J . Am. Chem. SOC.1993, 115, 2581-2589
2581
Structure and Total Synthesis of Sporol and Neosporol Fredrick E. Ziegler,' Chester A. Metcalf 111,' Ashwini Nangia,' and Gayle Schulte' Contribution from the Sterling Chemistry Laboratory and the Chemical Instrumentation Center, Yale University, New Haven, Connecticut 0651 1 Received October 19, 1992
Abstract: The complete details of the synthesis of sporol (1) and its formerly assigned structure, neosporol (2), are provided. A highly stereoselective Claisen rearrangement sets the Cs-C6 stereochemistry of the trichothecene skeleton. Subsequent functional group manipulation and ring closures led to the pentacyclic structures. The 1 H N M R studies that led to the structure reassignment are also discussed ~~
Owing to their diverse biological activity3 and unique variety of structures, the trichothecene mycotoxins have proved to be a challenge in organic synthe~is.~ As part of a programSato explore stereoselective methods for the synthesis of the trichothecene mycotoxins, we described in 1987 a new Claisen rearrangement approach to the stereoselective formation of the central CS-c.5 bond of the trichothecene mycotoxin^.^^.^ Prior to this time, solutions to this problem based upon the Claisen rearrangement had, at best, produced only moderate stereoselectivity. With a view toward applying this method toward the total synthesis of a recently reported, structurally compact trichothecene, ~ p o r o l ,isolated ~ from Fusarium sporotrichioides, we prepared a partially functionalized model of this substance. The compound obtained upon completion of the total synthesis was in full accord with the proposed structure of the natural product;6 however, a reinterpretation and repetition of IH N M R studies on the natural product, and the synthetic material, resulted in a reassignment of thestructure of sporol.9 The reassigned structure for sporol was confirmed by total synthesis.I0 In this paper, we present in more detail our studies, both spectroscopic and synthetic, on sporol (1) and neosporol (2), the original structure assigned to sporol. Sporol, a 1,3-dioxane, and neosporol, a 1,3-dioxolane, differ only in the size of these heterocyclic rings. Each of these intramolecular acetals bears an oxygen atom attached to a carbon bearing a methine hydrogen. In the case of sporol, the oxygen is attached to C,; in neosporol, the oxygen attachment is to C2. This difference in substitution pattern revealed itself in the NOES observed in the 1H N M R spectrum of each compound. N M R Analysis In the case of neosporol, irradiation of the C2-H (6 4.27, d, J = 3.7 Hz) caused NOE enhancement of the CI3-H (6 3.72) of ( I ) TakeninpartfromthePh.D.ThesesofA.N.(1988)andC.A.M.(1992), Yale University. (2)X-ray crystallographer, Chemical Instrumentation Center, Yale University. (3) (a) Fusarium: Mycotoxins, Taxonomy,andParhogeniciry;Chelkowski, J., Ed.; Elsevier: New York, 1989. (b) Joffe, A. Z. Fusarium Species: Their Biology and Toxicology; Wiley-Interscience: New York, 1986. (c) Trichorhecenes-Chemical Biological and Toxicological Aspects; Ueno, Y . ,Ed.; Elsevier: New York, 1983. (4)For reviews on the chemical synthesis of the trichothecenes, see: (a) Tamm, Ch.; Jeker, N. Tetrahedron 1989,45, 2385. (b) McDougal, P. G.; Schmuff, N. R. Prog. Chem. Org. Nar. Prod. 1985,47,153. ( 5 ) (a) Ziegler, F. E.;Sobolov. S. B. J . Am. Chem. Soc. 1990,112,2749. (b) Ziegler, F. E.;Nangia,A.;Schulte,G. J. Am. Chem.Soc. 1987,109,3987. ( 6 ) For a highly stereoselective Claisen rearrangement approach to this nucleus, see: Gilbert, J. C.; Kelly, T. A. Tefrahedron Left. 1989,30, 4193. For earlier Claisen routes, see ref 2 of this paper. (7)Corler, D. G.;Rottinghaus, G. E.; Tempesta, M. S. Tetrahedron Lerr. 1986,27. 427. (8)Ziegler, F. E.; Nangia, A.; Schulte, G. Tefrahedron Letr. 1988,29, I lim ."..,.
