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Diastereo- and Enantioselective Synthesis of 2-Substituted 3-Trialkylstannylcyclohexanones by Michael Addition of Trialkylstannyllithium to Cyclohexenone SAMP Hydrazone.

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[S] B. A. Vaartstra, J. C. Huffman, W. E. Streib, K. G. Caulton, Inorg. Chem.
1991,SO. 121-125.
[6] R. Hasselbring, Dissertation, Universitiit Gottingen, 1992.
[7] M. Veith, Chem. Rev. 1990, 90, 3-16.
M , = 990.67, monoclinic, soace
[XI Crystal data of 3: C,,H,,N,,Si,P,Ba,
group P2,/n. u = 1359.3(3), h = 2076.2(3), c = 2271.9(4) pm, /j =
98.62(3)'. V = 6.339(2) nm3, 2 = 4, e,,,,d=1.038 Mgm-'. F(000) =
2088. i.=71.073 pm, T = -12O'C, p(MoK.) = 0.832mm-'. Data were
collected o n a Stoe-Siemens-AED diffractometer. Intensities of a rapidly
cooled crystal with dimensions 0.4 x 0.3 x 0.2 mm in an oil drop were collected bythe2tl/wmethodintherangeof8" s 20 s 45'.Ofatotalof8447
reflections 8303 were independent and corrected for absorption.
8289 reflections were observed with Fo > 4u(F,). The R l values are
R, =
F , / / E F , = 0.082 ( F > 4 u F ) and wR2 = [ E n ( F z - F:)'/
~ i v ~ ' 3=~ 0.254
' ~ (all data) for i v - ' = u2(F:) (gi P)' g , P with
P = (Fz + 2F:)/3 and g , = 0.1 14, g 2 = 56.843. The relatively high R-value can be explained by a rotational disorder both of the Me,Si and the
Me,N groups. All carbon atoms in 3 were refined I n two positions with
half occupancy. In addition, a disordered n-hexane molecule is present in
the cell. 5 : C,,H,,,N,8Si,P,Ba,.
M , = 1963.19, triclinic, space group Pi.
u =1630.3(6), h = 1689.8(6), c = 1875.2(7) pm, a =71.30(2), fl = 82.4612).
;I =79.98(2)",
Y = 4.803(3) nm3, Z = 2, e,,,,, = 1.389 Mgm-3, F(000) =
2034, jl=7l.073pm. T = -12O"C, p(MoKz)=1.845mm-'. Data were
collected on a Stoe-Siemens-AED diffractometer. Intensities of a rapidly
cooled crystal with dimensions 0.3 x 0 3 x 0.2 mm in an oil drop were collected by the 2 H / u method in the range of 8' s 2 0 I 45'. Of a total of
16 839 reflections 12579 were independent and corrected for absorption,
and 12568 were observed with Fo > 4u(F,). The R-values are R1 = 0.044
( F > 4oF) and nR2 = 0.121 (all data), g, = 0.059, g, =16.630. Both
structures were solved with direct methods (SHELXS-90) [9] and refined
by full-matrix least-squares on F 2 with all data (SHELXL-92) [lo]. All
non-hydrogen atoms were refined anisotropically. The hydrogen atoms
were positioned with an ideal geometry and their positions calculated by
using a riding model. Further details of the crystal structure investigations
are available on request from the Director of the Cambridge Crystallographic Dam Centre. 12 Union Road, GB-Cambridge CB2 1 EZ (UK), by
quoting the full journal citation.
[Y] G. M. Sheldrick, Arm CrvstaNogr. Secr. A , 1990, 46, 467-473.
[lo] G. M. Sheldrick. SHELXL-92 University of Gottingen, Gottingen 1992.
