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Determination of the Relative Configuration by Distance Geometry Calculations with ProtonЦProton Distances from NOESY Spectra.

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a) A . Ftirrtner. J. Baumgartner. Telruhedron. 1993. 4Y, 8541-8560; b) R. E.
Ireland. T. K . Highsmith, L. D. Gegnas, J. L. Gleason, J. Org. Chern. 1992. 57,
5071 5073.
a) A. Fiirstner. H. Weidmann, J. Org. Chetn. 1989. 54. 2307-2311; b) A.
Fiirstiier. D. N . Jumbam. J. Teslic. H. Weidmann. rhirl. 1991, 56, 2213- 2217;
c ) A. Fiirstner. 7Lrruh~dronL e f l . 1990. 31. 3735-3738.
H . Pnulsen. Z. Gyorgydeak. M. Friedmann, Chrm. Ber. 1974. 107. 1568- 1578.
R. Kuhn. J. C. Jochims, Chem. Ber. 1960. Y3- 1047-1052.
Compound 9: W. Schorkhuber. E. Zbiral, Liebigs Ann. Chcwn. 1980. 14551469. Compound 3 b was prepared by Zemplen deacetylation of 3a. followed
by methylation (NaHiMel in dimethylformamide). for physical data see
Table 2.
Similar trapping experiments were successfully used in glycal syntheses, see:
a ) A. Fiirstner. H. Weidmann. J. Curhohjdr. Chern. 1988, 7. 773 783; b) A.
Fiirsliicr. L;rihi,o.s Ann. C/7en?.1993, 1211 -1217.
P. Erinert. A. Vasella. H d v . ChOn. Acru 1991. 74, 2043-2053.
Successful cyclirations by the addition of carbon-centered radicals onto nii ) D. L. J Clive. P. L. Beaulieu. L. Set, J. Org Chein.. 1984, 49, 13131314. b) J. K Dickson. R. Tsang, J. M . Llera. B. Fraser-Reid, i h d . 1989, 34,
5350 5356; c ) H. Pak, .I.
K . Dickson. B. Fraser-Reid. J. Am. Chen?. Sor.. 1989,
54. 5357 -5364; d ) R. A. Alonso. C. S. Burgey, B. V. Rao, G. D. Vite, R.
Vollerthun. M . A Zottola. B. Fraser-Reid, ;hid 1993. 11s. 6666- 6672; similar
failures c ) N. S. Smpkins, S . Stokes. A. J. Whittle. J. Cheni. SOC.Perkin Trun.s.
1 1992. 2471 2477; f) J. Marco-Contelles, C. Poruelo. M. L. Jimeno, L. Martinet. A. Martinez-Grau, J Org. Chew. 1992. 57, 2625-2631: g) B. W. A.
Yeung. 1. L. M . Contelles. B. Fraser-Reid. J Chem. SOC.Chrni. Convnun. 1989,
1160 1161.
Determination of the Relative Configuration by
Distance Geometry Calculations with ProtonProton Distances from NOESY Spectra **
urations of molecules that may be flexible. To answer this question we conducted "NOE-restrained" molecular dynamics calculations with heavily weighted experimental distances.[*' The
problem of the parametrization of the force field prevents the
general application of this approach. Since suitable parameters
are not available for many interesting systems such as polar
organometallic compounds, alternative procedures had to be
developed. The best approach appeared to be the application of
as many actual measurable quantities, in other words H-H distances, as possible.
In principle conformations can be determined from distance
data by distance geometry (DG) calculation^,[^^ 41 a procedure
used for the N M R spectroscopic structure determination of biopolymers.[31The absolute configuration of a stereogenic center
is determined by the sign of the "chiral volume" ( Vc)['I taken up
by the atoms bound to this chiral center. Typically a constant
value is maintained for the chiral volume in the calculations to
ensure the stereochemical integrity of the stereogenic center under consideration. If this chiral restraint is removed, the sense of
chirality can be inverted and a new conformational space is
opened up, within which a conformation can be found that
optimally fits the distances obtained from the NOESY data.
