J . Org. Chem. 1983,48,3269-3276
3269
Aureolic Acid Antibiotics: Synthesis of a Model Aglycon Richard W. Franck* and Thomas V. John Department of Chemistry, Fordham University, Bronx, New York 10458 Received M a r c h 14, 1982
Tetralone 34 has been synthesized in five steps and 21% overall yield. It contains four of the five chiral centers of the aglycon of the aureolic acids and lacks only an aromatic ring of the chromophore and a methyl group of the side chain, neither of which would be affected by the methodology developed for this work. The key reaction of the scheme is a Diels-Alder reaction between an o-quinone methide and a cyclic enol ether form of a sugar (glycal) (20). Thus, in one step, two chiral centers found in the sugar are merged with an aromatic framework and a third chiral center is induced. The fourth chiral center is introduced via a conversion of an unsaturated nitrile to an acyloin in a stereoselective double-bond hydroxylation.
Introduction Members of the aureolic acid group of antibiotics have been discovered and rediscovered many times since their initial identification in 1953. Various streptomyces gave birth to isolates named aureolic acid, mithramycin, LA7017, variamycin, olivomycins, NSC-A-649,chromomycins, B-599and aburamycins.' Not till 1968 did it become clear that all of the above were members of a single family.2 Relationships in the family can be summarized simply. There are two aglycons, differing only at C7, named olivin (1) and chromomycinone (2). The olivomycins (including
0Ac
I
CH
1 ',
p Olivomycin A
-1
-2
R R
= z
H , Olivin CH,, Chromomycinone
NSC-A-649) and the chromomycins (including aburamycins) have the same groups of di- and trisaccharides glycosidically linked to positions 6 and 2 of their aglycons. Aureolic acids (mithramycin, variamycin, LA-7017),just as the chromomycins, have aglycon 2 but have a different saccharide composition and linkage. The structure and stereochemistry of both aglycons was proven by using chemical and spectroscopic methods, not including X-ray, in Japan3 and the USSR4 with the last word on stereochemistry due to Russian work. Very recently, Thiem? using a very thorough analysis of 'H and 13CNMR data, has described the stereochemistry of all the glycosidic linkages in one member of each of the three major family groups. Thus 27 years after their discovery, the complete structure and stereochemistry of the aureolic acid class is finally known with certainty. One example, olivomycin A is shown. The only modern modification work on the antibiotics, in an effort to improve their antitumor activity, is due to Remers? Derivatization of the 2'-ketone and 8-phenolic hydroxyl gave compounds showing some promising effects. Synthetic studies have been carried out with both the saccharides and the aglycon; there are no published studies concerned with linking sugars to the aglycon. Remers has reviewed the saccharide synthesis program through 1977.l Recently, syntheses of olivomycose, the lone previously *Address correspondence to Hunter College, CUNY, New York, NY 10021.
unsynthesized member of the group, and disaccharides, which include olivomycose, have been reported.'^^ Other than the work to be described below, the only published experiments directed toward an aureolic acid aglycon synthesis are due to the groups of Weinreb and Thiem.g The Penn State results include a very convergent synthesis of tricyclic 3. The only functionality of the natural aglycon not included are the oxygens at C1' and C2; and concomitantly, the stereochemistry at Cl', C2, and C3 of the aglycon remains moot in model 3. The Hamburg work, which affords 4a and 4b,also does not solve the 1', 2,3 problem. Our researches have undertaken to deal with the problem of functionality and stereochemistry at these centers, and the sequel describes in detail our results, which have been (1)(a) Remers, W. A. "The Chemistry of Antitumor Antibiotics"; Wiley: New York, 1979;pp 133-75. (b) Skarbek, J. 0.;Brady, L. R. Lloydia 1976,38, 369-77. (2)Berlin, Y. A.; Kiseleva, 0. A.; Kolosov, M. N.; Shemyakin, M. M.; Soifer, V. S.; Vasina, I. V.; Yartaeva, I. V. Nature (London) 1968,218, 193-4. (3)Miyamoto, M.; Kawamatau, Y.; Kawashima, K.; Shimohara, M.; Tanaka, K.; Tatauoka, S.; Nakanishi, K. Tetrahedron 1967,23,421-427, and preceding papers. (4)Berlin, Y. A.; Kolosov, M. N.; Piotrovich, L. A. Tetrahedron Lett. 1970,1329-31,and preceding papers. (5)(a) Thiem, J.; Meyer, B. J. Chem. SOC.,Perkin Trans 2 1979, 1331-6. (b) Thiem, J.; Meyer, B. Tetrahedron 1981,37,551-8. (6)Kumar, V.; Remers, W. A.; Bradner, W. T. J . Med. Chem. 1980, 23,376-9. (7)Fuganti, C.;Grasselli, P. J. Chem. SOC.,Chem. Commun., 1978, 299-300. (8)(a) Thiem, J.; Elvers, J. Chem. Ber. 1979,112,818-22.(b) Thiem, J.; Karl, H. Ibid. 1980,113,3039-48.(c) Thiem, J.; Elvers, J. Ibid. 1980, 113,3049-57. (d) Thiem, J.; Meyer, B. Ibid. 1980,113,3058-66. (d) Thiem, J.; Meyer, B. Ibid. 1980, 113,3067-74. (9)(a) Hatch, R. P.; Shringapure, J.; Weinreb, S. M., J. Org. Chem. 1978,43,4172-77. (b) Dodd, J. H.; Weinreb, S. M. Tetrahedron Lett. 1979,3593-6. (c) Thiem, J.; W e d , H.-P. Ibid. 1980,21,3571-4;Liebigs Ann. Chem. 1981,2216-22. (d) Dodd, J. H.; Garigipati, R. S.; Weinreb, S. M. J. Org. Chem. 1982,47,4045-9.
0 1983 American Chemical Society
3270
J. Org. Chem., Vol. 48, No. 19, 1983
Franck and John Scheme I
3
Q '
4_a R = H , R ' = OH R = OH,R'= H
+
the subject of a brief communication.1° Our planning, outlined in Scheme I, was indebted to the precedent of Cava's anthracyclinone synthesis,'l which used an intermolecular Diels-Alder reaction of an o-quinone methide with a functionalized dienophile to construct an antibiotic framework. In addition, there have been many examples where intramolecular Diels-Alder reactions of o-quinone methides have been used in natural products synthesis.12 Furthermore, the well-known use of sugars to introduce chirality into noncarbohydrate molecules served as a fundamental element of our planning. Thus, the critical question initially posed by our scheme was whether a dihydropyranoid derivative of a sugar (glycal) could undergo Diels-Alder reaction with an o-quinone methide. Precedents for our desired reaction are sparse. There are six examples of unsaturated sugars participating in the Diels-Alder reaction,13 but the dienophilic bonds were activated, in one case by a nitro group and in the rest by carbonyls. An o-quinone methide (5) has been condensed with a simple enol ether (6) in one instance shown in eq l.14 In another case, the quinone methide was observed
16
a+ 0 Scheme I1
CN
10
11
m CN
2
14
5
6
/
7
8
(10) Franck, R. W.; John, T. V. J . Org. Chem. 1980,45, 1170-2. (11) Kerdesky, F. A. J.; Cava, M. P. J. Am. Chem. SOC.1978, 100, 3635-6. (12) Funk, R. L.; Vollhardt, K. P. C. Chem. SOC.Reu. 1980, 41-61. (13) (a) Jurczak, J.; Tkacs, M. Synthesis 1979,42-4. (b) Primeau, J. L.; Anderson, R. C.; Fraser-Reid,B. J.Chem. SOC.,Chem. Commun. 1980, 6-8. (c) Jones, G. Tetrahedron Lett. 1974, 2231-4. (d) Sisk, S. A.; Hutchinson, C. R. J . Org. Chem. 1979,44,3500-4. ( e ) Horton, D.; Machinami, T. J.Chem. Soc., Chem. Commun. 1981,88-90. (0 Baer, H. H.; Kienzle, F. J. Org. Chem. 1968, 33, 1823-30.
qn
OH
kN
15
to react only with the electron-poor dienophile in the presence of the unaffected enol ether in bicyclic 9.15 Thus, (14) Fleming, I.; Gianni, F. L.; Mah, T. Tetrahedron Lett. 1976,881-4. (15) Kametani, T.; Takeshita, M.; Namoto, H.; Fukomoto, K. Chem. Pharm. Bull. 1978,26, 556-62.
