14 or C-13), 37.4 (CH2, CH2CH2, C-14* or C-13*), 45.2 (CH2, CH2CHMe, C-4), 45.9 (CH2, CH2CHMe, C-4*), 59.27 (CH2, CH2O, C-9), 61.71 (CH2, CH2OSi, C-2′), 78.0 (CH, CHO, C-2), 79.3 (CH, CHO, C-2*), 102.6 (quat., C-7), 114.3 (quat., C-5), 127.6 (CH, ArH, m), 128.2 (CH, CH=CHCH2, C-11), 128.4 (CH, CH=CHCH2, C-11*), 129.5 (CH, ArH, p), 129.0 (CH, CH=CHCH2, C-12*), 129.8 (CH, CH=CHCH2, C-12), 134.1 (quat., ArSi), 135.6 (CH, ArH, o); m/z (EI): 492 (M+, 1%), 474 (M+ − H2O, 83), 447 (1), 435 (M+ − tBu, 55), 417 (13), 337 (6), 219 (14), 199 (69), 136 (56), 109 (100).
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp6
(2R,3R,5S,7R,11S,12S)- and (2R,3R,5R,7R,11R,12R)-2-[2′-(tert-Butyldiphenylsilyloxy)ethyl]-3-methyl-1,6,8-trioxadispiro[4.1.5.2]-11,12-epoxy-tetradecanes (33a,33c)
170
Dimethyldioxirane (2.0 mL of a ca. 0.1 M solution in acetone, 0.2 mmol) was added dropwise to a stirred solution of the major bis-spiroacetal band BC containing a 3 : 1 mixture of cis syn12a and trans anti12c (50 mg, 0.10 mmol), potassium carbonate (20 mg, 0.14 mmol) and activated 4 Å molecular sieves in acetone (2.0 mL) at 0 °C.
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp7
171
After stirring for 16 h at room temperature, further dimethyl dioxirane (1.0 mL, 0.1 mmol) was added and stirring continued for 8 h.
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp7
172
The reaction mixture was then filtered and the solvents removed under a reduced pressure to afford a pale yellow oil which was purified by flash column chromatography using hexane–diethyl ether (9 : 1–1 : 1) as eluant to afford the title compounds33a, 33c (40 mg, 3 : 1, 78%) as a colourless clear oil [Found (CI, NH3): MH+, 509.2718; C30H41O5Si requires Mr, 507.2723]; νmax/cm−1 (CDCl3): 2955, 2929, 2856, 1471, 1427, 1359, 1272, 1111, 1083, 999, 885, 840, 822, 739, 702, 614; δH (400 MHz, CDCl3): 0.90 (0.75H, d, J 6.9, Me*), 0.91 (2.25H, d, J 6.9, Me), 1.05 (9H, s, SitBuPh2), 1.58–1.72 (3H, m, H-1′ and H-4a), 1.79–2.36 (7H, m, H-4b, H-10, H-13 and H-14), 2.40–2.50 (1H, m, CHMe, H-3), 2.87 (0.25H, d, J12,11 3.9, CHOCHCH2, H-12*), 3.02 (0.75H, d, J12,11 3.9, CHOCHCH2, H-12*), 3.35 (0.75H, dd, J11,12 = J11,10a 3.9, CHOCHCH2, H-11), 3.39 (0.25H, dd, J11,12 = J11,10a 3.9, CHOCHCH2, H-11*), 3.42–3.48 (1H, m, CHaxHeqO, H-9eq), 3.70–3.82 (3H, m, H-2′ and H-9ax), 4.25–4.32 (1H, m, CHO, H-2), 7.34–7.43 (6H, m, SiArH, m and p), 7.67–7.70 (4H, m, SiArH, o); δC (100 MHz, CDCl3): 14.6 (CH3, Me), 19.2 (quat,. tBuPh2), 22.7 (CH2, CH2CH2O, C-10*), 