This method was applied for the assignment of diastereotopic
protons in proteins,[6' and we have demonstrated its suitability
for the determination of the configuration of a model comp ~ u n d . ~ Since
the stereogenic centers of interest were in a section of the molecule that could be determined quite well from
NOES (bridgehead positions), we wondered if this method was
generally applicable. To find out more about the potential of
DG calculations for the determination of relative configurations
we chose the much more flexible bisoxazolidine 1.r8]
Michael Reggelin,* Matthias Kock,
Kilian Conde-Frieboes, and Dale Mierke
Investigations of the structures of reactive organometallic compounds such as lithiated or titanated 2-alkenylsulfo~imides~~~
quite difficult. Studies of these species under the conditions required for their reaction, in other words at low temperatures and
in solution, are particularly problematic. Here N M R spectroscopy is the method of choice, since in principle the reaction
dynamics (e.g. conformational flexibility. configurational behavior) of the metalated intermediates can be examined, which
may aid in the interpretation of the stereochemical outcome of
the reaction.['] Often when no other method is available, only
the relationship between the configuration of the metalated intermediates and the stereochemistry of the products of a stereoselective organometallic reaction can provide information on the
stereochemistry of these intermediates. Thus, the development of
a method independent of postulated models of transition states
(e.g. Zimmerman-Traxler model) would be very valuable.
The obvious question is how N M R data (H-H distances,
coupling constants) can be used to determine the relative config[*I Dr. M . Reggelin. Dr. M. Kock, Dr. K . Conde-Frieboes
l i i s t i t u t fur Organische Chemie der Universitit
Maric-Curie-Strasse 11. D-60439 Frankfurt am Main ( F R G )
Tclefar. Int. code + (69)5800-9128
Dr. L). F Mirrke[+'
Orgaiiisch-chemisches lnstitut der Technischen Universitit Munchen
Lichtenhergstrasse 4. D-X5747 Garching ( F R G )
['I Precenl address:
Department of Chemistry. Clark University
Worcester. MA 01610 (USA)
[**I Thia work was supported by the Deutsche Forschungsgemeinschaft and the
Fonds der Cheinischen lndustrie (Habilitation fellowship for M. R. and postdoctoral fellowship for M. K . ) . We thank Prof. Dr. C. Griesinger and Prof. Dr.
Fl. Kesslei- for their generous support.
A i w ' i I Chcni. f n c . Ed. Eiig/. 1994. 33. N o . 7
In addition to the known stereogenic centers in the norpseudoephedrin section of the molecule, 1 has six additional centers
with unknown configurations. Two-dimensional N M R spectroscopy was used for the assignment of all of the protons in 1.['1
The analysis began with the differentiation of the two quasisymmetric halves of the molecule. The OH-bearing carbon atom
(C-11) was easy to identify, because it does not give rise to a
cross peak in the proton-detected H - C correlation spectrum
(HMQC1'O1).This atom has a heteronuclear long-range correlation (3JC,H)
with the proton at C-16 (HMBC["I), which was
used to identify the halves of the molecule. The 'H signals within
each half were assigned based on DQF-COSY and TOCSY
experiments.[121The arene protons were assigned with a selective
HMBC experiment (excitation with a 270" Gaussian pulse[i31).
Seven 400 MHz NOESY spectra were recorded for the determi-
ic? VCH V r r l u ~ . ~ ~ e s e / / . rnihH,
~ l i a / fD-6Y45l Weinheim, 1994
$ 10.00
+ 25.'0
nation of the H-H distances (mixing times: zmiX= 100,200,300,
400, 500, 800, 1200 ms). The cross peak between the geminal
protons on C-10 was used as a calibration peak ( r = 178 pm),
and the distances corresponding to the volume integrals of the
other cross peaks were calculated. Only results that were independent of the mixing time (generally up to
= 500 ms, initial
rate approximation) were used for the determination of the distances.
The DG calculations were conducted with a modified version[',
of the DISGEO program.[3,14] Ninety-nine structures
were calculated by "random metrization", optimized" 5 , 1 6 ] with
"distance bounds driven dynamics" (DDD)" I *I in fourdimensional space. and finally reduced to three-dimensional
space with the "embed" algorithm. These structures were again
refined with DDD.""' The planarity of amide functions and
aromatic rings, as well as the configurations of carbon atoms of
known chirality, were secured with a penalty function.[201The
chiral volumes of the six centers of unknown absolute configuration were removed from the list of chiral restraints.
The 99 structures generated could be divided into three structure families according to their "pseudoenergies"[201 from the
DDD calculations. The family with the lowest pseudoenergies
(between 47 and 52) consists of 70 structures, the next has 11
structures (pseudoenergies between 67 and 9 9 , and the last
family comprises 18 structures with very high pseudoenergies
(between 121 and 261). All the structures in the first two families
except one (in the second family) have the same absolute configurations at the six unknown stereogenic centers as in the crystal
structure.[2' I Even in the third, energetically unfavorable family
two structures (of 18) have the correct configurations. In the
superpositioned structures from the first family shown in Figure l a the conformations of the two inner five-membered rings
of oxazolidine I are close to those in the structure determined by
X-ray analysis. The intramolecular hydrogen bond between the
acidic hydrogen atom and the carbonyl oxygen atoms is also
accurately reproduced (Fig. 1c. d).
