J. Am. Chem. SOC.1994,116, 5108-5115
5108
Microbial Oxidation of Aromatics in Enantiocontrolled Synthesis. 3. Design of Amino Cyclitols (em-Nitrogenous) and Total Synthesis of (+)-Lycoricidine via Acylnitrosyl Cycloaddition to Polarized 1-Halo- 1,3-cycl~hexadienes~ Tomas Hudlicky;?? Horacio F. Olivo, and Bryan McKibben Contribution from the Chemistry Department, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061 -021 2 Received October 27, 1993"
Abstract: Oxidation of halogenated benzenes with bacterial dioxygenase from Pseudomonas putida 39D (whole cell fermentation) provided homochirall,3-cyclohexadiene-cis-diols 1 for the entire halogen series. These compoundswere investigated for their potential in cycloadditions with various dienophiles including propiolate, acylnitrosocompounds, benzyne, quinones, and nitrile oxides. All cycloadducts formed with the regiochemistry predicted from molecular modeling. A brief synthesis of (+)-lycoricidine concluded the application of acylnitrosocycloadditions. New adducts of quinones and nitrile oxides were identified, and potential for these compounds in the synthesis of novel polycyclic oxygenated compounds is indicated. Experimental and spectral data are provided for all compounds.
Introduction
?H
?H
In a recent reportla and in the preceding paper,Ib we have outlined elements of design that permit the conversion of cyclohexadiene-cis-diols 1 to cyclitols, inositols, furanose or pyranose carbohydrates, and the aza analogs of these two types of sugars, respectively. To execute an equally efficient design of amino cyclitols, it is necessary to provide a methodology that incorporates nitrogen onto the periphery of 1 in a regio- and stereocontrolled fashion. Amino cyclitols of type 2 or 3, or conduramines,constitute an important class of compounds,some which exhibit properties remarkably similar to those of known glycosidaseinhibitors derived from aza s ~ g a r s . ~ Their . ~ syntheses
48, R=H, lycoricidine 4b, R=OH.narciciasine
5
the previous paper,lb whereas nitrosyl cycloadditions-7provides the 1,4-disposition of substituents in 2. In this paper we report on the cycloaddition of various dienophiles to polarized l-halo1,3-dienes 1 (X = F, C1, Br, I) or their protected derivatives in an effort to determineelectronictrends in these dienes and thence to apply this strategy to a concise synthesis of (+)-lycoricidine (4a),8*9an important congener of the cancerostatic alkaloid pancratistatin (5),lC-13 for which this synthesis serves as a model study.
Results and Discussion can be approached, as outlined in eq 1, by either trans-1,2or cis-1,4 introduction of the amino and hydroxyl groups. To this end, epoxide opening with nitrogen nucleophiles can be utilized toward the preparation of compounds of type 3, as described in Recipient of the American Cyanamid Faculty Research Award, 1992. Abstract published in Advance ACS Abstracts, April 1, 1994. (1) (a) For the first part of this series, see: Hudlicky, T.; Mandel, M.; Rouden, J.; Lee, R. S.;Bachmann, B.; Dudding, T.; Yost, K. J.; Merola, J. S . J. Chem. Soc., Perkin Trans. I 1994,1553-1568. (b) For the second part, see: Hudlicky,T.; Rouden, J.; Luna,H.; Allen,S . J.Am. Chem. SOC., preceding paper in this issue. (2) For preliminary accounts of this work, see: (a) Hudlicky, T.; Olivo, H. F. Tetrahedron Lett. 1991,32,6077. (b) Hudlicky, T.; Olivo, H. F. J.Am. Chem. SOC.1992, 114, 9694. (c) Hudlicky, T.; McKibben, B. P. J. Chem. SOC.,Perkin Trans. I 1994, in press. (3) (a) For general references, see: The Amino Sugars: the Chemistry and Biology of Compounds ContainingAminosugars; Jeanloz, R. W., Balazs, E. A., Eds.; Academic Press: New York, 1965-1966; Vols. IA, IB, IIA, IIB. (b) Nishimura, Y. In Studies in Natural Products Chemistry; Atta-UrRahman, Ed.; Elsevier: Amsterdam, 1992;Vol. 10, Part F, p 495. (c) Legler, G. Ado. Carbohydr. Chem. Biochem. 