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Total Synthesis of the Pseudoguaianolide (+)-Confertin.

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The skeleton of 4 (Fig. 2)"' can be imagined as being
built up of an Fe3P "butterfly" (angle between the
FelFeZP2 and Fe3Fe2P2 planes = 123.9"), bridged by
Me,SiO-P=NSiMe, in the cis form as p3-PN ligand (dihedral angle OP1N1Si=32.l0). Both nitrogen atoms (NI
359.9 N2 359.8 ") are trigonal planar coordinated, and the
length of the PI-Nl bond (1.597(8)
lies in the expected
range (cf. Ref. [I]). The P2-N2 bond length (1.710(6) A) is
comparable with the P-N bond length in the phosphanediyl complex [p-(Me,Si),NP{Cr(CO),1,] (1.697(3) A)."'
O,
A)
Experimental
3 and 4: A suspension of 1 (755.5 mg, 1.5 mmol) in toluene (7 mL) was
treated with 835.7 mg (3 mmol) of 2 IS]. The mixture was stirred for 5 h at
90°C. After removal of the solvent (oil-pump vacuum), the dark-red, oily residue was taken up in 3 mL of acetonitrile and stored in the refrigerator for
2 d. The precipitate that formed was separated from the mother liquor and
then re-cooled (2 d, refrigerator). Altogether three crops of a red precipitate
were obtained; these were combined and taken up in 20mL of pentane.
After filtration over filter flocks and evaporation of the filtrate to 1 mL, darkred 4 crystallized at - 30°C as a mixture of diastereomers (1 :IS = 2 : I); yield
100 mg (8.2% referred to 1). Repeated recrystallization from ether at - 30°C
furnished pure 4 1 (X-ray structure analysis). On storing the combined acetonitrile filtrates in a refrigerator for three weeks an orange precipitate separated out, which upon recrystallization from a little pentane at -30°C furnished 5 mg (0.3%) of 3 (exclusively diastereomer l, X-ray structure analysis)
as orange crystals.
5 : The oily residue obtained after removal of toluene from the reaction solution of 1 and 2 was taken up in ether and cooled to -75°C for ca. 12 h; 5
separated as a black precipitate. This was dissolved in 30 mL of ether. After
filtration through filter flocks and evaporation of the filtrate to 3 mL, 193 mg
(22%) of 5 crystallized out on cooling to -75°C as a 3 : 1 mixture of 5a and
5b. The yield could be increased to 290 mg (33%) by allowing I and 2 to
react in a molar ratio of 1 : 1 in benzene for 1 h at 75°C.
Received: August 19, 1986;
supplemented: September 1 I, 1986 [Z 1907 IE]
German version: Angew. Chem. 99 (1987) 59
[ I ] Review: 0. J. Scherer, Angew. Chem. 97 (1985) 905; Angew. Chem. In /.
Ed. Engl. 24 (1985) 924.
121 a) E. Niecke, R. Ruger, W. W. Schoeller, Angew. Chem. 93 (198 I ) 1 110;
Angew. Chem. I n l . Ed. Engl. 20 (1981) 1034; b) E. Niecke, D. Gudat, W.
W. Schoeller, P. Rademacher, J . Chem. Soc. Chem. Commun. 1985. 1050;
c) E. Niecke, M. Engelmann, H. Zorn, B. Krebs, G. Henkel, Angew.
Chem. 92 (1980) 738; Angew. Chem. Inf. Ed. Engl. 19 (1980) 710.
131 E. W. Abel, S. A. Mucklejohn, Phosphorus Sulfur 9 (1981) 235, and references cited therein.
141 See, e.g., M. 0. Albers, D. J. Robinson, N. J. Coville, Coord. Chem. Reu.
69 (1986) 127; K. Knoll, G. Huttner, L. Zsolnai, I. Jibril, M. Wasiucionek,
J. Organomel. Chem. 294 (1985) 91 ; D. J. Brauer, S. Hietkamp, H. Sommer, 0. Stelzer, G. Miiller, C. Kruger, J . Organomel. Chem. 288 (1985) 35;
R. La1 De, H. Vahrenkarnp, 2. Nafurforsch. 8 4 1 (1986) 273.
[S] 3: monoclinic, P2,/n, a=12.585(2), 6=18.331(5), c=17.111(6)~,
b= 108.66(3)", Z = 4 , Y=3740.0 A',p,,,,,= 1.36g cm-'. 5564 measured reflections, 3163 observed (MoKn. F~>2.0a(F&2Q<47a), R=0.059,
R,=0.050. 4 : triclinic, P i , a = 12.649(3), 6 = 13.120(2), c= 12.187(4)
a = 108.55(2), fl= 107.65(2), y=83.55(2)", Z = 2 , V= 1826.8 A3,pp,,,= 1.49
g cm- '. 4599 measured reflections. 2655 observed (MoKorF522.0o(F3,
2c)C45"), R=0.09l, R,=OOXO t urrher details of the crystal structure
investigation are available on request from the Fachinformationszentrum
Energie, Physik, Mathematik GmbH, D-75 14 Eggenstein-Leopoldshafen
2 (FRG), on quoting the depository number CSD-52 124, the names of the
authors, and the journal citation.
