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Enantioselective and Enantioconvergent Syntheses of Building Blocks for the Total Synthesis of Cyclopentanoid Natural Products.

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elemental analyses, and crystal structure determinationsr6],
prove indirectly that the previously described rearrangements of RuCo2 complexes with acetylene ligandsC3llead to
isomers with vinylidene ligands
Enantioselective and Enantioconvergent Syntheses
of Building Blocks for the Total Synthesis of
Cyclopentanoid Natural Products**
The atomic arrangements in 1 and 2 (Fig. 1) indicate the
marked change in the bonding situation caused by the acetylene-vinylidene conversion. The CC multiple bond,
which in 1 is parallel to the metal atom triangle, is inclined
at ca. 47" to the triangular plane in 2; and is ca. 3 pm
longer in 2 than in 1. The vinylidene ligand can therefore
be considered as a M3C-CHR carbenium ion stabilized by
charge delocalization, as discussed previously for the isoelectronic (C0)9C03C-CHR cations[71.
Intermediates involved in the rearrangement of alkyne
complexes into isomeric 1-alkenylidene complexes have
not yet been observed, even for mono- and binuclear complexes. Initial migration of the acetylenic H atom to the
metal to form an acetylide complex, which then tautomerizes to the vinylidene complex, appears plausible[']. The
geometrical relationship between 2 and the acetylide complex 3I9] corroborates this. And also the ensuing step, the
hydrogenation to the alkylmethylidyne complex, which
e. g. is possible starting from H20s3(C0)9(CCHR)to afford
4121,requires only slight steric changes. The alkyne-alkenealkane conversion on a metal surface modeled by the se-
feldin A l [ l a l , 7-epi-brefeldin A 2['b1,and the ba-carbaprostacyclins 3a[Id1and 3b['", and the pentalenolactone E 4[lc1,
are rewarding synthetic targets. 1, 2[2a1,and 3a and 3b[2bJ
have been prepared enantioselectively by total synthesis
from the cyclopentenolactone 5 ; 4 has not yet been completely synthesized from ent-5[2c1.
We report here two novel
efficient routes to 5 and ent-5, starting from meso-tetrahydrophthalic anhydride.
By Hans-Joachim Gais* and Karl L. Lukas
R u C O ~ ( C O ) ~ ( ~ , - I ~ ~ - H C C ~RBuLCI )O ~ ( C O ) ~ ( ~ ~ - T ~ ~ - C C H ~ B U ) Because of their structures and biological properties, cy1
2
clopetanoid natural products and analogues such as bre-
OH
1, X = OH, Y = H
2, Y = 0 H . X = H
3a, R = n-C,H1,
HO,"
CH,
4
3
4
quence 1, 3, 2, 4 is therefore consistent with a "straightening out" of the C2 moiety above the metal atom plane.
Received: October 6, 1983 [Z 583 IE]
German version: Angew. Chem. 96 (1984) 139
CAS Registry numbers:
1, 88495-88-8; 2, 88495-89-0; RuCo,(CO),,, 78456-89-0; 3,3-dimethyl-l-butyne, 917-92-0
111 E. Sappa, A. Tiripicchio, P. Braunstein, Chem. Reu. 83 (1983) 203.
[2] A. J. Deeming in B. F. G. Johnson: Transition Metal Clusters, Wiley, New
York 1980, p. 391; C. J. Cooksey, A. J. Deeming, I. P. Rothwell, J. Chem.
Soc. Dalton Trans. 1981, 1718.
131 E. Roland, H. Vahrenkamp, J. Mol. Catal. 21 (1983) 233.
[4] E. Roland, H. Vahrenkamp, Organometallics 2 (1983) 1048.
[5] 'H-NMR data (CDClp, int. TMS) of 1: 6=1.19 (9H), 8.17 (OSH), 9.00
(0.5H); 2:6=1.15 (9H),5.80(1H). IR-data(C,H,,,cm-')of
1: 2095 w,
2056 vs, 2040 vs, 2030 vs, 2018 w, 2005 w, 1899 w; 2 : 2096 w, 2054 vs,
2045 vs, 2031 vs, 2014 m, 2008 sh. The two broad 'H-NMR signals of intensity 0.5 suggest a rapid interconversion between two isomers of 1,
whose CIC bonds are orientated respectively along an Ru-Co bond.