1990,28,3 19. (d) Sinnott, M. L. Chem. Rev. 1990, 90, 1171. (4) For reviews on conduritols, see: (a) Balci, M.; Sutbeyaz, Y.; Seccn, H. Tetrahedron 1990,46,3715. (b) Hudlicky, T.; Cebulak, M. Cyclitols and their Derivatives: A Handbook of Physical, Spectral. and Synthetic Data; VCH: New York, 1993. t
@
The enormouspotential of 1-halo-1,3-cyclohexadiene-cis-diols in enantioselective synthesis has been amply demonstrated, as evidenced by the number of reviews in this area.14 Figure 1 shows a number of useful chiral synthons derived from the protected chlorobenzenediol 6b. The diversity of transformationsthat this metabolite can undergo allows the preparation of many valuable building blocks for asymmetric synthesis. The originaldiscovery and isolation of the diol derived from toluene by GibsonIs more than 25 years ago has led to the present commercial availability ( 5 ) For a review on nitrosyl Diels-Alder reactions, see: Boger, D. L.; Weinreb, S . M. In Hetero Diels-Alder Methodology in Organic Synthesis; Wasserman, H. H., Ed.; Organic Chemistry Monographs 47; Academic Press: New York, 1987. (6) (a) For synthesesof amino conduritols via nitrosyl additions to arenetram-diols, see: Beier, B.; Schurrle, K.; Werbitzky, 0.;Piepersberg. W. J. Chem. Soc., Perkin Trans. I 1990,2255. Schurrle, K.; Beier, B.; Werbitzky, 0.;Piepersberg, W. Carbohydr. Res. 1991,212,321. (b) Braun, H.;Burger, W.; Kresze, G.; Schmidtchen, F. P.; Vaerman, J. L.; Viehe, H. G. Tetrahedrom Asymmetry 1990, I, 403. (7) For applicationsof the nitrosyl cycloadditionin the synthesisof natural products, see: (a) Keck, G. E.; Nickell, D. G. J. Am. Chem. SOC.1980,102, 3632. (b) Keck, G. E. Tetrahedron Lett. 1978, 4767. (c) Burkholder, T. P.; Fuchs, P. L. J. Am. Chem. SOC.1988,110,2431. (d) Iida, H.; Watanabe, Y.; Kibayashi, C. J . Am. Chem. SOC.1985,107, 5535. (e) Kresze, G.; Dittel, W. Liebigs Ann. Chem. 1981, 610. (0 Braun, H.; Burger, W.; Kresze, G.; Schmidtchen, F. P.; Vaerman, J. L.; Viehe, H. G. Tetrahedrom Asymmetry 1990,1,403. (8) Shishido, Y.; Kybayashi, C. J. Org. Chem. 1992,57,2876.
OOO2-7863/94/1516-5108$04.50/00 1994 American Chemical Society
J . Am. Chem. SOC., Vol. 116, No. 12, 1994 5109
Design of Amino Cyclitols (exo- Nitrogenous)
9
\
AH?
11
Figure 1. Some chiral synthons derived from chlorobenzene.
of many of the diols.16 Oxidation products 8 and 14 have been converted to D-chiro-inosit01.l~ Epoxide 7 has served as an (8) Syntheticapproaches to lycoricidine: (a) Thompson,R. C.; Kallmerten, J. J. Org. Chem. 1990,55,6076. (b) Keck, G. E.; Fleming, S. A. Tetrahedron Lert. 1978,4763. (c) Keck, G. E.; Boden, E.; Sonnewald, U. Tetrahedron Lett. 1981,22,2615. (d) Weller, T.; Seebach, D. Tetrahedron Lett. 1982,23,935. (e) Tsuda, Y.; Isobe, K. J. Chem. SOC.,Chem. Commun. 1971, 1555. (f) Compound 1, prepared by Keck using adjustments of a published model study (ref 8c), could not be successfully reduced to ii (Keck, G. E., private communication). (g) McIntosh, M. C.; Weinreb, S.M. J . Org. Chem. 1993, 58, 4823.
