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Double Michael reaction of Wieland-Miescher ketone
T
Vol. 5 I. No. 36. pp 989 I-9898, 1995 Copyright 0 1995 Elsewer Science Ltd Prmted m Great Britain. All rights rescrvcd 0040-402O/Y5 $9.50+0.00
Pergamon 0040-3020(05,00566-8
Double Michael
Hisahiro
Hagiwara,*
Reaction
Tetsuji
Okamoto,
of Wieland-Miescher
Nohuyuki
Harada
Ketone
and
IIisashi
Uda
Abstrclct: 1:nolatr of Wieland-Mreccher ketone 1 has reacted with methyl acrylate to give methyl ( IS*,2S*,3R*.hSt)-6-Inethyltricyclo[6.2.~.0*~~]dodecan-7, I2-dionl-carboxylate 5 whose structure has been determined by Xray crystallography after transformation of 5 into sultamamide 8a.
Construction of complex molecular architecture by multt-bond formation tn one pot operation has been one of current interest in synthetic organic chemistry. t Among various possrbilities by using cationic, anionic, radical. photochemical, thermal or organometalllc reaction (‘I(‘., successive carbon-carbon bond forming reaction initiated by inter- or intramolecular Michael reaction has provided a versatile process for making carbocyclic compounds2 Especially. annulation by successive hlichael-Michael procedure (double Michael reaction) has been useful with wide applicability. In order that Michael reaction proceeds successively, proton transfers between enolate and substrate must be suppressed because Michael reaction is essentially reversible. Reaction in aprotic media at low temperature fulfils such requirement. Since at least one intramolecular Michael reaction is required for annulation, Initial Michael donor is destrcd to be bifunctional having ability as a Michael accepter also. Toward thtj end. rcgio- and/or chemosclrctivc generation of enolate is needed on the initial Michael donor. Wieland-hliescher ketone 1 1s a good candtdate for such purpose due to its bifunctionality for Michael reaction. Some ye‘ars ago, Cirieco cr ui. have reported that by treatment with lithium diisopropylamide (LDA) Wieland-Miescher ketone 1 gave selectivrely At.?-enolate 2 which reacted with several electrophiles to give Cor O-alkylated products either in the presence or absence of hexamethylphosphoric triamide (HMPA).j
9892
H. HAGIWARA et ul.
We anticipated that the reaction of the A1,l- enolate 2 with a,P-unsaturated carbonyl compounds could lead to tticyclic compound 4 after successive two Michael reactions (Scheme 1). Enolate generated by treating Wieland-Miescher ketone (i)-1 with LDA at 0 “C? reacted with methyl acrylate to provide ester (3~).5 in 28% yield as a sole isolable product. Structure of the prtxluct of present reaction could not be determined rigorously, because it was difficult to discriminate the structure of the ester (?)-5 from another plausible structure of the ester (31-4 by spectroscopic means. An attempt to get the ester (+)-5 by alternative route have failed, in which monoprotected Wieland-Miescher ketone (+)-6 did not give any annulation product contrary to the successful result of similar system.5 Scheme I
2 iI
3 ii
path a I
path b 1
6 ewe
(i).5
Reagents and rnrulirinns: i, LDA, THF, 0 “C; ii, methyl acrylate, 0 “C to room temperature. X-Ray structure analysts was then carried out. Since the ester (+_)-5 was obtained as amorphous solid, we applied the following camphorsultam amide method.6 One of the authors recently reported that (lS,2R,4R)(-)-camphor sultam 7 was a very useful chiral auxiliary for optical resolution by HPLC and also for X-ray crystallographic determination of the absolute configuration of carboxylic acids. The camphorsultam amide method has the following advantages; i) a diastereomeric mixture of camphorsultam amides is easily separable by HPLC on silica gel; ii) camphorsultam amides generally crystallize as large prismatic crystals;
Double Michael
reaction of Wieland-Miescher
ketone
9893
iii) the absolute configurations of the amides obtained can be determined by the X-ray Bijvoet method and also by the internal reference method using the camphor part with known absolute configuration. Scheme 2 0
”
Reagents and condirion.s: i. ‘rq L NaOH, EtOfI, retlux; ii. SOCI~, room temperature; iii, KaH, benzene, d-camphorsultam 7, room temperature; iv, resolution by medium pressure LC. The ester (f)-5 was hydrolyzed to give carboxylic acid which was then converted to acid chloride (Scheme 2). The reaction of the acid chloride obtained with the anion of 7 afforded a diastereomeric mixture of sultamamides 8a and Xb, which was easily separable by medium pressure LC (MPLC) on silica &eL (hexane/EtOAc 1: 1). Less polar diastereomer Xa was recrystalized to give colorless prisms which were subjected to X-ray crystallography. The crystals were found to be monoclinic and the space group to be P21. which indicates As illustrated in Figure I, amide 8a has a skeleton of tricyclo[h.2.2.0 1.6ld(xlecan-7,12-dione, that the double Michael reaction proceeds via path b shown in Scheme 1. The absolute stereochemistry of 8a was determined to be (lR,2R,4s,sR,l’s,2’R,4’R) by the anomalous dispersion effect of sulfur atom. The absolute configuration determined was confirmed by the internal reference method using the camphor part. Figure 1
8a
9894
H.
HAGIWARA
et d.
