J. Am. Chem. Soc. 2000, 122, 11212-11218
Highly Enantioselective 1,2-Addition of Lithium Acetylide-EphedrateComplexes: Spectroscopic Evidence for Reaction Proceeding via a2:2 Tetramer, and X-ray Characterization of Related Complexes
Feng Xu,* Robert A. Reamer,* Richard Tillyer, Jordan M. Cummins, Edward J. J. Grabowski, Paul J. Reider, David B. Collum,† and John C. Huffman‡ Contribution from the Department of Process Research, Merck Research Laboratories, P.O. Box 2000,Rahway, New Jersey 07065, Department of Chemistry, Cornell UniVersity, Ithaca, New York 14853, andDepartment of Chemistry, Indiana UniVersity, Bloomington, Indiana 47405ReceiVed June 23, 2000. ReVised Manuscript ReceiVed September 22, 2000Abstract: The key step in the manufacturing process for the HIV reverse transcriptase inhibitor efavirenz (Sustiva) involves addition of the 2:2 tetrameric complex 6 [formed from lithium cyclopropylacetylide (5) and lithium (1R,2S)-N-pyrrolidinylnorephedrate (4)] to ketone 2, to give 3 in 95% yield and 98% enantioselectivity. Studies of acetylide-alkoxide complexes in solution by NMR spectroscopy and in the solid state by X-ray crystallography are described. Studies of the asymmetric addition reaction involving 2:2 tetramer 6 using low- temperature NMR spectroscopy provide conclusive evidence for formation of 2:1:1 tetramer 9 containing the product alkoxide 3. Observation of this reaction intermediate strongly supports the proposed reaction mechanism involving the tetramer 6 in the stereo-determining step. Introduction Scheme 1. Highly Enantioselective 1,2-Addition Reaction
Recent efforts within the Merck Research Laboratories to
discover new compounds for the treatment of HIV infection have resulted in indinavir (Crixivan), a protease inhibitor, as well as efavirenz (1)1-3 (Sustiva),4 a nonnucleoside reverse transcriptase inhibitor. Efavirenz has shown excellent potency against a variety of HIV-1 mutants when used in combination with Crixivan or with other reverse transcriptase inhibitors, and was recently approved for use by the FDA. A practical asymmetric synthesis5 of efavirenz has been implemented for large scale manufacture.6 The key step in this process (Scheme 1) involves the 1,2-addition of lithium cyclopropylacetylide (5)
to trifluoromethyl ketoaniline 2 using stoichiometric amounts of lithium (1R,2S)-N-pyrrolidinylnorephedrate (4) as chiral
‡ Indiana University. (1) Young, S. D.; Britcher, S. F.; Tran, L. O.; Payne, L. S.; Lumma, W.
C.; Lyle, T. A.; Huff, J. R.; Anderson, P. S.; Olsen, D. B.; Carrol, S. S.; Pettibone, D. J.; O’Brien, J. A.; Ball, R. G.; Balani, S. K.; Lin, J. H.; Chen, I.-W.; Schleif, W. A.; Sardana, V. V.; Long, W. J.; Byrnes, V. W.; Emini, E. A. Antimicrob. Agents Chemother. 1995, 39, 2602.
(2) Romero, D. L. Annu. Rep. Med. Chem. 1994, 29, 123. Tucker, T. J.;
Lyle, T. A.; Wiscount, C. M.; Britcher, S. F.; Young, S. D.; Sanders, W. M.; Lumma, W. C.; Goldman, M. E.; O’Brien, J. A.; Ball, R. G.; Homnick, C. F.; Schlief, W. A.; Emini, E. A.; Huff, J. R.; Anderson, P. S. J. Med. Chem. 1994, 37, 2437. Quinn, T. C. Lancet 1996, 348, 99. De Clercq, E.
Optimal enantioselectivity (98% ee) and full conversion (95%
J. Med. Chem. 1995, 38, 2491.
isolated yield)6 are obtained using THF as solvent and require
(3) Mayers, D.; Riddler, S.; Bach, M.; Stein, D.; Havlir, M. D.; Kahn,
J.; Ruiz, N.; Labriola, D. F. Interscience Conference on Antimicrobial Agents
(7) For examples for asymmetric 1,2-addition of acetylide mediated by
and Chemotherapy 37th Congress (ICAAC); Toronto, Ontario, Sept. 28-
chiral additives, see: Mukaiyama, T.; Suzuki, K.; Soai, K.; Sato, T. Chem.
Oct. 1, 1997. Mayers, D. Interscience Conference on Antimicrobial AgentsLett. 1979, 447. Mukaiyama, T.; Suzuki, K. Chem. Lett. 1980, 255. Niwa, and Chemotherapy 36th Congress (ICAAC); New Orleans, LA, September
S.; Soai, K. J. Chem. Soc., Perkin Trans. 1 1990, 937. Ramos Tombo, G.
