Control of the enantiochemistry of electrophilic substitutions of N-pivaloyl-α-lithio-o-ethylaniline: Stereoinformation transfer based on the method of organolithium formation

Full text of DOI:10.1021/ja951895w

J. Am. Chem. Soc. 1996, 118, 1575-1576
Control of the Enantiochemistry of Electrophilic
1575
Substitutions of N-Pivaloyl-r-lithio-o-ethylaniline:
Stereoinformation Transfer Based on the Method of
Organolithium Formation
Amit Basu and Peter Beak*
Department of Chemistry, UniVersity of Illinois
temperature for 45 min prior to cooling to -78 °C and
subsequent addition of TMSCl, (R)-3 is obtained in 72% yield
with 90% ee. The induction of high enantioselectivities by a
-25 °C to -78 °C sequence for a reaction which gives modest
selectivities under the usual -78 °C conditions suggests that a
warm-cool protocol should be investigated for other reactions
which afford low enantioselectivities.
The dianion 2 has been reacted in the prescence of (-)-
sparteine with a variety of electrophiles, including activated alkyl
halides, carbonyl compounds, and stannylating and silylating
agents using the warm-cool sequence of method B. Good
Urbana, Illinois 61801
ReceiVed June 12, 1995
Enantioselective reactions of organolithium reagents in the
presence of (-)-sparteine have been the focus of a number of
recent synthetic and mechanistic investigations.1-4 Factors that
have been demonstrated to affect, and even invert, the sense of
enantioselection include subtle modifications in the structure
of the organolithium species, directing group, chiral ligand,
solvent, and choice of electrophile.1-3 Effects of temperature,
where reported, involve decreasing selectivities with increasing
temperature, as expected.1c,4 The enantiochemistry has also been
independent of the method of generation of the organolithium
intermediate.5 We now wish to report an investigation of the
lateral lithiation of N-pivaloyl-o-ethylaniline (1) to give 2.
Subsequent electrophilic substitution of 2 affords the products
3-10 with good enantioselectivities in the presence of (-)-
sparteine.6 We are able to induce high enantioselectiVities in
the substitutions by employing a warm-cool protocol and to
inVert the sense of enantioselectiVity by changing the method
of formation of the organolithium intermediate. We provide
data which show that these observations can be ascribed to
diastereomeric complexes of 2/(-)-sparteine which can equili-
brate at -25 °C but are nonequilibrating at -78 °C with respect
to the rate of reaction with the electrophiles.
yields and enantioselectivities are obtained (Table 1). Absolute
configurations of products 4 and 11 were determined by
comparison with products of known configuration obtained by
independent syntheses.8 Assignments of absolute stereochem-
istry to 3 and 5-10 are based on their correspondence to (R)-4
and (S)-11 as the more retained isomers on the (S,S)-Whelk-O
chiral stationary phase HPLC column and the chiral recognition
models proposed by Pirkle.9 Deoxygenation of the benzalde-
hyde adduct 7 afforded (S)-9, indicating that the organolithium
reagent 2 reacts with carbonyl electrophiles and alkyl halides
with the same stereochemical sense at the benzylic carbon.10
Since Still’s seminal report in 1980, lithiodestannylation of
organostannanes of known configuration has served as a useful
probe of organolithium configurational stability.12 Transmeta-
lation of (R)-5 (70% ee) in both the absence and the presence
of TMEDA, followed by reaction with TMSCl, affords es-
sentially racemic 3 in both cases. However, lithiodestannylation
of enantioenriched (R)-5 (66% ee) with s-BuLi in the presence
of (-)-sparteine, followed by reactions with TMSCl or cyclo-
Treatment of the anilide 1 with sec-butyllithium (s-BuLi) at
-25 °C for 2 h generates the dilithio intermediate 2, which upon
cooling to -78 °C, followed by subsequent additions of (-)-
sparteine and TMSCl, affords the product (R)-3 in 52% yield
with 21% enantiomeric excess (ee).7 However, if the sparteine
is added at -25 °C and the solution allowed to stir at this
(1) (a) Thayumanavan, S.; Lee, S.; Liu, C.; Beak, P. J. Am. Chem. Soc.
1994, 116, 9755. (b) Beak, P.; Du, H. J. Am. Chem. Soc. 1993, 115, 2516.
(c) Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J. J. Am. Chem. Soc. 1994, 116,
3231.