The more polar diastereomer Xb was converted into ester (lS,2S,4R$S)-5 (Scheme 3). The sultamamide 8b was reduced with lithium aluminiumhydride (LAH) to give in 75 % yield trio1 which was oxidized with Jones reagent. Estetificstion of the resulting keto-acid with diazomethane furnished in 3X % yield (lS,2S,4/?,6.~)-5 which exhibited weak hut distinct Cotton effects in the CD spectrum: hext 304 nm, AF ~ 1.11, 294 nm, Ae -1 .I 3 and 216 nm, Ac +I .h7. Since the absolute configuration of the less polar diastereomer Xa was determined by X-ray crystallography, established to be (lS,2S,4K,hS). Scheme 3
RCU~EIZ~S
mtl
the absolute configuration
0 i,
r,,>rltiirior~c: I. LAH. TI IF: II. Jmrs
of [CD(-)304]-5’
was
0
reagent, acetone, 0 “C: iii, diazomethane,
Et20
order to get insight on the reaction parhu ;I). semiemptrical molecular orbital calculation by MOPA@ was carried out employing Ah11 Hamiltonian 111precise mode and revealed the preferential formation of the ester (k)-5 rather than the ester c&)-4. S-CIS conformation was chosen for methyl acrylate from observed relative sterecxhemistry of the ester 5. Calculated heat of formation of At.2- enolate 2 (AC H” -90.3X kcal mol-‘) and the A6,7-enolate 3 (Af Ho -84.79 kcal mol-t) indicated that the At.?- enolate 2 was thermodynamically more stable (more than 99.9% popul;ltion) providing that effect of salvation was came in both enolates 2 and 3. Actually, only A1,2-enolate 2 In
was trapped by u\ in iO? yield ah sllylenoi ether3 whose structure was apparent from its carbonyl absorption (V I671 cm’) in IR spectrum. On the other h.md. the smallest atomic orbital electron population of the 7x*-H among other protons CI to cvrhonyl groupi; .~lludcd LinetIc generation of the enolate 3. Cocfficientk of f lOML10 of the Ahs7-enol,l:c 3 at bolh reacting termini, C-7 and C-4a, were +0.783 and -O.lG, respecrlvely as shown 111Figure 2. 011 the other hand, f-1OMO of the At,‘-enolate 2 exhibited coefficients of +(I.793 and +().(X)6 at C-2 and (‘-4a, respectively. Providing that the second Michael addition occurred concurrently (differcncc between double Michael KS anion accelerated Diels-Alder reaction is subtle’), these results indicated that the present double Michael rraction proceeded from the A6,7-enolate 3, because the coefficient at C4a of the ;I’.2 -en&ire 2 &;I\ t(x) small and moreover the sign of the coefficient at C-4a was opposite to correlate wtth cx-c,lrhon of LUhlO of methyl acrylate Smaller energy gap between HOMO of the A6.7-enolate 3 and LLJMO of methyl acrylate (2E 2.59 eV) than that of the At ,2-enolate 2 (AE 2.87 eV) would also favor annulation from the Ah,‘-enolate 3. Though the At.?- enolate 2 was trapped by C- or 0-alkylation as noted in the work of Grieco of al..3 mode of present annulation pia path b to give the ester 5 was understood by frontier orbital theory.
Double IMIchael reaction of Wieland-Micscher
Figure 2
ketone
9895
HOMO of Er:olates 2 and 3 -0.489
+0 008
t +0 006 -0 024 [-2 62 eV] 2
+0.0003 [-2.54 eV] LllhlO
of .Methyl AU), late
3
\,I.@&+062 -o 42
[+0.049 eV]
Stereochemical course of the present reaction was explained by chelation control. Methyl acrylate approached to the Ah,‘-enolate 3 from less hindered a-face. After taking S-cis conformation by chelation of oxygen of ester carbonyl of methyl acrylate with Li cation on the A fi.%nolate 3. the double Michael reaction proceeded concurrently to afford the ester 5 In summary, we have shown that the douhlc xlich:irl reaction of Wiel;md-Mirscher ketone 1 with methyl acrylxe have proceeded from the Ah.‘- enolate 3 IYU p;lth b to gi\e the tricyclic ester 5 in symmetry allowed manner. Acknowledgment. ?‘hi\ \borj\ M;I\ xuppo~-ted ln part hy c(‘rants from the xlinistry of Education, Science, and Culture, Japan (General (1~1 No. Ol370016. I’rio~-~t) Area\ Nos. 01648501, 02230701, and 03214107, and Developmental Research No 0555101? to N 11 j
Experimental
All m.p.s were determined with ;I 51itamura Riken hot-qt;ige appxxtu\; and uere tlncorrected. IR spectra were recorded on a JASCO FT/lR-X300 ~pectrophotometcr for solutions in chloroform. ‘H h’MR spectra were obtained for solutions in deuterlc~chloroform with JEOLFX 9OQ (90 hlHz) or Bruker MSL-300 (300 MHz) instrument with tetramethylcllant xc internal st:tnd;ud. Mass spectra were run on a JEOL JMS-DX300 spectrometer with a JMA-?500 tl,~ra system. Circular dlchroic apectnrni wxs measured on a JASCO J-400X spectrophotometer. IIltraviolet qeztrurn \\a, obtained OII 3 JASCO l!he.\t-50 spectrophotometer. MPLC was carried out on a JASCO PRC-50 lnbtrument with a silica gel pached column. Anhydrous sodium sulfate was used for drying organic extr;tctL;. J‘IIF W;IS distilled from hcnzophenone kctyl before use.
9896
H. HAUWAKA
PI (il.