15-18, 1996. Ruiz, N.; Riddle, S.; Mayers, D.; Wagner, K.; Bach, M.;
M.; Didier, E.; Loubinoux, B. Synlett 1990, 547. Corey, E. J.; Cimprich,
Stein, D.; Kahn, J.; Labriola, D. RetroVirus and Opportunistic Infections
K. A. J. Am. Chem. Soc. 1994, 116, 3151. Ye, M.; Logaraj, S.; Jackman, 4th Annual Conference; Washington, D. C., January 22-26, 1997.
L. M.; Hillegass, K.; Hirsh, K.; Bollinger, A. M.; Grosz, A. L.; Mani, V.
(4) Efavirenz is sold under the trademark STOCRIN in certain countries. Tetrahederon 1994, 50, 6109. Huffman, M. A.; Yasuda, N.; DeCamp, A.
(5) Thompson, A. S.; Corley, E. G.; Huntington, M. F.; Grabowski, E.
E.; Grabowski, E. J. J. J. Org. Chem. 1995, 60, 1590. For 1,2-additions
J. J. Tetrahedron Lett. 1995, 36, 8937.
mediated by chiral lithium alkoxides, see: Mukaiyama, T.; Soai, K.; Sato,
(6) Pierce, M. E.; Parsons, R. L., Jr.; Radesca, L. A.; Lo, Y. S.; Silverman,
T.; Shimizu, H.; Suzuki, K. J. Am. Chem. Soc. 1979, 101, 1455. Alberts,
S.; Moore, J. R.; Islam, Q.; Choudhury, A.; Fortunak, J. M. D.; Nguyen,
A. H.; Wynberg, H. J. Am. Chem. Soc. 1989, 111, 7265. Alberts, A. H.;
D.; Luo, C.; Morgan, S. J.; Davis, W. P.; Confalone P. N.; Chen, C.; Tillyer,
Wynberg, H. J. Chem. Soc., Chem. Commun. 1990, 453. Gallagher, D. J.;
R. D.; Frey, L.; Tan, L.; Xu, F.; Zhao, D.; Thompson, A. S.; Corley, E. G.;
Wu, S.; Nikolic, N. A.; Beak, P. J. Org. Chem. 1995, 60, 8148. Hashimoto,
Grabowski, E. J. J.; Reamer, R.; Reider, P. J. J. Org. Chem. 1998, 63,
K.; Kitaguchi, J.; Mizuno, Y.; Kobayashi, T.; Shirahama, H. TetrahedronLett. 1996, 37, 2275. Lithium Acetylide-Ephedrate ComplexesJ. Am. Chem. Soc., Vol. 122, No. 45, 2000 11213
Scheme 2. Proposed Reaction Pathways Figure 1. Tetramer structures.
the use of 2.0 equiv of 5 and 2.0 equiv of alkoxide 4, which must be allowed to equilibrate at temperatures > -40 °C prior to reaction with keto aniline 2 at < -50 °C. Using 1.0 equiv
The requirement for 2.0 equiv of 4 and 5 for full conversion
each of equilibrated 4 and 5 provided only 50% conversion (98%
(or 1.0 equiv of tetramer) was explained in terms of the
ee) below -50 °C; subsequent warming of the reaction mixture
formation of an unreactive 2:1:1 complex 9 containing product
to 0 °C provided 90% conversion at the expense of selectivity
alkoxide, acetylide 5, and 2 equiv of ephedrate 4. This
(82% ee). Generation of the alkoxide-acetylide mixture at low
rationalization was consistent with the known low reactivity of
temperature without aggregate equilibration and subsequent
the closely related 3:1 alkoxide:acetylide complex (7 or 8).
reaction with keto-aniline 2 provided 3 in only 85% ee.8
Although these studies have enormously increased our
Initial mechanistic studies on this reaction employing 6Li,
understanding of lithium acetylide-alkoxide complexes, some
13C, and 15N NMR spectroscopy and MNDO calculations have
aspects of this interesting puzzle warranted further investigation.
shed much light on these experimental observations.8 6Li NMR
First, although there was ample evidence for generation of cubic
spectroscopic studies on THF solutions containing lithium
tetrameric alkoxide-acetylide complexes in THF, there was no
ephedrate 4 and lithium acetylide 5 in various proportions
reported evidence for the formation of these species in other
confirmed a slow aggregate equilibration at low temperature,
solvents or in the solid state. Second, although equimolar
which was rapid above -40 °C. It was determined that a 1:1
amounts of pyrrolidinylnorephedrine lithium alkoxide 4 and
mixture of 4 and 5 equilibrates to a single C2-symmetrical 2:2
acetylide 5 rapidly equilibrate to a single tetrameric complex 6
cubic tetramer 6 (Figure 1), which was fully characterized by
above -40 °C, this behavior had not been confirmed for other
6Li NMR spectroscopy. It was also shown that a 3:1 mixture
N-substituted 1,2-aminoalkoxide-acetylide mixtures. These
of 4 and 5 equilibrates to a single cubic tetramer, assigned as 7
points are particularly pertinent, given the observed solvent and
or 8 based on 6Li-13C and 6Li-15N couplings. The structure
aminoalkoxide structural effects on the enantioselectivity of the
of 7 was supported by MNDO model calculations (Figure 1).