The distinct structural fluctuations in the arene region, which
affect the precision of the description of the oxazolidine rings,
are a consequence of the isochronism of the 0- and nz-protons.
For this reason no individual distances from these protons are
Fig. I . a ) Superposition of 43 randomly chosen structures from the first structure
family obtained from D G calculations. b) Superposition of the crystal structure of
1 (dotted lined) and the D G structure (without the iirene units). c) The intramolecular hydrogen bond is reproduced In the D G structure. d) The corresponding section ofthc crystal structure with the hydrogen bond drawn in. (Nitrogen: light gray
circles. oxygen: dark gray circles).
available. The average chiral volumes for the first family and for
all calculated structures as well as the minimum and maximum
volumes are listed in Table 1 .
Table 1. Calculated c h i d volumes k; of the six unknown stereogenic centers in 1.
-9 146
[a] Here positive values correspond to an (R)-contigurated chiral center.
G = standard deviation. [h] Average chiral volume from the 70 structures ofthe first
family. [c] Average chiral volume from all 99 Ytructures. [d] Minimum and maximum volumes for all 99 structures.
Even after averaging over all structures. including those with
large deviations from the required distances, the correct absolute configurations are obtained for the previously unknown
chiral centers. This may be traced back to the fact that in general
even in the "high-energy family" only one stereogenic center is
determined incorrectly.
Received: September 6. 1993
Revised version: December 17. 1993 [26344IE]
German version: Angrw. Chern. 1994, 106. 822
[ I ] M. Reggelin. H. Weinberger. A n g o . Cheni. 1994, 106. 489-491; Angew
Clirm. In!. Ed. Erigl 1994, 33. 444-446.
[ 2 ] M Reggelin. H. Hoffmann, M. Kock. D. F. Mierke. J. Am. C'hrm. Soc. 1992,
114. 3272-3277.
[31 G . M. Crippen, T. F Havel, DOrunce Geomerri. und Mo/<wdurConformurion,
Research Studies Press. Somerset, UK, 1988.
[4] 1. D. Kuntz, J. F. Thomason. C. M. Oshiro, Methods Enrwzol. 1989, 1778,
159 ~ 2 0 4 .
[S] A, B. C. and D a r e the ligands on the stereogenic center X in order of decreasing
priority. The chiral volume (V,) spanned by these four points is one-sixth ofthe
oriented volume of the vectors extending from one point to the other three:
Vc = 1 ;6 A b . [BD 0Cb].If the vectors A b , Bb, C'D form a right-handed
coordinate system. the volume is positive ( ( S )configuration). if they form a
left-handed system. the volume is negative ( ( R )configuration).
[6] P. L. Weher. R. Morrison. D. Hare. J Mol. B i d . 1988, 204, 483 -487.
[7] D. F. Mierke. M. Reggelin. J Org. Chew. 1992. 37. 6365-6367
[8] K . Conde-Frieboes, Dissertation, Universitit Kiel. 1992.
[Y] ' H N M R (400 MHr. CDCI,. 300 K. TMS): 6 = 1.57 (19-CH3). 1.58 (4-CH3).
1.59;1.89 (2H-14). 1.66;2.56 (H-9P'"-.~,H-9P"-R).1.76!1.76 (2H-15). 1.82;
1.96 (H-13p'"~R!H-13P'"~S).
2.13;2.38 (H-lOP'"~s!H-lUn"~R).2.30 (H-12).
3.10(H-6),3.25(H-8). 3.44(H-19),3.76(H-4),4.02(11-OH).4.63(H-18),4.85
(H-3). 5.58 (H-I). 5.85 (H-16). 6.64 (H-26). 6.84 (H-22), 7.14 (H-23). 7.17
(H-27). 7 20 (H-24). 7.22 (H-2X). 7.24 (H-31). 7.43 (H-35), 7.56 (H-30), 7.74
(H-34). "C NMR (100 MHr. CDCI,, 300 K. TMS): 6 = 20.51 (19-CH,).