(9)Ziegler, F. E.;Nangia, A.; Tempesta, M. S. Tetrahedron Left. 1988, 29, 1665. (IO) Ziegler, F. E.; Metcalf, C. A., 111; Schulte, G. Tetrahedron Lett. 1992,33, 3117.
la
2a OH
2.21
lb
2b
2c
the methylene group and the C3-exo-H (6 1.90); the geminate C13-H (6 4.07) was too close to the irradiated signal for enhancement to be observed. Conversely, irradiation of the C3exo-H (6 1.90) caused collapse of the C2-H doublet to a singlet. However, irradiation of the C14 methyl group (6 0.90) caused enhancement of both of the C I jprotons, the Cd-exo-H (6 1.55), and the C7,-H (6 1.68, 2.11 A). Irradiation of the C16methyl group caused enhancement of both CIOprotons (6 2.09, 2 H, singlet) and the C ~ T H(6 1.78). Long-range coupling between the Cs+i (6 1.78) and the signal at d 2.09 (ostensibly only the Cloa-H through W-coupling) wasconfirmed through a 2D-COSY experiment. The presence of W-coupling (J = 1.4 Hz) between the C7,-H (6 1.68) and the C1sa-H (6 3.91) was confirmed upon irradiation of the former signal. Finally, either molecular models or, more quantitatively, MM2 calculations (see 2c) revealed that the CIsa-H (6 3.91) was nearly equidistant to the C3-endo-H (6 1.95,2.36 A) and theC4-endo-H (6 1.70, 2.27 A). This proximity was revealed by NOE enhancement, 3% and 6%, respectively, of both endo signals upon irradiation of the CI~,-H (6 3.91). Unlike neosporol, the methine proton of sporol is not proximate to the C14 methyl and CI, hydroxymethyl groups. Thus, irradiation of the C I 4methyl group produced NOE enhancement
OOO2-7863/93/1515-2581$04.00/0 0 1993 American Chemical Society
2582 J. Am. Chem. SOC.,Vol. 115, No. 7, 1993
Ziegler et al.
of the C13methylene protons (6 3.71, 3.84), the CI~,-H (6 3.79, 2.84 A), and the C 7 r H (6 1.60,2.43 A) but not the C3-H methine signal (6 4.55, 1 H, m)." The signal at C 7 r H (6 1.60) was correlated with the C7,-H (6 1.75) in the 2D-COSY spectrum. Indeed, irradiation at 6 1.75 in a homonuclear decoupling experiment removed the W-coupling to the C15a-H, thereby confirming the assignment of the C7,-H and C 7 r H . Irradiation of the proton at 6 4.55 effected NOE enhancement of the unobscured, highly coupled C2,-H (6 2.21) and C4,-H (6 2.29) in addition to the partially obscured C 2 r H (6 1.47) and C 4 8 H (6 1.23), withnoenhancement of theC13methylenegroup. When the C3-H was irradiated in a homonuclear decoupling experiment, the vicinal coupling of the C2 and C4 endo protons was removed, leaving geminal and W-coupling: C*,-H (6 2.21, J g e m = 11.7 Hz, Jw(4,) = 3.3 Hz), C4,-H (6 2.29, Jgem = 12.4 Hz, J w ( =~ 3.6 ~ )Hz). Moreover, the partially obscured C 2 r H (6 1.47) and C l r H (6 1.23) could also be seen to simplify. Independent irradiation of the C 2 r H and C 4 r H removed the coupling to their respective geminal protons. The proximity (2.06 A, see IC)of the C4,-H (6 2.29) and the C 1 5 r H (6 4.30; Jgem = 8.1 Hz, Jw7, = 3.4 Hz) was revealed as an 11% NOE enhancement of the former proton upon irradiation of the latter.12 These coupling patterns were corroborated by a 2D-COSY experiment. Thesestudiesdemonstrated that the methine proton was flanked by methylene groups that were not coupled to protons attached to contiguous carbons.
Scbeme I
o
NH20H.HCI
m
N H°CH2CH20H
'"EoH
/
PTsOH, C6H6 98%
reflux, 76% aq.EtOH
6
5
t-BuOK, HMPA L
co 8
7
Scheme I1 1) Swern oxidation
X I p o H
2) HCI CCH2Br, Zn/Hg, THF
9
* 10
79%
1) p-TsOH, MeOH
OTBDMS
2) (Im)$=S, CH2Ci2
n-Bu3SnH!