1,2-addition.5 Finally, there was no direct spectroscopic evidence
It was concluded that reaction of the ketoaniline 2 with the
supporting the proposed tetramer-based mechanism for the 1,2-
equilibrated 2:2 mixture of alkoxide and acetylide proceeds via
the 2:2 tetramer 6. A mechanism accounting for the observed
The studies described herein were carried out to further
stereochemical outcome was proposed on the basis of MNDO
explore the structures of acetylide-alkoxide complexes, to
calculations (Scheme 2)8,9 and was supported by several key
account for the experimental observations in the 1,2-addition,
observations: (1) the 2:2 tetramer 6 is the only detectable species
and to further substantiate the reaction mechanism proposed in
present after equilibration of the equimolar mixture of alkoxide
4 and acetylide 5 and prior to addition of ketone 2; (2) the 1,2- addition is fast at low temperature, as compared to the slow Results and Discussions
aggregate equilibration; (3) the reaction displays asymmetric amplification [50% ee N-pyrollidinylnorephedrine (4a) provides Lithium Acetylide-Alkoxide Complexes: Solvent Effects.
In the initial work on the asymmetric addition reaction, THFwas found to give the best enantioselectivity (98%).5 Compa-
(8) Thompson, A.; Corley, E. G.; Huntington, M. F.; Grabowski, E. J.
rable selectivity was observed in ethylene glycol dimethyl ether
J.; Remenar, J. F.; Collum, D. B. J. Am. Chem. Soc. 1998, 120, 2028.
(9) Reaction of the ketoaniline 2 with the tetramer 6 possibly occurs via
(DME) (92% ee), but lower ee’s were obtained in diethyl ether
formation of a precomplex (replacement of THF in 6 with the carbonyl of
(68% ee) or tert-butyl methyl ether (MTBE) (26% ee), and close
2). The sense of facial selectivity in this reaction as predicted by MNDO
to zero selectivity was observed in toluene. For reactions in
calculations is readily explained in terms of steric effects. In the preferred
THF, the maximum ee was obtained using solutions that had
transition state, the bulky aryl portion of 2 points away from the norephedrine substituents, as indicated in Scheme 3.
fully equilibrated to give a single 2:2 cubic tetramer 6 containing
11214 J. Am. Chem. Soc., Vol. 122, No. 45, 2000
Ring Size Effects on Reaction Enantioselectivity
a 6Li NMR was recorded in THF/hexane (1:1) at -60 °C. b 6Li NMR
was recorded in THF/hexane (1:1) at -40 °C.
and 11) were selected for this study to probe the effects of N-cycloalkyl ring size.10 Thus, the complexes were prepared using equimolar quantities of lithium acetylide 5 and norephe- drine alkoxides 4, 10, and 11. In each case, the formation of fully equilibrated tetrameric complexes was found to be complete at -40 °C to give two-line spectra as expected (Table 1). The 1,2-addition reactions were then performed at -70 °C to determine ee% (Table 1). These data clearly show that the size of the N-cycloalkyl substituent is critical in this process and confirms the initial observation that (1R,2S)-N-pyrrolidi- nylnorephedrine (4a) is optimal.9 Lithium Acetylide-Alkoxide Complexes: X-ray Crystal- lography. The tendency of lithium acetylides to form dimers, tetramers, and higher oligomers in the solid state is well-known. Lithium acetylides have been crystallized and characterized as tetramers by X-ray analysis,11 but structural studies on mixed lithium acetylide-lithium alkoxide complexes have not been carried out.12 Accordingly, we were quite interested in preparing X-ray quality crystals of these complexes to obtain structural information in the solid state. Figure 2. 6Li NMR spectra of equilibrated samples containing 4 and 5 (1:1) (a) in THF/hexane/toluene (5:5:1) at -40 °C, (b) in DME/
X-ray quality crystals were readily obtained from a 3:1
hexane/toluene (5:5:1) at -60 °C, (c) in Et2O/hexane/toluene (5:5:1)
mixture of alkoxide 4 and acetylide 5. A solution of 3.0 equiv
at -40 °C, and (d) in t-BuOMe/hexane/toluene (5:5:1) at -40 °C.
(1R,2S)-N-pyrrolidinylnorephedrine (4a) and 1.0 equiv cyclo- propylacetylene (5a) was treated with 4 equiv n-BuLi in THF/
2 mol of THF. This was the first piece of (circumstantial)evidence implicating the cubic tetramer itself in the addition
(10) Zhao, D.; Xu, F.; Chen, C.; Tillyer, R.; Tan, L.; Pierce, M.; Moore,
reaction. It was suspected that it might be possible to correlate
(11) Lithium acetylide X-ray structures: (a) Goldfuss, B.; Schleyer, P.
the observed solvent effects with the presence or absence of a
v. R.; Hampel, F. J. Am. Chem. Soc. 1997, 119, 1072. (b) Geissler, M.;
single tetrameric structure (related to 6), as determined from
Kopf, J.; Schubert, B.; Weiss, E.; Neugebauer, W.; Schleyer, P. v. R.;
6Li NMR spectra of the alkoxide-acetylide mixtures. Thus, the
Angew. Chem., Int. Ed. Engl. 1987, 26, 587. (c) Schubert, B.; Weiss, E. Angew. Chem., Int. Ed. Engl. 1983, 22, 496. (d) Schubert, B.; Weiss, E.