Aureolic Acid Antibiotics
J. Org. Chem., Vol. 48, No.
19, 1983 3271
Scheme I11
17
19
18
0
/W
J
r
20
our work began with a simple test of the first question mark of our scheme.
16
chain-to-be. Thus glucal triacetate 17 was deesterified by using methanol with a trace of methoxide to yield 18, which was ketalized, following the carefully defined conditions described by Fraser-Reid, with dimethoxypropane to yield (Scheme 111) the known 19.” Methylation of the remaining free hydroxyl with NaH, CHJ produced 20, our model dienophile in 35% overall yield from 17. After exclusion of the exo-endo ambiguity of the cyano group subsequent to Diels-Alder reaction, there are still two possible outcomes from the addition of 10 and 20. The desired outcome A has the protons at C3 and C1’ in a trans
0
0 9
Results and Discussion Cyanobenzocyclobutene 10 and dihydropyran 11 (Scheme 11) were heated for 3 h at 170 “C. A mixture of adducts 12 and 13 was obtained in 70% yield (ratio 3.7:l). They were separable by chromatography on silica gel and were characterized by their NMR spectra. That the adducts were simply stereoisomeric at the cyano groups and that regioisomer 14 was not present was shown by their quantitative conversion to bicyclic 15, characterized by its UV spectrum (Amm 224,231,275) and ita vinyl proton in the ‘H NMR spectrum (6 6.72, d, J = 4 Hz). Diradical, dipolar, and FMO arguments all rationalize the regioselective outcome of our reaction.l6 Furthermore, FMO theory also suggests that the pathway to endo product should not be overwhelminglyfavored. Unfortunately, the 9,1a coupling constants of 12 and 13 are not different enough to permit us to assign stereochemistry. Thus we do not know if endo or exo attack predominates. We next needed a sugar more highly substituted than dihydropyran. An examination of the aureolic acids revealed that the absolute configurations at side-chain carbons l’,3’, and 4’ were s,s,and R, respectively. However, if the chain were viewed as a carbohydrate with the terminal CH3 (C-5’) corresponding to C6 of a sugar, then the configurations of the side chain correspond to those of a sugar as follows: S C-1’ equivalent to R C2, S C3’ equivalent to S C4, R C4’ equivalent to R C5. For the ketone at side chain C2’ we could use the most readily available alcohol configuration at C3 of a sugar. This set of sidechain configurations corresponds to D-fucose (6-deoxygalactose), 2R,3S,4S,5R. The complete dihydropyran 16 required for the aureolic acids would be composed of a seven-carbon chain; thus a homologated D-fucose would need to be prepared. A more accessible sugar is the commercially available glucal triacetate 17. Inspection of its structure reveals that it is enantiomeric with our target 16 and is missing only the terminal methyl of the side(16) Fleming, I. ”Frontier Orbitals and Organic Chemical Reactions”; Wiley: Chichester, England, 1976; pp 132-140.
Endo A
Exo A
diaxial relationship and will arise from two unhindered transition states endo-A and em-A. The undesired outcome B has the proton at C3 cis to that at Cl’, corre-
Endo B
Exo B
sponding to an unnatural configuration, and will arise from transition states endoB and em-B. Clearly, endoB is very congested. The only hindrance in em-B is a small repulsion between a vinyl H of the quinone methide and the methyl ether of the dienophile. Essentially, the same analysis can be applied to the enantiomeric series of reactions that will be required for a total synthesis of the natural product beginning with sugar 16. A good precedent for a steric effect on the Diels-Alder reaction by an allylic substituent of the dienophile can be found in the cytochalasin work of Vedejs.la However, his addition was unquestionably endo selective since his dienophile carried an electron-withdrawing carbonyl group. In the sugar Diels-Alder work alluded to above, the allylic group was an anomeric hydroxyl or alkoxy1 and the dienophile was also electron poor and presumably endo se(17) Fraser-Reid,B.;Walker, D. L.; Tam, S. Y.-K.; Holder, N. L. Can. J . Chem. 1973,51, 3950-4. (18) Vedejs, E.;Gadwood, R. C. J. Org. Chem. 1978,43, 376-8.
Franck and John
3272 J. Org. Chem., Vol. 48, No. 19, 1983
lective. Thus, although the cited cases all did result in diene entry to the face opposite the allylic substituent, we could not be optimistic that, to the extent our reaction had an exo component, our result would favor the natural series. Subsequent to these steric arguments and the actual experiments that follow, Houk developed FMO arguments which suggest that the secondary antibonding orbital repulsions between the allylic substituent and the developing Diels-Alder transition state are crucial.lg In the present case, FMO and steric arguments lead to the same prediction. We quickly learned that sugar dienophile 20 was much less reactive than dihydropyran because when 20 and 10 were heated together at 150 “C, the only products isolated were dimers of 10, stereoisomers of structure 21 (ChartI), which presumably arise from the intermediate 4 + 2 adduct 22.20 In order to lower the concentration of reactive quinone methide, we lowered the reaction temperature to 110 “C and extended thermolysis to 10 days. Despite these mild conditions a 33% yield of dimers was obtained upon PLC elution with benzene/EtOAc in addition to material corresponding to addition of quinone methide to sugar. The adducts obtained were 23 (45%), 24 (20’70, mp 165-167 “C), 25 (9%),26 (14%, mp 142-144 “C), and 27 (470, mp 122-124 “C). The presence of five products required careful separation techniques; but since 23,24, and 27 are all useful for our synthesis, the addition reaction is viable as a synthetic step. Both 23 and 24, upon refluxing in methanol, underwent a p-elimination to afford 27 (eq 2). Thus, we assume that our isolation of 27 in the
initial reaction mixture is due to a similar elimination reaction taking place in the reaction vessel or in workup. The fact that two adducts epimeric at the cyano group formed was suggestive of a stereochemical outcome corresponding to series A described above. Only approach from the desired face of the dienophile would permit both exo and endo transition states. Furthermore, the observation of ready 8-elimination of adducts 23 and 24 was taken as evidence for their stereochemistry. Only in 23 and 24 are there large substituents located in an axial position interacting with two axial hydrogens in a 1,3 relationship. Interestingly, an axial alkyl group in the 2position of a tetrahydropyran has a conformational free energy value 50% greater than that for the same group in cyclohexane. Thus, the steric strain of the axial group bearing the cyano and aryl groups must be greater than 3 kcal/mol.21 The relief of this interaction would con(19) Caramella, P.;Rondan, N. G.; Paddon Row, M. M.; Houk, K. N. J . Am. Chem. SOC. 1981,103, 2438-40. (20) Jones, 0.W.; Kneen, G. J. Chem. SOC., Perkin Trans. 1 1976, 1647-54. (21) (a) Kleinpeter, E.;Duschek, C.; Muhlstadt, M., J. Prakt. Chem. 1978,320, 303-8. (b) Eliel, E.;Hargrave, K. D.; Pietrusiewicz, M.; Manoharan, J., “Abstracts of Papers”, 183rd National Meeting of the American Chemical Society, Las Vegas, NV, Mar 9,1982; American Chemical Society: Washington, D.C., 1982; ORG 22; J . Am. Chem. SOC.1982,104, 3635-43. (c) Franck, R. W. Tetrahedron 1983,39, in press.
