3884
Journal of the American Chemical Society
(13) (a) F. A. Van-Catledge, S. D. Ittel. and J. P. Jesson, J. Organomet. Chem., 168, C25 (1979); (b) S. D. lttel and C. A. Tolman, ibid., in press. (14) See the metal atom chemistry section: K. Klabunde, P. Timms, P. S. Skell, and S. D. Ittel. Inorg. Synth., 19, 59 (1979). (15) C. A. Tolman and P. E. Antle, J. Organomet. Chem., 159, C5 (1978). (16) C. A. Tolman, Chem. Rev., 77, 313 (1977). (17) The first mechanism was proposed in H. W. Whitlock, Jr., and R. L. Markezich, J. Am. Chem. SOC.,93,2590 (1971). and R. L. Markezich and H. W. Whitlock, Jr., ibid., 93, 2591 (1971). The second proposed mechanism is based on the direct observation of di-u species such as P. B. Hitchcock and R. Mason, Chem. Commun., 242 (1967), and G. K. Barker, M. Green, J. A. K. Howard, J. L. Spencer, and F. G. A. Stone, J. Am. Chem. Soc., 98, 3373 (1976). (18) C. A . Tolman, A. D. English, S. D. Ittel, and J. P. Jesson. Inorg. Chem., 17, 2374 (1978). (19) M. T. Mocella, M. J. D’Aniello. P. Meakin, and E. K. Barefield, Inorg. Chem., to be submitted. (20) J. R. Blackborow, R. H. Grubbs, K. Hildenbrand, E. A. K. von Gustorf, A. Miyashita, and A. Scrivanti, J. Chem. Soc., Dalton Trans., 2205 (1977). (21) 6 .E. Mann, J. Organomet. Chem., 141, C33 (1977). (22) S. D. Ittel, F. A. Van-Catledge, C. A. Tolrnan, and J. P. Jesson, J, Am. Chem. Soc., 100, 1317 (1978); J. M. Williams, R. K. Brown, A. J. Schultz, G. D. Stucky, and S. D. Ittel, ibid., 100, 7407 (1978); S. D. Ittel, F. A. Van-Catledge, and J. P. Jesson, ibid., in press. (23) M. Brookhart, K. J. Karel, and L. E. Nance. J. Organomet. Chem., 140, 203 (1977). (24) 0. S. Mills and G. Robinson, Proc. Chem. SOC., London. 241 (1960). (25) 0. S. Mills and G. Robinson, Acta Crystallogr., 16, 758 (1963). (26) F. A. Cotton, V. W. Day, B. A . Frenz, K. I. Hardcastle, and J. M. Troup, J. Am. Chem. Soc., 95,4522 (1973).
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(27) J. D. Warren and R. J. Clark, Inorg. Chem., 9, 373 (1970). (28) J. D. Warren, M. A. Busch, and R. J. Clark, lnorg. Chem., 11, 452 (1972). (29) L. Kryczynski and J. Takats, J. Am. Chem. Soc.. 96, 932 (1974). (30) C. G. Kreiter, S. Stuber, and L. Wackerle. J. Organomet. Chem., 66, C49 (1974). (31) J. L. Martin and J. Takats, J. Organomet. Chem., 80, C9 (1974). (32) M. A. Busch and R. J. Clark, Inorg. Chem., 14, 226 (1975). (33) T. H. Whitesides and R. A. Budnik, Inorg. Chem., 14, 664 (1975). (34) J.-Y. Lallemand, P. Laszlo, C. Muzette. and A. Stockis, J. Organomet. Cbem., 91, 71 (1975). (35) C. E. Ungermann and K. G. Caulton. J. Organomet. Chem., 94, C9 (19751. (36) D. Leibfritz and H. Tom Dieck, J. Organomet. Chem., 1 0 5 , 255 (1976). (37) L. Kruczynski and J. Takats, Inorg. Chem., 15, 3140 (1976). (38) J. Elzinga and H. Hogeveen, Tetrahedron Lett., 2383 (1976). (39) D. J. Cole-Hamilton and G. W. Wilkinson, Nouveau J. Chim., 1, 141 (1977). (40) T. A. Albright, P. Hoffman, and R. Hoffmann. J. Am. Cbem. SOC.,99, 754 (1977). (41) R. S. Berry, J. Chem. Phys., 32, 933 (1960). (42) P. Meakin. A. D. English, S. D. Ittel. and J. P. Jesson, J. Am. Chem. Soc., 97, 1254 (1975). (43) J. C. Bailar. Jr., Inorg. Nucl. Chem. Lett., 8 , 165 (1958). (44) P. Gillespie. P.Hoffman, H. Klusacek, D. Marguarding, S. Pfohl, F. Ramirez, E. A. Tsolis, and I. Ugi, Angew. Chem., Int. Ed. Engl., 10, 687 (1971). (45) P. S. Skell and L D. Wescott, J. Am. Chem. SOC..85, 1023 (1963). (46) G. R. Stevenson, I. Ocasio, and A . Bonilia, J. Am. Chem. Soc., 98, 5469 (1976). (47) W. R. Moore and H. R. Ward, J, Org. Chem., 27, 4179 (1962).