6Li NMR spectra shown in Figure 2 were obtained for solutions
Chem. Ber. 1983, 116, 3212.
containing equimolar amounts of acetylide 5 and alkoxide 4,
(12) Theoretical and spectroscopic studies of lithium acetylides: Buhl,
which had been allowed to equilibrate at 22 °C. In DME, a
M.; van Eikema Hommes, N. J. R.; Schleyer, P. v. R.; Fleischer, U.; Kutzelinigg, W. J. Am. Chem. Soc. 1979, 101, 2848. Ritchie, J. P.
spectrum similar to that in THF was observed, which supports
Tetrahedron Lett. 1982, 23, 4999. Fraenkel G.; Pramanik, P. J. Chem. Soc.,
formation of a tetrameric complex similar to 6 (possibly with Chem. Commun. 1983, 1527. Bachrach, S. M.; Streitwieser, A., Jr. J. Am.
an η1-bound DME in place of the THF). In diethyl ether, the
Chem. Soc. 1984, 106, 2283. Buhl, M.; van Eikema Hommes, N. J. R.;
Schleyer, P. v. R.; Fleischer, U.; Kutzelnigg, W. J. Am. Chem. Soc. 1991,
Li NMR spectrum showed two singlets, as in THF and DME,
113, 2459. Dorigo, A. E.; van Eikema Hommes, N. J. R.; Krogh-Jespersen,
but there were other species formed. In MTBE, a complex
K.; Schleyer, P. v. R. Angew. Chem., Int. Ed. Engl. 1992, 31, 1602. For
mixture of species was formed. The high enantioselectivity is
theoretical investigations of RLi/R′OLi mixed aggregates, see: Morey, J.;
observed only in solvents which allow for formation of a single
Costa, A.; Deya, P. M.; Suner, G.; Saa, J. M. J. Org. Chem. 1990, 55, 3902. Sorger, K.; Schleyer, P. v. R.; Fleischer, R.; Stalke, D. J. Am. Chem.
tetrameric complex at equilibrium prior to reaction with
Soc. 1996, 118, 6924. For investigations of RLi/R′OLi mixed aggregation,
see: McGarrity, J. F.; Ogle, C. A. J. Am. Chem. Soc. 1985, 107, 1805. Lithium Acetylide-Alkoxide Complexes: Ephedrine Sub-
McGarrity, J. F.; Ogle, C. A.; Brich, Z.; Loosli, H. J. Am. Chem. Soc. 1985, 107, 1810. Marsch, M.; Harms, K.; Lochmann, L.; Boche, G. Angew. Chem., stituents. In the initial studies, N-pyrrolidinylnorephedrine Int. Ed. Engl. 1990, 29, 308. Saa, J. M.; Martorelli, G.; Frontera, A. J.
lithium alkoxide 4 was identified as the optimal chiral mediator Org. Chem. 1996, 61, 5194. Goldfuss, B.; Schleyer, P. v. R.; Hampel, F. J.
on the basis of studying a variety of different chiral aminoalkox-
Am. Chem. Soc. 1996, 118, 12183. For recent investigations of RLi
ides in the addition reaction.5 Much of these data were generated
aggregation, see: Hoffmann, D.; Collum, D. B. J. Am. Chem. Soc. 1998, 120, 5810. Reich, H. J.; Green, D. P.; Medina, M. A.; Goldenberg, W. S.;
before the realization of slow aggregate equilibration and under
Gudmundsson, B. O.; Dykstra, R. R.; Phillips, N. H. J. Am. Chem. Soc.
conditions which did not guarantee complete equilibration of
1998, 120, 7201. Hilmersson, G.; Arvidsson, P. I.; Davidsson, O.;
complexes (-40 °C). Thus, a study of the aggregate equilibra-
Hakansson, M. J. Am. Chem. Soc. 1998, 120, 8143. Sugasawa, K.; Shindo, M.; Noguchi, H.; Koga, K. Tetrahedron Lett. 1996, 37, 7377. Hoppe, I.;
tions of various acetylide 5-alkoxide mixtures using 6Li NMR
Marsch, M.; Harms, K.; Boche, G.; Hoppe, D. Angew. Chem., Int. Ed. Engl.
was carried out. Three closely related aminoalkoxides (4, 10, 1995, 34, 2158. Lithium Acetylide-Ephedrate ComplexesJ. Am. Chem. Soc., Vol. 122, No. 45, 2000 11215
Figure 3. Perspective ORTEP drawings of 3:1 tetramer 8. Hydrogen atoms have been omitted for clarity.