Fig. 3. Representation of the different coordination modes of the four phosphazene ligands a - d in 5. Selected bond lengths [pm] and angles ["I: a: N1-PI
153.7(7), PI-N10 159.7(7), N10-P2 158.8(8), P2-N20 153.9(7), Ba4-Nll
304.5(7), Ba3-Nl0 313.8(7), Ba3-N20 297.9(7), Ba3-N21 307.3(7); Nl-P1-Nl0
120.3(4). PI-N10-PZ 134.5(5), NlO-P2-N20 120.7(4); b: N2-P3 154.4(6), P3N30 159.7(7), N30-P4 156.6(7). P4-N40 156.9(7). Bal-N31 304.1(6). Ba4-N30
293.8(7), Ba4-N40 286.8(6); N2-P3-N30 117.8(3), P3-N30-P4 158.6(5). N30-P4N40 109.4(3); c : N3-PS 154.8(7). PS-NSO 161.0(7), N50-P6 157.8(7), P6-N60
158.5(6). Ba2-N60 288.7(6), Ba2-N61 315.3(7); N3-PS-NS0 122.813). P5-N50P6 128.0(4), N50-P6-N60 121 .9(3);d: N4-P7 155.3(7), P7-N70 160.4(7), N70-P8
157.1(7), P8-N80 157.6(7), Ba3-N72 291.5(7), Bal-N70 291.2(7), Bdl-N80
287.4(6); N4-P7-N70 118.1(3). P7-N70-P8 lSS.O(S). N70-P8-N80 109.7(3).
solution of the barium compounds in toluene with water in
methanol or ethanol.
Exper h e n t a1 Procedure
3: A solution of 1.5 g (3.5 mmol) of 2 in 20mL n-hexane was added dropwise
to a solution of 1.0 g (1.7 mmol) of 1 in 20 mL n-hexane. The reaction mixture
was stirred at ambient temperature for 4 h. A pale yellow solution was obtained. After evacuation of all volatile compounds the spectroscopically pure
compound was obtained in quantitative yield. Further purification can be
achieved by recrystallization in n-hexane at 0°C. M.p. 220°C; ' H N M R
31PN M R (CDCI,. 85% H,PO,ext.) 6 = 5.2 (s); *9Si N M R (n-hexane/CDCI,)
6 =7.1 (s); IR(nuJol):C[cm-'] =1284b, 1256s. 1100s, 1063s. 979vs. 857s, 826s.
740s, 719s. 671m, 626m. 503vs; MS(E1): m/z 990 ( M t , 20%). 564 ( M + minus
one hgand. 100%); satisfactory C,H,N analysis for C,,H,,N,,P,Si,Ba
5 : A solution of 1.0 g (2.8 mmol) of 4 in 20mL n-hexane was added dropwise
t o a solution of 1.7 g (2.8 mmol) of 1 in 20 mL n-hexane and stirred at ambient
temperature for 6 h. A clear, pale yellow solution was obtained. After evacuation of all volatile compounds the white, foamy product remained in the reaction vessel (quantitative yield). M.p. 110°C; ' H N M R (C,D,. TMS ext.):
6 = 0.4 (s, 36H, SiMe,), 2.5-2.7 (m. 96H, NMe,); ,'P N M R (C,D,, 85%
H,PO, ext.) 6 = 9.8 (d), 26.4 (d); IR (nujol):C[cm-'] =1305s, 1244m. 1172s,
1080m. 969vs. 933m, 854s, 817s. 747m. 505vs; MS(E1): m/z 247 ( M minus two
Iigands; 50%). 355 (ligand; 100%).
Received: October 16, 1992 [Z 5632 IE]
German version: Angew. Chem. 1993, 105,625
Publication delayed on authors' request
[I] H. W Roesky, K . V. Katti, U. Seseke, M. Witt, E. Egert, R. Herbst, G. M.
Sheldrick, Angen. Chem. 1986, 98.447-448; Angew. Chem. Inr. Ed. Engl.
1986,25,477-478; H. W. Roesky, K. V. Katti, U. Seseke, H. G. Schmidt,
E. Egert, R. Herbst, G. M. Sheldrick, J. Chem. Soc., Dalton Truns. 1987,
847-849; K . V. Katti, H. W. Roesky, M. Rietzel, Inorg. Chem. 1987. 26,
4032-4035; K. V. Katti, U. Seseke, M. Witt, H. W Roesky, Phosphorus
Sulfur Relal. Elem. 1987,30,421-423; R. Hasselbring, H. W. Roesky, M.
Noltemeyer, Angen. Chem. 1992. 104. 613-615; Angew. Chem. Inr. Ed.
