UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl)
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.
General rights
It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons).
Disclaimer/Complaints regulations
If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible.
3 3
Attemptedd Seven-Membered Ring Formation via Carbonyl Coupling
3.11 Introduction
Havingg the left-hand fragment in hand, possibilities to join the fragments 1 and 2 were too be investigated (Scheme 3.1).
OMe e solanoeclepinn A Pgg = protective group
Obviously,, the synthesis of 2 is not an easy task and studies in this direction are ongoingg in these laboratories.1 In the meantime, it was envisioned that it would be useful to probee the coupling process by using a simplified model vinyl triflate 8, which would eventuallyy lead to tetracycle 3 (Scheme 3.2). This molecule contains the essential tetracyclic left-handd substructure of solanoeclepin A including the seven-membered ring. From the synthesiss of this fragment it will become clear whether the intended approach is viable. In addition,, compound 3 would be an interesting target for hatching activity tests.
3.22 Strategy
Ass depicted in the retrosynthetic analysis (Scheme 3.2), the target compound 3 should bee available from te-protected diol 4 after the appropriate functional group transformations. Thee latter compound was thought to arise from acyloin 5 upon oxidation of the a-hydroxyketonee followed by methylation. Acyloin 5 can be possibly constructed by an acyloin condensationn of diester 6, which makes the first disconnection between C-6 and C-7 an obviouss one. The second detachment can be made between C-9 and C-19. Ideally, this CC bondd should result from a chromium-mediated coupling reaction of aldehyde 7 with vinyl triflatee 8, which is readily available from ethyl 2-cyclohexanonecarboxylate.2
PgO O TBDPSO, , EtO O PgO O T B D P S OV/ - ~ x ^ / /9 9 T B D P S Ov/ \ X X Pgg = protective group O O 6 6
3.2.11 The Intramolecular Acyloin Condensation
Thee acyloin condensation has been well reviewed in the literature. Numerous intramolecularr cyclizations providing a wide range of ring sizes are known. For the synthesis off solanoeclepin A a seven-membered ring needs to be constructed. One of the many literaturee examples of this type involves the intramolecular ring closure of diester 9 to acyloinn 10 by Leonard and Robinson (eq 3.1).
CH2Ph h y — C 02E t t
Lr
E
' '
CH2Ph h Na a xylene,, reflux (3.1) )Ann important observation was made in the study of acyloin condensations of a,p-unsaturatedd esters.5 After the cyclization of ethyl cinnamate (11)
2-carbethoxy-3,4-diphenylcyclopentanonee (12) was isolated and not the expected acyloin (eq 3.2).
Ph--.0 0 OEt t Na a Ph h Et20,, reflux Phh \ (3.2) ) C02Et t 111 12(41%) not observed
Thee explanation for this outcome is depicted in eq. 3.3. The initial step in the reduction iss the transfer of one electron from sodium to ethyl cinnamate producing radical species 13, withh the free radical predominantly at the p-position.6 Radical anion 13 then dimerizes to
affordd dianion 14, which simply undergoes a Dieckmann condensation to give cyclopentanonee 12. Ph h
P P
OEt t Na a 11 1 Ph h O0N a ® ® OEt t 13 3 OO Na 13 3 p h ^ O E t t P h A O E t t \ _ © . . . O0N a © © 14 4 Prii \ C02Et t 122 (95%) (3.3) )Thee formation of the allylic radical was considered to be a potential problem for the acyloinn ester condensation of a,P-unsaturated ester 6 (eq 3.4). Most likely treatment with sodiumm would preferentially lead to diradical 15 so that the subsequent cyclization was expectedd to result in the predominant formation of intermediate 16. This fear was supported byy the lack of literature precedent, since no examples of acyloin ester condensations of highly functionalizedd oc,p-unsaturated esters are known. Moreover, the harsh conditions required for thee cyclization disqualified the acyloin strategy to a rather risky approach, and a search for milderr processes was initiated.
PgO, , Pgg = protective group Na a PgO O O0N a ® ® 15 5 PgO O
a a A
@ @ (3.4) ) 41 13.2.22 McMurry Coupling
AA different approach to the target structure would involve the intermediacy of diol 17 (Schemee 3.3). After oxidation of the diol and functional group transformation as previously describedd the desired compound should be accessible. A potentially viable method to constructt this diol is an intramolecular McMurry coupling of dialdehyde 18.7 The latter
shouldd be available from diester 6 by reduction of the ester groups to the corresponding aldehydes.. The diester is expected to result from a chromium-mediated coupling reaction of aldehydee 7 and vinyl triflate 8.
Schemee 3.3
Inn the McMurry coupling, CC bond formation between aldehyde and/or ketone carbonyll groups takes places upon treatment with low-valent titanium. According to the literaturee intramolecular pinacol formation of a,(3-unsaturated aldehydes is possible, although aa radical intermediate is proposed for these cyclizations.7 Striking examples can be found in thee synthesis of complex natural products. In the synthesis of Taxol® for example, Nicolaou andd coworkers used the McMurry coupling to cyclize dialdehyde 19 in the construction of the taxanee skeleton of 20 (eq 3.5).8
Q.. O OBn
TiCU'DME E
HOtt OH QBn
200 (23%)
Inn addition, during the synthesis of ceroplastol II by Kato and Takeshita an excellent eight-memberedd ring formation (22) via cyclization of dialdehyde 21 was achieved.
TiCLrZn n THF F
(3.6) )
222 (96%)
Thee pinacol coupling is still in development and is studied intensively.1 Recently, diastereoselectivee pinacol condensations using a vanadium catalyst were reported by Hirao andd coworkers.103 Considering these arguments, it was concluded that it should be possible to constructt the seven-membered ring via an intra-molecular pinacol coupling of dialdehyde 18 (Schemee 3.3).
3.33 Results and Discussion
3.3.11 Chromium-Mediated Coupling Reaction
Diesterr 6 was thought to be accessible via a chromium-mediated coupling reaction betweenn aldehyde 7 and vinyl triflate 8 (Scheme 3.3).11 The reaction of vinyl triflates with aldehydess is well-known to be mediated by CrCb in the presence of a catalytic amount of NiCl2.122 Excellent chemoselectivity in favor of aldehyde compared to ester groups was
observed."" Knochel and Rao reported that Barbiertype reactions of flhaloenones (23) or -enoatess with carbonyl compounds (24) induced by CrCl2 and a catalytic amount of NiCl2
generallyy provide allylic alcohols (25) in good yields (eq 3.7). O O (3.7) ) 24 4 CrCl2,, NiCl2 (cat.), DMF,, 45 °C, 5 h 23 3 OH H 25(91%) )
Indeed,, when aldehyde 7 and vinyl triflate 8 were subjected to the conditions of Knochell and Rao the formation of a,(3-unsaturated lactone 26 was observed (eq 3.8). Lactone 266 was isolated as a stable crystalline solid (mp 101 °C; [a]2 2D + 8.57 (c = 1.21, CHC13)) and,
surprisingly,, only a single isomer was found where a mixture of diastereomers was expected.
TBDPSO, ,
TfO. .
WS. .
TBDPSO, ,< V > ^ , O E tt CrCl2 (4 equiv), NiCl2 (cat.),
/ \\ T DMF, 50 °C, 18 h O O
7 7
(3.8) )
Thee mechanism of the reaction is shown in Scheme 3.4. It is assumed that Cr2+ reduces thee Ni + to Ni0.14'15 An oxidative addition of the vinyl triflate to the Ni -species and subsequentt transmetallation with Cr3+ leads to organochromium species 28. Addition of 28 to
aldehydee 7 then gives intermediate diester 29, which under the reaction conditions lactonizes too afford the a,(3-unsaturated lactone 26.
