9292
J . Am. Chem. SOC.1990, I 12, 9292-9299
0.I2 mmol) was added, and the solution was brought to reflux for 1 h. by MPLC on silica gel (elution with 8% ethyl acetate in petroleum ether) After being cooled to room temperature, the reaction mixture was pargave 184.4 mg (95.4%)of 42 as a white solid: mp 46-48 OC (crystallized titioned between water (2 mL) and ether (5 mL). The aqueous phase on standing at 0 "C);I R (neat, cm-I) 2960, 2930, 2860, 1740, 1460, was extracted with ether, and the combined organic layers were washed 1410, 1380. 1360, 1255, 1090, 1060,840, 770; 'H NMR (300 MHz, w i t h brinc, dricd, and conccntratcd. Purification by MPLC on Florisil C&) 6 3.53-3.5 I (m, 1 H), 2.08-1.99(m, 2 H). 1.92-1.24(series of (elution w i t h 25T cthyl acctatc in petroleum ether) gave 22 mg (78%) m, 14 H), 0.98(s, 9 H), 0.92(t. J = 7.3 Hz, 3 H), 0.79(d, J = 7.1 Hz, of 40 and its isomer 41 (ratio 4:l)as an oil: IR (neat, cm-I) 2950,2920, 3 H). 0.09 (s. 3 H), 0.07 (s, 3 H);"C NMR (75 MHz, C6D6) ppm 2850, 1740, 1450. 1375, 1260, 1100; 'H NMR (300 MHz, C,D,) 6 217.49,70.45,49.70,47.53,45.31.40.35,37.82,37.60,35.79,33.22, 5.70-5.68(in, I H ) , 5.58-5.57 (m. 1 H), 5.33-5.31(m,1 H ) , 2.77 (m, 29.66,26.39,26.16(3C),22.65,18.30,15.96,13.29,-4.19,-4.67; MS I H), 2.49-2.24(m, 2 H ) . 2.12-1.71(seriesof m, 13 H), 1.59-1.29(series m / z (M+) calcd 335.2406,obsd 335.2434. of m, 13 H ) , 0.89-0.81( m . 6 H), 0.77-0.71 (m, 6 H); MS m / z (M+) calcd 218.1670,obsd 218.1683. Acknowledgment. W e a r e grateful t o the National Institutes (3aR *,SS*,SaR *,7S*,8aS*,8bS*)-5-(~ert-Butyldimethylsiloxy)-6- of Health for their financial support of this work ( G r a n t No. ethyldecahydro-7-methyl-as-indacen-3(2H)-one (42). Alcohol 12 (1 30.4 GM-28468), Ruth Hsu for the X-ray crystallographic analysis, mg. 0.55mmol) and imidazole ( I 50 mg, 2.2 mmol) were dissolved in 2.5 and Dwight Macdonald for yield improvements a t several stages. mL of dimethylformamide under argon. t~rt-Butyldimethylsilyltriflate (0.22 mL, I . I-mmol) was added dropwise, and the solution was stirred Supplementary Material Available: Tables listing the experiat 25 'C for I h. A second equivalent of the triflate was added to the X-ray diffraction data, bond distances, bond angles, reaction mixture was stirring for 1 h before it was quenched with satuleast-squares Planes, Positional Parameters, and refined temperrated sodium bicarbonate solution (1.5mL). Water (1.5 mL) was added, a t u r e factor expressions for 2 5 - O P N B ( 1 2 pages). Ordering and the solution was extracted with ether. The combined organic layers werc washcd with brinc and dricd prior to concentration. Purification information is given on any current masthead page.
Total Synthesis of (+)-Ikarugamycin. 2. Elaboration of the Macrocyclic Lactam and Tetramic Acid Substructures and Complete Assembly of the Antibiotic Leo A. Paquette,* Dwight Macdonald,' and Lawrence G. Anderson Contribution from the Evans Chemical Laboratories, The Ohio State University. Columbus, Ohio 43210. Received April 27, 1990
Abstract: The antibiotic ikarugamycin ( 5 ) has k e n synthesized in a triply convergent and enantioselective manner. The previously prepared ketone I was first converted to acetylenic ester 2, an intermediate in which all eight of the stereogenic centers present in the carbotricyclic segment of 5 have been set in their proper absolute configuration. Very high levels of kinetic resolution wcrc achicvcd during I ,4-addition of vinylmagnesium bromide to aldimine 9. Following coupling of 2 to the ornithine segment 20, thc aldchydc group was unmasked and condensation was effected with phosphonate 23. After arrival at 3,the acyl ketene wab libcratcd thcrmally and macrocyclization occurred smoothly. The total synthesis was completed by partial hydrogenation of the triple bond, dchydrutivc rcmoval of the hydroxyl group in ring B, Dicckmann cyclization to form the tctramic acid, and deblocking of thc amidc nitrogen. The spectral propcrties of the synthetic material were identical with those of the natural product.