AIBN, toluene, c
3) TBSOTf, EtaN, CH2C12, 0 OC 41% (3 steps)
*
0
reflux, 60 % 11
Synthesis The strategy that was employed in the synthesis of sporol and neosporol had three basic components. First, a functionalized Claisen rearrangement would create the correct c5-c6 stereochemistry present in the trichothecene nucleus. Secondly, the respective dioxane and dioxolane rings would be formed by intramolecular acetalization. Finally, introduction of the cl6 methyl group and formation of the CS-0 bond would complete the pentacyclic framework.
-
In an earlier study, we were able to demonstrate that the prototypical rearrangement 3a 49 provided a 6:l ratio of diastereomers with the major isomer being formed through a chairlike transition state. Moreover, the rearrangement of the allyl silyl ether 3b 4b had proved to be more selective (16:l). Not surprisingly, C-C bond formation occurred trans to the silyl ether To achieve the pentacyclic structure of sporol and neosporol, a more functionalized cyclohexene ring of 3 was required. Thus, the rearrangements 3c 4c and 3d 4d were expected to provide the necessary functionality and appropriate stereochemistry to lead to their respective targets.
-
-
-
( I I ) This signal appeared to be a triplet (scale expansion, 500 MHz, ref 7) in the NMR studies conducted on natural sporol. The dihedral angle
between the methine proton and each of its four vicinal protons is -60°, which suggests that the signal may actually be a pentuplet with the outer peaks being of insufficient intensity to detect. The chemical shifts recorded for synthetic sporol (Experimental Section) are 0.01 6 units higher than those that were obtained for the natural material. The lower values are used for the sake of discussion. (12)-This NOE had been observed previously, but it had been misinterpreted.
OTBDMS
A
OTBDMS DMAP, CHpCI2 (84%, 2 steps)
R
12a, R = CH20H b, R = CHO
3
Dess-Martin periodinane
NaBH4, 13a, R = CHO M~OH b, R = CHzOH C, R = C H ~ O M Ms20, S ~ Et3N, DMAP
2
The preparation of the allyl vinyl ethers 3c and 3d required 0-alkylation of the anion of &keto nitrile 8 with the appropriate allylic electrophile. Functionalized 8-keto nitrile 8 (Scheme I) was prepared from hydroxy methylene ketone 5 by a modification of Wenkert's formylation of 3-ethoxycyclohex-2-en- l-onel3 that employed refluxing ether/NaH as opposed to benzene/NaOEt at room temperature. Traditional isoxazole formation led to a 5: 1 ratioof ,!?-keto isoxazole6and its structural isomer. Structure 6 was confirmed by fragmentati~nl~ of the isoxazole 7 to provide the @-keto nitrile 8 and its enol form upon acidification. In practice, the enolate was generated directly from the protected isoxazole 7. Allylic mesylate 13c, which is required for the synthesis of sporol, was prepared by radical cyclization (Scheme 11). Swern oxidation15 of alcohol 916 provided crude homoglyceraldehyde acetonide, which, upon addition of propargyl zinc bromide,I7 afforded a 12.5:1 ratio of acetylenes 10 to allenes. The diastereomeric acetylenes were formed with only modest selectivity (1.6:l). The radical cyclization was based upon the known preference for unstrainedlg cyclic thionocarbonates having the (13) (a) Wenkert, E.; Liu, L. H.; Fellows, W. D. J. Org. Chem. 1962,27, 2278. (b) Wenkert, E.; Gwdwin, T. E.Synrh. Commun. 1977, 7, 409. (14) (a) von Auwers, K.; Bahr, T.; Frese. E. Jusrus Liebigs Ann. Chem. 1925.441,54. (b) Johnson, W. S.;Shelberg, W. E.J . Am. Chem. Soc. 1945, 67, 1745. ( 1 5 ) Mancuso, A . J.; Huang, S.-L.;Swern, D. J . Org. Chem. 1978, 43, 2480. (16) (a) Mori, K.: Takigawa, T.; Matsuo, T. Tetrahedron 1979,35,933. (b) Meyers, A. I . ; Lawson, J. R. TetrahedronLett. 1982,23,4883. (c) Meyers, A. 1.; Lawson, J. R.; Walker, D. G.; Linderman, J. R. J. Org. Chem. 1986, 51. 5 1 1 1 .
(17) Daniels, R. G.; Paquette, L. A. Tetrahedron Letr. 1981, 22, 1579. (18) Ziegler. F. E.; Zheng, Z - L . J. Org. Chem. 1990, 55, 1416.