[6] 0. J. Scherer, H. Sitzmann, G. Wolmershauser, J . Organomel. Chem. 309
(1986) 77; diazadiphosphetidines: R. Keat, Top. Curr. Chem. 102 (1982)
82. and 0. J. Scherer, R. Anselmann, W. S. Sheldrick, J . Organomet.
Chem. 263 (1984) C 26.
(71 K. M. Flynn, B. D. Murray, M. M. Olmstead, P. P. Power, J . Am. Chem.
Sor. 105 (1983) 7460; cf. also [(iPr2NP)ZFel(C0)Y]:
R. B. King, F.-J. Wu,
E. M. Holt, Inorg. Chem. 25 (1986) 1733.
181 0. J. Scherer, N. Kuhn, Chem. Ber. 107 (1974) 2123.
A,
Angew Chem.
In!. Ed.
Engl. 26 (1987) No I
Total Synthesis of the Pseudoguaianolide
(+)-Confertin**
By Gerhard Quinkert, * Hans-Giinther Schmalz,
Egon- Walzer, Teresa Kowalczyk- Przewloka, Gerd Diirner,
and Jan W. Bats
The three-membered ring compounds l a (preparation,
see ref. [la]; absolute configuration, see ref. [lb]) or ent-la
(preparation, see ref. [lb, 21) serve as enantiomerically
pure building blocks in the synthesis of (+)-estrone,""]
(-)-norge~trel,'~]or (-)-methyl jasmonate.['b,21They are
accessible by chirality-inducing cyclopropanation and can
be transformed by stereospecific ring expansion into the
2-alkyl-3-vinyl-substituted cyclopentanone derivatives 2a/
3a, 2b/3b, or ent-2c/ent-3~'~~
(see Scheme 1).
1
2
3
a: R = H
b: R = C %
Scheme 1. Stereospecific ring expansion of enantiomerically pure threemembered ring building blocks of type 1 (preparation, see ref. [la, 51).
We have now employed the enantiomerically pure diastereomers 2d/3d, prepared from dimethyl (R)-Z-isopropenylcyclopropane-1,l-dicarboxylate 1 b (preparation and
absolute configuration, see ref. [5]),for the synthesis of the
sesquiterpene lactone (+)-confertin 14 (see Scheme 2).
In order to construct the hydroazulene system, we utilized an intermolecular Michael addition of the thermodynamically more stable enolate anion of 2d/3d onto acrylonitrile, which results in exclusive formation of the trunsadduct 4 , and a Lewis-acid-catalyzed intramolecular hetero-ene reaction of 7 to give a mixture of isomers 8 and 9 ,
which were not separated, but rather directly converted via
the constitutional isomers 10/11 into 12.
The ketone 12, whose structure was established by single-crystal X-ray diffraction analysis,['] reacts, under conditions of kinetic control, regioselectively at C7 and stereoselectively from the a side with ethyl a-bromoacetate
(93%)."' The resulting alkylation product was transformed
via 13 into (+)-confertin 14 in analogy to the synthesis of
(&)-confertin r a ~ - 1 4 ' ~
by' SchIessinger et al.19d1
and Heathcock et aLf90This represents the first total synthesis of an
enantiomerically pure pseudoguaianolide and makes accessible once again another cyclopentanoid target compound from a chiral cyclopropane derivative. Physical
[*] Prof. Dr. G. Quinkert, Dr. H.-G. Schmalz, DipLChem. E. Walzer,
Dr. T. Kowalczyk-Pnewloka, Dr. G. Diirner, Dr. I. W. Bats
lnstitut fur Organische Chemie der Universitat
Niederurseler Hang, D-6000 Frankfurt am Main 50 (FRG)
[**I This work was supported by the Deutsche Forschungsgemeinschaft
(Project 15/2), the Bundesminister fur Wirtschaft (Project AIF No.