In the preceding paper,* we developed a concisc, stcrcocontrollcd approach to 1. a tricyclic ketone which was intended to become thc dccnhydro-0.7-indaccnc subunit of ikarugamycin (S).' T h e appcndagc of functionnlizcd sidcchains onto ring C as in 2 was expcctcd to procccd with thc propcr stcreoselectivity by analogy to thc cstablishcd bchnvior of relatcd linear triquinanc ~ y s t c m s . ~ T h c rcactivc ccntcrs prcscnt in 2 werc to bc sclcctcd in ordcr to pcrniit convenient introduction of thc ornithine scgmcnt (SCC3) as wcll as thosc additional trigonal carbons that would ultimately allow for construction of the macrocyclic lactam as in 4. The final issucs at this stagc of inccption wcrc to involve dehydrativc removal of watcr to x t thc cyclohcxcnc doublc bond2 and Dicckmann ( I ) NSERC Postdoctoral Fcllow, 1987-1989. (2)Paquette. L. A:; Rominc, J. L.; Lin, H.-S.; Wright, J. J . Ani. Chem. Soc. preceding paper in this issuc. ( 3 ) ( a ) Jomon. K.; Kuroda. Y . ;Ajisaka. M.; Sakai, H. J . Antihioi. 1972. 25. 271. (b) Ito. S.: Hirata. Y . Tetrohedron Lelt. 1972, / / X I : 1185; 2257. (c) Ito. S.; Hirnto. Y . Bull. Chem. Soc. Jpn. 1977, 50, 227,1813. (4)( a ) Paqucttc. 1.. A . Top. Curr. Chem. 1979. 79, 41; 1984. 119. I. (b)
Paqucttc. L. A , ; Dohcrty. A . M. Polyquinone Chemistry; Springcr-Vcrlag: Berlin, 1987.
0002-7863/90/ 15 12-9292$02.50/0
cyclization to generate the tetramic acid ring ~ y s t e m . ~ Several additional tactical issues central to the projected synthesis in Scheme I derive from precedent developed by others in othcr contexts. T h e impact of this prior art on the retrosynthetic analysis will bc made known a t appropriate points below. This full account of our total synthesis of (+)-ikarugamycin elaborates upon findings announced in preliminary form6 alongside a communication by Bocckman and co-workcrs in which a n alternate route to the samc antibiotic was described.' I n both undertakings, thc complex target was approached in a manner that delayed to thc final stages the assembly of its sensitive and highly polar acyl tctrimic acid unit in ordcr to avoid the difficulties in manipulation and purification often associated with this class of compounds. ( 5 ) Scc. for cxomplc: ( a ) Bloomer, J. L.: Kapplcr. F. E. J . Chem. SOC., 1485. (b) Boeckman, R. K.. Jr.: Pcrni, R. B. J . Urg. Chivn. 1986. 51. 5486. (c) Ley, S. V.; Smith. S. C.; Woodward, P. R. Ti,tr~~hcndron Lett. 1988, 29, 5829. ( 6 ) Paqucttc. L. A,; Macdonald. D.: Anderson, L. G.; Wright, J . J . Am. Chrtn. Soc. 1989. 111. 8037. (7) Bocckman. R. K., Jr.; Wcidncr, C. H.; Pcrni, R. B.; Napier, J . J. J . Ani. C'hem. Sui,. 1989. I I I , 8036. Pivkin Truns. I 1976,
Q I990 Amcrican Chcmical Society
J . Am. Chem. SOC.,Vol. 112. No. 25, 1990 9293
Total Synthesis of Ikarugamycin. 2 Scheme I
QTBDMS
QTBDMS
OwNH-
Scheme I1 QJBDMS
1 . Dibal-H
2. H3O'
H
6
'
1. CHpCHMgBr,
MF 2. HQ
OTBDMS
12
11
QTBDMS
A 13
Results and Discussion Initial Pendant Group Attachment and Kinetic Resolution Studis. Vinylogous ester 6 was conveniently available in a one-pot procedure involving the formylation of 1 and dircct in situ 0 alkylation of the resultant cnolatc anion with isopropyl iodidcX
(Schcnic II). The regiospecificity of this one-carbon homologation follows, O f course. from the mechanistic demands Of the Ciaisen c o n d c n ~ a t i o n . ~Hydride reduction and acid hydrolysis of 6 made ( 8 ) J o h n w n , W. S.; Posvic, H . J . Am. Chem. SOC.1947, 69. 1361.
9294 J . Am. Chem. Soc., Vol. I 12, No. 25, 1990
Paquette et ai.
Scheme 111 QTBDMS
15
&Ae
16
available the a,(3-unsaturated aldehyde 7, thereby setting the stage for application of Koga's elegant noncatalytic asymmetric I ,4conjugate addition chemistry.I0 I n order to test the potential usefulness of this procedure in the present context, racemic 7 was condensed with L-tert-leucine tert-butyl ester (8). As expected, an inseparable 1: 1 mixture of the diastereomeric aldimines 9 and 10 resulted. The bidentate chelating ability of such a-amino acid esters toward Grignard rcagcnts is rccognized to fix the nitrogen and oxygen atoms in a manner where reasonable conformational As a consequence, the large a-tert-butyl rigidity substitucnt acts by virtue of its relative steric bulk to drive carbon-carbon bond formation to the opposite face of the complex. I n view of thc absolute configuration of 8, our intent to add vinylmagncsium bromide translates into enforced delivery of the vinyl group in the manner pictured in 11 and 12. However, these diastcrcomcrs constitute a "matched" and "mismatched" pair. Whcrc 11 is conccrncd, the vinyl group is to be guided onto the stcrically Icss-congcstcd @-face of the decahydro-as-framework and littlc itnpcdancc to thc 1,4-adaition should be experienced. On the othcr hand, thc compcting process for @-introductionof thc vinyl group in 12 should be kinetically disfavored by the concavc topography in the vicinity of the q p - d o u b l e bond. The major unccrtninty associated with this tactic was the extent to which stcric factors prcscnt in "mismatched" diastereomer 12 would prccludc ultimatc conversion to 14. W e remain unaware of any related attempt to capitalize upon steric compression within thc original aldehyde to override the controlling elements present in thc amino acid auxiliary. I n thc cvcnt. dropwisc trcatmcnt of >5 mol equiv of vinylmagnesium bromide to a cold (-36 "C) tetrahydrofuran solution of the 11/12 mixture followed by a 10%aqueous citric acid quench a t 0 "C gave rise to a difficultly separable 83:17 mixture of 13 and 14 ( ' H N M R analysis). With proper allowance for the quantity of 7 recovered, the efficiency of the vinylation was 48% and the actual yield of the desired 13 was 22%. I n order to ascertain the level of enantiomeric purity of 13, the 13/14 mixture was directly ketalized, hydroborated, and subjected to chromatographic purification. At this point. major alcohol 16 (Scheme I l l ) was easily obtained free of its diastereomer in excellent yield (84%for the two steps). The optical purity of the initially isolated crystalline product, [a]"D -45.1 ", was established through conversion to its Mosher ester12 to be 91%ee. Two recrystallizations of 16 from petroleum ether resulted in an increase in [.]25D to -48.9' corresponding to 98%ee. Further recrystallization provided enantiomcricnlly purc matcrial. -49.7O. (9) Hourc, H. 0.Modern Synthetic Reactions, Second Edition; W . A . Benjamin. Inc.: Mcnlo Park. CA. 1972: Chaptcr I I . ( I O ) (e) Hashimoto. S.: Yamada, S.: Koga, K . J . Am. Chem. Soc. 1976. 98. 7450. (b) Hashimoto, S.; Kogcn, H.; Tomioka, K.:Koga. K. Tetrahedron Left. 1979. 3009. (c) For a recent review of this field, consult the following: Tomioka, K.; Koga. K. I n Asynimerric Synthesis; Morrison, J. D., Ed.; Acadcmic Prcss: Ncw York. 1983: Vol. 2, Part A, Chaptcr 7 . ( I I ) ( a ) Yamada. S.; Hashimoto, S. Chem. Lett. 1976. 921. (b) Hashimoto. S.: Komcshima, N . ; Yamada. S.; Koga, K. Tetrahedron Lett. 1977, 2907. (c) Ilashimoto. S.; Yamada. S.; Koga, K . Chem. Pharni. Bull. Jpn. 1979, 27. 71 I. ( 12) Dnlc. .1. A.: Dull. D. I..; Mosher. H . S. J . Org, Chem. 1%9. 34, 2543.
18
6Me QJBDMS
6Me 2
Scheme Va 0
ti^,^,
20 0
"(a) HCOOH, I O "C, 3 h; (CH,),COOH; (b) ArCHO. NaBH,CN. McOH; (c) CIC02CH2CH=CH2, NaHCO,, dioxane, H,O; MeOH: H,O+: (d) CHIN,.
The synthesis was continued with alcohol of 98% ee quality to insure against possible complications from diastereomer formation. With 16 in hand, all eight of the stereogenic centers present in the carbotricyclic segment of ikarugamycin had been set in their proper absolute configuration. In order to take advantage of the known ease of conversion of aliphatic aldehydes to homologated acetylenic esters,13 16 was oxidized to 17 with PCC under buffered conditions and transformed into dibromoolefin 18 by reaction with carbon tetrabromide and triphenylphosphine in dichloromethane (Scheme IV). The conversion to 2 was brought about by reaction with n-butyllithium in tetrahydrofuran a t -78 "C for 35 min and a t 25 "C for 20 min, followed by capture of the lithium acetylide with methyl chloroformate. This chain lengthening, realized with exceptional efficiency (84% overall), advanccd matters to where amide bond construction had next to be dealt with. T o this end, the appropriately functionalized ornithine segment was assembled by converting thc known'ja 6-N-t-Boc protected amino acid 19a to the fully protected derivative 19c (Scheme V). T h c &amino group in 19c could bcst bc chcmosclcctively unniaskcd by cxposurc to formic acid a t 10 "C. This route to 20 provides for efficient differcntial blocking of the u-amino substitucnt. Removal of the allyl carbamate was destined to occur prior to manipulation of thc 2,4-dimcthoxybcnzyl functionality. ~~
( I 3) (a) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769. See also: (b) Kobayashi. S.; Mukaiyama. T. Chem. Left. 1974, 705. (c) Cha, J. K.; Cookc. P. J . Tetrahedron Left. 1907, 28. 5473.
Total Synthesis of Ikarugamycin. 2
J . Am. Chem. SOC.,Vol. 112, No. 25, 1990 9295
Scheme VI' QTBDMS
QTBDMS
___)
2
O h
OMe
0
21
' ( a ) K2C0,. McOti, tI2O: 2.4,6-(CH3),PhS02CI.T H F ; D M A P . 20; ( b ) acetone. (T sOH): ( c ) K N ( T M S ) 2 , 23, T HF : (d) Pd(PPh,),, PPh,, HOAc, T H F : ( c ) tolucnc. I IO O C . 4 h.