23.1 (CH2, CH2CH2O, C-10), 26.9 (CH3, tBuPh2), 33.4 (CH2, CH2CH2O, C-1′), 34.5 (CH, CHMe, C-3), 34.6 (CH2, CH2CHO, C-13 or C-14), 34.9 (CH2, CH2CHO, C-14 or C-13), 35.4 (CH2, CH2CHO, C-14* or C-13*), 44.4 (CH2, CH2CHMe, C-4), 51.3 (CH, CHOCHCH2, C-11), 53.4 (CH, CHOCHCH2, C-12), 56.7 (CH2, CH2O, C-9), 61.5 (CH2, CH2OSi, C-2′), 77.9 (CH, CHO, C-2), 78.1 (CH, CHO, C-2*), 103.4 (quat., C-7), 115.4 (quat., C-5), 127.6 (CH, ArH, m), 129.5 (CH, ArH, p), 134.0 (quat., ArSi), 135.6 (CH, ArH, o); m/z (EI): 508 (M+, 1%), 490 (M+-H2O, 10), 451 (21), 433 (10), 325 (32), 199 (100), 149 (63), 91 (65), 57 (78), 42 (67), 41 (68); m/z (CI, NH3): 509 (MH+, 41%), 491 (MH+ − H2O, 35), 475 (27), 325 (30), 216 (42), 199 (79), 109 (46), 91 (52), 78 (100), 75 (51).
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp7
(2R,3R,5S,7S,11R,12R)-2-[2′-(tert-Butyldiphenylsilyloxy)ethyl]-3-methyl-1,6,8-trioxadispiro[4.1.5.2]-11,12-epoxy-tetradecane (33b)
173
Using a similar procedure to that described for 33a, 33c above, band A containing trans syn bis-spiroacetal 12b (18 mg, 0.037 mmol) was reacted with dimethyldioxirane (2.0 mL, 0.2 mmol) to give the title compound33b (14 mg, 74%) as a colourless oil [Found (CI, NH3): MH+, 509.2718; C30H41O5Si requires Mr, 507.2723]; νmax/cm−1 (CDCl3): 2955, 2929, 2856, 1471, 1427, 1359, 1272, 1111, 1083, 999, 885, 840, 822, 739, 702, 614; δH (400 MHz, CDCl3): 0.96 (3H, d, JMe,3′ 7.0, CH3, Me), 1.05 (9H, s, SitBuPh2), 1.65–2.32 (11H, m, H-1′, H-3, H-4, H-10, H-13 and H-14), 2.92 (1H, d, J12,11 3.9, CHOCHCH2, H-12), 3.31 (1H, dd, J11,12 = J11,10a 3.9, CHOCHCH2, H-11), 3.42–3.50 (1H, m, CHaxHeqO, H-9eq), 3.70–3.86 (3H, m, H-2′ and H-9ax), 4.11–4.19 (1H, m, CHO, H-2), 7.34–7.43 (6H, m, SiArH, m and p), 7.67–7.70 (4H, m, SiArH, o); δC (100 MHz, CDCl3): 14.3 (CH3, Me), 19.2 (quat,. tBuPh2), 23.1 (CH2, CH2CH2O, C-10), 26.9 (CH3, tBuPh2), 33.8 (CH2, CH2CH2O, C-1′), 34.5 (CH, CHMe, C-3), 35.3 (CH2, CH2CHO, C-13 or C-14), 35.4 (CH2, CH2CHO, C-14 or C-13), 44.2 (CH2, CH2CHMe, C-4), 51.3 (CH, CHOCHCH2, C-11), 53.5 (CH, CHOCHCH2, C-12), 56.7 (CH2, CH2O, C-9), 61.5 (CH2, CH2OSi, C-2′), 79.2 (CH, CHO, C-2), 103.4 (quat., C-7), 115.4 (quat., C-5), 127.6 (CH, ArH, m), 129.5 (CH, ArH, p), 133.9 (quat., ArSi), 135.6 (CH, ArH, o); m/z (EI): 508 (M+, 1%), 490 (M+-H2O, 10), 451 (21), 433 (10), 325 (32), 199 (100), 149 (63), 91 (65), 57 (78), 42 (67), 41 (68); m/z (CI, NH3): 509 (MH+, 41%), 491 (MH+ − H2O, 35), 475 (27), 325 (30), 216 (42), 199 (79), 109 (46), 91 (52), 78 (100), 75 (51).