Only one of these isomers is observed in the crystalline state [6].
[6] 1:triclinic, Pi, a=1013.6(2), b=1328.4(2), c-820.4(1) pm, n=106.31(1),
p- 112.68(1), y=76.17(1)", 2 = 2 , 2928 reflections, R=0.061. 2: monoclinic, P2,/c, a=877.8(2), b = 1299.1(1), c = 1728.8(2) pm, 8=95.77(1)",
2 = 4 , 2911 reflections, R=0.046. Further details on the crystal structure
determination can be obtained from the Fachinformationszentrum Energie Physik Mathematik, D-75 14 Eggenstein-Leopoldshafen, by quoting
the depository number CSD 50592, the names of the authors, and the
journal citation.
[7] R. T. Edidin, J. R. Norton, K. Mislow, Orgnnometallics I (1982) 561.
[8] J. Wolf, H. Werner, 0. Serhadli, M. L. Ziegler, Angew. Chem. 95 (1983)
428; Angew. Chem. Int. Ed. Engl. 22 (1983) 414; J. Holton, M. F. Lappert,
R Pearce, P. I. W. Yarrow, Chem. Rev. 83 (1983) 135.
[9] M. Catti, G. Gervasio, S. A. Mason, J . Chem. SOC.Dalton Trans. 1977,
2260.
142
0 Verlag Chemie GmbH, 0-6940 Weinheim, 1984
5
Enantioselective saponification of the meso-diester 6
with commercial pig liver esterase (PLE) results in practically exclusive attack at the (1R)-ester group to afford the
enantiomerically pure (1S,2R)-monoester 7 [99%, 199%
ee, m.p.=28"C, [a]:& t26.1 (0.89, H20)], the reaction
proceeding on the mol scale (Scheme l)[2c33a,b1.
For the synthesis of 1 mol 7 , ca. 9000 U (90 mg) PLE, 1000 mL phosphate buffer (pH 7.0), 500 mL 2~ NaOH, and a reaction
time of 4 d at 25 "C are required. Enantiomer resolution of
rac-7 with ephedrine or dehydroabietylamine enables
large amounts of 7 and ent-7 [m.p.=28"C, [a]:!&-25.9
(0.90, H20)] to be obtained enantiomerically pure (92%,
1 9 9 % ee). The enantiomeric excess (ee) of 7 and ent-7 was
determined from the diastereomeric excess (de) of the
ephedrine salts, which in turn was determined by 'H-NMR
spectroscopy from the different signals of the ester groups.
Within the detection limits ( 1 l%), admixture of the respective other diastereomer did not occur. The absolute
configuration of 7 and ent-7 was established by X-ray
structure analysis of the (-)-(lR,2S)-ephedrine salt of ent7 [m.p. = 158"C, [a]g- 35.9 (2.00, MeOH)]. The "pseudosymmetric" structure of 7 and ent-7 permits both their
conversion into the lactones 8 [[a]? -85.4 (2.63, acetone)] or ent-8 na]$' 85.2 (2.64, acetone)] (enantioconvergence["), respectively, and the synthesis of 8 and ent-8
+
[*] Priv.-Doz. Dr. H.-J. Gais, Dr. K. L. Lukas ['I
Institut fiir Organische Chemie und Biochemie
der Technischen Hochschule
Petersenstrasse 22, D-6100 Darmstadt (FRG)
['I Present address: Chemische Werke Huls AG, D-5470 Marl (FRG)
[**I This work was supported by the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen lndustrie. We thank Prof. Dr. H . J . Lindner,
Darmstadt, for the X-ray structure analyses and Prof. Dr. H. Gunfher,
Siegen, for the 400 MHz 'H-NMR spectra.