Selection of the latter was predicated on existing claims of its suitability for, and ease of removal from, tetramic acid nuclei'4 and the purported stability of 5 to these deblocking condition^.^^ Having complctcd thc prcparation of 20, we anticipated subscqucnt construction of pivotal intermediate 3 to be straightforward. This prcmisc appeared especially true given the feasibility studics carlicr d o c ~ m c n t c d .The ~ approach was initiated by hydrolysis of 2 with potassium carbonate in aqueous mcthanol, activation of the carboxylic acid by conversion to a mixed carboxylic-sulfonic anhydride with mesitylenesulfonyl chloride, and in situ condcnsation with 20 in thc prescncc of 4-(dimethylaniino)pyridinc (Schcme VI). Once amide bond formation had becn accomplishcd (46% from 2), the aldehyde functionality was unmaskcd by transkctalization of 21 with dry acetone. These anhydrous conditions wcrc madc ncccssary in order to bypass concomitant dcblocking of thc silyl ether. Condensation of 22 with phosphonate 2316 proceeded fully as expcctcd. In contrast, initial cfforts to achievc clcavagc of the allyl carbamate rcsiduc in 24 by mcans of (Ph3P).,Pd" wcrc unsucccssful. The problem appeared to reside in the fact that the libcmtcd allylamine was proceeding to attack the reaction product nucleophilicity. Once this was recognized, it proved an easy matter to dctcr this side rcaction by having an appropriate amount of acctic acid prcscnt in thc tctrahydrofuran from the outset for neutralization purpses. Under these circumstances, 3 was isolated as a clcar glass in 717%yicld (67% conversion). T h e crucial macrocyclization was realized by heating dilute solutions of 3 in tolucnc for 4 h. As hoped, the extensivc representation of digonal and trigonal centers in the electrophilic1*acyl (14) (a) Schlessinger, R. H.: Bebernitz, G. R.: Lin, P.: Poss. A. J. J . Am. Chem. Soc. 1985,107, 1777. (b) DeShong, P.; Ramesh, S.; Elango, V.: Perez, J . Ibid. 1985. 107. 5219. (c) Bryan, D. B.: Hall, R. F.: Holden, K . G.; Huffman, W.F.: Glcason, J . G. /bid. 1977, 99, 2353. ( I 5 ) See footnote 19 of ref I3c. (16) (a) Bocckman, R. K . , Jr.; Thomas, A . J . J . Org. Chem. 1982, 47, 2823. (b) Boeckman, R. K . . Jr.; Pcrni. R. B.; McDonald, J . E.; Thomas, A. J. Org. Synth. 1987. 66. 194. (17) Jeffrey, P. D.; McCombic, S. W. J . Org. Chem. 1982, 47, 587. (18) (a) Hyatt. J . A.; Fcldman, P. L.;Clemens, R . J. J . Org, Chem. 1984. 49. 5105. (b) Clcmcns. R . J . ; Hyatt, J. A . /hid. 1985, 50. 2431.
kctenc 25 so generated greatly facilitated the desired intramolecular trapping. The 94% efficiency with which 26 was formed is particularly notable. With the macrocyclization successfully accomplished, the next step was to semisaturate the acetylenic triple bond. The Lindlar method proved satisfactory for this purpose (76% of 4, Scheme VII), although great care was required in monitoring the progress of rcaction. Our experience has been that the catalyst system bccomes more reactive with time as a color change from brown to black is observed. Accordingly, overreduction occurred if the hydrogenation process was not duly interrupted after 1 equiv of hydrogen had been adsorbed. Subsequent desilylation in anticipation of the requisite dehydration was easily accomplished in 86% yield with dilute solutions of 48% hydrofluoric acid in acetonitrile. Although 27 was indeed amenable to conversion to 28 when exposed to the Burgess reagentI9 in warm benzene in accord with our prototype thc yicld was only marginally acceptable (36%). This is because a t least two competing reactions operate concurrently. A small amount of the trisubstituted double isomer of 28 was isolated, suggesting that SN1 behavior was being exhibited by the system in a modest way. In addition, 'HN M R spectroscopy of impure byproducts provided indication that chemistry of a less well-defined nature was occurring between the inner salt and functional groups on the macrocyclic ring. Modification of the reaction solvent and tcmpcraturc might have improved matters, but the short supply of material precluded studies of this type. Conceivably, somewhat larger scale reactions would be more suited to enhanced efficiency. T o complete the synthesis, 28 was cyclized by Dieckmann condensation with KO-tert-Bu in tert-butyl alcohol a t room temperature. Fully aware of the disastrous potential for base-promoted racemization a t the chiral center residing in close proximity, we allowcd thc ring closure to proceed for only IO min. This rapid trcatmcnt afforded 29 as a product homogeneous by TLC in 66% (19) Burgess, E. M.: Penton, H. R.,Jr.;Taylor, E. A. J . Org. Chem. 1973, 26, 38. (20) Paquette. L. A,; Romine, J . L.: Lin, H.-S. Tetrahedron Lett. 1987, 28. 31.
Paquette et al.
9296 J . Am. Chem. SOC..Vol. 112, No. 25, 1990 Scheme V I P OY""
27,R=H
O
V
N
H
e &
7
H
29
O
Hd
Ar=
"(a)
CH,OC(O)NSO,r\lEt,. C,tI5. 1:( b ) t-BuOK
( ! ,:qui:).
H
9
r-RuOtI: (c) CF,COIH. 62 "C, 10 min.