Mcrh~i (lS*,2S*,4R*.hS*)-6-~~~(,~~l~ltri[,~[ 1~~~6.7.7.O1~~~rfo~fec~ur~-7,l2-dion-2-carho.~~late 5.To a stirred solution of LDA, prepared from cilisopropyl~~rnine (0.182 cm?, 1.3 mmol) and butyllithium (0.74 cm3, 1.6.5 mol dm3 in hexane, I .2 mmol) in TIFF (1 cmj). was added racemic Wieland-Miescher ketone 1 (I75 mg, I mmol) in THF (2 cm3) at 0 “C. The resulting solution became black and curdy. After being stirred for 20 mm, methyl acrylate (0.15 cm.j, 1.67 mmolj was added and stirring was continued overnight warming gradually to room temperature. The reaction was quenched by addition of aq. ammonium chloride and the product was extracted with ethyl acetate twice. Combined organic layers were washed with brine and evjaporated to dryness in KKUO. The residue was purified by MPLC ]eluent hexane:ethyl acetate (1: I)] to give the tricyclic ester 5 (74.4 mg. 28%); vmax/cm -I 3027, 2955, 172X, 1456, 143X. 1231, 1198, and 1173; 6(3OO MHz) 1.1X (3 H, s, hlej. I.35 (IH, ddd, .I 14.2, 4.3 and 2.9 Hz), I.5 2.21 (IH, dd. .I I9 and 2.2 III). 2.36 (111, dm. ./ I3 Hz) , 2.43 (IH, and 2 Hz), 3.01 (Ill, d, .I 19 Hz) and 3.7 (311, sj; rn:z 265 CM+ + (h9), lhO(1OOi, 145 (21) 121 (1x1 and SS (19’1 (Found:M +, 263.1359
(IH, d,./ 13 Hz), 1.X5-2.15 (SH, m), m), 2.7 (2H, m), 2.79 (IH, dd, J 14.3 1, 3%). 264 CM+, 16), 178 (Sh), 163 ClSH2004 requires m/z, 264.13615).
( IR*,3R*,3S*,6R*)-h-.U~~~~~~~~ri~~~~/~)[6.2.2.(~t~hl~i~~d~~~.~~~~-7, I2-dion-2-carhoxunlidc N-(l’S,2’R,4’R)_ 8a and 8b. --A solution of the tricyclic ester 5 (61.7 mg, 0.234 mmol) in aq. sodium hydroxide (I cm3, 1 mol dmij and ethanol (3 cm“) was heated under reflux for I.5 h under nitrogen. After being cooled to room temperature. hydrochloric acid (I mol dn-‘) was added. The product was extracted with ethyl acetate twice and combined organic layers were washed with brine. Evaporation of the extract afforded fine crystals of (lR*,2R*.4S*,hR”)-h-m~~f/~~~fri~~~~~~~~[6.2.2.Oi~h~dodecan-7,12-dion-2-carhox~lic acid (55.5 mg, 9S70) : Vmax/CTll -t 2956, 1708, 146h,~l3S6. 1309, 1322, 123.5, II86 and 909; 6 (90 MHz) 1.19 (3 H, Me), l.l--3.1 (I-1 II, mj and X.1 (I H, br. CO2H): m/i 251 (M+ +I , X%z), 250 (M+, 40) 178 (64), 163 (78), I60 (l(H)), 14s (35j and 55 (40) (Found:M +, 250.12034. CI4H I X04 requires m/z , 250.1205). ~czn~p/z~)r.sulf~lrr~
A solution of the acid (?7.2 mg, O.lS mmol) m thionyl chloride (0.5 cm3) was stirred at room temperature for I h. Excess thionyl chloride w,ts ev aporatetl ili ~UUO and the residue was used for further reaction without purification To a stirred suapen\ior of \cxiium hydride i I1 mg, hO’%( 0.3 mmol) in benzene (0.S ~111~) was added crystals of d~c;tmptlor~ultam (63 9 mg. 0.3 mmol) at room temperature under nitrogen. After being stirred for 1 h, a solution of acid chloride in benzene (2 cm3j was added at 0 “C and the resulting solution was stirred at room temperature for 3 h. The reaction was quenched by addition of water followed by hydrochloric acid (1 mol dm-3). The product was extracted with chloroform three times. Organic layers were washed with brine. Evapor,ttion of the extract followed by MP1.C separation [eluent hexane:ethyl acetate (l:l)] provided recovered tf-calnphorsultain (1.5.3 mg). Icss polar diasterromer Xa (10. I mg, 15%) and more polar diastereomer Sb (1 X.6 mg. 2X%). I.esr polar diastereomer 8a had: n1.p. 250 “C (decomposition); vmaxlcm-’ 364, 23SY. 2342, 1708, 1455. 1313. 13.3X. 1305. 1237, 1 I66 and 1133: 6 (i(X) MHz) 0.94 (3 H, s, Me), 1.09 (3 H, s, Me). I.15 (3 H, s, Me), 1.2 ~~l.S(~ll, mj, 1.5-1.75 (4H, m), 1.X-2.15 (lOH, m), 2.84 (11~. d, .I 14.3 Hz), 3.03 (111, t. .I X.9 llzj. 3.32 (ItI. d../ 19.3 Hzj, 3.43 (111, d,J 13.8 Hz), 351 (IH, d,J 13.X Hz) and 3.X7 (Ill. t. .I 6.5 tlrj : m/z 31X (hl+ + I. 8%). 447 (>I+, 23), 270 (3X), 232 (41) 204 (46). 161 (52j, I60 (IOOt. 136 tit)). I35 (601. 121 (.Jlj. 93 (35) and 55 (53) (Found:M+, 447.20767. Cz~Hii05NS requires \I. 417 20793) ‘\I~NY polar diasterromer 8h was recryatalized from chloroform and
Double Michael
hexane; mp. 22(&240
I-caction of Wteland-fvllcscher
ketone
9897
“C: ~~~~~,x/crn~I 2064. 23SY. 2343, 1712. 1356, 1413, 1338, 1264, 1236, and 1133;
6 (90 MHz) 0.9X (3 H, s. Me), 1.13 (6 II, br s. Me x 2) and l.(L3.0
(24 H, m); m/z 448 (M+ + 1, 7%).
447 (M+, 23), 232 (33). 204 (S6), 178 (33), I63 (Y(I), I62 (27). 160 (IO()), (Found:M+, 437.20776. C~~ll;~OsNS requires M. 447.20793). X-ray CQWZ~ Srrucrurr D~~UVIUUULUI c,fAmitk~ Xa recrystalization of amide 8a from chloroformfiexane.