0570-0833/84/0202-0142 $02.50/0
Angew. Chem. Int. Ed. Engl. 23 (1984) No. 2
from 7 by optional chemoselective reduction of the ester
or carboxy group to the hydroxymethyl group and subsequent lactonization (Scheme 1). For the ester group this
proceeds by reduction with sodium and ethanol in liquid
ammonia (7+.ent-8, 82%) or with LiBH(Et), (7+ent-8,
79%) and for the carboxy group via acid chloride and reduction with NaBH, in ethanol (7+8, 76%)IS1.Undesired
1 : I-mixture of the isomeric lactone diesters l l b and 12b
(91%). As expected12c1,
both the pure diesters and the mixture can be converted regioselectively with KOtBu into
the cyclopentenolactone 5 (82%) [m.p. = 120- 121"C,
[a]g= 190.0 (2.48, CH2C12); ent-5: m.p. = 120-121 "C,
[a]$' = - 189.3 (2.46, CH2C12)],which exists almost exclusively in the enol form. The structure of 5 is proved by 400
MHz 'H-NMR spectroscopy. A further structural proof
was provided by an X-ray structure analysis of the hydroxy
ester 13 [m.p.=98-10OoC, [a]$'
+49.3 (1.13, ethyl acetate)] (Scheme 2). Using the strategy we have described
here, 5 and ent-5 are accessible rationally and enantiomerically pure by enantioselective (7 steps, 50% and 6 steps,
53%, respectively) or enantioconvergent synthesis (8 steps,
37%) from meso-tetrahydrophthalic anhydride.
+
Received: September 1, 1983;
revised: October 21, 1983 [Z 535 IE]
German version: Angew. Chem. 96 (1984) 140
Scheme 1. a) PLE. b) (COCl)z, CHCls, 25°C; NaBH4, EtOH, -40°C; TsOH,
PhMe, 110°C. c) Na, EtOH, NH,, -78°C; NH4C1; conc. HCI. d) NaOH,
HzO, lOO"C, 48 h; conc. HCI. e) MeLi, EtzO, tetrahydrofuran, -78°C.
epimerization to afford the trans-lactones ent-9 and 9, respectively, in the conversion of 7 into 8 and ent-8, respectively, can be avoided within the limits of detection ( 2 1%).
For comparison, epimerization of 8 on the preparative
scale afforded 9 [m.p.=98"C, [a12 -155.0 (1.90, ace155.1 (1.91, acetone)],
tone)] [ent-9: m.p.=98"C, [a]$'
whose reduction to the known (1R,2R)-4-cyclohexene-1,2dimethanol [m.p. = 54"C, [a12 - 69.8 (2.97, CHC13)] allowed determination of the absolute configuration of 8 by
a chemical correlation12c*61
(Scheme 1). The ee-values of 8
and ent-8 were determined indirectly on the dimethyldiols
10 [m.p.=90-9l0C, [a]$' +77.0 (1.68, CH2C12)]and ent10 [rn.p.=90-9loC, [a]g -76.8 (1.63, CH2CIz)] by 'HNMR spectroscopy (300 MHz) in the presence of the chiral shift reagent Eu(tfc), from the methyl signals to 299%
[rac-10 +0.6 equiv. Eu(tfc), in CDCI, exhibits a W = 0 . 1 2
ppm]12c*61.
Within the limits of detection ( 20.5%), no admixture of the other isomer was detectable.
Oxidative ring cleavage of 8 leads to the dicarboxylic
acids l l a and 12a (87%), whose esterification affords a
+
CAS Registry numbers:
5, 88511-03-9; enf-5, 88586-04-3; mesa-6, 4841-84-3; 7, 88335-93-7; ent-7,
88335-94-8; enf-7.(-)-ephedrine, 88586-05-4; 8, 65376-03-6; ent-8, 8858606-5; 9, 88586-07-6; ent-9, 88586-08-7; 10, 88511-04-0; ent-10, 88586-09-8;
l l s , 88511-05-1; l i b , 88586-10-1; 12s. 88511-06-2; 12b, 88511-07-3; 13,
8851 1-08-4; (1R,2R)-4-cyclohexene-l,2-dimethanol,15679-28-4; meso-tetrahydrophthalic anhydride, 935-79-5
[I] a) C. Le Drian, A. E. Greene, J. Am. Chem. Sac. 104 (1982) 5473; b) C. P.