Structure and Total Synthesis of Sporol and Neosporol
substitution pattern of 11 to undergo preferable homolytic cleavage of the secondary C-0 bond in the presence of tri-n-butylstannyl radi~a1.I~However, unlike the former studies,I8 no products derived from primary C-0 bond fragmentation could be detected in the cyclization of thiocarbonate 11. The use of Swern conditions [(COCl)?,EtjN, DMSO] for the oxidation of homoallylic alcohol 12a proved troublesome. Although the desired conjugated aldehyde 13a was observed, the presence of methyl (methylthio) aldehydes 14 derived from a-alkylation of aldehyde 12b with the Pummerer intermediate formed from DMSO under the Swern conditions precluded this method of oxidation. The Dess-Martin periodinane proved to be the reagent of choice for this oxidation.20 The isomeric allylic mesylates 13c and 15b, the synthesis of which had been described p r e v i o ~ s l yhad , ~ ~to be prepared in situ because of their instability. Methanesulfonyl anhydride was employed rather than methanesulfonyl chloride because the derived mesylates were susceptible to displacement with chloride ion; the allylic chlorides did not function well as electrophiles. To maximize 0-alkylation of the anion of /?-keto nitrile 8, the fragmentation of isoxazole was effected with t-BuOK in HMPA; the potassium cation was ligated with 18-crown-6 and added to the solution of the mesylate. Because themesylates were prepared and employed in situ, excess t-BuOK was utilized to neutralize Et,N+ OTf- that was formed during the preparation of the mesylates. Products of C-alkylation were not detected. OTBDMS
OTBDMS
OHC 14
16
15a, R=H b, R=Ms
17
Rigorous purification of the allyl vinyl ether 3c, silylation of the reaction vessel, and rearrangement in 0.02 M nonane led to a 16:l ratio of crystalline 4c and a stereoisomer, as determined by integration of the vinyl signals in the ' H N M R spectrum.2' While the successful synthesis of neosporol ultimately confirmed the stereochemistry of 4c, the chairlike transition state and facial selectivity observed in the rearrangement of the prototype 3b was assumed to apply in this instance. The minor, crystalline stereoisomer was isolated from combined chromatographic fractions of several reactions. Both compounds were independently desilylated (aqueous HF/CH3CN, 0 0C)22and oxidized under Swern conditions to give different enones 17. This result demonstrated that the stereoisomersdiffered a t theCs46juncture and not at the silyloxy center. Accordingly, the minor isomer 16 arises through a boatlike transition state with C-C bond formation most likely occurring trans to the silyloxy group. Claisen rearrangement of allyl vinyl ether 3d,which was not plagued by elimination of 4d presumably because of the nonallylic nature of the silyloxy substituent, did not require silylated glassware. However, a 490-MHz IH N M R spectrum of the crude (19) (a) Ziegler, F. E.; Zheng, 2 . - L . Tetrahedron Lett. 1987, 28. 5973. (b) De Bernardo, S.; Tengi, J . P.; Sasso, G.; Weigele, M. Tetrohedron Leu. 1988, 29, 4077. (20) Dess, D. 8.; Martin, J . C. J . Org. Chem. 1983, 48, 4155. (21) Integration of the carbonitrile signals at 157.8 (4c) and 158.9 (16) ppm (pulse width 4 ps and repetition delay of 20 s) showed a 13:l ratio. (22) Newton, R. F.; Reynolds, D . P . ;Finch, M . A . W.;Kelly,D.R.; Roberts, S . M . Terrahedron Lett. 1979, 3981.