Schemee 3.4 O O TBDPSO„ „ CQ2Et t TfO O CQ2Et t TfONi i Ni°° - T ^ T Ni2+ Cr3++ Cr2+ C02Et t Cr3 +Q CQ2Et TBDPSO. . TBDPSO, ,
"gC" "
OEt t 7 7AA possible explanation for the excellent stereocontrol of the reaction is the chromium chelatee 31 (Scheme 3.5). Basically, there are six possible conformations of aldehyde 7 of whichh two (30 + 31) are considerably more stable. MM2 force field calculations (Chem3D™ versionn 5.0) on both conformations showed that the steric energy of conformation 31 (without chromiumm chelation) is 2.8 kcal/mol lower than conformation 30. An additional stabilizing effectt in conformation 31 might be the chromium chelation between the aldehyde and ester group.. For geometrical reasons, the other oxygen atoms cannot assist in the reaction by chelation.. These factors possibly lead to predominant formation of chelate 3 1 . Attack of the organochromiumm species onto the Si face of the aldehyde resulted in lactone isomer 26 as the solee product.
Schemee 3.5
OO OTBDPS
EtO. .
TBDPSQ Q
Itt was not possible to determine the relative configuration of the new stereogenic centerr by 'H NMR experiments. Therefore, an X-ray crystal structure of lactone 26 was desired.. Because the crystals of lactone 26 did not possess the required quality for X-ray measurementss it was decided to remove the apolar and flexible silyl protective group to promotee the crystallinity of the compound (eq 3.9).
T B D P S O ^ ^ X A - ,, HF-pyndme / " \\ C02Et 26 6 THF F C02Et t 322 (94%) (3.9) ) C02Et t 333 (83%)
Figuree 3.1 Crystal structure of 33.
Afterr TPAP mediated oxidation of alcohol 32 the crystalline ketone 33 was obtained (mpp 168.5-169.5 °C; [a]19D +98.0 (c = 1.25, CHC13)). After recrystallization, these crystals
weree suitable for an X-ray structure determination. The X-ray analysis of 33 revealed the (S)-configurationn at C-19 (Figure 3.1) and confirmed the absolute configuration of the other stereogenicc centers. It may be concluded that the highly stereoselective reaction of vinyl triflatee 8 with aldehyde 7 afforded the desired coupled product 26 bearing the correct configurationn of all stereocenters.
3.3.22 Formation of the Dialdehyde
Thee synthesis of dialdehyde 18 required reduction of the two carbonyl groups present inn lactone 26. A clean reduction to triol 34 was accomplished by rapid addition of lithium aluminumm hydride to the lactone at rt in Et20 (eq 3.10). Solvent and temperature appeared to bee crucial to achieve a good yield.
TBDPSO, , L1AIH4 4 TBDPSO, ,
CQ2Et t Et20,, rt, 15 min OH H (3.10) ) 26 6 OH H 34(61%) )
Beforee the primary hydroxyl groups could be oxidized, the secondary hydroxyl group hadd to be protected. The following three-step protective group strategy was used for this purposee (Scheme 3.6). First, both primary hydroxyl groups were protected as a silyl ether. Thenn alcohol 35 was protected as an acetate (36) and finally acidic cleavage of the two primaryy silyl ethers with camphorsulfonic acid (CSA) yielded diol 37 in good overall yield. Schemee 3.6 T B D P S Ov v TBDPSO^ ^ & &
V V
// Nz z
// \ OHH fCO CO
ss ^
OH H 34 4 TBDMSC11 T B D P S V * * pyridine,, D M F .OTBDMS S OAcc fXX XX
SS
OTBDMS Su
366 (89%) CSAA T B D P S V MeOH,, rt .OTBDMS S OHH r"£iu u
xSS ^
OTBDMS S 355 (85%) OAcc r"^0 ^0
// \
OH H 377 (76%) A c20 0 pyridine e 46 6Perruthenatee (TPAP) oxidation of diol 37, however, did not give the expected dialdehydee (Scheme 3.7). Instead, the eight-membered ring lactone 40 was rapidly formed in aa surprisingly good yield. This remarkable result is not unusual for oxidations of diols.16'17 Thee allylic alcohol is probably oxidized first to give aldehyde 38. Intramolecular attack of the remainingg hydroxyl group then results in the eight-membered ring lactol 39 and this process is apparentlyy faster than oxidation of the second primary hydroxyl group. The oxidizing agent thenn converts the lactol into lactone 40. Alternative oxidation methods such as pyridinium chlorochromatee and activated manganese dioxide could not circumvent this problem because alll these reactions proceed via the same lactol intermediate.
Schemee 3.7 TBDPSO. . TBDPSO. . AcOO r ^ \ T B D P S ON^v> — U U > ^ _ O ^ O H H 39 9 TBDPSO, , 400 (70%) 3.3.33 Formation of a Triene
Havingg established that the acyloin condensation of esters and the McMurry coupling off aldehydes could not be readily applied for the closure of the seven-membered ring, the attentionn was directed to the potential use of the ring-closing metathesis reaction of triene 42 ass will be discussed in Chapter 4 (eq 3.11).
AcO O AcO O
TBDPSO O TBDPSO O
41 1
(3-11) )
Inn order to prepare 42 it appeared possible to selectively cleave the allylic silyl group whenn the reaction temperature was kept at 0 °C (Scheme 3.8). Oxidation of alcohol 43 and subsequentt Wittig olefination of aldehyde 44 gave alkene 45 in good yield.
Schemee 3.8 T B D P S O ^ / \ \ // \ T B D P S O , ^ / ^ ^ // \ .OTBDMS S OAcc (
^6 ^6
OTBDMS S 36 6 OAcc r^^6^6
OTBDMS S-444 (85%) CSA A MeOH,, 0 C Ph3PMeBr, , «-BuLi i THF F T B D P S Ov v TBDPSO^ ^ OAcc <
^0 ^0
OTBDMS S 433 (84%) OAcc (***^0 ^0
OTBDMS S 45(81%) ) TPAP,, N M O acetone eHowever,, removal of the second terr-butyldimethylsilyl group appeared impossible sincee the acetate group of 45 partially migrated under the reaction conditions to the least hinderedd primary position and a 1:2 mixture of products 46 and 47 was isolated (eq 3.12).
TBDPSO. . TBDPSQ Q MeOH,, rt OTBDMS S 45(81%) ) OAcc r^ OH f T B D P S Ov/ \ A iN N (3.12) ) OH H 46(20%)) 1:2 OAc c 477 (40%)
Thesee disappointing results made the design of a new route to the triene necessary. Thiss new approach will be discussed in the next chapter.
3.44 Concluding Remarks
Inn this chapter, the coupling reaction between aldehyde 7 and vinyl triflate 8 with the aimm to construct the seven-membered ring has been described (Scheme 3.9). A chromium-mediatedd coupling resulted in lactone 26 with excellent stereocontrol. Compound 26 was transformedd in diol 37 in four steps. However, oxidation of this diol to the desired dialdehyde appearedd impossible and instead the eight-membered lactone 40 was obtained. Because of this unexpectedd result, this route to construct the seven-membered ring was abandoned. A new approachh will be discussed in the next chapter.
Schemee 3.9
TBDPSO. .
OO C02Et
'Y5ii
H
+
T f 0
Y S
CrC1
2'
NiC1
2<
cat
-),
< j Nv. O E tt k ^ J DMF, 50°C, 18h TBDPSO, ,
5<V V
44 steps O O TBDPSO, , AcO O TBDPSO. . 400 (70%) 3.55 AcknowledgmentsA.. E. van Ginkel is kindly thanked for the synthesis of aldehyde 7 and triflate 8. K. Goubitzz and J. Fraanje (Laboratory of Crystallography, University of Amsterdam) are gratefullyy acknowledged for the X-ray structure determination of ketone 33.
3.66 Experimental Section
Forr general experimental details, see Section 2.6.