Phenylseleno-* and Phenylsulfenolactonizations,* Two Highly Efficient and Synthetically Useful Cyclization Procedures K. C. Nicolaou,*3a’bS. P. S e i t ~W. , ~ J.~ Sipio,3band J. F. B l o ~ n t ~ ~ Contribution f r o m the Department of Chemistry. Uniceryity of Pennyylcania, Philadelphia, Prnnsylcania 19/04, and [he Chemical Research Department, Hoffniann-La Roche, Nutley, IVew Jersej 071 I O . Receiced December 12, 1978
Abstract: Phenylselenolactonizationand phenylsulfenolactonization, two new lactonization reactions, are described in detail. A series of unsaturated carboxylic acids was cyclized to phenylseleno- and phenylsulfenolactoncs by PhSeCl and PhSCI. respectively. These regio- and stereoselective ring closures are accompanied by the introduction into the organic structure of the synthetically useful PhSe and PhS groups and are. therefore. powerful synthetic methods. The phenylselenolactones so obtained are converted oxidatively with hydrogen peroxide and a variety of other oxidizing agents to unsaturated lactones and reductively to saturated lactones with Raney Ni or tri-n-butyltin hydride. The reversal of these cyclization rcactions is effected with sodium in liquid ammonia. The mildness of the reactions described and their applicability to complex c a m are demonstrated by the use of polyfunctional and sensitive substrates including prostanoid systems.
1. Introduction
Lactonization methodology plays an important role in modern organic synthetic chemistry not only because lactones occur in nature in great abundance and variety, but also because they constitute a particularly useful class of synthons. A major body of lactonieations involve the cyclization of open-chain hydroxy acids of which the most recent and elegant are the macrolide-forming reaction^.^ Another large category of lactonizations include those of unsaturated carboxylic acids ( I ) initiated by suitable electrophilic reagents. This latter class of ring closures, represented by eq 1 and proceeding by intramolecular capture of the reactive intermediate 11, is a useful reaction in that not only does it form lactones (111) but also at the same time it offers selective functionalization of unsaturated substrates. In the past the initiation of these cyclizations of olefinic carboxylic acids has been carried out by acid,5 lead tetraacetate,6 mercuric reagents,’ and halogens.8 The most common and useful of these lactonizations, the halolactonization reaction, is a powerful process in organic synthesis for 0002-7863/79/1501-3884$01 .OO/O
regio- and stereoselective functionalization of olefinic bonds even in acyclic systems.9a Its application to the stereocontrolled construction of complex natural products has been amply dem o n ~ t r a t e d .However, ~~.~ the usual requirement for aqueous basic media and the rather drastic conditions required to convert the halolactones to useful synthetic intermediates impose severe limitations to the scope of this method. The use of the other aforementioned lactonization procedures is even less widespread owing to the drastic conditions of the reactions 0 1979 American Chemical Society
Nicolaou et al.
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Phenylseleno- and Phenylsulfenolactonizations
3885
Scheme I. The Phenylselenolactonization Reaction
Se
SePh
la
1
.