yield. To our surprise, however, subsequent removal of the 2,4dimethoxybenzyl group in 29 was not readily accomphshcd. Realization of the final step was achieved only after an extensive search for the proper deprotection protocol. Any depnrcurc from the reaction conditions ultimately found effcctivc (CF,CC'OH, 62 OC. 10 min) gnvc ill-defined mntcrials. T h e idciiti!y of the cryzlallinc solid 50 produccd as (+)-ikarugamycin (Sj was confirmed by careful coniparison of its high-field (300 M H z ) and U V spectroscopic properties a s well as TLC mobility and optical rotation with that of an authentic sample of the natural antibiotic provided by Professor Boeckman. I t is rclcvnnt and perhaps useful to call attention to the high affinity of macrocyclic lactams 4 and 26-29 for the encapsulation of s4)dium ion. Washings of organic solutions of any of these materials with brine or other Na'X- solution is adequate to gcncratc complexes which are exceedingly difficult to dissociate into their componcnts. The same phenomenon surfaces when these lactanis iirc chromntogrnphed on silica gel. This adsorbent must thcrcforc be avoided in all purifications. Biosil A constitutes a scrviccable a l t c r n n t i ~ e . ~ ~ T h e tctal synthesis described above makes (+)-ikarugamycin available in 25 stepc (0.1 18 overall yield) from racemic 7,7-dinicthoxy-2-norborncn-5-one.demonstrates the synthetic potential of Koga's I .4-;isymmtric conjugate addition process, and confirms the ;ibsolulc stcrcochcmical assignment previously advanced for ( + ) - 5 by I t 0 and H i ~ i t a . ~ ~ Experimental Section Mclting points arc uncorrcctcd. Infrarcd spectra wcrc recorded on a Pcrkin-Elmer Model I320 spectrophotometer. 'H NMR spectra were rccordcd at 300 M H 7 and the I3C NMR data obtained at either 75 or 20 MHz as indicated. Mass spectra were measured on a Kratos MS-30 instrumcnt by Mr. Dick Wciscnbcrgcr at The Ohio State University Chemical Instrumentation Ccntcr. Elcnicntal analyscs wcrc performed at the Scandinavian Microanalytical Laboratory, Herlev, Denmark. All MPLC separations were conducted on Merck Lobar columns (Lichroprep Si-60) w i t h the hclp of a Fluid Mctcring INC pump and a Watcrs Associates Model R403 differential refractonicter detector. Thc Biosil A was 200-400 mesh. All reactions were performed undcr a n inert atmosphere (nitrogen or argon) unless otherwise indicated. Solvents were reagcnt grade and dried prior to use. (3 a R *,5S*,5aR * , 7 5 *, 8 a S * , 8 b S * ) - 5 - ( tert-Butyldimethylsiloxy)-6ethyldecahydro-2-(isopropoxymethylidene)-7-methyl-a~ -indacen-3( 2 H ) - o n e (6). A magnetically stirrcd solution of potassium hcxanicthyldisi1:i;lidc (39 nil. of 0.5 M i n tolucnc, 19 mniol) in dry tctriihydrofuran (60 mL) was blanketed w i t h nitrogen and trcatcd dropwisc ( 2 1 ) llirrch. .I.; Ahrcns. E. 11.. J r . J . B i d . Chcm. 1958. 233. 31 I .
no
with ketone I (3.37 g, 9.64 mmol) in the same solvent (20 mL) during 6 min. After 1 h at -78 "C, ethyl formate (1.70 mL, 21 mmol) was
introduced dropwise. Stirring was continued at -78 "C for 25 min, after which the tcmpcrature was allowed to warm slowly to 25 "C. After 3 h. thc reaction mixture was cooled to 0 'C, treated sequentially with HMPA (40 mL) and 2-iodopropane (1.90 mL, 19 mmol), and stirred at room tcmpcrature for I I h. Following partitioning bctween ether (200 m L ) and watcr (300 mL), the aqueous phase was extracted with ether, and thc combincd organic layers were dried and evaporated to give 6 (3.16 g, 78%) as a yellow oil consisting of a mixture of isomers which was customarily used without further purification. In a smaller scale reaction (500 mg of I ) , the products were separated and purified by MPLC on Florisil (elution with 10% ethyl acetate in petroleum ether). The EIZdistribution was 15:I and the total weight of the purc isomers was 399 mg (6710). For thc E isomer: colorlessoil; IR (neat, cm-I) 1710. 1640; 'H NMR (300 MHZ, C6D6) 6 7.55 (S, I H), 3.67-3.58 (m.2 H), 2.66-2.61 (m, 2 H ) , 2.46-2.43 (m, 1 H). 