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Studies towards the total synthesis of solanoeclepin A: synthesis of analogues
containing the tetracyclic left-hand substructure.
Benningshof, J.C.J.
Publication date
2001
Link to publication
Citation for published version (APA):
Benningshof, J. C. J. (2001). Studies towards the total synthesis of solanoeclepin A: synthesis
of analogues containing the tetracyclic left-hand substructure.
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4 4
Seven-Memberedd Ring Formation via Ring-Closing Metathesis
4.11 Introduction
Att the end of Chapter 3 it was concluded that it was impossible to construct the seven-memberedd ring of 1 via an intramolecular carbonyl coupling reaction. An alternative intermediatee in the construction of the densely-functionalized seven-membered ring could be dienee 2. Compound 1 was deemed accessible from 2 via oxidative functionalization of its leastt substituted double bond (Scheme 4.1).
Schemee 4.1
4.22 Strategy
Thee most frequently used method for regioselective formation of CC double bonds is thee Wittig reaction or modifications thereof.1 Inter- as well as intramolecular2 Wittig reactions aree known. By choosing the appropriate substituents on phosphorus and by selecting adequate conditionss for ylide formation the stereoselectivity of the Wittig reaction (EIZ ratio of the alkene)) can be controlled to a large extent. In literature the formation of unsaturated seven-memberedd rings via such reactions has also been described (Figure 4.1). For example, Becker andd coworkers3 cyclized the cycloheptene ring of hydrozulene 6 by an intramolecular Wittig reactionn and the same type of reaction was used to construct the cycloheptenone ring of (-)-reiswiginn A (7) by Park and coworkers.4
66 7
Figuree 4.1 Cycloheptenes prepared by Wittig reaction (dotted lines indicate site of ring closure)
Thee construction of intermediate 2 via an intramolecular Wittig reaction requires the usee of a phosphonium salt such as 3 as starting material. The synthesis of 3 might be accomplishedd starting from intermediate 9, which was described in the previous Chapter (Sectionn 3.3.2). Schemee 4.2 TBDPSO. . TBDPSO, , 44 steps TBDPSO, , (see:: Chapter 3) OTBDMS S 9 9 22 steps TBDPSO, , OTBDMS S 10 0 60 0
Seven-MemberedSeven-Membered Ring Formation via Ring-Closing Metathesis Alcoholl 9 was obtained from lactone 8 in four steps (Scheme 4.2). Introduction of the
iodidee was envisaged at this stage. Deprotection of the primary hydroxyl group of 10 followedd by oxidation might afford aldehyde 11. The latter should then be converted to the desiredd phosphonium salt 3. The number of functional group transformations necessary to synthesizee this phosphonium salt seriously disfavors this method.
AA second pathway to a CC double bond is the intramolecular McMurry coupling of aldehydes.. This approach is not applicable, because it appeared impossible to synthesize the requiredd dialdehyde 5 (see: Section 3.3.2).
AA third approach to the targeted seven-membered ring involves CC double bond formationn via ring-closing metathesis (RCM) of triene 4. Although this is a relatively new syntheticc method, its usefulness has already frequently been demonstrated and the number of applicationss are still expanding exponentially. A key feature of this reaction is the functional groupp compatibility of the metathesis catalysts, which in combination with the anticipated facilee accessibility of the required triene rendered this an attractive approach.
Thee versatility of this reaction in natural product synthesis is best demonstrated by two literaturee examples (Figure 4.2). The groups of Nicolaou5 and Danishefsky6 independently synthesizedd epothilone A (12) using RCM as one of the key steps. A macrocyclic ring closure too obtain the 13-membered ring of roseophilin (13) was reported by the groups of Fuchs7 and Hiemstra.8 8
Figuree 4.2 Natural products prepared by RCM (dotted lines indicate the site of ring closure)
4.2.11 Ring-Closing Metathesis
Hitherto,, the olefin metathesis9 reaction developed into a powerful tool for the formationn of CC bonds.10 The development of this process commenced with the discovery of Karll Ziegler that certain transition metal catalysts promote polymerization of olefins. Soon itt was discovered that some of these 'Ziegler-type' catalysts did not only lead to polymerization,, but could also effect a mutual alkylidene exchange reaction of alkenes (eq 4.1).. These first generation catalysts were poorly compatible with polar functional groups, whichh restricted their application to the production of unfunctionalized polymers.
R ii R? R33 R4 cat t - > ( ( R2 2 R4 4 (4.1) )
Thee breakthrough came with the discovery of reasonably stable tungsten and molybdenumm alkylidene complexes by Schrock and coworkers11 (14, Figure 4.3). These catalystss were compatible with polar functional groups and therefore could be used in more advancedd synthetic organic applications.
F 3 C
S ^ \ /
P h h Cvv J> RFsC-JL^^ j f J
F // R ^ ^ 144 (M = Mo, W) PCy3 3 C I ,, | R u = \ \ CI'' | Vh PCy3 3 15 5Figuree 4.3 Some metathesis catalysts
AA disadvantage of the Schrock catalysts was their extreme air and moisture sensitivity ass well as decomposition upon storage. The value of the RCM reaction in organic synthesis improvedd greatly after the Grubbs' ruthenium-based catalyst 15 became available.12
Schemee 4.3 (all individual steps involved are reversible not indicated in scheme)
CH2=CH2 2
H2CC [M]
Seven-MemberedSeven-Membered Ring Formation via Ring-Closing Metathesis
Thee generally accepted mechanism13 of the metathesis reaction consists of a sequence off formal [2+2] cycloadditions/cycloreversions involving the alkenes and metal alkylidenes (Schemee 4.3). All individual steps of the catalytic cycle are reversible and, as a consequence, thee overall transformation is reversible. Therefore, it is necessary to shift the equilibrium in onee direction to make the metathesis practical in preparative terms. Ring-closing metathesis off a diene (16) is an entropically driven process since one substrate molecule delivers two products.. Especially, if one of the products can be readily removed (i.e. the volatile ethene), thee desired cycloalkene (17) will accumulate in the reaction mixture.
Thee substitution pattern of the diene has a significant influence on the reactivity of the RCMM catalysts. Unsubstituted dienes (19, R = H) generally provide the cyclic products (20, R == H) with catalysts 14 or 15 in good to excellent yields (eq 4.2).9 1 4 When the double bonds
aree increasingly substituted (19, R = Me) the yield of the RCM process drops and only Schrock'ss molybdenum alkylidene complexes 14 afford the desired product. 14 4
EE E RR E E 9 cat 19 9 (4.2) ) EE = C02Et
Recently,, more active ruthenium-catalysts, such as 2 11 5 and 2214, have been reported inn the literature (Figure 4.4).16 The reactivity of these 'second-generation' ruthenium catalysts is,, without loss of functional group tolerance, significantly higher than that of Grubbs' catalystt 15 and comes close to or even surpasses that of the Schrock's molybdenum alkylidenee complexes 14.14'15 Ring-closure of diene 19 (R = H or Me) was accomplished by bothh catalysts (21 or 22) in moderate to good yields.14'17
f=\f=\ r^
CI*,, | Civ, | R u = \\ R u = \ C I '' I > h C I ' I > h PCy33 PCy3 211 22 Figuree 4.4 'Second generation' RCM catalystsBecausee of its functional group tolerance and excellent results, RCM was chosen as a keyy step in the seven-membered ring construction.
4.2.22 Retrosynthesis
Solanoeclepinn A analogue 1 was expected to be accessible from pinacol 23 via oxidationn of both hydroxyl groups to afford a 1,2-diketone (Scheme 4.4), followed by the appropriatee functionalization to the tetracyclic left-hand substructure. 1,2-Diol 23 was anticipatedd to be formed by oxidative functionalization of diene 2, which should arise from RCMM of 4. RCM precursor 4 should be available from lactone 24 using a similar functional groupp transformation strategy as was described in Chapter 3. Lactone 24 could probably be thee product of an analogous chromium-mediated coupling of aldehyde 25 and vinyl triflate 26 ass was discussed in the previous Chapter (Section 3.3.1).
Schemee 4.4 TBDPSO, , TBDPSO, , AcO O TBDPSO, ,
^2 ^2
TBDPSO, , AcO O =? =? OH H 23 3 AcO O TBDPSO, , 24 4 CQ2Et t4.33 Results and Discussion
4.3.11 Chromium-Mediated Coupling
Whenn aldehyde 25 and vinyl triflate 26 were subjected to the chromium-mediated couplingg conditions a,P-unsaturated lactone 24 and its diastereomer (27) were isolated (eq 4.3).. In this case a mixture of diastereomers was found, in contrast with the single isomer foundd in the chromium-mediated coupling discussed previously (Section 3.3.1).
Formation via Ring-Closing Metathesis TBDPSO, , C02Et t HH ^ 2 <T B D P S0 v^ X X TBDPSO. CrCl2,, NiCl2 (cat.) > < ^ > i ^ " " ^ DMF,, 50 °C, 18 h / \ || (4.3) ) 24(64%)) 69:31 277 (28%) Too understand the formation of this mixture the conformation of the aldehyde undergoingg nucleophilic attack is important (Scheme 4.5). In principal, there are six possible conformationss of aldehyde 25, two of which are significantly more stable (25a and 25b). Mostt likely, no chelation of chromium is possible in either case. MM2 force field calculations (Chem3D™™ version 5.0) on 25a and 25b show that the steric energy of conformation 25b is
1.99 kcal/mol lower than that of conformation 25a. This suggests conformation 25b to be predominantlyy present which, upon Si-attack of nucleophile 28, would lead to the major isomer. .
Schemee 4.5
OTBDPS S
25a a
Thee mixture of diastereomers could easily be separated by column chromatography. Comparisonn of the spectral data of lactone 24 with lactone 29 (see: Section 3.3.1, Figure 4.5) suggestss that the major isomer possesses the desired \9-{S) configuration. This hypothesis wass in a later stage unambiguously confirmed by X-ray analysis of the tetracyclic left-hand substructuree (1).