Gorst-Allman, P. S. Steyn, C. J. Rabie, J . Chem. Sac. Perkin Trans. 1 1982,
2387; c) L. A. Paquette, G. D. Annis, H. Schostarez, J. Am. Chem. SOC.
104 (1982) 6646; d) P. A. Aristoff, J. Org. Chem. 46 (1981) 1954; e) W.
Skuballa, H. Vorbriiggen, Angew. Chem. 93 (1981) 1080; Angew. Chem.
In?. Ed. Engl. 20 (1981) 1044.
[2] a) H.-J. Gais, T. Lied,Angew. Chem. Y6 (1984) 143;Angew. Chem. Int. Ed.
Engl. 23 (1984) 145; b) H.-J. Gais, K. L. Lukas, W. Ball, H. Sliwa, 29th
IUPAC Congress, Cologne, 1983, Abstr. 215; K. L. Lukas, Disserfafion,
Technische Hochschule Darmstadt 1983; c) H.-J. Gais, Habilitationsschrft. Technische Hochschule Darmstadt 1981.
[3] a) The enantioselective saponification of dimethyl mesa-1.2-hexahydrophthalate with PLE affords the monomethyl ester of (1S,2R)1,2-cyclohexanedicarboxylic acid (99%. 80% ee) (m.p. = 47-48 "C,
[a]$&=+25.OoC (c=0.96, EtOH) for 299% ee) [Zc]; b) Additional enantioselective saponifications with PLE: C. S. Chen, Y. Fujimoto, C. J. Sih,
J. Am. Chem. Sac. 103 (1981) 3580, and literature cited therein; M. Arita, K. Adachi, Y. Ito, H. Sawai, M. Ohno, J. Am. Chem. SOC.105 (1983)
4049, and literature cited therein.
[4] K.-K. Chen, N. Cohen, J. P. De Noble, A. C. Specian, Jr., G. Saucy, J.
Org. Chem. 41 (1976) 3497; B. M. Trost, J. M. Timko, J. L. Stanton, J .
Chem. SOC.Chem. Commun. 1978. 436.
(51 The enantioselective oxidation of meso-4-cyclohexene-l,2-dimethanol
with HLADH/NAD'/FMN offers an alternative route to 8 on the mmol
scale (76%, Z 99% ee) [6].
[6] I. J. Jakovac, H. B. Goodbrand, K. P. Lok, J. B. Jones, J . Am. Chem. Sac.
104 (1982) 4659.
8
Stereoselective Synthesis of
Q-4-Hydroxy-2-alkenoic Acid Esters from
Aldehydes and the d3-Building Block
Ethyl Lithiopropiolate**
A0
lla, R = H
l l b , R CH3
0
12a. R = H
12b, R = CH3
I
4
0
0
5
13
Scheme 2. a) O,, MeOH, -78°C; H202, HCOOH, 100°C. b) MeOH, H",
80°C. c) KOtBu, PhMe, 25°C; 50% H2SO4.d) NaBH4, MeOH, -78°C.
Angew. Chem. Int. Ed. Engl. 23 (1984) No. 2
By Hans-Joachim Gais*
7-epi-brefeldin A 2[lb1,
The macrolides brefeldin A
colletodiol 3["l, and cytochalasin B 4[ld1contain an ( 6 - 4 hydroxy-2-alkenoic acid structure element. For their direct
synthesis[" from aldehydes and building blocks which correspond to the d3-synthon 5, there are two methods: the
[*I Priv.-Doz. Dr. H.-J. Gais
Institut fur Organische Chemie und Biochemie
der Technischen Hochschule
Petersenstrasse 22, D-6100 Darmstadt (FRG)
[**I This work was supported by the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen Industrie.
0 Verlag Chemie GmbH, 0-6940 Weinheim, 1984
0570-0833/84/0202-0143 $02.50/0
143
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