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp8
(2R,3R,5S,7R,12S)- and (2R,3R,5R,7R,12R)-2-[2′-(tert-Butyldiphenylsilyloxy)ethyl]-3-methyl-1,6,8-trioxadispiro[4.1.5.2]tetradec-10-en-12-ol (34a,34c)
174
n-Butyllithium (0.36 mL of a 1.6 M solution in hexanes, 0.58 mmol) was added dropwise to a solution of freshly distilled diethylamine (60 μL, 0.58 mmol) in pentane (3.0 mL) at −40 °C.
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp9
175
The resultant slurry was stirred for 25 min then cooled to −78 °C and a solution of bis-spiroacetal epoxides cis syn33a and trans anti33c (38 mg, 3 : 1, 0.075 mmol) in pentane (1.5 mL) was added via syringe.
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp9
176
After 25 min the reaction was allowed to warm to room temperature and stirred for a further 2 h.
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp9
177
Saturated aqueous sodium bicarbonate (1.0 mL) was added after 2 h and the reaction mixture extracted with diethyl ether (2 × 5 mL).
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp9
178
The organic layer was washed with water (3 mL), brine (3 mL) and dried over potassium carbonate.
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp9
179
Removal of the solvent under a reduced pressure gave an orange oil which was purified by flash column chromatography using hexane–diethyl ether (4 : 1–1 : 1) as eluant to afford the title compounds34a, 34c (28 mg, 74%) as a colourless oil [Found (CI, NH3): MH+, 509.2747; C30H41O5Si requires Mr, 509.2723]; νmax/cm−1 (CDCl3): 3435, 2961, 2931, 2857, 1468, 1462, 1260, 1111, 1088, 988, 742, 703; δH (400 MHz, CDCl3): 0.88 (2.25H, d, J 6.9, Me), 0.98 (0.75H, d, J 6.9, Me*), 1.04 (9H, s, SitBuPh2), 1.59–1.75 (3H, m, H-1′ and H-4a), 1.88–2.45 (6H, m, H-3, H-4b, H-13 and H-14), 3.71–3.87 (3H, m, H-2′ and H-12), 4.09–4.11 (0.25H, m, CHaHbO, H-9a*), 4.12–4.16 (0.75H, m, CHaHbO, H-9a), 4.20–4.27 (1H, m, CHO, H-2), 4.28–4.31 (0.75H, m, CHaHbO, H-9b), 4.32–4.35 (0.25H, m, CHaHbO, H-9b*), 5.76–5.99 (2H, m, CH=CH, H-10 and H-11), 7.35–7.43 (6H, m, SiArH, m and p), 7.63–7.69 (4H, m, SiArH, o); δC (100 MHz, CDCl3): 14.3 (CH3, Me*), 14.6 (CH3, Me), 19.2 (quat., SitBuPh2), 26.9 (CH3, SitBuPh2), 31.4 (CH2, CH2CH2O, C-1′), 33.3 (CH2, CH2CH2, C-13 or C-14), 34.5 (CH, CHMe, C-3), 34.9 (CH2, CH2CH2, C-14 or C-13), 35.2 (CH, CHMe, C-3*), 35.4 (CH2, CH2CH2, C-14* or C-13*), 43.7 (CH2, CH2CHMe, C-4*), 44.0 (CH2, CH2CHMe, C-4), 61.4 (CH2, CH2O, C-9), 61.7 (CH2, CH2O, C-9*), 62.5 (CH2, CH2OSi, C-2′), 62.8 (CH2, CH2OSi, C-2′), 67.5 (CH, CHOH, C-12), 67.6 (CH, CHOH, C-12*), 77.8 (CH, CH2CHO, C-2), 79.3 (CH, CH2CHO, C-2*), 107.2 (quat., C-7), 107.6 (quat., C-7*), 115.2 (quat., C-5), 115.5 (quat., C-5*), 125.0 (CH, CH=CHCH2, C-10*), 126.0 (CH, CH=CHCH2, C-10), 127.6 (CH, ArH, m), 128.0 (CH, CH=CHCH2, C-11), 129.5 (CH, ArH, p), 129.8 (CH, CH=CHCH2, C-11*), 133.8 (quat., ArSi), 134.0 (quat., ArSi*), 135.6 (CH, ArH, o); m/z (CI, NH3): 509 (MH+, 11%), 491 (MH+ − H2O, 100), 216 (47), 199 (55), 196 (40), 78 (48).