Engl 1992, S / , 601 -603.
121 H. W. Roesky, M. Lucke, Angeu. Chem. 1989, lo/, 480-481; Angeil.
Chem. In!. Ed. Engl. 1989, 28, 493.
[3] M. F. Lappert, P. P. Power, A. R. Sanger, R. C. Srivastava. Metul and
Me~ulloidAmrdes. Ellis Horwood, Chichester. 1980; K. F. Tesh, T. P.
Hanusa, J. C. Huffman, Inorg. Chem. 1990, 29, 1584-1586.
[4] L. G. Hubert-Pfalzgraf, New J. Chem. 1987. / I . 663-675: K. G. Caulton.
L. G. Hubert-Pfalzgraf, Chem. Ree. 1990, 90. 969 -995.
VCH Verlugsgesellschuf~mhH, W-6940 Weinheirn, 1993
Diastereo- and Enantioselective Synthesis of
2-Substituted 3-Trialkylstannylcyclohexanones
by Michael Addition of Trialkylstannyllithium to
Cyclohexenone S AM P Hydrazone""
By Dieter Endew,* Khs-Jiirgen Heider,
and Gerhard Raabe
Organotin compounds have been shown to be valuable
building blocks for the construction of complex organic molecules.['l The l ,4-addition of trialkylstannyllithium to a$unsaturated carbonyl compounds described by Still et a1.L21
is a simple and efficient entry to functionalized tetraorganostannanes. In this reaction the enolate formed as an intermediate can be trapped by protons to give the simple adducts,
and by alkyl iodides to give the anti tandem adduct stereoselectively.12.31 In the reactions with enones and trialkylsilylchloride silylenolethers are obtained,[41and additions to
aldehydes provide the aldol products.[51 The trialkylstannylketones formed are homoenolate equivalentsr6]and can
be easily converted into interesting synthetic building blocks,
for example, 1,3-diols and dihydroxyketones,['] cyclopro pane^,[^. *I enones,[" unsaturated macrolides,"O1 isoxazolines," 'I bicyclo[3. I .O]hexanes,[' and spiroacetals.[' 31
Prof. Dr. D. Enders, Dlpl.-Chem. K.-J. Heider, Dr. G. Raabe
Institut fur Organische Chemie der Technischen Hochschule
Professor-Pirlet-Strasse 1, D-W-5100 Aachen (FRG)
This work was supported by the Fonds der Chemischen Industrie. We
thank Degussa AG, Schering AG. BASF AG, Bayer AG, and Hoechst AG
for gifts of chemicals.
OS70-0833/93/0404-0598 S 10.00+.25/0
Angen. Chem. Int. Ed. EngI. 1993, 32, No. 4
regard addition of trimethylstannyl anions gives poorer
chemical yields (43-82%) and better induction (de = 442 9 6 Yo)than the addition of tributylstannyl anions (yields
94-97%, de = 42-87%). In the case of 2-alkyl-3-trimethylstannylcyclohexanone SAMP hydrazones the isomer formed
in excess can be enriched by chromatography.
The stannylated hydrazones 4 are subsequently converted
to 3-trialkylstannylketones 5 by oxidative cleavage with
ozone in very good yield without epimerization and racemization (64-93%, d e 2 9 8 % , ee = 42- 296%). Ketones
5a-e separate as colorless oils and ketones 5f-h as colorless
solids that can be recrystallized from ethanol, n-hexane, or
diethyl ether.
When para-bromobenzylbromide is used as electrophile
the bromine atom of (S,S,S)-4ais exchanged for a trimethylstannyl group in a side reaction. In addition to (S,S,S)-4h
(43 YO)the stannylated product (S,S,S)-4iis obtained in a
yield of 22% [Eq.(l)]. The conjugate addition of cyano-
In the Michael addition of trialkylstannyl metal comp o u n d ~ ~or' ~trialkyktannylcuprates['
to x$-unsaturated
ketones and the subsequent reaction with alkyl iodides, the
trans products containing two new stereogenic centers are
formed diastereoselectively. Until now optically active
3-trialkylstannylketones have only been prepared by diastereoselective addition to enantiomerically pure cyclohexenones." 5a. b.