i
ii
(9) Total synthesis of lycoricidine: (a) Chida, N.; Ohtsuka, M.; Ogawa, S.Tetrahedron Lett. 1991,32,4525. (b) Paulsen, H.; Stubbe, M. Liebigs Ann. Chem 1983, 535. (c) Paulsen, H.; Stubbe, M. Tetrahedron Lett. 1982, 23, 3171. (d) Ohta,S.; Kimoto,S. Chem. Pharm. Bull. 1976,242977. (e) Ohta, S.; Kimoto, S. Tetrahedron Lett. 1975, 2279. (f) Chida, N.; Ohtsuka, M.; Ogawa, S.J. Org. Chem. 1993, 58, 4441. (g) Johnson, C. R. Abstracts of National Organic Symposium, Bozeman, MT, 1993. (h) Martin, S.F.; Tso, H.-H. Heterocycles 1993, 35, 85. (IO) Isolation of pancratistatin: (a) Pettit, G. R.; Gaddamidi, V.; Cragg, G. M.; Herald, D. L.; Sagawa, Y . J. Chem. SOC.,Chem. Commun. 1984, 1693. (b) Pettit, G. R.; Gaddamidi, V.; Cragg, G. M. J . Nat. Prod. 1984,47, 1018. Narciclasine: (c) Okamoto, T.; Torii, Y . ;Isogai, Y . Chem. Pharm. Bull. (Tokyo)1968,16,1860. Lycoricidine: (d) Okamoto,T.;Torii, Y . ;Isogai, Y. Chem. Pharm. Bull. (Tokyo) 1968, 16, 1860. (1 1) Biological properties of pancratistatin: (a) Pettit, G. R.; Gaddamidi, V.; Herald, D. L.; Singh, S.B.; Cragg, G. M.; Schmidt, J. M.; Boettner, F. E.; Williams, M.; Sagawa, Y .J. Nut. Prod. 1986,49, 995. Narciclasine: (b) Carrasco, L.; Fresno, M.; Vazquez, D. FEBSLett. 1975,52,236. (c) Jimenez, A.; Sanchez, L.; Vazquez, D. FEBS Lett. 1975, 55, 53. (d) Mondon, A,; Krohn, K. Chem. Ber. 1975,108,445. Lycoricidine: (e) Okamoto, T.; Torii, Y . ;Isogai, Y . Chem. Pharm. Bull. (Tokyo) 1968, 16, 1860. (f) Ceriotti, G. Nature (London) 1967,213,595. (g) Ugarkar, B. G.; DaRe, J.; Schubert, E. M. Synthesis 1987, 715. (12) Pancratistatin is in demand for clinical trials by the NCI (PA-92-27). It inhibits protein synthesis by a mechanism simila; to that of the Homoerythrina alkaloid homoharringtonine and other structurally related compounds. See: (a) Jimenez, A,; Sanchez, L.; Vazquez, D. FEBS Lett 1975, 60,66. (b) Jimenez, A.;Santos, A.; Alonso, G.; Vazquez, D. Biochim. Biophys. Acta 1976,425,342. (c) Baez, A.; Vazquez, D. Biochim. Biophys. Acta 1978, 518, 95. (d) Rivera, G.; Gosalbez, M.; Ballesta, J. P. G. Biochem. Biophys. Res. Commun. 1980,94,800. Natural abundance of pancratistatin: 0.039% (see ref 1 la). (13) Total synthesis of pancratistatin: Danishefsky, S.;Lee, J. Y . J. Am. Chem. SOC.1989,111,4829. Approaches to this target are being pursued as of this writing by C. H. Heathcock, C. R. Johnson, and G. E. Keck. (14) For recent reviews, see: (a) Brown, S.M.; Hudlicky, T. In Organic Synthesis: Theory and Applications;Hudlicky, T., Ed.; JAI Press: Greenwich, CT, 1993; Vol. 2, p 113.(b) Carless, H. A. J. Tetrahedron: Asymmetry 1992, 3, 795. (c) Widowson, D. A.; Ribbons, D. W. Janssen Chim. Acta 1990,8, 3. (d) Hudlicky,T.; Red, J. W. In Aduances in AsymmetncSynthesis; Hassner, A., Ed.; JAI Press: Greenwich, CT, 1994. ~~