2.15-1.98 (m,3 H), 1.89-1.80 (m.1 H), 1.75-1.66 (m, 2 H), 1.49-1.32 (m36 H), 1.12 (s. 9 H), 1.10-1.00 (rn, 2 H), 0.99 (d, J = 6.2 Hz, 6 H), 0.86 (d, J = 7.1 Hz, 3 H), 0.23 (s, 3 H), 0.20 (s, 3 H); MS M / Z ( M + - r-Bu) calcd 363.2356, obsd 363.2314. For the Z isomer: colorless oil; 1R (neat, cm-I) 1710, 1630; ' H NMR (300 MHZ, C6D6) 6 7.15 ( S , I H), 4.03-4.00 (m,I H), 3.53-3.45 (m, 2 H), 2.92-2.85 (m, I H), 2.5-1.5 (series of m, 5 H), 1.40-1.10 (ni, 5 H), 1.00-0.70 (m, 8 H), 0.95 (s, 9 H), 0.78 (d, J = 7.1 Hz, 6 H),0.06 (s, 6 H ) ; H S nil: (M+ - r-Bu) calcd 363.2356, obsd 363.2338. tert-Butyl (2S)-2-[[[(3aR*,5S*,5aR*,6S*,7S*,8aS*,8bR *)-54tertButyldimethylsiloxy)-6-ethyl-1,3a,4,5,5a,6,7,8,8a,8b-decahydro-7methyl-ss-indacen-2-yljmethylene]amino]-te (9) and Its Diastereomer (10). A hexane solution of diisobutylaluminum hydride (30.0 m L of 1.0 M , 30.0 mmol) was added dropwise during 12 min to a precooled (-78 "C) solution of unpurified 6 (as obtained above. 14.3 mmol) in dry methylene chloride (1 20 mL) under a nitrogen atmosphere. After being stirred for 2 h at -78 "C, the mixture was poured into cold (0 "C) 30% hydrochloric acid (75 mL) and well agitated for 3 h at 25 "C. Thc usual cxtractivc workup furnished a ycllow oil that was purified by HPLC (silica gel, elution with 4% ethyl acetate in petroleum ether) to give 2.5 g (48% overall from 1) of 7 as a faintly yellow oil: IR (neat, cm-I) 2960,2930,2860, 1680, 1460, 1375, 1255, 1175. 1090. 1005,860, 835, 775; ' H NMR (300 MHz, C,D,) 6 9.67 (s, I H), 6.00 (s, I H), 3.44-3.37 (m, I H). 2.51-2.43 (m, 2 H), 2.29-2.24 (m,I H), 2.06-1.97 (m, I H), 1.75-1.65 (m, 3 H), 1.62-1.49 (m,2 H). 1.39-1.16 (m,5 H), 0.99 (s, 9 H), 0.95 (t, J = 7.3 Hz. 3 H), 1.78 (d, J = 7.1 Hz. 3 H); I3C NMR (75 MH7.. C6D6)ppni 190.17, 156.45, 145.03, 71.61, 50.31, 48.27, 43.87, 39.99, 39.68, 38.40,34.25,34.14,33.18,25.84,22.30, 17.93, 15.10, 12.86, -4.07, -4.55; M S / I I / : (M' - /-Bu) calcd 305.1936, obsd 305.1945. Anal. Calcd for C22H3B02Si:C, 72.87; H, 10.56. Found: C. 72.71; H, 10.44. Thc ter/-butyl cstcr of L-/c,rt-lcucinc ( I .07 mL. 5.20 mmol) was added to a solution of cnal 7 (1.72 g, 4.74 mmol) in anhydrous cthcr (30 mL) containing rnagncsium sulfate ( I O g. 83 mniol) ;kt 25 "C undcr nitrogcn. Acctic x i d ( I 3 p l . , 0.23 mmol) was introduced, and stirring was con-
Total Synthesis of Ikarugamycin. 2 tinued for I 8 h. At this point, an additional 2 g ( I 7 mmol) of magnesium sulfate was added, and stirring was maintained for an additional 2 h. The mixture was filtered through Celite and evaporated to leave the 1 : l mixturc of tu$-unsaturated imincs 9 and 10 as a pale yellow oil: 'H NMR (300 MHz, C6D6) 6 8.01 (s, 0.5 H). 7.99 ( s , 0.5 H). 5.80 ( m , 1 H), 3.61 ( 8 , 0.5 H), 3.58 (5, 0.5 H), 3.45 (m,1 H), 2.95-2.45 (series of m, 3 H). 2.10-1.55 (scrics of m, 4 H), 1.39 (s, 4.5 H), 1.37 (5, 4.5 H), 1.182 (s, 4.5 H). 1.180 (s, 4.5 H), 1.02 (s, 4.5 H), 1.01 (s, 4.5 H), 1.50-0.75(scriesofm. 1 2 H ) , O . l l ( ~ , 1 . 5 H ) , 0 . 1 0 ( ~ , 3 H ) , 0 . 0 9 ( ~ , 1 . 5 H ) ; MS n t / : (M') calcd 530.4029. obsd 530.4039. This material was used dircctly without furthcr handling. ( 2 R ,3R ,3aR ,5R , 5 a S , 6 R ,7R,8aR , 8 b S ) - 5 - ( tert -ButyldimethylsiIoxy)-bethyldodecahydro-7-methyl-3-vinyl-as-indacene-2-carboxaldehyde (13). The imine mixture was taken up in dry tetrahydrofuran (80 mL) under nitrogen. and this solution was cooled to -36 "C while being stirred and treated dropwise with vinylmagnesium bromide ( I 5.0 mL of I M in tetrahydrofuran. 15.0 mmol) below -32 "C. After being stirred for an added 25 min. the yellow homogeneous solution was poured into cold (0 "C) 10% citric acid (180 m) during I O s with vigorous agitation. A small amount of ether was used to complete the transfer. After 3 h of stirring at 25 "C, the product was extracted into ether, and the combined organic phases wcrc washcd with watcr, saturated sodium bicarbonate solution, and brinc prior to drying. Solvcnt cvaporation followed by MPLC purification of thc rcsiduc (silica gcl, clution with 37, cthyl acctatc in petrolcum cthcr) gavc a 5:l mixture of diastereomers 13 and 14 (541 mg, 2 9 7 ) and rccovcrcd cnal 7 (930 mg, 547,). For pure 13 obtained by MPLC on silica gcl (clution with 4 7 cthyl acetate in petrolcum ether): IR (neat, cm-') 1725: 'H NMR (300 MHz, C6D6) d 9.38 (d, J = 2.6 Hz, 1 H ) , 5.52 (m. 1 H). 