1. x LRI I b X . Y h
P COO*
that are usually incompatible with a rather large number of important functionalities and protecting groups. In addition, the inability to elaborate the produced lactones to useful intermediates under acceptable conditions makes these conventional procedures even more limited. The necessity for a milder lactonization procedure for unsaturated carboxylic acids coupled with the recent successful applications of organoselenium and sulfur reagentst0in organic synthesis initiated by Sharpless' I and ReichI2 prompted us to investigate these reagents in connection with the above problem. At the outset of our work, it was known that electrophilic seleniumI3 and sulfur14 reagents would add to double bonds in a trans fashion but in a nonregioselective manner. Our hope was to develop synthetically useful intramolecular reactions involving trapping of the initially formed episelenonium or episulfonium ion by internal nucleophiles strategically placed in positions of the molecule favoring ring closure. This type of reaction, although of great potential value in the synthesis of heterocycles, has escaped systematic investigation.I5 In this paper we describe a new general method for internal lactonization of unsaturated carboxylic acids employing phenylselenenyl chloride (PhSeC1) or its sulfur counterpart, phenylsulfenyl chloride (PhSCI), which appears to be highly effective and can be carried out in organic media under very mild conditions and low temperatures. This discovery represents one of the most facile and mild lactonization procedures and introduces a t the same time into the organic molecule the phenylselenenyl (PhSe) or the phenylsulfenyl (PhS) moieties, two highly desirable groups on account of their synthetically fertile chemistries.I0 This is the first of several important synthetic applications we have discovered of this facile type of organoselenium-induced ring closure.
a
0
%Ph
0
h Iy
11. Results and Discussion
The Phenylselenolactonization Reaction. The phenylselenolactonization of unsaturated carboxylic acids is exemplified in Scheme I by the reaction of 4-cycloheptene-1 -carboxylic acid (1)16 with PhSeCl in methylene chloride at -78 OC, to afford the phenylselenolactone l a in quantitative yield. This rapid reaction proceeds in the absence or presence of base such as triethylamine, pyridine, or solid potassium carbonate. The use of base, however, to remove the liberated hydrogen chloride is advisable in sensitive cases to avoid destruction of the products. A preformation of the carboxylate salt with the organic base is essential for optimum yields. The initial step of this facile ring closure is presumably the reversible electrophilic addition of the phenylselenononium ion" to the double bond of 1 to give intermediate A. The reactive positive center is then intercepted intramolecularly by the carboxylic group leading to the observed product, phenylselenolactone la, with expulsion of hydrogen chloride. Based on the assumed S ~ 2 - t y p meche anism of the intramolecular capture of the selenonium ion and by analogy to the halolactonization reaction, the stereochemistry of the phenylselenolactones was assumed to be trans. This assumption was confirmed by an X-ray diffraction analysisls carried out on the phenylselenolactone Sa (vide infra) which showed, besides its six-membered-ring nature, the trans relationship of the phenylseleno group to the lactone functionality. To show the generality of this method a series of unsaturated
Reduction method A (Ra-Ni/Hz). Bu3SnH).
f J
b
Reduction method B (n-
carboxylic acids was utilized for the cyclization reaction. As indicated in Table I good to excellent yields of phenylselenolactones were obtained. In general, the ring closure occurs a t the carbon able to sustain the most stable carbonium ion, although subsequent rearrangement is possible to the thermodynamically most stable product. It appears that five-membered lactones are preferred over four- and six-membered and six- and seven- are preferred over seven- and eight-membered, respectively.
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3886
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FOOH
'SePh
PhSe
8b
8a
8
SePh
@ 10 COOH I
Qo 1Oa
C
c1 U
U
Figure 1. A stereoscopic structure of phenylselenolactone Sa.