tribute to the elimination being facile. Note that in 26 (from path B) one axial hydrogen remains to interact with the axial methylene substituent. Hence, we observe that triethylamine is required to force the p-elimination of 26 to yield 28 (eq 3), an epimer of 27 (vinyl H, 6 6.80). We assigned the regioisomeric adduct structure to 25 because it would not undergo @-eliminationbut simply epimerized to 25a upon treatment with triethylamine. Proton NMR, even at 270 MHz, is not an unambiguous diagnostic for stereochemistry in our system because every aliphatic hydrogen in adducts 23, 24, and 26, except for the hydrogen at C3 and the acetonide methyls, is deshielded so that there are signals for ten hydrogens in a chemical shift range of 1.5 ppm. Furthermore, nearly every proton is coupled to at least two others, except for the methyls and the proton a to the cyano group. A tentative assignment of CN stereochemistry in 23 was made by assigning the doublet at 6 4.10, J = 6 Hz, to the quasi-equatorial location developing from endo-A transition state, whereas in 24 the doublet for the 01 H was found at 6 4.43, J = 9 Hz, corresponding to the quasi-axial location arising from the exo-A transition state. The remaining resonances of adducts 23 and 24 showed remarkable agreement in chemical shift and coupling, as would be predicted since the molecules are otherwise identical. The major NMR difference between the “natural” isomer A family and the “unnatural” adduct 26 derived via transition state B was in the most shielded proton at C3. In the A series, both compounds exhibited a broad multiplet for the axial H at C3 at 6 2.38. In the B series, we assign the broad multiplet at 6 2.64 to the C3 proton, now equatorial to the tetrahydropyran ring. One is forced to conclude that the NMR evidence available for distinguishing between isomers in the A and B family is not definitive. Bicyclic cyanooctalin derivatives 27 and 28, in addition to their characterization by NMR, UV, and IR spectra, were also examined for their CD behavior. We assumed that their chromophore was the planar cyanostyrene, and we further assumed that, for CD purposes, their epimeric configurations at carbon 3 would be the major chiral perturbation of the chromophore. The spectra observed were A, 303 (Ae -0.93) and 250 (2.61) for 27 and 303 (A€ 0.82) and 255 (-1.46) for 28, essentially, equal and opposite. These data do not identify the chiralities at C3 of 27 and 28. But once the chirality is proven (vide infra), then the CD data may be used to further extend the theory of rotational effects on planar chromophores.22 In order to adjust its side-chain functionality to the desired state, six-membered acetonide 27 was treated with acetone and p-TosH (eq 4), whereupon it rearranged
31
quantitatively to five-membered acetonide 29. Clearly, the axial methyl in acetonide 27, with a steric energy of 4 (22) Snatzke, G. Angew. Chem., Zntl. Ed. Engl. 1979, 18, 363-79.
Aureolic Acid Antibiotics
J. Org. Chem., Vol. 48, No. 19, 1983 3273
kcal/mol, destabilizes the dioxane ring while the minimization of vicinal hydroxyalkyl eclipsing favors the dioxolane 29 formed at the chain terminus rather than the dioxolane that might have formed with the internal hydroxyls. The identical ketal rearrangement converted 28 to 30 (eq 5). Ketal 29 has the correct hydroxyl unveiled for generation of the side-chain ketone. Furthermore, ketal 29 is necessary for our chemical proof of stereochemistry at C3. When 29 is treated with a catalytic amount of pyridine and CuC1, it is cyclized to tetrahydrofuran 31, which has a cis-anti-cis array of substituents. A similar cyclization of epimeric ketal 30 to 32 does not take place because the product would be a very congested cis-syn-cis tetrahydrofuran. Taken together with the difference in ring-opening rates of the Diels-Alder adducts, and in the observed formation of both exo and endo adducts consistent with stereochemical predictions, this difference in tetrahydrofuran cyclization constitutes a reasonable proof that adducts 23 and 24 and their descendents 27 and 29 have the correct relative configuration at C3 for a synthesis of a “naturaln side chain. For completion of our scheme, ketal alcohol 29 was oxidized to ketal ketone 33 in 90% yield (eq 6) by using a modified Swern-Moffat reagentaZ3 29
CN
34 R-H 36 R s A c
33
Chromium reagents were not as useful for the oxidation. A modified Collins reagentz4produced some ketone but also afforded variable amounts of a ring-B aromatized species which was not completely characterized. The Corey PDC reagent25gave no oxidation of 29, but instead yielded the tetrahydrofuran 31 described above. With ketone 33 in hand, the side-chain elaboration was complete and there remained only the problem of converting the unsaturated cyanide into an acyloin. Precedent for such a conversion using vicinal hydroxylation had existed in the steroid literature. The method has recently been studied carefully by Watt.z6 Potassium permanganate and osmium tetraoxide (stoichiometric and catalytic) have been used for the glycol-forming step. In our hands the best reagent for oxidizing 33 was triphenylmethylphosphonium permanganate in CHzC12solvent at -78 OC.= There was obtained by PLC a 41% yield of 34 with acyloin hydroxyl trans to the side chain, corresponding to the natural stereochemistry of the aureolic acids. In addition, there was also obtained a 25% yield of 35, with the acyloin hydroxyl epimeric to that in 34. It
I
0 35a
8
35R.H
31 R z A c
is noteworthy that 35 exists largely as hemiketal 35a,
consistent with our assignment of the acyloin hydroxyl cis (23) Yoshimura, J.; Sato, K.; Hashimoto, H. Chem. Lett. 1977, 1327-30. (24) Garegg, P. J.; Samuelsson, B. Carbohydr. Res. 1978,67,267-70. (25) Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1978, 399-402. (26) Freerksen, R. W.; Raggio, M. L.; Thoms, C. A., Watt, D. S. J.Org. Chem. 1979,44, 702-10. (27) Reischl, W.; Zbiral, E. Tetrahedron 1979,35, 1109-10.