20.56 (C-141, 20.71 (C-10). 21.53 (4-CH3). 23.88 (C-9). 24.98 (C-l3), 36.68
(C-15). 51.26(C-12). 55.62(C-8), 56.30(C-6).62.48 (C-4).63.14(C-19),81.72
(C-13). 85.02 (C-3), 85.17 (C-18). 90.06 ( G I ) , 91.40 (C-161, 124.79 (C-22).
125.31 (C-26). 127.59 (C-24), 128.16 (C-28). 128.49 (C-27), 128.60 (C-23),
128.89 (C-30). 129.26 (C-31), 129.43 (C-35), 129.76 (C-34), 133.85 (C-32).
134.80 (C-36). 137.75 (C-25). 137.96 (C-21). 139.90 (C-29:C-33).
[lo] HMQC = Heteronuclear Multiple Quantum Coherence: A. Bax. S. Suhramanian, J. .Mugn. Rc.wn. 1986, 67. 565-569.
[ I l l HMBC = Heteronuclear Multiple-Bond Correlation: A. Ban, D. Marion, J
Mugn. R c m n . 1988, 78. 186-191; A. Bax. M. F. Summers. J. A m . Chem. Soc.
1986. 108. 209% 2094.
[12] D Q F = Douhle Quantum Filter. TOCSY = Total correlation spectroscopy;
A . Bax. D. G. Davis. J. Mugti. Rcsun. 1985, 65, 355 360.
[13] L. Einsley. G . Bodenhauaen. J Mugn. h'e.son. 1989.82, 211 221; H. Kessler,
P. Schmieder. M. Kock. M. Kurz, ;hid. 1990, K K , 615-618.
[I41 T. F. Havel, DISGEO. Quantum Chemistry Program Exchange (QCPE) No.
507, Indiana University. 1986.
[I51 T. F. Havel, Prog. Biuphi's. M o l . E d 1991. J6. 43-78.
[16] T F. Havel. Biu/~oIvnwr.s1990. 29. 1565-1585.
R. Kaptein. R. Boelens, R. M. Scheek. W F van Gunsteren, Biocheini$tfi.
1988, 27. 5389-5395.
R. M. Scheek. W. F. van Gunsteren, R. Kaptein, Mediods En;ymo/. 1989, 177.
204-2 18.
Both D D D refinements were conducted with 2500 steps and a step width of
20 fs tisine the SHAKE algorithm (J. P. Ryckaert, G . Ciccotti, H. J. C. Berendsen. J Conipui. Pliys, 1977, 23. 327-341) at a temperature of 300K with a
strong coupling to a temperature bath (every 10 steps) (H. J. C. Berendsen, J.
P. M . Postnia. W. F van Gunsteren, A. DiNola, J. R. Haak, J. Chem. P h p .
1984. XI, 3684-3690. The temperature was then reduced to 1 K. and the structures were DDD-refined with another 1000 steps and a weak coupling to the
temperature bath (every 50 steps)
The pseudoenergy ED,,,,, is a dimensionless number obtained from the following calculation: E,,,,,, = 0 . 5 k d , , ( r- reXp)' 0.5k,,,,(Vc - ~ - x p ) 2 .k,,, is the
force constant for weighting the difference between the calculated distance r
and the experimentally determined distance rerp.k,,,. is the force constant for
weighting the difference between the calculated chiral volume Vc and the chiral
volume of the initial structure V?". All values are derived from the D G structure refinement.
Further details of the crystal structure investigation may be obtained from the
Fachinformdtionszentrum Karlsruhe, D-76344 Eggenstein-Leopoldshafen
( F R G ) on quoting the depository number CSD-57938. the names of the authors. and the journal citation: J. Hirschler, B. Berger. M. Bolte, Actu Crystallog". S c c t . c', submitted.
[M(CO),(y4-NBD)] complexes (M = Cr, Mo). From an earlier
study it is known that NBD is hydrogenated in the presence of
the Mo complex mainly to give norbornene (NBN), whereas in
the presence of the Cr complex the hydrogenation leads to nortricyclene (NTC) and NBN in the ratio of 3 : 1 (see Fig. 1 ) .[*] The
activation here results from photolytic cleavage of a CO ligand
from the [M(CO),(q4-NBD)] complex.[91An H, molecule can be
coordinated to the resulting free coordination site of the
[M(CO),(q4-NBD)] fragment, leading to the formation of the
nonclassical hydrogen complex [M(CO),(q4-NBD)(q2-H,]. [ l o '
The other steps of the catalytic cycle, in which the M(CO),
group is the repeating unit, are shown in Scheme 1.