We report here for the first time on the regio-, diastereo-,
and enantioselective synthesis of 2-substituted 3-trialkylstannylcyclohexanones. The key step is the Michael addition
of trialkylstannyllithium to cyclohexenone SAMP or RAMP
hydrazone, ( S ) - 3 and (R)-3, respectively, which are readily
available from ( S ) -or (R)-l-amino-2-methoxymethylpyrrolidine (SAMP ( 9 - 2 or RAMP (R)-2,respectively) and cyclohexenone in 90% yield (Scheme 1).
1. (CH,),SnLi, THF,
-100°C --f -78'C
2. p-Br(C,H,)CH,Br,
ee = 85 - 296%
L O C H 3
1. R$nLi,THF,
-100°C + -7S'C
2. R2X, -lOO"C --f RT
K O C H 3
(tributylstannyl)methylcuprate[' '1 as nucleophile to (S)-3
and trapping of the resulting azaenolate with methyl iodide
leads, after oxidative cleavage, to the Michael-Michael adduct (S,S,S,R)d as the major product (yield 75 %,
de 2 75 YO),together with the simple tandem adduct (S,S)-4d
(yield 16%, d e 2 9 8 % , ee = 88%) [Eq.(2)]
Scheme 1 . Diastereo- and enantioselective synthesis of 2-substituted rruns-3trialkylstannylcyclohexanones (S,S)-5. RT = room temperature.
In tetrahydrofuran at - 100 "C trimethylstannyllithium
and tributylstannyllithium add to (S)-3 regioselectively at
the 4-position." 'I Trapping the resulting azaenolate with a
saturated solution of ammonium chloride leads to the simple
adducts (S,S)-4aand (S,S)-4b in only modest diastereomeric excess (de = 42-44%), whereas the trans tandem adducts
(S,S,S)-4c-h with equatorial substituents are obtained in
very good diastereomeric excess (de = 87- 2 9 6 % ) in the
reaction with alkyl iodides or bromides (Table 1). In this
Table 1 2-Substituted 3-trialkylstdnnylcyclohexanones5 prepared by asymmetric Michael addition.
Yield 4
de 4 [a]
Yield 5
I "/.I
c [el
43 b1
90/94 [g] (S,S.S)
2 9 6 [g]
[a]k5 (c,
de 5 [b]
ee 5 [c] [ X I
- 55.4
- 154.9
+ 156.2
- 94.9
- 69.9
- 122.7
t 98
t 98
t 96
85 [fl
93 [h1/296 [
2 96
[a] Determined by "C NMR spectroscopy (dbsohte configuration in parentheses). [b] Determined by ' H NMR spectroscopy. [c] The value for ee corresponds to the
dr value for hydrazone 4 (absolute configuration in parentheses). [d] Neat. [el RAMP used as chiral auxiliary. [f] Determined by I9F NMR spectroscopy after
reduction to the alcohol and esterification to the MTPA ester (see text). [g] After chromatography. [h] Measured by 'H NMR shift experiment with [Eu(hfc),]. [i] After
crystallization from ethanol. [j] Contains 22% 4i as by-product.
A n g i m . Chem. lnr. Ed. EnKl. 1993, 32, No. 4
Verlug.~gesell.schaftmbH, W-6940 Weinheim.f993
0570-0S33/93/0404-0599$ 10.00+ 2510
The enantiomeric excess of 5f was determined from its
'H N M R spectrum with [Eu(hfc),] (hfc = tris[3-(heptafluoropropyl(hydroxymethy1ene-d-camphorato])and that
of 5 c - e and Sg, h from the "F N M R spectra of the MTPA
esters (MTPA = 3,3,3-trifluoro-2-methoxy-2-phenylpropionic acid), obtained by diastereoselective reduction with
potassium tri-sec-butylhydroborate (K-Selectride)i'sl to
the (S,S,S)-2-alkyl-3-trialkylstannylcyclohexanol derivatives"'] and subsequent reaction with MTPA-C1.i201The
racemic reference compounds were obtained by addition of
the tin nucleophiles to cyclohexenone. The enantiomeric excesses determined in this fashion are in good agreement with
the diasteromeric excesses obtained from "C N M R spectra
at the stage of the hydrazone. Assignment of the absolute
configurations (2S,3S)and (2R,3R) are based on X-ray crystal analyses of the compounds 5fr2']and 5gI2'I (Fig. 1) obtained by tandem addition to ( S ) - 3 , and by circular dichroism (CD) measurements.[' 6a1 All the 3-trialkylstannylketones 5 prepared with SAMP as auxiliary show a
negative Cotton effect at 2 = 300 nm, whereas the RAMP
auxiliary leads to stannylketones with a positive Cotton effect.