TBDPSOv2 2
(+)-(ll?,2S,4fl,5S)-5-(terf-Butyldiphenylsilanyloxy)-3,3-di-- methyl-l-[(LS)-3-oxo-l,3»4,5,6,7-hexahydroisobenzofuran-l--yl]-7-oxabicyclo[2.2.1]heptane-2-carboxylicc acid ethyl ester (26).. To a solution of aldehyde 7 (1.03 g, 2.14 mmol) in DMF (8
mL)) was added vinyl triflate 8 (1.60 g, 5.30 mmol, 2.5 equiv) followedd by CrCl2 (1.33 g, 10.8 mmol, 5 equiv) and NiCl2 (7.4 mg, 57 umol, ca. 2 mol%).
Thee resulting green suspension was stirred at 50 °C for 16 h. After cooling the mixture to 0 °C,, the reaction was quenched by adding saturated aqueous NH4CI (5 mL) followed by water (155 mL). The aqueous mixture was extracted with EtOAc (3 x 40 mL). The combined organic layerss were washed with brine, subsequently dried on Na2SO"4 and the solvent was removed in
vacuo.vacuo. Column chromatography (petroleum ether/Et20 (4:1)) afforded lactone 26 (873 mg,
1.488 mmol, 69%) as a white solid. Rf= 0.23 (petroleum ether/Et20 (1:1)); mp 101.5 °C; [cc]22D
++ 8.57 (c = 1.2, CHCI3); IR 3070, 2935, 2858, 1760, 1737, 1111, 1066, 1024; !H NMR (400 MHz)) 8 7.64 (2H, d, J= 6.7 Hz, H), 7.55 (2H, d J = 6.7 Hz, H), 7.56-7.36 (6H, m, Ar-H),, 5.91 (1H, s, H-19), 4.30 (1H, d, J = 6.0 Hz, H-2), 4.12-4.07 (2H, m, OCH2CR3), 3.6 (1H,
s,, H-3), 2.83-2.77 (1H, m, H-ll or H-14), 2.44-2.39 (1H, m, H-ll or H-14), 2.27-2.24 (3H, m,, H-5 + H-ll + H-14), 1.77-1.72 (6H, m, H-l + H-12 + H-13), 1.22 (3H, t, J= 7.1 Hz, OCH2C//5),, 1.03 (9H, s, C(Ctfj)3), 0.86 (3H, s, CH3), 0.78 (3H, s, CH3); 13C NMR (100 MHz) 88 173.2 (C-7), 170.4 (C-6), 164.0 (C-9), 135.6, 135.4, 133.6, 133.1, 129.8, 127.8, 127.7, 127.6 (Ar),, 127.6 (C-8), 91.6 (C-3), 86.6 (C-10), 80.3 (C-19), 71.2 (C-2), 60.1 (C-5), 60.0 (OCH2CH3),, 43.0 (C-l), 41.5 (C-4), 26.6 (C(CH3)3), 24.9 (CH3), 24.5 (CH3), 24.2, 21.5, 21.6, 20.00 (C-l 1 + C-12 + C-13 + C-14), 18.8 (C(CH3)3), 14.1 (OCH2CH3); HRMS (FAB) [M+H+]
calcdd for QsHtsOfiSi: 589.2985, found: 589.2983; Anal, calcd for C^H^OfiSi: C 71.39, H 7.53,, found: C 71.30, H 7.42.
(+)-(lff,25,4/?,55)-5-Hydroxy-3,3-dimethyl-l-[(15)-3-oxo--
l,3,4,5,6,7-hexahydroisobenzofuran-l-yl]-7-oxabicyclo[2.2.1]--heptane-2-carboxylicc acid ethyl ester (32). A solution of lactone 26
(522 mg, 88 umol) in THF (1 mL) was cooled to 0 °C. To this solution wass added HF'pyridine (70% HF 30% pyridine, 0.2 mL). The mixture wass allowed to warm to rt and stirring was continued for 8 h. The reaction was carefully quenchedd by adding saturated aqueous NaHC03 (3 mL) and water (5 mL) and was extracted
withh EtOAc ( 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
chromatographyy (petroleum ether/Et20 (7:1 —> 3:1)) afforded alcohol 32 (29 mg, 83 umol,
94%)) as a white solid. Rf= 0.13 (petroleum ether/Et20 (1:3)); [a]20D + 17.3 (c = 1.37, CHC13);
IRR 3470 (br), 2941, 1756, 1738, 1670, 1159, 1008; 'H NMR (400 MHz) 8 5.92 (1H, s, H-l9), 4.377 (1H, d, J= 6.2 Hz, H-2), 4.19-4.10 (2H, m, OCtf2CH3), 3.89 (1H, s, H-3), 2.47-2.43 (3H, m,, 5 + ll +14), 2.30-2.18 (2H,m, ll + 14), 1.87 (1H, dd, J= 13.7, 6.7 Hz, H-1),, 1.75-1.61 (5H, m, H-12 + H-13 + OH), 1.27 (3H, t, J = 7.1 Hz, OCH2C//3), 1.20 (3H, s, CHCH33),), 1.12 (1H, d, J= 13.8 Hz, H-l), 1.06 (3H, s, CH3); 13C NMR (100 MHz) 8 173.0 (C-7), 170.55 (C-6), 163.0 (C-9), 128.1 (C-8), 92.2 (C-3), 87.0 (C-10), 80.3 (C-19), 70.2 (C-2), 60.3, (C-5),, 60.2 (OCH2CH3), 43.1 (C-l), 41.8 (C-4), 25.1 (CH3), 25.0 (CH3), 24.5, 21.5, 21.5, 20.1
(C-lll + C-12 + C-13 + C-14), 14.3 (OCH2CH3); HRMS (FAB) [M+H+] calcd for Ci9H2706:
351.1808,, found: 351.1813.
OO
(+)-(l/?,25,4/?)-3,3-Dimethyl-5-oxo-l-[(15)-3-oxo-l,3,4,5,6,7-hexa-11 p 7(13 hydroisobenzofuran-1 -yl]-7-oxabicyclo[2.2.1]heptane-2-carboxylic
^ p O ^ i s ^^ ^ acid ethyl ester (33). To a solution of alcohol 32 (29 mg, 83 umol) in
3
S<^vC02Eti22 acetone (2 mL) was added NMO (15 mg, 128 umol, 1.5 equiv) and
TPAPP (2.2 mg, 6.3 umol, 7.5 mol%). The dark mixture was stirred for 2 hh and was filtered over a thin pad of silica followed by exhaustive rinsing with EtOAc. Evaporationn of the solvent and column chromatography (CH2C12) purification afforded ketone 333 (24 mg, 69 umol, 83%) as a white solid, which was recrystallized from Et20 to give
transparentt crystals. Rf= 0.30 (petroleum ether/Et20 (1:1)); mp 168.5-169.5 °C; [a]2 lD + 98.0 (cc = 1.25, CHC13); IR 3022, 2942, 2865, 1753, 1212, 1018; 'H NMR (400 MHz) 5 5.94 (1H, s,, H-19), 4.22-4.17 (2H, m, OGr72CH3), 3.86 (1H, s, H-3), 2.71 (1H, s, H-5), 2.45-2.39 (2H, m,, H-ll +H-14), 2.30-2.18 (2H,m,H-ll +H-14), 1.97 (lH,d, J= 17.7 Hz, H-l), 1.91 (1H, d,, J= 17.8 Hz, H-l), 1.78-1.67 (4H, m, H-12 + H-13), 1.30 (3H, t, J= 7.2 Hz, OCH2Cr73), 1.222 (3H, s, CH3), 1.15 (3H, s, CH3); 13C NMR (100 MHz) 8 207.5 (C-2), 172.2 (C-7) 169.7 (C-6),, 162.3 (C-9), 128.9 (C-8), 89.6 (C-3), 82.0 (C-10), 79.9 (C-19), 60.8 (OCH2CH3), 59.6 (C-5),, 43.3 (C-l), 43.2 (C-4), 24.6 (CH3), 24.5 (C-ll or C-14), 24.0 (CH3), 21.5 (ll or
C-14),, 21.5, 20.1 (C-12 + C-13), 14.3 (OCH2CH3); Anal, calcd for Ci9H2406: C 65.50, H 6.94,
Found:: C 65.17, H 6.82.