4.96-4.92 (m. 2 H), 3.48 (m, 1 H), 2.37-2.20 (m, 2 H), 2.10-2.00 ( m . I H). 1.80-0.75 (scrics of m, 16 H). 1.01 ( s , 9 H), 0.85 (d, J = 7.1 Hz. 3 H), 0.10 (s, 3 H), 0.09 (s. 3 H); MS nil: (M+ - I-Bu) calcd 333.2250, obsd 333.2276. ( 2 R ,3R , 3 a S , 5 R , 5 a S , 6 R ,7R ,8aR , 8 b S ) - 5 - ( tert -Butyldimethylsiloxy)-6-ethyldodecahydro-7-methyl-3-vinyl-a~ -indacene-2-carboxaldehyde Dimethyl Acetal (15). A solution of the 5:l mixture of aldehydes (541 mg, 1.39 mmol) in trimethyl orthoformate (5 mL) was treated with p-toluenesulfonic acid monohydrate (8 mg). Stirring was continued for 30 min at 25 "C prior to neutralization with saturated sodium bicarbonate solution. The usual extractive workup gave crude 15 (600 mg, 99%). which was normally used without additional purification. A small amount of 15 was isolated in pure form (MPLC on silica gel. elution with 410 ethyl acetate in petroleum ether) as a colorless oil: 1R (neat. cm-I) 3080. 1640; IH NMR (300 MHz, C6D6) 6 5.74 (ddd. J = 17.7, 10.2, 8.4 Hz, I l i ) , 5.08 (dd, J = 17.7, 2.0 Hz, I H), 5.00 (dd, J = 10.2, 2.0 Hz, 1 H), 4.20 (d. J = 5.7 Hz. I H), 3.55 (m,I H), 3.20 ( s , 3 H), 3.17 (s, 3 H ) , 2.29-0.79 (scrics of m, 19 H), 1.02 (s, 9 H), 0.86 (d, J = 7.0 Hz. 3 H). 0.1 19 (5. 3 ti), 0.1 I 6 (s, 3 H); I3C NMR (75 MHz, C6D6) ppm 142.62. 113.53. 107.86, 73.53, 54.03, 53.50, 53.26. 51.23, 49.07, 48.13, 40.77,40.10. 39.85. 36.96. 33.56, 33.13, 26.29, 22.73. 18.28, 16.00. 13.28, -3.58. -4.25: MS n i l : (M' - t-Bu) calcd 379.2668. obsd 379.2703.
( 2 R , 3 R , J a S , 5 R , S a S , 6 R ,7R, 8 n R , 8 b S ) - 5 - ( tert -ButyldimethylsiI-
-indncene-2oxy )-6-ethyldodeccahydro-3-(2-hydroxyethyl)-7-methyl-as carboxaldehydc Dimethyl Acetal (16). Disiamylborane was prepared by the dropwise addition of 2-methyl-2-butene (5.0 mL, 48 mmol) to the borane-tetrahydrofuran complex (20 mL of I .2 M in tetrahydrfuran) at 0 "C under nitrogen. Stirring was continued for 3 h after which titration with ethylene glycol and measurement of the hydrogen evolution indicated 1.0 N. This solution was stored in the freezer and titrated prior to use. The disiamylborane solution (4.0 mL of 0.69 N in tetrahydrofuran, 2.8 mmol) was added to crude acetal 15 (600 mg) in dry tetrahydrofuran (8 mL) at 0 "C under nitrogen. Stirring was continued for 40 min after which ethanol (9 mL). 3 M sodium hydroxide solution (5.5 mL). and 30% hydrogen peroxide (5.5 mL) were introduced in sequence. After the mixture had been stirred at 25 "C for I O h, extractive workup with cthcr was undcrtakcn. Purification of the crude product by MPLC (silica gcl. clution with 35%) ethyl acetate in petroleum ether) gave alcohol 16 (465 mg, 7 4 1 ) and its diastcrcomcr (96 mg, 157,). The optical activity of 16 at this stagc, [nI2'D -45.1" (c 10.0, ether), was determined by the Mosher ester method to be 91% ee. Two recrystalli7ations of this material from petroleum ether gave colorlcss crystals: m p 82-83 "c:[fll2'D -48.9" (98% ee); 330 mg ( 5 2 % ) . Further rccryslnllizations to constant (r gave colorless prisms: mp 82-83 " C . [ u I 2 ' D -49.7" ( c 9.8. ether): IR (KBr. cm-I) 3600-3200; IH NMR (300 MH7, C,D,) 6 4.10 (d. J = 7.8 Hz. 1 H). 3.68 (m. 2 H). 3.45 (m, I H). 2.052 (s, 3 H), 2.048 (s, 3 H), 2.40-0.75 (series of m, 22 H), 1.04 (s, 9 ti). 0.94 (d, J = 7.3 Hz. 3 H). 0.130 (s. 3 H ) , 0.126 (s. 3 H); "C NMR (75 MHz, C6D6) ppm 109.17, 72.56. 61.04, 54.78, 51.82, 50.17, 47.87, 46.44,45.04,43.25,40.02.39.71. 39.12, 38.53. 33.79. 33.12. 26.27, 22.39, IX.23, 16.71, 13.44, -3.44, -4.28; MS n ~ / : (M' - CHJOH) ciilcd 365.2513, obsd 365.2573. Anal. Calcd for C26Hso0,Si: C. 68.67: H.
J . Am. Chem. S
.