(2) (a) Hoppe, I.; Marsch, M.; Harms, K.; Boche, G.; Hoppe, D. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2158. (b) Kaiser, B.; Hoppe, D. Angew.
Chem., Int. Ed. Engl. 1995, 34, 323. (c) Zschage, O.; Hoppe, D. Tetrahedron
1992, 48, 5657. (d) Hoppe, D.; Hintze, F.; Tebben, P.; Paetow, M.; Ahrens,
H.; Schwerdtfeger, J.; Sommerfeld, P.; Haller, J.; Guarnieri, W.; Kolcze-
wski,. S.; Hense, T.; Hoppe, I. Pure Appl. Chem. 1994, 66, 1479. (e)
Personal communication by M. Schlosser, June 1995. Apparently, M.
Schlosser and D. Limat were the first to observe a pronounced inversion
of steroselectivities when switching from hexane or Et2O to THF as the
solvent for the (-)-sparteine-mediated lithiation/substitution of Boc-N-
methyl benzyl amine. Schlosser, M.; Limat, D. J. Am. Chem. Soc. 1995,
117, 12342.
(3) Lautens, M.; Gajda, C.; Chiu, P. J. Chem. Soc., Chem. Commun.
1993, 1193. Denmark, S. E.; Nakajima, N.; Nicaise, O. J.-C. J. Am. Chem.
Soc. 1994, 116, 8797. Klein, S.; Marek, I.; Poisson, J.-F.; Normant, J.-F. J.
Am. Chem. Soc. 1995, 117, 8853. Muci, A.; Campos, K. R.; Evans, D. A.
J. Am. Chem. Soc. 1995, 117, 9075.
(4) For studies on the effect of temperature on the configurational stability
of related organolithium species, see: Gawley, R. E.; Zhang, Q. Tetrahedron
1994, 56, 6077. Elworthy, T. R.; Meyers, A. I. Tetrahedron 1994, 56, 6089.
Burchat, A. F.; Chong, J. M.; Park, S. B. Tetrahedron Lett. 1993, 34, 51.
Kawabata, T.; Wirth, T.; Yahiro, K.; Suzuki, H.; Fuji, K. J. Am. Chem.
Soc. 1994, 116, 10809.
(5) The two most common methods are deprotonation and tin/lithium
exchange (lithiodestannylation).
(6) For a review of the directed lateral lithation, see: Clark, R. D.;
Jahangir, A. Org. React. 1995, 47, 1.
(8) The organosilane 4 was subject to a Tamao-Fleming oxidation to
afford the hydroxy amide. The oxidation has been shown to proceed with
retention of configuration, even at a benzylic position. Fleming, I.; Henning,
R.; Parker, D. C.; Plant, H. E.; Sanderson, P. E. J. J. Chem. Soc., Perkin
Trans. 1 1995, 317. Oppolzer, W.; Mills, R. J.; Pachinger, W.; Stevenson,
T. HelV. Chim. Acta 1986, 69, 1542. This was correlated with a sample of
the enantioenriched alcohol independently prepared from commercially
available (S)-(-)-2-bromo-R-methylbenzyl alcohol. The MOM-protected
bromo alcohol was electrophilically aminated using Trost’s azidomethyl
phenyl sulfide methodology. Subsequent hydrolysis of the triazoline and
acylation of the resultant aniline, followed by deprotection of the MOM
ether, afforded (S)-14 in 86% ee. Trost, B. M.; Pearson, W. H. J. Am. Chem.
Soc. 1981, 103, 2483. The absolute configuration of 11 was determined
through independent chemical synthesis from (R)-3-phenylbutyric acid. The
sequence involves reduction of the acid to the alcohol and activation as the
tosylate, followed by a one-carbon homologation with methylmagnesium
bromide in the presence of the Tamura-Kochi catalyst. Nitration of the
alkane, followed by reduction and pivaloylation, affords the desired product.
See supporting information for full experimental details.
(9) Pirkle, W. H.; Welch, C. J.; Lamm, B. J. Org. Chem. 1992, 57, 3854.
(10) Preparation of the methyl oxalate ester of 7, followed by deoxy-
genation with Bu3SnH, afforded (S)-9 in 82% ee. Dolan, S. C.; MacMillan,
J. J. Chem. Soc., Chem. Commun. 1985, 1588.
(11) While the initial work was conducted in Et2O, a subsequent solvent
study revealed that MTBE afforded higher yields with little effect on the
enantioselectivities.