Fig. 1. Crystal structure of5g[22] (ORTEP[24], ellipsoids with 30% probability).
To our knowledge this is the first report of the asymmetric
Michael addition of tin nucleophiles and provides a
diastereo- and enantioselective entry to both enantiomeric
series of trans-2-alkyl-3-trimethylstannylcyclohexan0nes.~~~~
Initial results show that this process can also be applied to
open-chain a$-unsaturated aldehyde SAMP hydrazones.
Experimental Procedure
VCH Vcrlug.~ge.scll.schuf/
mhH, W-6940 Weinheim. 1993
Received. November 26, 1992 [Z 5706IEl
German version. Angew. Chem. 1993, 105, 592
[I] a) M. Pereyre. J:P. Quintard, A. Rdhm, Tin in Orgunic Synihesis, Butterworths, London, 1987; b) P. G . Harrison, Chemistry o/Tin, Blackie, Glasgow, 1989; c) I. Omae, J. Orgnnomer. Chem. Lihr. 1989, 21, 1-355;
d) Orgunotin Compound.7 in Orgunir Synthesi.s (Ed. : Y. Yamamoto) Te/ruhedron 1989. 45, 909-1230.
121 a ) W C. Still. J. Am. Chen7. Sor. 1977, 99. 4836-4838; b) W. C. Still, A.
Mitra. Terrahrdron Lett. 1978, 2659 -2662.
[3] Diastereoselective alkylation of 3-tributylstannylester enolates: G . J.
McGarvey. J M. Williams. J. Am. Chem. Soc. 1985, 107, 1435-1437.
[4] W. C. Still. J. Am. Chem. Soc. 1977, 99. 4186-4187.
I51 a ) T. Sato. M. Wdtdnabe. E. Murayama, Terruhedron Leir. 1986.27, 16211624: b)T. Sato. M . Watanabe. T. Watanabe, Y Onoda. E. Murayama, J.
Org. Chem. 1988. 53, 1894- 1899.
161 a) B. L. Chenard. TeelrahedronLett. 1986.27,2805-2808; b) H Ahlbrecht.
P. Weber. Synthesis 1989. 117--120; H. Ahlbrecht, P. Weber, hid. 1992,
1018 .1025; c) Homoenolate didnions of secondary 3-tributylstannylamides: R. Goswami. D . E. Corcoran, Tetruhedron Lett. 1982, 23, 14631466.
[7] M. Ochiai. S. Iwaki, T. Ukita, Y. Matsuura, M. Shiro, Y. Nagao, J. Am.
Chem. SOC.1988, lt0,4606--4610.
[XI a) D. D. Davis, R. L. Chambers. H. T. Johnson. J. Orgunomet. Chem.
1970. 25. C 1 3 - C t 6 ; b) I. Fleming, C. J. Urch,ihid. 1985, 285, 173-191.
[Y] a ) Substituted r,$unsaturated ketones: refJ2al;
. . b) y,D-unsaturated ketones: ref.[4]; c) 7.8- and other unsaturated carbonyl compounds: M.
Ochiai, T. Ukita, Y. Nagao, E. Fujita, J. Chrm. Sot,. Chem. Commun. 1984,
1007- 1008; M. Ochiai, T. Ukita, Y Nagao. E. Fujita, ibid. 1985,637-638;
M. Ochiai. S. Iwaki. T. Ukita, Y. Nagao. Chem. Lett. 1987, 133-136; M.
Ochiai. T. Ukita. S. ikawi, Y Nagao, E. Fujita, J Org. Chem. 1989, 54,
4832-4840: K. Nakatani, S. Isoe. Terruhedron Letr. 1985,26. 2209-2212;
J. E. Baldwin, R. M. Adlington, J. Robertson, Tetrahedron 1989. 45,909922.
a ) G. H. Posner, E. Asirvatham, K. S. Webb. S.-S. Jew. Tetruhedron Lett.