intermediate for (-) -pinitol synthesis.18 Lactone 1319has been used in the synthesis of an isostere for renin inhibitors,20 and ketones 9 and 10 have found use in the preparation of cyclitols21 and conduramines.2J This article examines the details of the synthesis and use of conduramine synthons 11and bicyclo[2.2.2]octanes 12, attained via the Diels-Alder reaction. We became interested in the cycloaddition potential of the 1-halodiene unit in 1in order to prepare a bridged bicyclic system. The cycloaddition potential of polarized dienes such as 1or 6 had not been realized until recently, although heteroatom-substituted dienesof theDanishefsky type have been amply used in synthesisF2 Simultaneously, Roberts,23 Ley,Z4and H ~ d l i c k have y ~ ~reported dimerization tendencies of acetonide derivatives of several diene diols, including those derived from bromobenzene, chlorobenzene, and (trifluoromethy1)benzene. Recently, acetonides of the diol derived from styrene have been reported to form several dimers stereoselectively.26 The free diols also undergo Diels-Alder reaction with phenyltria~olines,~~~2* and this observation has allowed determination of the absolute stereochemistry of several diols by either X-ray or N M R methods by relying on differential shifts of diastereomeric Mosher esters derived from 16.Z7
6
X=H,CF3,CH=CHz,Cl,Br
15
X=F,CI,Br.I,CFI,CH=CHz
16
Surprisingly, all of the reported dimerizations were highly regioand stereoselective; this phenomenon was explained by a less crowded transition state (anti addition) leading to 15. The regioselectivity of the cycloaddition can easily be rationalized by the vastly different electron content of the two olefins in either 1 or 6, which can be understood by analyzing the charge (15) Gibson,D. T.; Cardini, G. E.; Maseles, F. C.; Kallio,R. E. Biochemistry 1970, 9, 1631. (16) The diols derived from chloro- and bromobenzene are now prepared in crystalline form on a multikilogram scale by Genencor International, Inc.; over 20 other diols derived from substituted aromatic compounds are commercially available from the following sources: Genencor International, Inc., South San Francisco, CA; IC1 Fine Chemicals, Manchester, U. K.; Enzymatix, Cambridge, U. K.; Janssen Chimica, Geel, Belgium. (17) Mandel, M.; Hudlicky, T. J. Org. Chem. 1993, 58, 2331. (18) (a) Hudlicky, T.; Rulin, F.; Tsunoda, T.; Luna, H.; Andersen, C.; Price, J. Isr. J. Chem. 1991, 31, 229. (b) Hudlicky, T.; Price, J.; Rulin, F.; Tsunoda, T. J. Am. Chem. SOC.1990, 112. 9439. (19) (a) Mandel, M.; Hudlicky, T. Collect. Czech. Chem. Commun. 1993, 58,2517. (b) Hudlicky, T.; Luna, H.; Price, J. D.; Rulin, F. Tetrahedron Lett. 1989, 30, 4053. (c) Hudlicky, T.; Luna, H.; Price, J. D.; Rulin, F. J. Org. Chem. 1990,55, 4683. (20) (a) Baker, W. R.; Condon, S.L. J. Org. Chem. 1993,58, 3277. (b) Baker, W. R.; Condon, S.L. Tetrahedron Lett. 1992, 33, 1581. (21) Hudlicky, T.; Luna, H.; Olivo, H.; Andersen, C.; Nugent, T.; Price, J. J. Chem. SOC.,Perkin Trans. 1 1991,2907; Corrigendum, J. Chem. SOC., Perkin Trans. 1 1993, 535. (22) (a) Danishefsky, S.;Kitahara, T. J. Am. Chem. SOC.1974,96,7807. (b) Danishefsky, S.;Kitahara, T. J. Org. Chem. 1975, 40, 538. (23) (a) Downing, W.; Latouche, R.; Pittol, C. A,; Pryce, R. J.; Roberts, S.M.; Ryback,G.; Williams, J. 0.J . Chem.Soc., Perkin Trans. 