Selected Bond Lengths (Å) and Angles (deg) for 3:1
Tetramer 8 Figure 4. 4:2 hexamer 12 structure and its perspective ORTEP
drawings. Hydrogen atoms have been omitted for clarity.
alternative stereoisomer 7 (Figure 1) was predicted to be more
stable on the basis of MNDO model calculations. If the solutionand solid-state structures of the 3:1 tetramer are indeed different,
hexane at -10 to 0 oC under nitrogen. The mixture was
the behavior of the 3:1 alkoxide:acetylide mixture, which was
concentrated in vacuo, and the solvent ratio was adjusted toapproximately 40% THF in hexane at a concentration of about
prepared by dissolving the crystalline material in THF, would
0.15 M (for the 3:1 tetramer). X-ray quality single crystals were
require the facile conversion of 8 to 7 in solution.
obtained from this mixture at room temperature under an
Encouraged by our success in obtaining X-ray quality crystals
atmosphere of N2. The 1H, 6Li, and 13C NMR spectra measured
from the 3:1 complex, we attempted to prepare crystalline
on a solution prepared by dissolving the crystals in THF-d8 at
material from a solution of the 2:2 alkoxide 4:acetylide 5
room temperature were identical to the spectra previously
mixture. A crystalline solid was obtained from this mixture only
obtained from an equilibrated solution of the 3:1 aggregate.
with difficulty, and this required removal of most of the THF.
Treatment of this solution with ketoaniline 2 at -40 °C provided
Thus, a THF-hexane solution of a 1:1 mixture of cyclopropyl-
the addition product 3 in 99% ee and 60% yield, as expected
acetylene (5a) and (1R,2S)-N-pyrrolidinylnorephedrine (4a) was
for a reaction involving the 3:1 tetramer.8
treated with 2.0 equiv n-BuLi at -10 to 0 °C. The solution
The structure of the crystalline material, as determined by
was concentrated in vacuo and more hexane was added to adjust
X-ray diffraction analysis at -165 °C, was shown to be the 3:1
the solvent ratio to 1-2% THF in hexane (concentration of 2:2
tetramer 8 (Figure 1). The ORTEP drawing is displayed in
tetramer, approximately 0.2 M). X-ray quality single crystals
Figure 3, and the selected bond lengths and angles are
were obtained from this mixture at room temperature under a
summarized in Table 2. It is interesting that the three Li-C
nitrogen atmosphere. X-ray diffraction analysis carried out at
bonds in 3:1 tetramer 8 are slightly longer than the Li-O bonds,
which distorts the cubic structure somewhat. Surprisingly, the
2 revealed hexamer 12
(Figure 4). The ORTEP drawing is displayed in Figure 4, and
THF O-Li bond [O(55)-Li(2)] is almost the same length as
selected bond lengths and angles are summarized in Table 3.
other O-Li bonds and shorter than the N-Li bonds, whichindicates a strong binding of THF to lithium in the tetrameric
The preferential crystallization of the 4:2 hexamer 12 was
structure. Interestingly, each of the three internal O-Li-N
an interesting, yet unexpected, result, and all subsequent attempts
angles (inside the five membered ring) are right angles.
to obtain crystals of the 2:2 tetramer 6 have failed.13 Some
The structure of the 3:1 cubic tetramer 8 in the solid state is
interesting features of this 4:2 complex were noted. The C2-
identical to one of the two solution structures that are assigned
symmetrical hexamer 12 consists of two stacked chairlike six-
on the basis of the earlier NMR studies.8 However, the
membered rings (displaced approximately 60° relative to each
11216 J. Am. Chem. Soc., Vol. 122, No. 45, 2000
Selected Bond Lengths (Å) and Angles (deg) for 4:2
other) that contain two alkoxides and one acetylide. Two lithium
Figure 5. 6Li NMR spectrum at -100 °C after treatment of the 2:2
atoms (those directly opposite to the acetylide carbon atoms)
tetramer 6 with 0.5 equiv of ketone 2 in THF/pentane (1:1) at -100
are three-coordinate and are not bonded to THF. Additionally,
each of the four internal O-Li-N angles (within the five- membered ring) are close to right angles, which is similar to that observed in 3:1 tetramer 8.