J . Am. Chem. SOC.,Vol. 115, No. 7 , 1993 2583
Scheme I11
19c
3N HClldioxane OH
reflux
I
(oq 20
I I
BF3 Et2°*
-
CH2C12
-78 'C
NC
OH
21
rearrangement products suggested that as many as four diastereomers (13:2:1:1) had been formed. The major isomer was obtained in 68% yield after chromatography, and its structure was confirmed by single-crystal X-ray analysis. Two of the minor isomers, which had the same molecular ion in their high-resolution mass spectra and similar 'H N M R spectra, were isolated by chromatography from combined reaction mixtures. Their respective stereochemistries were not assigned. The next steps in the synthetic plans required the construction of the dioxolane (neosporol) and dioxane (sporol) ring systems. First, the neosporol case is considered. Allylic alcohol 18, which was readily prepared from 4c by desilylation with aqueous HF/CH3CN, was reluctant to undergo a carbonyl epoxide rearrangement23under the Kishi-Goto conditions24(m-CPBA, ClCH2CH2Cl,reflux) that had proved successful with the alcohol derived from silyl ether 4b.5b Epoxidation with trifluoroperoxyacetic acid, which was prepared from 90% peroxide in the presence of solid Na2CO3 as a buffer, led directly to the dioxolane 19n. The omission of buffer, or the use of Na2HP04as a buffer, led to unidentifiable products. The methylene protons of the newly formed dioxolane ring appeared as doublets (6 4.13 and 3.65) with J = 7.6 Hz, a value characteristic of a methylene group adjacent to oxygen in a five-membered ring.sb.2s The internal dioxolane ring of 19a served to protect the cyclohexanone carbonyl while the stereochemistry of the hydroxyl group of 19a was inverted to allow formation of the dioxolane ring system of neosporol. The Swern oxidation of 1911 afforded cyclopentanone 19b (39% from 18), which was reduced with LiAl(t-Bu0)3H from the convex face with stereoselectivity (1 2:l) to produce endo alcohol 19c (Scheme 111). Internal dioxolane exchange was readily effected with BF3.Et20 at-78 OC (19~-21). When thesameexperimentwasperformed at 0 OC, a mixture of ketal 21 and ketone 20 was obtained. The acyclic hydroxymethylene protons of ketal 21 (6 4.12 and 3.71) now displayed 12.5-Hz geminal coupling. Hydrolysis and rearrangement of ketal 19c in 3 N HCl/dioxane a t reflux led to the crystalline keto nitrile 20, whose structure was corroborated by single-crystal X-ray analysis. These reaction conditions reflect the robustness of the internal dioxolane. In comparison, when (23) (a) Demole, E.; Wuest, H . Helo. Chim. Acra 1967, 50, 1314. (b) Wasserman, H . H.; Barber, E. H . J . Am. Chem. SOC.1969, 9 / , 3674. (c) Anderson, W. K.; Veysoglu, T. J . Org. Chem. 1973, 38, 2267. (24) Kishi, Y . ;Aratani, M.; Tanino, H.; Fukuyama, T.; Goto, T. J . Chem. SOC.,Chem. Commun. 1972, 64. (25) Cf. compound 32 in: Ziegler, F. E.; Klein, S. I.; Pati, U. K.; Wang, T.-F. J . Am. Chem. SOC.1985, 107. 2730.
Ziegler et al.
2584 J. Am. Chem. SOC.,Vol. 115. No. 7, 1993 Scheme IV
(oq A
HF/CH&N Na2C03
CHpCI2
(from 29c)
Urea.H202,(F3CCO)zO
*
4d
Scheme V
m
NC
24
20
TH F
Na2C03,CH2C12
-
- 2
H
O
W OH
BF3Et20 CH2CI2
bH 29a* R=CN J LiAIH,; aq. HOAc b , R=CHO C, R = C H ~ O LiAIH4 H ~
P O
r?,
OH
MS20, DMAP, Et3N, CHpCI2
K20, DMSO 18-crown-6
-
1
27
28
OH
the alcohol 19a was heated in 3 N HCl/HOAc, rupture of the internal dioxolane occurred by @-eliminationto give a 2: 1 mixture of diol 22a and its monoacetate 22b.