1987, 28. 5071 -5074; b) G. H. Posner. K. S. Webb, E. Asirvatham, S.-S.
Jew. A. Degl'Innocenti, J Am. Chem. Sor. 1988. 110. 4754-4762.
H. Nishiyama. H. Arai. T. Ohki. K. Itoh. J. Am. Chem. Sor. 1985, 107,
L. Pbamondon. J. D. Wuest, J Org. Chem. 1991, 56, 2066 -2075, 20762081.
M. G. O'Shea, W. Kitching, Terruhedron 1989, 45, 1177-1186.
a) Tributylstannylmagnesium chloride: J.-C. Lahournere. J. Valade. J.
Orgunomet. Chem. 1971. 33. C 7 - C 10; b) Review of Trialkylstannyllithium compounds: T. Sato, Synthesis 1990, 259 -270; c) Trimethylstannylsodium: H. G. Kuivila. G . H Lein. J Urg. Chem. 1978, 43, 750751; d)Triphenylstannylpotsslum: R. J. P. Corriu, C. Guerin. J
Orgunomet. Chem. 1980, 197, C 19- C21.
a) E. Piers, H. E. Morton, J. M. Chong, Can. J. Chrm. 1987, 65, 78-87,
and references therein; E. Piers. R. D. Tillyer, J Org. Chem. 1988, 53.
5366-5369; b) B. H. Lipshutz. S . Sharma, D . C. Reuter, Tetruhedron Lerr.
1990, 31, 7253-7256; c) A. C. Oehlschlager, M. W. Hutzinger. R. Aksela,
s. Shdrmd. s. M. Singh, ihid. 1990, j f , 165-168, s. Shdrmd, A . C .
Oehlschlager, J Org. Citem. 1991, 56, 770-776; d) S. Sharma, A. C.
Oehlschlager. T<,lru/imdron1991, 47. 1177- 1184.
a ) Hudec, J Chem. Perkin Truns. I 1975, 1020-1023; b) E. Piers, J. Y
Roberge, 2trukedron Lett. 1991, 32, 5219 5222.
1.4-Addition of trimethylsilyllithium to cyclohexenone dimethylhydrazone: P. F. Hudrlik. A. M. Hudrlik. T. Yimenu, M. A. Waugh, G. Nagendrappd, Terrultedron 1988. 44, 3791 -3803.
H. C . Brown. S. Krishnamurthy, J Am. Chem. Soc. 1972. 94, 7259-7161.
In the reduction with lithium aluminum hydride the (lR,2S,2S)-cyclohexanols are obtained with low diastereomeric excesses. See also: G. Wickham, H . A. Olszowy, W. Kitching. J Org. Chem. 1982, 47, 3788-3793.
J. A. Dale, D. L. Dull. H. S. Mosher. J Org. Chem. 1969,34,2543-2549.
A crystal of suitable quality formed in diethyl ether a t -20°C. The compound crystallizes in the orthorhombic space group P2,2,2, (no. 19)
u = 6.637(1), h = 9.480(2). c = 23.977(2) A. A cell volume of 1508.7 A3,
Z = 4. and M, = 333.0, leads to a density of pLa,c= 1.466 gcm-'. Total
number of electrons per unit cell F(000) = 672. Enraf-Nonius CAD4 fourcircle diffractometer. graphite monochromator, Ri20-scans. 20 ' C . Mo,,
radiation (L = 0.71069 A), p = 16.91 cm-'. A total of 3432 unique reflections were recorded ( It k + 1. -h-k-1 Friedel pairs), of which 3183
were observed (I > 2n(l)). R, = 0.016, sinO/j.,,+, = 0.649. The structure
was solved by the heavy-atom method (XTAL3.0[23]). Hydrogen atom
positions were calculated. A total of 146 parameters were refined,
R = 0.046 ( R , = 0.044). The maximum residual electron density was
1.3 e k 3 . A',, = 0.04(6).