Dissolving the crystalline 4:2 hexamer 12 in THF at room
temperature, followed by cooling to -70 °C and reaction with ketone 2, provided the addition product 3 in 99% ee. Identical results were obtained by using an equilibrated solution of 4 equiv alkoxide 4 and 2 equiv acetylide 5, which suggests the formation of solutions having similar composition in both cases. To better understand these results, 6Li NMR spectra were recorded for both solutions in THF-d8. It was immediately apparent that dissolving the hexamer 12 in THF and a 4:2 mixture of alkoxide 4 and acetylide 5 generated in situ provide mixtures containing predominantly the 2:2 tetramer 6 and 3:1 tetramer 7 or 8. This is consistent with the highly enantioselective reactions that are observed in both cases with ketone 2 at -70 °C.5,8 The conclusion is that hexamer 12 is less stable than either tetrameric structure in THF, that equilibration is fast at room temp, and that 12 is not important in the addition reaction pathway. Acetylide-Transfer Mechanism: 6Li NMR Studies. Ac- Figure 6. 6Li NMR spectra at -100 °C after treatment the 2:2 tetramer
cording to the proposed mechanism outlined in Scheme 2,
6 with ketone 2 in THF/pentane (1:1) at -100 °C (a) using [1-13C]-
reaction of cubic tetramer 6 with the ketone 2 at low temperature
labeled acetylene 5a and (b) using [1-13C]-labeled acetylene 5a with
results in the rapid transfer of one acetylide to give a less-
reactive product complex 9 containing two ephedrates, one product alkoxide, and one acetylide. Strong support for this
NMR Spectroscopic Data for 2:1:1 Tetramer 9
mechanism was obtained by following the reaction using 6Li NMR spectroscopy. A solution of 1.0 equiv mixed 2:2 tetramer 6 in THF and hexane, generated as usual, was cooled to -100
°C.14 To this solution was added, slowly and with good mixing, a solution of approximately 0.5 equiv ketone 2 in THF. The 6Li NMR spectrum at -100 °C showed the appearance of four new singlets, with equal intensities (1.13, 0.95, 0.77, and 0.60 ppm) (Figure 5). Further conversion of the 2:2 tetramer to this four-line intermediate was achieved upon further addition of keto aniline 2.15
The four-line spectrum is fully consistent with the formation
of a mixed cubic tetramer 9 containing the product alkoxide
and provides the first strong evidence in favor of the 1,2-addition
reaction proceeding via the 2:2 tetramer 6. Employing [1-13C]-
labeled acetylene 5a revealed that three of four 6Li resonances
were split into doublets due to spin-spin coupling to 13C. This
coupling was verified by a 6Li NMR spectrum (spectrum B,Figure 6) with 13C decoupling. A broad signal at 116.2 ppm in
the 13C NMR spectrum at -100 °C is consistent with an alkyne
(13) Preferential crystallization of the 4:2 hexamer from the 2:2 mixture
bound to several 6Li nuclei, and a signal of equal intensity at
was found to occur reproducibly, regardless of solvent composition or
75.45 ppm is consistent with the alkyne carbon in the product
(14) The best quality spectral data were obtained at -100 °C. Interest-
alkoxide itself. Using 15N-labeled ephedrine 4a,10,16 revealed
ingly, subsequent warming to -70 °C did not afford any new species, but
that the 6Li NMR spectrum showed splitting of signals at 1.13
caused broadening of the signal assigned as LiC (Figure 5), which sharpened
and 0.95 ppm into doublets due to a coupling with 15N (Table
4). Using [15N]ketoaniline 2,6,17 the 6Li NMR spectrum obtained
(15) Reaction of the sample in the NMR tube with ketoaniline 2 provided
the product 3 in 99% ee.
at -100 °C showed no connection between the nitrogen atom
Lithium Acetylide-Ephedrate ComplexesJ. Am. Chem. Soc., Vol. 122, No. 45, 2000 11217
in addition product 3 and any lithium atom in the product
Icon Services Inc. n-Bu6Li was prepared21 in pentane from commercial
alkoxide complex. This is surprising because the 3:1 tetramer
6Li and n-butyl chloride and was filtered to remove solids before use. 15
8 features bonding of the nitrogen atom in each ephedrate to a
N-labeled (1R,2S)-N-pyrrolidineylnorephedrine 4a was prepared from
lithium atom in the tetramer.18 On the basis of these data, the
N-labeled (1R,2S)-norephedrine, which was synthesized from pro-
piophenone via a literature procedure using 15NH
product complex is assigned as the tetramer 9,19 the logical
labeled ketoaniline 2 was prepared from [15N]-4-chloroaniline using
product of asymmetric 1,2-addition of the tetramer 6 to the
the existing procedures.6 [15N]-4-Chloroaniline was prepared from
4-chlorobenzoic acid via Hofmann rearrangement using 15NH3 as thesource of the label.17
Instrument Descriptions. NMR Spectroscopic Analyses: For 1H,
Continued studies of lithium 1,2-aminoalkoxide-lithium
spectra were obtained on a Bruker AMX-400 operating at 399.87 MHz. 6Li and 13C spectra were recorded at 58.85 and 100.55 MHz,
acetylide mixtures have substantially increased our understand-
respectively. In the 6Li spectrum of tetramer 6 at -40 °C, the low-
ing of these complexes in solution and in the solid state. In
field signal was referenced to δ ) 1.19 ppm.8 Subsequent 6Li spectra
particular, it was confirmed that single tetrameric aggregates
were referenced to the 2H lock frequency. 13C spectra were referenced
are formed at equilibrium in THF and DME, while complex
to the high-field signal from THF-d8 (δ ) 25.4 ppm). Low-temperature
mixtures are present in diethyl ether and MTBE. In addition, it
calibration was determined using 4% CH3OH in CD3OD and the Bruker
was shown that equimolar mixtures of lithium acetylide 5 and
variable temperature calibration curve. 13C-decoupled 6Li spectra were
N-cycloalkyl lithium aminoalkoxides equilibrate to single tet-
obtained using standard Waltz-16 decoupling on an “X” tuneable 13C/
rameric species at approximately the same rate in THF and
confirmed that there is a substantial ring-size effect on the
X-ray Crystallography: All crystallographic studies were performed
enantioselectivity of the 1,2-addition reaction. X-ray crystal-
on a Picker four-circle goniostat using a locally designed interface and
lographic studies revealed a symmetrical cubic tetrameric
nitrogen gas flow cooling system of local design. In both studies,crystals were affixed to the end of glass fibers using silicone grease
structure 8 for the 3:1 aggregate which is in close agreement
and transferred to the system where they were cooled for characteriza-
with a structure proposed on the basis of solution NMR data.