(12) (a) Still, W. C.; Sreekumar, C. J. Am. Chem. Soc. 1980, 102, 1201.
(b) Aggarwal, V. K. Angew. Chem., Int. Ed. Engl. 1994, 33, 175 and
references cited therein.
(7) That a dilithio species is generated prior to addition of the diamine
or electrophile has been independently determined by quenching the reaction
at this point with MeOD. The product with deuterium incorporated at the
benzylic position was obtained in 98% yield and 94% deuterium incorpora-
1
tion as determined by H, 13C NMR, and mass spectral analysis.
0002-7863/96/1518-1575$12.00/0 © 1996 American Chemical Society

1576 J. Am. Chem. Soc., Vol. 118, No. 6, 1996
Communications to the Editor
Table 1. Yields and Enantioselectivities for Products 3-11 from
the Electrophilic Substitution of 2 in the Presence of (-)-Sparteine
in MTBE via the Warm-Cool Protocol11
remains invariant. Thus, the operation of these two pathways
for stereoinformation transfer, along with the ability to trans-
metalate an enantioenriched organostannane derivative, allows
access to both enantiomers with good enantioselection.
Our mechanistic hypothesis is consistent with the observation
that the dianion must be stirred in the presence of the ligand at
-25 °C for 45 min to obtain high asymmetric induction,
allowing sufficient time for equilibration of the diastereomeric
complexes to occur.14 If the (-)-sparteine is added at -25 °C
but allowed to stir for only 5 min before cooling to -78 °C
and subsequent addition of TMSCl, (R)-3 is obtained with only
39% ee.
electrophile
E
product
yield (%)
ee (%)
Me3SiCla
Me3Si
PhMe2Si
Me3Sn
(CH2)5C(OH)
PhCH(OH)
CH2dCHCH2
PhCH2
CH3(CH2)10
CH3CH2CH2
(R)-3
(R)-4
(R)-5
(R)-6
(R)-7
(S)-8f
(S)-9f
(S)-10f
(S)-11f
72
6b
77
90
79
66
77
82d
82
84
78
84
PhMe2SiCla
Me3SnCl
cyclohexanone
benzaldehyde
allyl bromidee
benzyl bromide
iodoundecane
allyl bromide
80
67c
67
56
62
g
100h
We presume by analogy that the lithiodestannylation of 5
occurs with retention of configuration to generate a complex
which is configurationally stable at -78 °C.12 Electrophilic
substitution must then occur with inversion.1a,15 Upon warming
the reaction mixture to -25 °C (eq 3), the complexes equilibrate
to generate the same ratio of diastereomeric complexes formed
by method B, affording the same enantiomer upon electrophilic
substitution.16 The occurrence of enantioinversions from (R)-5
at -78 °C with (-)-sparteine, but not with TMEDA, indicates
that TMEDA is not effective as an achiral mimic of (-)-
sparteine in this reaction sequence.17
In summary, the present results illustrate two ways in which
the enantiochemistry of the electrophilic substitutions of a
racemic benzylic organolithium reagent can be controlled. High
enantioselectivities can be obtained by allowing the diastereo-
meric complexes to equilibrate at -25 °C prior to cooling to
-78 °C. Lithiodestannylation of the enantioenriched orga-
nostannane at -78 °C, followed by electrophilic substitution,
provides products which are enantiomeric to those obtained by
the warm-cool protocol. Thus, enantiodivergent synthesis can
be achieved by choosing the appropriate substitution sequence
and reaction conditions. A warm-cool protocol may be useful
for inducing enantioselectivity in other organolithium/chiral
ligand reactions. We anticipate that a detailed investigation of
the mechanism of enantioinversion will afford insight into the
mechanism of the asymmetric substitution and provide avenues
for further development.
a Reaction conducted in Et2O. b The yield of unpurified product, as
determined by GC, is 85%. However, separation of 4 from 1
chromatographically proved difficult, accounting for the low yield.c A
2:1 ratio of unseparated diastereomers. d See footnote 10. e Reaction
conducted in ether/pentane (1/1 v/v). f The designation of (S)-config-
uration is a consequence of a change in substituent priority assignments.
g Prepared via hydrogenation of (S)-8. h Yield of hydrogenation reaction.
hexanone, afforded (S)-3 (62% ee) and (S)-6 (61% ee) with
virtually complete inversion of configuration (eqs 1 and 2).