TBDPSO. . T B D P S Ov^>X J ^ ^
/ < \\ C02Et
244 29 Figuree 4.5 Comparison of structures 24 and 29
4.3.22 Synthesis of the Ring-Closing Metathesis Precursor
Att this point, the a,P-unsaturated lactone 24 had to be converted into the RCM precursor.. A highly efficient six-step procedure was developed to accomplish this transformation.. The sequence started with the rapid lithium aluminum hydride reduction of lactonee 24 (Scheme 4.6). The same protective group strategy as discussed in Chapter 3 (Sectionn 3.3.2) was applied on diol 30. Thus, the primary hydroxyl group was protected as a
tert-butyldimethylsilyltert-butyldimethylsilyl ether (31) and the secondary hydroxyl group as an acetate to give compoundd 32. Schemee 4.6 O O O—ff OH T B D P S OV/ - ^ A ^ ^^ LiAlH4 TBDPSO» < / ^^ *---/ Et20, it, 30 min OH H TBDMSC1,, imidazole DMF F 24 4 ^uu .OTBDMS OHH \ TBDPSO, ,
W W
300 (93%) n.. JDTBDMS OACC r Ac20 0 pyridine e CH2C12 2 TBDPSO Ow> w>
311 (89%) 322 (92%)Thee allylic hydroxyl group was then selectively deprotected with a catalytic amount of camphorsulfonicc acid (CSA) to afford alcohol 33 (Scheme 4.7). The latter was oxidized by TPAP,, NMO to give aldehyde 34,19 which in crude form was subjected to a Wittig olefination
resultingg in RCM precursor 35 in an excellent overall yield of 67% over six steps. Schemee 4.7
TBDPSO, ,
TBDPSO, ,
OTBDMS S
CSAA (cat.) TBDPSO. . MeOH,, 0 °C
Ph3P=CH2 2
THF,, 0 °C
TBDPSO, ,
Seven-MemberedSeven-Membered Ring Formation via Ring-Closing Metathesis
Althoughh this pathway was very efficient, six steps were required to convert lactone 244 into the RCM precursor. A somewhat shorter route was therefore briefly investigated (eq 4.4).. If it were possible to generate organometallic species 37, this might undergo addition to aldehydee 25 and directly give diene 38.
O O TBDPSO„ „ transmetallation n HO O TBDPSO. . (4.4) )
Thee required bromide 36 was synthesized via a two-step literature procedure (eq 4.5). AA modified Villsmeier-Haack reaction of cyclohexanone20 and subsequent Wittig olefination211 of aldehyde 39 afforded the rather unstable vinyl bromide 36.
O O PBr3 3 DMF F B K V / \\ Ph 3P=CH2
HyHy
u u
THF F H H 39 9 366 (43% 2 steps) n-BuLi, , THF,, -78 °C thenn CeCl3 (4.5) ) 400 (98%) Inn a model reaction, it was investigated whether it would be possible to metallate bromidee 36 and react it with pivaldehyde. Treatment of 36 with «-butyllithium at low temperaturee afforded the organolithium species 37. When pivaldehyde was added, allylic alcoholl 40 was formed instantaneously in a yield of 56%. To increase the yield the organolithiumm species was transmetallated with Ce3+ by adding anhydrous CeCl3 to thereactionn mixture. Subsequent addition of pivaldehyde resulted in the alcohol 40 in virtually quantitativee yield. TBDPSO. . transmetallation n THF F 25 5 TBDPSO. . (4.6) )
Encouragedd by these results aldehyde 25 was treated with the organolithium species derivedd from 36 (eq 4.6). The latter, however, turned out to be too basic as a rapid decompositionn of aldehyde 25 into unidentifiable products was observed. The reaction of
aldehydee 25 with the corresponding organocerium species was also unsuccessful, because the nucleophilee appeared not reactive enough and the starting material was recovered completely. Moreover,, different organometallic compounds, such as organochromium and magnesium species,, were not sufficiently reactive and aldehyde 25 was recovered unchanged. It became evidentt that this approach to shorten the synthetic route failed and that the six-step protocol to thee RCM precursor had to be employed.
4.3.33 Ring-Closing Metathesis
Whenn triene 35 was dissolved in CH2C12 and subjected to a catalytic amount (ca. 10
mol%)) of Grubbs' catalyst (15) no cyclization was observed (Scheme 4.8). An additional amountt of catalyst and increase of the reaction temperature to reflux did not improve the situation.. To attain an even higher reaction temperature the triene was dissolved in toluene. Satisfyingly,, after the addition of 10 mol% of the catalyst cyclization of 35 at 70 °C was observed.. Unfortunately, there was still starting material remaining and because it could not bee separated form the product by column chromatography, it was decided to add more of the ruthenium-catalystt to achieve a complete conversion. In the presence of 1 equiv of Ru-catalystt all starting material was consumed after 16 h and purification afforded diene 41 in an excellentt yield. AcO O Schemee 4.8 AcO O
T B D P S
P P
%<r %<r
35 5 PCy3 3 Civ,, | Ru-cat.:: c rR u~ ^ PCy3 3 Ru-cat.. T B D pS O v ^ toluene,, x . 700 , 16 h / *r=\ r=\
M e s ^N- yN- M e s s Civ, , R u = \ \ Phh C I ' I Ph PCy3 3 15(1.00 equiv) 21 (0.15 equiv) 411 (99%)Althoughh a superb cyclization was achieved, this rather slow process required stoichiometricc amounts of the catalyst. A decrease of the amount of catalyst could not be achievedd by increasing (reflux) or decreasing (50 °C) the reaction temperature. Probably, the shortt half-life time of the original Grubbs' catalyst (approximately 40 min at 50 °C)22 is the explanationn for the high catalyst consumption. This problem was solved by using one of the neww generation ruthenium-based catalysts.15 Gratifyingly, only 15 mol% of the unsaturated imidazolin-2-ylidenee catalyst 2115 gave quantitative ring closure to form tetracyclic diene 41 afterr 16 h at 70 °C in toluene as the solvent.
Seven-MemberedSeven-Membered Ring Formation via Ring-Closing Metathesis
4.3.44 Introduction of the Oxygen Substituents
Havingg diene 41 available, the least-substituted double bond needed to be funtionalizedd with oxygen substituents. The first attempt consisted of the introduction of a 1,2-diketonee (42) in one step (eq 4.7) using a known oxidation with KMn04 in AC2O under
anhydrouss conditions. '
AcOO AcO
TBDPSCVV ^ \ /—(\ \ TBDPSO.
(4.7) )
41 1
Treatmentt of 41 under these conditions led to complete cleavage of the target olefin, resultingg in diacid 43 (eq 4.8). Apparently, these conditions were too harsh due to the sensitivityy of the CC double bond to oxidative cleavage.
AcO O
TBDPSCVV ^ J - KMn04 TBDPSO.
Becausee it was impossible to introduce the 1,2-diketone directly, a milder three-step proceduree was developed. First the least hindered double bond was dihydroxylated (Scheme 4.9).. A generally used method for this transformation is the osmium tetroxide catalyzed dihydroxylationn of alkenes.25 Good chemoselectivity for the least substituted double bond was expectedd as it is known that such oxidations are strongly dependent on the substitution of the alkene. .
Treatmentt of diene 41 with a catalytic amount of osmium tetroxide and N-methylmorpholinee A^-oxide as the stoichiometric oxidant did not result in the desired product andd starting material was recovered, presumably due to steric shielding of the double bond. Ass reported in the literature, the reactivity of osmium tetroxide can be increased by adding tertiaryy amines.26,27 Recent studies on the mechanistic details of amine-accelerated dihydroxylationn with osmium tetroxide by Corey and coworkers28'29 suggest that a 2:1 complexx of 4-(dimethylamino)pyridine (DMAP) and osmium tetroxide could be an effective reagentt for this transformation. In fact, this reagent caused smooth and selective dihydroxylationn of the least hindered double bond of 41 to form a 78:22 mixture of cw-diols
44aa and 44b.
Schemee 4.9 AcO O TBDPSO, , 41 1 TBDPSO, , AcO O
x^9 x^9
Os044 (1 equiv) DMAPP (2 equiv) Na2S03 ?-BuOH/H20(l:l) ) rt,, 30 min (84%) ) TBDPSO OThee next step in the procedure was the oxidation of the two hydroxyl groups (eq 4.9). Directt double oxidation of the mixture of 44 to the dione by using DMSO-based reagents did nott lead to isolatable products. The use of manganese dioxide or TPAP as the oxidant was alsoo unsuccessful. In these cases a rapid oxidation was observed causing CC bond cleavage to givee dialdehyde 45 in an almost quantitative yield.
AcO O
TBDPSO, , oxidativee TBDPSO,
reagent t (4.9) )
Facedd with this disappointing result, it became obvious that direct oxidation to the dionee was not possible. However, it appeared possible to oxidize the hydroxyl groups separately.. In analogy with a literature precedent, ' the more reactive allylic hydroxyl group off 44 could be oxidized with Fétizon's reagent to give ot-hydroxyketone 46.
AcO O TBDPSO O Dess-Martin n CH2C12 2 -200 °C -> rt AcO O TBDPSO, , 45(13%)) (4.10) OH H 46(81%) )
Itt was then found that 46 could be obtained even more efficiently from diol 44 using thee Dess-Martin periodinane (eq 4.10), if the reaction was carefully monitored to prevent overoxidation.. The a-hydroxyketone was obtained as a single isomer, presumably by equilibrationn of H-6 under the reaction conditions. In this isomer H-5 and H-6 have the
Seven-MemberedSeven-Membered Ring Formation via Ring-Closing Metathesis
configurationn {J = 12.2 Hz) to allow intramolecular hydrogen bond formation between the hydroxyll group and the ketone. Although this oxidation resulted in the a-hydroxyketone as thee major product the formation of dialdehyde 45 could not be suppressed completely.
Thee last step to the diketone was the oxidation of the second hydroxyl group. To preventt CC bond cleavage as observed during all previous oxidative methods an alternative oxidativee agent should be used. Usually a-hydroxyketones can be oxidized to oc-diketones by usingg cupric acetate,33 or less often chromium(III) oxide33 or bismuth trioxide. In the fifties Blomquistt and coworkers33 oxidized sebacoin (47) to sebacil (48) by using cupric acetate in aqueouss HOAc/MeOH (10:1) (eq 4.11).
OH H Cu(OAc>2 2 O O
(4.11) )
.00 uvnwm^u v v v.-Q
(10:1) )
477 48 (89%)
Althoughh the mechanism of this oxidation has not been elucidated it was reported, in 1959,, by Wendler and coworkers that this oxidation could be carried out in absence of HOAc. Cupricc acetate in hot methanol oxidized steroid 49 to the enolized oc-diketone 50 (eq 4.12).34'35
QQ O
AcO O AcO O
(4.12) )
Evenn though cupric acetate has not been used for the synthesis of seven-membered ringg 1,2-diketones, this reagent was investigated. Gratifyingly, treatment of compound 46 withh cupric acetate in hot methanol cleanly resulted in the desired 1,2-diketone (51), which existedd according to NMR data, completely in the enol form (Scheme 4.10).