Most of the unsaturated acids employed were either obtained from commercial sources or prepared according to published procedures. The dithiane acids 6 and 12 were pren
lactonization a t -78 "C produced a mixture of six- and seven-membered-ring lactones 8a and 8b observed by TLC and ' H N M R (220 MHz, CDC13: 8a, 7 5.27; 8b, 7 5.50; 8a:8bca. 3: 1 ) spectroscopy. On passage through a silica gel column, however, only one product, lactone Sa, was obtained in 85% yield. An X-ray diffraction analysis of lactone 8a established its bicyclo[4.2.2] nature. The stereoscopic structure of 8a is shown in Figure 1 .I8 The beneficial action of silica gel in converting rather cleanly the initially formed mixtures in these reactions to the thermodynamically stable product was also observed in the case of 3-buten-I-oic acid (IO). Thus, initial T L C analysis revealed what was presumed to be simple addition of PhSeCl across the double bond, whereas chromatography on silica gel yielded lactone loa. Similar phenomena were observed with a number of other unsaturated acids. The application of this new selenium-based methodology for lactone formation in polyfunctional and sensitive cases and the illustration of its usefulness in natural product synthesis were shown by the following sequences that could eventually lead to prostaglandins. The readily available cyclopentene derivative 16" was reduced to the alcohol 17 (LiAIH4-ether, 97%) and protected as the tetrahydropyranyl (18, 100%) or
P OR
6
-
12
pared from the dianion (2.2 equiv of LDA, 0 25 OC, T H F , 2 h) of the acid IVi9.20and the corresponding bromide in 85 and 90% yields, respectively. The attachment of this useful two-carbon appendage by this method seems to be quite general and proceeds in high yield.20 Alternatively the bromides were first coupled with dithiane and the products carboxylated (LDA-C02). The high tendency to initially capture a tertiary carbonium ion (carbon 0,intermediate B) and for the kinetic product to rearrange to a thermodynamically more stable lactone (7e --* 7a) was clearly seen in the phenylselenolactonizationof the
16. R 17, R 18. R 19. R
= COOCH, = CH20H = CH,OTHP =
PhSp
(J-p7a
B
i
eo 1
?e
acid 7. In this case the exclusive final product after chromatographic isolation on a silica column was the y-lactone 7a (IR vmaX1765 cm-I). However, careful I R analysis of the initially formed product revealed the @-lactone 7e (IR vmax 1820 cm-I) a s the sole substance. This material apparently rearranges rapidly to the thermodynamically more stable y-lactone by silica gel or even by itself a t ambient temperatures. 4-Cyclooctene- 1-carboxylic acid (8) l 6 on phenylseleno-
= THP 21, R = Si'BuMe,
CH,OSI'BUM~,
24
22.R-THP 23,R = SC=CH--), 4.78 (d, J = I O Hz, 1 H, H>C=CH-), 6.28 (s, 3 H, -OCH3), 6.58 (dd, J = 12, 12 Hz, CHS). 7.32 (d, J = 7 Hz, 2 H , CHS), 7.46 (d, J = I2 Hz, 2 H, CHl=CHCH2-), 7.79 (m, I H, CH2CH2S), 8.22 (m, I H, CH2CH2S); mass spectrum m/e (re1 intensity) 204 (M+, 13), 163 ( M -allyl,basepeak), 1 5 9 ( M - C 0 2 H , 4 2 ) , 119(10), 117(7),85(53). Anal. (CgH1202Sz) C, H. Reversal of the Phenylseleno- and Phenylsulfenolactonization Reactions. General Procedure. The reversal of the phenylseleno- and phenqlsulfenolactonizations to the unsaturated hydroxy acids indicated in Table I was carried out on I-mmol scale with sodium in liquid ammonia as illustrated below for the case of ( 1 a,4a,5a)-4-(phenylscleno)-6-oxabicyclo[3.2.2]nonan-7-one( l a ) ( l a -.+ I ) . To a stirred solution of sodium (230 mg, 10 mmol) in dry liquid ammonia (25 mL) cooled to -78 "C was added dropwise a solution of the phenylselenolnctonc l a (295 mg, I mmol) in dry ether (2 mL). The reaction mixture was stirred for 5 min at -78 "C and quenched with excess solid ammonium chloride and the cooling bath was removed. After the ammonia was allowed to evaporate by stirring at ambient temperature the residue was partitioned between water (25 mL) and ether (50 mL). The ether layer was separated and the aqueous phase extracted with ether (2 X 25 mL). Drying ( M g S 0 4 ) of the combined ether extracts and evaporation gave crude 4-cycloheptene- I -carboxylic acid ( l ) , which was purified by preparative layer chromatography, I 15 mg (82% yield), mp 66-67 "C ( M I h mp 65-67 "C), characterized bq spectral comparison to an authentic sample: I b I (80%, identical with an authentic sample); 2a 2 (77Y0,identical with an authentic sample); 2b -, 2 (79%, identical with an authentic sample); 3a 3 (78%. identical with an authentic sample); 9a 9 (80%. identical with 1 1 (75%, identical with an authentic an authentic sample; l l a sample). X-ray Analysis of Phenylselenolactone Sa. Crystals of Sa. obtained
-
-
-
-
-
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101:14
/ July 4, 1979
from ether-petroleum ether, were monoclinic, space roup P21/c, with a = 8.434 ( I ) , A, b = 10.566 ( I ) A, c = 15.137 (2) l , p = 96.01 (I)", and dcalcd = 1.461 g ~ m for - ~Z = 4 (ClsHlg02Se, mol wt 309.27). The intensity data were measured on a Hilger-Watts diffractometer (Ni-filtered Cu Ka radiation, 8-28 scans, pulse height discrimination). The size of the crystal used for data collection was approximately 0. I O X 0.20 X 0.25 mm; the data were corrected for absorption ( F = 39.8 cm-l). Of the 1892 independent reflections for 8 < 57O, 1643 were considered to be observed [ I > 2.5u(/)J. The structure was solved by the heavy-atom method and was refined by full-matrix least squares. In the final refinement, anisotropic thermal parameters were used for the heavier atoms and isotropic temperature factors were used for the hydrogen atoms. The hydrogen atoms were included in the structure factor calculations but their parameters were not refined. The final discrepancy indices are R = 0.039 and w R = 0.046 for the 1643 observed reflections. The final difference map ha5 no peaks -greater than f 0 . 2 e A-'.