Crystallographicc data for 33: monoclinic, P2i, a = 8.5854(7), b = 8.3775(7),, c = 12.428(1) A, (J = 103.395 °, V = 869.56(13) A3, Z = 2, Dx== 1.33 gem-3, X(CuKa) = 8.2 cm"1, F(000) = 372, -20 °C, Final R =
0.0566 for 1655 reflections.
Tablee 3.1 Bond distances of the non-hydrogen atoms (A) of 33 with standard deviations in parentheses
C(l)-C(2) ) C(l)-C(6) ) C(2)-C(3) ) C(2)-0(l) ) C(3)-C(4) ) C(3)-0(2) ) C(4)-C(7) ) C(4)-C(8) ) C(5)-C(6) ) 1.53(1) ) 1.55(1) ) 1.53(1) ) 1.21(1) ) 1.56(1) ) 1.46(1) ) 1.56(1) ) 1.54(1) ) 1.55(1) ) C(5)-C(9) ) C(6)-C(12) ) C(6)-0(2) ) C(9)-0(3) ) C(9)-0(4) ) C(10)-C(ll) ) C(10)-O(4) ) C(12)-C(19) ) C(12)-0(5) ) 1.50(1) ) 1.53(1) ) 1.449(7) ) 1.22(1) ) 1.33(1) ) 1.47(1) ) 1.47(1) ) 1.51(1) ) 1.438(8) ) C(13)-C(14) ) C(13)-0(5) ) C(13)-0(6) ) C(14)-C(15) ) C(14)-C(19) ) C(15)-C(16) ) C(16)-C(17) ) C(17)-C(18) ) C(18)-C(19) ) 1.45(1) ) 1.386(8) ) 1.202(8) ) 1.51(1) ) 1.331(8) ) 1.52(1) ) 1.54(1) ) 1.56(1) ) 1.48(1) )
Tablee 3.2 Bond angles of the non-hydrogen atoms (°) of 33 with standard deviations in parentheses
C(2)-C(l)-C(6) ) C(l)-C(2)-C(3) ) C(l)-C(2)-0(1) ) C(3)-C(2)-0(l) ) C(2)-C(3)-C(4) ) C(2)-C(3)-0(2) ) C(4)-C(3)-0(2) ) C(3)-C(4)-C(5) ) C(3)-C(4)-C(7) ) C(3)-C(4)-C(8) ) C(5)-C(4)-C(7) ) C(5)-C(4)-C(8) ) C(7)-C(4)-C(8) ) C(4)-C(5)-C(6) ) C(4)-C(5)-C(9) ) 100.2(5) ) 104.1(6) ) 128.2(6) ) 127.6(6) ) 108.2(6) ) 100.6(6) ) 102.7(6) ) 100.7(6) ) 107.77 (6) 112.2(7) ) 113.7(7) ) 112.1(6) ) 110.0(7) ) 102.0(5) ) 111.3(5) ) C(6)-C(5)-C(9) ) C(l)-C(6)-C(5) ) C(l)-C(6)-C(12) ) C(l)-C(6)-0(2) ) C(5)-C(6)-C(12) ) C(5)-C(6)-0(2) ) C(12)-C(6)-0(2) ) C(5)-C(9)-0(3) ) C(5)-C(9)-0(4) ) 0(3)-C(9)-0(4) ) C(ll)-C(10)-O(4) ) C(6)-C(12)-C(19) ) C(6)-C(12)-0(5) ) C(19)-C(12)-0(5) ) C(14)-C(13)-0(5) ) 116.8(7) ) 107.0(7) ) 114.9(5) ) 101.5(5) ) 117.9(6) ) 104.2(5) ) 109.6(7) ) 126.1(7) ) 109.9(7) ) 123.8(7) ) 111.3(6) ) 116.9(6) ) 107.1(6) ) 105.0(5) ) 108.0(5) ) C(14)-C(13)-0(6) ) 0(5)-C(13)-0(6) ) C(13)-C(14)-C(15) ) C(13)-C(14)-C(19) ) C(15)-C(14)-C(19) ) C(14)-C(15)-C(16) ) C(15)-C(16)-C(17) ) C(16)-C(17)-C(18) ) C(17)-C(18)-C(19) ) C(12)-C(19)-C(14) ) C(12)-C(19)-C(18) ) C(14)-C(19)-C(18) ) C(3)-0(2)-C(6) ) C(9)-O(4)-C(10) ) C(12)-0(5)-C(13) ) 131.6(7) ) 120.4(7) ) 125.6(6) ) 110.3(6) ) 124.0(7) ) 109.0(5) ) 126.7(8) ) 110.6(6) ) 110.9(5) ) 107.8(6) ) 126.2(5) ) 125.9(7) ) 97.3(6) ) 117.8(7) ) 108.8(5) ) 51 1
.OHH (-)-(S)-[(lfl,2*,4tf,5S)-5-(terf-Butyldiphenylsilanyloxy)-2-OHH 11 TBDPSOO /L10JL Jl hydroxymethyl-3,3-dimethyl-7-oxabicyclo[2.2.1]hept-1-yl]-(2-2 L o ] 55 I l13 hydroxymethylcyclohex-l-enyl)methanol (34). To a solution of 3
/ $ \\ (3l 12 lactone 26 (723 mg, 1.23 mmol) in Et20 (10 mL) was added at rt
OH H
lithiumm aluminum hydride (3.8 ml of a 1.0 M solution in Et20, 3.8
mmol,, 5 equiv) in one portion. After 10 min, the reaction mixture was cooled to 0 °C and quenchedd by adding aqueous saturated NaHCCh. After separation of the organic layer, the waterr layer was extracted with Et20 (2 x 20 mL). The combined organic layers were washed
withh brine and subsequently dried on Na2S04. Evaporation of the solvent afforded triol 34
(4155 mg, 0.75 mmol, 61%) as a colorless oil. Triol 34 was used unpurified in the next reaction.. Rf= 0.18 (petroleum ether/Et20 (1:3)); [a]21D -5.21 (c = 1.6, CHC13); IR 3427 (br),
2929,, 2856, 1245, 1110, 1069; 'H NMR (400 MHz) 5 7.63-7.60 (4H, m, Ar-H), 7.44-7.36 (6H,, m, Ar-H), 5.20 (1H, s, 19), 4.41 (1H, d, J= 10.7 Hz, 7), 4.31 (1H, d,J= 6.7 Hz, H-2),, 3.78 (1H, dd, J = 10,9, 10.8 Hz, H-6), 3.63 (1H, dd, J= 10.7, 2.7 Hz, H-7), 3.57-3.54 (1H, m,, H-6), 3.48 (1H, s, H-3), 3.46-3.38 (1H, m, OH), 2.58-2.54 (1H, m, H-ll or H-14), 2.33-2.288 (1H, m, ll or 14), 2.17-2.12 (1H, m,ll or 14), 2.03-1.99 (1H, m, ll or 14),, 1.96 (1H, dd, J= 12.9, 6.8 Hz, l), 1.78 (1H, d, J = 12.6 Hz, l), 1.66-1.48 (5H, m, H-55 + H-12 + H-13), 1.04 (9H, s, C(CH3)3), 0.77 (3H, s, CH3), 0.72 (3H, s, CH3). OHH 7 /0 T B D M S (-)-(5)-[(l«,2J?,4J?,55)-2-(terr-Butyldimethylsilanyloxy-TBDPSO^^onX^j^^ u methyl)-5-(te/*-butyldiphenylsilanyloxy)-3,3-dimethyl-7-3<^S^n'\^i33 oxabicyclo[2.2.1]hept-l-yl]-[2-(tert-butyldimethylsilanyl-44