135 (47) and 5.5 (44)
Single crystals were obtained as colorless prisms by A crystal (dimension 0.30 x 0.23 x 0.08 mm) was
selected for data collection and mounted on a Rigaku AFC-6B automated four circle diffractometer. The crystal was found to be monoclinic, and the unit cell parameters and orientation matrix were obtained. Data collection was carried out by using a 20-O scan: formula, C2df-I33NOgS; formula weight, 447.60; space group P21; a = 13.X8X (2) A, b = 6.9646 (5) A, c = 11.396 (2) A, !3 = 90.46 (I)‘. vol = 11 1 I.9 (2) A3; 2 = 2: p(calcd) = 3.337 g/cm3: p(obsd) = 1.340 g/cm3 (by flotation urn g a CCla-hexane solution); radiation, Cu Kn (1.54178 A): monochrometor, graphite crystal: linear absorption coefficient, 14.X3 cm-t; temperature, 20 “C; scan type, 2&O; scan speed, 2.0C/minute; scan range, 1.3” + 0.3’ tan H; 28 scan limits, 2-IW; standard reflections, 3 per SO reflections; indices. (0,1,1). t-3,0,2), (2,O.l): crystal stability, no indication of standard reflection decay during data collection; total reflections scanned. 2 163; unique data F. > 3.0 o(F,), 1910. The position of the most non+hydrogen atoms were found by the direct method, and then those of the remaining non-hydrogen atom\ were found by successive Fourier syntheses. All hydrogen atoms were found by the difference Fourier syntheses Full matrix le:lat-squares refinement of positional parameters and anisotropic thermal parametera for non-hydrogen atom\, including anomalous scattering factors of sulfur, oxygen, nitrogen and carbon atoms, led to the final convergence with R = 0.0402 and Rw = 0.0440 (final no. of variables, 379) for the (1R.~R,4S,6R,1’S,Z’R,3’R) the mirror image structure gave R = 0.03 14 and
R
absolute configuration, while a similar calculation for w = 0.03.57. In the full matrix least-squares calculation, the
isotropic thermal parameters of hydrogen atoms were not included as variables in the refinement, but calculated from the thermal parameters of the non-hydrogen atom\ to which the hydrogen atoms were attached. The absolute configuratlon of the sul~am amide of Xa I=V~~Y determined as illustrated in Figure 1 and formula 8a. The (IR.ZR,4S,6S) absolute configuration of the ~iiketo-carhoxylic part way also assigned by using the (1’S,2’R,4’R)-~-)-2,1O-camphorst~ltam part as an inter-nal reference of the absolute configuration. The lists of atomic parameters, bond lengths and hond angles of Xa are deposltcd at the Cambridge Crystallographic Data Center. The list of observed and calculated structure factors may be obtained from one of the authors (N.H.) upon request. McthJl (1 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 12-tiion-2-c.orholute 5.More polar diastereomer of the ~ultam amide Xb (hi mg, 0.14 mmol) In THF (5 cm3) was added LAH (40 mg, 1.08 mmol) at 0 “C under nitrogen. After being stirred for I h at room temperature, the reaction was quenched by addition of aq. ammonium chloride. Usual work up followed by flash chromatography gave trio1 (2S.2 mg, 75%). To a stirred solution of the trio1 (25.2 mg, 0.10.5 mmol) in acetone (4 cm3) was added Jones reagent dropwise at 0 “C. After being stirred for 30 min. the product was extracted with ethyl acetate twice. Organic
layers were treated with ethereal solution of diazomethane.
Evaporation of the mixture followed by repeated
9898
H. HAGIWARA
ft al.
(twice) MPLC purification of the residue afforded the tricyjclic ester 5 (10.6 mg, 38%) which crystallized spontaneously (m.p. 113.5.-l 14.5 “C); UV (EtOH) 1 max 295.6 (E 60) and 200 nm (P 1,000, end absorption); CD (EtOH) &xt 304 (AF -1.11). 294 (A& -1.13) and 216 nm (A& +1.67).
References 1. 2.
3. 4. 5. 6.
7. 8.
Tietze, L. F.; Beifuss, U. Anger. Chrm Inr. Ed. EngI. 1993,32. 131. Ihara, M.; Fukumoto, K. Angew. Chem. Inr. Ed. Engl. 1993,32, 1010; Hagiwara, H. J. Synrh. Org. Chem. Sot., Jpn. 1992.50, 713; Posner, G. H. Chem. Rev. 1986, 86, 831; Ihara, M.; Fukumoto, K. J. Synrh. Org. Chem. Sot., Jpn. 19X6,44, 96. Grieco. P. A.; Fertino, S.; Oguri, T. j. Org. Chem. 1979.44, 2593. Addition of Wieland-Miescher ketone to LDA at -78 “C gave solid which did not provide any annulation product even after warming up to room temperature. Weber, W.; Spitzner. D.: Kraus, W. .I. Chcm. Sot. C/rem. Common. 19X0, 1212; Spitzner, D.; Sawitzki, G. .1. Chcwl. SM. Perkin I 1988, 371. Harada. N.; Soutome. T.: Murai, S.: Uda, II. Tetruhudron: Asymm. 1993,4, 1755; Harada, N.; Hattori, T.; Suzuki, T.: Okamura, A.; Otto, 11.; Miyano, S.; Uda, H. Tetrahedron: Asymm. 1993, 4, 1789; Harada, N.; Soutome, T.; Nehira, T.; Uda, H.; Oi, S.; Okamura, A.; Miyano, S. .I. Am. Chem. sot. 1993, I IS, 7547. The prefix (CD(-)3041 indicates an enantiomer showing a negative CD Cotton effect at 304 nm. AM1 calculation was carried out wjith Apple Macintosh [MOPAC Ver. 6.00, Stewart, J. J. QCPE Bull. 1990, 20(4), 861.