OH
22a, R=H b, R=Ac
The oxidation reduction procedure that proved successful in the neosporol series was unsuitable in the sporol series. All efforts to oxidize alcohol 26a to thecyclopentanoneled to further reaction; ostensibly, the strained dioxolane ring suffered @-elimination, which was supported by the appearance of a vinyl signal at 6 6.07, and subsequent oxidation. Treatment of mesylate 26b with potassium superoxide effected inversion of the hydroxyl f~nction.2~ The crude alcohol 28 was exposed to catalytic camphorsulfonic acid/CH$12, which accomplished intramolecular conversion of the internal dioxolane ring to the dioxane. Finally, hydrolysis removed the ethylene glycol without affecting the dioxane ring to provide keto nitrile 27. The conversion 26a 27 was achieved in 32% overall yield. Like its neosporol counterpart 20, the structure of 27 was confirmed by single-crystal X-ray analysis. The final step in the synthesis of neosporol and sporol was viewed as the formation oftheoxabicyclo[2.2.2]octaneringsystem by acid-catalyzed cyclization of a primary alcohol and a tertiary carbocation. Both keto nitriles 20 and 27 required the conversion of the nitrile into a primary alcohol and the ketone into a tertiary alcohol or methylene olefin. Two pathways presented themselves. First, the progenitor ketals of 20 and 27 would permit initial manipulation of the nitrile with subsequent hydrolysis of the ketal and conversion to the tertiary alcohol. When this route was applied in the neosporol series, the keto diol 23 proved to be inert to the addition of MeLi, MeMgBr, and MeCeC12,2* owing to the presumed enolization or alkoxide addition to the carbonyl Traditional Wittig olefination as well as the Corey DMSO procedure30 were also unsuccessful. Consequently, initial functionalization of the carbonyl group was chosen as the preferred route. Keto nitrile 20 also underwent enolization with MeLi, and both enolization and addition with MeMgBr. However, MeCeC12 added to the carbonyl group to give a 5:l mixture of diols 29a (Scheme V). The neopentyl nitrile functionality of the major diol was reduced with LiAlH4 in refluxing T H F to the imine stage; hydrolysis provided aldehyde 29be31Prolonged exposure to the reduction conditions provided the amine. Reduction of the aldehyde to triol 29c was uneventful. Finally, exposure of the triol to BF,.Et20 in CH2CI2at 25 O C afforded neosporol2. These conditions for cyclization were shown earlier (Scheme 111) not to affect the dioxolane nucleus. The Conia Wittig olefination protocol3* (Scheme VI) proved successful in the conversion of keto nitrile 27 to olefin 30a, which was readily characterized by the appearance of exo-methylene vinyl signals at 6 4.82 and 4.78. Less over reduction of the nitrile
23
Although an experimental protocol had been established to construct the tetracyclic structure of keto nitrile 20, the transformation of silyl ether 4d to the analogous tetracyclic dioxane was not straightforward (Scheme IV). The desilylation of 4d to give alcohol 24 once again employed aqueous HF/CH$N albeit buffered with Na2C03. However, efforts to form the dioxolane 26a using the epoxidation conditions that were successful in the neosporol series led to unfavorable mixtures of triol 25 and dioxolane 26a. The presence of water was deemed to be detrimental in this reaction. After numerable attempts to optimize the formation of 2611, two satisfactory solutions to the problem were uncovered. Commercially available (Aldrich) urea/hydrogen peroxide complex26served as a source of anhydrous hydrogen peroxide. When buffered trifluoroperoxyaceticacidwas prepared from this reagent and was used as the oxidant, the dioxolane 26a and triol 25 were formed in a 7:2 ratio, from which mixture the dioxolane could be isolated in 45% yield upon chromatography. The methylene protons of the dioxolane ring of 26a displayed 7.1-Hz geminal coupling as opposed to 12.6-Hz coupling in the hydroxymethylene group of uncyclized triol 25. Alternatively, the portionwise addition of excess Ms20/Et3N to triol 25 led to its transformation into mesylate 26b, which was identical with the mesylate derived from alcohol 26a. The derivatization of the secondary hydroxyl group during the ring closure would prove to be a benefit to future transformations. (26) Cooper, M. S.; Heaney, H . ; Newbold. A. J.;Sanderson, W . R. Synleff 1990, 533.
(27) Corey, E. J.; Nicolaou, K. C.; Shibasaki, M.; Machida, Y.; Shiner, C . S. Tetrahedron Lett. 1975, 3183. (28) (a) Imamoto,T.;Sugiura, Y.;Yakayama, N. TetrohedronLeff.1984, 25, 4233. (b) Imamoto, T.; Kusumoto, T.;Tawarayama. Y.; Sugiura, Y.; Mita. T.;Hatanaka, Y.; Yokoyama, M. J . Org. Chem. 1984, 49, 3904. (29) Evidence for the existence of the hemiacetal form of keto diol 23 was evident in the 'HNMRspectrum. TheClcprotonsofthe ketoalcoholappeared at 6 3.95 (br s) while the same protons in the hemiacetal resonated at 6 4.32 and 4.22 (d. J , H = 12.5 Hz). Moreover, the C l l lprotons [6 2.85 (dd, J = 16.6, 1.5 Hz); 6 2.72 (d, J = 16.6 Hz)]integrated for fewer than the full complement of protons. (30) Greenwald, R.;Chaykovsky, M.;Corey, E. J . J . Org. Chem. 1963-28, 117R .