to the side chain in this minor isomer. There is a reasonable rationalization for the observed modest stereoselectivity of 62:38. Substrate 33 can exist in two conformations: E with side chain quasi-axial and F with side chain equatorial. Furthermore, from the coupling con-
‘CN
*v
1
/O’l
E
/
stant of H3 and H2 or 4.4 Hz, displayed in the NMR spectrum of 33, and the predicted%values for E (6 Hz) and F (2 Hz), we can calculate that the ratio of conformers E F is 6040. Furthermore, if we assume that E and F react with oxidizing agent at the same rate and that the oxidation of E is stereoselective to form 34 while of oxidation of F is selective to form 35, we would then calculate a ratio of products that would reflect the population of the conformers. An interesting observation is the variation in conformer populations, as evidenced by H3-H2 coupling in similar compounds 27, 28, 29, 30, 33, and 15 (Table I). Subtle differences in side-chain conformation must cause changes in nonbonded interactions at a level not obvious from an examination of models. Thus, at this writing, we have no logical basis for variation of structure to influence conformation. Further study of this feature of our system must be undertaken. The stereochemistry of 34 and 35 was ascertained by examining the NMR spectra of their acetates 36 and 37 prepared by treatment of the acyloins with acetic anhydride and pyridine. The major acetate 36 exhibited a J value for H(C2)-H(C3) of 12 Hz, clearly indicating a trans diaxial relationship and comparing well with the natural product value of 11.8 Hz. The minor isomer’s proton at C2 exhibited a doublet of J = 5 Hz, consistent with its assignment as equatorial. Further confirmatory data for 34 include its exhibiting two carbonyls at 1730 and 1680 cm-’, its typical aromatic acyloin UV maxima of 247 and 287 nm, and its molar rotation of +go. Comparable derivatives of the natural aglycon exhibit IR peaks of 1728 and 1690 cm-l, UV maxima of 260 and 301 nm, and a rotation of -25°.6,29 The disparity in the UV data is accounted for by the difference of a benu, and trioxynaphtho chromophore, while the opposite signs of rotation are a consequence of our starting with a sugar with chirality enantiomeric to that of the natural side chain. Again, the difference in rotational strength between the synthetic and natural compounds is due to the difference between the aromatic chromophores (compare rotations of l-phenylethanol, 42O, and 1-naphthylethanol, 74°).30 To summarize our experiments, a convergent, stereoselective synthesis of a model aureolic acid aglycon has been accomplished from readily available materials in five steps and 21% overall yield. (28) Garbisch, E. W., Jr. J. Am. Chem. SOC. 1964,86, 5561-4. (29) Miyamoto, M.; Morita, K.; Kawamatsu, Y.; Noguchi, S.; Maru-
moto, R.; Semi, M.; Nohara, S.; Nakadaira, Y., Lin, Y. Y., Nakanishi, K. Tetrahedron 1966, 22, 2761-72. (30) Barbieri, G.; Davoli, V.; Moretti, I.; Montanari, F.; Torre, G. J. Chem. SOC.C 1969, 731-5.
3274 J. Org. Chem., Vol. 48, No. 19, 1983
Franck and John
Chart I
21
X I
A
26
Table I. NMR J Values for the Vinyl H of 1-Cyanooctalins anu Their Predicted Conformer Populations compci
27 28 29
JH3-H2,
Hz
E:F
compd
5.0 3.5 4.0
75:25 35:65 50:50
30 33 15
JH3-H2,
Hz
E:F
3.5 4.4 4.0
35:65 60:40 50:50
Experimental Section Commerciallyavailable starting materials were used as supplied without further purification unless otherwise stated. Reactions were performed under dry atmospheric conditions unlesa specified otherwise. Merck 70-230 mesh silica gel was used for elution chromatography. Thin-layer chromatograms were done on silica gel coated microslides by using iodine, potassium permanganate spray, or short-wave ultraviolet light to visualize the spots. Preparative thin-layer plates were prepared by using Merck silica gel 60 PF-254. Dried and distilled solvents were used unless reported otherwise. Melting points were taken on a Fischer-Johns melting point apparatus and were uncorrected. Infrared spectra were recorded on a Perkin-Elmer 710B spectrometer. Nuclear magnetic resonance spectra were obtained a t 60 MHz on Varian A-60A and a t 100 MHz on XL-100 instruments with signals reported relative to internal tetramethylsilane. The 270-MHz and the 360-MHz spectra were furnished by the Northeast Regional NSF/NMR Facility at Yale University and Pennsylvania State University, respectively. The ultraviolet spectra were recorded on a Cary 15 spectrometer, and the circular dichroism curves were obtained on a Cary 60 ORD-CD instrument. The specific rotations were measured on a Perkin-Elmer 149 polarimeter. The medium-resolution chemical ionization mass spectra were furnished by the mass spectrometry center at Columbia University. High-resolution mass spectra were obtained a t the mass spectrometry center of the University of Pennsylvania. Elemental analyses were performed by the Spang Microanalytical Laboratory, Eagle Harbor, MI. 3,4,4a,5,10,10a-Hexahydro-l0-cyano-2H-naphtho[2,3-~1pyrans (12 and 13). A dry Pyrex glass tube (1 cm X 15 cm)