(Received in Jupun 10 April 1995; accepted IO July 1995)
Vol. 5 I. No. 36. pp 989 I-9898, 1995 Copyright 0 1995 Elsewer Science Ltd Prmted m Great Britain. All rights rescrvcd 0040-402O/Y5 $9.50+0.00
Pergamon 0040-3020(05,00566-8
Double Michael
Hisahiro
Hagiwara,*
Reaction
Tetsuji
Okamoto,
of Wieland-Miescher
Nohuyuki
Harada
Ketone
and
IIisashi
Uda
Abstrclct: 1:nolatr of Wieland-Mreccher ketone 1 has reacted with methyl acrylate to give methyl ( IS*,2S*,3R*.hSt)-6-Inethyltricyclo[6.2.~.0*~~]dodecan-7, I2-dionl-carboxylate 5 whose structure has been determined by Xray crystallography after transformation of 5 into sultamamide 8a.
Construction of complex molecular architecture by multt-bond formation tn one pot operation has been one of current interest in synthetic organic chemistry. t Among various possrbilities by using cationic, anionic, radical. photochemical, thermal or organometalllc reaction (‘I(‘., successive carbon-carbon bond forming reaction initiated by inter- or intramolecular Michael reaction has provided a versatile process for making carbocyclic compounds2 Especially. annulation by successive hlichael-Michael procedure (double Michael reaction) has been useful with wide applicability. In order that Michael reaction proceeds successively, proton transfers between enolate and substrate must be suppressed because Michael reaction is essentially reversible. Reaction in aprotic media at low temperature fulfils such requirement. Since at least one intramolecular Michael reaction is required for annulation, Initial Michael donor is destrcd to be bifunctional having ability as a Michael accepter also. Toward thtj end. rcgio- and/or chemosclrctivc generation of enolate is needed on the initial Michael donor. Wieland-hliescher ketone 1 1s a good candtdate for such purpose due to its bifunctionality for Michael reaction. Some ye‘ars ago, Cirieco cr ui. have reported that by treatment with lithium diisopropylamide (LDA) Wieland-Miescher ketone 1 gave selectivrely At.?-enolate 2 which reacted with several electrophiles to give Cor O-alkylated products either in the presence or absence of hexamethylphosphoric triamide (HMPA).j
9892
H. HAGIWARA et ul.
We anticipated that the reaction of the A1,l- enolate 2 with a,P-unsaturated carbonyl compounds could lead to tticyclic compound 4 after successive two Michael reactions (Scheme 1). Enolate generated by treating Wieland-Miescher ketone (i)-1 with LDA at 0 “C? reacted with methyl acrylate to provide ester (3~).5 in 28% yield as a sole isolable product. Structure of the prtxluct of present reaction could not be determined rigorously, because it was difficult to discriminate the structure of the ester (?)-5 from another plausible structure of the ester (31-4 by spectroscopic means. An attempt to get the ester (+)-5 by alternative route have failed, in which monoprotected Wieland-Miescher ketone (+)-6 did not give any annulation product contrary to the successful result of similar system.5 Scheme I
2 iI
3 ii
path a I
path b 1
6 ewe
(i).5
Reagents and rnrulirinns: i, LDA, THF, 0 “C; ii, methyl acrylate, 0 “C to room temperature. X-Ray structure analysts was then carried out. Since the ester (+_)-5 was obtained as amorphous solid, we applied the following camphorsultam amide method.6 One of the authors recently reported that (lS,2R,4R)(-)-camphor sultam 7 was a very useful chiral auxiliary for optical resolution by HPLC and also for X-ray crystallographic determination of the absolute configuration of carboxylic acids. The camphorsultam amide method has the following advantages; i) a diastereomeric mixture of camphorsultam amides is easily separable by HPLC on silica gel; ii) camphorsultam amides generally crystallize as large prismatic crystals;
Double Michael
reaction of Wieland-Miescher
ketone
9893
iii) the absolute configurations of the amides obtained can be determined by the X-ray Bijvoet method and also by the internal reference method using the camphor part with known absolute configuration. Scheme 2 0
”
Reagents and condirion.s: i. ‘rq L NaOH, EtOfI, retlux; ii. SOCI~, room temperature; iii, KaH, benzene, d-camphorsultam 7, room temperature; iv, resolution by medium pressure LC. The ester (f)-5 was hydrolyzed to give carboxylic acid which was then converted to acid chloride (Scheme 2). The reaction of the acid chloride obtained with the anion of 7 afforded a diastereomeric mixture of sultamamides 8a and Xb, which was easily separable by medium pressure LC (MPLC) on silica &eL (hexane/EtOAc 1: 1). Less polar diastereomer Xa was recrystalized to give colorless prisms which were subjected to X-ray crystallography. The crystals were found to be monoclinic and the space group to be P21. which indicates As illustrated in Figure I, amide 8a has a skeleton of tricyclo[h.2.2.0 1.6ld(xlecan-7,12-dione, that the double Michael reaction proceeds via path b shown in Scheme 1. The absolute stereochemistry of 8a was determined to be (lR,2R,4s,sR,l’s,2’R,4’R) by the anomalous dispersion effect of sulfur atom. The absolute configuration determined was confirmed by the internal reference method using the camphor part. Figure 1
8a
9894
H.
HAGIWARA
et d.