Acknowledgment. We wish to thank Dr. M. R. Uskokovic of Hoffmann-La Roche, Nutley, N.J., for kindly arranging the X-ray analysis. 'H N M R spectra were recorded on the Middle Atlantic Regional N M R Facility ( N I H No. RR542) at the Medical School of The University of Pennsylvania supervised by Dr. G . McDonald. This work was financially supported by the donors of the Petroleum Research Fund, administered by the American Chemical Society, Merck Sharp and Dohme, Rahway, N.J., and The University of Pennsylvania. Supplementary Material Available: A listing of properties and full spectral data of compounds 4a, 5a, 1 la-I5a, 8d, 9d, 15d, and 25 and Tables 11-V listing the final atomic parameters, final anisotropic thermal parameters, bond lengths, and bond angles in Sa (7 pages) Ordering information is given on any current masthead page.
References and Notes (1) Preliminary communication:Nicolaou, K. C.; Lysenko, 2. J. Am. Chem. SOC. 1977, 99, 3185. (2) Preliminary communication: Nicolaou, K. C.; Lysenko, 2. J. Chem. SOC., Chem. Comrnun. 1977,293. (3) (a) Fellow of the Alfred P. Sloan Foundation, 1979-1981. (b) University of Pennsylvania. (c) Hoffmann-La Roche. (4) (a) Nicolaou, K. C. Tetrahedron 1977, 33, 683. (b) Masamune, S.; Bates, G. S.; Corcoran, J. W. Angew. Chem., fnt. Ed. Engf. 1977, 16, 567. (c) Back, T. G. Tetrahedron 1977, 33, 3041. Klein. J J. Oro. Chem. 1958. 23. 1209. Moriar;y,-R.-M:; W i s h , H. G.: Gopal, H. Tetrahedron Lett. 1966, 4363. (a) Rowland, R. L.; Perry, W. L.; Friedman, H. L. J. Am. Chern. SOC.1951, 73, 1040. (b) Factor, A,; Traylor. T. G. J. Org. Chern. 1968, 33, 2607. House, H. 0."Modern Synthetic Reactions", 2nd ed.; W. A. Benjamin: New York, 1972; p 441. (a) Bartlett, P. D.; Myerson, J. J. Am. Chem. SOC. 1978, 100, 3950. (b) Erythromycins: Corey, E. J.; Trybulski, E. J.; Melvin, Jr., L. J.; Nicolaou, K. C.; Secrist, J. A,; Lett, R.; Sheldrake, P. W.; Falck, J. R.; Brunelle, D. J.; Haslanger, M. F.; Kim, S.; Yoo, S. ibid. 1978, 100, 4618. (c) Prostaglandins: Corey, E. J.; Schaaf, T. K.; Huber, W.; Koelliker, U.; Weinshenker, N. M. ibid. 1970, 92, 397. Review: Selenium: (a) Reich, H. J. In "Oxidation in Organic Chemistry", Part C; Trahanovsky, W., Ed.; Academic Press: New York, 1978; p 1. (b) Reich, H. J. Acc. Chem. Res. 1979, 12, 22. (c) Sharpless, K. B.; Gordon, K. M.; Lauer, R. F.; Patrick, D. W.; Singer, S. P.; Young, M. W. Chem. Scr. 1975, 8A, 9. (d) Ciive, D. L. J. Tetrahedron 1978, 34, 1049. Sulfur: Trost, B. M. Acc. Chem. Res. 1978, 7 1, 453. Reference 23. Sharpless, K. 8.; Lauer, R. F. J. Am. Chem. SOC.1973, 95, 2697. Reich, H. J.; Reich, I. L.; Renga, J. M. J. Am. Chem. SOC. 1973, 95, 5813. (a) Reich. H. J. J. Org. Chem. 1974, 39, 428. (b) Sharpless, K. 8.; Lauer, R. F. ibid. 1974, 39, 429. (c) Clive, D. L. J. J, Chem. SOC.,Chem. Cornrnun. 