pretreated with hexamethyldisilazane, was charged with cyanobenzocyclobutene 10 (125 mg, 0.969 mmol) and dihydropyran 11 (1600 mg, 19.02 mol). The glass tube, cooled in an acetone-dry ice bath, was sealed and then immersed in an oil bath maintained at 170-175 "C. After 3 h of heating, the tube was cooled and opened. The excess dihydropyran was evaporated under reduced pressure. The syrupy residue was then subjected to preparative thin-layer chromatography (PTLC) on silica gel. Four elutions with hexane followed by three elutions with hexane-ethyl acetate (955) gave unreacted 10 (23 mg) and naphthopyran 12 (92 mg) 54.6% (based on amount of 10 consumed) as colorless crystals: mp 98-100 "C (once crystallized from hexane-ethyl acetate, 95:5); 'H NMR (CDC1,270 MHz) 6 7.50-7.00 (4 H, m, aromatic), 4.22 (1H, d, J = 3.6 Hz, CHCN), 4.14 (1H, m, OC"), 4.01 (1 H, dd, J = 3.6, 1.5 Hz, OCHCHCN), 3.62 (1H, m, OCHH'), 3.18 (1 H, dd, J = 12,17 Hz, benzylic H), 2.66 (1H, dd, J = 6.6, 17 Hz, benzylic H), 2.00 (1H, m, CH), 1.90-1.40 (4 H, m, CH2CH2);IR umLU (film) 3075, 3040, 2250 (C=N), 1600, 1495, 1060 cm-'. Also obtained from the PTLC was napthopyran 13 (25 mg, 14.6%, based on amount of 10 consumed) as a colorless syrup: 'H NMR (CDCl,, 270 MHz) 6 7.29-7.14 (4 H, m, aromatic), 4.05-3.97 (3 H, m, CHCN, OCH-, OCHH?, 3.08 (1H, dd, J = 11.5 17 Hz, benzylic H), 2.72 (1 H, dd, J = 6.6, 17 Hz, benzylic H), 2.28 (1 H, m, CH), 1.85-1.45 (4 H, m, CH2CH2);IR u,, (film) 3075, 3040, 2250 ( C e N ) , 1600, 1495, 1450, 1060 cm-'. l-Cyano-3,4-dihydro-3-(3-hydroxypropy1)napht halene ( 15). A solution of cyanonaptho(2,3-b)pyran 12 (40 mg, 0.18 mmol) in ethyl acetate (2 mL) was refluxed with powdered alumina (150 mg, 1.47 mmol). After 24 h the mixture was filtered, and the solvent was concentrated under vacuum. The residue was then subjected to preparative thin-layer chromatography with carbon tetrachloride-ethyl acetate (7:3) as eluent to give the starting material 12 (8 mg) and the ring-opened naphthopyran 15 (29 mg) 73% as a colorless oil. The naptho[2,3-b]pyran13 (23 mg, 0.108 "01) when subjected to the above reaction using ethyl acetate (1mL) and alumina (100 mg, 0.98 mmol) gave the same ring-opened product 15: 21 mg (90%);'H NMR (CDCl,, 100 M H z ) 6 7.44-7.00 (4 H, m, aromatic),
~.~~(~H,J=~Hz,CH~(CN)),~.~~(~H,~,J= 3.01-2.54 (3 H, m), 1.60 (1 H, OH, exchangeable with D20), 1.74-1.36 (4 H, m, CH2CHd;IR u, (film) 3400 (OH), 3070,3020, (ethanol) 224 2230 (C=N), 1600,1490,1450,1050 cm-'; UV A, (e 38005), 231 (c 3580), 275 nm (c 1830);MS calcd for C14H15N0 213.12, obsd m / e (30 ev) (relative intensity) 213 (26, M'), 195 (4, M+ - H2O), 167 (74), 166 (71), 154 (loo), 153 (71), 129 (49), 127 (60), 115 (22), 97 (14), 83 (31), 57 (51), 44 (77), 43 (65), 41 (71). Preparation of DGlucal(l8). Triacetyl g l u m (17,40 g, 0.147 mol) was converted, using the procedure of Roth and Pigman,,' into D-glud (18): 17.28 g (80.4%); mp 56-58 "C (lit.31mp 57-59 "C); 'H NMR (acetone-& 100 MHz) 6 6.27 (1H, dd, J = 1.5,6 Hz, -OCH=CH), 4.62 (1H, dd, J = 2, 6 Hz, CH=CHO), 4.14 (1 H, m, -CHOH). 1,2-Dideoxy-4,6-0-isopropylidene-~-arab~no -hex-1-enopyranose (19). The method of Fraser-Reid et al." was adopted with a slight modification of the workup; namely, in our work the DMF solvent was removed by distillation rather than with water extraction. The physical properties of our sample of 19 are in agreement with those reported. 1,2-Dideoxy-4,6-04sopropylidene-3-0-methyl-D-arabho hex-1-enopyranose (20). Sodium hydride (4.2 g, 175 mmol), as a 50% dispersion in oil, in a dry flask under an atmosphere of nitrogen was washed with dry pentane (3 X 50 mL), and the resulting oil-free sodium hydride was suspended in dry glyme (50 mL) followed by the dropwise addition of a solution of 4,6-0isopropylidene D-glucal 19 (8.5 g, 45.6 mmol) in dry glyme (50 mL). The mixture was stirred at room temperature for 30 min before a solution of methyl iodide (15 g, 91.46 mmol) in dry glyme (25 mL) was added dropwise over a period of 20 min. after 1 h a further amount of methyl iodide (10 g, 60.1 mmol) was added and the stirring continued for 1h more. The mixture was then cooled in an ice bath and the excess sodium hydride quenched with absolute ethanol. Workup gave a light yellow liquid, which (31)Roth, W.; Pigman, W. "Methods in Carbohydrate Chemistry"; Academic Press: New York, 1963; Vol. 11, p 407.
J . Org. Chem., Vol. 48, No. 19, 1983 3275
Aureolic Acid Antibiotics
1070 cm-'; U V A, (ethanol) 273 (t 9200), 224 nm (c 20400); CD (ethanol) 303 (Ac -0.93), 250 nm (Ac 2.61). Anal. Calcd for C19H2,04N(329.1627): C, 69.28; H, 7.04; N, 4.25. Found: (329.1614): C, 69.34; H, 6.99; N, 4.25. Repeating the above procedure on the Diels-Alder adduct 23 (64 mg, 0.19 mmol) gave the ring-opened adduct 27 (60 mg, 94%), which was identical with the authentic sample obtained by the (4aR *,5aR *,1laR *,12aR *)-4,4a,5a,6,11,1la,12,12a-Octaring opening of the Diels-Alder adduct 24. hydro-6-cyano-l2(R )-methoxynaphtho[2,3-b ]pyrano[3,2d]-2,2-dimethyl-1,3-dioxins (23 and 24). A mixture of 10 (102 The stereoisomericDiels-Alder adduct 26 (24 mg, 0.073 mmol) was refluxed for 24 h in dry methanol (10 mL). The methanol mg, 0.79 mmol) and 4,6-0-isopropylidene 3-0-methyl glucal20 was evaporated under reduced pressure, and the residue was (8.3 g, 41.5 mmol) in a sealed Pyrex tube was heated at 110 "C purified by PTLC on silica gel with benzene-ethyl acetate (4:1, for 10 days. The reaction mixture was cooled, and the unreacted glucal 20 (7.8 g) was recovered by distillation under reduced v/v) to afford the unreacted 26 (R, 0.31, (10 mg) and 1-cyano3,4-dihydro-3(R*)-(l-methoxy-2,4-0-isopropylidene-3-hydroxypressure (60 "C (0.05 mm)). The residual mixture was subjected buty1)naphthalene (28): R, 0.13; 12 mg (50%); +0.1lo (c to PTLC on silia gel with benzene-ethyl acetate (9:l) as eluent with two developments to isolate the