tion and data collection. Details of the diffractometer, low-temperature
A new hexameric complex 12 was prepared by crystallization
facilities, and computational procedures employed by the Molecular
from a 2:2 mixture of alkoxide:acetylide and was characterized
Structure Center are available elsewhere.22 The structures were solved
by X-ray crystallography. This structure is not stable in the
by direct methods (SHELXTL) and Fourier methods and refined on
solution and provides mixtures containing predominantly the
F2 using full-matrix least-squares techniques. [1-13C]Cyclopropylacetylene (5a).8,23 To a solution of PPh3 (15.8
Further studies on the mechanism of the 1,2-addition reaction
g, 60.3 mmol) in 40 mL of dry methylene chloride at -40 °C was
have resulted in the spectroscopic characterization of the
added a solution of 13CBr4 (10.0 g, 30.1 mmol) in 40 mL of dry THF
tetrameric reaction intermediate 9, which leads us to conclude
at such a rate as to keep the temperature below -20 °C. After aging
that the reaction proceeds via the cubic tetramer 6 and that
15 min at -20 °C, the mixture was cooled to -70 °C, and Et3N (5.0mL, 36.2 mmol) was added dropwise. A solution of cyclopropane
pathways involving dimeric intermediates are not relevant in
carboxaldehyde (4.23 g, 60.3 mmol) in 5 mL of dichloromethane was
added at such a rate as to keep the temperature below -55 °C. Thereaction mixture was aged at -40 °C for 1.5 h (reaction completion
determined by GC analysis) and was then quenched in 50 mL of water. General Considerations. Unless otherwise noted, all of the reactions
The organic layer was separated, and the aqueous layer was extracted
and manipulations were carried out using dry glassware under a nitrogen
using 15 mL of dichloromethane. The combined organic solution was
atmosphere. All solvents were dried over 4-Å molecular sieves and
dried over Na2SO4 and concentrated under reduced pressure to give a
checked for water content by Karl-Fisher titration. 6Li (95%, enriched),
white slurry. 100 mL of hexane was added, and the solid was removed
by filtration through a thin pad of Celite. Concentration of the filtrate
3 (98%, enriched), and 15NH2OH‚HCl (99%, enriched) were
provided 5.5 g of [1-13C]-1,1-dibromocyclopropylethylene as a colorless
liquid (81% yield). The spectral data for this material exactly matched
(16) Oppolzer, W.; Tamura, O.; Sundarababu, G.; Signer, M. J. Am.Chem. Soc. 1992, 114, 5900. Soai, K.; Yokoyama, S.; Hayasaka, T. J. Org.
To a solution of 5.1 g (22.6 mol) of [1-13C]-1,1-dibromocyclopro-
Chem. 1991, 56, 4264.
pylethylene in 8 mL of dry toluene and 11 mL of dry THF was slowly
(17) Huang, X.; Keillor, J. W. Tetrahedron Lett. 1997, 38, 313.
added 5.0 mL of n-BuLi (50 mmol, 10 N in hexane) while keeping the
(18) It was pointed out correctly by a referee that the 3:1 tetramer 8
may not predict reactivity of the intermediate 9 due to differences in Li-N
°C. The reaction mixture was aged between
10 and 25 °C for 1 h (reaction completion determined GC analysis),
(19) The NMR data are also consistent with the diastereoisomers 13 and
and then 10 mL of 10% NH4Cl was added while keeping the
14. The structure 9 is proposed because it derived immediately from the
temperature below -15 °C. The organic phase was separated at 0 to
1,2-addition reaction, and it is plausibe that internal reorganization is slow
-5 °C and was dried over Na2SO4 at 0 °C. Short-path distillation of
the resulting solution under an atmosphere of nitrogen gave 14.0 g ofa solution of 13C-labeled cyclopropylacetylene solution in THF-hexane(7.2 wt % solution, 68% yield) and 55% overall yield. General Procedure for the Preparation of 2:2 Tetramer 6. To a
solution of (1R,2S)-N-pyrrolidinylnorephedrine (4a) (10.0 g, 45.79 mmol) and Ph3CH (10 mg) in 80 mL of dry THF was charged n-BuLi (1.6 M in hexane) while maintaining the temperature below -10 °C.
(21) Amonooneiger, E. H.; Shaw, R. A.; Skovlin, D. O.; Smith, B. C. Inorg. Synth. 1966, 8, 19.