Schemee 4.10 AcO O AcO O TBDPSO O Cu(OAc)2 2 MeOH,, 60 °C* TBDPSO O OH H 511 (75%) AcO O Ag20,, Mel DMF F TBDPSO O OMe e 522 (95%)
Compoundd 51 proved to be rather unstable, but it could be purified for characterization.. Methylation afforded, in excellent yield, the desired methyl enol ether 52 whichh was significantly more stable than 51.
4.3.55 Completion of the Synthesis and Hatching Activity Tests
Inn the last few steps the silyl ether was first cleaved with HF»pyridine (Scheme 4.11). Thee liberated hydroxyl group was then oxidized by using a TPAP oxidation. Removal of the acetatee group resulted in the desired compound 1 as a stable crystalline compound (mp 173 °C)) with a high optical rotation ([a]2 4D +495 (c = 0.6, CHC13)).
Schemee 4.11 TBDPSOv v
°^ ^
AcO O(^P (^P
OMe e 52 2 AcO O^ P P
OMe e 544 (91%) HFF «pyridine THF,, 0 °C K2C03 3 MeOH H»--°^ ^
AcO OH0
^CP P
OMe e 533 (77%) HO O \\ / \eCP P
OMe e 11 (82%) TPAP,, NMO acetone eUponn recrystallization of this solanoeclepin A substructure colorless crystals were obtained.. An X-ray crystal structure analysis (Figure 4.6) proved its identity, including the orientationn of the hydroxyl group that was introduced via the chromium mediated coupling. Comparisonn of the crystal structures of compound 1 and solanoeclepin A36 directly illustrates
thee resemblance of the tetracyclic left-hand substructure and the left-hand side of solanoeclepinn A. Most of the functional groups show a similar geometrical orientation.
Tablee 4.1 Comparison of 'H NMR spectra of 1 and solanoeclepin A (shifts in ppm)
H-199 H-3 OMe H - l a , H - l b Me Me compoundd 1 (CDCI3) ) solanoeclepinn A (D2O) ) 4.266 3.88 3.63 2.37,2.19 (J= 16.8 Hz) 1.45 1.23 4.022 4.04 3.26 2.61,261 (J = 17.9 Hz) 1.34 1.21 72 2
Seven-MemberedSeven-Membered Ring Formation via Ring-Closing Metathesis
Figuree 4.6 Comparison of the crystal structure of 1 (bottom) and solanoeclepin A (top)
Inn Table 4.1 the characteristic 'H NMR signals of compound 1 and solanoeclepin A3 7 aree depicted. The proton NMR data of compound 1 and solanoeclepin A clearly show similar chemicall shifts for the tetracyclic left-hand substructure.
HOO 11 12
OMe e
.. 11 JV
Hl22 + H-|3
2.22 2.0
HOO 11 12
OMe e
c„ „
c4 4
Figuree 4.8 125 MHz C NMR spectrum of compound 1
Too study if the left-hand side of solanoeclepin A is responsible for the biological activityy compound 1 was subjected to hatching activity tests. Incubation of the potato cyst nematodee eggs with the tetracyclic left-hand substructure 1 unfortunately did not result in any hatchingg of the juveniles. Thus, it can be concluded that the left-hand side of solanoeclepin A itselff is not responsible for the hatching activity and that at least some structural features of thee right-hand side are needed to induce hatching activity. Furthermore, it can be noted that thee base sensitivity of solanoeclepin A does not arise from the left-hand side. In the last step acetatee 54 was subjected to basic methanol and during this transformation no decomposition off the product, which was isolated in a high yield, was observed.
Schemee 4.12 HO O TBDPSO, , TfO O EtO O 25 5 26 6 -OPg g Pg g ÓMee ° ÓH solanoeclepinn A protectivee group T B D P S ON^vAH H TfO O EtO O 25 5 74 4
Seven-MemberedSeven-Membered Ring Formation via Ring-Closing Metathesis
Thee successful construction of the fully functionalized seven-membered ring is an importantt achievement in the context of an eventual total synthesis of solanoeclepin A. It was demonstratedd that 1 could be prepared starting from aldehyde 25 and vinyl triflate 26 (Scheme 4.12).. The route developed here paves the way for an enantioselective synthesis of solanoeclepinn A at the moment that vinyl triflate 55 becomes available.
4.44 Concluding Remarks
Inn this chapter a synthesis of the tetracyclic left-hand substructure (1) of solanoeclepin AA in enantiomeric pure form has been described (Scheme 4.13). This approach should eventuallyy make a synthesis of solanoeclepin A possible as soon as the appropriate right-hand sidee vinyl triflate becomes available. In this successful synthesis the top-side of the seven-memberedd ring was constructed via a highly efficient chromium mediated coupling o f aldehydee 25 and vinyl triflate 26, giving lactone 24 as the major diastereomer. Conversion of thee lactone carbonyl to a vinyl group led to RCM precursor 35. Subjection of the latter to the ruthenium-catalystt led to cyclization to the desired seven-membered ring in quantitative yield. Introductionn of the oxygen substituents was accomplished via dihydroxylation of the least substitutedd double bond and stepwise oxidation of diol 44. After removal of the silyl protectivee group and oxidation of the hydroxyl group the acetate was cleaved.
Schemee 4.13
TBDPSO, ,
C02Et t
TfO O CrCl
2,, NiCl2 (cat.) TBDPSO,
DMF,, 50 °C, 16 h 26 6
AcO O
66 steps TBDPSO. . Ru-cat.. (15mol%) toluene,, 70 °C AcO O Os044 (1 equiv) DMAP(2equiv)) T B D P S Ov r-BuOH/H20(l:l) ) oVii 0 H 44 4 66 steps ^ ^
°^ ^
OMe e 1 1 MM D +47.9 (c = 0.99, CHC13) AcO O TBDPSOv v\o' '
HO O 41 1 n24 4 mpp 173 °C, [ a ]/D +495 (c = 0.6, CHC13)Thee final product (1) was obtained as a colorless crystalline product in a 12% overall yieldd (13 steps from aldehyde 25). The relative configuration of all stereogenic centers was provenn by X-ray analysis. The solanoeclepin A analogue was subjected to hatching activity tests,, but appeared to be devoid of any hatching activity.
4.55 Acknowledgments
A.. E. van Ginkel is thanked for the synthesis of large quantities of aldehyde 25. M. IJsselstijnn is gratefully acknowledged for his investigations into the coupling reactions of vinyll bromide 36 with aldehyde 25. K. Goubitz and J. Fraanje (Laboratory of Crystallography,, University of Amsterdam) are acknowledged for the X-ray structure determinationn of compound 1. The HLB Research Center, Wijster (W. Saathof) performed the hatchingg activity tests.
4.66 Experimental Section
Forr general experimental details, see Section 2.6.
oo (+)-(3S)-3-[(ltf,2S,4ff,5S)-5-(terf-Butyldiphenylsilanyloxy)-3,3-11 ? ^ \8 ia
dimethyl-2-vinyl-7-oxabicyclo[2.2.1]hept-l-yl]-4,5,6,7-tetra-To*T5199\\ \13 hydro-3//-isobenzofuran-l-one (24). To a solution of aldehyde 3
/ K s T ll " 12 25 (280 mg, 0.65 mmol) in DMF (10 mL) was added vinyl triflate
266 (419 mg, 1.38 mmol, 2.1 equiv) followed by CrCl2 (320 mg,
2.611 mmol, 4 equiv) and NiCl2 (2.4 mg, 18.5 umol, ca. 1 mol%). The resulting green reaction
mixturee was stirred at 50 °C for 18 h. After cooling the mixture to 0 °C it was quenched by addingg saturated aqueous NH4CI (3 mL) followed by water (15 mL). The aqueous mixture wass extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine andd subsequently dried on Na2SÜ4 and the solvent was removed in vacuo. Column chromatographyy (petroleum ether/Et20 (9:1)) afforded diastereomeric lactones 24 (223 mg, 0.411 mmol, 64%) and 27 (104 mg, 0.19 mmol, 28%) as colorless viscous oils. Rf -24 = 0.51
(petroleumm ether/Et20 (1:1)); [a]21D +47.9 (c = 0.99, CHC13); IR 3071, 2933, 2857, 1760,
1111,, 1010; !H NMR (400 MHz) 5 7.65 (2H, d, J= 7.9 Hz, Ar-H), 7.55 (2H, d,J= 7.9 Hz, Ar-H),, 7.46-7.31 (6H, m, Ar-H), 5.67 (1H, ddd, J= 17.0, 10.4, 10.3 Hz, H-6), 5.13 (1H, dd, J == 10.1, 1.9 Hz, C=CH2), 5.07-5.03 (2H, m, H-19 + C=CH2), 4.31 (1H, d, J= 5.9 Hz, H-2), 3.588 (1H, s, H-3), 2.87-2.80 (1H, m, H-ll or H-14), 2.38-2.22 (3H, m, H-ll + H-14), 2.00 ( l H , d , J == 10.6Hz, H-5), 1.77-1.63 (6H,m, H-l +H-12 + H-13), 1.05 (9H, s, C(C//3)3), 0.78 (3H,, s, CHs), 0.65 (3H, s, CH3); 13C NMR (100 MHz) 8 160.9 (C-7), 135.7, 135.6 (Ar), 134.8 (C-6),, 133.9 (C-9), 133.4, 129.8, 128.1 (Ar), 127.8 (C-8), 127.7 (Ar), 118.7 (C=CH2), 92.2 (C-3),, 88.0 (C-10), 80.9 (C-19), 71.5 (C-2), 61.6 (C-5), 42.3 (C-l), 40.9 (C-4), 26.8 76 6
Seven-MemberedSeven-Membered Ring Formation via Ring-Closing Metathesis (C(CH3)3),, 25.5 (CH3), 24.8 (CH3), 24.6, 21.7, 21.6, 20.2 (C-ll + C-12 + C-13 + C-14), 18.3
(C(CH3)3);; HRMS (FAB) [M+H+] calcd for C34H4304Si: 543.2931, found: 543.2931.