581 I),the Fonds der Chemischen lndustrie, and Hoechst AG.
Q VCH Verlagsgeselkchaji mbH. 0.6940 Weinheim. 1987
0570-0833/87/0101-0061 $ 02.50/0
61
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Scheme 2. Synthesis of (+)-confertin 14 from 2d/3d: a) acrylonitrile, NaOMe, ether, room temperature (RT)), 2 h,
kugelrohr distillation (67%); b) NaBH,, MeOH, 0°C. 1.5 h (97%), product contains 5% of the OH epimer; c) tert-butyldimethylsilyl chloride (TBDMSCI), imidazole, dimethylformamide (DMF), 60 h, RT, kugelrohr distillation (93%); d )
diisobutylaluminum hydride (DIBAH), hexane, -60°C t o I O T , 4 h; then HCI, H 2 0 / E t 2 0 , 30 min, filtration through
SO,; e) Me2AICI, CH2C12, 0°C. 15 min, chromatography on S O 2 , product contains 8 and 9 in the ratio 1.7 : 1 (62%
based on 6); f) CrO,.2py, CH2C12,RT, 2 h, filtration through S O 2 ;g) H,, Rh (5% on A120J). ethyl acetate/AcOH =98/
2.4.5 bar, RT, 16 h; then Cr03.2py,CH2C12, RT, 2 h (60% based on a mixture of 8 and 9).
Table I . Physical data for selected synthetic intermediates as well as the
product.
data for some of the synthetic intermediates as well as the
product are presented in Table 1.
l b : IR (film): P=3080 (w), 1725 (s), 1650 (w), 890 c m - ' (m); 'H-NMR
(CDCI3): 6= 1.47 (dd, 1 H), 1.80 (s, 3H), 1.87 (dd, 1 H), 2.49 (t, I H), 3.68 ( s ,
3H), 3.75 (s, 3H), 4.71 (5, 1 H), 4.87 (s, 1 H); la]$= + 128.0" (c= 1.113 in
CHCI,); @(A): -4870 (227 nm) (CH,OH)
Received: September 10, 1986 [Z 1926 IE]
German version: Angew. Chem. 99 (1986) 82
2d: IR (film): V=3080 (w). 1740 (s), 1645 (m), 890 c m - ' (m); 'H-NMR
(CDCI,):S=l.O3(d,3H), 1.61-1.79(m, IH), 1.76(~,3H),2.01-2.46(m,5H),
4.81 (m. 1 H), 4.86 (m, 1 H); [a]$= 137.6" (e=0.864 in CHCI,); @A):
12450 (295). 12010 (303 nm) (dioxane)
a ) G. Quinkert, U. Schwartz, H. Stark, W. D. Weber, F. Adam, H. Baier,
G. Frank, G. Durner, Liebigs Ann. Chem. 1982. 1999; b) G. Quinkert,
H . 4 . Schmalz, E. M. Dzierzynski, G. Diirner, J. W. Bats, Angew. Chem.
98 (1986) 1023; Angew. Chem. Int. Ed. Engl. 25 (1986) 992.
4 : 1R (film): t=3080 (w), 2240 (m), 1735 (s), 1645 (m), 895 c m - ' (m); 'HG. Quinkert, F. Adam, G. Diirner, Angew. Chem. 94 (3982) 866; Angew.
NMR (CDCI,): 6=0.87 ( s , 3H), 1.77-2.64 (m, 12H), 4.81 (5, 1 H), 5.01 ( s ,
Chem. In!. Ed. Engl. 21 (1982) 856; Angew. Chem. Suppl. 1982. 1777.
1 HI; [alg= +81.5" (c=0.8899 in CHCI,); @(A): +5360 (300), +5630
H. Baier, G. Durner. G. Quinkert, Helu. Chim. Acta 68 (1985) 1054.
(308 nm) (dioxane)
a) G . Quinkert, H. Stark, Angew. Chem. 95 (1983) 651; Angew. Chem. Int.
Ed. Engl. 22 (1983) 637; b) G. Quinkert in W. Bartmann, B. M. Trost
8 : IR (film): G=3630-3100(m), 1255 (s), 1115 (s), 830(s), 7 7 0 c m - ' (s); 'H(Eds.): Se/ecfruiry--a Goolfor Syntheric Ef."ciency. Verlag Chemie, WeinNMR(CDCI,):~~O.O~(S,~H),O.O~(S,~H),O.~~(S,~H),O.~~(S,~H),
1.44heim 1984.
1.95 (m, IOH), 2.01-2.32 (m. 3H), 2.62 (d, I H), 3.61 (dd, 1 H), 4.03 (m, 1 H);
G. Quinkert, H.-G. Schmalz, E. Walzer, S. Gross, G Diirner, Angew.
[a]$=fS1.4" (c= 1.068 in CHCI,)
Chem. 98 (1986) 732; Angew. Chem. Int. Ed. Engl. 25 (1986) 732.