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp9
(2R,3R,5S,7R,12S)- and (2R,3R,5R,7R,12R)-12-Acetoxy-2-[2′-(tert-butyldiphenylsilyloxy)ethyl]-3-methyl-1,6,8-trioxadispiro[4.1.5.2]tetradec-10-ene (35a,35c)
180
A mixture of allylic alcohols 34a, 34c (3 : 1, 14 mg, 0.029 mmol), pyridine (1.5 mL), acetic anhydride (0.25 mL, 2.6 mmol) and a catalytic quantity of DMAP was stirred at room temperature for 60 min.
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp10
181
Saturated aqueous sodium bicarbonate (1.0 mL) was added and the reaction mixture extracted with dichloromethane (2 × 10 mL).
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp10
182
The organic layer was washed with brine, dried over a mixture of potassium carbonate and magnesium sulfate and eluted through a short column of silica.
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp10
183
Removal of the solvent under a reduced pressure afforded a 3 : 1 mixture of the title compounds35a, 35c (11 mg, 75%) as a pale yellow oil [Found (CI, NH3): MH+, 551.2825; C32H43O6Si requires Mr, 551.2830]; νmax/cm−1(neat): 3584, 2966, 2928, 2863, 1737, 1642, 1598, 1428, 1369, 1260, 1110, 1093, 1020, 799; δH (400 MHz, CDCl3): 0.90 (2.25H, d, J 6.9, Me), 0.97 (0.75H, d, J 6.9, Me*), 1.04 (9H, s, SitBuPh2), 1.58–1.75 (3H, m, H-1′ and H-4a), 1.81–2.42 (9H, m, H-3, H-4b, H-13, H-14 and OAc), [2.07 (2.25H, s, OAc) and 2.09 (0.75H, s, OAc*)], 3.72–3.82 (2H, m, CH2OSi, H-2′), 4.05–4.37 (3H, m, H-2 and H-9), 4.90 (0.25H, dd, J12,11 4.9 and J12,10 1.9, CHOAc, H-12*), 4.90 (0.75H, dd, J12,11 5.0 and J12,10 1.8, CHOAc, H-12), 5.80–6.05 (2H, m, CH=CH, H-10 and H-11), 7.35–7.43 (6H, m, SiArH, m and p), 7.63–7.69 (4H, m, SiArH, o); δC (100 MHz, CDCl3): 14.2 (CH3, Me*), 14.6 (CH3, Me), 19.2 (quat., SitBuPh2), 21.0 (CH3, OAc), 21.1 (CH3, OAc*), 26.9 (CH3, SitBuPh2), 33.4 (CH2, CH2CH2O, C-1′), 34.3 (CH2, CH2CH2, C-13 or C-14), 34.4 (CH, CHMe, C-3), 34.5 (CH2, CH2CH2, C-14* or C-13*), 34.7 (CH2, CH2CH2, C-14 or C-13), 44.4 (CH2, CH2CHMe, C-4), 46.1 (CH2, CH2CHMe, C-4*), 61.2 (CH2, CH2O, C-9), 61.4 (CH2, CH2O, C-9*), 62.6 (CH2, CH2OSi, C-2′), 67.9 (CH, CHOAc, C-12*), 69.0 (CH, CHOAc, C-12), 77.2 (CH, CH2CHO, C-2), 78.0 (CH, CH2CHO, C-2*), 104.7 (quat., C-7), 115.5 (quat., C-5), 120.9 (CH, CH=CHCH2, C-10*), 121.5 (CH, CH=CHCH2, C-10), 127.6 (CH, ArH, m), 129.5 (CH, ArH, p), 131.2 (CH, CH=CHCH2, C-11), 132.1 (CH, CH=CHCH2, C-11*), 133.9 (quat., ArSi), 135.6 (CH, ArH, o), 170.1 (quat., OAc); m/z (CI, NH3): 568 (M+ + NH3, 18%), 551 (MH+, 100), 553, (MH+ − H2O, 34), 475 (28), 381 (52), 274 (38), 263 (35), 216 (44), 196 (78), 94 (63), 78 (71).