adducts 23 (R, 0.48,78 mg, 3.24 X lo-,, CHCl,); 'H NMR (CDCl,, 100 MHz) b 7.50-7.02 (4 45%) and 24 (Rf0.59,34 mg, 20%), mp 165-167 "C (benzene-ethyl H, m, aromatic), 6.92 (1H, d, J = 3.5 Hz, CH=(CN), 3.90-3.50 (5 H,m), 3.52 (3 H, s, OCH,), 3.20-2.76 (3 H , m , CHCH,), 2.00 acetate, 91), along with the two quinone methide dimers 21a and (1H, OH, exchangeable with D20), 1.43 and 1.38 (6 H, pair of 21b (Rf0.88 and 0.78, respectively; 33 mg, 33%). S, (CH,),C); IR,Y (CHC1,) 3440 (OH), 2200 (CEN), 1600,1485, In addition to the above products was isolated the stereoisomer 1445,1375,1075 cm-'; UV A, (ethanol) 273 (t 9800), 224 nm (c (4&* ,5aS*,1l&*, 12&*)-4,4a,5a,6,11,1 la, 12,12a-octahydro-6cyano-l2(R)-methoxynaphtho[ 2,3-b]pyrano[ 3,2-d]-2,2-di21 150); CD,& ,, (ethanol) 303 (Ac 0.82), 255 nm (At -1.46); MS, calcd for C19H2304N329, m / e (relative intensity) 329 (11,M'), methyl-lI3-dioxin (26) [Rf0.33;(25 mg, 14%; mp 142-144 "C] and the regioisomer 4,4a,5a,6,11,1la,l2,12a-octahydro-1l-cyano-l2- 271 (38, M+ - (CH3)2CO),253 (5), 221 (8), 197 (12), 100 (100). Epimerization of Adduct 23 to Adduct 24. To adduct 23 (R)-methoxynaphtho[2,3-b]ppano[3,2-d]-2,2-dimethyl-l,3-dioxin (50 mg, 0.152 mmol) in ethyl acetate (3 mL) was added alumina (25) [R,O.38; 15 mg, 9%] and a mixture of the ring-opened adducts (E. Merck GF-254), and the solution was stirred for 4 h at room 27 and 28 [ R j 0.15; 7 mg, 4%1. 23: 'H NMR (CDC13100 MHz) 6 7.50 (4 H, m, aromatic), 4.54 temperature. The alumina was filtered off, and filtrate was evaporated under reduced pressure. The syrupy residue was (1H, dd, J = 6 Hz each, OCHCHCN), 4.10 (1 H, d, J = 6 Hz, CHCN), 4.00-3.52 (4 H, m), 3.44 (3 H, s, OCH,), 3.00 and 2.94 subjected to purification by PTLC on silica gel with benzeneethyl acetate (41 v/v) to afford the isomerized adduct 24 (26 mg, 52%), (2 H, pair of d, J = 17 Hz each benzylic H), 2.82 (1H, m, C4-H?), which was identical with the authentic sample independently 2.39 (1 H, dd, J = 12, 6 Hz, CH,CH,), 1.52 and 1.38 (6 H, pair isolated from the Diels-Alder reaction of cyanobenzocyclobutene of s, (CH,),C); IR,v (film),2225 (&N), 1445,1370,1265,1205, 10 and sugar 20. Also isolated was the ring-opened adduct 27 (15 1100,955,850,750cm-'; MS calcd for C19H2304N329, obsd m / e mg, 30%), mp 122-124 "C. (relative intensity) 329 (100, M'), 271 (86, M+ - (CH&CO), 239 (26), 227 (20), 187 (33), 157 (36), 142 (37), 72 (64). 4,4a,5a,6,1l,lla,l2,12a-Octahydro-ll-cyano12(R)-meth24: 'H NMR (CDCl,, 270 MHz) 6 7.54-7.19 (4 H, m, aromatic), oxynaphtho[2,3-b ]pyrano[3,2-d]-2,2-dimethyl-1,3-dioxin (25a). A mixture of the adduct 25 (40 mg, 0.122 mmol), methanol 4.50 (1H, dd, J = 5 , 9 Hz, OCHCHCN), 4.43 (1H, d, J = 9 Hz, (10 mL) and triethylamine (5 mL) was refluxed for 12 h. The CHCN), 3.97-3.52 (4 H, m), 3.44 (3 H, s, OCH,), 3.16 and 3.03 solvent was evaporated under reduced pressure, and the residue (2 H, pair of d, J = 17 Hz, benzylic H), 2.95 (1H, m, C4-H?),2.36 (1H, m, CHCH,Ph), 1.52 and 1.38 (6 H, pair of s, (CH,),C); IR was subjected to purification by PTLC on silica gel with benzene-ethyl acetate (3:2 v/v) to give product 25a epimeric to the v,, (CHCl3) 2225 (CEN), 1600,1458,1445, 1370,1120,1090,845 adduct 25 a t the carbon atom bearing the cyano group: Rf 0.58; cm-'; MS calcd for C19H2,04N329, obsd m / e (relative intensity) 34 mg (85%);mp 138-140 "C; 'H NMR (CDC13, 100 MHz) 6 329 (100, M+), 303 (9), 271 (22, M+ - (CH,)&O), 239 (18), 227 7.30-7.02 (4 H, m, aromatic), 4.70 (1H, m, OCHCH,Ph), 4.34 (1 (5), 100 (4). H, d , J = 2 Hz, CHCN), 3.86-3.54 (5 H, m), 3.40 (3 H, s, OCH,), Anal. Calcd for C1gH&4N C, 69.28; H, 7.04; N, 4.25. Found 3.12-2.88 (2 H, m, benzylic H), 2.42 (1H, ddd, J = 2, 6, 11 Hz, C, 69.53; H, 7.04; N, 4.07. CHCHCN), 1.54 and 1.38 (6 H, pair of S, (CH,),C); IR v,, (CHCl3) 26: 'H NMR (CDCI,, 100 MHz) 6 7.50-7.02 (4 H, m, aromatic), 2220 (C=N), 1600,1490,1450,1375,1260,1115,1090,935,850 4.24 (1 H, d, J = 4 Hz, CHCN), 4.10 (1 H, dd, J = 4, 2 Hz), cm-'. 3.96-3.22 (5 H, m), 3.47 (3 H, s, OCH3), 2.92 (2 H, m, benzylic l-Cyano-3,4-dihydro-3-(l-methoxy-3,4-0-isopropylideneH), 2.60 (1H, m, CHCH,), 1.50 and 1.42 (6 H, pair of s, (CH3),C); 2-hydroxybuty1)naphthalenes(29 and 30). To a solution of IR V , (Kl3r) 2225 (C=N), 1445,1370,1260,1200,1100,995,850, the six-membered acetonide 27 (130 mg, 0.634 mmol) in dry 740 cm-l; MS, calcd for ClgH2,04N 329, obsd m / e (relative inacetone (10 mL) was added a catalytic amount of p-toluenesulfonic tensity) 329 (100, M'), 271 (84, M+ - (CH3),CO), 239 (291, 201 acid, and the mixture stirred under reflux for 16 h. The acid was ( E ) , 142 (20), 100 (9), 72 (86). neutralized with powdered calcium oxide, and the inorganic salts 25 'H NMR (CDCl, 100 MHz) 6 7.64-7.06 (4 H, m, aromatic), were filtered off. The filtrate was evaporated, and the residue 4.40 (1 H, m, OCHCH,Ph), 4.03 (1 H, d, J = 4 Hz, CHCN), was subjected to purification by PTLC on silica gel with benz3.84-3.42 (4 H, m), 3.40 (3 H, s, OCH,), 3.30-2.90 (3 H, m, benzylic ene-ethyl acetate (3:2 v/v) to yield l-cyano-3,4-dihydro-3(S*)H C,-H?), 2.66 (1H, ddd, J = 4,6, 11Hz, CHCHCN), 1.50 and (l-methoxy-3,4-0-isopropylidene-2-hydroxybutyl)napht~ene(29) 1.36 (6 H, pair of s, (CH,),C); IR ,,v (film) 2230 (CEN), 1450, [Rf0.32; 120 mg, 92%] as a colorless waxy solid. The waxy solid 1370, 1265, 1205, 1100,955,860, 745 cm-'. crystallized on standing for a few days, mp 124-128 "C. l-Cyano-3,4-dihydro-3-(l-methoxy-2,4-0-isopropylidene29: 'H NMR (CDCl, 100 