OTBDMS oxymethyl)cyclohexenyl] methanol (35). To a solution of triol 344 (415 mg, 0.75 mmol) in CH2C12 (5 mL) was added pyridine (0.61 mL, 7.6 mmol, 10 equiv)
andd TBDMSC1 (343 mg, 2.28 mmol, 3 equiv). The reaction mixture was stirred at rt for 16 h. Thenn the solution was poured in water (30 mL) and extracted with Et20 (3 x 25 mL). The
combinedd organic layers were washed with brine and subsequently dried on Na2SC>4 and the
solventt was removed in vacuo. Column chromatography (petroleum ether/EtOAc (97:3)) affordedd protected alcohol 35 (496 mg, 0.64 mol, 85%) as a colorless oil. Rf- 0.41 (petroleum ether/EtOAcc (19:1)); [a]21D -7.11 (c = 1.00, CHCI3); IR 3425 (br), 2929, 2856, 1254, 1110,
1068;; 'H NMR (400 MHz) S 7.65 (2H, d, J = 7.9 Hz, Ar-H), 7.61 (2H, d,J = 7.9 Hz, Ar-H), 7.43-7.344 (6H, m, Ar-H), 4.95 (1H, s, H-19), 4.50 (1H, d, J = 12.4 Hz, H-7), 4.28-4.24 (2H, m,, H-2 + OH), 4.09 (1H, d, J= 12.4 Hz, H-7), 3.70 (1H, dd, J = 10.6, 10.5 Hz, H-6), 3.51 (1H,, dd, 10.7, 3.5 Hz, H-6), 3.37 (1H, s, H-3), 2.36-2.31 (2H, m, H-ll + H-14), 2.17-1.98 (2H,m,H-lll +H-14), 1.91 (1H, dd, J= 12.7, 6.8 Hz, H-l), 1.75 (lH,d, 12.8 Hz, H-l), 1.68-1.588 (4H, m, H-12 + H-13), 1.45 (1H, dd, J = 10.5, 3.4 Hz, H-5), 1.03 (9H, s, C(CH3)3), 0.92 (9H,, s, C(C//j)3), 0.88 (9H, s, C(CH3h), 0.74 (3H, s, CH3), 0.67 (3H, s, CH3), 0.08 (3H, s,
SiCHSiCH33),), 0.08 (3H, s, SiCH3), 0.08 (3H, s, SiCH3), 0.07 (3H, s, SiCH3); 13C NMR (50 MHz) 8
135.7,, 135.7, 134.5, 134.3 (Ar), 134.1 (C-9), 130.5 (C-8), 129.6, 129.5, 127.6, 127.5 (Ar), 52 2
91.55 3), 91.3 10), 71.4 2), 69.4 19), 63.4 7), 61.4 6), 56.8 5), 43.9 (C-4),, 41.0 (C-l), 31.9, 27.2 ( C - l l + C-14), 26.8 (C(CH3)3), 26.1 (C(CH3)3), 25.9 (C(CH3)3),
24.88 (CH3), 22.8, 22.7 (C-12 + C-13), 19.0 (C(CH3)3), 18.5 (C(CH3)3), 18.2 (C(CH3)3), 14.0
(CH3),, -5.1 (SiCH3), -5.6 (SiCH3); HRMS (FAB) [M+H+] calcd for C45H7605Si3: 779.4922,
found:: 779.4922.
OAC7/OTBDMSS (-HS)-Acetic acid
[(l/?,2tf,4tf,5£)-2-(terf-butyldimethyl-TBDPSO^^O^A^-LL 14
silanyloxymethyl)-5-(te/-*-buryldiphenylsilanyloxy)-3,3-di-33
^N1 1 \ ^1 3 methyl-7-oxabicyclo [2.2.1] hept-1 -yl] - [2-(terf-bu
tyldi-/ 4 \\ 61 12
OTBDMSS methylsilanyloxymethyl)cyclohex-enyl] methyl ester (36). Too a solution of alcohol 35 (150 mg, 0.18 mmol) in CH2CI2 (2 mL) was added acetic anhydridee (0.2 mL, 2.1 mmol, 12 equiv) and pyridine (2 mL). The reaction mixture was stirredd at 40 °C for 16 h. The brown solution was concentrated in vacuo and the product was purifiedd by column chromatography (petroleum ether/EtOAc (98:2)) to afford protected triol 366 (132 mg, 0.16 mmol, 89%) as a colorless oil. R/= 0.45 (petroleum ether/EtOAc (19:1)); [a]2 0DD -6.51 (c = 0.97, CHC13); IR 2932, 2858, 1760, 1112, 1068; 'H NMR (400 MHz) 8 7.64
(2H,, d, J= 7.9 Hz, Ar-H), 7.61 (2H, d, 7.9 Hz, Ar-H), 7.44-7.34 (6H, m, Ar-H), 5.75 (1H, s, H-19),, 4.41 (1H, d, J= 12.6 Hz, H-7), 4.32 (1H, dd, J = 6 . 6 , 1.9 Hz, H-2), 4.16 (1H, d, J = 12.66 Hz, H-7), 3.68 (1H, dd, J= 10.0, 4.3 Hz, H-6), 3.51 (1H, dd, J= 10.6, 10.0 Hz, H-6), 3.466 (1H, d, J= 1,8, H-3), 2.36 (1H, s, H-l 1 or H-14), 2.29-2.24 (1H, m, H-l 1 or H-14), 2.11-2.066 (2H, m, H - l l + H-14), 2.04 (3H, s, C(0)CH3), 1.83 (1H, dd, J= 12.6, 6.8 Hz, H-l), 1.66 (1H,, d, 12.6 Hz, H - l ) , 1.58-1.50 (4H, m, H-12 + H-13), 1.37 (1H, dd, J= 10.8, 4.3 Hz, H-5), 1.044 (9H, s, C(Cft)3), 0.96 (3H, s, CH3), 0.91 (9H, s, C(CH3h), 0.83 (9H, s, C(CH3)3), 0.67 (3H,, s, CH3), 0.09 (3H, s, S1CH3), 0.09 (3H, s, SiCH3), -0.02 (3H, s, SiCH3), -0.04 (3H, s, SiCHs);SiCHs); 13C NMR (100 MHz) 8 169.2 (C(0)CH3), 136.7 (C-9), 135.8, 135.7, 134.3, 134.1, 129.6,, 127.5 (Ar), 127.0 (C-8), 92.3 (C-3), 88.2 (C-10), 72.6 (C-19), 71.5 (C-2), 62.9 (C-7), 60.99 (C-6), 57.1 (C-5), 45.9 (C-4), 41.6 (C-l), 26.8 ( C - l l or C-14), 26.7 (C(CH3)3), 26.1 (C(CH3)3),, 25.8 (C(CH3)3), 25.5 (CH3), 23.1 (CH3), 22.7 (C-l 1 or C-14), 22.4 (C-12 or C-13), 20.99 (C(0)CH3), 19.1 (C-12 or C-13), 18.5 (C(CH3)3), 18.0 (C(CH3)3), -5.3 (SiCH3), -5.4
(SiCH3),, -5.6 (SiCH3), -5.7 (SiCH3); HRMS (EI) calcd for C47H7606Si3: 820.4950, found:
820.4888. .