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp10
(2R,3R,5S,7R,12S)- and (2R,3R,5R,7R,12R)-2-[2′-(tert-Butyldiphenylsilyloxy)ethyl]-3-methyl-1,6,8-trioxadispiro[4.1.5.2]tetradec-9-en-12-ol (11a,11c)
184
n-Butyllithium (0.120 mL of a 1.6 M solution in hexanes, 0.19 mmol) was added dropwise to a stirred solution of freshly distilled pyrrolidine (20 μL, 0.19 mmol) in THF (1.0 mL) at −40 °C.
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp11
185
The resultant slurry was stirred for 25 min then cooled to −78 °C before a solution of allylic alcohols 34a, 34c (18 mg, 3 : 1, 0.035 mmol) in THF (1.0 mL) was added via syringe.
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp11
186
After 30 min the reaction was allowed to warm slowly to room temperature and stirred for a further 16 h.
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp11
187
Saturated aqueous sodium bicarbonate (2 mL) was added and the reaction mixture extracted with diethyl ether (2 × 5 mL).
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp11
188
The organic layer was washed with water (2 mL), brine (2 mL) and dried over potassium carbonate.
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp11
189
Removal of the solvent under a reduced pressure, followed by flash column chromatography using hexane–diethyl ether (9 : 1) as eluant afforded a 3 : 1 mixture of the title compounds11a, 11c (9 mg, 50%) as a colourless oil [Found (EI): MH+, 508.2633; C30H40O5Si requires Mr, 509.2645]; νmax/cm−1(CDCl3): 3435, 2956, 2927, 2853, 1650, 1428, 1260, 1111, 1085, 1025, 742, 702; δH (400 MHz, CDCl3): 0.87 (0.75H, d, J 6.9, Me*), 0.89 (2.25H, d, J 6.9, Me), 1.04 (9H, s, SitBuPh2), 1.73–2.52 (11H, m, H-1′, H-3, H-4, H-11, H-13, H-14), 2.86 (1H, br s, OH), 3.74–3.82 (3H, m, H-2′ and H-12), 4.12–4.17 (0.25H, m, CHO, H-2*), 4.26–4.34 (0.75H, m, CHO, H-2), 4.64 (1H, m, OCH=CH, H-10), 6.17 (1H, m, OCH=CH, H-9), 7.36–7.42 (6H, m, SiArH, m and p), 7.64–7.69 (4H, m, SiArH, o); δC (100 MHz, CDCl3): 14.5 (CH3, Me), 19.2 (quat., SitBuPh2), 26.9 (CH3, SitBuPh2), 27.2 (CH2, CH=CHCH2, C-11), 29.2 (CH2, CH2CH2, C-13), 33.2 (CH2, CH2CH2O, C-1′), 34.7 (CH, CHMe, C-3), 34.9 (CH2, CH2CH2, C-14), 43.5 (CH2, CH2CHMe, C-4), 61.2 (CH2, CH2OSi, C-2′), 67.2 (CH, CHOH, C-12), 77.2 (CH, CH2CHO, C-2), 78.2 (CH, CH2CHO, C-2*), 98.7 (quat., C-7 and CH, OCH=CH, C-10), 115.2 (quat., C-5), 127.6 (CH, ArH, m), 129.5 (CH, ArH, p), 133.9 (quat., ArSi), 135.6 (CH, ArH, o), 141.2 (CH, OCH=CH, C-9); m/z (EI): 508 (MH+, 1%), 490 (M+ − H2O, 1), 451 (52), 433 (27), 235 (42), 199 (100), 183 (25), 135 (38), 85 (33).