A commercial 1.5s solution of n-butyllithium in n-hexane (3 mL) was concentrated to dryness under vacuum. The residual yellow oil was dissolved in 4 mL
anhydrous T H F at 0 ° C under inert gas, and 4.5 mmol hexaalkyldistannane
(degassed under high vacuum or distilled) was added. After 15 miii (hexabutyldistannane) or 2 h (hexamethyldistannane). the solution was cooled to
- 100 ' C , and after a further 10 min 3 mmol (S)-3was added dropwise. After
the suspension was allowed to warm up to -78' C over 3 h, an intensely yellow
solution was obtained and stirred at this temperature for 2 h. At - 100 ^C a
solution of 6 mmol electrophile in 4 mL T H F was slowly added dropwise. The
resulting solution was allowed to warm to room temperature within 15 min.
The volatile components were condensed under vacuum into a trap cooled in
liquid nitrogen, the residue was taken up in diethyl ether. washed with water
and saturated NaCl solution. dried over magnesium sulfate. and concentrated
to dryness. The crude product obtained can be used directly for the ozonolysis.
The 3-trialkylstannyl SAMP hydrdzones (S,S,S)-4 were purified by column
chromatography (silica gel, petroleum etheridiethyl ether 5 : 1 + 5 % triethylamine).
Ozone was passed through a solution of (S.S.S)-4 in dichloromethane a t
- 78 C until no more hydrazone could be detected by thin-layer chromatography (silica gel, petroleum etherldiethyl ether 5:l). After the excess ozone was
driven off by a stream of argon, the reaction mixture was allowed to warm up.
the solvent removed, and the product (S,S)-5 purified by column chromatography (silica gel, petroleum ether/diethyl ether 20: 1).
+ +
0570-OX33193j0404-0600 8 10.00 + .25.'0
Angeu'. Chem. I n t . Ed. Engl. 1993, 32, No. 4
[22] Suitable crystals formed at -20 ’C in diethyl ether. The substance crystallizes in the orthorhombic space group P2,2,2, (no. 19) u =7.645(1),
h = 16.255(3), c = 13.078(1) A. The cell volume of 1625.2 A3, 2 = 4, and
M , = 351.1. leads to a density of pca,c=1.435 g ~ m - Overall
~ .
number of
Der unit cell MOOOl
=712. Enraf-Nonius CAD4 four-circle difelectrons
fractometer, graphite monochromator, B/2O-scans, 0 ,’C, Ma,, radiation
(i= 0.71069
= 15.66 cm-’. A total of 3679 independent reflections
were recorded ( * [ 7 + k + 0, of which 3524 were observed ( I > 2a(I)).
R , = 0.027. sinH/%,,, = 0.649. The structure was solved by the heavyatom method (XTAL3.0 [23]). Some of the hydrogen atom positions could
be located, the remainder were calculated. A total of 164 parameters were
refined. R = 0.025 (R, = 0.030). The maximum residual electron density
was 0.3 e k J and X,,, = 0.03(3). Further details of the crystal structure
investigation may be obtained from the Fachinformationszentrum Karlsruhe. Gesellschaft fur wissenschaftlich-technische Information GmbH.
D-W-7514 Eggenstein-Leopoldsllafen 2 (FRG) on quoting the depository
number CSD-56952, the names of the authors. and the jonrnal citation.
S. R. Hall. J. M. Stewart. XTAL3.0 Re/ermr.e Munuul. Universitities of
Western Australia und Maryland, 1990.
C . K . Johnson. Report ORNL-3794, Oak Ridge National Laboratory,
Oak Ridge. Tennessee, 1965.
All compounds gave correct elemental analyses and spectra ( ‘ H NMR,
N M R . IR. UV) in agreement with their structures.
_ _
. ,s
Fig. 2. Target molecule 5 based on the stereochemistry of [3.3]metacyclophanes
with proven syn conformation of the [3.3]phane units; target molecule 12 based
on the stereochemistry of [2.2]metdcyclophanes with fixed unci Conformation of
the [2.2]phane units.
steps.[51Subsequent palladium-catalyzed ethynylation (a in
Scheme 1) furnished the trimethylsilyl(TMS)-protected cyclophane 2. The TMS groups were cleaved (b) to give 3, and
coupling of the alkyne moieties (c) led to diyne 4, which
could be hydrolyzed with trifluoroacetic acid (d) to yield 5.