V d . 112, No. 25, 1990 9297
11.08. Found: C. 68.64; I i . 1I.C'.
Methyl (ZR,3R.3aS,5R,5aS,6R,7R,8aR,8bS)-5-(terf-Butyldimethylsilox~)-6-ethyl-2-formyldodecshydro-7-methyl-as-indacene-3-tetrolate 2-(Dimethyl acetal) (2). A stirred mixture of pyridinium chlorochromatc (380 mg, 1.77 mmol) and sodium x e t a t e (290 mg, 3.54 mmol) in dry dichloromethane ( I 3 mL) was cooled to 0 "C and treated dropwise with a solution of alcohol 16 (330 mg, 0.726 mmol) in the same solvent (8 mL) during 2 min. Stirring was maintained for 2 h at 0 "C and for 2 h at 25 "C. The brown mixture was diluted with ether (50 mL) and filtered through Florisil (5 g, elution with ether). Flash chromatographic purification (silica gel, elution with 10% ethyl acetate in petroleum ether) furnished 290 mg (89?;) of 17 and 8.8 mg (3%) of unreacted alcohol. For 17: clear, colorless oil; 1R (neat, cm-I) 2700, 1726; ' H NMR (300 MHz, C@6) d 9.49 (t, J = 1.9 Hz, I H), 4.05 (d, J = 7.1 Hz, I H ) , 3.44 (m, I H), 3.08 (s, 3 H), 3.07 (s, 3 H), 2.39-2.31 (m, 1 H), 2.25-0.75 (series of m, 20 H), 1.03 (s, 9 H), 0.89 (d, J = 7.0 Hz, 3 H), 0.14 (s, 3 H), 0.12 (s, 3 H); I3C N M R (75 MHz, C6D6) ppm 200.84, 108.61, 72.80, 65.87, 54.47, 51.70, 50.60, 49.75, 48.36, 47.35, 43.19.42.69, 39.85, 39.54, 37.79, 33.92, 33.28, 26.22. 22.52, 18.27, 16.31, 15.57, 13.34, -3.62, -4.34; MS H I / : (M' - I-BuCH~OH) cakd 363.2355. obsd 363.2329; [.]25D -27.0" (c 0.1 I , cthcr) for 98% ce material. Carbon tctrabromide (420 mg. 1.3 mmol) dissolved in methylene chloride (3 mL) was added dropwise to a solution of triphenylphosphine (680 mg,2.5 mmol) in the same solvent (18 mL) at 0 "C under nitrogen. The bright yellow solution was stirred for 15 min prior to the dropwise addition of 17 (294 mg, 0.648 mmol) in methylene chloride (4 mL). The rcaction mixture was stirred for an additional 15 min, a t which point pyridine (0.3 1 mL. 3.8 mmol) was added to deter possible acetal cleavage
during subsequent processing. Extractive workup with ether following qucnching with saturated sodium bicarbonate solution provided a residual gum that was triturated several times with petroleum ether to remove most of the triphenylphosphine oxide. Final purification was achieved by chromatography on TLC mesh silica gel ( 4 g, elution with 4% ethyl acetate in petroleum ether), and 18 (395 mg, 100%) was obtained as a clear colorless oil: ' H N M R (300 MHz, C6D6) L 6.37 (t. J = 7.3 Hz, 1 H), 4.05 (d, J = 6.7 Hz, 1 H), 3.46 (m,1 H), 3.13 (s, 3 H), 3.10 (s, 3 H), 2.27-2.02 (series of m, 4 H), 1.84-1.71 (m, 5 H), 1.62-1.59 (m. 3 H). 1.48-1.25 (m, 6 H), 1.04 (s, 9 H), 1.01 (t, J = 7.5 Hz, 3 H), 0.89 (d, J = 7.1 Hz, 3 H), 0.16 (s, 3 H), 0.13 (s, 3 H); I3CN M R (75 MHz, C6D6) ppm 138.64, 108.65, 89.02, 72.86, 54.57, 52.06, 50.57, 48.40, 47.22, 46.56,42.43, 39.86, 39.81, 39.78, 38.31, 33.77, 33.28, 26.24, 22.54, 18.28, 16.33, 13.36,-3.57,-4.28; MS n i l ; ( M + - t-Bu) cakd 551.0988, obsd 551.1001: [ a I 2 ' -13.5" ~ (c 0.12, cthcr) for 98% ce material. n-Butyllithium (0.91 mL of 1.6 M in hexanes, 1.46 mmol) was added dropwisc to 18 (395 mg,0.694 mmol) in dry tetrahydrofuran (2.2 mL) at -78 "C undcr nitrogen. After 35 min of stirring a t -78 "C, the tcmpcrature was raised to 25 "C for 20 min. The reaction mixture was thcn recoolcd to -78 "C, at which point methyl chloroformate ( 1 13 pL, I .46 mmol) was introduced dropwise. After an additional 40 min at -78
"C, the mixture was allowed to warm to I O "C during I h. The addition of saturated sodium bicarbonate solution was followed by extractive workup with ether and MPLC purification on silica gel. Elution with IOYOethyl acetate in petroleum ether Tfforded 310 mg (94%) of 2 and 5.5 mg (2%) of the terminal acetyle i ,. For 2: clear colorless oil; IR (neat, cm-') 2240, 1718; ' H NMR (200 MHz, C6D,) L 4.06 (d, J = 2.1 Hz, 1 H ) , 3.50 (m, I H), 3.28 (s, 3 H),3.12 (s, 1 H), 3.09 (s, I H), 2.40 ( d d , J = 17.3.4.6Hz,I H),2.30(dd,J= 17.3,6.8Hz,I H ) , 2 . 1 5 ( m , I H). 2.05-1.60 (series of m, 8 H), 1.50-1.25 (m, 2 H), 0.15 (s, 3 H), 0.13 (s, 3 H); "C NMR (75 MHz, C6D6) ppm 154.05, 108.62, 88.68, 74.56,72.47,54.32,52.14,51.82,50.63,48.12,46.20,45.97,42.16, 39.81, 39.73, 37.52, 33.83, 26.20, 23.18, 22.52, 18.23, 16.32, 13.36.-3.79. -4.37: MS m / z (M+ - r-Bu) calcd 449.2723, obsd 449.2713; [