The more polar diastereomer Xb was converted into ester (lS,2S,4R$S)-5 (Scheme 3). The sultamamide 8b was reduced with lithium aluminiumhydride (LAH) to give in 75 % yield trio1 which was oxidized with Jones reagent. Estetificstion of the resulting keto-acid with diazomethane furnished in 3X % yield (lS,2S,4/?,6.~)-5 which exhibited weak hut distinct Cotton effects in the CD spectrum: hext 304 nm, AF ~ 1.11, 294 nm, Ae -1 .I 3 and 216 nm, Ac +I .h7. Since the absolute configuration of the less polar diastereomer Xa was determined by X-ray crystallography, established to be (lS,2S,4K,hS). Scheme 3
RCU~EIZ~S
mtl
the absolute configuration
0 i,
r,,>rltiirior~c: I. LAH. TI IF: II. Jmrs
of [CD(-)304]-5’
was
0
reagent, acetone, 0 “C: iii, diazomethane,
Et20
order to get insight on the reaction parhu ;I). semiemptrical molecular orbital calculation by MOPA@ was carried out employing Ah11 Hamiltonian 111precise mode and revealed the preferential formation of the ester (k)-5 rather than the ester c&)-4. S-CIS conformation was chosen for methyl acrylate from observed relative sterecxhemistry of the ester 5. Calculated heat of formation of At.2- enolate 2 (AC H” -90.3X kcal mol-‘) and the A6,7-enolate 3 (Af Ho -84.79 kcal mol-t) indicated that the At.?- enolate 2 was thermodynamically more stable (more than 99.9% popul;ltion) providing that effect of salvation was came in both enolates 2 and 3. Actually, only A1,2-enolate 2 In
was trapped by u\ in iO? yield ah sllylenoi ether3 whose structure was apparent from its carbonyl absorption (V I671 cm’) in IR spectrum. On the other h.md. the smallest atomic orbital electron population of the 7x*-H among other protons CI to cvrhonyl groupi; .~lludcd LinetIc generation of the enolate 3. Cocfficientk of f lOML10 of the Ahs7-enol,l:c 3 at bolh reacting termini, C-7 and C-4a, were +0.783 and -O.lG, respecrlvely as shown 111Figure 2. 011 the other hand, f-1OMO of the At,‘-enolate 2 exhibited coefficients of +(I.793 and +().(X)6 at C-2 and (‘-4a, respectively. Providing that the second Michael addition occurred concurrently (differcncc between double Michael KS anion accelerated Diels-Alder reaction is subtle’), these results indicated that the present double Michael rraction proceeded from the A6,7-enolate 3, because the coefficient at C4a of the ;I’.2 -en&ire 2 &;I\ t(x) small and moreover the sign of the coefficient at C-4a was opposite to correlate wtth cx-c,lrhon of LUhlO of methyl acrylate Smaller energy gap between HOMO of the A6.7-enolate 3 and LLJMO of methyl acrylate (2E 2.59 eV) than that of the At ,2-enolate 2 (AE 2.87 eV) would also favor annulation from the Ah,‘-enolate 3. Though the At.?- enolate 2 was trapped by C- or 0-alkylation as noted in the work of Grieco of al..3 mode of present annulation pia path b to give the ester 5 was understood by frontier orbital theory.
Double IMIchael reaction of Wieland-Micscher
Figure 2
ketone
9895
HOMO of Er:olates 2 and 3 -0.489
+0 008
t +0 006 -0 024 [-2 62 eV] 2
+0.0003 [-2.54 eV] LllhlO
of .Methyl AU), late
3
\,I.@&+062 -o 42
[+0.049 eV]
Stereochemical course of the present reaction was explained by chelation control. Methyl acrylate approached to the Ah,‘-enolate 3 from less hindered a-face. After taking S-cis conformation by chelation of oxygen of ester carbonyl of methyl acrylate with Li cation on the A fi.%nolate 3. the double Michael reaction proceeded concurrently to afford the ester 5 In summary, we have shown that the douhlc xlich:irl reaction of Wiel;md-Mirscher ketone 1 with methyl acrylxe have proceeded from the Ah.‘- enolate 3 IYU p;lth b to gi\e the tricyclic ester 5 in symmetry allowed manner. Acknowledgment. ?‘hi\ \borj\ M;I\ xuppo~-ted ln part hy c(‘rants from the xlinistry of Education, Science, and Culture, Japan (General (1~1 No. Ol370016. I’rio~-~t) Area\ Nos. 01648501, 02230701, and 03214107, and Developmental Research No 0555101? to N 11 j
Experimental
All m.p.s were determined with ;I 51itamura Riken hot-qt;ige appxxtu\; and uere tlncorrected. IR spectra were recorded on a JASCO FT/lR-X300 ~pectrophotometcr for solutions in chloroform. ‘H h’MR spectra were obtained for solutions in deuterlc~chloroform with JEOLFX 9OQ (90 hlHz) or Bruker MSL-300 (300 MHz) instrument with tetramethylcllant xc internal st:tnd;ud. Mass spectra were run on a JEOL JMS-DX300 spectrometer with a JMA-?500 tl,~ra system. Circular dlchroic apectnrni wxs measured on a JASCO J-400X spectrophotometer. IIltraviolet qeztrurn \\a, obtained OII 3 JASCO l!he.\t-50 spectrophotometer. MPLC was carried out on a JASCO PRC-50 lnbtrument with a silica gel pached column. Anhydrous sodium sulfate was used for drying organic extr;tctL;. J‘IIF W;IS distilled from hcnzophenone kctyl before use.
9896
H. HAUWAKA
PI (il.