Situ NMR Investigations of Photocatalyzed
Hydrogenations with Parahydrogen in the
Presence of Metal Carbonyl Compounds
of Group 6**
Angelika Thomas, Mathias H a a k e ,
Friedrich-Wilhelm Grevels, and Joachim Bargon*
Hydrogenations with parahydrogen @-H,) lead to nuclear spin
polarization effects in 'H NMR spectra.", The extreme sensitivity of this method enables organometallic-catalyzed hydrogenations to be investigated. The amplification of the signal by up
to lo5 fold, the PASADENA effect (Parahydrogen And Synthesis Allows Dramatically Enhanced Nuclear Alignment), results
from the breakdown of the H, symmetry during the hydrogenation;"] the in situ NMR method based on this is called parahydrogen induced polarization (PHIP)[2-s1and is suitable for the
detection of short-lived reaction intermediates.
A detailed analysis of the nuclear spin polarization pattern of
the reaction products (or intermediates) identifies directly the
positions of the transferred H, protons and thus indirectly allows conclusions about the nature of the intermediary binding
of the H, molecule to the organometallic complex.[3b1Labeling
experiments with D, are therefore unnecessary.
The systems studied previously were concerned with thermally induced hydrogenations in the presence of metal complexes of
Groups 8-10, which activate the H, molecule by an oxidative
addition.[2- 'I In this communication, the hydrogenation of norbornadiene (NBD) is used as example to show that also in the
photolytic activation of metal carbonyls of Group 6, the nuclear
spin polarization of p-H, is transferred to the reaction products.
The metal carbonyl compounds were used in the form of
[*] Prof Dr. J. Bargon. Dip1.-Chem. A. Thomas, M. Haake
lnstitut fur Physikalische Chemie der Universitit
Wcgelerstrasse 12, D-53115 Bonn (FRG)
Tekfax: Int. code (228)732-551
Prof Dr. F - W Grevels
Max-Planck-lnstitut fur Strahlenchemie, Miilheim an der Ruhr (FRG)
This work was supported by the Fonds der Chemischen Industrie and the
Bundesministerium fur Bildung und Wissenschaft (Graduiertenkolleg "Spektroskopie isolierter und kondensierter Molekiile")
Anpeit . Clien?. l n r . Ed.
End. 1994, 33. N o . 7
Scheme 1. Activation and catalytic cycle for the hydrogenation of NBD in the
presence of carbonyl complexes of group 6.
The polarization signals of the 1,2-hydrogenation product
NBN and also those of the homo-l,4-hydrogenation product
NTC were detected (Fig. 1). The PHIP signals of NBN are
identical with those which occur during thermally activated hydrogenations with the cationic rhodium catalyst [Rh(NBD)(PPh,),]PF, ,[3b1 although the H, molecule is activated in different ways. The analysis of the polarization pattern as an eight-spin
system with a computer program (PHIP 9, J. Kandels. dissertation, UniversitIt Bonn, FRG, 1992) developed for the PHIP
NMR method confirms the formation of cis-endo hydrogenated
NBN (Fig. 2 ) . The necessary NMR parameters were taken from
the literature (Scheme 2) .[lZ1
A prerequisite for the computer-assisted evaluation of the
experimental PHIP spectra is the assumption of a spontaneous
Spontaneous hydrogenation means that the
breakdown of the symmetry of the H, molecule occurs on
product formation. Thus, the H, molecule then cannot be bound
hydridically to the catalyst for a longer period of time, which for
[RhCI(PPh,),] is several milliseconds, since this would have resulted in the loss of the phase correlation because of the different
chemical shifts of the two protons by different precession frequencies. Also in the case of a classical dihydrido complex, only
an extremely short residence time of p-H, at the catalyst can
prevent a loss of the phase correlation, otherwise both hydrogen
atoms stemming from H, must be in chemically equivalent positions. Since the latter should apply for a q2-H, complex, in this
case the phase correlation of the nuclear spin is retained. A
product molecule with an AA'BB' nuclear spin system or one
with a partial spin system, as formed by the endo/exo protons of
NBN, is a particularly sensitive probe for exploring the chemical
environment in which the H, atoms occur in the course of the
A loss of the phase correlation of the H,
atoms prior to their transfer to the substrate (NBD) would lead
to considerable changes of the polarization pattern (Fig. 2c).
The best agreement between experiment and simulation occurs
under the assumption of spontaneous hydrogenation (see Fig. 2).
that is, the bond of the H, molecule in the intermediate catalyst
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geometry, protonцproton, calculations, relative, configuration, determination, noesy, spectral, distance
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