(+)-(3R)-3-[(l/?,2.S',4/?,55)-5-(fórt-Butyldiphenylsilanyloxy)-3,3-- dimethyl-2-vinyl-7-oxabicyclo[2.2.1]hept-l-yl]-4,5,6,7-tetra--hydro-3H-isobenzofuran-l-onee (27). Rfll = 0.32 (petroleum
ether/Et20(l:l));; [oc]22D = +43.2 (c = 1.13, CHC13); IR 3072, 2931,
2856,, 1758, 1111, 1024; 'H NMR (400 MHz) 5 7.68 (2H, d, J = 7.66 Hz, Ar-H), 7.64 (2H, d, J= 7.6 Hz, Ar-H), 7.43-7.37 (6H, m, Ar-H), 5.49 (1H, ddd, J = 17.0,, 10.5, 10.3 Hz, H-6), 5.09 (1H, s, H-19), 4.93 (1H, dd, J= 10.0, 1.8 Hz, C=CH2), 4.81 (1H,, d d , / = 17.0, 1.8 Hz, C=CH2), 4.34 (1H, dd, J =6.8, 2.0 Hz, H-2), 3.71 (1H, d,J = 1.8 Hz,, H-3), 2.40-2.31 (2H,m,H-ll + H-14), 2.21-2.17 (2H, m, H-11 +H-14), 1.84 (1H, d, / = 10.88 Hz, H-5), 1.80 (1H, dd, J= 12.7, 6.8 Hz, H-l), 1.74-1.61 (3H, m, H-l + H-12 + H-13), 1.57-1.533 (2H, m, H-12 + H-13), 1.06 (9H, s, C(CH3h), 0.78 (3H, s, CH3), 0.59 (3H, s, CH3); 13 CC NMR (100 MHz3) 5 161.2 (C-7), 135.8 (Ar), 135.7 (C-6), 135.3, 134.0 (Ar), 133.9 (C-8), 129.77 (Ar), 128.7 (C-9), 127.7 (Ar), 116.8 (C=CH2), 92.0 (C-3), 87.5 (C-10), 82.7 (C-19), 71.55 (C-2), 60.4 (C-5), 45.5 (C-l), 43.5 (C-4), 26.9 (C(CH3)3), 25.1 (CH3), 24.8 (ll or C-14),, 24.2 (CH3), 21.7 (C-ll or C-14), 21.3, 20.1 (C-12 + C-13), 19.0 (C(CH3)3); HRMS
(FAB)) [M+H+] calcd for C34H4304Si: 543.2931, found: 543.2902.
QHH 7 OH
(+)-(5)-[(l/?,25,4/?,55)-5-(tert-Butyldiphenylsilanyloxy)-3,3-di-TBDPSO«.2J^oXX i? methyl-2-vinyl-7-oxabicyclo[2.2.1]hept-l-yl]-(2-hydroxymethyl-3<~!JllLL 11LJ13 cyclohex-l-enyl)methanol (30). To a solution of lactone 24 (330
/ 4 \6| || 12 jjjg^ Qgj m r n oi ) jn Et20 (4 mL) was rapidly added lithium
aluminumm hydride (1.0 mL of a 1.0 M solution in Et20, 1 mmol, 1.7 equiv) in one portion at
rt.. The reaction mixture was stirred for 30 min and then quenched by adding EtOAc and few dropss of saturated aqueous Na2S04. The reaction mixture was dried on Na2S04 and filtration
andd evaporation of the solvent gave diol 30 (314 mg, 0.57 mmol, 93%) as a colorless viscous oil.. Rf = 0.28 (petroleum ether/Et20 (1:3)); [a]19D = +15.2 (c = 2.03, CHC13); IR 3420 (br),
3071,, 2929, 2857, 1113; 'H NMR (400 MHz) 8 7.64-7.61 (4H, m, Ar-H), 7.43-7.36 (6H, m, Ar-H),, 5.94 (1H, ddd, J = 16.9, 10.4, 10.3 Hz, H-6), 5.19 (1H, dd, J= 10.1,2.1 Hz, C=CH2\ 5.088 (1H, s, H-19), 5.07 (1H, dd, J = 17.0, 2.0 Hz, C=CH2), 4.38 (1H, d, J= 11.2 Hz, H-7), 4.322 (1H, dd, J= 6.5, 1.5 Hz, H-2), 3.63 (1H, s, H-3), 3.60-3.52 (1H, m, H-7), 3.41-3.28 (1H, brr s, OH), 2.61-2.52 (1H, m, H-l 1 or H-14), 2.31-2.10 (2H, m, H-ll + H-14), 2.08-1.99 (2H, m,, H-l +H-11 or H-14), 1.93 (1H, d, J= 10.1 Hz, H-5), 1.89 (1H, dd, J= 13.5, 7.3 Hz, H-l), 1.69-1.600 (4H, m, H-12 + H-13), 1.05 (9H, s, (C(CH3)3), 0.81 (3H, s, CH3), 0.67 (3H, s, CH3); 13 CC NMR (100 MHz) 8 136.5 (C-8), 136.3 (C-6), 135.8, 135.7, 134.0, 133.8 (Ar), 132.7 (C-9), 129.7,, 129.7, 127.7 (Ar), 116.6 (C=CH2), 91.4 (C-10), 90.6 (C-3), 72.8 (C-19), 69.8 (C-2), 63.11 (C-7), 62.0 (C-5), 44.2 (C-l), 43.4 (C-4), 29.7, 28.9 (C-ll + C-14), 26.9 (C(CH3)3), 26.3 (C-122 or C-13), 25.0 (CH3), 24.3 (CH3), 22.6 (C-12 or C-13), 19.0 (C(CH3)3); HRMS (FAB)
[M+Na+]] calcd for C3 4H46Na04Si: 569.3063, found: 569.3080.
OTBDMSS
(+)-(S)-[2-(tert-Butyldimethylsilanyloxymethyl)cyclohex-l-T B D P S O I S Z A S ^ J ^ , ^^
enyl]-[(li?^S,4JÏ,55)-5-(tert-butyldiphenylsilanyloxy)-3^-J133 dimethyl-2-vinyl-7-oxabicyclo[2.2.1]hept-l-yl]methanol
122
(31). T o a solution of diol 30 (312 mg, 0.55 mmol) in D M F (8
m L )) were added imidazole (112 m g , 1.65 mmol, 3 equiv) and TBDMSC1 (166 m g , 1.10 m m o l ,, 2 equiv). T h e reaction mixture was stirred at rt for 16 h and then poured in water (25 m L ) .. T h e aqueous layer w a s extracted with EtOAc (3 x 25 m L ) and the combined organic layerss were washed with brine and subsequently dried on N a2S 04. After evaporation of the
solventt and column chromatography purification (petroleum ether/Et20 (9:1)) alcohol 31 (323
m g ,, 0.48 mmol, 89%) was obtained as a colorless oil. Alcohol 31 could b e used crude in the nextt reaction. Rf= 0.63 (petroleum ether/Et20 (1:1)); [a]1 9D +6.14 (c = 1.32, CHC13); IR 3471
(br),, 3 0 7 1 , 2930, 2857, 1095; !H N M R (400 M H z ) 5 7.69-7.63 (4H, m, Ar-H), 7.45-7.36 (6H, m ,, Ar-H), 5.66 (1H, ddd, J = 17.0, 10.4, 10.3 H z , H-6), 5.01 (1H, dd, J = 10.0, 2.1 Hz, C=CHC=CH22),), 4.83 (1H, dd, J = 16.9, 2 . 1 , C=C//2), 4.37 (1H, dd, J= 6.7, 1.7 Hz, H-2), 3.96-3.93 (2H,, m , H-7 + H-19), 3.73-3.69 (1H, m, H-7), 3.52 (1H, s, H-3), 2.40 (1H, br s, OH), 2.04 (1H,, d, / = 12.7 Hz, H - l ) , 1.92-1.86 (1H, m, H - l 1 or H-14), 1.77-1.59 (5H, m, H - l 1 + H-14 + H-55 + H - l ) , 1.41-1.32 (4H, m , H-12 + H-13), 1.06 (9H, s, C(C//5)3), 0.91 (9H, s, C(Gf/j)3), 0.755 (3H, s, CH3), 0.60 (3H, s, CH3), 0.07 (6H, s, SiCH3); 13C N M R (100 M H z ) 5 136.3 (C-8),, 135.8 (C-6), 135.8, 134.2 (Ar), 134.0 (C-9), 129.6, 129.6, 127.6 (Ar), 116.6 (C=CH2), 92.5 (C-10),, 90.7 (C-3), 72.6 (C-19), 72.4 (C-2), 61.1 (C-7), 61.0 (C-5), 43.6 ( C - l ) , 41.5 (C-4), 27.66 ( C - l l or C-14), 26.9 (C(CH3)3), 26.6 ( C - l l or C-14), 26.1 (C(CH3)3), 25.1 (CH3), 24.3 ( C H3) ,, 2 1 . 1 , 20.6 (C-12 + C-13), 18.9 (C(CH3)3), 18.3 (C(CH3)3), -5.34 (SiCH3), -5.35 (SiCH3). .
O A c 77 JDTBDMS (+)-(£)-Acetic acid
[2-(tert-butyldimethylsilanyloxymethyl)-TBDPSO^AioA^i^i 44 cyclohexenyl]-[(l/?,25,4l?,55)-5-tert-butyldiphenylsilanyl-33
^5^N1 1 \-J13 oxy)3,3dimethyl2vinyl7oxabicyclo [2.2.1 ] hept1yl] -^^ 61 12 methyl ester (32). T o a solution of alcohol 31 (387 mg, 0.59
m m o l )) in CH2C12 (2 m L ) w a s added acetic anhydride (0.5 m L , 5.3 mmol, 10 equiv) and
pyridinee (200 u L , 2.5 mmol, 5 equiv) and stirring was continued at rt for 16 h. To get full conversionn the reaction mixture was stirred at 50 °C for 3 h. Then the mixture was poured into saturatedd aqueous N a H C 03 (50 m L ) and extracted with EtOAc (3 x 20 mL). The combined
organicc layers were washed with brine and subsequently dried on Na2SC>4. Evaporation of the
solventt gave acetate 3 2 (377 mg, 0.54 mmol, 92%) as an oil. Acetate 32 was used crude in the nextt reaction. Rf= 0.66 (petroleum ether/Et20 (1:1)); [ a ]2 0D +15.5 (c = 1.25, CHC13); IR 3072,
2 9 3 1 ,, 2857, 1747, 1234, 1113; ' H N M R (400 M H z ) 5 7.66-7.61 (4H, m, Ar-H), 7.42-7.35 (6H,, m , Ar-H), 5.74 (1H, s, H-19), 5.65 (1H, ddd, J = 16.9, 10.4, 10.2 Hz, H-6), 4.96 (1H, dd, 78 8
Seven-MemberedSeven-Membered Ring Formation via Ring-Closing Metathesis J=J= 10.0, 2.3 Hz, C=CH2), 4.79 (1H, dd, J= 16.9, 2.2 Hz, C=CH2), 4.47 (1H, d, J = 12.9 Hz, H-7),, 4.33 (1H, dd, J = 6.5, 1.7 Hz, H-2), 4.13 (1H, d, 7 = 12.9 Hz, H-7), 3.54 (lH,s, H-3), 2.40-2.311 (1H, m, H-ll or H-14), 2.17-1.99 (3H, m, H-ll + H-14), 1.94 (3H, s, C(0)Cf/5), 1.87-1.811 (2H, m, l + 5), 1.72 (1H, d, J= 12.6 Hz, l), 1.59-1.53 (4H, m, 12 + H-13),, 1.04 (9H, s, C(CH3)3), 0.92 (9H, s, C(CH3)3), 0.75 (3H, s, CH3), 0.63 (3H, s, CH3), 0.11
(3H,, s, SiCH3), 0.10 (3H, s, SiCH3); HRMS (FAB) [M+H+] calcd for C42H6305Si2: 703.4214,
found:: 703.4210.