(31) St0rk.G.;Wakamatsu,S. U.T.;Grieco.P.;Labovitz,J. J.Am.Chem. Sor. 1971, 93. 4945.
(32) Conia, J. M.; Limasset, J. C . Bull. SOC.Chim. Fr. 1967, 1936.
Structure and Total Synthesis of Sporol and Neosporol
J . Am. Chem. SOC.,Vol. 115, No. 7, 1993 2585
&
isoxazole 7: ' H NMR 6 8.08 (s, 1 H, aromatic), 4.04 (s, 4 H, ketal), 2.95 (s, 2 H), 2.60 (t. 2 H, J = 6.4 Hz), 1.93 (t, 2 H, J = 6.4 Hz); 13CNMR 6 165.3, 148.8, 110.9, 108.3, 64.6 (2X), 33.7, 31.7, 16.5. Anal. Calcd (from 30c) for CgHllN03: C, 59.66; H. 6.12. Found: C, 59.52; H, 6.16. 27 Ph,PCH,'Br1 Allyl Vinyl Ether 3c. To a solution of ketal isoxazole 7 (2.1 7 g, 12.0 OH CSA, CH2CIz t-BUOK. THF reflux mmol) in HMPA (24 mL) at I O "C was added t-BuOK (2.70 g, 24.0 reflux mmol)in small portions. After 1 h, 18-crown-6 (4.23 g, 16.0 mmol) was added and the reaction mixture was stirred for another 1 h. Meanwhile, 30a, R=CN 2 DIBAL; aq. H,SO~ a solution of allylic alcohol 15a ( I .93 g, 8.0 mmol),EtlN ( I .67 mL, 12.0 b, R=CHO mmol, 1.21 g), and 4-(dimethy1amino)pyridine (98 mg, 0.8 mmol) in c, R=CH,OHJ T H F (24 mL) was cooled to -25 "C. Methanesulfonic anhydride (1.81 g, 10.4 mmol; sublimed at 95-100 "C, 0.5 Torr) was added over IO min. function was observed when DIBAL was employed rather than After the solution had been stirred for another 15 min at -20 "C, the LiA1H4. Camphorsulfonic acid effected ring closure of diol 30c potassium enolate of 8 was added over 10 min via a pipet. The mixture to (f)-sporol, which was shown to be identical with natural was stirred at 0 "C for 3 h and then acidified to pH 4 with 5% HCI. material by 'HNMR, mass spectroscopy, and TLC behavior. Dilution with brine, extraction with Et20, and workup gave 9.8 g of crude material. Purification on silica gel (15% EtOAc/hexanes) provided 1.52 g (47%) of vinyl ether 3c. The vinyl ether was preceded by a higher RJ Experimental Section unidentifiable impurity which, when present, was associated with the All reactions were performed in flame-dried glassware under N2 unless formation of dienic byproducts in the subsequent Claisen rearrangement: otherwise noted. Et20 and tetrahydrofuran (THF) were distilled from R ~ 0 . 2 (20% 1 EtOAc/hexanes); mp 58-59 OC (EtlO/pentane); IH NMR sodium benzophenone ketyl under Nz. Hexanes, CH2C12, Et3N. diiso6 4.98 (br d, J = 6.5 Hz, 1 H, CH-OTBDMS), 4.66 (d, 1 H, J = 10.7 propylamine, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), Hz, O-CHl), 4.56 (d, 1 H, J = 10.7 Hz, O-CH*), 3.99 (s, 4 H, ketal), and hexamethylphosphoramide (HMPA) were distilled from CaH2. 2.53(~,2H),2.47-2.36(m,3H),2.33-2.18(m,2H),1.78(~,3H,vinyl Alkyllithiums were titrated by the method of Kofr01-1.~~ Workup means CH3), 1.78-1.60 (m, 3 H), 0.91 (s, 9 H, Si-r-Bu), 0.12 (s, 3 H, Si-CH3), drying organic extracts over anhydrous MgS04, filtering, and concen0.11 (s, 3 H, Si-CH3); 'IC NMR 6 164.2, 142.1, 132.6, 118.2, 106.8, trating under reduced pressure. Melting points are uncorrected. Spectra 84.9, 77.8, 64.6 (2X),62.5, 37.6, 35.9, 32.8, 30.5, 25.8 (3X), 23.6, 18.0, were recorded under the following conditions unless stated otherwise. 