O A c 77 ,OH (-)-(S)-Acetic acid
[(l/f,2J?,45,55)-5-(tert-butyldiphenylsilanyI-T B D P S QS2 A ^ O X<A1 44 oxy)-2-hydroxymethyl-3,3-dimethyl-7-oxabicyclo[2.2.1]hept-l-3 k ^ N . n ' \ / '1 33 yl]-[2-hydroxymethyl-cyclohex-l-enyl)methyl ester (37). To a
OHH solution of diol 36 (42 mg, 51 umol) in MeOH (1 mL) were added a feww crystals of CSA. The reaction mixture colored yellow immediately and decolorized after stirringg for 4 h. Then water was added (5 mL) and the aqueous layer was extracted with Et20 ( 4 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 (petroleum
ether/Et200 (1:3)) afforded diol 37 (23 mg, 39 umol, 76%) as a colorless oil. Rf = 0.27
(petroleumm ether/Et20 (1:3)); [a]20D -14.3 (c = 1.53, CHC13) IR 3385 (br), 2932, 2824, 1757,
1111,, 1069; 'H NMR (400 MHz) 5 7.64-7.57 (4H, m, Ar-H), 7.49-7.35 (6H, m, Ar-H), 5.07 (1H,, s, H-19), 4.34-4.30 (2H, m, H-2 + H-7), 4.28-4.15 (2H, m, H-6 + H-7), 3.58 (1H, d, J = 11.55 Hz, H-6), 3.51 (1H, s, H-3), 2.59-2.54 (1H, m, H-ll orH-14), 2.33-2.26 (1H, m, H-ll or H-14),, 2.16-2.09 (1H, m, H-ll or H-14), 2.03 (3H, s, C(0)CH3), 2.02-1.98 (1H, m, H-ll or H-14),, 1.93 (1H, dd, J= 13.0, 6.7 Hz, H-l), 1.79 (1H, d, J= 12.8 Hz, H-l), 1.66-1.55 (5H, m, H-55 + H-12 + H-13), 1.04 (9H, s, C(Cff3)3), 0.87 (3H, s, CH3), 0.71 (3H, s, CH3); 13C NMR (500 MHz) 8 170.1 (C(0)CH3), 136.4 (C-9), 135.7, 135.7, 133.9, 133.7 (Ar), 132.3 (C-8), 129.7,, 127.7, 127.7 (Ar), 92.2 (C-3), 89.6 (C-10), 71.1 (C-2), 68.8 (C-19), 62.8 (C-7), 60.2 (C-6),, 53.4 (C-5), 43.6 (C-4), 41.4 (C-l), 29.7, 29.4 (C-ll + C-14), 26.8 (C(CH3)3), 26.2 (C-122 or C-13), 25.0 (CH3), 23.5 (CH3), 22.8 (C-12 or C-13), 21.0 (C(0)CH3), 19.0 (C(CH3)3);
HRMSS (FAB) [M+Na+] calcd for C35H48Na06Si: 615.3118, found: 615.3068.
(+)-(2S,3R,5R,lOR,l9S)-Lsictont(+)-(2S,3R,5R,lOR,l9S)-Lsictont 40. To a solution of diol 37 (12
33
mg, 20 umol) in acetone (1 mL) were added NMO (7.0 mg, 60 umol,, 3 equiv) and TPAP (2.1 mg, 6.0 umol, 0.3 equiv). The dark mixturee was stirred for 90 min followed by filtration over a thin padd of silica and exhaustive rinsing with EtOAc. Evaporation of the solvent and column chromatographyy (petroleum ether/Et20 (1:1)) afforded lactone 40 (8.3 mg, 14 umol, 70%) as
aa colorless oil. Rf = 0.60 (petroleum ether/Et20 (1:3)); [cc]21D +26.7 (c = 1.29, CHC13); IR
3070,, 2935, 2859, 1761, 1744, 1671, 1235, 1112, 1025; 'H NMR (400 MHz, C6D6) 8 7.68
(2H,, d, J= 7.9 Hz, Ar-H), 7.62 (2H, d, J= 7.9Hz, Ar-H), 7.20-7.11 (6H, m, Ar-H), 4.60 (1H, s,, H-19), 4.40 (1H, dd, J= 11.2, 4.6 Hz, H-6), 4.23 (1H, dd, J= 6.6, 1.4 Hz, H-2), 4.10 (1H, dd,, J = 11.2, 8.4 Hz, H-6), 3.52 (1H, s, H-3), 2.89-2.78 (1H, m, H-l 1 or H-14), 2.21-2.14 (1H, m,, H-ll or H-14), 2.09-2.00 (2H, m, H-ll + H-14), 1.95 (3H, s, C(0)CH3), 1.57 (1H, m, H-5),, 1.49 (1H, dd, J= 13.0, 6.7 Hz, H-l), 1.40-1.21 (5H, m, H-l + H-12 + H-13), 1.13 (9H, s, C(CHC(CH33)i),)i), 0.76 (3H, s, CH3), 0.46 (3H, s, CH3); 13C NMR (100 MHz, C6D6) 8 172.8 (C-7), 170.88 (C(0)CH3), 163.1 (C-9), 136.8, 136.6, 135.0, 135.5 (Ar), 134.5 (C-8), 130.9, 130.9, 129.2,, 129.1 (Ar), 93.7 (C-3), 88.0 (C-10), 80.7 (C-19), 72.6 (C-2), 63.0 (C-6), 54.3 (C-5), 42.77 (C-4), 41.9 (C-l), 27.7 (C(CH3)3), 24.1 (CH3), 23.5 (CH3), 22.7, 22.6 (C-ll + C-14),
22.66 (C(0)CH3), 21.3, 21.3 (C-12 + C-13), 19.8 (C(CH3)3); HRMS (FAB) [M+H+] calcd for
C35H4506Si:: 589.2985, found: 589.2971.
OACC 7 ^OH OS)-Acetic acid
[(lR,2K,4i?,5S)-2-(terr-butyldimethylsUanyloxy-TBDPSO«^AioX^i== M me
thyl)-5-(fórt-butyldiphenylsilanyloxy)-3,3-dimethyl-7-oxa-33
> r N1 1^ ^1 3 bicyclo[2.2.1]hept-l-yl]-(2-hydroxymethylcyclohex-l-enyl)-44
OTBDMS methyl ester (43). A solution of protected triol 36 (197 mg, 0.24
mmol)) in MeOH (5 mL) was cooled to 0 °C and a few crystals of CSA were added. The mixturee was stirred at 0 °C for 3 h and water (6 mL) was added. The aqueous layer was 54 4
extractedd with Et20 (3 x 25 mL). The combined organic layers were washed with brine and subsequentlyy dried on Na2SC>4 and the solvent was removed in vacuo. Column chromatographyy (petroleum ether/Et20 (1:1)) afforded alcohol 43 (143 mg, 0.20 mmol, 84%)
ass a colorless oil. Rf = 0.47 (petroleum ether/Et20 (1:2)); 'H NMR (400 MHz) 5 7.65-7.60
(4H,, m, Ar-H), 7.45-7.36 (6H, m, Ar-H), 5.92 (1H, s, 19), 4.33 (1H, dd, J= 6.6, 1.5 Hz, 2),, 4.29 (1H, d, J= 11.6 Hz, 7), 3.76 (1H, d, 7 = 11.6 Hz, 7), 3.60-3.51 (3H, m, 3 + H-6),, 2.52-2.47 (1H, m, H-ll or H-14), 2.13-2.06 (2H, m, H-ll + H-14), 2.05 (3H, s, C(0)C//5), 1.922 (1H, dd, J= 12.8, 6.7 Hz, H-l), 1.89-1.83 (1H, m, H-ll or H-14), 1.76 (1H, d, J= 12.8 Hz,, H-l), 1.70-1.54 (4H, m, H-12 + H-13), 1.40 (1H, m, H-5), 1.04 (9H, s, C(C#j)3), 0.98 (3H,, s, CH3), 0.83 (9H, s, C(Cf/3)3), 0.69 (3H, s, CH3), -0.02 (3H, s, SiCH3), -0.04 (3H, s,
SiCHs);SiCHs); HRMS (FAB) [M+H+] calcd forC4iH62Na06Si2: 729.3983, found: 729.3956.