OAcc 7 rO H (^"Acetic a c i d
[(l*,2iS,4*,55)-5-terr-butyldiphenylsilanyloxy)-TBDPSOS2^VIOAV^SLL 3,3-dimethyl-2-vinyl-7-oxabicyclo [2.2.1 ]
hept-l-yl]-(2-hydroxy-3<°J>^^ 11lv Jia methylcyclohex-l-enyl)methyl ester (33). A solution of protected
" ^^ 1 12 alcohol 32 (428 mg, 0.61 mmol) in MeOH (20 mL) was cooled to 0 °C.. To this solution were added a few crystals of CSA and stirring was continued at 0 °C for 2 h.. Then saturated aqueous NaHC03 (3 mL) was added to quench the reaction followed by
waterr (15 mL). The aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organicc layers were washed with brine and subsequently dried on NaiSCM and the solvent was removedd in vacuo. Crude allylic alcohol 33 (364 mg, 0.62 mmol, 100%) was obtained as an colorlesss oil. Rf= 0.18 (petroleum ether/Et20 (1:1)); IR 3505 (br), 3070, 2930, 2856, 1743,
1234,, 1113, 1019; 'H NMR (400 MHz) 8 7.64-7.61 (4H, m, Ar-H), 7.44-7.37 (6H, m, Ar-H), 5.988 (1H, s, H-l9), 5.67 (1H, d d d , J = 16.9, 10.4, 10.3 Hz, H-6), 4.98 (1H, dd, J= 10.1,2.3 Hz,, C=CH2), 4.80 (1H, dd, J = 16.9, 2.2 Hz, C=CH2), 4.44 (1H, d, J = 11.5 Hz, H-7), 4.34 (1H,, dd, J= 6.6, 1.5 Hz, H-2), 3.68 (1H, d, 7 = 11.6 Hz, H-7), 3.64 (1H, s, H-3), 2.58-2.51 (1H,, m, H-ll or H-14), 2.09-1.97 (3H, m, H-ll + H-14), 1.94 (3H, s, C(0)CH3), 1.91 (1H, dd,, J = 12.9, 6.6 Hz, H-l), 1.87 (1H, d, J = 10.6 Hz, H-5), 1.72 (1H, d, J = 12.9 Hz, H-l), 1.64-1.522 (4H, m, H-12 + H-13), 1.05 (9H, s, C(CH3)3), 0.78 (3H, s, CH3), 0.66 (3H, s, CH3); 13 CC NMR (100 MHz) 5 169.5 (C(0)CH3), 137.5 (C-8), 136.0 (C-6), 135.7, 135.7, 133.8, 129.8,, 129.7 (Ar), 129.4 (C-9), 127.7, 127.7 (Ar), 116.6 (C=CH2), 91.7 (C-3), 89.1 (C-10), 71.77 (C-19), 71.6 (C-2), 62.8 (C-7), 61.4 (C-5), 43.3 (C-l), 42.4 (C-4), 29.1 (C-ll or C-14), 26.77 (C(CH3)3), 26.1 (C-ll or C-14), 25.5 (CH3), 24.7 (CH3), 22.5, 22.5 (C-12 + C-13), 20.6
(C(0)CH3),, 18.9 (C(CH3)3); HRMS (FAB) [M+Na+] calcd for C36H48Na05Si: 611.3169,
found:: 611.3168.
OACC 7 r^° (-HS)-Acetic acid [(l/?,2S,4tf ,5S)-5-tert-butyldiphenylsilanyl-TBDPSOs2/!\io/L^L??
oxy)-3,3-dimethyl-2-vinyl-7-oxabicyclo[2.2.1]hept-l-yl]-(2-3
\ / > *1 1\ /1 33 f°rmylcycl°hex-l-enyl)-(S)-methyl ester (34). To a solution of
44 6
1 12 allylic alcohol 33 (367 mg, 0.62 mmol) in acetone (20 mL) were addedd NMO (110 mg, 0.94 mmol, 1.5 equiv) and TPAP (6.6 mg, 18 umol, 3 mol%). The dark mixturee was stirred for 2 h and filtered over a thin pad of silica followed by exhaustive rinsing withh EtOAc. Evaporation of the solvent gave aldehyde 34 (353 mg, 0.60 mmol, 97%) as an
oil.. Rf = 0.68 (petroleum ether/Et20 (1:1)); [a]'UD -35.5 (c = 1.75, CHC13); IR 3071, 2935, 2859,, 1750, 1672, 1228, 1111; *H NMR (500 MHz) 8 10.18 (1H, s, H-7), 7.66-7.58 (4H, m, Ar-H),, 7.44-7.36 (6H, m, Ar-H), 6.23 (1H, s, H-19), 5.65 (1H, ddd, J= 16.9, 10.5, 10.0 Hz, H-6),, 5.01 (1H, dd, J= 10.0, 1.7 Hz, C=CH2), 4.84 (1H, dd, J= 16.9, 2.0 Hz, C=CH2), 4.35 (1H,, d, J= 6.6 Hz, H-2), 3.54 (1H, s, H-3), 2.37-2.18 (4H, m, H-ll + H-14), 1.99 (3H, s, C(0)C//j),, 1.95 (1H, dd, J= 12.7, 6.6 Hz, H-l), 1.87 (1H, d, J = 10.7 Hz, H-5), 1.66-1.59 (5H,, m, H-l + H-12 + H-13), 1.02 (9H, s, C(Ctf3)3), 0.74 (3H, s, Ctf3), 0.63 (3H, s, C#3); 13C NMRR (125 MHz) 5 191.3 (C-7), 169.4 (C(O)CH,), 151.3 (C-9), 136.6 (C-8), 135.7 (C-6), 135.6,, 133.9, 133.8, 129.7, 129.7, 127.7, 127.6 (Ar-H), 117.1 (C=CH2), 91.3 3), 88.2 (C-10),, 71.6 (C-19), 71.5 (C-2), 61.5 (C-5), 43.7 (C-l), 42.8 (C-4), 28.3 (C-ll or C-14), 26.7 (C(CH3)3),, 25.1 (CH3), 24.5 (CH3), 22.7 (C-ll or C-14), 21.9, 21.3 (C-12 + C-13), 20.5
(C(0)CH3),, 19.0 (C(CH3)3); HRMS (FAB) [M+H+] calcd for CseHnOsSi: 587.3193, found:
587.3179. .
OACC 7 {* (+)-(S)-Acetic acid
\{\R,25,4/?,55)-5-(/ert-butyldiphenylsilanyl-T B D P S O ^ ^ A I O X ^ !! 0
xy)-3,3-dimethyl-2-vinyl-7-oxabicyclo[2.2.1]hept-l-yl]-(2-3 kx^ 4>i i ' \ / ' i 33 vinylcyclohex-l-enyl)methyl ester (35). To a suspension of
y^\y^\ 6[| 12
"" methyltriphenylphosphonium bromide (860 mg, 1.90 mmol, 2.1 equiv)) in THF (15 mL) at 0 °C was added dropwise w-BuLi (1.13 mL of a 1.6 M solution in hexanes,, 1.80 mmol, 2.0 equiv). The yellow suspension was stirred at 0 °C for 1 h and aldehydee 34 (530 mg, 0.90 mmol) in THF (10 mL) was added via a double tipped needle. The reactionn mixture was stirred for 45 min and then quenched by adding saturated aqueous NaHC03.. The aqueous layer was extracted with EtOAc (3 x 30 mL). The combined organic
layerss were washed with brine and subsequently dried on Na2S04 and the solvent was removedd in vacuo. Column chromatography (petroleum ether/Et20 (9:1)) afforded triene 35
(4833 mg, 0.83 mmol, 92%) as an oil. Rf= 0.76 (petroleum ether/Et20 (1:1)); [oc]21D +8.51 (c =
2.1,, CHC13);IR 3072, 2932, 2858, 1747, 1234, 1113, 1027; 'H NMR (400 MHz) 5 7.66-7.60 (4H,, m, Ar-H), 7.42-7.34 (6H, m, Ar-H), 7.03 (1H, dd, J = 17.3, 11.1 Hz, H-7), 5.85 (1H, s, H-19),, 5.70 (1H, ddd, J = 16.9, 10.3, 10.3 Hz, H-6), 5.21 (1H, d, J = 17.2 Hz, C-7=C//2), 5.03 (1H,, d, J= 11.1 Hz, C-1=CH2), 4.97 (1H, dd, J= 10.1, 2.3 Hz, C-6=CH2), 4.80 (1H, dd, J = 16.9,, 2.2 Hz, C-6=CH2), 4.33 (1H, dd, J= 6.0, 2.2 Hz, H-2), 3.63 (1H, s, H-3), 2.32-2.18 (4H, m,, H-l 1 + H-14), 1.95 (3H, s, C(0)CH3), 1.85-1.83 (3H, m, 1+ 5), 1.65-1.54 (4H, m, H-122 + H-13), 1.02 (9H, s, C(CH3)3), 0.78 (3H, s, CH3), 0.66 (3H, s, CH3); 13C NMR (100 MHz) 88 169.3 (C(0)CH3), 136.6 (C-6), 135.7 (C-7), 135.7 (Ar), 134.3, 134.1 (C-8 + C-9), 132.7, 132.3,, 129.6, 129.6, 127.6, 127.6 (Ar), 116.2 (C-6=CH2), 111.7 (C-7=CH2), 91.4 (C-3), 89.8 (C-10),, 73.5 (C-19), 71.8 (C-2), 62.0 (C-5), 44.3 (C-l), 42.6 (C-4), 28.3 (C-ll or C-14), 26.8 (C(CH3)3),, 25.5 (C-ll or C-14), 25.3 (CH3), 24.7 (CH3)3), 22.5, 22.4 (C-12 + C-13), 20.7
(C(0)CH3),, 19.0 (C(CH3)3); HRMS (FAB) [M+H+] calcd for C^HwCUSi: 585.3400, found:
585.3400. . 80 0
Seven-MemberedSeven-Membered Ring Formation via Ring-Closing Metathesis AcOO 11 12 (+)-(25,,3*,55',10/?,195)-Diene 41. A solution of triene 35 (300
TBDPSOv^ja^pYY \1 3 mg, 513 umol) in toluene (70 mL, 7.3 mM) was thoroughly
' V V ^ 11 degassed with argon. Then catalyst 21 (64 mg, 75 umol, 15 mol%)
44 6
' was added and the brownish reaction mixture was stirred at 70 °C forr 16 h. After cooling to rt, the solvent was removed in vacuo. Column chromatography (petroleumm ether/Et20 (9:1)) afforded diene 41 (283 mg, 509 umol, 99%) as an oil. Rf= 0.75
(petroleumm ether/Et20 (1:1)); [a]22D +78.0 (c = 0.79, MeOH); IR 2941, 2860, 1740, 1240,
1108;; !H NMR (500 MHz) 8 7.68-7.60 (4H, m, Ar-H), 7.43-7.38 (6H, m, Ar-H), 5.70 (1H, d, J=J= 11.7 Hz, H-7), 5.50 (2H, m, H-6, H-19), 4.44 (1H, m, H-2), 3.62 (1H, s, H-3), 2.47-2.42 (lH,m,, H-ll orH-14), 2.05 (3H, s, C(0)CH3), 1.98-1.90 (3H, m, H-ll + H-14), 1,87 (1H, d,
J=J= 7.0 Hz, H-5), 1.67-1.49 (6H, m, H-l + H-12 + H-13), 1.05 (9H, s, C(CH3)3), 0.67 (6H, s, 2
xx CH3); HRMS (FAB) [M+H+] calcd for C35H4504Si: 557.3087, found: 557.3095.