1973,695. 1974, 100. (a) Kuhle, E. "The Chemistry of Sulfenic Acids", Georg Thieme Verlag: Stuttgart, 1973, and references cited therein. (b) Mueller, W. H.; Butler, P. E. J. Am. Chem. SOC. 1968, 90, 2075. (a) An isolated example of a related ring closure effected by arylselenenyl bromides in refluxing acetic acid has been reported: Campos, M. D. M.; Petragnani. N. Chem. Ber. 1960, 93, 317. (b) Subsequently to our work, Professor Sharpless also informed us of similar reactions: Lauer. R . F. Ph.D. Thesis, Massachusetts Institute of Technology, Cambridge, Mass.. 1974. (c) See also Clive, D. L. J.; Chittattu, G. J. Chem. Soc., Chem. COmmUn. 1977,484. Stork, G.; Landesman, H. D. J. Am. Chem. SOC.1956, 78, 5129. See also (a) Nicolaou, K. C.; Lysenko, 2.; Seitz. S,Org. Synth., in press. (b) Monson, R. S. "Advanced Organic Synthesis", Academic Press: New York, 1971; p 84. Schmid, G. H.; Garratt, D. G. Tetrahedron Lett. 1975, 3991. We are indebted to Dr. M. R. Uskokovic of Hoffmann-La Roche, Nutley, N.J., for the X-ray (carried out by J.F.B.) arrangement. Cossement, E.; Biname, R.; Ghosez, L. Tetrahedron Lett. 1974, 997. '
Rastetter, Richard
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Cope Rearrangement of sym-Oxepin Oxides
(20) Eliel, E. L.; Hartmann, A. A. J. Org. Chem. 1972, 37,505. (21) (a) Nicolaou, K. C.; Barnette, W. E. J. Chem. Soc., Chem. Commun. 1977, 331. (b)Corey, E. J.; Keck, G. E.; Szekely, I. J. Am. Chem. SOC.1977, 99, 2006. (22) (a) Reich, H. J.; Renga, J. M.; Reich, I. L. J. Am. Chem. SOC.1975, 97,5434. (b)Reich, H. J.; Woolowitz, S.; Trend, J. E.;Chow, F.; Wendelborn, D. F. J. Org. Chem. 1978, 43,1697. (23) Trost, B. M.; Salzmann, T. N.; Hiroi, K. J. Am. Chem. SOC. 1976, 98, 4887. (24) Nicolaou, K. C.; Lysenko, Z. Tetrahedron Lett. 1977, 1257. (25) Sevrin, M.; Ende Van, D.; Krief, A. Tetrahedron Lett. 1976, 2643. (26) Fieser, L. F.; Fieser, M. "Reagents for Organic Synthesis", Vol. 1; Wiley: New York, 1967; p 729. (27) (a) Nicolaou, K. C.; Gasic, G. P.; Barnete, W. E. Angew. Chem., /nt Ed. €ng/. 1978, 17,293. (b)Corey, E. J.; Pearce, H. L.; Szekely, I.; Ishigura, M. Tetrahedron Lett. 1978, 1023. (c) Clive, D. L. J.; Chittattu, G.; Wong, C. K. J. Chem. Soc., Chem. Commun. 1978,41. (28) (a) Preliminary communication: Nicolaou, K. C.; Sipio, W. J.; Magolda, R.