MHz) b 7.50-7.10 (4 H, m, aromatic), 3-hydroxybuty1)naphthalenes(27 and 28). Naphtho[2,3-b]6.83 (1H, d, J = 4 Hz, CHC(CN)), 4.14-3.80 (3 H, m), 3.54-3.30 pyrano[3,2-d]-2,2-dimethyl-1,3-dioxin (24, 123 mg, 0.37 mmol) (2 H,m),3.46 (3 H,s,0CH3),3.10-2.84 (3 H,m,CHCH,Ph), 2.24 in dry methanol (5 mL) was refluxed under nitrogen atmosphere, (1 H, OH, exchangeable with D20), 1.35 and 1.31 (6 H, pair of and the reaction was monitored by TLC. After 24 h, the methanol s, (CH,),C); IR Y(CHC13)3475 (OH), 2205 (CEN), 1600,1450, was evaporated under reduced pressure to give a waxy solid 1370,1220,1070,845,760 cm-'; MS calcd for C1&Ia04N 329, obsd residue, which when crystallized from petroleum ether-ethyl m / e (relative intensity) 329 (6, M'), 271 (9, m+ - (CH3)2CO),253 acetate (101) gave colorless crystals of l-cyano-3,4-dihydro-3(7), 221 (5), 197 (16), 153 (22), 118 (53), 100 (loo), 86 (55), 74 (39). ( S * ) - (l-methoxy-2,4-0-isopropylidene-3-hydroxybutyl)Anal. Calcd. for ClgH2304N(329.1627): C, 69.28; H, 7.04; N, naphthalene (27): 118 mg (96%); mp 122-124 "C; [aI2O~ -36.5" 4.25. Found (329.1641): C, 69.11; H, 7.13; N, 4.14. (C 2.02 X lo-,, CHC13); 'H NMR (CDCl3, 100 MHz) 6 7.52-7.08 Applying the above procedure to the isomeric six-membered (4 H, m, aromatic), 6.82 (1H, d, J = 5 Hz, CH==C(CN)),4.00-3.50 acetonide 28 (12 mg, 0.036 mmol) obtained l-cyano-3,4-di(5 H, m), 3.46 (3 H, s, OCH3), 3.16-2.78 (3 H, m, CH2CH), 1.90 hydro-3(R*)-(l-methoxy-3,4-0-isopropylidene-2-hydroxybutyl)(1H, OH, exchangeable with D20), 1.44 (6 H, s, (CH3),C);IR,,v naphthalene (30 10 mg, 83%) as a colorless thick oil. (CHC13) 3450 (OH), 2200 (CEN), 1600,1480,1445,1375,1090,
on distillation under vacuum gave the 4,6-0-isopropylidene-3-0methyl glucal20 (8.45 g, 92.46%) as a colorless liquid: bp 60 "C (0.05"); 'H NMR (CDCl,, 100 MHz) 6 6.27 (1H, dd, J = 1 , 6 Hz, OCH=CH), 4.75 (1HI dd, J = 1,6 Hz, OCH=Cm, 3.98-3.60 (5 H, m), 3.43 (3 H, s, OCH,), 1.54 and 1.43 (6 H, pair of singlets (CC14)3075,1640,1430,1380,1100,865cm-'. (CH,),C); IR,v
A,
3276 J. Org. Chem., Vol. 48, No. 19, 1983
Franck and John
3 0 'H NMR (CDCl,, 100 MHz) 6 7.50-7.04 (4 H, m, aromatic), Also isolated was the lactol3a,4-dihydro-l-hydroxy-l-(2,2-di6.87 (1H, d, J = 3.5 Hz, CH=(CN)), 4.18-3.83 (3 H, m), 3.58-3.26 methyl-1,3-dioxalan-4-yl)-3-methoxy-9-oxo-2H-naphtho[2,3-~]3H-furan (35a), mp 66-68 'C (petroleum ethen-ethyl acetate), (2 H, m), 3.52 (3 H, s, OCH,), 3.10-2.66 (3 H, m, CHCH2Ph),2.16 coexisting with a small amount of the ketone form 2(S*)(1 H, OH, exchangeable with DzO), 1.36 and 1.34 (6 H, pair of hydroxy-3,4-dihydro-3(l-methoxy-3,4-O-isopropylidine-2-oxoS, (CH3)ZC);IR ,,Y (CHCl3) 3470 (OH), 2205 (CEN), 1600,1445 cm-'. butyl)-1(2H)-naphthalenone(35): Rf0.23; 'H NMR (CDCl,, 60 2,3,3a,4,9,9a-Hexahydro-9-cyano-3-methoxy-2-(2,2-di- MHz) 6 7.90 (1 H, d, J = 8 Hz, aromatic), 7.56-7.20 (3 H, m, aromatic), 4.57 (1 H, d, J = 6 Hz, OCHC=O), 4.17-3.90 (3 H, methyl-l,3-dioxalan-4-yl)naphtho[2,3-b]furan (31). A mixture of dihydrocyanonaphthalene 29 (25 mg, 0.076 mmol), a few drops m, OCHCH,O), 3.73 (1H, d, J = 5.5 Hz, CHOCH3), 3.53 (3 H, of pyridine, and a trace amount of cuprous chloride in methylene s, OCHJ, 3.30-2.90 (3 H, m, PhCH2CH), 3.28 (1 H, OH, exchloride (2 mL) was stirred for 24 h. The reaction mixture was changeable with DzO), 1.26 and 1.24 (6 H, pair of s, (CH,),C; IR filtered through a small bed of silica gel under suction and washed ,v (film) 3450 (OH), 1685 (PHC=O), 1600,1460,1370,970,850, with ethyl acetate (15 mL), and the combined filtrate was 780 cm-'; UV ,A, (ethanol) 255 (c 9100), 290 nm (e 2200); MS evaporated under reduced pressure. The waxy residue was calcd for C18HzzOB 334, obsd m / e (relative intensity) 334 (7, M"), subjected to purification by PTLC on silica gel with benzeneethyl 316 (98, M" - HZO), 300 ( l l ) , 276 (51,258 (25), 247 (a), 246 (71), 204 (6), 188 (13), 170 (72), 160 (14), 144 (7, 116 (26), 106 (43), 100 acetate (3:l v/v) to give the ring-closed furan adduct 31 (R 0.34, 19 mg, 76%): 'H NMR (CDCl,, 270 MHz) 6 7.97 (1 H, J = (loo), 88 (63), 86 (30), 84 (17), 74 (64), 60 (72). 9 Hz, aromatic), 7.55 and 7.51 (2 H, pair of dd, J = 8, 9 Hz, Anal. Calcd for Cl8HBO6(334.1417): C, 64.66; H, 6.63. Found aromatic), 7.24 (1 H, d, J = 9 Hz, aromatic), 4.46 (1 H, d, J = (334.1367): C, 64.50; H, 6.54. 6 Hz, CHCN), 4.34 (1H, dd, J = 6,7 Hz, OCHCHCN), 4.20-4.00 2-Acetoxy-3,4-dihydro-3-( 1 - m e t h o x y - 3 , 4 - O- i s o propylidene-2-oxobutyl)-1(2H)-naphthalenones (36 and 37). (4 H, m), 3.85 (1 H, d d , J = 2, 4.5 Hz, OCHCHOCH,), 3.46 (3 H, s, OCH,), 3.01 (2 H, m, benzylic H), 2.80 (1H, m, CHCH2Ph), To a mixture of dry pyridine,(1.5 mL) and acetic anhydride (1 mL) was added 2(R)-hydroxy-l-tetralone(34,20 mg, 0.06 mmol). 1.41 and 1.36 (6 H, pair of s, (CH,),C); IR vm= (CHC13) 2220 ( C s N ) , 1595, 1450, 1380, 1365, 1220, 1060, 845 cm-'. The solution was kept at room temperature for 24 h. Water (10 mL) was added to the reaction mixture, which was then stirred l - C y a n 0 - 3 , 4 - d i h y d r o - 3 ( 5 * ) - ( l - m e t h o x y - 3 , 4 - 0 -isofor 10 min and worked up. The resulting yellow oil was purified propylidene-2-oxobuty1)naphthalene(33). To a solution of by PTLC on silica gel with benzen-thy1 acetate (41 v/v) to give dry dimethyl sulfoxide (186 mg, 2.38 mmol) in dry methylene 2(R*)-acetoxy-3,4-dihydro-3(S*)-( l-methoxy-3,rl-O-isochloride (3 mL) cooled in an acetone-dry ice bath was added propylidene-2-oxobutyl)-1(2Zf)-naphthalenone (36; R, 0.40) as a dropwise a solution of trifluoroacetic anhydride (275 mg, 1.79 syrup, which crystallized gradually when kept under vacuum mmol) in methylene chloride (1mL). The mixture was stirred for 15 min before a solution of the hydroxy compound 29 (98 mg, overnight (17 mg, 85%): mp 92-96 "C; [.]