9 : IR (film): P=3590-3020 (m), 3080 (w), 1630 (m), 1250 (s), 1120 (s), 880 (s).
rac-12: &,c,cd= 1.047 g/cm3; triclinic, space group P I ; a=7.0418(7),
830 (s), 770 c m - ' (s); 'H-NMR (CDCI,): 6=0.00 (s, 3H), 0.01 (s, 3H), 0.63
6 = 1 l.829(2), C = 12.783( 1) A,
= 7 l.OO( I), B= 78.21( I). y = 85.35( 1)' ;
(s, 3H), 0.87 (s, 9H), 1.08-1.26 (m, l H ) , 1.36-1.51 (m. 2H), 1.54-1.91 (m,
Y=985.4(3)
Enraf-Nonius CAD4 diffractometer; Cu,, radiation;
6H), 2.11 (t. 1 H), 2.41-2.54(m, 1 H), 2.81 (d, 1 H), 3.58 (t, 1 H), 3.77-3.87 (m,
half-circle to 2 8 = 120". 2838 unique reflections with I>a(I); structure
1 H), 4.75 (s, 1 H), 4.92 (s, I H); [a]?= -5.5" (c=0.728 in CHCI,)
determination by direct methods; R(F)=0.053, wR(F)=O.047: S D P pro12: M.p.=48-49"C (hexane); 1R (KBr): V= 1695 (s), I255 (s), 1240(s), 1115
gram system. Further details of the crystal structure investigation may be
(s), 870 (s), 830 (s), 770 c m - ' ( s ) ; 'H-NMR (CDCI,): 6=0.02 (s, 3 H), 0.03 (s,
obtained from the Fachinformationszentrum Energie, Physik, Mathe3 H), 0.69 (s, 3 H), 0.88 ( s , 9 H), 0.95 (d, 3 H), 1.39- 1.55 (m, 3 H), 1.64- I .98 (m.
matik GmbH, D-7514 Eggenstein-Leopoldshafen 2 (FRG), on quoting
4H), 2.04-2.14 (m, 1 H), 2.40-2.58 (m. 3H), 2.79 (dd, 1 H, 3.54 (t, I H);
the depository number CSD-51895, the names of the authors, and the
[alb= -34.6' (c=0.521 in CHCI,); @(A): -3960 (288 nm) (dioxane)
journal citation.
13: M.p.= 116-1 17°C (etherlpentane): 1R (KBr): C=2960 (m), 2875 (m),
Of the four C-H bonds in neighboring positions to the keto group, Ha1765 ( s ) , 1730 (s), 1245 (s), I170 c m - ' (s); 'H-NMR (CDCI,): 6 = 1.00 (s,
C7 undergoes preferential heterolysis for stereoelectronic reasons; the re3H), 1.03(d,3H), 1.36-1.59(m,4H), 1.61-1.87(m,3H), 1.99(m,IH),2.07(~,
sulting enolate is attacked rapidly from the ct side for both stereoelec3 H), 2.08-2.23 (m, 3 H), 2.70 (m, I H), 2.90 (dd, 1 H), 4.63 (t, I H), 4.72 (ddd,
tronic and steric reasons.
1 H);[a]b=+52.7" (c=0.621 in CHCI,)
, [9].
Concerning syntheses of r ~ c - 1 4 see
a) J. A. Marshall, R. H. Ellison, J. Am. Chem. Soe. 98 (1976) 4312; b) M.
14: M.p.= 144-145°C (acetonelhexane); IR (KBr): C=3090 (w). 1760 (s),
F. Semmelhack, A. Yamashita, J. C. Tomesch, K. Hirotsu, &id. lOO(1978)
1730 ( s ) , 1660 (m). 1270 (s), 1140 (s), 1005 (s), 985 c m - ' (s); 'H-NMR
5565: c) P. A. Wender, M. A. Eisenstat, M. P. Filosa, ibid. 101 (1979)
(CDCI?): 6= 1.02 (s, 3 H), 1.13 (d, 3 H), 1.64 (dd, 1 H), 1.78 (dd, 1 H), 1.802196: d) G. J. Quallich, R. M. Schlessinger, ibid. 101 (1979) 7627; e) F. E.
2.01 (m, 3H), 2.10-2.28 (m, 3H), 2.43 (dd, 1 H), 2.48-2.59 (m, 1 H), 3.05 (m.
Ziegler, JLM. Fang, J. Org. Chem. 46 (1981) 825; f) C. H. Heathcock, E.
I H), 4.69 (ddd, I H), 5.67 (d, I H), 6.29 (d, 1 H); [aJ$'=
+ 176.0' (c=0.374
G. DelMar, S. L. Graham, J . Am. Chem. SOC.104 (1982) 1907: g) A. G.
in CHCI,); @(A): -2940 (257), +5290 (298, sh), + % I 0 (303), f4135
Schultz, L. A. Motyka, M. Plummer, ibrd. 108 (1986) 1056; h) H.-G.
(312 nm. sh) (dioxane)
Schmalz, Dusertarion, Universitst Frankfurt am Main 1985.
+
+
+
A';
62
0 VCH Verlagsgesellschaft mhH. 0-6940 Wernherrn. 1987
0570-0833/87/0101-0062 $ 02 50/0
Angew. Chenz. Int Ed. Engl 26 (1987) No 1
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