(29) (30) (31) (32)
3893 L.; Claremon, D. A. J. Chem. Soc., Chem. Commun. 1979,83. (b) Subsequent to our initial work2 a new version of this reaction appeared: Trost, B. M.; Masahito, 0.; McDougal. P. G. J. Am. Chem. SOC. 1978, 100, 7103. Kato, M.; Kageyama, M.; Tanaka, R.; Kuwahara, K.; Yoshikoshi, A. J. Org. Chem. 1975, 40,1932. Klein, J. J. Am. Chem. SOC. 1959, 81,3611. Newman, M. S.; Vander Werf. C. A. J. Am. Chem. SOC.1945, 67, 233. Noland, N. E.; Cooley, J. H.; McVeigh, P. A. J. Am. Chem. SOC.1959, 81,
.---.
im 9
(33) Augustine, R. L.; Vag, L. A. J. Org. Chem. 1975, 40, 1074. (34) (a) Roberts, J. D.; Trumbul, Jr.. E. R.: Bennett, W.; Armstrong, R. J. Am. Chem. SOC. 1950, 72, 3116. (b) Beckmann, S.;Geiger, H. Chem. Ber. I. Am. Chsm. Soc.1972, 1961, 94,48. (c) Storm, D. R.; Koshland, 94.5805. (35) Boldt, P.; Thielecke, W.; Etzenmuller, 3er. 1969, 102, 4157. (36) Dean, C. S.; Jonas, D. A,; Graham, S . H.; 1. J. Chem. SOC.C 1968, 3045. '
--
.
Conformation and Cope Rearrangement of sym-Oxepin Oxides William H. Rastetter* and Thomas J. Richard Contribution from the Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139. Receioed August 28, I978
Abstract: The synthesis of a homologous series of transoid, bridged sym-oxepin oxides (loa-c) is described. The lower homologues, IOa,b, do not undergo facile Cope rearrangement to the sym-oxepin oxides 15a,b. The generation of transoid 1Oc led rapidly to the production of the Cope rearrangement product 15c. The differing reactivity in the series loa-c is attributed to the inability of lOa,b to interconvert with their cisoid isomers, 14a,b. The production of 15c is thought to occur via ring inversion of transoid 1Oc to cisoid 14c, followed by rapid Cope rearrangement (14c + 15c). Under forcing conditions IOa,b undergo epoxide opening and a subsequent rearrangement.
I n an elegant scheme Neuss and co-workers in 1968 postulated' the intermediacy of an oxepin oxide (1, Scheme I) during the fungal biogenesis of the aranotins (e.g., acetylaranotin, 2). Thus, it was suggested, the stereochemistry of the dihydrooxepin moiety of the aranotins is established by intramolecular displacement at carbon with Walden inversion in enzyme-bound epoxide 1. The first syntheses of a n oxepin oxide were communicated by Klein and Grimme,2a and by in 1974-197s. Subsequently, we detailed3 our conversion of benzene oxide oxepin to sym-oxepin oxide (3, R = H, Scheme [ I ) , and studied the conformation and Cope rearrangement of 3 (R = H ) by ' H N M R ~ p e c t r o s c o p yOther .~ studies revealed the Cope rearrangement of a methylated derivatives and helped define the scope6 of our synthetic approach to oxepin oxides. Further, we reported the synthesis of the bridgehead diene loa7 (Scheme 1V) and characterized a derivative of 10a by X-ray crystal The possible intermediacy of an enzyme-bound oxepin oxide in biogenesis (Scheme I) raises an intriguing question of stereochemistry. A priori one must consider two stereochemical outcomes for the Cope rearrangement of a chiral oxepin oxide (4, Scheme 111). In principle, 4 could interconvert, via Cope rearrangement, with its diastereomer 5 ( 5 # 4) or with its rotamer 6 (6 = 4). The interconversion 4 F= 5 would proceed via a transition state resembling cisoid conformation 3a (Scheme 11); the degenerate rearrangement 4 F= 6 would proceed via a transoid transition state9 (cf. 3b, Scheme 11). Thus, the stereochemical integrity of an intermediate, chiral oxepin oxide would depend on the rate and the geometrical requirements of the Cope rearrangement. Herein we report that oxepin oxides locked in transoid conformations d o not 0002-786317911 SO 1-3893$01.OO/O
Scheme
I
2
I Scheme
I1
R
0
3b
30 Scheme 111
5z 4
4
6.4
undergo facile Cope rearrangements, in sharp contrast to conformationally mobile oxepin oxides. 0 1979 American Chemical Society