Mcrh~i (lS*,2S*,4R*.hS*)-6-~~~(,~~l~ltri[,~[ 1~~~6.7.7.O1~~~rfo~fec~ur~-7,l2-dion-2-carho.~~late 5.To a stirred solution of LDA, prepared from cilisopropyl~~rnine (0.182 cm?, 1.3 mmol) and butyllithium (0.74 cm3, 1.6.5 mol dm3 in hexane, I .2 mmol) in TIFF (1 cmj). was added racemic Wieland-Miescher ketone 1 (I75 mg, I mmol) in THF (2 cm3) at 0 “C. The resulting solution became black and curdy. After being stirred for 20 mm, methyl acrylate (0.15 cm.j, 1.67 mmolj was added and stirring was continued overnight warming gradually to room temperature. The reaction was quenched by addition of aq. ammonium chloride and the product was extracted with ethyl acetate twice. Combined organic layers were washed with brine and evjaporated to dryness in KKUO. The residue was purified by MPLC ]eluent hexane:ethyl acetate (1: I)] to give the tricyclic ester 5 (74.4 mg. 28%); vmax/cm -I 3027, 2955, 172X, 1456, 143X. 1231, 1198, and 1173; 6(3OO MHz) 1.1X (3 H, s, hlej. I.35 (IH, ddd, .I 14.2, 4.3 and 2.9 Hz), I.5 2.21 (IH, dd. .I I9 and 2.2 III). 2.36 (111, dm. ./ I3 Hz) , 2.43 (IH, and 2 Hz), 3.01 (Ill, d, .I 19 Hz) and 3.7 (311, sj; rn:z 265 CM+ + (h9), lhO(1OOi, 145 (21) 121 (1x1 and SS (19’1 (Found:M +, 263.1359
(IH, d,./ 13 Hz), 1.X5-2.15 (SH, m), m), 2.7 (2H, m), 2.79 (IH, dd, J 14.3 1, 3%). 264 CM+, 16), 178 (Sh), 163 ClSH2004 requires m/z, 264.13615).
( IR*,3R*,3S*,6R*)-h-.U~~~~~~~~ri~~~~/~)[6.2.2.(~t~hl~i~~d~~~.~~~~-7, I2-dion-2-carhoxunlidc N-(l’S,2’R,4’R)_ 8a and 8b. --A solution of the tricyclic ester 5 (61.7 mg, 0.234 mmol) in aq. sodium hydroxide (I cm3, 1 mol dmij and ethanol (3 cm“) was heated under reflux for I.5 h under nitrogen. After being cooled to room temperature. hydrochloric acid (I mol dn-‘) was added. The product was extracted with ethyl acetate twice and combined organic layers were washed with brine. Evaporation of the extract afforded fine crystals of (lR*,2R*.4S*,hR”)-h-m~~f/~~~fri~~~~~~~~[6.2.2.Oi~h~dodecan-7,12-dion-2-carhox~lic acid (55.5 mg, 9S70) : Vmax/CTll -t 2956, 1708, 146h,~l3S6. 1309, 1322, 123.5, II86 and 909; 6 (90 MHz) 1.19 (3 H, Me), l.l--3.1 (I-1 II, mj and X.1 (I H, br. CO2H): m/i 251 (M+ +I , X%z), 250 (M+, 40) 178 (64), 163 (78), I60 (l(H)), 14s (35j and 55 (40) (Found:M +, 250.12034. CI4H I X04 requires m/z , 250.1205). ~czn~p/z~)r.sulf~lrr~
A solution of the acid (?7.2 mg, O.lS mmol) m thionyl chloride (0.5 cm3) was stirred at room temperature for I h. Excess thionyl chloride w,ts ev aporatetl ili ~UUO and the residue was used for further reaction without purification To a stirred suapen\ior of \cxiium hydride i I1 mg, hO’%( 0.3 mmol) in benzene (0.S ~111~) was added crystals of d~c;tmptlor~ultam (63 9 mg. 0.3 mmol) at room temperature under nitrogen. After being stirred for 1 h, a solution of acid chloride in benzene (2 cm3j was added at 0 “C and the resulting solution was stirred at room temperature for 3 h. The reaction was quenched by addition of water followed by hydrochloric acid (1 mol dm-3). The product was extracted with chloroform three times. Organic layers were washed with brine. Evapor,ttion of the extract followed by MP1.C separation [eluent hexane:ethyl acetate (l:l)] provided recovered tf-calnphorsultain (1.5.3 mg). Icss polar diasterromer Xa (10. I mg, 15%) and more polar diastereomer Sb (1 X.6 mg. 2X%). I.esr polar diastereomer 8a had: n1.p. 250 “C (decomposition); vmaxlcm-’ 364, 23SY. 2342, 1708, 1455. 1313. 13.3X. 1305. 1237, 1 I66 and 1133: 6 (i(X) MHz) 0.94 (3 H, s, Me), 1.09 (3 H, s, Me). I.15 (3 H, s, Me), 1.2 ~~l.S(~ll, mj, 1.5-1.75 (4H, m), 1.X-2.15 (lOH, m), 2.84 (11~. d, .I 14.3 Hz), 3.03 (111, t. .I X.9 llzj. 3.32 (ItI. d../ 19.3 Hzj, 3.43 (111, d,J 13.8 Hz), 351 (IH, d,J 13.X Hz) and 3.X7 (Ill. t. .I 6.5 tlrj : m/z 31X (hl+ + I. 8%). 447 (>I+, 23), 270 (3X), 232 (41) 204 (46). 161 (52j, I60 (IOOt. 136 tit)). I35 (601. 121 (.Jlj. 93 (35) and 55 (53) (Found:M+, 447.20767. Cz~Hii05NS requires \I. 417 20793) ‘\I~NY polar diasterromer 8h was recryatalized from chloroform and
Double Michael
hexane; mp. 22(&240
I-caction of Wteland-fvllcscher
ketone
9897
“C: ~~~~~,x/crn~I 2064. 23SY. 2343, 1712. 1356, 1413, 1338, 1264, 1236, and 1133;
6 (90 MHz) 0.9X (3 H, s. Me), 1.13 (6 II, br s. Me x 2) and l.(L3.0
(24 H, m); m/z 448 (M+ + 1, 7%).
447 (M+, 23), 232 (33). 204 (S6), 178 (33), I63 (Y(I), I62 (27). 160 (IO()), (Found:M+, 437.20776. C~~ll;~OsNS requires M. 447.20793). X-ray CQWZ~ Srrucrurr D~~UVIUUULUI c,fAmitk~ Xa recrystalization of amide 8a from chloroformfiexane.