Lithiodestannylation of (R)-5, followed by warming of the
reaction mixture to -25 °C for 2 h prior to cooling to -78 °C
and subsequent reaction with TMSCl, provides (R)-3 (85% ee)
(eq 3). Thus, either enantiomer of 3 and 6 can be obtained
from 1 by controlling the reaction conditions.
Acknowledgment. We are grateful to the National Institutes of
Health and the National Science Foundation for support of this work.
Two limiting mechanisms have been postulated to rationalize
the observed stereoselectivities of the asymmetric substitution
process.1,2 The first involves the preferential formation of one
diastereomer of the putative organolithium/(-)-sparteine com-
plex which reacts with an electrophile stereoselectively. This
requires configurational stability of the organolithium/chiral
ligand complex on the time scale of reaction with electrophiles.
A selective crystallization of one diastereomeric complex has
been reported by Hoppe.2b,c The second mechanism involves
diastereomeric complexes which are rapidly equilibrating on
the time scale of the reaction, with enantioselection arising as
a function of the energy difference between diastereomeric
transition states. In this case, the organolithium intermediate
is configurationally labile.13
If the substitution proceeded via rapidly equilibrating dia-
stereomeric complexes, the stereochemical outcome should be
independent of the method of organolithium formation, since a
common intermediate would be formed. As this is not observed,
we suggest that the reaction proceeds through the electrophilic
substitution of two diastereomeric complexes, which can be
formed under nonequilibrating (-78 °C) or equilibrating (-25
°C) conditions. At -25 °C, the complexes equilibrate to a
thermodynamic ratio, which can be maintained by rapid cooling
to -78 °C. At -78 °C, the ratio of diastereomeric complexes
is established by the method of generation and subsequently
Supporting Information Available: Experimental procedures and
characterization data for 1, 3-11, as well as procedures for enantio-
inversion experiments and determination of absolute configurations (20
pages). This material is contained in many libraries on microfiche,
immediately follows this article in the microfilm version of the journal,
can be ordered from the ACS, and can be downloaded from the Internet;
see any current masthead page for ordering information and Internet
access instructions.
JA951895W
(14) The diastereoselectivity of the addition of benzaldehyde to a
metalated isoquinoloyloxazoline has been reported to be higher at -65 °C
than at -78 °C. Zhang, P.; Gawley, R. E. Tetrahedron Lett. 1992, 33, 2945.
A related effect has been reported for the enantioselective amidocuprate-
mediated conjugate addition to enones. Rossiter, B. E.; Miao, G.; Swingle,
N. M.; Eguchi, M.; Hernandez, A. E.; Patterson, R. G. Tetrahedron:
Asymmetry 1992, 3, 231. The work of Schlosser and Limat (ref 2d) also
shows a time-dependent enantioselectivity, consistent with the formation
of diastereomeric complexes with (-)-sparteine.
(15) As far as we know, there is no known case of a lithiodestannylation
that proceeds with inversion of configuration at the tin-bearing carbon. On
the other hand, there are sporadic reports in the literature of electrophilic
substitutions that proceed with inversion of configuration, most notably
recent reports by both Hoppe and Gawley. Carstens, A.; Hoppe, D.
Tetrahedron 1994, 6097. Gawley, R. E.; Zhang, Q. J. Org. Chem. 1995,
60, 5763.
(16) If (rac)-5 is transmetalated at -78 °C in the presence of (-)-
sparteine, trapping with TMSCl affords (rac)-3. This indicates that there is
no kinetic resolution during the transmetalation step, consistent with the
formation of two nonequilibrating diastereomeric complexes in equal ratios.
However, if (rac)-5 is transmetalated at -78 °C in the presence of (-)-
sparteine and allowed to stir at -25 °C for 2 h prior to cooling to -78 °C
and trapping with TMSCl, (R)-3 is obtained with 85% ee.
(13) Asymmetric induction at a stereocenter capable of epimerizing under
the reaction conditions is an example of dynamic kinetic resolution. See:
Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. Jpn. 1995, 68,
36.
(17) For a discussion of the effectiveness of TMEDA as a bidentate ligand
for lithium, see: Collum, D. B. Acc. Chem. Res. 1992, 25, 448.