14.5, -4.5, -5.0; IR 221 1, 1641 cm-I. Anal. Calcd for C22H~N04Si: FTIR spectra were obtained in CHCll solution. ' H NMR spectra were C, 65.14; H, 8.70. Found: C, 65.02; H, 8.75. recorded at 250 MHz unless specified otherwise; I3C NMR spectra were &Keto Nitriles 4c and 16. A solution containing bis(trimethylsily1)recorded at 62.9 MHz. All NMR samples employed CDC13 (6 7.27 for acetamide (BSA)/pentane (1:20) was heated at a gentle reflux for 10 h. ' H NMR and 6 77.0 for "C NMR) as an internal standard. GC analysis The solution was cooled to 25 "C, and the BSA/pentane was discarded. was performed on a Hewlett-Packard 5890 series I1 capillary unit with The flask was rinsed four or five times with pentane and then dried in an SPB-5 (Supelco) 30 m X 0.25 mm column. a stream of N2. Allyl vinyl ether 3c (1.52 g, 3.75 mmol) and n-nonane 4,7-Dihydro-1,2-benzisoxazole-6(5H)-one(6). To a hexane-washed (1 87 mL) were added to the flask, and the reaction vessel was purged mechanically stirred suspension of NaH (16.0 g, 0.4 mol, 60%) in Et20 with N2. The solution was heated at reflux for 4 h; TLC showed complete (750 mL) was added absolute EtOH (2.5 mL). The suspension was consumption of starting material. The flask was cooled to 25 OC, and heated at a gentle reflux, and a solution of 3-etho~y-2-cyclohexenone~~ thesolvent was evaporated invacuo. Flash chromatography (1 5% EtOAc/ (35.0 g, 0.25 mol) and HC02Et (40.0 mL, 0.5 mol, 37.0 g; distilled from hexanes) of the residue afforded 745 mg (49%)
[email protected] CaH?) in Et10 (250 mL) was added over 1 h. The initial reaction was elution afforded 190 mg (12%) of a mixture of ,%keto nitriles 4c and 16 somewhat exothermic; heating was carefully monitored to maintain a and dienes. 4c: mp 138-139 OC (Et20/pentane); IH NMR 6 5.32 (d, gentle reflux. After the addition was complete, the reaction mixture was 1 H , J = 2.4Hz,exo-methylene),5.24(d, 1 H , J = 2.2Hz,exo-methylene), heated at reflux for 24 h. The reaction mixture was cooled to 25 OC and 4.30 (m, 1 H, CH-OTBDMS), 4.05-3.91 (m, 4 H, ketal), 3.22 (d, 1 H, diluted with cold water (500 mL). After the phases had been stirred for J = 13.5 H z , C i r H a x ) ,2.58 (dd, 1 H , J = 13.5, 2.7 Hz,Cl(rHeq), 2.38 15 min, the layers were separated and the Et20 layer was washed with (td, 1 H, J = 13.3, 4.3 Hz), 2.22-2.12 (m, 1 H), 2.05-1.89 (m. 4 H), 5% NaOH. The combined alkaline layers were washed with Et20 and 1.49 (s, 3 H, CH3), 1.60-1.40 (m, 2 H), 0.93 (s, 9 H, Si-r-Bu), 0.12 (s, acidified to pH 4 with 15% HCI at 0 OC. The acidified aqueous layer 3 H, Si-CH3), 0.10 (s, 3 H, %-CHI); I T NMR 6 196.9, 157.8, 119.0, was diluted with H20 (500 mL) and extracted thoroughly with CHCI3. 109.3, 108.7, 76.4, 65.0, 64.7, 57.7, 50.2, 45.3, 32.4, 32.1, 31.5, 27.7, The organic layer was washed with brine and worked up to provide 40.0 26.7,25.9(3X), 18.2,-4.6,-4.8;IR2233, 1735, 1656cm-I. AnaLCalcd g (95%) of crude material which was a tautomeric mixture of hydroxyfor C22H35N04Si: C, 65.14; H, 8.70. Found: C, 64.99; H, 8.75. methylene ketone 5 (6 7.20, d, J = 9.0 Hz, hydroxyl vinyl H) and hydroxy A pure sample of @-ketonitrile 16 was obtained in the following manner. enal (