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp11
(2R,3R,5S,7R,12S)- and (2R,3R,5R,7R,12R)-12-Acetoxy-2-[2′-(tert-Butyldiphenylsilyloxy)ethyl]-3-methyl-1,6,8-trioxadispiro[4.1.5.2]tetradec-9-ene (36a,36c)
190
Using a similar procedure to that described for 35a, 35c, a 3 : 1 mixture of homoallylic alcohols 11a, 11c (4.0 mg, 7.9 μmol) was reacted with pyridine (1.0 mL), acetic anhydride (0.1 mL, 1.0 mmol) and a catalytic quantity of DMAP.
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp12
191
The resultant pale yellow semi-solid was purified by flash column chromatography in a Pasteur pipette using hexane–diethyl ether (4 : 1) as eluant to afford a 3 : 1 mixture of the title compounds36a, 36c (2.9 mg, 67%) as a colourless oil [Found (CI, NH3): MH+, 551.2825; C32H43O6Si requires Mr, 551.2830]; νmax/cm−1(neat): 3585, 2955, 2929, 2870, 1737, 1658, 1511, 1455, 1265, 1240, 1110, 1018, 737; 702; δH (400 MHz, CDCl3): 0.87 (3H, br d, J 6.9, Me), 1.04 (9H, s, SitBuPh2), 1.59–1.74 (3H, m, H-1′ and H-4a), 1.88–2.02 (2H, m, H-13a and H-14a), 2.03 (2.25H, s, OAc), 2.04 (0.75H, s, OAc*), 2.06–2.41 (5H, m, H-3, H-4b, H-11a, H-13b and H-14b) 2.43–2.47 (1.5H, m, CH=CHCH2, H-11), 2.49–2.54 (0.5H, m, CH=CHCH2, H-11*), 3.75 (2H, t, J2′,1′ 6.7, CH2O, H-2′), 4.04–4.12 (0.25H, m, CHO, H-2*), 4.14–4.22 (0.75H, m, CHO, H-2), 4.63–4.72 (1H, m, OCH=CH, H-10), 4.98–5.03 (1H, m, CHOAc, H-12), 6.17–6.24 (1H, m, OCH=CH, H-9), 7.33–7.42 (6H, m, SiArH, m and p), 7.63–7.69 (4H, m, SiArH, o); δC (100 MHz, CDCl3): 14.6 (CH3, Me), 19.2 (quat., SitBuPh2), 21.2 (CH3, OAc), 24.3 (CH2, CH=CHCH2, C-11), 26.9 (CH3, SitBuPh2), 33.2 (CH2, CH2CH2, C-13), 33.5 (CH2, CH2CH2O, C-1′), 33.8 (CH2, CH2CH2O, C-1′*), 34.3 (CH, CHMe, C-3), 34.6 (CH2, CH2CH2, C-14), 44.4 (CH2, CH2CHMe, C-4), 61.4 (CH2, CH2OSi, C-2′), 69.2 (CH, CHOAc, C-12), 78.0 (CH, CH2CHO, C-2), 79.6 (CH, CH2CHO, C-2*), 98.0 (CH, OCH=CH, C-10), 105.0 (quat., C-7), 115.4 (quat., C-5), 127.6 (CH, ArH, m), 129.5 (CH, ArH, p), 133.9 (quat., ArSi), 135.6 (CH, ArH, o), 140.9 (CH, OCH=CH, C-9), 170.2 (quat., OAc); m/z (CI, NH3): 568 (M++ NH3, 4%), 551 (MH+, 83), 493 (15), 381 (44), 274 (44), 263 (35), 216 (37), 196 (84), 94 (100), 78 (89).
Type: Experiment |
Advantage: None |
Novelty: None |
ConceptID: Exp12