OAC7[^°° (S)-Acetic acid
[(lR,2JÏ,4/ï,55)-2-(terr-butyldimethylsilanyloxy-T B D P S ON2/% A ^ JJ 14 me thyl)-5-(terf-butyldiphenylsilanyloxy)-3,3-dimethyl-7-oxabi-3<K^-S,ii'\/'133 cyclo[2.2.1]hept-l-yl]-(2-formylcyclohex-l-enyl)methyl ester
OTBDMSS (44). To a solution of alcohol 43 (142 mg, 0.20 mmol) in acetone (4 mL)) were added NMO (35 mg, 0.30 mmol, 1.5 equiv) and TPAP (3.2 mg, 9.1 umol, 4.5 mol%).. The dark mixture was stirred for 30 min and was filtrated over a thin pad of silica followedd by exhaustive rinsing with EtOAc. The solvent was removed in vacuo. Column chromatographyy (petroleum ether/Et20 (2:1)) afforded aldehyde 44 (120 mg, 0.17 mmol,
85%)) as a colorless oil. Rf= 0.78 (petroleum ether/Et20 (1:2)); 'H NMR (400 MHz) 5 10.2
(1H,, s, H-7), 7.62-7.57 (4H, m, Ar-H), 7.44-7.35 (6H, m, Ar-H), 6.26 (1H, s, H-19), 4.32 (1H, dd,, J= 1.6, 6.6 Hz, H-2), 3.54-3.52 (2H, m, H-6), 3.46 (1H, s, H-3), 2.39-3.34 (2H, m, H-ll + H-14),, 2.26-2.21 (2H, m, H-ll + H-14), 2.09 (3H, s, C(0)CH3), 1.95 (1H, dd, J= 12.6, 6.7 Hz,, H-l), 1.68-1.47 (5H, m, H-l + H-12 + H-13), 1.41 (1H, dd, J= 7.2, 7.1 Hz, H-5), 1.01 (9H,, s, C(C//j)3), 0.92 (3H, s, CH3), 0.83 (9H, s, C(CH3)3), 0.66 (3H, s, CH3), -0.02 (3H, s, SiCtfj),, -0.04 (3H, s, SiCtf3); 13C NMR (100 MHz) 5 191.0 (C-7), 169.3 (C(0)CH3), 150.9 (C-8),, 136.6 (C-9), 135.6, 135.4, 133.9, 133.7, 129.6, 127.6 (Ar), 92.1 (C-3), 86.6 (C-10), 71.44 (C-2), 71.3 (C-19), 60.2 (C-6), 56.7 (C-5), 45.1 (C-l), 41.5 (C-4), 28.3 (C-ll or C-14), 26.77 (C(CH3)3), 25.7 (C(CH3)3), 25.3 (CH3), 23.1 (CH3), 22.7 ll or C-14), 21.8, 21.2 (C-122 + C-13), 20.7 (C(0)CH3), 18.7 (C(CH3)3), 18.0 (C(CH3)3), -5.73, -5.74 (SiCH3); HRMS
(FAB)) [M+H+] calcd for C4iH6i06Si2: 705.4007, found: 705.4046.
OAc?r^^ OS)-Acetic acid
[(l/?,2/?,4/?,55)-2-(tert-butyldimethylsilanyloxy-TBDPSOV2^OA^!! M me
thyl)-5-(tert-butyldiphenylsilanyIoxy)-3,3-dimethyl-7-oxabi-3lC V ^ i il\/J i 33 cyclo[2.2.1]hept-l-yl]-(2-vinylcyclohex-l-enyl)methylester (45).
OTBDMSS A suspension of methyltriphenylphosphonium bromide (125 mg, 0.355 mmol, 2.1 equiv) in THF (5 mL) was cooled to 0 °C and «-BuLi (0.21 mL of a 1.6 M solutionn in hexanes, 0.34 mmol, 2.0 equiv) was added. The yellow suspension was stirred at 0 55 5
°C°C for 1 h and aldehyde 44 (120 mg, 0.17 mmol) in THF (1.5 mL) was added via a double tippedd needle. The reaction mixture was allowed to warm to rt and stirring was continued for 22 h. Then acetone was added to quench the reaction (color changed from yellow to white) and thee reaction mixture was diluted with Et20 (10 mL). This solution was washed with water (20 mL)) and after separation of the organic layer, the aqueous layer was extracted with Et20 (2 x 155 mL). The combined organic layers were washed with brine and subsequently dried on Na2SC>44 and the solvent was removed in vacuo. Column chromatography (petroleum ether/EtOAcc (3:1)) afforded alkene 45 (97 mg, 0.14 mmol, 81%) as a colorless oil. Rf= 0.84
(petroleumm ether/Et20 (1:2)); 'H NMR (400 MHz) 8 7.69-7.63 (4H, m, Ar-H), 7.43-7.34 (6H,
m,, Ar-H), 7.03 (1H, dd, J= 17.1, 14.3 Hz, H-7), 5.98 (1H, s, H-19), 5.22 (1H, d, J= 17.1 Hz, C=CHC=CH22),), 5.06 (1H, d, J = 14.4 Hz, C=CH2), 4.33-4.31 (1H, m, H-2), 3.70 (1H, dd, J= 10.1, 4.44 Hz, H-6), 3.59 (1H, s, H-3), 3.52 (1H, dd, J= 10.5, 10.4 Hz, H-6), 2.32-2.15 (4H, m, H-ll ++ H-14), 2.04 (3H, s, C(0)CH3), 1.74-1.52 (6H, m, H-l + H-12 + H-13), 1.39 (1H, dd, J = 10.9,, 4.5 Hz, H-5), 1.02 (9H, s, C(CH3)3), 1.01 (3H, s, CH3), 0.83 (9H, s, C(C//3)3), 0.72 (3H, s,, CH3), -0.02 (3H, s, SiCH3), -0.04 (3H, s, SiCH3); 13C NMR (100 MHz) 8 169.5 (C(0)CH3),
135.88 (Ar), 135.5 (C-7), 135.1, 134.2 (Ar), 134.1 (C-9), 133.0 (Ar), 132.4 (C-8), 129.5, 127.7, 127.66 (Ar), 112.8 (C=CH2), 92.4 (C-3), 88.5 (C-10), 72.6 (C-19), 71.6 (C-2), 61.2 (C-6), 57.4
(C-5),, 46.7 (C-l), 41.7 (C-4), 30.3, 27.5 (C-l 1 + C-14), 26.8 (C(CH3)3), 25.8 (C(CH3)3), 25.7
(C-122 or C-13), 25.5 (CH3), 23.2 (CH3), 22.7 (C-12 or C-13), 20.9 (C(0)CH3), 19.0
(C(CH3)3),, 18.0 (C(CH3)3), -5.70, -5.71 (SiCH3); HRMS (FAB) [M+H+] calcd for
C42H6305Si2:: 703.4214, found: 703.4186.