Molecular Tweezers with a Hydrocarbon Skeleton
and Convergent Carboxyl Groups
By Ralf Guther, Martin Nieger, and Fritz Vogtle*
As preorganized, acyclic host compounds “molecular
tweezers” are distinguished by convergent functional groups
that can “grasp” guest molecuIes.”] To date only a few types
of compounds have been reported to be efficient molecular
tweezers; those prepared by Rebek et al. are the best
known.‘” We have been trying for a number of
utilize the characteristic features of cyclophane building
blocks for the convergent arrangement of functional
groups.l3I By linking two suitable cyclophane frameworks
we have now been able to preorganize the functional groups
so precisely that they are directly opposite each other when
the guest molecule is enclosed (Fig. 1). The stereochemistry
of [3.3]- and particularly [2.2]metacyclophanes offer interesting possibilities, which we will describe here.
Fig. 1. Schematic representation of host--guest recognition with the new type of
tweezer compounds (FG = functional group).
The double dithia[3.3]metacyclophane 5, which has a stiff
diyne bridge holding the two halves apart, exists exclusively
in the double syn conformation shown in Figure 2, in which
the two carboxyl groups are forced to face each other. Compound 5 was prepared in the following manner: 3,5-Dimethylbromobenzene and 3,5-dimethylbenzoic acid were
converted into 2,1 I-dithia[3.3]metacyclophane 1 in a few
[*] Prof. Dr F. Vogtle. DipLChem. R. Giither
lnstitut fur Organische Chemie und Biochemie der Universitlt
Gerhard-Domagk-Strasse 1. D-W-5300 Bonn 1 ( F R G )
Dr. M. Nieger
lnstitut fur Anorganische Chemie der Universitdt Bonn
A n g a t . C’lwm. int. Ed. Engl. 1993, 32. N o . 4
3 R = H
R = COptBu
R = COpH
Scheme 1. Synthesis of 5. a) Trimethylsilylacetylene/[(Ph,P),PdCl~]~Cul.triethylamine, 8 h a t 8 0 T , 90%; b) K,CO,, abs. methanol, 5 h a t room temperature (RT), 9 2 % ; c) CuCI/CuCI,, pyridine, 5 d at RT, 66%; d) CF,COOH,
30 min at RT, > 90%.
Figure 2 also shows the rigidly fixed, “double” [2.2]metacyclophane 12 in the anti conformation, which was prepared
as follows (the tert-butyl groups proved to be essential for
increased solubility): [Ig1 2,6-Dimethylaniline and 5-rert-butyl1,3-dimethylbenzene were converted into dithia[3.3]metacyclophane 6151
in a few steps. Oxidation (a in Scheme 2) led
to sulfone 7, subsequent vacuum pyrolysis (b) provided [2.2]metacyclophane 8. Palladium-catalyzed ethynylation (c) furnished the TMS-protected cyclophane 9; the T M S groups
were cleaved (d) to provide 10, which could be coupled directly giving diyne l l . Hydrolysis of the methyl ester groups
in the interior of the cyclophane, which are blocked by the
adjacent methylene groups, was possible only with LiI in
pyridine.‘” In addition to the target molecule 12, the monocarboxylic acid 13 was also always obtained.
Figure 3 shows the X-ray structure of the crystalline diester tweezer compound l l . l s l It can be seen that both
I2.2Jmetacyclophane units are in the desired anti conformation but twisted 180’ to each other about the diyne axis.
Since the molecule can twist freely about this axis in solution,
the desired conformation in which the two functional groups
face each other is possible.’91
The molecular recognition possible with the two new types
of tweezer compounds was tested first with diamines as guest
$-) VCH Ver/agsgeseiisrhufi mbH. W-6940 Weinhemi, 1993
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synthesis, michael, trialkylstannyllithium, samp, cyclohexenone, additional, enantioselectivity, diastereo, trialkylstannylcyclohexanones, substituted, hydrazone
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