%D 8.98' (c 8.2 x CHC1,); 'H NMR (CDC13, 100 MHz) 6 7.93 (1 H, d, J = 7 Hz, 0.30 mmol) in methyIene chloride (1 mL) was added dropwise. C8-H),7.6-7.08 (3 H, m, aromatic), 5.62 (1H, d, J = 12 Hz, C,-H), The mixture was stirred for 1.5 h and then quenched with tri4.70 (1 H, dd, J = 6, 7 Hz, OCHCH,O), 4.40-3.90 (3 H, m, ethylamine. Workup gave a light yellow syrup, which was purified by PTLC on silica gel with benzene-ethyl acetate (3:2 v/v) to CHOCH3,OCH,), 3.42 (3 H, s, OCHd, 3.35-2.98 (2 H, m, benzylic H), 2.68 (1H, m, CHCH2),1.47 and 1.38 (6 H, pair of s, (CH3),C); furnish the ketone 33 (R,0.56,91 mg, 93%) as a colorless oil: 'H NMR (CDCI,, 270 MHz) 6 7.48-7.14 (4 H, m, aromatic), 6.73 (1 IR v- (CHC13)1750-1690 (CH,C=O, ArC==O, C=O) cm-'; UV H, d, J = 4.4 Hz, CH=C(CN)), 4.73 (1 H, dd, J = 6, 8 Hz, A- (ethanol) 252 (e 37600), 295 nm (c 600);MS calcd for CpH2407 OCH,CHCO), 4.27-4.00 (3 H, complex m, CHOCH3,OCHJ, 3.46 376, obsd m / e (relative intensity) 376 (11, M+), 318 (47, M+ (CHdzCO),317 (25), 316 (90, M+-CH&OOH), 300 (111,258(100, (3 H, s, OCH,), 3.23-2.68 (3 H, complex m, CHCH,Ph), 1.42 and 1.39 (6 H, pair of s, (CH3),C); IR v- (film) 2225 (C=N), 1745 M" - (CHJZCO - CH&OOH), 246 (71), 230 (17), 202 (45), 187 (34), 186 (50), 170 (80), 116 (76), 100 (62), 84 (20), 60 (97). (C=O), 1450, 1375, 1210, 1050, 840, 760 cm-'; MS, calcd for Anal. Calcd for C d N O 7(376.1522): C, 63.82; H, 6.43. Found C1&IzlO,N 327, obsd m / e (relative intensity) 327 (8, M+),285 (la), (377.1600, M + 1): C, 63.96; H, 6.44. 269 (24, M" - (CH,)&O), 253 (9), 197 (3), 181 (12), 172 (13), 153 Applying the above procedure to the mixture of 2(S*)(32), 116 (loo), 100 (39), 84 (79), 72 (22). hydroxy-1-tetralone (35) and ita isomeric lactol35a (18 mg, 0.036 Anal. Calcd for C19Hz104N(327.1471): C, 69.71; H, 6.46; N, 4.28. Found (327.1480): C, 69.56; H, 6.58; N, 4.34. mmol) obtained 2(S*)-acetoxy-3,4-dihydro-3(S*)-(l-methoxy3,4-0-isopropylidene-2-oxobutyl)-1(2H)-naphthalenone (37): 7 2-Hydroxy-3,4-dihydro-3(S*)-( l-methoxy-3,4-0 - b o propylidene-2-oxobutyl)-1(2H)-naphthalenones(34 and 35). mg (35%); [CY]%D+7.52 (C 2.12 X lo4, CHCld 89 a 8 p . p : 'H NMR (CDCI,; 100 MHz) 6 7.90 (1H, d, J = 8 Hz, aromatic), 7.62-7.05 Triphenylmethylphosphonium permanganate (124 mg,0.31 "01) (3 H, m, aromatic), 5.80 (1H, d, J = 5 Hz, Cz-H),4.70 (1 H, dd, was dissolved with cautionz7in methylene chloride (3 mL) and J = 6, 7 Hz, OCHCH20), 4.32-3.38 (3 H, m, OCH,CHO, cooled to -70 "C in an acetone-dry ice bath. A solution of the unsaturated nitrile 33 (75 mg, 0.23 mmol) in methylene chloride CHOCH,), 3.34-3.02 (2 H, m, CHzPh),3.14 (3 H, s, OCH,), 2.70 (1H, m, CHCH,Ph), 2.23 (3 H, s, acetate), 1.48 and 1.36 (6 H, was added dropwise, and the mixture was stirred for 4 h. The reaction mixture was then quenched with saturated sodium bipair of s, (CH3),C); IR vmsl (CHCI,) 1750-1690 (CH,C=O, Arsulfite solution (1mL), and the mixture was slowly brought to C=O,M) cm-l; MS, calcd for C a x 0 7 376, obsd m / e (relative room temperature. More methylene chloride (15 mL) was added, intensity) 376 (13, M+), 318 (24, M+ - (CH3)&O), 316 (9, M+ CH3COOH),300 (7) 285 (43), 246 (14), 187 (20), 186 (9), 170 (20), and the organic layer was dried over anhydrous sodium sulfate. 116 (12), 100 (6), 84 (7), 60 (100). The solvent was concentrated, and the waxy solid when extracted with ethyl acetate gave a white precipitate of phosphonium salt, Acknowledgment. This research was supported by which was filtered off, and the fitrate waa then concentrated. The Grants RR-7150 and CA-27116 from DHSS. We are oily residue when subjected to PTLC on silica gel with benzene-ethyl acetate (3:2 v/v), two developments, gave the desired grateful to Professor S. M. Weinreb for many helpful 2(R*)-hydroxy-3,4-dihydro-3(S*)-( l-methoxy-3,4-0-isodiscussions concerning the problems of synthesis of the propylidene-2-oxobutyl)-l(2.H)-naphthalenone(34,Rf0.40,31 mg, aglycone. We also thank Dr. Louise Foley for many helpful 40.5%) as a colorless syrup: 'H NMR (CDCl,, 60 MHz) 6 7.98 suggestions concerning the carbohydrate literature and (1H, d, J = 7 Hz, aromatic), 7.57-7.08 (3 H, m aromatic),4.88-4.42 Professor Joachim Thiem for information about aureolic (2 H, m, OCHCH20,CHOH), 4.38-3.82 (3 H, m, OCH,, CHOCH,), acid antibiotics. 3.57 (3 H , s , OCH3),3.32-2.43 (3 H, m, CH2CH),3.24 (1H, OH, Registry NO. 10, 6809-91-2; 11, 110-87-2; 12 (isomer l), exchangeable with D20), 1.47 and 1.38 (6 H, pair of s, (CH3),C); 72777-12-9; 12 (isomer 2), 72727-00-5;15,72727-01-6; 19, 51450IR,Y (film)3450 (OH), 1730 (M), 1690 ( P h M ) , 1600,1460, 36-3; 20,72727-02-7;23,72727-03-8; 24,72777-13-0; 25, 72777-14-1; 1375,980,850, 780 cm-'; UV ,A, (ethanol): 247 (c 12 loo), 287 25a, 72727-04-9; 26, 72777-15-2; 27, 72727-05-0;20, 72777-16-3; 334, obsd m / e (relative innm (c 2100); MS calcd for Cl8Hz2OB 29,72727-06-1; 30,86833-35-4; 31,72727-07-2;33,72727-0a3; 34, tensity) 334 (13, M+), 316 (32, M+ - HzO), 277 (22), 276 (100, M+ 72727-09-4; 35, 72777-18-5;35a, 86784-91-0; 36, 86784-92-1;37, - (CH3)2CO),258 (ZO),247 (36), 246 (93), 204 (20), 188 (43), 160 86833-36-5. (371, 144 (461, 116 (34), 100 (60), 90 (17), 84 (171, 60 (78).
d,