(22) Chisholm, M. H.; Folting, K.; Huffman, J. C.; Kirkpatrick, C. C. Inorg. Chem. 1984, 23, 1021.
(23) (a) Ramirez, F.; Desai, N. B.; McKelvie, N. J. Am. Chem Soc. 1962,
(20) Dissociation of the tetramer 6 to its corresponding dimer followed 84, 1745. (b) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.
by reaction with ketone 2 and recombination to a single product 9 is
(c) Grandjean, D.; Pale, P.; Chuche, J. Tetrahedron Lett. 1994, 35, 3529.
(d) Baldwin, J. E.; Villarica, K. A. J. Org. Chem. 1995, 60, 186.
11218 J. Am. Chem. Soc., Vol. 122, No. 45, 2000
The amount of n-BuLi added at the red end point was noted. The same
addition of three-fourths of the theoretical amount of n-BuLi. Cyclo-
amount of n-BuLi was then added (total amount of n-BuLi, 91.58
propylacetylene (a solution either in THF-heptane or neat) was added
mmol), and then a solution of cyclopropylacetylene (5a) in THF-
at -10 to 0 °C until the reaction solution became colorless. The solution
heptane (45.8 mmol) was added below 0 °C until the red color
was aged at room temperature for 30 min and then concentrated in
disappeared. The mixture was aged at 0-5 °C for 30 min to complete
vacuo to a volume of approximately 10 mL. A portion (15mL) of THF
the formation of tetramer 6.
and 70 mL of pentane were added. The concentration of 3:1 tetramer
Generation of 6Li-Labeled Tetramer 6 and Observation of the
was approximately 0.15 M in approximately 30% THF:70% hydro-
Addition Reaction by 6Li NMR Spectroscopy. The 2:2 tetramer 6
carbon. The solution was allowed to stand at room temperature under
was prepared as described in the general procedure, except that the
a nitrogen atmosphere for 6 h, which resulted in the slow growth of
deprotonation of both ephedrine 4a and acetylene 5a was carried out
the 3:1 tetramer crystals 8.
using n-Bu6Li (1.4 M in pentane) below -70 °C. Immediately after
Crystallization of 4:2 Hexamer. A solution of the 2:2 tetramer 6
the addition of acetylene 5a, the solution was transferred into a 5-mm
in THF-hexane was generated as in the general procedure starting
NMR tube while taking care to maintain low temperature. Low-
from 5.0 g (27.47 mmol) norephedrine 4a. The solution was concen-
temperature 6Li NMR spectra were recorded on this solution as
trated in vacuo to a volume of approximately 7 mL, and 60 mL of
described in the general considerations section. The 6Li NMR spectrum
pentane was added. The concentration of 2:2 tetramer 6 was ap-
at -70 °C was quite complicated (see spectrum in Supporting
proximately 0.2 M in approximately 2% THF-hydrocarbon. The
Information). Upon gradual warming of the solution, growth of 2:2
solution was allowed to stand at room temperature under a nitrogen
tetramer peaks at 1.19 and 0.47 ppm was observed in the 6Li NMR
atmosphere for several days, which resulted in the slow growth of the
spectrum. As soon as the temperature reached to -40 °C, the formation
4:2 hexamer crystals 12.
of 2:2 tetramer 6 was complete (concentration, approximately 0.13 M).
Solutions of the 2:2 tetramer 6 solution in THF-hexane were Supporting Information Available: 6Li NMR spectra for
generated according to the general procedure using n-Bu6Li in pentane
the tetramers in Table 1 and the 3:1 tetramer. 6Li NMR spectra
and labeled or nonlabeled norephedrine 4a and acetylene 5a. A portion (0.4 mL) of the 2:2 tetramer solution (0.13 M, 0.052 mmol) was
after treatment of the 2:2 tetramer 6 with ketone 2 at -100 °C
transferred into a 5-mm NMR tube and cooled to -100 to -105 °C.
using 15N-labeled ketone 2 and using 15N-labeled ephedrine 4a. 6
A solution of labeled or nonlabeled ketone 2 (0.17 mL, 0.233 M, 0.040
Li NMR spectra at -40 °C (2:1 ratio of 4 and 5 generated in
mmol) in THF-d8 was slowly added with good mixing. NMR spectra
situ and equilibrated at room temperature, hexamer 12 crystals
were recorded starting at -100 °C (Table 4), as described in the text.
dissolved in THF-d8, and lithium ephedrate 4). X-ray structural
Spectra are also included as Supporting Information.
data for 8 and 12, including complete atomic coordinates and Crystallization of 3:1 Tetramer. To a solution of (1R,2S)-N-
thermal parameters, bond distances, and angles. This material
pyrrolydinylnorephedrine (4a) (5.0 g, 27.47 mmol) and Ph3CH (5 mg)
is available free of charge via the Internet at http:/pubs.acs.org.
in 40 mL of dry THF at -10 °C was added n-BuLi (1.6 M, 25.2 mL,40.18 mmol). The color of the reaction solution became red after the
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