1 1990,2613. (b) Mahon, M. F.; Molloy, K.; Pittol, C. A.; Pryce, R. J.; Roberts, S. M.; Ryback, G.; Sik, V.; William, J. 0.;Winders, J. A. J. Chem. SOC.,Perkin Trans. I 1991, 1255. (24) Ley, S.V.; Redgrave, A. J.; Taylor, S.C.; Ahmed, S.;Ribbons, D. W. Svnlert 1991. 741. (23) Hudlicky, T.; Boros, E. E.; Olivo, H. F.; Merola, J. S. J. Org. Chem. 1992, 57, 1026. (26) Hudlicky, T.; Boros, C. H. Tetrahedron Lett. 1993, 34, 2557. (27) Boyd, D. R.; Dorrity, M. R. J.; Hand, M. V.; Malone, J. F.; Sharma, N. D.; Dalton, H.; Gray, D. J.; Sheldrake, G. N. J. Am. Chem. SOC.1991, 113, 666. (28) Banwell, M. G.;Lambert, J. N.; Richards,S. L. Ausr. J. Chem. 1991, 44, 939.
5110 J. Am. Chem.Soc., Vol. 116. No. 12, 1994
Hudlicky et ai.
Table 1. Charge Distribution for Halobcnrene-cis-diolA ~ e t a n i d m ~ ~ Table 4. Cycloadditions of Nitrosyl Compounds
6
compd
X
CI
C6
6s
F CI
0.0622 4.1024 4,1980 4,2945
4.1750 4.1233 4.0838 4.0686
6b
~r
6c 6d
I
c5 4.1084 4.1272 4.1361 4.1419
c4 0.1700 4.1629 -0.1437 4.1384
X
compd
F
6
Table 2. HOMO Coefficients for Halobenzene-cis-diol Acetonidesz9
6b
C1
6c 6 . 2 6c 6c
Br Br Br Br
R
yield (9i)
product
CBz‘ CBr
24 54
21.
~
Bzb
Zlb 21e . . ~ 216
Ae
21e
CBz
74 ..
70 51
o-Br-piperonyl 211 a Cbz, benzyloxycarbonyl. Bz, benzoyl. Ac, acetyl,
80
Scheme 1 compd
X
CI
C6
cs
c4
66 6b
F
0.502 0.504 0.498 4.493
0.465
CI
4,359 4.354 4.348 0.350
4.516 4.498 4.473 0.465
Br
6c 6d
I
0.441
0.417 4,396
Table 3. Cycloadditions of Ethyl Propiolate
6
mmpd 6. 6b 6c 6d
X
1920
yield ($5)
F CI
4060 55:45 35:65 38:62
78 40 61 54
Br I
distribution of the carbon atoms in the polarized diene unit for the entire halogen series, as shown in Table 1. Predictionof regiocbemistryaccording to the frontier molecular orbital theory (Table 2) would establish the “ortho” adducts 17 as expected major products over the “meta” adducts 18 in cases where X is either an electron-donating01an electron-withdrawing group. x
_r
b.b, I? i w o r )
i n mnm
For our study we chose two series of dienophiles--ethyl propiolate to represent a polarized carbon-containing dienophile and acylnitroso compounds to establish the results for a highly polarized heterodienophile. The results of the cycloadditions of ethyl propiolate are shown in Table 3. The reactions were performed in refluxing benzene solution for 2-8 b, and results indicate stereospecific addition with poor regioselectivity with respect toortho and meta adducts. The expected major product, ortho adduct 20, predominated in all cases except that of chlorobenzene-cis-diol by -3:2 margin. The isomers were separated by flash chromatography and identified by NMR spectroscopy. The signal for the @-protonof the acrylate moiety appeanasa singletat66.8-7.0inadducts 19 becauseofadditional deshielding by the halogen atoms. It appears as a doublet (J = 7 Hz) in regioisomers 20. (29)We thank Professor James Tanko (Virginia Tech) for his help with AMI calculations (MOPAC. version 5.0, developed by Dewar).