AcOO 11 12 (2S,3R,5R,6S*,7R*,10R,19S)-mol 44. To a vigorously stirred 133 solution of diene 41 (162 mg, 291 umol) in tert-butanol (7 mL)
wass added DMAP (71.2 mg, 580 umol, 2 equiv). Then Os04 (7.4
mLL of a 1 wt.% solution in water (291 umol, 1 equiv)) was added inn one portion to the reaction mixture. The reaction mixture turned brown immediately and stirringg was continued for 30 min. Then Na2SÜ3 (189 mg, 1.50 mmol, 5 equiv) was added in onee portion. After stirring 30 min, the reaction mixture was filtered over a thin pad of silica to removee the solids and rinsed with MeOH (30 mL). Evaporation of the solvents in vacuo and columnn chromatography (petroleum ether/Et20 (1:3)) afforded a 78:22 mixture of c/s-diols 44 (1455 mg, 246 umol, 84%) as a white solid. Rf= 0.05 (petroleum ether/Et20 (1:1)); IR (KBr)
34366 (br), 3184, 2932, 1737, 1603, 1240, 1111; ]H NMR (500 MHz) 5 7.66 (2H, d, J= 7.8 Hz,, Ar-H), 7.62 (2H, d, J = 7.8 Hz, Ar-H), 7.44-7.35 (6H, m, Ar-H), 5.76 (0.2H, s, OH), 5.46-5.411 (0.7H, m, H-19 + OH), 5.41-5.30 (0.6H, m, H-19), 4.55-4.48 (1H, m, H-7), 4.42-4.40 (0.8H,, dd, J = 6.8, 2.9 Hz, H-2), 4.33-4.32 (0.2H, dd, J= 4.4, 2.9 Hz, H-2), 4.10 (1H, s, H-6), 3.700 (0.2H, s, H-3), 3.58 (0.8H, s, H-3), 2.48-2.40 (0.7H, m, H-ll or H-14), 2.34-2.31 (0.8H, m,, H-ll or H-14), 2.20 (1H, s, H-5), 2.07-2.01 (5.5H, m, H-l + H-ll + H-14 + C(O)Cft), 1.99-1.900 (2H,m, l + ll or 14), 1.89-1.80 (1H, m, OH), 1.73-1.43 (4H, m, 12 + H-13),, 1.16 (3H, s, CH3), 1.04 (9H, s, C(CH3)3), 0.69 (3H, s, CH3); HRMS (FAB) [M+H+]
calculatedd for C35U4106Sr. 591.3142, found: 591.3142.
AcOO 11 12 (+)-(25',3/?,51S',6/?,10^,195)-a-Hydroxyketone 46. To a solution
TBDPSOv2Aio4if~^133 of the mixture of diols 44 (37.8 mg, 64.0 umol) in CH2C12 (2 mL) 33
><jst^/^4 a t '2 0 °c w a s a d d e d Dess-Martin reagent (35 mg, 83 umol, 1.3 ÖHH equiv). The reaction mixture was allowed to warm to rt in 1 h and wass stirred for another 2 h. The reaction was quenched by adding saturated aqueous NaHC03 (33 mL) and saturated aqueous Na2S03 (3 mL). The aqueous layer was extracted with CH2CL
TBDPS0..2 2
( 3 x 1 00 mL). The combined organic layers were washed with brine and subsequently dried on Na2S044 and the solvent was removed in vacuo. Column chromatography (petroleum
ether/Et200 (3:1)) afforded a-hydroxyketone 46 (31.1 mg, 52 umol, 81%) as a white solid
[ a ]2 2DD +11.8 (c = 0.91, CHC13); and dialdehyde 45 (5.2 mg, 8.3 umol, 13%) as an oil. Rr46 =
0.544 (petroleum ether/Et20 (1:1)); IR 3458, 2937, 1746, 1645,1232, 1079; ' H NMR (400
MHz)) 5 7.66 (2H, d, J= 1.1 Hz, H), 7.62 (2H, d, J= 1.1 Hz, H), 7.46-7.37 (6H, m, Ar-H),, 5.30 (1H, s, 19), 4.77 (1H, dd, J= 12.2, 1.8 Hz, 6), 4.46 (1H, dd, J= 6.9, 3.1 Hz, H-2),, 3.72 (1H, d, J =1.8 Hz, OH), 3.67 (1H, s, H-3), 2.82-2.70 (1H, m, H - l l or H-14), 2.58-2.499 (1H, m, H - l l or H-14), 2.30-2.20 (1H, m, H - l l or H-14), 2.04 (3H, s, C(0)CH3), 2.03-1.966 (1H, m, H - l l or 14), 1.86 (1H, d d , / = 11.2, 6.9 Hz, l), 1.80-1.45 (6H, m, l + H-55 + H-12 + H-13), 1.19 (3H, s, CH3), 1.06 (9H, s, C(Cft)3), 0.66 (3H, s, CH3); 13C NMR (125 MHz)) 5 203.3 (C-7), 169.6 (C(0)CH3), 150.5 (C-9), 135.8, 135.7 (Ar), 134.7 (C-8), 133.6, 133.6,, 129.9, 129.8, 127.7, 127.7 (Ar), 93.4 (C-3), 85.4 (C-10), 76.7 (C-6), 73.8 (C-19), 72.4 (C-2),, 54.3 (C-5), 49.0 (C-l), 43.2 (C-4), 32.7 ( C - l l or C-14), 26.9 (C(CH3)3), 25.4 ( C - l l or C-14),, 23.7 (CH3), 22.4 (CH3), 21.9, 21.5 (C-12 + C-13), 21.1 (C(0)CH3), 19.0 (C(CH3)3);
H R M SS (FAB) [M+H+] calcd for C35H4506Si: 589.2985, found: 589.2966.
OAc7r^°° (-)-(25',3J?,55,10«,195)-Dialdehyde 45. ^ 4 5 = 0.32 (petroleum TBDPSO^^A^^J»» 4 ether/Et20 (1:1)); [a]2 2D -11.7 (c = 1.6, CHC13); IR 3071, 2937,
s V ^ i i l ^ J i 33 2859, 1751, 1717, 1672, 1224, 1109; ]H NMR (500 MHz) 5 10.28 " ^ oo 12 (1H, s, H-7), 9.58 (1H, d, J = 6 . 5 Hz, H-6), 7.61-7.57 (4H, m, Ar-H),, 7.46-7.37 (6H, m, Ar-H), 6.67 (1H, s, H-19), 4.34 (1H, dd, J = 6.5, 1.5 Hz, H-2), 3.67 (1H,, s, H-3), 2.40-2.36 (1H, m, H - l l or H-14), 2.26-2.20 (1H, m, H - l l or H-14), 2.17-2.14 (2H,, m, H - l l + H-14), 2.03 (3H, s, C(0)CH3), 1.99 (1H, d, J= 6.5 Hz, H-5), 1.86 (1H, dd, J == 13.0, 6.5 Hz, H-l), 1.65-1.57 (5H, m, H-l + H-12 + H-13), 1.03 (9H, s, C(CH3)3), 0.96 (3H, s,s, CH3), 0.71 (3H, s, CH3); 13C NMR (125 MHz) 5 202.2 (C-7), 190.7 (C-6), 169.2 (C(0)CH3),, 149.7 9), 137.4 8), 135.6, 135.6, 133.6, 133.4, 129.9, 127.8 (Ar), 91.2 (3),, 89.5 (10), 71.4 (19), 70.8 (2), 66.0 (5), 44.6 (l), 44.1 (4), 27.5 ( C - l l or C-14),, 26.7 (C(CH3)3), 25.1 (CH3), 24.7 (CH3), 22.8 ( C - l l or C-14), 21.7, 21.2 (C-12 + C-13),
20.44 (C(0)CH3), 19.0 (C(CH3)3); HRMS (FAB) [M+H+] calcd for QsH^OeSi: 589.2985,
found:: 589.2985.