OAcc 7r*^ (5)-Acetic acid [(l/?,2/?,4/?,55)-5-(tert-butyldiphenylsilanyloxy)-TBDPSOvp^ioX#A1 44
2-hydroxymethyl-3,3-dimethyl-7-oxabicyclo[2.2.1]hept-l-yl]-(2-33 ^L^S.11 \ ^1 3 vinylcyclohex-l-enyI)methyl ester (46). To a solution of olefin 45 44
OH (96 mg, 0.14 mmol) in MeOH (5 mL) were added a few crystals of CSA.. The reaction mixture was stirred at rt for 6 h. Saturated aqueous NaHC03 was added
andd the organic layer was separated. The aqueous layer was extracted with Et20 ( 3 x 1 0 mL) andd the combined organic layers were washed with brine and subsequently dried on Na2SC"4. Evaporationn of the solvent and column chromatography (petroleum ether/Et20(l:l)) afforded alcoholl 46 (17 mg, 28 umol, 20%) as a colorless oil and alcohol 47 (33 mg, 56 umol, 40%). RRrr4646 = 0.38 (petroleum ether/Et20 (1:2)); 'H NMR (400 MHz) 8 7.68-7.63 (4H, m, Ar-H),
7.44-7.366 (6H, m, Ar-H), 7.02 (1H, dd, J= 16.5, 10.9 Hz, H-7), 6.19 (1H, s, H-19), 5.24 (1H, d,, J= 16.6 Hz, C=CH2), 5.07 (1H, d, J = 10.8 Hz, C=CH2), 4.30 (1H, dd, J= 6.5, 1.6 Hz, H-2),, 3.71 (1H, d d , J = 11.2, 7.0 Hz, H-6), 3.60 (1H, d d , J = 11.1, 6.6 Hz, H-6), 3.53 (1H, d, J = 1.55 Hz, H-3), 2.36-2.16 (4H,m, H-ll + H-14), 2.04 (3H, s, C(0)CH3), 1.95 (1H, d, J= 12.7 Hz,, H-l), 1.79 (1H, dd, J= 12.9, 6.4 Hz, H-l), 1.62-1.49 (4H, m, H-12 + H-13), 1.46- 1.43 (1H,, m, H-5), 1.04 (9H, s, C{CH3)3), 0.90 (3H, s, CH3), 0.71 (3H, s, CH3). 56 6
[(lJ?,2/?,4/?,55)-Aceticc acid 5-(tert-butyldiphenylsilanyloxy)-l-TBDPSO^A^A^^II 14
[(S)-hydroxy-(2-vinylcydohex-l-enyl)-methyl]-3,3-dimethyl-7-J133 oxabicyclo[2.2.1]hept-2-ylmethyl ester (47). i?/-47 = 0.71 OACC 12 (petroleum ether/Et20 (1:2)); 'H NMR (400 MHz,) 8 7.69-7.63
(4H,, m, Ar-H), 7.43-7.34 (6H, m, Ar-H), 7.03 (1H, dd, J= 17.3, 10.9 Hz, H-7), 5.25 (1H, d, J == 17.3 Hz, C=CH2), 5.03 (1H, s, H-19), 5.02 (1H, d, J = 10.9 Hz, C=CH2), 4.35 (1H, dd, 7 = 11.5,, 7.2 Hz, H-6), 4.30 (1H, dd, J= 6.5, 2.0 Hz, H-2), 4.09 (1H, dd, J= 11.5, 7.7 Hz, H-6), 3.577 (1H, d, J = 1.9 Hz, 3), 2.55-2.47 (1H, m, l 1 or 14), 2.37-2.15 (3H, m, l 1 + 14),, 2.00 (1H, s, C(0)C//j), 1.87 (1H, d, J= 12.8 Hz, l), 1.80 (1H, dd, J= 12.9, 6.6 Hz, H-1),, 1.69-1.47 (4H, m, H-12 + H-13), 1.43-1.41 (1H, m, H-5), 1.02 (9H, s, C(CH3)3), 0.91 (3H, s,, Ctfj), 0.71 (3H, s, CH3).
3.77 References and Notes
11 For recent studies towards vinyl inflate 2, see: a) Blaauw, R. H.; Brière, J.-F.; de Jong, R.;; Benningshof, J. C. J.; van Ginkel, A. E.; Rutjes, F. P. J. T.; Fraanje, J. Goubitz, K.; Schenk,, H.; Hiemstra, H. J. Chem. Soc, Chem. Commun. 2000, 1463; b) Blaauw, R. H.;; Brière, J.-F.; de Jong, R.; Benningshof, J. C J.; van Ginkel, A. E.; Fraanje, J.; Goubitz,, K.; Schenk, H.; Rutjes, F. P. J. T.; Hiemstra, H. J. Org. Chem. 2001, 66, 233; c)) Brière, J.-F.; Blaauw, R. H.; Benningshof, J. C. J.; van Ginkel, A. E.; van Maarseveen,, J. H.; Hiemstra, H. Eur. J. Org. Chem. 2001, 2371; d) Blaauw, R. H.
IntramolecularIntramolecular [2+2] Photocycloadditions as an Approach towards the Right-Hand SideSide of Solanoeclepin A, PhD-Thesis, University of Amsterdam, 2001.
22 For the synthesis of 8, see: Piers, E.; Tse, H. L. A. Can. J. Chem. 1993, 71, 983. 33 For reviews on the acyloin condensation, see: a) McElvain, S. M. Org. React. 1948, 4,
256;; b) Ruhlmann, K. Synthesis 1971, 236; c) Bloomfield, J. J.; Owsley, D. C ; Nelke, J.. M. Org. React. 1976, 23, 259 and references cited therein.
44 Leonard, N. J.; Robinson, G. C. J. Am. Chem. Soc. 1953, 75, 2143.
55 Totten, E. L.; Freeman, R. C ; Powell, H.; Yarboro, T. L. J. Org. Chem. 1961, 26, 343. 66 a) Bowers, K. W.; Giese, R. W.; Grimshaw, J. G.; House, H. O.; Kolodny, N. H.;
Kronberger,, K.; Roe, D. K. J. Am. Chem. Soc. 1970, 92, 2783; b) Caine, D. Org. React.React. 1976,23, 1.
77 For a review on the McMurry coupling, see: a) McMurry, J. E. Chem. Rev. 1989, 89, 1513;; b) Lenoir, D. Synthesis 1989, 883; c) Fürstner, A.; Bogdanovic, B. Angew. Chem.Chem. Int. Ed. 1996, 35, 2442 and references cited therein.
88 a) Nicolaou, K. C ; Yang, Z.; Liu, J. J.; Ueno, H.; Nantermet, P. G.; Guy, R. K.; Claiborne,, C. F.; Renaud, J.; Couladouros, E. A.; Paulvannan, K.; Sorensen E. J. NatureNature 1994, 367, 630; b) Nicolaou, K. C ; Guy, R. K. Angew. Chem. Int. Ed. 1995, 34,34, 2079.
99 Kato, N.; Takeshita, H. J. Chem. Soc, Perkin Trans. 1 1989, 165.
100 a) Hirao, T.; Asahara, M.; Muguruma, Y.; Ogawa, A. J. Org. Chem. 1998, 63, 2812; b)) Hirao, T.; Takeuchi, H.; Ogawa, A.; Sakurai, H. Synlett 2000, 1658; c) Groth, U.; Jeske,, M. Synlett 2001, 129.
111 For a review on chromium(II) and chromium(III)-niediated couplings, see: a) Wessjohann,, L. A.; Scheid, G. Synthesis, 1999, 1; b) Fürstner, A. Chem. Rev. 1999, 99,991. .
122 Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki, H. Tetrahedron Lett. 1983, 24,24, 5281.
133 Knochel, P.; Rao, C. J. Tetrahedron 1993, 49, 29.
144 Takai, K.; Tagashira, M.; Kuroda, T.; Oshima, K.; Utimoto, K.; Nozaki, H. J. Am.
Chem.Chem. Soc. 1986,108, 6048.
155 Jin, H.; Uenishi, J.-L; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc. 1986,108, 5644. 166 For a review on TPAP oxidations, see: Ley, S. V.; Norman, J.; Griffith, W. P.;
Marsden,, S. P. Synthesis 1994, 639.
177 For a similar oxidation process to a 6-membered lactone, see: Lee, M ; Dceda, L; Kawabe,, T.; Mori,, S.; Kanematsu, K. J. Org. Chem. 1996, 61, 3406.