kNR
23
a
20
IY
kHI
2% R = CBz ZZb.R=H
21
Reagents: (i) BaSnH, AIBN, toluene: (ii) AI(Hg), THF, HzO.
Theadditionofnitrosyldienophileswas found tobebothstereoand regiospecific. Table 4 lists the results of additions with acylnitrosocompoundsgenerated in situ from N-hydroxyuretbane and BwN+IO4-in the presence of the diene derivatives; in most cases the yields were quite good (>70%). The oxazine adducts were reduced to the corresponding conduramines by Keck’s p~ocedure.”.’~Under carefully controlled conditions, amino ketones such as 23 could be generated selectively. This type of methodology provided for easy and concise synthesis of conduramine Z2b and allowed an extrapolation to the preparation of a morecomplexaminocyclitol,lywricidine, asa prelude toageneral approach to the narcissus alkaloids. Synthesisof (+)-Lycoricidine. The application of acylnitroso cycloadditionchemistry to the synthesis of lycoricidineappeared viable in view of the demonstrated success with regiochemical generation of conduramine units of type 2la-f.’ Thus oxazine 21f from the reaction of (o-bromopiperony1)hydroxamidewith 6c was reduced to conduramine. 22b was protected with isopropyldimethylsilyl chloride, yielding 23, the precursor for the Heck cyclization.)’ This compound was also prepared from
@yqg-ye(& OH
,.
R
NH
O
5. R=OH. pzncrmirstin
?‘,
OH
/
R
hl,
O
c.R=H. lymricidlis ab, R=OH. niircicliiiii!~
/Br
R’
0
23. R’=SIMT:IPr KLCRZ
22. by acylation with bromopiperonyl chloride, followed by protection with isopropyldimetbylsilyl chloride (Scheme 2) according to the procedure published by Piepershurg.68 S i n s the original report of cyclization of an isomer of 23 to the lycoricidine skeleton by Chida? several investigators have ~ ~our ~ initial reported success with this unusual c l o ~ u r e . 8 8 In wedescribed technical difficultiesin reproduc(30) For oxazine reduction. see: Keck, G. E.;Fleming, S.; Nickell, D.; Wcidcr. P. Svnth. Commun. 1979. 9. 281. (31)(a) Heck, R. F. Org. Reoh. 1982, 27, 345. Heck, R. F. In Comprehensiw Organic Synthesis;Trast, 8. M., Fleming, I., EAds.;Pergaman Press: Oxford, 1991;Vol. 4,Chapter 4.3.(b) Knochel, P. In Comprehensiw OrganicSydhesis;Trost, E. M., Fleming. I., Eds.: Pergamon Press: Oxford, 1991: VoI. 4, Chapter 4.4.
Design of Amino Cyclitols (exo-Nitrogenous)
Scheme 2
6-
ii
i
/
OH
X=CI,Br
l a . X=CI l b , X=Br
J. Am. Chem. SOC.,Vol. I 1 6, No. 12, 1994 51 11
&% \
6a. X=CI 6b, X=Br
1
29a, X=CI 2Yb. X=H
+
I iii 27
28a, X=CI
28b. X=H
30a. X=Ci 30b, X=H
22a, R1= H,Rz = CBZ 22b, RI=OH, R, =Br-piperonyl 2 2 ~R,=SIMcZPf, . R,=CBZ
E48 26: R=Ac R=H