135 (47) and 5.5 (44)
Single crystals were obtained as colorless prisms by A crystal (dimension 0.30 x 0.23 x 0.08 mm) was
selected for data collection and mounted on a Rigaku AFC-6B automated four circle diffractometer. The crystal was found to be monoclinic, and the unit cell parameters and orientation matrix were obtained. Data collection was carried out by using a 20-O scan: formula, C2df-I33NOgS; formula weight, 447.60; space group P21; a = 13.X8X (2) A, b = 6.9646 (5) A, c = 11.396 (2) A, !3 = 90.46 (I)‘. vol = 11 1 I.9 (2) A3; 2 = 2: p(calcd) = 3.337 g/cm3: p(obsd) = 1.340 g/cm3 (by flotation urn g a CCla-hexane solution); radiation, Cu Kn (1.54178 A): monochrometor, graphite crystal: linear absorption coefficient, 14.X3 cm-t; temperature, 20 “C; scan type, 2&O; scan speed, 2.0C/minute; scan range, 1.3” + 0.3’ tan H; 28 scan limits, 2-IW; standard reflections, 3 per SO reflections; indices. (0,1,1). t-3,0,2), (2,O.l): crystal stability, no indication of standard reflection decay during data collection; total reflections scanned. 2 163; unique data F. > 3.0 o(F,), 1910. The position of the most non+hydrogen atoms were found by the direct method, and then those of the remaining non-hydrogen atom\ were found by successive Fourier syntheses. All hydrogen atoms were found by the difference Fourier syntheses Full matrix le:lat-squares refinement of positional parameters and anisotropic thermal parametera for non-hydrogen atom\, including anomalous scattering factors of sulfur, oxygen, nitrogen and carbon atoms, led to the final convergence with R = 0.0402 and Rw = 0.0440 (final no. of variables, 379) for the (1R.~R,4S,6R,1’S,Z’R,3’R) the mirror image structure gave R = 0.03 14 and
R
absolute configuration, while a similar calculation for w = 0.03.57. In the full matrix least-squares calculation, the
isotropic thermal parameters of hydrogen atoms were not included as variables in the refinement, but calculated from the thermal parameters of the non-hydrogen atom\ to which the hydrogen atoms were attached. The absolute configuratlon of the sul~am amide of Xa I=V~~Y determined as illustrated in Figure 1 and formula 8a. The (IR.ZR,4S,6S) absolute configuration of the ~iiketo-carhoxylic part way also assigned by using the (1’S,2’R,4’R)-~-)-2,1O-camphorst~ltam part as an inter-nal reference of the absolute configuration. The lists of atomic parameters, bond lengths and hond angles of Xa are deposltcd at the Cambridge Crystallographic Data Center. The list of observed and calculated structure factors may be obtained from one of the authors (N.H.) upon request. McthJl (1 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 12-tiion-2-c.orholute 5.More polar diastereomer of the ~ultam amide Xb (hi mg, 0.14 mmol) In THF (5 cm3) was added LAH (40 mg, 1.08 mmol) at 0 “C under nitrogen. After being stirred for I h at room temperature, the reaction was quenched by addition of aq. ammonium chloride. Usual work up followed by flash chromatography gave trio1 (2S.2 mg, 75%). To a stirred solution of the trio1 (25.2 mg, 0.10.5 mmol) in acetone (4 cm3) was added Jones reagent dropwise at 0 “C. After being stirred for 30 min. the product was extracted with ethyl acetate twice. Organic
layers were treated with ethereal solution of diazomethane.
Evaporation of the mixture followed by repeated
9898
H. HAGIWARA
ft al.
(twice) MPLC purification of the residue afforded the tricyjclic ester 5 (10.6 mg, 38%) which crystallized spontaneously (m.p. 113.5.-l 14.5 “C); UV (EtOH) 1 max 295.6 (E 60) and 200 nm (P 1,000, end absorption); CD (EtOH) &xt 304 (AF -1.11). 294 (A& -1.13) and 216 nm (A& +1.67).
References 1. 2.
3. 4. 5. 6.
7. 8.
Tietze, L. F.; Beifuss, U. Anger. Chrm Inr. Ed. EngI. 1993,32. 131. Ihara, M.; Fukumoto, K. Angew. Chem. Inr. Ed. Engl. 1993,32, 1010; Hagiwara, H. J. Synrh. Org. Chem. Sot., Jpn. 1992.50, 713; Posner, G. H. Chem. Rev. 1986, 86, 831; Ihara, M.; Fukumoto, K. J. Synrh. Org. Chem. Sot., Jpn. 19X6,44, 96. Grieco. P. A.; Fertino, S.; Oguri, T. j. Org. Chem. 1979.44, 2593. Addition of Wieland-Miescher ketone to LDA at -78 “C gave solid which did not provide any annulation product even after warming up to room temperature. Weber, W.; Spitzner. D.: Kraus, W. .I. Chcm. Sot. C/rem. Common. 19X0, 1212; Spitzner, D.; Sawitzki, G. .1. Chcwl. SM. Perkin I 1988, 371. Harada. N.; Soutome. T.: Murai, S.: Uda, II. Tetruhudron: Asymm. 1993,4, 1755; Harada, N.; Hattori, T.; Suzuki, T.: Okamura, A.; Otto, 11.; Miyano, S.; Uda, H. Tetrahedron: Asymm. 1993, 4, 1789; Harada, N.; Soutome, T.; Nehira, T.; Uda, H.; Oi, S.; Okamura, A.; Miyano, S. .I. Am. Chem. sot. 1993, I IS, 7547. The prefix (CD(-)3041 indicates an enantiomer showing a negative CD Cotton effect at 304 nm. AM1 calculation was carried out wjith Apple Macintosh [MOPAC Ver. 6.00, Stewart, J. J. QCPE Bull. 1990, 20(4), 861.
(Received in Jupun 10 April 1995; accepted IO July 1995)