Acoo 11 12 (+)-(2S,3R,10R,19S)-Enol ketone 51. To a solution of oe-133 hydroxyketone 4 6 (23.4 mg, 39.8 umol) in MeOH (2 mL) was
addedd cupric acetate mono hydrate (31.2 mg, 172 umol, 4.3 equiv). OHH The blue mixture was stirred at 60 °C for 6 h. Then the green mixturee was cooled to rt and quenched with water (10 mL) followed by extraction with CH2CI22 ( 3 x 1 0 mL). The combined organic layers were washed with brine and subsequently driedd on Na2S04 and the solvent was removed in vacuo. Column chromatography (petroleum
ether/Et200 (4:1)) afforded enol ketone 51 (17.4 mg, 29.7 umol, 75%) as a white solid. Rf =
Seven-MemberedSeven-Membered Ring Formation via Ring-Closing Metathesis 0.611 (petroleum ether/Et20 (1:1)); [a] D +122.6 (c = 1.6, CHC13); IR 3385, 2934, 1742, 1604,
1236,, 1078; 'H NMR (500 MHz) 5 7.68 (2H, d, J= 6.6 Hz, Ar-H), 7.63 (2H, d, J= 6.6 Hz, Ar-H),, 7.46-7.38 (6H, m, Ar-H), 6.45 (1H, s, OH), 5.24 (1H, s, H-19), 4.43 (1H, dd, J = 6.8, 2.77 Hz, H-2), 3.74 (1H, s, H-3), 2.76-2.64 (2H, m, H-ll + H-14), 2.26-2.22 (1H, m, H-ll or H-14),, 1.98 (3H, s, C(O)GHj), 1.97-1.91 (1H, m, H-l), 1.78-1.75 (1H, m, H-l), 1.70-1.57 (5H,, m, H-ll or H-14 + H-12 + H-13), 1.19 (3H, s, CH3), 1.08 (9H, s, C(CH3)3), 0.84 (3H, s, CHCH33);); 13C NMR (125 MHz, C6D6) 6 188.7 (C-7), 170.6 (C(0)CH3), 146.3 (C-6), 141.1 (C-9), 136.9,, 136.9, 134.8, 134.8, 134.5, 130.9, 130.9, 129.2, 129.0 (C-5 + C-8 + Ar), 92.7 (C-3), 87.99 (C-10), 75.9 (C-19), 73.7 (C-2), 46.5 (C-l), 45.6 (C-4), 33.2 (C-ll or C-14), 27.8 (C(CH3)3),, 27.5 (C-ll or C-14), 24.4 (CH3), 22.8, 22.5 (C-12 + C-13), 20.8 (CH3), 20.5
(C(0)CH3),, 20.0 (C(CH3)3); HRMS (FAB) [M+H+] calcd for C35H4306Si: 587.2829, found:
587.2822. .
AcOO 11 12 (+)-(25',3i?,10/?,191y)-Methyl enol ether 52. To a solution of enol
133 ketone 51 (17.2 mg, 29.3 umol) in DMF (0.5 mL) was added iodomethanee (200 ul, 3.2 mmol, 109 equiv) and Ag20 (80 mg, 346
OMee w umol, 12 equiv) and the resulting gray suspension was stirred at rt forr 16 h. Then the reaction mixture was filtered over a thin pad of Celite® and the filtrate was washedd with Et20 (20 mL). Evaporation and column chromatography (petroleum ether/Et20 (3:1))) afforded methyl enol ether 52 (16.8 mg, 28.0 umol, 95%) as an oil. Rf = 0.52
(petroleumm ether/Et20 (1:1)); [oc]22D +152.6 (c = 1.1, CHC13); IR 2935, 1743, 1642, 1236,
1080;; 'H NMR (500 MHz) 8 7.74 (2H, d, J = 6.6 Hz, Ar-H), 7.64 (2H, d, J = 6.6 Hz, Ar-H), 7.47-7.399 (6H, m, Ar-H), 5.13 (1H, s, H-19), 4.39 (1H, dd, J= 6.8, 2.4 Hz, H-2), 3.69 (1H, s, H-3),, 3.48 (3H, s, OCH3), 2.68-2.59 (2H, m, H-l 1 + H-14), 2.15-2.11 (1H, m, H-l 1 or H-14), 1.955 (3H, s, C(O)Ctfi), 1.84-1.80 (2H, m, l + ll or 14), 1.77-1.65 (5H, m, l + H-122 + H-13), 1.18 (3H, s, CH3), 1.08 (9H, m, C(C//,)3), 0.81 (3H, s, CH3); 13C NMR (125 MHz)) 8 190.6 (C-7), 170.3 (C(O)CH,), 146.7 (C-6), 145.7 (C-9), 139.5 (C-5), 137.8 (C-8), 135.8,, 135.7, 133.7, 133.6, 129.9, 129.8, 127.8, 127.8 (Ar), 91.7 3), 86.5 10), 75.0 (C-19),, 71.6 (C-2), 59.4 (OCH3), 46.0 (C-l), 44.2 (C-4), 31.1 (C-ll or C-14), 26.9 (C(CH3)3), 26.33 (C-ll or C-14), 24.3 (CH3), 21.9, 21.7 (C-12 + C-13), 21.0 (CH3), 20.8 (C(0)CH3), 19.0
(C(CH3)3);; HRMS (FAB) [M+H+] calcd for C36H4506Si: 601.2985, found: 601.3024.
AcOO 11 12 (+)-(2S,3R,lOR,l9S)-Alcohol 53. A solution of protected alcohol 52 133 (26.3 mg, 43.8 umol) in THF (3 mL) was cooled to 0 °C. Then HF'pyridinee (70% HF 30% pyridine, 0.2 mL) was added and the reactionn mixture was allowed to warm to rt. After stirring the mixture at rtt for 3 h, the reaction was carefully quenched with saturated aqueous NaHC03 (3 mL) and
extractedd with CH2CI2 ( 3 x 5 mL). The combined organic layers were washed with brine and subsequentlyy dried on Na2SC>4 and the solvent was removed in vacuo. Column
TBDPS0^2 2
chromatographyy (petroleum ether/Et20 (1:1 -» 1:9)) afforded alcohol 53 (12.3 mg, 34.0 umol,
77%)) as a white solid. Rf = 0.23 (Et20); [a]22D +227.3 (c = 1.1, CHC13); IR 3470 (br), 2935,
1743,, 1645, 1237; 'H NMR (500 MHz) 6 5.17 (1H, s, 19), 4.39 (1H, dd, J = 6.9, 1.7 Hz, H-2),, 3.91 (1H, s, H-3), 3.59 (3H, s, OCH3), 2.67-2.61 (2H, m, H-l 1 + H-14), 2.24-2.18 (2H, m, H-lll +H-14), 1.98 (3H, s, C(0)CH3), 1.91-1.87 (1H, m, H-l), 1.79-1.61 (5H,m,H-l +H-12 ++ H-13), 1.36 (3H, s, CH3), 1.29 (3H, s, CH3); 13C NMR (125 MHz) 5 190.5 (C-7), 170.3 (C(0)CH3),, 146.6 (C-6), 145.6 (C-9), 138.7 (C-5), 138.6 (C-8), 91.9 (C-3), 86.9 (C-10), 74.7 (C-19),, 70.8 (C-2), 59.5 (OCH3), 45.9 (C-l), 44.7 (C-4), 31.3, 26.3 (C-ll + C-14), 24.4 (CH3),, 21.9, 21.7 (C-12 + C-13), 21.5 (CH3), 20.8 (C(0)CH3); HRMS (FAB) [M+H+] calcd forr C2oH2706: 363.1808, found: 363.1825.
Acoo 11 12 (+)-(3i?,10/?,195)-Ketone 54. To a solution of alcohol 53 (11.4 mg, 31.5 133 umol) in acetone (3 mL) was added NMO (8.8 mg, 75.2 umol, 2.4 equiv) andd a catalytic amount of TPAP. The dark mixture was stirred for 30 min andd the reaction mixture was filtered over a thin pad of silica followed by exhaustivee rinsing with EtOAc. The solvent was removed in vacuo. Column chromatography (pentane/EtzOO (4:1)) afforded ketone 54 (10.4 mg, 28.8 mmol, 91%) as an oil. Rf = 0.42
(petroleumm ether/Et20 (1:1)); [a]22D +423 (c = 1.3, CHCI3); IR 2935, 1769, 1746, 1643, 1233;
'HH NMR (500 MHz) 8 5.23 (1H, s, H-19), 3.88 (1H, s, H-3), 3.62 (3H, s, OCH3), 2.67-2.62 (2H,, m, H-ll + H-14), 2.48 (1H, d, 7 = 16.8 Hz, H-l), 2.22 (1H, d, J= 16.6 Hz, H-l), 2.18-2.144 (1H, m, H-ll or H-14), 2.01 (3H, s, C(0)CH3), 1.92-1.88 (1H, m, H-ll or H-14), 1.71-1.577 (4H, m, H-12 + H-13), 1.44 (3H, s, CH3), 1.29 (3H, s, CH3); 13C NMR (125 MHz) 8 207.33 (C-2), 189.9 (C-7), 170.1 (C(0)CH3), 147.0 6), 144.0 9), 139.0 5), 138.5 (C-8),, 88.8 (C-3), 86.8 (C-10), 74.0 (C-19), 59.6 (OCH3), 46.4 l), 44.6 4), 31.3, 26.4 (C-111 + C-14), 23.5 (CH3), 21.8, 21.6 (C-12 + C-13), 20.9 (CH3), 20.7 (C(0)CH3); HRMS
(FAB)) [M+H+] calcd for C2oH2506: 361.1651, found: 361.1648.
(+)-(3i?,10/?,195)-Ketonee (1). To a solution of ketone 54 (8.0 mg, 22 133 umol) in MeOH (2 mL) was added K2C03 (7.5 mg, 54 umol, 2.5 equiv).
Thee reaction mixture was stirred at rt for 1 h. Then the reaction mixture wass poured into saturated aqueous NaHC03 and extracted with CH2C12
( 3 x 55 mL). The combined organic layers were washed with brine and subsequently dried on Na2SC>44 and the solvent was removed in vacuo. Column chromatography (pentane/Et20 (2:3))
affordedd alcohol 1 (5.8 mg, 18 umol, 82%) as a white solid which was recrystallized form pentane/Et200 to give colorless crystals. Rf = 0.24 (petroleum ether/Et20 (1:3)); mp
172.5-173.55 °C; [oc]24D + 495 (c = 0.6, CHC13); IR 3474 (br), 2935, 1767, 1642; 'H NMR (500 MHz)
88 4.26 (1H, s, H-19), 3.88 (1H, s, H-3), 3.63 (3H, s, OCH3), 2.70-2.65 (1H, m, H-l 1 or H-14),
2.52-2.466 (1H, m, H-ll or H-14), 2.37 (1H, d, J= 16.8 Hz, H-l), 2.32 (1H, br s, OH), 2.19 (1H,, d, J= 16.8 Hz, H-l), 2.17-2.13 (1H, m, H-l 1 or H-14), 1.98-1.91 (1H, m, H-l 1 or H-14), 84 4
Seven-MemberedSeven-Membered Ring Formation via Ring-Closing Metathesis
1.73-1.611.73-1.61 (4H, m, H-12 + H-13), 1.45 (3H, s, CH3), 1.23 (3H, s, CH3); 13C NMR (125 MHz) 5 207.99 (C-2), 189.2 (C-7), 147.3 (C-6), 142.5 (C-9), 140.2 (C-5), 138.3 (C-8), 89.2 (C-10), 88.99 (C-3), 74.4 (C-19), 59.8 (OCH3), 46.5 (C-l), 44.3 (C-4), 32.1, 26.3 (C-l 1 + C-14), 23.6
(CH3),, 22.0, 21.7 (C-12 + C-13), 21.1 (CH3); HRMS (FAB) [M+H+] calcd for d g l ^ O s :
319.1546,, found: 319.1548. 0 7 7 4 >> ' o 30OMee 04 033 31
ii j2 Crystallographic data for 1: orthorhombic,P2i2,2i, a = 7.8483(9), b 133 = 8.1518(10), c = 24.541(5) A, V = 1570.1(4) A3, Z = 4, Dx = 1.35
gem-3,, X(CuKa) = 8.0 c m ' , F(000) = 680, -30 °C, Final R = 0.044 forr 1829 observed reflections.
Tablee 4.1 Bond distances of the non-hydrogen atoms (A) of 1 with standard deviations in parentheses C(l)-C(2) ) C(l)-C(10) ) C(2)-C(3) ) C(2)-0(2) ) C(3)-C(4) ) C(3)-0(l) ) C(4)-C(5) ) C(4)-C(29) ) C(4)-C(30) ) 1.515(5) ) 1.548(4) ) 1.519(5) ) 1.217(4) ) 1.554(5) ) 1.435(4) ) 1.530(4) ) 1.525(5) ) 1.545(5) ) C(5)-C(6) ) C(5)-C(10) ) C(6)-C(7) ) C(6)-0(3) ) C(7)-C(8) ) C(7)-0(4) ) C(8)-C(9) ) C(8)-C(14) ) C(9)-C(ll) ) 1.336(4) ) 1.508(4) ) 1.507(5) ) 1.375(4) ) 1.501(5) ) 1.213(4) ) 1.339(4) ) 1.515(5) ) 1.507(5) ) C(9)-C(19) ) C(10)-C(19) ) C(10)-O(l) ) C(ll)-C(12) ) C(12)-C(13) ) C(13)-C(14) ) C(19)-0(7) ) C(31)-0(3) ) 1.523(4) ) 1.501(4) ) 1.457(4) ) 1.508(5) ) 1.471(7) ) 1.535(6) ) 1.424(4) ) 1.435(4) )
Tablee 4.2 Bond angles of the non-hydrogen atoms (°) of 1 with standard deviations in parentheses C(2)-C(l)-C(10) ) C(l)-C(2)-C(3) ) C(l)-C(2)-0(2) ) C(3)-C(2)-0(2) ) C(2)-C(3)-C(4) ) C(2)-C(3)-0(l) ) C(4)-C(3)-0(l) ) C(3)-C(4)-C(5) ) C(3)-C(4)-C(29) ) C(3)-C(4)-C(30) ) C(5)-C(4)-C(29) ) C(5)-C(4)-C(30) ) C(29)-C(4)-C(30) ) C(4)-C(5)-C(6) ) C(4)-C(5)-C(10) ) 100.33 (3) 104.7(3) ) 127.3(3) ) 128.0(3) ) 107.9(3) ) 100.2(3) ) 103.6(2) ) 99.0(2) ) 113.4(3) ) 107.0(3) ) 114.3(3) ) 112.0(3) ) 110.5(3) ) 126.4(3) ) 105.5(2) ) C(6)-C(5)-C(10) ) C(5)-C(6)-C(7) ) C(5)-C(6)-0(3) ) C(7)-C(6)-0(3) ) C(6)-C(7)-C(8) ) C(6)-C(7)-0(4) ) C(8)-C(7)-0(4) ) C(7)-C(8)-C(9) ) C(7)-C(8)-C(14) ) C(9)-C(8)-C(14) ) C(8)-C(9)-C(ll) ) C(8)-C(9)-C(19) ) C(ll)-C(9)-C(19) ) C(l)-C(10)-C(5) ) 128.0(3 3 125.5(3 3 118.5(3 3 115.4(3 3 121.5(3 3 118.4(3 3 119.9(3 3 124.1(3 3 113.6(3 3 122.1(3 3 122.4(3 3 121.3(3 3 116.3(3 3 107.9(2 2 C(l)-C(10)-C(19)) 114.4(3) C(l)-C(10)-O(l)) 100.7(2) C(5)-C(10)-C(19)) 119.3(3) C(5)-C(10)-O(l)) 101.5(2) C(19)-C(10)-O(l)) 110.7(2) C(9)-C(ll)-C(12)) 113.5(3) C(ll)-C(12)-C(13)) 111.8(3) C(12)-C(13)-C(14)) 111.6(4) C(8)-C(14)-C(13)) 112.5(3) C(9)-C(19)-C(10)) 110.3(2) C(9)-C(19)-0(7)) 112.2(2) C(10)-C(19)-O(7)) 108.7(3) C(3)-O(l)-C(10)) 97.7(2) C(6)-0(3)-C(31)) 116.7(3)
4.77 References and Notes
Forr reviews of the Wittig reaction, see: a) Maercker, A. Org. React 1965, 14, 270; b) Maryanoff,, B. E.; Reitz, A. B. Chem Rev. 1989, 89, 863.
Forr review of intramolecular Wittig reactions, see: Becker, K. B. Tetrahedron 1980,
33 Becker, K. B.; Boschung, A. F.; Grob, C. A. Helv. Chim. Acta 1973, 56, 2733. 44 Kim, D.; Shin, K. J.; Kim, I. Y.; Park, S. W. Tetrahedron Lett. 1994,35, 7957. 55 Nicolaou, K. C ; He, Y.; Vourloumis, D.; Vallberg, H.; Roschangar, F.; Sarabia, S.;
Ninkovic,, S.; Yang, Z.; Trujillo, J. I. J. Am. Chem. Soc. 1997,119, 7960.
66 Meng, D.; Bertinato, P.; Balog, A.; Su, D.-S.; Kamenecka, T.; Sorensen, E. J.; Danishefsky,, S. J. J. Am. Chem. Soc. 1997,119,10073.
77 Kim, S. H.; Figueroa, L; Fuchs, P. L. Tetrahedron Lett. 1997, 38, 2601.
88 Bamford, S. J.; Luker, T.; Speckamp, W. N.; Hiemstra, H. Org. Lett. 2000,2, 1157. 99 Metathesis is a composite of the Greek words meta (change) and tithemi (place), see:
Calderonn Chem. Eng. News 1967,45, 51.
100 For recent reviews on olefin metathesis, see: a) Grubbs, R. H.; Chang, S. Tetrahedron
1998,, 54, 4413; b) Furstner, A. Angew. Chem. Int. Ed. 2000, 39, 3012; c) Trnka, T.
M.;; Grubbs, R. H. Ace. Chem. Res. 2001, 34, 18. 111 Schrock, R. R. Ace. Chem. Res. 1979, 12, 98.
122 Nguyen, S. T.; Johnson, L. K; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1992, 114,191114,191 A.
133 Hérisson, J.-L.; Chauvin, Y. Makromol Chem. 1970,141, 161. 144 Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,1,953.
155 Huang, J.; Stevens, E. D.; Nolan, S. P.; Petersen, J. L. J. Am. Chem. Soc. 1999, 121, 2674. .
166 For other ruthenium-based catalysts, see: a) Weskamp, T.; Kohl, F. J.; Hieringer, W.; Gleich,, D.; Herrmann, W. A. Angew. Chem. Int. Ed. 1999, 38, 2416; b) Kingsbury, J. S.;; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 791;; c) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc.
2000,, 122, 8168; d) Furstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H.-J.; Nolan,
S.. P. J. Org. Chem. 2000, 65, 2204.
177 Scholl, M.; Trnka, T. M.; Morgan, J. P.; Grubbs, R. H. Tetrahedron Lett. 1999, 40, 2247. .
188 For a detailed discussion, see: Section 3.3.1.
199 For a review on TPAP oxidations, see: Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden,, S. P. Synthesis 1998,639.
200 Coates, R. M.; Senter, P. D.; Baker, W. R. J. Org. Chem. 1982, 47, 3597. 211 Robertson, I. R.; Sharp, J. T. Tetrahedron, 1984, 40, 3095.
222 Ulman, M.; Grubbs, R. H. J. Org. Chem. 1999,64, 7202. 233 Jensen, H. P.; Sharpless, K. B. J. Org. Chem. 1974,39,2314. 244 Furstner, A.; Langemann, K. J. Am. Chem. Soc. 1997,119,9130.
255 For a review on osmium tetroxide hydroxylation, see: Schroder, M. Chem. Rev. 1980, 80,80, 187.
266 Criegee, R. Liebigs Ann. Chem. 1936, 522, 75.
277 Subbaraman, L. R.; Subbaraman, J.; Behrman, E. J. Bioinorg. Chem. 1971,1, 35. 288 Corey, E. J.; Sarshar, S.; Azimioara, M. D.; Newbold, R. C ; Noe, M. C. J. Am. Chem.
Soc.Soc. 1996, 7/5,7851.
299 Feng, H.; Bo, Y.; Altom, J. D.; Corey, E. J. J. Am. Chem. Soc. 1999,121, 6771. 300 Tronchet, J. M. J.; Tronchet, J.; Birkhauser, A. Helv. Chim. Acta 1970, 53, 1489.
Seven-MemberedSeven-Membered Ring Formation via Ring-Closing Metathesis 311 Broka, C. A.; Ruhland, B. J. Org. Chem. 1992, 57, 4888.
322 Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
333 a) Blomquist, A. T.; Liu, L. H.; Bohrer, J. C. J. Am. Chem. Soc. 1952, 74, 3643; b) Blomquist,, A. T.; Burge, Jr., R. E.; Sucsy, A. C. J. Am. Chem. Soc. 1952, 74, 3636. 344 Wendler, N. L.; Taub, D.; Graber, R. P. Tetrahedron 1959, 7, 173.
355 For more examples of this oxidation, see: a) Yoshida, K.; Kubota, T. Chem. Pharm. Bull.Bull. 1966, 14, 1370; b)Yasuo, K.; Hido, N.; Shigemas, L; Masaru, U.; Hiroshi, K.; Kazuo,, Y. Chem. Pharm. Bull. 1985, 33, 4829; c) Broka, C. A.; Ruhland, B. J. Org. Chem.Chem. 1992, 57, 4888.
366 Schenk, H.; Driessen, R. A. J.; de Gelder, R.; Goubitz, K.; Nieboer, H.; Briiggemann-Rotgans,, I. E. M ; Diepenhorst, P. Croat. Chem. Acta 1999, 72, 593.
377 Mulder, J. G.; Diepenhorst, P.; Plieger, P.; Briiggemann-Rotgans, I. E. M. PCT Int.
Appl.. WO 93/02,083; Chem. Abstr. 1993,118, 185844z.
